Transdermal formulations

Abstract

To provide a transdermal preparation that exhibits high stability of testosterone.SOLUTION: A transdermal preparation comprises testosterone and 2-mercaptobenzimidazole in a pasty preparation.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to a highly stable transdermal formulation of testosterone. [Background technology]

[0002] Testosterone is a male hormone (androgen) produced in the testes. Androgens play many important physiological roles, affecting muscle, bone, the central nervous system, the prostate, bone marrow, and sexual function. Testosterone replacement therapy, available in the form of injections, gels, and reservoir-type formulations, is used to treat sexual dysfunction due to congenital or acquired testosterone deficiency, as well as diseases or symptoms caused by age-related declines in testosterone levels, such as male menopause, metabolic syndrome, diabetes, insulin resistance, obesity, arteriosclerosis, osteoporosis, muscle weakness, cognitive decline, memory impairment, and depression. However, injections require frequent clinic visits and are difficult to maintain at physiological blood levels. Gel formulations present challenges, including difficulty in accurate administration and secondary exposure to other people after skin application.

[0003] In this regard, patches, particularly matrix-type transdermal preparations, can stably deliver a fixed amount of drug, and the desired drug can be administered, or administration can be interrupted or discontinued, simply by applying and removing the patch, with little risk of contamination to others. Regarding matrix-type transdermal preparations containing testosterone, patches using acrylate copolymers, which are oily bases, have been studied (Patent Documents 1 and 2). However, oily adhesives such as acrylate copolymer adhesives, rubber-based adhesives, and silicone-based adhesives have low drug release from the preparation. Therefore, to increase drug release, it is necessary to incorporate large amounts of drug solubilizers and drug absorption enhancers into the preparation, which results in poor formulation properties.

[0004] Meanwhile, water-soluble patches containing various drugs and based on a water-soluble polymer such as polyacrylic acid have been investigated, and preparations containing lactate esters as absorption enhancers for testosterone have also been investigated [Patent Document 3]. However, preparations containing lactate esters are highly irritating to the skin, and further improvements in terms of stability, such as reducing decomposition products, were necessary. [Prior art documents] [Patent documents]

[0005] [Patent Document 1] Special Publication No. 2002-542277 [Patent Document 2] Special Publication No. 2004-517965 [Patent Document 3] International Publication No. 2019 / 088010 Summary of the Invention [Problem to be solved by the invention]

[0006] The present invention has been made in view of the above-mentioned problems of the prior art, and an object of the present invention is to provide a transdermal preparation of testosterone that exhibits high stability. [Means for solving the problem]

[0007] As a result of intensive research to solve the above-mentioned problems, the present inventors discovered that the total amount of degradation products and the production of 6-hydroxytestosterone, a degradation product of testosterone, can be suppressed by adding 2-mercaptobenzimidazole to a testosterone-containing transdermal formulation, thereby completing the present invention.

[0008] That is, the present invention relates to the following. [1] A transdermal preparation containing testosterone and 2-mercaptobenzimidazole in a paste (hereinafter also referred to as the transdermal preparation of the present invention). [2] The transdermal preparation according to [1], wherein the amount of testosterone blended is 0.01 to 10% by weight and the amount of 2-mercaptobenzimidazole blended is 0.01 to 5% by weight, based on the weight of the plaster. [3] The transdermal administration formulation according to [1] or [2], further comprising polyacrylic acid or a salt thereof, a crosslinking agent, and a plasticizer containing propylene glycol in the plaster base. [4] The polyacrylic acid or a salt thereof is one or more selected from polyacrylic acid, sodium polyacrylate, and partially neutralized polyacrylic acid; The crosslinking agent is one or more selected from dihydroxyaluminum aminoacetate, magnesium aluminometasilicate, aluminum hydroxide, and synthetic hydrotalcite; and The transdermal administration formulation according to [3], wherein the plasticizer further comprises one or more selected from ethanol, glycerin, 1,3-butylene glycol, polypropylene glycol, D-sorbitol, and polyethylene glycol 400. [5] The polyacrylic acid or a salt thereof is one or more selected from polyacrylic acid, sodium polyacrylate, and partially neutralized polyacrylic acid; The crosslinking agent is one or more selected from dihydroxyaluminum aminoacetate, magnesium aluminometasilicate, and synthetic hydrotalcite; and The transdermal administration formulation according to [3], wherein the plasticizer further comprises one or more selected from ethanol, glycerin, and D-sorbitol. [6] The polyacrylic acid or salt thereof is polyacrylic acid; the crosslinker is magnesium aluminometasilicate; and The transdermal administration formulation described in [3], wherein the plasticizer is a combination of propylene glycol, ethanol, and glycerin. [7] The polyacrylic acid or salt thereof is polyacrylic acid; the crosslinker is magnesium aluminometasilicate; and The transdermal administration formulation according to [3], wherein the plasticizer is a combination of propylene glycol and glycerin. [8] The transdermal preparation according to any one of [3] to [7], wherein the amount of polyacrylic acid or a salt thereof is 1 to 20% by weight, the amount of crosslinking agent is 0.02 to 5% by weight, and the amount of plasticizer is 45 to 95% by weight, relative to the weight of the plaster. [9] The transdermal preparation according to any one of [1] to [8], further comprising an absorption enhancer in the plaster.

[10] The transdermal formulation according to [9], wherein the absorption enhancer is one or more fatty acid esters selected from isopropyl palmitate, isopropyl myristate, methyl laurate, hexyl laurate, and diethyl sebacate.

[11] The transdermal administration formulation according to [9], wherein the absorption enhancer is one or two fatty acid esters selected from methyl laurate and isopropyl myristate.

[12] The transdermal preparation according to any one of [9] to

[11] , wherein the amount of the absorption enhancer is 0.1 to 10% by weight based on the weight of the plaster.

[13] The transdermal administration formulation according to any one of [1] to

[12] , wherein the plaster contains testosterone; 2-mercaptobenzimidazole; polyacrylic acid; magnesium aluminometasilicate; a combination of propylene glycol, ethanol, and glycerin, or a combination of propylene glycol and glycerin; and one or two fatty acid esters selected from methyl laurate and isopropyl myristate.

[14] The transdermal preparation according to any one of [1] to

[13] , for preventing or treating a disease or symptom caused by a decrease in testosterone concentration.

[15] The transdermal formulation according to

[14] , wherein the disease or symptom caused by a decrease in testosterone concentration is one or more diseases or symptoms selected from the group consisting of hypogonadism, male menopause, metabolic syndrome, diabetes, insulin resistance, obesity, arteriosclerosis, osteoporosis, muscle weakness, cognitive decline, memory impairment, and depression. [Effects of the Invention]

[0009] The present invention provides a transdermal formulation that exhibits high testosterone stability. Furthermore, since the present invention does not require the use of highly skin-irritating substances such as lactate esters, it is possible to provide a transdermal formulation that exhibits low skin irritation. Furthermore, the transdermal formulation of the present invention can efficiently prevent or treat diseases or symptoms caused by decreased testosterone levels. DETAILED DESCRIPTION OF THE INVENTION

[0010] In this specification, the terms "contain" or "include" may be used interchangeably with "blended." Furthermore, in this specification, the terms "content" and "blended amount" may be used interchangeably.

[0011] The transdermal formulation of the present invention contains testosterone and 2-mercaptobenzimidazole in a plaster, usually containing polyacrylic acid or its salt, a crosslinking agent, and a plasticizer containing propylene glycol, and optionally containing an absorption enhancer and other ingredients. The plaster is usually a paste-like composition containing a plaster base and testosterone as a drug. In the transdermal formulation of the present invention, the mixture of polyacrylic acid or its salt and the crosslinking agent is referred to as the main base, and the mixture further containing the plasticizer containing propylene glycol, 2-mercaptobenzimidazole, and optionally other ingredients is referred to as the plaster base.

[0012] The amount of testosterone in the transdermal formulation of the present invention is not particularly limited as long as it is a therapeutically effective concentration, but is usually in the range of 0.01 to 10% by weight, preferably 0.2 to 4% by weight, and more preferably 0.5 to 2% by weight, based on the weight of the plaster. If the amount of testosterone is less than 0.01% by weight, sufficient transdermal absorption of the drug will not be achieved, while if it exceeds 10% by weight, the drug that does not dissolve in the formulation will crystallize, resulting in reduced active ingredient release and reduced formulation properties.

[0013] The 2-mercaptobenzimidazole in the transdermal preparation of the present invention has the effect of inhibiting the decomposition of testosterone.

[0014] The amount of 2-mercaptobenzimidazole in the transdermal formulation of the present invention is usually in the range of 0.01 to 5% by weight, preferably 0.05 to 3% by weight, and more preferably 0.1 to 1% by weight, based on the weight of the plaster. If the amount of 2-mercaptobenzimidazole is less than 0.01% by weight, the stability of the drug will decrease, and if the amount is more than 5% by weight, the formulation cost will increase, which is not preferable.

[0015] The polyacrylic acid or its salt in the transdermal formulation of the present invention increases the adhesive strength of the plaster by forming a crosslinked body with a crosslinking agent. Examples of polyacrylic acid or its salt include polyacrylic acid, sodium polyacrylate, and partially neutralized polyacrylic acid, and these can be used alone or in combination. In the present invention, polyacrylic acid is preferred.

[0016] The amount of polyacrylic acid or a salt thereof in the transdermal formulation of the present invention is generally 1 to 20% by weight, preferably 3 to 15% by weight, and more preferably 5 to 10% by weight, based on the weight of the plaster. Amounts less than 1% by weight are not preferred because a sufficient three-dimensional network structure is not formed, resulting in a weak gel. Amounts greater than 20% by weight are also undesirable because the plaster layer becomes too hard, resulting in a loss of adhesive strength.

[0017] The crosslinking agent in the transdermal preparation of the present invention forms a crosslinked body of polyacrylic acid or its salt, and maintains the shape of the plaster, and is selected from poorly soluble polyvalent metal salts. Examples of crosslinking agents include dihydroxyaluminum aminoacetate, magnesium aluminometasilicate, aluminum hydroxide, and synthetic hydrotalcite, and one or more of these can be used in combination. In the present invention, one or more selected from dihydroxyaluminum aminoacetate, magnesium aluminometasilicate, and synthetic hydrotalcite are preferred, and magnesium aluminometasilicate is more preferred.

[0018] The amount of crosslinking agent in the transdermal formulation of the present invention is generally in the range of 0.02 to 5 wt.%, preferably 0.05 to 4 wt.%, and more preferably 1 to 4 wt.%, based on the weight of the plaster. If the amount of crosslinking agent is less than 0.02 wt.%, crosslink formation is insufficient, and the shape retention of the plaster deteriorates. On the other hand, if the amount of crosslinking agent is more than 5 wt.%, crosslink formation increases, and the adhesiveness of the formulation deteriorates.

[0019] The transdermal formulation of the present invention generally contains propylene glycol as a plasticizer, which acts not only as a plasticizer but also as a dissolving agent for the base components.

[0020] In the present invention, propylene glycol can be blended in combination with other plasticizers. Examples of other plasticizers include ethanol, glycerin, 1,3-butylene glycol, polypropylene glycol, D-sorbitol, and polyethylene glycol 400, and one or more of these can be used in combination. One or more selected from ethanol, glycerin, and D-sorbitol are preferred, and one or two selected from ethanol and glycerin are more preferred. As the plasticizer, a combination of propylene glycol, ethanol, and glycerin, or a combination of propylene glycol and glycerin is particularly preferred.

[0021] The amount of plasticizer containing propylene glycol in the transdermal formulation of the present invention is generally 45 to 95% by weight, preferably 55 to 95% by weight, and more preferably 65 to 90% by weight, based on the weight of the plaster. If the amount of plasticizer is less than 45% by weight, the plaster's shape retention will be insufficient and its adhesive properties will deteriorate. Furthermore, even if the amount of plasticizer exceeds 95% by weight, the adhesiveness and shape retention of the plaster will be insufficient, which is also undesirable.

[0022] The transdermal formulation of the present invention may contain an absorption enhancer to increase the amount of drug absorbed. Examples of absorption enhancers that can be used include fatty acid esters such as isopropyl palmitate, isopropyl myristate, methyl laurate, hexyl laurate, and diethyl sebacate; ethanol; N-methyl-2-pyrrolidone; dimethyl sulfoxide; and crotamiton, and one or more of these may be used in combination. In the present invention, one or more fatty acid esters selected from isopropyl palmitate, isopropyl myristate, methyl laurate, hexyl laurate, and diethyl sebacate are preferred, one or two fatty acid esters selected from methyl laurate and isopropyl myristate are more preferred, and methyl laurate is particularly preferred.

[0023] The amount of absorption enhancer in the transdermal formulation of the present invention is usually 0.1 to 10% by weight, preferably 0.1 to 5% by weight, and more preferably 0.5 to 2% by weight, based on the weight of the plaster. If the amount of absorption enhancer is less than 0.1% by weight, the desired absorption amount will not be achieved. On the other hand, if the amount of absorption enhancer exceeds 10% by weight, the physical properties of the plaster will deteriorate and skin irritation will increase, which is undesirable.

[0024] In addition, the transdermal preparation of the present invention may contain various ingredients that are generally incorporated into ordinary topical preparations, etc. Examples of such ingredients include thickeners such as carboxymethylcellulose, surfactants such as polyoxyethylene sorbitan fatty acid esters, preservatives such as parahydroxybenzoates, antioxidants such as dibutylhydroxytoluene, refreshing agents such as L-menthol, silicon compounds such as light anhydrous silicic acid, inorganic fillers such as zinc oxide, flavoring agents such as peppermint oil, and colorants such as yellow ferric oxide, and these can be incorporated in appropriate amounts.

[0025] In the transdermal preparation of the present invention, the plaster preferably does not contain a lactic acid ester, such as methyl lactate, ethyl lactate, propyl lactate, butyl lactate, pentyl lactate, hexyl lactate, heptyl lactate, octyl lactate, nonyl lactate, decyl lactate, undecyl lactate, lauryl lactate, tridecyl lactate, myristyl lactate, pentadecyl lactate, cetyl lactate, heptadecyl lactate, and octadecyl lactate.

[0026] In the transdermal formulation of the present invention, the plaster preferably does not contain an oily adhesive, such as an adhesive made of a (meth)acrylate copolymer (e.g., an acrylate copolymer such as Duro-Tak 87-4098), a rubber-based adhesive (e.g., a styrene-isoprene-styrene block copolymer), or a silicone-based adhesive (e.g., BIO-PSA 7-4302, BIO-PSA 7-4101, BIO-PSA 7-4102, and BIO-PSA 7-4202, manufactured by Dow Corning).

[0027] The transdermal formulation of the present invention is useful for preventing or treating diseases or symptoms caused by decreased testosterone levels. Examples of such diseases or symptoms include one or more diseases or symptoms selected from the group consisting of hypogonadism, male menopause, metabolic syndrome, diabetes, insulin resistance, obesity, arteriosclerosis, osteoporosis, muscle weakness, cognitive decline, memory impairment, and depression. The transdermal formulation of the present invention is preferably used for preventing or treating hypogonadism or male menopause.

[0028] In the present invention, "prevention" refers to the act of administering the transdermal formulation of the present invention to an individual who has not yet developed a disease or symptom. "Treatment" refers to the act of administering the transdermal formulation of the present invention to an individual who has already developed a disease or symptom. Therefore, administering the formulation to an individual who has already developed a disease or symptom to prevent the worsening of symptoms, attacks, or recurrence is one aspect of "treatment."

[0029] The transdermal formulation of the present invention is typically administered to a patient, such as a human or animal, suffering from or at risk of the aforementioned disease or condition, preferably a human. The frequency of administration may vary depending on factors such as the severity of the disease or condition, the patient's age, weight, and sex, and the amount of testosterone in the transdermal formulation. When administered to a human, the transdermal formulation of the present invention is typically administered once or multiple times a day, for example, 1 to 3 times, 1 to 2 times, or once a day, or every few days, for example, once every 2 to 3 days.

[0030] In the transdermal preparation of the present invention, the adhesive is spread or coated between the support and the release liner. The support used in the transdermal preparation of the present invention is preferably thin and flexible so as to follow the movement of the body in order to prevent the preparation from peeling off after application. For example, there is no particular limitation as long as it is a variety of nonwoven fabrics, woven fabrics, films, sheets, etc., and specifically, woven or nonwoven fabrics made of fibers such as rayon, polyester, polyolefin, and urethane, or polymer films, foam sheets, and laminated films thereof, etc., are used.

[0031] Examples of release liners that cover the surface of the adhesive base include polyethylene, polypropylene, polyester, and these that have been treated with silicone for release.

[0032] Furthermore, due to the high adhesive strength of the transdermal formulation of the present invention, adhesive aids such as cover sheets are generally not required. However, when administered to humans over long periods of time, a cover sheet may be used as an auxiliary means to maintain good adhesion to the skin. The cover sheet is attached to the support side of the formulation and can be made of materials such as nonwoven fabric, cloth, net, knit, gauze, and film. Among these, materials with a certain degree of breathability are preferred to prevent stuffiness and rashes at the adhesion site. Specific cover sheet materials include polyester (fiber), polyethylene (fiber), polypropylene (fiber), rayon, cupra, and hemp. Examples of adhesives used in the adhesive layer of the cover sheet include acrylic adhesives such as alkyl acrylates, rubber adhesives such as styrene-isoprene-styrene block copolymers, and silicone adhesives.

[0033] The testosterone-containing transdermal formulation of the present invention can be prepared, for example, by the following method. First, polyacrylic acid or a salt thereof is heated and dissolved in a plasticizer such as propylene glycol. After cooling, the resulting solution is stirred and mixed with a plasticizer in which testosterone, an absorption enhancer such as methyl laurate, and 2-mercaptobenzimidazole have been dissolved and a crosslinker has been dispersed, to obtain a paste solution (hereinafter referred to as a non-aqueous paste). This non-aqueous paste is applied to a support, which is then covered with a release liner and cut to the desired size to obtain the transdermal formulation of the present invention. In the case of the transdermal formulation of the present invention, the application amount of the paste is 50 to 1,000 g / m 2 is.

[0034] The following are embodiments of the present invention. The present invention also encompasses any combination of the following embodiments, and any combination of the following embodiments with any of the embodiments described herein.

[0035] 1.Transdermal formulations [Aspect 1] A transdermal preparation of the present invention comprising testosterone and 2-mercaptobenzimidazole in a plaster matrix. [Aspect 2] A transdermal formulation according to Aspect 1 of the present invention, wherein the amount of testosterone blended is 0.01 to 10% by weight and the amount of 2-mercaptobenzimidazole blended is 0.01 to 5% by weight, based on the weight of the plaster. [Aspect 3] A transdermal formulation according to Aspect 1 of the present invention, wherein the amount of testosterone blended is 0.2 to 4 wt % and the amount of 2-mercaptobenzimidazole blended is 0.05 to 3 wt % relative to the weight of the plaster. [Aspect 4] A transdermal formulation according to Aspect 1 of the present invention, wherein the amount of testosterone blended is 0.5 to 2 wt % and the amount of 2-mercaptobenzimidazole blended is 0.1 to 1 wt % relative to the weight of the plaster. [Aspect 5] 5. The transdermal preparation of the present invention according to any one of Aspects 1 to 4, further comprising polyacrylic acid or a salt thereof, a crosslinking agent, and a plasticizer containing propylene glycol in the plaster base. [Aspect 6] Aspect 6. The transdermal administration formulation of the present invention according to aspect 5, wherein the polyacrylic acid or a salt thereof is one or more selected from polyacrylic acid, sodium polyacrylate, and partially neutralized polyacrylic acid. [Aspect 7] Aspect 6. The transdermal administration formulation of the present invention according to aspect 5, wherein the polyacrylic acid or a salt thereof is polyacrylic acid. [Aspect 8] Aspect 8. The transdermal administration formulation of the present invention according to any one of Aspects 5 to 7, wherein the crosslinking agent is one or more selected from dihydroxyaluminum aminoacetate, magnesium aluminometasilicate, aluminum hydroxide, and synthetic hydrotalcite. [Aspect 9] Aspect 8. The transdermal administration formulation of the present invention according to any one of Aspects 5 to 7, wherein the crosslinking agent is one or more selected from the group consisting of dihydroxyaluminum aminoacetate, magnesium aluminometasilicate, and synthetic hydrotalcite. [Aspect 10] Aspect 8. The transdermal administration formulation of the present invention according to any one of Aspects 5 to 7, wherein the crosslinking agent is magnesium aluminometasilicate. [Aspect 11] The transdermal administration formulation of the present invention according to any one of aspects 5 to 10, wherein the plasticizer further comprises one or more selected from ethanol, glycerin, 1,3-butylene glycol, polypropylene glycol, D-sorbitol, and polyethylene glycol 400. [Aspect 12] 11. The transdermal administration formulation of the present invention according to any one of Aspects 5 to 10, wherein the plasticizer further comprises one or more selected from the group consisting of ethanol, glycerin, and D-sorbitol. [Aspect 13] 11. The transdermal administration formulation of the present invention according to any one of Aspects 5 to 10, wherein the plasticizer further comprises one or two selected from ethanol and glycerin. [Aspect 14] 11. The transdermal administration formulation of the present invention according to any one of Aspects 5 to 10, wherein the plasticizer is a combination of propylene glycol, ethanol, and glycerin. [Aspect 15] Aspect 11. The transdermal administration formulation of the present invention according to any one of Aspects 5 to 10, wherein the plasticizer is a combination of propylene glycol and glycerin. [Aspect 16] The polyacrylic acid or a salt thereof is one or more selected from polyacrylic acid, sodium polyacrylate, and partially neutralized polyacrylic acid; The crosslinking agent is one or more selected from dihydroxyaluminum aminoacetate, magnesium aluminometasilicate, aluminum hydroxide, and synthetic hydrotalcite; and Aspect 6. The transdermal administration formulation of the present invention according to aspect 5, wherein the plasticizer further comprises one or more selected from ethanol, glycerin, 1,3-butylene glycol, polypropylene glycol, D-sorbitol, and polyethylene glycol 400. [Aspect 17] The polyacrylic acid or a salt thereof is one or more selected from polyacrylic acid, sodium polyacrylate, and partially neutralized polyacrylic acid; The crosslinking agent is one or more selected from dihydroxyaluminum aminoacetate, magnesium aluminometasilicate, and synthetic hydrotalcite; and Aspect 6. The transdermal administration formulation of the present invention according to aspect 5, wherein the plasticizer further comprises one or more selected from ethanol, glycerin, and D-sorbitol. [Aspect 18] The polyacrylic acid or salt thereof is polyacrylic acid; the crosslinker is magnesium aluminometasilicate; and The transdermal administration formulation of the present invention according to embodiment 5, wherein the plasticizer is a combination of propylene glycol, ethanol, and glycerin. [Aspect 19] The polyacrylic acid or salt thereof is polyacrylic acid; the crosslinker is magnesium aluminometasilicate; and A transdermal administration formulation of the present invention according to embodiment 5, wherein the plasticizer is a combination of propylene glycol and glycerin. [Aspect 20] 20. The transdermal formulation of the present invention according to any one of Aspects 5 to 19, wherein the amount of polyacrylic acid or a salt thereof is 1 to 20% by weight, the amount of crosslinking agent is 0.02 to 5% by weight, and the amount of plasticizer is 45 to 95% by weight, relative to the weight of the plaster. [Aspect 21] 20. The transdermal formulation of the present invention according to any one of Aspects 5 to 19, wherein the amount of polyacrylic acid or a salt thereof is 3 to 15% by weight, the amount of crosslinking agent is 0.05 to 4% by weight, and the amount of plasticizer is 55 to 95% by weight, relative to the weight of the plaster. [Aspect 22] 20. The transdermal formulation of the present invention according to any one of Aspects 5 to 19, wherein the amount of polyacrylic acid or a salt thereof is 5 to 10% by weight, the amount of crosslinking agent is 1 to 4% by weight, and the amount of plasticizer is 65 to 90% by weight, based on the weight of the plaster. [Aspect 23] Aspect 23. The transdermal preparation of the present invention according to any one of Aspects 1 to 22, further comprising an absorption enhancer in the plaster. [Aspect 24] A transdermal administration formulation of the present invention according to aspect 23, wherein the absorption enhancer is one or more selected from fatty acid esters selected from isopropyl palmitate, isopropyl myristate, methyl laurate, hexyl laurate, and diethyl sebacate; ethanol; N-methyl-2-pyrrolidone; dimethyl sulfoxide; and crotamiton. [Aspect 25] Aspect 24. The transdermal administration formulation of the present invention according to aspect 23, wherein the absorption enhancer is one or more fatty acid esters selected from isopropyl palmitate, isopropyl myristate, methyl laurate, hexyl laurate, and diethyl sebacate. [Aspect 26] Aspect 24. The transdermal administration formulation of the present invention according to aspect 23, wherein the absorption enhancer is one or two fatty acid esters selected from methyl laurate and isopropyl myristate. [Aspect 27] Aspect 24. The transdermal administration formulation of the present invention according to aspect 23, wherein the absorption enhancer is methyl laurate. [Aspect 28] Aspects 23 to 27: The transdermal preparation of the present invention according to any one of Aspects 23 to 27, wherein the amount of absorption enhancer blended is 0.1 to 10% by weight based on the weight of the plaster. [Aspect 29] Aspects 23 to 27: The transdermal preparation of the present invention according to any one of Aspects 23 to 27, wherein the amount of absorption enhancer blended is 0.1 to 5% by weight based on the weight of the plaster. [Aspect 30] Aspects 23 to 27: The transdermal formulation of the present invention according to any one of Aspects 23 to 27, wherein the amount of absorption enhancer blended is 0.5 to 2% by weight based on the weight of the plaster. [Aspect 31] Aspect 31. The transdermal preparation of the present invention according to any one of Aspects 1 to 30, wherein the paste does not contain a lactic acid ester. [Aspect 32] Aspect 32. The transdermal preparation of the present invention according to any one of Aspects 1 to 31, wherein the paste does not contain a (meth)acrylate copolymer. [Aspect 33] Aspect 33. The transdermal administration formulation of the present invention according to any one of Aspects 1 to 32, wherein the plaster does not contain a styrene-isoprene-styrene block copolymer. [Aspect 34] Aspect 34. The transdermal administration formulation of the present invention according to any one of Aspects 1 to 33, wherein the paste does not contain an oily adhesive. [Aspect 35] A transdermal formulation according to any one of Aspects 1 to 34, comprising testosterone, 2-mercaptobenzimidazole, polyacrylic acid or a salt thereof, a crosslinking agent, a plasticizer containing propylene glycol, and an absorption enhancer in a plaster base. [Aspect 36] A transdermal administration formulation according to Aspect 35, wherein the paste comprises testosterone, 2-mercaptobenzimidazole, polyacrylic acid or a salt thereof, a crosslinking agent, a plasticizer containing propylene glycol, and an absorption enhancer. [Aspect 37] The polyacrylic acid or salt thereof is polyacrylic acid; the cross-linking agent is magnesium aluminometasilicate; the plasticizer is a combination of propylene glycol, ethanol, and glycerin, or a combination of propylene glycol and glycerin; and A transdermal administration formulation according to aspect 35 or 36, wherein the absorption enhancer is one or two fatty acid esters selected from methyl laurate and isopropyl myristate. [Aspect 38] A transdermal administration formulation according to Aspect 37, wherein the absorption enhancer is methyl laurate. [Aspect 39] Aspects 35 to 39. The transdermal formulation of the present invention according to any one of Aspects 35 to 38, wherein the amount of testosterone is 0.01 to 10 wt %, the amount of 2-mercaptobenzimidazole is 0.01 to 5 wt %, the amount of polyacrylic acid or a salt thereof is 1 to 20 wt %, the amount of crosslinking agent is 0.02 to 5 wt %, the amount of plasticizer is 45 to 95 wt %, and the amount of absorption enhancer is 0.1 to 10 wt %, relative to the weight of the plaster. [Aspect 40] A transdermal formulation according to any one of Aspects 35 to 38, wherein the amount of testosterone, the amount of 2-mercaptobenzimidazole, the amount of polyacrylic acid or a salt thereof, the amount of crosslinker, the amount of plasticizer, the amount of 55 to 95% by weight, and the amount of absorption enhancer, relative to the weight of the plaster, are 0.2 to 4% by weight, 0.05 to 3% by weight, 3 to 15% by weight, 0.05 to 4% by weight, 55 to 95% by weight, and 0.1 to 5% by weight, respectively. [Aspect 41] A transdermal formulation according to any one of Aspects 35 to 38, wherein the amount of testosterone, the amount of 2-mercaptobenzimidazole, the amount of polyacrylic acid or a salt thereof, the amount of crosslinking agent, the amount of plasticizer, the amount of 65 to 90% by weight, and the amount of absorption enhancer, relative to the weight of the plaster, are 0.5 to 2% by weight.

[0036] 2. Uses of transdermal preparations [Aspect 42] 42. The transdermal preparation of the present invention according to any one of Aspects 1 to 41, for the prevention or treatment of a disease or symptom caused by decreased testosterone concentration. [Aspect 43] Aspect 43. The transdermal formulation of the present invention according to aspect 42, wherein the disease or symptom caused by decreased testosterone concentration is one or more diseases or symptoms selected from hypogonadism, male menopause, metabolic syndrome, diabetes, insulin resistance, obesity, arteriosclerosis, osteoporosis, muscle weakness, cognitive decline, memory impairment, and depression. [Aspect 44] A transdermal administration formulation of the present invention according to Aspect 42, wherein the disease or symptom caused by decreased testosterone concentration is hypogonadism or male menopause. [Aspect 45] Use of the transdermal formulation of the present invention according to any one of Aspects 1 to 41 in the manufacture of a medicament for the prevention or treatment of a disease or symptom caused by decreased testosterone concentration. [Aspect 46] The use according to aspect 45, wherein the disease or symptom caused by a decrease in testosterone concentration is one or more diseases or symptoms selected from hypogonadism, male menopause, metabolic syndrome, diabetes, insulin resistance, obesity, arteriosclerosis, osteoporosis, muscle weakness, cognitive decline, memory impairment, and depression. [Aspect 47] The use according to aspect 45, wherein the disease or symptom caused by decreased testosterone levels is hypogonadism or andropause. [Aspect 48] A method for preventing or treating a disease or symptom caused by decreased testosterone concentration, comprising administering to a patient the transdermal preparation of the present invention according to any one of Aspects 1 to 41. [Aspect 49] The method of embodiment 48, wherein the disease or symptom caused by decreased testosterone concentration is one or more diseases or symptoms selected from hypogonadism, male menopause, metabolic syndrome, diabetes, insulin resistance, obesity, arteriosclerosis, osteoporosis, muscle weakness, cognitive decline, memory impairment, and depression. [Aspect 50] The method of embodiment 48, wherein the disease or symptom caused by decreased testosterone levels is hypogonadism or andropause. [Aspect 51] Use of the transdermal formulation of the present invention according to any one of Aspects 1 to 41 in the prevention or treatment of a disease or symptom caused by decreased testosterone concentration. [Aspect 52] The use according to aspect 51, wherein the disease or symptom caused by decreased testosterone concentration is one or more diseases or symptoms selected from hypogonadism, male menopause, metabolic syndrome, diabetes, insulin resistance, obesity, arteriosclerosis, osteoporosis, muscle weakness, cognitive decline, memory impairment, and depression. [Aspect 53] 52. The use according to aspect 51, wherein the disease or symptom caused by decreased testosterone levels is hypogonadism or andropause.

[0037] Next, the present invention will be described in more detail with reference to examples, but the present invention is not limited to the following examples. Note that numerical values ​​in the examples are in "% by weight" unless otherwise specified. [Example]

[0038] Example 1 Glycerin and 1 / 3 of the amount of propylene glycol were mixed, and then polyacrylic acid was added and heated to dissolve. After cooling, a solution in which testosterone, methyl laurate, and 2-mercaptobenzimidazole were dissolved in 2 / 3 of the amount of propylene glycol and magnesium aluminometasilicate was dispersed was added and mixed with stirring to obtain a non-hydrous plaster. This non-hydrous plaster was applied to a support at 500 g / m 2 After uniformly applying the coating amount, the mixture was further covered with a release liner, crosslinked, and then cut into a desired size to obtain the transdermal preparation of Example 1. The blending amounts of each component are shown in Table 1.

[0039] Comparative Examples 1 to 9 The preparations were made in the same manner as in Example 1 using the blending amounts shown in Tables 1 and 2, except that no additive (Comparative Example 1), dibutylhydroxytoluene (Comparative Example 2), ascorbic acid (Comparative Example 3), tocopherol (Comparative Example 4), sodium pyrosulfite (Comparative Example 5), benzotriazole (Comparative Example 6), sodium edetate hydrate (Comparative Example 7), tocopherol acetate (Comparative Example 8), and isoascorbic acid (Comparative Example 9) were used instead of 2-mercaptobenzimidazole in Example 1.

[0040] Examples 2 to 9 The same preparation as in Example 1 was carried out using the blending amounts shown in Tables 3 and 4, except that the blending amounts of 2-mercaptobenzimidazole and glycerin were changed.

[0041] Example 10 Glycerin and 1 / 3 of the amount of propylene glycol were mixed, and then polyacrylic acid was added and heated to dissolve. After cooling, testosterone, methyl laurate, and 2-mercaptobenzimidazole were dissolved in a 2 / 3 amount of propylene glycol and ethanol mixture, and a solution in which magnesium aluminometasilicate had been dispersed was added and mixed with stirring to obtain a non-hydrous plaster. This non-hydrous plaster was applied to a support at 500 g / m 2 After uniformly applying the coating amount, the mixture was further covered with a release liner, crosslinked, and then cut into the desired size to obtain the transdermal formulation of Example 10. The blending amounts of each component are shown in Table 5.

[0042] Examples 11 to 13 The same preparation as in Example 10 was carried out using the blending amounts shown in Table 5, except that the blending amounts of testosterone, ethanol, and glycerin were changed.

[0043] [Table 1]

[0044] [Table 2]

[0045] [Table 3]

[0046] [Table 4]

[0047] [Table 5]

[0048] Test Example 1: Stability test (observation of coloration of formulation) The preparations obtained in Examples 1 to 9 and Comparative Examples 1 to 9 were placed in packaging materials such as aluminum bags and stored at 60°C for two weeks (2W). The preparations obtained in Examples 10 to 13 were stored at 60°C for three weeks (3W). After storage, the preparations were removed and visually inspected for coloration. The results are shown in Tables 1 to 5.

[0049] Test Example 2: Stability test (measurement of the amount of decomposition products) The amounts of decomposition products in the formulations obtained in Examples 1 to 9 and Comparative Examples 1 to 9 after storage (60°C, 2 weeks) were measured by HPLC. The amounts of decomposition products in the formulations obtained in Examples 10 to 13 after storage (60°C, 3 weeks) were also measured in the same manner.

[0050] HPLC measurement conditions Column: C8 column (4.6 x 150 mm, 3 μm) Mobile phase: (A) water and (B) acetonitrile were controlled under the gradient conditions in Table 6 below. [Table 6]

[0051] The total amount of testosterone-derived decomposition products and the amount of 6-hydroxytestosterone, a representative decomposition product, in the preparation after storage were determined. The results are shown in Tables 1 to 5.

[0052] Compared with Comparative Example 1, which did not contain 2-mercaptobenzimidazole, and Comparative Examples 2 to 9, which added an antioxidant instead of 2-mercaptobenzimidazole, Example 1, which contained 2-mercaptobenzimidazole, suppressed the generation of decomposition products. Coloring was observed in Comparative Examples 3 and 9, but no coloring was observed in Example 1. Furthermore, as can be seen from the results of Examples 1 to 13, it was confirmed that the generation of decomposition products was further suppressed in preparations containing 0.05% by weight or more of 2-mercaptobenzimidazole. [Industrial Applicability]

[0053] The present invention provides a transdermal formulation that exhibits high stability of testosterone. The transdermal formulation of the present invention is extremely useful, for example, for preventing or treating diseases or symptoms caused by decreased testosterone levels.

Claims

1. A transdermal preparation containing testosterone and 2-mercaptobenzimidazole in a plaster.

2. 2. The transdermal preparation according to claim 1, wherein the amount of testosterone is 0.01 to 10% by weight and the amount of 2-mercaptobenzimidazole is 0.01 to 5% by weight based on the weight of the plaster.

3. 2. The transdermal administration formulation according to claim 1, further comprising polyacrylic acid or a salt thereof, a crosslinking agent, and a plasticizer comprising propylene glycol in the paste.

4. The polyacrylic acid or a salt thereof is one or more selected from polyacrylic acid, sodium polyacrylate, and partially neutralized polyacrylic acid; The crosslinking agent is one or more selected from dihydroxyaluminum aminoacetate, magnesium aluminometasilicate, aluminum hydroxide, and synthetic hydrotalcite; and 4. The transdermal administration formulation according to claim 3, wherein the plasticizer further comprises one or more selected from the group consisting of ethanol, glycerin, 1,3-butylene glycol, polypropylene glycol, D-sorbitol, and polyethylene glycol 400.

5. The polyacrylic acid or a salt thereof is one or more selected from polyacrylic acid, sodium polyacrylate, and partially neutralized polyacrylic acid; The crosslinking agent is one or more selected from dihydroxyaluminum aminoacetate, magnesium aluminometasilicate, and synthetic hydrotalcite; and 4. The transdermal administration formulation according to claim 3, wherein the plasticizer further comprises one or more selected from the group consisting of ethanol, glycerin, and D-sorbitol.

6. The polyacrylic acid or salt thereof is polyacrylic acid; the crosslinker is magnesium aluminometasilicate; and 4. The transdermal administration formulation according to claim 3, wherein the plasticizer is a combination of propylene glycol, ethanol, and glycerin.

7. The polyacrylic acid or salt thereof is polyacrylic acid; the crosslinker is magnesium aluminometasilicate; and 4. The transdermal administration formulation according to claim 3, wherein the plasticizer is a combination of propylene glycol and glycerin.

8. 8. The transdermal preparation according to claim 3, wherein the amount of polyacrylic acid or a salt thereof is 1 to 20% by weight, the amount of crosslinking agent is 0.02 to 5% by weight, and the amount of plasticizer is 45 to 95% by weight, based on the weight of the plaster.

9. 2. The transdermal formulation according to claim 1, further comprising an absorption enhancer in the plaster.

10. 10. The transdermal formulation according to claim 9, wherein the absorption enhancer is one or more fatty acid esters selected from isopropyl palmitate, isopropyl myristate, methyl laurate, hexyl laurate, and diethyl sebacate.

11. 10. The transdermal administration formulation according to claim 9, wherein the absorption enhancer is one or two fatty acid esters selected from methyl laurate and isopropyl myristate.

12. 12. The transdermal preparation according to claim 9, wherein the amount of the absorption enhancer is 0.1 to 10% by weight based on the weight of the plaster.

13. 2. The transdermal administration formulation according to claim 1, comprising, in a plaster base, testosterone; 2-mercaptobenzimidazole; polyacrylic acid; magnesium aluminometasilicate; a combination of propylene glycol, ethanol, and glycerin, or a combination of propylene glycol and glycerin; and one or two fatty acid esters selected from methyl laurate and isopropyl myristate.

14. The transdermal administration preparation according to any one of claims 1 to 7, 9 to 11, and 13, for the prevention or treatment of a disease or symptom caused by a decrease in testosterone concentration.

15. The transdermal formulation according to claim 14, wherein the disease or symptom caused by a decrease in testosterone concentration is one or more diseases or symptoms selected from the group consisting of hypogonadism, male menopause, metabolic syndrome, diabetes, insulin resistance, obesity, arteriosclerosis, osteoporosis, muscle weakness, cognitive decline, memory impairment, and depression.

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