DE102009053562A1 - Pharmaceutical composition, useful for treating diabetes mellitus type 2 in a combination therapy with other antidiabetic agent, comprises rosiglitazone succinate as an active agent - Google Patents

Abstract

Pharmaceutical composition comprises rosiglitazone succinate as an active agent. An independent claim is also included for preparing a tablet, comprising: (i) preparing granules containing rosiglitazone succinate and excipients, (ii) preparing a tablet mixture containing the granules of step (i) and optionally excipients, (iii) pressing the tableting mixture, and optionally, (iv) applying a film coating on the tablet core obtained in step (iii); or (a) providing a powdered mixture containing rosiglitazone succinate and excipients, (b) pressing the powdered mixture, and optionally (c) applying a film coating on the tablet core obtained in step (b). ACTIVITY : Antidiabetic. No biological data given. MECHANISM OF ACTION : None given.

Description

The present invention relates to the salt of succinic acid with rosiglitazone (rosiglitazone succinate) as the active ingredient and pharmaceutical compositions containing this active ingredient, in particular tablets.

The preparation of rosiglitazone, ie 5- (4- [2- (N -methyl-N- (2-pyridyl) amino) ethoxy] benzyl) -2,4-thiazolidinedione is described in Example 30 of EP-A-0 306 228 described. Rosiglitazone is used as a salt of maleic acid, wherein rosiglitazone and maleic acid in a molar ratio of 1: 1, respectively, ie as rosiglitazone maleate under the trade name Avandia ^® in the strengths of 2 mg, 4 mg, and 8 mg based on the free base of rosiglitazone as Film tablet for the treatment of diabetes mellitus type 2 marketed. The active ingredient combination Rosiglitazonmaleat / glimepiride containing film-coated tablets of the strengths 4 mg / 1 mg, 4 mg / 2 mg, 8 mg / 2 mg, 4 mg / 4 mg and 8 mg / 4 mg, wherein the amount indicated for the rosiglitazone maleate on the free base are sold under the trade names Avandaryl ^® and Avaglim ^® . In addition, the combination rosiglitazone maleate / metformin hydrochloride film-coated tablets of the strengths of 2 mg / 1000 mg, 4 mg / 1000 mg, 1 mg / 500 mg, 2 mg / 500 mg and 4 mg / 500 mg, wherein the amount indicated for the rosiglitazone maleate on refers to the free base, marketed under the trade name Avandamet ^® for the treatment of diabetes mellitus type. 2 Rosiglitazone is an insulin sensitizer, ie an antidiabetic agent that increases the sensitivity of tissue to insulin.

It is known that rosiglitazone is poorly soluble in water. To increase the solubility of rosiglitazone in an aqueous medium, beats WO 94/05659 to use pharmaceutically acceptable acid addition salts of rosiglitazone as an active ingredient, in particular the salt of tartaric acid or maleic acid with rosiglitazone. Furthermore, in the prior art, salts of rosiglitazone with D - (-) - tartaric acid ( WO 02/12234 ), Fumaric acid ( WO 02/20517 ), Oxalic acid ( WO 2006/010345 ) and sulfuric acid ( EP-A-1 967 182 ) proposed. Also revealed WO 01/44240 the salt of rosiglitazone with a base, e.g. As the lithium, sodium, potassium or magnesium salt of rosiglitazone. The aforementioned acid addition salts are usually prepared by reacting rosiglitazone with the acid in a suitable reaction medium, while in the preparation of the alkali metal or alkaline earth metal salts of rosiglitazone, the latter is deprotonated with an alkali metal or alkaline earth metal base.

As another possibility, the solubility of rosiglitazone in an aqueous medium, e.g. B. in a physiological environment, and thus to improve the bioavailability of the drug suggests WO 03/045945 to micronize rosiglitazone or a pharmaceutically acceptable salt thereof and to adjust an average particle size (D50) of 500 nm to 5 μm. In order to agglomeration of the micronized drug particles in the subsequent further processing to a pharmaceutical composition, for. As tablet, it is proposed to achieve the micronization by wet grinding a rosiglitazone or a pharmaceutically acceptable salt thereof containing suspension, wherein the suspension is a surfactant as a stabilizer, eg. As sodium lauryl sulfate containing.

Revealed on the other side WO 2008/074097 in that the solubility of rosiglitazone or a pharmaceutically acceptable salt thereof in an aqueous medium and the bioavailability of the active substance are sufficiently high if an average particle size (D50) of from 5 μm to 20 μm was chosen for the particle size of the active substance.

Thus, it is apparent from the prior art that the solubility of rosiglitazone in an aqueous release medium can be increased by selecting a suitable pharmaceutically acceptable salt thereof and adjusting a suitable particle size to ultimately improve the bioavailability of the active ingredient.

Furthermore, it is off EP-A-1 854 794 It is known that rosiglitazone maleate may contain as an impurity an addition product of rosiglitazone to the CC double bond of maleic acid, which may also be referred to as "2- (rosiglitazonyl) butanedioic acid". This impurity may form during the manufacture of the active ingredient, its further processing into a pharmaceutical composition or storage thereof.

In view of the above-described prior art, it is an object of the present invention to provide a rosiglitazone-containing pharmaceutical composition wherein the active ingredient is to have a sufficiently high storage stability and solubility in an aqueous release medium.

This object is achieved by the subject matter specified in the claims.

It has been found that the salt of succinic acid with rosiglitazone, wherein rosiglitazone and succinic acid (butanedioic acid) are present in a molar ratio of 1: 1, in an aqueous release medium, e.g. In a physiological environment, has good solubility and, moreover, is more stable to the maleic acid salt due to the lack of C-C double bond in succinic acid. The present invention thus relates to the salt of succinic acid with rosiglitazone (rosiglitazone succinate).

The rosiglitazone succinate is obtained in a conventional manner by contacting the free base rosiglitazone with succinic acid in a reaction medium and then isolating the salt formed. Thus, as in Examples 1 and 2 of WO 94/05659 described, the rosiglitazone and succinic acid are dissolved in ethanol under heating to reflux, the rosiglitazone succinate during slow cooling of the solution and optionally storage at 0-5 ° C for several hours fails. Subsequently, the salt is replaced by z. B. Filtration and dried. But other solvents are suitable for the above reaction, for. For example, n-propanol, isopropanol, acetone, acetonitrile, tetrahydrofuran and mixtures of the above organic solvents with water.

The present invention also relates to a pharmaceutical composition containing the salt of succinic acid with rosiglitazone as active ingredient. Usually, the pharmaceutical composition according to the invention for oral administration is provided, although they are also parenteral z. B. can be administered in the form of an injection. Particularly suitable pharmaceutical compositions according to the present invention are solid dosage forms for oral administration, such as tablets and capsules, preferably film-coated tablets.

In a preferred embodiment, the composition according to the invention contains the rosiglitazone succinate in an amount corresponding to an amount of 1 mg to 12 mg, preferably 2 mg, 4 mg or 8 mg, rosiglitazone.

It has surprisingly been found that the solubility of rosiglitazone succinate in an aqueous release medium is sufficiently high that the composition according to the invention also has bioavailability for the non-micronized active ingredient as found for the marketed film-coated tablet containing rosiglitazone maleate. Usually, the average particle size (D50) of the active ingredient is equal to or more than 5 μm, preferably 10 μm to 100 μm, more preferably 20 μm to 80 μm and even more preferably 30 μm to 50 μm. The particle size can be determined by the commonly used methods, for. B. by laser diffraction with a Malvern Mastersizer S.

• i) Herstellen eines Granulats, enthaltend Rosiglitazonsuccinat und pharmazeutisch verträgliche Hilfsstoffe,
• ii) Herstellen einer Tablettiermischung, enthaltend das Granulat aus Schritt (i) und gegebenenfalls pharmazeutisch verträgliche Hilfsstoffe,
• iii) Verpressen der Tablettiermischung und gegebenenfalls
• iv) Aufbringen eines Filmüberzugs auf den in Schritt (iii) erhaltenden Tablettenkern.

The pharmaceutical composition of the invention is preferably a tablet or film-coated tablet obtainable by wet granulation, dry granulation or direct tabletting. Accordingly, the present invention also relates to a method for producing a tablet, comprising the steps:

• i) preparing a granulate containing rosiglitazone succinate and pharmaceutically acceptable auxiliaries,
• ii) preparing a tableting mixture comprising the granules from step (i) and, if appropriate, pharmaceutically acceptable auxiliaries,
• iii) pressing the tabletting mixture and optionally
• iv) applying a film coating to the tablet core obtained in step (iii).

In a particularly preferred embodiment, the granules in step (i) are prepared by wet granulation, it being possible to use water, an alcohol such as ethanol or isopropanol, and mixtures of the abovementioned solvents as the granulating liquid. In addition, the granulation optionally a binder z. As polyvinylpyrrolidone (povidone), hydroxypropylmethylcellulose (hypromellose) or hydroxypropyl cellulose.

In a particularly preferred embodiment, the granulating liquid contains an organic acid. In fact, it has been found that the rate of dissolution of the active ingredient rosiglitazone succinate in an aqueous medium increases if the active ingredient has been granulated in the presence of an organic acid. An organic acid in the sense of the present invention is a substance that is soluble in water and contains a carboxyl group (-CO ₂ H). As examples of an organic acid, mention may be made of acetic acid, oxalic acid, tartaric acid, succinic acid, fumaric acid, maleic acid, citric acid and ethylenediaminetetraacetic acid.

• i) Bereitstellen einer Pulvermischung, enthaltend Rosiglitazonsuccinat und pharmazeutisch verträgliche Hilfsstoffe,
• ii) Verpressen der Pulvermischung, und gegebenenfalls
• iii) Aufbringen eines Filmüberzugs auf den in Schritt (ii) erhaltenden Tablettenkern.

In addition, the present invention relates to a process for the preparation of the tablet according to the invention, which is a direct tabletting and comprises the steps:

• i) providing a powder mixture containing rosiglitazone succinate and pharmaceutically acceptable auxiliaries,
• ii) pressing the powder mixture, and optionally
• iii) applying a film coating to the tablet core obtained in step (ii).

Fillers, disintegrants, flow control agents, lubricants, solubilizers and binders may be used as pharmaceutically acceptable excipients.

As fillers z. As cellulose powder, calcium diphosphate, various starches such. Corn starch, microcrystalline cellulose, silicified microcrystalline cellulose, calcium carbonate, calcium lactate, dextrose, lactose (anhydrous or as monohydrate), mannitol and the like.

As disintegrants, starch derivatives such. Carboxymethyl starch sodium, partially pregelatinised starch (Starch ^1500® ), which may also act as a binder, cross-linked polyvinylpyrrolidone (crospovidone), low-substituted sodium carboxymethylcellulose, cross-linked sodium carboxymethylcellulose (croscarmellose sodium), microcrystalline cellulose, low-substituted hydroxypropylcellulose and the like be used.

As a lubricant for improving the flow properties or the flowability, in particular highly disperse silica, z. For example, a colloidal, anhydrous silicic acid, magnesium trisilicate, cellulose powder, talc, tricalcium phosphate and the like can be used.

As the lubricant for reducing the friction between the components of the tableting mixture and the tabletting tool, stearic acid, magnesium stearate, polyethylene glycol (eg, PEG 4000-8000), talc, and the like can be used particularly.

As already stated above, organic acids can be incorporated as solubilizers for the active ingredient in the pharmaceutical composition according to the invention. In addition, other solubilizers may be included as pharmaceutically acceptable excipients in the composition of the invention, for. As surface-active pharmaceutical excipients, such as. As anionic, amphoteric and nonionic surfactants. An example of an anionic surfactant is sodium lauryl sulfate, and an example of a nonionic surfactant is poly (oxyethylene) sorbitan fatty acid ester (polysorbate). However, complexing agents such as cyclodextrins (eg β-cyclodextrin) and derivatives thereof can also be used as solubilizers in the pharmaceutical composition according to the invention.

As a binder z. As maltodextrin, sucrose, polyvinylpyrrolidone (Povidone), vinylpyrrolidone / vinyl acetate copolymer (copovidone), polyethylene glycol / polyvinyl alcohol graft polymer (z. B. Kollicoat ^® IR) are used.

In a particularly preferred embodiment, the tablet of the invention is a film-coated tablet, wherein the composition for the film-coating under the trade name Opadry ^® is marketed and ZB hydroxypropyl methylcellulose (hypromellose), macrogol, hydroxypropyl cellulose, polyvinyl alcohol, titanium dioxide and, if appropriate, dyes or pigments may contain.

The pharmaceutical composition according to the invention may additionally contain another antidiabetic agent. Preferably, the other antidiabetic is a sulfonylurea or a biguanide, e.g. Metformin or a pharmaceutically acceptable salt thereof (eg the hydrochloride salt). In a particularly preferred embodiment, the sulfonylurea is selected from acetohexamide, carbutamide, chlorpropamide, glimepiride, glibenclamide, gliclazide, glibornuride, glipizide, gliquidone, glisoxepid, glycopyramide, glycodiazine, metahexamide, tolbutamide and tolazamide. The other antidiabetic can z. B. together with the Rosiglitazonsuccinat and optionally pharmaceutically acceptable excipients filled into a capsule or pressed into a tablet (direct tabletting). Should the pharmaceutical composition of the invention be in the form of a tablet prepared by wet or dry granulation, the other antidiabetic agent may be both intragranular and extragranular.

As in WO 98/57634 with regard to the combination of rosiglitazone maleate / metformin hydrochloride, up to 3000 mg metformin hydrochloride per day may be administered for the treatment of type 2 diabetes mellitus. The pharmaceutical composition according to the invention can thus Metformin hydrochloride in an amount of 250 mg, 500 mg, 750 mg, 850 mg or 1000 mg. In another embodiment, the tablet of the invention may contain glimepiride in an amount of 1 mg, 2 mg or 4 mg.

In addition, the composition of the invention can be used in a combination therapy with another antidiabetic for the treatment of diabetes mellitus type 2. In a preferred embodiment, the composition contains rosiglitazone succinate and optionally metformin hydrochloride, and the other antidiabetic agent is a sulfonylurea, preferably glimepiride. In another preferred embodiment, the composition of the invention contains rosiglitazone succinate and optionally glimepiride, and the other antidiabetic agent is a biguanide, preferably metformin or a pharmaceutically acceptable salt thereof (eg the hydrochloride salt).

Examples

The following examples describe film-coated tablets prepared by conventional methods such as wet granulation (Examples 1-3, 6 and 7), dry granulation (Example 4) or direct tabletting (Example 5). example 1 ingredients Mass [mg] dry mix Rosiglitazonsuccinat 5.3 Lactose monohydrate 109.9 corn starch 30.0 granulating Povidone K 30 4.0 Purified water qs Tabletting mixture magnesium stearate 0.80 tablet core 150.0 coating Opadry ^® 4.0 tablet 154.0 Example 2 ingredients Mass [mg] dry mix Rosiglitazonsuccinat 5.3 Lactose monohydrate 66.5 Microcrystalline cellulose 65.2 Croscarmellose sodium 9.0 Povidone K 30 3.0 granulating Purified water qs Tabletting mixture magnesium stearate 1.0 tablet core 150.0 coating Opadry ^® 4.0 tablet 154.0 Example 3 ingredients Mass [mg] dry mix Rosiglitazonsuccinat 5.3 mannitol 133.4 Sodium starch 6.0 granulating Hypromellose E 5 4.5 Purified water qs Tabletting mixture magnesium stearate 0.8 tablet core 150.0 coating Opadry ^® 4.0 tablet 154.0 Example 4 ingredients Mass [mg] dry mix Rosiglitazonsuccinat 5.3 Lactose monohydrate 118.0 Partially pre-gelatinized starch (Starch 1500 ^® ) 20.0 Low-substituted hydroxypropyl cellulose 4.5 magnesium stearate 0.8 Tabletting mixture magnesium stearate 0.8 tablet core 150.0 coating Opadry ^® 4.0 tablet 154.0 Example 5 ingredients Mass [mg] Tabletting mixture Rosiglitazonsuccinat 5.3 Microcrystalline cellulose 99.9 Partially pre-gelatinized starch (Starch 1500 ^® ) 44.0 stearic acid 0.8 tablet core 150.0 coating Opadry ^® 4.00 tablet 154.00 Example 6 ingredients Mass [mg] dry mix Rosiglitazonsuccinat 5.3 mannitol 97.9 Microcrystalline cellulose 30.0 crospovidone 8.0 granulating povidone 4.0 Succinic acid 4.0 Purified water qs Tabletting mixture magnesium stearate 0.8 tablet core 150.0 coating Opadry ^® 4.0 tablet 154.0 Example 7 ingredients Mass [mg] Dry mix for complexation Rosiglitazonsuccinat 5.3 β-cyclodextrin 20.0 dry mix Rosiglitazonsuccinat-β-cyclodextrin 25.3 complex Lactose monohydrate 111.4 crospovidone 7.5 granulating hydroxypropyl 5.0 Purified water qs Tabletting mixture magnesium stearate 0.8 tablet core 150.0 coating Opadry ^® 4.0 Film-coated tablet. 154.0

QUOTES INCLUDE IN THE DESCRIPTION

This list of the documents listed by the applicant has been generated automatically and is included solely for the better information of the reader. The list is not part of the German patent or utility model application. The DPMA assumes no liability for any errors or omissions.

Cited patent literature

• EP 0306228 A [0002]
• WO 94/05659 [0003, 0011]
• WO 02/12234 [0003]
• WO 02/20517 [0003]
• WO 2006/010345 [0003]
• EP 1967182 A [0003]
• WO 01/44240 [0003]
• WO 03/045945 [0004]
• WO 2008/074097 [0005]
• EP 1854794A [0007]
• WO 98/57634 [0028]

Claims (15)

Pharmaceutical composition containing the salt of succinic acid with rosiglitazone (rosiglitazone succinate) as active ingredient. A composition according to claim 1, wherein the rosiglitazone succinate is contained in an amount corresponding to an amount of 1 mg to 12 mg, preferably 2 mg, 4 mg or 8 mg, rosiglitazone. A composition according to claim 1 or 2, wherein the average particle size (D50) of the active ingredient is equal to or more than 5 μm, and preferably 10 μm to 100 μm, more preferably 20 μm to 80 μm and even more preferably 30 μm to 50 μm. A composition according to any one of claims 1 to 3 in the form of a solid dosage form for oral administration. A composition according to claim 4 in the form of a tablet. A composition according to any one of claims 1 to 5, which additionally contains another antidiabetic agent. A composition according to claim 6, wherein the other antidiabetic agent is a sulfonylurea or a biguanide, preferably metformin or a pharmaceutically acceptable salt thereof (eg the hydrochloride salt). The composition of claim 7, wherein the sulfonylurea is selected from acetohexamide, carbutamide, chlorpropamide, glimepiride, glibenclamide, gliclazide, glibornuride, glipizide, gliquidone, glisoxepid, glycopyramide, glycodiazine, metahexamide, tolbutamide and tolazamide. A composition according to any one of claims 1 to 8 for the treatment of type 2 diabetes mellitus in a combination therapy with another antidiabetic agent. A composition according to claim 9 wherein the composition comprises rosiglitazone succinate and optionally metformin hydrochloride and the other antidiabetic agent is a sulfonylurea, preferably glimepiride. A composition according to claim 9, wherein the composition contains rosiglitazone succinate and optionally glimepiride, and the other antidiabetic agent is a biguanide, preferably metformin or a pharmaceutically acceptable salt thereof (eg the hydrochloride salt). Process for the preparation of a tablet according to claim 5, comprising the steps: i) preparing a granulate containing rosiglitazone succinate and pharmaceutically acceptable auxiliaries, ii) preparing a tableting mixture comprising the granules from step (i) and, if appropriate, pharmaceutically acceptable auxiliaries, iii) pressing the tabletting mixture, and optionally iv) applying a film coating to the tablet core obtained in step (iii). The method of claim 12, wherein the granules in step (i) are made by wet granulation. The method of claim 13, wherein the granules contain an organic acid as a pharmaceutically acceptable excipient, e.g. Succinic acid and / or ethylenediaminetetraacetic acid. Process for the preparation of a tablet according to claim 5, comprising the steps: i) providing a powder mixture containing rosiglitazone succinate and pharmaceutically acceptable auxiliaries, ii) pressing the powder mixture, and optionally iii) applying a film coating to the tablet core obtained in step (ii).