RU2280450C1 - Medicinal agent possessing hypotensive effect and method for its preparing - Google Patents

Abstract

FIELD: pharmaceutical technology, pharmacy.

SUBSTANCE: invention relates to producing solid combined medicinal formulations of preparations showing the hypotensive effect on both systolic and diastolic arterial blood pressure, increasing the cardiac blood ejection and enhancing the tolerance to physical loading. Proposed medicinal agent comprises the following components, wt.-%: perindopril erbumin, 0.6-6.6; indapamide, 0.1-2.1; microcrystalline cellulose, 16.0-35.0; magnesium stearate, 0.3-1.7; aerosil, 0.2-1.0; croscarmelose sodium, 1.1-7.5, and lactose, the balance. Also, invention discloses a method for preparing the medicinal formulation. Invention provides reducing mechanical losses of perindopril erbumin and indapamide in the process of the formulation preparing, retaining their properties in intact state and enhancing biological availability of active substances.

EFFECT: improved and enhanced medicinal and pharmaceutical properties of agent.

3 cl, 2 tbl, 2 ex

Description

The invention relates to medicine, in particular to pharmacy, and can be used in the manufacture of solid combined dosage forms of drugs that have a hypotensive effect on both systolic and diastolic blood pressure, increasing cardiac output and increasing exercise tolerance.

As the closest analogue, the description of the drug NOLIPREL (NOLIPREL), which has a hypotensive effect, found on the site http://vidal.moslek.ru/view_drug-10247.htm (12.08.2004) was taken

This product is a tablet, 1 tablet contains perindopril 4 mg and indapamide 1.25 mg as active substances. Excipients: microcrystalline cellulose, lactose monohydrate, magnesium stearate, colloidal hydrophobic silicon dioxide (aerosil).

There is also a method of producing a drug having a hypotensive effect and containing indapamide as the active substance by mixing the active substance with milk sugar, microcrystalline cellulose, starch glycolate, granulation, drying, dry granulation, dusting with magnesium stearate and tabletting (RU 2003103482, application for invention, publ. 08/20/2004).

The disadvantages of the described method for manufacturing a dosage form include the fact that it leads to mechanical losses and a change in the properties of the active substance in the process of technological operations following mixing.

The objective of the invention is the creation of a combined drug in the form of tablets with strength and providing high bioavailability of the active substance, as well as the creation of a method of manufacturing a combined preparation that reduces the mechanical loss of the active substance and allows you to save its properties unchanged.

The technical result of the invention is to provide the introduction of the second active substance - perindopril erbumin - with minor losses in the manufacture of the product and maintaining its properties unchanged due to its introduction at a late stage - dusting - while ensuring high bioavailability of the active substances.

The technical result is achieved by a drug having a hypotensive effect, containing perindopril erbumin and indapamide as active ingredients, and microcrystalline cellulose, magnesium stearic acid and aerosil as auxiliary substances, and it additionally contains milk sugar and croscarmellose sodium as auxiliary substances in the following components, wt.%:

Perindopril erbumin 0.6-6.6 Indapamide 0.1-2.1 Microcrystalline cellulose 16.0-35.0 Magnesium stearic acid 0.3-1.7 Aerosil 0.2-1.0 Croscarmellose sodium 1.1-7.5 Milk sugar rest

The technical result is also achieved by a method of manufacturing a drug having a hypotensive effect, according to which all components are pre-sieved, then indapamide, milk sugar and microcrystalline cellulose are mixed, moistened with distilled water, wet granulation is carried out, drying, if necessary, subsequent dry granulation, dusting a mixture of perindopril erbumin, aerosil, croscarmellose sodium and stearic magnesium and tableting.

The invention consists in the following.

The proposed drug is a combination drug (Noliprel) containing an ACE inhibitor perindopril (tert-butylamine salt) and diuretic indapamide (a derivative of chlorosulfamoyl). The pharmacological effect is due to a combination of the individual properties of each component, as well as their synergism. The pronounced antihypertensive effect is associated with the synergism between perindopril and indapamide.

The drug improves endothelial function (increasing the release of vasodilating and reducing the production of arterial vasoconstrictor factors) and arterio-capillary microcirculation, increases vascular elasticity, reduces stiffness and improves the extensibility of arteries, reduces the thickness of the arterial wall and arterioles, which is accompanied by normalization of the ratio of elastin / collagen and functional resistance capillary bed, contributes to the regression of renal impairment (proteinuria, glomerulosclerosis).

While taking Noliprel, the activity of the renin-angiotensin-aldosterone system is inhibited and potassium excretion due to the action of indapamide is reduced.

Noliprel has a pronounced dose-dependent hypotensive effect on both systolic and diastolic blood pressure.

The antihypertensive effect of the drug does not depend on the age and position of the patient’s body and lasts 24 hours. A decrease in blood pressure occurs in less than 1 month and is not accompanied by tachycardia. Discontinuation of treatment is not accompanied by the appearance of associative symptoms.

In clinical studies, it was shown that the combination of perindopril and indapamide enhances the action of each of them.

Noliprel reduces left ventricular hypertrophy, improves arterial compliance, reduces OPSS and arteriole resistance, does not affect lipid metabolism (total cholesterol, cholesterol / HDL and LDL, triglycerides), does not affect carbohydrate metabolism even in patients with diabetes mellitus.

Perindopril is an ACE inhibitor. This enzyme catalyzes the conversion of angiotensin I to angiotensin II, which has vasoconstrictor properties; In addition, ACE stimulates the secretion of aldosterone and enhances the degradation of the vasodilator compound bradykinin to inactive heptapeptides. With the use of perindopril, there is a decrease in the secretion of aldosterone, as a result of this, on the basis of the feedback principle, the activity of renin in blood plasma increases; with prolonged use, the OPSS decreases, which is mainly due to the effect on the vessels in the muscles and kidneys. In this case, there is no delay in salts and water or reflex tachycardia.

Perindopril has a hypotensive effect in patients with low or normal levels of renin in the blood.

Perindopril reduces the load on the heart, exerting a vasodilating effect on the veins (apparently, by changing the metabolism of prostaglandins), as a result, preload is reduced and the end-diastolic pressure is reduced; reducing OPSS, which leads to a decrease in afterload.

The action of perindopril is due to the activity of the metabolite of perindoprilat.

Indapamide is a thiazide-like diuretic. It has the ability to inhibit reabsorption of sodium in the cortical segment of the loop of Henle. It causes a dose-dependent increase in the excretion of sodium and chlorine, and to a lesser extent potassium and magnesium in the urine, thereby increasing diuresis.

Indapamide reduces vascular hyperreactivity with respect to norepinephrine and reduces OPSS and resistance in arterioles.

As auxiliary substances that form the tablet, milk sugar, microcrystalline cellulose, magnesium stearic acid, aerosil and croscarmellose sodium are used.

The claimed content of all components and the introduction of croscarmellose sodium provide a high bioavailability of the active substances: experimental studies have shown that the average dissolution values reach 97% for perindopril and 90% for indapamide.

The introduction of the active substance - perindopril erbumin - at the stage of dusting allows you to reduce the mechanical loss of this substance and maintain its properties unchanged.

The invention is as follows.

Pre-sifted indapamide, milk sugar and microcrystalline cellulose are thoroughly mixed and moistened with distilled water until they are evenly moistened and granulated.

Wet granules are dried at a temperature of 45-50 ° C to a residual moisture of 1-1.4%. The dried granules are cooled to room temperature and dry granulation is carried out. The dry granulate is dusted with the addition of pre-sieved perindopril erbumin, aerosil, Na-croscarmellose and magnesium stearic acid. The mixture is stirred until a homogeneous tablet mass is formed.

Then the tablet mass is tabletted to obtain oblong-shaped tablets of a white or creamy white color with rounded edges, weighing 0.09 g.

Production example for dosage of 2.625 mg.

Pre-sifted indapamide 0.625 kg, milk sugar 60.2 kg and microcrystalline cellulose 20.8 kg are thoroughly mixed and moistened with distilled water until smooth and granulated.

Wet granules are dried at a temperature of 50 ° C to a residual moisture of 1-1.4%. If necessary, if the dried granules are stuck together, they are cooled to room temperature and dry granulation is carried out. Dry granulate is dusted by adding pre-sifted perindopril erbumin 2 kg, aerosil 0.86 kg, Na-croscarmellose 4.5 kg and magnesium stearic acid 1 kg. The mixture is stirred until a homogeneous tablet mass is formed.

Then the tablet mass is tabletted to obtain oblong tablets with rounded edges weighing 0.090 g in the amount of 86.87 kg. The composition of the obtained tablets are shown in table 1.

Production example for a dosage of 5.25 mg.

Pre-sifted indapamide 1.25 kg, milk sugar 60.2 kg and microcrystalline cellulose 18.2 kg are thoroughly mixed and moistened with distilled water until smooth and granulated.

Wet granules are dried at a temperature of 50 ° C to a residual moisture of 1-1.4%. If necessary, the dried granules are cooled to room temperature and dry granulation is carried out. Dry granulate is dusted by adding pre-sieved perindopril erbumin 4 kg, aerosil 0.86 kg, Na-croscarmellose 4.5 kg and magnesium stearic acid 1 kg. The mixture is stirred until a homogeneous tablet mass is formed.

Then the tablet mass is tabletted to obtain oblong tablets with rounded edges weighing 0.090 g in the amount of 86.87 kg.

The composition of the obtained tablets are shown in table 2.

Table 2. Composition of the tablet (Rec. No. 4): g % 1. Perindopril Erbumin 0.004 4.44 2. Indapamide 0.00125 1.39 3. Milk sugar 0.06018 66.87 4. Microcrystalline cellulose 0.01821 20,23 5. Magnesium stearic acid 0.001 1,11 6. Aerosil 0,00086 0.96 7. Na-croscarmellose 0.0045 5,0 Average tablet weight 0.09 one hundred

In a medicinal product made in accordance with the claimed group of inventions, a reduction in the mechanical loss of perindopril erbumin in the process of obtaining funds is achieved by introducing it at a late stage of manufacturing - dusting. This ensures the preservation of the properties of perindopril erbumin unchanged due to the fact that, introduced at a late stage, it is less subjected to processing compared to the closest analogue.

The proposed drug provides a high bioavailability of the active substance: experimental data showed that the average dissolution value of perindopril erbumin was: rec. No. 1 - 97.1%, rec. No. 2 - 97.8%, rec. No. 3 - 96.8%, rec. No. 4 - 97.2%; the average dissolution of indapamide was: rec. No. 1 - 90.6%, rec. No. 2 - 90.0%, rec. No. 3 - 89.9%, rec. No 4 - 91.3%.

Claims (3)

1. A drug having a hypotensive effect, containing perindopril erbumin and indapamide as active substances, and microcrystalline cellulose, magnesium stearic acid and aerosil as auxiliary substances, characterized in that it additionally contains milk sugar and croscarmellose sodium as auxiliary substances, with the following content of components, wt.%: Perindopril erbumin 0.6-6.6 Indapamide 0.1-2.1 Microcrystalline cellulose 16.0-35.0 Magnesium Stearic Acid 0.3-1.7 Aerosil 0.2-1.0 Croscarmellose sodium 1.1-7.5 Milk sugar Rest 2. A method of manufacturing a drug having a hypotensive effect, namely that all the components are pre-sieved, then indapamide, milk sugar and microcrystalline cellulose are mixed, moistened, wet granulation is carried out, drying, dusting using stearic acid magnesium and tabletting, characterized the fact that dusting is carried out with a mixture of perindopril erbumin, aerosil, croscarmellose sodium and stearic acid magnesium. 3. The method according to claim 2, characterized in that after drying, dry granulation is carried out.