WO2010136847A1

WO2010136847A1 - Coated metformin with pioglitazone solution

Info

Publication number: WO2010136847A1
Application number: PCT/IB2009/052200
Authority: WO
Inventors: Farhad Farshi; Recep Avci; Hasan Samuk; Serdar Soylemez; Fikret Koc; Erhan Koc
Original assignee: Abdi Ibrahim Ilac Sanayi Ve Ticaret Anonim Sirketi
Priority date: 2009-05-26
Filing date: 2009-05-26
Publication date: 2010-12-02
Also published as: TR201202048T2

Abstract

The present invention relates to coating of biguanide antihyperglycaemic agents (such as metformin hydrochloride) with solution of insulin sensitizers (such as thiazolidinediones; pi- oglitazone hydrochloride).

Description

Title of Invention: COATED METFORMIN WITH PI- OGLITAZONE SOLUTION

[1] The present invention relates to coating of biguanide antihyperglycaemic agents

(such as metforminhydrochloride)with solution of insulin sensitizers (such as thiazo- lidinediones ; pioglitazone hydrochloride).

[2] Metformin / Pioglitazone combination product saled under the brand name

Compectact™ is prepared by separate granulation of pioglitazone and metformin and tabletting thereof.

[3] Since the ratio of Metformin / Pioglitazone differs as 850mg /15 mg homogeneity problem may arise . This is especially the case when the particle size of actives and ex- cipients differs considerably. Another impact on dissolution is the very spare solubility of Pioglitazone HCl especially as crystalline particles.

[4] To solve above mentioned technical problems coating of metformin with pioglitazone solution approach is applied oursides. But this is not an easy task since pioglitazone HCl is insoluble in many pharmaceutically suitable solvents and if soluble vast amounts of solvent is needed for this purpose, which is not suitable for coating purposes.Trying some organic solvents showed none of them has enough completely dissolving capacity. After a series of trial and evaluation of the aspects we invented that using an acid is very helpful to diminish solvent amounts used to dissolve Pioglitazone HCl. We further found that adding water to organic solvent acid mixture further diminishes total amount of solvent used to dissolve Pioglitazone. Preferably Pioglitazone HCl is dissolved in a water miscible organic solvent / water/ acid mixture. More preferably Pioglitazone HCl is dissolved in Ethanol /water /diluted HCl in suitable proportions of the participant solvents to achieve a clear solution with suitable amount of total solvent used. Using less solvent amount is important due to shortening coat spraying times, saving solvent and such economical reasons. Using vast amounts of solvent would have also an effect on the dissolution and tabletting properties of the composition since Metformin HCl is fairly soluble in most organic solvents and water which would affect the consistency.

[5] The presence of phenyl ether and thiazolidinone groups in the molecule alleviate solution by adding further acid.

[6] EP 0 861 666 discloses that excipients are added to the active component or components and the resulting composition is compressed. Where necessary, the compressed product is coated, by the per se known technique, for masking the taste or for enteric dissolution or sustained release ( page 2, 0020) . EP 0 861 666 does not disclose that coating of metformin with pioglitazone hydrochloride solution.

[7] EP 1 231 918 claims a pharmaceutical composition characterized by thiazo- lidinedione and metformin hydrochloride are each dispersed within its own pharmaceutically acceptable carrier in the pharmaceutical composition. EP 1 231 918 points out that polyvinyl pyrollidone (or PVP) is particularly effective as a binder for use with metformin hydrochloride. However use of PVP informulations of pioglitazone destabilizes pioglitazone and impacts on stability. Therefore EP 1 231 918 delinetaes pioglitazone and metformin hydrochloride are each dispersed within its own pharmaceutically acceptable carrier in the pharmaceutical composition. EP 1 231 918 does not disclose coating of metformin with pioglitazone hydrochloride solution.

[8] EP 1 552 832 discloses a preparation coated with pioglitazone hydrochloride so as to obtain proper dissolution property of pioglitazone hydrochloride . In EP 1 552 832 , it is described that coating of metformin tablets with pioglitazone hydrochloride which is in dispersion form. All of the examples and claims explain coating of metfomin tablets with pioglitazone hydrochloride. It is not disclosed that coating of metformin with pioglitazone hydrochloride solution. In example 1, polyvinylpyrrolidone , polyethylene glycol 6000 and pioglitazone hydrochloride were dispersed in ethanol to give a coating solution (page 8, line 25). However it is only a dispersion process, there is no dissolving of pioglitazone namely it is not a solution since pioglitazone hydrochloride is not dissolved alone in ethanol. Thus process of EP 1 552 832 is only relevant to dispersions not dissolving.

[9] There is a need different approach from the prior art to create pharmaceutical compositions of pioglitazone and metformin.

[10] One aspect of this invention is coating of biguanide antihyperglycaemic agent with thiazolidinedione solution. Thiazolidinedione may be pioglitazone or its salts (preferable hydrochloride), rosiglitazone or its salt (preferable maleate) or any other thiazolidinedione.Biguanides may be phenformin, metformin, buformin, or a salt thereof (e.g., hydrochloride, fumarate, succinate) etc. Preferredbiguanide is metformin or a salt thereof (preferably metformin hydrochloride). Pharmaceutical formulations and combinations may contain further active ingredients along with them.

[11] Pioglitazone hydrochloride solution comprising ;

[12] (i) an inorganic acid or mixtures of inorganic acids or,

[13] (ii)anorganicacidor mixtures of organic acids or,

[14] (iii) mixtures of organic acids and inorganic acids or,

[15] (iv) mixture of an organic acid and an inorganic acid .

[16] - an organic solvent or mixtures of organic solventsand

[17] - optionally de-ionized water and,

[18] - optionally binder or binders. [19] Pioglitazone hydrochloride solution may further include suitable excipients. The character of the solution isinsulin sensitizer is completelydissolved.

[20] Organic solvents, used in preparation of solution are ,but not limited to, alcohols such as methanol, ethanol, propyl alcohol, isopropyl alcohol, 2-methyl-l-propanol etc. ; ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone etc. ; esters such as methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, ethyl formate etc. ; hydrocarbons such as heptane ; halogenated hydrocarbons such as dichloromethane. The organic solvent is preferably an alcohol and more preferably methanol, ethyl alcohol, propyl alcohol, isopropyl alcohol and the so on. Ethyl alcohol is mostly preferred. Organic solvents can be used alone or in combination with water.

[21] Preferable examples of organic acids are formic acid, acetic acid, fumaric acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, p- toluenesulfonic acid .

[22] Preferable examples of inorganic acid is hydrochloric acid which is in the form of solution in water.

[23] Mixtures of organic solvents may also be used. Using of mixtures of organic solvents can be in an appropriate ratio. Mixtures may contain water.

[24] The percentages pioglitazone / water / organic solvent / hydrochloric acideis critical due to poor solubility of pioglitazon hydrochloride and need for low solution amount. The solution comprising insulin sensitizer is in the range of from 0.01 % to 9.00 % , water is in the range of from 00.00 % to 70 %, organic solvent or mixtures of organic solvents are in the range of from 20 % to 75 %, acid or mixtures of acids are in the range of from 0.05 % to 50 % by weight, binder or mixtures of binders are are in the range of from 5 % to 35.

[25] Weight of acid is based on real amount of said acid.

[26] The binder, which is used in preparation solution, may be, but not limited to, starch, polyethyleneglycol, microcrystalline cellulose, hydroxypropyl cellulose, hydrox- ypropylmethyl cellulose,carboxymethylcellulose, sodium alginate,ethylcellulose, polyvinylpyrrolidone, pregelatinized starch, gelatin or mixtures thereof. Preferred binder is polyethyleneglycol or povidone or mixtures thereof .

[27] The solution can also be prepared without binder or mixtures of binders.

[28] It is important to completely dissolve Pioglitazon HCl in the granulation solution to surround the metformin hydrochloride particles.

[29] The pioglitazone hydrochloride solution of the present invention may contain further excipient or excipients.

[30] This invention describes coating particles of biguanide antihyperglycaemic agent with thiazolidinedione solution. On the other hand this invention embraces every kind of particles which include particles of biguanide antihyperglycaemic agent. It means that direct compression (DC) forms of biguanide antihyperglycaemic agent may also be used. DC forms are available on the market. In case of using DC forms of biguanide antihyperglycaemic agent , biguanide antihyperglycaemic agent particles adhere to other excipient or excipients. Of course, instead of receiving DC forms , biguanide antihyperglycaemic agent may be granulated with suitable excipient or excipients and then thiazolidinedione solution coating may be administered according to this invention .Particles of biguanide antihyperglycaemic agent alone may also be coated . Coexisting particles ,whatsoever, of biguanide antihyperglycaemic agent with other excipient or excipients can be coated according to this invention. Compressed dosage forms of biguanide antihyperglycaemicagent or pellets and dosage forms prepared by using this pellets of biguanide antihyperglycaemic agent can also becoated.

[31] In another aspect this invention embraces a method of coating of biguanide particles with thiazolidinedione solution.

[32] Method of coating has following steps ;

[33] (a) Ethyl alcohol, de-ionized water and hydrochloric acid are mixed in a solution tank.

[34] (b) Polyethyleneglycol or povidone or any other selected binder or mixtures thereof may be added to the solvent mixture slowly by continuous stirring.

[35] (c) The solution is mixed and checked for completely dissolving and if not continued to stir.

[36] (d) Pioglitazon Hydrochloride is added to solution and mixed . The solution checked for completely dissolving and if not continued to stir.

[37] (e) Metformin Hydrochloride is layed on the bed.

[38] (f)The prepared solution of Pioglitazon Hydrochloride is sprayed onto the Metformin

Hydrochloride particles in fluid bed or any other suitable vehicle .

[39] Steps set out above from a to f are called as Phase A in subjacent sections of this application.

[40] The present inventors have also invented that pharmaceutical formulation includes coating of metformin particles with pioglitazone hydrochloride solution shows same or identical and suitable dissolution properties when compared to reference (Competact™) product .

[41] According to this invention, pharmaceutical formulation exhibits a dissolution profile which has similarity factor (f2) of at least 50 to 100 in dissolution environments when compared to the reference (Competact ™ ) dissolution profile. Preferred dissolution mediums are 0.1 NHCI, pH 2.5, pH 4.5 and pH 6.8 . Dissolution tests are performed by a USP Method II - Paddle method at 37⁰C, 50 rpm,900 ml. As an exemplary dissolution profile in pH 2.5 medium is given (Figure 1).

[42] Another aspect of this invention is to provide pharmaceutical formulations. Pharma- ceutical formulations may be in the form of such as tablet, bilayer or trilayer tablet, caplet, capsule, granule, powder etc. These forms may be a controlled release, immediately release , sustained release, modified release and the like. Formulations may include excipients as disintegrants, binders, lubricants, coloring agents, pH regulators, surfactants, stabilizers, flavours, coating agents and the like . Pharmaceutical formulations should contain both at least a biguanide antihyperglycaemic agent and at least a thiazolidinedione agent. Further active pharmaceutical ingredient may be present in formulations and combinations.

[43] Disintegrants are such as but not limited to carboxymethyl cellulose, calcium car- boxymethyl cellulose, sodium carboxymethyl starch, modified starches, sodium starch glycolate, croscarmellose sodium, crospovidone, hydroxypropyl cellulose et. Preferred disintegrant is croscarmellose sodium.

[44] Binders are such as but not limited to starch, microcrystalline cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, sodium alginate,ethylcellulose, polyvinylpyrrolidone, pregelatinized starch, gelatin or mixtures thereof, etc. Preferred binder is microcrystalline Cellulose .

[45] Fillers are lactose, microcrystalline cellulose, silicified microcrystalline cellulose, powdered cellulose, calcium carbonate, dibasic calcium phosphate, tribasic calcium phosphate, sucrose, glucose, dextrates, dextrins, dextrose, fructose, lactitol, mannitol, sorbitol, starch or mixtures thereof. Preferred filler is lactose.

[46] Lubricants are magnesium stearate, magnesium lauryl sulphate,sodium stearyl fumarate, polyethylene glycol, stearic acid, colloidal silicon dioxide or mixtures thereof. Preferred lubricant is magnesium stearate

[47] The coating agent that can be used includes, for instance, ethylcellulose, hydrox- ymethylcellulose, polyethylene glycol, cellulose acetate phthalate, hydroxypropyl- methylcellulose phthalate, and Eudragit. Coating may further contain an excipient, for example, titanium oxide, talc, ferric oxide and the like. As a coating agent multifunction ingredient such as Opadry ® White YS-1R-7002 can also be used.

[48] In yet another aspect of this invention is to provide a preparation method of pharmaceutical formulation. The preparation of pharmaceutical formulation's steps are called as Phase B in this application. Phase B has following steps ;

[49] (a) Obtained granules from phase A are dried.

[50] (b) The prepared granules are sieved and blended with extra- granular excipients; such as lactose, microcrystalline cellulose and croscarmellose sodium.

[51] (c)The blended powder is lubricated by magnesium stearate or such excipients and compressed

[52] (d) Core tablets are coated with a suspension of Opadry ® white YS-lR-7002in de- ionized water. [53] (e) Film coated tablets are packaged.

[54] According to this invention, generally, in pharmaceutical formulations, metformin hydrochloride is from 70 to 90 %, pioglitazone hydrochloride is from 1 to 5 % , binder is from 5 to 15 %, filler is from 1 to 5 %, disintegrant is from 2 to 10 %, lubricant is from 0,1 to 5 %, coating agent is from 0.5 to 5 % by the total weight of the pharmaceutical formulation.

Claims

[Claim 1] A pharmaceutical composition includesat least both a biguanide antihy- perglycaemic agent and an insulin sensitizer characterized in that; (i) particles of biguanide antihyperglycaemic agent or (ii) granulated particles of biguanide antihyperglycaemic agent with an excipient or excipients or

(iii) ready for direct compression particles of biguanide antihyperglycaemic agent or

(iv) coexisting particles of biguanide antihyperglycaemic agent with other excipient or excipients or

(v)compressed dosage forms of biguanide antihyperglycaemic agent or (vi) pellets and dosage forms prepared by using this pellets of biguanide antihyperglycaemic agent are coated with insulin sensitizer solutionwherein insulin sensitizer is completely dissolved.

[Claim 2] As claimed in claim 1, insulin sensitizer solution comprising;

(a) an insulin sensitizer and

(b) an acid or mixtures of acids

(c) an organic solvent or mixtures of organic solvents and,

(d) optionally water and

(e) optionally a binder or mixtures of binders.

[Claim 3] As claimed in claim 2, the solution comprising insulin sensitizer is in the range of from 0.01 % to 9.00 % , water is in the range of from 00.00 % to 70 %, organic solvent or mixtures of organic solvents are in the range of from 20 % to 75 %, acid or mixtures of acids are in the range of from 0.05 % to 50 % by weight, binder or mixtures of binders are are in the range of from 5 % to 35.

[Claim 4] As claimed in claim 3, weight of acid is based on real amount. [Claim 5] As claimed in claim 2, organic solvent is selected from group consisting of methanol, ethanol, propyl alcohol, isopropyl alcohol, 2-methyl-l-propanol, acetone, methyl ethyl ketone, methyl isobutyl ketone, methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, ethyl formate, heptane, dichloromethane or mixtures thereof.

[Claim 6] As claimed in claim 2, an acid or mixtures of acids are (i) an inorganic acid or mixtures of inorganic acids or, (ii) an organic acid or mixtures of organic acids or, (iii) mixtures oforganic acids and inorganic acids or, (iv) mixture of an organic acid and an inorganic acid .

[Claim 7] As claimed in claim 6, organic acid is selected from group consisting of formic acid, acetic acid, fumaric acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, p-toluenesulfonic acid or mixtures thereof.

[Claim 8] As claimed in claim 6, inorganic acid is hydrochloric acid solution. [Claim 9] As claimed in claim 1, insulin sensitizer is thiazolidinedione [Claim 10] As claimed in claim 9, thiazolidinedione is pioglitazone hydrochloride. [Claim 11] As claimed in claim 1, biguanide antihyperglycaemic agent is metformin or its salts

[Claim 12] As claimed in claim 11, metformin is metformin hydrochloride [Claim 13] As claimed in claim 2 ,binder is selected from group consisting of starch, polyethyleneglycol, microcrystalline cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose,carboxymethylcellulose, sodium alginate,ethylcellulose, polyvinylpyrrolidone, pregelatinized starch, gelatin or mixtures thereof.

[Claim 14] As claimed in claim 1, to obtain a pharmaceutical composition , a preparation method of coating having steps of ;

(a) organic solvent or mixtures of organic solvents, de-ionized water and acid or mixtures of acids are mixed .

(b) binder or mixtures of binders are added to the solvent mixture slowly by continuous stirring.

(c) the solution is mixed and checked for completely dissolving

(d) insulin sensitizer is added to solution and mixed until completely dissolving

(e) biguanide antihyperglycaemic agent is layed on the bed

(f) the prepared solution of insulin sensitizer is sprayed onto the particles of biguanide antihyperglycaemic agent .

[Claim 15] As claimed in claim 1, pharmaceutical formulation is prepared by a method having following steps ;

(a) obtained granules from phase said in claim 14 are dried.

(b) the prepared granules are sieved and blended with extra-granular excipients

(c)the blended powder is lubricated and compressed by a tabletting machine.

(d) core tablets are coated with a suspension of film coating agent (Opadry ®) in de-ionized water.

(e) film coated tablets are packaged. [Claim 16] As claimed in claim 1, pharmaceutical composition comprising ;

(a) at least both a biguanide antihyperglycaemic agent and at least an insulin sensitizer and

(b) disintegrant or disintegrants and (c)binder or binders and

(d) filler or fillers and

(e) lubricant or lubricants and

(f) film coating agent or film coating agents

[Claim 17] As claimed in claim 16 , film coating agent is Opadry ® White YS- 1R-7002 [Claim 18] As claimed in claim 16, pharmaceutical formulation comprising metformin hydrochloride is from 70 to 90 %, pioglitazone hydrochloride is from 1 to 5 % , binder is from 5 to 15 %, filler is from 1 to 5 %, disintegrant is from 2 to 10 %, lubricant is from 0,1 to 5 %, coating agent is from 0.5 to 5 % by the total weight of the pharmaceutical formulation.

[Claim 19] As claimed in claim 16, disintegrant is selected from group consisting of carboxymethyl cellulose, calcium carboxymethyl cellulose, sodium carboxymethyl starch, modified starches, sodium starch glycolate, croscarmellose sodium, crospovidone, hydroxypropyl cellulose or mixtures thereof.

[Claim 20] As claimed in claim 16, binder is selected from group consisting of starch, microcrystalline cellulose, hydroxypropyl cellulose, hydrox- ypropylmethyl cellulose, sodium alginate,ethylcellulose, polyvinylpyrrolidone, pregelatinized starch, gelatin or mixtures thereof

[Claim 21] As claimed in claim 16, filler is selected from group consisting of lactose, microcrystalline cellulose, silicified microcrystalline cellulose, powdered cellulose, calcium carbonate, dibasic calcium phosphate, tribasic calcium phosphate, sucrose, glucose, dextrates, dextrins, dextrose, fructose, lactitol, mannitol, sorbitol, starch or mixtures thereof.

[Claim 22] As claimed in claim 16, lubricant is selected from group consisting of magnesium stearate, magnesium lauryl sulphate,sodium stearyl fumarate, polyethylene glycol, stearic acid, colloidal silicon dioxide or mixtures thereof .

[Claim 23] As claimed in claim 1, pharmaceutical formulation exhibits a dissolution profile which has similarity factor (f2) of at least 50 to 100 in dissolution environments when compared to the reference (Compectact

™ ) dissolution profile. [Claim 24] As claimed in claim 23, dissolution mediums are 0.1 NHCI, pH 2.5, pH

4.5 and pH 6.8 . [Claim 25] As claimed in claim 23 and 24, dissolution tests are performed by a

USP Method II - Paddle method at 37⁰C, 50 rpm,900 ml.