Title of Invention	A MEDICINAL SHAMPOO PREPARATION
Abstract	ABSTRACT "A MEDICINAL SHAMPOO PREPARATION" 2112/MAS/97 A shampoo composition comprising fro the treatment of seborrheic dermatitis compounds of the formula I atleast one anionic, cationic, non-ionic amphoteric surfactants at a pH of 4.5 to 6.5

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The present invnetion relates to serborrheic dermatitis. Seborrheic dermatitis is understood as meaning a disease of the scalp which differs from simple dandruff by the presence of erythema as a sign of inflammation, the more severe degree of scaling with occasional itching and stinging, as well as by the occurrence of eczematous changes at other body sites. It can occur in spots, but also more frequently attacks the whole scalp and often involves the forehead beyond the hair line, around the neck and the ears. In severe cases the scalp can undergo secondary infection, and the changes may then exhibit a spungy consistency, vesicle formation and crust formation and weep. Seborrheic dermatitis frequently occurs even in infancy and usually remits spontaneously at an age of 8 -12 months. In infants, the scalp changes consisting of erythema, scaling and sometimes vesicle formation and crust formation can regress spontaneously within a few weeks, intermittently reoccur or persist during the entire childhood. They are frequently combined with a similar process around the eyelids, nose and ears. Later, the affliction usually occurs after puberty and can remain for the entire life or even increase in severity. Approximately 1 - 3% of the population are affected by this disease. It is known that 1-hydroxy-2-pyridones and their salts exhibit activity against normal dandruff, which is characterized by a clinically noninflammatory scaling of the scalp -occurring in nearly all people (DE 22 34 009). The most promising type of treatment of seborrheic dermatitis was until now the topical application of corticosteroid preparations, more recently, however, topical therapy with substances having antimycotic activity has gained in importance. Whereas corticosteroid preparations display their activity exclusively by means of an effect on the inflammatory process, the antimycotic substances, such as ketoconazole, are active exclusively against the yeast fungi of the strain Pityrosporum assumed to be the cause of seborrheic dermatitis. The 1-hydroxy-2-pyridones according to the invention, however, combine the properties of both substance classes in one substance and exhibit both antiinflammatory activity and antimycotic activity against Pityrosporum strains. In comparison with ketoconazole - even after only a short topical contact time - the substances according to the invention concentrate rapidly in the skin layers relevant to the fungal growth and thus contribute to rapid healing. Whereas ketoconazole is inactive in vitro against gram-positive bacterid (Kinsman et al., J. Med. Microbiol (1983) 16, No. 2, IV), the hydroxypyridones according to the invention exhibit activity against gram-positive and gram-negative aerobic and anaerobic bacteria (Dittmar et al., Arzneim.- Forschung, (1981) 31 (II), No. 8a, pp. 1317 -1322). With respect to the treatment of cases of secondary infection, this is an extremely important finding. The compounds used according to the invention furthermore have very decisive advantages compared with ketoconazole with respect to their processing possibilities in pharmaceutical preparations. On account of their solubility in water, alcohols and aqueous-alcoholic solutions, the preparation of hair lotions and transparent gel preparations is possible without problems. The preparations according to the invention can also be employed for the treatment of Pityriasis versicolor, a superficial, noninflammatory skin fungus disorder on the body. optionally oxygen and/or sulfur atoms linked in a chain, where - if the radicals contain 2 or more oxygen and/or sulfur atoms - the latter must be separated from one another by at least 2 carbon atoms and where 2 adjacent carbon atoms can also be linked to one another by a double bond and the free valencies of the carbon atoms are saturated by H and/or (C1-C4)-alkyl groups, Ar is an aromatic ring system having up to two rings, which can be substituted by up to three radicals from the group consisting of fluorine, chlorine, bromine, methoxy, (C1-C4)-alkyl, trifluoromethyl and trifluoromethoxy, in free or in salt form, for the production of a pharmaceutical for the treatment of seborrheic dermatitis. In the radicals "Z", the carbon chain members are preferably CH2 groups. If the CH2 groups are substituted by C1-C4-alkyl groups, CH3 and C2H5 are preferred substituents. Exemplary radicals "Z" are: -0-, -S-, -CH2-, -(CH2)m- (m = 2 - 10), -C(CH3)2-, -CH2O-, -OCH2-, -CH2S-, -SCHj-, -SCH(C2H5)-, -CH=CH-CH20-, -0-CH2-CH=CH-CH20-, -OCH2-CH2O-, -OCH2-CH2CH2O-, -SCH2CH2CH2S-, -SCH2CH2CH2CH2O-, -SCH2CH2OCH2CH2O-, -SCH2CH2OCH2CH2O-CH2CH2S- or -S-CH2-C(CH2)2-CH2-S-. The radical "S" denotes a sulfur atom, the radical "O" denotes an oxygen atom. The term "Ar" denotes phenyl or condensed systems such as naphthyl, tetrahydronaphthyl and Indenyl, and also isolated systems such as those which are derived from biphenyl, diphenylalkanes, diphenyl ethers and diphenyl thioethers. In the formula I, the hydrocarbon radical R'* is an alkyl or cyclohexyl radical which can also be bonded to the pyridone ring via a methylene or ethylene group or can contain an endomethyl group. R"^ can also be an aromatic radical which, however, is preferably bonded to the pyridone radical via at least one aliphatic carbon atom. Important representatives of the compound class characterized by the formula I are: 6-[4-(4-chlorophenoxy)phenoxymethyl]-1-hydroxy-4-methyl-2-pyridone, 6-[4-(2,4-dichlorophenoxy)phenoxymethyl]-1-hydroxy-4-methyl-2-pyridone, 6-(biphenylyl-4-oxymethyl)-1 -hydroxy-4-methyl-2-pyridone, 6-(4-benzylphenoxymethyl)-1 -hydroxy-4-methyl-2-pyridone, 6-[4-(2,4-dichlorobenzyloxy)phenoxymethyl]-1-hydroxy-4-methyl-2-pyridone, 6-[4-(4-chlorophenoxy)phenoxymethyl]-1-hydroxy-3,4-dimethyl-2-pyridone, 6-[4-(2,4-dichlorobenzyl)phenoxymethyl]-1-hydroxy-3,4-dimethyl-2-pyridone, 6-[4-(cinnamyloxy)phenoxymethyl]-1-hydroxy-4-methyl-2-pyridone, 1-hydroxy-4-methyl-6-[4-(4-trifluoromethylphenoxy)phenoxymethyl]-2-pyridone, 1- hydroxy-4-methyl-6-cyclohexyl-2-pyridone, 1-hydroxy-4-methyl-6-(2,4,4-trimethylpentyl)-2-pyridone, 1-hydroxy-4-methyl-6-n-hexyl-, -6-isohexyl-, -6-n-heptyl-or-6-isoheptyl-2-pyridone, 1-hydroxy-4-methyl-6-octyl- or-6-isooctyl-2-pyridone, in particular 1-hydroxy-4-methyl-6-cyclohexylmethyl- or -6-cyclohexylethyl-2-pyridone, where the cyclohexyl radical in each case can also carry a methyl radical, 1-hydroxy-4-methyl-6-(2-bicyclo[2,2,1]heptyl)-2-pyridone, 1-hydroxy-3,4-dimethyl-6-benzyl-or -6-dimethylbenzyl-2-pyridone or 1 -hydroxy-4-methyl-6-(B-phenylethyl)-2-pyridone. The term "saturated" in this case designates those radicals which contain no aliphatic multiple bonds, i.e. no ethylenic or acetylenic bonds. The abovementioned compounds of the formula I can be employed both in free form and as salts, use in free form is preferred. If organic bases are used, poorly volatile bases are preferably employed, for example low molecular weight alkanolamines such as ethanolamine, diethanolamine, N-ethylethanolamine, N-methyldiethanolamine, triethanolamine, diethylaminoethanol, 2-amino-2-methyl-n-propanol, dimethylaminopropanol, 2-amino-2-methyl-propanediol, triisopropanol-amine. Further poorly volatile bases which may be mentioned, for example, are ethylenediamine, hexamethylenediamine, morpholine, piperidine, piperazine, cyclohexylamine, tributylamine, dodecylamine, N,N-dimethyldodecylamine, stearylamine, oleylamine, benzylamine, dibenzylamine, N-ethylbenzylamine, dimethylstearylamine, N-methylmorpholine, N-methylpiperazine, 4-methylcyclohexylamine, N-hydroxyethylmorpholine. The salts of quaternary ammonium hydroxides such as trimethylbenzylammonium hydroxide, tetramethylammonlum hydroxide or tetraethylammonium hydroxide can also be used, and furthermore guanidine and its derivatives, in particular its alkylation products. However, it is also possible to employ as salt-forming agents, for example, low molecular weight alkylamines such as methylamine, ethylamine or triethylamine. Salts with inorganic cations, for example alkali metal salts, in particular sodium, potassium or ammonium salts. alkaline earth metal salts such as, in particular, the magnesium or calcium salt, and salts with di- to tetravalent cations, for example the zinc, aluminum or zirconium salt, are also suitable for the compounds to be employed according to the invention. The active compounds of the formula I to be employed in the preparations can be prepared, for example, by the process according to US 2 540 218. For the use of the compounds mentioned according to the invention, liquid to semisolid pharmaceutical preparations are suitable, in particular hair lotions, shampoos, liquid soaps, and cream, ointment and gel preparations. In this case, these are always preparations which, depending on their actual intended use, are applied to the skin and/or to the scalp for a relatively short or relatively long time. An effective treatment of seborrheic dermatitis is brought about by the addition of the compounds according to the invention. If the preparations according to the invention are present as a shampoo, they can be in the form of a clear liquid, opaque liquid or cream, or can even be gelatinous. The surfactants on which these shampoos are based can be of anionic, cationic, nonionic and amphoteric nature and can also be present in a combination of these substances. However, anionic surfactants are preferably employed on their own or as a mixture with other anionic surfactants as base surfactants - if appropriate with addition of amphoteric surfactants as cosurfactant. Amphoteric surfactants are unimportant in practice as the sole detergents, as their foam behavior, thickenability and in some cases also skin and eye mucous membrane tolerability are only moderate. In combination with various anionic surfactants, however, exactly these properties are synergistically improved. This explains the relatively high importance of the amphoteric surfactants for the optimization of anionic shampoo bases. Likewise, nonionic surfactants can be employed as cosurfactants. Examples of anionic detergents of this type which may be mentioned are: i^iO"^2o)'^" ixamples of amphoteric surfactants which can be added to the shampoos are: N- (Ci2"^i8)"3" Suitable nonionic surfactants which can be employed as detergents are, for example: fatty alcohol ethoxylates (alkylpolyethylene glycols); alkylphenol jolyethylene glycols; alkylmercaptan polyethylene glycols; fatty amine ethoxylates / (alkylamine polyethylene glycols); fatty acid ethoxylates (acyl polyethylene glycols), polypropylene glycol ethoxylates (Pluronic®); fatty acid alkylolamides (fatty acid amide polyethylene glycols); sucrose esters; alky! polyglucosides; sorbitol esters and polyglycol ether. Suitable cationic surfactants are, for example, quaternary ammonium salts such as di-((Cio"^24)"3"^y')dimethylammonium chloride or bromide, preferably di-((Ci2'^i8)" alkyl)dimethylammonium chloride or bromide; (0^0-^24)' alkyldimethylethylammonium chloride or bromide; (Cio-C24)-alkyltrimethylammonium chloride or bromide, preferably cetyltrimethyl-ammonium chloride or bromide and (C2o-C22)-alkyltrimethylammonium chloride or bromide; (C.,o-C24)-alkyldimethylbenzylammonium chloride or bromide, preferably (C12-C18)-alkyldimethylbenzylammonium chloride; N-((C.|o-Ci8)-alkyl)pyridinium chloride or bromide, preferably N-((Ci2"^i6)"3"^y')pyidinium chloride or bromide; N-((Cio-Ci8)-alkyl)isoquinolinium chloride, bromide or monoalkyl-sulfate; N-((C^2"^18)" alkylolaminoformyl-methyl)pyridinium chloride; N-((Ci2-Ci8)-alkyl)-N-methylmorpholinium chloride, bromide or monoalkylsulfate, N-((Ci2"Ci8)"^"^y')-N-ethyl-morpholinium chloride, bromide or monoalkylsulfate; (C^g-Cis-)-alkylpentaoxoethylammonium chloride; diisobutylphenoxyethoxyethyl-dimethylbenzylammonium chloride; salts of N,N-diethylaminoethyl-stearylamide and -oleylamide with hydrochloric acid, acetic acid, lactic acid, citric acid, phosphoric acid; N-acylamidoethyl-N,N-diethyl-N-methylammonium chloride, bromide or monoalkylsulfate and N-acylamidoethyl-N,N-diethyl-N-benzylammonium chloride, bromide or monoalkylsulfate, where acyl is preferably stearyl or oleyl. The preparations according to the invention can additionally contain further additives, e.g. fragrances, colorants, opacifying agents and pearl luster agents, for example esters of fatty acids and potyols, magnesium and zinc salts of fatty acids, dispersions based on mixed polymers, thickening agents such as sodium, potassium and ammonium chloride, sodium sulfate, fatty acid alkylolamides, cellulose derivatives of natural gums, collagen hydrolyzates, and furthermore fats, oils, fatty alcohols, silicones, substances having a keratolytic and keratoplastic action, for example sulfur, salicyclic acid or enzymes. The shampoos are prepared in a manner known per se by combining the individual components and - if necessary - further processing suited to the respective type of preparation. Some of these various possible preparations are described by way of example in the working examples. The preparations according to the invention can also be present in the form of aqueous and aqueous-alcoholic hair lotions, even those in gel form and in aerosol form as a spray or foam. Alcohols employed are preferably ethanol and isopropyl alcohol. Further preparations in which the 1-hydroxy-2-pyridones can be used according to the invention are, for example, cream and ointment preparations, and products which are primarily used for the treatment of hairless head and body parts. All these preparations are also prepared - as already mentioned in the case of the shampoo - in a manner known per se with addition of the active compound employed according to the invention. Of the abovementioned 1-hydroxy-2-pyridones, the preparations according to the invention can contain one compound or alternatively two or more in combination. The pH of the preparations is in the physiological range for skin from approximately pH 4.5 to 6.5. While when using the compounds in salt form the adjustment of the pH range mentioned must be carried out using organic acids, this measure is not necessary when using the free compounds. The active compound is incorporated in the preparations according to the invention in amounts which are customarily between approximately 0.05 and approximately 10%. Within this range, the concentrations of the specific preparations depend on their intended use. Certain preparation forms such as concentrates, which are to be diluted before their use, can have considerably higher concentrations. If preparations are concerned which remain on the skin and on the scalp, for example gel preparations, ointments, creams or hair lotions, lower concentrations will be employed, for example from about 0.05% to about 1%, preferably from 0.1 to 0.5%. In higher concentrations, they will expediently be used if preparations are concerned which, optionally after dilution, only act on the scalp for a short time, for example shampoos or liquid soaps. In these cases, concentrations, for example, of approximately 0.2 to approximately 10%, preferably of approximately 0.5% to approximately 2%, may be expedient. The following quantitative data relate to the weight, if not stated otherwise. Example 1 A preparation according to the Invention has the following composition: Shampoo (based on anionic detergents) 1-Hydroxy-4-methyl-6-cyclohexyl-2(1H)-pyridone Sodium lauryldiglycol ether sulfate (27% strength solution) Disodium laurylpolyglycol ether sulfosuccinate (33% strength solution) Sodium chloride Water 1.00% 40.00 % 10.00% 2.50 % 46.50 % u. Example 2 A preparation according to the invention nas tne following composition: Shampoo (based on anionic detergent with amphoteric surfactant as cosurfactant) 1 -Hydroxy-4-methyl-6-cyclohexyl-2(1 H)pyridone Sodium lauryldiglycol ether sulfate (27% strength solution) Cocamidopropylbetaine (30% strength solution) Sodium chloride Water 1.00% 36.00 % 6.00 % 3.30 % 53.70 % Example 3 A preparation according to the invention has the following composition; Shampoo (based on anionic detergent with nonionic surfactant as cosurfactant) 1 -Hydroxy-4-methyl-6-cyclohexyl-2(1 H)-pyridone Sodium lauryldiglycol ether sulfate (27% strength solution) Lauryl alcohol polyglucoside Sodium chloride Water 1.50% 30.00 % 8.00 % 2.00 % 58.50 % Example 4 A preparation according to the invention has the following composition: Liquid soap 1 -Hydroxy-4-methyl-6-cyclohexyl-2(1 H)-pyridone 1.00 % Sodium lauryldiglycol ether sulfate (27% strength solution) 35.00 % Cocamidopolyglycol ether sulfate magnesium salt (30% strength solution) 8.00 % Cocamidopropylbetaine (30% strength solution) 10.00 % Lauryl alcohol glycol ether 2.00 % Sodium chloride 2.00 % Water 42.00 % Example 5 A preparation according to the invention has the following composition: Hair lotion 1-Hydroxy-4-methyl-6-[4(4-chlorophenoxy)phenoxymethyl]- 2(1H)pyridone 0.05% 2-Propanol 60.00 % Water 39.95 % Example 6 A preparation according to the invention has the following composition: Gel preparation 1 -Hydroxy-4-methylcyclohexyl-2(1 H)pyridone 0.75 % 2-Propanol 15.00% 2-Octyldodecanol 7.50 % Carbomer 4 000 000 0.50 % Polysorbate 60 1.50% Sodium hydroxide 0.18% Water 74.57 % Example 7 A preparation according to the invention has the following composition: Cream preparation 1-Hydroxy-4-methyl-6-cyclohexyl-2(1 H)pyridone, aminoethanol salt 1:1 1.00% 2-Octyldodecanol 7.50 % Liquid paraffin 7.50 % Stearyl alcohol 7.50 % Cetyl alcohol 7.50 % Polysorbate 60 3.00 % Sorbitan monostearate 2.00 % Lactic acid 90% strength 0.51 % Water 63.49 % Example 8 In a clinical study with a total of 180 patients, it was possible to show that the symptoms of seborrheic dermatitis of the scalp (severe scaling, inflammation, itching) could be effectively treated by a 1 - 2x weekly treatment with a 1% strength cyclopirox shampoo preparation over a period of 4 weeks. Example 9 In a clinical study, it was possible to treat 180 patients with seborrheic dermatitis of the scalp, the face and the upper body successfully by application of a 0.77% strength cyclopirox gel preparation over a period of 4 weeks. We claim: 1. A medicinal shampoo preparation, comprising a 1 -hydroxy-2-pyridone of the formula I selected from the group consisting of 1-hydroxy-4-methyl-6-cyclohexyh-2-(1 H)pyridone and 1-hydroxy-4-methyl-6-(2,4,4-trimethylpentyl)-2-(1H)pyridone and at least one anionic, cationic, nonionic or amphoteric surfactant or a mixture of the surfactants at a pH of 4.5 to 6.5. 2. The shampoo preparation as claimed In claim 1, wherein the surfactant employed is at least one anionic surfactant on its own or as a mixture v\th other anionic surfactants and/or amphoteric surfactants. 3. The shampoo preparation as claimed in claims 1 or 2, wherein the 1-hydroxy-2-pyridone of the formula I Is employed In a concentration of 0.2% to 10%, 4. The shampoo preparation as claimed in claim 1, wherein the 1-hydroxy-2-pyrldone of the formula I is employed in a concentration of 0.5% to 2%.

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