AU629288B2

AU629288B2 - Low dose benazepril and thiazide diuretic composition

Info

Publication number: AU629288B2
Application number: AU48703/90A
Authority: AU
Inventors: Armel Rosselet
Original assignee: Ciba Geigy AG
Current assignee: Novartis AG
Priority date: 1989-01-23
Filing date: 1990-01-22
Publication date: 1992-10-01
Anticipated expiration: 2010-01-22
Also published as: JP3009694B2; ZA90429B; LU87660A1; KR0141479B1; CH680568A5; IE900233L; GB2227172B; IT1239744B; DE10199041I1; IE61784B1; FR2641971A1; NL9000158A; DK175204B1; BE1002736A4; SE9000050L; HK98995A; DK17490A; AT401728B; DE4001496C2; KR900011465A

Description

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AUSTRALIA

Patents Act COMPLETE SPERCIFICTrATION FORM

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Ciba-Geigy AG Klybeckstrasse 141 4002 BASLE

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ARTHUR S. CAVE CO.

Patent Trade Mark Attornerys Level 10, 10 Barrack Street SYDNEY NSW 2000 Complete specification for the invention entitled "Lnw dose benazep .il/thiazide diuretic

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composition".

The following statement is a full description of this invention, including the best method of performing it know: to me:- I I I I lla- Ib -la- Low dose benazeprilthiazide diuretic composition The invention relates to a pharmaceutical composition for treating mild to moderate hypertension containing the angiotensin converting enzyme inhibitor benazepril in combination with thiazide diuretics, and to a method of treatment of hypertension utilizing this composition.

9* Bcnazepril hydrochloride is a new orally active, non-sulfhydril containing, angiotensin converting enzyme inhibitor having the structure 0

COOH

The compound is described in U.S. 4,410,520. Thiazide diuretics, the second component Sof the instant combination, have long been a mainstay of antihypertensive therapy. All of the active agents of the instant invention are well known compounds in the art; their synthesis, routes of administration, etc. are well known. Additionally, there has been some S literature published in recent years on combining angiotensin converting enzyme "inhibitors with thiazide diuretics. See for example US 4,472,380, especially columns 9 and 10 and example 127 thereof; US 4,217,347, especially columns 2-3 and the examples; American J. Hypert. 38-41 (1988); European patent application 0,215,357; J. Hypertension 1 (Suppl. 384 386 (1983); and Amer. J. Hypert. 1 part 13A-14A, Abstract 1226 (1988). However, each of these deal with angiotensin converting enzyme inhibiting drugs other than benazepril and/or diuretics in amounts substantially greater than that in the present invention. Probably the most significant reference is Merck's South African Patent Application 83 3903, claiming priority of US Application 383,435.

This reference discloses angiotensin converting enzyme inhibitors of benazepril type in amounts of 2.5-100 rag/day in combination with diuretics generically in the range of 0.5-100 mg/day. Hydrochlorothiazide is only mentioned in amounts of at least mg/day.

eu I II asaa rar~BRrrPP 9 sgl~XL~"' e *i It is an object of the present invention to provide a pharmaceutical composition to treat and a method of treating mild to moderate hypertension with a minimum amount of active agent while achieving pressure reductions not achievable with the individual active agents at the same dosage.

The invention is; a fixed ratio low dose combination of 4-6 mg benazepril or a pharmaceutically acceptable salt thereof with 80-120 of 1/8 of the initial daily antihypertensive clinically recommended dose of a thiazide diuretic given as a once daily dosage. The inventive composition is a daily unit dose for administration to a human adult having mild to moderate hypertension comprising about 4 to about 6 mg, preferably about 5 mg, benazepril hydrochloride or any other pharmaceutically acceptable salt of benazepril and about 80 to about 120 preferably about 100 of 1/8 the usual initial antihypertensiv adult clinical dose of a thiazide diuretic, when such diuretic is used alone.

Pharmaceutically acceptable salts of benazepril are acid addition salts with pharmacologically harmless acids, e.g. with inorganic acid, for example hydrochloric acid, sulfuric acid or phosphoric acid, or with organic carbonic, sulfonic or sulfo acids, for example acetic, propionic, glycolic, maleic, fumaric, tartaric, citric, benzoic, methanesulfonic, ethanesulfonic, or 2-hydroxyethanesulfonic acid. Preferred is the hydrr-hlorid,, i.e the acid addition salt with hydrochloic acid.

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Preferably the diuretic is selected from bendroflumethiazide (5 mg) chlorthalidone (25 mg) chlorothiazide (500 mg) hydrochlorothiazide (50 mg) hydroflumethiazide (50 mg) methylchlorothiazide (2.5 mg) polythiazide (2 mg) trichlonnethiazide (2 mg) benzthiazide (50 mg) cyclothiazide (2 mg) 0.5 0.75 mg; 2.5 3.75 mg; 50 75 mg; 3 7.5 mg; 5 7.5 mg; 0.25 0.38 mg; 0.2 0.3 mg; 0.2 0.3 mg; 0.5 0.75 mg; 0.2 0.3 mg.

The usual minimum initial clinical antihypertensive adult dose is shown in parenthesis, followed by the dosage range useful in this invention. The initial clinical dose applied I I e I I, Ilr;l lla~ssolssRP P as- -3nowadays may differ from the dose given in parenthesis in the list above for some cases.

For example hydrochlorothiazide is often given in an initial dose of 25 mg.

More preferably, the thiazide diuretic is selected from chlorothiazide, hydrochlorothiazide, methylchlorothiazide, and chlorthalidone. Most preferably, the thiazide diuretic is selected from chlorothiazide and hydrochlorothiazide; it is in particular hydrochlorothiazide.

The most advantageous composition comprises benazepril hydrochloride and hydrochlorothiazide 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 clinical double-blind randomized trial with 334 men and women having a sitting diastolic blood pressure of 95-114 mmHg, the efficacy of the preferred combination of the invention comprising 5 mg benazepril hydrochloride and 6.25 mg hydrochlorothiazide given once daily was compared with the efficacy of other compositions and of the single drugs during six weeks. The results are summarized in the following table: *p 0 0 0 0.

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5 mg benazeprila) 6.25 mg hydrochlorothiazide S 10 mg benazepril 12.5 mg hydrochlorothiazide mg benazepril 25 mg hydrochlorothiazide 20 mg benazepril mg hydrochlorothiazide mg benazepril 6.25 mg hydrochlorothiazide 5 mg benazepril 25 mg hydrochlorothiazide placebo placebo 9.9 mnmHg b 9.6 mmHg -13.9 mmHg 9.8 mmHg 6.9 mmHg -10.3 mmHg -10.7 mmHg 3.9 mmHg a) as the hydrochloride b) reduction of sitting diastolic blood pressure The clinical results demonstrate that the low dose composition of the invention has a surprising efficacy.

The composition can be put together by methods which are standard in the art in any convenient dosage form, including tablet, capsule, powder, etc. Any suitable pharmaceutical adjuvant or carrier may also be included. Administration may be by any route by which both benazepril and the thiazide diuretic may be simultaneously administered, but is most I I -4preferably oral. The most suitable dosage form is a solid oral dosage form suck~ as a tablet or capsule. While other antihypertensive active agents may be added, most preferably only benazepril and only one thiazide diuretic are present in any one cc-nposition.

The instant invention will be more fully understood by reference to the following ezfample, which illustrates, but does not limit the invention.

Example:, Film.-cated tablets, containing 6.25 nig 6-chloro-3,4-dihydro-2H- 1 ,2,4-benzothiadiazine-7-sulfonamide-l1, 1-dioxide and 5.00 mg 1-carboxymthlyl-3S-(1J1-ethoxycarbonyl-3-phenylproo~ylamino)-2,3 ,4,5-tetrahydro- 11--f] benzazepine-2-one hydro- 'chloride are prepared as follows: gueits (for 2'00tablets) 6:.core materials 6-chloro-3,4-dihydro-2H- 1,2,4-benzothiadiazinie-7-sulfonamide- 1, 1 -dioxide (micronized) 12.50 g l-carboxymethyl-3S-(l S-ethoxycarbonyl-3-phenylpropylamino)-2,3,4,5tetrahydro-1H-[lbenzaze-pine-2-one iydrochiloride 10.00 g hydroxypropylmethylcellulose 6,00 g hydrogenated castor oil 12.00 g lactose (ground) 423.50 g 00~polyvinyl-polypyrrolidone 20.00 g Film materials hydroxrypropylmethylcellulose 7.34 g polyethiyleneglycol 8000 (flakes) 1.34 g talcum 5.32 g titanium dioxide 2.00 g The 6-chloro-3,4-dihydro-2F1- 1 ,2,4-benzothiiadiazine-7-sulfonamide- 1, 1-dioxide, the 1-carboxymethyl-3S-( 1S-ethioxycarbonyl-3-phenylpropylamidno)-2,3,4,5-tetrahydro- lI-I- [1]benzazepine-2-one hydrochloride and the core hydroxypro;, i-rnethylcellulose are mixed with part of d~e 'Lactose, Thte remaining lactose is added and the mixture is granulated with water, dried, and milled. The remaining core ingredients are admixed therewith and the homogenous mixture is compressed into tablets, which are coated with an aqueous suspension of the above coating materials,

Claims

1. A low dose pharmaceutical composition for treating mild to moderate hypertension comprising 4 to 6 mg of benazepril or a pharmaceutically acceptable salt of benazepril and a thiazide diuretic in an amount of 80 to ,20 of 1/8 of the minimum recommended initial antihyperensive dose of said thiazide diuretic when used alone, each amount being per unit dose of said composition.

2. The composition of claim 1 wherein said thiazide diuretic is selected from bendro- flumethiazide, chlorthalidone, chlorothiazide, hydrochlorothiazide, hydroflumethiazide, methylchlorothiazide, polythiazid;-, trichlormethiazide, benzthiazide, and cyclothiazide.

3. The composition of claim 2 wherein said thiazide diuretic is hydrochlorothiazide.

4. The composition of claim 1 wherein said thiazide diuretic is present in an amount which is 1/8 of the minimum recommended initial antihypertensive dose when the thiazide diuretic is used alone.

5. The composition of claim 3 wherein said hydrochlnorontazide is present in an amount of 5mg to 7.5 mg per dose. 6, The composition of claim 5 wherein said hydrochlorothiazide is present in an amount S" of 6.25 mg per dose.

7. The composition of claim 1 wherein said benazepril or pharmaceutically acceptable salt thereof is benazepril hydrochloride.

8. The composition of claim 7 wherein said benazepril hydrochloride is present in an amount of 5 mg per dose.

9. The composition of claim 1 comprising 5 mg benazepril hydrochloride and 6.25 mg hydrochlorothiazide per dose. 1 -6- The composition of claim 1 which is a tablet, a powder, or a capsule.

11. The composition of claim 1 which is an oral tablet or oral capsule.

12. The composition of claim 1 substantially as herein described with reference to the example.

13. A method of treating mild to moderate hypertension comprising administering a com- position of claim 1.

14. The method of claim 12 wherein said administration is once daily. The method of claim 12 wherein said administration is orally.

16. A low dose pharmaceutical composition substantially as herein described with reference to any one of the foregoing Example. I r Dated this 14th day of July, 1992 CIBA-GEIGY AG By its Patent Attorneys DAVIES COLLISON CAVE a