WO2011010316A1

WO2011010316A1 - Pharmaceutical compositions of irbesartan

Info

Publication number: WO2011010316A1
Application number: PCT/IN2009/000411
Authority: WO
Inventors: Bandi Parthasaradhi Reddy; Pothireddy Venkateswar Reddy; Muppidi Vanaja Kumari
Original assignee: Hetero Research Foundation
Priority date: 2009-07-20
Filing date: 2009-07-20
Publication date: 2011-01-27

Abstract

The present invention relates to a stable pharmaceutical composition comprising highly dosed irbesartan together with pharmaceutically acceptable excipients. Additionally, the composition may contain hydrochlorothiazide.

Description

PHARMACEUTICAL COMPOSITIONS OF IRBESARTAN

FIELD OF THE INVENTION

The present invention relates to the stable pharmaceutical composition comprising irbesartan or pharmaceutically acceptable salts thereof, alone or in combination with hydrochlorothiazide, and optionally one or more additional excipients.

BACKGROUND OF THE INVENTION

Irbesartan, a compound having the chemical name 2-butyl-3-[p-(o-1/-/- tetrazol-5-ylphenyl)benzyl]-1 ,3-diazaspiro[4.4]non-1-en-4-one, is a potent, long- acting angiotensin Il receptor is described in US Patent No.5, 270, 317.

Irbesartan is commercially available as 75mg, 150mg, or 300mg tablets, which are sold under the trade name AVAPRO.

The combination composition of irbesartan and hydrochlorothiazide is commercially available as 150/12.5 mg, 300/12.5mg, or 300/25 mg tablets, which are sold under the trade name AVALIDE.

U.S. patent No. 6,342,247, which is incorporated by reference, reported that, irbesartan is a fluffy material with relatively low bulk, and tapped densities. In addition, irbesartan has certain undesirable flow characteristics. These properties make it difficult to formulate a large amount of the drug into a small tablet. Indeed, the 6,342,247, patent describes an oral formulation of irbesatan containing only up to 70% of the drug.

US patent No. 5,994,348 describes a pharmaceutical composition which comprising about 20 to 70% irbesartan and about 2 to 33% hydrochlorothiazide based on total weight and composition being free povidone and poloxamer.

EP patent No. 167,461 describes oral pharmaceutical formulation of irbesartan in cellactose 80° and/or spary dried lactose is used as filling agent, prepared by wet granulation method with alcohol as wetting agent.

WO Patent Application Publication No. 2005/025566 oral pharmaceutical formulation of irbesartan that are prepared by wet granulation method with alcohol as a wetting agent.

EP Patent Application No.1 ,806, 130 describes a solid pharmaceutical formulation which contains irbesartan hydrochloride and optionally hydrochlorothiazide, mannitol, low-substituted hydroxypropylcellulose and at least one lubricant selected from macrogol, talc and hydrogenated castor oil.

EP Patent Application No. 1 ,750,862 describes a composition which contains greater than 70% w/w irbesartan, a binder and a surfactant.

US Patent Application No. 2005/271720 describes a composition which contains 75% w/w irbesartan.

All the above mentioned patents are incorporated by references.

lnspite of all the above disclosed formulations of irbesartan, still there is a need for an improved formulation of irbesartan that contains a higher amount of the active ingredient.

Thus an object of the present invention is to provide the pharmaceutical formulation of irbesartan, having small weight, good dissolution, good flow property, reliable and robust pharmaceutical composition, which enable to have a formulation without any difficulty.

Another object of the present invention is to provide the pharmaceutical formulation of irbesartan in combination with hydrochlorothiazide, having small tablet, good dissolution, good flow property, reliable and robust oral solid pharmaceutical composition, which enable to have a formulation without any difficulty.

DETAILED DESCRIPTION OF THE INVENTION

According to one aspect of the present invention, there is provided a pharmaceutical composition which comprises about 65% to about 85% irbesartan or pharmaceutically acceptable salts thereof, about 3% to about 40% microcrystalline cellulose or mannitol, about 0.25% to about 10% polyvinylpyrrolidone or hydroxy propyl cellulose, about 1 % to about 15% carboxymethyl cellulose calcium or dibasic calcium phosphate or crospovidone of the total weight of the pharmaceutical composition, and optionally one or more additional excipients.

The pharmaceutical composition of the present invention has been found to have small tablet, good dissolution, good flow property, reliable and robust pharmaceutical formulation in comparison with other pharmaceutical compositions.

Preferably, the pharmaceutical composition of the present invention which comprises about 71 % to about 74% irbesartan or pharmaceutically acceptable salts thereof, about 12% to about 25% microcrystalline cellulose or mannitol, about 0.5% to about 7% polyvinylpyrrolidone or hydroxy propyl cellulose, and about 2% to about 10% calcium carboxymethyl cellulose or carboxymethyl cellulose calcium or dibasic calcium phosphate or crospovidone of the total weight of the pharmaceutical composition, and optionally one or more additional excipients.

Excipient selection depends on various factors, such as, the choice of active ingredient percentage, the objectives of the pharmaceutical formulation development and method of manufacture. The foremost property an excipient must possess is compatibility with active ingredients.

Preferably, the pharmaceutical composition is oral solid dosage forms.

The pharmaceutical composition may be for example, in the form of a tablet, a caplet, a pellet, a capsule, granules, a pill, powder or a sachet.

Preferably the pharmaceutical composition is in the form of a tablet and a capsule. The capsule may contain powder, compressed powder or granules.

Still more preferably, the oral solid pharmaceutical composition is in the form of a tablet.

The additional excipients may be a filler agent, a disintegrant agent, a binder, a glidant and a lubricant.

Preferably, the filler includes microcrystalline cellulose, mannitol, dibasic calcium phosphate, calcium carbonate, lactose, magnesium carbonate, magnesium oxide, lactose anhydrous, isomalt, sorbitol or mixtures thereof and more preferably microcrystalline cellulose and/or mannitol.

Preferably, the lubricants includes magnesium stearate, calcium stearate, stearic acid, a salt of stearic acid, talc, sodium stearyl fumarate, glyceryl behenate, magnesium silicate, magnesium trisilicate, macrogol, talc, hydrogenated castor oil or mixtures thereof and more preferably magnesium stearate and/or calcium stearate.

Preferably, the disintegratrants includes carboxymethyl cellulose calcium, croscarmellose sodium, starch, sodium starch glycolate, crospovidone, carboxymethylcellulose sodium, magnesium aluminium silicate or mixtures thereof and more preferably carboxymethyl cellulose calcium and/or croscarmellose sodium.

Preferably, the glidant may be for example colloidal anhydrous silica, talc or mixtures thereof and more preferably colloidal anhydrous silica. Preferably, the binder includes polyvinylpyrrolidone k-30, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl cellulose (low- substituted), starch or mixtures thereof and more preferably polyvinylpyrrolidone k-30 and/or hydroxypropyl cellulose.

Preferably, the coating agent includes hydroxypropyl methyl cellulose, polyvinyl alcohols, hydroxypropyl cellulose, macrogols or mixtures thereof and more preferably hydroxypropyl methyl cellulose and/or polyvinyl alcohols.

Preferably, the coloring agent includes titanium dioxide, red iron oxide, yellow iron oxide, black iron oxides and mixture thereof.

Other ingredients such as stabilizers, antioxidants and antiadherants, conventionally used for pharmaceutical formulations may also be included in the present formulation.

The preferred embodiment of the invention is suitable for forming irbesartan tablet which comprising in parts by weight from about 65% to about 85% irbesartan or pharmaceutically acceptable salts thereof, from about 3% to about 40% microcrystalline cellulose or mannifol, from about 0.25% to about 10% polyvinylpyrrolidone or hydroxy propyl cellulose, from about 0.5% to about 10% carboxymethyl cellulose calcium or dibasic calcium phosphate or crospovidone, from about 0.125% to about 2% colloidal anhydrous silica, from about 0.25% to about 5% calcium stearate, from about 1.5% to about 3.5%. Optionally additional excipient/s may be used. The additional excipients include pharmaceutical lubricants, disintegrators, binders, glidants, fillers or mixtures thereof.

According to another aspect of the present invention, there is provided the process for preparing the pharmaceutical composition which comprises mixing about 65% to about 85% irbesartan or pharmaceutically acceptable salts thereof, about 3% to about 40% microcrystalline cellulose or mannitol, about 0.25% to about 10% polyvinylpyrrolidone or hydroxy propyl cellulose, blend about 1% to about 15% carboxymethyl cellulose calcium or dibasic calcium phosphate or crospovidone of the total weight of the pharmaceutical composition, and optionally one or more additional excipients.

Preferably, the pharmaceutical compositions prepared according to process of the invention is oral solid dosage forms. Preferably, the oral solid pharmaceutical composition prepared according to process of the invention may be for example, in the form of a tablet, a caplet, a pellet, a capsule, granules, a pill, powder or a sachet.

Still more preferably, the oral solid pharmaceutical composition is prepared in the form of a tablet.

It has been found that the pharmaceutical process of the present invention are physically stable to pharmaceutical unit operations such as compression, thereby making pharmaceutical composition of the present invention amenable to pharmaceutical compounding operations, such as for example, tabletting.

Preferably, the tablet compositions are prepared by the process of direct compression, wet granulation or slugging, more preferably wet granulation.

The tablet may be also optionally coated with a coating agent.

According to another aspect of the present invention, there is provided the pharmaceutical composition which comprises about 65% to about 85% irbesartan or pharmaceutically acceptable salts thereof in combination with hydrochlorothiazide, about 3% to about 40% microcrystalline cellulose or mannitol, about 0.25% to about 10% polyvinylpyrrolidone or hydroxyl propyl cellulose, about 1% to about 15% carboxymethyl cellulose calcium or dibasic calcium phosphate or crospovidone of the total weight of the pharmaceutical composition, and optionally one or more additional excipients.

Preferably, the pharmaceutical composition of the present invention which comprises about 71% to about 74% irbesartan or pharmaceutically acceptable salts thereof in combination with hydrochlorothizide, about 12% to about 25% microcrystalline cellulose or mannitol, about 0.5% to about 7% polyvinylpyrrolidone or hydroxy propyl cellulose, about 2% to about 10% calcium carboxymethyl cellulose or dibasic calcium phosphate or crospovidone of the total weight of the pharmaceutical composition, and optionally one or more additional excipients.

Preferably, the pharmaceutical composition is oral solid dosage forms.

Preferably, the glidant may be for example colloidal anhydrous silica, talc or mixtures thereof and more preferably colloidal anhydrous silica.

Preferably, the binder includes polyvinylpyrrolidone k-30, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl cellulose (low- substituted), starch or mixtures thereof and more preferably polyvinylpyrrolidone k-30 and/or hydroxypropyl cellulose.

Preferably, the coating agent includes hydroxypropyl methyl cellulose, polyvinyl alcohols, hydroxypropyl cellulose, macrogols or mixtures thereof and more preferably hydroxypropyl methyl cellulose and/or polyvinyl alcohols. Preferably, the coloring agent includes titanium dioxide, red iron oxide, yellow iron oxide, black iron oxides and mixture thereof.

Other ingredients such as stabilizers, antioxidants, and antiadherants, conventionally used for pharmaceutical formulations may also be included in the present formulation.

The preferred embodiment of the invention is suitable for forming irbesartan and hydrochlorothiazide tablet which comprising in parts by weight from about 65% to about 85% irbesartan or pharmaceutically acceptable salts thereof, from about 1% to about 10% hydrochlorothiazide, from about 3% to about 40% microcrystalline cellulose or mannitol, from about 0.25% to about 10% polyvinylpyrrolidone or hydroxy propyl cellulose, from about 0.5% to about 10% carboxymethyl cellulose calcium or dibasic calcium phosphate or crospovidone, from about 0.125% to about 2% colloidal anhydrous silica, from about 0.25% to about 5% calcium stearate, from about 1.5% to about 4% opadry. Optionally additional excipient/s may be used. The additional excipients include pharmaceutical lubricants, disintegrators, binders, glidents, fillers or mixtures thereof.

According to another aspect of the present invention, there is provided the process for preparing the pharmaceutical composition which comprises mixing about 65% to about 85% irbesartan or pharmaceutically acceptable salts thereof in combination with hydrochlorothiazide, about 3% to about 40% microcrystalline cellulose or mannitol, about 0.25% to about 10% polyvinylpyrrolidone or hydroxy propyl cellulose, blend about 1% to about 15% carboxymethyl cellulose calcium or dibasic calcium phosphate or crospovidone of the total weight of the pharmaceutical composition, and optionally one or more additional excipients.

Preferably, the pharmaceutical composition prepared according to the process of the invention is oral solid dosage forms.

Preferably, the oral solid pharmaceutical composition prepared according to the process of the invention may be for example, in the form of a tablet, a caplet, a pellet, a capsule, granules, a pill, powder or a sachet.

It has been found that the pharmaceutical process of the present invention are physically stable to pharmaceutical unit operations such as compression, thereby making oral solid dosage of the present invention amenable to pharmaceutical compounding operations, such as for example, tabletting.

Preferably, the tablet pharmaceutical compositions are prepared by the process of direct compression, wet granulation or slugging, more preferably wet granulation.

The tablet may be also optionally coated with a coating agent.

The pharmaceutical composition of the present invention may be used for the treatment of hypertension.

EXAMPLES

Example 1

Preparation of an irbesartan tablet:

The tablets were prepared using the materials listed in table.

The tablets of example 1 and 2 were manufactured using the procedure which comprising the following steps: irbesartan, microcrystalline cellulose was done in a rapid mixer granulator and mixed for 5 to 20 minutes. Binder solution

(polyvinylpyrrolidone in purified water) is added to contents of rapid mixer granulator and mixed to get dough mass. The dough mass was dried, and dried granules passed through #20.

The blending of ingredients including above dried granules, calcium carboxymethyl cellulose, colloidal anhydrous silica and calcium stearate were weighted, transferred into a blender, and mixed to form a homogeneous power mixture; the resultant mixture was compressed into tablets of appropriate weight and hardness to obtain an irbesartan tablet.

The results of dissolution of irbesartan tablets 300 mg is shown below.

The example demonstrates the dissolution properties of the tablet prepared in accordance with the invention.

The tablets of the irbesartan and commercially available irbesartan tablets (i.e. AVAPRO) were tested for in vitro drug release in 1000 ml of 0.1 N hydrochloric acid, USP-II apparatus and speed operating at 50 rpm. The values for dissolution of irbesartan were greater than 80% in 10 minutes in irbesartan tablets.

Irbesartan tablets stability studies:

Stability studies were carried out at 40°C/75%RH and 60⁰C for two month are found that tablet composition was stable.

Example 2

The tablets were prepared using the materials listed in table.

The tablets of example 3 were manufactured using the procedure which comprising the following steps: irbesartan, microcrystalline cellulose was done in a rapid mixer granulator and mixed for 5 to 20 minutes. Binder solution (polyvinylpyrrolidone in purified water) is added to contents of rapid mixer granulator and mixed to get dough mass. The dough mass was dried, and dried granules passed through #20.

The blending of ingredients including above dried granules, calcium carboxymethyl cellulose, colloidal anhydrous silica and calcium stearate were weighted, transferred into a blender, and mixed to form a homogeneous power mixture; the resultant mixture was compressed into tablets of appropriate weight and hardness to obtain an irbesartan tablet; and the tablets was coated with opadry. Example 3

The tablets were prepared using the materials listed in table.

The tablets of example 4 and 5 were manufactured using the procedure which comprising the following steps: irbesartan, hydrochlorothiazide, microcrystalline cellulose was done in a rapid mixer granulator and mixed for 5 to 20 minutes. Binder solution (polyvinylpyrrolidone in purified water) is added to contents of rapid mixer granulator and mixed to get dough mass. The dough mass was dried, and dried granules passed through #20.

The blending of ingredients including above dried granules, calcium carboxymethyl cellulose, colloidal anhydrous silica and calcium stearate were weighted, transferred into a blender, and mixed to form a homogeneous power mixture; the resultant mixture was compressed into tablets of appropriate weight and hardness to obtain an irbesartan and hydrochlorothiazide tablet; and the tablets was coated with opadry.

Example 4

Preparation of an irbesartan and hydrochlorothiazide tablet:

The tablets were prepared using the materials listed in table.

The results of dissolution of irbesartan and hydrochlorothiazide tablets 300/25 mg is shown below.

The tablets of the irbesartan and hydrochlorothiazide and commercially available irbesartan and hydrochlorothiazide tablets (i.e. AVALIDE) were tested for in vitro drug release in 1000 ml of 0.1 N hydrochloric acid, USP-II apparatus and speed operating at 50 rpm. The values for dissolution of irbesartan were greater than 80% in 10 minutes and hydrochlorothiazide were greater than 80% in 10 minutes.

Example 5

Preparation of an irbesartan and hydrochlorothiazide tablet:

The tablets were prepared using the materials listed in table.

Claims

We claim:

1. A pharmaceutical composition of the present invention which comprises irbesartan or pharmaceutically acceptable salts thereof is about 65% to about 85%, microcrystalline cellulose or mannitol is about 3% to about 40%, polyvinylpyrrolidone or hydroxy propyl cellulose is about 0.25% to about

10%, carboxymethyl cellulose calcium or dibasic calcium phosphate or crospovidone is about 1% to about 15%, the total weight of the pharmaceutical composition, and optionally one or more additional excipients.

2. A pharmaceutical composition of the present invention which comprises irbesartan or pharmaceutically acceptable salts thereof is about 65% to about 85% in combination with hydochlorothiazide, microcrystalline cellulose or mannitol is about 3% to about 40%, polyvinylpyrrolidone or hydroxy propyl cellulose is about 0.25% to about 10%, carboxymethyl cellulose calcium or dibasic calcium phosphate or crospovidone is about 1 % to about 15%, the total weight of the pharmaceutical composition, and optionally one or more additional excipients.

3. The composition as claimed in claim 1 , wherein the pharmaceutical composition irbesartan or pharmaceutically acceptable salts thereof is about 71% to about 74%, microcrystalline cellulose or mannitol is about 12% to about 25%, polyvinylpyrrolidone or hydroxy propyl cellulose is about 0.5 to about 7%, calcium carboxymethyl cellulose or dibasic calcium phosphate or crospovidone is about 2% to about 10%, the total weight of the pharmaceutical composition, and optionally one or more additional excipients.

4. The composition as claimed in claim 2, wherein the pharmaceutical composition irbesartan or pharmaceutically acceptable salts thereof is about 71 % to about 74%, hydochlorothiazide, microcrystalline cellulose or mannitol is about 12% to about 25%, polyvinylpyrrolidone or hydroxy propyl cellulose is about 0.5% to about 7%, calcium carboxymethyl cellulose or dibasic calcium phosphate or crospovidone is about 2% to about 10%, the total weight of the pharmaceutical composition, and optionally one or more additional excipients.

5. The composition as claimed in claim 1 or 2, wherein the pharmaceutical composition in the form of a tablet, a caplet, a pellet, a capsule, granules, a pill, powder or a sachet.

6. The composition as claimed in claim 5, wherein the oral solid pharmaceutical composition is a tablet.

7. The composition as claimed in claim 1 or 2, wherein the additional excipient is selected from pharmaceutical filler, disintegrants, binders, lubricants, glidants, coating agents and coloring agents and a mixture thereof.

8. The composition as claimed in claim 7, wherein the filler is microcrystalline cellulose, mannitol, dibasic calcium phosphate, calcium carbonate, lactose, magnesium carbonate, magnesium oxide, lactose anhydrous, isomalt, sorbitol or mixtures thereof.

9. The composition as claimed in claim 8, wherein the filler is microcrystalline cellulose and/or mannitol.

10. The composition as claimed in claim 7, wherein lubricants is magnesium stearate, calcium stearate, stearic acid, a salt of stearic acid, talc, sodium stearyl fumarate, glyceryl behenate, magnesium silicate, magnesium trisilicate, macrogol, talc, hydrogenated castor oil or mixtures thereof.

11. The composition as claimed in claim 10, wherein lubricants is magnesium stearate and/or calcium stearate.

12. The composition as claimed in claim 7, wherein the disintegratrants is carboxymethyl cellulose calcium, croscarmellose sodium, starch, sodium starch glycolate, crospovidone, carboxymethylcellulose sodium, magnesium aluminium silicate or mixtures thereof.

13. The composition as claimed in claim 12, wherein the disintegratrants is carboxymethyl cellulose calcium and/or croscarmellose sodium.

14. The composition as claimed in claim 7, wherein the glidant is colloidal anhydrous silica, talc or mixtures thereof.

15. The composition as claimed in claim 14, wherein the glidant is colloidal anhydrous silica.

16. The composition as claimed in claim 7, wherein the binder is polyvinylpyrrolidone k-30, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl cellulose (low-substituted), starch or mixtures thereof.

17. The composition as claimed in claim 16, wherein the binder is polyvinylpyrrolidone k-30 and/or hydroxypropyl cellulose.

18. The composition as claimed in claim 7, wherein the coating agent is hydroxypropyl methyl cellulose, polyvinyl alcohols, hydroxypropyl cellulose, macrogols or mixtures thereof.

19. The composition as claimed in claim 18, wherein the coating agent is hydroxypropyl methyl cellulose and/or polyvinyl alcohols.

20. The composition as claimed in claim 7, wherein the coloring agent includes titanium dioxide, red iron oxide, yellow iron oxide, black iron oxides and mixture thereof.

21. The process as claimed in claim 1 , wherein the irbesartan or pharmaceutically acceptable salts thereof is about 65% to about 85%, microcrystalline cellulose or mannitol is about 3% to about 40%, polyvinylpyrrolidone or hydroxy propyl cellulose is about 0.25% to about 10%, carboxymethyl cellulose calcium or dibasic calcium phosphate or crospovidone is about 0.5% to about 10%, colloidal anhydrous silica is about 0.125 to about 2%, calcium stearate is about 0.25% to about 5% and/or opadry is about 0.5% to about 4%.

22. The process as claimed in claim 2, wherein the irbesartan or pharmaceutically acceptable salts thereof is about 65% to about 85%, hydrochlorothiazide is about 1% to about10%, microcrystalline cellulose or mannitol is about 3% to about 40%, polyvinylpyrrolidone or hydroxy propyl cellulose is about 0.25% to about 10%, carboxymethyl cellulose calcium or dibasic calcium phosphate or crospovidone is about 0.5% to about 10%, colloidal anhydrous silica is about 0.125 to about 2%, calcium stearate is about 0.25% to about 5% and/or opadry is about 0.5% to about 4%.

23. A process for preparing of pharmaceutical composition which comprises mixing irbesartan or pharmaceutically acceptable salts thereof is about 65% to about 85%, microcrystalline cellulose or mannitol is about 3% to about 40%, polyvinylpyrrolidone or hydroxy propyl cellulose is about 0.25% to about 10%, and blend carboxymethyl cellulose calcium or dibasic calcium phosphate or crospovidone is about 1 % to about 15%, the total weight of the pharmaceutical composition, and optionally one or more additional excipients.

24. A process for preparing of pharmaceutical composition which comprises mixing irbesartan or pharmaceutically acceptable salts thereof is about 65% to about 85% in combination with hydrochlorothiazide, microcrystalline cellulose or mannitol is about 3% to about 40%, and polyvinylpyrrolidone or hydroxy propyl cellulose is about 0.25% to about 10%, and blend carboxymethyl cellulose calcium or dibasic calcium phosphate or crospovidone is about 1% to about 15%, the total weight of the pharmaceutical composition, and optionally one or more additional excipients.

25. The process as claimed in claim 23 or 24, wherein the pharmaceutical composition in the form of a tablet, a caplet, a pellet, a capsule, granules, a pill, powder or a sachet.

26. The process as claimed in claim 25, wherein the oral solid pharmaceutical composition is a tablet.

27. The process as claimed in claim 26, wherein the tablets are prepared by direct compression, wet granulation or slugging or roll compaction.

28. The process as claimed in claim 27, wherein the tablets are prepared by wet granulation.

29. The method of use according to claim 1 and 2, wherein the pharmaceutical composition is used for treatment of hypertentsion.