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FORMULATION DEVELOPMENT AND IN VITRO CHARACTERIZATION OF GASTRORETENTIVE FLOATING MICROBALLOONS OF LABETALOL

HYDROCHLORIDE

A Dissertation submitted to

THE TAMIL NADU Dr. M.G.R MEDICAL UNIVERSITY CHENNAI – 600 032

in partial fulfilment of the requirements for the award of degree of

MASTER OF PHARMACY IN

PHARMACEUTICS

Submitted by G. THANGAKAMATCHI

Reg. No. 261711259

Under the guidance of

Dr. R. DEVI DAMAYANTHI, M. Pharm., Ph.D.

Assistant Professor Department of Pharmaceutics

COLLEGE OF PHARMACY MADRAS MEDICAL COLLEGE

CHENNAI – 600 003.

MAY – 2019

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DEPARTMENT OF PHARMACEUTICS COLLEGE OF PHARMACY MADRAS MEDICAL COLLEGE

CHENNAI-600 003 TAMILNADU

DATE:

CERTIFICATE

This is to certify that the dissertation entitled “FORMULATION DEVELOPMENT AND

IN VITRO

CHARACTERIZATION OF GASTRORETENTIVE FLOATING MICROBALLOONS OF LABETALOL HYDROCHLORIDE” submitted by THANGAKAMATCHI G with Register No.261711259 to The Tamil Nadu Dr. M.G.R.

Medical University examinations is evaluated.

1.

2.

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COLLEGE OF PHARMACY

MADRAS MEDICAL COLLEGE

CHENNAI-600 003 TAMILNADU

Dr. A. JERAD SURESH, M.Pharm, Ph.D., M.B.A.

Principal

CERTIFICATE

This is to certify that the dissertation entitled “FORMULATION DEVELOPMENT AND

IN VITRO

CHARACTERIZATION OF GASTRORETENTIVE FLOATING MICROBALLOONS OF LABETALOL HYDROCHLORIDE” submitted by THANGAKAMATCHI G with Register No.261711259 to The Tamil Nadu Dr. M.G.R.

Medical University is a bonafide work done by her during the academic year 2018-2019.

Place: Chennai-03 Date:

(A. JERAD SURESH)

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DEPARTMENT OF PHARMACEUTICS COLLEGE OF PHARMACY

MADRAS MEDICAL COLLEGE CHENNAI-600 003

TAMILNADU

Prof. K. ELANGO, M.Pharm., (Ph.D.) Professor and Head

CERTIFICATE

This is to certify that the dissertation entitled “FORMULATION DEVELOPMENT AND

IN VITRO

CHARACTERIZATION OF GASTRORETENTIVE FLOATING MICROBALLOONS OF LABETALOL HYDROCHLORIDE” submitted by THANGAKAMATCHI G with Register No.261711259 to The Tamil Nadu Dr. M.G.R.

Medical University is a bonafide work done by her during the academic year 2018-2019.

Place: Chennai-03

Date: (K.ELANGO)

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DEPARTMENT OF PHARMACEUTICS COLLEGE OF PHARMACY

MADRAS MEDICAL COLLEGE CHENNAI-600 003

TAMILNADU

Dr. R. DEVI DAMAYANTHI, M.Pharm., Ph.D., Assistant Professor

CERTIFICATE

This is to certify that the dissertation entitled “FORMULATION DEVELOPMENT AND

IN VITRO

CHARACTERIZATION OF GASTRORETENTIVE FLOATING MICROBALLOONS OF LABETALOL HYDROCHLORIDE” submitted by THANGAKAMATCHI G with Register No.261711259 to The Tamil Nadu Dr. M.G.R.

Medical University is a bonafide work done by her during the academic year 2018-2019 under my guidance.

Place: Chennai-03

Date: (R. Devi Damayanthi)

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LIST OF ABBREVIATIONS AND SYMBOLS

% Percentage

% w/v Percentage weight by volume

◦ Degree

°

C Degree Celsius

µg Micro gram

API Active Pharmaceutical Ingredients BCS Biopharmaceutical Classification System

CAD Coronary Artery Disease

CCB Calcium Channel Blockers

CHD Coronary Heart Disease

CHF Congestive Heart Failure

cm Centimeter

cum. Cumulative

EC Ethyl Cellulose

EUD Eudragit RS 100

F.Code Formulation Code

FDDS Floating Drug Delivery System FT-IR Fourier Transform Infra-Red

g Gram

GIT Gastro Intestinal Tract

GRDDS Gastro Retentive Drug Delivery System

GRT Gastro Retention Time

HCl Hydrochloric acid

HDL High Density Lipoproteins

HPMC Hydroxy Propyl Methyl Cellulose

Hrs Hours

ICH International Council of Harmonization

L Litre

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L.D Loading Dose

LDL Low Density Lipoproteins

M.D Maintenance Dose

M.W Molecular Weight

mg Milligram

Min. Minutes

ml Milliliter

mmHg Mercuric millimeter

NC No Change

O/W Oil in water

PhEur European pharmacopoeia

P. O Per Oral

PVA Poly Vinyl Alcohol

RH Relative Humidity

RPM Revolution Per Minute

SD Standard Deviation

Sec. Seconds

SEM Scanning Electron Microscopy

TG Triglycerides

USP United States Pharmacopoeia

UV Ultraviolet

Vis Visible

VLDL Very Low-Density Lipoproteins

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LIST OF FIGURES

FIGURE No. TITLE PAGE No.

1.1 Anatomy of stomach 3

1.2 Motility patterns of the GIT in fasted state 4

1.3 Approaches to Gastric Retention 6

1.4 Various systems of GRDDS 6

1.5 Effect of resultant weight during buoyancy on the

floating tendency of FDDS 7

1.6 Classification of Floating Drug Delivery System 11 1.7 Intra gastric floating gastrointestinal drug delivery

device 12

1.8 Inflatable gastrointestinal delivery system 12 1.9 Intragastric osmotically controlled drug delivery

system 13

1.10 Intra gastric bilayer floating tablet 14

1.11 Multiple Unit of Oral FDDS 15

1.12 Working Principle of Effervescent FDDS 15 1.13 Mechanism of microballoons formation 20

5.1 Renin Angiotensin System 48

8.1 Schematic Representation of Preparation of

Microballoons 62

9.1 FT-IR spectrum of Labetalol Hydrochloride 75 9.2 FT-IR spectrum of Labetalol Hydrochloride and

Ethylcellulose admixture 76

9.3 FT-IR spectrum of Labetalol Hydrochloride and

Eudragit RS100 admixture 77

9.4 FT-IR spectrum of Labetalol Hydrochloride and

Polyvinyl alcohol admixture 78

9.5 FT-IR spectrum of Labetalol Hydrochloride, 79

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FIGURE No. TITLE PAGE No.

Ethylcellulose and Eudragit RS100 admixture

9.6 FT-IR spectrum of optimized formulation F3 80 9.7 FT-IR spectrum of optimized formulation F8 81 9.8 Calibration Curve of Labetalol Hydrochloride in

pH1.2 82

9.9 Labetalol Hydrochloride Microballoons 83

9.10. Particle size distribution of Formulation F1 84 9.11 Particle size distribution of Formulation F2 85 9.12 Particle size distribution of Formulation F3 86 9.13 Particle size distribution of Formulation F4 87 9.14 Particle size distribution of Formulation F5 88 9.15 Particle size distribution of Formulation F6 89 9.16 Particle size distribution of Formulation F7 90 9.17 Particle size distribution of Formulation F8 91 9.18 Particle size distribution of Formulation F9 92 9.19 SEM Image of optimized formulation F3 94 9.20 SEM Image of optimized formulation F8 94 9.21 Percentage yield of Labetalol Hydrochloride

Microballoons 95

9.22 Percentage entrapment efficiency of Labetalol

Hydrochloride Microballoons 96

9.23 Percentage In vitro buoyancy of Labetalol

Hydrochloride Microballoons 97

9.24

In vitro release of formulations F1-F3

100 9.25

In vitro release of formulations F4-F6

101 9.26

In vitro release of formulations F7-F9

102 9.27

In vitro release of optimized formulations

103 9.28 Labetalol Hydrochloride Microballoons filled in

Hard Gelatin Capsules 104

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FIGURE No. TITLE PAGE No.

9.29 A plot of Zero order kinetics of C-F3 109

9.30 A plot of First order kinetics of C-F3 109

9.31 A plot of Higuchi release kinetics of C-F3 110

9.32 A plot of Korsmeyer-Peppas kinetics of C-F3 110

9.33 A plot of Hixon-Crowell Kinetics of C-F3 111

9.34 A plot of Zero order kinetics of C-F8 113

9.35 A plot of First order kinetics of C-F8 113

9.36 A plot of Higuchi release kinetics of C-F8 114

9.37 A plot of Korsmeyer-Peppas kinetics of C-F8 114

9.38 A plot of Hixon-Crowell Kinetics of C-F8 115

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LIST OF TABLES

TABLE No. TITLE PAGE No.

5.1 Classification of Hypertension 46

8.1 List of materials used 58

8.2 List of Equipment /Instruments used 59

8.3 Composition of Drug and Excipients for FT-IR spectra 61 8.4 Composition of Labetalol Hydrochloride Microballoons 63 8.5 Values of Angle of Repose, Compressibility Index and

Hausner’s Ratio 67

8.6 Uniformity of weight (I.P. Standard) 68

8.7 Disintegration time (I.P. Standard) 69

8.8 Diffusion exponent and solute release mechanism 72 9.1 Physical Compatibility of Drug and Polymers 74 9.2 FT-IR spectrum interpretation of LabetalolHydrochloride 75 9.3 FT-IR spectrum interpretation of Labetalol Hydrochloride

and Ethylcellulose admixture 76

9.4 FT-IR spectrum interpretation of Labetalol Hydrochloride

and Eudragit RS100 admixture 77

9.5 FT-IR spectrum interpretation of Labetalol Hydrochloride

and Polyvinyl alcohol admixture 78

9.6 FT-IR spectrum interpretation of Labetalol Hydrochloride,

Ethylcellulose and Eudragit RS100 admixture 79 9.7 FT-IR spectral interpretation of optimized formulation F3 80 9.8 FT-IR spectral interpretation of optimized formulation F8 81 9.9 Data for standard curve of Labetalol Hydrochloride in pH

1.2 82

9.10. Particle size distribution of Formulation F1 84

9.11 Particle size distribution of Formulation F2 85

9.12 Particle size distribution of Formulation F3 86

9.13 Particle size distribution of Formulation F4 87

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TABLE No. TITLE PAGE No.

9.14 Particle size distribution of Formulation F5 88 9.15 Particle size distribution of Formulation F6 89 9.16 Particle size distribution of Formulation F7 90 9.17 Particle size distribution of Formulation F8 91 9.18 Particle size distribution of Formulation F9 92 9.19 Average particle size of Microballoons 93 9.20 Percentage yield of Labetalol Hydrochloride

Microballoons 95

9.21 Percentage entrapment efficiency of Labetalol

Hydrochloride Microballoons 96

9.22 Percentage

In vitro

buoyancy of Labetalol Hydrochloride

Microballoons 97

9.23

In vitro drug release for all formulations

98 9.24

In vitro release of optimized formulations

102 9.25 Flow property measurements of optimized Microballoons 104 9.26 Uniformity of Weight of contents in capsules 105 9.27 Disintegration test for Capsules 105

9.28 Drug Content for Capsules 105

9.29

In vitro drug release study of C-F3

106 9.30

In vitro drug release study of C-F8

107 9.31 Release Kinetics of Optimized Formulation F3 108

9.32 Data for R

2

value of C-F3 111

9.33 Release Kinetics of Optimized Formulation F8 112

9.34 Data for R

2

value of C-F8 115

9.35 Stability data for Optimized capsules 116

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ACKNOWLEDGEMENT

I would like to thank all those people who made this thesis possible and an unforgettable experience for me.

I consider this is an opportunity to express my gratitude to all the dignities who have been involved directly or indirectly with the successful completion of this dissertation.

First of all, I thank the Almighty for giving me strength, endurance and showering his blessing to undertake this project and pursue with full dedication and giving us courage always to do hard work.

I acknowledge my sincere thanks to Dr. A. Jerad Suresh, M. Pharm., Ph.D.,MBA., Principal, College of Pharmacy, Madras Medical College, Chennai, for his continuous support in carrying out our project work in this institution.

I consider myself very much lucky with profound privilege and great pleasure in expressing our deep sense of gratitude to Prof. K. Elango, M. Pharm., (Ph.D.) Head, Department of Pharmaceutics, College of Pharmacy, Madras Medical College, Chennai. For his supportive suggestion, innovative ideas, help and encouragement have always propelled to perform better.

It is my privilege to express my gratitude to my guide Dr. R. Devi Damayanthi, M.Pharm, Ph.D., Assistant professor, Department of Pharmaceutics, College of Pharmacy, Madras Medical College, Chennai for her guidance to complete my project with precision.

I thank all teaching staff members Mr. K. Ramesh Kumar, M.Pharm., Associate Professor, Dr. N. Daisy Chella Kumari, M.Pharm., Ph.D., Assistant professor and Dr. N. Deattu M.Pharm., Ph.D., Assistant professor of the Department of Pharmaceutics, College of Pharmacy, Madras Medical College, Chennai, for their valuable suggestions, constant support and encouragement.

I extend my thanks to all non-teaching staff members Mr. M. Sayapathy and Mrs. M. Kumutha Department of Pharmaceutics College of Pharmacy, Madras Medical College, Chennai.

I would like to thank Dr. R. Radha, M.Pharm., Ph.D., for her timely help

and co-operation.

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I also thank Dr. P.G.Sunitha, M.Pharm., Ph.D., Department of Pharmaceutical Chemistry for guiding me with FTIR for my samples.

I express my sincere thanks to Mrs L.Suganthi Drugs inspector for acquiring me drug sample from Glan Pharma Pvt Ltd., Hyderabad for my project work.

I wish to put on my gratitude to Signet Chemicals Pvt Ltd., for generously offering Polyvinyl Alcohol for my project.

I profusely thank Mr. Murugan, Head, FR&D, Saimirra Innopharm Pvt Ltd., and Ms. Rajakkani for their guidance in drug release studies of my project work.

I express my sincere thanks to Professor and Head of the Department, Central Workshop, Department of Mechanical Engineering, College of Engineering, Anna University, Guindy, Chennai-25 for providing SEM Imaging facility in their campus.

I would like to express my heartiest thanks to My Parents and my brother G.K. Bala Subramaniam.

I would like to express my grateful thanks to my classmates, Aarthi C.K, Aravindh G, Nithya S, Prasath P, Rama K.P, Ranjitha R, Reka G, Sahul Hameed Niyaz U, Nandhini S, Meena Kumari V who stood beside me throughout my project.

I would like to extend my profound thanks to my seniors Keerthana K, Selva Priya A, Vel Murugan K, Manimegalai V for their valuable ideas to carry out the experimentation procedures.

I extend my cordial thanks to all my seniors, juniors & friends for their kind

support and co-operation.

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CONTENTS

S. No. TITLE PAGE No.

1 INTRODUCTION 1-25

2 REVIEW OF LITERATURE 26-41

3 AIM AND PLAN OF WORK 42-43

4 RATIONALE OF THE STUDY 44

5 DISEASE PROFILE 45-51

6 DRUG PROFILE 52-54

7 EXCIPIENTS PROFILE 55-57

8 MATERIALS AND METHODS 58-73

9 RESULTS AND DISCUSSION 74-116

10 SUMMARY AND CONCLUSION 117-119

11 BIBLIOGRAPHY 120-127

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INTRODUCTION…

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1. INTRODUCTION

Department of Pharmaceutics, Madras Medical College. Page 1

1.1. ORAL DRUG DELIVERY SYSTEM

There are numerous dosage forms into which a drug substance can be incorporated for the convenient and efficacious treatment of a disease. Dosage forms can be designed for administration by alternative delivery routes to maximize therapeutic response. Oral dosage forms are intended usually for the systemic effects resulting from drug absorption through the various epithelia and mucosa of the gastro- intestinal tract. An oral route is the most frequently used route for drug administration.

This is due to the following reasons:

 Oral route is the most convenient and uncomplicated

 Ease of administration and safety

 Improved patient compliance

 Cost-effectiveness

Disadvantages include slow onset of action, possibilities of irregular absorption and destruction of drugs by enzymes and secretions of the gastro-intestinal tract. The most popular oral dosage forms are tablets, capsules, suspensions, solutions and emulsions.

Oral solid dosage forms such as tablets and capsules have been formulated and developed as they are the most effective routes of administration of a new drug.

Nevertheless, it is probable that at least 90% of all drugs used to produce systemic effects are administered by the oral route. Tablets and capsules represent unit dosage forms in which one usual dose of the drug has been accurately placed.1,2

1.2 GASTRORETENTIVE DRUG DELIVERY SYSTEM (GRDDS)

The goal of any drug delivery system is to provide a therapeutic amount of drug at the proper site in the body and then maintain the desired drug concentration. Drug delivery systems are becoming increasingly sophisticated as pharmaceutical scientists acquire a better understanding of the physicochemical and biological parameters pertinent to their performance. Oral delivery of drugs is by far the most preferable route of drug delivery due to ease of administration, patient compliance and flexibility in formulation and handling of these forms.3,4 Approximately 50% of the drug delivery systems available in the market are oral drug delivery systems.5

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1. INTRODUCTION

Department of Pharmaceutics, Madras Medical College. Page 2

A major constraint in oral controlled drug delivery is that, not all drug candidates are absorbed uniformly throughout the Gastrointestinal Tract (GIT).6 Gastric emptying of dosage forms is an extremely variable process and ability to prolong and control emptying time is a valuable asset for dosage forms, which reside in the stomach for a longer period of time than conventional dosage forms. Several difficulties are faced in designing controlled release systems for 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.7-9

The extent of GIT drug absorption is related to contact time with the small intestinal mucosa.10 Conventional drug delivery system maintains the drug concentration within the therapeutically effective range needed for treatment, only when taken several times a day.11 Success of oral drug delivery system depends on its degree of absorption through GIT. Thus, the idea of enhancing drug absorption pioneered the idea of development of Gastroretentive drug delivery system (GRDDS).12 On the basis of the mechanism of mucoadhesion, floatation, sedimentation or by the simultaneous administration of pharmacological agents, the controlled gastric retention of solid dosage forms may be achieved, which delay gastric emptying.13

The single unit dosage forms have the disadvantage of a release all or nothing emptying process while the multiple unit particulate system pass through the GIT to avoid the vagaries of gastric emptying and thus release the drug more uniformly which results in more reproducible drug absorption and reduced risk of local irritation.14-15

1.2.1. BASIC GASTRO-INTESTINAL TRACT PHYSIOLOGY

The GI tract is essentially a tube about nine metres long that runs through the middle of the body from the mouth to the anus. The wall of the GI tract has the same general structure throughout most of its length, with some local variations for each region.

The stomach is an organ with a capacity for storage and mixing. Anatomically the stomach is divided into 3 regions: fundus, body, and antrum (pylorus) 16 (Figure no.

1.1).

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1. INTRODUCTION

Department of Pharmaceutics, Madras Medical College. Page 3

Figure no. 1.1: Anatomy of stomach

Under fasting conditions, the stomach is a collapsed bag with a residual volume of approximately 50 ml and contains a small amount of gastric fluid and air. Gastric emptying occurs during fasting as well as fed states. The GI tract is in a state of continuous motility consisting of two modes: inter-digestive motility pattern and digestive motility pattern. The former is dominant in the fasted state with a primary function of cleaning up the residual content of the upper GI tract, which cycle both through stomach and intestine every 2 to 3 hours. This is called the interdigestive myoelectric cycle or migrating myoelectric cycle (MMC) and is organised in cycles of activity and quiescence.17 Each cycle lasts 90–120 minutes and consists of four phases.

(Figure no. 1.2). The concentration of the hormone motilin in the blood controls the duration of the phases.18. The various phases are as below;

 Phase I (basal phase): Period of no contraction (40-60 minutes),

 Phase II (preburst phase): Period of intermittent contractions (20-40 minutes),

 Phase III (burst phase): Period of regular contractions at the maximal frequency that travel distally also known as housekeeper wave; includes intense and regular contractions for short period. It is due to this wave that all the un- digested material is swept out of the stomach down to the small intestine (10- 20 minutes),

 Phase IV: Period of transition between phase III and phase I (0-5 minutes).19

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1. INTRODUCTION

Department of Pharmaceutics, Madras Medical College. Page 4

Figure no. 1.2: Motility patterns of the GIT in fasted state

After the ingestion of a mixed meal, the pattern of contractions changes from fasted to that of fed state. This is also known as digestive motility pattern and comprises continuous contractions as in phase II of fasted state. These contractions result in reducing the size of food particles (to less than 1 mm), which are propelled toward the pylorus in a suspension form. During the fed state, onset of MMC is delayed resulting in slow down of gastric emptying rate. Orally administered controlled release dosage forms are subjected to basically two complications that are, short gastric residence time and unpredictable gastric emptying rate.

1.2.2. IDEAL PROPERTIES OF GASTRORETENTIVE DRUG DELIVERY SYSTEMS

 Effective retention in the stomach

 Sufficient drug loading capacity

 Controlled drug release profile

 Full degradation and evacuation after the drug release

 No effect on gastric motility including emptying pattern

 No other local effects20

1.2.3. SUITABLE DRUG CANDIDATES FOR GASTRORETENTIVE DRUG DELIVERY SYSTEMS

Sustained release in the stomach is useful for therapeutic agents that the stomach does not readily absorb, since sustained release prolongs the contact time of the agent in the stomach or in the upper part of the small intestine, which is where absorption occurs and contact time is limited. Under normal or average conditions, for example,

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1. INTRODUCTION

Department of Pharmaceutics, Madras Medical College. Page 5

material passes through the small intestine in as little as 1-3h For the floating system the drug candidates should have the appropriate properties like poor absorption in colonic region but are characterized by better absorption in the upper part of GI tract.

So, the ideal drug candidates should have the following criteria:

a) Primarily absorbed from stomach and upper part of GI tract, e.g., calcium supplement, cinnarizine.

b) Narrow absorption window in GI tract, e.g., riboflavin and levodopa.

c) Drugs that degrade in the colon, e.g., ranitidine HCl, metronidazole.

d) Drugs that act locally in the stomach, e.g., antacids and misoprostol.

e) Drugs that disturb normal colonic bacteria, e.g., amoxicillin trihydrate.

f) Drugs are locally active in the stomach, e.g., drugs used in the eradication of helicobacter pylori, which is now believed to be the causative bacterium for chronic gastritis and peptic ulcer (tetracycline).

g) Drugs have low solubility at high pH values, e.g., verapamil.15

1.2.4 APPROACHES TO DESIGN GASTRO RETENTIVE DOSAGE FORMS Various approaches have been pursued to increase the retention of an oral dosage form in the stomach. These systems include (Figure. 1.3, 1.4)

 Floating systems

 Bio adhesive systems

 Raft forming systems

 Swelling and expanding systems

 Super porous Hydrogels

 Magnetic systems

 High density systems21

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1. INTRODUCTION

Department of Pharmaceutics, Madras Medical College. Page 6

Figure no. 1.3: Approaches to Gastric Retention

Figure no. 1.4: Various systems of GRDDS Floating Drug Delivery Systems (FDDS)

These 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.22 However, besides a minimal gastric content needed to

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1. INTRODUCTION

Department of Pharmaceutics, Madras Medical College. Page 7

allow the proper achievement of the buoyancy retention principle, a minimal level of floating force (F) is also required to keep the dosage form reliably buoyant on the surface of the meal. To measure the floating force kinetics, a novel apparatus for determination of resultant weight (RW) has been reported in the literature. The RW apparatus operates by measuring continuously the force equivalent to F (as a function of time) that is required to maintain the submerged object. The object floats better if RW is on the higher positive side (Figure no.1.5). This apparatus helps in optimising FDDS with respect to stability and durability of floating forces produced in order to prevent the drawbacks of unforeseeable intragastric buoyancy capability variations.23

RW or F = F buoyancy – F gravity = (Df - Ds) gV

Where, RW = total vertical force, Df = fluid density, Ds= object density, V = volume and g = acceleration due to gravity.

Figure no. 1.5: Effect of resultant weight during buoyancy on the floating tendency of FDDS

Bioadhesive systems or mucoadhesive systems

These enable the localized retention of the system in the stomach. Bio adhesive drug delivery systems (BDDS) are used as a delivery device within the lumen to enhance drug absorption in a site-specific manner. This approach involves the use of bio adhesive polymers, which can adhere to the epithelial surface in the stomach. Some of the most promising excipients that have been used commonly in these systems include polycarbophil, carbophil, carbopol, lectins, chitosan and gliadin, etc22

Raft systems

Raft forming systems incorporate alginate gels. These have a carbonate component and, upon reaction with gastric acid, bubbles form in the gel, enabling floating25. These systems have received much attention for the delivery of antacids and

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1. INTRODUCTION

Department of Pharmaceutics, Madras Medical College. Page 8

drug delivery for gastrointestinal infections and disorders. The mechanism involved in the raft formation includes the formation of viscous cohesive gel in contact with gastric fluids, wherein each portion of the liquid swells forming a continuous layer called a raft. This raft floats on gastric fluids because of low bulk density created by the formation of CO2. Usually, the system contains a gel forming agent and alkaline bicarbonates or carbonates responsible for the formation of CO2 to make the system less dense and float on the gastric fluids. A patent assigned to Reckitt and Colman Products Ltd., describes a raft forming formulation for the treatment of helicobacter pylori (H. Pylori) infections in the GIT. 4,11

Swelling and expanding systems

These systems are sometimes referred to as plug type systems because they tend to remain lodged at the pyloric sphincter. These polymeric matrices remain in the gastric cavity for several hours even in the fed state. Sustained and controlled drug release may be achieved by selecting a polymer with the proper molecular weight and swelling properties. Upon coming in contact with gastric fluid, the polymer imbibes water and swells. The swollen system eventually will lose its integrity because of a loss of mechanical strength caused by abrasion or erosion or will burst into small fragments when the membrane ruptures because of continuous expansion. These systems also may erode in the presence of gastric juices so that after a predetermined time the device no longer can attain or retain the expanded configuration.2 The expandable GRDF’s are usually based on three configurations: a small ‘collapsed’ configuration which enables convenient oral intake; expanded form that is achieved in the stomach and thus prevents passage through the pyloric sphincter; and finally, another small form that is achieved in the stomach when the retention is no longer required i.e. after the GRDF has released its active ingredient, thereby enabling evacuation.

Super porous hydrogel systems

These swellable systems differ sufficiently from the conventional types to warrant separate classification. In this approach to improve gastric retention time (GRT) super porous hydrogels of average pore size >100 micrometre, swell to equilibrium size within a minute due to rapid water uptake by capillary wetting through numerous interconnected open pores. They swell to a large size (swelling ratio: 100 or more) and are intended to have sufficient mechanical strength to withstand pressure by gastric contraction. This is advised by co-formulation of hydrophilic particulate material.

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1. INTRODUCTION

Department of Pharmaceutics, Madras Medical College. Page 9

High density systems

Sedimentation has been employed as a retention mechanism for pellets that are small enough to be retained in the rugae or folds of the stomach body near the pyloric region, which is the part of the organ with the lowest position in an upright posture.

Dense pellets (approximately 3g/cm3) trapped in rugae also tend to withstand the peristaltic movements of the stomach wall. With pellets, the GI transit time can be extended from an average of 5.8–25 hours, depending more on density than on the diameter of the pellets. Commonly used excipients are barium sulphate, zinc oxide, titanium dioxide and iron powder, etc.

Magnetic systems

This system is based on a simple idea that the dosage form contains a small internal magnet and a magnet placed on the abdomen over the position of the stomach.

Used this technique in rabbits with bio adhesive granules containing ultrafine ferrite (g- Fe2O3). They guided them to the oesophagus with an external magnet (1700 G) for the initial 2 min and almost all the granules were retained in the region after 2 h. Although these systems seem to work, the external magnet must be positioned with a degree of precision that might compromise patient compliance.25

1.2.5. FACTORS AFFECTING GASTRIC RETENTION

 Density:

Density of the dosage form should be less than the gastric contents (1.004gm/ml).

 Size:

Dosage form unit with a diameter of more than 7.5 mm are reported to have an increased GRT competed to with those with a diameter of 9.9 mm.

 Shape:

The dosage form with a shape tetrahedron and ring shape devices with a flexural modulus of 48 and 22.5 kilo pounds per square inch (KSI) are reported to have better GRT, 90 to 100% retention at 24 hours compared with other shapes.

 Fed or Unfed State:

Under fasting conditions, the GI motility is characterized by periods of strong motor activity or the migrating myoelectric complexes (MMC) that occurs every 1.5 to 2 hours. The MMC sweeps undigested material from the stomach and if the timing of administration of the formulation coincides with that of the MMC, the GRT of the unit

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1. INTRODUCTION

Department of Pharmaceutics, Madras Medical College. Page 10 can be expected to be very short. However, in the fed state, MMC is delayed and GRT is considerably longer.

 Single or multiple unit formulation:

Multiple unit formulations show a more predictable release profile and insignificant impairing of performance due to failure of units, allow co administration of units with different release profiles or containing incompatible substances and permit a larger margin of safety against dosage form failure compared with single unit dosage forms.16

 Nature of the meal:

Feeding of indigestible polymers of fatty acid salts can change the motility pattern of the stomach to a fed state, thus decreasing the gastric emptying rate and prolonging the drug release.

 Caloric Content:

GRT can be increased between 4 to 10 hours with a meal that is high in proteins and fats.

 Frequency of feed:

The GRT can increase by over 400 minutes when successive meals are given compared with a single meal due to the low frequency of MMC.

 Gender:

Generally, females have slower gastric emptying rates than males. Stress increases gastric emptying rates while depression slows it down.

 Age:

Elderly people, especially those over 70 years have a significantly longer GRT.

 Posture:

GRT can vary between supine and upright ambulatory states of the patients.

 Diseased state of the individual:

Biological factors23also affect the gastric retention e.g. Crohn’s disease, gastrointestinal diseases and diabetes.

 Concomitant drug administration:

Anti-cholinergics like atropine and propentheline opiates like codeine and prokinetic agents like metoclopramide and cisapride22,23,25

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1. INTRODUCTION

Department of Pharmaceutics, Madras Medical College. Page 11 1.3. FLOATING DRUG DELIVERY SYSTEMS (FDDS)

These have a bulk density lower than gastric fluids and thus remain buoyant in stomach for a prolonged period of time, without affecting the gastric emptying rate.

While the system floats on gastric contents, the drug is released slowly at a desired rate from the system. After the release of drug, the residual system is emptied from the stomach. This results in an increase in gastric retention time and a better control of fluctuations in plasma drug concentrations.

1.3.1. Classification of Floating Drug Delivery System

Based on the mechanism of buoyancy, two distinctly different technologies have been utilized in development of FDDS (Figure no.1.6), which are:

Figure no. 1.6: Classification of Floating Drug Delivery System 1.3.1.1 Effervescent systems

1.3.1.1.1 Volatile liquid containing systems

a) Intragastric floating gastrointestinal drug delivery system:

These systems can be made to float in the stomach because of floatation chamber, which may be a vacuum or filled with air or a harmless gas, while drug reservoir is encapsulated inside a microporous compartment, as shown in Figure no.

1.7.

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1. INTRODUCTION

Department of Pharmaceutics, Madras Medical College. Page 12 Figure no. 1.7: Intra gastric floating gastrointestinal drug delivery device b) Inflatable gastrointestinal delivery systems:

In these systems an inflatable chamber is incorporated, which contains liquid ether that gasifies at body temperature to cause the chamber to inflate in the stomach.

These systems are fabricated by loading the inflatable chamber with a drug reservoir, which can be a drug, impregnated polymeric matrix, then encapsulated in a gelatine capsule. After oral administration, the capsule dissolves to release the drug reservoir together with the inflatable chamber. The inflatable chamber automatically inflates and retains the drug reservoir compartment in the stomach. The drug continuously released from the reservoir into the gastric fluid (Figure no. 1.8).

Figure no. 1.8: Inflatable gastrointestinal delivery system c) Intragastric osmotically controlled drug delivery systems:

It is comprised of an osmotic pressure-controlled drug delivery device and an inflatable floating support in a biodegradable capsule. In the stomach, the capsule quickly disintegrates to release the intragastric osmotically controlled drug delivery device. The inflatable support inside forms a deformable hollow polymeric bag that contains a liquid that gasifies at body temperature to inflate the bag. The osmotic pressure-controlled drug delivery device consists of two components; drug reservoir

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1. INTRODUCTION

Department of Pharmaceutics, Madras Medical College. Page 13 compartment and an osmotically active compartment. The drug reservoir compartment is enclosed by a pressure responsive collapsible bag, which is impermeable to vapour and liquid and has a drug delivery orifice. The osmotically active compartment contains an osmotically active salt and is enclosed within a semipermeable housing. In the stomach, the water in the GI fluid is continuously absorbed through the semipermeable membrane into osmotically active compartment to dissolve the osmotically active salt.

An osmotic pressure is thus created which acts on the collapsible bag and in turn forces the drug reservoir compartment to reduce its volume and activate the drug reservoir compartment to reduce its volume and activate the drug release of a drug solution formulation through the delivery orifice. The floating support is also made to contain a bio erodible plug that erodes after a predetermined time to deflate the support. The deflated drug delivery system is then emptied from the stomach (Figure no. 1.9).

Figure no. 1.9: Intragastric osmotically controlled drug delivery system 1.3.1.2. Gas-generating Systems

These buoyant delivery systems utilize effervescent reactions between carbonate/bicarbonate salts and citric/tartaric acid to liberate CO2, which gets entrapped in the gellified hydrocolloid layer of the systems thus decreasing its specific gravity and making it to float over chyme. These buoyant systems utilize matrices prepared with swellable polymers like methocel, polysaccharides like chitosan, effervescent components like sodium bicarbonate, citric acid and tartaric acid or chambers containing a liquid that gasifies at body temperature. The optimal stoichiometric ratio of citric acid and sodium bicarbonate for gas generation is reported to be 0.76:1. The common approach for preparing these systems involves resin beads loaded with bicarbonate and coated with ethyl cellulose. The coating, which is insoluble but

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1. INTRODUCTION

Department of Pharmaceutics, Madras Medical College. Page 14 permeable, allows permeation of water Thus, carbon dioxide is released, causing the beads to float in the stomach.

a) Intra gastric single layer floating tablets or Hydrodynamically Balanced System (HBS)

These are formulated by intimately mixing the CO2 generating agents and the drug with in the matrix tablet (Figure no.1.8). These have a bulk density lower than gastric fluids and therefore remain floating in the stomach unflattering the gastric emptying rate for a prolonged period. The drug is slowly released at a desired rate from the floating system and after the complete release the residual system is expelled from the stomach. This leads to an increase in the GRT and a better control over fluctuations in plasma drug concentration.

b) Intra gastric bilayered floating tablets

These are also compressed tablets as shown in (Figure no. 1.10) and contain two layers,

(i) Immediate release layer ii) Sustained release layer.

Figure no. 1.10: Intra gastric bilayer floating tablet c) Multiple Unit type floating pills

These systems consist of sustained release pills as ‘seeds’ surrounded by double layers. The inner layer consists of effervescent agents while the outer layer is of swellable membrane layer. When the system is immersed in dissolution medium at body temp, it sinks at once and then forms swollen pills like balloons, which float as they have lower density (Figure no. 1.11 and 1.12)

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1. INTRODUCTION

Department of Pharmaceutics, Madras Medical College. Page 15 Figure no. 1.11: Multiple Unit of Oral FDDS

Figure no. 1.12: Working Principle of Effervescent FDDS 1.3.2. Non-effervescent systems

These types of systems, after swallowing, swells unrestrained via imbibition of gastric fluid to an extent that it prevents their exit from the stomach. One of the formulation methods of such dosage forms involves the mixing of the drug with a gel, which swells in contact with gastric fluid after oral administration and maintains a relative integrity of shape and a bulk density of less than one within the outer gelatinous barrier. The air trapped by the swollen polymer confers buoyancy to these dosage forms. Excipients used most commonly in these systems include gel forming or highly swellable cellulose type hydrocolloids, polysaccharides and matrix forming material such as polycarbonate, polyacrylate, polymethacrylate, polystyrene as well as bio adhesive polymer such as chitosan and Carbopol, hydroxypropyl methyl cellulose (HPMC), polyvinyl acetate, agar, sodium alginate, calcium chloride, polyethylene oxide. This system can be further divided into four sub-types:

1.3.2.1. Colloidal gel barrier systems

Hydrodynamically balanced systems (HBS) contain drug with gel forming hydrocolloids meant to remain buoyant on stomach contents. These systems

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1. INTRODUCTION

Department of Pharmaceutics, Madras Medical College. Page 16 incorporate a high level of one or more gel forming highly swellable cellulose type hydrocolloids e.g. HEC, HPMC, NaCMC, Polysaccharides and matrix forming polymers such as polycarbophil, polyacrylates and polystyrene, incorporated either in tablets or in capsules. On coming in contact with gastric fluid, the hydrocolloid in the system hydrates and forms a colloidal gel barrier around the gel surface. The air trapped by the swollen polymer maintains a density less than unity and confers buoyancy to this dosage forms.

1.3.2.2. Microporous Compartment System

This technology is based on the encapsulation of drug reservoir inside a microporous compartment with aperture along its top and bottom wall. The peripheral walls of the drug reservoir compartment are completely sealed to prevent any direct contact of the gastric mucosal surface with the undissolved drug. In stomach the floatation chamber containing entrapped air causes the delivery system to float over the gastric contents. Gastric fluid enters through the apertures, dissolves the drug, and carries the dissolve drug for continuous transport across the intestine for absorption.

1.3.2.3. Alginate beads

Multiple unit floating dosage forms have been developed from freeze-dried calcium alginate. Spherical beads of approximately 2.5 mm in diameter can be prepared by dropping a sodium alginate solution in to aqueous solutions of calcium chloride, causing precipitation of calcium alginate. The beads are then separated snap and frozen in liquid nitrogen, and freeze dried at -40° for 24 h, leading to the formation of porous system, which can maintain a floating force over 12 h.26

1.4. HOLLOW MICROSPHERES

Microballoons are gastro retentive drug-delivery systems with non- effervescent approach. Microballoons (Hollow microsphere) are in strict sense, empty particles of spherical shape without core. These microspheres are characteristically free flowing powders comprising of proteins or synthetic polymers, ideally having a size less than 200 micrometer.27

Microballoons are considered as one of the most favourable buoyant systems with the unique advantages of multiple unit systems as well as better floating properties, because of central hollow space inside the microsphere. The novel techniques involved in their preparation include simple solvent evaporation method, emulsion-solvent diffusion method, single emulsion technique, double emulsion technique, phase separation coacervation technique, polymerization technique, spray drying and spray

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1. INTRODUCTION

Department of Pharmaceutics, Madras Medical College. Page 17 congealing method and hot melt encapsulation method. The slow release of drug at desired rate and better floating properties mainly depend on the type of polymer, plasticizer and the solvents employed for the preparation. Polymers such as polylactic acid, Eudragit® S and hydroxy propyl methyl cellulose. Cellulose acetate is used in the formulation of hollow microspheres, and the release of drug can be modulated by optimizing polymer concentration and the polymer -plasticizer ratio.28

Solid biodegradable microspheres incorporating a drug dispersed or dissolved throughout particle matrix have the potential for controlled release of drugs. Gastro- retentive floating microspheres are low density systems that have sufficient buoyancy to float over gastric contents and remain in stomach for prolonged period. As the system floats over gastric contents, the drug is released slowly at desired rate resulting in increased gastric retention with reduced fluctuations in plasma drug concentration.

Hollow microspheres / microballoons loaded with drug in their outer polymer shell are prepared by a novel method such as solvent evaporation or solvent diffusion/evaporation to create a hollow inner core. The drug and an enteric acrylic polymer mixture are dissolved in ethanol/dichloromethane solution and it is poured into an agitated solution of Poly Vinyl Alcohol (PVA) that as thermally controlled at 40 ºC.

After the formation of stable emulsion, the organic solvent is evaporated from the emulsion by increasing the temperature under pressure or by continuous stirring. The gas phase is generated in the droplet of dispersed polymer by the evaporation of dichloromethane and thus formed the hollow internal cavity in the microsphere of the polymer with drug. The microballoons is continuously float over the surface of an acidic dissolution media containing surfactant for more than 12 hours.29,30

1.4.1. Mechanisms of Microballoons

When microballoons come in contact with gastric fluid, the gel forms and polymers hydrate to form a colloidal gel barrier that controls the rate of fluid penetration into the device and consequent drug release. As the outer surface of the dosage form dissolves, the gel layer is maintained by the hydration of the adjacent hydrocolloid layer. The air trapped by the swollen polymer makes the density lower than the gastric fluid and confers buoyancy to the microspheres. However, a minimal gastric content needed to allow proper achievement of buoyancy.39,40 Hollow microspheres (Microballoons) of acrylic resins, Eudragit, Hypromellose, polyethylene oxide, cellulose acetate, polystyrene floatable shells, polycarbonate floating balloons and gelucire floating granules are the recent advancements.31

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1. INTRODUCTION

Department of Pharmaceutics, Madras Medical College. Page 18 1.4.2. Mechanism of drug release from the microballoons

The mechanism of drug release from multiparticulates can occur in the following ways:

Diffusion: On contact with aqueous fluids in the gastrointestinal tract (GIT), water diffuses into the interior of the particle. Drug dissolution occurs and the drug solutions diffuse across the release coat to the exterior.

Erosion: Some coatings can be designed to erode gradually with time, thereby releasing the drug contained within the particle.

Osmosis: In allowing water to enter under the right circumstances, an osmotic pressure can be built up within the interior of the particle. The drug is forced out of the particle into the exterior through the coating.32

1.4.3.Materials for preparation of Microballoons Drugs

Drugs with narrow therapeutic window in GI tract, mainly absorbed from stomach and upper part of GIT, locally act in the stomach, degrade in the colon, disturb normal colonic bacteria. E.g. Aspirin, Salicylic acid, Ethoxy benzamide, Indomethacin and Riboflavin, Para amino benzoic acid, Furosemide, Calcium supplements, Chlordiazepoxide, Scinnarazine, Riboflavin, Levodopa, Antacids, Misoprostol, Ranitidine HCl, Metronidazole and Amoxicillin trihydrate.

Polymers

Cellulose acetate, chitosan, eudragit, acrycoat, methocil, polyacrylates, polyvinyl acetate, carbopol, agar, polyethylene oxide, polycarbonates, acrylic resins and polyethylene.

Solvents

It should have good volatile properties, so that it should easily come out from the emulsion leaving hollow microspheres eg ethanol, dichloromethane (DCM), acetonitrile, acetone, isopropyl alcohol (IPA), dimethylformamide (DMF).

Processing Medium

It is used to harden the drug polymer emulsified droplets when the drug polymer solution is poured into it, should not interact with the former; mainly used processing medium are liquid paraffin, polyvinyl alcohol and water.

Surfactant

They are stabilizers or emulsifiers, play the role of hardening the microspheres as well. E.g. tween 80, span 80 and SLS.

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1. INTRODUCTION

Department of Pharmaceutics, Madras Medical College. Page 19 Cross linking agent

Chemical cross-linking of microspheres can be achieved using cross linking agents such as formaldehyde, glutaraldehyde or by using di acid chlorides such as terephthaloyl chloride. The method is limited to drugs that do not have any chemical interaction with the cross-linking agent.

Hardening agent

This helps to harden the microspheres formed in the processing medium e.g. n- hexane, petroleum ether (in case the processing medium is liquid paraffin).

1.4.4. Methods of preparation of microspheres Solvent Evaporation Method

The polymers for the development of such systems include Eudragit, HPMC KM4 and ethyl cellulose etc. Polymers are mixed with drug and further this mixture is dissolved in the solution of ethanol, acetone or dichloromethane either alone or in combination to get homogenous polymer solution. The resulting solution is poured into 100 mL of liquid paraffin rotating at 1500 rpm. The emulsion is formed and heated at 35oC temperature for 3hr. After the formation of a stable emulsion, the acetone or dichloromethane is completely evaporated and resulting solidified microspheres is filtered using Whatman filter paper. These hollow microspheres impart the floating and sustained properties.

Emulsion solvent diffusion method

The mixture of drug polymer is dissolved in the solution of ethanol:

dichloromethane and this mixture is adding dropwise to polyvinyl alcohol solution.

This solution is stirred at 1500 rpm for 1 hour and at different temperature ranges. In the emulsion solvent diffusion method, the affinity between the drug and organic solvent is stronger than that of organic solvent and aqueous solvent. The drug is dissolved in the organic solvent and the solution is dispersed in the aqueous solvent producing the emulsion droplets even though the organic solvent is miscible. The organic solvent diffuses gradually out of the emulsion droplets in to the surrounding aqueous phase and the aqueous phase diffuse into the droplets by which drug crystallizes.

Solvent diffusion-evaporation technique

This technique is with slight modification of both emulsion solvent evaporation method and emulsion solvent diffusion method. Drug, polymers and 0.1% of surfactant such as PEG are mixed in the solution of ethanol: dichloromethane (1:1) at room

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1. INTRODUCTION

Department of Pharmaceutics, Madras Medical College. Page 20 temperature. This solution is slowly introduced into 80 ml of 0.46% w/w of polyvinyl alcohol as emulsifier. This is using propeller agitator for 1 hour for evaporation of organic solution and then filtered it.

Spray drying

Spray drying is the most widely employed industrial process for particle formation and drying. It is an ideal process where the required particle size distribution, bulk density and particle shape can be obtained in a single step.

First of all, polymer is dissolved in a suitable volatile organic solvent such as dichloromethane, acetone etc. to form a slurry. The slurry is then sprayed into the drying chamber, concentration gradient of the solute forms inside the small droplet with the highest concentration being at the droplet surface. This is because the time of the solute diffusion is longer than that of the solvent in the droplets evaporating during the drying process. Subsequently, a solid shell appears leading toward formation of microspheres.

Separation of the solid products from the gases is usually accomplished by means of a cyclone separator while the traces of solvent are removed by vacuum drying and the products are saved for later use.

Figure no. 1.13: Mechanism of microballoons formation 1.4.5. Factors affecting physiochemical properties of Microballoons Stirring rate

It is obvious that the stirring rate affects size of microsphere. The size of the resulting microspheres decreases with increasing agitation, but the increase is not statistically significant. It may be inferred that the agitation speed over the study range is not able to break up the bulk of the polymer into finer droplets.

Temperature of preparation

The study of optimum preparation temperature with respect to microsphere cavity formation. The solution drug and polymer are poured into an aqueous solution

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1. INTRODUCTION

Department of Pharmaceutics, Madras Medical College. Page 21 of polyvinyl alcohol at various temperatures, i.e., 20, 30, 40 and 50 ºC. They conclude that preparation at 20 or 30 ºC provided porous microspheres having higher porosity with a surface so rough as to crumble upon touching. As the preparation temperature increases, particle size decreases. This is because at high temperature, emulsion is less viscous and it becomes much easier for the emulsion to be broken down into smaller droplets at the same power of mixing input. Microballoons prepared at high temperature are found to be a uniform internal pore distribution. Microspheres formed at higher temperature gives very slow release rates after their initial drug release.

Plasticizers

Due to the addition of plasticizer, it gives elasticity and flexibility to the wall of material so that it never gets brittle or ruptured under pressure. It is also observed that the release of the drug increased significantly with the increase of plasticizer concentration.

Volume of aqueous phase (Continuous phase)

The effect of various volumes on the formation of hollow microspheres. When the volume of aqueous phase increases the particle size decreases and thus buoyancy increases. Using of large volumes of the external aqueous phase reduces the required stirring times. The solubility of dichloromethane in water is 1% w/v. Using a larger volume (400 to 500 ml), the diffusion of dichloromethane into the aqueous phase, and hence the solidification of particles, occurred faster, when compared to a volume of 200 ml.

Solvent ratio

The bridging liquid plays a key role in microsphere preparation. Very small volume of the bridging liquid gives irregularly shaped microspheres while very large volume of bridging liquid prevents from solidifying of the emulsion droplets.

Therefore, the amount of dichloromethane needs to be carefully controlled. The ratio of dichloromethane with ethanol affects the morphology of the microspheres so optimized the ratio which can give best spherical shape. The ratio of ethanol to dichloromethane is 2:1 obtains the best result with spherical shape. Faster rate of solvent evaporation gives smooth surface, spherical shape and lower encapsulation.

Amount of polymer and viscosity

Smaller microballoons are formed at a lower polymer concentration and has a larger surface area exposed to dissolution medium giving faster release of drug.

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1. INTRODUCTION

Department of Pharmaceutics, Madras Medical College. Page 22 Effect of solvent

The effect of various organic solvents on the formation of microspheres by the solvent evaporation method. Dichloromethane is employed as polar internal organic solvent phase for preparation of microspheres because it is a good solvent for most of the polymers and drugs. However, it is observed that the microspheres obtained are not at all spherical in shape. To solve this problem, methanol is used, along with dichloromethane, in the preparation of microspheres. The microspheres so obtained will be a spherical, but lack of smooth texture. To avoid this problem, various solvents are critically screened on the basis of the boiling points, such as dichloromethane (39.75 ºC), acetone (56.5 ºC), methanol (64.7 ºC) and ethanol (78.4 ºC). It is observed that the boiling point increased from DCM to ethanol and so instead of DCM/methanol, ethanol is tried. Most of the water-soluble drugs and water-insoluble polymers are dissolved in ethanol and it is non-toxic and considered as good solvent. As ethanol have high boiling point in relation to other organic solvents such as dichloromethane, acetone, methanol etc., which prevents immediate polymer precipitation. The researchers observed that the microspheres so obtained were completely spherical, with a smooth surface.

Emulsifier concentration

The effect of emulsifier concentration on particle size is studied by the scientist.

They found that the particle size and size distribution is increased when the surfactant concentration is reduced from 1% to 0.25% (w/w). The role of the emulsifier (surfactant) is to decrease the interfacial tension between the dispersed droplets and the continuous phase, as well as to protect the droplets from collision and coalescence. At lower emulsifier concentrations, droplets are more likely to collide and fused to form larger globules; it is insufficient to shield the entire droplet surface. At higher concentration of emulsifier, it reduces the encapsulation efficiency. Hence, the optimum concentration of the emulsifier should be identified.

1.4.6. Advantages of Microballoons

 Reduces the dosing frequency and thereby improve the patient compliance.

 Better drug utilization will improve the bioavailability and reduce the incidence or intensity of adverse effects and despite first pass effect because fluctuations in plasma drug concentration is avoided, a desirable plasma drug concentration is maintained by continuous drug release.

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1. INTRODUCTION

Department of Pharmaceutics, Madras Medical College. Page 23

 Hollow microspheres are used to decrease material density and Gastric retention time is increased because of buoyancy.

 Enhanced absorption of drugs which solubilise only in stomach.

 Drug releases in controlled manner for prolonged period.

 Site-specific drug delivery to stomach can be achieved.

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

 Avoidance of gastric irritation, because of sustained release effect.

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

1.4.7 Limitations of microballoons

 The modified release from the formulations.

 The release rate of the controlled release dosage form may vary from a variety of factors like food and the rate of transit though gut.

 Differences in the release rate from one dose to another.

 Controlled release formulations generally contain a higher drug load and thus any loss of integrity of the release characteristics of the dosage form may lead to potential toxicity.

 Dosage forms of this kind should not be crushed or chewed.

1.4.8. Applications

 Solid and hollow microspheres vary widely in density and, therefore, are used for different applications. Hollow microspheres are typically used as additives to lower the density of a material. Solid microspheres have numerous applications depending on what material they are constructed of and what size they are.

 Hollow microspheres can greatly improve the pharmacotherapy of the stomach through local drug release, leading to high drug concentrations at the gastric mucosa, thus eradicating helicobacter pylori from the submucosal tissue of the stomach and making it possible to treat stomach and duodenal ulcers, gastritis and oesophagitis.

 These microspheres systems provide sustained drug release behaviour and release the drug over a prolonged period of time.

 The drugs recently reported to be entrapped in hollow microspheres include Prednisolone, Lansoprazole, Celecoxib, Piroxicam, Theophylline, Diltiazem

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1. INTRODUCTION

Department of Pharmaceutics, Madras Medical College. Page 24 hydrochloride, Verapamil hydrochloride, Riboflavin, Aspirin, Griseofulvin, Ibuprofen, and Terfenadine.

 Floating microspheres can greatly improve the pharmacotherapy of stomach through local drug release. Thus, eradicating Helicobacter pylori from sub- mucosal tissue of the stomach are useful in the treatment of peptic ulcers, chronic gastritis, gastroesophageal reflux diseases etc. Hollow microspheres of ranitidine HCl are also developed for the treatment of gastric ulcer.

 Floating microspheres are especially effective in delivery of sparingly soluble and insoluble drugs. It is known that as the solubility of a drug decreases, the time available for drug dissolution becomes less adequate and thus the transit time becomes a significant factor affecting drug absorption. For weakly basic drugs that are poorly soluble at an alkaline pH, hollow microspheres may avoid chance for solubility to become the rate-limiting step in release by restricting such drugs to the stomach. The gastro-retentive floating microspheres will alter beneficially the absorption profile of the active agent, thus enhancing its bioavailability.

 The floating microspheres can be used as carriers for drugs with so-called absorption windows, these substances, for example antiviral, antifungal and antibiotic agents (Sulphonamides, Quinolones, Penicillins, Cephalosporins, Aminoglycosides and Tetracyclines) are taken up only from very specific sites of the GI mucosa.

 Hollow microspheres of non-steroidal anti-inflammatory drugs are very effective for controlled release as well as it reduces the major side effect of gastric irritation; for example, floating microspheres of Indomethacin are quite beneficial for rheumatic patients.

1.4.9. Future Potential

It is expected that various new products using gastro retentive drug delivery technologies may magnify this possibility. Further investigations may concentrate on the microballoons concepts:

 Design of an array of gastro retentive drug delivery systems, each having narrow GRT for use according to the clinical need, e.g., dosage and state of disease.

 Determination of minimal cut-off size above that dosage forms retained in the GIT for prolonged period of time.

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1. INTRODUCTION

Department of Pharmaceutics, Madras Medical College. Page 25

 Design and development of gastro retentive drug delivery systems as a beneficial strategy for the treatment of gastric, duodenal cancers and treat Parkinson’s disease.

 Development of various anti-reflux formulation utilizing gastro retentive technologies.

 Exploring the eradication of Helicobacter pylori by using various antibiotics.33

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REVIEW OF

LITERATURE…

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AIM & PLAN OF

WORK…

References

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