“FORMULATION AND EVALUATION OF CONTROLLED RELEASE GASTRORETENTIVE DRUG DELIVERY SYSTEM OF GLIPIZIDE”

M. Pharm Dissertation Protocol Submitted to

Rajiv Gandhi University of Health Sciences, Karnataka

Bangalore– 560 041

By

Mr. AHIR HARESHKUMAR MANUBHAI B.Pharm

Under the Guidance of

Mr.SHIVANAND KALYANAPPA M.Pharm

Asst. Professor..

Department of Pharmaceutics,

Acharya & B.M. Reddy College of Pharmacy,

Soladevanahalli, Chikkabanavara (Post),

Hesaraghatta Main Road, Bangalore – 560 090.

2007-2009

RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES

KARNATAKA, BANGALORE.

ANNEXURE II

PROFORMA FOR REGISTRATION OF SUBJECT FOR DISSERTATION

1 / Name of the candidate and address /

Mr. AHIR HARESHKUMAR MANUBHAI

48, Hiranagar Society,
Trikam Nagar-2,L.H.Road,
Varachha, Surat-395 006,
St. Gujarat.
2 / Name of the Institution / Acharya and B.M. Reddy college of pharmacy, Chikkabanavara post ,
Hesaraghatta Main Road, Soladevanahalli,
Bangalore-560 090.
3 / Course of the study and subject / M. Pharmacy
(Pharmaceutics)
4 / Date of admission / June- 2007
5 / TITLE OF THE PROJECT:-
“FORMULATION AND EVALUATION OF CONTROLLED RELEASE GASTRORETENTIVE DRUG DELIVERY SYSTEM OF GLIPIZIDE”
6
6.1 / BRIEF RESUME OF INTENDED WORK:-
Need for the study:-
Gastro-retentive floating dosage form remains in stomach for prolonged period and so, it releases the drug with Pre-programmed rate resulting in increased gastric retention with reduced fluctuations in plasma drug concentration, maintains local concentration, increases bioavailability, increases half life of drug, decreases the wastage of drug and also improves patient compliance by reducing repetitive doses.1
Diabetes Mellitus is a chronic metabolic disorder characterized by high blood glucose concentration - hyperglycemia. There are two types of diabetes mellitus.
Type-1 diabetes is managed by insulin administration. In case of type-2 diabetes, treatment is initially dietary although oral hypoglycaemic drugs usually become necessary. There are many classes of oral anti-diabetic agents. The objective of the treatment is to achieve euglycaemia, by using an ideal dosage regimen. An ideal dosage regimen in the drug therapy of any disease is the one, which immediately attains the desired therapeutic concentration of drug in plasma and maintains it constant for the entire duration of treatment.
Glipizide is a second generation sulfonylurea, which is widely used for the management of type-2 diabetes. It has short biological half life (3.4±0.7 hrs) and bioavailability is 90 %(extended release). Moreover, site of absorption of Glipizide is in the stomach.12 Therefore, the objective of the present work is to develop a controlled release gastro-retentive drug delivery system for the drug Glipizide, for the better management of the disease, to minimize side effect as well as to improve patient compliance.
6.2 / REVIEW OF LITERATURE:-
Designed gastro-retentive drug delivery system of ranitidine hydrochloride using guar gum, xanthan gum, and hydroxy propyl methyl cellulose. Sodium bicarbonate was incorporated as a gas-generating agent. The effect of citric acid and stearic acid on drug release profile and floating properties was investigated. The addition of stearic acid reduces the drug dissolution due to its hydrophobic nature. A 32 full factorial design was applied to systemically optimize the drug release profile and the results showed that a low amount of citric acid and a high amount of stearic acid favour sustained release of ranitidine hydrochloride from a gastroretentive formulation. Hence, it could be concluded that a proper balance between a release rate enhancer and a release rate retardant could produce a drug dissolution profile similar to a theoretical dissolution profile of ranitidine hydrochloride.2
The application of hydrophobic lipid, Gelucire 43/01 for the design of multi-unit floating systems of a highly water-soluble drug, diltiazem HCl. Diltiazem HCl-Gelucire 43/01 granules were prepared by the melt granulation technique. The granules were evaluated for in vitro and in vivo floating ability, surface topography, and in vitro drug release. It could be concluded that Gelucire 43/01 can be considered as an effective carrier for design of a multi-unit FDDS of highly water-soluble drugs such as diltiazem HCl.3
Developed microballoons of riboflavin, which could float in JP XIII no. 1 solution (simulated gastric fluid). These were prepared by an emulsion solvent technique. To assess the usefulness of the intragastric floating property of the developed microballoons of riboflavin, riboflavin powder, nonfloating microspheres of riboflavin, and floating microballoons of riboflavin were administered to 3 volunteers. Riboflavin pharmacokinetics was assessed by urinary excretion data. It could be concluded that although excretion of riboflavin following administration of floating microballoons was not sustained in fasted state, it was significantly sustained in comparison to riboflavin powder and nonfloating microspheres in the fed state.4
Prepared floating alginate beads using gas-forming agents (calcium carbonate and sodium bicarbonate) and studied the effect of CO2 generation on the physical properties, morphology, and release rates. The study revealed that the kind and amount of gas-forming agent had a profound effect on the size, floating ability, pore structure, morphology, release rate, and mechanical strength of the floating beads. It was concluded that calcium carbonate formed smaller but stronger beads than sodium bicarbonate. Calcium carbonate was shown to be a less-effective gas-forming agent than sodium bicarbonate but it produced superior floating beads with enhanced control of drug release rates.5
Developed a matrix-floating tablet incorporating a high dose of freely soluble drug. The formulation containing 54.7% of drug, HPMC K4 M, Avicel PH 101, and a gas-generating agent gave the best results. It took 30 seconds to become buoyant. The comparison of gastric motility and stomach emptying between humans and dogs showed no big difference and therefore it was speculated that the experimentally proven increased gastric residence time in beagle dogs could be compared with known literature for humans, where this time is less than 2 hours.6
Developed sustained release floating capsules of nicardipine HCl. For floating, hydrocolloids of high viscosity grades were used and to aid in buoyancy sodium bicarbonate was added to allow evolution of CO2. In vitro analysis of a commercially available 20-mg capsule of nicardipine HCl (MICARD) was performed for comparison. Results showed an increase in floating with increase in proportion of hydrocolloid. Addition of sodium bicarbonate increased buoyancy. The optimized sustained release floating capsule formulation was evaluated in vivo and compared with MICARD capsules using rabbits at a dose equivalent to a human dose of 40 mg. Drug duration after the administration of sustained release capsules significantly exceeded that of the MICARD capsules. In the latter case the drug was traced for 8 hours compared with 16 hours in former case.7
Developed floating tablets of captopril using HPMC (4000 and 15 000 cps) and carbopol 934P. In vitro buoyancy studies revealed that tablets of 2 kg/cm2 hardness after immersion into the floating media floated immediately and tablets with hardness 4 kg/cm2 and then came to the surface after 3 to 4 minutes. Tablets in both cases remained floating for 24 hours. The tablet with 8 kg/cm2 hardness showed no floating capability. It was concluded that the buoyancy of the tablet is governed by both the swelling of the hydrocolloid particles on the tablet surface when it contacts the gastric fluids and the presence of internal voids in the center of the tablet .8
Prepared floating alginate beads incorporating amoxycillin. The beads were produced by dropwise addition of alginate into calcium chloride solution, followed by removal of gel beads and freeze-drying. The beads containing the dissolved drug remained buoyant for 20 hrs and high drug-loading levels were achieved.9
Prepared floating microparticles of ketoprofen, by emulsion solvent diffusion technique. Four different ratios of eudragit S 100 with eudragit RL were used. The formulation containing 1:1 ratio of the 2 above-mentioned polymers exhibited high percentage of floating particles in all the examined media as evidenced by the percentage of particles floated at different time intervals. This can be attributed to the low bulk density, high packing velocity, and high packing factor.10
Developed floating microparticles composed of polypropylene foam, eudragit S, ethyl cellulose (EC), and polymethyl metha acrylate (PMMA) and were prepared by solvent evaporation technique. High encapsulation efficiencies were observed and were independent of the theoretical drug loading. Good floating behavior was observed as more than 83% of microparticles were floating for at least 8 hours. At similar drug loading the release rates increased in the following order PMMA < EC < Eudragit S. This could be attributed to the different permeabilities of the drug in these polymers and the drug distribution within the system.11
6.3 / OBJECTIVE OF THE STUDY:-
Following are the objectives of the present study :
1.  To carry out pre-formulation studies for the possible drug/polymer/excipient interactions and micromeritics .
2.  To develop analytical methods for the estimation of drug in the formulations.
3.  To develop and formulate controlled release floating tablets (gastro-retentive) for Glipizide.
4.  To evaluate the formulated dosage forms based on physico-chemical characterization and in vitro release studies.
5.  To carry out short term stability studies on the most satisfactory formulation as per ICH guidelines at 30 ± 20C (65 ± 5 %RH) and 40 ± 20C (75 ± 5 %RH).
7
7.1
/
MATERIALS & METHODS:-
SOURCE OF DATA:-
1)  Review of literature from:
a)  Journal such as
i)  Indian Journal of Pharmaceutical Sciences
ii)  European Journal of Pharmaceutical Sciences
iii)  Journal of Controlled Release
iv)  International Journal of Pharmaceutics
v)  Drug Development and Industrial Pharmacy
vi)  Indian Drugs
b)  World Wide Web.
c)  I.I.Sc Library, Bangalore.
d)  J-Gate@Helinet.
e)  RGUHS Library.
7.2 / METHOD OF COLLECTION OF DATA:-.
1)  To carry out preformulation study
A.  Drug polymer interaction
B.  Micromeritic study
a)  Angle of repose
b)  Bulk density
c)  Porosity
d)  Percentage compressibility
2)  To develop and formulate floating/gastro-retentive tablets by direct compression/wet granulation methods using various polymers.
3)  Evaluation of the various properties of the formulated Floating tablets:-
a)  Physical properties:-
·  Diameter and Thickness
·  Hardness and Friability
·  Uniformity of Weight and Content
b)  Floating properties:-
·  Floating lag time
·  Total floating time
·  Swelling characteristics
c)  In vitro dissolution studies will be carried out in a USP Type-II dissolution apparatus containing Simulated Gastric Fluid (pH-1.2, without enzyme) for 24 hours.
4)  To carry out short term stability studies on the most satisfactory formulation as per ICH guidelines at 30 ± 20C (65 ± 5 %RH) and 40 ± 20C (75 ± 5 %RH) for 2 months.
7.3 / Does the study require any investigation or investigation to be conducted on patient or other humans or animals?
“NO”
7.4 / Has ethical clearance been obtained from your institution in case of 7.3?
“NOT APPLICABLE”
8 / REFEReNCES:-1.  Yeole P, Khan S, Patel V. Floating drug delivery system: need and development, Ind. J. Pharm. Sci. 2005; 67(3): 265-272.
2.  DaveBS,AminAF,PatelMM. Gastro retentive drug delivery system of ranitidine hydrochloride: formulation and in vitro evaluation,AAPS Pharm.Sci.Tech2004; 5(2): 34.
3.  ShimpiS, ChauhanB, MahadikKR, ParadkarA. Preparation and evaluation of diltiazem hydrochloride-Gelucire 43/01 floating granules prepared by melt granulation,AAPS Pharm.Sci.Tech2004; 5(2): 43.
4.  SatoY,KawashimaY. In vitro and in vivo evaluation of riboflavin containing microballoons for a floating controlled drug delivery system in healthy human volunteers, J. Cont. Rel.2003; 93(1): 39-47.
5.  ChoiBY,ParkHJ,HwangSJ,ParkJB. Preparation of alginate beads for floating drug delivery: effects of CO2 gas forming agents,Int. J. Pharm.2002; 239(1): 81-91.
6.  BaumgartnerS,KristelJ,VreerF,VodopivecP,ZorkoB. Optimization of floating matrix tablets and evaluation of their gastric residence time,Int. J. Pharm.2000; 195(1): 125-135.
7.  MoursyNM,AfifiNN,GhorabDM,El-SahartyY. Formulation and evaluation of sustained release floating capsules of Nicardipine hydrochloride,Pharmazie.2003; 58(1): 38-43.
8.  NurAO,ZhangJS. Captopril floating and/or bioadhesive tablets: design and release kinetics, Drug Dev. Ind. Pharm.2000; 26(9): 965-969.
9.  WhiteheadL,CollettJH,FellJT. Amoxicillin release from a floating dosage form based on alginates,Int. J. Pharm.2000;210(1):45-49.
10.  El-KamelAH, SokarMS, GamalSS, NaggarVF. Preparation and evaluation of ketoprofen floating oral drug delivery system,Int. J. Pharm.2001;220(1):13-21.
11.  StreubelA, SiepmannJ, BodmeierR. Floating micro particles based on low density foam powder,Int. J. Pharm.2002; 241(2): 279-292.
12.  PatelJK,PatelRP, AminAF,PatelMM. Formulation and evaluation of mucoadhesive glipizide microspheres, AAPS Pharm. Sci. Tech 2005;6:49-55.
9 / Signature of the candidate:
10 / Remarks of the Guide: / Recommended
11 / Name and Designation of:

11.1 Institutional Guide: / Mr. Shivanand Kalyanappa
Asst. Professor.
11.2 Signature:
11.3 Co-Guide: / --
11.4 Signature: /
--
11.5 Head of the Department: /
Dr. Roopa Karki
Dept. of Pharmaceutics
11.6 Signature
12 / 12.1 Remarks of the Principal / Recommended.
12.2 Signature
/
Dr. Goli Divakar
Principal
ACHARYA & B.M.REDDY COLLEGE OF PHARMACY,
SOLADEVANAHALLI,
HESARAGHATTA MAIN ROAD,
BANGALORE-90.