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FORMULATION AND EVALUATION OF DARIFENACIN HYDROBROMIDE EXTENDED RELEASE MATRIX TABLETS
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FORMULATION AND EVALUATION OF DARIFENACIN HYDROBROMIDE EXTENDED RELEASE MATRIX TABLETS
Presented by: S.Meraj sultana, Department of pharmaceutics, Narasaraopeta Institute Of Pharmaceutical Sciences.
1.INTRODUCTION• Oral route is the most oldest and convenient route for the administration of therapeutic agents because of
low cost of therapy and ease of administration leads to higher level of patient compliance.
• Approximately 50% of the drug delivery systems available in the market are oral drug delivery systems
and historically too, oral drug administration has been the predominant route for drug delivery.It does not
pose the sterility problem and minimal risk of damage at the site of administration.
• During the past three decades, numerous oral delivery systems have been developed to act as drug
reservoirs from which the active substance can be released over a defined period of time at a
predetermined and controlled rate.
• The oral controlled release formulation have been developed for those drug that are easily absorbed from
the gastrointestinal tract (GIT) and have a short half-life are eliminated quickly from the blood circulation.
• As these will release the drug slowly into the GIT and maintain a constant drug concentration in
the plasma for a longer period of time.
• In oral controlled drug delivery the amount of drug release is constantly predetermined and these
constant releases of drug provide a constant blood plasma level of the drug for optimal
therapeutic response. The oral controlled drug delivery has many advantages to conventional drug
delivery.
• The ideal and most important objectives of drug delivery are spatial placement and temporal
delivery of the drug.
• Spatial placement relates to targeting a drug to a specific organ or tissue, while temporal delivery
refers to controlling the rate of drug delivery to the target tissue.
The potential problems associated with conventional (multiple dosages) delivery are:
• If the dosing is not appropriate according to the biological half-life of the drug, the concentration
of drug level in blood may result in large "Peaks" and "Valleys".
• For example, drugs with short half-lives require frequent dosing to maintain constant therapeutic
levels.
• The drug blood level may not be within the therapeutic range at sufficiently early times, an
important consideration for certain disease states.
• Patient noncompliance with the multiple-dosing regimen can result in failure of the conventional
approach.
Frequently these problems are significant enough to make drug therapy with conventional dosage forms less desirable than sustained release drug therapy.
This fact, coupled with the intrinsic inability of conventional dosage forms to achieve spatial placement, is a compelling motive for investigation of sustained-release drug delivery systems.
2.EXTENDED RELEASE SYSTEM:
• Extended release drug delivery system achieves a slow release of the drug over an extended period of time
or the drug is absorbed over a longer period of time.
• Extended release dosage form initially releases an adequate amount of drug to bring about the necessary
blood concentration (loading dose, DL) for the desired therapeutic response and therefore, further amount
of drug is released at a controlled rate (maintenance dose, DM) to maintain the said blood levels for some
desirable period of time.
• Extended release formulation is an important program for new drug research and development to meet
several unmet clinical needs.
• There are several reasons for attractiveness of these dosage forms viz. provides increase bioavailability of
drug product, reduction in the frequency of administration to prolong duration of effective blood levels,
reduces the fluctuation of peak trough concentration and side effects and possibly improves the specific
distribution of the drug.
Objectives of Extended Release Drug Delivery System:
Every noval drug delivery system had a rationale for developing the dosage form likewise,
ERDDS also having some objectives that are discussed below:
Suitable Drug Candidate for Extended Release Drug Delivery System
• The drugs that have to be formulated as a ERDDS should meet following parameters.
• It should be orally effective and stable in GIT medium.
• Drugs that have short half-life, ideally a drug with half life in the range of 2 – 4 hrs makes a
good candidate for formulation into ER dosage forms eg. Captopril, Salbutamol sulphate.
• The dose of the drug should be less than 0.5g as the oral route is suitable for drugs given in dose
as high as 1.0g eg. Metronidazole.
• Therapeutic range of the drug must be high. A drug for ERDDS should have therapeutic range
wide enough such that variations in the release do not result in concentration beyond the
minimum toxic levels
Merits of Extended Release Drug Delivery System:
• The extended release formulations may maintain therapeutic concentrations over prolonged periods.
• Avoids the high blood concentration.
• Reduce the toxicity by slowing drug absorption.
• Minimize the local and systemic side effects.
• Improvement in treatment efficacy.
• Minimize drug accumulation with chronic dosing.
• Improvement of the ability to provide special effects.
• Enhancement of activity duration for short half life drugs.
Demerits of Extended Release Drug Delivery System:
• In case of acute toxicity, prompt termination of therapy is not possible.
• Less flexibility in adjusting doses and dosage regimens.
• Risk of dose dumping upon fast release of drug.
• High cost of preparation.
• The release rates are affected by various factors such as, food and the rate transit through the gut.
• The larger size of extended release products may cause difficulties in ingestion or transit through gut.
3.Matrix System
A polymer and active ingredient are mixed to form a homogenous mixture called as matrix system. The matrix
system is often used for a controlled drug release from a pharmaceutical dosage form; it is used for delay and
control release of the drug that is dissolved or dispersed in a resistant support.
Advantages of Matrix System :
• With proper control of manufacturing process, reproducible release profiles are possible.
• There is no risk of "dumping" a large part of dose, as the structure makes the immediate release of a small
amount of active principle unavoidable.
• Their capacity to incorporate active principle is large, which suits them to deliver large dosag
Principle of Modified Drug Release
Either of the following two principles can modify drug release:
1.Barrier principle • In this method the retardant material is imposed between the drug and elution medium. Drug release is by
diffusion of the drug through the barrier and or erosion of the barrier or permeation of the barrier by moisture.
2.Embedded matrix
• In this drug is dispersed or embedded in a matrix of retardant material that may be encapsulated in
particulate form or compressed into tablet. Drug release occurs by permeation of water leaching extraction
or diffusion of drug from the matrix and erosion of matrix material.
5.Mechanisms of Drug Release from Matrix
7. OVER ACTIVE BLADDER
• Overactive bladder (OAB) is a syndrome characterised by urinary urgency, with or without
urgency urinary incontinence(UUI) usually with frequency and nocturia, in the absence of
causative infection or pathologic conditions and suggestive of underlying detrusor
overactivity (phasic increases in detrusor pressure).
• Urgency, is defined as the sudden compelling desire to urinate, a sensation that is difficult
to defer.
• UUI is urinary leakage associated with urgency. Some women may have both stress
urinary incontinence and UUI, and this is called mixed urinary incontinence.
• Urinary frequency is defined as voiding 8 or more times in a 24-hour period.
• Nocturia is defined as the need to wake 1 or more times per night to void.
CAUSES:
• Overactive bladder is typically caused by spasms of the muscles of the bladder, resulting in an urge to urinate (hence, urge
incontinence).
• Overactive bladder is primarily a problem of the nerves and muscles of the bladder.
• Detrusor is one of the major muscles of the bladder. Its contraction in response to filling of the bladder by urine is one the steps in
the normal process of urination.
• The contraction and relaxation of the detrusor muscle is regulated by the nervous system. Approximately 300 cc of urine in the
bladder can signal the nervous to trigger muscles of the bladder to coordinate urination.
• Voluntary control of the sphincter muscles at the opening of the bladder can hold the urine in the bladder for longer. Up to 600 cc
of urine can be contained in a normal adult bladder.
• Overactive bladder typically results from inappropriate contraction of the detrusor muscle regardless of the amount of urine.
• There are also some causes of overactive bladder and urge incontinence with a normal nervous system. For example,
urinary tract infection, bladder stones, or bladder tumors can cause also cause overactivity of the detrusor muscle, leading to
overactive bladder.
TREATMENT OF OAB
• Anticholinergics inhibit the binding of acetylcholine to the muscarinic receptor in the detrusor, thereby suppressing
involuntary bladder contractions.
• They are associated with an increase in bladder volume voided, as well as a decrease in micturition frequency and
sensation of urgency.
• Muscarinic antagonists are the drugs that bind with muscarinic cholinergic receptors but do not activate them, thus
preventing access to acetylcholine; examples include atropine, scopolamine, propantheline, and pirenzepine.
• Muscarinic receptor are typical G protein coupled receptors and 5 molecular subtypes (M1,M2,M3,M4,M5) are
known.
• The odd numbered M1,M3,M5 are coupled with Gq to activate the ionositol phosphate path way while even
numbered recptors M2 and M4 act through Gi to inhibit the adenylate cyclise.Three of these (M1,M2,M3) are well
characterised.
• M1 receptors are found mainly on CNS and Perepheral neurons and gastric parietal cells. They mediate
excitatory effect by decreasing the k+ conductance which causes membrane depolarisation.
• M2 receptors (cardiac) occur in heart and also on presynaptic terminals of central and peripheral neurons.
They exhibit inhibitory effects by increasing k+ conductance and by inhibiting calcium channels.
• M3 receptors (glandular,smooth muscles) produce mainly excitatory effects i.e stimulation of glandular
secretions (salivary, bronchial, sweat,etc) and contractions of visceral smooth muscles.
• M3 receptors also mediate relaxation of smooth muscle.
LITERTURE REVIEW
1.Darifenacin hydrobromide sustained-release tablet and preparation method –Chuangxin pharmaceuticals RES AND
DEV CO LTD: This invention belongs to medicine technology field specifically relates to a darifenacin hydrobromide
slow release tablet and preparation method thereof the invention claims a darifenacin hydrobromide slow release tablet
adopts the new retardant carbomer relative to the existing technology high expression processing method of a half of the
retarding agent dosage of carbomer of occupying the preparation by weight 1%- 5% ~ it can achieve the same as the
exterior of the releasing speed and biological utilization degree; New method of a retarding agent dosage of is greatly
reduced it can greatly reduce the material the using amount of the technique is simple controllability is good the efficiency
is improved the production cost is reduced greatly.
2.K.P.Sampath Kumar et al., (2012), reviewed recent trends in scope and opportunities of control release oral drug delivery
systems. Many of new therapeutics under development are large molecules such as peptides, proteins, oligonucleotides,
and vaccines. Their physical, chemical, and biopharmaceutical attributes distinct from small molecule drugs demand novel
controlled release technologies to diminish barriers for oral delivery, such as instability in GI tract and poor absorption.
Those unmet technology needs create great opportunities for research, development, and innovation. It is optimistic that
breakthroughs in controlled oral delivery for water-insoluble drugs and biopharmaceuticals will have a significant impact
on pharmaceutical and biotechnology industry. This article examines several aspects in oral drug delivery requiring
implementation of novel ideas to improve oral drug delivery systems. Drug Delivery is a burgeoning field that represents
one of the major research and development focus areas of pharmaceutical industry today, with new drug delivery system
sales exceeding 10 billion dollars per year.
3.Harnish Patel et al., (2011), reviewed on Matrix Type Drug Delivery System. Matrix system are favoured
because of their simplicity, patient compliance etc, than traditional drug delivery (TDS) which have many
drawbacks like repeated administration, fluctuation in blood concentration level etc. Developing oral
sustained release matrix tablet with constant release rate has always been a challenge to the pharmaceutical
technologist. Most of drugs, if not formulated properly, may readily release the drug at a faster rate, and are
likely to produce toxic concentration of the drug on oral administration. Hydrophilic polymers have become
product of choice as an important ingredient for formulating sustained release formulations.
4.Ranjani et al., to develop model extended-release matrix tablet formulations for metoprolol tartarate(100mg)
sufficiently sensitive for regulatory policy development on scale-up and post approval changes for modified
release dosage forms. Several grades and levels of Methocel K4M, K15M, K100M filler binders were
studied. Three granulation process were evaluated direct compression, fluid-bed or high-shear granulation.
At a fixed polymer level, drug release from the higher viscosity grades (K100LV). The study led to the
choice of MethocelK100V as the hydrophilic matrix polymer and fluid-bed granulation as the process choice
for further evaluation of critical and non-critical formulation and processing variables.
AIM OF THE STUDY :
The aim of the present study is to develop a robust formulation of anti muscarinic drug as an
extended release matrix tablets. The polymers like HPMC K4M, HPMC K15M and HPMC K100M,
Metalose 60 SH-50 and Xanthum gum were used as extended release polymer to retard the drug
release. The invitro release pattern of final formulation was compared with the innovator.
OBJECTIVE
• The overall objective of the work is as follows
• To formulate and evaluate extended release Darifenacin hydrobromide by using various rate
controlling polymers.
• To study the drug release profiles of the dosage form and to develop an optimized dosage form with
better dissolution profile.
• To study the drug release profiles of formulations and To compare their drug-release profile with the
innovator.
• To determine the best fit dissolution profile for dosage form.
• To study the stability of dosage form.
PLAN OF WORK
1.Literature review
2.Procurement of API and Excipients
3.Preformulation Studies:
• API Characterization
• Drug Excipient Compatibility Studies
• FTIR Studies
• Formulation of Darifenacin Hydrobromide extended release
matrix tablets by using various drug: polymer ratios.
4.Precompression Characterization:
• Bulk Density• Tapped Density• Compressibility Index• Hausner’s Ratio• Angle of Repose 5.Postcompression Characterisation:
• Weight Variation• Hardness• Friability• Uniformity of drug content• In vitro dissolution studies• Comparison of drug release profile• Study of Drug release kinetics• Stability studies of the optimized formulation
Preformulation studies
Preformulation study was an investigation of physical and chemical properties of a drug substance alone and when combined with excipients. It was the first step in the rational development of dosage forms.
1. Objective /Purpose of Preformulation study:-• Pre-formulation studies on active pharmaceutical ingredients (API), inactive ingredients (Excipients), and their
combinations were carried out to serve following purposes:• To Finalize specifications of active pharmaceutical ingredients (API)• To Study the compatibility between active and inactive ingredient• Characterization of reference product.
2. Scope:-• The use of preformulation parameters maximizes the chances in formulating an acceptable, safe, efficacious and stable
product.
3. Class: - Preformulation study can divide in to two Subclasses.• API characterization, • Excipient Compatibility study
Active pharmaceutical ingredient (API) characterization:-• The API was characterized for its physicochemical properties of the bulk drug like physical appearance, solubility, bulk
density, tapped density, compressibility and sieve analysis.
FTIR Study • The compatibility between the drug and excipients is important; and was detected using infra-red spectra. • Infrared spectrum of drug alone and along with excipients should be tested and observe from 400 nm - 4000 nm.
12. DRUG PROFILE
• Name of Drug : Darifenacin hydrobromide
• Chemical Name : (S)-2-{1-[2-(2,3-dihydrobenzofuran-5-yl)ethyl]-3-
pyrrolidinyl}-2,2-diphenylacetamide hydrobromide
• Formula : C28H30N2O2.HBr.
• Molecular Weight : 507.47 Daltons
• Structure:
• Appearance : White to almost white, crystalline powder
• Solubility : Soluble in dichloromethane, sparingly soluble in ethanol, practically insoluble in water
• Storage : Store in a cool, dry place. Store in a tightly closed conatiner
• Stability : Stable under normal temperature & pressure
• Melting point : 229°C
• Pka (25oC) : 9.2
• Loss On Drying : Not more than 1.0%
• Pharmacological Class: Genitourinary antispasmodic agent; an Antimuscarinic agent.
• Therapeutic Category: Symptomatic treatment of urge incontinence and/or increased urinary frequency
and urgency as may occur in adult patients with overactive bladder syndrome.
• Mechanism of Action: Darifenacin has greater affinity for the M3 receptor than for the other known
muscarinic receptors (9- and 12-fold greater affinity for M3 compared to M1 and M5, respectively, and 59-
fold greater affinity for M3 compared to both M2 and M4). M3 receptors are involved in contraction of
human bladder and gastrointestinal smooth muscle, saliva production, and iris sphincter function
Pharmacokinetics:
• Absorption: Bioavailability of approximately 15% and 19% after 7.5 mg and 15 mg daily doses at steady state.
Maximum plasma levels are reached approximately 7 hours after administration of the prolonged-release tablets
and steady-state plasma levels are achieved by the sixth day of administration.
• Distribution: 98% of darifenacin are bound to plasma proteins; steady-state volume of distribution (V ss) is
estimated to be 163 liters.
• Metabolism: By CYP3A4 and CYP2D6; Three main metabolic routes:
• Monohydroxylation in the dihydrobenzofuran ring,
• Dihydrobenzofuran ring opening and
• N-dealkylation of the pyrrolidine nitrogen
• Elimination: Approx. 60% urine; 40% faeces.
• Clearance: 40 L/h.
• Half life: 4-6 hours
Pharmacodynamics
• Metabolized principally by CYP2D6 and CYP3A4.
Side effects:
• Adverse drug effects such as dry mouth, constipation and abnormal vision may be mediated
through effects on M3 receptors in these organs. Urinary retention, gastric retention, or
uncontrolled angle-closure glaucoma or risk of these conditions.
Recommended Dose:
• The recommended starting dose is 7.5 mg daily. After 2 weeks of starting therapy, patients
should be reassessed. For those patients requiring greater symptom relief, the dose may be
increased to 15 mg daily, based on individual response.
EXCIPIENT PROFILE
• Dibasic calcium phosphate
• Hypromellose (hydroxypropyl methylcellulose)
• Xanthan gum
• Magnesium stearate
DIBASIC CALCIUM PHOSPHATE
Table 1. Excipient profile of dibasic calcium phosphate
Synonyms A TAB; calcium monohydrogen phosphate; calcium orthophosphate, Di-Cafos AN, Dicalcium orthophosphate; E34 1; Emcompress Anhydrous; Fujicalin; phosphoric acid calcium salt (1 : 1); secodary calcium phosphate.
Description
Anhydrous dibasic calcium phosphate is a white, odorless,tasteless powder or crystalline solid. It occurs as triclinic crystals.
Functional Category
Tablet and capsule diluent.
Solubility: Practically insoluble in ether, ethanol and water; soluble in dilute acids.
Safety: Widely used in oral pharmaceutical products, food products, and toothpastes and is generally regarded as a relatively nontoxic and nonirritant material.
Applications: used both as an excipient and as a source of calcium in nutritional supplements.
HYPROMELLOSE
Table2. Excipient profile of Hypromellose
Synonyms Benecel, HPMC, Methocel, Hydroxy propyl methyl cellulose
Description
White or creamy white fibrous or granular, odorless, tasteless powder.
Functional Category Coating agent, film former, rate controlling polymer for sustained release, stabilizing agent, suspending agent, viscosity builder.
Solubility: Soluble in cold water, forming a viscous colloidal solution, practically insoluble in mixtures of ethanol and dichloromethane, mixtures of alcohol and water
Applications: High viscosity grades may be used to retard the release of drugs from a matrix at levels of 10-80%w/w in tablets and capsules .
XANTHUM GUM
Table3. Excipient profile of xanthum gum
Synonyms Corn sugar gum; E415; Grindsted; Keldent; Keltrol; polysaccharide B-1459; Rhodicare S; Rhodigel; Vanzan NF; xanthani gummi;Xantural.
Description
Xanthan gum occurs as a cream- or white-colored, odorless, freeflowing, fine powder.
Functional Category Gelling agent; stabilizing agent; suspending agent; sustained-release agent; viscosity-increasing agent.
Solubility: Practically insoluble in ethanol and ether; soluble incold or warm water.
Applications: Xanthan gum is widely used in oral and topical pharmaceutical formulations, cosmetics, and foods as a suspending and stabilizing agent.
Although primarily used as a suspending agent, xanthan gum has also been used to prepare sustained-release matrix tablets.
MATERIALS AND EQUIPMENT The following are the list of materials and equipments used in developing the
formulation:
S. No
Material Name of supplier
1.
Darifenacin HydrobromideShasun Chemicals
and Drugs Ltd
2. Dibasic Calcium phosphateSignet chemicals
Ltd.
3. HPMC K4M Colorcon
4. HPMC K15M Colorcon
5. HPMC K100 Colorcon
6. Metalose 60 SH 50Signet Chemicals
Ltd.
s.no Name of the
Instrument
Manufacturer
1
Electronic
weighing
balance
Sartorious
precision
balance
2Octagonal
Blender
Rimet kalveka
3Tablet hardness
tester
Pharmatron
tablet tester 8m
4Digital Vernier
callipers
Fischer
scientific
5Friability Tester
uspElectrolab
6
Bulk and
Tapped Density
Apparatus USP
Electrolab
7
dissolution
apparatus
USP I (basket)
Electro lab
S.NO INGREDIENTS USES
1 Darifenacin Hydrobromide Antispasmodic
2 Di-BasicCalciumPhosphate(A-Tab) Diluent
3 Methocel K 4 M(Viscocity =4000mpas) Matrix polymer and binder
4 Methocel K 15 M(Viscocity =1500mpas) Matrix polymer and binder
5 Methocel K 100 M(Viscocity =100000mpas) Matrix polymer and binder
6 HPMC (Viscocity= 50,4000,10000mpas)(Metalose 60 SH 50)
Matrix polymer and binder
7 Xanthan Gum Binder
8 Magnesium Stearate Lubrient
9 Opadry yellow Coating polymer
REFERENCES
1.Clive G Wilson and Patrick J Crowley. "Controlled Release in Oral Drug Delivery".
2.Modi S A, Gaikwad P D, Bankar V H, Pawar S P, Sustained release drug delivery system: A review,
International Journal of Pharma. Research and Development, 2011, 02(12), 147-59.
3.Chien Y W, "Novel Drug Delivery System", Marcel Dekker, New York, 2nd edition, Revised and Expanded, Vol
II, 1992, 139-140.
4.Aulton M E. "Hand Book of Pharmaceutics", ELBS with Churchill Livingstone, Hong Kong, 2001, 291-295.
5.Vallabh Prakashan, 1st edition, 1995, 347-3716.Increased warning time with Darifenacin: a new concept in the
management of urinary urgency Cardozo, Linda Dexon Andria, The journal of urology,173(4),p.1214-
1218,Apr 2005.
6.Darifenacin-Pharmacology and clinical usage. Steers,William D-urologic clinics of NA 33(4),p.475-482,Nov
2006.
7.Increased warning time with Darifenacin: a new concept in the management of urinary urgency Cardozo, Linda
Dexon Andria, The journal of urology,173(4),p.1214-1218,Apr 2005.