RU2649809C2 - Liquid homogeneous phase for transdermal pharmaceutical compositions - Google Patents

Abstract

FIELD: veterinary medicine.

SUBSTANCE: liquid homogeneous phase for transdermal pharmaceutical compositions is described that provides absorption of physiologically active substances through the animal skin in the absence of irritant effect, has anti-mucus properties and has a pH value in the range of 4 to 6. The phase consists of a low-viscosity mixture of ether and amide solvent and a high-viscosity mixture of penetrants. The phase can be used for delivery of local and systemic physiologically active agents to the mammalian organism.

EFFECT: convenience in storage and use under production conditions.

5 cl, 6 tbl, 38 ex

Description

FIELD OF THE INVENTION

The invention relates to the field of veterinary medicine, namely to the development of a liquid homogeneous phase for transdermal pharmaceutical compositions intended for transporting biologically active components of these compositions through the skin. In particular, the present invention provides an improved version of such “penetration enhancers” of biologically active compounds, since it does not cause an irritating effect, has a pH value of 4 to 6, and has organoleptic and physico-chemical properties that prevent animal licking. The proposed phase can be used to deliver local and systemic physiologically active agents to the mammal.

State of the art

In the early 70s of the XX century, the concept of prescribing drugs through the skin was first seriously advanced to achieve local or systemic effects. Since then, intensive research has been carried out in this area.

The transdermal drug delivery route provides several advantages over traditional routes. For example, a medicine can be delivered to desired tissues directly through adjacent areas of the skin. The transdermal route of drug delivery allows for slow, controlled release of the drug into systemic circulation, which creates a constant level of concentration of active substances in the bloodstream that is close to the minimum therapeutic level. Many drugs are difficult to deliver by traditional routes of administration; the percutaneous route may be a more effective way to achieve better bioavailability of these agents. The transdermal route of administration of drugs has the advantage that transdermal administration of drugs can be easily stopped if undesirable side effects occur during therapy. The use of transdermal methods of drug delivery allows avoiding drug interaction with food, possible side effects from the gastrointestinal tract (GIT) and the possibility of inactivation of the active substance during primary metabolism in the gastrointestinal tract.

Despite the advantages noted above, the number of transdermal compositions is limited. They cannot be used with many polar medicinal substances, as they penetrate the skin too slowly. This property is crucial since most drugs are polar compounds. In addition, many drugs cause a reaction and / or irritation to the skin at the point of use.

To increase the penetration rate of polar drugs through the skin, several methods are used: increase the concentration of the drug, use physical methods (for example, electrophoresis), use chemical compounds to increase the permeability of the separation membrane (“penetration enhancers” of biologically active substances (BAS)). The latter method is more practical since it is more convenient and efficient.

In the past two decades, a large number of compounds have been studied in terms of their effectiveness in increasing the rate of penetration of drugs through the skin. Classical examples of recognized active "penetration enhancers" are proton-acceptor solvents, in particular dimethyl sulfoxide (DMSO) and dimethylacetamide (DMAA). In addition, 2-pyrrolidone, N, N-diethyl-m-toluamide (DETA), 1-dodecylazacycloheptan-2-one, N, N-dimethylformamide, N-methyl-2-pyrrolidone and calcium thioglycolate are described as effective enhancers. In patents US 4980378, publ. 12/25/1990 and US 5082866, publ. 01/21/1992 a group of biodegradable absorption enhancers, which are N, N-disubstituted aminoacetates, is given. Biodegradable absorption enhancers can be used with the most polar medicinal substances, in addition, they do not cause a reaction and / or irritation to the skin at the place of their use.

Most often, dimethyl sulfoxide (DMSO), an aprotic bipolar solvent, is used as a transdermal agent. DMSO has anti-inflammatory, decongestant and local analgesic effects [Mashkovsky M.D. Medicines A manual for doctors - M .: New wave, 2012, S. 186-187]. DMSO (from 50% and more) penetrates biological membranes, including through the skin, contributing to a better and deeper penetration into the tissues of drugs used simultaneously with it. In [Rama B., Shantha A. Chemical penetration enhancers for enhance transdermal delivery of methotrexate: formulation, in vitro, ex vivo and in vivo characterization // Int. J. Pharm. Bio Sci, 2012, V. 3, Iss. 4, P. 36-47] describes the creation and study of in vivo and in vitro transdermal pharmaceutical compositions of methotrexate based on TWIN-80, Span-80, DMSO and isopropyl myristate. High penetrating ability of DMSO is noted in comparison with other agents (the best values are C _max , T _max , T _1/2 ).

With the above advantages, DMSO also has a number of significant drawbacks, such as unpleasant odor, itching and burning sensation at the site of application of the drug, the possibility of skin hyperemia, temporary appearance of garlic odor from the mouth (due to the presence of DMSO metabolite), cases of development of urticaria and Quincke's edema are possible In addition, it inhibits endogenous respiration, reduces tissue oxygenation. Very often the effect of hair bleaching occurs when using transdermal compositions based on DMSO, which is unacceptable when used in exhibition animals.

[Wathoni N., Pamudji J.S., Darijanto S. Effect of iontophoresis and penetration enhancers on the in vitro diffusion of a piroxicam gel // International Journal of Pharmacy and Pharmaceutical Sciences, 2012, V. 4, Iss. 4, P 215-218], a comparative study of the penetrating ability of gels was carried out with the content of DMSO (5%), TWIN 80 (5%), ethyl acetate (5%), ethanol (5%) and without penetrant for transdermal transfer of piroxicam. It was shown that gels containing DMSO, although they were 5 times more effective than gels that did not contain penetrants, were not the best choice for creating a transdermal composition. The maximum transfer rates showed compositions with a content of 5% ethanol and 5% ethyl acetate.

Titanogels are known as penetrants, however, they are inaccessible, have uncomfortable physicochemical properties for use as penetrants in veterinary medicine, in particular, they have high viscosity creating known problems when applying transdermal compositions based on them to the skin. The well-known titanium penetrant - a complex of tetracoptan hydroxotetrakis (hydroxy-3,4-dihydroxypropyl) -titanium with decane-1,2,3-trihydroxypropane - is non-toxic, exhibits high transdermal activity with respect to some pharmacologically active compounds [RU 1838318, publ. 08/30/1993]. Known silicon glycerates and glycerohydrogels based on them, with high transdermal activity [RU 2255939, publ. 07/10/2005; Khonina T.G., Chupakhin O.N., et al. Synthesis and biological activity of organosilicon titanium glycerohydrogels // Chem. Journal, 2009, Volume 43, No. 2, S. 26-32.]. However, the disadvantage of such silica gels is their low availability, lack of industrial production, poor physicochemical properties (for example, high viscosity), and the difficulty of applying compositions based on them to the skin. In addition, silica gels can have a stimulating effect on the growth of the coat of an animal [Orlov A.D. Shungite is a stone of pure water. - M .: Dilya, 2004], which is unacceptable when using drugs in exhibition animals.

Amide compounds also showed good penetrating ability. For example, N-methyl-2-pyrrolidone, which is a good solvent, miscible with water and most organic solvents [Abolghasem Jouyban, Mohammad A.A. Fakhree, and Ali Shayanfar Review of Pharmaceutical Applications of N-Methyl-2-Pyrrolidone // J Pharm Pharmaceut Sc 2010 Volume 13, Issue 4, P. 524-535]. In addition, chronic use of N-methyl-2-pyrrolidone has no toxic and mutagenic effects on animals [David A. Wells, Harvey F. Thomas, and George A. Digenis Mutagenicity and cytotoxicity of n-methyl-2-pyrrolidinone and 4 - (methylamino) butanoic acid in the Salmonella / microsome assay // Journal of Applied Toxicology 1988 Volume 8, Issue 2, P. 135-139]. Higher penetrating properties has 3-hydroxy-N-methyl-2-pyrrolidone [US 5032402, publ. 07/16/1991].

However, with a large number of advantages of amide penetrants, they also have disadvantages, such as imperfect absorption, frequent irritation of the skin, and high viscosity of the resulting compositions. In addition, amide penetrants containing an ester group are often unstable during storage, and may exhibit cardiotoxicity during systemic absorption.

Close to the claimed invention is a composition proposed in patent RU 2535095, publ. 12/10/2014. The proposed composition for transdermal administration of drugs into humans and animals consists of a solution of one or more drugs in a mixture of at least two solvents, one of which is N, N-dialkylamide of lower carboxylic acid or N-alkylpyrrolidone or a mixture of N, N α-dialkylamides and N-alkylpyrrolidones, and the second solvent is at least one monoterpen or one monoterpenoid or a mixture thereof, the volume ratio of the first and second solvent being t about 1/99 to 99/1. As active substances in the formula, emergency care products are provided that act on the central or peripheral nervous system, cardiovascular system, excretory system, drugs that affect metabolism, the immune system, antimicrobial, antiparasitic and antiviral agents. However, in the patent formula does not indicate specific solvents. In the patent disclosure, as examples of N, N-dialkylamides of lower carboxylic acids, N, N-dimethylacetamide, N, N-dimethylamides of formic, propionic acids, or N, N-diethylamides of formic, acetic, or propionic acids, or N-ethylpyrrolidone are provided; and the following compounds are given as monoterpenes: (+) - limonene, terpineol, menton, carvone, pinene, camphor, verbenol, verbena, verbanone, cineol, turpentine containing up to 78% terpenes and terpenoids, or eucalyptus oil containing at least 60 % terpenoids of 1,8-cineole, 1,8-epoxy-p-menthane and 1,4-cineole. However, monoterpenes (especially the proposed turpentine) have an irritating effect on the skin and a strong odor unacceptable to animals [https://ru.wikipedia.org/wiki/ Turpentine]. Irritation of the skin and the development of inflammation undoubtedly enhances the transdermal absorption of biologically active substances, however, ulcers resulting from ulcers, baldness (hair loss), and scars make such transdermal forms unacceptable.

Closest to the claimed invention is a patent of the company Merial Limited - RU 2497364, publ. 11/10/2013. The patent proposes a composition for a liquid external composition of veterinary use for the treatment and prevention of parasitic infections. As a transdermal composition, a mixture is proposed that ensures the solubility, stability and bioavailability of the active substance and consists of a glycol ether and a stability enhancer. In the claims proposed glycols selected from the group consisting of diethylene glycol monoethyl ether imonometilovogo ether, dipropylene glycol monoethyl ether ethylene glycol, ethylene glycol monomethyl ether, propylene glycol monomethyl ether, dibutyl ether, ethylene glycol monohexyl ether, ethylene glycol monophenyl ether, ethylene glycol diethyl ether, diethylene glycol monobutyl diethylene glycol ether , diethylene glycol dibutyl ether and diethylene glycol monohexyl ether.

However, the present invention has the following disadvantages. In the formula, the choice of the active substance in the proposed transdermal composition is limited, namely, clorsulon and macrocyclic lactone - ivermectin and eprinomectin. In addition, the concentration of the active substance is not indicated in the formula. In a detailed study of this patent, it was found that the maximum amount of clorsulon in the composition can be 20%, and avermectin - 0.5%. Thus, the proposed transdermal composition has a low solubility of macrocyclic lactones. The formula also does not mention co-solvents and surface-active substances (surfactants), widely offered in the description of the patent. Also, the pH level of the composition is not indicated, which is an essential parameter, because if the pH of the composition is incorrectly selected, the animal will experience discomfort and tend to comb or lick off the drug, providing an oral intake of high doses of the active substance.

It should be noted that under production conditions it is most attractive to have a universal phase from a limited number of components and, by varying the ratio of these components, to obtain transdermal medicinal compositions for various biologically active substances.

The aim of the invention is the search for the most universal phase for transdermal delivery of local and systemic physiologically active agents into the body of a mammal, while it (phase) must satisfy the following requirements:

1) provide effective absorption through the skin of biologically active substances;

2) should not have irritating properties, including with repeated use;

3) should not show disturbances in the condition of the coat - changes in color, tarnishing, loss, change in growth rate;

4) should not form a solid phase on the skin and coat after evaporation and absorption of the liquid components of the composition;

5) should have a moderate (for the forms of "Spot-on") or small (for sprays) viscosity, which is also important when packaging in the primary packaging;

6) should have a pH in the range from 4 to 6, which reduces the likelihood of skin disorders, and ensures storage stability of most biologically active components of the composition;

7) must not have an odor unpleasant for the animal and man;

8) must have properties that exclude the licking of animals of the skin and coat, because otherwise, unacceptably high doses of biologically active substances may be ingested orally (may cause intoxication);

9) it should not cause discomfort on the skin of the animal at the time of application and until the absorption of biologically active substances is completed, which reduces the likelihood of combing and licking the area of application of the drug to animals.

Disclosure of invention

In veterinary pharmaceuticals, especially in the treatment of small domestic animals (cats, dogs), transdermal forms of drugs are of great importance, because they are convenient to use, especially for cats, for which the use of oral forms is very difficult. The most interesting are anthelmintic drugs. In these preparations, one of the macrocyclic lactones — modified avermectins (ivermectin, eprinomectin, moxidectin, selamectin, etc.) as an antinematode component, and praziquantel as a cystocide are usually used as a BAS. Purely technological difficulties in this case are to obtain the necessary solubility of the biologically active substances in the composition, while ensuring sufficient storage stability, which in the case of macrocyclic lactones is not simply due to their easy hydrolyzability. Therefore, an oxygen-containing heterocyclic solvent of the ketal class is often used (for example, 1,2-isopropylidenglycerol, etc.), which dissolves both macrolactone, praziquantel, and penetrant, most often dimethyl sulfoxide (DMSO) in sufficient quantities. However, in an anhydrous environment, dimethyl sulfoxide often exhibits unacceptable effects - it changes the color of the coat in animals, causes skin irritation and hair loss. This forced us to replace dimethyl sulfoxide with N, N-diethyltoluamide - a suitable amide solvent, the penetrant properties of which are described in [RU 2165265, publ. 04/20/2001]. Moreover, even better pharmacokinetic parameters were obtained than in the case of DMSO. However, in both cases, the animals actively combed the site of application, tried to lick (which, as indicated, is very dangerous due to the possibility of intoxication with the oral intake of biologically active substances). It was found that in both cases, after absorption and evaporation of the liquid phase, a small coating of biologically active substances remained, which probably caused discomfort in the animals. In addition, some quantities of biologically active substances used in this case were not absorbed and lost. It unexpectedly turned out that a small addition of some nonionic surfactants eliminates the described effect and significantly increases the total absorption of biologically active substances, while providing a more favorable (“stretched”) pharmacokinetic curve, which reduces the likelihood of toxic effects. In addition, the stability of biologically active substances during storage of such compositions has increased. It was also unexpected to completely block the licking even in the first moments after application, which is probably due both to the favorable effect of the nonionic surfactants taken (meglumine stearylamide, polyoxyethylated tocopherol, polyoxyethylated lanolin, panthenol and their mixtures forming low-melting eutectic phases), as well as to unpleasant for an animal with organoleptic properties (bitter taste).

Especially effective is the use of ethoxylated tocopherol and ethoxylated lanolin, as favorably affects the skin of the animal at the site of application. The use of sphingosine ((2S, 3R) -2-amino-4-octadecene-1,3-diol) increases the moisture content of the dermis and reduces the degree of interaction of dermal cells, which for polar biologically active substances significantly increases transdermal absorption, but may not be very significant for biologically active substances low-polar type. 3- (octadecyloxy) -1,2-propanediol (batilol), being a strong nonionic surfactant, has a useful antimicrobial effect and, according to published data, it stimulates the metabolism and activity of immune cells, which can stimulate the transport of certain biologically active substances from subcutaneous tissue by phagocytes to critical organs (to for example, macrolide antibiotics). The best results for increasing transdermal absorption were obtained using a mixture of nonionic surfactants (hereinafter, penetrant mixtures).

The high efficiency of the use of alkyl glucoamides turned out to be unexpected, which allows to solve with maximum effect both problems of transdermal pharmaceutical compositions (TFA) of veterinary use - the complete absence of reaction on the part of the animal when the composition was applied to the skin and the exceptional stability of all studied surfactants, which could not be achieved using other nonionic surfactants types (see example 10-24). However, it was noted that with a decrease in the number of alkyl glucoamide less than 1 mass. % in a mixture of penetrants, the stability of the obtained compositions is sharply reduced (see example 9).

It should be noted that compounds of this type are not available on the market, but are easily obtained by the chemical scheme: by the interaction of aldose with N-alkylamine to form Schiff base, which is hydrogenated in the presence of Raney nickel to aminopolyol, followed by amidation of carboxylic acids with methyl esters [Lange K.R. Surfactants: synthesis, properties, analysis, application - St. Petersburg: Profession, 2007]. The cost of the obtained compounds is low. As a special case, N-methyl-N- (1,2,3,4,5-pentahydroxyhexyl) acylamides (where acyl is the residue of an aliphatic carboxylic acid with different lengths of an aliphatic radical) can be obtained from commercially available and inexpensive meglumine. Derivatives of natural sugars can be used as alkyl glucoamides: N-methyl-N- (1,2R, 3R, 4R, 5S-pentahydroxyhexyl)-octadecanamide, and / or N-ethyl-N- (1,2R, 3R, 4R, 5S-pentahydroxyhexyl) -octadecanamide, and / or N-butyl-N- (1,2R, 3R, 4R, 5S-pentahydroxyhexyl) -octadecanamide, and / or N-methyl-N- (1,2R, 3R, 4R, 5S-pentahydroxyhexyl) -decanamide, and / or N-ethyl-N- (1,2R, 3R, 4R, 5S-pentahydroxyhexyl) -decanamide, and / or N-butyl-N- (1,2R, 3R, 4R, 5S-pentahydroxyhexyl) -decanamide, and / or N-methyl-N- (1,2R, 3R, 4R, 5S-pentahydroxyhexyl) -hexanamide, and / or N-ethyl-N- (1,2R, 3R, 4R, 5S-pentahydroxyhexyl) hexanamide, and / or N-butyl-N- (1,2R, 3 R, 4R, 5S-pentahydroxyhexyl) hexanamide, and / or N-methyl-N- (1,2R, 3R, 4R, 5S-pentahydroxyhexyl) nonanamide, and / or N-ethyl-N- (1,2R, 3R, 4R, 5S-pentahydroxyhexyl) nonanamide, and / or N-butyl-N- (1,2R, 3R, 4R, 5S-pentahydroxyhexyl) nonanamide, and / or N-methyl-N- (1,2R, 3R, 4R, 5S-pentahydroxyhexyl) octanamide, and / or N-ethyl-N- (1,2R, 3R, 4R, 5S-pentahydroxyhexyl) octanamide, and / or N-butyl N- (1,2R, 3R, 4R, 5S-pentahydroxyhexyl) octanamide, and / or N-methyl-N- (1,2R, 3R, 4R, 5S-pentahydroxyhexyl) -undecanamide, and / or N-ethyl-N- (1,2R, 3R, 4R, 5S-pentahydroxyhexyl) -undecanamide, and / or N-butyl-N- (1,2R, 3R, 4R, 5S-pentahydroxyhexyl) -undecanamide, and / or N-methyl-N - (1,2R, 3R, 4R, 5S-pentahydroxyhexyl) dodecanamide, and / or N-ethyl-N- (1,2R, 3R, 4R, 5S-pentahydroxyhexyl) dodecanamide, and / or N-butyl-N - (1,2R, 3R, 4R, 5S-pentahydroxyhexyl) dodecanamide, and / or N-methyl-N- (1,2R, 3R, 4R, 5S-pentahydroxyhexyl) -tetradecanamide, and / or N-ethyl-N - (1,2R, 3R, 4R, 5S-pentahydroxyhexyl) -tetradecanamide, and / or N-butyl-N- (1,2R, 3R, 4R, 5S-pentahydroxyhexyl) -tetradecanamide, and / yl and N-methyl- N- (1,2R, 3R, 4R, 5S-pentahydroxyhexyl) hexadecanamide, and / or N-ethyl-N- (1,2R, 3R, 4R, 5S-pentahydroxyhexyl) hexadecanamide, and / or N-butyl- N- (1,2R, 3R, 4R, 5S-pentahydroxyhexyl) hexadecanamide, and / or N-methyl-N- (1,2R, 3R, 4S-tetrahydro xipentyl) octanamide and / or N-ethyl-N- (1,2R, 3R, 4S-tetrahydroxypentyl) octanamide and / or N-butyl N- (1,2R, 3R, 4S-tetrahydroxypentyl) octanamide and / or N-methyl-N- (1,2R, 3R, 4S-tetrahydroxypentyl) -undecanamide, and / or N-ethyl-N- (1,2R, 3R, 4S-tetrahydroxypentyl) -undecanamide, and / or N-butyl-N- (1,2R, 3R, 4S-tetrahydroxypentyl) -undecanamide, and / or N-methyl-N- (1,2R, 3R, 4S-tetrahydroxypentyl) -octadecanamide, and / or N-ethyl- N- (1,2R, 3R, 4S-tetrahydroxypentyl) -octadecanamide, and / or N-butyl-N- (1,2R, 3R, 4S-tetrahydroxypentyl) -octadecanamide, and / yl and N-methyl-N- ( 1,2R, 3R, 4S-tetrahydroxypentyl) -decanamide, and / or N-ethyl-N- (1,2R, 3R, 4S-tetrahydro sipentyl) -decanamide and / or N-butyl-N- (1,2R, 3R, 4S-tetrahydroxypentyl) -decanamide and / or N-methyl-N- (1,2R, 3R, 4S-tetrahydroxypentyl) -hexanamide and / or N-ethyl-N- (1,2R, 3R, 4S-tetrahydroxypentyl) hexanamide, and / or N-butyl N- (1,2R, 3R, 4S-tetrahydroxypentyl) hexanamide, and / or N-methyl-N- (1,2R, 3R, 4S-tetrahydroxypentyl) dodecanamide and / or N-ethyl-N- (1,2R, 3R, 4S-tetrahydroxypentyl) dodecanamide and / or N-butyl N- (1,2R, 3R, 4S-tetrahydroxypentyl) dodecanamide and / or N-methyl-N- (1,2R, 3R, 4S-tetrahydroxypentyl) nonanamide and / or N-ethyl-N- (1 , 2R, 3R, 4S-tetrahydroxypentyl) nonanamide, and / or N-butyl-N- (1,2R, 3R, 4S-tetrahydroxypentyl) nonanamide and / or N-methyl-N- (1,2R, 3R, 4S-tetrahydroxypentyl) tetradecanamide and / or N-ethyl-N- (1,2R, 3R, 4S-tetrahydroxypentyl) tetradecanamide, and / or N-butyl-N- (1,2R, 3R, 4S-tetrahydroxypentyl) -tetradecanamide, and / or N-methyl-N- (1,2R, 3R, 4S-tetrahydroxypentyl) -hexadecanamide, and / or N- ethyl N- (1,2R, 3R, 4S-tetrahydroxypentyl) hexadecanamide, and / or N-butyl N- (1,2R, 3R, 4S-tetrahydroxypentyl) hexadecanamide, and / or N-methyl-N- (1,2R, 3S-trihydroxypentyl) -hexanamide, and / or N-ethyl-N- (1,2R, 3S-trihydroxypentyl) -hexanamide, and / or N-butyl-N- (1,2R, 3S-trihydroxypentyl ) -hexanamide and / or N-methyl-N- (1,2R, 3S-trihydroxypenti ) -undecanamide and / or N-ethyl-N- (1,2R, 3S-trihydroxypentyl) -undecanamide and / or N-butyl-N- (1,2R, 3S-trihydroxypentyl) -undecanamide and / or N -methyl-N- (1,2R, 3S-trihydroxypentyl) nonanamide, and / or N-ethyl-N- (1,2R, 3S-trihydroxypentyl) nonanamide, and / or N-butyl-N- (1, 2R, 3S-trihydroxypentyl) nonanamide, and / yl and N-methyl-N- (1,2R, 3S-trihydroxypentyl) octadecanamide, and / or N-ethyl-N- (1,2R, 3S-trihydroxypentyl) - octadecanamide and / or N-butyl-N- (1,2R, 3S-trihydroxypentyl) octadecanamide and / or N-methyl-N- (1,2R, 3S-trihydroxypentyl) decanamide and / or N-ethyl -N- (1,2R, 3S-trihydroxypentyl) -decanamide, and / or N-butyl-N- (1,2R, 3S-trihydride hydroxypentyl) decanamide and / or N-methyl-N- (1,2R, 3S-trihydroxypentyl) octanamide and / or N-ethyl-N- (1,2R, 3S-trihydroxypentyl) octanamide and / or N-butyl-N- (1,2R, 3S-trihydroxypentyl) octanamide, and / or N-methyl-N- (1,2R, 3S-trihydroxypentyl) dodecanamide, and / or N-ethyl-N- (1 , 2R, 3S-trihydroxypentyl) dodecanamide and / or N-butyl-N- (1,2R, 3S-trihydroxypentyl) dodecanamide and / or N-methyl-N- (1,2R, 3S-trihydroxypentyl) - tetradecanamide and / or N-ethyl-N- (1,2R, 3S-trihydroxypentyl) tetradecanamide and / or N-butyl N- (1,2R, 3S-trihydroxypentyl) tetradecanamide and / or N-methyl -N- (1,2R, 3S-trihydroxypentyl) hexadecanamide, and / or N- ethyl N- (1,2R, 3S-trihydroxypentyl) hexadecanamide, and / or N-butyl N- (1,2R, 3S-trihydroxypentyl) hexadecanamide, and / or N-methyl-N- (1,2R , 3S, 4S-tetrahydroxypentyl) octadecanamide and / or N-ethyl-N- (1,2R, 3S, 4S-tetrahydroxypentyl) octadecanamide and / or N-butyl N- (1,2R, 3S, 4S -tetrahydroxypentyl) -octadecanamide, and / or N-methyl-N- (1,2R, 3S, 4S-tetrahydroxypentyl) -octanamide, and / or N-ethyl-N- (1,2R, 3S, 4S-tetrahydroxypentyl) - octanamide and / or N-butyl-N- (1,2R, 3S, 4S-tetrahydroxypentyl) octanamide and / or N-methyl-N- (1,2R, 3S, 4S-tetrahydroxypentyl) undecanamide, and / or N-ethyl-N- (1,2R, 3S, 4S-tetrahydroxypentyl) -undecanamide, and / or N- butyl N- (1,2R, 3S, 4S-tetrahydroxypentyl) -undecanamide and / or N-methyl-N- (1,2R, 3S, 4S-tetrahydroxypentyl) nonanamide and / or N-ethyl-N- (1,2R, 3S, 4S-tetrahydroxypentyl) nonanamide and / or N-butyl-N- (1,2R, 3S, 4S-tetrahydroxypentyl) nonanamide and / or N-methyl-N- (1,2R , 3S, 4S-tetrahydroxypentyl) -tetradecanamide, and / or N-ethyl-N- (1,2R, 3S, 4S-tetrahydroxypentyl) -tetradecanamide, and / or N-butyl-N- (1,2R, 3S, 4S -tetrahydroxypentyl) -tetradecanamide, and / or N-methyl-N- (1,2R, 3S, 4S-tetrahydroxypentyl) -decanamide, and / or N-ethyl-N- (1,2R, 3S, 4S-tetrahydroxypentyl) - decanamide and / or N-butyl-N- (1,2R, 3S, 4S-tetrahydroxypentyl) -decanamide, and / or N-m ethyl N- (1,2R, 3S, 4S-tetrahydroxypentyl) hexanamide and / or N-ethyl-N- (1,2R, 3S, 4S-tetrahydroxypentyl) hexanamide and / or N-butyl N- (1,2R, 3S, 4S-tetrahydroxypentyl) hexanamide, and / or N-methyl-N- (1,2R, 3S, 4S-tetrahydroxypentyl) dodecanamide, and / or N-ethyl-N- (1,2R , 3S, 4S-tetrahydroxypentyl) dodecanamide, and / or N-butyl-N- (1,2R, 3S, 4S-tetrahydroxypentyl) dodecanamide, and / or N-methyl-N- (1,2R, 3S, 4S -tetrahydroxypentyl) hexadecanamide and / or N-ethyl-N- (1,2R, 3S, 4S-tetrahydroxypentyl) hexadecanamide and / or N-butyl N- (1,2R, 3S, 4S-tetrahydroxypentyl) - hexadecanamide and / or N-methyl-N- (1,2R, 3R, 4S, 5R-pentahydroxyhexyl) octanamide, and / or N-ethyl-N- (1,2R, 3R, 4S, 5R-pentahydroxyhexyl) octanamide, and / or N-butyl N- (1,2R, 3R, 4S, 5R-pentahydroxyhexyl) octanamide, and / or N-methyl-N- (1,2R, 3R, 4S, 5R-pentahydroxyhexyl) dodecanamide, and / or N-ethyl-N- (1,2R, 3R, 4S, 5R-pentahydroxyhexyl) dodecanamide, and / or N-butyl-N- (1,2R, 3R, 4S, 5R-pentahydroxyhexyl) dodecanamide and / or N-methyl-N- (1,2R, 3R, 4S, 5R-pentahydroxyhexyl) hexadecanamide, and / or N-ethyl-N- (1,2R, 3R, 4S, 5R-pentahydroxyhexyl) hexadecanamide, and / yl and N-butyl-N- (1,2R, 3R, 4S, 5R-pentahydroxyhexyl) hexadecanamide and / or N-methyl-N- (1,2R, 3R, 4S, 5R-pentahydroxyhexyl) octadecanamide and / or N-ethyl-N- (1,2R, 3R, 4S, 5R-pentagide Roxyhexyl) octadecanamide and / or N-butyl N- (1,2R, 3R, 4S, 5R-pentahydroxyhexyl) octadecanamide and / or N-methyl-N- (1,2R, 3R, 4S, 5R- pentahydroxyhexyl) -decanamide, and / or N-ethyl-N- (1,2R, 3R, 4S, 5R-pentahydroxyhexyl) -decanamide, and / or N-butyl-N- (1,2R, 3R, 4S, 5R- pentahydroxyhexyl) -decanamide, and / or N-methyl-N- (1,2R, 3R, 4S, 5R-pentahydroxyhexyl) -hexanamide, and / or N-ethyl-N- (1,2R, 3R, 4S, 5R- pentahydroxyhexyl) hexanamide, and / or N-butyl N- (1,2R, 3R, 4S, 5R-pentahydroxyhexyl) hexanamide, and / or N-methyl-N- (1,2R, 3R, 4S, 5R- pentahydroxyhexyl) nonanamide, and / or N-ethyl-N- (1,2R, 3R, 4S, 5R-pentahydroxyhexyl) nonanamide, and / or N-butyl-N- (1,2R, 3R, 4S, 5R- pentahydroxyhexyl) nonanamide, and / or N-methyl-N- (1,2R, 3R, 4S, 5R-pentahydroxyhexyl) -undecanamide, and / or N-ethyl-N- (1,2R, 3R, 4S, 5R- pentahydroxyhexyl) -undecanamide, and / or N-6utyl-N- (1,2R, 3R, 4S, 5R-pentahydroxyhexyl) -undecanamide, and / or N-methyl-N- (1,2R, 3R, 4S, 5R- pentahydroxyhexyl) -tetradecanamide, and / or N-ethyl-N- (1,2R, 3R, 4S, 5R-pentahydroxyhexyl) -tetradecanamide, and / or N-butyl-N- (1,2R, 3R, 4S, 5R- pentahydroxyhexyl) -tetradecanamide, and / or N-methyl-N- (1,2R, 3R, 4S, 5S-pentahydroxyhexyl) -hexanamide, and / or N-ethyl-N- (1,2R, 3R, 4S, 5S- pentahydroxyhexyl) hexanamide, and / or N-butyl N- (1,2R, 3R, 4S, 5S-pentahydroxyhexyl) hexanamide, and / or N-methyl-N- (1,2R, 3R, 4S, 5S-pentahydroxyhexyl) -undecanamide, and / or N-ethyl-N- (1,2R, 3R, 4S, 5S-pentahydroxyhexyl) -undecanamide, and / or N-butyl-N- (1,2R, 3R, 4S, 5S-pentahydroxyhexyl) -undecanamide, and / or N-methyl-N- (1,2R, 3R, 4S, 5S-pentahydroxyhexyl) -octadecanamide, and / or N-ethyl-N- (1,2R, 3R, 4S, 5S-pentahydroxyhexyl) -octadecanamide, and / or N-butyl-N- (1,2R, 3R, 4S, 5S-pentahydroxyhexyl) -octadecanamide, and / or N-methyl-N- (1,2R, 3R, 4S, 5S-pentahydroxyhexyl) decanamide, and / or N-ethyl-N- (1,2R, 3R, 4S, 5S-pentahydroxyhexyl) decanamide, and / or N-butyl-N- (1,2R, 3R, 4S, 5S-pentahydroxyhexyl) decanamide and / or N-methyl-N- (1,2R, 3R, 4S, 5S-pentahydroxy xyl) nononamide and / or N-ethyl-N- (1,2R, 3R, 4S, 5S-pentahydroxyhexyl) nonanamide and / or N-butyl-N- (1,2R, 3R, 4S, 5S- pentahydroxyhexyl) nonanamide and / or N-methyl-N- (1,2R, 3R, 4S, 5S-pentahydroxyhexyl) octanamide and / or N-ethyl-N- (1,2R, 3R, 4S, 5S- pentahydroxyhexyl) octanamide and / or N-butyl N- (1,2R, 3R, 4S, 5S-pentahydroxyhexyl) octanamide and / or N-methyl-N- (1,2R, 3R, 4S, 5S- pentahydroxyhexyl) dodecanamide and / or N-ethyl-N- (1,2R, 3R, 4S, 5S-pentahydroxyhexyl) dodecanamide and / or N-6utyl-N- (1,2R, 3R, 4S, 5S- pentahydroxyhexyl) dodecanamide, and / or N-methyl-N- (1,2R, 3R, 4S, 5S-pentahydroxyhexyl) tetradecanamide, and / or N-ethyl-N- (1,2R, 3R, 4S, 5S- pentagide roxyhexyl) -tetradecanamide, and / or N-butyl-N- (1,2R, 3R, 4S, 5S-pentahydroxyhexyl) -tetradecanamide, and / or N-methyl-N- (1,2R, 3R, 4S, 5S- pentahydroxyhexyl) hexadecanamide, and / or N-ethyl-N- (1,2R, 3R, 4S, 5S-pentahydroxyhexyl) hexadecanamide, and / or N-butyl-N- (1,2R, 3R, 4S, 5S- pentahydroxyhexyl) hexadecanamide, and / or N-methyl-N- (1,2R, 3S, 4S, 5R-pentahydroxyhexyl) hexanamide, and / or N-ethyl-N- (1,2R, 3S, 4S, 5R- pentahydroxyhexyl) hexanamide, and / or N-butyl N- (1,2R, 3S, 4S, 5R-pentahydroxyhexyl) hexanamide, and / or N-methyl-N- (1,2R, 3S, 4S, 5R- pentahydroxyhexyl) nonanamide, and / or N-ethyl-N- (1,2R, 3S, 4S, 5R-pentahydroxyhexyl) nonanamide, and / and and N-butyl-N- (1,2R, 3S, 4S, 5R-pentahydroxyhexyl) nonanamide, and / or N-methyl-N- (1,2R, 3S, 4S, 5R-pentahydroxyhexyl) -tetradecanamide, and / or N-ethyl-N- (1,2R, 3S, 4S, 5R-pentahydroxyhexyl) -tetradecanamide, and / or N-butyl-N- (1,2R, 3S, 4S, 5R-pentahydroxyhexyl) -tetradecanamide, and / or N-methyl-N- (1,2R, 3S, 4S, 5R-pentahydroxyhexyl) -hexadecanamide, and / or N-ethyl-N- (1,2R, 3S, 4S, 5R-pentahydroxyhexyl) -hexadecanamide, and / or N-butyl-N- (1,2R, 3S, 4S, 5R-pentahydroxyhexyl) hexadecanamide, and / or N-methyl-N- (1,2R, 3S, 4S, 5R-pentahydroxyhexyl) octadecanamide, and / or N-ethyl-N- (1,2R, 3S, 4S, 5R-pentahydroxyhexyl) octadecanamide, and / or N-butyl-N- (1,2R, 3S, 4S , 5R-pentahydroxyhexyl) -octadecanamide, and / or N-methyl-N- (1,2R, 3S, 4S, 5R-pentahydroxyhexyl) -decanamide, and / or N-ethyl-N- (1,2R, 3S, 4S , 5R-pentahydroxyhexyl) -decanamide, and / or N-butyl-N- (1,2R, 3S, 4S, 5R-pentahydroxyhexyl) -decanamide, and / or N-methyl-N- (1,2R, 3S, 4S , 5R-pentahydroxyhexyl) octanamide and / or N-ethyl-N- (1,2R, 3S, 4S, 5R-pentahydroxyhexyl) octanamide and / or N-butyl N- (1,2R, 3S, 4S , 5R-pentahydroxyhexyl) octanamide, and / or N-methyl-N- (1,2R, 3S, 4S, 5R-pentahydroxyhexyl) -undecanamide, and / or N-ethyl-N- (1,2R, 3S, 4S , 5R-pentahydroxyhexyl) -undecanamide, and / or N-butyl-N- (1,2R, 3S, 4S, 5R-pentahydroxyhexyl) -undecanamide, and / or N-methyl -N- (1,2R, 3S, 4S, 5R-pentahydroxyhexyl) dodecanamide, and / or N-ethyl-N- (1,2R, 3S, 4S, 5R-pentahydroxyhexyl) dodecanamide, and / or N-butyl -N- (1,2R, 3S, 4S, 5R-pentahydroxyhexyl) dodecanamide, and / or N-methyl-N- (1,2R, 3S, 4R-tetrahydroxypentyl) -hexanamide, and / or N-ethyl-N - (1,2R, 3S, 4R-tetrahydroxypentyl) -hexanamide, and / or N-butyl-N- (1,2R, 3S, 4R-tetrahydroxypentyl) -hexanamide, and / or N-methyl-N- (1, 2R, 3S, 4R-tetrahydroxypentyl) -undecanamide, and / or N-ethyl-N- (1,2R, 3S, 4R-tetrahydroxypentyl) -undecanamide, and / or N-butyl-N- (1,2R, 3S, 4R-tetrahydroxypentyl) -undecanamide, and / or N-methyl-N- (1,2R, 3S, 4R-tetrahydroxypentyl) hexadecanamide, and / or N-ethyl-N- (1,2R, 3S, 4R-tetrahydroxypentyl) hexadecanamide, and / or N-butyl N- (1,2R, 3S, 4R-tetrahydroxypentyl) hexadecanamide, and / or N-methyl- N- (1,2R, 3S, 4R-tetrahydroxypentyl) -octadecanamide, and / or N-ethyl-N- (1,2R, 3S, 4R-tetrahydroxypentyl) -octadecanamide, and / or N-butyl-N- (1 , 2R, 3S, 4R-tetrahydroxypentyl) -octadecanamide, and / or N-methyl-N- (1,2R, 3S, 4R-tetrahydroxypentyl) -decanamide, and / or N-ethyl-N- (1,2R, 3S , 4R-tetrahydroxypentyl) -decanamide, and / or N-butyl-N- (1,2R, 3S, 4R-tetrahydroxypentyl) -decanamide, and / or N-methyl-N- (1,2R, 3S, 4R-tetrahydroxypentyl ) -nonanamide, and / or N-ethyl-N- (1,2R, 3S, 4R-tetrahydroxypentyl) nonanamide, and / or N-butyl-N- (1,2R, 3S, 4R-tetrahydroxypentyl) nonanamide, and / or N-methyl-N- (1,2R, 3S, 4R-tetrahydroxypentyl) octanamide, and / or N-ethyl -N- (1,2R, 3S, 4R-tetrahydroxypentyl) octanamide and / or N-butyl-N- (1,2R, 3S, 4R-tetrahydroxypentyl) octanamide and / or N-methyl-N- ( 1,2R, 3S, 4R-tetrahydroxypentyl) dodecanamide and / or N-ethyl-N- (1,2R, 3S, 4R-tetrahydroxypentyl) dodecanamide and / or N-butyl N- (1,2R, 3S, 4R-tetrahydroxypentyl) dodecanamide and / or N-methyl-N- (1,2R, 3S, 4R-tetrahydroxypentyl) tetradecanamide and / or N-ethyl-N- (1,2R, 3S, 4R- tetrahydroxypentyl) -tetradecanamide, and / or N-butyl N- (1,2R, 3S, 4R-tetrahydroxypentyl) -tetradecans and / or other optical isomers and racemates.

Of these, the most convenient physicochemical properties and technology for producing N-methyl-N- (1,2R, 3R, 4R, 5S-pentahydroxyhexyl) -octadecanamide (meglumine stearylamide).

The chemically close N- (3-hydroxypropyl) -2R, 4-dihydroxy-3,3-dimethylbutanamide (D-panthenol) is also similar in effects to alkyl glucoamides, but it is much less convenient due to its very high hygroscopicity and high viscosity (alkyl glucoamides under ordinary solid solids); it can be used as part of TFA alone or, better, in a mixture with alkyl glucoamides. N- (3-hydroxypropyl) -2,4-dihydroxy-3,3-dimethylbutyramide (DL-panthenol) and / or N- (4-hydroxybutyl) -2R, 4-dihydroxy-3.3 can also be used. dimethylbutyramide and / or N- (2-hydroxyethyl) -2R, 4-dihydroxy-3,3-dimethylbutyramide.

Alkylglucoamides can be used without additional additives, as many biologically active substances (for example, avermectins) form non-crystallizing mixtures with them (see example 10, 11, 16). The limiting content of alkyl glucoamides is regulated by the permissible viscosity of the composition and generally depends on the type and amount of biologically active substances used for TFA.

Sometimes, to obtain a liquid at the skin temperature of the animal composition of alkyl glucoamide with the used BAS, additives of other nonionic surfactants are necessary, for example, polyoxyethylated and polyoxypropylated phenols, such as polyoxyethylated and / or polyoxypropylated ionol and / or polyoxyethylated and / or polyoxypropylated α-tocopherol and / or polyoxyethylated β-tocopherol and / or polyoxyethylated γ-tocopherol and / or alpha-tocopherol-polyethylene glycol-1000-succinate (TPGS), and / or oxyethylated vitamin A and / or OP-4 and / or OP-7 and / or OP-10 and / or OP-20 and / or polyoxyethylated 4-methyl-2,6-ditretbutylphenol and / or polyoxyethylated 2,4,6-tritrebutylphenol, and / or neonol AF 9-4, and / or neonol AF 9-6, and / or neonol AF 9-8, and / or neonol AF 9-9, and / or neonol AF 9 -10, and / or neonol AF 9-12, and / or neonol AFB-10, and / or neonol AFB-12.

The most preferred in this group is the use of polyoxyethylated α-, β-, γ-tocopherols and alpha-tocopherol-polyethylene glycol-1000-succinate (TPGS), which have a beneficial effect on the skin of the animal, and are also antioxidants.

Also, non-ionic surfactants can be used polyoxyethylated alcohols such as polyoxyethylated lanolin and / or syntanol OS-10 grade A (polyoxyethylated (20) -stearyl ether) and / or syntanol OS-10 grade B and / or syntanol ALM and / or syntanol DS (polyoxyethylated (9) -lauryl ether or Brij 35 or Ukanil), and / or polyoxyethylated cetylstearyl alcohol, and / or polysorbate-20 (PEG-20 sorbitol monolaurate), and / or polysorbate-60 ( PEG-20 sorbitol monostearate) and / or polysorbate-65 (PEG-20 sorbitol tristearate) and / or polysorbate 80 (PEG-20 sorbitol mono oleate) and / or polysorbate 85 (PEG-20 sorbitol sorbitol) and / or PEG-10 sorbitol laurate and / or PEG-4 sorbitol monolaurate and / or PEG-6 sorbitol monolaurate and / or PEG-80 sorbitol laurate and / or PEG-20 sorbitol monopalmitate (polysorbate 40) and / or polyoxyethylated (4) sorbitol monostearate and / or polyoxyethylated (6) sorbitol monostearate and / or polyoxyethylated (8) sorbitol monostearate, and / or PEG-60 sorbitol tetrastearate, and / or POE-5 sorbitol monooleate, and / or PEG-6 sorbitol oleate, and / or POE-6 sorbitol tetraoleate, and / or PEG-30 sorbitol tetraoleate, and / or PEG- 40 sorbitol tetraoleate, and / or PEG-20 orbits monoisostearate and / or PEG-40 sorbitol hexaoleate and / or polioksietilirovannyy- (23) -laurilovy ether and / or polioksietilirovannyy- (10) -oleilovy ether and / or polioksietilirovannyy- (20) -oleilovy ether.

In addition to polyoxyethylated products, non-ionic surfactants can be used polyhydric alcohols with a hydrophobic moiety in the molecule, such as (2S, 3R) -2-amino-4-octadecene-1,3-diol (sphingosine) and / or its optical isomers and / or 1,2-decanediol and / or 1,2-pentanediol and / or 1,2-octanediol and / or 1,2-hexanediol (of which (2S, 3R) -2-amino-4 is most successful -octadecene-1,3-diol, since being the basis of sphingolipids of cell membranes, it has a softening and preparing effect on the skin, contributing to the penetration of biologically active substances).

Ethers such as 3- (octadecyloxy) -1,2-propanediol and / or 3 - [(2-ethylhexyl) oxy] -1,2-propanediol and / or isosorbide dimethyl ether can also be used as nonionic surfactants, and / or isosobide diethyl ether and / or isosorbide dibutyl ether and / or isosorbide didecyl ether (of which 3- (octadecyloxy) -1,2-propanediol and isosorbide dimethyl ether are preferred).

Similar results were obtained for transdermal forms with megestrol acetate, designed to control the sexual behavior of animals, block estrus, etc. In the absence of additives of nonionic surfactants, megestrol acetate was significantly destroyed during storage, there was a clear skin irritation in animals (redness, scratching) and the expected clinical effect was absent. The introduction of the proposed additives eliminated all the described undesirable effects and led to the appearance of the desired clinical effect (see examples 1, 6, 27 34). Identical results were obtained when developing analgesic transdermal compositions (see examples 7, 26, 31).

Thus, to ensure maximum absorption of biologically active substances, to stabilize them during storage, we use a mixture of nonionic surfactants that have high penetrant and stabilizing properties, but are hardly acceptable in pure form due to poor physicochemical properties (solid or very high viscosity, with a viscosity of more than 30,000 cps liquid). This mixture (a highly viscous mixture of penetrants) contains:

a) an amide component of the general formula

AcNRCH ₂ (CHX) _n CH ₂ Y

Where

R = H, a saturated or unsaturated aliphatic or heterocyclic radical;

Ac = R ¹ O— or ArCO—, where R ¹ is a saturated or unsaturated aliphatic or heterocyclic or hydroxyaliphatic radical, Ar is an aromatic radical;

n = 0 ÷ 4;

X = H, OH, OR ² ;

Y = OH, OR ³ , NR ⁴ R ⁵ ;

Where

R ² , R ³ - saturated or unsaturated aliphatic radicals,

R ⁴ , R ⁵ - H, saturated or unsaturated aliphatic radicals.

b) a polyoxyethylated or polyoxypropylated phenol of the general formula HO (CHRCH ₂ O) _n Ar

Where

Ar is a substituted or unsubstituted aromatic radical;

n is 2-27;

R = H, CH ₃ ;

c) a polyoxyethylated alcohol of the general formula

HO (CH ₂ CH ₂ O) _n R

Where

R is an aliphatic or alicyclic saturated or unsaturated radical;

n is 2-27;

d) an ether of the general formula ROR '

Where

R is an aliphatic saturated or unsaturated radical;

R 'is an aliphatic saturated or unsaturated radical, or a heterocyclic oxygen-containing radical

or a polyhydric alcohol radical of the general formula —CH ₂ (CHOX) _n CH ₂ OY

Where

X, Y — H, an aliphatic saturated or unsaturated radical;

n = 0 ÷ 4;

e) a polyhydric alcohol of the general formula RCH (X) CH (Y) CH ₂ (Z)

Where

R is a saturated or unsaturated aliphatic or alicyclic or aromatic radical;

X is H, OH, NR ¹ R ² , OR ³ , OAc, NR ⁴ Ac;

Y, Z is OH, NR ¹ R ² , OR ³ , OAc, NR ⁴ Ac;

where R ¹ - R ⁴ - H or an aliphatic radical;

Ac is the residue of a substituted or unsubstituted inorganic or carboxylic acid,

wherein at least two of the groups X, Y, Z are OH;

in the weight ratio a: b: c: d: e = (100 ÷ 1) :( 0 ÷ 99) :( 0 ÷ 99) :( 0 ÷ 99) :( 0 ÷ 99). In this case, the specific ratio of the components is selected from the conditions for the formation of a liquid eutectic mixture at the skin temperature of the animal and complete solubility in the mixture of penetrants of the used biologically active substances.

However, since the proposed surfactant mixture has a high viscosity (viscosity of more than 100 cPs at the skin temperature of the animal), a low viscosity mixture (viscosity less than 5 cPs) of pharmaceutically acceptable solvents (non-toxic, non-irritating to the skin) consisting of one or more compounds is used for ease of use from the group of oxygen-containing solvents - ethers or esters, heterocyclic ethers such as ketals, etc .; and one or more compounds from the group of amide solvents.

As ethereal solvents, 1,2,3-triacetoxypropane and / or triethyl citrate and / or glycerol tricaprylate and / or 1,2-isopropylidene glycerol and / or 1,2-propylene glycol formaldehyde and / or formalglycerol, and / or 3- (N-acetyl-N-butyl) aminoethyl propionate and / or benzyl benzoate and / or benzyl acetate and / or β-ethoxyethyl acetate and / or isopropyl myristate.

As amide solvents, N, N-diethyltoluamide and / or N, N-dimethylbenzoylamide, and / or 3- (N-acetyl-N-butyl) aminoethyl propionate, and / or α-pyrrolidone, and / or N-methyl-α -pyrrolidone and / or N-dodecyl-α-pyrrolidone and / or tetramethylurea and / or N, N-dimethylformamide and / or N, N-dimethylacetamide and / or 2- (2-ethylhexyl) -3a, 4,7,7a-tetrahydro-4,7-methano-1H-isoindole-1,3 (2H) -dione (MGK-264), and / or 2-oxo-1-pyrrolidinacetamide, and / or N, N- nicotinic acid diethylamide and / or N-benzoylpiperidine and / or phenoxyacetic acid N, N-diethylamide and / or 1-acetyl-1,2,3,4-tetrahydroquinoline and / or N- (α-hexyl oxymethyl) caprolactam and / or N- (α-hexyloxyethyl) caprolactam and / or N-methylneodecanamide and / or N-ethylneodecanamide and / or N-methylneoheptanamide and / or N-ethylneoheptanamide and / or N-methylneotridecanamide and / or N-ethylneotridecanamide and / or N-allyl-N-isobutyl-3,5-dimethylbenzamide and / or N-isopropoxypropyl-N-cyclohexenyl-3,5-benzamide and / or N-methoxyethyl-N β-cyclohexenyl-3,5-dimethylbenzamide and / or N-tetrahydrofurfuryl-3,5-dimethylbenzamide and / or N-isopropoxypropyl-3,5-dimethylbenzamide and / or bis-N, N-hexamethylene carbamide and / or N- ethyl N-crotonyl-orthotoluidine, and / or N-these l-N-sorbate-orthotoluidine, and / or N-ethyl-N-myristate-orthotoluidine, and / or N-ethyl-N-caprinate-orthotoluidine. In this case, amides that are solid under ordinary conditions (2-oxo-1-pyrrolidinacetamide; N, N-nicotinic acid diethylamide), which are readily soluble in ether solvents with the formation of low-viscosity solutions with a very high solubility with respect to most biologically active substances, can also be used. Very convenient 3- (N-acetyl-N-butyl) aminoethyl propionate (better known as IR3535), which is both an ether and amide solvent.

The stabilization of the pH value of the composition at the level of 4-6 was also important for the implementation of the necessary parameters of the drug, at higher and lower pH values, biologically active substances are quickly destroyed (for example, macrolactone, megestrol acetate), in addition, there is a possibility of irritation of the skin of the animal (see example 1, 36, 37). This pH value is easily obtained by the necessary additive during ionometric control of a suitable carboxylic acid: glycyrrhizic and / or succinic and / or lactic and / or pyruvic and / or citric and / or malic and / or tartaric and / or stearic and / or myristic and / or octanoic acid (see examples 7, 8, 9, etc.) and others.

When implementing a particular pharmaceutical composition, a penetrant mixture containing nonionic surfactants (amide component, polyoxyethylated or polyoxypropylated phenols, polyoxyethylated alcohols, ethers or polyhydric alcohols) is selected in such a way as to obtain a viscous mixture that does not contain the solid phase of selected biologically active substances at the skin temperature of the animal. When selecting the composition, it is convenient to use the method of differential scanning microcalorimetry. This highly viscous mixture is dissolved in a mixture of low viscosity solvents, where the selected biologically active substances are added in the required quantities, the pH of the composition is adjusted to a value of 4 to 6 by adding carboxylic acid, after which the pharmaceutical composition is packaged in a consumer container. The ratio of low viscosity solvent mixture: high viscosity penetrant mixture is selected from the needs of a particular production when packaged in consumer containers (disposable pipettes, droppers, sprays with a mechanical pump) and the convenience of using the drug when applied to the skin of an animal.

Thus, the developed liquid homogeneous phase, which includes a low-viscosity component from solvents and a high-viscosity mixture of penetrants, which does not create difficulties in packaging and use, at the same time provides effective absorption through the skin of biologically active substances, does not cause irritation of the skin, allergic reactions with repeated daily use , does not cause disturbances of the coat, does not form a solid phase on the skin after absorption and evaporation, does not have a smell, has a slightly acid reaction and organolepticity Its licking-free properties ensure the stability of biologically active substances of various classes taken during long-term storage.

To reliably block “licking”, which in some cases is a very dangerous phenomenon, 0.01-0.0001 masses can be added to the composition. % known substances with a very bitter taste of plant origin, such as naringin, and / or absintin, and / or aucubin, and / or erythaurin, and / or humulon, and / or lupulon, and / or gelenin, and / or artemisin, and / or santonin and / or standardized plant extracts containing these components and / or chemically synthesized, such as denatonium benzoate; however, the components taken can have an additional beneficial effect on the skin of the animal, for example, antioxidant, anti-inflammatory, etc. (see examples 25, 33). From practice it was found that the concentration of most known safe bitterness is less than 0.0001 mass. % do not give a noticeable increase in the denaturation effect, and the introduction of more than 0.01 mass. % impractical because does not enhance the denaturation effect and at the same time crystallization of bitterness used is possible; in addition, unacceptably increases the cost of the pharmaceutical composition.

Thus, a liquid homogeneous phase for transdermal compositions has been developed, which has high solubility to many used biologically active substances and effectively protects them from degradation during storage, has optimal physicochemical properties and ensures safety when used in animals of different species.

The transdermal composition based on megestrol acetate, prepared according to the recipe of the prototype (RU 2497364, publ. 10.11.2013) does not provide the desired clinical effect (see example 6) and has significantly less stability (see example 35). After applying Spot-on to the withers of guinea pigs, redness of the skin at the site of application of the preparation was observed, the animals showed anxiety, tried to comb the preparation (see example 1).

The implementation of the invention

Example 1 (Study of the irritating effect of the transdermal composition based on the proposed homogeneous phase)

Materials and methods:

A safety study was conducted on guinea pigs. Tests were conducted on 40 males aged 5-6 weeks, divided into 4 groups of 10 individuals each. Twice a day for 5 days, the drug was applied to pre-trimmed sections of the back with a glass rod, followed by rubbing. With the manifestation of skin reactions in the entire group, the experiment was stopped. In the absence of skin reactions in experimental animals, the experiment was continued (no more than 4 repetitions). The skin condition was examined daily 2 hours after application. Changes in the condition of the skin were recorded during the entire observation time and evaluated using a Dryse scale, the thickness of the skin fold (mm) was evaluated with a micrometer. The first group was applied the drug obtained in example 35 (prototype, megestrol); the second group - according to example 34 (megestrol); the third group - according to example 38 (without biologically active substances); the fourth - according to example 37.

Results:

In animals of the first and fourth experimental groups, strong steady redness of the skin at the site of application was observed, which caused the formation of a skin fold 0.3 mm thick, which did not disappear after 20 minutes; animals showed anxiety, tried to comb the drug. The application of drugs to animals of the second and third experimental groups for 20 days did not cause edema or mild erythema of the skin (0 points on the Dryse scale). The results of the study are shown in Table 1.

Example 2 (Study of the pharmacokinetics of a transdermal composition based on the proposed homogeneous phase)

Materials and methods:

In the experiment, 4 adult dogs were used.

Investigated 2 drugs:

Composition 1 (see example 25):

Triethyl citrate 300 g 3- (N-acetyl-N- 100 g butyl) aminoethyl propionate 1,2-isopropylidene glycerol 150 g Polyoxyethylated α-Tocopherol 50 g Polyoxyethylene lanolin 10 g N- (3-hydroxypropyl) -2R, 4-dihydroxy- 10 g 3,3-dimethylbutanamide (D-panthenol) N-methyl-N- (1,2R, 3R, 4R, 5S- 10 g pentahydroxyhexyl) octadecanamide 3- (octadecyloxy) -1,2-propanediol 10 g Lupulon 0.05 g Stearic acid 5 g Ivermectin 16.5 g Praziquantel 58 g

Composition 2:

Butylhydroxyanisole 3.6 g Lactic acid 28.8 g Dimethyl sulfoxide 28.8 g 1,2-isopropylidene glycerol 584 g Ivermectin 16.5 g Praziquantel 58 g

The animals were divided into 2 groups:

Group 1 - treatment with the preparation of Composition 1 (2 animals).

Group 2 - treatment with the preparation of Composition 2 (2 animals).

The treatment was carried out once by applying the preparations to the withers of the animals in order to study the pharmacokinetics of praziquantel and ivermectin during cutaneous application in therapeutic doses. Blood samples were taken for analysis in dogs before application of the drug (control samples) and after 6, 12, 24, 36 hours, 3, 4, 5, 7, 10, 12, and 14 days after application to 10 ml heparin labeled polymer tubes , plasma was obtained and samples were prepared according to the established procedure for quantitative determination of praziquantel by high pressure liquid chromatography with UV detection, ivermectin by high pressure liquid chromatography with fluorescence detection.

Results:

It was established that with the cutaneous use of the preparation of Composition 1, the concentration of praziquantel and ivermectin in the blood serum of dogs reaches a higher concentration and lasts longer for comparison with the preparation of Composition 2 (see Table 2).

Example 3 (Evaluation of the analgesic effect of the transdermal composition with lornoxicam based on the proposed homogeneous phase)

Materials and methods:

The analgesic effect of the preparation prepared according to example 7 was studied by the effect on the nociceptive response in the model of “vinegar cramps”. The tests were carried out on 30 mice weighing 20-25 g, divided into 3 groups of 10 animals each: 1st — control; 2nd — experimental using indomethacin, 3rd — experimental, receiving the preparation prepared according to Example 7. Intimetacin was administered intramuscularly in a dose of 10 mg / kg in the form of a suspension in a volume of 0.2 ml / mouse to mice of the 2nd experimental group. Animals of the 3rd experimental group were applied the studied drug on the skin in the withers between the shoulder blades at a dose of 0.03 ml per head. When applying a transdermal preparation in mice, there were no attempts to comb the place of application of the drug. The drugs were administered once a day for 5 days, the last injection was carried out one hour before the testing of pain sensitivity. The control group mice received equivolume amounts of physiological sodium chloride solution in a similar mode. The study of the pain reaction was carried out by intraperitoneal administration of a 0.75% solution of acetic acid in a dose of 0.1 ml per 10 g of body weight. Acetic acid was introduced into the lower quadrant of the abdomen to the right or left of the white line of the abdomen. Previously, the animal was fixed so that the skin on the abdomen was stretched as much as possible. The animal was lowered head down. The needle was inserted into the abdominal cavity at an angle of 30 °. Within 20 minutes after the injection, the number of “cramps” was calculated - convulsive contractions of the abdominal muscles, accompanied by extension of the hind limbs and arching of the back. The criterion of effectiveness is a decrease in pain response by at least 50%. At the end of the experiment, animals were euthanized by craniocervical dislocation. Statistical processing of data was carried out using t-student test. Differences were considered significant at p <0.05.

Results:

The transdermal form of lornoxicam (as in Example 7) is superior in effect to the equivalent oral dose of indomethacin. The results of the study are shown in Table 3.

Example 4 (Evaluation of the analgesic effect of the transdermal composition with nimesulide based on the proposed homogeneous phase)

Materials and methods:

The analgesic effect of the preparation prepared according to example 26 was studied on the model of “vinegar cramps”. The test aims to study acute visceral and somatically deep sensitivity. The tests were carried out on 30 mice weighing 20-25 g, divided into 3 groups of 10 animals each: 1st — control; 2nd — experimental using indomethacin, 3rd — experimental, receiving the preparation prepared according to Example 26. Intimetacin was administered intramuscularly in a dose of 10 mg / kg intramuscularly as a suspension in a volume of 0.2 ml / mouse to mice of the 2nd experimental group. Animals of the 3rd experimental group were applied the studied drug on the skin in the withers between the shoulder blades at a dose of 0.03 ml per head. When applying a transdermal preparation in rats, there were no attempts to comb the place of application of the drug. The drugs were administered once a day for 5 days, the last injection was carried out one hour before the testing of pain sensitivity. The control group mice received equivolume amounts of physiological sodium chloride solution in a similar mode. The study of the pain reaction was carried out by introducing into the lower quadrant of the abdomen to the right or left of the white line of the abdomen 0.75% solution of acetic acid in a dose of 0.1 ml per 10 g of body weight. Previously, the animal was fixed so that the skin on the abdomen was stretched as much as possible. The animal was lowered head down. Within 20 minutes after the injection, the number of “cramps” was calculated - convulsive contractions of the abdominal muscles, accompanied by extension of the hind limbs and arching of the back. The criterion of effectiveness is a decrease in pain response by at least 50%. Euthanasia of animals at the end of the experiment was carried out by cranio-church dislocation. Statistical processing of data was carried out using t-student test. Differences were considered significant at p <0.05.

Results:

The transdermal form of nimesulide (according to Example 26) is superior in effect to the equivalent oral dose of indomethacin. The results of the study are shown in Table 4.

Example 5 (Evaluation of the analgesic effect of the transdermal composition with flupirtine maleate based on the proposed homogeneous phase)

The analgesic effect of the preparation prepared according to example 31, was studied on the model of "vinegar cramps". The tests were carried out on 30 mice weighing 20-25 g, divided into 3 groups of 10 animals each: 1st — control; 2nd — experimental using indomethacin, 3rd — experimental, receiving the preparation prepared according to Example 31. Intimetacin at a dose of 10 mg / kg was intragastrically administered as a suspension in a volume of 0.2 ml / mouse to mice of the 2nd experimental group. Animals of the 3rd experimental group were applied the studied drug on the skin in the withers between the shoulder blades at a dose of 0.03 ml per head. When applying a transdermal preparation in rats, there were no attempts to comb the place of application of the drug. The drugs were administered once a day for 5 days, the last injection was carried out one hour before the testing of pain sensitivity. The control group mice received equivolume amounts of physiological sodium chloride solution in a similar mode. The study of the pain reaction was carried out by introducing into the lower quadrant of the abdomen to the right or left of the white line of the abdomen 0.75% solution of acetic acid in a dose of 0.1 ml per 10 g of body weight. Previously, the animal was fixed so that the skin on the abdomen was stretched as much as possible. The animal was lowered head down. Within 20 minutes after the injection, the number of “cramps” was calculated - convulsive contractions of the abdominal muscles, accompanied by extension of the hind limbs and arching of the back. The criterion of effectiveness is a decrease in pain response by at least 50%. Euthanasia of animals at the end of the experiment was carried out by cranio-church dislocation. Statistical processing of data was carried out using t-student test. Differences were considered significant at p <0.05.

Results:

The transdermal form of flupirtine maleate (according to Example 31) is superior in effect to the equivalent oral dose of indomethacin. The results of the study are shown in Table 5.

Example 6 (Assessment of the hormonal action of the transdermal composition with megestrol acetate based on the proposed homogeneous phase)

Materials and methods:

Tests were carried out on 10 sexually mature cats aged 3-5 years. Cellular content with an active exercise in a heated vivarium. Feeding was carried out on a standard diet using dry feed and canned food and with enough drinking water.

Of 10 individuals, 3 experimental groups were formed:

Group 1 - control, did not receive megestrol acetate (3 individuals);

Group 2 - experimental, received the drug according to example 34 (3 individuals);

3 group - experimental, received the drug according to example 35 (prototype) (4 individuals).

All cats at the beginning of the experiment were in an anestral pause, which was confirmed by clinical observations and hormonal studies.

Animal preparations were applied to the withers in the form of Spot-on in the amount of 1 ml once, then after two weeks with a course of 1 ml for 8 days, after half a year the experiment was repeated.

The amount of progesterone, testosterone and estradiol was determined by the method of radioimmunological analysis in samples of vaginal mucus, which was taken from all individuals before the start of the experiment for two weeks with an interval of 3 days and after the start of the experiment with an interval of 1 and 2 weeks, then samples were taken every 2 weeks in for half a year. To determine the hormones in the vaginal mucus, RIA-Estradiol-ST, RIA-Progesterone-ST, and RIA-Testosterone-ST manufactured by the Republic of Belarus prepared medical kits for analyzing hormones in human blood serum. Since steroid hormones do not have a specific antigenic specificity, they can be determined by these sets in animals, taking into account the peculiarities of the protein composition of the samples.

Results:

In all groups of animals, at the end of the experiment, no pathological physiological reactions were observed. The condition of the mucous membranes, wool, skin, and the food eatability corresponded to the indices of the control group.

In individuals of the second group, a change in the average level of hormones in the vaginal mucus of animals was observed while maintaining the level of seasonal fluctuations, which allows us to judge the absence of deep irreversible organic changes. In certain seasons, the drug increased the concentration of hormones by 1.5-2 times, which, apparently, explained the lack of clinical signs of hunting (see Table 6).

In individuals of the third group, changes in hormone concentrations were within seasonal fluctuations and were not significant compared with intact animals. There was no change in the behavior of animals compared with the intact group.

Example 7 (a> 1%; a, b, c, d, e present; biologically active substance - analgesic.)

195 g of 1,2,3-triacetoxypropane, 75 g of N, N-diethyltoluamide, 100 g of 1,2-isopropylidene glycerol, 2.5 g of N- (3-hydroxypropyl) - are introduced into a 1-liter beaker equipped with a stirrer. 2R, 4-dihydroxy-3,3-dimethylbutanamide (D-panthenol), 50 g of polyoxyethylated α-tocopherol, 5 g of polyoxyethylated lanolin, 10 g of 3- (octadecyloxy) -1,2-propanediol, 2.5 g of N-methyl -N- (1,2R, 3R, 4R, 5S-pentahydroxyhexyl) octadecanamide and 5 g of (2S, 3R) -2-amino-4-octadecene-1,3-diol (sphingosine). Mix the mass when heated to 60 ° C until the components are completely dissolved. Cool with stirring to room temperature. The addition of myristic acid under the control of an ionometer with an input impedance> 2 GOhm brought the pH to 5.51. To the resulting solution was added 1.58 g of lornoxicam. Mix the mass when heated to 40 ° C until the components are completely dissolved. The pH value is adjusted to 5.53 by the addition of succinic acid under the control of an ionometer with an input resistance> 2 GΩ. The total amount of acid spent adjusting the pH: myristic acid - 3 g, succinic acid - 2 g. When cooled to room temperature, the solution becomes cloudy. Get 446.58 g of the transdermal composition with the following parameters:

1. Description - liquid turbid mobile mass of bright yellow color;

2. Density - 1.08 g / cm ³ ;

3. pH 5.52;

4. The content of lornoxicam 3.74 mg / cm ³ .

5. Viscosity - 4.8 cps.

The drug is packaged in 1 ml polypropylene-polyvinyl chloride pipettes. After three years of storage, the parameters of the drug are as follows:

1. Description - mobile turbid liquid mass, a bright yellow solution;

2. Density - 1.09 g / cm ³ ;

3. pH 5.49;

4. The content of lornoxicam 3.68 mg / cm ³ ;

5. Viscosity - 4.7 cps.

Thus, the drug is stable when stored in vivo in polymer pipettes for three years.

Example 8 (a = 1%; a, b, c, d, e present; BAS - horm.)

Into a 2 liter beaker equipped with a stirrer, 496 g of 1,2,3-triacetoxypropane, 150 g of N, N-diethyltoluamide, 200 g of 1,2-isopropylidene glycerol, 1.3 g of N-methyl-N- are added (1 , 2R, 3R, 4R, 5S-pentahydroxyhexyl) octadecanamide, 100 g of polyoxyethylated α-tocopherol, 10 g of polysorbate-60, 10 g of 3- (octadecyloxy) -1,2-propanediol, 10 g (2S, 3R) -2 amino-4-octadecene-1,3-diol (sphingosine). Mix the mass when heated to 60 ° C until the components are completely dissolved. Cool with stirring to room temperature. The addition of stearic acid under the control of an ionometer with an input impedance> 2 GOhm brought the pH to 5.48. To the resulting solution was added 10 g of megestrol acetate. Mix the mass when heated to 40 ° C until the components are completely dissolved. The pH value is adjusted to 5.53 by adding stearic acid under the control of an ionometer with an input resistance> 2 GΩ. The total amount of stearic acid spent on adjusting the pH was 12 g. When cooled to room temperature, the solution becomes cloudy. Receive 999.3 g of the transdermal composition with the following parameters:

1. Description - mobile liquid turbid mass of light yellow color;

2. Density - 1.10 g / cm ³ ;

3. pH 5.50;

4. The content of megestrol acetate 10.85 mg / cm ³ ;

5. Viscosity 4.6 cps.

The drug is packaged in 1 ml polypropylene-polyvinyl chloride pipettes. After three years of storage, the parameters of the drug are as follows:

1. Description - mobile turbid liquid mass of yellow color;

2. Density - 1.11 g / cm ³ ;

3. pH 5.48;

4. The content of megestrol acetate 10.21 mg / cm ³ ;

5. Viscosity 4.7 cps.

Thus, the drug is stable when stored in vivo in polymer pipettes for three years.

Example 9 (a <1%; BAS - horm.)

Into a 2-liter beaker equipped with a stirrer, 395 g of 1,2,3-triacetoxypropane, 150 g of N, N-diethyltoluamide, 200 g of 1,2-isopropylidene glycerol, 100 g of polyoxyethylated α-tocopherol, 10 g of polyoxyethylated lanolin are added, and 0.5 g of N-methyl-N- (1,2R, 3R, 4R, 5S-pentahydroxyhexyl) octadecanamide. Mix the mass when heated to 60 ° C until the components are completely dissolved. Cool with stirring to room temperature. The pH is adjusted to 4.23 by the addition of stearic acid under the control of an ionometer with an input resistance> 2 GΩ. To the resulting solution was added 9.8 g of megestrol acetate. Mix the mass when heated to 40 ° C until the components are completely dissolved. Adjust the pH value by adding stearic acid to a value of 4.25 when controlled by an ionometer with an input resistance> 2 GΩ. The total amount of stearic acid spent on adjusting the pH was 13 g. When cooled to room temperature, the solution becomes cloudy. Receive 878.3 g of the transdermal composition with the following parameters:

1. Description - mobile liquid turbid mass of yellow color;

2. Density - 1.08 g / cm ³ ;

3. pH 4.28;

4. The content of megestrol acetate 11.85 mg / cm ³ .

5. Viscosity - 4.7 cps.

The drug is packaged in 1 ml polypropylene-polyvinyl chloride pipettes. After two years of storage, the parameters of the drug are as follows:

1. Description - mobile muddy liquid mass, light yellow solution;

2. Density - 1.10 g / cm ³ ;

3. pH 4.35;

4. The content of megestrol acetate 9.63 mg / cm ³ ;

5. Viscosity - 4.6 cps.

Thus, the drug is not stable when stored in vivo in polymer pipettes for two years.

Example 10 (a = 100%; BAS - horm.)

395 g of 1,2,3-triacetoxypropane, 150 g of N, N-diethyltoluamide, 200 g of 1,2-isopropylidene glycerol and 5 g of N-methyl-N- (1,2R) are introduced into a 2 L beaker equipped with a stirrer. , 3R, 4R, 5S-pentahydroxyhexyl) octadecanamide. Mix the mass when heated to 60 ° C until the components are completely dissolved. Cool with stirring to room temperature. The pH is adjusted to 4.25 by the addition of stearic acid under the control of an ionometer with an input resistance> 2 GΩ. 8.3 g of megestrol acetate are added to the resulting solution. Mix the mass when heated to 40 ° C until the components are completely dissolved. Adjust the pH value by adding stearic acid to a value of 4.24 when controlled by an ionometer with an input resistance> 2 GΩ. The total amount of stearic acid spent on adjusting the pH was 12 g. When cooled to room temperature, the solution becomes cloudy. Get 770.3 g of the transdermal composition with the following parameters:

1. Description - mobile liquid turbid mass of yellow color;

2. Density - 1.01 g / cm ³ ;

3. pH 4.23;

4. The content of megestrol acetate 11.01 mg / cm ³ .

5. Viscosity - 4.4 cps.

The drug is packaged in 1 ml polypropylene-polyvinyl chloride pipettes. After three years of storage, the parameters of the drug are as follows:

1. Description - mobile muddy liquid mass, light yellow solution;

2. Density - 1.03 g / cm ³ ;

3. pH 4.22;

4. The content of megestrol acetate 10.84 mg / cm ³ ;

5. Viscosity - 4.4 cps.

Thus, the drug is stable when stored in vivo in polymer pipettes for three years.

Example 11 (a = 100%; BAS - antihelm.)

300 g of triethyl citrate, 12 g of 3- (N-acetyl-N-butyl) aminoethyl propionate, 150 g of 1,2-isopropylidene glycerol and 10 g of N-methyl-N- (1, 2R, 3R, 4R, 5S-pentahydroxyhexyl) octadecanamide. Mix the mass when heated to 60 ° C until the components are completely dissolved. Cool with stirring to room temperature. The pH is adjusted to 5.50 by the addition of stearic acid under the control of an ionometer with an input resistance> 2 GΩ. To the resulting solution was added 12.2 g of ivermectin. Mix the mass when heated to 40 ° C until the components are completely dissolved. Adjust the pH level by adding stearic acid to a value of 5.52 when controlled by an ionometer with an input resistance> 2 GΩ. The total amount of stearic acid spent on adjusting the pH to the required value was 8 g. When cooled to room temperature, the solution becomes cloudy. Obtain 492.2 g of the transdermal composition with the following parameters:

1. Description - mobile turbid yellow liquid;

2. Density - 1.05 g / cm ³ ;

3. pH 5.53;

4. The content of ivermectin 25.53 mg / cm ³ ;

5. Viscosity - 4.7 cps.

The drug is packaged in 1 ml polypropylene-polyvinyl chloride pipettes. After three years of storage, the parameters of the drug are as follows:

1. Description - mobile liquid mass, turbid, light yellow;

2. Density - 1.10 g / cm ³ ;

3. pH 5.48;

4. The content of ivermectin 25.02 mg / cm ³ ;

5. Viscosity - 4.6 cps.

Thus, the drug is stable when stored in vivo in polymer pipettes for three years.

Example 12 (component a - exc .; component b = 100%; BAS - antihelm.)

300 g of triethyl citrate, 12 g of 3- (N-acetyl-N-butyl) aminoethyl propionate, 150 g of 1,2-isopropylidene glycerol and 100 g of polyoxyethylated α-tocopherol are added to a 1 liter beaker equipped with a stirrer. Mix the mass when heated to 60 ° C until the components are completely dissolved. Cool with stirring to room temperature. The pH is adjusted to 5.53 by the addition of stearic acid under the control of an ionometer with an input resistance> 2 GΩ. To the resulting solution was added 13.3 g of ivermectin. Mix the mass when heated to 40 ° C until the components are completely dissolved. Adjust the pH level by adding stearic acid to a value of 5.50 when controlled by an ionometer with an input resistance> 2 GOhm. The total amount of stearic acid spent on adjusting the pH to the required value was 8 g. When cooled to room temperature, the solution becomes cloudy. Get 583.3 g of the transdermal composition with the following parameters:

1. Description - mobile turbid yellow liquid;

2. Density - 1.09 g / cm ³ ;

3. pH 5.51;

4. The content of ivermectin 24.76 mg / cm ³ ;

5. Viscosity - 4.6 cps.

The drug is packaged in 1 ml polypropylene-polyvinyl chloride pipettes. After two years of storage, the parameters of the drug are as follows:

1. Description - mobile liquid mass, turbid, light yellow;

2. Density - 1.13 g / cm ³ ;

3. pH 5.48;

4. The content of ivermectin 20.03 mg / cm ³ ;

5. Viscosity - 4.6 cps.

Thus, the drug is not stable when stored in vivo in polymer pipettes for two years.

Example 13 (component - sc. Component c = 100%; BAS - anthelmint.)

300 g of triethyl citrate, 12 g of 3- (N-acetyl-N-butyl) aminoethyl propionate, 150 g of 1,2-isopropylidene glycerol and 10 g of PEG-10 sorbitol laurate are added to a 1 liter beaker equipped with a stirrer. Mix the mass when heated to 60 ° C until the components are completely dissolved. Cool with stirring to room temperature. The pH is adjusted to 5.52 by the addition of stearic acid under the control of an ionometer with an input resistance> 2 GΩ. To the resulting solution was added 11.3 g of ivermectin. Mix the mass when heated to 40 ° C until the components are completely dissolved. Adjust the pH level by adding stearic acid to a value of 5.55 when controlled by an ionometer with an input resistance> 2 GΩ. The total amount of stearic acid spent on adjusting the pH to the required value was 8 g. When cooled to room temperature, the solution becomes cloudy. Obtain 491.3 g of the transdermal composition with the following parameters:

1. Description - mobile turbid yellow liquid;

2. Density - 1.11 g / cm ³ ;

3. pH 5.57;

4. The content of ivermectin 25.31 mg / cm ³ ;

5. Viscosity - 4.5 cps.

The drug is packaged in 1 ml polypropylene-polyvinyl chloride pipettes. After two years of storage, the parameters of the drug are as follows:

1. Description - mobile liquid mass, turbid, light yellow;

2. Density - 1.08 g / cm ³ ;

3. pH 5.51;

4. The content of ivermectin 20.89 mg / cm ³ ;

5. Viscosity - 4.5 cps.

Thus, the drug is not stable when stored in vivo in polymer pipettes for two years.

Example 14 (component a - exc .; component d = 100%; BAS - antihelm.)

300 g of triethyl citrate, 12 g of 3- (N-acetyl-N-butyl) aminoethyl propionate, 150 g of 1,2-isopropylidene glycerol and 10 g of isosorbide dimethyl ether are added to a 1 liter beaker equipped with a stirrer. Mix the mass when heated to 60 ° C until the components are completely dissolved. Cool with stirring to room temperature. The pH is adjusted to 5.48 by the addition of stearic acid under the control of an ionometer with an input resistance> 2 GΩ. To the resulting solution was added 11.3 g of ivermectin. Mix the mass when heated to 40 ° C until the components are completely dissolved. Adjust the pH level by adding stearic acid to a value of 5.50 when controlled by an ionometer with an input resistance> 2 GOhm. The total amount of stearic acid spent on adjusting the pH to the required value was 8 g. When cooled to room temperature, the solution becomes cloudy. Obtain 491.3 g of the transdermal composition with the following parameters:

1. Description - mobile turbid yellow liquid;

2. Density - 1.04 g / cm ³ ;

3. pH 5.52;

4. The content of ivermectin 25.15 mg / cm ³ ;

5. Viscosity - 4.3 cps.

The drug is packaged in 1 ml polypropylene-polyvinyl chloride pipettes. After two years of storage, the parameters of the drug are as follows:

1. Description - mobile liquid mass, turbid, light yellow;

2. Density - 1.03 g / cm ³ ;

3. pH 5.45;

4. The content of ivermectin 20.90 mg / cm ³ ;

5. Viscosity - 4.3 cps.

Thus, the drug is not stable when stored in vivo in polymer pipettes for two years.

Example 15 (component a - exc .; component c = 100%; BAS - antihelm.)

300 g of triethyl citrate, 12 g of 3- (N-acetyl-N-butyl) aminoethyl propionate, 150 g of 1,2-isopropylidene glycerol and 10 g of (2S, 3R) -2-amino are introduced into a 1 L beaker equipped with a stirrer. -4-octadecene-1,3-diol (sphingosine). Mix the mass when heated to 60 ° C until the components are completely dissolved. Cool with stirring to room temperature. The pH is adjusted to 5.35 by the addition of stearic acid under the control of an ionometer with an input resistance> 2 GΩ. To the resulting solution was added 11.3 g of ivermectin. Mix the mass when heated to 40 ° C until the components are completely dissolved. Adjust the pH level by adding stearic acid to a value of 5.37 when controlled by an ionometer with an input resistance> 2 GΩ. The total amount of stearic acid spent on adjusting the pH to the required value was 8 g. When cooled to room temperature, the solution becomes cloudy. Obtain 491.3 g of the transdermal composition with the following parameters:

1. Description - mobile turbid yellow liquid;

2. Density - 1.07 g / cm ³ ;

3. pH 5.33;

4. The content of ivermectin 24.97 mg / cm ³ ;

5. Viscosity - 4.3 cps.

The drug is packaged in 1 ml polypropylene-polyvinyl chloride pipettes. After two years of storage, the parameters of the drug are as follows:

1. Description - mobile liquid mass, turbid, light yellow;

2. Density - 1.06 g / cm ³ ;

3. pH 5.24;

4. The content of ivermectin 19.34 mg / cm ³ ;

5. Viscosity - 4.2 cps.

Thus, the drug is not stable when stored in vivo in polymer pipettes for two years.

Example 16 (a = 100%; BAS - analgesic)

195 g of 1,2,3-triacetoxypropane, 75 g of N, N-diethyltoluamide, 100 g of 1,2-isopropylidene glycerol and 2.5 g of N-methyl-N- are introduced into a 1-liter beaker equipped with a stirrer. , 2R, 3R, 4R, 5S-pentahydroxyhexyl) octadecanamide. Mix the mass when heated to 60 ° C until the components are completely dissolved. Cool with stirring to room temperature. The addition of stearic acid under the control of an ionometer with an input impedance> 2 GOhm brought the pH to 5.48. To the resulting solution was added 1.40 g of lornoxicam. Mix the mass when heated to 40 ° C until the components are completely dissolved. Adjust the pH to 5.50 by adding stearic acid under the control of an ionometer with an input impedance> 2 GOhm. The total amount of stearic acid spent on bringing the pH to the required value was 4 g. When cooled to room temperature, the solution becomes cloudy. Get 377.9 g of the transdermal composition with the following parameters:

1. Description - liquid turbid mobile mass of bright yellow color;

2. Density - 1.08 g / cm ³ ;

3. pH 5.52;

4. The content of lornoxicam 3.89 mg / cm ³ .

5. Viscosity - 4.8 cps.

The drug is packaged in 1 ml polypropylene-polyvinyl chloride pipettes. After three years of storage, the parameters of the drug are as follows:

1. Description - mobile muddy liquid mass of bright yellow color;

2. Density - 1.07 g / cm ³ ;

3. pH 5.50;

4. The content of lornoxicam 3.68 mg / cm ³ ;

5. Viscosity - 4.7 cps.

Thus, the drug is stable when stored in vivo in polymer pipettes for three years.

Example 17 (component a - exc .; component b = 100%; BAS - analgesic.)

195 g of 1,2,3-triacetoxypropane, 75 g of N, N-diethyltoluamide, 100 g of 1,2-isopropylidene glycerol and 50 g of polyoxyethylated α-tocopherol are introduced into a 1 liter beaker equipped with a stirrer. Mix the mass when heated to 60 ° C until the components are completely dissolved. Cool with stirring to room temperature. The addition of stearic acid under the control of an ionometer with an input impedance> 2 GOhm brought the pH to 5.51. To the resulting solution was added 1.57 g of lornoxicam. Mix the mass when heated to 40 ° C until the components are completely dissolved. The pH value is adjusted to 5.47 by the addition of stearic acid under the control of an ionometer with an input resistance> 2 GΩ. The total amount of stearic acid spent on bringing the pH to the required value was 4 g. When cooled to room temperature, the solution becomes cloudy. Receive 425.57 g of the transdermal composition with the following parameters:

1. Description - liquid turbid mobile mass of bright yellow color;

2. Density - 1.10 g / cm ³ ;

3. pH 5.49;

4. The content of lornoxicam 3.91 mg / cm ³ .

5. Viscosity - 4.6 cps.

The drug is packaged in 1 ml polypropylene-polyvinyl chloride pipettes. After two years of storage, the parameters of the drug are as follows:

1. Description - mobile muddy liquid mass of bright yellow color;

2. Density - 1.09 g / cm ³ ;

3. pH 5.43;

4. The content of lornoxicam 2.59 mg / cm ³ ;

5. Viscosity - 4.7 cps.

Thus, the drug is not stable when stored in vivo in polymer pipettes for two years.

Example 18 (component a - exc .; component c = 100%; BAS - analgesic)

195 g of 1,2,3-triacetoxypropane, 75 g of N, N-diethyltoluamide, 100 g of 1,2-isopropylidene glycerol and 2.5 PEG-10 sorbitol laurate are introduced into a 1 liter beaker equipped with a stirrer. Mix the mass when heated to 60 ° C until the components are completely dissolved. Cool with stirring to room temperature. The addition of stearic acid under the control of an ionometer with an input impedance> 2 GOhm brought the pH to 5.54. To the resulting solution was added 1.40 g of lornoxicam. Mix the mass when heated to 40 ° C until the components are completely dissolved. Adjust the pH to 5.50 by adding stearic acid under the control of an ionometer with an input impedance> 2 GOhm. The total amount of stearic acid spent on bringing the pH to the required value was 4 g. When cooled to room temperature, the solution becomes cloudy. Get 377.9 g of the transdermal composition with the following parameters:

1. Description - liquid turbid mobile mass of bright yellow color;

2. Density - 1.07 g / cm ³ ;

3. pH 5.51;

4. The content of lornoxicam 3.90 mg / cm ³ .

5. Viscosity - 4.8 cps.

The drug is packaged in 1 ml polypropylene-polyvinyl chloride pipettes. After two years of storage, the parameters of the drug are as follows:

1. Description - mobile muddy liquid mass of bright yellow color;

2. Density - 1.08 g / cm ³ ;

3. pH 5.44;

4. The content of lornoxicam 2.06 mg / cm ³ ;

5. Viscosity - 4.7 cps.

Thus, the drug is not stable when stored in vivo in polymer pipettes for two years.

Example 19 (component a - exc .; component d = 100%; biologically active substances - analgesic)

195 g of 1,2,3-triacetoxypropane, 75 g of N, N-diethyltoluamide, 100 g of 1,2-isopropylidene glycerol and 2.5 g of isosorbide dimethyl ether are introduced into a 1 liter beaker equipped with a stirrer. Mix the mass when heated to 60 ° C until the components are completely dissolved. Cool with stirring to room temperature. The addition of stearic acid under the control of an ionometer with an input impedance> 2 GOhm brought the pH to 5.42. To the resulting solution was added 1.40 g of lornoxicam. Mix the mass when heated to 40 ° C until the components are completely dissolved. The pH value is adjusted to 5.45 by the addition of stearic acid under the control of an ionometer with an input resistance> 2 GΩ. The total amount of stearic acid spent on bringing the pH to the required value was 4 g. When cooled to room temperature, the solution becomes cloudy. Get 377.9 g of the transdermal composition with the following parameters:

1. Description - liquid turbid mobile mass of bright yellow color;

2. Density - 1.07 g / cm ³ ;

3. pH 5.46;

4. The content of lornoxicam 3.91 mg / cm ³ .

5. Viscosity - 4.6 cps.

The drug is packaged in 1 ml polypropylene-polyvinyl chloride pipettes. After two years of storage, the parameters of the drug are as follows:

1. Description - mobile turbid liquid mass, a bright yellow solution;

2. Density - 1.04 g / cm ³ ;

3. pH 5.40;

4. The content of lornoxicam 2.21 mg / cm ³ ;

5. Viscosity - 4.6 cps.

Thus, the drug is not stable when stored in vivo in polymer pipettes for two years.

Example 20 (component a - exc .; component e = 100%; biologically active substances - analgesic)

195 g of 1,2,3-triacetoxypropane, 75 g of N, N-diethyltoluamide, 100 g of 1,2-isopropylidene glycerol and 2.5 g of (2S, 3R) -2- are added to a 1 L beaker equipped with a stirrer. amino-4-octadecene-1,3-diol (sphingosine). Mix the mass when heated to 60 ° C until the components are completely dissolved. Cool with stirring to room temperature. The addition of stearic acid under the control of an ionometer with an input impedance> 2 GOhm brought the pH to 5.42. To the resulting solution was added 1.40 g of lornoxicam. Mix the mass when heated to 40 ° C until the components are completely dissolved. The pH value is adjusted to 5.55 by adding stearic acid under the control of an ionometer with an input resistance> 2 GΩ. The total amount of stearic acid spent on bringing the pH to the required value was 4 g. When cooled to room temperature, the solution becomes cloudy. Get 377.9 g of the transdermal composition with the following parameters:

1. Description - liquid turbid mobile mass of bright yellow color;

2. Density - 1.10 g / cm ³ ;

3. pH 5.52;

4. The content of lornoxicam 3.89 mg / cm ³ .

5. Viscosity - 4.5 cps.

The drug is packaged in 1 ml polypropylene-polyvinyl chloride pipettes. After two years of storage, the parameters of the drug are as follows:

1. Description - mobile turbid liquid mass, a bright yellow solution;

2. Density - 1.08 g / cm ³ ;

3. pH 5.47;

4. The content of lornoxicam 2.72 mg / cm ³ ;

5. Viscosity - 4.5 cps.

Thus, the drug is not stable when stored in vivo in polymer pipettes for two years.

Example 21 (component a - negative; component b = 100%; biologically active substances - horm.)

395 g of 1,2,3-triacetoxypropane, 150 g of N, N-diethyltoluamide, 200 g of 1,2-isopropylidene glycerol, 100 g of polyoxyethylated α-tocopherol are introduced into a 2 L beaker equipped with a stirrer. Mix the mass when heated to 60 ° C until the components are completely dissolved. Cool with stirring to room temperature. The pH is adjusted to 4.32 by the addition of stearic acid under the control of an ionometer with an input resistance> 2 GΩ. To the resulting solution was added 10 g of megestrol acetate. Mix the mass when heated to 40 ° C until the components are completely dissolved. Adjust the pH value by adding stearic acid to a value of 4.33 when controlled by an ionometer with an input resistance> 2 GΩ. The total amount of stearic acid spent on adjusting the pH was 12 g. When cooled to room temperature, the solution becomes cloudy. Get 867 g of the transdermal composition with the following parameters:

1. Description - mobile liquid turbid mass of yellow color;

2. Density - 1.10 g / cm ³ ;

3. pH 4.34;

4. The content of megestrol acetate 12.50 mg / cm ³ .

5. Viscosity - 4.5 cps.

The drug is packaged in 1 ml polypropylene-polyvinyl chloride pipettes. After two years of storage, the parameters of the drug are as follows:

1. Description - mobile muddy liquid mass, light yellow solution;

2. Density - 1.08 g / cm ³ ;

3. pH 4.28;

4. The content of megestrol acetate 8.91 mg / cm ³ ;

5. Viscosity - 4.6 cps.

Thus, the drug is not stable when stored in vivo in polymer pipettes for two years.

Example 22 (component a - negative; component c = 100%; biologically active substances - horm.)

395 g of 1,2,3-triacetoxypropane, 150 g of N, N-diethyltoluamide, 200 g of 1,2-isopropylidene glycerol, 10 g of PEG-10 sorbitol laurate are introduced into a 2-liter beaker equipped with a stirrer. Mix the mass when heated to 60 ° C until the components are completely dissolved. Cool with stirring to room temperature. The pH is adjusted to 4.45 by the addition of stearic acid under the control of an ionometer with an input resistance> 2 GΩ. To the resulting solution was added 9.0 g of megestrol acetate. Mix the mass when heated to 40 ° C until the components are completely dissolved. Adjust the pH value by adding stearic acid to a value of 4.43 when controlled by an ionometer with an input resistance> 2 GΩ. The total amount of stearic acid spent on adjusting the pH was 12 g. When cooled to room temperature, the solution becomes cloudy. Get 776 g of the transdermal composition with the following parameters:

1. Description - mobile liquid turbid mass of yellow color;

2. Density - 1.08 g / cm ³ ;

3. pH 4.40;

4. The content of megestrol acetate 12.43 mg / cm ³ .

5. Viscosity - 4.5 cps.

The drug is packaged in 1 ml polypropylene-polyvinyl chloride pipettes. After two years of storage, the parameters of the drug are as follows:

1. Description - mobile muddy liquid mass, light yellow solution;

2. Density - 1.10 g / cm ³ ;

3. pH 4.53;

4. The content of megestrol acetate 7.95 mg / cm ³ ;

5. Viscosity - 4.6 cps.

Thus, the drug is not stable when stored in vivo in polymer pipettes for two years.

Example 23 (component a - negative; component d = 100%; biologically active substances - horm.)

395 g of 1,2,3-triacetoxy propane, 150 g of N, N-diethyltoluamide, 200 g of 1,2-isopropylidene glycerol, 10 g of isosorbide dimethyl ether are introduced into a 2 L beaker equipped with a stirrer. Mix the mass when heated to 60 ° C until the components are completely dissolved. Cool with stirring to room temperature. The pH is adjusted to 4.51 by the addition of stearic acid under the control of an ionometer with an input resistance> 2 GΩ. To the resulting solution was added 9.0 g of megestrol acetate. Mix the mass when heated to 40 ° C until the components are completely dissolved. Adjust the pH value by adding stearic acid to a value of 4.50 when controlled by an ionometer with an input resistance> 2 GΩ. The total amount of stearic acid spent on adjusting the pH was 12 g. When cooled to room temperature, the solution becomes cloudy. Get 776 g of the transdermal composition with the following parameters:

1. Description - mobile liquid turbid mass of yellow color;

2. Density - 1.08 g / cm ³ ;

3. pH 4.48;

4. The content of megestrol acetate 12.38 mg / cm ³ .

5. Viscosity - 4.5 cps.

The drug is packaged in 1 ml polypropylene-polyvinyl chloride pipettes. After two years of storage, the parameters of the drug are as follows:

1. Description - mobile muddy liquid mass, light yellow solution;

2. Density - 1.10 g / cm ³ ;

3. pH 4.58;

4. The content of megestrol acetate 7.71 mg / cm ³ ;

5. Viscosity - 4.5 cps.

Thus, the drug is not stable when stored in vivo in polymer pipettes for two years.

Example 24 (component a - negative; component e = 100%; biologically active substances - horm.)

395 g of 1,2,3-triacetoxypropane, 150 g of N, N-diethyltoluamide, 200 g of 1,2-isopropylidene glycerol, 10 g of (2S, 3R) -2-amino are introduced into a 2-liter beaker equipped with a stirrer. 4-octadecene-1,3-diol (sphingosine). Mix the mass when heated to 60 ° C until the components are completely dissolved. Cool with stirring to room temperature. The pH is adjusted to 4.52 by the addition of stearic acid under the control of an ionometer with an input resistance> 2 GΩ. To the resulting solution was added 9.0 g of megestrol acetate. Mix the mass when heated to 40 ° C until the components are completely dissolved. Adjust the pH value by adding stearic acid to a value of 4.48 when controlled by an ionometer with an input resistance> 2 GΩ. The total amount of stearic acid spent on adjusting the pH was 12 g. When cooled to room temperature, the solution becomes cloudy. Get 776 g of the transdermal composition with the following parameters:

1. Description - mobile liquid turbid mass of yellow color;

2. Density - 1.10 g / cm ³ ;

3. pH 4.45;

4. The content of megestrol acetate 12.31 mg / cm ³ .

5. Viscosity - 4.5 cps.

The drug is packaged in 1 ml polypropylene-polyvinyl chloride pipettes. After two years of storage, the parameters of the drug are as follows:

1. Description - mobile muddy liquid mass, light yellow solution;

2. Density - 1.09 g / cm ³ ;

3. pH 4.58;

4. The content of megestrol acetate 8.01 mg / cm ³ ;

5. Viscosity - 4.6 cps.

Thus, the drug is not stable when stored in vivo in polymer pipettes for two years.

Example 25 (component e - ot .; BAS - anthelmint.)

300 g of triethyl citrate, 100 g of 3- (N-acetyl-N-butyl) aminoethyl propionate, 150 g of 1,2-isopropylidene glycerol, 50 g of polyoxyethylated α-tocopherol, 10 g of polyoxyethylated lanolin are introduced into a 2 L beaker equipped with a stirrer. 10 g of N- (3-hydroxypropyl) -2R, 4-dihydroxy-3,3-dimethylbutanamide (D-panthenol), 10 g of N-methyl-N- (l, 2R, 3R, 4R, 5S-pentahydroxyhexyl) - octadecanamide, 10 g of 3- (octadecyloxy) -1,2-propanediol and 0.05 g of lupulon. Mix the mass when heated to 60 ° C until the components are completely dissolved. Cool with stirring to room temperature. Stearic acid is added to a pH of 5.61 with an ionometer with an input impedance> 2 GΩ. To the resulting solution was added 16.5 g of ivermectin and 58 g of praziquantel. Mix the mass when heated to 40 ° C until the components are completely dissolved. Adjust the pH level by adding stearic acid to a value of 5.65 when controlled by an ionometer with an input resistance> 2 GΩ. The total amount of stearic acid required to adjust the pH was 5 g. When cooled to room temperature, the solution becomes cloudy. Get 719.55 g of the transdermal composition with the following parameters:

1. Description - liquid turbid mobile mass of light yellow color;

2. Density - 1.14 g / cm ³ ;

3. pH 5.62;

4. The content of ivermectin 25.51 mg / cm ³ ;

5. The content of praziquantel 90.1 mg / cm ³ ;

6. Viscosity - 4.7 cps.

The drug is packaged in 5 ml polypropylene-polyvinyl chloride pipettes. After three years of storage, the parameters of the drug are as follows:

1. Description - liquid mobile turbid mass of pale yellow color;

2. Density - 1.10 g / cm ³ ;

3. pH 5.64;

4. The content of ivermectin 24.94 mg / cm ³ ;

5. The content of praziquantel 88.92 mg / cm ³ ;

6. Viscosity - 4.6 cps.

Thus, the drug is stable when stored in vivo in polymer pipettes for three years.

Example 26 (component e - Ot .; BAS - analg.)

300 g of 1,2,3-triacetoxypropane, 115 g of N, N-diethyltoluamide, 153 g of 1,2-isopropylidene glycerol, 3.84 g of N- (3-hydroxypropyl) - are added to a 1-liter beaker equipped with a stirrer. 2R, 4-dihydroxy-3,3-dimethylbutanamide (D-panthenol), 77 g of polyoxyethylated α-tocopherol, 7.7 g of polyoxyethylated lanolin, 0.4 g of 3- (octadecyloxy) -1,2-propanediol, 0.4 g of isosorbide dimethyl ether; 3.9 g of N-methyl-N- (1,2R, 3R, 4R, 5S-pentahydroxyhexyl) octadecanamide. Mix the mass when heated to 60 ° C until the components are completely dissolved. Cool with stirring to room temperature. Tartaric acid is added with stirring to adjust the pH to 5.71 with an ionometer with an input impedance> 2 GΩ. To the resulting solution was added 7.7 g of nimesulide. Mix the mass when heated to 40 ° C until the components are completely dissolved. The pH value is adjusted to 5.70 by adding tartaric acid under the control of an ionometer with an input resistance> 2 GΩ. The total amount of tartaric acid spent on adjusting the pH was 4.5 g. When cooled to room temperature, the solution becomes cloudy. Obtain 673.44 g of the transdermal composition with the following parameters:

1. Description - turbid mobile liquid of bright yellow color;

2. Density - 1.10 g / cm ³ ;

3. pH 5.68;

4. The content of nimesulide 12.40 mg / cm ³ ;

5. Viscosity - 4.5 cps.

The drug is packaged in 1 ml polypropylene-polyvinyl chloride pipettes. After three years of storage, the parameters of the drug are as follows:

1. Description - mobile muddy liquid mass of bright yellow color;

2. Density - 1.08 g / cm ³ ;

3. pH 5.64;

4. The content of nimesulide 12.31 mg / cm ³ ;

5. Viscosity - 4.6 cps.

Thus, the drug is stable when stored in vivo in polymer pipettes for three years.

Example 27 (component e - ot .; BAS - horm.)

Into a 2-liter beaker equipped with a stirrer, 395 g of 1,2,3-triacetoxypropane, 150 g of N, N-diethyltoluamide, 200 g of 1,2-isopropylidene glycerol, 100 g of polyoxyethylated α-tocopherol, 10 g of polyoxyethylated lanolin are added, 5 g of N- (3-hydroxypropyl) -2R, 4-dihydroxy-3,3-dimethylbutanamide (D-panthenol), 5 g of N-methyl-N- (1,2R, 3R, 4R, 5S-pentahydroxyhexyl) -octadecanamide 5 g of PEG-10 sorbitol laurate and 5 g of 3- (octadecyloxy) -1,2-propanediol. Mix the mass when heated to 60 ° C until the components are completely dissolved. Cool with stirring to room temperature. The pH is adjusted to 4.30 by adding stearic acid under the control of an ionometer with an input resistance> 2 GΩ. To the resulting solution was added 10 g of megestrol acetate. Mix the mass when heated to 40 ° C until the components are completely dissolved. Adjust the pH value by adding stearic acid to a value of 4.32 when controlled by an ionometer with an input resistance> 2 GΩ. The total amount of stearic acid spent on adjusting the pH was 12 g. When cooled to room temperature, the solution becomes cloudy. Receive 897 g of the transdermal composition with the following parameters:

1. Description - mobile liquid turbid mass of yellow color;

2. Density - 1.10 g / cm ³ ;

3. pH 4.29;

4. The content of megestrol acetate 12,13 mg / cm ³ .

5. Viscosity - 4.7 cps.

The drug is packaged in 1 ml polypropylene-polyvinyl chloride pipettes. After three years of storage, the parameters of the drug are as follows:

1. Description - mobile muddy liquid mass of light yellow color;

2. Density - 1.08 g / cm ³ ;

3. pH 4.31;

4. The content of megestrol acetate 11.90 mg / cm ³ ;

5. Viscosity - 4.6 cps.

Thus, the drug is stable when stored in vivo in polymer pipettes for three years.

Example 28 (component d - ots .; BAS - horm.)

Into a 2-liter beaker equipped with a stirrer, 395 g of 1,2,3-triacetoxypropane, 150 g of N, N-diethyltoluamide, 200 g of 1,2-isopropylidene glycerol, 100 g of polyoxyethylated α-tocopherol, 10 g of polyoxyethylated lanolin are added, 5 g of N- (3-hydroxypropyl) -2R, 4-dihydroxy-3,3-dimethylbutanamide (D-panthenol), 5 g of N-methyl-N- (1,2R, 3R, 4R, 5S-pentahydroxyhexyl) -octadecanamide 5 g of PEG-10 sorbitol laurate, and 5 g of (2S, 3R) -2-amino-4-octadecene-1,3-diol (sphingosine). Mix the mass when heated to 60 ° C until the components are completely dissolved. Cool with stirring to room temperature. The pH is adjusted to 4.28 by the addition of stearic acid under the control of an ionometer with an input resistance> 2 GΩ. To the resulting solution was added 10 g of megestrol acetate. Mix the mass when heated to 40 ° C until the components are completely dissolved. Adjust the pH value by adding stearic acid to a value of 4.31 when controlled by an ionometer with an input resistance> 2 GΩ. The total amount of stearic acid spent on adjusting the pH was 12 g. When cooled to room temperature, the solution becomes cloudy. Receive 897 g of the transdermal composition with the following parameters:

1. Description - mobile liquid turbid mass of yellow color;

2. Density - 1.08 g / cm ³ ;

3. pH 4.32;

4. The content of megestrol acetate 12.06 mg / cm ³ .

5. Viscosity - 4.5 cps.

The drug is packaged in 1 ml polypropylene-polyvinyl chloride pipettes. After three years of storage, the parameters of the drug are as follows:

1. Description - mobile muddy liquid mass of light yellow color;

2. Density - 1.09 g / cm ³ ;

3. pH 4.30;

4. The content of megestrol acetate 11.84 mg / cm ³ ;

5. Viscosity - 4.5 cps.

Thus, the drug is stable when stored in vivo in polymer pipettes for three years.

Example 29 (component c - exp .; BAS - horm.)

In a 2-liter beaker equipped with a stirrer, 395 g of 1,2,3-triacetoxypropane, 150 g of N, N-diethyltoluamide, 200 g of 1,2-isopropylidene glycerol, 100 g of polyoxyethylated α-tocopherol, 5 g of N- ( 3-hydroxypropyl) -2R, 4-dihydroxy-3,3-dimethylbutanamide (D-panthenol), 5 g of N-methyl-N- (1,2R, 3R, 4R, 5S-pentahydroxyhexyl) -octadecanamide, 5 g of 3- (octadecyloxy) -1,2-propanediol, 2.5 g of -1,2-octanediol and 2.5 g of (2S, 3R) -2-amino-4-octadecene-1,3-diol (sphingosine). Mix the mass when heated to 60 ° C until the components are completely dissolved. Cool with stirring to room temperature. The pH is adjusted to 4.36 by the addition of stearic acid under the control of an ionometer with an input resistance> 2 GΩ. To the resulting solution was added 10 g of megestrol acetate. Mix the mass when heated to 40 ° C until the components are completely dissolved. Adjust the pH value by adding stearic acid to a value of 4.40 when controlled by an ionometer with an input resistance> 2 GΩ. The total amount of stearic acid spent on adjusting the pH was 12 g. When cooled to room temperature, the solution becomes cloudy. Get 887 g of the transdermal composition with the following parameters:

1. Description - mobile liquid turbid mass of yellow color;

2. Density - 1.12 g / cm ³ ;

3. pH 4.38;

4. The content of megestrol acetate 12,03 mg / cm ³ .

5. Viscosity - 4.7 cps.

The drug is packaged in 1 ml polypropylene-polyvinyl chloride pipettes. After three years of storage, the parameters of the drug are as follows:

1. Description - mobile muddy liquid mass of light yellow color;

2. Density - 1.08 g / cm ³ ;

3. pH 4.35;

4. The content of megestrol acetate 11.81 mg / cm ³ ;

5. Viscosity - 4.6 cps.

Thus, the drug is stable when stored in vivo in polymer pipettes for three years.

Example 30 (component d, e - exc .; BAS - antihelm.)

In a 2-liter beaker equipped with a stirrer, 100 g of N, N-diethyltoluamide, 550 g of 1,2-isopropylidene glycerol, 200 g of α-pyrrolidone, 20 g of polyoxyethylated α-tocopherol, 20 g of polyoxyethylated lanolin, 20 g of N- methyl N- (1,2R, 3R, 4R, 5S-pentahydroxyhexyl) octadecanamide, 20 g of 2-oxo-1-pyrrolidinacetamide, 50 g of N- (3-hydroxypropyl) -2R, 4-dihydroxy-3,3- dimethylbutanamide (D-panthenol). Mix the mass when heated to 60 ° C until the components are completely dissolved. Cool with stirring to room temperature. Glycyrrhizic acid is added to a pH value of 5.72 under the control of an ionometer with an input resistance> 2 GΩ. To the resulting solution was added 20 g of ivermectin and 85 g of praziquantel and stirred under heating to 40 ° C until complete dissolution. The pH level is adjusted by adding glycyrrhizic acid to a value of 5.20 when monitored by an ionometer with an input resistance of 2 GΩ. The total amount of glycyrrhizic acid required to adjust the pH was 25 g. When cooled to room temperature, the solution became cloudy. Obtain 1110 g of the transdermal composition with the following parameters:

1. Description - mobile turbid yellow liquid;

2. Density - 1.14 g / cm ³ ;

3. pH 5.18;

4. The content of ivermectin 20.08 mg / cm ³ ;

5. The content of praziquantel 87.08 mg / cm ³ ;

6. Viscosity - 4.6 cps.

The drug is packaged in 5 ml polypropylene-polyvinyl chloride pipettes. After three years of storage, the parameters of the drug are as follows:

1. Description - mobile muddy liquid mass of light yellow color;

2. Density - 1.09 g / cm ³ ;

3. pH 5.23;

4. The content of ivermectin 19.96 mg / cm ³ ;

5. The content of praziquantel 86.82 mg / cm ³ ;

6. Viscosity - 4.7 cps.

Thus, the drug is stable when stored in vivo in polymer pipettes for three years.

Example 31 (component d, e - exc .; BAS - analgesic.)

In a 500-ml beaker equipped with a heated magnetic stirrer, 100 g of 1,2-isopropylidene glycerol, 60 g of N, N-diethyltoluamide, 10 g of alpha-tocopherol-polyethylene glycol-1000-succinate (TPGS), 10 g of polyoxyethylated lanolin are added 10 g of N-methyl-N- (1,2R, 3R, 4R, 5S-pentahydroxyhexyl) octadecanamide, 10 g of 2-oxo-1-pyrrolidinacetamide, 100 g of α-pyrrolidone. Mix the mass when heated to 60 ° C until the components are completely dissolved. Cool with stirring to room temperature. Lactic acid is added to a pH value of 5.40 with an ionometer with an input impedance> 2 GΩ. To the resulting solution was added 16 g of flupirtine maleate and stirred under heating to 40 ° C until complete dissolution. Adjust the pH level by adding lactic acid to a value of 5.43 when controlled by an ionometer with an input resistance of 2 GΩ. The total amount of lactic acid required to adjust the pH was 4 g. When cooled to room temperature, the solution becomes cloudy. Obtain 320 g of the transdermal composition with the following parameters:

1. Description - moving mass, liquid, cloudy, dark yellow;

2. Density - 1.14 g / cm ³ ;

3. pH 5.38;

4. The content of flupirtine maleate 82.1 mg / cm ³ ;

5. Viscosity 4.8 cps.

The drug is packaged in 1 ml polypropylene-polyvinyl chloride pipettes. After three years of storage, the parameters of the drug are as follows:

1. Description - mobile liquid turbid mass of yellow color;

2. Density - 1.10 g / cm ³ ;

3. pH 5.46;

4. The content of flupirtine maleate 81.6 mg / cm ³ ;

5. Viscosity - 4.8 cps.

Thus, the drug is stable when stored in vivo in polymer pipettes for three years.

Example 32 (component d, e - exc .; BAS - analges; POE α-tocopherol and POE vitamin A)

In a 500-ml beaker equipped with a heated magnetic stirrer, 100 g of benzyl acetate, 60 g of N, N-diethyltoluamide, 5 g of polyoxyethylated α-tocopherol, 5 g of polyoxyethylated vitamin A, 10 g of polyoxyethylated lanolin, 10 g of N-methyl N- (1,2R, 3R, 4R, 5S-pentahydroxyhexyl) octadecanamide, 10 g of 2-oxo-1-pyrrolidinacetamide, 100 g of α-pyrrolidone. Mix the mass when heated to 60 ° C until the components are completely dissolved. Cool with stirring to room temperature. Citric acid is added to a pH of 5.64 with an ionometer with an input impedance> 2 GΩ. To the resulting solution was added 0.06 g of ketotifen and stirred under heating to 40 ° C until complete dissolution. Adjust the pH level by adding citric acid to a value of 5.60 when monitoring with an ionometer with an input resistance of 2 GOhm. The total amount of citric acid required to adjust the pH was 4 g. When cooled to room temperature, the solution becomes cloudy. 304.06 g of transdermal composition are obtained with the following parameters:

1. Description - mobile liquid turbid mass of pale yellow color;

2. Density - 1.09 g / cm ³ ;

3. pH 5.61;

4. The content of ketotifen 0.20 mg / cm ³ ;

5. Viscosity 4.6 cps.

The drug is packaged in 1 ml polypropylene-polyvinyl chloride pipettes. After three years of storage, the parameters of the drug are as follows:

1. Description - turbid liquid mobile mass of light yellow color;

2. Density - 1.10 g / cm ³ ;

3. pH 5.63;

4. The content of ketotifen 0.18 mg / cm ³ ;

5. Viscosity - 4.7 cps.

Thus, the drug is stable when stored in vivo in polymer pipettes for three years.

Example 33 (component d, e - exc .; BAS - horm.)

Into a 2-liter beaker equipped with a stirrer, 395 g of 1,2,3-triacetoxypropane, 150 g of N, N-diethyltoluamide, 200 g of 1,2-isopropylidene glycerol, 100 g of polyoxyethylated α-tocopherol, 10 g of polyoxyethylated lanolin are added, 10 g of N- (3-hydroxypropyl) -2R, 4-dihydroxy-3,3-dimethylbutanamide (D-panthenol), 0.005 g of naringin and 0.005 g of absintin. Mix the mass when heated to 60 ° C until the components are completely dissolved. Cool with stirring to room temperature. Malic acid is added to a pH of 4.41 with an ionometer with an input resistance> 2 GΩ. To the resulting solution was added 9.8 g of cyproterone acetate. Mix the mass when heated to 40 ° C until the components are completely dissolved. Adjust the pH level by adding malic acid to a value of 4.32 when controlled by an ionometer with an input impedance of 2 GOhm. The total amount of malic acid required to adjust the pH was 5 g. When cooled to room temperature, the solution becomes cloudy. Get 879.81 g of the transdermal composition with the following parameters:

1. Description - yellow liquid mobile turbid mass;

2. Density - 1.12 g / cm ³ ;

3. pH 4.31;

4. The content of cyproterone acetate 12.10 mg / cm ³ ;

5. Viscosity - 4.5 cps.

The drug is packaged in 5 ml polypropylene-polyvinyl chloride pipettes. After three years of storage, the parameters of the drug are as follows:

1. Description - mobile liquid mass, turbid, light yellow;

2. Density - 1.10 g / cm ³ ;

3. pH 4.42;

4. The content of cyproterone acetate 12.05 mg / cm ³ ;

5. Viscosity 4.5 cps.

Thus, the drug is stable when stored in vivo in polymer pipettes for three years.

Example 34 (component c, d - exc .; BAS - horm.)

In a 2-liter beaker equipped with a stirrer, 395 g of 1,2,3-triacetoxypropane, 150 g of N, N-diethyltoluamide, 200 g of 1,2-isopropylidene glycerol, 100 g of polyoxyethylated α-tocopherol, 5 g of N- ( 3-hydroxypropyl) -2R, 4-dihydroxy-3,3-dimethylbutanamide (D-panthenol), 5 g of N-methyl-N- (1,2R, 3R, 4R, 5S-pentahydroxyhexyl) -octadecanamide and 5 g of 1, 2-decanediol. Mix the mass when heated to 60 ° C until the components are completely dissolved. Cool with stirring to room temperature. The pH is adjusted to 4.21 by the addition of stearic acid under the control of an ionometer with an input resistance> 2 GΩ. To the resulting solution was added 10 g of megestrol acetate. Mix the mass when heated to 40 ° C until the components are completely dissolved. The pH value is adjusted by adding stearic acid to a value of 4.20 when controlled by an ionometer with an input resistance> 2 GΩ. The total amount of stearic acid spent on adjusting the pH was 12 g. When cooled to room temperature, the solution becomes cloudy. Get 882 g of the transdermal composition with the following parameters:

1. Description - mobile liquid turbid mass of yellow color;

2. Density - 1.10 g / cm ³ ;

3. pH 4.23;

4. The content of megestrol acetate 12.04 mg / cm ³ .

5. Viscosity - 4.5 cps.

The drug is packaged in 1 ml polypropylene-polyvinyl chloride pipettes. After three years of storage, the parameters of the drug are as follows:

1. Description - mobile muddy liquid mass of light yellow color;

2. Density - 1.09 g / cm ³ ;

3. pH 4.27;

4. The content of megestrol acetate 11.88 mg / cm ³ ;

5. Viscosity - 4.5 cps.

Thus, the drug is stable when stored in vivo in polymer pipettes for three years.

Example 35 (prototype)

350 g of carbitol, 2.5 g of glycerolformal, 12.5 g of Migliol-840 are added to a 1-liter beaker equipped with a stirrer. Mix the mass until the components are completely dissolved. To the resulting solution was added 4.4 g of megestrol acetate. Mix the mass when heated to 40 ° C until the components are completely dissolved. 369.4 g of transdermal composition are obtained with the following parameters:

1. Description - mobile liquid unclear mass, colorless;

2. Density - 1.01 g / cm ³ ;

3. The content of megestrol acetate 11.98 mg / cm ³ ;

The drug is packaged in 1 ml polypropylene-polyvinyl chloride pipettes. After 3 months of storage under natural conditions, the parameters of the drug are as follows:

1. Description - mobile muddy liquid colorless mass;

2. Density - 1.00 g / cm ³ ;

3. The content of megestrol acetate 4.01 mg / cm ³ ;

Thus, the drug prepared according to the prototype was not stable during storage.

Example 36 (pH> 6)

Into a 2-liter beaker equipped with a stirrer, 395 g of 1,2,3-triacetoxypropane, 150 g of N, N-diethyltoluamide, 200 g of 1,2-isopropylidene glycerol, 100 g of polyoxyethylated α-tocopherol, 10 g of polyoxyethylated lanolin are added, 5 g of N- (3-hydroxypropyl) -2R, 4-dihydroxy-3,3-dimethylbutanamide (D-panthenol) and 5 g of N-methyl-N- (1,2R, 3R, 4R, 5S-pentahydroxyhexyl) -octadecanamide . Mix the mass when heated to 60 ° C until the components are completely dissolved. Cool with stirring to room temperature. The pH of the resulting solution under the control of an ionometer with an input impedance> 2 GOhm was 6.51. To the resulting solution was added 9.8 g of megestrol acetate. Mix the mass when heated to 40 ° C until the components are completely dissolved. When cooled to room temperature, the solution becomes cloudy. Get 874.8 g of the transdermal composition with the following parameters:

1. Description - mobile liquid turbid mass of yellow color;

2. Density - 1.11 g / cm ³ ;

3. pH 6.52;

4. The content of megestrol acetate 12.10 mg / cm ³ .

5. Viscosity - 4.6 cps.

The drug is packaged in 1 ml polypropylene-polyvinyl chloride pipettes. After two years of storage, the parameters of the drug are as follows:

1. Description - mobile muddy liquid mass of light yellow color;

2. Density - 1.07 g / cm ³ ;

3. pH 6.43;

4. The content of megestrol acetate 3.18 mg / cm ³ ;

5. Viscosity - 4.6 cps.

Thus, the drug is not stable when stored in vivo in polymer pipettes for two years.

Example 37 (pH <4)

Into a 2-liter beaker equipped with a stirrer, 395 g of 1,2,3-triacetoxypropane, 150 g of N, N-diethyltoluamide, 200 g of 1,2-isopropylidene glycerol, 100 g of polyoxyethylated α-tocopherol, 10 g of polyoxyethylated lanolin are added, 5 g of N- (3-hydroxypropyl) -2R, 4-dihydroxy-3,3-dimethylbutanamide (D-panthenol) and 5 g of N-methyl-N- (1,2R, 3R, 4R, 5S-pentahydroxyhexyl) -octadecanamide . Mix the mass when heated to 60 ° C until the components are completely dissolved. Cool with stirring to room temperature. When monitoring with an ionometer with an input resistance> 2 GΩ, octanoic acid is added to a pH of 3.12. To the resulting solution was added 9.8 g of megestrol acetate. Mix the mass when heated to 40 ° C until the components are completely dissolved. The pH value is adjusted by the addition of octanoic acid under control by an ionometer with an input resistance> 2 GΩ to 3.10. The total amount of octanoic acid spent adjusting the pH was 18 g. When cooled to room temperature, the solution becomes cloudy. Receive 892.8 g of the transdermal composition with the following parameters:

1. Description - mobile liquid turbid mass of yellow color;

2. Density - 1.08 g / cm ³ ;

3. pH 3.11;

4. The content of megestrol acetate 10.32 mg / cm ³ .

5. Viscosity - 4.5 cps.

The drug is packaged in 1 ml polypropylene-polyvinyl chloride pipettes. After two years of storage, the parameters of the drug are as follows:

1. Description - mobile muddy liquid mass of light yellow color;

2. Density - 1.06 g / cm ³ ;

3. pH 3.14;

4. The content of megestrol acetate 10.18 mg / cm ³ ;

5. Viscosity - 4.5 cps.

Thus, the drug is stable when stored in vivo in polymer pipettes for two years.

In animal studies, the experimental groups showed strong steady redness of the skin at the site of application of the drug, which caused the formation of a skin fold 0.3 mm thick, which did not disappear after 20 minutes; animals showed anxiety, tried to comb the drug.

Example 38 (liquid phase without biologically active substances)

Into a 2-liter beaker equipped with a stirrer, 395 g of 1,2,3-triacetoxypropane, 150 g of N, N-diethyltoluamide, 200 g of 1,2-isopropylidene glycerol, 100 g of polyoxyethylated α-tocopherol, 10 g of polyoxyethylated lanolin are added, 5 g of N- (3-hydroxypropyl) -2R, 4-dihydroxy-3,3-dimethylbutanamide (D-panthenol) and 5 g of N-methyl-N- (1,2R, 3R, 4R, 5S-pentahydroxyhexyl) -octadecanamide . Mix the mass when heated to 60 ° C until the components are completely dissolved. Cool with stirring to room temperature. Octanoic acid is added to adjust the pH to 4.32 with an ionometer with an input impedance> 2 GΩ. The total amount of octanoic acid spent on adjusting the pH was 10 g. 875 g of a liquid homogeneous phase were obtained for transdermal pharmaceutical compositions with the following parameters:

1. Description - a mobile solution of pale yellow color;

2. Density - 1.08 g / cm ³ ;

3. pH 4.33;

4. Viscosity - 4.3 cps.

The product is packaged in 1 ml polypropylene-polyvinyl chloride pipettes. After three years of storage, the parameters of the drug are as follows:

1. Description - mobile transparent liquid of light yellow color;

2. Density - 1.11 g / cm ³ ;

3. pH 4.29;

4. Viscosity - 4.4 cps.

Thus, the phase is stable when stored under natural conditions in polymer pipettes for three years.

Claims (11)

1. The liquid homogeneous phase for transdermal pharmaceutical compositions, providing for the absorption of biologically active substances through the skin of the animal in the absence of an irritating effect, having organoleptic and physico-chemical properties that prevent animal licking, and having a pH value from 4 to 6, including a low-viscosity mixture with a viscosity of less than 5 cP at 20 ° C of at least one ether solvent and at least one amide solvent and the highly viscous penetran mixture dissolving in it s having a viscosity of over 100 cps at a temperature of the animal skin, thus penetrants mixture comprises: a) amide component - a component of a highly viscous penetrant mixture selected from the group consisting of N-methyl-N- (1,2R, 3R, 4R, 5S-pentahydroxyhexyl) -octadecanamide, and / or N-ethyl-N- (1,2R , 3R, 4R, 5S-pentahydroxyhexyl) -octadecanamide, and / or N-butyl-N- (1,2R, 3R, 4R, 5S-pentahydroxyhexyl) -octadecanamide, and / or N-methyl-N- (1,2R , 3R, 4R, 5S-pentahydroxyhexyl) -decanamide, and / or N-ethyl-N- (1,2R, 3R, 4R, 5S-pentahydroxyhexyl) -decanamide, and / or N-butyl-N- (1,2R , 3R, 4R, 5S-pentahydroxyhexyl) -decanamide, and / or N-methyl-N- (1,2R, 3R, 4R, 5S-pentahydroxyhexyl) -hexanamide, and / or N-ethyl-N- (1,2R , 3R, 4R, 5S-pentahydroxyhexyl) -hexanamide, and / or N-butyl-N- (1,2R, 3R, 4R, 5S-pentahydroxyhexyl) hexanamide, and / or N-methyl-N- (1,2R, 3R, 4R, 5S-pentahydroxyhexyl) nonanamide, and / or N-ethyl-N- (1,2R, 3R, 4R, 5S-pentahydroxyhexyl) nonanamide, and / or N-butyl-N- (1,2R, 3R, 4R, 5S-pentahydroxyhexyl) nonanamide, and / or N-methyl-N- (1,2R, 3R, 4R, 5S-pentahydroxyhexyl) octanamide, and / or N-ethyl-N- (1,2R, 3R, 4R, 5S-pentahydroxyhexyl) octanamide, and / or N-butyl-N- (1,2R, 3R, 4R, 5S-pentahydroxyhexyl) octanamide, and / or N-methyl-N- (1,2R, 3R, 4R, 5S-pentahydroxyhexyl) undecanamide, and / or N-ethyl-N- (1,2R, 3R, 4R, 5S-pentahydroxyhexyl) -undecanamide, and / or N-butyl-N- (1,2R, 3R, 4R, 5S-pentahydroxyhexyl) -undecanamide, and / or N-methyl-N- (1,2R, 3R, 4R, 5S-pentahydroxyhexyl) dodecanamide, and / or N-ethyl-N- (1,2R, 3R, 4R, 5S-pentahydroxyhexyl) dodecanamide, and / or N-butyl-N- (1,2R, 3R, 4R, 5S-pentahydroxyhexyl) dodecanamide, and / or N-methyl-N- (1,2R, 3R, 4R, 5S-pentahydroxyhexyl) -tetradecanamide, and / or N-ethyl-N- (1,2R, 3R, 4R, 5S-pentahydroxyhexyl) -tetradecanamide, and / or N-butyl-N- (1,2R, 3R, 4R, 5S-pentahydroxyhexyl) -tetradecanamide, and / or N-methyl-N- (1,2R, 3R, 4R, 5S-pentahydroxyhexyl) hexadecanamide and / or N-ethyl-N- (1,2R, 3R, 4R, 5S-pentahydroxyhexyl) hexadecanamide, and / or N-butyl-N- (1,2R, 3R, 4R, 5S-pentahydroxyhexyl) hexadecanamide, and / or N-methyl-N- (1,2R, 3R, 4S -tetrahydroxypentyl) octanoamide and / or N-ethyl-N- (1,2R, 3R, 4S-tetrahydroxypentyl) octanamide and / or N-butyl-N- (1,2R, 3R, 4S-tetrahydroxypentyl) - octanamide, and / or N-methyl-N- (1,2R, 3R, 4S-tetrahydroxypentyl) -undecanamide, and / or N-ethyl-N- (1,2R, 3R, 4S-tetrahydroxypentyl) -undecanamide, and / or N-butyl-N- (1,2R, 3R, 4S-tetrahydroxypentyl) -undecanamide, and / or N-methyl-N- (1,2R, 3R, 4S-tetrahydroxypentyl) -octadecanamide, and / or N-ethyl -N- (1,2R, 3R, 4S-tetrahydroxypentyl) octadecanamide, and / or N-butyl N- (1,2R, 3R, 4S-tetrahydroxypentyl) octadecanamide, and / or N-methyl-N- ( 1,2R, 3R, 4S-tetrahydroxypentyl) -decanamide, and / or N-ethyl-N- (1,2R, 3R, 4S- etrahydroxypentyl) -decanamide and / or N-butyl N- (1,2R, 3R, 4S-tetrahydroxypentyl) -decanamide and / or N-methyl-N- (1,2R, 3R, 4S-tetrahydroxypentyl) -hexanamide and / or N-ethyl-N- (1,2R, 3R, 4S-tetrahydroxypentyl) hexanamide, and / or N-butyl N- (1,2R, 3R, 4S-tetrahydroxypentyl) hexanamide, and / or N-methyl-N- (1,2R, 3R, 4S-tetrahydroxypentyl) dodecanamide and / or N-ethyl-N- (1,2R, 3R, 4S-tetrahydroxypentyl) dodecanamide and / or N-butyl N- (1,2R, 3R, 4S-tetrahydroxypentyl) dodecanamide and / or N-methyl-N- (1,2R, 3R, 4S-tetrahydroxypentyl) nonanamide and / or N-ethyl-N- (1 , 2R, 3R, 4S-tetrahydroxypentyl) nonanamide, and / or N-butyl N- (1,2R, 3R, 4S-tetrahydride xipentyl) nonanamide and / or N-methyl-N- (1,2R, 3R, 4S-tetrahydroxypentyl) tetradecanamide and / or N-ethyl-N- (1,2R, 3R, 4S-tetrahydroxypentyl) tetradecanamide and / or N-butyl-N- (1,2R, 3R, 4S-tetrahydroxypentyl) tetradecanamide, and / or N-methyl-N- (1,2R, 3R, 4S-tetrahydroxypentyl) hexadecanamide, and / or N-ethyl-N- (1,2R, 3R, 4S-tetrahydroxypentyl) hexadecanamide, and / or N-butyl N- (1,2R, 3R, 4S-tetrahydroxypentyl) hexadecanamide, and / or N-methyl- N- (1,2R, 3S-trihydroxypentyl) hexanamide and / or N-ethyl-N- (1,2R, 3S-trihydroxypentyl) hexanamide and / or N-butyl N- (1,2R, 3S trihydroxypentyl) hexanamide and / or N-methyl-N- (1,2R, 3S-trihydride hydroxypentyl) -undecanamide and / or N-ethyl-N- (1,2R, 3S-trihydroxypentyl) -undecanamide and / or N-butyl N- (1,2R, 3S-trihydroxypentyl) -undecanamide and / or N-methyl-N- (1,2R, 3S-trihydroxypentyl) nonanamide and / or N-ethyl-N- (1,2R, 3S-trihydroxypentyl) nonanamide and / or N-butyl N- (1 , 2R, 3S-trihydroxypentyl) nonanamide, and / or N-methyl-N- (1,2R, 3S-trihydroxypentyl) octadecanamide, and / or N-ethyl-N- (1,2R, 3S-trihydroxypentyl) - octadecanamide and / or N-butyl-N- (1,2R, 3S-trihydroxypentyl) octadecanamide and / or N-methyl-N- (1,2R, 3S-trihydroxypentyl) decanamide and / or N-ethyl -N- (1,2R, 3S-trihydroxypentyl) -decanamide, and / or N-butyl-N- (1,2 R, 3S-trihydroxypentyl) decanamide, and / or N-methyl-N- (1,2R, 3S-trihydroxypentyl) octanamide, and / or N-ethyl-N- (1,2R, 3S-trihydroxypentyl) octanamide and / or N-butyl-N- (1,2R, 3S-trihydroxypentyl) octanamide and / or N-methyl-N- (1,2R, 3S-trihydroxypentyl) dodecanamide and / or N-ethyl N- (1,2R, 3S-trihydroxypentyl) dodecanamide and / or N-butyl-N- (1,2R, 3S-trihydroxypentyl) dodecanamide and / or N-methyl-N- (1,2R, 3S -trihydroxypentyl) -tetradecanamide, and / or N-ethyl-N- (1,2R, 3S-trihydroxypentyl) -tetradecanamide, and / or N-butyl N- (1,2R, 3S-trihydroxypentyl) -tetradecanamide, and / or N-methyl-N- (1,2R, 3S-trihydroxypentyl) hexadecane id and / or N-ethyl-N- (1,2R, 3S-trihydroxypentyl) hexadecanamide and / or N-butyl N- (1,2R, 3S-trihydroxypentyl) hexadecanamide and / or N-methyl -N- (1,2R, 3S, 4S-tetrahydroxypentyl) -octadecanamide, and / or N-ethyl-N- (1,2R, 3S, 4S-tetrahydroxypentyl) -octadecanamide, and / or N-butyl-N- ( 1,2R, 3S, 4S-tetrahydroxypentyl) octadecanamide and / or N-methyl-N- (1,2R, 3S, 4S-tetrahydroxypentyl) octanamide and / or N-ethyl-N- (1,2R, 3S, 4S-tetrahydroxypentyl) octanamide, and / or N-butyl N- (1,2R, 3S, 4S-tetrahydroxypentyl) octanamide, and / or N-methyl-N- (1,2R, 3S, 4S- tetrahydroxypentyl) undecanamide and / or N-ethyl-N- (1,2R, 3S, 4S-tetrahydroxypentyl) undecane id and / or N-butyl-N- (1,2R, 3S, 4S-tetrahydroxypentyl) -undecanamide, and / or N-methyl-N- (1,2R, 3S, 4S-tetrahydroxypentyl) nonanamide, and / or N-ethyl-N- (1,2R, 3S, 4S-tetrahydroxypentyl) nonanamide, and / or N-butyl N- (1,2R, 3S, 4S-tetrahydroxypentyl) nonanamide, and / or N-methyl -N- (1,2R, 3S, 4S-tetrahydroxypentyl) -tetradecanamide, and / or N-ethyl-N- (1,2R, 3S, 4S-tetrahydroxypentyl) -tetradecanamide, and / or N-butyl-N- ( 1,2R, 3S, 4S-tetrahydroxypentyl) -tetradecanamide, and / or N-methyl-N- (1,2R, 3S, 4S-tetrahydroxypentyl) -decanamide, and / or N-ethyl-N- (1,2R, 3S, 4S-tetrahydroxypentyl) -decanamide, and / or N-butyl-N- (1,2R, 3S, 4S-tetrahydroxypentyl) -decans d, and / or N-methyl-N- (1,2R, 3S, 4S-tetrahydroxypentyl) -hexanamide, and / or N-ethyl-N- (1,2R, 3S, 4S-tetrahydroxypentyl) -hexanamide, and / or N-butyl-N- (1,2R, 3S, 4S-tetrahydroxypentyl) hexanamide, and / or N-methyl-N- (1,2R, 3S, 4S-tetrahydroxypentyl) dodecanamide, and / or N-ethyl -N- (1,2R, 3S, 4S-tetrahydroxypentyl) dodecanamide, and / or N-butyl N- (1,2R, 3S, 4S-tetrahydroxypentyl) dodecanamide, and / or N-methyl-N- ( 1,2R, 3S, 4S-tetrahydroxypentyl) hexadecanamide and / or N-ethyl-N- (1,2R, 3S, 4S-tetrahydroxypentyl) hexadecanamide and / or N-butyl N- (1,2R, 3S, 4S-tetrahydroxypentyl) hexadecanamide, and / or N-methyl-N- (1,2R, 3R, 4S, 5R-pentahydroxyhexyl) - octanamide and / or N-ethyl-N- (1,2R, 3R, 4S, 5R-pentahydroxyhexyl) octanamide and / or N-butyl-N- (1,2R, 3R, 4S, 5R-pentahydroxyhexyl) - octanamide and / or N-methyl-N- (1,2R, 3R, 4S, 5R-pentahydroxyhexyl) dodecanamide and / or N-ethyl-N- (1,2R, 3R, 4S, 5R-pentahydroxyhexyl) - dodecanamide and / or N-butyl-N- (1,2R, 3R, 4S, 5R-pentahydroxyhexyl) dodecanamide and / or N-methyl-N- (1,2R, 3R, 4S, 5R-pentahydroxyhexyl) - hexadecanamide and / or N-ethyl-N- (1,2R, 3R, 4S, 5R-pentahydroxyhexyl) hexadecanamide and / or N-butyl-N- (1,2R, 3R, 4S, 5R-pentahydroxyhexyl) - hexadecanamide and / or N-methyl-N- (1,2R, 3R, 4S, 5R-pentahydroxyhexyl) octadecanamide and / or N-ethyl-N- (1,2R, 3R, 4S, 5 R-pentahydroxyhexyl) -octadecanamide, and / or N-butyl-N- (1,2R, 3R, 4S, 5R-pentahydroxyhexyl) -octadecanamide, and / or N-methyl-N- (1,2R, 3R, 4S, 5R-pentahydroxyhexyl) -decanamide, and / or N-ethyl-N- (1,2R, 3R, 4S, 5R-pentahydroxyhexyl) -decanamide, and / or N-butyl-N- (1,2R, 3R, 4S, 5R-pentahydroxyhexyl) -decanamide, and / or N-methyl-N- (1,2R, 3R, 4S, 5R-pentahydroxyhexyl) -hexanamide, and / or N-ethyl-N- (1,2R, 3R, 4S, 5R-pentahydroxyhexyl) -hexanamide, and / or N-butyl-N- (1,2R, 3R, 4S, 5R-pentahydroxyhexyl) -hexanamide, and / or N-methyl-N- (1,2R, 3R, 4S, 5R-pentahydroxyhexyl) nonanamide, and / or N-ethyl-N- (1,2R, 3R, 4S, 5R-pentahydroxyhexyl) nonanamide, and / or N-butyl -N- (1,2R, 3R, 4S, 5R-pentahydroxyhexyl) nonanamide, and / or N-methyl-N- (1,2R, 3R, 4S, 5R-pentahydroxyhexyl) -undecanamide, and / or N-ethyl -N- (1,2R, 3R, 4S, 5R-pentahydroxyhexyl) -undecanamide, and / or N-butyl-N- (1,2R, 3R, 4S, 5R-pentahydroxyhexyl) -undecanamide, and / or N-methyl -N- (1,2R, 3R, 4S, 5R-pentahydroxyhexyl) -tetradecanamide, and / or N-ethyl-N- (1,2R, 3R, 4S, 5R-pentahydroxyhexyl) -tetradecanamide, and / or N-butyl -N- (1,2R, 3R, 4S, 5R-pentahydroxyhexyl) -tetradecanamide, and / or N-methyl-N- (1,2R, 3R, 4S, 5S-pentahydroxyhexyl) -hexanamide, and / or N-ethyl -N- (1,2R, 3R, 4S, 5S-pentahydroxyhexyl) -hexanamide, and / or N-butyl-N- (1,2R, 3R, 4S, 5S-pentahydroxyhexyl) -g Exanamide and / or N-methyl-N- (1,2R, 3R, 4S, 5S-pentahydroxyhexyl) -undecanamide, and / or N-ethyl-N- (1,2R, 3R, 4S, 5S-pentahydroxyhexyl) - undecanamide and / or N-butyl N- (1,2R, 3R, 4S, 5S-pentahydroxyhexyl) -undecanamide, and / or N-methyl-N- (1,2R, 3R, 4S, 5S-pentahydroxyhexyl) - octadecanamide and / or N-ethyl-N- (1,2R, 3R, 4S, 5S-pentahydroxyhexyl) octadecanamide and / or N-butyl-N- (1,2R, 3R, 4S, 5S-pentahydroxyhexyl) - octadecanamide and / or N-methyl-N- (1,2R, 3R, 4S, 5S-pentahydroxyhexyl) -decanamide and / or N-ethyl-N- (1,2R, 3R, 4S, 5S-pentahydroxyhexyl) - decanamide and / or N-butyl-N- (1,2R, 3R, 4S, 5S-pentahydroxyhexyl) -decanamide, and / or N-methyl-N- (1,2R, 3R, 4S, 5S-penta hydroxyhexyl) nonanamide and / or N-ethyl-N- (1,2R, 3R, 4S, 5S-pentahydroxyhexyl) nonanamide and / or N-butyl-N- (1,2R, 3R, 4S, 5S- pentahydroxyhexyl) nonanamide and / or N-methyl-N- (1,2R, 3R, 4S, 5S-pentahydroxyhexyl) octanamide and / or N-ethyl-N- (1,2R, 3R, 4S, 5S- pentahydroxyhexyl) octanamide and / or N-butyl N- (1,2R, 3R, 4S, 5S-pentahydroxyhexyl) octanamide and / or N-methyl-N- (1,2R, 3R, 4S, 5S- pentahydroxyhexyl) dodecanamide and / or N-ethyl-N- (1,2R, 3R, 4S, 5S-pentahydroxyhexyl) dodecanamide and / or N-butyl N- (1,2R, 3R, 4S, 5S- pentahydroxyhexyl) dodecanamide and / or N-methyl-N- (1,2R, 3R, 4S, 5S-pentahydroxyhexyl) tetradecanamide and / or N-ethyl-N- (1,2R, 3R, 4S , 5S-pentahydroxyhexyl) -tetradecanamide, and / or N-butyl-N- (1,2R, 3R, 4S, 5S-pentahydroxyhexyl) -tetradecanamide, and / or N-methyl-N- (1,2R, 3R, 4S , 5S-pentahydroxyhexyl) -hexadecanamide, and / or N-ethyl-N- (1,2R, 3R, 4S, 5S-pentahydroxyhexyl) -hexadecanamide, and / or N-butyl-N- (1,2R, 3R, 4S , 5S-pentahydroxyhexyl) -hexadecanamide, and / or N-methyl-N- (1,2R, 3S, 4S, 5R-pentahydroxyhexyl) -hexanamide, and / or N-ethyl-N- (1,2R, 3S, 4S , 5R-pentahydroxyhexyl) -hexanamide, and / or N-butyl-N- (1,2R, 3S, 4S, 5R-pentahydroxyhexyl) -hexanamide, and / or N-methyl-N- (1,2R, 3S, 4S , 5R-pentahydroxyhexyl) nonanamide, and / or N-ethyl-N- (1,2R, 3S, 4S, 5R-pentahydroxyhexyl) non anamide and / or N-butyl-N- (1,2R, 3S, 4S, 5R-pentahydroxyhexyl) nonanamide, and / or N-methyl-N- (1,2R, 3S, 4S, 5R-pentahydroxyhexyl) - tetradecanamide and / or N-ethyl-N- (1,2R, 3S, 4S, 5R-pentahydroxyhexyl) tetradecanamide and / or N-butyl-N- (1,2R, 3S, 4S, 5R-pentahydroxyhexyl) - tetradecanamide and / or N-methyl-N- (1,2R, 3S, 4S, 5R-pentahydroxyhexyl) hexadecanamide and / or N-ethyl-N- (1,2R, 3S, 4S, 5R-pentahydroxyhexyl) - hexadecanamide, and / or N-butyl-N- (1,2R, 3S, 4S, 5R-pentahydroxyhexyl) hexadecanamide, and / or N-methyl-N- (1,2R, 3S, 4S, 5R-pentahydroxyhexyl) - octadecanamide and / or N-ethyl-N- (1,2R, 3S, 4S, 5R-pentahydroxyhexyl) octadecanamide, and / or N-bu tyl-N- (1,2R, 3S, 4S, 5R-pentahydroxyhexyl) octadecanamide, and / or N-methyl-N- (1,2R, 3S, 4S, 5R-pentahydroxyhexyl) decanamide, and / or N- ethyl N- (1,2R, 3S, 4S, 5R-pentahydroxyhexyl) -decanamide, and / or N-butyl-N- (1,2R, 3S, 4S, 5R-pentahydroxyhexyl) -decanamide, and / or N- methyl N- (1,2R, 3S, 4S, 5R-pentahydroxyhexyl) octanamide, and / or N-ethyl-N- (1,2R, 3S, 4S, 5R-pentahydroxyhexyl) octanamide, and / or N- butyl-N- (1,2R, 3S, 4S, 5R-pentahydroxyhexyl) octanamide, and / or N-methyl-N- (1,2R, 3S, 4S, 5R-pentahydroxyhexyl) undecanamide, and / or N- ethyl N- (1,2R, 3S, 4S, 5R-pentahydroxyhexyl) -undecanamide, and / or N-butyl-N- (1,2R, 3S, 4S, 5R-pentahydroxyhexyl) -undecanamide, and / or N-methyl-N- (1,2R, 3S, 4S, 5R-pentahydroxyhexyl) dodecanamide, and / or N-ethyl-N- (1,2R, 3S, 4S, 5R-pentahydroxyhexyl) dodecanamide, and / or N-butyl-N- (1,2R, 3S, 4S, 5R-pentahydroxyhexyl) dodecanamide, and / or N-methyl-N- (1,2R, 3S, 4R-tetrahydroxypentyl) -hexanamide, and / or N-ethyl-N- (1,2R, 3S, 4R-tetrahydroxypentyl) hexanamide, and / or N-butyl N- (1,2R, 3S, 4R-tetrahydroxypentyl) hexanamide, and / or N-methyl- N- (1,2R, 3S, 4R-tetrahydroxypentyl) -undecanamide, and / or N-ethyl-N- (1,2R, 3S, 4R-tetrahydroxypentyl) -undecanamide, and / or N-butyl-N- (1 , 2R, 3S, 4R-tetrahydroxypentyl) -undecanamide, and / or N-methyl-N- (1,2R, 3S, 4R-tetrahydroxypentyl) hexadec amide and / or N-ethyl-N- (1,2R, 3S, 4R-tetrahydroxypentyl) hexadecanamide, and / or N-butyl N- (1,2R, 3S, 4R-tetrahydroxypentyl) hexadecanamide, and / or N-methyl-N- (1,2R, 3S, 4R-tetrahydroxypentyl) octadecanamide, and / or N-ethyl-N- (1,2R, 3S, 4R-tetrahydroxypentyl) octadecanamide, and / or N-butyl -N- (1,2R, 3S, 4R-tetrahydroxypentyl) octadecanamide, and / or N-methyl-N- (1,2R, 3S, 4R-tetrahydroxypentyl) decanamide, and / or N-ethyl-N- ( 1,2R, 3S, 4R-tetrahydroxypentyl) -decanamide, and / or N-butyl-N- (1,2R, 3S, 4R-tetrahydroxypentyl) -decanamide, and / or N-methyl-N- (1,2R, 3S, 4R-tetrahydroxypentyl) -nonanamide, and / or N-ethyl-N- (1,2R, 3S, 4R-tetrahydroxypentyl) -n nanamide and / or N-butyl-N- (1,2R, 3S, 4R-tetrahydroxypentyl) nonanamide, and / or N-methyl-N- (1,2R, 3S, 4R-tetrahydroxypentyl) octanamide, and / or N-ethyl-N- (1,2R, 3S, 4R-tetrahydroxypentyl) octanamide and / or N-butyl N- (1,2R, 3S, 4R-tetrahydroxypentyl) octanamide and / or N-methyl -N- (1,2R, 3S, 4R-tetrahydroxypentyl) dodecanamide and / or N-ethyl-N- (1,2R, 3S, 4R-tetrahydroxypentyl) dodecanamide and / or N-butyl N- ( 1,2R, 3S, 4R-tetrahydroxypentyl) dodecanamide and / or N-methyl-N- (1,2R, 3S, 4R-tetrahydroxypentyl) tetradecananamide and / or N-ethyl-N- (1,2R, 3S, 4R-tetrahydroxypentyl) -tetradecanamide, and / or N-butyl-N- (1,2R, 3S, 4R-tetrahydroxypentyl) -tet adecanamide, and / or their other optical isomers and racemates, and / or N- (3-hydroxypropyl) -2R, 4-dihydroxy-3,3-dimethylbutanamide (D-panthenol), and / or N- (3-hydroxypropyl) -2,4-dihydroxy-3,3-dimethylbutyramide (DL-panthenol), and / or N- (4-hydroxybutyl) -2R, 4-dihydroxy-3,3-dimethylbutyramide and / or N- (2-hydroxyethyl) -2R, 4-dihydroxy-3,3-dimethylbutyramide; b) polyoxyethylated or polyoxypropylated phenol - a component of a highly viscous penetrant mixture selected from the group consisting of polyoxyethylated and / or polyoxypropylated ionol and / or polyoxyethylated and / or polyoxypropylated α-tocopherol, and / or polyoxyethylated β-tocopherol, and / or polyoxyethylated γ and / or alpha-tocopherol-polyethylene glycol-1000-succinate (TPGS), and / or polyoxyethylene vitamin A, and / or OP-4, and / or OP-7, and / or OP-10, and / or OP- 20 and / or polyoxyethylated 4-methyl-2,6-ditretbutylpheno l, and / or polyoxyethylated 2,4,6-tritrebutylphenol, and / or neonol AF 9-4, and / or neonol AF 9-6, and / or neonol AF 9-8, and / or neonol AF 9-9, and / or neonol AF 9-10, and / or neonol AF 9-12, and / or neonol AFB-10, and / or neonol AFB-12; c) polyoxyethylated alcohol - a component of a highly viscous mixture of penetrants selected from the group consisting of polyoxyethylated lanolin and / or syntanol OS-10 grade A (polyoxyethylene- (20) stearyl ether) and / or syntanol OS-10 grade B, and / or ALM syntanol and / or DS syntanol (polyoxyethylated (9) lauryl ether or Brij 35 or Ukanil), and / or polyoxyethylated cetylstearyl alcohol, and / or polysorbate-20 (PEG-20 sorbitol monolaurate), and / or polysorbate -60 (PEG-20 sorbitol monostearate), and / or polysorbate-65 (PEG-20 sorbitol tristearate), and / or polysorbate 80 (PEG- 20 sorbitol monooleate), and / or polysorbate 85 (PEG-20 sorbitol trioleate), and / or PEG-10 sorbitol laurate, and / or PEG-4 sorbitol monolaurate, and / or PEG-6 sorbitol monolaurate, and / or PEG- 80 sorbitol laurate, and / or PEG-20 sorbitol monopalmitate (polysorbate 40), and / or polyoxyethylated (4) -sorbite monostearate, and / or polyoxyethylated (6) -sorbite monostearate, and / or polyoxyethylated (8) - sorbitol monostearate and / or PEG-60 sorbitol tetrastearate and / or POE-5 sorbitol monooleate and / or PEG-6 sorbitol oleate and / or POE-6 sorbitol tetraoleate and / or PEG-30 sorbitol tetraoleate and / or PEG-40 sorbitol tetraolea t, and / or PEG-20 sorbitol monoisostearate, and / or PEG-40 sorbitol hexaoleate, and / or polyoxyethylated (23) -lauryl ether, and / or polyoxyethylated (10) -oleyl ether, and / or polyoxyethylated- ( 20) oleyl ether; d) ether - a component of a highly viscous mixture of penetrants selected from the group consisting of 3- (octadecyloxy) -1,2-propanediol, and / or 3 - [(2-ethylhexyl) oxy] -1,2-propanediol, and / or isosorbide dimethyl ether and / or isosorbide diethyl ether and / or isosorbide dibutyl ether and / or isosorbide didecyl ether; f) polyhydric alcohol - a component of a highly viscous mixture of penetrants selected from the group consisting of (2S, 3R) -2-amino-4-octadecene-1,3-diol (sphingosine) and / or its optical isomers and / or 1,2- decanediol and / or 1,2-pentanediol and / or 1,2-octanediol and / or 1,2-hexanediol, in the weight ratio a: b: c: d: e = (100 ÷ 1) :( 0 ÷ 99) :( 0 ÷ 99) :( 0 ÷ 99) :( 0 ÷ 99), where the specific ratio of the components is chosen from the condition the formation of a liquid eutectic mixture at the skin temperature of the animal and complete solubility in the mixture of penetrants of biologically active substances used. 2. The liquid homogeneous phase according to claim 1, characterized in that bitterness is additionally added to the composition of the phase at a concentration of 0.01-0.0001 wt.%. 3. The liquid homogeneous phase according to claim 1, characterized in that naringin, and / or absintin, and / or aucubin, and / or erythaurine, and / or humulon, and / or lupulon, and / or gelenin are used as bitterness and / or artemisin and / or santonin and / or standardized plant extracts containing these components and / or denatonium benzoate. 4. The liquid homogeneous phase according to claim 1, characterized in that an organic acid from the class of carboxylic acids is used as a regulator of the pH level of the composition. 5. The liquid homogeneous phase according to claim 1, characterized in that glycyrrhizic acid and / or succinic acid and / or lactic acid and / or pyruvic acid and / or citric acid and / or malic are used as carboxylic acids. acid and / or tartaric acid and / or stearic acid and / or myristic acid and / or octanoic acid.