DESIGN AND EVALUATION OF PANTOPRAZOLE DELAY RELEASE CAPSULES

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1 RESEARCH ARTICLE DESIGN AND EVALUATION OF PANTOPRAZOLE DELAY RELEASE CAPSULES KOTTAKRANTHI KUMAR* 1, V.RAVEENDRANATH 1, LEELA MADHURI.P 1, N.DORABABU, S and M.D ZAKIR HUSSAIN Narsaraopet Institute of Pharmaceutical Science, Guntur Dt, (A.P), India 2. M.R.R College of Pharmacy, (A.P), India. ABSRACT: In recent years scientific and technological advancements have been made in the research and development of delay release delivery systems. There are so many oral delivery systems in that one of the advance techniques is Pellatization. Pantoprazole delay release capsules prepared by pellatization method that the pantoprazole is coated on inert sugar spheres by using povidonek-30 as a binder solutions and Hydroxypropylmethylcellose as coating agents and enteric coating agent Methacrylic acid copolymer(eudragit) used for delay release action. The prepared capsules were evaluated for content uniformity weight variation, in-vitro disintegration time, assay, and in-vitro drug release study. All the formulation exhibited assay, content uniformity within the range given in USP. Dissolution studies revealed that formulations trial batch-8 Showed 100% of drug release, at 60min.When compare with US dissolution parameters, with reference drug release. Thus, the capsules apart from fulfilling all official and other specifications and exhibited higher rate of drug release. KEYWORDS: Pantoprazole Hydroxy propyl methyl cellose, Povidone-30,Methacrylic acid copolymer. INTRODUCTION The treatment of acute diseases or chronic illness has been achieved by delivery of drugs to the patients for many years. These drug delivery systems include tablets, injectables, suspensions, creams, ointments, liquids and aerosols. Today these conventional drug delivery systems are widely used. The term drug delivery can be defined as techniques that are used to get the therapeutic agents inside the human body. Conventional drug therapy requires periodic doses of therapeutic agents. These agents are formulated to produce maximum stability, activity and bioavailability. For most drugs, conventional methods of drug administration are effective, but some drugs are unstable or toxic and have narrow therapeutic window. Some drugs also possess solubility problems. In such cases, a method of continuous administration of therapeutic agent is desirable to maintain fixed plasma levels in the body. Delay release drug delivery 2, 3 The delivery of drug at a rate or at a location determined by needs of body or disease state over a specified period of time. The oral controlled release systems are classified as follows: A) Continuous release systems B) Extended release systems C) Time release systems The release system is formulated to dissolve solely and release a drug over time. The advantages of Controlled release tablets capsules are Vol.1 (2) Nov-Dec-2010 An International Journal of Advances In Pharmaceutical Sciences 213

2 that they can often less frequently than instate release formulations. DELAY RELEASE DRUG DELIVERY SYSTEM :- The design of such system involves release of drugs only at a specific site in the gastrointestinal tract. The drugs contained in such a system are those that are: i) Destroyed in the stomach or by intestinal enzymes ii)known to cause gastric distress iii)absorbed from a specific intestinal site or iv) Meant to exert local effect at a specific gastrointestinal site The two types of delayed release systemsare: 1. Intestinal release systems 2. Colonic release systems 1.Intestinal release systems: A drug may be enteric coated for intestinal release for several known reasons such as to prevent gastric irritation, prevent destabilization in gastric phetc. 2. Colonic release systems: Drugs are poorly absorbed through colon but may be delivered to such a site for two reasonsa) Local action in the treatment of ulcerative colitis & b) Systemic absorption of protein and peptide drugs Advantage is taken of the fact that phsensitive bioerodible polymers like polymethacrylates release the medicament only at the alkaline ph of colon or use of divinylbenzene cross-linked polymers that can be cleaved only by the azoreductase of colonic bacteria to release free drug for local effect or systemic absorption.the present study PANTOPRAZOLE DELAYED RELEASE CAPSULES Pantoprazole Delayed Release Capsules comes under intestinal release systems. It is used to treat ulcers. The basic goal of controlled drug delivery system is to achieve a steady blood or tissue level of a drug at a specific site, which will be therapeutically effective and non-toxic. In this study, the entericcoated pellets and tablets deliver the drug almost at a predetermined rate locally for a specified period of time at a specific site by reducing adverse effect. Pantoprazole is a proton pump inhibitor used to treat peptic ulcer, duodenal ulcer, gastro oesophageal reflux disease by inhibiting the enzyme H + /K + ATPase, the acidic pump. It is also used to treat Zollinger- Ellison syndrome, erosive esophagitis. REASONS FOR DEVELOPING DELAY RELEASE DRUGDELIVERY SYSTEM The pantoprazole in tablet form of the prior art may cause problems in patients with swallowing difficulty, due to its size. This drawback is avoided with the use of multiparticulate formulations, since they may be dispersed in liquids at the moment of the administration. It should be kept in mind that pharmaceutical compositions formulated in tablets are subject to variations in their physicochemical properties such as hardness, disintegration time, and dissolution time and also on dissolution rate due to the compression process involved in their production. Such variations are of course undesirable in delayed release pantoprazole capsules, since the prediction of the dissolution rate is an extremely important factor for the efficiency of the formulation. Finally delayed release multi particulate formulations of pantoprazole of the invention advantageously provide a better drug release at the gastrointestinal tract compared with single tablets formulations. Vol.1 (2) Nov-Dec-2010 An International Journal of Advances In Pharmaceutical Sciences 214

3 Reason for selecting pellets The smaller size of each particle, provided by pellets (multiparticulate), also contributes to delay the release, since it reduces the influence of factors such as quality and periodicity of food ingestion and the activity periods and body rest during the day. The smooth surface and the uniform size of the pellets allow uniform coating not only for each pellet but also from batch to batch. The aim and objectives of the present study was to develop a pharmaceutically equivalent, stable, cost effective and quality improved formulation of pantoprazole enteric coated tablets and pellets to present it in the form of capsules (delayed release capsules) and these were compared with that of the marketed dosage form. To achieve this goal various prototype formulation trails were taken and evaluated with respect to the various quality control such as dissolution, assay, acid resistance and moisture content. The formula was finalized by comparing the invitro dissolution profile with that of the marketed tablets. MATERIALSAND METHODS Selected Excipients for Prototype Formulation (Table-1) S.No Name of the ingredients Category 1. Lactose monohydrate Diluent 2. Mannitol(perlitol SD200) Diluent 3. Micro crystalline cellulose Disintegrating agent 4. Polysorbate 80 Surfactant 5. Sodium lauryl sulphate Wetting agent 6. MC(Methocel E5 and E3) Binder 7. Sodium carbonate ph adjuster 8. Cross povidone Povidone K-30 Binder Disintegrating agent 10. Calcium stearate Glidant 11. Sub coating HPMC(Methocel E6) Subcoating material 12. Sicovit yellow Coloring agent 13. Propylene glycol Plasticizer 14. Titanium dioxide Coloring agent 15 Enteric coating Methacrylicacidcopolymer(Eud ragt) Enteric coating material 6. Talc Lubricant 17. Sodium hydroxide Alkalizer 18. Triethyl citrate Plasticizer 19. Polysorbate 80 Wetting agent 20. Purified water Vehicle List of Equipment S. No. EQUIPMENT (Table-2) 1 Electronic Single Pan Balance 2 Mesh # 12, 14, 16, 18, 40,60,100 MANUFACTURER Sartorius Retsec 3 Tapped density tester Electrolab 4 Analytical Sieve Shaker Retsec 5 Blender Rimek 6 Mechanical stirrer Remi motors, Bombay 7 Coating pan Ganscoater 8 Fluidized bed coater 3 kg Bectochem 9 Tray drier MACK 10 ph meter Digisum Electronics 11 Dissolution test apparatus Electrolab XXII 12 Stability chambers Thermolab 13 D.T Electro lab 14 Hardness tester Pharmatest 15 Friabilator (USP) Electro lab 16 Compression machine CLIT 17 Capsule filling machine Palm USP Vol.1 (2) Nov-Dec-2010 An International Journal of Advances In Pharmaceutical Sciences 215

4 FORMULATION DEVELOPMENT Pantoprazole delayed release capsules 8.,9 : Pantoprazole delayed release pellets were prepared by pelletazation through spheronisation and extrution method.the process was displayed in the below flow chart. MANUFACTURING FLOW CHART FOR PELLETS Mixing of all excipientsincluding Pantoprazole Sifting (#30) Dry blending by Triple Roller Mixer Preparation of binding agent Granulation by RMG Extruder Spheronization Drying Sifting of core pellets Preparation of sub coating solution Sub coating Preparation of enteric coating solution Enteric coating Sifting Capsule filling Step1: Mixing of all excipients All the excipients including API was mixed and passed through sieve number 30. Step 2: Preparation of binder solution HPMC was dissolved in purified water. Step 3: Granulation Granulation was done by adding binder solution to the powder blend in RMG. Step 4: Extruder The wet mass was passed through extruder having roller size of 0.8mm. Step 5: Spheronisation These extrudes were loaded in spheroids. The process was continued for 15minutes with the rpm of Step 6: Drying The wet pellets were dried in dryer at 40 0 C for half an hour. Step 7: Sifting The dried pellets were passed through sieve number18; the passed pellets were taken and passed through sieve number20. From sieve number20, retained pellets were taken for further process. Step 8: Sub coating 1. HPMC was dissolved in purified water. 2. This solution was used for sub coating of core pellets. 3. These sub coated pellets were passed through sieve number16, the pellets were again passed through Vol.1 (2) Nov-Dec-2010 An International Journal of Advances In Pharmaceutical Sciences 216

5 sieve number18 and the retained pellets in sieve number18 were taken for further process. Step 9: Enteric coating 1. All ingredients were weighed as per the formula given in the Table: Sodium carbonate and triethyl citrate were separately dissolved in water. 3. Talc was mixed with eudragit with the help of mechanical stirrer. 4. Sodium carbonate and triethyl citrate solution was added to eudragit and talc mixture. 5. This dispersion was used for enteric coating of sub coated pellets. 6. After completion of coating, the pellets were allowed to dry in the coating pan. 7. The weight of enteric coated pellets was checked for the build up. Step10: Enteric coated pellets sifting sieve number16 and collect the retains Totally 7 Formulation trails were done using the same procedure. During all the stages of the manufacturing process, temperature and humidity was maintained at 25 ± 5 0 C and 50 ± 10 % RH. To optimize the formulation, the pellets were characterized by physical and chemical parameters like pinholes, lumps, film cracking, acid resistance analysis, assay by HPLC method and drug release study. The results were shown in Table: 3& 4 EVALUATION OF CAPSULES 10,11 1. Weight variation test Individual weights of 20 capsules were taken and the average weight was calculated by using the following formula. (Weight of capsule-average weight) Weight variation = Average weight of capsules Weight variation should not be more than 7.5%. Enteric coated pellets were sifted through sieve number 12 and passed pellets were sifted through 2. Lock length It was tested by using venire calipers. 3. Dissolution and Assay For capsules same procedure followed as mentioned in the tablets. Results were shown in table: 4 &5 RESULTS AND DISCUSSION The present study was undertaken to formulate pantoprazole enteric coated tables and pellets presented in the form of capsules. The study involves preformulation studies of drug and excipients, formulation and processing development along with evaluation of tablets and pellets made with the optimized formulation. Finally delayed release tablets and capsules were evaluated by invitro methods. Results and discussion of the above studies are presented below Vol.1 (2) Nov-Dec-2010 An International Journal of Advances In Pharmaceutical Sciences 217

6 Table: 3: Physical Evaluations S no Parameter Trial 1 Trial 2 Trial 3 Trial 4 Trial 5 Trial 6 Trial 7 Weight in with in the 1 variation the 2 Lock length Not With in the With in the Table: 4:Chemical Evaluations S.no Parameter Trial1 Trial2 Trial 3 Trial4 Trial5 Tria6 Tria7 1 Assay% in in in in Not With in the With in the 2 Dissolution in in in in Not With in the With in the DISSOLUTION PROFILE OF TRAIL BATCHES %DRUG RELEASE PROFILE OF TRAIL BATCHES Vol.1 (2) Nov-Dec-2010 An International Journal of Advances In Pharmaceutical Sciences 218

7 %DRUG RELEASE Issn No: Fig. No:-1: DISSOLUTION PROFILE OF TRAIL BATCHES %DRUG RELEASE PROFILE OF TRAIL BATCHES INNOVATOR TRAIL-1 TRAIL-2 TRAIL-3 TRAIL-4 TRAIL-5 TRAIL-6 TRAIL TIME IN Hrs SUMMARY AND CONCLUSION Enteric coated pellets have minimum volume in size, greater surface area and more surface activity. The area of the drug loaded enteric coated pellets exposed to intestine fluid was more and release rate was also more. And also there was no need of disintegration time for pellets in capsules. Small volumes of pellets enter into the intestine very fast. Moreover there was no loss of drugs in acidic media like gastric fluid. When pellets expose to basic media like intestinal fluids it will disintegrate immediately and drug come to systemic circulation and showed maximum drug release. Drug release rate was more when compared with that of pantoprazole delayed release tablets. Coming to enteric coated tablet, it has large volume of size and need more time to enter into the intestine and also need time for disintegrate in intestine, so drug release was less. The pellets enter into intestine and then enteric coated material dissolves to release the drug. After that it was absorbed into systemic circulation. So it takes more time to release the drug. Finally I conclude like enteric coated pellets in capsule have more drug release rate then enteric coated tablets. REFERENCES 1.Rubinstein, M. H. Tablets. New York, 2000, Chien, Y. W.Med. Prog. Tech. 1989, 15, Chein, Y. W., Marcel Dekker Inc. New York. Vol , Mankar, N.C., Gandhi, S.D.and Joshi, S.B., Eastern Pharmacist, 1999, Remington, The science and pharmacy practice of pharmacy, 20 th Edn. 2002, Robinson, R.; Lee, V. H. Vol. 29; 3 rd ed., New York, 1995, Vol.1 (2) Nov-Dec-2010 An International Journal of Advances In Pharmaceutical Sciences 219

8 7. Selection guide to excipients-signet 8. Elchidana PA, Deshpande SG. J Control Release Jun 2; 59(3): A. M.; Llyod, A.W.; Swarbrick, J.; Eds. Taylor and Francis: London and New York, 2001, Lordi, N. G. 3 rd ed., Lachman, L.; Lieberman, H. A.; Kanig J. L. Eds.; Lea and Febiger: Philadelphia, 1991, S. P. Vyas and Roop K. Khar, 1 st edition, 2002, 6, The concept of complete remission of gastrooesophageal reflux disease: comparative efficacy of pantoprazole and esomeprazole using the Request questionnaire by Thomson AB et al in Clin Drug Investig. 2007; 27(10): Recent advances in chirally pure proton pump inhibitors and reported the proton pumps currently available in the market by Pai V, Pai N et al inj Indian Med Assoc Aug;105(8):469-70, 472, US patent A1Pantoprazole sodium multiparticulateare described in the patent which avoids sticking to nasogastric and gastronomy tubes. 15. International Patent2005/ A2 the invention relates to enteric coated tablets. ADDRESS FOR CORRESPONDENCE kranthikumarkotta@gmail.com Vol.1 (2) Nov-Dec-2010 An International Journal of Advances In Pharmaceutical Sciences 220