Patent GB-894424-A (GB)
Title: Pharmaceutical compositions for topical application comprising steroids
IPC: A61K31/573
Filed: 1960-06-24
Abstract: 1 - Dehydro - 6a  - methyl - 9a  - fluoro - 16a  - hydroxyhydrocortisone 16,17-acetonide and its 21 esters are prepared by the following reaction sequence: 6a -methylhydrocortisone acetate is reacted with semicarbazide hydrochloride in methanol and pyridine to form the 3,20-disemicarbazone which is refluxed under nitrogen with acetic anhydride, the mixture concentrated and treated with pyruvic acid and extracted with chloroform to give 6a -methyl-11b ,21-dihydroxy4,16-pregnadiene-3,20-dione 21 acetate which, by treatment with (a) osmium tertoxide and (b) anhydrous sodium sulphate and potassium bicarbonate yields 6a  - methyl - 11b , 16a , 17a , 21 - tetrahydroxy-4-pregnene-3,20-dione and its acetate.  The latter is reacted with sodium hydroxide in methanol under nitrogen to give 6a -methyl-16a -hydroxyhydrocortisone which is acetylated by acetic anhydride in pyridine to give 6a -methyl-16a -hydroxyhydrocortisone 16,21-diacetate which, on treatment with N-bromoacetamide in pyridine, yields 6a  - methyl - 16a , 17a , 21 - trihydroxy - 4, 9(11) - pregnadiene - 3, 20 - dione 16, 21 - di - acetate which is reacted with 71% perchloric acid and N-bromoacetamide in methylene chloride/water/-t-butyl alcohol to give 6a -methyl-9a  - bromo - 11b , 16a , 21 - tetrahydroxy - 4 - pregnene-3,20-dione 16,21-diacetate which, after treatment with anhydrous potassium acetate in acetone under reflux, and chromatographic separation, yields 6a  - methyl - 9b , 11b  - oxido - 16a , 17a , 21 - trihydroxy -4 - pregnene - 3, 20 - dione 16,21-diacetate which is treated with hydrofluoric acid and perchloric acid to give 6a -methyl-9a  - fluoro - 11b , 16a , 17a , 21 - tetrahydroxy - 4 - pregnene - 3,20 - dione 16, 21 - diacetate which is treated with potassium hydroxide in methanol to give 6a -methyl-9a -fluoro-16a -hydroxyhydrocortisone which is added, together with 3-ketobisnor-4-cholen-22-al, to a deep fermentation culture of Septomyxa affinis from which there is subsequently obtained 1-dehydro-6a -methyl-9a fluoro-16a -hydroxyhydrocortisone which is treated with perchloric acid in acetone to give 1-dehydro6a - methyl - 9a  - fluoro - 16a  - hydroxyhydro - cortisone 16,17-acetonide.  The preparation of numerous 21-esters and semiesters thereof by reaction (a) with the appropriate acid anhydride and; (b) with the appropriate acid chloride is described as is the preparation of sodium salts of hemi-esters by treatment of the hemi-ester with sodium hydroxide (aqueous) in acetone solution.ALSO:Pharmaceutical and veterinary compositions for topical application comprise 1-dehydro-6a -methyl - 9a  - fluoro - 16 - hydroxycortisone - 16, 17-acetonide and physiologically acceptable 21-esters thereof dispersed in a pharmaceutical carrier.  Optional additional active ingredients which may be included are: antibiotics, e.g. neomycin, the tetracyclines, novobiocin, erythromycin, bacitracin, polymyxin and penicillin, antifungal agents, e.g. iodochlorohydroxyquin and nystatin, vasoconstrictors, e.g. phenylephrine and isoproterenol and local anaesthetics, e.g. procaine hydrochloride, tetracaine hydrochloride, lidocaine hydrochloride and primoxine hydrochloride.  Specified esters of the steroid are the acetate, furoate, tertiary butyl acetate carbethoxylate, diphenylacetate, 2 - chloro - 4 - nitrobenzoate, 2-ethyl-isovalerate, a -ethyl-n-butyrate, cyclopentylcarboxylate, alkali metal salts of the hemisuccinate, hemiglutarate, hemib ,b -dimethylglutarate and hemimaleate and amine salts thereof, e.g. with diethanolamine and epinephrine, the phosphate and the xanthogenate.  Specified suitable pharmaceutical forms are: ointments, creams, lotions, jellies, powders (e.g. for insufflation), sprays (e.g. for oral and nasal use), aerosols, drops (e.g. for ears and eyes), rectal and vaginal suppositories.  The preferred concentration range for the principal active ingredient ranges from about 0.005 to 0.1% by weight.  A reaction sequence for the production of the active compounds is described (see Group IV (b)).