2,987,440 United States Patent Office Patented June 6, 1961 2 2,987,440 hitherto known had, in the non-crystalline state at room NJECTABLE HORMONE PREPARATIONS temperature, in practically all cases, the consistency of Karl Junkmann, Berlin, Josef Kathol, Berlin-Charlotten viscid resins or lacquers, whereas the melts produced ac burg, and Hans Richter, Berlin-Steglitz, Germany, as cording to the present invention, on cooling, crystallize signors to Schering A.G., Berlin, Germany, a corpora s only slowly and have the consistency of fluid oils. tion of Germany It was also in no way to be expected that it is possible No Drawing. Filed Mar. 17, 1958, Ser. No. 721,646 to produce physiologically effective hormone derivatives 2 Claims. (Cl. 167-65) with such low melting point. Their application, by means of a simple injection, constitutes an essential simplifica This invention relates to an injectable preparation com 10 tion, as compared with implantation, in the setting up of prising steroid hormones and/or non-steroid hormones comparatively large hormone depots in the organism. having the activity of such steroid hormones and more Further additions may be advantageously made in order particularly to an injectable preparation of a high con to dilute the hormone preparation so as to effect better centration in such steroid hormones and/or non-steroid dosage, since in setting up depots of less than about 100 hormones, said preparation being adapted to produce, on 5 mg., usually too great a proportion of an undesirable injection, a hormone depot of prolonged activity, and to hormone preparation remains behind in the injection a method of making such preparation. This application syringe. As suitable inert diluents there are employed is a continuation-in-part of our prior copending applica solvents which are known and hitherto used for dissolving tion Serial No. 325,044, filed December 9, 1952 now Such hormones, for example fatty oils and higher glycols. abanboned, which is in turn a continuation-in-part of our 20 Further additions may be made for improving their com prior copending application Serial No. 287,628, filed May patibility and for producing more protracted effects or 13, 1952 now Patent No. 2,840,508. for increasing absorption. For these purposes wax alco The hitherto most widely used method of administra hols are used with advantage. tion of such hormones is by intramuscular injection of oleaginous solutions thereof. However, such injections 25 The invention is based on the further observation, that must in many instances be repeated frequently at definite there exists a series of heretofore unknown esters which time intervals depending upon the resorbability of said are distinguished by their surprisingly high solubility in hormone by the organism. As these repeated injections the usual solvents used for injection. This could not be can be extremely irksome to the patient, in many cases, a expected since both the previously known esters of the method of treatment is employed which consists in the im 30 lower fatty acids and also those of the higher fatty acids plantation of hormone crystals of suitable size, thereby which were heretofore known, have exceedingly low solu setting up a depot in the organism, from which the latter bilities in the oils concerned, as is evident from the fol can derive its requirements over a long period of time. lowing table. In this table there are listed the solubility The method of crystal implantation has however, for vari of known steroid hormone compounds at room tempera ous reasons, not always proved satisfactory in practice. 35 ture in mg. per 1 ccm. of two typical solvents: A primary reason is that it is in fact a surgical operation, although only a minor one. Sesame Rape seed Therefore, attempts have been made to replace the Oil, mg. Oil, mg. method of setting up a depot by crystal implantation by Testosterone.------2 2 the more easily effected injection technique. Since nar 40 Testosterone propionate 2 18 Testosterone benzoate. less than 2 less than 2 row limits are placed upon the production of highly con Pregnenol-(3)-one-(20)-- less than 1 less than 1 centrated oleaginous solutions owing to the insufficient Pregnenol-(33)-one-(20) acetate- 20 5 solubility of the hormones in oils, one method, which has Desoxycorticosterone.------Pregnenol-(36)-one-(20) benzoate------less than 82 less than 27 been used, consists in the injection of crystal suspensions. Desoxycorticosterone acetate- 4 2 45 Desoxycorticosterone butyrat 15 4. However, this method also encounters certain difficulties, Desoxycorticosterone palmitate- 0 3. particularly with respect to the preparation of such sus Desoxycorticosterone stearate-- -- less than 5 ------pensions, and it can therefore in no wise be considered as Estradiol------1. 0.5 ideal. Estradiol-3-monobenzoate------Estradiol-3,17-dipropionate------less than 202 Some advance was made by the discovery of the so called protracted effect which is possessed by certain es 50 ters of such hormones as compared with the free hor A search for other more suitable solvents did not pro mones. Administration of such esters rendered it possi duce satisfactory results, since only very few of such sol ble to reduce the number of injections required; but even vents are tolerated by the body. - this method was limited by the relatively small size of the The above given table shows clearly that hormone esters depot which could be set up by a single injection. It was 55 with low molecular acids as well as esters with high mo not possible to produce sufficiently highly concentrated lecular acids are only slightly soluble in vegetable oils. oleaginous solutions of such esters due to their insufficient In accordance with this invention, the surprising dis Solubility in solvents conventionally used for intramuscu covery has been made that the hormone esters of aliphatic lar injection. - - acids which have six, seven, or eight carbon atoms ex hibit an especially high degree of oil solubility which The present invention is in part based on the observa 60 makes it possible to prepare for the first time, highly con tion that it is possible to reduce the melting point of said centrated, fluid, substantially water-free injectable hor hormones by converting them into their low melting es mone preparations, in which the hormone is present in ters or into low melting eutectic mixtures of esters. By concentrations of at least 50 mg. per cc., and even more, this means, the melting point could be reduced to such an at body temperatures. These high concentrations are in extent that the molten hormone compounds can be in striking contrast to the relatively low concentrations in jected directly without further addition of a diluent in the vegetable oils possible with presently known esters, as Same manner as the known oleaginous solutions. shown in the above table, which demonstrates clearly that The idea of injecting hormone preparations in the only relatively small amounts, not exceeding 20 mg. per molten form instead of in the form of solutions is novel cc. of Solvent at most, of the known esters are soluble in and hormone esters with sufficiently low melting points O the conventionally used vegetable oils. The present in were not heretofore known. Those hormones and de vention, for the first time, permits the administration to rivatives thereof with high melting points which were patients of large doses of steroid and like hormones by a 2,987,440 3 4. single injection of a liquid concentrated hormone prep esters described in Example 1, in widely varying propor aration. tions, clear melts are obtained which at body tempera In accordance with this invention, hormone esters hav ture and even at considerably lower temperatures, remain ing especially favorable oil solubility characteristics may more or less fluid and injectable. be prepared from caproic, oenanthic, or caprylic acids, To simplify production of injection preparations ac the preferred esters being those of testosterone and hex cording to this example, one may produce said esters di estrol. Examples of testosterone esters include the capro rectly in mixture with each other by esterifying testos ate, the oenanthate, and the caprylate, while examples of terone, instead of with the pure carboxylic acid anhydride hexestrol esters include the dioenanthate and the dica concerned, directly with a mixture of all the desired car prylate. The preparation of the testosterone esters is de 10 boxylic acid anhydrides. scribed in Example 1 below. The preparation of the hex EXAMPLE 3 estrol esters is carried out analogously. The novel esters may be incorporated molten if desired, Preparation of hexestrol di-oenanthate and of hexestrol in suitable oil carriers, including any of the injectable di-caprylate vegetable oils conventionally used for preparations of this 15 type, such as, for example, sesame oil or rape seed oil, in A mixture of 3 g. hexestrol (i.e. di-(4-hydroxy-phenyl)- accordance with known methods. In this highly concen ?y,6-hexane, 12 cc. of pyridine, and 6 cc. of oenanthic trated form, these preparations have been successfully acid anhydride is heated for 2 hours to 100 C. The re used for treatment of hormonal insufficiency. For ex action mixture is cooled, water is added thereto, and the ample, a substantially water-free solution of 250 mg. per 20 mixture is stirred for 18 hours. It is then extracted with cc. of testosterone oenanthate in an oil carrier, sold com ether and the ether solution is subsequently washed with merically under the designation Testoviron-Depot has N sulfuric acid, water, 5% sodium carbonate solution, and been successfully used for treatment of testicular hor again with water. The ethereal extract is dried over an monal insufficiency, as described in articles by J. A. hydrous sodium sulfate and the ether is distilled off. The 25 remaining oily crude ester crystallizes on spraying with Schneider, Aerztliche Wochenschrift, vol. 7, pages 381 some methanol and melts, on recrystallization from meth 5. g52). and H. Hagedorn, Die Medizinische, 1952, ano at 79-81 C. o. 45. The preparation of the hexestrol di-caprylate, melting The following examples illustrate the invention with at 77-78 C., is carried out analogously. out, however, limiting the same thereto. 30 These higher fatty acid esters of hexestrol have a better EXAMPLE 1. solubility in oily solvents than the lower esters and hex The heretofore unknown low melting testosterone es estrol itself. ters set forth below are introduced into ampoules and are For instance 50 mg. of hexestrol di-oenanthate or 50 used as such without any further diluent or other addition mg., of hexestrol di-caprylate are soluble in 1 cc. of ethyl 35 oleate at room temperature. for injection in the same manner oleaginous hormone so These solubilities can be further considerably increased lutions are used. by mixing the esters with each other. (a) Preparation of testosterone caproate We claim: - A mixture of 10 g. of testosterone, 40 cc. of pyridine, 1. An injectable, highly concentrated, substantially and 20 cc. of caproic acid anhydride is heated to 125 C. 40 water-free repository hormone ester composition, fluid at for 1/2 hours. The cooled reaction mixture is decom body temperature, said composition consisting essentially posed with water while stirring and cooling, allowing the of at least one hormone ester selected from the group con mixture to stand for some time at a temperature below sisting of testosterone caproate, testosterone oenanthate, room temperature; it is extracted with ether, and the ethe testosterone caprylate, hexestrol dioenanthate, and hex real solution is washed consecutively with dilute sulfuric estrol dicaprylate, and an injectable vegetable oil, said acid, water, 5% sodium hydroxide solution, and again hormone ester being dissolved in said oil in an amount with water. The crude ester, remaining on evaporation of substantially exceeding 50 mg. per cc. of composition. the dried ether solution, melts, after repeated recrystalliza 2. An injectable, highly concentrated, substantially water-free repository testosterone composition, fluid at tion from pentane, at 44.5-46.0 C. body temperature, said composition consisting of testoster (b) Preparation of testosterone oenanthate one oenanthate and an injectable vegetable oil, said tes When using oenanthic acid anhydride in the place of tosterone oenanthate being dissolved in said oil in an caproic acid anhydride and proceeding in the same man amount substantially exceeding 50 mg. per cc. of com as described above under (a), testosterone oenanthate position. melting at 36-37.5° C. is obtained. 55 (c) Preparation of testosterone caprylate References Cited in the file of this patent In the same manner as described under (a), there is FOREIGN PATENTS obtained, from testosterone and caprylic acid anhydride, 465,331 Great Britain ------May 5, 1937 testosterone caprylate melting at 44-45 C. 60 OTHER REFERENCES - EXAMPLE 2 By melting together any two, or better all three, of the Chem. Abst, vol. 35, 1941, page 65872.