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“Formulation and Evaluation of Bilayer Floating

Tablets for Diabetes Mellitus.

Thesis Submitted to

The Tamil Nadu Dr. M.G.R. Medical University

For the award of the degree of

In Partial Fulfillment of Full Time

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IN

PHARMACY

By

Mr. Dhananjay Machhindra Patil

M Pharm. (Pharmaceutics)

Under the guidance of Dr. C.VIJAYA RAGHVAN

M Pharm. PhD, Vice Principal, PSG college of Pharmacy

RVS College of Pharmaceutical Sciences Sulur, Coimbatore,

Tamilnadu.

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INDEX

CHPTER

NO. DESCRIPTION PAGE NO.

1 INTRODUCTION 1-24

2 AIM AND OBJECTIVE 25-27

3 LITERATURE REVIEW 28-35

4 PLAN OF WORK 36-37

5 DRUG PROFILE 38-43

6 EXCIPIENT PROFILE 44-65

7 MATERIALS AND METHODS 66-89

8 RESULTS AND DISCUSSION 90-156

9 SUMMARY AND CONCLUSION 157-160

10 REFERENCES 161-169

11 ANNEXURE

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Sr. No

Title Page No

1.1 List of drugs formulated as a single and multiple

unit forms of floating drug delivery system 24

6.1 Uses of HPMC 45

6.2 Uses of Microcrystalline cellulose 50

6.3 Uses of Sodium bicarbonate 55

6.4 Uses of Citric acid 58

6.5 Uses of Povidone 60

6.6 Uses of Sodium lauryl sulfate 65

7.1 Standard values of angle of repose (θ) 70

7.2 Standard values of Carr’s index and Hausner’s

ratio 72

7.3 Compositions of immediate release layer tablet

(50 mg) 74

7.4 Weight variation tolerances for uncoated tablets 75 7.5 a Composition of factorial batches using 32 full

factorial design 77

7.5 b Composition of factorial batches using 23 full

factorial design 78

7.6 a Composition of floating bioadhesive sustained

release tablets containing HPMC K4M for 100mg 79 7.6 b Composition of floating bioadhesive sustained

release tablets containing Na CMC for 100mg 80 7.6 c Composition of floating bioadhesive sustained

release tablets for HPMC K4M and Na CMC for 100mg

80

7.7 Compositions of bilayer floating bioadhesive tablet

(150 mg) 85

7.8 ICH guide lines for stability study 88

8.1 Wavelength of Repaglinide in 1.2 pH 90

8.2 Wavelength of Glipizide in 1.2 pH 91

8.3 IR peaks of Repaglinide and Glipizide 93

8.4 Interaction study between , drug polymer through

IR spectroscopy 96

8.5 Interaction study between two drugs through IR

spectroscopy 97

8.6 Standard calibration curve of Repaglinide in 1.2 pH

buffer 100

8.7 Standard calibration curve of Glipizide in 1.2 pH

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Sr. No

Title Page No

8.8a Solubility data of Repaglinide in various buffers 102 8.8b Solubility data of Glipizide in various buffers 103 8.9 Physical parameters of drug, polymers and

excipients 105

8.10 Evaluation parameters of superdisintegrant 106 8.11 Precompression parameters of immediate release

powder blend 107

8.12 Post compression parameters of immediate release

tablets 108

8.13 Dissolution data of immediate release layer tablets 110 8.14 Precompression parameters of floating bioadhesive

sustained release layer powder blend

112

8.15a Evaluation parameters of floating bioadhesive

sustained release layer tablets (HPMC K4M) 114 8.15b Evaluation parameters of floating bioadhesive

sustained release tablets (Na CMC) 115

8.15c Evaluation parameters of floating bioadhesive

sustained release tablets (HPMC K4M and Na CMC) 116

8.16 Results of swelling study 117

8.17 Dissolution data of Glipizide floating bioadhesive sustained release layer tablets in 1.2 pH buffer (HPMC K4M)

121

8.18 Dissolution data of Glipizide floating bioadhesive sustained release layer tablets in 1.2 pH buffer (Na CMC)

122

8.19 Dissolution data of Glipizide floating bioadhesive sustained release layer tablets in 1.2 pH buffer (HPMC K4M and Na CMC)

123

8.20 Release Kinetics data of optimized floating bioadhesive sustained release tablet in 1.2 pH buffer

130

8.21 Tablet adhesion retention period 134

8.22 Mucoadhesion strength study of sustained release layer

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Sr. No

Title Page No

8.23 Responses of 23Full Factorial Experimental Design 139

8.24a Evaluation parameter of bilayer floating bioadhesive tablets

144

8.24b Evaluation parameter of bilayer floating

bioadhesive tablets 145

8.25a Dissolution data of optimized batches of bilayer floating bioadhesive tablets in 1.2 pH buffer (n = 3)

(Immediate release layer)

147

8.25b Dissolution data of optimized batches of bilayer

floating bioadhesive tablets in 1.2 pH buffer 149 8.26a Evaluation parameters of batch F1A6 which was

kept for stability study 151

8.26b Evaluation parameters of batch F1C2 which was

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Sr. No

Tittle Page no

1.1 Ideal plasma concentration curve 3

1.2 Anatomy of stomach 4

1.3 Typical motility pattern 7

1.4 Bioadhesive system 9

1.5 High density system 11

1.6 Various forms of gastroretentive systems; floating, bioadhesive, swelling, high density

11

1.7 Different forms of expandable system 12

1.8 Low density system 13

1.9 Barrier formation by Raft system 14

1.10 Mechanism of floating system 15

1.11 Effervescent system 17

1.12 Mechanism of effervescent system 18

1.13 Hydrodynamically balanced system 19

1.14 Bilayer floating tablet 20

5.1 Structure of Repaglinide 38

5.2 Structure of Glipizide 41

6.1 Structure of Hydroxypropyl methyl cellulose 44 6.2 Structure of Sodium carboxymethyl cellulose 46 6.3 Structure of Microcrystalline cellulose 49

6.4 Structure of Sodium starch glycolate 51

6.5 Structure of Sodium bicarbonate 53

6.6 Structure of Citric acid 56

6.7 Structure of Povidone 59

6.8 Structure of Magnesium stearate 61

6.9 Structure of Sodium lauryl sulfate 63

7.3 Compression cycle for preparation of bilayer floating bioadhesive tablets

86

8.1a UV spectrum of Repaglinide in 1.2 pH buffer 90 8.2b UV spectrum of Glipizide in 1.2 pH buffer 91

8.3a IR spectrum of Repaglinide 92

8.3b Spectrum of Glipizide 92

8.4a DSC thermogram of pure Repaglinide 93

8.4b DSC thermogram of pure Glipizide 94

8.5 FTIR spectra of physical mixture of Glipizide and

HPMC K4M 95

8.6 FTIR spectra of physical mixture of Glipizide and

Na CMC

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Sr.No Title Page no

8.7 FTIR spectra of physical mixture of Repaglinide and Glipizide

97

8.8a DSC thermogram of physical mixture of immediate release layer

98

8.8b DSC thermogram of mixture of Glipizide, HPMC K4M, Na CMC and Effervescent system

99

8.9 Standard calibration curve of repaglinide in 1.2 pH buffer

100

8.10 Standard calibration curve of Glipizide in 1.2 pH buffer

102

8.11a Solubility profile of Repaglinide 103

8.11b Solubility profile of Glipizide 104

8.12 Wetting Study of immediate release tablet 109

8.13 Dissolution profile of immediate release layer tablet in 1.2 pH buffer

111

8.14a Swelling study of tablet formulation (A1-A9) in 1.2 pH at 37 ± 0.5 oC

118

8.14b Swelling study of tablet formulation (B1-B9) in 1.2 pH at 37 ± 0.5 oC

118

8.14c Swelling study of tablet formulation (C1-C8) in 1.2 pH at 37 ± 0.5 oC

119

8.15 Comparative In-vitro dissolution of floating bioadhesive sustained release layer tablets in 1.2 pH buffer (HPMC K4M). (Simulated gastric fluid without enzyme)

124

8.16 Comparative In-vitro dissolution of floating bioadhesive sustained release layer tablets in 1.2 pH buffer (Na CMC)(Simulated gastric fluid without enzyme)

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Sr.No Title Page no

8.17 Comparative In-vitro dissolution of floating-bioadhesive sustained release layer tablets in 1.2 pH buffer (HPMC K4M and Na CMC)

125

8.18 Comparative dissolution study of optimized floating sustained release layer tablets of different polymer combination in 1.2 pH buffer. (Simulated gastric fluid without enzyme)

125

8.19 Effect of HPMC K4M on In-vitro release of Glipizide in 1.2 pH

126

8.20 Effect of Na CMC on In-vitro release of Glipizide in 1.2 pH

127

8.21 Effect of HPMC K4M and Na CMC on In-vitro release of Glipizide in 1.2 pH

128

8.22 Effect of different stirring rate on In-vitro release of Glipizide in 1.2 pH

129

8.23 Zero order release for batch C2 130

8.24 First-order kinetics for batch C2 131

8.25 Higuchi kinetics for batch C2 131

8.26 Korsmeyer-Peppas equation for batch C2 132

8.27 Tablet adhesion study for different polymer combination

134

8.28 Tablet mucoadhesion strength study for different polymer combination

135

8.29a Response surface plot showing the effect of HPMC K4M and NaHCO3on percent cumulative drug

release (Y1)

136

8.29b Response surface plot showing the effect of HPMC K4M and NaHCO3 on floating lag time (Y2)

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Sr.No Title Page no

8.30 The relationship between the experimented and predicted values of percent cumulative drug release &floating lag time

138

8.31 Response surface plots showing the effect of HPMC K4M, Na CMC and NaHCO3 on percent cumulative

drug release (Y1)

140

8.32 Response surface plots showing the effect of HPMC K4M, Na CMC and NaHCO3 on floating lag time (Y2)

142

8.33 3D Response Cube Mode for % cumulative drug release and floating lag time

143

8.34 Photograph shows floating behavior a)- Tablet at 0 min. , b)- Tablet after 60 min c)- Tablet after 8 hr, d)- Tablet after 12 hrs. (Batch AC2)

146

8.35a Comparative dissolution study of optimized bilayer floating bioadhesive tablets in 1.2 pH buffer (n = 3, mean ± SD) (Immediate release profile)

148

8.35b Comparative dissolution study of optimized bilayer floating bioadhesive tablets in 1.2 pH buffer. (n = 3, mean ± SD) (Floating sustained layer release profile)

150

8.36a X-ray photographs at different time intervals for C2 batch (HPMC K4M and Na CMC)

154

8.36b X-ray photographs at different time intervals for A6 batch(HPMC K4M)

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List of Abbreviations

% Percentage

GIT Gastro intestinal tract

MEC Minimum effective concentration

IR Immediate release

SR Sustained release

ZODDS Zero order drug delivery system

hrs Hours

GRDD Gastro retentive drug delivery system

GRT Gastric retention time

HPMC Hydroxy propyl methyl cellulose

w/w weight by weight

v/v volume by volume

CAS Chemical abstract service

UV Ultra violet

IR Infra red spectroscopy

DSC Differential scanning calorimeter

FTIR Fourier transform infra red

KBR Potassium bromide

oC Degree Celsius

µg/ml Microgram per milliliter

pH Hydrogen ion concentration

mg/hr Milligram per hour

wt Weight

ml Mililitre

g Gram

RH Relative humidity

mg Miligram

mm Millimeter

M Mole

nm Nanometer

cm Centimeter

USP United State Pharmacopoeia

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BP British Pharmacopoeia

λmax Maximum wavelength

rpm Revolution per minute

mm Millimeter

HCl Hydrochloric acid

min Minutes

ml/min Milliliter per minute

µm Micrometer

PEG Polyethylene glycol

HBS Hydrodynamically balanced system

GFDDS gastric floating drug delivery system

CMC Carboxy methyl cellulose

Ph Eur European pharmacopoeia

LD Lethal dose

JP Japnese pharmacopoeia

IIG Inactive ingredient guideline

NF National formulary

IV Intravenous

PVP Polyvinyl pyrilidone

NaCMC Sodium carboxy methyl cellulose

TBD Tapped bulk density

LBD Loose bulk density

DT Disintegration time

BLT Buoyancy lag time

TFT Total floating time

SD Standard deviation

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CHAPTER 1

Introduction

Formulation and evaluation of bilayer tablets for Diabetes Mellitus 1

1 INTRODUCTION

1.1 Oral drug delivery system

Oral drug delivery is the most widely used route of administration for decades among all the routes that have been employed for the systemic delivery of drug via various pharmaceutical products of different dosage forms.1 90 % of all

drugs used to produce systemic effects are administered by oral route.2,3 In oral drug delivery system, there are many types of

dosage form are available to deliver the drug such as tablet, capsule, liquid. Tablet dosage form is most preferred because of their accurate dose, good physical and chemical stability, competitive unit production cost and an elegant distinctive appearance results in high level of patient acceptability.4

Orally administered drug must be absorbed through the gut which depends on the various factors such as gastric emptying, intestinal motility, mucosal surface area, degradation of the drug in the stomach and first pass effect. The absorption rate varies from stomach to intestine to increased surface area about 4500 cm2, intestinal mucosa and greater blood flow i.e. 1000

ml/min through the intestine capillaries compared to the gastric capillaries.5

1.1.1 Advantages of oral drug delivery

It is convenient, can be self administered, safe, pain free, easy to take.

Oral route is cheap. No need to sterilize.

Variety of dosage forms available such as fast release tablets, capsules, enteric coated, layered tablets, slow release, suspensions, and mixtures.

1.1.2 Disadvantages of oral drug delivery

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CHAPTER 1

Introduction

Formulation and evaluation of bilayer tablets for Diabetes Mellitus 2

First pass effect-drugs absorbed orally are initially transported to the liver via the portal vein.

Irritation to gastric mucosa, nausea and vomiting.

Destruction of drugs by gastric acid and digestive juices. Effect too slow for emergencies.

Unpleasant taste of some drugs.

Unable to use in unconscious patient.6

An oral drug delivery system providing a uniform drug delivery can only partly satisfy therapeutic and biopharmaceutical needs, as it doesn’t take into account the site specific absorption rates within the gastrointestinal tract (GIT). Therefore there is a need of developing drug delivery system that releases the drug at the right time, at the specific site and with the desired rate.

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CHAPTER 1

Introduction [image:14.595.150.540.77.356.2]

Formulation and evaluation of bilayer tablets for Diabetes Mellitus 3 Figure 1.1: Ideal plasma concentration curve7

1.2 Controlled drug delivery system

Controlled release system including release of drug in sufficient amount in order to achieve therapeutic drug level over an extended period of time.8

Controlled release product will optimize therapeutic effect and safety of a drug at the same time improving the patient convenience and compliance. By incorporating the dose for 24 hrs into one tablet or capsule from which the drug is released slowly. This formulation helps to avoid the side effects associated with low and high concentrations. The ideal drug delivery system should show a constant zero-order release rate and maintain the constant plasma concentrations.10

1.2.1 Advantages of controlled drug delivery system

Controlled release formulations may maintain therapeutic concentrations over prolonged periods.

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CHAPTER 1

Introduction

Formulation and evaluation of bilayer tablets for Diabetes Mellitus 4

Controlled release formulations have the potential to improve the patient compliance.

Reduce the toxicity by slowing drug absorption.

Increase the stability by protecting the drug from hydrolysis or other degradative changes in gastrointestinal tract.

Minimize the local and systemic side effects. Improvement in treatment efficacy.

Minimize drug accumulation with chronic dosing. Usage of less total drug.

Improvement the bioavailability of some drugs.

1.3 Overview of stomach

The stomach is a ‘J’ shaped enlargement of the GI tract directly inferior to the diaphragm in the epigastric, umbilical and left hypochondria regions of the abdomen. The stomach connects the esophagus to the duodenum, the first part of the small intestine.

Figure 1.2: Anatomy of stomach 1.3.1 Structure of stomach

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CHAPTER 1

Introduction

Formulation and evaluation of bilayer tablets for Diabetes Mellitus 5

the pyloric sphincter it curves upward to complete the J shape. Where the oesophagus joins the stomach the anterior region angles acutely upwards, curves downward forming the greater curvature and then slightly upward towards the pyloric sphincter.

The Stomach is divided into four regions namely as Cardia, Fundus, Body and Pylorus.

1.3.1.1 Cardia

The Cardia surrounds the superior opening of the stomach. The Cardia is the portion of the stomach surrounding the cardioesophageal junction, or cardiac orifice (the opening of the oesophagus into the stomach).

1.3.1.2 Fundus

The Fundus is the enlarged portion to the left and above the cardiac orifice.

1.3.1.3 Body

The body, or corpus, is the central part of the stomach.

1.3.1.4 Pylorus

The region of the stomach that connects to the duodenum is the pylorus. It has two parts, the pyloric antrum, which connects to the body of the stomach, and the pyloric canal, which leads into the duodenum. When the stomach is empty, the mucosa lies in larger folds, called rugae. The pylorus communicates with the duodenum of the small intestine via a sphincter called the pyloric sphincter. The concave medial border of the stomach is called the lesser curvature it is in left side of stomach, and the right side convex lateral border called greater curvature.10,11

1.4 Histology of the stomach

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Introduction

Formulation and evaluation of bilayer tablets for Diabetes Mellitus 6

Secretions from the gastric glands flow in to the gastric pits and then in to the lumen of the stomach. The glands contain three types of exocrine gland cells that secrete their products in to the stomach lumen mucous neck cells, chief cells, and parietal cells.11

1.5 Gastric emptying

The proximal part made of fundus and body acts as a reservoir for undigested material, whereas the antrum is the main site for mixing motions and act as a pump for gastric emptying by propelling actions. Gastric emptying occurs during fasting as well as fed states. The pattern of motility is however distinct in the 2 states. During the fasting state an inter digestive series of electrical events take place, which cycle both through stomach and intestine every 2 to 3 hours. This is called the inter digestive myoelectric cycle or migrating myoelectric cycle (MMC), which is further divided into following 4 phases as follows:

Phase I (Basal phase) lasts from 40 to 60 minutes with rare contractions. Phase II (Preburst phase) lasts for 40 to 60 minutes with intermittent action potential and contractions. As the phase progresses the intensity and frequency also increases gradually.

Phase III (Burst phase) lasts for 4 to 6 minutes. It includes intense and regular contractions for short period. It is due to this wave that all the undigested material is swept out of the stomach down to the small intestine. It is also known as the house keeper wave.

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CHAPTER 1

Introduction

Formulation and evaluation of bilayer tablets for Diabetes Mellitus 7 Figure 1.3: Typical motility pattern

1.6 Gastro retentive drug delivery system

Gastro retentive drug delivery is an approach to prolong gastric residence time, thereby targeting site specific drug release in the upper gastrointestinal tract (GIT) for local or systemic effects. Gastro retentive dosage forms can remain in the gastric region for long periods and hence significantly prolong the gastric retention time (GRT) of drugs.

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CHAPTER 1

Introduction

Formulation and evaluation of bilayer tablets for Diabetes Mellitus 8

better absorption and enhanced bioavailability. One of such difficulties is the inability to confine the dosage form in the desired area of the gastrointestinal tract. Drug absorption from the gastrointestinal tract is a complex procedure and is subject to many variables.

Gastro retentive systems can remain in the gastric region for several hours and hence significantly prolong the gastric residence time of drugs. Prolonged gastric retention improves bioavailability, reduces drug waste, and improves solubility for drugs that are less soluble in a high pH environment. It has applications also for local drug delivery to the stomach and proximal small intestine. Gastro retention helps to provide better availability of new products with new therapeutic possibilities and substantial benefits for patients.12,14

Drugs that are required to be formulated into gastro retentive dosage forms include

Drugs acting locally in the stomach.

Drugs that are primarily absorbed in the stomach. Drugs that is poorly soluble at alkaline pH.

Drugs with a narrow window of absorption. Drugs rapidly absorbed from the GI tract and Drugs that degrade in the colon.12

1.7 Approaches to prolong gastric retention time

A number of systems have been used to increase the gastric retention time (GRT) of dosage forms by employing a variety of concepts. These systems have been classified according to the basic principles of gastric retention.

1.7.1 Floating drug delivery system

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CHAPTER 1

Introduction

Formulation and evaluation of bilayer tablets for Diabetes Mellitus 9

gastric contents, the drug is released slowly at the desired rate from the system. After release of drug, the residual system is emptied from the stomach. This results in an increased GRT and a better control of the fluctuations in plasma drug concentration.15

1.7.2 Bioadhesive drug delivery system

Bioadhesive systems are those which bind to the gastric epithelial cell surface or mucin and serve as a potential means of extending the gastro retention of drug delivery system (DDS) in the stomach by increasing the intimacy and duration of contact of drug with the biological membrane. A bioadhesive substance is a natural or synthetic polymer capable of producing an adhesive interaction based on hydration mediated bonding mediated or receptor mediated adhesion with a biological membrane or mucus lining of GI mucosa.16

Figure 1.4: Bioadhesive system 1.7.3 Swelling system

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Introduction

Formulation and evaluation of bilayer tablets for Diabetes Mellitus 10

conventional hydrogel is a very slow process and several hours may be needed to reach an equilibrium state during which premature evacuation of the dosage form may occur. Super porous hydrogels, average pore size >100 µm, swell to equilibrium size within a minute, due to rapid water uptake by capillary wetting through numerous interconnected open pores. Moreover, the swell to a large size (swelling ratio ~100 or more) and are intended to have sufficient mechanical strength to withstand pressure by gastric contraction.

The most commonly used excipients in swelling system are gel forming or highly swellable cellulose type hydrocolloids, hydrophilic gums, polysaccharides and matrix forming materials such as polycarbonate, polyacrylatis, polymethacrylate, polystyrene as well as bioadhesive polymers such as Chitosan and carbopol.17

1.7.4 High density system

These systems, which have a density of 3 g/cm3, are retained in

the rugae of stomach and capable of withstanding its peristaltic Movements. The only major drawback with these systems is that it is technically difficult to manufacture them with a large amount of drug (>50%) and achieve required density of 2.4‐2.8 g/cm3. Diluents such as barium sulphate (density= 4.9), zinc

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CHAPTER 1

Introduction

Formulation and evaluation of bilayer tablets for Diabetes Mellitus 11 Figure 1.5: High density system

Figure 1.6: Various forms of gastroretentive systems, floating, bioadhesive, swelling, high density.

1.7.5 Expandable system

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Introduction

Formulation and evaluation of bilayer tablets for Diabetes Mellitus 12

dosage form should be of adequate size, so that it can be easily swallowed and should not cause gastric obstruction. It should also be considered, that after complete drug release from system, it can be evacuated easily from the gastric system. The concept of designing such expandable system is to prepare a carrier (e.g. capsule) and to incorporate in it, a compressed system which expands, as it comes in contact with the gastric contents. As, the size of the system increases and reaches to diameter or dimensions, greater than the size of the pyloric sphincter, it cannot leave the stomach while gastric emptying process.13

Figure 1.7: Different forms of expandable system

1.7.6 Low density system

It also called ‘‘Microballoons’’ because of the low-density. Gas-generating systems inevitably have a lag time before floating on the stomach contents, during which the dosage form may undergo premature evacuation through the pyloric sphincter. Low-density systems (<1 g/cm3) with immediate buoyancy have

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CHAPTER 1

Introduction

Formulation and evaluation of bilayer tablets for Diabetes Mellitus 13

The drug release and better floating properties mainly depend on the type of polymer, plasticizer and the solvents employed for the preparation. Polymers such as polycarbonate, Eudragit, Sand cellulose acetate were used in the preparation of hollow microspheres, and the drug release can be modulated by optimizing the polymer quantity and the polymer plasticizer ratio.19

Figure 1.8: Low density system 1.7.7 Raft forming system

Floating Rafts are used in the treatment of gastric esophageal reflux. This raft formulation based on an alginate biopolymer. On ingestion, this formulation reacts with gastric acid to form floating raft structure, which impedes the reflux of acid and food by acting as a physical barrier. The raft has a pH value higher than that of the stomach contents so that in the event of gastric reflux, the wall of the oesophagus is not subjected to irritation by HCL. Such formulation on entering the stomach forms a colloidal gel. Sodium alginate solution reacting with gastric acid and this gel floats on the surface of the gastric contents due to CO2 generation by gas generating excipients impeding reflux of

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CHAPTER 1

Introduction

Formulation and evaluation of bilayer tablets for Diabetes Mellitus 14 Figure 1.9: Barrier formation by Raft system

1.8 Floating drug delivery system

Floating drug delivery system is also called the hydrodynamically balanced system (HBS). Floating drug delivery systems (FDDS) 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 contents, the drug is released slowly at the desired rate from the system. After release of drug, the residual system is emptied from the stomach. This results in an increased GRT and a better control of the fluctuations in plasma drug concentration.

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Introduction

Formulation and evaluation of bilayer tablets for Diabetes Mellitus 15

FDDS with respect to stability and durability of floating forces produced in order to prevent the drawbacks of unforeseeable intra gastric buoyancy capability variations.19,21

F = F buoyancy - F gravity = (Df - Ds) gv Where,

F= Total vertical force Df = fluid density Ds = Object density v = Volume

g = Acceleration due to gravity.

Figure 1.10: Mechanism of floating system

1.8.1 Classification of floating drug delivery system

Based on the mechanism of buoyancy, floating systems can be classified into two distinct categories viz. effervescent and non-effervescent systems.

1.8.1.1 Effervescent system

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Introduction

Formulation and evaluation of bilayer tablets for Diabetes Mellitus 16

materials that have been reported are a mixture of sodium alginate and sodium bicarbonate, multiple unit floating pills that generate carbon dioxide when ingested, floating mini capsules with a core of sodium bicarbonate, lactose and polyvinylpyrrolidone coated with hydroxypropyl methylcellulose (HPMC).

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CHAPTER 1

Introduction

Formulation and evaluation of bilayer tablets for Diabetes Mellitus 17

utilize on automatically operated geometric obstruction that keeps the device floating in the stomach and prevents the system from passing through remainder of GIT. The different grades of HPMC were used to develop the eroding matrix. They concluded that duration of action was dependent on erosion rate of the incorporated polymer and the in vitro release of drug from developed device could be maintained up to 20 days.22,23

Figure 1.11: Effervescent system

1.8.1.1.1 Mechanism of effervescent system

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Introduction

Formulation and evaluation of bilayer tablets for Diabetes Mellitus 18

porosity, morphology and mechanical strength of beads. It was observed that amount of gas forming agent had a significant effect on size, floating ability, porosity, morphology, release rate and mechanical strength. Calcium carbonate formed smaller but stronger beads as compared to sodium bicarbonate. Calcium carbonate was found to be less effective gas generating agent than sodium bicarbonate. But it forms superior quality floating beads with significantly extended drug release.23

Figure 1.12: Mechanism of effervescent system

1.8.1.2 Non effervescent system

1.8.1.2.1 Colloidal gel barrier system

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CHAPTER 1

Introduction

Formulation and evaluation of bilayer tablets for Diabetes Mellitus 19

hydrocolloids in the system hydrate and form a colloidal gel barrier around its surface. This gel barrier controls the rate of fluid penetration into the device and consequent release of the drug.21

Figure 1.13: Hydrodynamically balanced system

1.8.1.2.2 Bilayer floating tablet

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Introduction

Formulation and evaluation of bilayer tablets for Diabetes Mellitus 20

The biphasic system is used mostly when maximum relief needs to be achieved quickly and it is followed by a sustained release phase. It also avoids repeated administration of drug. Coronary vasodilators, antihypertensive, antihistaminic, analgesics, antipyretics and antiallergenic agents are mainly suitable for this system. The biphasic system some time may contain two drugs in separate release layers.24,25

Figure 1.14: Bilayer floating tablet

1.9 Factors affecting gastric retention time

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CHAPTER 1

Introduction

Formulation and evaluation of bilayer tablets for Diabetes Mellitus 21 1.9.1 Density of dosage form

Density is the main factor affecting the gastric residence time of dosage form. A buoyant dosage form having a density less than that of the gastric fluids floats, since it is away from the pyloric sphincter, the dosage unit is retained in the stomach for a prolonged period. A density of less than 1.0 g/ml i.e. less than that of gastric contents has been reported. However, the floating force kinetics of such dosage form has shown that the bulk density of a dosage form is not the most appropriate parameter for describing its buoyancy capabilities.26

1.9.2 Volume of stomach

The resulting volume of stomach is 25 to 30 ml. When volume is large, the emptying is faster. Fluids taken at body temperature leave the stomach faster than colder or warmer fluids.

1.9.3 Size of dosage form

The size of the dosage form is another factor that influences gastric retention. The mean gastric residence times of non-floating dosage forms are highly variable and greatly dependent on their size, which may be small, medium, and large units. In fed conditions, the smaller units get emptied from the stomach during the digestive phase and the larger units during the housekeeping waves. In most cases, the larger the size of the dosage form, the greater will be the gastric retention time because the larger size would not allow the dosage form to quickly pass through the pyloric antrum into the intestine. Thus the size of the dosage form appears to be an important factor affecting gastric retention.19

1.9.4 Viscosity grade of polymer

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CHAPTER 1

Introduction

Formulation and evaluation of bilayer tablets for Diabetes Mellitus 22

floating properties. In addition, a decrease in the release rate was observed with an increase in polymer viscosity.26

1.9.5 Age

Gastric retention time is longer in geriatric patients, while it is lower in neonates and children when compared to normal adults.

1.9.6 Gender

Gastric retention time in male (3-4 hours) is less than the female (4-6 hours).

1.9.7 Fed or unfed state

Gastric retention time is less during fasting conditions as the gastric motility increases during fasting conditions.

1.9.8 Feed frequency

Higher the frequency of taking food, longer will be the gastro retention time.

1.10 Advantages of floating drug delivery system

Floating drug delivery system offers several advantages over conventional drug delivery system.

The gastroretentive systems are advantageous for drugs absorbed through the stomach, e.g. ferrous salts, antacids.

Acidic substances like aspirin cause irritation on the stomach wall when come in contact with it. Hence, HBS formulation may be useful for the administration of aspirin and other similar drugs.

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CHAPTER 1

Introduction

Formulation and evaluation of bilayer tablets for Diabetes Mellitus 23

forms if it remains in the solution form even at the alkaline pH of the intestine.

The gastroretentive systems are advantageous for drugs meant for local action in the stomach e.g. antacids.

When there is a vigorous intestinal movement and a short transit time as might occur in certain type of diarrhea, poor absorption is expected. Under such circumstances it may be advantageous to keep the drug in floating condition in stomach to get a relatively better response. FDDS improves patient compliance by decreasing dosing frequency.

Bioavailability enhances despite first pass effect because fluctuations in plasma drug concentration are avoided; a desirable plasma drug concentration is maintained by continuous drug release.

Better therapeutic effect of short half-life drugs can be achieved.

Gastric retention time is increased because of buoyancy. Enhanced absorption of drugs which solubilizing only in stomach.

Superior to single unit floating dosage forms as such microspheres releases drug uniformly and there is no risk of dose dumping.

Avoidance of gastric irritation, because of sustained release effect, floatability and uniform release of drug through multi particulate system.17,19,20

1.11 Limitations of floating drug delivery system

A high level of fluid in the stomach is required for drug delivery to float and work efficiently.

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CHAPTER 1

Introduction

Formulation and evaluation of bilayer tablets for Diabetes Mellitus 24

Drugs such as nifedipine, which under goes first pass metabolism may not be desirable for the preparation of these types of systems.

Drugs which are irritant to Gastric mucosa are also not desirable.

The drug substances that are unstable in the acidic environment of the stomach are not suitable candidates to be incorporated in the systems.18.

Table 1.1: List of drugs formulated as a single and multiple unit forms of floating drug delivery system

Dosages forms Drugs

Microspheres

Aspirin, Griseofulvin, p-nitroaniline,

Ibuprofen, Terfenadine, Tranilast, Verapamil, Repaglinide

Granules Diclofenac sodium, Indomethacin, Prednisolone

Films Cinnarizine

Powders Several basic drugs

Capsules Chlordiazepoxide HCl, Diazepam, Furosemide, L-Dopa, Misoprostol, Propranolol,

Urodeoxycholic acid

Tablets Acetaminophen, Acetylsalicylic acid,

Amoxicillin trihydrate, Ampicillin, Atenolol, Ciprofloxacin, Captopril, Chlorpheniramine maleate, Cinnarizine, Diltiazem, Fluorouracil, Isosorbide mononitrate, Isosorbide dinitrate, Piretanide, Prednisolone,

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References

Formulation and evaluation of bilayer tablets for Diabetes Mellitus 161

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25. Ali A, Sharma, S. Sustained release from two layer tablets of ibuprofen, Indian drugs, 30(4), 1993:183-187.

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28. Prabhakaran P, Satyanarayana D, Subrahmanayam EVS. Formulation and in vitro evaluation of gastric oral floating tablets of Glipizide. Indian J Pharm Educ Res.2008:42:174-183. 29. Ali J, Arora S, Ahuja A, Babbar A, Sharma R et.al. Formulation

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30. Lopes C, Lobo J, Pinto J, Costa P. Compressed matrix core tablet as a quick / slow dual component delivery system containing ibuprofen. Am Assoc Pharma Scientist.2007:8(3):1-8. 31. Tadros MI. Controlled release effervescent floating matrix tablets of ciprofloxacin hydrochloride: Development, optimization and in vitro–in vivo evaluation in healthy human volunteers. J Pharm Biopharm.2010:74(2)332–339.

32. Sonar G, Jain D, More D. Preparation and in vitro Evaluation of bilayer and Floating-bioadhesive tablets of Rosiglitazone Maleate. Asian J Pharm Sci.2007:2(4):161-169.

33. Rahman Z, Ali M Khar R. Design and evaluation of bilayer floating tablets of Captopril. Acta Pharm.2006:56:49-57.

34. Narendra C, Srinath M, Ganesh B. Optimization of bilayer floating tablets containing Metoprolol tartrate as a model drug for gastric retention. Am Assoc Pharm Scientist.2006:7(2):E1-E7.

35. Patel V, Patel N. Intragastric floating drug delivery system of Cefuroxime axetil: in vitro evaluation. Am Assoc Pharm Scientist.2006:7(1):E17-E23.

36. Yiqiao H, Xiaoqiang X, Minjie S, Feng Z. Floating matrix dosage form for phenoporlamine hydrochloride based on gas forming agent: In vitro and in vivo evaluation in healthy volunteers. Int J Pharm.2006:310:139-145.

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drug delivery system for Ofloxacin. Int J Pharm.2006:316:86-92.

38. Chavanpatil M, Jain P, Chaudhari S, Shear R, Vavia P.Development of sustained release gastroretentive drug delivery system for Ofloxacin: In vitro and in vivo evaluation. Int J Pharm.2005:304:178-184.

39. Zhao N, Augsburger L. The influence of swelling capacity of superdisintegrants in different pH media on the dissolution of hydrochlorothiazide from directly compressed tablet. Am Assoc Pharm Scientist.2005:6:E120-E126.

40. Chaudhari P, Chaudhari S, Kolhe S, Dave K, More D. Formulation and evaluation of fast dissolving tablets of famotidine. Indian drug.2005:42:641-648.

41. Azeem S, Sharma S. Immediate release drug delivery system: A review. Int J Biopharm and toxicol research.2011:1(1):24-47. 42. Karande A, Dhoke S, Yeole P 2005. Formulation and evaluation

of bilayer tablet with antihypertensive drugs having different release pattern. Indian drugs.2005: 43:44-50.

43. Shenoy V, Agarwal S, Pandey S. Optimizing fast dissolving dosage form of Diclofenac sodium by rapidly disintegrating agents. Int J Pharm Sci.2003:65:197-201.

44. Bhalla N, Goswami M. Floating drug delivery system. Int J Pharm Res Sci.2012:1(4):20-28.

45. Nur A, Zhang J. Captopril floating and /or bioadhesive tablets: design and release kinetics. Drug Dev Ind Pharm.2000:26(9):965-969.

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47. Chandira R, Palanisamy P, Jayakar B, Formulation and evaluation of bilayer floating tablets of Metformin hydrochloride. Int Res J Pharm.2012:3(2):257-266.

48. Pahwa R, Chhabra L, Lamba A, Jindal S, Rathour A. Formulation and in-vitro evaluation of effervescent floating tablets of an antiulcer agent. J Chem Pharm Res.2012:4(2):1066-1073.

49. Ramabargavi J, Pochaiah B, Meher C, Kishan S, Srujana B. Formulation and in vitro evaluation of gastroretentive floating tablets of Glipizide. J Chem. Pharm Res.2013:5(2):82-96.

50. Repaglinide [cited 2013 July 11]; Available from http://www.drugbank.ca/drugs/DB00912.

51. Absorption distribution metabolism excretion [cited 2013 July 26]; Available from http://wikipedia.org/wiki/ADME.

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from http://www.drugs.com/sfx/repaglinide-side-effects.html. 54. USP 30 NF 25. Webcom limited; 3110.

55. Indian pharmacopoeia, 2007. Volume 2. Controller of publication, Delhi; 550.

56. British Pharmacopoeia, 2009. Volume 1. Controller of Majesty’s stationary office for the department of health on behalf of Health ministers; p 845.

57. USP 30 NF 25. Webcom limited; 1453.

58. Rang H, Dael M, Ritter J, Moore P. Pharmacology. In: The endoc rine pancreas and control of blood glucose. Elsevier.5, 2006; p.385-393.

59. Glipizide [ cited 2013 February 8]; Available from http://www.drugbank.ca/drugs/DB01067

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ORAL.aspx?drugid=10094&drugname=glipizide+oral

61. Barar F S K. Essentials of Pharmacotherapeutics. In: Insulin and oral hypoglycemic agent. S Chand and company limited; p.345-347.

62. Inactive ingredient guideline limit; Available from

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64. British Pharmacopoeia, 2009. Volume 1. Controller of Majesty’s stationary office for the department of health on behalf of Health ministers; p1759.

65. Japanese pharmacopoeia, 2011. The Minister of Health, Labour and welfare; 520-521,645-646.

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73. Prasanth V, Eapen S, Kutty S, Rai A. Development and validation of UV spectroscopic methods for the estimation of repaglinide and metformin hydrochloride in synthetic mixture. Int J Pharm Sci Health Care.2012:2(2):150-158.

74. Behera B, Sahoo S, Dhal S, Barik B, Gupta B. Characterization of Glipizide loaded polymethacrylate microspheres prepared by an emulsion solvent evaporation method. Tropical J Pharm Res.2008:7(1):879-885.

75. Shams T, Sayeed M, Kadir M, Khan R, Jalil R, Islam Md. Thermal, infrared characterization and in vitro evaluation of Repaglinide solid dispersion. Scholars Research Library.2011:3(6):142-150.

76. Sathali A, Kavitha R. Enhancement of solubility of Repaglinide by Solid dispersion technique. Int J Chem Sci.2012:10(1):377-390.

77. Suma B, Gangadhar P, Ahad H, Mallapu R, Lavanya G. Fabrication and evaluation of Glipizide abelmochus esculentus fruit mucilage povidone controlled release matrix tablet. Int J Res Ayurveda Pharm.2011:2(2):592-596.

78. Mohite M, Maste M, Baravalisaya S, Tandel J. Analytical method development of Repaglinide in bulk and single component formulation. Int J Res.2013:4(1):136-137.

79. Sawant S, Dole M, Rathod D. Spectrophotometric determination of Glipizide in bulk and tablet dosage form by absorption maxima, first order derivative spectroscopy and area under the curve. Asian J Pharm Clin Res.2012:5(3):102-104.

80. Shukla M, Rathore P, Jain A, Nayak S. Enhanced solubility study of glipizide using different solubilization techniques. Int J Pharma Pharm Sci.2010;2(2):46-48.

81. Goodman and Gillman. The pharmacological basis of therapeutics. Mc-Graw Hill medical publishing division; p.

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83. USP 30 NF 25. Webcom limited: p.242, 674, 276, 277,731, 1981.

84. Jain G, Goswami J. Studies on formulation and evaluation of new superdisintegrants for dispersible tablets. Int J Pharma Excip.2005:37-43.

85. Bakre L, Jaiyeoba K. Evaluation of a new tablet disintegrant from dried pods of Abelmuscus Esclentus (Orka), Asian J Pharm Clin Res.2009:2(3):81-91.

86. Magnus A, Anthony O. Preliminary investigation into the use of Pleurotus tuber-regium powder as a tablet disintegrant. Tropical J Pharm Res.2002:1(1):29-37.

87. Bussemer T, Peppas N, Bodmeier R. Evaluation of the swelling, hydration and rupturing properties of the swelling layer of a rupturable pulsatile drug delivery system. Eur J Pharm Biopharm.2003:56(2):261-270.

88. Lachmann L, Lieberman H, Kanig J. The Theory and Practice of Industrial Pharmacy. Varghese pubilishing house, Bombay.1990:254-255.

89. Gohel MC, Parikh RK, Brahmbhatt BK, Shah AR. Preparation and assessment of novel co-processed super disintegrants consisting crospovidone and sodium starch glycolate: A technical note. Am Assoc Pharm Sci Tech.2007:8(1):E63-69. 90. Kuzhiyil J, Senthil A, Masurkar S, Kharat J, Narayanswami V.

Formulation and evaluation of immediate release Venlafexine Hydrochloride tablet: Comparative study of superdisintegrant and diluents. Int Res J Pharm.2012:3(4):324-329.

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92. Patel D, Patel N, Pandya N. Gastroretentive Drug Delivery System of Carbamazepine: Formulation Optimization Using Simplex Lattice Design. Am Assoc Pharm Scientist Tech.2007:8(1):E82-E86.

93. Chandira R, Arafath A, Bhowmik D, Jayakar B, Kumar K. Formulation and evaluation of bilayered floating tablet of Metformin hydrochloride. J Pharma.2012:1(5):23-34.

94. Dorozynski P, Jachowicz R, Kulinowski P, Kwiecinski S, Szybinski K, Skorka T. The polymers for the preparation of hydrodynamically balanced systems – methods of evaluation. Drug Dev Ind Pharm.2004:30(9):947–957.

95. Hajare A, Patil V. Formulation and characterization of Metformin hydrochloride floating tablet. Asian J Pharma Res.2012:2(3):111-117.

96. Anusha K, Swathi P, Raju K, Madhavi N, Sudhakar B, Murthy K. Design and In-vitro characterization of gastroretentive bilayer floating tablet of Metoprolol Tartrate. J Global Trends Pharm Sci.2013:4(2):1058-1066.

97. Pawar A, Dhumal R, Rajmane S, Dhumal S. Design and evaluation of bilayer floating tablet of Cefuroxime axetil for bimodal release. J Scientific Ind Res.2006:65:812-816.

98. Lalla J, Gurnancy R. Polymers for mucosal delivery-swelling and mucoadhesive evaluation. Indian Drug.2002:39:270-276.

99. ICH stability guideline Q1A (R2) for stability testing of new drug substances and products.

100. Nair S, Arumugam K, Mahalingam M. Formulation and evaluation of Escitalopram oxalate tablets. Int J Pharma Sci.2012:2(4):94-100.

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CHAPTER 2

Need and objective

Formulation and evaluation of bilayer tablets for Diabetes Mellitus 25

2. AIM AND OBJECTIVE

2.1 Need of the study

Oral route is considered as the most promising and convenient route for drug delivery. The benefits of long term delivery technology have not been fully realized for dosage forms designed for oral administration. The administration of food can delay the gastric emptying so the control placement of a drug delivery system in a specific region of gastrointestinal tract is needed. This is mainly due to the fact that the extent of drug absorption from gastrointestinal tract is determined by gastrointestinal physiology; irrespective of the control release properties of the device prolonged gastric retention improves bioavailability. These have led to the development of a unique oral controlled release dosage form with gastro retentive properties.

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Need and objective

Formulation and evaluation of bilayer tablets for Diabetes Mellitus 26

bioavailability and local irritation due to a large amount of drug delivered at a particular site of GIT.

The conventional dosage form is absorbed in the small intestine within 3-6 hrs after retain in the stomach for 0.5-2 hrs. The concept of gastroretentive drug delivery system came from the need to localize the drug at a certain site in the body. In oral drug delivery, drug absorption is limited because of the gastrointestinal transit time of the dosage form. When the site of drug absorption is mainly stomach or upper part of GIT, then it is mandatory to retain the dosage form at the site of absorption for longer duration, but the gastrointestinal transit is the limitation for such type of dosage forms. Gastric retentive dosage forms are designed to be retained in the stomach and prolong the gastric residence time of the drugs. The major site of drug absorption is upper part of GIT hence, release of drug at site of absorption enhance the therapeutic efficacy of drug.

Drugs which are highly soluble at low pH (gastric pH) and poorly soluble at high pH (intestinal pH), drugs having short biological half life e.g. Glipizide are the suitable drug candidates for the formulation of floating sustained drug delivery system.

Glipizide second generation sulfonylurea an oral hypoglycemic agent, is one of the most commonly prescribed drugs for the treatment of patients with type II diabetes mellitus, it having half-life 2-4 hrs. Gastroretentive drug delivery systems can be able to retain the dosage unit in the stomach and assist in improvement of solubility of drugs. Therefore, Glipizide is a suitable model drug candidate for gastroretentive formulation.

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CHAPTER 2

Need and objective

Formulation and evaluation of bilayer tablets for Diabetes Mellitus 27

to giving immediate release of Repaglinide because it having half life 1 hr so therapeutic effects obtain within a short time. As soon the process of reduction in glucose level get started in short period, then subsequently floating sustained release layer of Glipizide is going to maintain the glucose level for longer period which is approximately upto12 hrs.

2.2 Objectives

Formulation and evaluation of immediate release layer tablets.

Formulation and evaluation of floating bioadhesive sustained release tablets.

Formulation and evaluation of bilayer floating tablets by using optimized immediate and floating sustained release layer.

To avoid developing tolerance and unnecessary increasing concentration of the drug.

To study the effect of HPMC, NaCMC and effervescent system on release rate of Glipizide.

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CHAPTER 3

Literature review

Formulation and evaluation of bilayer tablets for Diabetes Mellitus 28

3. LITERATURE REVIEW

3.1 Prabhakara et al. (2008) The intention of this study was to develop a gastro retentive floating controlled drug delivery system by using Glipizide as a model drug. Tablets were prepared by direct compression method, and evaluated for various parameters. Tablet formulations were designed using hydroxypropyl methylcellulose as release retarding polymer(s) and sodium bicarbonate as a gas former.28

3.2 Ali et al. (2007) Formulated and developed

hydrodynamically balanced system for Metformin as a single unit floating capsule. Various grades of low density polymers were used. Formulation was optimized for In-vitro buoyancy and In-vitro release in simulated fed state gastric fluid. In-vivo study was done by gamma scintigraphy using New Zealand Albino rabbits.29

3.3 Lopes et al. (2007) They formulated quick/slow dual component delivery system containing Ibuprofen. Biphasic drug delivery means immediate release followed sustained release layer. Formulations were evaluated for in vitro drug release.30

3.4 Tadros et al. (2009) The purpose of this study was to develop a gastroretentive controlled release drug delivery system with swelling, floating, and adhesive properties. Tablets were prepared by direct compression method and evaluated for various parameters. Tablet formulations were designed using hydroxypropyl methylcellulose (HPMC K15M) and/or sodium alginate (Na alginate) as release retarding polymer(s) and sodium bicarbonate (NaHCO3) or calcium

carbonate (CaCO3) as a gas former. Tablets were evaluated

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Literature review

Formulation and evaluation of bilayer tablets for Diabetes Mellitus 29

3.5 Sonar et al. (2009) The aim of the present research was to

develop a bilayer and floating bioadhesive drug delivery system exhibiting a unique combination of floatation and bioadhesion to prolong residence in the stomach using Rosiglitazone maleate as a model drug. The in-vitro drug release, buoyancy lag time, detachment force and swelling index were evaluated. The in-vitro drug release from the tablet was controlled by the amount of HPMC in the sustained release layer. The floating ability of the tablets was studied by gamma scintigraphy. The release of Rosiglitazone maleate from the matrix tablet was followed the first-order release model. The concentration of HPMC significantly affects the drug release rate, buoyancy lag-time, detachment force and swelling characteristics of the tablets. The tablet was buoyant for up to 8 hrs in the human stomach.32

3.6 Rahman et al. (2006) Formulated and evaluated a bilayer floating tablet (BFT) of Captopril using HPMC K grade. Gas generating agent i.e. citric acid and sodium bicarbonate added in floating layer. Captopril and various polymers such as HPMC K15M, carbopol 934P were used. Tablets were prepared by direct compression method and In-vitro dissolution studies were carried out in a USP apparatus 2, in simulated gastric fluid (without enzyme, pH 1.2). Optimized formulation released approximately 95% drug in 24 hrs, floating lag time was 10 min and the tablets remained floated throughout study. In-vivo X-ray study was done on human volunteers and showed BFT significantly increased gastric residence time.33

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Literature review

Formulation and evaluation of bilayer tablets for Diabetes Mellitus 30

the GFDDS with total polymer content-to drug ratio (X1), polymer-to-polymer ratio (X2), and different viscosity grades of Hydroxypropyl methylcellulose (HPMC) (X3) as independent variables. Four dependent variables were considered: percentage of MT release at 8 hours, T50 %, diffusion coefficient, and floating time. The results indicated that X1 and X2 significantly affected the floating time and release properties, but the effect of different viscosity grades of HPMC (K4M and K100M) was no significant. Regression analysis and numerical optimization were performed to identify the best formulation. Fickian release transport was confirmed as the release mechanism from the optimized formulation.34

3.8 Patel et al. (2006) Developed of an intragastric drug delivery system for Cefuroxime axetil. The 32 full factorial design was

employed. Formulation was prepared by direct compression using HPMC K4M and HPMC K100LV in different ratio and studied the effect of sodium lauryl sulfate (SLS) on drug release from HPMC matrices.35

3.9 Hu Yiqiao et al. (2006) Prepared a floating sustained release matrix tablet of Phenoporlamine hydrochloride, which was a novel compound used for the treatment of hypertension by using gas forming agents. In vivo evaluation was carried out in human healthy volunteers.36

3.10 Chavanpatil et al. (2006) Oral sustained release

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Literature review

Formulation and evaluation of bilayer tablets for Diabetes Mellitus 31

HPMC K100M and a swelling agent, crospovidone in combinations were tried and optimized to get the release profile for 24 hrs. Formulations were evaluated for In-vitro drug release profile, swelling characteristics and In-vitro bioadhesion property. The In- vitro drug release followed Higuchi kinetics and the drug release mechanism was found to be of anomalous or non Fickian type.37

3.11 Chavanpatil et al. (2005) Sustained release (SR)-gastroretentive dosage forms (GRDF) enable prolonged and continuous input of the drug to the upper parts of the gastrointestinal (GI) tract and improve the bioavailability of medications that are characterized by a narrow absorption window. Different polymers, such as psyllium husk, HPMC K100M, crospovidone and its combinations were tried in order to get the desired sustained release profile over a period of 24 hrs. All formulations were evaluated for buoyancy lag time, duration of buoyancy, dimensional stability, drug content and In-vitro drug release profile. It was found that dimensional stability of the formulation increases with the increasing psyllium husk. We conclude that psyllium husk and HPMC K100M increases the dimensional stability of the formulations, which is necessary in case of once daily formulations. Sodium bicarbonate acts as a gas-generating agent, which is necessary in case of gastroretentive dosage forms. Crosspovidone improved the drug release profile and swelling factor of psyllium husk based formulations. We also conclude that channeling agents, such as betacyclodextrin were useful to increase the initial burst release from psyllium husk based formulations.38

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Literature review

Formulation and evaluation of bilayer tablets for Diabetes Mellitus 32

found that dissolution media affect on the efficiency of superdisintegrants. Ac-Di-Sol was found to be best among all superdisintegrants.39

3.13 Chaudhari et al. (2005) Formulated and evaluated fast dissolving tablets of famotidine using Ac-Di-Sol. They found that Ac-Di-Sol (3% and 5%) showed faster release of famotidine.40

3.14 Azeem et al. (2011) Has reviewed immediate release drug delivery system in which tablet is the most popular among all dosage forms existing today because of its convenience of self administration, compactness and easy manufacturing; however in many cases immediate onset of action is required than conventional therapy. The basic approach used in development tablets is the use of superdisintegrant like Cross linked Carboxymethylcellulose (Crosscarmalose), Sodium starch glycolate (Primo gel, Explotab), Polyvinylpyrrolidone (Polyplasdone) etc. which provide instantaneous disintegration of tablet after administration. Immediate release liquid dosage forms and parenteral dosage form have also been introduced for treating patients. Liquid dosage form can be suspensions with typical dispersion agents like hydroxypropyl methylcellulose, AOT (dioctylsulfosuccinate) etc.41

3.15 Karande et al. (2005) Formulated and evaluated bilayer tablet of Metoprolol tartrate and Hydrochlorothiazide. It was observed that bilayer tablet technology could be successfully used for the formulation of fixed dose combination of sustained release Metoprolol tartrate and immediate release hydro-chlorothiazide.42

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CHAPTER 3

Literature review

Formulation and evaluation of bilayer tablets for Diabetes Mellitus 33

cellulose showed better disintegrating property along with rapid release.43

3.17 Bhalla et al. (2012) Has reviewed floating drug delivery system in which Controlled release (CR) dosage forms have been extensively used to improve therapy with several important drugs. Incorporation of the drug in a controlled release gastroretentive dosage forms (CR-GRDF) which can remain in the gastric region for several hours would significantly prolong 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. Several approaches are currently utilized in the prolongation of the GRT, including floating drug delivery systems (FDDS), swelling and expanding systems, polymeric bioadhesive systems, high density systems, modified shape systems and other delayed gastric emptying devices. And also discussed current & recently developm

Figure

Figure 1.1: Ideal plasma concentration curve7
Figure 8.10 : Standard calibration curve of Glipizide in 1.2 pH buffer
Figure 8.11 b: Solubility profile of Glipizide
Table 8.9: Physical parameters of drug, polymers and excipients
+7

References

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