WO2013098578A1

WO2013098578A1 - Immediate release pharmaceutical composition of valsartan hydrochlorothiazide

Info

Publication number: WO2013098578A1
Application number: PCT/IB2011/003201
Authority: WO
Inventors: Ferhat FARSI
Original assignee: Abdi Ibrahim Ilac Sanayi Ve Ticaret Anonim Sirketi
Priority date: 2011-12-31
Filing date: 2011-12-31
Publication date: 2013-07-04

Abstract

The present invention relates to an immediate release pharmaceutical composition comprising a combination of valsartan and hydrochlorothiazide. More particularly, it relates to a pharmaceutical composition comprising valsartan, hydrochlorothiazide, low- substituted hydroxypropyl cellulose, and at least one pharmaceutical acceptable excipient, wherein the composition is prepared by wet granulation.

Description

IMMEDIATE RELEASE PHARMACEUTICAL COMPOSITION OF

VALSARTAN HYDROCHLOROTHIAZIDE

FIELD OF THE INVENTION

BACKGROUND OF THE INVENTION

Valsartan is chemically known as (S)-3-methyl-2-(N-{[2'-(2H-l,2,3,4-tetrazol-5-yl) biphenyl-4-yl] methyl} pentanamido) butanoic acid, as presented below in structural formula "Formula F:

Formula I

Hydrochlorothiazide is chemically known as 6-chloro-l,l-dioxo-3,4-dihydro-2H- l,2,4-benzothiadiazine-7-sulfonamide, as presented below in structural formula "Formula

Formula II

Valsartan is a non-peptide, orally active and specific angiotensin II antagonist acting on the ATI receptor subtype, and is used for the treatment of hypertension. It is also known to be effective in the treatment of congestive heart failure, angina (stable or unstable), myocardial infarction, atherosclerosis, diabetic nephropathy, diabetic cardiac myopathy, renal insufficiency, peripheral vascular disease, left ventricular hypertrophy, cognitive dysfunction, Alzheimer's disease, stroke, headache, and chronic heart failure, and is well tolerated. Combinations with hydrochlorothiazide and amlodipine are also known for the treatment of hypertension. Valsartan is commercially available under the trade name Diovan®.

Hydrochlorothiazide is a known diuretic drug of the thiazide class that acts by inhibiting the kidneys' ability to retain water. It is frequently used for the treatment of hypertension, congestive heart failure, symptomatic edema, diabetes insipidus, renal tubular acidosis, and the prevention of kidney stones.

Valsartan is disclosed in U.S. Patent 5,399,578, which describes a large number of acyl compounds. In examples 92 and 93 compositions comprising valsartan are granulated in a water solution.

E.P. Patent Application 09141 19 and 1410797 describe solid oral dosage forms of valsartan and hydrochlorothiazide which are prepared in absence of water. The process as described therein relates to compaction (dry granulation). The examples describe compositions comprising valsartan and crospovidone as disintegrant, wherein the amount of valsartan is more than 35 % by weight of the composition.

PCT Application 2000/38676 discloses solid oral dosage forms comprising valsartan, microcrystalline cellulose and crospovidone. The disclosure provides for compositions prepared by dry granulation and comprising more than 30% of microcrystalline cellulose by weight based on the total weight of the core components of the solid oral dosage form.

PCT Application 2001/97805 discloses tablet compositions comprising valsartan and hydrochlorothiazide which are alleged to be at least 1.2 times more bioavailable than capsule compositions. The compositions comprise valsartan or a pharmaceutically acceptable salt or hydrate thereof, filler, such as microcrystalline cellulose, and a disintegrant, such as crospovidone, wherein the filler is present in an amount of more than 30 % and disintegrant is present in an amount ranging from 20 % to 80 % by weight of the composition. The compositions are prepared by dry granulation.

Though dry granulation or compaction is a conventional process to prepare pharmaceutical compositions, the skilled person is aware of certain drawbacks of this process which may arise because of the complexity of the process and the equipment, dusting of the active ingredient, and reduction in compressibility characteristics. The wet granulation process may be used to overcome such drawbacks.

PCT Application 2006/066961 discloses pharmaceutical compositions comprising a combination of valsartan and hydrochlorothiazide prepared by aqueous granulation wherein valsartan has a defined particle size. The examples disclose compositions comprising valsartan, hydrochlorothiazide, and croscarmellose as a disintegrant, and excipients like diluent, binder, glidant and lubricant.

PCT Application 2008/056375 describes solid pharmaceutical compositions comprising valsartan and hydrochlorothiazide, which are prepared by wet granulation and wherein valsartan is present in an amount less than 35% by weight based on the total weight of the pharmaceutical composition.

PCT Application 2009/022169 discloses solid pharmaceutical composition comprising granules prepared by wet granulation, wherein granules comprise valsartan, and optionally hydrochlorothiazide, and at least one pharmaceutically acceptable excipient, such as crospovidone, and further characterized in that the core has a moisture content of 3% or less.

Compositions prepared by wet granulation generally comprise a disintegrant to promote the breaking of granules. The compositions disclosed in the art are prepared by wet granulation comprise a superdisintegrant, such as croscarmellose and crospovidone. Superdisintegrants provide for greater disintegrant efficacy at lower concentrations.

There is a need in the art for alternative compositions of valsartan and hydrochlorothiazide prepared by wet granulation. We have surprisingly found that robust compositions of valsartan and hydrochlorothiazide may be prepared by wet granulation without the need of superdisintegrants. The present invention discloses immediate release compositions prepared by wet granulation comprising valsartan, hydrochlorothiazide and low-substituted hydroxypropyl cellulose as the disintegrant.

SUMMARY OF THE INVENTION

Aspects of the invention relate to immediate release composition of valsartan and hydrochlorothiazide.

In one aspect it discloses an immediate release pharmaceutical composition comprising:

i) valsartan; ii) hydrochlorothiazide;

iii) low-substituted hydroxypropyl cellulose; and

iv) at least one pharmaceutical acceptable excipient,

wherein the low-substituted hydroxypropyl cellulose is the sole disintegrant and the composition is prepared by wet granulation.

In another aspect, it discloses a process for the preparation of immediate release pharmaceutical composition, wherein the process comprises:

i) mixing valsartan, at least one pharmaceutically acceptable excipient and

optionally low-substituted hydroxypropyl cellulose;

ii) granulating the mixture of step (i) with a solvent;

iii) drying the granules of step (ii);

v) mixing the granules of step (iii)with hydrochlorothiazide, low-substituted

hydroxypropyl cellulose and at least one pharmaceutically acceptable excipient;

vi) compressing the mixture of step (iv) in to a tablet; and

vii) optionally coating the tablet of step (v).

DETAILED DESCRIPTION OF THE INVENTION

The term "immediate release" as described herein means a composition which releases total amount of valsartan from the composition in less than 1 hour, in a media having a pH of 6.8.

The term "valsartan" as described herein is intended to include valsartan free base as well as pharmaceutically acceptable salts, as well as polymorphss of the base or the pharmaceutically acceptable salts thereof, including hydrates, solvates and anhydrous forms thereof. Valsartan is present in an amount ranging from about 20 % to about 80 %, more preferably about 20 % to about 50 % by weight of the composition. In one embodiment, valsartan is present in an amount of less than 35 % by weight of the composition.

Hydrochlorothiazide (also referred as "HCTZ" as described herein may be present in an amount ranging from about 0.5 % to about 10 %, more preferably about 1 % to about 5 % by weight of the composition. In a preferred embodiment, the combined amount of valsartan and hydrochlorothiazide may be present in an amount less than 35 % by weight of the composition. The term "superdisintegrants" as described herein is intended to mean disintegrants like cross-linked polyvinyl pyrrolidone (crospovidone), cross-linked carboxymethylcellulose sodium (croscarmellose), sodium starch glycolate, pregelatinized starch and sodium alginate. The pharmaceutical compositions as described herein do not comprise a superdisintegrant.

The term "low-substituted hydroxypropyl cellulose" or "L-HPC" as described herein means low-substituted hydroxypropyl ether of cellulose having a low substitution of the hydroxypropyl groups in the glucose unit. The hydroxyl-propoxy content may vary from 5 % to 15 %, more preferably from 8% to 11% of the polymer. In one preferred embodiment, the hydroxy-propoxy content is 11%. The molecular weight of L-HPC as described herein may vary from 1,00,000 - 1 ,50,000. Such polymers are commercially available, such as the one sold by ShinEtsu, under the brand name LH-1 1 , LH-21 , LH-22, LH-31, LH-32, LH-Bl and the like. The pharmaceutical compositions as described herein comprise L-HPC as the sole disintegrant. In a preferred embodiment, the L-HPC employed is LH-21. The L-HPC may be present in an amount ranging from about 1% to about 20 %, more preferably from about 5% to about 10% by weight of the composition.

The compositions as described herein may comprise at least one pharmaceutically acceptable excipient selected from a group comprising diluent, binder, glidant, lubricant, coloring agent and opacifying agent.

Diluent as described herein may be selected from a group comprising lactose, sucrose, , glucose, dextrose, microcrystalline cellulose, dibasic calcium phosphate, calcium sulphate, mannitol, erythritol, lactilol, maltitol, xylitol, sorbitol, starch, and mixtures thereof. The diluents may be present in an amount ranging from 20% to 80 %, more preferably from about 40 % to about 60 % by weight of the composition.

Binder as described herein may be selected from a group comprising polyvinyl pyrolidone, hydroxypropyl methylcellulose, methylcellulose, hydroxypropyl cellulose and mixtures thereof. The binder may be present in an amount ranging from about 1 % to about 10 % by weight of the composition.

Glidant as described herein may be selected from a group comprising colloidal silicon dioxide, talc, and mixtures thereof. The glidant may be present in an amount ranging from about 0.5 % to about 3 % by weight of the composition.

Lubricant as described herein may be selected from a group comprising magnesium stearate, stearic acid, talc, sodium stearyl fumarate, glyceryl behenate, and mixtures thereof. The lubricant may be present in an amount ranging from about 0.5 % to about 2 % by weight of the composition.

The pharmaceutical compositions as described herein may be prepared by techniques such as wet granulation.

For example, valsartan may be mixed with a diluent and optionally L-HPC, and the mixture may be granulated with water or an organic solvent. The organic solvent may be selected from the group comprising acetone, ethanol, isopropanol, dichloromethane, ethylacetate; and mixtures thereof. The solvent may also comprise a binder and the granulation may be carried out in conventional fluid bed granulator equipments, such as Glatt, Wurster or Rapid Mixer Granulator. In one embodiment, the binder may be present in the dry blend before granulation. The granules may be dried and may then be sieved using a sieving equipment such as Frewitt. The sieved granules may be mixed with hydrochlrothiazide, L-HPC and extragranular excipients such as diluent, lubricant and glidant and mixture processed into suitable composition such as tablet. The tablet may be coated with suitable coating composition such as the one commercially available under the trade name Opadry®. Such a coating composition may comprise excipients known to a skilled person such as a film-forming polymer, detackifying agent such as talc, coloring agent such as permitted FD&C dyes, opacifying agent such as titanium dioxide and/or iron oxide, plasticizer, and the like, or mixtures thereof.

In one embodiment an immediate release composition may be prepared by a process consisting of :

i) mixing valsartan and a diluent;

ii) granulating the mixture of step (i) with water;

iii) drying the granules of step (ii);

iv) mixing the granules of step (iii) with hydrochlorothiazide, L-HPC, diluent, lubricant and glidant;

v) compressing the mixture of step (iv) into a tablet; and

vi) optionally coating the tablet of step (v).

In another embodiment an immediate release composition may be prepared by a process consisting of :

i) mixing valsartan and a diluent;

ii) granulating the mixture of step (i) with acetone;

iii) drying the granules of step (ii); iv) mixing the granules of step (iii) with hydrochlorothiazide, L-HPC, diluent, lubricant and glidant;

v) compressing the mixture of step (iv) into a tablet; and

vi) optionally coating the tablet of step (v).

i) mixing valsartan , diluent and a glidant;

ii) granulating the mixture of step (i) with water;

iii) drying the granules of step (ii);

iv) mixing the granules of step (iii) with hydrochlorothiazide, L-HPC, lubricant, glidant, and optionally a diluent;

v) compressing the mixture of step (iv) into a tablet; and

vi) optionally coating the tablet of step (v).

i) mixing valsartan , diluent, L-HPC and optionally a glidant;

ii) granulating the mixture of step (i) with water;

iii) drying the granules of step (ii);

iv) mixing the granules of step (iii) with hydrochlorothiazide, L-HPC, lubricant, glidant and optionally a diluent;

v) compressing the mixture of step (iv) into a tablet; and

vi) optionally coating the tablet of step (v).

Certain specific aspects and embodiments of this invention are described in further detail by the examples below, where such examples are provided only for the purpose of illustration and are not intended to scope of the appended claims in any manner.

EXAMPLE 1

Ingredient Amount (in % w/w)

Intragranular

Valsartan 29.8

Lactose 29.8

Deionized Water q.s.

Extragranular HCTZ 2.3

L-HPC 9.3

Lactose 16.3

Microcrystalline cellulose 9.3

Colloidal silicon dioxide 1.9

Magnesium stearate 1.4

Total 100

PROCEDURE: Valsartan and lactose were loaded into a high shear mixer and mixed for five minutes. The dry mixture was granulated with deionized water and the wet granules were dried in fluid bed dryer. The dried granules were passed through an appropriate sieve. HCTZ, lactose, microcrystalline cellulose, L-HPC and colloidal silicon dioxide were passed through an appropriate sieve and mixed with the dried granules. Magnesium stearate was added to the mixture to lubricate and form the final mixture which was compressed into tablets using appropriate tooling.

EXAMPLE 2

PROCEDURE: Valsartan and lactose were loaded into a high shear mixer and mixed for five minutes. The dry mixture was granulated with acetone and the wet granules were dried in fluid bed dryer. The dried granules were passed through an appropriate sieve. HCTZ, lactose, microcrystalline cellulose, L-HPC and colloidal silicon dioxide were passed through an appropriate sieve and mixed with the dried granules. Magnesium stearate was added to the mixture to lubricate and form the final mixture which was compressed into tablets using appropriate tooling.

EXAMPLE 3

PROCEDURE: Valsartan, lactose, L-HPC and colloidal silicon anhydrous were loaded in a high shear mixer and mixed. The mixture was granulated with deionized water and the granules were dried in fluid bed dryer. The dried granules were passed through an appropriate sieve. HCTZ, lactose, microcrystalline cellulose, L-HPC and colloidal silicon dioxide were sifted and mixed with the dried granules. Magnesium stearate was added to the mixture and the mixture was compressed into tablets using appropriate tooling. EXAMPLE 4

PROCEDURE: Valsartan, lactose and colloidal silicon were mixed and the mixture was granulated with deionized water. The granules were dried and passed through an appropriate sieve. HCTZ, microcrystalline cellulose, L-HPC and colloidal silicon dioxide were sifted and mixed with the dried granules. Magnesium stearate was added to the mixture and the mixture was compressed into tablets using appropriate tooling.

EXAMPLE 5

L-HPC 9.3

Lactose monohydrate 16.3

Micro crystalline cellulose 9.3

Colloidal silicon dioxide 1.4

Magnesium stearate 1.4

Total 100

PROCEDURE: Valsartan, lactose monohydrate and colloidal silicon anhydrous were mixed and the mixture was granulated with deionized water. The granules were dried and passed through an appropriate sieve. HCTZ, lactose monohydrate, microcrystalline cellulose, L-HPC and colloidal silicon dioxide were sifted and mixed with the dried granules. Magnesium stearate was added to the mixture and the mixture was compressed into tablets using appropriate tooling.

COMPARATIVE EXAMPLE

PROCEDURE: Valsartan and lactose were loaded into a high shear mixer and mixed for five minutes. The dry mixture was granulated with acetone and the wet granules were dried in fluid bed dryer. The dried granules were passed through an appropriate sieve. HCTZ, lactose, microcrystalline cellulose, crospovidone and colloidal silicon dioxide were passed through an appropriate sieve and mixed with the dried granules. Magnesium stearate was added to the mixture to lubricate and form the final mixture which was compressed into tablets using appropriate tooling.

EXAMPLE 6

Comparative Disintegration Time of Co-Diovan™, Comparative Example and

Example 1, Example 4 and Example 5

The disintegration time was measured by performing the disintegration test as specified in USP. (USP <701>)

EXAMPLE 7

Comparative Dissolution Profile of Co-Diovan ¹ , Comparative Example and

Example 4 and Example 5 in USP Type-II Apparatus (pedal), 50 rpm, in 1000 ml pH 6.8 phosphate buffer at 37°C±0.5°C

The compositions of Example 4 and Example 5 possessed disintegration and dissolution profile comparatively similar to the reference product Co-Diovan™ tablets. The compositions of Example 4 and Example 5 comprising L-HPC as the sole disintegrant possessed improved disintegration and dissolution profile, in terms of increased dissolution of valsartan at 5 minute time-point, in comparison to the Comparative Example having crospovidone as the superdisintegrant.

Having thus described the invention with reference to particular embodiments and illustrative examples, those in the art may appreciate that modifications, additions and substitutions are possible, without departing from the scope and spirit of the invention as recited in the appended claims.

Claims

WE CLAIM:

1 ) An immediate release pharmaceutical composition comprising:

i) valsartan;

ii) hydrochlorothiazide;

iii) low- substituted hydroxypropyl cellulose; and

iv) at least one pharmaceutical acceptable excipient;

wherein the composition is prepared by wet granulation.

2) The composition of Claim 1 , wherein the low-substituted hydroxypropyl cellulose is the sole disintegrant.

3) The composition of Claim 1 , wherein the combined amount of valsartan and hydrochlro thiazide is present in an amount of less than 35 % by weight of the composition.

4) The composition of Claim 1 , wherein the low-substituted hydroxypropyl cellulose is present in an amount ranging from about 1 % to about 20 % by weight of the composition.

5) The composition of Claim 4, wherein the low-substituted hydroxypropyl cellulose is present in an amount ranging from about 5 % to about 15 % by weight of the composition.

6) The composition of Claim 1, wherein one or more pharmaceutically acceptable excipients are selected from a group consisting of diluent, binder, glidant and lubricant.

7) The composition of Claim 6, wherein the diluent is selected from a group consisting of lactose, sucrose, dextrose, microcrystalline cellulose, dibasic calcium phosphate, calcium sulphate, mannitol, erythritol, lactilol, maltitol, xylitol, sorbitol, starch, and mixtures thereof.

8) The composition of Claim 7, wherein the diluent is present in an amount ranging from about 20 % to about 80 % by weight of the composition.

9) The composition of Claim 8, wherein the diluent is present in an amount ranging from about 40 % to about 60 % by weight of the composition.

10) The composition of Claim 6, wherein the binder is selected from a group consisting of polyvinyl pyrolidone, hydroxypropyl methylcellulose, methylcellulose, hydroxypropyl cellulose and mixtures thereof.

1 1) The composition of Claim 10, wherein the binder is present in an amount ranging from about 1 % to about 10 % by weight of the composition.

12) The composition of Claim 6, wherein the glidant is selected from a group consisting of colloidal silicon dioxide, talc, stearic acid, and mixtures thereof.

13) The composition of Claim 12, wherein the glidant is present in an amount ranging from about 0.5 % to about 3 % by weight of the composition. 14) The composition of Claim 6, wherein the lubricant is selected from a group consisting of magnesium stearate, stearic acid, talc, sodium stearyl fumarate, glyceryl behenate, and mixtures thereof.

15) The composition of Claim 14, wherein the lubricant is present in an amount ranging from about 0.5 % to about 3 % by weight of the composition.

16) The composition of Claim 1, wherein the composition is a tablet.

17) An immediate release tablet composition comprising:

i) less than 35 % by weight of a combination valsartan and

hydrochlorothiazide;

ii) about 1% to about 20 % by weight of low-substituted hydroxypropyl

cellulose;

iii) about 20 % to about 80 % by weight of a diluent selected from a group consisiting of lactose, sucrose, dextrose, microcrystalline cellulose, dibasic calcium phosphate, calcium sulfate, mannitol, erythritol, lactilol, maltitol, xylitol, sorbitol and starch;

iv) about 0.5 % to about 3 % by weight of a glidant selected from a group

consisting of colloidal silicon dioxide, talc, and mixtures thereof.; and v) about 0.5 % to about 2 % by weight of a lubricant selected from a group consisting of magnesium stearate, stearic acid, talc, sodium stearyl fumarate, glyceryl behenate, and mixtures thereof.,

18) A process for the preparation of an immediate release pharmaceutical composition, wherein the process comprises:

i) mixing valsartan, at least one pharmaceutically acceptable excipient and

optionally low-substituted hydroxypropyl cellulose;

ii) granulating the mixture of step (i) with a solvent;

iii) drying the granules of step (ii);

iv) mixing the granules of step (iii) with hydrochlorothiazide, low-substituted hydroxypropyl cellulose and at least one pharmaceutically acceptable excipient;

v) compressing the mixture of step (iv) in to a tablet; and

vi) optionally coating the tablet of step (v).

19) The process of claim 17, wherein the solvent is water.

20) The process of claim 17, wherein the solvent is acetone.

21) The process of Claim 18, wherein the process comprises:

i) mixing valsartan , diluent and a glidant;

ii) granulating the mixture of step (i) with water;

iii) drying the granules of step (ii); iv) mixing the granules of step (iii) with hydrochlorothiazide, low-substituted hydroxypropyl cellulose, lubricant, glidant, and optionally a diluent; v) compressing the mixture of step (iv) into a tablet; and

vi) optionally coating the tablet of step (v).

22) The process of Claim 18, wherein the process comprises:

i) mixing valsartan , diluent, low-substituted hydroxypropyl cellulose and optionally a glidant;

ii) granulating the mixture of step (i) with water;

iii) drying the granules of step (ii);

iv) mixing the granules of step (iii) with hydrochlorothiazide, low-substituted hydroxypropyl cellulose, lubricant, glidant and optionally a diluent; v) compressing the mixture of step (iv) into a tablet; and

vi) optionally coating the tablet of step (v).