EP4499041A1

EP4499041A1 - Mirabegron formulation

Info

Publication number: EP4499041A1
Application number: EP23717848.8A
Authority: EP
Inventors: Sebastian Kalju KAPPES; Alf Lamprecht; Zheming NIU; Alexander Pfeifer
Original assignee: Rheinische Friedrich Wilhelms Universitaet Bonn
Current assignee: Rheinische Friedrich Wilhelms Universitaet Bonn
Priority date: 2022-03-30
Filing date: 2023-03-30
Publication date: 2025-02-05
Also published as: MX2024012001A; JP2025510868A; WO2023187116A1; CN119278028A; AU2023244508A1; CA3246727A1

Abstract

The present invention relates to a composition for topical and/or transdermal administration comprising mirabegron or a salt thereof, wherein the composition comprises: a) mirabegron or a salt thereof in a range from ≥ 0.01 wt.-% to ≤ 25 wt.-%; and b) a solvent selected from: - dimethyl sulfoxide (DMSO) in a range from ≥ 5 wt.-% to ≤ 99.99 wt.-%; or - a mixture of dimethyl sulfoxide in a range from ≥ 5 wt.-% to ≤ 97.99 wt.-%, and a further solvent selected from i) a monoalcohol in a range from ≥ 5 wt.-% to ≤ 94.99 wt.-%, or ii) glycerol, a glycol, a polyethylene glycol, a glycol ether, mixtures thereof, or mixtures with a monoalcohol in a range from ≥ 5 wt.-% to ≤ 60 wt.-%, or iii) water in a range from ≥ 2 wt.-% to ≤ 10 wt.-%; wherein the wt.-% are based on a total weight of the composition of 100 wt.-%.

Description

Mirabegron formulation

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

Overweight and obesity are major risk factors for many diseases. One in two citizens of the European Union is overweight, more than one in three is pre-obese and one in six is considered obese with a Body Mass Index (BMI) of over 30. In the United States, the prevalence of obesity is even more pronounced. These groups of people are significantly more at risk of developing cardiovascular diseases and diabetes mellitus. The aesthetic problems of the overweight also lead to social isolation and can lead to mental illnesses such as depression. The clinical picture of lipedema in this regard is particularly distressing. Eipedema is a chronic and progressive disease of the subcutaneous fatty tissue of the upper and lower extremities, which almost exclusively affects women. The disease is poorly understood, but it appears to be due to a pathological increase in adipose tissue through hypertrophy and hyperplasia, accompanied by fluid retention. This leads to a marked, delineated increase in volume of the affected body parts, especially the extremities, compared to the rest of the body. Combating obesity therefore has a direct benefit for the physical and mental health of each individual and the population.

Drugs that increase fat loss belong for the most part to the class of anorectic drugs. These are largely derived from amphetamines and suppress the appetite. Another possibility to support weight reduction is the use of lipase inhibitors. However, these substances require oral or injectable administration. In the case of systemic administration, however, serious side effects must be expected, since these compounds largely interfere with the metabolism of neurotransmitters in the brain. A topical application essentially reduces systemic absorption and respective side effects. WO 2007/011743 Al discloses compositions for treating regional fat deposits comprising long -acting beta- 2 adrenergic receptor agonists salmeterol or formoterol and a compound that reduces desensitization of the target tissue to the long-acting P2 -adrenergic receptor agonist, for example, glucocorticosteroids and/or ketotifen. The composition, for example, may be administered by injection and/or transdermally. However, pharmaceutically active compounds often show no or only suboptimal clinical efficacy upon topical administration because of poor penetration through the skin.

EP 3 206 678 Bl discloses a pharmaceutical composition for topical administration comprising a prodrug for an agonist and/or an antagonist for an adrenergic receptor, wherein the prodrug is an ester, for or use in a therapeutic method of shaping a mammalian body by modulation of subcutaneous fat tissue. One of the numerous cited P3 -adrenoceptor receptor agonists (“beta-agonist”) is mirabegron. A permeation of the prodrug provides a transport route via the skin, but the availability of the active ingredient depends on the activity of enzymes which are capable of releasing the agonist from the prodrug, and whether a therapeutic effect can be achieved that way is unknown. The permeation of naive adrenergic receptor agonists and antagonists is considered insufficient for adipositas therapy and/or lipolysis.

Mirabegron (INN) is a prescription medicine from the group of p3-sympathomimetics. It has been approved in the EU for the treatment of overactive bladder since 2012. Its physicochemical properties, however, are adversary to a dermal application and include a relatively high molecular weight and melting point, it is insoluble in water (water solubility 82 pg/mL) and only limited soluble in lipids. Thus, dissolving high amounts of mirabegron in water is impossible and aqueous mixtures with typically used polar cosolvents retain low solubility for mirabegron. Further, the solubility in lipids is limited and the application of products with high lipid content is unpleasant and reduces patient compliance

The object of the present invention is therefore to provide a composition allowing a topical or transdermal administration of mirabegron. The object is achieved by the composition according to claim 1. The object further is achieved by the composition for use according to claims 10 to 14. Advantageous embodiments are the subject of the dependent claims. The embodiments may be combined freely unless the context clearly indicates otherwise.

Accordingly, a composition for topical and/or transdermal administration comprising mirabegron or a salt thereof is provided, wherein the composition comprises: a) mirabegron or a salt thereof in a range from > 0.01 wt.-% to < 25 wt.-%; and b) a solvent selected from:

- dimethyl sulfoxide (DMSO) in a range from > 5 wt.-% to < 99.99 wt.-%; or

- a mixture of dimethyl sulfoxide in a range from > 5 wt.-% to < 97.99 wt.-%, and a further solvent selected from i) a monoalcohol in a range from > 5 wt.-% to < 94.99 wt.-%, or ii) glycerol, a glycol, a polyethylene glycol, a glycol ether, mixtures thereof, or mixtures with a monoalcohol in a range from > 5 wt.-% to < 60 wt.-%, or iii) water in a range from > 2 wt.-% to < 10 wt.-%; wherein the wt.-% are based on a total weight of the composition of 100 wt.-%.

It has surprisingly been found that dimethyl sulfoxide allows for a transdermal administration of mirabegron. In contrast to other compounds of the broad spectrum of permeation enhancers known in the art, DMSO facilitated skin permeation and an increased active delivery period for mirabegron was observed. It could further be shown that a mixture of dimethyl sulfoxide with alcohol or glycol ether could provide effective transdermal delivery of mirabegron. Pure dimethyl sulfoxide and mixtures thereof enabled sufficient maintenance of dissolved mirabegron on skin while showing high permeation. On the other hand, solutions or mixtures without dimethyl sulfoxide either lacked solubility, permeability, were too volatile or were toxicologically inacceptable.

As used herein, the term “mirabegron” (INN), formerly known as YM 178, refers to a p3-adrenergic receptor agonist (“beta-agonist”) of the following formula (1): Mirabegron is commercially available, in Europa under the tradename Betmiga®. Mirabegron is commercially used as non-salt free base. Also salts, preferably pharmaceutically acceptable salts, of mirabegron are usable. The term “pharmaceutically acceptable salts” refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids. Preferred salts include ammonium, calcium, magnesium, potassium and sodium salts as well as hydrochloride, sulfate, succinate, acetate, fumarate, tartrate, besilate and mesylate salts. Furthermore, mirabegron complexes, such as lauryl sulfate, octyl sulfate, myristyl sulfate, and cetyl sulfate salts/complexes are known and are usable.

As used herein, the term “topical” administration refers to that a substance, such as mirabegron, is applied to a particular place on or in the body, in particular to body surfaces such as skin or mucous membranes. As used herein, the term “transdermal” administration refers to that a substance, such as mirabegron, upon administration permeates the upper skin layers and distributes in the subcutaneous layers, namely dermis and subcutis.

If not specifically denoted otherwise, given % are weight% (wt.-%). The total amount of all components of the composition does not exceed 100 wt.-%. Regarding mirabegron, given wt.-% refer to the total weight of the composition. For example, 100 g of a 5% mirabegron solution in DMSO/ethanol (50/50, w/w) refers to 5 g mirabegron and 47.5 g of each of DMSO and ethanol.

Important for the solubility of mirabegron is the ratio of the solvents, in particular the weight by weight ratio (w/w) of DMSO to a further solvent od a mixture of further solvents. The weight by weight ratio of DMSO to a further solvent may be in a range of 9.5:0.5 to 0.5:9.5, depending on the nature of the further solvent. Still, the ratio of DMSO to the further solvent, given as 10/90 (w/w) or 50/50 (w/w), defines the solubility of mirabegron in the formulation, irrespective of the presence of excipients such as gelation agents or stabilizers.

For effective transdermal delivery of a compound from a formulation solvent system, several requirements need to be met. First, an adequate solubility of the active compound in the formulation needs to be provided. Further, increased solubility of the active compound in skin (both epidermal and dermal) needs to be observed (Penetration Enhancement). Last, sufficient solvent retention (limitation of solvent evaporation) on the skin needs to be provided to ensure state of molecular dispersion of the payload. It was observed that solvents with high solubility for mirabegron did not automatically allow for a permeation through the skin. For example, diethylene glycol monoethyl ether, which is commercially available under the tradename Transcutol®, provided high solubility when used without dimethyl sulfoxide but insufficient permeation of mirabegron. Other solvents such as ethanol provided high solubility and permeation, but no effect of mirabegron on lipolysis was observed. It is assumed that such a lack of efficacy of mirabegron may be due to evaporation of the solvent and precipitation of mirabegron.

Generally, polar aprotic solvents, short chain alcohols, glycols, and polyethylene glycols are suitable solvents for dissolving medium to high amounts of mirabegron. However, polar aprotic solvents such as N,N-Dimethylformamide and N-methyl pyrrolidone are toxicologically critical.

The composition comprises mirabegron as active ingridient. In embodiments, the composition comprises mirabegron or a salt thereof in a range from > 0.01 wt.-% to < 25 wt.-%, preferred in a range from > 0.01 wt.-% to < 20 wt.-%; preferably in a range from > 0.1 wt.-% to < 10 wt.-%, more preferably in a range from > 0.5 wt.-% to < 5 wt.-%, based on the total weight of the composition. Such concentrations provided good solubility and effects of mirabegron.

The composition comprises dimethyl sulfoxide (DMSO) in a range from > 5 wt.-% to < 99.99 wt.-%. It was found that formulations comprising less than 5 wt.-% provided low permeation of mirabegron.

In embodiments, the composition comprises one or more pharmaceutical excipient(s). In embodiments, the composition comprises one or more pharmaceutical excipient(s) selected from the group comprising antioxidants, penetration enhancers, gel forming agent, ointment components, preservatives, colorants, odorants, stabilizers, triglycerides, and mixtures thereof, and preferably is a gel forming agent.

Suitable excipients selected from ointment bases, gel formers, antioxidants, pH modulators, preservatives, colorants, and stabilizers preferably are selected from the group comprising alpha tocopherol, acetic acid, ammonia solution, anhydrous citric acid, ascorbic acid, ascorbyl palmitate, bentonite, benzalkonium chloride, benzyl alcohol, butylparaben, calcium acetate, carbomers, carocymethyl cellulose sodium, carnauba wax, carrageenan, castor oil, ceteareth-30, veteth-10, cetostearyl alcohol, cetyl alcohol, cholesterol, coconut oil, colloidal silicon dioxide, com oil, crospovidone, diethylene glycol monoethyl ether, dimethicone 100, docosanol, docusate sodium, etate disodium, ethylcellulose, ethylparaben, ferric oxide red, formic acid, gelatin, gylceryl monostearate, gylceryl oleate, hyaluronate sodium, 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, PEG/PPG-18/18 dimethicone, PEG-100 stearate, PEG-5 oleate, PEG-60 hydrogenated castor oil, PEG-75 lanolin, poloxamers, polyacrylic acid, polyethylene, polyethylene glycols, polysorbates, povidone, propylene glycol, quatemium-15, shea butter, simethicone, sodium bisulfite, sodium chloride, sodium hydroxide, sodium laureth-2 sulfate, sodium lauryl sulfate, sodium metabisulfite, sodium silicate, sorbic acid, stearic acid, thyme oil, triethanolamine, urea, vitamin E polyethylene succinate, wax, xanthan gum, zinc acetate, zinc oxide, and zinc stearate.

A preferred form of provision of the formulation is a gel. In embodiments, 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 comprise the gel forming agent, such as hydroxypropyl cellulose or hydroxyethyl cellulose, in a range of from > 1 wt.-% to < 20 wt.-%, preferably in a range of from > 2 wt.-% to < 10 wt.-%, based on a total weight of the composition of 100 wt.-%.

In embodiments, the composition comprises DMSO in a range from > 5 wt.-% to < 50 wt.-%, and a monoalcohol in a range from > 50 wt.-% to < 95 wt.-%, based on a total weight of the composition of 100 wt.-%.

Preferred are short-chained monoalcohols comprising up to 6 aliphatic carbon atomes. In preferred embodiments, the monoalcohol is a C₂-C₅ alcohol selected from the group of ethanol, n-propanol, isopropanol, n-butanol, isobutanol, tert. -butanol, or mixtures thereof. In preferred embodiments, the monoalcohol is ethanol. In further embodiments, the monoalcohol may be isobutanol. Gels providing good permeation results of mirabegron through the skin could be provided using a mixture of DMSO and ethanol as solvent. In embodiments, the composition comprises: a) mirabegron in a range from > 0.01 wt.-% to < 10 wt.-%; b) a mixture of dimethyl sulfoxide in a range from > 5 wt.-% to < 50 wt.-% and a C₂-C₅ alcohol, preferably ethanol, in a range from > 50 wt.-% to < 95 wt.-%, and c) 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 in a range from > 1 wt.-% to < 20 wt.-%, wherein the wt.-% are based on a total weight of the composition of 100 wt.-%.

In embodiments, compositions may comprise a triglyceride. Preferred are triglycerides are selected from the group comprising glyceryl monostearate and glyceryl oleate. In embodiments, the composition comprises a triglyceride, preferably selected from the group cpmprising glyceryl monostearate and glyceryl oleate, in a range from > 1 wt.-% to < 20 wt.-%, based on a total weight of the composition.

In other embodiments, aqueous solutions comprising DMSO are provided. In embodiments, the composition comprises dimethyl sulfoxide in a range from > 90 wt.-% to < 97.99 wt.-% and water in a range from > 2 wt.-% to < 10 wt.-%, preferably dimethyl sulfoxide in a range from > 90 wt.-% to < 94.99 wt.-% and water in a range from > 5 wt.-% to < 10 wt.-%. It was found that aqueous solutions of mirabegron comprising a high amount of DMSO provided sufficient solubility.

In further preferred embodiments, the formulation is a solution comprising DMSO.

In embodiments, a composition for topical and/or transdermal administration comprising mirabegron or a salt thereof is provided, wherein the composition comprises as solvent:

- dimethyl sulfoxide (DMSO) in a range from > 10 wt.-% to < 100 wt.-%, and optionally

- a monoalcohol in a range from > 10 wt.-% to < 90 wt.-% or

- glycerol, a glycol, a polyethylene glycol, a glycol ether, mixtures thereof, or mixtures with a monoalcohol in a range from > 10 wt.-% to < 60 wt.-%, wherein the wt.-% are based on a total weight of the solvent of 100 wt.-%. Particularly in embodiments where the formulation is provided as a solution, particularly solutions where excipients such as gel forming agents or triglyceride are not needed, the ratio of the solvents defines the solubility of mirabegron. Regarding the compositions or solutions described in the following paragraphs, for the solvents, given wt.-% are calculated on the basis of total weight of the solvent of 100 wt.-%. Regarding mirabegron, given wt.-% refer to the total weight of the composition. For example, 100 g of a 5% mirabegron solution in DMSO/ethanol (50/50, m/m) refers to 5 g mirabegron and 47.5 g of each of DMSO and ethanol.

In embodiments, the composition comprises 100 wt.-% DMSO, based on a total weight of the solvent of 100 wt.-%. Dimethyl sulfoxide provided high solubility and also very good permeation when used as only solvent. Further, addition of dimethyl sulfoxide to a further solvent was found to increase the solubility of mirabegron in the formulation, facilitate skin permeation, and also increase the active delivery period for mirabegron.

Binary mixtures comprising dimethyl sulfoxide and a monoalcohol or a glycol ether are preferred. Binary mixtures simplify formulating and enhance compatibility with further excipients.

In embodiments, the composition comprises DMSO in a range from > 10 wt.-% to < 90 wt.-% and a monoalcohol in a range from > 10 wt.-% to < 90 wt.-%, based on a total weight of the solvent of 100 wt.-%. Preferred are short-chained monoalcohols comprising up to 6 aliphatic carbon atomes. In preferred embodiments, the monoalcohol is a C₂-C₅ alcohol selected from the group of ethanol, n- propanol, isopropanol, n-butanol, isobutanol, tert.-butanol, or mixtures thereof. In preferred embodiments, the monoalcohol is ethanol. In further embodiments, the monoalcohol may be isobutanol.

Reducing DMSO content in mixtures with ethanol reduced permeation in vitro, and solutions or mixtures without dimethyl sulfoxide either lacked solubility or permeability. It was found that at least 5 wt.-% DMSO, based on 100 wt.-% of solvent, is necessary for sufficient permeation of mirabegron. It was further found that increasing amounts of DMSO in ethanolic mixtures facilitated permeation of mirabegron into the skin, while the addition of diethylene glycol monoethyl ether to DMSO decreased permeation of mirabegron into the skin. In embodiments of the composition, the composition comprises dimethyl sulfoxide in a range from > 10 wt.-% to < 50 wt.-% and ethanol in a range from > 50 wt.-% to < 90 wt.-%, based on a total weight of the solvents of 100 wt.-%. These ranges provided good solubility and permeation of mirabegron. Generally, a higher content of ethanol provides better permeation.

In embodiments, the composition comprises DMSO in a range from > 40 wt.-% to < 90 wt.-% and glycerol, a glycol, a polyethylene glycol, a glycol ether, mixtures thereof, or mixtures with a monoalcohol in a range from > 10 wt.-% to < 60 wt.-%, based on a total weight of the solvent of 100 wt.-%. Particularly, glycoles and polyethylene glycols provide high solubility for mirabegron. Glycoles 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 glycoles and polyethylene glycols may reduce or prevent permeation of mirabegron. In preferred embodiments 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, for example under the tradename Transcutol®. In embodiments of the composition, the composition comprises dimethyl sulfoxide in a range from > 40 wt.-% to < 90 wt.-% and diethylene glycol monoethyl ether in a range from > 10 wt.-% to < 60 wt.-%, based on a total weight of the solvents of 100 wt.-%. These ranges provided good solubility and permeation of mirabegron.

Also ternary mixtures of solvents are usable. Preferably, a composition comprising a ternary mixture has a higher amount of DMSO, for example in a range from > 20 wt.-% to < 80 wt.-%. In embodiments, the composition may comprise as solvents dimethyl sulfoxide (DMSO) in a range from > 20 wt.-% to < 80 wt.-%, and a mixture of a monoalcohol, glycerol, a glycol, a polyethylene glycol, or a glycol ether in a range from > 20 wt.-% to < 80 wt.-%, wherein the wt.-% are based on a total weight of the solvent of 100 wt.-%.

In embodiments of the composition, the composition comprises a cyclodextrin in a range of from > 1 wt.-% to < 20 wt.-%, based on a total weight of the solvent of 100 wt.-%. The addition of cyclodextrins increases the solubility of mirabegron and therefore allows to add more non-solvent to the binary or ternary mixtures. Preferred cyclodextrins are pharmaceutically acceptable cyclodextrins such as P-cyclodextrin and gamma-cyclodextrin as well as P-cyclodextrin derivatives used as excipients in medicines such as the sulfobutylether of P-cyclodextrin (SBE- -CD), the hydroxypropyl derivative of P-cyclodextrin (HP-P-CD), and randomly methylated P-cyclodextrin (RM-P-CD).

The solubility of mirabegron may be described using the Hansen solubility parameter theory. Hansen Solubility Parameters refer to the parameters 5D for Dispersion (van der Waals), 5P for Polarity (related to dipole moment) and 5H for hydrogen bonding. The parameters are determined according to Charles Hansen, Hansen Solubility Parameters, A User's Handbook, 2nd Edition from 2007. In embodiments, the solvent or mixture of solvents has Hansen solubility parameters (HSP) (determined according to User's Handbook, 2nd Edition) dD in a range of > 15 to < 19, dP > 8. It was found that high dP increases permeation, while high dH decreases permeation. In preferred embodiments, the composition has Hansen solubility parameters dD in a range of > 16 to < 18, dP in a range of > 12 to < 14 and/or dH in a range of < 14 to < 16, preferably dD of 16.6, dP 12.8 and dH of 14.8.

In embodiments, the composition comprises mirabegron or a salt thereof in a range from > 0.01 wt.-% to < 25 wt.-%, preferred in a range from > 0.01 wt.-% to < 20 wt.-%; preferably in a range from > 0.1 wt.-% to < 10 wt.-%, more preferably in a range from > 0.5 wt.-% to < 5 wt.-%, based on the total weight of the composition. Such concentrations provided good solubility and effects of mirabegron.

In embodiments, 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 usual topical compositions for application to a particular place on the body surface, such as the skin. Advantageously, a topical composition according to the invention provides for a transdermal administration of mirabegron. Preferably, the composition is in the form of a gel, an ointment, or a plaster, more preferred in the form of a gel or a spray. Dosage forms preferably are defined according to the definitions used by the skilled in the art, e.g. Pharm Eur, 10.0; 0132: Semi-solid preparations for cutaneous use. For the formulation of the respective formulations, the composition may comprise one or more pharmaceutically acceptable excipients in order to increase physical, chemical, and microbial stability as well as patient adherence of the formulation. The respective gel forming agents, surfactants, solubility enhancers, permeation enhancers, preservatives, antioxidants, complexing agents, cosolvents, emollients, fragrances, and colouring agents are known to the skilled person. Usable pharmaceutically acceptable carriers including hydrogels, cutaneous creams, cutaneous gels, cutaneous lotions, cutaneous ointments, cutaneous patches, cutaneous pastes, cutaneous poultices, cutaneous foams, cutaneous solutions, cutaneous sprays, and patches are known to the skilled person. Another preferred form of provision is a spray.

A further aspect refers to a composition for topical and/or transdermal administration comprising mirabegron or a salt thereof, wherein the composition provides a transdermal flux of mirabegron of at least 5 pg/cm² over 24 hours as measured in a Franz Diffusion Cell with an orifice of 1 cm² at 32°C according to USP (725). In embodiments, the flux is at least 10 pg/cm² over 24 hours, preferably at least 20 pg/cm² over 24 hours, more preferably at least 30 pg/cm² over 24 hours, even more preferably at least 50 pg/cm² over 24 hours, more preferably 100 pg/cm² over 24 hours measured according to USP (725).

In embodiments, the transdermal flux of mirabegron is measured in an infinite dose experiment on human skin in a Franz Diffusion Cell with an orifice of 1 cm² at 32°C according to USP (725). The term infinite dose experiment as used herein refers to an experiment conducted with an amount of test preparation applied to the skin where a maximum absorption rate of the test substance is achieved and maintained as defined in OECD Environmental Health and Safety Publications Series on Testing and Assessment No. 28, 2004 and described by 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.

Another aspect refers to a composition for topical and/or transdermal administration comprising mirabegron or a salt thereof, wherein the composition contains mirabegron in a molecular dispersed form. The term “molecular dispersion” as used herein refers to a dispersion of mirabegron where mirabegron is in form of separate molecules homogeneously distributed throughout the solvent.

In preferred embodiments, the compositions providing a transdermal flux of mirabegron of at least 5 pg/cm² or containing mirabegron in a molecular dispersed form are in the form of a gel or a solution or spray. In embodiments, the compositions comprise: a) mirabegron as active compound; b) a solvent selected from: - dimethyl sulfoxide (DMSO) in a range from > 5 wt.-% to < 99.99 wt.-%; or - a mixture of dimethyl sulfoxide in a range from > 5 wt.-% to < 97.99 wt.-%, and a further solvent selected from i) a monoalcohol in a range from > 5 wt.-% to < 94.99 wt.-%, or ii) glycerol, a glycol, a polyethylene glycol, a glycol ether, mixtures thereof, or mixtures with a monoalcohol in a range from > 5 wt.-% to < 60 wt.-%, or iii) water in a range from > 2 wt.-% to < 10 wt.-%; and optionally c) one or more pharmaceutical excipient(s), wherein the wt.-% are based on a total weight of the composition of 100 wt.-%.

In embodiments, the compositions comprise as solvent: - dimethyl sulfoxide in a range from > 10 wt.- % to < 100 wt.-%, and optionally - a monoalcohol in a range from > 10 wt.-% to < 90 wt.-% or - glycerol, a glycol, a polyethylene glycol, a glycol ether, mixtures thereof, or mixtures with a monoalcohol in a range from > 10 wt.-% to < 60 wt.-%, wherein the wt.-% are based on a total weight of the solvent of 100 wt.-%.

For the description of mirabegron and salts thereof, the compositions, solvents, and excipients, reference is made to the description above.

The compositions as described herein are usable for transdermal administration of mirabegron to the subcutaneous fat tissue. Subcutaneous fat tissue refers to a tissue layer just beneath the skin of a mammal, comprising adipocytes. A transdermal administration of the composition results in a locally increased concentration of mirabegron in the adipocytes with significantly reduced systemic drug concentration.

The composition provides effective transdermal delivery of mirabegron. This results in a high uptake of mirabegron in subcutaneous fat tissue, which fat tissue will respond to mirabegron by decreasing the quantity of subcutaneous fatty tissue and/or decrease the size of the single fat cells. Decreasing the quantity of subcutaneous fatty tissue will reduce overweight caused by fat cells and reduce obesity and lipedema.

Further, it was shown for mirabegon that upon transdermal application in ex-vivo human skin including subcutaneous adipose tissue expresion of browning markers was significantly increased. Thus, in embodiments, the composition as described above is for use in the treatment of obesity or lipedema or for providing lipolysis. A related aspect relates to a use of the composition as described above for the manufacture of a medicament for the treatment of obesity or lipedema, or for providing lipolysis. The composition hence may be a pharmaceutical composition. In another aspect, a method for the treatment of obesity or lipedema, or for providing lipolysis is provided, wherein the method comprises the step of administering to a subject in need thereof, for example a mammal such as a human, a therapeutically effective amount of a composition as described herein.

The term “lipolysis” as used herein refers to a procedure in which an active ingredient is applied to achieve local decrease of the quantity of subcutaneous fat tissue. The term “lipolysis” may refer to a treatment or to a cosmetic procedure.

The composition in other embodiments may be a cosmetic composition for cosmetic use. In another aspect, the invention refers to a use of the composition as described above in a cosmetic method for decreasing the quantity of subcutaneous fat tissue of a subject by topical application. In other words, in embodiments, the composition as described above is for use in in a cosmetic method for decreasing the quantity of subcutaneous fat tissue of a subject by topical application. In another aspect, a cosmetic method for decreasing the quantity of subcutaneous fat tissue of a subject, for example a mammal such as a human, is provided, wherein the method comprises the administration of the composition as described above. A decrease of the volume of subcutaneous fat tissue at a local site of the body by application of mirabegron may result in a cosmetic method without therapeutic benefit.

A further aspect refers to a use of mirabegron or a salt thereof for the manufacture of a transdermal medicament, preferably for use in the treatment of obesity or lipedema, or for providing lipolysis. In other words, a further aspect refers to mirabegron or a salt thereof for use as a transdermal medicament, preferably for use in the treatment of obesity or lipedema, or for providing lipolysis. Mirabegron and salts thereof can be administered transdermally using a composition comprising DMSO as described above. This allows for a transdermal application of mirabegron. For the description of mirabegron and salts thereof, the composition and the uses of mirabegron, reference is made to the description above. A further aspect refers to a composition as described herein for use in a transdermal treatment, preferably for use in the treatment of obesity or lipedema, or for providing lipolysis. For the description of mirabegron and salts thereof, the composition and the uses of mirabegron, reference is made to the description above.

Unless otherwise defined, the 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.

The Examples, which follow serve to illustrate the invention in more detail but do not constitute a limitation thereof.

The figures show:

Figure 1 A scheme of a Franz Diffusion Cell with an orifice of 1 cm² according to USP (725).

Figure 2 Figure 2a) shows the amount of mirabegron permeated per cm² of human abdominal skin over 24 h, Figure 2b) the amount of mirabegron permeated per cm² of murine skin over 24 h.

Figure 3 the amount of mirabegron permeated per cm² of human skin over 24 h from a solution of 5 wt.-% mirabegron in DMSO or mixtures of ethanol and DMSO.

Figure 4 the amount of mirabegron permeated per cm² of murine skin over 24 h from a solution of 3 wt.-% mirabegron in a mixture of ethanol and isopropyl myristate (90/10, m/m).

Figure 5 the amount of mirabegron permeated per cm² of murine skin over 24 h from a solution of 10 wt.-% mirabegron in a mixture of (50/50, m/m) Transcutol® (TC) and DMSO and of 3 wt.-% mirabegron in aquaeous mixtures of 40, 50 or 75 wt.-% Transcutol® and 60, 50 or 25 wt.-% water, respectively.

Figure 6 histological sections after haematoxylin and eosin staining of murine subcutaneous fat cells after 10 days of treatment with DMSO in Figure 6a) and 5 wt.-% mirabegron in DMSO in Figure 6b).

Figure 7 histological sections after haematoxylin and eosin staining of human subcutaneous fat cells after two days of treatment with with a mixture of 90 wt.-% ethanol and 10 wt.-% isopropyl myristate in Figure 7a) and 3 wt.-% mirabegron in a mixture of 90 wt.-% ethanol and 10 wt.-% isopropyl myristate in Figure 7b). Figure 8 histological sections after haematoxylin and eosin staining and UCP1 staining of murine subcutaneous fat cells after 10 days of treatment with DMSO/ethanol gels comprising 5 wt.-% mirabegron.

Figure 9 genexpression of thermogenese markers UCP1, Cidea, and PGCla and inflammation marker TNFa in Figures 9a), b), c), and d), respectively, after application of mirabegron.

Example 1

Determination of solubility of mirabegron in several solvents

Solubility was tested by adding mirabegron in increasing incremental amounts of 10 mg to 5 m of the respective solvent under stirring and subsequent sonification of solution/suspension for 5 min at ambient temperature in each step. Complete dissolution was assumed if a clear, increasingly yellow solution was obtained. It was observed that polar aprotic solvents, short chain alcohols, glycols, and polytheylene glycols were suitable solvents for dissolving mirabegron. Particularly, dimethyl sulfoxide (DMSO) (Sigma-Aldrich) and methanol (Fisher Scientific, UK), N-methylpyrrolidone (NMP) (VWR International S.A.S.) and Transcutol® (Gattefosse SAS) provided adequate solubility for mirabegron. However, methanol and N-methylpyrrolidone are toxicologically critical and not usable in pharmaceutical preparations.

Example 2

Determination of permeation of mirabegron from different formulations

Permeation was determined in Franz Diffusion Cell experiments. A scheme of a Franz Diffusion Cell is shown in Figure 1. A donor compartment (2) and a receptor compartment (4) are attached to each other using clamp attachment lug (6). Between donor compartment (2) and receptor compartment (4) a membrane (8) is mounted. The receptor compartment (4) has a sampling side arm (10). The formulation (3) to be determined is applied to the donor compartment (2). A receiver fluid (5) is contained in the receptor compartment (4). The Franz Diffusion Cell allows the measurement of the amount of mirabegron diffused across a membrane, such as abdominal human skin or mouse skin, in an acceptor medium. Mouse skin or excised human abdominal skin received from plastic surgery was used as membranes. Mouse skin was removed in full thickness from underlying tissue and was left unshaved. Human abdominal skin membranes were prepared by removing subcutaneous fatty tissue with a scalpel and then normalising to 400 pm thickness with a dermatome (Aesculap GA 643).

A Franz Diffusion Cell as defined in the United States Pharmacopeia (USP (725)) with an orifice area of 1.00 cm² (PermeGear) was used at 32°C. 8 m of a solution of 6 wt.-% Brij®98 (Acres Organics) in phosphate-buffered saline (PBS) pH 7.4 (NaCl 137 mmol/L (Merck, Darmstadt, Germany), KC1 2.7 mmol/L (Merck, Darmstadt, Germany), Na₂HPO₄ 10 mmol/L (Sigma- Aldrich, Steinbach, Germany), KH2PO4 1.8 mmol/L (Carl Roth, Karlsruhe, Germany) was used as receiver fluid in the receptor compartment. 200 mg of the respective sample formulations were provided in the donor compartment. Experiments were performed at 32°C. After respective intervals, samples from the receiver fluid were taken and analysed via High Performance Liquid Chromatography-Ultraviolet (HPLC-UV) using an LC-2030C 3D Plus HPLC system (Shimadzu Deutschland GmbH, Duisburg, Germany to provide the results of mass transport per unit of time and area (flux).

200 mg of formulations comprising mirabegron, based on the total weight of the formulation, in the solvents and solvent mixtures as given in tables 2 and 3 below were provided in the donor compartment. Solutions were prepared by dissolving the respective amount of mirabegron (Mehta API Pvt. Ltd., Mumbai, India) in the respective solvents or mixtures. Human skin as described above was used as membrane.

After 24 hours, samples from the receiver fluid were taken and analysed via HPLC-UV. The following tables 1 and 2 summarise the results of evaluation of permeation in Franz Diffusion Cell experiments after 24 h. the number of “+” signs indicates the measured strength of permeation. The ratio of solvents are given referring to wt.-% (m/m), i.e. DMSO/ethanol (50/50) refers to a mixture of 50 wt.- % each. Table 1: Results of solvent systems that allowed for permeation in Franz Diffusion Cell experiments after 24 h

The results of table 1 show that, generally, high dP values increased permeation. It was further observed that increasing amounts of DMSO in ethanolic mixtures facilitated permeation. However, addition of the excellent solvent Transcutol® to DMSO decreased permeation.

Table 2: Results of solvent systems that did not allow for evaluation of permeation in Franz Diffusion

Cell experiments after 24 h

The results of table 2 show that, solvents with a high solubility for mirabegron do not automatically allow for evaluation of permeation. It was further observed that water reduced solubility of mirabegron in mixtures especially in alcoholic mixtures, and mixtures containing water did not allow for permeation.

Example 3

Determination of permeation of mirabegron from DMSO containing formulations

The permeation of mirabegron from formulations containing DMSO through mouse or excised human abdominal skin was evaluated over a time period of 24 h. Permeation was determined in Franz Diffusion Cell experiments as described in example 2 above.

Solutions of 5 wt.-% mirabegron (Mehta API Pvt. Ltd., Mumbai, India) in DMSO were prepared and tested using murine skin or excised human abdominal skin. Samples were taken after 1, 2, 3, 4, 5, 6 and 24 hours and analysed. Figure 2 a) shows the amount of mirabegron permeated per cm² of human abdominal skin over 24 h, Figure 2 b) shows the amount of mirabegron permeated per cm² of murine skin over 24 h. As can be taken from Figures 2a) and b), mirabegron permeates murine and human skin within 24 h in substantial amounts. Flux was determined to 9. 18 pg per cm²*h for human skin and to 4.58 pg per cm²*h for murine skin.

Further, solutions of 3 wt.-% mirabegron in DMSO and in mixtures of 10 wt.-% DMSO and 90 wt.-% or 50 wt.-% DMSO and 50 wt.-% ethanol, were prepared and tested using human skin. Samples were taken after 2, 3, 4, 5, 6, 8 and 24 hours and analysed. Figure 3 shows the amount of mirabegron permeated per cm² of human skin over 24 h. As can be taken from Figure 3, increasing amounts of DMSO in ethanolic mixtures enhanced permeation in vitro.

Also, a solution of 3 wt.-% mirabegron in a mixture of 90 wt.-% ethanol and 10 wt.-% isopropyl myristate was prepared and tested using human skin. Samples were taken after 6, 7, 8 and 24 hours and analysed. Figure 4 shows the amount of mirabegron permeated per cm² of human skin over 24 h. As can be taken from Figure 4, permeation from ethanolic solution with isopropyl myristate was slower than from formulations containing DMSO, but after 24 h permeation was similar to 100 % DMSO.

Further, a solution of 10 wt.-% mirabegron in a mixture of 50 wt.-% DMSO and 50 wt.-% Transcutol® (Gattefosse SAS) or of 3 wt.-% mirabegron in aqueous mixtures of 40, 50 or 75 wt.-% Transcutol® and 60, 50 or 25 wt.-% water, respectively, were prepared and tested using human skin. Samples were analysed taken after 24 hours. Figure 5 shows the amount of mirabegron permeated per cm² of human skin over 24 h. As can be taken from Figure 5, while a mixture of DMSO and Transcutol® provided high permeation, mixtures containing water reduced permeation to below 5 pg/cm². This shows that water reduced the soluble amount of mirabegron in the formulation, and also reduced permeation.

Also, solutions of 3 wt.-% mirabegron in PEG 200 (Sigma- Aldrich, Steinbach, Germany), PEG 400 (Sigma-Aldrich), propylene glycole, water, Transcutol®, ethanol/gycerol (50/50) or ethanol/gycerol/isopropyl myristate (45/45/10) showed permeation of below 3 pg/cm² over human skin after 24 hours. This showed that solutions without dimethyl sulfoxide lacked permeability.

Example 4

Determination of lipolysis in vivo

The effect of a composition comprising 5 wt.-% mirabegron in dimethyl sulfoxide after transdermal administration was tested in vivo in C57BL/6 (25gr) mice. Mice were treated for 10 days with either DMSO placebo or 5 wt.-% mirabegron in dimethyl sulfoxide to both flanks of the animals in the respective experimental group. After 10 days mice were sacrificed and subcutaneous fat cells analysed. Fixing of freshly isolated tissue was performed by incubation in PBS containing 4% paraformaldehyde (PF A) for no more than 16 h and washed twice 5 min each with ice-cold PBS. Samples were then dehydrated in ethanol with increasing concentrations: 50 %, 70 %, 95 %, and 100 % (3 times, 20 min for each concentration). In a next step, samples were defatted by 3 successive incubation steps in xylol for 10 min each. Samples were further incubated twice in paraffin at 60°C for 1 hour, followed by overnight incubation at 60°C. Using cassettes the processed samples were then embedded in a warmed liquid paraffin solution and subsequently solidified for storage at room temperature. Sections of 5 pm thickness were taken with a microtome (Microm) for each staining, and the stained sections were then dried on histological slides for 24 hours at 40°C.

Removal of paraffin from histology slides was performed by three xylol washes for 5 minutes each. Samples were incubated in ethanol with decreasing concentrations: 100%, 95%, 90%, 75%, and 50% (for each concentration, wash twice for 2 minutes), followed by two more washes in H₂O (each wash for 5 minutes). Samples were incubated in hematoxylin for two seconds, after which the slides were rinsed under running water for 10 minutes. Subsequently, slides were stained with eosin for two minutes and washed in distilled water for 4 minutes with agitation. Increasing concentrations of ethanol were used for dehydration of tissue: 50%, 75%, 95%, and 100% (for each concentration, tissues were washed twice for 2 minutes) and followed by two more steps of wash in xylol, for 2 minutes each. In the end, slides were mounted using Roti-Histokitt.

Figure 6 shows histological sections after haematoxylin and eosin staining of murine subcutaneous fat cells after 10 days of treatment with DMSO as control in Figure 6a) and after 10 days of treatment with 5 wt.-% mirabegron in DMSO in Figure 6b). It can be taken from a comparison of Figures 6 a) and b) that the size of fat vacuoles in white adipose tissue of the mirabegron-treated group was significantly reduced compared to the control group.

Figure 7 shows histological sections after haematoxylin and eosin staining of human subcutaneous fat cells after two days treatment of human abdominal skin ex vivo with a mixture of 90 wt.-% ethanol and 10 wt.-% isopropyl myristate as control in Figure 7a) and after two days treatment with 3 wt.-% mirabegron in a mixture of 90 wt.-% ethanol and 10 wt.-% isopropyl myristate in Figure 7b). It can be taken from a comparison of Figures 7 a) and b) that the size of fat vacuoles in white adipose tissue of treated specimen was not significantly reduced compared to the control group. This shows that while a mixture of 90 wt.-% ethanol and 10 wt.-% isopropyl myristate provides permeation (as shown in Table 2), no effect was seen.

This shows that dimethyl sulfoxide and mixtures comprising dimethyl sulfoxide not only provided solubility, permeability, and toxicological acceptability, but also provided for a sufficient active delivery period for mirabegron to provide the desired effects upon transdermal administration in vivo.

Example 5

Determination of thermogenesis markers after application of mirabegron in vivo

The effect of mirabegron in dimethyl sulfoxide gel on thermogenesis markers after transdermal administration was tested in vivo in C57BL/6 (25gr) mice.

Mirabegron (MIR) (Swapnroop Drugs & Pharmaceuticals) was dissolved in DMSO (pharma grade, ITW Reagents) before the addition of ethanol (absolute, Sigma- Aldrich). Hydroxypropyl cellulose H (HPC-H) (Nippon Soda Co., Ltd.) was added to the DMSO/EtOH mixtures under stirring and the resulting suspensions were left tightly sealed until complete dissolution of gelling agent was observed. The exact compositions are summarised in Table 3 below.

Table 3 : compositions of mirabegron gels

Wild type (WT) C57BL/6 mice were split into groups of eight and treated with mirabegron gels (verum) or placebo, respectively. Mice were shaved on the flanks with an electric razor. 50 mg of gel were applied once a day to each flank for 10 d. 24 h after the last application of gel the animals were sacrificed and inguinal white adipose tissue (WATi) was removed and analyzed for browning marker expression by qPCR, western blot and histologically after haematoxylin and eosin, as well as UCP1 antibody staining. For histological ananlysis, tissue samples were fixed in 4% paraformaldehyde solution and embedded in paraffin. Sections of 5 pm thickness were stained with hematoxylin and eosin (H&E) and with UCP1 specific antibodies, respectively.

For isolation of RNA and real-time polymerase chain reaction (qPCR) tissues were homogenized with Trizol (ThermoFisher) for mRNA extraction and treated with chloroform with subsequent precipitation by addition of propan-2-ol and washing with 75% EtOH. Concentration of isolated RNA was spectrophotometrically analyzed with a Nanodrop 200 (ThermoFisher Scientific). Synthesis of cDNA was conducted with a ProtoScript II First Strand cDNA Synthesis Kit (New England Biolabs) according to the manufacturer's instructions. Analysis of amplification was performed by staining with SYBR Green Master Mix (ThermoFisher) and measurement on a QuantStudio 5 qPCR system (ThermoFisher). The 2^-ACT method was used to calculate the relative mRNA expression of genes normalized to the housekeeping gene HRPT for murine samples.

For Western Blot, proteins were isolated using RIPA lysis buffer containing 50 mM Tris pH 7.5, 150 mM sodium chloride, 1% NP-4O, 0.5% sodium deoxycholate, 0.1% sodium dodecyl sulfate, 0.1 mM EDTA, 0. 1 mM EGTA, 1 mM Na₃VO₄, 10 mM NaF, containing a protease inhibitor cocktail (Roche). The protein content was quantified by Bradford assay. Proteins were separated by 12% SDS-PAGE and transferred to a nitrocellulose membrane. For immunoblot primary antibodies of UCP1 (Sigma- Aldrich) and Calnexin and secondary anti-rabbit antibodies were used. Amersham ECL Western Blotting reagent was used to visualize proteins and detection was performed with an hnageQuant LAS 4000 mini (GE Healthcare). Quantification was conducted using Image J software.

H&E and UCP1 staining of mice inguinal white adipose tissue (WAT) showed that application of placebo gel to the flanks of WT C57BL/6 mice for 10 d did not show any morphological signs of browning, such as multiocular morphology or reduction of adipocyte size in H&E stained tissue. In contrast, treatment with mirabegron containing gels led to a pronounced reduction in lipid droplet size inside the adipocytes and their amount increased. Accordingly, immunostaining for UCP1 revealed extensively stained areas for mirabegron treated samples, while placebo-treated samples scarcely showed any stained regions, as can be seen in Figure 8. The immunostaining for UCP1, which is the key protein in non-shivering thermogenesis by mitochondria and exclusively expressed in brown adipose tissue, is considered a histologic confirmation of browning by application of mirabegron gels.

As can be seen in Figure 9, the expression of brown adipose tissue (BAT) specific gene markers was increased after mirabegron containing gel application. The expression of UCP1 was significantly increased by 8.2-fold and 12.0-fold for mirabegron containing gels 10 DMSO and 50 DMSO compared to Placebo, as can be seen in Figure 9a). For Cidea a 5.5-fold and 6.6-fold increase for mirabegron containing gels 10 DMSO and 50 DMSO compared to Placebo was observed as can be seen in Figure 9b). Treatment with mirabegron containing DMSO gels 10 DMSO and 50 DMSO further resulted in a significant increase of PGCla over placebo by factors of 2.5 and 3.0, respectively, as can be seen in Figure 9c). However, the expression of the inflammation marker TNFa was not increased compared to placebo for any gel, as can be seen in Figure 9d). Analysis of gene expression by qPCRthus showed an increase for all browning markers.

Also analysis of protein expression by western blot revealed bands of UCP1 for the mirabegron containing gels, while no bands were observable for placebo gel. Control bands of Calnexin were visible for all gels. Quantitative analysis of UCP1 expression normalized to Calnexin displayed significantly increased levels of UCP1 for mirabegron treated groups compared to placebo. This shows that the observed increase in gene expression translated into expression of UCP1 on the protein level, indicating that in the selected timeframe doses of mirabegron delivered from DMSO gels were sufficient to effectively induce browning of inguinal white adipose tissue.

This shows that gels of dimethyl sulfoxide and ethanol provided mirabegron formulations that successfully facilitated transdermal the transport of mirabegron and effectively induce classic characteristics of browning in inguinal white adipose tissue in mice in-vivo. Therefore, the topical administration of mirabegron in DMSO gels was shown to be a potential way of administration usable for providing lipolysis or being usable in the treatment of obesity, lipedema, or diabetes mellitus.

Example 6

Determination of permeation using low amount of DMSO Permeation was determined in Franz Diffusion Cell as defined in USP (725) with an orifice area of 1.00 cm² (PermeGear) using human skin as described in Example 2. A solution of 20 mg mirabegron in 49 mg DMSO and 931 mg ethanol (19: 1 (w/w)) was prepared by dissolving the respective amount of mirabegron (Mehta API Pvt. Ltd., Mumbai, India) in the respective solvent mixture. After 24 hours, a sample from the receiver fluid were taken and analysed via HPLC-UV. A permeation of less than 0.4 pg/cm² was found. This indicated a minimum amount of 5 wt.-% of DMSO in the formulation.

Claims

C l a i m s

1. A composition for topical and/or transdermal administration comprising mirabegron or a salt thereof, characterised in that the composition comprises: a) mirabegron or a salt thereof in a range from > 0.01 wt.-% to < 25 wt.-%; and b) a solvent selected from:

- dimethyl sulfoxide (DMSO) in a range from > 5 wt.-% to < 99.99 wt.-%; or

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

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

4. The composition according to any one of the preceding claims, characterised in that the composition comprises: a) mirabegron in a range from > 0.01 wt.-% to < 10 wt.-%; b) a mixture of dimethyl sulfoxide in a range from > 5 wt.-% to < 50 wt.-%, and a C₂-C₅ alcohol, preferably ethanol in a range from > 50 wt.-% to < 95 wt.-%, and c) a gel forming agent selected from the group comprising hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl methylcellulose, and mixtures thereof in a range from > 1 wt.-% to < 20 wt.-%, wherein the wt.-% are based on a total weight of the composition of 100 wt.-%.

5. The composition according to claim 1, characterised in that the composition comprises as solvent:

- dimethyl sulfoxide in a range from > 10 wt.-% to < 100 wt.-%, and optionally

- a monoalcohol in a range from > 10 wt.-% to < 90 wt.-% or

- glycerol, a glycol, a polyethylene glycol, a glycol ether, mixtures thereof, or mixtures with a monoalcohol in a range from > 10 wt.-% to < 60 wt.-%, wherein the wt.-% are based on a total weight of the solvent of 100 wt.-%.

6. The composition according to any one of the preceding claims, characterised in that the monoalcohol is a C2-C5 alcohol selected from the group of ethanol, n-propanol, isopropanol, n-butanol, isobutanol, tert.-butanol, or mixtures thereof, preferably ethanol.

7. The composition according to claim 5 or 6, characterised in that the composition comprises dimethyl sulfoxide in a range of from > 10 wt.-% to < 50 wt.-%, and ethanol in a range of from > 50 wt.-% to < 90 wt.-%, based on a total weight of the solvents of 100 wt.-%.

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

9. The composition according to claim 8, characterised in that the composition comprises dimethyl sulfoxide in a range of from > 40 wt.-% to < 90 wt.-% and diethylene glycol monoethyl ether in a range of from > 10 wt.-% to < 60 wt.-%, based on a total weight of the solvents of 100 wt.-%.

10. A composition for topical and/or transdermal administration comprising mirabegron or a salt thereof, characterised in that the composition provides a transdermal flux of mirabegron of at least 5 pg/cm² over 24 hours (measured in a Franz Diffusion Cell with an orifice of 1 cm² at 32°C according to USP (725)).

11. A composition for topical and/or transdermal administration comprising mirabegron or a salt thereof, characterised in that the composition contains mirabegron in a molecular dispersed form.

12. The composition according to any one of the preceding claims, characterised 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, and preferably is in the form of a gel or spray.

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

14. The composition according to any one of claims 1 to 12 for use in a cosmetic method for decreasing the quantity of subcutaneous fat tissue of a subject by topical application.

15. Mirabegron or a salt thereof for use as a transdermal medicament, preferably for use in the treatment of obesity or lipedema, or for providing lipolysis.