DE1047596B - Hormone preparation for rearing and for grazing cattle and sheep - Google Patents

Description

GERMAN

The present invention relates to the improvement the formation of meat in meat-feeding animals, such as Ox, cattle, calves, sheep and other cattle.

It is known to add small amounts of an estrogenic substance, such as diethylstilbestrol, to animal feed rations to promote growth and fat deposits. The administration of Diethylstilbestrol for similar purposes in poultry farming by injecting a suspension of crystalline Diethyl ether in a plasticized high molecular weight polymerize polyethylene glycol carriers of the »Carbowaxs type.

The administration of an estrogenic substance such as diethylstilbestrol has been successfully carried out economically although the addition of diethylstilbestrol as such to animal feed has proven to be disadvantageous proved: firstly because of the weight and mass of the premixed concentrate, which was too proportionate high shipping and storage costs, and secondly because of the difficulties involved in mixing of the premix are linked to the respective feed quantities. These difficulties lie In the manufacture of a uniform product, the danger to workers from inhaling hormone-containing substances Dust, etc. For the most part, these and other disadvantages have been eliminated. the Search for improved persistent mixtures, especially those that can be injected however continued, since these types of mixtures have only small dimensions and this creates the difficulties storage and cumbersome mixing work can be avoided.

In studies made by the inventors in this field, the administration of individual certain androgenic hormones, including testosterone, testosterone propionate, / l-4-androstenedione, Pregnenolone and estrogenic hormones, such as estradiol, estradiol benzoate, estradiol propionate and dipropionate, examined in pill form or as a single implant. The results of these experiments with relative expensive hormones showed that the lower quality of the Meat and the large feed consumption to achieve this weight gain this. Process uneconomical did.

At the time the best solution seemed to be the administration of a relatively cheap one; estrogenic substance, such as diethylstilbestrol, to be by injection. However, this procedure resulted in a "Ferninization", which was accompanied by undesirable and harmful side effects. The mainly occurring undesirable "effects on the cattle, which impair the quality of the meat, are hormone preparations for rearing and for
Fattening of cattle and sheep

Applicant:

Olin Mathieson Chemical Corporation,
New York, NY (V. St. A.)

Representative: Dr.-Ing. H, Ruschke, Berlin-Friedenau,

and Dipl.-Ing. K. Grentzenberg, Munich 27,

Pienzenauerstr. 2, patent attorneys

Claimed priority:
V. St. v. America 12/31/1956

Francis X. Gassner, Fort Collins, Col. (V. St. Α.),
has been named as the inventor

uneven fat deposition, predominantly in the buttocks and abdominal viscera, and slackening the pelvic ligaments, mainly the lower back and hip parts, leading to abnormal development of the lower back and tailbone vertebrae leads. Try to make these feminizing changes after they occur Reversing injections of androgenic hormones were unsuccessful.

In the course of further investigations it has now been found that when mixing the estrogenic Substance with appropriate amounts of androgenic hormone when injected or implanted the above indicated undesired anatomical changes did not occur. It was also found that when using androgenic and estrogenic substances in combination, the treated animals one showed considerable daily weight gain over the untreated animals while simultaneously consumed less or at least no more feed than the untreated animals. This latter The result was diametrically opposed to previous observations in this area, where the administration of a single hormone always seemed to be accompanied by higher feed consumption.

The simultaneous protogenic or lipogenic effects caused by the androgenic or estrogenic hormone when used together result in a daily weight gain that is greater than the sum of the daily weight gains that

809 700/199

by the same amounts of androgenic and estrogenic Substance can be achieved with single application.

In order to achieve the beneficial results described above, the androgenic hormone must be as found was present in excess of the estrogenic hormone and in the case of androgenic substances with the activity of testosterone and estrogen with the activity of diethylstilbestrol that Ratio of androgen to estrogen in parts by weight at least 4: 1 and preferably 5: 1. Higher androgen to estrogen ratios can be used but are common except in calves, not associated with any noteworthy additional improvements, so that is a ratio of 5: 1 as sufficient to prevent the unwanted feminizing effects of the estrogenic substance was detected. For calves, an androgen to estrogen ratio of around 10: 1 is used preferred. For an ox or a cattle, the injection was found to be at least about 60 mg up to about 240 mg of androgenic substance as satisfactory, with an amount of about 120 mg androgen such as Testosterone, for one administration (per dose) is preferred. For smaller animals, the quantities should be reduced, e.g. B. is said to be injected into a calf Amount of androgenic substance preferably in the range of about 50 to 100 mg at a ratio of androgenic to estrogenic substance of about 10: 1, and in a lamb the amount injected should be androgenic substance in the range of about 24 to 50 mg with an androgenic to estrogenic substance ratio of about 5: 1. Bigger and smaller amounts can be administered in multiple doses, albeit for a single injection The ranges given above for androgenic substances in connection with the given proportions to be preferred to estrogenic substance. Except for lambs, where treatment is common only lasts a short time and only requires one burst injection, multiple injections can be used The type described above used to increase weight gain in oxen, cattle and calves will.

The following examples illustrate the invention.

mg / injection 0.8 ecm 0.4 ecm Example VI ■ tone testosterone 60 24 Estradiol undecylate \ J \ J
12th Example VII 120 Testosterone enanthate .... 60 24 Diethylstilbestrol 12th Example VIII 60-120-240 Testosterone enanthate .... 30-60-120 12-24-48 Estradiol valerate 6-12-24 Example IX 120 Testosterone enanthate .... 60 24 Estradiol undecylate 12th mg / injection 0.4 or 0.8 ecm Example X 50-80-100 testosterone 5-8-10 Diethylstilbestrol Example XI 24-30-50 testosterone 4-6-10 Diethylstilbestrol

With antithyroid substance

45

Androgen + estrogen

Example XII

testosterone

Diethylstilbestrol ..,
Methimazole

Example XIII

Testosterone,

Estradiol valerate
Methimazole

Example XIV

Testosterone enanthate
Estradiol valerate
Methimazole

mg / injection 0.4 ecm I 0.8 ecm

60 12 12

60

12th

120 24 24

120 24 24

120 24 12

Example I.

testosterone

Diethylstilbestrol

Example II

testosterone

Diethylstilbestrol

Example III

testosterone

Polystyle estrol phosphate

Example IV

testosterone

Estradiol

Example V

testosterone

Estradiol valerate

mg / injection
0.4 ecm I 0.8 ecm androgen + estrogen + luteal hormone (progesterone)

60
12th

120
24

60
15th

60
12th

60
12th

120
24

240

120
30th

120
24

120
24

55

mg / injection 0.8 ecm 0.4 ecm Example XV 30-60-120 Testosterone enanthate .... 15-30-60 12-24-48 estradiol valerate 6-12-24 17-a-hydroxyprogesterone 30-60-120 caproat 15-30-60

60 In the above examples, the mixtures of Examples I to IX and XII to XIV in the for steers and cattle preferred doses, the mixture of Example X in the calves and the mixture of Example XI shown in the preferred dosages for lambs. If at least two doses are to be injected, half the minimum amount can be used, e.g. B. 30 mg androgenic hormone and 6 mg estrogen (see first mixture of Example VIII) for oxen and cattle. As in

1 04 / 5yt>

shown in Examples XII to XIV, an antithyroid agent can optionally also be used will.

In Example XV, half of the androgenic hormones are replaced by 17-a-hydroxyprogesterone caproate been. Even if 17-a-hydroxyprogesterone is biologically inert, capronate can still be beneficial Be added to the androgen-estrogen mixture as it is an active anabolic agent with certain androgenic properties is. This mix is among the preferred for oxen while the Mixture of Example I is preferred for cattle.

In over eighty experiments with more than 26,000 animals it was found that the injection of the above described Mixtures caused significantly more rapid weight gain than control animals that received the same amount of food without hormone administration. These factors offer more to the animal breeder Meat with less feed consumption. In these experiments it was also found that the treated Animals (a) practically no feminization, d. H. uneven fat distribution and strongly developed Sacrum and coccyx vertebrae, and (b) practically no masculinization or prominence of bull characteristics, d. H. narrow buttocks and strong necks showed. The lack of this undesirable For the breeder, traits mean improved quality, i. H. both more meat to be canned as well as more meat of better quality, namely more excellent and very good cuts.

The ingredients given in the above examples are advantageously combined with inert pharmaceutical Diluents and carriers are mixed as they are commonly used for injectable preparations will. Usually the concentrations are such that those given in the examples Quantities of about 0.5 to 1 ecm can be administered by injecting, with that in the examples specified amounts of 0.4 to 0.7 ecm in the preferred Area lie. The preferred carriers are in and contain injectable paste form the active hormone components in solution distributed in it. One of the preferred carriers consists of one Mixture of polymerized polyethylene glycols which polymerized about 1.5 to 2.0 parts by weight of liquid ice Polyethylene glycol with a molecular weight of about 200 to 300 per part by weight of solid, polymerized Contains polyethylene glycol with a molecular weight of about 4000. These substances are commercially available as polyethylene glycol 200 or 300 and polyethylene glycol 4000 (Carbowax) (See McClelland et al., Cheni. Eng. News, 23 [1945], p. 247).

The following examples serve to further illustrate the invention.

Example XVI

Testosterone 60 g

Diethylstilbestrol 12 g

Polyethylene glycol 200 256 g

Polyethylene glycol 4000 172 g

The testosterone and the diethylstilbestrol are mixed with the polyethylene glycol 200 and the mixture heated to about 65 to 70 ° C with constant gentle stirring until solution has occurred. That Polyethylene glycol 4000 (Carbowax) is added with mixing to the resulting solution and the Maintain temperature at about 65 to 70 ° C until all ingredients are dissolved. Possibly is of unsolved Substance filtered off. The temperature of the resulting solution is increased to about 80 to 85 ° C and pouring the hot mixture into injection ampoules of the injectable cartridge type. The Partons are then placed in a water bath at about 70 to 75 ° C and the mixture is allowed to stand until it solidifies. The paste mass prepared as above can be used for 500 injections of about 1 g, each containing 120 mg testosterone and 24 mg diethylstilbestrol, and administered using a multiple syringe will.

Example XVII

Testosterone enanthate 23 g

Estradiol valerate 4.6 g

Methimazole 2.3 g

Polyethylene glycol 200 95.6 g

Polyethylene glycol 4000 63.5 g

The active hormone components are with the polyethylene glycols, as described in Example XVI, mixed, and the methimazole is after addition and dissolution of the high molecular weight polyethylene glycol 4000 added to the heated mixture. The mass is then immediately poured into injection ampoules, as described in the example above. This mixture allows about 190 injections of 0.8 ecm, which contains about 120 mg testosterone enanthate, 24 mg estradiol valerate and 12 mg methimazole per injection contain.

The low molecular weight polyethylene glycol acts in the improved pasty mixtures described above both as a plasticizer and as a solvent for the active ingredients that are dissolved in Form are distributed throughout the high molecular weight polyethylene glycol. When the mass is injected and comes into contact with the body fluids, the active components crystallize out and are precipitated in situ as a uniform mixture. If, as in the case of the present invention, mixtures are used, the presence of the ingredients is in solution and not in suspended form prior to injection is important for the uniformity of the product. Further it has been found that the mixtures are stable and have the desired properties during the Storage · retained.

The results of one of the tests given above are explained in Table I below:

Table I.

55 Number of oxen. Comparison animals Treated
animals Number of feeding days 218 66 60 average days
lige weight to
take (kg) in the
Feeding time .... 80 65 Meat yield (%). 1.16 1.45 Quality < 62.8 * 63.3 I. 25%
excellent
75% very good 40%
excellent
60% very good

* Meat yield and quality of forty-four of the best of the two hundred and eighteen steers for comparison.

Claims (7)

The treated oxen shown in this table received an injection of 120 mg testosterone and 24 mg diethylstilbestrol. As shown in the table, the average daily weight gain of the treated oxen during the feeding period was about 300 g above that of the reference animals, so that they reached a fattening state in which they could be sold in 65 days compared with 80 days for the reference animals . The yield of slaughtered meat per carcass as well as the quality of the meat were better for the treated ox than for the untreated. The injectable mixtures of androgenic and estrogenic substances can optionally also advantageously take place simultaneously with oral feeding of diethylstilbestrol, as shown in Table II. Table II Example XVIII Comparison animalsTreated animalsNumber of oxen ..105105Number of feeding days6258Starting weight (kg) .380382Final weight (kg) 464469 Daily weight gain during the feeding time (kg) .... 1,361,49 Yield of slaughtered meat59 5762 07 Quality 100% {90% very good very good ~ 10% good 35 In this experiment, all oxen (control animals and treated animals) were fed the daily amount of 10 mg diethylstilbestrol approved by the USA government (FDA), and the treated animals were also given a mixture of 120 mg testosterone and 24 mg diethylsttlböstrol, prepared as described in Example XVI, injected. As shown in the table, the treated steers had a higher average daily weight gain than the control animals and reached the end of fattening and salable condition a few days before the control animals. The advantages of the injection of the mixture of andirogenic and estrogenic substance are further demonstrated by the meat yield increased by about 23% and the improved meat quality in the treated ox compared to the untreated. In the examples above, where the androgenic hormone is free testosterone and the estrogenic hormone is diethylstiubestrol (see Examples I and II), the mixtures have a relatively short effect and a single injection of the preferred amounts remains in the preferred ratio usually only active in the carcass for about 30 to 45 days. If longer activity is desired, e.g. B. up to 60 days and above, the long-acting esterified steroids, ζ. B. steroids esterified with a fatty acid having 4 to 12 carbon atoms can be used (see Examples VIII and IX). The following further examples illustrate the longer-acting mixtures. 7. » mg / injection in 0.4 or 0.8 ecm testosterone caprylate 120 estradiol 3,17-di-n-butyrate 24 Example XIX testosterone caprylate 60 17-α-hydroxyprogesterone enanthate 60 estradiol 3,17-di-n-butyrate 24 In den Examples XVIII and XIX, as well as in the other mixing examples described above, the active ingredients are evenly distributed in an injectable pharmaceutical carrier, preferably dissolved in the liquid and solid polyethylene glycols described above, with enough carrier being used that a single dose of about 0, 5 to 1.0 ecm. The preferred dosage (120 mg androgenic and 24 mg estrogenic hormone) can, for example, as shown in Examples XVIII and XIX, be administered in a single dosage of about 0.4 as well as 0.8 ecm. In Example XIX, the anabolic agent 17-α-hydroxyprogesterone caproate from Example XV was replaced by oxyprogesterone enanthate. As shown in these examples, the ratio of androgen plus anabolic agent to estrogenic substance is maintained at about 5: 1 (the preferred overall ratio of androgenic to estrogenic substance), with a single dose about 120 mg (60 mg androgenic substance + 60 mg anabolic agent) and 24 mg of estrogenic substance. In addition to the active hormones described, other derivatives and compounds characterized by androgenic activity and estrogenic activity, in the presence or absence of anabolic or antithyroid agents, can be used according to the invention. The mixtures are implanted or injected under the skin in a conventional manner, e.g. B. in the lower jaw or preferably in the base of one of the ears. P \ ϊι ·: ν r λΝ'11'üI'che. 1. Hormone preparation for rearing and fattening cattle and sheep, which is made from in a pharmaceutical carrier consists of sex hormones evenly distributed, characterized in that that these hormones consist of a mixture of an androgenic with an estrogenic substance exist in a weight ratio of at least 4: 1. 2. Hormone preparation according to claim 1, characterized in that the hormone mixture consists of Testosterone and diethylstilbestrol in a weight ratio of about 5: 1 and in a mixture of liquid and solid polymerized Polyätylgenglykalen in the form of an injectable Paste is evenly distributed. 3. Hormone preparation according to claim 1, especially for use as a single dose, characterized in that that the hormone mixture of 60 to 240 mg androgenic substance and 12 to 48 mg estrogenic substance, the ratio of androgenic to estrogenic substance in the Dasierungseinheit is about 4 to 10: 1. 4. Hormone preparation after. Claim 1, characterized characterized in that the dosage unit of 60 up to 240 mg of a fatty acid ester of testosterone, in particular of testosterone enanthate, and about. 12 to 48 mg of a fatty acid ester of estradiol, in particular of estradiol valerate. 5. Hormone preparation according to claim 1, characterized in that the dosage unit consists of about 30 to 120 mg of a fatty acid ester of testosterone, 30 to 120 mg of an anabolic one Means that is a fatty acid ester of 17-a-hydroxyprogesterone and there is about 12 to 48 mg of a fatty acid ester of estradiol, the weight ratio of the testosterone ester to the anabolic agent about 1: 1 and the weight ratio of testosterone ester and anabolic agent together to form the estradiol ester, for example 5: 1. 6. Hormone preparation according to claim 5, characterized in that the dosage unit is approximately 60 mg testosterone enanthate, about 60 mg 17-ct-hydroxypirogesterone caproate and contains approximately 24 mg of estradiol valerate. 7. Hormone preparation according to claim S, characterized in that the dosage unit is approximately 60 mg testosterone capryct, about 60 mg 17-ct-hy-'droxyprogesteronönanthate and contains about 24 mg of estradiol 3,17-di-n-butyrate. Considered publications:
German patent specification No. 892 854. © 809 700/199 12.