Progestational hormone / testosterone transdermal gel

Abstract

The present invention relates to a specific combination of progestational hormone and testosterone in a transdermal composition and its use in a method to ensure more effective male contraception with less side effects.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims priority to U.S. Provisional Patent Application No. 63 / 339,563, filed on May 9, 2022, the disclosure of which is incorporated herein by reference.

[0003] This invention was made with government support from the National Institutes of Health (NIH) under Grants HHSN27520130024I and HHSN275201500002I / HHSN275000010. The government has certain rights in this invention. Technical Field

[0004] The present invention relates to a specific combination of a progestogen and a testosterone in a transdermal composition for use in ensuring a male contraceptive method with additional health benefits. Background Art

[0005] Approximately 45% of pregnancies worldwide are unintended, resulting in adverse health outcomes, including maternal morbidity and mortality, as well as a significant societal burden. While many contraceptive methods are available to women, male contraceptive options are limited to withdrawal methods, condoms, and vasectomy. Condom use is inconsistent, with a typical failure rate of 13%, while vasectomy requires surgery and is not easily and reliably reversible.

[0006] Several reversible male hormonal contraceptive regimens have been tested in clinical studies, using testosterone alone or testosterone combined with a progestin.

[0007] Testosterone (referred to in this disclosure as T) is a male sex hormone produced in the testicles. It plays a vital role in the development of male genitalia in utero and during puberty. Testosterone hormone levels are important for normal male sexual development and function. It has been found that exogenous testosterone can be used in testosterone replacement therapy to treat symptoms of hypogonadism, such as loss of libido, depressed mood, and erectile dysfunction. For example, (FDA-approved testosterone gel formulation) 1.62% is a prescription topical medication used to treat symptoms of testosterone deficiency. The dose can be adjusted between a minimum of 20.25 mg testosterone (one pump actuation or a single 20.25 mg packet) and a maximum of 81 mg testosterone (four pump actuations or four 20.25 mg packets). The dose should be titrated based on the pre-dose morning serum testosterone concentration approximately 14 days and 28 days after starting treatment or after dose adjustments. In addition, serum testosterone concentrations should be assessed regularly thereafter, and serum T levels should be maintained between 350 ng / dL and 750 ng / dL. Studies have found that the use of testosterone at pharmacologically high doses results in reduced sperm production because it inhibits the production of gonadotropin-releasing hormone (GnRH), which in turn inhibits the production of luteinizing hormone (LH) and reduces endogenous testosterone production by Leydig cells, resulting in reduced testicular testosterone concentrations. Inhibition of GnRH production also inhibits the release of follicle stimulating hormone (FSH), which regulates spermatogenesis in Sertoli cells. Spermatogenesis, assessed by seminal sperm concentration, is often used as the primary outcome for evaluating the effectiveness of male contraceptives. Male contraceptive regimens are considered effective in preventing pregnancy when sperm concentrations are less than 1 million sperm / mL of semen. 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, FertilSteril., 1996Apr;65(4):821-9.

[0008] Studies have shown that weekly intramuscular injections of 200 mg / week of testosterone enanthate (a high pharmacological dose of testosterone ester) for 12 months have been shown to be a very effective contraceptive method with only 0.8 pregnancies per 100 person-years of exposure.

[0009] Progestins are synthetic progestogens most commonly used in female hormonal contraception and in hormone replacement therapy to prevent endometrial hyperplasia from estrogen resistance. The compound called 16-methylene-17α-acetoxy-19-norpregn-4-ene-3,20-dione or norgestrel acetate is a progestogen (also known by the trade name NES (NES) is a 19-norprogesterone derivative with a structure close to the physiological hormone progesterone. NES has strong antiovulatory and progestogenic properties and does not have androgenic, estrogenic or glucocorticoid effects at up to 2000 times the therapeutic level. In view of its high antiovulatory efficacy when administered systemically, it is believed that only very low doses of NES are required to achieve contraceptive effects, so it can be used in various non-oral drug delivery systems. Non-oral forms of NES have been widely studied, including transdermal gels, implants, and vaginal rings for female contraception. It has been approved by the U.S. Food and Drug Administration as a vaginal system for female contraception, used in combination with estrogen.

[0010] In men, studies have shown that the addition of progestin to T increases the rate and extent of spermatogenesis suppression. For example, Mahabadi et al. in "Combined Transdermal Testosterone Gel and the ProgestinNestorone Suppresses Serum Gonadotropins in Men" (J. Clin. Endocrinol Metab., July 2009, 94 (7), 2313-2320) disclosed that during a 20-day treatment period, transdermal NES gel (containing 6 or 8 mg / day of NES) and T gel (10 g / day of 1%, containing 100 mg / day of T), delivered 600 or 800 μg / day of NES and 10 mg / day of T to the body (approximately 10% of the steroid dose applied to the skin was absorbed), suppressing serum gonadotropins to 0.5 IU / liter or less in men using either gel alone. However, acne was reported in 10% of the subjects, and HDL cholesterol levels were lower in all T (alone or combined with NES 100 mg / d) gel treatment groups than in the NES alone group, suggesting that this reduction may be due to T administration. Large interindividual variability in serum total and free T concentrations was observed in all T gel treatment groups, with some subjects having serum T levels above the normal range. Mahabadi et al. suggested that lower doses of T may be needed to avoid high serum T levels and reduce HDL cholesterol levels. Serum gonadotropin in the Mahabadi study was used as a surrogate marker for spermatogenesis suppression, and it was assumed that the male contraceptive regimen was considered effective for preventing pregnancy when it was 1.0 IU / liter or less.

[0011] Ilani et al. later disclosed in "A New Combination of Testosterone and Nestorone Transdermal Gels for Male Hormonal Contraception" (J. Clin. Endocrinol Metab., October 2012, 97 (10), 3476-3486) the combined use of NES gel (containing 8 or 12 mg / day of NES) and T gel (10 g / day of 1%, containing 100 mg / day of T) for at least 20 weeks, delivered 800 or 1200 μg / day of NE and 10 mg / day of T to the body (about 10% of the steroid dose applied to the skin was absorbed), suppressing sperm concentrations to 1 million / mL or less in men than those using T gel alone. There was a wide variation in serum T levels within and between subjects. Three subjects had T concentrations exceeding 1800 ng / dl more than twice. In addition, acne was the most common adverse event, occurring in 21% of the subjects.

[0012] To predict who will respond to the NES / T gel hormonal contraceptive method, Roth et al. in “Characteristics associated with suppression of spermatogenesis in a malehormonal contraceptive trial using testosterone and gels”(Andrology, 2013 November, 1(6), 899-905) analyzed the research data in Ilani's paper. They concluded that serum The concentration of β-catenin was significantly correlated with the inhibition of spermatogenesis, while the concentration of serum T was not.

[0013] Anawalt et al. further pointed out in "Combined nestorone-testosterone gel suppresses serum gonadotropins to concentrations associated with effective hormonal contraception in men" (Andrology, November 2019, 7(6), 878-887) that a single gel formulation of 5 mL of gel containing 8.3 mg NES / 62.5 mg T per day during 28 days of treatment suppressed FSH and LH concentrations to ≤1.0 IU / L in more men compared with 4.4 mL of gel containing 62.7 mg T per day. Although the mean serum total T concentration (TC avg ) remained within the normal physiological range (300-1000 ng / dL) throughout the treatment period, but after the second day, the maximum serum total T content (TC max ) was above the normal physiological range. Similarly, in the study by Anawalt, serum gonadotropin was used as a surrogate marker for spermatogenesis inhibition. However, Anawalt did not show any study on the inhibition of sperm concentration by the 8.3 mg NES / 62.5 mg T gel combination.

[0014] There is a need to develop a safe, effective, reversible and easy-to-use male contraceptive method. This requires a way to find a formulation that reduces sperm count while maintaining testosterone levels within the normal range. Summary of the invention

[0015] The present disclosure provides a transdermal composition in unit dosage form for male contraceptive treatment, comprising about 7 mg to about 12 mg of 16-methylene-17α-acetoxy-19-norpregn-4-ene-3,20-dione, about 60 mg to about 100 mg of testosterone, and a pharmaceutically acceptable excipient.

[0016] The transdermal composition in unit dosage form may contain from about 8 mg to about 10 mg of 16-methylene 17α-acetoxy-19-norpregn-4-ene-3,20-dione and from about 70 mg to about 85 mg of testosterone.

[0017] The transdermal composition in unit dosage form may contain from about 8 mg to about 8.5 mg of 16-methylene 17α-acetoxy-19-norpregn-4-ene-3,20-dione and from about 73.5 mg to about 74.5 mg of testosterone.

[0018] A transdermal composition in unit dosage form may contain about 8.3 mg of 16-methylene 17α-acetoxy-19-norpregn-4-ene-3,20-dione and about 73.8 mg of testosterone.

[0019] The transdermal composition in unit dosage form may be in the form of a gel.

[0020] The transdermal composition in unit dosage form may be in the form of a hydroalcoholic gel comprising a C2 to C4 alcohol.

[0021] Transdermal compositions in unit dosage form may contain ethanol.

[0022] The transdermal composition in unit dosage form may comprise 50% to 85% wt / wt of the C2 to C4 alcohol.

[0023] Transdermal compositions in unit dosage form may also contain a penetration enhancer.

[0024] The transdermal composition in unit dosage form may also contain a penetration enhancer, namely isopropyl myristate.

[0025] The present disclosure also provides a method for male contraceptive treatment, comprising applying the transdermal composition in unit dosage form disclosed herein to the male body surface.

[0026] The transdermal composition in unit dosage form can be applied to the male body surface once a day.

[0027] The transdermal composition in unit dosage form may be applied to the surface of the upper arm or shoulder. BRIEF DESCRIPTION OF THE DRAWINGS

[0028] The nature and details of the present disclosure may be more fully understood with reference to the following detailed description, which in turn refers to the accompanying drawings, as shown below:

[0029] The figure shows the site of gel application on a male subject. DETAILED DESCRIPTION

[0030] Before describing in detail at least one embodiment of the present invention, it should be understood that the application of the present invention is not limited to the details set forth in the following description or the details illustrated by the examples. The present invention can have other embodiments, or can be practiced or implemented in various ways. Therefore, it should be understood that various modifications can be made to the exemplary embodiments, and other arrangements can be designed without departing from the spirit and scope of the present disclosure. It should also be understood that the wording and terminology used herein are for descriptive purposes only and should not be considered as limiting.

[0031] Unless otherwise specified herein, all percentages and ratios used herein are by weight of the total composition. Unless otherwise specified, all measurements herein are made at 25°C and normal pressure. Unless otherwise specified, all temperatures used herein are in degrees Celsius.

[0032] The present disclosure may include (open) the components described herein and other ingredients or elements, or be substantially composed thereof. As used herein, the term "comprising" refers to having the described elements, or their structural or functional equivalents, as well as any other elements not mentioned. Unless the context otherwise indicates, the terms "having" and "including" used herein should also be interpreted as open. The terms "comprising", "having" and "including" include the terms "consisting of" and "consisting essentially of". The term "consisting essentially of" herein means that the composition or method may include additional ingredients and / or steps, but the premise is that these additional ingredients or steps will not substantially change the characteristics of the claimed composition or method.

[0033] All ranges described herein include the endpoints and the ranges between the endpoints. Terms such as "about", "generally", "substantially" and the like should be interpreted as modifying the term or value so that it is not absolute, but not applicable to the prior art. These terms are defined by the circumstances understood by those skilled in the art and the terms they modify. This includes at least the degree of expected experimental error, technical error, and instrumental error for a given technology used to measure the value. Unless otherwise stated, the term "about" as used herein includes all values ​​within the range of ±10% of the specific value shown.

[0034] Unless otherwise indicated, as used herein, the terms "a" and "an" include plural references, for example, "an excipient" may refer to at least one excipient, as well as a plurality of excipients, including but not limited to different types of excipients.

[0035] As used herein, the term "and / or" when used in a list of two or more items means 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 comprising agents A, B, and / or C, the composition may comprise only A alone; B alone; C alone; 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.

[0036] The term "contraceptive" as used herein refers to a drug taken to prevent or reduce the possibility of pregnancy. The "contraceptive" disclosed herein may refer to one contraceptive, or a combination of two or more contraceptives.

[0037] As used herein, the terms contraceptive "treat," "treatment," or "therapy" refer to the administration of the present compositions to prevent or reduce the likelihood of pregnancy.

[0038] According to the present disclosure, the use of the terms "transdermal" or "topical" is meant to include transdermal (or transdermal) administration, that is, the delivery of active agents and other pharmaceutical compositions through the skin tissue into the blood by gels, creams, ointments, pastes, foams, swabs, gauzes, pads, lotions, sprays, aerosols, patches, etc.

[0039] Transdermal administration of active agents has many advantages over conventional oral administration. Advantages of transdermal systems include bypassing the portal circulation, thereby eliminating first-pass metabolism in the liver, convenient, uninterrupted treatment, improved patient compliance, reversibility of treatment (by removing the transdermal system from the skin), and direct delivery of the drug into the systemic circulation at a constant rate, and an extended half-life due to the skin reservoir effect.

[0040] One method of transdermal drug delivery involves the use of a patch that relies on diffusion of the active agent through a membrane. Many transdermal patch delivery systems are known, all of which include at least one adhesive layer for attaching the patch to the target site.

[0041] Gel formulations used herein refer to a form of composition that can be used to topically apply agents in a consistent manner, which helps to deliver the composition with minimal loss when delivering. Gels that are easy to apply should not be too thin, too greasy, or inconvenient for patients to use. Hydrogels are a macromolecular network that absorbs water and swells, but are insoluble in water due to the presence of hydrophilic functional groups that provide water absorption and cross-linked polymers that cause water insolubility. Aqueous alcohol gels (also referred to herein as hydroalcohol gels) are hydrogels with high alcohol concentrations. These gels have the advantage of being easy to administer. At the application site, alcohol, as a carrier or enhancer, allows skin penetration, then evaporates, and it is believed that the drug becomes supersaturated. The skin acts as a reservoir for the drug, which is delivered to the systemic blood circulation at a relatively constant rate over a period of several hours.

[0042] As used herein, the terms "active," "pharmacologically active," "therapeutically active," "pharmaceutically active," or "physiologically active" to describe an "ingredient" or "agent" refer to any chemical material or compound, alone or in combination, suitable for administration, such as transdermal administration, to induce a desired systemic effect.

[0043] As used herein, the terms "effective," "pharmacologically effective," "therapeutically effective," "pharmaceutically effective," or "physiologically effective" amount of an active agent refers to a nontoxic but sufficient amount of the compound, alone or in combination with one or more other compounds, to provide the desired therapeutic effect.

[0044] As used herein, the terms "synergy", "synergism", "synergistic effect" or "synergistic action" refer to the effect of the interaction of the actions of two agents so that the result of the combined action is greater than the expected result of the simple addition of the two agents acting alone.

[0045] As will be appreciated by those skilled in the art, the effective amount of the contraceptive used in the composition or the actual weight percentage of such agents may vary according to various factors, including, for example, the actual contraceptive activity of each agent in the composition for the treatment target, the synergistic effect of the combination of two or more such agents, the formulation of the composition, and the delivery mode of the composition. Other factors that need to be considered when determining the dosage of the active contraceptive are familiar to those skilled in the art, including the actual dosage form and delivery mode of the composition, such as whether the dosage form is used for extended release. Such activity can be determined according to conventional methods and the amount of the correspondingly formulated active agent.

[0046] As used herein, the term "unit dosage form" refers to a composition in a form that is administered to a subject in a single dosage.

[0047] As used herein, the term "daily dose" refers to the daily dosage of any active agent used alone or in combination in the composition to provide the desired therapeutic effect.

[0048] The term "pharmaceutically acceptable excipient" as used herein refers to carriers or vehicles, gelling agents or thickening agents, suspending agents, emollients, humectants, solubilizing agents, stabilizers, pH adjusters, penetration enhancers and preservatives that do not cause significant irritation to an organism and do not abrogate the biological activity and properties of the active agent being used.

[0049] The term "carrier" or "vehicle" as used herein refers to carrier materials suitable for transdermal administration, including any such materials known in the art, such as any liquid, gel, solvent, liquid diluent, solubilizer, etc., which are non-toxic and do not interact with other components of the composition in a deleterious manner. Examples of suitable carriers include water, alcohol, mineral oil, silicone, liquid sugars, waxes, petrolatum, and various other oils and polymeric materials.

[0050] As used herein, the term "penetration enhancer" refers to a material that helps increase the permeability of the skin to a pharmacologically active agent, thereby increasing the rate at which the pharmacologically active agent penetrates through the skin and enters the bloodstream.

[0051] NES, referred to in this disclosure as NES, is a progestogen, a synthetic 19-norprogesterone derivative. It is 16-methylene-17α-acetoxy-19-norpregn-4-ene-3,20-dione, and its structure is similar to the physiological hormone progesterone. NES has strong anti-ovulatory, anti-gonadotropic and progestogenic properties, and does not have androgenic, estrogenic or glucocorticoid effects at therapeutic levels.

[0052] Testosterone, referred to in this disclosure as T, is a male sex hormone produced in the testicles. It has been approved as a replacement therapy and is available in gel form (such as ) is listed for the treatment of the symptoms of testosterone deficiency. The term "testosterone" used herein refers not only to testosterone itself, but also to its enantiomers, isomers, tautomers, salts, chelates, esters, amides, derivatives and precursors thereof, such as DHT (dihydrotestosterone), 17-methyltestosterone, 17 [α]-methyltestosterone 3-cyclopentenol ether, testosterone enanthate, testosterone cypionate, testosterone undecanoate, testosterone cyclodextrin, testosterone cyclobutyl ester (testosterone buciclate). According to the disclosure, testosterone can be of natural origin or produced by semi-synthesis or synthesis process.

[0053] According to one aspect of the present disclosure, a transdermal composition for male contraceptive treatment is provided, which may include a combination of NES and T in respective pharmaceutically effective amounts, and a pharmaceutically acceptable excipient.

[0054] The composition may comprise about 0.1% to 0.3% w / w and about 1.0% to 2.5% wt / wt NES and T, respectively, preferably about 0.15% to 0.25% w / w and about 1.4% to 2% wt / wt, more preferably about 0.19% wt / wt and about 1.697% wt / wt.

[0055] In one embodiment, the composition is in unit dosage form, which may contain at least about 7 mg to about 12 mg of NES and at least about 60 mg to about 100 mg of T. The level of these hormones applied to the skin results in about 10% absorption, thus corresponding to an absorption rate of about 700-1200 μg / day of NES and about 6-10 mg / day of T to a subject applying this composition once a day. In another embodiment, the composition is in unit dosage form, which may contain at least about 7 mg to about 10 mg of NES and at least about 60 mg to about 95 mg of T. The level of these hormones applied to the skin results in about 10% absorption, thus corresponding to an absorption rate of about 700-1000 μg / day of NES and about 6-9.5 mg / day of T to a subject applying this composition once a day. Preferably, the composition in unit form may contain at least about 8 mg to about 10 mg of NES and at least about 70 mg to about 85 mg of T, which, when applied to the skin, provides a rate of absorption to a subject of about 800-1000 μg / day of NES and about 7-8.5 mg / day of T for a once daily application of such composition. More preferably, the composition in unit form may contain about 8 to 8.5 mg of NES and about 73.5 to 74.5 mg of T, which, when applied to the skin, provides a rate of absorption to a subject of about 800-850 μg / day of NES and 7.35-7.45 mg / day of T for a once daily application of such composition. In one embodiment, the composition in unit form may contain about 8.3 mg of NES and about 73.8 mg of T. Expressed in a different way, the absorption levels of these hormones may also be equated to corresponding plasma levels in a patient. In this regard, the amounts of these hormones required for the transdermal formulations of the present disclosure generally result in plasma levels of NES of at least about 600 to about 800 pmol / L and T of at least about 300 to about 1000 ng / dL, preferably 300 to 900 ng / dL.

[0056] It has been found that when used transdermally, this composition system not only effectively suppresses gonadotropin and sperm concentration, but also achieves effective suppression of sperm concentration in a short period of time. In addition, this composition has almost no side effects.

[0057] As mentioned above, the transdermal application of the combination of the composition with NES and T is preferably applied in the form of a gel. In particular, the gel can be a transparent, washable, cool to the touch, quick-drying, spreadable and / or non-greasy formulation. More preferably, the present transdermal composition is formulated as a hydrogel, most preferably as a hydroalcoholic gel.

[0058] In particular, the transdermal composition preferably in the form of a gel may further comprise a pharmaceutically acceptable excipient, including but not limited to a carrier, a gelling agent, an emollient, a humectant and a pH regulator.

[0059] The carrier or solvent in the transdermal composition may include, but is not limited to, water, alcohol, mineral oil, silicone, liquid sugar, wax, vaseline, and mixtures thereof. Depending on the type of carrier used, the carrier may account for about 90% to 99% wt / wt of the composition, preferably about 94% to 98% wt / wt or about 95% to 97% wt / wt, more preferably about 96% to 96.5%. Preferably, the carrier in the present transdermal composition may include water and C2 to C4 alcohol. Water may account for about 20% to 40% w / w of the composition, preferably about 25% to 32% wt / wt, or about 27% to 29%, more preferably about 28.0% to 28.5% wt / wt. C2 to C4 alcohols may also be used as penetration enhancers herein, preferably ethanol, isopropanol, n-propanol, or mixtures thereof, more preferably ethanol. The C2 to C4 alcohol may be present in the composition at about 50% to 85% wt / wt, or 52% to 83% wt / wt, preferably about 62% to 73% wt / wt, about 65% to 71% wt / wt, and about 66.5% to 69.5% wt / wt or about 67.5% to 68.5% wt / wt, more preferably about 67.9% wt / wt. The C2 to C4 alcohol is preferably ethanol. Ethanol may be present in the composition at about 50% to 85% wt / wt, preferably about 65% to 71% wt / wt, more preferably about 67.93% wt / wt.

[0060] The gelling or thickening agent may be present in an amount sufficient to change the viscosity of the composition. The gelling agent may be selected from carbomer; carboxyvinyl or polyacrylic acid, such as Carbopol 980 USP / NF / EP, or 940 NF, 981 or 941 NF, 1382 or 1342 NF, 5984 or 934 NF, ETD 2020, 2050, 934 PNF, 971 PNF, 974 PNF and Noveon AA-1 USP; cellulose derivatives, such as ethyl cellulose, hydroxypropyl methyl cellulose (HPMC), ethyl hydroxyethyl cellulose (EHEC), carboxymethyl cellulose (CMC), hydroxypropyl cellulose (HPC) (Klucel different grades), hydroxyethyl cellulose (HEC) (Natrosol grades), HPMCP 55 and Methocel grades; natural gums, such as gum arabic, xanthan gum, guar gum and alginates; polyvinyl pyrrolidone derivatives, such as Kollidon grades; polyoxyethylene-polyoxypropylene copolymers such as Lutrol F 68 and 127 grades; and mixtures thereof. Other gelling agents may include chitosan, polyvinyl alcohol, pectin and veegum grades. Tertiary amines, such as triethanolamine or triethanolamine, may also be added to thicken and neutralize the system.

[0061] Polymers or copolymers of acrylic acid, such as carbomer, act as gelling agents, promoting the release of lipophilic active agents and permeation enhancers.Preferably, the gelling agents are Lutrol F grades and Carbopol grades.

[0062] 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. Depending on the type of gelling agent used, the gelling agent can comprise about 0.2% to 3.0% wt / wt of the composition. For example, for polyacrylic acid, the content of the gelling agent is preferably between about 0.5% and 2% wt / wt, more preferably about 1.0% wt / wt.

[0063] Emollients and / or moisturizers in transdermal compositions can be used to enhance permeability (thus acting as penetration enhancers), soften and smooth the skin, or preserve and retain moisture. It includes, but is not limited to, isopropyl myristate, cetyl alcohol, cetearyl alcohol, cocoa butter, isobutyl palmitate, lanolin, liquid paraffin, polyethylene glycol, shea butter, silicone oil, stearic acid, stearyl alcohol, castor oil and mixtures thereof, and other oils. The content of the emollient / moisturizer can be about 0.2% to 4.0% wt / wt of the composition, preferably about 0.5% to 3.0% wt / wt. Preferably, the emollient / moisturizer in the present transdermal composition can include isopropyl myristate, which can account for about 0.2% to 3.0% wt / wt of the composition, preferably about 0.5% to 2.0% wt / wt, more preferably about 1.0% wt / wt.

[0064] pH adjusters or pH regulators in transdermal compositions can be used to maintain the desired pH value to obtain appropriate chemical and physical properties. They may include, but are not limited to, acids and solutions thereof, such as hydroxy acids such as lactic acid and tartaric acid, bases and solutions thereof, such as sodium hydroxide, calcium hydroxide, potassium hydroxide, ammonium hydroxide, and triamines and solutions thereof, such as triethanolamine, tromethamine, and tetrahydroxypropylethylenediamine, and buffers and solutions thereof, such as carbonate buffers, citrate buffers, phosphate buffers, and acetate buffers, tris buffers, or combinations thereof.

[0065] The present transdermal composition is preferably formulated to have a pH of about 3 to 9, preferably about 4 to 8, or about 5 to 7, more preferably about 5.7. Sodium hydroxide is preferably used as a pH adjuster in the present transdermal composition, and may be present at about 0.01% to 0.4% wt / wt, preferably about 0.015% to 0.03% wt / wt, more preferably about 0.028% wt / wt of the composition.

[0066] The transdermal composition may also contain additional penetration enhancers. Additional penetration enhancers may include, but are not limited to, ethylene glycol, diethylene glycol monoalkyl ether, fatty alcohol, acetone, acyl lactylates, acyl peptides, acyl sarcosinates, alkanolamine salts of fatty acids, alkylbenzene sulfonates, alkyl ether sulfates, alkyl sulfates, anionic surfactants, benzyl benzoate, benzyl salicylate, 1,4-butylene glycol, butyl benzoate, butyl laurate, butyl myristate, butyl stearate, cationic surfactants, citric acid, cocamidopropyl betaine, Decyl methyl sulfoxide, decyl oleate, dibutyl azelate, dibutyl phthalate, dibenzyl sebacate, dibutyl sebacate, dibutyl suberate, dibutyl succinate, dioctyl 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 azelaate, dioctyl sebacate, 1,4-dioxane, 1-dodecylazacycloheptan-2-one, dodecyl dimethylamine oxide, ethyl decanoate, ethyl hexanoate, ethyl octanoate, 2-ethylhexyl nonanoate, ethyl lactate, ethyl laurate, ethyl myristate, 1-ethyl-2-pyrrolidone, ethyl salicylate, hexyl laurate, 2-hydroxyoctanoic acid, 2-hydroxypropionic acid, -Hydroxypropionic acid, isethionate, isopropyl isostearate, isopropyl palmitate, guar hydroxypropyltrimonium chloride, 2,5-hexanediol, kaolin, lanolin, lauryl alcohol, lanolin alcohol, fatty acid metal salt, methyl nicotinate, 2-methyl-2-propanol, 1-methyl-2-pyrrolidone, 5-methyl-2-pyrrolidone, methyl taurine, milolan, nonionic surfactant, octanol, octylphenoxypolyethoxyethanol, oleyl amide, amyl alcohol (pleyl alcohol), 2,4-pentanediol, phenoxyethanol, phosphatidylcholine, phosphine oxide, polyalkoxylated ether glycolate, poly(diallylpiperidinium chloride), poly(dipropyldiallylammonium chloride), polyglycerol esters, polyoxyethylene lauryl ether, polyoxyethylene stearate, polyoxypropylene 15 stearyl ether, poly(vinylpyridinium chloride), 1-propanol, 2-propanol, propylene glycol dipelargonate, pyroglutamic acid, 2-pyrrolidone, pyruvic acid, quaternary ammonium salt 5, quaternary ammonium salt 18, quaternary ammonium salt 19 , quaternary ammonium salt 23, quaternary ammonium salt 31, quaternary ammonium salt 40, quaternary ammonium salt 57, quaternary ammonium salt, quaternized poly (dimethylaminoethyl methacrylate), quaternized poly (vinyl alcohol), sapamine hydrochloride, sodium cocoamidopropionate, sodium dioctyl sulfosuccinate, sodium laurate, sodium lauryl polyether sulfate, sodium lauryl sulfate, sugar esters, sulfosuccinates, tetrahydrofuran, tetrahydrofurfuryl alcohol, ethylene glycol monoethyl ether, triethanolamine dodecylbenzene sulfonate, triethanolamine oleate, urea and its derivatives and mixtures thereof.In addition to the C2-C4 alcohol (preferably ethanol), emollients and / or humectants as the above-mentioned penetration enhancers, additional penetration enhancers may optionally be present in the composition in an amount of about 0.2% to 3.0% wt / wt, preferably about 0.5% to 2.0% wt / wt, depending on the type of penetration enhancer used.

[0067] The composition may also include one or more additives, including but not limited to moisturizers, deodorants, antiperspirants, preservatives, antioxidants, emulsifiers, sealants, solubilizers and surfactants. The additives may account for about 0% to 10% wt / wt of the composition, preferably about 0% to 5% wt / wt. The type and amount of the additive can be determined by those skilled in the art using conventional methods.

[0068] Suitable humectants for use in the present compositions include, but are not limited to, glycerin, propylene, ethylene glycol, sorbitol, and glyceryl triacetate.

[0069] Representative examples of deodorants useful in the present compositions include, but are not limited to, quaternary ammonium compounds such as cetyltrimethylammonium bromide, cetylpyridinium chloride, benzethonium chloride, diisobutylphenoxyethoxyethyldimethylbenzyl ammonium chloride, sodium N-lauroyl sarcosinate, sodium N-palmitoyl sarcosinate, lauroyl sarcosine, N-myristoyl glycine, potassium N-lauroyl sarcosinate, stearyltrimethylammonium chloride, sodium aluminum hydroxyl lactate, tricetylmethyl ammonium chloride, 2,4,4'-trichloro-2'-hydroxydiphenyl ether, diaminoalkylamides such as L-lysine cetylamide, heavy metal salts of citric acid, salicylic acid and piroctone, especially zinc salts and acids thereof, heavy metal salts of pyrithione, especially zinc pyrithione and zinc phenol sulfate. Other deodorizing agents include, but are not limited to, odor absorbing materials such as carbonates and bicarbonates, for example, alkali metal carbonates and bicarbonates, ammonium and tetraalkylammonium carbonates and bicarbonates, especially sodium and potassium salts, or any combination of the foregoing.

[0070] Antiperspirants may be incorporated into the compositions in dissolved or particulate form and include, for example, aluminum or zirconium astringent salts or complexes.

[0071] Suitable preservatives that can be used in the present compositions include, but are not limited to, one or more alkanols, disodium EDTA (ethylenediaminetetraacetic acid), EDTA salts, EDTA fatty acid conjugates, isothiazolinones, parabens such as methylparaben and propylparaben, propylene glycol, sorbates, urea derivatives such as diazinyl urea, or any combination thereof.

[0072] Suitable antioxidants for use in the present composition include, but are not limited to, tocopherol and its derivatives, ascorbic acid and its derivatives, butylated hydroxyanisole, butylated hydroxytoluene, fumaric acid, malic acid, propyl gallate, metabisulfate and its derivatives, and mixtures thereof.

[0073] Suitable emulsifiers for use in the present compositions include, but are not limited to, one or more sorbitol, alkoxylated fatty alcohols, alkyl polyglycosides, soaps, alkyl sulfates, mono- and di-alkyl phosphates, alkyl sulfonates, acyl isosulfates, or any combination thereof.

[0074] Suitable occlusive agents for use in the present compositions 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 oil, walnut oil, palm nut oil, pistachio oil, sesame oil, rapeseed oil, canola 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.

[0075] Representative examples of solubilizers that can be used in the context of the present compositions include, but are not limited to, complex-forming solubilizers such as citric acid, ethylenediaminetetraacetic acid, sodium metaphosphate, succinic acid, urea, cyclodextrin, polyvinylpyrrolidone, diethylammonium o-phthalate, and micelle-forming solubilizers such as Tweens and Spans, such as Tween 80. Other solubilizers that can be used in the compositions of the present disclosure are, for example, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene n-alkyl ethers, n-alkylamine n-oxides, poloxamers, organic solvents, phospholipids, and cyclodextrins.

[0076] The composition may also include anionic, nonionic or cationic surfactants.

[0077] The transdermal composition in a unit dosage form comprising about 8.3 mg NES, about 73.8 mg 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. Applying this unit dosage gel form to the male body surface every day can provide a subject with an absorption rate of about 830 μg / day of NES and 7.38 mg / day of T.

[0078] The male body surface may include, but is not limited to, the abdomen, armpits, arms, back, thighs, and shoulders, preferably the upper arms and shoulders.

[0079] The gel may preferably be packaged in any suitable container, indicating use, and may be squeezed or dispensed therefrom, such as a squeezable tube, syringe, etc., directly onto the male body surface. The volume of gel so contained is conveniently and preferably selected to constitute a predetermined dose, such as a single daily dose, or two or more daily doses, etc., to facilitate administration of the desired controlled dose. The package may be initially sealed and may be opened for use. If there is more than one dose, the package is preferably resealed by a suitable closure device.

[0080] A preferred package is a container, such as a can or the like, equipped with a pump dispenser that delivers a metered unit dose upon activation. Another preferred package is a moisture and airtight package containing a unit dose. The contents of the package can be squeezed out so that they can be applied directly to the male's body surface.

[0081] However, as described above, other formulations suitable for transdermal delivery of the two steroids NES and T described herein are also possible. This transdermal delivery can be carried out by a transdermal patch or transdermal spray, cream, ointment, aerosol, metered dose transdermal system (MTDS) or other passive or active transdermal device to be absorbed through the skin surface. In each case, for each transdermal administration of the composition of the unit dosage form, the required amount of NES and T, 8.3 mg NES and 73.8 mg T, respectively, is sufficient to produce at least about 830 μg / day NES and 7.38 mg / day T daily dose absorption, which is a key factor associated with the present disclosure. The transdermal matrix patch is about 20 to 30 cm 2 These goals can also be achieved by providing NES and T on the surface of the tablet, providing 830 μg / day of NES and 7.38 mg / day of T every day. Therefore, those of ordinary skill in the art can easily produce corresponding patches, sprays, ointments, aerosols, etc. using conventional systems containing the specific active ingredients disclosed herein.

[0082] According to one aspect of the present disclosure, a method for male contraceptive treatment is provided, which may include applying a transdermal composition to the male body surface, wherein the transdermal composition comprises a combination of NES and T each having a pharmacologically effective amount and a pharmaceutically acceptable excipient.

[0083] The transdermal composition used in this method is as described above. The transdermal composition in unit dosage form can be applied one to four times a day, applied at intervals within a day, and applied within a few days as needed. The dosage level can be evaluated by those skilled in the art. Preferably, the transdermal composition in unit dosage form can be applied once a day to provide the body with an absorption rate of about 830 μg / day of NES and 7.38 mg / day of T, preferably in the form of a gel of 1-10 mL, preferably 4-8 mL, more preferably 5 mL, applied once a day.

[0084] The male body surface may include, but is not limited to, the abdomen, armpits, arms, back, thighs, and shoulders, preferably the upper arms and shoulders.

[0085] As shown in the examples described in detail below, the combined NES / T gel (8.3 mg / 73.8 mg) in unit dosage form disclosed in the present disclosure has a higher T concentration (73.8 mg) and a small volume per dose (5 mL), and when applied to the upper arm and shoulder of men once a day, can effectively suppress gonadotropin to less than 1.0 IU / L, and the serum NES level is comparable to the level intended to suppress gonadotropin, for example, the combined NES / T gel in unit dosage form has a concentration of 8.3 mg / 62 mg in 5 mL of gel, similar to that disclosed by Anawalt et al.

[0086] In addition, sperm concentration studies have shown that the present transdermal composition containing a higher T concentration (73.8 mg) in a combined NES / T gel (8.3 mg / 73.8 mg) in a unit dose form inhibits spermatogenesis more rapidly than the composition containing a lower T concentration (62 mg) in a combined NES / T gel (8.3 mg / 62 mg) in a unit dose form used by Anawalt et al. For example, spermatogenesis was inhibited to less than 1 million / mL in subjects treated with the present composition in a unit dose form comprising a combined NES / T gel at a concentration of 8.3 mg / 73.8 mg an average of 8.9 days faster, and in 25% of the subjects 17.5 days faster, than with a composition containing a combined NES / T gel at a concentration of 8.3 mg / 62.5 mg in a unit dose form.

[0087] Furthermore, subjects treated with the present transdermal composition containing a higher concentration of T (73.8 mg) in the unit dosage form (8.3 mg / 73.8 mg) of NES / T combination gel showed fewer side effects, although the opposite may be true.

[0088] Adding an appropriate dose of T to the achieved NES dose would be a transdermal form of administration for male contraceptive purposes with the additional benefits noted above.

[0089] Example

[0090] Preparation of low-T and high-T NES / T gels

[0091] All excipients used in the compositions are well known substances having monographs in the European Pharmacopoeia and the United States Pharmacopoeia / National Formulary which are commonly and widely used in topical preparations.

[0092] Prepare a unit dosage form of low T concentration NES / T gel using the ingredients in Table 1:

[0093] Table 1

[0094]

[0095] This low T NES / T gel contained 0.19% wt / wt and 1.43% wt / wt of NES and T, respectively.

[0096] Prepare a unit dosage form of high T concentration NES / T gel using the ingredients in Table 2:

[0097] Table 2

[0098]

[0099]

[0100] This high T NES / T gel contained 0.19% wt / wt and 1.697% wt / wt of NES and T, respectively.

[0101] Each NES / T gel was prepared according to the following steps. A 0.1 N sodium hydroxide solution was prepared by dissolving sodium hydroxide in water. An ethanol aqueous solution was prepared by mixing ethanol and water, and isopropyl myristate was added to the ethanol solution. After isopropyl myristate was dissolved, Stir the mixture until The testosterone was then added and the resulting mixture was stirred until the testosterone was dissolved. The remaining water was added to the solution and further mixed until it was visually uniform. Carbopol 980 was then added and the mixture was stirred until fully hydrated. The previously prepared 0.1 N sodium hydroxide solution was added to the hydrated gel and mixed to complete the preparation of the NES / T gel complex.

[0102] Treatment with Low-T and High-T NES / T Gel

[0103] Male subjects in good health were selected based on general and reproductive history and randomly divided into low-T and high-T groups during the efficacy phase, and low-T and high-T NES / T gels containing low-T (NES 8.3 mg / T 62.5 mg in unit dosage form) and high-T (NES 8.3 mg / T 73.8 mg in unit dosage form) concentrations were administered once daily, respectively.

[0104] At the study enrollment visit, male subjects were given a sufficient supply of gel to last until the next visit. The gel comes in a metered pump canister that contains enough gel for 30 doses, which is enough for 2 weeks. The pump canister is brought back at each visit and weighed on a central calibrated scale for metering. The NES / T Combination Gel Metered Pump Canister is designed for male subjects to prime the pump once to deliver 2.5 mL of gel into the palm of one hand and then gently rub the gel into the skin of the other upper arm and shoulder. Repeat the process with the other hand and apply it to the other arm and shoulder, for a total of 5 mL of gel per day.

[0105] Detailed instructions for applying the gel via the metered pump canister were also provided to male subjects at the enrollment visit. The first dose of Low-T / High-T gel was administered at the enrollment visit under direct observation by the investigator. The date and time of treatment initiation were recorded in the source documents.

[0106] Male subjects were provided with a male daily study medication log to record the date and time of gel application, any changes in the application site, and any medications taken and / or medical issues noted by the male subjects each week. These study medication logs were reviewed and collected at each visit. Medication and adverse events recorded by male subjects were collected and recorded in source documents.

[0107] During the suppression phase, the male participants took the Low-T / High-T gel once daily, but during this time, sperm levels were suppressed and they relied on another method of contraception. During the efficacy phase, the couple did not use any other contraceptive method and relied solely on the male partner's once-daily use of the Low-T / High-T gel to prevent pregnancy.

[0108] Apply the Low T / High T gel to male subjects each morning according to the following regimen:

[0109] The gel should be applied to clean, dry skin at about the same time every morning, usually after showering.

[0110] The pump canister cap should not be removed until the male participant is ready to use the gel.

[0111] Male participants should wash their hands and then push the pump to deliver the gel to their hands.

[0112] Male participants should press the pump once to deliver the appropriate amount of gel into the palm of one hand and then gently rub the gel into the skin of the opposite upper arm and shoulder as indicated by the shaded area in the figure. This process should be repeated using the other hand and the opposite upper arm and shoulder to complete the prescribed daily dose of gel.

[0113] If a dose is missed, administer immediately.

[0114] Once the application area is dry, cover it with clothing.

[0115] Wash your hands and wrists thoroughly with soap and water after each application of the gel.

[0116] Avoid fire, flames or smoking until the gel is dry.

[0117] Male study participants should avoid swimming, showering, or washing the administration site for at least 2 hours after administration.

[0118] After the gel has dried, cover the area where the gel was applied with clothing, or shower before close skin contact with women or children.

[0119] Wait at least 8 hours between each application of the gel.

[0120] Blood samples were collected from subjects every 4 weeks (28 days) of treatment for pharmacokinetic and safety assessments, including hormone measurements (such as serum NES and T concentrations), safety laboratory tests (such as complete blood count, metabolic panel, cholesterol panel and PSA), and semen analysis (such as sperm concentration). Subjects also obtained medication records for any observable side effects, including headache, mood changes, and acne.

[0121] Table Y below records the total number of subjects who participated in the study and the number of subjects with sperm counts <= 1 million who entered the efficacy phase.

[0122] Table Y

[0123]

[0124] Table Y shows the number of subjects with sperm inhibition <= 1 million sperms, accounting for 72.2% of the subjects enrolled in the low T concentration formulation, while the number of subjects with sperm inhibition <= 10,000 sperms accounted for 81.7% of the high T concentration formulation, with a difference of 9.5% from low T concentration to high T concentration formulation. In addition, the number of subjects who entered the efficacy stage for the low T and high T concentration formulations was 63.0% and 73.2%, respectively. Since sperm inhibition is known to be directly related to NES concentration, sperm inhibition and entry into the efficacy stage are expected to be unrelated to T concentration. However, Table Y shows a significant difference between low T and high T concentration formulations in terms of sperm inhibition and entry into the effective period. The superior performance of the high T concentration formulation disclosed herein is highly unusual and unexpected.

[0125] For eligible subjects in the Low T and High T groups who had their first sperm concentration of 1 million / ml or less at or before 17 weeks, the number of days from enrollment to reaching such a low sperm concentration is recorded in Table 3 below:

[0126] Table 3

[0127]

[0128] Table 3 shows the summary of the number of days from enrollment to first sperm suppression (concentration <= 1 million / mL) for the low-T and high-T groups. Among eligible subjects, the high-T concentration formulation suppressed sperm production an average of 8.9 days faster to <= 1 mil / mL compared to the low-T concentration formulation group. In addition, in 25% of the subjects, the high-T concentration formulation group suppressed sperm production to <= 1 mil / mL 17.5 days faster than the low-T concentration formulation group.

[0129] It has been found that through It can inhibit the production of LH, FSH and sperm. In low T and high T concentration preparations, The concentration remained constant. Therefore, it would be expected that the speed at which sperm inhibition was achieved would be the same. The observation that the higher T concentration formulation achieved faster sperm inhibition in the NES 8.3mg / T 73.8mg gel was unexpected.

[0130] Table 4 below summarizes the side effects of subjects in the low T and high T groups:

[0131] Table 4

[0132]

[0133]

[0134] *Adverse events (AEs) were coded using the Medical Dictionary for Regulatory Activities (MedDRA), version 21.0.

[0135] ^Only one major adverse event, disease-related, was reported.

[0136] Table 4 shows that the incidence of adverse events was unexpectedly lower in the high T concentration formulation compared to the low T concentration formulation group. In the low T group, 91.9% of the subjects reported at least one adverse event, while only 86.2% of the subjects in the high T group reported adverse events. Table 4 above also shows a subset of all diseases / categories defined by the Medical Dictionary for Regulatory Activities. It is expected that high T formulations with increased T concentrations will produce more adverse events; however, the incidence of adverse events related to increased T concentration hormones, such as headaches, mood changes, and acne, was greatly affected by the decrease in the number of adverse events of high T formulations. Among them, the lower incidence of acne in the high T group compared to the low T group was an unexpected result. In addition, the study termination rate in the high T group seems to be lower.

[0137] Ilani et al. (2012) reported that the most common adverse event when using 100 mg T was acne, which occurred in 21% of subjects. Anawalt et al. (2019) disclosed the use of a lower dose of T (62.5 mg) to reduce and minimize androgenic acne. This lower dose of T was expected to reduce the incidence of acne. In fact, Table 4 above shows that treatment with 62.5 mg T in NES 8.3 mg / T 62.5 mg gel resulted in acne in 17.6% of subjects. Even more surprisingly, the inventors found that the use of a high T concentration formulation in NES 8.3 mg / T 73.8 mg gel reduced the occurrence of acne to a greater extent. The incidence of acne in the high T group was only 10%, while the incidence of acne in the low T group was 17.6%. For a person of ordinary skill in the art, this is completely contrary to expectations, that the addition of T is expected to increase acne.

[0138] Industrial Applicability

[0139] The present disclosure provides a composition for male contraceptive treatment. The specific composition and amount thereof can provide a transdermal product, preferably in the form of a gel, which can be easily and advantageously applied to the male body surface to achieve an effective and reversible contraceptive effect.

Claims

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

2. The transdermal composition for male contraceptive treatment according to claim 1, wherein the content of 16-methylene-17α-acetoxy-19-norpregn-4-ene-3,20-dione is about 0.15% to about 0.25% w / w, and the content of testosterone is about 1.4% to 2% wt / wt.

3. The transdermal composition for male contraceptive treatment according to claim 1, wherein the content of 16-methylene-17α-acetoxy-19-norpregn-4-ene-3,20-dione is about 0.19% w / w, and the content of testosterone is about 1.697 wt / wt.

4. The transdermal composition for male contraceptive treatment according to claim 1, wherein the transdermal composition is in the form of a gel.

5. A transdermal composition in unit dosage form for male contraceptive treatment comprising from about 7 mg to about 12 mg of 16-methylene-17α-acetoxy-19-norpregn-4-ene-3,20-dione, from about 60 mg to about 100 mg of testosterone and a pharmaceutically acceptable excipient.

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

7. A transdermal composition in unit dosage form according to claim 5, wherein the content of 16-methylene-17α-acetoxy-19-norpregn-4-ene-3,20-dione is about 8 mg to about 8.5 mg, and the content of testosterone is about 73.5 mg to about 74.5 mg.

8. The transdermal composition in unit dosage form according to claim 5, wherein the content of 16-methylene-17α-acetoxy-19-norpregn-4-ene-3,20-dione is about 8.3 mg and the content of testosterone is about 73.8 mg.

9. The transdermal composition in unit dosage form according to claim 5, wherein the transdermal composition is in the form of a gel.

10. The transdermal composition in unit dosage form according to claim 9, wherein the transdermal composition in gel form is a hydroalcoholic gel comprising a C2 to C4 alcohol.

11. The transdermal composition in unit dosage form according to claim 10, wherein the C2 to C4 alcohol is ethanol.

12. The transdermal composition in unit dosage form according to claim 10, wherein the C2 to C4 alcohol is present in an amount of 50% to 85% wt / wt.

13. The transdermal composition in unit dosage form of claim 5, wherein the excipient comprises a penetration enhancer.

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

15. A method for male contraceptive treatment, comprising applying the transdermal composition in unit dosage form according to claim 1 to the male body surface.

16. A method for male contraceptive treatment, comprising applying the transdermal composition in unit dosage form according to claim 5 to the male body surface.

17. The method for male contraceptive treatment according to claim 16, wherein the transdermal composition in unit dosage form is applied to the male body surface once a day.

18. The method of claim 16, wherein the transdermal composition in unit dosage form comprises from about 8 mg to about 8.5 mg of 16-methylene-17α-acetoxy-19-norpregn-4-ene-3,20-dione and from about 73.5 mg to about 74.5 mg of testosterone.

19. The male contraceptive treatment method of claim 16, wherein the transdermal composition in unit dosage form comprises about 8.3 mg of 16-methylene 17α-acetoxy-19-norpregn-4-ene-3,20-dione and about 73.8 mg of testosterone.

20. The male contraceptive treatment method of claim 16, wherein the transdermal composition is in the form of a gel.

Images