IE59308B1

IE59308B1 - A pharmaceutical composition for the treatment of high blood pressure

Info

Publication number: IE59308B1
Application number: IE239286A
Authority: IE
Original assignee: Hoechst Ag
Priority date: 1985-09-09
Filing date: 1986-09-08
Publication date: 1994-02-09
Also published as: PH23716A; JPS6261928A; DE3685177D1; FI863594A0; IE862392L; DK427886D0; DE3685177T; EP0215357B1; KR870002844A; NZ217489A; EP0215357A3; JPH089549B2; FI863594A; EP0215357A2; IL79965A0; IL79965A; ZA866810B; DK427886A; HUT41640A; PT83322A

Abstract

The preparation contains an angiotensin converting enzyme inhibitor and a loop diuretic.

Description

It is known that the high blood pressure of patients with essential hypertension can be reduced using inhibitors of angiotensin converting enzyme (ACE inhibitors), such as captopril or enalapril (Therapiewoche 29 [1979] 7746; Lancet 2 [1981] 543-546). However, a certain percentage of patients with essential hypertension do not respond to substances of this type (Drug Devel. Eval. 4. [1980] 8291).

It has been disclosed that the antihypertensive action 10 of enalapril or captopril is potentiated by the addition of diuretically effective amounts of a diuretic of the thiazide type or analogous compounds (Brunner et al., Clin. Exp. Hypertension 2 [1980] 639-657; McGregor et al., Br. Med. J. 284 [1982] 693-696). It is generally assumed that this effect is based on stimulation by the diuretic of the renin-angiotensin system via a loss of salt and volume (P.J.S. Chin et al., J. Pharm. Pharmacol. 37 [1985] 105).

There is a report in Arzneim.-Forsch./Drug Res. 34 (II) [1984] 1417-1425 of investigations into the cardiovascular action of 2-[N-[(S)-1-carboxy-3-phenylpropyl]L-alanyl ] - (IS, 3S, 5S) -2-azabicyclo[ 3.3.0] octane-3-carboxylic acid (ramiprilate). This entailed animals being pretreated with furosemide or piretanide for several days for the purpose of sodium depletion.

We have now found, surprisingly, that ACE inhibitors combined with loop diuretics in low dosage effectively lower blood pressure.

Thus the invention relates to pharmaceutical compositions containing a) an angiotensin converting enzyme inhibitor or its physiologically tolerated salt and b) a loop diuretic or its physiologically tolerated salt.

Loop diuretics within the meaning of the present invention include furosemide and piretanide. As is evident from the name, the main point of attack of these diuretics, which have a short but potent effect, is the loop of Henle (cf. Mutschler, Arzneimittelwirkungen (Effects of drugs) 4th Edition, Stuttgart 1981, pages 486 and 487). The compound of Rx the formula I s’ (I) R3 COOHH2N°2S^ in which R1 denotes chlorine, R2 denotes hydrogen, and R3 denotes 2-furylmethylamino is a particularly suitable example.

(II) Suitable ACE inhibitors are described in, for example, US Patent 4,129,571, US Patent 4,154,960, US Patent 4,374,829, European Patent A-79,522, European Patent A-79,022, European Patent A-49,658, European Patent A-51,301, US Patent 4,454,292, US Patent 4,374,847, European Patent A-72,352, US Patent 4,350,704, European Patent A-50,800, European Patent A-46,953, US Patent 4,344,949, European Patent A-84,164, US Patent 4,470,972, European Patent A-65,301 and European Patent A-52,991.

Orally active ACE inhibitors are advantageous, such as, for example, ramipril, perindopril and others. Orally active ACE inhibitors are described in, for example, Brunner et al., J. Cardiovasc. Pharmacol. 7 (Suppl. I) [1985] S2-S11.

The ACE inhibitors of the formula III H in which R denotes hydrogen, methyl, ethyl or benzyl, which are disclosed in European Patent A-79,022 are suitable, in particular the compound of the formula III in which R denotes ethyl (ramipril).

(IV) in which R* denotes hydrogen, (C1-Cll)-alkyl or benzyl, which are disclosed in European Patent A-81,164, are also suitable, in particular the compound of the formula IV in which R* denotes ethyl.

Thus, preferred compositions according to the invention are those which contain a compound of the formula IV with R* - ethyl together with piretanide or furosemide, but in particular those which contain ramipril together with piretanide and which contain ramipril together with furosemide.

The combination of ACE inhibitors and loop diuretics effects a potent and persistent lowering of blood pressure and can thus be used for the treatment of high blood pressure of various etiologies. It is a particularly interesting fact that there is not an additive behavior of the actions of the two components; on the contrary, a synergistic effect is observed. In spontaneously hypertensive rats there is a lowering of blood pressure with the combination even when it contains doses of an ACE inhibitor, such as ramipril, which alone have no effect, when they are combined with doses of a loop diuretic, such as piretanide, which alone have no diuretic effect (subdiuretic doses). This shows that loop diuretics, in particular compounds of the abovementioned formula I, are able to stimulate the renin-angiotensin system without showing a diuretic and saluretic effect. No such effect is achieved with compounds of the hydrochlorothiazide type.

For the reasons mentioned, the composition according to the invention is superior to the individual components for the treatment of high blood pressure, since it allows smaller doses of the components to be administered, and thus reduces any toxicological problems there may be.

The invention also relates to a process for the preparation of a composition of this type, which comprises conversion into a suitable form for administration of a) an angiotensin converting enzyme inhibitor of the formula (III) or (IV) or its physiologically tolerated salt, and b) a loop diuretic of the formula (II) or (II') or its physiologically tolerated salt, together with physiologically acceptable vehicles and, where appropriate, other auxiliaries or additives.

The invention furthermore relates quite generally to products containing a) an angiotensin converting enzyme inhibitor of the formula (III) or (IV) or its physiologically tolerated salt, and b) a loop diuretic of the formula (II) or (II') or its physiologically tolerated salt in a subdiuretic dose, as a combination product for concurrent, separate or sequential administration for the treatment of high blood pressure.

The ratio by weight of ACE inhibitor: loop diuretic in the said compositions and products varies depending on the activity of the active compounds, preferably between 10 : 1 and 1 : 500. For ramipril (=A) + piretanide (=B), for example, A : B preferably varies between 4 : 1 and 1 : 10, in particular between 2 : 1 and 1 : 3. In contrast, with ramipril (=A) + furosemide (=C) the ratio A : C is preferably 1 : 1 to 1 : 200, in particular 1 : 4 to 1 : 40.

By reason of their pK. value the loop diuretics of the formulae (II) and (II') (pKa of furosemide: 3.8) form salts with ACE inhibitors of the formulae (III) and (IV), the compound of the formula (II) and (II) being converted into its cation with protonation of the NH group in the compound of the formulae (III) and (IV). If the compound of the formula (III) or (IV) (R = H) is in the form of a zwitterion, a carboxylate group is protonated.

Hence the invention also relates to a salt of a loop diuretic of the formula (II) or (II') with an ACE inhibitor, and to pharmaceutical compositions and products which contain such a salt . If necessary, the said compositions and products can additionally contain a loop diuretic of the formula (II) or (II') in the free form, or its physiologically tolerated salt, or an ACE inhibitor in the free form, or its physiologically tolerated salt.

Preferred salts of compounds of the formula (II) or (II') are those with compounds of the formula III or IV, in particular those of piretanide or furosemide with ramipril or a compound of the formula IV with R* = ethyl.

The salts are prepared by dissolving stoichiometric amounts of the reactants in a suitable solvent, and depositing the salts in solid form by concentration, cooling or addition of another solvent in which they are less soluble. The salts can be processed to give compositions or products in the manner described above.

The doses of the ACE inhibitor and of the loop diuretic in the compositions or products according to the invention are each preferably selected so that the ACE inhibitor and/or the loop diuretic would alone show no effect or not a full effect. Thus, a dose of the loop diuretics which is far below the ED50, for instance at its threshold diuretic dose, suffices. The sufficient doses of the ACE inhibitors as components are those which are at approximately the minimum dose adequate for plasma ACE inhibition (for determination, see: Metzger et al., Arzneim.Forsch./Drug Res. 34 (II) . 1402, 1403); thus, they can be below those which are required for an acute lowering effect on blood pressure when an ACE inhibitor is used alone.

For the use according to the invention in mammals, preferably in humans, for example the doses of an ACE inhibitor of the abovementioned formula III or IV range, for example, from 0.05 to 2 mg/kg/day, and in those of a loop diuretic range from 0.2 to 25 mg/kg/day.

The compositions or products according to the invention can be administered parenterally or orally. The oral administration form is preferred.

The pharmacologically utilizable combinations of the present invention and their salts can be used for the preparation of pharmaceutical products which contain an effective amount of the active substances together with vehicles, and which are suitable for enteral and parenteral administration. Use is preferably made of tablets or gelatin capsules which contain the active compounds together with diluents, for example lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and/or glycine, and lubricants such as diatomaceous earth, talc, stearic acid or its salts, such as magnesium or calcium stearate, and/or polyethylene glycol. Tablets likewise contain binders, such as magnesium aluminum silicate, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and/or polyvinylpyrrolidone, and, if necessary, colorant, flavorings and sweeteners.

Injectable solutions are preferably isotonic aqueous solutions or suspensions which can be sterilized and may contain auxiliaries such as preservatives, stabilizing agents, wetting and/or emulsifying agents, solubilizers, salts to regulate the osmotic pressure and/or buffer substances.

The pharmaceutical products according to the invention, which may contain, if desired, further pharmacologically valuable substances, are prepared by, for example, conventional mixing, granulating and coating processes, and contain 0.1% to about 75%, preferably about 1% to about 50%, of the active compounds.

This entails the active compounds being mixed or dissolved together with the abovementioned auxiliaries and additives in a mixing device at 5 - 50®C and then, for example, compressed to form tablets or dispensed into gelatin capsules or ampoules.

The examples which follow serve to illustrate the present invention without the latter being restricted to them.

Example 1 Effect of the combination of rami pri T (=A) and piretanide (=B) on the spontaneously hypertensive rat spontaneously hypertensive rats (Wistar-Kyoto) are attached to instruments and kept in metabolism cages during the tests. Ramipril ("A) (1 mg/kg) and piretanide (=B) (1.2 and 16 mg/kg) are administered orally in Tylose using a stomach tube. The control group received only Tylose. The amount of urine excreted after 5 hours, the sodium excretion after 5 hours and the mean arterial pressure were determined.

Table 1 Excretion of urine over 5 hours Amount of urine (pl/100g.5h) lose (1 ml/kg) 460165 A (1 mg/kg) 760+185 B (1 mg/kg) 900+180 B (2 mg/kg) 1470+140 B (16 mg/kg) 3520+405 (1 mg/kg) + B (1 mg/kg) 1100+145 (1 mg/kg) + B (2 mg/kg) 1545+130 (1 mg/kg) + B (16 mg/kg) 35901285 Table 2 Excretion of sodium over 5 hours 1¾. (xlSDISEM) (mmol/150g.5h) Tylose (1 ml/kg) 0.02110.0009+0.003 A (1 mg/kg) 0.08010.049 ±0.016 B (1 mg/kg) 0.08210.057 ±0.021 B (2 mg/kg) 0.15610.063 ±0.022 B (16 mg/kg) 0.46210.146 ±0.052 A (1 mg/kg) A (1 mg/kg) A (1 mg/kg) + B (1 mg/kg) + B (2 mg/kg) + B (16 mg/kg) 0.15710.050 0.15810.033 0.51310.076 .321 .012 .031 The change in the mean blood pressure (MBPt) as a % of the initial blood pressure (MBP0) with time is shown in the figure. The individual lines in this figure have the following meanings: Tylose (1 mg/kg): line h A (1 mg/kg): line a B (1 mg/kg): line b B (2 mg/kg): line c B (16 mg/kg): line d A (1 mg/kg) + B (1 mg/kg): line g A (1 mg/kg) + B (2 mg/kg): line f A (1 mg/kg) + B (16 mg/kg): line e Example 2 Preparation of an oral combination product from ramipril (-A) and piretanide (=B) 1,000 tablets containing 1 mg of each of A and B were prepared using the following auxiliaries: 140 g 7.5 g 2.5 g 2.5 g A 1 g Β 1 g Corn starch Gelatin Microcrystalline cellulose Magnesium stearate A and B are mixed with an aqueous solution of gelatin. The mixture is dried and milled to form granules. Microcrystalline cellulose and magnesium stearate together with corn starch are mixed with the granules. The resulting granules are compressed to form 1,000 tablets, each tablet containing 1 mg of each of A and B.

Example 3 Preparation of a parenteral combination product of ramipril (=A) and piretanide (=B) The preparation of an injection solution for the treatment of hypertension is described below: A 0.25 g B 0.25 g Methylparaben 5 g Propylparaben 1 g Sodium chloride 25 g Water for injections 5 1 A, B, the preservatives and sodium chloride are dissolved in water for injection and made up to 5 1 with water for injections. The solution is sterilized by filtration and dispensed under aseptic conditions into pre-sterilized bottles which are closed with sterilized rubber caps. Each bottle contains 5 ml of solution.

Example 4 Preparation of an oral combination product of ramipril(=A) and furosemide (=C) 1000 tablets which contain 5 mg of A and 20 mg of C were 5 prepared with the following auxiliaries: A C Corn starch Gelatin Microcrystalline cellulose Magnesium stearate g 20 g 140 g 7.5 g 2.5 g 2.5 g A and C are mixed with an aqueous gelatin solution. The mixture is dried and milled to form granules. Microcrystalline cellulose and magnesium stearate together with corn starch are mixed with the granules. The resulting granules are compressed to form 1000 tablets, each tablet containing 5 mg of A and 20 mg of C.

Example 5 In analogy to Example 2, tablets containing 4 mg of 20 ramipril and 1 mg of piretanide per tablet are prepared.

Example 6 In analogy to Example 2, tablets containing 0.5 mg of ramipril and 5 mg of piretanide per tablet are prepared.

Example 7 In analogy to Example 4, tablets containing 25 mg of ramipril and 30 mg of furosemide per tablet are prepared.

Example 8 In analogy to Example 4, tablets containing 1 mg of ramipril and 25 mg of furosemide per tablet are prepared.

Claims

1. Patent claims

1. A pharmaceutical composition containing a) an angiotensin converting enzyme inhibitor or its physiologically tolerated salt and 5 b) a loop diuretic or its physiologically tolerated salt, which contains the loop diuretic of the formula (II) or (II') in a subdiuretic dose, and contains an angiotensin converting enzyme inhibitor of the formula (III) or (IV) (S) CH - CH I COOR (HI) in which R denotes hydrogen, mehtyl, ethyl or benzyl, 15 or i (IV) in which R 4 denotes hydrogen, (Cj-Ci,)-alkyl or benzyl.

2. A composition as claimed in claim 1, wherein the angiotensin converting enzyme inhibitor has the formula (III) or (IV) in which R and R 4 denoted ethyl.

3. A process for the preparation of a composition as claimed in one of claims 1-2, which comprises conversion into a suitable form for administration of a) an angiotensin converting enzyme inhibitor or its salt and b) a loop diuretic or its physiologically tolerated salt together with physiologically acceptable vehicles and, where appropriate, other auxiliaries or additives .

4. A composition as claimed in one of claims 1-2 for use as a medicine for the treatment of high blood pressure.

5. A product containing a) an angiotensin converting enzyme inhibitor or its physiologically tolerated salt and b) a loop diuretic or its physiologically tolerated salt as combination product for concurrent, separate or sequential administration for the treatment of high blood pressure, whose components are defined as in claim 1. I

6. A pharmaceutical” composition according to Claim 1, substantially as hereinbefore described with particular reference to the accompanying Examples.

7. A process according to Claim 3 for the 5 preparation of a composition, substantially as hereinbefore described with particular reference to the accompanying Examples.

8. A pharmaceutical composition whenever prepared by a process claimed in Claim 3 or 7. F. R. KELLY & CO.,