Progestogen-only oral contraception

Abstract

A method of providing progestogen-only contraception.

Description

[Technical field]

[0001] The present invention relates to a method of providing oral contraception comprising at least once daily oral administration of a dosage form containing a progestogen, preferably levonorgestrel (hereinafter LNG) or norgestrel (hereinafter NG), wherein the progestogen is the only active ingredient in the dosage form. [Background technology]

[0002] Progestogen-only pills (POPs) have been available for many years but remain limited in their acceptability among both women seeking contraception and the physicians who prescribe them. Their mechanism of action is multifaceted and includes primarily peripheral mechanisms of action such as alterations in cervical mucus properties, endometrial changes, and tubal motility. Ovulation suppression may occur in some subjects.

[0003] Progestogen-only pills tend to be administered at levels below ovulation suppression, such as 0.03 mg LNG, 0.075 mg NG, 0.35 mg norethisterone, 0.3 mg norethisterone acetate, and 0.7 mg megestrol acetate. However, the failure rate of POP is higher than that of combined contraceptive pills, and therefore the acceptability is limited. For example, the LNG-only pill (MICROLUT®, 28mini®) with 0.03 mg LNG / day remains a niche product, despite the significant advantage of not increasing the risk of thrombosis as with the major combined oral contraceptives (COCs) currently on the market.

[0004] Desogestrel, a POP given at 0.075 mg per day, offers better contraceptive efficacy because the prescribed dose exceeds ovulation suppression levels, but bleeding effects remain problematic. For every pregnancy that may be prevented with desogestrel 0.075 mg, five women have been reported to discontinue early due to irregular bleeding. With drospirenone, irregular bleeding problems are controlled by a four-day drug holiday. However, bleeding patterns remain suboptimal, and contraceptive efficacy appears to be less than that of desogestrel-POP.

[0005] Thus, POPs remain a niche market due to their relatively poor contraceptive efficacy, bleeding issues, and / or dosing schedule.

[0006] In post-coital (emergency) hormonal contraception, LNG is used in very high doses, for example, 1.5 mg LNG once or 0.75 mg per day for two consecutive days. US 2011 / 0245211 describes such use of LNG in very high doses for emergency contraception, followed by administration of low doses of POP until the next menstruation. US 2011 / 0245211 suggests that low doses of POP can be less than 0.150 mg, but this application only describes the use of 0.30 mg LNG as a bridge method until the next menstruation when starting regular contraception.

[0007] WO 2014 / 072245 describes a POP dosing regimen in which LNG is administered continuously, i.e. daily, in a dosage range of between 0.60 mg and 0.100 mg, without any further pharmacoactive agents, additives or adjuvants. Oettel et al., "The Progestin-Only Pill (POP) Is Not a Niche Option: New Preclinical and Clinical Data about the Interrelations between Levonorgestrel-Dose, Peripheral as Well as Central Contraceptive Effects and Bleeding Behavior," J. Reproduktionsmed Endokrinol, December 2015 (Special Issue 1): pp. 1-5, reports that the LNG 0.90 mg / day regimen described in WO 2014 / 07245 did not result in bleeding irregularities and that the LNG 0.90 mg / day regimen produced a more favorable bleeding profile than the LNG 0.60 mg / day regimen. Based on the data presented in WO 2014 / 07245 and the Oetter 2015 paper, it was believed that when LNG is administered orally in amounts greater than 0.100 mg / day, an estrogenic compound would be necessary to avoid the undesirable side effects of higher doses of LNG. More specifically, it was believed that the following undesirable side effects could occur when LNG is administered to a subject in amounts greater than 0.100 mg / day for contraceptive purposes: (i) estrogen deficiency due to excessive suppression of ovarian follicular development, with undesirable effects such as mood lability, vasomotor symptoms / hot flashes, genital atrophy, osteopenia / osteoporosis, and / or (ii) androgenic side effects.

[0008] There remains a need for a POP that has high contraceptive efficacy (i.e., complete or substantially complete ovulation suppression), an acceptable bleeding pattern, is free of hypoestrogenic side effects, and can be taken daily with or without the need for a progestogen pill holiday. Summary of the Invention [Means for solving the problem]

[0009] The present invention provides new POP contraceptive regimens that meet the above needs and others.

[0010] In one embodiment, the invention is a method of providing contraception to a human subject or patient in need or desiring of contraception, comprising oral administration of a POP dosage form comprising LNG or NG. In one embodiment, the POP dosage form comprises 0.110 mg to 0.150 mg of LNG administered once daily. In another embodiment, the POP dosage form comprises 0.220 mg to 0.300 mg of NG administered once daily. The above methods provide high contraceptive efficacy, acceptable bleeding patterns, reduced hypoestrogenic side effects and / or reduced androgenic side effects.

[0011] In some embodiments of the invention, the LNG or NG is the only pharma- ceutical active agent, additive, or adjuvant administered for contraceptive purposes. In some aspects of this embodiment, the contraceptive method and particularly the dosage form does not include any additional hormones, such as estrogen compounds, including but not limited to ethinyl estradiol, does not include any folate salts, such as folic acid, or combinations thereof.

[0012] In one embodiment, the methods of the invention include administering the same dose of LNG or NG for at least one month or more from the initiation of the desired contraceptive treatment. This aspect of the invention does not require dose titration of LNG or NG for the first 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or more days.

[0013] In one embodiment, the method of the invention involves administration of a dosage form, preferably a solid oral dosage form such as a tablet or capsule, containing 0.110 mg to 0.150 mg of LNG or 0.220 mg to 0.300 mg of NG, the dosage form being administered once a day at the same dose for at least 23 days or more without the need for interruption or cessation of administration of LNG or NG. Administration of the same dose may continue for a period of time including, but not limited to, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 125 days, or for longer periods including, but not limited to, 6, 12, 18, 24, 30, 36, 42, 48 months.

[0014] In one embodiment, the methods of the invention comprise administration of a dosage form, preferably a solid oral dosage form such as a tablet or capsule, containing 0.110 mg to 0.150 mg of LNG or 0.220 mg to 0.300 mg of NG, administered once daily at the same dose for at least 23, 24, 25, 26, 27, 28, 29, or 30 days, followed by 1, 2, 3, 4, 5, 6, 7, or 8 days of discontinuation during which no LNG or NG is administered and / or no additional hormone, such as estrogen, is administered. After the interruption period, once-daily administration of a dosage form containing 0.110 mg to 0.150 mg of LNG or 0.220 mg to about 0.300 mg of NG is resumed for at least 23, 24, 25, 26, 27, 28, 29, or 30 days, followed by an additional interruption of 1, 2, 3, 4, 5, 6, 7, or 8 days during which no LNG or NG is administered and / or no additional hormones such as estrogen are administered. This pattern of administration and interruption can be repeated for up to 6, 12, 18, 24, 30, 36, 42, 48 months or more.

[0015] In certain embodiments of the invention, the daily dose of LNG or NG is an amount that results in average estradiol levels of greater than 120 pmol / L, greater than 125 pmol / L, greater than 130 pmol / L, greater than 135 pmol / L, greater than 140 pmol / L, greater than 145 pmol / L, or greater than 150 pmol / L after 28 days of treatment, preferably after 45 days of treatment, and most preferably for the entire duration of treatment. In certain embodiments of this aspect, the mean estradiol levels after at least 45 days or more of once daily administration of an oral dosage form of LNG or NG should result in mean estradiol plasma concentrations of less than 375 pmol / L, 350 pmol / L, 325 pmol / L, 300 pmol / L, 290 pmol / L, 280 pmol / L, 270 pmol / L, 260 pmol / L, 250 pmol / L, 240 pmol / L, 230 pmol / L, 220 pmol / L, 210 pmol / L, or 200 pmol / L.

[0016] In one embodiment of the invention, the daily dose of LNG or NG is such that after at least 5, 6, 7, 8, 9 or 10 days of once-daily administration of an oral dosage form of LNG or NG, the mean progesterone level (P) is less than 5 nmol / L, preferably less than 4 nmol / L, and most preferably less than 3.5 nmol / L. Such P levels should be maintained during active treatment, i.e., the period of once-daily administration of LNG or NG.

[0017] In one embodiment of the invention, the daily dose of LNG or NG is an amount that provides an average LNG plasma concentration of: Approximately 2 hours after a single daily dose of LNG or NG, the concentration is about 800 pg / mL to about 2600 pg / mL, preferably about 1000 pg / mL to about 2500 pg / mL, more preferably about 1200 pg / mL to about 2400 pg / mL, and most preferably at least about 1600 pg / mL to about 2300 pg / mL; Approximately 6 hours after a single daily administration of LNG or NG, the concentration is about 300 pg / mL to about 1200 pg / mL, preferably about 350 pg / mL to about 1000 pg / mL, more preferably about 400 pg / mL to about 900 pg / mL, and most preferably at least about 700 pg / mL or more. Approximately 24 hours after a single daily administration of LNG or NG, the concentration is about 200 pg / mL to about 800 pg / mL, preferably about 250 pg / mL to about 700 pg / mL, more preferably about 300 pg / mL to about 600 pg / mL, and most preferably at least about 350 pg / mL or more. It is.

[0018] In one embodiment, the daily dose of LNG or NG provides a mean maximum LNG plasma concentration (C) of at least about 900 pg / mL, preferably at least about 1000 pg / mL, more preferably at least about 1100 pg / mL, and most preferably at least about 1200 pg / mL. max ), and the time to maximum LNG plasma concentration (T max ) is the amount provided.

[0019] In one embodiment of the invention, the daily dose of LNG or NG is determined based on the mean area under the concentration curve (AUC) 24 hours after administration (AUC 0-24 ) is at least about 14,000 hr·pg / mL, preferably at least about 14,500 hr·pg / mL, and most preferably at least about 14,700 hr·pg / mL. 0-24 should have an AUC of less than 20,000 hr·pg / mL, preferably less than 19,000 hr·pg / mL, and most preferably less than 18,500 hr·pg / mL.

[0020] In one embodiment of the invention, the method comprises providing to a subject or patient in need of or desiring oral contraception a kit containing 23, 24, 25, 26, 27, 28, 29 or 30 tablets and instructions to take one tablet once daily, preferably in the morning, with or without food, each tablet containing 0.110 mg to 0.150 mg of LNG or 0.220 mg to 0.300 mg of NG and at least one pharma- ceutically acceptable excipient. In one aspect of this embodiment, the tablets are blister-packaged. [Brief description of the drawings]

[0021] [Figure 1] 1 is a flow chart showing the condition of subjects reported in the study of Example 2. [Figure 2A] 1 shows the mean follicle diameter over time reported in the study of Example 2. [Figure 2B] 1 shows the mean estradiol (E2) serum concentrations over time reported in the study of Example 2. [Figure 2C] 1 shows the mean follicle stimulating hormone (FSH) serum concentrations over time reported in the study of Example 2. [Figure 2D] 1 shows the mean luteinizing hormone (LH) serum concentrations over time reported in the study of Example 2. [Figure 2E] 1 shows the mean progesterone (P) serum concentrations over time reported in the study of Example 2. [Diagram 3]1 shows the mean plasma concentrations after 55 (±1) days of treatment with 0.095 mg, 0.115 mg, or 0.135 mg of LNG per day reported in the study of Example 2. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0022] Unless otherwise noted, all terms are intended to have their ordinary meaning in the art and are used as they would be used by one of ordinary skill in the art at the time of this disclosure. Throughout this application, singular forms such as "a," "an," and "the" are often used for convenience, but it should be understood that these singular forms are intended to encompass the plural, unless otherwise specified or the context clearly requires only the singular. It should also be understood that all publications, patents, books, journal articles, and the like referred to in this application are incorporated by reference in their entirety for all purposes, unless inconsistent with this disclosure.

[0023] The term "levonorgestrel" or "LNG" (17α-ethynyl-18-methyl-19-nortestosterone; also known as 17α-ethynyl-18-methylestr-4-en-17β-ol-3-one and 13β-ethyl-17α-hydroxy-18,19-dinorpregn-4-en-20-yn-3-one) as used herein is the d-isomer of the racemic compound norgestrel or "NG."

[0024] As used herein, the term "progestogen" refers broadly to a class of steroid hormones that bind to and activate the progesterone receptor. The term progestogen includes both natural and synthetic progestogens. A natural progestogen is progesterone. Synthetic progestogens are sometimes called progestins.

[0025] "About" means having a value sufficiently close to the reference value so as to have the same or substantially the same properties as the reference value. Thus, depending on the context, "about" can mean, for example, ±10%, ±9%, ±8%, ±7%, ±6%, ±5%, ±4%, ±3%, ±2%, ±1%, or less than ±1%.

[0026] "Pharmaceutically acceptable" refers to materials or methods that can be used in a pharmaceutical drug or pharmaceutical composition.

[0027] The terms "dosage form," "pharmaceutical formulation," and "pharmaceutical composition" may be used interchangeably and refer to a drug or active pharmaceutical ingredient that is mixed or combined with one or more pharmaceutical excipients for delivery of the drug to a subject or patient. The dosage forms described herein may be in a variety of dosage forms, such as oral solid dosage forms or oral liquid dosage forms. In some embodiments, the dosage form is a tablet or capsule dosage form.

[0028] "Administering" includes oral administration unless otherwise specified. "Administering" can also include the step of prescribing or dispensing a dosage form containing a particular compound, such as LNG. "Administering" can also include providing instructions for carrying out a method involving a particular compound or a dosage form containing that compound.

[0029] "Immediate release" (also known as instant release or IR) refers to a dosage form that releases or delivers one or more drugs or pharmaceutical agents substantially immediately upon administration, resulting in substantially complete dissolution within about 1 hour (or less), preferably less than 45 minutes, and most preferably within about 30 minutes, when tested in a United States Pharmacopeia dissolution apparatus using 500-900 mL of aqueous medium.

[0030] The terms "subject" and "patient" may be used interchangeably unless otherwise indicated, and include humans, preferably premenopausal females requiring or desiring contraception.

[0031] One embodiment of the dosage form that can be used in the present invention is a tablet or capsule containing a therapeutic amount of LNG or NG. The tablet or capsule may contain one or more pharma- ceutically acceptable additives and 0.110 mg to 0.150 mg of LNG, preferably about 0.115 mg to about 0.145 mg of LNG, more preferably about 0.115 mg to about 0.140 mg of LNG. Alternatively, the tablet or capsule may contain one or more pharma- ceutically acceptable additives and 0.220 mg to 0.300 mg of NG, preferably about 0.230 mg to about 0.290 mg of NG, more preferably about 0.230 mg to about 0.280 mg of NG. Some embodiments of the tablet used in the present invention contain about 0.115 mg, about 0.120 mg, about 0.125 mg, about 0.130 mg, about 0.135 mg, about 0.140 mg, or about 0.145 mg of LNG and one or more pharma- ceutically acceptable excipients. Alternatively, the tablet used in the present invention contains about 0.230 mg, about 0.240 mg, about 0.250 mg, about 0.260 mg, about 0.270 mg, about 0.280 mg, or about 0.290 mg of NG and one or more pharma- ceutically acceptable excipients. The tablet releases LNG or NG in an immediate release manner. In the dosage form used in the present invention and / or the method of the present invention, the LNG or NG is the only drug or active pharmaceutical ingredient. The dosage form and / or method of the present invention should also not contain other potentially pharma- ceutically active materials or should not include the administration of other contraceptive-related pharma- ceutically active materials such as folates or folic acid. The methods of the present invention include the co-administration of other non-contraceptive drugs, such as, but not limited to, analgesics, antidiabetics, cardiovascular / hypertensive drugs, cholesterol-lowering drugs, antibiotics, antifungals, antidepressants, antipsychotics, muscle relaxants, sedatives, or combinations thereof.

[0032] One or more pharma- ceutically acceptable additives that can be used in the present invention include lubricants, fillers, binders, disintegrants, flow agents, solubilizers, flavoring agents, pH adjusters, antioxidants, chelating agents, or mixtures thereof.Examples of the additives described above are well known in the art and are described in the Handbook of Pharmaceutical Excipients, 2009, 6th edition, and the United States Pharmacopeia, 2006, 29th edition, pp.3257-3261, which are incorporated herein by reference.

[0033] In one embodiment, the dosage form used in the present invention comprises at least one filler or diluent, at least one binder and at least one lubricant or flow agent, or a combination thereof. Preferably, the dosage form is a tablet prepared by granulating the LNG or NG with at least one filler and at least one binder, mixing the granulation with one or more lubricants and flow agents, and compressing the mixture into a tablet.

[0034] Examples of fillers that may be employed in solid dosage forms of the invention include dibasic calcium phosphate (anhydrous), microcrystalline cellulose, calcium carbonate, magnesium carbonate, calcium sulfate, powdered cellulose, silicified microcrystalline cellulose, magnesium carbonate, magnesium oxide, starch, lactose, sucrose, mannitol, and mixtures thereof.

[0035] Examples of binders that may be employed in the solid dosage forms of the present invention include acacia, povidone, hypromellose, hydroxypropylcellulose, hydroxyethylcellulose, polyethylene oxide, polymethacrylates, methylcellulose, ethylcellulose, pregelatinized starch, gelatin, tragacanth, zein, or mixtures thereof. Preferably, the binder is selected from povidone, hypromellose, hydroxypropylcellulose, hydroxyethylcellulose, polymethacrylates, methylcellulose, gelatin, and ethylcellulose, or mixtures thereof. Particularly preferred binders include water-soluble binders such as povidone, hypromellose, hydroxypropylcellulose, gelatin, and mixtures thereof. When the binder is a polymeric binder, it is preferred that the binder has a low molecular weight and / or exhibits a viscosity of less than 200 mPa·s, preferably less than 100 mPa·s, and most preferably less than 50 mPa·s, when tested at a concentration of 2% (w / v) in an aqueous preparation at 20°C.

[0036] Examples of disintegrants that can be employed in solid dosage forms of the invention include croscarmellose sodium, starch, crospovidone, sodium starch glycolate, alginic acid, calcium carboxymethylcellulose, sodium carboxymethylcellulose, calcium carboxymethylcellulose, powdered cellulose, chitosan, guar gum, magnesium aluminum silicate, methylcellulose, sodium alginate, and mixtures thereof.

[0037] Examples of flow agents that can be employed in solid dosage forms of the present invention include colloidal silicon dioxide, corn starch, talc, and mixtures thereof.

[0038] Examples of lubricants that can be employed in solid dosage forms of the invention include magnesium stearate, sodium stearyl fumarate, stearic acid, glyceryl behenate, polyethylene glycol (preferably the polyethylene glycol has a molecular weight of 6000 or greater), polyoxyethylene stearate, magnesium lauryl sulfate, sodium oleate, and mixtures thereof.

[0039] The tablets may also include one or more water-soluble aesthetic or protective coatings. The tablets may be placed in conventional pharmaceutical packages, such as polyethylene or polypropylene bottles, with or without a desiccant, which are hermetically sealed and capped with a child-resistant closure. The coated tablets may be placed in conventional blister packs.

[0040] The method of the present invention provides contraception to a subject or patient, preferably a premenopausal human female, in need or desire of contraception. The method comprises orally administering once daily, preferably in the morning, with or without food, a dosage form, preferably a solid dosage form, containing 0.110 mg to 0.150 mg of LNG, preferably about 0.115 mg to about 0.145 mg of LNG, more preferably about 0.115 mg to about 0.140 mg of LNG. Alternatively, the method comprises orally administering once daily, preferably in the morning, with or without food, a dosage form, preferably a solid dosage form, containing 0.220 mg to 0.300 mg of NG, preferably about 0.230 mg to about 0.290 mg of NG, more preferably about 0.230 mg to about 0.280 mg of NG. Although not required, daily administration should occur at approximately the same time each day, i.e., about every 24 hours ± 2 hours.

[0041] The methods of the present invention provide highly effective contraception by completely (100%) or substantially completely (90%, 91%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) inhibiting ovulation.

[0042] The methods of the invention may result in an acceptable bleeding pattern, i.e., light bleeding or spotting as a mean occasion for less than 17, 16, 15, 14, or 13 days during the first 5-7 days after initiation of the method or during any 28 day cycle excluding the first treatment cycle. As used herein, a treatment cycle generally refers to a 23-30 day dosing regimen, preferably a 28 day dosing regimen.

[0043] The methods of the present invention provide reduced hypoestrogenic and / or reduced androgenic side effects, which may be due to the maintenance of acceptable estradiol plasma levels, preferably 17β-estradiol (E2) plasma levels. In one embodiment of the invention, the daily dose of LNG or NG is an amount that provides an average E2 level of greater than 120 pmol / L, 125 pmol / L, 130 pmol / L, 135 pmol / L, 140 pmol / L, 145 pmol / L, or 150 pmol / L and less than 375 pmol / L, 350 pmol / L, 325 pmol / L, 300 pmol / L, 290 pmol / L, 280 pmol / L, 270 pmol / L, 260 pmol / L, 250 pmol / L, 240 pmol / L, 230 pmol / L, 220 pmol / L, 210 pmol / L, or 200 pmol / L after 28 days of treatment, preferably after 45 days of treatment, and most preferably for the entire duration of treatment.

[0044] The methods of the invention may further include administering the same dose of LNG or NG for at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or more months of continuous treatment or cycles from the initiation of the desired contraceptive treatment. The invention obviates the need for dose titration of LNG or NG after the first cycle.

[0045] Although not required, the method of the present invention includes administering a dosage form, preferably a solid oral dosage form such as a tablet or capsule, containing about 0.110 mg to about 0.150 mg of LNG or about 0.220 mg to about 0.300 mg of NG, with or without a break between cycles. For example, the dosage form can be administered once a day, preferably at the same dose, for at least a 23, 24, 25, 26, 27, 28, 29, or 30 day cycle, followed by a break of 1, 2, 3, 4, 5, 6, 7, or 8 days, during which a placebo, i.e., no LNG or NG, and / or no additional hormonal agent, such as an estrogen, including but not limited to ethinyl estradiol, is administered. After the administration interruption period, once daily administration of a dosage form containing about 0.110 mg to about 0.150 mg of LNGN or about 0.220 mg to about 0.300 mg of NG is resumed for at least 23, 24, 25, 26, 27, 28, 29, or 30 days, followed by an additional 1, 2, 3, 4, 5, 6, 7, or 8 days of interruption. This pattern of administration and interruption can be repeated for up to 6, 12, 18, 24, 30, 36, 42, 48 months or more.

[0046] In one embodiment of the invention, the daily dose of LNG or NG is an amount that provides an average LNG plasma concentration, preferably a steady-state LNG plasma concentration, of: Approximately 2 hours after a single daily dose of LNG or NG, the concentration is about 800 pg / mL to about 2600 pg / mL, preferably about 1000 pg / mL to about 2500 pg / mL, more preferably about 1200 pg / mL to about 2400 pg / mL, and most preferably at least about 1600 pg / mL to about 2300 pg / mL; Approximately 6 hours after a single daily administration of LNG or NG, the concentration is about 300 pg / mL to about 1200 pg / mL, preferably about 350 pg / mL to about 1000 pg / mL, more preferably about 400 pg / mL to about 900 pg / mL, and most preferably at least about 700 pg / mL or more. Approximately 24 hours after a single daily administration of LNG or NG, the concentration is about 200 pg / mL to about 800 pg / mL, preferably about 250 pg / mL to about 700 pg / mL, more preferably about 300 pg / mL to about 600 pg / mL, and most preferably at least about 350 pg / mL or more. Or a combination of the above.

[0047] In one embodiment, the daily dose of LNG or NG is preferably at steady state to provide a mean maximum LNG plasma concentration (C) of about 900 pg / mL to about 2700 pg / mL, preferably about 1000 pg / mL to about 2600 pg / mL, more preferably about 1100 pg / mL to about 2500 pg / mL, and most preferably at least about 1500 pg / mL to about 2400 pg / mL. max ), and time to maximum LNG plasma concentration (T) of about 0.5 hours to about 6 hours, preferably about 0.75 hours to about 5 hours, and most preferably about 1 hour to about 4 hours. max ) is the amount provided.

[0048] In certain embodiments of the invention, the daily dose of LNG or NG preferably provides, at steady state, a mean area under the concentration-time curve (AUC) 24 hours after administration of at least about 14,000 h·pg / mL, preferably at least about 14,500 h·pg / mL, and most preferably at least about 14,700 h·pg / mL. 0-24 In one embodiment, the AUC 0-24 should have an AUC of less than 20,000 hr·pg / mL, preferably less than 19,000 hr·pg / mL, and most preferably less than 18,500 hr·pg / mL.

[0049] In one embodiment of the invention, the method provides an average progesterone plasma level (P) of less than 5 nmol / L, preferably less than 4 nmol / L, and most preferably less than 3.5 nmol / L after at least 5, 6, 7, 8, 9, or 10 days of once daily administration of the oral LNG or NG dosage form. Said P level should be maintained throughout the treatment or treatment cycle.

[0050] The following are merely examples and are not intended to be limiting in any way.

[0051] [Example] [Example 1] LNG tablets that can be used in the process of the present invention were prepared by dissolving LNG in a combination of chloroform and ethanol along with a small amount of povidone (part A). This solution was granulated with lactose and corn starch, followed by further granulation with purified water and povidone (part B) solution.

[0052] The resulting granules were dried, sized, mixed with colloidal silicon dioxide and magnesium stearate, and compressed into tablets. The composition of the tablets is shown in Table 1-1 below.

[0053] [Table 1-1]

[0054] Other granulation techniques such as slugging, granulation fluids and fillers, disintegrants and lubricants may also be used without departing from this disclosure.

[0055] [Example 2] The above tablets prepared in Example 1 were tested in a single-center, open-label, adaptive design study to evaluate the effects of different high doses of LNG administered once daily for 28 days for two consecutive treatment cycles on hormones, ovarian function and vaginal bleeding patterns in healthy menstruating women.

[0056] Study participants were healthy female volunteers aged 18-45 years with a body mass index (BMI) ≥ 18 kg / m 2, nonsmokers if >30 years old, and smokers of up to 10 cigarettes per day if ≤30 years old. Major exclusion criteria were liver disease, risk factors for venous or arterial thromboembolic disease, known cycle irregularities, pregnancy or breastfeeding in the previous 3 cycles, and use of any disease or medication that may affect the safety, absorption, or pharmacokinetics of the study drug. Subjects were required to use barrier contraception or abstain from heterosexual intercourse for the duration of the study.

[0057] The study used an adaptive design. Up to five treatment groups were planned, with each group consisting of 30 women, at least five of whom had a BMI ≥ 30 kg / m 2 Doses were planned to be 0.060 mg, 0.075 mg, 0.095 mg, 0.115 mg, or 0.135 mg per day.

[0058] The initial dose was 0.095 mg per day. Selection of subsequent doses was determined by the occurrence of ovulation in the previous treatment group. Once the lowest dose that completely inhibited ovulation was identified, the study was stopped and higher and lower doses were investigated.

[0059] After screening, subjects were provided with a washout cycle if they were using hormonal contraception. Pretreatment cycles were monitored to assess whether subjects had ovulatory cycles. Follicular growth was measured by transvaginal ultrasound (TVUS) every 3 days (±1) until ovulation was observed. If ovulation occurred by day 27 (±1) and postovulatory progesterone (P) concentrations were ≥16 nmol / L, subjects were eligible and received study medication.

[0060] Subjects began taking the study drug on the first day of menstrual bleeding after the pretreatment cycle. One tablet was administered orally at approximately the same time each morning for 56 consecutive days. Patients were scheduled to attend treatment visits every 3 days (±1) from day 3 (±1) through day 27 (±1) and from day 31 (±1) through day 55 (±1). At each visit, the diameter of the largest follicle-like structure (FLS) and serum follicle-stimulating hormone (FSH), luteinizing hormone (LH), estradiol (E2), and P concentrations were measured.

[0061] Subjects were excluded from the study if active FLS was present on treatment day 3 (±1). If ovulation was suspected on TVUS, additional visits for P measurement were scheduled 2, 4, and 6 days after suspected ovulation.

[0062] After the last treatment day, evaluations continued every 3 days (±1) until ovulation was observed, with P measurements taken 2 days (±1) and, if necessary, 4 days (±1) after ovulation. End-of-study testing was performed 6 days (±1) after ovulation or on day 30 (±1) if ovulation had not been observed by then.

[0063] Serum SHBG concentrations were measured after ovulation in the pretreatment cycle, on treatment day 55 (±1), and at the end of study. Multiple-dose PK parameters were investigated in approximately 15 subjects per dose group, 5 of whom had a BMI ≥ 30 kg / m 2 Blood samples for LNG measurements were taken pre-dose and 0.5, 1, 2, 3, 4, 6, and 24 hours post-dose on day 55 (±1) of treatment.

[0064] During the study period, subjects recorded their daily vaginal bleeding. During the treatment period, subjects also recorded the times when they took study medication.

[0065] At each visit, subjects were asked about adverse events and use of concomitant medications. Safety and pregnancy tests were performed periodically throughout the study. Physical examinations were performed at screening and at the end of the study.

[0066] The primary outcome was ovarian activity according to the Hoogland-Skouby score (Table 1-2), measured during each 28-day treatment period (Hoogland HJ, Skouby SO. Ultrasound assessment of ovarian activity following oral contraceptives. Contraception 1993; 47: pp.583-90).

[0067] [Table 1-2]

[0068] If ovulation was observed during treatment, the subsequent luteal phase was evaluated using the Landgren criterion: the luteal phase was considered adequate if the P concentration was >16 nmol / L for at least 5 days (Landgren et al., Hormonal effects of the 300 μg norethisterone (NET) minipill. 1. Daily steroid levels in 43 subjects during A pretreatment cycle and during the second month of NET administration, Contraception 1980;21: pp.87-113). TVUS measurements of the maximum FLS diameter (average of two directions) were performed using a Voluson E8 Expert device (GE Medical Systems). Serum FSH, LH, E2, P, and SHBG concentrations were measured by validated chemiluminescent microparticle immunoassays (Abbott, Longford, Ireland). All pharmacodynamic parameters were assessed descriptively.

[0069] Plasma LNG concentrations were measured by a validated liquid chromatography coupled to tandem mass spectrometry (ACC, Leidersbach, Germany). PK parameters were derived by noncompartmental analysis. Analysis of variance (ANOVA) was used to determine area under the curve (AUC) and maximum concentration (C) as the basis for calculation of 90% confidence intervals. max Point estimates and confidence intervals for ) values ​​and treatment comparisons calculated by parametric analysis were used for each treatment group and for BMI < 30 and ≥ 30 kg / m 2 Descriptive statistics for subgroups were calculated.

[0070] The composition of the subjects is shown in Figure 1. The mean (±SD) age was 33.3 (±6.2) years, and the mean BMI was 25.4 (±4.9) kg / m2 for all groups. 2, 23.7 (±3.0) kg / m in the low BMI subgroup. 2 , and 33.5 (±3.1) kg / m in the high BMI subgroup. 2 It was.

[0071] Based on the adaptive design, three doses were tested: 0.095 mg, 0.115 mg, and 0.135 mg of LNG. The distribution of Hoogland-Skouby scores is shown in Table 2.

[0072] [Table 2]

[0073] Two subjects in the LNG 0.095 mg group (BMI 30.8 and 22.0 kg / m 2 ) ovulated during treatment period 1 and had an adequate luteal phase according to the Lundgren criteria (P>16 nmol / L for ≥5 days). The lowest dose at which no ovulation occurred was 0.115 mg LNG per day. Also, no subject in the highest dose group (0.135 mg) ovulated as defined by the Hoogland-Skouby score. One subject in this group (BMI 20.4 kg / m 2 ) had an FLS of 12.3 mm on day 3 of treatment and P concentrations between 6.64 and 12.19 nmol / L from days 5 to 11. She may have had abnormal ovulation of small follicles, preceded by a blunted LH peak and followed by an inadequate luteal phase.

[0074] In all treatment groups, the majority of subjects had a Hoogland-Skouby score of 4, i.e., active FLS. With the exception of two ovulations in the lowest dose group, there was no clear trend toward lower scores, i.e., greater ovarian suppression, with increasing doses of LNG.

[0075] The maximum diameter of the maximum FLS, and the maximum and mean E2 concentrations per cycle and per subject over the entire treatment period are shown in Table 3.

[0076] [Table 3]

[0077] The time course of mean FLS diameter and hormone concentrations are shown in Figures 2A-2E. The results were consistent with Hoogland-Skouby scores, with most subjects experiencing follicular growth and a concomitant increase in E2 concentration during treatment. FLS diameter and E2 concentration were similar in the 0.095 mg and 0.115 mg groups. In the 0.135 mg group, FLS diameter was smaller in both treatment cycles and E2 concentration was lower in the first treatment period, indicating that more follicular growth inhibition occurred in the highest dose group. The differences between groups were smaller in treatment period 2, where E2 concentration remained stable and was lower than in treatment period 1. The mean mean E2 concentration per subject over the entire treatment period was 241, 219, and 180 pmol / L in the 0.095, 0.115, and 0.135 mg groups, respectively. At both doses, mean E2 concentrations were ≥110 pmol / L (30 pg / mL) in 80-90% of subjects and ≥73.4 pmol / L (20 pg / mL) in all subjects, except for one in the 0.115 mg group.

[0078] Mean FSH concentrations declined slightly during treatment period 1 due to negative feedback from rising E2 levels. All individual LH concentrations were below 12.1 IU / L, except for one ovulatory subject in the 0.095 mg group who had an LH peak of 68.0 IU / L. No preovulatory LH peaks were observed in the other ovulatory subjects. All individual P concentrations were below 5 nmol / L during treatment, except for two ovulatory subjects in the 0.095 mg group, one subject with ovulatory abnormalities in the 0.135 mg group, and one other subject who had a single P concentration of 5.85 nmol / L at the first treatment visit, likely a carryover from pretreatment cycles.

[0079] No clear differences were observed in maximum FLS diameter and E2 intensity between the two BMI groups.

[0080] In the majority of subjects, ovulation occurred within the 30-day posttreatment period after which P concentrations were ≥ 16 nmol / L. In one or two subjects per dose group, P concentrations remained below 16 nmol / L after ovulation. In one or two subjects per group, ovulation did not occur within 30 days. Ovulation was observed a mean of 15.5, 14.1, and 12.8 days after the last treatment in the 0.095, 0.115, and 0.135 mg dose groups, respectively.

[0081] In all treatment groups, SHBG concentrations were suppressed by approximately 60% at the end of Treatment Period 2. At the end-of-study test, an average of 22 days after the last treatment, the mean SHBG concentration had not yet returned to baseline.

[0082] Mean plasma LNG concentrations after study drug administration on days 55 ± 1 are shown in Figure 3. Maximum values ​​were reached 1 hour after dosing and declined rapidly thereafter. Mean PK parameters are shown in Table 4. Statistical evaluation showed dose proportionality for total exposure over the observed dosing interval and a trend toward negligible maximum exposure as dose increased (Figure 3B-C). At all doses, no significant differences were observed in subjects with a BMI of ≥ 30 kg / m 2 A trend towards lower exposure was observed in the subgroup.

[0083] [Table 4]

[0084] The mean (±SD) number of days with bleeding or spotting during the treatment period excluding the first 7 days was 12.3 (±8.6), 14.5 (±9.4), and 16.0 (±11.5), with medians of 11.5, 14.5, and 13.0 days in the 0.095, 0.115, and 0.135 mg groups, respectively. Spotting was the most common type of bleeding, and bleeding, when it occurred, was primarily light.

[0085] Findings regarding acne (the primary symptom of androgen elevation) are shown in Table 5.

[0086] [Table 5]

[0087] The number of acne events in the three LNG-POP groups was low, mitigating concerns about an increased risk of androgen-related side effects with LNG-POP.

[0088] The study drug was well tolerated. The most commonly reported adverse events were headache, nasopharyngitis, and follicular cysts. One subject discontinued early due to dizziness, which was probably related to the study treatment. There was one serious adverse event (pneumonia), which was unrelated to treatment. There were no clinically relevant changes in physical examination results or routine laboratory values. One subject became pregnant during follow-up, with conception occurring long after the last study treatment.

[0089] The results showed that increasing doses of LNG-POP consistently inhibited ovulation. The lowest effective dose was 0.115 mg per day. Most subjects experienced follicular development and a corresponding increase in E2 levels, but LH surge and normal ovulation were inhibited during treatment with 0.115 mg or 0.135 mg of LNG per day. Abnormal ovulation was possible in the 0.135 mg group, but did not appear to result in pregnancy. The ovulation suppression potential of 0.115 mg and 0.135 mg LNG was greater than that of the conventional POP of 0.03 mg LNG.

[0090] In general, progestogen-only preparations do not completely suppress follicular development and E2 production, thus preventing the occurrence of hypoestrogenic side effects, especially bone loss. In all LNG-treated groups, the mean E2 concentrations were well above 110 pmol / L (30 pg / mL), which is the lower limit expected to avoid promoting bone loss and other hypoestrogenic side effects (e.g., vaginal dryness, mood changes).

[0091] It was unexpectedly found that at higher doses of LNG (i.e., greater than 0.10 mg), not only did complete ovulation inhibition occur, but the bleeding pattern was no worse than at lower doses, and the higher doses appeared to have a better safety profile than expected. Typically, at this dose range, for oral contraception, LNG is commonly combined with an estrogen (such as E2) to overcome estrogen deficiency (hypoestrogenism) and increased androgenic risk. However, the adverse and undesirable side effects mentioned above do not appear to be present with these higher doses of LNG-POP.

[0092] The invention described herein can be practiced in the absence of any element or elements, limitations or limitations not specifically disclosed herein. Thus, for example, in each example herein, any of the terms "comprising", "consisting essentially of" and "consisting of" may be replaced with any of the other two terms. The terms and expressions employed are used as terms of description and are not meant to be limiting, and the use of such terms and expressions is not intended to exclude any equivalents of the features shown and described or portions thereof, recognizing that various modifications are possible within the scope of the invention as claimed. Thus, although the invention has been specifically disclosed by preferred embodiments and optional features, it should be understood that modifications and variations of the concepts disclosed herein may be utilized by those skilled in the art, and such modifications and variations are deemed to be within the scope of the invention as defined by the claims.

[0093] (Additional Note) (Appendix 1) 1. A method of providing contraception to a human subject desiring contraception, comprising orally administering to said subject once daily a dosage form comprising about 0.110 mg to about 0.150 mg of levonorgestrel (LNG) for a treatment period of at least 28 days.

[0094] (Appendix 2) 2. The method of claim 1, wherein the dosage form comprises about 0.115 mg of LNG, about 0.120 mg of LNG, about 0.125 mg of LNG, about 0.130 mg of LNG, about 0.135 mg of LNG, about 0.140 mg of LNG, or about 0.145 mg of LNG, and at least one pharma- ceutically acceptable excipient.

[0095] (Appendix 3) 2. The method of claim 1, wherein the LNG is the sole pharmacologic active agent, additive, or adjuvant and is administered to the subject for contraceptive purposes during the treatment period.

[0096] (Appendix 4) 2. The method of claim 1, wherein the subject is not administered an estrogen compound during the treatment period.

[0097] (Appendix 5) 2. The method of claim 1, wherein the subject is not administered folate during the treatment period.

[0098] (Appendix 6) 2. The method of claim 1, wherein there is no dose titration of the LNG during the treatment period.

[0099] (Appendix 7) 2. The method of claim 1, wherein the treatment period is at least 55 days or more during which the once daily administration of the LNG dosage form occurs without interruption in administration of the LNG dosage form.

[0100] (Appendix 8) 2. The method of claim 1, wherein the treatment period is at least 180 days or more during which the once daily administration of the LNG dosage form occurs without interruption of administration of the LNG dosage form.

[0101] (Appendix 9) 2. The method of claim 1, wherein the dosage form is a tablet comprising the LNG and at least one pharma- ceutically acceptable excipient.

[0102] (Appendix 10) A method of providing contraception to a human subject desiring contraception, comprising orally administering to said subject a tablet comprising from about 0.115 mg to about 0.145 mg of levonorgestrel (LNG) and one or more pharma- ceutically acceptable excipients over a treatment period of at least 28 days.

[0103] (Appendix 11) 11. The method of claim 10, wherein the tablet comprises about 0.115 mg of LNG, about 0.120 mg of LNG, about 0.125 mg of LNG, about 0.130 mg of LNG, about 0.135 mg of LNG, about 0.140 mg of LNG, or about 0.145 mg of LNG, and at least one pharma- ceutically acceptable excipient selected from a lubricant, a filler, a binder, a disintegrant, a flow agent, a solubilizer, a flavoring agent, a pH adjuster, an antioxidant, a chelating agent, or a mixture thereof.

[0104] (Appendix 12) 11. The method of claim 10, wherein the subject is not administered estrogen during the treatment period.

[0105] (Appendix 13) 11. The method of claim 10, wherein the subject is not administered folate during the treatment period.

[0106] (Appendix 14) 11. The method of claim 10, wherein the LNG is not titrated during the treatment period.

[0107] (Appendix 15) 11. The method of claim 10, wherein the treatment period is at least 60 days or more during which the once daily administration of the LNG tablet is performed without interruption of administration of the LNG tablet.

[0108] (Appendix 16) 11. The method of claim 10, wherein the treatment period is at least 180 days or more during which the once daily administration of the LNG tablet is performed without interruption of administration of the LNG tablet.

Claims

1. A dosage form for use in providing contraception to a human subject desiring contraception, said dosage form comprising from about 0.125 mg to about 0.150 mg of levonorgestrel (LNG), being orally administered once daily to said subject over a treatment period of at least 28 days, said LNG being the only pharmaceutical active agent, additive or adjuvant administered to said subject for contraceptive purposes during said treatment period, and no estrogen compound being administered to said subject during said treatment period.

2. The dosage form according to claim 1, wherein said dosage form comprises about 0.125 mg of LNG, about 0.130 mg of LNG, about 0.135 mg of LNG, about 0.140 mg of LNG or about 0.145 mg of LNG, and at least one pharmaceutically acceptable additive.

3. The dosage form according to claim 1, wherein no folate is administered to said subject during said treatment period.

4. The dosage form according to claim 1, wherein no dose titration of said LNG is performed during said treatment period.

5. The dosage form according to claim 1, wherein said treatment period is at least 55 days or more during which the once-daily administration of said dosage form of LNG is carried out without interruption of the administration of said dosage form of LNG.

6. The dosage form according to claim 1, wherein said treatment period is at least 180 days or more during which the once-daily administration of said dosage form of LNG is carried out without interruption of the administration of said dosage form of LNG.

7. The dosage form according to claim 1, wherein said dosage form is a tablet comprising said LNG and at least one pharmaceutically acceptable additive.

8. A tablet for use in providing contraception to a human subject desiring contraception, consisting of from about 0.130 mg to about 0.140 mg of levonorgestrel (LNG) and one or more pharmaceutically acceptable additives, said tablet being orally administered to said subject over a treatment period of at least 28 days, said LNG being the only pharmaceutical active agent, additive or adjuvant administered to said subject for contraceptive purposes during said treatment period, and no estrogen compound being administered to said subject during said treatment period.

9. The tablet according to claim 8, wherein the tablet comprises about 0.135 mg of LNG and at least one pharmaceutically acceptable additive selected from lubricants, fillers, binders, disintegrants, fluidizing agents, solubilizing agents, flavoring agents, pH adjusters, antioxidants, chelating agents, or mixtures thereof.

10. The tablet according to claim 8, wherein folate is not administered to the subject during the treatment period.

11. The tablet according to claim 8, wherein the dosage of LNG is not adjusted during the treatment period.

12. The tablet according to claim 8, wherein the treatment period is at least 60 days or more during which the once-daily administration of the LNG tablet is carried out without interruption of the administration of the LNG tablet.

13. The tablet according to claim 8, wherein the treatment period is at least 180 days or more during which the once-daily administration of the LNG tablet is carried out without interruption of the administration of the LNG tablet.

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