BE1027858B1 - Pharmaceutical composition for contraception in women - Google Patents

Abstract

The invention relates to a composition comprising: - at least one progestational compound, or a salt or a solvate thereof; and - mesterolone, or a salt or solvate thereof.

Description

-1- BE2019 / 5904 Description Title of the invention: Pharmaceutical composition for contraception in women

The invention relates to a pharmaceutical composition for contraception in women.

[0002] Controlling the birth rate has been both a societal issue for several decades, and which continues to be relevant in view of the increase in the world population.

[0003] There are many options for birth control, and a method that has been widely used for decades, is to control female births through the use of birth control pills.

Contraceptive pills currently on the market, and authorized by health authorities in industrial countries inhibit ovulation by suppressing the secretion of pituitary hormones: follicle-stimulating hormone (FSH) and luteinizing hormone, hormones controlling the woman's menstrual cycle.

[0005] Consequently, the secretion of all ovarian steroids is also suppressed, including estrogen, progesterone and androgens.

The principle of these pills is to provide a dose of estrogen and / or - progestogen hormone so as to induce what is called pituitary feedback and inhibit the production in particular of FSH and LH by the pituitary gland.

[0007] These contraceptive pills also have a more general effect on the production of steroid hormones, and in particular suppress the secretion of estrogen, progesterone but also androgens.

[0008] Although contraceptive pills have a very significant effect on the control of birth rates by women themselves, these pills are not without effect on the general metabolism and certain undesirable effects are observed in many users. These effects vary among women and with the hormonal combinations used, and range from headaches and mood swings, to much more severe symptoms including the onset of breast cancer.

[0009] Also, and despite the positive impact of these pills on birth control, there is a real need to eliminate the unwanted effects caused by them, in particular to avoid serious complications for users.

The object of the invention is to overcome these drawbacks.

-2- BE2019 / 5904

One of the aims of the invention is to provide a composition which retains its contraceptive properties but limits the undesirable effects observed when taking the pills currently on the market.

[0012] The invention also relates to a composition comprising: - at least one progestogen compound, or a salt or a solvate thereof; and - mesterolone, or a salt or a solvate thereof.

The invention is based on the surprising finding made by the applicant that the addition of mesterolone to a contraceptive composition comprising a progestogen improves the state of health of users of said composition, and above all prevents or treats the adverse effects of taking progestin.

[0003] Mesterolone, or 10-methyl-4.50-dinydrotestosterone; or else 1α-methyl-5a-androstan-17B-ol-3-one, is a synthetic steroid exhibiting anabolic and androgenic activities. Mesterolone has the following formula:

[0004] [Chem 1]

OH Ll TS ed AT ENST to GE a

H

[0005] The Applicant has come to the conclusion that the progressive decrease in androgenic hormones in women under contraceptive treatment has a detrimental effect on energy production. This decrease can be counteracted by the administration of mesterolone concomitantly with the use of the hormonal contraceptive agent.

[0006] In humans, dihydrotestosterone (DHT) deficiency is the first step in anabolic hormone deficiency. This is because DHT is a final hormone of androgen anabolism, testosterone being a precursor of DHT, as dehydroepiandrosterone (DHEA) is a precursor of testosterone.

Neither testosterone nor DHEA can replace dihydrotestosterone. Also, such substitution treatment cannot significantly counteract DHT deficiencies in the long term.

[0007] The production of testosterone from the ovaries is always, in general in premenopausal women, greater than the production of estradiol.

Formally, testosterone is not a sex hormone, it is an anabolic hormone in women, hormone that directs the construction of structures

-3- BE2019 / 5904 bodily. To become a sex hormone testosterone must be converted into dinhydrotestosterone - the true sex hormone in women. Without testosterone, women's libido is reduced. Testosterone is also the chemical precursor of estradiol. This means that when testosterone is introduced into the body, part of that testosterone is transformed into estradiol, the proliferative hormone.

[0008] The clinical contraceptive studies unfortunately focus on estrogen and progestin without taking into account the very large normal production of androgens by the ovaries in young women.

[0009] Mesterolone, a derivative of DHT, although known for a long time has been neglected by the medical profession because it has only a weak anabolic power.

[0010] Women are excluded from treatment with mesterolone by the pharmaceutical industry, with good reason because the dose of the tablets sold is suitable for men only. Thus, no mesterolone treatment is ever given to women due to inappropriate dosages.

[0011] In the invention, mesterolone is combined with at least one progestin compound, that is to say a steroidal compound with an action similar to that of progesterone. This progestogen can be, without limiting the scope of the invention:

- Levonorgestrel or (=) - 13-ethyl-17-ethynyl-17-hydroxy- 1,2,6,7,8,9,10,11,12,13,14,15,16,17 -tetradecahydrocyclopenta [a] phenanthren-3-one, of the following formula 2:

[0013] [Chem 2] y <OH

H GE VV / OE

- Desogestrel or (8S, 95, 10R, 13S, 145, 17R) -13-ethyl-17-ethynyl-11-methylene-1,2,3,6,7,8,9,10,12 , 14,15,16-dodecaidrocyclopenta [a] phenanthrene-17-ol of the following formula 3:

[0015] [Chem 3]

-4- BE2019 / 5904

LÀ = „OH pen” AN

0.

SES cs he ‚or

- norethisterone or (17a) -17-hydroxy-19-norprégn-4-en-20-yn-3-one of the following formula 4:

[0017] [Chem 4] 0H a “PS |

[0018] Other progestins can also be used such as lynestrenol norgestrienone, levonorgestrel, gestodene, norgestimate, drospirenone, cyproterone acetate, nomegestrol acetate, norelgestromin or dienogest.

In the context of an above-mentioned combination, this composition can be used as a contraceptive, having the effect of thickening the cervical mucus, that is to say that it prevents the passage of sperm, and reduce the thickness of the endometrium to make the uterus unsuitable for implantation. These effects are then combined with those of mesterolone which will prevent or reduce the undesirable effects of taking progestin

In an advantageous embodiment, the invention relates to the above-mentioned composition, further comprising at least one osteogen, or a salt or a solvate thereof.

In combination with the above-mentioned progestogen compound, the composition according to the invention may further contain an estrogen such as estradiol, estetrol or - ethynyl estradiol.

Also, advantageously in the invention, the aforementioned composition can comprise:

[0023] - estradiol, mesterolone, and one or less of the following progestins: desogestrel, norethisterone, lynestrenol norgestrienone,

-5- BE2019 / 5904 gestodene, norgestimate, drospirenone, cyproterone acetate, nomegestrol acetate, norelgestromin or dienogest, or

- ethynyl estradiol, mesterolone, and one or less of the following progestins: desogestrel, norethisterone, lynestrenol norgestrienone, gestodene, norgestimate, drospirenone, cyproterone acetate, nomegestrol acetate, norelgestromin or dienogest, or

[0025] - estetrol of mesterolone, and one or less of the following progestins: desogestrel, norethisterone, lynestrenol norgestrienone, gestodene, norgestimate, drospirenone, cyproterone acetate, l ' nomegestrol acetate, norelgestromin or dienogest.

Advantageously, the invention relates to the above-mentioned composition, where the composition comprises from 5 to 10 mg of mesterolone.

In the invention, by "5 to 10 mg" is meant doses of 5 mg, 5.1 mg, 5.2 mg, 5.3 mg, 5.4 mg, 5.5 mg, 5 , 6 mg, 5.7 mg, 5.8 mg, 5.9 mg, 6 mg, 6.1 mg, 6.2 mg, 6.3 mg, 6.4 mg, 6.5 mg, 6.6 mg, 6.7 mg, 6.8 mg, 6.9 mg, 7 mg, 7.1 mg, 7.2 mg, 7.3 mg, 7.4 mg, 7.5 mg, 7.6 mg, 7.7 mg, 7.8 mg, 7.9 mg, 8 mg, 8.1 mg, 8.2 mg, 8.3 mg, 8.4 mg, 8.5 mg, 8.6 mg, 8, 7 mg, 8.8 mg, 8.9 mg, 9 mg, 9.1 mg, 9.2 mg, 9.3 mg, 9.4 mg, 9.5 mg, 9.6 mg, 9.7 mg , 9.8 mg, 9.9 and 10 mg.

Advantageously, the progestins are present at a dose of either 0.15 mg for desogestrel, or 0.075 mg for gestodene, or 3 mg for drospirenone.

[0029] Estrogens are used in doses of 30 to 50 g for estradiol, and 20 µg for ethynyl estradiol.

Also disclosed is the use of the above composition as a contraceptive.

The invention also relates to a pharmaceutical composition comprising: - at least one progestin compound, or a salt or a solvate thereof; and - mesterolone, or a salt or a solvate thereof in association with a pharmaceutically acceptable vehicle.

Such a pharmaceutical composition can be in the form of a cachet, a pill, a powder soluble in a liquid or intended to be suspended in a liquid, for example in the form of a syrup. , a gel, an injectable solution, an impregnated composition allowing transdermal administration or through the mucous membranes. Those skilled in the art are able to determine the most appropriate dosage form to allow the administration of the desired dose.

-6- BE2019 / 5904

In the invention, the above-mentioned dose is moreover administered daily. This means that the dose can be administered in a single take, or in several takes, for example twice a day (morning and evening for example) or even three times a day (morning, noon and evening for example) according to the recommendations of the doctor.

Here again, those skilled in the art will know how to adapt the dosage regimen according to the individual to be treated, the objective being to administer the above-mentioned dose.

[0034] In addition to the aforementioned mesterolone, the composition may comprise other substances whose function is to promote the effect of mesterolone without however having as such a specific preventive or therapeutic effect on arteriosclerosis. Mention may be made, for example, of one or more additives such as those chosen from fillers, preservatives such as methyl parahydroxybenzoate, propyl parahydroxybenzoate or m-cresol, antioxidants, stabilizing agents such as L hydrochloride. -lysine, acidifying and basifying agents, opacifiers, etc.

Advantageously, the invention relates to the above-mentioned pharmaceutical composition, further comprising at least one osteogen, or a salt or a solvate thereof.

Still more advantageously, the invention relates to the aforementioned composition where the pharmaceutical composition comprises from 5 to 10 mg of - mesterolone.

The invention also relates to a composition as defined above as a medicament.

As mentioned above, the composition can be used to counteract unwanted effects caused by absorption of progestins or estrogen-progestins.

The invention also relates to an above-mentioned composition, or pharmaceutical composition, for its use for the prevention or treatment of the adverse effects of hormonal contraception in women.

[0040] All birth control pills can cause a significant decrease in testosterone production thus producing depression, urination problems, decreased libido and, possibly, breast cancer, it seems logical to produce birth control pills containing a physiological amount of androgens. This is why the applicant proposes such a composition. Because testosterone is a precursor to estradiol, testosterone cannot be used in combination with an estrogen-progestogen composition because, since testosterone is aromatizable, it will increase the production of estradiol.

-7- BE2019 / 5904

[0041] This is a pharmaceutical composition which mixes an estrogen-progestin contraceptive with mesterolone to compensate for the testosterone-hydrotestosterone deficit produced by the estrogen-progestin used alone; mesterolone having properties of testosterone and dihydrotestosterone. Obviously advantageously, an estrogen-progestogen contraceptive pill will comprise mesterolone in physiological doses of 5 to 10 mg, for a daily intake.

[0042] Composition for its above-mentioned use, where said undesirable effects of hormonal contraception in women are chosen from: - dyspareunia, - urinary disorders, in particular chronic cystitis, incontinence and urination emergencies, - coagulation disorders , and in particular thrombosis, in particular deep vein thrombosis, and associated embolisms, or even cerebral hemorrhages, - breast cancer, in particular hormone-dependent breast cancer, - Polycystic ovary syndrome, - head, and - complaints of depression in women.

[0043] A method of preventing or treating the adverse effects of hormonal contraception in women is also disclosed, comprising a step of administering to a woman in need an effective dose, in particular 5 to 10 mg of mesterolone.

The formal demonstration of the effectiveness of the composition according to the invention is very simple since the disorders and the undesirable effects linked to progestational or estrogen-progestational hormonal contraception are due to an induced deficiency in testosterone and DHT, a deficiency which can be bypassed by intake of mesterolone.

[0045] Example - Case of a woman born in 1954.

[0046] A 54-year-old woman consulted in December 2003 for problems with hot flashes, tendino-myalgia and anxiety, nightmares and disturbed sleep.

This woman was on hormonal contraceptive between 18 and 23 years, then from 27 to 30 years and resumed hormonal contraceptive treatment from 1998 and 2002. Since this woman is menopausal.

[0048] Her medical records show that while taking the contraceptive she - presented the symptoms for which she consulted, and that she developed recurrent cystitis for 20 years.

-8- BE2019 / 5904

At the beginning of 2003 she was treated with TSH to reduce her symptoms, but spontaneously stopped the treatment in August 2003.

It is then placed under 10 mg mesterolone per day (5 mg morning and evening) and a check is carried out approximately 6 months later (end of April 2004).

His blood and urine tests in 2003 and in 2004 (6 months later are shown in Table 1 below:

[0052] [Table 1] == EE [a Low Hb 1647 | 117 188 | | GRenmilliers [5300 | 3800 [450 | | GB 110000 [4000 | 5000 | | IN% ® [75 48 48 | | you [do | ATI 1140 80 | 100 | | | Creactve | | <01 [<01 || | Glyc & mie [110 70 179 | M | Urea OO | 48 | 15 123 | J | | Total chol [200 - | 100 | 206 | | | HDLchol [92 4 JM | T4liore [160 - | 07 | 109 | | | Talibre | 88 | 165 - | 28 | TSH | 45 10.3 | 224 | LH 165 | l8 19723 | __ | FSH [130 [30 1898 | __ | | Progesterone OO | <t2 | <12 | 044 | | 170H Prog 133 102 10 || Testosterone [50 1 JM LO | | Andostanediol Gu [540 | 50 [382 | | Adione OO | [<t2 | <12 107 | | IGF1 1388 | 43 1188 | | Calcium 24h [300 80 | 201 | | | Creatinine / 24h [18 106 [128 | | cortisol / 24h OO [270 _ | 75 | 188 | | degcollagen 1676 | O 1688 | __ | ee - T | Androsterone 1 | 3000 | 500 | 600 | 600 | | Ethiocholanolone [3200/500 [700 | 600 | | 11OH-etiocholan [800 - | 100 | 600 - | 500_ |

-9- BE2019 / 5904 17CO total 14000 5000 6000 12700

These data show that the symptoms of menopause, similar to those of hormonal contraception (which is none other than induced menopause) are suppressed after treatment with a daily dose of 10 mg of mesterolone.

Claims (9)

-10- BE2019 / 5904 Claims 1. A composition comprising - at least one progestogen compound, or a salt or a solvate thereof; and - mesterolone, or a salt or a solvate thereof. 2. A composition according to claim 1, further comprising at least one estrogen, or a salt or a solvate thereof. 3. A composition according to claim 1 or 2, wherein the composition comprises from 5 to 10 mg of mesterolone. 4. Pharmaceutical composition comprising, - at least one progestational compound, or a salt or a solvate thereof; and - mesterolone, or a salt or a solvate thereof in association with a pharmaceutically acceptable vehicle. 5. A pharmaceutical composition according to claim 4, further comprising at least one estrogen, or a salt or a solvate thereof. 6. A pharmaceutical composition according to claim 4 or claim 5, wherein the pharmaceutical composition comprises 5 to 10 mg of mesterolone. 7. Compositions according to any one of claims 1 to 3, as a medicament. 8. Composition according to any one of claims 1 to 3, or pharmaceutical composition according to any one of claims 4 to 6, for its use for the prevention or treatment of the adverse effects of hormonal contraception in women. 9. A composition for its use according to claim 8, wherein said undesirable effects of hormonal contraception in women are chosen from: - dyspareunia, - urinary disorders, in particular chronic cystitis, incontinence and urination emergencies, - 11 - BE2019 / 5904 - coagulation disorders, and in particular thrombosis, in particular deep vein thrombosis, and associated embolisms, or even cerebral hemorrhages - breast cancer, in particular hormone-dependent breast cancer , - Polycystic ovary syndrome, - headaches, and - complaints of depression in women