Name: Pharmaceutical DosageChapter 12: Suppositories and InsertsSuppositories

From the Latin word, supponere meaning “to place under” Semisolid dosage forms for insertion into the body orifices Melt, soften, or dissolve and exert localized or systemic

effects Types

Rectal suppository Cylindrical and tapered at one end Bullet-shaped 1 gram for infants and 2 grams for adult

Vaginal suppository Pessaries Globular oviform or conical in shape 3 to 5 grams in weight

Urethral suppository Bougies Pencil-shaped: 4 to 5nm For males: weigh 4 grams, 100 to

150mm long For females: 2 grams, 60 to 70mm long

Advantages of Suppositories Taken when a drug:

Cannot be tolerated: cause to vomit orally Cannot be swallowed: cause choking Decomposed or inactivated by pH or enzymes in

the GIT Destroyed in the liver (oral administration)

Disadvantages of Suppositories Inconvenient, absorption is irregular and difficult to predict

Local Action Suppository base melts distributing the medicaments to the

tissue of the region Rectal suppository: relieves constipation or pain, irritation,

itching and inflammation like hemorrhoids and other anorectal conditions

Glycerin suppositories: laxative action by irritating the mucous membranes through its dehydrating action

Vaginal suppository for localized effects: contraceptives (Nonoxynol 9) and antiseptic in feminine hygiene and specific agents to combat invading pathogens (Trichomonas vaginalis, Candida [monilia] albicans, Hemophilus vaginalis)

Urethral suppository: antibacterial and local anesthetic prepared to urethral examination, contraceptive agents

Systemic action Mucous membrane of the rectum and vagina: permits

absorption of many soluble drugsExamples of Rectal Suppository for Systemic Effects

Aminophylline and theophylline: relief of asthma Prochlorperazine and chlorpromazine: nausea and vomiting

and as tranquilizers Chloral hydrate: sedative and hypnotic Oxymorphone HCl: narcotic analgesic Ergotamine tartrate: migraine syndrome Aspirin: analgesic and antipyretic

Advantages over Oral Therapy of the Rectal Route of Administration for Achieving Systemic Effects

Drugs Destroyed or inactivated by the pH or enzymatic

activity of the stomach or intestines need not to be exposed to these destructive environments

Destroyed by portal circulation: may bypass the liver after rectal absorption

Irritating to the stomach may be given without causing such irritation

Route is: Convenient for administration of drugs to adult or

pediatric patients who may be unable or unwilling to swallow medications

Effective in the treatment of patients with vomiting episodes

Some Factors of Drug Absorption from Rectal Suppositories Physiologic factors

Colonic contents Drug have greater absorption in the

absence of fecal matter Other conditions (diarrhea, colonic

obstruction due to tumor growths and tissue dehydration) influence rate and degree of drug absorption

Circulation route Drugs rectally absorbed: bypass the

portal circulation, thus enable drugs (destroyed in the liver) to exert systemic effects

Lymphatic circulation also assists in the absorption of rectally administered drug.

pH and lack of buffering capacity of the rectal fluids

Rectal fluids neutral in pH and have no effective buffer capacity therefore drugs do not chemically changed

Physicochemical factors of the drug Drug

Relative solubility of the drug in lipid and in water

Particle size of the dispersed drug Suppository base

Ability to melt, soften, and dissolve at body temperature

Ability to release the drug substance Its hydrophilic or hydrophobic

characterFor Systemic Drug Action Using Cocoa Butter Base

Preferable to incorporate ionized form (salt form) to maximize bioavailability

Physicochemical Factors of Suppository Base Lipid-water solubility

A lipophilic drug distributed in a fatty suppository base in low concentration has lesser tendency to escape to the surrounding aqueous fluids than a hydrophilic substance in fatty base.

Particle size Influences released and dissolved amount in

absorption The smaller, the readily the dissolution and

greater chance for rapid absorption.Suppository Base

Capable of melting, softening, or dissolving to release its drug components for absorption

Undesirable Characteristics of a Base Interacts with the drug, inhibiting its release: drug

absorption prevented or delayed Irritating to the mucous membrane of the rectum, initiating

a colonic response and prompt to a bowel movement: negating drug release and absorption

Classification of Suppository Base Fatty or oleaginous bases

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Frequently employed since cocoa butter (triglyceride) is a member of other triglycerides

Wecobee bases: derived from coconut oil

Witepsol bases: saturated fatty acids C12 to C18

Other fatty oleaginous materials Hydrogenated fatty acids of vegetable

oils (palm kernel oil and cottonseed oil) Fat based compounds containing compounds of

glycerin HMW fatty acids: palmitic and stearic acids (glyceryl monostearate and glyceryl monopalmitate)

Water-soluble or water-miscible bases Main members of this group are bases of:

Glycerinated gelatino Have tendency to absorb

moisture due to the hygroscopic nature of glycerin causing the following effect:

May lose their shape and consistency

May lose dehydrating effect and be irritating to the tissues upon insertion

o Remedy Water present

minimizes these effects

Suppository is moistened with water prior to insertion (reduce tendency of base to draw water from the mucous membranes and irritates tissue)

Bases of polyethylene glycolso Polymers of ethylene oxide

and water prepared to various chain lengths, molecular weight ranges of 200, 400, 600, 1000, 1500, 1540, 3350, 4000, 6000, and 8000 and physical states

Do not melt at body temperature and dissolve slowly in the body’s fluids

Slower release of medication from the base once inserted

Permits the convenient storage without need of refrigeration and without danger of softening excessively in warm weather

Do not leak from the orifice

Dipped in water before use to avoid irritation of mucous membrane

Miscellaneous bases Mixture of oleaginous and water-miscible

materials Mixture of many fatty acids with emulsifying

agents capable of forming without emulsion: also referred as “hydrophilic” suppository base

A soap as a base like glycerin suppositories which have sodium stearate

Cocoa Butter A triglyceride (glycerin + one or different fatty acids)

primarily of oleopalmitostearin and oleodistearin Melts between 30o to 36oC Ideal suppository base, melting just below body

temperature maintaining solidity at room temperature Exhibits marked polymorphism (to exist in several different

crystalline forms, with the triglyceride content) Crystalline form represents a metastable condition (α

crystals with lower melting point), slow transition to the more stable β form of crystals (greater stability and high melting point)

Slowly and evenly melted on a water bath Avoid formation of unstable crystalline form Ensure the retention in the liquid of the more

stable β crystals Lowers the melting point when incorporated: phenol and

chloral hydrate Solidifying agents melted with cocoa butter to compensate

for the softening effect of the added substances Cetyl esters wax (20%) Beeswax (4%)

Different Preparations of Suppositories Molding from melt or fusion (commonly employed in small

scale and industrial scale) Cold compression Hand molding or rolling and shaping Compression in a tablet press

Preparation of Suppositories Preparation by molding

Melting of the base preferably in water or stream bath to avoid local overheating

Incorporating the required medicament: either emulsified or suspend in it

Pouring the melt into the cooled metal mold which are usually chrome or nickel plate

Allowing the melt to cool and congeal thoroughly using refrigerator in a small scale or refrigerated air on a larger scale

Removing the formed suppositories from the mold

Suppository Molds Made from stainless steel, aluminium, bass or plastic Separated into sections (longitudinally), opened for

cleaning before and after a batch preparation of suppository Scratches should be avoided especially the plastic

Lubricating the Molds Before the melt is poured:

Facilitates cleaning and easy removal of the molded suppository

Lubricant used: thin coating mineral oil or expressed almond oil applied with the finger to the molding surface

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Seldom necessary when the suppository base is cocoa butter or PEG (contract sufficiently on cooling within the mold to separate from the inner surfaces and allow easy removal)

Necessary when glycerinated gelatine suppositories are prepared

Calibration of Molds Calibrate each of suppository molds for the suppository

bases to have proper quantity of medicament Suppositories are weighed and the total weight and average

weight of each are recorded Suppositories are carefully melted in a calibrated beaker

(determine the volume of the mold) The volume of the melt is determined for the total number

as well as the average of one suppositoryDetermination of the Amount of Base Required

First method Total volume needed: volume of the drug

substance Second method

Requires the following steps: Weigh the active ingredient for the

preparation of a single suppository Dissolve or mix it with a portion of

melted base insufficient to fill one cavity of the mold

Place the mixture to the mold Add additional melted base to the

cavity to completely fill the mold Remove the suppository from the mold

and weigh Total weight of the suppository:

Weight of the ingredient = amount of the base needed X number of suppositories to make = total base needed

Preparing and Pouring of the Melt Weighed suppository base material is melted (least possible

heat0 over water bath Medicinal substance incorporated into a portion of the

melted base by mixing on a glass or porcelain tile with spatula, stir and allowed to cool almost to its congealing point

The pouring must be continuous to prevent ‘layering’ which may lead to a product easily broken on handling

When solidified: the excess material is scraped off the top of the mold with spatula. The mold is placed in the freezer to hasten hardening of the suppository.

When suppositories are hard, the mold is removed from the freezer and dislodged the suppositories from the mold.

Generally, little pressure is required to let fall the suppository of their mold.

Preparation by Compression Prepared by forcing the mixed mass of the suppository base

and the medicament into special molds using suppository molding machines

On a small scale a mortar is heated in warm water before use and then dried, the softening of the base and the mixing process are greatly facilitated forming a paste-like consistency

Suppository mass is placed in the cylinder Pressure is applied from one end (by turning

wheel) and the mass is forced out at the other end A movable end plate at the back of the die is

removed (die is filled with mass)

Additional pressure is applied to the mass in the cylinder

Formed suppositories are ejectedAdvantages of Preparation by Compression

Method is simple Resulting suppository is more elegant that of hand molding Avoid the possibilities of sedimentation of the insoluble

solids in the suppository baseDisadvantages of Preparation by Compression

Too slow for large scale operation Triturate in a mortar, then formed in into a ball in the palms

of the hands previously cooled in the ice water A broad bladed spatula or flat board is used to roll it to a

cylinder on a pile tile Cut with a spatula into sections and shaped desired

Compression in a Tablet Press Carbon dioxide releasing tablet (compressed rectal

suppository) Made of dried sodium biphosphate, NaHCO3 and

starch Dipped or sprayed with a coating of water soluble

PEG to add film for protection of the core for the aid in insertion into rectum

Vaginal compressed tablet Contains active ingredients and lactose

and/or phosphoric acids for adjusting the acidity of the vagina to pH 5

Information Patients Need to Know About Suppositories Using half of a suppository should cut it lengthwise with

clean razor blade Dispensed in paper, foil, or plastic wrappings Removal of wrapper before insertion

Packaging and Storage Packaging

Glycerin suppository and glycerinated gelatin suppository Tightly closed containers to prevent

moisture change Cocoa butter based suppository

Individually wrapped or separated in compartment bases

Light sensitive drugs Individually wrapped in opaque material (metallic foil)

Storage Cocoa butter suppository base

Below 300°C or 860°F In a refrigerator: 2o to 80oC or 68o to

770oF Glycerinated gelatin suppository Below 350°F Controlled room temperature

20o to 250°C or 68o to 770°F PEG suppository base

Room temperature Stored of high humidity

Absorbs moisture and becomes spongy Extreme dryness

Lose moisture and becomes brittleVaginal Inserts (Vaginal Tablets)

More widely used than the vaginal suppositories Easier to manufacture, more stable and less messy Avoid accompanied with a plastic inserter for easy

placement Contain same types of anti-infective and hormonal

substances as vaginal suppositories Prepared by tablet compression and formulated with:

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Base or filler: lactose Disintegrating agent: starch Dispersing agent: PVP Lubricant: magnesium stearate

Some are capsules of gelatin containing medication to be released intravaginally

Also used rectally, insertion facilitated by lightly wetting with water

Other Inserts Tablet and capsules

Vaginal tablet and inserts Oinments, creams, and aerosol forms Protofoam

Jellies and gels Contraceptive sponge Intrauterine progesterone drug delivery system Progestasert Powders Solutions Vaginal douches Enemas Retention and evacuation enemas Suspensions Barium sulfate suspension

Table 12.1: Examples of Rectal Suppositories

Suppository Commercial Product Active ConstituentType of Effect

Category and Comments

Bisacodyl Dulcolax (Ciba) 10 mg Local Cathartic. Base: hydrogenated vegetable oil

Chlorpromazine Thorazine (SmithKline Beecham) 25, 100 mg SystemicAntiemetic; tranquilizer. Base: glycerin, glyceryl

monopalmitate, glyceryl monostearate, hydrogenated fatty acids of coconut and palm kernel oils

Hydrocortisone Anusol-HC (Warner-Lambert) 25 mg LocalPruritus ani, inflamed hemorrhoids, other inflammatory

conditions of the anorectum. Base: hydrogenated glyceridesHydromorphone Dilaudid (Knoll) 3 mg Systemic Analgesic. Base: cocoa butter with silicone dioxide

Mesalamine Canasa (Axcan Scandipharm) 500 mg Local Anti-inflammatory. Base: hard fatOxymorphone Numorphan (Endo) 5 mg Systemic Analgesic. Base: Polyethylene glycols 1000 and 3350

ProchlorperazineCompazine (SmithKline

Beecham)2.5, 5, 25 mg Systemic

Antiemetic. Base: glycerin, monopalmitate, glyceryl monostearate, hydrogenated fatty acids of coconut and palm

kernel oils

Promethazine Phenergan (Wyeth-Ayerst) 12.5, 25, 50 mg SystemicAntihistamine, antiemetic, sedative: used to manage allergic conditions; preoperative sedation or nausea and vomiting;

motion sickness. Base: cocoa butter, white wax.

Table 12.2: Examples of Vaginal Suppositories and TabletsProduct

(Manufacturer)Active Ingredients Category and

CommentsAVC Suppositories

(Novavax)Sulfanilamide 1.05g For Candida albicans

infectionsMonistat 7

Suppositories (Advanced Care

Products)

Miconazole nitrate 200mg

Antifungal for local vulvovaginal candidiasis (moniliasis)

Mycelex-G Vaginal Tablets (Bayer)

Clotrimazole 500mg Vulvovaginal yeast (Candida) infections

Semicid Vaginal Contraceptive Inserts (Robins Healthcare)

Nonoxynol-9 100mg Nonsystemic reversible birth

control

Multiple choices: Try it!Choices:

A. Rectal suppository B. Vaginal suppository C. Urethral suppository D. Local Action E. Systemic actionF. Tablet and capsules

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G. Ointments, creams, and aerosol formsH. Intrauterine progesterone drug delivery systemI. SolutionsJ. EnemasK. Suspensions

Questions:

1. ___ Protofoam2. ___ Globular oviform or conical in shape3. ___ Rectal suppository: relieves constipation or

pain, irritation, itching and inflammation like hemorrhoids and other anorectal conditions

4. ___ For males: weigh 4 grams, 100 to 150mm long

5. ___ Vaginal tablet and inserts6. ___ Cylindrical and tapered at one end 7. ___ For females: 2 grams, 60 to 70mm long8. ___ Mucous membrane of the rectum and

vagina: permits absorption of many soluble drugs

9. ___ Progestasert10. ___ Glycerin suppositories: laxative action by

irritating the mucous membranes through its dehydrating action

11. ___ Barium sulfate 12. ___ Retention and evacuation13. ___ Vaginal douches

Choices:

A. Aminophylline and theophyllineB. Prochlorperazine and chlorpromazineC. Chloral hydrateD. Oxymorphone HClE. Ergotamine tartrateF. AspirinG. Wecobee basesH. Witepsol basesI. Cocoa butterJ. Cocoa butter suppository baseK. Glycerinated gelatin suppository

Questions:

1. ___ Nausea and vomiting and as tranquilizers2. ___ Relief of asthma 3. ___ Narcotic analgesic4. ___ Derived from coconut oil5. ___ Saturated fatty acids C12 to C18

6. ___ Analgesic and antipyretic7. ___ Migraine syndrome8. ___ Sedative and hypnotic9. ___ Melts between 30o to 36oC10. ___ Below 350°F11. ___ In a refrigerator: 2o to 80oC or 68o to 770oF

Choices:

A. Colonic contentsB. Circulation routeC. pH and lack of buffering capacity of the rectal

fluidsD. Physicochemical factors of the drugE. Undesirable characteristics of a base

F. For systemic drug action using cocoa butter base

G. Different preparations of suppositoriesH. Suppository moldsI. First methodJ. Second method

Questions:

1. ___ Some factors of drug absorption from rectal suppositories

2. ___ Drug has greater absorption in the absence of fecal matter

3. ___ Irritating to the mucous membrane of the rectum, initiating a colonic response and prompt to a bowel movement: negating drug release and absorption

4. ___ Lymphatic circulation also assists in the absorption of rectally administered drug.

5. ___ Rectal fluids neutral in pH and have no effective buffer capacity therefore drugs do not chemically changed

6. ___ Preferable to incorporate ionized form (salt form) to maximize bioavailability

7. ___ Cold compression8. ___ Made from stainless steel, aluminium, bass

or plastic9. ___ Weigh the active ingredient for the

preparation of a single suppository10. ___ Total volume needed: volume of the drug

substance

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