Antiarrhythmic, antianginal pharmaceutical composition

 

The invention relates to the field of medicine. The pharmaceutical composition contains as active ingredient a therapeutically effective amount of amiodarone hydrochloride, and the target additives, starch, microcrystalline cellulose, oksipropilmetiltselljuloza, polyvinylpyrrolidone, stearic acid or its salts, Aerosil when a certain ratio of these components. The composition is made in the form of tablets. The composition contains a small number of targeted supplements, pills easily release the active substance, which ensures its high bioavailability. The tablets meet the requirements of Gosfarmakapei XI ed. 5 C.p. f-crystals, 1 table.

The invention relates to medicine, specifically to medicinal agent with antiarrhythmic and antianginal activity - amiodarone.

Normalizing influence on the broken rhythm of cardiac contractions can have substances belonging to different classes of chemical compounds belonging to different pharmacological groups.

Amiodarone, which is the antianginal agent, has simpaticescoe action and limits therefore the effect of catecholamines on the Sabbath. src="https://img.russianpatents.com/chr/945.gif">and-adrenergic receptors of the cardiovascular system, not causing complete their blockade. However, it activates the Central sympathetic tone. Unlike drugs, completely blocking-adrenergic receptors, amiodarone virtually no negative inotropic action. The drug reduces the resistance of the coronary vessels, increase coronary blood flow, reducing urezhaet heart, reduces the need for oxygen, increases energy reserves of the myocardium; slightly lowers peripheral vascular resistance and systemic arterial pressure. Along with antianginal action of amiodarone has a pronounced antiarrhythmic effect as if supraventricular and ventricular arrhythmias. In addition, amiodarone is used to treat patients with chronic ischemic heart disease with syndrome of angina (stress and rest). In connection with the antiarrhythmic effect of the drug is shown, the combination of angina with cardiac rhythm disturbance (Mashkovsky, M. D. "Drug", M, "Medicine", 1984, T. 1, S. 425-426).

Recently there was information on the use of amiodarone for the its medical application, although it is contrary to the common opinion, according to which it is believed that amiodarone is unacceptable for patients suffering from heart failure, however, the development of pharmaceutical compositions of evidence is relevant. In addition, the Russian market insufficiently provided with this drug, in addition amiodarone very costly because of the necessity to buy drug abroad.

It is known that the most common dosage form of amiodarone are tablets containing 0.2 g of amiodarone (Mashkovsky, M. D., S. 426), however, information about the composition of the tablets and auxiliary substances in open publications are scarce.

Described pharmaceutical composition in oral form, containing amiodarone (EP 0133176, 1985), of the following composition, mg: amiodarone - 100; mannitol - 141,5; maize starch - 30; polyvinylpyrrolidone - 12; saccharin sodium - 0,5; cyclamate sodium - 5; alginic acid - 8; magnesium stearate - 3. The disadvantage of this composition is the large number of auxiliary substances: 200% per unit of active substances of amiodarone. In addition, the high cost of individual components.

In the same patent, and the patent EP 0796617, 1997 proposed antiarrhythmic composicion - 12; colloidal silicon 2,4; magnesium stearate is 4.6. Because cardiovascular diseases are more vulnerable elderly people that have, as a rule, is not one disease, and sometimes several, often diabetes, the presence of a large amount of sugar (lactose) in the dosage form is undesirable, given the long-term use of amiodarone.

In the patent of the Russian Federation 2169556, 2001, described composition antiarrhythmic medicines of the following composition (mg per tablet: amiodarone hydrochloride 200; lactose - 90; talc powder - 4; potato starch - 60; microcrystalline cellulose - 29; calcium stearate - 10; polyvinylpyrrolidone - 7. The disadvantages of this structure should be attributed to the high content of lactose, as well as a significant number of auxiliary substances to 100% per unit mass of amiodarone.

The objective of the invention is the creation of an antiarrhythmic, antianginal pharmaceutical compositions on the basis of evidence, not containing sugar, meets all the requirements of Gosfarmakapei XI edition.

This is achieved antiarrhythmic, antianginal pharmaceutical composition on the basis of the evidence, containing a therapeutically effective amount of amiodarone g is nsiproperties (OPMC), polyvinylpyrrolidone, stearic acid or its salts, are presented in the following ratio of components, % by mass unit of active ingredient: Starch - 14,5-25,3 MKC - 38,2-55,0 OPMC - 1.0 to 4.3 Polyvinylpyrrolidone - 2,1-5,7 Stearic acid or its salt - 0,8-2,0 Aerosil - 0.9 To 3.0 Starch is preferably used potato and/or corn, as well as salts of stearic acid is predominantly magnesium stearate.

The pharmaceutical composition is made in a solid form, mostly in the form of tablets containing 0,190 - 0,210 g of amiodarone hydrochloride.

The pills get way with wet granulation.

The obtained tablets do not contain sugar, meet all the requirements of Gosfarmakapei XI ed. and regulatory requirements on the drug amiodarone. In addition, they have a high bioavailability (see table), which is connected, possibly, with a lower content of auxiliary substances (not more than 95% per unit mass of amiodarone).

The following examples illustrate the invention.

Example 1. Mix the powder 120 g of amiodarone hydrochloride, 24,27 g (20,2% by weight of active substance) of corn starch and 54.7 g (45,6%) MCC until smooth and moisturize the 3% aqueous solution OPMC (2,88 g (2,4%) dry OPMC). A lot of proposalsare. The resulting mass optivault mixture of powders: 4,2 g (3.5%) polyvinylpyrrolidone, 1.8 g (1,5%) of magnesium stearate and 2.1 g (1.75 per cent) of Aerosil and ready tabletow mixture tabletirujut on a tablet press. Get 570 tablets with a total weight of 199,5 g and the content in one tablet in the middle 0,199 g of amiodarone hydrochloride. The resulting tablets have a high bioavailability and meet all regulatory requirements (see table).

Example 2. Obtaining tablets amiodarone carried out as in example 1 based on 120 g of amiodarone hydrochloride, 17,46 g (14,55%), potato starch, 45,9 g (38,2%) MCC, 1.26 g (1,05%) OPMC, 2.58 g (2,1%) polyvinylpyrrolidone, 1.0 g (0,8%) of stearic acid and 1.1 g (0,9%) of Aerosil. Get 525 tablets total weight 181,12 g and the content in one tablet, on average, 0,207 g of amiodarone hydrochloride, which meet all regulatory requirements and have high bioavailability (see table).

Example 3. Obtaining tablets amiodarone carried out as in example 1 based on 120 g of amiodarone hydrochloride, 30,3 g (25,25%), potato starch, 66,0 g (55,0%) MCC, 15,1 g (4,25%) OPMC, of 6.78 g (5,65%) polyvinylpyrrolidone, 2,34 g (1,95%) of magnesium stearate and of 3.54 g (2,95%) of Aerosil. Receive 618 tablets total weight 221,24 g and the content in one tablet, on average, 0,192 g Amida(see table).

Claims

1. Antiarrhythmic, antianginal pharmaceutical composition comprising as active ingredient a therapeutically effective amount of amiodarone hydrochloride, as the target additives, microcrystalline cellulose, polyvinylpyrrolidone, starch, characterized in that it further comprises oksipropilmetiltselljuloza, Aerosil, stearic acid or its salt in the following ratio of components, % by mass unit of active ingredient: Starch - 14,5-25,3
Microcrystalline cellulose - 38,2-55,0
Oksipropilmetiltselljuloza - 1,0-4,3
Polyvinylpyrrolidone - 2,1-5,7
Stearic acid or its salt - 0,8-2,0
Aerosil is 0.9 to 3.0
2. The pharmaceutical composition under item 1, characterized in that the starch it contains mainly potato and/or corn starch.

3. The pharmaceutical composition under item 1 or 2, characterized in that salts of stearic acid it contains mainly magnesium salt.

4. The pharmaceutical composition according to any one of paragraphs. 1-3, characterized in that it is made mostly in the form of solid dosage forms.

5. The pharmaceutical composition p is I composition according to any one of paragraphs. 1-5, characterized in that it contains in each tablet 0,190-0,210 g of amiodarone hydrochloride.

 

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The invention relates to phenylselenenyl guanidium alkenylboronic acid of the formula (I)

< / BR>
where T means

< / BR>
moreover, R(A) denotes hydrogen, fluorine, chlorine, bromine, iodine, CN, IT, OR(6), (C1-C4)-alkyl, Or(CH2)aCbF2b+l, (C3-C8-cycloalkyl or NR(7)R(8); where

r denotes zero or 1;

a represents zero, 1, 2, 3 or 4;

b means 1, 2, 3 or 4;

R(6) means (C1-C4)-alkyl, (C1-C4)-perfluoroalkyl, (C3-C6)-alkenyl, (C3-C8-cycloalkyl, phenyl or benzyl;

and the phenyl nucleus is not substituted or is substituted by 1-3 substituents selected from the group consisting of F, Cl, CF3, methyl, metoxygroup and NR(9)R(10);

where

R(9) and R(10) mean hydrogen, (C1-C4)-alkyl or (C1-C4)-perfluoroalkyl;

R(7) and R(8) independently of one another are specified for R(6) the value, or

R(7) and R(8) together mean 4 or 5 methylene groups, of which one CH2group can be replaced by oxygen, sulfur, NH, N-CH3or N-benzyl;

R(B) R(C) and R(D) independently from each other are specified for R(A) mn is od CN, OR(12), (C1-C8)-alkyl, Op(CH2)fCgF2g+l, (C3-C8-cycloalkyl or (C1-C9)heteroaryl;

R denotes zero or 1;

f is zero, 1, 2, 3 or 4;

g means 1, 2, 3, 4, 5, 6, 7 or 8;

R(12) means (C1-C8)-alkyl, (C1-C4)-perfluoroalkyl, (C3-C8)-alkenyl, (C3-C8-cycloalkyl, phenyl or benzyl,

and the phenyl nucleus is not substituted or is substituted by 1-3 substituents selected from the group consisting of F, Cl, CF3, methyl, metoxygroup and NR(13)R(14); where

R(13) and R(14) denote hydrogen, (C1-C4)-alkyl or (C1-C4)-perfluoroalkyl;

R(E) has independently specified for R(F) value;

R(1) independently has a specified T value; or

R(1) means hydrogen, -OkCmH2m+l, -On(CH2)pCqF2q+1, fluorine, chlorine, bromine, iodine, CN, -(C= O)-N=C(NH2)2, -SOrR(17), -SOr2NR(31)R(32), -Ou(CH2)vWITH6H5, -Ou2-(C1-C9-heteroaryl or-Su2-(C1-C9-heteroaryl;

k is zero or 1;

m means zero, 1, 2, 3, 4, 5, 6, 7 or 8;

n denotes zero or 1;

p denotes zero, 1, 2, 3 or 4;

q is 1, 2,with hydrogen, (C1-C8)-alkyl or (C1-C8)-perfluoroalkyl or

R(31) R(32) together form a 4 or 5 methylene groups, of which one CH2group can be replaced by oxygen, sulfur, NH, N-CH3or N-benzyl;

R(17) implies (C1-C8)-alkyl;

u means zero or 1;

u2 means zero or 1;

v means zero, 1, 2, 3 or 4;

and the phenyl nucleus is not substituted or is substituted by 1-3 substituents selected from the group consisting of F, Cl, CF3, methyl, metoxygroup, -(CH2)wNR(21)R(22), NR(18)R(19) and (C1-C9)-heteroaryl;

where

R(18) R(19), R(21) R(22) independently of one another denote (C1-C4)-alkyl or (C1-C4)-perfluoroalkyl;

w is 1, 2, 3 or 4;

moreover, a heterocycle (C1-C9)-heteroaryl not substituted or is substituted by 1-3 substituents selected from the group consisting of F, C1, CF3, methyl or metoxygroup;

R(2), R(3), R(4) and R(5) independently of one another are specified for R(1); or

R(1) and R(2) or R(2) and R(3) together mean a group-CH-CH=CH-CH-, which is not substituted or is substituted by 1-3 substituents selected from the group consisting of F, C1, CF3, methyl, metoxygroup, -(CH2)w2NR(24)R(25) and NR(26)R(27);

where
is 1, 2, 3, or 4;

and the molecule contains at least two residue is T, at most three;

and their pharmaceutically acceptable salts

The invention relates to the field of medicine and relates to pharmaceutical compositions for the treatment of complex and coronary heart disease, myocardial infarction, myocardiodystrophy, rhythm disturbances associated with the use of cardiac glycosides
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