A method of obtaining a pharmaceutical composition for oral administration containing tolperisone (options)

 

(57) Abstract:

The invention relates to the pharmaceutical industry. Crystalline racemic tolperisone cover in the column using a flow of air with a mixture of methanol and a solution of synthetic, semisynthetic or natural hydrogels in chloroform. In aqueous saturated solution of tolperisone suspended microcapsules containing tolperisone. Synthetic, semisynthetic or natural hydrogel granularit after adding water. The granules are dried and mixed with tolperisone, with the hydrogel solution in ethanol, then granularit. The granules are mixed with auxiliary substances and tabletirujut. Tolperison, lactose and hydrogel granularit with the addition of an aqueous solution containing the dye. Granules with magnesium stearate and high disperse silicon dioxide are passed through a sieve and homogenized in the mixer the Mixture is pressed into tablets. The invention improves the absorption of the product. 4 C. and 18 h.p. f-crystals.

The invention relates to pharmaceutical compositions for oral administration containing tolperisone or its salt.

Containing tolperisone medicines are known in various forms of predanie of tolperisone or its salts.

Also known for other forms of use of medicines containing tolperisone. Thus, in the patent application of Japan JP-51091315-A describes a stable syrup of tolperisone, which is intended for oral administration.

Tolperison is received international name muscle relaxant ((RS)-2,4'-dimethyl-3-piperidinemethanol) with the total formula C16H23NO.

Tolperison and its salts are known as biologically active substances to improve various symptoms in relation to spastic paralysis, but also muscle tone, which is caused by diseases such as cervical syndrome, arthritis and back pain.

Negative oral introduction of tolperisone or its salt is bystrootverdevayuschey action, so containing tolperisone drugs must be taken every day, many times, and corruption can occur in the gastrointestinal tract of the patient.

The disadvantage of percutaneous application, which is known from European patent EP-0295411-IN is only lack of percutaneous absorption of pharmaceutical bioactive substances of tolperisone.

Biologically active substance taper is 10% (+)-isomer of tolperisone. Still completely unclear whether formed is present in the blood (human) racemate (90:10) by pererazgibanie or due to increased resorption (-)-isomer.

The basis of the invention is to obtain a composition containing telperion or its salt, which can be administered orally, without the drawbacks of known oral input compositions on the basis of tolperisone.

According to the invention this problem is solved by using the composition described in paragraph 1 of the claims.

Preferred and preferred options proposed according to the invention compositions are the object of dependent claims.

Bystrootverdevayuschey in the case known oral compositions on the basis of tolperisone or its salts as a result of the proposed action according to the invention the composition is replaced with prolonged action, as the composition is prepared such that the biologically active substance tolperisone or its salt is released only prolongirovanne. In the case of proposed according to the invention the composition is particularly preferred that the prolongation vysvobozhdennym in the gut.

The advantages of a controlled release pharmaceutical biologically active substances is well known in the pharmaceutical field and are, inter alia, that the desired content of biologically active substances in the blood can be maintained: for a relatively long period of time, so that the patient no longer need to take medication every day, many times.

Proposed according to the invention the composition of the slow release of tolperisone or its salts can be, for example, in combination with various hydrogels, which can be synthetic, semi-synthetic or natural origin.

Oral compositions with prolonged release of biologically active substances - in this case, tolperisone or its salt should be adjustable so that the speed and release profiles could be fitted in accordance with the physiological and chronotherapeutics requirements. This provides the composition according to the invention. Studies have shown that (-)-isomer and (+)-isomer of tolperisone almost equally effective. So also racemic mixtures of isomers of the tx2">

In the proposed according to the invention the compositions of tolperison may be in the form of a racemate (50:50) or in the form of deviating from the racemate (50:50) of racemic mixtures. Also use the racemates, in which the content of (-)-isomer is higher than that of (+)-isomer. The racemates with a predominant share (-)-isomer of tolperisone (2,4'-dimethyl-3-piperidino-propiophenone) can be in the form of racemates (90:10).

The following are examples of pharmaceutical compositions according to the present invention.

Example 1

Crystalline comparisonmethod (racemate (50:50) with a grain size of 30 and 60 mesh make functioning with the help of the air flow column to coat and cover with a mixture of solution of polymer in chloroform, which contains ethylcellulose and hydroxypropylcellulose, and methanol. The solution for coating injected into the column under a pressure of 2.5 bar at a speed of 60 ml/min inlet Temperature is approximately 60oC.

After the coating is finished, from the bottom of the column for coating remove quick-drying, provided with a polymer coating crystals of tolperisone.

Example 2

According to this example, the get out tolperisone and contains suspended in water microencapsulated of tolperison. Tolperison is contained in a saturated aqueous solution corresponding to its solubility quantity. By introducing a suspension of containing tolperisone microcapsules in saturated telperion water excipient you can have tolperison in sufficient dose. This can be achieved thanks to the fact that comparison is in the form of suspensions containing tolperisone microcapsules and tolperisone in aqueous solution as necessary, depending on the circumstances, the ratio of mixture components. The number of tolperisone in the microcapsules can be increased to account for the number of replaced the microcapsules solution tolperisone.

Example 3

According to this example, first, get a binder for sustained release of biologically active substances of tolperisone and then to it add biologically active substance tolperisone (racemate (50:50)), and then, finally, pressed tablets. Binder for prolonged release of tolperisone get the fact that the respective amounts of xanthan resin, resin carob, calcium sulphate and dextrose in the dry state are mixed in a high speed mixer / granulator for two minutes. During the mixing the crystals are dried in the fluidized bed dryer. Thus obtained dried granules are then milled to a grain size of 20 mesh. Get, for example, a binder of a mixture consisting of 25% xanthan resin, 25% resin carob, 40% cellulose, 10% calcium sulphate and 10% water is added during granulation. Immediately after this binder for extended release mixed with desirable, depending on the circumstances, a number of tolperisone, which is used in the form of cleaners containing hydrochloride salt, in a high-speed mixer / granulator for two minutes. When operating the mixer to the mixture add a solution of ethyl cellulose in ethanol and the mixture granularit within two minutes. The obtained granules are dried in a fluidized bed dryer and then ground to a grain size of 20 mesh. After adding suitable for tabletting auxiliary means (for example, sodium fumarate) is stirred for 5 minutes. This final mixture is pressed into tablets.

The rate of release of the thus obtained tablets can be influenced by increasing the amount of resin in the compositions, as this reduces the release of biologically active substances (tolperisone). So, for example, with the emer 4

Including comparisonmethod (racemate (50:50)) as a biologically active substance tablet slow release of biologically active substances contains:

temperaturerelated;

lactose;

methylhydroxypropylcellulose;

dye;

water to form granules;

magnesium stearate;

highly dispersed silicon dioxide.

To obtain tablets, proceed as follows:

The dye is mixed; with water; temperaturerelated, lactose and methylhydroxypropylcellulose is introduced into the granulator, fluidized bed and granularit with the aqueous solution containing the dye. The obtained granules with magnesium stearate and high disperse silicon dioxide are passed through a sieve with wide holes 1.25 mm and homogenized in the mixer. Thus obtained mixture is pressed into tablets in the car for tableting.

Example 5

According to the method of example 1 to obtain a composition that contains a racemate (90: 10) (with a predominant share (-)-isomer) of tolperisone.

Example 6

According to the method of example 2 to obtain a composition that contains a racemate (80: 20) (with a predominant share (-)-isomer) of tolperisone.

P(-)-isomer) of tolperisone.

Example 8

According to the method of example 3 to obtain a composition that contains a racemate (90: 10) (with a predominant share (-)-isomer) of tolperisone.

Example 9

According to the method of example 4 to obtain a composition that contains a racemate (65: 35) (with a predominant share (-)-isomer) of tolperisone.

Example 10

According to the method of example 4 to obtain a composition that contains a racemate (90: 10) (with a predominant share (-)-isomer) of tolperisone.

In General, the exemplary embodiment of the invention can be described as follows:

The pharmaceutical composition contains tolperison or its salt as a biologically active substance in the form of a racemic mixture, which may be a racemate (50:50) or a racemate with a predominant share (-)-isomer of tolperisone. Intended for oral administration the pharmaceutical composition was prepared in the form of a solid or liquid oral input medicines and biologically active substance tolperisone, which is in the form of a racemate (50:50) or in the form of a racemate with a predominant share (-)-isomer or (+)-isomer, prolongirovanne is released from the composition in the organism, preferably in the gut.

1. The way the om composition is intended for sustained release of biologically active substances of tolperisone, characterized in that the crystalline racemic tolperisone in functioning with the help of the air flow column for coating the cover with a mixture of methanol and a solution of synthetic, semisynthetic or natural hydrogels in chloroform.

2. The method according to p. 1, characterized in that as hydrogels used ethylcellulose and hydroxypropylcellulose.

3. The method according to p. 1 or 2, characterized in that the solution injected into the column for coating under a pressure of 2.5 bar and a speed of 60 ml/min

4. The method according to any of paragraphs.1-3, characterized in that the solution for coating injected into the column at a temperature of 60C at the entrance.

5. The method according to any of paragraphs.1-4, characterized in that the applied coating on crystalline temperaturerelated in the form of a racemate (50:50).

6. The method according to any of paragraphs.1-4, characterized in that the applied coating on crystalline temperaturerelated in the form of a racemate (90:10) with a predominant share (-)-isomer.

7. A method of obtaining a pharmaceutical composition for oral administration containing tolperisone or its salt, and the composition is intended for sustained release of biologically sports is spenderat microcapsules, containing tolperisone.

8. The method according to p. 7, characterized in that the dissolved and contained in the microcapsules of tolperison is in the form of the racemate (50:50).

9. The method according to p. 7, characterized in that the dissolved and contained in the microcapsules of tolperison is in the form of the racemate (80:20) with a predominant share (-)-isomer.

10. The method according to p. 7, characterized in that the dissolved and contained in the microcapsules of tolperison is in the form of the racemate (70:30) with a predominant share (-)-isomer.

11. A method of obtaining a pharmaceutical composition for oral administration containing tolperisone or its salt, and the composition is intended for sustained release of biologically active substances of tolperisone, characterized in that the binder receive the fact that synthetic, semisynthetic or natural hydrogel granularit after adding water, the obtained granules are dried, the thus obtained granular binder are mixed with tolperisone, with stirring, mixed with a solution of synthetic, semisynthetic or natural hydrogel in ethanol and then granularit obtained granules are mixed with the auxiliary for tabletting cf the water xanthan resin, resin carob, calcium sulfate.

13. The method according to p. 11 or 12, characterized in that the hydrogel is mixed with dextrose in a dry condition and thus obtained mixture granularit after adding water.

14. The method according to any of paragraphs.11-13, characterized in that the granular binder and tolperison mixed under stirring with a solution of ethyl cellulose in ethanol.

15. The method according to any of paragraphs.11-14, characterized in that the binder get that mix 25% xanthan resin, 25% resin carob, 40% cellulose, 10% calcium sulphate and 10% water based on the total amount added during granulation.

16. The method according to any of the p. 11 or 15, characterized in that as a support for tabletting tools used fumarate sodium.

17. The method according to any of paragraphs.11-16, characterized in that tolperison used in the form of the racemate (90:10) with a predominant share (-)-isomer.

18. A method of obtaining a pharmaceutical composition for oral administration containing tolperisone or its salt, and the composition is intended for sustained release of biologically active substances of tolperisone, characterized in that the and adding water, containing the dye solution thus obtained granules with magnesium stearate and high disperse silicon dioxide are passed through a sieve and homogenized in the mixer and thus the resulting mixture is pressed into tablets.

19. The method according to p. 18, characterized in that the hydrogel used methylhydroxypropylcellulose.

20. The method according to p. 18 or 19, characterized in that the granules with magnesium stearate and high disperse silicon dioxide are passed through a sieve with wide openings of 1.25 mm

21. The method according to any of paragraphs.18-20, characterized in that tolperison used in the form of the racemate (65:35) with a predominant share (-)-isomer.

22. The method according to any of paragraphs.18-20, characterized in that tolperison used in the form of the racemate (90:10) with a predominant share (-)-isomer.

 

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