NZ232182A

NZ232182A - Composition of benazepril and a thiazide diuretic

Info

Publication number: NZ232182A
Application number: NZ232182A
Authority: NZ
Inventors: Armel Rosselet
Original assignee: Ciba Geigy Ag
Priority date: 1989-01-23
Filing date: 1990-01-19
Publication date: 1991-06-25
Also published as: GB2227172A; CA2008126A1; IT1239744B; DK175204B1; SE506179C2; DK17490A; IT9047548A0; KR0141479B1; DK17490D0; BE1002736A4; HK98995A; GB9001054D0; KR900011465A; DE4001496A1; SA90100151B1; DE4001496C2; FR2641971B1; NL194958B; NL194958C; AT401728B

Description

<div class="application article clearfix" id="description"> New Zealand Paient Spedficaiion for Paient Number £32182 © 232182 01 a NO DRAWINGS Priority Date(s): .. 2&...L:.'SS: Complete Specification FUed:^).^. Class: P.O. Journal. No: O Patents Form No. 5 NEW ZEALAND PATENTS ACT 1953 COMPLETE SPECIFICATION LOW DOSE BENAZEPRIL/THIAZIDE DIURETIC COMPOSITION WE, CIBA-GEIGY AG, a Swiss Corporation of Klybeckstrasse 141, 4002 Basle, Switzerland, hereby declare the invention, for which We pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statement; - 1 - (followed by Page la) 232182 - la - 4-17427/=/CGC 1398 Low dose benazepril/thiariHft 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. Benazepril hydrochloride is a new orally active, non-sulfhydril containing, angiotensin converting enzyme inhibitor having the structure The compound is described in U.S. 4,410,520. Thiazide diuretics, the second component of 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 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. 1(1), 38-41 (1988); European 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 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 23-100 mg/day in combination with diuretics genetically in the range of 0.5-100 mg/day. Hydrochlorothiazide is only mentioned in amounts of at least 10 mg/day. C00CH2CH3 COOH (followed by Page 2) 232182 -2- 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 pharmaceu-tically acceptable salt thereof with 80-120 % of Vs 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 pharmaceutical^ acceptable salt of benazepril and about 80 % to about 120 %, preferably about 100 %, of tyg the usual initial antihypertensive 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 add, sulfuric acid or phosphoric acid, or with organic carbonic, sulfonic or sulfo acids, for example acetic, propionic, glycolic, maleic, fumade, tartaric, citric, benzoic, methanesulfonic, ethanesulfonic, or 2-hydroxyethanesulfonic acid. Preferred is the hydrochloride, i.e. die acid addition salt with hydrochloric acid. Preferably the diuretic is selected from bendroflumethiazide (5mg) 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 J mg; methylchlorothiazide (2.5 mg) 0.25 - 0.38 mg; polythiazide (2mg) 02. - 0.3 mg; trichlormethiazide (2mg) 0.2 - 0.3 mg; benzthiazide (50 mg) 0.5 - 0.75 mg; cyclothiazide (2mg) 02, - 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 232 182 -3- nowadays 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: 5 mg benazepril^ + 6.25 mg hydrochlorothiazide 10 mg benazepril + 125 mg hydrochlorothiazide 20 mg benazepril + 25 mg hydrochlorothiazide 20 mg benazepril 25 mg hydrochlorothiazide 20 mg benazepril + 6.25 mg hydrochlorothiazide 5 mg benazepril + 25 mg hydrochlorothiazide placebo - 9.9 mmHgW - 9.6 mmHg -13.9 mmHg - 9.8 mmHg - 6.9 mmHg -103 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 die 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 </div>

Claims

<div class="application article clearfix printTableText" id="claims"> 232 1 -4- preferably oral. The most suitable dosage form is a solid oral dosage form such 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 composition. The instant invention will be more fully understood by reference to the following example, which illustrates, but does not limit the invention. Example: Rlm-coated tablets, containing 6.25 mg 6-chloro-3,4-dihydio-2H-1,2,4-benzo-thiadiazme-7-sulfonamide-1,1 -dioxide and 5.00 mg 1 -carboxymethyl-3S-( 1 S-ethoxy-carbonyl-3-phenylpropylamino)-2,3,4,5-tetrahydro-lH-[l]benzazepine-2-one hydrochloride are prepared as follows: Ingredients (for 2*000 tablets) core materials 6-chloro-3,4-dihydro-2H-l ,2,4-benzothiadiazine-7-sulfonamide- 1,1-dioxide (micronized) 12.50 g l-carboxymethyl-3S-(lS-ethoxycarbonyl-3-phenylpropylamino)-2,3,4,5- tetrahydxx>-lH-[l]benzazepine-2-one hydrochloride 10.00 g hydroxypropylmethylcellulose 6.00 g hydrogenated castor oil 12.00 g lactose (ground) 42350 g polyvinyl-polypyrrolidone 20.00 g FItti materials hydroxypropylmethylcellulose 7.34 g polyethyleneglycol 8000 (flakes) 134 g talcum 5.32 g titanium dioxide 2.00 g The 6-chloro-3,4-dihydro-2H-1 ,2,4-benzothiadi azine-7 -sulfonamide-1,1 -dioxide, the l-carboxymethyl-3S-(lS-ethoxycaibonyl-3-phenylpiopylamino)-23»4,5-tetrahydro-lH-[l]benzazepine-2-one hydrochloride and the core hydroxypropyl-methylcellulose are mixed with part of die lactose. The remaining lactose is added and die mixture is granulated with water, dried, and milled. The remaining core ingredients are admixed therewith and die homogenous mixture is compressed into tablets, which axe coated with an aqueous suspension of the above coating materials. -5- 232182 WHAT WE CLAIM IS:

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 120 % of Vg of the minimum recommended initial antihypertensive 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, polythiazide, trichlorme thiazide, 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 tyg of the minimum recommended initial antihypertensive dose when the thiazide diuretic is used alone. Q,

5. The composition of claim 3 wherein said hydrochlorothiazide is present in an amount of 5 mg to 7.5 mg per dose.

6. The composition of claim 5 wherein said hydrochlorothiazide is present in an amount of 6.25 mg per dose.

7. The composition of claim 1 wherein said benazepril or pharmaceutical^ 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 hydroS5oride and 625~r hydrochlorothiazide per dose. 232182 -6-

10. 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. FO 7.4/KB/gb* CIBA-GEIGY AG / 4. AWAmjuo NBy their attorneys V BALDWIN, SON & CAREY </div>