Formulation Development and Evaluation Of

“FORMULATION DEVELOPMENT AND EVALUATION OF

FLOATING DRUG DELIVERY SYSTEM OF H-1 ANTIHISTAMINIC DRUG”

DISSERTATION PROTOCOL

SUBMITTED TO

RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES

BANGALORE, KARNATAKA.

BY

SHAH HARSH DIPAKKUMAR

M.PHARM, PART-I

DEPARTMENT OF PHARMACEUTICS

NARGUND COLLEGE OF PHARMACY

BANGALORE-85

RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES,

BANGALORE, KARNATAKA.

ANNEXURE-II

1. / NAME OF THE CANDIDATE
AND ADDRESS (IN BLOCK LETTERS) / SHAH HARSH DIPAKKUMAR
NARGUND COLLEGE OF PHARMACY,
DATTATREYANAGAR, II MAIN,
100 FT RING ROAD, BSK III STAGE,
BANGALORE-85
KARNATAKA.
2. /

NAME OF THE INSTITUTION

/ NARGUND COLLEGE OF PHARMACY,
DATTATREYANAGAR, II MAIN,
100 FT RING ROAD, BSK III STAGE,
BANGALORE-85
KARNATAKA.
3. /

COURSE OF STUDY AND SUBJECT

/ MASTER OF PHARMACY IN PHARMACEUTICS
4. / DATE OF ADMISSION OF COURSE / 1st JUNE 2010
5. /

TITLE OF TOPIC:

/ “FORMULATION DEVELOPMENT AND EVALUATION OF
FLOATING DRUG DELIVERY SYSTEM OF H-1 ANTI-HISTAMINIC DRUGS”

PROFORMA FOR REGISTRATION OF SUBJECTS FOR DISSERTATION

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8 / BRIEF RESUME OF THE INTENDED WORK:
6.1 NEED FOR THE STUDY:
H-1 Anti-histaminics are useful mainly in motion sickness and to a lesser extent in morning sickness, vertigo. They act mainly on H-1 receptor of histamine.
Drugs like Promethazine, Diphenhydramine, Dimenhydrinate, Cyclizine, and Cinnarizine are used as H-1 Anti-histaminics.
Cinnarizine has poor bioavailability, and has half life of 3.4 hours. Cinnarizine solubility in alkaline pH is very low, therefore its absorption from the intestine would be low. So, for the better bioavailability cinnarizine is formulated in the form of floating drug delivery system. Gastro retentive delivery system prolonging the gastric retention of a delivery system is sometimes desirable for achieving therapeutic benefit of drugs that are absorbed from the proximal part of GIT and drugs that are less soluble in or degraded by the alkaline pH may benefit from prolonged gastric retention. Hence, their oral bioavailability can be improved and dose can be reduced.
Gastro intestinal retention depends on many factors such as density of dosage form, fasting and fed condition, nature of meal taken, sleep, posture, etc. It also depends strongly on a complicated and unpredictable gastric emptying with migrating myoelectric complex motility of stomach. Various delivery systems like floating, swelling, mucoadhesive, high density formulation etc have been developed to achieve gastroretention. Among these floating drug delivery systems are simple to fabricate and attractive cost wise.
Floating drug delivery system have a bulk density less than gastric fluids and so remain buoyant in the stomach without affecting gastric emptying rate for a prolonged period of time. While the system is floating on the gastric content, the drug is released slowly at the desired rate. After release of drug the residual system is emptied from the stomach. This results in an increased GRT (gastro retention time) and a better control of the fluctuation in plasma drug concentration. Further gastro retentive dosage forms fabricated for extended release may improve therapy with several advantages. They can remain in the gastric regions for several hours, thus significantly prolonging the gastric residence time of drugs and improve bioavailability, reduce drug waste and enhance the solubility of drugs that are less soluble in high pH environment.
6.2  REVIEW OF LITERATURE :
Ø  Krogel I et al., demonstrated floating or pulsatile drug delivery system based on coated effervescent cores. The disintegrant properties of microcrystalline cellulose as inert filler instead of lactose supported the film rupturing. Beside the core composition, also the mechanical properties of the film influence the release behavior. The less flexible ethyl cellulose film ruptured at the edge of the tablet upon increasing pressure leaving a wide orifice, whereas the more flexible Eudragit RS films expanded, leading to only small fissures.1
Ø  Dave B et al., have demonstrated that by using gel forming polymer HPMC K4M and gas generating agent sodium bicarbonate in-vitro buoyancy can be achieved and citric acid is used to achieve buoyancy under elevated pH of the stomach. Thus by selecting suitable composition of release rate enhancer and release retardant, the desired dissolution can be achieved.2
Ø  Anand Kumar et al., formulated and evaluated the floating microspheres with cimetidine for prolongation of gastric retention. These were prepared by solvent evaporation method by using polymers hydroxypropyl methyl cellulose (HPMC) and ethyl cellulose (EC). In-vitro data obtained for floating microspheres of cimetidine showed excellent floating ability, good buoyancy and prolonged drug release. They concluded that the prepared floating microspheres may have the potential to be used in multiple unit delivery devices.3
Ø  Chavanpatil MD et al., formulated a novel sustained release, swellable and bioadhesive gastro retentive drug delivery system of ofloxacin. In this they demonstrated that the formulation of ofloxacin gastro retentive drug delivery system using psyllium husk and HPMC K100M in combination shows significant bioadhesion as compared to that of the polymers used alone.4
Ø  Gambhire M et al., developed and evaluated an oral floating matrix tablet formulation of diltiazem hydrochloride. In that they have shown the effervescent based floating drug delivery is a promising approach to achieve in-vitro buoyancy by using gel forming polymer methocel K100M CR and gas generating agent sodium bicarbonate.5
Ø  Khan F et al., have prepared and evaluated theophylline loaded gastroretentive floating tablets of methocel K4M. They have demonstrated that low amount of floating agent and high amount of methocel favors sustained release of theophylline from the gastroretentive tablet formulation.6
Ø  Garg R et al., have reviewed controlled release gastroretentive dosage forms for prolonged and continuous input of the drug to the upper part of the gastro intestinal tract, and bioavailability of medication that is characterized by narrow absorption window. Based on literature survey, they concluded that drug absorption in the gastro intestinal tract is a variable process, prolonging gastric retention of the dosage form and extends the time for drug absorption. Thus gastroretentive dosage forms provide an additional advantage for drugs that are absorbed form extends the upper segments of gastrointestinal tract, i.e., stomach, duodenum and jejunum.7
Ø  Arun Kumar N et al., formulated and evaluated the oral floating tablets of atorvastatin calcium. They develop an oral floating system for atorvastatin calcium with the use of a swellable polymer, release retardant and an alkalizing agent which proved to be an ideal formulation, as it released the drug in controlled manner for extended period of time by maintaining the buoyancy.8
Ø  Garg R et al., have demonstrated the preparation and evaluation of gastro- retentive floating of Silymarin. They have shown that HPMC in combination with crospovidone and microcrystalline cellulose can be a promising polymer for effervescent GRDDS (gastroretentive drug delivery system). On the other hand non effervescent floating formulations based on polypropylene foam powder were able to control drug release over prolonged period of time. The developed floating tablets of silymarin may be used for prolonged drug release, thereby improving bioavailability and patient compliance.9
Ø  Nagarwal C et al., Formulated and evaluated in-vitro release kinetics and bioavailability of gastroretentive Cinnarizine Hydrochloride tablets. The release of Cinnarizine from polymer matrix formulation containing HPMC K4100LV showed good Buoyancy with very short lag time which is of 45s and long floatation time of more than 12h in simulated gastric fluid.10
Ø  Patel S et al., demonstrated formulation and evaluation of Clarithromycin by using different polymers. Among the polymers used to improve the gastric residence, time , cellulose polymers (HPMC K4M, HPMC K15M) showed better control over drug release.11
Ø  Xiaoqiang X et al., demonstrated in-vitro and in- vivo evaluation of floating matrix dosage form for Phenoporlamine hydrochloride using polymers like HPMC K4M and Carbopol 971P and gas forming agent sodium bicarbonate. In-vivo evaluation of six healthy male human volunteers demonstrated that floating matrix tablet containing more of carbopol 971P was capable of sustained delivery of the drug for longer periods increased bioavailability.12
Ø  Sungthongjeen S et al., developed the multi-unit floating drug delivery system based on gas formation technique. The system contained cores coated with effervescent layer and polymeric membrane. Only the system using Eudragit RL30D as polymeric membrane could float as Eudragit RL30D had high water and low CO2. Permeability with high flexibility. The system could float completely within 3 min and maintain the buoyancy over a period of 24 hours. The multiple-unit FDDS with rapid floating and sustained drug release was obtained and it could be promising gastroretentive drug delivery system.13
Ø  Jagdale S et al., demonstrated the formulation and evaluation of gastroretentive drug delivery system of propranolol hydrochloride. Floating tablets were prepared by blending drug, HPC, Sodium alginate, HPMC and gas generating agent. Tablets formulated with HPC, sodium alginate, and HPMC E15LV failed to produce matrix of required strength. The formulation containing Xanthan gum shows good drug retaining abilities but floating abilities were found to be poor. It was concluded that formulation containing HPMC K4M gave the best in-vitro release.14
Ø  Bhosale V et al., studied the effect of polymer concentration and viscosity grade of HPMC K4M and 50 cps on atenolol release from gastric floating Drug Delivery system and suggested that as the proportion and viscosity of matrix polymer increases, cumulative percent drug release decreases.15
6.3 OBJECTIVES OF THE STUDY:
The present study involves formulation development for prolongation of gastric residence of an H-1 Anti-histaminic drugs and their in-vitro evaluation.
The objectives of the present study are highlighted as given below;
Ø  To evaluate compatibility between drug-polymer and excipients.
Ø  To carry out pre-formulation studies.
Ø  To develop formulation of controlled release floating delivery system.
Ø  To evaluate post compression parameters like
·  Weight variation
·  Hardness
·  Friability
·  Content uniformity
·  Floating time
·  Specific Gravity
·  In vitro buoyancy studies
·  Weight gain and water uptake
Ø  Evaluation of developed formulation for in-vitro drug release studies.
Ø  Stability studies of selected formulations as per ICH Guidelines.
MATERIALS AND METHODS:
7.1 Materials:
·  Drugs: Promethazine, Diphenhydramine, Dimenhydrinate, Cyclizine, Cinnarizine are used as H-1 Anti-histaminics.
·  Polymers: HPMC of different viscosity grades, , Ethyl cellulose, PVP, Carbopol, Eudragit, polyethylene oxide, Methocel, etc.
·  Gas generating agent: Sodium Bicarbonate, Potassium bicarbonate , Citric acid etc.
·  Lubricant: Talc, Magnesium stearate, calcium stearate, PEG, lauryl sulfate, Hydrogenated vegetable oil, sodium benzoate, glyceryl monostearate, and polyethylene glycol, etc.
·  Swelling agent: Crospovidone, microcrystalline cellulose etc.
·  Diluents: Lactose, Mannitol, etc.
·  Binder: Xanthum gum, Guar gum, microcrystalline cellulose, highly-dispersed silica, polyethylene glycol, polyvinylpyrrolidone, natural gum, synthetic gum, and gelatin, etc.
7.2 METHODS:
1.  Floating drug delivery system;
·  Non-effervescent system
Ø  Colloidal gel barrier system
Ø  Microporous compartment system
Ø  Alginate beads
Ø  Hollow microspheres/ microballons
·  Effervescent system
Ø  Volatile liquid containing system
Ø  Gas generating system
A.  SOURCE OF DATA
1.  Library: Nargund College of Pharmacy.
2.  E-library: Nargund College of Pharmacy.
3.  From the official books (IP, BP, and USP).
4.  Internet.
5.  RGUHS Library, Bangalore.
6.  International and national Pharmaceutical abstracts etc.
B. Web sites:
www.sciencedirect.com
www.pubmed.com
www.google.com
www.ijp-online.com
C. Text Books:
o  Raymond C Rowe, Paul J Sheskey and Sian C Owen. Hand book of pharmaceutical excipients; Fifth edition.
o  Herbert A. Lieberman, Leon Lachman and Joseph B.Schwatz. Pharmaceutical dosage forms: Tablets volumes 1, 2 & 3.
o  James Swarbrick. Encyclopedia of pharmaceutical technology: Third edition.
o  Leon Lachman, Herbert A. Lieberman, Joseph L. Kanig. The theory and practice of Industrial Pharmacy: Third edition.
o  Goodman & Gilman’s “The pharmacological basis of therapeutics” 10th edition, international edition.
o  Yie W. Chien “Novel drug delivery systems” 2nd edition revised and expanded.
o  N. K. Jain “Progress in controlled and novel drug delivery system”.
D. JOURALS & ARTICLES:
·  International Journal of Pharmaceutical Science.
·  Journal of Controlled Release.
·  International Journal of Pharmaceutics.
·  European Journal of Pharmaceutical and Biopharmaceutics.
·  AAPS Pharm Sci Tech. (American Association of Pharmaceutical Scientist).
·  European Journal of Pharmaceutical Sciences.
7.3. Method Of Data Collection;
1.  Literature survey using internet and scientific journals
2.  Experimental studies which include;
·  The drug and the excipients are evaluated for the compatibility studies using FTIR etc.
·  Pre- formulation parameters evaluation.
·  Post-formulation parameters and in-vitro dissolution studies for the development formulation.
·  UV/Vis. Spectrophotometric method, HPLC method etc. for the estimation of drug in in-vitro dissolution sample.
·  Statistical analysis of all the results.
7.4. Does the study require any investigation or intervention to be conducted on patients or other humans or animals? If so, please mention briefly.
-NO-
7.5. Has ethical clearance been obtained from your institution in case of 7.4?
- NOT APPLICABLE-
LIST OF REFERENCES:
1.  Krogel I, Bodmeier R. Floating or Pulsatile drug delivery system based on coated effervescent cores. International Journal of Pharmaceutics. 1999 May;187:175-84.
2.  Dave B, Amin A and Patel M. Gastroretentive drug delivery of Ranitidine Hydrochloride: Formulation and In-Vitro evaluation of AAPS pharmSciTech. 2004;5(2).
3.  Srivastava A, Ridhrkar D, Wadhwa S. Floating microspheres of Cimetidine; Formulation, Characterization and In-Vitro evaluation. Acta pharm. 2005;55:277-85.
4.  Chavanpatil M, Jain P, Chaudhari S, Shear R, Vavia PR. Novel sustain release, Swellable and bioadhesive gastroretentive drug delivery system for Ofloxacin. International Journal of pharmaceutics. 2006.
5.  Gambhire M, Ambade K, Kurma S, Kadam V. Development and In-Vitro Evaluation of an oral Floating Matrix Tablet Formulation of Diltiazem Hydrochloride. AAPS PharmSciTech, 2007 Sep;8(3).
6.  Khan F, Mohamed SR, Mohamed ZR et al. Preparation and In-Vitro Evaluation of Theophylline loaded gastroretentive floating tablets of Methocel K4M. Dhaka. J Pharma sci. 2008 June;7(1):65-70.
7.  Garg Rajeev, Gupta GD. Process in Controlled Gastroretentive Delivery System, Tropical Journal of Pharmaceutical Research. 2008 Sep;7(3):1055-66.
8.  N Arun Kumar, Rani C and Mohanraj KP. Formulation and In-Vitro evaluation of oral floating tablet of Atorvastatin. RJPT. 2008 Oct-Sep;(4).
9.  Garg R, and Gupta GD. Preparation and evaluation of gastroretentive floating tablet of Silymarin. Chem pharm bull. 2009;57(6):545-9.