Compositions and methods relating to alopecia

Abstract

Provided herein are compositions and methods for targeting dermal white adipose tissue for the stimulation and regeneration of hair follicles.

Description

[Technical field]

[0001] cross reference This application claims the benefit of U.S. Provisional Patent Application No. 63 / 150,411, filed February 17, 2021, which is incorporated by reference in its entirety. [Background technology]

[0002] background Hair loss or alopecia is a common disorder resulting from heterogeneous etiology. A variety of treatments are available to prevent or reduce hair loss and stimulate hair growth. However, these treatments may not be the most effective at preventing or reducing hair loss or stimulating hair growth. Summary of the Invention

[0003] overview Methods and compositions for hair follicle stimulation and regeneration are described herein.In some cases, the methods and compositions described herein target dermal white adipose tissue (dWAT).In some cases, the methods and compositions described herein target dWAT include peroxisome proliferator-activated receptor (PPAR)-gamma (PPAR-gamma) agonists, activators of PGC-1α, metabolic influencers of dWAT lipolysis, M2 macrophage polarizing compounds, local activators of insulin growth factor 1 (IGF-1), activators or stimulators of autophagy, one or more peptides, or combinations thereof.

[0004] An embodiment described herein is a composition for targeting dermal white adipose tissue (dWAT) to stimulate or regenerate hair follicles, comprising (a) tripeptide-1, (b) hexapeptide-12, and (c) a PPAR-gamma agonist, said composition stimulating or regenerating hair follicles. In one feature, tripeptide-1 comprises palmitoyl tripeptide-1, myristoyl tripeptide-1, or a combination thereof. In one feature, hexapeptide-12 comprises palmitoyl hexapeptide-12, myristoyl hexapeptide-12, or a combination thereof. In one feature, the composition further comprises hexapeptide-38. In one feature, hexapeptide-38 is actyl-hexapeptide-38. In one feature, hexapeptide-38 is encapsulated in a liposome. In one feature, the composition further comprises an octapeptide. In one aspect, the PPAR-gamma agonist is a thiazolidinedione (TZD), aleglitazar, farglitazar, muraglitazar, tesaglitazar, or a combination thereof. In one aspect, the PPAR-gamma agonist is derived from a plant source. In one aspect, the PPAR-gamma agonist is a natural product. In one aspect, the composition further comprises an M2-macrophage polarizing compound. In one aspect, the M2-macrophage polarizing compound is a flavonoid, a terpenoid, a glycoside, a lignan, a coumarin, an alkaloid, a polyphenol, a quinone, or a combination thereof. In one aspect, the M2-macrophage polarizing compound is arctigenin. In one aspect, the M2-macrophage polarizing compound is lupeol, malivatol A, geraniin, aloe-emodin, quercetin, curcumin, apigenin, tacrolimus, or niacinamide, or a combination thereof. In one aspect, the M2-macrophage polarizing compound is derived from a plant source. In some aspects, the plant source is Arctium lappa plant, curcumin, luteolin, piperine, resveratrol, silibinum, baicalin, or a combination thereof.In one aspect, the composition further comprises a local activator of insulin growth factor 1 (IGF-1). In one aspect, the local activator of insulin growth factor 1 (IGF-1) is capsaicin, an isoflavone, or a combination thereof. In one aspect, the local activator of insulin growth factor 1 (IGF-1) is capsaicin. In one aspect, the composition further comprises an activator of PGC-1α. In some embodiments, the PPAR-gamma agonist comprises adiponectin or an adiponectin mimetic. In some embodiments, the adiponectin mimetic comprises AdipoRon, ADP355, ADP399, JT003, 6-C-β-D-glucopyranosyl-(2S,3S)-(+)-5,7,30,40-tetrahydroxydihydroflavonol (GTDF), osmotin, or a combination thereof. In some embodiments, the composition further comprises a Jak-STAT inhibitor. In some embodiments, the Jak-STAT inhibitor comprises ruxolitinib, tofacitinib, or a combination thereof.

[0005] An embodiment described herein is a method for stimulating or regenerating hair follicles comprising administering a composition described herein. In one aspect, the method stimulates hair growth.

[0006] An aspect described herein is a method for preventing or reducing hair loss comprising administering a composition described herein.

[0007] Incorporation by Reference All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference. [Brief description of the drawings]

[0008] The novel features of the invention are set forth with particularity in the appended claims. A better understanding of the features and advantages of the present invention will be obtained by reference to the following detailed description that sets forth illustrative embodiments, in which the principles of the invention are utilized, and the accompanying drawings (hereinafter "Figure" and "FIG.") in which:

[0009] [Figure 1] 1 shows a schematic diagram of a hair follicle. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0010] Detailed Description definition Throughout this disclosure, various embodiments are presented in a range format. It should be understood that the description in range format is merely for convenience and brevity and should not be construed as an inflexible limitation on the scope of any embodiment. Thus, the description of a range should be considered to have specifically disclosed all possible subranges and individual numerical values ​​within the range to the tenth of the unit of the lower limit, unless the context clearly dictates otherwise. For example, the description of a range such as 1 to 6 should be considered to have specifically disclosed subranges such as 1 to 3, 1 to 4, 1 to 5, 2 to 4, 2 to 6, 3 to 6, etc., as well as individual values ​​within that range, for example, 1.1, 2, 2.3, 5, and 5.9. This applies regardless of the breadth of the range. The upper and lower limits of these intervening ranges may independently be included in the smaller ranges and are also encompassed within the disclosure, subject to any specifically excluded limit in the stated range. Where the stated range includes one or both of the limits, ranges excluding either or both of those included limits are also included in the disclosure, unless the context clearly dictates otherwise.

[0011] The terminology used herein is merely for the purpose of describing particular embodiments and is not intended to limit any embodiment. As used herein, the singular forms "a," "an," and "the" are intended to include the plural forms as well, unless the context clearly dictates otherwise. It will be further understood that the terms "comprises" and / or "comprising," as used herein, specify the presence of stated features, integers, steps, operations, elements, and / or components, but do not preclude the presence or addition of one or more other features, integers, steps, operations, elements, components, and / or groups thereof. As used herein, the term "and / or" includes any and all combinations of one or more of the associated listed items.

[0012] As used herein, unless specifically stated otherwise or clear from the context, the term "about" in reference to a numerical value or range of numerical values ​​is understood to mean the stated numerical value and that numerical value + / - 10%, or 10% below the recited lower limit and 10% above the recited upper limit for the recited values ​​in the range.

[0013] Methods and compositions for targeting dermal white adipose tissue Methods and compositions for targeting dermal white adipose tissue (dWAT) are described herein. Targeting dWAT can result in stimulation or regeneration of hair follicles. The methods and compositions described herein, in some embodiments, include a PPAR-gamma agonist, an activator of PGC-1α, a metabolic influencer of dWAT lipolysis, an M2 macrophage polarizing compound, a local activator of insulin growth factor 1 (IGF-1), an activator or stimulator of autophagy, one or more peptides, or a combination thereof. In some embodiments, one or more peptides are tripeptides (e.g., tripeptide-1). In some embodiments, one or more peptides are hexapeptides (e.g., hexapeptide-12 and hexapeptide-38). In some embodiments, one or more peptides are octapeptides (e.g., GPHGVRQA).

[0014] Signaling mechanisms and cellular crosstalk occur throughout the micro- and macro-environments surrounding the hair follicle. In particular, progenitor cells in the bulge region and dermal papilla may play an important role in hair follicle regeneration. Here, signals can bind to and affect hair follicle stem cells that orchestrate hair regeneration. Bulge stem cells are important for the circulatory regeneration of hair follicles, during which the hair follicle switches from the growth phase (anagen) through the regression phase (catagen) to the relatively resting phase (telogen). Furthermore, signals in the tissue macro-environment originating from dermal fibroblasts, adipocytes (dWAT), preadipocytes, and nerve fibers may contribute to hair follicle circulation. In both the bulge region and dermal papilla, the interactions of induced fibroblasts, myofibroblasts, macrophages, keratinocytes, pericytes, and ASCs may play interrelated roles in hair cell homeostasis. All of these cell phenotypes can be found in the dWAT surrounding the hair follicle, and therefore dWAT may be a major influential organ in this region and may play a role in hair follicle pathways and stimulation, see FIG.

[0015] The present invention describes a method for targeting dermal white adipose tissue (dWAT), comprising administering an active agent via hair follicle, wherein the active agent is delivered to dWAT via hair follicle.In some cases, low molecular weight active agent is delivered through hair follicle via dWAT.In some cases, the active agent has a molecular weight of about 600 Daltons (Da) or less. In some cases, the active agent has a molecular weight of at least 50, 75, 100, 125, 150, 175, 200, 225, 250, 275, 300, 325, 350, 375, 400, 425, 450, 475, 500, 525, 550, 575, 600, 625, 650, 675, 700, 725, 750, 775, 800, 825, 850, 875, 900, 925, 950, 975, 1000 Daltons (Da), or 1000 Daltons. (Da), or about 50, 75, 100, 125, 150, 175, 200, 225, 250, 275, 300, 325, 350, 375, 400, 425, 450, 475, 500, 525, 550, 575, 600, 625, 650, 675, 700, 725, 750, 775, 800, 825, 850, 875, 900, 925, 950, 975, 1000 Daltons (Da), or greater than 1000 Daltons (Da). In some cases, the active agent has a molecular weight of at least 1000, 1100, 1200, 1300, 1400, 1500, 1600, 1700, 1800, 1900, 2000, 2100, 2200, 2300, 2400, 2500, 2600, 2700, 2800, 2900, 3000, 4000, 5000, 6000, 7000, 8000, 9000, 10000 Daltons (Da), or 10000 Daltons. (Da), or about 1000, 1100, 1200, 1300, 1400, 1500, 1600, 1700, 1800, 1900, 2000, 2100, 2200, 2300, 2400, 2500, 2600, 2700, 2800, 2900, 3000, 4000, 5000, 6000, 7000, 8000, 9000, 10000 Daltons (Da), or greater than 10000 Daltons (Da).In some cases, the active agent has a molecular weight in the range of about 50 to about 1000, about 100 to about 900, about 200 to about 800, about 300 to about 700, or about 400 to about 600 Daltons (Da). Alternatively, or in combination, the active agent is a peptide or other active agent encapsulated in a liposome to improve skin penetration through the hair follicle.

[0016] In some embodiments, the composition is a topical composition. In some embodiments, the composition is an aqueous formulation. In some embodiments, the composition is an anhydrous formulation.

[0017] Regulators of lactate dehydrogenase (Ldh) activity Methods and compositions for targeting regulators of lactate dehydrogenase (Ldh) activity are described herein.Normally, human hair follicles use one or more of aerobic glycolysis and glutaminolysis to power their metabolism.During metabolic processes, hair follicle stem cells in the bulge and hair germ can take up glucose and generate lactate by increased lactate dehydrogenase (Ldh) activity in the bulge.In many cases, activation of Ldh activity or increased Ldh activity can stimulate hair cycle.Therefore, pharmacological inhibition of pyruvate entry into mitochondria can increase Ldh activity and accelerate hair cycle.

[0018] There are several pharmacological pathways that inhibit MPC and thereby increase Ldh activity. For example, TZDs can inhibit MPC activity. For example, the glitazones, members of the thiazolidinedione family, can be potent inhibitors of MPC. In some cases, the mitochondrial pyruvate carrier (MPC) can alter Ldh activity. Normally, the mitochondrial pyruvate carrier (MPC) is a protein that mediates the import of pyruvate across the inner membrane of mitochondria. In some cases, inhibition of pyruvate oxidation by blocking the MPC complex increases Ldh activity by providing more substrate for the enzyme to convert to lactate. This then activates the hair cycle and stimulates dormant hair follicles. In some cases, autophagy can be elevated throughout the anagen phase of the hair growth cycle. In some cases, autophagy induction by the longevity metabolites α-KG and α-KB, as well as small molecule mTOR inhibitors and AMPK activators, can initiate hair follicle activation and hair regeneration.

[0019] In some embodiments, the modulator of Ldh activity is a member of the thiazolidinedione (TZD) family. In some embodiments, the modulator of Ldh activity is a TZD. In some embodiments, the modulator of Ldh activity is a glitazone.

[0020] PPAR-gamma agonists Methods and compositions for targeting dWAT to stimulate hair follicles and promote hair follicle regeneration are described herein. In some embodiments, the methods and compositions include an agent that stimulates peroxisome proliferator-activated receptor (PPAR)-gamma (PPAR-gamma). In some embodiments, the agent that stimulates PPAR-gamma is a PPAR-gamma agonist. In some embodiments, the PPAR-gamma agonist is a thiazolidinedione (TZD), aleglitazar, farglitazar, muraglitazar, tesaglitazar, adiponectin, or a combination thereof. Exemplary thiazolidinediones include, but are not limited to, pioglitazone, rosiglitazone, rivoglitazone, and troglitazone. In some embodiments, the PPAR-gamma agonist is derived from a plant source. In some embodiments, the plant source is tea plant (Camellia sinensis), soybean (Glycine max), palm oil (Elaeis guineensis), ginger (Zingiber officinale), grapes and wine (Vitis vinifera), or herbs or spices (e.g., Origanum vulgare, Rosmarinus officinalis, Salvia officinalis, Thymus vulgaris). In some embodiments, the PPAR-gamma is a natural product.Exemplary natural products include, but are not limited to, flavonoids (e.g., luteolin, quercetin, kaempferol, catechin, hydroxychalcones, biochanin A, genistein, hydroxydaidzein, and 6'-hydroxy-O-desmethylangolensin), neolignans (e.g., honokiol and magnolol), stilbenes (e.g., resveratrol and amorphastilbol), amorfurthins (e.g., amorfurthin 1, amorfurthin 1, and amorfurthin B), polyacetylenes (e.g., falcarindiol), sesquiterpene lactones (e.g., deoxyelephantopine), and diterpene quinone derivatives (e.g., sargaquinonic acid and sargahydroquinonic acid).

[0021] PPAR-gamma coactivator Described herein are methods and compositions for targeting dWAT to stimulate hair follicles and promote hair follicle regeneration, which in some embodiments include an agent that modulates peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α). In some embodiments, the agent that modulates PGC-1α is a PGC-1α agonist. In some embodiments, the agent that modulates PGC-1α is a peptide. In some embodiments, the peptide is hexapeptide-38.

[0022] M2 Macrophage-Polarizing Compounds Usually, macrophages are involved in stimulating the hair cycle. In some cases, they are involved in matrix removal during hair follicle regression, as well as hair follicle stem cell activation and anagen induction. In some cases, macrophage-specific pharmacological inhibition of Wnt production retards hair follicle growth. In some cases, perifollicular macrophages contribute to the activation of skin epithelial stem cells as a novel additional cue that regulates their regenerative activity. In some cases, M2-phenotype macrophages are involved in stimulating anagen. In some cases, M2-phenotype macrophages are involved through the IGF-1 pathway.

[0023] Described herein are methods and compositions for targeting dWAT to stimulate hair follicles and promote hair follicle regeneration, the methods and compositions comprising, in some embodiments, an M2 macrophage polarizing compound. In some embodiments, the M2 macrophage polarizing compound is a flavonoid, a terpenoid, a glycoside, a lignan, a coumarin, an alkaloid, a polyphenol, a quinone, or a combination thereof. In some embodiments, the M2 macrophage polarizing compound is arctigenin. In some embodiments, the M2 macrophage polarizing compound is lupeol, marivatol A, geraniin, aloe-emodin, quercetin, curcumin, apigenin, tacrolimus, niacinamide, or a combination thereof. In some embodiments, the M2 macrophage polarizing compound is derived from a plant source. In some embodiments, the plant is an Arctium lappa plant, curcumin, luteolin, piperine, resveratrol, silivinum, baicalin, or a combination thereof.

[0024] Adiponectin Described herein are methods and compositions for targeting dWAT to stimulate hair follicles and promote hair follicle regeneration, comprising adiponectin or an adiponectin mimetic. Sometimes, pharmacological ligands of PPAR-γ can attenuate fibroblast activation and myofibroblast differentiation, preventing the loss of dWAT and improving organ fibrosis. In some embodiments, adiponectin is a PPAR-γ ligand. In some embodiments, adiponectin is a PPAR-γ agonist. In some embodiments, adiponectin stimulates PPAR-γ activity. Typically, adiponectin can be a secreted adipokine. In some cases, adiponectin is about 30 kDa. Targeting cellular adiponectin receptors with synthetic agonist peptides can potentially increase the dWAT compartment, which has a positive effect on hair follicle (HF) growth. In some cases, targeting adiponectin is difficult due to the complex structure of adiponectin, its insolubility, and its relatively short half-life. In some cases, adiponectin mimetics that mimic the biological activity of adiponectin can be used. In some embodiments, the adiponectin mimetics are small molecules. In some embodiments, the adiponectin mimetics are short peptides based on adiponectin.

[0025] In some embodiments, synthetic agonist peptides include, but are not limited to, AdipoRon. In some embodiments, AdipoRon has motif similarity with GCPR ligand and AMPK activator. In some embodiments, synthetic agonist peptides include, but are not limited to, one or more of ADP355, ADP399, and JT003. In some embodiments, plant-based small molecules can function as adiponectin mimetics. In some embodiments, plant-based small molecules that function as adiponectin mimetics include, but are not limited to, one or more of 6-C-β-D-glucopyranosyl-(2S,3S)-(+)-5,7,30,40-tetrahydroxydihydroflavonol (GTDF) and osmotin.

[0026] In some embodiments, the methods and compositions described herein include adiponectin or an adiponectin mimetic. In some embodiments, the methods and compositions provided herein include a PPAR-γ ligand. In some embodiments, the PPAR-γ ligand includes adiponectin or an adiponectin mimetic. In some embodiments, the adiponectin mimetic is a small molecule. In some embodiments, the adiponectin mimetic is an adiponectin receptor agonist. In some embodiments, the adiponectin mimetic is a synthetic small molecule agonist of adiponectin receptor 1 (AdipoR1). In some embodiments, the small molecule agonist is AdipoRon. In some embodiments, the composition includes an adiponectin mimetic. In some embodiments, the adiponectin mimetic is an adiponectin-based short peptide. In some embodiments, the adiponectin mimetic is ADP355. In some embodiments, the adiponectin mimetic is ADP399. In some embodiments, the adiponectin mimetic is GTDF. In some embodiments, the adiponectin mimetic is JT003. In some embodiments, the adiponectin mimetic is plant-based. In some cases, the plant-based adiponectin mimetic is GTDF. In some cases, the plant-based adiponectin mimetic is osmotin.

[0027] growth factors In some cases, dWAT may regulate human hair growth and pigmentation through secretion of growth factors. Examples of such growth factors include, but are not limited to, hepatocyte growth factor (HGF). In some embodiments, growth factors involved in hair growth and pigmentation may be secreted from adipose-derived stem cells (ADSCs). In some embodiments, growth factors secreted from ADSCs include, but are not limited to, platelet-derived growth factor (PDGF), vascular endothelial growth factor (VEGF), IGF-binding protein precursor, and fibronectin. These growth factors may perform various functions to stimulate hair growth. In some embodiments, PDGF may induce and maintain anagen. In some embodiments, VEGF may increase hair growth through hair follicle angiogenesis. In some embodiments, IGF-1 may improve hair follicle cell migration, survival, and proliferation.

[0028] Described herein are methods and compositions for targeting dWAT to stimulate hair follicles and promote hair follicle regeneration, which in some embodiments include a growth factor activator. In some embodiments, the growth factor activator is a local activator of hepatocyte growth factor 1 (HGF-1). In some embodiments, the growth factor activator is a local activator of insulin growth factor 1 (IGF-1). In some embodiments, the local activator of IGF-1 is capsaicin, isoflavone, vascular endothelial growth factor (VEGF), or TGF-β. In some embodiments, the growth factor activator is a local activator of PDGF. In some embodiments, the local activator of PDGF is tripeptide-1. In some embodiments, the growth factor activator is a local activator of HGF. In some embodiments, the local activator of HGF is tripeptide-1. In some embodiments, the growth factor activator is octapeptide 45. In some embodiments, the growth factor activator is Vitamin D.

[0029] peptide The methods described herein for targeting dermal white adipose tissue, in some embodiments, include administering a composition comprising one or more peptides. In some embodiments, the one or more peptides are encapsulated in a liposome.

[0030] In some cases, the peptide is present at about 50 ppm or less to 1000, 5000, 10000, 50000, 100000, 500000 ppm or more, e.g., 100 ppm of peptide. The topical formulation can contain 0.01% or less (e.g., 0.001%) to 10% or more by weight, e.g., 0.01% to 0.02%, 0.03%, 0.04%, 0.05%, 0.1%, 1% to 5% or 10% by weight of the first peptide. In some cases, the composition comprises multiple peptides. In some cases, the peptides of the plurality of peptides are present in about 50 ppm or less to 1000, 5000, 10000, 50000, 100000, 500000 ppm or more, such as 100 ppm of peptide, or any other suitable amount. The composition may include 0.01% or less (e.g., 0.001%) to 10% or more by weight of peptide, such as 0.01% to 0.02%, 0.03%, 0.04%, 0.05%, 0.1%, 1% to 5% or 20% by weight. The amount of peptide in the base can be adjusted up or down.

[0031] The compositions described herein, in some embodiments, comprise a plurality of peptides. In some embodiments, each peptide of the plurality of peptides comprises at least 0.00001%, 0.0003%, 0.0005%, 0.001%, 0.001%, 0.005%, 0.0055%, 0.01%, 0.02%, 0.05%, 0.10%, 0.25%, 0.50%, 0.75%, 1.0%, 1.5%, 2.0%, 2.5%, 3.0%, 3.5%, 4.0%, 4.5%, 5.0%, 5.5%, 6.0%, 6.5%, 7.0%, 8%, 9%, 10%, or more by weight. is provided at greater than 10 wt.%, or about 0.00001 wt.%, 0.0003 wt.%, 0.0005 wt.%, 0.001 wt.%, 0.001 wt.%, 0.005 wt.%, 0.0055 wt.%, 0.01 wt.%, 0.02 wt.%, 0.05 wt.%, 0.10 wt.%, 0.25 wt.%, 0.50 wt.%, 0.75 wt.%, 1.0 wt.%, 1.5 wt.%, 2.0 wt.%, 2.5 wt.%, 3.0 wt.%, 3.5 wt.%, 4.0 wt.%, 4.5 wt.%, 5.0 wt.%, 5.5 wt.%, 6.0 wt.%, 6.5 wt.%, 7.0 wt.%, 8 wt.%, 9 wt.%, 10 wt.%, or greater than 10 wt.%. In some embodiments, each peptide of the plurality of peptides is provided in the range of about 0.25% to about 10%, about 0.5% to about 8%, about 0.75% to about 6%, or about 1% to about 4% by weight. In some embodiments, each peptide of the plurality of peptides is provided in the range of about 0.001% to about 6%, about 0.002% to about 4%, about 0.01% to about 3%, or about 0.02% to about 2% by weight.

[0032] In some embodiments, the peptide is tripeptide-1, hexapeptide-12, octapeptide, hexapeptide-38, or a combination thereof. In some embodiments, the peptide is functionalized with an acetyl group. For example, the peptide is acetyl hexapeptide-38. In some embodiments, the octapeptide is GPHGVRQA. In some embodiments, the peptide is encapsulated in a liposome.

[0033] In some embodiments, tripeptide-1 is at least 0.00001%, 0.0003%, 0.0005%, 0.001%, 0.001%, 0.005%, 0.0055%, 0.05%, 0.10%, 0.25%, 0.50%, 0.75%, 1.0%, 1.5%, 2.0%, 2.5%, 3.0%, 3.5%, 4.0%, 4.5%, 5.0%, 5.5%, 6.0%, 6.5%, 7.0%, 8%, 9%, 10%, or 10% by weight. % by weight (wt.), or greater than about 0.00001%, 0.0003%, 0.0005%, 0.001%, 0.001%, 0.005%, 0.0055%, 0.05%, 0.10%, 0.25%, 0.50%, 0.75%, 1.0%, 1.5%, 2.0%, 2.5%, 3.0%, 3.5%, 4.0%, 4.5%, 5.0%, 5.5%, 6.0%, 6.5%, 7.0%, 8%, 9%, 10%, or greater than 10% by weight. In some embodiments, tripeptide-1 is provided in the range of about 0.25% to about 10%, about 0.5% to about 8%, about 0.75% to about 6%, or about 1% to about 4% by weight.

[0034] In some embodiments, hexapeptide-12 is at least 0.00001%, 0.0003%, 0.0005%, 0.001%, 0.001%, 0.005%, 0.0055%, 0.05%, 0.10%, 0.25%, 0.50%, 0.75%, 1.0%, 1.5%, 2.0%, 2.5%, 3.0%, 3.5%, 4.0%, 4.5%, 5.0%, 5.5%, 6.0%, 6.5%, 7.0%, 8%, 9%, 10%, or 10% by weight. %. In some embodiments, hexapeptide-12 is provided in the range of about 0.25% to about 10%, about 0.5% to about 8%, about 0.75% to about 6%, or about 1% to about 4% by weight.

[0035] In some embodiments, hexapeptide-38 is at least 0.00001%, 0.0003%, 0.0005%, 0.001%, 0.001%, 0.005%, 0.0055%, 0.01%, 0.02%, 0.05%, 0.10%, 0.25%, 0.50%, 0.75%, 1.0%, 1.5%, 2.0%, 2.5%, 3.0%, 3.5%, 4.0%, 4.5%, 5.0%, 5.5%, 6.0%, 6.5%, 7.0%, 8%, 9%, 10%, or %. In some embodiments, hexapeptide-38 is provided in the range of about 0.25% to about 10% by weight, about 0.5% to about 8% by weight, about 0.75% to about 6% by weight, or about 1% to about 4% by weight. In some embodiments, hexapeptide-38 is provided in the range of about 0.001% to about 6%, about 0.002% to about 4%, about 0.01% to about 3%, or about 0.02% to about 2%. In some embodiments, hexapeptide-38 is provided in the range of about 0.005% to about 0.02% by weight.

[0036] In exemplary embodiments, the weight ratio of the first peptide to the second peptide in the topical formulation is 1 part first peptide to 0.2-10 parts second peptide, 1-10 parts second peptide, 1-8 parts second peptide, or 1-5.5 parts second peptide. The following nomenclature is used herein to refer to various amino acids: alanine (also referred to herein as "Ala" or "A"), arginine (also referred to herein as "Arg" or "R"), asparagine (also referred to herein as "Asn" or "N"), aspartic acid (also referred to herein as "Asp" or "D"), cysteine ​​(also referred to herein as "Cys" or "C"), glutamic acid (also referred to herein as "Glu" or "E"), glutamine (also referred to herein as "Gln" or "Q"), glycine (also referred to herein as "Gly" or "G"), histidine (also referred to herein as "His" or "H"), isoleucine (also referred to herein as "Ala" or "A"), riboflavin (also referred to herein as "R" or "R"), riboflavin (also referred to herein as "R" or "R"), isoleucine (also referred to herein as "R" or "R"). "Ile" or "I"); leucine (also referred to herein as "Leu" or "L"); lysine (also referred to herein as "Lys" or "K"); methionine (also referred to herein as "Met" or "M"); phenylalanine (also referred to herein as "Phe" or "F"); proline (also referred to herein as "Pro" or "P"); serine (also referred to herein as "Ser" or "S"); threonine (also referred to herein as "Thr" or "T"); tryptophan (also referred to herein as "Trp" or "W"); tyrosine (also referred to herein as "Tyr" or "Y"); and valine (also referred to herein as "Val" or "V").

[0037] In some embodiments, the first peptide is a dipeptide. Suitable dipeptides include, but are not limited to, those having the following amino acid sequence: KK, KP, CK, KC, KT, DF, NF, VW, YR, or TT. In some embodiments, the dipeptide has the following amino acid sequence: KV. In other embodiments, the first peptide is a tripeptide. Suitable tripeptides include, but are not limited to, those having the following amino acid sequence: HGG, RKR, GHK, GKH, GGH, GHG, KFK, or KPK. In some embodiments, the tripeptide has the following amino acid sequence: KVK. In some embodiments, the first peptide is a tetrapeptide. Suitable tetrapeptides include, but are not limited to, those having the following amino acid sequence: GQPR, KTFK, AQTR, or RSRK. In some embodiments, the tetrapeptide has the following amino acid sequence: KDVY. In some embodiments, the second peptide is a pentapeptide. Suitable pentapeptides include, but are not limited to, those having the following sequence of amino acids: KTTKS, YGGFX, or KLAAK. In some embodiments, the second peptide is a hexapeptide. Suitable hexapeptides include, but are not limited to, those having the following sequence of amino acids: VGVAPG or GKTTKS. In some embodiments, the hexapeptide has the following amino acid sequence: FVAPFP. In some embodiments, the second peptide is a heptapeptide. Suitable heptapeptides include, but are not limited to, those having the amino acid sequence RGYYLLE, or heptapeptide-6 (prosirtuin peptide). The composition may contain two or more peptides, such as two dipeptides and one pentapeptide, one tripeptide and one hexapeptide, one dipeptide, one tripeptide, and one heptapeptide, provided that the composition contains at least one dipeptide, tripeptide, or tetrapeptide and at least one pentapeptide, hexapeptide, or heptapeptide.In some embodiments, the composition comprises a tripeptide and one or more hexapeptides. In some embodiments, the tripeptide is tripeptide-1. In some embodiments, a first hexapeptide of the one or more hexapeptides is hexapeptide-12. In some embodiments, a second hexapeptide of the one or more hexapeptides is hexapeptide-38.

[0038] The peptides can be functionalized. For example, the peptides can be functionalized with fatty acids such as myristoleic acid, palmitoleic acid, sapienic acid, oleic acid, elaidic acid, vaccenic acid, linoleic acid, linoelaidic acid, alpha-linolenic acid, arachidonic acid, eicosapentaenoic acid, erucic acid, docosahexaenoic acid, caprylic acid, capric acid, lauric acid, palmitic acid, stearic acid, arachidic acid, behenic acid, lignoceric acid, cerotic acid, and the like. Examples include palmitoyl hexapeptide-12 (Pal-VGVAPG), palmitoyl tripeptide-1 (Pal-GHK), myristoyl hexapeptide-12 (Myr-VGVAPG), myristoyl tripeptide-1 (Myr-GHK). Palmitoyl or myristoyl functionalization may be desirable in certain embodiments, as they exhibit enhanced penetration when compared to other fatty acids. In some embodiments, the peptide is functionalized with a chemical group. For example, the peptide is functionalized with acetyl. An example includes acetyl hexapeptide-38. In some cases, the peptide is functionalized with a functional group containing 14 carbons or less. In some cases, the peptide is functionalized with a functional group containing 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 or less carbons, or more than 20 carbons. In some cases, the peptide is non-palmitoylated. Without being limited to a particular theory, in some embodiments, the incorporation of the peptide into a liposome increases the lipophilicity of the peptide, whether functionalized or not functionalized.

[0039] Some embodiments of the methods and compositions provided herein include glycine-histidine-lysine (GHK) as the first peptide. GHK is a peptide sequence that is rarely found in common protein classes, but is frequently found in extracellular matrix proteins. The small size of GHK allows it to approach membrane receptors much more easily than larger peptides. Furthermore, its unique copper-binding structure enhances copper transport in and out of cells, promoting wound healing through several different but related pathways. Due to its strong copper-binding structure, GHK can be provided in the form of GHK-Cu (copper-bound GHK form).

[0040] In the compositions, the tripeptide is typically present in an amount from about 50 ppm or less to about 100, 200, 300, 400, or 500 ppm or more, for example, 50 ppm to 150 ppm.

[0041] In the composition, the hexapeptide is typically present in an amount from about 50 ppm or less to about 100, 200, 300, 400, or 500 ppm or more, for example, 50 ppm to 150 ppm.

[0042] The peptides may be advantageously provided in a base suitable for combination with other components of the liposomal composition. The base may include one or more components such as thickeners / binders (e.g., pentaerythrityl tetraisostearate), softeners / dispersants (e.g., caprylic / capric triglyceride), solvents (e.g., propylene carbonate), and / or rheology modifiers / anti-settling agents (e.g., disteardimonium hectorite).

[0043] Metabolic influencers of dWAT lipolysis Various metabolites and metabolic pathways can affect dWAT size. In some embodiments, lipolysis and fatty acid release can increase dWAT size. In some embodiments, amino acids can increase dWAT size, thereby stimulating hair growth. In some embodiments, the compositions disclosed herein include a metabolic regulator of dWAT lipolysis. In some embodiments, the metabolic regulator of dWAT lipolysis is an amino acid. In one aspect, the amino acid is l-carnitine. In some embodiments, L-carnitine can stimulate hair growth by increasing energy supply to the energy-consuming anagen hair matrix. In some embodiments, L-carnitine can stimulate human scalp hair growth in vitro by upregulating proliferation and downregulating apoptosis in follicular keratinocytes. In some embodiments, L-carnitine can function as a substitute for lipolysis and amino acid release, which are reduced when dWAT volume is reduced.

[0044] Melatonin Melatonin, which is usually an antioxidant, may be associated with stimulating hair growth. In some cases, melatonin has positive effects resulting from topical application of melatonin solution in women and men with early androgenetic alopecia or generalized alopecia. In some embodiments, the compositions disclosed herein include melatonin. In some embodiments, the compositions disclosed herein include a melatonin receptor modulator. In some embodiments, the melatonin receptor is MT1, MT2, or RORα. In some embodiments, stimulation of the melatonin receptor may upregulate hair growth. Examples of such melatonin receptors may include, but are not limited to, MT1, MT2, and RORα.

[0045] Autophagy In many cases, autophagy may be elevated as HF naturally progresses through anagen and may be beneficial for hair growth stimulation. Typically, autophagy induction can occur through a variety of pathways. For example, the longevity metabolites α-ketobutyrate (α-KB) and α-ketoglutarate (α-KG), as well as activators of AMP-activated protein kinase (AMPK), can stimulate autophagy. In some cases, inhibitors of the mammalian target of rapamycin (mTOR) can activate autophagy, thereby initiating hair follicle activation and hair regeneration.

[0046] The methods and compositions disclosed herein may include a component that stimulates autophagy in hair follicle cells. In some embodiments, the component that stimulates autophagy is hexapeptide-11, α-KB, α-KG, 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR), metformin, oligomycin, rapamycin, or a combination thereof. In some embodiments, the component that stimulates autophagy is an mTOR inhibitor. In some embodiments, the mTOR inhibitor is oligomycin. In some embodiments, the mTOR inhibitor is rapamycin. In some embodiments, the component that stimulates autophagy is an AMPK stimulator. In some embodiments, the AMPK stimulator is metformin.

[0047] Mitochondrial pyruvate carrier (MPC) complex inhibitors Mitochondria-derived energy sources can affect hair follicle dormancy and mitochondrial pyruvate carrier (MPC) inhibition. That is, MPC complex inhibitors can activate dormant hair follicles. In some embodiments, the compositions disclosed herein include MPC complex inhibitors. In some embodiments, the MPC complex inhibitors are members of the thiazolidinedione family. In one aspect, the members of the thiazolidinedione family are glitazones.

[0048] Jak-STAT inhibitors In many cases, the Jak-STAT signaling pathway is important for cell signaling. Inhibition of Jak-STAT signaling can usually promote hair growth by stimulating activation. In some cases, it can lead to the proliferation of HF stem cells. In some cases, local treatment with a Jak-STAT inhibitor can result in more robust hair growth than systemic treatment in androgenetic alopecia (AA). In some embodiments, the compositions described herein include a Jak-STAT inhibitor. In some embodiments, the compositions described herein reduce the activity of the Jak-STAT signaling pathway. In some embodiments, the compositions described herein inhibit the activity of the Jak-STAT signaling pathway. In one aspect, the Jak-STAT inhibitor is ruxolitinib. In one aspect, the Jak-STAT inhibitor is tofacitinib.

[0049] Wnt / b-catenin and BMP signaling Typically, stimulatory Wnt / β-catenin signaling pathway and inhibitory bone morphogenetic protein (BMP) signals may be involved in the intrinsic activation of hair follicle stem cells (HF-SCs), or bulge stem cells, and the transition of hair follicles (HFs) to anagen. Often, these signals arise from DPs that maintain HF-SCs in a quiescent state and generate synchronous cyclic waves of BMP activity that decline when waves of Wnt expression occur, thereby controlling HF cycling. In some cases, HF growth stimulatory signals may be propagated during the transition from telogen to adjacent HFs. In some cases, Wnt signaling genes within the fibroblast growth factor family may be underexpressed and BMP signaling may be increased in aged dWAT. In some cases, some plant-derived chemicals may promote hair growth by activating Wnt / b-catenin signaling. In some embodiments, the compositions described herein include plant-derived chemicals that promote hair growth by activating Wnt / b-catenin signaling. In some embodiments, plant-derived chemicals include, but are not limited to, Prunus mira Koehne nut oil, red ginseng oil, and loliolide.

[0050] Corticosterone and Stress Provided herein are compositions and methods that reduce stress-induced inhibition of hair follicle stem cell (HF-SC) activation and hair growth. In some embodiments, the compositions restore expression of growth arrest specific 6 (Gas6). In some cases, stress can affect the state of hair follicles. In some cases, the stress hormone corticosterone can regulate hair follicle stem cell (HF-SC) dormancy and hair growth. Under chronic stress, elevated corticosterone levels can prolong HF-SC dormancy and maintain hair follicles in a state of extended telogen phase. In some cases, corticosterone can act on the dermal papilla to suppress expression of a gene / protein called growth arrest specific 6 (Gas6), which in turn is an HF-SC receptor that stimulates hair growth. In some embodiments, restoring Gas6 expression overcomes stress-induced inhibition of HF-SC activation and hair growth.

[0051] Fibroblast growth factor 5 (FGF5) The compositions and methods provided herein can regulate the release of FGF5 by perifollicle macrophages. In some cases, regulating the release of FGF5 can increase the transition of hair follicles to anagen. In some cases, the regulation is an increase in the release of FGF5. Normally, mature HFs can have a separate immune system. In many cases, the HF valve and HF bulge can represent areas of immune privilege, the disruption of which causes distinct inflammatory hair loss disorders. For example, perifollicle mast cells and macrophages are involved in the regulation of HF growth through anagen and the transition to catagen. In some cases, sustained release of fibroblast growth factor 5 (FGF5) by perifollicle macrophages can regulate the anagen-catagen switch. In some cases, altered release of Wnt signals by perifollicle macrophages can contribute to the establishment of the refractory and competent phases of telogen, and the proliferation of cues that induce anagen.

[0052] Penetration enhancers Various types of penetration enhancers may be used with the compositions described herein. In some embodiments, the penetration enhancer comprises a fatty acid, a terpene, an alcohol, a pyrrolidone, a sulfoxide, laurocapram, a surfactant, an amide, an amine, a lecithin, a polyol, a quaternary ammonium compound, a silicone, an alkanoate, or a combination thereof.

[0053] Fatty acids and alcohols enhance the penetration of peptides and aid in the formulation, e.g., methanoic acid, ethanoic acid, propanoic acid, butanoic acid, isobutyric acid, pentanoic acid, hexanoic acid, heptanoic acid, octanoic acid, nonanoic acid, decanoic acid, myristoleic acid, isovaleric acid, palmitoleic acid, sapienic acid, oleic acid, elaidic acid, vaccenic acid, linoleic acid, linoleic acid, α-linolenic acid, arachidonic acid, eicosapentaenoic acid, erucic acid, docosahexaenoic acid, caprylic acid, capric acid, lauric acid, palmitic acid, stearic acid, arachidic acid, behenic acid, lignoceric acid, cerotic acid, medium chain fatty acids, e.g., C 6-12 It may be used to impart a silky feel to fatty acids etc. Typical amounts when used in the composition are from 1% to 4% by weight.

[0054] Other components Other components may include anti-inflammatory agents, antioxidants, plant-derived chemicals, and solubility enhancers. Exemplary anti-irritants include, but are not limited to, panthenyl triacetate and naringenin, which are natural plant extracts that reduce redness and moisture loss from the skin. Typical amounts of anti-irritants when used in the composition are 1% to 4% by weight.

[0055] Exemplary anti-inflammatory agents include, but are not limited to, Arnica montana extract. Arnica montana extract contains components such as essential oils, fatty acids, thymol, pseudoguaianolide sesquiterpene lactones, and flavanone glycosides, which may exhibit anti-inflammatory effects. The typical amount of anti-irritant when used in the composition is 1% to 4% by weight.

[0056] Exemplary antioxidants include but are not limited to niacinamide.Niacinamide reduces the protein expression level of DKK-1, which is expressed as hydrogen peroxide induced by the reduction of intracellular reactive oxygen species (ROS) production in dermal papilla cells.Therefore, niacinamide can promote hair growth by preventing oxidative stress-induced cell senescence and early catagen transition of hair follicles. In some embodiments, niacinamide is provided at at least or greater than about 0.001%, 0.005%, 0.01%, 0.02%, 0.05%, 0.10%, 0.20%, 0.25%, 0.50%, 0.75%, 1.0%, 1.5%, 2.0%, 2.5%, 3.0%, 3.5%, 4.0%, or 4%. In some embodiments, the Dunaliella salina extract is provided at about 2%.

[0057] Exemplary antioxidants include, but are not limited to, Dunaliella salina extract. Dunaliella salina extract contains components such as beta-carotene, which may exhibit antioxidant properties. Typical amounts of anti-inflammatory agents when used in the composition are 0.1% to 2% by weight. In some embodiments, a Dunaliella salina extract is provided at at least or greater than about 0.001%, 0.005%, 0.01%, 0.02%, 0.05%, 0.10%, 0.20%, 0.25%, 0.50%, 0.75%, 1.0%, 1.5%, 2.0%, 2.5%, 3.0%, 3.5%, 4.0%, or 4%. In some embodiments, the Dunaliella salina extract is provided at about 0.0027%.

[0058] Exemplary antioxidants include, but are not limited to, piroctone olamine, zinc pyrithione, zinc carbonate, niacinamide, panthenol, and caffeine.

[0059] Certain components of the formulation tend to be difficult to solubilize in conventional formulations. Phosphatidylserine and oleuropein are known to exhibit solubility problems. In some embodiments, siloxane polymers, such as caprylyl methicone, are used to solubilize phosphatidylserine in anhydrous formulations. In some embodiments, panthenyl triacetate and naringenin are used to solubilize oleuropein. For topical compositions containing about 0.05% to about 0.1% by weight of phosphatidylserine and / or about 0.05% to about 0.1% by weight of oleuropein, caprylyl methicone in an amount of about 0.5% to about 1% by weight can solubilize phosphatidylserine in anhydrous formulations. In some embodiments, phosphatidylserine is provided at at least or greater than about 0.001%, 0.005%, 0.01%, 0.02%, 0.05%, 0.10%, 0.20%, 0.25%, 0.50%, 0.75%, 1.0%, 1.5%, 2.0%, 2.5%, 3.0%, 3.5%, 4.0%, or 4%. In some embodiments, phosphatidylserine is provided at about 0.05% by weight. In some embodiments, the phosphatidylserine is provided at about 0.25% by weight. In some embodiments, the phosphatidylserine is provided at about 1% by weight.In some embodiments, oleuropein is at least 0.001%, 0.005%, 0.01%, 0.02%, 0.05%, 0.10%, 0.20%, 0.25%, 0.50%, 0.75%, 1.0%, 1.5%, 2.0%, 2.5%, 3.0%, 3.5%, 4.0%, 4.5%, 5.0%, 5.5%, 6.0%, 6.5%, 7.0%, 8%, 9%, 10%, or 10% by weight. %, or greater than about 0.001%, 0.005%, 0.01%, 0.02%, 0.05%, 0.10%, 0.20%, 0.25%, 0.50%, 0.75%, 1.0%, 1.5%, 2.0%, 2.5%, 3.0%, 3.5%, 4.0%, 4.5%, 5.0%, 5.5%, 6.0%, 6.5%, 7.0%, 8%, 9%, 10%, or greater than 10% by weight (wt.). In some embodiments, oleuropein is provided in the range of about 0.001% to about 6% by weight, about 0.002% to about 4% by weight, about 0.01% to about 3% by weight, about 0.02% to about 2% by weight, or about 0.01% to about 0.05% by weight. In some embodiments, oleuropein is provided at about 0.010% by weight. In some embodiments, oleuropein is provided at about 0.020% by weight. In some embodiments, oleuropein is provided at about 0.050% by weight.

[0060] Bentonite clay can be used in conjunction with peptides to impart penetrating and adsorbent properties to the composition and aid in stabilizing emulsions. Other clays such as hectorite and magnesium aluminum silicate can also be used. Bentonite or other clays can be modified to obtain organically modified clay compounds. Salts (e.g., quaternary ammonium salts) of fatty acids (e.g., hydrogenated fatty acids) can be reacted with hectorite or other clays. As provided herein, fatty acids are referred to and described using conventional nomenclature as used by those of skill in the art. Saturated fatty acids do not contain carbon-carbon double bonds. Unsaturated fatty acids contain at least one carbon-carbon double bond. Monounsaturated fatty acids contain only one carbon-carbon double bond. Polyunsaturated fatty acids contain two or more carbon-carbon double bonds. Double bonds in fatty acids are generally cis, although trans double bonds are possible. The position of the double bonds can be indicated as Δn, where n indicates the lower numbered carbon of each pair of double-bonded carbon atoms. Total carbon number: number of double bonds, Δ 二重結合位置 For example, 20:4Δ can be used to specify 5,8,11,14refers to a fatty acid having 20 carbon atoms and 4 double bonds, the double bonds being located between carbon atoms 5 and 6, carbon atoms 8 and 9, carbon atoms 11 and 12, and carbon atoms 14 and 15, with carbon atom 1 being the carbon of the carboxylic acid group. Stearate (octadecanoate) is a saturated fatty acid. Oleate (cis-Δ9-octadecanoate) is a monounsaturated fatty acid, and linoleate (all-cis-Δ9,12,15-octadecanoate) is a polyunsaturated fatty acid. Fatty acids suitable for use can contain 5 to 30 carbon atoms, for example, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 carbon atoms. The fatty acid may be fully saturated or may contain as many double bonds as practical for the chain length. Fatty acids suitable for functionalizing hectorite or other clays include palmitic acid and stearic acid. Dialkyl quaternary cationic modifiers include dipalmoyldimonium chloride and distearyldimonium chloride. Amidoamine quaternary cationic modifiers include palmitamidopropyltrimonium chloride cetearyl alcohol and palmitamidopropyltrimonium chloride.

[0061] In some embodiments, the peptides are mixed with a suitable carrier, diluent, or excipient, which may contain auxiliary substances such as wetting or emulsifying agents, pH buffering agents, gelling or viscosity enhancing additives, preservatives, flavoring agents, coloring agents, etc., depending on the route of administration and the preparation desired. See, for example, "Remington: The Science and Practice of Pharmacy", Lippincott Williams & Wilkins; 20th edition (June 1, 2003) and "Remington's Pharmaceutical Sciences," Mack Pub. Co.; 18th and 19th editions (December 1985 and June 1990, respectively). Such preparations may include complexing agents, metal ions, polymeric compounds such as polyacetic acid, polyglycolic acid, hydrogels, dextran, liposomes, microemulsions, micelles, unilamellar or multilamellar vesicles, erythrocyte ghosts, or spheroblasts. Suitable lipids for the composition include, but are not limited to, monoglycerides, diglycerides, sulfatides, lysolecithin, phospholipids, saponins, bile acids, etc. The presence of such additional components may affect the physical state, solubility, stability, release rate, clearance rate, and penetration of the active ingredient.

[0062] The topical composition comprises the peptide composition described herein and a dermatologically acceptable vehicle. The vehicle may be aqueous or non-aqueous. The dermatologically acceptable vehicle used in the topical composition may be in the form of a lotion, gel, ointment, liquid, cream, or emulsion. When the vehicle is an emulsion, the emulsion may have a continuous aqueous phase and a discontinuous non-aqueous or oily phase (oil-in-water emulsion), or a continuous non-aqueous or oily phase and a discontinuous aqueous phase (water-in-oil emulsion). When topically administered in liquid or gel form, a liquid carrier such as water, petroleum, oils of animal or vegetable origin, e.g., peanut oil, mineral oil, soybean oil, or sesame oil, or synthetic oils, may be added to the active ingredient. Saline, dextrose, or other sugar solutions, or glycols such as ethylene glycol, propylene glycol, or polyethylene glycol are also suitable liquid carriers. The pharmaceutical composition may also be in the form of an oil-in-water emulsion. The oil phase can be a vegetable oil, such as olive oil or peanut oil, a mineral oil, such as liquid paraffin, or a mixture thereof.Suitable emulsifiers include naturally occurring gums, such as gum acacia and gum tragacanth, naturally occurring phospholipids, such as soybean lecithin, esters or partial esters derived from fatty acids and hexitol anhydrides, such as sorbitan monooleate, and the condensation products of these partial esters with ethylene oxide, such as polyoxyethylene sorbitan monooleate.The emulsion can also contain colorants and flavoring agents.

[0063] In certain embodiments, silicone elastomers (e.g., dimethicone crosspolymers) are used to increase the delivery and penetration of peptides into the skin. An alternative to increasing the molecular weight (as in silicone gums) or adding fillers (as in silicone compounds) is to partially crosslink the siloxane polymer and disperse this material in a suitable silicone-carrying fluid. The resulting dimethicone crosspolymers (also known as silicone elastomers in the personal care industry) are different from basic polydimethylsiloxanes (PDMS) due to the crosslinking between linear polymers. These materials can be used in peptide formulations and also offer advantages in scar treatment, wound protection, and enzyme delivery. In skin care applications, the aesthetics of silicone elastomers (including those with functional groups) and their ability to absorb various oils (e.g., by dimethicone / vinyl dimethicone crosspolymers such as Dow Corning® 9506 Elastomer Powder) are two of the desirable properties of elastomers. Silicone elastomers have a different skin feel than any of the silicone fluids described as "smooth," "soft," and "dried." This can be altered by controlling the amount of liquid phase in the formulation, and therefore the degree of swelling. Dimethicone crosspolymers, due to their film-forming properties, can be used as a delivery system for active ingredients such as peptides described herein, or other formulation components such as oil-soluble vitamins and sunscreens. Sunscreens such as octyl methoxycinnamate may be delivered more efficiently from formulations containing silicone elastomers, resulting in higher Sun Protection Factors (SPFs). Silicone elastomer blends can be used to enhance SPF in oil-in-water formulations containing organic sunscreens. For example, in tests conducted on SPF, the addition of 4% silicone elastomer blends to a suncare formulation containing organic sunscreens increased the SPF from 5.7 to 18. This property of silicone elastomers allows for maximizing the effectiveness of sunscreens in the formulation while reducing the amount required to achieve the desired SPF.As a result, the cost of the formulation can be reduced along with potential irritation caused by the sunscreen active. Thus, a higher SPF can be achieved with the same amount of UV absorber, resulting in improved performance without adding to the cost of the formulation. Silicone elastomers can be produced from linear silicone polymers by various crosslinking reactions, for example, by hydrosilylation reactions in which vinyl groups react with silicon hydrides. A common process involves a linear silicone polymer having reactive sites along the polymer chain that react with a crosslinker. Dimethicone crosspolymers can be produced either as gels made from suspensions of swollen elastomer particles in a carrier fluid (e.g., a mixture of high molecular weight silicone elastomers in cyclopentasiloxane, such as Dow Corning® 9040 Silicone Elastomer Blend) or as spray-dried powders (dimethicone / vinyl dimethicone crosspolymers, such as Dow Corning® 9506 Elastomer Powder). A gel form with desirable attributes is cyclomethicone, but low viscosity dimethicone and organic fluids can also be used. Examples of dimethicone crosspolymers in suspension or gel form are high molecular weight silicone elastomer (12%) in decamethylcyclopentasiloxane (e.g., Dow Corning® ST-Elastomer 10) and mixtures of high molecular weight silicone elastomer in cyclopentasiloxane (e.g., Dow Corning® 9040 Silicone Elastomer Blend), which typically have an elastomer content in the range of 10% to 20% by weight.

[0064] Pharmaceutical excipients used in topical preparations of the peptide compositions may be selected from the group consisting of solvents, emollients and / or emulsifiers, oil bases, preservatives, antioxidants, tonicity modifiers, penetration enhancers and solubilizers, chelating agents, buffers, surfactants, one or more polymers, and combinations thereof.

[0065] Suitable solvents for aqueous or hydrophilic liposome compositions include water, ethyl alcohol, isopropyl alcohol, mixtures of water and ethyl and / or isopropyl alcohol, glycerin, ethylene, propylene or butylene glycol, DMSO, and mixtures thereof. In some embodiments, glycerin is provided at least 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, or more than 12%, or about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, or more than 12%. In some embodiments, glycerin is provided at least 7% or about 7%. In some embodiments, glycerin is provided in the range of about 1% to about 12%, about 2% to about 11%, or about 3% to about 10%. Suitable solvents for hydrophobic compositions include mineral oil, vegetable oil, and silicone oil. If necessary, the peptide compositions described herein may be dissolved or dispersed in a hydrophobic oil phase, and the oil phase may then be emulsified in an aqueous phase containing water, alone or in combination with lower alcohols, glycerin, and / or glycols. It is generally preferred to apply anhydrous compositions, since the presence of water can lead to irritation upon administration to skin tissues undergoing laser treatment, chemical peeling, skin ablation, and the like. Anhydrous formulations may also act to prevent the development of aqueous irritant contact dermatitis in damaged or sensitive skin, which can lead to rashes and skin irritation, and delay wound healing and improvement of skin quality. Tsai, TF, Maibach, HI How irritant is water? An overview. Contact Dermatitis 41(6)(1999):311-314 (explaining contact dermatitis caused by water as an irritant). However, in certain embodiments, it may be acceptable to provide an aqueous composition or allow a limited amount of water to be present. For example, water may be present, but in an amount below the threshold that may cause irritation when applied to damaged skin. Osmotic shock or osmotic stress is a sudden change in solute concentration surrounding a cell, causing an abrupt change in water movement across the cell membrane.Under conditions of high salt, substrate, or any solute concentration in the supernatant, water is drawn out of the cell by osmosis. This also inhibits the transport of substrates and cofactors into the cell, thus "shocking" the cell. Alternatively, at low concentrations of solutes, water enters the cell in large quantities, causing the cell to either swell and burst, or undergo apoptosis. Certain of the formulations described herein can be advantageously used when it is desired to minimize osmotic shock.

[0066] The viscosity of the composition can be maintained at a selected level using a pharma- ceutically acceptable thickening agent. Suitable viscosity enhancers or thickening agents that can be used to prepare viscous gels or creams with aqueous bases include sodium polyacrylate, xanthan gum, polyvinylpyrrolidone, acrylic acid polymers, carrageenan, hydroxyethyl cellulose, hydroxypropyl cellulose, methyl cellulose, ethyl cellulose, propyl cellulose, hydroxypropyl methyl cellulose, polyethoxylated polyacrylamides, polyethoxylated acrylates, and polyethoxylated alkanethiols. Methyl cellulose is preferred because it is readily and economically available and easy to handle. Other suitable thickening agents include, for example, xanthan gum, carboxymethyl cellulose, hydroxypropyl cellulose, carbomer, and the like. The preferred concentration of the thickening agent depends on the thickening agent selected. An amount that achieves the selected viscosity is preferably used. Viscous compositions are usually prepared from solutions by adding such thickening agents or by using a base with an acceptable level of viscosity.

[0067] Suitable emollients include hydrocarbon oils and waxes such as mineral oil, petrolatum, paraffin, ceresin, ozokerite, microcrystalline wax, polyethylene, squalene, perhydrosqualene, silicone oils, triglyceride esters, acetoglyceride esters such as acetylated monoglycerides, ethoxylated glycerides such as ethoxylated glyceryl monostearate, alkyl esters of fatty acids or dicarboxylic acids.

[0068] Suitable silicone oils for use as emollients include dimethylpolysiloxane, methyl(phenyl)polysiloxane, and water-soluble and alcohol-soluble silicone glycol copolymers.Suitable triglyceride esters for use as emollients include vegetable and animal fats and oils, including castor oil, safflower oil, cottonseed oil, corn oil, olive oil, cod liver oil, almond oil, avocado oil, coconut oil, sesame oil, and soybean oil.

[0069] Suitable esters of carboxylic acids or diacids for use as softening agents include methyl, isopropyl, and butyl esters of fatty acids.Specific examples of alkyl esters include hexyl laurate, isohexyl laurate, isohexyl palmitate, isopropyl palmitate, decyl oleate, isodecyl oleate, hexadecyl stearate, decyl stearate, isopropyl isostearate, dilauryl lactate, myristyl lactate, and cetyl lactate, and alkenyl esters of fatty acids, such as oleyl myristate, oleyl stearate, and oleyl oleate.Specific examples of dibasic acid alkyl esters include diisopropyl adipate, diisohexyl adipate, bis(hexyldecyl) adipate, and diisopropyl sebacate.

[0070] Other suitable classes of emollients or emulsifiers that can be used in the compositions include fatty acids, fatty alcohols, fatty alcohol ethers, ethoxylated fatty alcohols, fatty acid esters of ethoxylated fatty alcohols, and waxes.

[0071] Specific examples of fatty acids for use as emollients include pelargonic acid, lauric acid, myristic acid, palmitic acid, stearic acid, isostearic acid, hydroxystearic acid, oleic acid, linoleic acid, ricinoleic acid, arachidic acid, behenic acid, and erucic acid.Specific examples of fatty alcohols for use as emollients include lauryl, myristyl, cetyl, hexadecyl, stearyl, isostearyl, hydroxystearyl, oleyl, ricinoleyl, behenyl, and erucyl alcohol, and 2-octyldodecanol.

[0072] Specific examples of waxes suitable for use as emollients include lanolin and its derivatives, including lanolin oil, lanolin wax, lanolin alcohol, lanolin fatty acid, isopropyl lanolate, ethoxylated lanolin, ethoxylated lanolin alcohol, ethoxylated cholesterol, propoxylated lanolin alcohol, acetylated lanolin, acetylated lanolin alcohol, lanolin alcohol linoleate, lanolin alcohol recinolate, acetate of lanolin alcohol recinolate, acetate of lanolin alcohol recinolate, acetate of ethoxylated alcohol ester, hydrogenolysates of lanolin, hydrogenated lanolin, ethoxylated hydrogenated lanolin, ethoxylated sorbitol lanolin, and liquid and semisolid lanolin.Also usable as waxes include hydrocarbon waxes, ester waxes, and amide waxes. Useful waxes include beeswax, spermaceti, wax esters such as myristyl myristate and stearyl stearate, beeswax derivatives such as polyoxyethylene sorbitol beeswax, and vegetable waxes including carnauba and candela wax.

[0073] Polyhydric alcohols and polyether derivatives may be used as solvents and / or surfactants in the composition.Suitable polyhydric alcohols and polyethers include propylene glycol, dipropylene glycol, polypropylene glycol 2000 and 4000, poly(oxyethylene-co-oxypropylene) glycol, glycerol, sorbitol, ethoxylated sorbitol, hydroxypropyl sorbitol, polyethylene glycol 200-6000, methoxypolyethylene glycol 350, 550, 750, 2000, and 5000, poly[ethylene oxide] homopolymer (100,000-5,000,000), polyalkylene glycols and derivatives, hexylene glycol, 2-methyl-2,4-pentanediol, 1,3-butylene glycol, 1,2,6-hexanetriol, 2-ethyl-1,3-hexanediol, vicinal glycols with 15-18 carbon atoms, and polyoxypropylene derivatives of trimethylpropane.

[0074] Polyhydric alcohol esters may be used as emulsifiers or softeners.Suitable polyhydric alcohol esters include ethylene glycol mono- and di-fatty acid esters, diethylene glycol mono- and di-fatty acid esters, polyethylene glycol (200-6000) mono- and di-fatty acid esters, propylene glycol mono- and di-fatty esters, polypropylene glycol 2000 monooleate, polypropylene glycol 2000 monostearate, ethoxylated propylene glycol monostearate, glyceryl mono- and di-fatty acid esters, polyglycerol polyfatty acid esters, ethoxylated glyceryl monostearate, 1,3-butylene glycol monostearate, 1,3-butylene glycol distearate, polyoxyethylene polyol fatty acid esters, sorbitan fatty acid esters, and polyoxyethylene sorbitan fatty acid esters.

[0075] Suitable emulsifiers for use in the compositions include anionic, cationic, nonionic, and zwitterionic surfactants. Preferred ionic emulsifiers include phospholipids such as lecithin and derivatives.

[0076] For example, sterols, including cholesterol and cholesterol fatty acid esters, amides such as fatty acid amides, ethoxylated fatty acid amides, and fatty acid alkanolamides, may also be used as emollients and / or penetration enhancers.

[0077] Pharmaceutically acceptable preservatives can be used to increase the shelf life of the composition. Other suitable preservatives and / or antioxidants for use in the composition include, and can be used, benzalkonium chloride, benzyl alcohol, phenol, urea, parabens, butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), tocopherol, thimerosal, chlorobutanol, and the like, as well as mixtures thereof. When preservatives such as antioxidants are used, the concentration is typically about 0.02% to about 2% based on the total weight of the composition, although greater or lesser amounts may be desirable depending on the agent selected. The reducing agents described herein can be advantageously used to maintain good shelf life of the formulation. In general, the anhydrous formulations of the embodiments are observed to exhibit sufficient stability, so that preservatives can be omitted from the formulation.

[0078] Suitable chelating agents for use in the compositions include ethylenediaminetetraacetic acid, its alkali metal salts, its alkaline earth metal salts, its ammonium salts, and its tetraalkylammonium salts.

[0079] The carrier preferably has a pH of about 4.0 to 10.0, more preferably about 6.8 to about 7.8. The pH can be controlled using a buffer or other pH adjusting agent. Suitable pH adjusting agents include phosphoric acid and / or phosphate salts, citric acid and / or citrate salts, hydroxide salts (i.e., calcium hydroxide, sodium hydroxide, potassium hydroxide), and amines such as triethanolamine. Suitable buffers include buffers that contain solutions of monopotassium phosphate and dipotassium phosphate and maintain a pH of 5.8 to 8, and buffers that contain solutions of monosodium phosphate and disodium phosphate and maintain a pH of 6 to 7.5. Other buffers include citric acid / sodium citrate, and dibasic sodium phosphate / citric acid. The peptide composition of the embodiment is preferably isotonic with the blood or other body fluids of the recipient. The isotonicity of the composition can be achieved using sodium tartrate, propylene glycol, or other inorganic or organic solutes. Sodium chloride is particularly preferred. Buffers can be used, such as acetic acid and salts, citric acid and salts, boric acid and salts, and phosphoric acid and salts. It may be desirable to include a reducing agent in the formulation, such as vitamin C, vitamin E, or other reducing agents known in the pharmaceutical art.

[0080] Surfactants such as anionic detergents, e.g., sodium lauryl sulfate, dioctyl sodium sulfosuccinate, and dioctyl sodium sulfonate, cationic detergents, e.g., benzalkonium chloride or benzethonium chloride, or nonionic detergents, e.g., polyoxyethylene hydrogenated castor oil, glycerol monostearate, polysorbates, sucrose fatty acid esters, methylcellulose, or carboxymethylcellulose, can be used as excipients.

[0081] In certain embodiments, it may be advantageous to include additional agents with pharmacological activity. Anti-infectives include anthelmintics (mebendazole), antibiotics including aminoglycosides (gentamicin, neomycin, tobramycin), antifungal antibiotics (amphotericin b, fluconazole, griseofulvin, itraconazole, ketoconazole, nystatin, micatin, tolnaftate), cephalosporins (cefachlor, cefazolin, cefotaxime, ceftazidime, ceftriaxone, cefuroxime, cephalexin), beta-lactam antibiotics (cefotetan, meropenem), chloramphenicol, macrolides (azithromycin, clarithromycin, erythromycin), penicillins (penicillin G sodium salt, amoxicillin, ampicillin, dicloxacillin, nafcillin, piperacillin, thiamine, thiamine), thiamine, ... calcillin), tetracyclines (doxycycline, minocycline, tetracycline), bacitracin, clindamycin, colistimethate sodium, polymyxin b sulfate, vancomycin, antibacterial agents (including acyclovir, amantadine, didanosine, efavirenz, foscarnet, ganciclovir, indinavir, lamivudine, nelfinavir, ritonavir, saquinavir, stavudine, valacyclovir, valganciclovir, zidovudine), quinolones (ciprofloxacin, levofloxacin), sulfonamides (sulfadiazine, sulfisoxazole), sulfones (dapsone), furazolidone, metronidazole, pentamidine, sulfanilamidum crystallinum, gatifloxacin, and sulfamethoxazole / trimethoprim.Anesthetics may include, but are not limited to, ethanol, bupivacaine, chloroprocaine, levobupivacaine, lidocaine, mepivacaine, procaine, ropivacaine, tetracaine, desflurane, isoflurane, ketamine, propofol, sevoflurane, codeine, fentanyl, hydromorphone, marcaine, meperidine, methadone, morphine, oxycodone, remifentanil, sufentanil, butorphanol, nalbuphine, tramadol, benzocaine, dibucaine, ethyl chloride, xylocaine, and phenazopyridine. Anti-inflammatory agents include nonsteroidal anti-inflammatory drugs (NSAIDs) such as aspirin, celecoxib, choline magnesium trisalicylate, diclofenac potassium, diclofenac sodium, diflunisal, etodolac, fenoprofen, flurbiprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, melenamic acid, nabumetone, naproxen, naproxen sodium, oxaprozin, piroxicam, rofecoxib, salsalate, sulindac, and tolmetin, and corticosteroids, Examples include, but are not limited to, cortisone, hydrocortisone, methylprednisolone, prednisone, prednisolone, betamethasone, beclomethasone dipropionate, budesonide, dexamethasone sodium phosphate, flunisolide, fluticasone propionate, triamcinolone acetonide, betamethasone, fluocinonide, betamethasone dipropionate, betamethasone valerate, desonide, desoximetasone, fluocinolone, triamcinolone, clobetasol propionate, and dexamethasone.

[0082] In certain embodiments, the addition of emollients, emulsion stabilizers, humectants, excipients, and other compounds may be modified to enhance the sensory properties of the topical composition, including, but not limited to, skin feel (silky softness, lightness, creaminess, etc.), absorbency (the time required for the product to lose its moist feel and become undetectable on the skin), consistency, hardness, spreadability (e.g., viscosity, onset of flow, shear rate), adhesion, shape integrity, gloss, hydrophilicity or hydrophobicity, etc. Preferably, the composition has high spreadability and low viscosity properties. Compositions with such properties have been shown to have enhanced "silky" or "light" skin feel ratings (see, e.g., Bekker, M. Webber, G., Louw, N. Relating rheological measurements to primary and secondary skin feeling when mineral-based and Fischer-Tropsch wax-based cosmetic emulsions and jellies are applied to the skin, International Journal of Cosmetic Science 2013, 35(4), pp. 354-61).

[0083] therapeutic use The methods and compositions described herein for targeting dermal white adipose tissue (dWAT) may result in stimulation or regeneration of hair follicles. In some cases, the methods and compositions described herein promote hair growth. In some cases, the methods and compositions described herein reduce or prevent alopecia.

[0084] Alopecia can include various types of hair loss. In some cases, the hair loss is male or female pattern hair loss, alopecia areata, telogenic alopecia, anagenic alopecia, or a combination thereof. In some cases, the hair loss is caused by an infection. Exemplary infections that cause hair loss include, but are not limited to, dissecting cellulitis, fungal infections (e.g., tinea capitis), folliculitis, secondary syphilis, and demodex folliculorum. In some cases, the hair loss is caused by a drug or medicine (e.g., chemotherapy). In some cases, the hair loss is caused by trauma, including, but not limited to, traction alopecia, frictional alopecia, trichotillomania, radiation therapy, chemotherapy, and surgery. In some cases, the hair loss is caused by a disease or disorder. In some cases, the hair loss is caused by mucinous alopecia, biotinidase deficiency, chronic inflammation, diabetes, lupus erythematosus, cicatricial alopecia, telogenic alopecia, tufted folliculitis, and genetic characteristics.

[0085] In some embodiments, the methods and compositions described herein are used in conjunction with hair loss treatment. In some embodiments, the hair loss treatment is non-invasive. In some cases, the hair loss treatment is invasive. In some cases, the hair loss treatment includes topical administration of a drug. In some cases, the hair loss treatment includes ingestion of a drug. In some cases, the hair loss treatment includes hair transplant surgery, scalp reduction, or a combination thereof. Exemplary hair transplant surgeries include, but are not limited to, micrografts, slit grafts, and punch grafts. In some cases, the hair loss treatment includes the use of platelet-rich plasma.

[0086] In some cases, the compositions described herein are administered once a day, twice a day, three times a day or more. In some embodiments, the compositions described herein are administered daily, every day, every other day, five days a week, once a week, every other week, two weeks a month, three weeks a month, once a month, twice a month, three times a month or more. In some embodiments, the compositions described herein are administered twice a day, for example, in the morning and in the evening. In some embodiments, the liposomal compositions described herein are administered for at least 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 1 week, 2 weeks, 3 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, 18 months, 2 years, 3 years, 4 years, 5 years, 10 years or more.

[0087] In some cases, the compositions described herein are administered to the site of hair loss. In some cases, the compositions described herein are administered to the site to prevent hair loss. Hair loss can occur on any part of the body. In some cases, the compositions described herein are administered to the site to promote hair growth.

[0088] The compositions described herein can be used before hair loss treatment.In some cases, the compositions described herein are administered up to 1 day, up to 2 days, up to 3 days, up to 5 days, or more than 5 days before hair loss treatment.In some cases, the compositions described herein are administered once or over a period of time such as daily, multiple times a week, weekly, once every two weeks, monthly, or less frequently before hair loss treatment.In some cases, the compositions described herein are administered once or over a period of time such as daily, multiple times a week, weekly, once every two weeks, monthly, or less frequently before hair loss treatment.

[0089] The compositions described herein may be administered during hair loss treatment.

[0090] The compositions described herein can be administered after hair loss treatment.In some cases, the compositions described herein are administered after hair loss treatment for up to 1 day, up to 2 days, up to 3 days, up to 5 days, or more than 5 days.In some cases, the compositions described herein are administered after hair loss treatment, either once or over a period of time, such as daily, multiple times per week, weekly, once every two weeks, monthly, or less frequently.In some cases, the compositions described herein are administered after hair loss treatment, either once or over a period of time, such as daily, multiple times per week, weekly, once every two weeks, monthly, or less frequently.

[0091] Stability testing Stability testing of the compositions can be carried out as follows.

[0092] High temperature testing is now commonly used as a predictor of long term stability. High temperature testing can be performed at 37°C (98°F) and 45°C (113°F). If the product is stored at 45°C for 3 months (and shows acceptable stability), it should be stable at room temperature for 2 years. A good controlled temperature is 4°C (39°F), with most products showing excellent stability. In some cases, the product is also subjected to -10°C (14°F) for 3 months.

[0093] In some cases, the stability of the product is evaluated by undergoing three cycles of temperature testing from -10°C (14°F) to 25°C (77°F). In such cases, the product is placed at -10°C for 24 hours, then placed at room temperature (25°C) for 24 hours. This completes one cycle. An even more stringent test is a five cycle test from -10°C to 45°C, which places a great deal of stress on the emulsion.

[0094] The dispersed phase (of an oil-in-water emulsion) tends to separate and rise to the top of the emulsion, forming a layer of oil droplets. This phenomenon is called creaming. Creaming is one of the first signs of approaching emulsion instability. A test method to predict creaming is centrifugation. The emulsion is heated to 50°C (122°F) and centrifuged at 3000 rpm for 30 minutes. The resulting product is then inspected for signs of creaming.

[0095] Both the formulation and the packaging may be sensitive to UV light. The product is placed in a glass and the actual packaging is placed in a light box with broad spectrum output. Another glass bottle completely covered in aluminum foil acts as a control. Discoloration of the product can be observed.

[0096] For all the above tests, color, odor / scent, viscosity, pH value, and, if available, particle size uniformity and / or particle agglomeration under a microscope may be observed.

[0097] Embodiment Numbered embodiment 1 is a composition for targeting dermal white adipose tissue (dWAT) to stimulate or regenerate hair follicles, comprising: (a) tripeptide-1, (b) hexapeptide-12, (c) PPAR-gamma agonist and Including, Stimulate or regenerate hair follicles, The composition includes: Numbered embodiment 2 includes the composition of numbered embodiment 1, wherein tripeptide-1 comprises palmitoyl tripeptide-1, myristoyl tripeptide-1, or a combination thereof. Numbered Embodiment 3 includes the composition of numbered embodiment 1, wherein the hexapeptide-12 comprises palmitoyl hexapeptide-12, myristoyl hexapeptide-12, or a combination thereof. Numbered Embodiment 4 includes the composition of numbered embodiment 1, further comprising hexapeptide-38. Numbered Embodiment 5 includes the composition of numbered embodiment 4, wherein the hexapeptide-38 is acetyl-hexapeptide-38. Numbered Embodiment 6 includes the composition of numbered embodiment 5, wherein the hexapeptide-38 is encapsulated in a liposome. Numbered embodiment 7 comprises the composition of numbered embodiment 1, further comprising an octapeptide. Numbered embodiment 8 includes the compositions of numbered embodiment 1, wherein the PPAR-gamma agonist is a thiazolidinedione (TZD), aleglitazar, farglitazar, muraglitazar, tesaglitazar, or a combination thereof. Numbered embodiment 9 includes the composition of numbered embodiment 1, wherein the PPAR-gamma agonist is derived from a plant source. Numbered embodiment 10 includes the composition of numbered embodiment 1, wherein the PPAR-gamma agonist is a natural product. Numbered embodiment 11 includes the composition of numbered embodiment 1, further comprising an M2-macrophage polarizing compound. Numbered embodiment 12 includes the composition of numbered embodiment 11, wherein the M2-macrophage polarizing compound is a flavonoid, terpenoid, glycoside, lignan, coumarin, alkaloid, polyphenol, quinone, or combinations thereof. Numbered embodiment 13 includes the composition of numbered embodiment 11, wherein the M2-macrophage polarizing compound is arctigenin. Numbered embodiment 14 includes the composition of numbered embodiment 11, wherein the M2-macrophage polarizing compound is lupeol, marivatol A, geraniin, aloe-emodin, quercetin, curcumin, apigenin, tacrolimus, or niacinamide, or a combination thereof. Numbered embodiment 15 includes the composition of numbered embodiment 11, wherein the M2-macrophage polarizing compound is derived from a plant source. Numbered embodiment 16 includes the composition of numbered embodiment 15, wherein the botanical source is Arctium lappa plant, curcumin, luteolin, piperine, resveratrol, silibinum, baicalin, or combinations thereof. Numbered embodiment 17 comprises the composition of numbered embodiment 1, further comprising a local activator of insulin growth factor 1 (IGF-1). Numbered embodiment 18 includes the composition of numbered embodiment 17, wherein the local activator of insulin growth factor 1 (IGF-1) is capsaicin, an isoflavone, or a combination thereof. Numbered embodiment 19 includes the composition of numbered embodiment 17, wherein the local activator of insulin growth factor 1 (IGF-1) is capsaicin. Numbered embodiment 20 includes the composition of numbered embodiment 1, further comprising an activator of PGC-1α. Numbered embodiment 21 includes the composition of claim 1, wherein the PPAR-gamma agonist comprises adiponectin or an adiponectin mimetic. Numbered embodiment 22 includes the composition of claim 21, wherein the adiponectin mimetic comprises AdipoRon, ADP355, ADP399, JT003, 6-C-β-D-glucopyranosyl-(2S,3S)-(+)-5,7,30,40-tetrahydroxydihydroflavonol (GTDF), osmotin, or a combination thereof. Numbered embodiment 23 includes the composition of claim 1, further comprising a Jak-STAT inhibitor. Numbered embodiment 24 includes the composition of claim 23, wherein the Jak-STAT inhibitor comprises ruxolitinib, tofacitinib, or a combination thereof. Numbered embodiment 25 includes a method for stimulating or regenerating hair follicles comprising administering the composition of numbered embodiment 1. Numbered embodiment 26 includes the method of numbered embodiment 25 for stimulating hair growth. Numbered embodiment 27 includes a method for preventing or reducing hair loss comprising administering the composition of numbered embodiment 1.

Claims

1. Tripeptide-1, Hexapeptide-12, PPAR-gamma agonists and A composition comprising:

2. 2. The composition of claim 1, wherein the tripeptide-1 comprises palmitoyl tripeptide-1, myristoyl tripeptide-1, or a combination thereof.

3. 3. The composition of claim 1 or 2, wherein the hexapeptide-12 comprises palmitoyl hexapeptide-12, myristoyl hexapeptide-12, or a combination thereof.

4. The composition of any one of claims 1 to 3, further comprising hexapeptide-38 or hexapeptide-11.

5. The composition of any one of claims 1 to 4, wherein the PPAR-gamma agonist comprises a thiazolidinedione (TZD), aleglitazar, farglitazar, muraglitazar, tesaglitazar, pioglitazone, rosiglitazone, rivoglitazone, troglitazone, or a combination thereof.

6. 6. The composition of any one of claims 1 to 5, wherein the PPAR-gamma agonist comprises adiponectin or an adiponectin mimetic, the adiponectin mimetic comprising one or more selected from the group consisting of AdipoRon, ADP355, ADP399, JT003, 6-C-β-D-glucopyranosyl-(2S,3S)-(+)-5,7,30,40-tetrahydroxydihydroflavonol (GTDF), and osmotin.

7. 7. The composition of any one of claims 1 to 6, further comprising an M2-macrophage polarizing compound selected from the group consisting of flavonoids, terpenoids, glycosides, lignans, coumarins, alkaloids, polyphenols, quinones, or combinations thereof.

8. 8. The composition of any one of claims 1 to 7, further comprising one or more M2-macrophage polarizing compounds selected from the group consisting of arctigenin, lupeol, marivatol A, geraniin, aloe-emodin, quercetin, curcumin, apigenin, tacrolimus, and niacinamide, luteolin, piperine, resveratrol, silibinum, and baicalin.

9. The composition according to any one of claims 1 to 8, further comprising a local activator of insulin growth factor 1 (IGF-1).

10. The composition according to any one of claims 1 to 9, further comprising an activator of PGC-1α.

11. The composition of any one of claims 1 to 10, further comprising a Jak-STAT inhibitor.

12. The composition of claim 11, wherein the Jak-STAT inhibitor comprises ruxolitinib, tofacitinib, or a combination thereof.

13. 13. The composition of any one of claims 1 to 12, further comprising L-carnitine, melatonin, Prunus mira Koehne nut oil, red ginseng oil, loliolide, hexapeptide-11, alpha-ketobutyrate (alpha-KB), alpha-ketoglutarate (alpha-KG), 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR), metformin, oligomycin, rapamycin, vitamin D, capsaicin, isoflavones, vascular endothelial growth factor (VEGF), TGF-β, or a combination thereof.

14. A composition according to any one of claims 1 to 13 for stimulating or regenerating hair follicles or for preventing or reducing hair loss.

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