Mirabegron preparations

Abstract

The present invention relates to a composition for topical and / or transdermal administration comprising mirabegron or a salt thereof, the composition comprising: a) mirabegron or a salt thereof in the range of ≧0.01 wt.-% to ≦25 wt.-%; and b) a solvent, the solvent being: dimethyl sulfoxide (DMSO) in the range of ≧5 wt.-% to ≦99.99 wt.-%; or and a solvent selected from i) a monoalcohol in the range of ≧5 wt.-% to ≦94.99 wt.-%, or ii) glycerol, glycol, polyethylene glycol, glycol ether, mixtures thereof, or mixtures with monoalcohols in the range of ≧5 wt.-% to ≦60 wt.-%, or iii) a further solvent selected from water in the range of ≧2 wt.-% to ≦10 wt.-%, where the wt.-% is based on the total weight of the composition of 100 wt.-%.

Description

[Technical field]

[0001] The present invention relates to a composition for topical and / or transdermal administration comprising mirabegron or a salt thereof.

[0002] Overweight and obesity are major risk factors for many diseases. One in two European Union citizens is overweight, more than one in three is pre-obese, and one in six is ​​considered obese with a Body Mass Index (BMI) above 30. In the United States, the prevalence of obesity is even more pronounced. These groups of people are at significantly increased risk of developing cardiovascular disease and diabetes. The aesthetic problems of being overweight can also lead to social isolation and may result in mental disorders such as depression. The clinical picture of lipedema in this regard is particularly distressing. Cellular edema is a chronic, progressive disease of the subcutaneous adipose tissue of the upper and lower extremities that affects almost exclusively women. The disease is poorly understood but is thought to be due to a pathologic increase in adipose tissue through hypertrophy and hyperplasia accompanied by fluid retention. This results in a significant and distinct increase in the volume of the affected body parts, especially the limbs, compared to the rest of the body. Combating obesity therefore has direct benefits to the physical and mental health of individuals and populations.

[0003] Most of the drugs that increase fat loss belong to the class of eating disorder drugs. Many of these are amphetamine-derived and suppress the appetite. Another possibility for aiding weight loss is the use of lipase inhibitors. However, these substances require oral or injectable administration. However, when administered systemically, these compounds severely interfere with the metabolism of neurotransmitters in the brain, and serious side effects must be expected.

[0004] Topical application substantially reduces systemic absorption and the respective side effects. US Patent No. 5,939,633 discloses a composition for treating localized fat deposits comprising the long-acting beta2-adrenergic receptor agonist salmeterol or formoterol and a compound that reduces desensitization of target tissues to long-acting beta2-adrenergic receptor agonists, such as glucocorticosteroids and / or ketotifen. The composition may be administered, for example, by injection and / or transdermal administration. However, pharma- ceutical active compounds often exhibit no or suboptimal clinical efficacy when administered topically due to poor penetration into the skin.

[0005] US Patent No. 5,399,633 discloses a pharmaceutical composition for topical administration comprising a prodrug for an adrenergic receptor stimulant and / or antagonist, the prodrug being an ester for use in a therapeutic method for shaping the mammalian body by regulating subcutaneous adipose tissue. One of the many cited β3-adrenoceptor receptor agonists ("beta agonists") is mirabegron. Although permeation of the prodrug provides a transport route through the skin, the effectiveness of the active ingredient depends on the activity of an enzyme that can release the irritant from the prodrug, and it is unknown whether a therapeutic effect can be achieved in that manner. The penetration of naive adrenoceptor agonists and antagonists may be insufficient for the treatment of adiposity and / or lipolysis.

[0006] Mirabegron (INN) is a prescription medication from the group of beta-3 sympathomimetics. Mirabegron has been approved in the EU since 2012 for the treatment of overactive bladder. However, the physicochemical properties of mirabegron are hostile to transdermal application and include a relatively high molecular weight and melting point, it is insoluble in water (aqueous solubility 82 μg / mL) and has only limited solubility in lipids. Thus, it is not possible to dissolve large amounts of mirabegron in water, and aqueous mixtures with typically used polar co-solvents retain low solubility for mirabegron. Furthermore, solubility in lipids is limited and application of products with high lipid content is uncomfortable, reducing patient compliance. [Prior art documents] [Patent documents]

[0007] [Patent Document 1] International Publication No. 2007 / 011743(A1) [Patent Document 2] European Patent No. 3 206 678(B1) Summary of the Invention [Means for solving the problem]

[0008] It is therefore an object of the present invention to provide a composition which allows the topical or transdermal administration of mirabegron.

[0009] This object is achieved by the composition according to claim 1. This object is further achieved by a composition for use according to claims 10 to 14. Advantageous embodiments are the subject matter of the dependent claims. The embodiments may be freely combined unless the context clearly dictates otherwise.

[0010] Thus, there is provided a composition for topical and / or transdermal administration comprising mirabegron or a salt thereof, the composition comprising: a) ≧0.01 wt.-% to ≦25 wt.-% of mirabegron or a salt thereof; b) a solvent, - dimethyl sulfoxide (DMSO) in the range of ≥ 5 wt.-% to ≤ 99.99 wt.-%; or - dimethyl sulfoxide in the range of ≧5 wt.-% to ≦97.99 wt.-% and a solvent selected from i) a monoalcohol in the range of ≧5 wt.-% to ≦94.99 wt.-%, or ii) glycerol, glycol, polyethylene glycol, glycol ether, mixtures thereof or mixtures with monoalcohols in the range of ≧5 wt.-% to ≦60 wt.-%, or iii) water in the range of ≧2 wt.-% to ≦10 wt.-%, Here, wt.-% is based on the total weight of the composition being 100 wt.-%.

[0011] Surprisingly, it has been found that dimethylsulfoxide enables transdermal administration of mirabegron. In contrast to other compounds known in the art that are broad-spectrum penetration enhancers, DMSO promoted skin penetration and increased duration of active delivery was observed for mirabegron. Furthermore, it could be shown that a mixture of dimethyl sulfoxide with an alcohol or glycol ether could provide an effective transdermal delivery of mirabegron. Pure dimethyl sulfoxide and its mixtures showed high penetration while allowing sufficient maintenance of dissolved mirabegron in the skin. On the other hand, solutions or mixtures without dimethylsulfoxide were either lacking in solubility, lacking in permeability, too volatile, or toxicologically unacceptable.

[0012] The term "mirabegron" (INN), as used herein, formerly known as YM178, refers to a β3-adrenergic receptor agonist ("beta agonist") of formula (1) below.

[0013] [ka]

[0014] Mirabegron is commercially available in Europe under the trade name Betmiga®. Mirabegron is commercially used as the non-salt free base. Salts of mirabegron, preferably pharma- ceutically acceptable salts, may also be used. The term "pharmaceutically acceptable salts" refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids. Preferred salts include the ammonium, calcium, magnesium, potassium, and sodium salts, as well as the hydrochloride, sulfate, succinate, acetate, fumarate, tartrate, besylate, and mesylate salts. Additionally, mirabegron complexes such as lauryl sulfate, octyl sulfate, myristyl sulfate, and cetyl sulfate / complexes are known and can be used.

[0015] As used herein, the term "topical" administration refers to the application of a substance, such as mirabegron, to a particular location on or in the body, particularly to a body surface, such as the skin or mucous membrane. The term "transdermal" administration as used herein indicates that a substance, such as, for example, mirabegron, upon administration penetrates the upper skin layers and distributes into the subcutaneous layers, i.e., the dermis and subcutaneous tissue.

[0016] Unless specifically indicated otherwise, the percentages given are weight percent (wt.-%). The total amount of all components of the composition does not exceed 100 wt.-%. The wt.-% given for mirabegron refers to the total weight of the composition. For example, 100 g of a 5% mirabegron solution in DMSO / ethanol (50 / 50, w / w) represents 5 g of mirabegron and 47.5 g each of DMSO and ethanol.

[0017] Important for the solubility of mirabegron is the ratio of the solvents, in particular the weight by weight ratio (w / w) of DMSO to the further solvent or (od) mixture of further solvents. The weight to weight ratio of DMSO to the further solvent may range from 9.5:0.5 to 0.5:9.5 depending on the nature of the further solvent. The ratio of DMSO to further solvent given as 10 / 90 (w / w) or 50 / 50 (w / w) still defines the solubility of mirabegron in the formulation, regardless of the presence of excipients such as gelling agents or stabilizers.

[0018] For effective transdermal delivery of a compound from a formulation solvent system, several requirements must be met. First, adequate solubility of the active compound in the formulation must be provided. Furthermore, an increase in the solubility of the active compound in the skin (both epidermis and dermis) must be observed (Penetration Enhancement). Finally, sufficient solvent retention (limited solvent evaporation) in the skin must be provided to ensure a state of molecular dispersion of the payload. It was observed that a solvent with high solubility for mirabegron does not automatically enable penetration into the skin. For example, diethylene glycol monoethyl ether, commercially available under the trade name Transcutol®, provided high solubility when used without dimethyl sulfoxide, but poor penetration of mirabegron. Other solvents such as ethanol provided high solubility and penetration, but no effect of mirabegron on lipolysis was observed. It is speculated that this lack of efficacy of mirabegron may be due to evaporation of the solvent and precipitation of mirabegron.

[0019] In general, polar aprotic solvents, short chain alcohols, glycols, and polyethylene glycols are suitable solvents for dissolution media for large amounts of mirabegron. However, polar aprotic solvents such as N,N-dimethylformamide and N-methylpyrrolidone are toxicologically hazardous.

[0020] The composition comprises mirabegron as an active ingredient. In an embodiment, the composition contains mirabegron or a salt thereof in the range of ≧0.01 wt.-% to ≦25 wt.-%, preferably in the range of ≧0.01 wt.-% to ≦20 wt.-%, preferably in the range of ≧0.1 wt.-% to ≦10 wt.-%, more preferably in the range of ≧0.5 wt.-% to ≦5 wt.-% based on the total weight of the composition. Such concentrations provided good solubility and efficacy of mirabegron.

[0021] The composition comprises dimethylsulfoxide (DMSO) in the range of ≧5 wt.-% to ≦99.99 wt.-%. Formulations containing less than 5 wt.-% were found to provide less permeation of mirabegron.

[0022] In an embodiment, the composition comprises one or more pharmaceutical excipient(s). In an embodiment, the composition comprises one or more pharmaceutical excipient(s) selected from the group comprising antioxidants, penetration enhancers, gel formers, ointment components, preservatives, colorants, odorants, stabilizers, triglycerides, and mixtures thereof, preferably a gel former.

[0023] Suitable excipients selected from ointment bases, gel formers, antioxidants, pH adjusters, preservatives, colorants, and stabilizers are preferably alpha tocopherol, acetic acid, ammonia solution, anhydrous citric acid, ascorbic acid, ascorbyl palmitate, bentonite, benzalkonium chloride, benzyl alcohol, butylparaben, calcium acetate, carbomer, sodium carocymethyl cellulose, carnauba wax, carrageenan, castor oil, ceteareth-30, veteth-10, cetostearyl alcohol, cetyl alcohol, cholesterol, coconut oil, colloidal silicon dioxide, corn oil, crospovidone, diethylene glycol monoethyl ether, dimethicone 100, docosanol, sodium docusate, disodium etate, ethylcellulose, ethylparaben, ferric oxide red.red), formic acid, gelatin, gylceryl monostearate, gylceryl oleate, sodium hyaluronate, hydrochloric acid, hydrogenated castor oil, hydroxyethyl cellulose, hydroxyproyl cellulose, hypromellose, isopropyl myristate, isopropyl palmitate, lanolin, lavender oil, lecithin, linoleic acid, magnesium silicate, magnesium stearate, medium chain triglycerides, menthol, methylcellulose, methylparaben, minral oil, myristic acid, myristyl alcohol, oleic acid, olive oil, paraffin, peanut oil, PEG 6-32 stearate / glycol stearate In one embodiment, the inactive ingredient is selected from the group consisting of glycerin, PEG / PPG-18 / 18 dimethicone, PEG-100 stearate, PEG-5 oleate, PEG-60 hydrogenated castor oil, PEG-75 lanolin, poloxamer, polyacrylic acid, polyethylene, polyethylene glycol, polysorbate, povidone, propylene glycol, quaternium-15, shea butter, simethicone, sodium bisulfite, sodium chloride, sodium hydroxide, sodium laureth-2 sulfate, sodium lauryl sulfate, sodium disulfite, sodium silicate, sorbic acid, stearic acid, thyme oil, triethanolamine, urea, vitamin E polyethylene succinate, wax, xanthan gum, zinc acetate, zinc oxide, and zinc stearate.

[0024] The preferred form of presentation of the formulation is a gel. In an embodiment, the composition comprises a gel forming agent selected from the group comprising hydroxypropyl cellulose, preferably high-substituted hydroxypropyl cellulose (HPC-H), hydroxyethyl cellulose, hydroxypropyl methylcellulose (HPMC), and mixtures thereof. The composition may contain a gel-forming agent, such as, for example, hydroxypropyl cellulose or hydroxyethyl cellulose, in the range of ≧1 wt.-% to ≦20 wt.-%, preferably ≧2 wt.-% to ≦10 wt.-%, based on the total weight of the composition at 100 wt.-%.

[0025] In an embodiment, the composition comprises DMSO in the range of ≧5 wt.-% to ≦50 wt.-% and monoalcohol in the range of ≧50 wt.-% to ≦95 wt.-% based on the total weight of the composition of 100 wt.-%.

[0026] Preferred are short chain monoalcohols containing up to 6 aliphatic carbon atoms. In a preferred embodiment, the monoalcohol is selected from the group of ethanol, n-propanol, isopropanol, n-butanol, isobutanol, tert.-butanol, or mixtures thereof. 2 ~C 5 It's alcohol. In a preferred embodiment, the monoalcohol is ethanol. In a further embodiment, the monoalcohol may be isobutanol.

[0027] Using a mixture of DMSO and ethanol as the solvent, a gel could be provided that provided good permeation results of mirabegron into the skin. In an embodiment, the composition comprises: a) mirabegron in the range of ≧0.01 wt.-% to ≦10 wt.-%; b) Dimethyl sulfoxide in the range of ≧5 wt.-% to ≦50 wt.-% and C in the range of ≧50 wt.-% to ≦95 wt.-% 2 ~C 5 a mixture of alcohol, preferably ethanol; c) in the range of ≧1 wt.-% to ≦20 wt.-% of a gel former selected from the group comprising hydroxypropyl cellulose, preferably highly substituted hydroxypropyl cellulose (HPC-H), hydroxyethyl cellulose, hydroxypropyl methyl cellulose (HPMC), and mixtures thereof; Here, wt.-% is based on the total weight of the composition being 100 wt.-%.

[0028] In an embodiment, the composition may include a triglyceride. Preferred triglycerides are selected from the group comprising glyceryl monostearate and glyceryl oleate. In an embodiment, the composition comprises in the range of ≧1 wt.-% to ≦20 wt.-% of a triglyceride, preferably selected from the group comprising glyceryl monostearate and glyceryl oleate, based on the total weight of the composition.

[0029] In another embodiment, an aqueous solution comprising DMSO is provided. In an embodiment, the composition comprises dimethyl sulfoxide in the range of ≧90 wt.-% to ≦97.99 wt.-% and water in the range of ≧2 wt.-% to ≦10 wt.-%, preferably dimethyl sulfoxide in the range of ≧90 wt.-% to ≦94.99 wt.-% and water in the range of ≧5 wt.-% to ≦10 wt.-%. Aqueous solutions of mirabegron containing large amounts of DMSO were found to provide sufficient solubility.

[0030] In a further preferred embodiment, the formulation is a solution comprising DMSO.

[0031] In an embodiment, a composition for topical and / or transdermal administration is provided, comprising mirabegron or a salt thereof, the composition comprising as a solvent: - dimethyl sulfoxide (DMSO) in the range of ≧10 wt.-% to ≦100 wt.-%; and optionally - monoalcohols in the range of ≥ 10 wt.-% to ≤ 90 wt.-%; or - containing ≧10 wt.-% to ≦60 wt.-% of glycerol, glycols, polyethylene glycols, glycol ethers, mixtures thereof or mixtures with monoalcohols, Here, wt.-% is based on the total weight of the solvent being 100 wt.-%.

[0032] Particularly in embodiments where the formulation is provided as a solution, particularly where excipients such as gel-forming agents or triglycerides are not required, the ratio of solvents dictates the solubility of mirabegron. With respect to the compositions or solutions described in the following paragraphs, the wt.-% given for the solvent is calculated based on a total weight of 100 wt.-% of the solvent. The wt.-% given for mirabegron refers to the total weight of the composition. For example, 100 g of a 5% solution of mirabegron in DMSO / ethanol (50 / 50, m / m) represents 5 g of mirabegron and 47.5 g each of DMSO and ethanol.

[0033] In an embodiment, the composition comprises 100 wt.-% DMSO based on a total weight of 100 wt.-% solvent. Dimethylsulfoxide provided very good penetration along with high solubility when used as the sole solvent. Furthermore, it was found that the addition of dimethyl sulfoxide as an additional solvent increased the solubility of mirabegron in the formulation, enhanced skin penetration, as well as increased the active delivery period for mirabegron.

[0034] Binary mixtures comprising dimethylsulfoxide and a monoalcohol or a glycol ether are preferred. The two-component mixture simplifies formulation and facilitates compatibility with additional excipients.

[0035] In an embodiment, the composition comprises DMSO in the range of ≧10 wt.-% to ≦90 wt.-% and monoalcohol in the range of ≧10 wt.-% to ≦90 wt.-% based on a total weight of 100 wt.-% solvent. Preferred are short chain monoalcohols containing up to 6 aliphatic carbon atoms. In a preferred embodiment, the monoalcohol is selected from the group of ethanol, n-propanol, isopropanol, n-butanol, isobutanol, tert.-butanol, or mixtures thereof. 2 ~C 5 It's alcohol. In a preferred embodiment, the monoalcohol is ethanol. In a further embodiment, the monoalcohol may be isobutanol.

[0036] Reducing the DMSO content in mixtures with ethanol reduced permeation in vitro, and solutions or mixtures without dimethylsulfoxide lacked either solubility or permeability. It was found that for sufficient penetration of mirabegron, at least 5 wt.-% DMSO based on 100 wt.-% solvent was required. Furthermore, it was found that increasing the amount of DMSO in the ethanol mixture enhanced the skin permeation of mirabegron, whereas adding diethylene glycol monoethyl ether to DMSO decreased the skin permeation of mirabegron. In an embodiment of the composition, the composition comprises dimethyl sulfoxide in the range of ≧10 wt.-% to ≦50 wt.-% and ethanol in the range of ≧50 wt.-% to ≦90 wt.-% based on a total weight of 100 wt.-% solvent. These ranges provided good solubility and penetration of mirabegron. Generally, a higher content of ethanol provides better penetration.

[0037] In an embodiment, the composition comprises DMSO in the range of ≧40 wt.-% to ≦90 wt.-% and glycerol, glycol, polyethylene glycol, glycol ether, mixtures thereof, or mixtures with monoalcohols in the range of ≧10 wt.-% to ≦60 wt.-% based on a total weight of 100 wt.-% solvent. In particular, glycol and polyethylene glycol provide high solubility for mirabegron. The glycols and polyethylene glycols may be selected from the group of ethylene glycol, propylene glycol, and polyethylene glycol. However, solvents with high solubility for mirabegron, such as glycol and polyethylene glycol, may reduce or prevent the penetration of mirabegron. In a preferred embodiment of the composition, a glycol ether is present. Preferably, the glycol ether is diethylene glycol monoethyl ether. Diethylene glycol monoethyl ether (IUPAC name 2-(2-ethoxyethoxy)ethanol) is commercially available under trade names such as Transcutol®. In an embodiment of the composition, the composition comprises dimethyl sulfoxide in the range of ≧40 wt.-% to ≦90 wt.-% and diethylene glycol monoethyl ether in the range of ≧10 wt.-% to ≦60 wt.-% based on a total weight of 100 wt.-% solvent. These ranges provided good solubility and penetration of mirabegron.

[0038] Ternary mixtures of solvents may also be used. Preferably, the composition comprising the ternary mixture has a higher amount of DMSO, for example in the range of ≧20 wt.-% to ≦80 wt.-%. In an embodiment, the composition may comprise as a solvent dimethylsulfoxide (DMSO) in the range of ≧20 wt.-% to ≦80 wt.-% and a mixture of monoalcohols, glycerol, glycols, polyethylene glycols, or glycol ethers in the range of ≧20 wt.-% to ≦80 wt.-%, where the wt.-% is based on the total weight of the solvent, which is 100 wt.-%.

[0039] In an embodiment of the composition, the composition comprises in the range of ≧1 wt.-% to ≦20 wt.-% cyclodextrin based on a total weight of 100 wt.-% solvent. The addition of cyclodextrin increases the solubility of mirabegron, allowing more non-solvent to be added to the binary or ternary mixture. Preferred cyclodextrins are pharma- ceutically acceptable cyclodextrins, such as β-cyclodextrin and gamma-cyclodextrin, as well as β-cyclodextrin derivatives used as excipients in pharmaceuticals, such as sulfobutylether of β-cyclodextrin (SBE-β-CD), hydroxypropyl derivative of β-cyclodextrin (HP-P-CD), and randomly methylated β-cyclodextrin (RM-β-CD).

[0040] The solubility of mirabegron may be explained using the Hansen solubility parameter theory. The Hansen Solubility Parameters indicate the parameters δD for Dispersion (van der Waals), δP for Polarity (related to the dipole moment), and δH for Hydrogen Bonding. These parameters are defined according to Charles Hansen, "Hansen Solubility Parameters, A User's Handbook", 2nd Edition, 2007. In an embodiment, the solvent or mixture of solvents has a Hansen Solubility Parameter (HSP) (as defined according to the User's Handbook, 2nd Edition) in the range of dD ≧15 to ≦19, dP ≧8. It was found that a high dP increases permeation, whereas a high dH decreases permeation. In a preferred embodiment, the composition has Hansen Solubility Parameters of dD in the range of ≧16 to ≦18, dP in the range of ≧12 to ≦14, and / or dH in the range of ≦14 to ≦16, preferably a dD of 16.6, a dP of 12.8, and a dH of 14.8.

[0041] In an embodiment, the composition comprises mirabegron or a salt thereof in the range of ≧0.01 wt.-% to ≦25 wt.-%, preferably in the range of ≧0.01 wt.-% to ≦20 wt.-%, preferably in the range of ≧0.1 wt.-% to ≦10 wt.-%, more preferably in the range of ≧0.5 wt.-% to ≦5 wt.-%, based on the total weight of the composition. Such concentrations provided good solubility and efficacy of mirabegron.

[0042] In an embodiment, the composition is in the form of a topical composition. Preferably, the topical composition is selected from the group consisting of a gel, an ointment, a cream, a foam, a lotion, a paste, a solution, a spray, or a plaster. Such formulations are typically topical compositions for application to a specific location on a body surface, such as the skin. Advantageously, the topical composition according to the invention provides transdermal administration of mirabegron. Preferably, the composition is in the form of a gel, ointment, or plaster, more preferably in the form of a gel or spray. The dosage form is preferably defined according to the definitions used by those skilled in the art, such as, for example, Pharm Eur, 10.0;0132: "Semi-solid preparations for cutaneous use". For each of the formulations, the compositions may contain one or more pharma- ceutically acceptable excipients to increase the physical, chemical, and microbiological stability of the formulation as well as patient adherence. The respective gel formers, surfactants, solubility enhancers, penetration enhancers, preservatives, antioxidants, complexing agents, cosolvents, emollients, fragrances, and colorants are known to those skilled in the art. Pharmaceutically acceptable carriers that can be used are known to those of skill in the art, including hydrogels, skin creams, skin gels, skin lotions, skin ointments, skin patches, skin pastes, skin compresses, skin foams, skin solutions, skin sprays, and patches. Another preferred delivery form is as a spray.

[0043] A further embodiment provides a composition for topical and / or transdermal administration comprising mirabegron or a salt thereof, the composition being administered at a concentration of 1 cm at 32° C. according to USP(725). 2 At least 5 μg / cm over 24 hours as measured in a Franz Diffusion Cell with an orifice of 2 provides a transdermal flux of mirabegron of 100 mg / kg. In embodiments, the flux is at least 10 μg / cm over a 24 hour period measured according to USP(725). 2 , preferably at least 20 μg / cm for 24 hours 2 , more preferably at least 30 μg / cm for 24 hours 2 , and even more preferably at least 50 μg / cm for 24 hours. 2 , more preferably 100 μg / cm for 24 hours 2 It is.

[0044] In an embodiment, the transdermal flux of mirabegron is 1 cm at 32° C. according to USP(725). 2 The dose is measured in infinite dose experiments on human skin in a Franz diffusion cell with an orifice of 1. The term infinite dose experiment as used herein refers to an experiment performed by applying and maintaining on the skin an amount of the test preparation at which the maximum absorption rate of the test substance is achieved, as defined in the OECD Environmental Health and Safety Publications Series on Testing and Assessment, No. 28, 2004, and described in Lau WM, Ng KW (2017) Finite and Infinite Dosing, in Dragicevic N, Maibach HI (eds.), Percutaneous Penetration Enhancers Drug Penetration Into / Through the Skin: Methodology and General Considerations, Springer Berlin Heidelberg, Berlin, Heidelberg, pp 35-44.

[0045] Another embodiment provides a composition for topical and / or transdermal administration comprising mirabegron or a salt thereof, the composition containing mirabegron in a molecularly dispersed form. The term "molecular dispersion" as used herein refers to a dispersion of mirabegron when it is in the form of separate molecules that are homogeneously distributed throughout the solvent.

[0046] In a preferred embodiment, at least 5 μg / cm 2The composition providing a transdermal flux of mirabegron or containing mirabegron in molecularly dispersed form is in the form of a gel or solution or spray.

[0047] In an embodiment, the composition comprises a) mirabegron as an active compound; b) a solvent selected from: dimethyl sulfoxide (DMSO) in the range of ≧5 wt.-% to ≦99.99 wt.-%; or dimethyl sulfoxide in the range of ≧5 wt.-% to ≦97.99 wt.-% and a further solvent selected from i) a monoalcohol in the range of ≧5 wt.-% to ≦94.99 wt.-%, or ii) glycerol, glycol, polyethylene glycol, glycol ether, mixtures thereof, or mixtures with monoalcohols in the range of ≧5 wt.-% to ≦60 wt.-%, or iii) water in the range of ≧2 wt.-% to ≦10 wt.-%, and optionally c) one or more pharmaceutical excipient(s), where wt.-% is based on the total weight of the composition of 100 wt.-%.

[0048] In an embodiment, the composition comprises as solvent: dimethyl sulfoxide in the range of ≧10 wt.-% to ≦100 wt.-% and optionally a monoalcohol in the range of ≧10 wt.-% to ≦90 wt.-% or ≧10 wt.-% to ≦60 wt.-% of glycerol, glycol, polyethylene glycol, glycol ether, mixtures thereof, or mixtures with monoalcohols, where the wt.-% is based on the total weight of the solvent, which is 100 wt.-%.

[0049] For the description of mirabegron and its salts, compositions, solvents and excipients, reference is made to the above descriptions.

[0050] The compositions described herein can be used for the transdermal administration of mirabegron to subcutaneous adipose tissue. Subcutaneous adipose tissue refers to the layer of tissue just below the skin of a mammal that contains adipocytes. Transdermal administration of the composition results in a local increase in the concentration of mirabegron in fat cells while significantly reducing the systemic drug concentration.

[0051] The composition provides effective transdermal delivery of mirabegron. This would result in greater uptake of mirabegron in subcutaneous adipose tissue, which would respond to mirabegron by decreasing the amount of subcutaneous adipose tissue and / or decreasing the size of a single adipocyte. Reducing the amount of subcutaneous adipose tissue will reduce excess weight caused by adipocytes and reduce obesity and cellulite.

[0052] Furthermore, mirabegon was shown to significantly increase the expression of browning markers upon transdermal application in ex vivo human skin containing subcutaneous adipose tissue.

[0053] Thus, in an embodiment, the compositions described above are for use in the treatment of obesity or cellulite, or for providing lipolysis. A related aspect relates to the use of the above-described composition for the manufacture of a medicament for the treatment of obesity or cellulite, or for providing lipolysis. Thus, the composition may be a pharmaceutical composition. In another aspect, a method is provided for treating obesity or cellulite, or for providing lipolysis, comprising administering to a subject in need thereof, e.g., a mammal, e.g., a human, a therapeutically effective amount of a composition described herein.

[0054] The term "lipolysis" as used herein refers to a procedure in which active ingredients are applied to achieve a localized reduction in the amount of subcutaneous adipose tissue. The term "lipolysis" may refer to a therapeutic or cosmetic procedure.

[0055] In other embodiments, the composition may be a cosmetic composition for cosmetic use. In another aspect, the present invention provides for the use of a composition as described above in a cosmetic method for reducing the amount of subcutaneous adipose tissue in a subject by topical application. In other words, in an embodiment, the composition described above is for use in a cosmetic method for reducing the amount of subcutaneous adipose tissue in a subject by topical application. In another aspect, there is provided a cosmetic method for reducing the amount of subcutaneous adipose tissue in a subject, such as a mammal, e.g., a human, comprising administration of a composition as described above. Reduction in the volume of subcutaneous adipose tissue at localized sites on the body by application of mirabegron may result in a non-therapeutic cosmetic method.

[0056] A further embodiment refers to the use of mirabegron or a salt thereof for the manufacture of a transdermal drug, preferably for use in the treatment of obesity or cellulite or for providing lipolysis. In other words, a further embodiment refers to mirabegron or a salt thereof, preferably for use in the treatment of obesity or cellulite, or for use as a transdermal drug for providing lipolysis. Mirabegron and its salts can be administered transdermally using the DMSO-containing compositions described above. This allows for transdermal application of mirabegron. For the description of mirabegron and its salts, compositions and uses of mirabegron, reference is made to the above descriptions.

[0057] A further embodiment refers to a composition as described herein, preferably for use in the treatment of obesity or cellulite, or for use in a transdermal procedure to provide lipolysis. For the description of mirabegron and its salts, compositions and uses of mirabegron, reference is made to the above descriptions.

[0058] Unless defined otherwise, technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

[0059] The following examples serve to illustrate the invention in more detail but do not constitute a limitation thereof. [Brief description of the drawings]

[0060] [Figure 1] FIG. 1 shows a scheme of a Franz-type diffusion cell with a 1 cm orifice according to USP(725). [Figure 2a)] FIG. 1 shows the amount of mirabegron that permeated per cm2 of human abdominal skin over a 24-h period. [Figure 2b] FIG. 1 shows the amount of mirabegron that permeated per cm2 of mouse skin over a 24-h period. [Diagram 3] FIG. 1 shows the amount of mirabegron permeated per cm2 of human skin over 24 h from a solution of 5 wt.-% mirabegron in DMSO or a mixture of ethanol and DMSO. [Figure 4] FIG. 1 shows the amount of mirabegron that permeated per cm2 of mouse skin over 24 h from a solution of 3 wt.-% mirabegron in a mixture of ethanol and isopropyl myristate (90 / 10, m / m). [Diagram 5] FIG. 1 shows the amount of mirabegron permeated per cm2 of mouse skin over 24 h from a 10 wt.-% solution of mirabegron in a mixture of Transcutol® (TC) and DMSO (50 / 50, m / m), and a 3 wt.-% solution of mirabegron in aqueous mixtures of 40, 50, or 75 wt.-% Transcutol® and 60, 50, or 25 wt.-% water. [Figure 6] FIG. 6a) shows a tissue section of mouse subcutaneous adipocytes after hematoxylin and eosin staining 10 days after treatment with DMSO, and FIG. 6b) shows a tissue section of mouse subcutaneous adipocytes after treatment with 5 wt.-% mirabegron in DMSO. [Figure 7] FIG. 7a) shows hematoxylin and eosin stained tissue sections of human subcutaneous adipocytes 2 days after treatment with 3 wt.-% mirabegron in a mixture of 90 wt.-% ethanol and 10 wt.-% isopropyl myristate, and FIG. 7b) shows hematoxylin and eosin stained tissue sections of human subcutaneous adipocytes 2 days after treatment with 3 wt.-% mirabegron in a mixture of 90 wt.-% ethanol and 10 wt.-% isopropyl myristate. [Figure 8] FIG. 1 shows tissue sections after hematoxylin and eosin staining and UCP1 staining of mouse subcutaneous adipocytes after 10 days of treatment with DMSO / ethanol gel containing 5 wt.-% mirabegron. [Figure 9] 9a), b), c), and d), respectively, show the gene expression of thermogenetic markers UCP1, Cidea, and PGC1α, and the inflammatory marker TNFα, after application of mirabegron. Example 1

[0061] Determination of the solubility of mirabegron in several solvents At each step, solubility was tested by adding increasing increments of 10 mg of mirabegron to 5 mL of the respective solvent under stirring followed by sonication of the solution / suspension for 5 minutes at ambient temperature. Complete dissolution was considered when a clear, gradually yellow solution was obtained. It was observed that polar aprotic solvents, short chain alcohols, glycols, and polytheylene glycols were suitable solvents for dissolving mirabegron. In particular, dimethyl sulfoxide (DMSO) (Sigma-Aldrich) and methanol (Fisher Scientific, UK), N-methylpyrrolidone (NMP) (VWR International SAS) and Transcutol® (Gattefosse SAS) provided suitable solubility for mirabegron. However, methanol and N-methylpyrrolidone are toxicologically hazardous and cannot be used in pharmaceutical preparations. Example 2

[0062] Determination of Mirabegron Permeation from Different Formulations Permeation was determined in Franz diffusion cell experiments. A schematic of a Franz-type diffusion cell is shown in FIG. The donor compartment (2) and receptor compartment (4) are attached to one another using clamp attachment lugs (6). A membrane (8) is fitted between the donor compartment (2) and the receptor compartment (4). The receptor compartment (4) has a sampling side arm (10). The formulation to be determined (3) is applied to the donor compartment (2). The receiver fluid (5) is contained within the receptor compartment (4). Franz-type diffusion cells allow the measurement of the amount of mirabegron that has diffused across a membrane, for example abdominal human skin or mouse skin, into the acceptor medium.

[0063] Mouse skin or excised human abdominal skin obtained from plastic surgery was used as membranes. Mouse skin was stripped of full thickness from underlying tissue and left unshaven. Human abdominal skin membranes were prepared by removing subcutaneous adipose tissue with a scalpel and then standardizing to a thickness of 400 μm with a dermatome (Aesculap GA643).

[0064] 1.00cm 2 Franz-type diffusion cells (PermeGear) as defined in the United States Pharmacopeia (USP(725)) with an orifice area of ​​100 μm were used at 32° C. Phosphate-buffered saline (PBS) pH 7.4 (NaCl 137 mmol / L (Merck, Darmstadt, Germany), KCl 2.7 mmol / L (Merck, Darmstadt, Germany), Na 2 HPO 4 10mmol / L (Sigma-Aldrich, Steinbach, Germany), KH 2 PO 4 8 mL of a 6 wt.-% solution of Brij® 98 (Acros Organics) at 1.8 mmol / L (Carl Roth, Karlsruhe, Germany) was used as receiver fluid in the receptor compartment. 200 mg of each sample formulation was provided in the donor compartment. The experiments were carried out at 32°C. After each interval, samples were taken from the receiver fluid and analyzed via High Performance Liquid Chromatography-Ultraviolet (HPLC-UV) using an LC-2030C3D Plus HPLC system (Shimadzu Deutschland GmbH, Duisburg, Germany) to provide results of mass transport (flux) per unit of time and area.

[0065] 200 mg of formulation containing mirabegron based on the total weight of the formulation in the solvents and solvent mixtures given in Tables 2 and 3 below was provided in the donor compartment. Solutions were prepared by dissolving respective amounts of mirabegron (Mehta API Pvt. Ltd., Mumbai, India) in respective solvents or mixtures. The human skin described above was used as the membrane.

[0066] After 24 hours, samples were taken from the receiver fluid and analyzed via HPLC-UV. Tables 1 and 2 below summarize the results of the Franz diffusion cell experiments evaluating permeation after 24 hours. The number of "+" signs indicates the strength of the measured penetration. Solvent ratios are given with reference to wt.-% (m / m), i.e. DMSO / ethanol (50 / 50) indicates a mixture of 50 wt.-% of each.

[0067] [Table 1]

[0068] The results in Table 1 show that generally higher dP values ​​increased penetration. Furthermore, it was observed that increasing the amount of DMSO in the ethanol mixture enhanced the penetration. However, the addition of the excellent solvent Transcutol® to DMSO reduced permeation.

[0069] [Table 2]

[0070] The results in Table 2 show that a solvent with high solubility for mirabegron does not automatically allow for the assessment of permeation. Furthermore, it was observed that water reduces the solubility of mirabegron in the mixture, especially in alcohol mixtures, and that mixtures containing water do not allow for permeation. Example 3

[0071] Determination of Mirabegron Permeation from DMSO-Containing Formulations The permeation of mirabegron from formulations containing DMSO through mouse or excised human abdominal skin was evaluated over a 24 h period. Permeation was determined in Franz diffusion cell experiments as described in Example 2 above.

[0072] A solution of 5 wt.-% mirabegron (Mehta API Pvt. Ltd., Mumbai, India) in DMSO was prepared and tested using mouse skin or excised human abdominal skin. Samples were taken and analyzed after 1, 2, 3, 4, 5, 6, and 24 hours. Figure 2a) shows the effect of 1 cm of human abdominal skin over a period of 24 h. 2 Figure 2b) shows the amount of mirabegron that penetrated into a 1 cm 2 The figure shows the amount of mirabegron that penetrated per unit area. As can be seen from Figures 2a) and b), substantial amounts of mirabegron penetrate mouse and human skin within 24 h. cm for human skin 2 * Flux of 9.18μg per hour and cm2 on mouse skin 2 A flux of 4.58 μg per hour was determined.

[0073] Additionally, solutions of 3 wt.-% mirabegron in DMSO, and in mixtures of 10 wt.-% DMSO with 90 wt.-% or 50 wt.-% DMSO with 50 wt.-% ethanol were prepared and tested on human skin. Samples were taken and analyzed after 2, 3, 4, 5, 6, 8, and 24 hours. Figure 3 shows the effect of 1 cm of human skin over a 24-h period. 2 The figure shows the amount of mirabegron that penetrated per unit area. As can be seen from Figure 3, increasing the amount of DMSO in the ethanol mixture enhanced the in vitro permeation.

[0074] In addition, a solution of 3 wt.-% mirabegron in a mixture of 90 wt.-% ethanol and 10 wt.-% isopropyl myristate was prepared and tested on human skin. Samples were taken and analyzed after 6, 7, 8, and 24 hours. Figure 4 shows the effect of 1 cm of human skin over a 24-hour period. 2 The figure shows the amount of mirabegron that penetrated per unit area. As can be seen from FIG. 4, permeation from the ethanol solution with isopropyl myristate was slower than from the formulation containing DMSO, but after 24 h permeation was similar to 100% DMSO.

[0075] Additionally, solutions of 10 wt.-% mirabegron in a mixture of 50 wt.-% DMSO and 50 wt.-% Transcutol® (Gattefossé SAS) or 3 wt.-% mirabegron in aqueous mixtures of 40, 50, or 75 wt.-% Transcutol® and 60, 50, or 25 wt.-% water were prepared and tested on human skin. Samples taken after 24 hours were analyzed. Figure 5 shows the effect of 1 cm of human skin over a 24-hour period. 2 The figure shows the amount of mirabegron that penetrated per unit area. As can be seen from FIG. 5, the mixture of DMSO and Transcutol® provided high permeation, whereas the mixture containing water reduced permeation to 5 μg / cm 2 It was reduced to less than This indicates that water reduced the soluble amount of mirabegron in the formulation and therefore reduced the permeation.

[0076] In addition, a 3 wt.-% solution of mirabegron in PEG200 (Sigma-Aldrich, Steinbach, Germany), PEG400 (Sigma-Aldrich), propylene glycol, water, Transcutol®, ethanol / gycerol (50 / 50) or ethanol / gycerol / isopropyl myristate (45 / 45 / 10) demonstrated a 3 μg / cm2 concentration of mirabegron on human skin after 24 hours. 2 showed less penetration. This demonstrated that the solution without dimethylsulfoxide lacked osmolarity. Example 4

[0077] Determination of in vivo lipolysis The efficacy of a composition containing 5 wt.-% mirabegron in dimethylsulfoxide following transdermal administration was examined in vivo in C57BL / 6 (25 gr) mice. Mice were treated for 10 days with either DMSO placebo or 5 wt.-% mirabegron in dimethylsulfoxide on both flanks of animals in each experimental group. Ten days later, the mice were sacrificed and the subcutaneous adipocytes were analyzed.

[0078] Freshly isolated tissue was fixed by incubation in 4% paraformaldehyde (PFA) in PBS for up to 16 h, followed by two washes for 5 min each in ice-cold PBS. Samples were then dehydrated in increasing concentrations of ethanol: 50%, 70%, 95%, and 100% (three times for each concentration, 20 min). In the next step, the samples were delipidated by three successive incubation steps in xylol for 10 min each. The samples were further incubated in paraffin at 60°C for 1 hour twice, followed by an overnight incubation at 60°C. The cassettes were then used to embed the processed samples in a warm liquid paraffin solution, which was then allowed to solidify for storage at room temperature. For each staining, 5 μm thick sections were taken with a microtome (Microm), and the stained sections were then dried on tissue slides at 40° C. for 24 hours.

[0079] Paraffin was removed from tissue slides with three xylol washes for 5 min each. Samples were incubated in decreasing concentrations of ethanol: 100%, 95%, 90%, 75%, and 50% (2 washes for 2 min for each concentration), followed by further HO. 2 Washed twice in O (5 min each wash). The samples were incubated in hematoxylin for 2 seconds, after which the slides were rinsed under running water for 10 minutes. The slides were then stained with eosin for 2 min and washed in distilled water for 4 min with agitation. For dehydration of the tissue, increasing concentrations of ethanol were used: 50%, 75%, 95%, and 100% (for each concentration, the tissue was washed twice for 2 min), followed by two further washing steps in xylol for 2 min each. Finally, the slides were mounted using Roti-Histokitt.

[0080] FIG. 6 shows histological sections of mouse subcutaneous adipocytes after hematoxylin and eosin staining, FIG. 6a) after 10 days of treatment with DMSO as a control, and FIG. 6b) after 10 days of treatment with 5 wt.-% mirabegron in DMSO. As can be seen from a comparison of Figures 6a) and b), the size of fat vacuoles in white adipose tissue in the mirabegron-treated group was significantly reduced compared to the control group.

[0081] FIG. 7 shows histological sections of human subcutaneous adipocytes after hematoxylin and eosin staining, with FIG. 7a) showing after 2 days of treatment of ex vivo human abdominal skin with a mixture of 90 wt.-% ethanol and 10 wt.-% isopropyl myristate as a control, and FIG. 7b) showing after 2 days of treatment with 3 wt.-% mirabegron in a mixture of 90 wt.-% ethanol and 10 wt.-% isopropyl myristate. As can be seen from a comparison of Figures 7a) and b), the size of fat vacuoles in the white adipose tissue of the treated samples was not significantly reduced compared to the control group. This indicates that a mixture of 90 wt.-% ethanol and 10 wt.-% isopropyl myristate provides penetration but no effect was observed (as shown in Table 2).

[0082] This indicates that dimethyl sulfoxide and mixtures containing dimethyl sulfoxide not only provided solubility, permeability, and toxicological acceptability, but also provided mirabegron with a sufficient active delivery period to provide the desired effect upon transdermal administration in vivo. Example 5

[0083] Determination of thermogenesis markers following application of mirabegron in vivo The effects of mirabegron on thermogenic markers following percutaneous administration in dimethyl sulfoxide gel were examined in vivo in C57BL / 6 (25gr) mice.

[0084] Mirabegron (MIR) (Swapnroop Drugs & Pharmaceuticals) was dissolved in DMSO (pharmaceutical grade, ITW Reagents) followed by the addition of ethanol (absolute, Sigma-Aldrich). Hydroxypropyl cellulose H (HPC-H) (Nippon Soda Co., Ltd.) was added to the DMSO / EtOH mixture under stirring, and the resulting suspension was sealed and left to stand until complete dissolution of the gelling agent was observed. Its exact composition is summarized in Table 3 below.

[0085] [Table 3]

[0086] Wild type (WT) C57BL / 6 mice were divided into groups of eight and treated with mirabegron gel (verum) or placebo. The flanks of the mice were shaved with an electric razor. 50 mg of gel was applied to each flank once daily for 10 days. 24 h after the final application of the gel, the animals were sacrificed and the inguinal white adipose tissue (WATi) was removed and analyzed for browning marker expression by qPCR, Western blot, and histologically after hematoxylin and eosin, and UCP1 antibody staining.

[0087] For histological analysis, tissue samples were fixed in 4% paraformaldehyde solution and embedded in paraffin. Sections 5 μm thick were stained with hematoxylin and eosin (H&E) and UCP1-specific antibody, respectively.

[0088] For RNA isolation and real-time polymerase chain reaction (qPCR), tissues were homogenized with Trizol (ThermoFisher) for mRNA extraction, treated with chloroform, precipitated by adding propan-2-ol, and washed with 75% EtOH. The concentration of isolated RNA was analyzed spectrophotometrically by Nanodrop 200 (ThermoFisher Scientific). Synthesis of cDNA was performed with the ProtoScript II First Strand cDNA Synthesis Kit (New England Biolabs) according to the manufacturer's instructions. Amplification was analyzed by staining with SYBR Green Master Mix (Thermo Fisher) and measurement in a QuantStudio5 qPCR system (Thermo Fisher). 2 -ΔCT The relative mRNA expression of genes normalized to the housekeeping gene HRPT for mouse samples was calculated using the method.

[0089] For Western blots, the buffer used was 50 mM Tris pH 7.5, 150 mM sodium chloride, 1% NP-40, 0.5% sodium deoxycholate, 0.1% sodium dodecyl sulfate, 0.1 mM EDTA, 0.1 mM EGTA, 1 mM Na, containing protease inhibitor cocktail (Roche). 3 VO 4 , proteins were isolated using RIPA lysis buffer containing 10 mM NaF. Protein content was quantified by Bradford assay. Proteins were separated by 12% SDS-PAGE and transferred to nitrocellulose membranes. For immunoblotting, primary antibodies against UCP1 (Sigma-Aldrich) and calnexin, and secondary anti-rabbit antibody were used. Proteins were visualized using Amersham ECL Western blotting reagents and detection was performed by ImageQuant LAS4000 mini (GE Healthcare). Quantification was performed using ImageJ software.

[0090] H&E and UCP1 staining of mouse inguinal white adipose tissue (WAT) showed that application of placebo gel to the flanks of WT C57BL / 6 mice for 10 days did not show any morphological signs of browning, such as multiocular morphology or reduced adipocyte size in H&E stained tissue. In contrast, treatment with the mirabegron-containing gel led to a significant reduction in the size of lipid droplets inside the adipocytes and their amount increased. Thus, as can be seen in FIG. 8, immunostaining for UCP1 showed extensive areas of staining for the mirabegron-treated samples, whereas the placebo-treated samples hardly showed any areas of staining.

[0091] Immunostaining for UCP1, a key protein in mitochondrial non-shivering thermogenesis and expressed exclusively in brown adipose tissue, is considered as histological confirmation of browning due to application of mirabegron gel.

[0092] As seen in FIG. 9, the expression of brown adipose tissue (BAT)-specific gene markers increased after application of the mirabegron-containing gel. As shown in FIG. 9a), the expression of UCP1 was significantly increased by 8.2-fold and 12.0-fold for the mirabegron-containing gels at 10 DMSO and 50 DMSO compared to placebo. For Cidea, as can be seen in FIG. 9b), a 5.5-fold and 6.6-fold increase was observed for the mirabegron-containing gels 10DMSO and 50DMSO compared to placebo. As can be seen in FIG. 9c), treatment with mirabegron-containing DMSO gel at 10 DMSO and 50 DMSO further resulted in a significant increase in PGC1α by a factor of 2.5 and 3.0, respectively, over placebo. However, as can be seen in FIG. 9d), expression of the inflammatory marker TNFα was not increased for any of the gels compared to placebo. Thus, analysis of gene expression by qPCR showed an increase for all browning markers.

[0093] In addition, analysis of protein expression by Western blot showed a UCP1 band for the mirabegron-containing gels, but no band could be observed for the placebo gels. A control band for calnexin was visible for all gels. Quantitative analysis of UCP1 expression normalized to calnexin showed significantly increased levels of UCP1 for the mirabegron-treated group compared to placebo. This indicates that the observed increase in gene expression was translated into expression of UCP1 at the protein level, indicating that the dose of mirabegron delivered from the DMSO gel in the selected time frame was sufficient to effectively induce browning of inguinal white adipose tissue.

[0094] This indicates that the dimethyl sulfoxide and ethanol gel successfully promoted transdermal delivery of mirabegron and provided a mirabegron formulation that effectively induced classical features of browning in mouse inguinal white adipose tissue in vivo. Thus, it has been demonstrated that topical administration of mirabegron in DMSO gel may be usable to provide lipolysis or may be a mode of administration that can be used to treat obesity, cellulite, or diabetes. Example 6

[0095] Determining permeation using small amounts of DMSO As described in Example 2, human skin was used to make 1.00 cm 2 Permeation was determined in Franz-type diffusion cells (Permegia) as defined in USP(725) with an orifice area of ​​0.01 mm. Solutions of 20 mg of mirabegron in 49 mg of DMSO and 931 mg of ethanol (19:1 (w / w)) were prepared by dissolving the respective amounts of mirabegron (Mehta API Pvt. Ltd., Mumbai, India) in the respective solvent mixtures. After 24 hours samples from the receiver fluid were taken and analyzed via HPLC-UV. 0.4μg / cm 2 Less than 100% penetration was found. This indicated that 5 wt.-% DMSO was the minimum amount in the formulation.

Claims

1. A composition for topical and / or transdermal administration comprising mirabegron or a salt thereof, the composition comprising: a) ≧0.01 wt.-% to ≦25 wt.-% of mirabegron or a salt thereof; b) a solvent, - dimethyl sulfoxide (DMSO) in the range of ≧5 wt.-% to ≦99.99 wt.-%; or - dimethyl sulfoxide in the range of ≧5 wt.-% to ≦97.99 wt.-% and a solvent selected from i) a monoalcohol in the range of ≧5 wt.-% to ≦94.99 wt.-%, or ii) glycerol, glycol, polyethylene glycol, glycol ether, mixtures thereof or mixtures with monoalcohols in the range of ≧5 wt.-% to ≦60 wt.-%, or iii) water in the range of ≧2 wt.-% to ≦10 wt.-%, wherein said wt.-% is based on a total weight of said composition of 100 wt.-%.

2. 2. The composition of claim 1, characterized in that the composition comprises c) one or more pharmaceutical excipient(s).

3. 3. The composition according to claim 2, characterized in that the pharmaceutical excipient is selected from the group comprising antioxidants, penetration enhancers, gel formers, ointment components, preservatives, colorants, odorants, stabilizers, triglycerides, and mixtures thereof, preferably a gel former.

4. The composition, a) mirabegron in the range of ≧0.01 wt.-% to ≦10 wt.-%; b) Dimethylsulfoxide in the range of ≧5 wt.-% to ≦50 wt.-% and C in the range of ≧50 wt.-% to ≦95 wt.-% ２ ~C ５ a mixture of alcohol, preferably ethanol; c) a gel-forming agent selected from the group consisting of hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl methyl cellulose, and mixtures thereof, in the range of ≧1 wt.-% to ≦20 wt.-%; 10. The composition according to any one of the preceding claims, characterized in that said wt.-% is based on a total weight of said composition of 100 wt.-%.

5. The composition comprises as a solvent - dimethyl sulfoxide in the range of ≧10 wt.-% to ≦100 wt.-%; and optionally - monoalcohols in the range of ≧10 wt.-% to ≦90 wt.-%; or - containing glycerol, glycol, polyethylene glycol, glycol ether, mixtures thereof or mixtures with monoalcohols in the range of ≧10 wt.-% to ≦60 wt.-%; 2. The composition of claim 1, wherein said wt.-% is based on a total weight of said solvent of 100 wt.-%.

6. The monoalcohol is selected from the group consisting of ethanol, n-propanol, isopropanol, n-butanol, isobutanol, tert-butanol, or mixtures thereof. ２ ~C ５ 10. The composition according to any one of the preceding claims, characterized in that it is an alcohol, preferably ethanol.

7. 7. The composition according to claim 5 or 6, characterized in that the composition comprises dimethyl sulfoxide in the range of ≧10 wt.-% to ≦50 wt.-% and ethanol in the range of ≧50 wt.-% to ≦90 wt.-% based on a total weight of the solvent of 100 wt.-%.

8. 10. A composition according to any one of the preceding claims, characterized in that a glycol ether is present, preferably diethylene glycol monoethyl ether.

9. 9. The composition of claim 8, characterized in that the composition comprises ≧40 wt.-% to ≦90 wt.-% dimethyl sulfoxide and ≧10 wt.-% to ≦60 wt.-% diethylene glycol monoethyl ether, based on a total weight of 100 wt.-% of the solvent.

10. A composition for topical and / or transdermal administration comprising mirabegron or a salt thereof, the composition being soluble in water (1 cm at 32° C. according to USP (725) ２ at least 5 μg / cm over 24 hours (measured in a Franz diffusion cell with an orifice of ２ A composition comprising:

11. A composition for topical and / or transdermal administration comprising mirabegron or a salt thereof, characterized in that said composition contains mirabegron in a molecularly dispersed form.

12. 10. The composition according to any one of the preceding claims, characterized in that the composition is in the form of a topical composition, preferably selected from the group consisting of a gel, an ointment, a cream, a foam, a lotion, a paste, a solution, a spray or a plaster, preferably in the form of a gel or a spray.

13. A composition according to any one of claims 1 to 12 for use in the treatment of obesity or cellulite, or for providing lipolysis.

14. A composition according to any one of claims 1 to 12 for use in a cosmetic method for reducing the amount of subcutaneous adipose tissue in a subject by topical application.

15. Preferably, mirabegron or a salt thereof for use in the treatment of obesity or cellulite, or for use as a transdermal drug for providing lipolysis.

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