WO2005082329A2

WO2005082329A2 - Process for the preparation of solid dosage forms of valsartan and hydrochlorthiazide

Info

Publication number: WO2005082329A2
Application number: PCT/IB2005/000340
Authority: WO
Inventors: Romi Barat Singh; Girish Karanth; Vishnubhotla Nagaprasad
Original assignee: Ranbaxy Laboratories Limited
Priority date: 2004-02-19
Filing date: 2005-02-10
Publication date: 2005-09-09
Also published as: WO2005082329A3; WO2005082329B1

Abstract

The present invention relates to solid dosage forms comprising valsartan in a core and hydrochlorthiazide (HCTZ) in a coating layer; and process of preparation thereof.

Description

PROCESS FORTHE PREPARATION OF SOLID DOSAGE FORMS OFVALSARTAN AND HYDROCHLORTHIAZIDE Field of the Invention The present invention relates to solid dosage forms comprising valsartan in a core and hydrochlorthiazide (HCTZ) in a coating layer; and processes of preparation thereof. Background of the Invention Valsartan is a non-peptide, orally active and specific angiotensin II antagonist acting on the ATi receptor subtype. Valsartan is N-(l-oxopentyl)-N-{[2'-(lH-tetrazol-5- yl) [1, 1 '-biphenyl] -4 -yl] methyl] - L - valine. HCTZ is a loop diuretic, known as 6-chloro-3,4-dihydro-2H-l,2,4-benzothiadiazine-7-sulfonamide 1, 1 dioxide. The combination is indicated for treatment of hypertension, in patients failing to achieve the desired effect with monotherapy. Both valsartan and HCTZ are low density solid materials. Thus, preparation of solid dosage forms of acceptable size, suitable for oral administration, is a challenging task. The above problem is addressed in U.S. Patent Nos. 6,294,197 and 6,485,745 by preparing compressed tablets of valsartan and HCTZ by dry granulation techniques. Dry granulation converts fluffy material into granules that have higher bulk density and better flow characteristics than the original material. The process comprises: blending valsartan, HCTZ and at least one pharmaceutically acceptable additive to form a mixture; subjecting the mixture to compression to form a coprimate; converting the coprimate into a granulate; and compressing the granulate to form the compressed tablet. However there is still a need for alternate approaches for the preparation of solid dosage forms such as capsules, multiple unit systems, sachets and the like, of reasonable size, comprising combinations of valsartan and HCTZ. Summary of the Invention The present inventors have discovered that solid dosage forms of acceptable size may be prepared by coating cores containing valsartan, with an HCTZ layer and processing these into solid dosage forms. Hence in one general aspect, there provided solid dosage forms comprising a core and coating layer, wherein the core contains valsartan and the coating layer contains HCTZ . In another general aspect, there are provided processes for the preparation of solid dosage forms of valsartan and HCTZ comprising: (a) preparing a core by (i) blending valsartan and at least one intragranular pharmaceutically acceptable additive and (ii) granulating the blend to form a compact mass; (b) coating the core with a layer of HCTZ; (c) optionally blending the coated core with extragranular pharmaceutically acceptable additive; and (d) processing into a solid dosage form. In another general aspect, there are provided processes for the preparation of solid dosage forms of valsartan and HCTZ comprising: (a) preparing a core by (i) blending valsartan and at least one intragranular pharmaceutically acceptable additive, (ii) granulating the blend, (iii) blending the granules with extragranular pharmaceutically acceptable additive, and (iv) compressing to form a compact mass; and (b) coating with a layer of HCTZ to form a solid dosage form. In another general aspect, there are provided methods of treating hypertension in a mammal by administering to the mammal a solid dosage form comprising a core and coating layer, wherein the core contains valsartan and the coating layer contains HCTZ. Coating HCTZ as a separate layer over the valsartan core helps in improving the processabihty of the blend for compression of cores containing valsartan and thereby providing solid dosage forms of acceptable size, suitable for oral administration. The term "core" as used herein refers to a compact mass having a determined shape, comprising valsartan and at least one pharmaceutically acceptable additive. The core should be able to withstand the rigors of coating with HCTZ layer, and further processing into solid dosage form. Specific examples of suitable cores may include tablet, granule, pellets, and the like. The terms "Valsartan" and "HCTZ" as used herein may include their free forms or pharmaceutically acceptable salts thereof. Valsartan and HCTZ may be used in the solid dosage forms in amounts which either reduce or halt the progress of the pathological condition being treated or which otherwise cure the condition partly or completely. The amount of valsartan may vary from about 10 to about 350 mg, and that of HCTZ may vary from about 6 to about 60 mg. The term "pharmaceutically acceptable additive" as used herein may include all physiologically inert additives used in the pharmaceutical art of dispensing. Examples may include binders, diluents, disintegrants, surfactants, plasticizers, lubricants/glidants, coloring agents, opacifiers, film-forming polymers, and the like. Examples of binders can include, for example, methyl cellulose, hydroxypropylcellulose, hydroxypropyl methylcellulose, carboxymethyl cellulose, polyvinylpyrrolidone, gelatin, gum arabic, ethyl cellulose, polyvinyl alcohol, pullulan, pregelatinized starch, agar, tragacanth, sodium alginate, and the like. Examples of disintegrants can include, for example, sodium starch glycolate, croscarmellose sodium, crospovidone, low substituted hydroxypropyl cellulose, and the like. Examples of diluents can include cellulose powdered, dextrates, dextrins, dextrose excipients, fructose, kaolin, lactitol, lactose, mannitol, sorbitol, starch, starch pregelatinized, sucrose, sugar compressible, sugar confectioners, and the like. Examples of lubricants and glidants can include, for example, magnesium stearate, colloidal anhydrous silica, stearic acid, magnesium stearate, calcium stearate, talc, hydrogenated castor oil, sucrose esters of fatty acid, microcrystalline wax, yellow beeswax, white beeswax, and the like. Examples of surfactants can include both non-ionic and ionic (Cationic, Anionic and Zwitterionic) surfactants suitable for use in pharmaceutical compositions. These can include, for example, polyethoxylated fatty acids and its derivatives, for example, polyethylene glycol 400 distearate, polyethylene glycol - 20 dioleate, polyethylene glycol 4 -150 mono dilaurate, or polyethylene glycol -20 glyceryl stearate; alcohol - oil transesterification products, for example, polyethylene glycol - 6 corn oil; polyglycerized fatty acids, for example polyglyceryl - 6 pentaoleate; propylene glycol fatty acid esters, for example, propylene glycol monocaprylate; mono and diglycerides, for example, glyceryl ricinoleate; sterol and sterol derivatives, for example, sitosterol; sorbitan fatty acid esters and its derivatives, for example, polyethylene glycol - 20 sorbitan monooleate, or sorbitan monolaurate; polyethylene glycol 8 alkyl ether or phenols, for example, polyethylene glycol - 20 cetyl ether, or polyethylene glycol 10 - 100 nonyl phenol; sugar esters, for example, sucrose monopalmitate; polyoxyethylene polyoxypropylene block copolymers known as "poloxamer"; ionic surfactants, for example, sodium caproate, sodium glycocholate, soy lecithin, sodium stearyl filmarate, propylene glycol alginate, octyl sulfosuccinate disodium, or palmitoyl carnitine; and the like. Examples of plasticizers can include, for example, polyethylene glycol, tri ethyl citrate, triacetin, diethyl phthalate, dibutyl sebacate and the like. Examples of opacifiers can include, for example, titanium dioxide and the like. Example of film forming polymers can include, for example, ethylcellulose, hydroxypropyl methylcellulose, hydroxypropylcellulose, methylcellulose, carboxymethyl cellulose, hydroxymethylcellulose, hydroxyethylcellulose, cellulose acetate, hydroxypropyl methylcellulose phthalate, cellulose acetate phthalate, or cellulose acetate trimellitate; waxes such as polyethylene glycol; methacrylic acid polymers such as Eudragit ® RL and RS; and the like. Alternatively, commercially available coating compositions comprising film-forming polymers marketed under various trade names, such as Opadry® may also be used for coating. Examples of coloring agents include any FDA approved colors for oral use. The term "intragranular pharmaceutically acceptable additive," as used herein, refers to those additives, which are present in granules. The term "extragranular pharmaceutically acceptable additive," as used herein, refers to those additives with which granules can be blended before being processed into suitable solid dosage form. In one embodiment, fixed dose combination tablets of valsartan and HCTZ may be prepared by a process comprising: (a) blending valsartan with intragranular pharmaceutically acceptable additives, (b) granulating the blend, (c) blending the granules with extragranular pharmaceutically acceptable additives, (d) compressing the granules into a core, and (e) coating the core with a solution/dispersion of HCTZ and pharmaceutically acceptable additives. In another embodiment, fixed dose combination tablets of valsartan and HCTZ may be prepared by a process comprising: (a) blending valsartan with intragranular pharmaceutically acceptable additives, (b) granulating the blend, (c) coating the granules with a solution/dispersion of HCTZ and pharmaceutically acceptable additives, (d) blending the coated granules with extragranular pharmaceutically acceptable additives, and (e) compressing the granules into a tablet. Tablets prepared by any of the embodiments above, may be further coated with one or more non-functional polymeric layers, if desired. In another embodiment, fixed dose combination capsules of valsartan and HCTZ may be prepared by a process comprising: (a) blending valsartan and pharmaceutically acceptable additives, (b) granulating the blend, (c) coating the granules with a solution/dispersion of HCTZ and pharmaceutically acceptable additives, (d) blending the coated granules with pharmaceutically acceptable additives, and (e) filling into a capsule. The granules may be prepared either by wet granulation or dry granulation techniques. Dry granulation may be carried out using, for example, roller compaction or slugging techniques. The coating layer over the cores may be applied as solution dispersion of HCTZ and pharmaceutically acceptable additives, using any technique, such as spray coating in a conventional coating pan or fluidized bed processor; dip coating and the like. Example of solvents used for preparing a solution/dispersion of the coating layer or as a granulating fluid can include, for example, methylene chloride, isopropyl alcohol, acetone, methanol, ethanol, water and the like and mixtures thereof. The invention is further illustrated by the following examples, which is for illustrative purposes and do not limit the scope of the invention in any way.

Examples

Table 1. Valsartan core and HCTZ layer composition (Examples 1-3)

"Opadry Brown for 160/12.5mg and Opadry White 160/25mg & 80/12.5mg strengths. Process

1. Valsartan and Crospovidone were sifted together.

2. Carboxymethyl cellulose Calcium, Croscarmellose Sodium, Microcrystalline Cellulose, Pregelatinized Starch and Colloidal Silicon Dioxide were sifted through s sieve.

3. Blends of step 1 and step 2 were blended together.

4. Magnesium Stearate was sifted through a sieve and added to the blend of step 3 and mixed.

5. The blend of step 4 was compacted in roller compactor and the compacts were milled in an oscillating granulator.

6. The blend of step 5 was sifted.

7. Microcrystalline Cellulose, Crospovidone and Colloidal Silicon Dioxide were sifted through a sieve and transferred to the blend of step 6 and mixed.

8. Talc and Magnesium Stearate were sifted through a sieve and added to the blend of step 7 and mixed.

9. The mix of step 8 was compressed into suitable size tablets.

10. HCTZ was dissolved in a mixture of acetone and water.

11. Opadry was dispersed in the solution of step 10 under mechanical stirring.

12. The tablets were coated using the dispersion of Step 11.

Table 2. Valsartan core and hydrochlorthiazide layer composition (Examples 4-6)

Example 4-6 were prepared as per the process given for example 1-3. In vitro dissolution study In vitro release of valsartan and hydrochlorthiazide as per composition of example 1 and 4 was studied in 1000 ml 0.067 M phosphate buffer (pH 6.8) in USP type II apparatus at 50 rpm. The results of the study is shown in Table 3. Table 3. In vitro release of drug

While there have been shown and described what are the preferred embodiments of the invention, one skilled in the pharmaceutical formulation art will appreciate that various modifications in the dosage form and process can be made without departing from the scope of the invention as it is defined by the appended claims.

Claims

We Claim: 1. A solid dosage form comprising a core and a coating layer, wherein the core contains valsartan and the coating layer contains HCTZ. 2. The solid dosage form according to claim 1, wherein the solid dosage form further comprises intragranular and/or extragranular pharmaceutically acceptable additives selected from the group consisting of binders, diluents, disintegrants, surfactants, plasticizers, lubricants/glidants, coloring agents, opacifiers, and film-forming polymers. 3. The solid dosage form according to claim 1, wherein the core is a tablet, granule, or pellet. 4. The solid dosage form according to claim 1, wherein the dosage form is a tablet or capsule. 5. A process for the preparation of solid dosage forms of valsartan and HCTZ comprising: (a) preparing a core by (i) blending valsartan and at least one intragranular pharmaceutically acceptable additive, and (ii) granulating the blend to form a compact mass; (b) coating the core with a layer of HCTZ; and (c) processing into a solid dosage form. 6. The process according to claim 5, wherein the coated core of step (b) is further blended with at least one extragranular pharmaceutically acceptable additive. 7. A process for the preparation of solid dosage forms of valsartan and HCTZ comprising: (a) preparing a core by (i) blending valsartan and at least one intragranular pharmaceutically acceptable additive, (ii) granulating the blend, (iii) blending the granules with extragranular pharmaceutically acceptable additive, and (iv) compressing to form a compact mass; and (b) coating with a layer of HCTZ to form a solid dosage form. 8. The process according to claim 5 or 7, wherein the granulation is carried out by wet or dry granulation. 9. The process according to claim 5 or 7, wherein the coating layer is applied as a solution or dispersion of HCTZ and pharmaceutically acceptable additive in one or more solvent selected from the group consisting of methylene chloride, isopropyl alcohol, acetone, methanol, ethanol, and water. 10. The process according to claim 5 or 7, wherein the coating layer is applied by a spray coating technique, or by dip coating. 11. A method of treating hypertension in a mammal by administering to the mammal a solid dosage form comprising a core and coating layer, wherein the core contains valsartan and the coating layer contains HCTZ.