Improves cerebral blood circulation, antiaggregative tool and method thereof

 

(57) Abstract:

The tool is made in the form of a solid dosage form comprising a core coated. The core contains, wt%: pentoxifylline 30 - 67, Aerosil 0.1 to 10, starch 10 - 40, lactose 6 - 28,8, salt of stearic acid of 0.1 to 1.0, talc of 0.1 to 3.0. The shell is, wt.%: from methylcellulose or oksipropilmetiltselljulozy 30 - 70, tween 80 15 - 35 and titanium dioxide 15 - 35. The method of obtaining funds involves mixing of pentoxifylline with filler. The filler is a combination of Aerosil, starch and lactose. The resulting mixture is moistened with distilled water or starch paste when the mass ratio of the humidifier and irrigated mass 1 : (1,8-3,0), respectively. Next, perform a wet granulation, drying, dry granulation, the introduction of a salt of stearic acid and talc, forming granules and application shell. The new tool is stable during storage, easily releases the active substance, which ensures its high bioavailability. The method allows to produce a dosage form with satisfactory strength. 2 S. and 4 C.p. f-crystals, 1 table.

The invention relates to the field of medicine and is suitable for treating disorders perique cerebrovascular insufficiency, ischemic heart disease ischemic condition after myocardial infarction, vascular pathology of the organs of sight and hearing, diabetic angiopathy.

Pentoxifylline (or 3,7-dihydro-3,7-dimethyl-1-(5 - oxohexyl)-1H-purine-2,6-dione) - spasmolysant from the group of purines [Mashkovsky M. D. Medicines, T. 1, ed. 12-e, M, 1993, S. 529]. The connection has a vasodilator effect, improves microcirculation and blood rheology, increases the supply of oxygen to tissues, inhibit phosphodiesterase, and contributes to the accumulation of camp in the cells.

Among the variety of different medicines on the basis of pentoxifylline convenience and ease of use definitely produce solid dosage forms, and research and development of compounds in this series continues to the present time.

In the Federal Republic of Germany patent N 3127231, 1983, described the medicinal product on the basis of pentoxifylline in the form of granules or pellets. The core composition contains, by weight. %:

Sugar core of 28.6,

Pentoxifylline - 28,6,

Talc - 7,1,

Silicon dioxide is 2.9,

The rest of the ingredients (sucrose, gum, talc) is 32.8.

The shell consists of a polyacrylic resin (Eudragit L30D), polietilen Janie sugar cores 70% sugar syrup, in addition gum and talc, followed by a dusting of wet granules powdery mixture of pentoxifylline, talc and silicon dioxide and the application shell. To increase bioavailability of drugs some of the granules (30%) crush and add to unground the granules. The resulting mixture may be enclosed in gelatin capsules. However, to obtain tablets pentoxifylline is necessary to enter in the composition of auxiliary ingredients. In addition, the content of talc in the composition greatly exceeds the limit recommended by the global Fund XI (less than 3%).

In the patent of Russia No. 2092161, 1997, describes a drug containing pentoxifylline and auxiliary ingredients in the following ratio, wt%.:

Pentoxifylline - 50-70,

Ethylcellulose - 20-35,

Microcrystalline cellulose - 7-15,

Target additive (calcium stearate) - 0,5-4,0.

This tool is produced by mixing pentoxifylline with auxiliary substances, moistening the mixture with a solution of ethyl cellulose, wet granulation, drying, dusting and pelletizing. If necessary, the tablets covered with a film sheath, but the sheath material is not privategsm the release of pentoxifylline from dosage forms. However, at the same time increases the time of exposure of the active substance in the gastrointestinal tract, which may increase the adverse reactions after taking the drug (nausea, vomiting, diarrhea). In addition, the prolongation of the release of pentoxifylline reduces its bioavailability due to the effect of "first pass" through the liver.

Therefore, still relevant is the problem of creating improves cerebral blood circulation, antiaggregative of the drug on the basis of pentoxifylline quick release of the active principle (more than 75% within 45 min), which, of course, necessary to replenish the register of medicines.

The technical result obtained by implementing the present invention, is that the new tool is stable when stored and easily releases the active substance, which ensures its high bioavailability, as well as the sequence of operations and their technological options that allow you to produce a dosage form of the required quality, in particular with satisfactory strength.

This technical result is achieved by the fact that the proposed remedy includes a core containing as on the ol stearic acid and talc, and a shell, which is derived from methyl cellulose, tween 80 and titanium dioxide.

The ingredients contained in the kernel in the following ratio, wt.%:

Pentoxifylline - 30,0-67,0,

Aerosil - 0,1 - 10,0,

Starch - 10,0-40,0,

Milk sugar - 6,0-28,8,

Salt of stearic acid is 0.1 to 1.0,

Talc - 0,1-3,0.

Declare the proportion of ingredients is best found experimentally and provides the necessary kernel composition.

Introduction to composition as auxiliary substances Aerosil, starch or milk sugar along with salt of stearic acid and talc within the specified limits ensured the stability of the composition during storage at a satisfactory strength of the core tablet and ease of release from it the active substance (not less than 97% in 45 min). As a salt of stearic acid can be used stearates of calcium, or magnesium, or other metals.

The proposed medication is in the form of a solid dosage form having a shell, preferably in tablet form that provides maximum adaptability for subsequent packaging. The presence of a shell of the claimed composition additional views of the dosage form. The optimal ratio of ingredients in the shell is, wt.%:

The methylcellulose or oksipropilmetiltselljuloza - 30,0-70,0,

Twin 80 - 15,0-35,0,

Titanium dioxide - 15,0-35,0.

Use as a basic shell derivatives methylcellulose - soluble methylcellulose or oksipropilmetiltselljulozy and as fillers - tween 80 and titanium dioxide allows to obtain a membrane having a sufficient strength and protects the core from the surrounding atmosphere. In addition, the application of the specified shell along with the core of the claimed composition causes a rapid and targeted release of pentoxifylline from dosage forms (Wednesday dissolution in 45 min goes 97-100% active ingredient, GF XI - not less than 75%), which in turn increases the bioavailability of the drug and minimizes the possibility of side effects.

The method of obtaining the claimed medicinal products that contain pentoxifylline and pharmaceutically acceptable excipients, includes the specified mixing the active substance with a filler, which is a combination of Aerosil, starch and lactose, moistening the mixture with a mass ratio wvla the group of salts of stearic acid and talc, the subsequent formation of granules and coating shell. Use upon receipt of the granulate as a filler combination of Aerosil, starch and lactose when the claimed value of the humidifier and irrigated mass provides good adhesion of pentoxifylline and auxiliary substances, which contributes to a significant increase in the strength of the core tablets. This significantly reduces the rejection of tablets in the process of applying a protective coating and subsequent packaging. As a humidifier, you can use distilled water or starch paste, however, the latter option requires the introduction of a technological process additional stage of preparation of starch paste. Conduct after drying, the dry granulation improves the adhesion between the active and auxiliary substances, which further increases the strength of the core tablets (up to 11 kg).

It is advisable to carry out the drying of the granules to a residual moisture content of 1-3%. Higher humidity causes caking of the granules, making it difficult to obtain a homogeneous mixture and conducting tabletting, lower humidity increases rejection tablets (spalls, delamination).

Received pharmaceutically), stable during storage and has a shelf life of over 2 years.

Was investigated the relative bioavailability of the proposed drug in comparison with the known drug on the basis of pentoxifylline. Studies were performed on rabbits male breed chinchilla after a single injection of drugs per os at a dose of 33 mg/kg was Found that the relative bioavailability of a new composition in comparison with the known is 113%.

The invention is illustrated by the following examples.

Example 1. Mix the sifted powders of pentoxifylline (100.0 g), Aerosil (14,95 g), lactose (13.8 g) and dry potato starch (92.0 g) hydrate of 85.5 g of distilled water, mix to a uniform distribution of moisture, granularit on the unit for the production of granulate through a grid hole diameter of 2 mm and dried to a residual moisture content of 1-2%. After dry granulation to crushed to a granular type of 6.75 g of talc and 2.25 g of magnesium stearate and the mixture tabletirujut. The obtained kernel with an average weight of 0.23 g is applied film-forming composition containing 3,78% methylcellulose, 0,81% tween 80 and 13,82% of titanium dioxide. Layering is carried out to obtain a satisfactory film thickness. The obtained tablets (229,2 g) is similar. The obtained tablets meet the requirements of the pharmaceutical agent. The results are presented in the table.

1. Improves cerebral blood circulation, antiaggregative means in the form of a solid dosage form that includes a core containing as active substance pentoxifylline and as excipients salt of stearic acid, coated, wherein the core further comprises Aerosil, starch, milk sugar and talc in the following ratio of ingredients, wt.%:

Pentoxifylline - 30,0 - 67,0

Aerosil - 0,1 - 10,0

Starch - 10,0 - 40,0

Milk sugar - 6,0 - 28,8

Salt of stearic acid - 0,1 - 1,0

Talc - 0,1 - 3,0

and the shell is derived from methyl cellulose, tween 80 and titanium dioxide.

2. Improves cerebral blood circulation antiaggregative tool under item 1, characterized in that the shell contains these ingredients in the following ratio, wt.%:

The methylcellulose or oksipropilmetiltselljuloza - 30,0 - 70,0

Twin 80 - 15,0 - 35,0

Titanium dioxide - 15,0 - 35,0

3. Improves cerebral blood circulation antiaggregative tool under item 1 or 2, characterized in that it is made in the form of tablets.

5. The method according to p. 4, characterized in that the humidifier use distilled water or starch paste.

6. The method according to p. 4 or 5, characterized in that drying the wet granulate is carried out to a residual moisture content of 1 - 3%.

 

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