Patent GB-741656-A (GB)
Title: Manufacture of highly concentrated preparations of steroid hormones suitable for injection
IPC: A61K38/22
Filed: 1952-03-17
Abstract: The invention is concerned with injectable steroid hormone preparations containing more than 50 mg. hormone substance per c.c. and comprising (a) sundry mixtures melting at 37 DEG  C. or lower or (b) oleaginous solutions of the hormone esters of aliphatic carboxylic acids containing 4-14 carbon atoms.  The preparation of several esters is described, viz.:-  Testosterone caproate, oenanthate and caprylate by heating testosterone, pyridine and the corresponding anhydride, decomposing with water and extracting with ether.  Mixed esters may be produced.  Desoxycorticosterone caprylate by dissolving at 90 DEG  C. 21 - diazo - pregnenol - (3) - one - (20) in caprylic acid until evolution of nitrogen is complete, distilling off caprylic acid under vacuum, crystallizing from hexane, purifying, treating with cyclohexanone a solution in toluene of the pregnene-(5)-diol-(3:21)-one-(20)caprylate - (21) so produced, adding aluminium isopropylate solution, boiling, adding glacial acetic acid, cooling, and steam distilling in the presence of kieselguhr.  The residual liquid is extracted with acetone, the latter distilled off, the residue dissolved in hexane, filtered, evaporated, redissolved in hexane and chromatographed over alumina.  Desoxycorticosterone caprylate is extracted with benzene.  Desoxycorticosterone palmitate by heating 21 - diazo - pregnene - (5) - ol - (3) - one - (20) in dioxane with palmitic acid till evolution of nitrogen is complete, diluting with ether, allowing to stand over sodium hydroxide, separating the liquid and washing with ether and 21-palmitoxypregnene - (5) - ol - (3) - one - 20 crys-tallized.  This is oxidized by dissolving in toluene, adding cyclohexanone and aluminium isopropylate and boiling.  The mixture is worked up as in the case of the caprylate.  Desoxycorticosterone palmitate-caprylate mixture by allowing desoxycorticosterone to stand in a pyridine solution of palmityl and capryl chlorides.  The mixture is treated with ether, shaken with acid, then sodium carbonate solution, dried, filtered and evaporated.  Oestrone caprylate and oenanthate by dissolving oestrone in caustic potash solution and reacting with capryl and oenanthyl chlorides respectively.  17,Ethinyl-oestradiol-monobutyrate by heating ethinyl - oestradiol, pyridine and butyric anhydride, cooling, stirring with water, extracting with ether and washing with acid and alkali solutions.  17 - Ethinyl - oestradiol - monovalerate, -mono-caproate, mono-oenanthate, -monocaprylate and monopropionate are prepared by analogous methods.ALSO:An injectable steroid hormone preparation containing more than 50 mg. hormone substance per c.c. and melting at 37 DEG C. or below consists of a mixture having a melting point below that of at least one of its constituents and comprising either two or more steroid hormones or esters thereof, or a steroid hormone or an ester thereof and an inert substance which reduces the melting point to the desired degree, e.g. an oleaginous diluent, inert steroids, such as androstane, coprostanone, norcholanic acid ethyl ester, hydrocarbons, alcohols, ketones, pyrocatechol monomethyl ether (guiacol), ethyl carbamate (urethane) phenyl salicylate (salol).  Other additives are fatty oils, higher glycols, wax alcohols.  The following mixtures are specified : a melt of one, two or three of the esters testosterone caproate, oenanthate and caprylate, or of desoxycorticosterone caprylate and palmitate (or a mixed desoxycorticosterone palmitate-caprylate ester produced by reaction), or of oestrone caprylate and oenanthate, or of testosterone propionate, progesterone or desoxycorticosterone and phenyl salicylate ; an injection solution of testosterone propionate or progesterone, phenyl salicylate, ethyl lactate and sesame oil ; a salve like preparation of testosterone propionate, phenyl salicylate, cetyl alcohol, benzyl alcohol, ethyl lactate and sesame oil ; a melt of desoxycorticosterone acetate, phenyl salicylate and cetyl alcohol, or of testosterone propionate or progesterone and urethane (to which latter melts may be added ethyl lactate or propylene glycol), or of guiacol and testosterone propionate, progesterone or desoxycorticosterone acetate (which latter melts may be diluted with sesame oil).  The invention also embraces an injectable preparation consisting of an oleaginous solution of a steroid hormone ester of an aliphatic carboxylic acid of 4-14 carbon atoms, which solution contains more than 50 mg. hormone substance per c.c.  Examples are solutions in sesame oil of 17-ethinyl-oestradiol monobutyrate,-monovalerate, -monocaproate, -mono-oenanthate, and -mono-caprylate, of testosterone caproate, -caprylate and -oenanthate, of desoxycorticosterone caprylate, and of oestrone oenanthate and caprylate.  The preparation of many of the esters is described (see Group IV(b)).