“FORMULATIONAND EVALUATION OF DELAYED RELEASE DRUG DELIVERY SYSTEM FOR PROTON PUMPINHIBITOR.”            DESSERTATIONPROTOCOL       SUBMITTED TO RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES KARNATAKA, BANGALORE              BYGANESHCHAKRADHAR PATILM.PHARM,PART-IDEPARTMENTOF PHARMACEUTICS(2010-2011)       RAJIV GANDHI UNIVERSITY OF HEALTHSCIENCES,BANGALORE,KARNATAKA.ANNEXURE-II PROFORMAFOR REGISTRATION OF SUBJECTS FOR DISSERTATION   width=613 >   1.   NAME OF THE CANDIDATE AND ADDRESS (IN BLOCK LETTERS)    GANESH CHAKRADHAR PATIL NARGUND COLLEGE OF PHARMACY, DATTATREYANAGAR, II MAIN, 100 FT RING ROAD, BSK III STAGE, BANGLORE-85 KARNATAKA.     2.   NAME OF THE INSTITUTION     NARGUND COLLEGE OF PHARMACY, DATTATREYANAGAR, II MAIN, 100 FT RING ROAD, BSK III STAGE, BANGLORE-85 KARNATAKA.     3.   COURSE OF STUDY AND SUBJECT   MASTER OF PHARMACY IN PHARMACEUTICS     4.   DATE OF ADMISSION OF COURSE       30th JUNE 2010   5.   TITLE OF TOPIC     “FORMULATION AND EVALUATION OF DELAYED RELEASE DRUG DELIVERY SYSTEM FOR PROTON PUMP INHIBITOR.”          >   6.                                                                                                                                                                                                                                                                                                                                                                                                                                                     7                                                                                                             8.                                                                                                         BRIEF RESUME OF THE INTENDED WORK:   6.1 NEED FOR THE STUDY:    Oral drug delivery has been known for decades has the most widely utilized route of administration among all the routes that have been explored for the systemic delivery of different dosage forms. Proton-pump inhibitors (PPIs) have been very efficacious for the management of a variety of acid-related disorders such as dyspepsia, peptic ulcer, gastroesophageal reflux disease, laryngopharngeal reflux, Barrett’s esophagus, gastrinomas, Zollinger -Ellison syndrome.   PPIs are acid-labile, weak bases that require protection from acid activation (protonation) in the stomach before they reach their principle site of absorption in the proximal small intestine.   Delayed release PPI formulations are protected from gastric acid degradation by enteric coating(s), which are very effective in preventing premature acid activation in the lumen of the stomach. Examples of enteric coating polymers includes: Methacrylic acid copolymers posses free carboxylic acid groups, forming salts with alkalis and having appreciable solubility at pH in excess of 5.5, Other enteric coating polymers like Cellulose acetate phthalate, Polyvinyl phthalate and Hydroxy propyl methylcellulose phthalate are substances which are anionic polymers or copolymers which are insoluble in acidic media but acquire water solubility at near neutral pH values due to ionization of functional groups along the polymer chain, Some of the PPIs are Omeprazole, Lansoprazole, Esomeprazole, Pantoprazole, Rabeprazole , etc.    Proton pump inhibitors act by irreversibly blocking the hydrogen/potassium adenosine triphosphatase enzyme system (the H+/K+ ATPase, or, more common, gastric proton pump) of the gastric parietal cells. The proton pump is the terminal stage in gastric acid secretion, being directly responsible for secreting H+ ions into the gastric lumen, making it an ideal target for inhibiting acid secretion. They also inhibit gastric mucosal carbonic anhydrase.           ADVANTAGES OF  ENTERIC COATING DRUG DELIVERY SYSTEM Ø  To prevent degradation of acid sensitive active pharmaceutical agents Ø  To prevent irritation of stomach by certain drugs like sodium salicylate Ø  Delivery of active pharmaceutical agents into intestine Ø  To provide a delayed release component for repeat action tablet.   6.2 REVIEW OF LITERATURE :   Few reported work of  delayed release drug delivery system for proton pump   inhibitors are as follow:      Martinek al, comparatively studied Pumaprazole a reversible proton pump inhibitor and Omeprazole a irreversible proton pump inhibitor for the treatment of Helicobacter pylori infection and claimed that increase in intragastric pH is the effect which is related to Halicobacter pylori  infection and not of an increased activation of acid inhibitory agents (Omeprazole) in the parietal cell compartment.1 Dekkers C et al studied the clinical efficacy of proton pump inhibitors in 205 patients with active duodenal ulcers by administrating either 20mg Rabeprazole or 20mg Omeprazole once daily for 2 to 4 weeks. The results stated that Rabeprazole produced a slightly higher rate of healing than Omeprazole; 98% and  93% respectively.2  Sachs et al stated that a combination therapy of reversible proton pump inhibitor (eg.Pumaprazole) and antimicrobially-agent for treating a disorder caused by Helicobacter, including a effective amount of polymer to control release of the least part of the reversible proton pump inhibitor, by which onset of action of antimicrobially-active agent takes place significantly faster than on oral administration thereof with a non-slow release reversible proton pump inhibitor.3 Marchetti et al stated PPIs can participate in several drug interactions, because they reduce gastric acidity, PPIs can reduce the bioavailability of drugs requiring a low pH for absorption, such as ampicillin, cyanocobalamin, iron, digoxin and ketoconazole. Similarly, sucralfate decreases the absorption of Omeprazole and Lansoprazole, therefore administration of these agents should be separated by at least 30 min.4 Proton pump inhibitors are acid-labile, and require an enteric coating to protect them from degradation in the stomach when given orally and this leads to delayed absorption and onset of action of the proton pump inhibitors.5  Cremonini et al claimed that the proton pump inhibitors therapy reduces symptoms in Non-Cardiac Chest Pain (NCCP) and may be useful as a diagnostic agent in identifying abnormal oesophageal acid reflux.6 Dr.Udupa N et al stated that Proton pump inhibitors were introduced in 1980 for the treatment of heartburn, ulcers and gastroesophageal reflux disease, erosive esophagitis, Zollinger-Ellison syndrome.7 Pilotto et al comparatively studied  proton pump inhibitors by including a total of 320 patients over 65 years with endoscopically diagnosed esophagitis were randomly assigned to one of the following treatment for 8 wks: 1)  Omeprazole 20 mg/d; 2) Lansoprazole 30 mg/d; 3) Pantoprazole 40 mg/d; 4) Rabeprazole 20 mg/d. And concluded, in elderly patients,  Pantoprazole and Rabeprazole were significantly more effective than Omeprazole in healing esophagitis and than Omeprazole or Lansoprazole in improving symptoms.8 Fock et al stated that H2-receptor antagonists (eg. Cimetidine, Ranitidine, Famotidine) suppress gastric acid secretion by competitively and reversibly blocking the H2 receptor on the gastric parietal cell. On the other hand, proton pump inhibitor causes irreversible inhibition of the final step in gastric acid secretion.9 Reddy et al carried out development and validation of RP-HPLC for the Pantoprazole Sodium Sesquihydrate in pharmaceutical dosage form and human plasma.10 Nair et al claim methacrylic polymers are most suitable for enteric coating. These provide greater protection to the core under acidic condition while at the same time show the fastest drug release under intestinal pH.11   6.3 OBJECTIVES OF THE STUDY:   The present study is to formulate and evaluate the delayed release drug delivery system for proton pump inhibitors.  Analytical method development for the active pharmaceutical ingredients. Preformulation studies including drug and excipients compatibility.    Precompression characteristic of granules and table properties. Evaluation of the core tablet by different evaluation parameters studies like:  a)  Hardness  b)  Friability test c)  Uniformity of weight and thickness d) Disintegration time   e)  Drug content uniformity and assay f)  In vitro Dissolution studies   §  Formulation of the delayed release tablet by enteric coating. §  Evaluation of the enteric coated tablet by different evaluation parameters studies like: a)  Hardness b)  Friability test c)  Uniformity of weight and thickness d)  Disintegration time e)  Drug content uniformity and assay f)  In vitro Dissolution studies g)  Acid resistance in 0.1 N HCL h)  Statistical evaluation of stability data.   6.4  MATERIALS AND METHODS:   Materials  ü  Drug:-   Some of the PPIs that can be used are Pantoprazole, Omeprazole, Rabeprazole, Lansoprazole, Picoprazole, Esomeprazole etc. ü  Coloring agents:-   Orange, sunset yellow etc. ü  Disintegrants:-   Sodium starch glycolate, Sodium alginate. ü  Lubricants:-   Sodium Stearyl Fumarate, Magnesium Stearate. ü  Diluents:-   Microcrystalline cellulose, , Di calcium Phosphate, Mannitol,  Lactose. ü  Binders:-   Starch, Polyvinyl pyrollidone,  Hydroxy propyl methyl cellulose, methyl cellulose, ethyl cellulose, ü  Polymers:-   Cellulose acetate phthalate, Polyvinyl phthalate, Hydroxy propyl  methylcellulose phthalate.   7.1. Source of Data 1.  Library: Nargund college of pharmacy 2.  e-library: Nargund college of pharmacy     Web sites:   Books:  §  Raymond C Rowe, Paul J Sheskey and Sian C Owen. Hand book of pharmaceutical excipients; Fifth edition §  KD Tripathi, Essentials of medical pharmacology, fifth edition §  Indian Pharmacopoeia 2007.     7.2. Method of Collection of Data Spectrophotometric or HPLC method for the estimation of drug. Formulation is prepared using enteric coating polymers. The formulations will be evaluated for the thickness uniformity, content uniformity, and weight variation. In vitro release of drug from the formulation is studied using dissolution apparatus. Mechanism of release of drug from the formulation is evaluated. Statistical analysis. Stability study of the selected formulation.     7.3. Does the study require any investigation or intervention to be conducted on patients or other humans or animals? If so, please mention briefly.   -NO-   7.4. Has ethical clearance been obtained from your institution in case of 7.3? - NOT APPLICABLE-     LIST OF REFERENCES:   1)  Martinek J, Blum AL, Stolte M, Hartmann M, Verdu EF, Luhmann R et al. Effect of Pumaprazole (BY841), a novel reversible proton pump antagonist and of Omeprazole, on intragastric acidity before and after cure of Helicobacter pylori infection. Aliment Pharmacol Ther. 1999;13:27-34. 2)  Dekkers C, Beker J, Thjodleifsson B Alimentary Pharmacology Therapy. 1999;13:179-86. 3)  Sachs et al. BYK Gulden Lomberg Chemische Fabrik GmbH. Oral Pharmaceutical Composition with Delayed Release of Active ingredient for Reversible Proton Pump Inhibitors. United States Patent US 6132768. 2000 Oct 17. 4)  Marchesti F, Gerarduzzi T, Ventura A. Digestive and Liver Disease. 2003;35:738-46. 5)  Horn JR, Howden CW. Review article: Similarities and Differences among delayed-release proton-pump inhibitors. Aliment Pharmacol Ther. 2005;22(3):20-24. 6)   Cremonini F, Wise J, Moayyedi P, Talley NJ. Diagnostic and Therapeutic Use of proton pump inhibitors in Non-Cardiac Chest Pain. American Journal of Gastroenterology. 2005;1226-32. 7)  Dr.Udupa N, Sreedhar D, Kumar D, Pise A, Janodia MD. Proton Pump Inhibitors- An-Overview. Latest Reviews. 2006;4(3). 8)  Pilotto A, Franceschi M, Leandro G, Scarcellic, D’Ambrosio PL, Paris F, et al. Comparison of four proton pump inhibitors for the short-term treatment of esophagitis in elderly patients. World Journal of Gastroenterology. 2007;13(33):4467-72. 9)  Fock, Ming K, Ang, Leong T, Bee, Choo L, et al.Proton pump inhibitors: Do Differences in Pharmacokinetics Translate into Differences in Clinical Outcomes? Clinical Pharmacokinetics. 2008 Jan 01;47(1):1-6. 10)  Reddy P, Battu, Reddy NKK. Development and validation of RP-HPLC  for the Pantoprazole Sodium Sesquihydrate in pharmaceutical dosage forms and Human Plasma. Indian Journal of ChemTech Research. 2009 April-June;1(2):195-98. 11)  Nair AB, Gupta R, Kumria R, Jacob S, Attimarad M. Formulation an evaluation of enteric coating tablets of proton pump inhibitor. Journal of Basic and Clinical Pharmacy. 2010;01(04):215-21.   >   9   SIGNATURE OF THE CANDIDATE     (GANESH CHAKRADHAR PATIL)   10   REMARKS OF THE GUIDE     RECOMMENDED FOR DISSERTATION WORK.   11 NAME & DESIGNATION OF :         11.1   GUIDE             11.2   SIGNATURE     RAMA  BUKKA M.PHARMACY ASSISTANT  PROFESSOR DEPT.OF PHARMACEUTICS NARGUND COLLEGE OF PHARMACY         11.3  CO-GUIDE           11.4   SIGNATURE     SACHIN R MUNDADE Dy. GENERAL MANAGER-R&D(Formulation) MICRO LABS LIMITED-KUDULU, BANGALORE-68.           11.5  HEAD OF THE DEPARTMENT             11.4   SIGNATURE     Dr. C.S.R. LAKSHMI PROFESSOR HEAD OF THE DEPARTMENT OF PHARMACEUTICS NARGUND COLLEGE OF PHARMACY.   12.   12.1  REMARKS OF THE PRINCIPAL             12.2 SIGNATURE   FORWARDED AND RECOMMENDED FOR FAVORABLE CONSIDERATION.             (D.S. PURANIK)   PRINCIPAL    
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