Formulation and Evaluation of Sustained Release Tablets of Glucosamine Sulphate s1

“FORMULATION DEVELOPMENT AND EVALUATION OF ORODISPERSIBLE TABLETS OF PROTON PUMP INHIBITOR”

DISSERTATION PROTOCOL

SUBMITTED TO RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES BANGALORE, KARNATAKA.

BY CHAUDHARI JITESH JAGDISH I Year M. PHARM, DEPARTMENT OF PHARMACEUTICS, NARGUND COLLEGE OF PHARMACY, BANGALORE- 85. KARNATAKA. (2009-2011) RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES, BANGALORE, KARNATAKA.

ANNEXURE – II PROFORMA FOR REGISTRATION OF SUBJECTS FOR PG DISSERTATION

1. NAME OF THE CHAUDHARI JITESH JAGDISH CANDIDATE & NARGUND COLLEGE OF PHARMACY, ADDRESS (IN DATTATREYA NAGAR,2nd MAIN, BLOCK LETTERS) 100 FT RING ROAD,BSK 3rd STAGE BANGALORE-560085

2. NAME OF THE IN NARGUND COLLEGE OF PHARMACY, STITUTION DATTATREYA NAGAR,2nd MAIN, 100 FT RING ROAD,BSK 3rd STAGE BANGALORE-560085

3. COURSE OF STUDY MASTER OF PHARMACY IN AND SUBJECT PHARMACEUTICS

4. DATE OF ADMISSION TO 15th JUNE 2009 COURSE

5. TITLE OF THE “FORMULATION DEVELOPMENT AND TOPIC EVALUATION OF ORODISPERSIBLE TABLETS OF PROTON PUMP INHIBITOR” 6. BRIEF RESUME OF THE INTENDED WORK

6.1 NEED FOR THE STUDY

The aim of this research project is to prepare orodispersible tablets of proton pump inhibitors (K/H-ATPase) by suitable methods and evaluate their in-vitro properties. Some of the proton pump inhibitors are Omeprazole, Lansoprazole, Pantoprazole, Rabeprazole, Picoprazole etc. Recently United States pharmacopoeia (USP), center for drug evaluation and research (CDER), has approved orally disintegrating (OD) Tablet technology. USFDA defined OD tablet as “A solid dosage form containing medicinal substances, which disintegrates rapidly, usually within a matter of seconds, when placed upon the tongue”. Recently European pharmacopoeia also adopted the term “orodispersible tablet” as a tablet that is intended to be placed in the mouth where it disperses rapidly before swallowing. These dosage forms dissolve or disintegrate in the patient’s mouth within 15 seconds to 3 minutes without the need of water or chewing. Despite various terminologies used like, fast dissolve, quick dissolve, rapid melt, quick disintegrating, mouth dissolving, orally disintegrating, orodispersible, melt-in-mouth, tablets etc. are same terms which are here to offer unique form of drug delivery with many advantages over the conventional oral solid dosage forms. The bioavailability of most of the proton pump inhibitors followed by oral administration is usually very low, since they undergoes degradation very rapidly in the stomach and hence first- pass metabolism in the liver. Thus, various oral dosage forms such as enteric-coated granule, enteric-coated tablet and inclusion complex with cyclodextrin have been developed to improve their bioavailability. An attempt has also been made to develop omeprazole rectal suppository as an alternative dosage form; however they yielded unsatisfactory results. The requirements to develop orodispersible tablets are as follows: . Most elderly patients, children, patients with difficulty in swallowing (Dysphagia) have difficulty swallowing conventional tablets or capsules. . Conventional proton pump inhibitors get degraded in the acidic environment of stomach as their degradation is pH dependent and degradation increases with decrease in the pH. . These proton pump inhibitors get metabolized in the liver- as a result higher doses are required. Thus, an orodispersible tablet is needed to be developed to overcome the above issues present with the conventional formulations. Omeprazole, Lansoprazole, Pantoprazole, Rabeprazole, Picoprazole, etc are used for treating acid-induced inflammation and ulcers of the stomach and duodenum; gastroesophageal reflux disease (GERD); erosive esophagitis, heartburn; prevention of upper gastrointestinal bleeding in critically ill patients; and Zollinger-Ellison Syndrome. They are also used in combination with antibiotics for eradicating H. pylori infection of the stomach. Omeprazole 5-methoxy-2-(((4-methoxy-3,5- dimethyl- 2-pyridinyl)methyl)sulfinyl)-1H- benzimidazole). Pantoprazole 5-(difluromethoxy)-2-[[(3,4-dimethoxy-2-pyridinyl)methyl]sulfinyl] -1 H-benzimidazole etc. are benzimidazole substitution that exhibits potent and long-lasting inhibition of gastric acid secretion by selectively interacting with the gastric proton pump (K /H -ATPase) in the parietal cell secretory membrane.

 Challenges in the development of orodispersible tablets 1) Rapid disintegration of tablet in the oral cavity. 2) Compatible with taste masking technology. 3) Retaining drug properties. 4) Avoid increase in tablet size. 5) Have sufficient mechanical strength. 6) Minimum or no residue in mouth. 7) Protection from atmospheric parameters such as moisture, temperature etc. 8) Good package design. 6.2 REVIEW OF LITERATURE:

 Kumaresan C. demonstrated different ways for the formulation of the oral dispersible tablets and how the product performance depends on the drug suitability and excipients selections in the delivery system. He described the ideal characteristics of the drug and examples of excipients required in the oral dispersible formulation, taste masking methods and manufacturing methods.1

 Bandari S, Mittapalli RK, Gannu R, Rao YM. presented a complete overview on the formulation of orodispersible tablets right from the formulation aspects to the packaging of the orodispersible tablets. They also included various methods which can be incorporated for the formulation of the orodispersible tablets like2: o Lyophilization or Freeze-drying. o Moulding. o Cotton candy process. o Spray drying. o Mass extrusion. o Compaction.

 Yamamoto Y, et al. demonstrated the relation between powder characteristics and disintegration time of tablets in the mouth (DTM) revealed that a high bulk density results in a short DTM. Tablets producing a DTM less than 60s were obtained when the powder bulk density was greater than 0.5g/mL. They have also demonstrated that the tablets with a short DTM value tended to possess low hardness; however, the use of high-compressibility excipients in the formulation increased the hardness to values greater than 3kg.3

 Abdelbary G, Eouani C, Prinderre P, Joachim J, Reynier Jp, Piccerelle Ph. demonstrated the use of the texture analyser in the in-vitro determination of the disintegration behaviour of different rapid disintegrating tablet (RDT) was shown to be very successful, convenient and precise. Further they have shown the new operating structure for a better simulation of the in-vivo conditions, where the use of the perforated grid on which the tablet is placed minimises the operating error that might occur when using an adhesive tape. This structure mimics the situation in the patient’s mouth.5  Schiermeier S and Schmidt PC during their investigation, proved that it is possible to prepare dispersible tablets by a direct compression method. This tablet offers several advantages over conventional solid dosage forms when administered to children and elderly patients.6

 Choi HG and Kim CK concluded that two omeprazole tablets composed of [omeprazole/sodium alginate/HPMC/magnesium oxide (20/24/6/50mg/tab)] and [(20/30/0/50mg/tab)], which could be attached onto the human cheek without collapse and could stabilize omeprazole in human saliva for at least 4 hours, are potential candidates for omeprazole buccal adhesive tablets.7

 Sharma S and Gupta GD showed that the use of superdisintegrants for preparation of fast dissolving tablets is highly effective. They used three different superdisintegrants-Ac-Di- Sol, Crospovidone and sodium starch glycolate to achieve fast dispersion of tablet.8

 Choi HG, et al. have demonstrated the utility of buccal adhesive tablets based on in-vivo evaluation of these omeprazole tablets.12 6.3 OBJECTIVES OF THE STUDY:

The aim of the present work is to formulate and evaluate the fast orodispersible tablet of proton pump inhibitors.  In this study, an attempt will be made to develop an orodispersible tablet of proton pump inhibitors.  Absorption of drug is from the oral cavity into the systemic circulation thus it will bypass the hepatic circulation and metabolism.  The stability of proton pump inhibitors in aqueous solution is pH dependent; the rate of degradation increases with decreasing pH. So there is a need to increase their stability.  Proton pump inhibitors are very slightly soluble in water thus to increase their solubility.  To decrease the dose of proton pump inhibitors.  To increase patient convenience and compliance.  To compare the various formulation using different excipients and choosing the best formulation as per ICH guidelines.

MATERIALS AND METHOD

7. MATERIALS:

1. Some of the commonly used gastric proton pump (K /H -ATPase) inhibitors:- o Omeprzole, Lansoprazole, Pantoprazole, Rabeprazole, Picoprazole etc. 2. Super disintegrants:- o Crospovidone, Cross carmellose sodium, Sodium starch glycolate, Acrylic acid derivatives, Sodium Alginate, NS-300, ECG-505, L-HPC etc 3. Flavoring agents:- o lemon Oil, Clofibrate, Isosorbide 5-mononitrate etc 4. Colouring agents:- o Sunset yellow, Orange etc. 5. Sweetning agents:- o Aspartame, Sodium saccharine, Sucrose, Mannitol etc. 6. Effervesent Mixture:- o Sodium bicarbonate, Citric acid, Tartaric acid, Sodium Salt of Alginic acid, etc.

METHODS: Some of the commonly methods which are planned to be used for the formulation of the orodispersible tablets of proton pump inhibitors are: o Lyophilization or Freeze-drying. o Moulding. o Cotton candy process. o Spray drying. o Mass extrusion. o Compaction. o Direct compression.

7.1 SOURCE OF DATA:

1. Library: Nargund college of pharmacy. 2. e-library: Nargund college of pharmacy. 3. Official books ( IP, BP, USP, EP). 4. RGUHS Library, Bangalore. 5. International and national Pharmaceutical abstracts etc.

A. Journals & articles :

 Asian Journal of Pharmaceutics.

 International Journal of Pharmaceutics.

 Journal of Controlled Release.

 European Journal of Pharmaceutics.

B. Internet Browsing.

 www.sciencedirect.com

 www.google.com

 www.pubmed.com  www.pharmainfo.net

7.2 METHODS OF DATA COLLECTION:

1. Literature survey using internet and scientific journals. 2. Experimental studies which includes:  The formulation evaluated for the compatibility studies using thermal analysis such as DSC, TGA and XRD techniques.  Formulation development and evaluation.  Granular properties, tablet properties and in-vitro dissolution studies for the developed formulation.  Spectrophotometeric, HPLC, FTIR methods etc for the estimation of drug and for analysis of in-vitro dissolution samples.  Statistical analysis of all the results.

7.3 Does the study require any investigation or intervention to be conducted on patients or other human or animals?

7.4 Has ethical clearance been obtained from your institute?

-NOT APPLICABLE LIST OF REFERENCES 8. 1) C.Kumaresan. Orally Disintegrating Tablet-Rapid Disintegration, Sweet Taste, And Target Release Profile. 2008 Sep;6(5). 2) Bandari S, Mittapalli RK, Gannu R, Rao YM. Orodispersible tablets: An overview. Asian Journal of Pharmaceutics 2008 Jan. 3) Yamamoto Y, Fujii M, Watanabe K, Tsukamoto M, et al. Effect of powder characteristics on oral tablet disintegration. International Journal of Pharmaceutics 2009;365:116-120. 4) Indian pharmacopoeia 2007. The controller of publication Delhi. I56, 1473-5 (Vol 3). 5) Abdelbary G, Eouani C, Prinderre P, Joachim J, Reynier Jp, Piccerelle Ph. Determination of the in vivo disintegration profile of rapidly disintegration tablets and correlation with oral disintegration. International Journal of Pharmaceutics 2005;292: 29-41. 6) Schiermeier S, Schmidt PC. Fast dispersible ibuprofen tablets. European Journal of Pharmaceutics 2002;15:295-305. 7) Choi HG, Kim CK. Development of omeprazole buccal adhesive tablets with stability enhancement in human saliva. Journal of Controlled Release 2000; 68: 397-404. 8) Sharma S, Gupta GD, Formulation and characterization of fast –dissolving tablet of promethazine theoclate. Asian Journal of Pharmaceutics 2008 Jan. 9) Hardman JG, Limbird LE, Gilman G. The pharmacological basis of therapeutics. 10th ed. New Delhi: McGraw-Hill; 2001. p. 1005-20. 10) Rang HP, Dale MM, Ritter JM, Flower RJ. Rang and Dale’s Pharmacology. 6th ed. United Kingdom: Churchill Livingstone Elsevier; 2008. p. 338-89. 11) Rowe RC, Sheskey PJ, Owen SC. Hand book of pharmaceutical exipients. 5TH ed. Great Britan: Pharmaceutical Press; 2006. p. 22-704. 12) Choi HG, Kim CK, Jung JH, et al. Formulation and in vivo evaluation of omeprazole buccal adhesive tablet. Journal of Controlled Release 2000;68:405-12. 13) Wilson, Gisvold, Block JH. Textbook of organic medicinal and pharmaceutical chemistry. 11th ed. Philadelphia: Lippincott Williams and Wilkins. p. 722-27. 14) British Pharmacopoeia 1998, United Kingdom: The stationary office; 959-61 (Vol 3).

9. SIGNATURE OF THE CANDIDATE

(CHAUDHARI JITESH JAGDISH) 10. REMARKS OF THE GUIDE RECOMMENDED FOR DISSERTATION WORK.

11. NAME AND DESIGNATION OF

11.1 GUIDE Dr. GOPAL MURALIDHARAN PROFESSOR DEPT. OF PHARMACEUTICS NARGUND COLLEGE OF PHARMACY

SIGNATURE 11.2 CO-GUIDE (1) Mr. SATEESHA S. B ASSISANT PROFESSOR DEPT. OF PHARMACEUTICS NARGUND COLLEGE OF PHARMACY

SIGNATURE 11.3 CO-GUIDE(2) MR. HARISH JAIN DIRECTOR, EMBIOTIC LABORATORIES (P) LIMITED.

SIGNATURE 11.4 HEAD OF THE DEPT. Dr. CSR LAKSHMI PROFESSOR AND HEAD DEPT. OF PHARMACEUTICS NARGUND COLLEGE OF PHARMACY,

SIGNATURE 12. REMARKS OF THE FORWARDED AND RECOMMENDED FOR PRINCIPAL FAVORABLE CONSIDERATION.

SIGNATURE (M.S. HARISH)