RU2464022C2 - Stable dosage form of amorphous perindopril salts, method for preparing it industrially and using for treating hypertension - Google Patents

Abstract

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to medicine and pharmaceutical industry, and concerns a method for preparing a dosage form of alkali or alkali-earth perindopril salts in the amorphous form wherein perindopril in the form of a free acid is dissolved in alcohol, neutralised by an aqueous solution of an alkali or alkali-earth base; thereafter this solution is sprayed over inert substances for preparing a granulate and dried in a warm air flow at 30-50°C or in vacuum. Before tableting, the granulate is added with substances for improving tableting or additive active substances, such as diurectics, preferentially indapamide.

EFFECT: developing the method for preparing the dosage form of the alkali or alkali-earth perindopril salts in the amorphous form.

7 cl, 5 ex

Description

Technical field

The present invention relates to the field of pharmaceutical chemistry, in particular to amorphous pirendopril salts of formula 1:

where B ⁺ is an alkaline or alkaline earth cation, a method for their production on an industrial scale and their use for the treatment of hypertension.

The most famous and most used salt of perindopril is perindopril erbumine, namely the salt with tertiary butylamine, which is a very effective vasoconstrictor and antihypertensive agent. The low boiling point of tert-butylamine makes this salt very thermosensitive and prone to decomposition at elevated temperatures. Therefore, the drug resistance time is rather short, especially in countries with high average daily temperatures. Thus, a method for producing more stable drug compositions is required.

Description of the Related Art

Known compositions contain the active ingredient perindopril erbumin in various polymorphic forms, formula II:

Such polymeric forms are protected by relevant patent applications: α-form by WO 01/87835 A1, β-form by WO 01/87836 A1 and γ-form by WO 01.83439 A1.

It is known to use an additive of weak basic components, mainly solid sodium bicarbonate, to improve the stability of compositions containing perindopril erbumin, as shown in patent WO 2005/094793 A and DE 102004019845 A1, where perindopril remains in the form of erbumine salt and does not react with alkaline additives.

Patent application US 6,696,481 describes a salt of perindopril with arginine, which is more stable than the erbumine salt. At the same time, the disadvantages of the erbumine salt have been formulated, and it is also mentioned that the perindopril sodium salt in its pure form is unstable for the production of medicines, because it turns into oil and decomposes in air.

Previous patent application WO 2007/058634 A1 describes the preparation of stable perindopril compositions in the form of amorphous sodium salts on an inert carrier based on perindopril erbumin or perindopril erbumin hydrate.

SUMMARY OF THE INVENTION

According to the present invention, stable compositions of amorphous perindopril salts are prepared directly from perindopril (acid) without an intermediate step of an erbumine salt. Perindopril free acid is an erbumine salt

(2S, 3aS, 7aS) -1 - [(2S) -2 - [[(1S) -1- (ethoxycarbonyl) butyl] amino] -1-oxopropyl] octahydro-1H-indole-2-carboxylic acid having formula III:

It is formed as a result of synthesis in the form of a viscous oil, which is not prone to crystallization, but can be solidified by drying in high vacuum.

The free acid of formula III can be used in the form of an oil, a thickened substance, a crystalline form, in aqueous solutions, or in the form of solutions in aqueous mixtures.

The authors found that salts of perindopril with alkaline and alkaline earth bases can be obtained directly when perindopril is dissolved in alcohol, to which a solution of a suitable base in water is added with vigorous stirring in a 1: 1 molar ratio. The resulting solution is then sprayed onto the calculated amount of inert tabletting ingredients (lactose, starch, cellulose) and dried in a stream of warm air at 30-50 ° C or in vacuum.

Other additives are mixed with the dried substrates thus obtained (primary granulate), optionally also other active substances (diuretics) and by grinding to obtain the final mixture, the secondary granulate, which is further tableted. Conventional disintegrating agents (such as croscarmeleza, crospovidone, aerosil, etc.) that improve tablet disintegration can also be added to the primary granulation product at this stage.

This method is more successful and modern compared with the previous method proposed by the authors (WO 2007/058634 A1), since it allows to achieve higher yields of valuable substances and, thus, is less expensive. An advantage of the new method is the higher purity of granular and pelletized sodium perindoprilate, due to the lack of traces of tert-butamine, which is known to be contained in the perindopril erbumine salt.

A mixture of perindopril with diuretics, such as indapamide, is very useful for the effective treatment of hypertension.

This method can also be used to obtain the above compositions by grinding into powder the first granulate obtained after granulating the composition in an air stream with other necessary ingredients, where finely ground indapamide is added at the same time. The ratio of perindopril to indapamide is usually 4: 1.25.

The invention is illustrated by the following examples and is not limited to them.

Example 1

Perindopril (free acid) (7.9 g, 21.4 mmol) was dissolved separately in ethanol (96%; 35 ml). A solution of sodium bicarbonate (2.0 g, 23.8 mmol) in water (35 ml) was prepared separately. Both solutions were combined and stirred for 10 minutes, the pH should be in the range from 7.0 to 7.5.

The mixture was then sprayed in a stream of warm air having a temperature of 30-50 ° C on a pre-prepared mixture consisting of lactose (142 g), corn starch (6 g) and microcrystalline cellulose (42.6 g). The resulting material was dried with a warm air stream to a water content of 0.5-1.5% (K. Fischer method). About 200 g of primary granulate was obtained containing 4.17% perindopril sodium.

Corn starch (5.8 g), talc (4.7 g) and magnesium stearate (2.4 g) were added by trituration to the resulting solution, which was further thoroughly homogenized. The obtained (second) granulate was used for tabletting and 90 mg tablets were obtained. These tablets contained 3.52 mg of perindopril sodium and corresponded to the usual therapeutic dose of 4.0 mg of perindopril erbumin.

Example 2

Perindopril (7.9 g, 21.4 mmol) was dissolved in ethanol (96%; 35 ml). A solution of sodium hydroxide (0.86 g, 21.4 mmol) in water (30 ml) was obtained. Both solutions were combined, thoroughly mixed and the pH was adjusted in the range of 7.0-7.5. After that, the solution, together with other ingredients, was applied to the granules and tableted as described in Example 1.

Example 3

Perindopril (7.9 g, 21.4 mmol) was dissolved in ethanol (96%; 35 ml), the resulting solution was slowly added with vigorous stirring to a suspension of calcium hydroxide (0.95 g, 12.8 mmol) and then stirred for 30 minutes . The pH should be in the range of 7.0 to 7.5.

The resulting slightly turbid solution was filtered to clear of impurities.

Then the solution was applied to the granules and tableted as described in example 1.

Example 4

Perindopril (7.9 g, 21.4 mmol) was dissolved in ethanol (96%; 35 ml). Separately, a solution of sodium bicarbonate (2.0 g, 23.8 mmol) in water (35 ml) was obtained. Both solutions were combined and stirred for 10 min, the pH was in the range from 7.9 to 7.5. This mixture was further sprayed in a stream of hot air having a temperature of 30-50 ° C. into a pre-prepared mixture consisting of lactose (140.0 g), corn starch (5.9 g) and microcrystalline cellulose (41.75 g). The mixture was dried in a stream of warm air to achieve a water content of 0.5-1.5%. 196 g of granulate was obtained, which was further mixed and homogenized with indapamide (2.95 g), corn starch (5.9 g), talc (4.7 g) and magnesium stearate (2.4 g). This final granulate was used to make 90 mg tablets containing 3.53 mg of perindopril sodium (corresponding to 4.0 mg of perindopril erbumin) and 1.25 mg of indapamide.

Example 5

Composition for 22,000 tablets of perindopril sodium. Each tablet contains 3.53 mg of sodium perindoprilat (corresponding to 4 mg of perindopril erbumin).

Perindopril (acid) 0.079 kg

Lactose Monohydrate 1.420 kg

Microcrystalline cellulose 0.426 kg

Corn starch 0.118 kg

Magnesium stearate 0.024 kg

Talc 0.047 kg

Sodium bicarbonate 0.018 kg

Total 2,132 kg

Granulation:

Perindopril (acid) (0.079 kg) was dissolved in ethanol (96%; 400 ml). Separately, a solution of sodium bicarbonate (0.018 kg) in water (200 ml) was obtained. Both solutions were mixed. In the WSG granulator type GLATT GPCG-1, a dry mixture was obtained from the following ingredients:

Lactose Monohydrate 1.420 kg

Corn starch 0.059 kg

Microcrystalline cellulose 0.426 kg

A solution of sodium perindoprilat (ethanol / water) was sprayed onto a dry mixture of ingredients at a temperature of 35-42 ° C for two hours. The final moisture content of the primary granulate is 1-1.5% of water.

In the next step, the primary sodium perindoprilate granulate was mixed in a homogenizer with the following ingredients:

Corn starch 0.059 kg

Talc 0.047 kg

Magnesium stearate 0.024 kg

The final granulate was used for tabletting. He was tabletted in a KILIAN RLA tablet machine at a speed of 30,000 tablets / hour.

Claims (7)

1. A method of obtaining a stable dosage form of the amorphous salt of perindopril formula I:

where B ⁺ is an alkali or alkaline earth metal cation, characterized in that perindopril in the form of a free acid of formula III:

dissolved in alcohol and neutralized with an aqueous solution of an alkaline or alkaline earth base and the resulting neutral salt solution is sprayed onto a homogeneous mixture of inert ingredients to obtain a granulate which is dried in a vacuum or a stream of warm air, substances to facilitate tabletting or other active substances, preferably diuretics, are added, and then homogenize and tablet. 2. The method according to claim 1, characterized in that the free acid of the formula III is used in the form of an oil, a resinous substance, crystals, aqueous solutions or solutions in aqueous mixtures. 3. The method according to claim 1, characterized in that the alkaline earth metal is calcium or magnesium and the alkali metal is sodium or potassium, preferably sodium. 4. The method according to claim 1, characterized in that the base is an alkali or alkaline earth metal hydroxide, oxide, carbonate or hydrogen carbonate. 5. The method according to claim 1, characterized in that the drying is carried out at a temperature of from 30 ° C to 50 ° C. 6. The method according to claim 1, characterized in that substances having diuretic activity, preferably indapamide, as another active substance, are mixed with the mixture in the last granulation phase. 7. The use of a stable dosage form obtained in accordance with paragraphs.1-6 as a drug having antihypertensive and vasodilator activity.