Treatment of androgenetic alopecia

Abstract

A liquid pharmaceutical composition for use in the topical treatment of androgenetic alopecia in a patient in need thereof, the composition comprising 2.5 mg / ml latanoprost, at least 85% (v / v) 1-perfluorohexyloctane (F6H8) and about 8 to 12% (v / v) isopropanol, wherein the composition is in form of a solution.

Description

[0001] TREATMENT OF ANDROGENETIC ALOPECIA

[0002] The present invention relates to topical compositions which are useful for the treatment of androgenetic alopecia.

[0003] Background art

[0004] Androgenetic alopecia (also known as androgenic 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.

[0005] 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.

[0006] Latanoprost is an isopropyl ester prodrug of the acid metabolite, which is a prostaglandin F2oc analogue. 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.

[0007] Blume-Peytavi (J. Am. Acad. Dermatol. 2012 May; 66(5):794-800) describes a doubleblind 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. It is therefore an object of the present invention to provide an effective topical treatment of androgenetic alopecia. In a further aspect, it is an objective of the invention to provide pharmaceutical 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. These and further objects will become clear on the basis of the description of the invention and the patent claims.

[0008] Summary of the invention

[0009] The objective of the present invention is to provide a liquid pharmaceutical composition comprising 2-3 mg / ml latanoprost, at least 85% (v / v) 1-perfluorohexyloctane (F6H8) and about 8 to 12% (v / v) isopropanol, which may be used to treat androgenetic alopecia. The objective of the present invention is attained by the claims.

[0010] It was surprisingly found that the composition of the present invention penetrates effectively to or into hair follicles. Accordingly, treatment of androgenetic alopecia 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.

[0011] Description of the drawings

[0012] Figure 1: Design of the Proof-Of-Concept Phase lb / 2a Clinical Study

[0013] Detailed description of the invention

[0014] In a first aspect the present invention provides a liquid pharmaceutical composition comprising 2 to 3 mg / ml latanoprost, at least 85% (v / v) 1-perfluorohexyloctane (F6H8) and about 8 to 12% (v / v) isopropanol for use in the topical treatment androgenetic alopecia, wherein the composition is in form of a solution.

[0015] In a second aspect, the invention relates to a method of treating androgenetic alopecia, comprising administering a liquid composition comprising 2 to 3 mg / ml latanoprost, at least 85% (v / v) 1-perfluorohexyloctane (F6H8) and about 8 to 12% (v / v) in the form of a solution to a subject in need of treatment. In a third aspect, the present invention relates to the use of a liquid composition comprising 2 to 3 mg / ml latanoprost, at least 85% (v / v) 1-perfluorohexyloctane (F6H8) and about 8 to 12% (v / v) isopropanol for the topical treatment androgenetic alopecia, wherein the composition is in form of a solution.

[0016] In a fourth aspect, the invention relates to the use of a liquid composition comprising 2 to 3 mg / ml latanoprost, at least 85% (v / v) 1-perfluorohexyloctane (F6H8) and about 8 to 12% (v / v) isopropanol in the manufacture of a medicament for the topical treatment androgenetic alopecia, wherein the composition is in form of a solution.

[0017] In a fifth aspect, the present invention provides for a kit comprising a composition described according to the first aspect of the invention, namely for use in the treatment of androgenetic alopecia, wherein the composition comprises or consist of 2 to 3 mg / ml latanoprost, at least 87 to 89% 1-perflurohexyloctane and about 10% (v / v) isopropanol, wherein the kit comprises a container for holding the composition and instructions for using the composition in the treatment of androgenetic alopecia.

[0018] The invention is described in the following with respect to the first aspect. All embodiments described below are applicable and combinable with the second, third and fourth aspect.

[0019] According to the first aspect of the invention, the liquid composition for use comprises latanoprost at a concentration of 2 to 3 mg / ml. Preferably, the composition for use in the topical treatment androgenetic alopecia comprises latanoprost at a concentration of 2.5 mg / ml, which is equivalent to a concentration of 0.25% (w / v).

[0020] In the present invention the composition for use may comprise 1-perfluorohexyloctane (F6H8) in an amount of from about 85 % (v / v) to about 90 % (v / v), preferably from about 86 % (v / v) to about 90 % (v / v), more preferably from about 87 % (v / v) to about 90 % (v / v), with respect to the total volume of the composition. In a most preferred embodiment of the present invention, the composition for use comprises 1- perflurohexyloctane (F6H8) in an amount from about 89 % (v / v) to about 90% (v / v) with respect to the total volume of the composition.

[0021] In some embodiments, the composition for use comprises at least 85% (v / v) of 1- perfluorohexyl-octane, preferably at least 87% (v / v), more preferably at least 88% (v / v) or even more preferably at least 89% (v / v) of 1-perfluoorhexyloctane, with respect to the total volume of the composition. In a particular embodiment, the composition for use comprises at least 90% (v / v) of 1-perfluorohexyloctane, with respect to the total volume of the composition.

[0022] In certain embodiments, the composition for use may comprise isopropanol in an amount of from about 8 % (v / v) to about 12 % (v / v), preferably from about 9 % (v / v) to about 11 % (v / v), with respect to the total volume of the composition. In a particular embodiment, the composition for use comprises about 10 % (v / v), with respect to the total volume of the composition.

[0023] In some embodiments, the composition for use may comprise or consist of 2.5 mg / ml latanoprost, 1-perflurohexyloctane (F6H8) in an amount of from about 88 % (v / v) to about 90% (v / v) and isopropanol in an amount of about 10% to 12 % (v / v), or the composition for use may comprise or consist of 2.5 mg / ml latanoprost, 1- perflurohexyloctane (F6H8) in an amount of from about 89 % (v / v) to about 90% (v / v) and isopropanol in an amount of about 10 to 11 % (v / v), with respect to the total volume of the composition.

[0024] Further, the composition for use may comprise or consist of 2.5 mg / ml latanoprost, 1- perflurohexyl-octane (F6H8) in an amount of from about 88 % (v / v) to about 92% (v / v) and isopropanol in an amount of about 8% to 12 % (v / v), or the composition for use may comprise or consist of 2.5 mg / ml latanoprost, 1-perflurohexyloctane (F6H8) in an amount of from about 89 % (v / v) to about 91% (v / v) and isopropanol in an amount of about 9 to 11 % (v / v), with respect to the total volume of the composition.

[0025] In preferred embodiments the sum of the vol % (v / v) of 1-perfluorohexyloctane (F6H8) and isopropanol add to 100 % (v / v). In alternative preferred embodiments, no further solvent, e.g., ethanol, is present. In particular preferred embodiment, the composition for use may comprise or consist of 2.5 mg / ml latanoprost, 1-perflurohexyl-octane (F6H8) in an amount of from about 90% (v / v) and isopropanol in an amount of about 10 % (v / v), with respect to the total volume of the composition.

[0026] The present invention provides a composition for use in the topical treatment of androgenetic alopecia, wherein the composition comprises or consists of 2.5 mg / ml latanoprost dissolved:

[0027] (i) in at least 88 to 92% (v / v) 1-perflurohexyloctane and about 8 to 12 % (v / v) isopropanol,

[0028] (ii) in at least 89 to 91% (v / v) 1-perflurohexyloctane and about 9 to 11 % (v / v) isopropanol, or

[0029] (hi) in about 90% (v / v) 1-perflurohexyloctane and about 10% (v / v) isopropanol

[0030] (iv) in at least 89% (v / v) 1-perflurohexyloctane and about 9 to 11% (v / v) isopropanol

[0031] (v) in at least 88% (v / v) 1-perflurohexyloctane and about 8 to 12% (v / v) isopropanol

[0032] Preferably, the present invention provides a composition for use in the topical treatment of androgenetic alopecia, wherein the composition comprises or consists of:

[0033] (i) 2.5 mg / ml of latanoprost, 90% (v / v) 1-perflurohexyloctane and 8 to 10% (v / v) isopropanol

[0034] (ii) 2.5 mg / ml of latanoprost, 90% (v / v) 1-perflurohexyloctane and 9 to 10% (v / v) isopropanol

[0035] (hi) 2.5 mg / ml of latanoprost, 90% (v / v) 1-perflurohexyloctane and about 10%

[0036] (v / v) isopropanol

[0037] In a preferred embodiment, the composition for the use in the topical treatment of androgenetic alopecia is a liquid solution that comprises or consists of latanoprost at a concentration of 2 to 3 mg / ml, at least 85% (v / v) 1-perflurohexyloctane (F6H8) and 8 to 12% (v / v) isopropanol. Further preferred is a composition for the use in the topical treatment of androgenetic alopecia in form of a liquid solution that comprises or consists of latanoprost at a concentration of 2 to 3 mg / ml, 87 to 89% (v / v) 1-perflurohexyloctane (F6H8), about 10% (v / v) isopropanol, with respect to the total volume of the composition.

[0038] In certain embodiments, the composition for use as defined above comprises 2- perfluorhexyloctane. 2-perfluorohexyloctane may be present in the composition for use at a concentration of up to 3% (v / v), up to 1% (v / v), up to 0.5% (v / v) or up to about 0.3% (v / v), with respect to the total volume of the composition.

[0039] Accordingly, composition for the use in the topical treatment of androgenetic alopecia is a liquid solution that comprises or consists of 2 to 3 mg / ml of latanoprost, dissolved in:

[0040] (i) at least 86% (v / v) of 1-perflurohexyloctane, 9 to 11% (v / v) of isopropanol, and optionally up to 3% (v / v) of 2-perflurohexyloctane

[0041] (ii) at least 88% (v / v) of 1-perflurohexyloctane, 9 to 11% (v / v) of isopropanol, and optionally up to 1% (v / v) of 2-perflurohexyloctane

[0042] (hi) at least 88.5% (v / v) of 1-perflurohexyloctane, 9 to 11% (v / v) of isopropanol, and optionally up to 0.5% (v / v) of 2-perflurohexyloctane

[0043] (iv) at least 88.7% (v / v) of 1-perflurohexyloctane, 9 to 11% (v / v) of isopropanol, and optionally up to 0.3% (v / v) of 2-perflurohexyloctane

[0044] (v) at least 87% (v / v) of 1-perflurohexyloctane, about 10 % (v / v) of isopropanol, and optionally up to 3% (v / v) of 2-perflurohexyloctane

[0045] (vi) at least 89% (v / v) of 1-perflurohexyloctane, about 10 % (v / v) of isopropanol, and optionally up to 1% (v / v) of 2-perflurohexyloctane

[0046] (vii) at least 89.5% (v / v) of 1-perflurohexyloctane, about 10 % (v / v) of isopropanol, and optionally up to 0.5% (v / v) of 2-perflurohexyloctane

[0047] (viii) at least 89.7% (v / v) of 1-perflurohexyloctane, about 10 % (v / v) of isopropanol, and optionally up to 0.3% (v / v) of 2-perflurohexyloctane

[0048] In a further embodiment, the composition for the use in the topical treatment of androgenetic alopecia is a liquid solution that comprises or consists of 2.5 mg / ml of latanoprost, dissolved in:

[0049] (i) at least 86% (v / v) of 1-perflurohexyloctane, 9 to 11% (v / v) of isopropanol, and optionally up to 3% (v / v) of 2-perflurohexyloctane (ii) at least 88% (v / v) of 1-perflurohexyloctane, 9 to 11% (v / v) of isopropanol, and optionally up to 1% (v / v) of 2-perflurohexyloctane

[0050] (hi) at least 88.5% (v / v) of 1-perflurohexyloctane, 9 to 11% (v / v) of isopropanol, and optionally up to 0.5% (v / v) of 2-perflurohexyloctane

[0051] (iv) at least 88.7% (v / v) of 1-perflurohexyloctane, 9 to 11% (v / v) of isopropanol, and optionally up to 0.3% (v / v) of 2-perflurohexyloctane

[0052] (v) at least 87% (v / v) of 1-perflurohexyloctane, about 10 % (v / v) of isopropanol, and optionally up to 3% (v / v) of 2-perflurohexyloctane

[0053] (vi) at least 89% (v / v) of 1-perflurohexyloctane, about 10 % (v / v) of isopropanol, and optionally up to 1% (v / v) of 2-perflurohexyloctane

[0054] (vii) at least 89.5% (v / v) of 1-perflurohexyloctane, about 10 % (v / v) of isopropanol, and optionally up to 0.5% (v / v) of 2-perflurohexyloctane

[0055] (viii) at least 89.7% (v / v) of 1-perflurohexyloctane, about 10 % (v / v) of isopropanol, and optionally up to 0.3% (v / v) of 2-perflurohexyloctane

[0056] The 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. Preferably, the composition for the use of the present invention is topically administered to one of more target areas on the scalp of the patient suffering from androgenetic alopecia. The one or more target areas of the scalp are preferably located on the frontal region, the midscalp region and / or the vertex, more preferably the target areas are along the leading edge of the vertex balding area of the patient suffering from androgenetic alopecia. The composition for the use is topically administered in liquid form of droplets to one of more the target areas on the scalp of the patient. Administering the composition as droplets may be accomplished by dispensing the liquid composition from a pipette or a dropper.

[0057] Preferably, the composition for use is topically administered in form of one or more single droplets of 9 to 13 pl volume, preferably administered as one or more single droplets of 8 to 12 pl volume, more preferably administered as one or more single droplets of about 9 to 11 pl volume, even more preferably the composition for use is topically administered as one or more single droplets of about 10 pl volume. In a preferred embodiment, the composition for the use is administered 1- to 4-times per day administered to the one or more target areas of the scalp of the patient suffering from androgenetic alopecia. Preferably, the composition for use is administered once, twice, 3 -times or 4-times to the one or more target areas of the scalp of the patient, more preferably, the composition for use is administered once, twice, 3-time or 4-times per day as single droplets of 10 pl (or 9 to 13 pl, or 8 to 12 pl, or 9 to 11 pl) to the one or more target areas of the scalp of the patient. Most preferably, the composition for use is administered twice per day (b.i.d.) to the one or more target areas of the scalp of the patient.

[0058] In a further embodiment, the composition for use is administered at a dose of about 20- 30 pg, or 22-28 pg, or 22-33 pg, or about 25-26 pg, or about 25 pg latanoprost per single droplet to the one or more target areas of the scalp of the patient suffering from androgenetic alopecia.

[0059] Preferably, the composition for the use of the present invention is topically administered to an individual suffering from androgenetic alopecia. The subject is preferably a human subject, which may be a male or a female subject, preferably the subject is a male subject.

[0060] The composition for use is administered to a patient aged 18 to 60 years, preferably the composition is administered to a patient aged 25 to 60 years.

[0061] The “target area hair count (TAHC)” describes the hair density in a predefined target area, expressed as the number of hairs per square centimetre in said target area. The relative change of target area hair count (TAHC) in relation to baseline (before treatment) is typically utilized to determine the effectiveness of treatment.

[0062] An effective treatment of androgenetic alopecia may be measured by determining the change of the target area hair count (TAHC) in the one or more target areas of the scalp of the patient. By doing so, it was found that the composition for use according to the present invention, in particular the composition for use comprising 2.5 mg / ml latanoprost, such as composition (1), is highly effective in increasing the hair counts, such as the target area hair counts (TAHC), in the one or more target areas on the scalp of the patient (see Table 1). Preferably, the composition for use, in particular the composition for use comprising 2.5 mg / ml latanoprost, such as composition (1), is effective in the treatment of androgenetic alopecia, in particular effective in increasing the TAHC (Target Area Hair Counts) in the one or more target areas on the scalp of the patient, as determined in comparison to the hair counts in said target areas on the scalp before treatment (at baseline).

[0063] Further, the topical treatment of patients with single droplets of about 10 pl (or about 11 pl) of the composition for use comprising 2.5 mg / ml latanoprost (such as composition (1)) achieves an increase in the TAHC (Target Area Hair Counts) in the one or more target areas on the scalp of the patient that is comparable or superior to topical treatment with single droplets of about 50 pl of an aqueous composition comprising 50 mg / ml minoxidil (Minoxidil 5.00 % (4)) when administered to comparable target areas on the scalp of a patient.

[0064] In a further embodiment, the twice daily topical treatment with single droplets of about 10 pl of the composition for use comprising 2.5 mg / ml latanoprost (such as composition (1)) over a 6-month period achieves an increase in the TAHC (Target Area Hair Counts) in the one or more target areas on the scalp of the patient that is comparable or superior to topical treatment with single droplets of about 50 pl of an aqueous composition comprising 50 mg / ml minoxidil (5% minoxidil), when administered to comparable target areas on the scalp of a patient.

[0065] It was found that the twice daily topical administration of 10 pl droplets of the composition for use comprising 2.5 mg / ml latanoprost (such as composition (1)) over a 6-month period achieves a comparable or improved hair growth compared to the one observed upon twice topical administration of 50 pl droplets of an aqueous composition comprising 50 mg / ml minoxidil for the same period of time.

[0066] “Hamilton-Norwood” grading (Norwood OT., South Med J. 1975 68(ll):1359-65) is used to classify the stages of male pattern baldness. It is one of the widely accepted and reproducible classification system for the male pattern hair loss (androgenetic alopecia). It is a visual guide denoting 7 different grade of hair thinning, with higher numbers indicating higher severity of hair loss, translating to higher severity of androgenetic alopecia. In some embodiments, the subject or patient to be treated with the composition for use of the present invention is suffering from moderate to severe androgenetic alopecia. The severity of alopecia may be characterized by the Norwood Hamilton-grade. The composition for use according to the present invention is preferably administered to a patient suffering from androgenetic alopecia characterized by a Norwood Hamilton- grade III to V, more preferably the composition as defined above is administered to a patient suffering from androgenetic alopecia that is characterized by a Norwood Hamilton-grade IV or V, or to a patient characterized by a Norwood Hamilton-grade V.

[0067] Surprisingly it was found that the composition for use according to the present invention, in particular the composition for use comprising 2.5 mg / ml latanoprost, such as composition (1), is highly effective in patients with more severe androgenetic alopecia, such as patients characterized by a Norwood Hamilton-grade IV or V, or patients characterized by a Norwood Hamilton-grade V. Herein, an effective treatment may be measured by determining the change of the target area hair count (TAHC) in the one or more target areas of the scalp of the patient characterized by Norwood Hamilton- grade (see Table 2). Accordingly, the composition for use according to the present invention, in particular the composition for use comprising 2.5 mg / ml latanoprost, such as composition (1), is effective in increasing and / or stimulating the hair growth in a patient suffering from androgenetic alopecia, wherein the patient is characterized by a Norwood Hamilton-grade of IV or V, preferably the patient is characterized by a Norwood Hamilton-grade ofV.

[0068] Surprisingly, it was found that the responder rate of patients to which the composition for use, in particular the composition for use comprising 2.5 mg / ml latanoprost, such as composition (1), was administered was higher in comparison to treatment with an aqueous composition comprising 50 mg / ml minoxidil (Minoxidil 5.00 % (4)) (see Table 3). Herein, the topical treatment with the composition comprising 2.5 mg / ml latanoprost (such as composition (1)) achieves in about 41% of the patients an increase of more than 15 % in the TAHC (Target Area Hair Counts), in comparison to about 25% of patients treated with a topical aqueous composition comprising 50 mg / ml minoxidil (Minoxidil 5.00 % (4)). Further, the topical treatment with the composition comprising 2.5 mg / ml latanoprost (such as composition (1)) achieves in about 28% of the patients an increase of more than 15 % in the TAHC (Target Area Hair Counts), in comparison to about 18% of patients treated with a topical aqueous composition comprising 50 mg / ml minoxidil (Minoxidil 5.00 % (4)).

[0069] The “anagen” phase is the active growth phase of hair follicles. During this phase the hair grows about 1 cm every 28 days. Scalp hair stays in this active phase of growth for 2-7 years.

[0070] The “telogen” phase is the resting phase of the hair follicle when hair strands remain in their follicles but are not actively growing. An estimate of 10-15% of hairs are in the telogen phase at any given moment. The telogen phase lasts approximately 4-6 weeks until the hair falls out.

[0071] The “anagen to telogen ratio” describes the ratio of growing hairs (with hair follicles being in the anagen phase) and non-growing hairs (with hair follicles being in the telogen phase).

[0072] Surprisingly, it was found that the treatment with the composition for use according to the present invention is effective in increasing the anagen to telogen ratio in the hair follicles in the one or more target areas on the scalp of the patient. Preferably, the twice daily topical administration of the composition for use comprising 2.5 mg / ml latanoprost (such as composition (1)) over a 6 month period results in an increased number of hair follicles in the anagen phase and / or a decreased number of hair follicles in the telogen phase, with respect to the hair follicles in the one or more target areas on the scalp of the patient. Further, the twice daily topical administration of the composition for use comprising 2.5 mg / ml latanoprost (such as composition (1)) over a 6 month period increases the length of the anagen phase and / or a decreases the length of the telogen phase, with respect to the hair follicles in the one or more target areas on the scalp of the patient suffering from androgenetic alopecia.

[0073] In a preferred embodiment, the composition for the use is not in form of an ointment, more preferably the composition for the use is topically administered to the one or more target areas of the scalp in form of a single droplets and not in form of an ointment. In a further preferred embodiment, 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, C 12-24 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. Herein, a solid thickening agent is a compound that is not liquid, preferably said compound is not liquid at 20°C.

[0074] In the second aspect, the present invention provides a method of treating androgenetic alopecia.

[0075] Preferably, the present invention provides a method of treating androgenetic alopecia, the method comprising topically administering to a subject a composition as described according to the first aspect of the invention.

[0076] The aforementioned method of treating androgenetic alopecia is effective in delivering the active ingredient to or into the hair follicle. More preferably, the method of treating androgenetic alopecia is effective in delivering latanoprost, preferably in its active form as latanoprost free acid, to or into the hair follicle.

[0077] Further, the aforementioned method is effective in increasing the TAHC (Target Area Hair Counts) in the one or more target areas on the scalp of the patient, as determined in comparison to the hair counts in said target areas on the scalp before treatment (at baseline).

[0078] The aforementioned method of treating androgenetic alopecia is effective in patients with more severe androgenetic alopecia, such as patients characterized by a Norwood Hamilton-grade IV or V, or patients characterized by a Norwood Hamilton-grade V. In particular, the aforementioned method of treatment is effective in increasing and / or stimulating the hair growth in a patient suffering from androgenetic alopecia that is characterized by a N orwood Hamilton-grade of IV or V, or in a patient that is characterized by a Norwood Hamilton-grade of V. Further, the aforementioned method of treatment is highly effective is increasing the anagen to telogen ratio in the hair follicles in the one or more target areas on the scalp of the patient. Preferably, the aforementioned method comprising twice daily topical administration of the composition comprising 2.5 mg / ml latanoprost (such as composition (1)) over a 6 month period to a patient suffering from androgenetic alopecia results in an increased number of hair follicles in the anagen phase and / or a decreased number of hair follicles in the telogen phase, with respect to the hair follicles in the one or more target areas on the scalp of the patient.

[0079] In the fifth aspect, the present invention provides for a kit comprising a composition described according to the first aspect of the invention, namely for use in the treatment of androgenetic alopecia, wherein the composition comprises or consist of 2 to 3 mg / ml latanoprost, at least 87 to 89% 1-perflurohexyloctane and about 10% (v / v) isopropanol, wherein the kit comprises a container for holding the composition and instructions for using the composition in the treatment of androgenetic alopecia. Preferably, the kit comprises a composition described according to the first aspect of the invention, namely for use in the treatment of androgenetic alopecia, wherein the composition comprises or consist of 2.5 mg / ml latanoprost, at least 87 to 89% 1-perflurohexyloctane and about 10% (v / v) isopropanol, wherein the kit comprises a container for holding the composition and instructions for using the composition in the treatment of androgenetic alopecia. More preferably, the kit comprises a composition described according to the first aspect of the invention, namely for use in the treatment of androgenetic alopecia, wherein the composition comprises or consist of 2.5 mg / ml latanoprost, about 90% 1- perflurohexyloctane and about 10% (v / v) isopropanol, wherein the kit comprises a container for holding the composition and instructions for using the composition in the treatment of androgenetic alopecia.

[0080] Preferably, the container, comprised in the kit, is adapted to administer single droplets of the composition to be administered to one or more target areas on the scalp of the patient, preferably to one or more target areas of the frontal region, the midscalp region and / or the vertex, more preferably the container is adapted to administer single droplets of the composition to one or more target areas of the vertex. The container may be part of a pipette or a dropper that allows for dispensing single droplets of the liquid composition, thereby allowing for topically administration of the liquid composition to one or more target areas of the frontal region, the midscalp region and / or the vertex of a patient suffering from androgenetic alopecia. Preferably, the container is adapted to administer single droplets of the composition at a volume of about 9 to 13 pl, 8 to 12 pl, 9 to 11 pl or about 10 pl to one or more target areas on the scalp of the patient.

[0081] The following list of numbered items are embodiments comprised by the present invention:

[0082] 1. A liquid pharmaceutical composition for use in the topical treatment of androgenetic alopecia in a patient in need thereof, the composition comprising 2 to 3 mg / ml latanoprost, at least 85% (v / v) 1-perfluorohexyloctane (F6H8) and about 8 to 12% (v / v) isopropanol, wherein the composition is in form of a solution.

[0083] 2. The composition for use according to any preceding item, wherein the composition comprises or consists of 2 to 3 mg / ml latanoprost, at least 87% (v / v) 1-perfluorohexyloctane (F6H8), about 10% (v / v) isopropanol, and optionally up to 3% (v / v) 2-perfluorohexyloctane.

[0084] 3. The composition for use according to item 1, wherein latanoprost is present at a concentration of about 2.5 mg / ml.

[0085] 4. The composition for use according to any preceding item, wherein the composition comprises or consists of 2.5 mg / ml latanoprost, at least 89% (v / v) F6H8, 10% (v / v) isopropanol, and optionally up to 1% (v / v) 2- perfluorohexyloctane.

[0086] 5. The composition for use according to any preceding item, wherein the composition consists of 2.5 mg / ml latanoprost, about 90% (v / v) F6H8 and 10% (v / v) isopropanol.

[0087] 6. The composition for use according to any preceding item, wherein the composition is water-free, free of a preservative, and / or free of a surfactant.

[0088] 7. The composition for use according to any preceding item, wherein the composition is topically administered to the patient as one or more single droplets of 9 to 13 pl volume, preferably administered as one or more single droplets of 8 to 12 pl volume, more preferably administered as one or more single droplets of about 9 to 11 pl volume, even more preferably the composition is topically administered as one or more single droplets of about 10 pl volume. The composition for use according to any preceding item, wherein the composition is topically administered to one or more target areas on the scalp of the patient, preferably to one or more target areas of the frontal region, the midscalp region and / or the vertex, more preferably the composition is administered to one or more target areas of the vertex. The composition for use according to any preceding item, wherein the composition is administered 1- to 4-times per day to the scalp of the patients, preferably the composition is administered 2-times per day. The composition for use according to any preceding item, wherein the composition is administered at a dose of about 20-30 pg, or 22-28 pg, or 22-33 pg, or about 25-26 pg, or about 25 pg latanoprost per single droplets. The composition for use according to any preceding item, wherein the composition is administered to a patient suffering from moderate to severe androgenetic alopecia. The composition for use according to any preceding item, wherein the composition is administered to a male or female patient, preferably to a male patient. The composition for use according to any preceding item, wherein the composition is administered to a patient aged 18 to 60 years, preferably the composition is administered to a patient aged 25 to 60 years. The composition for use according to any preceding item, wherein the composition is administered to a patient suffering from androgenetic alopecia, wherein the patient is characterized by a Norwood Hamilton-grade of 111 or V, preferably the composition is administered to a patient characterized by a Norwood Hamilton- grade of IV or V. The composition for use according to any preceding item, wherein the treatment is effective in increasing / stimulating the hair growth in a patient suffering from androgenetic alopecia, wherein the patient is characterized by a Norwood Hamilton-grade of IV or V, preferably the patient is characterized by a Norwood Hamilton-grade ofV. The composition for use according to any preceding item, wherein the treatment is effective in increasing the hair counts in the one or more target areas on the scalp of the patient, preferably wherein the treatment is effective in increasing the TAHC (Target Area Hair Counts) in the one or more target areas on the scalp of the patient, as determined in comparison to the hair counts in said target areas on the scalp before treatment (at baseline). The composition for use according to any preceding item, wherein the topical treatment with single droplets of about 10 pl (or about 11 pl) of the composition comprising 2.5 mg / ml latanoprost (preferably composition (1)) achieves an increase in the TAHC (Target Area Hair Counts) in the one or more target areas on the scalp of the patient that is comparable or superior to topical treatment with single droplets of about 50 pl of an aqueous composition comprising 50 mg / ml minoxidil (5% minoxidil) to comparable target areas on the scalp of a patient. The composition for use according to any preceding item, wherein the twice daily topical treatment with single droplets of about 10 pl of the composition comprising 2.5 mg / ml latanoprost (preferably composition (1)) over a 6-month period achieves an increase in the TAHC (Target Area Hair Counts) in the one or more target areas on the scalp of the patient that is comparable or superior to topical treatment with single droplets of about 50 pl of an aqueous composition comprising 50 mg / ml minoxidil (5% minoxidil) to comparable target areas on the scalp of a patient. The composition for use according to any preceding item, wherein the twice daily topical administration of 10 pl droplets of the composition comprising 2.5 mg / ml latanoprost (preferably composition (1)) over a 6-month period achieves a comparable or improved hair growth observed upon twice topical administration of 50 pl of an aqueous composition comprising 50 mg / ml minoxidil for the same period of time. The composition for use according to any preceding item, wherein the topical treatment with the composition comprising 2.5 mg / ml latanoprost (preferably composition (1)) achieves in about 41% of the patients an increase of more than 15 % in the TAHC (Target Area Hair Counts), in comparison to about25% of patients treated with a topical aqueous composition comprising 50 mg / ml minoxidil (5% minoxidil). The composition for use according to any preceding item, wherein the topical treatment with the composition comprising 2.5 mg / ml latanoprost (preferably composition (1)) achieves in about 28% of the patients an increase of more than 20 % in the TAHC (Target Area Hair Counts), in comparison to about 18% of patients treated with a topical aqueous composition comprising 50 mg / ml minoxidil (5% minoxidil). The composition for use according to any preceding item, wherein the treatment is effective in increasing the anagen to telogen ratio in the hair follicles in the one or more target areas on the scalp of the patient. The composition for use according to any preceding item, wherein the twice daily topical administration of the composition comprising 2.5 mg / ml latanoprost (preferably composition (1)) over a 6 month period results in an increased number of hair follicles in the anagen phase and / or a decreased number of hair follicles in the telogen phase, with respect to the hair follicles in the one or more target areas on the scalp of the patient. The composition for use according to any preceding item, wherein the twice daily topical administration of the composition comprising 2.5 mg / ml latanoprost (preferably composition (1)) over a 6 month period increase the length of the anagen phase and / or a decreases the length of the telogen phase, with respect to the hair follicles in the one or more target areas on the scalp of the patient. A kit comprising a composition described according to items 1 to 24, a container for holding the composition and instructions for using the composition in the treatment of androgenetic alopecia. The kit according to item 25, wherein the container is adapted to administer single droplets of about 9 to 13 pl of the composition to one or more target areas on the scalp of the patient suffering from androgenetic alopecia. Examples

[0089] Example 1: Formulations

[0090] The following composition were utilized in the Clinical Study of Example 2: composition (1) = latanoprost (0.25%) in F6H8 / isopropanol (1): 2.5 mg / ml latanoprost dissolved in 90% (v / v) 1-perfluorhexyloctane and 10% (v / v) isopropanol. composition (2) = latanoprost (0.05%) in F6H8 / isopropanol (2): 0.5 mg / ml latanoprost dissolved in 90% (v / v) 1-perfluorhexyloctane and 10% (v / v) isopropanol. composition (3) = vehicle (F6H8 / isopropanol) (3): solution of 90% (v / v) 1- perfluorhexyloctane and 10% (v / v) isopropanol composition (4) = Minoxidil 5.00 % (4), comparator: 5% Minoxidil (commercial Men’s Regaine Extra Strength 5% Minoxidil Topical Solution)

[0091] Example 2: Clinical Study

[0092] A Proof-Of-Concept Phase lb / 2a randomized, vehicle, and comparator-controlled study was conducted to measure the safety, tolerability, and the hair growth response to topical water-free latanoprost compositions (1) and (2) in comparison to the vehicle (3) and a minoxidil comparator solution (4) in 120 males with Androgenetic Alopecia. The design of the clinical study is shown in Figure 1.

[0093] Included in the study were males, aged 18 to 60 years, with active androgenetic alopecia on the vertex area of the scalp consistent with Norwood-Hamilton Grades of 111 through V.

[0094] The liquid, water-free compositions (1), (2) and (3) were applied twice daily as single droplets of about 10 pl to the target area of the study subjects, while the aqueous comparator Minoxidil (4) was applied twice daily as single droplets of 50 pl. The droplets were applied to the target area of about 2 square centimetres along the leading edge of the vertex balding area of the study subjects. During the study it was observed that the comparator Minoxidil (4) appeared as a sticky formulation, while the water-free compositions (1), (2) and (3) drained and dried quickly.

[0095] The Outcome Measures included:

[0096] Results:

[0097] The analysis of the study results showed that 0.25% latanoprost composition (1) increased the mean hair density (TAHC) to baseline by 12.3% after 6 months of treatment, with a significant treatment efficacy against vehicle (3) (p= 0.008) (see Table 1 below). A significant treatment efficacy of (1) against vehicle (3) was already achieved after 3 months of treatment (p= 0.002).

[0098] In comparison, the comparator market product 5% Minoxidil (4), increased the mean hair density (TAHC) to baseline only by 9.8% after 6 months of treatment.

[0099] The 0.05%. latanoprost composition (2) was not effective compared to vehicle (3) with regard to the TAHC study endpoint.

[0100] Table 1: Target area hair count (TAHC) Surprisingly, the 0.25% latanoprost compositions (1) was highly effective in the treatment of patients characterized by a more severe grade of androgenetic alopecia, namely characterized by the Norwood-Hamilton (NH) Grade IV or V. In patients characterized by Norwood-Hamilton (NH) Grade IV or V, the 0.25% latanoprost compositions (1) revealed to be more effective, as compared to the comparator market product 5% Minoxidil (4), see Table 2 below. Without being bound by theory, this surprising finding may be related to a yet unknown difference in mode of action.

[0101] Table 2: Treatment Effect: Severity of Androgenetic Alopecia

[0102] The water-free 0.25% latanoprost compositions (1) showed overall a higher responder rate in %TAHC after 6 months of treatment. In particular, the responder rates, as defined as a change of TAHC of >15% (or >20%) were higher for 0.25% latanoprost compositions (1), as compared to the comparator market product 5% Minoxidil (4), see Table 3 below:

[0103] Table 3: Responder Rate

[0104] The water-free latanoprost compositions (1) and (2) were well tolerated. None of the graded reactions were classed as adverse events according to protocol and none led to discontinuation or interruption of treatment.

Claims

Claims1. A liquid pharmaceutical composition for use in the topical treatment of androgenetic alopecia in a patient in need thereof, the composition comprising 2.5 mg / ml latanoprost, at least 85% (v / v) 1-perfluorohexyloctane (F6H8) and about 8 to 12% (v / v) isopropanol, wherein the composition is in form of a solution.

2. The composition for use according to any preceding claim, wherein the composition comprises or consists of 2.5 mg / ml latanoprost, at least 89% (v / v) F6H8, 10% (v / v) isopropanol, and optionally up to 1% (v / v) 2- perfluorohexyloctane.

3. The composition for use according to any preceding claim, wherein the composition consists of 2.5 mg / ml latanoprost, about 90% (v / v) F6H8 and about 10% (v / v) isopropanol.

4. The composition for use according to any preceding claim, wherein the composition is topically administered to the patient as one or more single droplets of 9 to 13 pl volume, preferably administered as one or more single droplets of 8 to 12 pl volume, more preferably administered as one or more single droplets of about 9 to 11 pl volume, even mor preferably administered as one or more single droplets of about 10 pl volume.

5. The composition for use according to any preceding claim, wherein the composition is topically administered to one or more target areas on the scalp of the patient, preferably to one or more target areas of the frontal region, the midscalp region and / or the vertex, more preferably the composition is administered to one or more target areas of the vertex.

6. The composition for use according to any preceding claim, wherein the composition is administered 1- to 4-times per day to the scalp of the patients, preferably the composition is administered 2-times per day.

7. The composition for use according to any preceding claim, wherein the composition is administered at a dose of about 20-30 pg, or 22-28 pg, or 22-33 pg, or about 25-26 pg, or about 25 pg latanoprost per single drop.

8. The composition for use according to any preceding claim, wherein the composition is administered to a patient suffering from androgenetic alopecia,wherein the patient is characterized by a Norwood Hamilton-grade of III or V, preferably the composition is administered to a patient characterized by a Norwood Hamilton-grade of IV or V.

9. The composition for use according to any preceding claim, wherein the treatment is effective in increasing the hair growth in a patient suffering from androgenetic alopecia, wherein the patient is characterized by a Norwood Hamilton-grade of IV or V.

10. The composition for use according to any preceding claim, wherein the treatment is effective in increasing the hair counts in the one or more target areas on the scalp of the patient, preferably wherein the treatment is effective in increasing the TAHC (Target Area Hair Counts) in the one or more target areas on the scalp of the patient, as determined in comparison to the hair counts in said target areas on the scalp before treatment (at baseline).

11. The composition for use according to any preceding claim, wherein the topical treatment with single droplets of about 10 pl of the composition achieves an increase in the TAHC (Target Area Hair Counts) in the one or more target areas on the scalp of the patient that is comparable or superior to topical treatment with single droplets of about 50 pl of an aqueous composition comprising 50 mg / ml minoxidil (Minoxidil 5.00 % (4)) to comparable target areas on the scalp of a patient.

12. The composition for use according to any preceding claim, wherein the topical treatment with the composition achieves in about 41% of the patients an increase of more than 15 % in the TAHC (Target Area Hair Counts), in comparison to about 25% of patients treated with a topical aqueous composition comprising 50 mg / ml minoxidil (5% minoxidil).

13. The composition for use according to any preceding claim, wherein the treatment is effective in increasing the anagen to telogen ratio in the hair follicles in the one or more target areas on the scalp of the patient.

14. A kit comprising a composition described according to claims 1 to 13, a container for holding the composition and instructions for using the composition in the treatment of androgenetic alopecia.

5. The kit according to claim 14, wherein the container is adapted to administer single droplets of about 9 to 13 pl of the composition to one or more target areas on the scalp of the patient suffering from androgenetic alopecia.

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