RU2001120008A - Advanced in vivo topical, non-invasive topical preparation - Google Patents

Claims (50)

1. A preparation containing penetrants capable of penetrating into the pores of the barrier even when the average diameter of said pores is less than the average diameter of said penetrants, characterized in that the preparation contains at least one viscosity modifier in an amount that increases the viscosity of the preparation in comparison with the viscosity of the corresponding preparation without a thickener by a maximum of 5 nm / s, so that it becomes possible to spread it on the surface for application and hold on this surface, and / or, at least at least one antioxidant in an amount that reduces the growth of the oxidative index to less than 100% in 6 months, and / or at least one bactericidal agent in an amount that reduces the number of bacteria from 1 million microorganisms added per g of the total weight of the drug, up to less than 100 in the case of aerobic bacteria, up to less than 10 in the case of enterobacteria and up to less than 1 in the case of Pseudomonas aeruginosa or Staphilococcus aureus, for 4 days. 2. The drug according to claim 1, characterized in that the at least one viscosity modifier is added in an amount that increases the viscosity of the drug to 1 nm / s, and more preferably, to 0.2 nm / s. 3. The drug according to claim 1 or 2, characterized in that the said at least one antioxidant is added in an amount that reduces the growth of the oxidative index to less than 100% in 12 months, and more preferably to less than 50% in 12 month 4. The drug according to any one of claims 1 to 3, characterized in that the said at least one bactericidal agent is added in an amount that reduces the number of bacteria from 1 million microorganisms added per 1 g of the total weight of the drug to less than 100 in the case of aerobic bacteria, up to less than 10 in the case of enterobacteria and up to less than 1 in the case of Pseudomonas aeruginosa or Staphilococcus aureus, after 3 days, and, more preferably, after 1 day. 5. The preparation according to any one of claims 1 to 4, characterized in that the viscosity modifier is selected from pharmaceutically acceptable hydrophobic polymers, such as partially esterified cellulose derivatives, which are carboxymethyl, hydroxyethyl, hydroxypropyl, hydroxypropylmethyl or methyl cellulose, fully synthetic hydrophilic polymers, which are polyacrylates, polymethacrylates, floor (hydroxyethyl) -, poly (hydroxypropyl) -, poly (hydroxypropylmethyl) methacrylate, polyacrylonitrile, metal sulfonate, polyethylene, lyoxyethylenes, polyethylene glycols, polyethylene glycol lactide, polyethylene glycol diacrylate, polyvinyl pyrrolidone, polyvinyl alcohols, poly (propyl methacrylamide), poly (propylene fumarate-ethylene glycol) copolymer, poloxamers, crosslinked, hydrochloric acid; natural resins, which are alginates, carrageenan, guar gum, gelatin, tragacanth, (amidated) pectin, xanthan gum, chitosan collagen, agarose; mixtures thereof and other derivatives or copolymers and / or other pharmaceutically, or at least biologically acceptable polymers. 6. The drug according to claim 5, characterized in that the weight content of the polymer is in the range of 0.05-10%, more preferably 0.1-5%, even more preferably 0.25-3.5%, and most preferably 0.5-2%. 7. The drug according to any one of claims 1 to 6, characterized in that the antioxidant is selected from synthetic phenolic antioxidants, such as bottled hydroxyanisole (BHL), butylated hydroxytoluene (BHT) and di-tert.butylphenol (LY178002, LY256548, HWA-131 , BF-389, CI-986, PD-127443, E-5119, BI-L-239XX), tert-butylhydroquinone (TBHQ), propyl gallate (PG), 1-O-hexyl-2,3,5-trimethylhydroquinone (HTHQ), aromatic amines, including diphenylamine, p-alkylthio-o-anisidine, ethylenediamine derivatives, carbazole and tetrahydroindenoindole, phenols and phenolic acids, including guaiacol, hydroquinone, vanillin, gall acids and their esters, protocatechuic acid, quinic acid, syringic acid, ellagic acid, salicylic acid, nordigidrogvayaretovaya acid (NDGA) and eugenol; tocopherols and their derivatives, including tocopheryl acylate, β-acetate, β-laurate, β-myristate, palmitate, oleate, linoleate or any other suitable tocopheryl lipoate, tocopheryl-POE succinate, trolox and the corresponding amide and thiocarboxamide analogues; ascorbic acid and its salts, isoascorbate, (2, or 3, or 6) -o-alkyl ascorbic acids, ascorbic esters, including 6-o-lauroyl, myristoyl, palmitoyl, oleoyl or linoleoyl-L-ascorbic acid, non-steroidal anti-inflammatory agents (NSAIDs such as indomethacin, diclofenac, mefenamic acid, flufenamic acid, phenylbutazone, oxyphenbutazone, acetylsalicylic acid, naproxen, diflunisal, ibuprofen, ketoprofen, piroxicam, penicillamine, penicinquinchlorin, hydroxyquinoline, hydroxyquinoline, hydrochlorin, hydrochloride, chlorofin, phenobarbital, acetaminophen, aminosalicylic acids and derivatives; methotrexate, probucol, antiarrhythmic drugs, including amiodarone, apridine, azocainol; ambroxol, tamoxifen, b-hydroxy tamoxifen, calcium antagonists, including nifedipine, nizoldipin, nimodipine, nimodipine, nimodipine, including atenolol, propranolol, nebivolol, sodium bisulfite, sodium metabisulfite, thiourea, chelating agents such as EDTA, GDTA, desferral, various endogenous defense systems such as transferrin, lacto errin, ferritin, ceruloplasmin, haptogloboin, hemopexin, albumin, glucose, ubiquinol-10), enzymatic antioxidants, such as superoxide dismutase, and metal complexes with tax activity, including catalase, glutathione peroxidase and less complex molecules, such as uric acid, beta-carotene, acid, flavonoids, including flavones, flavonols, flavonones, flavanonals and chalcones, anthocyanins, N-acetylcysteine, mesna, glutathione, derivatives of thiohistidine, triazoles, tannins, cinnamic acid, hydroxycinnamic acids and their ester s, including coumaric acids and esters, caffeic acid and its esters, ferulic acid, (iso-) chlorogenic acid and synapic acid, spice extracts including extracts of cloves, cinnamon, sage, rosemary, nutmeg, oregano, cloves, carnosic acid , carnosol, carzolic acid, rosmarinic acid, rosmarin diphenol, gentisic acid, ferulic acid; extracts from oatmeal, such as avenantramide 1 and 2; thioethers, dithioethers, sulfoxides, tetraalkylthiuram disulfides, phytic acid, steroid derivatives, including U74006F, tryptophan metabolites, including 3-hydroxykynurenine, 3-hydroxyanthranilic acid) and organochalcogenides. 8. The drug according to claim 7, characterized in that the concentration of BHA or BHT is 0.001-2 wt.%, More preferably 0.0025-0.2 wt.%, And most preferably 0.005-0.02 wt.% the concentration of TBHQ and PG is 0.001-2 wt.%, more preferably 0.005-0.2 wt.%, and most preferably 0.01-0.02 wt.%, the concentration of tocopherols is 0.005-5 wt.%, more preferably 0.01-0.5 wt.%, and most preferably 0.05-0.075 wt.%, the concentration of ascorbic esters is 0.001-5 wt.%, more preferably 0.005-0.5 wt.% and most preferably 0.01-0.15 wt.%, ascorbine concentration hydrochloric acid is 0.001-5 wt.%, more preferably 0.005-0.5 wt.%, and most preferably 0.01-0.1 wt.%, the concentration of sodium bisulfite or sodium metabisulfite is 0.001-5 wt.% , more preferably, 0.005-0.5 wt.%, and most preferably, 0.01-0.15 wt.%, the concentration of thiourea is 0.0001-2 wt.%, more preferably 0.0005-0.2 wt.%, and most preferably, 0.001-0.01 wt.%, most usually 0.005 wt.%, the concentration of cysteine is 0.01-5 wt.%, more preferably 0.05-2 wt.%, and most preferably 0.1-1.0 wt.%, most typically 0.5 wt.%, mon concentration otioglycerol is 0.01-5 wt.%, more preferably 0.05-2 wt.%, and most preferably 0.1-1.0 wt.%, most typically 0.5 wt.%, NDGA concentration is about 0.0005-2 wt.%, more preferably about 0.001-0.2 wt.%, and most preferably, about 0.005-0.02 wt.%, most usually 0.01 wt.%, glutathione concentration is about 0.005-5 wt.%, more preferably about 0.01-0.5 wt.%, and most preferably, about 0.05-0.2 wt.%, most typically 0.1 wt.%, the concentration of EDTA is about 0.001-5 wt.%, even more preferably, about 0.005-0.5 wt.%, and it is preferably about 0.01-0.2 wt.%, most typically 0.05-0.975 wt.%, the concentration of citric acid is about 0.001-5 wt.%, even more preferably about 0.005-3 wt.% and most preferably about 0.01-0.2 wt.%, most typically, about 0.3-2 wt.%. 9. The drug according to any one of claims 1 to 8, characterized in that the bactericidal agent is selected from short chain alcohols, including ethyl and isopropyl alcohol, chlorobutanol, benzyl alcohol, chlorobenzyl alcohol, dichlorobenzyl alcohol, hexachlorophene, phenolic compounds such as cresol , 4-chloro-m-cresol, p-chloro-m-xylene, dichlorophen, hexachlorophen, povidone iodine, parabens, in particular alkyl parabens, such as methyl, ethyl, propyl, or butyl paraben, benzyl α-paraben, acids such as sorbic acid, benzoic acid and their salts, are quaternary x ammonium compounds, such as alkonium salts, for example, bromide, benzalkonium salts, such as chloride or bromide, cetrimonium salts, for example, bromide, phenoalkine salts, such as phenodeodesinium bromide, cetylpyridinium chloride and other salts; mercury compounds such as phenylmercury acetate, borate or nitrate, thiomersal chlorhexidine or its gluconate, or any compounds with antibiotic activity of biological origin, or their corresponding mixtures. 10. The drug according to claim 9, characterized in that the volume concentration of short-chain alcohols in the case of ethyl, propyl, butyl or benzyl alcohol is preferably up to 10 wt.%, More preferably up to 5 wt.%, And most preferably , about 0.5-3 wt.%, and the volumetric concentration of chlorobutanol is preferably 0.3-0.6 wt.%, the volumetric concentration of parabens, in particular in the case of methylparaben, is 0.05-0.2 wt. % and in the case of propyl paraben 0.002-0.02 wt.%, the volume concentration of sorbic acid is 0.05-0.2 wt.%, and in uchae benzoic acid 0.1-0.5 wt.%, the bulk concentration of phenols, triclosan, is 0.1-0.3 wt.%, and bulk concentration of chlorhexidine is 0.01-0.05 wt.%. 11. A preparation containing penetrants capable of penetrating into the pores of the barrier even when the average diameter of said pores is less than the average diameter of said penetrants, and the agents associated with said penetrants are corticosteroids, mainly glucocorticoids or mineralocorticosteroids, characterized in that the relative content of corticosteroids is higher than 0.1 wt.% of the total dry weight of the drug. 12. The drug according to claim 11, characterized in that at least one viscosity modifier and / or at least one antioxidant and / or at least one bactericidal agent according to any one of claims 1 are added to the formulation -10. 13. The drug according to claim 11 or 12, characterized in that the corticoid is selected from alklonetasone dipropionate, amcinonide, beclomethasone dipropionate, betamethasone, betamethasone-17-valerate, betamethasone-17.21-divalerate, betamethasone-21-acetate, betamethasone-21 -butyrate, betazone-21-propionate, betazone-21-valerate, betamethasone benzoate, betamethasone dipropionate, betamethasone valerate, budesonide, clobetasol propionate, clobetasone butyrate, cortexolone, corticosterone, cortisone, cortisone dezonetasone-21-azette-21-azetazetone 17-pro propionate, deoxycorticosterone, desonide, deoxymethasone, dexamethasone, diflorasone diacetate, diflucortolone valerate, flukortolona acetonide, flumethasone pivalate, fluocinolone acetonide, fluocinonide, butilfluokortina, fluocortolone, 9-alpha-ftorkortizona, 9-alpha-ftorgidrokortizona, 9-alpha-ftorprednizalona, Fluprednidene acetate, fluradrenolone, chalcinonide, hydrocortisone, hydrocortisone 17-acetate, hydrocortisone 17-butyrate, hydrocortisone 17-propionate. hydrocortisone 17-valerate, hydrocortisone 21-acetate, hydrocortisone 21-butyrate, hydrocortisone 21-propionate, hydrocortisone 21-valerate, 17-alpha-hydroxyprogesterone, methylprednisolone acetate, mometasone fuorate, prednisone, prednisone, prednisone 17-acetate , progesterone, triamcinolone, triamcinolone acetonide. 14. A preparation according to any one of claims 1 to 13, characterized in that the penetrants are suspended or dispersed in a polar liquid in the form of liquid droplets surrounded by a membrane-like shell of one or more layers, said shell containing at least two types or two forms of amphiphilic substances with a tendency to coarsen, provided that said at least two substances differ in solubility in said liquid by at least 10 times, or otherwise, that said two substances, being in the form of homoaggregates, its soluble substance, or heteroaggregates, for any combination of both of these substances, have a preferred smaller average diameter than the diameter of homoaggregates containing only a less soluble substance, or otherwise, provided that the presence of a more soluble substance lowers the average elastic energy of the membrane-like shell to close to the value of thermal energy. 15. The drug according to 14, characterized in that the more soluble substance tends to solubilize the drop and that the content of such a substance is up to 99 mol% of the solubilization concentration or otherwise, corresponds to 99 mol% of the saturation concentration in the non-solubilized drop, no matter how high she was not. 16. The drug according to clause 15, wherein the content of the more soluble substance is less than 50%, especially less than 40% and most preferably less than 30% of the specified concentration of solubilization of the specified substance. 17. The drug according to clause 15, wherein the content of a more soluble substance is less than 80%, preferably less than 65% and, most preferably, less than 50% of the specified saturation concentration of the specified substance in a drop. 18. The drug according to any one of paragraphs.14-17, characterized in that the less soluble of the aggregating substances is a lipid or lipid-like substance, in particular, a polar lipid, while a substance more soluble in a suspending liquid and increasing the adaptability of the drops, refers to surfactants , or otherwise, has surfactant-like properties. 19. The drug according to p. 18, characterized in that the lipid or lipid-like substance is a lipid or lipoid from a biological source or the corresponding synthetic lipid or any of its modifications, said lipid preferably belongs to the class of pure phospholipids corresponding to the general formula:

where R ₁ and R ₂ represent an aliphatic chain, usually C _10-20 acyl or α-alkyl or a partially unsaturated fatty acid residue, in particular, oleoyl, palmitoleyl, elaidoyl, linoleyl, linoleyl, linolenyl, linolenoyl, arachidoyl, lauroyl, myristoyl, palmitoyl or stearoyl; and where R ₃ is hydrogen, 2-trimethylamino-1-ethyl, 2-amino-1-ethyl, C _1-4 -alkyl-, carboxy-substituted C _1-5 -alkyl, hydroxy-substituted C _2-5 -alkyl, carboxy and hydroxy-substituted C _2-5 -alkyl, carboxy and amino-substituted C _2-5 -alkyl, inositol, sphingosine, or salts of these substances, wherein said lipids also include glycerides, isoprenoid lipids, steroids, sterols or sterols, sulfur-containing or carbohydrate-containing lipids, or any other lipid-forming lipids, in particular semi-protonated liquid fatty acids; said lipid is selected from the group consisting of phosphatidylcholines, phosphatidylethanolamines, phosphatidylglycerols, phosphatidylinositols, phosphatidic acids, phosphatidylserines, sphingomyelins and other sphingophospholipids, glycosphingolipids, ceramidegolipoligides, other ceramidegolipoligides, glyphospholiposides and other or any other glycolipids, whereby two similar or different chains can be connected oefirnoy bond with the main chain as in diacyl and dialkenoyl compound or connect with the main chain ether (ether) bond as in dialkyl-lipids. 20. The preparation according to p. 18, characterized in that the surfactant (surfactant) or surfactant-like substance is non-ionic, zwitterionic, anionic or cationic surfactant, especially a salt of a fatty acid, or an alcohol salt, an alkyl-three salt (di / methylammonium, an alkyl sulfate salt, a monovalent salt of cholate, deoxycholate, glycocholate, glycodeoxycholate, taurodeoxycholate, taurocholate, etc., acyl or alkanoyl dimethylamine oxide, in particular N, N, N, N, N, N, N), - (acyldimethylammonium) -al cansulfate, N-acyl sulfobetaine, polyethylene glycol octylphenyl ether, in particular nonaethylene glycol octyl phenyl ether, polyethylene ether, in particular nonaethylenodecyl ether; polyethylene glycol isoacyl ether, in particular octaethylene glycol isotridecyl ether; polyethylene acyl ether, in particular octa-ethylene dodecyl ether, polyethylene glycol sorbitan acyl ether, such as polyethylene glycol-20-monolaurate (Tween 20) or polyethylene glycol-20-sorbitan-monooleate (Tween 80), polyhydroxyethylenethyl ether, in particular, -polyamide cetyl stearyl or-oleyl ether, as in polyhydroxyethylene-4, or 6, or 8, or 10, or 12 - lauryl ether (as in the Brij series) or in the corresponding ester, for example, such as polyhydroxyethylene-8-stearate (Myrj 45) , -laurate or -oleate, and and in polyethoxylated castor oil 40, sorbitan monoalkylate (e.g. in Arlacel or Span), in particular sorbitan monolaurate, acyl or alkanoyl-N-methylglucamide, in particular, either in decanoyl or dodecanoyl-N-methylglucamide, alkyl sulphate (salt), for example, in lauryl or oleyl sulfate. sodium deoxycholate, sodium glycodeoxycholate, sodium oleate, sodium taurate, a fatty acid salt such as sodium elaidate, sodium linoleate, sodium laurate, lysophospholipid, such as n-octadecylene (= oleoyl) -glycerophosphatidic acid, -phosphoryl-glycerol, or β-acyl, for example, lauryl or oleyl glycerophosphatidic acid, β-phosphorylglycerol, or β-phosphoryl serine, n-tetradecyl-glycero-phosphatidic acid, β-phosphorylglycerol, or β-phosphoryl-serine, corresponding palmitoyl-phenyl-phyloidelide Enikeev short chain phospholipid, or a corresponding short chain phospholipid, or else, a surfactant polilipid. 21. The drug according to any one of paragraphs.14-20, characterized in that the average penetrant diameter is 30-500 nm, preferably 40-250 nm, even more preferably 50-200 nm, and most preferably 60-150 nm. 22. The drug according to any one of paragraphs.14-20, characterized in that the average penetrant diameter is 2-25 times larger than the average pore diameter in the barrier, preferably 2.25-15 times larger, even more preferably 2.5- 8 times larger, and most preferably 3-6 times larger than the indicated average pore diameter. 23. The drug according to any one of paragraphs.14-22, characterized in that the mass of the droplets of the carrier in dry form in the preparation for human or animal skin is 0.01 to 40 wt.% Of the total weight of the drug, in particular 0.1 - 30 wt.%, Particularly preferably 0.5 to 20 wt.%, And most preferably 1-10 wt.%. 24. The drug according to any one of paragraphs.14-22, characterized in that the mass of all drops of the carrier in dry form in the preparation for the mucous membrane of a person or animal is 0.0001-30 wt.% The total weight of the drug. 25. The drug according to any one of claims 1 to 24, characterized in that the suspension of the carrier has a pH of 4-10, preferably 5-9, and most often up to 8.5, which is required to achieve maximum stability of the drug. 26. The drug according to any one of paragraphs.11-25, characterized in that the corticosteroid content is 0.1-20 wt.%, More preferably 0.25-10 wt.% And even more preferably 0.5-5 wt. % of the total mass of dry carriers loaded with a drug substance. 27. The drug according to p. 26, characterized in that the relative content of corticosteroids in the case of triamcinolone or one of its derivatives, such as acetonide, below 2 wt.% Of the total mass of dry carriers loaded with a drug substance, even more preferably below 1 weight %, and most preferably below 0.5% by weight. 28. The drug according to p. 26, characterized in that the relative content of corticosteroids in the case of hydrocortisone or one of its derivatives is below 20 wt.% Of the total mass of dry carriers loaded with a drug substance, even more preferably below 12.5 wt.%, and most preferably below 5 wt.%. 29. The drug according to p. 26, characterized in that the relative content of corticosteroids in the case of dexamethazole or one of its derivatives is below 15 wt.% Of the total mass of dry carriers loaded with the drug substance, even more preferably below 10 wt.%, And most preferably below 5 wt.%. 30. The drug according to p. 26, characterized in that the relative content of corticosteroids in the case of clobetasol or one of its derivatives, such as propionate, is below 15 wt.% Of the total weight of dry carriers loaded with the drug substance, even more preferably below 10 weight %, and most preferably below 5% by weight. 31. The drug according to PP.26-30, characterized in that the content of the specified corticosteroid is below the maximum saturation, defined as the content at which the corticosteroid begins to crystallize on the outer surface of the carrier. 32. The drug according to claims 1 to 29, characterized in that to accelerate the action of the drug substance add enhancer - a substance that accelerates its penetration. 33. The drug according to p, characterized in that the penetration enhancer is selected from 1-acyl-azacycloheptan-2-ones (azones), 1-acyl-glucosides, 1-acyl-polyoxyethylenes, 1-acyl-saccharides, 2-n -acyl-cyclohexanones, 2-n-acyl-1,3-dioxalanes (SEPA), 1,2,3-triacyl-glycerols, 1-alkanols, 1-alkanoic acids, 1-alkyl-beta-D-thioglucosides, 1 -alkyl glycerides, 1-alkyl-propylene glycols, 1-alkyl-polyoxyethylenes, (1-alkyl) -2-pyrrolidones, alkyl acetoacetates, alkylene glycols, alkyl methyl sulfoxides (alkyl DMSO), alkyl propionates, alkyl sulfates, diacyl succinates, diacyl-N, N-dim ethylaminoanethates (DDAA), diacyl-N, N-dimethylaminoisopropionates (DDAIP), phenyl-alkyl amines. 34. The drug according to p. 33, characterized in that the volume concentration ranges of the used enhancers are up to 5% for 1-caprylporylene glycol, 6-10% for 1- [2- (decylthio) ethyl] -azacyclopentan-2-one (= HPE -101), <10% for 1-dodecanol, <10% for 1-dodecylazacyclopentan-2-one (= azone), and about 10% for 2-n-nonyl-1,3-dioxolane (SEPA), <10 % for 2-n-octylcyclohexanone, up to and, preferably, about 20% for DMSO, up to and about 5-40% for ethanol, at least 10% for ethylene glycol, up to 30% for ethyl acetate, 5-50% for glycerol, up to 75% for isopropanol, 1-20% for isopropyl myristate, between 1 and 20% for olein hydrochloric acid and oleyl alcohol, about 1% for oleyl-polyoxyethylene ether, at least 10% for propylene glycol. 35. The drug according to PP.11-34, characterized in that the specified corticosteroid is added in an amount that allows you to apply the dose of the drug relative to the surface area, expressed by the total dry mass of penetrant per surface unit, 0.1 mg cm ^-2 - 15 mg cm ^{- 2} , more preferably 0.5 mg cm ^-2 - 10 mg cm ^-2 , particularly preferably 0.75 mg cm ^-2 - 5 mg cm ^-2 , and most preferably 1 mg cm ^-2 - 2.5 mg cm ^-2 , if it is desirable that the specified corticosteroid has a therapeutic effect deep in the subcutaneous region, for example, in muscles and ligaments, tissues , or otherwise, in internal tissues, including the entire body. 36. The drug according to PP.11-34, characterized in that the specified corticosteroid is added in an amount that makes it possible to use the drug in surface doses, expressed by the total mass of dry penetrant per unit surface area, comprising 1-250 mg cm ^-2 , preferably 2.5-100 mg cm ^-2 , more preferably 5-50 mg cm ^-2 , and most preferably 7.5-20 mg cm ^-2 , if you want the specified corticosteroid to show mainly local, then There is a superficial rather than systemic therapeutic effect. 37. The drug according to PP.11-36, characterized in that the viscosity and, if necessary, other properties of the drug are selected in such a way as to make it possible to spray, smear, roll or rub the drug on the treated surface, in particular, using a spray gun, spender (spender), roller or sponge, as it is more convenient to do this. 38. A method of preparing a preparation for non-invasive in vivo application according to any one of claims 1 to 25, characterized in that penetrants capable of binding to molecules of these agents and / or include molecules of these agents are formed from at least one amphiphilic substance, at least one polar liquid, at least one surfactant or surfactant, at least one corticosteroid in an amount of more than 0.1 wt.% of the total dry matter in the preparation and, if necessary, other conventional ingredients gradients, which together form said formulation. 39. The method according to § 38, wherein the at least one surfactant or surfactant, at least one amphiphilic substance, at least one hydrophilic liquid, and the agent are dissolved to form a solution and, if necessary are mixed separately, and the resulting (partial) mixture of solutions is then combined, followed by induction, preferably by mechanical action, such as shaking, mixing, vibration, homogenization, ultrasound, shear, freezing and thawing , Or filtration under suitable pressure, the formation of penetrants that bind to the agent, and / or incorporate the agent. 40. The method according to § 38 or 39, wherein said amphiphilic substances are either used as such or dissolved in a physiologically compatible polar liquid, which may be water or mixed with water, or in a solvation mediating agent, together with the polar solution . 41. The method according to § 38 or 39, characterized in that the amphiphilic substances are dissolved in volatile alcohols, in particular ethanol, or in pharmaceutically acceptable organic solvents, which are then removed mainly by evaporation, before preparing the final preparation. 42. The method according to p. 40 or 41, characterized in that the polar solution contains at least one surfactant or surfactant. 43. The method according to any of paragraphs 38-42, characterized in that the formation of these penetrants is caused by adding the desired substances to the liquid phase, evaporation from the reversed phase, spraying or dialysis, if necessary, by mechanical action, such as shaking, stirring, mainly , high-speed mixing, vibration, homogenization, ultrasound, shear, freezing and thawing, or filtering under appropriate, mainly low (1 MPa) or moderate (up to 10 MPa) pressure. 44. The method according to item 43, wherein the formation of these penetrants is caused by filtration, and the filter material has pores with a size of 0.01-0.8 microns, preferably 0.02-0.3 microns, and most preferably 0, 05-0.15 microns, with several filters can be used in series or in parallel. 45. The method according to any one of claims 38-44, wherein said agents and penetrants are forced to bind to each other, at least partially, after the formation of said penetrants, for example, after injection of a solution of a drug substance in a pharmaceutically acceptable liquid, such such as ethanol, 1- and 2-propanol, benzyl alcohol, propylene glycol, polyethylene glycol (molecular weight 200-400 Da) or glycerin in a suspension medium, said penetrants being obtained in advance by a similar or any other industrial method, and whether simultaneously with the inlet of the drug substance, if you want to use a co-solution of the drug substance and at least some of the ingredients are penetrant. 46. The method according to any one of claims 38-45, wherein said penetrants, with which the agent molecules are associated and / or into which the agent is incorporated, are prepared immediately before application of the preparation, if convenient, from the corresponding concentrate or lyophilisate. 47. The non-invasive application of corticosteroids using penetrants according to any one of claims 1 to 37, characterized in that the surface dose expressed by the total mass of dry penetrant applied per unit area is chosen to be 0.1-15 mg cm ^-2 , preferably 0.5-10 mg cm ^-2 , particularly preferably 0.75-5 mg cm ^-2 , and most preferably 1-2.5 mg cm ^-2 , if it is desired that said corticosteroid has a therapeutic effect deep in the subcutaneous region , for example, in muscles and ligaments, tissues, or otherwise, in internal tissues, including the entire organ Lowland. 48. The method of non-invasive application of corticosteroids using penetrants according to any one of claims 1-37, characterized in that the surface dose, expressed by the total mass of dry penetrants applied per unit surface area, is 1-250 mg cm ^-2 , preferably 2, 5-100 mgcm ^-2 , more preferably 5-50 mg cm ^-2 , and most preferably 7.5-20 mg cm ^-2 , if it is desired that said corticosteroid render mainly local, i.e. surface, not a systemic therapeutic effect. 49. The method of non-invasive application of corticosteroids associated with penetrants according to any one of claims 1 to 37, or encapsulated in them, characterized in that the preparation is applied by spraying, spreading, rolling or grinding on the treated surface, in particular using a spray gun, spender, roller or sponge. 50. The use of the drug according to any one of claims 1 to 37 for the treatment of inflammatory disease, dermatosis, renal or hepatic insufficiency, adrenal insufficiency, aspiration syndrome, Behcet syndrome, bites and burns (nettle, stinging insects), blood diseases such as colds hemagglutinin disease, hemolytic anemia, eosinophilia, hemoplastic anemia, macroglobulinemia, hemorrhagic purpura, in addition, for the treatment of bone diseases, cerebral edema, Cogan syndrome, congenital adrenal hyperplasia, violation connective tissue, such as lichen, lupus erythematosus, polymyalgia rheumatism, polymyositis and dermatomyositis, epilepsy, eye diseases such as cataracts, Graves ophthalmopathy, hemangioma, herpes infections, neuropathies, retinal vasculitis, some gastrointestinal disorders such as inflammation , nausea and damage to the esophagus, hypercalcemia, infections, such as ocular (such as infectious mononucleosis), Kawasaki disease, severe pseudoparalytic myasthenia gravis, various pain      syndromes such as postherpetic neuralgia, polyneuropathies, pancreatitis, respiratory disorders such as asthma, for the treatment of rheumatoid disease and osteoarthritis, rhinitis, sarcoidosis, skin diseases such as baldness, eczema, erythema essudativeis, lichen, pemphigus fibrosis and pemazorgoides urticaria, and vascular disorders.