SK50252005A3 - Pharmaceutical composition containing perindopril erbumine, method of its preparation and stabilisation - Google Patents

Abstract

The subject matter of the invention is a pharmaceutical preparation comprising perindopril erbumine in a stable form within the rage 1 to 40 % by weight and at least one excipient and/or a mixture of excipients within the range 1 % - 99 % by weight, whereas at least one excipient is a substance of basic character maintaining pH 7.1 to 14. The subject matters of the invention are also a method of preparing, stabilising and packing of an oral pharmaceutical preparation in the dosage form of tablets, and/or coated tablets, and/or capsules which is used as an oral therapeutic of hypertension. The principle of manufacturing method consists in preparation of a compound comprising an alkalising excipient by dry mixing of powder components, and/or briqueting, and/or compacting, and modification of particle size of a compound. The compound prepared in this way may be used for compression of tablet cores, and/or tablets, and/or micro-tablets, and/or preparation of pellets, and/or micro-pellets, and/or powders and/or granules, and/or fill in capsules.

Description

A pharmaceutical composition comprising perindopril erbumine, a process for its preparation and stabilization

Technical field

The invention is in the field of pharmacy and relates to a pharmaceutical composition comprising perindopril erbumine and to a process for the preparation of a composition comprising perindopril erbumine and to a process for stabilizing a product prepared therefrom. The mixture can be used to prepare cores, tablets, microtablets. for pellet preparation. micropellet. powders, granules and capsules. The preparation is used for the treatment of hypertension. acts as an ACE-inhibitor.

BACKGROUND OF THE INVENTION

At present, the dose of perindopril erbumine in the world of fast-acting oral formulations of the world is in the range of 2 mg to 8 mg. The drawback of the drug is low, the stability of the product under the conditions of 40 ^{° C} ± 2 ° C. RH 75% = 5% resp. 30 ° C ± 2 ° C. RH 60% ± 5% prepared from the active substance perindopril erbumine (AP1) described in patent EP 1 354 873 (patent application WO003087050). Therefore, in the above application, stabilization of a pharmaceutical formulation is described using a new perindopril salt (perindopril arginine salt). The pharmaceutical preparation prepared from the arginine salt exhibits substantially higher stability under defined conditions:

25 ^; C = 2 ° C. RH 60% = 5%

30% ’= 2%. RH 60% ± 5%

40% = 2%. RH 75% = 5%.

as a pharmaceutical preparation prepared from perindopril erbumine (perindopril tert-butylamine).

EP 1 354 873 (patent application WO03087050) describes the preparation of tablets containing various salts of perindopril. the heat load of individual products containing various salts of perindopril was also monitored. The arginine salt of perindopril was selected on the basis of the tests. which was monitored in a stability test under the conditions defined above. Based on these results, the arindine salt of perindopril is more suitable for the preparation of a stable pharmaceutical formulation than the use of perindopril epinephrine (perindoprilbutyltin).

EP 1 354 873 (WO003087050) does not disclose the stabilization of a pharmaceutical product containing perindopril erbumine. On the basis of the above measures, it appears from the stability point of view that the preparation of a stable pharmaceutical product containing perindopril is possible or not. preferably using the arginine salt of perindopril.

However, perindopril erbtimine is still used in the pharmaceutical industry for the preparation of tablets used in human medicine as an oral therapeutic for hypertension.

GB 2,394,660 discloses the stabilization of a pharmaceutical composition comprising an ACE inhibitor. also perindopril. in the absence of an acidic component having a large specific surface area, an example of which is colloidal silicon dioxide.

According to GB 2 394 660 A, product stabilization is essentially ensured by this. that in the process of preparing the mixture resp. Colloidal silicon dioxide was not used in the tablets.

In the two patents described above, the stability tests and the " in the compatibility tests, they track two major impurities labeled in PhEur. 4 as impurities B and F.

Impurity B is (2S, 3aS, 7aS) -1 - [(S 1 -N- [f S] -1-carboxybutyl] -alanyl] -octahydro-1H-indole-

Impurity F is ethyl (2S) -2 - [(3S.5aS.9aS.10aS) -3-methyl-1,4-dioxoperhydropyrazino

SUMMARY OF THE INVENTION

The present invention provides a pharmaceutical composition comprising, in a stable dosage form, perindopril erbumine in the range of 1-40% by weight and at least one pharmaceutical excipient and / or a mixture of pharmaceutical excipients in the range of 1-99% by weight, wherein at least one pharmaceutical excipient is basic. adjusting the pH of the mixture in the range of pH 7.1 to 14.

The basic substances are pharmaceutical excipients adjusting the pH in the range 7.1 to 14, preferably pH adjusting in the range 7.1 to 12.

The basic substances are from the group of oxides, hydroxides, bicarbonates, phosphates, hydrogen phosphates, dihydrogen phosphates, alkali metal and alkaline earth metal citrates and their hydrates.

According to another embodiment, the pharmaceutical composition comprising perindopril erbumine is in the form of a tablet and / or a coated tablet and / or a capsule cartridge containing the active ingredient perindopril erbumine in an amount of from 1 mg to 50 mg, which is 1 to 40% by weight. and that the main excipients in the mixture are basic pH-adjusting agents in an amount of 0.1 to 40% by weight, and the other excipients are polyols, and / or mixtures thereof, and / or mixtures of polyols and other fillers, and / or mixtures of polyols and glidants, and / or mixtures of polyols and glidants, and / or mixtures of polyols and glidants, and / or mixtures of polyols and glidants and disintegrants, and / or mixtures of polyols and glidants, disintegrants and other fillers.

According to another preferred embodiment, the pharmaceutical composition comprises 0.1 to 40% by weight, preferably 0.1 to 15% by weight. % of a basic substance.

According to another embodiment, the pharmaceutical composition comprises 1 to 99% by weight, preferably 10 to 95% by weight of polyols and / or mixtures thereof, preferably mannitol and / or mixtures thereof.

According to another embodiment, the pharmaceutical composition comprises 1 to 99% by weight, preferably 10 to 40% by weight, of other fillers, preferably microcrystalline cellulose with reduced water content.

According to another embodiment, the pharmaceutical composition comprises 1 to 25% by weight, preferably 1.5 to 10% by weight, of a disintegrant or disintegrants, preferably croscarmellose sodium.

According to another embodiment, the pharmaceutical composition comprises 0.1 to 10% by weight, preferably 0.5 to 4% by weight, of a glidant or glidants, preferably magnesium stearate.

J

The present invention also provides a process for the preparation of a pharmaceutical composition which comprises preparing a mixture of the active ingredient and at least one basic excipient by dry mixing and / or briquetting, and / or compacting, by adjusting the particle size of the mixture in the range of to 2000 µm, preferably 800 µm. the mixture thus prepared is used for the compression of cores and / or tablets, and ^from or micro-tablets, and / or for the preparation of pellets, and / or micropellets, and / or powders and / or granules, and / or fillers in capsules.

It is also an object of the present invention that the pharmaceutical form of the pharmaceutical composition is packaged in pharmaceutical containers to prevent moisture from penetrating the composition, preferably a composition composed of Al (aluminum) / OPA (oriented polyamide) / PVC (polyvinyl chloride) / Al (aluminum).

The present invention also relates to a process for stabilizing a mixture or mixture. a dosage form comprising perindopril erbumine as active ingredient used in the treatment of hypertension.

The selection of the factors causing the instability of the perindopril erbumine-containing formulation was carried out based on a series of compatibility tests of the mixtures of perindopril erbumine and pharmaceutical excipients and the stress tests of the finished product. Relative humidity has been identified as one of the major factors causing the increase of impurity B. Therefore, its elimination in excipients, in the preparation process and during the storage period is appropriate. The main factor causing stabilization of impurity F was a pH shift to the pH range of 7.1-14.

The essence of stabilization of the mixture or of the pharmaceutical product consists in that the mixture is prepared by dry mixing and / or briquetting and / or compacting (absence of water in the preparation process -> stabilization of impurity B perindopril erbumine) with the addition of a pharmaceutical auxiliary modifying the reaction of the mixture to a pH of 7.1 - 14 (stabilization of impurity F perindopril erbumine), by adjusting the particle size of the mixture.

The mixture thus prepared may be used for compressing cores, and / or tablets, and / or microtablets, and / or for preparing pellets, and / or micropellets, and / or powders and / or granules, and / or as a capsule fill.

The above-mentioned dosage forms thus prepared are packaged in an aluminum container or a container. a combination of aluminum-aluminum enriched with different types of polymers used in the pharmaceutical industry as packaging material - stabilizing impurity B (preventing moisture ingress).

Said methods of preparation do not include stressful processes such as introducing a wetting agent into the active ingredient / excipient mixture. Said methods of preparation and selection of excipients according to the invention also ensure very good stability of the formulation and the desired physical properties of the dosage form.

The mixture or mixture described in the invention is described herein. in addition to the active substance perindopril erbumine (perindopril tert-butylamine), the dosage form contains:

.0 and mixtures basifying agents, respectively. dosage form and other excipients such as: microcrystalline cellulose and polyols - such as fillers and flow modifiers, glidants to facilitate tabletting, tablet disintegration aids.

Conventional excipients such as: sodium bicarbonate, powdered sodium and potassium hydroxide, sodium citrate and its hydrates, potassium phosphate, sodium phosphate, dihydrogen potassium phosphate, dihydrogen sodium phosphate were used as pH-shift agents to pH 7.1 to 14. , magnesium oxide and other alkalizing aids

Microcrystalline cellulose used as a pharmaceutical excipient in the pharmaceutical industry was used. This, by its properties, ensures sufficient flow properties of the mixture and good compressibility in the preparation of moldings (cores, tablets, micro-tablets, pellets, micropellets).

The polyols used are pharmaceutical excipients which are ideal for dry solid formulation formulations. Their physico-chemical parameters ensure very good stability and satisfactory physico-chemical

-6parameters of tablets. According to the present invention, the above properties have been repeatedly achieved by using physically modified polyols e.g. mannitol.

The modified mannitol (Pearlitol) used is a white, crystalline powder (or granulate).

Due to its properties it ensures very good flow properties of the mixture and very good direct compressibility. Other properties are low hygroscopicity and chemical stability. These properties contribute to the excellent stability of the perindopril erbumine formulation prepared according to the present invention.

The following were used as disintegrants: starches, modified starches, cellulose derivatives, cross-linked polyvinyl pyrrolidones and others.

As glidants used in the pharmaceutical industry, salts of higher aliphatic acids have been used, for example: stearates, olefins, lauryl sulfates and others.

The essence of the technological process is that the active substance perindopril erbumine; and / or at least one pharmaceutical auxiliary compound:

- a substance with a basic reaction (stabilization of impurity F of perindopril erbumine) shifting the pH reaction to a range of 7.1 to 14, preferably a pH of 7.1 to 12; in an amount of 0.1 to 40 wt. %, preferably 0.1 to 15 wt. %

or with a mixture of microcrystalline cellulose, preferably microcrystalline cellulose with reduced water content (contributes to the stabilization of impurity B perindopril erbumine); and / or a substance with a basic reaction (stabilization of impurity F of perindopril erbumine) shifting the pH reaction to the range of 7.1 to 14, preferably pH 7.1 to 12; in an amount of 0.1 to 40 wt. %, preferably 0.1 to 15 wt. %

or with a mixture of 1 to 99% by weight. %, preferably 50 to 90 wt. % of a polyol group having a particle size of 10 to 1000 µm; and / or mannitol having a particle size of 100 to 520 µm, preferably 180 to 360 µm; and / or microcrystalline cellulose, preferably microcrystalline cellulose having a reduced water content (contributing to the stabilization of impurity B of perindopril erbumine); and / or a substance with a basic reaction (stabilization of the impurity F of perindopril erbumine) shifting the pH reaction to a range of 7.1 to 14, preferably a pH of 7.1 to 11; in an amount of 0.1 to 40 wt. %, preferably 0.1 to 15 wt. %

or with a mixture of 1 to 99% by weight. %, preferably 50 to 90 wt. % of a polyol group having a particle size of 10-1000 µm; and / or mannitol having a particle size of 100 to 520 µm, preferably 180 to 360 µm; and / or microcrystalline cellulose, preferably microcrystalline cellulose having a reduced water content (contributing to the stabilization of impurity B of perindopril erbumine); and / or a substance with a basic reaction (stabilization of the impurity F of perindopril erbumine) shifting the pH reaction to a range of 7.1 to 14, preferably

- 7 pH 7.1 to 12; in an amount of 0.1 to 40 wt. %, preferably 0.1 to 15 wt. %; and / or 1 to 25 wt. %, preferably 1.5 to 10% by weight of a disintegrant, preferably croscarmellose sodium;

or a mixture of 1 to 99 wt. %, preferably 50 to 90 wt. % of a polyol group having a particle size of 10 to 1000 µm; and / or mannitol having a particle size of 100 to 520 µm, preferably 180 to 360 µm; and / or microcrystalline cellulose, preferably microcrystalline cellulose with reduced water content (contributes to the stabilization of impurity B perindopril erbumine); and / or a substance with a basic reaction (stabilization of impurity F of perindopril erbumine) shifting the pH reaction to a range of 7.1 to 14, preferably a pH of 7.1 to 12; in an amount of 0.1 to 40 wt. %, preferably 0.1 to 15 wt. %; and / or 0.1 to 10 wt. %, preferably 0.5 to 4 wt. % glidant, preferably magnesium stearate.

From these mixtures, it is possible to prepare a mixture or mixtures thereof. tablets dry way in several ways, respectively. combinations thereof:

1. direct tabletting (preparation of mixture -> solid dosage form)

2. compacting (preparation of compacting mixture - + particle size adjustment -> solid dosage form)

3. briquetting (preparation of briquetting mixture -> particle size adjustment ->

solid dosage form)

The solid dosage forms of the invention thus prepared guarantee the reproducibility of the manufacturing process.

The advantage of these processes is the energy and time-consuming nature, in particular of the first of the above mentioned processes for the preparation of the mixture and the solid dosage forms containing perindopril erbumine.

The above processes for the preparation of a mixture of active ingredient and excipients; and solid dosage forms containing perindopril erbumine by direct tableting (without the addition of water or without increasing moisture as one of the most important factors causing the growth of impurity B perindopril erbumine), respectively. use of adjuvants with reduced water content, resp. with a lower hygroscopicity and the choice of pH-shifting excipients according to the invention make it possible to prepare a stable mixture of the active ingredient and excipients

-8tank respectively. stable solid dosage forms having satisfactory physical and chemical parameters.

By shifting the pH to the alkaline area, the stability of impurity F, which was within the limits of the stress tests when tested in the stress tests, was significantly improved, thus the active substance perindopril erbumine was more stable in the formulation described herein using an alkalizing component than impurities F.

Last but not least, it is also important in the process of stabilizing the preparation according to the invention to eliminate moisture penetration by using a suitable pharmaceutical packaging for this purpose (eg: aluminum-aluminum combinations enriched with various types of polymers used as packaging material in the pharmaceutical industry) ) - stabilization of impurity B.

DETAILED DESCRIPTION OF THE INVENTION

The invention is illustrated in the examples without being limited thereto.

Example 1:

(a) a pharmaceutical preparation containing in the composition of tablets:

composition Weight in g Weight% Perindopril erbumine 0.00400 g 2,50% Microcrystalline cellulose 0,03200 g 20,00% mannitol 0.11200 g 70.00% Magnesium oxide 0.00080 g 0,50% Croscarmellose sodium 0.00800 g 5,00% Magnesium stearate 0.00320 g 2,00% Together: 0.16000 g 100.00%

(b) the method of its preparation:

The active ingredient is introduced together with a portion of microcrystalline cellulose into a homogenizer. The mixture is homogenized for 10 minutes. The mixture is then sieved through a sieve with a mesh side length of 0.40 mm (Premix I). The remaining portion of microcrystalline cellulose is added to prernix 1 together with magnesium oxide, homogenized for 15 minutes. The mixture is then sieved through a sieve with a mesh side length of 0.40 mm (Premix II). The premix II is transferred to a homogenizer, mannitol and croscarmellose sodium are added. The mixture was homogenized for 15 minutes. The homogenised raw materials from the previous steps are:

-9Add magnesium stearate. The mixture was homogenized for 15 minutes. Tablets of the prescribed weight and appearance are compressed from the mixture thus prepared.

Example 2:

(a) a pharmaceutical preparation containing in the tablet formulation:

Perindopril erbumine 0.00200 g 2.50% Microcrystalline cellulose 0.00800 g 10.00% mannitol 0,06600 g 82.50% Sodium bicarbonate 0.00240 g 3,00% Croscarmellose sodium 0.00120 g 1.50% Magnesium stearate 0.00040 g 0,50% Together: 0,08000 g 100.00%

(b) the method of its preparation:

The active ingredient is introduced together with a portion of microcrystalline cellulose into a homogenizer. The mixture is homogenized for 10 minutes. The mixture is then sieved through a sieve with a mesh side length of 0.40 mm (Premix I). The remainder of microcrystalline cellulose is added to premix I together with sodium bicarbonate, homogenized for 15 minutes. The mixture is then sieved through a sieve with a mesh side length of 0.40 mm (Premix II). The premix II is transferred to a homogenizer, mannitol and croscarmellose sodium are added. The mixture was homogenized for 15 minutes. Magnesium stearate is added to the homogenized raw materials from the previous steps. The mixture was homogenized for 15 minutes. Tablets of the prescribed weight and appearance are compressed from the mixture thus prepared.

Example 3:

(a) a pharmaceutical preparation containing in the composition of tablets:

composition Perindopril erbumine Weight in g 0.00800 g Weight% 2,50% Microcrystalline cellulose 0.12800 g 40,05% mannitol 0.11360 g 35,50% Sodium citrate 0,04800 g 15.00% Croscarmellose sodium 0.01600 g 5.00% Magnesium stearate 0.00640 g 2,00% Together: 0,32000 g 100.00%

(b) the method of its preparation:

The active ingredient is introduced together with a portion of microcrystalline cellulose into a homogenizer. The mixture is homogenized for 10 minutes. The mixture is then sieved through a sieve with a mesh side length of 0.40 mm (Premix I). The remainder of the microcrystalline is added to premix I

- 10 cellulose together with sodium citrate, homogenized for 15 minutes. The mixture is then sieved through a sieve with a mesh side length of 0.40 mm (Premix II). The premix II is transferred to a homogenizer, mannitol and croscarmellose sodium are added. The mixture was homogenized for 15 minutes. Magnesium stearate is added to the homogenized raw materials from the previous steps. The mixture was homogenized for 15 minutes. Tablets of the prescribed weight and appearance are compressed from the mixture thus prepared.

Example 4:

(a) a pharmaceutical preparation containing, in the composition of a coated tablet:

Perindopril erbumine 0.00400 g 2,50% mannitol 0.15200 g 95.00% Sodium hydroxide 0.00080 g 0,50% Magnesium stearate 0.00320 g 2,00% Together: 0.16000 g 100.00% Mixture of film-forming substances 0.00800 g 5% of the core Purified Water / Ethanol 0,04500 g -

(b) the method of its preparation:

The active ingredient is introduced together with a portion of microcrystalline cellulose into a homogenizer. The mixture is homogenized for 10 minutes. The mixture is then sieved through a sieve with a mesh side length of 0.40 mm (Premix I). The remaining portion of microcrystalline cellulose is added to premix I together with sodium hydroxide, homogenized for 15 minutes. The mixture is then sieved through a sieve with a mesh side length of 0.40 mm (Premix II). The premix II is transferred to a homogenizer, and / or 4 mannitol batches are added. The mixture was homogenized for 15 minutes. The homogenized raw material of the preceding step, the '/ ₂ batch magnesium stearate. The mixture was homogenized for 15 minutes. From the mixture thus prepared, briquettes with a strength of 40-70 N are pressed, which are then ground through a sieve with a mesh size of 0.8 mm. The residue from the mannitol feed is added to the mixture thus prepared. The mixture was stirred for 15 minutes. The second half of the magnesium stearate batch is added to the blended mixture in the homogenizer. Stir 15 minutes. The cores are pressed from the finished mixture on a tablet press. The cores are then coated with a film-forming suspension.

Example 5:

(a) a pharmaceutical preparation containing in the composition of tablets:

composition Weight in g Weight% Perindopril erbumine 0.00400 g 2,50% Microcrystalline cellulose 0.11760 g 73.50% mannitol 0.01600 g 10.00% Sodium citrate dihydrate 0.00800 g 5,00% Croscarmellose sodium 0.00800 g 5,00% Magnesium stearate 0.00640 g 4,00% Together: 0.16000 g 100.00%

(b) the method of its preparation:

The active ingredient is introduced together with a portion of microcrystalline cellulose into a homogenizer. The mixture is homogenized for 10 minutes. The mixture is then sieved through a sieve with a mesh side length of 0.40 mm (Premix I). The remaining portion of microcrystalline cellulose is added to premix I together with sodium citrate dihydrate, homogenized for 15 minutes. The mixture is then sieved through a sieve with a mesh side length of 0.40 mm (Premix II). Premix II is transferred to a homogenization apparatus, add '/ ₂ and the shaft of mannitol The feed croscarmellose sodium. The mixture was homogenized for 15 minutes. Magnesium stearate feed is added to the homogenized raw materials from the previous steps. The mixture is homogenized for 15 minutes. The mixture thus prepared is compacted and then compacted through a sieve having a mesh size of 0.8 mm. 50% of the mannitol feed and the remaining croscarmellose sodium are added to the mixture thus prepared. The mixture was stirred for 15 minutes. The second half of the magnesium stearate batch is added to the blended mixture in the homogenizer. Stir 15 minutes. The finished mixture is filled into OPA / Alu / PVC bags.

Example 6:

(a) a pharmaceutical preparation containing in the composition of tablets:

composition Weight in g Weight% Perindopril erbumine 0.0040 g 40.00% Microcrystalline cellulose 0.0008 g 8.00% mannitol 0.0035 g 35.00% Sodium hydrogen phosphate 0.0005 g 5,00% Croscarmellose sodium 0.0010 g 10.00% Magnesium stearate 0.0002 g 2,00% Together: 0.0100 g 100.00%

- 12b) method of its preparation:

The active ingredient is introduced together with a portion of microcrystalline cellulose into a homogenizer. The mixture is homogenized for 10 minutes. The mixture is then sieved through a sieve with a mesh side length of 0.40 mm (Premix I). The remainder of microcrystalline cellulose is added to premix I together with sodium hydrogen phosphate, homogenized for 15 minutes. The mixture is then sieved through a sieve with a mesh side length of 0.40 mm (Premix II). The premix II is transferred to a homogenizer, mannitol and croscarmellose sodium are added. The mixture was homogenized for 15 minutes. Magnesium stearate is added to the homogenized raw materials from the previous steps. The mixture was homogenized for 15 minutes. Microtablets of the prescribed weight and appearance are pressed from the mixture thus prepared.

Example 7:

(a) a pharmaceutical preparation containing in the composition of tablets:

composition Weight in g Weight% Perindopril erbumine 0.00400 g 2,50% Microcrystalline cellulose 0,03200 g 20,00% mannitol 0.11120 g 69.50% Potassium phosphate 0.00160 g 1,00% Croscarmellose sodium 0.00800 g 5,00% Magnesium stearate 0.00320 g 2,00% Together: 0.16000 g 100.00%

(b) the method of its preparation:

The active ingredient is introduced together with a portion of microcrystalline cellulose into a homogenizer. The mixture is homogenized for 10 minutes. The mixture is then sieved through a sieve with a mesh side length of 0.40 mm (Premix 1). The remainder of microcrystalline cellulose is added to premix I together with potassium phosphate, homogenized for 15 minutes. The mixture is then sieved through a sieve with a mesh side length of 0.40 mm (Premix II). The premix II is transferred to a homogenizer, mannitol and croscarmellose sodium are added. The mixture was homogenized for 15 minutes. Magnesium stearate is added to the homogenized raw materials from the previous steps. The mixture was homogenized for 15 minutes. The finished mixture is filled into gelatin capsules.

-13 Example 8:

(a) a pharmaceutical preparation containing in the composition of tablets:

composition Perindopril erbumine Weight in g 0.00200 g Weight% 1,00% Microcrystalline cellulose 0,04000 g 20,00% mannitol 0.14380 g 71.90% Potassium hydroxide 0.00020 g 0.10% Croscarmellose sodium 0.01000 g 5,00% Magnesium stearate 0.00400 g 2,00% Together: 0,20000 g 100.00%

(b) the method of its preparation:

The active ingredient is introduced together with a portion of microcrystalline cellulose into a homogenizer. The mixture is homogenized for 10 minutes. The mixture is then sieved through a sieve with a mesh side length of 0.40 mm (Premix I). The remainder of microcrystalline cellulose is added to premix I together with potassium hydroxide, homogenized for 15 minutes. The mixture is then sieved through a sieve with a mesh side length of 0.40 mm (Premix II). The premix II is transferred to a homogenizer, ‘from the mannitol feed and‘ from the croscarmellose sodium feed are added. The mixture was homogenized for 15 minutes. To the homogenized raw materials from the previous steps, a magnesium stearate feed is added. The mixture was homogenized for 15 minutes. The mixture thus prepared is compacted and then compacted through a sieve having a mesh size of 0.8 mm. 50% of the mannitol feed and the remaining croscarmellose sodium are added to the mixture thus prepared. The mixture was stirred for 15 minutes. The second half of the magnesium stearate batch is added to the blended mixture in the homogenizer. Stir 15 minutes. The finished mixture is filled into gelatin capsules.

Example 9:

(a) a pharmaceutical preparation containing in the composition of tablets:

composition Weight in g Weight% Perindopril erbumine 0.00400 g 2,50% Microcrystalline cellulose 0,03200 g 20,00% mannitol 0.11200 g 70.00% Magnesium oxide 0.00080 g 0,50% Croscarmellose sodium 0.00800 g 5,00% Magnesium stearate 0.00320 g 2,00% Together: 0.16000 g 100.00%

- 14 (b) the method of its preparation:

The active ingredient is introduced together with a portion of microcrystalline cellulose into a homogenizer. The mixture is homogenized for 10 minutes. The mixture is then sieved through a sieve with a mesh side length of 0.40 mm (Premix I). The remaining portion of microcrystalline cellulose is added to premix I together with magnesium oxide, homogenized for 15 minutes. The mixture is then sieved through a sieve with a mesh side length of 0.40 mm (Premix II). The premix II is transferred to a homogenizer, mannitol and croscarmellose sodium are added. The mixture was homogenized for 15 minutes. Magnesium stearate is added to the homogenized raw materials from the previous steps. The mixture was homogenized for 15 minutes. Tablets of the prescribed weight and appearance are compressed from the mixture thus prepared. The finished tablets are packed in a blister of PVC / PVDC / Al foil.

Example 10:

(a) a pharmaceutical preparation containing in the composition of tablets:

composition Perindopril erbumine Weight in g 0.00400 g Weight% 2,50% Microcrystalline cellulose 0,03200 g 20,00% mannitol 0.11200 g 70.00% Magnesium oxide 0.00080 g 0,50% Croscarmellose sodium 0.00800 g 5,00% Magnesium stearate 0.00320 g 2,00% Together: 0.16000 g 100.00%

(b) the method of its preparation:

The active ingredient is introduced together with a portion of microcrystalline cellulose into a homogenizer. The mixture is homogenized for 10 minutes. The mixture is then sieved through a sieve with a mesh side length of 0.40 mm (Premix I). The remaining portion of microcrystalline cellulose is added to premix I together with magnesium oxide, homogenized for 15 minutes. The mixture is then sieved through a sieve with a mesh side length of 0.40 mm (Premix II). The premix II is transferred to a homogenizer, mannitol and croscarmellose sodium are added. The mixture was homogenized for 15 minutes. Magnesium stearate is added to the homogenized raw materials from the previous steps. The mixture was homogenized for 15 minutes. Tablets of the prescribed weight and appearance are compressed from the mixture thus prepared. The finished tablets are packed in a blister of OPA / Alu / PVC / Al foil.

Dissolution results of the active substance

The in vitro dissolution of perindopril erbumine is monitored for:

Equipment used: Ph.Eur. Dissolution equipment, paddles: 50 rpm.

Medium: 0.1 M HCl ¹ , 500 mL volume

Temperature: 37 ° C ± 0.5 ° C

Determination of drug dissolution: HPLC

The dissolution of the active compound is illustrated by way of example no. 9 and 10 and the dissolution results are shown in the table.

Table:

Dissolution of the active substance:

Time: Amount of active substance released (%) 5 minutes 10 minutes 15 minutes 30 minutes 45 minutes 60 minutes 101.6 101.6 101.4 101.7 102.3 101.7

The results of the dissolution of the active ingredient indicate that within 5 minutes the entire amount of active ingredient is released.

Stability results of the formulation

The content of related substances (purity) is illustrated by the embodiment No. 1 and No. 1, respectively. 9 and 10 and the dissolution results are shown in the table.

Stabilization of impurity B - comparison of tablets with alkalizing component in PVC / PVDC / A1 blister and alu-al blister

PVC / PVDC / AI cover Cover Alu-A at Perindopril erbumine content Impurity B limit 0,60% Perindopril erbumine content Impurity B limit 0,60% Day 0 100,80% 0.10% 100.80% 0.10% conditions 6 month stability 25 ° C ± 2 ° C, RH 60% ± 5% 99.10% 0.36% 100,80% 0.13% 30 ° C ± 2 ° C RH 65% ± 5% 97.50% 2.80% 100.00% 0.14% 40 ° C ± 2 ° C RH 75% ± 5% 87.40% 12.50% 99.80% 0.55%

Perindopril tablets were evaluated according to Ph.Eur. 4th

- 16Stabilization of impurity F - comparison of tablets in Alu-Al without alkalizing component and with alkalizing component

Tablets without alkalizing component Tablets with an alkalizing component Perindopril erbumine content Impurity F limit 0,40% Perindopril erbumine content Impurity F limit 0,40% Day 0 100.80% 0,07% 100,80% 0,07% conditions 6 month stability 25 ° C ± 2 ° C, RH 60% ± 5% 99.90% 0.36% 100,80% 0.08% 30 ° C ± 2 ° C RH 65% ± 5% 98,30% 1.9% 100.00% 0.09% 40 ° C ± 2 ³ C, 75% RH ± 5% 96.70% 2,70% 99.80% 0.10%

Perindopril tablets were evaluated according to Ph.Eur. 4th

Industrial applicability of the invention

The invention is useful in the pharmaceutical manufacture of stable forms - mixtures, cores, tablets, coated tablets, micro-tablets, for the preparation of pellets, micropellets, powders, granules and capsules.

The perindopril erbumine dosage forms can be used therapeutically in the treatment of hypertension.

Claims (10)

PATENT CLAIMS A pharmaceutical composition comprising, in a stable dosage form, perindopril erbumine in the range of 1-40% by weight and at least one pharmaceutical excipient and / or a mixture of pharmaceutical excipients in the range of 1-99% by weight, characterized in that at least one pharmaceutical excipient is a pH-adjusting substance in the range of pH 7.1 to 14. A pharmaceutical composition comprising perindopril erbumine according to claim 1, characterized in that the substances of basic nature are pharmaceutical auxiliaries adjusting the pH in the range 7.1 to 14, preferably pH adjusting in the range 7.1 to 12. Pharmaceutical composition containing perindopril erbumine according to claims 1 and 2, characterized in that the substances of basic character are selected from the group of oxides, hydroxides, bicarbonates, phosphates, hydrogen phosphates, dihydrogen phosphates, alkali metal and alkaline earth metal citrates and their hydrates. Pharmaceutical preparation containing perindopril erbumine according to claims 1 to 3, characterized in that it is in the form of a tablet and / or a coated tablet and / or a capsule filling in which the active substance perindopril erbumine is contained in an amount of 1 mg to 50 mg, 1 to 40% by weight, and that the main excipient in the mixture is a basic pH-adjusting agent according to claims 1 to 3, in an amount of 0.1 to 40% by weight, and the other excipients are polyol, and / or their mixtures and / or mixtures of polyols and other fillers, and / or mixtures of polyols and disintegrants, and / or mixtures of polyols and glidants, and / or mixtures of polyols and glidants, and / or mixtures of polyols and glidants and disintegrants, and / or or mixtures of polyols and glidants, disintegrants and other fillers. Pharmaceutical preparation containing perindopril erbumine according to claims 1 to 4, characterized in that it contains 0.1 to 40% by weight, preferably 0.1 to 15% by weight. % of a basic substance. Pharmaceutical composition containing perindopril erbumine according to claims 1 to 5, characterized in that it contains 1 to 99% by weight, preferably 10 to 95% by weight of polyols and / or mixtures thereof, preferably mannitol and / or mixtures thereof. - 187. The perindopril erbumine-containing pharmaceutical composition according to claims 1 to 6, characterized in that it contains 1 to 99% by weight, preferably 10 to 40% by weight of other fillers, preferably microcrystalline cellulose with reduced water content. A perindopril erbumine-containing pharmaceutical composition according to claims 1 to 7, characterized in that it comprises: The composition according to claim 1, characterized in that it contains 1 to 25% by weight, preferably 1.5 to 10% by weight, of a disintegrant or disintegrants, preferably croscarmellose sodium. Pharmaceutical preparation containing perindopril erbumine according to claims 1 to 8, characterized in that it contains 0.1 to 10% by weight, preferably 0.5 to 4% by weight, of a glidant or glidants, preferably magnesium stearate. Process for the preparation of a pharmaceutical preparation according to claims 1 to 9, characterized in that the mixture of the active ingredient and the at least one excipient is prepared by dry mixing and / or briquetting, and / or compacting, by adjusting the particle size of the mixture in the range 100 to 2000 µm. , preferably 800 µm, the mixture thus prepared is used for the compression of cores, and / or tablets, and / or microtablets, and / or for the preparation of pellets, and / or micropellets, and / or powders and / or granules, and / or as a capsule filling. Process for stabilizing a pharmaceutical composition comprising perindopril erbumine according to claims 1 to 10, characterized in that the dosage form is packaged in pharmaceutical containers to prevent moisture penetration to the composition, preferably a coating composed of Al (aluminum) / OPA (oriented polyamide) / PVC (polyvinyl chloride) / Al (aluminum).