Classifications

• • 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
• • 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
  • A61K31/557—Eicosanoids, e.g. leukotrienes or prostaglandins
  • A61K31/5575—Eicosanoids, e.g. leukotrienes or prostaglandins having a cyclopentane, e.g. prostaglandin E2, prostaglandin F2-alpha
• • 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
  • A61K47/24—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing atoms other than carbon, hydrogen, oxygen, halogen, nitrogen or sulfur, e.g. cyclomethicone or phospholipids
• • 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
  • 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
  • A61P17/00—Drugs for dermatological disorders
  • A61P17/14—Drugs for dermatological disorders for baldness or alopecia
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P5/00—Drugs for disorders of the endocrine system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P5/00—Drugs for disorders of the endocrine system
  • A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
  • A61P5/26—Androgens

Definitions

• the present invention relates to topical compositions which are useful for the treatment of diseases and conditions affecting a pilosebaceous unit, in particular for the treatment of hair disorders.
• a pilosebaceous unit is composed of the hair follicle, the hair shaft and sebaceous glands.
• This structure is present on the surface of the mammalian skin and is considered to be an important pathway for the percutaneous absorption of topically applied drugs.
• the pilosebaceous unit is the main factory for hormone production, in particular can synthesize androgens. When stimulated by hormones such as androgens, sebaceous glands secrete a lipid-rich sebum that protects the hair and provides the skin with a hydrophobic barrier that can serve as protection.
• the hair follicle is an invagination of the epidermis extending deep into the dermis.
• Targeted drug delivery to hair follicle is relevant with regard to diseases like androgenetic alopecia and alopecia areata.
• Access to the hair follicle is difficult due to structural aspect of hair follicle and its chemical environment.
• the keratinous layers of the inner and outer root sheaths and the glassy membrane surrounding the entire follicle may restrict passage of molecules deep within the follicle.
• sebum discharge into the follicle is constant and effective drug delivery and pharmacological effects depend upon the interactions between the drug and sebum. (Indian Journal of Pharmacology 2000; 32: 269-281).
• An androgen-dependent condition, disease, disorder, or syndrome is a medical condition that is, in part or full, dependent on, or is sensitive to, the presence of androgenic activity in the body.
• Known androgen-dependent conditions include among others androgenic alopecia and hirsutism.
• Alopecia also known as hair loss or baldness, refers to the loss of hair from parts of the head or body.
• Hirsutism refers to the male pattern hair distribution in women. Both conditions cause significant psychologic distress.
• Androgenetic alopecia affects both men and women. In men it produces male pattern hair loss with bitemporal recession and vertex baldness. In women it produces female pattern hair loss with diffuse alopecia over the mid-frontal scalp. Androgen dependent conditions may be treated with drugs with antiandrogen actions, including androgen receptor antagonists such as cyproterone acetate, spironolactone, and bicalutamide, 5a-reductase inhibitors such as finasteride and dutasteride, CYP17A1 inhibitors, gonadotropin-releasing hormone (GnRH) analogues and/or other antigonadotropins. Topical minoxidil and oral finasteride are approved by the Food and Drug Administration (USA) for the treatment of male androgenetic alopecia. Both medications prevent further hair loss, but only partially reverse baldness, and require continuous use to maintain the effect.
• androgen receptor antagonists such as cyproterone acetate, spirono
• Hirsutism is excessive body hair on parts of the body where hair is normally absent or minimal.
• hirsutism has been considered a marker of increased androgen levels in females from increased production of androgens (i.e testosterone) either by the adrenals or due to an ovarian disease.
• Spironolactone (SPA) is an androgen blocker. The starting dose is 50 mg twice daily and may be increased to a total daily dose of 200 mg.
• the 5-RA inhibitors finasteride, a 5-alpha reductase inhibitor has been found to be effective in the treatment of hirsutism. ( Indian J Dermatol. 2010 Jan-Mar; 55(1): 3-7).
• eyelashes serve a protective function and, as with all hairs on the body, are generated by the continuous cycling of hair follicles. Similar to other hair follicles on the body, eyelash follicles are connected to sebaceous glands. Individuals can experience the loss of previously normal eyelashes, which may or may not be accompanied by the destruction of their respective hair follicles.
• madrosis also referred to as milphosis
• Hypotrichosis is a rare condition in which there is little or no hair growth on the head, including the brows above the eyes and the edge of the eyelids, or other areas of the body where hair normally grows.
• EP280233 IB 1 describes bimatoprost 0,03 % w/v for use in a method of growing eyelashes in post chemotherapeutic patients.
• bimatoprost ophthalmic solution 0.03% is to be applied daily to the skin of the upper eyelid margin at the base of the eyelashes using a sterile single-use-per-eye applicator.
• Latanoprost is an isopropyl ester prodrug of the acid metabolite, which is a prostaglandin F2a analog.
• US6262105B1 describes methods of enhancing hair growth using prostaglandins, specifically exemplifying latanoprost. This patent also describes topical preparations having varying amounts (0.1-10%) of active ingredient.
• Blume-Peytavi J. Am. Acad. Dermatol. 2012 May; 66(5):794-800 describes a double-blind placebo-controlled pilot study to assess the efficacy of a 24-week topical treatment by latanoprost 0.1% on hair growth and pigmentation in healthy volunteers with androgenetic alopecia.
• the aqueous latanoprost formulation (0.1% latanoprost, 50% ethanol, 20% propylene glycol, water) used in the study comprises high amount of ethanol which can provoke unpleasant reactions and inflammation, especially when applied to sensitive areas like the eyelids.
• a further object is to provide a treatment which effectively delivers prostaglandins or antiandrogens to the hard to reach pilosebaceous unit or components thereof, namely to or into the hair follicle, the hair shaft and sebaceous glands.
• compositions that contain cosolvents, such as alcohols, at a significant lower concentration, as compared to aqueous compositions, which utilize alcohols in higher concentrations as penetration enhancers and which thus may lead to skin irritation or contact dermatitis, when used on a regular basis.
• the objective of the present invention is to provide a pharmaceutical composition which may be used to treat or prevent a disease or condition affecting a pilosebaceous unit such as androgenetic alopecia, hirsutism, hypotrichosis, alopecia of the eyebrows and of the eyelashes.
• a disease or condition affecting a pilosebaceous unit such as androgenetic alopecia, hirsutism, hypotrichosis, alopecia of the eyebrows and of the eyelashes.
• composition of the present invention penetrates effectively into the skin and the hairs, preferably into the pilosebaceous unit of the skin and the hairs or components thereof, such as the hair follicle, the hair shaft and sebaceous glands of the skin and the hairs. Accordingly, treatment of diseases associated with the pilosebaceous unit, in particular diseases of the hair, can be conveniently achieved by topical application and without the side effects associated with the use of water based formulations, characterized by high amounts of cosolvents and other components which can be irritating, in particular for delicate areas like the eyelids.
• Figure 1 Uptake of latanoprost from latanoprost formulations after 2 hours of incubation. The concentration of latanoprost is expressed in pg per cm 2 of skin.
• Expl and Exp2 refer to formulation 1 (0,5 mg/ml latanoprost in 1-perfluorobutylpentane and l%v/v ethanol);
• Exp3 refers to formulation 2 (0,1 mg/ml in 1-perfluorobutylpentane and 1 %v/v ethanol)
• Exp4 refers to formulation 3 (0.5 mg/ml latanoprost in 50% ethanol, 20 % propylene glycol and water solution), as described in Example 1.
• “Punch hair” 10x2 mm skin punch with at least one hair;
• skin punch 10x2 mm skin punch without hair.
• Data are mean values ⁇ standard deviation from experiments performed in triplicate.
• Figure 2 Uptake and biotransformation to latanoprost acid from latanoprost formulations after 2 hours of incubation.
• the latanoprost acid amount is expressed in pg per cm 2 of skin. Part of latanoprost was bio transformed to latanoprost acid during incubation.
• Expl and Exp2 refer to formulation 1 (0,5 mg/ml latanoprost in 1-perfluorobutylpentane and 1% v/v ethanol); Exp3 refers to formulation 2 (0,1 mg/ml in 1-perfluorobutylpentane and 1% v/v ethanol) and Exp4 refers to formulation 3 (0.5 mg/ml latanoprost in 50% ethanol, 20 % propylene glycol and water solution), as described in Example 1.
• “Punch hair” 10x2 mm skin punch with at least one hair;
• skin punch 10x2 mm skin punch without hair. Data are mean values ⁇ standard deviation from experiments performed in triplicate.
• Figure 3 Total uptake of latanoprost from latanoprost formulations after 2 hours of incubation.
• Expl and Exp2 refer to formulation 1 (0,5 mg/ml latanoprost in 1- perfluorobutylpentane and 1% v/v ethanol);
• Exp3 refers to formulation 2 (0,1 mg/ml in 1- perfluorobutylpentane and 1% v/v ethanol)
• Exp4 refers to formulation 3 (0.5 mg/ml latanoprost in 50% ethanol, 20 % propylene glycol and water solution), as described in Example 1.
• “Punch hair” 10x2 mm skin punch with at least one hair;
• skin punch 10x2 mm skin punch without hair.
• Data are mean values from experiments performed in triplicate.
• FIG. 4 Latanoprost penetration tissue. Depicted is the amount of latanoprost expressed in pg/ml in the eyelashes and the skin samples of Example 2 at three time points.
• the values at each time point are from four independent replicates ⁇ standard deviation.
• FIG. 5 Latanoprost acid distribution. Depicted is the amount of latanoprost acid expressed in pg/ml in the eyelashes and the skin samples of Example 2 at three time points. The values at each time point are from four independent replicates ⁇ standard deviation.
• the present invention provides a composition comprising an active ingredient and a semifluorinated alkane for use in the topical treatment of a disease or condition affecting a pilosebaceous unit, wherein the disease or condition affecting the pilosebaceous unit is selected from androgenetic alopecia, hirsutism, hypotrichosis, alopecia of the eyebrows and of the eyelashes.
• the present invention provides a composition comprising an active ingredient and a semifluorinated alkane for use in the topical treatment of a disease or condition affecting one or more components of the pilosebaceous unit, selected from the hair follicle, the hair shaft and the sebaceous gland, wherein the disease or condition affecting the pilosebaceous unit is selected from androgenetic alopecia, hirsutism, hypotrichosis, alopecia of the eyebrows and of the eyelashes.
• the disease or condition affecting a pilosebaceous unit is a hair disorder selected from androgenetic alopecia, hirsutism, hypotrichosis, alopecia of the eyebrows and of the eyelashes.
• the active ingredient is selected from prostaglandin analogs (also known as prostaglandin analogues) or antiandrogens.
• the prostaglandin analog is prostaglandin F2a analogue.
• the active ingredient is a prostaglandin F2a analogue is selected from latanoprost, bimatoprost, and travoprost.
• the active ingredient is latanoprost or bimatoprost, more preferably the active ingredient is latanoprost.
• the antiandrogen is a steroidal antiandrogen.
• the steroidal antiandrogen is selected from cortexolone 17a-propionate, cyproterone acetate, spironolactone, finasteride and dutasteride.
• the active ingredient is cortexolone 17a- propionate.
• semifluorinated alkane also referred to as “SFA” throughout this document, as used herein refers to a linear or branched compound composed of at least one perfluorinated segment (F-segment) and at least one non-fluorinated hydrocarbon segment (H-segment).
• the semifluorinated alkane is a linear or branched compound composed of one perfluorinated segment (F-segment) and one non-fluorinated hydrocarbon segment (H- segment).
• said semifluorinated alkane is a compound that exists in a liquid state within the temperature range of 4° to 40°C.
• the F- and the H-segment of the linear or branched semifluorinated alkane comprise, independently from one another, 2 to 10 carbon atoms.
• the semifluorinated alkane is a linear compound of the formula (I) CF3(CF2)n(CH2)mCH3, wherein n and m are integers independently selected from each other from the range of 2 to 10.
• the linear semifluorinated alkane may be referred to as FnHm, wherein F means the perfluorinated hydrocarbon segment, H means the non- fluorinated hydrocarbon segment and n, m is the number of carbon atoms of the respective segment.
• F4H5 is used for 1-perfluorobutyl-pentane.
• the semifluorinated alkane is a semifluorinated alkane of formula (I) CF3(CF2)n(CH2)mCH3 wherein n is selected from 3 to 5 and m is selected from 4 to 9. More preferred is a semifluorinated alkane selected from the group consisting of F4H5, F4H6,
• the semifluorinated alkane is selected from F4H5 and F6H8.
• Most preferred is a semifluorinated alkane selected from F4H5, F6H8 and F6H10.
• the semifluorinated alkane is a semifluorinated alkane of formula (I) CF3(CF2)n(CH2)mCH3 wherein n is selected from 3 to 5 and m is selected from 4 to 7.
• the composition may comprise a semifluorinated alkane in an amount of from about 90 % (v/v) to about 99 % (v/v), more preferably from about 95 % (v/v) to about 99 % (v/v) with respect to the total volume of the composition.
• the composition comprises a semifluorinated alkane in an amount of from about 97 % (v/v) to about 99% (v/v) with respect to the total volume of the composition.
• the composition may comprise a solubilizing agent such as, for example, an organic cosolvent, an oily excipient and/or an oil selected from glyceride oils, liquid waxes and liquid paraffin.
• a solubilizing agent such as, for example, an organic cosolvent, an oily excipient and/or an oil selected from glyceride oils, liquid waxes and liquid paraffin.
• examples of potentially useful oily excipients comprise triglyceride oils, mineral oil, medium chain triglycerides (MCT), oily fatty acids, isopropyl myristate, oily fatty alcohols, esters of sorbitol and fatty acids, oily sucrose esters or any other substance which is physiologically tolerated or squalane.
• the solubilizing agent is selected from ethanol, isopropanol, MCT or squalane.
• the solubilizing agent is a liquid, more preferably the solubilizing agent is not semi-solid or solid
• the composition comprises a cosolvent.
• the cosolvent is ethanol or isopropanol, or an alcohol selected from ethanol and isopropanol.
• the composition comprises a cosolvent in an amount of up to 2 % (v/v), more preferably of up to 1,5 % (v/v) and most preferably of up to 1,0 % (v/v) with respect to the total volume of the composition.
• the composition comprises ethanol in an amount of up to 2 % (v/v), more preferably of up to 1,5 % (v/v) and most preferably of up to 1,0 % (v/v) with respect to the total volume of the composition.
• the cosolvent is present at a concentration of from 0.5 to 3.0 % (v/v), more preferably 0.5 to 2.0 % (v/v), most preferably 0.5 to 2.0% (v/v) with respect to the total volume of the composition.
• the composition comprises an alcohol as a cosolvent, which is present at a concentration of from 0.5 to 3.0 % (v/v), more preferably 0.5 to 2.0 % (v/v), even more preferably 0.5 to 2.0 % (v/v), most preferably 0.5 to 1.0% (v/v) with respect to the total volume of the composition.
• the composition is substantially free of a preservative. In a preferred embodiment, the composition is substantially free of water.
• the term ‘substantially free’, or alternatively ‘essentially free’ in reference to a composition constituent refers to the presence of said constituent in no more than trace amounts and that if present in trace amounts the constituent provides no technical contribution to the composition.
• the composition for the use according to the present invention is substantially free of water and of a preservative.
• the composition for the use of the present invention is provided as a clear solution, wherein the active ingredient is fully dissolved in the semifluorinated alkane. Furthermore, the composition for the use according to the present invention is preferably provided in sterile form.
• the composition consists of an active ingredient dissolved in a semifluorinted alkane, and optionally a solubilizing agent.
• the composition consist of a prostaglandin analogue dissolved in a semifluorinted alkane, and optionally a solubilizing agent or the composition consist of an antiandrogen dissolved in a semifluorinted alkane, and optionally a solubilizing agent.
• the present invention provides a composition comprising or consisting of a prostaglandin analogue dissolved in semifluorinated alkane, and optionally a solubilizing agent, for use in the topical treatment of androgenetic alopecia or alopecia of the eyebrows and of the eyelashes.
• a composition comprising or consisting of a prostaglandin analogue dissolved in a semifluorinated alkane and an alcohol, for use in the topical treatment of androgenetic alopecia
• the prostaglandin analogue is selected from latanoprost, bimatoprost and travoprost
• the semifluorinated alkane is selected from F4H5 or F6H8
• the alcohol is selected from ethanol or isopropanol.
• the present invention provides a composition for use in the topical treatment of androgenetic alopecia, wherein the composition comprises or consists of : (i) latanoprost dissolved in F4H5 and ethanol,
• the present invention provides a composition for use in the topical treatment of androgenetic alopecia, wherein the composition comprises or consists of :
• the present invention provides a composition comprising or consisting of 0.05 to 0.5 mg/ml (or 0.1 to 0.5 mg/ml) of a prostaglandin analogue dissolved in semifluorinated alkane, and optionally a solubilizing agent, for use in the topical treatment of androgenetic alopecia or alopecia of the eyebrows and of the eyelashes. More preferably, a composition comprising or consisting of 0.05 to 0.5 mg/ml.
• the present invention provides a composition for use in the topical treatment of androgenetic alopecia, wherein the composition comprises or consists of :
• the present invention provides a composition for use in the topical treatment of androgenetic alopecia, wherein the composition comprises or consists of :
• the present invention provides a composition for use in the topical treatment of androgenetic alopecia, wherein the composition comprises or consists of :
• the composition for the use in the topical treatment of androgenetic alopecia is a liquid solution that consists of latanoprost at a concentration of 0.05 to 0.5 mg/ml, a semifluorinated alkane selected from F4H5 or F6H8 and optionally an alcohol that is present at a concentration of up to 2% (v/v) with respect to the total volume of the composition.
• composition for the use in the topical treatment of androgenetic alopecia is a liquid solution that consists of latanoprost at a concentration of 0.05 to 0.5 mg/ml, a semifluorinated alkane selected from F4H5 or F6H8 and optionally a liquid solubilizing agent
• the composition for the use in the topical treatment of androgenetic alopecia is a liquid solution that consists of latanoprost at a concentration of 0.05 to 0.5 mg/ml, a semifluorinated alkane selected from F4H5 or F6H8 and optionally a liquid solubilizing agent selected from glyceride oils, liquid waxes and liquid paraffin, triglyceride oils, mineral oil, medium chain triglycerides (MCT), oily fatty acids, isopropyl myristate, oily fatty alcohols, esters of sorbitol and fatty acids, oily sucrose esters
• the present invention provides a composition comprising or consisting of a antiandrogen dissolved in semifluorinated alkane, and optionally a solubilizing agent, for use in the topical treatment of androgenetic alopecia.
• a composition comprising or consisting of cortexolone 17a-propionate dissolved in a semifluorinated alkane and optionally an alcohol, for use in the topical treatment of androgenetic alopecia is provided, wherein the semifluorinated alkane is selected from F4H5 or F6H8, and wherein the optional alcohol is selected from ethanol or isopropanol.
• the present invention provides a composition comprising or consisting of cortexolone 17a-propionate dissolved in F4H5, for use in the topical treatment of androgenetic alopecia.
• composition for the use of the present invention is administered topically.
• a topical medication is a medication that is applied to a particular place on or in the body.
• Topical administration means application to body surfaces such as the skin or mucous membranes.
• the composition for the use of the present invention is administered to a part of the skin selected from the scalp, the face, the chest, the eyelids.
• the composition for the use of the present invention is topically administered to a particular part of the skin in form of a liquid, more preferably the composition for the use is topically administered in liquid form of droplets, as film or as spray (mist) to skin.
• Administering the composition as droplets may be accomplished by dispensing the liquid composition from a pipette or a dropper.
• Administering the composition as film may be accomplished by dispending the liquid composition from a roll-on.
• Administering the composition as spray or mist may be accomplished by dispensing the liquid composition from a spray device.
• the liquid composition for the use of the present invention is topically administered as droplets from a dropper or a pipette, or as a film from a roll-on, or as a spray or mist from a spray device.
• the composition for the use of the present invention is topically administered or dispensed in liquid form from a pipette, a dropper, a spray device or from a roll-on device to the scalp, the face, the chest, the eyelids or the eyelashes of a subject.
• the composition for the use is not in form of an ointment, more preferably the composition for the use is topically administered to a particular part of the skin in form of a liquid and not in form of an ointment.
• the composition for the use does not comprise a solid thickening agent, more preferably the composition for the use does not comprise a solid thickening agent selected from plant waxes, animal waxes, petroleum derived waxes, solid and semisolid triglycerides, C12-24 fatty acids, C8-18 glycerides, fatty alcohols, fatty alcohols derivatives, even more preferably the composition for the use does not comprise a solid thickening agent selected from plant waxes, animal waxes, petroleum derived waxes, solid and semisolid triglycerides, cetyl alcohol, cetyl palmitate, tetradecanol.
• a solid thickening agent is a compound that is not liquid, preferably said compound is not liquid at 20°C.
• the composition for the use of the present invention is administered to an individual suffering from hair loss, preferably to a subject suffering or suspected to be suffering from androgenetic alopecia, hirsutism, hypotrichosis, alopecia of the eyebrows and of the eyelashes.
• the subject is preferably a human subject, but may be also an animal, such as a dog.
• a human subject suffering from hair loss may be a male or a female subject.
• the present invention provides a method of treating or preventing a disease or condition associated with a pilosebaceous unit, the method comprising topically administering to a subject a composition comprising an active ingredient and a semifluorinated alkane, wherein the disease or condition associated with a pilosebaceous unit is selected from androgenetic alopecia, hirsutism, hypotrichosis, alopecia of the eyebrows and of the eyelashes.
• the present invention provides a method of treating or preventing a disease or condition associated with a pilosebaceous unit or one or more components thereof, the method comprising topically administering to a subject a composition comprising an active ingredient and a semifluorinated alkane, wherein the disease or condition associated with a pilosebaceous unit is selected from androgenetic alopecia, hirsutism, hypotrichosis, alopecia of the eyebrows and of the eyelashes and wherein the one or more components of the pilosebaceous unit are selected from the hair follicle, the hair shaft and the sebaceous gland.
• the aforementioned method of treating or preventing a disease or condition associated with a pilosebaceous unit or one or more components thereof is effective in delivering the active ingredient to or into the pilosebaceous unit or one or more components thereof, preferably the method is effective in delivering the active ingredient to the hair follicle, the hair shaft and/or the sebaceous gland.
• the method of treating or preventing a disease or condition associated with a pilosebaceous unit or one or more components thereof is effective in delivering a prostaglandin or an antiandrogen to or into the pilosebaceous unit or one or more components thereof, preferably the method is effective in delivering a prostaglandin or an antiandrogen to the hair follicle, the hair shaft and/or the sebaceous gland.
• the present invention provides for a composition for use in a method of prevention or therapy of a disease or condition associated with a pilosebaceous unit, wherein the composition comprises an active ingredient and a semifluorinated alkane, wherein said composition is therapeutically effective in treating or preventing a disease or condition associated with a pilosebaceous unit, wherein the disease or condition associated with a pilosebaceous unit is selected from androgenetic alopecia, hirsutism, hypotrichosis, alopecia of the eyebrows and of the eyelashes.
• the present invention provides for a kit comprising a composition according to the first aspect of the invention, namely for use in the prevention or therapy of a disease or condition associated with a pilosebaceous unit, wherein the composition comprises an active ingredient and a semifluorinated alkane, wherein the kit comprises a container for holding the composition and instructions for using the composition.
• the container comprised in the kit is part of a pipette, dropper, spray or a roll-on device that allows for dispensing the liquid composition, thereby allowing for topically administration of the liquid composition to the scalp, the face, the chest, the eyelids or the eyelashes of a subject.
• the present invention provides for the use of the composition according to the first aspect of the invention, for the manufacture of a medicament for the treatment or prevention of a disease or condition affecting a pilosebaceous unit, or a component thereof, wherein the disease or condition affecting the pilosebaceous unit is selected from androgenetic alopecia, hirsutism, hypotrichosis, alopecia of the eyebrows and of the eyelashes.
• the present invention provides for a method of stimulating the growth of eyelashes comprising administering topically to the eyelid of a subject a composition comprising a prostaglandin F2a analogue and a semifluorinated alkane, preferably a composition comprising or consisting of latanoprost, 1-perfluorobutylpentane and ethanol.
• a composition comprising an active ingredient and a semifluorinated alkane for use in the topical treatment of a disease or condition affecting a pilosebaceous unit, wherein the disease or condition affecting the pilosebaceous unit is selected from androgenetic alopecia, hirsutism, hypotrichosis, alopecia of the eyebrows and of the eyelashes.
• composition for the use according to item 1 wherein the active ingredient is selected from a prostaglandin analogue and an antiandrogen.
• composition for the use of any preceding items, wherein the disease or condition affecting the pilosebaceous unit is selected from androgenetic alopecia, hypotrichosis of the eyelashes, alopecia of the eyebrows and of the eyelashes.
• the antiandrogen is a steroidal antiandrogen, preferably selected from cortexolone 17a-propionate, cyproterone acetate, spironolactone, finasteride, dutasteride.
• the prostaglandin F2a analogue is present at a concentration of from 0.05 to 0.5 mg/ml.
• composition for the use of any preceding items, wherein the composition further comprises a cosolvent, preferably an alcohol selected from ethanol and isopropanol.
• a cosolvent preferably an alcohol selected from ethanol and isopropanol.
• composition for the use of item 12, wherein the semifluorinated alkane is selected from 1-perfluorohexyloctane and 1-perfluorobutylpentane.
• composition for the use of any preceding items, wherein the cosolvent is present a concentration of up to 3% (v/v), preferably up to 2% (v/v), more preferably up to 1% (v/v) with respect to the total volume of the composition.
• the semifluorinated alkane is 1- perfluorobutylpentane, or wherein the semifluorinated alkane is 1-perfluorohexyloctane.
• composition for the use of any preceding items, wherein the composition is free of water and/or preservatives.
• composition for the use of any preceding items, wherein the composition is in the form of a solution, preferably the composition is in form of a liquid solution.
• a method of treating or preventing a disease or condition affecting a pilosebaceous unit comprises topically administering a composition as defined in any of the preceding items to a subject suffering from a disease or condition affecting a pilosebaceous unit, wherein the disease or condition affecting a pilosebaceous unit is selected from androgenetic alopecia, hirsutism, hypotrichosis, alopecia of the eyebrow and of the eyelashes.
• kits comprising the pharmaceutical composition according to any one of items 1 to 25 and a container for holding the composition.
• composition for the use of items 1 to 25, wherein the disease or condition affecting a pilosebaceous unit is selected from alopecia of the eyelashes and of the eyebrows, hypotrichosis of the eyelashes, preferably alopecia of the eyelashes.
• composition for the use of item 29, wherein the active ingredient is latanoprost.
• a method of stimulating the growth of the eyelashes comprising administering topically to the eyelids a composition comprising a prostaglandin F2a analogue and a semifluorinated alkane.
• prostaglandin analogue is latanoprost, preferably at a concentration of from 0.05 to 0.5 mg/ml.
• composition further comprises a cosolvent, preferably ethanol.
• composition for the use according to item 37 wherein the semifluorinated alkane is selected from 1-perfluorobutylpentane (F4H5) or 1-perfluorohexyloctane (F6H8) and wherein the solubilizing agent is an alcohol, preferably selected from ethanol or isopropanol.
• the semifluorinated alkane is selected from 1-perfluorobutylpentane (F4H5) or 1-perfluorohexyloctane (F6H8) and wherein the solubilizing agent is an alcohol, preferably selected from ethanol or isopropanol.
• composition for the use according to item 37 wherein the semifluorinated alkane is selected from 1-perfluorobutylpentane (F4H5) or 1-perfluorohexyloctane (F6H8) and wherein the solubilizing agent is an oily excipient, preferably selected from MCT and squalane. 41.
• the composition, wherein the composition is free of a solid thickening agent.
• composition for the use according to items 37-42 wherein the composition is topically administered to a part of the skin selected from the scalp, the face, the chest, the eyelids or the eyelashes, preferably the composition is administered to the scalp.
• composition for the use according to items 37-44, wherein the composition is topically administered in form of a liquid preferably the composition is dispensed in liquid form from a spray device or from a roll-on device.
• kit according to item 28 wherein the container is part of a spray, a pipette, a dropper or a roll-on device for dispensing the liquid composition.
• a composition comprising an active ingredient and a semifluorinated alkane for use in the topical treatment of a disease or condition affecting a pilosebaceous unit, wherein the disease or condition affecting the pilosebaceous unit is selected from androgenetic alopecia, hirsutism, hypotrichosis, alopecia of the eyebrows and of the eyelashes.
• composition for the use of item Al wherein the active ingredient is selected from a prostaglandin analogue and an antiandrogen.
• composition for the use of any preceding items, wherein the disease or condition affecting the pilosebaceous unit is selected from androgenetic alopecia, hypotrichosis, alopecia of the eyebrows and of the eyelashes.
• the antiandrogen is a steroidal antiandrogen, preferably selected from cortexolone 17a-propionate, cyproterone acetate, spironolactone, finasteride, dutasteride.
• composition for the use of any preceding items, wherein the composition further comprises a cosolvent.
• composition for the use of item A9 wherein n is selected from 3 to 5 and m is selected from 4 to 7.
• composition for the use of any preceding items, wherein the composition is free of water and/or preservatives.
• composition for the use of any preceding items, wherein the composition is in the form of a solution.
• kits comprising the composition for use according to any preceding items, wherein the kit comprises a container holding the composition and instructions for use
• Example 1 Penetration of latanoprost solution in minipig skin and their hair roots
• Formulation 1 latanoprost (Yonsung Fine Chemicals, purity 100.2%) dissolved at a concentration of 0.5 mg/ml in a solution of 1-perfluorobutyl-pentane and 1% v/v ethanol.
• Formulation 2 latanoprost (Yonsung Fine Chemicals, purity 100.2%) dissolved at a concentration of 0.1 mg/ml in a solution of 1-perfluorobutyl-pentane and 1% v/v ethanol.
• Formulation 3 latanoprost (Yonsung Fine Chemicals, purity 100.2%) dissolved at a concentration of 0.5 mg/ml in a solution of water, 50% v/v ethanol, 20% propylene glycol.
• the vehicle of formulation 3 corresponds to the aqueous vehicle of Blume-Peytavi (J. Am. Acad. Dermatol. 2012 May; 66(5):794-800), containing a high amount of ethanol (50% (v/v)).
• Biological material abdominal and dorsal full skin, R1 and part of LI region, of 5 months old Gottingen minipig skin.
• FDC Franz Diffusion Cells
• Donor and acceptor chambers were made of glass. Twelve frozen full thickness skin disks were punched with a diameter of 30 mm. After complete defrosting and equilibration to room temperature, the punches were clamped into Franz diffusion cells (FDC). Each skin disc was dried with wipes, clamped in between the corresponding FDCs having an inner diameter of 15 mm (1.767 cm 2 skin diffusion area) and an acceptor volume of approximately 12 ml. The receiver compartment of the cells was filled with PBS (phosphate buffered saline). Incubation was started by addition of 800 Dl of test formulation 1-3. Then, all FDCs were transferred into a cabinet at 32 °C.
• PBS phosphate buffered saline
• each skin surface was still covered by the respective formulation.
• the remaining test formulations were collected with a pipette and pooled in three incubation solution samples, corresponding to formulation 1, 2 and 3, respectively. Afterwards, the skin surfaces were dried with wipes and on each skin a tape was applied and then removed twice.
• latanoprost incubation solutions were analysed via HPLC for the content of latanoprost after two hours incubation. Neither in incubation solution 1 (test formulation 1) nor in incubation solution 2 (test formulation 2) was detected any latanoprost acid.
• each skin disc 20 skin discs having a diameter of 2 mm were obtained by punching with a disposable biopsy punch, which was put on top of the skin and pressed through the full thickness of the skin. Specifically, ten discs with at least one hair and ten discs of skin without hair were punched. Hairs on the minipig skin could be recognized without magnification.
• the discs with hairs contain a higher content of pilosebaceous units including hair follicle, hair shaft and sebaceous glands.
• the ten punches with hair and without hair obtained by each disc were placed respectively in pre-weighed tubes and the weight was determined.
• Experiment 1 corresponds to samples incubated with formulations 1, 2 and 3 respectively.
• the corresponding FDCs were numbered 1,2,3 for experiment 1; 7,8,9 for experiment 3; 10, 11, 12 for experiment 4.
• the punches in experiments 1, 3 and 4 were obtained by punching first the skin with at least one hair and then by punching the skin discs without hair.
• Experiment 2 corresponds to samples incubated with formulation 1, but the order the punches were obtained was different from the other experiments. In this case, the punches without hair were obtained before punching the skin with hair.
• the corresponding FDCs were numbered 4,5 and 6
• Formulation 2 (0.1 mg/ml) did also outperform formulation 3 (0.5 mg/ml) by far, although containing significant less amount of latanoprost, that further underlines the surprising effect that the SFA-bases compositions deliver latanoprost more efficiently to/into the pilosebaceous units including hair follicle, hair shaft and sebaceous glands as compared to state of the art aqueous latanoprost-containing compositions.
• Latanoprost acid was detected in the samples, as shown in Figure 2.
• the presence of latanoprost acid is an indication of esterase activities in both punch skin (skin without hair) and punch skin with hair.
• the punches with hair were shown to have a higher content of latanoprost acid than punches without hair.
• Test formulation 0,5 mg/ml latanoprost (Yonsung, Purity 100,2 %) in 1-perfluorobutylpentane (Novaliq) and 1% v/v ethanol (Merck, Secco solve dried).
• Biological material fresh pig’s eyes with eyelids, not in buffer solution during transport from the slaughterhouse to the laboratory.
• the upper eyelids were separated from the eye with scissors, forceps and scalpel. Each eyelid was placed in a glass vessel and incubation with the test formulation was started by addition of 1 ml of formulation. Since the eyelashes had different lenghts, before incubation the eyelashes were shortened to standardise the incubation procedure. After incubation according to the plan in Table 3, the eyelids were washed with 1-perfluorobutylpentane eight times and eyelashes were plucked and weighted, as shown in Table 3.
• the eyelids were punched with a 4 mm (0,126 cm 2 ) biopsy tool 5 times (total area 0,628 cm 2 ). The skin and the conjunctiva were then separated. Extraction via addition of 400 ml ACN (acetonitrile) to each sample at room temperature on orbital shaker (150 rpm) and minirotator (Biosan maximum level) for 2 hours. Then the samples were centrifuged for 5 minutes at 13000 rpm. The supernatant collected from the samples was stored at -20 °C till analysis.
• ACN acetonitrile
• the amount of latanoprost and of the bio transformed latanoprost acid in the tissues and eyelashes were determined via HPLC.
• the mean assay values for latanoprost acid were corrected with a factor of 1,1 as the molecular weight of latanoprost acid is lower than the weight of latanoprost.
• Cortexolone 17a-propionate (developmental code name CB-03-01; 21 -Hydroxy-3, 20- dioxopregn-4-en-17-yl propionate; CAS Registry Number: 19608-29-8) was dissolved in 1- perfluorbutylpentane (F4H5) to result in a solution of 1% (w/w) CB-03-01 in F4H5.
• FDC Franz Diffusion Cells

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