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PHARMANEST - An International Journal of Advances In Pharmaceutical Sciences Vol. 2 (1) January - February 2011 www.pharmanest.net

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FORMULATION AND INVITRO EVALUATION OF ENTERIC COATEDTABLETS OF DIDANOSINE

*Vivek Kumar Undralla, 1Haranadh Reddy S, 1Sreerama Krishna T, 2A Seetha Devi, 2P Teja and 3KPR Chowdary*,1 Donbosco college of Pharmacy, Guntur, Andhra Pradesh, India.

2 Hindu College of Pharmacy, Guntur, Andhra Pradesh,3 Vishwabharathi College of Pharmaceutical sciences, Guntur, Andhra Pradesh,

INTRODUCTIONFrom time immemorial, drugs have been an inseparablepart of mankind’s history since they fulfill one of our mostbasic necessities. To administer these drugs in anappealing and palatable form and in the required amountand rate, they have to be developed into an acceptabledosage form. Thus, the concept of formulationdevelopment was evolved, resulting in solid, liquid andsemi-solid dosage form.

Solid dosage formsSolid dosage forms are widely prevalent due to their age-old application. Especially, oral solid formulations hold ahigh potential as they serve to be most convenient for theadministration of drugs. These have been developed intoa wide range of formulations from conventional dosageforms for immediate release of the drug to controlledrelease dosage forms(1) for the constant rate of drugrelease. Oral route is the most convenient and commonlyused method of drug delivery. The most commonly usedpharmaceutical solid dosage forms today includegranules, pellets, tablets and capsules Conventionalmedication systems that require multi-dose therapy arenot with out problems. With a view to overcoming theseproblems, the current trend in pharmaceutical researchis to design and develop new formulations, therebyenhancing the therapeutic efficacy of existing drugs

Controlled release (2) (CR) / Sustained release (SR)technology has rapidly emerged over the past threedecades as a new interdisciplinary science that offersnovel approaches to the delivery of bioactive agents intothe systemic circulation for a prolonged period at a

predetermined rate. The choice of drug to be delivered,clinical needs, and drug pharmacokinetics are some ofthe important considerations in the development of CR /SR formulations, in addition to the relationship betweenthe rates of drug release from the delivery system to themaximum achievable rate of drug absorption in to thesystemic circulation. The therapeutic advantages ofCR / SR systems over the conventional dosage formshave been amply documented in the literature. One ofthe important advantages is the reduced dosing frequency,thereby improving patient compliance and therapeuticefficacy. In order to be divisible, a CR / SR dosage formmust not loose its release characteristics upon division toavoid dose dumping.(3)

Although a variety of dosage forms have beendeveloped for the preparation of oral CR / SRformulations, they broadly fall in to two categories: singleunit dosage forms and multiple (multiparticulate) dosageforms.

Modified release delivery systems may be dividedconveniently in to four categories.

A) Delayed release (4) (Enteric coated drug deliverysystem)

B) Sustained release(5)

i) Controlled release

ii) Extended release

C) Site specific targeting

D) Receptor targeting

ABSTRACTThe project was undertaken with an aim to formulate, and evaluate Didanosine Enteric coated tablets using differentpolymers as release retarding agent . and overcome the gastric juice incompatability, Preformualtion study was doneinitially and results directed for the further course of formulation . Based on preformualtion studies different formulationbatches of Didanosine was prepared using selected excipient . Granules were evaluated for tests loss on drying ,bulk density , tapped density , compressibility index, Hausner ratio . Tablets were tested for weight variation ,thickness , hardness , friability and in vitro drug release as per official procedure . Change in dissolution parameterstudy made it suitable for minute physiological variables. Formulation of sustained release tablet of Didanosinecontaining 20 % of Ethyl cellulose Std 100p, diluents MCC and with binder Povidone i.e formulation batch F6 can betaken as an ideal or optimized formulation of Enteric coated sustained release tablets for 12 hour release as it full fillsall the requirements for sustained release tablet.



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Rate limiting step of Rate limiting step ofControlled drug delivery conventional dosage formSystem

DELAYED -ACTION AND ENTERIC COATED TABLETSThe delayed-action tablet dosage form is intended torelease a drug after some time delay, or after the tablethas passed through one part of the GI tract into another.The enteric coated tablet is the most common exampleof a delayed-action tablet product. All enteric coated(6)

tablets (which remain intact in the stomach but quicklyrelease in the upper intestine) are a type of delayed-actiontablet. Not all delayed – action tablets are enteric or areintended to produce the enteric effect.The compendia specifications for an enteric coated tabletare that all of the six tablets placed in separate tubes ofthe UPS disintegration apparatus (using discs) remainintact after 30 min of exposure in simulated gastric fluidat 37ÚC± 2ÚC and then disintegrate within the timespecified for that product’s monograph. If one or twotablets fail to disintegrate completely in the intestinal fluid,the test is repeated on 12 additional tablets; not less than16 of the total 18 tablets tested must disintegratecompletely. Prior to gastric exposure, the tablets areimmersed in water at room temperature for 5 minutes.The coatings that are used today to produce enteric effectsare primarily mixed acid functionality and acid esterfunctionality synthetic or modified natural polymers.Cellulose acetate phthalate has the longest history of useas an enteric coating. More recently, polyvinyl acetatephthalate(7) and hydroxypropyl methylcellulose phthalatehave come into use. All three polymers have the commonfeature of containing the dicarboxylic acid, phthallic acid,in partially esterified form. These polymers, being acidesters, are insoluble in gastric media that have a pH ofup to about 4; they are intended to hydrate and begindissolving as the tablets leave the stomach, enter theduodenum (pH of 4 to 6),and move further along the smallintestine, where the pH increases to a range of 7 to 8.The primary mechanism by which these polymers losetheir film integrity, thereby admitting intestinal fluid andreleasing drug, is ionization of the residual carboxyl groupson the chain and subsequent hydration. The presence ofesterase in the intestinal fluid that break down esterlinkages of the polymer chains may also play some role,as may surface activity effects of bile salts and othercomponents in bile that enter the upper small intestinevia the bile duct.

Fig 2: Schematic representing the rate limiting step in the

design of controlled drug delivery system

ObjectiveThe objective of the present study is to developcompetitive enteric sustained release tablets ofDidanosine for a period of 12hrs, by preparing granulesusing different polymers and study the effect of polymerson their release pattern.

Enteric coatings(8) are employed for a number oftherapeutic, safety, and medical reasons. Some drugsare irritating when directly exposed to the gastric mucosa,including aspirin and strong electrolytes such as NH4Cl.While for most people the occasional aspirin tablet maynot cause irritation, those on daily doses of aspirin, suchas arthritics, may find gastric upset a major problem.

Enteric coating is one method of reducing or eliminationirritation from such drugs. There are other drugs that ifreleased in the stomach may produce nausea andvomiting. The low pH of the stomach destroys others drugs(for example, erythromycin), and hence enteric coatingmay be necessary to bring the drug through thatenvironment to the more neutral intestinal contents. Yetanother reason for enteric coating may be the desire torelease the drug undiluted and in the highest concentrationpossible within the intestine. (Examples are intestinalantibacterial or antiseptic agents and intestinalvermifuges.) As in the case of repeat-action and othercontrolled-release dosage forms, the influence of alteringthe release profile of the drug on total drug bioavailability,distribution, and pharmacokinetics must be investigated.



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PREFORMULATION STUDIESPreformulation testing is an investigation of physicalproperties of a drug substances alone and when combinedwith excipients. It is the first step in the rationaldevelopment of dosage forms.

Identification of drugThe identification of drug was done by Differential scaningchromatography (DSC). The DSC spectrum of pure drugdidanosine is shown

DSC Studies methodDSC studies(9) were performed for pure drug. Accuratelyweighed 5-6 mg samples were hermetically sealed inaluminium pans and heated at constant rate of 10oC/minover a temperature range of 40 to 300 oC. Inertatmosphere was maintained by purging nitrogen gas at aflow rate of 50ml/min. Indium/zinc standards were usedto calibrate the temperature and enthalpy scale.

MANUFACTURING PROCEDURE OF ENTERIC COATEDTABLETS

Weighing & Sifting: Accurately weigh requires quantity ofdidanosine and sifted through #40 mesh.

Mixing: Ethylcellulose, Microcrystalline cellulose, povidonewere passed through #40 mesh and added to the abovegranular material and blended for 5 min and prepare dampmass and finally pass through #24 mesh and allow thegranules at 40ÚC.

Lubrication: Magnesium stearate and aerosil were passedthrough 60#and added to the above blended material.

Compression: compress the blend into tablets with punchsize of 20 x 7mm rod shaped

Coating: Tablets are taken in a coating pan and coatinghave done.

Preparation of coating solution: Take required quantity ofisopropyl alcohol stir with propeller stirrer to form vortex.Add quantity of Eudragit in vortex stir for 25 mins. Maintainthe solution without air bubbles then use the solution forcoating. Quantity of tablets to be coated is 100 TabEXPERIMENTAL

FORMULATION OF DIDANOSINE ENTERICCOATED SUSTAINED RELEASE TABLETS



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DISSOLUTION TESTMany procedures have been proposed for determiningdissolutions rates from solid dosage form. In the presentinvestigation 8 baskets dissolutions apparatus investigatedthat drug release from the tablets. Dissolution studies(10)

were performed using USP standard dissolutionapparatus at 37 ± 0.5ºC.Using one tablet at a time in avessel. The basket was immersed in 900ml of dissolutionmedium and rotated at 50 rpm. The dissolution Mediaused was initially 0.1N Hcl up to 2hrs, then continuationwith fasted buffer having pH6.8During the test 10ml of the sample was withdrawn atspecific time intervals 1, 2, 4, 6, 8, 10, 12 hrs after eachwithdrawal, same volume of fresh dissolution medium wasadded to maintained sink conditions. Different aliquotswere suitably diluted. The absorbance was measured inthe UV spectrophotometer at ëmax 248nm.In the present study (In house specification) apparatusI was for the determination of drug release

VII. STABILITY STUDYFor all the pharmaceutical dosage forms it is important todetermine the stability of the dosage form. This will includestorage at both normal and exaggerated temperatureconditions, with the necessary extrapolations to ensurethe product will, over its designed shelf life, providemedication for absorption at the same rate as whenoriginally formulated. The design of the formal stabilitystudies for the drug product should be based on theknowledge of the behavior and properties of the drugsubstance and formal stability studies on the drugsubstance



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MethodTen tablets were individually wrapped using aluminum foiland packed in ambered color screw cap bottle and put atabove specified condition in incubator for 2 months. Aftertwo months tablets were evaluated for content uniformityand invitro drug release.

ObservationPhysical evaluation report

No significant difference was observed in the weight ofindividual tablets from the average weight. The data ofuniformity of content indicated that tablets of all batcheshad drug content within pharmacopoeia limits. Thehardness of tablets of all batches are in acceptable limits,which shows in the literature. All the formulation showed% friability less than 1% that indicates ability of tablets ofwithstands shocks, which may encounter. No significantdifference was observed in the thickness of individualtablet from the average weight.Standard calibration curve of Didanosine tablets wereprepared in two media i.e 0.1N Hcl and phosphate buffer6.8pH. Correlation coefficient values indicate the linearcorrelation between concentration and absorbance andfollowing lamberts beers law.

The release of Didanosine from enteric coated sustainedrelease tablet of various formulations varied according tothe ratio and degree of the polymer. In case of tablet ofF1 containing Drug & 10% Ethyl cellulose Med 70p, withpovidone and MCC shows the 91% of drug release within 8hrs, In case of Formulation F2 containing Drug and15%Ethyl cellulose Med 70 P with povidone, MCC showsmaximum release in 8hrs only,.In case of tablet of F3 containing Drug & 20% Ethylcellulose Med 70p, with povidone and MCC shows the95% of drug release with in 10hrs, In case of FormulationF4 containing Drug and 10%Ethyl cellulose Std 100 Pwith povidone, MCC shows maximum release in 10hrsonly, In case of tablet of F5 containing Drug & 15% Ethylcellulose Std 100p, with povidone and MCC shows the96% of drug release with in 10hrs, In case of FormulationF6 containing Drug & Ethyl cellulose Std 100FP 20%,povidone, MCC, shows accurate results that is drugrelease up to 12hrs. In case of Formulation F7 containingDrug and 10%Ethyl cellulose Med 50 P with povidone,MCC shows maximum release in 10hrs only, In case ofFormulation F8 containing Drug and 15%Ethyl celluloseMed 50 P with povidone, MCC shows maximum releasein 10hrs only, In case of Formulation F9 containing Drugand 12%Ethyl cellulose Med 50 P with povidone, MCCshows maximum release in 10hrs only, from the abovedata In case of tablet of F6 containing Drug & Ethylcellulose Std 100FP 20%, povidone, MCC, showsaccurate results that is drug release up to 12hrs.No significant change was observed in Formulation-6 fromthe stability study results, After the stability study allphysical and dissolution test and assay have done andshows no change observed.

RESULTS AND DISCUSSIONThe procured sample of Didanosine was tested for itsidentification. The manufacturer also was confirmed ofquality and purity of sample.The drug – excipients compatibility was done ataccelerated temperature 25oC/55% ± 5% and 30o C/60% ± 5% relative humidity. Opened and closed vialmethods were used. The result doesn’t show any physicalchange to the mixture after 30 days. This fact concludedthat the drug and Excipient are compatible with each other.The Enteric coated sustained release tablet of Dedanosinewere prepared by wet granulation method, They wereevaluated for weight variation, drug content, friability,hardness, and thickness for all batches (F1 to F9).



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REFFERENCES1. Rubinstein, M. H. Tablets. In Pharmaceutics: The Scienceof dosage form design. Aulton, M. E. Ed.; Churchill Livingstone: New York, 2000, pp. 305.

2. Chien, Y. W. Rate control drug delivery systems:controlled release vs. sustained release. Med. Prog.Techn. 1989, 15, 21-46.

3. Chein, Y. W. Novel Drug Delivery System Vol. 14,Marcel Dekker Inc. New York. 1992, pp. 139-196.

4. Grass, G. M.; Robinson, J. R. Sustained andControlled release drug delivery systems. In ModernPharmaceutics. Vol. 40; 2nd ed., Banker, G. S.;Rhodes, C. T.; Eds.; Marcel Dekker Inc: New York.1990, pp. 635-638.

5. Lordi, N. G. Sustained release dosage forms. In TheTheory and Practice of Industrial Pharmacy. 3rd ed.,Lachman, L.; Lieberman, H. A.; Kanig J. L. Eds.;Lea and Febiger: Philadelphia, 1991, pp. 430-435.

6. Robinson, R.; Lee, V. H. Influence of Drug Propertiesand route of Drug Administration on the design ofsustained and controlled release drug deliverysystem. In Controlled Drug Delivery Fundamentalsand Applications. Vol. 29; 3rd ed., Robinson, R.;Lee, V. H.; Eds.; Marcel Dekker Inc: New York, 1995,pp. 3-35.

7. Lee, V. H. L.; Yang, J. J. Oral Drug Delivery. In DrugDelivery and Targeting. Hillery, A. M.; Llyod, A.W.;Swarbrick, J.; Eds. Taylor and Francis: London andNew York, 2001, pp.165- 168.

8. Hui, Ho- Wah; Robinson, J. R. Design andFabrication of Oral controlled release release drugdelivery systems. In Controlled Drug DeliveryFundamentals and Applications. Vol. 29; 3rd ed.,Robinson, R.; Lee, V. H.; Eds.; Marcel Dekker Inc:New York, 1995, pp. 373-378

9. Aulton, M. E. Pharmaceutics The Science of DosageForm Design. Churchill Livingstone. 2002, 2nd ed.,pp. 414-418.

10. Shargel, L.; Wu- Pong, S.; Yu, A. B. AppliedBiopharmaceutics and Pharmacokinetics. 5th ed.,Mc. Graw Hill, 2005, pp. 515-520.10.

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