US2840508A - Injectable steroid hormone preparations and method of making same - Google Patents

Description

United States Patent No Drawing. Application May 13, 1952 Serial No. 287,628

Claims priority, application Germany May 17, 19 51 7 w 2 Claims. (Cl- 167-74) preparation and more particularly to an injectable steroid hormone preparation of high hormone concentration, said preparation being adapted to produce, on injection, a hor-. mone depot of prolonged activity, and to a method of making same.

The hitherto most widely used method of administration of hormones is by intramuscular injection of oleaginons solutions. However, such injections must in many.in-. stances be repeated frequently at definite time intervals 1 corresponding to the resorption .ofthe hormone byjth e organism. As this method can be extremely irksonie'to' the patient, in many cases a method of treatment has been employed which consists in the implantation of hormone ments over a long period. The method of crystal implantation has however, for various reasons, not always proved satisfactory in practice. A primary reason is that it is in fact a surgical operation, although only aminor;

one. I

Attempts have therefore been made to replace the methodof setting up a depot by crystal implantation by the more easily effected injection technique. Since 1m row limitsare placed upon the production of highly concentrated oleaginons solutions owing to-the insufiicient solubility of the hormones in oils, one method which has been used consists in the injection of crystal suspensions However, this method also encounters certain difliculties, particularly in relation to the production of said suspensions, and it can therefore in no wise be considered as ideal.

ters of steroid hormones ascompared with the free hor mones. They rendered it possible for the first time in therapy to effect a desirable reduction in the number of the injections required, a limit still being imposed, how--.

ever, by the relatively small size of the depot which could be set up by a singleinjection. The production of sufliciently highly concentrated oleaginons solutions'was still I rendered impossible owing to the insufficient solubility of I the esters used in the customary solvents for intramuscular injection.

The present invention is in part based on the observation that it is possible to reduce the melting point of the hormones to be implanted by conversion into their low melting esters, or into low melting eutectic IIllXtlllfiSxOf esters, to such an extent that the molten hormone compounds can be directly injected without further diluent in the same manner as the known oleaginons solutions. This feature of the invention is illustrated in Examples 1 to 4 below.

The idea of injecting hormone preparations inlthe and steroid hormone esters with sufiiciently low melting Some advance was made by the discovery of the so- H called protracted effect which is possessed by certain cs V I .15 This invention relates to an injectable steroid hormone crystals of suitable size, thereby setting up a'depot in the organism, from which the latter can 'derive its require-j 2,840,508 Patented June 24, 1958 hoe points, such as those set out in the examples below were- Those hormones and derivatives 1 not hitherto known. thereof with high melting points which were hitherto known had, in thenon-crystalline state at room temperature, in practically all cases the consistency of viscid resins 1 or lacquers, whereas the melts produced according to the 7 present invention,on cooling, only crystallise-slowly and have the consistency of fluid oils.

It was also in no way-to be expected that it is possible to produce physiologically suitable steroid hormone derivatives withsu-ch low melting point. Theirapplication by means of a simpleinjection constitutes an essential simplification, as compared with implantation, in the setting up of comparatively large hormone depots in 1 organism.

According to a further feature of this invention, instead of mixtures of different esters of the same hormone, in

cases where simultaneous application of several hormones is desired, there can be employed with particular advanthe enol esters others among the customary hormone derivatives are alsoiconcerned, insofar as they possess low melting points; Further additions or diluents are not absolutely necessary but they may in some cases he .of advantage especially when they are of such a nature as to chest further decrease of the'm elting point.

Furthermore, according to this invention, it is not necessary'for the production of preparations comprising mix-. tures of steroid hormones of lowmelting point to produce this effect of decreasing the melting pointby admixture of molten form instead of in the form of solutions isnovel 1 other hormones or hormone deriyatives, but an admixture of non-hormones'may alsobe suitable for the same purpose. I a

Thus, for example, the inert steroids androstane (M. P,

50 C.), coprostanone' (M.'P. 63? C.) and noncholanic acid ethyl ester (M. P. 66 C.) have a strong etfec'tin reducing the melting points of the hormoneesters. However, this e'ifectis not :at all limited to substances of steroidfgroupl Ithas been shown that this effect is possessedt 'uite generally by substances the melting points of which are relatively low, that'is to say below about-65 C.,'

insofaras-they form homogeneous melts with the hormones concerned. Advantageously such substances are I selected that are chemically inertto the greatest possible extent,-s o'that they are tolerated by the body, as, for instance, hydrocarbons, alcohols .and their derivatives,

ketones and so on. Actual selection can obviously be made by an expert bearing the aboye points in mind. As further examples of suitable substances 5 there may be mentioned, pyrocatechol monomethyl ether (guaiacol), ethyl carbamate (urethane). and phenylsali cylate (salol) According to a still further feature of the invention, in this method of, producing low melting hormone preparations not only such steroid hormone derivatives can be used as themselves possess-relatively low melting points but also others-even including those which are in general used in the unesterified free form, as, for example, pro

gesterone. 7

Further additions may be advantageous as diluents,

tions may be important for the purposes of improvingjithe tolerance and rendering the effect more protracted or for As suitable inert diluents there are concerned.

increasing absorption. For these purposes wax alcohols are of advantage.

Examples 5-119 below illustrate such highly concentrated steroid hormone preparation which are suitable for injection. i

The invention is based on thefurthcr observation, as a result of research on comparative solubilities of known andnew hormone esters, that there exists a series of I Sesame Oil, Rapeseed mg. Oil, mg.

Testosterone 2 2. Testosterone proplonate. l2 18. Testosterone benzoate-.. less than 2... less than 2. Pregneno1-(3)-one(20) less than l less than 1. Pregneno1-(3B)-one-(20) acetate. 20 15. Pregnenol-(36)-one-(20) benzoate less than 2... less than 2. Desoxycortlcosterone 8.. 7. Desoxycorticosterone acetate- 4. 2. Desoxyeortlcosterone butyrate. 4. Desoxycorticosterone palmitate. 10- 3. Desoxycortlcosterone stearateless than 5.

radio] 1-.-; 0.5. Estradlol-Zi-monobenzoate less-than l. 2. Estradlol-Ii, 17-diproplonate 20.

A search for other more suitable solvents has previously produced no, satisfactory result on account of the narrow limits imposed by the required tolerance.

In viewof the fairly uniformly low solubilities of the hitherto known esters, among which there were represented both these of high molecular. acids and also those of the low molecular acids, it could therefore not be assumed that the intermediate esters would behave in an essentiallyditferent manner.

{It is the .more surprising that the esters of *aliphatic acids with more, than three carbon atoms, especially such with 4-14 carbon atoms," which, in addition, may be more or less saturated, are distinguishedby a considerably higher solubility substantially exceeding 50 mg. per cc. of solution. Moreover, here also the oil solubility of a particular hormone ester can in most cases be increased considerably by admixture of a second hormone ester. This feature is illustrated in Examples 20-23 below.

The following examples therefore illustrate the inven tron:

EXAMPLE 1 Theihitherto undescribed low melting testosterone esters set. forth below are introduced into ampoulesfor injection purposes. in the manner customary for oleagin- A mixture of 10 grams of testosterone, 40 cc. of pyridine and 20 cc. of caproic acid anhydride is heated for 1% hours to C. The cooled reaction mixture is decomposed with water while stirring and cooling After prolonged standing at a temperature below room temperature, the whole is extracted with ether and the e thereal solutionis washed consecutively with dilute sulfuric acid, water, 5% sodium hydroxide solution, and again with water. The crude ester remaining on evaporation of the dried ether solution, after repeated recrystallisation from pcntane, melts at 44.546.0-C.

. (b) Preparation-of testosterone oerzanthate ,By thesame reaction and working up procedure, there is obtained, by the use of oenanthicacid anhydride, testes terone oenanthate of M. P. 3637.S C.

(c) Preparation of testosterone caprylate 1 In the same manner there is obtained, from testosterone and caprylic acid anhydride, testosterone caprylate of M. P. 44-45 C.

EXAMPLE 2 By melting together any two, or better three, of the esters described in Examplel, in mixture ratios which may vary relatively widely and are preferably about 1:1 or 1:1:1, respectively, clear melts are obtained which at body temperature and also at considerably lower temperatures, remain more or less fluid.

To simplify production of injection preparations according to this example, one may proceed in such a manner that the desired esters, instead of being produced individually, are produced directly in mixture with each other by esterifying testosterone, instead of with the pure carboxylic acid anhydride concerned, directly with mixtures of the desired carboxylic acid anhydrides.

EXAMPLE 3 (a) .Preparation of pregnene-(5)-diol-(3,21 )-one-(20)- caprylate-(ZJ) from 21 -diaz0-pregnen0lone 1.72 grams of 21-diazopregnenol-(3)-one-(20) are dissolved in 12 cc. of caprylic acid while heating slowly to 90 C. and the whole is left for 20 minutes at this temperature until evolution of nitrogen has ceased. The unreacted caprylic acid is then distilled off in a vacuum at C. After recrystallisation from hexane 1.65 grams remain. This product, in chloroform solution, is purified over a small column of alumina, extracted by shaking with sodium bicarbonate solution and water, and recrystallised from hexane. The pregnenediolone caprylate produced has a melting point of 75-80" C.

Prepardr ion of desoxycorticosterone caprylate from pregnene-(5)-diol-(3,2I -one-(20)-caprylale-(21) 750 mg. of the above produced pregnenediolone caprylate are dissolved in 60 cc. of dry toluene and mixed with 10.5 cc. of cyclohexane. To the boiling solution 3.3 cc; of aluminum isopropylate solution (about 25 percent) are gradually added and the whole is maintained at boiling point for 25 minutes. Then 0.22 cc. of glacial acetic acid is' added and, after cooling, the solution is subjected to steam distillation in the presence of 2.5 grams of'kieselguhr. The residual liquid is filtered with suction dried, and extracted with acetone. After distill ing off the acetone, the residue is dissolved in hexane and filtered over a small column of alumina for purification. After evaporation, 550 mg. remain. This crude product is dissolved in hexane and chromatographed over a column of alumina. The desoxycorticosterone caprylate with a melting point of 62-63 C. is extracted with benzene as first eluting agent. After recrystallisation from hexane the melting point is 6363.5 C.

(b) Preparation of a mixture of desoxycorticosterone palmitate and desoxycorticosterone caprylate from 21- diazo pregnenolone 3.4 grams of 2l-diazo pregnene-(5 )-ol-(3)-one-('20), in 20 cc. of dry dioxane, are heated with 12 grams of palmitic acid in a glycerol bath at 1209 C. until evolution of nitrogen has ceased (for about 2 hours). The

to stand for 15 hours over sodium hydroxide pellets. Thereupon the liquid is separated from the deposited flakes of sodium palmitate and is filtered through a layer of about 50 grams of alumina, followed by thorough washing with ether and crystallisation. There are obtained 3.1 grams of 21-pahnitoxy pregnene-(5)-ol-(3)- one-(20) of M. P. 98-102 C., which is suitable for further processing without additional purification.

For oxydation, 2.9 grams of this substance are dissolved in 100 cc. of toluene, 20 cc. of cyclohexanone and 1.3 grams of aluminum isopropylate are added and the solution is boiled for 4 hours. After working up in the same manner as described for the preparation of the caprylate, 2.1 grams of desoxycorticosterone palmitate of M. P. 57-58 C. are obtained. By recrystallisation,

the melting point can be raised to 62-63. C. By fusion of this ester together with desoxycorticosterone caprylate within a wide range of proportions, melts are obtained which solidify only at low temperatures so that they can be used for injection.

() Preparation of a desoxycorticosterone palmitate-caprylate mixture 0.35 grams of desoxycorticosterone are allowed to stand for 4 hours at room temperature with a solution of 0.27 grams of palmityl chloride and 0.17 grams of capryl chloride in 1 cc. of pyridine. The whole is thereupon treated with 500 cc. of ether, shaken with 2N- hydrochloric acid, then with sodium carbonate solution and with water, dried over sodium sulfate, filtered through a layer of 1 gram of alumina, and evaporated. The ester mixture remains as a fluid mass which can be caused to solidify at the temperature of ice.

EXAMPLE 4 One. may proceed. with the esters of estrone in the same manner .as described in Example 2. .For instance, the caprylate (M. P.,68.5-70 C.) and the oenanthate (M. P.. 64-65 C.) ofestIone are suitable for such use. T hemelting points of the mixtures, 'the composition of which may vary in proportion within a wide range, are so low that .the melts can beinjected. The preparation of these esters can be carried out as follows:

('a) Preparation of. estrone caprylate Ggrams of estrone are dissolved, while heating, in 1.5 I

liters'of 5% potassium hydroxide solution and, after coolingt'o 0 5 C., shaken for 15 minutes with 7.5 cc. of capryl chloride. Eurthjer 7.' 5 cc. of the acid chloride are then added and shaking is continued for a further 30 minutes. The precipitated ester is filtered by suction, thoroughly washed on the filter with sodium'carbonate solution and water, and dried in a vacuum desiccator.

Yield: 8.76 grams vof erude caprylate of M. P. 6670 C. After recrystallisation from hexane and methanol the pure caprylate melts at 68.770 C. Y

(b) Preparation of estrone oenanthate 6 grams of estrone are reacted under the same conditions as described above with oenanthyl chloride. 855 grams of crude ester of M. P. 59.5-62 C. are obtained. The pure oenanthate melts at 64-65 C.

EXAMPLE 5 EXAMPLEG I A 1 part of progesterone is mixedv with 3.5 parts of phenyl parts of urethane.

salicylate and the whole is molten at 45 C. ,A clear, homogeneous melt remaining liquid at low temperatures, being capable of injection, and containing 250 mg. of progesterone per cc. is obtained.

EXAMPLE 7 1 part of progesterone is treated as above'de'scribed with 4.5 parts of phenyl salicylate. A melt suitable for injection is obtained containing 200 mg. of progesterone per cc.

EXAMPLE 8 I part of desoxycorticosterone acetate is mixed with 4.5 parts of phenyl salicylate and is molten at 60 C. A stable injectable preparation is produced containing 200 mg. of desoxycorticosterone acetate per cc. fluid at room temperature (about 18 C.).

EXAMPLE 9 There is produced according to Example 4 a melt from 1 part of testosterone propionate and 1 part of phenyl salicylate, 1 part of ethyl lactate and 2.5 parts of sesame oil are added thereto, yielding an oleaginous'injection liquid which contains 200 mg. of testosterone propionate per cc. By varying the fatty oil proportion, solutions of higher or lower hormone content can be obtained.

EXAMPLE 10 By the method according to Example 4, 1 part of progesterone is molten with 2 parts of phenyl salicylate. 0.5 part of ethyl lactate and 2 parts of sesame oil are then added to the melt whereby an injection solution is obtained which contains 200 mg. of progesterone per'cc.

EXAMPLE 11 EXAMPLE 12 1 part of desoxycorticosterone acetate and 2 parts of phenyl salicylate are molten according to Example 5 0.6' part of cetyl alcohol are introduced into the melt, yielding a preparation which can be injected at body temperature and contains 300 mg. of desoxycorticosterone acetate per cc.

EXAMPLE 13 Y 2 parts of testosterone propionate are molten together with 5 parts of urethane at about 50 C. The melt remains liquid at 44 C. 1 cc. of this meltcontains 300 mg. of testosterone propionate.

EXAMPLE 14 2 parts of progesterone are molten together with 5 The melt remains fluidat 38 C. 1 cc. of this melt contains 300 mg. of progesterone.

EXAMPLE 15 Melts as in Examples 13 and 14 are diluted with suitable injectable liquids. They constitute injection fluids which are stable at a temperature considerably below' EXAMPLE 16 1 part of guaiacol (M. P. 28? C.) is molten with 2 parts of testosterone propionate. The melt remains liquid;

1 cc. of thesemelts contains 200 mg."

even ata. low temperature (under 10 C.). 1 cc. of this melt contains 400mg. of testosterone propionate.

2 parts of desoxycorticosterone acetate are molten with 2 parts of guaiacol; The melt is fluid below room temperature.

EXAMPLE 19 Guaiacohhormoiie melts obtained according to Examples 16m 18 are diluted with injection liquids. For

instance, 1 part of guaiacol and 2 parts testosterone V propionate are molten and 2.2 cc. of sesame oil added thereto. A clear, stable injection liquid is obtained, 1 cc. of which contains 400 mg. of testosterone propionate.

EXAMPLE 20 Inthe case of esters of 17-ethinyl estradiol the solubility at room temperature inl cc. of sesame oil of the 3-monopropionate is only about 20 mg. The acetate is still less soluble, while the solubility of the butyrate is over 100 mg. and that of the valerate, caproate, and oenanthate are over 75 mg. and of the caprylate over 150 mg. The preparation of these hitherto undescribed esters is carried out, for instance, according to the following directions:

(0) Preparation of l7-ethinyl estradiol mono/butyrate (b) Preparation of 17-ethinyl estradiol monovalerate The monovalerate is obtainable in the same manner as described for the butyrate, by using valeric acid anhydride. The melting point of the pure ester, after repeated recrystallisation from ether-hexane, is 98-99 C.

(c) Preparationof l7-ethinyl estradiol riwrzocaproat'e The monocaproate is obtained in the same manner as described for the butyrate by using caproic acid anhydride. The melting point of thepure ester, after repeated recrystallisation from ether-hexane, amounts to 71-72? C.

(:1) Preparation of I 7-etlzz'rtyl estmdiol monooanantha te The monooenanthate is. obtained; in the same manner as described for the butyrate by using oenanthic acid anhydride. .The melting point of the pure ester, after rcpeated recrystallisation from ether-hexane is 67-68 C.

(e) Preparation of 17-ethinylbestradi0l molwcaprylate The monocaprylate is obtained in the same manneras described for the butyrate by using caprylic acid anhydride. The melting point of the pure ester, after repeated recrystallisation from ether-hexane, is 575S C.

(f) Preparation of l7-ethinyl estradiol nwnopmpionaie A mixture of grams of 17-ethinyl estradiol, 20 cc. of pyridine, and 10 cc. of propionic acid anhydride is heated for 1% hours to 115 C." The cooled reaction mixture is decomposed with water, while stirring and cooling. After stirring at room temperature for several hours, the mixture isextracted with ether and the other solution is washed consecutively with jdilute sulfuric acid, water, dilute sodium carbonate solution, and again with water.

8 The dried ether solution is evaporated and the oily resi' due is tritu'rated, with hexane, whereby crystallisation gradually sets in. The crystalline paste'is filtered with strong suction and the crystallisate is purified by repeated recrystallisation from hexane-acetone. The pure 17-eth' iuyl estradiol monopropionate melts at 124-125 C.

EXAMPLE 21 In the case of the testosterone esters, as set forth in the table above, the solubility of the monopropionate in 1 cc. of sssum: oil at room temperature is 12 mg. and'that of the monobenzoate less than 2 mg. On the other hand, the solubility of the caproate is more than 550 mg, that of the oenanthate more than 900 mg. and that of. the caprylate more than 600 mg. These solubilities can be further considerably increased by mixing the various esters. A triester mixture is obtained which possesses practically unlimited solubility in sesame oil.

The preparation of the 'caproic, caprylic and oenanthic esters of testosterone is described in Example 1.

EXAMPLE 22 In the case of desoxycorticosterone the solubility maximum which is reached in the case of the esters of the acids of average molecular weight, is likewise clearly recognizable on reference to the table above, the solubility' of the caprylate in 1 cc. of sesame oil at room temperature being mg.

To prepare the'hitherto unknown caprylate of desoxycorticosterone, the latter compound is esterified in the same manner as described in previous examples. In addition, for instance, the process described in Example 3 may be used. 7

EXAMPLE 23 The same excellent solubility of the esters of aliphatic carboxylic acids of medium number of carbon atoms is found in the case of estrone. Thus,for instance, more than 100 mg. of the oenanthate and more than 75 mg. of the caprylate are soluble at room temperature in 1 cc. of sesame oil. Moreover it was found that a mixture of the two esters is still more readily soluble. Also by mixing esters of difierent steroid hormones the solubility is increased. The specified, hitherto partly unknown, esters, are prepared for instance,1as described in Example 4. Other hormone derivatives of low melting point which can be used in practicing this invention are, for instance, certain hormone ethers, enol ethers, and acetals, especially those .of higher molecular, preferably straight chain aliphatic alcohols. Especially suitable compounds of this type are, for instance, the.3-enol butyrate of testosterone- 17-butyrate'having a melting point of 67-69 C. and a solubility in sesame oil of mg. per cc., and the 3-enol valerate of testosterone-l7-valerate having a melting point of 76-79" C. and a solubility in sesame oil of 135 mg. per cc. Such and other enol esters of testosterone and other steroid hormones containing keto groups are obtained, for instancefby heating the ketonic steroid hormone with the correspoudingacylating agent at a temperature of at least. about C. for a sufficient time to form an enol derivative which is acylated at the enolic hydroxyl group. Thus; the 3-enol butyrate of testosterone- 17-butyrate is obtained by heating a mixture of 1 part of testosterone-17-n-butyrate, 2 parts of sodium butyrate, and 40parts of n-butyric acid anhydride to boiling under reflux for about 5. hours. The reaction mixture is then poured into water and the reaction product is extracted with ether. After the ethereal extract has been washed with dilute sodium carbonatesolution, dilute caustic alkali solution, and Water, it is dried by means of sodium sulfate and the solvent is evaporated. The residue is recrystallized from alcoholf The 3-enol .valerate of testoster0ne-17-valerate' is obtained in an analogous manner. In general, enol esters of testosterone-17-esters with L aliphatic'carboxylic acids having at least 4 carbon atoms in their molecule are suitable compounds of relatively high solubility in customary steroid hormone solvents and having a relatively low melting point.

The term steroid hormone as used herein and in the claims annexed hereto comprises not only the free hormones of steroid structure themselves or mixtures of the same but also their derivatives as they are mentioned herein ormixtures of the same with the free hormones or with other hormones or with other derivatives or with derivatives of other hormones.

We claim:

1. An injectable concentrated, substantially water-free repository hormone composition, fluid at body temperature, which composition consists of an ester of a steroid hormone selected from the group consisting of estrogenic, androgenic, progestational, and adrenocortical steroid hormones, said steroid hormone ester having a melting point above body temperature, and a non-toxic substance selected from the group consisting of guaiacol, phenyl salicylate, and urethane, said substance having a melting point below about 65 C. and forming, on melting together with said steroid hormone ester, a homogeneous molten mixture therewith, said steroid hormone ester and said organic substance being present in said repository hormone composition in the form of a molten homogeneous mixture remaining stable in its fluid form, the steroid hormone ester content of said mixture substantially exceeding 50 mg. per g. thereof.

2. In a process for the manufacture of an injectable.

concentrated, water-free repository hormone composition, the step which comprises melting together an ester of a steroid hormone selected from the group consisting of estrogenic, androgenic, progestational, and adrenocortical steroid hormones, said steroid hormone ester having a melting point above body temperature, and a non-toxic content substantially exceeding mg. per g. thereof.

References Cited in thefile of this patent UNITED STATES PATENTS 2,109,490 Miescher Feb. 22, 1938 2,228,397 Miescher Jan. 14, 1941 2,248,438 Ruzicka July 8, 1941 2,265,183 Miescher Dec. 9, 1941 2,308,833 Ruzicka Jan. 19, 1943 2,265,976 Inhoifen Dec. 9, 1943 2,566,358 Ott Sept. 4, 1951 2,675,342 Lee Apr. 13, 1954 FOREIGN PATENTS 919,146 France Nov. 18, 1946 215,556 Switzerland Oct. 1, 1941 487,267 Great Britain June 17, 1938 416,256 Great Britain Sept. 13, 1934 515,566 Great Britain June 6, 1939 OTHER REFERENCES J. A. P. A., vol. 12, No. 4, April 1951, p. 222 (Practical

Claims (1)

1. AN INJECTABLE CONCENTRATED, SUBSTANTIALLY WATER-FREE REPOSITORY HORMONE COMPOSITION, FLUID AT BODY TEMPERATURE, WHICH COMPOSITION CONSISTS OF AN ESTER OF AE STEROID HORMONE SELECTED FROM THE GROUP CONSISTING OF ESTROGENIC, ANDROGENIC, PROGESTATIONAL, AND ADRENOCORTICAL STEROID HORMONES, SAID STEROID HORMONE ESTER HAVING A MELTING POINT ABOVE BODY TEMPERATURE, AND A NON-TOXIC SUBSTANCE SELECTED FROM THE GROUP CONSISTING OF GUAIACOL, PHENYL SALICYLATE, AND URETHANE, SAID SUBSTANCE HAVING A MELTING POINT BELOW ABOUT 65*C. AND FORMING, ON MELTING TOGETHER WITH SAID STEROID HORMONE ESTER, A HOMOGENEOUS MOLTEN MIXTURE THEREWITH, SAID STEROID HORMONE ESTER AND SAID ORGANIC SUBSTANCE BEING PRESENT IN SAID REPOSITORY HORMONE COMPOSITION IN THE FORM OF A MOLTEN HOMOGENEOUS MIXTURE REMAINING STABLE IN ITS FLUID FORM, THE STEROID HORMONE ESTER CONTENT OF SAID MIXTURE SUBSTANTIALLY EXCEEDING 50 MG. PER G. THEREOF.