WO2006092732A2

WO2006092732A2 - Stable solid dosage form of antihypertensive agent

Info

Publication number: WO2006092732A2
Application number: PCT/IB2006/000535
Authority: WO
Inventors: Umesh Mutt Hangaji; Hidaythulla Shamshuddin Aga; Kishor Dattatray Deo; Sivakumaran Meenakshisunderam
Original assignee: Aurobindo Pharma Ltd
Priority date: 2005-03-04
Filing date: 2006-02-28
Publication date: 2006-09-08
Also published as: WO2006092732A3

Abstract

The present invention relates to stable pharmaceutical compositions of antihypertensive agent. More particularly, the present invention relates to stable solid dosage forms of benazepril hydrochloride. The invention also relates to a process for the preparation of stable solid dosage forms of benazepril hydrochloride.

Description

STABLE SOLID DOSAGE FORM OF ANTIHYPERTENSIVE AGENT

Field of the invention

The present invention relates to stable pharmaceutical compositions of antihypertensive agent. More particularly, the present invention relates to stable solid dosage forms of benazepril hydrochloride.

The present invention also relates to a process for the preparation of stable solid dosage forms of benazepril hydrochloride.

Background of the invention

Benazepril is 3 -[[1 -(ethoxycarbonyl)-3 -phenyl-( 1 S)-propyl] amino] -2,3 ,4,5 - tetrahydro-2-oxo- IH-I -(3 S)-benzazepine-l -acetic acid. It is marketed as monohydrochloride under the trade names LOTENSIN® in US and CIBACEN® in Europe. Benazepril hydrochloride is disclosed in U.S. Pat. No. 4,410,520, as an angiotensin converting enzyme inhibitor used as antihypertensive agent. Benazeprilat is the diacid form of benazepril formed by cleavage of the ester group, and is the active metabolite of benazepril. Benazepril and Benazeprilat may be administered in free or pharmaceutically acceptable salt form.

LOTENSIN®, is supplied as tablet containing 5mg, 10mg, 20mg & 40mg of benazepril hydrochloride for oral administration in the United States. LOTENSIN® comprise, in addition to benazepril hydrochloride as active ingredient, various inactive ingredients, which include a lubricant to avoid sticking & picking of powder blend to the punches in the tabletting process. According to the literature for LOTENSIN™, the lubricant used in the 5 mg and 10 mg tablets is hydrόgenated castor oil, while that used in the 40 mg tablets is magnesium stearate. Ηydrogeήated castor oil is having additional application of lubricating die walls. Magnesium stearate is the most commonly used lubricant in pharmaceutical tablets.. However, it accelerates the rate of degradation of benazepril hydrochloride. Hence, the tablets of benazepril hydrochloride, which contain magnesium stearate, have a shorter shelf life than would be the case without magnesium stearate. It appears that 40 mg tablets could not be made using hydrogenated castor oil as the . only lubricant (i.e. without magnesium stearate) because hydrogenated castor oil is relatively ineffective as a lubricant, and is not sufficiently effective to eliminate sticking in the higher strength (40 mg) tablets.

US 6,737,419 describes tablets of benazepril hydrochloride prepared by employing zinc stearate as the lubricant.

JP 2002-322064 describes a process for preparing stable benazepril tablets by using additives not containing an alkali metal and an alkaline earth metal.

It appears from the literature that there is possibility for the degradation of benazepril hydrochloride in a tablet containing magnesium stearate as lubricant. In order to avoid the possible degradation of benazepril with lubricants, inventors of the present invention found sodium stearyl fumarate, talc, colloidal silicon dioxide or their combination as lubricants for preparing stable tablets of benazepril. In addition, the inventors of the present invention found that shelf life and stability of solid dosage forms of the benazepril hydrochloride is increased when sodium steaiyl fumarate alone or in combination with talc or colloidal silicon dioxide is used as lubricant.

Objective of the invention

Accordingly, the main objective of present invention is to provide solid dosage forms of benazepril or its pharmaceutically acceptable salts, using lubricants, which are compatible with benazepril, and stable during storage. .

Yet another objective of the present invention is to provide simple, cost effective and efficient process for preparing stable solid dosage forms of benazepril or its pharmaceutically acceptable salts. ^• ■ Summary of the invention

According to the main embodiment of the present invention, there is provided stable solid dosage form comprising benazepril or its pharmaceutically acceptable salts and a lubricant selected from the group consisting of sodium stearyl fumarate, talc, colloidal silicon dioxide, glyceryl dibehenate and the like or mixtures thereof.

Detailed description of the invention

In an embodiment of the present invention, the stable solid dosage forms of benazepril further comprise pharmaceutically acceptable excipients such as diluents, di^'sintegrants, binders, glidants and the like.

Ih yet another embodiment, the stable solid dosage form of benazepril further comprises diuretics. Suitable diuretics according to the present invention include furosemide, spironolactone, chlorthalidone, amiloride, triamterene, and thiazide diuretics such as hydrochlorothiazide, chlorothiazide, flumethiazide, and bendroflumethiazide.

In an embodiment of the present invention, the strength of benazepril used is 5 mg to 40 mg per dosage form.

The term pharmaceutically acceptable salts as used herein includes inorganic or organic acids such as hydrochloride, hydrobromide, sulphate, nitrate, phosphate, formate, mesylate, citrate, benzoate, fumarate, maleate, tartrate and succinate.

Sodium stearyl fumarate is an inert, hydrophilic tablet lubricant having good anti-adherent property, and shows less retardant effect on dissolution rate than magnesium stearate. The tablets made with sodium stearyl fumarate exhibit less sensitivity to blending time and have superior hardness characteristics compared to tablets produced with magnesium stearate even at higher concentration.

Suitable glidants used in. accordance with the present invention are selected from talc, cornstarch, and colloidal silicon dioxide. Suitable diluents used in accordance with the present invention are selected from calcium phosphate-dibasic, calcium carbonate, lactose, sucrose, cellulose- microcrystalline, cellulose powdered, calcium silicate, kaolin, starch, starch pregelatinized, polyols such as mannitol, sorbitol, lactitol, xylitol, maltitol, sucrose or combinations thereof.

Suitable disintegrants used in accordance with the present invention are selected from croscarmellose sodium, crospovidone, sodium starch glycolate, sodium carboxymethylcellulose, hydroxypropylcellulose, xanthan gum, alginic acid, alginates, carbopols and the like or combination thereof.

Suitable binders according to the present invention are selected from methyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, polyvinylpyrrolidone, gelatin, gum arabic, ethyl cellulose, polyvinyl alcohol, starch, pregelatinized starch, agar, tragacanth, sodium alginate, propylene glycol, alginate, plasdone and the like.

In another embodiment of the present invention, the lubricant used is in the range from about 0.2 to 3.0 % by weight of the composition.

In an embodiment, the solid dosage form of the present invention include tablets and capsules.

The different formulation processes that can be employed for making the disclosed formulations are dry granulation (slugging, compaction), wet granulation, and direct compression.

Benazepril tablets prepared by any of the above methods may optionally be coated with film forming materials such as hydroxypropyl methylcellulose, hydroxypropyl cellulose, and the like.

In yet another embodiment of the present invention, there is provided wet granulation process' for the preparation of stable solid dosage form comprising benazepril or its pharmaceutically acceptable salts and a lubricant selected from- the group consisting of sodium stearyl fumarate, talc, colloidal silicon dioxide, glyceryl dibehenate and the like or mixtures thereof, comprising the steps of: i) blending benazepril with one or more diluents, disintegrants, binders, ii) granulating the blend obtained in step (i) with a solvent, iii) mixing the granules of step (ii) with one or more diluents, and disintegrants, iv) lubricating the blend of step . (iii), and v) compressing the blended granules to obtain tablet.

The solvent used for preparing granules can be an aqueous and/or non-aqueous solvent. The non- aqueous solvent selected from alcohol or isopropyl alcohol.

The following examples further exemplify the inventions and are not intended to limit the scope of the inventions. It is obvious to those skilled in the art to find out the composition for other dosage forms and substitute the equivalent excipients^' as described in this specification or with the one known to the industry.

The processing steps that were involved in making benazepril tablets described in example 1-4 are as given below:

(i) sifted benazepril hydrochloride, lactose, pregelatinized starch, microcrystalline cellulose, and crospovidone,

(ii) mixed the materials of step (i) in a rapid mixer granulator,

(iii) granulated the blend of step (ii) with purified water,

(iv) dried the granules of step (iii),

(v) blended the dried granules of step (iv) with extragranular crospovidone in octagonal blender, . .

(vi) lubricated the blend with sodium steaiyl fumarate,

(vii) compressed the lubricated blend to obtain tablets, and coated the core tablets with film forming materials. Example 5

The processing steps that were involved in making benazepril tablets are as given below:

(ii) mixed the materials of step (i) in a rapid mixer granulator,

(iii) granulated the blend of step (ii) with purified water,

(iv) dried the granules of step (iii),

(v) blended the dried granules of step (iv) with extragranular crospovidone and colloidal silicon dioxide in octagonal blender,

(vi) lubricated the blend with sodium stearyl fumarate,

(vii) compressed the lubricated blend to obtain tablets, and coated the core tablets with film forming materials. Example 6

(ii) mixed the materials of step (i) in a rapid mixer granulator,

(iii) granulated the blend of step (ii) with purified water,

(iv) dried the granules of step (iii),

(v) blended the dried granules of step (iv) with extragranular colloidal silicon dioxide, talc, and crospovidone in octagonal blender,

(vi) lubricated the blend with sodium stearyl fumarate, (vii) compressed the lubricated blend to obtain tablets, and coated the core tablets with film forming materials. Example 7

Example 8

The processing steps that were involved in making benazepril tablets given in examples 7 & 8 are as given below:

(ii) mixed the materials of step (i) in a rapid mixer granulator,

(iii) granulated the blend of step (ii) with purified water,

(iv) dried the granules of step (iii),

(vi) compressed the blend of step (v) to obtain tablets, and coated the core tablets with film forming materials.

Example 9

(i) sifted benazepril hydrochloride, hydrochlorothiazide, lactose, pregelatinized starch, microcrystalline cellulose, and crospovidone,

(ii) mixed the materials of step (i) in a rapid mixer granulator,

(iii) granulated the blend of step (ii) with purified water,

(iv) dried the granules of step (iii),

(v) blended the dried granules of step (iv) with extragranular colloidal silicon dioxide, and crospovidone in octagonal blender,

(vi) lubricated the blend with sodium stearyl fumarate,

(vii) compressed the lubricated blend to obtain tablets, and coated the core tablets with film forming materials.

Example 10

Tablets of examples 8 and 9 as well as tablets with LOTENSIN® tablets (5 mg) were stored at 80 ⁰C for 2 days and then tested by an HPLC method to determine the degradation products as a percentage of the initial benazepril hydrochloride content. The results are shown in table 1.

Table 1

It can be seen from the table 1, that the percentage of degradation is much lower for the tablets of examples 8 and 9 (which comprise sodium stearyl fumarate and talc / colloidal silicon dioxide as lubricant) than for either the tablets of example 10 (magnesium stearate as lubricant) or LOTENSIN® 5 mg tablets (hydrogenated vegetable oil as lubricant).

Claims

Claims :

1. A stable solid dosage form comprising benazepril or its pharmaceutically acceptable salts and a lubricant selected from the group consisting of sodium stearyl fumarate, talc, colloidal silicon dioxide, glyceryl dibehenate or mixtures thereof.

2. The solid dosage form according to claim 1, further comprises diluents, disintegrants, binders, and glidants.

3. The solid dosage form according to claim 2, wherein the diluent is selected from calcium phosphate-dibasic, calcium carbonate, lactose, sucrose, cellulose- microcrystalline, cellulose powdered, calcium silicate, kaolin, starch, starch pregelatinized, polyols such as mannitol, sorbitol, lactitol, xylitol, maltitol, sucrose and combinations thereof.

4. The solid dosage form according to claim 2, wherein the disintegrant is selected from croscarmellose sodium, crospovidone, sodium starch glycolate, sodium carboxymethylcellulose, hydroxypropylcellulose, xanthan gum, alginic acid, alginates, carbopols or combinations thereof.

5. The solid dosage form according to claim 2, wherein the binder is selected from methyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, polyvinylpyrrolidone, gelatin, gum arabic, ethyl cellulose, polyvinyl alcohol, starch, pregelatinized starch, agar, tragacanth, sodium alginate, propylene glycol, alginate, or plasdone.

6. The solid dosage form according to claim 1, further comprise diuretic selected from furosemide, spironolactone, chlorthalidone, amiloride, triamterene, and thiazide diuretics such as hydrochlorothiazide, chlorothiazide, flumethiazide, and bendroflumethiazide.

7. A process for the preparation of form comprising benazepril or its pharmaceutically acceptable salts and a lubricant selected from the group consisting of sodium stearyl fumarate, talc, colloidal silicon dioxide, glyceryl dibehenate or mixtures thereof, comprising the steps of: i) blending benazepril with one or more diluents, disintegrants, binders, ii) granulating the blend obtained in step (i) with a solvent, iii) mixing the granules of step (ii) with one or more diluent, disintegrants, iv) . lubricating the blend of step (iii), and v) compressing the blended granules to obtain tablet.