WO2007049291A1

WO2007049291A1 - Novel solid dosage forms of valsartan and rochlorothiazide

Info

Publication number: WO2007049291A1
Application number: PCT/IN2006/000040
Authority: WO
Inventors: Makarand Krishna Kumar Avachat; Nikhil Prabhakar Malewar; Pavan Kumar Vitta
Original assignee: Lupin Limited
Priority date: 2005-10-27
Filing date: 2006-01-06
Publication date: 2007-05-03

Abstract

A novel solid oral dosage forms comprising valsartan and hydrochlorothiazide (HCTZ) and a process of forming the same. The novel solid oral dosage form comprises a core comprising an effective amount of valsartan or a pharmaceutically acceptable salt thereof, and pharmaceutically acceptable additives suitable of the preparation of solid oral dosage form; and an outer coating comprising an effective amount of hydrochlorothiazide (HCTZ). The process of preparation of the novel solid oral dosage form of valsartan, comprises blending valsartan with the pharmaceutically acceptable excipients, dry granulation, milling and screening to obtain granules, said granules being subsequently compressed to tablets and coated, wherein hydrochlorothiazide is added in the coating dispersion.

Description

NOVEL SOLID DOSAGE FORMS OF VALSARTAN AND ROCHLOROTHIAZIDE

FIELD OF INVENTION

The present invention relates to novel solid oral dosage forms comprising valsartan and hydrochlorothiazide (HCTZ) and a process of forming the same.

BACKGROUND OF INVENTION

Valsartan was first disclosed in the U.S. patent 5,399,578. It is an angiotensin II antagonist, known to be effective in the treatment of congestive heart failure and reducing blood pressure irrespective of age, sex or race and is also well tolerated. Hydrochlorothiazide is a thiazide diuretic and was first disclosed in the U.S. patent 3,163,645.

Combination of valsartan (10 to 250mg) with HCTZ (6 to 60mg) has been found to be a more efficient treatment of hypertension. Valsartan was found to have a greater efficacy in reducing elevated blood pressure to normal levels than it would have if used at the same dose range in monotherapy. Similarly, when hydrochlorothiazide is being administered in combination with valsartan, the diuretic agent is more effective as compared to monotherapy at the dose range indicated.

Formulations using a combination of these two drugs are described in U.S. patent Nos: 6,294,197; 6,485,745 and 6,858,228.

U.S. patent No: 6,294,197 describes a compressed solid oral dosage form comprising of valsartan and HCTZ, wherein the active constituent is more than 35% by weight based on total weight of the compressed solid oral dosage form, of the active ingredient, obtained by dry granulation.

PCT application WO 2005/041941 relates to a pharmaceutical composition containing valsartan, optionally a combination of valsartan with hydrochlorothiazide, obtainable by direct tabletting. The present invention relates to a novel solid oral dosage form comprising valsartan and HCTZ. OBJECT OF THE INVENTION

An object of the invention is to provide a novel solid oral dosage form comprising a) a core comprising an effective amount of valsartan or a pharmaceutically acceptable salt thereof, and pharmaceutically acceptable additives suitable for the preparation of solid oral dosage forms; and b) an outer coating comprising an effective amount of hydrochlorothiazide .

Another object of this invention is to provide a process of preparation of novel solid oral dosage form of valsartan, the said process comprising the steps of blending valsartan with the pharmaceutically acceptable excipients, dry granulation inclusive of milling and screening to obtain granules, said granules being subsequently compressed to tablets and coated, wherein hydrochlorothiazide is added in the coating dispersion.

DETAILED DESCRIPTION OF THE INVENTION The present invention is related to novel solid oral dosage forms comprising a) a core comprising an effective amount of valsartan or a pharmaceutically acceptable salt thereof, and pharmaceutically acceptable additives suitable of the preparation of solid oral dosage form; and b) an outer coating comprising an effective amount of hydrochlorothiazide (HCTZ).

"Solid oral dosage form" includes granules, pellets, spheroids, beads, microspheres, ion- exchange resins, tablets, capsules and the like prepared by conventional methods well known to a person skilled in the art.

The pharmaceutically acceptable excipients in the solid oral dosage form include but are not limited to disintegrants, binders, lubricants, glidants, fillers or diluents.

Disintegrants, include but are not limited to, cross linked polyvinylpyrrolidone

(crospovidone, polyplasdone, kollidon XL); starches such as modified starches, pregelatinized starch, maize starch, pregelatinized starch, dried starch and sodium starch glycolate; gum such as alginic acid, sodium alginate, guar gum; croscarmellose sodium, cellulose products such as microcrystalline cellulose and its salts, microfine cellulose, low substituted hydroxypropylcellulose and mixtures thereof; ion exchange resins like polacrilin potassium; most preferably crosslinked polyvinylpyrrolidone, crospovidone, crosslinked CMC and Ac-Di-SoI.

Binders include, but are not limited to, starches such as potato starch, wheat starch, corn starch; microcrystalline cellulose such as products known under the registered trade marks Avicel, Filtrak, Heweten or Pharmacel; celluloses such as hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropylmethyl cellulose, ethyl cellulose, sodium carboxy methyl cellulose; natural gums like acacia, alginic acid, guar gum; liquid glucose, dextrin, povidone, syrup, polyethylene oxide and mixtures thereof.

Lubricants may be selected from, but are not limited to, those conventionally known in the art such as Mg, Al or Ca or Zn stearate, polyethylene glycol, glyceryl behenate, mineral oil, sodium stearyl fumarate, stearic acid, hydrogenated vegetable oil and talc.

Glidants include, but are not limited to, silicon dioxide; magnesium trisilicate, powdered cellulose, starch, talc and tribasic calcium phosphate.

Fillers or diluents, which include, but are not limited to confectioner's sugar, compressible sugar, dextrates, dextrin, dextrose, fructose, lactitol, mannitol, sucrose, starch, lactose, xylitol, sorbitol, talc, microcrystalline cellulose, calcium carbonate, calcium phosphate dibasic or tribasic, calcium sulphate, and the like can be used.

One or more of these additives can be selected and used by the skilled artisan having regard to the particular desired properties of the solid oral dosage form. The amount of each type of additive employed, e.g. glidant, binder, disintegrant, filler or diluent and lubricant may vary within ranges conventional in the art. The solid dosage form of the invention, wherein the core can be formed by various methods known in the art such as by dry granulation, wet granulation, direct compression, extrusion spheronization, layering and the like.

The solid oral dosage form of the invention is further coated, wherein coating or the coating layer comprises hydrochlorothiazide and one or more excipients selected from the group comprising of coating agents, plasticizers, antitacking agents, surfactants, coloring agents and opacifiers.

Coating agents are one or more selected from the group comprising, but are not limited to, polysaccharides such as maltodextrin; alkyl celluloses such as methyl or ethyl cellulose, hydroxyalkylcelluloses (e.g. hydroxypropylcellulose or hydroxypropylmethylcelluloses); polyvinylpyrrolidone, polyvinyl alcohol, copolymers of vinylpyrrolidone and vinyl acetate (e.g. marketed under the brand name of Plasdone) and polymers based on methacrylic acid such as those marketed under the brand name of Eudragit; alginate based coatings; these may be applied from aqueous or non-aqueous systems or combinations of aqueous and non - aqueous systems as appropriate. The solvent used in the non-aqueous coating comprises isopropyl alcohol, acetone, methanol and mixtures thereof. Purified water is used in the aqueous coating.

Plasticizers are selected from the group comprising, but are not limited to, dibutyl phthalate, triethyl citrate, polyethylene glycol, polyethylene derivative such as polysorbate and mixtures thereof.

Antitacking agents are one or more selected from the group comprising, but are not limited to, talc, stearic acid its salts and derivatives, and colloidal silicon dioxide.

Surfactants are one or more selected from the group comprising, but are not limited to, polysorbates and sodium lauryl sulphate. Coloring agents may be selected from, but are not limited to, those conventionally known in the art such as titanium dioxide, iron oxide red, sunset yellow, black iron oxide, yellow iron oxide etc.

Coating can be done using numerous known methods employed in the art, e.g. spray coating in a fluidized bed, or by any known methods using apparatus available in conventional pans or perforated pans.

The present invention also covers a novel solid dosage oral dosage forms comprising valsartan and HCTZ, wherein valsaratan is present in the core as well as coating.

Within the scope of the invention, it also covers a novel solid oral dosage forms comprising valsartan and HCTZ, wherein HCTZ is present in the core as well as coating. The following non-limiting examples serve to illustrate the invention.

EXAMPLES;

Brief Manufacturing Process

1. The sifted components except a part of microcrystalline cellulose, crosslinked polyvinylpyrrolidone and colloidal silicon dioxide are blended in a suitable blender. 2. The blended material is compacted to form slugs/compacts.

3. The compacted material is further sieved again to form granules. The remaining portion of the microcrystalline cellulose, crosslinked polyvinylpyrrolidone and colloidal silicon dioxide are added and blended in a suitable blender.

4. The prepared granules are lubricated and compressed into the tablets.

5. Hydrochlorothiazide is dispersed or dissolved in the aqueous coating solution.

6. The tablets are then coated using aqueous coating solution.

Dissolution Study The in vitro specifications for generic products should be established based on a dissolution profile. In the case of a generic drug product, the dissolution specifications are generally the same as the reference listed drug.

A dissolution test was carried out in 1000 ml of 0.05M phosphate buffer media pH 6.8. The dissolution apparatus used was USP II, at 50 RPM. The following compositions were tested: immediate release tablets comprising of 160mg of valsartan and 25mg of hydrochlorothiazide, prepared according to example 1 as test and DIOVAN HCT^® having valsartan 160mg and 25mg hydrochlorothiazide, by Novartis as reference. The results obtained are summarized below in table 1.

Table 1. Comparative dissolution profiles of the Valsartan/ Hydrochlorothiazide immediate release tablets against commercially available immediate release tablets DIOVAN HCT^®.

Claims

1. A novel solid oral dosage form comprising a) a core comprising an effective amount of valsartan or a pharmaceutically acceptable salt thereof, and pharmaceutically acceptable additives suitable of the preparation of solid oral dosage form; and b) an outer coating comprising an effective amount of hydrochlorothiazide (HCTZ).

2. A novel solid oral dosage form according to claim 1, wherein valsartan is present in a unit dose from lOmg to 250mg, and hydrochlorothiazide is present in a unit dose from 6mg to 60mg.

3. The novel solid oral dosage form of claim 1, wherein the pharmaceutically acceptable additives are selected from the group comprising fillers or diluents, binders, lubricants, glidants and disintegrants.

4. The novel solid oral dosage form of claim 1, wherein the diluent is one or more selected from the group comprising confectioner's sugar, compressible sugar, dextrates, dextrin, dextrose, lactitol, fructose, mannitol, sucrose, starch, lactose, dibasic or tribasic calcium phosphate, calcium carbonate, calcium sulphate, xylitol, sorbitol, talc, micro-crystalline cellulose or mixtures thereof.

5. The novel solid oral dosage form of claim 1, wherein the binder is one or more selected from the group comprising methyl cellulose, hydroxypropylcellulose, low substituted hydroxypropylcellulose, hydroxypropyl methylcellulose, sodium carboxymethylcellulose, ethyl cellulose, microcrystalline cellulose, potato starch, wheat starch, corn starch, pregelatinised maize starch, polyvinylpyrrolidone, acacia, alginic acid, guar gum; liquid glucose, dextrin, povidone, syrup, polyethylene oxide and mixtures thereof.

6. The novel solid oral dosage form of claim 1, wherein the lubricant is one or more selected from the group comprising Mg, Al, Zn or Ca stearate, polyethylene glycol, mineral oil, sodium stearyl fumarate, stearic acid, hydrogenated vegetable oil, glyceryl behenate, talc and mixtures thereof.

7. The novel solid oral dosage form of claim 1, wherein the glidant is one or more selected from the group comprising silicon dioxide, colloidal silica, powdered cellulose, talc, tribasic calcium phosphate and mixtures thereof.

8. The novel solid oral dosage form of claim 1, wherein the disintegrant is one or more selected from the group comprising cross linked polyvinylpyrrolidone, maize starch, dried starch, pregelatinized starch, sodium starch glycolate, alginic acid, sodium alginate, guar gum, croscarmellose sodium, microcrystalline cellulose and its salts, microfine cellulose, low substituted hydroxypropylcellulose, ion exchange resins and mixtures thereof.

9. A process of preparation of novel solid oral dosage form of valsartan, the said process comprising the steps of blending valsartan with the pharmaceutically acceptable excipients, dry granulation, milling and screening to obtain granules, said granules being subsequently compressed to tablets and coated, wherein hydrochlorothiazide is added in the coating dispersion.

10. The novel solid oral dosage form of claim 1, wherein coating layer further comprises one or more excipients selected from the group comprising coating agents, plasticizers, antitacking agents, surfactants, coloring agents and opacifiers.

11. The novel solid oral dosage form of claim 10, wherein the coating agent is one or more selected from the group comprising maltodextrin, methyl or ethyl cellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, polyvinyl alcohol, copolymers of vinylpyrrolidone and vinyl acetate, methacrylic acid and alginates.

12. The novel solid oral dosage form of claim 10, wherein the plasticizer is selected from the group comprising dibutyl phthalate, triethyl citrate, polyethylene glycol, polyethylene derivatives like polysorbates and mixtures thereof.

13. The novel solid oral dosage form of claim 10, wherein the antitacking agent is one or more selected from the group comprising talc, colloidal silicon dioxide, stearic acid, its salts and derivatives.

14. The novel solid oral dosage form of claim 10, wherein the surfactant is one or more selected from the group comprising polysorbates and sodium lauryl sulphate.

15. The novel solid oral dosage form as in claim 1 is in the form of tablets.

16. The novel solid oral dosage form as in claim 1, wherein a therapeutically effective amount of valsartan is present in the core as well as in the coating.

17. The novel solid oral dosage form as in claim 1, wherein a therapeutically effective amount of HCTZ is present in the core as well as in the coating.