Method for preparing preparation and preparation for transdermal administration of nicotine

FIELD: medicine, narcology, pharmacy.

SUBSTANCE: invention relates to nicotine-containing preparations possessing prolonged stimulating effect and used in loss the smoking habit. The preparation is prepared by a method involving preparing a gel-base by addition of 2.5-3.0% gel of hydroxypropylcellulose in ethanol to 10-13% ethanol solution of copolymer of N-vinylpyrrolidone with organic unsaturated acid ester in the mass ratio copolymer of N-vinylpyrrolidone with organic unsaturated acid ester : hydroxypropylcellulose in gel-base = (7.0-1):(7.5-1). Then cetyl alcohol, isopropyl myristate, propylene glycol, preliminary melted stearic acid, colloidal silicon dioxide and nicotine are added successively to the prepared gel-base at constant stirring and temperature 30-35°C. Invention provides enhancing the prolonged effect of the preparation.

EFFECT: improved preparing method, enhanced and valuable properties of preparation.

3 cl, 1 tbl, 2 ex

 

The invention relates to nikotinsoderzhaschie drugs with prolonged stimulant.

It is known that Smoking cessation, when the concentration of nicotine in the plasma decreases, smokers need to smoke, nicotine stimulation.

Known nikotinsoderzhaschie drugs that facilitate the process of weaning from Smoking by satisfying the needs of the smoker to nicotine stimulation, representing pill (RU 2153338), solutions for injection into the nose (EN 2118897), aerosols for oral use (GB 1528391), chewing gum (US 3901248), patches (DE 3438284). All these drugs do not allow you to control incoming dose of nicotine, and besides, are not sufficiently prolonged action.

Closest to the invention is a method of obtaining the drug for transdermal administration of nicotine by mixing the copolymer of N-vinylpyrrolidone with ether unsaturated organic acid, propylene glycol, hydroxypropylcellulose, isopropylmyristate, stearic acid, Aerosil, cetyl alcohol, nicotine, and ethanol (US 6479076). The process is carried out with preliminary preparation of gel-basics by simultaneous mixing of all components, with the exception of nicotine, followed by the introduction of nicotine obtained by mixing the Oia gel-based. In experiments with laboratory rats, the concentration of nicotine in plasma was decreased after 24 hours more than 4 times compared to 2 hours after application on the skin and more than 5 times compared to the maximum.

The technical task of the invention is to increase prolonged action of the drug.

This technical result is achieved in that in the method of producing drug for transdermal administration of nicotine by mixing the copolymer of N-vinylpyrrolidone with ether unsaturated organic acid, propylene glycol, hydroxypropylcellulose, isopropylmyristate, stearic acid, colloidal silicon dioxide, cetyl alcohol, nicotine, and ethanol with the preliminary preparation of a gel-basis of preparing the gel-Foundation by introducing 10-13% ethanol solution of a copolymer of N-vinylpyrrolidone with ether unsaturated organic acid 2,5-3,0% gel hydroxypropylcellulose in ethanol, at mass ratio of the copolymer of N-vinylpyrrolidone with ether unsaturated organic acid: hydroxypropylcellulose gel-based from 7,0:1 to 7.5:1, then at 30-35°and With constant stirring to the resulting gel-based consistently give cetyl alcohol, isopropylmyristate, propylene glycol, pre-molten stearic acid, colloidal silicon dioxide and nicotine, and PR is the process carried out at the following ratio of components, wt.%:

the gel-Foundation88,5 is 91.5
propylene glycol1,90-2,00
isopropylmyristate1,30-1,40
stearic acid1,90-2,00
colloidal silicon dioxide0,90-1,00
cetyl alcohol1,90-2,00
nicotinerest

The increase in prolonged action is due to the fact that the drug for transdermal administration of nicotine get the above.

As a copolymer of N-vinylpyrrolidone with ether unsaturated organic acid can be used various copolymers, but it is preferable to use copolymers of N-vinylpyrrolidone with esters of methacrylic, crotonic or acrylic acid with the concentration of ester in the copolymer is preferably from 20 to 80 wt.%. The preferred molecular weight of the copolymer 60000-80000. Such copolymers are widely known, they are received by radical copolymerization of the respective comonomers, for example, by the method described in US 6479076.

As colloidal silicon dioxide can be used Aerosil 300, Cab-o-sil and others

The technical result can be obtained only by the above mass ratio of the component is in, strictly defined, also mentioned above, the sequence of their introduction, as well as the temperature of mixing of the gel-base with other components. The deviation of any of the terms leads to a sharp drop in the duration of active drug action.

The following examples illustrate the invention.

Example 1.

Pre-prepare a 3% gel hydroxypropylcellulose in ethanol by mixing the components and store it in the cold. Separately by mixing the components is prepared 12,2% solution of the copolymer in ethanol. Use a copolymer of N-vinylpyrrolidone with loraleticialora with the content of N-vinylpyrrolidone and 70 wt.% and a molecular weight of 74,000. Then the solution of the copolymer, stirring constantly, enter the gel hydroxypropylcellulose in an amount corresponding to a mass ratio of copolymer:hydroxypropylcellulose of 7.0:1, and receive a gel-based.

In a closed vessel equipped with a stirrer and a water jacket containing 22,75 g (91,35 wt.%) gel-basics consistently with constant stirring enter value (0.475) g (1,90 wt.%) of cetyl alcohol, 0,350 g (1,40 wt.%) isopropylmyristate, 0,500 g (2.00 wt.%) propylene glycol, 0,500 g (2.00 wt.%) pre-molten stearic acid, 0,250 g (1.00 wt.%) Aerosil 300 and 0,175 g of nicotine. The process is carried out at 30°C.

After stirring for 2-chasov preparation containing of 0.35 wt.% nicotine, ready for study is pharmakinetic. The viscosity of the drug received 10000 cps.

For the study they used 40 rats at 250 g each, which daily was applied to shaved areas on the surface spins at 0.24 g of the preparation according to the invention and according to US 6479076 containing of 0.35 wt.% the nicotine. The level of nicotine in the blood plasma was determined by the content leggierissimo metabolite of nicotine.

The test results of example 1 and comparative example according to US 6479076 shown in the table.

Table.

The nicotine content in plasma on day 4, ng/ml
Time after use of the drug, an hour.Example 1Comparative example
24745
45348
65957
164326
243711

From the data given in the table, it follows that the preparation according to the invention shows the result several times surpasses the performance of known drug.

Example 2.

The product was prepared according to example 1, but when the mass ratio

the gel-based copyimagetoclipboard of 7.5:1 and following

the ratio of components, wt.%:

table width="90%" border="1" cellpadding="0" cellspacing="0" frams="none"> the gel-Foundation89,6propylene glycol2,00isopropylmyristate1,40stearic acid2,00colloidal silicon dioxide1,00cetyl alcohol2,00nicotine2,00

The resulting preparation was used in clinical trials in healthy volunteers. On the skin of each volunteer was applied to 0.5 ml of the drug. Urine samples were taken before use and immediately after 4, 16, 24 and 36 hours after drug application. The results of the test and comparative US 6479076 showed that the drug for transdermal administration of nicotine in example 2 as in example 1, has a longer active effect: in contrast to the known drug, terminated after 28 hours, after 36 hours, the preparation according to the invention still had active action.

1. The method of producing drug for transdermal administration of nicotine by mixing the copolymer of N-vinylpyrrolidone with ether unsaturated organic acid, propylene glycol, hydroxypropylcellulose, isopropylmyristate, stearic acid, colloidal silicon dioxide, cetyl alcohol, nicotine, and ethanol prior the preparation of the gel base, characterized in that the prepared gel-Foundation by introducing 10-13%ethanol solution of a copolymer of N-vinylpyrrolidone with ether unsaturated organic acid 2,5-3,0%gel hydroxypropylcellulose in ethanol at a mass ratio of the copolymer of N-vinylpyrrolidone with ether unsaturated organic acid: hydroxypropylcellulose in the gel-based from 7.0:1 to 7.5:1, then at 30-35°and With constant stirring to the resulting gel-based consistently give cetyl alcohol, isopropylmyristate, propylene glycol, pre-molten stearic acid, colloidal silicon dioxide and nicotine, and the process is carried out at the following ratio, wt.%:

The gel-Foundation88,5 is 91.5
Propylene glycol1,90-2,00
Isopropylmyristate1,30-1,40
Stearic acid1,90-2,00
Colloidal silicon dioxide0,90-1,00
Cetyl alcohol1,90-2,00
NicotineRest

2. The method according to claim 1, characterized in that as a copolymer of N-vinylpyrrolidone with ether unsaturated organic acid is used, the copolymers of N-vinylpyrrolidone with methacrylic esters, to itonovoy or acrylic acid with the concentration of ester in the copolymer is from 20 to 80 wt.%.

3. Preparation for transdermal administration of nicotine, comprising a copolymer of N-vinylpyrrolidone with ether unsaturated organic acid, propylene glycol, hydroxypropylcellulose, isopropylmyristate, stearic acid, colloidal silicon dioxide, cetyl alcohol, nicotine and ethanol, characterized in that it is obtained by the method according to claim 1.



 

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