Male oral contraceptive

Abstract

The invention relates to an oral dosage unit for use in a method of contraception in a human male, said oral dosage units containing GnRH antagonist and dehydroepiandrosterone (DHEA), the method comprising once daily oral administration of the oral dosage unit to the human male during a period of at least 7 days. This contraceptive method is convenient, effectively suppresses spermatogenesis and is reversible. Another aspect of the invention relates to a dosage unit comprising: • GnRH antagonist selected from: o 50-250 mg relugolix; o 167-833 mg linzagolix; o 113-583 mg elagolix; • 100-800 mg dehydroepiandrosterone.

Description

[0001] MALE ORAL CONTRACEPTIVE

[0002] TECHNICAL FIELD OF THE INVENTION

[0003] The present invention relates to a male oral contraceptive, more particularly a male oral contraceptive comprising a combination of (i) gonadotropin-releasing hormone (GnRH) antagonist and (ii) dehydroepiandrosterone.

[0004] BACKGROUND OF THE INVENTION

[0005] Most modern contraceptive methods are for women. Men generally have two options: condoms or vasectomies. Both these methods have their positives — condoms continue to play a vital role in infection prevention and are a widely used, easily accessible method of contraception; likewise, vasectomy is a highly effective permanent method of contraception. However, they are not adequate for many sexually active men who wish to have control over their fertility.

[0006] Potential novel male contraceptives can be divided into those based on a hormonal approach, acting via gonadotrophin suppression, and non-hormonal methods. Hormonal strategies for male contraception involve the hypothalamic-pituitary-testicular (HPT) axis, using exogenous testosterone in combination with progestogen to drive the negative feedback response and suppress GnRH, FSH and LH. Exogenous replacement of testosterone prevents hypogonadal side effects from HPT axis suppression but is not delivered at high enough concentrations to support spermatogenesis directly. Non-hormonal methods can act at any point during spermatogenesis or can target sperm maturation, detachment, motility or transport out of the testis.

[0007] Progress in developing a reversible male contraceptive has been slow. While the hormonal approach has been shown to be capable of providing effective and reversible contraception, there remains no product available. Clinical studies of a self-administered gel containing a combination of testosterone and the progestogen Nestorone® are underway, complementing the largely injectable methods previously investigated. Novel long-acting steroids with both androgenic and progestogenic activity are also in clinical trials.

[0008] Gonadotropin-releasing hormone (GnRH) antagonists are a class of medications that antagonise the GnRH receptor by competing with natural GnRH for binding to GnRH receptors, thus decreasing or blocking GnRH action in the body. GnRH antagonists are used in the treatment of prostate cancer, endometriosis, uterine fibroids, female infertility in assisted reproduction, and for other indications. Currently approved GnRH antagonists include the peptide molecules abarelix, cetrorelix, degarelix, and ganirelix and the small-molecule compounds elagolix and relugolix. GnRH antagonists are administered by subcutaneous injection (cetrorelix, degarelix, ganirelix), by intramuscular injection (abarelix), or by oral administration (elagolix, relugolix). Another non-peptide and orally active GnRH antagonist that is in development is linzagolix.

[0009] Gava et al. (Update on male hormonal contraception, Therapeutic Advances in Endocrinology and Metabolism (2019), Vol. 10: 1-9) provide an overview of all hormonal contraceptive regiments tested in man:

[0010] • Hormonal contraceptive injectable regimes using testosterone only

[0011] • Hormonal contraceptive injectable regimes using testosterone combined with other molecules (progestin or GnRH antagonists)

[0012] • Hormonal contraceptive transdermal regimes using testosterone and Nestorone: gel-gel combination

[0013] • Oral formulations (new androgens with androgenic and progestogenic activity: dimethandrolone undecanoate (DMAll), 11-beta-methyl-19-nor-testosterone 17-beta- dodecylcarbonate (11-pMNTDC))

[0014] DE19650352A1 describes an oral contraceptive for men, containing (i) at least one component dehydroepiandrosterone (DHEA) or at least one compound that splits off DHEA after ingestion or is converted into DHEA and (ii) at least one gestagen (progestogen).

[0015] SUMMARY OF THE INVENTION

[0016] The inventors have devised an oral dosage unit that can suitably be used to achieve reversible contraception in human males.

[0017] A first aspect of the invention relates to an oral dosage unit for use in a method of contraception in a human male, said oral dosage units containing GnRH antagonist and dehydroepiandrosterone (DHEA), the method comprising once daily oral administration of the oral dosage unit to the human male during a period of at least 7 days. The present method of male contraception is convenient, effectively suppresses spermatogenesis and is reversible.

[0018] In human males, DHEA is metabolised to form testosterone and estradiol. Thus, while administration of the GnRH antagonist in accordance with the present method suppresses production of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) by the anterior pituitary gland, and consequently suppresses endogenous production of testosterone and estradiol, co-administration of DHEA ensure that symptoms of hypoandrogenicity and hypoestrogenicity are effectively avoided.

[0019] Another aspect of the invention relates to a dosage unit comprising:

[0020] • GnRH antagonist selected from: o 50-250 mg relugolix; o 167-833 mg linzagolix; o 113-583 mg elagolix;

[0021] • 100-800 mg dehydroepiandrosterone.

[0022] A final aspect of the invention relates to a package comprising at least 28 oral dosage units, said oral dosage units being arranged within the package in a fixed sequence, the total number of dosage units in the package being a multiple of 7.

[0023] DETAILED DESCRIPTION OF THE INVENTION

[0024] A first aspect of the invention relates to an oral dosage unit for use in a method of contraception in a human male, said oral dosage units containing GnRH antagonist and dehydroepiandrosterone, said method comprising once daily oral administration to the human male of the oral dosage unit during a period of at least 7 days.

[0025] The term "comprise" and variations thereof, such as, "comprises" and "comprising" as used herein should be construed in an open, inclusive sense, meaning that the embodiment described includes the recited features, but that it does not exclude the presence of other features. The same holds for the terms “contain”, “contains” and “ containing”.

[0026] The singular forms "a," "an," and "the" as used herein should be construed to include plural referents unless the content clearly dictates otherwise. It should also be noted that the term "or" is employed in its broadest sense, that is, as meaning "and / or" unless the content clearly dictates otherwise. Numerical ranges expressed in the format "from x to y" are understood to include x and y.

[0027] Whenever components A and B are said to be present in a weight ratio of x:y, what is meant is that the concentration of component A in wt.% divided by the concentration of component B in wt.% equals x:y.

[0028] Ratios mentioned herein are based on weight / weight, unless indicated otherwise. Similarly, all percentages are percentages by weight (w / w) unless otherwise indicated.

[0029] When multiple preferred ranges are described in the format "from x to y" for a specific feature, it should be understood that all ranges combining the different endpoints are also contemplated.

[0030] If, for a particular component, a range of 0% to y% or less than y% is recited, said component may be absent.

[0031] Additionally, should a particular component be recited as "at least y%", said component may be present in a concentration of y% to 100%.

[0032] The term "GnRH antagonist" as used herein refers to a class of medications that bind to the GnRH receptor without activating said receptor.

[0033] The term "estrogen" as used herein refers to a class of natural or synthetic steroid hormones that bind to and activate the estrogen receptors.

[0034] The term "estradiol" as used herein refers to estra-1 ,3,5(10)-triene-3,17p-diol. The term "estradiol" also encompasses hydrates thereof, such as estradiol hemihydrate.

[0035] The term "estriol" as used herein refers to estra-1 ,3,5(10)-triene-3,16a,17p-triol. The term "estriol" also encompasses hydrates thereof, such as estriol monohydrate.

[0036] The term "estetrol" as used herein refers to estra-1 ,3,5(10)-triene-3,15a,16a,17p-triol. The term "estetrol" also encompasses hydrates thereof, such as estetrol monohydrate.

[0037] The term "ethinyl estradiol" as used herein refers to 17a-ethynylestra-1 , 3,5(10)-triene-3,17p- diol. The term "ethinyl estradiol" also encompasses hydrates thereof, such as ethinyl estradiol hemi-hydrate. The term “dehydroepiandrosterone” as used herein refers to 3p-hydroxyandrost-5-en-17-one. The term “dehydroepiandrosterone” (DHEA) as used herein also encompasses dehydroepiandrosterone sulfate (DHEA-S).

[0038] The term "progestogen" as used herein refers to a class of natural or synthetic steroid hormones that bind to and activate the progesterone receptor.

[0039] The term "prodrug" as used herein refers to a substance that, after oral administration, is metabolised into a pharmaceutically active drug. Thus, for instance, a prodrug of estradiol is a substance that is metabolised into estradiol after oral administration. Estradiol valerate is an example of a prodrug of estradiol. Preferably, such prodrugs are derivatives wherein the hydrogen atom of at least one of the hydroxyl groups has been substituted by an acyl radical of a hydrocarbon carboxylic, sulfuric, sulfonic acid or sulfamic acid of 1-25 carbon atoms, or combinations thereof.

[0040] The term "oral dosage unit" as used herein refers to a pharmaceutical formulation designed to be taken through the mouth and swallowed.

[0041] The present contraceptive method effectively suppresses spermatogenesis. Preferably, the present method achieves a suppression of sperm concentration to less than 10 million / ml in the ejaculate, more preferably less than 5 million / ml, most preferably, to less than 1 million / ml in the ejaculate. Methods for determining the sperm concentration are known to the skilled person, such as the method defined by ISO 23162:2021.

[0042] The contraceptive method preferably comprises once daily oral administration of the oral dosage unit during a period of at least 14 days. More preferably, it comprises once daily oral administration of the oral dosage unit during a period of at least 28 days, even more preferably during a period of at least 56 days, yet more preferably during a period of at least 84 days.

[0043] The GnRH antagonist that is employed in accordance with the present invention preferably is selected from relugolix, linzagolix, elagolix. More preferably, the GnRH antagonist is selected from relugolix and linzagolix. Most preferably, the GnRH antagonist is relugolix.

[0044] In the contraceptive method of the present invention, the GnRH antagonist that is present in the oral dosage unit is preferably selected from:

[0045] • 50-250 mg relugolix;

[0046] • 167-833 mg linzagolix; and 113-583 mg elagolix.

[0047] In a preferred embodiment of the invention, the oral dosage unit contains 80-200 mg relugolix, more preferably 90-160 mg relugolix, most preferably 100-140 mg relugolix.

[0048] In another preferred embodiment, the oral dosage unit preferably contains 267-667 mg elagolix, preferably 300-533 mg elagolix and most preferably 333-467 mg elagolix.

[0049] In yet another preferred embodiment, the oral dosage unit contains 180-450 mg linzagolix, preferably 203-360 mg linzagolix, most preferably 225-315 mg linzagolix.

[0050] The oral dosage unit used in the present method preferably contains 100-800 mg, more preferably 150-700 mg, and still more preferably 200-600 mg dehydroepiandrosterone.

[0051] In a preferred embodiment, the oral dosage unit used in the contraceptive method does not comprise progestogen.

[0052] In accordance with a preferred embodiment of the invention, the oral dosage unit used in the method according to the present invention comprises:

[0053] • GnRH antagonist selected from: o 50-250 mg relugolix; o 167-833 mg linzagolix; o 113-583 mg elagolix;

[0054] • 100-800 mg dehydroepiandrosterone.

[0055] In a preferred embodiment, besides GnRH antagonist and DHEA, the oral dosage units used in the contraceptive method contains estrogen. The presence of estrogen in the oral dosage unit ensures that sufficient estrogen is provided to avoid symptoms of hypoestrogenism, especially in case a relatively low dose of DHEA is administered.

[0056] The estrogen that is employed in accordance with the present invention is preferably selected from ethinyl estradiol, estradiol, a prodrug of estradiol, estriol, a prodrug of estriol, estetrol, a prodrug of estetrol and combinations thereof. More preferably, the estrogen is selected from ethinyl estradiol, estradiol, estradiol valerate, estetrol and combinations thereof. Even more preferably, the estrogen is selected from ethinyl estradiol, estradiol, estetrol and combinations thereof. In one particularly preferred embodiment, the estrogen employed in the present method is ethinyl estradiol. In another particularly preferred embodiment, the estrogen employed is estetrol.

[0057] The estrogen in the oral dosage unit is preferably selected from:

[0058] • 5-40 mg estetrol;

[0059] • 2-12 pg ethinyl estradiol;

[0060] • 0.3-2 mg estradiol; and

[0061] • 10-60 mg estriol.

[0062] The oral dosage unit preferably contains 7-20 mg of estetrol. Most preferably, the oral dosage unit contains 8-15 mg of estetrol.

[0063] In another preferred embodiment, the oral dosage unit contains 3-10 pg ethinyl estradiol, and most preferably 4-8 pg ethinyl estradiol.

[0064] In a further preferred embodiment, the oral dosage unit contains 0.5-1.0 mg estradiol or estradiol valerate. Most preferably, the oral dosage unit contains 0.7-0.8 mg of estradiol or estradiol valerate.

[0065] In yet another embodiment, the oral dosage unit contains 20-40 mg of estriol. Most preferably, the oral dosage unit contains 25-35 mg of estriol.

[0066] In a particularly preferred embodiment of the invention, the oral dosage unit comprises:

[0067] • 80-200 mg relugolix;

[0068] • 200-600 mg dehydroepiandrosterone;

[0069] • 7-20 mg estetrol; and

[0070] • no progestogen.

[0071] Another aspect of the invention relates to an oral dosage unit comprising:

[0072] • GnRH antagonist selected from: o 50-250 mg relugolix; o 167-833 mg linzagolix; o 113-583 mg elagolix;

[0073] • 100-800 mg dehydroepiandrosterone. Preferably, the GnRH antagonist is selected from relugolix and linzagolix. Most preferably, the GnRH antagonist is relugolix.

[0074] In a preferred embodiment of the invention, the oral dosage unit contains 80-200 mg relugolix, more preferably 90-160 mg relugolix, most preferably 100-140 mg relugolix.

[0075] In another preferred embodiment, the oral dosage unit contains 267-667 mg elagolix, preferably 300-533 mg elagolix and most preferably 333-467 mg elagolix.

[0076] In yet another preferred embodiment, the oral dosage unit contains 180-450 mg linzagolix, preferably 203-360 mg linzagolix, most preferably 225-315 mg linzagolix.

[0077] The oral dosage unit preferably contains 150-700 mg, and still more preferably 200-600 mg dehydroepiandrosterone.

[0078] In a preferred embodiment, the oral dosage unit does not comprise progestogen.

[0079] In accordance with a preferred embodiment of the invention, the oral dosage unit according to the present invention comprises:

[0080] • GnRH antagonist selected from: o 50-250 mg relugolix; o 167-833 mg linzagolix; o 113-583 mg elagolix;

[0081] • 100-800 mg dehydroepiandrosterone.

[0082] In a preferred embodiment, besides GnRH antagonist and DHEA, the oral dosage unit contains estrogen, more preferably estrogen selected from ethinyl estradiol, estradiol, a prodrug of estradiol, estriol, a prodrug of estriol, estetrol, a prodrug of estetrol and combinations thereof. Even more preferably, the estrogen is selected from ethinyl estradiol, estradiol, estradiol valerate, estetrol and combinations thereof. Yet more preferably, the estrogen is selected from ethinyl estradiol, estradiol, estetrol and combinations thereof. In one particularly preferred embodiment, the estrogen employed in the present method is ethinyl estradiol. In another particularly preferred embodiment, the estrogen employed is estetrol.

[0083] The estrogen in the oral dosage unit is preferably selected from:

[0084] • 5-40 mg estetrol; 2-12 g ethinyl estradiol;

[0085] 0.3-2 mg estradiol; and 10-60 mg estriol.

[0086] The oral dosage unit preferably contains 7-20 mg of estetrol. Most preferably, the oral dosage unit contains 8-15 mg of estetrol.

[0087] In another preferred embodiment, the oral dosage unit contains 3-10 pg ethinyl estradiol, and most preferably 4-8 pg ethinyl estradiol.

[0088] In a further preferred embodiment, the oral dosage unit contains 0.5-1.0 mg estradiol or estradiol valerate. Most preferably, the oral dosage unit contains 0.7-0.8 mg of estradiol or estradiol valerate.

[0089] In yet another embodiment, the oral dosage unit contains 20-40 mg of estriol. Most preferably, the oral dosage unit contains 25-35 mg of estriol.

[0090] In a particularly preferred embodiment of the invention, the oral dosage unit comprises:

[0091] • 80-200 mg relugolix;

[0092] • 200-600 mg dehydroepiandrosterone;

[0093] • 7-20 mg estetrol; and

[0094] • no progestogen.

[0095] Another aspect of the present invention relates to a package comprising at least 28 oral dosage units according to the present invention. More preferably, the package comprises at least 56 oral dosage units, most preferably 84-168 dosage units.

[0096] Preferably, the oral dosage units are arranged within the package in a fixed sequence, the total number of dosage units in the package being a multiple of 7.

[0097] Preferably, the oral dosage units are accommodated separately within the package.

[0098] According to a particularly preferred embodiment, date indications are provided adjacent to each oral dosage unit. According to a particularly preferred embodiment, the oral dosage units are arranged in a blister pack.

[0099] The invention is further illustrated by the following non-limiting examples.

[0100] EXAMPLES

[0101] Example 1

[0102] A blind, randomized, placebo-controlled study is conducted to investigate the effect of 28 days of once daily oral administration of GnRH antagonist and DHEA on healthy males.

[0103] Sixty healthy men (aged 18-50 years) are divided into three equally sized groups. During a period of 28 days each group receives a tablet that is orally administered once daily. Each group receives a different tablet:

[0104] • Control group: placebo

[0105] • Reference group: 120 mg relugolix

[0106] • Treatment group: 120 mg relugolix + 500 mg dehydroepiandrosterone

[0107] Subjects undergo 24-hour pharmokinetic sampling on days 1 , 7, 14 and 28.

[0108] Compared to the Control group, marked suppression of LH (<1.0 IU / L) and FSH (<1.0 I U / L) is observed in the Reference group and the Treatment group.

[0109] The subjects in the Reference group, unlike the subjects in the Control group and Treatment group, also show a pronounced suppression of serum testosterone (<50 ng / dL) and serum estradiol (<10 pg / mL).

[0110] Example 2

[0111] An oral dosage that is suited for use in a contraceptive method according to the present invention is progestogen-free and contains:

[0112] • 400 mg linzagolix; and

[0113] • 500 mg dehydroepiandrosterone

[0114] Example 3

[0115] An oral dosage that is suited for use in a contraceptive method according to the present invention is progestogen-free and contains: 270 mg elagolix; and

[0116] 500 mg dehydroepiandrosterone

[0117] Example 4 An oral dosage that is suited for use in a contraceptive method according to the present invention is progestogen-free and contains:

[0118] • 120 mg relugolix;

[0119] • 250 mg dehydroepiandrosterone; and

[0120] • 15 mg estetrol.

Claims

CLAIMS1 . An oral dosage unit for use in a method of contraception in a human male, said oral dosage units containing GnRH antagonist and dehydroepiandrosterone, said method comprising once daily oral administration of the oral dosage unit to the human male during a period of at least 7 days.

2. Oral dosage unit for use in a contraceptive method according to claim 1 , wherein the oral dosage unit does not contain progestogen.

3. Oral dosage unit for use in a contraceptive method according to claim 1 or 2, wherein the GnRH antagonist is selected from relugolix, linzagolix, elagolix and combinations thereof.

4. Oral dosage unit for use in a contraceptive method according to any one of the preceding claims, wherein the oral dosage unit contains GnRH antagonist selected from:• 50-250 mg relugolix;• 167-833 mg linzagolix;• 113-583 mg elagolix;5. Oral dosage unit for use in a contraceptive method according to any one of the preceding claims, wherein the oral dosage unit contains 100-800 mg dehydroepiandrosterone.

6. Oral dosage unit for use in a contraceptive method according to any one of the preceding claims, wherein the oral dosage unit comprises:• 80-200 mg relugolix;• 200-600 mg dehydroepiandrosterone; and• no progestogen.

7. Oral dosage unit for use in a contraceptive method according to any one of the preceding claims, wherein the oral dosage unit contains estrogen selected from ethinyl estradiol, estradiol, a prodrug of estradiol, estriol, a prodrug of estriol, estetrol, a prodrug of estetrol and combinations thereof.

8. Oral dosage unit for use in a contraceptive method according to any one of the preceding claims, wherein the oral dosage unit contains estrogen selected from:5-40 mg estetrol;2-12 pg ethinyl estradiol;• 0.3-2 mg estradiol; and• 10-60 mg estriol.

9. Oral dosage unit comprising:• GnRH antagonist selected from: o 50-250 mg relugolix; o 167-833 mg linzagolix; o 113-583 mg elagolix;• 100-800 mg dehydroepiandrosterone.

10. Oral dosage unit according to claim 9, wherein the oral dosage unit does not contain progestogen.

11. Oral dosage unit according to claim 9 or 10, comprising 80-200 mg relugolix.

12. Oral dosage unit according to any one of claims 9-11, wherein the oral dosage unit contains 200-600 mg dehydroepiandrosterone.

13. Oral dosage unit according to any one of claims 9-12, wherein the oral dosage unit contains estrogen selected from:• 5-40 mg estetrol;• 2-12 pg ethinyl estradiol;• 0.3-2 mg estradiol; and• 10-60 mg estriol.

14. A package comprising at least 28 oral dosage units according to any one of claims 9-12, said oral dosage units being arranged within the package in a fixed sequence, the total number of dosage units in the package being a multiple of 7.

15. Package according to claim 14, wherein the package is a blister pack.