Progestin / Testosterone Transdermal Gel

Abstract

The present disclosure relates to a specific combination of a progestin and testosterone in a transdermal composition and its use in methods for improving effectiveness while ensuring male contraception and reducing side effects.

Description

Technical Field

[0001] [Cross - Reference to Related Applications] This application claims priority to U.S. Provisional Patent Application No. 63 / 339,563, filed May 9, 2022, the disclosure of which is hereby incorporated by reference in its entirety.

[0002] This invention was made with government support under HHSN27520130024I and HHSN275201500002I / HHSN275000010 awarded by the National Institutes of Health (NIH). The government has certain rights in this invention.

[0003] The present disclosure relates to a specific combination of progestin and testosterone in a transdermal composition for use in a method for ensuring male contraception while having additional health benefits.

Background Art

[0004] Approximately 45% of pregnancies worldwide are unintended, contributing to undesirable health problems, including maternal morbidity and mortality, as well as a significant social burden. Despite the availability of many contraceptive methods for women, male contraceptive methods are limited to withdrawal, condoms, and vasectomy. Condoms have the drawbacks of inconsistent use and a typical use failure rate of 13%, while vasectomy requires surgery and is neither easy nor certain in terms of reversibility.

[0005] Several reversible male hormonal contraceptive regimens have been tested in clinical trials using either testosterone alone or a combination of testosterone and progestin.

[0006] Testosterone (referred to as T throughout the present disclosure) is a male hormone produced in the testes. Testosterone plays a crucial role in the development of male genitalia during fetal development and puberty. Testosterone hormone levels are important for normal sexual development and function in men. Exogenous testosterone has been found to be usable in testosterone replacement therapy for treating symptoms of hypogonadism, such as decreased libido, depression, and erectile dysfunction. For example, AndroGel® (an FDA-approved testosterone gel formulation) 1.62% is a topical prescription drug used for treating symptoms of testosterone deficiency. The dosage can be adjusted between a minimum of 20.25 mg of testosterone (one pump actuation or one 20.25 mg sachet) to a maximum of 81 mg of testosterone (four pump actuations or four 20.25 mg sachets). The dosage is to be increased gradually based on the serum testosterone concentration before morning administration approximately 14 and 28 days after the start of treatment or after dosage adjustment. In addition, the serum testosterone concentration is to be evaluated regularly thereafter, and the serum T level is to be maintained between 350 ng / dL and 750 ng / dL. Testosterone has been found to cause a decrease in sperm production when used at pharmacologically high doses. The reason for the decrease in sperm production is that high-dose testosterone inhibits gonadotropin-releasing hormone (GnRH) production, which in turn inhibits luteinizing hormone (LH) production and leads to a decrease in endogenous testosterone production by Leydig cells, thereby reducing the testicular testosterone concentration. The inhibition of GnRH production also inhibits follicle-stimulating hormone (FSH) release, which controls spermatogenesis in Sertoli cells. Spermatogenesis is evaluated by sperm concentration in semen and is commonly used as a major evaluation item for assessing the effectiveness of male contraceptives. When the sperm concentration is less than 1 million spermatozoa per mL of semen, the male contraceptive regimen is judged to be effective in preventing pregnancy.See "Contraceptive efficacy of testosterone-induced azoospermia and oligozoospermia in normal men," World Health Organization Task Force on Methods for the Regulation of Male Fertility, Fertil Steril., 1996 Apr;65(4):821-9.

[0007] In the study, intramuscular injection of 200 mg / week of testosterone enanthate, a pharmacologically high-dose testosterone ester, once a week for 12 months resulted in only 0.8 pregnancies per 100 person-years of exposure, demonstrating it to be a highly effective contraceptive.

[0008] Progestin is the synthetic progestogen most frequently used in female hormonal contraception and also for the purpose of preventing endometrial hyperplasia by estrogen without antagonistic effects in hormone replacement therapy. The compound called 16-methylene-17α-acetoxy-19-norpregna-4-en-3,20-dione or segesterone acetate is a progestin (also identified by the trade name NESTORONE® and referred to as NES throughout this disclosure) that includes a 19-nor-progesterone derivative and has a structure similar to the physiological hormone progesterone. NES has strong ovulation-suppressing properties and progesterone-like properties and, at therapeutic levels up to X2000, is not associated with androgenic, estrogenic, or glucocorticoid effects. Considering its high intensity of ovulation-suppressing action when administered systemically, NES is thought to require only extremely low doses for contraceptive efficacy and, thus, can be used in various parenteral delivery systems. NES has been extensively studied in parenteral forms, such as transdermal gels, implants, and intravaginal rings for female contraception. NES was first formulated as a vaginal system in combination with estrogen for female contraception and has been approved by the FDA.

[0009] Trials in men have shown that adding a progestin to T increases the rate and degree of spermatogenesis suppression. For example, Mahabadi et al. in “Combined Transdermal Testosterone Gel and the Progestin Nestorone Suppresses Serum Gonadotropins in Men,” J.Clin.Endocrinol Metab., July 2009, 94(7), 2313 - 2320, delivered 600 or 800 μg / day of NES and 10 mg / day of T to the body by treating with a combination of a transdermal NES gel (containing 6 or 8 mg / day of NES) and a T gel (Testogel® 1% at 10 g / day, containing 100 mg / day of T) for 20 days (approximately 10% of the steroid dose applied on the skin was absorbed), and disclosed that serum gonadotropins were suppressed to below 0.5 IU / liter in significantly more men compared to when either gel was used alone. However, acne was reported in 10% of the subjects, and in all T (100 mg / day, alone or in combination with NES) gel treatment groups, a decrease in HDL cholesterol levels occurred compared to the NES alone group. This decrease was suggested to be likely secondary to T administration. Large inter - individual variations in serum total T concentration and free T concentration were observed in all T gel treatment groups, and in some subjects, high serum T levels above the normal range were observed. Mahabadi et al. suggested that it may be necessary to reduce the dose of T to avoid high serum T levels and decreased HDL cholesterol levels. Serum gonadotropins in the Mahabadi trial were used as a surrogate marker for spermatogenesis suppression, and it was assumed that when the value was below 1.0 IU / liter, the male contraceptive regimen was judged effective for pregnancy prevention.

[0010] Subsequently, Ilani et al. in "A New Combination of Testosterone and Nestorone Transdermal Gels for Male Hormonal Contraception," J.Clin.Endocrinol Metab., October 2012, 97(10), 3476-3486, delivered 800 or 1,200 μg / day of NES and 10 mg / day of T to the body by treating with a combination of NES gel (containing 8 or 12 mg / day of NES) and T gel (Testogel® 1% at 10 g / day, containing 100 mg / day of T) daily for at least 20 weeks (approximately 10% of the dose of steroid applied on the skin was absorbed), and disclosed that sperm concentration was suppressed to 1 million cells / mL or less in significantly more men compared to when using the T gel alone. Serum T levels showed large intra- and inter-subject variability. Three subjects had T concentrations exceeding 1,800 ng / dl on three or more occasions. Furthermore, acne was the most frequently observed adverse event, noted in 21% of the subjects.

[0011] For the purpose of predicting who responds to hormonal contraception methods with NES / T gels, Roth et al. in "Characteristics associated with suppression of spermatogenesis in a male hormonal contraceptive trial using testosterone and NESTORONE(R) gels," Andrology, 2013 November, 1(6), 899-905, analyzed the data of the trial described in Ilani's paper. Roth et al. concluded that serum NESTORONE® concentration is significantly associated with spermatogenesis suppression, while serum T concentration is not.

[0012] Furthermore, Anawalt et al. in "Combined nestorone-testosterone gel suppresses serum gonadotropins to concentrations associated with effective hormonal contraception in men," Andrology, 2019 November, 7(6), 878-887, applied a single gel formulation containing 8.3 mg NES / 62.5 mg T in 5 mL of the gel agent daily for a 28-day treatment, and disclosed that FSH and LH concentrations were significantly suppressed to ≤ 1.0 IU / L in more men compared to the case of daily application of 62.7 mg T in 4.4 mL of the gel agent. The average serum total T concentration (T C avg ) in the NES-T group remained within the normal physiological range (300 - 1,000 ng / dL) throughout the entire treatment period, but the maximum serum total T concentration (T C max ) exceeded the normal physiological range after the second day. Serum gonadotropins were also used as a surrogate marker for spermatogenesis suppression in the Anawalt study. However, Anawalt did not show any consideration regarding sperm concentration suppression by the 8.3 mg NES / 62.5 mg T-containing gel agent.

[0013] There is a need to develop a male contraceptive method that is easy to apply, safe, effective, and reversible. For this purpose, an approach is also needed to find a formulation that reduces sperm count while maintaining testosterone levels within the normal range.

Summary of the Invention

[0014] According to the present disclosure, there is provided a percutaneous composition in unit dosage form for male contraceptive treatment, comprising about 7 mg to about 12 mg of 16-methylene-17α-acetoxy-19-norpregna-4-ene-3,20-dione, about 60 mg to about 100 mg of testosterone, and a pharmaceutically acceptable excipient.

[0015] The transdermal composition in unit dosage form can contain 16-methylene-17α-acetoxy-19-norpregna-4-en-3,20-dione in an amount of about 8 mg to about 10 mg and testosterone in an amount of about 70 mg to about 85 mg.

[0016] The transdermal composition in unit dosage form can contain 16-methylene-17α-acetoxy-19-norpregna-4-en-3,20-dione in an amount of about 8 mg to about 8.5 mg and testosterone in an amount of about 73.5 mg to about 74.5 mg.

[0017] The transdermal composition in unit dosage form can contain 16-methylene-17α-acetoxy-19-norpregna-4-en-3,20-dione in an amount of about 8.3 mg and testosterone in an amount of about 73.8 mg.

[0018] The transdermal composition in unit dosage form can be in the form of a gel.

[0019] The transdermal composition in unit dosage form is C 2 ~C 4 It can be in the form of a hydroalcoholic gel containing C alcohol.

[0020] The transdermal composition in unit dosage form can contain ethanol.

[0021] The transdermal composition in unit dosage form can contain C alcohol in an amount of 50% to 85% wt / wt. 2 ~C 4 It can contain alcohol.

[0022] The transdermal composition in unit dosage form can further contain a penetration enhancer.

[0023] The transdermal composition in unit dosage form can further contain a penetration enhancer, and the penetration enhancer is isopropyl myristate.

[0024] According to the present disclosure, there is also provided a method for male contraception, which includes the step of applying the transdermal composition in unit dosage form disclosed herein to the body surface of a male.

[0025] The transdermal composition in unit dosage form can be applied once a day to the body surface of a male.

[0026] The transdermal composition in unit dosage form can be applied to the surface of the upper arm or shoulder.

[0027] The essence and details of the present disclosure can be better understood by referring to the following "Modes for Carrying Out the Invention", which refers to the following drawings here.

Brief Description of the Drawings

[0028]

Figure 1

Modes for Carrying Out the Invention

[0029] Before describing at least one embodiment of the present invention in detail, it should be understood that the present invention is not limited to the details described in the following description or illustrated in the examples in its application. The present invention can take other embodiments or be implemented or carried out in various ways. Therefore, it should be understood that many modifications can be made to these exemplary embodiments without departing from the spirit and scope of the present disclosure, and other configurations can be devised. It should also be understood that the expressions and technical terms in this specification are for the purpose of explanation and should not be construed in a limiting sense.

[0030] In this specification, all percentages and ratios are by weight relative to the total composition, unless otherwise indicated. Unless otherwise specified, all measurements performed this time were carried out at 25°C and standard atmospheric pressure. In this specification, unless otherwise specified, all temperature units used are in degrees Celsius.

[0031] The present disclosure can include (without limitation) or consist essentially of the components and other components or elements described herein. The term "comprising" as used herein means having one or more additional arbitrary other elements not described, in addition to the elements or their equivalents in structure or function described. The terms "having" and "including" are also to be construed as non-limiting herein, unless the context suggests otherwise. The terms "comprising", "having" and "including" encompass the terms "consisting of" and "consisting essentially of". The term "consisting essentially of" as used herein means that the composition or method can include additional components and / or steps, provided that such additional components and / or steps do not substantially change the characteristics of the claimed composition or method.

[0032] All ranges described herein include both endpoints and the values therebetween. Terms such as "about", "generally", "substantially", etc. are to be construed as modifying a term or value to indicate that the term or value is not absolute and not what can be read from the prior art description. The meaning of such terms is defined by the context, and terms bearing such modifications are understood by those skilled in the art. This includes, at a minimum, the degree of experimental error, technique error, and instrumental error expected in the case of a given technique used to measure a value. The term "about" as used herein encompasses all values within a range of a specific value indicating ±10% unless otherwise indicated.

[0033] The terms "a" and "an" include the plural herein, unless otherwise indicated. Thus, for example, "an excipient" can mean at least one excipient and a plurality of excipients, such as, but not limited to, different types of excipients.

[0034] The term "and / or" means, in the context of this specification, when used in a listing of two or more items, that any one of the listed features may be present, or any combination of two or more of the listed features may be present. For example, if a composition is described as containing agent A, B and / or C, the composition can contain A only; B only; C only; a combination of A and B; a combination of A and C; a combination of B and C; or a combination of A, B and C.

[0035] The term "contraceptive" refers, in the context of this specification, to an agent administered to prevent pregnancy or reduce the likelihood of pregnancy. "Contraceptive" may refer, in the context of this specification, to one contraceptive or a combination of two or more contraceptives.

[0036] The terms "treat", "treatment" or "therapy" refer, in the context of this specification, with respect to a contraceptive agent, to administering the composition to achieve prevention of pregnancy or reduction of the likelihood of pregnancy.

[0037] The use of the terms "transdermal" or "topical" is, in the context of this disclosure, intended in each case to include transdermal (or through the skin) administration, i.e., delivering an active agent and other pharmaceutical compositions via the skin tissue into the bloodstream by means of a gel, cream, ointment, paste, foam, swab, gauze, pad, lotion, spray, aerosol, patch, etc.

[0038] Transdermal delivery of an active agent has many advantages over conventional oral administration. The advantages of a transdermal system include bypassing the portal circulation, thereby avoiding first-pass metabolism in the liver; being convenient; being a non-interrupted therapy; improving patient compliance; being reversible (by removing the transdermal system from the skin); and the agent being delivered directly into the circulatory system at a constant rate; and, given the skin reservoir effect, having an extended half-life.

[0039] One method of transdermal delivery involves the use of a patch, which relies on the diffusion of the active agent through a membrane. Several transdermal patch delivery systems are known, all of which include at least one adhesive layer for attaching the patch to the target site.

[0040] As used herein, a gel formulation is a form of composition that can be used to topically administer an agent in a continuous manner, which facilitates the delivery of the composition and minimizes leakage during delivery. A gel formulation that is easy to apply should not be overly loose, oily, or otherwise inconvenient for the patient to use. A hydrogel is a polymer network that absorbs water and swells but does not dissolve in water due to the presence of both hydrophilic functional groups that provide water absorption and cross-linked polymers that cause water insolubility. An aqueous-alcoholic gel (also referred to interchangeably herein as a hydroalcoholic gel) is a hydrogel having a high alcohol concentration. Such gels have the advantage of being easy to administer. At the application site, the alcohol acts as a vector or enhancer to enable skin penetration and then evaporates, so that the drug is thought to become supersaturated. The skin functions as a reservoir for the drug, and the drug is delivered to the systemic blood circulation at a relatively constant rate over a period of several hours.

[0041] The terms "active", "pharmacologically active", "therapeutically active", "pharmaceutically active" or "physiologically active" for describing a "constituent" or "agent" mean, in this specification, any chemical substance or compound that is used alone or in combination and is suitable for administration, for example transdermal administration, to induce a desired systemic effect.

[0042] The terms "effective", "pharmacologically effective", "therapeutically effective", "pharmaceutically effective" or "physiologically effective" amount of an active agent mean, in this specification, an amount of a compound that is non-toxic but sufficient to produce the desired therapeutic effect when used alone or in combination with one or more other compounds.

[0043] The terms "synergy", "synergism", "synergistic effect" or "synergistic action" mean, in this specification, the effect in which the actions of two agents interact, such that the result of the combined action exceeds the result expected when the two agents acting separately are simply added together.

[0044] The effective amount of a contraceptive, or the actual weight percentage of such an agent used in a composition, can vary depending on various factors, as will be understood by those skilled in the art, such as the actual contraceptive activity of each agent in the composition against the target to be treated, the synergistic effect by combining two or more such agents, the formulation of the composition and the mode of delivery of the composition, etc. Other factors to be considered when determining the dosage of an active contraceptive are well known to those skilled in the art, and such factors include the actual dosage form, and the mode of delivery of the composition, for example, whether the dosage form is intended for sustained release. Such activity can be determined by conventional methods and the amount of the active agent formulated thereby.

[0045] The term "unit dose form" refers, in this specification, to a composition that is in a form to be administered to a subject in a single dose.

[0046] As used herein, the term "daily dosage" refers to the daily dosage of any active agent used alone or in combination in a composition to achieve a desired therapeutic effect.

[0047] As used herein, the term "pharmaceutically acceptable excipient" refers to a carrier or vehicle, a gelling or thickening agent, a suspending agent, a skin softening agent, a humectant, a solubilizing agent, a stabilizing agent, a pH adjuster, a penetration enhancer, and a preservative, which do not cause significant irritation to the living body and do not inactivate the biological activity and properties of the applied active agent.

[0048] As used herein, the term "carrier" or "vehicle" refers to a carrier substance suitable for transdermal administration and includes any such substance known in the art, for example, any liquid, gel, solvent, liquid diluent, solubilizing agent, etc., which is non-toxic and does not interact detrimentally with other components of the composition. Suitable examples of carriers include water, alcohol, mineral oil, silicone, liquid sugar, wax, petroleum jelly, and various other oils and polymeric substances.

[0049] As used herein, the term "penetration enhancer" refers to a substance that increases the rate at which a pharmacologically active agent penetrates the skin and enters the bloodstream by assisting in increasing the skin permeability to the pharmacologically active agent.

[0050] Throughout the present disclosure, NESTORONE® is referred to as NES and is a progestin, i.e., a synthetic 19-nor-progesterone derivative. NESTORONE® is 16-methylene-17α-acetoxy-19-norpregna-4-ene-3,20-dione, which has a structure similar to that of the physiological hormone progesterone. NES has strong ovulation-suppressing properties, anti-gonadotropic properties, and progesterone-like properties and is not associated with androgenic, estrogenic, or glucocorticoid effects at therapeutic levels.

[0051] Testosterone, referred to as T throughout the present disclosure, is a male hormone produced in the testes. Testosterone is approved as a replacement therapy and is commercially available in gel form for the treatment of symptoms of testosterone deficiency (e.g., AndroGel®). The term "testosterone" as used herein refers not only to testosterone itself but also to its enantiomers, isomers, tautomers, salts, chelates, esters, amides, derivatives, and prodrugs, as well as precursors thereof, such as DHT (dihydrotestosterone), 17-methyltestosterone, 17α-methyl-testosterone 3-cyclopentyl enol ether, testosterone enanthate, testosterone cypionate, testosterone undecanoate, testosterone cyclodextrin, testosterone buciclate. According to the present disclosure, testosterone may be of natural origin or may be produced by a semi-synthesis or synthetic process.

[0052] According to one aspect of the present disclosure, a transdermal composition for male contraception is provided, the composition can comprise a combination of NES and T, each in a pharmaceutically effective amount, and a pharmaceutically acceptable excipient.

[0053] The composition can comprise NES and T at about 0.1% - 0.3% w / w and about 1.0% - 2.5% wt / wt, respectively, preferably about 0.15% - 0.25% w / w and about 1.4% - 2% wt / wt, more preferably about 0.19% wt / wt and about 1.697% wt / wt.

[0054] In one embodiment, the present composition is in unit dosage form, and this unit dosage form can contain at least about 7 mg to a maximum of about 12 mg of NES and at least about 60 mg and a maximum of about 100 mg of T. Since approximately 10% of these hormones at this level is absorbed when applied on the skin, the absorption rate in the subject when such a composition is applied once a day corresponds to about 700 - 1,200 μg / day for NES and about 6 - 10 mg / day for T. In another embodiment, the present composition is in unit dosage form, and this unit dosage form can contain at least about 7 mg and a maximum of about 10 mg of NES and at least about 60 mg and a maximum of about 95 mg of T. Since approximately 10% of these hormones at this level is absorbed when applied on the skin, the absorption rate in the subject when such a composition is applied once a day corresponds to about 700 - 1,000 μg / day for NES and about 6 - 9.5 mg / day for T. Preferably, the present composition in unit form can contain at least about 8 mg to a maximum of about 10 mg of NES and at least about 70 mg to a maximum of about 85 mg of T. When applied on the skin, the absorption rate in the subject when such a composition is applied once a day is about 800 - 1,000 μg / day for NES and about 7 - 8.5 mg / day for T. More preferably, the present composition in unit form can contain about 8 - 8.5 mg of NES and about 73.5 - 74.5 mg of T. When applied on the skin, the absorption rate in the subject when such a composition is applied once a day is about 800 - 850 μg / day for NES and about 7.35 - 7.45 mg / day for T. In one embodiment, the present composition in unit form can contain about 8.3 mg of NES and about 73.8 mg of T. In other words, it may also be possible to consider these absorption levels of these hormones to be equivalent to the corresponding plasma levels in the patient. Considering this, the amounts of these hormones required for the transdermal formulation of the present disclosure are generally at plasma levels, at least about 600 to a maximum of about 800 pmol / L for NES and at least about 300 to a maximum of about 1000 ng / dL for T, preferably 300 - 900 ng / dL.

[0055] When such a composition system is used in a transdermal manner, it has been found to not only provide effective suppression of gonadotropin and sperm concentration, but also achieve such effective suppression of sperm concentration in a short treatment period. Furthermore, such a composition caused few side effects.

[0056] As described above, the transdermal application of this composition containing the combination of NES and T is preferably in the form of a gel. In particular, this gel can be transparent, washable with water, have a refreshing feel, be quick-drying, spreadable, and / or be a non-greasy formulation. More preferably, the transdermal composition of the present disclosure is formulated as an aqueous gel, most preferably as a hydroalcoholic gel.

[0057] In particular, the transdermal composition, preferably in gel form, can further contain pharmaceutically acceptable excipients, such as, but not limited to, carriers, gelling agents, emollients, humectants, and pH adjusters.

[0058] The carrier or alternative vehicle in the present transdermal composition can include, but is not limited to, water, alcohol, mineral oil, silicone, liquid sugar, wax, petrolatum, and mixtures thereof. The carrier can be present in about 90% - 99% wt / wt, preferably about 94% - 98% wt / wt, or about 95% - 97% wt / wt, more preferably about 96% - 96.5% of the composition, depending on the type of carrier used. Preferably, the carrier in the present transdermal composition can include water and C 2 ~C 4 alcohol. Water can be present in about 20% - 40% w / w, preferably about 25% - 32% wt / wt, or about 27% - 29%, more preferably about 28.0% - 28.5% w / w of the composition. C 2 ~C 4Alcohol can also function as a penetration enhancer in this percutaneous composition, preferably ethanol, isopropanol, n-propanol, or a mixture thereof, more preferably ethanol. C 2 ~C 4 Alcohol can be present in about 50% - 85% wt / wt, or 52% - 83% wt / wt of this composition, preferably about 62% - 73% wt / wt, about 65% - 71% wt / wt, about 66.5% - 69.5% wt / wt, or about 67.5% - 68.5 wt / wt, more preferably about 67.9% wt / wt. C 2 ~C 4 Alcohol is preferably ethanol. Ethanol can be present in about 50% - 85% wt / wt of this composition, preferably about 65% - 71% wt / wt, more preferably about 67.93% wt / wt.

[0059] A gelling agent, or alternative thickener, can be present in an amount sufficient to change the viscosity of the composition. Gelling agents include carbomers; carboxyethylene or polyacrylic acids such as Carbopol 980 USP / NF / EP, or 940 NF, 981 or 941 NF, 1382 or 1342 NF, 5984 or 934 NF, ETD2020, 2050, 934P NF, 971 PNF, 974P NF, and Noveon AA-1 USP, etc.; cellulose derivatives such as ethyl cellulose, hydroxypropyl methyl cellulose (HPMC), ethyl hydroxyethyl cellulose (EHEC), carboxymethyl cellulose (CMC), hydroxypropyl cellulose (HPC) (different grades of Klucel), hydroxyethyl cellulose (HEC) (Natrosol grades), HPMCP55, and Methocel grades, etc.; natural gums such as gum arabic, xanthan gum, guar gum, and alginate, etc.; polyvinyl pyrrolidone derivatives such as Kollidon grades, etc.; polyoxyethylene polyoxypropylene copolymers such as Lutrol F grades 68 and 127, etc.; and can be selected from the group including mixtures thereof. Other gelling agents can include chitosan, polyvinyl alcohol, pectin, and veegum® grades. Also, the system can be thickened and neutralized by including a tertiary amine such as triethanolamine or trolamine, etc.

[0060] Polymers or copolymers of acrylic acid, such as carbomers, etc., act as gelling agents to facilitate the release of lipophilic activators and penetration enhancers. The gelling agents are preferably Lutrol F grades and Carbopol grades.

[0061] The amount and type of gelling agent in the transdermal composition can be selected to provide the desired product consistency and / or viscosity to facilitate application to the skin. The gelling agent can be present in the composition from about 0.2% to 3.0% wt / wt, depending on the type of gelling agent used. For example, if the gelling agent is polyacrylic acid, it can preferably be present in an amount between about 0.5% and 2% wt / wt, more preferably about 1.0% wt / wt.

[0062] Skin softeners and / or humectants in the transdermal composition can be used to promote penetration (and thus function as penetration enhancers), to soften and smooth the skin, or to retain moisture. Skin softeners and / or humectants include, but are not limited to, isopropyl myristate, cetyl alcohol, cetearyl alcohol, cocoa butter, isopropyl palmitate, lanolin, liquid paraffin, polyethylene glycol, shea butter, silicone oil, stearic acid, stearyl alcohol, castor oil, and mixtures thereof, as well as other oils. The skin softener / humectant can be present in the composition from about 0.2% to 4.0% wt / wt, preferably from about 0.5% to 3.0% wt / wt, depending on the type of skin softener / humectant used. Preferably, isopropyl myristate can be mentioned as the skin softener / humectant in the present transdermal composition, and isopropyl myristate can be present in the composition from about 0.2% to 3.0% wt / wt, preferably from about 0.5% to 2.0% wt / wt, more preferably around 1.0% wt / wt.

[0063] pH adjusters or alternative pH regulators in the transdermal composition can be used to maintain the desired pH for proper chemical and physical properties. Examples of pH adjusters or alternative pH regulators include, but are not limited to, acids and their solutions, such as hydroxy acids, for example lactic acid and tartaric acid; bases and their solutions, such as sodium hydroxide, calcium hydroxide, potassium hydroxide, ammonium hydroxide, etc.; and tertiary amines and their solutions, such as triethanolamine, tromethamine and tetrahydroxypropyl ethylenediamine; and buffers and their solutions, such as carbonate buffers, citrate buffers, phosphate buffers and acetate buffers, Tris buffers, etc.; or combinations thereof.

[0064] The transdermal composition of the present disclosure is preferably formulated such that the pH value is about 3 to 9, preferably the pH value is about 4 to 8 or about 5 to 7, more preferably the pH value is about 5.7. Sodium hydroxide is preferably used in the present transdermal composition as a pH adjuster and can be present in the composition from about 0.01% to 0.4% wt / wt, preferably from about 0.015% to 0.03% wt / wt, more preferably around 0.028% wt / wt.

[0065] This percutaneous composition can further contain an additional penetration enhancer. Examples of the additional penetration enhancer include, but are not limited to, glycol, monoalkyl ethers of diethylene glycol, fatty alcohols, acetone, acyl lactylates, acyl peptides, acyl sarcosinates, alkanolamine salts of fatty acids, alkylbenzene sulfonates, alkyl ether sulfates, alkyl sulfates, anionic surface-active agents, benzyl benzoate, benzyl salicylate, butane-1,4-diol, butyl benzoate, butyl laurate, butyl myristate, butyl stearate, cationic surface-active agents, citric acid, cocoamidopropyl betaine, decyl methyl sulfoxide, decyl oleate, dibutyl azelate, dibutyl phthalate, dibenzyl sebacate, dibutyl sebacate, dibutyl suberate, dibutyl succinate, dicapryl adipate, didecyl phthalate, diethylene glycol, diethyl sebacate, diethyl-m-toluamide, di(2-hydroxypropyl) ether, diisopropyl adipate, diisopropyl sebacate, N,N-dimethylacetamide, dimethyl azelate, N,N-dimethylformamide, 1,5-dimethyl-2-pyrrolidone, dimethyl sebacate, dimethyl sulfoxide, dioctyl adipate, dioctyl azelate, dioctyl sebacate, 1,4-dioxane, 1-dodecylazacycloheptan-2-one, dodecyldimethylamine oxide, ethyl caprate, ethyl caproate, ethyl caprylate, 2-dehyl-hexyl pelargonate, ethyl 2-hydroxypropanoate, ethyl laurate, ethyl myristate, 1-ethyl-2-pyrrolidone, ethyl salicylate, hexyl laurate, 2-hydroxyoctanoic acid, 2-hydroxypropanoic acid, 2-hydroxypropionic acid, isethionate, isopropyl isostearate, isopropyl palritate, guar hydroxypropyltrimonium chloride, hexane-2,5-diol, kheliin, lamepon®, lauryl alcohol, maypon, metal salts of fatty acids, methyl nicotinate, 2-methylpropan-2-ol, 1-methyl-2-pyrrolidone, 5-methyl-2-pyrrolidone, methyl tauride, miranol®, nonionic surfactants, octyl alcohol, octylphenoxypolyethoxyethanol, oleic acid ethanolamide, pleyl alcohol, pentane-2,4-diol, phenoxyethanol, phosphatidylcholine, phosphine oxides, polyalkoxylated ether glycolates, poly(diallylpiperidinium chloride), poly(dipropyldiallylammonium chloride), polyglycerol esters, polyoxyethylene lauryl ether, polyoxy:polyoxyethylene stearate, polyoxypropylene 15 stearyl ether, poly(vinylpyridinium chloride), propan-1-ol, propan-2-ol, propylene glycol diperargonate, pyroglutamic acid, 2-pyrrolidone, pyruvic acid, quaternium 5, quaternium 18, quaternium 19, quaternium 23, quaternium 31, quaternium 40, quaternium 57, quaternary amine salts, quaternized poly(dimethylaminoethyl methacrylate), quaternized poly(vinyl alcohol), sapamin hydrohloride, sodium cocoaminopropionate, sodium dioctyl sulphonsuccinate, sodium laurate, sodium lauryl ether sulphate, sodium lauryl sulphate, sugar esters, sulphonosuccinates, tetrahydrofuran, tetrahydrofurfuryl alcohol, transcutol®, triethanolamine dodecylbenzenesulphonate, triethanolamine oleate, urea and its derivatives, and mixtures thereof can be mentioned. As the penetration enhancer described above, C, 2 ~C 4In addition to alcohol, preferably ethanol, a skin softening agent and / or a moisturizing agent, an additional penetration enhancer may be present in the composition, and depending on the type of penetration enhancer used, it ranges from about 0.2% to 3.0% wt / wt of the composition, preferably from about 0.5% to 2.0% wt / wt.

[0066] The composition can further include one or more additives, and examples of such additives include, but are not limited to, humectants, deodorants, antiperspirants, preservatives, antioxidants, emulsifiers, occlusive agents, solubilizers, and surfactants. The additives can be present from about 0% to 10% wt / wt% of the composition, preferably from about 0% to 5% wt / wt. The type and amount of the additives can be determined by those skilled in the art using conventional methods.

[0067] Examples of humectants include, but are not limited to, glycerin, propylene, glycol, sorbitol, and triacetin, as suitable ones that can be used in the context of the present composition.

[0068] As antiseptics, representative examples that can be used in the context of the compositions of the present disclosure include, but are not limited to, quaternary ammonium compounds such as cetyltrimethylammonium bromide, cetylpyridinium chloride, benzethonium chloride, diisobutylphenoxyethoxyethyldimethylbenzylammonium chloride, sodium N-lauroylsarcosinate, sodium N-palmithyl sarcosinate, lauroyl satcosine, N-myristoyl glycine, potassium N-lauroylsarcosinate, stearyl trimethylammonium chloride, sodium aluminum chlorohydroxylactate, tricetylmethylammonium chloride, 2,4,4'-trichloro-2'-hydroxydiphenyl ether, diaminoalkylamides such as L-lysine hexadecylamide, heavy metal salts of citric acid, salicylic acid and piroctose, especially zinc salts, and heavy metal salts of these acids, especially zinc pyrithione and zinc phenolsulfate. Other antiseptics include, but are not limited to, odor-absorbing substances such as carbonates and bicarbonates, for example carbonates and bicarbonates of alkali metals, carbonates and bicarbonates of ammonium and tetraalkylammonium, especially sodium and potassium salts, or any combination thereof.

[0069] The antiperspirant can be incorporated into the composition either in solubilized form or in particulate form, and examples include astringent salts or complexes of aluminum or zirconium.

[0070] As preservatives, suitable ones that can be used in the context of the present composition include, but are not limited to, one or more alkanols, disodium EDTA (ethylenediaminetetraacetate), EDTA salts, EDTA fatty acid conjugates, isothiazolinone, parabens such as methylparaben and propylparaben, propylene glycol, sorbate, urea derivatives such as diazolindinyl urea, or any combination thereof.

[0071] As antioxidants, suitable ones that can be used in the context of this composition include, but are not limited to, tocopherol and derivatives, ascorbic acid and derivatives, butylated hydroxyanisole, butylated hydroxytoluene, fumaric acid, malic acid, propyl gallate, metabisulfate and derivatives, and mixtures thereof.

[0072] As emulsifiers, suitable ones that can be used in the context of this composition include, but are not limited to, one or more sorbitans, alkoxylated fatty alcohols, alkyl polyglycosides, soaps, alkyl sulfates, monoalkyl and dialkyl phosphates, alkyl sulfonates, acyl isothionates, or any combination thereof.

[0073] As occlusives, suitable ones that can be used in the context of this composition include, but are not limited to, petrolatum, mineral oil, beeswax, silicone oil, lanolin and oil-soluble lanolin derivatives, saturated and unsaturated fatty alcohols such as behenyl alcohol, hydrocarbons such as squalane, and various animal and vegetable oils such as almond oil, peanut oil, wheat germ oil, linseed oil, jojoba oil; apricot kernel, walnut, palm nut, pistachio nut, sesame seed, rapeseed oil; castor oil, corn oil, peach kernel oil, poppy seed oil, pine oil, castor oil, soybean oil, avocado oil, safflower oil, coconut oil, hazelnut oil, olive oil, grape seed oil and sunflower seed oil, etc.

[0074] Examples of solubilizers that can be used in the context of the present composition include, but are not limited to, complex-forming solubilizers such as citric acid, ethylenediaminetetraacetate, sodium metaphosphate, succinic acid, urea, cyclodextrin, polyvinylpyrrolidone, diethylammonium - ortho - benzoate, etc., and micelle - forming solubilizers such as tween (registered trademark) and span, for example, TWEEN80. Other solubilizers that can be used in the composition of the present disclosure include, for example, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene n - alkyl ethers, n - alkylamine n - oxides, poloxamers, organic solvents, phospholipids, and cyclodextrins.

[0075] The present composition can further contain an anionic, nonionic or cationic surfactant.

[0076] A transdermal composition in unit dosage form containing about 8.3 mg of NES, about 73.8 mg of T, and a pharmaceutically acceptable excipient can have a gel form with a volume of 1 - 10 mL, preferably 4 - 8 mL, more preferably 5 mL. When such a unit dosage gel form is applied once a day to the body surface of a male, the absorption rate in the subject can be about 830 μg / day for NES and 7.38 mg / day for T.

[0077] Examples of the body surface of a male include, but are not limited to, the abdomen, axilla, arm, back, thigh, and shoulder, preferably the upper arm and shoulder.

[0078] The gel preparation is preferably packaged in any suitable container, such as an extrudable tube, syringe, etc., on which the usage method is indicated and which can be directly extruded or dispensed onto the body surface of a male. The volume of the gel preparation contained in such a form is selected to be convenient and preferable, such as constituting a predetermined dose, for example, one dose per day or two or more doses per day, in order to facilitate the administration of a desired controlled dose. The package can be initially sealed and opened during use. When there are doses exceeding one dose, it is preferable that the package can be resealed by appropriate closing means.

[0079] A preferred package is a container, such as a canister, to which a dispensing pump that delivers a constant unit dose during operation is attached. Another preferred package is a small moisture- and air-impermeable pack containing a unit dose. The contents in the small pack can be extruded in a form that can be directly applied onto the body surface of a male.

[0080] On the other hand, as described above, it is also possible to use other preparations suitable for the transdermal delivery of the two steroids NES and T described in this specification. Transdermal delivery can be carried out by a transdermal patch, or by a transdermal spray, cream, ointment, aerosol, metered dose transdermal system (MTDS), or other passive or active transdermal devices for absorption through the skin surface. These cases are for transdermally applying the unit-dose form of the present composition, and in any of them, the required amounts of NES and T are decisive important factors regarding the present disclosure. The amounts are such that NES is 8.3 mg and T is 73.8 mg, and are respectively sufficient amounts to bring about an absorption of at least about 830 μg / day for NES and 7.38 mg / day for T in a daily dose. 20 - 30 cm 2Even a transdermal matrix patch that delivers both NES and T to the front and back surfaces, delivering approximately 830 μg / day for NES and 7.38 mg / day for T daily, can achieve the said objective. Therefore, a person skilled in the art can easily produce corresponding patches, sprays, ointments, aerosols, etc. by using a conventional system together with the specific active ingredients of the present disclosure described herein.

[0081] According to one aspect of the present disclosure, a method of male contraception is provided, and this method can include the step of applying a transdermal composition containing a combination of NES and T in a pharmacologically effective amount and a pharmaceutically acceptable excipient to the body surface of a male.

[0082] Regarding the transdermal composition used in such a method, it is as described above. The transdermal composition in unit dosage form can be applied 1 to 4 times a day at intervals, if necessary, even just once a day or over several days. The dosage level can be understood by a person skilled in the art. Preferably, the transdermal composition in unit dosage form can be applied once a day so as to be absorbed by the body at a rate of approximately 830 μg / day for NES and 7.38 mg / day for T. Preferably, a gel form with a volume of 1 to 10 mL, preferably 4 to 8 mL, more preferably 5 mL can be applied once a day.

[0083] Examples of the body surface of a male include, but are not limited to, the abdomen, armpit, arm, back, thigh, and shoulder, preferably the upper arm and shoulder.

[0084] As will be shown in detail in the examples described below, when the NES / T combination gel agent in a unit dosage form with a higher T concentration (73.8 mg) in a small volume (5 mL) per administration (8.3 mg / 73.8 mg) disclosed in the present disclosure is applied once a day to the upper arm and shoulder of a male, as a result, effective suppression of gonadotropin to less than 1.0 IU / L is obtained, and the serum NES level is similar to that obtained with a unit dosage form of the NES / T combination gel agent having a concentration of 8.3 mg / 62 mg in 5 mL of gel, which targets the suppression of gonadotropin and is disclosed in the literature of Anawalt et al.

[0085] In addition, from the sperm concentration test, the present transdermal composition in a unit dosage form with a higher T concentration (73.8 mg) in the NES / T combination gel agent (8.3 mg / 73.8 mg) was shown to suppress spermatogenesis faster than the composition in a unit dosage form used in the literature of Anawalt et al., that is, the composition in a unit dosage form with a lower T concentration (62 mg) in the NES / T combination gel agent (8.3 mg / 62 mg). For example, the suppression of spermatogenesis to less than 1.0 million / mL in subjects treated with the present composition in a unit dosage form containing the NES / T combination gel at a concentration of 8.3 mg / 73.8 mg occurred 8.9 days earlier on average in the subjects and 17.5 days earlier in 25% of the subjects compared to the case where the composition in a unit dosage form containing the NES / T combination gel at a concentration of 8.3 mg / 62.5 mg was used.

[0086] Furthermore, the subjects treated with the present transdermal composition (8.3 mg / 73.8 mg) in a unit dosage form with a higher T concentration (73.8 mg) in the NES / T combination gel showed almost no side effects, although the occurrence of adverse effects was expected.

[0087] Adding an appropriate dose of T to an established dose of NES will result in a transdermal delivery form for male contraception with the additional benefits discussed above.

Examples

[0088] [Preparation of NES / T Gel Agents with Low T and High T] All the excipients used in this composition are well-known substances and are described in both Ph.Eur. and USP / NF, which are generally widely used in the case of topical preparations.

[0089] Using the components described in Table 1 below, a unit-dose form of NES / T gel agent with a low T concentration was prepared.

[0090] JPEG2025516643000002.jpg109170

[0091] The low T concentration NES / T gel agent contained NES and T at 0.19% wt / wt and 1.43% wt / wt, respectively.

[0092] Using the components described in Table 2 below, a unit-dose form of NES / T gel agent with a high T concentration was prepared.

[0093] JPEG2025516643000003.jpg109170

[0094] The high T concentration NES / T gel agent contained NES and T at 0.19% wt / wt and 1.697% wt / wt, respectively.

[0095] Each NES / T gel was prepared according to the following procedure. The 0.1N sodium hydroxide solution was prepared by dissolving sodium hydroxide in water. The ethanol aqueous solution was prepared by mixing ethanol and water, and isopropyl myristate was added to this ethanol solution. After the isopropyl myristate was dissolved, NESTORONE (registered trademark) was added. This mixture was stirred until NESTORONE (registered trademark) was dissolved. Subsequently, testosterone was added, and the resulting mixture was stirred until testosterone was dissolved. The remaining water was added to this solution and further mixed until visually homogeneous. Then Carbopol 980 was added, and this mixture was stirred until completely hydrated. The previously prepared 0.1N sodium hydroxide solution was added to this hydrated gel and mixed to complete the bulk compounding of the NES / T gel.

[0096] [Treatment with Low-T and High-T NES / T Gels] Male subjects were selected based on their general and reproductive medical histories as being in good health and randomly assigned to a low-T group and a high-T group. The former group was administered a low-T concentration NES / T gel containing a low T concentration (NES 8.3 mg / T 62.5 mg in unit dosage form), and the latter group was administered a high-T concentration NES / T gel having a high T concentration (NES 8.3 mg / T 73.8 mg in unit dosage form), once daily over the efficacy phase.

[0097] At the time of test registration visit, sufficient gel was supplied to male subjects to last until the next visit. The gel was provided in the form of a metered pump canister containing a sufficient amount for 30 applications, i.e., an appropriate amount for two weeks. The pump canister was returned at each visit, and weighing for the purpose of test drug management was performed using a central calibrated scale at the clinical trial facility. The metered pump canister of the NES / T combination gel is designed such that 2.5 mL of gel is dispensed when the male subject operates the pump once. Once the gel is dispensed onto the palm of one hand, the subject is then asked to gently apply it to the skin of the opposite upper arm and shoulder. By repeating this process using the other hand and applying it to the opposite arm and shoulder, a total of 5 mL of gel is applied daily.

[0098] At the registration visit, detailed instructions for the application of the gel using a metered pump canister were also provided to male subjects. The first administration of the low T / high T gel was applied under the direct observation of the study staff at the registration visit. The start date and time of the treatment were recorded in the source documents.

[0099] Male subjects were provided with a male daily study medication log, which is for male subjects to record weekly the date and time of gel application, any changes that occurred at the application site, as well as any medications used and / or medical problems noticed. This study medication log was checked and collected at each visit. Data on medications and adverse events recorded by male subjects were collected and recorded in the source documents.

[0100] During the suppression phase, male subjects applied the low T / high T gel once a day, but relied on another method for contraception during this period when sperm levels were suppressed. During the efficacy evaluation phase, the couple did not use any other contraceptive methods and relied solely on the method of the male partner applying the low T / high T gel once a day for pregnancy prevention.

[0101] The low T / high T gel agent was applied to male subjects every morning according to the following protocol. The gel agent shall be applied daily, every morning at approximately the same time, usually after shower, to clean and dry skin. The cap of the pump canister shall not be removed until the male participant is ready to use the gel agent. The male participant shall wash his hands and then press the pump to dispense the gel agent into his hand. The male participant shall press the pump once to dispense an appropriate amount of the gel agent onto the palm of one hand and then gently apply the gel agent to the skin of the opposite upper arm and shoulder. The application sites are indicated by the shaded areas in the drawing. Repeat this process using the other hand to meet the prescribed daily dose of the gel agent in combination with the opposite upper arm and shoulder. If it is noticed that the administration has been forgotten, apply it immediately. If the application site is dry, cover that area with clothing. After each application of the gel agent, wash the hands and wrists carefully with soap and water. Avoid fire, flame or smoking until the gel agent is dry. Male study participants shall avoid swimming, showering or washing the application site for at least 2 hours after application. Once the gel agent is dry, wear clothing over the gel agent application area or take a shower before close skin contact with a female or child. The application intervals of the gel agent shall be at least 8 hours apart.

[0102] Blood samples of the subjects were collected every 4 weeks (28 days) of treatment and subjected to pharmacokinetic tests and safety assessments, such as hormone assays (e.g., NES and T concentrations in serum), laboratory tests related to safety (e.g., complete blood count, metabolic panel, cholesterol panel and PSA, etc.), and semen analysis (e.g., sperm concentration, etc.). The subjects were also provided with a drug administration record tool for any observable side effects, such as headache, mood swings and acne, etc.

[0103] In the following Table Y, the total number of subjects registered in this test, those whose sperm count reached ≤ 1 million, and those incorporated into the efficacy evaluation phase were recorded.

[0104] JPEG2025516643000004.jpg48170

[0105] In Table Y, among the registered subjects assigned to the low T concentration formulation, the number of subjects with sperm suppression (sperm count ≤ 1 million) was 72.2%. In contrast, for those assigned to the high T concentration formulation, the number of subjects with sperm suppression (sperm count ≤ 1 million) was 81.7%. It has been shown that when using the high T concentration formulation, a difference of 9.5% is brought about compared to when using the low T concentration formulation. Furthermore, the number of subjects incorporated into the efficacy evaluation phase was 63.0% for the low T concentration formulation and 73.2% for the high T concentration formulation, respectively. Since it is known that sperm suppression is directly related to the NES concentration, it was expected that sperm suppression and incorporation into the efficacy evaluation phase would be independent of the T concentration. However, Table Y shows a clear difference in sperm suppression and incorporation into the efficacy evaluation phase between the low T concentration formulation and the high T concentration formulation. The excellent performance of the high T concentration formulation of the present disclosure is extremely different and unexpected.

[0106] The following Table 3 shows the eligible subjects in the low T group and the high T group respectively, and the number of days required to reach the low sperm concentration from the registration date for those subjects who first had a sperm concentration of 1 million / ml or less at the 17 - week time point or earlier.

[0107] JPEG2025516643000005.jpg56170

[0108] Table 3 shows a summary of the number of days from registration until sperm suppression with a concentration ≤ 1 million / mL was first observed in both the low-T and high-T groups. Looking at the eligible subjects, suppression of sperm production to ≤ 1 million / mL occurred, on average, 8.9 days earlier in the high-T concentration formulation group compared to the low-T concentration formulation group. Additionally, in 25% of the subjects, suppression of sperm production to ≤ 1 million / mL occurred 17.5 days earlier in the high-T concentration formulation group compared to the low-T concentration formulation group.

[0109] Suppression of LH, FSH, and sperm production has been found to be achieved by NESTORONE®. The NESTORONE® concentration was kept the same in both the low-T and high-T concentration formulations. Therefore, it was expected that the rate of achieving sperm suppression would be equivalent. However, quite unexpectedly, faster achievement of sperm suppression was observed in the high-T concentration formulation in the form of the NES 8.3 mg / T 73.8 mg gel.

[0110] Table 4 below summarizes and shows the side effects observed in the subjects in the low-T and high-T groups, respectively.

[0111] JPEG2025516643000006.jpg130170

[0112] Table 4 shows an extremely unexpected result that the high T concentration formulation group has a lower number of AE expressions compared to the low T concentration formulation group. In the low T group, 91.9% of the subjects reported at least one AE, while in the high T group, only 86.2% of the subjects reported it. The subset of all disorders / categories defined by the Medical Dictionary of Regulatory Activities is also shown in Table 4 above. It was expected that the high T formulation with increased T concentration would cause more AEs, but the incidence rates of AEs related to the hormonal increase of T concentration, such as headache, mood change, and acne, were greatly affected by the decrease in the number of AEs in the high T formulation. Among these, an extremely unexpected outcome obtained from the data was, for example, that in the high T group, the incidence rate of acne was lower than that in the low T group. In addition, the high T group's test seemed to have a lower test discontinuation rate.

[0113] Ilani et al. (2012) reported that the most frequently observed adverse event when using 100 mg of T was acne, which occurred in 21% of the subjects. Anawalt et al. (2019) disclosed that when using a lower dose of T (62.5 mg), androgenic acne was reduced and minimized. It was expected that such a lower dose of T would reduce the incidence rate of acne. In fact, Table 4 above shows that when treated with 62.5 mg of T in the NES 8.3 mg / T 62.5 mg gel formulation, acne occurred in 17.6% of the subjects. However, even more surprisingly, the inventors found that when using a high T concentration formulation in the form of the NES 8.3 mg / T 73.8 mg gel formulation, the occurrence of acne was significantly reduced. The high T group showed an acne incidence rate of only 10%, while the low T group showed an acne incidence rate of 17.6%. This was completely contrary to what those skilled in the art had expected, namely, the expectation that acne would increase if T was added.

Industrial Applicability

[0114] The present disclosure provides a composition for male contraception. This particular composition and its amount can preferably be provided in the form of a gel agent, a transdermal product that can be easily and advantageously applied to the male body surface to achieve an outcome of effective and reversible contraception.

Claims

1. A transdermal composition for male contraception comprising approximately 0.1% to approximately 0.3% w / w of 16-methylene-17α-acetoxy-19-norpregna-4-ene-3,20-dione, approximately 1.0% to approximately 2.5% wt / wt of testosterone, and a pharmaceutically acceptable excipient.

2. The transdermal composition for male contraception according to claim 1, wherein the 16-methylene-17α-acetoxy-19-norpregna-4-ene-3,20-dione is contained in an amount of about 0.15% to about 0.25% w / w, and the testosterone is contained in an amount of about 1.4% to 2% wt / wt.

3. The transdermal composition for male contraception according to claim 1, comprising 16-methylene-17α-acetoxy-19-norpregna-4-ene-3,20-dione in an amount of about 0.19% w / w and testosterone in an amount of about 1.697% wt / wt.

4. A transdermal composition for male contraception according to claim 1, which is in gel form.

5. A transdermal composition in unit dose form for male contraception, comprising approximately 7 mg to approximately 12 mg of 16-methylene-17α-acetoxy-19-norpregna-4-ene-3,20-dione, approximately 60 mg to approximately 100 mg of testosterone, and pharmaceutically acceptable excipients.

6. The transdermal composition in a unit dose form according to claim 5, wherein the 16-methylene-17α-acetoxy-19-norpregna-4-ene-3,20-dione is contained in an amount of about 8 mg to about 10 mg, and the testosterone is contained in an amount of about 70 mg to about 85 mg.

7. The transdermal composition in a unit dose form according to claim 5, wherein the 16-methylene-17α-acetoxy-19-norpregna-4-ene-3,20-dione is contained in an amount of about 8 mg to about 8.5 mg, and the testosterone is contained in an amount of about 73.5 mg to about 74.5 mg.

8. The transdermal composition in a unit dose form according to claim 5, wherein the 16-methylene-17α-acetoxy-19-norpregna-4-ene-3,20-dione is contained in an amount of about 8.3 mg and the testosterone is contained in an amount of about 73.8 mg.

9. A transdermal composition in a unit dose form according to claim 5, which is in gel form.

10. A gel-type transdermal composition, C ２ ~C ４ A transdermal composition in a unit dose form according to claim 9, which is an alcohol-containing aqueous alcohol gel.

11. Said C ２ ~C ４ The transdermal composition in a unit dose form according to claim 10, wherein the alcohol is ethanol.

12. Said C ２ ~C ４ A transdermal composition in a unit dose form according to claim 10, comprising alcohol in an amount of 50% to 85% wt / wt.

13. The transdermal composition in a unit dose form according to claim 5, wherein the excipient comprises a penetration enhancer.

14. The transdermal composition in unit dose form according to claim 13, wherein the penetration enhancer is isopropyl myristate.

15. Use of the transdermal composition according to claim 1 for manufacturing a formulation for male contraception to be applied to the body surface of a male.

16. Use of the transdermal composition according to claim 5 for manufacturing a formulation for male contraception to be applied to the body surface of a male.

17. The use according to claim 16, wherein the formulation is applied to the surface of a man's body once a day.

18. The use according to claim 16, wherein the unit dose form of the transdermal composition comprises about 8 mg to about 8.5 mg of 16-methylene-17α-acetoxy-19-norpregna-4-ene-3,20-dione and about 73.5 mg to about 74.5 mg of testosterone.

19. The unit dose form of the transdermal composition comprises about 8.3 mg of the 16-methylene-17α-acetoxy-19-norpregna-4-ene-3,20-dione and about 73.8 mg of the testosterone, as used in claim 16.

20. The transdermal composition is in gel form, as used in claim 16.

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