Composition for percutaneous steroid medicines and containing the drug

 

(57) Abstract:

The invention can be used in the formation to create a steroid medicines percutaneous injection. The composition comprises a therapeutically effective amount of a steroid tools, pharmaceutically acceptable adhesive matrix and the absorption promoter. The absorption promoter consists of diethyleneglycol ether selected from dietilaminoetilovogo ether, dietilaminoetilovogo ether or mixtures thereof, and the second component is a complex ester sorbitan. The second component is selected from monolaurate sorbitan, monooleate sorbitan or mixtures thereof. The mass ratio diethyleneglycol ether and ether complex sorbitan is in the range from 1:4 to 4:1. Preparation for percutaneous steroid injection means includes a protective layer based, impervious to steroid tools, layer-tank medicines containing the claimed composition and the covering layer. The latter is attached to the other side of the layer of the tank medicines. The covering layer is capable of protecting the composition of the medicinal product from the environment until such time as he is removed to bring the layer of the tank lekarna patient controlled rate over an extended period of time. The use of the drug prevents the decomposition of steroid funds in the digestive tract when bioavailability of steroid funds. 2 S. and 11 C.p. f-crystals, 5 tab., 5 Il.

The invention relates to compositions for percutaneous steroid drugs, which uses a mixture of diethyleneglycol ether and ether complex sorbitan as a promoter of suction; and percutaneous drug containing the specified composition.

The background to the invention

Delivery of drugs through the skin has a number of advantages compared to conventional oral introduction, which causes problems such as unpredictable speed suction drugs, metabolic degradation of the drug and other side effects, such as irritation of the gastrointestinal tract caused by drug and its metabolites. Namely, percutaneous drug delivery reduces the above problems and delivers the drug with a controlled rate over an extended period of time appointed by improving the bioavailability lekarstvennoye through the skin, the Horny layer of the skin acts as a barrier to the penetration of drugs into the systemic circulation. Accordingly, in compositions for percutaneous delivery of drugs using different promoters suction or amplifiers permeability, which facilitates the penetration of drugs through the stratum corneum. For example, the U.S. patents NN 4006218, 3551554, 4568343, 4746515, 4379454, 4906463, 4440777, 4783450 and 5212199 reveal as such promoters dimethyl sulfoxide (DMSO), dimethylformamide, monolaurate of polyethylene glycol, monolaurate glycerol, ethanol, monolaurate propylene glycol, eucalyptol, lecithin, and esters with sorbitane.

Diethylethylenediamine ether, which was used as a solubilizer in the preparations of naproxen, nitroglycerin, phenylbutazone and prazepam, also, as reported, was effective as a promoter suction when percutaneous introduction of theophylline and prostaglandin E2 (Touitou et al. International Journal of Pharmaceutics, 70, 159-166 (1991) and Watkinson, A. et al., there, 74, 229-236 (1991)).

Other promoters suction, previously known in this area include a mixture of linoleic acid and propylene glycol (European patent publication N 261429) and a mixture of N-(hydroxyethyl)PIR is langille (U.S. patents NN 4537776, 4764379 and 4973468).

Conventional percutaneous drugs can be divided into three types: type of tank, type simple matrix type multi-layer plates. Drug type simple matrix, as described in U.S. patents NN 4314577, 4438139 and 4839174, includes drug dispersed in a layer made of a pressure-sensitive adhesive matrix. This preparation can be done quite cheaply by using a simple manufacturing process. However, it has the disadvantage, which is that the rate of release of drugs in the initial stage of high, and then drops sharply.

In addition, there is the need to deliver a large dose of the drug over a long period of time with the help of a product type, a simple matrix. For this purpose, attempts were made to improve the content of the drug in the matrix to a level beyond the threshold of solubility of the drug in the matrix, i.e., attempts to oversaturate the matrix of the drug. However, the glut is a thermodynamically unstable state, and medication in this drug has the tendency to form Christa is icon and a copolymer of polyvinylpyrrolidone and vinyl acetate, however, their efficiency, as it turned out, was negligible (Ma, X. et al., there, 142, 115- 119 (1996)).

Accordingly, there is a need for an improved drug matrix type for percutaneous administration of drugs with a constant and high rate of release of drug over an extended period of time, as well as the high content of non-crystalline drug. The authors of the present invention has succeeded in developing an improved composition for percutaneous injection of steroid medications, which contains a new absorption promoter that can satisfy the above needs. Unexpectedly, it was found that dietilenglikoluretan ether and ester sorbitan, each of which separately has been known as the absorption promoter, have limited effectiveness, when combined, create a synergistic effect, i.e. a mixture diethyleneglycol ether and ether complex sorbitane, as it turns out, is a great effective absorption promoter for percutaneous steroid medicines.

A brief description of the nature of the invention

Thus, in order Wendyh funds.

Another objective of the present invention is to provide a percutaneous preparation comprising the above composition.

In accordance with one aspect of the present invention, a composition for percutaneous injection of steroid medications, comprising: a therapeutically effective amount specified drugs; absorption promoter consisting essentially of diethyleneglycol ether and ether complex sorbitan; and pharmaceutically acceptable adhesive matrix.

Brief description of drawings

These and other objectives and features of the present invention will be better understood through the following description of the invention in conjunction with the following accompanying drawings, in which:

Fig. 1 depicts a schematic cross section of a variant invented a pharmaceutical preparation for percutaneous delivery of a steroid drug;

Fig. 2 depicts the changes in the cumulative amount of estradiol, transported through the skin of the mouse, devoid of wool, depending on time and type of the used absorption promoter;

Fig. 3 depicts the change of the cumulative number of norethisterone azeta the motor absorption;

Fig. 4 depicts the change of the cumulative number of norethisterone acetate, transported through the skin of the human body, depending on time and type of the used absorption promoter; and

Fig. 5 depicts the change of the cumulative number of norethisterone acetate, transported through the skin of the human body, depending on the time and content of monolaurate sorbitan and dietilaminoetilovogo ether.

Detailed description of the invention

The present invention relates to compositions for percutaneous steroid drugs, including steroid drug; the mixture diethyleneglycol ether and ether complex sorbitan used as a promoter suction; and pharmaceutically acceptable adhesive matrix.

Examples of steroid drugs for use in the compositions of the present invention include estrogens, such as estradiol, ethinyl estradiol and esters of estradiol; Progestogens such as norethisterone, norethisterone acetate, medroxyprogesterone acetate, desogestrel, gestation and levonorgestrel; androgens, such as testosterone, testosterone propionate, testosterone, Enan is on steroid medicines which is used in the invented compositions may vary from 0.05 to 30%, preferably from 0.1 to 10% of the total weight of the composition.

The absorption promoter of the present invention is composed of dietilaminoetilovogo ether and ether complex sorbitan mixed in a weight ratio of from 1: 4 to 4:1, preferably from 1:2 to 2:1. Diethylethylenediamine esters that are suitable for use in the present invention include diethylethylenediamine ether and diethylethylenediamine ether, and suitable esters sorbitan include monolaurate sorbitan and monooleate sorbitan.

The total amount of the mixture diethyleneglycol ether and ether complex sorbitan used in the compositions according to the invention, can vary from 5 to 30%, preferably from 5 to 25% of the total weight of the composition, and the weight ratio of these two components is maintained in the aforementioned range.

Pharmaceutically acceptable adhesive matrix used in the present invention may be any known in this field, for example, adhesives based on polyacrylate, such as ethyl-, butyl - and 2-ethyl hexyl acrylate, polyisobutylene and sizerandy, antioxidants, stabilizers and dyes.

Preparation for percutaneous injection of steroid medications in accordance with another aspect of the present invention can be manufactured using: protective layer, impermeable to steroid drugs; layer-tank medicines containing the above-mentioned composition of the present invention, one side of which is laminated on the protective layer; and a cover layer attached to the other side of the layer of the reservoir of the medication; and the specified coating layer capable of protecting the composition from the environment until such time as he is removed to bring the layer-tank medicines in contact with skin.

The drug of the present invention may optionally include an extension of the adhesive layer, which are selected from well-known in this field, for example, a ring-shaped adhesive layer firmly attached on the periphery of a layer-tank medicines and protective layer basis.

Fig. 1 shows a schematic cross section of a variant of the drug for percutaneous delivery of a steroid drug means any layer-the base 3 and the extension of the adhesive layer 4.

The composition according to the invention for percutaneous delivery of steroid drugs has the following advantages: it is a composition of type simple matrix, which can be produced cheaply; the application of improved absorption promoter, described above, makes it possible to maintain the intensive flow of drugs over an extended period of time, the true speed of penetration of the medicinal product subject to the kinetics of zero order; and the formation of crystals drugs inhibited even at high levels of drugs, due to the use of this improved absorption promoter. The dose that is administered to the patient using the compositions of the present invention can be controlled by selection of the ratio of content in the composition of the medicinal product and promoter of absorption.

The following examples are intended to further illustrate the present invention without limiting its scope.

To determine the rate of penetration of drugs through the skin

The flux, or rate of penetration through the skin (SEC), medicinal corpse of a man or carved in female mice, devoid of wool, aged 6 weeks) were placed in a diffusion chamber Valia-Chien (Crown Glass, USA) so that the stratum corneum of the skin facing out from the camera, and then fixed on the skin preparation for percutaneous introduction, containing one or more steroid drugs. The camera was added 3.4 ml of physiological saline containing 40% polyethylene glycol 400 (Sigma Scientific Co.) and was stirred during the whole period of the experiment. After that, periodically taking samples of the physiological salt solution volume of 100 μl and subjected to liquid chromatography high resolution to determine the cumulative amount of drug transported through the skin. The rate of penetration through the skin (SEC) drug was calculated by regression analysis of cumulative amounts of drug in a time-dependent (µg/cm2/h).

The process described above was repeated 3 times and determine the average value SPK medicines.

Referential example 1. Preparation and testing of compositions for percutaneous introduction, containing the usual promoters absorption (skin of the mice deprived of wool).

The mixture was poured on impermeable protective layer-based (Scotchpak 1109, 3M Co.) to obtain a matrix layer of a thickness of 1000 μm. The resulting material is composed of a protective layer, covered with a matrix layer was dried in an oven at a gradual rise in temperature from 60o120oC. the resulting material was left in the open air for 1 hour, and then it was eliminirovali coating layer (Scotchpak 1012, 3M Co.). The resulting preparation for percutaneous introduction of medicines kept at room temperature.

Was determined by the rate of penetration of drugs through the skin of the mouse, devoid of wool; the results are presented in table 1 and Fig.2 and 3.

Fig. 2 and 3 depict the changes in the cumulative amount of estradiol and norethisterone acetate, transported through the skin, depending on time and type of the used absorption promoter.

As can be seen from table 1 and Fig. 2 and 3, the compositions containing monolaurin sorbitan (reference example 1-4) and squalene (reference example 1-5) as a promoter of the ditch was observed the formation of crystals of medicines.

Referential example 2. Preparation and testing of compositions for percutaneous introduction, containing the usual promoters of absorption (skin of the human body).

Was manufactured and tested four composition for percutaneous drug delivery, as described in reference example 1, except that instead of the skin of the mouse used the skin of the human body and used 4 wt.% norethisterone acetate (NETA) together with promoters suction presented in table 2. The results are presented in table 2 and Fig. 4.

As can be seen from table 2 and Fig. 4, the compositions containing monolaurin sorbitan (reference example 2-2), squalene (reference example 2-3) and diethylethylenediamine ester (reference example 2-4) as a promoter absorption, increased the rate of penetration of the net through the skin of the human body to a much lesser extent than when using a mouse skin devoid of hair. In addition, all of the above reference examples, we observed formation of crystals of medicines, in addition to example 2-4, in which the absorption promoter was used diethylethylenediamine ether.

Examples 1-3 and comparative examples 1-6.

It was manufactured in the example 1, except that the skin of the human body and 0.4 wt.% estradiol and 2.7 wt.% norethisterone acetate (NETA) was used together with promoters suction presented in table 3.

As a positive control in the comparative example 6 used a commercial preparation tank types, i.e. Estragest(EG, CibaGaigy, Switzerland). The results are presented in table 3 and Fig. 5.

As can be seen from table 3 and Fig. 5, the compositions of the present invention containing a mixture of dietilaminoetilovogo ether (DEGREE) and monolaurate sorbitan (LFM) in the ratio DEGREE to the LFM in the range from 0.5 to 2 (examples 1, 2 and 3) as an absorption promoter, showed a stronger increase of the speed of penetration of drugs through the skin of the human body in comparison with those in comparative examples 1-6. The rate of penetration of drugs is clearly subordinate to the kinetics of zero order. In addition, in examples 1, 2 and 3 was not observed the formation of crystals of the drug.

Example 4 and comparative examples 7-10.

Was manufactured and tested five compositions for percutaneous drug delivery, as described in siloc the mi absorption, presented in table 4.

As can be seen from table 4, the compositions of the present invention containing a mixture of dietilaminoetilovogo ether (DEGREE) and monolaurate sorbitan (LFM) (example 4) as a promoter suction, showed a stronger increase of the speed of penetration of drugs compared with those using DEGREE or LFM separately (comparative examples 8 and 9).

Examples 5-7 and comparative examples 11-12.

Was manufactured and tested five compositions for percutaneous drug delivery, as described in reference example 1, except that the skin of the human body and 0.8 wt.% estradiol was used together with promoters suction presented in table 5.

As can be seen from table 5, the compositions of the present invention containing a mixture of dietilaminoetilovogo ether (DEGREE) and monolaurate sorbitan (LFM) in a weight ratio of DEGREE and LFM from 1 to 4 (examples 5, 6 and 7), showed a speed increase penetration of estradiol through the skin of the human body.

1. Composition for percutaneous injection of steroid medications, including therapeutically effective the group, consisting of dietilaminoetilovogo ether, dietilaminoetilovogo ether or mixtures thereof, and the complex ester sorbitan selected from the group consisting of monolaurate sorbitan, monooleate sorbitan or mixtures thereof, at mass ratio diethyleneglycol ether and ether complex sorbitane in the range from 1:4 to 4:1, and pharmaceutically acceptable adhesive matrix.

2. Composition under item 1, in which the ratio diethyleneglycol ether and ether complex sorbitan is in the range from 1:2 to 2:1.

3. Composition under item 1, in which the steroid drug is an estrogen, progestogen, androgen, or their mixture.

4. The composition according to p. 3, in which extrogen is estradiol, ethinyl estradiol or an ester of estradiol.

5. The composition according to p. 3, in which the progestogen is norethisterone, norethisterone acetate, medroxyprogesterone acetate, desogestrel, gestation or levonorgestrel.

6. The composition according to p. 3, in which the androgen is testosterone, testosterone propionate, testosterone enanthate, testosterone cypionate, methyltestosterone, or dehydroepiandrosterone.

7. Composition under item 1, in which the number of steroid Le is Roy the number of steroid drugs varies from 0.1 to 10% of the total weight of the composition.

9. Composition under item 1, in which the number of promoter absorption varies from 5 to 30% of the total weight of the composition.

10. The composition according to p. 9, in which the number of promoter absorption varies from 5 to 25% of the total weight of the composition.

11. Composition under item 1, in which the adhesive matrix is a polyacrylate adhesive, polyisobutylene or silicone rubber.

12. Preparation for percutaneous steroid medicines, including a protective layer based, impervious to steroid drugs, layer-tank medicines containing composition under item 1, one side of which is laminated on the protective layer basis, and the coating layer attached to the other side of the layer of the tank medicines and specified coating layer capable of protecting the composition of the medicinal product from the environment until such time as he is removed to bring the layer of the tank medicines in contact with skin.

13. The drug under item 12, which further includes an adhesive layer.

 

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