WO2024124206A1

WO2024124206A1 - Topical compositions for treating and preventing hair loss and hair graying

Info

Publication number: WO2024124206A1
Application number: PCT/US2023/083234
Authority: WO
Inventors: Ralf Paus
Original assignee: Hairdao Payments Llc; Cutaneon - Skin & Hair Innovations Gmbh
Priority date: 2022-12-08
Filing date: 2023-12-08
Publication date: 2024-06-13

Abstract

The present disclosure relates in some aspects to pharmaceutical compositions, such as topical compositions, useful for treating or preventing hair loss and/or hair graying in a subject. In some aspects, also provided are kits comprising the compositions, and methods of using the compositions for treating a condition, such as hair loss or hair graying.

Description

TOPICAL COMPOSITIONS FOR TREATING AND PREVENTING HAIR LOSS AND HAIR GRAYING

INVENTOR: Ralf Paus

CROSS-REFERENCE

[01] Priority is claimed under PCT Article 8(1) and Rule 4.10 to U.S. Provisional App. No. 63/431,126, filed December 8, 2022, and U.S. Provisional App. No. 63/530,854, filed August 4, 2023, both of which are incorporated by reference for all purposes as if fully set forth herein.

FIELD OF THE INVENTION

[02] The present disclosure relates in some aspects to pharmaceutical compositions, such as topical compositions, useful for treating or preventing hair loss and/or hair graying in a subject. In some aspects, also provided are kits comprising the compositions, and methods of using the compositions for treating a condition, such as hair loss or hair graying.

BACKGROUND OF THE INVENTION

[03] Pattern hair loss, also known as androgenetic alopecia, is a hair loss condition that affects up to 50% of men and 25% of women by the age of 50 (Vary JC, Med Clin North Am. 2015;99(6):1195— 1211). The cause of pattern hair loss remains unclear, and may be related to oxidative stress, the scalp microbiome, and/or hormonal abnormalities. There is a lack of available treatments for pattern hair loss, particularly those that are effective and do not cause undesirable side effects. Therefore, the continued prevalence of pattern hair loss leaves an unmet need to alleviate and treat this condition.

INCORPORATION BY REFERENCE

[04] Each cited patent, publication, and non-patent literature is incorporated by reference in its entirety, as if each was incorporated individually, and as if each Is fully set forth herein. However, no such citation should be construed as an admission that a cited reference comes from an area that is analogous or directly applicable to the invention, nor should a citation be construed as an admission that a document or underlying information, in any jurisdiction, is prior art or forms part of the common general knowledge in the art.

BRIEF SUMMARY OF THE INVENTION

[05] The following is a simplified summary of some embodiments of the invention in order to provide a basic understanding thereof. This summary is not an extensive overview of the invention. It is not intended to identify key or critical elements of the invention or to delineate the scope of the invention. Its sole purpose is to present some embodiments and aspects of the invention in a simplified form as a prelude to the more detailed description that follows.

[06] In a first aspect, provided is a topical composition, useful for treating or preventing hair loss comprising: (I) triiodothyronine (T3); (II) a pharmaceutically acceptable excipient; and (ill) a solvent system. [07] In some embodiments, th© topical composition comprises between about 1 nM and 30 nM of T3. In some embodiments, the topical composition comprises about 10 nM of T3.

[08] to some embodiments, the pharmaceutically acceptable excipient is a penetration enhancer, carrier, diluent, emulsifier, stabilizer, viscosity modifying agent, adhesion modifying agent, preservative, antioxidant, adhesive polymer, solubilizing agent, colorant, binder, humectant, surfactant, or gelling agent, to some embodiments, the pharmaceutically acceptable excipient is a hydroxyalkyl cellulose, In some embodiments, the pharmaceutically acceptable excipient is hydroxypropylcellulose.

[09] In some embodiments, the topical composition comprises between about 1% and 10% (w/v) of hydroxypropylceiiulose. In some embodiments, the topical composition comprises about 5% (w/v) of hydroxypropyl cellulose.

[10] to some embodiments, the solvent system comprises an alcohol, to some embodiments, the solvent system comprises ethanol or propylene glycol. In some embodiments, the solvent system comprises between about 10% and 70% (v/v) of ethanol. In some embodiments, the solvent system comprises about 60% (v/v) of ethanol. In some embodiments, the solvent system comprises about 30% (v/v) of ethanol, to some embodiments, the solvent system comprises between about 10% and 90% (v/v) of propylene glycol, to some embodiments, the solvent system comprises about 20% (v/v) of propylene glycol, to some embodiments, the solvent system comprises about 50% (v/v) of propylene glycol, in some embodiments, the solvent system comprises water. In some embodiments, the solvent system comprises between about 1% and 30% (v/v) of water. In some embodiments, the solvent system comprises about 10% (v/v) of water.

[11] Also provided is a topical composition, useful for treating or preventing hair loss comprising: (i) triiodothyronine (T3); (ii) hydroxypropylcellulose; and (ill) a solvent system,

[12] Also provided is a topical composition, useful for treating or preventing hair loss comprising: (i) triiodothyronine (T3); (II) hydroxypropylceiiulose; (ill) ethanol; (Iv) propylene glycol; and (v) water.

[13] Also provided is a topical composition, useful for treating or preventing hair loss comprising: (I) about 10 nM of triiodothyronine (T3); (ii) about 5% (w/v) of hydroxypropylceiiulose; (iii) about 60% (v/v) of ethanol; (iv) about 20% (v/v) of propylene glycol; and (v) about 10% (v/v) of water,

[14] to some embodiments, the topical composition further comprises an additional active agent. In some embodiments, the additional active agent is an amino acid, antioxidant, anti-inflammatory agent, analgesic, 5-alpha reductase inhibitor, cannabinoid, immunosuppressant, immunostimulant, anti-cancer agent, antiulcer agent, antihistamine, terpene, vitamin, vasodilator, or vasoconstrictor. In some embodiments, the additional active agent is rapamycin, finasteride, dutasteride, or minoxidil, in some embodiments, the additional active agent is thyroxine (T4).

[15] In some embodiments, the topical composition is in lyophilized form.

[16] to another aspect, provided is the topical composition of any of the disclosed embodiments, for use in treating or preventing hair loss.

[17] In another aspect, provided is the use of the topical composition of any one of the disclosed embodiments for the manufacture of a medicament for treating or preventing hair loss.

[18] Also provided is a method of treating or preventing hair loss in a subject, comprising administering to the subject the topical composition of any one of the disclosed embodiments.

[19] In some embodiments, the method comprises administering to the subject between about 0.1 and 10 mL of the composition per unit dose. In some embodiments, the method comprises administering to the subject about 1 mL of the composition per unit dose. In some embodiments, the method comprises administering to the subject between about 1 ng and 10 ng of T3 per unit dose. In some embodiments, the method comprises administering to the subject about 6.5 ng of T3 per unit dose.

[20] In some embodiments, the composition is administered daily. In some embodiments, the composition is administered every other day. In some embodiments, the composition is administered every other day for several consecutive weeks followed by a prolonged period without administration. In some embodiments, the composition is administered every other day for two consecutive weeks followed by a prolonged period without administration. In some embodiments, the prolonged period without administration is at least two weeks.

[21] In some embodiments, the hair loss is caused by androgenetic alopecia, alopecia areata, persistent patchy alopecia areata, alopecia totalis, alopecia universalis, diffuse alopecia areata, ophiasis alopecia, cicatricial alopecia, lichen planopilaris, frontal fibrosing alopecia, central centrifugal cicatricial alopecia (CCCA), traction alopecia, alopecia barbae, or postpartum alopecia.

[22] In some embodiments, the method results in increased hair shaft production. In some embodiments, hair shaft production is increased by 1%, 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100% compared to baseline values measured prior to administration of the composition.

[23] In some embodiments, the method results in prolonged anagen hair growth phase. In some embodiments, the anagen hair growth phase is prolonged by 1%, 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100% compared to baseline values measured prior to administration of the composition.

[24] In some embodiments, the method results in increased expression of FGF7. In some embodiments, the expression of FGF7 is increased by 1%, 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100% compared to baseline values measured prior to administration of the composition.

[25] In some embodiments, the method results in increased proliferation of bulge epithelial stem cells. In some embodiments, bulge epithelial stem cell proliferation is increased by 1%, 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100% compared to baseline values measured prior to administration of the composition.

[26] In some embodiments, the method results in increased expression of keratin 15. In some embodiments, the expression of keratin 15 is increased by 1%, 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100% compared to baseline values measured prior to administration of the composition.

[27] In some embodiments, the method results in decreased expression of p-S6. In some embodiments, the expression of p-S6 is decreased by 1%, 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100% compared to baseline values measured prior to administration of the composition.

[28] in another aspect, provided is the topical composition of any of the disclosed embodiments, for use in treating or preventing hair graying.

[29] In another aspect, provided is the use of the topical composition of any of the disclosed embodiments for the manufacture of a medicament for treating or preventing hair graying.

[30] Also provided is a method of treating or preventing hair graying in a subject, comprising administering to the subject the topical composition of any of the disclosed embodiments.

[31] In some embodiments, the topical composition comprises: (i) about 1 nM of triiodothyronine (T3);

(ii) about 5% (w/v) of hydroxypropylceilulose; (iii) about 30% (v/v) of ethanol; (iv) about 50% (v/v) of propylene glycol; and (v) about 10% (v/v) of water.

[32] In some embodiments, the method results in decreased hair depigmentation. In some embodiments, hair depigmentation is decreased by 1%, 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100%. In some embodiments, the method results in hair repigmentation.

[33] The foregoing has outlined broadly and in summary certain pertinent features of the disclosure so that the detailed description of the invention that follows may be better understood, and so that the present contribution to the art can be more fully appreciated. Hence, this summary is to be considered as a brief and general synopsis of only some of the objects and embodiments disclosed herein, is provided solely for the benefit and convenience of the reader, and is not intended to limit in any manner the scope, or range of equivalents, to which the claims are lawfully entitled. Additional features of the invention are described hereinafter. It should be appreciated by those in the art that all disclosed specific compositions and methods are only exemplary, and may be readily utilized as a basis for modifying or designing other compositions and methods for carrying out the same purposes. Such equivalent compositions and methods will be appreciated to be also within the scope and spirit of the invention as set forth in the claims. It also will be appreciated that headings within this document are being utilized only to expedite its review by a reader. They should not be construed as limiting the invention in any manner.

BRIEF DESCRIPTION OF THE FIGURES

[34] To further clarify various aspects of the invention, a more particular description is rendered by reference to certain exemplary embodiments illustrated in the figures. It will be appreciated that these figures depict only illustrated embodiments of the invention and should not be considered limiting of its scope. They are merely provided as exemplary illustrations of certain concepts of some embodiments of the invention. These figures, and the elements depicted therein, are not necessarily drawn to consistent scale or to any scale. Unless context suggests otherwise, like elements are indicated by like numerals. Certain aspects of the invention are therefore further described and explained with additional specificity and detail, but still by way of example only, with reference to the accompanying figures in which:

[35] FIG. 1A shows the percentage of hair follicle (HF) growth after 6 days of topical treatment with either Vehicle Formulation A (Form. A), T3 (1 nm and 10 nm) in Form A., and T4(1 μM and 10 μM) in Form. A. Mean +/- SEM; n=8 HFs from 1 donor (Vehicle, T3, and T4) and 24 HFs from 3 donors (Vehicle and T3+T4 combination); Mann-Whitney test.

[36] FIG. 1B shows the percentage of hair follicle growth after 6 days of topical treatment with either Vehicle Formulation B (Form. B), T3 (1 nm and 10 nm) in Form B., and T4(1 μM and 10 μM) in Form. B. Mean +/- SEM; n=8 HFs from 1 donor (Vehicle, T3, and T4) and 24 HFs from 3 donors (Vehicle and T3+T4 combination); Mann-Whitney test.

[37] FIG. 2A shows 6 mm hairy skin biopsies at one day of topical treatment (A, C, E) and six days of topical treatment (B, D, F) withVehicle Formulation A (A, B), 1 nM T3 in Form. A (C, D), and 10 nM T3 in Form. A (E, F).

[38] FIG. 2B shows 6 mm hairy skin biopsies at one day of topical treatment (A, C, E) and six days of topical treatment (B, D, F) with Vehicle Formulation B (A, B), 1 nM T3 in Form. B (C, D), and 10 nM T3 in Form. B (E, F).

[39] FIG. 3A shows the percentage of hair follicles in each hair cycle stage following administration of Vehicle Formulation A, T3 (1 nm and 10 nm) in Form A., T4(1 μM and 10 μM) in Form. A, and a combination of T3+T4 in Form A. Mean +/- SEM; n=20-35 HFs from 3 donors; Mann-Whitney test.

[40] FIG. 3B shows the percentage of hair follicles in each hair cycle stage following administration of Vehicle Formulation B, T3 (1 nm and 10 nm) in Form B., T4(1 μM and 10 μM) in Form B, and a combination of T3+T4 in Form B. Mean +/- SEM; n=20-35 HFs from 3 donors; Mann-Whitney test.

[41] FIG. 4A shows the percentage of hair follicles in each hair cycle stage following administration of Formulation A, T3 (1 nm and 10 nm) in Form A., T4(1 μM and 10 μM) in Form. A, and a combination of T3+T4 in Form A. Mean +/- SEM; n=20-35 HFs from 3 donors; Mann-Whitney test.

[42] FIG. 4B shows the percentage of hair follicles in each hair cycle stage following administration of Formulation B, T3 (1 nm and 10 nm) in Form B., T4(1 μM and 10 μM) in Form. B, and a combination of T3+T4 in Form B. Mean +/- SEM; n=20-35 HFs from 3 donors; Mann-Whitney test.

[43] FIG. 5 shows images of Warthin-Starry histochemical stain (left column), Ki-67 immunofluorescence (middle column), and Casp-3 immunofluorescence (right column) in anagen hair follicles treated with Vehicle Formulation A, 1 nM T3 in Form. A, and 10 nM T3 in Form A.

[44] FIG. 6A shows the percentage of Ki-67⁺ cells in the hair matrix after treatment with Vehicle Formulation A, T3 (1 nm and 10 nm) in Form A., T4(1 μM and 10 μM) in Form. A, and a combination of T3+T4 in Form A. Mean +/- SEM; n=17-22 HFs from 2 donors; Mann-Whitney test, *p <0.05.

[45] FIG. 6B shows the percentage of Ki-67⁺ cells in the hair matrix after treatment with Vehicle Formulation B, and T3 (1 nm and 10 nm) in Form B., T4(1 μM and 10 μM) in Form. B, and a combination of T3+T4 in Form B. Mean +/- SEM; n=18-28 HFs from 2 donors; Mann-Whitney test.

[46] FIG. 7 shows confocal images of Ki-67 immunofluorescence signal in anagen hair follicles treated with Vehicle Formulation A, 1 nM T3 in Form. A, and 10 nM T3 in Form A.

[47] FIG. 8A shows melanin production after treatment with Vehicle Formulation A, T3 (1 nm and 10 nm) in Form A., T4 (1 μM and 10 μM) in Form. A, and a combination of T3+T4 in Form A. Mean +/- SEM; n=17-33 HFs from 3 donors; Mann-Whitney test.

[48] FIG. 8B shows melanin production after treatment with Vehicle Formulation B, T3 (1 nm and 10 nm) in Form B., T4(1 μM and 10 μM) in Form. B, and a combination of T3+T4 in Form B. Mean +/- SEM; n=15-29 HFs from 3 donors; Mann-Whitney test.

[49] FIG. 9 shows the Warthin-Starry histochemical stain for intrafollicular melanin granules treated with Vehicle Formulation A, 1 nM T3 in Form. A, and 10 nM T3 in Form A.

[50] FIG. 10A shows the level of gp100 expression in anagen hair follicles treated with Vehicle Formulation A, T3 (1 nm and 10 nm) in Form A., T4(1 μM and 10 μM) in Form. A, and a combination of T3+T4 in Form A. Mean +/- SEM; n=13-22 HFs from 3 donors; Student t test, “p<0.05.

[51] FIG. 10B shows the level of gp100 expression in anagen hair follicles treated with Vehicle Formulation B, T3 (1 nm and 10 nm) in Form B., T4(1 μM and 10 μM) in Form. B, and a combination of T3+T4 in Form B. Mean +/- SEM; n= 13-22 HFs from 3 donors; Student t test, *p<0.05.

[52] FIG. 11 A shows the level of MITF expression in anagen hair follicles treated with Vehicle Formulation A, T3 (1 nm and 10 nm) in Form A., T4(1 μM and 10 μM) in Form. A, and a combination of T3+T4 in Form A. Mean +/- SEM; 13-22 HFs from 3 donors; Student t test, *p<0.05.

[53] FIG. 11B shows the level of MITF expression in anagen hair follicles treated with Vehicle Formulation B, T3 (1 nm and 10 nm) in Form B., T4(1 μM and 10 μM) in Form. B, and a combination of T3+T4 in Form B. Mean +/- SEM; n- 13-22 HFs from 3 donors; Student t test.

[54] FIG. 12 shows confocal images of gp100 (left column) and MITF (right column) immunofluorescence signal in anagen hair follicles treated with Vehicle Formulation A, 1 nM T3 in Form. A, and 10 nM T3 in Form A.

[55] FIG. 13A shows the level of MTCO1 expression in HM tips treated with Vehicle Formulation A, T3 (1 nm and 10 nm) in Form A., T4(1 μM and 10 μM) in Form. A, and a combination of T3+T4 in Form A. Mean +/- SEM; n=30-35 HFs from 3 donors; Mann-Whitney test, *p<0.05, ***p<0.001 .

[56] FIG. 13B shows the level of MTCO1 expression in HM tips treated with Vehicle Formulation B, T3 (1 nm and 10 nm) in Form B., T4(1 μM and 10 μM) in Form. B, and a combination of T3+T4 in Form B. Mean +/- SEM; n=21 -30 HFs from 3 donors; Mann-Whitney test, *p<0.05, **p<0.01 , ***p<0.001 . [57] FIG. 14A shows the level of MTCO1 expression in the outer root sheath (ORS) treated with Vehicle Formulation A, T3 (1 nm and 10 nm) in Form A., T4(1 μM and 10 μM) in Form. A, and a combination of T3+T4 in Form A. Mean +/- SEM; n=30-35 HFs from 3 donors; Mann-Whitney test, *p<0.05, **p<0.01 , ***p<0.001 .

[58] FIG. 14B shows the level of MTCO1 expression in the ORS treated with Vehicle Formulation B, T3 (1 nm and 10 nm) in Form B., T4 (1 μM and 10 μM) in Form. B, and a combination of T3+T4 in Form B. Mean +/- SEM; n=21 -30 HFs from 3 donors; Mann-Whitney test, *p<0.05, **p<0.01 , ***p<0.001 .

[59] FIG. 15A shows the level of K15 expression in bulge cells treated with Vehicle Formulation A, T3 (1 nm and 10 nm) in Form A., T4 (1 μM and 10 μM) in Form. A, and a combination of T3+T4 in Form A. Mean +/- SEM; n=21 -34 HFs from 3 donors. Mann-Whitney test, *p<0.05, **p<0.01.

[60] FIG. 15B shows the level of K15 expression in bulge cells treated with Vehicle Formulation B, T3 (1 nm and 10 nm) in Form B., T4(1 μM and 10 μM) in Form. B, and a combination of T3+T4 in Form B. Mean +/- SEM; n=21 -34 HFs from 3 donors. Mann-Whitney test.

[61] FIG. 16A shows the number of K15⁺ cells in the bulge treated with Vehicle Formulation A, T3 (1 nm and 10 nm) in Form A., T4(1 μM and 10 μM) in Form. A, and a combination of T3+T4 in Form A. Mean +/- SEM; n=21-34 HFs from 3 donors. Mann-Whitney test.

[62] FIG. 16B shows the number of K15⁺ cells in the bulge treated with Vehicle Formulation B, T3 (1 nm and 10 nm) in Form B., T4(1 μM and 10 μM) in Form. B, and a combination of T3+T4 in Form B. Mean +/- SEM; n=21 -34 HFs from 3 donors. Mann-Whitney test, *p<0.05, **p<0.01 ..

[63] FIG. 17A shows the number of proliferative K15 cells (cells positive for K15 and Ki67) in the bulge treated with Vehicle Formulation A, T3 (1 nm and 10 nm) in Form A., T4(1 μM and 10 μM) in Form. A, and a combination of T3+T4 in Form A. Mean +/- SEM; n=21 -34 HFs from 3 donors. Mann-Whitney test.

[64] FIG. 17B shows the number of proliferative K15 cells (cells positive for K15 and Ki67) in the bulge treated with Vehicle Formulation B, T3 (1 nm and 10 nm) in Form B., T4(1 μM and 10 μM) in Form. B, and a combination of T3+T4 in Form B. Mean +/- SEM; n=21 -34 HFs from 3 donors. Mann-Whitney test.

[65] FIG. 18A shows the number of apoptotlc K15 cells (cells positive for K15 and Cas3) in the bulge treated with Vehicle Formulation A, T3 (1 nm and 10 nm) in Form A., T4(1 μM and 10 μM) in Form. A, and a combination of T3+T4 in Form A. Mean +/- SEM; n=21-34 HFs from 3 donors. Mann-Whitney test, *p<0.05, **p<0.01.

[66] FIG. 18B shows the number of apoptotlc K15 cells (cells positive for K15 and Cas3) in the bulge treated with Vehicle Formulation B, T3 (1 nm and 10 nm) in Form B., T4(1 μM and 10 μM) in Form. B, and a combination of T3+T4 in Form B. Mean +/- SEM; n=21-34 HFs from 3 donors. Mann-Whitney test, *p<0.05, **p<0.01.

[67] FIG. 19 shows confocal images of K15 (left column), Ki67 (middle column), and Cas3 (right column) immunofluorescence signal in bulge cells treated with Vehicle Formulation A, 1 nM T3 in Form. A, and 10 nM T3 in Form A.

[68] FIG. 20A shows the level of IGF-1 expression in ORS keratinocytes treated with Vehicle Formulation A, T3 (1 nm and 10 nm) in Form A., T4 and(11 μ0M μM) in Form. A, and a combination of T3+T4 in Form A. Mean +/- SEM; n=18-35 HFs from 3 donors; Mann-Whitney test.

[69] FIG. 208 shows the level of IGF-1 expression in ORS keratinocytes treated with Vehicle Formulation B, T3 (1 nm and 10 nm) in Form B., T4 and(11 μ0M μM) in Form. B, and a combination of T3+T4 in Form B. Mean +/- SEM; n-18-35 HFs from 3 donors; Mann-Whitney test.

[70] FIG. 21A shows the level of TGFp-2 expression in ORS keratinocytes treated with Vehicle Formulation A, T3 (1 nm and 10 nm) in Form A., T4 and(11 μ0M μM) in Form. A, and a combination of T3+T4 in Form A. Mean +/- SEM; n-20-28 HFs from 3 donors; Mann-Whitney test.

[71] FIG. 21B shows the level of TGFp-2 expression in ORS keratinocytes treated with Vehicle Formulation B, T3 (1 nm and 10 nm) in Form B., T4 and(11 μ0M μM) in Form. B, and a combination of T3+T4 in Form B. Mean +/- SEM; n=22-35 HFs from 3 donors; Mann-Whitney test.

[72] FIG. 22 shows confocai images of TGFp-2 immunofluorescence signal in ORS keratinocytes treated with Vehicle Formulation A, 1 nM T3 in Form. A, and 10 nM T3 in Form A.

[73] FIG. 23A shows the level of FGF7 expression in the ORS treated with Vehicle Formulation A, T3 (1 nm and 10 nm) in Form A., T4 ( a1nd μM 10 μM) in Form. A, and a combination of T3+T4 in Form A. Mean +/- SEM; n=24-32 HFs from 3 donors; Student t test, **p<0.01 , ***p<0.001 .

[74] FIG. 23B shows the level of FGF7 expression in the ORS treated with Vehicle Formulation B, T3 (1 nm and 10 nm) in Form B., T4 ( a1n μdM 10 μM) in Form. B, and a combination of T3+T4 in Form B. Mean +/- SEM; n=17-33 HFs from 3 donors; Student t test.

[75] FIG. 24 shows confocal images of FGF7 immunofluorescence signal in ORS keratinocytes treated with Vehicle Formulation A, 1 nM T3 in Form. A, and 10 nM T3 in Form A.

[76] FIG. 25A shows the level of pS6 expression in hair matrix keratinocytes treated with Vehicle Formulation A, T3 (1 nm and 10 nm) in Form A., T4 and(11 μ0M μM) in Form. A, and a combination of T3+T4 in Form A. Mean +/- SEM; n=24-32 HFs from 3 donors; Mann-Whitney test, **p<0.01 .

[77] FIG. 25B shows the level of pS6 expression in hair matrix keratinocytes treated with Vehicle Formulation B, T3 (1 nm and 10 nm) in Form B., T4 and(11 μ0M μM) in Form. B, and a combination of T3+T4 in Form B. Mean +/- SEM; n=22-34 HFs from 3 donors; Mann-Whitney test, *p<0.05.

[78] FIG. 26A shows the level of K85 expression in the hair matrix keratinocytes treated with Vehicle Formulation A, T3 (1 nm and 10 nm) in Form A., T4 and(11 μ0M μM) in Form. A, and a combination of T3+T4 in Form A. Mean +/- SEM; n=22-34 HFs from 3 donors; Mann-Whitney test, **p<0.01 .

[79] FIG. 26B shows the level of K85 expression in the pre-cortical hair matrix treated with Vehicle Formulation B, T3 (1 nm and 10 nm) in Form B., T4 and(11 μ0M μM) in Form. B, and a combination of T3+T4 in Form B. Mean +/- SEM; n=22-34 HFs from 3 donors; Mann-Whitney test, **p<0.01 . [80] FIG. 27 shows confocal images of K85 immunofluorescence signal in the pre-cortical hair matrix treated with Vehicle Formulation A, and 10 nM T3 in Form A.

[81] FIG. 28A shows the amount of CD31⁺ endothelial cells in the dermis after treatment with Vehicle Formulation A, T3 (1 nm and 10 nm) in Form A., T4 and(11 μ0M μM) in Form A., and a combination of T3+T4 in Form A. Mean +/- SEM; n=22-34 HFs from 3 donors; Mann-Whitney test, *p<0.05, **p<0.01 .

[82] FIG. 28B shows the amount of CD31⁺ endothelial cells in the dermis after treatment with Vehicle Formulation B, T3 (1 nm and 10 nm) in Form B., T4 an(d1 1 μ0M μM) in Form B., and a combination of T3+T4 in Form B. Mean +/- SEM; n=22-34 HFs from 3 donors; Mann-Whitney test, *p<0.05, **p<0.01 .

[83] FIG. 29 shows a confocal image of CD31 immunofluorescence signal in the dermis treated with Vehicle Formulation A, and 10 nM T3 in Form A.

DETAILED DESCRIPTION OF THE INVENTION

[84] While various aspects and features of certain embodiments are summarized above, the following detailed description illustrates several exemplary embodiments in further detail to enable one of skill in the art to practice such embodiments, and to make and use the full scope of the invention claimed. The described examples are provided for illustrative purposes and are not intended to limit the scope of the invention or its applications. It will be understood that many modifications, substitutions, changes, and variations in the described examples, embodiments, applications, and details of the invention illustrated herein can be made by those skilled in the art without departing from the spirit of the invention, or the scope of the invention as described in the appended claims. It also will be appreciated that the headings within this document are being utilized only to expedite its review by a reader. They should not be construed as limiting the invention in any manner.

[85] The scope of the invention includes all embodiments and formulations thereof, not only those expressly described below, and it will be understood that many modifications, substitutions, changes, and variations in the described embodiments, applications, and details of the invention illustrated herein can be made by those skilled in the art without departing from the spirit of the invention, or the scope of the invention as set forth in the appended claims.

A. General Definitions and Terms

[86] As used in this specification and the appended claims, the singular forms “a,” “an,” and “the” include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to “an active agent” includes reference to a combination of two or more active agents, and reference to “an excipient” includes reference to a combination of two or more excipients. While the term “one or more" may be used, its absence (or its replacement by the singular) does not signify the singular only, but simply underscores the possibility of multiple agents or ingredients in particular embodiments. The terms “comprising,” “including,” “such as,” and “having” are inclusive and not exclusive (i.e., there may be other elements in addition to the recited elements). The term “or” is used herein to mean, and is used interchangeably with, the term “and/or,” unless context clearly indicates otherwise.

[87] Unless otherwise indicated, all numbers expressing quantities of ingredients, properties such as concentration, reaction conditions, and so forth, used to describe and claim certain embodiments of the invention are to be understood as being modified in some instances by the term “about." Accordingly, in some embodiments, the numerical parameters set forth in the written description and attached claims are approximations that can vary depending upon the desired properties sought to be obtained by a particular embodiment. In some embodiments, “about” refers to plus or minus five percent (±5%) of the recited unit of measure. The term “substantially,” where it is applied to modify a feature or limitation herein, will be read in the context of the invention and in light of the knowledge in the art to provide the appropriate certainty, e.g„ by using a standard that is recognized in the art for measuring the meaning of “substantially” as a term of degree, or by ascertaining the scope as would one of skill in the art.

[88] In some embodiments, the numerical parameters should be construed in light of the number of reported significant digits and by applying ordinary rounding techniques. Notwithstanding that the numerical ranges and parameters setting forth the broad scope of some embodiments of the invention are approximations, the numerical values set forth in the specific examples are reported as precisely as practicable. The numerical values presented in some embodiments may contain certain errors necessarily resulting from the standard deviation found in their respective testing measurements.

[89] Unless defined otherwise, all technical and scientific terms herein have the meaning as commonly understood by one having ordinary skill in the art to which this invention belongs, who as a shorthand may be referred to simply as “one of skill.” Further definitions that may assist the reader in understanding the disclosed embodiments are as follows; however, it will be appreciated that such definitions are not intended to limit the scope of the invention, which shall be properly interpreted and understood by reference to the full specification (as well as any plain meaning known to one of skill in the relevant art) in view of the language used in the appended claims. The terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting.

[90] Herein, “hair cycle staging” refers to anagen (growth phase), catagen (transitional phase), and telogen (resting phase), the key stages of human hair (Paus et al. J Investigative Derm. 2001 ;117(1 ):3-15).

[91] Herein, “melanin” refers to a complex polymer that originates from the amino acid tyrosine. Melanin is present in human skin in varying degrees, and is responsible for your unique eye, hair, and skin color (Cao et al. J Am Chem Soc. 2021 ; 143(7):2622-2637).

[92] Herein, “Ki-67” refers to a monoclonal antibody that can be used to determine the numbers of cycling cells in hair follicles (Baar et al. Acta Derm Venereol. 1992;72(2):161-164).

[93] Herein, “caspase-3” is a caspase protein that interacts with caspase-8 and caspase-9. Caspases are regulators of programmed cell death, and very likely some specific caspases may function as mediators of the hair growth cycle (Sawaya et al. Eur J Dermatol. 2001 ;11 (4):304-308). [94] Herein, “IGF-1,” or "insulin-like growth factor 1,” refers to an anagen prolonging growth factor. IGF-1 shares a high degree of structural and functional homology with insulin and exhibits anti-apoptotic effects (Ahn et al. Ann Dermatol. 2012;24(1 ):26-31 ).

[95] Herein, “KGF/FGF7,” or “keratinocyte growth factor/fi broblast growth factor-7,” refers to an anagen prolonging growth factor.

[96] Herein, “TGF0-2,” or “transforming growth factor beta 2,” refers to a catagen promoting growth factor (Xu et al. Bone Research. 2018;6(2):1 -31 ).

[97] Herein “MTCOI,” or “mitochondrial cytochrome C oxidase subunit I,” refers to a component of the cytochrome c oxidase, the last enzyme in the mitochondrial electron transport chain which drives oxidative phosphorylation (Vidali et al. J Invest Dermatol. 2016;136(10):2003-2012).

[98] Herein, “Gp100” refers to a well-recognized and sensitive tracker of melanosome transfer between melanocytes and keratinocytes (Singh et al. Exp Dermatol. 2008;17(5):418-426).

[99] Herein, “MITF,” or “melanocyte inducing transcription factor,” refers to the key transcription factor for melanocyte development and differentiation (Levt et al. Trends Mol Med. 2006;12(9):406-414).

[100] Herein, “p-S6” refers to the direct downstream kinase of mTORCI . An increase in p-S6 indicates activation of mTORCI which is involved in aging and hair graying (Suzuki et al. EMBO Reports. 2023;24:e56574).

[101] Herein, “K85” is a sensitive marker for the amount of hair shaft keratin production (Ramot et al. Br J Dermatol. 2013; 169(1 ):146-51).

[102] Herein, “CD31,” also known as “platelet endothelial cell adhesion molecule-1” is a marker of intracutaneous angiogenesis, measured by CD31 immunoreactivity and the number of CD31 positive cells. CD31 is a transmembrane homophilic receptor that is expressed by endothelial cells, platelets, granulocytes, macrophages, dendritic cells, T- and B- calls, and natural killer cells (Berg et al. J Cell Sci. 2013;126(11):2343-2352.

[103] Herein, “treating” or “treatment” of a disorder, such as hair loss, a hair loss condition, or androgenetic alopecia includes any treatment of the disorder in a mammal, preferably in a human, and includes: (a) preventing a disorder from occurring in a patient who may be predisposed to the disorder but has not yet been diagnosed with it; (b) inhibiting a disorder, i.e., arresting its development, and including prophylaxis; (c) relieving a disorder, i.e., causing regression of the disorder or its clinical symptoms; (d) protection from or relief of a symptom or pathology caused by or related to a disorder; (e) reduction, decrease, inhibition, amelioration, or prevention of onset, severity, duration, progression, frequency or probability of one or more symptoms or pathologies associated with a disorder; and (f) prevention or inhibition of a worsening or progression of symptoms or pathologies associated with a disorder or comorbid with a disorder.

[104] Herein, “an effective amount," a “therapeutically effective amount,” or “a pharmacologically effective amount” refers to an amount of an active agent (e.g. triiodothyronine (T3), thyroxine (T4), or a combination thereof) that is non-toxic and sufficient to provide the desired therapeutic effect with performance at a reasonable benefit/risk ratio attending any medical treatment. The effective amount will vary depending upon the subject, the weight and age thereof, the severity of the symptoms or degree of health benefit sought, the manner of administration, and the like, all of which can readily be determined by one of skill in the art.

[105] Herein, “therapeutic effect" or “therapeutic efficacy” means the responses(s) in a subject, and preferably a human, after treatment that are judged to be desirable and beneficial. Hence, depending on the symptoms to be treated, or improvement in health or functioning sought, and depending on the particular constituent(s) of the methods of the disclosure under consideration, those responses shall differ, but would be readily understood by those of skill in the art.

[106] As used herein, the terms “subject,” “user,” “patient,” and “individual” are used interchangeably, and refer to a human, a mammal, or any other animal susceptible to hair loss, a hair loss condition, or androgenetic alopecia. Preferably, the subject is a human. The subject may be a human infant, a human child, a human adult, or an elderly human. Such terms will be understood to include one who has an indication for which a method described herein may be efficacious, or who otherwise may benefit by the invention. In general, all of the disclosed methods will be appreciated to work for all individuals, although individual variation is to be expected, and will be understood. The disclosed methods of treatment also can be modified to treat multiple patients at once, including couples or families. Hence, these terms will be understood to also mean two or more individuals.

[107] Generally, the nomenclature used and procedures performed herein are those known in fields relating to one or more aspects of the invention, such as biology, biochemistry, dermatology, pharmacology, and medical science, and are those that will be well known and commonly employed in such fields. Standard techniques and procedures will be those generally performed according to conventional methods in the art.

[108] Still additional definitions and abbreviations are provided elsewhere herein.

B. Topical Compositions

[109] The present disclosure relates in some aspects to methods of treating or preventing hair loss (e.g., caused by a hair loss condition, such as androgenetic alopecia) in a subject (e.g., preferably a human). In some aspects, the disclosure further relates to pharmaceutical (e.g., topical) compositions and kits used in the methods. In some aspects, useful features of the disclosed methods include curing or alleviating the symptoms of a subject suffering from a hair loss condition, such as androgenetic alopecia.

[110] Without being bound by theory, thyroid hormones may have the potential to stimulate proliferation and differentiation of stem cells both in the hair matrix through the downregulation of TGF0-2, a significant catagen promoting growth factor, and the hair bulge through the upregulation of K15 expression, an upregulator of epithelial progenitor markers. See, for example, Paus et al. The J Clin Endocrinol Metab. 2008;93(11):4381— 4388; Paus et al. J Invest Dermatol. 2014; 134(1): 33-42; Paus, et al. PLoS One. 2019;14(3):e0212659; Paus et ai. J Investigative Derm. 2016;136:1711-1714; and Paus et al. Experimental Derm. 2020;29(9):910-923; each of which is hereby incorporated by reference in its entirety. Additional mechanisms of action likely exist but remain unknown, due to the complexity of the plethora of intra-cellular reactions downstream of both free and bound thyroid hormones.

[111] In one aspect, provided is a topical composition comprising a therapeutically effective amount of triiodothyronine (T3), thyroxine (T4), or a combination thereof. In some embodiments, the topical composition comprises T3 and T4. In some embodiments, the composition comprises a therapeutically effective amount of T3. In some embodiments, the composition comprises a therapeutically effective amount of T4. In some embodiments, the composition comprises a therapeutically effective amount of both T3 and T4. In some embodiments, the composition comprises a therapeutically acceptable amount of a combination of T3 and T4. In some embodiments, the composition is suitable for topical or transdermal administration. In some embodiments, the composition is formulated for topical administration. In some embodiments, the composition is formulated for transdermal administration. In some embodiments, the topical composition comprises a pharmaceutically acceptable excipient.

[112] In another aspect, provided is a topical composition, useful for treating or preventing hair loss comprising: (i) T3; (ii) a pharmaceutically acceptable excipient; and (iii) a solvent system. In some embodiments, the topical composition contains T3 as the only active ingredient. Hence, also provided is a topical composition, useful for treating or preventing hair loss comprising: (i) T3 as the only active ingredient; (ii) a pharmaceutically acceptable excipient; and (iii) a solvent system. Also provided is a topical composition, useful for treating or preventing hair loss consisting essentially of: (i) T3; (ii) a pharmaceutically acceptable excipient; and (iii) a solvent system.

[113] In another aspect, provided is a topical composition, useful for treating or preventing hair graying comprising: (i) T3; (ii) a pharmaceutically acceptable excipient; and (iii) a solvent system. In some embodiments, the topical composition comprises T3 as the only active ingredient. Hence, also provided is a topical composition, useful for treating or preventing hair graying comprising: (i) T3 as the only active ingredient; (ii) a pharmaceutically acceptable excipient; and (iii) a solvent system. Also provided is a topical composition, useful for treating or preventing hair graying, consisting essentially of: (i) T3; (ii) a pharmaceutically acceptable excipient; and (iii) a solvent system.

[114] In some embodiments, a disclosed topical composition does not comprise T4. In some embodiments, the topical composition does not comprise iodothyronamine (T1a). In some embodiments, the topical composition does not comprise thyronamine (TOa). In some embodiments, the topical composition does not comprise a cardiac glycoside. In some embodiments, the topical composition does not comprise a sterol. In some embodiments, the composition does not comprise a phytosterol. In some embodiments, the composition does not comprise 13-sitosterol. In some embodiments, the composition does not comprise a hormone other than the thyroid hormone (e.g., T3 or T4). In some embodiments, the topical composition does not comprise human growth hormone. In some embodiments, the topical composition does not comprise insulin. In some embodiments, the topical composition does not comprise estradiol. In some embodiments, the topical composition does not comprise an estrogen source. In some embodiments, the topical composition does not comprise a dihydrotestosterone blocker. In some embodiments, the topical composition does not comprise a progesterone source. In some embodiments, the topical composition does not comprise oestradiol benzoate. In some embodiments, the topical composition does not comprise medroxyprogesterone acetate. In some embodiments, the topical composition does not comprise a vasodilator. In some embodiments, the topical composition does not comprise a monoamine oxidase inhibitor. In some embodiments, the topical composition does not comprise an IL-15 polynucleotide, polypeptide or a compound which binds to an antibody which specifically recognizes the IL-15 polypeptide or which specifically binds to an IL-15 receptor alpha chain.

[115] In some embodiments, the composition comprises T3 at a concentration of between about 1 nM and 30 nM. In some embodiments, the composition comprises T3 at a concentration of iess than about 1 nM, about 1 nM, about 2 nM, about 3 nM, about 4 nM, about 5 nM, about 6 nM, about 7 nM, about 8 nM, about 9 nM, about 10 nM, about 15 nM, about 20 nM, about 25 nM, about 30 nM, or greater than about 30 nM, including ranges in between these values. In some embodiments, the composition comprises T3 at a concentration of iess than about 1 nM. In some embodiments, the composition comprises T3 at a concentration of about 1 nM. In some embodiments, the composition comprises T3 at a concentration of about 2 nM. In some embodiments, the composition comprises T3 at a concentration of about 3 nM. In some embodiments, the composition comprises T3 at a concentration of about 4 nM. In some embodiments, the composition comprises T3 at a concentration of about 5 nM. In some embodiments, the composition comprises T3 at a concentration of about 6 nM. In some embodiments, the composition comprises T3 at a concentration of about 7 nM. In some embodiments, the composition comprises T3 at a concentration of about 8 nM. In some embodiments, the composition comprises T3 at a concentration of about 9 nM. In some embodiments, the composition comprises T3 at a concentration of about 10 nM. In some embodiments, the composition comprises T3 at a concentration of about 15 nM. In some embodiments, the composition comprises T3 at a concentration of about 20 nM. In some embodiments, the composition comprises T3 at a concentration of about 25 nM. In some embodiments, the composition comprises T3 at a concentration of about 30 nM. In some embodiments, the composition comprises T3 at a concentration of greater than about 30 nM.

[116] in some embodiments, the composition comprises T3 at a concentration of between about 1 pM and 15 pM. In some embodiments, the composition comprises T3 at a concentration of less than about 1 pM, about 1 yM, about 2 pM, about 3 yM, about 4 pM, about 5 yM, about 6 pM, about 7 pM, about 8 pM, about 9 pM, about 10 pM, about 11 pM, about 12 pM, about 13 pM, about 14 pM, about 15 pM, or greater than about 15 pM. In some embodiments, the composition comprises T3 at a concentration of less than about 1 pM. In some embodiments, the composition comprises T3 at a concentration of about 1 pM. In some embodiments, the composition comprises T3 at a concentration of about 2 pM. in some embodiments, the composition comprises T3 at a concentration of about 3 pM, In some embodiments, the composition comprises T3 at a concentration of about 4 pM. In some embodiments, the composition comprises T3 at a concentration of about 5 pM. In some embodiments, the composition comprises T3 at a concentration of about 6 pM. In some embodiments, the composition comprises T3 at a concentration of about 7 pM. In some embodiments, the composition comprises T3 at a concentration of about 8 pM. in some embodiments, the composition comprises T3 at a concentration of about 9 pM. In some embodiments, the composition comprises T3 at a concentration of about 10 pM. In some embodiments, the composition comprises T3 at a concentration of about 11 pM. In some embodiments, the composition comprises T3 at a concentration of about 12 pM. In some embodiments, the composition comprises T3 at a concentration of about 13 pM. In some embodiments, the composition comprises T3 at a concentration of about 14 pM. In some embodiments, the composition comprises T3 at a concentration of about 15 pM. In some embodiments, the composition comprises T3 at a concentration of greater than about 15 pM.

[117] In some embodiments, the composition comprises T3 at a concentration of about 50 pM, 60 pM, 70 pM, 80 pM, 90 pM, 100, 110 pM, 120 pM, 130 pM, 140 pM, 150 pM, 160 pM, 170 pM, 180 pM, 190 pM, or 200 pM, or doses between these values. In some embodiments, the composition comprises 13 at a concentration of about 50 pM. In some embodiments, the composition comprises T3 at a concentration of about 60 pM, in some embodiments, the composition comprises T3 at a concentration of about 70 pM. In some embodiments, the composition comprises T3 at a concentration of about 80 pM. In some embodiments, the composition comprises T3 at a concentration of about 90 pM. In some embodiments, the composition comprises T3 at a concentration of about 100 pM. In some embodiments, the composition comprises T3 at a concentration of about 110 pM, in some embodiments, the composition comprises T3 at a concentration of about 120 pM, In some embodiments, the composition comprises T3 at a concentration of about 130 pM, In some embodiments, the composition comprises T3 at a concentration of about 140 pM. In some embodiments, the composition comprises T3 at a concentration of about 150 pM. In some embodiments, the composition comprises T3 at a concentration of about 160 pM. In some embodiments, the composition comprises T3 at a concentration of about 170 pM. In some embodiments, the composition comprises T3 at a concentration of about 180 pM. in some embodiments, the composition comprises T3 at a concentration of about 190 pM. In some embodiments, the composition comprises T3 at a concentration of about 200 pM.

[118] In some embodiments, the composition comprises T4 at a concentration of between about 1 pM and 30 pM. In some embodiments, the composition comprises T4 at a concentration of iess than about 1 pM, about 1 pM, about 2 pM, about 3 pM, about 4 pM, about 5 pM, about 6 pM, about 7 pM, about 8 pM, about 9 pM, about 10 pM, about 15 pM. about 20 pM, about 25 pM, about 30 pM, or greater than about 30 pM, including ranges in between these values. In some embodiments, the composition comprises T4 at a concentration of less than about 1 pM. In some embodiments, the composition comprises T4 at a concentration of about 1 pM. In some embodiments, the composition comprises T4 at a concentration of about 2 pM, In some embodiments, the composition comprises T4 at a concentration of about 3 pM. In some embodiments, the composition comprises T4 at a concentration of about 4 pM. In some embodiments, the composition comprises T4 at a concentration of about 5 pM. In some embodiments, the composition comprises T4 at a concentration of about 6 pM. In some embodiments, the composition comprises T4 at a concentration of about 7 pM. In some embodiments, the composition comprises T4 at a concentration of about 8 pM. In some embodiments, the composition comprises T4 at a concentration of about 9 pM. In some embodiments, the composition comprises T4 at a concentration of about 10 pM. In some embodiments, the composition comprises T4 at a concentration of about 15 pM. In some embodiments, the composition comprises T4 at a concentration of about 20 pM. in some embodiments, the composition comprises T4 at a concentration of about 25 pM. In some embodiments, the composition comprises T4 at a concentration of about 30 pM. In some embodiments, the composition comprises T4 at a concentration of greater than about 30 pM.

[119] In some embodiments, the composition comprises T4 at a concentration of between about 10 pM and 15,000 pM. in some embodiments, the composition comprises T4 at a concentration of less than about 10 pM, about 10 pM, about 20 pM, about 50 pM, about 100 pM, about 250 pM, about 500 pM, about 1,000 pM, about 2,500 pM, about 5,000 pM, about 10,000 pM, about 12,000 pM, about 15,000 pM, or greater than about 15,000 pM. including ranges in between these values. In some embodiments, the composition comprises T4 at a concentration of less than about 10 pM. In some embodiments, the composition comprises T4 at a concentration of about 10 pM. In some embodiments, the composition comprises T4 at a concentration of about 20 pM. In some embodiments, the composition comprises T4 at a concentration of about 50 pM. In some embodiments, the composition comprises T4 at a concentration of about 100 pM. In some embodiments, the composition comprises T4 at a concentration of about 250 pM. In some embodiments, the composition comprises T4 at a concentration of about 500 pM. In some embodiments, the composition comprises T4 at a concentration of about 1 ,000 pM. In some embodiments, the composition comprises T4 at a concentration of about 2,500 pM. In some embodiments, the composition comprises T4 at a concentration of about 5,000 pM. In some embodiments, the composition comprises T4 at a concentration of about 10,000 pM. In some embodiments, the composition comprises T4 at a concentration of about 12,000 pM. In some embodiments, the composition comprises T4 at a concentration of about 15,000 pM. In some embodiments, the composition comprises T4 at a concentration of greater than about 15,000 pM. [120] In some embodiments, the composition comprises T4 at a concentration of about 50 nM, 60 nM, 70 nM, 80 nM, 90 nM, 100, 110 nM, 120 nM, 130 nM, 140 nM, 150 nM, 160 nM, 170 nM, 180 nM, 190 nM, or 200 nM. or doses between these values. In some embodiments, the composition comprises T4 at a concentration of about 50 nM. In some embodiments, the composition comprises T4 at a concentration of about 60 nM. In some embodiments, the composition comprises T4 at a concentration of about 70 nM. In some embodiments, the composition comprises T4 at a concentration of about 80 nM. In some embodiments, the composition comprises T4 at a concentration of about 90 nM. In some embodiments, the composition comprises T4 at a concentration of about 100 nM. In some embodiments, the composition comprises T4 at a concentration of about 120 nM. In some embodiments, the composition comprises T4 at a concentration of about 130 nM. In some embodiments, the composition comprises T4 at a concentration of about 140 nM. In some embodiments, the composition comprises T4 at a concentration of about 150 nM. In some embodiments, the composition comprises T4 at a concentration of about 160 nM. in some embodiments, the composition comprises T4 at a concentration of about 170 nM. In some embodiments, the composition comprises T4 at a concentration of about 180 nM. In some embodiments, the composition comprises T4 at a concentration of about 190 nM. In some embodiments, the composition comprises T4 at a concentration of about 200 nM.

[121] In some embodiments, the composition comprises T3 and T4 at a T3:T4 ratio of between about 1:100 and about 1:10,000. In some embodiments, the composition comprises T3 and T4 at a T3:T4 ratio of between about 1:100 and about 1:1,000. In some embodiments, the composition comprises T3 and T4 at a

T3:T4 ratio of about 1:100, 1 :200, 1:300, 1:400, 1 :500, 1:600, 1 :700, 1 :800, 1:900, or 1:1,000, including ranges in between these values. In some embodiments, the composition comprises T3 and T4 at a T3:T4 ratio of less than about 1 :100. In some embodiments, the composition comprises T3 and T4 at a T3:T4 ratio of about 1:100. In some embodiments, the composition comprises T3 and T4 at a T3:T4 ratio of about

1:200. In some embodiments, the composition comprises T3 and T4 at a T3:T4 ratio of about 1 :300. In some embodiments, the composition comprises T3 and T4 at a T3:T4 ratio of about 1:400. In some embodiments, the composition comprises T3 and T4 at a T3:T4 ratio of about 1:500. In some embodiments, the composition comprises T3 and T4 at a T3:T4 ratio of about 1:600. In some embodiments, the composition comprises T3 and T4 at a T3:T4 ratio of about 1:700. In some embodiments, the composition comprises T3 and T4 at a T3:T4 ratio of about 1:800. In some embodiments, the composition comprises T3 and T4 at a T3:T4 ratio of about 1:900. In some embodiments, the composition comprises T3 and T4 at a T3:T4 ratio of about 1 :1 ,000. in some embodiments, the composition comprises T3 and T4 at a T3:T4 ratio of greater than about 1 :1,000. In some embodiments, the composition comprises T3 and T4 at a T3:T4 ratio of between about 1 :1,000 and about 1:10,000. In some embodiments, the composition comprises T3 and T4 at a T3:T4 ratio of about 1:1,000. In some embodiments, the composition comprises T3 and T4 at a T3:T4 ratio of about 1:2,000. In some embodiments, the composition comprises T3 and T4 at a T3:T4 ratio of about 1 :3,000. In some embodiments, the composition comprises T3 and T4 at a T3:T4 ratio of about 1 :4,000, in some embodiments, the composition comprises T3 and T4 at a T3:T4 ratio of about 1 :5,000, in some embodiments, the composition comprises T3 and T4 at a T3:T4 ratio of about 1 :6,000. In some embodiments, the composition comprises T3 and T4 at a T3:T4 ratio of about 1 :7,000. In some embodiments, the composition comprises T3 and T4 at a T3:T4 ratio of about 1 :8,000. in some embodiments, the composition comprises T3 and T4 at a T3:T4 ratio of about 1 :9,000. in some embodiments, the composition comprises T3 and T4 at a T3:T4 ratio of about 1 :10,000. in some embodiments, the composition comprises 13 and T4 at a T3:T4 ratio of greater than about 1 :10,000.

[122] In some embodiments, the composition comprises T3 at a concentration of about 100 pM and T4 at a concentration of about 100 nM. In some embodiments, the composition comprises T3 at a concentration of about 100 pM, T4 at a concentration of about 100 nM, and a therapeutically effective amount of rapamycin. In some embodiments, the composition comprises T3 at a concentration of about 10 nM and T4 at a concentration of about 1 pM. In some embodiments, the composition comprises T3 at a concentration of about 10 nM and T4 at a concentration of about 10 pM. In some embodiments, the composition comprises T3 at a concentration of about 1 nM and T4 at a concentration of about 10 pM.

[123] In some embodiments, the topical composition comprises: a. triiodothyronine (T3); b. thyroxine (T4); and c. a solvent.

[124] In some embodiments, the topical composition comprises: a. triiodothyronine (T3); b. thyroxine (T4); and c. ethanol.

[125] In some embodiments, the topical composition comprises: a. triiodothyronine (T3); b. thyroxine (T4); and c. water.

[126] In some embodiments, the topical composition comprises: a. triiodothyronine (T3); b. thyroxine (T4); and c. propylene glycol.

[127] In some embodiments, the topical composition comprises: a. triiodothyronine (T3); b. thyroxine (T4); c. ethanol; and d. water.

[128] In some embodiments, the topical composition comprises: a. triiodothyronine (T3); b. thyroxine (T4); c. ethanol; and d. propylene glycol.

[129] In some embodiments, the topical composition comprises: a. triiodothyronine (T3); b. thyroxine (T4); c. propylene glycol; and d. water.

[130] In some embodiments, the topical composition comprises: a. triiodothyronine (T3); b. thyroxine (T4); c. ethanol; d. propylene glycol; and e. water.

[131] In some embodiments, the topical composition comprises: a. triiodothyronine (T3); b. thyroxine (T4); c. hydroxypropylcellulose; and d. a solvent.

[132] In some embodiments, the topical composition comprises: a. triiodothyronine (T3); b. thyroxine (T4); c. hydroxypropylcellulose; and d. ethanol.

[133] In some embodiments, the topical composition comprises: a. triiodothyronine (T3); b. thyroxine (T4); c. hydroxypropylcellulose; and d. water.

[134] In some embodiments, the topical composition comprises: a. triiodothyronine (T3); b. thyroxine (T4); c. hydroxypropylcellulose; and d. propylene glycol.

[135] In some embodiments, the topical composition comprises: a. triiodothyronine (T3); b. thyroxine (T4); c. hydroxypropylcellulose; d. ethanol; and e. water.

[136] In some embodiments, the topical composition comprises: a. triiodothyronine (T3); b. thyroxine (T4); c. hydroxypropylcellulose; d. ethanol; and e. propylene glycol.

[137] In some embodiments, the topical composition comprises: a. triiodothyronine (T3); b. thyroxine (T4); c. hydroxypropylcellulose; d. propylene glycol; and e. water.

[138] In some embodiments, the topical composition comprises: a. triiodothyronine (T3); b. thyroxine (T4); c. hydroxypropylcellulose; d. ethanol; e. propylene glycol; and f. water.

[139] In some embodiments, the topical composition comprises: a. triiodothyronine (T3); and b. a solvent.

[140] In some embodiments, the topical composition comprises: a. triiodothyronine (T3); and b. ethanol.

[141] In some embodiments, the topical composition comprises: a. triiodothyronine (T3); and b. water.

[142] In some embodiments, the topical composition comprises: a. triiodothyronine (T3); and b. propylene glycol.

[143] In some embodiments, the topical composition comprises: a. triiodothyronine (T3); b. ethanol; and c. water.

[144] In some embodiments, the topical composition comprises: a. triiodothyronine (T3); b. ethanol; and c. propylene glycol.

[145] In some embodiments, the topical composition comprises: a. triiodothyronine (T3); b. propylene glycol; and c. water.

[146] In some embodiments, the topical composition comprises: a. triiodothyronine (T3); b. ethanol; c. propylene glycol; and d. water.

[147] In some embodiments, the topical composition comprises: a. triiodothyronine (T3); b. hydroxypropylcellulose; and c. a solvent.

[148] In some embodiments, the topical composition comprises: a. triiodothyronine (T3); b. hydroxypropylcellulose; and c. ethanol.

[149] In some embodiments, the topical composition comprises: a. triiodothyronine (T3); b. hydroxypropylcellulose; and c. water.

[150] In some embodiments, the topical composition comprises: a. triiodothyronine (T3); b. hydroxypropylcellulose; and c. propylene glycol.

[151] In some embodiments, the topical composition comprises: a. triiodothyronine (T3); b. hydroxypropylcellulose; c. ethanol; and d. water.

[152] In some embodiments, the topical composition comprises: a. triiodothyronine (T3); b. hydroxypropylcellulose; c. ethanol; and d. propylene glycol.

[153] In some embodiments, the topical composition comprises: a. triiodothyronine (T3); b. hydroxypropylcellulose; c. propylene glycol; and d. water.

[154] In some embodiments, the topical composition comprises: a. triiodothyronine (T3); b. hydroxypropylcellulose; c. ethanol; d. propylene glycol; and e. water.

[155] In some embodiments, the topical composition comprises: a. thyroxine (T4); and b. a solvent.

[156] In some embodiments, the topical composition comprises: a. thyroxine (T4); and b. ethanol.

[157] In some embodiments, the topical composition comprises: a. thyroxine (T4); and b. water.

[158] In some embodiments, the topical composition comprises: a. thyroxine (T4); and b. propylene glycol.

[159] In some embodiments, the topical composition comprises: a. thyroxine (T4); b. ethanol; and c. water.

[160] In some embodiments, the topical composition comprises: a. thyroxine (T4); b. ethanol; and c. propylene glycol.

[161] In some embodiments, the topical composition comprises: a. thyroxine (T4); b. propylene glycol; and c. water.

[162] In some embodiments, the topical composition comprises: a. thyroxine (T4); b. ethanol; c. propylene glycol; and d. water.

[163] In some embodiments, the topical composition comprises: a. thyroxine (T4); b. hydroxypropylcellulose; and c. a solvent.

[164] In some embodiments, the topical composition comprises: a. thyroxine (T4); b. hydroxypropylcellulose; and c. ethanol.

[165] In some embodiments, the topical composition comprises: a. thyroxine (T4); b. hydroxypropylcellulose; and c. water.

[166] In some embodiments, the topical composition comprises: a. (T3); b. thyroxine (T4); c. hydroxypropylcellulose; and d. propylene glycol. [167] In some embodiments, the topical composition comprises: a. thyroxine (T4); b. hydroxypropylcellulose; c. ethanol; and d. water.

[168] In some embodiments, the topical composition comprises: a. thyroxine (T4); b. hydroxypropylcellulose; c. ethanol; and d. propylene glycol.

[169] In some embodiments, the topical composition comprises: a. thyroxine (T4); b. hydroxypropylcellulose; c. propylene glycol; and d. water.

[170] In some embodiments, the topical composition comprises: a. thyroxine (T4); b. hydroxypropylcellulose; c. ethanol; d. propylene glycol; and e. water.

[171] In some embodiments, the composition further comprises a therapeutically effective amount of an additional active compound. In some embodiments, the additional active agent is selected to provide synergistic effects. In embodiments, “synergistic effects” will be understood to include increases in potency, bioactivity, bioaccessibility, bioavailability, or therapeutic effect, that are greater than the additive contributions of the components acting alone, and/or are greater than the contribution of the isolated compounds on their own. Numerous methods known to those of skill in the art exist to determine whether there is synergy as to a particular effect, i.e., whether, when two or more components are mixed together, the effect is greater than the sum of the effects of the individual components when applied alone, thereby producing “1+1 > 2.” One such method is the isobologram analysis (or contour method) (Huang et al. 2019).

[172] In embodiments, the additional active agent is selected to provide an additional therapeutic effect, such as antioxidant, anti-inflammatory, analgesic, antinociceptive, immunostimulant, immunosuppressive, anti-cancer, antiemetic, antiulcer, antihistamine, vasodilating, and vasoconstricting effects. [173] In embodiments, the additional active agent is an amino acid, antioxidant, anti-inflammatory agent, analgesic, 5-alpha reductase inhibitor, cannabinoid, immunosuppressant, immunostimulant, anti-cancer agent, antiulcer agent, antihistamine, terpene, vitamin, vasodilator, or vasoconstrictor. These active agents may be in ion, freebase, or salt form, include polymorphs, and may be isomers.

[174] In some embodiments, the additional active compound is rapamycin. In some embodiments, the additional active compound is rapamycin. In some embodiments, the additional active compound is finasteride. In some embodiments, the additional active compound is dutasteride. In some embodiments, the additional active compound is minoxidil.

[175] In another aspect, provided is a topical composition according to any disclosed embodiment, for use in treating hair loss. In some embodiments, the hair loss is caused by androgenetic alopecia.

[176] In yet another aspect, provided is the use of a topical composition of disclosed embodiment for treating or preventing hair loss, in some embodiments, the hair loss is caused by androgenetic alopecia.

[177] In some embodiments, the topical compositions may be administered and dosed in accordance with good medical practice, taking into account the method and scheduling of administration, prior and concomitant medications and medical supplements, the clinical condition of the individual patient and the severity of the underlying disease, the patient’s age, sex, body weight, and other such factors relevant to medical practitioners, and knowledge of the particular compound(s) used. Dosage levels thus may differ from patient to patient, for individual patients across time, and for different compositions and formulations, but shall be able to be determined with ordinary skill.

[178] Determination of appropriate dosing shall include not only the determination of single dosage amounts, but also the determination of the number and timing of doses, and the time(s) of day or time(s) preferable for administration.

[179] The present disclosure further provides kits comprising the disclosed compositions. In some embodiments, the kits provide disclosed compositions in unit dosage form. Kits generally comprise suitable packaging. The kits may comprise one or more containers comprising any composition described herein. Each component (if there is more than one component) can be packaged in separate containers or some components can be combined in one container where cross-reactivity and shelf life permit. The kits may be in unit dosage forms, bulk packages (e.g., multi-dose packages) or sub-unit doses.

[180] Disclosed kits, for example, may contain sufficient dosages of a disclosed composition for an individual for an extended period, such as any of a week, 2 weeks, 3 weeks, 4 weeks, 6 weeks, 8 weeks, 3 months, 4 months, 5 months, 7 months, 8 months, 9 months, or more. Kits may also include multiple unit doses and instructions for use and be packaged in quantities sufficient for storage at home or a retail location. The kits may optionally include a set of instructions, generally written instructions, although electronic storage media (e.g., magnetic diskette or optical disk) containing instructions are also acceptable, relating to the use of component(s) of the methods of the present disclosure. The instructions included with the kit generally include information as to the components and their administration to an individual.

[181] In some embodiments, a disclosed composition (whether in unit dosage form or not) may be provided in lyophilized form. Lyophilization, also known as freeze-drying, is a process commonly used to preserve and stabilize pharmaceutical compounds and compositions. Lyophilization may result in a dry and shelf-stable product that can subsequently be reconstituted before use. Lyophilization of a disclosed composition may provide several advantages. For example, in some embodiments, a disclosed composition in lyophilized form has improved stability (e.g., improved shelf-stability) and/or reduced susceptibility to chemical, thermal, or biological degradation, as compared to the same composition when not provided in lyophilized form. In some embodiments, a disclosed composition in lyophilized form has reduced weight and/or volume, which may reduce the cost and overall difficulty of transporting, storing, distributing, and using the composition, as compared to the same composition when not provided in lyophilized form.

C. Methods

[182] In one aspect, provided is a method of treating or preventing hair loss in a subject, the method comprising administering to the subject a therapeutically effective amount of a disclosed topical composition. In some embodiments, the method comprises administering to the subject a therapeutically effective amount of T3. In some embodiments, the method comprises administering to the subject a therapeutically effective amount of T4. in some embodiments, the method comprises administering to the subject a therapeutically effective amount of both T3 and T4. In some embodiments, the hair toss is caused by androgenetic alopecia.

[183] In some embodiments, the T3, T4, or a combination thereof is administered topically. In some embodiments, the T3 is administered topically. In some embodiments, the T4 is administered topically. In some embodiments, both the T3 and the T4 are administered topically (l.e., the combination Is administered topically).

[184] In some embodiments, the T3 and T4 are administered simultaneously. The simultaneous administration of the T3 and T4 can be achieved, for example, by administering a composition (e.g., a disclosed topical composition) that contains both T3 and T4. In another embodiment, the simultaneous administration of the T3 and T4 can be achieved, for example, by simultaneous administration of separate T3 and T4 compositions.

[185] In some embodiments, the T3 is administered at a concentration of between about 1 nM and 30 nM. In some embodiments, the T3 is administered at a concentration of less than about 1 nM, about 1 nM, about 2 nM, about 3 nM, about 4 nM, about 5 nM, about 6 nM, about 7 nM, about 8 nM, about 9 nM, about 10 nM, about 15 nM, about 20 nM, about 25 nM, about 30 nM or greater than about 30 nM, including ranges in between these values, in some embodiments, the T3 is administered at a concentration of less than about 1 nM, In some embodiments, the T3 is administered at a concentration of about 1 nM, In some embodiments, the T3 is administered at a concentration of about 2 nM, In some embodiments, the T3 is administered at a concentration of about 3 nM. In some embodiments, the T3 Is administered at a concentration of about 4 nM. In some embodiments, the T3 is administered at a concentration of about 5 nM. in some embodiments, the T3 is administered at a concentration of about 6 nM, In some embodiments, the T3 is administered at a concentration of about 7 nM. in some embodiments, the T3 is administered at a concentration of about 8 nM, In some embodiments, the T3 is administered at a concentration of about 9 nM. in some embodiments, the T3 is administered at a concentration of about 10 nM, In some embodiments, the T3 is administered at a concentration of about 15 nM, In some embodiments, the T3 is administered at a concentration of about 20 nM. In some embodiments, the T3 is administered at a concentration of about 25 nM. in some embodiments, the T3 is administered at a concentration of about 30 nM. In some embodiments, the T3 is administered at a concentration of greater than about 30 nM,

[186] In some embodiments, the T3 is administered at a concentration of between about 1 pM and 15 pM. in some embodiments, the T3 is administered at a concentration of less than about 1 pM, about 1 pM, about 2 pM, about 3 pM, about 4 pM, about 5 pM, about 6 pM, about 7 pM, about 8 pM, about 9 pM, about 10 pM, about 11 pM, about 12 pM, about 13 pM, about 14 pM, about 15 pM, or greater than about 15 pM, including ranges in between these values. In some embodiments, the T3 is administered at a concentration of less than about 1 pM. In some embodiments, the T3 is administered at a concentration of about 1 pM. In some embodiments, the T3 is administered at a concentration of about 2 pM. In some embodiments, the T3 is administered at a concentration of about 3 pM. In some embodiments, the T3 is administered at a concentration of about 4 pM. in some embodiments, the T3 is administered at a concentration of about 5 pM. In some embodiments, the T3 is administered at a concentration of about 6 pM, in some embodiments, the T3 Is administered at a concentration of about 7 pM. In some embodiments, the T3 is administered at a concentration of about 8 pM, In some embodiments, the T3 is administered at a concentration of about 9 pM. in some embodiments, the T3 is administered at a concentration of about 10 pM. In some embodiments, the T3 is administered at a concentration of about 11 pM. In some embodiments, the T3 is administered at a concentration of about 12 pM. In some embodiments, the T3 is administered at a concentration of about 13 pM. In some embodiments, the T3 Is administered at a concentration of about 14 pM. In some embodiments, the T3 is administered at a concentration of about 15 pM. In some embodiments, the T3 Is administered at a concentration of greater than about 15 pM.

[187] In some embodiments, the T3 is administered at a concentration of about 50 pM, 60 pM, 70 pM, 80 pM, 90 pM, 100, 110 pM, 120 pM, 130 pM, 140 pM, 150 pM, 160 pM, 170 pM, 180 pM, 190 pM, or 200 pM, or doses between these values, in some embodiments, the T3 is administered at a concentration of about 50 pM, In some embodiments, the T3 is administered at a concentration of about 60 pM. In some embodiments, the T3 is administered at a concentration of about 70 pM. In some embodiments, the T3 is administered at a concentration of about 80 pM. In some embodiments, the T3 is administered at a concentration of about 90 pM. In some embodiments, the T3 is administered at a concentration of about 100 pM. In some embodiments, the T3 is administered at a concentration of about 110 pM, In some embodiments, the T3 is administered at a concentration of about 120 pM. in some embodiments, the T3 is administered at a concentration of about 130 pM. In some embodiments, the T3 is administered at a concentration of about 140 pM, In some embodiments, the T3 is administered at a concentration of about 150 pM. In some embodiments, the T3 is administered at a concentration of about 160 pM. In some embodiments, the T3 is administered at a concentration of about 170 pM. In some embodiments, the T3 is administered at a concentration of about 180 pM. In some embodiments, the T3 is administered at a concentration of about 190 pM In some embodiments, the T3 is administered at a concentration of about 200 pM.

[188] In some embodiments, the T4 is administered at a concentration of between about 1 pM and 30 pM. In some embodiments, the T4 is administered at a concentration of less than about 1 pM, about 1 pM, about 2 pM, about 3 pM. about 4 pM, about 5 pM, about 6 pM, about 7 pM, about 8 pM, about 9 pM, about 10 pM, about 15 pM, about 20 pM, about 25 pM, about 30pM, or greater than about 30 pM. In some embodiments, the T4 is administered at a concentration of less than about 1 pM, In some embodiments, the T4 is administered at a concentration of about 1 pM. In some embodiments, the T4 is administered at a concentration of about 2 pM. In some embodiments, the T4 is administered at a concentration of about 3 pM, In some embodiments, the T4 is administered at a concentration of about 4 pM, In some embodiments, the T4 is administered at a concentration of about 5 pM, In some embodiments, the T4 is administered at a concentration of about 6 pM. In some embodiments, the T4 is administered at a concentration of about 7 pM. In some embodiments, the T4 Is administered at a concentration of about 8 pM, In some embodiments, the T4 is administered at a concentration of about 9 pM, In some embodiments, the T4 is administered at a concentration of about 10 pM, In some embodiments, the T4 is administered at a concentration of about 15 pM. In some embodiments, the T4 is administered at a concentration of about 20 pM. In some embodiments, the T4 is administered at a concentration of about 25 pM. In some embodiments, the T4 is administered at a concentration of about 30 pM, In some embodiments, the T4 is administered at a concentration of greater than about 30 pM.

[189] In some embodiments, the T4 is administered at a concentration of between about 10 pM and 15,000 pM. In some embodiments, the T4 is administered at a concentration of less than about 10 pM, about 10 pM, about 20 pM, about 50 pM, about 100 pM, about 250 pM, about 500 pM, about 1,000 pM, about 2,500 pM, about 5,000 pM, about 10,000 pM, about 12,000 pM, about 15,000 pM, or greater than about 15,000 pM, including ranges in between these values. In some embodiments, the T4 is administered al a concentration of iess than about 10 pM. In some embodiments, the T4 is administered at a concentration of about 10 pM. In some embodiments, the T4 is administered at a concentration of about 20 pM. In some embodiments, the T4 is administered at a concentration of about 50 pM. In some embodiments, the T4 is administered at a concentration of about 100 pM. In some embodiments, the T4 is administered at a concentration of about 250 pM. In some embodiments, the T4 is administered at a concentration of about 500 pM. In some embodiments, the T4 is administered at a concentration of about 1,000 pM. In some embodiments, the T4 is administered at a concentration of about 2,500 pM. in some embodiments, the T4 is administered at a concentration of about 5,000 pM. In some embodiments, the T4 is administered at a concentration of about 10,000 pM, In some embodiments, the T4 is administered at a concentration of about 12,000 pM. In some embodiments, the T4 is administered at a concentration of about 15,000 pM. in some embodiments, the T4 is administered at a concentration of greater than about 15,000 pM.

[190] In some embodiments, the T4 is administered at a concentration of about 50 nM, 60 nM, 70 nM, 80 nM, 90 nM, 100, 110 nM, 120 nM, 130 nM, 140 nM, 150 nM, 160 nM, 170 nM, 180 nM, 190 nM, or 200 nM, or doses between these values. In some embodiments, the T4 is administered at a concentration of about 50 nM. In some embodiments, the T4 is administered at a concentration of about 60 nM. In some embodiments, the T4 is administered at a concentration of about 70 nM. in some embodiments, the T4 is administered at a concentration of about 80 nM. In some embodiments, the T4 is administered at a concentration of about 90 nM. In some embodiments, the T4 is administered at a concentration of about 100 nM. in some embodiments, the T4 is administered at a concentration of about 120 nM. In some embodiments, the T4 is administered at a concentration of about 130 nM. In some embodiments, the T4 is administered at a concentration of about 140 nM. In some embodiments, the T4 is administered at a concentration of about 150 nM. In some embodiments, the T4 is administered at a concentration of about 160 nM. In some embodiments, the T4 is administered at a concentration of about 170 nM. In some embodiments, the T4 is administered at a concentration of about 180 nM, In some embodiments, the T4 is administered at a concentration of about 190 nM. In some embodiments, the T4 is administered at a concentration of about 200 nM.

[191] In some embodiments, the T3 and T4 are administered at a T3:T4 ratio of between about 1 :100 and about 1:10,000. In some embodiments, the T3 and T4 are administered at a T3:T4 ratio of between about 1:100 and about 1:1 ,000. In some embodiments, the T3 and T4 are administered at a T3:T4 ratio of about 1:100, 1:200, 1:300, 1 :400, 1:500, 1 :600, 1 :700, 1 :800, 1:900, or 1 :1,000. In some embodiments, the T3 and T4 are administered at a T3:T4 ratio of iess than about 1:100. In some embodiments, the T3 and T4 are administered at a T3:T4 ratio of about 1:100. In some embodiments, the T3 and T4 are administered at a T3:T4 ratio of about 1 :200. in some embodiments, the T3 and T4 are administered at a T3:T4 ratio of about 1 :300. In some embodiments, the T3 and T4 are administered at a T3:T4 ratio of about 1:400. In some embodiments, the T3 and T4 are administered at a T3:T4 ratio of about 1 :500. in some embodiments, the T3 and T4 are administered at a T3:T4 ratio of about 1 :600. in some embodiments, the T3 and T4 are administered at a T3:T4 ratio of about 1 :700. In some embodiments, the T3 and T4 are administered at a T3:T4 ratio of about 1 :800. In some embodiments, the T3 and T4 are administered at a T3:T4 ratio of about 1 :900. in some embodiments, the T3 and T4 are administered at a T3:T4 ratio of about 1:1,000, In some embodiments, the T3 and T4 are administered at a T3:T4 ratio of greater than about 1:1.000. in some embodiments, the T3 and T4 are administered at a T3:T4 ratio of between about 1 :1 ,000 and about 1 :10,000. In some embodiments, the T3 and T4 are administered at a T3:T4 ratio of about 1:1,000. In some embodiments, the T3 and T4 are administered at a T3:T4 ratio of about 1 :2, 000. In some embodiments, the T3 and T4 are administered at a T3:T4 ratio of about 1 :3 ,000. In some embodiments, the T3 and T4 are administered at a T3:T4 ratio of about 1 :4,000. In some embodiments, the T3 and T4 are administered at a T3:T4 ratio of about 1:5,000. In some embodiments, the T3 and T4 are administered at a T3:T4 ratio of about 1:6,000. In some embodiments, the T3 and T4 are administered at a T3:T4 ratio of about 1:7,000. In some embodiments, the T3 and T4 are administered at a T3:T4 ratio of about 1:8,000. In some embodiments, the T3 and T4 are administered at a T3:T4 ratio of about 1 :9,000. in some embodiments, the T3 and T4 are administered at a T3:T4 ratio of about 1 :10,000. In some embodiments, the T3 and T4 are administered at a T3:T4 ratio of greater than about 1:10,000.

[192] in some embodiments, the T3 is administered at a concentration of about 100 pM and the T4 is administered at a concentration of about 100 nM. In some embodiments, the T3 is administered at a concentration of about 10 nM and the T4 is administered at a concentration of about 1 pM. In some embodiments, the T3 is administered at a concentration of about 10 nM and the T4 is administered at a concentration of about 10 pM. In some embodiments, the T3 is administered at a concentration of about 1 nM and the T4 is administered at a concentration of about 10 pM.

[193] In some embodiments, the total unit dose volume of a disclosed topical composition is between about 0.1 mL and 10 mL. In some embodiments, the total unit dose volume is about 0.1 mL, about 0.5 mL, about 1 mL, about 2 mL, about 3 mL, about 4 mL, about 5 mL, about 6 mL, about 7 mL, about 8 mL, about 9 mL, or about 10 mL. In some embodiments, the total unit dose volume Is about 0.1 mL. In some embodiments, the total dose volume is about 0.5 mL. In some embodiments, the total unit dose volume is about 1 mL. In some embodiments, the total unit dose volume is about 2 mL. In some embodiments, the total dose volume of a disclosed pharmaceutical composition is about 3 mL. In some embodiments, the total unit dose volume Is about 4 mL. In some embodiments, the total unit dose volume is about 5 mL. In some embodiments, the total unit dose volume is about 6 mL. In some embodiments, the total unit dose volume is about 7 mL. In some embodiments, the total unit dose volume is about 8 mL. In some embodiments, the total dose volume of a disclosed pharmaceutical composition is about 9 mL. In some embodiments, the total unit dose volume is about 10 mL. [194] In some embodiments, disclosed methods are performed in accordance with good medical practice, taking into account the method and scheduling of administration, prior and concomitant medications and medical supplements, the clinical condition of the individual patient and the severity of the underlying disease, the patient’s age, sex, body weight, and other such factors relevant to medical practitioners, and knowledge of the particular compound(s) used. Dosage levels thus may differ from patient to patient, for individual patients across time, and for different compositions and formulations, but shall be able to be determined with ordinary skill.

[195] In some embodiments, the topical composition is administered every other day for a period of time, followed by a prolonged period without administration. For example, in some embodiments, the topical composition is administered every other day for 1 week followed by a prolonged period without administration. In some embodiments, the topical composition is administered every other day for 2 weeks followed by a prolonged period without administration. In some embodiments, the topical composition is administered every other day for 3 weeks followed by a prolonged period without administration. In some embodiments, the topical composition is administered every other day for 4 weeks followed by a prolonged period without administration. In some embodiments, the topical composition is administered every other day for 5 weeks followed by a prolonged period without administration. In some embodiments, the topical composition is administered every other day for 6 weeks followed by a prolonged period without administration.

[196] In some embodiments, the prolonged period without administration lasts for one day. In some embodiments, the prolonged period without administration lasts for 2 days. In some embodiments, the prolonged period without administration lasts for 3 days. In some embodiments, the prolonged period without administration lasts for 4 days. In some embodiments, the prolonged period without administration lasts for 5 days. In some embodiments, the prolonged period without administration lasts for 6 days. In some embodiments, the prolonged period without administration lasts for 7 days. In some embodiments, the prolonged period without administration lasts for 10 days. In some embodiments, the prolonged period without administration lasts for 14 days. In some embodiments, the prolonged period without administration lasts for 30 days.

[197] In some embodiments, the topical composition is administered every day for several consecutive days followed by a prolonged period without administration. For example, in some embodiments, the topical composition is administered every day for 2 consecutive days followed by a prolonged period without administration. In some embodiments, the topical composition is administered every day for 3 consecutive days followed by a prolonged period without administration. In some embodiments, the topical composition is administered every day for 4 consecutive days followed by a prolonged period without administration. In some embodiments, the topical composition is administered every day for 5 consecutive days followed by a prolonged period without administration. In some embodiments, the topical composition is administered every day for 6 consecutive days followed by a prolonged period without administration. In some embodiments, the topical composition is administered every day for 7 consecutive days followed by a prolonged period without administration. In other embodiments, the topical composition is administered for only one day followed by a prolonged period without administration.

[198] In some embodiments, the prolonged period without administration lasts for one day. In some embodiments, the prolonged period without administration lasts for 2 days. In some embodiments, the prolonged period without administration lasts for 3 days. In some embodiments, the prolonged period without administration lasts for 4 days. In some embodiments, the prolonged period without administration iasts for 5 days. In some embodiments, the prolonged period without administration lasts for 6 days. In some embodiments, the prolonged period without administration lasts for 7 days. In some embodiments, the prolonged period without administration iasts for 10 days. In some embodiments, the prolonged period without administration lasts for 14 days. In some embodiments, the prolonged period without administration lasts for 30 days.

[199] In some embodiments, the T3, T4, or a combination thereof are administered in a topical composition. In some embodiments, a disclosed method comprises administering a combination of T3 and T4. In some embodiments, the T3 and T4 are in the same composition. In other embodiments, the T3 and T4 are in different compositions.

[200] It will be appreciated that the frequency or duration of a disclosed method may be increased or reduced, as indicated by the clinical outcome desired, status of the pathology or symptom, any adverse side effects of the treatment or therapy, or concomitant medications. In some embodiments, the subject is subjected to a disclosed method every day for several consecutive days followed by a prolonged period without administration. This is referred to herein as “pulsed dosing” or “pulsed therapy.” to some embodiments, the subject is subjected to a disclosed method every day for 2 consecutive days followed by a prolonged period without administration, in some embodiments, the subject is subjected to a disclosed method every day for 3 consecutive days followed by a prolonged period without administration. In some embodiments, the subject is subjected to a disclosed method every day for 4 consecutive days followed by a prolonged period without administration. In some embodiments, the subject is subjected to a disclosed method every day for 5 consecutive days followed by a prolonged period without administration. In some embodiments, the subject is subjected to a disclosed method every day for 6 consecutive days followed by a prolonged period without administration. In some embodiments, the subject is subjected to a disclosed method every day for 7 consecutive days followed by a prolonged period without administration. In some embodiments, the subject is subjected to a disclosed method every day for 10 consecutive days followed by a prolonged period without administration. In some embodiments, the subject is subjected to a disclosed method every day for 14 consecutive days followed by a prolonged period without administration, in some embodiments, the subject is subjected to a disclosed method for only one day followed by a prolonged period without administration.

[201] In some embodiments, the prolonged period without administration lasts one day, In some embodiments, the prolonged period without administration lasts 2 days. In some embodiments, the prolonged period without administration lasts 3 days. In some embodiments, the prolonged period without administration lasts 4 days. In some embodiments, the prolonged period without administration lasts 5 days. In some embodiments, the prolonged period without administration lasts 6 days. In some embodiments, the prolonged period without administration lasts 7 days. In some embodiments, the prolonged period without administration lasts 10 days. In some embodiments, the prolonged period without administration lasts 14 days. In some embodiments, the prolonged period without administration lasts 30 days.

[202] In some embodiments, the amount of T3 administered during a single administration of a disclosed topical composition (l.e., per unit dose) is between about 0.00001 pg and about 0.1 pg. In some embodiments, the amount of T3 administered per unit dose Is between about 0.00001 pg and about 0.001 pg. In some embodiments, the amount of T3 administered per unit dose is between about 0.00001 pg and about 0.01 pg. In some embodiments, the amount of T3 administered per unit dose is between about 0.001 pg and about 0.01 pg. in some embodiments, the amount of T3 administered per unit dose is between about 0.01 pg and about 0.1 pg.

[203] In some embodiments, the amount of T3 administered per unit dose is between about 1 ng and 20 ng. In some embodiments, the amount of T3 administered per unit dose is between about 1 ng and 10 ng. In some embodiments, the amount of T3 administered per unit dose is between about 5 ng and 10 ng. In some embodiments, the amount of T3 administered per unit dose is about 1 ng, 2 ng, 3 ng, 4 ng, 5 ng, 6 ng, 7 ng, 8 ng, 9 ng, or 10 ng. In some embodiments, the amount of T3 administered per unit dose is about 6.5 ng,

[204] In some embodiments, the amount of T3 administered per unit dose is between about 0.1 ng and 1 ng. In some embodiments, the amount of T3 administered per unit dose is about 0.1 ng, 0.2 ng, 0.3 ng, 0.4 ng, 0.5 ng, 0.6 ng, 0.7 ng, 0.8 ng, 0.9 ng, or 1.0 ng. In some embodiments, the amount of T3 administered per unit dose is about 0.65 ng.

[205] In some embodiments, the amount of T4 administered during a single administration of a disclosed topical composition (i.e., per unit dose) is between about 0.1 pg and about 100 pg. In some embodiments, the amount of T4 administered per unit dose is between about 0.1 pg and about 1 pg. In some embodiments, the amount of T4 administered per unit dose is between about 0.1 pg and about 10 pg. in some embodiments, the amount of T4 administered per unit dose is between about 1 pg and about 10 pg, In some embodiments, the amount of T4 administered per unit dose is between about 10 pg and about 100 pg.

[206] In some embodiments, disclosed compositions are formulated as a unit dosage form, each dosage containing an effective amount of the active ingredient(s), for example in the dosage amounts disclosed above. The term “unit dosage form” refers to a physically discrete unit suited as unitary dosages to be consumed by the individual, each unit containing a predetermined quantity of active material calculated to produce the desired effect(s). Unit dosage forms are often used for ease of administration and uniformity of dosage. Unit dosage forms can contain a single or individual dose or unit, a sub-dose, or an appropriate fraction thereof, of the composition.

[207] In embodiments wherein a disclosed composition is used to create a desired effect, it will be readily appreciated that dose and dosage may vary depending upon the general health, age, gender, and race of the individual, bioavailability, potential adverse systemic, regional, or local side effects, the presence of any disorders or diseases in the individual, and other factors that will be appreciated by those in the art (e.g., medical or familial history).

[208] In general, dose amount, frequency, or duration may be increased or reduced, as indicated by the therapeutic outcome(s) or effects) desired, the beneficial outcome(s) or effect(s) desired, and/or by the specific subjective outcome(s) or effect(s) desired.

[209] Those in the art will appreciate the factors that may influence the dosage, frequency, and timing required to provide an amount sufficient or effective for providing a desired effect, and to do so depending on the type of desired effect and to avoid or minimize adverse effects.

[210] Dosage levels may differ from patient to patient, for individuals across time, and for different compositions and formulations, but shall be able to be determined with ordinary skill. Determination of appropriate dosing shall include not only the determination of single dosage amounts, but also the determination of the number and timing of doses, and the time(s) of day or time(s) preferable for administration.

D. Excipients

[211] In some embodiments, a disclosed composition is formulated for topical administration (e.g., as a topical dosage form), for example through the use of one or more pharmaceutically acceptable excipients. Topical dosage forms include transmucosal and transdermal formulations, such as aerosols, emulsions, sprays, ointments, salves, gels, pastes, lotions, liniments, oils, and creams. Pharmaceutically acceptable excipients include, for example, penetration enhancers, carriers, diluents, emulsifiers, stabilizers, solvents and cosolvents, viscosity modifying agents (e.g., thickeners), adhesion modifying agents (e.g., tackifiers), preservatives, antioxidants, adhesive polymers, solubilizing agents, colorants, binders, humectants, surfactants, gelling agents, and other such ingredients as will be generally known to one of skill in the art.

[212] Pharmaceutical formulations may be prepared as liquid suspensions or solutions using a sterile liquid, such as but not limited to, an oil, water, an alcohol, and combinations of these pharmaceutically suitable surfactants, suspending agents, and emulsifying agents. Suspensions may include oils. Such oils include peanut oil, sesame oil, cottonseed oil, corn oil, and olive oil. Suitable oils also include carrier oils such as MCT and long chain triglyceride (LCT) oils. Suspension preparation may also contain esters of fatty acids such as ethyl oleate, isopropyl myristate, fatty acid glycerides, and acetylated fatty acid glycerides. Suspension formulations may include alcohols, (such as ethanol, isopropyl alcohol, hexadecyl alcohol), glycerol, and propylene glycol. Ethers, such as polyethylene glycol), petroleum hydrocarbons such as mineral oil and petrolatum, and water may also be used in suspension formulations. A suspension can thus include an aqueous liquid or a non-aqueous liquid, an oil-in-water liquid emulsion, or a water-in-oil emulsion.

[213] “Pharmaceutically acceptable” as used in connection with an excipient or other ingredient means that the ingredient is generally safe and, within the scope of sound medical judgment, suitable for use in contact with the cells of humans and other animals without undue toxicity, irritation, allergic response, or complication, and commensurate with a reasonable risk/benefit ratio. In some embodiments, “pharmaceutically acceptable” means that a particular ingredient has been approved by the FDA for topical use in cosmetic products.

[214] In some embodiments, the composition comprises a penetration enhancer. Without being bound by theory, penetration enhancers are generally characterized by their ability to increase the permeability of biological barriers, such as scalp skin. In some embodiments, including a penetration enhancer in the composition increases the bioavailability of the active agent(s) (e.g., T3, T4, and/or any additional active ingredients) by improving the ability of the active agent(s) to diffuse into the skin tissue. Penetration enhancers include, for example, include fatty acids and oils such as castor oil, coconut oil, medium chain triglycerides (MCT), jojoba oil, sunflower oil, argan oil, almond oil, olive oil, mineral oil, petroleum jelly, cocoa butter, shea butter, or other esters, triglycerides, or functional derivatives thereof. In some embodiments, the penetration enhancer is 1,2-lauryl ether, aprotinin, azone, benzalkonium chloride, benzalkonium bromide, cetylpyridinium chloride, cetyltrimethyl ammonium, cyclodextrin, dextran sulfate, glycol, lauric acid, lauric acid, propylene, lysophosphatidylcholine, menthol, phosphatidylcholine, polyoxyethylene, polysorbate 80, sodium EDTA, chitosan, sodium glycocholate, sodium deoxyglycocholate, sodium lauryl sulfate, sodium salicylate, sodium taurocholate, dimethyl sulfoxide, or a combination thereof. In some embodiments, the penetration enhancer is selected from a group comprising lower chain alcohol with a carbon chain length of 1 to 5, sodium glycocholate, sodium deoxycholate, sodium taurocholate, sodium glycodeoxychoiate, sodium taurodeoxyeholate, oleic acid, capric acid, lauric acid, lecithin, myristic acid, palmitic acid, fysophosphatidylchoiine, phosphatidylcholine, azone, cyclodextrin, sodium lauryl sulphate, Polyoxyethylene-9-lauryl ether, Polyoxythylene-20-cetyiether, Benzalkonium chloride, cetylpyridinium chloride, Vitamin E TPGS, Caprylocaproyl poiyoxylglycerides, Stearoyl Macrogolglycerides, Propylene Glycol Dicaprylocaprate or mixtures thereof. In some embodiments, compositions of the disclosure may comprise a penetration enhancer at a concentration of about 0.01%, about 0.02%, about 0.05%, about 0.1%, about 0.2%, about 0.3%, about 0.4%, about 0.5%, about 0.6%, about 0.7%, about 0.8%, about 0.9%, about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, about 20%, about 21%, about 22%, about 23%, about 24%, about 25%, about

26%, about 27%, about 28%, about 29%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 61%, about 62%, about 63%, about 64%, about 65%, about 66%, about

67%, about 68%, about 69%, about 70%, about 75%, about 75%, and about 80% of the composition, on a weight or volume basis.

[215] In some embodiments, the base may further include a conditioning agent to prevent drying of the skin and hair in combination with the active agent(s) (e.g., T3, T4, and/or any additional active ingredients). Representative conditioning agents may include, but are not limited to, glycerin, propylene glycol, alpha hydroxyl acids, urea, lactic acid, oils, lanolin and silicone and its derivatives. In some embodiments, conditioning agents are physically and chemically compatible with the essential components of the composition, and do not otherwise unduly impair product stability, aesthetics or performance. In some embodiments, the concentration of the conditioning agent in the composition is sufficient to provide the desired conditioning benefits, as will be apparent to one of ordinary skill in the art. The concentration may vary with the conditioning agent, the conditioning performance desired, the average size of the conditioning agent particles, the type and concentration of other components, and other like factors.

[216] In some embodiments, the composition comprises a carrier. Carriers can be designed to give controlled release profiles, improved circulation times and better penetration across the epithelium. In some embodiments, the carrier is a hydrophobic drug carrier. Hydrophobic drug carriers can have the advantage of exhibiting slow sustained release and may adhere well to biological surfaces. Hydrophobic drug carriers can have slow (i.e., extended) release kinetics, or may also be constructed to have a rapid or immediate release profile. New techniques include the development of hydrophilic coatings on hydrophobic nanoparticles to improve their transport across tissue surfaces while retaining the slow-release profiles. These include polyethylene glycol and chitosan coatings. (See, e.g., de la Fuente, et al. Nanomedicine 2008;3:845-857.) Any of a variety of pharmaceutically acceptable carriers may be used including, without limitation, aqueous media such as water, saline, glycine, hyaluronic acid and the like; solid carriers such as starch, magnesium stearate, mannitol, sodium saccharin, talcum, cellulose, glucose, sucrose, lactose, trehalose, magnesium carbonate, and the like; solvents; dispersion media; coatings; antibacterial and antifungal agents; isotonic and absorption delaying agents; or any other inactive ingredient. Selection of a pharmacologically acceptable carrier can depend on the mode of administration. Non-limiting examples of specific uses of such pharmaceutical carriers can be found in Pharmaceutical Dosage Forms and Drug Delivery Systems (Howard C. Ansel et al., eds., Lippincott Williams & Wilkins Publishers, 7th ed. 1999); Remington: The Science and Practice of Pharmacy (Alfonso R. Gennaro ed., Lippincott, Williams & Wilkins, 20th ed. 2000); Goodman & Gilman's The Pharmacological Basis of Therapeutics (Joel G. Hardman et al., eds., McGraw-Hill Professional, 10th ed. 2001); and Handbook of Pharmaceutical Excipients (Raymond C. Rowe et al., APhA Publications, 4th edition 2003). In some embodiments, compositions of the disclosure may comprise a carrier at a concentration of about 0.01%, about 0.02%, about 0.05%, about 0.1%, about 0.2%, about 0.3%, about 0.4%, about 0.5%, about 0.6%, about 0.7%, about 0.8%, about 0.9%, about 1 %, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, about 20%, about 21%, about 22%, about 23%, about 24%, about 25%, about 26%, about 27%, about 28%, about 29%, about 30%, about 35%, about 40%, about 45%, about

50%, about 55%, about 60%, about 61%, about 62%, about 63%, about 64%, about 65%, about 66%, about 67%, about 68%, about 69%, about 70%, about 75%, about 75%, and about 80% of the composition, on a weight or volume basis.

[217] In some embodiments, the composition comprises an emulsifier. The emulsifier may be an anionic, cationic, or neutral emulsifier. In certain embodiments, the emulsifier is an anionic emulsifier selected from the group consisting of alkyl sulfate, aralkyl sulfates, alkyl ethoxy ether sulfates, alkaryl sulphonates, alkyl succinates, alkyl sulfosuccinates, N-alkoyl sarconsinates, isethionates, N-acyl taurate, sodium lauryl sulfate, sodium laureth sulfate, sodium oleyl succinate, sodium dodecylbenzenesulfonate, and sodium lauryl sarconsinate. Exemplary non-ionic or neutral emulsifiers include sorbitan ester, ethoxylated sorbitan ester, ethoxylated alkyl ether, ethoxylated fatty acid ether, fatty alcohol, ethoxylated fatty alcohol, and esters of glycerin and fatty acids. In certain embodiments, the emulsifiers are synthetic or natural polymers. In certain embodiments, the emulsifier includes silicon. In certain embodiments, the emulsifier is a silicone (e.g. dimethicone, phenyltrimethicone, PEG dimethicone, PPG dimethicone, etc.). In some embodiments, compositions of the disclosure may comprise an emulsifier at a concentration of about 0.01%, about 0.02%, about 0.05%, about 0.1%, about 0.2%, about 0.3%, about 0.4%, about 0.5%, about 0.6%, about 0.7%, about 0.8%, about 0.9%, about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, about 20%, about 21%, about 22%, about 23%, about 24%, about

25%, about 26%, about 27%, about 28%, about 29%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 61%, about 62%, about 63%, about 64%, about 65%, about

66%, about 67%, about 68%, about 69%, about 70%, about 75%, about 75%, and about 80% of the composition, on a weight or volume basis.

[218] In some embodiments, the composition comprises an anti-dandruff agent or or other ingredients which are commonly applied to the scalp or hair, including antimicrobial agents, where desirable, generally in amounts found useful in topical applications. One of ordinary skill in the art can easily determine the type and amount of anti-dandruff agent chosen for use in formulations according to the present invention.

[219] In some embodiments, the composition comprises an antioxidant. The antioxidant may be amino acids (e.g. glycine, histidine, tyrosine, tryptophan) and derivatives thereof, imidazoles (e.g. urocanic acid) and derivatives thereof peptides, such as D,L-carnosine, D-carnosine, L-carnosine and derivatives thereof (e.g. anserine), carotenoids, carotenes (e.g. p-carotene, lycopene) and derivatives thereof, chlorogenic acid and derivatives thereof, liponic acid and derivatives thereof (e.g. dihydroliponic acid), aurothioglucose, propylthiouracil and other thiols (e.g. thiorodoxin, glutathione, cysteine, cystine, cystamine and the glycosyl, N-acetyl, methyl, ethyl, propyl, amyl, butyl, and lauryl, palmitoyl, oleyl, y-linoleyl, cholesteryl and glyceryl esters thereof) and salts thereof, dilauryl thiodipropionate, distearyl thiodipropionate, thiodipropionic acid and derivatives thereof (esters, ethers, peptides, lipids, nucleotides, nucleosides and salts) and sulfoximine compounds (e.g. buthionine sulfoximines, homocysteine sulfoximines, buthionine sulfones, penta, hexa and heptathionine sulfoximine), in very low tolerated doses (e.g. pmol to pmol/kg), and furthermore (metal)chelators (e.g. a-hydroxy-fatty acids, palmitic acid, phytic acid, lactoferrin), a-hydroxy acids (e.g. citric acid, lactic acid, malic acid), humic acid, gallic acid, bile extracts, bilirubin, biliverdin, EDTA and derivatives thereof, unsaturated fatty acids and derivatives thereof (e.g. y-linolenic acid, linoleic acid, oleic acid), folic acid and derivatives thereof, ubiquinone and ubiquinol and derivatives thereof vitamin C and derivatives thereof (e.g. sodium ascorbate, ascorbyl palmitate, magnesium ascorbyl phosphate, ascorbyl acetate), tocopherol and derivatives (e.g. vitamin E acetate, tocotrienol), vitamin A and derivatives (vitamin A palmitate) and coniferyl benzoate of benzoic resin, rutinic acid and derivatives thereof, a-glycosylrutin, ferulaic acid, furfurylideneglucitol, carnosine, butylhydroxytoluene, butylhydroxyanisole, nordihydroguajak resin acid, nordihydroguaiaretic acid, trihydroxybutyrophenone, uric acid and derivatives thereof, mannose and derivatives thereof, zinc and derivatives thereof (e.g. ZnO, ZnSO4), selenium and derivatives thereof (e.g. selenium methionine), stilbenes and derivatives thereof (e.g. stilbene oxide, trans-stilbene oxide).

[220] In embodiments, the composition comprises a vitamin. The vitamin may be riboflavin (vitamin B2), niacinamide (vitamin B3), pantothenic acid (vitamin B5), pyridoxine (vitamin B6), biotin (vitamin B7).

[221] In some embodiments, the composition comprises a conventional thickener. The conventional thickener may be crosslinked polyacrylic acids and derivatives thereof, polysaccharides and derivatives thereof, such as xanthan gum, agar agar, alginates or tyloses, cellulose derivatives (e.g. carboxymethylcellulose or hydroxycarboxymethylcellulose), fatty alcohols, monoglycerides and fatty acids, polyvinyl alcohol and polyvinylpyrrolidone. Nonionic thickeners are preferably used.

[222] In some embodiments, the composition comprises a cosmetically and/or dermo-cosmetically active substance. A cosmetically and/or dermo-cosmetically active substance may be color-imparting active substances, skin- and hair-pigmenting compositions, tinting compositions, tanning compositions, bleaches, keratin-hardening substances, antimicrobial active substances, light filter active substances, repellent active substances, substances having hyperemic activity, substances having keratolytic and keratoplastic activity, antidandruff active substances, antiphlogistic agents, substances having keratinizing activity, antioxidant active substances or substances active as free radical scavengers, skin-moisturizing substances or skin humectants, refatting active substances, substances having antierythematous or antiallergic activity, branched fatty acids, such as 18-methyleicosanoic acid, and mixtures thereof.

[223] In embodiments, the composition comprises a perfume oil. Natural fragrances are extracts of blossoms (lily, lavender, rose, jasmine, neroli, ylang-ylang), stalks and leaves (geranium, patchouli, petitgrain), fruits (anise, coriander, caraway, juniper), fruit peels (bergamot, lemon, orange), roots (mace, angelica, celery, cardamom, costus, iris, calmus), woods (pinewood, sandalwood, guajak wood, cedar wood, rosewood), herbs and grasses (tarragon, lemongrass, sage, thyme), needles and branches (spruce, fir, pine, dwarf pine), resins and balsams (galbanum, elemi, benzoin, myrrh, olibanum, opoponax). Typical synthetic fragrance compounds are products of the type consisting of the esters, ethers, aldehydes, ketones, alcohols and hydrocarbons. Essential oils of low volatility, which are generally used as aroma components, are also suitable as perfume oils, e.g. sage oil, chamomile oil, clove oil, balm oil, mint oil, cinnamon leaf oil, lime tree blossom oil, juniper oil, vetiver oil, oliban oil, galbanum oil, labolanum oil and lavandin oil. Bergamot oil, dihydromyrcenol, lilial, lyral, citronellol, phenylethyl alcohol, a-hexylcinnamaldehyde, geraniol, benzylacetone, cyclamenaldehyde, linalool, Boisambrene®Forte, ambroxan, indole, hedione, sandelice, lemon oil, mandarin oil, orange oil, allylamyl glycolate, cyclovertal, lavandin oil, muscatel sage oil, G39 damascone, Bourbon geranium oil, cyclohexyl salicylate, Vertofix®Coeur, iso-E-Super®, Fixolide®NP, evemyl, iraldein gamma, phenylacetic acid, geranyl acetate, benzyl acetate, rose oxide, romillate, irotyl and floramat.

[224] In some embodiments, the topical composition comprises a hydroxyalkyl cellulose. Hydroxyalkyl celluloses can have multiple functions when included as an excipient. For example, a hydroxyalkyl cellulose may act as any of a penetration enhancer, carrier, emulsifier, stabilizer, viscosity modifying agent, adhesion modifying agent, antioxidant, adhesive polymer, solubilizing agent, binder, humectant, and/or gelling agent. In some embodiments, the topical composition comprises hydroxymethylcellulose. In some embodiments, the topical composition comprises hydroxyethylcellulose. In some embodiments, the topical composition comprises hydroxypropylcellulose.

[225] In some embodiments, the composition comprises a solvent, and optionally a cosolvent. Any solvent(s) and cosolvent(s) may be collectively referred to as a “solvent system.” Without being bound by theory, the solvent system chosen can affect the stability, bioavailability, and overall efficacy of the composition. In some embodiments, the solvent system is capable of dissolving or solubilizing the active ingredients and any included excipients at the desired concentration(s), and should be stable and compatible with components (e.g, T3, T4, any additional active agent(s), and any other excipients) in the composition. In some embodiments, wherein the solvent system comprises more than one solvent, the ratio of cosolvents is optimized, for example to increase the penetration or bioavailability of an active ingredient. Preferred solvent systems are also safe and non-toxic for human consumption. In some embodiments, potential adverse effects, such as irritation or allergic reactions, are considered and minimized during selection of solvents included in a solvent system of the disclosure. Solvents that may be included in disclosed compositions may include, without limitations, water, ethanol, polyhydric alcohols (e.g., glycerin), 1,3-butylene glycol, propylene glycol, hexylene glycol, propane diol, ethylene glycol, diethylene glycol, dipropylene glycol, diglycerin, sorbitol, other sugars which are liquid at room temperature, water-soluble alkoxylated nonionic polymers such as polyethylene glycol, and combinations thereof. Solvents may be present, individually or in total (if more than one solvent is included), in the composition in an amount ranging from about 0.1 wt% to about 95 wt% (calculated as the total weight of solvents in the composition divided by the total weight of the composition).

[226] In some embodiments, the solvent system is an aqueous solvent system. In some embodiments, the solvent system comprises water. In some embodiments, the composition comprises between about 0.1% (v/v) and 90% (v/v) of water. In some embodiments, a disclosed pharmaceutical composition comprises between about 0.1% (v/v) and 1% (v/v) of water. In some embodiments, a disclosed pharmaceutical composition comprises between about 0.1% (v/v) and 10% (v/v) of water. In some embodiments, a disclosed pharmaceutical composition comprises between about 1% (v/v) and 90% (v/v) of water. In some embodiments, a disclosed pharmaceutical composition comprises between about 1% (v/v) and 50% (v/v) of water. In some embodiments, a disclosed pharmaceutical composition comprises between about 1% (v/v) and 30% (v/v) of water. In some embodiments, the solvent system comprises ethanol. In some embodiments, a disclosed pharmaceutical composition comprises between about 5% (v/v) and 50% (v/v) of water. In some embodiments, a disclosed pharmaceutical composition comprises between about 5% (v/v) and 30% (v/v) of water. In some embodiments, a disclosed pharmaceutical composition comprises between about 5% (v/v) and 20% (v/v) of water. In some embodiments, a disclosed pharmaceutical composition comprises between about 10% (v/v) and 20% (v/v) of water. In some embodiments, a disclosed pharmaceutical composition comprises about 10% (v/v) of water. In some embodiments, a disclosed pharmaceutical composition comprises about 15% (v/v) of water. In some embodiments, a disclosed pharmaceutical composition comprises about 20% (v/v) of water.

[227] In some embodiments, the solvent system comprises ethanol. In some embodiments, a disclosed pharmaceutical composition comprises about 60% (v/v) of ethanol. In some embodiments, a disclosed pharmaceutical composition comprises between about 10% (v/v) and 70% (v/v) of ethanol. In some embodiments, a disclosed pharmaceutical composition comprises between about 10% (v/v) and 60% (v/v) of ethanol. In some embodiments, the solvent system comprises ethanol. In some embodiments, a disclosed pharmaceutical composition comprises between about 15% (v/v) and 55% (v/v) of ethanol. In some embodiments, a disclosed pharmaceutical composition comprises between about 20% (v/v) and 50% (v/v) of ethanol. In some embodiments, a disclosed pharmaceutical composition comprises between about 20% (v/v) and 40% (v/v) of ethanol. In some embodiments, a disclosed pharmaceutical composition comprises between about 25% (v/v) and 35% (v/v) of ethanol. In some embodiments, a disclosed pharmaceutical composition comprises about 25% (v/v) of ethanol. In some embodiments, a disclosed pharmaceutical composition comprises about 30% (v/v) of ethanol. In some embodiments, a disclosed pharmaceutical composition comprises about 35% (v/v) of ethanol.

[228] In some embodiments, the solvent system comprises propylene glycol. In some embodiments, a disclosed pharmaceutical composition comprises about 20% (v/v) of propylene glycol. In some embodiments, a disclosed pharmaceutical composition comprises between about 10% (v/v) and 90% (v/v) of propylene glycol. In some embodiments, a disclosed pharmaceutical composition comprises between about 20% (v/v) and 80% (v/v) of propylene glycol. In some embodiments, the solvent system comprises propylene glycol. In some embodiments, a disclosed pharmaceutical composition comprises between about 30% (v/v) and 70% (v/v) of propylene glycol. In some embodiments, a disclosed pharmaceutical composition comprises between about 40% (v/v) and 60% (v/v) of propylene glycol. In some embodiments, a disclosed pharmaceutical composition comprises between about 45% (v/v) and 55% (v/v) of propylene glycol. In some embodiments, a disclosed pharmaceutical composition comprises about 45% (v/v) of propylene glycol. In some embodiments, a disclosed pharmaceutical composition comprises about 50% (v/v) of propylene glycol. In some embodiments, a disclosed pharmaceutical composition comprises about 55% (v/v) of propylene glycol.

[229] In some embodiments, a disclosed pharmaceutical composition comprises a viscosity modifying agent. In some embodiments, the viscosity modifying agent is a thickener. Common thickeners include but are not limited to: acrylates, carbomers, cellulose matrices, silicones, carrageenans, gums, resins, polysaccharides, and high melting point waxes and oils such as beeswax, coconut oil, palm oil, soybean oil, stearic acid, rapeseed, cocoa butter, shea butter, gums, rosins, resins, paraffins, and petroleum jelly. In some embodiments, the viscosity modifying agent is a carbohydrate. Exemplary carbohydrates include monosaccharides, disaccharides, oligosaccharides, and polysaccharides. Exemplary polysaccharides include cellulose, methylcellulose, hydroxypropylmethylcellulose, chitin, galactoarabinan, polygalactose, and polyarabinose. Exemplary glycerides includes hydroxystearic acid monoglyceride, hydroxystearic acid diglyceride, isostearic acid monoglyceride, isostearic acid diglyceride, oleic acid monoglyceride, oleic acid diglyceride, ricinoleic acid monoglyceride, ricinoleic acid diglyceride, linoleic acid monoglyceride, linoleic acid diglyceride, linolenic acid monoglyceride, linolenic acid diglyceride, erucic acid monoglyceride, erucic acid diglyceride, tartaric acid monoglyceride, tartaric acid diglyceride, citric acid monoglyceride, citric acid diglyceride, malic acid monoglyceride, malic acid monoglyceride, malic acid diglyceride, and mixture thereof. In some embodiments, the viscosity modifying agent is a polymer. The polymer may be a natural or synthetic polymer. Natural polymers include polysaccharides, nucleic acid, and proteins. Synthetic polymers include polyesters, polyureas, polycarbonates, polyvinyl alcohol, polyamides, polyethers, polyesters, polyamines, polytyrosines, polyanhydrides, polyphosphazenes, polyacrylamides, polyacrylates, polymethacrylates, polyvinylpyrrolidone, etc. Exemplary thickening agents include alginate derivatives, preneutralized carbomer 430, hydrophilic silicas, polysaccharides, xanthan gum, guar guar, agar agar, carboxymethylcellulose, hydroxyethylcellulose, polyacrylates, polyacrylamides, polyvinylpyrrolidone, and salts. In some embodiments, compositions of the disclosure may comprise a viscosity modifying agent at a concentration of about 0.01%, about 0.02%, about 0.05%, about 0.1%, about 0.2%, about 0.3%, about 0.4%, about 0.5%, about 0.6%, about 0.7%, about 0.8%, about 0.9%, about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, about 20%, about 21%, about 22%, about 23%, about 24%, about 25%, about 26%, about 27%, about 28%, about 29%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 61%, about 62%, about 63%, about 64%, about 65%, about 66%, about 67%, about 68%, about 69%, about 70%, about 75%, about 75%, and about 80% of the composition, on a weight or volume basis.

[230] For example, in some embodiments, a disclosed pharmaceutical composition comprises hydroxypropylcellulose as a viscosity modifying agent. It will be appreciated, however, that hydroxypropylcellulose or another disclosed excipient may perform multiple functions when included in a composition, as noted elsewhere herein. In some embodiments, a disclosed pharmaceutical composition comprises between about 1% (w/v) and about 10% (w/v) of hydroxypropylcellulose. In some embodiments, a disclosed pharmaceutical composition comprises about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, or about 10% (w/v) of hydroxypropylcellulose.

[231] In some embodiments, a disclosed pharmaceutical composition comprises an adhesion modifying agent. In some embodiments, a disclosed pharmaceutical composition comprises an adhesive polymer. Adhesive polymers have physicochemical properties that allow prolonged binding to tissue surfaces. In some embodiments, inclusion of an adhesive polymer in the composition increases the amount of time that an active agent is in contact with, and can diffuse across, a barrier (e.g., scalp skin). In some embodiments, the adhesive polymer is chitosan, gelatin guar gum, lectins, sodium alginate, soluble starch, tragacanth, xanthan gum deacetylated gum, polyacrylic acid, polyvinyl alcohol, hydroxypropylmethylcellulose, hydroxyethylcellulose, hydroxypropyl cellulose, sodium carboxymethylcellulose, a thiomer, polycarbophil, hyaluronic acid, dermatan sulfate, or a combination thereof. In some embodiments, the adhesion modifying agent is a tackifier. Common tackifiers include but are not limited to gums, resins (natural or modified), carbomers, or other natural or synthetic polymers. In some embodiments, compositions of the disclosure may comprise a adhesion modifying agent at a concentration of about 0.01%, about 0.02%, about 0.05%, about 0.1%, about 0.2%, about 0.3%, about 0.4%, about 0.5%, about 0.6%, about 0.7%, about 0.8%, about 0.9%, about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, about 20%, about 21%, about 22%, about 23%, about 24%, about 25%, about 26%, about 27%, about 28%, about 29%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 61%, about 62%, about 63%, about 64%, about 65%, about 66%, about 67%, about 68%, about 69%, about 70%, about 75%, about 75%, and about 80% of the composition, on a weight or volume basis.

[232] In some embodiments, a disclosed pharmaceutical composition comprises a preservative. Preservatives can be used to inhibit microbial growth or increase stability of the composition, thereby prolonging the shelf life of the composition. Suitable preservatives are known in the art and include EDTA, EGTA, benzalkonium chloride or benzoic acid or benzoates (e.g., sodium benzoate), vitamin A, vitamin C (ascorbic acid), citric acid, vitamin E, and tocopherol.

[233] In some embodiments, a disclosed pharmaceutical composition comprises an antioxidant. Without being bound by theory, antioxidants generally can delay or inhibit the oxidative decomposition of components of disclosed compositions (e.g., active agents, such as T3, T4, or any other active ingredients), which may thereby improve the stability and extend the shelf-life of disclosed compositions. In some embodiments, the antioxidant is a-tocopherol, ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, methionine, citric acid, ascorbic acid, sodium ascorbate, sodium thiosulfate, sodium bisulfite, sodium metabisulfite, ascorbyl palmitate, thioglycerol, propyl gallate, cysteine, or a combination thereof. In some embodiments, the antioxidant is a cyclodextrin, D-a-tocopherol, rosmarinic acid, or a combination thereof. In some embodiments, compositions of the disclosure may comprise an antioxidant at a concentration of about 0.01%, about 0.02%, about 0.05%, about 0.1%, about 0.2%, about 0.3%, about 0.4%, about 0.5%, about 0.6%, about 0.7%, about 0.8%, about 0.9%, about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, about 20%, about 21%, about 22%, about 23%, about 24%, about 25%, about 26%, about 27%, about 28%, about 29%, about

30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 61%, about 62%, about 63%, about 64%, about 65%, about 66%, about 67%, about 68%, about 69%, about 70%, about

75%, about 75%, and about 80% of the composition, on a weight or volume basis.

[234] In some embodiments, the composition may include one or more vitamins. Any vitamin having a property, for example, to nourish the hair, inhibit hair loss and/or enhance hair growth may be used. Representatively, suitable vitamins may include, but are not limited to, essential B vitamins such as thiamine, riboflavin, niacin, vitamin B6, folic acid, vitamin B12, biotin and pantothenic acid. In some embodiments, the concentration of the vitamin in the composition is sufficient to provide the desired benefit of treating hair loss and/or promoting hair growth while remaining compatible with disclosed compositions (e.g., active agents, such as T3, T4, or any other active ingredients). Such concentration can vary with the vitamin selected, the effect desired and the type and concentration of other components, and other like factors. Representatively, the composition may include between 1 mg and 200 mg of a vitamin(s), and in some embodiments between 50 mg and 250 mg of the vitamin(s). [235] In some embodiments, a disclosed pharmaceutical composition comprises a solubilizing agent. Without being bound by theory, solubilizing agents generally form complexes with active ingredients which can have different physicochemical properties than the active ingredient alone. The properties of the complexes can increase the solubility of T3, T4, or any other active ingredient(s) in the composition. In some embodiments, the solubilizing agent is a water-soluble organic solvent, a non-ionic surfactant, a water insoluble lipid, an organic liquid, a cyclodextrin, or a phospholipid. In some embodiments the solubilizing agent is a water-soluble enhancing agent. In some embodiments, the water-soluble enhancing agent is polyethylene glycol 300, polyethylene glycol 400, ethanol, propylene glycol, xanthan gum, glycerin, N-methyl-2-pyrrolidone, dimethylacetamide, dimethylsulfoxide, or a combination thereof. In some embodiments, the solubilizing agent is propylene glycol. In some embodiments, the solubilizing agent is xanthan gum. In some embodiments the solubilizing agent is a non-ionic surfactant. In some embodiments, the non-ionic surfactant is Cremophor EL, Cremophor RH 40, Cremophor RH 60, d-tocopherol polyethylene glycol 1000 succinate, polysorbate 20, polysorbate 80, Solutol HS 15, sorbitan monooleate, poloxamer 407, Labrafil M-1944CS, Labrafil M-2125CS, Labrasol, Gellucire 44/14, Softigen 767, mono- and di-fatty acid esters of PEG 300, 400, or 1750, or a combination thereof. In some embodiments the solubilizing agent is an organic liquid. In some embodiments, the organic liquid is beeswax, d-alpha-tocopherol, oleic acid, or a medium-chain mono- or diglyceride. In some embodiments the solubilizing agent is a cyclodextrin. In some embodiments, the solubilizing agent is alpha-cyclodextrin, beta-cyclodextrin, gamma-cyclodextrin, hydroxypropyl-beta-cyclodextrin, and sulfobutylether-beta-cyclodextrin. In some embodiments, the solubilizing agent is alpha-cyclodextrin. In some embodiments, the solubilizing agent is beta-cyclodextrin. In some embodiments, the solubilizing agent is gamma-cyclodextrin. In some embodiments, the solubilizing agent is hydroxypropyl-beta-cyclodextrin. In some embodiments, the solubilizing agent is sulfobutylether-beta-cyclodextrin. In some embodiments the solubilizing agent is a phospholipid. In some embodiments, the phospholipid is hydrogenated soy phosphatidylcholine, distearoylphosphatidylglycerol, L-alpha-dimyristoylphosphatidylcholine, or L-alpha-dimyristoylphosphatidylglycerol. In some embodiments, the solubilizing agent is lecithin. In some embodiments, compositions of the disclosure may comprise solubilizing agent at a concentration of about 0.01%, about 0.02%, about 0.05%, about 0.1%, about 0.2%, about 0.3%, about 0.4%, about 0.5%, about 0.6%, about 0.7%, about 0.8%, about 0.9%, about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, about 20%, about 21%, about 22%, about 23%, about 24%, about 25%, about 26%, about 27%, about 28%, about 29%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 61%, about 62%, about 63%, about 64%, about 65%, about 66%, about 67%, about 68%, about 69%, about 70%, about 75%, about 75%, or about 80% of the composition, on a weight or volume basis. [236] In some embodiments, a disclosed pharmaceutical composition comprises a colorant. Suitable colorants and/or dyes and/or pigments may include, but not be limited to, colors such as e.g., white, black, yellow, blue, green, pink, red, orange, violet, indigo, brown, and combinations thereof, pigments such as, e.g., Timica Extra Large Sparkles, titanium dioxide and chromium oxide greens, ultramarine blues and pinks and ferric oxides. Colorants and/or dyes and/or pigments may be present, individually or in total (if more than one colorant and/or dye and/or pigment is included), in disclosed compositions in an amount ranging from about 0.01 wt% to about 5 wt% (calculated as the total weight of colorants and/or dyes and/or pigments in the composition divided by the total weight of the composition). Colorants may be present, individually or in total (if more than one colorant is included), in disclosed compositions in an amount ranging from about 0.01 wt% to about 5 wt% (calculated as the total weight of colorants in the composition divided by the total weight of the composition).

[237] In some embodiments, a disclosed pharmaceutical composition comprises a binder. Suitable binders include, without limitations, polyvinylpyrrolidone (PVP), marine colloids, carboxyvinyl polymers, starches, cellulosic polymers such as hydroxyethylcellulose, carboxymethylcellulose (carmellose), hydroxypropylmethylcellulose, hydroxyethylpropylcellulose, hydroxybutyl methyl cellulose, and salts thereof (e.g., carmellose sodium), natural gums such as karaya, xanthan, carrageenans, gellan gum, locust bean gum, gum arable and tragacanth, chitosan, colloidal magnesium aluminum silicate, and colloidal silica. Binders may be present, individually or in total (if more than one binder is included), in disclosed compositions in an amount ranging from about 0.01 wt% to about 5 wt% (calculated as the total weight of binders in the composition divided by the total weight of the composition).

[238] In some embodiments, a disclosed pharmaceutical composition comprises a humectant. Humectants, such as low molecular weight polyethylene glycol (e.g., PEG6-PEG12), may be present, individually or in total (if more than one humectant is included), in the composition in an amount of up to about 10 wt%, up to about 5 wt%, up to about 3 wt%, up to about 1 wt%, or up to about 0.1 wt% (calculated as the total weight of humectants in the composition divided by the total weight of the composition).

[239] In some embodiments, a disclosed pharmaceutical composition comprises a surfactant. The surfactants that can be included in the composition may be anionic, nonionic, or amphoteric compounds. Suitable examples of anionic surfactants are one or more of higher alkyl sulfates such as potassium or sodium lauryl sulfate, higher fatty acid monoglyceride monosulfates, such as the salt of the monosulfated monoglyceride of hydrogenated coconut oil fatty acids, alkyl sulfonates such as sodium dodecyl benzene sulfonate, higher fatty sulfoacetates, higher fatty acid esters of 1,2 dihydroxypropane sulfonate. Examples of water soluble nonionic surfactants are condensation products of ethylene oxide with various hydrogen-containing compounds that are reactive therewith and have long hydrophobic chains (e.g., aliphatic chains of about 12 of 20 carbon atoms), which condensation products contain hydrophilic polyoxyethylene moieties, such as condensation products of poly (ethylene oxide) with fatty acids, fatty alcohols, fatty amides and other fatty moleties, and with propylene oxide and polypropylene oxides, e.g., Pluronic materials such as Pluronic F127. Exemplary suitable alkyl polyglycoside (APG) surfactant(s) that may be used in the composition may comprise APG C8-C10, APG C10-C16, decyl glucoside, coco-glucoside, anionic APG carboxylate, sodium lauryl glucose carboxylate, lauryl glucoside, D-glucopyranose (oligomeric, CIO-16 glycosides, carboxymethyl ethers, sodium salts), C12-C16 fatty alcohol glycoside, and combinations thereof. Exemplary APG surfactant(s) that may be used may have an industry designation of Plantaren® 2000 N UP/MB, Plantapon® LGC Sorb, Plantaren® 1200 N UP/MB, and Plantaren® 818 UP/MB. Surfactants may be present, individually or in total (if more than one surfactant is included) in the composition in an amount ranging from about 0.01 wt% to about 10 wt% (calculated as the total weight of surfactants in the composition divided by the total weight of the composition).

[240] In some embodiments, a disclosed pharmaceutical composition comprises a gelling agent. Exemplary gelling agent(s) that may be issued in disclosed compositions may comprise pectins, starches, and gelatin forms derived from animals or from plants (e.g., pork gelatin). The pectin in the composition may include, e.g., high methoxyl pectin, low methoxyl pectin, or a combination thereof. In some embodiments, the pectin is amidated pectin. In other embodiments, the pectin is non-amidated pectin. In certain embodiments, the pectin is a combination of amidated pectin and non-amidated pectin. The gelatin in the composition may include Type A gelatin, Type B gelatin, a hide or skin gelatin (e.g., calf skin, pig skin) and/or a bone gelatin (e.g., calf bone, pig bone) used alone or in combination. Gelling agent(s) may be present, individually or in total (if more than one gelling agent is included) in the composition in an amount ranging from about 0.1 wt% to about 20 wt% (calculated as the total weight of gelling agents in the composition divided by the total weight of the composition). In some embodiments, the composition does not comprise a gelling agent.

[241] Depending on unit dosage volume and total volume, the composition may be provided as a final packaged product (e.g., in a bottle or any other suitable container). In some embodiments, the bottle is a dropper bottle, a fine mist spray bottle, a pump bottle, a glass bottle, or a plastic bottle. In some embodiments, the bottle is a dropper bottle. In some embodiments, the bottle is a fine mist spray bottle. In some embodiments, the bottle is a pump bottle. In some embodiments, the bottle is a glass bottle. In some embodiments, the bottle is a plastic bottle. In some embodiments, the bottle is between about 15 mL and 90 mL. In some embodiments, the bottle is about 15 mL (i.e., about 0.5 ounces). In some embodiments, the bottle is about 20 mL. In some embodiments, the bottle is about 30 mL (i.e., about 1 ounce) . In some embodiments, the bottle is about 40 mL. In some embodiments, the bottle is about 50 mL. In some embodiments, the bottle is about 60 mL (i.e., about 2 ounces). In some embodiments, the bottle is about 70 mL. In some embodiments, the bottle is about 80 mL. In some embodiments, the bottle is about 90 mL (i.e., about 3 ounces). In some embodiments, the bottle is greater than 90 mL. [242] In some embodiments, a disclosed excipient may perform more than one function when included in a composition. For example, hydroxypropylcellulose may function to modify the viscosity of the composition, while also affecting the composition’s adhesive properties, or stabilizing an active agent in the composition, promoting emulsification, or another function as described herein.

[243] One of ordinary skill in the art appreciates that the selection of a suitable excipient for use in a disclosed composition may depend on a variety of factors. Relevant factors in the selection of the appropriate excipient(s), include, for example, compatibility of the excipient with the active agents (e.g., T3, T4, any additional active agent(s)), desired penetration kinetics of the active agents, processing parameters, biocompatibility, and user preferences.

E. Exemplary Features of Disclosed Compositions and Methods

[244] In some embodiments, disclosed compositions and methods produce fewer adverse effects (e.g., side effects) than a comparative method or composition, such as the standard of care for a particular hair loss condition (e.g., androgenetic alopecia). Without being bound by theory, it is proposed that thyroid hormones (e.g., T3, T4) could be hypothetically mostly absorbed by the epidermis and dermis before entering the bloodstream. This would localize potential side effects and likely be mitigated by pulsing the therapy, as described in various embodiments herein.

[245] In some embodiments, the hair loss is caused by alopecia. In some embodiments, the hair loss is caused by androgenetic alopecia, alopecia areata, persistent patchy alopecia areata, alopecia totalis, alopecia universalis, diffuse alopecia areata, ophiasis alopecia, cicatricial alopecia, lichen planopilaris, frontal fibrosing alopecia, central centrifugal cicatricial alopecia (CCCA), traction alopecia, alopecia barbae, or postpartum alopecia. In some embodiments, the hair loss is caused by androgenetic alopecia. In some embodiments, the hair loss is male pattern baldness. In some embodiments, the hair loss is female pattern baldness.

[246] In some embodiments, a disclosed composition or method is particularly suitable for administration to a subject with certain qualities (e.g., biomarkers) indicative of high likelihood of treatment success, or low risk of treatment. For example, in some embodiments, only subjects below a threshold thyroid hormone level (e.g., level of T3, T4) or another biomarker are subjected to a disclosed method or composition. In some embodiments, a subject is subjected to bloodwork before treatment with a disclosed method or composition.

[247] The present disclosure further provides kits for carrying out the methods of the disclosure, which comprises one or more thyroid hormones (e.g., T3, T4, or a combination thereof) described herein, or a pharmaceutical composition comprising one or more thyroid hormones (e.g., T3, T4, or a combination thereof) as described herein.

[248] In embodiments, administration of a disclosed composition increases hair shaft production. Hair shaft production refers to the amount of hair produced by a hair follicle. In some embodiments, the composition increases the hair shaft production by 1%, 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100%.

[249] In embodiments, administration of a disclosed composition prolongs the anagen hair growth phase. The anagen phase is the first of three hair growth stages, during which hair is actively produced by a hair follicle. In embodiments, the composition prolongs the anagen phase by 1%, 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100%.

[250] In embodiments, administration of a disclosed composition increases expression of FGF7. FGF7 is a growth factor which promotes hair growth by regulating the initiation and prolongation of the anagen hair growth stage. In embodiments, the composition increases the expression of FGF7 by 1%, 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100%.

[251] In embodiments, administration of a disclosed composition increases the proliferation of bulge epithelial stem cells. Bulge epithelial stem cells are located within the bulge region of hair follicles, have high proliferative capacity, and multipotency to regenerate keratinocytes, sebaceous glands, and epidermis tissue. In embodiments, the composition increases the proliferation of bulge stem cells by 1%, 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100%.

[252] In embodiments, administration of a disclosed composition increases expression of keratin 15. Keratin 15 is a widely used biomarker for bulge epithelial stem cells. The increase of keratin 15 indicates an increased presence of bulge epithelial stem cells. In embodiments, the composition increases the expression of keratin 15 by 1%, 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100%.

[253] In embodiments, administration of a disclosed composition decreases the expression of p-S6. p-S6 is a direct downstream kinase to mechanistic target of rapamycin complex 1 (mTORCI), which is linked to both aging and increased hair graying. A decrease in p-S6 expression indicates the downregulation of this pathway. In embodiments, the composition decreases the expression of p-S6 by 1%, 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100%.

[254] In embodiments, administration of a disclosed composition decreases the rate of hair graying, otherwise known as depigmentation, in a subject. Hair graying/depigmentation may be caused by a dysfunction of differentiated melanocytes in the hair follicle pigmentary unit. Hair graying/depigmentation is generally temporarily reversible, and pigmentation can be initiated in a follicle that has previously ceased pigmentation. Hair graying/depigmentation can become irreversible once hair follicle melanocyte stem cells are depleted. Without being bound by theory, a disclosed topical composition downregulates mTORCI, a protein complex which negatively regulates human hair follicle growth and pigmentation (Suzuki T et al. EMBO Rep. 2023;24(7):e56574). Without being bound by theory, the downregulation of mTORCI by the topical composition promotes hair growth and pigmentation.

[255] In embodiments, a disclosed composition decreases depigmentation by 1%, 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100%. In embodiments, the composition increases repigmentation by 1%, 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100%.

[256] In embodiments, a disclosed composition prevents the initiation of depigmentation in hair follicles. In embodiments, the composition prevents 1%, 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100% of hair follicles from initiating depigmentation in a subject. In embodiments, the composition increases the amount of hair follicles producing pigment by 1%, 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100%.

F. Examples

[257] The following examples are included for illustrative purposes only and are not intended to limit the scope of the invention.

EXAMPLE 1: Human Skin Organ Culture Studies

[258] Purpose: The study described herein was tests the effects of administration of disclosed topical compositions on human scalp skin in organ culture. Prior work (e.g., (Paus, et al. J. Clin. Endocrinol. Metab. 2008;93(11):4381™4388) tested applying thyroid hormones to hair follicles extracted from the scalp through a solution infused into the culture itself. In this work, T4 increased hair matrix keratinocyte proliferation and prolonged the anagen phase of the hair foilicle cycle, while T3 mitigated hair matrix keratinocyte apoptosis.

[259] The current study was conducted by applying disclosed topical compositions to scalp skin.

[260] Methods:

[261] Skin Biopsy: Skin biopsies (4 mm) containing terminal hair follicles were prepared and placed at air liquid interface within serum-free supplemented William’s E media (Samra et al. Int J Mol Sci. 2023;24(2); Gherardini et al. Int J Cosmet Sci. 2019;41 (2):164-182) and incubated at 37°C in a humidified atmosphere of 5% CO 35, 43. After 24 hours of culture for equilibration, skin biopsies were treated topically with 2 pL of viscous formulation containing ethanol, hydroxypropylcellulose, propylene glycol and purified water prepared in the laboratory. The formulation enhances test agent penetration and is very viscous, thus, preventing test compound spill-over from the skin surface into the medium either containing culture medium for the vehicle, or T3 (1 nM or 10 nM) or T4 or 10(1 pM μM), or a combination (T3 10 nM + T4 10 MM).

[262] Skin surface was cleaned before every topical treatment and culture media was changed on days 1 , 3, and 5. Two biopsies per experimental group were placed in cryomatrix and snap-frozen in liquid nitrogen for further analysis at day 6.

[263] Snap frozen samples were sectioned with a cryostat (Leica) and 7 pM sections were collected. Consecutive sections of each full-length hair follicle were collected and slides were stored at -80°C until further analysis.

[264] Immunochemistrv: To evaluate proliferating and apoptotic keratinocytes in the hair matrix, cryosections were fixed with 4% paraformaldehyde in PBS and pre-incubated in 10% goat serum, followed by incubation with a mouse anti-Ki-67 antibody (1 :800 ; Cell Signalling Technology) and a rabbit anti-human Cleaved-Caspase-3 (1 :400; Cell Signalling Technology) overnight at 4°C. After 3 washes in PBS, sections were incubated with corresponding secondary antibodies, goat anti - rabbit IgG - Alexa fluor 488 and Goat anti - mouse IgG - Alexa Fluor 555 (1 :400; Life Technologies) for 45 minutes at 37°C.

[265] IGF-1. To evaluate IGF-1 protein expression 58, 40, tissue cryosections were fixed in acetone followed by an incubation with rabbit anti-human IGF-1 antibody (1 :250; Novus biological) overnight at 4°C. Secondary antibody incubation was performed at RT for 45 minutes using goat anti-rabbit IgG - Alexa Fluor 555 antibody (1 :400; Life Technologies) for 45 minutes at 37°C.

[266] TGF0-2. To evaluate TGF[3-2 protein expression 58, 40, tissue cryosections were fixed in acetone followed by an incubation with rabbit anti-human TGF-02 antibody (1:400; Proteintech) overnight at 4°C. Secondary antibody incubation was performed at RT for 45 min using goat anti-rabbit IgG - Alexa Fluor 488 antibody (1 :400; Life Technologies) for 45 minutes at 37°C.

[267] K15. To evaluate K15 protein expression, tissue cryosections were fixed in 4% paraformaldehyde in PBS and pre-incubated in 10% goat serum, followed by incubation with a mouse anti-human CK15-FITC conjugated antibody (1:200; Novus biological) 2 hours at 37°C.

[268] K85. To evaluate K85 protein expression, tissue cryosections were fixed in acetone followed by an incubation with guinea pig anti-human CK85 antibody (1:1000; Progen) overnight at 4°C. Secondary antibody incubation was performed at RT for 45 min using goat anti-guinea pig Alexa Fluor 594 antibody (1:400; Life Technologies) for 45 minutes at 37°C.

[269] gp100/MITF. To evaluate gp100/MITF protein expression, tissue cryosections were fixed in Methanokacetone (1:1) and permeabilized and blocked in 10% Goat serum + 0.3% Triton X-100 in TBS followed by an incubation with mouse anti-MITF antibody (1 :50; Abeam) and a rabbit anti-human NKI-beteb (gp100) antibody (1:100; Abeam) overnight at 4°C. After 3 washes in TBS, sections were incubated with corresponding secondary antibodies, goat anti-mouse IgG-FITC (1 :400; Jackson immunoresearch) and goat anti-rabbit IgG-Alexa Fluor 555 (1:400; Life Technologies) for 45 minutes at 37°C. An additional amplification step with an Anti FITC Alexa Fluor 488 antibody (1 :400; Life Technologies) for 30 minutes at 37°C.

[270] MTCOI. To evaluate MTCOI protein expression, tissue cryosections were fixed in 4% paraformaldehyde and permeabilized and blocked in 10% Goat serum + 0.3% Triton X-100 in PBS followed by an incubation with a rabbit anti-human MTCO1 antibody (1 :50; Abeam) overnight at 4°C. After 3 washes in PBS, sections were incubated with a goat anti-rabbit IgG-FITC antibody (1 :400; Jackson immunoresearch) for 45 minutes at 37°C. An additional amplification step with an Anti FITC Alexa Fluor 488 antibody (1 :400; Life Technologies) for 30 minutes at 37°C.

[271] FGF7. To evaluate FGF7 protein expression, tissue cryosections were fixed in acetone followed by an incubation with rabbit anti-KGF/FGF7 antibody (1 :100; Novus biological) overnight at 4°C. Secondary antibody incubation was performed at RT for 45 min before using a goat anti-rabbit IgG - Alexa Fluor 488 antibody (1 :400; Life Technologies).

[272] p-S6. To evaluate p-S6 protein expression, tissue cryosections were fixed in 4% paraformaldehyde followed by an incubation with a rabbit anti-Phospho-S6 Ribosomal Protein (1:200; Cell Signaling Technology) overnight at 4°C. Secondary antibody incubation was performed at RT for 45 minutes using a goat anti-rabbit IgG - Alexa Fluor 488 antibody (1 :400; Life Technologies).

[273] CD31. To evaluate CD31 protein expression, tissue cryosections were fixed in acetone followed by an incubation with a mouse anti-human CD31 (1: 50; Agilent) overnight at 4°C. Secondary antibody incubation was performed at RT for 45 min before using Goat anti - mouse IgG - Alexa Fluor 555 (1:400; Life Technologies).

[274] Negative control for primary antibody was used by omitting the primary antibody. Counterstaining to visualize nuclei and embedding was performed with 4',6-diamidino-2-phenylindole (DAPI)/Fluoromount (EMS).

[275] Quantitative (Immuno-)HistomorDhometry and Image Culture: Images of the evaluation areas were taken at original magnifications of 100* or 200* with Keyence-Biozero 9100 microscope (Keyence Corporation, Japan) and associated software (Biozero-ll Analyzer; Keyence Corporation, Japan). The different areas of interest, namely the dermis (for CD31 number and expression), the hair bulge (for K15 expression), the hair bulb (for ki-67/Casp-3, Warthin-Starry, FGF7, p-S6, MTCOI, K85, gp100/MITF) and proximal outer root sheath (ORS) (for IGF-1, TGF0-2) were imaged at magnifications of 100x or 200x. Melanin content, K15, FGF7, p-S6, MTCOI, K85, gp100/MITF, IGF-1, TGF0-2 were quantified in defined reference areas by measuring the relative staining intensity in ImageJ. The percent of proliferative and apoptotic HM keratinocytes (Ki-67+ or Casp-3+ cells among DAPI+ cells) were quantified in the bulb.

[276] For hair cycle staging, HFs were microscopically evaluated using Warthin-Starry histochemistry and Ki-67/caspase-3 immunostaining as previously described (Haslam et al. J Invest Dermatol 2018; Oh et al. J Invest Dermatol 2016; Alam et al. Br J Dermatol. 2020). Hair cycle staging was studied by calculating the % of HFs in each hair cycle phase: anagen VI, early, mid or late catagen.

Statistical Analysis: All data are expressed as mean ± SEM or fold change of mean ± SEM over vehicle, and Gaussian distribution of the data was analyzed using D'Agostino and Pearson omnibus normality test. Significant differences were analyzed using either unpaired Student's t-test for parametric data, or Mann-Whitney test for nonparametric data, comparing the results of each tested group using GraphPad Prism 9 (GraphPad Software). p<0.05 was considered statistically significant.

Vehicle Formulation and Experimental Design: The two vehicle formulations chosen for topically applying T3 and T4 peptide hormone compositions were designed on the basis of their likelihood to enhance penetration and transfollicular absorption of thyroid hormones, containing only FDA-approved and cosmetic-approved topical ingredients. [277] A turbidity test was performed to establish satisfactory dissolution and mixture of all ingredients. The turbidity test showed perfect dissolution of both T3 and T4 at the highest concentrations tested (T3 =

10 nM and T4 = 10pM).

[278] The concentrations of T3 and T4 in Formulation A were varied as follows:

[279] The experiments of this example were conducted according to the following timeline:

[280] Human scalp skin was sourced from five donors:

[281] Donor 1 : Scalp Skin, male, African-American (T3 & T4 applied alone)

[282] Donor 2: Scalp Skin, male, African-American (T3 & T4 applied alone)

[283] Donor 3: Scalp Skin, Female, Hispanic (T3 & T4 in combination)

[284] Donor 4: Scalp Skin, Female, Jamaican (T3 & T4 in combination)

[285] Donor 5: Scalp Skin, Male, Mediterranean (T3 & T4 applied alone and in combination)

[286] Skin punches were collected at day 0 from temporal scalp skin. Punch biopsies were then placed in culture in 5% CO₂ at air/i iquid interphase. 2 pL of treatment (vehicle T3 or T4) was applied on day 1 , day 3, and day 5 after previously removing any left over of previous application. On day 6, the skin biopsies were embedded in cryomatrix and snap-frozen in liquid nitrogen before being processed for quantitative-(immuno)histomorphometry.

[287] Results:

[288] Hair Shaft Production: As shown in FIG. 1 A, topical T3 (1 nm and 10 nm) and T4 ) in (1 μM Formulation A tendentially promote hair shaft production. As shown in FIG. 1B, topical T4 (10pM) and the T3+T4 combination in Formulation B promotes hair growth, while T3 (10nM) in Formulation B decreases it. Results are presented as percentage of hair follicle production from day 1 of treatment to day 6 of treatment. FIG. 2A and FIG. 2B shows photographs of representative skin punches for the Formulation A trial and Formulation B trial, respectively. The measurements for T3 and T4 in Formulation A are derived from one donor, as the samples from two donors were damaged and could not be analyzed.

[289] Anagen Duration: Results in FIGS. 3A, 4A, and 5 show that T3 (1 nm and 10 nm) and 10 pM T4 in Formulation A prolong the anagen hair follicle cycle, thereby likely promoting hair growth in microdissected scalp hair follicles ex vivo after thyroid hormone addition to the culture medium (imitated systematic application). The degree of anagen and catagen is reflected by the Ki-67 and Casp-3 Immunofluorescence signal in FIG. 5. Ki-67 is a biomarker of hair matric keratinocyte proliferation, while Casp-3 is a biomarker of apoptosis. In Formulation A, the greatest percentage increase of hair follicles in prolonged anagen cycle was seen following application of T4 (10 pM). The T3+T4 combination in Formulation A resulted in a decrease in the percent of hair follicles in anagen. As shown in FIG. 3B and FIG. 4B respectively, in Formulation B, T3 (10nM) and T4 (10pM) prolong anagen duration, and the T3+T4 combination does not affect hair growth stage. Results are shown as mean in percent ± SEM.

[290] The weakest biological activity level of the hair follicle is in the telogen stage (Lin et al. Front Cell Dev Biol. 2022; 10:899095). These results indicate that topical thyroid hormone application likely reduces AGA-associated hair shaft shedding (telogen effluvium). This is novel evidence that topical thyroid hormone treatment prolongs the anagen cycle duration In human scalp skin.

[291] Thus, both topical thyroid hormones are likely to 1.) inhibit telogen effluvium in AGA patients, and 2.) prolong the window during which miniaturized vellus can be reconverted into terminal hair follicles (only during the anagen cycle). In Formulation A, combining 1 nM T3 and 10 pM T4 had the opposite effect from their application alone, suggesting that this combination may induce premature catagen.

[292] Hair Matrix Keratinocyte Proliferation: As shown in FIG. 6A and FIG. SB, 10 pM of topical T4 and the T3+T4 combination decrease hair matrix keratinocyte proliferation on human scalp skin in both Formulation A and Formulation B. The results in FIG. 6A confirm the anagen inhibition by the T3+T4 combination observed in FIG. 4A. Both concentrations of T3 and 1 pM of T4 do not have a notable effect on hair matrix keratinocyte proliferation. Results are presented as percentage of Ki-67* cells in the hair matrix.

[293] Results for Formulation A are also shown in FIG. 7, where Ki-67‘, Casp-3, and DAPI ceils were detected. Similar results were observed for Formulation B. No caspase-3* cells were detected in any of the groups, which is expected in anagen hair follicles within healthy scalp skin.

[294] Melanin Production: The results shown in FIG, 8A and FIG. 8B show that in both Formulation and Formulation B, when only weli-pigmented anagen hair follicles were assessed, thyroid hormones did not further stimulate melanin production. In Formulation A, T3 (10 nM) and the T3-T4 combination showed a slight, nonsignificant increase in the melanin content of the assessed hair follicles. This suggests that, within intact scalp skin, topically applied thyroid hormones exert no major effects on melanogenesis. FIG. 9, from the Formulation A trial, shows that no pigmentary abnormalities were seen that indicate hair follicle damage (melanin clumping or ectopic melanin granules), suggesting that topical thyroid hormones are well-tolerated by the hair follicles.

[295]

Quantitative Masson-Fontana histochemistry was used to assess hair follicle pigmentation when T3, T4, or the combination of T3+T4 was added to a serum-free medium of microdissected, organ-cultured human scalp hair follicles that were in anagen VI stage. The biomarker gp100 demarcates premelanomes produced by melanocytes. It is used as a sensitive tracker of melanosome transfer between melanocytes and keratinocytes, a sign of activity in the hair follicle pigmentary unit. MITF was upregulated In the 1 nM T3 and combination conditions. MITF key transcription factor for melanocyte development and differentiation. MITF regulates expression of numerous pigmentation genes to promote melanocyte differentiation. Though pigment production itself was not stimulated, the hair follicle pigmentary unit appeared to be activated, as indicated by stronger gp100 immuno-reactivity and longer gp100+ melanocyte dendrites. For more information about gp100 expression and melanosome/melanin granules, see, e.g., Singh et al. Exp. Dermatol. 2008:17(5>):418-426. These results may indicate a partial hair follicle “rejuvenating” effect of topical T3 and T4. The partial “rejuvenating” effect may be advantageous in an AGA model because AGA-affected hair follicles express some molecular markers of premature aging.

[296] The results in FIG 10A and FIG. 11 A show that, in Formulation A, topical T3 (1 nM and 10 nM) and the T3+T4 combination significantly activate the hair follicle pigmentary unit, as assessed via gp100 and MITF immunoreactivity. The results in FIG. 10B and FIG. 11 B show that, in Formulation B, the T3+T4 combination significantly decreases hair follicle pigmentary unit activity, while T3 and T4 alone tendentially increase it. FIG. 12 shows the increase in gp100 and MITF immunoexpression in the hair follicle pigmentary unit due application of the T3 compositions in Formulation A.

[297] MTCO1 Expression: MTCO1 is a component of the cytochrome c oxidase, the last enzyme in the mitochondrial electron transport chain which drives oxidative phosphorylation. Hence, MTCO1 is a useful screening parameter for probing mitochondrial activity and excesses thereof.

[298] The results shown FIG. 13A and FIG. 14A show no indication that thyroid hormones in Formulation A overstimulate mitochondrial activity, which may increase reactive oxygen species and cause oxidative damage. Contrarily, 10 pM T4 and the T3+T4 combination in Formulation A decreased MTCO1 expression, suggesting that its application may have a counter-regulatory reduction of mitochondrial activity in long-term T4 administration. This indicates that topical thyroid hormones are expected to have low risk of causing oxidative damage. The results shown in FIG. 13B show that in Formulation B, T3 (1 nm and 10 nm) and the T3+T4 combination significantly decrease MTCO1 expression in the hair follicle epithelium, and FIG. 14B shows that the T4 (10 μM) composition does the same in the ORS. As in Formulation A, the compositions in Formulation B also show no indication that the thyroid hormones overstimulate mitochondrial activity.

[299] Hair Follicle Epithelial Stem Cell Proliferation: FIG. 15A shows that, in Formulation A, T3 (10 nM) and T4 (1 μM) increase K15 expression in the bulge. FIG. 15B shows that, in Formulation B, the T4 compositions tendentially increase K15 expression in the bulge, but not to significance. Higher K15 expression tends to be associated with improved epithelial stem cell function thus these results suggest that topical thyroid hormones activate hair follicle epithelial stem cells. Hence, the activation of hair follicle epithelial stem cells could inhibit hair follicle miniaturization and facilitate its reversal. FIG. 16A shows that the thyroid hormones in Formulation A did not have an effect on K15⁺ cell proliferation, whereas FIG. 16B shows that the T4 compositions in Formulation B significantly increase K15⁺ cell proliferation. K15+ ceil proliferation may be desirable, in the sense that it could antagonize hair follicle miniaturization in AGA, but undesirable in that it also may lead to the differentiation of KI 5+ cells into K6/K16+ ORS keratinocytes, which could deplete the bulge stem cell niche long-term (Tiede et ai. Eur. J. Ceil Biol. 2007:86(7):355-376).

[300] Further, in Formulation A, T3 (10 nM) and T4 ()1 te μnMd to stimulate hair follicle stem cell proliferation, as reported as the percent of cells expressing both K15 and Ki67 in FIG. 17A and FIG. 18A. However, the application of T3 (10 nm), T4 (10 pM), and the T3+T4 combination may also promote stem cell apoptosis. As shown in FIG. 17B, T3 in Formulation B tends to stimulate hair follicle epithelial stem cell proliferation. Surprisingly, the T3 (1 nm) composition Formulation B also may promote apoptosis, as shown in FIG. 18B. Increased K15+ cell proliferation together with increased apoptosis in the bulge could indicate a homeostatic mechanism. For example, excess stem cells induced by T3 proliferation may be apoptosed through a stem cell niche sculpting process. FIG. 19 shows the increase in Ki67 immunofluorescence in the T3 (10 nm) treatment in Formulation A as compared to the vehicle.

[301] IGF-1 Expression: FIG. 20A shows that in Formulation A, T4 ) and t(h1e μ TM3 + T4 combination tends to increase IGF-1 protein expression in ORS keratinocytes. Though the difference compared to vehicle is not significant, this tendency suggests that upregulation of IGF-1 may be a mechanism underlying their anagen prolongation effects. FIG. 20B shows that, in Formulation B, the T3+T4 combination significantly increases IGF-1 expression in ORS keratinocytes.

[302] TGFB-2 Expression: FIG. 21A shows that, in Formulation A, neither T3, T4, nor the T3 + T4 combination have an effect on TGFp-2 protein expression in ORS keratinocytes. This is a promising result as TGFp-2 promotes the onset of the catagen phase, limiting hair production. FIG. 21 B shows that, in Formulation B, the T4 (1 μM) composition significantly increases TGF[3-2 protein expression in ORS keratinocytes. Stimulation of TGF[3~2 production, i.e. the key physiological catagen-promoting growth factor, is undesirable for hair loss management. FIG. 22 demonstrates no difference in TGF3-2 immunofluorescence between the vehicle and T3 treatments for Formulation A.

[303] FGF7 Expression: FIG, 23A shows that, in Formulation A, T3 (1 nm) and T4 ) alone an(1d t μhMe T3+T4 combination significantly increase the expression of the FGF7 protein in ORS keratinocytes. FIG.

23B shows that, in Formulation B, the T3 (1 nm and 10 nm) and the T4 and 10( μ1 M μ)M tend to increase FGF7 protein expression in ORS keratinocytes, but not to significance. FGF7 is an important hair growth-promoting factor, whose inhibition suppresses hair growth. FIG. 24 shows a significant increase in FGF7 immunofluorescence in the T3 (1 nm) treatment, and a tendential increase in FGF7 immunofluorescence in the T3 (10 nm), compared to the vehicle alone in Formulation A.

[304] p-S6 Expression: FIG. 2SA shows that, in Formulation A, the T3+T4 combination significantly increases p-S6 in hair matrix keratinocytes. FIG. 25B shows that, in Formulation B, the T3 (10nM) composition significantly decreases pS6 in hair matrix keratinocytes, while the T4 (10 μM) and T3+T4 combination may increase it. pS6 is a direct downstream kinase of mTORCI, and thus an Increase In p-S6 indicates an increase in mTORCI activity. mOTRCI activity is involved in both aging and hair graying. In Formulation A, the T3 and T4 compositions do not increase p-S6, indicating that they do not stimulate this hair graying mechanism. In Formulation B, T3 (10nM) may downregulate mTORCI and thus slow hair graying, a desirable quality for hair loss management.

[305] K85 Expression: FIG. 26A shows that, in Formulation A, T4 (10 μM) and the T3+T4 combination significantly downregulate the expression of the Keratin 85 (K85) protein in the pre-cortical hair matrix. FIG. 26B shows that, in Formulation B, the T3+T4 combination significantly decreases K85 expression in the pre-cortical hair matrix while T3 (1 nm) and T4 ) m(1ay μM increase it. K85 is a sensitive marker for the amount of hair shaft keratin production, thus its downregulation signals a decrease in keratin production. The T3 formulations do not significantly decrease K85, and in fact T3 (10 nm) tends to increase its production. FIG. 27 shows the K85 immunofluorescence signal from both T3 treatments compared to the vehicle alone in Formulation A in pre-cortical hair matrix cells.

[306] CD3V Expression: FIG. 28A shows that, in Formulation A, the T3 (1 nm) and T4 (10 μM) alone significantly increase the number of CD31⁺ endothelial cells in the dermis. FIG. 28B shows that, in Formulation B, T3 (1 nM) and T4 (10 μM) significantly increase the number of CD31⁺ endothelial cells in the dermis. An increased CD31⁺ cell number in the dermis suggests that thyroid hormones stimulate angiogenesis which could result in increased hair follicle perfusion. If angiogenesis does occur, T3/T4 may also enhance hair follicle secretion of VEGF-A and thereby promote hair follicle and/or skin recovery. FIG. 29 shows the CD31 immunofluorescence signal from both T3 treatments compared to the vehicle alone in Formulation A.

[307] Discussion: These results show that both topical thyroid hormones (T3 and T4) prolong anagen in both vehicle formulations (Form. A and Form. B). It is likely that administration of disclosed topical compositions inhibits telogen effluvium in AGA patients and prolongs the window during which miniaturized vellus can be reconverted into terminal hair follicles. This anagen prolonging effect is likely mediated primarily through stimulation of FGF-7 and/or IGF-1 expression.

[308] The significant downregulation of MTCO1 expression in both HM and ORS keratinocytes may represent a reduced mitochondrial activity. This reduced MTCO1 expression may be beneficial in the case of AGA, since MTCO1 is reportedly upregulated in DP fibroblasts of balding affected scalp skin (Chew et al. Exp Dermatol. 2022;31 (6):906-917). Disclosed topical compositions are well-tolerated by the HF (no pigmentary abnormalities) and do not overstimulate HF mitochondria (low oxidative damage risk).

[309] Several biomarkers did change in the anagen hair bulb, suggesting that administration of a topical composition successfully impacts on the hair bulb, demonstrating sufficient penetration of T3 and T4. The topical compositions stimulated the HF pigmentary unit, but not melanin production itself within the examined time window. Further research may comprise determining whether this indicates that the compositions partially rejuvenate the HF. This pro-pigmentary effect in addition to the reduced p-S6 expression may indicate that longer-term administration exerts anti-graying effects. Moreover, reduced mTORCI activity may also exert anti-aging effects and may prolong anagen (Suzuki et al. EMBO Reports. 2023;24:e56574).

[310] This example further demonstrates that disclosed topical compositions may activate bulge epithelial stem cells. This could inhibit HF miniaturization and facilitate its reversal. Indeed, treatment first induced proliferation of K15+ cells before stimulating their apoptosis at longer term as we see for the tested topical composition comprising the T3/T4 combination in Form. A, and the composition comprising 1 nM of T3 in Form. B (Tiede S et al. Eur J Cell Biol. 2010;89(10):769-777). However, the overall number of K15+ cells was not reduced. This effect may also represent a physiological mechanism by which human scalp HFs stabilize the bulge size via apoptosis induction and thus potentially limit tumor formation. Topical compositions also stimulated CD31+ cells, which may reflect increased angiogenesis. This would not only potentially increase HF size, but may also exert anti-aging effects (Keren A et al. Sci Adv. 2022;8(25):eabm6756).

[311] Furthermore, topical compositions comprising T3 (1 nM) in Form. A are promising; further work may comprise a follow-up study with scalp skin that contains at least 20-25% of gray or white HFs to assess the impact on hair loss and hair graying. In addition, follow-up analyses may be conducted to expand the range of aging biomarkers, hair shaft keratins, mitochondrial markers (i.e. PGC1a, TFAM, porin), HF pigmentation, tyrosinase activity in situ, a-MSH, and additional stem cell markers including CD34, CD200, and K6.

«-> = no significant change from vehicle; f relative to vehicle; | decrease relative to vehicle; * p<0.05;

** p<0.01; **• p<0.001 EXAMPLE 2: Clinical Study Design for Assessing Efficacy of Disclosed Topical Compositions

[312] Purpose: To measure the efficacy of disclosed topical combinations and methods for treating or preventing hair loss.

[313] Eligibility: All subjects undergo collection of medical history and physical examination. A treatment group is established which includes individuals experiencing hair loss (e.g., as a result of androgenetic alopecia or another like condition). Hair loss, including various underlying causes thereof, is diagnosed in an individual according to diagnostic techniques known to those of skill. The treatment group will be administered a disclosed topical composition as described herein. A control group is also established. The control group will be administered a topical composition that does not comprise an active agent (e.g., the vehicle formulation). Subjects will be over the age of 18 years. Subjects can withdraw from the study for any time, and for any reason. Subjects unwilling to participate in the study, or having a medical condition that contraindicates them for treatment with a disclosed method or combination will also be excluded from the study.

[314] Study Design Overview: The treatment group will be administered a topical composition comprising (i) 10 nM of triiodothyronine (T3); (ii) 5% (w/v) of hydroxypropylcellulose; (iii) 60% (v/v) of ethanol; (iv) 20% (v/v) of propylene glycol; and (v) 10% (v/v) of water. The topical composition will be administered in a treatment cycle of administration every other day for two consecutive weeks, followed by one week without administration. The control group will be administered a vehicle formulation comprising (i) 5% (w/v) of hydroxypropylcellulose; (ii) 60% (v/v) of ethanol; (iii) 20% (v/v) of propylene glycol; and (iv) 10% (v/v) of water. The vehicle formulation will be administered to the control group according to the same treatment cycle as the treatment group. At the end of each treatment cycle, overall hair growth will be assessed according to techniques known to one of skill (e.g., for measuring hair shaft production). Subjects will also be subjected to laboratory testing for biomarkers of hair growth, including melanin production, and the expression of the proteins IGF-1 , FGF7, TGFp-2, MITF, p-S6, K85, CD31, gp100, MTCO1, and K15; which can be measured according to techniques described herein and otherwise known in the art.

[315] Results: Subjects in the treatment group are expected to show increased hair growth (e.g., increased hair shaft production) and/or decreased rate of hair loss, relative to the control group. Subjects in the treatment group are also expected to show Improvements in one or more biomarkers indicative of successful treatment (e.g., prolonged anagen hair growth phase, increased expression of FGF7, increased proliferation of bulge epithelial stem cells, increased expression of keratin 15, or decreased expression of p-S6). Topically administered T3 (10nM) in Form. B induced anagen prolongation, increased IGF-1 and FGF-7 expression, and significantly reduced p-S6 and MTCO1 expression (see Example 1). This clinical trial will perform scalp skin biopsies before and at the end of treatment to be able to systematically compare the short-term preclinical data generated here with long-term topical application data in vivo, namely with respect to the long-term response of K15+ eHFSCs, hair shaft quality, anti-aging, and mitochondrial effects.

EXAMPLE 3: Individual Administration of Disclosed Topical Compositions for Treating Hair Loss

[316] Described herein are exemplary treatment protocols for treating or preventing hair loss in individuals in need thereof.

[317] Patient 1: Patient 1 is diagnosed with androgenetic alopecia and suffers from hair loss. Patient 1 self-administers a topical composition comprising (i) 10 nM of triiodothyronine (T3); (ii) 5% (w/v) of hydroxypropylcellulose; (iii) 60% (v/v) of ethenol; (iv) 20% (v/v) of propylene glycol; and (v) 10% (v/v) of water. The topical composition is administered in a treatment cycle of administration every other day for two consecutive weeks, followed by one week without administration. After one treatment cycle, Patient 1 experiences increased hair growth (e.g., increased hair shaft production). Patient 1 also exhibits improvements in one or more biomarkers indicative of successful treatment (e.g., prolonged anagen hair growth phase, increased expression of FGF7, increased proliferation of bulge epithelial stem cells, increased expression of keratin 15, or decreased expression of p-S6).

[318] Patient 2: Patient 2 is diagnosed with alopecia areata and suffers from hair loss. Patient 2 self-administers a topical composition comprising (I) 10 nM of triiodothyronine (T3); (ii) 5% (w/v) of hydroxypropylcellulose; (iii) 60% (v/v) of ethanol; (iv) 20% (v/v) of propylene glycol; and (v) 10% (v/v) of water. The topical composition is administered in a treatment cycle of administration every other day for two consecutive weeks, followed by one week without administration. After four treatment cycles, Patient 2 experiences a decreased rate of hair loss. Patient 2 also exhibits improvements in one or more biomarkers indicative of successful treatment (e.g., prolonged anagen hair growth phase, increased expression of FGF7, increased proliferation of bulge epithelial stem cells, increased expression of keratin 15, or decreased expression of p-S6).

[319] Patient 3: Patient 3 is diagnosed with alopecia totalis and suffers from total hair loss. Patient 3 self-administers a topical composition comprising (I) 10 nM of triiodothyronine (T3); (ii) 5% (w/v) of hydroxypropylcellulose; (iii) 60% (v/v) of ethanol; (iv) 20% (v/v) of propylene glycol; and (v) 10% (v/v) of water. The topical composition is administered in a treatment cycle of daily administration for three consecutive days, followed by one week without administration. After two treatment cycles, Patient 3 experiences increased hair growth (e.g., increased hair shaft production). Patient 1 also exhibits improvements In one or more biomarkers Indicative of successful treatment (e.g., prolonged anagen hair growth phase, increased expression of FGF7, increased proliferation of bulge epithelial stem cells, increased expression of keratin 15, or decreased expression of p-S6)„

[320] Patient 4: Patient 4 is diagnosed with persistent patchy alopecia areata and suffers from hair loss. Patient 4 self-administers a topical composition comprising (i) 10 nM of triiodothyronine (T3); (ii) 5% (w/v) of hydroxypropylcellulose; (iii) 30% (v/v) of ethanol; (iv) 50% (v/v) of propylene glycol; and (v) 10% (v/v) of water. The topical composition is administered in a treatment cycle of administration every other day for two consecutive weeks, followed by one week without administration. After three treatment cycles, Patient 4 experiences a decreased rate of hair loss. Patient 4 also exhibits improvements in one or more biomarkers indicative of successful treatment (e.g., prolonged anagen hair growth phase, increased expression of FGF7, increased proliferation of bulge epithelial stem cells, increased expression of keratin 15, or decreased expression of p-S6).

EXAMPLE 4: Individual Administration of Disclosed Topical Compositions for Treating Hair Graying

[321] Described herein are exemplary treatment protocols for treating or preventing hair graying in individuals In need thereof.

[322] Patient 5: Patient 5 is experiencing hair graying. Patient 5 self-administers a topical composition comprising (I) 1 nM of triiodothyronine (T3); (ii) 5% (w/v) of hydroxypropyicellulose; (iii) 30% (v/'v) of ethanol; (iv) 50% (v/v) of propylene glycol; and (v) 10% (v/v) of water. The topical composition is administered in a treatment cycle of administration every other day for two consecutive weeks, followed by one week without administration. Beginning after one treatment cycle, Patient 5 experiences gradual repigmentation of their hair.

[323] Patient 6: Patient 6 is experiencing hair graying. Patient 6 self-administers a topical composition comprising (i) 1 nM of triiodothyronine (T3); (ii) 5% (w/v) of hydroxypropyicellulose; (iii) 30% (v/v) of ethanol; (iv) 50% (v/v) of propylene glycol; and (v) 10% (v/v) of water. The topical composition is administered in a treatment cycle of administration every other day for two consecutive weeks, followed by one week without administration. Beginning after one treatment cycle, Patient 6 experiences a decreased rate of hair graying (e.g.. decreased hair depigmentation, .

[324] The foregoing description, for purposes of explanation, uses specific nomenclature to provide a thorough understanding of the invention. However, it will be apparent to one skilled in the art that specific details are not required in order to practice the invention. Thus, the foregoing description of specific embodiments of the invention is presented for purposes of illustration and description. It is not intended to be exhaustive or to limit the invention to the precise compositions, formulations, methods, or the like disclosed; many modifications and variations are possible in view of the above teachings. The embodiments were chosen and described in order to best explain the principles of the invention and its practical applications, through the elucidation of specific examples, and to thereby enable others skilled in the art to best utilize the invention and various embodiments with various modifications as are suited to the particular use contemplated, when such uses are beyond the specific examples disclosed. Accordingly, the scope of the invention shall be defined solely by the following claims and their equivalents.

Claims

CLAIMS The invention claimed is:

1. A topical composition, useful for treating or preventing hair loss comprising:

I. triiodothyronine (T3);

II. a pharmaceutically acceptable excipient; and iii. a solvent system.

2. The topical composition of claim 1 , comprising between about 1 nM and 30 nM of T3.

3. The topical composition of claim 2, comprising about 10 nM of T3.

4. The topical composition of claim 1 , wherein the pharmaceutically acceptable excipient is a penetration enhancer, carrier, diluent, emulsifier, stabilizer, viscosity modifying agent, adhesion modifying agent, preservative, antioxidant, adhesive polymer, solubilizing agent, colorant, binder, humectant, surfactant, or gelling agent.

5. The topical composition of claim 1 , wherein the pharmaceutically acceptable excipient is a hydroxyalkyl cellulose.

6. The topical composition of claim 1 , wherein the pharmaceutically acceptable excipient is hydroxypropylcellulose.

7. The topical composition of claim 6, comprising between about 1 % and 10% (w/v) of hydroxypropylcellulose.

8. The topical composition of claim 7, comprising about 5% (w/v) of hydroxypropylcellulose.

9. The topical composition of claim 1 , wherein the solvent system comprises an alcohol.

10. The topical composition of claim 1 , wherein the solvent system comprises ethanol or propylene glycol.

11. The topical composition of claim 1 , wherein the solvent system comprises between about 10% and 70% (v/v) of ethanol.

12. The topical composition of claim 11 , wherein the soivent system comprises about 60% (v/v) of ethanol.

13. The topical composition of claim 11 , wherein the solvent system comprises about 30% (v/v) of ethanol.

14. The topical composition of claim 1 , wherein the solvent system comprises between about 10% and

90% (v/v) of propylene glycol.

15. The topical composition of claim 14, wherein the solvent system comprises about 20% (v/v) of propylene glycol.

16. The topical composition of claim 14, wherein the solvent system comprises about 50% (v/v) of propylene glycol.

17. The topical composition of claim 1 , wherein the solvent system comprises water.

18. The topical composition of claim 17, wherein the solvent system comprises between about 1 % and 30% (v/v) of water.

19. The topical composition of ciaim 17, wherein the solvent system comprises about 10% (v/v) of water.

20. A topical composition, useful for treating or preventing hair loss comprising: triiodothyronine (T3); hydroxypropylcellulose; and lii. a solvent system.

21. A topical composition, useful for treating or preventing hair loss comprising: triiodothyronine (T3); hydroxypropylcellulose; iil. ethanol; iv. propylene glycol; and

V. water.

22. A topical composition, useful for treating or preventing hair loss comprising: about 10 nM of triiodothyronine (T3); about 5% (w/v) of hydroxypropylcellulose; lii. about 60% (v/v) of ethanol; iv. about 20% (v/v) of propylene glycol; and v. about 10% (v/v) of water.

23. The topical composition of claim 1, further comprising an additional active agent.

24. The topical composition of claim 23, wherein the additional active agent is an amino acid, antioxidant, anti-inflammatory agent, analgesic, 5-alpha reductase inhibitor, cannabinoid, immunosuppressant, immunostimulant, anti-cancer agent, antiulcer agent, antihistamine, terpene, vitamin, vasodilator, or vasoconstrictor.

25. The topical composition of claim 23, wherein the additional active agent is rapamycin, finasteride, dutasteride, or minoxidil.

26. The topical composition of claim 23, wherein the additional active agent is thyroxine (T4).

27. The topical composition of claim 1, in lyophilized form.

28. The topical composition of any one of claims 1-27, for use In treating or preventing hair loss.

29. Use of the topical composition of any one of claims 1-27 for the manufacture of a medicament for treating or preventing hair loss.

30. A method of treating or preventing hair loss in a subject, comprising administering to the subject the topical composition of any one of claims 1-27.

31. The method of claim 30, comprising administering to the subject between about 0.1 and 10 ml of the composition per unit dose.

32. The method of claim 31, comprising administering to the subject about 1 mL of the composition per unit dose.

33. The method of claim 30, comprising administering to the subject between about 1 ng and 10 ng of T3 per unit dose.

34. The method of claim 33, comprising administering to the subject about 6.5 ng of T3 per unit dose.

35. The method of claim 30, wherein the composition is administered daily.

36. The method of claim 30, wherein the composition is administered every other day.

37. The method of claim 30, wherein the composition is administered every other day for several consecutive weeks followed by a prolonged period without administration.

38. The method of claim 37, wherein the composition is administered every other day for two consecutive weeks followed by a prolonged period without administration.

39. The method of claim 37 or 38, wherein the prolonged period without administration is at least two weeks.

40. The method of claim 30, wherein the hair loss is caused by androgenetic alopecia, alopecia areata, persistent patchy alopecia areata, alopecia totalis, alopecia universalis, diffuse alopecia areata, ophiasis alopecia, cicatricial alopecia, lichen planopilaris, frontal fibrosing alopecia, central centrifugal cicatricial alopecia (CCCA), traction alopecia, alopecia barbae, or postpartum alopecia.

41. The method of claim 30, resulting in increased hair shaft production.

42. The method of claim 41, wherein hair shaft production is increased by 1%, 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100% compared to baseline values measured prior to administration of the composition.

43. The method of claim 30, resulting in prolonged anagen hair growth phase.

44. The method of claim 43, wherein the anagen hair growth phase is prolonged by 1%, 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100% compared to baseline values measured prior to administration of the composition.

45. The method of claim 30, resulting in increased expression of FGF7.

46. The method of claim 45, wherein the expression of FGF7 is increased by 1%, 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100% compared to baseline values measured prior to administration of the composition.

47. The method of claim 30, resulting in increased proliferation of bulge epithelial stem cells.

48. The method of claim 47, wherein bulge epithelial stem cell proliferation is increased by 1%, 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100% compared to baseline values measured prior to administration of the composition.

49. The method of claim 30, resulting in increased expression of keratin 15.

50. The method of claim 49, wherein the expression of keratin 15 is increased by 1%, 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100% compared to baseline values measured prior to administration of the composition.

51. The method of claim 30, resulting in decreased expression of p-S6.

52. The method of claim 49, wherein the expression of p-S6 is decreased by 1%, 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100% compared to baseline values measured prior to administration of the composition.

53. The topical composition of any one of claims 1-27, for use in treating or preventing hair graying.

54. Use of the topical composition of any one of claims 1-27 for the manufacture of a medicament for treating or preventing hair graying.

55. A method of treating or preventing hair graying in a subject, comprising administering to the subject the topical composition of any one of claims 1-27.

56. The method of claim 55, wherein the topical composition comprises: about 1 nM of triiodothyronine (T3); about 5% (w/v) of hydroxypropyicellulose; iii. about 30% (v/v) of ethanol; iv. about 50% (v/v) of propylene glycol; and v. about 10% (v/v) of water.

57. The method of claim 55, resulting in decreased hair depigmentation.

58. The method of claim 57, wherein hair depigmentation is decreased by 1%, 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100%.

59. The method of claim 55, resulting in hair repigmentation.