Topical Compositions for Treating or Preventing Hair Loss and Graying

Abstract

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

Description

[Technical Field]

[0001] In some aspects, the present disclosure relates to pharmaceutical compositions, such as topical compositions, useful for treating or preventing hair loss and / or graying in a subject. In some aspects, kits containing the compositions and methods of using the compositions to treat disorders such as hair loss and graying are also provided. [Background technology]

[0002] Pattern alopecia, also known as male pattern baldness, is a form of hair loss that affects up to 50% of men and 25% of women by age 50 (Vary JC, Med Clin North Am. 2015;99(6):1195-1211). The cause of pattern alopecia remains unknown and may be related to oxidative stress, the scalp microbiome, and / or hormonal abnormalities. Treatments for pattern alopecia are lacking, particularly those that are effective and do not cause unwanted side effects. As a result, pattern alopecia continues to be prevalent and there is an unmet need to alleviate and treat this condition. References

[0003] Each cited patent, publication, and non-patent document is incorporated by reference as if it were individually incorporated in its entirety and as if fully set forth herein, except that such citation should not be construed as an admission that the cited documents are from fields analogous or directly applicable to the present invention, nor should such citation be construed as an admission that any document or the information underlying it is prior art or forms part of the common general knowledge in the art in any jurisdiction. Summary of the Invention

[0004] The following presents 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, and it is not intended to identify key elements or 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.

[0005] In a first aspect, a topical composition useful for treating or preventing hair loss is provided, the composition comprising: (i) triiodothyronine (T3); (ii) a pharmaceutically acceptable excipient; and (iii) a solvent system.

[0006] In some embodiments, the topical composition comprises about 1 nM to 30 nM T3, hi some embodiments, the topical composition comprises about 10 nM T3.

[0007] In some embodiments, the pharmaceutically acceptable excipient is a penetration enhancer, carrier, diluent, emulsifier, stabilizer, viscosity modifier, adhesion modifier, preservative, antioxidant, adhesive polymer, solubilizer, colorant, binder, humectant, surfactant, or gelling agent. In some embodiments, the pharmaceutically acceptable excipient is hydroxyalkyl cellulose. In some embodiments, the pharmaceutically acceptable excipient is hydroxypropyl cellulose.

[0008] In some embodiments, the topical composition comprises about 1% to 10% (w / v) hydroxypropyl cellulose, hi some embodiments, the topical composition comprises about 5% (w / v) hydroxypropyl cellulose.

[0009] In some embodiments, the solvent system comprises alcohol. In some embodiments, the solvent system comprises ethanol or propylene glycol. In some embodiments, the solvent system comprises about 10% to 70% (v / v) ethanol. In some embodiments, the solvent system comprises about 60% (v / v) ethanol. In some embodiments, the solvent system comprises about 30% (v / v) ethanol. In some embodiments, the solvent system comprises about 10% to 90% (v / v) propylene glycol. In some embodiments, the solvent system comprises about 20% (v / v) propylene glycol. In some embodiments, the solvent system comprises about 50% (v / v) propylene glycol. In some embodiments, the solvent system comprises water. In some embodiments, the solvent system comprises about 1% to 30% (v / v) water. In some embodiments, the solvent system comprises about 10% (v / v) water.

[0010] Also provided is a topical composition useful for treating or preventing hair loss, the composition comprising (i) triiodothyronine (T3), (ii) hydroxypropyl cellulose, and (iii) a solvent system.

[0011] Also provided is a topical composition useful for treating or preventing hair loss, the composition comprising: (i) triiodothyronine (T3), (ii) hydroxypropyl cellulose, (iii) ethanol, (iv) propylene glycol, and (v) water.

[0012] Also provided is a topical composition useful for treating or preventing hair loss, the composition comprising: (i) about 10 nM triiodothyronine (T3); (ii) about 5% (w / v) hydroxypropyl cellulose; (iii) about 60% (v / v) ethanol; (iv) about 20% (v / v) propylene glycol; and (v) about 10% (v / v) water.

[0013] In some embodiments, the topical composition further comprises an additional active ingredient. In some embodiments, the additional active ingredient is an amino acid, an antioxidant, an anti-inflammatory agent, an analgesic, a 5-alpha reductase inhibitor, a cannabinoid, an immunosuppressant, an immunostimulant, an anti-cancer agent, an anti-ulcer agent, an antihistamine, a terpene, a vitamin, a vasodilator, or a vasoconstrictor. In some embodiments, the additional active ingredient is rapamycin, finasteride, dutasteride, or minoxidil. In some embodiments, the additional active ingredient is thyroxine (T4).

[0014] In some embodiments, the topical composition is in lyophilized form.

[0015] In another aspect, a topical composition of any of the disclosed embodiments is provided for use in treating or preventing hair loss.

[0016] In another aspect, there is provided a use of a topical composition of any of the disclosed embodiments for the manufacture of a medicament for the treatment or prevention of hair loss.

[0017] Also provided is a method for treating or preventing hair loss in a subject, the method comprising administering to the subject a topical composition of any of the disclosed embodiments.

[0018] In some embodiments, the method comprises administering to the subject about 0.1-10 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 about 1 ng-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.

[0019] 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 an extended period of time without administration. In some embodiments, the composition is administered every other day for two consecutive weeks, followed by an extended period of time without administration. In some embodiments, the extended period of time without administration is at least two weeks.

[0020] In some embodiments, the hair loss is due to male pattern baldness, alopecia areata, persistent patchy alopecia areata, alopecia totalis, alopecia universalis, diffuse alopecia areata, alopecia serpiginosa, cicatricial alopecia, lichen planus folliculitis, frontal fibrosing alopecia, central centrifugal cicatricial alopecia (CCCA), traction alopecia, beard alopecia, or postpartum alopecia.

[0021] In some embodiments, the method results in an increase in hair shaft production, ie, an increase of 1%, 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100% compared to a baseline measured before administration of the composition.

[0022] In some embodiments, the method results in an increase in the duration of anagen hair growth, ie, the duration of anagen hair growth is increased by 1%, 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100% compared to a baseline measured before administration of the composition.

[0023] In some embodiments, the method results in increased expression of FGF7, ie, FGF7 expression is increased by 1%, 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100% compared to a baseline level measured before administration of the composition.

[0024] In some embodiments, the method results in increased proliferation of bulge epithelial stem cells, ie, bulge epithelial stem cell proliferation is increased by 1%, 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100% compared to a baseline level measured before administration of the composition.

[0025] In some embodiments, the method results in increased expression of keratin 15. In some embodiments, expression of keratin 15 is increased by 1%, 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100% compared to a baseline level measured before administration of the composition.

[0026] In some embodiments, the method results in a decrease in expression of p-S6, ie, the expression of p-S6 is reduced by 1%, 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100% compared to a baseline level measured before administration of the composition.

[0027] In another aspect, a topical composition of any disclosed embodiment is provided for use in treating or preventing gray hair.

[0028] In another aspect, there is provided a use of the topical composition of any of the disclosed embodiments for the manufacture of a medicament for the treatment or prevention of gray hair.

[0029] Also provided is a method for treating or preventing gray hair in a subject, the method comprising administering to the subject a topical composition of any of the disclosed embodiments.

[0030] In some embodiments, the topical composition comprises: (i) about 1 nM triiodothyronine (T3), (ii) about 5% (w / v) hydroxypropyl cellulose, (iii) about 30% (v / v) ethanol, (iv) about 50% (v / v) propylene glycol, and (v) about 10% (v / v) water.

[0031] In some embodiments, the method results in reduced hair bleaching. In some embodiments, hair bleaching is reduced by 1%, 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100%. In some embodiments, the method results in recoloring of the hair.

[0032] The foregoing has outlined broadly and succinctly the gist of the present disclosure so that the detailed description thereof may be better understood, and so that the present invention may more fully appreciate its contribution to the art. Accordingly, this Summary is to be considered as a brief and general overview of only some of the objects and embodiments disclosed herein, and is provided solely for the convenience and convenience of the reader. It is not intended to limit in any way the scope of the claims or their equivalents, to which they are legally entitled. Additional features of the present invention are described below. Those skilled in the art should understand that the specific compositions and methods disclosed are illustrative and may readily utilize them as a basis for modifying or designing other compositions and methods to accomplish the same purposes. Such equivalent compositions and methods are understood to be within the scope and spirit of the present invention as set forth in the claims. It should also be understood that the headings herein are used solely to expedite the reader's review and should not be construed as limiting the invention in any way. [Brief explanation of the drawings]

[0033] To further clarify various aspects of the present invention, a more particular description will be made by reference to certain exemplary embodiments illustrated in the drawings. These drawings illustratively depict only embodiments of the invention and are not intended to limit its scope. They are provided solely to illustrate certain concepts of some embodiments of the invention. These drawings and the elements shown therein are not necessarily drawn to consistent or any scale. Similar elements are designated by the same numerals unless the context indicates otherwise. Accordingly, certain aspects of the present invention will be described with additional specificity and detail, but by way of example only, with reference to the accompanying drawings. [Figure 1A] Figure 1A shows hair follicle (HF) growth rates after 6 days of topical treatment with either Vehicle Formulation A (Form. A), T3 (1 nM and 10 nM) in Form. A, or T4 (1 μM and 10 μM) in Form. A. Mean ± standard error; n = 8 hair follicles from 1 donor (Vehicle, T3, and T4) and n = 24 hair follicles from 3 donors (Vehicle and T3 + T4 combined); Mann-Whitney test was performed. [Figure 1B] Figure 1B shows hair follicle growth rates after 6 days of topical treatment with either vehicle Formulation B (Form. B), T3 (1 nM and 10 nM) in Form. B, or T4 (1 μM and 10 μM) in Form. B. Mean ± standard error; n = 8 hair follicles from 1 donor (vehicle, T3, and T4) and n = 24 hair follicles from 3 donors (vehicle and T3 + T4 combined); Mann-Whitney test was performed. [Figure 2A] Figure 2A shows 6 mm haired skin biopsies on days 1 (A, C, E) and 6 (B, D, F) of topical treatment with Vehicle Formulation A (A, B), 1 nM T3 in Form. A (C, D), and 10 nM T3 in Form. A (E, F). [Figure 2B] Figure 2B shows 6 mm haired skin biopsies on days 1 (A, C, E) and 6 (B, D, F) of topical treatment with Vehicle Formulation B (A, B), 1 nM T3 in Formulation B (C, D), and 10 nM T3 in Formulation B (E, F). [Figure 3]Figure 3A shows the percentage of hair follicles in each hair cycle stage after administration of Vehicle Formulation A, T3 (1 nM and 10 nM) in Form A, T4 (1 μM and 10 μM) in Form A, and the combination of T3 and T4 in Form A. Mean ± standard error; n = 20–35 hair follicles from 3 donors; Mann-Whitney test was performed. Figure 3B shows the percentage of hair follicles in each hair cycle stage after administration of Vehicle Formulation B, T3 (1 nM and 10 nM) in Form B, T4 (1 μM and 10 μM) in Form B, and the combination of T3 and T4 in Form B. Mean ± standard error; n = 20–35 hair follicles from 3 donors; Mann-Whitney test was performed. [Figure 4] Figure 4A shows the percentage of hair follicles in each hair cycle stage after administration of Formulation A, T3 (1 nM and 10 nM) in Form A, T4 (1 μM and 10 μM) in Form A, and the combination of T3 and T4 in Form A. Mean ± standard error; n = 20–35 hair follicles from 3 donors; Mann-Whitney test was performed. Figure 4B shows the percentage of hair follicles in each hair cycle stage after administration of Formulation B, T3 (1 nM and 10 nM) in Form B, T4 (1 μM and 10 μM) in Form B, and the combination of T3 and T4 in Form B. Mean ± standard error; n = 20–35 hair follicles from 3 donors; Mann-Whitney test was performed. [Figure 5] Figure 5 shows images of Warthin-Starley histochemical staining (left column), Ki-67 immunofluorescence (center 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. [Figure 6A] Figure 6A shows the percentage of Ki-67 positive cells in 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 the combination of T3 and T4 in Form A. Mean ± standard error; n = 17–22 hair follicles from 2 donors; *p < 0.05 by Mann-Whitney test. [Figure 6B] Figure 6B shows the percentage of Ki-67 positive cells in hair matrix after treatment with vehicle Formulation B, T3 (1 nM and 10 nM) in Formulation B, T4 (1 μM and 10 μM) in Formulation B, and the combination of T3 and T4 in Formulation B. Mean ± standard error; n = 18–28 hair follicles from 2 donors; Mann-Whitney test was performed. [Figure 7] FIG. 7 shows confocal images of Ki-67 immunofluorescence signals in anagen hair follicles treated with vehicle Formulation A, 1 nM T3 in Form A, and 10 nM T3 in Form A. [Figure 8A] Figure 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 the combination of T3 and T4 in Form A. Mean ± standard error; n = 17–33 hair follicles from 3 donors; Mann-Whitney test was performed. [Figure 8B] Figure 8B shows melanin production after treatment with vehicle Formulation B, T3 (1 nM and 10 nM) in Formulation B, T4 (1 μM and 10 μM) in Formulation B, and the combination of T3 and T4 in Formulation B. Mean ± standard error; n = 15–29 hair follicles from 3 donors; Mann-Whitney test was performed. [Figure 9] FIG. 9 shows Warthin-Starley histochemical staining of melanin granules in hair follicles treated with vehicle Formulation A, 1 nM T3 in Form A, and 10 nM T3 in Form A. [Figure 10A] Figure 10A shows gp100 expression levels 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 the combination of T3 and T4 in Form A. Mean ± standard error; n = 13–22 hair follicles from 3 donors; Student's t-test was performed, *p < 0.05. [Figure 10B]Figure 10B shows gp100 expression levels in anagen hair follicles treated with vehicle Formulation B, T3 (1 nM and 10 nM) in Formulation B, T4 (1 μM and 10 μM) in Formulation B, and the combination of T3 and T4 in Formulation B. Mean ± standard error; n = 13–22 hair follicles from 3 donors; Student's t-test was performed, *p < 0.05. [Figure 11A] Figure 11A shows MITF expression levels 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 the combination of T3 and T4 in Form A. Mean ± standard error; n = 13–22 hair follicles from 3 donors; Student's t-test was performed, *p < 0.05. [Figure 11B] Figure 11B shows MITF expression levels in anagen hair follicles treated with vehicle Formulation B, T3 (1 nM and 10 nM) in Formulation B, T4 (1 μM and 10 μM) in Formulation B, and the combination of T3 and T4 in Formulation B. Mean ± standard error; n = 13–22 hair follicles from 3 donors; Student's t-test was performed. [Figure 12] FIG. 12 shows confocal images of gp100 (left column) and MITF (right column) immunofluorescence signals in anagen hair follicles treated with vehicle Formulation A, 1 nM T3 in Form A, and 10 nM T3 in Form A. [Figure 13A] Figure 13A shows MTCO1 expression levels 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 the combination of T3 and T4 in Form A. Mean ± standard error; n = 30–35 hair follicles from 3 donors; Mann-Whitney test was performed, with *p < 0.05 and ***p < 0.001. [Figure 13B]Figure 13B shows MTCO1 expression levels in HM tips treated with vehicle Formulation B, T3 (1 nM and 10 nM) in Formulation B, T4 (1 μM and 10 μM) in Formulation B, and the combination of T3 and T4 in Formulation B. Mean ± standard error; n = 21–30 hair follicles from 3 donors; Mann-Whitney test was performed with *p<0.05, **p<0.01, and ***p<0.001. [Figure 14A] Figure 14A shows MTCO1 expression levels in outer root sheaths (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 the combination of T3 and T4 in Form A. Mean ± standard error; n = 30–35 hair follicles from 3 donors; Mann-Whitney test was performed with *p<0.05, **p<0.01, and ***p<0.001. [Figure 14B] Figure 14B shows MTCO1 expression levels in 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 the combination of T3 and T4 in Form B. Mean ± standard error; n = 21–30 hair follicles from 3 donors; Mann-Whitney test was performed with *p<0.05, **p<0.01, and ***p<0.001. [Figure 15A] Figure 15A shows K15 expression levels 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 the combination of T3 and T4 in Form A. Mean ± standard error; n = 21–34 hair follicles from 3 donors. Mann-Whitney test was performed, with *p<0.05 and **p<0.01. [Figure 15B]Figure 15B shows K15 expression levels in bulge cells treated with vehicle Formulation B, T3 (1 nM and 10 nM) in Formulation B, T4 (1 μM and 10 μM) in Formulation B, and the combination of T3 and T4 in Formulation B. Mean ± standard error; n = 21–34 hair follicles from 3 donors. Mann-Whitney test was performed. [Figure 16A] Figure 16A shows the number of K15-positive 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 the combination of T3 and T4 in Form A. Mean ± standard error; n = 21–34 hair follicles from 3 donors. Mann-Whitney test was performed. [Figure 16B] Figure 16B shows the number of K15-positive cells in the bulge treated with vehicle Formulation B, T3 (1 nM and 10 nM) in Formulation B, T4 (1 μM and 10 μM) in Formulation B, and the combination of T3 and T4 in Formulation B. Mean ± standard error; n = 21–34 hair follicles from 3 donors. Mann-Whitney test was performed, with *p < 0.05 and **p < 0.01. [Figure 17A] Figure 17A shows the number of proliferating K15 cells (K15 and Ki67 positive 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 the combination of T3 and T4 in Form A. Mean ± standard error; n = 21–34 hair follicles from 3 donors. Mann-Whitney test was performed. [Figure 17B] Figure 17B shows the number of proliferating K15 cells (K15 and Ki67 positive cells) in the bulge treated with vehicle Formulation B, T3 (1 nM and 10 nM) in Formulation B, T4 (1 μM and 10 μM) in Formulation B, and the combination of T3 and T4 in Formulation B. Mean ± standard error; n = 21–34 hair follicles from 3 donors. Mann-Whitney test was performed. [Figure 18A]Figure 18A shows the number of apoptotic K15 cells (K15 and Cas3-positive 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 the combination of T3 and T4 in Form A. Mean ± standard error; n = 21–34 hair follicles from 3 donors. Mann-Whitney test was performed with *p<0.05 and **p<0.01. [Figure 18B] Figure 18B shows the number of apoptotic K15 cells (K15 and Cas3-positive cells) in the bulge treated with vehicle Formulation B, T3 (1 nM and 10 nM) in Formulation B, T4 (1 μM and 10 μM) in Formulation B, and the combination of T3 and T4 in Formulation B. Mean ± standard error; n = 21–34 hair follicles from 3 donors. Mann-Whitney test was performed, with *p < 0.05 and **p < 0.01. [Figure 19] Figure 19 shows confocal images of K15 (left column), Ki67 (middle column), and Cas3 (right column) immunofluorescence signals in bulge cells treated with vehicle Formulation A, 1 nM T3 in Form A, and 10 nM T3 in Form A. [Figure 20A] Figure 20A shows IGF-1 expression levels in ORS keratinocytes treated with vehicle Formulation A, T3 (1 nM and 10 nM) in Form A, T4 (1 μM and 10 μM) in Form A, and the combination of T3 and T4 in Form A. Mean ± standard error; n = 18–35 hair follicles from 3 donors; Mann-Whitney test was performed. [Figure 20B] Figure 20B shows IGF-1 expression levels in ORS keratinocytes treated with vehicle Formulation B, T3 (1 nM and 10 nM) in Formulation B, T4 (1 μM and 10 μM) in Formulation B, and the combination of T3 and T4 in Formulation B. Mean ± standard error; n = 18–35 hair follicles from 3 donors; Mann-Whitney test was performed. [Figure 21A]Figure 21A shows TGFβ-2 expression levels in ORS keratinocytes treated with vehicle Formulation A, T3 (1 nM and 10 nM) in Form A, T4 (1 μM and 10 μM) in Form A, and the combination of T3 and T4 in Form A. Mean ± standard error; n = 20–28 hair follicles from 3 donors; Mann-Whitney test was performed. [Figure 21B] Figure 21B shows TGFβ-2 expression levels in ORS keratinocytes treated with vehicle Formulation B, T3 (1 nM and 10 nM) in Formulation B, T4 (1 μM and 10 μM) in Formulation B, and the combination of T3 and T4 in Formulation B. Mean ± standard error; n = 22–35 hair follicles from 3 donors; Mann-Whitney test was performed. [Figure 22] FIG. 22 shows confocal images of TGFβ-2 immunofluorescence signals in ORS keratinocytes treated with vehicle Formulation A, 1 nM T3 in Form. A, and 10 nM T3 in Form. A. [Figure 23A] Figure 23A shows FGF7 expression levels in 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 the combination of T3 and T4 in Form A. Mean ± standard error; n = 24–32 hair follicles from 3 donors; Student's t-test was performed, with **p<0.01 and ***p<0.001. [Figure 23B] Figure 23B shows FGF7 expression levels in ORS treated with vehicle Formulation B, T3 (1 nM and 10 nM) in Formulation B, T4 (1 μM and 10 μM) in Formulation B, and the combination of T3 and T4 in Formulation B. Mean ± standard error; n = 17–33 hair follicles from 3 donors; Student's t-test was performed. [Figure 24] FIG. 24 shows confocal images of FGF7 immunofluorescence signals in ORS keratinocytes treated with vehicle Formulation A, 1 nM T3 in Form A, and 10 nM T3 in Form A. [Figure 25A] Figure 25A shows pS6 expression levels in hair matrix keratinocytes treated with vehicle Formulation A, T3 (1 nM and 10 nM) in Form A, T4 (1 μM and 10 μM) in Form A, and the combination of T3 and T4 in Form A. Mean ± standard error; n = 24–32 hair follicles from 3 donors; Mann-Whitney test was performed, **p < 0.01. [Figure 25B] Figure 25B shows pS6 expression levels in hair matrix keratinocytes treated with vehicle Formulation B, T3 (1 nM and 10 nM) in Formulation B, T4 (1 μM and 10 μM) in Formulation B, and the combination of T3 and T4 in Formulation B. Mean ± standard error; n = 22–34 hair follicles from 3 donors; *p < 0.05 by Mann-Whitney test. [Figure 26A] Figure 26A shows K85 expression levels in hair matrix keratinocytes treated with vehicle Formulation A, T3 (1 nM and 10 nM) in Form A, T4 (1 μM and 10 μM) in Form A, and the combination of T3 and T4 in Form A. Mean ± standard error; n = 22–34 hair follicles from 3 donors; Mann-Whitney test was performed, **p < 0.01. [Figure 26B] Figure 26B shows K85 expression levels in anterior cortical hair matrix cells treated with vehicle Formulation B, T3 (1 nM and 10 nM) in Formulation B, T4 (1 μM and 10 μM) in Formulation B, and the combination of T3 and T4 in Formulation B. Mean ± standard error; n = 22–34 hair follicles from 3 donors; Mann-Whitney test was performed, **p < 0.01. [Figure 27] FIG. 27 shows confocal images of K85 immunofluorescence signals in anterior cortical hair matrix cells treated with 10 nM T3 in Vehicle Formulation A, Form A. [Figure 28A]Figure 28A shows the amount of CD31-positive endothelial cells in the dermis treated with vehicle Formulation A, T3 (1 nM and 10 nM) in Form A, T4 (1 μM and 10 μM) in Form A, and the combination of T3 and T4 in Form A. Mean ± standard error; n = 22–34 hair follicles from 3 donors; Mann-Whitney test was performed, with *p<0.05 and **p<0.01. [Figure 28B] Figure 28B shows the amount of CD31-positive endothelial cells in the dermis treated with vehicle Formulation B, T3 (1 nM and 10 nM) in Formulation B, T4 (1 μM and 10 μM) in Formulation B, and the combination of T3 and T4 in Formulation B. Mean ± standard error; n = 22–34 hair follicles from 3 donors; Mann-Whitney test was performed, with *p<0.05 and **p<0.01. [Figure 29] FIG. 29 shows confocal images of CD31 immunofluorescence signals in dermis treated with 10 nM T3 in Vehicle Formulation A, Form A. DETAILED DESCRIPTION OF THE INVENTION

[0034] While various aspects and features of certain embodiments have been summarized above, the following detailed description will further detail several exemplary embodiments to enable those skilled in the art to implement these embodiments and to make and use the full scope of the claimed invention. The described examples are provided for illustrative purposes and are not intended to limit the scope of the invention or its application. It should be understood that many modifications, substitutions, changes, and variations may be made by those skilled in the art to the examples, embodiments, applications, and details described herein without departing from the spirit of the invention or the scope of the invention as claimed. It should also be understood that the headings herein are used solely to expedite the reader's review and should not be construed as limiting the invention in any manner.

[0035] The scope of the present invention includes all embodiments and formulations thereof, not just those explicitly described below, and it should be understood that many modifications, substitutions, changes and variations may be made by those skilled in the art to the embodiments, applications and details described herein without departing from the spirit of the invention or the scope of the invention as set forth in the claims. A. General Definitions and Terminology

[0036] 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 "active ingredients" is intended to include a combination of two or more active ingredients, and reference to "excipients" is intended to include a combination of two or more excipients. While the term "one or more" is sometimes used, its absence (or substitution for the singular) does not imply a singularity, but rather emphasizes the possibility of multiple components or materials in a particular embodiment. Terms such as "comprise," "contain," "for example," and "having" are inclusive and not exclusive (i.e., other elements may be present in addition to the listed elements). As used herein, the term "or" is synonymous with and / or and can be used interchangeably unless the context clearly dictates otherwise.

[0037] Unless otherwise indicated, all numbers expressing quantities, concentrations, and other properties of ingredients, reaction conditions, and the like, used to describe and claim particular embodiments of the present invention should be understood as being modified in some cases by the term "about." Accordingly, in some embodiments, the numerical parameters set forth in the specification and attached claims are approximations that may vary depending upon the desired properties sought to be obtained by a particular embodiment. In some embodiments, "about" means plus or minus five percent (±5%) of the stated unit. As used herein, when the term "substantially" modifies a feature or limitation, it is to be interpreted to provide the appropriate degree of certainty in light of the context of the invention and the knowledge of one of ordinary skill in the art. For example, by using art-recognized standards for measuring the degree of "substantially" or by specifying a range that would be understood by one of ordinary skill in the art.

[0038] In some embodiments, the numerical parameters should be construed in light of the number of reported significant digits and 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 possible. The numerical values ​​presented in some embodiments may contain certain errors necessarily resulting from the standard deviation in their respective testing measurements.

[0039] Unless otherwise defined, all technical and scientific terms used herein have the meanings commonly understood by those skilled in the art to which the invention belongs. This skilled person may be referred to simply as "one of skill." Further definitions are provided below to aid in understanding the disclosed embodiments, but these definitions are not intended to limit the scope of the invention, which should be properly interpreted and understood based on the entire specification (and the ordinary meaning known to those skilled in the relevant art) and the language of the appended claims. The terms used herein are used only for the purpose of describing specific embodiments and are not intended to be limiting.

[0040] As used herein, the term "stage of the hair cycle" refers to the main stages of human hair growth: anagen, catagen, and telogen (Paus et al. J Investigative Derm. 2001;117(1):3-15).

[0041] As used herein, "melanin" refers to a complex polymer derived from the amino acid tyrosine. Melanin is present in varying degrees in human skin and determines the color of eyes, hair, and skin (Cao et al. J Am Chem Soc. 2021;143(7):2622-2637).

[0042] As used herein, "Ki-67" refers to a monoclonal antibody used to determine the number of cycling cells in hair follicles (Baar et al. Acta Derm Venereol. 1992;72(2):161-164).

[0043] As used herein, "caspase-3" is a caspase protein that interacts with caspase-8 and caspase-9. Caspases are regulators of programmed cell death, and specific caspases likely function as mediators of the hair growth cycle (Sawaya et al. Eur J Dermatol. 2001;11(4):304-308).

[0044] As used herein, "IGF-1" or "insulin-like growth factor 1" refers to a growth factor that prolongs the anagen phase. IGF-1 shares high structural and functional homology with insulin and exhibits anti-apoptotic effects (Ahn et al. Ann Dermatol. 2012;24(1):26-31).

[0045] As used herein, "KGF / FGF7" or "keratinocyte growth factor / fibroblast growth factor 7" refers to a growth factor that prolongs the anagen phase.

[0046] As used herein, "TGFβ-2" or "transforming growth factor beta 2" refers to a growth factor that promotes catagen (Xu et al. Bone Research. 2018;6(2):1-31).

[0047] As used herein, "MTCOI" or "mitochondrial cytochrome c oxidase subunit I" refers to a component of cytochrome c oxidase, the final enzyme in the mitochondrial electron transport chain, which drives oxidative phosphorylation (Vidali et al. J Invest Dermatol. 2016;136(10):2003-2012).

[0048] As used herein, "Gp100" refers to what is widely recognized as a sensitive tracer of melanosome transfer between melanocytes and keratinocytes (Singh et al. Exp Dermatol. 2008;17(5):418-426).

[0049] As used herein, "MITF" or "melanocyte-inducing transcription factor" refers to a key transcription factor in the growth and differentiation of melanocytes (Levt et al. Trends Mol Med. 2006;12(9):406-414).

[0050] As used herein, "p-S6" refers to a kinase directly downstream of mTORC1. Increased p-S6 activity indicates activation of mTORC1, which is involved in aging and hair graying (Suzuki et al. EMBO Reports. 2023;24:e56574).

[0051] As used herein, "K85" is a highly sensitive marker of hair shaft keratin production (Ramot et al. Br J Dermatol. 2013;169(1):146-51).

[0052] As used herein, "CD31" is known as "platelet endothelial cell adhesion molecule-1" and is a marker of intradermal angiogenesis measured by CD31 immunoreactivity and the number of CD31-positive cells. CD31 is a transmembrane homophilic receptor expressed by endothelial cells, platelets, neutrophils, macrophages, dendritic cells, T and B cells, and natural killer cells (Berg et al. J Cell Sci. 2013;126(11):2343-2352).

[0053] As used herein, "treatment" or "treating" includes treating a mammal, preferably a human, for a condition such as hair loss, alopecia, or male pattern baldness, including: (a) preventing the onset of disease in patients who are predisposed to developing the disease but have not yet been diagnosed; (b) suppression of the disease, i.e., arrest and prevention of its progression; (c) disease remission, i.e., causing regression of the disease or its clinical symptoms; (d) protection from or alleviation of symptoms or conditions caused by or associated with the disease; (e) reducing, diminishing, inhibiting, ameliorating, or preventing the onset, severity, duration, progression, frequency, or probability of one or more symptoms or conditions associated with a disease; (f) Preventing or inhibiting the worsening or progression of symptoms or conditions associated with a disease or comorbidity.

[0054] As used herein, the terms "effective amount," "therapeutically effective amount," or "pharmacologically effective amount" refer to a non-toxic amount of an active ingredient (e.g., triiodothyronine (T3), thyroxine (T4), or a combination thereof) sufficient to exert a desired therapeutic effect in any medical treatment at a reasonable benefit / risk ratio. The effective amount may vary depending on the subject, their weight and age, the severity of the symptoms or the extent of the health benefit sought, the method of administration, etc., all of which can be readily determined by one of ordinary skill in the art.

[0055] As used herein, "therapeutic effect" or "therapeutic efficacy" refers to a response observed in a subject, preferably a human, following treatment that is deemed desirable and beneficial. Accordingly, these responses will vary depending on the condition being treated, the improvement in health or function desired, and the specific components of the disclosed methods, as would be readily understood by one of skill in the art.

[0056] As used herein, the terms "subject," "user," "patient," and "individual" are interchangeable and refer to a human, mammal, or other animal that may suffer from hair loss, alopecia, 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 person. These terms are understood to include anyone for whom the methods described herein may be effective or who may benefit from the present invention. Generally, it is understood that all disclosed methods will work for all individuals, but it is understood that individual differences may exist. The disclosed treatment methods can also be modified to treat multiple patients simultaneously, such as couples or families. Thus, these terms are understood to refer to more than one individual.

[0057] The nomenclature used and procedures performed herein are those known in the fields relevant to one or more aspects of the invention, such as biology, biochemistry, dermatology, pharmacology and medicine, and are widely known and commonly used in the art. Standard techniques and procedures are generally performed in accordance with conventional methods in the art.

[0058] Additional definitions and abbreviations are provided elsewhere in this specification. B. Topical Compositions

[0059] In some embodiments, the present disclosure relates to methods for treating or preventing hair loss (e.g., due to a hair loss condition, such as male pattern baldness) in a subject (e.g., preferably a human). In some embodiments, the present disclosure also relates to pharmaceutical (e.g., topical) compositions and kits for use in the methods. In some embodiments, useful features of the disclosed methods include curing or alleviating symptoms in a subject suffering from a hair loss condition, such as male pattern baldness.

[0060] Without being bound by theory, thyroid hormone may stimulate stem cell proliferation and differentiation by downregulating TGFβ-2 (a key catagen-promoting growth factor) in hair matrix cells and upregulating K15 expression (an upregulator of epithelial progenitor cell marker) in the hair follicle bulge. See, e.g., 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 al., J Investigative Derm. 2016;136:1711-1714; and Paus et al., Experimental Derm. 2020;29(9):910-923. Each of these publications is incorporated herein by reference in its entirety. Additional mechanisms of action likely exist but are as yet unknown due to the complexity of the diversity of intracellular responses downstream of free and bound thyroid hormone.

[0061] In one aspect, a topical composition is provided 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 therapeutically effective amounts 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.

[0062] In another aspect, a topical composition useful for treating or preventing hair loss is provided, the composition 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. Accordingly, a topical composition useful for treating or preventing hair loss is also provided, the composition 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, the topical composition consisting essentially of (i) T3; (ii) a pharmaceutically acceptable excipient; and (iii) a solvent system.

[0063] In another aspect, a topical composition useful for treating or preventing gray hair is provided, the composition 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. Accordingly, a topical composition useful for treating or preventing gray hair is also provided, the composition 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 gray hair, the topical composition consisting essentially of (i) T3; (ii) a pharmaceutically acceptable excipient; and (iii) a solvent system.

[0064] In some embodiments, the disclosed topical compositions are T4-free. In some embodiments, the topical compositions are iodothyronamine (T1a). In some embodiments, the topical compositions are thyronamine (T0a). In some embodiments, the topical compositions are cardiac glycoside-free. In some embodiments, the topical compositions are sterol-free. In some embodiments, the composition is plant sterol-free. In some embodiments, the composition is 13-sitosterol-free. In some embodiments, the composition is hormone-free other than thyroid hormones (e.g., T3 or T4). In some embodiments, the topical compositions are human growth hormone-free. In some embodiments, the topical compositions are insulin-free. In some embodiments, the topical compositions are estradiol-free. In some embodiments, the topical compositions are estrogen-free. In some embodiments, the topical compositions are dihydrotestosterone-blocking agents-free. In some embodiments, the topical compositions are progesterone-free. In some embodiments, the topical compositions are estradiol benzoate-free. In some embodiments, the topical compositions are medroxyprogesterone acetate-free. In some embodiments, the topical compositions are vasodilator-free. In some embodiments, the topical compositions are monoamine oxidase inhibitor-free. In some embodiments, the topical composition does not comprise a compound that binds to an IL-15 polynucleotide, polypeptide, or an antibody that specifically recognizes an IL-15 polypeptide, or a compound that specifically binds to the IL-15 receptor alpha chain.

[0065] In some embodiments, the composition comprises T3 at a concentration ranging from about 1 nM to 30 nM. In some embodiments, the composition comprises T3 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 between these values. In some embodiments, the composition comprises T3 at a concentration of less 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 greater than about 30 nM.

[0066] In some embodiments, the composition comprises T3 at a concentration ranging from about 1 μM to 15 μM. In some embodiments, the composition comprises T3 at a concentration of less than about 1 μM, about 1 μM, about 2 μM, about 3 μM, about 4 μM, about 5 μM, about 6 μM, about 7 μM, about 8 μM, about 9 μM, about 10 μM, about 11 μM, about 12 μM, about 13 μM, about 14 μM, about 15 μM, or greater than about 15 μM. In some embodiments, the composition comprises T3 at a concentration of less than about 1 μM. In some embodiments, the composition comprises T3 at a concentration of about 1 μM. In some embodiments, the composition comprises T3 at a concentration of about 2 μM. In some embodiments, the composition comprises T3 at a concentration of about 3 μM. In some embodiments, the composition comprises T3 at a concentration of about 4 μM. In some embodiments, the composition comprises T3 at a concentration of about 5 μM. In some embodiments, the composition comprises T3 at a concentration of about 6 μM. In some embodiments, the composition comprises T3 at a concentration of about 7 μM. In some embodiments, the composition comprises T3 at a concentration of about 8 μM. In some embodiments, the composition comprises T3 at a concentration of about 9 μM. In some embodiments, the composition comprises T3 at a concentration of about 10 μM. In some embodiments, the composition comprises T3 at a concentration of about 11 μM. In some embodiments, the composition comprises T3 at a concentration of about 12 μM. In some embodiments, the composition comprises T3 at a concentration of about 13 μM. In some embodiments, the composition comprises T3 at a concentration of about 14 μM. In some embodiments, the composition comprises T3 at a concentration of about 15 μM. In some embodiments, the composition comprises T3 at a concentration greater than about 15 μM.

[0067] In some embodiments, the composition comprises T3 at a concentration of about 50 pM, 60 pM, 70 pM, 80 pM, 90 pM, 100 pM, 110 pM, 120 pM, 130 pM, 140 pM, 150 pM, 160 pM, 170 pM, 180 pM, 190 pM, or 200 pM, or a dose between these values. In some embodiments, the composition comprises T3 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.

[0068] In some embodiments, the composition comprises T4 at a concentration ranging from about 1 μM to 30 μM. In some embodiments, the composition comprises T4 at a concentration of less than about 1 μM, about 1 μM, about 2 μM, about 3 μM, about 4 μM, about 5 μM, about 6 μM, about 7 μM, about 8 μM, about 9 μM, about 10 μM, about 15 μM, about 20 μM, about 25 μM, about 30 μM, or greater than about 30 μM, including ranges therebetween. In some embodiments, the composition comprises T4 at a concentration of less than about 1 μM. In some embodiments, the composition comprises T4 at a concentration of about 1 μM. In some embodiments, the composition comprises T4 at a concentration of about 2 μM. In some embodiments, the composition comprises T4 at a concentration of about 3 μM. In some embodiments, the composition comprises T4 at a concentration of about 4 μM. In some embodiments, the composition comprises T4 at a concentration of about 5 μM. In some embodiments, the composition comprises T4 at a concentration of about 6 μM. In some embodiments, the composition comprises T4 at a concentration of about 7 μM. In some embodiments, the composition comprises T4 at a concentration of about 8 μM. In some embodiments, the composition comprises T4 at a concentration of about 9 μM. In some embodiments, the composition comprises T4 at a concentration of about 10 μM. In some embodiments, the composition comprises T4 at a concentration of about 15 μM. In some embodiments, the composition comprises T4 at a concentration of about 20 μM. In some embodiments, the composition comprises T4 at a concentration of about 25 μM. In some embodiments, the composition comprises T4 at a concentration of about 30 μM. In some embodiments, the composition comprises T4 at a concentration greater than about 30 μM.

[0069] In some embodiments, the composition comprises T4 at a concentration ranging from about 10 μM to 15,000 μM. In some embodiments, the composition comprises T4 at a concentration of less than about 10 μM, about 10 μM, about 20 μM, about 50 μM, about 100 μM, about 250 μM, about 500 μM, about 1,000 μM, about 2,500 μM, about 5,000 μM, about 10,000 μM, about 12,000 μM, about 15,000 μM, or greater than about 15,000 μM, including ranges therebetween. In some embodiments, the composition comprises T4 at a concentration of less than about 10 μM. In some embodiments, the composition comprises T4 at a concentration of about 10 μM. In some embodiments, the composition comprises T4 at a concentration of about 20 μM. In some embodiments, the composition comprises T4 at a concentration of about 50 μM. In some embodiments, the composition comprises T4 at a concentration of about 100 μM. In some embodiments, the composition comprises T4 at a concentration of about 250 μM. In some embodiments, the composition comprises T4 at a concentration of about 500 μM. In some embodiments, the composition comprises T4 at a concentration of about 1,000 μM. In some embodiments, the composition comprises T4 at a concentration of about 2,500 μM. In some embodiments, the composition comprises T4 at a concentration of about 5,000 μM. In some embodiments, the composition comprises T4 at a concentration of about 10,000 μM. In some embodiments, the composition comprises T4 at a concentration of about 12,000 μM. In some embodiments, the composition comprises T4 at a concentration of about 15,000 μM. In some embodiments, the composition comprises T4 at a concentration greater than about 15,000 μM.

[0070] In some embodiments, the composition comprises T4 at a concentration of about 50 nM, 60 nM, 70 nM, 80 nM, 90 nM, 100 nM, 110 nM, 120 nM, 130 nM, 140 nM, 150 nM, 160 nM, 170 nM, 180 nM, 190 nM, or 200 nM, or a dose 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.

[0071] In some embodiments, the composition comprises T3 and T4 in a ratio of about 1:100 to about 1:10,000. In some embodiments, the composition comprises T3 and T4 in a ratio of about 1:100 to about 1:1,000. In some embodiments, the composition comprises T3 and T4 in a 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 therebetween. In some embodiments, the composition comprises T3 and T4 in a ratio of less than about 1:100. In some embodiments, the composition comprises T3 and T4 in a ratio of about 1:100. In some embodiments, the composition comprises T3 and T4 in a ratio of about 1:200. In some embodiments, the composition comprises T3 and T4 in a ratio of about 1:300. In some embodiments, the composition comprises T3 and T4 in a ratio of about 1:400. In some embodiments, the composition comprises T3 and T4 in a ratio of about 1:500. In some embodiments, the composition comprises T3 and T4 in a ratio of about 1:600. In some embodiments, the composition comprises T3 and T4 in a ratio of about 1:700. In some embodiments, the composition comprises T3 and T4 in a ratio of about 1:800. In some embodiments, the composition comprises T3 and T4 in a ratio of about 1:900. In some embodiments, the composition comprises T3 and T4 in a ratio of about 1:1,000. In some embodiments, the composition comprises T3 and T4 in a ratio of greater than about 1:1,000. In some embodiments, the composition comprises T3 and T4 in a ratio of about 1:1,000 to about 1:10,000. In some embodiments, the composition comprises T3 and T4 in a ratio of about 1:1,000. In some embodiments, the composition comprises T3 and T4 in a ratio of about 1:2,000. In some embodiments, the composition comprises T3 and T4 in a ratio of about 1:3,000. In some embodiments, the composition comprises T3 and T4 in a ratio of about 1:4,000.In some embodiments, the composition comprises T3 and T4 in a ratio of about T3:T4 of about 1:5,000. In some embodiments, the composition comprises T3 and T4 in a ratio of about 1:6,000. In some embodiments, the composition comprises T3 and T4 in a ratio of about 1:7,000. In some embodiments, the composition comprises T3 and T4 in a ratio of about 1:8,000. In some embodiments, the composition comprises T3 and T4 in a ratio of about 1:9,000. In some embodiments, the composition comprises T3 and T4 in a ratio of about 1:10,000. In some embodiments, the composition comprises T3 and T4 in a ratio greater than about 1:10,000.

[0072] In some embodiments, the composition comprises about 100 pM T3 and about 100 nM T4. In some embodiments, the composition comprises about 100 pM T3, about 100 nM T4, and a therapeutically effective amount of rapamycin. In some embodiments, the composition comprises about 10 nM T3 and about 1 μM T4. In some embodiments, the composition comprises about 10 nM T3 and about 10 μM T4. In some embodiments, the composition comprises about 1 nM T3 and about 10 μM T4.

[0073] In some embodiments, the topical composition comprises: a. Triiodothyronine (T3); b. Thyroxine (T4); and C. Solvent.

[0074] In some embodiments, the topical composition comprises: a. Triiodothyronine (T3); b. Thyroxine (T4); and C. Ethanol.

[0075] In some embodiments, the topical composition comprises: a. Triiodothyronine (T3); b. Thyroxine (T4); and c. Water.

[0076] In some embodiments, the topical composition comprises: a. Triiodothyronine (T3); b. Thyroxine (T4); and c.Propylene glycol.

[0077] In some embodiments, the topical composition comprises: a. Triiodothyronine (T3); b. Thyroxine (T4); c. ethanol; and d.Water.

[0078] In some embodiments, the topical composition comprises: a. Triiodothyronine (T3); b. Thyroxine (T4); c. ethanol; and d. Propylene glycol.

[0079] In some embodiments, the topical composition comprises: a. Triiodothyronine (T3); b. Thyroxine (T4); c. propylene glycol; and d.Water.

[0080] In some embodiments, the topical composition comprises: a. Triiodothyronine (T3); b. Thyroxine (T4); c. Ethanol; d. propylene glycol; and e. Water.

[0081] In some embodiments, the topical composition comprises: a. Triiodothyronine (T3); b. Thyroxine (T4); c. hydroxypropyl cellulose; and d. Solvent.

[0082] In some embodiments, the topical composition comprises: a. Triiodothyronine (T3); b. Thyroxine (T4); c. hydroxypropyl cellulose; and d. Ethanol.

[0083] In some embodiments, the topical composition comprises: a. Triiodothyronine (T3); b. Thyroxine (T4); c. hydroxypropyl cellulose; and d.Water.

[0084] In some embodiments, the topical composition comprises: a. Triiodothyronine (T3); b. Thyroxine (T4); c. hydroxypropyl cellulose; and d. Propylene glycol.

[0085] In some embodiments, the topical composition comprises: a. Triiodothyronine (T3); b. Thyroxine (T4); c. Hydroxypropyl cellulose; d. ethanol; and e. Water.

[0086] In some embodiments, the topical composition comprises: a. Triiodothyronine (T3); b. Thyroxine (T4); c. Hydroxypropyl cellulose; d. ethanol; and e. Propylene glycol.

[0087] In some embodiments, the topical composition comprises: a. Triiodothyronine (T3); b. Thyroxine (T4); c. Hydroxypropyl cellulose; d. propylene glycol; and e. Water.

[0088] In some embodiments, the topical composition comprises: a. Triiodothyronine (T3); b. Thyroxine (T4); c. Hydroxypropyl cellulose; d. Ethanol; e. propylene glycol; and f.Water.

[0089] In some embodiments, the topical composition comprises: a. Triiodothyronine (T3); and b. Solvent.

[0090] In some embodiments, the topical composition comprises: a. Triiodothyronine (T3); and b. Ethanol.

[0091] In some embodiments, the topical composition comprises: a. Triiodothyronine (T3); and b.Water.

[0092] In some embodiments, the topical composition comprises: a. Triiodothyronine (T3); and b.Propylene glycol.

[0093] In some embodiments, the topical composition comprises: a. Triiodothyronine (T3); b. ethanol; and c. Water.

[0094] In some embodiments, the topical composition comprises: a. Triiodothyronine (T3); b. ethanol; and c.Propylene glycol.

[0095] In some embodiments, the topical composition comprises: a. Triiodothyronine (T3); b. propylene glycol; and c. Water.

[0096] In some embodiments, the topical composition comprises: a. Triiodothyronine (T3); b. Ethanol; c. propylene glycol; and d.Water.

[0097] In some embodiments, the topical composition comprises: a. Triiodothyronine (T3); b. hydroxypropyl cellulose; and C. Solvent.

[0098] In some embodiments, the topical composition comprises: a. Triiodothyronine (T3); b. hydroxypropyl cellulose; and C. Ethanol.

[0099] In some embodiments, the topical composition comprises: a. Triiodothyronine (T3); b. hydroxypropyl cellulose; and c. Water.

[0100] In some embodiments, the topical composition comprises: a. Triiodothyronine (T3); b. hydroxypropyl cellulose; and c.Propylene glycol.

[0101] In some embodiments, the topical composition comprises: a. Triiodothyronine (T3); b. Hydroxypropyl cellulose; c. ethanol; and d.Water.

[0102] In some embodiments, the topical composition comprises: a. Triiodothyronine (T3); b. Hydroxypropyl cellulose; c. ethanol; and d. Propylene glycol.

[0103] In some embodiments, the topical composition comprises: a. Triiodothyronine (T3); b. Hydroxypropyl cellulose; c. propylene glycol; and d.Water.

[0104] In some embodiments, the topical composition comprises: a. Triiodothyronine (T3); b. Hydroxypropyl cellulose; c. Ethanol; d. propylene glycol; and e. Water.

[0105] In some embodiments, the topical composition comprises: a. Thyroxine (T4); and b. Solvent.

[0106] In some embodiments, the topical composition comprises: a. Thyroxine (T4); and b. Ethanol.

[0107] In some embodiments, the topical composition comprises: a. Thyroxine (T4); and b.Water.

[0108] In some embodiments, the topical composition comprises: a. Thyroxine (T4); and b.Propylene glycol.

[0109] In some embodiments, the topical composition comprises: a. Thyroxine (T4); b. ethanol; and c. Water.

[0110] In some embodiments, the topical composition comprises: a. Thyroxine (T4); b. ethanol; and c.Propylene glycol.

[0111] In some embodiments, the topical composition comprises: a. Thyroxine (T4); b. propylene glycol; and c. Water.

[0112] In some embodiments, the topical composition comprises: a. Thyroxine (T4); b. Ethanol; c. propylene glycol; and d.Water.

[0113] In some embodiments, the topical composition comprises: a. Thyroxine (T4); b. hydroxypropyl cellulose; and C. Solvent.

[0114] In some embodiments, the topical composition comprises: a. Thyroxine (T4); b. hydroxypropyl cellulose; and C. Ethanol.

[0115] In some embodiments, the topical composition comprises: a. Thyroxine (T4); b. hydroxypropyl cellulose; and c. Water.

[0116] In some embodiments, the topical composition comprises: a.(T3); b. Thyroxine (T4); c. hydroxypropyl cellulose; and d. Propylene glycol.

[0117] In some embodiments, the topical composition comprises: a. Thyroxine (T4); b. Hydroxypropyl cellulose; c. ethanol; and d.Water.

[0118] In some embodiments, the topical composition comprises: a. Thyroxine (T4); b. Hydroxypropyl cellulose; c. ethanol; and d. Propylene glycol.

[0119] In some embodiments, the topical composition comprises: a. Thyroxine (T4); b. Hydroxypropyl cellulose; c. propylene glycol; and d.Water.

[0120] In some embodiments, the topical composition comprises: a. Thyroxine (T4); b. Hydroxypropyl cellulose; c. Ethanol; d. propylene glycol; and e. Water.

[0121] In some embodiments, the composition further comprises a therapeutically effective amount of an additional active compound. In some embodiments, the additional active ingredient is selected to provide a synergistic effect. In embodiments, "synergistic effect" is understood to include an increase in potency, bioactivity, bioavailability, bioaccessibility, or therapeutic effect that is greater than the sum of the contributions of each component acting alone, including when the isolated compound contributes alone. Many methods are known to those skilled in the art for determining whether a particular effect is synergistic, i.e., whether the effect of two or more components combined is greater than the sum of the effects of each component applied alone, i.e., "1 + 1 > 2." One example is isobologram analysis (or contour analysis) (Huang et al., 2019).

[0122] In embodiments, the additional active ingredient is selected to provide an additional therapeutic effect, such as antioxidant, anti-inflammatory, analgesic, analgesic anti-sensitization, immunostimulatory, immunosuppressive, anti-cancer, antiemetic, antiulcer, antihistamine, vasodilator and vasoconstrictor.

[0123] In embodiments, the additional active ingredient is an amino acid, antioxidant, anti-inflammatory agent, analgesic, 5α-reductase inhibitor, cannabinoid, immunosuppressant, immunostimulant, anti-cancer agent, anti-ulcer agent, antihistamine, terpene, vitamin, vasodilator, or vasoconstrictor. These active ingredients may be in ionic, free base, or salt form, including polymorphs, and may be isomeric.

[0124] 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.

[0125] In another aspect, a topical composition according to any of the disclosed embodiments is provided for use in treating hair loss, in some embodiments, the hair loss is due to androgenetic alopecia.

[0126] In a further aspect, there is provided a use of the topical compositions of the disclosed embodiments for treating or preventing hair loss. In some embodiments, the hair loss is due to androgenetic alopecia.

[0127] In some embodiments, topical compositions are administered and dosed in accordance with good medical practice, taking into account the method and scheduling of administration, pre-existing and concomitant medications and ancillary medications, the individual patient's clinical condition and the severity of the underlying disease, the patient's age, sex, weight, and other factors relevant to the medical professional, as well as knowledge of the particular compound being used. Thus, dosages may vary from patient to patient, over time in the same patient, and for different compositions and formulations, but are determinable by one of ordinary skill in the art.

[0128] Determining the appropriate dosage includes not only determining the amount of a single dose, but also determining the number and timing of doses, as well as the appropriate time of day for administration.

[0129] The present disclosure further provides kits containing the disclosed compositions. In some embodiments, the kits provide the disclosed compositions in unit dosage form. The kits generally include suitable packaging. The kits may include one or more containers containing any of the compositions described herein. When multiple components are present, each component may be packaged in a separate container, or some components may be combined in the same container if cross-reactivity and shelf life permit. The kits may be in unit dosage form, bulk packaging (e.g., multi-dose packaging), or sub-unit doses.

[0130] For example, the disclosed kits can contain dosages of the disclosed compositions sufficient for an individual to use over an extended period of time, e.g., 1 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. The kits can also contain multiple unit dosages and instructions for use and can be packaged in quantities sufficient for home or retail storage. The kits optionally include instructions, typically written instructions (although instructions on electronic storage media (e.g., magnetic diskettes or optical discs) are also acceptable), that provide information regarding the use of the components of the disclosed methods. The instructions included with the kits typically provide information regarding the components and how to administer them to an individual.

[0131] In some embodiments, the disclosed compositions (whether in unit dosage form or not) may be provided in lyophilized form. Lyophilization, also called freeze-drying, is a process commonly used for preserving and stabilizing pharmaceutical compounds and compositions. Lyophilization results in a dry, shelf-stable product that can be reconstituted prior to use. Lyophilization of the disclosed compositions can provide several advantages. For example, in some embodiments, the disclosed compositions in lyophilized form have improved stability (e.g., shelf stability) and / or reduced susceptibility to chemical, thermal, or biological degradation compared to the same composition in non-lyophilized form. In some embodiments, the disclosed compositions in lyophilized form have reduced weight and / or volume, thereby reducing the cost and overall difficulty of transporting, storing, distributing, and using the composition compared to the same composition in non-lyophilized form. C. Method

[0132] In one aspect, a method for treating or preventing hair loss in a subject is provided, the method comprising administering to the subject a therapeutically effective amount of the 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 therapeutically effective amounts of both T3 and T4. In some embodiments, the hair loss is due to androgenetic alopecia.

[0133] In some embodiments, T3, T4, or a combination thereof is administered topically. In some embodiments, T3 is administered topically. In some embodiments, T4 is administered topically. In some embodiments, both T3 and T4 are administered topically (i.e., a combination is administered topically).

[0134] In some embodiments, T3 and T4 are administered simultaneously. Simultaneous administration of T3 and T4 can be achieved, for example, by administering a composition containing both T3 and T4 (e.g., the disclosed topical composition). In another embodiment, simultaneous administration of T3 and T4 can be achieved, for example, by simultaneously administering separate T3 and T4 compositions.

[0135] In some embodiments, T3 is administered at a concentration of about 1 nM to 30 nM. In some embodiments, 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 therebetween. In some embodiments, T3 is administered at a concentration of less than about 1 nM. In some embodiments, T3 is administered at a concentration of about 1 nM. In some embodiments, T3 is administered at a concentration of about 2 nM. In some embodiments, T3 is administered at a concentration of about 3 nM. In some embodiments, T3 is administered at a concentration of about 4 nM. In some embodiments, T3 is administered at a concentration of about 5 nM. In some embodiments, T3 is administered at a concentration of about 6 nM. In some embodiments, T3 is administered at a concentration of about 7 nM. In some embodiments, T3 is administered at a concentration of about 8 nM. In some embodiments, T3 is administered at a concentration of about 9 nM. In some embodiments, T3 is administered at a concentration of about 10 nM. In some embodiments, T3 is administered at a concentration of about 15 nM. In some embodiments, T3 is administered at a concentration of about 20 nM. In some embodiments, T3 is administered at a concentration of about 25 nM. In some embodiments, T3 is administered at a concentration of about 30 nM. In some embodiments, T3 is administered at a concentration greater than about 30 nM.

[0136] In some embodiments, T3 is administered at a concentration of about 1 μM to 15 μM. In some embodiments, T3 is administered at a concentration of less than about 1 μM, about 1 μM, about 2 μM, about 3 μM, about 4 μM, about 5 μM, about 6 μM, about 7 μM, about 8 μM, about 9 μM, about 10 μM, about 11 μM, about 12 μM, about 13 μM, about 14 μM, about 15 μM, or greater than about 15 μM, including ranges therebetween. In some embodiments, T3 is administered at a concentration of less than about 1 μM. In some embodiments, T3 is administered at a concentration of about 1 μM. In some embodiments, T3 is administered at a concentration of about 2 μM. In some embodiments, T3 is administered at a concentration of about 3 μM. In some embodiments, T3 is administered at a concentration of about 4 μM. In some embodiments, T3 is administered at a concentration of about 5 μM. In some embodiments, T3 is administered at a concentration of about 6 μM. In some embodiments, T3 is administered at a concentration of about 7 μM. In some embodiments, T3 is administered at a concentration of about 8 μM. In some embodiments, T3 is administered at a concentration of about 9 μM. In some embodiments, T3 is administered at a concentration of about 10 μM. In some embodiments, T3 is administered at a concentration of about 11 μM. In some embodiments, T3 is administered at a concentration of about 12 μM. In some embodiments, T3 is administered at a concentration of about 13 μM. In some embodiments, T3 is administered at a concentration of about 14 μM. In some embodiments, T3 is administered at a concentration of about 15 μM. In some embodiments, T3 is administered at a concentration greater than about 15 μM.

[0137] In some embodiments, T3 is administered at a concentration of about 50 pM, 60 pM, 70 pM, 80 pM, 90 pM, 100 pM, 110 pM, 120 pM, 130 pM, 140 pM, 150 pM, 160 pM, 170 pM, 180 pM, 190 pM, or 200 pM, or at doses between these values. In some embodiments, T3 is administered at a concentration of about 50 pM. In some embodiments, T3 is administered at a concentration of about 60 pM. In some embodiments, T3 is administered at a concentration of about 70 pM. In some embodiments, T3 is administered at a concentration of about 80 pM. In some embodiments, T3 is administered at a concentration of about 90 pM. In some embodiments, T3 is administered at a concentration of about 100 pM. In some embodiments, T3 is administered at a concentration of about 110 pM. In some embodiments, T3 is administered at a concentration of about 120 pM. In some embodiments, T3 is administered at a concentration of about 130 pM. In some embodiments, T3 is administered at a concentration of about 140 pM. In some embodiments, T3 is administered at a concentration of about 150 pM. In some embodiments, T3 is administered at a concentration of about 160 pM. In some embodiments, T3 is administered at a concentration of about 170 pM. In some embodiments, T3 is administered at a concentration of about 180 pM. In some embodiments, T3 is administered at a concentration of about 190 pM. In some embodiments, T3 is administered at a concentration of about 200 pM.

[0138] In some embodiments, T4 is administered at a concentration of about 1 μM to 30 μM. In some embodiments, T4 is administered at a concentration of less than about 1 μM, about 1 μM, about 2 μM, about 3 μM, about 4 μM, about 5 μM, about 6 μM, about 7 μM, about 8 μM, about 9 μM, about 10 μM, about 15 μM, about 20 μM, about 25 μM, about 30 μM, or greater than about 30 μM. In some embodiments, T4 is administered at a concentration of less than about 1 μM. In some embodiments, T4 is administered at a concentration of about 1 μM. In some embodiments, T4 is administered at a concentration of about 2 μM. In some embodiments, T4 is administered at a concentration of about 3 μM. In some embodiments, T4 is administered at a concentration of about 4 μM. In some embodiments, T4 is administered at a concentration of about 5 μM. In some embodiments, T4 is administered at a concentration of about 6 μM. In some embodiments, T4 is administered at a concentration of about 7 μM. In some embodiments, T4 is administered at a concentration of about 8 μM. In some embodiments, T4 is administered at a concentration of about 9 μM. In some embodiments, T4 is administered at a concentration of about 10 μM. In some embodiments, T4 is administered at a concentration of about 15 μM. In some embodiments, T4 is administered at a concentration of about 20 μM. In some embodiments, T4 is administered at a concentration of about 25 μM. In some embodiments, T4 is administered at a concentration of about 30 μM. In some embodiments, T4 is administered at a concentration greater than about 30 μM.

[0139] In some embodiments, T4 is administered at a concentration of about 10 μM to 15,000 μM. In some embodiments, T4 is administered at a concentration of less than about 10 μM, about 10 μM, about 20 μM, about 50 μM, about 100 μM, about 250 μM, about 500 μM, about 1,000 μM, about 2,500 μM, about 5,000 μM, about 10,000 μM, about 12,000 μM, about 15,000 μM, or greater than about 15,000 μM, including ranges therebetween. In some embodiments, T4 is administered at a concentration of less than about 10 μM. In some embodiments, T4 is administered at a concentration of about 10 μM. In some embodiments, T4 is administered at a concentration of about 20 μM. In some embodiments, T4 is administered at a concentration of about 50 μM. In some embodiments, T4 is administered at a concentration of about 100 μM. In some embodiments, T4 is administered at a concentration of about 250 μM. In some embodiments, T4 is administered at a concentration of about 500 μM. In some embodiments, T4 is administered at a concentration of about 1,000 μM. In some embodiments, T4 is administered at a concentration of about 2,500 μM. In some embodiments, T4 is administered at a concentration of about 5,000 μM. In some embodiments, T4 is administered at a concentration of about 10,000 μM. In some embodiments, T4 is administered at a concentration of about 12,000 μM. In some embodiments, T4 is administered at a concentration of about 15,000 μM. In some embodiments, T4 is administered at a concentration greater than about 15,000 μM.

[0140] In some embodiments, T4 is administered at a concentration of about 50 nM, 60 nM, 70 nM, 80 nM, 90 nM, 100 nM, 110 nM, 120 nM, 130 nM, 140 nM, 150 nM, 160 nM, 170 nM, 180 nM, 190 nM, or 200 nM, or at a dose between these values. In some embodiments, T4 is administered at a concentration of about 50 nM. In some embodiments, T4 is administered at a concentration of about 60 nM. In some embodiments, T4 is administered at a concentration of about 70 nM. In some embodiments, T4 is administered at a concentration of about 80 nM. In some embodiments, T4 is administered at a concentration of about 90 nM. In some embodiments, T4 is administered at a concentration of about 100 nM. In some embodiments, T4 is administered at a concentration of about 120 nM. In some embodiments, T4 is administered at a concentration of about 130 nM. In some embodiments, T4 is administered at a concentration of about 140 nM. In some embodiments, T4 is administered at a concentration of about 150 nM. In some embodiments, T4 is administered at a concentration of about 160 nM. In some embodiments, T4 is administered at a concentration of about 170 nM. In some embodiments, T4 is administered at a concentration of about 180 nM. In some embodiments, T4 is administered at a concentration of about 190 nM. In some embodiments, T4 is administered at a concentration of about 200 nM.

[0141] In some embodiments, T3 and T4 are administered at a T3:T4 ratio of about 1:100 to about 1:10,000. In some embodiments, T3 and T4 are administered at a T3:T4 ratio of about 1:100 to about 1:1,000. In some embodiments, 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, T3 and T4 are administered at a T3:T4 ratio of less than about 1:100. In some embodiments, T3 and T4 are administered at a T3:T4 ratio of about 1:100. In some embodiments, T3 and T4 are administered at a T3:T4 ratio of about 1:200. In some embodiments, T3 and T4 are administered at a T3:T4 ratio of about 1:300. In some embodiments, T3 and T4 are administered at a T3:T4 ratio of about 1:400. In some embodiments, T3 and T4 are administered at a T3:T4 ratio of about 1:500. In some embodiments, T3 and T4 are administered at a T3:T4 ratio of about 1:600. In some embodiments, T3 and T4 are administered at a T3:T4 ratio of about 1:700. In some embodiments, T3 and T4 are administered at a T3:T4 ratio of about 1:800. In some embodiments, T3 and T4 are administered at a T3:T4 ratio of about 1:900. In some embodiments, T3 and T4 are administered at a T3:T4 ratio of about 1:1,000. In some embodiments, T3 and T4 are administered at a T3:T4 ratio of greater than about 1:1,000. In some embodiments, T3 and T4 are administered at a T3:T4 ratio of about 1:1,000 to about 1:10,000. In some embodiments, T3 and T4 are administered at a T3:T4 ratio of about 1:1,000. In some embodiments, T3 and T4 are administered at a T3:T4 ratio of about 1:2,000. In some embodiments, T3 and T4 are administered at a T3:T4 ratio of about 1:3,000. In some embodiments, T3 and T4 are administered at a T3:T4 ratio of about 1:4,000.In some embodiments, T3 and T4 are administered at a T3:T4 ratio of about 1:5,000. In some embodiments, T3 and T4 are administered at a T3:T4 ratio of about 1:6,000. In some embodiments, T3 and T4 are administered at a T3:T4 ratio of about 1:7,000. In some embodiments, T3 and T4 are administered at a T3:T4 ratio of about 1:8,000. In some embodiments, T3 and T4 are administered at a T3:T4 ratio of about 1:9,000. In some embodiments, T3 and T4 are administered at a T3:T4 ratio of about 1:10,000. In some embodiments, T3 and T4 are administered at a T3:T4 ratio of greater than about 1:10,000.

[0142] In some embodiments, T3 is administered at a concentration of about 100 pM and T4 is administered at a concentration of about 100 nM. In some embodiments, T3 is administered at a concentration of about 10 nM and T4 is administered at a concentration of about 1 μM. In some embodiments, T3 is administered at a concentration of about 10 nM and T4 is administered at a concentration of about 10 μM. In some embodiments, T3 is administered at a concentration of about 1 nM and T4 is administered at a concentration of about 10 μM.

[0143] In some embodiments, the total volume of a unit dose of the disclosed topical compositions is about 0.1 mL to 10 mL. In some embodiments, the total 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 volume is about 0.1 mL. In some embodiments, the total dose is about 0.5 mL. In some embodiments, the total volume of a unit dose is about 1 mL. In some embodiments, the total volume of a unit dose is about 2 mL. In some embodiments, the total dose of the disclosed pharmaceutical compositions is about 3 mL. In some embodiments, the total volume of a unit dose is about 4 mL. In some embodiments, the total volume of a unit dose is about 5 mL. In some embodiments, the total volume of a unit dose is about 6 mL. In some embodiments, the total volume of a unit dose is about 7 mL. In some embodiments, the total volume of a unit dose is about 8 mL. In some embodiments, the total volume of a unit dose is about 9 mL. In some embodiments, the total volume of the unit dose is about 10 mL.

[0144] In some embodiments, the disclosed methods are carried out in accordance with good medical practice, taking into account the method and scheduling of administration, pre- and co-administered medications and adjuncts, the individual patient's clinical condition and severity of underlying disease, the patient's age, sex, and weight, and other factors relevant to the medical professional, as well as knowledge of the particular compound being used. Thus, dosage levels may vary from patient to patient, or over time in the same patient, and even for different compositions or formulations, but are determinable by one of ordinary skill.

[0145] In some embodiments, the topical composition is administered every other day for a regular period, followed by an extended period of time without administration. For example, in some embodiments, the topical composition is administered every other day for one week, followed by an extended period of time without administration. In some embodiments, the topical composition is administered every other day for two weeks, followed by an extended period of time without administration. In some embodiments, the topical composition is administered every other day for three weeks, followed by an extended period of time without administration. In some embodiments, the topical composition is administered every other day for four weeks, followed by an extended period of time without administration. In some embodiments, the topical composition is administered every other day for five weeks, followed by an extended period of time without administration. In some embodiments, the topical composition is administered every other day for six weeks, followed by an extended period of time without administration.

[0146] In some embodiments, the extended period of time without administration lasts 1 day. In some embodiments, the extended period of time without administration lasts 2 days. In some embodiments, the extended period of time without administration lasts 3 days. In some embodiments, the extended period of time without administration lasts 4 days. In some embodiments, the extended period of time without administration lasts 5 days. In some embodiments, the extended period of time without administration lasts 6 days. In some embodiments, the extended period of time without administration lasts 7 days. In some embodiments, the extended period of time without administration lasts 10 days. In some embodiments, the extended period of time without administration lasts 14 days. In some embodiments, the extended period of time without administration lasts 30 days.

[0147] In some embodiments, the topical composition is administered daily for several consecutive days, followed by an extended period of no administration. For example, in some embodiments, the topical composition is administered daily for two consecutive days, followed by an extended period of no administration. In some embodiments, the topical composition is administered daily for three consecutive days, followed by an extended period of no administration. In some embodiments, the topical composition is administered daily for four consecutive days, followed by an extended period of no administration. In some embodiments, the topical composition is administered daily for five consecutive days, followed by an extended period of no administration. In some embodiments, the topical composition is administered daily for six consecutive days, followed by an extended period of no administration. In some embodiments, the topical composition is administered daily for seven consecutive days, followed by an extended period of no administration. In other embodiments, the topical composition is administered for only one day, followed by an extended period of no administration.

[0148] In some embodiments, the extended period of time without administration lasts 1 day. In some embodiments, the extended period of time without administration lasts 2 days. In some embodiments, the extended period of time without administration lasts 3 days. In some embodiments, the extended period of time without administration lasts 4 days. In some embodiments, the extended period of time without administration lasts 5 days. In some embodiments, the extended period of time without administration lasts 6 days. In some embodiments, the extended period of time without administration lasts 7 days. In some embodiments, the extended period of time without administration lasts 10 days. In some embodiments, the extended period of time without administration lasts 14 days. In some embodiments, the extended period of time without administration lasts 30 days.

[0149] In some embodiments, T3, T4, or a combination thereof is administered in an external composition. In some embodiments, the disclosed method comprises administering a combination of T3 and T4. In some embodiments, T3 and T4 are present in the same composition. In other embodiments, T3 and T4 are present in different compositions.

[0150] It is understood that the frequency or duration of the disclosed methods may be increased or decreased depending on the desired clinical outcome, the state of the disease state or condition, side effects of the treatment or therapy, or concomitant medications. In some embodiments, a subject receives the disclosed methods daily for several consecutive days, followed by an extended period of time off administration. This is referred to herein as "pulse administration" or "pulse therapy." In some embodiments, a subject receives the disclosed methods daily for two consecutive days, followed by an extended period of time off administration. In some embodiments, a subject receives the disclosed methods daily for three consecutive days, followed by an extended period of time off administration. In some embodiments, a subject receives the disclosed methods daily for four consecutive days, followed by an extended period of time off administration. In some embodiments, a subject receives the disclosed methods daily for five consecutive days, followed by an extended period of time off administration. In some embodiments, a subject receives the disclosed methods daily for six consecutive days, followed by an extended period of time off administration. In some embodiments, a subject receives the disclosed methods daily for seven consecutive days, followed by an extended period of time off administration. In some embodiments, a subject receives the disclosed methods daily for ten consecutive days, followed by an extended period of time off administration. In some embodiments, a subject receives the disclosed methods daily for fourteen consecutive days, followed by an extended period of time off administration. In some embodiments, subjects receive the disclosed methods for only one day and then are off-label for an extended period of time.

[0151] In some embodiments, the extended period of time without administration lasts 1 day. In some embodiments, the extended period of time without administration lasts 2 days. In some embodiments, the extended period of time without administration lasts 3 days. In some embodiments, the extended period of time without administration lasts 4 days. In some embodiments, the extended period of time without administration lasts 5 days. In some embodiments, the extended period of time without administration lasts 6 days. In some embodiments, the extended period of time without administration lasts 7 days. In some embodiments, the extended period of time without administration lasts 10 days. In some embodiments, the extended period of time without administration lasts 14 days. In some embodiments, the extended period of time without administration lasts 30 days.

[0152] In some embodiments, the amount of T3 administered in a single administration (i.e., unit dose) of the disclosed topical composition is about 0.00001 μg to about 0.1 μg. In some embodiments, the amount of T3 administered per unit dose is about 0.00001 μg to about 0.001 μg. In some embodiments, the amount of T3 administered per unit dose is about 0.00001 μg to about 0.01 μg. In some embodiments, the amount of T3 administered per unit dose is about 0.001 μg to about 0.01 μg. In some embodiments, the amount of T3 administered per unit dose is about 0.01 μg to about 0.1 μg.

[0153] In some embodiments, the amount of T3 administered per unit dose is about 1 ng to 20 ng. In some embodiments, the amount of T3 administered per unit dose is about 1 ng to 10 ng. In some embodiments, the amount of T3 administered per unit dose is about 5 ng to 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.

[0154] In some embodiments, the amount of T3 administered per unit dose is about 0.1 ng to 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.

[0155] In some embodiments, the amount of T4 administered in a single administration (i.e., unit dose) of the disclosed topical compositions is about 0.1 μg to about 100 μg. In some embodiments, the amount of T4 administered per unit dose is about 0.1 μg to about 1 μg. In some embodiments, the amount of T4 administered per unit dose is about 0.1 μg to about 10 μg. In some embodiments, the amount of T4 administered per unit dose is about 1 μg to about 10 μg. In some embodiments, the amount of T4 administered per unit dose is about 10 μg to about 100 μg.

[0156] In some embodiments, the disclosed compositions are formulated as unit dosage forms, each dosage unit containing, for example, the above-mentioned dosage amount of the active ingredient. Here, "unit dosage form" refers to a physically discrete unit suitable for individual ingestion, each unit containing a predetermined amount of the active ingredient calculated to produce the desired effect. Unit dosage forms are often used for ease of administration and uniformity of dosage. A unit dosage form may contain a single dose, a partial dose, or an appropriate fraction thereof of the composition.

[0157] In embodiments in which the disclosed compositions are used to produce a desired effect, it will be readily understood that the dosage and frequency of administration may vary depending on the individual's general health, age, sex, race, bioavailability, the possibility of systemic, local or local side effects, the presence or absence of a disorder or disease in the individual, and other factors that one of skill in the art would understand (e.g., medical or family history).

[0158] Generally, dosage, frequency or duration may be increased or decreased depending on the desired therapeutic outcome or effect, preferred outcome or effect, and / or particular subjective outcome or effect.

[0159] Those skilled in the art will understand the factors that may affect the dosage, frequency, and timing needed to provide an amount sufficient or effective to produce a desired effect, and will be able to do so depending on the type of effect desired and to avoid or minimize side effects.

[0160] Dosage levels may vary from patient to patient, or from individual to individual, over time, and even for different compositions or formulations, but can be determined by one of ordinary skill. Determining the appropriate dosage includes not only determining the single dose, but also determining the number and timing of administrations, and the preferred time of day for administration.

[0161] In some embodiments, the disclosed compositions are formulated for topical administration (e.g., as a topical dosage form), e.g., by 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 modifiers (e.g., thickeners), adhesion modifiers (e.g., tackifiers), preservatives, antioxidants, adhesive polymers, solubilizers, colorants, binders, humectants, surfactants, gelling agents, and other ingredients commonly known to those skilled in the art.

[0162] Pharmaceutical preparations can be prepared as liquid suspensions or solutions using sterile liquids such as oils, water, alcohols, and combinations of these pharmaceutically suitable surfactants, suspending agents, and emulsifying agents. Suspensions can include oils. Such oils include peanut oil, sesame oil, cottonseed oil, corn oil, and olive oil. Suitable oils also include MCT and long-chain triglyceride (LCT) oils as carrier oils. Suspension preparations can also include fatty acid esters such as ethyl oleate, isopropyl myristate, fatty acid glycerides, and acetylated fatty acid glycerides. Suspension formulations can include alcohols (e.g., ethanol, isopropyl alcohol, hexadecyl alcohol), glycerol, and propylene glycol. Ethers (e.g., polyethylene glycol), petroleum hydrocarbons such as mineral oil and petrolatum, and water can also be used in suspension formulations. Thus, suspensions can include aqueous or non-aqueous liquids, water-in-oil liquid emulsions, or oil-in-water emulsions.

[0163] As used herein, "pharmaceutically acceptable" with respect to excipients and other ingredients means that the ingredient is generally safe and, within the scope of reasonable medical judgment, suitable for use in contact with the cells of humans and other animals without undue toxicity, irritation, allergic response, or complications, and is commensurate with a reasonable risk / benefit ratio. In some embodiments, "pharmaceutically acceptable" means that the particular ingredient has been approved by the FDA for topical use in cosmetics.

[0164] In some embodiments, the composition includes a penetration enhancer. Without being bound by theory, penetration enhancers are generally characterized by their ability to increase the permeability of a biological barrier, such as scalp skin. In some embodiments, the inclusion of a penetration enhancer in the composition increases the bioavailability of the active ingredient (e.g., T3, T4, and / or other additional active ingredients) by improving their ability to diffuse into skin tissue. Penetration enhancers include, for example, 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, petrolatum, cocoa butter, shea butter, and 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, cetyltrimethylammonium, cyclodextrin, dextran sulfate, glycol, lauric acid, propylene laurate, 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 the group consisting of lower alcohols having a carbon chain length of 1 to 5, sodium glycocholate, sodium deoxycholate, sodium taurocholate, sodium glycodeoxycholate, sodium taurodeoxycholate, oleic acid, capric acid, lauric acid, lecithin, myristic acid, palmitic acid, lysophosphatidylcholine, phosphatidylcholine, azone, cyclodextrin, sodium lauryl sulfate, polyoxyethylene-9-lauryl ether, polyoxyethylene-20-cetyl ether, benzalkonium chloride, cetylpyridinium chloride, vitamin ETPGS, caprylocaproyl polyoxylglyceride, stearoyl macrogolglyceride, propylene glycol dicaprylocaprate, or mixtures thereof.In some embodiments, the disclosed compositions may comprise 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 The composition may comprise 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% penetration enhancer.

[0165] In some embodiments, the base may further comprise a conditioning agent to prevent dryness of the skin and hair in combination with the active ingredient (e.g., T3, T4, and / or other additional active ingredients). Representative conditioning agents include, but are not limited to, glycerin, propylene glycol, alpha-hydroxy acids, urea, lactic acid, oils and fats, lanolin, and silicones and their derivatives. In some embodiments, the conditioning agent is physically and chemically compatible with the essential components of the composition and does not unduly impair the stability, aesthetics, or performance of the product. In some embodiments, the concentration of the conditioning agent in the composition is an amount sufficient to provide the desired conditioning benefit, as will be apparent to those skilled in the art. The concentration may vary depending on the conditioning agent, the desired conditioning performance, the average size of the conditioning agent particles, the type and concentration of other ingredients, and other similar factors.

[0166] In some embodiments, the composition includes a carrier. The carrier can be designed to provide a controlled release profile, improved circulation time, and enhanced permeability across epithelia. In some embodiments, the carrier is a hydrophobic drug carrier. Hydrophobic drug carriers can have the advantage of exhibiting sustained release and good adhesion to biological surfaces. Hydrophobic drug carriers can have slow (i.e., prolonged) release kinetics or can be constructed to have a rapid or immediate release profile. Emerging technologies include developing hydrophilic coatings on hydrophobic nanoparticles to improve transport across tissue surfaces while maintaining the release profile. These include polyethylene glycol and chitosan coatings. (See, e.g., de la Fuente, et al. Nanomedicine 2008;3:845-857.) A variety of pharmaceutically acceptable carriers can be used, including, but not limited to, aqueous vehicles such as water, saline, glycine, hyaluronic acid, and the like; solid carriers such as starch, magnesium stearate, mannitol, sodium saccharin, talc, cellulose, glucose, sucrose, lactose, trehalose, magnesium carbonate, and the like; solvents; dispersion media; coatings; antibacterial and antifungal agents; isotonic and absorption delaying agents; and other inactive ingredients. The choice of pharmaceutically acceptable carrier can depend on the route of administration.Non-limiting examples of specific uses of such pharmaceutical carriers are described in Pharmaceutical Dosage Forms and Drug Delivery Systems (eds. Howard C. Ansel et al., Lippincott Williams & Wilkins Publishers, 7th ed., 1999); Remington: The Science and Practice of Pharmacy (ed. Alfonso R. Gennaro, Lippincott, Williams & Wilkins, 20th ed., 2000); Goodman & Gilman's The Pharmacological Basis of Therapeutics (eds. Joel G. Hardman et al., McGraw-Hill Professional, 10th ed., 2001); and Handbook of Pharmaceutical Excipients (Raymond C. Rowe et al., APhA Publications, 4th ed., 2003). In some embodiments, the disclosed compositions may comprise 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 31%, about 32%, about 33%, about 34%, about 35%, about 36%, about 37%, about 38%, about 39%, about 40%, about 41%, about 42%, about 43%, about 44%, about 45%, about 46%, about 47%, about 48%, about 49%, about 50%, about 51%, about 52%, about 53%, about 54%, about 55%, about 56%, about 57%, about 58%, about 59%, about 60%, about 61%, about 62%, about 63%, about 64%, about 65%, about 66%, about 67%, about 68%, about 69%, about 70%, about 71%, about 72%, about 73%, about 74%, about 75%, about 76%, about 77%, about 78%, about 79%, about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about The composition may comprise 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 a carrier.

[0167] In some embodiments, the composition includes an emulsifier. The emulsifier may be anionic, cationic, or neutral emulsifier. In certain embodiments, the emulsifier is an anionic emulsifier selected from the group consisting of alkyl sulfates, aralkyl sulfates, alkyl ethoxy ether sulfates, alkaryl sulfonates, alkyl succinates, alkyl sulfosuccinates, N-alkoyl sarcosinates, isethionates, N-acyltaurates, sodium lauryl sulfate, sodium laureth sulfate, sodium oleyl succinate, sodium dodecylbenzenesulfonate, and sodium lauryl sarcosinate. Representative nonionic or neutral emulsifiers include sorbitan esters, ethoxylated sorbitan esters, ethoxylated alkyl ethers, ethoxylated fatty acid ethers, fatty alcohols, ethoxylated fatty alcohols, and esters of glycerin and fatty acids. In certain embodiments, the emulsifier is a synthetic or natural polymer. In certain embodiments, the emulsifier includes silicone. In certain embodiments, the emulsifier is a silicone (e.g., dimethicone, phenyl trimethicone, PEG dimethicone, PPG dimethicone, etc.). In some embodiments, the disclosed compositions may contain 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 31%, about 32%, about 33%, about 34%, about 35%, about 36%, about 37%, about 38%, about 39%, about 40%, about 41%, about 42%, about 43%, about 44%, about 45%, about 46%, about 47%, about 48%, about 49%, about 50%, about 51%, about 52%, about 53%, about 54%, about 55%, about 56%, about 57%, about 58%, about 59%, about 60%, about 61%, about 62%, about 63%, about 64%, about 65%, about 66%, about 67%, about 68%, about 69%, about 70%, about 72%, about 73%, about 74%, about 75%, about 76%, about 77%, about 78%, about 79 The emulsion may contain 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% emulsifier.

[0168] In some embodiments, the compositions include other ingredients typically applied to the scalp or hair, including anti-dandruff or anti-bacterial agents, if desired, in amounts typically found useful for topical application. One of skill in the art can readily determine the type and amount of anti-dandruff agent to select for use in the formulations of the present invention.

[0169] In some embodiments, the composition comprises an antioxidant. Antioxidants include 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, and L-carnosine and derivatives thereof (e.g., anserine), carotenoids, carotenes (e.g., β-carotene, lycopene) and derivatives thereof, chlorogenic acid and derivatives thereof, lipoic acid and derivatives thereof (e.g., dihydrolipoic acid), aurothioglucose, propylthiouracil, and other thiols (e.g., thioredoxin, glutathione, cysteine, cystine, cystamine, and glycosyl groups thereof, N-acetylglucosamine, acetylcholine, acetylcysteine ​​... cetyl, methyl, ethyl, propyl, amyl, butyl, lauryl, palmitoyl, oleyl, gamma-linoleyl, cholesteryl and glyceryl esters) and their salts, dilauryl thiodipropionate, distearyl thiodipropionate, thiodipropionic acid and its derivatives (esters, ethers, peptides, lipids, nucleotides, nucleosides and salts), sulfoximine compounds (e.g. buthionine sulfoximine, homocysteine ​​sulfoximine, buthionine sulfone, penta-, hexa- and heptathionine sulfoximine), used at very low tolerated doses (e.g. pmol-μmol / kg).Furthermore, (metal) chelating agents (e.g., α-hydroxy fatty acids, palmitic acid, phytic acid, lactoferrin), α-hydroxy acids (e.g., citric acid, lactic acid, malic acid), humic acid, gallic acid, bile extract, bilirubin, biliverdin, EDTA and its derivatives, unsaturated fatty acids and their derivatives (e.g., γ-linolenic acid, linoleic acid, oleic acid), folic acid and its derivatives, ubiquinone and ubiquinol and their derivatives, vitamin C and its derivatives (e.g., sodium ascorbate, ascorbyl palmitate, magnesium ascorbate, ascorbyl acetate), tocopherol and its derivatives (e.g., vitamin E acetate, tocopherol), enol), vitamin A and its derivatives (vitamin A palmitate), benzoic acid resin coniferyl benzoate, rutinic acid and its derivatives, α-glycosylrutin, ferulic acid, furfurylidene glucitol, carnosine, butylhydroxytoluene, butylhydroxyanisole, nordihydroguaiac resin acid, nordihydroguaiaretic acid, trihydroxybutyrophenone, uric acid and its derivatives, mannose and its derivatives, zinc and its derivatives (e.g., zinc oxide, zinc sulfate), selenium and its derivatives (e.g., selenium methionine), stilbene and its derivatives (e.g., stilbene oxide, trans-stilbene oxide).

[0170] In an embodiment, the composition comprises vitamins, including riboflavin (vitamin B2), niacinamide (vitamin B3), pantothenic acid (vitamin B5), pyridoxine (vitamin B6), and biotin (vitamin B7).

[0171] In some embodiments, the composition contains a conventional thickener. Conventional thickeners include cross-linked polyacrylic acid and its derivatives, such as xanthan gum, agar, alginates, or tylose, polysaccharides and their derivatives, cellulose derivatives (e.g., carboxymethylcellulose or hydroxycarboxymethylcellulose), fatty alcohols, monoglycerides and fatty acids, polyvinyl alcohol, and polyvinylpyrrolidone. Nonionic thickeners are preferably used.

[0172] In some embodiments, the composition comprises a cosmetic and / or dermocosmetic active, including coloring actives, skin and hair pigmenting compositions, coloring compositions, tanning compositions, bleaching agents, keratin-hardening agents, antibacterial actives, light filter actives, repellent actives, hyperemic actives, keratolytic and keratinizing actives, antidandruff actives, anti-inflammatory agents, keratinizing actives, antioxidant or free radical scavenging actives, skin moisturizing or humectants, refatting actives, anti-erythema or anti-allergic actives, branched fatty acids (e.g., 18-methyl eicosanoic acid), and mixtures thereof.

[0173] In an embodiment, the composition comprises a fragrance oil.Natural fragrances are extracts of flowers (lily, lavender, rose, jasmine, neroli, ylang-ylang), stems and leaves (geranium, patchouli, petitgrain), fruits (anise, coriander, caraway, juniper), peels (bergamot, lemon, orange), roots (mace, angelica, celery, cardamom, costus, iris, calamus), woods (pinewood, sandalwood, guaiacwood, cedarwood, 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).Representative synthetic fragrance compounds are products of the ester, ether, aldehyde, ketone, alcohol and hydrocarbon types. Low-volatility essential oils commonly used as fragrance ingredients are also suitable as perfume oils, such as sage oil, chamomile oil, clove oil, balm oil, mint oil, cinnamon leaf oil, linden flower oil, juniper oil, vetiver oil, olivan oil, galbanum oil, labranum oil and lavandin oil, bergamot oil, dihydromyrcenol, lilial, lyral, citronellol, phenylethyl alcohol, α-hexylcinnamaldehyde, geraniol, benzyl acetone, cyclamen aldehyde, linalool, Boisambrene® Fort e, Ambroxan, Indole, Hedione, Sandelice, Lemon Oil, Mandarin Oil, Orange Oil, Allyl Amyl Glycolate, Cyclovertal, Lavandin Oil, Muscatel Sage Oil, G39 Damascone, Bourbon Geranium Oil, Cyclohexyl Salicylate, Vertofix® Coeur, iso-E-Super®, Fixolide® NP, Evemil, Iraldein Gamma, Phenylacetic Acid, Geranyl Acetate, Benzyl Acetate, Rose Oxide, Romilate, Irotyl, and Floramat.

[0174] In some embodiments, the topical composition comprises hydroxyalkyl cellulose. When formulated as an excipient, hydroxyalkyl cellulose can have multiple functions. For example, hydroxyalkyl cellulose can act as a penetration enhancer, carrier, emulsifier, stabilizer, viscosity modifier, adhesion modifier, antioxidant, adhesive polymer, solubilizer, binder, moisturizer, and / or gelling agent. In some embodiments, the topical composition comprises hydroxymethyl cellulose. In some embodiments, the topical composition comprises hydroxyethyl cellulose. In some embodiments, the topical composition comprises hydroxypropyl cellulose.

[0175] In some embodiments, the composition includes a solvent and, optionally, a co-solvent. Any solvent and co-solvent may be collectively referred to as a "solvent system." Without being bound by theory, the selected solvent system may affect the stability, bioavailability, and overall efficacy of the composition. In some embodiments, the solvent system is capable of dissolving or solubilizing the active ingredient and any excipients to be incorporated at the desired concentrations, and is stable and compatible with the components in the composition (e.g., T3, T4, additional active ingredients, and other excipients). In some embodiments, when the solvent system includes one or more solvents, the ratio of the co-solvents is optimized to, for example, enhance the permeability or bioavailability of the active ingredient. Preferred solvent systems are safe and non-toxic for human ingestion. In some embodiments, potential adverse effects, such as irritation or allergic reactions, are considered and minimized when selecting the solvents included in the disclosed solvent systems. Solvents that can be included in the disclosed compositions include, but are not limited to, water, ethanol, polyhydric alcohols (e.g., glycerin), 1,3-butylene glycol, propylene glycol, hexylene glycol, propanediol, ethylene glycol, diethylene glycol, dipropylene glycol, diglycerin, sorbitol, other sugars that are liquid at room temperature, water-soluble alkoxylated nonionic polymers (e.g., polyethylene glycol), and combinations thereof. The solvent, alone or in combination (if multiple solvents are included), can be present in the composition in an amount of from about 0.1% to about 95% by weight (calculated as the total weight of solvents in the composition divided by the total weight of the composition).

[0176] 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 about 0.1% (v / v) to 90% (v / v) water. In some embodiments, the disclosed pharmaceutical compositions comprise about 0.1% (v / v) to 1% (v / v) water. In some embodiments, the disclosed pharmaceutical compositions comprise about 0.1% (v / v) to 10% (v / v) water. In some embodiments, the disclosed pharmaceutical compositions comprise about 1% (v / v) to 90% (v / v) water. In some embodiments, the disclosed pharmaceutical compositions comprise about 1% (v / v) to 50% (v / v) water. In some embodiments, the disclosed pharmaceutical compositions comprise about 1% (v / v) to 30% (v / v) water. In some embodiments, the solvent system comprises ethanol. In some embodiments, the disclosed pharmaceutical compositions comprise about 5% (v / v) to 50% (v / v) water. In some embodiments, the disclosed pharmaceutical compositions comprise about 5% (v / v) to 30% (v / v) water. In some embodiments, the disclosed pharmaceutical compositions comprise about 5% (v / v) to 20% (v / v) water. In some embodiments, the disclosed pharmaceutical compositions comprise about 10% (v / v) to 20% (v / v) water. In some embodiments, the disclosed pharmaceutical compositions comprise about 10% (v / v) water. In some embodiments, the disclosed pharmaceutical compositions comprise about 15% (v / v) water. In some embodiments, the disclosed pharmaceutical compositions comprise about 20% (v / v) water.

[0177] In some embodiments, the solvent system comprises ethanol. In some embodiments, the disclosed pharmaceutical compositions comprise about 60% (v / v) ethanol. In some embodiments, the disclosed pharmaceutical compositions comprise about 10% (v / v) to 70% (v / v) ethanol. In some embodiments, the disclosed pharmaceutical compositions comprise about 10% (v / v) to 60% (v / v) ethanol. In some embodiments, the solvent system comprises ethanol. In some embodiments, the disclosed pharmaceutical compositions comprise about 15% (v / v) to 55% (v / v) ethanol. In some embodiments, the disclosed pharmaceutical compositions comprise about 20% (v / v) to 50% (v / v) ethanol. In some embodiments, the disclosed pharmaceutical compositions comprise about 20% (v / v) to 40% (v / v) ethanol. In some embodiments, the disclosed pharmaceutical compositions comprise about 25% (v / v) to 35% (v / v) ethanol. In some embodiments, the disclosed pharmaceutical compositions comprise about 25% (v / v) ethanol. In some embodiments, the disclosed pharmaceutical compositions comprise about 30% (v / v) ethanol, hi some embodiments, the disclosed pharmaceutical compositions comprise about 35% (v / v) ethanol.

[0178] In some embodiments, the solvent system comprises propylene glycol. In some embodiments, the disclosed pharmaceutical compositions comprise about 20% (v / v) propylene glycol. In some embodiments, the disclosed pharmaceutical compositions comprise about 10% (v / v) to 90% (v / v) propylene glycol. In some embodiments, the disclosed pharmaceutical compositions comprise about 20% (v / v) to 80% (v / v) propylene glycol. In some embodiments, the solvent system comprises propylene glycol. In some embodiments, the disclosed pharmaceutical compositions comprise about 30% (v / v) to 70% (v / v) propylene glycol. In some embodiments, the disclosed pharmaceutical compositions comprise about 40% (v / v) to 60% (v / v) propylene glycol. In some embodiments, the disclosed pharmaceutical compositions comprise about 45% (v / v) to 55% (v / v) propylene glycol. In some embodiments, the disclosed pharmaceutical compositions comprise about 45% (v / v) propylene glycol. In some embodiments, the disclosed pharmaceutical compositions comprise about 50% (v / v) propylene glycol. In some embodiments, the disclosed pharmaceutical compositions comprise about 55% (v / v) propylene glycol.

[0179] In some embodiments, the disclosed pharmaceutical compositions include a viscosity modifier. In some embodiments, the viscosity modifier is a thickening agent. Common thickening agents include, but are not limited to, acrylates, carbomers, cellulose matrices, silicones, carrageenans, gums, resins, polysaccharides, and high-melting waxes and oils such as beeswax, coconut oil, palm oil, soybean oil, stearic acid, rapeseed, cocoa butter, shea butter, gums, rosin, resins, paraffin, and petrolatum. In some embodiments, the viscosity modifier is a carbohydrate. Representative carbohydrates include monosaccharides, disaccharides, oligosaccharides, and polysaccharides. Representative polysaccharides include cellulose, methylcellulose, hydroxypropylmethylcellulose, chitin, galactoarabinan, polygalactose, and polyarabinose. Representative glycerides include 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 mixtures thereof. In some embodiments, the viscosity modifier is a polymer. The polymer may be a natural or synthetic polymer. Natural polymers include polysaccharides, nucleic acids, and proteins. Synthetic polymers include polyesters, polyureas, polycarbonates, polyvinyl alcohols, polyamides, polyethers, polyesters, polyamines, polytyrosines, polyanhydrides, polyphosphazenes, polyacrylamides, polyacrylates, polymethacrylates, polyvinylpyrrolidones, and the like.Representative thickening agents include alginic acid derivatives, pre-neutralized Carbomer 430, hydrophilic silica, polysaccharides, xanthan gum, guar gum, agar, carboxymethyl cellulose, hydroxyethyl cellulose, polyacrylates, polyacrylamides, polyvinylpyrrolidone and salts. In some embodiments, the disclosed compositions may comprise 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 The viscosity modifier may comprise 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%.

[0180] For example, in some embodiments, the disclosed pharmaceutical compositions include hydroxypropyl cellulose as a viscosity modifier. However, as noted elsewhere herein, hydroxypropyl cellulose or other disclosed excipients may serve multiple other functions when incorporated into a composition. In some embodiments, the disclosed pharmaceutical compositions include about 1% (w / v) to about 10% (w / v) hydroxypropyl cellulose. In some embodiments, the disclosed pharmaceutical compositions include about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, or about 10% (w / v) hydroxypropyl cellulose.

[0181] In some embodiments, the disclosed pharmaceutical compositions include an adhesion modifier. In some embodiments, the disclosed pharmaceutical compositions include an adhesive polymer. The adhesive polymer has physicochemical properties that allow it to bond to the tissue surface for a long period of time. In some embodiments, the inclusion of an adhesive polymer in the composition extends the time that the active ingredient can contact and diffuse through a barrier (e.g., scalp skin). In some embodiments, the adhesive polymer is chitosan, gelatin, guar gum, lectin, sodium alginate, soluble starch, tragacanth, xanthan gum deacetylated gum, polyacrylic acid, polyvinyl alcohol, hydroxypropyl methylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, sodium carboxymethylcellulose, thiomer, polycarbophil, hyaluronic acid, dermatan sulfate, or a combination thereof. In some embodiments, the adhesion modifier 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, the disclosed compositions may comprise 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 The composition may comprise 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% adhesion modifier.

[0182] In some embodiments, the disclosed pharmaceutical compositions include a preservative. Preservatives are used to inhibit microbial growth or improve the stability of the composition, thereby extending the shelf life of the composition. Suitable preservatives are known to those skilled in the art and include EDTA, EGTA, benzalkonium chloride, or benzoic acid or benzoate salts (e.g., sodium benzoate), vitamin A, vitamin C (ascorbic acid), citric acid, vitamin E, and tocopherol.

[0183] In some embodiments, the disclosed pharmaceutical compositions include an antioxidant. Without being bound by theory, antioxidants generally can slow or inhibit oxidative degradation of components of the disclosed compositions (e.g., active ingredients, T3, T4, or other active ingredients), which may improve the stability and shelf life of the disclosed compositions. In some embodiments, the antioxidant is α-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 cyclodextrin, D-α-tocopherol, rosmarinic acid, or a combination thereof. In some embodiments, the disclosed compositions may comprise 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 It may contain 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% antioxidant.

[0184] In some embodiments, the composition may include one or more vitamins. Any vitamin with properties such as hair nourishing, preventing hair loss, and / or promoting hair growth may be used. Typically, suitable vitamins 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 effect of treating hair loss and / or promoting hair growth while being compatible with the disclosed compositions (e.g., active ingredients such as T3, T4, or other active ingredients). Such concentrations may vary depending on the vitamin selected, the desired effect, the type and concentration of other ingredients, and other similar factors. Typically, the composition may contain 1 mg to 200 mg of the vitamin, and in some embodiments, 50 mg to 250 mg of the vitamin.

[0185] In some embodiments, the disclosed pharmaceutical compositions include a solubilizer. Without being bound by theory, solubilizers generally form complexes with active ingredients, and these complexes may have different physicochemical properties than the active ingredient alone. The properties of the complex may improve the solubility of the T3, T4, or other active ingredient in the composition. In some embodiments, the solubilizer 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 solubilizer is a water solubility enhancer. In some embodiments, the water solubility enhancer is polyethylene glycol 300, polyethylene glycol 400, ethanol, propylene glycol, xanthan gum, glycerin, N-methyl-2-pyrrolidone, dimethylacetamide, dimethyl sulfoxide, or a combination thereof. In some embodiments, the solubilizer is propylene glycol. In some embodiments, the solubilizer is xanthan gum. In some embodiments, the solubilizer is a non-ionic surfactant. In some embodiments, the nonionic surfactant is Cremophor EL, Cremophor RH40, Cremophor RH60, d-tocopherol polyethylene glycol 1000 succinate, polysorbate 20, polysorbate 80, Solubiltol HS15, sorbitan monooleate, poloxamer 407, Labrafil M-1944CS, Labrafil M-2125CS, Labrafil, Gerlcia 44 / 14, Softigen 767, fatty acid monoesters and diesters of PEG 300, 400, or 1750, or combinations thereof. In some embodiments, the solubilizing agent is an organic liquid. In some embodiments, the organic liquid is beeswax, d-α-tocopherol, oleic acid, or a medium-chain monoglyceride or diglyceride. In some embodiments, the solubilizing agent is cyclodextrin. In some embodiments, the solubilizing agent is α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin, hydroxypropyl-β-cyclodextrin, and sulfobutylether-β-cyclodextrin, hi some embodiments, the solubilizing agent is α-cyclodextrin.In some embodiments, the solubilizing agent is β-cyclodextrin. In some embodiments, the solubilizing agent is γ-cyclodextrin. In some embodiments, the solubilizing agent is hydroxypropyl-β-cyclodextrin. In some embodiments, the solubilizing agent is sulfobutylether-β-cyclodextrin. In some embodiments, the solubilizing agent is a phospholipid. In some embodiments, the phospholipid is hydrogenated soybean phosphatidylcholine, distearoylphosphatidylglycerol, L-α-dimyristoylphosphatidylcholine, or L-α-dimyristoylphosphatidylglycerol. In some embodiments, the solubilizing agent is lecithin. In some embodiments, the compositions of the present disclosure may contain 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 31%, about 32%, about 33%, about 34%, about 35%, about 36%, about 37%, about 38%, about 39%, about 40%, about 41%, about 42%, about 43%, about 44%, about 45%, about 46%, about 47%, about 48%, about 49%, about 50%, about 51%, about 52%, about 53%, about 54%, about 55%, about 56%, about 57%, about 58%, about 59%, about 60%, about 61%, about 62%, about 63%, about 64%, about 65%, about 66%, about 67%, about 68%, about 69%, about 70%, about 71%, about 72%, about 73%, about 74%, about 75%, about 76%, about 77%, about 78%, about 79%, about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 8 The composition may comprise about 6%, 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% solubilizing agent.

[0186] In some embodiments, the disclosed pharmaceutical compositions include a colorant. Suitable colorants and / or dyes and / or pigments include, but are not limited to, colors such as white, black, yellow, blue, green, pink, red, orange, purple, indigo, brown, and combinations thereof, as well as pigments such as Timica Extra Large Sparkles, titanium dioxide and chromium oxide green, ultramarine blue and pink, and iron oxide. The colorants and / or dyes and / or pigments, individually or in combination, may be present in the composition in an amount ranging from about 0.01% to about 5% by weight (calculated by the total weight of the colorants and / or dyes and / or pigments in the composition divided by the total weight of the composition), either individually or in combination. The colorants, individually or in combination, may be present in the composition in an amount ranging from about 0.01% to about 5% by weight (calculated by the total weight of the colorants in the composition divided by the total weight of the composition), either individually or in combination.

[0187] In some embodiments, the disclosed pharmaceutical compositions include a binder. Suitable binders include, but are not limited to, polyvinylpyrrolidone (PVP), marine colloids, carboxyvinyl polymers, starch, hydroxyethyl cellulose, carboxymethyl cellulose (carmellose), hydroxypropyl methylcellulose, hydroxyethyl propyl cellulose, hydroxybutyl methylcellulose and salts thereof (e.g., carmellose sodium), karaya gum, xanthan gum, carrageenan, gellan gum, natural gums such as locust bean gum, gum arabic, and gum tragacanth, chitosan, colloidal magnesium aluminum silicate, and colloidal silica. The binders, individually or in combination, may be present in the composition in an amount ranging from about 0.01% to about 5% by weight (calculated by dividing the total weight of binders in the composition by the total weight of the composition), either individually or in combination.

[0188] In some embodiments, the disclosed pharmaceutical compositions include a humectant, such as low molecular weight polyethylene glycols (e.g., PEG6 to PEG12), which may be present individually or in combination in an amount of up to about 10% by weight, up to about 5% by weight, up to about 3% by weight, up to about 1% by weight, or up to about 0.1% by weight (calculated by dividing the total weight of the humectants in the composition by the total weight of the composition).

[0189] In some embodiments, the disclosed pharmaceutical compositions include a surfactant. Surfactants that can be included in the compositions can be anionic, nonionic, or amphoteric compounds. Examples of suitable anionic surfactants include higher alkyl sulfates, such as potassium or sodium lauryl sulfate; higher fatty acid monoglyceride monosulfates, such as salts of monosulfated monoglycerides of hydrogenated coconut oil fatty acids; alkyl sulfonates, such as sodium dodecylbenzenesulfonate; higher fatty sulfoacetates; and 1,2-dihydroxypropanesulfonates of higher fatty acid esters. Examples of water-soluble nonionic surfactants include condensation products of ethylene oxide with various hydrogen-containing compounds (e.g., those having an aliphatic chain of about 12 to 20 carbon atoms), which contain hydrophilic polyoxyethylene groups, such as condensation products of poly(ethylene oxide) with fatty acids, fatty alcohols, fatty amides, and other fatty groups, and with propylene oxide and polypropylene oxide (e.g., Pluronic materials, Pluronic F127, etc.). Representative alkyl polyglycoside (APG) surfactants that can be used in the composition include APG C8-C10, APG C10-C16, decyl glucoside, coco glucoside, anionic APG carboxylate, sodium lauryl glucose carboxylate, lauryl glucoside, D-glucopyranose (oligomer, C10-16 glycoside, carboxymethyl ether, sodium salt), C12-C16 fatty alcohol glycoside, and combinations thereof. Representative APG surfactants that can be used include those with industry designations such as Plantaren® 2000 N UP / MB, Plantapon® LGC Sorb, Plantaren® 1200 N UP / MB, and Plantaren® 818 UP / MB. The surfactants, individually or in total when multiple surfactants are present, may be present in the composition in an amount ranging from about 0.01% to about 10% by weight (total weight of surfactants in the composition divided by total weight of the composition).

[0190] In some embodiments, the disclosed pharmaceutical compositions include a gelling agent. Exemplary gelling agents that can be used in the disclosed compositions include pectin, starch, and forms of gelatin derived from animal or plant sources (e.g., pork gelatin, etc.). The pectin in the composition may include 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 and non-amidated pectin. The gelatin in the composition may include Type A gelatin, Type B gelatin, hide or skin-derived gelatin (e.g., calf hide, pig skin, etc.), and bone-derived gelatin (e.g., calf bone, pig bone, etc.), alone or in combination. The gelling agents, individually or in combination, may be present in the composition in an amount ranging from about 0.1% to about 20% by weight (calculated by dividing the total weight of gelling agents in the composition by the total weight of the composition). In some embodiments, the composition does not include a gelling agent.

[0191] Depending on the unit dose and total amount, the composition may be provided as a final packaged product (e.g., a bottle or 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 about 15 mL to 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.

[0192] In some embodiments, the disclosed excipients may serve multiple functions when included in the composition, for example, hydroxypropyl cellulose functions to adjust the viscosity of the composition, while also affecting the adhesive properties of the composition, stabilizing active ingredients in the composition, promoting emulsification, or other functions described herein.

[0193] Those skilled in the art will appreciate that the selection of an appropriate excipient for use in the disclosed compositions may depend on a variety of factors, including, for example, compatibility of the excipient with the active ingredient (e.g., T3, T4, additional active ingredient, etc.), permeation rate of the active ingredient, manufacturing parameters, biocompatibility, and user preference. E. Exemplary Features of the Disclosed Compositions and Methods

[0194] In some embodiments, the disclosed compositions and methods exhibit fewer side effects (e.g., adverse reactions) than comparable methods or compositions, such as standard treatments for certain hair loss conditions (e.g., male pattern baldness). Without being bound by theory, it is hypothesized that thyroid hormones (e.g., T3, T4) are likely to be absorbed primarily by the epidermis and dermis before entering the bloodstream. This likely localizes potential side effects, which can be further mitigated by pulsed administration of the treatment, as described in the embodiments herein.

[0195] In some embodiments, hair loss is caused by alopecia.In some embodiments, hair loss is caused by androgenetic alopecia, alopecia areata, persistent patchy alopecia areata, alopecia totalis, alopecia universalis, diffuse alopecia areata, alopecia serpiginosa, cicatricial alopecia, lichen planus folliculitis, frontal fibrosing alopecia, central centrifugal cicatricial alopecia (CCCA), traction alopecia, beard alopecia or postpartum alopecia.In some embodiments, hair loss is caused by androgenetic alopecia.In some embodiments, hair loss is androgenetic alopecia.In some embodiments, hair loss is female-pattern alopecia.

[0196] In some embodiments, the disclosed compositions or methods are particularly suitable for administration to subjects with certain characteristics (e.g., biomarkers) that indicate a higher likelihood of successful treatment or a lower risk of treatment. For example, in some embodiments, only subjects with thyroid hormone levels (e.g., T3, T4 levels) or other biomarkers below a threshold are candidates for administration of the disclosed methods or compositions. In some embodiments, subjects undergo blood testing prior to treatment with the disclosed methods or compositions.

[0197] The present disclosure further provides kits for practicing the disclosed methods, which kits include one or more thyroid hormones (e.g., T3, T4, or a combination thereof) described herein, or pharmaceutical compositions comprising one or more thyroid hormones (e.g., T3, T4, or a combination thereof).

[0198] In some embodiments, administration of the disclosed compositions increases hair shaft production. Hair shaft production refers to the amount of hair produced by a hair follicle. In some embodiments, the compositions increase hair shaft production by 1%, 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100%.

[0199] In some embodiments, administration of the disclosed compositions increases the growth period of anagen hair. Anagen is the first of three hair growth phases, during which hair is actively produced by the hair follicle. In some embodiments, the compositions increase the anagen phase by 1%, 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100%.

[0200] In some embodiments, administration of the disclosed compositions increases expression of FGF7. FGF7 is a growth factor that promotes hair growth by regulating the initiation and elongation of anagen hair. In some embodiments, the compositions increase FGF7 expression by 1%, 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100%.

[0201] In some embodiments, administration of the disclosed compositions increases proliferation of bulge epithelial stem cells. Bulge epithelial stem cells reside in the bulge region of hair follicles and have high proliferation potential and the multipotency to regenerate keratinocytes, sebaceous glands, and epidermal tissue. In some embodiments, the compositions increase proliferation of bulge stem cells by 1%, 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100%.

[0202] In some embodiments, administration of the disclosed compositions increases expression of keratin 15. Keratin 15 is a widely used biomarker for bulge epithelial stem cells. Increased keratin 15 indicates increased abundance of bulge epithelial stem cells. In some embodiments, the compositions increase keratin 15 expression by 1%, 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100%.

[0203] In some embodiments, administration of the disclosed compositions reduces expression of p-S6. p-S6 is a direct downstream kinase of the target of rapamycin complex 1 (mTORC1) and is associated with both aging and increased hair graying. Decreased p-S6 expression indicates downregulation of this pathway. In some embodiments, the compositions reduce p-S6 expression by 1%, 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100%.

[0204] In some embodiments, administration of the disclosed compositions reduces the rate of hair graying, i.e., bleaching, in a subject. Hair graying / bleaching may be caused by dysfunction of differentiated melanocytes in the hair follicle pigmentary unit. Hair graying / bleaching is generally temporarily reversible, and pigment production can resume even in hair follicles that previously stopped producing pigment. Hair graying / bleaching may become irreversible if hair follicle melanocyte stem cells are depleted. Without being bound by theory, the disclosed topical compositions downregulate mTORC1, a protein complex that negatively regulates human hair follicle growth and pigmentation (Suzuki T et al. EMBO Rep. 2023;24(7):e56574). Without being bound by theory, downregulation of mTORC1 by the topical compositions promotes hair growth and pigmentation.

[0205] In some embodiments, the disclosed compositions reduce bleaching by 1%, 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100%. In some embodiments, the compositions increase re-pigmentation by 1%, 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100%.

[0206] In some embodiments, the disclosed compositions prevent the onset of pigmentation in hair follicles. In some embodiments, the compositions prevent the onset of pigmentation in 1%, 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100% of hair follicles in a subject. In some embodiments, the compositions increase the amount of pigment-producing hair follicles by 1%, 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100%. F. Working Example

[0207] The following examples are for illustrative purposes only and are not intended to limit the scope of the present invention. [Example]

[0208] [Human skin organ culture test] Objective: The study described herein examined the effects of the disclosed topical compositions on human scalp skin in organ culture. Previous studies (e.g., Paus et al., J. Clin. Endocrinol. Metab. 2008;93(11):4381-4388) examined the application of thyroid hormones dissolved in the culture medium itself to hair follicles isolated from the scalp. In this study, T4 promoted hair matrix keratinocyte proliferation and extended the anagen phase of the hair follicle cycle, while T3 inhibited apoptosis of hair matrix keratinocytes.

[0209] The study was conducted by applying the disclosed topical composition to scalp skin.

[0210] method:

[0211] Skin biopsies: 4 mm skin biopsies containing terminal hair follicles were prepared and placed at the air-liquid interface in serum-free, supplemented William's E medium (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% CO2. After 24 h of incubation for equilibration, the skin biopsies were topically treated with 2 μL of a viscous formulation containing ethanol, hydroxypropyl cellulose, propylene glycol, and purified water. This formulation facilitates penetration of the test substance and, due to its high viscosity, prevents leakage of the test compound from the skin surface into the medium. The medium contained either control alone, T3 (1 nM or 10 nM), T4 (1 μM or 10 μM), or a combination (T3 10 nM + T4 10 μM).

[0212] The skin surface was wiped before each topical treatment, and the culture medium was changed on days 1, 3, and 5. Two biopsies per experimental group were placed in a cryomatrix and flash-frozen in liquid nitrogen on day 6 and then stored for further analysis.

[0213] The snap-frozen samples were sectioned using a cryostat (Leica) to obtain 7 μm sections. Serial sections were taken for each full-length hair follicle, and the slides were stored at −80°C until further analysis.

[0214] Immunochemistry: To assess proliferation and apoptosis of keratinocytes in the hair matrix, cryosections were fixed in 4% paraformaldehyde / PBS, preincubated in 10% goat serum, and then incubated overnight at 4°C with mouse anti-Ki-67 antibody (1:800; Cell Signaling Technology) and rabbit anti-human cleaved-caspase-3 antibody (1:400; Cell Signaling Technology). After three washes with PBS, they were incubated for 45 minutes at 37°C with the corresponding secondary antibodies, goat anti-rabbit IgG-Alexa Fluor 488 and goat anti-mouse IgG-Alexa Fluor 555 (1:400; Life Technologies).

[0215] To assess IGF-1:IGF-1 protein expression, tissue cryosections were fixed in acetone and incubated overnight at 4°C with rabbit anti-human IGF-1 antibody (1:250; Novus Biologicals). Secondary antibody incubation was performed at room temperature for 45 minutes, followed by goat anti-rabbit IgG-Alexa Fluor 555 antibody (1:400; Life Technologies) for 45 minutes at 37°C.

[0216] To assess TGFβ-2 protein expression, tissue cryosections were fixed in acetone and incubated with rabbit anti-human TGF-β2 antibody (1:400; Proteintech) overnight at 4°C. Secondary antibody incubation was performed at room temperature for 45 minutes, followed by goat anti-rabbit IgG-Alexa Fluor 488 antibody (1:400; Life Technologies) for 45 minutes at 37°C.

[0217] To assess K15:K15 protein expression, tissue cryosections were fixed in 4% paraformaldehyde / PBS, preincubated with 10% goat serum, and then incubated with mouse anti-human CK15-FITC conjugated antibody (1:200; Novus biological) for 2 h at 37°C.

[0218] To assess K85:K85 protein expression, tissue cryosections were fixed in acetone and incubated with guinea pig anti-human CK85 antibody (1:1000; Progen) overnight at 4°C. Secondary antibody incubation was performed at room temperature for 45 minutes, followed by goat anti-guinea pig Alexa Fluor 594 antibody (1:400; Life Technologies) for 45 minutes at 37°C.

[0219] gp100 / MITF: To assess gp100 / MITF protein expression, tissue cryosections were fixed in methanol:acetone (1:1), permeabilized, and blocked with 10% goat serum + 0.3% Triton X-100 / TBS. Then, they were incubated overnight at 4°C with mouse anti-MITF antibody (1:50; Abcam) and rabbit anti-human NKI-beteb (gp100) antibody (1:100; Abcam). After three washes with TBS, they were incubated for 45 minutes at 37°C with the corresponding secondary antibodies: goat anti-mouse IgG-FITC (1:400; Jackson Immunoresearch) and goat anti-rabbit IgG-Alexa Fluor 555 (1:400; Life Technologies). An amplification step was then performed for 30 minutes at 37°C with anti-FITC Alexa Fluor 488 antibody (1:400; Life Technologies).

[0220] To assess MTCOI protein expression, tissue cryosections were fixed in 4% paraformaldehyde, permeabilized and blocked with 10% goat serum + 0.3% Triton X-100 in PBS, and then incubated overnight at 4°C with rabbit anti-human MTCO1 antibody (1:50; Abcam). After three washes with PBS, the sections were incubated for 45 minutes at 37°C with goat anti-rabbit IgG-FITC antibody (1:400; Jackson Immunoresearch). An additional amplification step was performed for 30 minutes at 37°C with anti-FITC Alexa Fluor 488 antibody (1:400; Life Technologies).

[0221] To assess FGF7 protein expression, tissue cryosections were fixed in acetone and incubated overnight at 4°C with rabbit anti-KGF / FGF7 antibody (1:100; Novus Biologicals). Secondary antibody incubation was performed at room temperature for 45 minutes with goat anti-rabbit IgG-Alexa Fluor 488 antibody (1:400; Life Technologies).

[0222] To assess p-S6 protein expression, tissue cryosections were fixed in 4% paraformaldehyde and incubated overnight at 4°C with rabbit anti-Phospho-S6 Ribosomal Protein antibody (1:200; Cell Signaling Technology). Secondary antibody incubation was performed at room temperature for 45 minutes with goat anti-rabbit IgG-Alexa Fluor 488 antibody (1:400; Life Technologies).

[0223] To assess CD31 protein expression, tissue cryosections were fixed with acetone and incubated with mouse anti-human CD31 antibody (1:50; Agilent) overnight at 4°C. Secondary antibody incubation was performed with goat anti-mouse IgG-Alexa Fluor 555 (1:400; Life Technologies) for 45 min at room temperature.

[0224] Negative controls for primary antibodies were performed by omitting the primary antibody. Counterstaining for nuclear visualization and embedding was performed with 4′,6-diamidino-2-phenylindole (DAPI) / Fluoromount (EMS).

[0225] Quantitative (immunohistomorphometry) and image analysis: Images of the evaluation area were captured at 100x or 200x magnification using a Keyence-Biozero 9100 microscope (Keyence Corporation, Japan) and accompanying software (Biozero-II Analyzer; Keyence Corporation, Japan). Regions of interest included the dermis (CD31 count and expression), hair follicle bulge (K15 expression), hair bulb (Ki-67 / Casp-3, Warthin-Starry, FGF7, p-S6, MTCOI, K85, gp100 / MITF), and proximal outer root sheath (IGF-1, TGFβ-2). Melanin content, K15, FGF7, p-S6, MTCOI, K85, gp100 / MITF, IGF-1, and TGFβ-2 were quantified by measuring relative staining intensity in defined reference areas using ImageJ. The percentage of proliferative and apoptotic HM keratinocytes (Ki-67+ or Casp-3+ cells / DAPI+ cells) was quantified in hair bulbs.

[0226] For hair cycle staging, HFs were microscopically evaluated using Warthin-Starry histochemistry and Ki-67 / caspase-3 immunostaining (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 performed by calculating the percentage of HFs in each hair cycle phase (anagen VI, early, mid, and late catagen). Statistical analysis: All data were expressed as mean ± standard error or fold change of mean ± standard error relative to control. Gaussian distribution of data was analyzed using D'Agostino and Pearson omnibus normality tests. Significant differences were determined using an unpaired Student's t-test for parametric data and a Mann-Whitney test for nonparametric data. Results for each test group were compared using GraphPad Prism 9 (GraphPad Software). p < 0.05 was considered statistically significant. Control Formulations and Experimental Design: The two control formulations selected for topical application of the T3 and T4 peptide hormone compositions were designed based on their potential to enhance thyroid hormone penetration and transfollicular absorption and contain only FDA-approved and cosmetically approved ingredients for topical use.

[0227] Turbidity tests were performed to confirm adequate dissolution and mixing of all components, and the results showed that both T3 (10 nM) and T4 (10 μM) were completely dissolved, even at the highest concentrations. [Table 1]

[0228] The concentrations of T3 and T4 in formulation A were varied as follows: [Table 2]

[0229] The experiments in this example were carried out according to the following timeline: [Table 3]

[0230] Human scalp skin was provided by five donors.

[0231] Donor 1: scalp skin, male, African American (T3 and T4 alone)

[0232] Donor 2: scalp skin, male, African American (T3 and T4 alone)

[0233] Donor 3: scalp skin, female, Hispanic (T3 and T4 combined application)

[0234] Donor 4: Scalp skin, female, Jamaican (T3 and T4 combined application)

[0235] Donor 5: scalp skin, male, Mediterranean (T3 and T4 applied alone and in combination)

[0236] Skin punches were taken from the temporal scalp skin on day 0. Punch biopsies were incubated at the air / liquid interface under 5% CO2. 2 μL of treatment (control, T3, or T4) was applied on days 1, 3, and 5 after removal of the previous application. On day 6, skin biopsies were embedded in cryomatrix, flash-frozen in liquid nitrogen, and processed for quantitative (immunohistomorphometric) analysis.

[0237] result:

[0238] Hair Shaft Production: As shown in Figure 1A, topical T3 (1 nM and 10 nM) and T4 (1 μM) in Formulation A significantly promoted hair shaft production. As shown in Figure 1B, topical T4 (10 μM) and the T3 + T4 combination in Formulation B promoted hair growth, while T3 (10 nM) in Formulation B reduced it. Results are shown as the percentage of hair follicle production from day 1 to day 6 of treatment. Figures 2A and 2B are photographs of representative skin punches from the Formulation A and Formulation B studies, respectively. T3 and T4 measurements in Formulation A were obtained from one donor because two donor samples were damaged and unanalyzable.

[0239] Anagen Duration: The results in Figures 3A, 4A, and 5 indicate that T3 (1 nM and 10 nM) and 10 μM T4 in Formulation A prolonged the anagen hair follicle cycle and therefore likely promoted hair growth in an ex vivo microdissection model of human scalp hair follicles after the addition of thyroid hormone to the culture medium. The extent of anagen and catagen is indicated by Ki-67 and Casp-3 immunofluorescence signals in Figure 5. Ki-67 is a biomarker of hair matrix keratinocyte proliferation, and Casp-3 is a biomarker of apoptosis. In Formulation A, the greatest increase in the percentage of hair follicles with a prolonged anagen cycle was observed after application of T4 (10 μM). The combination of T3 and T4 in Formulation A reduced the percentage of anagen hair follicles. As shown in Figures 3B and 4B, in Formulation B, T3 (10 nM) and T4 (10 μM) prolonged the anagen duration, while the combination of T3 and T4 had no effect on the hair growth phase. The results are shown as mean values ​​(%) ± standard error.

[0240] The weakest biological activity of hair follicles occurs during the resting (telogen) phase (Lin et al. Front Cell Dev Biol. 2022;10:899095). These results suggest that topical thyroid hormone administration likely suppresses AGA-associated hair shaft shedding (telogen effluvium). This is novel evidence that topical thyroid hormone treatment extends the anagen cycle in human scalp skin.

[0241] Therefore, both topical thyroid hormones likely 1.) inhibit telogen effluvium in patients with AGA and 2.) prolong the period during which miniaturized vellus hairs can revert to terminal hair follicles (anagen-only). In formulation A, the combination of 1 nM T3 and 10 μM T4 had the opposite effect to the effects of either treatment, suggesting that this combination may induce early catagen.

[0242] Hair matrix keratinocyte proliferation:As shown in Figures 6A and 6B, topical T4 (10 μM) and the T3 + T4 combination reduced hair matrix keratinocyte proliferation in human scalp skin in both Formulation A and Formulation B. The results in Figure 6A confirm the anagen inhibition observed in Figure 4A with the T3 + T4 combination. Both concentrations of T3 and 1 μM T4 had no significant effect on hair matrix keratinocyte proliferation. Results are presented as the percentage of Ki-67+ cells in the hair matrix.

[0243] The results for Formulation A are also shown in Figure 7, where Ki-67+, Casp-3, and DAPI cells were detected. Similar results were observed with Formulation B. Caspase 3+ cells were not detected in either group, which is an expected finding in anagen hair follicles in healthy scalp skin.

[0244] Melanin production: The results shown in Figures 8A and 8B indicate that in both Formulation A and Formulation B, thyroid hormone did not further stimulate melanin production when only well-pigmented anagen hair follicles were evaluated. In Formulation A, T3 (10 nM) and the T3-T4 combination slightly increased the melanin content of the evaluated hair follicles, but this was not significant. This suggests that topical thyroid hormone does not significantly affect melanogenesis in healthy scalp skin. Figure 9 for the Formulation A study shows that no pigmentary abnormalities (melanin aggregates or ectopic melanin granules) indicative of hair follicle damage were observed, suggesting that topical thyroid hormone is well tolerated by hair follicles.

[0245] Hair follicle pigmentary unit (gp100 and MITF expression):Quantitative Masson-Fontana histochemistry was used to assess pigmentation in microdissected and tissue-cultured anagen VI human scalp hair follicles in serum-free medium supplemented with T3, T4, or a combination of T3 and T4. The biomarker gp100 indicates premelanosomes produced by melanocytes. It is a sensitive indicator of melanosome transfer between melanocytes and keratinocytes and a sign of follicular pigmentary unit activity. MITF expression was elevated in 1 nM T3 and the combination treatment. MITF is a key transcription factor in melanocyte development and differentiation, regulating the expression of numerous pigment genes and promoting melanocyte differentiation. Although pigment production itself was not stimulated, enhanced gp100 immunoreactivity and the extension of gp100+ melanocyte dendrites suggested activation of the follicular pigmentary unit. For details on gp100 expression and melanosomes / melanin granules, see, for example, Singh et al. Exp. Dermatol. 2008;17(5):418-426. These results suggest a partial "rejuvenating" effect of topical T3 and T4 on hair follicles. This partial "rejuvenating" effect may be advantageous in AGA models, where AGA-affected hair follicles express some molecular markers of premature aging.

[0246] The results in Figures 10A and 11A show that topical T3 (1 nM and 10 nM) and the T3+T4 combination significantly activated hair follicle pigmented units, as measured by gp100 and MITF immunoreactivity, in Formulation A. The results in Figures 10B and 11B show that the T3+T4 combination significantly reduced hair follicle pigmented unit activity, while T3 and T4 alone tended to increase activity, in Formulation B. Figure 12 shows that application of the T3 composition in Formulation A increased gp100 and MITF immunoreactivity in hair follicle pigmented units.

[0247] MTCO1 Expression:MTCO1 is a component of cytochrome c oxidase, the final enzyme in the mitochondrial electron transport chain that drives oxidative phosphorylation. Therefore, MTCO1 is a useful screening parameter for examining mitochondrial activity and its excess.

[0248] The results shown in Figures 13A and 14A indicate that thyroid hormones in Formulation A do not overstimulate mitochondrial activity, increasing reactive oxygen species and causing oxidative damage. Conversely, T4 (10 μM) and the T3 + T4 combination in Formulation A reduced MTCO1 expression, suggesting that chronic T4 administration may result in a counterregulated decrease in mitochondrial activity. This indicates that topical thyroid hormones pose a low risk of causing oxidative damage. The results shown in Figure 13B indicate that T3 (1 nM and 10 nM) and the T3 + T4 combination in Formulation B significantly reduced MTCO1 expression in hair follicle epithelium, and Figure 14B shows that the T4 (10 μM) formulation exhibits a similar effect in ORS. Similar to Formulation A, the formulation in Formulation B also showed no signs of thyroid hormones overstimulating mitochondrial activity.

[0249] Hair follicle epithelial stem cell proliferation: Figure 15A shows that T3 (10 nM) and T4 (1 μM) in Formulation A increase K15 expression in the bulge. Figure 15B shows that T4 in Formulation B increases K15 expression in the bulge, but not significantly. Because increased K15 expression tends to be associated with improved epithelial stem cell function, these results suggest that topical thyroid hormone activates hair follicle epithelial stem cells. Therefore, activation of hair follicle epithelial stem cells may suppress hair follicle miniaturization and promote its reversal. Figure 16A shows that thyroid hormone in Formulation A did not affect K15+ cell proliferation, while Figure 16B shows that T4 in Formulation B significantly increases K15+ cell proliferation. While K15+ cell proliferation is desirable in the sense that it may antagonize hair follicle miniaturization in AGA, it is unclear whether K15+ cells are involved in the K6 / K16 proliferation. +This may be undesirable as it may differentiate into outer root sheath keratinocytes and deplete the bulge stem cell niche in the long term (Tiede et al. Eur. J. Cell Biol. 2007;86(7):355-376).

[0250] Furthermore, in formulation A, T3 (10 nM) and T4 (1 μM) tended to stimulate hair follicle stem cell proliferation, reported as the percentage of cells expressing both K15 and Ki67 in Figures 17A and 18A. However, application of T3 (10 nM), T4 (10 μM), and the combination of T3 and T4 may also promote stem cell apoptosis. As shown in Figure 17B, T3 in formulation B tended to stimulate hair follicle epithelial stem cell proliferation. Surprisingly, the T3 (1 nM) composition in formulation B also promoted apoptosis, as shown in Figure 18B. The increased proliferation and apoptosis of K15+ cells in the bulge may indicate a homeostatic mechanism. For example, excess stem cells induced by T3 proliferation may be removed by apoptosis through the sculpting of the stem cell niche. Figure 19 shows the increase in Ki67 immunofluorescence following T3 (10 nM) treatment in formulation A compared to the control.

[0251] IGF-1 Expression: Figure 20A shows that T4 (1 μM) and the T3+T4 combination in Formulation A tended to increase IGF-1 protein expression in ORS keratinocytes. Although there was no significant difference compared to the control, this trend suggests that upregulation of IGF-1 may be the mechanism underlying the anagen extension effect. Figure 20B shows that the T3+T4 combination in Formulation B significantly increased IGF-1 expression in ORS keratinocytes.

[0252] TGFβ-2 Expression:Figure 21A shows that in Formulation A, neither T3, T4, nor the combination of T3 and T4 affected TGFβ-2 protein expression in ORS keratinocytes. This is a promising result, as TGFβ-2 promotes catagen initiation and limits hair production. Figure 21B shows that in Formulation B, the T4 (1 μM) composition significantly increased TGFβ-2 protein expression in ORS keratinocytes. Stimulation of TGFβ-2 production, a physiological catagen-promoting growth factor, is undesirable in managing hair loss. Figure 22 shows that there was no difference in TGFβ-2 immunofluorescence between control and T3 treatment in Formulation A.

[0253] FGF7 expression: Figure 23A shows that T3 (1 nM) and T4 (1 μM) alone and the combination of T3 and T4 significantly increased FGF7 protein expression in ORS keratinocytes in Formulation A. Figure 23B shows that T3 (1 nM and 10 nM) and T4 (1 μM and 10 μM) in Formulation B tended to increase FGF7 protein expression in ORS keratinocytes, but not significantly. FGF7 is an important hair growth-promoting factor, and its inhibition suppresses hair growth. Figure 24 shows a significant increase in FGF7 immunofluorescence with T3 (1 nM) treatment in Formulation A, and a trend increase with T3 (10 nM) compared to control alone.

[0254] p-S6 expression:Figure 25A shows that in Formulation A, the combination of T3 and T4 significantly increased p-S6 in hair matrix keratinocytes. Figure 25B shows that in Formulation B, T3 (10 nM) significantly decreased p-S6 in hair matrix keratinocytes, while T4 (10 μM) and the combination of T3 and T4 may increase it. pS6 is a direct downstream kinase of mTORC1, and therefore, increased p-S6 indicates increased mTORC1 activity. mTORC1 activity is involved in both aging and hair graying. In Formulation A, T3 and T4 did not increase p-S6, indicating that they do not stimulate this graying mechanism. In Formulation B, T3 (10 nM) downregulated mTORC1, potentially delaying hair graying, a desirable property for hair loss management.

[0255] K85 expression: Figure 26A shows that T4 (10 μM) and the T3+T4 combination significantly down-regulate keratin 85 (K85) protein expression in pre-hair matrix cells in Formulation A. Figure 26B shows that the T3+T4 combination significantly reduces K85 expression in pre-hair matrix cells in Formulation B, while T3 (1 nM) and T4 (1 μM) may increase it. K85 is a sensitive marker of hair shaft keratin production, and its down-regulation indicates decreased keratin production. T3 formulations do not significantly reduce K85; rather, T3 (10 nM) tends to increase its production. Figure 27 shows the K85 immunofluorescence signal of pre-hair matrix cells treated with T3 in Formulation A compared to control alone.

[0256] CD31+ expression: Figure 28A shows that T3 (1 nM) and T4 (10 μM) alone in formulation A inhibited CD31 expression in the dermis. +Figure 28B shows that T3 (1 nM) and T4 (10 μM) significantly increase the number of CD31+ endothelial cells in the dermis in Formulation B. The increase in CD31+ cell numbers in the dermis suggests that thyroid hormone may stimulate angiogenesis and increase hair follicle perfusion. If angiogenesis occurs, T3 / T4 may also promote VEGF-A secretion by hair follicles, promoting hair follicle and / or skin recovery. Figure 29 shows the CD31 immunofluorescence signal of both T3 treatments in Formulation A compared to the control alone.

[0257] Consideration: These results demonstrate that both topical thyroid hormones (T3 and T4) prolong anagen with both control formulations (Formulation A and Formulation B). Administration of the disclosed topical compositions likely inhibits telogen effluvium in patients with AGA and prolongs the period during which miniaturized vellus hairs can reconvert into terminal hair follicles. This anagen-prolonging effect is likely mediated primarily through stimulation of FGF-7 and / or IGF-1 expression.

[0258] The significant downregulation of MTCO1 expression in both HM and ORS keratinocytes may indicate reduced mitochondrial activity. This reduction in MTCO1 expression may be beneficial in cases of androgenetic alopecia (AGA), as MTCO1 has been reported to be upregulated in DP fibroblasts in balding scalp (Chew et al. Exp Dermatol. 2022;31(6):906-917). The disclosed topical composition is well tolerated by hair follicles (no pigmentation abnormalities) and does not overstimulate hair follicle mitochondria (low risk of oxidative damage).

[0259] Several biomarkers were altered in the anagen hair bulb. This suggests that topical application of the composition had a significant effect on the hair bulb, indicating sufficient penetration of T3 and T4. The topical composition stimulated the follicular pigmentary unit but not melanin production within the evaluation period. Future studies may include examining whether this indicates partial rejuvenation of the hair follicle by the composition. This pigment-promoting effect and reduced p-S6 expression may indicate an anti-graying effect with long-term administration. Furthermore, reduced mTORC1 activity may have an anti-aging effect and extend the anagen phase (Suzuki et al. EMBO Reports. 2023;24:e56574).

[0260] This example further demonstrates that the disclosed topical composition can activate bulge epithelial stem cells, which can inhibit hair follicle miniaturization and promote its reversal. Indeed, treatment initially induced K15+ cell proliferation and then stimulated apoptosis over time (observed with the T3 / T4 combination in Formulation A and the 1 nM T3 composition in Formulation B). However, the total number of K15+ cells did not decrease. This effect may indicate a physiological mechanism by which human scalp hair follicles stabilize bulge size and limit tumor formation through apoptosis induction. The topical composition also stimulated CD31+ cells, which may reflect increased angiogenesis. This may not only increase hair follicle size but also have anti-aging effects (Keren A et al. Sci Adv. 2022;8(25):eabm6756).

[0261] Furthermore, topical compositions containing T3 (1 nM) in formulation A show promise, and future studies may include follow-up studies evaluating the effects on hair loss and graying using scalp skin containing at least 20-25% white or gray hair follicles. Additionally, follow-up analyses may be conducted to expand the range of aging biomarkers, hair shaft keratin, mitochondrial markers (PGC1α, TFAM, porin), hair follicle pigmentation, in situ tyrosinase activity, and additional stem cell markers, such as α-MSH, CD34, CD200, and K6. [Table 4] [Example]

[0262] Clinical Trial Design for Evaluating the Efficacy of the Disclosed Topical Compositions the purpose: The objective of the present invention is to determine the effectiveness of the disclosed topical compositions and methods in treating or preventing hair loss.

[0263] Eligibility criteria: A medical history and physical examination will be conducted for all subjects. A treatment group will be established, including individuals experiencing hair loss (e.g., as a result of male pattern baldness or other similar disorders). Hair loss and its various underlying causes will be diagnosed for each individual according to diagnostic techniques known to those skilled in the art. The treatment group will be administered the disclosed topical composition described herein. A control group will also be established. The control group will be administered a topical composition without an active ingredient (e.g., a control formulation). Subjects will be 18 years of age or older. Subjects may withdraw from the study at any time for any reason. Subjects who do not wish to participate in the study or who have a medical condition that contraindicates treatment with the disclosed method or combination will also be excluded from the study.

[0264] Study design overview:The treatment group receives a topical composition containing (i) 10 nM triiodothyronine (T3), (ii) 5% (w / v) hydroxypropyl cellulose, (iii) 60% (v / v) ethanol, (iv) 20% (v / v) propylene glycol, and (v) 10% (v / v) water. The topical composition is administered every other day for two consecutive weeks, followed by one week off. The control group receives a control formulation containing (i) 5% (w / v) hydroxypropyl cellulose, (ii) 60% (v / v) ethanol, (iii) 20% (v / v) propylene glycol, and (iv) 10% (v / v) water. The control formulation is 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 is assessed according to techniques known to those skilled in the art (e.g., measuring hair shaft production). Subjects will also undergo laboratory testing for biomarkers of hair growth, including melanin production and expression of IGF-1, FGF7, TGFβ-2, MITF, p-S6, K85, CD31, gp100, MTCO1, and K15 proteins, which can be measured according to techniques described herein and known in the art.

[0265] result: Subjects in the treatment group are expected to demonstrate increased hair growth (e.g., increased hair shaft production) and / or decreased hair loss rate compared to the control group. Subjects in the treatment group are also expected to demonstrate improvement in one or more biomarkers indicative of successful treatment (e.g., increased anagen hair growth period, increased FGF7 expression, increased proliferation of bulge epithelial stem cells, increased keratin 15 expression, or decreased p-S6 expression). Topically administered T3 (10 nM, Formulation B) induced an increase in anagen hair growth period, increased expression of IGF-1 and FGF-7, and significant decreases in p-S6 and MTCO1 expression (see Example 1). In this clinical trial, scalp skin biopsies will be performed before and at the end of treatment to systematically compare short-term preclinical data obtained here with long-term topical application data (in vivo). Specifically, the long-term response of K15+ eHFSCs, hair shaft quality, anti-aging effects, and mitochondrial effects will be compared. [Example]

[0266] Separate Administration of the Disclosed Topical Compositions for Treating Hair Loss Described herein are representative treatment protocols for individuals in need of treatment or prevention of hair loss.

[0267] Patient 1: Patient 1 has been diagnosed with androgenetic alopecia and is suffering from hair loss. Patient 1 self-administers a topical composition containing (i) 10 nM triiodothyronine (T3), (ii) 5% (w / v) hydroxypropyl cellulose, (iii) 60% (v / v) ethanol, (iv) 20% (v / v) propylene glycol, and (v) 10% (v / v) water. The topical composition is administered every other day for two consecutive weeks, followed by one week off. After one treatment cycle, Patient 1 experiences increased hair growth (e.g., increased hair shaft production). Patient 1 also shows improvement in one or more biomarkers indicative of successful treatment (e.g., increased anagen hair growth period, increased FGF7 expression, increased proliferation of bulge epithelial stem cells, increased keratin 15 expression, or decreased p-S6 expression).

[0268] Patient 2: Patient 2 has been diagnosed with alopecia areata and is experiencing hair loss. Patient 2 self-administers a topical composition containing (i) 10 nM triiodothyronine (T3), (ii) 5% (w / v) hydroxypropyl cellulose, (iii) 60% (v / v) ethanol, (iv) 20% (v / v) propylene glycol, and (v) 10% (v / v) water. The topical composition is administered every other day for two consecutive weeks, followed by one week off. After four treatment cycles, Patient 2 experiences a decrease in the rate of hair loss. Patient 2 also shows improvement in one or more biomarkers indicative of successful treatment (e.g., an increase in the duration of anagen hair growth, increased expression of FGF7, increased proliferation of bulge epithelial stem cells, increased expression of keratin 15, or decreased expression of p-S6).

[0269] Patient 3:Patient 3 has been diagnosed with alopecia totalis and is suffering from hair loss across his entire scalp. Patient 3 self-administers a topical composition containing (i) 10 nM triiodothyronine (T3), (ii) 5% (w / v) hydroxypropyl cellulose, (iii) 60% (v / v) ethanol, (iv) 20% (v / v) propylene glycol, and (v) 10% (v / v) water. The topical composition is administered daily for three consecutive days, followed by one week off treatment. After two treatment cycles, Patient 3 experiences increased hair growth (e.g., increased hair shaft production). Patient 3 also shows improvement in one or more biomarkers indicative of successful treatment (e.g., increased anagen hair growth period, increased FGF7 expression, increased proliferation of bulge epithelial stem cells, increased keratin 15 expression, or decreased p-S6 expression).

[0270] Patient 4: Patient 4 has been diagnosed with persistent patchy alopecia areata and is experiencing hair loss. Patient 4 self-administers a topical composition containing (i) 10 nM triiodothyronine (T3), (ii) 5% (w / v) hydroxypropyl cellulose, (iii) 30% (v / v) ethanol, (iv) 50% (v / v) propylene glycol, and (v) 10% (v / v) water. The topical composition is administered every other day for two consecutive weeks, followed by one week off. After three treatment cycles, Patient 4 experiences a decrease in the rate of hair loss. Patient 4 also shows improvement in one or more biomarkers indicative of successful treatment (e.g., an increase in the duration of anagen hair growth, increased expression of FGF7, increased proliferation of bulge epithelial stem cells, increased expression of keratin 15, or decreased expression of p-S6). [Example]

[0271] Separate Administration of the Disclosed Topical Compositions for Treating Gray Hair Described herein are representative treatment protocols for individuals in need of treatment or prevention of gray hair.

[0272] Patient 5:Patient 5 is experiencing graying of hair. Patient 5 self-administers a topical composition containing (i) 1 nM triiodothyronine (T3), (ii) 5% (w / v) hydroxypropyl cellulose, (iii) 30% (v / v) ethanol, (iv) 50% (v / v) propylene glycol, and (v) 10% (v / v) water. The topical composition is administered every other day for two consecutive weeks, followed by one week off treatment cycles. After one treatment cycle, Patient 5 experiences gradual recoloring of hair.

[0273] Patient 6: Patient 6 is experiencing hair graying. Patient 6 self-administers a topical composition containing (i) 1 nM triiodothyronine (T3), (ii) 5% (w / v) hydroxypropyl cellulose, (iii) 30% (v / v) ethanol, (iv) 50% (v / v) propylene glycol, and (v) 10% (v / v) water. The topical composition is administered every other day for two consecutive weeks, followed by one week off treatment cycles. After one treatment cycle, Patient 6 experiences a decrease in the rate of hair graying (e.g., decreased hair bleaching).

[0274] The foregoing description uses specific language to provide a thorough understanding of the invention. However, it will be apparent to those skilled in the art that specific details are not required to practice the invention. Accordingly, the foregoing description of specific embodiments of the invention has been presented for purposes of illustration and description. It is not intended to limit the invention to the precise compositions, formulations, methods, etc. disclosed, or to be exhaustive. Many modifications and variations are possible in light of the above guidance. The embodiments have been chosen and described to best explain the principles of the invention and its practical application through specific examples, and to enable those skilled in the art to optimally utilize the invention and its various embodiments, with various modifications suited to particular uses. The scope of the present invention, therefore, is to be defined only by the following claims and equivalents thereof.

Claims

1. 1. A topical composition useful for treating or preventing hair loss, comprising: i. Triiodothyronine (T3); ii. a pharmaceutically acceptable excipient; and iii. Solvent system A topical composition comprising:

2. 10. The topical composition of claim 1, comprising about 1 nM to 30 nM T3.

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

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

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

6. 10. The topical composition of claim 1, wherein the pharmaceutically acceptable excipient is hydroxypropyl cellulose.

7. 7. The topical composition of claim 6, comprising about 1% to 10% (w / v) hydroxypropyl cellulose.

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

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

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

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

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

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

14. 10. The topical composition of claim 1, wherein the solvent system comprises about 10% to 90% (v / v) propylene glycol.

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

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

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

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

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

20. 1. A topical composition useful for treating or preventing hair loss, comprising: i. Triiodothyronine (T3); ii. Hydroxypropyl cellulose; and iii. Solvent system A topical composition comprising:

21. 1. A topical composition useful for treating or preventing hair loss, comprising: i. Triiodothyronine (T3); ii. Hydroxypropyl cellulose; iii. ethanol; iv. propylene glycol; and v. water A topical composition comprising:

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

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

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

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

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

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

28. A topical composition according to any one of claims 1 to 27 for use in the treatment or prevention of alopecia.

29. 28. Use of a topical composition according to any one of claims 1 to 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 a topical composition according to any one of claims 1 to 27.

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

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

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

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

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

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

37. 31. The method of claim 30, wherein the composition is administered every other day for several consecutive weeks, followed by an extended period of no administration.

38. 38. The method of claim 37, wherein the composition is administered every other day for two consecutive weeks, followed by an extended period of no administration.

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

40. 31. The method of claim 30, wherein the hair loss is due to androgenetic alopecia, alopecia areata, persistent patchy alopecia areata, alopecia totalis, alopecia universalis, diffuse alopecia areata, alopecia serpiginosa, cicatricial alopecia, lichen planus folliculitis, frontal fibrosing alopecia, central centrifugal cicatricial alopecia (CCCA), traction alopecia, beard alopecia, or postpartum alopecia.

41. 31. The method of claim 30, which results in increased hair shaft production.

42. 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 a baseline value measured before administration of the composition.

43. 31. The method of claim 30, which results in an increase in the growth period of anagen hair.

44. 44. The method of claim 43, wherein the growth period of anagen hair is extended by 1%, 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or 100% compared to a baseline value measured before administration of the composition.

45. 31. The method of claim 30, which results in increased expression of FGF7.

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

47. 31. The method of claim 30, which results in increased proliferation of bulge epithelial stem cells.

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

49. 31. The method of claim 30, which results in increased expression of keratin 15.

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

51. 31. The method of claim 30, which results in a decrease in expression of p-S6.

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

53. A topical composition according to any one of claims 1 to 27 for use in the treatment or prevention of grey hair.

54. Use of a topical composition according to any one of claims 1 to 27 for the manufacture of a medicament for the treatment or prevention of grey hair.

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

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

57. 56. The method of claim 55, which results in reduced bleaching of hair.

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

59. 56. The method of claim 55, which results in recoloring of hair.

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