WO2021084541A1

WO2021084541A1 - Treatment of hair loss disorders with a topical egfr inhibitor

Info

Publication number: WO2021084541A1
Application number: PCT/IL2020/051131
Authority: WO
Inventors: Moshe Arkin; Marcel Zighelboim; Ori NOV; Karine Neimann
Original assignee: Sol Gel Technologies Ltd
Current assignee: Sol Gel Technologies Ltd
Priority date: 2019-10-31
Filing date: 2020-10-29
Publication date: 2021-05-06
Anticipated expiration: 2022-04-30

Abstract

Disclosed are topical compositions and methods of treatment of hair loss by topical administration to a subject in need thereof of a composition comprising a therapeutically effective amount of at least one EGFR inhibitor and optionally at least one additional active agent. Also disclosed are methods of treatment of hair loss disorders by combining topical administration to a subject in need thereof of a composition comprising at least one EGFR inhibitor and optionally at least one additional active agent with oral administration of at least one additional active agent. Alternatively, the topical administration is combined with scalp cooling during therapy.

Description

TREATMENT OF HAIR LOSS DISORDERS WITH A TOPICAL EGFR INHIBITOR

FIELD OF THE INVENTION

[001] The present disclosure, in some embodiments, relates to topical compositions and methods of treatment of hair loss disorders by topical administration to a subject in need thereof a composition comprising at least one Epidermal Growth Factor Receptor (EGFR) inhibitor, more particularly, but not exclusively, by topical administration of a composition comprising erlotinib. The topical compositions of this disclosure are useful for the treatment, prevention or amelioration of hair loss disorders, like hair loss disorders caused by chemotherapy or irradiation. BACKGROUND OF THE INVENTION

[002] Epidermal Growth Factor Receptor inhibitors drugs (also known as EGFR inhibitors, EGFRi, EGFR tyrosine kinase inhibitors or EGFR-TKis) like erlotinib, gefitinib, osimertinib and brigatinib target the EGFR (a known oncogene) and are used for the systemic treatment of some forms of cancer (lung, colon). [003] There is no FDA-approved US-marketed EGFR inhibitor drug for topical use. The EGFR inhibitor erlotinib is sold as oral tablets (Tarceva). Similarly, gefitinib (Iressa), osimertinib (Tigresso) and brigatinib (Alunbrig) are sold as oral tablets.

[004] There is an unmet need for compositions and methods of topical treatment of hair loss disorders, devoid of systemic side-effects. SUMMARY OF THE INVENTION

[005] The present disclosure provides topical compositions and methods of treatment of hair loss disorders by topical administration to a subject in need thereof of a composition comprising a therapeutically effective amount of at least one EGFR inhibitor and optionally at least one additional active agent. In the latter case, the administration is carried out by topical application to the affected area on the scalp or skin of the subject of a single composition or two separate compositions, in either order. BRIEF DESCRIPTION OF THE DRAWINGS

[006] The subject matter regarded as the invention is particularly pointed out and distinctly claimed in the concluding portion of the specification. The invention, however, both as to organization and method of operation, together with objects, features, and advantages thereof, may best be understood by reference to the following detailed description when read with the accompanying drawings in which:

[007] Fig. 1 presents hair matrix keratinocyte apoptosis after administration of paclitaxel and Erlotinib Hydrochloride (EH). n=6 means 6 anagen HFs/group. (HF refers to Hair Follicles).

[008] Fig 2. presents percentage of K15/ histone protein from the H2A family (gH2A.C) + cells in the bulge basal layer after treatment with of paclitaxel and Erlotinib Hydrochloride (EH). n=6 means 6 anagen HFs/group; Dunn’s multiple comparison test: # p<0.05

Mann-Whitney test: *p<0.05, ** p<0.01.

[009] Fig 3. presents K15 expression in the hair matrix after treatment with paclitaxel and Erlotinib Hydrochloride (EH). n=6 means 6 anagen HFs/group; Mann-Whitney test: ** p<0.01. [0010] Fig 4. presents K15⁺ cells in the bulge basal layer after treatment with paclitaxel and

Erlotinib Hydrochloride (EH). n=6 means 6 anagen HFs/group; Mann-Whitney test: *p<0.05, ** p<0.01.

[0011] Fig 5. illustrates that 0.5mM and 2mM erlotinib hydrochloride significantly and tendentially protect the hair follicle from apoptosis of K15+ cells in the bulge basal layer induced by lOOnM paclitaxel treatment, while erlotinib hydrochloride alone does not display any effect. n=6 HFs/group from one healthy donor, Mean±SEM, GraphPad Prism 6; D’Agostino-Pearson omnibus normality test, no Gaussain distribution, Kruskal Wallis test p<0.0001, Dunn’s multiple comparison test, ### p<0.0001, Mann-Whitney test. **p<0.01.

[0012] It will be appreciated that for simplicity and clarity of illustration, elements shown in the figures have not necessarily been drawn to scale. For example, the dimensions of some of the elements may be exaggerated relative to other elements for clarity. Further, where considered appropriate, reference numerals may be repeated among the figures to indicate corresponding or analogous elements. DETAILED DESCRIPTION OF THE INVENTION

[0013] Systemic treatment with EGFR inhibitors is known to induce side-effects including diarrhea and cutaneous conditions like xerosis, pruritus, hair changes and alopecia, nail alterations and hand and foot reactions. The most common skin reaction reported in patients treated with EGFR-TKis is a follicular acneiform eruption also known as “acne -like rash” or “folliculitis.” (Hirsh V., Current Oncology, [S.I.], v. 18, n. 3, p. 126-138, June 2011).

[0014] Inhibition of EGFR is thought to alter keratinocyte proliferation, differentiation, migration, and attachment, which may explain the papulopustular reaction and xerosis seen with EGFR-TKIs. [0015] It occurred to the present inventors that EGFR inhibitors’ hair changes side -effect has the potential to prevent, cure or alleviate a number of hair loss disorders despite the known alopecia side- effect. The EGFRi-induced alopecia side -effect (Chen C.A. et al. JAAD Case Rep. 2015, Sep; 1(5); 289-291) is actually teaching away from the instant disclosure.

[0016] In order to prevent systemic side-effects, the instant disclosure uses topical instead of systemic compositions for the treatment of hair loss disorders. The optional addition of at least one additional active agent for the preemptive treatment of eventual cutaneous EGFR inhibitors side- effects avoids, prevents or minimizes said cutaneous side-effects.

[0017] The EGFR inhibitor side-effects reported in the medical literature are the result of oral (systemic) treatment with EGFR inhibitors. The compositions and methods of treatment of the present disclosure use topical instead of oral administration, thus avoiding systemic effects, and present an advantageous cutaneous side -effects profile as compared to the EGFR inhibitor oral products.

[0018] Some of the hair loss disorders contemplated for treatment with the methods of this disclosure are alopecia selected from alopecia areata totalis, alopecia areata universalis and androgenetic alopecia, telogen effluvium, tinea capitis, hypotrichosis and hereditary hypotrichosis simplex (see below). Hair loss (alopecia or baldness)

[0019] Hair loss (alopecia) refers to loss of hair from parts or all of the head or body. The following types of hair loss are known: male -pattern hair loss, female-pattern hair loss, alopecia areata, alopecia totalis and alopecia universalis. Telogen effluvium

[0020] This form of hair loss manifests itself by a characteristic temporary and reversible thinning or hair loss, usually at the top of the head.

Tinea capitis (tinea tonsurans or ringworm)

[0021] Hair loss is sometimes caused by a mycosis or dermatophytosis fungal infection of the scalp, eyebrows and eyelashes.

Hypotrichosis (sparse hair)

[0022] This is an autosomal recessive condition affecting hair growth and causing sparse hair.

[0023] Hypotrichosis simplex (HHS) is a rare form of hereditary hair loss. It may be scalp-limited or generalized. Compositions

[0024] The present disclosure provides topical compositions comprising from about 0.01% to about 1% w/w, from about 1% to about 3% w/w, from about 3% to about 5% w/w or from about 5% to about 10% w/w at least one EGFR inhibitor; and optionally from about 0.01% to about 1% w/w, from about 1% to about 3% w/w or from about 3% to about 5% w/w at least one additional active agent; and a carrier suitable for topical administration.

[0025] The at least one EGFR inhibitor is selected from erlotinib, gefitinib, lapatinib, cetuximab, panitumumab, vandetanib, necitumumab, osimertinib and combinations thereof.

[0026] The optional at least one additional active agent is selected: from a first group comprising menadione, ketoconazole, dapsone, cevimeline, spironolactone, tretinoin, pimecrolimus, tetracycline, a sunscreen, doxycycline, epidermal growth factor (EGF), lycopene, threolone, synthomycine, erythromycin, Vitamin K3 or combinations thereof, in a concentration of from about 0.01% to about 1% w/w, from about 1% to about 3% w/w or from about 3% to about 5% w/w; or from a second group comprising minoxidil, finasteride, biotin, ketoconazole, a cyclin-dependent kinase (CDK4/6) inhibitor, a corticosteroid, calcipotriene, tapinarof, a Janus kinase inhibitor (JAK inhibitor), a phosphodiesterase-4 inhibitor (PDE4 inhibitor), a vasoconstrictor or combinations thereof, in a concentration of from about 0.01% to about 1% w/w, from about 1% to about 3% w/w, from about 3% to about 5% w/w; or from active agents in both groups.

[0027] Typical non-exclusive examples of a CDK4/6 inhibitor are ribociclib, palbociclib, abemaciclib or combinations thereof.

[0028] Typical non-exclusive examples of a JAK inhibitor are tofacitinib, abrocitinib, ruxolitinib, delgocitinib, oclacitinib, baricitinib, peficitinib or combinations thereof.

[0029] Typical non-exclusive examples of a PDE4 inhibitor are apremilast, roflumilast, crisaborole, cilomilast, ibudilast, piclamilast or combinations thereof. [0030] Typical non-exclusive examples of a vasoconstrictor are oxymetazoline, phenylephrine, epinephrine, xylometazoline, naphazoline, tetryzoline, angiotensin ii, vasopressin, felypressin, midodrine or combinations thereof.

[0031] Without wishing to be bound by theory, the vasoconstrictor in the compositions of this disclosure decreases blood flow to the hair follicles. As a result, for example in chemotherapy, a lesser amount of cytotoxic drugs reaches the hair follicles and the hair follicles are less damaged.

[0032] Treatment of breast cancer patients with CDK4/6 inhibitors with aromatase inhibitors is known to induce alopecia (Chan D. et ah, J. of Clin. Oncology, 37, no. 17, suppl.) a finding which teaches away from treatment of alopecia with CDK4/6 inhibitors.

[0033] The at least one additional active agent of the first group plays the role of preemptive treatment of eventual cutaneous EGFR inhibitors side -effects avoids, prevents or minimizes said cutaneous side -effects. [0034] The at least one additional active agent of the second group plays the role of augmenting the EGFR inhibitor’ s therapeutic effect in the treatment, prevention or alleviation of a hair loss disorder in a subject in need thereof, by an additive and/or synergistic effect between the EGFR inhibitor and the at least one additional active agent of the second group. [0035] The present disclosure provides a topical composition comprising at least one EGFR inhibitor and a carrier suitable for topical administration.

[0036] The present disclosure also provides a topical composition comprising at least one EGFR inhibitor, optionally at least one additional active agent and a carrier suitable for topical administration. [0037] The present disclosure also provides a topical composition comprising at least one EGFR inhibitor and a carrier suitable for topical administration, optionally at least one additional active agent and a penetration enhancer.

[0038] The penetration enhancer in the compositions of the present disclosure is selected from DMSO (dimethylsulfoxide), MSM (methylsulfonylmethane), ethanol, isopropyl alcohol, dimethyl isosorbide, isopropyl myristate, oleic acid, a polyethylene glycol, hexylene glycol, glycofurol and combinations thereof. The penetration enhancer has dual functionality and may act also as solvent.

[0039] Optionally, the composition of this disclosure may further comprise at least one ingredient selected from a moisturizer, a skin barrier, urea, ammonium lactate and combinations thereof, in a concentration of from about 0.01% to about 1% w/w, from about 1% to about 3% w/w, or from about 3% to about 5% w/w.

[0040] Examples 1-6 detail the preparation and stability of erlotinib hydrochloride compositions comprising 0.5% w/w, 0.75% w/w, 1% w/w and 1.25% w/w erlotinib hydrochloride formulated as topical gels comprising various combinations of penetration enhancers, solvents, preservatives, thickeners and gelling agents. [0041] Examples 7-9 detail the preparation of compositions comprising 1% w/w erlotinib hydrochloride in combination with either 1% w/w tapinarof or 0.5% w/w tofacitinib citrate (a Janus kinase inhibitor also known as JAK inhibitor) or 0.5% w/w apremilast (a phosphodiesterase-4 inhibitor, also known as PDE4 inhibitor), formulated as topical gels, comprising various combinations of penetration enhancers, solvents, preservatives, thickeners and gelling agents.

[0042] Example 10 details a study conducted with erlotinib and paclitaxel on a human microdissected full length HFs from Follicular unit extraction (FUEs) of a 39 years old male donor. The study was conducted in 2 concentrations of the erlotinib.

[0043] Erlotinib HC1 at concentrations of up to 1.25% w/w in all the compositions of Examples 1- 10 is entirely solubilized. Erlotinib HC1 at higher concentrations is only partly solubilized.

Methods of treatment

[0044] It is an object of the present disclosure to provide a method of treatment, prevention or alleviation of a hair loss disorder in a subject in need thereof, by topical administration to a subject in need thereof of a therapeutically effective amount of one of the following compositions:

[0045] A topical composition for treatment, prevention or alleviation of a hair loss disorder in a subject in need thereof, comprising at least one EGFR inhibitor in a concentration of from about 0.01% to about 1% w/w, from about 1% to about 3% w/w, from about 3% to about 5% w/w or from about 5% to about 10% w/w.

[0046] A topical composition for treatment, prevention or alleviation of a hair loss disorder in a subject in need thereof, comprising at least one EGFR inhibitor in a concentration of from about 0.01% to about 1% w/w, from about 1% to about 3% w/w, from about 3% to about 5% w/w or from about 5% to about 10% w/w; and at least one additional active agent selected from a first group comprising menadione, ketoconazole, dapsone, cevimeline, spironolactone, tretinoin, pimecrolimus, tetracycline, a sunscreen, doxycycline, epidermal growth factor (EGF), lycopene, threolone, synthomycine, erythromycin, Vitamin K3 or any combinations thereof, in a concentration of from about 0.01% to about 1% w/w, from about 1% to about 3% w/w or from about 3% to about 5% w/w. [0047] A topical composition for treatment, prevention or alleviation of a hair loss disorder in a subject in need thereof, comprising at least one EGFR inhibitor in a concentration of from about 0.01% to about 1% w/w, from about 1% to about 3% w/w, from about 3% to about 5% w/w or from about 5% to about 10% w/w; and at least one additional active agent selected from a second group comprising minoxidil, finasteride, biotin, ketoconazole, a cyclin-dependent kinase (CDK4/6) inhibitor, a corticosteroid, calcipotriene, tapinarof a Janus kinase inhibitor (JAK inhibitor), a phosphodiesterase-4 inhibitor (PDE4 inhibitor), a vasoconstrictor or any combinations thereof, in a concentration of from about 0.01% to about 1% w/w, from about 1% to about 3% w/w, from about 3% to about 5% w/w.

[0048] A topical composition for treatment, prevention or alleviation of a hair loss disorder in a subject in need thereof, comprising at least one EGFR inhibitor in a concentration of from about 0.01% to about 1% w/w, from about 1% to about 3% w/w, from about 3% to about 5% w/w or from about 5% to about 10% w/w; and further comprising at least one additional active agent; wherein the at least one additional active agent is a combination of at least one active agent selected from a first group and at least one active agent selected from a second group; wherein the first group comprises menadione, ketoconazole, dapsone, cevimeline, spironolactone, tretinoin, pimecrolimus, tetracycline, a sunscreen, doxycycline, epidermal growth factor (EGF), lycopene, threolone, synthomycine, erythromycin, Vitamin K3 or any combinations thereof, in a concentration of from about 0.01% to about 1% w/w, from about 1% to about 3% w/w or from about 3% to about 5% w/w; and wherein the second group comprises minoxidil, finasteride, biotin, ketoconazole, a cyclin- dependent kinase (CDK4/6) inhibitor, a corticosteroid, calcipotriene, tapinarof, a Janus kinase inhibitor (JAK inhibitor), a phosphodiesterase-4 inhibitor (PDE4 inhibitor), a vasoconstrictor or any combinations thereof, in a concentration of from about 0.01% to about 1% w/w, from about 1% to about 3% w/w, or from about 3% to about 5% w/w.

[0049] Said at least one EGFR inhibitor and said at least one additional active agent in all the above compositions and methods exhibit an additive and/or synergistic effect. [0050] It is an object of the present disclosure to provide a method of treatment, prevention or alleviation of a hair loss disorder in a subject in need thereof, wherein the hair loss disorder is the result of chemotherapy or irradiation. [0051 ] The said hair loss disorder in the methods of this disclosure is selected from alopecia selected from alopecia areata totalis, alopecia areata universalis and androgenetic alopecia, telogen effluvium, tinea capitis, hypotrichosis and hereditary hypotrichosis simplex.

[0052] It is an object of the present disclosure to provide a method of treatment, prevention or alleviation of a hair loss disorder in a subject in need thereof comprising once or twice daily topical application of a therapeutically effective amount of said composition of this disclosure to the scalp or skin portion of the subject affected by the said hair loss until the hair loss disorder is cured, prevented or alleviated or according to doctor’ s instructions.

[0053] In some embodiments, said EGFR inhibitor in the methods and compositions of this disclosure is erlotinib.

[0054] It is an object of the present disclosure to provide said method or composition, wherein said carrier suitable for topical administration comprises from about 10% w/w to about 99% w/w of at least one penetration enhancer and/or solvent. The at least one penetration enhancer and/or solvent is selected from DMSO (dimethylsulfoxide), MSM (methylsulfonylmethane), ethanol, isopropyl alcohol, dimethyl isosorbide, isopropyl myristate, oleic acid, a polyethylene glycol, hexylene glycol, glycofurol and combinations thereof.

Topical/oral combination methods of treatment

[0055] In addition to the methods of treatment, prevention or alleviation of a hair loss disorder in a subject in need thereof, by topical administration to a subject in need thereof of a therapeutically effective amount of one of the above compositions, the instant disclosure also provides combination treatment comprising topical administration to a subject in need thereof of a therapeutically effective amount of one of the above compositions, accompanied by oral (systemic) administration of a therapeutically effective amount of at least one additional active agent.

[0056] In addition to the methods of treatment, prevention or alleviation of a hair loss disorder in a subject in need thereof, by topical administration to a subject in need thereof of a therapeutically effective amount of at least one EGFR inhibitor in a concentration of from about 0.01 % to about 1 % w/w, from about 1% to about 3% w/w, from about 3% to about 5% w/w or from about 5% to about 10% w/w, accompanied by oral (systemic) administration of a therapeutically effective amount of at least one additional active agent. [0057] It is an object of the present disclosure to provide a topical/oral combination method of treatment, prevention or alleviation of a hair loss disorder in a subject in need thereof, wherein the orally administered at least one additional active agent is selected from minoxidil, a Janus kinase inhibitor (JAK inhibitor), a phosphodiesterase-4 inhibitor (PDE4 inhibitor), a vasoconstrictor, a cyclin-dependent kinase (CDK4/6) inhibitor and combinations thereof.

[0058] It is another object of the present disclosure to provide a topical/oral combination method of treatment, prevention or alleviation of a hair loss disorder in a male subject in need thereof, wherein the orally administered at least one additional active agent is a therapeutically effective amount of finasteride. Topical/hypothermic combination methods of treatment

[0059] It is yet another object of the present disclosure to provide in addition to the methods of treatment, prevention or alleviation of a hair loss disorder in a subject in need thereof, by topical administration to a subject in need thereof of a therapeutically effective amount of one of the above compositions or topical/oral method of treatment, the instant disclosure also provides a combination treatment comprising topical administration to a subject in need thereof of a therapeutically effective amount of one of the above compositions, accompanied by scalp cooling (hypothermia) of a subject in need thereof during therapy.

Embodiments

[0060] In some embodiments, there is provided a topical composition for treatment, prevention or alleviation of a hair loss disorder in a subject in need thereof, comprising at least one EGFR inhibitor in a concentration of from about 0.01% to about 1% w/w, from about 1% to about 3% w/w, from about 3% to about 5% w/w or from about 5% to about 10% w/w; and optionally from about 0.01% to about 1% w/w, from about 1% to about 3% w/w or from about 3% to about 5% w/w at least one additional active agent; and a carrier suitable for topical administration.

[0061] In some embodiments, there is provided a composition for treatment, prevention or alleviation of a hair loss disorder in a subject in need thereof, comprising at least one EGFR inhibitor in a concentration of from about 0.01% to about 1% w/w, from about 1% to about 3% w/w, from about 3% to about 5% w/w or from about 5% to about 10% w/w; optionally from about 0.01% to about 1% w/w, from about 1% to about 3% w/w or from about 3% to about 5% w/w at least one additional active agent; and a carrier suitable for topical administration; wherein the at least one additional active agent is selected from a first group comprising a sunscreen, menadione, ketoconazole, dapsone, cevimeline, spironolactone, tretinoin, pimecrolimus, tetracycline, doxycycline, epidermal growth factor (EGF), lycopene, threolone, synthomycine, erythromycin, Vitamin K3 or any combinations thereof, in a concentration of from about 0.01% to about 1% w/w, from about 1% to about 3% w/w or from about 3% to about 5% w/w.

[0062] In some embodiments, there is provided a composition for treatment, prevention or alleviation of a hair loss disorder in a subject in need thereof, comprising at least one EGFR inhibitor in a concentration of from about 0.01% to about 1% w/w, from about 1% to about 3% w/w, from about 3% to about 5% w/w or from about 5% to about 10% w/w; optionally from about 0.01% to about 1% w/w, from about 1% to about 3% w/w or from about 3% to about 5% w/w at least one additional active agent; and a carrier suitable for topical administration; wherein the at least one additional active agent is selected from a second group comprising minoxidil, finasteride, biotin, ketoconazole, a cyclin-dependent kinase (CDK4/6) inhibitor, a corticosteroid, calcipotriene, tapinarof, a Janus kinase inhibitor (JAK inhibitor), a phosphodiesterase-4 inhibitor (PDE4 inhibitor), a vasoconstrictor or any combinations thereof, in a concentration of from about 0.01% to about 1% w/w, from about 1% to about 3% w/w, or from about 3% to about 5% w/w.

[0063] In some embodiments, there is provided a composition for treatment, prevention or alleviation of a hair loss disorder in a subject in need thereof, comprising at least one EGFR inhibitor in a concentration of from about 0.01% to about 1% w/w, from about 1% to about 3% w/w, from about 3% to about 5% w/w or from about 5% to about 10% w/w; optionally from about 0.01% to about 1% w/w, from about 1% to about 3% w/w or from about

3% to about 5% w/w at least one additional active agent; and a carrier suitable for topical administration; wherein the at least one additional active agent is a combination of at least one active agent selected from a first group and at least one active agent selected from a second group; wherein the first group comprises menadione, ketoconazole, dapsone, cevimeline, spironolactone, tretinoin, pimecrolimus, tetracycline, a sunscreen, doxycycline, epidermal growth factor (EGF), lycopene, threolone, synthomycine, erythromycin, Vitamin K3 or any combinations thereof, in a concentration of from about 0.01% to about 1% w/w, from about 1% to about 3% w/w or from about 3% to about 5% w/w; and wherein the second group comprising minoxidil, finasteride, biotin, ketoconazole, a cyclin-dependent kinase (CDK4/6) inhibitor, a corticosteroid, calcipotriene, tapinarof, a Janus kinase inhibitor (JAK inhibitor), a phosphodiesterase-4 inhibitor (PDE4 inhibitor), a vasoconstrictor or any combinations thereof, in a concentration of from about 0.01% to about 1% w/w, from about 1% to about 3% w/w, or from about 3% to about 5% w/w.

[0064] In some embodiments, there is provided a composition comprising at least one EGFR inhibitor in a concentration of from about 0.01% to about 1% w/w, from about 1% to about 3% w/w, from about 3% to about 5% w/w or from about 5% to about 10% w/w; optionally from about 0.01% to about 1% w/w, from about 1% to about 3% w/w or from about 3% to about 5% w/w at least one additional active agent; and a carrier suitable for topical administration; wherein the at least one additional active agent is selected from a first group, a second group or from combination thereof; wherein the first group comprises menadione, ketoconazole, dapsone, cevimeline, spironolactone, tretinoin, pimecrolimus, tetracycline, a sunscreen, doxycycline, epidermal growth factor (EGF), lycopene, threolone, synthomycine, erythromycin, Vitamin K3 or any combinations thereof, in a concentration of from about 0.01% to about 1% w/w, from about 1% to about 3% w/w or from about 3% to about 5% w/w; wherein the second group comprises minoxidil, finasteride, biotin, ketoconazole, a cyclin-dependent kinase (CDK4/6) inhibitor, a corticosteroid, calcipotriene, tapinarof, a Janus kinase inhibitor (JAK inhibitor), a phosphodiesterase-4 inhibitor (PDE4 inhibitor), a vasoconstrictor or any combinations thereof, in a concentration of from about 0.01% to about 1% w/w, from about 1% to about 3% w/w, from about 3% to about 5% w/w; and wherein the composition further comprises at least one ingredient selected from a moisturizer, a skin barrier, urea, ammonium lactate and any combinations thereof, in a concentration of from about 0.01 % to about 1% w/w, from about 1% to about 3% w/w, or from about 3% to about 5% w/w.

[0065] In some embodiments, there is provided any of the above compositions, wherein the at least one EGFR inhibitor is selected from erlotinib, gefitinib, lapatinib, cetuximab, panitumumab, vandetanib, necitumumab, osimertinib and combinations thereof. [0066] In some embodiments, there is provided any of the above compositions, wherein said composition is a cream, an ointment, a gel, a lotion, a spray, a shampoo, a patch or a foam.

[0067] In some embodiments, there is provided a method of treatment, prevention or alleviation of a hair loss disorder, by topical administration to a subject in need thereof of a therapeutically effective amount of a composition comprising at least one EGFR inhibitor in a concentration of from about 0.01% to about 1% w/w, from about 1% to about 3% w/w, from about 3% to about 5% w/w or from about 5% to about 10% w/w; optionally from about 0.01% to about 1% w/w, from about 1% to about 3% w/w or from about 3% to about 5% w/w at least one additional active agent; and a carrier suitable for topical administration; wherein the at least one additional active agent is selected from a first group, a second group or from combination thereof; wherein the first group comprises menadione, ketoconazole, dapsone, cevimeline, spironolactone, tretinoin, pimecrolimus, tetracycline, a sunscreen, doxycycline, epidermal growth factor (EGF), lycopene, threolone, synthomycine, erythromycin, Vitamin K3 or any combinations thereof, in a concentration of from about 0.01% to about 1% w/w, from about 1% to about 3% w/w or from about 3% to about 5% w/w; wherein the second group comprises minoxidil, finasteride, biotin, ketoconazole, a cyclin-dependent kinase (CDK4/6) inhibitor, a corticosteroid, calcipotriene, tapinarof, a Janus kinase inhibitor (JAK inhibitor), a phosphodiesterase-4 inhibitor (PDE4 inhibitor), a vasoconstrictor or any combinations thereof, in a concentration of from about 0.01% to about 1% w/w, from about 1% to about 3% w/w, or from about 3% to about 5% w/w.

[0068] In some embodiments, there is provided a method of treatment, prevention or alleviation of a hair loss disorder in a subject in need thereof, by topical administration to a subject in need thereof of a therapeutically effective amount of a composition comprising at least one EGFR inhibitor in a concentration of from about 0.01% to about 1% w/w, from about 1% to about 3% w/w, from about 3% to about 5% w/w or from about 5% to about 10% w/w; optionally, from about 0.01% to about 1%, from about 1% to about 3% or from about 3% to about 5% w/w at least one additional active agent; and a carrier suitable for topical administration.

[0069] In some embodiments, there is provided a method of treatment, prevention or alleviation of a hair loss disorder in a subject in need thereof, by topical administration to a subject in need thereof of a therapeutically effective amount of a composition comprising at least one EGFR inhibitor in a concentration of from about 0.01% to about 1% w/w, from about 1% to about 3% w/w, from about 3% to about 5% w/w or from about 5% to about 10% w/w; optionally from about 0.01% to about 1% w/w, from about 1% to about 3% w/w or from about 3% to about 5% w/w at least one additional active agent; and a carrier suitable for topical administration; wherein the at least one additional active agent is selected from: a first group comprising menadione, ketoconazole, dapsone, cevimeline, spironolactone, tretinoin, pimecrolimus, tetracycline, a sunscreen, doxycycline, epidermal growth factor (EGF), lycopene, threolone, synthomycine, erythromycin, Vitamin K3 or any combinations thereof, in a concentration of from about 0.01% to about 1% w/w, from about 1% to about 3% w/w or from about 3% to about 5% w/w.

[0070] In some embodiments, there is provided a method of treatment, prevention or alleviation of a hair loss disorder in a subject in need thereof, by topical administration to a subject in need thereof of a therapeutically effective amount of a composition comprising at least one EGFR inhibitor in a concentration of from about 0.01% to about 1% w/w, from about 1% to about 3% w/w, from about 3% to about 5% w/w or from about 5% to about 10% w/w; optionally from about 0.01% to about 1% w/w, from about 1% to about 3% w/w or from about 3% to about 5% w/w at least one additional active agent; and a carrier suitable for topical administration; wherein the at least one additional active agent is selected from a second group comprising minoxidil, finasteride, biotin, ketoconazole, a cyclin-dependent kinase (CDK4/6) inhibitor, a corticosteroid, calcipotriene, tapinarof, a Janus kinase inhibitor (JAK inhibitor), a phosphodiesterase- 4 inhibitor (PDE4 inhibitor), a vasoconstrictor or any combinations thereof, in a concentration of from about 0.01% to about 1% w/w, from about 1% to about 3% w/w, or from about 3% to about 5% w/w.

[0071 ] In some embodiments, there is provided a method of treatment, prevention or alleviation of a hair loss disorder in a subject in need thereof, by topical administration to a subject in need thereof of a therapeutically effective amount of a composition comprising at least one EGFR inhibitor in a concentration of from about 0.01% to about 1% w/w, from about 1% to about 3% w/w, from about 3% to about 5% w/w or from about 5% to about 10% w/w; optionally from about 0.01% to about 1%, from about 1% to about 3% or from about 3% to about 5% w/w at least one additional active agent; and a carrier suitable for topical administration; wherein the at least one additional active agent is a combination of at least one active agent selected from a first group and at least one active agent selected from a second group; wherein the first group comprises menadione, ketoconazole, dapsone, cevimeline, spironolactone, tretinoin, pimecrolimus, tetracycline, a sunscreen, doxycycline, epidermal growth factor (EGF), lycopene, threolone, synthomycine, erythromycin, Vitamin K3 or any combinations thereof, in a concentration of from about 0.01% to about 1% w/w, from about 1% to about 3% w/w or from about 3% to about 5% w/w; and wherein the second group comprises minoxidil, finasteride, biotin, ketoconazole, a cyclin-dependent kinase (CDK4/6) inhibitor, a corticosteroid, calcipotriene, tapinarof, a Janus kinase inhibitor (JAK inhibitor), a phosphodiesterase-4 inhibitor (PDE4 inhibitor), a vasoconstrictor or any combinations thereof, in a concentration of from about 0.01% to about 1% w/w, from about 1% to about 3% w/w, or from about 3% to about 5% w/w.

[0072] In some embodiments, there is provided a method of treatment, prevention or alleviation of a hair loss disorder in a subject in need thereof, by topical administration to a subject in need thereof a therapeutically effective amount of the composition comprising at least one EGFR inhibitor in a concentration of from about 0.01% to about 1% w/w, from about 1% to about 3% w/w, from about 3% to about 5% w/w or from about 5% to about 10% w/w; optionally from about 0.01% to about 1% w/w, from about 1% to about 3% w/w or from about 3% to about 5% w/w at least one additional active agent; and a carrier suitable for topical administration; wherein the at least one additional active agent is selected from a first group, a second group or from combination thereof; wherein the first group comprises menadione, ketoconazole, dapsone, cevimeline, spironolactone, tretinoin, pimecrolimus, tetracycline, a sunscreen, doxycycline, epidermal growth factor (EGF), lycopene, threolone, synthomycine, erythromycin, Vitamin K3 or any combinations thereof, in a concentration of from about 0.01% to about 1% w/w, from about 1% to about 3% w/w or from about 3% to about 5% w/w; and wherein the second group comprising minoxidil, finasteride, biotin, ketoconazole, a cyclin-dependent kinase (CDK4/6) inhibitor, a corticosteroid, calcipotriene, tapinarof, a Janus kinase inhibitor (JAK inhibitor), a phosphodiesterase-4 inhibitor (PDE4 inhibitor), a vasoconstrictor or combinations thereof, in a concentration of from about 0.01% to about 1% w/w, from about 1% to about 3% w/w, from about 3% to about 5% w/w or any combinations thereof; wherein said at least one EGFR inhibitor and said at least one additional active agent exhibit an additive or synergistic effect.

[0073] In some embodiments, there is provided a method of treatment, prevention or alleviation of a hair loss disorder in a subject in need thereof, by topical administration to a subject in need thereof a therapeutically effective amount of a composition comprising at least one EGFR inhibitor in a concentration of from about 0.01% to about 1% w/w, from about 1% to about 3% w/w, from about 3% to about 5% w/w or from about 5% to about 10% w/w; optionally from about 0.01% to about 1% w/w, from about 1% to about 3% w/w or from about 3% to about 5% w/w at least one additional active agent; and a carrier suitable for topical administration; wherein the at least one additional active agent is selected from a first group, a second group or from combination thereof; wherein the first group comprising menadione, ketoconazole, dapsone, cevimeline, spironolactone, tretinoin, pimecrolimus, tetracycline, a sunscreen, doxycycline, epidermal growth factor (EGF), lycopene, threolone, synthomycine, erythromycin, Vitamin K3 or any combinations thereof, in a concentration of from about 0.01% to about 1% w/w, from about 1% to about 3% w/w or from about 3% to about 5% w/w; wherein the second group comprising minoxidil, finasteride, biotin, ketoconazole, a cyclin-dependent kinase (CDK4/6) inhibitor, a corticosteroid, calcipotriene, tapinarof, a Janus kinase inhibitor (JAK inhibitor), a phosphodiesterase-4 inhibitor (PDE4 inhibitor), a vasoconstrictor or any combinations thereof, in a concentration of from about 0.01% to about 1% w/w, from about 1% to about 3% w/w, from about 3% to about 5% w/w; wherein the hair loss disorder is the result of chemotherapy or irradiation.

[0074] In some embodiments, there is provided a method of treatment, prevention or alleviation of a hair loss disorder in a subject in need thereof, by topical administration to a subject in need thereof of a therapeutically effective amount of a composition comprising at least one EGFR inhibitor in a concentration of from about 0.01% to about 1% w/w, from about 1% to about 3% w/w, from about 3% to about 5% w/w or from about 5% to about 10% w/w; optionally from about 0.01% to about 1% w/w, from about 1% to about 3% w/w or from about 3% to about 5% w/w at least one additional active agent; and a carrier suitable for topical administration; wherein the at least one additional active agent is selected from a first group, a second group or from combination thereof; wherein the first group comprises menadione, ketoconazole, dapsone, cevimeline, spironolactone, tretinoin, pimecrolimus, tetracycline, a sunscreen, doxycycline, epidermal growth factor (EGF), lycopene, threolone, synthomycine, erythromycin, Vitamin K3 or any combinations thereof, in a concentration of from about 0.01% to about 1% w/w, from about 1% to about 3% w/w or from about 3% to about 5% w/w; wherein the second group comprises minoxidil, finasteride, biotin, ketoconazole, a cyclin-dependent kinase (CDK4/6) inhibitor, a corticosteroid, calcipotriene, tapinarof, a Janus kinase inhibitor (JAK inhibitor), a phosphodiesterase-4 inhibitor (PDE4 inhibitor), a vasoconstrictor or any combinations thereof, in a concentration of from about 0.01% to about 1% w/w, from about 1% to about 3% w/w, or from about 3% to about 5% w/w; and wherein the hair loss disorder is selected from alopecia selected from alopecia areata totalis, alopecia areata universalis and androgenetic alopecia, telogen effluvium, tinea capitis, hypotrichosis and hereditary hypotrichosis simplex.

[0075] In some embodiments, there is provided a method of treatment, prevention or alleviation of a hair loss disorder in a subject in need thereof, by topical administration to a subject in need thereof a therapeutically effective amount of a composition comprising at least one EGFR inhibitor in a concentration of from about 0.01% to about 1% w/w, from about 1% to about 3% w/w, from about 3% to about 5% w/w or from about 5% to about 10% w/w; optionally from about 0.01% to about 1% w/w, from about 1% to about 3% w/w or from about 3% to about 5% w/w at least one additional active agent; and a carrier suitable for topical administration; wherein the at least one additional active agent is selected from a first group, a second group or from combination thereof; wherein the first group comprises menadione, ketoconazole, dapsone, cevimeline, spironolactone, tretinoin, pimecrolimus, tetracycline, a sunscreen, doxycycline, epidermal growth factor (EGF), lycopene, threolone, synthomycine, erythromycin, Vitamin K3 or any combinations thereof, in a concentration of from about 0.01% to about 1% w/w, from about 1% to about 3% w/w or from about 3% to about 5% w/w; wherein the second group comprises minoxidil, finasteride, biotin, ketoconazole, a cyclin-dependent kinase (CDK4/6) inhibitor, a corticosteroid, calcipotriene, tapinarof, a Janus kinase inhibitor (JAK inhibitor), a phosphodiesterase-4 inhibitor (PDE4 inhibitor), a vasoconstrictor or any combinations thereof, in a concentration of from about 0.01% to about 1% w/w, from about 1% to about 3% w/w, or from about 3% to about 5% w/w; and wherein said method comprises once or twice daily topical application of a therapeutically effective amounts of the said composition to the scalp or body portion of the subject affected by the said hair loss until the hair loss disorder is cured, prevented or alleviated or according to doctor’s instructions.

[0076] In some embodiments, there is provided any of the preceding methods or compositions, wherein the EGFR inhibitor is erlotinib.

[0077] In some embodiments, there is provided any of the preceding methods or compositions, wherein said carrier suitable for topical administration comprises from about 10% w/w to about 99% w/w at least one penetration enhancer and/or solvent. In other embodiments, the compositions comprises from about 10% w/w to about 50% w/w, from about 30% w/w to about 70% w/w, from about 20% w/w to about 99% or from about 50% w/w to about 99%.

[0078] In some embodiments, there is provided any of the preceding methods or compositions, wherein said carrier suitable for topical administration comprises from about 10% w/w to about 99% w/w at least one penetration enhancer and/or solvent selected from DMSO (dimethylsulfoxide), MSM (methylsulfonylmethane), ethanol, isopropyl alcohol, dimethyl isosorbide, isopropyl myristate, oleic acid, a polyethylene glycol, hexylene glycol, glycofurol and combinations thereof.

[0079] In some embodiments, there is provided a combination method of treatment, prevention or alleviation of a hair loss disorder in a subject in need thereof, comprising topical administration to a subject in need thereof of a therapeutically effective amount of one of the above compositions, further comprising the oral administration to said subject a therapeutically effective amount of an active agent selected from minoxidil, a Janus kinase inhibitor (JAK inhibitor), a phosphodiesterase-4 inhibitor (PDE4 inhibitor), a vasoconstrictor, a cyclin-dependent kinase (CDK4/6) inhibitor and combinations thereof. [0080] In some embodiments, there is provided a combination method of treatment, prevention or alleviation of a hair loss disorder in a male subject in need thereof, comprising topical administration to a subject in need thereof of a therapeutically effective amount of one of the above compositions, further comprising the oral administration to said male subject a therapeutically effective amount of finasteride.

[0081 ] In some embodiments, there is provided a combination method of treatment, prevention or alleviation of a hair loss disorder in a subject in need thereof, comprising topical administration to said subject of a therapeutically effective amount of one of the above compositions, accompanied by scalp cooling (hypothermia) of said subject during therapy. [0082] In some embodiments, the composition for use and methods of this invention increase/promotes/improve regeneration of new hair follicles, shorten hair recovery period after chemotherapy induced alopecia, maintain all cell lineages of the follicle and/or maintain hair follicle from the early catagen phase.

[0083] In some embodiments, the composition for use and methods of this invention prevent apoptosis of keratinocytes stem cells (K15⁺), and thereby increase/promotes/improve regeneration of new hair follicles.

[0084] In some embodiments, the composition for use and methods of this invention shorten hair recovery period after chemotherapy induced alopecia.

[0085] In some embodiments, the composition for use and methods of this invention maintain all cell lineages of the follicle.

[0086] In some embodiments, the composition for use and methods of this invention maintains hair follicle from the early catagen phase.

Definitions [0087] As used herein, the terms “pharmaceutically active agent” or “active agent” or “active pharmaceutical ingredient” or “API” are interchangeable and mean the ingredient is a pharmaceutical drug which is biological active and is regulatory approved or approvable as such. [0088] Whenever a numerical range is indicated herein, it is meant to include any cited numeral (fractional or integral) within the indicated range. The phrases “ranging/ranges between” a first indicate number and a second indicate number and “ranging/ranges from” a first indicate number “to” a second indicate number are used herein interchangeably and are meant to include the first and second indicated numbers and all the fractional and integral numerals therebetween.

[0089] The dimensions and values disclosed herein are not to be understood as being strictly limited to the exact numerical values recited. Instead, unless otherwise specified, each such dimension is intended to mean both the recited value and a functionally equivalent range surrounding that value. For example, a dimension disclosed as “10 pm” is intended to mean “about 10 pm”. [0090] As used herein, numerical ranges preceded by the term “about” should not be considered to be limited to the recited range. Rather, numerical ranges preceded by the term “about” should be understood to include a range accepted by those skilled in the art for any given element in microcapsules or formulations according to the present disclosure.

[0091] The term “about” as used herein means within an acceptable error range for a particular value as determined by one of ordinary skill in the art, which will depend in part on how the value is measured or determined, i.e., the limitations of the measurement system. For example, “about” can mean a range of up to 10%, more preferably up to 5%, and still more preferably up to 1% of a given value. Where particular values are described in the application and claims, unless otherwise stated, the meaning of the term “about” is within an acceptable error range for the particular value. [0092] The terms "comprise", "comprising", "includes", "including", “having” and their conjugates mean "including but not limited to".

[0093] The term “consisting of’ means “including and limited to”.

[0094] The term "consisting essentially of" means that the composition, method or microcapsules may include additional ingredients, steps and/or parts, but only if the additional ingredients, steps and/or parts do not materially alter the basic and novel characteristics of the claimed composition, method or structure. [0095] As used herein, the singular form "a", "an" and "the" include plural references unless the context clearly dictates otherwise. For example, the term "a compound" or "at least one compound" may include a plurality of compounds, including mixtures thereof.

[0096] As used herein the term "method" refers to manners, means, techniques and procedures for accomplishing a given task including, but not limited to, those manners, means, techniques and procedures either known to, or readily developed from known manners, means, techniques and procedures by practitioners of the chemical, pharmacological, biological, biochemical and medical arts.

[0097] It is appreciated that certain features of the disclosure, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the disclosure, which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable sub-combination or as suitable in any other described embodiment of the disclosure.

[0098] Certain features described in the context of various embodiments are not to be considered essential features of those embodiments, unless the embodiment is inoperative without those elements.

EXAMPLES

Example 1

[0099] Preparation and Stability of a 0.75% Topical Erlotinib HC1 Gel Composition 0.75% erlotinib; 70% DMSO;

Composition:

Procedure:

• Erlotinib hydrochloride was dissolved in DMSO at 40 C

• Methylparaben was added under stirring

• Carbopol^® was added under stirring

• 2-phenoxyethanol was dissolved in propylene glycol and added

• The formulation was stirred and homogenized to obtain a homogeneous gel

Stability results

Example 2 [00100] Preparation and Stability of a 0.5% Topical Erlotinib HC1 Gel Composition

0.5% erlotinib; 70% DMSO;

Composition:

Procedure:

Erlotinib hydrochloride was dissolved in DMSO at 40 C Methylparaben was added under stirring Carbopol^® was added under stirring 2-phenoxyethanol was dissolved in propylene glycol and added

The formulation was stirred and homogenized to obtain a homogeneous gel Stability results

Example 3 [00101] Preparation and Stability of a 0. 5% Topical Erlotinib HC1 Gel Composition

0.5% erlotinib; 45.5% DMSO Composition:

Procedure:

Example 4 [00102] Preparation and Stability of a 0.5% Topical Erlotinib HC1 Gel Composition

0.5% erlotinib; 50% EtOH 70%

Composition:

Procedure:

Erlotinib hydrochloride was dissolved in EtOH at 40 C Methylparaben was added under stirring Carbopol^® was added under stirring 2-phenoxyethanol was dissolved in propylene glycol and added

Example 5 [00103] Preparation and Stability of a 1.25% Topical Erlotinib HC1 Gel Composition

1.25% erlotinib; 95% DMSO;

Composition:

Example 6

[00104] Preparation and Stability of a 1% Topical Erlotinib HC1 Gel Composition

1% erlotinib; 49% PEG-400; 30% PEG-3350 Composition:

Procedure:

Propylene glycol, PEG-400 and PEG-3350 were stirred at 70 C to obtain a homogeneous liquid Erlotinib hydrochloride was added under stirring 2-phenoxyethanol was dissolved in propylene glycol and added The formulation was cooled to room temperature

Example 7

[00105] Preparation and Stability of a 1% Erlotinib HC1 + 1% Tapinarof Topical Gel Composition (Prophetical)

Procedure:

Erlotinib hydrochloride is dissolved in DMSO at 40 C Tapinarof is added under stirring Methylparaben is added under stirring Carbopol^® is added under stirring

2-phenoxyethanol is dissolved in propylene glycol and added.

The formulation is stirred and homogenized to obtain a homogeneous gel

Example 8 [00106] Preparation of a 1% Erlotinib HC1 + 0.5% Tofacitinib Citrate Topical Gel

Composition (Prophetical)

Procedure:

Erlotinib hydrochloride is dissolved in DMSO at 40 C Tofacitinib citrate is added under stirring Methylparaben is added under stirring Carbopol^® is added under stirring

2-phenoxyethanol is dissolved in propylene glycol and added

The formulation is stirred and homogenized to obtain a homogeneous gel

Example 9 [00107] Preparation of a 1% Erlotinib HC1 + 0.5% Apremilast Topical Gel Composition

(Prophetical)

Procedure:

Erlotinib hydrochloride is dissolved in DMSO at 40 C Apremilast is added under stirring Methylparaben is added under stirring Carbopol^® is added under stirring

2-phenoxyethanol is dissolved in propylene glycol and added

The formulation is stirred and homogenized to obtain a homogeneous gel

Example 10 ex vivo hair follicle study

[00108] This study evaluates the activity of erlotinib to protect the hair follicle from the early catagen phase or the damage following chemotherapy treatment (paclitaxel).

[00109] Human microdissected full length Hair Follicles (HFs) from Follicular unit extractions (FUEs) of a 39 years old male donor (HF-MF-20-118), More than 60 anagen VI HFs were reserved at day 0. After quality control, at day 1, the experiment was conducted with 30 anagen (5 groups - 6 anagen HFs/group) VI HFs. The study was conducted in 2 concentrations of the erlotinib representing the low and high ranges of IC50.

[00110] The evaluation of catagen phase and apoptosis/proliferation of the keratinocytes in the hair matrix were contracted. The tests were also expended to the bulge and stem cells. The Study description:

[00111] At day 0: microdissection of 61 full length anagen HFs. Take pictures (50x).

At day 1: take pictures (50x, 200x).

[00112] Macroscopic selection of 30 anagen VI HFs for culture (6HFs/group). Cultivation of HFs that grow more than 5% in average. The medium was changed and the treatment of HFs corresponding to experimental groups (as described in the table below). [00113] At day 2: take pictures (50x, 200x). The medium was changed and the treatment of HFs corresponding to experimental groups (as described in the table below).

[00114] At day 3: take pictures (50x, 200x). Treatment of HFs with 0.5mM erlotinib hydrochloride (EH) and embed the HFs for the protein analysis.

Results

[00115] As shown in Fig 1., the treatment with paclitaxel (chemotherapy) tendentially increases hair matrix keratinocytes apoptosis, which seems to be prevented by erlotinib administration. [00116] As shown in Fig 2., the percentage of K15/ histone protein from the H2A family (gH2A.C)⁺ cells in the bulge basal layer after treatment with of paclitaxel and erlotinib hydrochloride (EH) is lower in comparison to the administration of paclitaxel alone.

[00117] Paclitaxel significantly induces positive cells amongst K15⁺ cells in the bulge which is tendentially which is prevented by erlotinib. gH2A.C - histone protein from the H2A family. Detection of this histone is a marker of double strand breaks - chromatin damage;

[00118] K15+ cells - marker for stem cells, which are pluripotent cells that can become keratinocytes; [00119] Bulge - where most of the hair follicle stem cells are reside.

[00120] From the results shown in Fig.2 it is concluded that inhibition of EGFR prevents stem cells apoptosis which can become and reside in the hair follicles as keratinocytes to regenerate new hair.

[00121] As shown in Fig. 3 erlotinib alone tendentially increases K15 expression (stem cells marker) in hair matrix keratinocytes and significantly prevents from K15 decrease induced by Paclitaxel. From the results shown in Fig.2 it is concluded that EGFR inhibitor works not only on an organ target - (e.g. hair follicle bulge), but also on specific cells (even in a different organ - e.g. hair follicle bulb) which strengthen the mechanism of action of the erlotinib.

[00122] As shown in Fig 4. high dose erlotinib seems to significantly increases the percentage of K15 positive cells in the bulge basal layer when combined with paclitaxel.

[00123] As shown in Fig 5. erlotinib significantly protects the hair follicle from apoptosis of K15⁺ cells in the bulge basal layer induced by Paclitaxel treatment, while erlotinib alone does not display any effect.

[00124] The results of this experiment show that Erlotinib tendentially prevents paclitaxel -induced keratinocytes apoptosis. Erlotinib does not display a negative effect on hair follicles. Erlotinib and paclitaxel do not impact on keratinocytes proliferation. Beneficial role of erlotinib in preventing paclitaxel-induced hair follicle stem cells apoptosis. Anti-apoptotic effect of erlotinib does not result in hair follicle protection from paclitaxel-induced premature catagen

[00125] In summary: while erlotinib does not protect premature catagen development, it prevents apoptosis of keratinocytes stem cells (kl5⁺) which are able to regenerate new hair follicles and maintain all cell lineages of the follicle. The EGFR antagonist increased hair regeneration or shorten hair recovery period after chemotherapy induced alopecia

Claims

CLAIMS What is claimed is:

1. A topical composition for treatment, prevention or alleviation of a hair loss disorder in a subject in need thereof, comprising at least one EGFR inhibitor in a concentration of from about 0.01% to about 1% w/w, from about 1% to about 3% w/w, from about 3% to about 5% w/w or from about 5% to about 10% w/w; optionally from about 0.01% to about 1%, from about 1% to about 3% or from about 3% to about 5% w/w at least one additional active agent; and a carrier suitable for topical administration.

2. The composition of claim 1, wherein the at least one additional active agent is selected from a first group comprising menadione, ketoconazole, dapsone, cevimeline, spironolactone, tretinoin, pimecrolimus, tetracycline, a sunscreen, doxycycline, epidermal growth factor (EGF), lycopene, threolone, synthomycine, erythromycin, Vitamin K3 or any combinations thereof, in a concentration of from about 0.01% to about 1% w/w, from about 1% to about 3% w/w or from about 3% to about 5% w/w.

3. The composition of claim 1, wherein the at least one additional active agent is selected from a second group comprising minoxidil, finasteride, biotin, ketoconazole, a cyclin-dependent kinase (CDK4/6) inhibitor, a corticosteroid, calcipotriene, tapinarof a Janus kinase inhibitor (JAK inhibitor), a phosphodiesterase-4 inhibitor (PDE4 inhibitor), a vasoconstrictor or any combinations thereof, in a concentration of from about 0.01% to about

1% w/w, from about 1% to about 3% w/w, or from about 3% to about 5% w/w.

4. The composition of claim 1, wherein the at least one additional active agent is a combination of at least one active agent selected from a first group and at least one active agent selected from a second group; wherein the first group comprises menadione, ketoconazole, dapsone, cevimeline, spironolactone, tretinoin, pimecrolimus, tetracycline, a sunscreen, doxycycline, epidermal growth factor (EGF), lycopene, threolone, synthomycine, erythromycin, Vitamin K3 or any combinations thereof, in a concentration of from about 0.01% to about 1% w/w, from about 1% to about 3% w/w or from about 3% to about 5% w/w; and wherein the second group comprises minoxidil, finasteride, biotin, ketoconazole, a cyclin-dependent kinase (CDK4/6) inhibitor, a corticosteroid, calcipotriene, tapinarof, a Janus kinase inhibitor (JAK inhibitor), a phosphodiesterase -4 inhibitor (PDE4 inhibitor), a vasoconstrictor or any combinations thereof, in a concentration of from about 0.01 % to about 1% w/w, from about 1% to about 3% w/w or from about 3% to about 5% w/w.

5. The composition of any one of claims 1-4, further comprising at least one ingredient selected from a moisturizer, a skin barrier, urea, ammonium lactate and combinations thereof, in a concentration of from about 0.01% to about 1% w/w, from about 1% to about 3% w/w or from about 3% to about 5% w/w.

6. The composition of any one of claims 1-5, wherein the at least one EGFR inhibitor is selected from erlotinib, gefitinib, lapatinib, cetuximab, panitumumab, vandetanib, necitumumab, osimertinib and combinations thereof.

7. The composition of any one of claims 1-6, wherein said composition is a cream, an ointment, a gel, a lotion, a spray, a shampoo, a patch or a foam.

8. A method of treatment, prevention or alleviation of a hair loss disorder in a subject in need thereof, by topical administration to a subject in need thereof of a therapeutically effective amount of the composition of any one of claims 1-7.

9. A method of treatment, prevention or alleviation of a hair loss disorder in a subject in need thereof, by topical administration to a subject in need thereof of a therapeutically effective amount of the composition of claim 1.

10. A method of treatment, prevention or alleviation of a hair loss disorder in a subject in need thereof, by topical administration to a subject in need thereof of a therapeutically effective amount of the composition of claim 2.

11. A method of treatment, prevention or alleviation of a hair loss disorder in a subject in need thereof, by topical administration to a subject in need thereof of a therapeutically effective amount of the composition of claim 3.

12. A method of treatment, prevention or alleviation of a hair loss disorder in a subject in need thereof, by topical administration to a subject in need thereof of a therapeutically effective amount of the composition of claim 4.

13. A method of treatment, prevention or alleviation of a hair loss disorder in a subject in need thereof, by topical administration to a subject in need thereof a therapeutically effective amount of the composition of any one of claims 1-7, wherein said at least one EGFR inhibitor and said at least one additional active agent exhibit an additive or synergistic effect.

14. The method of any one of claims 8-13, wherein the hair loss disorder is the result of chemotherapy or irradiation.

15. The method of any one of claims 8-14, wherein the hair loss disorder is selected from alopecia selected from alopecia areata totalis, alopecia areata universalis and androgenetic alopecia, telogen effluvium, tinea capitis, hypotrichosis and hereditary hypotrichosis simplex.

16. The method of any one of claims 8-15, wherein said method comprises once or twice daily topical application of a therapeutically effective amount of said composition to the scalp or skin portion of the subject affected by the said hair loss until the hair loss disorder is cured, prevented or alleviated or according to doctor’s instructions.

17. The method or composition of any one of the preceding claims, wherein the EGFR inhibitor is erlotinib.

18. The method or composition of any one of the preceding claims, wherein said carrier suitable for topical administration comprises from about 10% w/w to about 99% w/w at least one penetration enhancer and/or solvent.

19. The method or composition of any one of the preceding claims, wherein said carrier suitable for topical administration comprises from about 10% w/w to about 99% w/w at least one penetration enhancer and/or solvent selected from DMSO (dimethylsulfoxide), MSM (methylsulfonylmethane), ethanol, isopropyl alcohol, dimethyl isosorbide, isopropyl myristate, oleic acid, a polyethylene glycol, hexylene glycol, glycofurol and combinations thereof.

20. The method of any one of claims 8-19, further comprising the oral administration to a subject in need thereof a therapeutically effective amount of an active agent selected from minoxidil, a Janus kinase inhibitor (JAK inhibitor), a phosphodiesterase-4 inhibitor (PDE4 inhibitor), a vasoconstrictor, a cyclin-dependent kinase (CDK4/6) inhibitor and combinations thereof.

21. The method of any one of claims 8-20, further comprising the oral administration to a male subject in need thereof a therapeutically effective amount of finasteride.

22. The method of any one of claims 8-21, further comprising scalp cooling of said subject in need thereof during therapy.

23. The method of any one of claims 9-22, wherein the method prevents apoptosis of keratinocytes stem cells (kl5⁺), and thereby increase/promotes/improves regeneration of new hair follicles.

24. The method of any one of claims 9-22, wherein the method shortens hair recovery period after chemotherapy induced alopecia.

25. The method of any one of claims 9-22, wherein the method maintains hair follicle from the early catagen phase.