Film-forming pharmaceutical composition for transdermal injection

 

(57) Abstract:

The invention relates to pharmaceutical compositions for transdermal administration. It contains, if necessary, (a) polymer wasalways matrix capable of forming a soft film after drying, selected from cellulosic polymers, or copolymers, or copolymers of vinylpyrrolidone/vinyl acetate, (b) active principle, (C) the promoter percutaneous absorption current beginning, in the amount of 15 to 30% by weight of the composition, (d) a nonaqueous physiologically acceptable solvent capable of dissolving wasalways matrix, the active principle and the promoter percutaneous absorption and quickly evaporate upon contact with the skin. The composition is sprayed, and the active substance does not change under the action of liver enzymes. 2 C. and 35 C.p. f-crystals, 15 PL.

The present invention relates to pharmaceutical compositions for transdermal administration.

The invention concerns, in particular, pharmaceutical compositions for transdermal administration, capable after drying to form on the skin soft film, as well as the matrix used in such pharmaceutical compositions.

Transdermal introduction m the nature and possesses certain advantages, such as lack of gastrointestinal side effects, as well as changes of the active substance under the action of liver enzymes.

However, to achieve efficiency in the mentioned way of introduction should provide a percutaneous penetration of the drug over a long period of time and in a quantity sufficient to achieve the specific content of the active agent in the blood plasma that is compatible with therapeutic treatment.

Estradiol and other hormones are substance that is absorbed through the skin using an appropriate formulation, which includes this hormone.

Because low doses of estradiol, components 50-120 PG/ml plasma, sufficient to obtain a clinical effect, for example, in the treatment of estrogen-deficiency, estradiol is the best active beginning with transdermal administration.

For this route of administration has proposed various systems and devices, allowing you to enter into the blood stream controlled quantity of drugs in General and estradiol in particular.

It is known, for example, a device for the transdermal injection, usually referred to as "the patch", which is a capacity, wypolnena by skin contact microporous membrane, the permeability for the beginning of the current regulates its diffusion and, consequently, its dosage.

Despite the opportunities offered by the specified device, in particular for the introduction of estradiol, it is preferable to use other systems. Indeed it is known that the patch could come loose from the skin, and that, moreover, often it is unaesthetic appearance.

Proposed were also gels containing estradiol. However, this pharmaceutical form, when used, can have some drawbacks, mainly its stickiness to the touch, unpleasant to the patient, the difficulty of compliance with the input dose of the current start and the complexity of the control surface.

There are also many other systems, allowing transdermal to enter medical operating beginnings.

In this respect, it is possible to cause the sprayed composition containing, in particular, polymers capable of forming a film when in contact with skin and vysalivatel active principle for introducing it through the skin. Compositions of this type are described, for example, in patent EP 0319555 contain active principle, a polymer matrix, forming after drying, flexible tape, solvent, triglyceride fatty acids with medium chain length, propylene, carbonate, and the solvent matrix that can evaporate on the skin surface and, finally, the propellant, providing a dispersion of a specified composition contained in the corresponding device.

However, the matrix consisting of ethyl cellulose, undesirable due to its ability to cause clogging of spray.

In the framework of the present invention, an experiment was conducted with a sprayable composition according to the above patent EP containing 2% of estradiol as active beginning.

As a result of tests conducted on the bare skin of the rat was registered receipt of estradiol only of the order of 0.03 MCHC-1cm-2in equilibrium, which allows us to predict very limited results and the effectiveness of the use of these compositions on the reduced area of the skin with therapeutic treatment.

In addition, compositions, similar to those proposed in the aforementioned patent and characterized by the presence of gas propellant, such as halogenated hydrocarbon, more and more criticized because of the potential dangers that they pose to the environment.

In addition e is th smell, quite unpleasant for the patient and his surroundings.

There are also many other pharmaceutical composition for external use containing the active start, solvent, and other ingredients.

As an example you can refer to patent EP 55396, which describes protivomikrobnye compositions containing

the cellulose ether;

- 2-10% dissecting agent, such as isopropylmyristate or isopropylpalmitate;

- 1-8% of a solubilizer;

0.05 to 1% active start;

- solvent, for example isopropanol.

However, these compositions, although they can be used for external skin application, be absolutely unsuitable for spray application, even after the addition of 10-40% of the gas propellant, as recommended, because they are too viscous and can cause various failures, such as clogging of the nozzle.

You can also specify the patent application EP 319964 describing the film-forming antifungal composition comprising

- 0.1 to 1.5% of tolnaftate;

- 10-20% of a copolymer of dimethylaminoethylmethacrylate with methacrylate;

0.5 to 10% of ester of fatty acid;

- solvent type of alcohol and, possibly, 0.1 to 5% derived cegesti methacrylate derivatives gives it an unpleasant odor.

Finally, you can specify the patent application EP 289900, describing the antibacterial composition for external application containing

0.5 to 10% antibacterial current start;

is 1-30% water-insoluble polymer, in particular ethyl cellulose or copolymer of polyvinylpyrrolidone;

- 0.5 to 40% of plasticizer, as a rule, essential oils, playing the role of promoter percutaneous absorption;

- 50-95% of a solvent, for example ethanol.

As you know, essential oils contain mostly terpene derivatives.

In the framework of the present invention, an experiment was conducted with a composition that is similar to that described in the patent and which contain estradiol as active start and lemon, which is a terpene, as a promoter of percutaneous absorption. However, this composition has provided only a very small percutaneous diffusion of receipt of the applicable beginning.

Thus it would be interesting to develop a composition that provides transdermal diffusion of medicinal active principles, in particular, estradiol, from minor surface coverage and in amounts compatible with therapeutic treatment of full otsutstvie compositions for transdermal administration of estradiol and other drug substances from the film, formed on the skin, which is not inherent in the above-mentioned disadvantages and which is capable of limited and controlled coverage area to put in the blood flow active principle uniformly, continuously and quantities in the plasma that reaches therapeutic threshold in a wide range.

Thus, the object of the invention is a pharmaceutical composition for transdermal administration, containing

1) if necessary, wasalways polymer matrix capable of forming a soft film after drying;

2) active principle;

3) the promoter percutaneous absorption current start;

4) non-aqueous, physiologically acceptable solvent capable of dissolving wasalways matrix, the active principle and the promoter percutaneous absorption, and quickly evaporate upon contact with the skin.

In this description under the "active principle" is understood or medicinal substance, which after its introduction causes prophylactic or therapeutic response, or Association of two or more substances of the specified type.

The polymer matrix is selected, generally, from polymers or copolymers capable of simultaneously form a soft film poznakomitsya based 0-6% by weight of the composition according to the invention, for example, from 4 to 6% or 5%. It is preferable to use a matrix in an amount of from 1 to 5, mostly 5%.

Such a matrix is selected from polymers or copolymers, which are soluble in the physiological solvent to form a homogeneous solution.

Among the polymers and copolymers that meet the above criteria, preference is given to polymers and copolymers of cellulose, in particular, because after drying, they are resistant to abrasion and adequate mechanical strength. Due to this property of cellulose matrix of this type when washing water is not dissolved and remain active principle.

As examples of such cellulosic polymers and copolymers suitable for use in compositions according to the invention, it is possible to call ethylcellulose, butylacetoacetate, propionitriles and vaccinated or unvaccinated the hypromellose, such as, for example, suktsinatdegidrogenazy.

However, ethylcellulose is a preferred polymer of cellulose and, therefore, the preferred polymer wasalways matrix for formation of soft plait is pyrrolidone with vinyl acetate, for example polyvinylpyrrolidones, hereafter referred to as PVP VA.

Consequently, more specifically, an object of the invention is a pharmaceutical composition for transdermal administration, containing

1) polymer wasalways matrix forming after drying, soft film, selected from polymers and copolymers of cellulose or of copolymers of vinylpyrrolidone with vinyl acetate;

2) active principle, in particular estradiol;

3) the promoter percutaneous absorption current start;

4) non-aqueous, physiologically acceptable solvent capable of dissolving wasalways matrix, the active principle and the promoter percutaneous absorption and quickly evaporate upon contact with the skin.

The active principle is selected from medicinal substances soluble in the physiologically acceptable solvent and able to penetrate through the epidermis and dermis in a quantity sufficient to provide a therapeutically effective blood concentration of the skin surface is small, but sufficient space.

Such substances are selected from active principles, with a relatively short half-life of the organism and significant fisiolog active principle according to the invention, you can specify different medicinal substances, can be successfully introduced into the compositions according to the invention. Such substances can be selected from the following groups:

bronchodilator agent, for example sodium chromoglycate, salbutamol or theophylline;

diuretic, such as furosemide or hydrochlorothiazide;

antibacterial, such as penicillin, cephalosporin, tetracycline, oxytetracycline, chlortetracycline and chloramphenicol;

the remedy against acne, such as erythromycin;

analgesic or sedative, such as pentobarbital or its sodium salt, secobarbital and its sodium salt or codeine;

psychoactive drug, for example 3-(2-aminopropyl)-indolacetic or 3-(2-aminobutyl)-indolacetic;

anxiolytic agent such as diazepam, chlordiazepoxide, reserpine, chlorpromazine or thiopropazate;

a hormone, such as adrenocorticosteroid, for example 6-methylprednisolone;

androgenic steroid, such as testosterone or methyltestosterone;

estrogenic steroid, such as estrone or ethinylestradiol;

progestational steroid, such as 17 - hydroxyprogesterone, medroxyprogesterone or its acetate, 19-norprogesterone, is oxen;

febrifuge, for example acetylsalicylic acid; salicylamide, sodium salicylate or methyl salicylate;

narcotic painkiller, such as morphine or strong pain reliever;

means for lowering blood sugar, such as sulfanilamide, in particular glipizid, glibert, hlorpropamid or insulin;

antispasmodic agent, such as atropine or bromide methscopolamine;

protivotumanki means, for example lobelin or nicotine;

antimalarial drug, for example 4-aminoquinoline or 9-aminoquinoline;

beta-blocking agent, such as metoprolol;

anti-arthritis agent, such as sulindac;

not steroid anti-inflammatory agent such as ibuprofen or naproxen;

the remedy for osteoporosis, such as etidronate, tiludronate or their sodium salts;

the treatment, such as ascorbic acid;

vasodilating agent, such as dipyridamole, trinitrin or dinitrate treatment of isosorbide;

the remedy against hypertonie, such as propranolol, prazosin, diltiazem or clonidine;

the remedy for Parkinson's disease, such as hydrochlorothiazide methyldopa or selegiline;

the medium is Tovarkovo means, for example tamoxifen;

a nutritional Supplement such as vitamins, volatile acids or volatile fatty acids.

These medicinal operating beginnings, along with estradiol, are introduced into the compositions according to the invention, in particular, the rate of 0.1-20% by weight of the composition, provided that each active principle when transdermique the application is entered in the individual quantities known from the prior art or adapted to such a route of administration.

For example, estradiol may be present in the compositions according to the invention in amounts of 0.5-6% by weight of the composition, in particular from 0.5 to 4%, preferably from 1 to 2%.

As mentioned above, the compositions according to the invention can contain the active principle in the form of an Association of several drugs selected from the groups listed above.

As an example, you can specify on astroprojection Association for the treatment of menopausal symptoms, consisting of estrogenic steroid, such as estradiol and progestational steroid, such as acetate norethindrone, or contraceptive Association, for example, levonorgestrel/estradiol.

For gastite skin, in the polymer matrix or to the current early type promoter percutaneous absorption. The last part of the compositions according to the invention mainly in the amount of from 15 to 30% by weight of the composition, preferably 15-25%, for example 20%.

The above-mentioned promoter percutaneous absorption is chosen in such a way that it created a substantial transdermal flux input of the active substance to achieve the desired concentration in the plasma through an acceptable skin area coverage, i.e., through the area of skin covering less than 150 cm2mainly from 10 to 40 cm2for example 30 cm2.

The promoter percutaneous absorption is considered effective if it has the ability to quickly overcome the skin barrier, increasing the permeability of the skin without irritating it, and to favor diffusion of the current start, select take into account the kinetics and concentration, which can persist for some time.

This promoter is selected from substances that are soluble in physiological nonaqueous solvent, able to quickly evaporate upon contact with the skin.

Preferably it is chosen from the following link which they the above characteristics, i.e.:

esters of aliphatic fatty acids, mainly of esters with a total carbon atoms of 10 to 30, possibly substituted by one or two hydroxyl, carboxyl or allochrony C1-C4as, for example, acetoxy, or possibly interrupted by one or two ethylene bonds or one or two oxygen atoms of simple ether;

aliphatic fatty alcohols, primary alcohols C10-C30possibly substituted by one or two hydroxyl, carboxyl or allochrony C1-C4for example acetoxy, or possibly interrupted by one or two ethylene bonds or one or two oxygen atoms of simple ether.

The most preferred promoters absorption selected from the above esters of aliphatic fatty acids or aliphatic fatty alcohols, the following:

a) esters of aliphatic fatty acids of General formula

< / BR>
in which R denotes a branched or linear alkylenes or alkyl group, a C2-C17possibly substituted by hydroxyl, carboxyl or alloctype C1-C4, R11means the group-CH2-CH2-O-(CH2)2-O-CH2-CH3and esters of aliphatic fatty acids containing at least 10 carbon atoms and not more than 2 hydroxyl groups;

b) aliphatic fatty alcohols of General formula

R2-OH (II)

in which R2means alkyl group, a C10-C20.

As specific compounds, showed the best ability to accelerate percutaneous absorption of active principles, in particular estradiol, you can specify:

2-ethylhexyl-2-ethylhexanoate (compound 1)

isopropylmyristate (compound 2)

monistat of monoethylene ether of diethylene glycol (compound 3)

isopropylpalmitate (compound 4)

2-octyldodecanol (compound 5)

2-ethylhexyl-undecylenate (compound 6)

2-ethylhexyl-succinate (compound 7)

2-ethylhexyl-12-hydroxystearate (compound 8)

2-ethylhexyl-12-acetoxystyrene (compound 9)

isostearate glycerol (compound 10)

hexyl-laurate (compound 11)

2-ethylhexyl-2-ethylhexanoate is a preferred promoter of absorption, particularly for percutaneous who logicheskie acceptable solvent, capable of dissolving wasalways matrix, the active principle and the promoter percutaneous absorption are selected from compounds with a relatively low boiling point, in particular with a boiling point below 100oC at atmospheric pressure, so that it quickly evaporates in the evaporation upon contact with the skin and thus contributed to the formation of a film when dry, without causing local irritation.

Such physiologically compatible solvents are number 44-84,9% by weight of the final composition and are selected from volatile compounds, such as dichloromethane, ethanol, isopropanol or ethyl acetate.

Ethanol and isopropanol are the best solvents. However, ethanol is preferable according to the invention, because it efficiently promotes the formation of very uniform films and quickly evaporates upon contact with the skin.

Thus, the invention applies, in particular, transdermal composition that contains

1) 0-6% polymer vasilevousa matrix capable after drying to form a soft film that is chosen in particular from cellulose polymers or copolymers, such as ethyl cellulose;

2) Nacala, in particular 15-25% of ester of the fatty acid or fatty alcohol selected from

2-ethylhexyl-2-ethylhexanoate;

isopropylmyristate;

myristate of monoethylene ether of diethylene glycol;

isopropylpalmitate;

2-octyldodecanol;

2-ethylhexyl-undecylenate;

2-ethylhexyl-succinate;

2-ethylhexyl-12-hydroxystearate;

2-ethylhexyl-12-acetoxystyrene;

isostearate glycerol;

hexyl-laurate;

4) 44-84,9% nonaqueous physiologically acceptable solvent capable of dissolving wasalways matrix, the active principle and the promoter percutaneous absorption and quickly evaporate upon contact with the skin, in particular ethanol or isopropanol.

Compositions according to the invention can be prepared by the classical method by mixing the components in the specified proportions.

For example, when mixing is possible to dissolve the promoter percutaneous absorption in physiological solvent, then add the active principle and at the end - wasalways matrix.

The components in the composition, are known products or products that can be obtained by known methods, some of ut be applied by any means for a pre-defined skin area, for example in the area of 10 to 40 cm2in particular the area of 30 cm2and mostly direct plating using a metering pump of a known type and commercially available, without resorting to the propellant, such as compressed or liquefied gas.

Although the prior art shows the opposite, it was unexpectedly observed that vasilevousa matrix of ethyl cellulose does not cause clogging due to the buildup at the outlet of the nozzle pulverizadores head, resulting in compositions according to the invention can be sprayed without the use of gas propellant and without fear of damaging the tank atomizer.

If desired, you can nevertheless apply the composition according to the invention by comminution of capacity, equipped with a metering valve and containing additionally a compressed gas propellant, such as nitrogen or nitrous oxide, or liquefied gas such as butane.

Another object of the invention is a matrix for transdermal pharmaceutical compositions containing

a) a polymer matrix, intended for vysalivaniya current beginning and capable of forming a soft film after drying;

b) the promoter crestworth wasalways matrix and the promoter percutaneous absorption and quickly evaporate upon contact with the skin.

The polymer matrix is selected from polymers or copolymers, in particular of cellulose polymers or copolymers, such as those listed above, and the promoter percutaneous absorption is selected from esters of aliphatic fatty acids or aliphatic fatty alcohols, for example, as described above, in particular esters of the formula I or alcohols of the formula II.

As physiologically acceptable non-aqueous solvent is used, the compound having a boiling point below 100oC at atmospheric pressure, for example, above.

These components matrix for transdermal pharmaceutical compositions are distributed in such a way that the composition containing the active principle, vasilevousa matrix is 0-6%, the promoter percutaneous absorption - 15-30% and physiologically acceptable non-aqueous solvent - 44-84,9%, the above percentages are calculated on the weight of the pharmaceutical end of the song.

The above matrix can be prepared by the classical method by mixing appropriate proportions of the different ingredients.

Film-forming compositions and matrices for transdermal compositions according to the invention have neospora the Ola, thus, what stands out is controlled and constant amount in the plasma over a fairly long period of not less than 12 hours through the area applied on the skin coating of the order of 10-40 cm2.

The amount in the blood of the applicable beginning compatible with therapeutic treatment, in contrast to the compositions and matrices known transdermal compositions, which are described in the example in the patent EP 0319555.

In addition, compositions and matrices for transdermal compositions according to the invention are completely devoid of any unpleasant odor, are superimposed in the form of a homogeneous film on a certain area of the skin and therefore there is no need to use gas propellant harmful to the environment.

Such films possess elasticity and abrasion resistance sufficient to remedy any damage on the skin of the patient and more easily tolerated by the patient compared with the known transdermal means, because of the thinness of the layer and the absence of any coverage there is no violation of the water-gas exchange with the environment.

Finally, the compositions according to the invention, forming a soft film, providing what they completely invisible.

To confirm the specified properties of the compositions and films of them were conducted biological tests in vitro and in vivo.

I. in vitro Tests

A. Matrix: 5% ethyl cellulose

Active principle: estradiol

Percutaneous passage of the beginning of the current introduced into the absorption promoter, can be estimated by the number of applicable beginning, penetrating through the skin.

Experiments using the compositions according to the invention was carried out in vitro diffusion cells Franz, which make it very easy to reproduce the experimental conditions, which facilitates comparative studies.

The diffusion cell with the receiving compartment with a volume of 30 ml were specifically designed to study the type of "spray", the sprayed onto the skin surface area of 10 cm2.

During the test, carried out according to the method described in Curr. Probl. Dermatol. 7, 58-68 (1978) investigated the percutaneous absorption of estradiol through biopsy samples taken from the dorsal skin of the rat bespoleznogo cover of size 10 cm2and placed in the above-mentioned diffusion cells.

This coating was applied to 50 μl of the composition according to the invention, sotiriadou the fluid, contact termicheskoi the surface of the skin.

Because the permeability of the skin to the passage of the current start sometimes differed greatly from one batch of animals to another, the results are used primarily for comparison within the same series of studies.

a) Composition with a content of 2% estradiol, wt.%:

ethylcellulose - 5

estradiol - 2

the promoter percutaneous absorption - 20

ethanol - 73

In the first series of experiments, carried out with compounds 1, 2, 5, 6, 8, 9 and 11, were registered receipt of estradiol from 0,115 to 0,330 MCHC-1cm-2in the second series with compounds 1, 2, 7 and 10 the flow is from 0,121 to 0,290 MCHC-1cm-2and in the third series with compounds 1, 3 and 4 the flow was from the strength of 0.159 to 0,280 MCHC-1cm2.

These results show that quantitative incoming connections 2-11 comparable with the same level recorded for compound 1, with no significant difference has not been established.

There was conducted an additional series of experiments using the compositions according to the invention, having the following composition, wt.%

utilze the table. 1 (see the end of the description).

These results indicate that the diffusion flow of estradiol increases proportional to the concentration of promoter in the composition.

However, when its content is higher than 20% is not observed more characteristic of increasing the number of percutaneous penetration of estradiol, however, this number remains high, as is shown in table. 2 results (see the end of the description).

For comparison, we also conducted tests using

compositions according to the invention, containing in weight%:

ethylcellulose - 5

estradiol - 2

connection 1 - 20

ethanol - 73

- and the well-known compositions according to the patent EP 0319555 (compositions X and Y), containing, in wt.%:

estradiol - 2

N-butyl ester of poly (methacrylic acid - 3,66

polyvinylpyrrolidone VA (PVP VA*) (50% ethanol solution) - 6,66

ethanol - 11,66

macropollutants - 1,66

methylene chloride - 74,36

*PVP VA: there were used two types of PVP / VA, one of which contains 30% polyvinylpyrrolidone (PVP / VA 335 ISP) (composition X) and another with a content of 70% polyvinylpyrrolidone (PVP / VA 735 ISP) (composition Y).

Received RESM the superiority of the compositions according to the invention over compositions peers, since the flow of the active substance exceeds 8-9 times a similar measure known compositions.

Additionally, we performed the test compositions X and Y caused by the coating on the aluminum surface area of 10 cm2that after drying, the solvents were brought into contact with the skin according to the method described in the aforementioned patent EP 0319555 showed that percutaneous diffusion receipt of estradiol were respectively 0,0090,011 and 0,0020,003 MCHC-1cm-2.

b) Compositions with a content of 1% estradiol

Was held another series of similar tests to confirm the advantages of the compositions according to the invention before identical transdermal compositions, which were replaced by the promoter of percutaneous absorption, in order to assess the properties of the compounds of formula I.

With this purpose used a composition of the following composition, wt.%:

ethylcellulose - 5

estradiol - 2

connection Z - 20

ethanol - 74

Compound Z was either a promoter percutaneous absorption of the above formula I or the compound known from the prior art.

We also carried out a comparative test using helr>*; triethanolamine: 1%*; purified water in a quantity sufficient to 100%), the trademarked "OESTROGELR".

*: wt.%.

Obtained results are shown in table. 4 (see the end of the description).

These results show that percutaneous diffusion of receipt of estradiol per cm2when using the compositions according to the invention containing the compound 1, is significantly higher in 3-4 times, the same indicator when using the sprayed composition, which was replaced by compound 1.

In the case of applying the gel it was noted that percutaneous diffusion of receipt of the applicable beginning in 7-8 times were less than the same receipt when using the compositions according to the invention.

If the results be expressed through the actual surface coating, i.e., 30 cm2for the composition according to the invention and 100 cm2for product OESTROGELthen these results show that the active principle of the compositions according to the invention for 24 hours diffuses twice as fast compared with the gel, because there were about 40 μg to gel and 80 µg for compositions according to the invention.

the Nations, containing 1% estradiol according to the invention, which was filtered through 8 hours after their application, found no effect on the diffusion current start, even after 30 hours after application on the skin.

Based on the above results, we can conclude that transdermal composition according to the invention are evident superiority over the other investigated compositions, which are caused in particular by the presence of promoter percutaneous absorption current beginning, effectively contributing significant percutaneous diffusion receipts specified current beginning.

Such significant transdermal flows allow to conclude that the higher the ability of the compositions according to the invention to generate plasma, based on the same surface of the skin of the coating, the amount of the active substance, more appropriate therapeutic treatment.

b) a Composition containing 2%, 4% and 6% estradiol

Performed tests similar to those described above in section 1.A., to demonstrate the effect of the concentration of estradiol on its passage through the skin.

Used the next song is Holocene results are given in table. 5 (see the end of the description).

B. Matrix: 0%, 2%, 3%, 4%, 5% and 6% ethyl cellulose

Active principle: estradiol

Tests similar to those described in section 1.A. the test was conducted in vitro diffusion cell type of Franz cells with the composition according to the invention, having the following composition, wt.%:

ethylcellulose - Et

estradiol - 2

connection 1 - 20

ethanol - (78-Et)

Obtained results are shown in table. 6 (see the end of the description).

These results show that the concentration of ethyl cellulose having a negligible impact on the amount of estradiol in equilibrium.

C. Matrix: 5% ethyl cellulose

Existing start; estradiol, selegiline, ibuprofen, clonidine, testosterone, acetate norethindrone, acetylsalicylic acid.

Performed test in vitro diffusion cells Franz similar test with estradiol described above. (section 1.A.).

The conducted quantitative research concerned effectors, radiolabelled.

With this purpose, deposited 50 μl of a composition containing 10 μm Ci radiolabelled current beginning at 10 cm2

Experiments with different operating principles were carried out in comparison with compositions containing 17 estradiol labeled with isotope tritium, isotopic dilution (2,4,6,7-3H-estradiol).

a) Active principle: selegiline

The experiments carried out with the use of molecules labeled with tritium by isotope dilution, gave the following results:

1st series of experiments (see tab. 7 at the end of the description).

2nd series of experiments (see tab. 8 at the end of the description).

b) Active principle: ibuprofen.

The experiments carried out with the use of molecules labeled with tritium by isotope dilution, gave the following results:

1st series of experiments (see tab. 9 at the end of the description).

Additional comparative experiment, conducted with a composition containing 5% of ethyl cellulose, 2% ibuprofen and 93% ethanol, showed percutaneous diffusion of receipt of the active principle in the number 0,780 MCHC-1cm-2.

This result clearly indicates that the connection 1 plays the role of promoter transdermal absorption of ibuprofen.

2nd series of experiments (see tab. 10 at the end of the description).

C) Active principle: clonidine

The experiments carried out with the aid shall ulitity, are given in table. 11 (see the end of the description).

Additional comparative experiment, conducted with a composition containing 5% of ethyl cellulose, 2% clonidine and 93% ethanol, showed percutaneous diffusion proceeds in the amount of 0,0790,118 MCHC-1cm-2.

This result indicates that compound 1 plays the role of promoter transdermal absorption of clonidine.

g) Active principle: testosterone

The experiments carried out with the use of molecules labeled with tritium by isotope dilution (1,2,6,7-3H-testosterone), gave the results shown in the table. 12 (see the end of the description).

Additional experience carried out with a composition containing 5% of ethylcellulose, 2% testosterone and 93% ethanol, showed percutaneous diffusion proceeds in the amount of 0,4430,190 MCHC-1cm-2.

This result indicates that compound 1 plays the role of promoter transdermal absorption of testosterone.

d) Active principle: acetate norethindrone

The experiments carried out with the use of molecules labeled with tritium by isotope dilution, gave the results shown in the table. 13 (see the end of the description).

More showed percutaneous diffusion proceeds in the amount of 0,0660,026 MCHC-1cm-2that suggests that the connection 1 plays the role of promoter transdermal absorption of acetate norethindrone.

e) Active principle: acetylsalicylic acid

The experiments carried out with the use of molecules labeled with 14C by isotope dilution (carboxyl14C acetylsalicylic acid), gave the results shown in the table. 14 (see the end of the description).

, Matrix: polyvinylpyrrolidones.

Active principle: estradiol

Was carried out a series of experiments similar to those described in section 1. A. to quantify percutaneous diffusion proceeds of estradiol from the compositions according to the invention, containing a matrix of polyvinylpyrrolidones (PVP / VA).

Were used in the composition of the following composition, wt.%:

PVP / VA - P

estradiol - 2

connection 1 - 20

ethanol - (78-P)

and compared with the composition C according to the invention, containing a matrix of ethyl cellulose, wt.%:

ethylcellulose - 5

estradiol - 2

connection 1 - 20

ethanol - 73

Obtained results are shown in table. 15 (see the end of the description).

For conducting compare the total also the matrix, the solvent and the gas propellant, which were similar to the components described in the patent EP 0319555, namely a 2.5% PVP-VA, 2.5% n-butyl ester of methacrylic acid, 15% ethanol, 13% dichloromethane and 61.5% freon, to which was added 5% of compound 1 used in the present invention as a promoter.

However, such a composition with a content of 2% estradiol failed to get, as active principle is not soluble in this mixture.

The composition of the following composition, wt.%:

PVP VA - 3

estradiol - 2

connection 1 - 25

ethanol - 70

provided percutaneous diffusion proceeds in the amount of 0,2320,028 MCHC-1cm-2.

II. In vivo studies

We also conducted experiments in vivo, in particular, on dwarf pig Yucatán breed weighing 13 kg, which struck

to 100 μl of the composition with a content of 2% estradiol according to the invention by spraying onto the skin surface area of 30 cm2that corresponds to 1.5 mg of estradiol,

to 2.5 g of OESTROGEL gelby smearing a thin layer of the skin surface area of 100 cm2that corresponds to 1.5 mg of estradiol.

Then determined through different periods of time the amount of estradiol in plasma the plasma estradiol, obtained using the composition according to the invention and OESTROGEL gelwere, respectively, about 390 PG/ml and 170 PG/ml after 8 hours after application, and about 304 PG/ml 160 PG/ml after day after application.

Therefore, the composition according to the invention is approximately twice as effective OESTROGEL gelthe number of seconds entered in the blood within one day.

Similar comparative tests carried out with the known from the prior art compositions X and Y, also showed a significant superiority of the compositions according to the invention the content of estradiol in the blood in quantity and for a long time.

Following non-limiting examples illustrate the obtaining of the compositions according to the invention and a matrix for transdermal compositions according to the invention.

Example 1

Transdermal composition containing estradiol

Prepare 100 g of the transdermal composition of the following composition, wt.%:

ethylcellulose 6 MPAC - 5

estradiol - 2

2-ethylhexyl-2-ethylhexanoate - 20

ethanol - 73

by mixing 73 g of ethanol and 20 g of ethylhexyl-2-ethylhexanoate when paramasivam 2 g of estradiol and after complete dissolution (5 minutes) introduce 5 g of ethyl cellulose with a viscosity of 6 mPas under vigorous stirring, in order to avoid the formation of clots. The final solution is a homogeneous, slightly opalescent.

For spray application: aluminum vessels are filled with 5 ml of the above solution and provided with pushbutton pump.

To start the pump before the first use of double-clicked.

Examples 2-38

Transdermal compositions containing estradiol

Using the same method as in example 1 to prepare a transdermal composition of the following composition, wt.%:

Example 2

ethylcellulose - 5

estradiol - 1

2-ethylhexyl-2-ethylhexanoate - 20

ethanol - 74

Example 3

ethylcellulose - 5

estradiol - 2

2-ethylhexyl-12-acetoxystyrene - 20

ethanol - 73

Example 4

ethylcellulose - 5

estradiol - 1,5

hexyl-laurate - 20

ethanol - 73,5

Example 5

ethylcellulose - 5

estradiol - 2,5

2-octyldodecanol - 20

ethanol is 72.5

Example 6

ethylcellulose - 5

estradiol - 3

2-ethylhexyl-12-acetoxystyrene - 20

ethanol - 72

Example 7

ethylcellulose - 2

estradiol - 1

2-ethylhexyl-2-ethylhexanoate - 20

ethanol - 77

Example 8

ethylcellulose - 5

R> estradiol - 2

2-ethylhexyl-2-ethylhexanoate - 20

ethanol - 88

Example 10

ethylcellulose - 5

estradiol - 2

2-ethylhexyl-2-ethylhexanoate - 15

ethanol - 78

Example 11

ethylcellulose - 5

estradiol - 2

2-ethylhexyl-2-ethylhexanoate - 20

isopropanol - 73

Example 12

ethylcellulose - 5

estradiol - 4

2-ethylhexyl-2-ethylhexanoate - 20

ethanol/isopropanol 30/70 - 71

Example 13

ethylcellulose - 5

estradiol - 6

2-ethylhexyl-2-ethylhexanoate - 20

isopropanol - 69

Example 14

estradiol - 2

2-ethylhexyl-2-ethylhexanoate - 20

ethanol - 78

Example 15

ethylcellulose - 2

estradiol - 2

2-ethylhexyl-2-ethylhexanoate - 20

ethanol - 76

Example 16

ethylcellulose - 3

estradiol - 2

2-ethylhexyl-2-ethylhexanoate - 20

ethanol - 75

Example 17

ethylcellulose - 4

estradiol - 2

2-ethylhexyl-2-ethylhexanoate - 20

ethanol - 74

Example 18

ethylcellulose - 6

estradiol - 2

2-ethylhexyl-2-ethylhexanoate - 20

ethanol - 72

Example 19

ethylcellulose - 5

selegilin - 10

2-ethylhexyl-2-ethylhexanoate - 20

ethanol - 65

Example 20

ethylcellulose - 5

isopropylmyristate - 20

ethanol - 65

Example 22

ethylcellulose - 5

ibuprofen - 2

2-ethylhexyl-2-ethylhexanoate - 20

ethanol - 73

Example 23

ethylcellulose - 5

ibuprofen - 2,5

2-ethylhexyl-2-succinat - 20

ethanol is 72.5

Example 24

ethylcellulose - 5

ibuprofen - 2

2-ethylhexyl-2-succinate - 20

ethanol - 73

Example 25

ethylcellulose - 5

clonidine - 2

2-ethylhexyl-2-ethylhexanoate - 20

ethanol - 73

Example 26

ethylcellulose - 5

testosterone - 2

2-ethylhexyl-2-ethylhexanoate - 15

ethanol - 78

Example 27

ethylcellulose - 5

acetate norethindrone - 3

2-ethylhexyl-2-ethylhexanoate - 20

ethanol - 72

Example 28

ethylcellulose - 5

acetate norethindrone - 2

2-ethylhexyl-succinate - 20

ethanol - 73

Example 29

ethylcellulose - 5

acetate norethindrone - 2

2-ethylhexyl-2-ethylhexanoate - 20

ethanol - 73

Example 30

ethylcellulose - 5

acetylsalicylic acid - 2

2-ethylhexyl-2-ethylhexanoate - 20

ethanol - 73

Example 31

ethylcellulose - 5

acetylsalicylic acid - 2

2-ethylhexyl-succinate - 20

ethanol - 73

Example 32

3

estradiol - 2

2-ethylhexyl-2-ethylhexanoate - 20

ethanol - 75

Example 34

PVP VA - 4

estradiol - 2

2-ethylhexyl-2-ethylhexanoate - 20

ethanol - 74

Example 35

PVP VA - 5

estradiol - 2

2-ethylhexyl-2-ethylhexanoate - 20

ethanol - 73

Example 36

PVP VA - 3

estradiol - 2

2-ethylhexyl-2-ethylhexanoate - 25

ethanol - 70

Example 37

ethylcellulose - 5

estradiol - 2

2-ethylhexyl-2-ethylhexanoate - 30

ethanol - 63

Example 38

Matrix for transdermal composition

Cook 98 g matrix for transdermal composition by mixing for 30 seconds 73 g of ethanol and 20 g of 2-ethylhexyl-2-ethylhexanoate. Then add 5 g of ethyl cellulose with a viscosity of 6 mPas under vigorous stirring to eliminate the formation of clots.

The resulting matrix suitable for introduction into it of the current start and obtain thus pharmaceutical compositions containing 2 wt.% the specified current start, suitable for spraying.

1. Pharmaceutical composition for transdermal administration, characterized in that it contains an active principle; the promoter percutaneous absorption of the applicable beginning in to the operating start, and the promoter percutaneous absorption and quickly evaporate upon contact with the skin, and the promoter percutaneous absorption selected from a complex ester of aliphatic fatty acids, soluble in nonaqueous physiologically acceptable solvent of General formula I

< / BR>
in which R denotes a branched or linear alkylenes or alkyl group, a C2- C17possibly substituted by hydroxyl, carboxyl or allochrony C1- C4;

R1means a branched or linear alkyl group, a C3- C8possibly substituted by one or two hydroxyl groups, or R1means the group-CH2-CH2-O-(CH2)2-O-CH2-CH3and esters of aliphatic fatty acids containing at least 10 carbon atoms and not more than 2 hydroxyl groups;

aliphatic fatty alcohol, soluble in nonaqueous physiologically acceptable solvent of General formula II

R2-OH,

in which R2means alkyl group, a C10- C20.

2. The pharmaceutical composition under item 1, characterized in that it contains wasalways polymer matrix, soluble in nonaqueous physiologically acceptable solvent, the LASS="ptx2">

3. The pharmaceutical composition according to p. 2, characterized in that the polymer vasilevousa matrix is up to 6% by weight of the composition.

4. The pharmaceutical composition according to p. 2, characterized in that the polymer matrix is 1 to 5% by weight of the composition.

5. The pharmaceutical composition according to one of paragraphs.1 to 4, characterized in that the active principle is 0.1 - 20% by weight of the composition.

6. The pharmaceutical composition according to one of paragraphs.1 to 5, characterized in that the promoter percutaneous absorption is 15 - 25% by weight of the composition.

7. The pharmaceutical composition according to one of paragraphs.1 - 6, characterized in that the nonaqueous physiologically acceptable solvent is 44 - 84,9% by weight of the composition.

8. The pharmaceutical composition according to one of paragraphs.2 to 7, characterized in that vasilevousa polymer matrix is a polymer or copolymer of cellulose, soluble in nonaqueous physiologically acceptable solvent.

9. The pharmaceutical composition according to p. 8, characterized in that the polymer or copolymer of cellulose is ethylcellulose, butylacetat cellulose, propionate cellulose or vaccinated or unvaccinated hydroxypropylmethylcellulose is ethylcellulose.

11. The pharmaceutical composition according to one of paragraphs.1 to 10, characterized in that the active substance is soluble in non-aqueous, physiologically acceptable solvent and selected from the following groups: bronchodilator agent, diuretic, antibacterial, anti-acne, analgesic or sedative, psychoactive drug, anxiolytic agent, a hormone, androgenic steroid estrogenic steroid, progestational steroid, thyroid hormone, febrifuge, narcotic, or other analgesic agent, an agent for lowering blood sugar, antispasmodic agent, protivotumanki tool, an antimalarial drug, beta-blocking agent, anti-arthritis agent, non-steroidal anti-inflammatory agent, tool against osteoporosis remedy for skin whitening, vasodilator agent, anti-hypertension, anti-Parkinson, anti-migraine, birth control agent, antiulcer agent, an anti-cancer agent, nutrient additive.

12. The pharmaceutical composition according to one of paragraphs.1 - 11, characterized in that the active principle selected the lots.

13. The pharmaceutical composition according to p. 12, wherein the estradiol is contained in the amount of 0.5 - 6% by weight of the composition.

14. The pharmaceutical composition according to p. 13, wherein the estradiol is contained in the amount of 1 - 2% by weight of the composition.

15. The pharmaceutical composition according to one of paragraphs.1 - 11, characterized in that it contains a mixture of active principles, formed progestational and estrogenic steroids.

16. The pharmaceutical composition according to one of paragraphs.1 - 15, characterized in that R1means ISO-propyl, 2-ethyl-hexoloy or 1,2-hydroxyethyloxy group.

17. The pharmaceutical composition under item 1, characterized in that the promoter percutaneous absorption selected from 2-ethylhexyl-2-ethylhexanoate, isopropylmyristate, myristate of monoethylene ether of diethylene glycol, isopropylpalmitate, 2-oxidational, 2-ethylhexyl-undecylenate, 2-ethylhexyl-succinate, 2-ethylhexyl-12-hydroxystearate, 2-ethylhexyl-12-acetoxystyrene, isostearate glycerin, vexillata.

18. The pharmaceutical composition under item 1 or 16, characterized in that the promoter percutaneous absorption is 2-ethylhexyl-2-ethylhexanoate.

19. Pharmaceutical composizione with a boiling point below 100oC at atmospheric pressure.

20. The pharmaceutical composition according to p. 19, characterized in that the compound with a boiling point below 100oWith is dichloromethane, ethanol, isopropanol or ethyl acetate.

21. The pharmaceutical composition according to p. 19, characterized in that the physiologically acceptable solvent is ethanol.

22. The pharmaceutical composition according to paragraphs.1 and 2, characterized in that the polymer or copolymer of cellulose is ethylcellulose, the effective agent is estradiol, the promoter percutaneous absorption is 2-ethylhexyl-2-ethylhexanoate, physiologically acceptable solvent is ethanol.

23. The pharmaceutical composition according to p. 22, characterized in that it contains 3% ethyl cellulose, 2% estradiol, 20% 2-ethylhexyl-2-ethylhexanoate, 75% ethanol.

24. The pharmaceutical composition according to paragraphs.1 and 2, characterized in that it contains 5% ethyl cellulose, 2% estradiol, 20% 2-ethylhexyl-2-ethylhexanoate, 73% of ethanol.

25. The pharmaceutical composition according to paragraphs.1 and 2, characterized in that it contains 5% ethyl cellulose, 1% of estradiol, 20% 2-ethylhexyl-2-ethylhexanoate, 74% ethanol.

26. The pharmaceutical composition according to paragraphs.1 and 2 distinguish the 27. Composition according to one of paragraphs.1 to 26, characterized in that it is intended for application by direct deposition without the use of compressed or liquefied gas-propellant.

28. Composition according to one of paragraphs.1 to 27, characterized in that it is applied on the skin area 10 - 40 cm2.

29. Matrix for transdermal pharmaceutical composition, characterized in that it contains a polymer matrix to vysalivaniya the beginning of the current, capable of forming a soft film after drying and selected from polymers and copolymers of cellulose; the promoter percutaneous absorption of the applicable beginning in the amount of 15 to 30% by weight of the composition; nonaqueous physiologically acceptable solvent capable of dissolving visaliayou matrix, and the promoter percutaneous absorption and quickly evaporate upon contact with the skin, and the promoter percutaneous absorption selected from a complex ester of aliphatic fatty acids, soluble in nonaqueous physiologically acceptable solvent of General formula

< / BR>
in which R denotes a linear or branched alkyl or alkilinity group C2- C17possibly substituted by hydroxyl, carboxyl or allochrony C1- C4;

R1means the group-CH2-CH2-O-(CH2)2-O-CH2-CH3and esters of aliphatic fatty acids containing at least 10 carbon atoms and not more than 2 hydroxyl groups; aliphatic fatty alcohol, soluble in non-aqueous physiological acceptable solvent, the General formula

R2-OH,

in which R2means alkyl group, a C10- C20.

30. Matrix for the pharmaceutical composition according to p. 29, characterized in that the polymer or copolymer of cellulose is ethylcellulose, butylacetat cellulose, propionate cellulose or vaccinated or unvaccinated hypromellose.

31. The matrix for a pharmaceutical composition for p. 30, characterized in that the polymer or copolymer of cellulose is ethylcellulose.

32. Matrix for the pharmaceutical composition according to one of paragraphs.29 to 31, characterized in that the promoter percutaneous absorption selected from 2-ethylhexyl-2-ethylhexanoate, isopropylmyristate, myristate of monoethylene ether of diethylene glycol, isopropylpalmitate, 2-oxidational, 2-ethylhexyl-undecylenate, 2-ethylhexyl-succinate, 2-ethylhexyl-12-hydroxystearate, 2-ethylhexyl-12-acetoxystyrene is the rpm die, the promoter percutaneous absorption is 2-ethylhexyl-2-ethylhexanoate.

34. The matrix for a pharmaceutical composition for PP.29 to 33, characterized in that the nonaqueous physiologically acceptable solvent is a compound with a boiling point below 100oC at atmospheric pressure.

35. The matrix for a pharmaceutical composition for p. 34, characterized in that the compound with a boiling point below 100oWith is dichloromethane, ethanol, isopropanol or ethyl acetate.

36. The matrix for a pharmaceutical composition for p. 34, characterized in that the compound with a boiling point below 100oIs ethanol.

37. Matrix for the pharmaceutical composition according to one of paragraphs.29 to 36, characterized in that the specified pharmaceutical compositions containing the active principle, vasilevousa matrix is 0 to 6%, the promoter percutaneous absorption 15 - 30% and nonaqueous physiologically acceptable solvent 44 - 84,9%, and these values are expressed in mass% relative to the finished pharmaceutical compositions.

 

Same patents:

The invention relates to medicine, namely the new system for the percutaneous introduction of at least two active principles, consisting at least of two combined funds
The invention relates to medicine, namely to ophthalmology, and is intended for surgical strengthen the sclera with progressive myopia, and scleroplastic operations in other pathological conditions of the eye

The invention relates to medicine
The invention relates to the field of medicine and concerns of drugs used in dentistry for the treatment of oral cavity and gums

The invention relates to the transdermal administration of drugs
The invention relates to the field of pharmaceutical technology

The invention relates to medicine and relates to a medicinal product "Oil of scaninavia", which is anti-inflammatory and antimicrobial agent and is applied topically for the treatment of various locally occurring inflammatory processes

The invention relates to a transdermal therapeutic system for the controlled delivery of estradiol or its pharmaceutically acceptable derivatives individually or in combination with gestagens, as levonorgestrel, in the skin of a human or animal, its application and how you can get
Yellow card // 2125855
The invention relates to the medical industry, for the production of irritating and distracting medium - mustard, and can be used for the preparation of dosage forms in the form of bags of cells

The invention relates to medicine, in particular to pulmonology

The invention relates to a sulphamate derivatives derivatives of 1,3,5(10)-estratriene General formula (I), where R1- COR3, -COOR4, -CONR5R6, -SO2R4or-SO2NR5R6where R3and R4independently C1- C5alkyl, C3- C6cycloalkyl or phenyl, R5and R6independently C1- C5alkyl; R2is a hydrogen atom or a C1- C5alkyl; R7and R8independently a hydrogen atom or a C1- C5alkoxygroup; R9and R10is a hydrogen atom or together a methylene group; R11- R13independently a hydrogen atom or hydroxyl group, optionally esterified physiologically acceptable inorganic or organic acids, or R12and R13quinil to 5 carbon atoms and R8, R11and R12independently located in theor-position

The invention relates to 17-deformation-estratriene, to a method for their production and to their use for pharmaceutical products (medicines)

Hypotensive agent // 2142802
The invention relates to medicine, primarily to cardiology

The invention relates to a transdermal therapeutic system for the controlled delivery of estradiol or its pharmaceutically acceptable derivatives individually or in combination with gestagens, as levonorgestrel, in the skin of a human or animal, its application and how you can get

acyl(hydr)oxosteroid with antitumor activity" target="_blank">

The invention relates to the chemistry of steroids and related specifically to 3-OR-di-(2-chloroethyl)aminecontaining 11-acyl(HYDR)oxosteroid with antitumor activity General formula (I), where R = COCH2C6H4N(CH2CH2Cl)2; R1=-OCOCH3+-CCH;-OCOC2H5+-H; R2= H, OCOH, COCH3

FIELD: organic chemistry, steroids, pharmacy.

SUBSTANCE: invention describes unsaturated 14,15-cyclopropanoandrostanes of the general formula (I):

wherein R1 means hydrogen atom (H), hydroxy-group (OH); R2 means hydroxy-group (OH), hydrogen atom (H); R3 means hydrogen atom (H), (C1-C10)-alkyl at α- or β-position; R4 means halogen atom (F, Cl, Br) or pseudohalogen group (azide, rhodanide), hydroxy-group (OH), perfluoroalkyl; R5 means (C1-C4)-alkyl; if double bond is at 1,2-position then R4 can mean hydrogen atom (H). Also, invention relates to a method for preparing these compounds and pharmaceutical compositions containing these compounds. Compounds of the formula (I) are compounds eliciting gestagenic and/or androgenic effect.

EFFECT: improved preparing method, valuable medicinal properties of compounds.

11 cl, 1 tbl, 9 ex

Up!