HU226950B1 - The magnesium salt of enalapril and antihypertensive pharmaceutical composition containing it - Google Patents

Abstract

The object of the present invention is the compound of (1S)-N-ethoxycarbonyl-3-phenylpropyl)-L-alanyl-L-prolin (international name: enalapril) in the form of its alkaline and alkaline earth metal salts and the solvates of these salts of general formula (I) wherein X is calcium, potassium or magnesium. The invention is related to the use of the above titled new salt forms in drugs for the treatment of cardiovascular diseases.

Description

The present invention relates to a novel enalapril salt. More particularly, the invention is a known drug; enalapril {under its chemical name: (1S) -N- (1-Ethoxycarbonyl-3-phenylpropyl) -L-alanyl-L-proline}, and an antihypertensive pharmaceutical composition containing it.

One of the most prominent representatives of ACE inhibitors discovered as antihypertensives and successfully used in other circulatory indications is enalapril (see EP 12 401). Enalapril is chemically a L-alanyl-L-proline derivative containing a substituted side chain. It is also known that enalapril is included in the pharmacopoeia as the enalapril maleate salt.

There is a large body of data in the literature suggesting that enalapril maleate appears to be quite degradable during drug formulation, even in tablet formulation. Therefore, numerous publications address the stability of the active ingredient in pharmaceutical formulation. The most important publications and patent publications in this topic can be divided into three groups:

1. An enalapril maleate-containing tablet is stabilized by various acidic substances. Vitamin C is used as an acidic material (see, for example, EP 264 888) or an amino acid salt such as glycine hydrochloride (EP 468 929).

2. The tablet containing enalapril maleate is coated with a polymeric protective coating. Such a solution is described, for example, in EP 317 878.

3. It is also known to use enalapril maleate in the form of the sodium salt in the tablet (see EP 545 194). However, the patent does not disclose the physical, physico-chemical data of the sodium salt. According to our own experimental data, the sodium salt of enalapril is an oily liquid, and the potassium salt of enalapril can only be isolated by lyophilization, so the known alkali metal salts of enalapril have several pharmaceutical disadvantages and are difficult to handle.

A common object of the above-described solutions was to reduce the degradation of the enalapril maleate in the formulation, i.e., to prevent or minimize the formation of the diketopiperazine compound by ring closure and the enalaprilat degradation product by hydrolysis.

It is a proven fact that the enalapril molecule is degradable and can itself be converted to enalapril diketopiperazine, which has no biological effect. Hydrolysis results in the formation of enalaprilat, which is also inactive after oral administration as it is not absorbed. Due to its amphoteric nature, enalapril can form salts with both acids and bases. These salts may be suitable for tablet formulation, but each salt will exhibit different stability during tablet formulation and storage.

The formation of the ring closure decomposition product is acid catalyzed, as already reported in L. Gu and R. G. Strickley, Int. J. of Pharmaceutics, 1990, 60, 99-107.

Even with the use of a polymer protective coating, an optimum pH is required for a stable tablet, which is achieved by adding a base (e.g., sodium carbonate) by adjusting the pH to 5.5-8.0.

However, when a base is used, there is a risk of hydrolysis in the presence of water, i.e. formation of an enalaprilat degradation product.

It is therefore an object of the present invention to provide a method for the preparation of a stable pharmaceutical composition of enalapril by the simplest method of pharmaceutical technology.

In our experiments, it has been found that the above object can be perfectly achieved by preparing new salts of enalapril, preferably alkaline earth metal salts, which have not been described before and are used in the formulation of the drug. In particular, the properties of the magnesium salt have been found to be favorable for pharmaceutical formulation. In this way, wet granulation technology is not required, but even direct tableting is possible.

The present invention thus relates to the magnesium salt of (1S) -N- (1-ethoxycarbonyl-3-phenylpropyl) -L-alanyl-L-proline (commonly known as enalapril) and hydrates of this salt.

The invention further provides an antihypertensive pharmaceutical composition containing the above magnesium salt as an active ingredient.

Advantageous advantages of the novel salt according to the invention are primarily found in tablet formulation and drug formulation.

Previous processes, such as EP 545 194, employed wet granulation tabletting, whereby the enalapril maleate drug substance was first dissolved in an aqueous solution with alkali hydroxide, then lactose was added to the solution and dried at 40-50 ° C. tableting was carried out with the aid of excipients. In an aqueous alkaline medium, the active ingredient is hydrolyzed to a partially inactive enalaprilat during prolonged drying.

The new magnesium salt of enalapril is suitable for direct tabletting, which eliminates the disadvantage of previous wet granulation tabletting. After homogenization of the new enalapril magnesium salt with known excipients (e.g. lactose, microcrystalline cellulose and stearic acid), tabletting can be performed directly.

According to the present invention, one preferred method of preparing the magnesium salt of enalapril is the following: forming an enalapril potassium salt from an enalapril base by means of a stoichiometric potassium hydroxide solution and then separating the enalapril magnesium salt using a stoichiometric magnesium sulfate.

The penetration capacity of the enalapril magnesium salt, as measured by the CACO-2 absorption model, differs significantly from the drug substance enalapril maleate known and used so far. Thus enalapril2

EN 226 950 Β1 magnesium salt may form the basis of a sustained release prolonged release formulation.

A further advantage of the enalapril magnesium salt is that it is also suitable for direct tableting. Enalapril maleate is degraded by direct tabletting as the content of the enalapril diketo-piperazine is three times higher than the original value in the formulation, i.e. the malalate salt of enalapril is unsuitable for direct tabletting. In contrast, the enalapril magnesium salt is stable upon direct tabletting and does not significantly increase its enalapril diketopiperazine content.

Example 1

Enalapril calcium salt dihydrate

To a solution of 3.76 g (10 mmol) of enalapril base in 40 mL of tetrahydrofuran was added 0.21 g (5 mmol) of calcium hydride under ice-water cooling. After stirring for half an hour, water (0.18 mL, 10 mmol) was added, and after stirring for two hours, the solvent was evaporated. The residue was dissolved in ethyl acetate (30 mL) to give the title compound as a white powder after evaporation. Melting point: 55-61 ° C. [a] ^{2 3} D: -64 ° (c 2, methanol)

Example 2

Enalapril magnesium

The solution of enalapril hydrochloride in ethanol (300 ml, 0.132 mol) prepared in accordance with Hungarian patent application HU 208 026 was evaporated in vacuo. The residue was dissolved in dichloromethane (200 ml), cooled to +5 ° C and extracted with a mixture of potassium hydroxide solution (5.26 N, 0.132 mol) and water (50 ml). To the dichloromethane solution was added 50 ml of water and 25 ml of 5.26 N potassium hydroxide solution. After stirring, the phases are separated and the organic phase is extracted with 50 ml of water. The water was evaporated in vacuo (10 mbar) and to the residue were added dichloromethane (300 mL) and anhydrous magnesium sulfate (36 g). After stirring for 3 hours, ethyl acetate (300 mL) was added to the reaction mixture, and the precipitated K ₂ SO ₄ was filtered and washed with ethyl acetate (100 mL).

The mother liquor was evaporated in vacuo and n-hexane (200 mL) was added and evaporated. The title product was a white powder, 46.1 g, 86% yield.

C ₂₀ H ₂₇ Mg _{0 5} Ν ₂ Ο ₅ χΗ ₂ Ο Ms: 405.60 Melting point: 62.2-69.5 ° C

[a] ^{2 5} D = -70.69 ° (c 2, methanol) Analysis calculated Because enalapril 92.56% 92.50% Mg ²⁺ 2.99% 2.89% Water 4.44% 4.34%

Example 3

Generation tablet

substance name Each tablet! quantity Enalapril magnesium salt monohydrate (see Example 2) (expressed as base) 5.0-20.0 mg Lactose monohydrate 77.5-92.5 mg Microcrystalline cellulose 50.5 mg crospovidone 0.5 mg stearic 1.5 mg Altogether 150.0 mg

2.5 mg, 5 mg, 10 mg, 20 mg technology

The excipients are passed through a 0.8 mm sieve.

The internal phase excipients (drug, lactose, microcrystalline cellulose, PVP K30) are homogenized in a slow speed container homogenizer for 5 minutes.

The stearic acid excipient, the outer phase excipient, is also homogenized for 2 minutes.

The powder blend homogenized with the outer phase is tableted on a rotary tabletting machine.

Claims (2)

PATENT CLAIMS A magnesium salt of (1S) -N- (1-Ethoxycarbonyl-3-phenylpropyl) -L-alanyl-Lproline (internationally known as enalapril) and hydrates of this salt. An antihypertensive pharmaceutical composition, comprising the salt of claim 1 as an active ingredient. Published by the Hungarian Patent Office, Budapest Responsible leader: Richard Szabó Head of Department