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WO2025073804A1 - Composition comprenant un agoniste du récepteur bêta-2-adrénergique pour administration transdermique - Google Patents

Composition comprenant un agoniste du récepteur bêta-2-adrénergique pour administration transdermique Download PDF

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Publication number
WO2025073804A1
WO2025073804A1 PCT/EP2024/077802 EP2024077802W WO2025073804A1 WO 2025073804 A1 WO2025073804 A1 WO 2025073804A1 EP 2024077802 W EP2024077802 W EP 2024077802W WO 2025073804 A1 WO2025073804 A1 WO 2025073804A1
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Prior art keywords
composition
range
water
salbutamol
vol
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English (en)
Inventor
Alexander Pfeifer
Zheming NIU
Sebastian Kalju KAPPES
Alf Lamprecht
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Rheinische Friedrich Wilhelms Universitaet Bonn Koerperschaft Des Oeffentlichen Rechts
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Rheinische Friedrich Wilhelms Universitaet Bonn Koerperschaft Des Oeffentlichen Rechts
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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0014—Skin, i.e. galenical aspects of topical compositions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/20—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing sulfur, e.g. dimethyl sulfoxide [DMSO], docusate, sodium lauryl sulfate or aminosulfonic acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/08—Solutions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q19/00—Preparations for care of the skin
    • A61Q19/06—Preparations for care of the skin for countering cellulitis

Definitions

  • 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 local administration of active substances is also known, whereby the active substance is applied directly into the site of action.
  • One possibility to realise this is a direct injection into the fatty tissue. This is practised in some cases of small to medium local fat deposits by injecting a mixture of phosphatidylcholine and deoxycholate. However, this surface -active mixture leads to a localised lipolysis effect at the injection site and is typically associated with several injections and corresponding side effects such as pain, haematoma and the like.
  • an absorption 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 p2-adrenergic receptor agonists clenbuterol, formoterol, salmeterol, fenoterol and salbutamol are not yet commercially available as a transdermal dosage form.
  • salbutamol refers to a P2 -adrenergic receptor agonist (“P2 -agonist”).
  • P2 -agonist P2 -adrenergic receptor agonist
  • Salbutamol also is denoted 4-[2-(tert-butylamino)-l-hydroxyethyl]-2-(hydroxymethyl)phenol and is known by CAS identifier 18559-94-9.
  • Salbutamol is available commercially as a racemic diastereomer of R- and S-enantiomer in a 1 : 1 ratio.
  • the salbutamol salt that is commercially available is a racemic mixture of salbutamol hemisulfate, depicted by the following formula (2):
  • clenbuterol refers to a P2 -adrenergic receptor agonist (“P2 -agonist”) depicted by the following formula (3):
  • 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, hemisulfate, succinate, acetate, fumarate, tartrate, besilate and mesylate salts.
  • solvent refers to a substance, usually a liquid, which is capable of at least partially dissolving a compound, particularly one or several of an active compound selected from salbutamol, formoterol, salmeterol, fenoterol, and clenbuterol, thus providing a solution, a dispersion or a suspension.
  • the amount of dissolved compound depends on the nature of the compound and the solvent, which may dissolve a compound in total or in parts.
  • solvent also includes a dispersant.
  • solution also includes a dispersion or a suspension.
  • dimethyl sulfoxide is used as solvent, where dimethyl sulfoxide may be used as only solvent or together with one or more further solvents in a mixture, preferably in a binary solvent mixture.
  • - water a monoalcohol, glycerol, a glycol, a polyethylene glycol, a glycol ether, or mixtures thereof, in a range from > 5 wt.-% to ⁇ 95 wt.-%, wherein the wt.-% are based on a total weight of the solvent of 100 wt.-%.
  • the monoalcohol is ethanol
  • the composition comprises dimethyl sulfoxide in a range of from > 5 wt.-% to ⁇ 55 wt.-%, or in a range of from > 10 wt.-% to ⁇ 50 wt.-%, and ethanol in a range of from > 45 wt.-% to ⁇ 95 wt.-%, or in a range of from > 50 wt.-% to ⁇ 90 wt.-%, based on a total weight of the solvents of 100 wt.-%.
  • the composition preferably comprises formoterol, salmeterol, fenoterol, or a salt thereof as active ingredient.
  • purified water is considered a suitable quality of water.
  • the production and control of purified water is known to the skilled person and referred to in Ph. Eur. Monograph 0008.
  • Purified water is a preferred type of water for use in the composition. Purified water is commercially available.
  • a composition comprising a compound selected from the group comprising formoterol, salbutamol, salmeterol, fenoterol, or a salt thereof may comprise DMSO in a range from > 5 wt.-% to ⁇ 90 wt.-% and glycerol, a glycole such as propylene glycol (PG), a polyethylene glycol (PEG), dimethyl formamide (DMF), N-methyl-2 -pyrrolidone (NMP), a glycol ether, mixtures thereof, or mixtures with a monoalcohol in a range from > 10 wt.-% to ⁇ 95 wt.-%, based on a total weight of the solvent of 100 wt.-%.
  • PG propylene glycol
  • PEG polyethylene glycol
  • DMF dimethyl formamide
  • NMP N-methyl-2 -pyrrolidone
  • a glycol ether mixtures thereof, or mixtures with a monoalcohol in a range from >
  • ternary solvent mixtures comprising dimethyl sulfoxide, a monoalcohol, and water are preferred for composition comprising formoterol, salbutamol, salmeterol, or fenoterol as active ingredient.
  • the composition comprises dimethyl sulfoxide, a monoalcohol and water, each in an amount in a range of from > 20 wt.-% to ⁇ 40 wt.-%, based on a total weight of the solvent of 100 wt.-%.
  • the monoalcohol preferably is selected from ethanol, n-propanol, isopropanol, n-butanol, isobutanol, tert. -butanol, or mixtures thereof.
  • a further aspect refers to a composition for transdermal administration comprising formoterol, salbutamol, salmeterol, fenoterol, or a salt thereof, wherein the composition provides a transdermal flux of formoterol, salbutamol, salmeterol, fenoterol, of at least 5 pg/cm 2 over 24 hours as measured in a Franz Diffusion Cell with an orifice of 1 cm 2 at 32°C according to USP (725).
  • the flux is at least 10 pg/cm 2 over 24 hours, preferably at least 20 pg/cm 2 over 24 hours, more preferably at least 30 pg/cm 2 over 24 hours, even more preferably at least 50 pg/cm 2 over 24 hours, more preferably 100 pg/cm 2 over 24 hours measured according to USP (725).
  • compositions for transdermal administration comprising a compound selected from the group comprising salbutamol, clenbuterol, or a salt thereof, and at least one of a monoalcohol or water.
  • compositions for transdermal administration comprising salbutamol or a salt thereof, and a monoalcohol, preferably ethanolic formulations of salbutamol.
  • composition for transdermal administration comprising salbutamol or a salt thereof, and comprising:
  • wt.-% water, dimethyl isosorbide, isopropylmyristate, glycerol, a glycol, a polyethylene glycol, a glycol ether, or mixtures thereof, in a range from > 5 wt.-% to ⁇ 90 wt.-%; wherein the wt.-% are based on a total weight of the solvent of 100 wt.-%.
  • ethanolic formulations comprising isopropylmyristate, water or glycol ether as further solvent could provide transdermal delivery of salbutamol.
  • Solvents selected from dimethyl isosorbide, isopropyl myristate, glycerol, a glycol, a polyethylene glycol, a glycol ether, or mixtures thereof can increase permeation.
  • Glycoles and polyethylene glycols may be selected from the group of ethylene glycol, propylene glycol, and polyethylene glycol.
  • the monoalcohol is a C2-C5 alcohol selected from the group of ethanol, n-propanol, isopropanol, n- butanol, isobutanol, tert. -butanol, or mixtures thereof.
  • the monoalcohol is selected from ethanol, isopropanol, and n-butanol, isobutanol. Most preferred is ethanol.
  • the composition comprises salbutamol or a salt thereof in a range from > 0.01 wt.-% to ⁇ 25 wt.-%, preferably in a range from > 1 wt.-% to ⁇ 10 wt.-%, more preferably in a range from > 2.5 wt.-% to ⁇ 5 wt.-%, based on the total weight of the composition.
  • a further aspect refers to a composition for transdermal administration comprising salbutamol or a salt thereof, wherein the composition provides a transdermal flux of salbutamol of at least 5 pg/cm 2 over 24 hours as measured in a Franz Diffusion Cell with an orifice of 1 cm 2 at 32°C according to USP (725).
  • the flux is at least 10 pg/cm 2 over 24 hours, preferably at least 20 pg/cm 2 over 24 hours, more preferably at least 30 pg/cm 2 over 24 hours, even more preferably at least 50 pg/cm 2 over 24 hours, more preferably 100 pg/cm 2 over 24 hours measured according to USP (725).
  • the transdermal flux is measured in an infinite dose experiment on human skin in a Franz Diffusion Cell with an orifice of 1 cm 2 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.
  • 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.
  • Further embodiments refer to compositions for transdermal administration comprising clenbuterol or a salt thereof and comprising at least one of a monoalcohol or water.
  • composition for transdermal administration comprising clenbuterol or a salt thereof, and comprising:
  • aqueous and alcoholic compositions of clenbuterol allowed for a transdermal administration. It could be shown that mixtures of water and at least one of ethanol, glycol ether or dimethyl isosorbide could provide effective transdermal delivery of clenbuterol, as well as mixtures of ethanol and isopropylmyristate.
  • solvents selected from dimethyl sulfoxide, dimethyl isosorbide, glycerol, a glycol, a polyethylene glycol, a glycol ether, or mixtures thereof provided good permeation of clenbuterol.
  • Glycoles and polyethylene glycols may be selected from the group of ethylene glycol, propylene glycol, and polyethylene glycol.
  • 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®.
  • purified water is considered a suitable quality of water.
  • the production and control of purified water is known to the skilled person and referred to in Ph. Eur. Monograph 0008.
  • Purified water is a preferred type of water for use in the composition. Purified water is commercially available. Alcoholic solutions of clenbuterol are usable for transdermal application. Preferred are short-chained monoalcohols comprising up to 6 aliphatic carbon atoms.
  • the composition comprising a clenbuterol or a salt thereof may comprise as solvent water in a range of from > 45 vol.-% to ⁇ 95 vol.-% and diethylene glycol monoethyl ether (Transcutol®) or dimethyl isosorbide in a range of from > 5 vol.-% to ⁇ 55 vol.-%, based on a total volume of the solvents of 100 vol.-%.
  • solvent water in a range of from > 45 vol.-% to ⁇ 95 vol.-% and diethylene glycol monoethyl ether (Transcutol®) or dimethyl isosorbide in a range of from > 5 vol.-% to ⁇ 55 vol.-%, based on a total volume of the solvents of 100 vol.-%.
  • clenbuterol provided aqueous solutions comprising diethylene glycol monoethyl ether sufficient permeation after topic application to achieve a reduction in adipocyte size.
  • the composition comprising clenbuterol may comprise water in a range from > 80 vol.-% to ⁇ 90 vol.-% and dimethyl isosorbide in a range from > 10 vol.-% to ⁇ 20 vol.-%, based on a total volume of the solvent of 100 vol.-%. It was found that in vitro permeation of clenbuterol could be achieved from a formulation comprising only 12.5 vol.-% dimethyl isosorbide and as low as 0.1 wt.-% of clenbuterol.
  • compositions according to the invention are usable for transdermal administration.
  • the compositions are in the form of atopical composition.
  • 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.
  • atopical composition according to the invention provides for a transdermal administration of the compound.
  • 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.
  • 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.
  • the composition comprises one or more pharmaceutical excipient(s).
  • 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.
  • a gel composition preferably comprises DMSO as a solvent, DMSO in a range from > 5 wt.-% to ⁇ 95 wt.-%, preferably in a range of from > 5 wt.-% to ⁇ 55 wt.-%, or in a range of from > 10 wt.-% to ⁇ 50 wt.-%, based on a total weight of the solvent of 100 wt.-%.
  • the further solvent preferably is selected from water or an monoalcohol such as ethanol.
  • 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 in a range of from > 1 wt.-% to ⁇ 20 wt.-%, preferably in a range of from > 2 wt.-% to ⁇ 10 wt.-% or of from > 4 wt.-% to ⁇ 5 wt.- %, based on a total weight of the composition of 100 wt.-%.
  • HPC-H high-substituted hydroxypropyl cellulose
  • HPMC hydroxypropyl methylcellulose
  • a gel composition comprises hydroxypropyl cellulose, preferably high-substituted hydroxypropyl cellulose (HPC-H), in a range of from > 2.5 wt.-% to ⁇ 5 wt.-%, and formoterol, salbutamol, salmeterol, fenoterol or clembuterol in a range from > 0.1 wt.-% to ⁇ 10 wt.- %, based on a total weight of the composition of 100 wt.-%, and a binary solvent mixture of DMSO in a range from > 10 wt.-% to ⁇ 50 wt.-% and ethanol or water in a range from > 50 wt.-% to ⁇ 90 wt.-% based on a total weight of the solvent of 100 wt.-%.
  • HPC-H high-substituted hydroxypropyl cellulose
  • 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, gy
  • compositions may comprise a mono-, di- or triglyceride.
  • triglycerides are selected from the group comprising glyceryl monostearate and glyceryl oleate.
  • the composition comprises a triglyceride, preferably selected from the group comprising glyceryl monostearate and glyceryl oleate, in a range from > I wt.-% to ⁇ 20 wt.-%, based on a total weight of the composition.
  • the composition may comprise a cyclodextrin in a range of from > I wt.-% to ⁇ 20 wt.-%, based on a total weight of the solvent of 100 wt.-%.
  • the addition of cyclodextrins may increase the solubility of the active compound.
  • Preferred cyclodextrins are pharmaceutically acceptable cyclodextrins such as P-cyclodextrin and gamma-cyclodextrin as well as -cyclodextrin derivatives used as excipients in medicines such as the sulfobutylether of P-cyclodextrin (SBE-P-CD), the hydroxypropyl derivative of P-cyclodextrin (HP-P-CD), and randomly methylated P-cyclodextrin (RM-P-CD).
  • SBE-P-CD sulfobutylether of P-cyclodextrin
  • HP-P-CD hydroxypropyl derivative of P-cyclodextrin
  • RM-P-CD randomly methylated P-cyclodextrin
  • composition provides effective transdermal delivery of the active compound. This results in a high uptake in subcutaneous fat tissue, to which fat tissue will respond 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.
  • compositions as described above are in the manufacture of a medicament for the treatment of obesity or lipedema or for providing lipolysis.
  • a related aspect relates to the compositions as described above for use in the treatment of obesity or lipedema, or for providing lipolysis.
  • the composition hence may be a pharmaceutical composition.
  • 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.
  • lipolysis refers to a procedure in which an active ingredient is applied to achieve local decrease of the quantity of subcutaneous fat tissue.
  • lipolysis may refer to a treatment or to a cosmetic procedure.
  • a decrease of the volume of subcutaneous fat tissue at a local site of the body by application of a compound selected from the group comprising formoterol, salbutamol, salmeterol, fenoterol, or clenbuterol may result in a cosmetic method without therapeutic benefit.
  • Figure 4 Histologic sections of inguinal white adipose tissue of mice after treatment with 0.4% (w/v) clenbuterol containing gel based on a 50/50 (%v/v) mixture of water and Transcutol® for 10 d after haematoxylin and eosin staining in Figure 4B compared to placebo control ( Figure 4A) and after UCP1 staining in Figure 4D compared to placebo control in Figure 4C.
  • DMSO dimethyl sulfoxide
  • Figure 8 Histologic sections of inguinal white adipose tissue of mice after treatment with placebo or 10% (w/w) salbutamol hemisulfate containing gel, referring to the weight of solution, on base of a 50/50 (%w/w) mixture of water and ethanol for 10 days after haematoxylin and eosin staining in Figure 8B compared to placebo control ( Figure 8A) and after UCP1 staining in Figure 8D compared to placebo control in Figure 8C.
  • Figure 13 Permeation time profile of salbutamol hemisulfate, salmeterol xinafoate, formoterol fumarate dihydrate, and fenoterol hydrobromide over 600 pm thick murine skin from a 72 pM solution in a ternary mixture of DMSO, ethanol and water (30/35/35, %(w/w/w)).
  • DuroTAK® 387-2054 and DuroTAK® 387-2510 were gifts from Henkel (Diisseldorf- Holthausen, Germany). Pharma grade dimethyl sulfoxide was obtained from ITW Reagents (Monza, Italy). Parteck® MXP was a donation by Merck KGaA (Darmstadt, Germany). Hydroxypropyl Cellulose H and Hydroxypropyl Cellulose SL were kindly donated by Nippon Soda Co., Ltd. (Tokyo, Japan).
  • Gels were prepared by dissolving the respective compound in its solvent mixture and subsequent successive addition of gelling agent under stirring until the agent was completely dissolved.
  • clenbuterol For clenbuterol the flow rate was set to 0.3 mL/min and eluent consisted of 25/75 (%v/v) methanol (MeOH) and 0.2% (v/v) triethylamine (TEA) solution adjusted to pH 3 with orthophosphoric acid.
  • the flow rate was set to 0.3 mL/min and the mobile phase consisted of 55/45 (%v/v) ACN and 0.2% TEA solution adjusted to pH 3 with orthophosphoric acid.
  • the column temperature was maintained at 40°C and the autosampler kept at 25°C.
  • the injection volume was 2 pL and the fluorometric detection was conducted at an excitation wavelength of 340 nm and an emission wavelength of 415 nm.
  • the limit of quantification was below 100 ng/mL.
  • the flow rate was set to 0.3 mL/min and the mobile phase consisted of 25/75 (%v/v) MeOH and 0,01 M KH2PO4 buffer adjusted to pH 6.5 with 0,1 M NaOH.
  • the column temperature was maintained at 40°C and the autosampler kept at 25°C.
  • the injection volume was 2 pL and the fluorometric detection was conducted at an excitation wavelength of 285 nm and an emission wavelength of 345 nm.
  • the limit of quantification was below 100 ng/mL.
  • Human abdominal skin with underlying subcutaneous fatty tissue was cut into appropriately sized rectangular pieces after surgery without prior freezing and placed into petri dishes that were filled with 20 mL of DMEM containing 10% fetal bovine serum and 1% penicillin/streptomycin. A volume of 0.2 mL formulation was applied to the skin with a syringe and spread across a rectangular area of 6 cm 2 . Dishes were closed and incubated in a drying cabinet for 3 d at 32°C to simulate the outer skin temperature. After incubation, skin was taken from the dishes and fatty tissue directly adjacent to the dermis was sampled for further analysis of gene expression by real-time PCR.
  • Tissues were homogenized with Trizol 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, Waltham, MA, USA).
  • Solubility of formoterol fumarate dihydrate was tested in water, tetrahydrofiiran (THF), dimethyl isosorbide (DMI), propylene carbonate (PC), Transcutol® (TC), Miglyol® 812 (MCT812), cocoyl caprylocaprate (CC), ethanol (EtOH), polyethylene glycol 300 (PEG300), propylene glycol (PG), dimethyl formamide (DMF), dimethyl sulfoxide (DMSO), N-Methyl-2 -pyrrolidone (NMP) and methanol (MeOH) as described above.
  • THF tetrahydrofiiran
  • DI dimethyl isosorbide
  • PC propylene carbonate
  • TC Transcutol®
  • MCT812 Miglyol® 812
  • MCT812 cocoyl caprylocaprate
  • EtOH ethanol
  • PEG300 polyethylene glycol 300
  • PG propylene glycol
  • DMF
  • Table 2 Solubility of formoterol fumarate dihydrate in water, tetrahydrofiiran (THF), dimethyl isosorbide (DMI), propylene carbonate (PC), Transcutol® (TC), Miglyol® 812 (MCT812), cocoyl caprylocaprate (CC), ethanol (EtOH), polyethylene glycol 300 (PEG300), propylene glycol (PG), dimethyl formamide (DMF), dimethyl sulfoxide (DMSO), N-Methyl-2 -pyrrolidone (NMP) and methanol (MeOH).
  • formoterol fumarate dihydrate was insoluble in the apolar excipients MCT812 and cocoyl caprylocaprate as no amount of dissolved formoterol fumarate dihydrate (FF) could be detected, which is surely due to its salt form (Tab. 5).
  • the solubility of formoterol fumarate dihydrate (FF) was also low in highly polar PC. In water, THF, and DMI the solubility was below 1 mg/mL and about a magnitude higher in polar protic solvents containing alcoholic groups, such as EtOH or TC: The highest solubility was found in polar aprotic solvents, such as DMSO, DMF, and NMP.
  • the Franz Diffusion Cell had a donor compartment and a receptor compartment attached to each other using clamp attachment lug. Between donor compartment and receptor compartment was a membrane mounted. The receptor compartment had a sampling side arm. The formulation to be determined was applied to the donor compartment. A receiver fluid was contained in the receptor compartment. The Franz Diffusion Cell had an orifice of 1 cm 2 . Experiments were conducted at 32°C according to USP (725). 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 solution of 6.17 wt.-% formoterol fumarate dihydrate (w/w, equivalent to 5% formoterol free base) was prepared by dissolving formoterol fumarate dihydrate in DMSO.
  • FIG. 2 shows the results of treatment of mice with 6.17% (w/w) formoterol fumarate dihydrate solution for 10 days on expression of browning markers.
  • treatment significantly increased mRNA expression of the browning markers UCP1, CIDEA and PGCla, while DIO2 and TNFa were not significantly changed in white adipose tissue compared to placebo controls.
  • Example 4
  • Solubility of clenbuterol was tested in water, isopropyl myristate, Miglyol® 812, propylene carbonate, dimethyl isosorbide, polyethylene glycol 300 (PEG300), propylene glycol, Transcutol®, and ethanol as described above. The results are listed in Table 3 below.
  • DMI dimethyl isosorbide
  • PEG300 polyethylene glycol 300
  • PG propylene glycol
  • TC Transcutol®
  • EtOH ethanol
  • Solubility of clenbuterol was further tested in binary mixtures of water with ethanol, Transcutol® (TC), and dimethyl isosorbide (DMI). The results are listed in Table 4 below. As can be taken from Table 4, solubility increased with decreasing amount of water.
  • FIG. 3 illustrates the permeation time profiles of clenbuterol from the tested binary mixtures of ethanol/isopropyl myristate (EtOH IPM), ethanol/water (EtOH W), Transcutol®/water (TC_W), and dimethyl isosorbide/water (DMI W).
  • EtOH IPM ethanol/isopropyl myristate
  • EtOH W ethanol/water
  • TC_W Transcutol®/water
  • DMI W dimethyl isosorbide/water
  • mice were treated with the gelled formulation and inguinal white adipose tissue (WATi) was analyzed for browning marker expression by qPCR and histologically after hematoxylin and eosin, as well as UCP1 antibody staining as described above.
  • WATi inguinal white adipose tissue
  • Figure 5 shows the results of treatment of mice with aqueous clenbuterol gel on expression of browning markers UCP1, CIDEA, DIO2, PGCla, and TNFa in Figures Figure 5 A, B, C, D and E, respectively.
  • treatment significantly increased mRNA expression of the browning markers CIDEA and PGCla, while UCP1, DIO2 and TNFa were not significantly changed in white adipose tissue compared to placebo control.
  • mice were treated with the gelled formulation and inguinal white adipose tissue (WATi) was analyzed for browning marker expression by qPCR and histologically after hematoxylin and eosin, as well as UCP1 antibody staining as described above.
  • WATi inguinal white adipose tissue
  • Figure 6 shows the results of treatment of mice with ethanolic/aqueous clenbuterol gel on expression of browning markers UCP1, CIDEA, DIO2, PGCla, and TNFa in Figures Figure 6A, B, C, D and E, respectively.
  • treatment significantly increased mRNA expression of the browning markers CIDEA and PGCla, while UCP1, DIO2 and TNFa were not significantly changed in inguinal white adipose tissue compared to placebo control.
  • FIG. 8 shows histological sections of inguinal white adipose tissue after haematoxylin and eosin staining and UCP1 antibody staining.
  • Figure 8B an increase in lipid droplets and reduction in adipocyte size in verum treated mice compared to placebo as depicted in Figure 8A was seen.
  • No differences in UCP1 expression from antibody-stained sections could be observed between placebo, depicted in Figure 8C, and verum treated groups, depicted in Figure 8D, was seen.
  • Figure 10 shows the amount of salbutamol hemisulfate permeated per cm 2 of human abdominal skin after 5 h and 24 h. As can be taken from Figure 10, high permeated amounts of 212.2 ⁇ 84.4 pg/cm 2 salbutamol hemisulfate after 24 h were achieved.
  • Table 12 Compositions, resulting flux and extrapolated lag times from ternary mixtures of dimethyl sulfoxide (DMSO), ethanol and water (30/35/35, %w/w/w) tested in permeation experiments.
  • DMSO dimethyl sulfoxide
  • Table 12 Compositions, resulting flux and extrapolated lag times from ternary mixtures of dimethyl sulfoxide (DMSO), ethanol and water (30/35/35, %w/w/w) tested in permeation experiments.
  • Figure 13 illustrates the permeation time profiles of salmeterol xinafoate from the tested ternary mixtures of dimethyl sulfoxide (DMSO), ethanol and water. As can be taken from Table 12 and Figure 13, the ternary formulations provided a good permeated amount after 24 h and flux.
  • DMSO dimethyl sulfoxide
  • Table 14 Compositions, resulting flux and extrapolated lag time of salbutamol hemisulfate from mixtures of dimethyl sulfoxide (DMSO), ethanol (EtOH), glycerol, water and a urea solution (20 % (w/w) in water), tested in permeation experiments in infinite dose. Data is presented as mean ⁇ SD,
  • Sample for comparison was a 30/35/35% (w/w/w) ternary mixture of dimethyl sulfoxide, ethanol and water denoted “without gelling agent“. Samples were taken after 24 h and analysed via HPLC using a fluorescence detector. Table 15 below summarises the compositions and results.
  • the formulations showed a good permeated amount after 24 h and flux. There was no significant difference in permation over 24 h and flux depending on the amount of gelling agent.
  • Figure 14 illustrates the permeation time profiles of 72 pM solutions of salbutamol hemisulfate, salmeterol xinafoate, formoterol fumarate dihydrate and fenoterol hydrobromide in mixtures of dimethyl sulfoxide (DMSO), ethanol (EtOH) and water (30/35/35 w/w/w) over murine skin.
  • DMSO dimethyl sulfoxide
  • EtOH ethanol
  • water (30/35/35 w/w/w/w
  • the ternary formulations provided a good permeated amount after 24 h.

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Abstract

La présente invention concerne une composition pour administration transdermique, la composition comprenant un composé choisi dans le groupe comprenant du formotérol, du salbutamol, du salmétérol, du fénotérol, un mélange de ceux-ci ou un sel de celui-ci, et du diméthylsulfoxyde. L'invention concerne en outre une composition comprenant un composé choisi dans le groupe comprenant du salbutamol, du clenbutérol ou un sel de celui-ci, et comprend au moins l'un parmi un monoalcool ou de l'eau.
PCT/EP2024/077802 2023-10-04 2024-10-02 Composition comprenant un agoniste du récepteur bêta-2-adrénergique pour administration transdermique Pending WO2025073804A1 (fr)

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US20100137267A1 (en) * 2006-10-17 2010-06-03 John Daniel Dobak Formulations for treatment of adipose tissue, cutaneous tissue and disorders, and muscular tissue
CN101626759B (zh) * 2006-10-17 2014-08-06 利特拉公司 用于治疗甲状腺眼病的组合物和制剂
EP3206678B1 (fr) 2014-10-14 2019-12-11 Sculpt B.V. Façonnage du corps

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DE29612123U1 (de) * 1996-07-11 1996-09-12 Kafl, Johann, 83730 Fischbachau Dermapermeables (hautdurchlässiges) Gel (Salbe) zur subcutanen Lipidmetabolisierung (Unterhautfettverbrennung) und Behandlung von Cellulite
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