DK175204B1 - Low dose diuretic benazepril / thiazide preparation - Google Patents

Description

in DK 175204 B1

The invention relates to a pharmaceutical composition for the treatment of mild to moderate hypertension containing the inhibitor benazepril for the angiotensin converting enzyme in combination with thiazide diuretics and a method of treating hypertension using this preparation.

Benazepril hydrochloride is a novel orally active inhibitor of angiotensin-converting enzyme that does not contain mercapto and has the formula .XV. v HCl

y— »mi NH

L COOCH2CH3

XCOOH

The compound is disclosed in U.S. Patent No. 4,410,520. Thiazide diuretics, the second component of the present combination, have long been a driving force in antihypertensive treatment. All the active ingredients of the invention are well known compounds; their synthesis, mode of administration, etc. are well known. Furthermore, some literature has been published in recent years on combining inhibitors of angiotensin converting enzyme with x thiazide diuretics, cf. U.S. Pat.

No. 4,472,380, especially columns 9 and 10, and example 127, U.S. Patent No. 4,217,347, especially columns 2-3 and the examples,

American J. Hypert. 1 (1), 38-41 (1988), European Patent Application No. 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, all of these other drugs which inhibit angiotensin converting enzyme are related to benazepril and / or diuretics in substantially greater amounts than in the present invention. Probably the most important reference is ZA Patent Application No. 83,390

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Priority from US Patent Application No. 383,435. This one

By reference, inhibitors of angiotensin converting I describe

In the benazepril type enzyme in amounts of 2.5-100 mg / day in I

In combination with diuretics generally in the range 0.5-100 I

mg / day. Hydrochlorothiazide is only mentioned in amounts of at least I

For 10 mg / day. IN

It is an object of the present invention to provide

You provide a pharmaceutical composition for treating and I

In a method of treating mild to moderate hyper- I

tension with a minimal amount of active agent while I

pressure reductions are obtained that cannot be achieved by the individual I

active agents at the same dose. IN

The invention relates to a low dose solid I combination

15 ratios of 4-6 mg of benazepril or a pharmaceutical I

In acceptable salt thereof with 80-120% of 1/8 of the antihy

pertinently clinically recommended daily starting dose of I

a thiazide diuretic given as a daily dose at once. IN

The composition of the invention is a daily unit dose of I

In 20 administration to an adult with mild to moderate I

hypertension comprising approx. 4 to approx. 6 mg, preferably I

ca. 5 mg, benazepril hydrochloride or any I

other pharmaceutically acceptable salt of benazepril and ca. IN

In 80% to approx. 120%, preferably approx. 100%, of 1/8 of the semen

In 25 regular antihypertensive adult clinical dose I

I of a thiazide diuretic when such a diuretic reaches 7 I

used alone. IN

In pharmaceutically acceptable salts of benazepril, acid di- I

In ionic salts with pharmacologically harmless acids, for example I

In inorganic acid, e.g. hydrochloric acid, sulfuric acid or phos- I

phoric acid, or with organic carbon, carboxyl, sulfone I

or sulfo acids, e.g. acetic acid, propionic acid, I

glycolic acid, maleic acid, fumaric acid, tartaric acid, citric acid, I

H benzoic acid, methanesulfonic acid, ethanesulfonic acid or I

2-hydroxyethanesulfonic acid. The hydrochloride, i.e. acid di- I

The preferred salt of hydrochloric acid is preferred.

Preferably, the diuretic is selected from λ bendroflumethiazide (5 mg) 0.5 - 0.75 mg, 5 chlorthalidone (25 mg) 2.5 - 3.75 mg, chlorothiazide (500 mg) 50 75 mg, hydrochlorothiazide (50 mg) 5 7.5 mg, hydroflumethiazide (50 mg) 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 and cyclothiazide (2 mg) 0.2 - 0.3 mg

The usual minimal clinical antihypertensive adult starting dose is shown in parentheses followed by the dose range applicable according to the invention. The clinical starting dose used nowadays may in some cases differ from the dose given in the above list in brackets. Thus, hydrochlorothiazide is often given at a starting dose of 25 mg.

Preferably, the thiazide diuretic is selected from chlorothiazide, hydrochlorothiazide, methyl chlorothiazide and chlorthalidone. It is particularly preferred that the thiazide diuretic is selected from chlorothiazide and hydrochlorothiazide, especially hydrochlorothiazide.

The most advantageous composition comprises benazepril hydrochloride and hydrochlorothiazide in a weight ratio of approx. 0.8 to 1, e.g. ca. 5 mg of benazepril hydrochloride and approx. 6.25 mg of hydrochlorothiazide. 1 in a clinically randomized double blind trial of 334 men and women with a sitting diastolic blood pressure of 95-114 mmHg, the effectiveness of the preferred combination of the invention comprising 5 mg of benazepril is compared.

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In hydrochloride and 6.25 mg hydrochlorothiazide given once I

In daily with the effect of other preparations and of the individual I

In medication for 6 weeks. The results are summarized in I

In the following table: r I

In 5 mg benazepril 3 + 6.25 mg hydrochlorothiazide -9.9 mmHgb)

10 mg benazepril +12.5 mg hydrochlorothiazide -9.6 mmHg I

20 mg benazepril +25 mg hydrochlorothiazide -13.9 mmHg I

In 20 mg benazepril -9.8 mmHg I

25 mg hydrochlorothiazide -6.9 mmHg I

In 20 mg benazepril + 6.25 mg hydrochlorothiazide -10.3 mmHg I

5 mg benazepril +25 mg hydrochlorothiazide -10.7 mmHg I

placebo -3.9 mmHg I

a) as the hydrochloride I

B) reduction of sitting diastolic blood pressure I

The clinical results show that the low dose preparation according to I

The invention has a surprising effect. IN

The preparation may be formulated in known standard methods on I

any suitable dosage form, including tablet, I

20 capsule, powder, etc. Any suitable pharmaceutical aid

agent or carrier may also be included. You may submit the submission

happen by any means by which both benazepril and thiazide I

the diuretic may be administered simultaneously, but preferably occurs I

orally. The most convenient dosage form is a solid / I

Oral dosage, such as a tablet or capsule. Although there

Other antihypertensive agents may be added, I

it is particularly preferred that only benazepril and only one thiazide I

diuretics are present in each preparation. IN

The invention is further illustrated by the following example, I

30 which, however, is not intended to limit the invention. IN

DK 175204 B1 5

Example

Film-coated tablets containing 6.25 mg of 6-chloro-3,4-dihydro-2H-1,2,4-benzothiadiazine-7-sulfonamide-1,1-dioxide and 5,00 mg of 1-carboxymethyl-3S - (1S-Ethoxycarbonyl-3-phenyl-propylamino) -2,3,4,5-tetrahydro-1H- [1] benz-azepin-2-one hydrochloride is prepared as follows:

Ingredients (for 2000 tablets)

Core Materials 10 6-Chloro-3,4-dihydro-2H-1,2,4-benzothiadiazine-7-sulfonamide-1,1-dioxide (micronized) 12.50 g of 1-carboxymethyl-3S- (1S-ethoxycarbonyl-3 -phenylpropylamino) -2,3,4,5-tetrahydro-1H- [1] benzazepin-2-one hydrochloride 10.00 g hydroxypropyl methyl cellulose 6.00 g hydrogenated castor oil 12.00 g lactose (ground) 423.50 g polyvinyl-polypyrrolidone 20.00 g

Film Materials Hydroxypropylmethylcellulose 7.34 g polyethylene glycol 8000 (flakes) 1.34 g talc 5.32 g titanium dioxide 2.00 g 6-Chloro-3,4-dihydro-2H-1,2,4-benzothiadiazine-7-sulfonamide The 1,1-dioxide and 1-carboxymethyl-3S- (1S-ethoxycarbonyl-3-phenylpropylamino) -2,3,4,5-tetrahydro-1Η- [1] benzazepin-2-one hydrochloride and core material hydroxypropylmethylcellulose 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 ingredients are thus mixed, and the homogeneous mixture is pressed into tablets,

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You are coated with an aqueous suspension of the above

In coating materials. IN

H

Claims (9)

A low-dose pharmaceutical composition for the treatment of mild to moderate hypertension, characterized in that it comprises approx. 4 to approx. 6 mg of benazepril or a pharmaceutically acceptable salt of benazepril and a thiazide diuretic in an amount of approx. 80% to 120% of 1/8 of the minimum recommended antihypertensive starting dose of the thiazide diuretic when used alone, each amount being 10 unit dose of the preparation. Composition according to claim 1, characterized in that the thiazide diuretic is selected from bendroflumethiazide, chlorothalidone, chlorothiazide, hydrochlorothiazide, hydroflumethiazide, methyl chlorothiazide, polythiazide, trichloromethiazide, benzthiazide and cyclothiazide. Composition according to claim 2, characterized in that the thiazide diuretic is hydrochlorothiazide. A composition according to claim 1, characterized in that the thiazide diuretic is present in an amount which is 1/8 of the minimum 20 recommended starting antihypertensive dose when the thiazide diuretic is used alone. Composition according to claim 3, characterized in that the hydrochlorothiazide is present in an amount of approx. 5 mg to approx. 7.5 mg per dosage. Composition according to claim 5, characterized in that the hydrochlorothiazide is present in an amount of approx. 6.25 mg per dosage. Composition according to claim 1, characterized in that benzepril or a pharmaceutically acceptable salt thereof is benazepril hydrochloride. I DK 175204 B1 I I I Composition according to claim 7, characterized in that benzene azepril hydrochloride is present in an amount of approx. 5 mg I I per dosage. I I '' I A composition according to claim 1, characterized in that it comprises 5 mg of benazepril hydrochloride and 6.25 mg of hydrochloric acid. dosage. IN Composition according to claim 1, characterized in that it is a tablet, powder or capsule. A composition according to claim 1, characterized in that it is an oral tablet or an oral capsule. IN