Contraceptive kit comprising oral dosage units containing dehydroepiandrosterone

Abstract

The invention relates to a contraceptive kit comprising: · 23 to 25 first oral dosage units, each first oral dosage unit containing a combination of 100-165 µg of levonorgestrel, 20-40 µg of ethinylestradiol and 40-120 mg of dehydroepiandrosterone; and · 3 to 5 second oral dosage units, each second oral dosage unit containing 40-120 mg of dehydroepiandrosterone, no progestogen and no estrogen; wherein the sum of the number of first oral dosage unit and the number of second oral dosage units in the contraceptive kit equals 28. The contraceptive kit of the invention provides high contraceptive reliability and produces less undesirable side-effects than commercially available combined oral contraceptives.

Description

[0001] CONTRACEPTIVE KIT COMPRISING ORAL DOSAGE UNITS CONTAINING DEHYDROEPIANDROSTERONE

[0002] TECHNICAL FIELD OF THE INVENTION

[0003] The present invention relates to a contraceptive kit comprising (i) oral dosage units containing a combination of levonorgestrel, ethinylestradiol and dehydroepiandrosterone and (ii) oral dosage units containing dehydroepiandrosterone, no progestogen and no estrogen.

[0004] The invention further relates to the use of such a kit in the prevention of pregnancy in a female of child bearing age, said use comprising successive daily oral administration of the dosage units containing the combination of levonorgestrel, ethinylestradiol and dehydroepiandrosterone, followed by successive daily oral administration of the dosage units containing dehydroepiandrosterone, no progestogen and no estrogen.

[0005] BACKGROUND OF THE INVENTION

[0006] Combined oral contraceptives (COCs) contain two important hormones: a progestogen and an estrogen. Combined oral contraceptive pills were developed to prevent ovulation by suppressing the release of gonadotropins. COCs, inhibit follicular development and prevent ovulation as a primary mechanism of action.

[0007] COCs reduce levels of androgen, especially testosterone, by inhibiting ovarian and adrenal androgen synthesis and by increasing levels of sex hormone-binding globulin (SHBG). Zimmerman et al. (The effect of combined oral contraception on testosterone levels in healthy women: a systematic review and meta-analysis, Human Reproduction Update, Vol.20, No.1 pp. 76-105, 2014) report that a literature review and meta-analysis demonstrates that COCs decrease circulating levels of total testosterone and free testosterone, and increase SBHG concentrations. Due to the SHBG increase, free testosterone levels decrease twice as much as total testosterone.

[0008] Microgynon® 30 is a commercially available COC that is provided in a blister pack that contains 21 tablets, each containing 150 pg of levonorgestrel and 30 pg of ethinylestradiol.

[0009] Smith et al. (Prescribing testosterone and DHEA: The role of androgens in women, Cleveland Clinic Journal of Medicine Vol. 88, no. 1 , January 2021 , 35-43) observe that In women, the androgens testosterone and dehydroepiandrosterone (DHEA) play important physiologic roles in reproductive tissues, mood, cognition, the breast, bone, muscle, vasculature, and other systems. According to the authors, evidence suggests that testosterone therapy in women is associated with few adverse events when serum hormone levels remain within physiologic ranges.

[0010] US 5,583,129 describes a method of inducing contraception in a female of reproductive age who has not yet reached premenopause, comprising administering to said female a composition comprising an estrogen selected from 2.0 to 6.0 mg of 17p-estradiol and 0.015 to 0.020 mg of ethinylestradiol; and a gestagen selected from 0.05 to 0.075 mg of gestodene, 0.075 to 0.125 mg of levonorgestrel, 0.06 to 0.15 mg of desogestrel, 0.06 to 0.15 mg of 3-ketodesogestrel, 0.1 to 0.3 mg of drospirenone, 0.1 to 0.2 mg of cyproterone acetate, 0.2 to 0.3 mg of norgestimate and 0.35 to 0.75 mg of norethisterone; wherein the composition is administered for 23 or 24 days, beginning on day one of the menstrual cycle, followed by 5 or 4 pill-free or sugar pill days, during a total of 28 days in the administration cycle.

[0011] WO 99 / 13882 describes a method of contraception which comprises administering to a female of child bearing age a combination of a progestin at a daily dosage equivalent to 30- 150 pg levonorgestrel and an estrogen at a daily dosage equivalent to 10-20 pg ethinylestradiol for 23-25 days per menstrual cycle beginning on day 1 of the menstrual cycle; wherein the same dosage of the progestin and estrogen combination is administered in each of the 23-25 days, followed by the administration of a progestin at a daily dosage equivalent to 10-100 pg levonorgestrel for 3-5 days; wherein the same dosage of the progestin is administered in each of the 3-5 days; such that the number of days of administration of the progestin and estrogen combination plus the number of days of administration of progestin is equal to 28 per menstrual cycle.

[0012] WO 03 / 041719 describes a kit comprising a plurality of hormone-containing dosage units for use in a method of contraception in mammalian females, said method comprising the administration to the female of dosage units containing at least two different steroids, including an androgen, in a therapeutically effective amount to inhibit ovulation, wherein the androgen is administered continuously during a period of at least 28 days.

[0013] WO 2013 / 012326 describes a tablet having a weight of 30-200 mg, said tablet consisting of: • 60-100 wt.% of granules consisting of: 50-90% by weight of the granules of dehydroepiandrosterone (DHEA); 6-35%) by weight of the granules of microcrystalline cellulose;

[0014] 0-20%) by weight of the granules of one or more other pharmaceutically acceptable granule ingredients; and

[0015] • 0-40 wt.%) of one or more other pharmaceutically acceptable tablet components.

[0016] Van Lunsen et al. (Maintaining physiologic testosterone levels during combined oral contraceptives by adding dehydroepiandrosterone: II. Effects on sexual function. A phase II randomized, double-blind, placebo-controlled study, Contraception 98 (2018) 56-62) describe an exploratory randomized, double-blind, placebo-controlled, comparative, crossover study. Subjects discontinued their oral contraceptive (OC) for one cycle before being randomized for 10 cycles to a 30 pg ethinylestradiol / levonorgestrel OC or a 30-pg ethinylestradiol / drospirenone OC, along with daily use of 50 mg dehydroepiandrosterone (DHEA) or placebo during five OC cycles before crossing over from DHEA to placebo or the reverse for another five cycles. First, the effect on sexual function of five OC cycles + placebo was compared to baseline. Then, the effect of five OC cycles + DHEA was compared to the OC + placebo.

[0017] SUMMARY OF THE INVENTION

[0018] The present invention relates to a contraceptive kit for use in the prevention of pregnancy in a female of child bearing age that provides high contraceptive reliability and that produces less undesirable side-effects than commercially available combined oral contraceptives.

[0019] The contraceptive kit according to the invention comprises:

[0020] • 23 to 25 first oral dosage units, each first oral dosage unit containing a combination of 100-165 pg of levonorgestrel, 20-40 pg of ethinylestradiol and 40-120 mg of dehydroepiandrosterone; and

[0021] • 3 to 5 second oral dosage units, each second oral dosage unit containing 40-120 mg of dehydroepiandrosterone, no progestogen and no estrogen; wherein the sum of the number of first oral dosage unit and the number of second oral dosage units in the contraceptive kit equals 28.

[0022] The invention also relates to a method of preventing pregnancy in a female of child bearing age using the contraceptive kit of the present invention, said method comprising successive daily oral administration of 23 to 25 of the first oral dosage units, followed by successive daily oral administration of 3 to 5 of the second oral dosage units.

[0023] DETAILED DESCRIPTON OF THE INVENTION

[0024] A first aspect of the invention relates to a contraceptive kit comprising:

[0025] • 23 to 25 first oral dosage units, each first oral dosage unit containing a combination of 100-165 pg of levonorgestrel, 20-40 pg of ethinylestradiol and 40-120 mg of dehydroepiandrosterone; and

[0026] • 3 to 5 second oral dosage units, each second oral dosage unit containing 40-120 mg of dehydroepiandrosterone, no progestogen and no estrogen; wherein the sum of the number of first oral dosage unit and the number of second oral dosage units in the contraceptive kit equals 28.

[0027] The term “oral dosage unit” as used herein refers to a dosage unit that can suitably be administered perorally. Examples of oral dosage units include tablets, capsules and lozenges.

[0028] The term “ethinylestradiol” as used herein refers to (1 R,3aS,3bR,9bS,11aS)-1-ethynyl-11a- methyl-1H,2H,3H,3aH,3bH,4H,5H,9bH,10H,11H,11aH-cyclopenta[a]phenanthrene-1,7-diol (8R,9S, 13S, 14S, 17R)-17- Ethi ny I- 13-methyl-7,8,9, 11 ,12,13,14,15,16,17-decahydro-6H- cyclopenta[a]phenanthren-3,17-diol (or 17a-ethynylestra-1,3,5(10)-triene-3,17p-diol).

[0029] The term “levonorgestrel” as used herein refers to 8R,9S,10R,13S,14S,17R)-13-Ethyl-17- ethynyl-17-hydroxy-1 ,2,6,7,8,9,10,11 ,12,13,14,15,16,17-tetradecahydro-3H- cyclopenta[a]phenanthren-3-one (or 17a-ethynyl-17p-hydroxy-18a-homo-estr-4-en-3-one).

[0030] The term “dehydroepiandrosterone” as used herein refers to (3aS,3bR,7S,9aR,9bS,11aS)-7- Hydroxy-9a,11a-dimethyl-2,3,3a,3b,4,6,7,8,9,9a,9b,10,11 ,11a-tetradecahydro-1 H- cyclopenta[a]phenanthren-1-one (or 5-Androsten-3-beta-hydroxy-17-one).

[0031] The term “estrogen” as used herein refers to substances that are capable of binding and activating human estrogen receptors.

[0032] The term “progestogen” as used herein refers to substances that are capable of binding and activating human progesterone receptors. The term “androgen” as used herein refers to substances that are capable of binding and activating human androgen receptors.

[0033] The term “or” as used herein should be construed as “and / or”, unless specified otherwise.

[0034] The term “a” or “an” as used herein is defined as “at least one” unless specified otherwise.

[0035] Numerical ranges expressed in the format “from x to y” are understood to include x and y.

[0036] Ratios mentioned herein are based on weight / weight, unless indicated otherwise. Similarly, all percentages are percentages by weight (w / w) unless otherwise indicated.

[0037] 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.

[0038] If, for a particular component, a range of 0% to y% or less than y% is recited, said ingredient may be absent.

[0039] According to a preferred embodiment of the present invention, both the first oral dosage units and the second oral dosage units are separately packaged, and individually removable. This is suitably achieved if the kit is blister pack.

[0040] The first oral dosage units preferably contain 25-35 pg of ethinylestradiol. 28-32 pg of ethinylestradiol and most preferably 30 pg of ethinylestradiol.

[0041] The first oral dosage units preferably contain 105-160 pg of levonorgestrel, more preferably 110-155 pg of levonorgestrel. According to a particularly preferred embodiment, the first oral dosage unit contains a small dose of 115-130 pg of levonorgestrel

[0042] Both the first and the second oral dosage units preferably contain not more than 100 mg of dehydroepiandrosterone, more preferably not more than 80 mg of dehydroepiandrosterone, even more preferably not more than 60 mg of dehydroepiandrosterone, yet more preferably not more than 55 mg of dehydroepiandrosterone, especially not more than 52 mg of dehydroepiandrosterone. Both the first and the second oral dosage units preferably contain at least 45 mg of dehydroepiandrosterone, more preferably at least 48 mg of dehydroepiandrosterone. Most preferably, both the first and second dosage units contain 50 mg of dehydroepiandrosterone.

[0043] Contraceptive kit according to any one of the preceding claims, wherein the kit comprises 24 first oral dosage units and 4 second oral dosage units.

[0044] According to a preferred embodiment, the contraceptive kit of the present invention comprises:

[0045] • 24 first oral dosage units, each first oral dosage unit containing a combination of 150 pg of levonorgestrel, 30 pg of ethinylestradiol and 50 mg of dehydroepiandrosterone; and

[0046] • 4 second oral dosage units, each second oral dosage unit containing 50 mg of dehydroepiandrosterone, no progestogen and no estrogen.

[0047] According to a particularly preferred embodiment, the contraceptive kit of the present invention comprises:

[0048] • 24 first oral dosage units, each first oral dosage unit containing a combination of 120 pg of levonorgestrel, 30 pg of ethinylestradiol and 50 mg of dehydroepiandrosterone; and

[0049] • 4 second oral dosage units, each second oral dosage unit containing 50 mg of dehydroepiandrosterone, no progestogen and no estrogen.

[0050] The first oral dosage units as well as the second oral dosage units preferably are tablets or capsules, most preferably tablets.

[0051] Both the first as well as the second oral dosage units preferably have an individual weight in the range of 70-200 mg, more preferably in the range of 100-180 mg and most preferably of 140-165 mg.

[0052] The kit of the present invention preferably contains in total 28 oral dosage units, i.e. it contains no oral dosage units than the first and second oral dosage units.

[0053] According to a particularly preferred embodiment, the kit comprises instructions for use, said use comprising successive daily oral administration of the first oral dosage units, followed by successive daily oral administration of the second oral dosage units. Another aspect of the invention relates a method of preventing pregnancy in a female of child bearing age, said method using a contraceptive kit as described herein before and said method comprising successive daily oral administration of the first oral dosage units, followed by successive daily oral administration of the second oral dosage units.

[0054] The successive oral administration of the first oral dosage units preferably starts within 5 days, more preferably within 3 days and most preferably within 1 day after the onset of a menstrual period.

[0055] According to a particularly preferred embodiment, the female using the contraceptive kit of the present invention has recently used an androgen-free oral contraceptive and is suffering from a symptom of androgen deficiency. Examples of androgen deficiency that may be remedied or suppressed by the contraceptive kit of the present invention include mood dysfunction, tiredness, loss of sexual interest, sleeping problems, apathy, cognition and memory problems and headache.

[0056] In one embodiment of the invention the symptom of androgen deficiency the female is suffering from is mood dysfunction. In another embodiment, the symptom of androgen deficiency the female is suffering from is tiredness. In yet another embodiment, the symptom of androgen deficiency the female is suffering from is loss of sexual interest.

[0057] The invention is further illustrated by the following non-limiting examples.

[0058] EXAMPLES

[0059] Example 1

[0060] A randomized, double-blind, placebo-controlled, comparative crossover study is conducted in 300 oral contraceptive (OC) users (18-35 years). In accordance with study protocol, each participant discontinued her contraceptive pill for three cycles (the baseline period). After the baseline period, participants received two successive OC treatments:

[0061] • Treatment 1 : 6 cycles of treatment comprising 24 days with daily administration of 30 pg ethinyl estradiol + 150 pg levonorgestrel + 50 mg dehydroepiandrosterone (DHEA), followed by 4 days with daily administration of 50 mg DHEA;

[0062] • Treatment 2: 6 cycles of treatment comprising 24 days with daily administration of 30 pg ethinyl estradiol + 150 pg levonorgestrel, followed by 4 days with daily administration of placebo. The participants are randomly assigned (50:50) to either the group that starts with Treatment 1 or the group that starts with the Treatment 2. The participants and investigators are blinded to the order in which participants are assigned to the two different treatments.

[0063] Vaginal spotting and bleeding is scored daily by the participants in a diary and the effects on general well-being are scored at baseline and at the end of the study on a psychometric rating scale. The psychometric rating scale used is especially suited for identifying differences in a population of healthy young women. The scale is a 24-item (placid, sleepy, jittery, intense, lacking confidence, energetic, sensitive, tired, well-balanced, at-rest, drowsy, fearful, lively, sickly, in a good mood, irritable, clutched-up, quiet, full-ofpep, optimistic, moody, active, tense, sad), 4-point (yes, definitely; yes, a bit; no, in fact not; no, definitely not) scale to be scored by the woman herself.

[0064] Two questionnaires assessing sexual function, the Female Sexual Function Index (FSFI) and the Female Sexual Distress Scale-Revised (FSDS-R), are completed at baseline and prior to each laboratory session. FSFI measures sexual function on six domains: desire, arousal, lubrication, orgasm, satisfaction and pain. An FSDS-R total score >15 combined with an FSFI total score b26.55 is indicative of sexual dysfunction.

[0065] It is found that both OC treatments (with and without DHEA) are well tolerated. No clinically relevant changes are noted for vital signs, body weight, lipids and glucose. Consistent inhibition of ovulation is observed during both OC treatments.

[0066] Results show that less vaginal breakthrough spotting and bleeding is reported by participants during Treatment 1, that generally better scores are obtained on items in the domain of energy (viz. tired, drowsy, energetic, placid and clutched-up) and that less side effects occur than during the Treatment 2 (without DHEA).

[0067] The results further show that significant decreases are observed in self-ratings of sexual arousability, desire and desire for sex with a partner with both OC treatments relative to baseline. The observed decreases, however, are significantly less pronounced during Treatment 1 than during the Treatment 2.

[0068] Example 2

[0069] A randomized, double-blind, placebo-controlled, comparative crossover study is conducted in 500 oral contraceptive (OC) users (18-35 years). In accordance with study protocol, each participant discontinued her contraceptive pill for three cycles (the baseline period). After the baseline period, participants received two successive OC treatments:

[0070] • Treatment 1 : 6 cycles of treatment comprising 24 days with daily administration of 30 pg ethinyl estradiol + 120 pg levonorgestrel + 50 mg dehydroepiandrosterone (DHEA), followed by 4 days with daily administration of 50 mg DHEA;

[0071] • Treatment 2: 6 cycles of treatment comprising 21 days with daily administration of 30 pg ethinyl estradiol + 150 pg levonorgestrel + 50 mg dehydroepiandrosterone (DHEA), followed by 7 days with daily administration of 50 mg DHEA.

[0072] The participants are randomly assigned (50:50) to either the group that starts with Treatment 1 or the group that starts with Treatment 2. The participants and investigators are blinded to the order in which participants are assigned to the two different treatments.

[0073] The results show that Treatment 1 , despite the lowering of the levonorgestrel dose, provides more effective prevention of pregnancy than Treatment 2. In all other aspects both treatments are found to be comparable.

Claims

CLAIMS1. A contraceptive kit comprising:• 23 to 25 first oral dosage units, each first oral dosage unit containing a combination of 100-165 pg of levonorgestrel, 20-40 pg of ethinylestradiol and 40-120 mg of dehydroepiandrosterone; and• 3 to 5 second oral dosage units, each second oral dosage unit containing 40-120 mg of dehydroepiandrosterone, no progestogen and no estrogen; wherein the sum of the number of first oral dosage unit and the number of second oral dosage units in the contraceptive kit equals 28.

2. Contraceptive kit according to claim 1, wherein both the first oral dosage units and the second oral dosage units are separately packaged, and individually removable.

3. Contraceptive kit according to claim 2, wherein the kit is a blister pack.

4. Contraceptive kit according to any one of the preceding claims, wherein the first oral dosage units contain 140-160 pg of levonorgestrel.

5. Contraceptive kit according to any one of the preceding claims, wherein the first oral dosage units contain 25-35 pg of ethinylestradiol.

6. Contraceptive kit according to any one of the preceding claims, wherein the first and second oral dosage units contain 45-55 mg of dehydroepiandrosterone.

7. Contraceptive kit according to any one of the preceding claims, wherein the kit comprises 24 first oral dosage units and 4 second oral dosage units.

8. Contraceptive kit according to any one of the preceding claims, wherein the first and second oral dosage units are tablets having an individual weight in the range of 70-200 mg.

9. Contraceptive kit according to any one of the preceding claims, wherein the kit comprises:24 first oral dosage units, each first oral dosage unit containing a combination of 120 pg of levonorgestrel, 30 pg of ethinylestradiol and 50 mg of dehydroepiandrosterone; and• 4 second oral dosage units, each second oral dosage unit containing 50 mg of dehydroepiandrosterone, no progestogen and no estrogen.

10. Contraceptive kit according to any one of the preceding claims, wherein the kit comprises instructions for use, said use comprising successive daily oral administration of the first oral dosage units, followed by successive daily oral administration of the second oral dosage units.11 . A contraceptive kit for use in the prevention of pregnancy in a female of child bearing age, said contraceptive kit being a contraceptive kit according to any one of the preceding claims and said use comprising successive daily oral administration of the first oral dosage units, followed by successive daily oral administration of the second oral dosage units.

12. Contraceptive kit for the use according claim 11 , wherein the successive oral administration of the first oral dosage units starts within 5 days after the onset of a menstrual period.

13. Contraceptive kit for the use according to claim 11 or 12, wherein the female has recently used an androgen-free oral contraceptive and is suffering from a symptom of androgen deficiency.

14. Contraceptive kit for the use according to any one of claims 11-13, wherein the symptom of androgen deficiency is tiredness.

15. Contraceptive kit for the use according to any one of claims 11-13, wherein the symptom of androgen deficiency is mood dysfunction.