Formulation for topical non-invasive application in vivo

Abstract

A formulation comprising molecular arrangements capable of penetrating pores in a barrier, owing to penetrant adaptability, despite the fact that the average diameter of said pores is smaller than the average penetrant diameter, provided that the prenetrants can transport agents or else enable agent permeation through the pores after penetrants have entered pores, characterized in that the formulation comprises at least one consistency builder in an amount that increases the formulation to maximally 5 Nm/s so that spreading over, and retention at, the application area is enabled and/or at least one antioxidant in an amount that reduces the increase of oxidation index to less than 100% per 6 months and/or at least one microbiocide in an amount that reduces the bacterial count of 1 million germs added per g of total mass of the formulation to less than 100 in the case of aerobic bacteria, to less than 10 in the case of entero-bacteria, and to less than 1 in the case of Pseudomonas aeruginosa or Staphilococcus aureus , after a period of 4 days.

1 . A formulation comprising molecular arrangements capable of penetrating pores in a barrier, owing to penetrant adaptability, despite the fact that the average diameter of said pores is smaller than the average penetrant diameter, provided that the penetrants can transport agents or else enable agent permeation through the pores after penetrants have entered pores, 
 characterised in that the formulation comprises at least one consistency builder in an amount that increases the formulation viscosity above that of the non-thickened corresponding formulation to maximally 5 Nm/s so that spreading over, and retention at, the application area is enabled and/or at least one antioxidant in an amount that reduces the increase of oxidation index to less than 100% per 6 months and/or at least one microbicide in an amount that reduces the bacterial count of 1 million germs added per g of total mass of the formulation to less than 100 in the case of aerobic bacteria, to less than 10 in the case of entero-bacteria, and to less than 1 in the case of  Pseudomonas aeruginosa  or  Staphilococcus aureus , after a period of 4 days.    
   
   
       2 . Formulation according to  claim 1 , characterised in that said at least one consistency buildner is added in an amount that increases the formulation viscosity to up to 1 Ns/m 2  and more preferably to up to 0.2 Ns/m 2 .  
   
   
       3 . Formulation according to  claim 1  or  2 , 
 characterised in that said at least one antioxidant is added in an amount that reduces the increase of oxidation index to less than 100% per 12 months and more preferably to less than 50% per 12 months.    
   
   
       4 . Formulation according to any one of the preceding claims, 
 characterised in that said at least one microbicide is added in an amount that reduces the bacterial count of 1 million germs added per g of total mass of the formulation to less than 100 in the case of aerobic bacteria, to less than 10 in the case of entero-bacteria, and to less than 1 in the case of  Pseudomonas aeruginosa  or  Staphilococcus aureus , after a period of 3 days, and more preferably after a period of 1 day.    
   
   
       5 . Formulation according to any of the preceding claims, 
 characterised in that the consistency builder is selected from pharmaceutically acceptable hydrophilic polymers, such as partially etherified cellulose derivatives, comprising carboxymethyl-, hydroxyethyl-, hydroxypropyl-, hydroxypropylmethyl- or methyl-cellulose; completely synthetic hydrophilic polymers comprising polyacrylates, polymethacrylates, poly(hydroxyethyl)-, poly(hydroxypropyl)-, poly(hydroxypropylmethyl)methacrylate, polyacrylonitrile, methallyl-sulphonate, polyethylenes, polyoxiethylenes, polyethylene glycols, polyethylene glycol-lactide, polyethylene glycol-diacrylate, polyvinylpyrrolidone, polyvinyl alcohols, poly(propylmethacrylamide), poly(propylene fumarate-co-ethylene glycol), poloxamers, polyaspartamide, (hydrazine cross-linked) hyaluronic acid, silicone; natural gums comprising alginates, carrageenan, guar-gum, gelatine, tragacanth, (amidated) pectin, xanthan, chitosan collagen, agarose; mixtures and further derivatives or co-polymers thereof and/or other pharmaceutically, or at least biologically, acceptable polymers.    
   
   
       6 . Formulation according to  claim 5 , 
 characterised in that the polymer weight fractions are in the range between 0.05% and 10%, more preferably are in the range between 0.1% and 5%, even more preferably are in the range between 0.25% and 3.5% and most preferably are in the range between 0.5% and 2%.    
   
   
       7 . Formulation according to any one of the preceding claims, 
 characterised in that the anti-oxidant is selected from synthetic phenolic antioxidants, such as butylated hydroxyanisol (BHA), butylated hydroxytoluene (BHT) and di-tert-butylphenol (LY178002, LY256548, HWA-131, BF-389, CI-986, PD-127443, E-5119, BI-L-239XX, etc.), tertiary butylhydroquinone (TBHQ), propyl gallate (PG), 1-O-hexyl-2,3,5-trimethylhydroquinone (HTHQ); aromatic amines (diphenylamine, p-alkylthio-o-anisidine, ethylenediamine derivatives, carbazol, tetrahydroindenoindol); phenols and phenolic acids (guaiacol, hydroquinone, vanillin, gallic acids and their esters, protocatechuic acid, quinic acid, syringic acid, ellagic acid, salicylic acid, nordihydroguaiaretic acid (NDGA), eugenol); tocopherols (including tocopherols (alpha, beta, gamma, delta) and their derivatives, such as tocopheryl-acylate (e.g. -acetate, -laurate, myristate, -palmitate, -oleate, -linoleate, etc., or an y other suitable tocopheryl-lipoate), tocopheryl-POE-succinate; trolox and corresponding amide and thiocarboxamide analogues; ascorbic acid and its salts, isoascorbate, (2 or 3 or 6)-o-alkylascorbic acids, ascorbyl esters (e.g. 6-o-lauroyl, myristoyl, palmitoyl-, oleoyl, or linoleoyl-L-ascorbic acid, etc.); non-steroidal anti-inflammatory agents (NSAIDs), such as indomethacine, diclofenac, mefenamic acid, flufenamic acid, phenylbutazone, oxyphenbutazone acetylsalicylic acid, naproxen, diflunisal, ibuprofene, ketoprofene, piroxicam, penicillamine, penicillamine disulphide, primaquine, quinacrine, chloroquine, hydroxychloroquine, azathioprine, phenobarbital, acetaminephen); aminosalicylic acids and derivatives; methotrexate, probucol, antiarrhythmics (amiodarone, aprindine, asocainol), ambroxol, tamoxifene, b-hydroxytamoxifene; calcium antagonists (nifedipine, nisoldipine, nimodipine, nicardipine, nilvadipine), beta-receptor blockers (atenolol, propranolol, nebivolol); sodium bisulphite, sodium metabisulphite, thiourea; chellating agents, such as EDTA, GDTA, desferral; miscellaneous endogenous defence systems, such as transferrin, lactoferrin, ferritin, cearuloplasmin, haptoglobion, haemopexin, albumin, glucose, ubiquinol-10); enzymatic antioxidants, such as superoxide dismutase and metal complexes with a similar activity, including catalase, glutathione peroxidase, and less complex molecules, such as beta-carotene, bilirubin, uric acid; flavonoids (flavones, flavonols, flavonones, flavanonals, chacones, anthocyanins), N-acetylcystein, mesna, glutathione, thiohistidine derivatives, triazoles; tannines, cinnamic acid, hydroxycinnamatic acids and their esters (coumaric acids and esters, caffeic acid and their esters, ferulic acid, (iso-) chlorogenic acid, sinapic acid); spice extracts (e.g. from clove, cinnamon, sage, rosemary, mace, oregano, allspice, nutmeg); camosic acid, camosol, carsolic acid; rosmarinic acid, rosmaridiphenol, gentisic acid, ferulic acid; oat flour extracts, such as avenanthramide 1 and 2; thioethers, dithioethers, sulphoxides, tetralkylthiuram disulphides; phytic acid, steroid derivatives (e.g. U74006F); tryptophan metabolites (e.g. 3-hydroxykynurenine, 3-hydroxyanthranilic acid), and organochalcogenides.    
   
   
       8 . Formulation according to  claim 7 , 
 characterised in that the concentration of BHA or BHT is between 0.001 and 2 w-%, more preferably is between 0.0025 and 0.2 w-%, and most preferably is between 0.005 and 0.02 w-%, of TBHQ and PG is between 0.001 and 2 w-%, more preferably is between 0.005 and 0.2 w-%, and most preferably is between 0.01 and 0.02 w-%, of tocopherols is between 0.005 and 5 w-%, more preferably is between 0.01 and 0.5 w-%, and most preferably is between 0.05 and 0.075 w-%, of ascorbic acid esters is between 0.001 and 5, more preferably is between 0.005 and 0.5, and most preferably is between 0.01 and 0.15 w-%, of ascorbic acid is between 0.001 and 5, more preferably is between 0.005 and 0.5 w-%, and most preferably is between 0.01 and 0.1 w-%, of sodium bisulphite or sodium metabisulphite is between 0.001 and 5, more preferably is between 0.005 and 0.5 w-%, and most preferably is between 0.01-0.15 w-%, of thiourea is between 0.0001 and 2 w-%, more preferably is between 0.0005 and 0.2, and most preferably is between 0.001-0.01 w-%, most typically 0.005 w-%, of cysteine is between 0.01 and 5, more preferably is between 0.05 and 2 w-%, and most preferably is between 0.1 and 1.0 w-%, most typically 0.5 w-%, of monothioglycerol is between 0.01 and 5 w-%, more preferably is between 0.05 and 2 w-%, and most preferably is between 0.1-1.0 w-%, most typically 0.5 w-%, of NDGA is between 0.0005-2 w-%, more preferably is between 0.001-0.2 w-%, and most preferably is between 0.005-0.02 w-%, most typically 0.01 w-%, of glutathione is between 0.005 and 5 w-%, more preferably is between 0.01 and 0.5 w-%, and most preferably is between 0.05 and 0.2 w-%, most typically 0.1 w-%, of EDTA is between 0.001 and 5 w-%, even more preferably is between 0.005 and 0.5 w-%, and most preferably is between 0.01 and 0.2 w-%, most typically between 0.05 and 0.975 w-%, of citric acid is between 0.001 and 5 w-%, even more preferably is between 0.005 and 3 w-%, and most preferably is between 0.01-0.2, most typically between 0.3 and 2 w-%.    
   
   
       9 . Formulation according to any one of the preceding claims, 
 characterised in that the microbicide is selected from short chain alcohols, comprising ethyl and isopropyl alcohol, chlorbutanol, benzyl alcohol, chlorbenzyl alcohol, dichlorbenzylalcohol, hexachlorophene; phenolic compounds, such as cresol, 4-chloro-m-cresol, p-chloro-m-xylenol, dichlorophene, hexachlorophene, povidon-iodine; parabenes, especially alkyl-parabenes, such as methyl-, ethyl-, propyl-, or butyl-paraben, benzyl paraben; acids, such as sorbic acid, benzoic acid and their salts; quaternary ammonium compounds, such as alkonium salts, e.g. a bromide, benzalkonium salts, such as a chloride or a bromide, cetrimonium salts, e.g. a bromide, phenoalkecinium salts, such as phenododecinium bromide, cetylpyridinium chloride and other salts; mercurial compounds, such as phenylmercuric acetate, borate, or nitrate, thiomersal, chlorhexidine or its gluconate, or any antibiotically active compounds of biological origin, or any mixture thereof.    
   
   
       10 . Formulation according to  claim 9 , 
 characterised in that the bulk concentration of short chain alcohols in the case of ethyl, propyl, butyl or benzyl alcohol is up to 10 w %, more preferably is up to 5 w-%, and most preferably is in the range between 0.5-3 w-%, in the case of chlorobutanol is in the range between 0.3-0.6 w-%; bulk concentration of parabens, especially in the case of methyl paraben is in the range between 0.05-0.2 w-%, and in the case of propyl paraben is in the range between 0.002-0.02 w-%; bulk concentration of sorbic acid is in the range between 0.05-0.2 w-%, and in the case of benzoic acid is in the range between 0.1-0.5 w-%; bulk concentration of phenols, triclosan, is in the range between 0.1-0.3 w-%, and bulk concentration of chlorhexidine is in the range between 0.01-0.05 w-%.    
   
   
       11 . Formulation comprising molecular arrangements capable of penetrating pores in a barrier, owing to penetrant adaptability, despite the fact that the average diameter of said pores is smaller than the average penetrant diameter, provided that the penetrants can transport agents or else enable agent permeation through the pores after said penetrants have entered said pores, the agents associated with said penetrants being glucocorticoids or mineralocorticosteroids (corticosteroids), 
 characterised in that the relative content of corticosteroids is above 0.1 weight-%, relative to total dry mass of the formulation.    
   
   
       12 . Formulation according to  claim 11 , 
 characterised in that at least one consistency builder and/or at least one anti-oxidant and/or at least one microbicide according to any one of the claims  1  through to  10  is added to the formulation.    
   
   
       13 . Formulation according to  claim 11  or  12 , 
 characterised in that the corticosteroid is selected from alclonetasone dipropionate, amcinonide, beclomethasone dipropionate, betamethasone, betamethasone 17-valerate, betamethasone 17,21-divalerate, betarnethasone 21-acetate, betamethasone 21-buytrate, betamethasone 21-propionate, betamethasone 21-valerate, betamethasone benzoate, betamethasone dipropionate, betamethasone valerate, budesonide, clobetasol propionate, clobetasone butyrate, cortexolone, corticosterone, cortisone, cortisone 17-acetate, 21-deoxybetamethasone, 21-deoxybetamethasone 17-propionate, deoxycorticosterone, desonide, desoxymethasone, dexamethasone, diflorasone diacetate, diflucortolone valerate, fluclorolone acetonide, flumethasone pivalate, fluocinolone acetonide, fluocinonide, fluocortin butyl, fluocortolone, 9-alpha-fluorocortisone, 9-alpha-fluorohydrocortisone, 9-alpha-fluoroprednisolone, fluprednidene acetate, flurandrenolone, halcinonide, hydrocortisone, hydrocortisone 17-acetate, hydrocortisone 17-butyrate, hydrocortisone 17-propionate, hydro cortisone 17-valerate, hydrocortisone 21-acetate, hydrocortisone 21-butyrate, hydrocortisone 21-propionate, hydrocortisone 21-valerate, 17-alpha-hydroxyprogesterone, methylprednisolone acetate, mometasone furoate, prednisolone, prednisone, prednisone 17-acetate, prednisone 17-valerate, progesterone, triamcinolone, triamcinolone acetonide.    
   
   
       14 . Formulation according to any one of the preceding claims, 
 characterised in that the penetrants are suspended or dispersed in a polar liquid in the form of fluid droplets surrounded by a membrane-like coating of one or several layers, said coating comprising at least two kinds or forms of amphiphilic substances with a tendency to aggregate, provided that said at least two substances differ by at least a factor of 10 in solubility in said liquid or else that said substances when in the form of homo-aggregates, for the more soluble substance, or of hetero-aggregates, for any combination of both said substances, have a preferred average diameter smaller than the diameter of the homo-aggregates containing merely the less soluble substance; or else provided that the presence of the more soluble substance lowers the average elastic energy of the membrane-like coating in the vicinity of thermal energy.    
   
   
       15 . Formulation according to  claim 14 , 
 characterised in that the more soluble substance tends to solubilise the droplet and the content of such substance is up to 99 mol-% of solubilising concentration or else corresponds to up to 99 mol-% of the saturating concentration in the unsolubilised droplet, whichever is higher.    
   
   
       16 . Formulation according to  claim 15 , 
 characterised in that the content of the more soluble substance is below 50%, especially below 40% and most preferably below 30%, of said solubilising concentration of said substance.    
   
   
       17 . Formulation according to  claim 15 , 
 characterised in that the content of the more soluble substance is below 80%, preferably below 65% and most preferably below 50% of said saturation concentration of said substance in the droplet.    
   
   
       18 . Formulation according to any one of  claims 14  to  17 , 
 characterised in that the less soluble amongst the aggregating substances is a lipid or lipid-like material, especially a polar lipid, whereas the substance which is more soluble in the suspending liquid and which increases the droplet adaptability belongs to surfactants or else has surfactant-like properties.    
   
   
       19 . Formulation according to  claim 18 , 
 characterised in that the lipid or lipid-like material is a lipid or a lipoid from a biological source or a corresponding synthetic lipid or any of its modifications, said                           lipid preferably belonging to the class of pure phospholipids with the chemical formula    where R 1  and R 2  is an aliphatic chain, typically a C 10-20 -acyl, or -alkyl or partly unsaturated fatty acid residue, in particular, an oleoyl-, palmitoeloyl-, elaidoyl-, linoleyl-, linolenyl-, linolenoyl-, arachidoyl-, vaccinyl-, lauroyl-, myristoyl-, palmitoyl-, or stearoyl chain; and where R 3  is hydrogen, 2-trimethylamino-1-ethyl, 2-amino-1-ethyl, C 1-4 -alkyl, C 1-5 -alkyl substituted with carboxy, C 2-5 -alkyl substituted with hydroxy, C 2-5 -alkyl substituted with carboxy and hydroxy, or C 2-5 -alkyl substituted with carboxy and amino, inositol, sphingosine, or salts of said substances, said lipid comprising also glycerides, isoprenoid lipids, steroids, sterines or sterols, of sulphur- or carbohydrate-containing lipids, or any other bilayer-forming lipids, in particular half-protonated fluid fatty acids, said lipid is selected from the group comprising phosphatidylcholines, phosphatidylethanolamines, phosphatidylglycerols, phosphatidylinositols, phosphatidic acids, phosphatidylserines, sphingomyelins or other sphingophospholipids, glycosphingolipids (including cerebrosides, ceramidepolyhexosides, sulphatides, sphingoplasmalogens), gangliosides and other glycolipids or synthetic lipids, in particular with corresponding sphingosine derivatives, or any other glycolipids, whereby two similar or different chains can be ester-groups-linked to the backbone (as in diacyl and dialkenoyl compound) or be attached to the backbone with ether bonds, as in dialkyl-lipids.    
   
   
       20 . Formulation according to  claim 18 , 
 characterised in that the surfactant or surfactant-like material is a nonionic, a zwitterionic, an anionic or a cationic surfactant, especially a fatty-acid or -alcohol, an alkyl-tri/di/methyl-ammonium salt, an alkylsulphate salt, a monovalent salt of cholate, deoxycholate, glycocholate, glycodeoxycholate, taurodeoxycholate, taurocholate, etc., an acyl- or alkanoyl-dimethyl-aminoxide, esp. a dodecyl-dimethyl-aminoxide, an alkyl- or alkanoyl-N-methylglucamide, N-alkyl-N,N-dimethylglycine, 3-(acyldimethylammonio)-alkanesulphonate, N-acyl-sulphobetaine, a polyethylene-glycol-octylphenyl ether, esp. a nonaethylene-glycol-octylphenyl ether, a polyethylene-acyl ether, esp. a nonaethylen-dodecyl ether, a polyethylene-glycol-isoacyl ether, esp. a octaethylene-glycol-isotridecyl ether, polyethylene-acyl ether, esp. octaethylenedodecyl ether, polyethylene-glycol-sorbitane-acyl ester, such as polyethylenglykol-20-monolaurate (Tween 20) or polyethylenglykol-20-sorbitan-monooleate (Tween 80), a polyhydroxyethylene-acyl ether, esp. polyhydroxyethylene-lauryl, -myristoyl, -cetylstearyl, or -oleoyl ether, as in polyhydroxyethylene-4 or 6 or 8 or 10 or 12, etc., -lauryl ether (as in Brij series), or in the corresponding ester, e.g. of polyhydroxyethylen-8-stearate (Myrj 45), -laurate or -oleate type, or in polyethoxylated castor oil 40, a sorbitane-monoalkylate (e.g. in Arlacel or Span), esp. sorbitane-monolaurate, an acyl- or alkanoyl-N-methylglucamide, esp. in or decanoyl- or dodecanoyl-N-methylglucamide, an alkyl-sulphate (salt), e.g. in lauryl- or oleoyl-sulphate, sodium deoxycholate, sodium glycodeoxycholate, sodium oleate, sodium taurate, a fatty acid salt, such as sodium elaidate, sodium linoleate, sodium laurate, a lysophospholipid, such as n-octadecylene(=oleoyl)-glycerophosphatidic acid, -phosphorylglycerol, or -phosphorylserine, n-acyl-, e.g. lauryl or oleoyl-glycero-phosphatidic acid, -phosphorylglycerol, or -phosphorylserine, n-tetradecyl- glycero-phosphatidic acid, -phosphorylglycerol, or -phosphorylserine, a corresponding palmitoeloyl-, elaidoyl-, vaccenyl-lysophospholipid or a corresponding short-chain phospholipid, or else a surface-active polypeptide.    
   
   
       21 . Formulation according to any one of  claims 14  to  20 , 
 characterised in that the average penetrant diameter is between 30 nm and 500 nm, preferably between 40 nm and 250 nm, even more preferably between 50 nm and 200 nm and most preferably between 60 nm and 150 nm.    
   
   
       22 . Formulation according to any one of  claims 14  to  20 , 
 characterised in that the average diameter of the penetrant is 2 to 25 times bigger than the average diameter of the pores in the barrier, preferably between 2.25 and 15 times bigger, even more preferably between 2.5 and 8 times bigger and most preferably between 3 and 6 times bigger than said average pore diameter.    
   
   
       23 . Formulation according to any one of claims  14  through to  22 , 
 characterised in that the dry weight of all carrier droplets in a formulation for the use on human or animal skin is 0.01 weight-% (w-%) to 40 w-% of total formulation mass, in particular between 0.1 w-% and 30 w-%, particularly preferably between 0.5 w-% and 20 w-%, and most preferably between 1 w-% and 10 w-%.    
   
   
       24 . Formulation according to any one of claims  14  through to  22 , 
 characterised in that the dry weight of all carrier droplets in a formulation for the use on human or animal mucosa is 0.0001 w-% to 30 w-% of total formulation mass.    
   
   
       25 . Formulation according to any one of the claims  1  through to  24 , 
 characterised in that the pH of carrier suspension is between 4 and 10, preferably between 5 and 9, and even more often up to 8.5, as required to maximise the stability of formulation.    
   
   
       26 . A method for preparing a formulation for non-invasive application in vivo, according to any one of the preceding claims, 
 characterised in that penetrants capable of associating and/or incorporating said agent molecules are formed from at least one amphiphilic substance, at least one polar fluid, at least one edge-active substance or surfactant, at least one corticosteroid in an amount of more than 0.1 w-% based on total dry mass of the formulation, and, in case, other customary ingredients, which together form said formulation.    
   
   
       27 . The method of  claim 26 , 
 characterised in that at least one edge-active substance or surfactant, at least one amphiphilic substance, at least one hydrophilic fluid and the agent are dissolved to form a solution and, if required, are mixed separately, the resulting (partial) mixtures or solutions then being combined to subsequently induce, preferably by action of mechanical energy, such as shaking, stirring, vibrating, homogenising, ultrasonication, shear, freezing and thawing, or filtration using convenient driving pressure, the formation of penetrants that associate with and/or incorporate the agent.    
   
   
       28 . The method of claims  26  or  27 , 
 characterised in that said amphiphilic substances are either used as such, or dissolved in a physiologically compatible polar fluid, which may be water or miscible with water, or in a solvation-mediating agent, together with a polar solution.    
   
   
       29 . The method of claims  26  or  27 , 
 characterised in that said amphiphilic substances are dissolved in highly volatile alcohols, in especially ethanol, or in pharmaceutically acceptable organic solvents, which are then removed, esp. by evaporation, prior to making final preparation.    
   
   
       30 . The method as claimed in claims  28  or  29 , 
 characterised in that the polar solution contains at least one edge-active substance or surfactant.    
   
   
       31 . The method according to any one of claims  26  through to  30 , 
 characterised in that the formation of said penetrants is induced by the addition of required substances into a fluid phase, evaporation from a reverse phase, by injection or dialysis, if necessary under the influence of mechanical stress, such as shaking, stirring, in especially high velocity stirring, vibrating, homogenising, ultrasonication, shearing, freezing and thawing, or filtration using convenient, in especially low (1 MPa) or intermediate (up to 10 MPa), driving pressure.    
   
   
       32 . The method of  claim 31 , 
 characterised in that the formation of said penetrants is induced by filtration, the filtering material having pores sizes between 0.01 μm and 0.8 μm, preferably between 0.02 μm and 0.3 μm, and most preferably between 0.05 μm and 0.15 μm, whereby several filters may be used sequentially or in parallel.    
   
   
       33 . The method according to any one of claims  26  through to  32 , 
 characterised in that said agents and penetrants are made to associate, at least partly, after the formation of said penetrants, e.g. after injecting a solution of the drug in a pharmaceutically acceptable fluid, such as ethanol, 1-and 2-propanol, benzyl alcohol, propylene glycol, polyethylene glycol (molecular weight: 200-400 D) or glycerol into the suspending medium, said penetrants being formed previously, using the corresponding or some other suitable manufacturing method, or simultaneously with the drug injection, if required using a co-solution of the drug and, at least some, penetrant ingredients.    
   
   
       34 . The method according to any one of the claims  26  through to  33 , 
 characterised in that said penetrants, with which the agent molecules are associated and/or into which the agent is incorporated, are prepared just before the application of the formulation, if convenient from a suitable concentrate or a lyophylisate.    
   
   
       35 . Formulation according to any one of claims  11  through to  25 , 
 characterised in that the content of corticosteroids is between 0.1 w-% and 20 w-%, more preferably between 0.25 w-% and 10 w-% and even more preferably between 0.5 w-% and 5 w-%, relative to total dry mass of drug-loaded carriers.    
   
   
       36 . Formulation according to  claim 35 , 
 characterised in that the relative content of corticosteroids in the case of triamcinolone or one of its derivatives, such as acetonide, is below 2 w-%, relative to total dry mass of the drug-loaded carriers, even more preferably is below 1 w-% and most preferably is below 0.5 w-%.    
   
   
       37 . Formulation according to  claim 35 , 
 characterised in that the relative content of corticosteroids in the case of hydrocortisone or one of its derivatives is below 20 w-%, relative to total dry mass of the drug-loaded carriers, even more preferably is below 12.5 w-% and most preferably is below 5 w-%.    
   
   
       38 . Formulation according to  claim 35 , 
 characterised in that the relative content of corticosteroids in the case of dexamethasone or one of its derivatives is below 15 w-%, relative to total dry mass of the drug-loaded carriers, even more preferably is below 10 w-% and most preferably is below 5 w-%.    
   
   
       39 . Formulation according to  claim 35 , 
 characterised in that the relative content of corticosteroids in the case of clobetasol or one of its derivatives, such as propionate is below 15 w-%, relative to total dry mass of the drug-loaded carriers, even more preferably is below 10 w-% and most preferably is below 5 w-%.    
   
   
       40 . Formulation according to  claims 35  to  39 , 
 characterised in that the content of said corticosteroid is below the saturation maximum, defined as the content of corticosteroid at which the corticosteroid begins to crystallise in or outside the carrier.    
   
   
       41 . Formulation according to claims  1  through to  25  and  35  through to  38 , 
 characterised in that in order to speed up drug action a permeation enhancer is added.    
   
   
       42 . Formulation according to  claim 41 , 
 characterised in that the permeation 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-dioxolanes (SEPA), 1,2,3-triacyl-glycerols, 1-alkanols, 1-alkanoic acids, 1-alkyl-acetates, 1-alkyl-amines, 1-alkyl-n-alkyl-polyoxyethylenes, 1-alkyl-alkylates, n-alkyl-beta-D-thioglucosides, 1-alkyl-glycerides, 1-alkyl-propyleneglycols, 1-alkyl-polyoxyethylenes, (1-alkyl-)2-pyrrolidones, alkyl-acetoacetates, alkylene-glycols, alkyl-methyl-sulphoxides (alkyl-DMSO), alkyl-propionates, alkyl-sulphates, diacyl-succinates, diacyl-N,N-dimethylaminoacetates (DDAA), diacyl-N,N-dimethylaminoisopropionates (DDAIP), phenyl-alkyl-amines.    
   
   
       43 . Formulation according to  claim 42 , 
 characterised in that the bulk concentration range of the used enhancers is up to and around 5% for 1-capryl-propylene glycol, 6-10% for 1-[2-(decylthio)ethyl]azacyclopentan-2-one (=HPE-101), <10% for 1-dodecanol, <10% for 1-dodecyl-azacycloheptan-2-one (=azone), in the range of 10% for 2-n-nonyl-1,3-dioxolane (SEPA), <10% for 2-n-octylcyclohexanone, up to, and preferably around, up to 20% for DMSO, up to, and between 5% and 40% for ethanol, in the range of 10% or higher 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 oleic acid and oleyl-alcohol, of the order of around 1% for oleyl-polyoxyethylene-ether, at least 10% for propylene glycol.    
   
   
       44 . Formulation according to claims  11  through to  25  and  35  through to  43 , 
 characterised in that said corticosteroid is added in an amount which enables the formulation to be applied corresponding to an area dose, as expressed by the total dry mass of penetrant applied per unit area, of between 0.1 mg cm −2  and 15 mg cm −2 , more preferably between 0.5 mg cm −2  and 10 mg cm −2 , particularly preferably between 0.75 mg cm −2  and 5 mg cm −2  and most preferably between 1 mg cm −2  and 2.5 mg cm −2 , if said corticosteroid is desired to exert a therapeutic effect in the deep subcutaneous, e.g. muscle or joints, tissue or else in the remote tissues, including the whole body.    
   
   
       45 . Formulation according to claims  11  through to  25  and  35  through to  43 , 
 characterised in that said corticosteroid is added in an amount which enables the formulation to be applied with an area dose, as expressed by the total dry mass of penetrant applied per unit area, of between 1 μg cm −2  and 250 μg cm −2 , more preferably between 2.5 and 100 μg cm −2 , even more preferably between 5 μg cm −2  and 50 μg cm −2  and most preferably between 7.5 μg cm −2  and 20 μg cm −2 , if said corticosteroid is desired to exert a mainly local, that is, superficial, rather than systemic therapeutic effect.    
   
   
       46 . Formulation according to claims  11  through to  25  and  35  through to  45 , 
 characterised in that consistency and, if necessary other characteristics of the formulation are appropriately selected to enable spraying, smearing, rolling or sponging of the formulation on the application area in particular by using a sprayer, spender, roller or sponge, as appropriate.    
   
   
       47 . A method for non-invasive application of corticosteroids by means of penetrants according to any one of the preceding claims, 
 characterised in that the area dose, as expressed by the total dry mass of penetrant applied per unit area, is selected to be between 0.1 mg cm −2  and 15 mg cm −2 , preferably between 0.5 mg cm −2  and 10 mg cm −2 , particularly preferably between 0.75 mg cm −2  and 5 mg cm −2  and most preferably between 1 mg cm −2  and 2.5 mg cm −2 , if said corticosteroid is desired to exert a therapeutic effect in the deep subcutaneous, e.g. muscle or joints, tissue or else in the remote tissues, including the whole body.    
   
   
       48 . A method for non-invasive application of corticosteroids by means of penetrants according to any one of the preceding claims, 
 characterised in that the area-dose, as expressed by the total dry mass of penetrants applied per unit area, is between 1 μg cm −2  and 250 μg cm −2 , preferably between 2.5 μg cm −2  and 100 μg cm −2 , more preferably between 5 μg cm −2  and 50 μg cm −2  and most preferably between 7.5 μg cm −2  and 20 μg cm −2 , if said corticosteroid is desired to exert a mainly local, that is, superficial, rather than systemic therapeutic effect.    
   
   
       49 . A method for non-invasive application of corticosteroids associated with or encapsulated into said penetrants according to any one of the preceding claims, 
 characterised in that the formulation is applied by spraying, smearing, rolling or sponging on the application area in particular by using a sprayer, spender, roller or sponge, as appropriate.    
   
   
       50 . Use of a formulation in accordance with any one of the preceding claims for the treatment of inflammatory disease, dermatosis, kidney or liver failure, adrenal insufficiency, aspiration syndrome, Behcet syndrome, bites and stings, blood disorders, such as cold-haemagglutinin disease, haemolytic anemia, hypereosinophilia, hypoplastic anemia, macroglobulinaemia, trombocytopenic purpura, furthermore, for the management of bone disorders, cerebral oedema, Cogan's syndrome, congenital adrenal hyperplasia, connective tissue disorders, such as lichen, lupus erythematosus, polymyalgia rheumatica, polymyositis and dermatomyositis, epilepsy, eye disorders, such as cataracts, Graves'ophthalmopathy, haemangioma, herpes infections, neuropathies, retinal vasculitis, scleritis, for some gastro-intestinal disorders, such as inflammatory bowel disease, nausea and oesophageal damage, for hypercalcaemia, infections, e.g. of the eye (as in infections mononucleosis), for Kawasaki disease, myasthenia gravis, various pain syndromes, such as postherpetic neuralgia, for polyneuropathies, pancreatitis, in respiratory disorders, such as asthma, for the management of rheumatoid disease and osteoarthritis, rhinitis, sarcoidosis, skin diseases, such as alopecia, eczema, erythema multiforme, lichen, pemphigus and pemphigoid, psoriasis, pyoderma gangrenosum, urticaria, in case of thyroid and vascular disorders.