WO2005060942A1

WO2005060942A1 - Extended release pharmaceutical composition of metformin

Info

Publication number: WO2005060942A1
Application number: PCT/IB2004/004330
Authority: WO
Inventors: Ashish Gogia; Shaik Srinivasa Rao; Saravanan Kannu Samy; Sivakumaran Meenakshisunderam
Original assignee: Aurobindo Pharma Ltd
Priority date: 2003-12-19
Filing date: 2004-12-20
Publication date: 2005-07-07

Abstract

The present invention relates to an extended release dosage form for highly water soluble antidiabetic drug metformin or its pharmaceutically acceptable salts. This invention also relates to methods for preparing the concerned extended release dosage form for metformin or its pharmaceutically acceptable salts systems.

Description

EXTENDED RELEASE PHARMACEUTICAL COMPOSITION OF METFORMIN Field of the invention The present invention relates to an extended release dosage form for highly water soluble antidiabetic drug metformin or its pharmaceutically acceptable salts. This invention also relates to methods for preparing the concerned extended release dosage form for metformin or its pharmaceutically acceptable salts systems. Background of the invention Metformin hydrochloride is an oral antidiabetic and is a biguanide derivative (1,1-dimethylbiguanide monohydrochloride). Metformin tablets containing metformin hydrochloride are marketed under the trade name Glucophage and Glucohpage XR (extended release). Metformin hydrochloride has intrinsically poor permeability in the lower portion of the gastrointestinal tract leading to absorption almost exclusively in the upper part of the gastrointestinal tract. Its oral bioavailability is in the range of 40 to 60% decreasing with increasing dosage, which suggests some kind of saturable absorption process, or permeability/transit time limited absorption. It also has a very high water solubility (>300 mg/ml at 25 °C), this can lead to difficulty in providing a slow release rate from a formulation and problems in controlling the initial burst of drug from such a formulation. These two difficulties are further compounded by the high unit dose usually required for metformin hydrochloride. A further problem with highly water-soluble drugs to be formulated into a controlled release dosage form is that a significant and variable burst of the drag can occur from these systems. The burst of a highly water-soluble drug is the initial rapid release of drug that occurs from oral controlled release dosage forms when first contacting fluid, such as gastric fluids, prior to release controlling mechanisms of the dosage form establishing themselves and a stable release rate being provided. Hydration of any polymer matrix used to formulate the dosage form is a prerequirement of establishing a stable release rate. Thus, a readily hydrating polymer is required to establish the desired stable release rate. However, if the polymer used is slow to hydrate, then an undesirable variable burst can occur. Typical prior art techniques for creating a controlled release oral dosage form would involve either matrix systems or multi particulate systems. Matrix systems may be formulated by homogeneously mixing drug with hydrophilic polymers, such as hydroxypropylmethylcellulose, hydroxypropylcellulose, polyethylene oxide, carbomer, certain methacrylic acid derived polymers, sodium alginate, or mixtures thereof and compressing the resultant mixture into tablets. Hydrophobic polymers, such as ethyl cellulose, certain polymeric methacrylic acid esters, cellulose acetate butyrate, poly(ethylene-co-vinyl- acetate) may be uniformly incorporated with the above materials to give additional control of release. A further alternative involves embedding drug within a wax-based tablet, by granulation or simply mixing of drug with a wax, such as carnauba wax, microcrystalline wax or commercially available purified fatty acid esters. US patent 6,340,475 discloses a controlled release oral dosage form for metformin, where the said dosage form comprises a solid polymeric matrix with metformin dispersed therein. US patent 6,033,685 discloses a tablet for the controlled release of an active agent comprising (a) a matrix layer comprising an active agent embedded in a non-swelling, non-erodible hydrophobic matrix; (b) a first barrier layer applied to a single face of the matrix layer; and (c) an optional second barrier layer laminated to the opposite face of the matrix layer; wherein the matrix layer comprises up to about 80% active agent and from about 5% to about 80% by weight of nonswellable waxes or polymeric material insoluble in aqueous medium, and the first and second barrier layers independently comprise (1) polymeric material exhibiting a high degree of swelling and gelling in aqueous medium or (2) nonswellable wax or polymeric material insoluble in aqueous medium. US 6,475,521 and 6,660,300 discloses a pharmaceutical formulation comprising (1) an inner solid particulate phase, and (2) an outer solid continuous phase in which particles of the inner solid particulate phase are dispersed and embedded, the particles of the inner solid particulate phase comprising (a) a pharmaceutical having a high water solubility selected from metformin or a pharmaceutically acceptable salt thereof; and (b) an extended release material, and the outer solid continuous phase comprising an extended release material, wherein the total extended release material content in both the inner solid particulate phase and the outer solid continuous phase is within the range from about 25 to about 75% by weight of the pharmaceutical formulation. US 6,524,618 describes an extended-release matrix formulation capable of being directly compressed into tablets comprising (a) about 30 to about 60% of metformin hydrochloride having a particle size of about 150 to about 600 microns, (b) one or more pharmaceutically acceptable polymers selected from the group consisting of polyethylene oxide, hydroxypropyl cellulose, hydroxyethyl cellulose and ethyl cellulose (c) about 5 to about 40% of a pharmaceutically acceptable insoluble filler; (d) about 0.1 to about 3% by weight a glidant; and (e) about 0.1 to about 3% by weight a acceptable lubricant. US 2004/0161461 and US 20030170302 describes an extended release pharmaceutical tablet comprising: (i) a core comprising by weight, based on the core weight, about 70% to about 99% metformin and pharmaceutically acceptable excipients; and (ii) a coating surrounding said core, wherein said coating is permeable to metformin, said extended release tablet exhibiting a dissolution profile such that after about 2 hours, from about 7% to about 60% of the metformin is released; after about 4 hours, from about 15% to about 90%) of the metformin is released; after about 8 hours, from about 50% to about 100% of the metformin is released; after about 12 hours, more than about 75% of the metformin is released. US 2003/0187074 describes an oral delivery system for the treatment of non-insulin dependent diabetes mellitus in humans for the controlled release of a biguanide or pharmaceutically acceptable salt thereof, comprising: a pharmaceutically effective amount of a biguanide or pharmaceutically acceptable salt of the biguanide; and a water-insoluble polymeric carrier comprising a water-insoluble polymer; wherein the delivery system provides a pH-independent, controlled release of the biguanide or pharmaceutically acceptable salt of the biguanide over an extended period of time. US Patent 5,955,106 discloses a composition comprising metformin as the active substance and a hydrocolloid forming retarding agent, wherein the pharmaceutical composition has a residual moisture content of about 0.5-3% by weight. US patent 6,576,259 discloses a sustained release formulation for tacrolimus or its hydrate in a solid base, where the solid base is selected from a group consisting of water-soluble polymer and a wax. WO 03/011255 discloses a gastric retention controlled drag delivery system comprising : (a) a controlled release core comprising a drag, a highly swellable polymer and a gas generating compound, said core being capable of swelling and achieving floatation rapidly while maintaining its physical integrity in gastrointestinal fluids for prolonged periods, and (b) a rapidly releasing coat composition comprising the same drag as in the core and pharmaceutically acceptable excipients, wherein the coating composition surrounds the core such that the system provides a biphasic release of the drag in gastrointestinal fluids. This publication discloses a biphasic extended release dosage form comprising core and coating the core and provides for immediate release and extended release of the drug, which makes the process costlier and complex. By providing relatively constant, controlled drug delivery, these systems avoided the overdose and the under dose effects. These improvements provided effective medication with reduced side effects, and achieved these results with reduced dosing frequency. Most extended-release forms are designed so that the administration of a single dosage unit provides the immediate release of an amount of drag that promptly produces the desired therapeutic effect and also a gradual and continual release of additional amounts of drug to maintain this level of effect over an extended period of time to overcome frequent or multiple dosing. In this type of dosage form, the design is based on the particular qualities of each individual drug. In the case of Metformin HC1, which is a very highly soluble drug, it is imperative to control the release in order to obtain a controlled release formulation. Other advantages of extended-release products are reduced side effects and increased patient convenience. These advantages relate to the fact that extended-release preparations are designed to maintain the blood concentration of the drag at a desired level over a prolonged period of time thereby reducing the frequency of dosing and thus ensuring patient compliance. While continuing our efforts to develop extended release formulations of metformin, the inventors of the present invention found that monophasic floating based dosage forms comprising a matrix of polymer and carbonate resulted in comparatively similar in vitro dissolution profiles. Floating or buoyant systems are designed to have a low density and thus float on gastric contents after administration until the system either disintegrates (and presumably the resultant particles empty from the stomach) or the device absorbs fluid to the point where its density is such that it loses buoyancy and can pass more easily from the stomach with a wave of motility responsible for gastric emptying. Objective of the invention The object of the present invention is to prepare monophasic extended release pharmaceutical dosage forms of poorly compressible drag, metformin which will have adequate hardness and good reproducibility that releases the drug in a controlled manner over an extended period of time. Yet another objective of the present invention is to provide monophasic extended release dosage form, which is uncoated, simple and economic.

Summary of the invention Accordingly, the present invention provides an extended release monophasic dosage form of metformin or its pharmaceutically acceptable salts comprising a matrix of polymer and carbonate and one or more pharmaceutically acceptable excipients. The present invention also relates to a process for the preparation of an extended released dosage form of metformin using a matrix of polymer and carbonate which comprises preparing a matrix of polymer and carbonate and mixing metformin or its pharmaceutically acceptable salt, with the matrix and optionally with fillers, disintegrants in rapid mixer granulator and granulating the resulting blend with solution of binder in aqueous or non aqueous solvent, drying the granules, lubricating the dried granules with lubricants compressing the lubricated blend to form extended release tablets. Detailed description of the invention The floating system predominantly depends upon the principle of buoyancy and thus contains one or more of the gas/effervescence generating components like the carbonates, bicarbonates or the acids in the composition. When the floating based dosage forms reaches the stomach, water permeates into these dosage forms and triggers the releε -~~^ι~— ^■*^< — ^{* Λ}~ ^e — ⁺¹ generating components. Once the gas generation starts the floating based dosage forms will start experiencing less bulk density than the gastric fluids and so remains buoyant in the stomach for a prolonged period of time. While the system is floating on the gastric contents the drag is released slowly at the desired rate from the system. The extended release dosage forms of the present invention are monophasic and uncoated which releases the drug for prolong period of time. The extended release dosage forms of the present invention comprises drug and a matrix of polymer and carbonate in the ratio of 1 : 0.1 to 1 : 1.2. The extended release dosage forms of the present invention comprises drag and carbonate in the ratio of 1 : 0.01 to 1 : 0.3. The extended release dosage form of the present invention further comprises wax material. The term pharmaceutically acceptable excipients as used in this invention comprise binders, dispersing agents, fillers, lubricants or glidants and the like. The disintegrating agent used in accordance with the present invention is selected from crosscarmellose sodium, crosspovidone, sodium starch glycolate, sodium carboxymethyl cellulose, hydroxypropyl cellulose, xanthan gum, alginic acid, alginates, carbopols and the like or combination thereof. The diluents used according to the present invention are selected from calcium phosphate-dibasic, cellulose-microcrystalline, cellulose powdered, calcium silicate, polyols such as mannitol, sorbitol, xylitol, maltitol, sucrose and combinations thereof. Suitable binders according to the present invention are selected from methylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, povidone, copovidone, gelatin, gum arabic, ethyl cellulose, polyvinyl alcohol, starch, pregelatinized starch, agar, tragacanth, sodium alginate. Suitable lubricants according to the present invention are selected from talc, magnesium stearate, stearic acid, zinc state, sodium lauryl sulfate, sodium stearyl fumarate, hydrogenated vegetable oil, glyceryl behenate and suitable glidants include colloidal silicon dioxide or talc, preferably colloidal silicon dioxide. Suitable polymers according to present invention are selected from hydrophilic polymers such as polyvinylpyrrolidone; alginate or its salts; cellulose polymer such as hydroxypropylmethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose phthalate, methylcellulose, carboxymethyl cellulose sodium, hydroxyethyl cellulose and the like; polyethylene oxide, carbopol, pectin, cyclodextrins, galactomannan, polyethylene glycol (PEG) and hydrophobic polymers such as ethyl cellulose, methacrylate copolymers (for example, Eudragits such as Eudragit E, R, S, RS, LD, etc.) or amino methacrylate copolymers and combination thereof. The presence of carbonate in the present invention is playing a pivotal role in controlling the release of metformin hydrochloride to the optimum level by imparting a degree of hydrophobic nature to the dosage form. Moreover carbon dioxide liberates from the carbonates on interaction with the gastro intestinal fluids, thereby providing the buoyant nature to the dosage form by reducing the apparent specific gravity of the dosage form, thus resulting in the prolonged gastric retention of the dosage form. The different carbonates that can be used for the carbonate-polymer matrix can be selected from-calcium carbonate, sodium carbonate, magnesium carbonate, barium carbonate and zinc carbonate. Suitable waxes according to the present invention are selected from the following groups without limitations on the usage of other group waxes- glycerin monostearate and sucrose fatty acid esters [for example, mono-, di- or triesters of sucrose with moderate to higher fatty acids, with 8 to 20 carbon atoms, for example caprylic acid, capric acid, lauric acid, myristic acid, palmitic acid, stearic acid, arachic acid, behenic acid, oleic acid, linoleic acid, and the like). Additional examples of wax include polyglycerin fatty acid ester; glyceryl behenate, hydrogenated vegetable oil and the like.

The present invention provides a simple, non-complex and more economic process for the preparation of an extended release dosage form, which comprises the steps of : i) sifting metformin hydrochloride, polymers and carbonate and other optionally fillers, disintegrants, ii) mixing the sifted material of step (i) in a rapid mixer granulator, iii) granulating the blend of step (ii) with a binder in a solvent, iv) drying the wet mass of step (iii) in a fluid bed drier, v) milling the dried granules using multimill, vi) optionally mixing the dried granules with disintegrants and filler vii) lubricating the blend of step (vi) with lubricants and vi) compressing the lubricated blend of step (vii) to get extended release tablets of metformin. The following examples further exemplify the inventions and are not intended to limit the scope of the inventions. It is obvious to those skilled in the art to find out the composition for other dosage forms and substitute the equivalent excipients as described in this specification or with the one known to the industry.

Example 1

Ingredient Qty/tablet [%w/w] Metformin Hydrochloride 40-50

Hydroxy propyl methyl Cellulose 10-30

Hydroxy propyl cellulose 1-9

Sodium Alginate 1-16 Ammonio methacrylate copolymer 1-10

Microcrystalline Cellulose 0.5-9

Calcium Carbonate 2-25

Polyvinyl Pyrrolidone 0.5-8

Croscarmellose Sodium 1-12

Polyethylene oxide 1-18

Sodium bicarbonate 0.5-12

Magnesium stearate 0.5-14 Total 100

i) sifted metformin hydrochloride, hydroxypropylmethyl cellulose, hydroxypropyl cellulose, sodium alginate, ammonio methacrylate copolymer, microcrystalline cellulose, calcium carbonate ii) the sifted material of step (i) are mixed well in rapid mixer granulator iii) the blend of step (ii) was granulated with a solution of polyvinyl pyrrolidone in isopropyl alcohol iv) the wet mass of step (iii) was dried in a fluid bed drier, v) the dried granules are milled using multimill vi) the dried granules are mixed with crosscarmellose sodium, polyethylene oxide and sodium bicarbonate in an octagonal blender, vii) the blend obtained in step (vi) was lubricated with magnesium stearate and vi) the lubricated blend of step (vii) is compressed into metformin hydrochloride extended release tablets. Dissolution data for the carbonate-polymer matrix system

"F2" is similarity factor used to compare multipoint dissolution profiles

The similarity factor F₂ as defined by FDA [food and drag administration, USA] and EMEA [European agency for evaluation of medicines, EUROPE] is a logarithmic reciprocal square root transformation of one plus the mean squared (the average sum of squares) differences of drug percent dissolved between the test and reference products: f₂ = 50 x log ■ 1 + OO

Where n is the number of dissolution time points, and R_t and T_t are the reference and test dissolution values (mean of at least 12 dosage units) at time t. Example 2

Example 3

The processing steps that are involved in making extended release tablets comprising metformin, polymer and carbonate given below example 2 and 3 : i) sifted metformin hydrochloride, hydroxypropylmethyl cellulose, carbomer 941, polyethylene oxide, calcium carbonate, microcrystalline cellulose, ii) the sifted material of step (i) are mixed well in rapid mixer granulator iii) the blend of step (ii) was granulated with a solution of povidone and copovidone in isopropyl alcohol iv) the wet mass of step (iii) was dried in a fluid bed drier, v) the dried granules are milled using multimill and lubricated with magnesium stearate and vi) the lubricated blend of step (v) is compressed into metformin hydrochloride extended release tablets.

Dissolution data for the carbonate-polymer matrix system

Claims

We claim :

1. An extended release monophasic dosage form of metformin or its pharmaceutically acceptable salts comprising a matrix of polymer and carbonate and one or more pharmaceutically acceptable excipients. 2. The extended release dosage form as claimed in claim 1, wherein the drag and a matrix of polymer and carbonate is present in the ration of 1 : 0.1 to 1 : 1.

2.

3. The extended release dosage form as claimed in claim 1, wherein the drug and carbonate is present in the ration of 1 : 0.01 to 1 : 0.3

4. The dosage form as claimed in claim 1, wherein the one or more pharmaceutically acceptable excipients are selected from binders, dispersing agents, fillers, lubricants or glidants.

5. The dosage form as claimed in claim 1, wherein the polymer is selected from polyvinylpyrrolidone; alginate or its salts; cellulose polymer such as hydroxypropylmethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose phthalate, methylcellulose, carboxymethyl cellulose sodium, hydroxyethyl cellulose and the like; polyethylene oxide, carbopol, pectin, cyclodextrins, galactomannan, polyethylene glycol (PEG) and hydrophobic polymers such as ethyl cellulose, methacrylate copolymers or amino methacrylate copolymers and combination thereof.

6. The dosage form as claimed in claim 1, wherein the carbonate is selected calcium carbonate, sodium carbonate, magnesium carbonate, barium carbonate and zinc carbonate.

7. The dosage form as claimed in claim 4, wherein the disintegrating agent used in accordance with the present invention is selected from crosscarmellose sodium, crosspovidone, sodium starch glycolate, sodium carboxymethyl cellulose, hydroxypropyl cellulose, xanthan gum, alginic acid, alginates, carbopols and the like or combination thereof.

8. The dosage form as claimed in claim 4, wherein the filler is selected from calcium phosphate-dibasic, cellulose-microcrystalline, cellulose powdered, calcium silicate, polyols such as mannitol, sorbitol, xylitol, maltitol, sucrose and combinations thereof.

9. The dosage form as claimed in claim 4, wherein the binder is selected from methylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, povidone, copovidone, gelatin, gum arabic, ethyl cellulose, polyvinyl alcohol, starch, pregelatinized starch, agar, tragacanth, sodium alginate and ammmonio methacrylate copolymer and combination thereof.

10. The dosage form as claimed in claim 4, wherein the lubricant is selected from talc, magnesium stearate, stearic acid, zinc state, sodium lauryl sulfate, sodium stearyl fumarate, hydrogenated vegetable oil, glyceryl behenate and suitable glidants include colloidal silicon dioxide or talc, preferably colloidal silicon dioxide.

11. The extended release dosage form as claimed in claim 1, further comprises wax material.

12. The extended release dosage form as claimed in claim 1, which floats in the gastric fluid.

13. A process fort the preparation of an extended release dosage form, which comprises the steps of : i) sifting metformin hydrochloride, polymers and carbonate and other optionally fillers, disintegrants, ii) mixing the sifted material of step (i) in a rapid mixer granulator, iii) granulating the blend of step (ii) with a binder in a solvent, iv) drying the wet mass of step (iii) in a fluid bed drier, v) milling the dried granules using multimill, vi) optionally mixing the dried granules with disintegrants and filler vii) lubricating the blend of step (vi) with lubricants and vi) compressing the lubricated blend of step (vii) to get extended release tablets of metformin.

14. Use of an extended release dosage form of metformin or its pharmaceutically acceptable salts as claimed in any of the preceding claims 1- 12, for the treatment of diabetes.

15. A method for the treatment of diabetes comprising an extended release dosage form of metformin or its pharmaceutically acceptable salts as claimed in claims 1-12.