RU2229298C1 - Pharmaceutical composition eliciting cardiovascular effect and method for it preparing - Google Patents

Abstract

FIELD: medicine, pharmaceutical technology, pharmacy. SUBSTANCE: composition is made as a solid medicinal formulation that comprises pentoxifylline as an active substance and the following accessory substances: aerosil, starch, microcrystalline cellulose, lactose, stearate and, optionally, polyvinylpyrrolidone. Novel pharmaceutical composition is prepared by wetting granulation of a mixture consisting of pentoxifylline as an active component and accessory substances: starch, microcrystalline cellulose, lactose, aerosil with the amount from 0 to 100 wt.-% of total amount of aerosil in the composition and, optionally, polyvinylpyrrolidone followed by drying, powdering dry granules with stearate and the remained part of aerosil, and tableting the final mixture. Medicinal formulation can be covered with film envelope based on cellulose derivative but on the base of methylcellulose or hydroxypropylmethylcellulose preferably. The solid dosed formulation based on pentoxifylline shows stability for erosion of surface layer in the process of applying a film envelope and, as results, tablets of the preparation have the satisfactory shape. Deviations in the content of active component correspond to requirements of The State Pharmacopoeia of XI Edition. The preparation is stable in storage and releases active substance easily. EFFECT: improved preparing method, valuable pharmaceutical and medicinal properties of composition. 12 cl, 4 ex

Description

The invention relates to medicine and is suitable for the treatment of disorders of peripheral and cerebral circulation, including obliterating endarteritis, Raynaud's disease, atherosclerotic cerebrovascular insufficiency, coronary heart disease, ischemic conditions after myocardial infarction, vascular pathology of the organs of vision and hearing, diabetic angiopathies.

Pentoxifylline or 3,7-dimethyl-1- (5-oxohexyl) -xanthine, or 1- (5-oxohexyl) -theobromine is a cardiovascular agent from the purine group. The compound has a vasodilating effect, blocks phosphodiesterase and promotes the accumulation of cAMP in cells, improves microcirculation and rheological properties of blood - inhibits platelet aggregation and reduces blood viscosity, helps to improve tissue oxygen supply.

Among the variety of different drugs based on pentoxifylline, solid dosage forms unambiguously distinguish convenience and ease of use, and research and development of formulations in this series continue to this day. The substance of pentoxifylline does not have flowability, therefore, in order to obtain high-quality tablets, the introduction of auxiliary substances is required.

Russian patent No. 2092161, 1997 describes a medicine containing pentoxifylline as an active ingredient and cellulose derivatives (microcrystalline cellulose and ethyl cellulose) and a stearic acid salt as active ingredients.

The specified tool is obtained by mixing pentoxifylline with excipients, moistening the mixture with a solution of ethyl cellulose, wet granulation, drying, dusting and tableting. If necessary, the tablets are film coated. The above composition is characterized by a slow release of pentoxifylline, which is not always acceptable.

In the patent of the Russian Federation No. 2190408, 2002, a solid dosage form is proposed, including a core that consists of pentoxifylline, starch, milk sugar, stearic acid and a surface modifier, which is used as a mixture of methylcellulose and polyvinylpyrrolidone. The specified core has a shell based on a derivative of cellulose.

A method of obtaining this composition includes wetting a mixture of pentoxifylline, milk sugar, methyl cellulose and starch with a solution of polyvinylpyrrolidone, granulating the wet mass and drying the granulate to a residual moisture content of 1-2%. After dry granulation, stearic acid is added to the crushed granulate, the mixture is tabletted and a film-forming composition is applied to the obtained cores to obtain a film of a satisfactory thickness.

The patent of the Russian Federation No. 2157209, 2000 describes a cardiovascular agent in the form of a solid dosage form, which includes a core containing pentoxifylline and excipients - aerosil, starch, milk sugar, talc and stearic acid salt, and a shell based on a cellulose derivative.

A well-known drug is obtained by the traditional method of wet granulation, which includes moistening a mixture of pentoxifylline with Aerosil, starch and milk sugar, wet granulation, drying, dry granulation, the introduction of a stearic acid salt.

Known drugs are stable during storage and easily release the active substance. However, tablet cores with known compositions are characterized by high porosity and water permeability, which complicates the process of coating the cores with a film shell due to blurring of the surface layer of the core.

Another disadvantage of the known compositions is that the necessary component of the composition is talc, which has a harmful effect on the human body. During treatment, as a rule, a long course of taking the drug is required (up to 1 month), which significantly increases the risk of adverse consequences from the introduction of a large amount of talc in the dosage form into the patient's body.

The objective of the present invention is to create a pharmaceutical composition of cardiovascular action in the form of a solid dosage form, which is resistant to blur the surface layer during the application of the film coating, and, as a result, the new drug has a satisfactory appearance, and deviations in the content of the active substance correspond the requirements of the current State Pharmacopoeia of the XI edition (GF XI), while the drug is stable during storage and easily releases the active substance.

To solve this problem, a pharmaceutical composition of cardiovascular action is proposed, containing pentoxifylline as an active ingredient and aerosil, starch, milk sugar, stearic acid salt and, additionally, microcrystalline cellulose in the following ratio of ingredients, wt.%:

Pentoxifylline 31.0-60.0

Aerosil 0.2-3.5

Starch 11.0-25.0

Microcrystalline composition 5.0-29.6

Milk sugar 2.0-25.0

Salt of stearic acid 0.2-1.5

The composition is in the form of a tablet, which can be coated to improve the organoleptic properties of the film coating, preferably based on a cellulose derivative, more preferably methyl cellulose or hydroxypropyl methyl cellulose.

The claimed proportion of ingredients is optimal, found experimentally and ensures the achievement of a technical result corresponding to the task, namely, the obtained tablet has high abrasion resistance (abrasion resistance not less than 99.0%) and resistance to erosion of the surface layer during coating, in as a result, the finished dosage form has a satisfactory appearance (without roughness) and deviations in the content of the active substance do not exceed the limits defined emye GF XI. The drug also easily releases the active substance and is stable during storage. In addition, the presence of talc in the new composition is not necessary, which reduces the side effect of the drug.

The starch used according to the invention can be potato and / or corn and / or rice and / or modified starch. As the latter, it is preferable to use sodium glycolate starch (commercial products - modified starch brand "Primozhel" or brand "Explotab").

As the salt of stearic acid, calcium, magnesium, aluminum or other metal stearates are used, preferably calcium stearate and / or magnesium stearate.

The inventive tool may additionally include polyvinylpyrrolidone, which allows to obtain granules more uniform in particle size distribution. It is preferable to use medium molecular weight polyvinylpyrrolidone.

A method of obtaining the claimed pharmaceutical composition includes wet granulation of a mixture of the active substance - pentoxifylline with auxiliary substances - starch, microcrystalline cellulose, milk sugar, aerosil, the amount of which is from 0 to 100 wt.% Of the total amount of aerosil in the composition, and, optionally, polyvinylpyrrolidone, and subsequent drying, dusting of the dry granules and tableting of the final mixture.

Distilled water, starch paste or, if polyvinylpyrrolidone is added to the composition, an aqueous solution of the latter can be used as a humidifier.

Wet granulation can be carried out either in the traditional way on the installation for producing granulate from wet mixtures by wiping the wet mass through a perforated mesh or in a fluidized (fluidized) bed. In the latter case, the operations of mixing, granulating, drying, and, if necessary, and dusting can be carried out in one installation - a fluidized bed apparatus, which, firstly, simplifies the process flow diagram, and secondly, reduces the process time, since the granulation time is reduced especially drying the obtained granulate.

To powder dry granules, a stearic acid salt or its mixture with aerosil is used. The latter can be introduced into the pharmaceutical composition either before wet granulation together with the active substance, or at the stage of dusting, or in two doses - part of the aerosil before wet granulation and the remainder together with the stearic acid salt. The preferred amount of aerosil introduced in the dusting step is 30.0-100.0 wt.% Of the total amount of aerosil in the composition.

The dusting composition may also include starch. The preferred amount of starch used for dusting is 5.0-40.0% of the total mass of starch contained in the dosage form.

Repeated granulation after drying further improves the technological parameters of the tablet mass and, accordingly, reduces the rejection of tablets during the tabletting process.

If it is necessary to create a dosage form with a coating, the preparation method can be supplemented by a step of coating, preferably based on a cellulose derivative, more preferably methyl cellulose or hydroxypropyl methyl cellulose.

The invention is illustrated by the following examples, which are merely illustrative and in no way limit the present invention.

Example 1. A mixture of sieved powders of pentoxifylline (89.7 g; 43.5 wt.%), Aerosil (4.1 g; 2.0 wt.%), Microcrystalline cellulose (41.2 g; 20.0 wt.% ), milk sugar (38.1 g; 18.5 wt.%) and dry potato starch (23.2 g; 11.25 wt.%) moisten 85.5 g of distilled water, mix until the moisture is evenly distributed, granulate on installation for producing granulate and dried to a residual moisture content of 2%. After dry granulation, the resulting mass was dusted with a mixture of 2.05 g of magnesium stearate (1.0 wt.%) And part of starch (25.0 wt.% Of the total amount of starch). The total amount of starch in the composition is 15.0 wt.%. The finished mixture is pressed on a tablet machine. Get tablets with an average weight of 0.23 g, the abrasion resistance is 99.5%, the content of the main substance is 0.099 g (according to GF XI from 0.095 to 0.105 g), the release of the active substance (test "dissolution") is 98% after 45 min (according to GF XI - not less than 75%). A film-forming composition containing 3.78% oxypropyl methylcellulose, 0.81% tween 80 and 0.82% titanium dioxide is applied to the obtained tablets to obtain a film of a satisfactory thickness. The resulting coated tablets have a smooth, uniform surface (in accordance with the requirements of the Global Fund XI) and have a shelf life of more than 2 years.

Example 2. In the apparatus of the fluidized bed to a mixture of powders 224.2 g of pentoxifylline (43.5 wt.%), 41.2 g of microcrystalline cellulose (8.0 wt.%), 25.8 g of milk sugar (5.0 wt. %) and 122.4 g of corn starch (23.75 wt.%) add a 15% aqueous solution of medium molecular weight polyvinylpyrrolidone (polyvinylpyrrolidone - 15.5 wt.%) by spraying this solution over a fluidized mass. The wet granulate is dried at an inlet air temperature of 50 ° C to a residual moisture of 3.5 wt.% And the dried granules are dusted with a mixture of 5.1 g of calcium stearate (1.0 wt.%), 10.15 g of aerosil (2.0 wt. %) and 6.4 g of modified Primrose starch (1.25 wt.%). The finished mass is pressed on a tablet machine, and a film-forming composition is applied to the obtained tablets with an average weight of 0.23 g, having an abrasion resistance of 99.7%. Layering is continued until a film of satisfactory thickness is obtained. The content of ingredients in the shell,% by weight of the core: hydroxypropylmethyl cellulose - 2.17, titanium dioxide - 0.38, polyethylene glycol - 1.33. The resulting coated tablets satisfy the pharmacopoeial requirements in appearance, the content of pentoxifylline is 0.1 g (according to GF XI from 0.095 to 0.105 g).

Example 3. The preparation of tablets is carried out according to example 1, based on 31.0 wt.% Pentoxifylline, 0.2 wt.% Aerosil, 29.6 wt.% Microcrystalline cellulose, 25.0 wt.% Milk sugar, 11.0 wt. .% corn starch, 3.0 wt.% polyvinylpyrrolidone and 0.2 wt.% magnesium stearate, with the difference that 1% polyvinylpyrrolidone solution is used as a humidifier, all starch is introduced before granulation, and the amount of aerosil introduced at the dusting stage is 30 wt.% of the total amount of aerosil. The core tablets have an abrasion resistance of 99.3%. After applying a film coating on the basis of methyl cellulose, the resulting pentoxifylline tablets correspond to pharmacopoeial requirements in appearance and content of the active substance.

Example 4. The preparation of tablets is carried out as in example 2, based on 60.0 wt.% Pentoxifylline, 3.5 wt.% Aerosil, 5.0 wt.% Microcrystalline cellulose, 2.0 wt.% Milk sugar, 18.0 wt. wt.% starch, 10.0 wt.% polyvinylpyrrolidone and 1.5 wt.% magnesium stearate, with the difference that a 10% solution of polyvinylpyrrolidone is used as a humidifier, and the amount of starch introduced in the dusting stage is 40 wt.% from the total amount of starch in the composition. The core tablets have an abrasion resistance of 99.6%. After applying a film coating based on hydroxypropylmethyl cellulose, the resulting pentoxifylline tablets comply with pharmacopoeial requirements.

Claims (12)

1. The pharmaceutical composition in the form of a solid dosage form, having a cardiovascular effect, which contains pentoxifylline as an active ingredient and excipients aerosil, starch, milk sugar and stearic acid salt, characterized in that it additionally contains microcrystalline cellulose in the following ratio ingredients, wt.%: Pentoxifylline 31.0-60.0 Aerosil 0.2-3.5 Starch 11.0-25.0 Microcrystalline cellulose 5.0-29.6 Milk sugar 2.0-25.0 Salt of stearic acid 0.2-1.5 2. The pharmaceutical composition according to claim 1, characterized in that it contains potato and / or corn and / or modified starch as starch. 3. The pharmaceutical composition according to claim 1 or 2, characterized in that it contains magnesium and / or calcium salts as the stearic acid salt. 4. The pharmaceutical composition according to any one of claims 1 to 3, characterized in that it further comprises polyvinylpyrrolidone. 5. The pharmaceutical composition according to any one of claims 1 to 4, characterized in that it has a film-forming shell based on a cellulose derivative. 6. The pharmaceutical composition according to claim 5, characterized in that it contains methyl cellulose or hydroxypropyl methyl cellulose as a cellulose derivative. 7. A method of obtaining a pharmaceutical composition having a cardiovascular effect and characterized in any one of claims 1 to 4, comprising wet granulating a mixture of the active substance - pentoxifylline with auxiliary substances - starch, microcrystalline cellulose, milk sugar, aerosil, the amount of which is from 0 up to 100% of the total amount of aerosil in the composition, and, optionally, polyvinylpyrrolidone and subsequent drying, dusting of the dry granules with the stearic acid salt and the remainder of the aerosil la and tabletting the final mixture. 8. The method according to claim 7, in which wet granulation is carried out in a fluidized bed. 9. The method according to claim 7 or 8, in which at the stage of dusting using aerosil in an amount of 30.0-100.0% of the total amount of aerosil in the composition. 10. The method according to any one of claims 7 to 9, in which part of the starch is used for dusting. 11. The method according to claim 10, in which the amount of starch used for dusting is 5.0-40.0% of the total amount of starch in the composition. 12. The method according to any one of claims 7 to 11, in which, after drying, dry granulation is carried out.