KR0141479B1 - Low Dose Benazapril / Thiazide Diuretic Compositions - Google Patents

Abstract

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Description

Low Dose Benazapril / Thiazide Diuretic Composition

The present invention relates to a pharmaceutical composition for treating mild hypertension or moderate solid pressure, comprising an angiotensin converting enzyme inhibitor benzapril in combination with a thiazide diuretic, and a method for treating hypertension using the composition.

Benazapril Aridrochloride is a novel orally active angiotensin converting enzyme inhibitor of the following structural formula containing no sulfhydryl group.

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This compound is described in US Pat. No. 4,410,520. Thiazide diuretics, the second component of the composition of the present invention, have long been a major component of hypertension treatment. All active agents of the present invention are compounds known in the art, and the synthesis, administration method, and the like of these compounds are well known. In addition, literature has recently been published on combining angiotensin converting enzyme inhibitors with thiazide diuretics (see US Pat. Nos. 4,472,380, in particular columns 9 and 10, and Example 127; U.S. Patent No. 4,217347, in particular Columns 2-3 and Examples; American J. Hypert, 1 (1), 38-41 (1988): Turup patent application 0,215,357; J. Hypertension 1 (Suppl. 2), 384-386 (1983); And Amer. J. Hypert. 1 (3 part 2), 13A-14A, Abstract 1226 (1988). However, each of these inventions uses substantially higher amounts of angiotensin converting enzyme inhibitors than in the present invention, unlike bezapril and / or diuretics. Perhaps the most important reference is South African patent application 833903 (Merck), which claims priority of US patent application 383,435. This document describes the combination of an angiotensin converting enzyme inhibitor in the form of benzapril, 2.5-100 mg / day, with a diuretic, generally 0.5-100 mg / day. Hydrochlorothiazide is only mentioned in amounts of 10 mg / day or more.

It is an object of the present invention to provide pharmaceutical compositions and methods for treating mild hypertension to moderate hypertension with minimal amounts of active agents while achieving blood pressure drops that cannot be achieved with each active agent at the same dose.

The present invention provides a thiazide diuretic with 80 to 120% of the clinically recommended daily dose for treatment of initial hypertension given as a once daily dosage form and 4 to 6 mg of benazapril or medicament. It relates to a fixed dosage of low dose mixtures of their acceptable salts. The compositions of the present invention may be treated with about 4 to about 6 mg, preferably about 5 mg of benzapryl hydrochloride or other pharmaceutically acceptable salts of benzapril, and when used alone, a conventional initial hypertension treatment. Daily unit for administration to adults with mild hypertension or moderate hypertension, comprising thiazide diuretics, from about 80 to about 120%, preferably about 100%, of one eighth of the adult's clinical dosage for Dosage.

Pharmaceutically acceptable salts of benzapril are pharmaceutically harmless acids such as inorganic acids (e.g. hydrochloric acid, equivalent and phosphoric acid) or organic carbonic acid, sulfonic or sulfoic acid (e.g. acetic acid, propionic acid, Acid addition salts with glycolic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, methanesulfonic acid, ethanesulfonic acid and 2-hydroxyethanesulfonic acid). Preference is given to hydrochloride, ie acid addition salts with hydrochloric acid.

The minimum dose of an adult for conventional early clinical hypertension treatment is shown in parentheses, followed by a range of dosages useful in the present invention. The initial clinical doses administered today may differ from those given in parentheses for some cases. For example, the initial dosage of hydrochlorothiazide is often given at 25 mg.

More preferably, thiazide diuretics are selected from chlorothiazide, hydroxychlorothiazide, methylchlorothiazide and chlorothalidone. Most preferably, tideide diuretics are selected from chlorothiazide and hydroxychlorothiazide, with hydrochlorothiazide being particularly preferred.

The most advantageous compositions contain benzapryl hydrochloride and hydrochlorothiazide in a weight ratio of about 0.8 to 1, for example, about 5 mg of benazapril hydrochloride and about 6.25 mg of hydroclothiazide.

In a clinical double-blind randomized trial of 334 men and women with a single diastolic blood pressure of 95 to 114 mmHg, 5 mg of benzapryl hydrochloride and 6.25 mg of hydrochlorothiazide, presented in a single daily dose The efficacy of the preferred mixtures of the present invention is compared to the efficacy of other compositions and the efficacy of the daily agent for six weeks. The results are summarized in the following table:

a) as a hydrochloride

b) drop in diastolic blood pressure

Clinical results show that the low dose compositions of the present invention have surprising efficacy.

The composition may be formulated in a convenient dosage form including tablets, capsules, powders and the like by methods common in the art. Suitable pharmaceutical adjuvants or carriers may be included. Benazapril and thiazide diuretics may be administered in a manner that can be administered simultaneously, but most preferably oral administration. Most suitable dosage forms are solid oral dosage forms such as tablets or capsules. Although other active agents for the treatment of hypertension may be added, most preferably only benzapril and one thiazide diuretic are present in one composition.

The invention may be understood in more detail with reference to the following examples which are illustrated, but are not intended to limit the invention.

Example: 6.25 mg 6-chloro-3, 4-dihydro-2H-1, 2, 4-benzothiadiazine-7-sulfonamide-1, 1-dioxide and 5.00 mg 1-carboxymethyl-3S A coating tablet containing-(1S-ethoxycarbonyl-3-phenylpropylamino) -2, 3, 4, 5-tetrahydro-1H- [1] benzazin-2-one hydrochloride is as follows. Manufactures:

6-chloro-3, 4-dihydro-2H-1, 2, 4-benzothiadiazine-7-sulfonamide-1, 1-dioxide, 1-carboxymethyl-3S- (1S-ethoxycarbonyl- 3-phenylpropylamino) -2, 3, 4, 5-tetrahydro-1H- [1] benzazin-2-one hydrochloride and core hydroxypropyl-methylcellulose are mixed with a portion of lactose. The remaining lactose is added and the mixture is granulated with water, dried and milled. The remaining core component is combined with it and the homogeneous mixture is compressed into tablets and then coated with an aqueous suspension of the coating material.

Claims (11)

About 4 to about 6 mg of benazapril or a pharmaceutically acceptable salt of benazapril and a thiazide diuretic alone, per unit dose of the composition, may be used at the recommended minimum dose for treating initial hypertension. A low dose dosage composition for treating mild to moderate to moderate hypertension, comprising about 80 to 120% of a thiazide diuretic in an eighth ratio. The thiazide diuretic according to claim 1, wherein the thiazide diuretic is selected from bend flumetiazide, chlorothalidin, chlorothiazide, hydrochlorothiazide, hydrflumethiazide, methylchlorothiazide, polythiazide, trichlormethiazide, The composition selected from benzthiazide and cyclothiazide. The composition of claim 2 wherein the thiazide diuretic is hydrochlorothiazide. The composition of claim 1, wherein when thiazide diuretic is used alone, it is present in an amount of one eighth of the minimum dosage recommended for treating initial hypertension. The composition of claim 3, wherein the hydrochlorothiazide is present in an amount from about 5 to about 7.5 mg per dose. 6. The composition of claim 5, wherein the hydrochlorothiazide is present in an amount of about 6.25 mg per dose. The composition of claim 1, wherein the benazapril or pharmaceutically acceptable salt thereof is benazapril hydrochlorolide. 8. The composition of claim 7, wherein the benazapril hydrochloride is present in an amount of about 5 mg per dose. The composition of claim 1 containing 5 mg of benzapryl hydrochloride and 6.25 mg of hydrochlorothiazide per dose. The composition of claim 1 which is a tablet, powder or capsule. The composition of claim 1 which is an oral tablet or oral capsule.