FR233M - - Google Patents

Description

FRENCH REPUBLIC

MINISTRY OF INDUSTRY

INDUSTRIAL PROPERTY SERVICE

SPECIAL MEDICINAL PATENT

P.Y. No. 836.449 International Classification:

N ° 233 M A 61 k - C 07 c

Medicinal product based on fluoxymesterone and ethinyl estradiol.

Company known as: THE UPJOHN COMPANY residing in the United States of America.

Requested on August 22, 1960, at 4:48 p.m., in Paris.

Issued by decree of February 27, 1961.

(Official Bulletin of Industrial Property [B.S.M.], No. 6 of 1961.)

(Patent application filed in the United States of America on February 24, 1959, under No. 794,831,

on behalf of Mr. Marvin Henry Kuizenga.)

(Patent resulting from the division of the invention patent application, P.V. No. 819,350, filed February 23, 1960.)

The present invention relates to a novel combination of steroids containing an androgenic substance and an estrogenic substance. The new pharmaceutical composition received the name "Halodrin". It is a combination of fluoxymesterone, corresponding to the following formula:

9 alpha - fluoro - 11 beta - hydroxy -17 - methyl -testosterone, and ethinyl-estradiol, the formula of which is: 17-ethinyi-estradiol.

The novel pharmaceutical composition can be conveniently prepared by mixing the two therapeutically active ingredients, and including in the formulation of their appropriate oral doses suitable pharmaceutical excipients or carriers.

Example 1. - Compressed tablets. - 100,000 compressed tablets are prepared from the ingredients of the following types, taken in the amounts indicated below:

In each tablet

Total mg

g

1

fluoxymesterone

100

0.02

Ethinyl estradiol Codex

2

60

Codex sugar and cane powder.

6,000

2.6

Codex tragacanth powder

260

60

6,000

Fluoxymesterone, ethinyl estradiol, sugar, tragacanth and lactose are thoroughly mixed in the form of powders, and granulated with a 50% solution of sucrose. The wet mass is sieved, dried and re-screened, then a mixture of 300 g of talc and 100 g of calcium stearate is added to lubricate. Tablets of the appropriate weight are then compressed on a rotary tablet making machine. The clinical use of the tablets is in doses of 2 to 4 tablets per day in the treatment of osteoporosis and androgen and estrogen deficiencies.

Example 2. - Compressed tablets. - Following the procedure of Example 1, compressed tablets are prepared using 1 g of ethinyl estradiol instead of the amount used in Example 1. Each tablet contains 1.0 mg of fluoxymesterone and 0.01 mg ethinyl estradiol. Clinical use of the tablets is in doses of 2 to 4 tablets per day to relieve inflammatory symptoms associated with osteoporosis and androgen and estrogen deficiency.

Example 3. - Soft elastic capsules. - 100,000 soft elastic capsules are prepared from the following amounts and types of ingredients:

In each capsule

Totai

m g

S

1.5

Fluoxymesterone

150

0.01

Ethinyl estradiol Codex

1.0

Corn oil

q. s.

Fluoxymesterone and ethinyi-estradiol are uniformly dispersed in corn oil and the dispersion is encapsulated in soft elastic capsules by the conventional technique. The capsules are used in doses of 2 to 4 capsules per day for the treatment of osteoporosis and androgenic and estrogen deficiencies, and satisfactory results are obtained.

Pharmacological properties. - The androgen-estrogen combination exerts a stimulating effect on

1 - 41500

Price of the booklet: 1 NF

[233 M] -

protein synthesis, favorably influences bone formation and exerts an inhibitory influence on that of gonadotropins of the anterior pituitary gland. The combination keeps the uterine endometrium in an atrophic state.

Therapeutic applications. —- Menopause: estrogenic substances, as well as androgenic substances, have been used for many years to combat the symptoms of menopause. The use of estrogen-only substances, however, has the disadvantage of inducing endometrial activity resulting in forced vaginal discharge, while the use of androgenic substances alone leads, in some cases, to virilizing effects. . Evidence has accumulated to indicate that the combination androgen-estrogen therapy for menopause almost completely eliminates these side effects, even after many weeks of treatment, and yet at the same time provides a adequate symptom relief, exerting a beneficial trophic effect on the vaginal epithelium and maintaining the endometrium in an atrophic or post-menopausal state. Additionally, since women normally secrete androgenic hormones as well as estrogen hormones, the use of an estrogenic substance in combination with an androgenic substance provides more balanced physiological replacement therapy. The additive metabolic benefits of the combination of androgenic and estrogenic substances give a feeling of well-being to the patient going through menopause and allow her a smoother transition to non-reproductive physiology with minimal interference with the normal changes resulting from the menopause. The same metabolic effects fight senile atrophy and result in increased muscle strength.

The effective dose of the androgen-estrogen combination is significantly less than that of either hormone given separately. In general, to combat the symptoms of menopause, "Halodrin" has been shown to be a combination of choice over a period of years. With this combination, the forced flow is reduced to a minimum. In a series of 150 menopausal patients, 80.6% achieved complete relief from treatment combining an androgenic substance and an estrogenic substance with 0.66% uterine discharge, while in a comparable series of 102 patients who were administered only estrogen, only 25.5% achieved total relief of symptoms with uterine discharge in 33% of patients.

The critical age of men. - The combination of androgenic and estrogenic substances is used to relieve symptoms resulting from reduced functioning of the sex glands in men who are at least 60 years of age. Although this syndrome is still the subject of controversy, the symptoms presented have been reported to include asthenia, decreased libido, irritability, arthralgia, insomnia, loss of memory, and dizziness. In. In general, the results of treatment with this combination in patients exhibiting these symptoms have been encouraging, and have included favorable personality changes, improvement in mental status, and an incidental drop in blood pressure. In a series of 9 patients treated with this combination because of their critical age, 8 presented a favorable reaction.

Osteoporosis. - Combination therapy is recommended in the treatment of various types of osteoporosis, in particular for senile and post-menopausal osteoporosis, and for osteoporosis which develops in some patients following prolonged treatment with adrenal cortex hormones.

Osteoporosis is a general disease of the bones, in which a disturbance in tissue metabolism results in a lack of formation of the basic protein substance on which calcium is deposited. The mineral salts deposited on the organic framework gradually dissipate, and the structure of the bone becomes fragile. Urinary excretion of calcium and phosphorus may be increased. In osteoporosis following menopause and in senile osteoporosis, the causative factors include:

1. Old age, with the corresponding loss of sex hormones;

2 ° Atrophy due to lack of exercise, and

3 ° A lack of proteins, since nitrogenous matters are necessary for the formation of the basic protein substance of bone.

In osteoporosis developing in association with prolonged treatment with adrenal cortical hormones, one of the important etiological factors is the persistence of a negative nitrogen balance, which leads to a deficiency in the formation of the substance fundamental protein of the bones and the subsequent pathological changes in these bones.

The combination of the invention has been found to have anabolic action and cause retention of calcium and phosphorus. The anabolic action is more marked in the case of androgenic substances than in that of estrogenic substances, while the calcium retention effect is generally more intense in the case of estrogenic substances. The combination of the invention has been shown in metabolism studies to cause:

1 ° A higher retention of calcium than that obtained by each of the agents taken in isolation, and

2 ° Maximum retention of nitrogen and phosphorus. The average retention ratio is that expected for bone and soft tissue anabolism.

The clinical response to therapy by the combination of the invention in the case of osteoporosis is often marked. Considerable or total pain relief can be expected within a short period of time, usually a few weeks; frequently there is weight gain accompanied by a general feeling of well-being and increased strength and activity. Although clinical improvement is often evident within weeks of initiation of treatment, radiological evidence of recalcification has been difficult to see, but it has been shown to exist after as short as eighteen months. . Signs suggesting increased calcification may be obtained earlier from bone biopsies, as well as from the study of calcium in the urine, indicating a reversal of the previously negative calcium balance. In a series of 34 patients with postmenopausal osteoporosis, 29 had a satisfactory response to treatment with

- [233 M]

combination of the invention, judging by the relief of their pain.

ABSTRACT

As a useful medicament in hormonal treatment, the combination of 9 alpha-fluoro-11 beta-hydroxy-17-methyl-testosterone and 17-ethyl-nyl-estradiol:

1 ° It has been found that its pharmacological properties are:

at. Stimulation of protein synthesis;

b. Favorable influence on bone formation;

vs. Inhibitory influence of that of gonado-trophins of the anterior pituitary gland, and,

d. Maintenance of the uterine endometrium in an atrophic state.

2 ° It has been found that this medication is useful in the treatment of the following disorders:

at. Symptoms of menopause,

b. Symptoms of critical age in humans,

and c. Osteoporosis.

Company known as: THE UPJOHN COMPANY

Vicarious :

SlMONNOT, RlNUY & BLUNDEIJ

For the sale of booklets, contact the Imprimerie NationaLe, 27, rue de la Convention, Paris (15 *).