LU87660A1 - LOW-DOSED COMPOSITION CONTAINING BENAZEPRIL AND A THIAZIDE DIURETIC - Google Patents

Description

Low dose composition containing benazepril and a thiazide diuretic

The invention relates to a pharmaceutical composition for the treatment of mild or moderate high blood pressure containing the "angiotensin converting enzyme" inhibitor benazepril in combination with thiazide diuretics and a method for the treatment of high blood pressure using this composition.

Benazepril hydrochloride is a new, orally active, sulfhydril group-free "angiotensin converting enzyme" (ACE) inhibitor of the formula

The compound is described in U.S. Patent 4,410,520. Thiazide diuretics, the second component of the compositions according to the invention, have long been used in the therapy of hypertension. All active substances of the present invention are described in the prior art; their synthesis, mode of administration, etc. are well known. In addition, literature has recently been published on simultaneous administration of "angiotensin converting enzyme" inhibitors and thiazide diuretics; see, for example, US Patent 4,472,380, particularly Columns 9 and 10 and Example 127; U.S. Patent 4 * 217 * 347, particularly Column 2-3 and the examples; American J. Hypert. 1 (1), 38-41 (1988); European patent application 215 * 357; J. Hypertension 1 (Suppl. 2), 384-386 (1983); and Amer. J. Hypert. 1 (3, part 2), 13A-14A, abstract 1226 (1988). By contrast, these publications describe ACE-inhibiting active substances other than benazepril and / or diuretics in amounts which are substantially higher than those used in this invention. Probably the most important publication is South African patent application 83 3903 (Merck), which claims the priority of US application 383 * 435.

This publication describes ACE inhibitors of the benazepril type in amounts of 2.5 to 100 mg / day in combination with diuretics in the general range of 0.5 to 100 mg / day. Hydrochlorothiazide is only mentioned in amounts of at least 10 mg / day.

The present invention relates to a pharmaceutical composition for the treatment of mild to moderate high blood pressure with a minimal amount of active substance and a method for the treatment of high blood pressure using this composition. With the composition according to the invention, a reduction in blood pressure is achieved which cannot be achieved with the individual active substances in the same dosage.

The invention relates to a low-dose composition in a fixed ratio of 4-6 mg benazepril or a pharmaceutically acceptable salt of benazepril to 80-120% of an amount of a thiazide diuretic which corresponds to Vs the usual, clinically recommended starting dose with antihypertensive effect as a once-daily dose. The composition according to the invention is a daily unit dose for use in adult people with low to moderate high blood pressure. It contains about 4 to about 6 mg, preferably about 5 mg, of benazepril hydrochloride or any other pharmaceutically acceptable salt of benazepril and about 80 to about 120%, preferably about 100%, of the amount of a thiazide diuretic, which is V8 of the usual starting antihypertensive clinical dose for adults, if such a diuretic is used alone.

Salts from Benazepril that can be used pharmaceutically are acid addition salts with pharmacologically acceptable acids, e.g. with inorganic acids, e.g. Hydrochloric acid, sulfuric acid or phosphoric acid, or with organic carboxylic, sulfonic or sulfo acids, e.g. Acetic acid, propionic acid, glycolic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, methanesulfonic acid, ethanesulfonic acid or 2-hydroxyethanesulfonic acid. Preferred is the hydrochloride, i.e. the acid addition salt with hydrochloric acid.

The diuretic is preferably one of the following compounds:

Bendroflumethiazide (5 mg) 0.5-0.75 mg;

Chlorthalidone (25 mg) 2.5 - 3.75 mg;

Chlorothiazide (500 mg) 50-75 mg;

Hydrochlorothiazide (50 mg) 5 - 7.5 mg;

Hydroflumethiazide (50 mg) 5-7.5 mg;

Methyl chlorothiazide (2.5 mg) 0.25-0.38 mg;

Polythiazide (2 mg) 0.2-0.3 mg;

Trichloromethiazide (2 mg) 0.2-0.3 mg;

Benzthiazide (50 mg) 0.5-0.75 mg;

Cyclothiazide (2 mg) 0.2-0.3 mg.

The usual minimum, clinically hypotensive, starting dose for adults is given in parentheses, followed by the dose range in compositions according to the present invention. The clinical starting doses used today may differ in individual cases from the values given in brackets in the above list. For example, hydrochlorothiazide is often administered at an initial dose of 25 mg.

A thiazide diuretic selected from chlorothiazide, hydrochlorothiazide, methylchlorothiazide and chlorothalidone is particularly preferred. Chlorothiazide and hydrochlorothiazide, in particular hydrochlorothiazide, are very particularly preferred as the thiazide diuretic.

A preferred composition contains benazepril hydrochloride and hydrochlorothiazine in a weight ratio of about 0.8 to 1, for example about 5 mg benazepril hydrochloride and about 6.25 mg hydrochlorothiazide.

In a double-blind clinical study in 334 men and women with a diastolic blood pressure of 95-114 mmHg (seated), the effect of the preferred combination according to the invention of 5 mg benazepril hydrochloride with 6.25 mg hydrochlorothiazide was administered once daily for six weeks, compared with the effect of other compositions and the individual active ingredients alone. The results are summarized in the following table: 5 mg benazepril ^ + 6.25 mg hydrochlorothiazide - 9.9 mmHgb) 10 mg benazepril + 12.5 mg hydrochlorothiazide - 9.6 mmHg 20 mg benazepril + 25 mg hydrochlorothiazide -13.9 mmHg 20 mg benazepril - 9.8 mmHg 25 mg hydrochlorothiazide - 6.9 mmHg 20 mg benazepril + 6.25 mg hydrochlorothiazide -10.3 mmHg.

5 mg benazepril + 25 mg hydrochlorothiazide -10.7 mmHg

Placebo - 3.9 mmHg a) as hydrochloride b) reduction in diastolic blood pressure, measured while sitting

The clinical results show that the low-dose composition according to the invention has a surprising effect.

The pharmaceutical composition according to the invention can be produced in any dosage form, for example tablets, capsules, powders, etc., by standard methods. Any common pharmaceutical carrier or excipient may be included. The composition can be administered in any manner in which benazepril and the thiazide diuretic are given simultaneously, but preferably orally. The preferred dosage form is a solid oral dosage form, for example tablets or capsules. It is possible to add other antihypertensive agents, but preferably the composition contains only benazepril and only one thiazide diuretic.

The following example illustrates the present invention, but in no way limits it.

Example: film-coated tablets containing 6.25 mg 6-chloro-3,4-dihydro-2H-l, 2,4-benzthia-diazine-7-sulfonamide-l, l-dioxide and 5.00 mg l-carboxymethyl-3S- (IS-ethoxycarbonyl-3-phenylpropylamino) -2,3,4,5-tetrahydro-lH- [l] benzazepin-2-one hydrochloride are wet-produced as follows:

Ingredients (for 2000 tablets)

Tablet core 6-chloro-3,4-dihydro-2H-l, 2,4-benzthiadiazine-7-sulfonamide-1,1-dioxide (micronized) 12.50 g l-carboxymethyl-3S- (lS-ethoxycarbonyl-3- phenylpropylamino) -2,3,4,5-tetrahydro-lH- [l] benzazepin-2-one hydrochloride 10.00 g

Hydroxypropylmethylcellulose 6.00 g hydrogenated castor oil 12.00 g

Lactose (ground) 423.50 g

Polyvinyl polypyrrolidone 20.00 g

Film cover

Hydroxypropylmethyl cellulose 7.34 g

Polyethylene glycol 8000 (flakes) 1.34 g

Talc 5.32 g

Titanium dioxide 2.00 g

The 6-chloro-3,4-dihydro-2H-1,2,4-benzthiadiazine-7-sulfonamide-1,1-dioxide, the l-carboxymethyl-3S- (lS-ethoxycarbonyl-3-phenylpropylamino) -2, 3,4,5-tetrahydro-lH- [l] benzazepin-2-one hydrochloride and the core material hydroxypropylmethyl cellulose are mixed with part of the lactose. The remaining lactose is added and the mixture is granulated with water, dried and ground. The remaining core components are mixed in and the homogeneous mixture is pressed into tablets which are coated with an aqueous suspension of the above-mentioned film components.

Claims (11)

1. A low dose pharmaceutical composition for the treatment of hypertension containing about 4 to about 6 mg of benazepril or any pharmaceutically acceptable salt of benazepril per dose unit and about 80% to about 120% of an amount of a thiazide diuretic, the Vs of the recommended minimum initial dose with hypotensive effect corresponds to this thiazide diuretic when used alone. 2. The composition according to claim 1, wherein the thiazide diuretic is bendro-flumethiazide, chlorothalidone, chlorothiazide, hydrochlorothiazide, hydroflumethiazide, methylchlorothiazide, polythiazide, trichloromethiazide, benzothiazide or cyclothiazide. 3. The composition of claim 2, wherein the thiazide diuretic is hydrochlorothiazide. 4. The composition according to claim 1, wherein the thiazide diuretic is present in an amount which corresponds to Vs of the recommended minimum starting dose with hypotensive effect of this thiazide diuretic when used alone. 5. The composition of claim 3 containing about 5 mg to about 7.5 mg hydrochlorothiazide. 6. The composition according to claim 5 containing about 6.25 mg of hydrochlorothiazide. 7. The composition of claim 1, wherein benazepril or the pharmaceutically acceptable salt thereof is benazepril hydrochloride. 8. The composition according to claim 7 containing 5 mg of benazepril hydrochloride. 9. The composition according to claim 1 containing 5 mg of benazepril hydrochloride and 6.25 mg of hydrochlorothiazide. 10. The composition according to claim 1 in the form of a tablet, a powder or a capsule. 11. The composition according to claim 1 in the form of an orally administrable tablet or capsule.