vedavathi 2

DESIGN, DEVELOPMENT AND EVALUATION OF BILAYERED TABLETS CONTAINING ACARBOSE AS IMMEDIATE RELEASE AND METFORMIN AS SUSTAINED RELEASEBY

Vedhavathi S .VDISSERTATION SUBMITTED TO THE RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES,KARNATAKA, BANGALORE

IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF

MASTER OF PHARMACY

INPHARMACEUTICS

UNDER THE GUIDANCE OF

Dr. C.S.R LAKSHMI

DEPARTMENT OF PHARMACEUTICS NARGUND COLLEGE OF PHARMACY BANGALORE-85.

FEBRUARY 2011

RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES, KARNATAKA, BANGALORE.

DECLARATION BY THE CANDIDATE

I hereby declare that the matter embodied in the dissertation entitled Design, Development and Evaluation of Bilayered Tablets containing Acarbose as Immediate Release and Metformin as Sustained Release is a bonafide and genuine research work carried out by me under the guidance of Dr. C.S.R Lakshmi, Head of Department of Pharmaceutics, Nargund college of pharmacy, Bangalore.

Date:

Place: Bangalore

Ms. Vedhavathi S.V Department of Pharmaceutics, Nargund College of Pharmacy, Bangalore 85.

NARGUND COLLEGE OF PHARMACY BANGALORE-85

CERTIFICATE BY THE GUIDE

This is to certify that the dissertation entitled Design, Development and Evaluation of Bilayered Tablets containing Acarbose as Immediate Release and Metformin as Sustained Release is a bonafide research work carried out by Ms. Vedhavathi S.V submitted in partial fulfillment for the award of the degree of Master of Pharmacy in Pharmaceutics by the Rajiv Gandhi University of Health Sciences, Karnataka, Bangalore.

Date

Place: Bangalore

Dr. C.S.R Lakshmi HOD of Pharmaceutics, Nargund College of Pharmacy, Bangalore 85.


CERTIFICATE BY THE CO-GUIDE

This is to certify that the dissertation entitled Design, Development and Evaluation of Bilayered Tablets containing Acarbose as Immediate Release and Metformin as Sustained Release is a bonafide research work carried out by Ms. Vedhavathi S.V submitted in partial fulfillment for the award of the degree of Master of Pharmacy in Pharmaceutics by the Rajiv Gandhi University of Health Sciences, Karnataka, Bangalore.

Date

Place: Hosur

Mr. Durai Venkadesh .R Deputy manager, FR&D, Micro Labs Ltd, Hosur


ENDORSEMENT BY THE HEAD OF DEPARTMENT

This is to certify that the dissertation entitled Design, Development and Evaluation of Bilayered Tablets Containing Acarbose as Immediate Release and Metformin as Sustained release is a bonafide research work carried out by Ms. Vedhavathi S.V submitted in partial fulfillment for the award of the degree of Master of Pharmacy in Pharmaceutics by the Rajiv Gandhi University of Health Sciences, Karnataka, Bangalore. This work was carried out by her in the library and laboratories of Micro Labs Ltd. Hosur under the guidance Dr. C.S.R Lakshmi, Head of Department of Pharmaceutics, Nargund College of Pharmacy, Bangalore.

Date

Place: Bangalore

Dr. C. S. R. Lakshmi HOD Pharmaceutics, Nargund College of Pharmacy, Bangalore 85.


ENDORSEMENT BY THE PRINCIPAL

This is to certify that the dissertation entitled Design, Development and Evaluation of Bilayered Tablets containing Acarbose as Immediate Release and Metformin as Sustained Release is a bonafide research work carried out by Ms. Vedhavathi S.V submitted in partial fulfillment for the award of the degree of Master of Pharmacy in Pharmaceutics by the Rajiv Gandhi University of Health Sciences, Karnataka, Bangalore. This work was carried out by her in the library and laboratories of Micro Labs Ltd. Hosur under the guidance of Dr. C.S.R Lakshmi, Head Of Department of pharmaceutics, Nargund College of Pharmacy.

Date Place: Bangalore

Dr. L. V. G. Nargund Principal, Nargund College of Pharmacy, Bangalore 85.

COPYRIGHT

I hereby declare that the Rajiv Gandhi University of Health Sciences, Karnataka shall have the rights to preserve, use and disseminate this dissertation / thesis in print or electronic format for academic / research purpose.

Date

Place: Bangalore

Ms. Vedhavathi S.V Department of Pharmaceutics, Nargund College of Pharmacy, Bangalore 85.

Rajiv Gandhi University of Health Sciences, Karnataka.

Though words are seldom sufficient to express gratitude and feelings, it somehow gives me an opportunity to acknowledge those who helped me during the tenure of my study. The work of dissertation preparation was a challenging task and fascinating experience.

I consider myself very much lucky with profound privilege and great pleasure in expressing my deep sense of gratitude to work under the guidance of Dr.C.S.R Lakshmi, Head Of Department of Pharmaceutics , Nargund college of pharmacy, for her continuous guidance, supportive suggestion, innovative ideas, with constant inspiration, help and encouragement have always propelled me to perform better.

It is my privilege and honor to extend my profound gratitude and express my indebtedness to Dr L.V.G Nargund, Director of Nargund institute,Bangalore, for his enduring support. He has been generous with providing facilities to carry out this work.

I would also like to thank Prof. C. R. Mahendra Shetty, Prof. Y. R. Shivaraj, Dr. Gopal Muralidharan, Asst. prof. Mrs. Preeti Karwa, Asst. prof. Mrs. Rama Rajesha, Pof. Mrs. Ritu Kimbahune, Lect. Mrs. Prachi kabra, Asst. prof. Mrs.C. D. Saraswathi, Lect. Mrs. Jayanthi A. and Lect. Mr. Atul Kakade for their helpful suggestion and advice.

I express my sincere thanks and respectful regards to the Executive Vice President Mr. K. Rajeshkshirsagar, Formulation R&D, Micro Labs Ltd., Hosur in acknowledging all the facilities provided to us to carry out this work with great ease and precision.

I owe my gratitude to Mr. Sanjay C Pawar, Assistant general manager, Formulation R&D, Micro Labs Ltd., Hosur for his teaching and moral support.

I extend my gratitude and express my sincere thanks to my guide in industry, Mr. R. Durai venkadesh, Deputy Manager, Formulation R&D, Micro Labs Ltd., Hosur for his valuable guidance and support throughout this work.

I express my deepest and very special thanks to all the staff members of entire Formulation R&D, Documentation team, Analytical R&D and management of M/s. Micro Labs Ltd., Hosur, for allowing me to carry out this project successfully. The words are insufficient to thank Jitesh, Anup, Sagar and Ravindharan, who stood beside me each and every hour during my project and given me constant support.

Most of all I would like to thank my beloved Parents, Brother, and all other dearest friends for their priceless support, love and encouragement throughout the entire tenure of this course.

Vedhavathi S.V

LIST OF ABBREVIATIONS USED

API APS BP BHA BHT BD CPR CCS Conc. cm CMC CI cp DCP DM DCL et al FDA

: Active Pharmaceutical Ingredient : Amino Propyl Silane : Alpha : British Pharmacopoeia : Butylated Hydroxyanisole : Butylated Hydroxytoluene : beta : Bulk Density : Cumulative percent release : Croscarmellose sodium : Concentration : Centimeter : Carboxy Methyl Cellulose : Carrs index : Centi Poise : Di Calcium Phosphate : Diabetes mellitus : Directly compressible lactose : and others : Food and Drug administration

Fig. FTIR gm GI GIT GMP Hrs HR HCl HPMC HPLC IB IP IR ICH IDDM IVIVC KBr L - HPC M mg

: Figure : Fourier transformed infrared spectroscopy : gram : Gastrointestinal : Gastrointestinal tract : Good Manufacturing Practice : hours : Hausners ratio : Hydrochloric Acid : Hydroxy Propyl Methyl Cellulose : High performamce liquid chromatography : Ibuprofen : Indian pharmacopoeia : immediate release : International Conference on Harmonization : Insulin dependent diabetes mellitus : invitro- invivo corelation : Potasium bromide : low substituted Hydroxy propyl cellulose : Molar : milligram

mm ml min MTH g NIDDM NC pH Ph.Eur PVP PDA rpm R2 RT RSD RH SD Sec. SSG SR

: millimeter : milliliter : minute : Metoclotramide Hydrochloride : microgram : Non insulin dependent diabetes mellitus : No change : Negative logarithm of hydrogen ion concentration : European Pharmacopoeia : poly vinyl pyrolidone : Photodiode Array : revolutions per minute : Correlation factor : Real time : Relative Standard Deviation : Relative Humidity : Standard dviation : Second : Sodium starch glycolate : Sustained release

t

: Time required to reduce the amount to half of its original concentration

TDD TD temp. USP UV v w WS

: Traditional drug delivery : Tapped Density : Temperature : United States Pharmacopoeia : Ultraviolet : Volume : Weight : Working Standard

ABSTRACTBACKGROUND AND OBJECTIVE Hyperglycemia is the technical term for high blood glucose (sugar). Hyperglycemia happens when the body has too little or not enough insulin or when the body cant use insulin properly. The main objective of the present research work was to develop a bilayer tablet of immediate release Acarbose and sustained release Metformin Hydrochloride, which is used as an Anti-hyperglycemic agent which improves glucose tolerance in patients with the type 2 diabetes by lowering both basal and postprandial plasma glucose and by inhibiting the - glucosidase inhibitor.

METHOD Metformin Hydrochloride has biological half-life nearly about 6 hours, so, an attempt was made in the direction of preparation and optimization of a combination of sustained release and immediate release in a single tablet. In sustained release layer sodium carboxy methyl cellulose and hydroxy propyl methyl cellulose K4M were used as retarding materials and in immediate release layer croscarmellose sodium was used as a superdisintegrent to give the faster release of Acarbose. The tablets were prepared by wet granulation method and by direct compression. Granules were evaluated for precompression parameters and the tablets were evaluated for post compression parameters.

RESULTS The formulation gave an initial bursting effect and followed by sustained release for 8 hours. Final formulation showed release of drug up to 96.75% in 8 hours. The formulation F- 9b and F- 9c were prepared based on optimized formulation F- 9a for stability studies. The stability batches F-9b and F-9c showed no significant changes during stability studies when stored at 40oC/75%RH for three months according to ICH guidelines. FTIR studies revealed that there was no interaction between the drugs and polymers used in the study. INTERPRETATION AND CONCLUSION The drug release from optimized formulation (F-9a) was found to be diffusion process which follows non fickian type of diffusion. It also showed almost linear regression in Higuchis plot which confirms that diffusion is one of the mechanisms for drug release. In this study optimized fomulation F-9a released the drug till 8 hours. KEY WORDS Bilayer tablets, Metformin Hydrochloride, Acarbose, hydroxy propyl methyl cellulose K4M, sodium carboxy methyl cellulose, and croscarmellose sodium.

TABLE OF CONTENTS

1. Introduction

...

1

2. Aims & Objectives

...

27

3. Review of Literature

29

4. Methodology

42

5. Results

....

102

6. Discussion

....

130

7. Conclusion

....

137

8. Summary

....

138

9. Bibliography

.

140

10. Annexure

.

146

LIST OF TABLESTable No. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 Tables Materials used with their company name Excipient profile Hydroxy Propyl Methyl Cellulose Excipient profile Croscarmellose sodium Excipient profile Magnesium stearate Excipient profile Povidone Excipient profile Calcium phosphate dibasic anhydrous Excipient profile Carboxymethylcellulose sodium Excipient profile Colloidal silicon dioxide Excipient profile Talc Excipient profile Sunset yellow lake Excipient profile Butylated Hydroxyanisole Excipient profile Butylated hydroxytoluene Excipient profile Hydroxypropyl Cellulose, Low-Substituted Excipient profile Sodium starch glycolate Equipments used with their company name Solubility studies Dissolution limits Composition of Metformin HCl Sustained Release layer Composition of Acarbose Immediate Release layer Angle of repose as an indication of granule flow properties Carrs index as an indication of granule flow properties Page No. 43 53 54 55 56 57 58 59 60 61 62 63 64 65 66 69 72 73 74 80 81

22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39

Hausners ratio as an indication of granule flow properties Weight variation parameters Storage Conditions Evaluation of drug (Metformin HCl) characterization Evaluation of drug (Acarbose) characterization Results of loss on drying of Metformin HCl bulk drug Results of evaluation of Metformin HCl bulk powder Results of loss on drying of Acarbose bulk drug Results of evaluation of Acarbose bulk powder Characteristic peak of pure Metformin HCl Characteristic peak of Metformin HCl SR layer Characteristic peak of pure Acarbose Characteristic peak of Acarbose IR layer Exipient compatibility for Metformin HCl Exipient compatibility for Acarbose Evaluation of granules of Metformin HCl sustained release Layer Evaluation of granules of Acarbose immediate release Layer Evaluation of bilayer tablets Metformin HCl SR and Acarbose IR: F-1 to F- 9a Evaluation of In vitro dissolution and Assay of bilayer tablets Metformin HCl SR and Acarbose IR: F-1 to F-9a. In vitro release study of Bilayer tablets of different formulation.

81 83 99 102 103 104 104 104 105 106 107 108 109 111 112 114 114 117

40 41

118 120

42

Data of various parameters of model fitting for Metformin HCl for optimized formulation F 9a. Data of various parameters of model fitting for Metformin HCl for different formulation. Evaluation of Bilayer tablets of Stability Batch: F-9b Evaluation of in vitro dissolution and assay of bilayer tablets of stability Batch: F-9b Evaluation of Bilayer tablets of Stability Batch: F-9c Evaluation of in vitro dissolution and assay of bilayer tablets of stability Batch: F-9c

123

43 44 45 46 47

126 127 127 128 129

LIST OF FIGURESFig. No. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 Figure No. Cross section of bilayer tablet Multilayer Compression Bilayer tablet compression machine Sustained release drug delivery system Matrix tablet Diffusion release pattern. Osmotic release pattern Chemical structure of Metformin Hydrochloride Chemical structure of Acarbose Drug-Excipient Compatibility Studies by FTIR Manufacturing process flow chart FTIR spectrum of pure Metformin HCl FTIR spectrum of Metformin HCl Layer FTIR spectrum of pure Acarbose FTIR spectrum of Acarbose Layer Chromatogram of sample B (metformin HCl) Chromatogram of sample A (Acarbose) and standard chromatogram CPR of different formulation of Acarbose IR layer CPR of different formulation of Metformin HCl SR layer CPR of F-9a of Metformin HCl SR layer and Acarbose IR layer Plot showing zero order kinetics of formulation F-9a. Plot showing First order kinetics of formulation F 9a. Plot showing Higuchi model of formulation F- 9a. Plot showing Peppas model of formulation F- 9a. Photograph of Bilayer tablets Page No. 6 10 10 11 19 20 21 44 48 70 77 106 107 108 109 115 116 121 121 122 124 124 125 125 129

DESIGN DEVELOPMENT AND EVALUATION OF BILAYERED TABLETS CONTAINING ACARBOSE AS IMMEDIATE RELEASE AND METFORMIN AS SUSTAINED RELEASE

INTRODUCTION Oral route is one of the most popular routes of drug delivery due to its ease of administration, patient compliance, least sterility constraints and flexible design of dosage form. 1.1 Tablets: 1, 2 Over 90% of the formulations manufactured today are ingested orally. This shows that this class of formulation is the most popular worldwide and the major attention of the researcher is towards this direction. With advancement in technology and increase in awareness, towards modification in standard tablet is done to achieve better acceptability as well as bioavailability because of which newer and more efficient tablet dosage forms are being developed. The main reasons behind formulation of different types of tablets are to create a delivery system that is relatively simple and inexpensive to manufacture, provide the dosage form that is convenient from patients perspective and utilize an approach that is unlikely to add complexity during regulatory approval process. To understand each dosage form, tablets here are classified by their route of administration and by the type of drug delivery system they represent within that route. Overview on types and class of tablets: A) Oral tablets for ingestion: These tablets are meant to be swallowed intact along with a sufficient quantity of potable water. Exceptions are chewable tablet and oral dispersible tablets. Standard compressed tablets this class includes tablets like, Multiple compressed tablets, compression coated tablet, layered tablet, modified release tablet etc.

DEPERTMENT OF PHARMACEUTICS, NARGUND COLLEGE OF PHARMACY

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B) Tablets used in the oral cavity: The tablets under this group are aimed to release active pharmaceutical ingredient in the oral cavity or to provide local action in this region. The tablets under this category avoids first-pass metabolism, decomposition in gastric environment, nauseatic sensations and gives rapid onset of action. The tablets formulated for this region are designed to fit in proper region of oral cavity. This class includes tablets like lozenges and troches, sublingual tablet, buccal tablet, dental cones, oral dispersible tablet etc. C) Tablets administered by other routes: These tablets are administered by other route except for the oral cavity and so the drugs are avoided from passing through gastro intestinal tract. These tablets may be inserted into other body cavities or directly placed below the skin to be absorbed into systemic circulation from the site of application. This class includes tablets like vaginal tablet, implants etc. D) Tablets used to prepare solution: The tablets under this category are required to be dissolved first in water or other solvents before administration or application. This solution may be for ingestion or parenteral application or for topical use depending upon type of medicament used. This class includes tablets like effervescent tablet, hypodermic tablet. 1.2 Bilayer tablets: 1 Definition: Dual release tablet is a unit compressed tablet dosage form intended for oral application. It contains two layers in which one layer having conventional or immediate release part of single or multiple actives; another layer is sustained or controlled release


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part of single or multiple actives. They are also called as Bilayer tablet, multi-layer matrix tablet. A bilayer tablet is a type of multiple compressed tablets. Tablets are composed of two layers of granulation compressed together. Monograms and other distinctive marking may be compressed in the surface of the bilayer tablets. Coloring the separate layer provide many possibilities for unique tablets identity. Applications: Bilayer tablets are mainly used in the combination therapy. Bilayer tablets are used to deliver the loading dose and sustained dose of the same or different drugs. Bilayer tablets are used for bilayer floating tablets in which one layer is floating layer another one is immediate release layer of the drug. Bilayer tablets are used to deliver the two different drugs having different release profiles. Advantages: They are used as an extension of a conventional technology. Potential use of single entity feed granules. Separation of incompatible components. Patient compliance is enhanced leading to improved drug regimen efficacy. Patient convenience is improved because fewer daily doses are required compared to traditional delivery system. Maintain physical and chemical stability. Retain potency and ensure dose accuracy.Page 3



Disadvantages: Adds complexity and bilayer rotary presses are expensive. Insufficient hardness, layer separation, reduced yield. Inaccurate individual layer weight control. Cross contamination between the layers.

ADVANTAGES OF BILAYER TABLET OVER CONVENTIONAL TABLETS: Blood level of a drug can be held at consistent therapeutic levels for improved drug delivery, accuracy, safety and reduced side effects. Reduction of adverse effects can be accomplished by targeting the drug release to the absorption site as well as controlling the rate of release, enabling the total drug content to be reduced. Patient convenience is improved because fewer daily doses are required compared to traditional delivery systems. Patient compliance is enhanced leading to improved drug regimen efficacy. Bilayer tablets readily lend themselves to repeat action products, where in one layer on layered tablet provides the initial dose, rapidly disintegrate in the stomach. The other layers are insoluble in gastric media but are released in the intestinal environment. In bilayer tablets, where in one layer on layered tablet provides as immediate release and other layer acts as sustained release. In sustained release drug delivery system, several approaches are available to add the loading dose to the maintenance dose such as simple addition of a sustained dose of a drug to the sustained portion and placement of initial dose in a tablet coat with the sustaining portion in the core as in compression coated tablets.DEPERTMENT OF PHARMACEUTICS, NARGUND COLLEGE OF PHARMACY Page 4


An alternative approach for having the loading dose and maintenance dose in a tablet is the formulation of drug in a multi layered tablet or bilayer tablet system3. This bilayer approach is a convenient method. Hence it makes possible to formulate sustained release preparations with the immediate release quantity in one layer and the slow release portion will disintegrate rapidly after ingestion thus providing the initial dose of medication for immediate onset of action, where as the another layer in the matrix layer remain intact during most of the time of its passage through the intestine, while dissolving slowly (sustained manner) from its exposed faces in this passage, which helps to maintain the blood level initially reached 4. LAYER THICKNESS: Layer thickness can be varied within a reasonable proportion within the limitations of the tablets press. Thickness is dependent on the fineness of the granulation1. SIZE AND SHAPES: Size is limited by the capacity of the machine with the total thickness being the same as for a single layer tablet. Many shapes other than round are possible and are limited only by the ingenuity of the die maker. However, deep concavities cause

distortion of the layers. Therefore, standard concave and flat-face beveled edge tooling make for the best appearance, especially when layers are of different colors.


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1.2.1 THE SHAPE OF THE PUNCHES: Punches with beveled edges or concave faces will make the top and bottom layers of a three layer tablets and appear thinner than the middle one. Flat-faced tooling will produce equal thickness of the layers, but unfortunately, the edges of the tablets tend to clip readily. Cross section of the layer tablets:

Fig no. 1 Cross section of bilayer tablet 1. Upper layer 2. Lower layer The above Figure - 1 illustrates how the shape of the upper punch determines the shape of the layers. If the upper punch faces have the monogram or other markings, the bonding between the layers will be strengthened because the device will act as key between the layers. 1.2.2 Ideal properties for bilayer tablets press: Preventing capping and separation of the two individual layers that constitute the bilayer tablet. Preventing cross-contamination between the two layers. Producing a clear visual separation between the two layers. High yield and accurate and individual weight control of the two layers.


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1.2.3 Types of bilayer tablet press: 1. Single sided tablet press. 2. Double sided tablet press. 3. Bilayer tablet press with displacement monitoring.

1.

Single sides press: The simplest design is a single sided press with both chambers of the doublet feeder separated from each other.

Each chamber is gravity or forced fed with different powers, thus producing the two individual layers of the tablets.

When the die passes under the feeder, it is at first loaded with the first layer powder followed by the second layer powder.

Then the entire tablet is compressed in one or two steps.

Limitations of single sided press: No weight monitoring / control of the individual layers. No distinct visual separation between the two layers. Very short first layer dwell time due to the small compression roller, possibly resulting in poor de-aeration, capping, and hardness problems. This may be corrected by reducing the turret-rotation speed (to extend the dwell time) but with the consequence of lower tablet output.


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Dwell time: Dwell time is defined as the time during which compression force is above 90% of its peak value. Longer dwell times are a major factor in producing a quality tablet, especially when compressing a difficult formulation. Compression force: Many bilayer formulations requires a first layer compression force of less than 100 daN in order to retain the ability to bond with the second layer. Above 100daN, this ability may be lost and bonding between both layers may not be sufficient, resulting in low hardness of the bilayer tablet and separation of the two layers. 2. Double sided tablet presses Most double sided tablet presses with automated production control use compression force to monitor and control tablet weight. The effective peak compression force exerted on each individual tablet or layer is measured by the control system at the main compression of the layer. This measured peak compression force is the signal used by the control system to reject out of tolerance tablets and correct the die fill depth when required. 3. Bilayer tablet press with displacement: The displacement tablet weight control principle is fundamentally different from the principle based upon compression force. When measuring displacement, the control system sensitivity does not depend on the tablet weight but depends on the applied precompression force.


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Advantages: Weight monitoring / control for accurate and independent weight control of the individual layers. Low compression force exerted on the first layer to avoid capping and separation of the two individual layers. Independence from the machine stiffness Increased dwell time at pre-compression of both first and second layer to provide sufficient hardness at maximum turret speed. Maximum prevention of cross-contamination between the two layers Clear visual separation between the two layers and maximized yield.

1.2.4 Multi-layer compression basics: Presses can be designed specifically for multi-layer compression or a standard double-sided press can be converted for multi-layers: The multilayer tablets concept has been long utilized to develop sustained release formulation. Such a tablet has a fast releasing layer and may contain bilayer or triple layers to sustain the drug release. The pharmacokinetic advantage relies on the fact that drug release from fast releasing granules leads to a sudden rise in blood concentration however, the blood level is maintained at steady state as the drug is released from the sustained granules.


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Fig no. 2 Multilayer Compression

Fig no. 3 Bilayer tablet compression machine


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1.3 Controlled / Sustained release drug delivery system: For many disease states the ideal dosage regimen is that by which an acceptable therapeutic concentration of drug at the site (s) of action is attainted immediately and is then maintained constant for the desired duration of the treatment. Over the past 30 years as the expense and complication involved in marketing new drug entities have increased, with concomitant recognition of the therapeutic advantage of modified release per oral dosage forms, greater attention has been focused on development of sustained, controlled release and delayed release system. There are several reasons for the attractiveness of this dosage form. It is generally recognized that for many disease states, a substantial number of therapeutically effective compounds already exist. The effectiveness of these drugs however is often limited by side effects or the necessity to administer the compound in a clinical setting.

1.3.1

Sustained release drug delivery system:

Fig no. 4 Sustained release drug delivery systemDEPERTMENT OF PHARMACEUTICS, NARGUND COLLEGE OF PHARMACY Page 11


Sustained release drug delivery system has been constantly used to retard the release of therapeutic agents such that its appearances in the circulation is delayed or prolonged and its plasma profile is sustained in duration. The onset of its pharmacological action is often delayed and duration of therapeutic action is sustained.

SUSTAINED RELEASE CONCEPT: 5 The goal of any drug delivery system is to provide a therapeutic amount of the drug to the proper site in the body to achieve promptly and then maintain, the desired drug concentration that is the drug delivery system should deliver drug at a rate dictated by the needs of the body over the period of treatment. This idealized objective points to the two aspects most important to the drug delivery, namely, spatial placement and temporal delivery of a drug. Spatial placement relates to targeting a drug to a specific organ or tissue, While temporal delivery refers to the controlling the rate of drug delivery to the tissue. An appropriately designed sustained release drug delivery system can be a major advance toward solving these two problems. It is for this reason that the science and technology responsible for development of sustained release pharmaceuticals have been and continued to be the focus of great deal of attention in both industrial and academic laboratories.


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The bulk of research has been directed at oral dosage forms that satisfy the temporal aspect of drug delivery but many of the newer approaches under investigation may allow for spatial placement as well. Goal in designing delayed release sustained or controlled drug delivery system The goal in designing delayed release sustained or controlled drug delivery system is to: Reduce the frequency of dosing or to increase effectiveness of the drug by localization at the site of action, reducing the dose required, or providing uniform drug delivery. It would be a single dose for the duration of treatment whether it is for days or weeks, as with infection, or for the life time of the patient, as in hypertension or diabetes. It should deliver the active entity directly to the site of action, minimizing or eliminating side effects. This may necessitate delivery to specific receptors or to localization to cells or to specific areas of the body. The safety margin of high potency drug can be increased and the incidence of both local and systemic adverse side effects can be reduced in sensitive patient. 1.4 Mechanism of drug release for sustained release drug delivery system: On exposure to aqueous fluid, hydrophilic matrices take up water, and polymer starts hydrating to form a gel layer. Drug release is controlled by diffusions barriers / or by surface erosion. An initial burst of soluble drug may occur due to surface leaching when a matrix containing a swellable glassy polymer comes in contact with an aqueous medium, there is an abrupt change from a glassy to a rubbery state which is associatedDEPERTMENT OF PHARMACEUTICS, NARGUND COLLEGE OF PHARMACY Page 13


with swelling process with time, water infiltrates deep into the case increasing the thickness by the gel layer. Concomitantly the second layer becomes fully hydrated and starts dissolving or eroding. When water reaches the center of the system and the concentration of drug falls below the solubility value, the release rate of drug begins to reduce. At the same time, an increase in thickness of the barrier layer with time increases the diffusion path length, reducing the rate of drug release. Drug release kinetic associated with these gel layer dynamic, range initially from Fickian to anomalous (Non Fickian) and subsequently from quasi Constant ( near Zero order ) to constant. In general, two major factors control the drug release from swelling controlled matrix system. They include 1. The rate of aqueous medium infiltration into the matrix, followed by a relaxation process (hydration, gelation or swelling). 2. The rate of matrix erosion. Swelling of HPMC matrix tablet was higher for higher molecular weight. They attributed this to the large hydrodynamic volume occupied by higher molecular weight chain when hydrated. As the polymer chain becomes more hydrated and the gel becomes more dilute, the disentanglement concentration may be reached, i.e., the critical polymer concentration below which the polymer chain disentangles and get detached from gelled matrix.


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1.5 Sustained release dosage form:Advantages: 1. It improves patient compliance 2. It may improve the pathophysiology of the disease. a. It minimizes or eliminates local side effects. b. It minimizes or eliminates systemic side effects. c. It obtains less potentiation or reduction in drug activity with chronic use. d. It minimizes drug accumulation with chronic dosing 3. It improves the efficiency in treatment a. It cures or controls the condition more promptly b. It improves bioavailability of some drugs c. Reduction in fluctuation in steady-state levels and therefore better control of disease condition. d. Make use of special effects e.g. sustained release aspirin for morning relief of arthritis by dosing before bedtimes. 4. Improved therapy a. Sustained blood level- the dosage form provided uniform drug availability or blood levels unlike peak and valley pattern obtained by intermittent administration. b. Attenuation of adverse effects- the incidence and intensity of undesirable side effects caused by excessively high peak drug concentration resulting from the administration of conventional dosage forms is reduced.


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Disadvantages: 1. Cost is very high. 2. Unpredictable and often poor IVIVC. 3. Dose dumping. 4. Reduce potential for dosage adjustment of drugs normally administered in varying strengths 5. For oral SR dosage forms there is an additional disadvantage that the effective drug release period is influenced and limited by GI residence time. 6. Retrieval of the drug is difficult in case of toxicity, poisoning or hypersensitivity reactions. 1.6 Criteria to be met by drug proposed to be formulated in sustained release dosage forms: a) Desirable half-life: The half life of a drug is an index of its residence time in the body. If the drug has a short half life (less than 2 hrs), the dosage form may contain a prohibitively large quantity of the drug. On the other hand, drug with elimination half life of eight hours or more are sufficiently sustained in the body, when administered in conventional dosage from, and controlled release drug delivery system is generally not necessary in such cases. Ideally, the drug should have half-life of three to four hours.


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b) High therapeutic index: Drugs with low therapeutic index are unsuitable for incorporation in controlled release formulations. If the system fails in the body, dose dumping may occur, leading to fatalities eg. Digitoxin. c) Small dose: If the dose of a drug in the conventional dosage form is high, its suitability as a candidate for controlled release is seriously undetermined. This is chiefly because the size of a unit dose controlled release formulation would become too big, to administer without difficulty. d) Desirable absorption and solubility characteristics: Absorption of poorly water soluble drug is often dissolution rate limited. Incorporating such compounds into controlled release formulations is therefore unrealistic and may reduce overall absorption efficiency. e) Desirable absorption window: Certain drugs when administered orally are absorbed only from a specific part of GIT. This part is referred to as the absorption window. Drugs exhibiting an absorption window like fluorouracil, thiazide diuretics, if formulated as controlled release dosage form are unsuitable.


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f) First pass clearance: Delivery of the drug to the body in desired concentrations is seriously hampered in case of drugs undergoing extensive hepatic first pass metabolism, when administered in controlled release forms. 1.7 Benefits of modified drug delivery system: Decrease in dosing frequency. Reduced peak to trough ratio of drug in systemic circulation. Reduced rate of rise of drug concentration in blood. Sustained & Consistent blood level with in the therapeutic window. Enhanced bioavailability. Customized delivery profiles. Reduced side effects, improved patient compliance.

1.8 Sustained release matrix system of highly water soluble drugs: Matrix systems are favored because of their simplicity, patient compliance etc, than Traditional drug delivery (TDS) which have many drawbacks like repeated administration, fluctuation in blood concentration level etc. Developing oral sustained release matrix tablets for highly water-soluble drugs with constant release rate has always been a challenge to the pharmaceutical technologist. Most of highly water-soluble drugs, if not formulated properly, may readily release the drug at a faster rate, and are likely to produce toxic concentration of the drug on oral administration.


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Hydrophilic polymers have become a product of choice as an important ingredient for formulating sustained release formulations of highly water-soluble drugs.

Drug release through matrix system is determined by water penetration, polymer swelling, drug dissolution, drug diffusion and matrix erosion.

Highly water-soluble drugs like Metformin, metoprolol tartrate, diltiazem, tramadol, ranitidine have been formulated as sustained release matrix tablets.

1.8.1

Matrix Technology Classically matrix products exhibit first order (or perhaps square-root-of-time)

drug release characteristics. In order to achieve zero order release characteristics, its necessary to employ specially designed materials or strategies that seek to manipulate tablet structure or geometry for which combination of conventional HPMC matrix technology with upper and lower layer is necessary. This helps to moderate drug release by increase in surface area with concomitant reduction in drug concentration within the device.

Fig no. 5 Matrix tablet


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DRUG RELEASE MECHANISM Release of medicament can follow various mechanisms; A) Diffusion: Diffusion is a rate limiting step for the release of drug. Diffusion is the driving force where the movement of drug molecules occurs from high concentration in the tablet to lower concentration in gastro intestinal fluids. This movement depends on surface area exposed to gastric fluid, diffusion pathway, drug concentration gradient and diffusion coefficient of the system.

Fig no. 6 Diffusion release pattern.

In practice, we can follow either of the two methods, 1. The drug is formulated in an insoluble matrix. The gastric fluid penetrates the dosage form and dissolves the medicament and release the drug through diffusion. 2. The drug particles are coated with polymer of defined thickness so as the portion of drug slowly diffuse through the polymer to maintain constant drug level in blood. B) Dissolution: Dissolution is a rate limiting step for the release of drug. The drugs with poor water solubility (BCS class 2 and 4) are inherently sustained release forms. While forDEPERTMENT OF PHARMACEUTICS, NARGUND COLLEGE OF PHARMACY Page 20


water soluble drugs, its possible to incorporate a water insoluble carrier to reduce dissolution of the drug particles are coated with this type of materials e.g. Polyethylene Glycol. One may skip the use of disintegrating agent to promote delayed release.

C) Osmotic pressure: Osmotic pressure is a rate limiting step for the release of drug. Osmosis is a phenomenon in which the flow of liquid occurs from lower concentration to higher concentration through a semi permeable membrane which allows transfer of liquid only. The whole drug is coated with a semi permeable membrane with a hole on one end of tablet made by a laser beam. The gastric fluid penetrates through the membrane, solubilizes the drug and increases the internal pressure which pumps the drug solution out of the aperture and releases the drug in gastric environment. The delivery rate is constant provided that the excess of drug present inside the tablet. But it declines to zero once the concentration drops below saturation.

Fig no. 7 Osmotic release pattern


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D) Release controlled by ion exchange: Ion exchangers are water insoluble resinous materials containing salt forming anionic or cationic groups. While manufacturing, the drug solution is mixed with resin and dried to form beads which are tableted. The drug release depends upon high concentration of charged ions in gastro intestinal tract where, the drug molecules are exchanged and diffused out of the resin into the surrounding fluid. This mechanism relies upon the ionic environment of resin and not pH or enzyme on absorption site.

1.9 HYPERGLYCAEMIA:6 Hyperglycemia is the technical term for high blood glucose (sugar). High blood glucose happens when the body has too little or not enough insulin or when the body cant use insulin properly. Three peptide hormones secreted by the pancreas occupy a central role in the regulation of metabolism of carbohydrates, lipids and amino acids. They are insulin,

glucagons and somatostatin. Insulin is the primary hormone which is responsible for controlling the storage and utilization of cellular nutrients. It activates the transport system and the enzymes involved in the intracellular utilization and storage of glucose, amino acids and fatty acids. Insulin inhibits catabolic process such as the breakdown of glycogen, fat and protein. Whereas the overall effect of insulin is hypoglycemic, the other pancreatic hormone glucagons mobilizes glucose from its store and causes hyperglycemia, the third pancreatic hormone somatostatin, originally discovered as hypothalamic hormone, inhibits the secretion of both insulin and glucagons.


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1.9.1 Diabetes mellitus:7 Definition: The term mellituria means sweet urine. It is a part of metabolic syndrome of multi-factorial etiology characterized by chronic hyperglycemia with disturbance of carbohydrate, fat and protein metabolism and water and electrolyte imbalance resulting from defects in insulin secretion and insulin action or both. Deficiency of effective insulin in the body cause a disease called diabetes mellitus in which there is altered metabolism of lipid, carbohydrates and protein. This results in hyperglycaemia and glycosuria. A) Early signs of hyperglycaemia in diabetes include: Polydipsia (increased thirst) Headaches Difficulty concentrating Polyurea (increased urinary output) Ketonaemia and ketourea (presence of ketone bodies in the blood and urine, respectively) Blur sight, Fatigue (weak, tired feeling) Itches on skin and mucus membranes Permanent hunger Outstanding tiresomeness/lack of energy. Sudden weight loss, Blood glucose more than 180mg/dl.


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B) Prolonged hyperglycaemia in diabetes may result in: Vaginal and skin infections. Slow-healing cuts and sores. Nerve damage causing painful cold or insensitive feet, loss of hair on the lower extremities, and/or erectile dysfunction. Stomach and intestinal problems such as chronic constipation or diarrhea. Decreased vision.

C) Two major types of Diabetes mellitus: 1. Type I / Insulin Dependent Diabetes Mellitus (IDDM), juvenile onset diabetes mellitus. 2. Type II / Non Insulin Dependent Diabetes Mellitus (NIDDM), maturity onset diabetes mellitus. Type I: There is cell destruction in pancreatic islets, Type IA: Majority of cases is autoimmune antibodies that destroy cells are detectable in blood. Type IB: There are idiopathic no cell antibody is found. In all type I cases circulating insulin levels are low or very low, and patients are more prone to ketosis. This type is less common and has a low degree of genetic predisposition. Type II: There is no loss or moderate reduction is cell mass, insulin in circulation is low, normal or even high, no anti cell antibody is demonstrate, has a high degree of genetic predisposition, generally has a late onset (past middle age) over 90% cases are type 2 diabetes mellitus.


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D) Causes: Abnormality in gluco-receptor of cells so that they respond at higher glucose concentration. Reduced sensitivity of peripheral tissues to insulin, reduction in number of insulin receptors, down regulation of insulin receptors. Many hypertensive are hyperinsulinemic but normoglycemic, exhibit insulin resistance, hyperinsulinemia has been implicated in causing angiopathy. Excess of hyperglycemic hormones (glucagons etc)/obesity, causes relative insulin deficiency the cells lag behind. Diagnostic criteria Diagnosis is by history of symptoms of polydipsia, polyuria recurrent infections, fatigue, unexplained weight loss and blurring of vision with blood sampling. The cut off values of venous plasma samples are: Fasting blood sugar 126 mg/ dl (After minimum 8 hrs of fasting) Random blood sugar 200 mg/dl (Sample taken at any time of the day) Postprandial blood sugar 200 mg/dl (2 hrs postprandial state) Oral glucose tolerance test is the gold standard for diagnosis of DM.

Problems in diagnosis Stress hyperglycemia should not be confused with DM Asymptomatic patient require several sugar samples to confirm the diagnosis


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The hypoglycaemic drugs can be discussed under two categories insulin preparation which are used parentrally only and oral hypoglycaemic agents 1.9.2 Insulin and insulin preparation: 1.9.3 Oral hypoglycaemic drugs:9 1) Sulfonyl Ureas First generation: Tolbutamide, Chlorpropamide Second generation: Glibenclamide (glyburide), Glipizide, Gliclazide,

Glimepiride. 2) Biguanides:Phenformin, Metformin 3) Meglitinide Analogues: Repaglinide, Nateglinide 4) Thiazolidine Diones: Rosiglitozone, Pioglitazone 5) Glucosidase Inhibitors: Acarbose, Miglitol.


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2. AIM & OBJECTIVE OF THE STUDY Aim of the study: The aim of the study is to formulate and evaluate the bilayer tablets containing sustained release layer of Metformin Hydrochloride 500 mg and Immediate release layer containing Acarbose 50 mg for treatment of type 2 diabetes mellitus. Rational behind the suitability of Metformin Hydrochloride 500 mg SR and Acarbose 50 mg IR for drug delivery system. The half-life of Metformin Hydrochloride is 5-6 hrs, hence it is a suitable candidate for the design of sustained release drug delivery system. The Bilayer effect of Metformin Hydrochloride and Acarbose was always greater than the sum of their individual effect. Patient compliance is improved when two drugs are used in a single dosage form rather than taking individual. By using sustained release dosage form the therapeutically effective concentration can be maintained for longer time than the conventional dosage form. By the use of sustained release dosage form, saw tooth kinetics of blood levels associated with conventional multi dosage can be eliminated. By using the sustained release dosage form incident of the local and systemic adverse effects can be reduced.


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Reason for the formulating as Bilayer tablets: Bilayer tablets are preferred when the release profile of the drugs are different from one another (i.e.) in the present case 50 mg Acarbose has to be released Immediately and the remaining 500 mg of Metformin Hydrochloride has to be released maintained. Moreover Metformin Hydrochloride release should be less in stomach and further release should be increased in the intestine and completed within eight hours. Hence an attempt was made to develop a bilayer tablet comprising of Metformin Hydrochloride sustained Release and Acarbose immediate release layers with the following objectives. To improve the patient compliance when the drug has been used in an extended release dosage form rather than conventional tablets. To enhance bioavailability For better clinical effects To reduce the incidence of adverse effects. in a sustained manner, so that therapeutic concentration can be


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3. REVIEW OF LITERATURE RELATED TO METFORMIN HYDROCHLORIDE Rachmani R. et al. have evaluated the safety of continued use of Metformin in patients with contraindications to this agent. Some 393 patients with type 2 diabetes mellitus (serum creatinine 130-220 mol/l) were studied. Among them were 266 patients with coronary heart disease (CHD), 94 with congestive heart failure (CHF), and 91 with chronic obstructive pulmonary disease (COPD), all of whom had been treated with Metformin. The patients were randomized to either continue or to stop Metformin and were then followed for 4 years. The results of analysis were the patients who stopped taking Metformin showed a rise in body mass index and in hemoglobin significantly greater than those who continued the drug. There were no cases of lactic acidosis.10 Mubeen G. and Noor K., have developed and validated a simple and sensitive spectrophotometric method for the estimation of Metformin Hydrochloride in bulk and in tablet formulations. Here the primary amino group of Metformin Hydrochloride reacts with Ninhydrin in alkaline medium to form a violet colour chromogen, which is determined spectrophotometrically at 570 nm. It obeyed Beers law in the range of 8-18 g/ml. Percentage recovery of the drug for the proposed method was found to be accurate and precise for routine estimation of Metformin Hydrochloride in bulk and from tablet dosage forms.11 Hoffman A. et al. have studied the pharmacokinetic and pharmacodynamic aspects of gastroretentive dosage forms. Controlled release gastroretentive dosage forms (CR-GRDF) enable prolonged and continuous input of the drug to the upper parts of the


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gastrointestinal (GI) tract and improve the bioavailability of medications that are characterized by a narrow absorption window. CR-GRDF provide a means to utilize all the pharmacokinetic (PK) and pharmacodynamic (PD) advantages of controlled release dosage forms for such drugs. Thus, CR-GRDF may improve therapy with clinically used medications, as well as enable oral administration of drugs, or drug candidates, that hitherto had to be infused parenterally. 12 Mubeen G. et al. have developed and validated a simple and sensitive spectrophotometric method for the estimation of Metformin Hydrochloride in bulk and in tablet formulation. Here the primary amino group of Metformin Hydrochloride was oxidized using hydrogen peroxide to form a yellow chromogen, which is determined spectrophotometrically at 400 nm. It obeyed Beers law in the range of 4-26mcg/ml. The percentage recovery of the drug for the proposed method ranged from 99-101.3% indicating no interference of the tablet excipients. The proposed method was found to be accurate and precise for routine estimation of Metformin hydrochloride in bulk and in tablet dosage forms.13 Hamdan et al. a simple and a stability indicating capillary electrophoresis method was developed and validated for the analysis of metformin hydrochloride in tablet formulations. The method was validated in accordance with the ICH requirements, which involved accuracy, precision, linearity, selectivity and both limit of detection and limit of quantitation. The limit of detection and limit of quantitation were 2.0g/ml and 8.0g/ml, respectively. The stability indicating capability of the method was established by enforced degradation studies combined with peak purity assessment using photodiode array detection.14DEPERTMENT OF PHARMACEUTICS, NARGUND COLLEGE OF PHARMACY Page 30


Armagan O. have developed three spectrophotometric methods and one HPLC method for analysis of anti-diabetic drugs in tablets. The two spectrophotometric methods were based on the reaction of rosiglitazone (RSG) with 2, 3-dichloro-5,6-dicyano-1,4benzoquinone (DDQ) and bromocresol green (BCG). The third spectrophotometric method consists of a zero-crossing first-derivative spectrophotometric method for simultaneous analysis of RSG and Metformin (MTF) in tablets. The fourth method is a rapid stability-indicating HPLC method developed for the determination of RSG. The proposed methods have been successfully applied to the tablet analysis.15

Mathew F. et al. have formulated Metformin Hydrochloride matrix tablets by sintering technique and they evaluated them. Since metformin hydrochloride is widely chosen as the first line drug in the treatment of type 2 DM, because of its minimal risk and maximum efficacy this formulation was taken into consideration. Matrix tablets reduce the frequency of dose administration, and are found to have increased patient complaince. A relatively recent technique called sintering technique was involved in the formulation which aims to extend the release of Metformin hydrochloride from the matrix tablets. After formulation the tablets where subjected to preformulation studies, micromeritic studies, stability studies and other tablet evaluation methods. 16

Kumar R. have formulated sustained release floating matrix tablets of Metformin Hydrochloride. Floating matrix tablets of Metformin hydrochloride were developed and evaluated for increase in bioavailability by increasing gastric residence time and sustained release of drug on the upper part of gastrointestinal tract thereby diminishing side effects and enhanced patient compliance. Metformin hydrochloride, an oralDEPERTMENT OF PHARMACEUTICS, NARGUND COLLEGE OF PHARMACY Page 31


antidiabetic having narrow absorption window in the upper part of gastrointestinal tract, was formulated as floating matrix tablet using gas generating agent (potassium bicarbonate) and hydrophilic gelling polymer hydroxyl propyl methyl cellulose (hypromellose) by wet granulation technique. The prepared formulations were evaluated for floating time and in vitro drug release characteristics using modified dissolution method. All formulations possessed good floating properties with total floating time more than 12 hours.17

Ching-Ling C. et al. in their article demonstrated the bioequivalence of two marketed IR tablet products of a Class III drug, metformin hydrochloride, that where rapidly dissolving and have similar in vitro dissolution profiles. The effect of race on the systemic exposure of Metformin was also explored. A randomized, open-label, twoperiod crossover study was conducted in 12 healthy Chinese male volunteers. Each subject received a single-dose of 500 mg of each product after an overnight fasting. The plasma concentrations of Metformin were followed for 24 h. No significant formulation effect was found for the bioequivalence metrics: areas under concentrationtime curve (AUC0t, AUC0) and maximal concentration (Cmax). Based on their results, it was concluded that the two IR products are bioequivalent. The pharmacokinetic parameters of Metformin in Chinese for both products were similar and were in good agreement with those reported for Metformin IR tablets in other ethnic populations. This study serves as an example for supporting biowaiver for BCS Class III drugs.18


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Hu L. et al. have prepared Metformin Hydrochloride sustained release pellets by centrifugal granulation method. The influence of surface modification by Talc, the effects of Eudragit types and ratios, as well as the correlation between invitro release and invivo absorption were investigated in detail. Experimental results indicated that Talc modification made a decisive contribution to controlling the drug release by avoiding drug dumping. Following coating with a blend of Eudragit L30D-55 and Eudragit

NE30D (1:20), at 7% or 10% coating level, respectively. The pellets acquired perfect sustained- release properties and good relative bioavailability. The use of two Eudragit polymers with different features as coating materials produced the desired results.19 Mandal U. et al. designed an oral sustained release matrix tablet of Metformin HCl to optimize the drug release profile using response surface methodology. Tablets where prepared by non-aqueous wet granulation method using HPMC K15M as matrix forming polymer. A central composite design for 2 factors at 3 levels each was employed to systematically optimize drug release profile. The formulated tablets followed Higuchi drug release kinetics and diffusion was the dominant mechanism of drug release, resulting in release within 8 hours. 20 Basak SC. et al. have formulated Metformin Hydrochloride as a hydrophobic matrix sustained release tablet employing wax materials and the sustained release behavior of the fabricated tablet was investigated. Sustained release matrix tablets containing 500mg Metformin HCl were developed using different bees wax

combinations. The tablets were prepared by wet granulation technique. The formulation was optimized on the basis of acceptable tablet properties and in vitro drug release. The resulting formulation produced monolithic tablets with optimum hardness, uniformDEPERTMENT OF PHARMACEUTICS, NARGUND COLLEGE OF PHARMACY Page 33


thickness, consistent weight uniformity and low friability. Statistically significant differences were found among the drug release profile from different bees wax combination matrices.21 Corti G. et al. have developed a Metformin Hydrochloride sustained release formulation. The method proposed is based on direct-compressed matrix tablets consisting of a combination of Metformin Hydrochloride with the hydrophobic Triacetyl-cyclodextrin (TACD), dispersed in a polymeric material. Different polymers were tested as excipients, i.e. Hydroxypropyl methylcellulose, Xanthan gum, Chitosan, Ethylcellose, Eudragit L100-55, and Precirol. Compatibility among the formulation components was assessed by DSC analysis. All the tablets were examined for drug release pattern in simulated gastric and jejunal fluids used in sequence to mimic the GI transit. Release studies demonstrated that blends of a hydrophobic swelling polymer (Hydroxypropylmethylcellulose or Chitosan) with a pH-dependent one (Eudragit L10055) were more useful than single polymers in controlling drug release. Moreover, the main role played by the MH-TACD system preparation method (i.e. grinding or spraying) in determining the behavior of the final formulation was evidenced. In fact, for a given matrix- tablet composition, different sustained-release effects were obtained by varying the relative amounts of MH- TACD as ground or spray-dried product.22 Naim et al. have studied the effect of model cationic drug Metformin Hydrchloride on swelling and erosion and in turn, the release of potassium chloride and drug itself, from -carrageenam matrices. Water uptake by the matrix up to 2 hours was found to increase with KCl concentration from the plain matrix. Erosion was not affected by concentration of KCl. Incorporation of drug favours water uptake, but in presence ofDEPERTMENT OF PHARMACEUTICS, NARGUND COLLEGE OF PHARMACY Page 34


KCl it was found to be reduced. Drug-containing matrices have shown higher release of KCl as compared with plain batches. Drug release was retarded as KCl concentration increased up to 5%, above which the reduced cohesivity of the matrix caused increase in drug release.23 Palmer F. et al. Extended release (ER) formulation of Metformin hydrochloride (HCl) presents the formulator with significant challenges due to its poorinherent compressibility, high dose and high water solubility. This study investigates the possibility for development of a direct compression ER matrix tablet using hypromellose.24

RELATED TO ACARBOSE: Kumar G. et al. have developed Spectrophotometric Method for Acarbose from bulk and in its tablet dosage form. A simple rapid spectrophotometeric method has been developed for estimation of Acarbose from bulk drug and tablet dosage form by using potassium permanganate and sodium hydroxide as oxidizing agent. The method is based on the formation of green colored complex of drug with 0.1 N alkaline potassium permanganate having absorbance maxima at 625 nm. The method is applied to the marketed tablet formulation. The developed method was found to be simple, sensitive and reproducible and can be used for routine analysis of Acarbose from bulk and tablet dosage form.25 Kumar G. et al. formulated Monolithic matrix tablets of Acarbose as controlled release tablets employing Hydroxypropyl methylcellulose and Eudragit in differentDEPERTMENT OF PHARMACEUTICS, NARGUND COLLEGE OF PHARMACY Page 35


concentrations and combinations, and investigated sustained release behavior of the fabricated tablets. Controlled released matrix tablets containing 350mg Acarbose were developed using different drug: polymers combination. Tablet prepared by direct compression method were subjected to physical characterization. Formulation was optimized on the basis of acceptable properties and in-vitro drug release. In-vitro drug release was carried out using USP Type II at 50 rpm in 900 ml of acidic dissolution medium (pH 1.2) for 1hr, followed by 900 ml alkaline dissolution medium (pH 7.4) upto 12 hr. Their result suggested that the drug release rate was strongly influenced by the type of polymer and concentration of polymer. To analyze the release mechanism zero order, Higuchi model and Kosmeyer -Peppas model were used. The use of simplified methodology is demonstrated to evolve unified mathematical model.26 Kumar G. et al. formulated Hydrogel matrix tablets of Acarbose using hydroxypropyl methyl cellulose and guar gum with the aim to study of release kinetics and to attain a near zero order release. In-vitro dissolution studies were carried out using USP type 2 dissolution test apparatus. The release of drug followed a typical Higuchian pattern. Matrix tablets formulated employing hydroxypropyl methyl cellulose and guar gum slow release of Acarbose over a period of 12 h and were found suitable for maintenance portion of oral controlled release tablets. Acarbose release from these tablets was diffusion controlled and followed zero order kinetics after a lag time of 1h. 27


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RELATED TO BILAYER TABLETS:

Shiyani B. et al. formulated bi-layer tablets of Metoclopramide Hydrochloride (MTH) and Ibuprofen (IB). MTH was formulated as immediate release layer by using various disintegrants like Ac-Di-Sol, Polyplasdone XL, Explotab, Agar and Gellan Gum. IB was formulated as sustained release layer using hydrophilic matrix [hydroxy propyl methyl cellulose (HPMC K4M)].28 Atram SC. et al. developed an optimized bilayer tablet for antihypertension patients using Metoprolol succinate and Amlodipine besylate as model drug candidates by optimization technique. A 32 factorial design was employed in formulating bilayer tablet with individual release layers i.e. sustained release layer and immediate release layer. The independent variables selected both cases HPMC(X1), Starch 1500 (X2) and SSG (X1), MCC (X2), respectively. Two dependent variables were considered: t50 (Y1), Q1 (Y2) and t50 (Y1), Q2 (Y2), respectively. The main effect and interaction terms were quantitatively evaluated using mathematical model. Bilayer tablets were evaluated for thickness, hardness, friability, drug content and in vitro dissolution studies. The drug release of Amlodipine besylate and Metoprolol succinate depicted non-fickian diffusion and Super Case II transport mechanism, respectively.29 Amrutkar JR. et. formulated bilayer tablet of Metformin Hydrochloride and Gliclazide. Sustained release layer of Metformin Hydrochloride as an immediate layer of Gliclazide was optimized separately and then constituted in bilayer tablets. Hydrogenated castor oil and HPMC K100m polymers were used in combination as matrix forming agent for sustaining Metformin release. Effect of these polymers concentration andDEPERTMENT OF PHARMACEUTICS, NARGUND COLLEGE OF PHARMACY Page 37


different diluents were studied. Effect was evaluated by swelling studies and dissolution studies of prepared matrix formulations. f2 value was taken as basis to optimize the sustained release formula. Drug to polymer ratio (125:1:4) with lactose monohydrate as a diluent to showed better performance among all and shows Higuchi model as the best suited. Sodium starch glycolate at the concentration range of 16 % gives fastest disintegration i.e. in 17 sec.30 Kulkarni A. et al. formulated bilayer floating tablets comprising two layers, i.e. Lovastatin as immediate release and Atenolol as controlled release layers. The immediate release layer comprised sodium starch glycollate as a super disintegrant and the sustained release layer comprised HPMC K100M and xanthan gum as the release retarding polymers. Sodium bicarbonate was used as a gas generating agent. Direct compression method was used for formulation of the bilayer tablets. All formulations floated for more than 12 h. More than 90% of lovastatin was released within 30 min. HPMC K100M and xanthan gum sustained the release of atenolol from the controlled release layer for 12h.31 Patra CN. et al. developed a bilayer tablet of propranolol hydrochloride using superdisintegrant sodium starch glycolate for the fast release layer and water immiscible polymers such as ethylcellose, Eudragit RLPO and Eudragit RSPO for the suataining layer. In vitro dissolution studies were carried out in a USP 24 apparatus . The formulations gave a initial burst effect to provide the loading dose of the drug followed by sustained release for 12 h from the sustaining layer of matrix embedded tablets. In vitro dissolution kinetics followed the Higuchi model via a non-Fickian diffusion controlled release mechanism after the initial burst release. FT-IR studies revealed that there was no interaction between the drug and polymers used in the study. Statistical


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analysis (ANOVA) showed no significant difference in the cumulative amount of drug release after 15 min, but significant difference (p < 0.05) in the amount of drug released after 12 h from optimized formulations was observed.32 Ramesh et al. developed bilayered sustained release matrix tablets of Metformin HCl (SR) 1000mg and Pioglitazone HCl 15mg. The tablets were prepared using sodium carboxymethylcellulose (SCMC) and Hydroxypropyl Methyl Cellulose [HPMC K4M & HPMC (15cps)] as bio-adhesive polymers and cross carmellose sodium to act as an impermeable backing layer. The physico-chemical property of the finished product complies with the in-house specifications of Micro Labs Limited. The formulations gave an immediate release effect followed by sustained release for 8 h which indicates bimodel release of Metformin HCl from the matrix tablets. The data obtained were fitted into Higuchis models. Analysis of n values of Korsmeyer equation indicated that the drug release involved both diffusional and dissolutional mechanisms.33 Arunachalam A. et al. formulated and evaluated bilayer sustained release tablets of Metoprolol Succinate and Telmisartan. The combination of these two drugs in a single dosage form will enhance the patient compliance and prolong cardiovascular system. Various polymers, such as hydroxypropyl methylcellulose K4M (HPMC- K4M), hydroxy propyl methylcellulose K100M (HPMC- K100M), MCC pH102, Lactose DCL 11, Bronopol, were studied. The HPMC K4M was found to be best in controlling the release. The tablets were prepared by Direct Compression method and the prepared blend and tablets were evaluated for their physicochemical properties and in-vitro dissolution studies were carried out for all the bi-layered tablets developed using USP dissolution apparatus type 2 (paddle). It was found that the tablet F1-F6 showed 50% release ofDEPERTMENT OF PHARMACEUTICS, NARGUND COLLEGE OF PHARMACY Page 39


Metoprolol succinate in first hour and the remaining was released for eight hours. However, Telmisartan was found to be released as per the USP specifications.34 Gohel MC. et al. formulated the bilayer tablets containing paracetamol as immediate release and diclofenac sodium as modified release. A 2 3 full factorial design was adopted using the amount of polyethylene glycol, microcrystalline cellulose and crospovidone as independent variables for fabricating paracetamol tablets. Diclofenac sodium tablets were prepared using hydroxypropyl methylcellulose as a matrixing agent. The results of analysis of variance showed that the friability of paracetamol was distinctly influenced by the formulation variables. The in vitro drug release behaviour of diclofenac sodium tablets was compared with a marketed formulation. The optimized formulations of paracetamol and diclofenac sodium were used for the manufacturing of bilayer tablets. 35 Mehul P. et al. studied the challenges in the formulation of bilayered tablets. Several pharmaceutical companies are currently developing bilayer tablets, for a variety of reasons: patent extension, therapeutic, marketing to name a few. To reduce capital investment, quite often existing but modified tablet presses are used to develop and produce such tablets. This article explains why the development and production of quality bilayer tablets needs to be carried out on purpose-built tablet presses to overcome common bilayer problems, such as layer-separation, insufficient hardness, inaccurate individual layer weight control, cross-contamination between the layers, reduced yield, etc. Using a modified tablet press may therefore not be the best approach in producing a quality bilayer tablet under GMP-conditions, especially when high production output is required. 36


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Remya PN. et al. developed a formulation of bilayer tablets of ibuprofen and methocarbamol using povidone K-30 as the binder. The basic aim of any bilayer tablet formulation is to separate physically or chemically incompatible ingredients and to produce repeat action or prolonged action tablet. A total number of nine formulations have been taken to optimize and develop a robust and stable formulation. Wet granulation process was used for the formulation of both layers and the final film coated tablets were evaluated for the thickness, weight variation, hardness, friability, disintegration time, dissolution study. Among the formulations tablets of formulation -8 was taken as optimized formula due to its higher rate of dissolution and compiled all the other parameters with the official specifications.37


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4. METHODOLOGY 4.1 Plan of Work: 1. Design of bilayer tablets formulations: sustained release (layer ) by wet granulation method and immediate release (layer ) by direct compression. 2. Drug-excipient compatibility studies by IR. 3. Evaluation for the precompression parameters of the formulations prepared by both direct and wet granulation method: Bulk density Tapped density Angle of repose Carrs index Hausners ratio 4. Evaluation of bilayer tablets formulations: Physical appearance Hardness and friability Drug content uniformity In vitro dispersion time In vitro dissolution rate 5. Short-term stability studies for the selected formulations.


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4.2 Materials and equipments: Table no.1 Materials used with their company name. Sr.No Materials 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 Metformin Hydrochloride Acarbose Sodium CMC Dibasic Calcium Phosphate Hydroxy Propyl Methylcellulose (HPMC K4M) Hydroxy Propyl Methylcellulose (HPMC 15 cps) Povidone (PVP K-30) Colloidal Silicon Dioxide (Aerosil-200) Croscarmellose Sodium (Primellose) Talc Magnesium Stearate Sunset yellow Low substituted Hydroxy Propyl Cellulose(L-HPC) Butyl Hydroxy Anisole (BHA) Butyl Hydroxy Toluene (BHT) Anhydrous Lactose DCL 15 Manufacturer/Supplier Wanbury Ltd, India. Huadong Medicine co.Ltd. Pioma Chemicals, India. Sudeep pharma Ltd, India. Shin Etsu Chemicals Co, Ltd. Feicheng Ruitai Fine Chem, Ltd. BASF Ltd, Germany. Cabot Sanmar Ltd, India. DMV Fonterra excipients, Ltd. Prakash & Co, Ltd. Amishi Drugs & Chemicals, India. Roha Chemicals, India. Shin-Etsu chemicals Co, Ltd. Lobha Chemicals. Merck Limited. DMV Fonterra excipients, Ltd.


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4.3 Drug Profile: 1) METFORMIN HYDROCHLORIDE: 2, 38 Therapeutic category: Hypoglycaemic Structure:

Fig no. 8 Chemical structure of Metformin Hydrochloride

Metformin hydrochloride (N, N dimethyl imidodicarbo nimidic diamide hydrochloride) Molecular formula: C4H11N5.HCl Molecular weight: 165.62. Description: White to off-white crystalline compound. Appearance: White crystals. Solubility: Freely soluble in water, slightly soluble in alcohol, practically insoluble in acetone and in methylene chloride. Melting point: 222oc to 226oc Water: Not more than 0.5%.DEPERTMENT OF PHARMACEUTICS, NARGUND COLLEGE OF PHARMACY Page 44


Dose: 500mg to 3000mg (3g) daily, in divided doses. Usual strengths: 500 mg; 850 mg. Mechanism of Action: Metformin is an anti-hyperglycemic agent which improves glucose tolerance in patients with type 2 diabetes, lowering both basal and postprandial plasma glucose. Its pharmacologic mechanisms of action are different from other classes of oral antihyperglycaemic agents. Metformin decreases hepatic glucose production, decreases intestinal absorption of glucose, and improves sensitivity by increasing peripheral glucose uptake and utilization. Pharmacodynamics: Absorption: Metformin is rapidly absorbed from the gastrointestinal tract and give adequate plasma levels. Indications: Monotherapy for adults with Type 2 Diabetes Mellitus, where non pharmacological treatment like controlled diet, weight reduction and exercise have failed to control blood sugar levels. Metformin is especially useful if the patient is obese, as it helps to reduce weight however, there is no contraindication to the use of the drug in patients who are not overweight, as it helps to normalize weight and blood sugar levels rather than reduce it below normal. It may be added as a co-prescription with Sulphonylureas, Glitazones and or Insulin, where the latter when given alone failed to control hyperglycemia.


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Dosage and administration: For treatment of Type 2 Diabetes mellitus uncontrolled by diet alone. For Monotherapy Oral dosage for adults: Initially, Metformin 250 mg to 500 mg is given twice daily with the meal. Metformin 1000mg formulation should be given for higher dosage requirement. In order to monit0r the response to treatment, an estimation of blood glucose levels should be carried out at regular intervals, if adequate glycemic control is not achieved with the maximum dose of Metformin 4000 mg. Similarly, in those who do not have adequate glycemic control with maximum dosages of insulin secretagogues like Sulphonyureas or glitazones, it can be added and the dosage of all oral hypoglycemic agents treated as per individual requirement with proper blood glucose monitoring. Adults and Elderly If there is no adequate response after 4 weeks of the maximum dose of Metformin as described in monotherapy without adequate response consider the gradual addition of an oral Sulphonylurea. If after 1-3 months of concominants therapy, responses are unsatisfactory, consider insulin therapy and discontinuation of insulin secretagogues if required. Contraindications: Renal disease/dysfunction; Serum Creatinine Level 1.5 mg/dl as a result of, cardiovascular shock, acute myocardial infraction, septicemia, congestive heart failure requiring pharmacological treatment.DEPERTMENT OF PHARMACEUTICS, NARGUND COLLEGE OF PHARMACY Page 46


Do not administer Metformin in patients who have known Metformin hypersensitivity. Use Metformin with caution in the elderly. Metformin is substantially excreted by the kidney and the risk of adverse reactions is greater in patients with reduced renal function. Because aging is associated with decline in renal function, care should be taken with dose selection and titrations. Metformin is classified in FDA as pregnancy risk category B. Drug interactions Vitamin B12 absorption is retarted by Metformin. Metformin absorption is increased by Nifedipine. Metformin activity is increased by ACE inhibitors, salicylates, NSAIDs. Metformin action is decreased by Thiazide diuretics, Progestins, Estrogens, Oral contraceptives, phenytoin, Quinolones. Adverse reactions Metformin is usually well tolerated. The most common side-effect is minor gastrointestinal disturbance, which is often self-liminting or minimized by lowering the dose. Lactic acidosis has occurred but is very rare, and is usually due to a specific contraindicated state rather than the drug. In patients with metabolic acidosis, even if there is an evidence of ketoacidosis it must be stopped and the condition treated as a medical emergency. It does not lower blood sugar levels in non-diabetics when used as a monotherapy. Weight loss often occurs during therapy and levels of serum cholesterol, triglycerides and pre--lipoproteins may be lowered.


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2) ACARBOSE: 2, 38 Therapeutic category: Oral Hypoglycaemic, - glucosidase inhibitor. Structure:

Fig no. 9 Chemical Structure of Acarbose O-4, 6-Dideoxy-4-[[(1S, 4R, 5S, 6S)-4, 5, 6-trihydroxy-3-(hydroxymethyl) cyclohex-2enyl]amino]--D-glucopyranosyl-(14)-O- pyranose. Molecular formula: C25H43NO18 Molecular weight: 646.0 Description: White or yellowish amorphous powder hygroscopic compound. Appearance: White amorphous powder. Solubility: Very soluble in water, soluble in methanol, practically insoluble in methylene chloride. Melting point: 90oc to 105oc Water: Not more than 4%. Dose: 25mg 3 times daily, increasing to 100mg 3 times a daily. Usual strengths: 25 mg, 50mg and 100mg.DEPERTMENT OF PHARMACEUTICS, NARGUND COLLEGE OF PHARMACY Page 48

-D-glucopyranosyl

-(14)-D-gluco-


Mechanism of Action: Acarbose is a - glucosidase inhibitor, it reduces intestinal absorption of starch, dextrin and disaccharides by inhibiting the action of intestinal brush broder glucosidase. Acarbose inhibits alpha-glucosidase enzymes in the brush border of the small intestines and pancreatic alpha-amylase. Pancreatic alpha-amylase hydrolyzes complex starches to oligosaccharides in the lumen of the small intestine, whereas the membrane-bound intestinal alpha-glucosidases hydrolyze oligosaccharides,

trisaccharides, and disaccharides to glucose and other monosaccharides in the small intestine. Inhibition of the enzyme - glucosidase slows the absorption of carbohydrates. Less glucose is absorbed because the carbohydrates are not broken down into glucose molecules. In diabetic patients, the short-term effect of these drug therapies is to decrease current blood glucose levels and the long-term effect is a reduction in HbA1c level. This reduction averages an absolute decrease of 0.7%, which is a decrease of about 10% in typical HbA1c values in diabetes studies. - glucosidase inhibitors can have profound effects on hemoglobin A1c (HbA1c) levels in severely hyperglycemic type 2 DM patients. However, in patients with mild to moderate hyperglycemia, the glucose-lowering potential of - glucosidase inhibitors (assessed by hemoglobin A1c levels) is about 30% to 50% of that of other oral antidiabetic agents. - glucosidase inhibitors do not stimulate insulin release and therefore do not result in hypoglycemia. These agents may be considered as monotherapy in elderly patients or in patients with predominantly postprandial hyperglycemia.


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- glucosidase inhibitors typically are used in combination with other oral antidiabetic agents and/or insulin. The drugs should be administered at the start of a meal. They are poorly absorbed. Acarbose is an oral a-glycosidase inh

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