US3313701A - Testosterone composition of matter and process - Google Patents

Description

United States Patent ()fifice BfilBJdl Patented Apr. 11, 1967 3,313,701 TESTUSTERONE COMPfiSlTION OF MATTER AND PROCESS John C. Babcock and J Allan Campbell, Kalamazoo, Mich, assignors to The Upjohn Company, Kalamazoo, Mich., a corporation of Delaware No Drawing. Filed Aug. 27, 1963, Ser. No. 304,978 4 Claims. (Cl. 167-74) This application is a continuation-in-part of application Ser. No. 114,621, filed June 5, 1961.

This invention relates to therapeutic compositions containing 7a,17a-dimethyltest0sterone and to a method for their use.

In the treatment of clinical conditions calling for an increase in the storage of protein and the stimulation of tissue growth, the administration of anabolic agents is frequently beset by concomitant androgenic side effects in the agents employed. The development of male sexual characteristics in the course of anabolic therapy is a limiting factor with agents heretofore available.

Comparative studies have shown that 7a,17a-dimethy1 testosterone (J. Am. Chem. Soc, 81:4069 [1959]) offers an unexpected split between anabolic and androgenic activities at therapeutically effective anabolic dosage levels. With this agent it is possible to provide anabolic therapy which is essentially free of undesirable androgenic side effects. This split in activity provides a sharp departure from related compounds in the art. For example, the anabolic/androgenic ratio as obtained in rigidly controlled, double cross-over studies of anabolic activity in monkeys and androgenic activity in rats is 1.9 for 7a,17a-dimethyltestosterone as compared with 1 for methyltestosterone, a commonly used standard. In humans, the anabolic potency is significantly greater than other commonly used anabolic steroids.

A temporary and useful repression of breast tumors is observed on therapy with this compound.

A daily oral dose of from about 0.25 to about 5 mg. per day of 7a,17a-dimethyltestosterone has been found to provide highly effective anabolic therapy essentially free of undesirable androgenic side effects. The same regimen is appropriate for clinical utilization of the antitumor activity described. The exact dosage schedule, of course, must be determined individually according to the subjects age, weight, response to the medication and severity of the condition being treated. In general, however, a regimen of about 0.01 to about 0.03 mg./kg. bodyweight/day is preferred for children and about 0.02 to about 0.08 mg./kg. bodyweight/day for adults.

In adapting the active ingredient for use in mammals, including humans, the novel compositions are suitably presented for administration in unit dosage form as tablets, pills, capsules, powders, Wafers, cachets, granules, oral dispersions, and the like.

For preparing solid compositions such as tablets, the active ingredient in crystalline, powdered, or micronized form is mixed with a conventional tableting component such as lactose, cornstarch, dicalcium phosphate, terra alba (calcium sulfate), talc, stearic acid, calcium stearate, 'gums, and functionally similar materials constituting pharmaceutical diluents or carriers. The tablets or pills can be laminated or otherwise compounded to provide a dos-age form affording the advantage of prolonged or delayed action or of predetermined successive action of the enclosed medication. For example, the tablet or pill can comprise an inner dosage and outer dosage component, the latter being in the form of an envelope over the former. The two components can be separated by an enteric layer which serves to resist disintegration in the stomach and permits the inner component to pass intact into the duodenum or to be delayed in release. A variety of materials can be used for such enteric layers or coatings, such materials including a number of polymeric acids or mixtures of polymeric acids with such materials as shellac, shellac and cetyl alcohol, cellulose acetate phthalate and the like. A particularly advantageous sustained release coating comprises a styrene ma-leic acid copolymer.

The liquid forms in which the novel compositions of this invention can be incorporated include aqueous solutions or suspensions, as well as elixirs and similar pharmaceutical vehicles. Suitable dispersing or suspending agents for aqueous suspensions include the synthetic and natural gums such as tragacanth, acacia, dextran, methylcellulose, polyvinylpyrrolidone, gelatin and the like.

The term unit dosage form as used in the specification and claims herein refers to physically discrete units suitable as unitary dosages for human subjects, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect in association with the required pharmaceutical diluent, carrier or vehicle. The specification for the novel unit dosage forms of this invention are dictated by and directly dependent on (a) the unique characteristics of the active material and the particular therapeutic effect to be achieved and (b) the limitations inherent in the art of compounding such an active material for therapeutic use in humans, as disclosed in detail in this specification, these being features of the present invention. Examples of suitable unit dosage forms, as heretofore described, are tablets, capsules, pills, powder packets, wafers, cachets, granules, solutions or suspensions for oral use, suppositories, and segregated multiples of any of the foregoing, and other forms alluded to herein.

The following examples illustrate the best mode contemplated for carrying out this invention, but these examples are not to be construed as limiting the scope thereof.

EXAMPLE 1TABLETS A batch of 10,000 compressed tablets, each containing 1 mg. of 7a,17ct-dimethyltestosterone, is prepared from the following ingredients:

, Gm. 7a,17ot-dimethyltestosterone 10 Lactose 40 The finely powdered steroid and lactose are thoroughly mixed and granulated with syrup-starch paste. Starch and calcium stearate are used as lubricants, and the tablets are compressed in the usual manner.

Administration of these tablets is on a schedule of 1 tablet daily for adults to stimulate weight gain.

EXAMPLE 2TABLETS In the formulation of Example 1, 2.5 gm. or 50 gm. can be substituted for the 10 gm. of 7a,17a-dimethyltestosterone to give tablets containing 0.25 mg. or 5 mg., respectively, which can be administered on the same schedule for anabolic therapy.

EXAMPLE 3ORAL ANAB OLIC ACTIVITY This test was carried out using the method of Stucki et al., Endocrinology 66:585 (1960). Young adult female monkeys were ovariectomized and acclimated to a balance ward of rigidly controlled environment. Each day the animals were oifered 200 ml. of water and an amount of constant composition diet sufficient to permit slow weight gain if no anabolic agent were administered. During control and drug periods alike, each animal was given twice a day one sugar cube soaked in 0.6 ml. of a multiple vitamin preparation. Oral drug administration was accomplished by instilling the requisite amount of an alcohol solution of the test compound into the sugar cube several hours before it was soaked with the vitamin suspension and given to the animal.

All the animals were kept on balance continuously. Collection of faeces, urine and food remnants was made every other day at the time body weights were obtained. Homogenates of the collections were prepared and aliquots analyzed using a modified Kjeldahl procedure for total nitrogen and a flame photometer for potassium. Daily balance was calculated by comparison of these values with those obtained from food analyses.

In all experiments either a spot single point assay or a quantitative twin crossover assay design (Finney, Statistical Method in Biological Assay, 1952, p. 265; Hafner Publishing Co., New York) involving four monkeys or a double-twin crossover design involving eight monkeys was employed. In crossover experiments two doses of the standard, fiuoxymesterone (9a-fluoro-11/3,17,B-dihydroxy- 17 u-methyl-4-androstene-3-one) and two doses of the test compound (based on results in preliminary spot assays) were employed. Each drug period was 14 days in length. The first drug period was preceded by a 1014 day control period and similar control periods separated the two drug periods and followed the second drug period.

To determine the anabolic effect produced by a test compound, the average amount of nitrogen retained per day for the last eight treatment (preand post-drug control) days was calculated. The difference between predrug control and treatment values (A pre) and the difference between post-drug control and treatment values (A post) was then calculated for each monkey. By the use of appropriate statistical methods for the twin crossover assay, potency of the test drug was then calculated and expressed in terms of the standard (fluoxymesterone) for each parameter of nitrogen retention using A pre-, A postand on-drug values. Potassium balance data were similarly treated. Body weight gain during drug treatment was also used to calculate drug potency.

The average of all seven estimates of potency was then determined. By suitable conversion, potency can also be expressed in terms of other drugs, for example, methyltestosterone. Results obtained with quantitative double twin cross-over assays on 7a,17a-dimethyltestosterone and methyltestosterone are presented in the following table:

TABLE.ANABOLIC POTENCIES OF 7a.17a-DIMETHYL- TESTOSTERONE AND METHYLTESTOSTERONE RELA- TIVE TO STANDARD DRUG, FLUOXYMESTERONE 4 EXAMPLE 4ANDROGENIC ACTIVITY The procedure employed was that described by Lyster et al., Endocrinology, 58: 781 (1956). The test animals were rats of the Upjohn-Sprague-Dawley colony which were castrated at 26 to 27 days of age. Beginning on the day following castration and continuing for 9 days, the animals were given orally a suspension of test compound in cottonseed oil in predetermined dosage. On the day following the last dosage the rats were sacrificed and the seminal vesicles (exclusive of coagulating gland and contained secretion) were weighed. Multiple point parallel line assays with 5 or more rats per point were used for quantitative potency estimates. The average weights of the seminal vesicles for the animals in each dosage level were determined and compared with results obtained using the standard, methyltestosterone. The androgenic activity of the test compound was expressed as a multiple of that of methyltestosterone. Results were as follows:

Androgenic activity X methyltestosterone 7a,17a-dimethyltestosterone 3 EXAMPLE 5ANABOLIC THERAPY In clinical studies on over 200 humans, 7a,17u-dimethyltestosterone has produced the benefits of anabolic therapy at clinically efiective doses of 0.25 to 5 mg. per day without significant signs of androgenicity (acne, voice change, hirsutism, etc.).

EXAMPLE 6-COMBINATION THERAPY Gm. 70c,17oc-diII1CthYlt8StOSt6I0n6 0.5 Tetracycline phosphate complex 125 Starch, bolted 50 Calcium stearate 1 Talc 1 The starch, talc and calcium stearate are thoroughly mixed and the finely divided active ingredients incorporated into the mixture. The resulting material is milled, screened and filled into telescoping capsules by conventional methods. One capsule or more daily is given for combined anabolic and antibacterial therapy.

For more comprehensive antibacterial therapy in con junction with anabolic therapy, from about 25 to about 250 mg. of novobiocin can be included in each capsule of the above formulation for similar administration.

What is claimed is:

1. A therapeutic composition comprisingzin oral unit dosage form, from about 0.25 to about 5 mg. of 7a,17adimethyltestosterone, dispersed in a pharmaceutical carner.

2. A therapeutic composition comprising: in oral unit dosage form, from about 0.25 to about 5 mg. of 70:,1701- dimethyltestosterone and from about to about 250 mg. of tetracycline, demethyltetracycline, oxytetracycline, or chlortetracycline, dispersed in a pharmaceutical carrier.

3. A method for inducing anabolic effects in mammals essentially free of accompanying androgenic eifects comprising: administering orally 7a,17a-dimethyltestosterone in an amount sufiicient to induce anabolic etfects but essentially free of accompanying androgenic effects.

4. A method for inducing anabolic effects in humans essentially free of accompanying androgenic effects com- 3,313,701 5 6 prising: administering o rally from about 0.25 to about OTHER REFERENCES 5 dally of 7"lh'dunethyltestostemne' Campbell et al., Journal of the American Chemical References Cited by the Examiner Society 4069-1075 (1951) UNITED STATES PATENTS 5 ALBERT T. MEYERS, Pruinary Examiner. 2,965,541 12/1960 Byrnes 167-65 JULIAN LEVHT Exammer- 3,017,323 1/1962 Gordon 16765 SAM ROSEN, LEROY B. RANDALL,

3,138,529 6/1964 Takesue 16765 Assistant Examiners.

Claims (1)

1. 3. A METHOD FOR INDUCING ANABOLIC EFFECTS IN MAMMALS ESSENTIALLY FREE OF ACCOMPANYING ANDROGENIC EFFECTS COMPRISING: ADMINISTERING ORALLY 7A,17A-DIMETHYLTESTOSTERONE IN AN AMOUNT SUFFICIENT TO INDUCE ANABOLIC EFFECTS BUT ESSENTIALLY FREE OF ACCOMPANYING ANDROGENIC EFFECTS.