Topical composition comprising prostaglandin analogue

Abstract

To provide a topical composition useful for the treatment of hair disorders such as androgenetic alopecia, hirsutism, alopecia of the eyebrow and eyelashes, and hypotrichosis.SOLUTION: Provided is a composition for topical treatment of diseases or conditions affecting the pilosebaceous unit or its components, the composition comprising a prostaglandin analogue as an active ingredient, and further comprising a co-solvent and a semi-fluorinated alkane.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to topical compositions useful in the treatment of diseases and conditions affecting the pilosebaceous unit, particularly in the treatment of hair disorders. [Background technology]

[0002] The pilosebaceous unit (PSM) is composed of a hair follicle, hair shaft, and sebaceous gland. This structure is present on the surface of mammalian skin and is thought to be an important pathway for the percutaneous absorption of topically applied drugs. Within the skin, the PSM is the primary factory for hormone production, specifically the synthesis of androgens. When stimulated by hormones such as androgens, the sebaceous gland secretes lipid-rich sebum, which protects the hair and provides the skin with a hydrophobic barrier that can act as a barrier.

[0003] Hair follicles are invaginations of the epidermis that extend deep into the dermis. Targeted drug delivery to hair follicles is relevant to diseases such as androgenetic alopecia and alopecia areata. Access to hair follicles is difficult due to the structural aspects of the hair follicle and its chemical environment. The keratin layers of the inner and outer root sheaths and the hyaline membrane surrounding the entire hair follicle may restrict the passage of molecules deep within the hair follicle. Furthermore, sebum excretion into the hair follicle is a constant and effective drug delivery, and pharmacological effects depend on the interaction between the drug and sebum. (Indian Journal of Pharmacology 2000;32:269-281)

[0004] Androgen-dependent conditions, diseases, disorders or syndromes are medical conditions that are partially or completely dependent on or sensitive to the presence of androgen activity in the body.Known androgen-dependent conditions include, among others, androgenetic alopecia and hirsutism.Also known as hair loss or baldness, alopecia refers to hair loss from a part of the head or body.Hirsutism refers to male-pattern hair distribution in women.Both conditions cause significant psychological distress.

[0005] Androgenetic alopecia (also known as male pattern baldness) affects both men and women. In men, it results in male-pattern hair loss with bitemporal receding and vertex baldness. In women, it results in female-pattern hair loss with widespread alopecia on the central frontal scalp.

[0006] Androgen-dependent conditions can be treated with drugs with antiandrogenic effects (including androgen receptor antagonists such as cyproterone acetate, spironolactone, and bicalutamide, 5α-reductase inhibitors such as finasteride and dutasteride, CYP17A1 inhibitors, gonadotropin-releasing hormone (GnRH) analogs, and / or other antigonadotropins). Topical minoxidil and oral finasteride are approved by the United States Food and Drug Administration (USA) for the treatment of androgenetic alopecia in men. Both drugs prevent further hair loss but only partially reverse baldness, requiring continued use to maintain efficacy.

[0007] Hirsutism is excess hair in areas of the body where hair is normally absent or minimal. Classically, hirsutism has been thought to be a marker of elevated androgen levels in women due to increased production of androgens (i.e., testosterone) by the adrenal glands or due to ovarian disease. Spironolactone (SPA) is an androgen blocker. The starting dose is 50 mg twice daily, which can be increased to a total daily dose of 200 mg. Finasteride, a 5-alpha reductase inhibitor, a 5-RA inhibitor, has been shown to be effective in treating hirsutism. (Indian J Dermatol.2010 Jan-Mar;55(1):3-7)

[0008] Physiologically, eyelashes perform a protective function and, like all hair on the body, are produced by a continuous cycle of hair follicles. Like other hair follicles on the body, eyelash follicles are connected to sebaceous glands. Individuals may also experience the loss of previously normal eyelashes, which may or may not be accompanied by the destruction of individual hair follicles. This condition, eyelash loss (also known as trichiasis), can have many causes, including alopecia areata, infection, endocrine disorders such as hypothyroidism, medications, radiation, or trauma.

[0009] Hypotrichosis is a rare condition in which there is little or no hair growth on the head, including the eyebrows and eyelid margins above the eyes, or other areas of the body where hair normally grows.

[0010] EP 2802331 B1 describes 0.03 w / v % bimatoprost for use in a method for promoting eyelash growth in post-chemotherapy patients.

[0011] When prescribed for the treatment of eyelash hypotrichosis, bimatoprost ophthalmic solution 0.03% is instilled daily into the skin of the upper eyelid margin at the base of the eyelashes using a sterile single-use eyedropper.

[0012] Latanoprost is an isopropyl ester prodrug of an acidic metabolite, a prostaglandin F2α analog. U.S. Patent No. 6,262,105 B1 describes a method for enhancing hair growth using prostaglandins, specifically exemplified by latanoprost. This patent also describes topical formulations with varying amounts (0.1-10%) of the active ingredient.

[0013] Blume-Peytavi (J. Am. Acad. Dermatol. 2012 May;66(5):794-800) described a double-blind, placebo-controlled pilot study to evaluate the efficacy of 24 weeks of topical treatment with latanoprost 0.1% on hair growth and pigmentation in healthy volunteers with androgenetic alopecia. The aqueous latanoprost formulation used in the study (0.1% latanoprost, 50% ethanol, 20% propylene glycol, water) contains a large amount of ethanol, which may cause unpleasant reactions and irritation, especially when applied to sensitive areas such as the eyelids.

[0014] Therefore, the object of the present invention is to provide an effective topical treatment for diseases or conditions that affect the pilosebaceous unit, such as androgenetic alopecia, hirsutism, hypotrichosis, and alopecia of eyebrows and eyelashes.A further object is to provide a treatment that effectively delivers prostaglandins or antiandrogens to or into the difficult-to-reach pilosebaceous unit or its components, namely, hair follicles, hair shafts, and sebaceous glands.In a further aspect, the object of the present invention is to provide a pharmaceutical composition that contains a significantly lower concentration of cosolvents such as alcohol compared to aqueous compositions that utilize higher concentrations of alcohol as penetration enhancers and therefore may cause skin irritation or contact dermatitis when used regularly.These and further objects will be apparent based on the description of the present invention and the claims. [Prior art documents] [Patent documents]

[0015] [Patent Document 1] European Patent No. 2802331B1 [Patent Document 2] U.S. Patent No. 6,262,105 B1 [Non-patent literature]

[0016] [Non-Patent Document 1] Indian Journal of Pharmacology 2000;32:269-281 [Non-patent document 2] Indian J Dermatol.2010 Jan-Mar;55(1):3-7 [Non-patent document 3] Blume-Peytavi(J.Am.Acad.Dermatol.2012 May;66(5):794-800) Summary of the Invention [Problem to be solved by the invention]

[0017] The object of the present invention is to provide a pharmaceutical composition that can be used to treat or prevent diseases or conditions affecting the pilosebaceous unit, such as androgenetic alopecia, hirsutism, hypotrichosis, alopecia of the eyebrows and eyelashes, etc. The object of the present invention is achieved by the claims. [Means for solving the problem]

[0018] The compositions of the present invention effectively penetrate the skin and hair, preferably the skin and the pilosebaceous unit or its components, such as the skin and hair follicles, hair shafts, and sebaceous glands. Thus, treatment of diseases associated with the pilosebaceous unit, particularly hair diseases, can be conveniently achieved by topical application without the side effects associated with the use of aqueous formulations characterized by large amounts of cosolvents and other ingredients that can be irritating, especially in delicate areas such as the eyelids. [Brief explanation of the drawings]

[0019] [Figure 1]Figure 1 shows the uptake of latanoprost from latanoprost formulations after 2 hours of incubation. Latanoprost concentrations are expressed in μg per cm2 of skin. As described in Example 1, Exp1 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 a solution of 50% ethanol, 20% propylene glycol, and water). "Punch_hair" = 10 x 2 mm skin punch with at least one hair; "Skin_punch" = 10 x 2 mm skin punch without hair. Data are the mean ± standard deviation of experiments performed in triplicate.

[0020] [Figure 2] Figure 2 shows the uptake of latanoprost acid from latanoprost formulations and the bioconversion of latanoprost formulations to latanoprost acid after 2 hours of incubation. The amount of latanoprost acid is expressed in μg per cm of skin. A portion of the latanoprost was biotransformed to latanoprost acid during incubation. As described in Example 1, Exp1 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 a solution of 50% ethanol, 20% propylene glycol, and water). "Punch_hair" = 10 x 2 mm skin punch with at least one hair; "Skin_punch" = 10 x 2 mm skin punch without hair. Data are mean ± standard deviation of experiments performed in triplicate.

[0021] [Figure 3]Figure 3 shows the total uptake of latanoprost from latanoprost formulations after 2 hours of incubation. As described in Example 1, Exp1 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 a solution of 50% ethanol, 20% propylene glycol, and water). "Punch_hair" = 10 x 2 mm skin punch with at least one hair; "Skin_punch" = 10 x 2 mm skin punch without hair. Data are the average of experiments performed in triplicate.

[0022] [Figure 4] Figure 4 shows the penetration of latanoprost into tissues, showing the amount of latanoprost in μg / ml in the eyelash and skin samples of Example 2 at three time points.

[0023] Values ​​for each time point are from four independent replicate experiments ± standard deviation.

[0024] [Figure 5] 5 shows the distribution of latanoprost acid, expressed in μg / ml, in the eyelash and skin samples of Example 2 at three time points. Values ​​at each time point are from four independent replicate experiments ± standard deviation. DETAILED DESCRIPTION OF THE INVENTION

[0025] In a first aspect, the present invention provides a composition comprising an active ingredient and a semi-fluorinated alkane for use in the topical treatment of a disease or condition affecting the pilosebaceous unit, wherein the disease or condition affecting the pilosebaceous unit is selected from androgenetic alopecia, hirsutism, hypotrichosis, alopecia of the eyebrows and eyelashes.

[0026] In some embodiments, the present invention provides a composition comprising an active ingredient and a semi-fluorinated alkane for use in the topical treatment of a disease or condition affecting one or more components of the pilosebaceous unit selected from a hair follicle, a hair shaft, and a sebaceous gland, wherein the disease or condition affecting the pilosebaceous unit is selected from androgenetic alopecia, hirsutism, hypotrichosis, alopecia of the eyebrows and eyelashes.

[0027] The disease or condition affecting the pilosebaceous unit is a hair disorder selected from androgenetic alopecia, hirsutism, hypotrichosis, alopecia of the eyebrows and eyelashes.

[0028] Preferably, the active ingredient is selected from a prostaglandin analogue (also known as a prostaglandin analogue) or an antiandrogen.

[0029] The prostaglandin analog is preferably a prostaglandin F2α analog. Preferably, the active ingredient is a prostaglandin F2α analog selected from latanoprost, bimatoprost, and travoprost. In a preferred embodiment, the active ingredient is latanoprost or bimatoprost, more preferably the active ingredient is latanoprost.

[0030] The antiandrogen is preferably a steroidal antiandrogen. Preferably, the steroidal antiandrogen is selected from cortexolone 17α-propionate, cyproterone acetate, spironolactone, finasteride and dutasteride. In a preferred embodiment, the active ingredient is cortexolone 17α-propionate.

[0031] The term "semi-fluorinated alkane," also referred to throughout this specification as "SFA," as used herein refers to a linear or branched-chain compound composed of at least one fully fluorinated segment (F segment) and at least one non-fluorinated hydrocarbon segment (H segment). Preferably, the semi-fluorinated alkane is a linear or branched-chain compound composed of one fully fluorinated segment (F segment) and one non-fluorinated hydrocarbon segment (H segment). Preferably, the semi-fluorinated alkane is a compound that exists in a liquid state within a temperature range of 4°C to 40°C.

[0032] Preferably, the F and H segments of the linear or branched semi-fluorinated alkane contain, independently of one another, 2 to 10 carbon atoms. According to a preferred embodiment of the present invention, the semi-fluorinated alkane is a linear compound of formula (I) CF3(CF2)n(CH2)mCH3, where n and m are integers independently selected from the range of 2 to 10.

[0033] According to another nomenclature, linear semi-fluorinated alkanes can also be referred to as FnHm, where F refers to the fully fluorinated hydrocarbon segment, H refers to the non-fluorinated hydrocarbon segment, and n and m are the number of carbon atoms in each segment. For example, F4H5 is used in 1-perfluorobutyl-pentane. In a preferred embodiment of the present invention, the semi-fluorinated alkane is a semi-fluorinated alkane of the formula (I)CF3(CF2)n(CH2)mCH3, where n is selected from 3 to 5 and m is selected from 4 to 9. More preferably, the semi-fluorinated alkane is selected from the group consisting of F4H5, F4H6, F4H8, F4H10, F6H8, and F6H10, or from the group consisting of F4H5, F4H6, F4H7, F4H8, F4H9, and F6H8. Even more preferably, the semi-fluorinated alkane is selected from F4H5 and F6H8. Even more preferably, the semi-fluorinated alkane is selected from F4H5, F6H8 and F6H10. In a further preferred embodiment of the present invention, the semi-fluorinated alkane is of formula (I)CF3(CF2)n(CH2)mCH3, where n is selected from 3 to 5 and m is selected from 4 to 7.

[0034] In the present invention, the composition may contain the semi-fluorinated alkane in an amount of about 90% (v / v) to about 99% (v / v), more preferably about 95% (v / v) to about 99% (v / v), based on the total volume of the composition. In the most preferred embodiment of the present invention, the composition contains the semi-fluorinated alkane in an amount of about 97% (v / v) to about 99% (v / v), based on the total volume of the composition.

[0035] In some embodiments, the composition may contain a solubilizing agent, such as an organic cosolvent, an oily excipient, and / or an oil selected from glyceride oil, liquid wax, and liquid paraffin. Examples of oily excipients that may be useful include triglyceride oil, mineral oil, medium-chain triglyceride (MCT), oily fatty acid, isopropyl myristate, oily fatty alcohol, sorbitol-fatty acid ester, oily sucrose ester, or any other physiologically acceptable substance or squalane. Preferably, the solubilizing agent is selected from ethanol, isopropanol, MCT, or squalane. Preferably, the solubilizing agent is liquid, and more preferably, the solubilizing agent is not semi-solid or solid.

[0036] In a preferred embodiment, the composition comprises a co-solvent. Preferably, the co-solvent is ethanol or isopropanol, or an alcohol selected from ethanol and isopropanol. In a preferred embodiment, the composition comprises a co-solvent in an amount of up to 2% (v / v), more preferably up to 1.5% (v / v), and most preferably up to 1.0% (v / v), based on the total volume of the composition. In a more preferred embodiment, the composition comprises ethanol in an amount of up to 2% (v / v), more preferably up to 1.5% (v / v), and most preferably up to 1.0% (v / v), based on the total volume of the composition.

[0037] Preferably, the co-solvent is present in a concentration of 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), relative to the total volume of the composition.

[0038] More preferably, the composition comprises alcohol as a co-solvent, which is present in a concentration of 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), and most preferably 0.5 to 1.0% (v / v) relative to the total volume of the composition.

[0039] In a preferred embodiment, the composition is substantially free of preservatives. In a preferred embodiment, the composition is substantially free of water. As understood herein, the term "substantially free" or alternatively "essentially free" with respect to a composition component refers to the presence of no more than trace amounts of said component, whereby when present in trace amounts, the component does not provide a technical contribution to the composition.

[0040] In a further preferred embodiment, the composition for use according to the invention is substantially free of water and preservatives.

[0041] In a preferred embodiment, the composition for use according to the invention is provided as a clear solution in which the active ingredient is completely dissolved in the semi-fluorinated alkane. Furthermore, the composition for use according to the invention is preferably provided in sterile form.

[0042] In a preferred embodiment, the composition consists of an active ingredient dissolved in a semifluorinated alkane and optionally a solubilizing agent. Preferably, the composition consists of a prostaglandin analog dissolved in a semifluorinated alkane and optionally a solubilizing agent, or the composition consists of an antiandrogen dissolved in a semifluorinated alkane and optionally a solubilizing agent.

[0043] Preferably, the present invention provides a composition for use in the topical treatment of androgenetic alopecia or alopecia of the eyebrows and eyelashes, comprising or consisting of a prostaglandin analog dissolved in a semi-fluorinated alkane and, optionally, a solubilizing agent. More preferably, the present invention provides a composition for use in the topical treatment of androgenetic alopecia, comprising or consisting of a prostaglandin analog dissolved in a semi-fluorinated alkane and an alcohol, wherein the prostaglandin analog is selected from latanoprost, bimatoprost, and travoprost, the semi-fluorinated alkane is selected from F4H5 or F6H8, and the alcohol is selected from ethanol or isopropanol. Even more preferably, the present invention provides a composition for use in the topical treatment of androgenetic alopecia, comprising or consisting of: (i) Latanoprost dissolved in F4H5 and ethanol; (ii) latanoprost dissolved in F4H5 and isopropanol; (iii) latanoprost dissolved in F6H8 and ethanol, or (iv) Latanoprost dissolved in F6H8 and isopropanol.

[0044] Preferably, the present invention provides a composition for use in the topical treatment of androgenetic alopecia, comprising or consisting of: (i) 0.05-0.5 mg / ml of latanoprost dissolved in F4H5 (ii) 0.1 to 0.5 mg / ml of latanoprost dissolved in F4H5 (iii) about 0.1 mg / ml of latanoprost dissolved in F4H5 (iv) 0.05-0.5 mg / ml latanoprost dissolved in F6H8 (v) 0.1-0.5 mg / ml latanoprost dissolved in F6H8 (vi) Approximately 0.1 mg / ml of latanoprost dissolved in F6H8

[0045] In a further preferred embodiment, the present invention provides a composition for use in the topical treatment of androgenetic alopecia or alopecia of the eyebrows and eyelashes, comprising or consisting of 0.05 to 0.5 mg / ml (or 0.1 to 0.5 mg / ml) of a prostaglandin analog dissolved in a semi-fluorinated alkane, and optionally a solubilizing agent. More preferably, the present invention provides a composition for use in the topical treatment of androgenetic alopecia, comprising or consisting of 0.05 to 0.5 mg / ml (or 0.1 to 0.5 mg / ml) of a prostaglandin analog dissolved in a semi-fluorinated alkane and alcohol, wherein the prostaglandin analog is selected from latanoprost, bimatoprost, and travoprost, the semi-fluorinated alkane is selected from F4H5 or F6H8, and the alcohol is selected from ethanol or isopropanol. More preferably, the present invention provides a composition for use in the topical treatment of androgenetic alopecia, comprising or consisting of: (i) 0.05-0.5 mg / ml latanoprost dissolved in F4H5 and ethanol; (ii) 0.05-0.5 mg / ml latanoprost dissolved in F4H5 and isopropanol; (iii) 0.05-0.5 mg / ml latanoprost dissolved in F6H8 and ethanol; (iv) 0.05-0.5 mg / ml latanoprost dissolved in F6H8 and isopropanol; (v) 0.1-0.5 mg / ml latanoprost dissolved in F4H5 and ethanol; (vi) 0.1-0.5 mg / ml latanoprost dissolved in F4H5 and isopropanol; (vii) 0.1 to 0.5 mg / ml of latanoprost dissolved in F6H8 and ethanol; or (viii) 0.1-0.5 mg / ml latanoprost dissolved in F6H8 and isopropanol.

[0046] Even more preferably, the present invention provides a composition for use in the topical treatment of androgenetic alopecia, comprising or consisting of: (i) 0.05-0.5 mg / ml latanoprost dissolved in F4H5 and up to 1% (v / v) ethanol; (ii) 0.05-0.5 mg / ml latanoprost dissolved in F4H5 and up to 1% (v / v) isopropanol; (iii) 0.05–0.5 mg / ml latanoprost dissolved in F6H8 and up to 1% (v / v) ethanol; (iv) 0.05-0.5 mg / ml latanoprost dissolved in F6H8 and up to 1% (v / v) isopropanol; (v) 0.1-0.5 mg / ml latanoprost dissolved in F4H5 and up to 1% (v / v) ethanol; (vi) 0.1 to 0.5 mg / ml latanoprost dissolved in F4H5 and up to 1% (v / v) isopropanol; (vii) 0.1 to 0.5 mg / ml of latanoprost dissolved in F6H8 and up to 1% (v / v) ethanol; or (viii) 0.1–0.5 mg / ml latanoprost dissolved in F6H8 and up to 1% (v / v) isopropanol.

[0047] In a further preferred embodiment, the present invention provides a composition for use in the topical treatment of androgenetic alopecia, comprising or consisting of: (i) 0.05-0.5 mg / ml latanoprost dissolved in F4H5 and squalane; (ii) 0.05-0.5 mg / ml latanoprost dissolved in F4H5 and MCT; (iii) 0.05-0.5 mg / ml latanoprost dissolved in F6H8 and squalane; (iv) 0.05-0.5 mg / ml latanoprost dissolved in F6H8 and MCT; (v) 0.1-0.5 mg / ml latanoprost dissolved in F4H5 and squalane; (vi) 0.1-0.5 mg / ml latanoprost dissolved in F4H5 and MCT; (vii) 0.1 to 0.5 mg / ml of latanoprost dissolved in F6H8 and squalane; or (viii) 0.1-0.5 mg / ml latanoprost dissolved in F6H8 and MCT.

[0048] Preferably, the composition for use in the topical treatment of androgenetic alopecia is a liquid solution consisting of latanoprost at a concentration of 0.05 to 0.5 mg / ml, a semi-fluorinated alkane selected from F4H5 or F6H8, and optionally an alcohol present in a concentration of up to 2% (v / v) relative to the total volume of the composition.

[0049] More preferably, the composition for use in the topical treatment of androgenetic alopecia is a liquid solution consisting of latanoprost at a concentration of 0.05 to 0.5 mg / ml, a semi-fluorinated alkane selected from F4H5 or F6H8, and optionally a liquid solubilizer; more preferably, the composition for use in the topical treatment of androgenetic alopecia is a liquid solution consisting of latanoprost at a concentration of 0.05 to 0.5 mg / ml, a semi-fluorinated alkane selected from F4H5 or F6H8, and optionally a glyceride oil, liquid wax and liquid paraffin, triglyceride oil, mineral oil, medium oil, Preferably, the composition for use in the topical treatment of androgenetic alopecia is a liquid solution comprising latanoprost at a concentration of 0.05 to 0.5 mg / ml, a semi-fluorinated alkane selected from F4H5 or F6H8, and optionally a liquid solubilizer selected from medium-chain triglycerides (MCTs), oily fatty acids, isopropyl myristate, oily fatty alcohols, esters of sorbitol and fatty acids, oily sucrose esters, or squalane, and most preferably, the composition for use in the topical treatment of androgenetic alopecia is a liquid solution comprising latanoprost at a concentration of 0.05 to 0.5 mg / ml, a semi-fluorinated alkane selected from F4H5 or F6H8, and optionally a liquid solubilizer selected from medium-chain triglycerides (MCTs) or squalene.

[0050] In a preferred embodiment, the present invention provides a composition for use in the topical treatment of androgenetic alopecia, comprising or consisting of an antiandrogen dissolved in a semi-fluorinated alkane and optionally a solubilizing agent. More preferably, the present invention provides a composition for use in the topical treatment of androgenetic alopecia, comprising or consisting of cortexolone 17α-propionate dissolved in a semi-fluorinated alkane and optionally an alcohol, wherein the semi-fluorinated alkane is selected from F4H5 or F6H8, and the optional alcohol is selected from ethanol or isopropanol. Even more preferably, the present invention provides a composition for use in the topical treatment of androgenetic alopecia, comprising or consisting of cortexolone 17α-propionate dissolved in F4H5.

[0051] The composition for use of the present invention is administered locally.Topical agents are agents that are applied to specific locations on or within the body.Topical administration refers to application to a body surface such as skin or mucous membrane.In a preferred embodiment, the composition for use of the present invention is administered to a part of the skin selected from the scalp, face, chest, and eyelid.

[0052] Preferably, the composition for use of the present invention is topically administered to a specific area of ​​the skin in liquid form; more preferably, the composition for use is topically administered to the skin in the form of liquid droplets, as a film, or as a spray (mist). Administering the composition as droplets can be achieved by dispensing the liquid composition from a pipette or dropper. Administering the composition as a film can be achieved by dispensing the liquid composition from a roll-on. Administering the composition as a spray or mist can be achieved by dispensing the liquid composition from a spray device. Preferably, the liquid composition for use of the present invention is topically administered as droplets from a dropper or pipette, or as a film from a roll-on, or as a spray or mist from a spray device. Most preferably, the composition for use of the present invention is topically administered or dispensed in liquid form from a pipette, dropper, spray device, or roll-on device to the scalp, face, chest, eyelids, or eyelashes of a subject.

[0053] In a preferred embodiment, the composition for this use is not in the form of an ointment, more preferably the composition for use is administered topically to a particular area of ​​the skin in the form of a liquid rather than in the form of an ointment.

[0054] In a further preferred embodiment, the composition for use does not comprise a solid thickener, more preferably the composition for use does not comprise a solid thickener selected from vegetable waxes, animal waxes, petroleum-derived waxes, solid and semi-solid triglycerides, C12-24 fatty acids, C8-18 glycerides, fatty alcohols, fatty alcohol derivatives, even more preferably the composition for use does not comprise a solid thickener selected from vegetable waxes, animal waxes, petroleum-derived waxes, solid and semi-solid triglycerides, cetyl alcohol, cetyl palmitate, tetradecanol, wherein the solid thickener is a compound that is not liquid, preferably said compound is not liquid at 20°C.

[0055] Preferably, the composition for use of the present invention is administered to the individual suffering from hair loss, preferably the individual suffering from or suspected to suffer from androgenetic alopecia, hirsutism, hypotrichosis, alopecia of eyebrows and eyelashes.The subject is preferably human, but can also be an animal such as dog.The human subject suffering from hair loss can be male or female.

[0056] In a second aspect, the present invention provides a method for treating or preventing a disease or condition associated with the pilosebaceous unit, the method comprising topically administering to a subject a composition comprising an active ingredient and a semi-fluorinated alkane, wherein the disease or condition associated with the pilosebaceous unit is selected from androgenetic alopecia, hirsutism, hypotrichosis, and alopecia of the eyebrows and eyelashes.

[0057] Preferably, the present invention provides a method for treating or preventing a disease or condition associated with the pilosebaceous unit or one or more of its components, comprising the step of topically administering to a subject a composition comprising an active ingredient and a semi-fluorinated alkane, wherein the disease or condition associated with the pilosebaceous unit is selected from androgenetic alopecia, hirsutism, hypotrichosis, alopecia of the eyebrows and eyelashes, and the pilosebaceous unit or one or more of its components is selected from a hair follicle, a hair shaft, and a sebaceous gland.

[0058] The above-mentioned method for treating or preventing a disease or condition associated with the pilosebaceous unit or one or more of its components is effective for delivering an active ingredient to or into the pilosebaceous unit or one or more of its components, preferably, the method is effective for delivering an active ingredient to a hair follicle, a hair shaft, and / or a sebaceous gland.More preferably, the method for treating or preventing a disease or condition associated with the pilosebaceous unit or one or more of its components is effective for delivering a prostaglandin or an antiandrogen to or into the pilosebaceous unit or one or more of its components, preferably, the method is effective for delivering a prostaglandin or an antiandrogen to a hair follicle, a hair shaft, and / or a sebaceous gland.

[0059] In a third aspect, the present invention provides a composition for use in a method for the prevention or treatment of a disease or condition associated with the pilosebaceous unit, the composition comprising an active ingredient and a semi-fluorinated alkane, the composition being therapeutically effective in the treatment or prevention of a disease or condition associated with the pilosebaceous unit, wherein the disease or condition associated with the pilosebaceous unit is selected from androgenetic alopecia, hirsutism, hypotrichosis, alopecia of the eyebrows and eyelashes.

[0060] In a fourth aspect, the present invention provides a kit comprising a composition according to the first aspect of the invention, i.e. a composition for use in the prevention or treatment of a disease or condition associated with the pilosebaceous unit, said composition comprising an active ingredient and a semi-fluorinated alkane, a container for holding the composition and instructions for using the composition.

[0061] Preferably, the container included in the kit is part of a pipette, dropper, spray or roll-on device that allows for dispensing of the liquid composition, thereby allowing for topical administration of the liquid composition to the scalp, face, chest, eyelids or eyelashes of a subject.

[0062] In a fifth aspect, the present invention provides the use of a 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 the 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 eyelashes.

[0063] In a sixth aspect, the present invention provides a method for stimulating eyelash growth, comprising topically administering to the eyelid of a subject a composition comprising a prostaglandin F2α analogue and a semi-fluorinated alkane, preferably a composition comprising or consisting of latanoprost, 1-perfluorobutylpentane and ethanol.

[0064] It should be understood that all embodiments detailed above in relation to the composition for use according to the first aspect of the invention may be applied to all other aspects 2 to 6 of the invention.

[0065] The following numbered list of items are embodiments encompassed by the present invention. 1. A composition comprising an active ingredient and a semi-fluorinated alkane for use in the topical treatment of a disease or condition affecting the pilosebaceous unit, wherein the disease or condition affecting the pilosebaceous unit is selected from androgenetic alopecia, hirsutism, hypotrichosis, and alopecia of the eyebrows and eyelashes.

[0066] 2. The composition for use according to item 1, wherein the active ingredient is selected from prostaglandin analogues and antiandrogens.

[0067] 3. The composition for use according to item 2, wherein the prostaglandin analogue is a prostaglandin F2α analogue.

[0068] 4. The composition for use according to any of items 1 to 3, wherein the disease or condition affecting the pilosebaceous unit is selected from androgenetic alopecia, eyelash hypotrichosis, alopecia of the eyebrows and eyelashes.

[0069] 5. A composition for use according to any of items 1 to 4, wherein the prostaglandin F2α analogue is selected from latanoprost, bimatoprost, travoprost.

[0070] 6. A composition for use according to any of items 1 to 5, wherein the antiandrogen is a steroidal antiandrogen, preferably selected from cortexolone 17α-propionate, cyproterone acetate, spironolactone, finasteride, dutasteride.

[0071] 7. The composition for use according to item 6, wherein the disease or condition affecting the pilosebaceous unit is selected from hirsutism and androgenetic alopecia.

[0072] 8. A composition for use according to any of items 1 to 7, wherein the prostaglandin F2α analogue is present in a concentration of 0.05 to 0.5 mg / ml.

[0073] 9. A composition for use according to any of items 1 to 8, wherein the prostaglandin F2α analogue is present in a concentration of 0.1 to 0.5 mg / ml.

[0074] 10. A composition for use according to any of items 1 to 9, further comprising a co-solvent, preferably an alcohol selected from ethanol and isopropanol.

[0075] 11. The composition for use according to any of items 1 to 10, wherein the semi-fluorinated alkane is of formula (I) CF3(CF2)n(CH2)mCH3, where n and m are integers independently selected from the range of 3 to 9.

[0076] 12. The composition for use according to item 11, wherein n is selected from 3 to 5 and m is selected from 4 to 7.

[0077] 13. The composition for use according to item 12, wherein the semi-fluorinated alkane is selected from 1-perfluorohexyl octane and 1-perfluorobutyl pentane.

[0078] 14. The composition for use according to any of items 1 to 13, wherein the semi-fluorinated alkane is present in a concentration of at least 95% (v / v), preferably at least 97% (v / v), relative to the total volume of the composition.

[0079] 15. The composition for use according to any of items 1 to 14, wherein the semi-fluorinated alkane is present in a concentration of up to 99.9% (v / v), preferably up to 99% (v / v), relative to the total volume of the composition.

[0080] 16. A composition for use according to any of items 1 to 15, wherein the co-solvent is ethanol.

[0081] 17. The composition for use according to any of items 1 to 16, wherein the cosolvent is present in a concentration of at most 3% (v / v), preferably at most 2% (v / v), more preferably at most 1% (v / v), relative to the total volume of the composition.

[0082] 18. A composition for use according to any of items 1 to 17, wherein the active ingredient is latanoprost.

[0083] 19. The composition for use according to item 18, comprising latanoprost in a concentration of 0.05 to 0.5 mg / ml, preferably 0.1 to 0.5 mg / ml.

[0084] 20. A composition for use according to item 19, wherein the semi-fluorinated alkane is 1-perfluorobutylpentane or the semi-fluorinated alkane is selected from 1-perfluorohexyloctane.

[0085] 21. A composition for use according to any of items 1 to 20, wherein the prostaglandin analogue is latanoprost present in a concentration of 0.1 mg / ml to 0.3 mg / ml.

[0086] 22. A composition for use according to any of items 1 to 21, which does not contain water and / or preservatives.

[0087] 23. A composition for use according to any of items 1 to 22, which is in the form of a solution, preferably in the form of a liquid solution.

[0088] 24. A composition for use according to any of items 1 to 23, wherein the disease or condition affecting the pilosebaceous unit is androgenetic alopecia.

[0089] 25. A composition for use according to any of items 1 to 24, wherein the active ingredient is selected from latanoprost, bimatoprost, cortexolone 17α-propionate, spironolactone.

[0090] 26. A method for treating or preventing a disease or condition affecting the pilosebaceous unit, comprising topically administering a composition according to any of items 1 to 25 to a subject suffering from a disease or condition affecting the pilosebaceous unit, wherein the disease or condition affecting the pilosebaceous unit is selected from androgenetic alopecia, hirsutism, hypotrichosis, alopecia of the eyebrows and eyelashes.

[0091] 27. Use of a pharmaceutical composition according to any of items 1 to 25 for the manufacture of a medicament for the treatment of a disease or condition affecting the pilosebaceous unit, wherein the disease or condition affecting the pilosebaceous unit is selected from androgenetic alopecia, hirsutism, alopecia of the eyebrows and eyelashes, and hypotrichosis.

[0092] 28. A kit comprising the pharmaceutical composition according to any one of items 1 to 25 and a container holding the composition.

[0093] 29. The composition for use according to items 1 to 25, wherein the disease or condition affecting the pilosebaceous unit is selected from alopecia of the eyelashes and eyebrows, eyelash hypotrichosis, preferably alopecia of the eyelashes.

[0094] 30. A composition for use according to item 29, wherein the active ingredient is latanoprost.

[0095] 31. The composition for use according to item 30, wherein latanoprost is present in a concentration of 0.05 to 0.5 mg / ml, preferably 0.1 to 0.5 mg / ml, more preferably 0.5 mg / ml.

[0096] 32. A composition for use according to item 30 or 31, which is effective in stimulating eyelash growth.

[0097] 33. A method for stimulating eyelash growth, comprising topically administering to the eyelid a composition comprising a prostaglandin F2α analog and a semi-fluorinated alkane.

[0098] 34. The method according to item 33, wherein the prostaglandin analogue is latanoprost, preferably at a concentration of 0.05 to 0.5 mg / ml.

[0099] 35. The method according to item 33 or 34, wherein the semi-fluorinated alkane is 1-perfluorobutylpentane.

[0100] 36. The method according to any of items 33 to 35, wherein the composition further comprises a co-solvent, preferably ethanol.

[0101] 37. A composition for use according to items 1 to 25, for use in the topical treatment of androgenetic alopecia, comprising or consisting of 0.05 to 0.5 mg / ml of latanoprost dissolved in a semi-fluorinated alkane, and optionally a solubilizer.

[0102] 38. A composition for use according to item 37, wherein the semi-fluorinated alkane is selected from 1-perfluorobutylpentane (F4H5) or 1-perfluorohexyloctane (F6H8), and the solubilizer is an alcohol, preferably selected from ethanol or isopropanol.

[0103] 39. The composition for use according to item 38, wherein the alcohol is present in a concentration of up to 2% (v / v), preferably up to 1% (v / v), relative to the total volume of the composition.

[0104] 40. The composition for use according to item 37, wherein the semi-fluorinated alkane is selected from 1-perfluorobutylpentane (F4H5) or 1-perfluorohexyloctane (F6H8), and the solubilizer is an oily excipient, preferably selected from MCT and squalane.

[0105] 41. A composition for use according to items 37 to 40, which does not contain a solid thickener.

[0106] 42. A composition for use according to items 37 to 41, which is not in the form of an ointment.

[0107] 43. The composition for use according to items 37 to 42, which is administered topically to a part of the skin selected from the scalp, face, chest, eyelids or eyelashes, preferably to the scalp.

[0108] 44. The composition for use according to items 37 to 43, which is administered topically to a subject suffering from hair loss.

[0109] 45. A composition for use according to items 37 to 44, which is topically administered in liquid form, preferably dispensed in liquid form from a spray or roll-on device.

[0110] 46. ​​A composition for use according to items 37 to 45, which is effective for delivering latanoprost to or into the pilosebaceous unit or a component thereof.

[0111] 46. ​​A composition for use according to items 37 to 46, which is effective for delivering latanoprost to or into the hair follicle, hair shaft and / or sebaceous gland.

[0112] 47. The method according to item 26, which is effective to deliver a prostaglandin analog or antiandrogen to or within the pilosebaceous unit or one or more components thereof.

[0113] 48. The method according to item 47, which is effective in delivering latanoprost to hair follicles, hair shafts and / or sebaceous glands.

[0114] 49. The kit of item 28, wherein the container is part of a spray, pipette, dropper, or roll-on device for dispensing the liquid composition.

[0115] The following list of numbered items A1-A15 are embodiments encompassed by the present invention. A1. A composition comprising an active ingredient and a semi-fluorinated alkane for use in the topical treatment of a disease or condition affecting the pilosebaceous unit, wherein the disease or condition affecting the pilosebaceous unit is selected from androgenetic alopecia, hirsutism, hypotrichosis, and alopecia of the eyebrows and eyelashes.

[0116] A2. The composition for use according to item A1, wherein the active ingredient is selected from prostaglandin analogues and antiandrogens.

[0117] A3. The composition for use according to paragraph A1 or A2, wherein the disease or condition affecting the pilosebaceous unit is selected from androgenetic alopecia, hypotrichosis, alopecia of the eyebrows and eyelashes.

[0118] A4. A composition for use according to any of paragraphs A1 to A3, wherein the prostaglandin analogue is a prostaglandin F2α analogue, preferably selected from latanoprost, bimatoprost, travoprost.

[0119] A5. The composition for use according to any of paragraphs A1 to A4, wherein the antiandrogen is a steroidal antiandrogen, preferably selected from cortexolone 17α-propionate, cyproterone acetate, spironolactone, finasteride, dutasteride.

[0120] A6. The composition for use according to item A5, wherein the disease or condition affecting the pilosebaceous unit is selected from hirsutism and androgenetic alopecia.

[0121] A7. A composition for use according to any of paragraphs A1 to A6, wherein the prostaglandin F2α analogue is present in a concentration of 0.05 to 0.5 mg / ml.

[0122] A8. A composition for use according to any of paragraphs A1 to A7, further comprising a co-solvent.

[0123] A9. The composition for use according to any of items A1 to A8, wherein the semi-fluorinated alkane is of formula (I) CF3(CF2)n(CH2)mCH3, where n and m are integers independently selected from the range of 3 to 9.

[0124] A10. The composition for use according to item A9, wherein n is selected from 3 to 5 and m is selected from 4 to 7.

[0125] A11. The composition for use according to any of paragraphs A1 to A10, wherein the prostaglandin F2α analog is latanoprost.

[0126] A12. A composition for use according to paragraph A11, comprising latanoprost at a concentration of 0.05-0.5 mg / ml, ethanol and 1-perfluorobutylpentane.

[0127] A13. A composition for use according to any of items A1 to A12, which does not contain water and / or preservatives.

[0128] A14. A composition for use according to any of items A1 to A13, which is in the form of a solution.

[0129] A15. A kit comprising a composition for use according to any of paragraphs A1 to A14, comprising a container holding said composition and instructions for use. [Example]

[0130] Penetration of latanoprost solution into minipig skin and its hair roots

[0131] 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.

[0132] 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.

[0133] 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 large amount of ethanol (50% (v / v)).

[0134] Biological material: Full thickness skin of the abdomen and back, part of the R1 and L1 regions of a 5-month-old Goettingen minipig.

[0135] For incubation experiments, Franz Diffusion Cells (FDC) with an inner diameter of 15 mm and an acceptor volume of 12 ml were used. The donor and acceptor chambers were made of glass.

[0136] Twelve frozen full-thickness skin discs were punched with a diameter of 30 mm. After complete thawing and equilibration to room temperature, the punches were clamped into a Franz diffusion cell (FDC). Each skin disc was dried with a wipe and placed in a 15 mm inner diameter (skin diffusion area 1.767 cm). 2 The receiver compartment of the cell was filled with PBS (phosphate-buffered saline). Incubation was initiated by adding 800 μL of test formulations 1 to 3. All FDCs were then transferred to a 32°C cabinet.

[0137] At the end of the 2-hour incubation period, each skin surface was still covered with its respective formulation. The remaining test formulation was collected with a pipette and pooled into three incubation solution samples corresponding to formulations 1, 2, and 3. The skin surfaces were then wiped dry, and tape was applied to each skin surface and then removed twice.

[0138] After 2 hours of incubation, the latanoprost incubation solutions were analyzed by HPLC for latanoprost content. No latanoprost acid was detected in either Incubation Solution 1 (Test Formulation 1) or Incubation Solution 2 (Test Formulation 2).

[0139] Table 1 below shows the results for the incubation solutions after 2 hours of incubation: Incubation Solution 3 (Test Formulation 3) was not tested for latanoprost content.

[0140] [Table 1]

[0141] From each skin disc, 20 skin discs with a diameter of 2 mm were obtained by placing a disposable biopsy punch on the skin and punching it through the entire thickness of the skin. Specifically, 10 discs with at least one hair and 10 discs without hair were punched out. Hair on the minipig skin could be recognized without magnification. Discs with hair contained more pilosebaceous units, including hair follicles, hair shafts, and sebaceous glands. The 10 punches with hair and 10 punches without hair obtained from each disc were placed into pre-weighed tubes, respectively, and their weights were determined. After weighing, extraction of latanoprost and latanoprost acid was initiated by adding 400 μL of ACN (acetonitrile) to each tube. After 2 hours of extraction on an orbital shaker (150 rpm) and a minirotator (Biosan, maximum level) at room temperature, all tubes were centrifuged at 13,000 rpm for 5 minutes. Aliquots of the supernatant were transferred to HPLC vials and stored at −20°C until analysis.

[0142] Table 2 reports the weights of the punched tissues. Experiments 1, 3, and 4 correspond to samples incubated with Formulations 1, 2, and 3, respectively. The corresponding FDCs were numbered 1, 2, and 3 for Experiment 1; 7, 8, and 9 for Experiment 3; and 10, 11, and 12 for Experiment 4. The punches for Experiments 1, 3, and 4 were obtained by first punching a skin disk containing at least one hair, followed by punching a hairless skin disk. Experiment 2 corresponds to a sample incubated with Formulation 1, but the order in which the punches were obtained was different from the other experiments. In this case, a hairless punch was obtained, followed by punching a skin disk containing hair. The corresponding FDCs were numbered 4, 5, and 6. [Table 2]

[0143] The amount of latanoprost and the amount of latanoprost acid that permeated the skin discs after incubation with the test formulations was assessed by HPLC analysis and is shown in Figures 1-3.

[0144] As shown in Figure 1, micrograms / cm 2 The latanoprost uptake, as expressed by (I) above, was higher in the haired skin punches than in the non-haired skin punches, demonstrating that latanoprost is efficiently delivered to the haired skin punches, which contain a greater proportion of the contents of the pilosebaceous unit, including the hair follicle, hair shaft, and sebaceous gland. Latanoprost uptake in the haired punches followed the order Formulation 1 > Formulation 2 > Formulation 3, demonstrating that anhydrous SFA-based Formulations 1 and 2 were superior to aqueous latanoprost Formulation 3. This is even more surprising considering the high content of the penetration enhancer ethanol in Formulation 3, at 50% (v / v). Formulation 2 (0.1 mg / ml) also contained significantly less latanoprost, yet was far superior to Formulation 3 (0.5 mg / ml), further highlighting the surprising effect of SFA-based compositions in more efficiently delivering latanoprost to / into the pilosebaceous unit, including the hair follicle, hair shaft, and sebaceous gland, compared to state-of-the-art aqueous latanoprost-containing compositions.

[0145] Furthermore, the uptake of latanoprost after incubation in Formulations 1 and 2 was higher than that after incubation in Formulation 3 for both haired and hairless skin.

[0146] As shown in Figure 2, latanoprost acid was detected in the samples. The presence of latanoprost acid is an indication of esterase activity in both the punch skin (skin without hair) and the punch skin with hair. The punch with hair showed a higher content of latanoprost acid than the punch without hair. Therefore, this case again demonstrates that the SFA-based compositions (Formulations 1-2) highly efficiently deliver latanoprost to / into the pilosebaceous unit, which includes the hair follicle, hair shaft, and sebaceous gland, where the prodrug latanoprost is converted to latanoprost acid.

[0147] Furthermore, significant differences in the total amount of latanoprost were observed among the four experiments, as shown in Figure 3. For example, in Experiment 1 (anhydrous SFA-based formulation 1), the total content of latanoprost for punches with hair was 0.22 μg / cm in Experiment 4 (aqueous formulation with high ethanol content 3). 2 12.83μg / cm 2 This translated into a more than 50-fold higher content.

[0148] Therefore, compared to the aqueous latanoprost formulation (Formulation 3), the delivery of latanoprost to hair-bearing skin, which contains a higher content of the pilosebaceous unit, including the hair follicle, hair shaft, and sebaceous gland, appears to be favorable when skin discs are incubated with semifluorinated alkane-based Formulations 1 and 2. [Example]

[0149] Penetration of latanoprost solutions in 1-perfluorobutyl-pentane into the roots of porcine eyelashes

[0150] Test formulation: 0.5 mg / ml latanoprost (Yonsung, purity 100.2%) in 1-perfluorobutylpentane (Novaliq) and 1% v / v ethanol (Merck, Secco solve dried).

[0151] Biological material: fresh porcine eyes with eyelids that had not been in buffer during transport from the slaughterhouse to the laboratory.

[0152] The upper eyelids were separated from the eyes with scissors, forceps, and a scalpel. Each eyelid was placed in a glass container, and incubation with the test formulation was initiated by adding 1 ml of formulation. Due to differences in eyelash length, the eyelashes were shortened prior to incubation to standardize the incubation procedure. After incubation according to the schedule in Table 3, the eyelids were washed eight times with 1-perfluorobutylpentane, and the eyelashes were plucked and weighed, as shown in Table 3.

[0153] [Table 3]

[0154] After plucking the eyelashes, 4mm (0.126cm) 2 ) biopsy instrument five times (total area 0.628 cm 2 The eyelids were punched out, and the skin and conjunctiva were then separated.

[0155] Each sample was extracted with 400 ml of ACN (acetonitrile) on an orbital shaker (150 rpm) and a minirotator (Biosan Max Level) for 2 hours at room temperature. The samples were then centrifuged at 13,000 rpm for 5 minutes. The supernatants collected from the samples were stored at -20°C until analysis.

[0156] The amounts of latanoprost and biotransformed latanoprost acid in tissues and eyelashes were determined by HPLC. For calculations, the average assay value of latanoprost acid was corrected by a factor of 1.1 because the molecular weight of latanoprost acid is smaller than that of latanoprost.

[0157] Figure 4 shows the amount of latanoprost in different tissues at different time points. Latanoprost appears to have a preferred affinity for the outer portion of the hair shaft, the eyelashes. Relatively small amounts of latanoprost were detected in the skin area containing the remaining components of the pilosebaceous unit, including the hair follicle, sebaceous gland, and hair shaft, where the eyelashes were not plucked. Figure 5 shows the amount of latanoprost acid at three different time points. A significant increase in the concentration of latanoprost acid in the skin samples was observed. After 2 hours of incubation, the detected concentration of latanoprost acid in the skin was 1.2 μg / ml, reached 11.4 μg / ml at 15 hours, and reached 21.5 μg / ml after 25 hours of incubation. This demonstrates not only the efficient delivery of latanoprost to the pilosebaceous unit, including the hair follicle, sebaceous gland, and hair shaft, where the eyelashes were not plucked, but also its enzymatic conversion to latanoprost acid. With regard to the eyelashes, after 25 hours of incubation, a small amount of latanoprost acid was detected. Without wishing to be bound by theory, it is assumed that this small amount of latanoprost acid is due to lower esterase activity in the eyelashes compared to the skin. [Example]

[0158] Cortexolone 17α-propionate penetration

[0159] Cortexolone 17α-propionate (development code name CB-03-01; 21-hydroxy-3,20-dioxopreg-4-en-17-ylpropionate; CAS registration number: 19608-29-8) was dissolved in 1-perfluorobutylpentane (F4H5) to obtain a 1% (w / w) solution of CB-03-01 in F4H5.

[0160] Franz diffusion cell (FDC) experiments revealed that cortexolone 17α-propionate was effectively and rapidly delivered to layers of the skin, including the stratum corneum, epidermis, and dermis. Interestingly, particularly large amounts of cortexolone 17α-propionate were found in the dermis, the layer of skin in which hair follicles extend as part of the pilosebaceous unit.

Claims

1. 1. A composition comprising an active ingredient and a semi-fluorinated alkane for use in the topical treatment of a disease or condition affecting the pilosebaceous unit or a component thereof, wherein the disease or condition affecting the pilosebaceous unit is androgenetic alopecia and the active ingredient is a prostaglandin analogue.

2. The composition for use according to claim 1, wherein the prostaglandin analogue is a prostaglandin F2α analogue, preferably selected from latanoprost, bimatoprost, and travoprost.

3. 3. The composition for use according to claim 1 or 2, wherein the prostaglandin analog is latanoprost.

4. 4. A composition for use according to any one of claims 1 to 3, wherein the components of the pilosebaceous unit are selected from a hair follicle, a hair shaft and / or a sebaceous gland.

5. The composition for use according to any of claims 1 to 4, wherein latanoprost is present in a concentration of 0.05 to 0.5 mg / ml.

6. 6. A composition for use according to any preceding claim, further comprising a co-solvent.

7. 7. The composition for use according to claim 6, wherein the co-solvent is an alcohol, preferably selected from ethanol or isopropanol.

8. The semi-fluorinated alkane has the formula (I)CF ３ (CF ２ )n(CH ２ ) mCH ３ 8. The composition for use according to any one of claims 1 to 7, wherein n and m are integers independently selected from the range of 3 to 9.

9. 9. The composition for use according to any of claims 1 to 8, wherein the semi-fluorinated alkane is selected from 1-perfluorobutylpentane (F4H5), 1-perfluorobutylhexane (F4H6), 1-perfluorobutyloctane (F4H8), 1-perfluorohexylhexane (F6H6) and 1-perfluorohexyloctane (F6H8), preferably the semi-fluorinated alkane is selected from 1-perfluorobutylpentane (F4H5) and 1-perfluorohexyloctane (F6H8).

10. 10. The composition for use according to any one of claims 1 to 9, wherein the semi-fluorinated alkane is 1-perfluorobutylpentane.

11. 11. A composition for use according to any of claims 1 to 10, in the form of a solution, preferably in the form of a liquid solution.

12. 12. The composition for use according to any one of claims 1 to 11, comprising latanoprost at a concentration of 0.05 to 0.5 mg / ml, 1-perfluorobutylpentane, and optionally ethanol at a concentration of up to 1% (v / v) relative to the total volume of the composition.

13. 13. A composition for use according to any one of claims 1 to 12, which is free of water and / or preservatives.

14. 14. A composition for use according to any preceding claim, which is free of solid thickeners.

15. 15. A composition for use according to any one of claims 1 to 14 which is not in the form of an ointment.

16. 16. The composition for use according to any one of claims 1 to 15, which is administered topically to a part of the skin selected from the scalp, face, chest, eyelids or eyelashes, preferably to the scalp.

17. 17. The composition for use according to any one of claims 1 to 16, which is administered topically to a subject suffering from hair loss.

18. 18. The composition for use according to any one of claims 1 to 17, which is administered topically in liquid form, preferably wherein the liquid composition is administered in the form of drops, as a film or as a spray onto the skin.

19. 19. The composition for use according to any one of claims 1 to 18, which is dispensed from a pipette, dropper, spray device or roll-on device.

20. 20. A composition for use according to any preceding claim, which is effective to deliver latanoprost to or within the pilosebaceous unit or component thereof.

21. 21. A composition for use according to any preceding claim, which is effective to deliver latanoprost to or into a hair follicle, hair shaft and / or sebaceous gland.

22. 22. A kit comprising a composition for use according to any one of claims 1 to 21, comprising a container holding said composition and instructions for use.

23. 23. The kit of claim 22, wherein the container is part of a dispensing device.

24. 24. The kit of claim 23, wherein the dispensing device is a pipette, dropper, spray, or roll-on device.

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