Drug-based tamoxifen

 

(57) Abstract:

The invention relates to medicine, in particular to methods for the preparation on the basis of tamoxifen, which is one of the main contemporary antiestrogens, used mainly in the treatment of cancer. The method of obtaining medicines on the basis of tamoxifen citrate in the form of tablets includes grinding, sieving and mixing of tamoxifen, starch, lactose, adding to the resulting mixture solution of polyvinylpyrrolidone, drying the resulting granules at 50-60oWith, mixing with magnesium stearate and the subsequent compaction and tableting. In this advance the starch is mixed with 0,3-0,7% starch paste, ekstragiruyut at 50-60oC and the resulting pellet was processed IR radiation in a resonant mode with a wavelength of 0.8-1.2 μm and a current density of 20 to 22 kW/m2. The method allows to increase the bioavailability of substances by increasing its solubility in water. table 1.

The present invention relates to medicine, in particular to methods for the preparation on the basis of tamoxifen, which is one of the main contemporary antiestrogens, primenyaemoi/-phenyl/-TRANS-1.2-diphenyl-1-butene - is hormonal antineoplastic drug (Mashkovsky M. D. Medicines, M., 2000). In U.S. patent 4536516 described tamoxifen and its acceptable salts tamoxifen citrate.

The drug should have a high biological availability, which is determined by the degree of absorption of funds. The bioavailability can be affected by many factors, including the medical form and various properties such as dissolution rate of the drug. Poor bioavailability is a significant problem encountered in the design of pharmaceutical compositions, particularly those containing the active ingredient is poorly soluble in water, such as tamoxifen. Poorly water-soluble drugs are usually removed from the gastrointestinal tract before it enters the circulatory system. In addition, a poorly water-soluble drugs to be unsafe for intravenous administration, which often applies completely soluble drugs.

It is known that the dissolution rate of the drug in the form of particles increases with increasing surface area, production premises.

Other methods of obtaining compositions on the basis of tamoxifen, improving its bioavailability include the introduction of drugs in polymers, for example sharedstorage polymers (U.S. Pat. RF 2113221).

A method of obtaining medicines on the basis of tamoxifen in the form of matrix granules extended to the obtained thermoplastic by extrusion of a melt consisting of a combination of inert lipophilic and hydrophilic matrices containing tamoxifen (U.S. Pat. RF 2155031).

However, such methods are characterized by certain problems and limitations. For example, to get dosage forms medications often require a large amount of polymer, the receipt of such pharmaceutical compositions is very difficult.

A method of obtaining medicines on the basis of tamoxifen in the form of tablets, which consists in sifting through a sieve of tamoxifen in the form acceptable salt, for example, tamoxifen citrate, starch and other fillers, thorough mixing of the components. To the resulting mixture in powder form, add a solution of polyvinylpyrrolidone. The resulting granules are dried at 50-60oWith and sift. Then to Gran the Noah car (U.S. Pat. RF 2132682). Suitable fillers used lactose, sucrose, cellulose, calcium silicate, etc.

This method is the closest technical solution to the claimed method. The main disadvantage of it is the lack of bioavailability due to poor solubility of the drug.

The purpose of this invention is to improve the bio availability of funds by increasing its solubility in water.

This goal is achieved through the use of the method of obtaining medicines on the basis of tamoxifen citrate in the form of tablets, including grinding, sieving and mixing of tamoxifen, starch, lactose, adding to the resulting mixture solution of polyvinylpyrrolidone, drying the resulting granules at 50-60oWith, mixing with magnesium stearate and subsequent compaction and tableting. In this advance the starch is mixed with 0,3-0,7% starch paste, ekstragiruyut at 50-60oC and the resulting pellet was processed IR radiation in a resonant mode with a wavelength of 0.8-1.2 microns and a current density of 20 to 22 kW/m2.

An example implementation of the method.

ω and continuously stirred for 7 minutes Then the solution advocated for 10-15 minutes and drain excess water. Swollen starch is fed into the extruder mark A1-CCP, where the extrusion at 50-60oWith the number of revolutions of the auger 50 min-1the diameter of the outlet of 3.5 mm, the Obtained starch granules are placed on the tray with a layer thickness of single grains and processed IR radiation in a resonant mode with a wavelength of 0.8-1.2 μm, the current density of the radiation 20 to 22 kW/m2for 60-70 C. Further processed in a resonant mode, the starch is subjected to crushing and grinding to the desired size. The quality of the resulting starch is characterized by a content of dextrins, degree of gelatinization, swelling in water for 1 h

The experimental results for the pre-treatment of starch are summarized in table.

Starch without pre-treatment had the following characteristics: content dextrins 18.9%, the degree of gelatinization of 16.1%, the solubility in water of 3.2 ml at 1 h

2. Getting pills

Tamoxifen, lactose and pre-treated starch is sifted through a sieve of 45 mesh. and mix thoroughly. The resulting powder is mixed with a 0.5% solution of the polyvinylpyrrolidone. The obtained granules are dried p what're asked and pressed on a tablet machine. The use of the method will produce a tablet weight of 0.18 g of the following composition, g:

Tamoxifen citrate - 0,0152 (0.01 g tamoxifen)

Lactose - 0,1172

Starch - 0,01418

Polyvinylpyrrolidone - 0,004

Magnesium stearate - 0,0018

The proposed method is quite simple and convenient, has advantages in comparison with other methods of preparation of medicines on the basis of tamoxifen.

The experimental results for the pre-treatment of starch are summarized in table.

Testing the bioavailability of

Biological availability of medicines on the basis of tamoxifen obtained by the present method, was studied by introducing it to the dogs by means of a gastric probe. Took their plasma samples through a cannula introduced into the head of Vienna. The levels of tamoxifen in plasma was checked after 24 hours the relative bioavailability of tamoxifen was 54% higher than similar indicator obtained by applying the tablets of tamoxifen, obtained by the method prototype.

The method of obtaining medicines on the basis of tamoxifen citrate in the form of tablets, including grinding, sieving and mixing of tamoxifen, brahmapuri 50-60oWith, mixing with magnesium stearate and the subsequent compaction and tableting, characterized in that the starch is mixed with 0,3-0,7% starch paste, ekstragiruyut at 50-60oC and the resulting pellet was processed IR radiation in a resonant mode with a wavelength of 0.8-1.2 μm and a current density of 20 to 22 kW/m2.

 

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