RU2479310C2 - Pharmaceutical composition for treating arterial hypertension and congestive cardiac failure and method for preparing it - Google Patents

Abstract

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to medicine, more specifically to an agent to be used for treating arterial hypertension and congestive cardiac failure. A pharmaceutical composition contains ramipril, a combination of sodium bicarbonate and arginine as a stabiliser, lactose monohydrate, microcrystalline cellulose, hypromellose, sodium croscarmellose, glidant and a lubricant and optionally a dying agent. A method for preparing the pharmaceutical composition involves moisturising of a mixture of ramipril, lactose monohydrate, microcrystalline cellulose, sodium bicarbonate, and optionally the dying agent in a solution of hypromellose and arginine, granulation, drying, dry granulation, addition of sodium croscarmellose, glidant and the lubricant, and tableting of the prepared mixture. The pharmaceutical composition in the form of a solid dosage form is characterised by decreased formation of all impurities, including ramiprilate and diketopiperazine ramipril, fast release of the active substance, high strength and storage stability of the quality characteristics guaranteed within more than 2 years of shelf life.

EFFECT: preparing the agent for treating arterial hypertension and congestive cardiac failure.

11 cl, 2 tbl, 12 ex

Description

The invention relates to the field of medicine, specifically to a tool that can be used to treat arterial hypertension and congestive heart failure.

Ramipril, 1-ethyl ester (2S, 3aS, 6aS) -1 [(S) -N - [(S) -1-carboxy-3-phenylpropyl] alanyl] octahydrocyclopenta [b] pyrrole-2-carboxylic acid is an inhibitor angiotensin-converting enzyme (ACE). Ramipril is used to treat hypertension, heart failure, paralysis, myocardial infarction, diabetes and diseases of the cardiovascular system. Ramipril and its acidic form, ramiprilat, are described in patent EP 0097022 B1.

Obtaining stable pharmaceutical compositions of ramipril is difficult, since ramipril is prone to some types of degradation. It can undergo cyclization via internal nucleophilic attack, hydrolysis and oxidation, forming substituted diketopiperazines, ramipril diacid and products of deeper degradation.

US 2003/0215526 discloses pharmaceutical compositions of an ACE inhibitor comprising a therapeutically effective amount of a decomposition sensitive ACE inhibitor, or a salt thereof; an alkali or alkaline earth metal carbonate in an amount exceeding stoichiometric to an ACE inhibitor or its salt, and a pharmaceutically acceptable carrier.

EP 0 280 999 B1 describes a composition comprising an ACE inhibitor, an alkali or alkaline earth metal carbonate and a saccharide in which an ACE inhibitor is stabilized against decomposition due to the presence of the other ingredients mentioned. In the patent specification, suitable saccharides are lactose and mannitol. Modified starch is also mentioned in the description as a disintegrant. However, the known compositions with ramipril as the active substance are not sufficiently stabilized against degradation.

EP 0 317 878 B1 describes a stable compressed pharmaceutical composition comprising a compound of a certain formula (which ramipril is suitable for), where, to stabilize before compression, a compound of this formula is a) coated with a physiologically acceptable protective polymer coating, or b) mixed with a physiologically acceptable buffer that provides maintaining the pH of the pharmaceutical composition in the presence of moisture in the range from slightly acidic to slightly alkaline values, where sodium bicarbonate is excluded from the list of possible cure buffers, or c) mixed with a physiologically acceptable buffer, ensuring the pH of the pharmaceutical composition in the presence of moisture in the range from weakly acidic to slightly alkaline, and coated with a physiologically acceptable polymer protective coating, where, if stabilized according to item b) alkaline carbonate or alkaline earth metal, sugar is not added to the composition. The disadvantages of this composition include the complexity of manufacturing technology.

The Russian patent application RU 2007120821 (WO 2006/052968) describes a pharmaceutical composition that contains ramipril coated with a component of the mixture, wherein the component of the mixture is selected from glyceryl behenate, glyceryl stearate, stearyl alcohol, macrogol stearate ether, palmitostearate, ethylene glycol, polyethylene glycol, polyethylene cetyl alcohol, lauryl alcohol, amylopectin, poloximer or combinations thereof, preferably glyceryl behenate. However, this composition has problems with the release of the active substance.

In Russian application RU 2006133453 (WO2005079762) a multilayer tablet is proposed comprising a first layer containing telmisartan in a dissolving tablet matrix and a second layer containing ramipril in a disintegrating tablet matrix. To stabilize telmisartan, the dissolving matrix may contain an alkaline agent selected from the group consisting of alkali metal hydroxides, alkaline amino acids, for example arginine, and meglumine, preferably sodium hydroxide. The use of arginine to stabilize ramipril is not indicated.

Eurasian patent EA 11862 describes a pharmaceutical composition of ramipril, comprising as a stabilizing substance a combination of sodium bicarbonate and calcium sulfate dihydrate (prototype). Known composition as auxiliary substances may include a disintegrating agent, a binding agent, for example starch, and a glidant, for example sodium stearyl fumarate. The known composition is particularly stable with respect to the formation of diketopiperazine, however, the applicable stabilizer is not effective against the formation of other degradation products, for example ramipril diacid.

The objective of this invention is to provide a drug for the treatment of arterial hypertension and congestive heart failure based on ramipril in the form of a solid dosage form, exhibiting high therapeutic activity, stable during storage, characterized by high values of the release rate of the active substance and having a shelf life of more than 2 years.

The problem is solved by a pharmaceutical composition containing ramipril, a combined stabilizing substance based on sodium bicarbonate, a filler, a binder, a disintegrant, a sliding substance, characterized in that it contains a combination of sodium bicarbonate and arginine as a stabilizing substance.

The composition may further comprise a dye, preferably iron oxide yellow or iron oxide red. As the filler, lactose monohydrate, microcrystalline cellulose or a combination thereof can be used, preferably a combination of lactose monohydrate and microcrystalline cellulose in a ratio of 6-10 parts of lactose monohydrate to 1 part of microcrystalline cellulose. Hypromellose or starch, preferably hypromellose, may be used as a binder. Sodium carboxymethyl starch, crospovidone or croscarmellose sodium are used as a disintegrant, preferably croscarmellose sodium. Glidants include glidant and lubricant. As the glidant, colloidal silicon dioxide, methylated silicon dioxide or a combination thereof is used, preferably a combination of colloidal silicon dioxide and methylated silicon dioxide in a 1: 1 ratio. Sodium stearyl fumarate is preferably used as the lubricant.

The active substance in the proposed composition is ramipril. Ramipril - an ACE inhibitor, is a prodrug from which the active metabolite ramiprilat is formed in the body, has a vasodilating effect. It is used for arterial hypertension, chronic heart failure.

In a preferred embodiment of the invention, the composition comprises ramipril and a combined stabilizer in the following ratio, parts by weight

Ramipril - 1.0

Sodium bicarbonate - 0.005-1.0

Arginine - 0.002-1.0

The introduction of arginine in combination with sodium bicarbonate significantly reduced the formation of impurities such as ramipril diacid and other impurities, which are further referred to in the text as unidentifiable impurities, while maintaining good inhibition of the formation of ramipril diketopiperazine.

Studies have shown high stability of the claimed composition. The stability of the drug was studied during storage (table 1). The claimed composition showed excellent stability in the formation of an impurity of diacid (impurity E) and other impurities indicated as the sum of unidentifiable impurities, while maintaining good stability in the formation of an impurity of diketopiperazine, the content of the latter was 0.9-1.0% after a year of storage and after 2 years 1.8-2.0%. The amount of impurity is indicated relative to the initial content of ramipril

Table 1 Impurities,% Examples (shelf life, - / 1 year / 2 years) one 5 7 12 Impurity of diacid 0.02 / 0.13 / 0.15 0.02 / 0.10 / 0.11 0.02 / 0.12 / 0.15 0.05 / 0.08 / 0.11 The sum of unidentifiable impurities 0.07 / 0.18 / 0.20 0,07 / 0,15 / 0,17 0.05 / 0.15 / 0.18 0.08 / 0.11 / 0.15

The resulting tablets have sufficient strength, high release rate of the active substance, stable quality indicators and shelf life of more than 2 years.

The preferred ratio of the ingredients of the claimed composition is, parts by weight:

Ramipril - 1.0

Sodium bicarbonate - 0.01-1.0

Arginine - 0.005-1.0

Filler - 1.4-745.6

Binder - 0.01-3.2

Disintegrant - 0.03-12.8

Glidant - 0.03-12.8

Lubricant - 0.02-6.4

Dye 0.001-0.06

A distinctive feature of the method of obtaining the claimed composition, which includes moistening a mixture of ramipril, filler, sodium bicarbonate and, optionally, dye with a solution of a binder and arginine, granulation, drying, dry granulation, adding a disintegrant, glidant and lubricant, and tableting the finished mixture, is the introduction of arginine in a solution in conjunction with a binder.

The new pharmaceutical composition is preferably in the form of a tablet.

Examples of the invention are presented in Table 2. Typical example (example 1). If there is a dye in the composition of the tablet mass, in order to achieve uniform coloring of the tablets, a mixture of a part of the filler and dye is separately prepared. To do this, pre-sieved (2 times) yellow iron / red oxide iron powder is mixed with a small amount of sifted filler powder and the resulting mixture is manually sieved three times through a sieve with a mesh size of 114 μm.

The pre-sifted powders of the substance of ramipril, filler, sodium bicarbonate and the pre-prepared mixture of part of the filler with dye are mixed until homogeneous, granulated with a humidifier solution containing a binder and arginine, dried and the granules obtained are dried and ground. A disintegrant, a glidant and a lubricant are added to the crushed granulate and the finished mass is tabletted. Get tablets with an average weight of 0.100 g (dosage 1.25 mg), 0.200 g (dosage 2.5 mg), 0.13 g (dosage 5 mg) and 0.26 g (dosage 10 mg) and strength 65 ÷ 85 N (dosage 1.25 mg), 90 ÷ 110 N (dosage 2.5 mg), 80 ÷ 95 N (dosage 5 mg) and 95 ÷ 105 N (dosage 10 mg).

The resulting tablets satisfy the regulatory requirements for a pharmaceutical agent. Dissolution,% release of ramipril into the dissolution medium - 0.1 N hydrochloric acid solution - after 30 minutes (HPLC) - 100 (at least 75 according to regulatory documents), ramipril content in one tablet (HPLC) - 1.25 mg (dosage 1 , 25 mg), 2.5 mg (dosage 2.5 mg), 5.0 mg (dosage 5 mg) and 10.0 mg (dosage 10 mg). The resulting tablets have a shelf life of more than 2 years.

Claims (11)

1. A pharmaceutical composition for treating cardiovascular diseases in the form of a solid dosage form that contains the active substance ramipril in a therapeutically effective amount, a combination of sodium bicarbonate and arginine as a stabilizer, lactose monohydrate, microcrystalline cellulose, hypromellose, croscarmellose sodium, glidant and lubricant. 2. The pharmaceutical composition according to claim 1, characterized in that it further contains a dye. 3. The pharmaceutical composition according to claim 2, characterized in that it contains yellow oxide as iron dye or red iron oxide. 4. The pharmaceutical composition according to claim 2, characterized in that it contains ramipril, sodium bicarbonate and arginine in the following ratio, parts by weight:
Ramipril one Sodium bicarbonate 0.005-1.0 Arginine 0.002-1.0 5. The pharmaceutical composition according to claim 4, characterized in that it contains, as a glidant, a combination of colloidal silicon dioxide and methylated silicon dioxide and stearyl fumarate as a lubricant. 6. The pharmaceutical composition according to claim 5, characterized in that it is made in the form of tablets. 7. The pharmaceutical composition according to claim 6, characterized in that it contains ramipril in one tablet in an amount of 1.25 mg. 8. The pharmaceutical composition according to claim 6, characterized in that it contains 2.5 mg of ramipril in one tablet. 9. The pharmaceutical composition according to claim 6, characterized in that it contains 5 mg of ramipril in one tablet. 10. The pharmaceutical composition according to claim 6, characterized in that it contains 10 mg of ramipril in one tablet. 11. A method for producing a pharmaceutical composition according to claims 1-10, which comprises wetting a mixture of ramipril, lactose monohydrate, microcrystalline cellulose, sodium bicarbonate and, optionally, dye with a solution of hypromellose and arginine, granulation, drying, dry granulation, adding croscarmellose sodium, glidant and lubricant and tabletting of the finished mixture.