Mirabegron formulations

Abstract

The present invention relates to a composition for topical and / or transdermal application comprising mirabegron or a salt thereof, wherein the composition comprises: a) > = 0.01 wt.-% to < = 25 wt.-% mirabegron or a salt thereof; and b) a solvent selected from the group consisting of:-> = 5 wt.-% to < = 99.99 wt.-% dimethyl sulfoxide (DMSO); or > = 5 wt.-% to < = 97.99 wt.-% of a mixture of dimethyl sulfoxide with other solvents selected from i) > = 5 wt.-% to < = 94.99 wt.-% of a monohydric alcohol, or ii) > = 5 wt.-% to < = 60 wt.-% of glycerol, ethylene glycol, polyethylene glycol, glycol ether, mixtures thereof, or a mixture with a monohydric alcohol, or iii) > = 2 wt.-% to < = 10 wt.-% of water; wherein wt.-% is based on 100 wt.-% of the total weight of the composition.

Description

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

[0002] Overweight and obesity are major risk factors for many diseases. One in two citizens in the European Union is overweight, more than one in three are pre-obese, and one in six is ​​considered obese with a body mass index (BMI) of more than 30. In the United States, the prevalence of obesity is even more pronounced. These populations are at significantly increased risk of cardiovascular disease and diabetes. The aesthetic problems caused by excess weight also lead to social isolation and may contribute to psychiatric disorders such as depression. In this regard, the clinical manifestations of lipedema are particularly distressing. Lipedema is a chronic, progressive disease of subcutaneous adipose tissue in the upper and lower limbs that affects almost exclusively women. The disease is not well understood, but it appears to be caused by a pathological increase in adipose tissue through hypertrophy and hyperplasia, accompanied by fluid retention. This results in a marked and noticeable 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 for the physical and mental health of every individual and population.

[0003] Drugs that increase fat loss mostly belong to the class of anorectic drugs. These are mainly derived from amphetamines and suppress appetite. Another possibility to support weight loss is the use of lipase inhibitors. However, these substances need to be administered orally or by injection. However, in the case of systemic administration, serious side effects must be taken into account, since these compounds significantly interfere with the metabolism of neurotransmitters in the brain.

[0004] Topical application substantially reduces systemic absorption and corresponding side effects. WO2007 / 011743A1 discloses a composition for treating localized fat deposition, which comprises a long-acting beta-2 adrenergic receptor agonist salmeterol or formoterol, and a compound that reduces the desensitization of the target tissue to the long-acting beta2-adrenergic receptor agonist, such as a glucocorticoid and / or ketotifen. The composition can be administered, for example, by injection and / or percutaneous administration. However, due to poor permeability through the skin, pharmaceutically active compounds generally do not show clinical effects or only show undesirable clinical effects when applied topically.

[0005] EP3206678 B1 discloses a pharmaceutical composition for topical administration, comprising a prodrug of an adrenergic receptor agonist and / or antagonist, wherein the prodrug is an ester, and the pharmaceutical composition is used or employed in a therapeutic method for shaping the mammalian body by regulating subcutaneous adipose tissue. One of the many cited β3-adrenergic receptor agonists ("β-agonists") is mirabegron. The penetration of the prodrug provides a transport route through the skin, but the availability of the active ingredient depends on the activity of an enzyme that can release the agonist from the prodrug, and it is unclear whether a therapeutic effect can be achieved in this way. The penetration of naive adrenergic receptor agonists and antagonists is considered insufficient for obesity treatment and / or lipolysis.

[0006] Mirabegron (INN) is a prescription drug from the group of β3-sympathomimetic drugs. The drug has been approved in the EU for the treatment of overactive bladder since 2012. However, its physicochemical properties are not favorable for dermal application, the molecular weight and melting point are relatively high, it is insoluble in water (water solubility is 82 μg / mL) and only limitedly soluble in lipids. Therefore, it is impossible to dissolve large amounts of mirabegron in water, and the solubility of mirabegron in aqueous mixtures with commonly used polar cosolvents is low. In addition, the solubility in lipids is limited, and the application of products with a high lipid content is uncomfortable and reduces patient compliance.

[0007] It is therefore an object of the present invention to provide a composition allowing the topical or transdermal administration of mirabegron.

[0008] This object is achieved by a composition according to claim 1. The object is further achieved by a composition for use according to claims 10 to 14. Advantageous embodiments are subject matter of the dependent claims. The embodiments can be combined freely unless the context clearly indicates otherwise.

[0009] Therefore, a composition comprising mirabegron or a salt thereof for topical and / or transdermal administration is provided, wherein the composition comprises:

[0010] a) ≥ 0.01 wt.-% to ≤ 25 wt.-% of mirabegron or a salt thereof; and

[0011] b) a solvent selected from the group consisting of:

[0012] - ≥5 wt.-% to ≤99.99 wt.-% of dimethyl sulfoxide (DMSO); or

[0013] - mixtures of ≥5 wt.-% to ≤97.99 wt.-% of dimethyl sulfoxide and other solvents selected from the group consisting of: i) ≥5 wt.-% to ≤94.99 wt.-% of monohydric alcohols, or ii) ≥5 wt.-% to ≤60 wt.-% of glycerol, ethylene glycol, polyethylene glycol, glycol ethers, mixtures thereof, or mixtures with monohydric alcohols, or iii) ≥2 wt.-% to ≤10 wt.-% of water;

[0014] Herein the wt.-% are based on the total weight of the composition 100 wt.-%.

[0015] Surprisingly, dimethyl sulfoxide allows transdermal administration of mirabegron. Compared with other compounds of broad-spectrum penetration enhancers known in the art, DMSO is conducive to skin penetration, and it is observed that the effective delivery period of mirabegron increases. It can be further shown that a mixture of dimethyl sulfoxide and alcohol or glycol ether can effectively deliver mirabegron transdermally. Pure dimethyl sulfoxide and its mixture can fully maintain dissolved mirabegron on the skin while showing high permeability. On the other hand, solutions or mixtures without dimethyl sulfoxide either have poor solubility, poor permeability, or too strong volatility, or unacceptable toxicity.

[0016] The term "mirabegron" (INN), formerly known as YM 178, as used herein, refers to a β3-adrenergic receptor agonist ("β-agonist") of the following formula (1):

[0017]

[0018] Mirabegron is available in Europe under the trade name Mirabegron is commercially used as a non-salt free base. Salts of Mirabegron can also be used, preferably pharmaceutically acceptable salts. The term "pharmaceutically acceptable salt" 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 hydrochlorides, sulfates, succinates, acetates, fumarates, tartrates, benzenesulfonates and mesylates. In addition, Mirabegron complexes, such as dodecyl sulfate / complexes, octyl sulfate / complexes, tetradecyl sulfate / complexes, and hexadecyl sulfate / complexes are also known and can be used.

[0019] As used herein, the term "topical" administration refers to applying a substance, such as mirabegron, to a specific location on or in the body, particularly a body surface such as the skin or mucous membranes. As used herein, the term "transdermal" administration refers to a substance, such as mirabegron, that, after administration, penetrates the upper skin layers and is distributed in the subcutaneous layers, i.e., the dermis and subcutaneous tissue.

[0020] If not otherwise specifically stated, the % given are % by weight (wt.-%). The total amount of all components of the composition does not exceed 100 wt.-%. With regard to mirabegron, the wt.-% given relates to the total weight of the composition. For example, 100 g of a 5% solution of mirabegron in DMSO / ethanol (50 / 50, w / w) refers to 5 g mirabegron, 47.5 g DMSO and 47.5 g ethanol.

[0021] Important for the solubility of mirabegron is the ratio of solvents, in particular the weight ratio (w / w) of DMSO to another solvent or other solvent mixture. The weight ratio of DMSO to another solvent may range from 9.5:0.5 to 0.5:9.5, depending on the nature of the other solvent. Nevertheless, the ratio of DMSO to other solvents, i.e. 10 / 90 (w / w) or 50 / 50 (w / w), determines the solubility of mirabegron in the formulation, regardless of the presence or absence of excipients such as gelling agents or stabilizers.

[0022] In order to effectively deliver compounds transdermally from a formulation solvent system, several requirements need to be met. First, sufficient solubility of the active compound in the formulation needs to be provided. In addition, it is necessary to observe an increase in the solubility of the active compound in the skin (epidermis and dermis) (permeation enhancement). Finally, it is necessary to provide sufficient solvent retention (limit solvent evaporation) on the skin to ensure the molecular dispersion state of the payload. It has been observed that solvents with high solubility for mirabegron will not automatically allow permeation through the skin. For example, diethylene glycol monoethyl ether (available under the trade name Commercially available) provides very high solubility without the use of dimethyl sulfoxide, but provides insufficient permeability of mirabegron. Other solvents such as ethanol provide high solubility and permeability, but no effect of mirabegron on lipolysis was observed. It is speculated that the lack of efficacy of mirabegron may be due to solvent evaporation and precipitation of mirabegron.

[0023] In general, polar aprotic solvents, short-chain alcohols, ethylene glycol, and polyethylene glycol are suitable solvents for dissolving moderate to large amounts of mirabegron. However, polar aprotic solvents such as N,N-dimethylformamide and N-methylpyrrolidone are toxicologically hazardous.

[0024] The composition comprises mirabegron as an active ingredient. In an embodiment, based on the total weight of the composition, the composition comprises ≥0.01wt.-% to ≤25wt.-% of mirabegron or a salt thereof, preferably in the range of ≥0.01wt.-% to ≤20wt.-%; preferably in the range of ≥0.1wt.-% to ≤10wt.-%, more preferably in the range of ≥0.5wt.-% to ≤5wt.-%. Such a concentration provides good solubility and effect of mirabegron.

[0025] The composition comprises ≥5 wt.-% to ≤99.99 wt.-% dimethyl sulfoxide (DMSO). It was found that formulations with a content below 5 wt.-% provide low permeability of mirabegron.

[0026] In an embodiment, the composition comprises one or more pharmaceutical excipients. In an embodiment, the composition comprises one or more pharmaceutical excipients selected from the group consisting of antioxidants, penetration enhancers, gelling agents, ointment components, preservatives, colorants, flavor enhancers, stabilizers, triglycerides and mixtures thereof, preferably a gelling agent.

[0027] Suitable excipients selected from ointment bases, gelling agents, antioxidants, pH adjusters, preservatives, colorants and stabilizers are preferably selected from the group comprising alpha-tocopherol, acetic acid, aqueous ammonia, anhydrous citric acid, ascorbic acid, ascorbyl palmitate, bentonite, benzalkonium chloride, benzyl alcohol, butyl paraben, calcium acetate, carbomer, sodium carboxymethylcellulose, carnava wax, carrageenan, castor oil, ceteareth-30, ceteareth-10, cetearyl alcohol, cetyl alcohol, cholesterol, coconut oil, colloidal silicon dioxide, corn oil, crospovidone, diethylene glycol monoethyl ether, dimethicone 100, behenyl alcohol, docusate sodium, etate disodium disodium), ethylcellulose, ethylparaben, red iron oxide, formic acid, gelatin, glyceryl monostearate, glyceryl oleate, sodium hyaluronate, hydrochloric acid, hydrogenated castor oil, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, isopropyl myristate, isopropyl palmitate, lanolin, lavender oil, lecithin, linoleic acid, magnesium silicate, magnesium stearate, medium chain triglycerides, menthol, methylcellulose, methylparaben, mineral 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 Glycol, Polysorbate, Povidone, Propylene Glycol, Quaternium-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.

[0028] The formulation is preferably provided in the form of a gel. In an embodiment, the composition comprises a gelling agent selected from the group consisting of hydroxypropyl cellulose, preferably highly substituted hydroxypropyl cellulose (HPC-H), hydroxyethyl cellulose, hydroxypropyl methyl cellulose (HPMC) and mixtures thereof. Based on the total weight of the composition 100 wt.-%, the composition may comprise ≥1 wt.-% to ≤20 wt.-%, preferably ≥2 wt.-% to ≤10 wt.-% of a gelling agent, such as hydroxypropyl cellulose or hydroxyethyl cellulose.

[0029] In an embodiment, the composition comprises ≥5 wt.-% to ≤50 wt.-% DMSO and ≥50 wt.-% to ≤95 wt.-% monohydric alcohol, based on the total weight of the composition 100 wt.-%.

[0030] Preferred are short chain monohydric alcohols containing up to 6 aliphatic carbon atoms. In a preferred embodiment, the monohydric alcohol is a C 2+ selected from the group consisting of ethanol, n-propanol, isopropanol, n-butanol, isobutanol, tert-butanol or mixtures thereof. 2 -C 5 Alcohol. In a preferred embodiment, the monohydric alcohol is ethanol. In a further embodiment, the monohydric alcohol may be isobutanol.

[0031] Using a mixture of DMSO and ethanol as a solvent can provide a gel with good skin penetration of mirabegron. In an embodiment, the composition comprises:

[0032] a) ≥ 0.01 wt.-% to ≤ 10 wt.-% of mirabegron;

[0033] b) ≥5 wt.-% to ≤50 wt.-% of dimethyl sulfoxide and ≥50 wt.-% to ≤95 wt.-% of C 2 -C 5 A mixture of alcohols, preferably ethanol, and

[0034] c) ≥ 1 wt.-% to ≤ 20 wt.-% of a gelling agent selected from the group comprising hydroxypropylcellulose, preferably highly substituted hydroxypropylcellulose (HPC-H), hydroxyethylcellulose, hydroxypropylmethylcellulose (HPMC) and mixtures thereof,

[0035] Herein the wt.-% are based on the total weight of the composition 100 wt.-%.

[0036] In an embodiment, the composition may comprise a triglyceride. Preferred triglycerides are selected from the group comprising glyceryl monostearate and glyceryl oleate. In an embodiment, the composition comprises ≥1 wt.-% to ≤20 wt.-% of triglycerides, preferably selected from the group comprising glyceryl monostearate and glyceryl oleate, based on the total weight of the composition.

[0037] In other embodiments, an aqueous solution comprising DMSO is provided. In an embodiment, the composition comprises ≥90 wt.-% to ≤97.99 wt.-% of dimethyl sulfoxide and ≥2 wt.-% to ≤10 wt.-% of water, preferably ≥90 wt.-% to ≤94.99 wt.-% of dimethyl sulfoxide and ≥5 wt.-% to ≤10 wt.-% of water. It was found that an aqueous solution of mirabegron comprising a large amount of DMSO provides sufficient solubility.

[0038] In a further preferred embodiment, the formulation is a solution comprising DMSO.

[0039] In an embodiment, there is provided a composition comprising mirabegron or a salt thereof for topical and / or transdermal administration, wherein the composition comprises as a solvent:

[0040] - ≥10 wt.-% to ≤100 wt.-% of dimethyl sulfoxide (DMSO), and optionally

[0041] - ≥ 10 wt.-% to ≤ 90 wt.-% of monohydric alcohols, or

[0042] - ≥10 wt.-% to ≤60 wt.-% of glycerol, ethylene glycol, polyethylene glycol, glycol ethers, mixtures thereof or mixtures with monohydric alcohols,

[0043] The wt.-% are based on the total weight of the solvent, 100 wt.-%.

[0044] In particular, in embodiments where the formulation is provided as a solution, in particular a solution where no excipients such as gelling agents or triglycerides are required, the proportion of the solvent determines the solubility of mirabegron. For the compositions or solutions described in the following paragraphs, the wt.-% given for the solvent is calculated based on the total weight of the solvent as 100 wt.-%. With respect to mirabegron, the wt.-% given relates 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, 47.5 g DMSO and 47.5 g ethanol.

[0045] In an embodiment, the composition comprises 100 wt.-% DMSO, based on the total weight of the solvent, 100 wt.-%. Dimethyl sulfoxide provides high solubility and also provides very good permeability when used as the sole solvent. In addition, it was found that the addition of dimethyl sulfoxide to another solvent increases the solubility of mirabegron in the formulation, promotes skin penetration, and increases the effective delivery period of mirabegron.

[0046] Binary mixtures comprising dimethyl sulfoxide and a monohydric alcohol or glycol ether are preferred. Binary mixtures simplify formulation and enhance compatibility with other excipients.

[0047] In an embodiment, the composition comprises ≥10 wt.-% to ≤90 wt.-% of DMSO and ≥10 wt.-% to ≤90 wt.-% of a monohydric alcohol, based on the total weight of the solvent 100 wt.-%. Preference is given to short-chain monohydric alcohols containing up to 6 aliphatic carbon atoms. In a preferred embodiment, the monohydric alcohol is a C 2-hydroxy-1-hydroxy-1-propanol selected from the group consisting of ethanol, n-propanol, isopropanol, n-butanol, isobutanol, tert-butanol or mixtures thereof. 2 -C 5 Alcohol. In a preferred embodiment, the monohydric alcohol is ethanol. In a further embodiment, the monohydric alcohol may be isobutanol.

[0048] Reducing the DMSO content in a mixture containing ethanol reduces in vitro permeability, while solutions or mixtures without dimethyl sulfoxide lack solubility or permeability. It was found that at least 5wt.-% of DMSO was required to fully penetrate Mirabegron based on 100wt.-% of the solvent. It was further found that an increase in the amount of DMSO in the ethanol mixture promoted the penetration of Mirabegron into the skin, while adding diethylene glycol monoethyl ether to DMSO reduced the penetration of Mirabegron into the skin. In an embodiment of the composition, the composition comprises ≥10wt.-% to ≤50wt.-% of dimethyl sulfoxide and ≥50wt.-% to ≤90wt.-% of ethanol, based on the total weight of the solvent 100wt.-%. These ranges provide good solubility and permeability of Mirabegron. In general, the higher the ethanol content, the better the permeability.

[0049] In an embodiment, based on the total weight of the solvent 100wt.-%, the composition comprises ≥40wt.-% to ≤90wt.-% of DMSO and ≥10wt.-% to ≤60wt.-% of glycerol, ethylene glycol, polyethylene glycol, glycol ether, a mixture thereof or a mixture with a monohydric alcohol. In particular, ethylene glycol and polyethylene glycol provide high solubility for mirabegron. Ethylene glycol and polyethylene glycol can be selected from ethylene glycol, propylene glycol and polyethylene glycol. However, solvents that provide high solubility of mirabegron, such as ethylene glycol and polyethylene glycol, may reduce or prevent the penetration of mirabegron. In a preferred embodiment of the composition, ethylene glycol ether is present. Preferably, the ethylene glycol ether is diethylene glycol monoethyl ether. Diethylene glycol monoethyl ether (IUPAC name 2-(2-ethoxyethoxy)ethanol) is commercially available, for example under the trade name Obtained. In an embodiment of the composition, based on the total weight of the solvent 100 wt.-%, the composition comprises ≥40 wt.-% to ≤90 wt.-% of dimethyl sulfoxide and ≥10 wt.-% to ≤60 wt.-% of diethylene glycol monoethyl ether. These ranges provide good solubility and permeability of mirabegron.

[0050] Ternary mixtures of solvents can also be used. Preferably, the composition comprising the ternary mixture has a higher amount of DMSO, for example ≥20 wt.-% to ≤80 wt.-%. In an embodiment, the composition may comprise as solvent: ≥20 wt.-% to ≤80 wt.-% of dimethyl sulfoxide (DMSO), and ≥20 wt.-% to ≤80 wt.-% of a mixture of monohydric alcohol, glycerol, ethylene glycol, polyethylene glycol or glycol ether, wherein the wt.-% is based on the total weight of the solvent 100 wt.-%.

[0051] In an embodiment of the composition, the composition comprises ≥1 wt.-% to ≤20 wt.-% cyclodextrin, based on the total weight of the solvent 100 wt.-%. The addition of cyclodextrin increases the solubility of mirabegron, thereby allowing more non-solvent to be added to the binary or ternary mixture. Preferred cyclodextrins are pharmaceutically acceptable cyclodextrins, such as β-cyclodextrin and γ-cyclodextrin, and β-cyclodextrin derivatives used as excipients in medicines, such as sulfobutyl ether of β-cyclodextrin (SBE-β-CD), hydroxypropyl derivative of β-cyclodextrin (HP-β-CD), and randomly methylated β-cyclodextrin (RM-β-CD).

[0052] The solubility of mirabegron can be described by the Hansen solubility parameter theory. Hansen solubility parameters refer to the parameters δD of dispersion (van der Waals forces), δP of polarity (related to dipole moment), and δH of hydrogen bonding. These parameters are determined according to the Hansen Solubility Parameters User's Manual, 2007, 2nd edition, by Charles Hansen. In an embodiment, the solvent or solvent mixture has a Hansen solubility parameter (HSP) (determined according to the User's Manual, 2nd edition) dD≥15 to ≤19, dP≥8. It was found that high dP increases permeability, while high dH reduces permeability. In a preferred embodiment, the Hansen solubility parameters of the composition are dD≥16 to ≤18, dP≥12 to ≤14 and / or dH≤14 to ≤16, preferably dD is 16.6, dP is 12.8 and dH is 14.8.

[0053] In an embodiment, the composition comprises ≥0.01 wt.-% to ≤25 wt.-% of mirabegron or its salt, 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 provide good solubility and effect of mirabegron.

[0054] In an embodiment, the composition is in the form of a topical composition. Preferably, the topical composition is selected from the group consisting of gel, ointment, cream, foam, lotion, paste, solution, spray or plaster. Such preparations are usually common topical compositions for application to specific parts of the body surface (e.g., skin). Advantageously, a topical composition according to the present invention provides mirabegron for transdermal administration. 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 definition used by those skilled in the art, such as Pharm Eur, 10.0; 0132: Semi-solid preparations for cutaneous use. For the preparation of the corresponding preparation, the composition may include one or more pharmaceutically acceptable excipients to increase the physical, chemical and microbiological stability of the preparation and patient compliance. Corresponding gelling agents, surfactants, dissolution promoters, penetration enhancers, preservatives, antioxidants, complexing agents, cosolvents, emollients, fragrances and coloring agents are known to those skilled in the art. Available pharmaceutically acceptable carriers, including hydrogels, skin creams, skin gels, skin lotions, skin ointments, skin patches, skin pastes, skin poultices, skin foams, skin solutions, skin sprays and patches, are known to the skilled person. Another preferred presentation form is a spray.

[0055] Another aspect relates to a composition for topical and / or transdermal administration comprising mirabegron or a salt thereof, wherein, according to USP (725), at 32°C with an orifice of 1 cm 2 The composition provides at least 5 μg / cm 2 In an embodiment, the flux is at least 10 μg / cm2 over 24 hours as measured according to USP (725). 2 , preferably at least 20 μg / cm within 24 hours 2 , more preferably at least 30 μg / cm within 24 hours 2 , even more preferably at least 50 μg / cm2 over 24 hours 2 , more preferably at least 100 μg / cm2 in 24 hours 2 .

[0056] In an embodiment, according to USP (725), at 32°C with an orifice of 1 cm 2 Infinite dose experiments were performed on human skin in a Franz diffusion cell to measure the transdermal flux of Mirabegron. The term "infinite dose experiment" used herein refers to an experiment in which a certain amount of a test preparation is applied to the skin to reach and maintain the maximum absorption rate of the test substance, as defined in OECD Environmental Health and Safety Publications Series on Testing and Assessment No. 28, 2004 and 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.

[0057] Another aspect relates to a composition comprising mirabegron or a salt thereof for topical and / or transdermal administration, wherein the composition contains mirabegron in molecularly dispersed form. The term "molecular dispersion" as used herein refers to a dispersion of mirabegron, wherein mirabegron is uniformly distributed throughout a solvent in the form of independent molecules.

[0058] In a preferred embodiment, at least 5 μg / cm 2 The transdermal flux of mirabegron or the composition containing mirabegron in molecularly dispersed form is in the form of a gel, a solution or a spray.

[0059] In an embodiment, the composition comprises: a) mirabegron as the active compound; b) a solvent selected from: - ≥5 wt.-% to ≤99.99 wt.-% dimethyl sulfoxide (DMSO); or - ≥5 wt.-% to ≤97.99 wt.-% of a mixture of dimethyl sulfoxide and another solvent selected from: i) ≥5 wt.-% to ≤94.99 wt.-% of a monohydric alcohol, or ii) ≥5 wt.-% to ≤60 wt.-% of glycerol, ethylene glycol, polyethylene glycol, glycol ether, a mixture thereof, or a mixture with a monohydric alcohol, or iii) ≥2 wt.-% to ≤10 wt.-% of water; and optionally c) one or more pharmaceutically acceptable excipients, wherein the wt.-% is based on the total weight of the composition 100 wt.-%.

[0060] In an embodiment, the composition comprises as solvent: - ≥10 wt.-% to ≤100 wt.-% of dimethyl sulfoxide, and optionally - ≥10 wt.-% to ≤90 wt.-% of a monohydric alcohol, or - ≥10 wt.-% to ≤60 wt.-% of glycerol, ethylene glycol, polyethylene glycol, glycol ethers, mixtures thereof, or mixtures with monohydric alcohols, wherein the wt.-% are based on the total weight of the solvent 100 wt.-%.

[0061] For the description of mirabegron and its salts, compositions, solvents and excipients, reference is made to the above description.

[0062] The compositions described herein can be used to transdermally administer mirabegron to subcutaneous adipose tissue. Subcutaneous adipose tissue refers to the tissue layer beneath the skin of mammals, including fat cells. Transdermal administration of the composition results in a local increase in the concentration of mirabegron in fat cells, while systemic drug concentrations are significantly reduced.

[0063] The composition provides efficient transdermal delivery of mirabegron. This results in a high uptake rate of mirabegron in subcutaneous adipose tissue, which responds to mirabegron by reducing the amount of subcutaneous adipose tissue and / or reducing the size of individual adipocytes. Reducing the amount of subcutaneous adipose tissue will reduce excess body weight caused by adipocytes and reduce obesity and lipedema.

[0064] Furthermore, studies have shown that when mirabegron is applied percutaneously to ex vivo human skin (including subcutaneous adipose tissue), the expression of browning markers is significantly increased.

[0065] Thus, in an embodiment, the composition as described above is used to treat obesity or lipedema or to provide lipolysis. A related aspect relates to the use of the above composition in the manufacture of a medicament for treating obesity or lipedema or providing lipolysis. Thus the composition can be a pharmaceutical composition. On the other hand, a method for treating obesity or lipedema, or providing lipolysis, is provided, wherein the method comprises the step of administering a therapeutically effective amount of a composition as described herein to a subject in need thereof (e.g., a mammal, such as a human).

[0066] As used herein, the term "lipolysis" refers to the procedure of applying active ingredients to achieve a localized reduction in the amount of subcutaneous adipose tissue. The term "lipolysis" may refer to a therapeutic or cosmetic procedure.

[0067] The composition in other embodiments can be a cosmetic composition for cosmetic purposes. On the other hand, the present invention relates to the use of the above-mentioned composition in a cosmetic method for reducing the amount of subcutaneous fat tissue of an object by topical application. In other words, in an embodiment, the composition as described above is used in a cosmetic method for reducing the amount of subcutaneous fat tissue of an object by topical application. On the other hand, a cosmetic method for reducing the amount of subcutaneous fat tissue of an object (e.g., a mammal, such as a human) is provided, wherein the method includes applying a composition as described above. A cosmetic method without a therapeutic effect can be obtained by reducing the volume of subcutaneous fat tissue of a local part of the body using mirabegron.

[0068] Another aspect relates to the use of mirabegron or its salt in the manufacture of a transdermal medicament, which is preferably used to treat obesity or lipedema or to provide lipolysis. In other words, another aspect relates to mirabegron or its salt used as a transdermal medicament, which is preferably used to treat obesity or lipedema or to provide lipolysis. Mirabegron and its salts can be administered transdermally using a composition comprising DMSO as described above. This allows transdermal application of mirabegron. For the description of mirabegron and its salts, the composition and use of mirabegron, reference is made to the description above.

[0069] Another aspect relates to a composition as described herein for use in transdermal treatment, preferably for the treatment of obesity or lipedema or for providing lipolysis.For the description of mirabegron and its salts, compositions and uses of mirabegron, reference is made to the above description.

[0070] 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.

[0071] The following examples are used to illustrate the present invention in more detail but are not intended to limit the present invention.

[0072] The attached figure shows:

[0073] Figure 1 : According to USP (725), with 1cm 2 Scheme of a Franz diffusion cell with orifice.

[0074] Figure 2 : Figure 2 a) shows the average cm per 24 hours 2 The amount of mirabegron that penetrates the human peritoneal skin, Figure 2 b) per cm in 24 hours 2 The amount of mirabegron that penetrates through rat skin.

[0075] Figure 3 : From a 5 wt.-% solution of mirabegron in DMSO or a mixture of ethanol and DMSO, per cm 2 The amount of mirabegron that penetrates human skin.

[0076] Figure 4 : From a 5 wt.-% solution of mirabegron in a mixture of ethanol and isopropyl myristate (90 / 10, m / m), the 2 The amount of mirabegron that penetrates through rat skin.

[0077] Figure 5 : from 10wt.-% mirabegron in (50 / 50, m / m) (TC) and DMSO, and from 3 wt.-% mirabegron in 40 wt.-%, 50 wt.-% or 75 wt.-% and 60 wt.-%, 50 wt.-% or 25 wt.-% of water in an aqueous mixture, per cm 2 The amount of mirabegron that penetrates through rat skin.

[0078] Figure 6 :DMSO( Figure 6 a) and a 5 wt.-% solution of mirabegron in DMSO ( Figure 6 b) Histological sections of mouse subcutaneous adipocytes stained with hematoxylin and eosin after 10 days of treatment.

[0079] Figure 7 : A mixture of 90 wt.-% ethanol and 10 wt.-% isopropyl myristate ( Figure 7 a) and a solution of 3 wt.-% mirabegron in a mixture of 90 wt.-% ethanol and 10 wt.-% isopropyl myristate ( Figure 7 b) Histological sections of human subcutaneous adipocytes stained with hematoxylin and eosin after two days of treatment.

[0080] Figure 8: Histological sections of rat subcutaneous adipocytes after hematoxylin and eosin staining and UCP1 staining after 10 days of treatment with DMSO / ethanol gel containing 5 wt.-% mirabegron.

[0081] Fig. 9 :After the application of mirabegron, the thermogenic markers UCP1, Cidea, PGC1α and the inflammatory marker TNFα( Fig. 9 a, b, c, d) Gene expression patterns, respectively.

[0082] Example 1

[0083] Determination of the solubility of mirabegron in several solvents

[0084] The solubility was tested by adding mirabegron in increments of 10 mg to 5 mL of the respective solvent under stirring, followed by sonication of the solution / suspension at ambient temperature for 5 minutes in each step. If the solution obtained was clear and gradually turned yellow, the solution was considered to be completely dissolved. It was observed that polar aprotic solvents, short-chain alcohols, ethylene glycol and polyethylene glycol 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 (Gattefossé SAS) provides adequate solubility for mirabegron. However, methanol and N-methylpyrrolidone are toxicologically hazardous and cannot be used in pharmaceutical formulations.

[0085] Example 2

[0086] Permeability determination of mirabegron in different preparations

[0087] Permeability was determined in Franz diffusion cell experiments. Figure 1 A schematic diagram of a Franz diffusion cell is shown. The donor chamber (2) and the receiving chamber (4) are connected to each other using a clamp connection ear (6). A membrane (8) is installed between the donor chamber (2) and the receiving chamber (4). The receiving chamber (4) has a sampling side arm (10). The preparation (3) to be measured is applied to the donor chamber (2). A receiving fluid (5) is contained in the receiving chamber (4). The Franz diffusion cell allows the measurement of the amount of mirabegron that diffuses through a membrane (e.g., abdominal human skin or mouse skin) in a receiving medium.

[0088] Mouse skin or human abdominal skin removed during plastic surgery was used as the membrane. Mouse skin was peeled off from the underlying tissue in full thickness without shaving. Human abdominal skin membranes were prepared by removing subcutaneous adipose tissue with a scalpel and then standardized to 400 μm thickness with a dermatome (Aesculap GA 643).

[0089] A Franz diffusion cell conforming to the United States Pharmacopeia (USP (725)) with an orifice area of ​​1.00 cm was used at 32 °C. 2 (PermeGear). 8 mL of 6 wt.-% 98 (Acros Organics) in 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 1.8mmol / L (Carl Roth, Karlsruhe, Germany) solution was used as the receiving fluid in the receiving chamber. 200mg of the corresponding sample preparation was provided in the donor chamber. The experiment was carried out at 32°C. After the corresponding interval, samples were taken from the receiving fluid and analyzed by high performance liquid chromatography-ultraviolet (HPLC-UV) using a LC-2030C 3D Plus HPLC system (Shimadzu Deutschland GmbH, Duisburg, Germany) to provide mass transport results (flux) per unit time and area.

[0090] 200 mg of a formulation containing mirabegron (based on the total weight of the formulation) was provided in the donor chamber, and the solvents and solvent mixtures thereof were as shown in Tables 2 and 3 below. Solutions were prepared by dissolving the corresponding amount of mirabegron (Mehta API Pvt. Ltd., Mumbai, India) in the corresponding solvents or mixtures. Human skin as described above was used as a membrane.

[0091] After 24 hours, a sample was taken from the receiving fluid and analyzed by HPLC-UV. The following Tables 1 and 2 summarize the results of the evaluation of the permeability in the Franz diffusion cell experiment after 24 hours. The number of "+" signs indicates the measured permeability. The solvent ratios are expressed in wt.-% (m / m), i.e. DMSO / ethanol (50 / 50) refers to a mixture of 50 wt.-% of each.

[0092] Table 1: Results for solvent systems that allowed permeation in Franz diffusion cell experiments after 24 hours

[0093]

[0094] The results in Table 1 show that, in general, high dP values ​​increase permeability. It was further observed that increasing the amount of DMSO in the ethanol mixture promoted permeability. However, adding the excellent solvent to DMSO Reduce permeability.

[0095] Table 2: Results for solvent systems for which permeability could not be assessed in Franz diffusion cell experiments after 24 hours

[0096]

[0097]

[0098] The results in Table 2 show that the permeability cannot be automatically assessed for solvents with high solubility of mirabegron. It was further observed that water reduced the solubility of mirabegron in mixtures, especially in alcohol mixtures, and that mixtures containing water did not allow permeation.

[0099] Example 3

[0100] Determination of the permeability of mirabegron from formulations containing DMSO

[0101] The permeation of mirabegron from formulations containing DMSO through mouse or excised human abdominal skin was evaluated over a 24 hour period. Permeability was determined in a Franz diffusion cell assay as described in Example 2 above.

[0102] A 5 wt.-% solution of mirabegron (Mehta API Pvt. Ltd., Mumbai, India) in DMSO was prepared and tested using rat skin or excised human abdominal skin. Samples were taken after 1, 2, 3, 4, 5, 6 and 24 hours and analyzed. Figure 2 a) shows the average cm per 24 hours 2 The amount of mirabegron that penetrates the human peritoneal skin, Figure 2 b) shows the average cm per 24 hours 2 The amount of mirabegron that penetrated the mouse skin. Figure 2 As can be seen from a) and 2b), mirabegron penetrates into mouse and human skin to a large extent within 24 hours. The human skin flux was determined to be 9.18 μg / cm 2 / h, mouse skin flux was measured to be 4.58μg / cm 2 / h.

[0103] In addition, 3 wt.-% mirabegron solutions in DMSO, and 3 wt.-% mirabegron solutions in a mixture of 10 wt.-% DMSO and 90 wt.-% ethanol, 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 analyzed. Figure 3 Shows the number of cm per 24 hours 2 The amount of mirabegron that penetrates human skin. Figure 3 It can be seen that increasing amounts of DMSO in the ethanol mixture enhanced the in vitro permeability.

[0104] In addition, 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 analyzed. Figure 4 Shows the number of cm per 24 hours 2 The amount of mirabegron that penetrates human skin. Figure 4 It can be seen that permeation from the ethanol solution containing isopropyl myristate was slower than from the formulation containing DMSO, but after 24 hours permeation was similar to 100% DMSO.

[0105] In addition, 10 wt.-% mirabegron in 50 wt.-% DMSO and 50 wt.-% (Gattefossé SAS) mixture, or 3 wt.-% mirabegron in 40 wt.-%, 50 wt.-% or 75 wt.-% and 60 wt.-%, 50 wt.-% or 25 wt.-% water in an aqueous mixture and tested using human skin. Samples were taken for analysis after 24 hours. Figure 5 Shows the number of cm per 24 hours 2 The amount of mirabegron that penetrates human skin. Figure 5 It can be seen that although DMSO and The mixture provided high permeability, but the aqueous mixture reduced the permeability to 5 μg / cm 2 This suggests that water reduces the soluble amount of mirabegron in the formulation and also reduces permeability.

[0106] In addition, 3 wt.% mirabegron was prepared in PEG 200 (Sigma-Aldrich, Steinbach, Germany), PEG 400 (Sigma-Aldrich), propylene glycol, water, Solutions in ethanol / glycerol (50 / 50) or ethanol / glycerol / isopropyl myristate (45 / 45 / 10) showed a permeation of less than 3 μg / cm2 through human skin after 24 hours 2 This indicates that the solution without DMSO lacks permeability.

[0107] Example 4

[0108] Determination of fat breakdown in vivo

[0109] The effect of a composition containing 5 wt.-% mirabegron in dimethyl sulfoxide solution after percutaneous administration was tested in vivo in C57BL / 6 (25 gr) mice. In each experimental group, both sides of the flank of the animals were treated with DMSO placebo or 5 wt.-% mirabegron in dimethyl sulfoxide for 10 days. After 10 days, the mice were sacrificed and subcutaneous adipocytes were analyzed.

[0110] Freshly isolated tissues were placed in PBS containing 4% paraformaldehyde (PFA) and incubated for no more than 16 hours, then washed twice with ice-cold PBS for 5 minutes each time to fix. The samples were then dehydrated in increasing concentrations of ethanol: 50%, 70%, 95% and 100% (3 times, 20 minutes for each concentration). Next, the samples were incubated in xylene for 3 consecutive times for 10 minutes each time to defat. The samples were further incubated in paraffin at 60°C twice for 1 hour each time, and then incubated at 60°C overnight. The treated samples were then embedded in a warm liquid paraffin solution using a box, subsequently solidified and stored at room temperature. A slicer (Microm) was used to make slices with a thickness of 5 μm each time the staining was performed, and the stained slices were then placed on histological slides and dried at 40°C for 24 hours.

[0111] Paraffin was removed from histological slides by three xylene washes (5 min each). Samples were incubated in decreasing concentrations of ethanol: 100%, 95%, 90%, 75%, and 50% (two washes at each concentration, 2 min each), followed by HO. 2 O wash twice (5 minutes each wash). Incubate the sample in hematoxylin for two seconds, then rinse the slides under running water for 10 minutes. Subsequently, the slides are stained with eosin for two minutes and washed in distilled water for 4 minutes with stirring. The tissue is dehydrated using increasing concentrations of ethanol: 50%, 75%, 95% and 100% (for each concentration, the tissue is washed twice, each time for 2 minutes), followed by two steps of washing in xylene, each for 2 minutes. Finally, the slides are mounted using Roti-Histokitt.

[0112] Figure 6 Shown is the DMSO control after 10 days of treatment ( Figure 6a) and a 5 wt.-% mirabegron solution in DMSO ( Figure 6 b) Histological sections of mouse subcutaneous adipocytes stained with hematoxylin and eosin after 10 days of treatment. Figure 6 a) and Figure 6 As can be seen from the comparison of b), the size of lipid vesicles in white adipose tissue of the mirabegron-treated group was significantly reduced compared with the control group.

[0113] Figure 7 Shown are the results of two-day treatment of excised human abdominal skin with a mixture of 90 wt.-% ethanol and 10 wt.-% isopropyl myristate as a control ( Figure 7 a), and a mixture of 3 wt.-% mirabegron in 90 wt.-% ethanol and 10 wt.-% isopropyl myristate for two days ( Figure 7 b) Histological section of human subcutaneous adipocytes stained with hematoxylin and eosin. Figure 7 a) and Figure 7 As can be seen from the comparison of b), the size of lipid vesicles in the white adipose tissue of the treated specimens was not significantly reduced compared to the control group. This indicates that although the mixture of 90 wt.-% ethanol and 10 wt.-% isopropyl myristate provided permeability (as shown in Table 2), no effect was observed.

[0114] This suggests that DMSO and mixtures containing DMSO not only provide solubility, permeability and toxicological acceptability, but also provide a sufficient active delivery period for mirabegron to provide the desired effect upon transdermal administration in vivo.

[0115] Example 5

[0116] Determination of thermogenic markers after in vivo administration of mirabegron

[0117] The effects of mirabegron in dimethyl sulfoxide gel on markers of thermogenesis following transdermal administration were tested in C57BL / 6 (25 gr) mice.

[0118] Mirabegron (MIR) (Swapnroop Drugs & Pharmaceuticals) was dissolved in DMSO (pharmaceutical grade, ITW reagent), and then ethanol (absolutely pure, Sigma-Aldrich) was added. Hydroxypropylcellulose H (HPC-H) (Nippon Soda Co., Ltd.) was added to the DMSO / EtOH mixture under stirring, and the resulting suspension was tightly sealed until the gelling agent was observed to be completely dissolved. The exact composition is summarized in Table 3 below.

[0119] Table 3: Composition of Mirabegron Gel

[0120]

[0121]

[0122] Wild-type (WT) C57BL / 6 mice were divided into eight groups and treated with mirabegron gel (verum) or placebo. The hair on the flanks of the mice was shaved with an electric razor. 50 mg of gel was applied to each flank once a day for 10 days. 24 hours after the last application of gel, the animals were sacrificed, and the inguinal white adipose tissue (WATi) was removed and analyzed by qPCR, Western blot, and histology after hematoxylin and eosin staining and UCP1 antibody staining for the expression of browning markers.

[0123] For histological analysis, tissue samples were fixed in 4% paraformaldehyde solution and embedded in paraffin. 5 μm thick sections were stained with hematoxylin and eosin (H&E) and UCP1 specific antibody, respectively.

[0124] To isolate RNA and perform real-time polymerase chain reaction (qPCR), tissues were homogenized with Trizol (ThermoFisher) to extract mRNA and treated with chloroform, followed by precipitation by adding isopropanol and washing with 75% EtOH. The concentration of isolated RNA was analyzed spectrophotometrically using Nanodrop 200 (ThermoFisher Scientific). cDNA synthesis was performed using ProtoScriptII First Strand cDNA Synthesis Kit (New England Biolabs) according to the manufacturer's instructions. Amplification analysis was performed by staining with SYBR Green Master Mix (ThermoFisher) and measuring on a QuantStudio 5qPCR system (ThermoFisher). 2 -ΔCT The relative mRNA expression of genes in mouse samples was calculated by normalization to the housekeeping gene HRPT.

[0125] For Western blotting, a 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 3 VO 4Proteins were isolated using RIPA lysis buffer (100 mM NaF, 10 mM NaF, and a protease inhibitor cocktail (Roche). Protein content was quantified by Bradford assay. Proteins were separated by 12% SDS-PAGE and transferred to nitrocellulose membranes. For immunoblotting, primary antibodies to UCP1 (Sigma-Aldrich) and Calnexin and anti-rabbit secondary antibodies were used. Proteins were visualized using Amersham ECL Western blotting reagents and detected using ImageQuant LAS 4000mini (GE Healthcare). Quantification was performed using ImageJ software.

[0126] H&E and UCP1 staining of inguinal white adipose tissue (WAT) of mice showed that 10 days after the application of the placebo gel to the flanks of WTC57BL / 6 mice, there was no morphological sign of browning, such as multi-eye morphology or a decrease in the size of adipocytes in H&E stained tissues. In contrast, treatment with the gel containing mirabegron resulted in a significant decrease in the size of lipid droplets within adipocytes, while their number increased. Thus, UCP1 immunostaining showed a large number of stained areas in mirabegron-treated samples, while placebo-treated samples had almost no stained areas, as shown in Figure 2. Figure 8 shown.

[0127] UCP1 is a key protein in mitochondrial non-shivering thermogenesis and is expressed exclusively in brown adipose tissue, and immunostaining for UCP1 was considered histological confirmation of browning after application of mirabegron gel.

[0128] like Fig. 9 As shown in Figure 2, the expression of brown adipose tissue (BAT)-specific gene markers increased after the application of the gel containing mirabegron. Compared with the placebo, the expression of UCP1 was significantly increased by 8.2-fold and 12.0-fold in the gel containing mirabegron at 10 DMSO and 50 DMSO. Fig. 9 For Cidea, the gel containing mirabegron increased 10DMSO and 50DMSO by 5.5 and 6.6 times, respectively, compared with the placebo. Fig. 9 Treatment with DMSO gel containing mirabegron at 10 DMSO and 50 DMSO further resulted in a significant increase in PGC1α compared to placebo, increasing to 2.5-fold and 3.0-fold, respectively. Fig. 9 However, the expression of the inflammatory marker TNFα was not increased by any of the gels compared with placebo, as shown in Fig. 9 Thus, gene expression analysis by qPCR showed that all browning markers were increased.

[0129] In addition, protein expression analysis by Western blot revealed that there was a UCP1 band in the gel containing mirabegron, while no band was observed in the placebo gel. A control band for Calnexin was visible in all gels. Quantitative analysis of UCP1 expression (normalized to Calnexin) showed that UCP1 levels were significantly increased in the mirabegron-treated group compared to the placebo group. This indicates that the observed increase in gene expression translates into UCP1 expression at the protein level, indicating that the dose of mirabegron delivered from the DMSO gel at the selected time was sufficient to effectively induce browning of inguinal white adipose tissue.

[0130] This indicates that the DMSO and ethanol gel-delivered mirabegron formulation successfully promoted the transdermal transport of mirabegron and effectively induced the classic features of browning of inguinal white adipose tissue in mice. Therefore, topical administration of mirabegron in DMSO gel appears to be a potential route of administration for providing lipolysis or for the treatment of obesity, lipedema, or diabetes.

[0131] Example 6

[0132] Use a small amount of DMSO to measure permeability

[0133] As described in Example 2, permeability was determined using a Franz diffusion cell (PermeGear) as defined in USP (725) for human skin with an orifice area of ​​1.00 cm 2 The corresponding amount of mirabegron (Mehta API Pvt. Ltd., Mumbai, India) was dissolved in the corresponding solvent mixture to prepare a solution of 20 mg mirabegron in 49 mg DMSO and 931 mg ethanol (19:1 (w / w)). After 24 hours, a sample was taken from the receiving fluid and analyzed by HPLC-UV. The permeability was found to be less than 0.4 μg / cm 2 This indicates that the minimum amount of DMSO in the formulation is 5 wt.%.

Claims

1. A composition comprising mirabegron or a salt thereof for topical and / or transdermal administration, characterized in that The composition comprises: a) ≥ 0.01 wt.-% to ≤ 25 wt.-% of mirabegron or a salt thereof; and b) a solvent selected from the group consisting of: - ≥5 wt.-% to ≤99.99 wt.-% of dimethyl sulfoxide (DMSO); or - mixtures of ≥5 wt.-% to ≤97.99 wt.-% of dimethyl sulfoxide and other solvents selected from the group consisting of: i) ≥5 wt.-% to ≤94.99 wt.-% of monohydric alcohols, or ii) ≥5 wt.-% to ≤60 wt.-% of glycerol, ethylene glycol, polyethylene glycol, glycol ethers, mixtures thereof, or mixtures with monohydric alcohols, or iii) ≥2 wt.-% to ≤10 wt.-% of water; Herein the wt.-% is based on the total weight of the composition 100 wt.-%.

2. The composition according to claim 1, characterized in that The composition comprises c) one or more pharmaceutically acceptable excipients.

3. The composition according to claim 2, characterized in that The pharmaceutical excipient is selected from the group consisting of antioxidants, penetration enhancers, gelling agents, ointment components, preservatives, colorants, flavor enhancers, stabilizers, triglycerides and mixtures thereof, preferably a gelling agent.

4. A composition according to any one of the preceding claims, characterized in that The composition comprises: a) ≥ 0.01 wt.-% to ≤ 10 wt.-% of mirabegron; b) a mixture of ≥5 wt.-% to ≤50 wt.-% of dimethyl sulfoxide and ≥50 wt.-% to ≤95 wt.-% of a C2-C5 alcohol, preferably ethanol, and c) ≥ 1 wt.-% to ≤ 20 wt.-% of a gelling agent selected from the group consisting of hydroxypropylcellulose, hydroxyethylcellulose, hydroxypropylmethylcellulose and mixtures thereof, Herein the wt.-% is based on the total weight of the composition 100 wt.-%.

5. The composition according to claim 1, characterized in that The composition comprises the following as a solvent: - ≥10 wt.-% to ≤100 wt.-% of dimethyl sulfoxide, and optionally - ≥ 10 wt.-% to ≤ 90 wt.-% of monohydric alcohols, or - ≥10 wt.-% to ≤60 wt.-% of glycerol, ethylene glycol, polyethylene glycol, glycol ethers, mixtures thereof or mixtures with monohydric alcohols, The wt.-% are based on the total weight of the solvent, 100 wt.-%.

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

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

8. A composition according to any one of the preceding claims, characterized in that Ethylene glycol ethers are present, preferably diethylene glycol monoethyl ether.

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

10. A composition comprising mirabegron or a salt thereof for topical and / or transdermal administration, characterized in that According to USP (725), at 32°C with an orifice of 1 cm 2 The composition provides at least 5 μg / cm 2 of mirabegron transdermal flux.

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

12. A 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 is 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 treating obesity or lipedema or for providing lipolysis.

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

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

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