JPH02233616A - Benazepuril/thiazide diuretic composition of low dosage - Google Patents

Abstract

PURPOSE: To prepare a composition, comprising bezenapril or its salt and a thiazide diuretic agent and capable of treating a lesser degree to a medium degree of hypertension in a lower dose than that when used alone. CONSTITUTION: This composition comprises bezenapril in about 4-6mg, preferably about 5mg dose at a time or its pharmaceutically permissible salt and a thiazide diuretic agent in an amount of 80-120%, preferably 100% based on 1/8 of the minimal antihyopertensive initial dose recommended when used alone. Bendroflumethiazide, Chlorthalidone, Chlorothiazide, hydrochlorothiazide, hydroflumethiazide, methylchlorothiazide, polythiazide, trichloromethiazide, benzthiazide and dichloroazide are cited as the thiazide diuretic agent. The most preferred composition comprises bezenapril hydrochloride and hydrochlorothiazide at about 0.8-1 weight ratio.

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Application] The present invention relates to a pharmaceutical composition for treating mild to moderate hypertension containing the angiotensin converting enzyme inhibitor benazepril in combination with a thiazide diuretic; This article relates to a method for treating hypertension using this composition. [Prior Art and Problems to be Solved by the Invention] Benazepril hydrochloride is a novel, orally active, sulfhydryl-free angiotensin-converting enzyme inhibitor having the following structure. This compound is described in US Pat. No. 4,410,520. Thiazide diuretics, the second component of the combination of the invention, have long been the mainstay of antihypertensive therapy. All of the active ingredients of the present invention are compounds well known in the art, and their synthesis, routes of administration, etc. are well known. Additionally, some literature has been published in recent years regarding the combination of angiotensin converting enzyme inhibitors with thiazide diuretics.

See, e.g., U.S. Pat. No. 4,472,380, particularly paragraphs 9 and 10, and Example 127; U.S. Pat. No. 4,217.
．． No. 347, especially stages 2-3 and Examples; As+er
ican J. tl ert U soil (1), 38-4
1 (1988); European Patent No. 0.215,357; J. H ertension earth (enlargement 2), 38
4-386 (1983) i and ha er. J. h
On μmk (3, part 2), 13A-14A, 77'
See X-7 1226 (1988).
However, none of these deals with angiotensin converting enzyme inhibitors and/or diuretics other than benazepril in substantially higher amounts than the present invention. Perhaps the most important reference is U.S. Patent Application No. 383. 43
Merck South African Patent Application No. 83 3903 which claims priority to No. 5. This reference indicates that 2.
Angiotensin converting enzyme inhibitors of the benazepril type are disclosed in amounts of 5 to 100 μ/day. However, hydrochlorothiazide is only mentioned in amounts of at least 10/day.

It is an object of the present invention to provide pharmaceutical compositions and methods of treatment for the treatment of mild to moderate hypertension with minimal amounts of active ingredients, while achieving in simultaneous dosing a blood pressure reduction that cannot be achieved with the individual active agents. It is to provide. [Means for Solving the Problems] The present invention provides 4 to 6 m
80% to 12 g of benazepril or a pharmaceutically acceptable salt thereof and 1/8 of the initial daily dose recommended for antihypertension.
Concerning a fixed ratio low dose combination with 0% thiazide diuretic. The compositions of the present invention have a daily dose of about 4 mg to about 6 mg for administration to adults with mild to moderate hypertension.
■ Preferably about 5 mg of benazepril hydrochloride or any other pharmaceutically acceptable salt of benazepril and 1/1/2 of the usual clinical antihypertensive adult initial dose when the thiazide diuretic is used alone. 80% to about 120%, preferably about 100% of a thiazide diuretic. Pharmaceutically acceptable salts of benazepril include physiologically harmless acids such as inorganic acids such as hydrochloric acid, sulfuric acid or phosphoric acid;
or with organic carboxylic or sulfonic acids such as acetic acid, propionic acid, glycolic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, methanesulfonic acid, ethanesulfonic acid or 2-hydroxyethanesulfonic acid. It is an acid addition salt. Hydrochlorides, ie acid addition salts with hydrochloric acid, are preferred. Preferably, the diuretic is selected from:

Bendroflumethiazide (5mg) 0. 5-0.7
5mg; Chlorthalidone (25mg) 2.
5-3.75mg; Chlorothiazide (500
■) 50-75mg; Hydrochlorothiazide (5
0■') 5-7.5mg hydroflumethiazide
(50■) 5-7.5mg methylchlorothiazide (2.5mg) 0.25-0.38■ boritiazide
(2■) 0.2-0.3■ Trichlormethiazide (2■) 0.2-0.3■ Benzthiazide
(50■) 0. 5 - 0.75mg cyclothiazide (2■) 0.2-0.3M. The usual clinical minimum antihypertensive adult initial dose is indicated in the cutlet,
Dosage ranges useful in the present invention are then presented. The clinical initial doses applied today may differ in some cases from the amounts indicated in the brackets of the above list. For example, hydrochlorothiazide is often given in an initial dose of 25 mg. More preferably, the thiazide diuretic is selected from chlorothiazide, hydrochlorthiazide, methylchlorothiazide and chlorthalidone. Most preferably, the thiazide diuretic is selected from chlorothiazide and hydrochlorthiazide;
Hydrocrothiazide is particularly preferred. The most advantageous composition comprises benazepril hydrochloride and hydrochlorthiazide in a weight ratio of about 0.8 to 1;
For example, it comprises about 5 mg of benazepril hydrochloride and about 6.25 g of hydroxiothiazide. 95-114mlg
Efficacy of a preferred combination of the present invention comprising 5 mg benazebril hydrochloride and 6.25 mg hydroxorothiazide in a clinical double-blind randomized study in 334 men and women with a seated diastolic blood pressure of was compared to the efficacy of another composition and a single drug over a 6 week period. The results are summarized in the following table: Benazepurinole a) 5 mg + Hydrox oral thiazide 6.
25mg - 9.9peng 11gb) Benazepril lO■ + Hydrox oral thiazide 12.5f
flg-9. 6 mmHg Benazepril 20■ + Hydrochlorothiazide 25mg1
3.9wllg benazepril 20■ -9. 3 a
m+Hg hydrochlorothiazide 25mg -6.
9 mmflg Benazepril 20 ■ + Hydrochlorothiazide 6.25 mg - 10.3 mHg Benazepril 5 mg + Hydrochlorothiazide 25 mg - 10.7 Hg Placebo -3.9 Hg
b) Reduction in diastolic blood pressure as the hydrochloride salt.Clinical results demonstrate that the low dose compositions of the present invention have surprising efficacy.

The composition can be formulated in any convenient dosage form, including tablets, capsules, powders, etc., by methods standard in the art. It may also contain any suitable pharmaceutical adjuvants or carriers. Administration may be by any route that allows for simultaneous administration of both benazepril and the thiazide diuretic, but is most preferably oral. The most suitable dosage forms are solid oral dosage forms such as tablets or capsules. Most preferably only benazepril and only one thiazide diuretic are present in any one composition, although other antihypertensive actives may be added.

The invention will be more fully understood with reference to the following examples which illustrate but do not limit the invention.

'JLkfM: 6.251g of 6-chloro3.4
-dihydro-2H-1. 2, 1-penzothiadiazine-7-sulfonamide-1,1-dioxide and 5.00 mg of 1-ethoxycarbonyl-3-phenylpropylamino-
2.3.4.5-Tetrahydro-IH-(1) Film-coated tablets containing pensacehin-2-one hydrochloride are prepared as follows: ti (for 2.000 tablets) -chloro3,4-dihydro-2H-1,2,4-penzothiadiazine-7-sulfonamide 1,1-dioxide (finely ground) 12.50 g l-carboxymethyl-33-( is-ethoxycarbonyl-3-phenylbropylamino)-2. 3.
4. 5-tetrahydride-IH-[1) Penzazepin-2-one hydrochloride 10.00 g Hydroxypropyl methylcellulose 6.00 g Hydrogenated castor oil 12.00 g Lactose (ground) 423.50 g
Polyvinylpyrrolidone 20.00 g
1 Z4''~, ] Material Hydroxypropyl Methyl Cellulose 7.34 g Polyethylene Glycol 8000 (Flake) 1.3
4g talc 5.32g titanium dioxide 2. OOg6-chloro3.4-dihydro-2H-1.2.4-penzothiadiazine-7-sulfonamide-1.1-dioxide,
l-carboxymethyl-33-(Is-ethoxycarbonyl-3-phenylpropylamino)-2.3.4.5
-Tetrahydro-IH- (1) Mix penzazepin-2-one hydrochloride and hydroxypropyl methylcellulose towards the core material with a portion of lactose. Add the remaining lactose and granulate the mixture with water, dry, and pulverize. The remaining core ingredients are mixed therein and the homogeneous mixture is compressed into tablets, which are coated with an aqueous suspension of the coating material described above.

Claims (1)

Claims: 1. A low-dose pharmaceutical composition for treating mild to moderate hypertension, comprising about 4 mg to about 6 mg of benazepril or a pharmaceutically acceptable salt of benazepril, and used alone. a thiazide diuretic in an amount of about 80% to 120% of 1/8 of the recommended minimum antihypertensive initial dose of the thiazide diuretic in the case where the amount of each component is per single dose of said composition.
A composition comprising. 2. The thiazide diuretic is bendroflumethiazide,
2. The composition of claim 1 selected from the group consisting of chlorthalidone, chlorothiazide, hydrochlorothiazide, hydroflumethiazide, methylchlorothiazide, vorithiazide, trichlormethiazide, benzthiazide and cyclothiazide. 3. The composition of claim 2, wherein the thiazide diuretic is hydrochlorothiazide. 4. The thiazide diuretic is 1/8 of the minimum antihypertensive initial dose recommended when the thiazide diuretic is used alone.
A composition according to claim 1, wherein the composition is present in an amount of . 5. The composition of claim 3, wherein the hydrochlorothiazide is present in an amount of about 5 mg to about 7.5 mg per dose. 6. The hydrochlorothiazide is about 6.25 m per dose.
6. The composition of claim 5, wherein the composition is present in an amount of g. 7. The composition according to claim 1, wherein the benazepril or a pharmaceutically acceptable salt thereof is benazepril hydrochloride. 8. The composition of claim 7, wherein said benazepril hydrochloride is present in an amount of about 5 mg per dose. 9. 5mg benazepril hydrochloride and 6.25mg per dose
The composition of claim 1, comprising hydrochlorothiazide. 10. The composition according to claim 1, which is a tablet, powder or capsule. 11. The composition according to claim 1, which is an oral tablet or an oral capsule.