RU2314099C1 - Pharmaceutical composition - Google Patents

Abstract

FIELD: medicine, pharmacy.

SUBSTANCE: invention relates to a pharmaceutical composition comprising enalapril maleate, lactose, potato starch, polyvinylpyrrolidone and magnesium stearate wherein a medium-molecular polyvinylpyrrolidone aqueous solution is used as polyvinylpyrrolidone, and the pharmaceutical composition comprises indapamide and aerosil additionally. The pharmaceutical composition is made as an enveloped-covered core in the following ratio of the core components, wt.-%: enalapril maleate is taken in the therapeutically effective dose; indapamide, 1.1-2.6; aerosil, 0.2-0.4; potato starch, 20.0-40.0; medium-molecular polyvinylpyrrolidone aqueous solution with the concentration 12%, 1.7-2.3; magnesium stearate, 0.8-1.0, and lactose, the balance. The claimed composition provides enhancing the hypotensive effect based on design of the composition comprising enalapril maleate and indapamide. The selected qualitative and quantitative composition excludes sticking tablet mass on equipment in tablets making process, loss of active substance and change of the ratio mass of components in ready tablets as compared to the measured one. Invention provides high strength and stability of tablets in storage.

EFFECT: improved and valuable properties of pharmaceutical composition, improved preparing method.

2 tbl

Description

The invention relates to medicine, in particular to a tablet form of chemotherapeutic agents for the treatment of arterial hypertension and congestive heart failure.

With a long course of treatment, solid forms in the form of tablets and capsules are most suitable for oral administration.

The tablet is one of the most convenient dosage forms of chemotherapeutic drugs, because maintains a qualitative and quantitative composition for a long time, is convenient to use and store.

A wide range of drugs for the treatment of hypertension are known, in particular, angiotensin converting enzyme inhibitors can be attributed to them. One of the representatives of this group of drugs is enalapril (S-1- [N- [1- (ethoxycarbonyl) -3-phenylpropyl] -L-alanyl-L-proline maleate (Mashkovsky MD. Medicines. - M., 2000).

Enalapril is a prodrug; in the body, it hydrolyzes with the formation of enalaprilat, which is an inhibitor of the angiotensin converting enzyme. It is used in the treatment of arterial hypertension, with congestive heart failure, with acute myocardial infarction, and is prescribed for patients suffering from hypertensive crises.

Enalapril, like most drug substances, does not have the ability to direct tabletting. Therefore, to create stable for a sufficiently long time, satisfying the pharmacopoeial requirements of the dosage form, it is necessary to introduce excipients in amounts determined by pharmaceutical and therapeutic expediency.

Known drugs based on enalapril, used as antihypertensive agents, which in addition to the aforementioned active substance also contain auxiliary pharmaceutically acceptable substances.

Thus, a solid dosage form is known that contains enalapril maleate and excipients in the following ratio of components, wt.%:

Lactose 48-52 Starch 33-42 Polyvinylpyrrolidone 1-2 Calcium or Magnesium Stearate one Enalapril maleate Therapeutically effective amount

(US Pat. RF 2140261 C1, A61K 31/4045, 10.27.1999).

The disadvantages of the technical solution include the high starch content (33-42 wt.%), Which causes a sharp decrease in tablet strength and, most importantly, a decrease in disintegration (IA Muravyov. Drug Technology. - M .: Medicine, 1971, p. 602 ) In addition, an alcohol solution of polyvinylpyrrolidone is used as a moisturizing agent in the manufacturing process, which creates certain technological difficulties. So, the use of a flammable substance - ethyl alcohol - requires compliance with certain safety procedures, and possibly requires additional equipment. The release of ethyl alcohol vapor into the atmosphere is also undesirable.

The closest technical solution to the proposed is a solid dosage form of an antihypertensive drug made of a pharmaceutical composition comprising enalapril maleate and target additives in the following ratio, wt.%:

Enalapril maleate 4,5-5,5 Sodium bicarbonate 0.5-1.5 Milk sugar 70-90 Potato starch 7-15 Polyvinylpyrrolidone 1.0-3.6 Magnesium stearate 0.4-1.02

(US Pat. RU 2165251, C1 A61K 31/4045, 04/20/2001).

The disadvantages of the technical solution include the use of an alcoholic solution of polyvinylpyrrolidone in the production process.

An object of the invention is to enhance the effect of the therapeutic antihypertensive effect by creating a complex composition, including enalapril maleate and indapamide.

To solve the technical problem in a pharmaceutical composition comprising enalapril maleate, milk sugar, potato starch, polyvinylpyrrolidone and magnesium stearate, an aqueous solution of polyvinylpyrrolidone is used as polyvinylpyrrolidone, and it additionally contains indapamide and aerosil, while the pharmaceutical composition is made in the form of a coated core the following ratio of core ingredients, wt.%:

enalapril maleate Therapeutically effective amount indapamide 1.1-2.6 aerosil 0.2-0.4 potato starch 20.0-24.0 medium molecular weight aqueous solution 1.7-2.3 polyvinylpyrrolidone concentration 12-20% magnesium stearate 0.8-1.0 milk sugar Rest

The invention is illustrated as follows.

The pharmacological effect of the drug is due to a combination of the individual properties of each component, as well as their synergism.

Enalapril maleate inhibits ACE, which promotes the transition of angiotensin I to angiotensin II, reduces the secretion of aldosterone, which leads to the elimination of spasm and the expansion of peripheral arteries.

Enalapril maleate is effective in any stage of arterial hypertension: mild, moderate and severe. The decrease in diastolic and systolic blood pressure occurs both in the supine position and standing. The maximum antihypertensive effect is observed 4-6 hours after a single dose and lasts for 24 hours.

In patients sensitive to the action of the drug, normalization of blood pressure is not accompanied by reflex tachycardia. The withdrawal of the drug does not lead to the development of a hypertensive reaction.

The pharmacological properties of indapamide are close to thiazide diuretics, and its effect is associated with inhibition of the reverse absorption of sodium ions in the cortical segment of the nephron loop.

Indapamide increases urinary excretion of sodium, chlorine and, to a lesser extent, potassium and magnesium ions. Such an action leads to an increase in diuresis and, ultimately, to a hypotensive effect lasting 24 hours.

In addition, the hypotensive effect of indapamide is associated with the ability of the drug to increase the elasticity of artery walls and lower peripheral vascular resistance. The use of indapamide leads to a decrease in hypertrophy of the left ventricle of the heart, a decrease in the production of free and stable oxygen radicals.

Indapamide does not affect kidney function.

The combination of an ACE inhibitor (enalapril maleate) and a thiazide diuretic (indapamide) reduces the risk of hypokalemia, which is characteristic when taking other diuretic drugs.

Aerosil - LiO _{2 is a} white, amorphous, powdery powder, used as a moving substance (GOST 14922-77).

Magnesium stearate is used as a lubricant (TU 6-09-16-1533-90). A lubricant is used to remove adherence to parts in appropriate tablet presses.

Milk sugar is a filler (GFH st. 589 Ph.Eur. 1997, p.1071).

Medium molecular weight polyvinylpyrrolidone is used as a binder in the composition of the tablet (ND H2-10112-99).

It is advisable to use an aqueous solution as the solution of polyvinylpyrrolidone in which the optimal concentration of polyvinylpyrrolidone is from 3 to 20%, more preferably from 12 to 20%. The introduction of sodium dodecyl sulfate into the solution makes it possible to improve the wettability of the dry ingredients during the wetting process and, thereby, the uniformity of the obtained granules.

Potato starch (GOST 7699-78) is a disintegrating agent. It is used to accelerate the disintegration of the tablet after swallowing to ensure rapid release of the drug.

The presence of the shell improves the appearance of the dosage form, protects it from mechanical damage, and also further increases the stability of the drug during storage. Preferably, the shell is made on the basis of a derivative of cellulose - hydroxypropylmethyl cellulose. Additionally, the shell may include a filler, such as titanium dioxide, talc, and a plasticizer, such as polyethylene glycol, tween 80, or a combination of these compounds. The optimal ratio of these ingredients in the shell is, wt.%:

tween 80, or polyethylene glycol - 3.0-28.5 talc - 0-10,0 titanium dioxide - 1-30,0 hydroxypropyl methylcellulose rest

It is allowed to create a pink color to use the dye lotion red 2C.

A method for producing a tablet includes:

1) dry mixing of enalapril maleate and indapamide with milk sugar, potato starch;

2) wet granulation with a 10-15% aqueous solution of PVP;

3) drying the mass;

4) the introduction of lubricating and moving substances: magnesium stearate and aerosil;

5) pressing the granulate to obtain tablet cores;

6) preparation of the shell - film suspension - by dissolving and homogenizing the components;

7) coating the resulting nuclei.

Layering is carried out until a film of satisfactory thickness is obtained. The composition of enalapril maleate with indapamide reduces the risk of hypokalemia, which is characteristic for taking other diuretic drugs. The protection of the core with the shell allows you to get a stable dosage form during storage.

Tablets may contain 5 mg and 10 mg of enalapril maleate as active ingredient, and 1.2 and 2.4 mg respectively of indapamide.

Examples of specific performance are summarized in table 1. The experimental results are summarized in table 2.

Due to the selected qualitative and quantitative composition of the pharmaceutical composition, the preparation of tablets is not accompanied by the adherence of the tablet mass to the equipment, the loss of the active substance and the change in the mass ratio of the components in the finished tablets relative to the calculated one are also practically eliminated. The properties of the tablet are preserved throughout the shelf life (up to 2 years).

Table 1 No. Structure Quantity,% one enalapril maleate 4.3 indapamide 1,1 aerosil 0.4 starch cards. 20,0 magnesium stearate 0.8 polyvinylpyrrolidone 1.7 milk sugar rest 2 enalapril maleate 4.7 indapamide 1.3 aerosil 0.3 starch cards. 21.0 magnesium stearate 0.9 polyvinylpyrrolidone 2,3 milk sugar rest 3 enalapril maleate 5.3 indapamide 1,2 aerosil 0.2 starch cards. 22.0 magnesium stearate 1,0 polyvinylpyrrolidone 2.0 milk sugar rest four enalapril maleate 9.7 indapamide 2.6 aerosil 0.4 starch cards. 2.0 magnesium stearate 0.8 polyvinylpyrrolidone 17 milk sugar rest 5 enalapril maleate 10 indapamide 2,4 aerosil 0.3 starch cards. 24.0 magnesium stearate 0.9 polyvinylpyrrolidone 2,3 milk sugar rest 6 enalapril maleate 10.3 indapamide 2.2 aerosil 0.2 starch cards. 22.0 magnesium stearate 1,0 polyvinylpyrrolidone 2.0 milk sugar rest

table 2 Composition number Storage Quality Compressive strength, kg / s Abrasion,% 1 month 1 year 2 years one Color is white, meets the requirements Color is white, meets the requirements Color is white, meets the requirements 3.4 0.05 2 Color is white, meets the requirements Color is white, meets the requirements Color is white, meets the requirements 3.4 0.05 3 Color is white, meets the requirements Color is white, meets the requirements Color is white, meets the requirements 3.4 0.08 four Color is white, meets the requirements Color is white, meets the requirements Color is white, meets the requirements 3.4 0.08 5 Color is white, meets the requirements Color is white, meets the requirements Color is white, meets the requirements 3.3 0.09 6 Color is white, meets the requirements Color is white, meets the requirements Color is white, meets the requirements 3.3 0.09

Claims (1)

A pharmaceutical composition comprising enalapril maleate, milk sugar, potato starch, polyvinylpyrrolidone and magnesium stearate, characterized in that an aqueous solution of polyvinylpyrrolidone with a concentration of 12-20% is used as polyvinylpyrrolidone and it additionally contains indapamide and aerosil, in which the pharmaceutical composition is made coated core in the following ratio of core ingredients, wt.%: enalapril maleate therapeutically effective amount indapamide 1.1-2.6 aerosil 0.2-0.4 potato starch 20.0-24.0 medium molecular weight aqueous solution polyvinylpyrrolidone with a concentration of 12-20% 1.7-2.3 magnesium stearate 0.8-1.0 milk sugar rest