Pharmaceutical composition having anti-ulcer activity, and how you can get

 

(57) Abstract:

The pharmaceutical composition is made in the form of solid dosage forms, mainly in the form of tablets. The core of the solid dosage form contains, wt%: hydrochloride ranitidine 60,0 - 75,0, Aerosil 0,1 - 10,0, starch 4,0 - 16,0, microcrystalline cellulose 8,5 - 20,3, milk sugar 4,5 - 15,0, polyvinylpyrrolidone 0,1 - 1,3 and magnesium stearate 0.3 to 1.0. The nuclear envelope consists of, in wt.%, copolymer of methacrylic acid 15,0 - 50,0, polyethylene glycol 1,0 - 20,0 and titanium dioxide 36,0 - 84,0. The method of obtaining the pharmaceutical composition includes a mixture of ranitidine hydrochloride with filler, wet granulation, drying, dry granulation, molding granules and application shell. A new pharmaceutical composition is stable during storage, has satisfactory strength and provides high bioavailability of the active substance is ranitidine hydrochloride. 2 s and 5 C.p. f-crystals, 1 table.

The invention relates to the field of medicine and is suitable for the treatment of gastric ulcer and duodenal ulcers, erosive and reflux esophagitis, syndrome Zollinger-Ellison and other diseases associated with gastric hypersecretion and prevention strazii gastro-intestinal juice in operations under General anesthesia.

Known antiulcer agent - ranitidine (or N-[2-[[[5-(dimethylamino)methyl] -2-furylmethyl] thio]ethyl]-N'-methyl-2-nitro-1,1-attentionin) [Mashkovsky M. D. Medicines, T. 1, ed. 12-e, M, 1993, S. 359] . Ranitidine is an antagonist of H2receptors and its mechanism of action is based on the binding of H2-receptors of parietal cells of the gastric mucosa, resulting in suppressed basal and stimulated gastric secretion. In medical practice ranitidine is usually applied in the form of hydrochloride.

In the international application WO 95/27486, 1995, describes oral compositions of ranitidine or its salts, including the hydrochloride ranitidine. Composition based hydrochloride ranitidine contains, wt%:

The kernel Hydrochloride ranitidine - 18,7

Microcrystalline cellulose - 80,6,

Magnesium stearate - 0,7,

and shell, which consists of oksipropilmetiltselljulozy, titanium dioxide, triacetin and yellow iron oxide.

However, the composition is characterized by a relatively low content of active substance (less than 20%), which requires taking additional doses of the drug or a significant increase in the weight of the tablet to create the required therapeutic the Xia pharmaceutical composition, described in the patent of Russia No. 2131264, publ. 10.06.99 (prototype). It contains ranitidine and excipients in the following ratio, wt.%:

Ranitidine - 53,3 - 59,4

Microcrystalline cellulose - 37,4 - 44,8

Polyvinylpyrrolidone - 1,4 - 2,0

Magnesium stearate - 0.5 to 1.2

This antiulcer composition was prepared by mixing ranitidine and microcrystalline cellulose, then hold wet granulation by spraying a water-alcohol solution of polyvinylpyrrolidone above the fluidized mass, the granulate is dried, add magnesium stearate and the mixture tabletirujut.

However, the absence of membrane significantly reduces the stability of specified pharmaceutical form, and, accordingly, its expiration date, and the quantitative and qualitative composition of ingredients of the core tablet is not possible to obtain a satisfactory quality of the drug after the application of the shell.

Therefore, still relevant is the creation of solid dosage forms of ranitidine hydrochloride, which satisfies all of the requirements of the pharmaceutical agent.

The technical result obtained by implementing the present invention, is that the new perspecive 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 pharmaceutical composition having anti-ulcer activity, includes a core containing the active ingredient of ranitidine hydrochloride and as auxiliary substances Aerosil, starch, microcrystalline cellulose, lactose, polyvinylpyrrolidone and magnesium stearate coated, which consists of a copolymer of methacrylic acid, polyethylene glycol and titanium dioxide

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

Hydrochloride ranitidine - 60,0 - 75,0

Aerosil - 0,1 - 10,0

Starch - 4,0 - 16,0

Microcrystalline cellulose is 8.5 - 20,3

Milk sugar - 4,5 - 15,0

Polyvinylpyrrolidone - 0,1 - 1,3

Magnesium stearate - 0,3 - 1,0

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

Introduction to composition as the target additives Aerosil, starch and lactose ndelag allowed to increase compared with the prototype of the content of active substance (over 60%) and the stability of the composition during storage at a satisfactory strength of the core tablet and the ease of release of the active substance.

Noncompliance found ratios of ingredients in the kernel does not allow to obtain the necessary quality and stability of the composition during storage.

The proposed pharmaceutical composition 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, first, further enhances the stability of the composition during storage and lengthens the shelf life of the drug, secondly, improves its appearance. The optimal ratio of these ingredients in the shell is, wt.%:

Copolymer of methacrylic acid - 15,0 - 50,0

The glycol - 1,0 - 20,0

Titanium dioxide - 36,0 - 84,0

As the basis of the shell most acceptable was a copolymer of methacrylic acid, and as fillers - polyethylene glycol and titanium dioxide. Joint use of these ingredients in the following amounts to produce a membrane having a sufficient strength and protects the core from external atmosphere. In addition, the use of the specified shell along with the core of the claimed composition causes a rapid and targeted high is setoudeh substances, on GF XI - not less than 75% after 45 min), which in turn increases the bioavailability of the drug and minimizes the possibility of side effects.

A method of obtaining a pharmaceutical composition with anti-ulcer activity, containing ranitidine hydrochloride and pharmaceutically acceptable additives target, includes the specified mixing the active substance with a filler, which is a combination of starch, microcrystalline cellulose and lactose, moistening the mass of the water-alcohol solution of polyvinylpyrrolidone when the mass ratio of the humidified by weight of 1: (to 5.2 and 9.8), respectively, wet granulation, drying, dry granulation, the introduction of Aerosil, magnesium stearate and the rest of the starch, followed by the formation of granules and coating shell. Use upon receipt of the granulate as a filler combination of starch, microcrystalline cellulose and lactose when the claimed value of the humidifier and irrigated mass provides good adhesion of ranitidine hydrochloride and excipients, which contributes to a significant increase in the durability of core tablets (up to 12 - 13 kg) at lower binder content (p is of the protective coating and subsequent packaging. Suitable mass ratio of water and 96% ethyl alcohol in a moisturizing solution is 1:0.75 to 1.25 times, but this interval is not strictly limited. The concentration of the polyvinylpyrrolidone in the solution is 1.0 - 7.0 percent.

The number you enter in the composition after dry granulation starch is 5.0 - 14.0% of the total weight of the starch contained in the dosage form. The rest of the starch used as a filler. The change of this ratio affects the fluid properties of the granules and prevents the normal process of tableting.

The optimum residual moisture content of the pellets after drying is 2 - 3%. Higher humidity causes caking of the granules, thereby making it difficult to obtain a homogeneous mixture and conducting tabletting, lower humidity increases rejection tablets (spalls, delamination).

The obtained pharmaceutical composition complies with the requirements of the global Fund XI (in appearance, dissolution and other indicators), stable in storage and has a shelf life of over 2 years.

The invention is illustrated by the following examples.

Example 1. Mix the sifted powders ranitidine (62,4 g), mo is 4 g 1% solution of polyvinylpyrrolidone in 50% aqueous ethanol, mix to a uniform distribution of moisture, granularit on the unit for the production of granulate through a grid hole diameter of 3 mm and dried to a residual moisture content of 2 to 3%. Dry granulation is performed on the device for producing granules of dry mixes. It crushed the granulate add a mixture of 0.8 g of dry potato starch, 0.1 g of Aerosil and 0.3 g of magnesium stearate, and then tabletirujut. The obtained kernel with an average weight of 0.26 g is applied film-forming composition containing 6.9% of the methacrylic acid copolymer (Eudragit E-100), 4.6% of polyethylene glycol, 11.5% of titanium dioxide in a mixture of acetone and aqueous alcohol. Layering is carried out to obtain a satisfactory film thickness. The obtained tablets with an average weight 0,273 g satisfy the requirements of the pharmaceutical agent.

Examples 2, 3 perform similarly. The obtained tablets meet the requirements of the pharmaceutical agent. The results are presented in the table.

1. Pharmaceutical composition having anti-ulcer activity, in the form of a solid dosage form that includes a core containing the active ingredient of ranitidine hydrochloride and as auxiliary substances microcline contains Aerosil, starch and lactose in the following ratio of ingredients, wt.%:

Hydrochloride ranitidine - 60,0 - 75,0

Aerosil - 0,1 - 10,0

Starch - 4,0 - 16,0

Microcrystalline cellulose is 8.5 - 20,3

Milk sugar - 4,5 - 15,0

Polyvinylpyrrolidone - 0,1 - 1,3

Magnesium stearate - 0,3 - 1,0

and the shell consists of a copolymer of methacrylic acid, polyethylene glycol and titanium dioxide.

2. The pharmaceutical composition under item 1, characterized in that the shell contains these ingredients in the following ratio, wt.%:

Copolymer of methacrylic acid - 15,0 - 50,0

The glycol - 1,0 - 20,0

Titanium dioxide - 36,0 - 84,0

3. The pharmaceutical composition under item 1 or 2, characterized in that it is made in the form of tablets.

4. A method of obtaining a pharmaceutical composition, characterized in PP.1 to 3, which includes the specified mixing the active substance with a filler, which is a combination of starch, microcrystalline cellulose and lactose, moistening the mass of the water-alcohol solution of polyvinylpyrrolidone when the mass ratio of the humidified mass 1 : 5,2 and 9.8, respectively, wet granulation, drying, dry granulite shell.

5. The method according to p. 4, wherein 5,0 - 14,0% of the mass contained in a unit dosage form of starch, enter into the composition after dry granulation, and the rest of the starch is introduced into the composition of the filler.

6. The method according to p. 4, characterized in that the mass ratio of water and 96% ethyl alcohol in a moisturizing solution is 1 : 0,75 - 1,25 respectively.

7. The method according to any of paragraphs.4 to 6, characterized in that the drying of the wet granulate is carried out to a residual moisture content of 2 to 3%.

 

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