International J. Pharm Cmpd'gMay_June 2002

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ofPHARMACEUTICAL

COMPOUNDING

I N T E R N A T I O N A L J O U R N A L

C O M P O U N D I N G F O R H E A L T H , W E L L N E S S , A N D G E R I A T R I C P A T I E N T S

V O L U M E 6 N O . 3

Page 171 Estrogen Replacement Therapy in theTreatment of Alzheimer’s Disease

Page 178 Lollipops: The Evolution of a Dosage FormPage 186 How To Perform a Study in Your Pharmacy

Page 194 Basics of Compounding: Iontophoresis,Part 1

Page 210 The Treatment of Canine Atopic DiseasePage 216 A Review of pH and Osmolarity

http://www.gallipot.com

T A B L E O F C O N T E N T S

DEPARTMENTS

163 PreScription – From the Editor

163 Erratum

236 Index of Advertisers

237 Calculations – Shelly J. Prince, PhD, RPh

238 Continuing Education Questions

240 PostScription – Patsy Angelle, PD, FIACP, FACA

FORMULATIONS

199 Anhydrous Emollient Dry Skin Lotion

200 Antiseptic Protective Ointment

201 Camphor, Menthol, and Eucalyptol Rubefacient Ointment

202 Carbidopa 2-mg/mL and Levodopa 250-mg/mL Oral Suspension

203 Ergoloid Mesylates 15 mg/mL and Selegiline HCl 6.25 mg/mL in Pluronic Lecithin Organogel

204 Misoprostol 0.0024%, Metronidazole2%, and Pentoxifylline 5% Decubitus Ulcer Cream

205 Nicotine 2-mg Lollipops206 Nicotine Medication Stick

207 Podophyllum, Lactic Acid, and SalicylicAcid Wart Mixture

208 Vitamin B12 1-mg/mL Nasal Spray

PEER REVIEWED

226 Stability of Ampicillin Sodium, Nafcillin Sodium, and Oxacillin Sodium in AutoDose Infusion SystemBags – Yanping Zhang, BS; andLawrence A. Trissel, BS, RPh

230 Compatibility Screening of Precedex During Simulated Y-Site Administration with Other Drugs –Lawrence A. Trissel, BS, RPh;Christopher A. Saenz; Delshalonda S. Ingram; Kimberly Y. Williams; and Julie P. Retzinger, RN

234 Stability of Cefotaxime Sodium AfterReconstitution in 0.9% Sodium Chlo-ride Injection and Storage in Polypro-pylene Syringes for Pediatric Use – V. Das Gupta, PhD

Cover Photo by MARK RUTLEDGE © 2002

161International Journal of Pharmaceutical CompoundingVol. 6 No. 3 May/June 2002

COMPOUNDING FOR HEALTH, WELLNESS, AND GERIATRIC PATIENTS

164 Healthful Living: Good Practices for Good Health – Kathy Jackson, RPh,

FIACP

168 Compounding for Geriatric Patients – Eldon Armstrong, RPh, CGP, FIACP,

FACA, FASCP

171 Estrogen Replacement Therapy in the Treatment of Alzheimer’s Disease –

Jennifer Osburn, PharmD (Candidate)

178 Lollipops: The Evolution of a Dosage Form – Dave Mason, DPh, FIACP; and

Shannon Fields, PhTech

180 Book Reviews: Wellness, Nutrition, and Geriatrics – Dana Reed-Kane,

PharmD, FIACP, FACA; and Lisa D. Ashworth, RPh

GENERAL INTEREST

184 Compounding in History: The Road to Wellville – Dennis B. Worthen, PhD

186 How To Perform a Study in Your Pharmacy with Little or No Effort – Dana

Reed-Kane, PharmD, FIACP, FACA

188 Technology Spotlight: Electric Mixing Machines – Gary Schneider, RPh

189 Treatment of Pain with a Topically Applied Combination of Indomethacin

and Piroxicam – Eric R. Vetter, RPh, PharmD (Candidate); and Lawrence Curtis, RPh

193 Medications Discontinued in the United States – Lisa D. Ashworth, RPh

194 Basics of Compounding: Iontophoresis, Part 1 – Loyd V. Allen, Jr, PhD, RPh

SPECIALTY COMPOUNDING

210 The Treatment of Canine Atopic Disease – Gigi Davidson, BS, RPh, DICVP

216 A Review of pH and Osmolarity – Marc Stranz, PharmD; and Eric S. Kastango,

RPh, MBA, FASHP

COMPOUNDING SUPPORT & QUALITY CONTROL

221 Featured Excipient: The Sorbitan Esters – Loyd V. Allen, Jr, PhD, RPh

224 Standard Operating Procedure: Developing Standard Operating Procedures

– Loyd V. Allen, Jr, PhD, RPh

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Editorial

Editor-in-Chief Loyd V. Allen, Jr, PhD, RPhExecutive Editor Shelly CappsMedical Editor Jane VailAssistant to Editor-in-Chief LaVonn WilliamsContributing Authors Lisa D. Ashworth, RPh

Gigi Davidson, BS, RPh, FSVHP, DICVPEric S. Kastango, RPh, MBA, FASHP

Shelly J. Prince, PhD, RPhDennis B. Worthen, PhD

Contributing Editor Peter R. Ford, BSPharm, FACA, FIACP

ADDRESS: 122 N. Bryant, Edmond, OK 73034-6301 USA TEL: 800-757-4572 FAX: 405-330-5622

Design

Design Director Carolyn Rose

Subscription & Reader Services

Circulation Director Andy Bernick

Interactive Media & Special Projects Designer Jordana Ford

ADDRESS: PO Box 340205, Austin, TX 78734 USATEL: (toll free) 888-588-4572, 512-261-3179

FAX: 512-608-9828

Advertising

Director of Advertising Lauren Bernick

ADDRESS: PO Box 340205, Austin, TX 78734 USATEL: 800-661- 4572 FAX: 800-494-4572

EMAIL: [email protected]

Board of Directors

Jake Beckel, RPhShelly Capps

Mike Collins, RPhPat Downing, RPh

Bob Scarbrough, RPh

Editorial Board

Harvey Ahl, RPhDiane Boomsma, RPh

Marianna Foldvari, PhD, RPhPeter R. Ford, BSPharm, FACA, FIACP

Paul F. Grassby, PhD, MRPharmS Hetty A. Lima, RPh, FASHP

Dave Mason, RPh, FIACPJohn Preckshot, RPh, FIACP

Lawrence A. Trissel, BS, RPh, FASHP

David J. Woods, MPharm, MRPharmS, FHPA

WEBSITE www.ijpc.com

See our Website for subscription services, back issueorders, products, and an index.

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PHARMACEUTICALCOMPOUNDING


The International Journal of Pharmaceuti-cal Compounding (IJPC), ISSN No. 1092-4221, is published 6 times per year by IJPC,122 N. Bryant St, Edmond OK 73034, USA. ANNUAL SUBSCRIPTION RATES(All rates in US dollars)North America – Standard: $125, institutional: $150, student: $90.All other destinations – Standard: $190,

institutional: $215, student: $95.Electronic issue downloads (no print copy)– Standard: $125, institutional: $150, stu-dent: $90.Back issues are available – Nine or fewer for$20 per issue, 10 or more for $15 per is-sue. Call 888-588-4572 to order back issues or subscriptions.All rights reserved. Permission is grant-

ed for libraries and others registered withthe Copyright Clearance Center, Inc, 222Rosewood Drive, Danvers, MA 01923USA, to photocopy articles for a base feeof $5 per copy of the article plus $2 per page.Requests for bulk orders should be ad-dressed to the editor.Copyright 2002 by the International Journal of Pharmaceutical Compounding.™

F R O M T H E E D I T O R

International Journal of Pharmaceutical CompoundingVol. 6 No. 3 May/June 2002

163

Isn’t it great to be alive? Health and well-ness are the themes of this issue of thejournal, in addition to compounding for thespecial health needs of geriatric patients.Never in the history of the world has so muchmoney been spent in the pursuit of healthand wellness.

Health and wellness can be maintained —or regained. It is easiest and best to main-tain a state of health and well-being by eat-ing a healthful diet, exercising, and adopt-ing a healthful lifestyle. Those practices oftenobviate the time, effort, and money spenttrying to regain good health. I have oftenwondered why we seem to spend the firsthalf of life burning the candle at both endsand the last half trying to put the drops ofwax back together.

Developing and maintaining healthfulhabits can result in healthier and happiermature adults. We as compounding phar-macists can individualize patient care by of-fering our patients nutritional supplements,recommendations for lifestyle changes, andcounseling about medication use. We canhelp patients maintain good health by ad-dressing minor ailments or discomforts asthey arise and by helping our clients elim-inate harmful habits such as smoking orovereating. In many cases, innovativedosage forms (nicotine lollipops, troches,gummy gels, sublingual drops, etc) can beused effectively in smoking cessation orweight reduction programs.

Our clients will benefit from our efforts

to ensure their health and wellness, and we have probably been neglecting those services too long. Promoting the vital com-ponents of good health may be just theniche for those of us who want to expandthe scope of their services and better servetheir patients.

Loyd V. Allen, Jr, PhD, RPh

™

Erratum: In the article, “Bacterial Endotoxins and Pyrogens,” which was publishedin IJPC volume 5, number 4 (July/August 2001), page 262, column 2, in the section“Intrathecal Limits for Pyrogens,” the third sentence should read: The EU limit would then be 13 EU/hr, or 13 EU/0.042 mL, or a 312 EU/mL crit-ical endotoxin load allowed for a nonpyrogenic intrathecal drug product.

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164 International Journal of Pharmaceutical CompoundingVol. 6 No. 3 May/June 2002

The Importance of DietA healthful diet is an essential component of lasting good health.

Poor eating habits lead to an increased risk of obesity, diabetes,high blood pressure, and heart disease. Understanding the basicprinciples of nutrition is important in ensuring compliance withhealthful eating habits. Proteins, carbohydrates, and fats are thecomponents of food. The body requires proteins for growth andmuscle development. Carbohydrates and fats supply energy. Vi-tamins and minerals do not provide calories, but they facilitatethe conversion of other elements into energy.Thousands of magazines and a vast array of diet books outline

“successful” methods of shedding fat and decreasing weight.

GOOD PRACTICES forGOOD HEALTHKathy Jackson, RPh, FIACPThe Family Pharmacy Compounding Pharmacy LaPorte, Texas

The body is the temple in which we live. Adopting a health-ful lifestyle often requires rediscovering common sense and tak-ing the initiative—every day—to maintain well-being. Regular“health maintenance” enables the human body to work best andlast longer. The body, which is a product of the nutrients it re-ceives, is composed of 60% water, 20% body fat, and a 20% mixof proteins and carbohydrates, related organic compounds, and minerals.1 Healthful nutrition is vital to maintaining ideal bodycomposition. What we eat is what we are and how we feel. Thequality of the nutrients consumed can make the difference be-tween good health and illness.

America is the most agriculturally productive nation in the his-tory of the world. We as Americans also benefit from the mostexpensive and technologically advanced healthcare system avail-able. In spite of those factors, many of us today are victims of diet-related obesity and heart disease. We love fast food, and our gro-cery stores are packed with “junk food.” We choose our foodaccording to preferences of taste, cost, convenience, and psychologicgratification, all of which are independent of the purpose of nutrition, which is to provide the materials necessary to grow, repair, and fuel the body.

We often process, blend, hydrogenate, refine, and disassembleour food until very little nourishment remains. Through years ofinactivity, many of us morph a fit physique into the habitus of a“couch potato.” We pollute our food, air, and water supply witha frightening array of contaminants. Then, when poor nutritionevolves into poor health, we use potent drugs to subdue thesymptoms of illness.

HEALTHFULLIVING:

GOODPRACTICES forGOOD HEALTH

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Manufacturers of special diet foods—from liquid high-protein mealsubstitutes to appetite-killing bars and snacks—make extravagantclaims to sell hope to weight-conscious consumers. Many over-the-counter ephedrine-containing products are touted to help con-sumers burn fat and decrease body weight without much effort.Patients are often the victims of advertising that leads them tobelieve in a quick-fix pill purported to conquer any of a varietyof diseases. Even vitamins have been promoted as substances thatcan counteract the effects of a junk-food diet.

Fad diets can be very dangerous. The pharmacist can help ed-ucate patients about the dangers of quick-weight-loss productsthat do not address the need for a nutritious diet and a lifestylethat includes regular exercise.

The most sensible approach to good nutrition is to adopt (fora lifetime) a diet that is low in refined carbohydrates, includes ad-equate proteins and fats, and is rich in fruits and vegetables. Com-bining a healthful diet with a regular exercise program and a pos-itive mental attitude is the best approach to achieving andmaintaining good health.

The Essential Role of Glucose and InsulinGlucose

Glucose is the body’s major source of energy; it is also the onlyform of energy that the brain can use effectively. During diges-tion and metabolism, the liver converts all of the carbohydratesand about half of the protein from a meal into glucose, which isthen released into the bloodstream. In response to an increasingglucose level, the pancreas secretes extra insulin, which is the hor-mone that enables cells to convert glucose into energy.2 Exces-sive carbohydrate consumption can negatively affect the body’sendocrine function and can lead to hyperinsulinemia and even-tually to insulin resistance.3

Insulin Insulin, the body’s “master hormone,” has an essential role in

the use, storage, and metabolism of every nutrient in the humanbody. It affects membrane permeability, protein and fat synthe-sis, mineral and micronutrient use and storage, glucose uptake,and the metabolism of every cell. It also plays an important rolein the flow of nutrients into and waste products out of cells.4

Insulin resistance is a decrease in the response of peripheral tis-sues to insulin.5 Excess insulin release plays a role in the devel-opment of hypertension, diabetes, an elevated level of triglycerides,and obesity.6 Other health problems caused by excess insulin in-clude blood coagulation disorders, cancer, gout, sleep apnea,iron-overload disease, gastroesophageal reflux, peptic ulcer dis-ease, and polycystic ovary disease.4

The glycemic index is used to classify foods according to theireffect on the blood glucose level. Not all carbohydrates are equalin their stimulation of insulin release. Carbohydrates that stim-ulate the most insulin secretion are termed “high-glycemic-in-dex carbohydrates.” Low-glycemic-index carbohydrates do not stim-

ulate insulin release. It is safe to assume that highly processed foodshave a higher glycemic index.7 Patients should be advised toavoid processed, refined, or enriched foods8 because refining candeplete important nutrients that are essential to a healthful diet.9

Refined sugar and processed grain products such as candies, cook-ies, pies, cakes, and pastries are almost immediately absorbed bythe gastrointestinal tract and produce a rapid secretion of largequantities of insulin. An increased insulin level promotes fat de-position and other undesirable effects. The long-term consump-tion of a diet that consists predominantly of high-glycemic-in-dex carbohydrates can lead to the development of insulinresistance.9,10 However, unrefined carbohydrates such as fruits,vegetables, whole grains, and dried beans require further diges-tive alteration before they are absorbed. This subsequently caus-es a proportionate reduction in the rate and quantity of insulinsecretion, which results in less fat storage and less weight gain.Studies9,11 have indicated that in 6 weeks, low-glycemic-index di-ets produced a 7% decrease in the level of cholesterol in non-in-sulin–dependent diabetic patients and a 15% decrease in that lev-el in nondiabetic patients.

The Keys to Good HealthPhysical Activity

Regular physical activity is tremendously beneficial to overallhealth. Thirty minutes of vigorous aerobic exercise daily is es-sential to lowering the level of insulin; it also increases circula-tion and reduces fibrinogen production and the levels of triglyc-erides and cholesterol. In addition, exercise also decreases the bloodglucose level and increases peripheral tissue sensitivity to insulin.10,12

VitaminsVitamin supplementation is also essential to good health. The

human body requires approximately 60 minerals, 16 vitamins, 12amino acids, and 3 essential fatty acids daily to regulate key meta-bolic processes. If those nutrients are not supplied by food or vi-tamin supplementation, vitamin deficiencies that could lead to se-rious health problems will occur.

AntioxidantsAntioxidants are key to the fight against free radicals, which are

linked to heart disease, cancer, cataracts, stroke, Parkinson’s dis-ease, and many other disorders. Antioxidants act as free-radicalscavengers that help to prevent disease.13 Important antioxidantsinclude vitamins C, E, and A; β-carotene; selenium; coenzyme Q10;α-lipoic acid; mixed tocopherols; and mixed carotenoids. Freshfruits and vegetables are an excellent source of essential antioxi-dants. Biotin is used to improve glycemic response by improvingthe metabolism of carbohydrates, fats, and amino acids.3 Insulinproduction requires zinc,14 and chromium is important for glu-cose metabolism and insulin production.14

ProteinsProteins control metabolism and provide the structural basis for

tissues such as muscle and skin. They enable the body to grow

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and repair itself and are essential to the function of the immunesystem. Protein-rich foods are of animal origin (meat, fish, poul-try, eggs, milk) or plant origin (wheat, rice, nuts, beans, lentils).

Individual protein requirements are often calculated accordingto body weight measured in kilograms. The body weight in kilo-grams must be multiplied by 0.8 to determine the daily numberof grams of protein required daily to maintain health. The amountof protein needed daily may vary among individuals. Pregnant womenand highly trained athletes have a high daily protein requirement.1

FatsFats, especially essential fatty acids, are vital to good health. They

facilitate the absorption of fat-soluble vitamins, are involved inproducing hormones, help support and protect vital organs, andinsulate the body from cold. Fats are also an excellent source ofenergy. However, excessive consumption of foods high in saturatedfats has been linked to heart disease and certain types of cancer.

Linoleic acid, which is an omega-6 fatty acid obtained from plant-based sources such as evening primrose oil or flaxseed oil, exertsa cardioprotective effect. Linolenic acid, an omega-3 fatty acid foundin all fish and seafood (especially cold-water fish such as salmon,sardines, and lake trout), may help to prevent blood clots that causemyocardial infarction or stroke. The Western diet consists pri-marily of saturated fats that are detrimental to health and oftenlacks the essential fatty acids mentioned above.

FiberFiber intake is also important to good health. A daily intake of

natural fiber is crucial to good health and energy. Dietary fiber ismost abundant in plant products such as fruits, grains, and veg-etables. The American Gastroenterological Association recommendsthe consumption of 30 to 35 g of fiber daily.15 An increased in-take of dietary fiber ensures the timely transit of foods throughthe gastrointestinal tract and thus alleviates constipation and he-morrhoids. A high-fiber diet has been shown clinically to reduce atherosclerosis; dietary fats and cholesterol bind with fiber in thedigestive system and are eliminated via defecation.16

Evidence indicates that an increased intake of dietary fiber canexert a protective effect on the colon and may decrease the riskof colorectal cancer.17 High-fiber diets are helpful in controllingthe blood glucose level in patients with type 2 diabetes. Fiber canalso lower insulin secretion by reducing the absorption of carbo-hydrates.9,18

WaterWater is a requirement of all living cells. The type and the

amount of liquid consumed are as important as the intake of nu-trients to maintaining good health. Water is the basis of essen-tial body fluids such as blood and lymph. It lubricates joints, isa constituent of saliva, provides a protective cushion for tissues,and helps to eliminate toxic waste products from the body. Atleast 8 glasses of water purified by the reverse-osmosis processshould be consumed daily.

Rules To Remember Good health is our most valuable earthly asset; what we do with

it is our responsibility. Building a more healthful lifestyle is noth-

ing more than following a consistent pattern of good choices madeone at a time. Small changes in dietary habits, incorporating reg-ular exercise into the daily routine, minimizing stress, and ensuringadequate rest produce a visible improvement in overall health andwell-being. Pharmacists, as well as other healthcare profession-als, have a unique opportunity and responsibility to model and pro-mote a sound plan for wellness.

References

1. Whitney E, Hamilton E. Understanding Nutrition. 4th ed. New York:WestPublishing Company; 1987:2-3, 83, 171.

2. Eades M, Eades M. Protein Power. New York:Bantam Books; 1999:12, 28.3. Werbach M, Moss J. Textbook of Nutritional Medicine. Tarzana, CA:Third

Line Press; 1999:8, 10-11, 320, 328.4. Eades M, Eades M. The Protein Power Life Plan. New York:Warner Books;

2000:11, 22-25, 132, 168.5. Hardman J, Limbird L, eds. Goodman and Gilman’s The Pharmacological

Basis of Therapeutics. 9th ed. New York: McGraw-Hill; 1996:1495.6. Wolever TM, Jenkins DJ, Vuksan V, et al. Beneficial effect of low-glycemic

index diet in overweight NIDDM subjects. Diabetes Care 1992;15:562-564.7. Jenkins DJ, Wolever TM, Taylor RH, et al. Glycemic index of foods: A phys-

iological basis for carbohydrate exchange. Am J Clin Nutr 1981;34:362-366.

8. Liu S, Manson JE, Stampfer MJ, et al. A prospective study of whole-grainintake and risk of type 2 diabetes mellitus in US women. Am J Public Health2000;90:1409-1415.

9. Steward H, Bethea M, Andrews S. Sugar Busters! New York:BallantinePublishing Group; 1998:19, 41, 58-60.

10. Liu S, Manson JA. Dietary carbohydrates, physical inactivity, obesity, andthe “metabolic syndrome” as predictors of coronary heart disease. CurrOpin Lipidol 2001;12:395-404.

11. Jenkins DJ, Wolever TM, Kalmusky J, et al. Low-glycemic index diet in hyperlipidemia: Use of traditional starchy foods. Am J Clin Nutr 1987;46:66-71.

12. Kanaley J, Weinstock R. Nonpharmacologic therapy in the treatment ofinsulin resistance. Curr Opin Endocrinol Diabetes 2001;8:219-225.

13. Azen S, Qian D, Mack W, et al. Effect of supplementary antioxidant vita-min intake on carotid arterial wall intima-media thickness in a controlledclinical trial of cholesterol lowering. Circulation 1996;94:2369-2372.

14. Pelton R, LaValle J, Hawkins E. Drug-Induced Nutrient Depletion. 2nd ed.Cincinnati:Natural Health Resources; 200:9, 320, 370.

15. American Gastroenterological Association. American Gastroenterologi-cal Association Position Statement: Impact of dietary fiber on colon can-cer occurrence. Gastroenterology 2000;118:1233-1234.

16. Ludwig D, Pereira MA, Kroenke CH, et al. Dietary fiber, weight gain, andcardiovascular disease risk factors in young adults. JAMA 1999;282:1539-1546.

17. Young-In K. AGA technical review: Impact of dietary fiber on colon can-cer occurrence. Gastroenterology 2000;118:1235-1237.

18. Salmeron J, Ascherio A, Rimm EB, et al. Dietary fiber, glycemic load, andrisk of NIDDM in men. Diabetes Care 1997;20:545-550.

Address correspondence to: Kathy Jackson, RPh, FIACP, Family Pharmacy, Kathy Jackson, RPh, FIACP, 10406 W. Main, Suite B,La Porte, TX 77571-4300. E-mail: Kathy@familypharmacy. c c .■

http://www.spectrumrx.com

Today, older Americans visit their doctors 22% more oftenthan they did in the mid-1980s, and according to statistics1 re-leased by the Centers for Disease Control and Prevention, physi-cians are prescribing more drugs for patients of all ages.

Many elderly patients experience multiple illnesses and a diminishedphysical capacity, for which they frequently take medications.Those patients have a much higher risk of experiencing disablingside effects from treatment, as well as adverse drug reactions. Al-most 25% of all hospital and nursing home admissions of olderadults are caused by the improper use of medications by patients.2

Changes in the American Healthcare System

Efforts to reform our healthcare system to meet the demandsof geriatric patients must certainly be made. Many older patientsare literally dying for the system to change. The following rec-ommendations for healthcare reform were issued by the Alliancefor Aging Research in August 19983:■ Provide a list of medications that are potentially inappropri-

ate for the treatment of older patients.■ Require manufacturers to perform premarketing and post-

marketing studies of medication effects in frail elderly patients.■ Provide geriatric-relevant labeling for nonprescription med-

ications.■ Coordinate data collection, monitoring, and analysis of med-

ication-related problems by age group.■ Encourage healthcare professionals to be competent in geri-

atric pharmacotherapy. Many healthcare professionals are making special efforts to

meet the needs of elderly patients. The pharmacist who is activein community service, knowledgeable about the medications usedto treat the elderly, and has good communication skills can en-sure better health for elderly patients.

Practice CompetenceThe pharmacist may choose to provide medication counseling

services to elderly patients and to others. He or she must be ableto perform clinical evaluations, conduct “medical sleuthing” byusing interview techniques, and recognize opportunities for non-chemical interventions. Having experience in drug regimen re-view and disease state management in nursing home settings isinvaluable.

The role of the consultant pharmacist has been designed to usethe expertise of the pharmacist to prevent the misuse of medica-tions (such as major tranquilizers) in treating elderly patients. TheAmerican Society of Consultant Pharmacists (ASCP) has been theleading national organization in geriatric pharmacy since 1969. TheASCP promotes the role of senior-care pharmacists who practicein community settings and provide care for ambulatory senior cit-izens. That organization provides training in pharmacotherapy forpharmacists who treat patients with disorders such as Parkinson’sdisease or Alzheimer’s disease. It also offers training in the med-ication management of geriatric patients with psychiatric disor-ders and in skin and wound care for elderly patients. In addition,the ASCP assisted in launching the Commission for Certificationin Geriatric Pharmacy, which offers a demanding certification processto pharmacists specializing in health care for the elderly.

Practice CommunicationMedication counseling must be well-documented and then oral-

ly communicated effectively to the patient and to selected mem-bers of his or her healthcare team (if warranted). We have foundit effective to summarize the information orally to the patient andto provide a detailed written report to the primary caregiver. Pa-tient involvement should be encouraged throughout the process.

Historically, the pharmacist has served as the patient-physicianliaison. Pharmacists can simplify a physician’s orders into languageunderstandable to the patient. In that role, we are the guardiansof both the patient and the prescribing healthcare practitioner.

The Practice SiteThe goal of the Medication Checkup Center (MCC) of Columbia,

South Carolina, is to provide a stand-alone pharmacy practice inwhich the art and science of pharmacy are practiced primarily forelderly clients. It includes a working knowledge of dosage alter-natives and a command of communication techniques, as well asan evaluation of the patient’s drug regimen and a clinical evalu-ation of treatment options. It does not include an inventory ofmedications.

“People need to gather up all their prescription drugs and showtheir doctors and pharmacists what they’re [taking]. These pro-fessionals can work up a suitable drug regimen for the patient,”said Harold J. Washington, Jr, a Los Angeles pharmacist and pres-ident of the California Pharmacists Association.3 Mr. Washing-ton’s statement, although true, tends to simplify a complex process.

Consider the PossibilitiesThe pharmacists at MCC consider whether the client’s illness-

es may have been misdiagnosed, overlooked, or dismissed as partof the normal aging process. Many healthcare professionals arenot trained to recognize the effects of diseases and drugs on se-nior citizens.4 Determining the appropriateness of treatment in-cludes identifying the effects of overuse, misuse, and underuse ofmedications. Often, the pharmacist will refer the patient to oth-er healthcare professionals. For example, we at MCC have oftenreferred patients to sleep evaluation centers. The effects of sleepdisorders, some of which produce symptoms similar to those ofmuscle movement disorders, can undermine a treatment plan. Sleep

Compounding for

GeriatricPatientsEldon Armstrong, RPh, CGP, FIACP, FACA, FASCPSandlapper Consultant Pharmacists, Columbia, South Carolina

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apnea, which is most common in men and the obese, has only re-cently been regarded as a serious problem.5 The symptoms of sleepapnea can often be easily recognized, and the patient who “feelstired all the time” may not be suffering adverse drug effects.

Some sufferers of another sleep disorder, restless leg syndrome(RLS), are often overlooked. Self-treatment often includes tak-ing doses of diphenhydramine or acetaminophen. Diphenhy-dramine has been listed for more than a decade as inappropriatefor use by the elderly.6 It is also essential that physicians and phar-macists know the recommendations for using acetaminophen totreat elderly individuals with impaired liver function.

Optional therapy for the muscle cramps associated with RLSmay involve the local application of transdermal ointments and gels. This obviates the hazards of using systemic drug therapies such as clonazepam, a long-acting benzodiazepinethat can cause falling and confusion in the elderly patient. Transdermal medications recommended for the treatment of minor episodes of RLS include ketoprofen, cyclobenzaprine,gabapentin, or lorazepam.

At MCC, we often suggest treatment with a specific medicationfor the prescriber’s consideration. For example, most patients withPeyronie’s disease do not always mention that problem to theirphysician and erroneously assume that no treatment is availablefor that condition. We identified Peyronie’s disease in several

patients who discussed their symptoms with us. The physiciansof those patients responded positively to our recommendation ofusing verapamil, a topically applied calcium channel blocker, astreatment, although that therapy is not listed in standard drug reference books. Those who followed the directions for using verapamil experienced reduced discomfort during intercourse.

The medication checkup should include a review of the patient’sdrug therapy. The pharmacist must be knowledgeable about dos-ing parameters, contraindications, and drug interactions. For ex-ample, a thiazide-type diuretic that is ineffective because of a pa-tient’s low creatinine clearance rate may be replaced by a “loop”diuretic such as furosemide. The use of a compounded formula-tion of slow-release furosemide helped to improve the compli-ance of one of our patients who followed a complex polypharma-cy regimen for the treatment of congestive heart failure.

A 93-year-old man who is our client recently wanted to dis-cuss options for treating impotence. His primary care physicianhad denied this patient, who has a cardiac condition, treatmentwith sildenafil. The patient did not like the alternative of usinga penile erection pump, which we first suggested. We ultimate-ly recommended treatment with a sterile mixture of three med-ications administered as penile injections. The doctor agreed withour suggestion and trained the patient to self-administer thatcombination treatment.

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Table 1. Sample of a Precounseling Questionnaire for Elderly Patients.

To our patients: We are dedicated to helping you obtain the very best possible healthcare management. Please indicate your

reasons for scheduling a checkup at (practice site name here).

Patient name

Please describe all suspected side effects that may be caused by your treatment.

Please describe any concerns about particular medicines.

Other

❐ Do you think that you may be experiencing drug interac-tions?

❐ Are your current medications not as effective as you wishthey were?

❐ Do you want a better understanding of your medicines?

❐ Do you think that you may be experiencing adverse drugreactions?

❐ Do you want to develop a vitamin or herbal medicationplan?

❐ Do you want to control the cost of your medications?

Name of your practice site

Add the name, mailing and e-mail addresses, and fax and telephone numbers of the practice site.

Practice EducationThe pharmacist must also analyze the learning ability of the client

and his or her understanding of the treatment. The goal of edu-cation has always been to empower the student. It is no longerjudicious for the medical team to continue the past practice ofshrouding the treatment plan in secrecy and excluding active par-ticipation by the patient.

The term “ high-maintenance patient” refers to those who nev-er seem satisfied, are well-read, and are always inquiring aboutchanges and improvements. That type of patient (such as the typ-ical patient with osteoporosis who is treated at MCC) is fast be-coming the norm. Such patients are often confused about the in-tentions of the medical team. Many have benefited from the useof bioidentical hormone therapy instead of expensive treatmentssuch as selective-estrogen-receptor modulators or antiresorptivetherapies.

We offer to evaluate the diet of our clients to ensure that theirconsumption of calcium and magnesium is adequate. By suggest-ing combinations of vitamins or herbal products, we may be able toreduce the total number of medications taken daily by some patients.

The Patient’s Medicine CabinetMedication counseling must also include a review of the patient’s

over-the-counter medications, herbal preparations, and nu-traceuticals. Clients are asked to bring the contents of their med-icine cabinet, including medications for the treatment of hemor-rhoids, to the counseling session so that we can identify possibledrug interactions or medication-related side effects.7

Reviewing the patient’s medicines also provides an indicationabout his or her more “private” concerns such as impotence, lossof memory, and anxiety or depression.

The current popularity of herbal remedies has increased the de-mand for more knowledgeable pharmacists. The kavalactones (theactive muscle relaxant in kava), are associated with hepatic tox-icity that can be harmful to the elderly patient. Recent reports8

have now resulted in the removal of kava from the market in Switzer-land, and similar action may be taken in Germany. A trained phar-macist, however, can recommend customized doses in transder-mal gel formulations that pose fewer risks to the elderly patient.

Define Essential Goals for Your Patients and Your Practice

The pharmacist is a positive part of the healthcare team for el-derly patients, and the needs of that population will increase. Thefirst decision in the process of becoming a more effective phar-macist for elderly patients is that of making a commitment. Thatcommitment involves spending more time reading pertinent lit-erature, obtaining additional training in compounding for the el-derly, and developing assessment ability and communication skillsthat apply to older patients.

The pharmacist must also select the best vehicles for patient ed-ucation, such as brochures, advertisements, and presenting talkson pertinent subjects. Partnerships with local senior centers andorganizations that provide benevolent services may yield free ad-vertising for the practice or the opportunity to write guest columns

in local publications. However, none of those methods is successfulwithout intense community networking.

The pharmacist should establish a practice site that is separatefrom the dispensing pharmacy practice. Physicians and patientsvalue the pharmacist who is objective and is not merely a promoterof products. Perhaps the practice site will be used to provide ser-vice only a few days each week. A pharmacist specialist might alsobe hired to provide additional service at the practice site.

The decision to affix a sufficient charge for services is essentialto success. Paying a fair price for the services of a skilled com-pounding pharmacist is acceptable to most patients and to the med-ical community. Consumers are already expressing a willingnessto pay for pharmacists’ services that reduce the risk of medica-tion-related problems.9 Our experiences at the MCC indicate thatmost are willing to pay even more when the results include a bet-ter quality of life.

The goals of drug therapy in the elderly10 include alleviatingpain, suffering, and disability; improving functional capacity;promoting the patient’s quality of life; and prolonging his or herlife. Those goals can be accomplished if the current US health-care system is retooled and rededicated so that care for geriatricpatients is more important. Most pharmacists have been trainedto focus on the drugs used in treatment and on providing serviceto physicians rather than on the needs of their patients and theintent of therapy. Encouraging patient compliance is critical tothe success of treatment.

Pharmacists are proven and respected professionals. Those ofus who commit to providing service to the elderly must integratechanges into our practice of pharmacy as we apply our knowledgeof all possible drug-related interventions.

References1. [No author listed.] Older Americans seeing physicians more often. Reuters

Medical News. 2001. Available at: http://www.medscape.com/reuters/prof/2001/07/07.18/20010717publ002.html. [Accessed July 26, 2001.]

2. Marsa L. Improved medications have a downside for seniors. LA Times.October 22, 2001: S1.

3. [No author listed]. Panel cites policies for prevention of medication mis-use in elderly. Am J Health Syst Pharm 1998;55:1654.

4. Murphy J. Senate Committee on Aging. Washington Post. May 30, 1999.5. Margen S, Lasnof J, Chaput L. A lot of night music. UC Berkley Wellness

Letter 2000;May:5. 6. General Accounting Office/HEHS. Prescription Drugs and the Elderly.

Washington, DC: United States General Accounting Office. 7. Halas C. Optimizing drug use in elderly patients. American Druggist

1999;October:56.8. Shaver K, Jellin JM, Burson SC. Supplements, kava’s days may be num-

bered. Pharmacist’s Letter 2002;18:6.9. Dong-Chur S. Consumers’ willingness to pay for pharmacy services that

reduce risk of medication-related problems. J Am Pharm Assoc2000;40:818-827.

10. Sloan R. Principles of drug therapy in geriatric patients. Am Fam Physi-cian 1992; June:10.

Address correspondence to: Eldon Armstrong, RPh, CGP, FIACP,FACA, FASCP, 1518 Taylor Street, Columbia, SC. E-mail: [email protected]. ■

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■ IntroductionAlzheimer’s disease (AD), which is one of the most common neu-

rodegenerative disorders, has become a focus of clinical researchas the lifespan for men and women in developed countries increases.AD is characterized by a progressive loss of memory and othercognitive abilities.1 It occurs 2 to 3 times more frequently in womenthan in men. Increasing age, a family history of the disease, andprior head trauma are risk factors for the development of AD.2

The exact mechanism of action of AD is not completely un-derstood. β-Amyloid, a proteolytic fragment of the β-amyloid pre-cursor protein (APP), accumulates intracranially in patients withAD and forms senile plaques. As the disease progresses, neu-rofibrillary tangles and neuritic plaques form, a central core ofβ-amyloid protein develops in the neurons of the cerebrum, andthe level of acetylcholine (ACh) in the brain decreases. A chron-ic inflammatory process that is induced by the reaction of microgliaand astrocytes to β-amyloid also occurs in those with AD.1,3 Mu-tations within the APP coding sequence can lead to enhanced for-mation of β-amyloid,4 which is toxic to neurons; the damage thatit produces increases in the presence of reactive free radicals. Adecreased level of apolipoprotein E has been reported in patientswith AD, and that decrease is greater in patients with theapolipoprotein E type 4 allele.1

The decrease in the concentration of ACh that is associated withAD has been the main focus of new pharmacotherapies.1 Currently,the only therapies approved for the treatment of AD are thosethat increase the level of ACh in the brain by inhibiting central-ly active acetylcholinesterase (AChE), which is the enzyme thathydrolyzes ACh.

■ Estrogen-Mediated ActionsThe actions of neurosteroids in the prevention and treatment

of AD have been the focus of recent investigations.5-12 The fol-lowing estrogen-mediated actions are relevant to the pathologicmechanism of action of AD: Decreased accumulation of β-amyloidIncreased synthesis of AChEnhanced expression of neurotrophins Anti-inflammatory activity of estrogenCytokine regulation Prevention of cerebral vasculature disruption Antioxidant activityIncreased utilization of glucose Regeneration of neurons in the brainIncrease in the number of synapses

The neuroactive steroid hormone progesterone is also believedto stimulate the production and proliferation of myelin.

Decreased Accumulation of β-Amyloid Ovariectomized rodent models that demonstrate long-term es-

trogen deprivation exhibit an increase in the level of β-amyloidin the brain, which causes impaired memory.13-16 Research indi-cates that estrogen blocks β-amyloid–induced neuronal cell deathvia estrogen receptor-α (ER-α)–dependent pathways.17 Estrogenhas been shown to enhance the antiapoptotic protein Bcl-xL, whichreduces β-amyloid–induced apoptosis; this suggests a novel mech-anism of estrogen-induced neuroprotection.18 Estrogen also ap-pears to enhance the clearance of β-amyloid through microglia,which are key components of the immune system that remove β-amyloid deposits from the brain. Whether the enhanced clear-ance of β-amyloid is estrogen-receptor-β (ER-β) dependent or re-ceptor independent is unknown.19 AChE, a protein also found insenile plaques, has recently been found to form complexes withthe β-amyloid peptide that are more cytotoxic than β-amyloid fib-rils alone. Both β-amyloid and β-amyloid-AChE complexes areameliorated by estradiol therapy, which provides protectionagainst amyloid-induced toxicity at the cellular level.20 Physio-logic doses of estradiol have significantly reduced the productionof endogenous β-amyloid in primary cortical neurons.21,22

Increased Synthesis of AChStudies indicate that estrogens, which are neuroactive steroid

hormones, affect the neuronal function of the basal forebrain.23

Estrogen receptors (predominantly estrogen receptor-α [ER-α]) are present on cholinergic neurons in the basal forebrain ofrats, and estrogen may directly regulate the activity of cholin-ergic neurons via those receptors.24 Low-affinity nerve growthfactor (NGF) receptors are located on cholinergic neurons, asis ER-α.1

Choline acetyltransferase (ChAT), the ACh-synthesizing enzyme,is directly affected by estrogen.25 The ChAT messenger ribonu-cleic acid (mRNA) and trkA (NGF receptor) mRNA are de-creased after the loss of ovarian function.26-28 Studies indicate thatthe level of ChAT mRNA may be significantly increased by es-trogen25,27-33 and progesterone,28,30,31 but the beneficial effects ofreplacement therapy may be limited only to women.29 Accordingto some studies,30 estrogen and progesterone replacement mayenhance spatial memory and reduce the performance deficits that are associated with a decreased level of ACh, but other stud-ies31-34 do not concur. Raloxifene, a selective estrogen receptormodifier, may also exert a beneficial effect on cholinergic

Jennifer Osburn, PharmD (Candidate)University of Houston College of Pharmacy, Houston, Texas

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Estrogen Replacement Therapy

in the Treatment ofALZHEIMER’S DISEASE

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neurotransmission in the brain without producing the undesir-able stimulation of breast or uterine tissue that is associated withhormone replacement therapy.35

Enhanced Expression of NeurotrophinsCholinergic neurons require neurotrophic growth factors

(neurotrophins such as NGF and brain-derived nerve factor[BDNF]) for their survival. Estrogen enhances the expressionof neurotrophins, which, acting through their respective receptors,activate cholinergic neurons.36 Long-term loss of ovarian func-tion leads to a decline in the production of high-affinity NGFreceptors and in a decrease in the responsiveness of cholinergicneurons to endogenous NGF. Basal forebrain cholinergic declinethat exceeds the effect of normal aging results.26,30 Studies alsoindicate that estrogen deprivation leads to a reduction of bothNGF26,37 and BDNF37 mRNA levels. Estrogen 28,30,33 and pro-gesterone30 have been shown to significantly increase the levelof trkA mRNA. Estrogen is more effective in maintaining BDNFmRNA in the hippocampus than in the cerebral cortex; this sug-gests a regional difference in the neurosteroid requirement forBDNF expression.37

Anti-Inflammatory Activity of β-Amyloidβ-Amyloid induces an inflammatory reaction in the brain that

is an essential component of the pathologic effect of AD. Thisreaction is characterized by the adhesion and transmigration ofleukocytes across the vessel walls, disruption of the endotheli-um, and platelet activation.38 It has been suggested by Salem etal39 that estradiol may inhibit inflammatory responses by sup-pressing the homing and activation of inflammatory cells as wellas the production of tumor necrosis factor-α (TNF-α) and in-terferon-γ (IFN-γ). Results of the Postmenopausal Estrogen/Pro-gestin Interventions (PEPI) Study40 suggest that estrogen ther-apy produces early adverse inflammatory effects on vasculatureby increasing the concentration of C-reactive protein, an in-flammatory factor, after which a beneficial anti-inflammatory ef-fect occurs from a reduction in the level of soluble E-selectin.Another study by Bruce-Keller et al41 indicates that estrogen mayattenuate the progression of neurodegenerative diseases by es-trogen-receptor–dependent activation of mitogen-activated pro-tein (MAP) kinase. MAP kinase is involved in estrogen-mediat-ed pathways in microglial cells. The involvement of estrogen inthe anti-inflammatory pathway is yet another mechanism by whichestrogen may protect against AD.40,41

Cytokine RegulationThe neurodegenerative β-amyloid plaques seen in patients with

AD cause an upregulation of the proinflammatory cytokines in-terleukin-1 (IL-1) and interleukin-6 (IL-6).42 Nitric oxide (NO)exerts a protective anti-inflammatory effect on the endotheli-um by decreasing the level of IL-6 in the brain. Estrogen, whichaffects specific receptors on brain cells, can block IL-6 produc-tion by promoting vascular NO synthesis.43 NO synthesis is rapidafter estrogen administration and does not decline after re-peated administration.44 IL-1 activity may be potentially decreasedby means of estrogen-receptor–mediated action as well.43

Prevention of Cerebral Vasculature Disruption Cerebral blood vessel dysfunction is induced by a chronic

inflammatory reaction mediated by β-amyloid. In rodent mod-els, conjugated equine estrogens (CEE) prevented endothelialand vessel wall disruption resulting from β-amyloid–induced inflammatory reactions. Those reactions include plasma leak-age, platelet and mast-cell activation, and the adhesion andtransmigration of leukocytes. The protective effects of estrogenagainst β-amyloid–induced cytotoxicity were lost when CEE ther-apy was discontinued.45,46

In separate studies,47,48 Wise and Dubal used a model of cere-bral artery occlusion and physiologic levels of estradiol re-placement therapy to demonstrate the profound protective ef-fects of estradiol against ischemic brain injury. Improved bloodflow protects the brain from metabolic injury caused by hypoxia.Estrogen replacement therapy can prevent cognitive dysfunc-tion and decrease the risk of neurodegenerative conditions suchas AD and stroke.

Antioxidant ActivityOxidative neuronal cytotoxicity is attenuated by estradiol-17α,

estradiol-17β, and estrone.49 In some studies,49-53 estrogen-receptorantagonists did not reverse the antioxidant effect of estrogen. Thissuggests that the antioxidant effect of estrogen is not receptor me-diated but may instead be due to free-radical scavenging. Otherfindings54,55 have suggested that estradiol provides better antioxidantprotection than does α-tocopherol (vitamin E), but some stud-ies56 indicate that both natural and synthetic vitamin E exertedgreater neuroprotective effects than did estradiol.

Increased Utilization of GlucoseDisturbances in cerebral energy metabolism and deterioration

in memory function in animal models have been decreased by estra-diol administration.57 Some findings58 suggest that the beneficialeffects of estrogen on neuronal tissue are produced by the up-regulation of glucose transporters and increased insulin-likegrowth factor 1 (IGF-1) expression. Glucose transporters wereimpaired when synapses were experimentally exposed to β-amy-loid and ferrous sulfate. When the synapses were pretreated withestradiol, the glucose transport impairment was prevented.59

The effect of estrogen on regional cerebral glucose metabo-lism was evaluated by means of positron-emission tomography,and the study results suggested that brain metabolic activity wasaffected by estrogen depletion.60 ChAT converts choline intoACh via the acetylation of acetyl-coenzyme A, the synthesis ofwhich is decreased in the presence of low glucose turnover inthe demented brain.61

Regeneration of Neurons in the Brain The formation of axodendritic and spinal synapses is facilitat-

ed by estrogen.62,63 Apolipoprotein E has an important role in re-generating synaptic circuitry after neural injury. The combinedeffect of apolipoprotein E and estrogen modulates the neurolog-ic effects of AD.64

Increase in the Number of SynapsesEstrogen has been shown to increase the density of dendritic

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spines on CA1 pyramidal cell dendrites and to increase the num-ber of spinal synapses.65 The findings of Yankova et al65 also sug-gest that estrogen facilitates the formation of new synaptic con-nections between previously unconnected hippocampal neurons.Studies66 show that estradiol may increase spine density and en-hance N-methyl-D-aspartate (NMDA)-dependent calcium signalsin spines and dendrites; this could reduce the threshold for theinduction of NMDA-dependent synaptic plasticity. In rodentmodels, an elevated estradiol level is associated with an increaseddensity of dendritic spine synapses on CA1 pyramidal cells, whichincreases hippocampal excitability as well as the potential for synap-tic plasticity.67,68 IGF-1 is believed to be involved in estrogen-in-duced synaptic plasticity, which may depend on the activation ofboth the estrogen receptor and the IGF-1 receptor.69

Facilitating Myelin Production and Proliferation

Neurosteroids, which are synthesized primarily by glial cells,regulate the synthesis of myelin proteins. Neurosteroids demon-strate an important role in myelin repair. Schwann cells synthe-size progesterone and its direct precursor pregnenolone. Block-age of the local synthesis or action of progesterone impairsremyelination. The formation of new myelin sheaths is enhancedby progesterone administration.70

■ Clinical TrialsObservational studies and randomized clinical trials5 of estro-

gen replacement therapy with or without progestin therapy havesuggested that estrogen protects against age-associated decreas-es in cognition (particularly memory) in postmenopausal women.The results of the Women’s Health Initiative, a 15-year study con-ducted by the National Institutes of Health, are expected in 2005.That trial is the first long-range study in which the effects of hor-mone replacement in older women are studied. Estrogens appearto prevent β-amyloid–induced cell death and to protect remain-ing neurons from further cytotoxic effects. Results from thatstudy could provide insight about the effects of estrogen re-placement therapy on cognitive function and AD.6

In general, most studies to date have confirmed that estrogenreplacement therapy enhances memory and various other cog-nitive functions. Those results7-12 provide support for the hy-pothesis that estrogen helps maintain aspects of short-term andlong-term verbal memory in women but has no effect or exertsa negative influence on visual spatial memory. Flaws in studiesstill remain: small sample sizes, variances in the cognitive examinations used, study durations, the type of estrogen re-placement therapy administered, and whether all appropriate hor-mone levels were monitored throughout the study period. A few

http://www.pharma-tek.com

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studies71-73 have failed to demonstrate apositive association between estrogen re-placement therapy and enhanced cognitivefunction and memory, but those studieswere limited by a small sample size and ashort duration of therapy.

■ Components ofHormone ReplacementTherapy

Studies74,75 indicated that decreases inestradiol were associated with AD in post-menopausal women but that significantvariances in estrone levels were not. Atthe time of this writing, many studies5-12,

71-73 of the effects of estradiol and CEE (butnot bioidentical hormones) on AD inwomen have been conducted. Human es-trogen consists of 10% to 20% estrone, 10%to 20% estradiol, and 60% to 80% estri-ol. In contrast, CEE consists of 75% to 80%estrone, 5% equilin, 5% to 19% estradiol,and other estrogens.76 Because of findingsthat postmenopausal women with AD have

a decreased level of estradiol,74,75 hormonereplacement should include estradiol as amajor component. Supplementation withbioidentical hormones supplies physio-logic amounts of estradiol and replaces es-trone and estriol. The use of bioidenticalhormones77-79 also prevents side effectsthat may be caused by the use of CEE, whichcontains equine hormones and metabo-lites80-82 foreign to the human body in ad-dition to estradiol and estrone.

■ ConclusionMany exciting prospects lie ahead in the

quest for a cure for AD. Studies of the ben-eficial effects of estrogen replacementtherapy may include evaluating the effectof estrogen on decreasing β-amyloid ac-cumulation, increasing ACh synthesis, re-ducing inflammation, protecting the vas-culature of the central nervous system, andincreasing antioxidant protection againstfree radicals. Less is known about the ef-fects of enhancing the expression of neu-

rotrophins, regulating cytokines, increas-ing glucose utilization, enabling neuron re-generation, increasing synaptic numbers,and facilitating myelin production and pro-liferation, but plausible mechanisms bywhich neurosteroids may protect against ADhave been identified. AD remains a com-plex multifactorial challenge for clinicians.Collaborative interdisciplinary efforts maylead to further advancements in the pre-vention and understanding of AD and inthe treatment of those whom it afflicts. Ran-domized, placebo-controlled studies oflarge sample sizes over extended periods oftime are needed before the benefits of es-trogen replacement therapy for patients withAD can be fully explained.

References 1. Oettel M, Schillinger E, eds. Estrogens and

Antiestrogens II: Pharmacology and Clinical Application of Estrogens and Antiestrogens.1st ed. New York: Springer-Verlag Berlin Hei-delberg; 1999:473-503.

2. Fraser I, ed. Estrogens and Progestogens in Clinical Practice. 1st ed. New York: ChurchillLivingstone 1998:691-692.

3. McGreer PL, McGreer EG. The inflammatory re-sponse system of brain: Implications for thera-py of Alzheimer and other neurodegenera-tive diseases. Brain Res Brain Res Rev 1995;21:195-218.

4. Gandy S, Petanceska S. Regulation of Alzheimerbeta-amyloid precursor trafficking and metab-olism. Biochim Biophys Acta 2000;1502: 44-52.

5. Sherwin BB. Estrogen effects on cognition inmenopausal women. Neurology 1997;48(suppl7):S21-S26.

6. Diaz Brinton R, Chen S, Montoya M, et al. Thewomen’s health initiative estrogen replacementtherapy is neurotrophic and neuroprotective.Neurobiol Aging 2000;21:475-496.

7. Kawas C, Resnick S, Morrison A, et al. A prospec-tive study of estrogen replacement therapy andthe risk of developing Alzheimer’s disease: TheBaltimore Longitudinal Study of Aging. Neurol-ogy 1997;48:1517-1521.

8. Maki P, Zonderman A, Resnick S. Enhanced ver-bal memory in nondemented elderly women receiving hormone-replacement therapy. Am JPsychiatry 2001;158:227-233.

9. Fillit H, Weinreb H, Cholst I, et al. Observationsin a preliminary open trial of estradiol therapyfor senile dementia-Alzheimer’s type. Psycho-neuroendocrinology 1986;11:337-345.

10. Kampen DL, Sherwin BB. Estrogen use and ver-bal memory in healthy postmenopausal women.Obstet Gynecol 1994;83:979-983.

11. Honjo H, Ogino Y, Naitoh K, et al. In vivo effectsby estrone sulfate on the central nervous sys-tem-senile dementia (Alzheimer’s type). J SteroidBiochem 1989;34:521-525.

12. Costa MM, Reus VI, Wolkowitz OM, et al. Estro-

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gen replacement therapy and cognitive declinein memory-impaired post-menopausal women.Biol Psychiatry 1999;46:182-188.

13. Petanceska SS, Nagy V, Frail D, et al. Ovariec-tomy and 17beta-estradiol modulate the levelsof Alzheimer’s amyloid beta peptides in brain. Exp Gerontol 2000;35:1317-1325.

14. Petanceska SS, Nagy V, Frail D, et al. Ovariec-tomy and 17beta-estradiol modulate the levelsof Alzheimer’s amyloid beta peptides in brain. Neurology 2000;54:2212-2217.

15. Yamada K, Tanaka T, Zou LB, et al. Long-term de-privation of oestrogens by ovariectomy poten-tiates beta-amyloid-induced working memorydeficits in rats. Br J Pharmacol 1999;128:419-427.

16. Shi J, Panickar KS, Yang SH, et al. Estrogen attenuates over-expression of beta-amyloidprecursor protein messenger RNA in an animal model of focal ischemia. Brain Res 1998;810:87-92.

17. Kim H, Bang OY, Jung MW, et al. Neuroprotec-tive effects of estrogen against beta-amyloidtoxicity are mediated by estrogen receptorsin cultured neuronal cells. Neurosci Lett 2001;302:58-62.

18. Pike CJ. Estrogen modulates neuronal Bcl-xL ex-pression and beta-amyloid-induced apoptosis:Relevance to Alzheimer’s disease. J Neurochem1999;72:1552-1563.

19. Li R, Shen Y, Yang LB, et al. Estrogen enhancesuptake of amyloid beta-protein by microglia de-rived from the human cortex. J Neurochem2000;75:1447-1454.

20. Bonnefont AB, Munoz FJ, Inestrosa NC. Estro-gen protects neuronal cells from the cytotoxic-ity induced by acetylcholinesterase-amyloidcomplexes. FEBS Lett 1998;441:220-224.

21. Vincent B, Smith JD. Effect of estradiol on neu-ronal Swedish-mutated beta-amyloid precursorprotein metabolism: Reversal by astrocytic cells.Biochem Biophys Res Commun 2000;271:82-85.

22. Xu H, Gouras GK, Greenfield JP, et al. Estrogenreduces neuronal generation of Alzheimer beta-amyloid peptides. Nat Med 1998;4:447-451.

23. Mufson EJ, Cai WJ, Jaffar S, et al. Estrogen receptor immunoreactivity within subregions ofthe rat forebrain: Neuronal distribution and association with perikarya containing cholineacetyltransferase. Brain Res 1999;849:253-274.

24. Shughrue PJ, Scrimo PJ, Merchenthaler I. Es-trogen binding and estrogen receptor charac-terization (ERalpha and ERbeta) in the choliner-gic neurons of the rat basal forebrain.Neuroscience 2000;96:41-49.

25. Gibbs RB, Wu D, Hersh LB, et al. Effects of es-trogen replacement on the relative levels ofcholine acetyltransferase, trkA, and nervegrowth factor messenger RNAs in the basalforebrain and hippocampal formation of adult rats.Exp Neurol 1994;129:70-80.

26. Gibbs RB. Impairment of basal forebrain cholin-ergic neurons associated with aging and long-term loss of ovarian function. Exp Neurol 1998;151:289-302.

27. Gibbs RB. Effects of estrogen on basal fore-

brain cholinergic neurons vary as a function of dose and duration of treatment. Brain Res1997; 757:10-16.

28. Gibbs RB. Fluctuations in relative levels ofcholine acetyltransferase mRNA in different regions of the rat basal forebrain across the estrous cycle: Effects of estrogen and proges-terone. J Neurosci 1996;16:1049-1055.

29. Luine VN. Estradiol increases choline acetyl-transferase activity in specific basal forebrainnuclei and projection areas of female rats.Exp Neurol 1985;89:484-490.

30. Gibbs RB. Oestrogen and the cholinergic hy-pothesis: Implications for oestrogen replace-ment therapy in postmenopausal women. NovartisFound Symp 2000;2310:94-107; discussion 107-111.

31. Gibbs RB. Effects of gonadal hormone replace-ment on measures of basal forebrain choliner-gic function. Neuroscience 2000;101:931-938.

32. Honjo H, Kikuchi N, Hosoda T, et al. Alzheimer’sdisease and estrogen. J Steroid Biochem Mol Biol2001;76:227-230.

33. Singer CA, McMillan PJ, Dobie DJ, et al. Effectsof estrogen replacement on choline acetyl-transferase and trkA mRNA expression in the basal forebrain of aged rats. Brain Res 1998;789:343-346.

34. Lapchak PA, Araujo DM, Quirion R, et al. Chron-

ic estradiol treatment alters central cholinergicfunction in the female rat: Effect on cholineacetyltransferase activity, acetylcholine con-tent, and nicotinic autoreceptor function. BrainRes 1990;525:249-255.

35. Wu X, Glinn MA, Ostrowski NL, et al. Raloxifeneand estradiol benzoate both fully restore hippocampal choline acetyltransferase activityin ovariectomized rats. Brain Res 1999;847:98-104.

36. McMillan PJ, Singer CA, Dorsa DM. The effectsof ovariectomy and estrogen replacement on trkA and choline acetyltransferase mRNAexpression in the basal forebrain of the adult female Sprague-Dawley rat. J Neurosci 1996;16:1860-1865.

37. Singh M, Meyer EM, Simpkins JW. The effect of ovariectomy and estradiol replacement onbrain-derived neurotrophic factor messengerribonucleic acid expression in cortical and hippocampal brain regions of female Sprague-Dawley rats. Endocrinology 1995;136: 2320-2324.

38. Thomas T, Bryant M, Clark L, et al. Estrogen and raloxifene activities on beta-amyloid-induced inflammatory reaction. Microvasc Res2001;61:28-39.

39. Salem ML, Hossain MS, Nomoto K. Mediation ofthe immunomodulatory effect of beta-estradiol

http://www.pccarx.com

W E L L N E S S


on inflammatory responses by inhibition of recruitment and activation of inflammatory cellsand their gene expression of TNF-alpha andIFN-gamma. Int Arch Allergy Immunol 2000;121:235-245.

40. Cushman M, Legault C, Barrett-Connor E, et al.Effect of postmenopausal hormones on inflam-mation-sensitive proteins: The Postmenopaus-al Estrogen/Progestin Interventions (PEPI) Study.Circulation 1999;100:717-722.

41. Bruce-Keller AJ, Keeling JL, Keller JN, et al. Anti-inflammatory effects of estrogen on microglialactivation. Endocrinology 2000;141:3646-3656.

42. McCarty MF. Vascular nitric oxide, sex hormonereplacement, and fish oil may help to prevent Alzheimer’s disease by suppressing synthesis of acute-phase cytokines. Med Hypotheses1999;53:369-374.

43. Knoferl MW, Diodato MD, Angele MK, et al. Dofemale sex steroids adversely or beneficiallyaffect the depressed immune responses in malesafter trauma-hemorrhage? Arch Surg 2000;135:425-433.

44. Lopez-Jaramillo P, Teran E. Improvement in func-tions of the central nervous system by estrogenreplacement therapy might be related with an increased nitric oxide production. Endothelium1999;6:263-266.

45. Thomas T, Rhodin JA, Sutton ET, et al. Estrogenprotects peripheral and cerebral blood vesselsfrom toxicity of Alzheimer peptide amyloid-betaand inflammatory reaction. J Submicrosc CytolPathol 1999;31:571-579.

46. Thomas T, Rhodin J. Vascular actions of estro-gen and Alzheimer’s disease. Ann N Y Acad Sci2000;903:501-509.

47. Wise PM. Estradiol: A protective factor in the adultbrain. J Pediatr Endocrinol Metab 2000;13 (sup-pl 6):1425-1429.

48. Dubal DB, Wise PM. Neuroprotective effects ofestradiol in middle-aged female rats. Endocri-nology 2001;142:43-48.

49. Bae YH, Hwang JY, Kim YH, et al. Anti-oxidativeneuroprotection by estrogens in mouse corticalcultures. J Korean Med Sci 2000;15:327-336.

50. Behl C. Amyloid beta-protein toxicity and oxidativestress in Alzheimer’s disease. Cell Tissue Res1997;290:471-480.

51. Howard SA, Brooke SM, Sapolsky RM. Mecha-nisms of estrogenic protection against gp120-induced neurotoxicity. Exp Neurol 2001;168:385-391.

52. Culmsee C, Vedder H, Ravati A, et al. Neuropro-tection by estrogens in a mouse model of focalcerebral ischemia and in cultured neurons: Evidence for a receptor-independent antioxida-tive mechanism. J Cereb Blood Flow Metab 1999;19:1263-1269.

53. Behl C, Moosmann B, Manthey D, et al. The fe-male sex hormone oestrogen as neuroprotectant:Activities at various levels. Novartis Found Symp2000;230:221-234; discussion, 234-238.

54. Ayres S, Tang M, Subbiah MT. Estradiol-17betaas an antioxidant: Some distinct features when

compared with common fat-soluble antioxidants.J Lab Clin Med 1996;128:367-375.

55. Akova B, Surmen-Gur E, Gur H, et al. Exercise-induced oxidative stress and muscle performancein healthy women: Role of vitamin E supple-mentation and endogenous oestradiol. Eur J ApplPhysiol 2001;84:141-147.

56. Behl C. Vitamin E protects neurons against ox-idative cell death in vitro more effectively than17-beta estradiol and induces the activity of thetranscription factor NF-kappaB. J Neural Transm2000;107:393-407.

57. Lannert H, Wirtz P, Schuhmann V, et al. Effectsof estradiol (-17beta) on learning, memory andcerebral energy metabolism in male rats after intracerebroventricular administration of strep-tozotocin. J Neural Transm 1998;105:1045-1063.

58. Cheng CM, Cohen M, Wang J, et al. Estrogen aug-ments glucose transporter and IGF1 expressionin primate cerebral cortex. FASEB J 2001;15: 907-915.

59. Keller JN, Germeyer A, Begley JG, et al. 17Beta-estradiol attenuates oxidative impairment ofsynaptic Na+/K+-ATPase activity, glucose transport, and glutamate transport induced by amyloid beta-peptide and iron. J Neurosci Res1997;50:522-530.

60. Eberling JL, Reed BR, Coleman JE, et al. Effectof estrogen on cerebral glucose metabolism in postmenopausal women. Neurology 2000;55:875-877.

61. Meier-Ruge WA, Bertoni-Freddari C. Mitochon-drial genome lesions in the pathogenesis of spo-radic Alzheimer’s disease. Gerontology 1999;45:289-297.

62. Matsumoto A, Arai Y. Synaptogenic effect of estrogen on the hypothalamic arcuate nucleusof the adult female rat. Cell Tissue Res 1979;198:427-433.

63. Matsumoto A, Arai Y. Neuronal plasticity in thedeafferented hypothalamic arcuate nucleus ofadult female rats and its enhancement by treat-ment with estrogen. J Comp Neurol 1981;197:197-205.

64. Teter B, Harris-White ME, Frautschy SA, et al.Role of apolipoprotein E and estrogen in mossyfiber sprouting in hippocampal slice cultures. Neuroscience 1999;91:1009-1016.

65. Yankova M, Hart SA, Woolley CS. Estrogen increases synaptic connectivity between singlepresynaptic inputs and multiple postsynapticCA pyramidal cells: A serial electron-micro-scopic study. Proc Natl Acad Sci U S A 2001;98:3525-3530.

66. Pozzo-Miller LD, Inoue T, Murphy DD. Estradiolincreases spine density and NMDA-dependentCa2+ transients in spines of CA1 pyramidal neu-rons from hippocampal slices. J Neurophysiol1999;81:1404-1411.

67. Woolley CS. Estrogen-mediated structural andfunctional synaptic plasticity in the female rathippocampus. Horm Behav 1998;34:140-148.

68. Brake WG, Alves SE, Dunlop JC, et al. Novel tar-

get sites for estrogen action in the dorsal hip-pocampus: An examination of synaptic proteins.Endocrinology 2001;142:1284-1289.

69. Cardona-Gomez GP, Trejo JL, Fernandez AM, et al. Estrogen receptors and insulin-like growthfactor-I receptors mediate estrogen-dependentsynaptic plasticity. Neuroreport 2000;11:1735-1738.

70. Schumacher M, Baulieu EE. Neurosteroids: Synthesis and functions in the central and peripheral nervous systems. Ciba Found Symp1995; 191:90-106; discussion 106-112.

71. Binder EF, Schechtman KB, Birge SJ, et al. Ef-fects of HRT on cognitive performance in elderlywomen. Maturitas 2001;38:137-146.

72. Polo-Kantola P, Portin R, Polo O, et al. The effect of short-term estrogen replacement therapy on cognition: A randomized, double-blind cross-over trial in postmenopausal women.Obstet Gynecol 1998;91:459-466.

73. Barrett-Connor E, Kritz-Silverstein D. Estrogenreplacement therapy and cognitive function inolder women. JAMA 1993;269:2637-2641.

74. Manly JJ, Merchant CA, Jacobs DM, et al. En-dogenous estrogen levels and Alzheimer’s disease among postmenopausal women. Neu-rology 2000;54:833-837.

75. Cunningham CJ, Sinnott M, Denihan A, et al. En-dogenous sex hormone levels in postmenopausalwomen with Alzheimer’s disease. J Clin EndocrinolMetab 2001;86:1099-1103.

76. Wright JV, Schliesman B, Robinson L. Compar-ative measurements of serum estriol, estradiol,and estrone in non-pregnant, premenopausalwomen: A preliminary investigation. Altern MedRev 1999;4:266-270.

77. Taylor M. Alternatives to conventional hormonereplacement therapy. Compr Ther 1997;23:514-532.

78. Hargrove JT, Maxson WS, Wentz AC, et al.Menopausal hormone replacement therapy withcontinuous daily oral micronized estradiol andprogesterone. Obstet Gynecol 1989;73:606-612.

79. de Lignieres B, MacGregor EA. Risks and ben-efits of hormone replacement therapy. Cepha-lalgia 2000;20:164-169.

80. Shen L, Qiu S, Chen Y, et al. Alkylation of 2'-de-oxynucleosides and DNA by the Premarinmetabolite 4-hydroxyequilenin semiquinone radical. Chem Res Toxicol 1998;11:94-101.

81. Chen Y, Shen L, Zhang F, et al. The equine estrogenmetabolite 4-hydroxyequilenin causes DNA single-strand breaks and oxidation of DNA basesin vitro. Chem Res Toxicol 1998;11:1105-1011.

82. Chen Y, Liu X, Pisha E, et al. A metabolite of equineestrogens, 4-hydroxyequilenin, induces DNAdamage and apoptosis in breast cancer celllines. Chem Res Toxicol 2000;13:342-350.

Address correspondence to: Jennifer Osburn,21731 Tara Park Drive, Hempstead, TX77445. E-mail: [email protected]. ■

Several years ago, I decided to try my hand at making lollipops.I purchased a 12-cavity lollipop mold, a dozen bulldog clips, a can-dy thermometer, and a couple of pounds of sugar, and I was readyto go! A little research into candy making left me somewhat lessenthusiastic: hard-ball stage, hard-crack stage, soft-ball stage, etc.Then, after sweating in the lab with the hot plate on high as thesyrup boiled for hours only to reach the next “texture” stage, Iwas even more disheartened. After realizing that this procedurehad to be performed almost every time lollipops are made, I ut-tered the words bequeathed to me by my late father, “To hell withthat noise.”

If At First You Don’t Succeed. . .Accustomed to thinking outside the box, I eyed some sorbitol

candies that hung on a rack at the front of our store. After we hadzapped them a few times in the microwave — voila! — liquid can-dy that was ready to mix with medication and be poured into lol-lipop or troche molds. After a few painful episodes (physically andemotionally), I learned that if I didn’t heat the candy too much,it would cool and harden in 6 to 8 hours. If the mix was super-heated, it might take overnight to set.

I wasn’t making a lot of lollipops at the time, but I was satisfiedthat I had solved a problem and now had a new tool in my arse-nal of dosage forms. For me, formulating lollipops was now out

of the “huge pain” category. Not long afterwards, I respondedto a post on Pitcher Mountain (the electronic bulletin board ofGeorge Roentsch, RPh) from Phil Pylant of Village Pharmacyin Houston, Texas. He was facing the same frustrations with lol-lipop making that I had encountered. I faxed him a copy of thecandy label I used and some of my auxiliary patient handouts.The next thing I knew, he was successfully making high-doseanalgesic lollipops for his ear, nose, and throat (ENT) special-ists to prescribe for their patients.

Joe Wise (Wise Pharmacy, Littleton, Colorado) became the nextperson to carry the torch. He and Randy Carr (Carr Drug, NewOrleans, Louisiana) had been collaborating on their lollipop mak-ing. They used the hard-candy methods and had been fightingthe sugar-candy–hard-ball mold battle for some time. However,they persevered and have had success with lollipops as a dosageform because Randy perfected his method of making them. Un-fortunately, that technique could not easily be re-created in thepharmacy setting. The usual compounding laboratory equipmentcannot provide the high temperature and extended heating thatmaking lollipops requires. Randy would measure the ingredients,take them home, and use an old Sears Crock Pot that was perfectfor the purpose. The dosage form was of the desired quality, butthe technique was by no means efficient. Joe and Randy had trieda few different molds as part of the usual trial-and-error methodthat is essential to innovation. Often, the molds would come apartor warp as a result of the heat. The process required creativity:The mold was once sealed with several forks from the restaurantnext door.

The Benefits of NetworkingWhile at a seminar to present a talk on the success of his lollipop

dosage form, Joe explained that he had made some placebo lollipops,which had been distributed to all of his professional contactsin his business community. Almost everyone who received a lol-lipop was either fascinated or perplexed. During or shortly afterJoe’s presentation, Phil Pylant presented a talk on the methodin which sorbitol is heated to create a liquid candy for use informulations; he stressed how easy that is when compared withother current methods. Joe decided to try the “sorbitol method”and was pleasantly surprised. His lollipop business exploded.He contacted a candy company, established communications,and enabled other pharmacists to buy the candies in bulk andwithout wrappers.

A number of pharmacists were not too excited about the lol-lipop mold that was available at that time. It was awkward andmessy to use, and it did not produce the desired elegant dosageform that patients and prescribers expected from their pharma-cists. Dan Crouch, the sourcing manager at Professional Com-pounding Centers of America, Inc (PCCA), heard what he calleda “chorus of voices”: a series of complaints that served as his callto action. He used those demands for change as an opportunityto fill a particular need for his clients. He was sure that he could

W E L L N E S S


LOLLIPOPS: The Evolution of a Dosage Form

Dave Mason, DPh, FIACPShannon Fields, PhTechInnovative Pharmacy, Edmond, Oklahoma

W E L L N E S S


design a better mold that would result in a higher quality dosageform, and he approached the company management with hisideas for improvement. They approved Dan’s concept and com-missioned the project.

Dan quickly drew a sketch of a prototype model. The only ma-jor stumbling block was determining how to prevent the lollipopsticks from “bottoming out” in the mold. However, after measuringscores of sticks, he thought about using a tapered-hole design. Theentire redesign process, from budding concept to fruition, tookonly 6 months. Dan’s greatest satisfaction came from not only solv-ing a problem for the pharmacists with whom he worked but alsofrom having helped a close friend and family member.

The applications of lollipops as dosage forms soon became ap-parent to Eric Holgate (Custom Prescription Shoppe, Augusta,Georgia). Shortly after having seen the new lollipop mold, he hearda talk-radio host’s comments on legislation pertaining to nicotineand tobacco company lawsuits. He then thought of using lollipopsto aid smoking cessation, because that dosage form provides thehand-to-mouth action that is one of the most persistent obsta-cles to quitting smoking. He began preparing nicotine lollipopsfor that purpose for his patients and prescribers. The success ofthat formulation enabled Eric to build a virtual franchise ontechniques for quitting smoking. He now offers his clients a ba-sic protocol for smoking cessation that includes food recipes, coun-

seling materials, and even an audiotape.A pharmacist working in my pharmacy heard Eric’s presenta-

tion on smoking cessation at a seminar and brought the idea hometo me. I followed his lead and developed the same program thathe had presented. Our nicotine lollipops became very popular atour pharmacy and at other pharmacies in our metro area after theywere featured in a human interest story by a local news station.The formulation works quite well.

What Goes Around Comes Around: The Path to Success

As I was making a batch of nicotine lollipops one morning, itoccurred to me how this venture has come full circle. My minis-cule contribution several years ago has been adopted, nurtured,and improved by several people. Each imparted his or her par-ticular skill, talent, or flair, and the success of that dosage formhas grown exponentially. My small contribution has returnedmany dividends, all of which resulted from the spirit of giving,sharing, networking, and collaborating to produce the best pos-sible answer to a need.

Address correspondence to: Dave Mason, DPh, FIACP, 1716 S.Kelly, Edmond, OK 73013. E-mail: [email protected]. ■

http://www.meridian-nacp.com

Natural ApproachesIndex to DrugInteractions, Depletions,and ComplementsBaylor Rice, RPh, and Jennifer EdelbluteACHS, LLC, Midlothian,Virginia; [email protected], 888-879-7713★★★★★ An excellent resource on nutri-ent depletion

This index was written by a pharmacistfor the pharmacist. It is a reference guidedesigned to save time required to locate in-formation on drug interactions, depletions,and complements. It is well-referencedand is a compilation of the best informa-tion from references such as the following:■ German Commission E monographsystem for phytomedicines: A model forregulatory reform in the United States.In: Phytomedicines of Europe: Chemistryand Biological Activity (American Chem-ical Society, Distributed by Oxford Uni-versity Press, Washington, DC; 1998)■ Review of Natural Products, 2001 (Facts& Comparisons, St. Louis, MO; 1998)■ PDR for Herbal Medicines 1999. 2nd ed.(Medical Economics, Montvale, NJ; 1999)■ Drug-Induced Nutrient Depletion Hand-book (Lexi-Comp, Inc, Hudson, OH; 1999)■ Encyclopedia of Nutritional Supple-ments: The Essential Guide for ImprovingYour Health Naturally (Prima Publishing,Rocklin, CA; 1996)■ The Healing Power of Herbs (Prima

Communications, Inc, Rocklin, CA; 1995)Information in this text is presented in a

three-ring binder and is updated annual-ly. It is indexed by drug, drug category, andnatural ingredient (herb or nutrient) andcontains more than 60 drug or drug cate-gories and natural ingredients. The effectsof the natural ingredients (depletions, com-plements, or interactions) are also listed.Mechanisms of action and references arealso provided.

This reference is easy to use, and findinginformation takes only a few minutes. Un-like other similar references, it containsonly documented information about de-pletions, complements, and drug interac-tions. It is exactly what the pharmacistneeds to recommend a natural product.Other reference texts contain extensive in-formation on chemical compositions,dosage forms, and pharmacology. Althoughthose topics are very valuable, locating in-formation specifically on drug depletions isvery time-consuming. This book is con-siderably more expensive than the Drug-In-duced Nutrient Depletion Handbook, but it ismuch easier and faster to use, much moreconcise, and contains only relevant infor-mation, so it is worth the extra expense. Foran additional cost, you can obtain cus-tomized natural medicine monographs, pa-tient evaluation forms, and disease-statecondition protocols for use in your phar-macy, as well as technical support and as-sistance.

Drug-Induced NutrientDepletion Handbook,2nd edRoss Pelton, RPh, PhD, CCN; James B.LaValle, RPh, DHM, NMD, CCN; ErnestB. Hawkins, RPh, MS; and Daniel L.Krinsky, RPh, MS Lexi-Comp, Inc, Hudson, Ohio; and Nat-ural Health Resources, Inc, Cincinnati,Ohio; 2001. $29.95www.lexi.com, 800-837-LEXI★★★ An inexpensive reference on nutri-ent depletion

This well-referenced, 591-page pockethandbook is packed with facts about nu-trient depletion, as well as other drug in-formation. It lists drugs by US and Cana-dian brand and generic names andcontains hundreds of entries. Drugs are list-ed with and without depletions, whichaccounts for the number of entries, and thebook is indexed by drug and by nutrient.However, it does not contain informa-tion on drug-nutrient interactions, as didthe first edition, nor is information on herbsor complementary therapy included. Al-though this reference contains extensiveinformation about the subjects mentionedabove, it includes no more facts on nutri-ent depletion than do similar referenceshalf its size. It is difficult and time-con-suming to use, and the reader is referredto several different pages and sectionsthroughout the book when monographs onnutrients or information about drug de-pletion, studies, and abstracts are sought.This reference is a great resource for an-swering an occasional drug-informationquestion because it is inexpensive andcontains pertinent and essential informa-tion on nutrient depletion. However, forthe pharmacist who wants to use that typeof information daily to assist in making rec-ommendations about nutrients, the Nat-ural Approaches Index to Drug Interac-t ions , Deplet ions , and Complements ismuch more complete, user-friendly, andconcise.

BOOK REVIEWS:WELLNESS, NUTRITION,and GERIATRICS

W E L L N E S S


Dana Reed-Kane, PharmD, FIACP, FACAReed’s Compounding PharmacyTucson, ArizonaLisa D. Ashworth, RPhCoppell, Texas

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Recipes & Remedies:Prescription for HealthyLivingCalifornia Pharmacists Association, Sacra-mento, California; or Favorite RecipesPress, Nashville, Tennessee; 2000. $19.95www.cpha.com 800-444-3851, ext. 321★★ Gift idea!

This beautifully illustrated, elaborate,award-winning gourmet cookbook is a col-lection of 125 recipes compiled by the Cal-ifornia Pharmacists Association. It con-tains amazing full-color pictures of andrecipes for appetizers, entrees, desserts,and more. This cookbook includes tips forhealthful living and information about dis-ease awareness and prevention, propermedication use and storage, and commonherb and food interactions. It also offers tipson how to modify recipes to make themheart healthful, low salt, or vegetarian.However, the recipes are complex and mayrequire some ingredients, utensils, andcooking equipment that are not alwayshousehold staples.Dana Reed-Kane, PharmD, FIACP, FACA

Geriatric DosageHandbook, 7th edTodd P. Semla, PharmD, BCPS, FCCP;Judith L. Beizer, PharmD, FASCP; and Martin D. Higbee, PharmD, CGPLexi-Comp, Inc, Hudson, Ohio; 2002.$39.95 www.lexi.com ★★★★ A very useful reference

The authors of this book have written an outstanding text that contains current,

accurate information about medicationsused to treat geriatric patients (those old-er than 65 years of age). Any pharmacistwho provides services to that populationshould have the Geriatric Dosage Handbookreadily available. Medications are listedalphabetically by generic and brand names,and description fields are featured in bold-face. “Special Geriatric Considerations,” adescription field exclusive to this publica-tion, provides useful information aboutmedications associated with an increasedrisk of adverse events and the adjustmentof a dose or dosage to decrease the incidenceof adverse events in geriatric patients.

The charts in this text, which are concise,accurate, and easy to access, include topicson drug therapy for the treatment of glau-coma; the management of hyperlipidemia,osteoporosis, Parkinson’s disease, consti-pation, and heart failure; and a list of tabletsthat cannot be crushed or altered. Thewell-organized guidelines from the HealthCare Financing Administration (HCFA)on the use of medications (especially the

unnecessary use of anxiolytic or hypnoticdrugs in long-term healthcare facilities)are of particular interest to the consultantpharmacist.

Some elderly patients travel to Mexico orCanada to purchase prescription medica-tions at prices much lower than thosecharged in the United States. The de-scription field titled “Canadian BrandNames” provides useful information, andthe 216-page index of international brandnames (which includes the trade names ofmedications from 21 countries and theUnited States) can also be used by olderadults who travel worldwide. Who knowswhen a patient visiting a foreign countrymight lose his or her medication?

Although the Geriatric Dosage Hand-book contains extensive information on itssubject, its size enables the reader to carryit in a lab coat pocket or luggage. Howev-er, older readers with poor eyesight mightprefer to use a magnifying lens to read thistext, which is set in small type. Lisa D. Ashworth, RPh ■



Healthful Habits and Remedies from a Century Ago

The latter part of the 19th century markedthe beginning of an industry devoted topopular how-to health manuals and healthfads that continued well into the next cen-tury and into the present. From the public’sperspective, such printed materials and ideas were welcome. The causes of many dis-eases were poorly understood, and thehealth system offered little to combat or explain debility and chronic disease. Infec-tious illnesses such as tuberculosis, pneu-monia, and venereal diseases continued tobe major causes of death. Even many of

those in thei n c r e a s i n gmiddle classcould not af-ford a doctorand his treat-ments.

In the late1800s, therewas greatinterest inthe generalsubjects of

health and wellness, which were then knownas “hygiene.” Health fads of the time in-cluded phrenology and palmistry. Practi-tioners of those pseudosciences claimedthat they could understand a patient’s dis-ease and personality by studying the shapeof his or her head or the length of the heartline. It was the period during which curesand restorative powers were attributed toelectrotherapy, mechanotherapy, hy-drotherapy, and a host of other therapies.Food was seen as both the cause and the curefor the ills of the day.

Leaders of the Wellness Movement

The names of three individuals involvedwith the dietary movement (Samuel Gra-ham, John Harvey Kellogg, MD, and C.W.Post) were memorialized and became partof the vernacular.

Samuel Graham (1794 – 1851) was a min-ister, reformer, and avid vegetarian whotook on causes ranging from the dangers offeather beds and corsets to white bread andpork. He was most renowned, however, forhis theories on the association of diet andmasturbation and advanced the theory thatdiet influenced sexuality. He championedthe use of coarsely ground wheat flour(quickly named “graham flour”), which be-came the basic ingredient in graham crack-ers. John Harvey Kellogg, MD, (1852 –1943) was a physician and vegetarian whotransformed a struggling Seventh Day Ad-ventists’ home in Battle Creek, Michigan,into the major sanitarium* of the day. J. H.Kellogg was also an inventor: He is said tohave developed the electric blanket. In ad-dition, he devised cold cereals as breakfastfood for his patients at the Battle Creek San-itarium. His brother, William, commer-cialized one flaked cold cereal as “Kellogg’sCorn Flakes.”

Charles William Post (1854 – 1914), aninventor and businessman, was a patient at the Kellogg sanitarium. He viewed cereals and coffee substitutes as healthproducts and promoted them via consumeradvertising. He developed the dried cere-

al Grape Nuts which he claimed was a“brain food” that could also cure tubercu-losis. He was also the developer of Postum, a cereal-based coffee substitute.

Each of those men believed that healthcould be achieved and maintained onlythrough the properuse of food and theequally importantissue of elimina-tion. Kellogg wasparticularly givento the use of en-emas to cleansethe bowels. Hecautioned againstthe habitual useof laxatives andbelieved thatlaxative abuseincreased con-stipation in-stead of cur-ing it. As aremedy fordry, hard stool, herecommended theuse of “Neptune’sgirdle,” or “wet ab-domen.” That process included the bed-time routine of placing, on the patient’s ab-domen, a towel that had been soaked in coldwater, wrung out, and covered with dryflannel. The patient was then wrapped inthe flannel-covered towel, which providedwarmth overnight. The towel was removedthe next morning, and the patient was in-structed to “dip the hand in cold water andpercuss the bowels very thoroughly for fiveminutes. Go to stool within a half hour af-ter breakfast. Have a regular time.”2

In T.C. Boyle’s novel The Road to Wellville,one of the characters is introduced to theBattle Creek Sanitarium,* where bowelhealth and hygiene are emphasized.

We’re going to start you out for the firstthree days on psyllium seeds and hijiki. Thepsyllium is hygroscopic, it absorbs water andwill expand in your stomach, scouring youout as it passes through you just as surely asif a tiny army of janitors were down thereequipped with tiny scrub brushes. The samewith the hijiki—perfectly indigestible. Likeeating a broom—but that broom will sweepyou clean.3

Other physicians used a broad range of

G E N E R A L I N T E R E S T


Dennis B. Worthen, PhDLloyd Library and MuseumCincinnati, Ohio

Compounding in History:THE ROAD TO WELLVILLE

Suggestions on the mode of preservinghealth and attaining old age:Perfect nutrition is essential. Theprocess of digestion must be completelyand perfectly accomplished.Great attention must be paid to the habitual condition of the organs of excretion—particularly the bowels andthe skin.1

An old postcard showing the Battle Creek Sanitarium.

An early Kellogg’s advertising

trade card.



Formula 1. Mild Laxative.

Rx For 3 pintsCoarse balmony 4 oz

Chelone glabraButternut bark 4 oz

Inner bark and unripe fruit of butternut or white walnut (Juglans cinerea)

Senna 4 ozLeaves of Cassia acutifolia

Bicarbonate of soda 1/2 ozEssence of peppermint 1/2 ozSugar 2 lbs

Directions: Simmer the first 3 ingredients in 5 pints of wa-ter for 2 hours, strain, and add the sugar to the water. Thenslowly evaporate to 3 pints. Add the soda and peppermint.Dose: One tablespoon every 3 hours.

Formula 2. Liver Pills for All Obstructions of the Liver,Gall Ducts, and Bowel.

RxLeptandrin 3 drachms

A resinoid prepared from Leptandravirginica

Apocynin 1 drachm A tincture prepared from Indian hemp(Apocynum cannabinum)

Shavings of white Castile soap 2 drachmsEssence of peppermint qs

Directions: Soften the soap with a small amount of the essenceof peppermint and mix the powders into a pill mass.Dose: Two pills at bedtime.

The Pharmacist’s ToastMay his occupation never become a drug

in the market, as long as he sticks like hisown plasters, to business! May he neverbe bruised in the mortar of adversity bythe pestle of misfortune, and may his risein his profession be as accurately markedas his graduated measure. May his careerbe as unsullied as distilled water and assmooth and pleasant as pure Narbonnehoney! May his success never be alloyed

by a mixture of ill-luck or a tincture of re-gret! May his counter prove the cruciblewhereby he transmutes human ailmentsinto precious metal and precipitates thegolden deposit into his own pocket! Mayhe never be called upon to swallow the bit-ter pill of disappointment or be macerat-ed in the bitter spirit of enmity! Shouldfickle Fortune ever refuse him her smiles,may he find an antidote in the soothingopiate of woman’s love, be strengthenedby the tonic of experience and purified by

the sudorific of patience! Thus, his bestdays being evaporated and the lamp of existence past trimming, when Dr. Deathsends to his shop the dreadful prescriptionendorsed “To be taken at bedtime” and labeled and directed for heaven.

The Apothecary March 1943 Editor’s note: Dr. Dennis Worthen discoveredthis article while scanning journals for mate-rial on World War II. It is reprinted from TheApothecary, a regional journal for north-eastern America that is no longer in print. ■

medicines to cause evacuation of the bow-els. Those remedies were divided into fivegroups according to the action and thor-oughness desired. Laxatives provided thegentlest action (Formula 1).4 Mild cathar-tics were used for thorough bowel cleans-ing without irritation. Cholagogue cathar-tics acted on the liver by increasing bilesecretion (Formula 2).4 Hydragogue cathar-tics produced large volumes of watery dis-charge, and irritant cathartics produced avigorous evacuation of the bowel.5

Illness and the IntellectNot all the theories regarding health and

wellness focused exclusively on the diges-tive tract. Arnold Lorand explored geriatrics,including the possible postponement ofaging by practicing hygienic measures. Inhis book, Old Age Deferred, he offered ad-vice to “brainworkers” (something of par-ticular interest to pharmacists, teachers, andwriters). He commented on the physical ap-pearance of those who earned their living

by intellectual pursuits. They, he theo-rized, were subject to chronic constipationand nervous and intestinal disorders becauseblood was diverted from the digestive tractto the brain during intellectual activities.His solution was that:

Intellectual activity should, if possible, besuspended a full hour before and after meals.Congestion of the brain likewise interfereswith proper sleep, which, as a rule, can onlybecome truly deep when the brain is blood-less. Intellectual efforts should therefore beavoided for a period of one to two hours be-fore going to bed, and especially one shouldnot read in bed.6

References1. Fitch SS. A Treatise on Health, Its Aids and Hin-

drances Containing an Exposition of the Caus-es and Cures of Disease and the Laws of Life.NY:Pudney and Russell; 1857:505-506.

2. Kellogg JH. Man the Masterpiece of Plain TruthsPlainly Told About Boyhood, Youth, and Manhood.Des Moines:WD Conduit; 1889:588-589.

3. Boyle TC. The Road to Wellville. NY;Viking;1992:117.

4. Cook WH. Woman’s Book of Health: A Guide forthe Wife, Mother, and the Nurse. 8th ed. Cincin-nati:W Wesley Cook Publisher; 1884:399-400.

5. Scudder JM. Domestic Medicine or Home Bookon Health, A Popular Treatise on Anatomy, Phys-iology, Hygiene, Materia Medica, Surgery, Prac-tice of Medicine and Nursing. Cincinnati, OH:JHawley & Co; 1865:198.

6. Lorand A. Old Age Deferred: The Causes of OldAge and Its Postponement by Hygienic and Ther-apeutic Measures. 3rd ed. Philadelphia, PA:FADavis; 1912:423.

Address correspondence to: Dennis B.Worthen, PhD, The Lloyd Library and Mu-seum, 917 Plum Street, Cincinnati, OH45202. E-mail: [email protected] ■

*According to Dorland’s Illustrated MedicalDictionary (26th ed, Philadelphia:WB Saun-ders Co; 1985), the term “sanitarium” wascoined to refer to the Seventh Day Adven-tist institution in Battle Creek, Michigan,to distinguish it from institutions called“sanitoriums” providing care for patientswith psychiatric disorders or tuberculosis.

Have you ever created a magnificent compound? Hasthat compound ever been rejected by a provider becauseyou did not have a study to prove its safety and effec-tiveness? If so, you may consider performing a study inyour pharmacy to do just that. You might be concernedabout whether you have the time or expertise, but per-forming a study can be as easy as calling the nearestcollege of pharmacy.

Sources of Assistance in Performing a Study

Most pharmacy programs today require their students to com-plete a senior project before graduation, and compounding phar-macies are an excellent source of interesting and pertinent sub-jects. If you have a unique program, service, or formulation, thenyou have good material for a study. Students are eager to publishan article on work in which they have participated and thus dis-tinguish themselves from their colleagues. The International Jour-nal of Pharmaceutical Compounding is an excellent journal in whichto publish studies pertaining to compounding. In this age of crit-icism from the medical and legal communities, compounding phar-macists must prove the worth of their products and services. It isimportant to validate our work as compounders. Conducting andpublishing studies lend validity to our mission and our professionalobjectives.

Students are excellent at performing pharmacy-based studies.They are taught research methods and techniques in school andcan aid community practitioners with their knowledge. The worldof drug information is constantly changing, and pharmacy stu-dents have kept abreast of recent information, up-to-date tech-niques, and various methods of data collection. They can help com-munity pharmacists to be up-to-date as well.

We provide such unique services and create a wide variety ofproducts for patients! It is a shame not to network with our col-leagues to share information of interest. This sharing helps ourprofession and benefits patients as well. Reach out to pharmacystudents. You may be able to secure help in conducting a studythat provides valid information for a professional audience as youintroduce a student to the wonderful opportunities available incompounding pharmacy.

How To Find Your Intern or ResidentHere are suggestions for finding and working with a student in

your pharmacy:■ Contact a local college or school of pharmacy about your in-

terest in having a student perform a study in your pharmacy.■ Send a list of possible topics to be studied.■ Collaborate with a professor (perhaps from the disciplines of

pharmacy practice, ambulatory practice, or pharmaceutics) inthe college of pharmacy.

Hire a student to work in your pharmacy as an intern full-time, part-time, or during the summer. ■ Contact a local college or school of pharmacy about methods

of advertising opportunities for interns in your pharmacy.■ Students can be a great asset to your business. They take great

pride in their work and are constantly seeking knowledge. Theycan also perform more tasks than a technician can; this willmake your job much easier.

■ After a student has worked in the pharmacy, he or she can iden-tify ideas for projects and studies to conduct.

■ Pharmacy students are pharmacists in training, and the expe-rience of working on scholarly research and publishing a re-lated article can benefit you and your intern.


How To Perform a Study in YourPharmacy withLittle or No Effort


Dana Reed-Kane, PharmD, FIACP, FACAReed’s Compounding PharmacyTucson, Arizona

http://www.chemipharm.com

Become a preceptor for students at a local college or schoolof pharmacy.■ Contact colleges of pharmacy about your interest in be-

coming a preceptor. Each school usually has a clerkship co-ordinator. Some programs pay preceptors for their time andexpertise.

■ If a college of pharmacy is not nearby, you can become a pre-ceptor at a school of pharmacy. Some may require that you of-fer housing for the student, but this is not always a prerequisite.

■ Most schools of pharmacy require students to complete 4- to6-week internships or rotations through various practice sites.

■ Pharmacy students are not paid during their rotations withpreceptors, so this may offset the costs of training, housing,etc. Students often have more to offer you than you have tooffer them.

■ Contact your student before he or she accepts the assignmentin your pharmacy to discuss conducting a study.

Develop a residency program in your pharmacy.■ Residents are pharmacists who have just graduated from phar-

macy school. Students often undertake a residency to gain moreknowledge in certain specialty areas of pharmacy practice be-fore they enter the work force.

■ Residents’ salaries usually amount to about half that of a staffpharmacist’s wages. In return for the reduced pay, residents

expect a valuable learning experience.■ A resident is usually expected to work on special projects, per-

form studies, develop programs, and serve as a member of thepharmacy staff. If you are interested in developing a diseasemanagement program on diabetes, osteoporosis, asthma, an-ticoagulation, heart disease, women’s health, or men’s healthor in creating a new service such as compounding, a residentcould help develop, manage, market, study, and facilitate yourprogram of interest.

■ For the pharmacist, residents are even more valuable than in-terns. Hiring a resident is a great way in which to train a newpharmacist to work for you.

■ Many organizations sponsor and accredit residency programs.For more information on how to establish a residency programin your pharmacy, contact the American Society of Health-System Pharmacists (ASHP), the American Pharmaceutical Association (APhA), the National Community Pharmacists Association (NCPA), or the International Academy of Com-pounding Pharmacists (IACP).

■ Assistance in developing a residency program can be obtainedfrom a college of pharmacy.

Address correspondence to: Dana Reed-Kane, PharmD, FIACP,FACA, Reed’s Compounding Pharmacy, 2729 E. Speedway, Tucson, AZ 85716. ■



http://www.medisca.com

Electronic Mixing Machines: The BenefitsCompounding pharmacists are always looking for ways to im-

prove compounding procedures, provide pharmaceutically elegantpreparations, and reduce nonproductive time. In Germany, whereacquiring an ointment mill is a prerequisite to obtaining a phar-macy license, the Electro Mortar and Pestle (EMP) is consideredan approved alternative. In 1994, the German-made Unguator Mix-ing System, a mechanical mixing unit, was designed to facilitatethe preparation and compounding of ointments, creams, and a widerange of other pharmaceutical formulations. Various products ofhigh or low viscosity (emulsions, suspensions, lotions, gels, creams,pastes, ointments) can be prepared hygienically and easily withthe Unguator. Ingredients can be weighed and added to one ofseveral Unguator jars before being mixed; wetting agents and pre-mixing are unnecessary. Homogeneous formulations are pre-pared quickly and precisely in each jar, and the closed, air-tightsystem prevents microbiologic contamination. The product qual-

ity is excellent, andthe clean-up is min-imal. The finished com-

pound remains in its Unguator jar, which is then used for bothdispensing and storage. This ensures maximum shelf life for theproduct. Each jar is equipped with a sliding, push-up bottom thatfacilitates the expulsion of air before and after the ingredients aremixed. Each jar lid accepts a special tip designed to accommo-date the flow of preparations of various viscosities. The jar tipsprovide the benefits of ointment tubes without the hassles of fill-ing and sealing. Instead of unscrewing the container and remov-ing product with a contaminated finger or implement, the patientcan withdraw a small amount of the formulation from the jar tip.

EMP Models and AccessoriesTwo models of the EMP are available. The Cito-Unguator-e is

fully automatic. It mixes quantities between 15 and 500 mL. Mix-ing time and speed are set before the jar is attached. During theuse of Cito-Unguator-e, the mixing blade and arm move the jarup and down automatically; this ensures that the ingredients in-side the jar are homogeneous after being mixed. After the phar-macist has compounded a particular formulation a few times, rou-tine settings can be documented for that preparation, which canthen be mixed in the same manner whenever it is prepared andregardless of the operator.

Although it has electronic features of operation, the Cito-Un-guator-B requires some manual operation (the ingredients in thejar must be mixed manually with an up-and-down motion). TheCito-Unguator-B is designed to mix quantities up to 200 mL.

Two types of mixing blades are included with either model. Eachstandard mixing blade consists of a titanium hardened metal shaftwith a uniquely shaped polyoximethylene blade. Several sizes ofblades matched to the corresponding Unguator jar are available.This optimizes mixing results. The blades work nicely for blend-ing powders. Disposable mixing blades are also available. Afterthe ingredients have been mixed, the blade remains in the jar topreserve the closed system, prevent contamination of the final prepa-ration, and reduce clean-up time.

Several accessories are also available. Unguator jar coupling ortransfer adapters connect jar tips so that the pharmacist can mixingredients in larger volumes and transfer the mixture into smalljars for dispensing. Several applicator tip sizes that direct the med-ication to a precise area can be obtained. Some imaginative phar-macists use those tips to fill oral dosing syringes and for otherunique and innovative purposes.



Gary Schneider, RPhGallipot, Inc, St. Paul, Minnesota

TECHNOLOGY SPOTLIGHT: ELECTRIC MIXING MACHINES

Special Features of Unguator EMPs■ Quick, precise, homogeneous prepa-ration of formulations in a dual-purposejar.■ A closed-air system minimizes micro-biologic contamination.■ Excellent product quality, minimalcleanup.■ Ensured reproducibility of formula-tions.

For more information, contact:Gary Schneider, Martin Erickson III, orClark Zander, Gallipot, Inc, 2020 SilverBell Road, St. Paul, MN 55122, 800-423-6967

The Electro mortar and pestle is alsosupplied by Professional CompoundingCenters of America (PCCA), 800-331-2498; and Spectrum Pharmacy Products,800-791-3210, ext. 301. ■



Abstract We evaluated 30 patient charts to de-

termine the effectiveness of a topically ap-plied combination of indomethacin andpiroxicam in the treatment of os-teopathologic pain of various intensitiesin hospice patients. The study was designedas a retrospective follow-up to determinewhether that combination of drugs re-sulted in pain reduction. The level of painexperienced by each subject was noted atthree intervals after the administration ofthe topical indomethacin and piroxicamcombination in gel form. Patients’ painscores were reduced by a median of 2points on a 10-point scale; those results

did not reach statistical significance.Twenty-one of the 30 subjects treatedwith the combination of topically appliedindomethacin and piroxicam noted an im-provement in their pain score.

IntroductionIn the hospice setting, it is important to

remember that the best therapy may be onefor which the traditional dosing route is in-effective. The compounding pharmacistcan play a crucial role in designing appro-

priate therapy for hospice patients and inimproving the outcome of treatment.

Nonsteroidal anti-inflammatory drugs(NSAIDs) have long been recognized as avaluable analgesic option for patients withmany different types of pain. In fact,NSAIDs are considered first-line drugsof choice in the treatment of osteopatho-logic pain, which is an ailment that afflictsmany hospice patients.1-6 NSAIDs are of-ten used to treat other types of pain (mus-cle ache, arthritis) as well.3,7

INDOMETHACIN AND PIROXICAMEric R. Vetter, RPh, PharmD (Candidate)Ferris State UniversityBig Rapids, Michigan

Lawrence Curtis, RPhPortage PharmacyPortage, Michigan

TREATMENT OF PAIN WITH A

TOPICALLY APPLIEDCOMBINATION OF

http://www.germfree.com

NSAIDs are cost-effective as primary oradjuvant therapy for controlling pain inhospice patients and should therefore beused whenever clinically appropriate.1,8 Se-lecting effective treatment for patients un-able to take oral medication is a challengefor the hospice team. No topically appliedNSAIDs have been approved by the Foodand Drug Administration and are there-fore unavailable in the United States, andonly indomethacin and aspirin are com-mercially available in suppository form.9

A number of NSAIDs such as flurbipro-fen, ibuprofen, indomethacin, ketoprofen,ketorolac, naproxen, and piroxicam are systemically absorbed when applied topically, and most NSAIDs have been effective in treating osteopathologic painin controlled trials.10 Topical use ofNSAIDs may also be associated with a de-crease in side effects, although that claimrequires further investigation.11

Materials and MethodsWe conducted a retrospective follow-

up study of 30 patients with various pri-mary or metastatic malignancies. Al-though pain ratings varied among the pa-tients studied, all required analgesia. Thegoal of our study was to determine the level of analgesia provided by applying a combination of indomethacin and pirox-icam in gel form to the inner wrist. Wehave been using that preparation since

1997 to treat osteopathologic pain in hos-pice patients. Indomethacin and piroxi-cam were selected as the active compo-nents because both of those productsproduce analgesia when applied topical-ly.10,12 In addition, it was felt that thepharmacokinetic profile of each agentimproved the effectiveness of that com-bination of drugs, because indomethacinis usually considered to be the more ef-fective of the two and piroxicam has alonger duration of action.3,13-14 Therefore,the combination of indomethacin andpiroxicam maximizes the effectiveness ofthe medication and its duration of effect.

We usually prepare indomethacin-pirox-icam gel (IPG) in a concentration of in-domethacin 50 milligrams and piroxicam10 milligrams per milliliter in a Pluroniclecithin organogel (PLO) base. We have alsocompounded IPG in concentrations of100/20 mg/mL, 100/10 mg/mL, and 25/5mg/mL for various patients. Our physiciansusually order the 50/10 formulation. Inour study, only one patient used a differ-ent concentration.

The subjects in our study were identifiedby means of a drug utilization program in-stalled in our pharmacy computer. Wesearched all compounded drugs containingindomethacin and piroxicam that were dis-pensed by our pharmacy between January1, 1998, and September 1, 2000, and thesearch results produced our patient popu-lation. We limited the search to one hos-pice group, although our pharmacy providesservices for several. Sixty-five men andwomen (age range, 38 to 94 years) were iden-tified via the computer program. All haddocumented symptoms of osteopatholog-ic pain that ranged in duration from 3 daysto 4 weeks and required treatment.

Patients were included in the study ifthey were undergoing treatment with IPG(50/10 mg/mL, 100/10 mg/mL, 100/20mg/mL, or 25/5 mg/mL) as verified bythe chart review. A visual analog scale(VAS) was used by the primary hospicenurse to evaluate and record the pain lev-el of each patient. Our VAS had a range-of-pain rating from 0 to 10, where 0 rep-resented “no pain” and 10 represented the“worst pain possible.” Subjects selectedfor the study must have had a VAS pain rat-ing of greater than or equal to 1 and a me-dian pain rating of less than or equal to 9at the initiation of treatment with IPG. AVAS rating must have been recorded for pa-tients with new-onset pain within 24 hoursof the initiation of treatment with IPG. Forpatients with chronic pain, a VAS record-ed within 3 days of the initiation of treat-ment with IPG was acceptable. All patientsmust have had a VAS recorded no more than3 days after the initiation of treatmentwith the gel to be included in the study. Theonly patients excluded as participants werethose treated for neuropathic pain.

Hospice medical records were availablefor 60 (92%) of the 65 patients identified.The date on which treatment with IPG wasinitiated was identified via chart review. Wecollected data on each patient’s age, gen-der, race, use of opioids, and whether or not he or she was ambulatory at initiationof therapy. The dose and directions for application, including application site, were noted when that information wasavailable. We recorded and used the fivemost recent VAS results for each patient;if five results were unavailable, we used allavailable ratings. For patients who experi-enced chronic pain, we recorded the fivemost recent VAS ratings obtained before



Table 1. Demographics of PatientsTreated with Indomethacin andPiroxicam Gel for Pain.*

Variable No. PatientsAge (mean) 77 yrsAge range 38 - 94 yrsRace

Caucasian 28Black 1Asian 1

Opioid use at initiation of treatment 26

Ability to walkYes 16No 9Not noted 5

* n = 30.

Table 2. Visual Analog Scale Results of Patients Treated with Indomethacinand Piroxicam Gel for Pain.

Baseline VAS First VAS (median) Patients (median)

Pain relieved after treatment (n = 21) 3 0

Pain maintained after treatment (n = 5) 4 4

No improvement in pain treatment (n = 4) 2.75 7VAS = Visual analog scale.



the initiation of treatment with IPG. Forpatients with new-onset pain, only the fiveVAS ratings recorded after new pain hadbegun were used. Patient demographicdata are listed in Table 1.

Of the 60 patients reviewed, 8 were ex-cluded because no VAS rating had beenrecorded before the first use of IPG, 12 wereexcluded because no rating had been as-signed within the mandatory 3 days afterthe initiation of therapy, 5 patients had nei-ther a “before” nor “after” VAS rating, 2had a VAS rating of 0 at the initiation oftreatment with IPG, 2 more were exclud-ed because their chart contained no recordof IPG use, and 1 patient was excluded be-cause she was being treated for neuro-pathic pain.

ResultsThirty patients were included in the fi-

nal evaluation of the effectiveness of top-ically applied IPG in treating pain. Painscore data were evaluated for each patientby taking a patient’s median pain rating be-fore the administration of IPG and com-paring it with the rating at three points intime: the first available rating (n = 30), therating 1 week after the initiation of thera-py with topical IPG (n = 25), and the rat-ing 2 weeks after the initiation of therapywith topical IPG (n = 17). The medianpain rating before the administration of

IPG was 3 (range, 2 to 6). Twenty-one of a total of 30 patients re-

ported an improvement in pain indicatedby a reduction in the VAS rating within 3days after treatment with IPG. Five patientsnoted no change in their pain after treat-ment with IPG, and the remaining four pa-tients noted greater pain after treatment(Table 2). Figure 1 features a graph of thepain ratings of the 30 subjects before andafter treatment with IPG was initiated.The points on the line in the center of thegraph represent patients who experiencedno change in their level of pain. Any pointbelow the line represents an improvementin pain relief, and any point above the linerepresents no improvement. Thirteen of the21 patients who experienced pain reliefreported having no pain at all (VAS = 0) ontheir first evaluation after treatment withIPG was initiated. Figure 2 shows the trendtoward an improvement in the level of painafter treatment with IPG.

A Wilcoxon signed rank confidence in-terval and test for the median were con-ducted to evaluate the data. At the first eval-uation point, there was a median decreaseof 2 points on the VAS (95% CI, 0.5 - 2).That decrease approached but did notreach statistical significance (P = 0.089). One week after the initiation of treatment,the median decrease was 2 points (95% CI,0 - 2). That decrease was not statistically

significant (P = 0.125). The median decreaseat the 2-week interval was again an absolutevalue of 2 points (95% CI, 0.5 - 3), but again,that was not statistically significant (P =0.638).

Patients were also evaluated to deter-mine whether pain relief varied accordingto gender. Pain scores were evaluated whenthe first VAS rating was obtained (P =0.676), 1 week after the initiation of ther-apy (P = 0.157), and 2 weeks after the ini-tiation of therapy (P = 0.564), but no dif-ferences in the level of pain according togender were found. A chi-square test of in-dependence was conducted to determinewhether opioid use or ambulatory status anda change in the VAS were related, but thoserelationships were not significant.

Because many charts did not contain anobjective VAS rating, the patients’ subjec-tive statements of effect, regardless of theirVAS scores, were also evaluated. Fifty-sev-en charts were reviewed; patients withoutverification of IPG use and the patientwith neuropathic pain were excluded. Nosubjective statements about the degree ofpain relief resulting from treatment withIPG were noted in 31 (54%) of the 57charts evaluated. Twenty-three of the re-maining 26 charts contained positive state-ments about treatment-related pain relief,and only 3 listed IPG as ineffective.

Figure 1. Visual Analog Scale Pain Ratings of Patients Treated with Indomethacin-Piroxicam Gel (IPG).

Patient Pain Ratings

Rating before treatment with IPGNo improvement (n = 4)

Improvement (n = 21)

10

9

8

7

6

5

4

3

2

1

00 1 2 3 4 5 6 7 8 9 10

Ratin

g af

ter t

reat

men

t with

IPG

Figure 2. Effect of Treatment with Indomethacin-Piroxicam Gel (IPG).

Patient Pain Ratings

Rating before treatment with IPGNo improvement (n = 4)

Improvement (n = 21)

10

9

8

7

6

5

4

3

2

1

00 1 2 3 4 5 6 7 8 9 10

Ratin

g af

ter t

reat

men

t with

IPG

y = 0.6312x



DiscussionAnalyses of these results suggest that IPG is a valid primary or

adjuvant agent in the treatment of pain, especially osteopathologicor arthritic pain. We would have preferred that a decrease occurredin the amount of opioid analgesics used by our patients. Unfor-tunately, many patients receive opioids as needed for pain con-trol, and we were unable to determine from our chart review whetherthe use of opioids changed in our subjects after treatment withIPG was initiated. Most patients with cancer-related pain requirea combination of opioid and nonopioid medications.

Although the trend and overall effectiveness of IPG was good,the benefit of treatment did not reach statistical significance. Webelieve this is due primarily to the small sample size of our study.Seventy percent of our patients treated with IPG noted a reduc-tion in their pain. In most patients, pain relief was noted withinthe first 24 hours of the initiation of treatment with IPG, althoughmore time was required in some cases. The benefit of that topi-cally applied NSAID was maintained during the 2-week reviewperiod. Patients who report that the effect of the medication di-minishes over time can be treated with IPG every 6 or 8 hours,but most of our patients indicated that a 12-hour dosing sched-ule was sufficient to maintain a reduced level of pain.

ConclusionHospice patients often require many different forms of thera-

py to control pain. Controlling that pain while the patient is un-dergoing significant changes in his or her disease state is often achallenge for the hospice team. This is especially true when oralmedications can no longer be administered. NSAIDs, which areeffective and do not cause central nervous system or respiratorydepression, remain a favorite treatment for pain in those patients.The role of the compounding pharmacist in preparing topicalNSAIDs should not be ignored. We believe that this retrospec-tive analysis paves the way for a well-designed, randomized, con-trolled trial that will prove the benefit of topical NSAID combi-nations in the treatment of chronic pain.

AcknowledgmentsWe thank our statistician, Diana Cucos, for reviewing the re-

sults of this study, and the staff of the Hospice of Holland in Hol-land, Michigan, for allowing us to evaluate the effectiveness of IPGin their patients.

References

1. Thurlimann B, de Stoutz ND. Causes and treatment of bone pain of ma-lignant origin. Drugs 1996;51:383-398.

2. Payne R. Mechanisms and management of bone pain. Cancer 1997;80(suppl):1608-1613.

3. Bushnell TG, Justins DM. Choosing the right analgesic. A guide to selec-tion. Drugs 1993;46:394-408.

4. Gordon RL. Prolonged central intravenous ketorolac continuous infusionin a cancer patient with intractable bone pain. Ann Pharmacother1998;32:193-196.

5. Levick S, Jacobs C, Loukas DF, et al. Naproxen sodium in treatment of bonepain due to metastatic cancer. Pain 1988;35:253-258.

6. Lomen PL, Samal BA, Lamborn KR, et al. Flurbiprofen for the treatment ofbone pain in patients with metastatic breast cancer. Am J Med 1986;80:83-87.

7. Gotzsche P. Non-steroidal anti-inflammatory drugs. BMJ 2000;320:1058-1061.

8. Bailes J. Cost aspects of palliative cancer care. Semin Oncol 1995;22(suppl 3):64-66.

9. [No author listed.] Drug Facts and Comparisons. St. Louis, MO:Facts andComparisons; 2000.

10. Moore RA, Tramer MR, Carroll D, et al. Quantitative systematic review oftopically applied non-steroidal anti-inflammatory drugs. BMJ 1998;316:333-338.

11. Vaile JH, Davis P. Topical NSAIDs for musculoskeletal conditions. A re-view of the literature. Drugs 1998;56:783-799.

12. El-Faham TH, Safwat SM. Comparative study of the release and anti-in-flammatory activity of indomethacin from topical formulations. Pharm Ind1992;54:82-86.

13. Indocin [package insert].West Point, PA: Merck; 1998.14. Feldene [package insert]. Memphis, TN: Pfizer; 1999.

Address correspondence to: Lawrence Curtis, RPh, Portage Phar-macy, 1256 East Centre Street, Portage, MI 49002. E-mail:[email protected]. ■

http://www.kalcheminternational.com

Ergotamine is an alkaloid derived from ergot, the sclerotium ofthe fungus Claviceps purpurea, which develops in the ovary of rye(Secale cereale). Ergot has powerful vasoconstricting and oxytocicactions.1 Ergotamine is slowly and incompletely absorbed fromthe gastrointestinal tract.2

Ergotamine Tartrate Tablets(Ergostat, Ergomar, Gynergen, others)2

This medication has been available since 1951, as manufacturedby Lilly.3 At one time, ergotamine tartrate tablets were manufacturedby Parke-Davis. While on the market, ergotamine tartrate was avail-able in 1-mg (oral) and 2-mg (sublingual) tablets. When discon-tinued from the market in 1996, it was available in a 2-mg sub-lingual tablet.4Indications. Treatment for migraines or cluster headaches. A doseof 2 mg is to be taken or given at the onset of headache, and 2 mgcan be taken every 30 minutes thereafter as needed up to a max-imum dose of 6 mg during one headache or migraine episode.2 Apatient should not ingest more than 10 mg per week.2 Overdosageis the primary cause of adverse effects produced by ergotamine;the smallest amount needed to relieve headache should be ad-ministered. The extent and rapidity of pain relief are directly pro-

portional to the promptness with which ergotamine tartratetablets are administered after the onset of headache. When treat-ment is administered early in the course of a headache, the required dosage needed may be decreased considerably. If the headache has reached its peak, more medication is requiredto relieve symptoms, and the incidence of drug-related side effects increases.

References1. Parfitt K, ed. MARTINDALE: The Complete Drug Reference. 32nd ed. London:The

Pharmaceutical Press; 1999:1576.2. Gilman AG, Goodman LS, Gilman A. Goodman and Gilman’s: The Pharmaco-

logical Basis of Therapeutics. 6th ed. New York:Macmillan; 1980:946.3. Kastrup EK. Facts and Comparisons. St. Louis, MO:Facts and Comparisons; 1951.4. Drake E, Drake R. Saunders Pharmaceutical Word Book 2001.

Philadelphia:PA:WB Saunders Company; 2001.

Address correspondence to: Lisa D. Ash-worth, RPh, 638 Havencrest Lane,Coppell, TX 75019-5722. ■

MEDICATIONS DISCONTINUED IN THE UNITED STATES



Don’tmiss the related

formulas featured on the IJPC Website at

www.ijpc.com.

Lisa D. Ashworth, RPh, Coppell, Texas

IInnttrroodduuccttiioonnThe transdermal administration of drugs

has an important role in modern drug ther-apy. The transdermal route is now used pri-marily to administer nonionized drugs thatare required in a relatively small dosage. Inthat method of treatment, the laws of pas-sive diffusion transport the nonionizeddrug through the rate-limiting dermal

membrane (the stratum corneum). Ionizeddrugs, however, do not easily penetratethe stratum corneum and are thus unsuit-able in routine transdermal dosage formsunless an external source of energy en-ables the drug to penetrate that barrier. Iniontophoresis (IP), that external source ofenergy takes the form of an applied directelectrical current. Electrical energy assiststhe movement of ions across the stratum

corneum according to the basic electricalprinciple that “like charges repel each oth-er and opposite charges attract.”

In practice, a solution of the drug in a pador a gel is placed on the skin. An active elec-trode is placed on this pad or gel, and thereturn electrode is placed elsewhere onthe body. A small electrical current (usu-ally less than 1 mA) is applied for a peri-od of time (usually 15 to 20 minutes). Thedrug travels through the tissue and can thusexert its local effect or is carried by the microcirculation to produce an eventualsystemic effect.

HHiissttoorryy ooff IIPPIP (cataphoresis, ionic treatment, elec-

trolytic treatment, ion transfer, electro-phoresis) was invented early in this centurywhen, in 1908, Le Duc demonstrated thations could be driven across the skin bymeans of an electric current.1,2 From thattime until 1924, many studies of ophthal-mologic IP were conducted, but the resultswere not always successful. Adverse se-quelae included corneal scarring, burnedtissue, and (occasionally) the induction ofelectrical shock. In 1911, Albrecht3 stud-ied the successful use of IP in which acombination of cocaine and epinephrine wasused to anesthetize the tympanic mem-brane. However, only limited anesthesia tothe external auditory meatus was achievedwith that technique. Those and other ma-jor technical problems were associated withthe early use of IP, which was virtually dis-



Continuing EducationGoal: To provide pharmacists, pharma-

cy students, and pharmacy technicianswith supportive information on the basics of compounding solutions foriontophoretic administration

Objectives: After reading and studying thearticle, the reader will be able to:

1. Discuss the history of iontophoresis2. Discuss the applications of ion-

tophoresis2. Discuss the general process of ion-

tophoresis3. Describe the variables that affect

iontophoresis4. List at least five drugs that are

administered iontophoretically

BASICS OF COMPOUNDING

IONTOPHORESISLoyd V. Allen, Jr, PhD, RPh

Table 1. Drugs and Chemicals First Investigated for Use in Iontophoresis.

Year Drug Name 1937 Histamine Cl 1941 Ragweed pollen extract1942 Sulfa drugs, grasses1950 Sodium iodide1954 Citrate1955 Phosphorus, hyaluronidase1964 Lidocaine HCl1965 Iodine, penicillin 1967 Hydrocortisone phosphate, pilocarpine, zinc, esterified glucocorticoids 1969 Sodium salicylate1973 Lidocaine HCl, phenylbutazone1974 Methylene blue, potassium iodide1975 Calcium, insulin1977 Vidarabine monophosphate, idoxuridine, acetic acid, triamcinolone1978 Procaine HCl, cocaine HCl, bupivacaine HCl, mepivacaine HCl, prilocaine

HCl, epinephrine bitartrate, levarterenol bitartrate, phenylephrine HCl,methylprednisolone sodium succinate, hydrocortisone sodium succinate,methotrexate, cyclophosphamide, bleomycin, doxorubicin, adenosine salts(var), uridine salts (var), thymidine salts, thymine arabinoside

1980 Dexamethasone sodium phosphate1981 Zinc oxide1982 Copper, vasopressin, alkaloids, papaverine, nicotinic acid, lidocaine HCl

with epinephrine HCl1983 Sodium fluoride, 6-hydroxydopamine1984 Gentamicin sulfate, N-acetylcysteine, sodium cefoxitin, benzydamine,

fluorescein1986 Metoprolol, fluorescein, cefazolin sodium, ticarcillin, cortisone, sodium

benzoate, thyrotropin-releasing hormone, sulfadiazine, sulfapyridine, sulfathiazole, sulfacetamide

1987 Diphenhydramine HCl, catecholamines, oxycodone

PART1

carded until the early 1940s. At that time,it was again used in the experimental (andsuccessful) transfer of penicillin and sulfa-diazine into the infected eyes of animals.1,2

Over the years, studies have chronicledthe iontophoretic administration of vari-ous medications in the treatment of wide-ly varying disorders: glycopyrronium bro-mide for hyperhidrosis, sodium salicylate

for palmar and plantar warts, steroids forPeyronie’s disease, acetic acid for calciumdeposits in muscle and joint disorders, andα-chymotrypsin for inflammatory reac-tions involving joints and soft tissues.Some studies1 have included the ion-tophoretic administration of local anes-thetics combined with steroids to treatmuscle and tendon injuries.

IP of penicillin into burn eschars hasbeen used to decrease the risk of severe in-fection in patients who have sustainedburns, and histamine has been administerediontophoretically to induce local capillarydilatation, which enables the accurate de-termination of blood gases. It has also beenused to promoted the healing of chronicsclerotic ulcers. IP of local anesthetic



Table 2. Drugs Used for Iontophoresis.

Percent Drug Solution Concentration Use or Indication PolarityAcetic acid 2 - 5 Calcium deposits, calcified tendonitis NegativeAtropine sulfate 0.001 - 0.01 Hyperhidrosis PositiveCalcium chloride 2 Myopathy, myospasm, immobile joints PositiveSodium chloride 2 Sclerosant, scar tissue, adhesions, keloids NegativePotassium citrate 2 Rheumatoid arthritis NegativeCopper sulfate 2 Astringent, fungus infection PositiveDexamethasone sodium phosphate 0.4 Tendonitis, bursitis, arthritis, Negative

tenosynovitis, Peyronie’s diseaseEstriol Varies Acne scars PositiveFentanyl citrate Varies Analgesia PositiveFluoride sodium 2 Desensitization of teeth PositiveGentamicin sulfate 0.8 Otochondritis PositiveGlycopyrronium bromide 0.05 Hyperhidrosis PositiveHyaluronidase 150 U/mL Enhancement of absorption, edema, Positive

solution scleroderma, lymphedemaIdoxuridine 0.1 Herpes simplex NegativeIodine ointment 4.7 Sclerosant, antimicrobial, fibrosis, Negative

adhesions, scar tissue, “trigger finger”Iron oxide or titanium oxide Varies Skin pigmentation PositiveLidocaine hydrochloride with or 4 Dermal anesthetic, trigeminal neuralgia Positive

without epinephrine (1:50,000 - 1:100,000)

Lithium chloride 2 Gouty arthritis PositiveMagnesium sulfate 2 Muscle relaxant, vasodilator, myalgias, Positive

neuritis, deltoid bursitis, low-back spasmMetholoyl chloride 0.25 Vasodilator, muscle relaxant, radiculitis, Positive

varicose ulcers Meladinine sodium 1 Vitiligo NegativeMethylphenidate hydrochloride Varies Attention deficit disorder PositiveMorphine sulfate 0.2 - 0.4 Analgesia PositivePilocarpine hydrochloride Varies Sweat test for cystic fibrosis PositivePoldine methyl sulfate 0.05 - 0.5 Hyperhidrosis NegativePotassium iodide 10 Scar tissue NegativeSodium salicylate 2 Analgesic, sclerosant, plantar warts, Negative

scar tissue, myalgiasTretinoin Varies Acne scars PositiveWater 100 Palmar, plantar, or axillary hyperhidrosis Positive and negative Zinc oxide suspension 20 Antisepsis, ulcers, dermatitis, wound healing Positive

agents has been used during tooth extrac-tion and the treatment of infected tooth rootcanals, as well as to deposit fluoride intothe dentin of teeth.

For some years, many practitioners haveconsidered using IP to administer insulinto patients with diabetes. That method oftreatment has several advantages. IP isused to administer continuous subcuta-neous insulin infusions, and when suit-able patient-adjusted current control ispermitted it is theoretically feasible to administer insulin in both baseline andbolus dosages. No transcutaneous pene-tration by needle is necessary, and there-fore localized infections, inflammation,and localized fibrosis are prevented, as iscrystallization, because insulin does not traverse narrow tubing.

Harris4 concluded that IP is a clinically

effective, painless, and safe mode of deliv-ering ionized anti-inflammatory drugs toinflamed tissues. Also, DeLacerda5 hasdemonstrated that IP is more effective thantreatment with muscle relaxants, analgesics,or hydrocollator-ultrasonographic modal-ities in the administration of anti-inflam-matory drugs to treat shoulder-girdle my-ofascial syndrome. Many drugs such aslidocaine, dexamethasone, and sodium flu-oride, which have been investigated fortheir potential use in IP, are used for thetreatment of that syndrome today (Table 1).

MMeecchhaanniissmm ooff AAccttiioonn ooff IIPP

During IP, a potential gradient throughthe skin tissue is created with an appliedelectrical current or voltage. That energy

induces an increased migration of ionicdrugs into the skin by electrostatic repul-sion at the active electrode: Negative ionsare delivered by the cathode and positiveions by the anode. A typical iontophoret-ic device consists of a battery, a micro-processor controller, a drug reservoir, andelectrodes.

AAddvvaannttaaggeess ooff IIPPThe advantages of IP include providing

a controlled rate of drug delivery (by vary-ing the current density, pulsed voltage,drug concentration, and ionic strength);eliminating the effects of erratic drug ab-sorption, first-pass metabolism, and gas-trointestinal incompatibility with somedrugs; reducing side effects and minimiz-ing interpatient variability; obviating therisks of infection, inflammation, and fibrosisassociated with continuous injection or in-fusion; and enhancing patient complianceby providing a convenient, noninvasivetherapeutic regimen. In addition, IP unitsare being manufactured in increasinglysmaller sizes.

DDiissaaddvvaannttaaggeess ooff IIPPUsing IP also has disadvantages. Im-

properly placed electrodes can cause burns.That problem has been minimized, how-ever; newer IP units are powered by a bat-tery pack instead of household current,and the current used is very low. Compli-ance with a current-time recommendationaccording to the method used also preventsiontophoretic burns. The formation of un-desirable vesicles and bullae in treated skincan be avoided by periodically interrupt-ing a unidirectional treatment current witha relatively short pulse of current of the op-posite direction. There is also the minorinconvenience of using an electrical device.

DDrruuggss AAddmmiinniisstteerreedd vviiaa IIPP

IP is also used to administer pilocarpineto patients with cystic fibrosis, to treat ex-cessive perspiration (hyperhidrosis), to in-duce local anesthesia with lidocaine, toreduce inflammation by means of dexa-methasone, and (as mentioned) to apply flu-oride to the teeth (Table 2). Drugs such ascorticosteroids, nonsteroidal anti-inflam-matory agents, and other anesthetics are of-ten delivered via IP. Other medications

TTaabbllee 44.. DDrruuggss UUsseedd iinn VVeetteerriinnaarryy IIoonnttoopphhoorreessiiss..**

Drug Solution Polarity Used

Nonsteroidal anti-inflammatory drugsPhenylbutazone NegativeFlunixin meglumine NegativeKetoprofen Negative

Corticosteroids and other anti-inflammatory agentsDexamethasone sodium phosphate NegativeBetamethasone NegativePrednisolone sodium succinate Negative

AntibioticsGentamicin sulfate PositiveAmikacin sulfate PositiveCeftiofur sodium Negative

Local anestheticLidocaine HCI Positive

*Adapted from: Product information 801419. Revision B. St. Paul, MN:Empi, Inc; 1996.



TTaabbllee 33.. EEqquuiippmmeenntt UUsseedd ffoorr IIoonnttoopphhoorreessiiss..

Manufacturer (Location) Brand NameEmpi, Inc (St. Paul, MN) Dupela

Henley Healthcare (Sugarland, TX) Dynaphorb

Iomed (Salt Lake City, UT) Phoresor IIb

LifeTech, Inc (Houston, TX) Iontophorb

General Medical Co (Los Angeles, CA) Lectro Patchb

Wescor Inc (Logan, UT) Sweat-Chekb

Scandipharm (Birmingham, AL) CF Indicatorb

a Dual-channel system. b Single-channel system.

undergoing evaluation for that purpose in-clude analgesics, nicotine, drugs used to treatAIDS-related symptoms, insulin, antineo-plastic drugs, and proteins. IP is also use-ful in veterinary medicine.1

IIoonnttoopphhoorreettiicc DDeevviicceessDuring IP, (as described previously), an

electric current is transferred from theelectrodes through the ionized drug solu-tion as ionic flow. The drug ions are movedto the skin, where ionic repulsion contin-ues and the drug is moved throughwhichever pathways are available (poresor possibly disrupted stratum corneum). Thedrug-containing electrode (the “active elec-trode”) is placed over the affected site, andthe other electrode (the “passive elec-trode”) is placed elsewhere on the body. Cur-rent densities up to 0.5 mA/cm2 producelittle or no discomfort for the patient. Thelarger the electrode surface, the greater thecurrent needed to transport the drug.

Early devices used for IP were largeand cumbersome. Today, however, thesize of such devices ranges between thatof a small flashlight to a Walkman-ra-dio–size device. In some newer devices,the need for additional wiring has beeneliminated because the electrodes havebeen incorporated into the unit. In the nearfuture, devices used for IP will be smalland flat and will be equipped with self-contained batteries incorporated into adosage unit the size of a transdermalpatch. Miniaturization of such devicesthat use smaller, more powerful batteriesand electronics is now possible. The nextgeneration of patches used for IP may alsoprovide an electronic record of the date,time, and quantity of each dose deliv-ered, as well as information about pa-tient compliance. Currently, however, IPinvolves the use of a device (Table 3) at-tached to electrodes that contain a solu-tion of the drug to be administered.

VVeetteerriinnaarryy UUssee ooff IIPPDrugs such as those listed in Table 4 are

used for IP in veterinary patients. Variouselectrodes, drug concentrations, anddosages are required according to the sizeand anatomic requirements of the animalpatient.

RReeffeerreenncceess1. Banga AK. Electrically Assisted Transdermal

and Topical Drug Delivery. Bristol PA:Taylor &Francis Group; 1998.

2. Tyle P. In: Proceedings of the Bio-Expo ‘86.The American Commercial and Industrial Con-ference and Exposition in Biotechnology.Stoneham, MS:Butterworth; 1986:583-594.

3. Albrecht N. Arch Orhenkeil Kd 1911;85:198-212.

4. Harris PR. Iontophoresis: Clinical research inmusculoskeletal inflammatory conditions. JOrthopaed Sports Phys Ther 1980;4:109-112.

5. DeLacerda FG. Shoulder girdle myofascial syn-drome. A biomechanical analysis.Occup HealthSaf 1982;51:45-46. ■



http://www.appdc.com

http://www.medi-dose.com

METHOD OF PREPARATION1. Calculate the required quantity of each ingredient for the

total amount to be prepared.2. Accurately weigh and/or measure each ingredient.3. Melt the cocoa butter and white petrolatum together at a tem-

perature of about 40°C.4. Incorporate the light olive oil, mix well, and cool.5. Pour into a plastic squeeze bottle that has a dispenser tip.6. Package and label.

PACKAGINGPackage in a tight, light-resistant container.

LABELINGFor external use only. Keep out of the reach of children.

STABILITYA beyond-use date of 6 months can be used for this prepara-

tion.1

USEThis thick lotion has been used to treat very dry skin. It has

excellent emollient properties and is often applied at bedtime.

QUALITY CONTROLActual yield compared with theoretical yield, physical observa-

tion.

DISCUSSIONDry skin (especially during the winter in a cold climate) is very

common. The low relative humidity indoors during the winter incold climates causes the loss of moisture from the skin, which be-comes dry, cracked, painful, and sometimes infected. A goodemollient preparation applied at least once daily and allowed toremain in place facilitates dermal hydration by minimizing theevaporation of water from the skin surface. A thicker or thinnerpreparation can be easily prepared from this formulation.

Olive oil is obtained by carefully crushing and pressing recentlycollected ripe olives in a mill and a press. When that process doesnot break the putamen, the highest grade oil (virgin oil, sublimeoil, first-expressed oil) is obtained. Olive oil is a pale yellow orlight greenish-yellow oily liquid that has a slight characteristicodor and taste. It is slightly soluble in alcohol and has a specificgravity between 0.910 and 0.915. Olive oil is used in making oint-ments, liniments, emulsions, and various other dosage forms. Itis also used as an emollient laxative.1,2

Cocoa butter (Theobroma oil) is a yellowish or white brittle solidthat has a slight odor of cocoa. It is derived from natural sourcesand is composed primarily of the triglycerides of saturated andunsaturated fatty acids. It melts between 31°C and 34°C, is freelysoluble in chloroform and in ether, and is slightly soluble in 95%ethanol. Heating to a temperature greater than 36°C lowers thesolidification point of cocoa butter because of its polymorphic na-ture and the formation of a metastable form. Cocoa butter shouldbe stored at temperatures less than 25°C. It is used as a suppos-itory base and is also a major ingredient in chocolate.2

White petrolatum (white petroleum jelly, white soft paraffin) is awhite, translucent, soft unctuous mass that is inert, odorless, andtasteless. It is a mixture of semisolid saturated hydrocarbons ob-tained from petroleum. It is used primarily in the following top-ical formulations in the concentrations listed: emollient creams(10% to 30%), topical emulsions (4% to 25%), and topical oint-ments (up to 100%). White petrolatum has a specific gravity ofabout 0.815 to 0.880 and melts in a temperature range between38°C and 60°C. It is practically insoluble in ethanol, in glycerin,and in water but is soluble in chloroform and in most fixed andvolatile oils. It is stable, but when exposed to light it may discol-or as a result of the oxidation of impurities. That oxidation canbe minimized by the addition of a suitable antioxidant such as buty-lated hydroxyanisole, butylated hydroxytoluene, or α-tocopherol.Heating white petrolatum to a temperature above its melting range(about 70°C) for extended times should be avoided, but it can besterilized by dry heat.3

REFERENCES1. United States Pharmacopeia XXIV/National Formulary 19. Rockville MD:US

Pharmacopeial Convention, Inc; 1999:2487, 2698-2702.2. Reilly WJ Jr. Pharmaceutical necessities. In: Gennaro AR, ed. Reming-

ton: The Science and Practice of Pharmacy. 19th ed. Easton PA:Mack Pub-lishing Company; 1995:1400, 1409.

3. Weller PJ. Petrolatum: In: Kibbe AH, ed. Handbook of Pharmaceutical Ex-cipients. 3rd ed. Washington DC:American Pharmaceutical Association;1994:331-333.

F O R M U L A T I O N S

RxFor 100 g Olive oil, light 20 gCocoa butter 40 gWhite petrolatum 40 g

Anhydrous Emollient Dry Skin Lotion


Antiseptic Protective Ointment


METHOD OF PREPARATION1. Calculate the required quantity of each ingredient for the to-

tal amount to be prepared.2. Accurately weigh and/or measure each ingredient.3. Mix the menthol and phenol together until the mixture has

liquified. Add the resorcinol and then the salicylic acid.4. Mix the Peruvian balsam with the castor oil; then add the ju-

niper tar and benzocaine and mix.5. Melt the white petrolatum at 60°C and sift into it the previ-

ously mixed bismuth subnitrate and zinc oxide.6. Add the mixture from step #4 and mix well.7. Allow the mixture to begin cooling. Then blend in the mate-

rials from step #3 and mix thoroughly.8. Package and label.


LABELINGFor external use only. Keep out of the reach of children. Use

only as directed.

STABILITYA beyond-use date of 6 months can be used for this preparation.1

USEThis ointment has been used to treat minor skin abrasions, in-

sect bites, and other skin irritations.

QUALITY CONTROLTheoretical yield compared with actual yield, physical obser-

vation.

DISCUSSIONMenthol (C10H20O, MW 156.27) occurs as colorless, hexagonal,(usually) needlelike crystals that are found in fused masses or asa crystalline powder. Menthol is slightly soluble in water but isvery soluble in alcohol. It is freely soluble in glacial acetic acid,in mineral oil, and in fixed and volatile oils.1

Phenol (C6H5OH, carbolic acid, MW 94.11) occurs as colorlessto light pink, interlaced or separate, needle-shaped crystals or as

a white or light pink crystalline mass. It is soluble 1 g in 15 mLof water and is very soluble in each of the following: alcohol, glyc-erin, chloroform, ether, or fixed and volatile oils. Phenol is usedas a caustic, a disinfectant, and a topical anesthetic.2

Salicylic acid (C7H6O3, MW 138.12) occurs as white crystals that usu-ally resemble fine needles or as a fluffy, white, crystalline powder.1

Resorcinol (C6H6O2, resorcin, MW 110.11) occurs as white or al-most white needle-shaped crystals or powder with a faint, char-acteristic odor and a sweetish taste that becomes bitter. It acquiresa pink tint when exposed to light and air. It is freely soluble ineach of the following: water, alcohol, glycerin, and ether.1

Peruvian balsam (balsam of Peru) is a balsam that exudes from thetrunk of Myroxylon balsamum var. pereirae (Leguminosae). It has beenused in the treatment of eczema, pruritus, hemorrhoids, and scabies.3

Castor oil is a fixed oil obtained from the seed of Ricinus communisL. (Euphorbiaceae). It occurs as a pale yellow or almost colorless,transparent, viscid liquid that has a faint, mild odor and a blandtaste.4

Juniper tar (cade oil, juniper tar oil) occurs as a dark brown, clear,thick liquid that has a tarry odor and a faintly aromatic bitter taste.Juniper tars and tar oils are used to treat eczema, psoriasis, dan-druff, and other skin disorders.1,3

Benzocaine (C9H11NO2, ethyl aminobenzoate, MW 165.19) oc-curs as small white crystals or as a white, crystalline, odorless pow-der. It is stable in air and produces local anesthesia when placedon the tongue. It is very slightly soluble in water and is freely sol-uble in alcohol and in ether. It is a topical anesthetic of the estertype that produces low systemic toxicity.1

Bismuth subnitrate [Bi5O(OH)9(NO3)4, bismuth hydroxide nitrateoxide, MW 1461.99] occurs as a white slightly hygroscopic pow-der. It is practically insoluble in water and in alcohol and is read-ily dissolved by hydrochloric acid or by nitric acid.1

Zinc oxide (ZnO, MW 81.39) occurs as a very fine, odorless,amorphous, white or yellowish white powder that is free from grit-ty particles. Zinc oxide is a mild astringent and is applied topi-cally as a soothing and protective treatment for eczema and mildskin disorders.1,3

White petrolatum (white petroleum jelly, white soft paraffin) is awhite, translucent, soft unctuous mass that is inert, odorless, andtasteless.5

References1. United States Pharmacopeia XXIV/National Formulary 19. Rockville,

MD:US Pharmacopeial Convention, Inc; 1999:2278, 2290, 2367, 2382, 2395,2403, 2698-2702.

2. Reilly WJ Jr. Pharmaceutical necessities. In: Gennaro AR, ed. Reming-ton: The Science and Practice of Pharmacy. 20th ed. Lippincott Williams& Wilkins, Baltimore MD; 2000:1045-1046.

3. Reynolds JEF, ed. MARTINDALE: The Extra Pharmacopoeia. 30th ed. Lon-don:The Pharmaceutical Press; 1993:769-772, 1401.

4. Tolman KG. Gastrointestinal and liver drugs. In: Gennaro AR, ed. Remington:The Science and Practice of Pharmacy. 19th ed. Easton, PA:Mack Pub-lishing Company; 1995:897.

5. Weller PJ. Petrolatum: In: Kibbe AH, ed. Handbook of Pharmaceutical Ex-cipients. 3rd ed. Washington, DC:American Pharmaceutical Association;1994:331-333.

RxFor 100 gMenthol 1 gPhenol 1 gSalicylic acid 3 gResorcinol 2 gPeruvian balsam 2 gCastor oil 2 gJuniper tar (cade oil) 1 mLBenzocaine 5 gBismuth subnitrate 10 gZinc oxide 20 gWhite petrolatum 53 g



total amount to be prepared.2. Accurately weigh and/or measure each ingredient.3. Mix the camphor, menthol, and eucalyptol to form a eutectic

liquid.4. Use a beaker to heat the white wax until it has melted; then

remove the melted wax from the heat and add the white petro-latum and cocoa butter and mix well.

5. When the ointment is almost cool, incorporate the eutecticliquids and mix well.

6. Package and label.


LABELINGFor external use only. Keep out of the reach of children.


tion.1

USEThis ointment has been used to treat sore muscles and joints

and to relieve the mild symptoms of arthritis.


vation.

DISCUSSIONCamphor (C10H16O, MW 152.23) occurs as colorless or white crys-tals, granules, or crystalline masses or as colorless to white,translucent, tough masses. It has a penetrating, characteristic odorand a pungent, aromatic taste. Camphor has a specific gravity ofabout 0.99 and will slowly volatilize at room temperature. It isslightly soluble in water, very soluble in alcohol, and soluble infixed oils and volatile oils. Camphor is obtained from Cinnamo-mum camphora (Lauraceae) and is purified by sublimation, or it maybe prepared synthetically. Topically applied camphor is used as arubefacient and mild analgesic.1,2

Menthol (C10H20O, MW 156.27) occurs as a crystalline powderor as colorless hexagonal crystals that are usually needlelike or infused masses. It has a pleasant, peppermint-like odor. Menthol is

slightly soluble in water, very soluble in alcohol, and freely sol-uble in glacial acetic acid, in mineral oil, and in fixed and volatileoils. A soft mass forms when it is triturated with each of the fol-lowing: camphor, chloral hydrate, and phenol, as well as with manyother substances.1

Eucalyptol (C10H18O, cajuputol, cineol, MW 154.25) occurs as acolorless liquid with an aromatic, camphoraceous odor. It is ob-tained from eucalyptus oil, cajuput oil, and other oils. It is solu-ble 1 in 2 of 70% alcohol. It should be stored in a cool place inan airtight container and protected from light.2

White wax (white beeswax, cera alba, bleached wax) occurs in thinlayers as a yellowish-white solid that is somewhat translucent. Ithas a faint, characteristic odor and is free from rancidity. Whitewax is a chemically bleached form of yellow wax and has similarapplications. It has a specific gravity of approximately 0.95 to 0.96and melts at about 61°C to 65°C. It is insoluble in water, spar-ingly soluble in cold alcohol, and completely soluble in ether andin fixed and volatile oils. White wax is used as a stiffening agent,an emulsion stabilizer, and a controlled-release vehicle. It is in-compatible with oxidizing agents.1,3

Cocoa butter (Theobroma oil) is a yellowish or white brittle solidwith a slight odor of cocoa. It is derived from natural sources andis composed primarily of the triglycerides of saturated and un-saturated fatty acids. It melts at a temperature between 31°C and34°C, is freely soluble in chloroform and in ether, and is slight-ly soluble in 95% ethanol. Heating to a temperature higher than36°C lowers the solidification point of cocoa butter because ofits polymorphic nature and the formation of a metastable form.Cocoa butter should be stored at a temperature lower than 25°C.It is used as a suppository base and is also a major ingredient inchocolate.4

White petrolatum (white petroleum jelly, white soft paraffin) is awhite, translucent, soft unctuous mass that is inert, odorless, andtasteless. It is used primarily in topical pharmaceutical formula-tions. White petrolatum has a specific gravity of approximately0.815 to 0.880 and melts in a range between 38°C and 60°C. Itis practically insoluble in ethanol, in glycerin, and in water but issoluble in chloroform and in most fixed and volatile oils.5

REFERENCES1. United States Pharmacopeia XXIV/National Formulary 19. Rockville,

MD:US Pharmacopeial Convention, Inc; 1999:2278, 2402, 2698-2702.2. Reynolds JEF, ed. MARTINDALE: The Extra Pharmacopoeia. 30th ed.

London:The Pharmaceutical Press; 1993:1347-1348, 1354. 3. Fazzi AA, Kibbe AH. White wax. In: Kibbe AH, ed. Handbook of Pharma-

ceutical Excipients. 3rd ed. Washington DC:American Pharmaceutical Association; 2000:595-596.

4. Reilly WJ Jr. Pharmaceutical necessities. In: Gennaro AR, ed. Reming-ton: The Science and Practice of Pharmacy. 19th ed. Easton, PA:Mack Publishing Company; 1995:1409.

5. Weller PJ. Petrolatum: In: Kibbe AH, ed. Handbook of Pharmaceutical Excipients. 3rd ed. Washington, DC:American Pharmaceutical Associa-tion; 1994:331-333.


RxFor 100 g Camphor 5 gMenthol 5 gEucalyptol 5 gWhite wax 10 gCocoa butter 10 gWhite petrolatum qs 100 g

Camphor, Menthol, and Eucalyptol Rubefacient Ointment


Carbidopa 2-mg/mL and Levodopa 20-mg/mL Oral Suspension



tal amount to be prepared.2. Accurately weigh and/or measure each ingredient.3. Thoroughly mix the carbidopa and levodopa powders in a

mortar with a pestle.Aqueous4. Add the propylene glycol and mix to form a smooth paste.5. Slowly add the Ora-Plus with mixing between each addition.6. Add sufficient Ora-Sweet or Ora-Sweet SF to volume and mix

well.7. Package and label.Nonaqueous4. Mix the saccharin with the active drug powders.5. Incorporate the flavor and almond oil and mix well.6. Package and label.

PACKAGINGPackage in a tight, light-resistant container with minimal head-

space (oral syringes are best).

LABELINGShake well before taking. Use only as directed. Keep out of the

reach of children. Store in a refrigerator.

STABILITYWhen the aqueous preparation is stored in a refrigerator, a be-

yond-use date of 7 days should be appropriate; the oil-basedpreparation should be stable for at least 30 days.1,2

QUALITY CONTROLFinal yield compared with theoretical yield, pH, physical ap-

pearance.

DISCUSSIONCarbidopa (C10H14N2O4

.H20, MW 244.24) occurs as a white tocreamy white odorless or practically odorless powder. It is slight-ly soluble in water, freely soluble in 3 N hydrochloric acid, andpractically insoluble in alcohol. Carbidopa should be protected fromlight. It is a decarboxylase inhibitor; it inhibits the decarboxyla-tion of levodopa to dopamine. Concurrent administration of car-bidopa with levodopa inhibits the peripheral decarboxylation oflevodopa by the aromatic L-amino acid decarboxylase without affecting the metabolism of levodopa within the central nervous

system; as a result, more levodopa is available for transport to thebrain. Commercially available combinations of carbidopa and lev-odopa are in ratios of 1:4 or 1:10 (carbidopa to levodopa).3,4

Levodopa (C9H11NO4, MW 197.19) occurs as a white to off-whiteodorless crystalline powder. In the presence of moisture, it is rapid-ly oxidized by atmospheric oxygen and darkens. It is slightly sol-uble in water, freely soluble in 3 N hydrochloric acid, and insol-uble in alcohol. It should be stored in a tight container andprotected from light. It is used either alone or in combination withthe decarboxylase inhibitor carbidopa in the treatment of parkin-sonian syndrome. Because levodopa is unstable, it must be preparedin an acidic vehicle and the resultant preparation must be assigneda brief beyond-use date, or it must be prepared in a nonaqueousvehicle.1,3,4

Propylene glycol (C3H8O2) occurs as a clear, colorless, viscous, prac-tically odorless liquid with a sweet taste.5

Ora-Plus is an oral suspending vehicle with a pH of approximate-ly 4.2 and an osmolality of about 230 mOsm/kg. It contains pu-rified water, microcrystalline cellulose, sodium carboxymethyl-cellulose, xanthan gum, carrageenan, sodium phosphate, andcitric acid as buffering agents; simethicone as an antifoaming agent;and potassium sorbate and methylparaben as preservatives.6

Ora-Sweet syrup is a flavoring vehicle buffered to a pH of ap-proximately 4.2. The osmolality of Ora Sweet is about 3240mOsm/kg. It contains purified water, sucrose, glycerin, sorbitol(5%), flavoring, sodium phosphate, and citric acid as buffering agentsand potassium sorbate and methylparaben as preservatives.6

Ora-Sweet SF is a sugar-free, alcohol-free syrup buffered to a pHof approximately 4.2. The osmolality of Ora-Sweet SF is 2150mOsm/kg. It contains water, sodium saccharin, xanthan gum, glyc-erin, sorbitol, citric acid, and sodium citrate as buffers; methyl-paraben, propylparaben, and potassium sorbate as preservatives;and flavoring.6Saccharin (C7H5NO3S, MW 183.18) is an intense sweetening agent.It occurs as odorless white crystals or as a white crystalline pow-der. Saccharin is soluble to the extent of 1 g in 290 mL of water,1 g in 50 mL of glycerin, and 1 g in 31 mL of 95% ethanol.7Almond oil (sweet almond oil) is a clear, pale, straw-colored or color-less, almost odorless, oily liquid with a bland taste. Its specific grav-ity ranges from 0.910 to 0.915, and it is slightly soluble in alcohol.1

References1. United States Pharmacopeia XXIV/National Formulary 19. Rockville, MD:US

Pharmacopeial Convention, Inc; 1999:2369, 2383, 2505-2506, 2698-2702.2. Trissel LA. Trissel’s Stability of Compounded Formulations. 2nd ed. Wash-

ington DC:American Pharmaceutical Association; 2000:214-215.3. McEvoy GK, ed. AHFS Drug Information 2001. Bethesda MD:American So-

ciety of Health-System Pharmacists; 2001:2383-2388.4. Reynolds JEF. MARTINDALE:The Extra Pharmacopoeia. London:The Phar-

maceutical Press; 1993:840-847.5. Dandiker Y. Propylene glycol. In: Kibbe A, ed. Handbook of Pharmaceuti-

cal Excipients. 3rd ed. Washington, DC: American Pharmaceutical Asso-ciation; 2000:442-444.

6. Ora-Sweet, Ora-Sweet SF, and Ora-Plus [package insert]. Minneapolis, MN:Paddock Laboratories, Inc.

7. Higton FR, Thurgood DM. Saccharin. In: Kibbe A, ed. Handbook of Phar-maceutical Excipients. 3rd ed. Washington, DC: American PharmaceuticalAssociation; 2000:454-456.

RxFor 100 mL Aqueous NonaqueousCarbidopa 200 mg 200 mgLevodopa 2 g 2 gPropylene glycol 5 mL —Ora-Plus 50 mL —Ora-Sweet or Ora-Sweet SF qs 100 mL —Saccharin — 100 mgFlavor (tangerine or other) — qsAlmond oil — qs 100 mL



tal amount to be prepared.2. Accurately weigh and/or measure each ingredient.3. Mix the ergoloid mesylates and the selegiline HCl in the propy-

lene glycol to form a smooth mixture.4. Add the lecithin:isopropyl palmitate mixture and mix well.5. Add sufficient Pluronic F127 20% gel and mix with a shear-

ing action until the gel is well-dispersed.6. Package and label.Note: The lecithin:isopropyl palmitate solution can be preparedby mixing 0.2 g of sorbic acid, 50 g of soy lecithin, and 50 g ofisopropyl palmitate. The Pluronic F127 solution can be preparedby mixing 0.2 g of sorbic acid, 20 g of Pluronic F127, and suf-ficient purified water to make 100 mL.


LABELINGFor external use only. Keep out of the reach of children. Use

only as directed.

STABILITYA beyond-use date of 14 days can be used for this preparation.1

USEErgoloid mesylates and selegiline gel are used to treat mild men-

tal impairment.

QUALITY CONTROLTheoretical compared with practical yield, physical observation.

DISCUSSIONErgoloid mesylates (C31H41N5O5.CH4O3S, dihydroergocornine me-sylate, MW 659.79; C35H41N5O5.CH4O3S, dihydroergocristinemesylate, MW 707.84; C32H43N5O5.CH4O3S, dihydro-alpha-er-gocryptine mesylate, MW 673.82; C32H43N5O5.CH4O3S, dihy-dro-β-ergocryptine mesylate, MW 673.82) occur as a white tooff-white microcrystalline or amorphous practically odorlesspowder. They are slightly soluble in water (1:50) and are solu-ble in alcohol (1:30). A 0.5% solution in water has a pH of 4.2to 5.2. Ergoloid mesylates should be protected from light andstored at a temperature that does not exceed 25°C.1 They are usedas an adjunct to the treatment of mild-to-moderate dementia inthe elderly, especially (in an oral dosage of 3 or 4.5 mg daily) to

treat the symptoms of mild-to-moderate impairment of mentalfunction.1,2

Selegiline HCl (C13H17N.HCl, MW 223.74) occurs as a white, odor-less, crystalline powder with a pKa of 7.5. It is freely soluble inwater. Selegiline HCl is a stereoselective monoamine oxidase(MAO) inhibitor; it is also the levorotatory isomer of dimethylpropynylphenethylamine and is structurally related to pargyline.It is used in the symptomatic treatment of parkinsonian syndrome.Selegiline is metabolized to methylamphetamine and ampheta-mine, which are excreted in the urine.1-3

Propylene glycol (C3H8O2) occurs as a clear, colorless, viscous, prac-tically odorless liquid with a sweet taste resembling that of glyc-erin. It has a specific gravity of 1.038 g/mL and is miscible witheach of the following: acetone, chloroform, 95% ethanol, glyc-erin, and water. It is not miscible with fixed oils or with light min-eral oil. It will, however, dissolve some essential oils. Propyleneglycol is actually a better solvent than glycerin. It is similar to ethanolas an antiseptic and is also used in cosmetics and in the food in-dustry as a vehicle for flavors and emulsifiers. It is stable and maybe mixed with many other solvents. Because propylene glycol ishygroscopic, it should be stored in an airtight container and pro-tected from light. Its incompatibilities include potassium per-manganate.4

Lecithin is partially soluble in water but will hydrate to formemulsions. It is used as an emulsifying and solubilizing agent.5

Isopropyl palmitate is a colorless mobile liquid with a very slightodor. It is soluble in alcohol and is insoluble in water, in glycerin,and in propylene glycol.6

Pluronic F127 is usually available in powdered form. It is either odor-less or has a mild odor. It melts at about 56°C and is freely solu-ble in water, in alcohol, and in isopropyl alcohol.7

The patient should be advised that as the preparation is rubbedon the skin and warms up, it may become slightly more viscousand resistant to rubbing.


MD:US Pharmacopeial Convention, Inc; 1999:2396, 2698-2702. 2. Reynolds JEF; ed. MARTINDALE:The Extra Pharmacopoeia. London:The

Pharmaceutical Press; 1993:849-850, 1356, 2376.3. McEvoy GK, ed. AHFS Drug Information 2001. Bethesda, MD:American So-

ciety of Health-System Pharmacists; 2001:2391-2396. 4. Dandiker Y. Propylene glycol. In: Kibbe AH, ed. Handbook of Pharmaceu-

tical Excipients. 3rd ed. Washington, DC:American Pharmaceutical As-sociation; 2000:442-444.

5. Fowler K. Lecithin. In: Kibbe AH, ed. Handbook of Pharmaceutical Excip-ients. 3rd ed. Washington, DC:American Pharmaceutical Association;2000:292-294.

6. Taylor AK. Isopropyl palmitate. In: Kibbe AH, ed. Handbook of PharmaceuticalExcipients. 3rd ed. Washington, DC:American Pharmaceutical Associa-tion; 2000:267-268.

7. Collett JH, Popli H. Poloxamer. In: Kibbe AH, ed. Handbook of PharmaceuticalExcipients. 3rd ed. Washington, DC:American Pharmaceutical Associa-tion; 2000:386-388.


RxFor 100 mL Ergoloid mesylates 1.5 gSelegiline HCl 625 mgPropylene glycol 5 mLLecithin:isopropyl palmitate (1:1) 22 mLPluronic F127 20% gel qs 100 mL

Ergoloid Mesylates 15 mg/mL and Selegiline HCl 6.25 mg/mL in Pluronic Lecithin Organogel


Misoprostol 0.0024%, Metronidazole 2%, and Pentoxifylline 5% Decubitus Ulcer Cream



tal amount to be prepared.2. Accurately weigh and/or measure each ingredient.3. Pulverize the misoprostol tablets to a fine powder.4. Incorporate the metronidazole and pentoxifylline powders and

mix well.5. Add propylene glycol to form a smooth, uniform paste.6. Geometrically incorporate the paste into the hydrophilic oint-

ment (Dermabase, Vanicream) and mix well.7. Package and label.


LABELINGFor external use only. Use only as directed. Keep out of the reach

of children.

STABILITYWhen this preparation is stored in a refrigerator, a beyond-use

date of 2 weeks can be used.1

USEThis preparation has been used to treat recalcitrant decubitus

ulcers.

QUALITY CONTROLFinal yield compared with theoretical yield, physical observa-

tion, viscosity.

DISCUSSIONDecubitus ulcers are a very common and very real problem in

bedfast geriatric patients. These skin ulcers become very difficultto treat and can cause generalized sepsis. The preparation describedhere has been observed to increase blood flow in treated areas,and the combined effects of misoprostol (a protectant) and me-tronidazole (an anti-infective agent) tend to increase the rate ofhealing of decubitus ulcers.Misoprostol (C22H38O5, Cytotec, MW 382.53) is a synthetic ana-log of prostaglandin E1 (alprostadil). It occurs as a water solubleviscous liquid. It is a gastric antisecretory and antiulcerative agentthat exerts a protective effect on the gastroduodenal mucosa. Cy-totec tablets contain either 100 µg or 200 µg of misoprostol, aswell as hydrogenated castor oil, hydroxypropyl methylcellulose,microcrystalline cellulose, and sodium starch glycolate.2,3

Metronidazole (C6H9N3O3, MW 171.15) occurs as white to pale

yellow, odorless crystals or crystalline powder. It is stable in airbut darkens when exposed to light. It is sparingly soluble in waterand in alcohol but is only slightly soluble in ether and in chloroform.1

Pentoxifylline (C13H18N4O3, oxpentifylline, MW 278.31) is a syn-thetic trisubstituted xanthine derivative that is structurally relat-ed to caffeine, theobromine, and theophylline. It occurs as awhite, odorless, crystalline powder that has a bitter taste. It is sol-uble to the extent of about 77 mg/mL in water and 63 mg/mL inalcohol. Pentoxifylline and its metabolites reduce blood viscosi-ty and are reported to increase blood flow to ischemic tissues andto improve tissue oxygenation in patients with peripheral vascu-lar disease.3-4

Propylene glycol (C3H8O2) occurs as a clear, colorless, viscous, prac-tically odorless liquid with a sweet taste resembling that of glyc-erin. It has a specific gravity of 1.038 g/mL and is miscible witheach of the following: acetone, chloroform, 95% ethanol, glyc-erin, and water. Because propylene glycol is hygroscopic, it shouldbe stored in an airtight container and protected from light.5

Hydrophilic ointment is a water-washable oil-in-water emulsionbase containing methylparaben, propylparaben, sodium laurylsulfate, propylene glycol, stearyl alcohol, white petrolatum, andpurified water.6,7

Dermabase cream is an unscented, washable, oil-in-water emulsioncream base. It contains purified water (about 45%), mineral oil,petrolatum, cetostearyl alcohol, propylene glycol, sodium laurylsulfate, isopropyl palmitate, imidazolidinyl urea, methylparaben,and propylparaben. It is a smooth, white, water-washable creamthat has a slight, pleasant odor. It is preserved and is compatiblewith a wide variety of agents.8

Vanicream is an oil-in-water emulsion base containing white petro-latum, cetearyl alcohol, ceteareth-20, sorbitol, propylene glycol,simethicone, glyceryl monostearate, polyethylene glycol mono-stearate, and sorbic acid. It is free of dyes, perfume, lanolin, parabens,and formaldehyde and is a stable and widely compatible cream.9


MD:US Pharmacopeial Convention, Inc; 1999:2279, 2698-2702.2. [No author listed.] Physicians’ Desk Reference. 56th ed. Montvale NJ:Med-

ical Economics Company; 2002:3202-3203. 3. McEvoy GK, ed. AHFS Drug Information 2001. Bethesda, MD:American So-

ciety of Health-System Pharmacists; 2001:1473-1477, 2837-2842.4. Reynolds JEF, ed. MARTINDALE:The Extra Pharmacopoeia. London:The

Pharmaceutical Press; 1993:1311-1312.5. Dandiker Y. Propylene glycol. In: Kibbe A, ed. Handbook of Pharmaceuti-

cal Excipients. 3rd ed. Washington, DC:American Pharmaceutical Asso-ciation; 2000:442-444.

6. Reilly WJ Jr. Pharmaceutical necessities. In: Gennaro AR, ed. Reming-ton: The Science and Practice of Pharmacy. 19th ed. Easton, PA:Mack Pub-lishing Company; 1995:1402.

7. Block LH. Medicated applications. In: Gennaro AR, ed. Remington: TheScience and Practice of Pharmacy. 19th ed. Easton, PA:Mack PublishingCompany; 1995:1586.

8. Dermabase cream [package insert]. Minneapolis, MN:Paddock Labora-tories, Inc.

9. Vanicream [package insert]. Rochester, MN:Pharmaceutical Specialties, Inc.

RxFor 100 gMisoprostol 200-µg tablets 12 tabletsMetronidazole 2 gPentoxifylline 5 gPropylene glycol qsHydrophilic ointment qs 100 g



tal amount to be prepared.2. Accurately weigh and/or measure each ingredient.3. Disperse the nicotine polacrilex in the alcohol.4. Melt the sorbitol candies at a temperature that is not higher

than 70°C.5. Add the nicotine dispersion and mix well.6. Add the stevia and mix well; then add the flavor.7. Cool the mixture slightly and pour it into lollipop molds

while the mixture is still fluid.8. Allow the mixture to cool, and remove it from the molds. The

lollipops can be dusted with powdered sugar if they are sticky.9. Package and label. For unique packaging, drill a hole in the

cap of a plastic vial for tablets or capsules and insert a lollipopinto the cap from the underside before securing the cap.

Note: The sucrose lollipop base can be prepared with powdered sugar(42 g), light corn syrup (16 mL), and purified water (24 mL). Com-bine those three ingredients in a beaker and stir until they are well-mixed. Cover the mixture and heat it on a hot plate at a high settinguntil the mixture boils. Continue boiling for 2 minutes. Uncover themixture, remove it from the heat, and allow it to set for a few minutes.Then add the nicotine salicylate solution and mix thoroughly. Add thestevia and flavor, mix well, and pour the mixture into molds.


LABELINGUse only as directed. Keep out of the reach of children.


tion.1

USEThis preparation has been used as a smoking-cessation aid.


vation, weight.

DISCUSSIONNovel dosage forms (chewing gum, transdermal patches, lol-

lipops), which are often used as part of a smoking-cessation program, can contribute to participants’ success and are increasingin popularity. Nicotine polacrilex [(C4H6O2)x (C10H10)y] (C10H14N2) is a com-plex of nicotine with a methacrylic acid polymer. Nicotine can beabsorbed from the gastrointestinal or respiratory tract and throughintact skin. Absorption of the nicotine base is more rapid than thatof the polacrilex form. Note: Prior to compounding, check the nico-tine equivalent of the polacrilex actually used.2,3

Alcohol (ethyl alcohol, ethanol, grain alcohol) is a clear, colorless,mobile, volatile liquid that has a slight, characteristic odor and aburning taste.4

Stevia (honey leaf, yerba dulce) in powder form is a relatively newsweetening agent from the leaves of the Stevia rebaudiana (Bertoni)plant. It is natural, nontoxic, and safe and occurs as a white, crys-talline, hygroscopic powder.5

Sorbitol candies are commercially available in different flavors. Dif-ferent brands can be tried to determine patients’ preferences.Sucrose occurs in the following forms: colorless crystals, crystallinemasses, or blocks or as a white crystalline powder that is odorlessand has a sweet taste. It has a melting range of 160°C to 186°Cand exhibits some decomposition when melted. Sucrose is solu-ble in water 1:0.5, in alcohol 1:400, and in 95% ethanol 1:170.When heated, it caramelizes at temperatures higher than 160°C.When sucrose is used in candy-based products, some inversionof sucrose to dextrose and fructose occurs at temperatures rang-ing from 110°C to 145°C. Fructose may cause stickiness but in-hibits cloudiness and/or graininess. This inversion process is en-hanced in the presence of acids and at temperatures higher than130°C.6

Corn syrup, which is used to prepare the lollipop base in this for-mulation, is made by the enzymatic breakdown of cornstarch. Itis very widely used in commercial products today. Karo, the mostpopular brand of corn syrup, also contains natural vanilla flavor.

References1. United States Pharmacopeia XXIV/National Formulary 19. Rockville MD:US

Pharmacopeial Convention, Inc; 1999:2698-2702.2. McEvoy GK, ed. AHFS Drug Information 2001. Bethesda MD:American So-

ciety of Health-System Pharmacists; 2001:1335-1352. 3. Budavari S, ed. The Merck Index. 12th ed. Whitehouse Station, NJ:Merck

& Co, Inc; 1996:1119-1120.4. Weller PJ. Alcohol. In: Kibbe AH, ed. Handbook of Pharmaceutical Excipients.

3rd ed. Washington DC:American Pharmaceutical Association; 2000:7-9.5. Reynolds JEF, ed. MARTINDALE: The Extra Pharmacopoeia. 30th ed. Lon-

don:The Pharmaceutical Press; 1993:1049.6. Hamlow EE, Armstrong NA, Pickard A. Sucrose. In: Kibbe AH, ed. Hand-

book of Pharmaceutical Excipients. 3rd ed. Washington DC:AmericanPharmaceutical Association; 2000:539-543.


Nicotine 2-mg Lollipops


RxFor 100 LollipopsNicotine polacrilex 1.1 g

(equiv to 200 mg nicotine)Alcohol 95% 17 mLStevia powder extract 1.25 gFlavor qsSorbitol candies qs

or Sucrose lollipop base qsNote: The size of the lollipop mold must be determined beforethe final weight of the base that will be used is selected.

Nicotine Medication Stick



tal amount to be prepared.2. Accurately weigh and/or measure each ingredient.3. Melt the PEG 3350 and the PEG 300 to about 60°C and mix

well.4. Cool slightly and add the nicotine polacrilex while the mix-

ture is still fluid.5. Pour the mixture into medication stick tubes and allow it to

cool.6. Package and label.


LABELINGUse only as directed. Keep out of the reach of children. Store

in a cool place.


ton.1

USEThis preparation has been applied to the skin to aid in smok-

ing cessation.


vation, weight.

DISCUSSIONMany methods and techniques are used in smoking-cessation

programs, which are quite popular. Reducing addiction to nico-tine has been accomplished in many dosage forms, includingchewing gum and (because nicotine is well-absorbed through theskin) transdermal patches. Nicotine polacrilex [(C4H6O2)x (C10H10)y] (C10H14N2) is a com-plex of nicotine with a methacrylic acid polymer. Nicotine can beabsorbed from the gastrointestinal or respiratory tract and throughintact skin. Absorption of the nicotine base is more rapid than thatof the polacrilex form. The base nicotine, a pyridine alkaloid, isa naturally occurring autonomic drug. Nicotine is a highly puri-fied extract obtained from the dried leaves of the tobacco plant(Nicotiana tabacum [Solanaceae]). Nicotine occurs as a basic, col-orless to pale yellow, very hygroscopic, oily, volatile liquid that

has an unpleasant, pungent odor and a sharp, burning, persistenttaste. It is soluble in water and in alcohol. Nicotine can be ab-sorbed from the gastrointestinal or respiratory tract and throughintact skin. Absorption of the nicotine base is more rapid than thatof the acid salts. Note: Prior to compounding, check the nicotineequivalent of the polacrilex actually used.2,3

Polyethylene glycol (Carbowax, polyoxyethylene glycol, PEG) is anaddition polymer of ethylene oxide and water. At room temper-ature, PEGs with a molecular weight of 200 to 600 are liquid, andthose with a molecular weight higher than 1000 are solid. Theliquid PEGs are clear, colorless or slightly yellow, viscous liquidswith a slight but characteristic odor and a bitter, slightly burningtaste. The density of the liquid PEGs ranges 1.11 to 1.14 g/mL.The freezing point for PEG 300 is -15°C to -8°C. Solid PEGsare white or off-white pastes or waxy flakes. Those with a mo-lecular weight higher than 6000 are available as free-flowingpowders. The density of the solid PEGs is in the range of 1.15g/mL to 1.21 g/mL. The melting point for PEG 3350 is in therange of 48°C to 54°C. The PEGs are soluble in water and mis-cible in all ratios with other PEGs. The liquid PEGs are solublein each of the following: acetone, alcohols, glycerin, and glycols.The solid PEGs are soluble in each of the following: acetone,dichloromethane, ethanol, and methanol and are slightly solublein aliphatic hydrocarbons and in ether. The solid PEGs are, how-ever, insoluble in fats, in fixed oils, and in mineral oil. The PEGsare chemically stable, do not support microbial growth, and donot become rancid. They can be sterilized by autoclaving, filtra-tion, or gamma irradiation. Listed incompatibilities include somecolors (dyes) and possible discoloration in the presence of iron.When mixed with a PEG, penicillin and bacitracin may be lessbactericidal, and the parabens may lose some preservative effica-cy. PEG bases may soften when mixed with phenol, with tannicacid, or with salicylic acid. When mixed with a PEG, sulfonamidesor dithranol may discolor and sorbitol may precipitate. Polyeth-ylene, polyvinyl chloride, and cellulose-ester membranes (filters)may soften or be dissolved by the PEGs. When applied topical-ly, especially to mucous membranes, the PEGs may cause irrita-tion or stinging. In parenteral products, up to a maximum con-centration of PEG 300 of 30% can be used.4

References1. United States Pharmacopeia XXIV/National Formulary 19. Rockville MD:US

Pharmacopeial Convention, Inc; 1999:2698-2702.2. McEvoy GK, ed. AHFS Drug Information 2001. Bethesda MD:American So-

ciety of Health-System Pharmacists; 2001:1335-1352. 3. Budavari S, ed. The Merck Index. 12th ed. Whitehouse Station NJ:Merck

& Co, Inc; 1996:1119-1120.4. Price JC. Polyethylene glycol. In: Kibbe AH, ed. Handbook of Pharmaceutical

Excipients. 3rd ed. Washington DC:American Pharmaceutical Association;2000:392-398.

RxFor twenty 5-g sticksNicotine polacrilex 3.3 gPolyethylene glycol (PEG) 3350 31.4 gPolyethylene glycol (PEG) 300 68 g



tal amount to be prepared.2. Accurately weigh and/or measure each ingredient.3. Dissolve the podophyllum and salicylic acid in the acetone.4. Add that mixture to about 50 mL of the flexible collodion.5. Add the lactic acid while stirring and continue to stir until all

the ingredients have dissolved.6. Add sufficient flexible collodion to volume and mix well.7. Package in a light-resistant container and label.


LABELINGKeep tightly closed. Keep away from flame and heat.

STABILITYA beyond-use date of 6 months can be used for this formula.1

USEThis solution has been used to treat warts.

QUALITY CONTROLFinal yield compared with theoretical yield, physical observa-

tion.

DISCUSSIONWarts (verruca), which are flesh-colored growths caused by hu-

man papillomavirus, are characterized by circumscribed hyper-trophy of the papillae of the corium and thickening of themalpighian, granular, and keratin layers of the epidermis. Theterm also refers to epidermal verrucous tumors of nonviral caus-es.2 Warts are often treated with keratolytics in a vehicle like flex-ible collodion, which maintains close contact between the drugand the skin. In this preparation, the solvents evaporate to leavethe drug impregnated in the film and thus in intimate contactwith the skin.Podophyllum resin occurs as an amorphous powder that varies incolor from light brown to greenish yellow. The color darkens whenthe resin is subjected to a temperature higher than 25°C or whenit is exposed to light. It has a slight, peculiar, faintly bitter taste.An alcohol solution of podophyllum resin is acid to moistened lit-mus paper. Podophyllum resin is soluble in alcohol, in which itexhibits a slight opalescence, and it is partially soluble in ether.It is an antimitotic and caustic agent prepared from podophyllum

(American mandrake, May-apple root), which is obtained fromvarious plant families including Podophyllaceae, Coniferae, andBerberidaceae. It is a powdered mixture of the resins extracted frompodophyllum by percolation with alcohol and subsequent pre-cipitation from the concentrated percolate upon addition to acid-ified water.1,3

Lactic acid (propanoic acid) occurs as a colorless or yellowish, prac-tically odorless, syrupy, hygroscopic liquid. It has a specific grav-ity of about 1.20 and is miscible with water and with alcohol. TheUnited States Pharmacopeia (USP) specifies a mixture of lactic acidand lactic acid lactate equivalent to 85% to 90% w/w of C3H6O3.Lactic acid prepared by the fermentation of sugars is levorotato-ry, and that prepared synthetically is racemic.1

Salicylic acid (C7H6O3, MW 138.12) occurs as white crystals thatare usually in fine needles or as a fluffy white crystalline powder.It is stable in air and may have a slightly yellow or pink tint. Ithas a faint, mint-like odor. Salicylic acid is slightly soluble in wa-ter (1 g in 460 mL and 1 g in 15 mL of boiling water) and is freelysoluble in alcohol (1 g in 3 mL). It should be protected from light.1

Acetone (C3H6O, 2-propanone, MW 58.08) occurs as a transpar-ent, colorless, mobile, volatile liquid that has a characteristic odor.A 50% aqueous solution of acetone is neutral to litmus. Acetoneis miscible with each of the following: water, alcohol, ether, andmost volatile oils. It has a specific gravity of not more than 0.789and a boiling point of about 56°C. Acetone is used as a solvent.1

Flexible collodion occurs as a clear or slightly opalescent viscousliquid that is colorless or slightly yellow. It has the odor of ether.The odor of camphor becomes noticeable as the odor of ether evap-orates.1

References1. United States Pharmacopeia XXIV/National Formulary 19. Rockville MD:

US Pharmacopeial Convention, Inc; 1999:2264, 2275, 2290, 2363, 2391,2698-2702.

2. Spraycar M, ed. Stedman’s Medical Dictionary. 26th ed. Baltimore,MD:Williams & Wilkins; 1995:1930-1931.

3. McEvoy GK, ed. AHFS Drug Information 2001. Bethesda MD:American Society of Health-System Pharmacists; 2001:3457-3459.


RxFor 100 mLPodophyllum resin 15 gLactic acid 5 gSalicylic acid 10 gAcetone 15 mLFlexible collodion qs 100 mL

Podophyllum, Lactic Acid, and Salicylic Acid Wart Mixture


Vitamin B12 1-mg/1-mL Nasal Spray



total amount to be prepared.2. Accurately weigh and/or measure each ingredient.3. Dissolve the parabens in the propylene glycol.4. Heat 9 mL of purified water and add the paraben-containing

solution and the sodium chloride.5. Cool and dissolve the vitamin B12. Add additional purified wa-

ter to volume if required.6. Filter through a sterile 0.2-µg filter into a sterile metered nasal

spray container.7. Package and label.


LABELINGFor nasal administration. Keep out of the reach of children. Clean

the nasal tip with an antibacterial agent after each use.

STABILITYA beyond-use date of 6 months can be used for this solution.1

USEVitamin B12 nasal spray is used to administer vitamin B12 non-

invasively.

QUALITY CONTROLTheoretical yield compared with actual yield, pH, clarity, os-

molality.

DISCUSSIONThe nasal administration of medications is becoming popular.

In humans, the mucosal membrane surface available for drug ab-sorption is significant; it enables the rapid, complete absorptionof many drugs that have appropriate physicochemical character-istics and are administered in relatively low doses. Vitamin B12 (C63H88CoN14O14P, cyanocobalamin, MW 1355.37)occurs as dark red crystals or as an amorphous or crystalline redpowder. In the anhydrous form, it is very hygroscopic. When ex-posed to air, vitamin B12 may absorb about 12% of its weight inwater. It is sparingly soluble in water and is soluble in alcohol.The pH of the USP injection of vitamin B12 is in the range of 4.5to 7.0. This vitamin should be stored in a tight container and pro-tected from light.1

Sodium chloride (MW 58.44) is available as a white crystalline pow-der or as colorless crystals. It has a saline taste and is used in a

variety of parenteral and nonparenteral pharmaceutical formula-tions. It is used to prepare isotonic solutions for use in parenter-al, ophthalmic, or nasal preparations. Sodium chloride is solublein water (1 g in 2.8 mL), in glycerin (1 g in 10 mL), and in 95%ethanol (1 g in 250 mL). It can also decrease the solubility of methyl-paraben in aqueous solution.1,2

Methylparaben (C8H8O3, methyl hydroxybenzoate, methyl parahy-droxybenzoate, MW 152.15) is available as colorless crystals or as a white, crystalline powder that is odorless or almost odor-less and has a slight burning taste. An antimicrobial preservative,it is most effective in solutions that have a pH of between 4 and 8, and its efficacy decreases at a higher pH level. One gramof methylparaben is soluble in each of the following: 400 mL of water, 3 mL of 95% ethanol, 60 mL of glycerin, 200 mL of peanutoil, and 5 mL of propylene glycol. It is practically insoluble inmineral oil. Methylparaben is incompatible with each of the fol-lowing: nonionic surfactants (its antimicrobial activity is reduced),bentonite, magnesium trisilicate, talc, tragacanth, sodium alginate,essential oils, sorbitol, and atropine. It may sorb to some plastics,and it discolors in the presence of iron.3

Propylparaben (C10H12O3, propyl hydroxybenzoate, propyl parahy-droxybenzoate, MW 180.20) is available as a white, crystalline,odorless, tasteless powder. It is most effective in solution at a pHbetween 4 and 8, and its efficacy decreases at a higher pH level.One gram of propylparaben is soluble in each of the following:2500 mL of water, 1.1 mL of ethanol, 250 mL of glycerin, 3330mL of mineral oil, 70 mL of peanut oil, and 3.9 mL of propyleneglycol.4

Propylene glycol (C3H8O2) occurs as a clear, colorless, viscous, prac-tically odorless liquid with a sweet taste resembling that of glyc-erin. It has a specific gravity of 1.038 g/mL and is miscible witheach of the following: acetone, chloroform, 95% ethanol, glyc-erin, and water. Because propylene glycol is hygroscopic, it shouldbe stored in an airtight container and protected from light.5

Purified water has been obtained by distillation, ion exchange, re-verse osmosis, or some other suitable process. It is miscible withmost polar solvents and is chemically stable in all physical states(ice, liquid, and steam). 6


MD:US Pharmacopeial Convention, Inc; 1999:1529, 2373, 2698-2702.2. Cable CG. Sodium chloride. In: Kibbe AH, ed. Handbook of Pharmaceuti-

cal Excipients. 3rd ed. Washington, DC:American Pharmaceutical Asso-ciation; 2000:478-481.

3. Reiger MM. Methylparaben. In: Kibbe AH, ed. Handbook of Pharmaceu-tical Excipients. 3rd ed. Washington, DC:American Pharmaceutical As-sociation; 2000:340-344.

4. Rieger MM. Propylparaben. In: Kibbe AH, ed. Handbook of Pharmaceuti-cal Excipients. 3rd ed. Washington, DC:American Pharmaceutical Asso-ciation; 2000:450-453.

5. Dandiker Y. Propylene glycol. In: Kibbe AH, ed. Handbook of Pharmaceu-tical Excipients. 3rd ed. Washington, DC:American Pharmaceutical As-sociation; 2000:442-444.

6. Ellison A, Nash RA, Wilkin MJ. Water. In: Kibbe AH, ed. Handbook of Phar-maceutical Excipients. 3rd ed. Washington, DC:American Pharmaceuti-cal Association; 2000:580-584.

RxFor 10 mLVitamin B12 10 mgSodium chloride 90 mgMethylparaben 10 mgPropylparaben 10 mgPropylene glycol 1 mLPurified water qs 10 mL


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A large part of the care provided by most veterinary practicesconsists of treating dermatologic disorders. Owners usually bringtheir pet to a veterinary clinic after it has exhibited long bouts ofchronic scratching that are annoying and result in superficial lac-erations and secondary bacterial infection. Veterinarians treat dogs,cats, and horses for a variety of skin problems, including allergy-related dermatitis from flea bites or food, skin infections (pyo-derma), hormonally induced or immune-mediated skin diseases,and parasites. “Atopy” is defined by the American College of Vet-erinary Dermatologists as a “genetically disposed tendency to de-velop IgE-mediated allergy to environmental allergens.” Theclinical manifestation of atopy is termed “atopic disease” (AD).Young dogs are often afflicted with AD, which is usually causedby an allergic reaction resulting from exposure to environmentalantigenic pollens, mold spores, or house dust. Atopic dermatitisis one of the most common skin problems caused by AD.

The pathogenesis of AD is poorly understood. Although thereis a genetic predisposition to its development, the rapid increasein the incidence of AD over the last few decades in both humansand animals suggests that the cause is environmental rather thangenetic. Many environmental allergens (dust mites; house dust;pollen from grasses, trees, and weeds; mold spores; epidermal anti-gens that produce contact dermatitis; and insect antigens such asthose caused by flea bites) have been implicated in the pathogenesisof canine AD.

The clinical signs of canine AD vary from dog to dog, but themost common sign is a primary lesion manifested by pruritus ofthe face, paws, ears, extremities, or ventrum (chest and belly).Primary lesions may result in secondary lesions, such as those causedby trauma from scratching, chronic inflammation, and secondarybacterial infections. Other signs include red-brown salivary stain-ing, excoriations, self-induced alopecia, dry lusterless hair, hy-

perpigmentation, scaling, and lichenification. According to theresults of one study,1 atopic otitis externa is present in as manyas 86% of dogs and AD-related conjunctivitis occurs in as manyas 50% of canine patients.

The treatment of canine AD is multimodal and complex. It in-cludes allergen avoidance, the establishment of “skin barriers,”and the use of anti-inflammatory drugs, allergen-specific im-munotherapy (“allergy shots”), and antibiotics. Using any one ofthose agents as monotherapy is usually ineffective, and most cli-nicians combine therapies to successfully treat canine AD. Manytreatment products are either not commercially available or arenot intended for use in veterinary patients. Many of those thatare intended for veterinary use are flavored with offending food-based allergens. By working with veterinary dermatologists, thecompounding pharmacist can play a valuable role in providing der-matologic therapies (tables 1 and 2) that are allergen-free and de-signed for use in specific veterinary patients.

Allergen Avoidance and BarriersOne of the first steps in managing AD is to remove “flare fac-

tors” (flea saliva, certain foods, dust mite saliva and excrement,molds, pollens, danders, dusts, and other causes of allergic reac-tion) from the animal’s environment. However, no controlled stud-ies document the remission of AD after allergen-avoidance ther-apy alone, and complete prevention of contact with pollens andmolds is impossible. At some point, all dogs must visit the out-doors and are then exposed to specific environmental allergens.Bathing the atopic dog frequently (especially after it has been out-side) limits the extent of exposure to allergens. Dogs with AD alsoappear to have an increased sensitivity to flea salivary antigens.A complete flea-avoidance program should be initiated in all pa-tients with active or suspected AD.2

Improving the integrity of the epidermal lipid barrier of the skincreates an effective barrier against allergens. In atopic humans,topical skin creams have recently been used to prevent contactdermatitis (pure petrolatum provides the best dermal protec-tion), and topically applied fatty acids such as the ceramides canrestore the epidermal lipid barrier,3 although such skin creamshave not been clinically tested in dogs with AD. The epidermalceramides might also be restored by a diet rich in linoleic acid.However, controlled studies of the effectiveness of those agentsin treating canine AD have not been performed.

Allergies to foods can be controlled by the use of an “elimina-tion diet” in which common protein meat sources are replaced bya novel protein and carbohydrate to which the dog has not beenexposed. Novel protein diets, which may contain lamb or evenkangaroo, are used when dogs exhibit an allergic reaction to tra-ditional meat sources such as beef, pork, or chicken. Diets con-taining hydrolyzed proteins are also available; they are based onthe theory that the low-molecular-weight peptides they containare too small in size to provoke IgE cross-linking on mast cells.Unfortunately, little evidence exists to support or refute the ef-fectiveness of those diets. Until blinded, randomized, controlledstudies of the management of canine AD have been conducted,veterinary clinicians must define the clinical course of treatmenton a patient-by-patient basis.

S P E C I A L I T Y


The Treatment of

Gigi Davidson, BS, RPh, DICVPNorth Carolina State University, College of Veterinary Medicine,Raleigh, North Carolina

Anti-Inflammatory AgentsBecause complete allergen avoidance is not practical, anti-in-

flammatory drugs (NSAIDs) can be used to reduce the clinical signsof canine AD. NSAIDs can be classified into two categories:drugs such as cyclosporine, which prevent mast cell degranula-tion, and those that prevent the effects of histamine (H1-recep-tor antagonists, misoprostol, pentoxifylline, tacrolimus, cy-closporine, glucocorticoids). The latter group of drugs usuallyinhibits the late-phase allergic reaction, but drugs such as gluco-corticoids or cyclosporine (the most effective anti-inflammatorydrugs) inhibit both immediate- and late-phase allergic IgE-me-diated mast cell activation. Currently, ample evidence4 indicatesthat prednisone and/or prednisolone are effective in treating ca-nine AD, and fair evidence5-8 suggests that cyclosporine, miso-prostol, and pentoxifylline are also effective for that purpose. Be-cause almost all medications used to treat canine AD are designedfor use in humans, many drugs must be modified for use in ca-nine patients. The compounding pharmacist has an important rolein the veterinary care triad and can provide custom-compound-ed, patient-specific therapies for dogs with AD.

GlucocorticoidsGlucocorticoids are the most commonly prescribed drugs in the

treatment of canine AD, for which they are very effective. Theyexert an anti-inflammatory effect on cytokine production. Theirmechanism of action involves influencing or interfering withgene transcription to prevent the activation of immune-mediat-ed inflammatory components such as T-lymphocytes, eosinophils,macrophages, and endothelial, dendritic, and epithelial cells. Inaddition to exerting their inhibitory effects, glucocorticoids alsoactivate anti-inflammatory genes to translate proteins such as leuko-cyte proteinase inhibitor, lipocortin-1, and interleukin-1 recep-tor antagonist.9,10 Lipocortin-1 is responsible for the inhibitionof the enzyme that converts membrane phospholipids into arachi-donic acid, which is the precursor of the potent mediators of in-flammation such as prostaglandins, prostacyclin, thromboxanes,and leukotrienes.

Various topical glucocorticoid therapies have been used in thetreatment of canine AD. A 1% hydrocortisone nonrinse condi-tioner reduced histamine-induced wheal diameter in dogs but hadno effect on late-phase IgE-mediated cutaneous reactions.11 A0.015% triamcinolone spray evaluated in several studies12,13 de-creased inflammatory wheals as well as dermal cell infiltration af-ter inflammatory challenge. Topically applied dexamethasone0.1% was effective in treating a small number of clinical cases ofcanine AD when other agents had failed (T Olivry, G Davidson,unpublished data, 2000-2001). Repeated topical applications ofglucocorticoids can produce adverse effects. Epidermal atrophyand hyalinization of the dermal collagen similar to that exhibit-ed by humans receiving prolonged topical glucocorticoid thera-py have been reported.14 The long-term use of topical glucocor-ticoids can result in dramatic skin atrophy and subepidermalvascularization.15

Oral glucocorticoid formulations are the agents most com-monly used to treat canine AD. Treatment regimens with orallyadministered prednisone, prednisolone, and methylprednisolonehave resulted in good-to-excellent control of that disorder.4,16,17

However, few clinical studies have proven the efficacy of long-acting glucocorticoid preparations, which also produce a greaterincidence of adverse effects than do short-acting or intermedi-ate-acting glucocorticoids. For example, long-term systemic ther-apy with any glucocorticoid can lead to hyperadrenocorticism (Cush-ing’s disease) and may also trigger a urinary tract infection.18 Asa result, long-acting glucocorticoids are not recommended for thetreatment of canine AD.

Antihistamines Veterinary dermatologists frequently recommend using anti-

histamines to control the symptoms of canine AD. Although cur-rently published studies do not provide enough evidence to sup-port the use of antihistamines for that purpose, many veterinaryclinicians concur that several antihistaminic agents may be triedindividually in sequence for 7 to 14 days until the efficacy of aprotocol can be determined. Using antihistamines to treat dogswith AD is based on the hypothesis (from human evidence) thathistamine release from mast cells is primarily responsible for cu-taneous inflammatory response. This hypothesis has not yet beenproven in dogs, however, and the relative lack of antihistamine

S P E C I A L T Y


Table 1. Compounds Potentially Useful in Treating Canine Atopic Disease.

Allergen-specific immunotherapy (eg, “allergy shots”)Barrier creams containing combinations of ceramides, choles-

terol, or free fatty acidsChlorpheniramine capsulesFlavored suspensions containing chlorpheniramineMedicated treats containing clemastine Dexamethasone 0.1% in an aqueous transermal penetrating baseDexamethasone 0.1% topical lotionFlavored suspensions containing diphenhydramine Medicated treats containing diphenhydramine Hydrocortisone 1% topical shampoos, lotions, ointments, and

gelsFlavored suspensions containing hydroxyzine Medicated treats containing hydroxyzine Flavored suspensions containing methylprednisolone Medicated treats containing methylprednisolone Misoprostol capsulesMedicated treats containing misoprostol Pentoxifylline capsulesMedicated treats containing pentoxifylline Flavored suspensions containing prednisone or prednisoloneMedicated treats containing prednisone or prednisolone Specific allergen-free treats or medication vehicles (eg, novel pro-

tein food sources or flavorings to which the dog is not aller-gic)

Tacrolimus topical lotions (0.1% to 0.3%)Triamcinolone 0.015% topical sprays

efficacy in this species indicates possible other mechanisms of in-flammatory response. Antihistamines used with clinical successto treat canine AD include hydroxyzine, diphenhydramine, chlor-pheniramine, and clemastine.19-22 Two studies25-26 indicate thatloratadine and terfenadine are ineffective in treating canine AD,even though loratadine has shown superior histamine-blockingeffects in in vitro experiments involving canine cutaneous mastcells.27 Adverse events caused by antihistamine use in dogs (se-dation, panting, excitation, anticholinergic effects, trembling,ataxia, hyperesthesia, hypersalivation, exacerbation of itching) aremild. One case28 of toxicity from terfenadine in a dog indicatesthat extreme caution should be used when drugs newly approvedfor human use are administered to dogs. When evaluating anti-histamine use in any dog, most veterinary dermatologists agreethat the beneficial effect, if any, occurs within the first 7 to 14days of treatment and that the adverse effect of sedation may be

responsible in part for the clinical impression of efficacy.

MisoprostolMisoprostol, a prostaglandin E1 (PGE1) analog approved as a

gastric cytoprotectant, also exerts potent antiallergic effects.Prostaglandin stimulates the production of cyclic adenosinemonophosphate (AMP), which blocks the secretion of cytokinesby TH1 cells. Misoprostol also produces an anti-inflammatoryeffect by inhibiting lymphocyte proliferation, granulocyte acti-vation, and the synthesis of proinflammatory cytokines such asinterleukin-1 and tumor necrosis factor-α. The effect of miso-prostol in the treatment of canine AD has been well researched;according to one study,7 it produced an improvement of 61% intreated subjects.

CyclosporineCyclosporine is a potent immunomodulatory agent that inhibits

the function of many cell types involved in cutaneous inflam-

S P E C I A L T Y


Table 2. Treatment Regimens for Canine Atopic Disease.

Drug Regimen Adverse Effects CommentsChlorpheniramine 0.4 mg/kg PO BID Possible lethargy, sedation, diarrhea, In dogs with AD, response rates to

vomiting, anorexia, dry mouth, chlorpheniramine tend to be lowurinary retention (25% response at best). Extremely

bitter taste may be masked by compounding.

Clemastine 0.04 - 0.1 mg/kg Sedation, lethargy, dry Controlled studies19-22 indicate thePO BID mouth, urinary retention highest response rate (30%) to clemastine

(as opposed to other antihistamines) in dogswith canine AD.

Cyclosporine 5 mg/kg PO Nephrotoxicity, hepatotoxicity, Doses may be reduced. Coadministration ofevery day hyperlipidemia (reported in humans), ketoconazole, which inhibits the metabolism

gastrointestinal upset, potential of cyclosporine and the lipoprotein thatneurotoxicity, hypertension binds cyclosporine in the blood, thereby

increasing the amount of free cyclosporine.23

Dexamethasone 0.1% in 5% Polyuria, polydipsia, polyphagia, gastric Fewer adverse effects are associated withtopical gel ulceration, diarrhea, epidermal atrophy, topical use than with systemic use.

elevated level of liver enzymes, induction of hyperadrenocorticism (Cushing’s disease), diabetes, trigger for urinary tract infection

Diphenhydramine 2.2 mg/kg PO q 8 hr Sedation, lethargy, dry mouth, Likely to be less effectiveurinary retention, diarrhea, vomiting, than clemastine or chlorpheniramine.anorexia

Hydrocortisone 1% conditioner Polyuria, polydipsia, polyphagia, gastric Fewer adverse effects are associatedapplied topically ulceration, diarrhea, elevated level of with topical use as opposed to systemic use.

liver enzymes, epidermal atrophy,induction of hyperadrenocorticism(Cushing’s disease), diabetes, trigger for urinary tract infection

Hydroxyzine 1 to 2 mg/kg PO Sedation, lethargy, fine rapid tremors, May be less effective than clemastineBID - TID whole-body rapid tremors, and chlorpheniramine.

seizures (rarely)

mation, immune reactions (lymphocytes and Langerhans’ cells),and allergic response (effector cells such as mast cells andeosinophils). The antiallergic effects (but not the adverse effects)produced by cyclosporine are remarkably similar to those pro-duced by glucocorticoids. Long-term toxicity studies29 in dogs(45 mg/kg/day orally for 1 yr) indicated that side effects fromglucocorticoid treatment included emesis, diarrhea, anorexia,weight loss, generalized cutaneous papillomatosis, hyperplasticgingivitis, and periodontitis, all of which resolved after a 12-weekrecovery period. In those studies, there were no indications ofhepatic, renal, or myelotoxic effects from the use of cyclosporine.A drug interaction with ketoconazole can increase the blood lev-el of free cyclosporine.23

TacrolimusTacrolimus inhibits T-lymphocyte response to antigens and

downregulates cytokine production. Unlike cyclosporine, tacro-limus is effective after topical application. The safety and effica-cy of 0.3% tacrolimus lotion in dogs with AD were evaluated ina recent study.30 The degree of erythema significantly decreasedin all dogs receiving tacrolimus, and none of the dogs studied suf-fered adverse effects from treatment. At this time, evidence prov-ing the efficacy of tacrolimus in treating canine AD is insufficient,but the encouraging results from the study cited above indicatethat topical tacrolimus may be a valuable therapeutic agent forthat purpose. The systemic use of tacrolimus, which is apparent-ly more toxic than cyclosporine, is not recommended.24

S P E C I A L T Y


Table 2, continued

Drug Regimen Adverse Effects CommentsMethylprednisolone 0.4 to 0.8 mg/kg Polyuria, polydipsia, polyphagia, gastric Intermediate duration of action (12 to 36 hr)

PO every day ulceration, diarrhea, epidermal atrophy, in dogs and thus a good choice for candidatex 7 days elevated level of liver enzymes, induction for alternate-day administrationthen q 48 hr of hyperadrenocorticism (Cushing’s

disease), diabetes, trigger for urinarytract infection

Misoprostol 3 to 6 µg/kg PO Gastrointestinal distress, diarrhea, Adverse effects may be reduced by givingTID x 30 days abdominal pain, vomiting, flatulence misoprostol with food. Pregnant women

should avoid all contact with misoprostol.

Pentoxifylline 10 mg/kg PO Vomiting, anorexia, tachycardia, central Extensively metabolized to metabolites that BID - TID nervous system stimulation are responsible for pharmacologic effects

(eg, local therapy is not advised)

Prednisolone 0.5 to 1 mg/kg PO Polyuria, polydipsia, polyphagia, gastric Long-term therapy should be avoided; then 0.2 to 0.5 ulceration, diarrhea, elevated level long-acting glucocorticoid therapy should mg/kg PO q 48 hr of liver enzymes, induction of be avoided.maintenance hyperadrenocorticism (Cushing’s disease)

or diabetes, trigger for urinary tract infection, epidermal atrophy

Prednisone 0.5 to 1 mg/kg PO Polyuria, polydipsia, polyphagia, gastric Long-term therapy should be avoided; daily then 0.2 to 0.5 ulceration, diarrhea, elevated level long-acting glucocorticoid therapy should mg/kg PO q 48 hr of liver enzymes, induction of hyper- be avoided.maintenance adrenocorticism (Cushing’s disease)

or diabetes, trigger for urinary tract infection, epidermal atrophy

Tacrolimus 0.3% lotion Nephrotoxicity, hepatotoxicity, Tacrolimus is apparently more toxic thanadministered 0.1 gastrointestinal upset cyclosporine when used systemically in mL/kg topically dogs, and its use is not recommended.24

daily

Triamcinolone 0.015% spray Polyuria, polydipsia, polyphagia, gastric Fewer adverse effects aretopically ulceration, diarrhea, elevated level associated with topical useevery day of liver enzymes, induction of as opposed to systemic use.

hyperadrenocorticism (Cushing’s disease) or diabetes, trigger for urinary tract infection, epidermal atrophy

S P E C I A L T Y


Pentoxifylline is a phosphodiesterase inhibitor characterized bymultiple immunomodulatory properties. It suppresses interleukinand tumor necrosis factor and decreases leukocyte adhesion andaggregation. In a randomized, blinded, placebo-controlled trial,8orally administered pentoxifylline at a twice-daily dosage of 10mg/kg produced a significant improvement in the erythema andpruritus associated with canine AD. None of the dogs studied ex-perienced adverse effects from treatment with pentoxifylline. Be-cause pentoxifylline is rapidly eliminated after oral administration,frequent daily dosing or topical administration may be consideredto increase efficacy.

Allergen-Specific ImmunotherapyFor many dogs with AD, eliminating exposure to allergens is not

possible, and response to pharmacotherapy is unsatisfactory. Inthose cases, decreasing the immunologic response to allergen ex-posure may be of benefit. Allergen-specific immunotherapy hasbeen defined as “the practice of administering gradually increas-ing quantities of an allergen extract to an allergic subject to ame-liorate the symptoms associated with subsequent exposure to thecausative allergen.”31 There is little evidence-based experience forthe use of immunotherapy in dogs. However, extrapolation fromhuman experience indicates that this modality could be useful intreating dogs with clinically demonstrable allergen-specific IgE

antibodies, unavoidable allergen contact, and signs that have notresponded to drugs. Dogs that cannot tolerate the side effects ofother drugs and that have owners who can afford the expense ofthe regimen and are competent at administering injections mayalso benefit from allergen-specific immunotherapy.

Antibiotic TherapyMany animals with AD have secondary infections caused by mi-

crobes and/or associated secretory toxins that serve as flare fac-tors, increase the production of IgE, and activate dermal inflam-matory cells. Because of those potential allergen triggers, antibiotictherapy is instrumental in treating any case of AD. Regardless ofwhether the clinical signs of infection are present in a dog withAD, the veterinary clinician should evaluate the results of appro-priate cultures and sensitivities and treat the patient accordingly.In this article, antibiotic therapy is not examined in detail, but af-ter a clinician has determined the nature of an AD-related microbialinfection, systemic and/or topical anti-infective agents are usual-ly used as treatment.

Patient MonitoringBecause frequent adjustments to therapy are required in the treat-

ment of canine AD, follow-up examinations should be scheduledevery 2 to 8 weeks after a new treatment protocol has been initi-ated. Symptoms such as pruritus, self-trauma, pyoderma, and pos-sible adverse reactions to drug therapy should be monitored. Af-ter the dog appears to be asymptomatic and an acceptable levelof control has been achieved, follow-up examinations should beperformed (preferably) every 3 months but less frequently thanevery 12 months. Periodic evaluations of complete blood countresults, a serum chemistry profile, and urinalysis are recom-mended for dogs receiving immunosuppressive therapy such as glu-cocorticoids, cyclosporine, or tacrolimus.

PrognosisVery few cases of AD resolve spontaneously. Treatment is always

indicated; without it, the degree of pruritus worsens, and signsand symptoms are present for periods of increasing durationthroughout the patient’s life. Most treated animals, however, be-come asymptomatic and regain a good quality of life.

SummaryCanine AD is a complex allergic reaction to environmental al-

lergens, and multifaceted drug therapies that treat the symptomsof that disorder are available. However, because many of those drugsare intended for use only in humans, they are designed for oral ad-ministration and subsequent disposition in a gastrointestinal tractthat is longer and less acidic than its canine counterpart. As a re-sult, those medications may be less bioavailable in carnivorous vet-erinary patients. Dogs suffering from AD also benefit from med-ications (possibly compounded ones) that treat conditions secondaryto AD, such as otitis externa or conjunctivitis. The compoundingpharmacist can play a valuable role in providing patient-specificpreparations, client education, and patient monitoring. He or shecan ensure that medication regimens safely achieve the desired effects and do not contain offending allergenic substances.

References

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1. Muse R, Griffin CE, Rosenkrantz WS. The prevalenceof otic manifestations and otitis externa in allergicdogs. In: Proceedings of the Annual Meeting of theAmerican Academy of Veterinary Dermatology andthe American College of Veterinary Dermatology. Vol.12. Las Vegas, NV;1996:33.

2. Carlotti DN, Jacobs DE. Therapy, control and pre-vention of flea allergy dermatitis in dogs and cats.Vet Dermatol 2000;11:83-98.

3. Treffel P, Gabhard B, Juch R. Evaluation of barriercreams: An in vitro technique on human skin. ActaDerm Venereol 1994;74:7-11.

4. Mueller RS, Bettenay SV. Long-term immunothera-py of 146 dogs with atopic dermatitis—A retro-spective study. Aust Vet Pract 1996;26:128-132.

5. Olivry T, Rivierre C, Jackson HA, et al. Cyclosporinedecreases skin lesions and pruritus in dogs with atopicdermatitis: A blinded randomized prednisolone-controlled trial. Vet Dermatol. In press.

6. Olivry T, Guaguère E, Héripret D. Treatment of ca-nine atopic dermatitis with the prostaglandin E1 analog misoprostol: An open study. J DermatolTreatment 1997;8:243-247.

7. Olivry T, Rivierre C, Jackson HA, et al. A placebo-controlled blinded trial of misoprostol monothera-py for canine atopic dermatitis: Effects on dermalcellularity and cutaneous tumor necrosis factor-agene transcription. Vet Dermatol 2000;11(suppl 1):47.

8. Marsella R, Nicklin CF. Double-blinded cross-overstudy on the efficacy of pentoxifylline for canine atopy.Vet Dermatol 2000;11:255-260.

9. Barnes PH. Anti-inflammatory actions of glucocorti-coids: Molecular mechanisms. Clin Sci 1998;94:557-572.

10. Adcock IM, Ito K. Molecular mechanisms of corti-costeroid actions. Monaldi Arch Chest Dis 2000;55:256-266.

11. Thomas RC, Logas D, Radosta L, et al. Effects of a1% hydrocortisone conditioner on haematologicaland biochemical parameters, adrenal function test-ing and cutaneous reactivity to histamine in normaland pruritus dogs. Vet Dermatol 1999;10:109-116.

12. DeBoer DJ, Cooley AJ. Use of induced cutaneous im-mediate type hypersensitivity reactions to evaluateanti-inflammatory effects of triamcinolone topical so-lution in three dogs. Vet Dermatol 2000;11:25-33.

13. DeBoer DF. Efficacy of triamcinolone topical solu-tion for the management of allergic pruritus in dogs.In: Proceedings of the 23rd Annual Meeting of the American Academy of Veterinary Dermatology.Norfolk, VA:American College of Veterinary Der-matology; 2001:16.

14. Kimura T, Doi K. Dorsal skin reactions of hairless dogsto topical treatment with corticosteroids. ToxicolPathol 1999;27:528-535.

15. Gross TL, Walder EJ, Ihrke PJ. Subepidermal bullous dermatosis due to topical corticosteroidtherapy in dogs. Vet Dermatol 1997;8:127-131.

16. Guaguère E, Lasvergeres F, Arfi L. Efficacy or oralmethylprednisolone in the symptomatic treatmentof allergic dermatitis. Prat Med Chir Anim Cie1996;31:171-175.

17. Paradis M, Scott DW, Giroux D. Further investi-gations on the use of nonsteroidal and steroidalantiinflammatory agents in the management ofcanine pruritus. J Am Anim Hosp Assoc 1991;27:44-48.

18. Ihrke PJ, Norton AL, Ling VG, et al. Urinary tract in-fection associated with long-term corticosteroid

administration in dogs with chronic skin diseases.J Am Vet Med Assoc 1985;186:43-46.

19. Paradis M, Lemay S, Scott DW. The efficacy ofclemastine (Tavist), a fatty acid-containing prod-uct (Derm Caps), and the combination of bothproducts in the management of canine pruritus. VetDermatol 1991;2:17-20.

20. Paterson S. Use of antihistamines to control pru-ritus in atopic dogs. J Small Anim Pract 1994;35:412-419.

21. Miller WH, Scott DW, Wellington JR. A clinical tri-al on the efficacy of clemastine in the managementof allergic pruritus in dogs. Can Vet J 1993;34:25-27.

22. Paradis M, Scott DW, Giroux D. Further investiga-tions on the use of nonsteroidal and steroidal anti-inflammatory agents in the management of caninepruritus. J Am Anim Hosp Assoc 1991;27:44-48.

23. Keogh A, Spratt P, McCosker C, et al. Ketoconazoleto reduce the need for cyclosporine after cardiactransplantation. N Engl J Med 1995;333: 628-633.

24. Vaden SL. Cyclosporine and tacrolimus. SeminVet Med Surg (Small Anim) 1997;12:161-166.

25. Scott DW, Miller WH Jr, Cayatte SM, et al. Failureof terfenadine as an antipruritic agent in atopicdogs: Results of a double-blinded, placebo-con-trolled study. Can Vet J 1994;35:286-288.

26. Paradis M. Nonsteroidal antipruritic drugs in dogsand cats: An update. Bull Can Acad Vet Dermatol1996;12:3-7.

27. Garcia G, DeMora F, Ferre L, et al. Effect of H1 anti-histamines on histamine release from dispersedcanine cutaneous mast cells. Am J Vet Res 1997;58:293-297.

28. Otto CM, Greentree WF. Terfenadine toxicosis in dogs.J Am Vet Med Assoc 1994;205:1004-1006.

29. Ryffel B, Donatsch P, Madörin M, et al. Toxicologi-cal evaluations of cyclosporin A. Arch Toxicol1983;53:107-141.

30. Marsella R, Nicklin CF. Randomized double blind, pla-cebo-controlled, cross over pilot study to evaluatethe use of 0.3% tacrolimus lotion for atopic dermatitisin dogs. In: Proceedings of the Annual Meeting ofthe American Academy of Veterinary Dermatology.Norfolk, VA:American College of Veterinary Der-matology; 2001:43.

31. Bousquet J, Lockey R, Malling HJ. Allergen im-munotherapy: Therapeutic vaccines for allergic dis-eases. A WHO Position paper. J Allergy Clin Immunol1998;102:558-562.

Address correspondence to: Gigi Davidson,BS, RPh, DICVP, North Carolina StateUniversity, College of Veterinary Medicine,Raleigh, NC 27606. E-mail: [email protected]. ■

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http://www.gallipot.com

Pharmacists have been extemporaneous-ly compounding medications to meet pa-tient needs for centuries. After the indus-trial revolution, many compoundingfunctions that had been performed by phar-macists were undertaken by pharmaceuti-cal manufacturers, and the pharmacist’srole gradually became primarily that ofdispensing commercial mass-producedmedications to patients. During the 1970sand 1980s, some pharmacists comple-mented dispensing with patient counseling.1

The demand for extemporaneously pre-pared medications in oral or parenteraldosage forms has increased significantly.Historically, pharmacy as a profession hasapplied the principles of secundum artemto ensure that only high-quality prepara-tions were compounded. However, thoseprinciples have not adequately provided themost robust evidence-based decision-mak-ing tools in the past.

The delivery of pharmaceutical care re-quires specialized knowledge about manypatient-related and medication-relatedconsiderations such as pharmacology, vas-cular access devices and their placement,compounding considerations (osmolarity,pH, stability, particulate matter), deliverysystems, and patient management.2 This ar-ticle addresses patient morbidity and mor-tality associated with the effect of osmo-

larity and pH on compounded liquids forparenteral administration. Strategies thatminimize the effects of osmolarity and pHare also presented.

Vascular damage (phlebitis) caused byinfusates of incorrect pH and osmolarityoccurs frequently. The development ofphlebitis, which increases the patient’s riskof local catheter-related infection, can becaused by mechanical trauma from catheterinsertion, catheter material, catheter dwelltime or duration of use, particulate matter,and chemically mediated factors.3

pH and OSMOLARITYpH

The pH scale is a measurement of the con-centration of hydrogen ions (H+) in a so-lution. The scale ranges from 0 to 14; 0 isthe most acidic, 7 is neutral, and 14 is themost alkaline (ie, basic). It is a logarithmicscale based on the power of 10; a changeof 1 pH unit equals a 10-fold change in theconcentration of hydrogen ions. The pHof human blood is about 7.35. Any changesin pH (even those that seem insignificant),effect great changes in the hydrogen ion concentration. In Table 1,4 examples of common household and medicationacids and bases and their relative pH and

hydrogen ion concentrations are listed.Which pH values damage cells? The

degree of cellular damage from eitherlow or high pH is determined by the typeof tissue exposed to the pH and the du-ration of exposure. Phenytoin sodium(Dilantin) applied topically does not pro-duce the same cellular toxicity as it doeswhen administered parenterally. In vitroexperiments have demonstrated that so-lution pH values of 2.3 and 11 kill venousendothelium cells on contact. The near-er the pH value is to 7.4, the less the dam-age that occurs. Limited research data,however, pertain to the effects of less ex-treme pH conditions.

Titratable AcidityAlthough pH is a measure of hydrogen ion

content, titratable acidity is a measure of thereservoir of hydrogen ions within a solution.Phlebitis is more likely to be caused by a solution with a high titratable acidity and alower pH. Venous endothelial cells at sitesdistal to the catheter tip are subject to cel-lular insult because more time is requiredfor the hydrogen ion content in the in-fusate to be neutralized by the blood. Titrat-able acidity has not been well-studied to dateand requires further investigation.

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A REVIEW of pH ANDOSMOLARITY

Table 1. Common Acidic and Basic Medications and Household Products: pH and Hydrogen Ion Concentrations.

H+ pH Household Products Medications5

Acid 10,000,000 0 Hydrochloric acid1,000,000 1 Stomach acid

100,000 2 Lemon juice10,000 3 Vinegar Dopamine HCl

1,000 4 Soda100 5 Rainwater Potassium chloridea

10 6 MilkNeutral 1 7 Pure waterBase 1/10 8 Egg whites Furosemide

1/100 9 Baking soda1/1,000 10 Tums antacid

1/10,000 11 Ammonia Ganciclovir sodium1/100,000 12 Mineral lime - Ca(OH)2 Phenytoin sodium

1/1,000,000 13 Drano1/10,000,000 14 Sodium hydroxide

H+ = Concentration of hydrogen ions compared to that in pure water.a Abbott Laboratories, Abbott Park, Illinois.

Marc Stranz, PharmDInfusion Services Omnicare, IncCovington, Kentucky

Eric S. Kastango, RPh, MBA, FASHPClinical IQ, LLCMadison, New Jersey

OsmolalityOsmosis occurs when, to produce equi-

librium, a substance in solution crosses a membrane from an area of lower concentration to an area of higher con-centration. The concentration of parti-cles dissolved in solution expressed as osmoles of solute per kilogram of solventis referred to as “osmolality.” In human plasma, the concentration of dissolvedparticles is about 290 x 10-3 M; therefore,its osmolarity is 290 mOsm/L (285 - 310mOsm/L). Water, for example, flows froman area of low osmolarity to an area of highosmolarity at a rate directly proportionalto the difference (gradient) in osmolalityuntil equilibrium is reached.

The osmotic pressure of a solution canbe expressed as either osmolality or os-molarity. Osmolality refers to the num-ber of milliosmoles per kilogram of sol-vent. This value can be calculated ordetermined experimentally by osmome-try. Osmolarity, which is the number ofmilliosmoles per liter of solution, is wide-ly used in clinical practice because it ex-presses concentration as a function ofvolume. Osmolarity cannot be measuredexperimentally but must be calculatedfrom osmolality by means of a conversionfactor.

Solutions containing the same concen-tration of particles are iso-osmotic (isotonic).0.9% Sodium chloride solution (normalsaline solution) is iso-osmotic with bloodand the venous endothelium; the solutioncauses no movement of water into or outof endothelial cells. Cellular damage does

not occur when endothelial cells contact aniso-osmotic solution.

Solutions with a lower osmolality (alower concentration of dissolved particles)than 0.9% sodium chloride solution areconsidered hypotonic. 0.45% Sodiumchloride solution and sterile water forinjection are examples of hypotonic so-lutions. Infused fluid is drawn into venousendothelial cells and blood cells, whichhave a relatively high osmolality. Whenthose cells absorb too much water, theyrupture or undergo hemolysis. Hypoton-ic solutions such as 0.45% sodium chlo-ride are used to replenish water deficitsor to reduce the final osmolarity of cer-tain drugs in solution.

Solutions with a higher osmolality (ahigher concentration of dissolved parti-cles) than that of normal saline are con-sidered hypertonic. 5% Dextrose and0.9% sodium chloride injection, any typeof amino acid solution, and 50% dextroseinjection are examples of hypertonic so-lutions. The intravenous administrationof hypertonic solutions draws fluid fromthe endothelium and blood cells, whichcauses the cells to shrink. That vascularinsult renders cells susceptible to furtherdamage. The degree and immediacy of thatdamage are determined by the osmolari-ty of the infused solution. Potassium chlo-ride solution (2 mEq/mL) has an ap-proximate osmolarity of 4000 mOsm/L.

Current recommendations from theUnited States Pharmacopeia for the label-ing of intravenous fluids produced by phar-maceutical manufacturers require that

osmolarity be stated on the product pack-age, but there are no formal requirementsfor the determination of solution osmo-larity.6 Osmolarity labeling requirementsfor pharmacy-prepared intravenous ad-mixtures do not exist. Osmolarity data foradmixtures can be obtained only from theliterature or by calculation from publishedosmolality values. The formula used to de-termine drug-solution osmolarity calcula-tions is not accurate and is best determinedby direct measurement via osmometry.2

INFUSION NURSING SOCIETY RECOMMENDATIONS

To minimize or prevent vascular dam-age from extreme infusate pH or osmo-larity, the Infusion Nursing Society (INS) has published recommendationsbased on a number of factors, includingthe physiologic location of the venousaccess device. In Table 2,7 those recom-mendations are presented.

METHODS of COMPENSATIONBuffering Capacity

As mentioned earlier, the normal rangeof the pH of blood is between 7.35 and 7.45.That range is necessary for the normal func-tioning of critical metabolic processes. ApH not within that range is physiologicallystabilized by three primary mechanisms: theaction of buffer systems, respiratory con-trol, and renal control. Buffer systems useproteins, hemoglobin, and bicarbonate-phosphate mixtures. The carbonic acid-bi-carbonate system of the body is a chemi-cal buffer mechanism that uses a weak acidand conjugate base to maintain the desiredpH range. When acidic or basic drugs areinfused, the carbonic acid-bicarbonate sys-tem releases the appropriate weak acid orconjugate base to maintain a pH near 7.4.As the infusate leaves the catheter tip, thepH is neutralized by the carbonic acid-bi-carbonate system. The time required forneutralization of the pH is a function ofthe strength of the acid or base and its titrat-able acidity. The respiratory and renal pHcontrol systems of the body monitor andcompensate for pH via a series of complexprocesses.

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Table 2. Infusion Nursing Society Recommendations for Minimization or Prevention ofVascular Damage from Extremes in Infusate pH or Osmolarity.

Blood Flow Osmolarity Vessel (mL/min)8 (mOsm/L) Solution pHSuperior vena cava 2000 > 900 < 5 or > 9

Subclavian vein and/or proximal axillary vein 800 500 - 900 < 5 or > 9

Cephalic and basilic veins in the upper arms 40 - 95 < 500 5 - 9

Laminar Flow “Laminar flow” refers to the movement of air or fluid in layers

and without fluctuation or turbulence. Pharmacists are familiarwith the concept of laminar flow because they use specialized equip-ment to create aseptic working environments for the preparationof parenteral products. Laminar flow can be applied to the infu-sion of solutions into the bloodstream.

According to the principle of laminar flow, infusate leaving thecatheter travels in a layer parallel to but separate from the sur-rounding blood flow. Neutralization occurs during the slow dif-fusion of blood at the contact surface between the laminar bloodflow and the laminar flow of the infused solution. As the infusateslows to the rate of blood flow, the infusate and blood mingle dis-tal to the catheter tip. At that point, venous endothelial cells areexposed to the irritating solution, especially in smaller veins inwhich the amount of blood flow cannot further minimize the lo-cal effects of the infusate.

Animal studies9 have shown evidence of venous lumen damagedistal to the catheter tip. That finding is supported by studies in-dicating that increasing the infusion rate of irritating solutionsreduces the potential for the development of phlebitis;cephalosporins and other antibiotics are irritating to peripheralveins but can be administered in an intravenous “push” withoutproducing an increased incidence of phlebitis.10-12 Attempts have

been made to use the ratio of the infusion rate to the blood flowrate to estimate the risk of phlebitis caused by irritating intrave-nously administered solutions. Because the blood and the infusateflow in a laminar manner, the neutralization process and achiev-ing osmotic equilibrium may take longer than expected. If thatmethod of determining the risk of phlebitis is used, the locationof the catheter tip and blood flow in the infused area must be known.

CHEMICAL PHLEBITIS In VIVOAnimal Models

To date, the effects of pH and osmolarity have been studied mosteffectively in animal models. According to Kuwahara et al,13 theeffects of infusions of solutions at various pH values and infusiontimes were studied. When the effects of 6-hour infusions throughperipheral vessels were compared, a solution with a pH of 4.5 re-sulted in a 100% incidence of severe phlebitic changes, a pH of5.9 caused mild-to-moderate phlebitic changes in 50% of the an-imal subjects, a pH of 6.3 caused mild damage in 20% of thosesubjects, and a pH of 6.5 caused no significant damage. When thepH value was 6.5, extending the duration of the infusion did notproduce phlebitis.

Other trials14,15 have indicated that a solution with a pH of 3 to11 did not induce phlebitic changes when drugs were adminis-tered over a few minutes. When the same acidic solution volumewas infused over 5 hours, 1 hour, or 30 minutes, fewer inflam-mation-related changes were noted after the more rapid infusions.No trials have studied the effect of slowing the infusion of high-ly acidic or basic infusates to increase dilution.

Both pH and titratable acidity must be considered when the ad-ministration of peripheral parenteral nutrition is required.16 An-imal studies16,17 indicate that the higher the titratable acidity ofan infusate, the greater the proximal and distal phlebitic changes.When the principles of laminar flow were applied, tolerance toosmolarity in peripheral veins was demonstrated in animal mod-els. When other factors were controlled, those studies indicatedthat the peripheral tolerance was directly related to the osmolarityand duration of the infusion. The faster the infusion of hyper-tonic infusates, the greater the vein tolerance, which was 820mOsm/kg for 8-hour infusions, 690 mOsm/kg for 12-hour infu-sions, and 550 mOsm/kg for 24-hour infusions.

Human ModelsHuman tolerance of pH and osmolarity has not been as well re-

searched (or understood) as it has been in animal models; how-ever, human tolerance to pH and osmolarity is similar to that ofanimals. There is a direct relationship between the pH and os-molarity of an infusate and the development of phlebitis. The in-cidence of phlebitis increases as infusate pH and osmolarity in-crease, and it decreases according to the baseline pH andosmolarity of blood. The exact point at which osmolarity and pHbecome significant risk factors in humans is not known.

The outcomes of human studies of osmolarity-induced phlebitishave been inconsistent. Gazitua et al18 classified three risk levelsof phlebitis caused by infusate osmolarity. The lowest risk of phlebitisoccurred when a solution osmolarity lower than 450 mOsm/L wasused, a moderate risk occurred at 450 to 600 mOsm/L, and thehighest risk occurred when the solution osmolarity exceeded 600

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http://www.cleanzones.com

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mOsm/L. That study provided evidence-based science used by the INS to define anosmolarity of 500 mOsm/L as the outer lim-it of peripheral vein tolerance. The abil-ity to tolerate different levels of infusatepH and osmolarity varies significantlyamong patients.

Few human trials have been conductedto measure the effect of pH on peripheralveins. Some studies18-21 indicate that neu-tralizing the pH of the infusate to 7 to 7.4significantly reduces the incidence ofphlebitis. To date, no trial of human patientshas identified a pH range that correspondsto the potential for the development ofphlebitis. The physiochemical propertiesof medication indicate that very few druginfusions are stable at pH 7. The accept-ed pH range of 5 to 9 for solutions infusedperipherally represents clinically significantvariances from the ideal pH of 7.4. How-ever, factors such as blood flow, infusion rate,venous access device, catheter tip location,and variations in patient tolerance to thepH of the infusate influence the occurrenceof pH-induced phlebitis in spite of thechallenges posed by the pH value of finaldrug admixtures.

Exceptions to the RulesSome exceptions to the rules of pH and

osmolarity cannot be easily explained. Cer-tain isotonic, pH-neutral infusates (eg, am-photericin B, cladribine, erythromycin,foscarnet, imipenem, meropenem, pamid-ronate, nafcillin, oxacillin, chemothera-peutic drugs) cause phlebitis, perhaps be-cause they can produce a direct cellular insultto the endothelial cells.

Secundum ArtemDuring manufacturing, the pH of many

medications is adjusted with either hy-drochloric acid and/or sodium hydroxideto ensure drug stability and a long shelf life.The solubility of weakly acidic or basic med-ications is a direct function of solutionpH, which controls both the portion of med-ication that is in an ionized form (eg, thatis metabolically active) and the solubilityof the nonionized form of the medication.6

Sodium salts (phenobarbital, phenytoin,methotrexate) are considered weak acidsand must be formulated at a high pH toensure solubility. If, during the prepara-tion of a solution, the pH is lowered, the

aqueous solubility of the medication maybe exceeded and the potential for pre-cipitation exists. Medications that areconsidered weak bases are similarly af-fected; their formulation must result in alow pH to ensure solubility.

The effect of pH on solubility is best il-lustrated in parenteral nutrition solutionsin which calcium salts (calcium gluconateor calcium chloride) interact with phos-phates. The lower the pH of the final so-lution, the more stable the formulation,because the calcium and phosphate ionsremain ionized. As the pH increases, theions become less ionized, and precipita-tion can occur. Ready-to-use formula-tions of medications are not always iso-osmotic or of neutral pH. Stability is theprinciple concern with those formula-tions. Premade frozen medications (eg, cer-tain antibiotics) are formulated with ster-ile water or dextrose injection to producebetter solution tonicity.

Diluting medications that are extreme-ly acidic (vancomycin hydrochloride) orextremely alkaline (phenytoin sodium) ingreater volumes of fluid to affect solutionpH is not an effective method of mediat-ing pH-induced effects. A solution that actsas a buffer must affect the titratable acid-ity of a medication by contributing eithercarbonic acid or hydroxide. Neither 5%dextrose injection nor 0.9% sodium chlo-ride injection has an inherent buffering ca-pacity; therefore the pH of the final in-fusate containing those substances isdetermined by the pH of the medicationand not the base solution. Final osmolar-ity can be altered by using other base so-lutions such as lactated Ringer’s solution,5% dextrose injection, dextrose 5% inlactated Ringer’s injection (D5LR), or0.45% sodium chloride injection.

The osmolarity of most parenteral med-ication solutions (antibiotics, antineo-plastics, etc) is usually less than 400

http://www.spectrumrx.com

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mOsm/L. Parenteral nutrition solutions usually have a much high-er final osmolarity because of the number of cations and anionsin solution.

CONCLUSION The osmolarity of drug solutions should not be the primary con-

sideration in the prevention of infusion-related phlebitis. Manyapproaches can be used to ensure that the osmolarity of an infusate(with the exception of parenteral nutrition solutions) remains be-low the recommended INS guideline of 500 mOsm/L.

According to data from anecdotal clinical practice and exten-sive studies of animal and human subjects, pH is the most signif-icant cause of phlebitis. Current INS standards state that an in-fusate pH of 5 to 9 can be tolerated by peripheral veins. Animaland human data also suggest that variance from a pH of 7.4 caus-es damage to venous endothelium tissue. Other unknown mitigatingfactors prevent phlebitis from occurring in a large percentageof patients who receive infusions.

The best method of preventing patient morbidity and mortal-ity caused by infusion therapy is to consider all primary and sec-ondary factors that cause phlebitis, such as the dilution of themedication, the composition of the base infusate solution, therate of infusion, and the type, size, material, and location of the

venous access device and tip. Additional research on the princi-ple of laminar flow must be conducted to identify methods (suchas the intravenous push of antibiotics) of administering highlyacidic or highly alkaline infusates.

References1. RidgeRx Compounding. Available at: http://www.RidgeRx.com/story.ntml.

Accessed January 12, 2002.2. Kastango ES, Hadaway L. New perspectives on vancomycin use in home

care. Part 1. IJPC 2001;6:465-469.3. Pearson ML. Guideline for prevention of intravascular device-related in-

fection. US Department of Health and Human Services, Centers for Dis-ease Control and Prevention, Atlanta, Georgia. Available online:http://www.cdc.gov/ncidod/hip/iv/iv.htm. 1999. Accessed January 12, 2002.

4. Carpi A. Acids and bases: An introduction. Available at: http://www.visionlearning.com/library/science/chemistry-2/CHE2.2-acid_base.htm. 2000.

5. Trissel LA. Handbook of Injectable Drugs. 11th ed. Bethesda, MD:Ameri-can Society of Health-System Pharmacists; 2001.

6. CmcIssues: Consulting services for the pharmaceutical industry Website.Available online: http://www.cmcissues.com/Methods/osmolarity.htm.Accessed on January 10, 2002.

7. Intravenous Nurses Society. Intravenous nursing standards of practice.J Intraven Nurs 2000;23(suppl):S37-S38.

8. Kokotis K. Preventing chemical phlebitis. Nursing 98. Available at: http://www.springnet.com/ce/p118a.htm. Accessed May 28, 2001.

9. Kuwahara T, Asanami S, Tamura T, et al. Effects of pH and osmolarity onphlebitic potential of infusion solutions for peripheral nutrition. J ToxicolSci 1998;23:77-85.

10. Poole SM, Nowobilski-Vasilios A, Free F. Intravenous push medicationsin the home. J Intraven Nurs 1999;22:209-215.

11. Nowobilski-Vasilios A, Poole SM. Development and preliminary outcomesof a program for administering antimicrobials by IV push in home care.Am J Health Syst Pharm 1999;56:76.

12. Vickery TR, Hatheway JG, Edgar SP, et al. Concentrated vancomycin andadministration via central venous catheters in the alternate-care setting.Poster presented at: ASHP Midyear Clinical Meeting; 1990; Las Vegas, NV.

13. Kuwahara T, Asanami S, Kawauchi Y, et al. Experimental infusion phlebitis:Tolerance pH of peripheral veins. J Toxicol Sci 1999;24:113-121.

14. Simamora P, Pinsuwan S, Alvarez JM, et al. Effect of pH on injection phlebitis.J Pharm Sci 1995;84:520-522.

15. Hessov I, Bojsen-Mooller M. Experimental infusion thrombophlebitis. Im-portance of the infusion rate. Eur J Intensive Care Med 1976;2:103-105.

16. Kuwahara T, Asanamia T, Kubo S. Experimental infusion phlebitis: Impor-tance of titratable acidity on phlebitic potential of infusion solution. ClinNutr 1996;15:129-132.

17. Kuwahara T, Asanamia T, Kubo S. Experimental infusion phlebitis: Toler-ance osmolarity of peripheral venous endothelial cells. Nutrition 1998; 14:496-501.

18. Gazitua R, Wilson K, Bistrian BR, et al. Factors determining peripheral veintolerance to amino acid infusions. Arch Surg 1979;114:897-900.

19. Fonkalsrud E, Pederson BM, Murphy J, et al. Reduction of infusion throm-bophlebitis with buffered glucose solutions. Surgery 1968;63:280-284.

20. Eremin O, Marshall V. Complications of intravenous therapy: Reduction bybuffering of intravenous fluid preparation. Med J Aust 1977;2:528-531.

21. Fujita M, Hatori N, Shimizu M, et al. Neutralization of prostaglandin E1 in-travenous solution reduces infusion phlebitis. Angiology 2000;51:719-723.

Address correspondence to: Marc Stranz, PharmD, 100 E. River Center Boulevard, Suite 1700, Covington, KY 41011. E-mail: [email protected].■

http://www.isotechdesign.com

S U P P O R T


IntroductionThe sorbitan esters, which are commonly used in pharmaceu-

ticals, cosmetics, and food products, are usually regarded as non-toxic, nonirritating materials. They are also called “sorbitan fat-ty acid esters” and occur as monoesters and diesters. The sorbitanmonoesters include a group of mixtures of partial esters of sorbitoland its monohydrides and dianhydrides with fatty acids. The sor-bitan diesters include a group of mixtures of partial esters of sor-bitol and its monoanhydride with fatty acids.

The sorbitan esters are widely used as lipophilic, nonionic, sur-factant emulsifying agents for preparing water-in-oil preparationssuch as emulsions, creams, and ointments for topical use. Theycan be used alone to produce stable water-in-oil emulsions andmicroemulsions, as well as in combination with varying propor-tions of a polysorbate to produce either water-in-oil or oil-in-wa-ter emulsions or creams.1 Sorbitan esters are used for the followingpurposes in the concentrations listed: as emulsifying agents (con-centration range, 1% to 15% when used alone or 1% to 10% whenused in combination with hydrophilic emulsifiers), in ointmentsto increase water retention (1% to 10%), as a solubilizing agentfor poorly soluble ingredients in a lipophilic base (1% to 10%),and as a wetting agent for insoluble, active ingredients in alipophilic base (0.1% to 3%). Three of the sorbitan esters (sor-bitan monolaurate, sorbitan monopalmitate, and sorbitan tri-

oleate) have been used to prepare an emulsion for intramuscularadministration at a concentration of 0.01% to 0.05%. The Foodand Drug Administration (FDA) Inactive Ingredients Guide1 in-cludes the sorbitan esters used in inhalations, intramuscular in-jections, and ophthalmic, oral, topical, or vaginal preparations.

Usually, sorbitan esters occur as a cream to amber-colored liq-uid or solid that has a distinctive odor and taste. There are manysorbitan esters, but only six (sorbitan monolaurate, sorbitanmonooleate, sorbitan monopalmitate, sorbitan monostearate, sor-bitan sesquioleate, and sorbitan trioleate) are official; they are list-ed in the United States Pharmacopeia XXV/National Formulary 20(USP XXV/NF 20).2

Brand names of the sorbitan esters include Arlacel or Span (themost common), Ablunol, Alkamuls, Armotan, Capmul, Crill,Drewmulse, Drewsorb, Durtan, Famodan, Glycomul, Hodag,Lamesorb, Liposorb, Montane, Nikkol, Nissan Nonion, NorfoxSorbo, Polycon, Protachem, Prote-sorb, S-Maz, Sorbester, or Sor-birol. The numerical designations accompanying the chemical namesof the sorbitan esters are listed in Table 1.

Preparation of Sorbitan EstersThe sorbitan esters are prepared by dehydrating sorbitol to form

a hexitan (1,4-sorbitan). This hexitan is then esterified with theappropriate fatty acid. The sesquiesters are equimolar mixturesof the monoesters and the diesters. The presence of the long-chainfatty acids yields a lipophilic molecule. The sorbitan esters (Spans,

Featured Excipient: THE

SORBITANESTERS

Continuing EducationGoal: To provide compounding pharmacists with supportive

information on the selection and use of the sorbitan estersas wetting and emulsifying agents.

Objectives: After reading and studying the article, the reader willbe able to:

1. Discuss the different sorbitan esters, their preparation, andtheir nomenclature

2. Select an appropriate sorbitan ester according to the activeand other ingredient(s) and the dosage form desired

3. Use a selected sorbitan ester and the dosage form being prepared to determine the appropriate method of com-pounding and the order of mixing and processing

4. Discuss the properties of the various sorbitan esters and theirstorage requirements

Table 1. Nomenclature, Number Designation, and Approximate Molecular Weight of the Sorbitan Esters.

Common Name Chemical Name No Formula MW

Sorbitan monolaurate Sorbitan monododecanoate 20 C18H34O6 346

Sorbitan monooleate (Z)-Sorbitan mono-9-octadecenoate 80 C24H44O6 429

Sorbitan monopalmitate Sorbitan monohexadecanoate 40 C22H42O6 403

Sorbitan monostearate Sorbitan mono-octadecanoate 60 C24H46O6 431

Sorbitan sesquioleate (Z)-Sorbitan sesqui-9-octadecenoate 83 C33H60O6.5 561

Sorbitan trioleate (Z,Z,Z)-Sorbitan tri-9-octadecenoate 85 C60H108O8 958

MW = Molecular weight.

Loyd V. Allen, Jr, PhD, RPh

S U P P O R T


Arlacels, etc) are oil dispersible or oil soluble and have a hydrophile-lipophile (HLB) balance of less than 8.6.

HLB Values The HLB of surface-active agents depends on the chemical make-

up of the specific agent. Each molecule of a surface-active agenthas both a hydrophilic portion and a lipophilic portion, one ofwhich is predominant. If the hydrophilic portion of the mole-cule is predominant, the ratio of the hydrophilic to the lipophilicportion is high (as is the HLB), the resultant preparation has anaqueous external phase, and an oil-in-water dispersion or emul-sion results. If the lipophilic portion is predominant (as it is inthe sorbitan esters), the ratio of the hydrophilic to the lipophilicportion is low (as is the HLB), the resultant preparation has anoily external phase, and a water-in-oil dispersion or emulsion isproduced.

Common and Chemical NamesIn Table 1, sorbitan esters are listed by common and chemi-

cal names and approximate molecular weight. In Table 2, in-formation on the physicochemical properties (HLB values, spe-cific gravity, viscosity, and solubility in different liquids) ofthose esters is featured. The flash point for the sorbitan estersis greater than 149°C. In this article, only the six official sorbi-tan esters included in the USP XXV/NF 20 are described.

Sorbitan monolaurate (Arlacel 20, Span 20) occurs as a yellowto amber-colored oily liquid that has a bland, characteristic odor.It is insoluble in water but is soluble in mineral oil. It is slight-ly soluble in cottonseed oil and in ethyl acetate and has a pourtemperature of 16°C to 20°C. Sorbitan monolaurate should bepackaged in a tight container.1-2

Sorbitan monooleate (Arlacel 80, Span 80) occurs as a viscousyellow to amber-colored oily liquid that has a bland, charac-teristic odor. It is insoluble in water and in propylene glycol butis miscible with mineral and vegetable oils. It has a pour tem-perature of -12°C and should be packaged in a tight contain-er.1-2

Sorbitan monopalmitate (Arlacel 40, Span 40) occurs as acream-colored waxy solid that has a faint fatty odor. It is in-soluble in water but is soluble in warm absolute alcohol. In warm

Table 2. Physicochemical Characteristics of the Sorbitan Esters.

Viscosity SolubilityName HLB SpG (mPa) Water Alcohol, USP Vegetable Oil Mineral Oil

Sorbitan monolaurate 8.6 1.01 3900 - 4900 I — SS S

Sorbitan monooleate 4.3 1.01 970 - 1080 I — M M

Sorbitan monopalmitate 6.7 1.00 Solid I Sa Sb S

Sorbitan monostearate 4.7 — Solid I, D — — S

Sorbitan sesquioleate 3.7 1.00 1500 I S Sc S

Sorbitan trioleate 1.8 0.95 200 - 250 I S Sc S

HLB = Hydrophile-lipophile balance.SpG = Specific gravity.MPa = Megapascal.

I = Insoluble. D = Dispersible in warm water.M = Miscible

S = Soluble (awarm absolute alcohol, bsolublewith haze, ccheck for specific oils).

SS = Slightly soluble.

A comprehensive collection of over 350 formulas featured inthe International Journal of Pharmaceutical Compounding(IJPC), is now available in an electronic format.

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ofPHARMACEUTICAL

COMPOUNDING


mineral oil and peanut oil, it is soluble but exhibits a haze. Itmelts at 43°C to 48°C. Sorbitan monopalmitate should be pack-aged in a well-closed container.1-2

Sorbitan monostearate (Arlacel 60, Span 60) occurs as a cream-colored to tan, hard, waxy solid that has a bland odor and taste.It is insoluble in water and in acetone but is dispersible in warmwater. It is soluble above 50°C in mineral oil but exhibits a haze.Sorbitan monostearate melts at 53°C to 57°C and should be pack-aged in a well-closed container.1-2

Sorbitan sesquioleate (Arlacel 83) occurs as a viscous yellowto amber-colored oily liquid. It is insoluble in water and in propy-lene glycol but is soluble in each of the following: alcohol, iso-propyl alcohol, cottonseed oil, and mineral oil. It should be pack-aged in a tight container.1-2

Sorbitan trioleate (Arlacel 85, Span 85) occurs as a yellow to amber-colored oily liquid. It is insoluble in water and in propylene glycolbut is soluble in each of the following: alcohol, isopropyl alcohol,corn oil, cottonseed oil, and mineral oil. Sorbitan trioleateshould be packaged in a tight container.1-2

Sorbitan Esters in FormulationsIn Table 3, the uses for and concentrations of the sorbitan es-

ters are listed. The HLB value of each of the sorbitan esters andthe required HLB value of each ingredient in a formulation canbe used to select one or a combination of sorbitan esters a for-mulation. A combination of emulsifiers (rather than a singleagent) can be used to produce a more stable emulsion. For ex-ample, the molecular association of polysorbate 40 (Tween 40) andsorbitan monooleate (Span 80) in the stabilization of emulsionshas been discussed.3 The hydrocarbon portion of the sorbitanmonooleate molecule is in the oil globule, and the sorbitan rad-ical is in the aqueous phase. Because the sorbitan “heads” of thesorbitan monooleate molecules are bulky, the hydrocarbon “tails”of the molecules are prevented from closely associating in the oilphase. Added polysorbate 40 orients at the interface so that partof the hydrocarbon tail of the sorbitan monooleate molecule isin the oil phase and the remainder of the chain (with the sorbi-tan ring and the polyoxyethylene chains) is in the water phase.The hydrocarbon chains of the polysorbate 40 molecule arearranged in the oil so that the sorbitan monooleate 80 chains are

between them, and an effective attraction caused by van derWaals forces results. This strengthens the interfacial film and thestability of an oil-in-water emulsion against particle coalescence.

In the formulation of stable emulsions, the type of emulsion formedis a function of the HLB value of the combination of sorbitan es-ters used. Experimentation is often required to determine the com-bination of ingredients that produces the most stable emulsion.Sorbitan esters are stable and relatively easy to use in the formulationof stable preparations; they are stable in the presence of strongacids and bases, although a mixture of sorbitan esters with thosematerials results in gradual saponification.1

References1. Lawrence MJ. Sorbitan esters (sorbitan fatty acid esters). In: Kibbe AH,

ed. Handbook of Pharmaceutical Excipients. 3rd ed. Washington, DC:Amer-ican Pharmaceutical Association; 2000:511-514.

2. US Pharmacopeial Convention, Inc. United States Pharmacopeia XXV/Na-tional Formulary 20. Rockville, MD:US Pharmacopeial Convention, Inc;2002:2397, 2622-2624.

3. Martin A. Physical Pharmacy. 4th ed. Philadelphia PA:Lea & Febiger;1993:488-490. ■

S U P P O R T


Table 3. Approximate Percentages of the SorbitanEsters According to Use.

Application Percent

Wetting agent 0.1 - 3

Solubilizing agent 1 - 10

Emulsifying agent (water-in-oil; alone) 1 - 15

Emulsifying agent (water-in-oil; in combination) 1 - 10

Increase water-holding capacity of ointments 1 - 10

S U P P O R T


Pharmacy compounding requires the development and main-tenance of standard operating procedures (SOPs) to ensure qual-ity and minimize the number of errors that occur. A commitmentto maintaining quality must be a priority of top management, andit must also involve all individuals in the organization. The pur-pose of the quality system is to ensure adequate controls through-out the compounding and dispensing processes. The heart of anyquality system involves the use of SOPs, which are written ap-proved documentation that is followed in the day-to-day opera-tion of the pharmacy. A good document system supports but doesnot guarantee a good-quality system.

Documents are written to link people with their operational re-sponsibilities. Failure and error often occur when:■ Individuals do not know their responsibilities.

■ Individuals have not been properly trained.■ Individuals have not been provided the resources necessary to

perform their work.■ Individuals do not take their responsibilities seriously.

SOPs are step-by-step instructions (which must be approved byqualified individuals), for the reliable, consistent performance ofroutine tasks involved in formulation development, purchasing,compounding, testing, maintenance, the handling of materials, qual-ity assurance, and dispensing. SOPs should exist for all compounding,quality control, packaging, and labeling functions. Master formularecords should also be written to provide adequate instruction inand the documentation of compounding procedures, as well as forthe safe operation, cleaning, maintenance, and care of the facili-ty and equipment.

SOPs usually consist of the following topics: title or number,purpose or scope, responsibility, equipment/materials, process orprocedures, information about the company, and the signaturesof authors or those designated pertinent responsibilities withinthe respective department. SOPs should include detailed task per-formance, the name of the operator assigned to the task, and thereason(s) for which the task must be performed. SOPs should bewritten either by or with the assistance of the individual(s) whoperform that task and should be reviewed (at least annually) bythose involved with the performance of the task. ■

Standard Operating Procedure:

Developing StandardOperating ProceduresLoyd V. Allen, Jr, PhD, RPh

Call 888-588-4572 to order your copy.

SOPS30 Standard Operating Procedures preparedand compiled by the International Journal ofPharmaceutical Compounding now at yourfingertips in a convenient CD-ROM.

■ Open the PDF file on your computer and printcopies for your records. Some pages haveinteractive form fields that can be filled-inand printed. Includes Adobe Acrobat Reader©for Windows 95, 98, 2000 or NT.

■ Organized in the following categories: Facility;Equipment; Personnel; Process, General; Process,Aseptic; Product and Other.

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for CompoundingPharmacy

Now includes all 2001 SOPs Includes the following SOPs:• Monitoring Air Temperature and Humidity• Calibration of Hot Plates• Cleaning Glassware• Cleaning, Inspecting and Flow-Accuracy

Testing of Ambulatory Pumps• Electronic Balance Maintenance/Calibration• Performing Class A Prescription Torsion Balance Performance Tests• Pipette Calibration• Use, Standardization and Care of a pH Meter• Assignment of a Beyond-Use Date for Compounded Preparations• Assignment of Beyond-Use Dates• Basic Compounding Documentation: The Batch Control Sheet• Basic Compounding Documentation: The Master Formula Form• General Aseptic Procedures Carried Out at a Laminar Airflow Workbench• Maintenance of a Horizontal Laminar Airflow Hood• Operation of a Dry-Heat Sterilizing Oven and Validation of this Procedure• Particulate Testing for Sterile Products• Performing Physical Quality Assessment for Suppositories, Troches,

Lollipops and Sticks• Performing Physical Quality Assessment of Ointments/Creams/Gels• Quality Assessment for Injectable Solutions• Quality Assessment of Oral and Topical Liquids• Quality Assessment of Parenteral Nutrition Products• Quality Assessment of Special Hard-Gelatin Capsules• Quality Assessment of Powder-Filled, Hard-Gelatin Capsules• Environmental Compounding

New 2001 SOPs• Purchasing Chemicals for Pharmaceutical Compounding• Certificates of Analysis of Materials Used for Pharmaceutical Compounding• Establishing and Maintaining a Compounding Pharmacy Reference Library• Maintenance of the Cleanroom• Developing a Capsule Formulation• Training Personnel

If you have already purchased the SOP CD and would like a Free Downloadof the 2001 update, send an email with your name, address and phonenumber to: [email protected].

S U P P O R T


STANDARD OPERATING PROCEDURE

Title Number

Purpose/scope

Responsibility

Equipment/materials

Procedure

1.

2.

3.

4.

5.

6.

7.

8.

9.

10.

11.

12.

13.

14.

15.

Company name

Date written Written by

Date approved Approved by

Date approved Approved by


P E E R R E V I E W E D

IntroductionThe AutoDose Infusion System (Tan-

dem Medical, Inc, San Diego, California)is a new, simplified infusion system for theadministration of antibiotics that is suitablefor patient or caregiver operation and foruse by healthcare providers. In the Auto-Dose system, specially designed multi-chamber drug solution reservoirs (AutoDosebags) composed of ethylene vinyl acetate

(EVA) are used. In a simple automatedprocess, the system provides an infusion lineflush, antibiotic administration, a secondinfusion line flush, and the reinstillation ofheparin sodium lock solution. Althoughstudies1 of the physical and chemical sta-bility of many antibiotics in glass andpolyvinyl chloride (PVC) containers havebeen reported, no published information

is available on the stability of ampicillinsodium, nafcillin sodium, or oxacillin sodi-um in EVA containers. Consequently,studies must be conducted to determine thephysical and chemical stability of the an-tibiotic solutions of those drugs in Auto-Dose Infusion System bags before theyare used in the clinical setting.

The purpose of this study was to evalu-ate the physical and chemical stability ofthree common penicillin antibiotic solutionsthat were packaged in AutoDose InfusionSystem bags and were stored and evaluat-ed at appropriate intervals for up to 7 daysat 23°C and up to 30 days at 4°C.

Materials and MethodsMaterials

Empty AutoDose Infusion System bagsthat had been sterilized by gamma irradi-ation (Tandem Medical, Inc, San Diego, Cal-ifornia) were supplied by the manufactur-er. The following materials were obtainedcommercially: ampicillin sodium injection(Lot # 0D19993, Apothecon, Princeton,New Jersey) and its reference standard(Lot J, United States Pharmacopeia,Rockville, Maryland), nafcillin sodium in-jection (Lot # 0B18804, Apothecon), andits reference standard (Lot H, UnitedStates Pharmacopeia), and oxacillin sodi-um injection (Lot # 08540, Apothecon)and its reference standard (Lot I, UnitedStates Pharmacopeia). The reference stan-dards were used without further purifica-tion. The mobile phase components wereall of a grade suitable for HPLC analysis.The water used was also HPLC grade andwas prepared immediately before use.MethodsPreparation and Sampling of Solutions. Eachof the penicillin antibiotics was reconsti-

AbstractThe objective of this study was to evaluate the physical and chemical stability of

ampicillin sodium 1 g/100 mL, nafcillin sodium 1 g/100 mL, and oxacillin sodium1 g/100 mL, each of which was admixed in 0.9% sodium chloride injection and pack-aged in an AutoDose Infusion System bag.

Triplicate test samples were prepared by reconstituting the penicillin antibioticsand bringing the required amount of each drug to a final volume of 100 mL with0.9% sodium chloride injection. The test solutions were packaged in AutoDose bags,which are ethylene vinyl acetate plastic containers designed for use in the AutoDoseInfusion System. Samples were stored protected from light and were evaluated atappropriate intervals for up to 7 days at 23°C and up to 30 days at 4°C.

Physical stability was assessed by means of a multistep evaluation procedure thatincluded both turbidimetric and particulate measurement as well as visual inspec-tion. Chemical stability was assessed with stability-indicating high-performance liq-uid chromatographic (HPLC) analytical techniques based on the determination ofdrug concentrations initially and at appropriate intervals over the study periods.

All the penicillin admixtures were initially clear when viewed in normal fluores-cent room light. When the admixtures were viewed with a Tyndall beam, a trace hazewas observed with the ampicillin sodium and nafcillin sodium mixtures but not withthe oxacillin sodium mixture. Measured turbidity and particulate content were lowand exhibited little change in the ampicillin sodium and oxacillin sodium samplesthroughout the study. The nafcillin sodium samples stored at room temperature re-mained clear, but a microprecipitate developed in the refrigerated samples between14 and 21 days of storage. All samples were essentially colorless throughout the study.

HPLC analysis indicated some decomposition in the samples. Ampicillin sodium,which was the least stable, exhibited a 10% loss after 24 hours at 23°C. In the sam-ples stored at 4°C, ampicillin losses were 6% and 11% after 3 days and 5 days, re-spectively. Nafcillin sodium exhibited a 10% loss after 5 days at 23°C. Less than 3%loss occurred after 14 days at 4°C, but the microprecipitation that developed resultedin the termination of that portion of the study. Oxacillin sodium was the most sta-ble; it exhibited less than a 10% loss after 7 days at 23°C and less than a 5% loss af-ter 30 days at 4°C.

Ampicillin sodium, nafcillin sodium, and oxacillin sodium exhibited physical andchemical stability consistent with previous studies on these drugs. The AutoDoseInfusion System bags did not adversely affect the physical and chemical stability ofthose three penicillin antibiotics.

Stability of Ampicillin Sodium, Nafcillin Sodium,and Oxacillin Sodium in AutoDose Infusion System Bags

Yanping Zhang, BS

Lawrence A. Trissel, BS, RPh Clinical Pharmaceutics ResearchDivision of PharmacyThe University of TexasM. D. Anderson Cancer CenterHouston, Texas



tuted with 0.9% sodium chloride injec-tion (Lot # C466706, Baxter HealthcareCorporation, Deerfield, Illinois) accordingto the instructions in the product labeling.After dissolution had occurred, the ap-propriate amounts of the reconstituted an-tibiotic solutions were brought to a finalvolume of 100 mL with 0.9% sodium chlo-ride injection. The test solutions werepackaged in AutoDose Infusion Systembags for testing. All manipulations were per-formed in a biological safety cabinet. Thenominal concentration for the antibioticsused in this testing was 1 g/100 mL. Trip-licate test solutions of each antibiotic wereprepared. The test solutions were stored at4°C and 23°C and were protected from light.Aliquots were removed from each bag ini-tially and at appropriate time intervals upto 7 days at 23°C and up to 30 days at 4°C.Sample evaluation was discontinued whenthe drug content decreased to below 90%of the initial concentration or a physical in-stability was observed. Physical Compatibility. The physical stabil-ity of the admixtures was assessed by vi-

sual examination and by measuring turbidity and particle size and content.2-4

Five milliliters of each sample solution wastransferred to 15-mL borosilicate glassculture tubes (Kimble, Division of Owens-Illinois, Toledo, Ohio) with polypropyl-ene screw caps (Kimble). The tubes hadbeen previously triple-washed in high-performance–liquid-chromatographic-grade water and dried. To minimize theeffects of scratches and imperfections inthe glass, a thin layer of silicone oil wasapplied to the tube exteriors. Visual ex-aminations were performed in normal dif-fuse fluorescent room light by means of ahigh-intensity monodirectional light(Tyndall beam; Dolan-Jenner Industries,Woburn, Massachusetts) viewed with theunaided eye.3

The turbidity of each sample was mea-sured by means of a color-correcting tur-bidimeter (Ratio X/R, Hach Company,Loveland, Colorado). Triplicate deter-minations were made on each of the sam-ples. The particle content of the sampleswas quantified with a light obscuration

particle sizer/counter (Model 8003, Hiac-Royco, Division of Pacific ScientificCompany, Silver Spring, Maryland) todetermine particle content in the sizerange of 1.04 to 112 µm (the validated detection limits of the particle sizer/counter). Triplicate determinations weremade on those samples. Physical instabilitywas defined as visible particulate matter,haze, color change, or a change (increaseor decrease) in measured turbidity of 0.5nephelometric turbidity unit (NTU) ormore.2-4

Analysis by High-Performance Liquid Chro-matography (HPLC). Antibiotic concentra-tions were determined by means of sta-bility-indicating HPLC assay methods.The details of the analytical methods de-veloped for use in this study are cited inTable 1. Two high-performance liquidchromatographs (Alliance 2960 and LCModule-1 Plus, Waters Corporation, Mil-ford, Massachusetts) were used for analy-sis of the drugs; each consisted of a mul-tisolvent delivery pump, an autosampler,and a multiple wavelength ultraviolet

Table 1. High-Performance Liquid Chromatographic Analytical Methods Used To Determine the Stability of AmpicillinSodium, Nafcillin Sodium, and Oxacillin Sodium in AutoDose Infusion System Bags.

Ampicillina Nafcillinb Oxacillinc

Mobile phased 90% 0.067 M sodium phosphate, 70% 0.05 M sodium 76% 0.04 M sodiummonobasic (pH 4) acetate (pH 7) acetate (pH 7) 10% acetonitrile 30% acetonitrile 24% acetonitrile

Column Symmetry C18, 5 µm, Kromasil C18 Kromasil C18250 x 4.6 mm id, 5 µm, 250 x 4.6 id, 5 µm, 250 x 4.6 id,Cat # WA7054275 Cat # 00G-3033-E0 Cat # 00G-3033-E0

Flow rate 1.0 mL/min 1.0 mL/min 1.25 mL/minDetection 254 nm, 0.5 AUFS 280 nm, 0.5 AUFS 225 nm, 0.5 AUFSSample dilution 1:50 water 1:100 water 1:100 water Sample injection volume 20 µL 10 µL 10 µLRetention times

Ampicillin 8.6 min — —Nafcillin — 9.4 min —Oxacillin — — 10.8 min

Decomposition products 3.6, 4.7, 5.2, 2.4, 3.2, 3.5, 6.1, Multiple 2.2 - 2.6, 3.7, 6 min 6.4, 8.2 min 4.3, 6.1, 7.3, 9.6 min

a Precision: 100.1 ± 0.2 µg/mL, mean ± SD, n = 10; percent relative standarddeviation, 0.1%; standard curves range, 100 to 300 µg/mL; correlation co-efficient, > 0.9999; intraday and interday coefficients of variation, 0.6%and 1.1%, respectively.

b Precision: 100.2 ± 0.2 µg/mL, mean ± SD, n = 10; percent relative standarddeviation, 0.2%; standard curves range, 50 to 150 µg/mL; correlation co-efficient, > 0.9999; intraday and interday coefficients of variation, 0.5%

and 0.8%, respectively.c Precision: 99.9 ± 0.2 µg/mL, mean ± SD, n = 10; percent relative standard

deviation, 0.2%; standard curves range, 25 to 150 µg/mL; correlation co-efficient, > 0.9999; intraday and interday coefficients of variation, 1.6%and 0.4%, respectively.

d Mobile phases delivered isocratically.



light detector. The systems were controlled and integrated bypersonal computers equipped with chromatography managementsoftware (Millennium 32 Chromatography Manager, Waters Cor-poration). Duplicate HPLC determinations were performed ontriplicate samples of each test admixture solution.

The analytical methods for each of the drugs were demonstratedto be stability indicating by accelerated degradation. The an-tibiotic solutions were mixed with each of the following: 1 Nsodium hydroxide, 1 N hydrochloric acid, and 3% hydrogen per-oxide and were also subjected to heating. Loss of the intact drugswas observed, and there was no interference by the degradationproduct peaks or other drug peaks with the peak of the intactsubject drug.

The initial concentrations of ampicillin sodium, nafcillin sodi-um, and oxacillin sodium were defined as 100%, and subsequentsample concentrations were expressed as a percentage of initialconcentration. The stability of the drug was defined as not lessthan 90% of the initial drug concentration remaining in the ad-mixtures.

Results and DiscussionAll of the admixtures were initially clear when viewed in nor-

mal fluorescent room light. Ampicillin sodium and nafcillin sodi-um exhibited a trace haze when viewed with a Tyndall beam;oxacillin sodium exhibited no visually apparent haze. The ad-mixtures had measured turbidities of less than 0.5 NTU.Changes in measured haze were found to be negligible in theampicillin sodium and oxacillin sodium samples during thestudy. The nafcillin sodium samples exhibited slight increases

in measured haze of 0.4 NTU or less. The samples were essentiallycolorless throughout the study.

Measured particulates of 10 µm or larger were found to be fewin number in all ampicillin sodium and oxacillin sodium sam-ples and remained so throughout the observation periods for eachdrug at both storage temperatures. The nafcillin sodium sam-ples were initially clear, and the room temperature samples re-mained clear throughout the observation period. However, therefrigerated samples were clear during 14 days of storage, but amicroparticulate precipitation developed after 21 days. The re-frigerated nafcillin sodium samples were determined to be phys-ically unstable at that time point because of that precipitation,and the study was terminated.

The results of the HPLC analysis for each of the test drugs areshown in Table 2. Ampicillin sodium was the least stable of thethree penicillins tested. The stability of that drug was adequatefor only 24 hours at a room temperature of 23°C and for 3 daysunder refrigeration at 4°C. An unacceptable drug loss occurredafter those time points.

The nafcillin sodium samples were more stable. Nafcillinsodium remained stable for 5 days with an approximate 10% lossof drug in 5 days at 23°C. However, a drug loss of about 15%was found after 7 days of storage at room temperature. Whenthe samples were stored under refrigeration, less than a 3% lossof drug had occurred after 14 days. The analysis of the sampleswas terminated after that time point because of the micropar-ticulate precipitation (Table 2).

Oxacillin sodium exhibited the greatest stability of the three penicillins evaluated in this study. At a room temperature of

Table 2. Stability of Ampicillin Sodium 1g/100 mL, Nafcillin Sodium 1 g/100 mL, and Oxacillin Sodium 1 g/100 mL in 0.9% Sodium Chloride Injection in AutoDose Infusion System Bags at 4˚C and 23˚C.

Percentage of Initial Concentration Remaininga

Time Ampicillin Sodiumb Nafcillin Sodiumc Oxacillin Sodiumd

(days) 23°C 4°C 23°C 4°C 23°C 4°C

1 90.7 ± 0.8 97.2 ± 1.1 99.0 ± 1.3 99.5 ± 1.2 96.9 ± 0.7 98.4 ± 1.1

3 79.6 ± 0.3 94.2 ± 0.9 96.7 ± 1.7 98.8 ± 1.3 95.8 ± 0.7 99.0 ± 0.9

5 —e 89.1 ± 1.2 90.3 ± 1.8 — 93.3 ± 0.7 —

7 — — 85.5 ± 0.8 98.5 ± 1.3 90.7 ± 0.2 98.7 ± 0.9

14 — — — 97.8 ± 1.9 — 96.1 ± 1.2

21 — — — Precipitatione, f — 95.6 ± 1.030 — — — Precipitatione, f — 95.5 ± 0.7

a Mean ± SD for duplicate determinations of trip-licate samples, n = 6.

b Initial concentrations of the triplicate sampleswere 10.4, 10.6, and 10.3 mg/mL for the samplesstored at 23°C and 10.6, 10.3, and 10.4 mg/mL forthe samples stored at 4°C.

c Initial concentrations of the triplicate sampleswere 9.8, 10.0, and 9.7 mg/mL for the samplesstored at 23°C and 9.9, 10.0, and 9.8 mg/mL forthe samples stored at 4°C.

d Initial concentrations of the triplicate sampleswere 9.7, 9.7, and 9.9 mg/mL for the samples

stored at 23°C and 9.7, 9.9, and 9.8 mg/mL for thesamples stored at 4°C.

e Analysis not performed at this time point. f Microprecipitation observed.



23°C, a drug loss of about 10% had occurred after 7 days of storage. Under refrigeration, the drug remained stable through-out the study and exhibited a drug loss of less than 5% after 30days of storage at 4°C (Table 2).

The stability of ampicillin sodium, nafcillin sodium, andoxacillin sodium in the AutoDose Infusion System bags paral-lels that reported in previously published results1 of the stabilitiesof those drugs in infusion solutions stored in glass and PVC con-tainers. The absence of an adverse effect on drug stability is alsoconsistent with the results of evaluations5-8 of other drugsstored in AutoDose Infusion System bags.

ConclusionAmpicillin sodium, nafcillin sodium, and oxacillin sodium ex-

hibited physical and chemical stability consistent with the resultsof other studies. The EVA reservoir used in the AutoDose Infu-sion System did not adversely affect the physical and chemical sta-bility of those three penicillin antibiotics.

AcknowledgmentThis study was supported by a grant (LS00-240) from Tandem

Medical, Inc, San Diego, California.

References1. Trissel LA. Handbook on Injectable Drugs. 11th ed. Bethesda, MD:Amer-

ican Society of Health-System Pharmacists; 2000.2. Trissel LA, Bready BB. Turbidimetric assessment of the compatibility of

taxol with selected other drugs during simulated Y-site injection. Am JHosp Pharm 1992;49:1716-1719.

3. Trissel LA, Martinez JF. Turbidimetric assessment of the compatibility oftaxol with 42 other drugs during simulated Y-site injection. Am J Hosp Pharm1993;50:300-304.

4. Trissel LA, Martinez JF. Physical compatibility of melphalan with select-ed drugs during simulated Y-site administration. Am J Hosp Pharm1993;50:2359-2363.

5. Xu QA, Trissel LA, Saenz CA, et al. Stability of three cephalosporin an-tibiotics in AutoDose Infusion System bags. J Am Pharm Assoc. In press.

6. Xu QA, Trissel LA, Saenz CA, et al. Stability of gentamicin sulfate and to-bramycin sulfate in AutoDose Infusion System bags. IJPC. 2002;6:152-154.

7. Zhang Y, Trissel LA. Stability of ciprofloxacin and vancomycin hydrochloridein AutoDose Infusion System bags. Hosp Pharm 2001;36:1170-1173.

8. Zhang Y, Trissel LA. Stability of piperacillin and ticarcillin I Autodose In-fusion System Bags. Ann Pharmacother 2001;1360-1363.

Address correspondence to: Lawrence A. Trissel, BS, RPh, Divi-sion of Pharmacy, Box 90, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX77030. ■

Each issue includes:■ A review of relevant compounding literature.■ A physician- or pharmacist-written case study.

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IntroductionPrecedex (dexmedetomidine, Abbott

Laboratories, Abbott Park, Illinois) is anα2-adrenoreceptor agonist that produces se-dation and is used in initially intubated andmechanically ventilated patients treated inan intensive care setting.1 Precedex is ad-ministered as an intravenous infusion bymeans of a controlled-infusion device overperiods not exceeding 24 hours.1 In addi-tion to Precedex, patients may be receiv-ing many other drugs (anti-infectives, anti-emetics, antihistamines, diuretics, steroids,analgesics, or other supportive-care drugs)by simultaneous or sequential Y-site ad-ministration. The potential exists for thedevelopment of physical incompatibilitiesduring the Y-site administration of Precedexwith those other agents or components oftheir formulations. The compatibility ofPrecedex with a number of drugs is citedin the labeling.1 Its compatibility withmany other drugs is unknown. The purposeof this study was to evaluate the physicalcompatibility of Precedex diluted for in-fusion during simulated Y-site administra-tion with 95 other drugs by means of visu-al observation, turbidity measurement, andelectronic particle content measurement(where warranted).

Materials and MethodsMaterials

Precedex (Lot 60-462-DK, Abbott Lab-oratories, Inc) was supplied as a 100-µg/mLinjection in 2-mL vials. For this testing, thePrecedex injection was diluted to a con-centration of 4 µg/mL in 0.9% sodiumchloride injection, USP, (Lot 70-135-JT, Ab-bott Laboratories), which is recommendedin the product labeling.1 The 95 secondaryadditives were studied at the concentrationscited in Table 1.

Allen et al2 reported that the mixing ofan intravenous fluid in an administrationset with a secondary additive through a Y-injection site occurs in a 1:1 ratio. To sim-ulate this inline mixing, a 5-mL sample ofPrecedex 4 µg/mL was combined with a 5-mL sample of each of the study drug so-lutions individually in colorless 15-mLborosilicate glass screw-cap culture tubes(Kimble, Div of Owens-Illinois, Toledo,Ohio) with polypropylene caps (Kimble) as described elsewhere.3 Except for drugsthat should not be filtered, the sample solutions were filtered through 0.22-µm filters (Millex-GS, Millipore Corporation,Bedford, Massachusetts) into the tubes.Each combination was prepared in dupli-cate, and the order of drug addition was reversed between the two samples. All

manipulations were carried out in a Class100 biological safety cabinet.Methods

Visual examination of all samples wasperformed with the unaided eye in normallaboratory fluorescent light. Combinationswith no obvious visual incompatibility wereexamined further with a Tyndall beam, ahigh-intensity monodirectional lightsource (Dolan-Jenner Industries, Woburn,Massachusetts) as described elsewhere.4

Inspections were performed over the first15 minutes after sample preparation and atintervals of 1 and 4 hours after samplepreparation. The samples were stored atroom temperature (approximately 23˚C)under constant fluorescent light.

Control solutions for this study includ-ed the following:Precedex 4 µg/mL in 0.9% sodium chlo-

ride injectionPrecedex 4 µg/mL in 0.9% sodium chlo-

ride injection diluted to 2 µg/mL as anequal parts mixture with 0.9% sodiumchloride injection

Precedex 4 µg/mL in 0.9% sodium chlo-ride injection diluted to 2 µg/mL sepa-rately with 5% dextrose injection

Secondary additive solutions Incompatibility was defined as any visi-

ble particulate matter, substantial haze, orchange in turbidity from that in the con-trols; a color change; or gas evolution.

The samples were also assessed immedi-ately after preparation and at 1 and 4 hoursafter preparation by means of a color-cor-recting turbidimeter (Ratio X/R, Hach

Lawrence A. Trissel, BS, RPhChristopher A. SaenzDivision of Pharmacy, The University of Texas, M. D. Anderson Cancer CenterHouston, TexasDelshalonda S. IngramKimberly Y. WilliamsTexas Southern UniversityHouston, TexasJulie P. Retzinger, RNAbbott Laboratories, Hospital ProductsDivisionAbbott Park, Illinois

AbstractThe physical compatibility of Precedex with 95 selected other drugs during sim-

ulated Y-site injection was evaluated by visual observation, turbidity measurement,and electronic particle content assessment (when appropriate).

Five-milliliter samples of Precedex 4 µg/mL in 0.9% sodium chloride injection werecombined with 5 mL of each of 95 other drugs. The other test drugs included anti-infectives, analgesics, antihistamines, diuretics, steroids, and other supportive-caredrugs undiluted or diluted in 0.9% sodium chloride injection or 5% dextrose injec-tion (for amphotericin B). Visual examinations were performed with the unaided eyein normal diffuse fluorescent light and with a Tyndall beam (a high-intensity monodi-rectional light beam) to enhance the visualization of small particles and low-levelturbidity. The turbidity of each sample was measured as well, as was the particle con-tent of samples with no visible incompatibility. Evaluation of the samples was per-formed initially and at 1 and 4 hours after preparation.

Ninety-three of the 95 test drugs were compatible with the Precedex dilution dur-ing the 4-hour observation period; however, both amphotericin B and diazepam re-sulted in precipitation. Precedex, which is incompatible with amphotericin B anddiazepam, should not be administered simultaneously with those drugs.

Compatibility Screening of Precedex During Simulated Y-Site Administration with Other Drugs


Company, Loveland, Colorado) as previ-ously described.4,5 Some drug products areinherently hazy. The use of the tur-bidimeter permits quantification of that hazeand the assessment of any changes, whethervisually apparent or not. For relativelyclear drugs such as Precedex, an incom-patibility has been defined as an increasein measured turbidity exceeding 0.5 neph-

elometric turbidity unit (NTU) that did notoccur upon simple dilution alone.

All combinations without visible incom-patibility were evaluated further with anelectronic particle sizer-counter (Model8003, Hiac-Royco, Div of Pacific ScientificCompany, Silver Spring, Maryland) to doc-ument the absence of substantial subvisu-al particle burden. Three-milliliter portions

were tested to evaluate particles that rangedin size from 1.04 to 112 µm (the validateddetection limit of the particle sizer-counter).

Results and Discussion Precedex 4 µg/mL in 0.9% sodium chlo-

ride injection appeared clear and colorlessin normal diffuse fluorescent room light and


Table 1. Solutions and Drugs Tested for Compatibility with Precedex.

ConcentrationDrug Manufacturer Lot Number (mg/mL)a,b

Supportive-care and other drugsAlfentanil hydrochloride Taylor 61230 0.5c

Aminophylline Abbott 59-141-DK 2.5Amiodarone hydrochloride Wyeth-Ayerst 060092 4Bretylium tosylate American Regent 0299 4Bumetanide Bedford 165886 0.04Butorphanol tartrate Apothecon 9K16110 0.04Calcium gluconate American Pharmaceutical Partners 302962 40Chlorpromazine hydrochloride Elkins-Sinn 039022 2Cimetidine hydrochloride American Regent 9391 12Cisatracurium besylate Glaxo Wellcome 0B1498 0.5Dexamethasone sodium phosphate American Regent 0233 1Diazepam Abbott 608253B 5c

Digoxin Elkins-Sinn 100086 0.25c

Diltiazem hydrochloride Baxter 00H108 5c

Diphenhydramine hydrochloride Parke-Davis 01509P 2Dobutamine hydrochloride Astra 90Z007 4Dolasetron mesylate Hoechst 70-008-35 2Dopamine hydrochloride Abbott 63-206-DK 3.2Droperidol American Regent 0612 2.5c

Enalaprilat Bedford 188660 0.1Ephedrine hydrochloride Taylor 51080 5Epinephrine hydrochloride American Regent 0795 0.05Esmolol Baxter 0042 10Famotidine Merck 0613K 2Fenoldopam mesylate Abbott D29002A 0.08Furosemide American Regent 0606 3Granisetron hydrochloride SmithKline Beecham 70K49 0.05Haloperidol lactate McNeil X2512 0.2Heparin sodium Abbott 70-546-DK 100c,d

Hydrocortisone sodium succinate Pharmacia & Upjohn 82DXY 1Hydromorphone hydrochloride Astra 002002 0.5Hydroxyzine hydrochloride Elkins-Sinn 119034 2Inamrinone lactate Abbott 65-121-DK 2.5Isoproterenol hydrochloride Abbott 56-487-DK 0.02Ketorolac tromethamine Abbott 67-11-DK 15c

Labetalol Abbott 702003A 2Lidocaine hydrochloride Astra 001019 10Lorazepam ESI Lederle 010010 0.5 Magnesium sulfate American Pharmaceutical Partners 100636 100Meperidine hydrochloride Astra 004003 10Methylprednisolone sodium succinate Pharmacia & Upjohn 09DYX 5Metoclopramide hydrochloride Faulding 0054-51 5c

Milrinone lactate Sanofi B670TJ 0.2

Continued on next page



Nalbuphine hydrochloride Astra 908034 10c

Nitroglycerin American Regent 0275 0.4Norepinephrine bitartrate Abbott 70-495-DK 0.12Ondansetron hydrochloride Glaxo Wellcome 0ZP2298 1Potassium chloride Abbott 36-168-DK 0.1e

Procainamide hydrochloride Elkins-Sinn 080037 10Prochlorperazine edisylate SmithKline Beecham 110C43 0.5Promethazine hydrochloride Elkins-Sinn 090151 2Propofol Astra-Zeneca 4Z86B 10c

Ranitidine hydrochloride Glaxo Wellcome 0ZP0206 2Rapacuronium bromide Organon 300495B 20c

Remifentanil hydrochloride Abbott 660015Z 0.25Rocuronium bromide Organon 3500450 1Sodium bicarbonate American Regent 0597 1c,e

Sodium nitroprusside Baxter 99J102 2f

Sufentanil citrate Abbott 64-512-DK 0.05c

Theophylline Abbott 51-192-JT 4c

Verapamil hydrochloride Abbott 67-266-DK 1.25Anti-infective drugsAmikacin sulfate Apothecon 9E11917 5Amphotericin B Apothecon 0B26137 0.6g

Ampicillin sodium Apothecon 0D19993 20Ampicillin sodium-sulbactam sodium Pfizer T499A 20/10Azithromycin Pfizer 116733 2Aztreonam Bristol-Myers Squibb 0A3688 40Cefazolin sodium Lilly 1547A30 20Cefepime hydrochloride Bristol-Myers Squibb 0E31701 20Cefoperazone sodium Roerig W179B 40Cefotaxime sodium Hoechst-Roussel 040497 20Cefotetan sodium Zeneca 3071C 20Cefoxitin sodium Merck 3838K 20Ceftazidimeh Glaxo Wellcome 0ZP1418 40Ceftizoxime sodium Fujisawa 302173 20Ceftriaxone sodium Roche U6173 20Cefuroxime sodium Glaxo Wellcome 9ZP1344 30Ciprofloxacin Bayer 0BAA 1Clindamycin phosphate Abbott 65-384-DK 10Doxycycline hyclate American Pharmaceutical Partners 100671 1Erythromycin lactobionate Abbott 69879Z7 5Fluconazole Pfizer PS095612 2c

Gatifloxacin Bristol-Myers Squibb 0A20878 2Gentamicin sulfate American Pharmaceutical Partners 100477 5Linezolid Pharmacia & Upjohn 98D24Z07 2c

Levofloxacin Ortho-McNeil W7413 5Metronidazole Baxter PS103515 5c

Ofloxacin Ortho-McNeil 7GAB5 4Piperacillin sodium Lederle 800-104 40Piperacillin sodium-tazobactam sodium Lederle 464-693 40/5Sulfamethoxazole-trimethoprim Gensia Sicor 99H123 4/0.8Ticarcillin disodium SmithKline Beecham 62 655 DA 30Ticarcillin disodium-clavulanate potassium SmithKline Beecham RR 3693 31Tobramycin sulfate Gensia Sicor 00A123 5Vancomycin hydrochloride Abbott 69840Z7 10

a Nominal concentration.b Tested in 0.9% sodium chloride injection, USP,

unless specified otherwise.

c Tested undiluted.d Units per milliliter.e Milliequivalents per milliliter.

f Protected from light.g Tested in 5% dextrose injection, USP. h Sodium carbonate formulation.

ConcentrationDrug Manufacturer Lot Number (mg/mL)a,b

Table 1, continued


when viewed with a Tyndall beam; measuredturbidity was less than 0.1 NTU. Similar-ly, dilution with an equal volume of 5% dex-trose injection or 0.9% sodium chloride in-jection resulted in solutions with essentiallyno haze and measured turbidities of less than0.1 NTU throughout the 4-hour observa-tion period.

Of the 95 drug combinations tested withPrecedex, 93 were physically compatible.The combination solutions were visuallyclear with no haze or particulate formationunder normal diffuse fluorescent roomlight and when viewed with a Tyndallbeam. Measured haze levels for the com-patible combinations of Precedex and so-lutions were near the expected level. Theabsence of substantial particle burden inthe samples with no visually apparent in-compatibility was documented via electronicparticle counting. Those compatible com-binations exhibited little change in measuredturbidity throughout the study period andhad a low particle content in the size rangeof 1.04 to 112 µm. However, amphotericinB and diazepam exhibited physical incom-patibility (gross precipitation) when com-bined with Precedex.Amphotericin B

Gross precipitation visible to the unaid-ed eye was observed when amphotericin Bwas admixed with Precedex. Such grossprecipitation has been reported to occurwhen many other drugs were mixed withamphotericin B.6 In addition, the mea-sured turbidity for that combination wassubstantially higher than that seen with Pre-cedex or amphotericin B alone (Table 2).

DiazepamWhen diazepam was mixed with Pre-

cedex, a dense white turbid precipitate thatcould easily be seen in normal room lightdeveloped (Table 2). Because of its poor wa-ter solubility, diazepam is formulated forinjection by means of a mixed solvent sys-tem that includes propylene glycol 40%,ethanol 10%, benzyl alcohol 1.5%, and ben-zoic acid/sodium benzoate 5%.6 The finaldiazepam concentration in those samplesafter dilution for testing was 2.5 mg/mL,which is well above the aqueous solubili-ty of diazepam (0.05 mg/mL).7 A similarprecipitate forms when diazepam is dilut-ed to 2.5 mg/mL with 5% dextrose injec-tion alone or with other drugs.6,8-11 Con-sequently, the precipitate that formed is theresult of diluting diazepam in an aqueousmedium rather than a specific incompat-ibility with the Precedex formulation.

ConclusionPrecedex is physically compatible for 4

hours at room temperature with 93 drugsevaluated in this study during simulated Y-site administration. However, precipita-tion resulted when Precedex was combinedwith amphotericin B or diazepam. As a re-sult, those drugs should not be administeredsimultaneously with Precedex.Acknowledgment

Supported by a research grant (LS01-036-1) from Abbott Laboratories, Inc, AbbottPark, Illinois. References1. Precedex [package insert]. Abbott Park, IL:

Abbott Laboratories; 2000.

2. Allen LV Jr, Levinson RS, Phisutsinthrop D.Compatibility of various admixtures with sec-ondary additives at Y-injection sites of intra-venous administration sets. Am J Hosp Pharm1977;34:939-943.

3. Trissel LA, Martinez JF. Physical compatibili-ty of melphalan with selected drugs duringsimulated Y-site administration. Am J HospPharm 1993;50:2359-2363.

4. Trissel LA, Bready BB. Turbidimetric assess-ment of the compatibility of taxol with select-ed other drugs during simulated Y-site injec-tion. Am J Hosp Pharm 1992;49:1716-1719.

5. Trissel LA, Martinez JF. Turbidimetric assess-ment of the compatibility of taxol with select-ed other drugs during simulated Y-site injec-tion. Part 2. Am J Hosp Pharm 1993;50:300-304.

6. Trissel LA. Handbook on Injectable Drugs. 11thed. Bethesda, MD: American Society of Health-System Pharmacists; 2000.

7. Trissel LA. Trissel’s Stability of CompoundedFormulations. 2nd ed. Washington, DC: Amer-ican Pharmaceutical Association; 2000.

8. Trissel LA, Williams KY, Gilbert DL. Compatibilityscreening of linezolid during simulated Y-siteadministration with other drugs and infusionsolutions. J Am Pharm Assoc 2000;40:515-519.

9. Trissel LA, Gilbert DL, Williams KY. Compatibilityscreening of gatifloxacin during simulated Y-site administration with other drugs. HospPharm 1999;34:1409-1416.

10. Trissel LA, Martinez JF, Gilbert DL. Compatibilityof cisatracurium besylate with selected drugsduring simulated Y-site administration. Am JHealth Syst Pharm 1997;54:1735-1741.

11. Trissel LA, Williams KY, Baker MB. Compatibilityof Hextend during simulated Y-site administrationwith other drugs. IJPC 2001;5:69-73.

Address correspondence to: Lawrence A. Trissel,BS, RPh, Division of Pharmacy, Box 90, The Uni-versity of Texas M. D. Anderson Cancer Center, 1515Holcombe Boulevard, Houston, TX. 77030. ■


Table 2. Measured Turbidities of Selected Admixtures of Precedex.

Mean ± SD Nephelometric Turbidity Unit(s) (n = 3)Test Drug and Sample 0 hr 1 hr 4 hrPrecedex 4 µg/mL in NSa 0.074 ± 0.003 0.072 ± 0.002 0.081 ± 0.002Precedex 2 µg/mL in NS b 0.079 ± 0.005 0.089 ± 0.004 0.077 ± 0.004Precedex 2 µg/mL in D5W c 0.083 ± 0.002 0.089 ± 0.003 0.085 ± 0.002Amphotericin B 3.90 ± 0.12 7.08 ± 0.11 7.92 ± 0.16

A 21.4 ± 0.3 20.3 ± 0.3 22.2 ± 0.3B 15.6 ± 0.2 15.6 ± 0.1 16.3 ± 0.2

Diazepam 0.092 ± 0.002 0.092 ± 0.003 0.098 ± 0.001A 188 ± 2 281 ± 6 241 ± 2B 209 ± 4 282 ± 6 261 ± 1

NS = 0.9% Sodium chloride injection.D5W = 5% Dextrose injection.A = Test drug solution added to Precedex.B = Precedex added to test drug solution.

a Representative Precedex infusion admixture.b Representative Precedex infusion samples

diluted with an equal volume of 0.9% sodiumchloride injection to a concentration of 2 µg/mLas a control.

c Representative Precedex infusion samplesdiluted with an equal volume of 5% dextroseinjection to a concentration of 2 µg/mL as acontrol.



IntroductionCefotaxime sodium (Figure 1) powder for

injection is used extensively to treat manydifferent diseases, such as urinary tractinfections and lower respiratory tract in-fections. Before it is used, it is dissolvedin 0.9% sodium chloride injection to aconcentration of 50 mg/mL. The result-ing admixture is usually filled into 5-mLpolypropylene syringes for pediatric use.The manufacturer recommends that the re-sulting admixture be used within 24 hourswhen stored at room temperature andwithin 7 days when stored at 5˚C in the re-frigerator.1 Gupta and Gunter2 studiedthe stability of cefotaxime sodium in 0.9%sodium chloride injection and 5% dex-trose injection at a concentration of 10mg/mL. The resulting injections werestored in polyvinyl chloride (PVC) bags atroom temperature and at 5˚C. Accordingto those authors, the loss in potency was

less than 10% after 42 days of storage at5˚C and after 1 day of storage at 25˚C.

The purpose of this investigation was todetermine the stability of cefotaxime sodi-um injection (50 mg/mL) in 0.9% sodiumchloride when packaged in polypropylenesyringes and stored at 5˚C and 25˚C and todetermine whether the drug is adsorbed ontothe syringes.

Materials and MethodsChemicals and Reagents

All the chemicals and reagents were USP-NF or ACS grade and were used withoutfurther purification. The cefotaxime sodi-um powder for injection was from com-mercial lot # 120416 (Aventis Pharmaceu-tical Company, Kansas City, Missouri).Equipment

A high-performance liquid chromatog-raphy (HPLC) system (an M-45 pump anda Model 484 multiple wavelength detector

[Waters Associates, Milford, Massachu-setts]) equipped with an injector (Model7125, Rheodyne, Cotati, California) and arecorder (Omniscribe 5213-12, Houston In-struments, Austin, Texas) were used. Thecolumn used (Cat # 58220U, Supleco C8,15 cm, 4.6 mm id, 5 µm) was obtainedfrom Supleco Co, Bellefonte, Pennsylva-nia. All pH values were measured with aBeckman SS-3 Zeromatic pH meter (Beck-man Instruments, Fullerton, California).Chromatographic Conditions

The mobile phase contained 9.5% (v/v)acetonitrile in water containing 0.02 Mammonium acetate buffer. The pH of themobile phase was approximately 6.9. Theflow rate was 1.3 mL/min, the sensitivitywas 0.7 AUFS at 290 nm, the chart speedwas 30.5 cm/hr, and the temperature wasambient.

Preparation of Injection for Stability Studies

Cefotaxime sodium (0.5 g per vial of freebase) was used to prepare the injections forstability studies. The powder for injec-tion, which was equivalent to 5 g of cefo-taxime, was dissolved in sufficient 0.9% sodi-um chloride injection (Lot # PS105619,Baxter Healthcare Corp, Deerfield, Illinois)to bring it to 100 mL (50 mg of cefotaximeper milliliter of injection). The injectionwas immediately filled into 5-mL poly-propylene syringes (Cat # 301-603, BectonDickinson & Co, Franklin Lake, New Jer-sey). The syringes were divided into 2groups (9 syringes per group). One groupwas stored in the refrigerator at 5˚C (± 1˚C),and another group was stored in the re-frigerator at 25˚C (± 1˚C). On day zero, theinjection was assayed and the pH valuewas recorded. The contents of the syringeswere assayed again at appropriate intervals,and the pH values were recorded. A 10-mLquantity of injection was also stored at25˚C in a 25-mL volumetric flask to de-termine whether the drug exhibited prob-

AbstractA stability-indicating high-performance liquid chromatographic assay method was

used to study the stability of cefotaxime sodium (50 mg/mL) in 0.9% sodium chlo-ride injection in polypropylene syringes at 5˚C and 25˚C. The concentrations of thedrug were directly related to peak heights, and the percent relative standard devia-tion based on 5 injections was 1.1. There were at least three products of decompo-sition that separated from the intact drug. At 5˚C, the decomposition was less than3% when stored for 18 days, and at 25˚C, the loss in potency was less than 10% af-ter 1 day of storage. When stored for 18 days at 5˚C, the pH value decreased from5.3 to 5.2. The pH value of the injection decreased from 5.3 to 5.0 when stored at25˚C for 1 day. The drug was not adsorbed onto the syringes, and the intensity ofthe light yellow color did not change significantly during storage at 5˚C but increasedduring storage at 25˚C.

Stability of Cefotaxime Sodium After Reconstitution in 0.9% Sodium Chloride Injection and Storage in Polypropylene Syringes for Pediatric Use

Figure 1. Structure of Cefotaxime Sodium.

V. Das Gupta, PhDPharmaceutics Division, University ofHouston, Houston, Texas

H2N

N

S

NN

O

H H S

OCH3

COONa

CH2OCOCH3

CONHC

lematic adsorption (ie, onto the polypro-pylene syringes).Preparation of Standard Solutions

A 105.3-mg quantity of the powder forinjection was accurately weighed (105.3 mgis equivalent to 100 mg of cefotaxime freebase) and was dissolved in sufficient wa-ter to make 100 mL of solution. Those stocksolutions were used to prepare solutionsof lower concentrations as needed. Be-cause the percent relative standard devia-tion (RSD) was very good (1.1) as a resultof the use of 80 µL of injection, the internalstandard was not used in this study. Themost commonly used standard solution ofthe drug (100 µg/mL) was prepared by di-luting 2.5 mL of the stock solution to 25mL with water.Preparation of Assay Solutions

A 2.0-mL quantity of the assay solutionwas diluted to 100 mL with water. It wasthen further diluted 2.5 mL to 25 mL withwater. Decomposition of Cefotaxime Sodium

A 25-mL quantity of the freshly preparedstandard solution (100 µg/mL) was boiledin a 150-mL beaker on a hot plate. After40 seconds, the solution was allowed to cool,the volume was brought to 25 mL with wa-ter, and the solution was injected into thechromatograph.

Assay Procedure andCalculations

An 80-µL quantity of assay solution wasinjected into the chromatograph under theconditions described. For comparison, a sim-ilar volume of the standard solution con-

taining the same concentration of the drug(based on the label claim) was injected.Because peak heights of the drug are directly

related to the concentrations (60 to 110µg/mL), the results were calculated bymeans of a simple equation:

(Ph)a/Ph)s x 100 = Percentage of the labelclaim found

where (Ph)a is the peak height of drug ofthe assay solution and (Ph)s is the peakheight of the standard solution. The resultsare presented in Table 1.

Results and DiscussionAssay Method

The assay method developed is precise andaccurate and has a percent RSD of 1.1based on 5 readings. Apparently, the largeinjection volume (80 µL) did produce ac-curate and precise results without the useof an internal standard. The concentrationsof the drug were directly related to the peakheights (range tested, 60 to 110 µg/mL).



Table 1. Assay Results for Cefotaxime Sodium Injection (50 mg/mL) Stored in Becton-Dickinson 5-mL Syringes.a

Percent of the Label Claim Based on 100% on Day Zero When Stored at Percent RSD

Time (days) 5˚C 25˚C n = 51 ND 98.3 1.12 ND 89.8 1.13 100.2 81.8 1.0/1.19 99.7 ND 1.0

18 97.1 ND 1.1a At 5˚C, there was no significant change in the

physical appearance of the injection, and at25˚C, the injection gradually discolored fromlight yellow to dark yellow. The pH value at5˚C decreased from 5.3 to 5.2 after 18 days of

storage, at 25˚C it decreased to 5.0 after 1 dayof storage, and it further decreased to 4.7 af-ter 3 days of storage.

ND = Not determined on this day.RSD = Relative standard deviation.

Peaks 1 through 4 represent cefotaxime and its products of decomposition (2 through 4),respectively. Chromatogram A is from a standard solution, and B is from an assay so-lution after 3 days of storage at 25˚C (Table 1). Chromatogram C is identical to B butwas developed at 262 nm (AUFS 1.3) and shows incomplete separation. ChromatogramD is from a decomposed sample (see text) in which only 62.3% of the drug remained in-tact. For chromatographic conditions, see the text.

Figure 2. Sample Chromatograms of Cefotaxime Sodium and Its Products of Decomposition.

Time (Minutes)

Det

ecto

r Res

pons

e

Inje

ct

Inje

ct

Inje

ct

Inje

ctA B C D

1

11

1

2

3

433

0 4 0 4 0 4 0 4



It is important that the volume of injection (80 µL) be kept thesame to ensure a linear relationship between the concentrationsand the peak heights. The standard solution, which was decom-posed by heat, produced at least 3 additional peaks from the prod-ucts of decomposition (Figure 2D). All products of decomposi-tion eluted before the drug peak. Although the sensitivity of theassay method was higher by about 45% at 262 nm, the wavelengthof 290 nm was preferred because of the complete separation ofthe drug from the products of decomposition (Figure 2B vs Fig-ure 2C). Apparently, one product of decomposition did not ab-sorb light at 290 nm.

At 5˚C, the loss in potency of cefotaxime after 18 days of stor-age was less than 3%, and the pH value of the injection had de-creased from 5.3 to 5.2. Therefore, at 5˚C a beyond-use date (BUD)of at least 18 days is appropriate. The manufacturer has recom-mended a BUD of only 7 days.1 There was no adsorption of drugonto the syringes because the injection, which was stored in theglass volumetric flask for 1 day, produced results similar to thoseof the sample, which was stored in polypropylene syringes. Thepotency of cefotaxime injection had decreased to 98.3% (Table1) after 1 day of storage at 25˚C, and the pH value had decreasedfrom 5.3 to 5.0. After 2 days of storage at 25˚C, the potency was

89.8%, and the pH value was 4.9. After 3 days of storage at 25˚C,the potency had decreased to 81.8%, and the pH value was 4.7.When cefotaxime injection is stored at 25˚C, a BUD of 1 day isthe maximum. At 5˚C, there was no significant change in the ap-pearance of the injection after 18 days of storage, and at 25˚C,the intensity of the light yellow color increased with the lengthof storage.

ConclusionCefotaxime sodium (50 mg/mL) in 0.9% sodium chloride in-

jection, when stored in 5-mL polypropylene syringes, was stablefor 1 day at room temperature and for at least 18 days when storedat 5˚C.References1. Claforan [package insert]. Kansas City, MO:The Aventis Pharmaceuticals;

June, 2000.2. Gupta VD, Gunter JM. Stability of cefotaxime sodium and moxalactam di-

sodium in dextrose 5% and sodium chloride 0.9% injections. Am J IV TherClin Nutr 1983;10:20, 27-29.

Address correspondence to: V. Das Gupta, PhD, Pharmaceutics Di-vision, University of Houston, 1441 Moursund St, Houston, TX77030. [email protected] ■

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Health Care Logistics800-848-1633 or 888-HCL-INTL (888-425-4685) . . . . . . . . . . . . . . . . . . . . . . . Insert

Kalchem International888-298-9905 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 192

Mallinckrodt, Inc800-325-8888 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 177

Medisca866-MEDISCA or 866-633-4722. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 187

Paddock Laboratories, Inc800-328-5113 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 193

Pharmaceutical Specialties, Inc800-325-8232 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 229

Pharma-Tek, Inc800-645-6655 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 173

Professional Compounding Centers of America (PCCA)800-331-2498 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 175, 182, 183, BC

Respiratory Distributors, Inc800-872-8672 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . IBC

Spectrum Pharmacy Products, Inc800-791-3210 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 167, 219

SOFTWARE

Application Design Consultants877-343-0229 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 197

STORE DESIGN

Robert P. Potts & Assoc800-255-5498 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 174

TESTING LABORATORIES

Analytical Research Laboratories800-393-1595 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 214

CONTINUING EDUCATION

Meridian Pharmaceutical800-687-7850, ext 106 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 179

PHARMACY AUTOMATION

ScriptPro800-606-7628 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 163

PUBLICATIONS

Specialized Clinical Services800-488-6424 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 181

IJPC Compounding CDs888-588-4572 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 209

IJPC Formulizer888-588-4572 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 222

IJPC SOPs888-588-4572 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 224

Rx TRIAD281-461-3946 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 229

I n d e x o f A d v e r t i s e r s

C A L C U L A T I O N S


1The dose of a drug is 2.5 mg and is supplied as a solution witha concentration of 1:200 w/v. This solution is administered

with a dropper that has a drop factor of 12 gtt/mL. How many dropswould be needed to supply this dose?

2.5 mg/dose x 1 g/1000 mg x 200 mL/1 g x 12 gtt/mL = 6 gtt/dose

2 You need to prepare 12 suppositories, each of which contains350 mg of drug. You know that the calibrated volume of the

suppository mold to be used is 2.3 mL; therefore, you weigh 350 mgof the drug and mix it with 1 g of the suppository base that you willuse to prepare the prescription. You melt this mixture and pour itinto a cavity in your suppository mold. You also melt a smallamount of the suppository base alone and pour it into the cavity tocompletely fill it. After the suppository has cooled, you remove itfrom the mold and find that it weighs 1.95 g. How much drug andsuppository base will you need to prepare this prescription (allowfor 2 extra suppositories)?

1.95 g/supp - 0.35 g drug/supp = 1.6 g of base/supp

350 mg/supp x 14 supp = 4900 mg = 4.9 g of drug needed

1.6 g/supp x 14 supp = 22.4 g of base needed

3The Cockcroft-Gault equation for the calculation of creatinineclearance (CrCl) in men is as follows:

CrCl (mL/min) = [(140 - age in yr) x body weight in kg]/(72 x serum creatinine in mg/dL)

What would be the creatinine clearance for a 78-year-old man whoweighs 210 lbs and has a serum creatinine level of 2.8 mg/dL?

Patient’s body weight = 210 lb x 1 kg/2.2 lb = 95.45 kg

CrCl = [(140 - 78) x 95.45 kg]/(72 x 2.8 mg/dL) = 29.35 mL/min

4Rx Zephiran Chloride Solution (17% w/v) qs Purified water qs 240 mL

Sig: One (1) tsp diluted to 1 GAL with water to make a 1:8500 dilution

A. What would be the concentration in milligrams per milliliter ofZephiran chloride in the dispensed solution?

1 g/8500 mL x 3785 mL/GAL x 1 GAL = 0.445 g of Zephiran chloridein 1 GAL of 1:8500 solution

Therefore, each teaspoonful of the dispensed solution should contain 0.445 g of Zephiran chloride

0.445 g/tsp x 1000 mg/g x 1 tsp/5 mL = 89.06 mg/mL

B. How many milliliters of Zephiran chloride 17% solution shouldbe used to prepare the prescription?

89.06 mg/mL x 240 mL x 1 g/1000 mg = 21.37 g of Zephiran chloride needed

21.37 g x 100 mL/17 g = 125.73 mL

5 A patient is to use an albuterol inhaler by inhaling 2 puffsevery 4 to 6 hours as needed. An albuterol inhaler contains

200 inhalations. How long should this inhaler last for this patient?

Maximum dose = 2 inhalations q 4 hr = 12 inhalations/day

200 inhalations x 1 day/12 inhalations = 16.67 days

6 Five college students were asked how many hours they spentexercising per week with the following results:

Student # 1: 2 hrStudent # 2: 4.2 hrStudent # 3: 0.75 hrStudent # 4: 6.5 hrStudent # 5: 3.25 hr

What are the mean, median, and standard deviations for those data?

Array: 0.75 hr, 2 hr, 3.25 hr, 4.2 hr, 6.5 hr

Mean = (0.75 + 2 + 3.25 + 4.2 + 6.5)hr/5 = 16.7 hr/5 = 3.34 hr

Median = middle or third value = 3.25 hr

The formula for standard deviation (σ) is as follows:

σ = Sum of (deviations)2 = Σ (x-x)2

= Σ d2

Number of values-1 n-1 n-1

First, find the deviations by subtracting the mean from each value.Then, square each deviation as shown below:Value d d2

0.75 hr - 3.34 hr = -2.59 hr 6.7081 hr2

2 hr - 3.34 hr = -1.34 hr 1.7956 hr2

3.25 hr - 3.34 hr = -0.09 hr 0.0081 hr2

4.2 hr - 3.34 hr = 0.86 hr 0.7396 hr2

6.5 hr - 3.34 hr = 3.16 hr 9.9856 hr2

Sum of (deviations)2 = 19.237 hr2

σ = 19.237 hr2= 2.19 hr

5-1

Address correspondence to: Shelly J. Prince, PhD, RPh, School of Pharmacy, Southwestern Oklahoma State University, 100Campus Drive, Weatherford, OK 73096 ■

CalculationsShelly J. Prince, PhD, RPh

Southwestern Oklahoma State University School of PharmacyWeatherford, Oklahoma

Basics of Compounding forIontophoresis, Part 1. Page 194

1. Using patches and gels for trans-dermal administration is effectiveprimarily for drugs.

A. IonizableB. Nonionizable

2. The rate-limiting factor for ab-sorption across the skin is the:

A. Stratum corneumB. Stratum germinativumC. Stratum granulosumD. Stratum spinosumE. Stratum lucidum

3. Which energy form does ion-tophoresis, a facilitated diffusionmethod, use?

A. UltrasoundB. ElectricityC. Penetration enhancers D. LightE. Radiation

4. How many electrodes are requiredfor iontophoresis?

A. OneB. TwoC. ThreeD. FourE. Five

5. Iontophoresis works well whendrugs in a solid form are used.

A. TrueB. False

5. Iontophoresis is a form of con-trolled drug delivery.

A. TrueB. False

6. In some cases, iontophoresis caneliminate the need for injections.

A. TrueB. False

7. Iontophoresis was introduced inwhich year?

A. 1848B. 1879C. 1908D. 1924E. 1945

8. Originally, most of the work on ion-tophoresis was investigated for theadministration of drugs into the:

A. Oral cavityB. EarC. EyeD. NoseE. Skin

9. Which current densities can usual-ly be tolerated by the body with lit-tle or no discomfort?

A. 0.5 µA/cm3

B. 0.5 mA/cm3

C. 0.5 mA/cm2

D. 0.5 A/cm2

E. 0.5 W/cm3

10. Iontophoresis devices of the futurewill be very similar in size to thetransdermal patches of today.

A. TrueB. False

11. Which of the following drugs doesnot require positive polarity?

A. Atropine sulfateB. Fentanyl citrateC. Lithium chlorideD. Morphine sulfate E. Sodium salicylate

12. Which polarity is required for dexa-methasone sodium phosphate?

A. PositiveB. Negative

13. Which of the following veterinarydrugs requires positive polarity?

A. Ceftiofur sodiumB. Prednisolone sodium succinateC. KetoprofenD. PhenylbutazoneE. Gentamicin sulfate

14. Which of the following can use ei-ther negative or positive polarity?

A. Acetic acidB. EstriolC. IdoxuridineD. Potassium iodideE. Water

15. Which of the following can be ad-ministered iontophoretically for the treatment of attention deficitdisorder?

A. Atropine sulfateB. Calcium chlorideC. HyaluronidaseD. IdoxuridineE. Methylphenidate hydrochloride

Featured Excipient: The Sorbitan Esters. Page 221

16. The sorbitan esters are and

.

A. Hydrophilic, anionicB. Hydrophilic, nonionicC. Lipophilic, anionicD. Lipophilic, nonionicE. Lipophilic, cationic

C O N T E D


Two Hours of Continuing Education from the International Journal of Pharmaceutical Compounding

For ACPE Credit: Quest Educational Services, Inc, is approvedby the American Council on Pharmaceutical Education as aprovider of continuing pharmaceutical education.

Pharmacists successfully participating in this program (those

obtaining a grade of 70% or higher) will receive 2 contact hours(0.2 CEUs) within 4 to 5 weeks after we receive the answer sheetor the online form.

PROGRAM EXAMINATION. Please indicate your exam responses by circling only ONE answer for each question.

ACPE No. 748-999-02-035-H04This lesson is no longer valid for CE credit after 5-15-2005.®

17. Sorbitan esters will produce whichtype of emulsions?

A. Oil-in-waterB. Water-in-oil

18. Other names for the sorbitan estersinclude:

A. ArlacelB. SpanC. GlycomulD. LiposorbE. All the above

19. In which concentrations are theSpans usually used alone to prepareemulsions?

A. < 0.1% B. 0.2% to 0.9%C. 1% to 15%D. 16% to 20%E. 21% to 25%

20. The Arlacels are usually preparedfrom which starting material?

A. DextroseB. LactitolC. MannitolD. PolyglycolE. Sorbitol

21. Which of the following sorbitan es-ters is a solid at room temperature?

A. Arlacel 20B. Arlacel 40C. Arlacel 80D. Arlacel 83E. Arlacel 85

22. The most lipophilic Span is:

A. Sorbitan monolaurateB. Sorbitan monopalmitateC. Sorbitan monostearate D. Sorbitan sesquioleate E. Sorbitan trioleate

23. The Span easiest to pour because ithas the lowest viscosity is:

A. Sorbitan monolaurateB. Sorbitan monooleateC. Sorbitan monostearateD. Sorbitan sesquioleateE. Sorbitan trioleate

24. The Spans are very soluble in water.

A. TrueB. False

25. Which of the following would floathighest if layered on water?

A. Sorbitan monolaurateB. Sorbitan monooleateC. Sorbitan monopalmitateD. Sorbitan sesquioleateE. Sorbitan trioleate

C O N T E D


Please help us evaluate this continuing education program byresponding to the following questions:

1. My practice setting isA. Community based C. Hospital basedB. Managed care based D. Consultant or other

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3. The test questions corresponded well with the information presented.A. Yes B. No

4. Approximately how long did it take you to read the journal AND respond to the test questions?

ACPE No. 748-999-02-035-H04

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To receive credit, send the completed registration form, the testanswer sheet (original or a photocopy of both pages), and a checkfor $6 payable to “Quest” to: QUEST EDUCATIONALSERVICES, INC, P.O. Box 743, Tolland, CT 06084.

http://www.bandbpharmaceuticals.com

International Journal of Pharmaceutical CompoundingVol. 6 No. 3 May/June 2002

Building Relationships with Special Patient Populations

The paradigm of improved health care can begin or end withthe compounding pharmacist. Compliance variables have long beenan issue, especially in special patient populations such as thosewith allergies or severe dietary restrictions. Patients who are un-able to take commercially available prescribed medications or sup-plements receive less effective health care. Compounding phar-macists can be very effective in resolving those difficulties.

Relationships are the texture of life and are fast becoming anintegral facet in successful independent pharmacies. As rapportbetween the patient and the pharmacist develops, the exchangeof information improves the quality of health care rendered.

Patient Profile Being attentive during the dialogue with a patient will make your

work easier and more efficient as you develop a profile for himor her. During the initial conversation, you can collect demographicinformation, open the lines of communication, and establish theframework of the patient-pharmacist-physician relationship. Thistriad is the best foundation for providing excellent health care.

During your initial meeting with the patient, document his orher preferences regarding flavors, foods, and colors; specific dis-likes; and color, dye, or food restrictions. Write specific notes anddetails that will help you to remember the patient’s health con-dition and special requests or concerns. Using a prepared outlinedesigned for each of the subsets of patients with whom you workfacilitates that documentation.

Prescription Preparation for Patients with Special Pharmaceutical Needs

Before compounded prescriptions are prepared and dispensedfor patients with special needs, consider the following factors:1. Use pure, active ingredient powders as a first choice. Decreaseparticle size as much as is reasonable. Coarse residues can be moreof a hindrance to the texture-sensitive patient than are un-pleasant tastes or odors. If a mixture appears coarse when it iswet, homogenize it or use an ointment mill to reduce the par-ticle size further. 2. Some fillers and binders in conventional tablet preparationsmay not be tolerated by the patient. Review the inactive ingredi-ent lists closely. Hint: If you must use tablets with coatings or shells,sift after trituration and before final incorporation.3. Color tracers used to ensure proper dispersion should becarefully chosen with regard to patient sensitivity.4. Proper selection of dosing containers and devices makes ad-ministration easier. Keep your patient and caregiver in mindwhen those selections are made.5. Flavor only as necessary. Consider pH and volume changeswith every addition. Mask bitter medications appropriately by se-lecting proper alternatives for the dispersion of active ingredi-

ents. Prepare flavor samples for patients who might need a littleextra care.

Keep in mind that the cellular chemistry of your patient is stressed.Add nothing to formulations that will further compromise the pa-tient’s biochemical or physiologic status. Consider all ingredientswhen you develop formulas. Every patient is different, and an ex-isting formula may require adjustments to fit individual needs.

Table 1 lists ingredients that can be used for the treatment ofmore sensitive patients as well as ingredients to be avoided. Thatlist is not all-inclusive. If additives must be used, consider theirproperties and pharmacokinetics and use them sparingly. If youare uncertain about whether to use an ingredient, omit it. Sim-ple is better.

Professional PrioritiesAdopt an attitude of service to the patient, the caregiver, and

the physician. Enjoy your work. Keep seeking knowledge andincreasing your expertise. As compounding pharmacists, we aremembers of the healthcare team, and our level of skill must beexcellent.

In our work, we must give sincere consideration to humanitar-ian values. Time-consuming formulations that require multipleingredients, extra preparation, and the use of dispensing devicesaffect the monetary bottom line, but the essence of compound-ing is not always linked to financial compensation. Taking extrasteps to solve problems will deliver a bounty far greater than thatof reimbursement. Special patient populations need us. Stretchyour abilities to meet challenges, go the extra mile, and make adifference for your patients!

Suggested Reading ■ Allen LV Jr. The Art, Science, and Technology of PharmaceuticalCompounding. Washington, DC: American Pharmaceutical Asso-ciation; 1998.■ Gennaro AR, Chase GD, Marderosian AD. Remington, The Sci-ence and Practice of Pharmacy. 20th ed. Baltimore, MD: LippincottWilliams & Wilkins; 2000.■ Reynolds JEF, ed. Martindale: The Extra Pharmacopoeia. 30thed. London: The Pharmaceutical Press; 1993.

Address correspondence to: Patsy Angelle, PD, FIACP, FACA,Prescription Compounds, 7414 Picardy, Suite C, Baton Rouge, LA70808. E-mail: [email protected] ■

P O S T S C R I P T I O N

PostScriptionPatsy Angelle, PD, FIACP, FACAPrescription Compounds, Baton Rouge, Louisiana

240

Ingredients Tolerated by Most Allergy-Prone PatientsAcaciaAcesulfame potassium CelluloseLecithin (except in soy-sensitive

patients)PectinPotassium sorbateSorbitolStevia

Ingredients To AvoidArtificial colors and flavors,

including FD & CAspartameButylated hydroxytolueneProducts derived from cornLactoseMonosodium glutamateNitratesSugar and syrupsVanillin

Table 1. Compounding for Sensitive Patients.
