SA90100151B1 - A combination low-dose benazepril/thiazide diuretic - Google Patents

Abstract

Abstract: This invention relates to a low-dose fixed ratio compound of benazepril and a diuretic thiazide used for the treatment of high blood pressure. It contains in particular about 4 to 6 mg of benazepril hydrochloride and about 5 to 7.5 mg of hydrochlorothiazide in a single dose. Suitable alternative thiazide derivatives are bendroflumethiazide, chlorthalidone, chlorothiazide, hydrochlorothiazide, hydroflumethiazide, methylchlorothiazide, polythiazde, trichlormethiazide, benzthiazide, and cyclothiazide. iazide

Description

Low-dose compound of benazepril / thiazide diuretic Full description Background of the invention This invention relates to a pharmaceutical compound for the treatment of mild to moderate high blood pressure containing benazepril an enzyme converting Angiotensin in combination with thiazide diuretics ¢ and M method for the treatment of hypertension using this compound. And benazepril hydrochloride is a sulfhydryl compound for oral administration that contains an angiotensin converting enzyme inhibitor with the formula: 1 wit NH N. 0 COOCHACH;

COOH 0 The compound was described in US Patent No. 44169718. Thiazide diuretics were the second ingredient in this mixture. All the active substances (Jal sal) which are the subject of this invention are well known compounds in this field; Also, the methods of manufacturing it and the methods of eating it, etc.; well known. In addition, there have been some descriptions published in recent years of mixing or combining angiotensin-converting enzyme inhibitors with thiazide diuretics, Lil. thiazide diuretics, for example, US Pat. No. 77786; In particular column 4 and 01 and example 117 of this patent; and the American patent, especially the PY columns and examples;

1" 4 v ¢eYVovoVv-, EP No. American J.Hypert. 1(1). 38-41 (1988) and Amer.

J.

hypert. 1(3, part 2), 13A-5J.

Hypertension 1 (Suppl. 2), 284-386 (1983), however; Each of them deals with enzyme-inhibiting drugs. 14A Abstract 1229(1998) and/or benazepril diuretics differ from the benazepril angiotensin converting enzyme in much greater amounts than in this invention. Probably the most important reference of all is 0M which claims precedence under Merck South African Patent Application No. 477457 as enzyme conversion US Application No. 475 7/87.. This reference discloses algebraic enzyme inhibitors 0.001 to 0.001 / day in amounts of benazepril of the type benazepril angiotensin mg / day. It mentions 001 seo in a mixture with diuretics, qualitatively ranging between

00 Hydrochlorothiazide only in amounts of 10 mg/day.

General description of the invention The objective of this invention is to provide a pharmaceutical compound for the treatment of mild to moderate high blood pressure with the lowest possible amount of an active agent while achieving a decrease in blood pressure that could not be achieved with the individual active agents at the same dose.

\o The invention is a fixed ratio low dose mixture of ; To 1 mg of benazepril or its pharmaceutically acceptable salt with 860 to 71760 of 1/4 of the medically recommended initial anti-hypertensive daily dose of a thiazide diuretic taken as a single dose one a day. The composition of the invention is a fixed daily dose to be taken by an adult who suffers from blood pressure

0 High to Medium High This dose includes; To 6 pale, preferably about © mg of benazepril hydrochloride, or any other pharmaceutically acceptable salt of benazepril, and 700 to 7171, preferably about 7000 of 1/8 the usual initial medical dose. For high blood pressure in adults from a thiazide diuretic when this diuretic is used alone.

Yo and the pharmacologically acceptable salts of benazepril are salts with the addition of acid with harmless acids such as inorganic acid, for example hydrochloric acid or hydrochloric acid.

AEA

¢ Sulfuric acid or phosphoric acid or with organic carbonic or sulfonic acids or sulfo-organic acids, for example acetic acid, propionic acid or glycolic glycolic, maleic, fumaric, tartaric, citric, 5-benzoic, methanesulfonic, ethanesulfonic, or 7-hydroxyacenesulfonic acid 2-hydroxyethanesulfonic acid. It is preferable to choose hydrochloride, i.e. salt by adding an acid with hydrochloric acid. It is preferable to choose a diuretic from: bendroflumethiazide (z) © v,Yo— +0 | (pale mg chlorothalidone | (5 ¥ mg) z 0,¥— ‎pale ¥,Yo z chlorothiazide | (044 mg) | Vo-ou mg of hydrochlorothiazide | (04 mg) | V,0-0 mg hydroflumethiazide hydroflumethiazide | :8 mg) | V,0—-0 mg methylchlorothiazide Z (?5,? mg) | FA — 4 Yo , + mg polythiazide | (7 mg) Z 0 — Rh pale trichloromethazide oF — LY | (pale Y) | trichlormethiazide mg benzthiazide | (04 mg) | 0-0 V, mg element (ek) cvlotiazide 34 45s 1 The amounts in parentheses indicate the usual clinical minimum initial antihypertensive dose for adults; It is followed by the useful dose rate in this invention. The initial medical dose used (Ula) may differ from the dose indicated in the brackets in the aforementioned list in some cases. For example, hydrochlorothiazide is given as an initial dose of 1 mg. Vo and better; The thiazide diuretic is chosen from chlorothiazide and hydrochlorothiazide J fs hydrochlorothiazide.

° methylchlorothiazide and chiorthalidone. It is preferable to choose a thiazide diuretic from chlorothiazide and hydrochlorothiazide; The best preferred is hydrochlorothiazide in particular.

° The most distinguished composition includes benazepril hydrochloride and hydrochlorothiazide in a weight ratio of about 0.8 to 1; For example, about a pale of benazepril hydrochloride and about mg of -hydrochlorothiazide

In a double-blind, randomized clinical trial on TYE, a man and a woman had hypertension

0 blood on dilation of the heart in the seated position from 40 to MVE mm Hg; A comparison was made between

Potency of the preferred mixture of the invention comprising *# mg of hydrochloride

gbenazepril hydrochloride 1.19 mg of hydrochlorothiazide

Once-a-day hydrochlorothiazide and the effectiveness of other formulations

and efficacy of individual drugs within six weeks. The following is a summary of the results in the following table:

A# mg betazuril A 7 0/16 mg ‎ons as - | tiie 0 mg betaaziril + Te mg hydrochlorothiazide 4570 lagos faq mg betaaziril + *,? Hydrochlorolazid 17.7 mg) Losses eee smelt som ele Yee mg Betaziryl + 315 mg nT som 1 mg © benazeryl + a elt (Sele) Placcho Sees 0) hypotension when the heart is dilated in the esd position

+ Clinical results show that the low-dose formulation subject of the invention includes impressive efficacy. And the composition can be formed by standard methods in this field in any usual dosage form, including tablets, capsules, powders, etc. Any suitable pharmaceutical adjuvant or carrier may also be added. It can be taken in any way in which both benazepril and las thiazide diuretic can be taken at the same time. But it is preferable to take it orally. The most appropriate dosage form is the solid dosage form by means of art such as tablets or capsules. Although active anti-hypertensive agents can be added; Most preferably, there is only 0 benazepril and only 1 thiazide diuretic in any one formulation. Detailed Description This invention will be understood more clearly by referring to the following example that illustrates the invention without specifying it. Example: film-coated tablets are prepared containing 6,759 mg of 6-chloro-3,4-dihydro-2H-1,2,4-benzothiadiazine-7-sulfonamide-1,1-dioxide 0 mg of hydrochloride 1-carboxymethyl-3S-(IS-ethoxy carbonyl-3-phenylpropylamino)- 2,3,4,5-tetrahydro-1H-[1]benzazepine-2-one hydrochloride as follows: ingredients 00050 aad) Tablet) Inner material 6-chloro-3,4-dihydro-2H-1,2,4-benzothiadiazine-7- (Gd precision powder) 15 g sulfonamide-1,1-dioxide (micronized) 0 1-carboxymethyl-3S-(IS-ethoxycarbonyl-3-g phenylpropylamino)-2,3,4,5-tetrahydro-1H-[1]benzazepine-2-one hydrochloride 0 hydroxypropylmethylcellulose g Cu) 0 hydrogenated castor oil g 1 4

No lactose (powder) £YY,0 lactose (ground) 0 g polyvinyl-polypyrrolidone 0 g Film coating material Hydroxypropylmethylcellulose 4 g hydroxypropylmethylcellulose Polyethylene glycol 80060 (flakes) YE Polyethyleneglycol 8000 (flakes) 7 g talcum yo titanium dioxide g 6-chloro-3,4-dihydro-2H-1,2,4-benzothiadiazine-7 g sulfonamide-1,1-dioxide and 1-carboxymethyl-3S hydrochloride-(IS-ethoxy carbonyl-3-phenylpropylamino)- 2,3,4,5-tetrahydro- 1H-[1]benzazepine-2 -one hydrochloride 5 hydroxypropyl substances — methyl cellulose, internal hydroxypropylmethylcellulose with part of the lactose. © The remaining lactose is added and the mixture is ele granulated, dried and ground. The remaining internal components are mixed together and the homogeneous mixture is pressed into tablets, which are covered with an aqueous suspension of the aforementioned packaging materials.

Claims (1)

A protective elements 1-1 a low-dose pharmaceutical compound for the treatment of mild to moderate high blood pressure is formed; to 1 mg of benazepril or a pharmaceutically acceptable salt of benazepril, benazepril and a thiazide diuretic; thiazide diuretic in the amount of TAY to 7171 fu The lowest single anti-hypertensive initial dose © page for daily administration of the thiazide diuretic mentioned when used alone; Where is the amount per dose of the aforementioned compound. -Y 1 is compound according to element 1 ; Where the thiazide 5p Saal 0 diuretic is chosen from bendroflumethiazide and chlorthalidone © | chlorothiazide, hydrochlorothiazide, and hydroflumetazide; Hydroflumethiazide, methylchlorothiazide, polythiazide, trichlormethiazide, benzthiazide, and cyclo .cyclothiazide ub 1 01 *- compound according to item 7; Where the aforementioned thiazide diuretic is ¥ hydrochlorothiazide .1 hydrochlorothiazide ;- compound Ty of any protective elements from 1 to “; where the said thiazide diuretic is present in an amount equal to/than the lowest recommended initial antihypertensive dose when using the said thiazide diuretic alone. = O 1 compound, la, for waist VV, in which the aforementioned hydrochlorothiazide 7 is present in an amount from ~ mg to less than mg per dose. 1 +- installed according to the protection character * ; The said hydrochlorothiazide 0 is present in an amount of about ¥0.1 mg per dose. benazepril to 6; where benazepril 1 is a compound according to any of the claims of 7-01. said benazepril hydrochloride or its pharmaceutically acceptable salt is benazepril hydrochloride of claim 7; where benazepril hydrochloride ly is the said 1-* compound Present in an amount of approximately * mg per dose. benazepril hydrochloride Y ; contains # mg hydrochloride 1 of Claim 0 Smt and 1.79 mg hydrochlorothiazide 50220:11 hydrochloride betazepril 0 per dose hydrochlorothiazide | In tablet form 01 formulated according to claim element 11-1 for oral administration. capsule or capsule; Already mentioned in this description to a large extent with 1 compound according to claim VY indicating the example. AEA