Brightening compositions and methods of use

Abstract

Disclosed herein are compositions and methods for improving pigmentation. The compositions described herein comprise one or more peptides.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Patent Application No. 63 / 249,477, filed September 28, 2021, the entire contents of which are incorporated herein by reference. [Background technology]

[0002] background Skin, hair, and eye color are due to melanin produced in melanosomes. The amount of melanin produced in a given individual varies based on multiple genetic and environmental factors, including exposure to ultraviolet light. Overproduction of melanin in the skin causes hyperpigmentation, which can lead to melasma, freckles, and age spots. Therefore, understanding the regulation of melanin production and its underlying mechanisms is important in identifying targets for the prevention and treatment of pigmentation disorders. Summary of the Invention

[0003] Quick Overview Disclosed herein are compositions and methods for regulating pigmentation.In some cases, the compositions and methods described herein reduce melanocyte activation, inhibit melanin synthesis, reduce melanin transfer, cause the exfoliation of keratinocytes containing melanosomes or the autophagy of melanosomes, or combinations thereof.

[0004] An embodiment described herein is a topical composition for improving pigmentation, comprising one or more dipeptides, hexapeptide-11, and hexapeptide-12, wherein the topical composition improves pigmentation. In one feature, the topical composition further comprises one or more photosomes. In one feature, the one or more photosomes are present in a range of about 0.1 wt.% to about 2 wt.%. In one feature, the one or more photosomes are present in a range of about 0.25 wt.% to about 1 wt.%. In one feature, the topical composition further comprises one or more liposomes. In one feature, the one or more photosomes encapsulate one or more liposomes. In one feature, the one or more dipeptides are dipeptide-51. In one feature, the one or more dipeptides are dipeptide-12. In one feature, the one or more dipeptides include dipeptide-51 and dipeptide-12. In one feature, hexapeptide-11 is present at 50-150 ppm. In one feature, hexapeptide-11 is present in the range of about 0.004 weight percent (wt.%) to about 0.100 wt.%. In one feature, hexapeptide-11 is encapsulated in a first liposome of the one or more liposomes. In one feature, hexapeptide-12 is encapsulated in a second liposome of the one or more liposomes. In one feature, hexapeptide-11 and hexapeptide-12 are encapsulated in a first liposome of the one or more liposomes. In one feature, hexapeptide-12 includes palmitoyl hexapeptide-12, myristoyl hexapeptide-12, or a combination thereof. In one feature, hexapeptide-12 is present at 1-10 ppm. In one feature, hexapeptide-12 is present in a range of about 0.001 weight percent (wt.%) to about 0.025 wt.%. In one feature, the topical composition further comprises lactoferrin. In one feature, the lactoferrin is present at about 0.25 wt.% or less. In one feature, the lactoferrin is present at about 0.005 wt.% to about 0.25 wt.%. In one feature, the lactoferrin is encapsulated in a third liposome of the one or more liposomes.In one feature, the topical composition further comprises lactoferrin, and the lactoferrin, hexapeptide-11, and hexapeptide-12 are encapsulated in a first liposome of the one or more liposomes. In one feature, the topical composition further comprises phosphatidylserine. In one feature, the phosphatidylserine is present at about 0.075 wt.% or less. In one feature, the phosphatidylserine is present in a range of about 0.005 wt.% to about 0.1 wt.%. In one feature, the phosphatidylserine is present at 5.0 wt.% or less. In one feature, the topical composition further comprises silymarin, milk thistle (Silybum marianum) extract, or a derivative thereof. In one feature, the silymarin, milk thistle extract, or a derivative thereof is present in a range of about 0.1 wt.% to about 1.0 wt.%. In one feature, silymarin, milk thistle extract, or derivatives thereof are present in the range of about 0.2 wt.% to about 3.0 wt.%. In one feature, silymarin, milk thistle extract, or derivatives thereof are provided in one or more liposomes or one or more photosomes. In one feature, the topical composition further comprises sesamol. In one feature, sesamol is present in the range of about 0.002 wt.% to about 0.050 wt.%. In one feature, the topical composition further comprises tranexamic acid. In one feature, tranexamic acid is provided in one or more liposomes or one or more photosomes. In one feature, tranexamic acid is present in the range of about 1 wt.% to about 10 wt.%. In one feature, tranexamic acid is present in the range of about 0.25 wt.% to about 6.25 wt.%. In one aspect, the topical composition further comprises squalane, Dunaliella salina extract, or a combination thereof. In one aspect, the squalane, Dunaliella salina extract, or a combination thereof is present in a range of about 1 wt.% to about 10 wt.%. In one aspect, the topical composition further comprises Ashwagandha (Withania somnifera) extract. In one aspect, the Ashwagandha extract is present in a range of about 0.020 wt.% to about 0.500 wt.%.In one aspect, the Ashwagandha extract is present in the range of about 0.50 wt.% to about 2.5 wt.%. In one aspect, the topical composition further comprises gallic acid. In one aspect, the gallic acid is diglucosyl gallic acid. In one aspect, the gallic acid is present in the range of about 0.40 wt.% to about 10 wt.%. In one aspect, the topical composition further comprises hesperidin. In one aspect, the hesperidin is glucosyl hesperidin. In one aspect, the hesperidin is present in the range of about 0.020 wt.% to about 0.50 wt.%. In one aspect, the topical composition further comprises Pancratium maritimum. In one aspect, the Pancratium maritimum is present in a range of about 0.50 wt.% to about 5.0 wt.%. In one aspect, the topical composition further comprises niacinamide. In one aspect, the niacinamide is present in a range of about 1 wt.% to about 10 wt.%. In one aspect, the topical composition further comprises Thermus thermophilus ferment. In one aspect, the Thermus thermophilus ferment is present in a range of about 0.01 wt.% to about 7.5 wt.%, about 0.05 wt.% to about 7.5 wt.%, or about 0.10 wt.% to about 7.5 wt.%, e.g., about 0.20 wt.% to 7.5 wt.%, or 0.3 wt.% to 7.5 wt.%. In one feature, the topical composition further comprises Tremella fuciformis. In one feature, the Tremella fuciformis is present in the range of about 0.20 wt.% to about 5.0 wt.%. In one feature, the topical composition further comprises phenoxyethanol, ethylhexylglycerin, caprylyl glycol, caprylhydroxamic acid, glycerin, lecithin, carnosine, tocopherol, phenoxyethanol, betaine, 1,2-hexanediol, plankton extract, fructose, sodium acrylates copolymer, dimethicone, caprylyl methicone, propanediol, or combinations thereof. In one feature, the topical composition is aqueous.

[0005] An embodiment described herein is a method of improving pigmentation as a result of a pigmentation disorder or disease comprising administering a topical composition described herein. In one aspect, the pigmentation disorder or disease is hyperpigmentation. In one aspect, the pigmentation disorder or disease is post-inflammatory hyperpigmentation (PIH). In one aspect, the pigmentation disorder or disease is focal hypopigmentation or diffuse hypopigmentation. In one aspect, the pigmentation disorder or disease is acanthosis nigricans, senile lentigines, albinism, incontinentia pigmenti, lentigines, melasma, pityriasis alba, or progressive pigmented purpura.

[0006] 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]

[0007] [Figure 1] Factors that affect pigmentation, as well as strategies and agents that can be used to treat pigmentation diseases or disorders are presented. [Diagram 2] The effect of exogenous influences on different pigmentation pathways is shown. The abbreviations listed are as follows: for surface receptors on melanocytes: EDNRB = endothelin receptor B, MC1R = melanocortin-1 receptor-agonist αMSH, Wnt pathway, SCF = stem cell factor; for cytokines and mediators in keratinocytes and fibroblasts: PLA = phospholipase A, AA = arachidonic acid, PGE2 = prostaglandin E2, bFGF = basic fibroblast growth factor, ET-1 = endothelin-1, αMSH = alpha melanocyte stimulating hormone, NO = nitric oxide, plasmin, COX2, IL-1, histamine, MMP; for enzymes and transcription factors in melanocytes: MITF = microphthalmia-associated transcription factor, TYR = tyrosinase, TRP-2 = tyrosinase-related protein 2, TRP-1 = tyrosinase-related protein 1. [Figure 3A]1 shows the expression levels of MEK in melanocytes after treatment with lactoferrin (Lacto), peptide derived from lactoferrin (TCV), hexapeptide-12 (Hex12), tripeptide-1 and hexapeptide-12 (TriHex), hexapeptide-11 (Hex11), tranexamic acid (Tran acid), octapeptide (Octa), phosphatidylserine (phos), cannabidiol (CBD), and all (All). [Figure 3B] FIG. 1 shows the expression levels of ERK in melanocytes after treatment with lactoferrin (Lacto), peptide derived from lactoferrin (TCV), hexapeptide-12 (Hex12), tripeptide-1 and hexapeptide-12 (TriHex), hexapeptide-11 (Hex11), tranexamic acid (Tran acid), octapeptide (Octa), phosphatidylserine (phos), cannabidiol (CBD), and all (All). [Figure 3C] POMC expression levels in melanocytes after treatment with lactoferrin (Lacto), peptide derived from lactoferrin (TCV), hexapeptide-12 (Hex12), tripeptide-1 and hexapeptide-12 (TriHex), hexapeptide-11 (Hex11), tranexamic acid (Tran acid), octapeptide (Octa), phosphatidylserine (phos), cannabidiol (CBD), and all (All). [Figure 3D] 1 shows expression levels of CTNNB1 in melanocytes after treatment with lactoferrin (Lacto), peptide derived from lactoferrin (TCV), hexapeptide-12 (Hex12), tripeptide-1 and hexapeptide-12 (TriHex), hexapeptide-11 (Hex11), tranexamic acid (Tran acid), octapeptide (Octa), phosphatidylserine (phos), cannabidiol (CBD), and all (All). [Figure 4] FIG. 1 shows the expression of various genes following treatment of melanocytes with hexapeptide-12 (Hex-12). [Diagram 5]FIG. 1 shows the expression of various genes following treatment of melanocytes with lactoferrin (Lacto). [Figure 6A] FIG. 1 shows expression of SCF in keratinocytes after treatment with lactoferrin (Lacto), peptide derived from lactoferrin (TCV), tripeptide-1 (Tri), hexapeptide-12 (Hex12), tripeptide-1 and hexapeptide-12 (TriHex), hexapeptide-11 (Hex11), tranexamic acid (Tran acid), octapeptide (Octa), phosphatidylserine (phos), cannabidiol (CBD), and all (All). [Figure 6B] FIG. 1 shows expression of LIF in keratinocytes after treatment with lactoferrin (Lacto), a peptide derived from lactoferrin (TCV), tripeptide-1 (Tri), hexapeptide-12 (Hex12), tripeptide-1 and hexapeptide-12 (TriHex), hexapeptide-11 (Hex11), tranexamic acid (Tran acid), octapeptide (Octa), phosphatidylserine (phos), cannabidiol (CBD), and all (All). [Figure 6C] POMC expression in keratinocytes after treatment with lactoferrin (Lacto), peptide derived from lactoferrin (TCV), tripeptide-1 (Tri), hexapeptide-12 (Hex12), tripeptide-1 and hexapeptide-12 (TriHex), hexapeptide-11 (Hex11), tranexamic acid (Tran acid), octapeptide (Octa), phosphatidylserine (phos), cannabidiol (CBD), and all (All). [Figure 6D]Figure 1 shows endothelin gene expression in keratinocytes after treatment with lactoferrin (Lacto), lactoferrin derived peptide (TCV), tripeptide-1 (Tri), hexapeptide-12 (Hex12), tripeptide-1 and hexapeptide-12 (TriHex), hexapeptide-11 (Hex11), tranexamic acid (Tran acid), octapeptide (Octa), phosphatidylserine (phos), cannabidiol (CBD), and all (All). [Figure 6E] FIG. 1 shows expression of PGE2 in keratinocytes after treatment with lactoferrin (Lacto), peptide derived from lactoferrin (TCV), tripeptide-1 (Tri), hexapeptide-12 (Hex12), tripeptide-1 and hexapeptide-12 (TriHex), hexapeptide-11 (Hex11), tranexamic acid (Tran acid), octapeptide (Octa), phosphatidylserine (phos), cannabidiol (CBD), and all (All). [Figure 6F] Figure 1 shows expression of NGF in keratinocytes after treatment with lactoferrin (Lacto), peptide derived from lactoferrin (TCV), tripeptide-1 (Tri), hexapeptide-12 (Hex12), tripeptide-1 and hexapeptide-12 (TriHex), hexapeptide-11 (Hex11), tranexamic acid (Tran acid), octapeptide (Octa), phosphatidylserine (phos), cannabidiol (CBD), and all (All). [Figure 7] Individual hexapeptide-11 (Hex-11) activities for various genes are shown. [Figure 8A] 1 shows expression of EDN1 following treatment of endothelial cells with lactoferrin (Lacto), a peptide derived from lactoferrin (TCV), hexapeptide-12 (Hex12), tripeptide-1 and hexapeptide-12 (TriHex), hexapeptide-11 (Hex11), tranexamic acid (Tran acid), octapeptide (Octa), phosphatidylserine (phos), cannabidiol (CBD), and all (All). [Figure 8B] FIG. 1 shows the expression of SCF following treatment of endothelial cells with lactoferrin (Lacto), a peptide derived from lactoferrin (TCV), hexapeptide-12 (Hex12), tripeptide-1 and hexapeptide-12 (TriHex), hexapeptide-11 (Hex11), tranexamic acid (Tran acid), octapeptide (Octa), phosphatidylserine (phos), cannabidiol (CBD), and all (All). [Figure 8C] FIG. 1 shows expression of TGFB1 following treatment of endothelial cells with lactoferrin (Lacto), a peptide derived from lactoferrin (TCV), hexapeptide-12 (Hex12), tripeptide-1 and hexapeptide-12 (TriHex), hexapeptide-11 (Hex11), tranexamic acid (Tran acid), octapeptide (Octa), phosphatidylserine (phos), cannabidiol (CBD), and all (All). [Figure 9] Figure 1 shows the individual phosphatidylserine activities towards EDN1 and other melanogenic genes. [Figure 10A] 1 shows expression of PMEL following treatment of endothelial cells with lactoferrin (Lacto), a peptide derived from lactoferrin (TCV), hexapeptide-12 (Hex12), tripeptide-1 and hexapeptide-12 (TriHex), hexapeptide-11 (Hex11), tranexamic acid (Tran acid), octapeptide (Octa), phosphatidylserine (phos), cannabidiol (CBD), and all (All). [Figure 10B] Figure 1 shows tyrosinase gene expression following treatment of endothelial cells with lactoferrin (Lacto), peptide derived from lactoferrin (TCV), hexapeptide-12 (Hex12), tripeptide-1 and hexapeptide-12 (TriHex), hexapeptide-11 (Hex11), tranexamic acid (Tran acid), octapeptide (Octa), phosphatidylserine (phos), cannabidiol (CBD), and all (All). [Figure 10C]FIG. 1 shows expression of MC1 / 4R following treatment of endothelial cells with lactoferrin (Lacto), a peptide derived from lactoferrin (TCV), hexapeptide-12 (Hex12), tripeptide-1 and hexapeptide-12 (TriHex), hexapeptide-11 (Hex11), tranexamic acid (Tran acid), octapeptide (Octa), phosphatidylserine (phos), cannabidiol (CBD), and all (All). [Figure 10D] 1 shows expression of EDNRB following treatment of endothelial cells with lactoferrin (Lacto), peptide derived from lactoferrin (TCV), hexapeptide-12 (Hex12), tripeptide-1 and hexapeptide-12 (TriHex), hexapeptide-11 (Hex11), tranexamic acid (Tran acid), octapeptide (Octa), phosphatidylserine (phos), cannabidiol (CBD), and all (All). [Figure 11] 1 shows the expression of MITF following treatment of endothelial cells with lactoferrin (Lacto), a peptide derived from lactoferrin (TCV), hexapeptide-12 (Hex12), tripeptide-1 and hexapeptide-12 (TriHex), hexapeptide-11 (Hex11), tranexamic acid (Tran acid), octapeptide (Octa), phosphatidylserine (phos), cannabidiol (CBD), and all (All). [Figure 12A] FIG. 1 shows expression of ERK1 / 2 (MAPK3 / MAPK1) following treatment of endothelial cells with lactoferrin (Lacto), a peptide derived from lactoferrin (TCV), hexapeptide-12 (Hex12), tripeptide-1 and hexapeptide-12 (TriHex), hexapeptide-11 (Hex11), octapeptide (Octa), phosphatidylserine (phos), cannabidiol (CBD), and all (All). [Figure 12B]1 shows the expression of JNK following treatment of endothelial cells with lactoferrin (Lacto), a peptide derived from lactoferrin (TCV), hexapeptide-12 (Hex12), tripeptide-1 and hexapeptide-12 (TriHex), hexapeptide-11 (Hex11), octapeptide (Octa), phosphatidylserine (phos), cannabidiol (CBD), and all (All). [Figure 12C] AKT1 expression after treatment of endothelial cells with lactoferrin (Lacto), a peptide derived from lactoferrin (TCV), hexapeptide-12 (Hex12), tripeptide-1 and hexapeptide-12 (TriHex), hexapeptide-11 (Hex11), octapeptide (Octa), phosphatidylserine (phos), cannabidiol (CBD), and all (All). [Figure 13] 1 shows a modified mMASI scoring rubric for assessing the efficacy of test products according to the present disclosure. [Figure 14A] Clinical photographs at baseline and 12 weeks are shown for a study subject who started on study with severe hyperpigmentation and was treated with test product (A, B) and HQ 4% (C), a subject who started on study with moderate hyperpigmentation and was treated with test product (D, E) and HQ 4% (F), and a subject who started on study with mild hyperpigmentation and was treated with test product (G) and HQ 4% (H). [Figure 14B] See legend to Figure 14A. [Figure 14C] See legend to Figure 14A. [Figure 14D] See legend to Figure 14A. [Figure 14E] See legend to Figure 14A. [Figure 14F] See legend to Figure 14A. [Figure 14G] See legend to Figure 14A. [Figure 14H] See legend to Figure 14A. [Figure 15]Clinical photographs of subjects undergoing long-term treatment (up to 5 months) with the test product are presented, demonstrating the long-term effectiveness of the test product in reducing hyperpigmentation. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0008] 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.

[0009] 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.

[0010] 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.

[0011] composition peptide The compositions described herein include one or more peptides. In some embodiments, the one or more peptides described herein improve pigmentation, including hyperpigmentation. In some embodiments, the one or more peptides regulate post-inflammatory hyperpigmentation, melasma, or aging. In some embodiments, aging hyperpigmentation is caused by UV exposure or inflammation.

[0012] In some embodiments, the one or more peptides include hexapeptide-11. In some embodiments, hexapeptide-11 promotes activation of proteasome, autophagy, chaperone, and antioxidant response related genes. In some embodiments, the one or more peptides include hexapeptide-11, tripeptide-1, and hexapeptide-12.

[0013] In some embodiments, hexapeptide-11, tripeptide-1, and hexapeptide-12 provide a synergistic effect on gene expression. In some cases, hexapeptide-11, tripeptide-1, and hexapeptide-12 regulate MITF gene expression. In some cases, hexapeptide-11, tripeptide-1, and hexapeptide-12 increase MITF downregulation by at least or about 0.5, 1, 2, 3, 4, 5, or more than 5 fold compared to hexapeptide-11, tripeptide-1, and hexapeptide-12 individually.

[0014] The peptides described herein, in some embodiments, in combination, improve pigmentation, autophagy of melanosomes, reduction of MITF, or a combination thereof. For example, tripeptide-1 and hexapeptide-12 improve macrophage function. In some embodiments, tripeptide-1 and hexapeptide-11 improve macrophage function. In some embodiments, tripeptide-1, hexapeptide-11, and hexapeptide-12 improve macrophage function. For example, hexapeptide-11 combined with one or more different peptides, such as tripeptide-1, hexapeptide-12, or a combination thereof, can stimulate autophagy and macrophage cluster formation and improve melanosome removal.

[0015] The compositions described herein include varying concentrations of peptides. In some cases, the peptides are present at about 50 ppm or less to 1000, 5000, 10000, 50000, 100000, 500000 ppm or more, for example, 100 ppm of peptide. In some cases, the peptides are present at about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 50, 75, 100, 200, 300, 400, 500, 600, 700, 800, 900, 1000, or more than 1000 ppm. In some cases, the peptide is present in the range of about 1 to about 100, about 1 to about 50, about 1 to about 40, about 1 to about 30, about 1 to about 20, about 1 to about 10, about 5 to about 90, about 10 to about 80, about 20 to about 60, or about 30 to about 50 ppm. In some cases, the peptide is present at about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 50, 75, 100, 200, 300, 400, 500, 600, 700, 800, 900, 1000, or greater than 1000 micrograms per milliliter (ug / mL). In some cases, the peptide is present in the range of about 1 to about 100, about 1 to about 50, about 1 to about 40, about 1 to about 30, about 1 to about 20, about 1 to about 10, about 5 to about 90, about 10 to about 80, about 20 to about 60, or about 30 to about 50 micrograms per milliliter. In some cases, the peptide is present in about 0.01% to about 10% by weight, about 0.01% to about 0.02% by weight, about 0.01% to about 0.03% by weight, about 0.01% to about 0.04% by weight, about 0.01% to about 0.05% by weight, about 0.01% to about 0.1% by weight, about 1% to about 5% by weight, or about 1% to about 10% by weight (wt.%).

[0016] The compositions described herein, in some embodiments, comprise one or more peptides. In some cases, a peptide of the one or more peptides is present at 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. In some cases, a peptide of the one or more peptides is present at about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 50, 75, 100, 200, 300, 400, 500, 600, 700, 800, 900, 1000, or more than 1000 ppm. In some cases, a peptide of the one or more peptides is present in a range of about 1 to about 100, about 1 to about 50, about 1 to about 40, about 1 to about 30, about 1 to about 20, about 1 to about 10, about 5 to about 90, about 10 to about 80, about 20 to about 60, or about 30 to about 50 ppm. In some cases, a peptide of the one or more peptides is present at about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 50, 75, 100, 200, 300, 400, 500, 600, 700, 800, 900, 1000, or greater than 1000 micrograms per milliliter (ug / mL). In some cases, a peptide of the one or more peptides is present in the range of about 1 to about 100, about 1 to about 50, about 1 to about 40, about 1 to about 30, about 1 to about 20, about 1 to about 10, about 5 to about 90, about 10 to about 80, about 20 to about 60, or about 30 to about 50 micrograms. In some cases, a peptide of the one or more peptides is present in about 0.01% to about 10% by weight, about 0.01% to about 0.02% by weight, about 0.01% to about 0.03% by weight, about 0.01% to about 0.04% by weight, about 0.01% to about 0.05% by weight, about 0.01% to about 0.1% by weight, about 1% to about 5% by weight, or about 1% to about 10% by weight (wt.%).In some embodiments, a peptide of the one or more peptides is provided at at least or about 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 than 10% by weight (wt.%). In some embodiments, a peptide of the one or more 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 one or more 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. In some embodiments, the peptide is tripeptide-1, hexapeptide-12, hexapeptide-11, octapeptide, or combinations thereof.

[0017] In the composition, the tripeptide is typically present in an amount of about 50 ppm or less to about 100, 200, 300, 400, or 500 ppm or more, e.g., 50 ppm to 150 ppm. In the composition, the hexapeptide is typically present in an amount of about 50 ppm or less to about 100, 200, 300, 400, or 500 ppm or more, e.g., 50 ppm to 150 ppm.

[0018] In some embodiments, tripeptide-1 is provided at at least or 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 more than 10% by weight (wt.%). In some embodiments, tripeptide-1 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, tripeptide-1 is provided at least or about 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, or more than 25 ppm. In some embodiments, tripeptide-1 is provided in the range of about 0.25 to about 10, about 0.5 to about 8, about 1 to about 6, or about 2 to about 4 ppm. In some embodiments, tripeptide-1 is provided in the range of about 1 to about 10 ppm. In some embodiments, tripeptide-1 is provided at at least about 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, or greater than 25 micrograms per milliliter (ug / mL). In some embodiments, tripeptide-1 is provided in the range of about 0.25 to about 10, about 0.5 to about 8, about 1 to about 6, or about 2 to about 4 micrograms per milliliter.

[0019] In some embodiments, hexapeptide-12 is provided at at least or about 0.00001%, 0.0003%, 0.0005%, 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 more than 10% by weight (wt.%). In some embodiments, hexapeptide-12 is provided in the range of about 0.00001% to about 10% by weight, about 0.0003% to about 9% by weight, about 0.0005% to about 8% by weight, or about 0.001% to about 4% by weight (wt.%). In some embodiments, hexapeptide-12 is provided at least or about 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, or more than 25 ppm. In some embodiments, hexapeptide-12 is provided in the range of about 1 to about 10 ppm. In some embodiments, hexapeptide-12 is provided in the range of about 0.25 to about 10, about 0.5 to about 8, about 1 to about 6, or about 2 to about 4 ppm. In some embodiments, hexapeptide-12 is provided at at least about 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, or greater than 25 micrograms per milliliter (ug / mL). In some embodiments, hexapeptide-12 is provided in the range of about 0.25 to about 10, about 0.5 to about 8, about 1 to about 6, or about 2 to about 4 micrograms per milliliter.

[0020] In some embodiments, hexapeptide-12 is provided at at least or about 30, 40, 50, 60, 70, 80, 90, 100, 200, 300, 400, 500, 600, 700, 800, 900, 1000, 2000, or more than 2000 micrograms (ug). In some embodiments, hexapeptide-12 is provided in the range of about 30 to about 2000ug. In some embodiments, hexapeptide-12 is provided in the range of about 40 to about 1000, about 50 to about 900, about 60 to about 800, about 70 to about 700, about 80 to about 600, or about 90 to about 500ug. In some embodiments, hexapeptide-12 is provided at at least or about 0.150ug. In some embodiments, hexapeptide-12 is provided at at least or about 450ug.

[0021] In some embodiments, hexapeptide-11 is provided at at least or about 0.00001%, 0.0003%, 0.0005%, 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 than 10% by weight (wt.%). In some embodiments, hexapeptide-11 is provided in the range of about 0.00001% to about 10% by weight, about 0.0003% to about 8% by weight, about 0.0005% to about 6% by weight, about 0.001% to about 4% by weight, about 0.005% to about 2% by weight, or about 0.01% to about 1% by weight (wt.%). In some embodiments, hexapeptide-11 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-11 is provided in the range of about 0.005% to about 0.02% by weight. In some embodiments, hexapeptide-11 is provided at at least about 0.1 ppm, 3 ppm, 5 ppm, 10 ppm, 50 ppm, 55 ppm, 500 ppm, 1,000 ppm, 2,500 ppm, 5,000 ppm, or greater than 5,000 ppm. In some embodiments, hexapeptide-11 is provided in the range of about 5 ppm to about 100 ppm, about 10 ppm to about 1000 ppm, about 50 ppm to about 1500 ppm, or about 500 ppm to about 5,000 ppm. In some embodiments, hexapeptide-11 is about 1000 ppm. In some embodiments, hexapeptide-11 is provided at at least or about 5, 10, 20, 25, 50, 75, 100, 150, 200, 250, 300, 350, 400, 450, 500, or more than 500 micrograms per milliliter (ug / mL).In some embodiments, hexapeptide-11 is provided in the range of about 25 to about 250, about 50 to about 200, about 75 to about 150, about 200 to about 300, or about 200 to about 400 micrograms per milliliter.

[0022] In some embodiments, hexapeptide-11 is provided at at least or about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 20, 30, 40, 50, 60, 70, 80, 90, or about 100 milligrams (mg). In some embodiments, hexapeptide-11 is provided in the range of about 1 to about 100 mg. In some embodiments, hexapeptide-11 is provided in the range of about 2 to about 90, about 3 to about 80, about 4 to about 70, or about 5 to about 60 mg. In some embodiments, hexapeptide-11 is provided at at least or about 6 mg. In some embodiments, hexapeptide-11 is provided at at least or about 18 mg.

[0023] In some embodiments, the octapeptide is provided at at least or 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 more than 10% by weight (wt.%). In some embodiments, the octapeptide is provided in a 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, the octapeptide is provided in a concentration of at least about 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, or greater than 200 parts per million (ppm). In some embodiments, the octapeptide is provided at a concentration of about 10 to about 190 ppm, about 20 to about 180 ppm, about 30 to about 170 ppm, about 40 to about 160 ppm, about 50 to about 150 ppm, about 60 to about 140 ppm, about 70 to about 130 ppm, about 80 to about 120 ppm, or about 90 to about 110 ppm. In some embodiments, the octapeptide is provided at a concentration of about 100 ppm. In some embodiments, the octapeptide is provided at a concentration of at least about 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, or greater than 200 ug / mL. In some embodiments, the octapeptide is provided at a concentration of about 10 to about 190 ug / mL, about 20 to about 180 ug / mL, about 30 to about 170 ug / mL, about 40 to about 160 ug / mL, about 50 to about 150 ug / mL, about 60 to about 140 ug / mL, about 70 to about 130 ug / mL, about 80 to about 120 ug / mL, or about 90 to about 110 ug / mL. In some embodiments, the octapeptide is provided at a concentration of about 100 ug / mL.

[0024] 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), and 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. 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.

[0025] 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).

[0026] Silymarin Silymarin is derived from the milk thistle plant Silybum marianum. Silybinin, the main component of silymarin, can have antioxidant and photoprotective effects by minimizing UV radiation effects such as oxidative stress, inflammation, edema, erythema, and DNA damage. In some cases, silibinin prevents melanin production and reduces the expression of tyrosinase protein without affecting cell survival. Silymarin cream has been found to be more effective than intradermal tranexamic acid in studies on patients with melasma. In some cases, silymarin inhibited the production of interleukin-1 beta (IL-1β) and PGE-2 produced by cyclooxygenase-2 (COX-2) in keratinocytes and macrophages. In some cases, silibinin reduces inducible nitric oxide synthase (iNOS) and COX-2, as well as NF-κB.

[0027] The compositions described herein, in some embodiments, include silymarin, milk thistle extract, or derivatives thereof. In some embodiments, the silymarin, milk thistle extract, or derivatives thereof is silybin. In some embodiments, the silymarin, milk thistle extract, or derivatives thereof is silychristin. In some embodiments, the silymarin, milk thistle extract, or derivatives thereof is silydianin. In some embodiments, silymarin, milk thistle extract, or derivatives thereof are provided at least 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 more than 4% by weight (wt.%). In some embodiments, silymarin, milk thistle extract, or derivatives thereof are provided in the range of about 0.25% to about 10%, about 0.1% to about 2.5%, or about 0.5% to about 8% by weight (wt.%). In some embodiments, silymarin, milk thistle extract, or derivatives thereof are provided in the range of about 0.001% to about 6%, about 0.002% to about 4%, about 0.01% to about 3%, about 0.02% to about 2%, or about 0.2% to about 3% by weight (wt.%). In some embodiments, silymarin, milk thistle extract, or derivatives thereof constitutes about 0.7% or less by weight. In some embodiments, silymarin, milk thistle extract, or derivatives thereof are provided at at least or about 10, 50, 100, 200, 500, 1000, 2000, 2500, 5000, 7500, 10000, 15000, 20000, 25000, 30000, 35000, 40000, or greater than 40000 ppm.In some embodiments, silymarin, milk thistle extract, or derivatives thereof are provided in the range of about 2500 ppm to about 100000 ppm, about 1000 ppm to about 25000 ppm, about 5000 ppm to about 80000 ppm, about 75000 ppm to about 60000 ppm, or about 1000 ppm to about 40000 ppm. In some embodiments, silymarin, milk thistle extract, or derivatives thereof are provided in the range of about 10 ppm to about 60000 ppm, about 20 ppm to about 40000 ppm, about 100 ppm to about 30000 ppm, or about 200 ppm to about 20000 ppm. In some embodiments, silymarin, milk thistle extract, or derivatives thereof are provided at at least or about 5, 10, 15, 20, 25, 30, 35, or 40 micrograms per mL (ug / mL).In some embodiments, silymarin, milk thistle extract, or derivatives thereof are provided in the range of about 1 to about 50, about 5 to about 45, about 10 to about 40, or about 15 to about 35 ug / mL.

[0028] In some embodiments, silymarin, milk thistle extract, or derivatives thereof are provided at at least or about at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 20, 30, 40, 50, 60, 70, 80, 90, or about 100 milligrams (mg). In some embodiments, silymarin, milk thistle extract, or derivatives thereof are provided in the range of about 1 to about 100, about 2 to about 90, about 3 to about 80, about 4 to about 70, or about 5 to about 60 milligrams (mg). In some embodiments, silymarin, milk thistle extract, or derivatives thereof are provided at about 6 milligrams (mg). In some embodiments, silymarin, milk thistle extract, or derivatives thereof are provided at about 18 milligrams (mg).

[0029] In some embodiments, silymarin, milk thistle extract, or derivatives thereof are provided with lecithin, carnosine, tocopherol, glycerin, phenoxyethanol, water, or combinations thereof. In some embodiments, silymarin, milk thistle extract, or derivatives thereof are provided with at least or 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 more than 4% (wt.%) lecithin, carnosine, tocopherol, glycerin, phenoxyethanol, water, or combinations thereof. In some embodiments, silymarin, milk thistle extract, or derivatives thereof are provided with about 0.25% to about 10% by weight, about 0.1% to about 2.5% by weight, about 0.5% to about 8% by weight (wt.%) of lecithin, carnosine, tocopherol, glycerin, phenoxyethanol, water, or combinations thereof. In some embodiments, silymarin, milk thistle extract, or derivatives thereof are provided with 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 0.2% to about 3% by weight (wt.%) of lecithin, carnosine, tocopherol, glycerin, phenoxyethanol, water, or combinations thereof.

[0030] In some embodiments, silymarin, milk thistle extract, or derivatives thereof are provided with phospholipids. In some embodiments, silymarin, milk thistle extract, or derivatives thereof are provided with at least or more 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% (wt.%) of phospholipids. In some embodiments, silymarin, milk thistle extract, or derivatives thereof are provided with phospholipids in the range of about 0.25% to about 10%, about 0.1% to about 2.5%, or about 0.5% to about 8% (wt.%) of phospholipids. In some embodiments, silymarin, milk thistle extract, or derivatives thereof are provided with phospholipids in the range of about 0.001% to about 6%, about 0.002% to about 4%, about 0.01% to about 3%, about 0.02% to about 2%, or about 0.2% to about 3% (wt.%).

[0031] In some embodiments, silymarin, milk thistle extract, or derivatives thereof are encapsulated in liposomes or photosomes. In some embodiments, silymarin, milk thistle extract, or derivatives thereof are provided with lecithin, phosphatidylcholine, or combinations thereof for encapsulation in liposomes or photosomes. In some embodiments, silymarin, milk thistle extract, or derivatives thereof provided with lecithin, phosphatidylcholine, or combinations thereof for encapsulation in liposomes or photosomes is present in an amount of about 0.00001%, 0.0003%, 0.0005%, 0.001%, 0.001%, 0.005%, 0.0055%, 0.0 ... The silymarin, milk thistle extract, or derivatives thereof provided with lecithin, phosphatidylcholine, or combinations thereof for inclusion in liposomes or photosomes 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.

[0032] Tranexamic acid Tranexamic acid (TXA) is a plasmin inhibitor used to prevent fibrinolysis and reduce blood loss. It is a synthetic derivative of lysine and exerts its effect by reversibly blocking the lysine-binding site on the plasminogen molecule, preventing plasminogen from binding to basal keratinocytes, thereby inhibiting the conversion of plasminogen to plasmin and thus reducing the production of prostaglandins (especially PGE-2). UV exposure is involved in the pathogenesis of melasma in some cases. UV irradiation can induce plasminogen activator synthesis in keratinocytes and increase plasmin activity, which stimulates the release of arachidonic acid (AA) via phospholipase. Free AA can stimulate melanogenesis via its metabolic product, PGE-2. In some cases, the release of AA is increased by plasmin in endothelial cells. An increase in plasmin itself can elevate α-MSH, which activates melanin synthesis in melanocytes. Plasmin can also increase the release of basic fibroblast growth factor (bFGF), a potent melanocyte growth factor. All of these processes can result in more melanin production in the skin. In some cases, plasmin plays an important role in angiogenesis. Plasmin converts extracellular matrix-bound VEGF into a freely diffusible form. TXA, a plasmin inhibitor, can suppress angiogenesis and inhibits neovascularization induced by bFGF. In addition, TXA resembles tyrosine in its structure, which means that it can competitively inhibit the enzymatic activity of tyrosinase. In some cases, TXA reduces the levels of VEGF and ET-1, which may be involved in the increased vascularity in melasma lesions.

[0033] The compositions described herein, in some embodiments, include tranexamic acid (TXA). In some embodiments, TXA is provided at least or 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%, 7.5%, 8.0%, 8.5%, 9.0%, 9.5%, 10.0%, or more than 10.0% by weight (wt%). In some embodiments, TXA is provided in the range of about 0.25% to about 10% by weight, about 0.1% to about 2.5% 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 (wt%). In some embodiments, TXA 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 0.25% to about 6.25% by weight (wt%). In some embodiments, TXA is provided at about 1.25% by weight or less than about 1.25% by weight (wt%). In some embodiments, TXA is provided at least or at about 10 ppm, 50 ppm, 100 ppm, 200 ppm, 500 ppm, 1000 ppm, 2000 ppm, 2500 ppm, 5000 ppm, 7500 ppm, 10000 ppm, 15000 ppm, 2000 ppm, 25000 ppm, 3000 ppm, 35000 ppm, 4000 ppm, 45000 ppm, 5000 ppm, 55000 ppm, 6000 ppm, 65000 ppm, 7000 ppm, 75000 ppm, 8000 ppm, 85000 ppm, 9000 ppm, 95000 ppm, 10000 ppm, or more than 10000 ppm. In some embodiments, TXA is provided in the range of about 2500 ppm to about 10000 ppm, about 1000 ppm to about 25000 ppm, about 5000 ppm to about 8000 ppm, about 7500 ppm to about 6000 ppm, or about 10000 ppm to about 4000 ppm.In some embodiments, TXA is provided in the range of about 10 ppm to about 6000 ppm, about 20 ppm to about 4000 ppm, about 100 ppm to about 3000 ppm, or about 200 ppm to about 2000 ppm. In some embodiments, TXA is about 5000 ppm. In some embodiments, TXA is provided at least or about 10, 50, 100, 200, 500, 1000, 2000, 2500, or 5000 micrograms per milliliter (ug / mL). In some embodiments, TXA is provided in the range of about 10 to about 5000 ug / mL, about 50 to about 4000 ug / mL, about 100 to about 3000 ug / mL, about 150 to about 2000 ug / mL, or about 500 to about 1500 ug / mL.

[0034] In some embodiments, TXA is provided at least or about at least 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 200, 300, 400, 500, or more than 500 milligrams (mg). In some embodiments, TXA is provided in the range of about 5 to about 500, about 10 to about 400, about 15 to about 300, about 20 to about 200, or about 25 to about 100 milligrams (mg). In some embodiments, TXA is provided at about 30 milligrams (mg). In some embodiments, TXA is provided at about 90 milligrams (mg).

[0035] The compositions described herein, in some embodiments, comprise tranexamic acid (TXA) encapsulated in liposomes or photosomes. In some embodiments, the TXA encapsulated in the liposome or photosome is provided at about 0.00001 wt%, 0.0003 wt%, 0.0005 wt%, 0.001 wt%, 0.001 wt%, 0.005 wt%, 0.0055 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% (wt.%). In some embodiments, TXA encapsulated in liposomes or photosomes 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.

[0036] Compositions described herein, in some embodiments, include tranexamic acid (TXA) provided with water, mannitol, phosphatidylcholine, glycerin, cholesterol, potassium sorbate, sodium benzoate, niacinamide, xanthan gum, sodium chloride, or combinations thereof. In some embodiments, TXA provided with water, mannitol, phosphatidylcholine, glycerin, cholesterol, potassium sorbate, sodium benzoate, niacinamide, xanthan gum, sodium chloride, or combinations thereof is at least or about 0.001%, 0.005%, 0.01%, 0.02%, 0.05%, 0.10%, 0.20%, 0.40%, 0.60%, 0.80%, 0.90%, 0.10%, 0.25%, 0.40%, 0.50%, 0.60%, 0.70%, 0.80%, 0.90%, 0.95%, 0.95%, 0.90 ... In some embodiments, the composition may be provided in an amount of 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%, 7.5%, 8.0%, 8.5%, 9.0%, 9.5%, 10.0% or greater than 10.0% by weight (wt%). In some embodiments, TXA provided with water, mannitol, phosphatidylcholine, glycerin, cholesterol, potassium sorbate, sodium benzoate, niacinamide, xanthan gum, sodium chloride, or combinations thereof is provided in the range of about 0.25% to about 10% by weight, about 0.1% to about 2.5% 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 (wt%). In some embodiments, TXA provided with water, mannitol, phosphatidylcholine, glycerin, cholesterol, potassium sorbate, sodium benzoate, niacinamide, xanthan gum, sodium chloride, or combinations thereof 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 0.25% to about 6.25% by weight (wt%).In some embodiments, TXA provided with water, mannitol, phosphatidylcholine, glycerin, cholesterol, potassium sorbate, sodium benzoate, niacinamide, xanthan gum, sodium chloride, or a combination thereof is provided at about 1.25 wt% or less. In some embodiments, TXA provided with water, mannitol, phosphatidylcholine, glycerin, cholesterol, potassium sorbate, sodium benzoate, niacinamide, xanthan gum, sodium chloride, or a combination thereof is provided at about 4.0 wt% or less. In some embodiments, the TXA provided with water, mannitol, phosphatidylcholine, glycerin, cholesterol, potassium sorbate, sodium benzoate, niacinamide, xanthan gum, sodium chloride, or a combination thereof is at least or about 10 ppm, 50 ppm, 100 ppm, 200 ppm, 500 ppm, 1000 ppm, 2000 ppm, 2500 ppm, 5000 ppm, m, 7500 ppm, 10000 ppm, 15000 ppm, 2000 ppm, 25000 ppm, 3000 ppm, 35000 ppm, 4000 ppm, 45000 ppm, 5000 ppm, 55000 ppm, 6000 ppm, 65000 ppm, 7000 ppm, 75000 ppm, 8000 ppm, 85000 ppm, 9000 ppm, 95000 ppm, 10000 ppm, or greater than 10000 ppm. In some embodiments, TXA provided with water, mannitol, phosphatidylcholine, glycerin, cholesterol, potassium sorbate, sodium benzoate, niacinamide, xanthan gum, sodium chloride, or a combination thereof is provided in the range of about 2500 ppm to about 10000 ppm, about 1000 ppm to about 25000 ppm, about 5000 ppm to about 8000 ppm, about 7500 ppm to about 6000 ppm, or about 10000 ppm to about 4000 ppm.In some embodiments, TXA provided with water, mannitol, phosphatidylcholine, glycerin, cholesterol, potassium sorbate, sodium benzoate, niacinamide, xanthan gum, sodium chloride, or a combination thereof is provided in the range of about 10 ppm to about 6000 ppm, about 20 ppm to about 4000 ppm, about 100 ppm to about 3000 ppm, or about 200 ppm to about 2000 ppm. In some embodiments, TXA provided with water, mannitol, phosphatidylcholine, glycerin, cholesterol, potassium sorbate, sodium benzoate, niacinamide, xanthan gum, sodium chloride, or a combination thereof is about 5000 ppm. In some embodiments, TXA provided with water, mannitol, phosphatidylcholine, glycerin, cholesterol, potassium sorbate, sodium benzoate, niacinamide, xanthan gum, sodium chloride, or a combination thereof is provided at at least or about 10, 50, 100, 200, 500, 1000, 2000, 2500, or 5000 micrograms per milliliter (ug / mL). In some embodiments, TXA provided with water, mannitol, phosphatidylcholine, glycerin, cholesterol, potassium sorbate, sodium benzoate, niacinamide, xanthan gum, sodium chloride, or a combination thereof is provided in the range of about 10 to about 5000 ug / mL, about 50 to about 4000 ug / mL, about 100 to about 3000 ug / mL, about 150 to about 2000 ug / mL, or about 500 to about 1500 ug / mL.

[0037] In some embodiments, TXA provided with water, mannitol, phosphatidylcholine, glycerin, cholesterol, potassium sorbate, sodium benzoate, niacinamide, xanthan gum, sodium chloride, or combinations thereof is provided at at least or about at least 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 200, 300, 400, 500, or more than 500 milligrams (mg). In some embodiments, TXA provided with water, mannitol, phosphatidylcholine, glycerin, cholesterol, potassium sorbate, sodium benzoate, niacinamide, xanthan gum, sodium chloride, or a combination thereof is provided in the range of about 5 to about 500, about 10 to about 400, about 15 to about 300, about 20 to about 200, or about 25 to about 100 milligrams (mg). In some embodiments, TXA provided with water, mannitol, phosphatidylcholine, glycerin, cholesterol, potassium sorbate, sodium benzoate, niacinamide, xanthan gum, sodium chloride, or a combination thereof is provided in about 30 milligrams (mg). In some embodiments, TXA provided with water, mannitol, phosphatidylcholine, glycerin, cholesterol, potassium sorbate, sodium benzoate, niacinamide, xanthan gum, sodium chloride, or a combination thereof is provided in about 90 milligrams (mg).

[0038] The compositions described herein, in some embodiments, include tranexamic acid (TXA) and niacinamide encapsulated in vegan deep release nanovesicles. In some embodiments, TXA is provided at least or about 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%, 7.5%, 8.0%, 8.5%, 9.0%, 9.5%, 10.0%, or more than 10.0% by weight (wt%). In some embodiments, niacinamide is provided at at least or about 0.01%, 0.02%, 0.05%, 0.10%, 0.20%, 0.25%, 0.50%, 0.75%, 1.0%, 1.5%, 2.0%, or more than 2.0% by weight (wt.%).

[0039] In some embodiments, the nanovesicles comprise an average particle size of about or at least 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 200, 300, 400, or 500 nanometers (nm). In some embodiments, the average particle size of the nanovesicles ranges from about 10 to about 500, about 20 to about 400, about 30 to about 300, about 40 to about 200, about 50 to about 150 nm, about 100 to about 400, or about 150 to about 300 nm. In some embodiments, the nanovesicles comprise a polydispersity index (PdI) ranging from 0 to about 0.2. In some cases, the polydispersity index is about 0.01, 0.025, 0.05, 0.1, 0.25, 0.3, 0.35, 0.4, 0.45, 0.5, 0.55, 0.6, 0.65, 0.7, 0.75, or 0.8. In some cases, the polydispersity index is in the range of about 0.01 to about 0.8, about 0.025 to about 0.75, about 0.05 to about 0.6, or about 0.1 to about 0.3. In some cases, the polydispersity index is less than about 0.5.

[0040] Compositions described herein include tranexamic acid (TXA), which in some embodiments is provided with water, mannitol, phosphatidylcholine, glycerin, tranexamic acid, cetyl alcohol, decyl glucoside, potassium sorbate, sodium benzoate, niacinamide, xanthan gum, sodium chloride, or a combination thereof. In some embodiments, TXA, which is provided with water, mannitol, phosphatidylcholine, glycerin, tranexamic acid, cetyl alcohol, decyl glucoside, potassium sorbate, sodium benzoate, niacinamide, xanthan gum, sodium chloride, or a combination thereof, is at least or about 0.001%, 0.005%, 0.01%, 0.02%, 0.05%, 0.10%, 0.20%, 0.30%, 0.40%, 0.50%, 0.60%, 0.70%, 0.80%, 0.90%, 0.10%, 0.25%, 0.40%, 0.50%, 0.60%, 0.70%, 0.80%, 0.9 ... %, 0.20 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%, 7.5 wt%, 8.0 wt%, 8.5 wt%, 9.0 wt%, 9.5 wt%, 10.0 wt%, or greater than 10.0 wt% (wt%). In some embodiments, TXA provided with water, mannitol, phosphatidylcholine, glycerin, tranexamic acid, cetyl alcohol, decyl glucoside, potassium sorbate, sodium benzoate, niacinamide, xanthan gum, sodium chloride, or combinations thereof is provided in the range of about 0.25% to about 10% by weight, about 0.1% to about 2.5% 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 (wt%).In some embodiments, TXA provided with water, mannitol, phosphatidylcholine, glycerin, tranexamic acid, cetyl alcohol, decyl glucoside, potassium sorbate, sodium benzoate, niacinamide, xanthan gum, sodium chloride, or a combination thereof 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 0.25% to about 6.25% by weight (wt%). In some embodiments, TXA provided with water, mannitol, phosphatidylcholine, glycerin, tranexamic acid, cetyl alcohol, decyl glucoside, potassium sorbate, sodium benzoate, niacinamide, xanthan gum, sodium chloride, or a combination thereof is provided in the range of about 1.25% by weight (wt%) or less than about 1.25% by weight (wt%). In some embodiments, TXA provided with water, mannitol, phosphatidylcholine, glycerin, tranexamic acid, cetyl alcohol, decyl glucoside, potassium sorbate, sodium benzoate, niacinamide, xanthan gum, sodium chloride, or combinations thereof is provided at about 4.0 weight percent (wt%) or less. In some embodiments, TXA provided with water, mannitol, phosphatidylcholine, glycerin, tranexamic acid, cetyl alcohol, decyl glucoside, potassium sorbate, sodium benzoate, niacinamide, xanthan gum, sodium chloride, or combinations thereof is provided at at least or about 10 ppm, 50 ppm, 100 ppm, 200 ppm, 500 ppm, 1000 ppm, 2000 ppm, 2500 ppm, 3000 ppm, 4000 ppm, 5000 ppm, 6000 ppm, 7000 ppm, 8000 ppm, 9000 ppm, 10000 ppm, 15000 ppm, 20000 ppm, 30000 ppm, 40000 ppm, 50000 ppm, 60000 ppm, 70000 ppm, 80000 ppm, 90000 ppm, 100000 ppm, 15000 ppm, 100000 ppm, 15000 ppm, 200000 ppm, 25000 ppm, 30000 ppm, 40000 ppm, 50000 ppm, 60000 ppm, 70000 ppm, 80000 ppm, 90000 ppm, 100000 ppm, 100000 ppm, 100000 ppm, 100000 ppm, 100000 ppm, 10 pm, 5000 ppm, 7500 ppm, 10000 ppm, 15000 ppm, 2000 ppm, 25000 ppm, 3000 ppm, 35000 ppm, 4000 ppm, 45000 ppm, 5000 ppm, 55000 ppm, 6000 ppm, 65000 ppm, 7000 ppm, 75000 ppm, 8000 ppm, 85000 ppm, 9000 ppm, 95000 ppm, 10000 ppm, or greater than 10000 ppm.In some embodiments, TXA provided with water, mannitol, phosphatidylcholine, glycerin, tranexamic acid, cetyl alcohol, decyl glucoside, potassium sorbate, sodium benzoate, niacinamide, xanthan gum, sodium chloride, or combinations thereof is provided in the range of about 2500 ppm to about 10000 ppm, about 1000 ppm to about 25000 ppm, about 5000 ppm to about 8000 ppm, about 7500 ppm to about 6000 ppm, or about 10000 ppm to about 4000 ppm. In some embodiments, TXA provided with water, mannitol, phosphatidylcholine, glycerin, tranexamic acid, cetyl alcohol, decyl glucoside, potassium sorbate, sodium benzoate, niacinamide, xanthan gum, sodium chloride, or a combination thereof is provided in the range of about 10 ppm to about 6000 ppm, about 20 ppm to about 4000 ppm, about 100 ppm to about 3000 ppm, or about 200 ppm to about 2000 ppm. In some embodiments, TXA provided with water, mannitol, phosphatidylcholine, glycerin, tranexamic acid, cetyl alcohol, decyl glucoside, potassium sorbate, sodium benzoate, niacinamide, xanthan gum, sodium chloride, or a combination thereof is about 5000 ppm. In some embodiments, TXA provided with water, mannitol, phosphatidylcholine, glycerin, tranexamic acid, cetyl alcohol, decyl glucoside, potassium sorbate, sodium benzoate, niacinamide, xanthan gum, sodium chloride, or combinations thereof is provided at at least or about 10, 50, 100, 200, 500, 1000, 2000, 2500, or 5000 micrograms per milliliter (ug / mL).In some embodiments, TXA provided in water, mannitol, phosphatidylcholine, glycerin, tranexamic acid, cetyl alcohol, decyl glucoside, potassium sorbate, sodium benzoate, niacinamide, xanthan gum, sodium chloride, or combinations thereof is provided in the range of about 10 to about 5000 ug / mL, about 50 to about 4000 ug / mL, about 100 to about 3000 ug / mL, about 150 to about 2000 ug / mL, or about 500 to about 1500 ug / mL.

[0041] In some embodiments, TXA provided with water, mannitol, phosphatidylcholine, glycerin, tranexamic acid, cetyl alcohol, decyl glucoside, potassium sorbate, sodium benzoate, niacinamide, xanthan gum, sodium chloride, or combinations thereof is provided at or about at least 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 200, 300, 400, 500, or more than 500 milligrams (mg). In some embodiments, TXA provided with water, mannitol, phosphatidylcholine, glycerin, tranexamic acid, cetyl alcohol, decyl glucoside, potassium sorbate, sodium benzoate, niacinamide, xanthan gum, sodium chloride, or a combination thereof is provided in the range of about 5 to about 500, about 10 to about 400, about 15 to about 300, about 20 to about 200, or about 25 to about 100 milligrams (mg). In some embodiments, TXA provided with water, mannitol, phosphatidylcholine, glycerin, tranexamic acid, cetyl alcohol, decyl glucoside, potassium sorbate, sodium benzoate, niacinamide, xanthan gum, sodium chloride, or a combination thereof is provided in about 30 milligrams (mg). In some embodiments, TXA provided with water, mannitol, phosphatidylcholine, glycerin, tranexamic acid, cetyl alcohol, decyl glucoside, potassium sorbate, sodium benzoate, niacinamide, xanthan gum, sodium chloride, or combinations thereof is provided at about 90 milligrams (mg).

[0042] The compositions described herein, in some embodiments, include tranexamic acid (TXA) provided with water, mannitol, phosphatidylcholine, glycerin, tranexamic acid, cetyl alcohol, decyl glucoside, potassium sorbate, sodium benzoate, niacinamide, xanthan gum, sodium chloride, or combinations thereof, wherein mannitol is at least or about 0.001%, 0.005%, 0.01%, 0.0 ... It may be provided in an amount of 2%, 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%, 7.5%, 8.0%, 8.5%, 9.0%, 9.5%, 10.0% or greater than 10.0% by weight (wt%). In some embodiments, mannitol is provided in the range of about 0.25% to about 10% by weight, about 0.1% to about 2.5% by weight, about 0.5% to about 8% by weight, about 0.75% to about 6% by weight, about 1% to about 4% by weight, or about 4% to about 7% by weight (wt%).

[0043] The compositions described herein, in some embodiments, include tranexamic acid (TXA) provided with water, mannitol, phosphatidylcholine, glycerin, tranexamic acid, cetyl alcohol, decyl glucoside, potassium sorbate, sodium benzoate, niacinamide, xanthan gum, sodium chloride, or combinations thereof, and the phosphatidylcholine is at least or about 0.001%, 0.005%, 0.01%, 0.002%, 0.004%, 0.005%, 0.006%, 0.008%, 0.009%, 0.01%, 0.02%, 0.03%, 0.04%, 0.05%, 0.06%, 0.07%, 0.08%, 0.09%, 0.1%, 0.1%, 0.1%, 0.2%, 0.25%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 0.9%, 10%, 10%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 6 It may be provided in an amount of .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%, 7.5%, 8.0%, 8.5%, 9.0%, 9.5%, 10.0% or greater than 10.0% by weight (wt%). In some embodiments, phosphatidylcholine is provided in the range of about 0.25% to about 10% by weight, about 0.1% to about 2.5% by weight, about 0.5% to about 8% by weight, about 0.75% to about 6% by weight, about 1% to about 4% by weight, or about 3% to about 6% by weight (wt%).

[0044] The compositions described herein, in some embodiments, include tranexamic acid (TXA) provided with water, mannitol, phosphatidylcholine, glycerin, tranexamic acid, cetyl alcohol, decyl glucoside, potassium sorbate, sodium benzoate, niacinamide, xanthan gum, sodium chloride, or combinations thereof, wherein the glycerin is at least or about 0.001%, 0.005%, 0.01%, 0.0 ... It may be provided in an amount of 2%, 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%, 7.5%, 8.0%, 8.5%, 9.0%, 9.5%, 10.0% or greater than 10.0% by weight (wt%). In some embodiments, glycerin is provided in the range of about 0.25% to about 10%, about 0.1% to about 2.5%, about 0.5% to about 8%, about 0.75% to about 6%, about 1% to about 4%, or about 2% to about 4% by weight (wt%).

[0045] The compositions described herein, in some embodiments, comprise tranexamic acid (TXA) provided with water, mannitol, phosphatidylcholine, glycerin, tranexamic acid, cetyl alcohol, decyl glucoside, potassium sorbate, sodium benzoate, niacinamide, xanthan gum, sodium chloride, or combinations thereof, wherein the tranexamic acid is at or near 0.001%, 0.005%, 0.01%, 0.002%, 0.004%, 0.005%, 0.01%, 0.005 ... 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%, 7.5%, 8.0%, 8.5%, 9.0%, 9.5%, 10.0% or greater than 10.0% (wt%). In some embodiments, tranexamic acid is provided in the range of about 0.25% to about 10% by weight, about 0.1% to about 2.5% by weight, about 0.5% to about 8% by weight, about 0.75% to about 6% by weight, about 1% to about 4% by weight, or about 2% to about 3% by weight (wt %).

[0046] The compositions described herein, in some embodiments, include tranexamic acid (TXA) provided with water, mannitol, phosphatidylcholine, glycerin, tranexamic acid, cetyl alcohol, decyl glucoside, potassium sorbate, sodium benzoate, niacinamide, xanthan gum, sodium chloride, or combinations thereof, wherein cetyl alcohol is at least or about 0.001%, 0.005%, 0.01%, 0.02%, 0.03%, 0.04%, 0.05%, 0.06%, 0.07%, 0.08%, 0.09%, 0.10%, 0.11%, 0.12%, 0.13%, 0.14%, 0.15%, 0.16%, 0.17%, 0.18%, 0.19%, 0.20%, 0.21%, 0.22%, 0.23%, 0.24%, 0.25%, 0.26%, 0.27%, 0.28%, 0.29%, 0.30%, 0.31%, 0.32%, 0.33%, 0.34%, 0.35%, 0.36%, 0.37%, 0.38%, 0.39%, 0.40%, 0.41%, 0.42%, 0.43%, 0.44%, 0.45%, 0.46%, 0.47%, 0.48%, 0.49%, 0.50%, 0.51%, 0.52%, 0.53%, 0.54%, 0.55%, 0.56%, 0.57%, 0.58%, 0.60%, 0.61%, 0.62%, 0.70%, 0.75%, 0.80%, 0.85%, 0.90%, The composition may be provided in an amount of 0.05%, 0.10%, 0.20%, 0.25%, 0.50%, 0.6%, 0.75%, 0.8%, 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%, 7.5%, 8.0%, 8.5%, 9.0%, 9.5%, 10.0% or greater than 10.0% (wt%). In some embodiments, cetyl alcohol is provided in the range of about 0.25% to about 1.0%, about 0.1% to about 2.5%, about 0.5% to about 0.8%, about 0.75% to about 2%, or about 0.6% to about 0.8% by weight (wt%).

[0047] The compositions described herein, in some embodiments, include tranexamic acid (TXA) provided with water, mannitol, phosphatidylcholine, glycerin, tranexamic acid, cetyl alcohol, decyl glucoside, potassium sorbate, sodium benzoate, niacinamide, xanthan gum, sodium chloride, or combinations thereof, wherein decyl glucoside is at least or about 0.001%, 0.005%, 0.01%, 0.02%, 0.03%, 0.04%, 0.05%, 0.06%, 0.07%, 0.08%, 0.09%, 0.10%, 0.11%, 0.12%, 0.13%, 0.14%, 0.15%, 0.16%, 0.17%, 0.18%, 0.19%, 0.20%, 0.21%, 0.22%, 0.23%, 0.24%, 0.25%, 0.26%, 0.27%, 0.28%, 0.29%, 0.30%, 0.31%, 0.32%, 0.33%, 0.34%, 0.35%, 0.36%, 0.37%, 0.38%, 0.39%, 0.40%, 0.41%, 0.42%, 0.43%, 0.44%, 0.45%, 0.46%, 0.47%, 0.48%, 0.49%, 0.50%, 0.51%, 0.52%, 0.53%, 0.54%, 0.55%, 0.56%, 0.57%, 0.58%, 0.60%, 0.61%, 0.62%, 0.70%, 0.75%, 0.80%, 0.85%, 0. The composition may be provided in an amount of 0.05%, 0.10%, 0.20%, 0.25%, 0.50%, 0.6%, 0.75%, 0.8%, 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%, 7.5%, 8.0%, 8.5%, 9.0%, 9.5%, 10.0% or greater than 10.0% (wt%). In some embodiments, decyl glucoside is provided in the range of about 0.25% to about 1.0%, about 0.1% to about 2.5%, about 0.5% to about 0.8%, about 0.75% to about 2%, or about 0.6% to about 0.8% by weight (wt%).

[0048] The compositions described herein, in some embodiments, include tranexamic acid (TXA) provided with water, mannitol, phosphatidylcholine, glycerin, tranexamic acid, cetyl alcohol, decyl glucoside, potassium sorbate, sodium benzoate, niacinamide, xanthan gum, sodium chloride, or combinations thereof, wherein potassium sorbate is at least or about 0.001%, 0.005%, 0.01%, 0.02%, 0.04%, 0.06%, 0.08%, 0.09%, 0.10%, 0.11%, 0.12%, 0.13%, 0.14%, 0.15%, 0.16%, 0.17%, 0.18%, 0.19%, 0.20%, 0.21%, 0.22%, 0.23%, 0.24%, 0.25%, 0.26%, 0.27%, 0.28%, 0.29%, 0.30%, 0.31%, 0.32%, 0.33%, 0.34%, 0.35%, 0.36%, 0.37%, 0.38%, 0.39%, 0.40%, 0.41%, 0.42%, 0.43%, 0.44%, 0.45%, 0.46%, 0.47%, 0.48%, 0.49%, 0.50%, 0.50%, 0.51%, 0.52%, 0.53%, 0.54%, 0.55%, 0.56%, 0.57%, 0.58%, 0.60%, 0.61%, 0.62%, 0.70%, 0.75%, 0.80%, 0.85%, 0.90%, 0.91%, 0.92%, The composition may be provided in an amount of 0.05%, 0.10%, 0.20%, 0.25%, 0.50%, 0.6%, 0.75%, 0.8%, 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%, 7.5%, 8.0%, 8.5%, 9.0%, 9.5%, 10.0% or greater than 10.0% by weight (wt%). In some embodiments, potassium sorbate is provided in the range of about 0.25% to about 1.0%, about 0.1% to about 2.5%, about 0.5% to about 0.8%, about 0.75% to about 2%, or about 0.6% to about 0.8% by weight (wt%).

[0049] The compositions described herein, in some embodiments, include tranexamic acid (TXA) provided with water, mannitol, phosphatidylcholine, glycerin, tranexamic acid, cetyl alcohol, decyl glucoside, potassium sorbate, sodium benzoate, niacinamide, xanthan gum, sodium chloride, or combinations thereof, wherein sodium benzoate is at least or about 0.001%, 0.005%, 0.01%, 0.02%, 0.04%, 0.06%, 0.08%, 0.09%, 0.10%, 0.11%, 0.12%, 0.13%, 0.14%, 0.15%, 0.16%, 0.17%, 0.18%, 0.19%, 0.20%, 0.21%, 0.22%, 0.23%, 0.24%, 0.25%, 0.26%, 0 The composition may be provided in an amount of 0.05%, 0.10%, 0.20%, 0.25%, 0.50%, 0.6%, 0.75%, 0.8%, 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%, 7.5%, 8.0%, 8.5%, 9.0%, 9.5%, 10.0% or greater than 10.0% by weight (wt%). In some embodiments, sodium benzoate is provided in the range of about 0.25% to about 1.0%, about 0.1% to about 2.5%, about 0.5% to about 0.8%, about 0.75% to about 2%, or about 0.6% to about 0.8% by weight (wt%).

[0050] The compositions described herein, in some embodiments, include tranexamic acid (TXA) provided with water, mannitol, phosphatidylcholine, glycerin, tranexamic acid, cetyl alcohol, decyl glucoside, potassium sorbate, sodium benzoate, niacinamide, xanthan gum, sodium chloride, or combinations thereof, wherein niacinamide is at least or about 0.001%, 0.005%, 0.01%, 0.02%, 0.03%, 0.04%, 0.05%, 0.06%, 0.07%, 0.08%, 0.10%, 0.12%, 0.16%, 0.18%, 0.19%, 0.20%, 0.21%, 0.22%, 0.23%, 0.24%, 0.25%, 0.26%, 0.27%, 0.28%, 0.29%, 0.30%, 0.31%, 0.32%, 0.33%, 0.34%, 0.35%, 0.36%, 0.37%, 0.38%, 0.39%, 0.40%, 0.41%, 0.42%, 0.43%, 0.44%, 0.45%, 0.46%, 0.47%, 0.48%, 0.49%, 0.50%, 0.51%, 0.52%, 0.53%, 0.54%, 0.55%, 0.56%, 0.57%, 0.58%, 0.60%, 0.61%, 0.62%, 0.70%, 0.75%, 0.80%, 0.85%, 0.90%, 0.95%, 0.96%, 0.97%, 0.98%, 0.99%, 0.89%, The composition may be provided in an amount of 0.05%, 0.10%, 0.20%, 0.25%, 0.50%, 0.6%, 0.75%, 0.8%, 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%, 7.5%, 8.0%, 8.5%, 9.0%, 9.5%, 10.0% or greater than 10.0% (wt%). In some embodiments, niacinamide is provided in the range of about 0.25% to about 1.0%, about 0.1% to about 2.5%, about 0.5% to about 0.8%, about 0.75% to about 2%, or about 0.6% to about 0.8% by weight (wt%).

[0051] The compositions described herein, in some embodiments, include tranexamic acid (TXA) provided with water, mannitol, phosphatidylcholine, glycerin, tranexamic acid, cetyl alcohol, decyl glucoside, potassium sorbate, sodium benzoate, niacinamide, xanthan gum, sodium chloride, or combinations thereof, wherein the xanthan gum is at least or about 0.001%, 0.005%, 0.01%, 0.02%, 0.03%, 0.04%, 0.05%, 0.06%, 0.07%, 0.08%, 0.10%, 0.12%, 0.16%, 0.18%, 0.19%, 0.20%, 0.21%, 0.22%, 0.23%, 0.24%, 0.25%, 0.26%, 0.27%, 0.28%, 0.29%, 0.30%, 0.31%, 0.32%, 0.33%, 0.34%, 0.35%, 0.36%, 0.37%, 0.38%, 0.39%, 0.40%, 0.41%, 0.42%, 0.43%, 0.44%, 0.45%, 0.46%, 0.47%, 0.48%, 0.49%, 0.50%, 0.51%, 0.52%, 0.53%, 0.54%, 0.55%, 0.56%, 0.57%, 0.58%, 0.60%, 0.61%, 0.62%, 0.70%, 0.75%, 0.80%, 0.85%, 0.90%, 0.95%, 0.96%, 0.97%, 0.98%, 0.99%, 0.89 The composition may be provided in an amount of 0.05%, 0.10%, 0.20%, 0.25%, 0.50%, 0.6%, 0.75%, 0.8%, 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%, 7.5%, 8.0%, 8.5%, 9.0%, 9.5%, 10.0% or greater than 10.0% (wt%). In some embodiments, xanthan gum is provided in the range of about 0.25% to about 1.0%, about 0.1% to about 2.5%, about 0.5% to about 0.8%, about 0.75% to about 2%, or about 0.6% to about 0.8% by weight (wt%).

[0052] The compositions described herein, in some embodiments, include tranexamic acid (TXA) provided with water, mannitol, phosphatidylcholine, glycerin, tranexamic acid, cetyl alcohol, decyl glucoside, potassium sorbate, sodium benzoate, niacinamide, xanthan gum, sodium chloride, or combinations thereof, wherein the sodium chloride is at least or about 0.001%, 0.005%, 0.01%, 0.02%, 0.05%, 0.06%, 0.08%, 0.10%, 0.12%, 0.16%, 0.18%, 0.19%, 0.20%, 0.25%, 0.26%, 0.27%, 0.28%, 0.30%, 0.35%, 0.36%, 0.37%, 0.38%, 0.39%, 0.40%, 0.41%, 0.42%, 0.43%, 0.44%, 0.45%, 0.46%, 0.47%, 0.48%, 0.49%, 0.50%, 0.51%, 0.52%, 0.53%, 0.54%, 0.55%, 0.56%, 0.57%, 0.58%, 0.60%, 0.61%, 0.62%, 0.63%, 0.64%, 0.65%, 0.70%, 0.75%, 0.80%, 0.85%, 0.90%, 0.91%, 0.92%, 0.93%, 0.94%, 0.95%, 0.96%, 0.97%, 0.98%, 0.99%, 0.99%, 0.99%, 0.99%, 0.98%, 0.99%, 0.99%, The composition may be provided in an amount of 0.05%, 0.10%, 0.20%, 0.25%, 0.50%, 0.6%, 0.75%, 0.8%, 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%, 7.5%, 8.0%, 8.5%, 9.0%, 9.5%, 10.0% or greater than 10.0% (wt%). In some embodiments, sodium chloride is provided in the range of about 0.25% to about 1.0% by weight, about 0.1% to about 2.5% by weight, about 0.5% to about 0.8% by weight, about 0.75% to about 2% by weight, or about 0.6% to about 0.8% by weight (wt%).

[0053] Lactoferrin Lactoferrin (Lf) is an 80 kDa iron-binding glycoprotein of the transferrin family found in external secretions (tears, saliva, milk, nasal and bronchial secretions, gastrointestinal fluids, etc.). Lactoferrin effects range from antibacterial to anti-inflammatory and immunomodulatory activity, and it has high iron-binding affinity. Lactoferrin can downregulate TNFα and other cytokine production (IL-1) by local skin cells and may be involved in the resolution of bruises and the prevention of post-inflammatory hyperpigmentation. Lactoferrin may also have a positive effect on wound healing. Lactoferrin is also a plasmin inhibitor and may have an effect on endothelial cell-induced hyperpigmentation, especially melasma.

[0054] In some cases, tryptic peptide fragments derived from lactoferrin promote receptor-mediated MITF degradation. In some cases, tryptic peptide fragments have an inhibitory effect on pigmentation.

[0055] The compositions described herein, in some embodiments, include transferrin. In some embodiments, the transferrin is lactoferrin. In some embodiments, the compositions include trypsinized fragments of lactoferrin. In some embodiments, the compositions include peptides derived from lactoferrin. In some embodiments, the compositions include variants or fragments of lactoferrin. In some cases, the peptides derived from lactoferrin include at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, or more than 30 amino acids of SEQ ID NO:1. Exemplary peptides derived from lactoferrin include, but are not limited to, PRKNVRWCT (SEQ ID NO: 2), LGFLRIP (SEQ ID NO: 3), GYSGAFKC (SEQ ID NO: 4), TCVRR (SEQ ID NO: 5), TCVRRAF (SEQ ID NO: 6), WNSLKDKKSCH (SEQ ID NO: 7), LFNDNTECLAKLG (SEQ ID NO: 8), TTLKNLR (SEQ ID NO: 9), QGLDKCVPNSKE (SEQ ID NO: 10), VKKANE (SEQ ID NO: 11), LAKLGGRP (SEQ ID NO:12), GDVAFVK (SEQ ID NO:13), NLNREDFRL (SEQ ID NO:14), ALGFLRI (SEQ ID NO:15), TTLKNLR (SEQ ID NO:16), DALNLDG (SEQ ID NO:17), LAEDV (SEQ ID NO:18), RAFALEC (SEQ ID NO:19), GAVAKFFS (SEQ ID NO:20), NLRETA (SEQ ID NO:21), EEQKKC (SEQ ID NO:22), CVPNSKEKY (SEQ ID NO:23), and QAYPNL (SEQ ID NO:24).

[0056] (Table 1) TIFF2024535424000001.tif84166

[0057] In some cases, lactoferrin has antibacterial activity. In some cases, lactoferrin has antibacterial activity against bacteria, fungi, yeast, viruses, parasites, or combinations thereof. In some cases, lactoferrin includes antibiofilm activity. In some cases, lactoferrin interacts with bacterial surfaces and destabilizes microbial membranes. In some cases, lactoferrin chelates iron to disrupt microbial membranes.

[0058] In some embodiments, lactoferrin is provided at at least 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 greater than 4% (wt.%). In some embodiments, lactoferrin is provided in the range of about 0.005% to about 0.1%, 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, lactoferrin 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 2.5% by weight, or about 0.02% to about 2% by weight (wt.%). In some embodiments, lactoferrin is provided at about 0.025% by weight or less. In some embodiments, lactoferrin is provided at about 0.05% by weight or less. In some embodiments, lactoferrin is provided at about 0.10% by weight or less. In some embodiments, lactoferrin is provided at at least about 5, 10, 20, 25, 50, 75, 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, 1000, or greater than 1000 micrograms per milliliter (ug / mL). In some embodiments, lactoferrin is provided in the range of about 5 to about 1000, about 10 to about 900, about 30 to about 800, about 50 to about 700, about 60 to about 600, or about 100 to about 500 micrograms per milliliter (ug / mL). In some embodiments, lactoferrin is provided at at least about 1 parts per million (ppm), 2 ppm, 3 ppm, 4 ppm, 5 ppm, 6 ppm, 7 ppm, 8 ppm, 9 ppm, 10 ppm, or greater than 10 ppm. In some embodiments, lactoferrin is provided at about 5 ppm.In some embodiments, lactoferrin is provided in the range of about 1 to about 10, about 2 to about 9, about 3 to about 8, or about 4 to about 6 ppm.

[0059] In some embodiments, lactoferrin is provided at at least or about at least 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 200, 300, 400, 500, or more than 500 milligrams (mg). In some embodiments, lactoferrin is provided in the range of about 5 to about 500, about 10 to about 400, about 15 to about 300, about 20 to about 200, or about 25 to about 100 milligrams (mg). In some embodiments, lactoferrin is provided at about 30 milligrams (mg). In some embodiments, lactoferrin is provided at about 90 milligrams (mg).

[0060] In some embodiments, the peptides derived from lactoferrin are provided at least 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 greater than 4% by weight (wt.%). In some embodiments, the peptides derived from lactoferrin are provided in the range of about 0.005% to about 0.1%, 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, the peptides derived from lactoferrin are 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 2.5% by weight, or about 0.02% to about 2% by weight (wt.%). In some embodiments, the peptides derived from lactoferrin are provided at about 0.025% by weight or less. In some embodiments, the peptides derived from lactoferrin are provided at about 0.05% by weight or less. In some embodiments, the peptides derived from lactoferrin are provided at about 0.10% by weight or less. In some embodiments, the lactoferrin-derived peptides are provided at at least about 5, 10, 20, 25, 50, 75, 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, 1000, 2000, 3000, 4000, 5000, or more than 5000 micrograms per milliliter (ug / mL). In some embodiments, the lactoferrin-derived peptides are provided in the range of about 5 to about 5000, about 10 to about 4000, about 20 to about 3000, about 25 to about 2000, about 50 to about 1000, or about 75 to about 950 ug / mL. In some embodiments, the lactoferrin-derived peptides are provided at about 100 ug / mL.In some embodiments, the peptides derived from lactoferrin are provided at about 1000 ug / mL. In some embodiments, the peptides derived from lactoferrin are provided at at least about 100 parts per million (ppm), 200 ppm, 300 ppm, 400 ppm, 500 ppm, 600 ppm, 700 ppm, 800 ppm, 900 ppm, 1000 ppm, 1100 ppm, 1200 ppm, 1300 ppm, 1400 ppm, 1500 ppm, 1600 ppm, 1700 ppm, 1800 ppm, 1900 ppm, 2000 ppm, or greater. In some embodiments, the lactoferrin-derived peptide is provided in the range of about 100 ppm to about 1900 ppm, about 200 ppm to about 1800 ppm, about 200 ppm to about 1700 ppm, about 400 ppm to about 1600 ppm, about 500 ppm to about 1500 ppm, about 600 ppm to about 1400 ppm, about 700 ppm to about 1300 ppm, about 800 ppm to about 1200 ppm, or about 900 ppm to about 1100 ppm. In some embodiments, the lactoferrin-derived peptide is provided in the range of about 10 ppm to about 1000 ppm, about 50 ppm to about 1000 ppm, about 100 ppm to about 1000 ppm, or about 500 ppm to about 1000 ppm.

[0061] In some embodiments, the peptides derived from lactoferrin are provided at at least or about at least 5, 10, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 60, 75, 80, 85, 90, 100, 200, 300, 400, 500, or more than 500 milligrams (mg). In some embodiments, the peptides derived from lactoferrin are provided in the range of about 5 to about 500, about 10 to about 400, about 15 to about 300, about 20 to about 200, or about 25 to about 100 milligrams (mg). In some embodiments, the peptides derived from lactoferrin are provided at about 30 milligrams (mg). In some embodiments, the peptides derived from lactoferrin are provided at about 90 milligrams (mg).

[0062] Cannabidiol Cannabidiol (CBD) can reduce the activity of the NF-κB pathway, which is the primary pathway that regulates the expression of pro-inflammatory genes. Furthermore, CBD upregulates the activation of the STAT3 transcription factor, which is an element of the homeostatic mechanism(s) that induce anti-inflammatory events. NF-κB can regulate IL-1 beta and IL-6 cytokines. CBD can reduce ongoing pro-inflammatory processes and enhance anti-inflammatory events. In a carrageenan-induced inflammation model in rats, CBD reduced PGE2, nitric oxide (NO), and malondialdehyde production, along with COX activity.

[0063] The compositions described herein, in some embodiments, include cannabidiol (CBD). In some embodiments, CBD is provided at at least about 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, or greater than 200 ug / mL. In some embodiments, CBD is provided in the range of about 10 to about 190 ug / mL, about 20 to about 180 ug / mL, about 30 to about 170 ug / mL, about 40 to about 160 ug / mL, about 50 to about 150 ug / mL, about 60 to about 140 ug / mL, about 70 to about 130 ug / mL, about 80 to about 120 ug / mL, or about 90 to about 110 ug / mL. In some embodiments, CBD is provided at about 100 ug / mL. In some embodiments, CBD is provided at at least 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 more than 4% by weight (wt.%). In some embodiments, CBD is provided in the range of about 0.25% to about 10%, about 0.1% to about 2.5%, about 0.5% to about 8%, about 0.75% to about 6%, or about 1% to about 4% by weight. In some embodiments, CBD 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. In some embodiments, CBD is provided at at least or greater than about 10, 50, 100, 200, 500, 1000, 2000, 2500, 5000, 7500, 10000, 15000, 20000, 25000, 30000, 35000, 40000, or 40000 ppm. In some embodiments, CBD is provided in a range of about 2500 ppm to about 100,000 ppm, about 1000 ppm to about 25,000 ppm, about 5,000 ppm to about 80,000 ppm, about 75,000 ppm to about 60,000 ppm, or about 1,000 ppm to about 40,000 ppm.In some embodiments, CBD is provided in a range of about 10 ppm to about 60,000 ppm, about 20 ppm to about 40,000 ppm, about 100 ppm to about 30,000 ppm, or about 200 ppm to about 20,000 ppm.

[0064] Ashwagandha Extract While other depigmenting agents generally inhibit tyrosinase, Ashwagandha extract (10ug / mL) works by interrupting the ET-1-induced intracellular signaling cascade, mainly consisting of PKC and MAPK pathways, which in turn leads to downregulation of the melanocyte master transcription factor MITF. Reduction of MITF function can then suppress the expression and function of its downstream targets, which results in the attenuation of the synthesis of melanin. Ashwagandha extract can function as a therapeutic tool for ET-1-related hyperpigmentation disorders, such as UVB-melanosis and age spots. Ashwagandha extract can also provide blue light protection and / or help fibroblasts fight the harmful effects of artificial visible light.

[0065] The compositions described herein, in some embodiments, include an Ashwagandha extract (also known as an Ashwagandha root extract). In some embodiments, the Ashwagandha extra is provided at at least about 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 35, 40, or more than 40 micrograms per milliliter (ug / mL). In some embodiments, the Ashwagandha extract is provided in the range of about 0.5 to about 20, about 1 to about 19, about 2 to about 18, about 3 to about 17, about 4 to about 16, about 5 to about 15, about 6 to about 14, about 7 to about 13, about 8 to about 12, or about 9 to about 11 ug / mL. In some embodiments, the Ashwagandha extract is provided at at least about 10 ug / mL. In some embodiments, the Ashwagandha extract is provided at at least about 20 ug / mL.In some embodiments, the Ashwagandha extract is provided at at least or 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 more than 4% by weight (wt.%). In some embodiments, the Ashwagandha extract is provided in the range of about 0.005% to about 0.1% by weight, 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 (wt.%). In some embodiments, the Ashwagandha extract 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 2.5% by weight, about 0.02% to about 2% by weight, or about 0.02% to about 0.5% by weight (wt.%). In some embodiments, the Ashwagandha extract is provided at about 0.025 wt.% or less than about 0.025 wt.%. In some embodiments, the Ashwagandha extract is provided at about 0.05 wt.% or less than about 0.05 wt.%. In some embodiments, the Ashwagandha extract is provided at about 0.10 wt.% or less.In some embodiments, the Ashwagandha extract is provided at or above about at least 0.5, 0.75, 1.0, 1.2, 1.4, 1.6, 1.8, 2, 4, 6, 8, or 10 micrograms (ug).In some embodiments, the Ashwagandha extract is provided in the range of about 0.5 to about 2, about 0.75 to about 5, or about 1.0 to about 4 micrograms (ug).

[0066] The compositions described herein, in some embodiments, include Ashwagandha extract provided with fructose, glycerin, water, or a combination thereof. In some embodiments, the Ashwagandha extract provided with fructose, glycerin, water, or a combination thereof is provided at least about 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 35, 40, or more than 40 micrograms per milliliter (ug / mL). In some embodiments, the Ashwagandha extract provided with fructose, glycerin, water, or a combination thereof is provided in the range of about 0.5 to about 20, about 1 to about 19, about 2 to about 18, about 3 to about 17, about 4 to about 16, about 5 to about 15, about 6 to about 14, about 7 to about 13, about 8 to about 12, or about 9 to about 11 ug / mL. In some embodiments, the Ashwagandha extract provided with fructose, glycerin, water, or a combination thereof is provided at least about 10 ug / mL. In some embodiments, the Ashwagandha extract provided with fructose, glycerin, water, or a combination thereof is provided at least about 20 ug / mL. In some embodiments, the Ashwagandha extract provided with fructose, glycerin, water, or combinations thereof is provided at at least or 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 more than 4% by weight (wt.%). In some embodiments, the Ashwagandha extract provided with fructose, glycerin, water, or combinations thereof is provided in the range of about 0.005% to about 0.1%, 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 (wt.%).In some embodiments, the Ashwagandha extract provided with fructose, glycerin, water, or a combination thereof 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 2.5% by weight, about 0.02% to about 2% by weight, about 0.02% to about 0.5% by weight (wt.%). In some embodiments, the Ashwagandha extract provided with fructose, glycerin, water, or a combination thereof is provided at about 1.0 wt.% or less than about 1.0 wt.%. In some embodiments, the Ashwagandha extract provided with fructose, glycerin, water, or a combination thereof is provided at about 0.025 wt.% or less than about 0.025 wt.%. In some embodiments, Ashwagandha extract provided with fructose, glycerin, water, or a combination thereof is provided at about 0.05 wt.% or less. In some embodiments, Ashwagandha extract provided with fructose, glycerin, water, or a combination thereof is provided at about 0.10 wt.% or less. In some embodiments, Ashwagandha extract provided with fructose, glycerin, water, or a combination thereof is provided at at least or greater than about 0.5, 0.75, 1.0, 1.2, 1.4, 1.6, 1.8, 2, 4, 6, 8, or 10 micrograms (ug). In some embodiments, Ashwagandha extract provided with fructose, glycerin, water, or a combination thereof is provided in the range of about 0.5 to about 2, about 0.75 to about 5, or about 1.0 to about 4 micrograms (ug).

[0067] Gallic Acid Gallic acid (GA), a dietary phenolic present in plants and fruits, may provide beneficial effects against hyperpigmentation, possibly through its antioxidant properties. Gallic acid is a phenolic compound that can suppress melanogenesis in melanoma cells. Gallic acid can downregulate melanogenesis-regulating genes, including TYR, TRP-1, and Dct expression, at the transcriptional and translational levels. In some cases, GA effectively suppressed MITF expression by downregulating the cAMP-mediated PKA / CREB signaling cascade. UV-B-induced hyperpigmentation in mouse skin was significantly cleared by topical application of GA for 4 weeks.

[0068] In some embodiments, the compositions described herein include gallic acid (e.g., diglucosyl gallic acid). In some cases, GA is present at about 50 ppm or less to 1000, 5000, 10000, 50000, 100000, 500000 ppm or more, such as 100 ppm GA. In some cases, GA is present at about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 50, 75, 100, 200, 300, 400, 500, 600, 700, 800, 900, 1000, or more than 1000 ppm. In some cases, GA is present in the range of about 1 to about 100, about 1 to about 50, about 1 to about 40, about 1 to about 30, about 1 to about 20, about 1 to about 10, about 5 to about 90, about 10 to about 80, about 20 to about 60, or about 30 to about 50 ppm. In some cases, GA is present at about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 50, 75, 100, 200, 300, 400, 500, 600, 700, 800, 900, 1000, or greater than 1000 micrograms per milliliter (ug / mL). In some cases, GA is present in the range of about 1 to about 100, about 1 to about 50, about 1 to about 40, about 1 to about 30, about 1 to about 20, about 1 to about 10, about 5 to about 90, about 10 to about 80, about 20 to about 60, or about 30 to about 50 ug / mL. In some cases, GA is present in about 0.01% to about 10% by weight, about 0.01% to about 0.02% by weight, about 0.01% to about 0.03% by weight, about 0.01% to about 0.04% by weight, about 0.01% to about 0.05% by weight, about 0.01% to about 0.1% by weight, about 1% to about 5% by weight, or about 1% to about 10% by weight (wt.%). In some cases, GA is present in about 2.0 wt.% or less than about 2.0 wt.%.

[0069] In some embodiments, gallic acid (e.g., diglucosyl gallic acid) is provided with glycerin, water, or a combination thereof. In some cases, the gallic acid (e.g., diglucosyl gallic acid) provided with glycerin, water, or a combination thereof is present at about 50 ppm or less to 1000, 5000, 10000, 50000, 100000, 500000 ppm or more, such as 100 ppm GA. In some cases, the gallic acid (e.g., diglucosyl gallic acid) provided with glycerin, water, or a combination thereof is present at about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 50, 75, 100, 200, 300, 400, 500, 600, 700, 800, 900, 1000, or more than 1000 ppm. In some cases, the gallic acid (e.g., diglucosyl gallic acid) provided with the glycerin, water, or combination thereof is present in a range of about 1 to about 100, about 1 to about 50, about 1 to about 40, about 1 to about 30, about 1 to about 20, about 1 to about 10, about 5 to about 90, about 10 to about 80, about 20 to about 60, or about 30 to about 50 ppm. In some cases, the gallic acid (e.g., diglucosyl gallic acid) provided with the glycerin, water, or combination thereof is present in an amount of about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 50, 75, 100, 200, 300, 400, 500, 600, 700, 800, 900, 1000, or greater than 1000 micrograms per milliliter (ug / mL). In some cases, the gallic acid (e.g., diglucosyl gallic acid) provided with glycerin, water, or a combination thereof is present in the range of about 1 to about 100, about 1 to about 50, about 1 to about 40, about 1 to about 30, about 1 to about 20, about 1 to about 10, about 5 to about 90, about 10 to about 80, about 20 to about 60, or about 30 to about 50 ug / mL.In some cases, the gallic acid (e.g., diglucosyl gallic acid) provided with glycerin, water, or a combination thereof is present at about 0.01% to about 10% by weight, about 0.01% to about 0.02% by weight, about 0.01% to about 0.03% by weight, about 0.01% to about 0.04% by weight, about 0.01% to about 0.05% by weight, about 0.01% to about 0.1% by weight, about 1% to about 5% by weight, or about 1% to about 10% by weight (wt.%). In some cases, the gallic acid (e.g., diglucosyl gallic acid) provided with glycerin, water, or a combination thereof is present at about 2.0 wt.% or less than about 2.0 wt.%. In some cases, the gallic acid (eg, diglucosyl gallic acid) provided with the glycerin, water, or combination thereof is present at about 1.0 wt.% or less.

[0070] Sesamol Sesamol (3,4-methylenedioxyphenol) is an active lignin isolated from sesame (Sesamum indicum). In melan-a cells, sesamol can inhibit melanin biosynthesis and the activity of intracellular tyrosinase by decreasing cyclic adenosine monophosphate (cAMP) accumulation. Sesamol can decrease the expression of melanogenesis-related genes, such as TYR, TRP-1, TRP-2, MITF, and MC1R. Sesamol can inhibit melanin biosynthesis.

[0071] The compositions described herein include sesamol in some embodiments. In some embodiments, sesamol is provided at a concentration of at least about 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, or greater than 100 μM. In some embodiments, sesamol is provided at a concentration ranging from about 5 to about 100 μM, about 10 to about 90 μM, about 20 to about 80 μM, about 30 to about 70 μM, or about 40 to about 60 μM. In some embodiments, sesamol is provided at a concentration of about 50 μM. In some cases, sesamol is present at about 50 ppm or less to 1000, 5000, 10000, 50000, 100000, 500000 ppm or more, e.g., 100 ppm of sesamol. In some cases, sesamol is present at about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 50, 75, 100, 200, 300, 400, 500, 600, 700, 800, 900, 1000, or greater than 1000 ppm. In some cases, sesamol is present in a range of about 1 to about 100, about 1 to about 50, about 1 to about 40, about 1 to about 30, about 1 to about 20, about 1 to about 10, about 5 to about 90, about 10 to about 80, about 20 to about 60, or about 30 to about 50 ppm. In some cases, sesamol is present at about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 50, 75, 100, 200, 300, 400, 500, 600, 700, 800, 900, 1000, or greater than 1000 micrograms per milliliter (ug / mL). In some cases, sesamol is present in the range of about 1 to about 100, about 1 to about 50, about 1 to about 40, about 1 to about 30, about 1 to about 20, about 1 to about 10, about 5 to about 90, about 10 to about 80, about 20 to about 60, or about 30 to about 50 ug / mL. In some embodiments, sesamol is provided at about 100 ug / mL. In some cases, sesamol is present at at least or about at least 0.001%, 0.002%, 0.003%, 0.004%, 0.005%, 0.01%, 0.05%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, or more than 0.5% by weight (wt.%).In some cases, sesamol is present at about 0.002% to about 0.05%, about 0.001% to about 0.5%, about 0.002% to about 0.4%, about 0.003% to about 0.3%, about 0.004% to about 0.2%, or about 0.005% to about 0.05% by weight (wt.%). In some cases, sesamol is present at at least or about 0.01 wt.%.

[0072] In some embodiments, sesamol is provided at at least or about at least 0.25, 0.5, 0.75, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 20, 30, 40, 50, or more than 50 milligrams (mg). In some embodiments, sesamol is provided in the range of about 5 to about 50, about 10 to about 40, or about 20 to about 30 milligrams (mg). In some embodiments, sesamol is provided at about 3 milligrams (mg). In some embodiments, sesamol is provided at about 9 milligrams (mg).

[0073] Acteoside Acteoside is a phenylpropanoid glycoside extracted from the leaves of Rehmannia glutinosa. Acteoside can inhibit tyrosinase activity and melanin synthesis in both cell-free assay systems and cultured B16F10 melanoma cells. Acteoside can decrease the levels of TYR, TRP-1, and MITF proteins and increase ERK phosphorylation. In some cases, acteoside suppressed melanin formation induced by α-MSH and showed a UV-absorbing effect.

[0074] The compositions described herein, in some embodiments, include acteoside. In some embodiments, acteoside is provided at a concentration of at least about 50, 100, 200, 300, 400, 500, 600, 700, 800, 900, 1000, or more than 1000 μM. In some embodiments, acteoside is provided at a concentration ranging from about 50 to about 1000 μM, about 100 to about 900 μM, about 200 to about 800 μM, about 300 to about 700 μM, or about 400 to about 600 μM. In some embodiments, acteoside is provided at a concentration of about 500 μM. In some cases, acteoside is present at about 50 ppm or less to 1000, 5000, 10000, 50000, 100000, 500000 ppm or more, such as 100 ppm acteoside. In some cases, acteoside is present at about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 50, 75, 100, 200, 300, 400, 500, 600, 700, 800, 900, 1000, or more than 1000 ppm. In some cases, acteoside is present in the range of about 1 to about 100, about 1 to about 50, about 1 to about 40, about 1 to about 30, about 1 to about 20, about 1 to about 10, about 5 to about 90, about 10 to about 80, about 20 to about 60, or about 30 to about 50 ppm. In some cases, acteoside is present at about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 50, 75, 100, 200, 300, 400, 500, 600, 700, 800, 900, 1000, or greater than 1000 micrograms per milliliter (ug / mL). In some cases, acteoside is present in the range of about 1 to about 100, about 1 to about 50, about 1 to about 40, about 1 to about 30, about 1 to about 20, about 1 to about 10, about 5 to about 90, about 10 to about 80, about 20 to about 60, or about 30 to about 50 micrograms per milliliter. In some cases, acteoside is present in about 0.01% to about 10% by weight, about 0.01% to about 0.02% by weight, about 0.01% to about 0.03% by weight, about 0.01% to about 0.04% by weight, about 0.01% to about 0.05% by weight, about 0.01% to about 0.1% by weight, about 1% to about 5% by weight, or about 1% to about 10% by weight (wt.%).

[0075] Oleuropein Oleuropein, a potent anti-inflammatory antioxidant derived from the olive tree, exhibited 90% tyrosinase inhibitory activity and the inhibitory pattern was non-competitive competitive.

[0076] The compositions described herein, in some embodiments, include oleuropein. In some cases, oleuropein is present at about 50 ppm or less to 1000, 5000, 10000, 50000, 100000, 500000 ppm or more, for example, 100 ppm oleuropein. In some cases, oleuropein is present at about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 50, 75, 100, 200, 300, 400, 500, 600, 700, 800, 900, 1000, or more than 1000 ppm. In some cases, oleuropein is present in the range of about 1 to about 100, about 1 to about 50, about 1 to about 40, about 1 to about 30, about 1 to about 20, about 1 to about 10, about 5 to about 90, about 10 to about 80, about 20 to about 60, or about 30 to about 50 ppm. In some cases, oleuropein is present at about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 50, 75, 100, 200, 300, 400, 500, 600, 700, 800, 900, 1000, 1200, 1400, 1600, 1800, 2000, or greater than 2000 micrograms per milliliter (ug / mL). In some cases, oleuropein is present in the range of about 10 to about 1000, about 10 to about 500, about 10 to about 400, about 10 to about 300, about 10 to about 200, about 100 to about 1000, about 200 to about 800, about 300 to about 600, or about 200 to about 1200 ug / mL. In some cases, oleuropein is present at about 0.01 wt.% to about 10 wt.%, about 0.01 wt.% to about 0.02 wt.%, about 0.01 wt.% to about 0.03 wt.%, about 0.01 wt.% to about 0.04 wt.%, about 0.01 wt.% to about 0.05 wt.%, about 0.01 wt.% to about 0.1 wt.%, about 0.03 wt.% to about 0.750 wt.%, about 0.1 wt.% to about 5 wt.%, or about 0.1 wt.% to about 10 wt.%. In some cases, oleuropein is present at about 0.15 wt.% or less.

[0077] In some embodiments, oleuropein is provided at least or about at least 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 200, 300, 400, 500, or more than 500 milligrams (mg). In some embodiments, oleuropein is provided in the range of about 5 to about 500, about 10 to about 400, about 15 to about 300, about 20 to about 200, or about 25 to about 100 milligrams (mg). In some embodiments, oleuropein is provided at about 30 milligrams (mg). In some embodiments, oleuropein is provided at about 90 milligrams (mg).

[0078] Hesperidin Hesperidin is one of the citrus flavonoids shown to be active against various oxidative stress-mediated diseases. Hesperidin can inhibit melanosome transport in melanocytes and showed skin lightening effect in pigmented reconstituted epidermis model. Rab27A, melanophilin, and myosin Va create a complex to bind melanosomes with phosphatidylserine, thereby binding melanosomes with plasma membrane. Darkly pigmented melanocytes with significantly higher RAB27A expression can transfer significantly more melanosomes to keratinocytes than lightly pigmented melanocytes in co-culture and in vivo. Hesperidin may have depigmenting effect by blocking Rab27A-melanophilin interaction.

[0079] In some embodiments, hesperidin is glucosyl hesperidin. Glucosyl hesperidin is a highly soluble bioflavonoid. When cosmetics containing glucosyl hesperidin are applied to skin, an enzyme naturally present in skin called a-glucosidase slowly releases the health benefits of hesperidin.By promoting surface circulation, glucosyl hesperidin improves skin tone and color, and is effective in treating dark circles under the eyes, dull complexion, tired skin, aging skin, and puffy skin.

[0080] In some embodiments, the compositions provided herein include hesperidin (e.g., glucosyl hesperidin). In some cases, the hesperidin is present at about 50 ppm or less to 1000, 5000, 10000, 50000, 100000, 500000 ppm or more, such as 100 ppm hesperidin. In some cases, the hesperidin is present at about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 50, 75, 100, 200, 300, 400, 500, 600, 700, 800, 900, 1000, or more than 1000 ppm. In some cases, hesperidin is present in the range of about 1 to about 100, about 1 to about 50, about 1 to about 40, about 1 to about 30, about 1 to about 20, about 1 to about 10, about 5 to about 90, about 10 to about 80, about 20 to about 60, or about 30 to about 50 ppm. In some cases, hesperidin is present at about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 50, 75, 100, 200, 300, 400, 500, 600, 700, 800, 900, 1000, or greater than 1000 micrograms per milliliter (ug / mL). In some cases, hesperidin is present in the range of about 1 to about 100, about 1 to about 50, about 1 to about 40, about 1 to about 30, about 1 to about 20, about 1 to about 10, about 5 to about 90, about 10 to about 80, about 20 to about 60, or about 30 to about 50 ug / mL. In some cases, hesperidin is present at about 0.01 wt.% to about 10 wt.%, about 0.01 wt.% to about 0.02 wt.%, about 0.01 wt.% to about 0.03 wt.%, about 0.01 wt.% to about 0.04 wt.%, about 0.01 wt.% to about 0.05 wt.%, about 0.01 wt.% to about 0.1 wt.%, about 0.020 to about 0.50 wt.%, about 1 wt.% to about 5 wt.%, or about 1 wt.% to about 10 wt.%. In some cases, hesperidin is present at about 0.10 wt.% or less than about 0.10 wt.%. In some cases, hesperidin is present at about 0.25 wt.% or less than about 0.25 wt.%.

[0081] Sideroxylon Inerme L. stem bark The compositions described herein, in some embodiments, include a Sideroxylon inerme extract. In some cases, the Sideroxylon inerme extract is present at about 50 ppm or less to 1000, 5000, 10000, 50000, 100000, 500000 ppm or more, such as 100 ppm of Sideroxylon inerme extract. In some cases, the Sideroxylon inerme extract is present at about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 50, 75, 100, 200, 300, 400, 500, 600, 700, 800, 900, 1000, or more than 1000 ppm. In some cases, the Sideroxylon inerme extract is present in the range of about 1 to about 100, about 1 to about 50, about 1 to about 40, about 1 to about 30, about 1 to about 20, about 1 to about 10, about 5 to about 90, about 10 to about 80, about 20 to about 60, or about 30 to about 50 ppm. In some cases, the Sideroxylon inerme extract is present in an amount of about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 50, 75, 100, 200, 300, 400, 500, 600, 700, 800, 900, 1000, or greater than 1000 micrograms per milliliter (ug / mL). In some cases, the Sideroxylon inerme extract is present in the range of about 1 to about 100, about 1 to about 50, about 1 to about 40, about 1 to about 30, about 1 to about 20, about 1 to about 10, about 5 to about 90, about 10 to about 80, about 20 to about 60, or about 30 to about 50 ug / mL. In some cases, the Sideroxylon inerme extract is present in the range of about 0.01% to about 10% by weight, about 0.01% to about 0.02% by weight, about 0.01% to about 0.03% by weight, about 0.01% to about 0.04% by weight, about 0.01% to about 0.05% by weight, about 0.01% to about 0.1% by weight, about 1% to about 5% by weight, or about 1% to about 10% by weight (wt.%).

[0082] Parthenolide Parthenolide is a sesquiterpene lactone compound and is the active substance in the medicinal herb, feverfew (Tanacetum parthenium), which can be used in inflammation. Parthenolide is an NF-κB inhibitor, which can block UVB-mediated skin changes by inhibiting NF-kB-mediated gene expression and reducing the production of bFGF and MMP-1 from cells. In some cases, bFGF production is induced by ultraviolet light and promotes the proliferation of skin keratinocytes and melanocytes.

[0083] The compositions described herein, in some embodiments, include parthenolide. In some embodiments, parthenolide is provided at least 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 more than 4% by weight (wt.%). In some embodiments, parthenolide is provided in the range of about 0.25% to about 10%, about 0.1% to about 2.5%, about 0.5% to about 8%, about 0.75% to about 6%, or about 1% to about 4% by weight. In some embodiments, parthenolide 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, or about 0.02% to about 2% by weight (wt.%). In some embodiments, parthenolide is provided at least or greater than about 10, 50, 100, 200, 500, 1000, 2000, 2500, 5000, or 5000 ppm. In some embodiments, parthenolide is provided in the range of about 25 ppm to about 100 ppm, about 100 ppm to about 250 ppm, about 50 ppm to about 800 ppm, about 75 ppm to about 600 ppm, or about 10 ppm to about 400 ppm. In some embodiments, parthenolide is provided in a range of about 10 ppm to about 60 ppm, about 20 ppm to about 40 ppm, about 100 ppm to about 300 ppm, or about 200 ppm to about 2000 ppm.

[0084] Pancratium maritimum In some cases, melanin release by melanocytes to keratinocytes is stimulated by neuropeptides released by nerve fibers present in the epidermis that contain substance P. Pancratium maritimum extract (PME, sea lily extract) is able to inhibit melanin transfer, at least in part, through its action on substance P receptors present on melanocyte dendrites, providing an effective and original solution for the treatment of pigmented spots.

[0085] The compositions described herein, in some embodiments, include a Pancratium maritimum extract. In some cases, the Pancratium maritimum extract is present at about 50 ppm or less to 1000, 5000, 10000, 50000, 100000, 500000 ppm or more, such as 100 ppm Pancratium maritimum extract. In some cases, the Pancratium maritimum extract is present at about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 50, 75, 100, 200, 300, 400, 500, 600, 700, 800, 900, 1000, or more than 1000 ppm. In some cases, the Pancratium maritimum extract is present in the range of about 1 to about 100, about 1 to about 50, about 1 to about 40, about 1 to about 30, about 1 to about 20, about 1 to about 10, about 5 to about 90, about 10 to about 80, about 20 to about 60, or about 30 to about 50 ppm. In some cases, the Pancratium maritimum extract is present at about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 50, 75, 100, 200, 300, 400, 500, 600, 700, 800, 900, 1000, or greater than 1000 micrograms per milliliter (ug / mL). In some cases, the Pancratium maritimum extract is present in the range of about 1 to about 100, about 1 to about 50, about 1 to about 40, about 1 to about 30, about 1 to about 20, about 1 to about 10, about 5 to about 90, about 10 to about 80, about 20 to about 60, or about 30 to about 50 ug / mL. In some cases, the Pancratium maritimum extract is present at about 0.01 wt.% to about 10 wt.%, about 0.01 wt.% to about 0.02 wt.%, about 0.01 wt.% to about 0.03 wt.%, about 0.01 wt.% to about 0.04 wt.%, about 0.01 wt.% to about 0.05 wt.%, about 0.01 wt.% to about 0.1 wt.%, about 0.5 wt.% to about 5 wt.%, about 1 wt.% to about 5 wt.%, or about 1 wt.% to about 10 wt.%. In some cases, the Pancratium maritimum extract is present at at least or about at least 1.5 wt.%.

[0086] The compositions described herein, in some embodiments, include a Pancratium maritimum extract provided with glycerin, water, or a combination thereof. In some cases, the Pancratium maritimum extract is present in an amount of about 50 ppm or less to 1000, 5000, 10000, 50000, 100000, 500000 ppm or more of the Pancratium maritimum extract provided with glycerin, water, or a combination thereof, such as 100 ppm of the Pancratium maritimum extract provided with glycerin, water, or a combination thereof. In some cases, the pancratium maritimum extract provided with glycerin, water, or a combination thereof is present in an amount of about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 50, 75, 100, 200, 300, 400, 500, 600, 700, 800, 900, 1000, or greater than 1000 ppm. In some cases, the pancratium maritimum extract provided with glycerin, water, or a combination thereof is present in an amount of about 1 to about 100, about 1 to about 50, about 1 to about 40, about 1 to about 30, about 1 to about 20, about 1 to about 10, about 5 to about 90, about 10 to about 80, about 20 to about 60, or about 30 to about 50 ppm. In some cases, the pancratium maritimum extract provided with glycerin, water, or a combination thereof is present in an amount of about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 50, 75, 100, 200, 300, 400, 500, 600, 700, 800, 900, 1000, or greater than 1000 micrograms per milliliter (ug / mL). In some cases, the pancratium maritimum extract provided with glycerin, water, or a combination thereof is present in an amount of about 1 to about 100, about 1 to about 50, about 1 to about 40, about 1 to about 30, about 1 to about 20, about 1 to about 10, about 5 to about 90, about 10 to about 80, about 20 to about 60, or about 30 to about 50 ug / mL.In some cases, the pancratium maritimum extract provided with glycerin, water, or a combination thereof is present at about 0.01 wt.% to about 10 wt.%, about 0.01 wt.% to about 0.02 wt.%, about 0.01 wt.% to about 0.03 wt.%, about 0.01 wt.% to about 0.04 wt.%, about 0.01 wt.% to about 0.05 wt.%, about 0.01 wt.% to about 0.1 wt.%, about 0.5 wt.% to about 5 wt.%, about 1 wt.% to about 5 wt.%, or about 1 wt.% to about 10 wt.%. In some cases, the pancratium maritimum extract provided with glycerin, water, or a combination thereof is present at at least or about at least 1.5 wt.%.

[0087] Autophagy Agents In some cases, the compositions described herein include an autophagy agent for degrading melanosomes. In some cases, the autophagy agent is present at about 50 ppm or less to 1000, 5000, 10000, 50000, 100000, 500000 ppm or more, for example, 100 ppm of the autophagy agent. In some cases, the autophagy agent is present at about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 50, 75, 100, 200, 300, 400, 500, 600, 700, 800, 900, 1000, or more than 1000 ppm. In some cases, the autophagy agent is present in the range of about 1 to about 100, about 1 to about 50, about 1 to about 40, about 1 to about 30, about 1 to about 20, about 1 to about 10, about 5 to about 90, about 10 to about 80, about 20 to about 60, or about 30 to about 50 ppm. In some cases, the autophagy agent is present at about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 50, 75, 100, 200, 300, 400, 500, 600, 700, 800, 900, 1000, or greater than 1000 micrograms per milliliter (ug / mL). In some cases, the autophagy agent is present in the range of about 1 to about 100, about 1 to about 50, about 1 to about 40, about 1 to about 30, about 1 to about 20, about 1 to about 10, about 5 to about 90, about 10 to about 80, about 20 to about 60, or about 30 to about 50 micrograms per milliliter. In some cases, the autophagy agent is present in about 0.01% to about 10% by weight, about 0.01% to about 0.02% by weight, about 0.01% to about 0.03% by weight, about 0.01% to about 0.04% by weight, about 0.01% to about 0.05% by weight, about 0.01% to about 0.1% by weight, about 1% to about 5% by weight, or about 1% to about 10% by weight (wt.%).

[0088] In some cases, the autophagy agent includes water, 1,2-hexanediol, pentasodium tetracarboxymethyl dipeptide-51, pentasodium tetracarboxymethyl acetyl hydroxyprolyl dipeptide-12, or a combination thereof. In some cases, the autophagy agent includes water, 1,2-hexanediol, pentasodium tetracarboxymethyl dipeptide-51, pentasodium tetracarboxymethyl acetyl hydroxyprolyl dipeptide-12, or a combination thereof, at about 50 ppm or less to 1000, 5000, 10000, 50000, 100000, 500000 ppm or more of the autophagy agent, for example, 100 ppm. In some cases, the autophagy agent comprises water, 1,2-hexanediol, pentasodium tetracarboxymethyl dipeptide-51, pentasodium tetracarboxymethyl acetyl hydroxyprolyl dipeptide-12, or a combination thereof present at about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 50, 75, 100, 200, 300, 400, 500, 600, 700, 800, 900, 1000, or greater than 1000 ppm. In some cases, the autophagy agent includes water, 1,2-hexanediol, pentasodium tetracarboxymethyl dipeptide-51, pentasodium tetracarboxymethyl acetyl hydroxyprolyl dipeptide-12, or a combination thereof present in a range of about 1 to about 100, about 1 to about 50, about 1 to about 40, about 1 to about 30, about 1 to about 20, about 1 to about 10, about 5 to about 90, about 10 to about 80, about 20 to about 60, or about 30 to about 50 ppm. In some cases, the autophagy agent comprises water, 1,2-hexanediol, pentasodium tetracarboxymethyl dipeptide-51, pentasodium tetracarboxymethyl acetyl hydroxyprolyl dipeptide-12, or a combination thereof present at greater than about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 50, 75, 100, 200, 300, 400, 500, 600, 700, 800, 900, 1000, or 1000 micrograms per milliliter (ug / mL).In some cases, the autophagy agent comprises water, 1,2-hexanediol, pentasodium tetracarboxymethyl dipeptide-51, pentasodium tetracarboxymethyl acetyl hydroxyprolyl dipeptide-12, or a combination thereof present in a range of about 1 to about 100, about 1 to about 50, about 1 to about 40, about 1 to about 30, about 1 to about 20, about 1 to about 10, about 5 to about 90, about 10 to about 80, about 20 to about 60, or about 30 to about 50 micrograms per milliliter. In some cases, the autophagy agent comprises water, 1,2-hexanediol, pentasodium tetracarboxymethyl dipeptide-51, pentasodium tetracarboxymethyl acetyl hydroxyprolyl dipeptide-12, or a combination thereof, present at about 0.01% to about 10% by weight, about 0.01% to about 0.02% by weight, about 0.01% to about 0.03% by weight, about 0.01% to about 0.04% by weight, about 0.01% to about 0.05% by weight, about 0.01% to about 0.1% by weight, about 1% to about 5% by weight, or about 1% to about 10% by weight (wt.%). In some cases, the autophagy agent comprises water, 1,2-hexanediol, pentasodium tetracarboxymethyl dipeptide-51, pentasodium tetracarboxymethyl acetyl hydroxyprolyl dipeptide-12, or a combination thereof, present at about 1.5% by weight.

[0089] Niacinamide Niacinamide is a form of vitamin B3. Once synthesized, melanin pigment is packaged into melanosomes and transferred from melanocytes to their neighboring basal keratinocytes via melanocyte dendrites. To inhibit this transfer, niacinamide can reduce the formation of dendrites. In some embodiments, niacinamide helps to rebalance pigmentation, refine pores, and improve skin elasticity and resilience. In some embodiments, niacinamide enhances the effectiveness of products designed for blemished skin, dry and sensitive skin, and mature skin. In some embodiments, niacinamide protects UV-stressed skin.

[0090] The compositions described herein, in some embodiments, include niacinamide. In some embodiments, niacinamide is provided at least about 0.25 wt.%, 0.5 wt.%, 1 wt.%, 1.5 wt.%, 2 wt.%, 2.5 wt.%, 3 wt.%, 3.5 wt.%, 4 wt.%, 4.5 wt.%, 5 wt.%, 5.5 wt.%, 6 wt.%, 6.5 wt.%, 7 wt.%, 7.5 wt.%, 8 wt.%, 8.5 wt.%, 9 wt.%, 9.5 wt.%, 10 wt.%, or more than 10 wt.% (wt.%). In some embodiments, niacinamide is provided in the range of about 0.25 wt.% to about 10 wt.%, about 0.5 wt.% to about 9.5 wt.%, about 1 wt.% to about 9 wt.%, about 1.5 wt.% to about 8.5 wt.%. In some embodiments, niacinamide is provided at least or about at least 2.0 wt.%.

[0091] White fungus Tremella fuciformis can inhibit melanin production. The compositions described herein, in some embodiments, include Tremella fuciformis extract (also known as Tremella fuciformis ascocyst extract or White Wood Ear Extract). In some embodiments, the Tremella fuciformis extract is derived from an edible mushroom. In some embodiments, the Tremella fuciformis extract provides moisture and antioxidant properties.

[0092] In some embodiments, Tremella fuciformis extract is provided at at least or about 0.001 weight percent (wt.%), 0.005 wt.%, 0.01 wt.%, 0.02 wt.%, 0.05 wt.%, 0.10 wt.%, 0.20 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.%, or greater than 4 wt.%. In some embodiments, Tremella fuciformis extract is provided in the range of about 0.25 wt.% to about 10 wt.%, about 0.1 wt.% to about 2.5 wt.%, about 0.5 wt.% to about 8 wt.%, about 0.75 wt.% to about 6 wt.%, or about 1 wt.% to about 4 wt.%. In some embodiments, Tremella fuciformis extract is provided in the range of about 0.001 wt.% to about 6 wt.%, about 0.002 wt.% to about 4 wt.%, about 0.01 wt.% to about 3 wt.%, about 0.02 wt.% to about 2 wt.%, or about 0.20 wt.% to about 5.0 wt.%. In some embodiments, Tremella fuciformis extract is provided at least or about at least 1.0 wt.%.

[0093] In some embodiments, Tremella fuciformis extract is provided with water, betaine, glycerin, or a combination thereof. In some embodiments, Tremella fuciformis extract provided with water, betaine, glycerin, or a combination thereof is provided at least or about 0.001 weight percent (wt.%), 0.005 wt.%, 0.01 wt.%, 0.02 wt.%, 0.05 wt.%, 0.10 wt.%, 0.20 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.%, or greater than 4 wt.%. In some embodiments, the Tremella fuciformis extract provided with water, betaine, glycerin, or a combination thereof is provided in a range of about 0.25 wt.% to about 10 wt.%, about 0.1 wt.% to about 2.5 wt.%, about 0.5 wt.% to about 8 wt.%, about 0.75 wt.% to about 6 wt.%, or about 1 wt.% to about 4 wt.%. In some embodiments, the Tremella fuciformis extract provided with water, betaine, glycerin, or a combination thereof is provided in a range of about 0.001 wt.% to about 6 wt.%, about 0.002 wt.% to about 4 wt.%, about 0.01 wt.% to about 3 wt.%, about 0.02 wt.% to about 2 wt.%, or about 0.20 wt.% to about 5.0 wt.%. In some embodiments, Tremella fuciformis extract provided with water, betaine, glycerin, or combinations thereof is provided at at least or about at least 1.0 wt%.

[0094] Thermus thermophilus extract Thermus thermophilus fermentation can act as an antioxidant, particularly with respect to PGE2. The compositions described herein, in some embodiments, include Thermus thermophilus fermentation (also known as Thermus thermophilus extract). In some cases, the Thermus thermophilus extract is present at about 50 ppm or less to 1000, 5000, 10000, 50000, 100000, 500000 ppm or more, e.g., 100 ppm Thermus thermophilus extract. In some cases, the Thermus thermophilus extract is present at about 0.01, 0.05, 0.1, 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 50, 75, 100, 200, 300, 400, 500, 600, 700, 800, 900, 1000, or greater than 1000 ppm. In some cases, the Thermus thermophilus extract is present in a range of about 0.01 to about 11, about 0.1 to about 100, about 1 to about 100, about 1 to about 50, about 1 to about 40, about 1 to about 30, about 1 to about 20, about 1 to about 10, about 5 to about 90, about 10 to about 80, about 20 to about 60, or about 30 to about 50 ppm. In some cases, the Thermus thermophilus extract is present at about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 50, 75, 100, 200, 300, 400, 500, 600, 700, 800, 900, 1000, or greater than 1000 micrograms per milliliter (ug / mL). In some cases, the Thermus thermophilus extract is present in a range of about 1 to about 100, about 1 to about 50, about 1 to about 40, about 1 to about 30, about 1 to about 20, about 1 to about 10, about 5 to about 90, about 10 to about 80, about 20 to about 60, or about 30 to about 50 ug / mL. In some cases, the Thermus thermophilus extract is present at about 0.01 weight percent (wt.%) to about 10 wt.%, about 0.01 wt.% to about 0.02 wt.%, about 0.01 wt.% to about 0.03 wt.%, about 0.01 wt.% to about 0.04 wt.%, about 0.01 wt.% to about 0.05 wt.%, about 0.01 wt.% to about 0.1 wt.%, about 0.3 wt.% to about 7.5 wt.%, about 1 wt.% to about 5 wt.%, or about 1 wt.% to about 10 wt.%.In some cases, the Thermus thermophilus extract is present at a concentration of at least about 0.01 wt.% or at least about 1.5 wt.%.

[0095] The compositions described herein, in some embodiments, include Thermus thermophilus fermentation extract provided with glycerin. In some cases, the Thermus thermophilus extract and glycerin are present at about 50 ppm or less to 1000, 5000, 10000, 50000, 100000, 500000 ppm or more, such as 100 ppm Thermus thermophilus extract and glycerin. In some cases, the Thermus thermophilus extract and glycerin are present at about 0.01, 0.1, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 50, 75, 100, 200, 300, 400, 500, 600, 700, 800, 900, 1000, or more than 1000 ppm. In some cases, the Thermus thermophilus extract and glycerin are present in the range of about 0.01 to about 100, about 1 to about 100, about 1 to about 50, about 1 to about 40, about 1 to about 30, about 1 to about 20, about 1 to about 10, about 5 to about 90, about 10 to about 80, about 20 to about 60, or about 30 to about 50 ppm. In some cases, the Thermus thermophilus extract and glycerin are present in an amount of about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 50, 75, 100, 200, 300, 400, 500, 600, 700, 800, 900, 1000, or greater than 1000 micrograms per milliliter (ug / mL). In some cases, the Thermus thermophilus extract and glycerin are present in the range of about 1 to about 100, about 1 to about 50, about 1 to about 40, about 1 to about 30, about 1 to about 20, about 1 to about 10, about 5 to about 90, about 10 to about 80, about 20 to about 60, or about 30 to about 50 ug / mL. In some cases, the Thermus thermophilus extract and glycerin are present at about 0.01 weight percent (wt.%) to about 10 wt.%, about 0.01 wt.% to about 0.02 wt.%, about 0.01 wt.% to about 0.03 wt.%, about 0.01 wt.% to about 0.04 wt.%, about 0.01 wt.% to about 0.05 wt.%, about 0.01 wt.% to about 0.1 wt.%, about 0.3 wt.% to about 7.5 wt.%, about 1 wt.% to about 5 wt.%, or about 1 wt.% to about 10 wt.%.In some cases, the Thermus thermophilus extract and glycerin are present in a concentration of at least about 0.01 wt.% or at least about 1.5 wt.%.

[0096] Phytoene and Phytofluene The compositions described herein, in some embodiments, include phytoene, phytofluene, or a combination thereof. Phytoene and phytofluene are colorless carotenoids derived from saltwater microalgae that modulate prostaglandin E-2 (PGE-2).

[0097] In some embodiments, phytoene, phytofluene, or a combination thereof is provided at least about 0.5%, 1.0%, 2.0%, 3.0%, 4.0%, 5.0%, 6.0%, 7.0%, 8.0%, 9.0%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, or greater than 20% by weight (wt.%). In some embodiments, phytoene, phytofluene, or a combination thereof is provided in a range of about 0.5% to about 20% by weight, about 1.0% to about 15% by weight, about 2.0% to about 12% by weight, about 3.0% to about 10% by weight, or about 4.0% to about 8% by weight (wt.%). In some cases, phytoene, phytofluene, or a combination thereof is provided at at least or about 5.0 wt.%. In some cases, phytoene, phytofluene, or a combination thereof is present at greater than about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 50, 75, 100, 200, 300, 400, 500, 600, 700, 800, 900, 1000, or 1000 micrograms per milliliter (ug / mL). In some cases, phytoene, phytofluene, or a combination thereof is present in the range of about 1 to about 100, about 1 to about 50, about 1 to about 40, about 1 to about 30, about 1 to about 20, about 1 to about 10, about 5 to about 90, about 10 to about 80, about 20 to about 60, or about 30 to about 50 ug / mL.

[0098] White Horehound White horehound (Marrubium vulgare) may reduce the level of ET-1. The compositions described herein, in some embodiments, include a white horehound extract. In some cases, the white horehound extract is present at about 50 ppm or less to 1000, 5000, 10000, 50000, 100000, 500000 ppm or more, such as 100 ppm of white horehound extract. In some cases, the white horehound extract is present at about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 50, 75, 100, 200, 300, 400, 500, 600, 700, 800, 900, 1000, or more than 1000 ppm. In some cases, the White Horehound extract is present in the range of about 1 to about 100, about 1 to about 50, about 1 to about 40, about 1 to about 30, about 1 to about 20, about 1 to about 10, about 5 to about 90, about 10 to about 80, about 20 to about 60, or about 30 to about 50 ppm. In some cases, the White Horehound extract is present at about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 50, 75, 100, 200, 300, 400, 500, 600, 700, 800, 900, 1000, or greater than 1000 micrograms per milliliter (ug / mL). In some cases, the White Horehound extract is present in the range of about 1 to about 100, about 1 to about 50, about 1 to about 40, about 1 to about 30, about 1 to about 20, about 1 to about 10, about 5 to about 90, about 10 to about 80, about 20 to about 60, or about 30 to about 50 ug / mL. In some cases, the White Horehound extract is present in about 0.01% to about 10% by weight, about 0.01% to about 0.02% by weight, about 0.01% to about 0.03% by weight, about 0.01% to about 0.04% by weight, about 0.01% to about 0.05% by weight, about 0.01% to about 0.1% by weight, about 1% to about 5% by weight, or about 1% to about 10% by weight (wt.%).

[0099] Polypodium Leucotomos Rheum vulgare or Phlebodium aureum contains compounds that may fight inflammation and prevent skin damage. The compositions described herein, in some embodiments, contain Rheum vulgare extract. In some cases, the Rheum vulgare extract is present at about 50 ppm or less to 1000, 5000, 10000, 50000, 100000, 500000 ppm or more, e.g., 100 ppm Rheum vulgare extract. In some cases, the Rheum vulgare extract is present at about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 50, 75, 100, 200, 300, 400, 500, 600, 700, 800, 900, 1000, or more than 1000 ppm. In some cases, the Rheum vulgare extract is present in the range of about 1 to about 100, about 1 to about 50, about 1 to about 40, about 1 to about 30, about 1 to about 20, about 1 to about 10, about 5 to about 90, about 10 to about 80, about 20 to about 60, or about 30 to about 50 ppm. In some cases, the Rheum vulgare extract is present at about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 50, 75, 100, 200, 300, 400, 500, 600, 700, 800, 900, 1000, or greater than 1000 micrograms per milliliter (ug / mL). In some cases, the Rheum vulgare extract is present in the range of about 1 to about 100, about 1 to about 50, about 1 to about 40, about 1 to about 30, about 1 to about 20, about 1 to about 10, about 5 to about 90, about 10 to about 80, about 20 to about 60, or about 30 to about 50 ug / mL. In some cases, the Rheum vulgare extract is present in about 0.01% to about 10% by weight, about 0.01% to about 0.02% by weight, about 0.01% to about 0.03% by weight, about 0.01% to about 0.04% by weight, about 0.01% to about 0.05% by weight, about 0.01% to about 0.1% by weight, about 1% to about 5% by weight, or about 1% to about 10% by weight (wt.%).

[0100] Phosphatidylserine The compositions described herein, in some embodiments, comprise phosphatidylserine. In some embodiments, phosphatidylserine is provided at a concentration of at least about 0.01%, 0.02%, 0.03%, 0.04%, 0.05%, 0.06%, 0.07%, 0.08%, 0.09%, 0.10%, 0.11%, 0.12%, 0.13%, 0.14%, 0.15%, 0.16%, 0.17%, 0.18%, 0.19%, 0.20% by weight or less, or greater than 0.20% (wt.%). In some embodiments, phosphatidylserine is provided at a concentration of about 0.01% to about 0.2%, about 0.02% to about 0.15%, about 0.03% to about 0.1%, or about 0.04% to about 0.1% (wt.%). In some embodiments, phosphatidylserine is present at about 0.075% or less (wt.%). In some embodiments, phosphatidylserine is provided at a concentration of about 0.05% or less (wt.%). In some embodiments, phosphatidylserine is provided at a concentration of at least about 100, 200, 300, 400, 500, 600, 700, 800, 900, 1000, 1100, 1200, 1300, 1400, 1500, 1600, 1700, 1800, 1900, 2000, or greater than 2000 parts per million (ppm) per milliliter. In some embodiments, the phosphatidylserine is provided at a concentration of about 100 to about 1900 ppm, about 200 to about 1800 ppm, about 300 to about 1700 ppm, about 400 to about 1600 ppm, about 500 to about 1500 ppm, about 600 to about 1400 ppm, about 700 to about 1300 ppm, about 800 to about 1200 ppm, or about 900 to about 1100 ppm. In some embodiments, the phosphatidylserine is provided at a concentration of about 1000 ppm.In some embodiments, phosphatidylserine is provided at a concentration of at least about 100, 200, 300, 400, 500, 600, 700, 800, 900, 1000, 1100, 1200, 1300, 1400, 1500, 1600, 1700, 1800, 1900, 2000, or greater than 2000 micrograms per milliliter (ug / mL). In some embodiments, the phosphatidylserine is provided at a concentration of about 100 to about 1900 ug / mL, about 200 to about 1800 ug / mL, about 300 to about 1700 ug / mL, about 400 to about 1600 ug / mL, about 500 to about 1500 ug / mL, about 600 to about 1400 ug / mL, about 700 to about 1300 ug / mL, about 800 to about 1200 ug / mL, or about 900 to about 1100 ug / mL. In some embodiments, the phosphatidylserine is provided at a concentration of about 500 to about 1000 ug / mL.

[0101] In some embodiments, the phosphatidylserine is provided at least or about at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 200, 300, 400, 500, or more than 500 milligrams (mg). In some embodiments, the phosphatidylserine is provided in the range of about 20 to about 500, about 30 to about 400, about 40 to about 300, about 50 to about 200, about 60 to about 100, about 70 to about 95, or about 80 to about 90 milligrams (mg). In some embodiments, the phosphatidylserine is provided at about 15 milligrams (mg). In some embodiments, the phosphatidylserine is provided at about 20 milligrams (mg). In some embodiments, lactoferrin is provided at about 45 milligrams (mg).

[0102] Heptasodium hexacarboxymethyl dipeptide-12 (HHD12) HHD12 can stimulate autophagy in keratinocytes. Melanosomes are normally transferred to neighboring keratinocytes and then naturally degraded by autophagy. However, when skin is constantly exposed to sunlight, pathogens, and hormonal changes, the autophagy process is disrupted and melanosomes cannot be degraded. The accumulation of undegraded melanosomes in keratinocytes leads to skin pigmentation. HHD12 activates autophagy to degrade melanosomes in keratinocytes and at the same time inhibits melanosome uptake into keratinocytes.

[0103] In some embodiments, HHD12 is present at about or at least about 0.01 weight percent (wt.%), 0.05 wt.%, 0.1 wt.%, 0.5 wt.%, 1 wt.%, 2 wt.%, 3 wt.%, 4 wt.%, 5 wt.%, 6 wt.%, 7 wt.%, 8 wt.%, 9 wt.%, or 10 wt.%. In some embodiments, HHD12 is present in a range of about 0.01 wt.% to about 10 wt.%, about 0.05 wt.% to about 9 wt.%, about 0.1 wt.% to about 8 wt.%, about 0.5 wt.% to about 7 wt.%, or about 1 wt.% to about 6 wt.%. In some embodiments, HHD12 is present in a range of about 0.2 wt.% to about 5 wt.%. In some embodiments, HHD12 is present at about 1.0 wt.% or less.

[0104] Liposomes Described herein are liposomal compositions for improved distribution, efficacy, bioavailability, and / or activity. The liposomal compositions can improve the distribution, efficacy, bioavailability, and / or activity of active ingredients by improving delivery and tissue (e.g., skin) penetration. In some cases, the improved delivery and skin penetration is due to the active ingredient being incorporated (e.g., encapsulated) in the liposome. In some cases, the active ingredient is a peptide encapsulated in the liposome. In some cases, the peptide encapsulated in the liposome allows for efficient interfollicular transdermal delivery.

[0105] The liposome compositions described herein may include a peptide encapsulated in the liposome. In some embodiments, the peptide is hexapeptide-12. In some embodiments, the peptide is hexapeptide-11. In some embodiments, the peptide is functionalized with a palmitoyl group. In some embodiments, the peptide is functionalized with an acetyl group. In some embodiments, the peptide encapsulated in the liposome is lactoferrin.

[0106] In some embodiments, the peptide encapsulated in the liposome is about or greater than about 10, 25, 50, 100, 200, 300, 400, 500, 600, 700, 800, 900, 1000, 1500, 2000, 3000, 4000, 5000, or 5000 Da. In some embodiments, the peptide encapsulated in the liposome is in the range of about 10 to about 5000, about 25 to about 4000, about 50 to about 3000, about 100 to about 2000, or about 200 to about 1000 Da. In some embodiments, the peptide encapsulated in the liposome is about 500 to about 800 Da.

[0107] In some embodiments, the average particle size of the liposomes is 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 200, 300, 400, or 500 nanometers (nm). In some embodiments, the average particle size of the liposomes is in the range of about 10 to about 500, about 20 to about 400, about 30 to about 300, or about 40 to about 200 nm. In some embodiments, the average particle size of the liposomes is about 110 nm.

[0108] In some embodiments, the liposome is a photosome. The photosome, in some embodiments, includes DNA repair technology and / or uses the DNA repair enzyme photolyase to repair broken UV-induced dimers. In some embodiments, the photosome includes a plankton extract, lecithin, water, or a combination thereof. In some embodiments, the photosome includes a plankton extract and lecithin, and in some cases, the compositions described herein include one or more photosomes. In some cases, the photosome is present at at least or about 0.01%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1%, 2%, 3%, 4%, or 5% by weight (wt.%). In some cases, the photosomes are present in a range of about 0.01% to about 5%, about 0.1% to about 4%, about 0.2% to about 3%, or about 0.3% to about 2% by weight (wt.%). In some cases, the photosomes are present in a range of about 0.1% to about 2 wt.%.

[0109] The compositions described herein, in some embodiments, include one or more photosomes and one or more liposomes. In some embodiments, each liposome of the one or more liposomes encapsulates at least one peptide. In some embodiments, each liposome of the one or more liposomes encapsulates a different peptide. In some embodiments, each liposome of the one or more liposomes encapsulates a different peptide, including hexapeptide-11, hexapeptide-12, lactoferrin, a peptide derived from lactoferrin, or a combination thereof. In some embodiments, the one or more liposomes encapsulate one or more peptides, and the one or more peptides include hexapeptide-11, hexapeptide-12, lactoferrin, a peptide derived from lactoferrin, or a combination thereof.

[0110] In some embodiments, a first liposome of the one or more liposomes encapsulates at least one peptide. In some embodiments, a first liposome of the one or more liposomes encapsulates a non-palmitoylated hexapeptide. In some embodiments, a first liposome of the one or more liposomes encapsulates hexapeptide-11. In some embodiments, a first liposome of the one or more liposomes encapsulates hexapeptide-12. In some embodiments, a first liposome of the one or more liposomes encapsulates lactoferrin. In some embodiments, a first liposome of the one or more liposomes encapsulates a peptide derived from lactoferrin. In some embodiments, a first liposome of the one or more liposomes encapsulates a non-palmitoylated hexapeptide and lactoferrin. In some embodiments, a first liposome of the one or more liposomes encapsulates hexapeptide-11 and hexapeptide-12. In some embodiments, a first liposome of the one or more liposomes encapsulates hexapeptide-11 and lactoferrin. In some embodiments, a first liposome of the one or more liposomes encapsulates a peptide derived from hexapeptide-11 and lactoferrin. In some embodiments, a first liposome of the one or more liposomes encapsulates hexapeptide-12 and lactoferrin. In some embodiments, a first liposome of the one or more liposomes encapsulates a peptide derived from hexapeptide-12 and lactoferrin. In some embodiments, a first liposome of the one or more liposomes encapsulates hexapeptide-11, hexapeptide-12, and lactoferrin. In some embodiments, a first liposome of the one or more liposomes encapsulates a peptide derived from hexapeptide-11, hexapeptide-12, and lactoferrin. In some embodiments, a first liposome of the one or more liposomes encapsulates hexapeptide-11, lactoferrin, and a peptide derived from lactoferrin.In some embodiments, a first liposome of the one or more liposomes encapsulates hexapeptide-12, lactoferrin, and a peptide derived from lactoferrin, in some embodiments, a first liposome of the one or more liposomes encapsulates hexapeptide-11, hexapeptide-12, lactoferrin, and a peptide derived from lactoferrin.

[0111] In some embodiments, a first liposome of the one or more liposomes encapsulates hexapeptide-11, and a second liposome of the one or more liposomes encapsulates lactoferrin. In some embodiments, a first liposome of the one or more liposomes encapsulates hexapeptide-11, and a second liposome of the one or more liposomes encapsulates hexapeptide-12. In some embodiments, a first liposome of the one or more liposomes encapsulates hexapeptide-11, and a second liposome of the one or more liposomes encapsulates a peptide derived from lactoferrin. In some embodiments, a first liposome of the one or more liposomes encapsulates hexapeptide-12, and a second liposome of the one or more liposomes encapsulates lactoferrin. In some embodiments, a first liposome of the one or more liposomes encapsulates hexapeptide-12 and a second liposome of the one or more liposomes encapsulates a peptide derived from lactoferrin. In some embodiments, a first liposome of the one or more liposomes encapsulates lactoferrin and a second liposome of the one or more liposomes encapsulates a peptide derived from lactoferrin.

[0112] In some embodiments, a first liposome of the one or more liposomes encapsulates hexapeptide-11, a second liposome of the one or more liposomes encapsulates hexapeptide-12, and a third liposome of the one or more liposomes encapsulates lactoferrin. In some embodiments, a first liposome of the one or more liposomes encapsulates hexapeptide-11, a second liposome of the one or more liposomes encapsulates hexapeptide-12, and a third liposome of the one or more liposomes encapsulates a peptide derived from lactoferrin. In some embodiments, a first liposome of the one or more liposomes encapsulates hexapeptide-11, a second liposome of the one or more liposomes encapsulates lactoferrin, and a third liposome of the one or more liposomes encapsulates a peptide derived from lactoferrin. In some embodiments, a first liposome of the one or more liposomes encapsulates hexapeptide-12, a second liposome of the one or more liposomes encapsulates lactoferrin, and a third liposome of the one or more liposomes encapsulates a peptide derived from lactoferrin.

[0113] In some embodiments, a first liposome of the one or more liposomes encapsulates hexapeptide-11, a second liposome of the one or more liposomes encapsulates hexapeptide-12, a third liposome of the one or more liposomes encapsulates lactoferrin, and a fourth liposome of the one or more liposomes encapsulates a peptide derived from lactoferrin.

[0114] The compositions described herein, in some embodiments, include one or more photosomes encapsulating one or more liposomes encapsulating one or more peptides. In some embodiments, the photosomes encapsulate liposomes encapsulating one peptide. In some embodiments, the photosomes encapsulate liposomes encapsulating hexapeptide-11. In some embodiments, the photosomes encapsulate liposomes encapsulating hexapeptide-12. In some embodiments, the photosomes encapsulate liposomes encapsulating lactoferrin. In some embodiments, the photosomes encapsulate liposomes encapsulating a peptide derived from lactoferrin. In some embodiments, the photosomes encapsulate liposomes encapsulating two or more peptides. In some embodiments, the photosomes encapsulate liposomes encapsulating two or more peptides, the two or more peptides including hexapeptide-11, hexapeptide-12, lactoferrin, a peptide derived from lactoferrin, or a combination thereof. In some embodiments, the photosome encapsulates one or more liposomes, each liposome of the one or more liposomes encapsulating a different peptide, hi some embodiments, the photosome encapsulates one or more liposomes, each liposome of the one or more liposomes encapsulating a different peptide, including hexapeptide-11, hexapeptide-12, lactoferrin, a peptide derived from lactoferrin, or a combination thereof.

[0115] The compositions described herein, in some embodiments, include one or more photosomes that encapsulate one or more liposomes. In some embodiments, the one or more photosomes encapsulate one or more liposomes that encapsulate one or more peptides. In some embodiments, the one or more photosomes encapsulate one or more liposomes, and each liposome of the one or more liposomes encapsulates a different peptide, including hexapeptide-11, hexapeptide-12, lactoferrin, a peptide derived from lactoferrin, or a combination thereof. In some embodiments, the one or more photosomes encapsulate one or more liposomes that encapsulate one or more peptides, and the one or more peptides include hexapeptide-11, hexapeptide-12, lactoferrin, a peptide derived from lactoferrin, or a combination thereof.

[0116] In some embodiments, the one or more photosomes encapsulate one or more liposomes, and a first liposome of the one or more liposomes encapsulates hexapeptide-11. In some embodiments, the one or more photosomes encapsulate one or more liposomes, and a first liposome of the one or more liposomes encapsulates hexapeptide-12. In some embodiments, the one or more photosomes encapsulate one or more liposomes, and a first liposome of the one or more liposomes encapsulates lactoferrin. In some embodiments, the one or more photosomes encapsulate one or more liposomes, and a first liposome of the one or more liposomes encapsulates a peptide derived from lactoferrin.

[0117] In some embodiments, the one or more photosomes encapsulate one or more liposomes, a first liposome of the one or more liposomes encapsulates hexapeptide-11, and a second liposome of the one or more liposomes encapsulates lactoferrin. In some embodiments, the one or more photosomes encapsulate one or more liposomes, a first liposome of the one or more liposomes encapsulates hexapeptide-11, and a second liposome of the one or more liposomes encapsulates hexapeptide-12. In some embodiments, the one or more photosomes encapsulate one or more liposomes, a first liposome of the one or more liposomes encapsulates hexapeptide-11, and a second liposome of the one or more liposomes encapsulates a peptide derived from lactoferrin. In some embodiments, the one or more photosomes encapsulate one or more liposomes, a first liposome of the one or more liposomes encapsulates hexapeptide-12, and a second liposome of the one or more liposomes encapsulates lactoferrin. In some embodiments, the one or more photosomes encapsulate one or more liposomes, a first liposome of the one or more liposomes encapsulates hexapeptide-12, and a second liposome of the one or more liposomes encapsulates a peptide derived from lactoferrin. In some embodiments, the one or more photosomes encapsulate one or more liposomes, a first liposome of the one or more liposomes encapsulates lactoferrin, and a second liposome of the one or more liposomes encapsulates a peptide derived from lactoferrin.

[0118] In some embodiments, the one or more photosomes encapsulate one or more liposomes, a first liposome of the one or more liposomes encapsulates hexapeptide-11, a second liposome of the one or more liposomes encapsulates hexapeptide-12, and a third liposome of the one or more liposomes encapsulates lactoferrin. In some embodiments, the one or more photosomes encapsulate one or more liposomes, a first liposome of the one or more liposomes encapsulates hexapeptide-11, a second liposome of the one or more liposomes encapsulates hexapeptide-12, and a third liposome of the one or more liposomes encapsulates a peptide derived from lactoferrin. In some embodiments, the one or more photosomes encapsulate one or more liposomes, a first liposome of the one or more liposomes encapsulates hexapeptide-11, a second liposome of the one or more liposomes encapsulates lactoferrin, and a third liposome of the one or more liposomes encapsulates a peptide derived from lactoferrin. In some embodiments, the one or more photosomes encapsulate one or more liposomes, a first liposome of the one or more liposomes encapsulates hexapeptide-12, a second liposome of the one or more liposomes encapsulates lactoferrin, and a third liposome of the one or more liposomes encapsulates a peptide derived from lactoferrin.

[0119] In some embodiments, the one or more photosomes encapsulate one or more liposomes, a first liposome of the one or more liposomes encapsulates hexapeptide-11, a second liposome of the one or more liposomes encapsulates hexapeptide-12, a third liposome of the one or more liposomes encapsulates lactoferrin, and a fourth liposome of the one or more liposomes encapsulates a peptide derived from lactoferrin.

[0120] In some embodiments, the average particle size of each of the liposomes of the one or more liposomes or each photosome of the one or more photosomes is 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 200, 300, 400, or 500 nanometers (nm). In some embodiments, the average particle size of each of the liposomes of the one or more liposomes or each photosome of the one or more photosomes ranges from about 10 to about 500, about 20 to about 400, about 30 to about 300, or about 40 to about 200 nm. In some embodiments, the average particle size of each of the liposomes of the one or more liposomes or each photosome of the one or more photosomes is about 110 nm.

[0121] In some embodiments, the average particle size of each of the liposomes of the one or more liposomes or each photosome of the one or more photosomes is about or at least about 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 200, 300, 400, 500, 600, 700, 800, 900, or 1000 nanometers (nm). In some embodiments, the average particle size of each of the liposomes of the one or more liposomes or each photosome of the one or more photosomes is in the range of about 10 to about 1000, about 20 to about 900, about 30 to about 800, about 40 to about 700, about 50 to about 600, about 60 to about 500, about 70 to about 400, or about 80 to about 300 nm. In some embodiments, the average particle size of each of the liposomes of the one or more liposomes or each photosome of the one or more photosomes is about or at least about 220 nm.

[0122] In some embodiments, the compositions described herein, including one or more photosomes and one or more liposomes, are prepared in one or more steps. In some embodiments, in the first step, one or more peptides, lactoferrin, peptides derived from lactoferrin, or combinations thereof are combined. In some embodiments, one or more peptides are hexapeptide-11. In some embodiments, one or more peptides are hexapeptide-12. In some embodiments, one or more peptides are hexapeptide-11 and hexapeptide-12. In some embodiments, in the second step, a second liposome is added. In some embodiments, the second liposome is a photosome.

[0123] Lecithin and other phospholipids can be used to prepare liposomes containing the peptide compositions described herein. In some embodiments, liposomes are used to prepare one or more peptides. In some embodiments, the peptides are functionalized with acetyl groups. The formation of lipid vesicles occurs when phospholipids such as lecithin are placed in water, which results in the formation of a bilayer or a series of bilayers, each separated by water molecules, when sufficient energy is provided. Liposomes can be made by sonicating phospholipids in water. Low shear rates create multi-layered liposomes. Continued high shear sonication tends to form smaller unilamellar liposomes. Hydrophobic chemicals can dissolve in the phospholipid bilayer membrane. The lipid bilayer of the liposome delivers the peptide compositions described herein.

[0124] The phospholipids used to prepare the liposomal compositions described herein may comprise a transition phase temperature of about 10° C. to about 25° C. In some cases, the phospholipids comprise a transition phase temperature of about 10° C., 12° C., 14° C., 16° C., 18° C., 20° C., 22° C., 24° C., 26° C., 28° C., 30° C., 32° C., 34° C., 36° C., 38° C., 40° C., or greater than 40° C. In some cases, the phospholipids comprise a transition phase temperature in the range of about 10° C. to about 40° C., about 12° C. to about 36° C., about 14° C. to about 32° C., about 16° C. to about 20° C., or about 21° C. to about 25° C.

[0125] The topical composition may contain micelles, or aggregates of surfactant molecules, dispersed in an aqueous solution. Micelles can be prepared by dispersing an oil solvent in an aqueous solution containing a surfactant, where the surfactant concentration exceeds the critical micelle concentration. The resulting composition contains micelles, i.e., spherical oil droplets.

[0126] The liposome composition may contain micelles or aggregates of surfactant molecules dispersed in an aqueous solution. Micelles can be prepared by dispersing an oil solvent in an aqueous solution containing a surfactant, where the surfactant concentration exceeds the critical micelle concentration. The resulting formulation contains micelles, i.e., spherical oil droplets surrounded by a membrane of polar surfactant molecules, dispersed in an aqueous solvent.

[0127] Described herein, in some embodiments, is a method for preparing a composition comprising a peptide encapsulated in a liposome, comprising combining a peptide and a solvent to form a mixture and contacting the mixture with an aqueous solution comprising liposomes. In some cases, the contacting is performed at a temperature of about 10° C. to about 25° C. In some cases, the contacting is performed at a temperature of about 10° C., 12° C., 14° C., 16° C., 18° C., 20° C., 22° C., 24° C., 26° C., 28° C., 30° C., 32° C., 34° C., 36° C., 38° C., 40° C., or greater than 40° C. In some cases, the contacting is performed at a temperature ranging from about 10° C. to about 40° C., from about 12° C. to about 36° C., from about 14° C. to about 32° C., from about 16° C. to about 20° C., or from about 21° C. to about 25° C.

[0128] The method for preparing a composition comprising a peptide encapsulated in liposomes may include the use of a solvent. In some cases, the solvent is water. In some cases, the solvent is an organic solvent. Exemplary organic solvents include, but are not limited to, petroleum ether, cyclohexane, toluene, carbon tetrachloride, dichloromethane, chloroform, diethyl ether, diisopropyl ether, ethyl acetate, butanol, n-propanol, ethanol, methanol, polyethylene glycol, propylene glycol, and pyridine. In some cases, the solvent is glycol. In some cases, the solvent is butylene glycol. In some cases, the solvent is caprylyl glycol. In some cases, the solvent is propanediol (propylene glycol).

[0129] Solvents can be used in various percentages. In some cases, the solvent is provided at least or 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 more than 10% by weight. The solvent can be propanediol, butylene glycol, or caprylyl glycol.

[0130] The methods described herein, in some embodiments, include combining a peptide and a solvent to form a mixture and contacting the mixture with an aqueous solution containing liposomes, the aqueous solution comprising a percentage of water and a percentage of liposomes. In some cases, the aqueous solution comprises at least or about 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or more than 90% water. In some cases, the aqueous solution comprises in the range of about 10% to about 95%, about 20% to about 90%, about 30% to about 85%, about 40% to about 80%, or about 50% to about 60% water. In some cases, the aqueous solution comprises at least or about 20%, 30%, 40%, 50%, 60%, or more than 60% liposomes. In some cases, the aqueous solution contains liposomes in the range of about 10% to about 80%, about 20% to about 70%, or about 30% to about 60%. The ratio of liposomes to water can be in the range of about 1:9 to about 3:7. In some cases, the ratio of liposomes to water can be at least or about 1:10, 1:9, 1:8, 1:7, 1:6, 1:5, 1:4, 1:3, or 1:2.

[0131] The methods for producing liposomal compositions described herein can result in an entrapment efficiency of 100% or less. In some cases, the entrapment efficiency is 50%, 60%, 70%, 80%, 90%, 95%, 99%, or 99.5% or less.

[0132] Described herein are liposome compositions in which the peptide constitutes a percentage of the composition. In some embodiments, the peptide is provided at least or about 0.0001%, 0.0005%, 0.00055%, 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 more than 10% of the composition. In some embodiments, the peptide is provided at at least about 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 22%, 24%, 26%, 28%, 30%, or more than 30% of the composition. In some embodiments, the peptide is provided in the range of about 0.001% to about 6%, about 0.002% to about 4%, about 0.01% to about 5%, or about 0.02% to about 2% by weight. In some embodiments, the peptide is provided at about 0.03% of the composition.

[0133] Described herein are liposome compositions in which liposomes constitute a percentage of the composition. In some embodiments, liposomes are provided at least or about 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 22%, 24%, 26%, 28%, 30%, or more than 30% of the composition. In some embodiments, liposomes are provided in the range of about 5% to about 90%, about 10% to about 80%, about 20% to about 70%, about 30% to about 60%, about 10% to about 30%, or about 20% to about 40%.

[0134] The liposome compositions described herein, in some embodiments, comprise an average particle size of up to 220 nanometers (nm). In some cases, the average particle size is up to 100 nm, 105 nm, 110 nm, 115 nm, 120 nm, 125 nm, 130 nm, 135 nm, 140 nm, 145 nm, 150 nm, 155 nm, 160 nm, 165 nm, 170 nm, 175 nm, 180 nm, 185 nm, 190 nm, 195 nm, 200 nm, 205 nm, 210 nm, 215 nm, 220 nm, 230 nm, 240 nm, 250 nm, 260 nm, 270 nm, 280 nm, 290 nm, 300 nm, 320 nm, 340 nm, 360 nm, 380 nm, or 400 nm. In some cases, the average particle size is about 100 nm, 105 nm, 110 nm, 115 nm, 120 nm, 125 nm, 130 nm, 135 nm, 140 nm, 145 nm, 150 nm, 155 nm, 160 nm, 165 nm, 170 nm, 175 nm, 180 nm, 185 nm, 190 nm, 195 nm, 200 nm, 205 nm, 210 nm, 215 nm, 220 nm, 230 nm, 240 nm, 250 nm, 260 nm, 270 nm, 280 nm, 290 nm, 300 nm, 320 nm, 340 nm, 360 nm, 380 nm, or 400 nm. In some cases, the average particle size ranges from about 50 nm to about 500 nm, from about 100 nm to about 400 nm, from about 150 nm to about 220 nm, from about 180 nm to about 220 nm, or from about 190 nm to about 210 nm.

[0135] In some cases, the liposome composition includes an active agent having a molecular weight of about 600 Daltons (Da) or less. In some cases, the active agent has a molecular weight of at least 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, or more than 1000 Daltons (Da). In some cases, the active agent has a molecular weight of at least 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, or more than 6000 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). In some cases, the active agent is a peptide. In some cases, the active agent is a peptide encapsulated in a liposome.

[0136] The polydispersity index (PdI) of the liposome compositions described herein, in some embodiments, ranges from 0 to about 0.2. In some cases, the polydispersity index is about 0.01, 0.025, 0.05, 0.1, 0.25, 0.3, 0.35, 0.4, 0.45, 0.5, 0.55, 0.6, 0.65, 0.7, 0.75, or 0.8. In some cases, the polydispersity index is in the range of about 0.01 to about 0.8, about 0.025 to about 0.75, about 0.05 to about 0.6, or about 0.1 to about 0.3. In some embodiments, the average particle size of the liposomes is 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 200, 300, 400, or 500 nanometers (nm).

[0137] In some cases, the intercept of the liposome compositions described herein ranges from about 0.85 to about 0.95. In some cases, the intercept is an amplitude. In some cases, the intercept is at least or about 0.65, 0.70, 0.75, 0.80, 0.85, 0.90, or 0.95.

[0138] In some embodiments, the liposome comprises propanediol, lecithin, or a combination thereof, in some embodiments, the propanediol is provided at at least or 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 more than 10% by weight (wt.%). In some embodiments, propanediol 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, or about 0.02% to about 2% by weight. In some embodiments, lecithin is provided at at least or 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 more than 10% by weight (wt.%). In some embodiments, lecithin 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, or about 0.02% to about 2% by weight. In some embodiments, the liposome comprises propanediol and lecithin.In some embodiments, propanediol and lecithin are provided at at least or 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 more than 10% by weight (wt.%). In some embodiments, the propanediol and lecithin are 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. In some embodiments, the propanediol and lecithin are provided at about 0.90% by weight.

[0139] Described herein are liposome compositions that include improved distribution, efficacy, bioavailability, and / or activity. The liposome compositions may include improved distribution, efficacy, bioavailability, and / or activity compared to compositions that do not contain liposomes. In some cases, the distribution is improved by at least or about 0.5-fold, 1.0-fold, 1.5-fold, 2.0-fold, 2.5-fold, 3.0-fold, 4.0-fold, 4.5-fold, 5-fold, or more than 5-fold compared to compositions that do not contain liposomes. In some cases, the efficacy is improved by at least or about 0.5-fold, 1.0-fold, 1.5-fold, 2.0-fold, 2.5-fold, 3.0-fold, 4.0-fold, 4.5-fold, 5-fold, or more than 5-fold compared to compositions that do not contain liposomes. In some cases, bioavailability is improved by at least or about 0.5-fold, 1.0-fold, 1.5-fold, 2.0-fold, 2.5-fold, 3.0-fold, 4.0-fold, 4.5-fold, 5-fold, or more than 5-fold compared to compositions that do not contain liposomes. In some cases, activity is improved by at least or about 0.5-fold, 1.0-fold, 1.5-fold, 2.0-fold, 2.5-fold, 3.0-fold, 4.0-fold, 4.5-fold, 5-fold, or more than 5-fold compared to compositions that do not contain liposomes. Distribution, efficacy, bioavailability, and / or activity may be improved by at least or about 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or more than 90% compared to compositions that do not contain liposomes.

[0140] The liposome compositions and methods described herein are, in some embodiments, topical compositions. In some cases, the liposome compositions do not include oil. In some cases, the liposome compositions do not include preservatives. In some embodiments, the liposome formulation is an aqueous formulation. In some embodiments, the liposome formulation is an anhydrous formulation. In some cases, the liposome composition comprises a pH in the range of about 5 to about 8. In some cases, the liposome composition comprises a pH of at least or about 2, 3, 4, 5, 6, 7, 8, 9, or 10.

[0141] The methods and compositions described herein may result in improved follicular penetration. In some cases, follicular penetration is improved by at least or about 0.5 times, 1.0 times, 1.5 times, 2.0 times, 2.5 times, 3.0 times, 4.0 times, 4.5 times, 5 times, or more than 5 times. Follicular penetration may be improved by at least or about 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or more than 90%. In some cases, the compositions result in follicular penetration to a depth of at least or about 0.5, 0.75, 1, 1.25, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 7, 8, 9, 10, or more than 10 millimeters.

[0142] Other Ingredients Other ingredients may include anti-inflammatory agents, antioxidants, and solubility enhancers. Exemplary anti-irritants include, but are not limited to, panthenyl triacetate and naringenin. Panthenyl triacetate and naringenin are natural plant extracts that reduce redness and moisture loss from the skin. A typical amount of anti-irritant when used in the composition is 1% to 4% by weight (wt.%).

[0143] Exemplary antioxidants include, but are not limited to, Sympetrum nigricans extract and squalane. Sympetrum nigricans extract includes components such as beta-carotene, which may exhibit antioxidant properties. A typical amount of anti-inflammatory agent when used in a composition is 0.1% to 2.5% by weight (wt.%). In some embodiments, Sympetrum nigricans extract is provided at least or 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 more than 4% by weight. In some embodiments, the beard flea extract is provided in the range of about 0.001% to about 4.0%, about 0.01% to about 3.0%, about 0.1% to about 2.5%, or about 0.50% to about 1.5%. In some embodiments, the beard flea is provided in the range of about 1% to about 12%, about 2% to about 11%, or about 3% to about 10% by weight. In some embodiments, the beard worm is provided at 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%, 5.0%, 6.0%, 7%, 8%, 9%, 10%, 11%, 12%, or more than 12% by weight. In some embodiments, squalane is provided at least 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 greater than 4% by weight. In some embodiments, squalane is provided in the range of about 0.001% to about 4.0%, about 0.01% to about 3.0%, about 0.1% to about 2.5%, or about 0.50% to about 1.5%.In some embodiments, squalane is provided in the range of about 1% to about 12%, about 2% to about 11%, or about 3% to about 10% by weight. In some embodiments, squalane is provided at 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%, 5.0%, 6.0%, 7%, 8%, 9%, 10%, 11%, 12%, or greater than 12% by weight. In some embodiments, the beard flea extract and squalane are provided at least 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 more than 4% by weight. In some embodiments, the beard flea and squalane extract are provided in the range of about 0.001% to about 4.0%, about 0.01% to about 3.0%, about 0.1% to about 2.5%, or about 0.50% to about 1.5%. In some embodiments, the beard flukes and squalane are provided in the range of about 0.001% to about 4.0%, about 0.01% to about 3.0%, about 0.1% to about 2.5%, or about 0.50% to about 1.5%. In some embodiments, the beard flukes and squalane are provided in the range of about 1% to about 12% by weight, about 2% to about 11% by weight, or about 3% to about 10% by weight.

[0144] 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, and the like, 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. Lipids suitable for the composition include, but are not limited to, monoglycerides, diglycerides, sulfatides, lysolecithin, phospholipids, saponin, bile acids, and the like.

[0145] In some embodiments, the compositions described herein include phosphatidylserine, phospholipids, tocopherol, ascorbyl palmitate, or a combination thereof. In some embodiments, the phosphatidylserine, phospholipids, tocopherol, ascorbyl palmitate, or a combination thereof is provided at 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 more than 4% by weight (wt.%). In some embodiments, phosphatidylserine, phospholipids, tocopherol, ascorbyl palmitate, or combinations thereof are 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, phosphatidylserine, phospholipids, tocopherol, ascorbyl palmitate, or combinations thereof are 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, or about 0.02% to about 5% by weight. In some embodiments, phosphatidylserine, phospholipids, tocopherol, ascorbyl palmitate, or combinations thereof are provided at about 0.05% by weight or less.

[0146] In some embodiments, the additive is betaine, which in some embodiments is provided in a 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, or about 0.02% to about 5% by weight.

[0147] In some embodiments, the compositions described herein include caprylyl glycol, caprylhydroxamic acid, glycerin, or a combination thereof, in some embodiments, caprylyl glycol, caprylhydroxamic acid, glycerin, or a combination thereof is provided in a 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 5% by weight. In some embodiments, caprylyl glycol, caprylhydroxamic acid, glycerin, or combinations thereof are provided at 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 greater than 4% by weight (wt.%). In some embodiments, the compositions described herein include caprylyl glycol. In some embodiments, caprylyl glycol 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 5% by weight. In some embodiments, caprylyl glycol is provided at 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 more than 4% by weight (wt.%). In some embodiments, the compositions described herein include caprylhydroxamic acid. In some embodiments, caprylhydroxamic acid 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 5% by weight.In some embodiments, caprylhydroxamic acid is provided at 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 greater than 4% by weight (wt.%). In some embodiments, glycerin 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 5% by weight. In some embodiments, glycerin is provided at 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 greater than 4% by weight (wt.%).

[0148] In some embodiments, the compositions described herein include a sodium acrylate copolymer, lecithin, or a combination thereof, in some embodiments, the sodium acrylate copolymer, lecithin, or a combination thereof is provided in a 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 5% by weight. In some embodiments, the sodium acrylate copolymer, lecithin, or combination thereof is provided at 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%, 6.0%, 7%, 8%, 9%, 10%, 11%, 12%, or greater than 12% by weight. In some embodiments, the sodium acrylate copolymer, lecithin, or combination thereof is provided in a range of about 1% to about 12%, about 2% to about 11%, or about 3% to about 10% by weight. In some embodiments, the sodium acrylate copolymer, lecithin, or combinations thereof are 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 5% by weight. In some embodiments, the sodium acrylate copolymer is provided in the range of about 1% to about 12%, about 2% to about 11%, or about 3% to about 10% by weight. In some embodiments, the sodium acrylate copolymer is provided at 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%, 6.0%, 7%, 8%, 9%, 10%, 11%, 12%, or greater than 12% by weight.In some embodiments, lecithin 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 5% by weight. In some embodiments, glycerin is provided at least or about 7%. In some embodiments, lecithin is provided in the range of about 1% to about 12%, about 2% to about 11%, or about 3% to about 10% by weight. In some embodiments, lecithin is provided at 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%, 5.0%, 6.0%, 7%, 8%, 9%, 10%, 11%, 12%, or more than 12% by weight.

[0149] In some embodiments, the compositions described herein include titanium dioxide, tin oxide, silica, or a combination thereof. In some embodiments, the titanium dioxide, tin oxide, silica, or a combination thereof 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 5% by weight. In some embodiments, the titanium dioxide, tin oxide, silica, or a combination thereof is provided in the range of 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 more than 4% by weight (wt.%). In some embodiments, titanium dioxide 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 5% by weight. In some embodiments, titanium dioxide is provided at 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 greater than 4% by weight (wt.%). In some embodiments, tin oxide 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 5% by weight. In some embodiments, tin oxide is provided at 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 greater than 4% by weight (wt.%). In some embodiments, silica is provided in a 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, or about 0.02% to about 5% by weight.In some embodiments, silica is provided at 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 greater than 4 weight percent (wt.%).

[0150] The presence of such additional ingredients may affect the physical state, solubility, stability, release rate, clearance rate, and penetration of the active ingredient.

[0151] 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(s). 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.

[0152] 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 compositions and also offer advantages in scar treatment, periwound 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 composition ingredients such as oil-soluble vitamins and sunscreens. Sunscreens such as octyl methoxycinnamate can be delivered more efficiently from compositions containing silicone elastomers, resulting in a higher sun protection factor (SPF). Silicone elastomer blends can be used to enhance the SPF in oil-in-water compositions containing organic sunscreens. For example, in tests conducted on SPF, the addition of 4% silicone elastomer blends to suncare compositions containing organic sunscreens increased the SPF from 5.7 to 18.This property of silicone elastomers allows the effectiveness of sunscreen agents in a composition to be maximized while reducing the amount required to achieve a desired SPF. As a result, composition costs can be reduced, as well as potential irritation caused by sunscreen actives. Thus, a higher SPF can be achieved with the same amount of UV absorber, resulting in improved performance without adding to composition costs. 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 a gel made from a suspension of elastomer particles swollen 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 a spray-dried powder (dimethicone / vinyl dimethicone crosspolymer, such as Dow Corning® 9506 Elastomer Powder). A gel form with desirable attributes is cyclomethicone, although low viscosity dimethicones 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 elastomer contents in the range of 10% to 20% by weight.

[0153] In some embodiments, the composition includes dimethicone. In some embodiments, dimethicone is provided at least about 0.001 wt.%, 0.005 wt.%, 0.01 wt.%, 0.02 wt.%, 0.05 wt.%, 0.10 wt.%, 0.20 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.%, or more than 4.0 wt.% (wt.%). In some embodiments, dimethicone is provided at about 0.5 wt.%. In some embodiments, dimethicone is provided in the range of about 0.001 wt.% to about 4.0 wt.%, about 0.01 wt.% to about 3.0 wt.%, about 0.1 wt.% to about 2.5 wt.%, or about 0.50 wt.% to about 1.5 wt.%. In some embodiments, dimethicone is provided at about 0.25% by weight. In some embodiments, dimethicone is provided at about 0.5% by weight. In some embodiments, dimethicone is provided at about 1% by weight.

[0154] In some embodiments, the composition comprises a siloxane polymer. In some embodiments, the siloxane polymer is caprylyl methicone. In some embodiments, caprylyl methicone is provided at least or about 0.001% by weight, 0.005% by weight, 0.01% by weight, 0.02% by weight, 0.05% by weight, 0.10% by weight, 0.20% by weight, 0.25% by weight, 0.50% by weight, 0.75% by weight, 1.0% by weight, 1.5% by weight, 2.0% by weight, 2.5% by weight, 3.0% by weight, 3.5% by weight, 4.0% by weight, or more than 4.0% by weight (wt.%). In some embodiments, caprylyl methicone is provided at about 0.5% by weight. In some embodiments, caprylyl methicone is provided in the range of about 0.001% to about 4.0%, about 0.01% to about 3.0%, about 0.1% to about 2.5%, or about 0.50% to about 1.5% by weight. In some embodiments, caprylyl methicone is provided at about 0.25% by weight. In some embodiments, caprylyl methicone is provided at about 0.5% by weight. In some embodiments, caprylyl methicone is provided at about 1% by weight.

[0155] 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 bond 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.

[0156] 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.

[0157] 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 or about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, or more than 12% by weight (wt.%). In some embodiments, glycerin is provided at least 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% by weight. In some embodiments, butylene glycol is provided at least about 0.0025 wt%, 0.005 wt%, 0.075 wt%, 0.01 wt%, 0.025 wt%, 0.05 wt%, 0.75 wt%, 1 wt%, 2 wt%, 3 wt%, 4 wt%, 5 wt%, 6 wt%, 7 wt%, 8 wt%, 9 wt%, 10 wt%, 11 wt%, 12 wt%, or more than 12 wt%. In some embodiments, butylene glycol is provided in the range of about 0.01 wt% to about 10 wt%, about 0.025 wt% to about 5 wt%, or about 0.05 wt% to about 1.25 wt%. Suitable solvents for the hydrophobic composition 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. In some embodiments, anhydrous compositions are applied because the presence of water can cause irritation upon administration to skin tissues subjected to laser treatment, chemical peels, skin peeling, and the like. Anhydrous compositions may also act to prevent the development of aqueous irritant contact dermatitis in damaged or sensitive skin, which can cause 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 limited amounts of water to be present. For example, water may be present, but in amounts below a threshold that may cause an irritating sensation when applied to damaged skin. Osmotic shock or osmotic stress is a sudden change in solute concentration around the cell, causing a sudden change in the movement of water across the cell membrane. Under conditions of either high concentrations of salt, substrate, or any solute 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 solute, water enters the cell in large quantities, causing the cell to either swell, burst, or undergo apoptosis. Certain of the compositions described herein can be used advantageously when it is desirable to minimize osmotic shock.

[0158] The compositions described herein may include varying amounts of solvent. In some embodiments, the solvent is water. In some embodiments, the solvent is at least about 10 wt%, 15 wt%, 20 wt%, 25 wt%, 30 wt%, 35 wt%, 40 wt%, 45 wt%, 50 wt%, 55 wt%, 60 wt%, 65 wt%, 70 wt%, 75 wt%, 80 wt%, 85 wt%, 90 wt%, 95 wt%, or more than 95 wt% (wt.%). In some embodiments, the solvent is in the range of about 10 wt% to about 95 wt%, about 20 wt% to about 90 wt%, about 30 wt% to about 85 wt%, about 40 wt% to about 80 wt%, or about 50 wt% to about 75 wt%.

[0159] 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.

[0160] The viscosity of the compositions described herein, in some embodiments, ranges from about 8,000 centipoise (cps) to about 30,000 cps. In some embodiments, the viscosity is at least or about 4,000, 5,000, 6,000, 7,000, 8,000, 9,000, 10,000, 11,000, 12,000, 13,000, 14,000, 15,000, 16,000, 17,000, 18,000, 19,000, 20,000, 21,000, 22,000, 23,000, 24,000, 25,000, 26,000, 27,000, 28,000, 29,000, 30,000, 31,000, 32,000, 33,000, 34,000, 35,000, 36,000, 37,000, 38,000, 39,000, 40,000, or greater than 40,000 cps. In some embodiments, the composition comprises a viscosity in the range of about 4,000 to about 40,000, about 6,000 to about 38,000, about 8,000 to about 36,000, about 10,000 to about 34,000 cps, about 12,000 to about 32,000 cps, or about 14,000 to about 30,000 cps.

[0161] 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. In some embodiments, the emollient is caprylic / capric triglyceride.

[0162] In some embodiments, the emollient is provided at at least about 0.0025%, 0.005%, 0.075%, 0.01%, 0.025%, 0.05%, 0.75%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, or greater than 12% by weight. In some embodiments, the emollient is provided in a range of about 0.01% to about 10%, about 0.01% to about 2.5%, about 0.025% to about 5%, or about 0.05% to about 1.25% by weight. In some embodiments, caprylic / capric triglycerides are provided at at least about 0.0025%, 0.005%, 0.075%, 0.01%, 0.025%, 0.05%, 0.75%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, or greater than 12% by weight. In some embodiments, caprylic / capric triglycerides are provided in the range of about 0.01% to about 10%, about 0.01% to about 2.5%, about 0.025% to about 5%, or about 0.05% to about 1.25% by weight.

[0163] 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.

[0164] 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.

[0165] 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.

[0166] 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.

[0167] 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 candelilla wax.

[0168] 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 trimethylolpropane.

[0169] 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.

[0170] Suitable emulsifiers for use in the compositions include anionic, cationic, nonionic, and zwitterionic surfactants. Preferred ionic emulsifiers include phospholipids such as lecithin and derivatives.

[0171] 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.

[0172] 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 composition. In general, the anhydrous compositions of the embodiments are observed to exhibit sufficient stability, so that preservatives can be omitted from the composition.

[0173] Suitable chelating agents for use in the composition include ethylenediaminetetraacetic acid, its alkali metal salts, its alkaline earth metal salts, its ammonium salts, and its tetraalkylammonium salts. In some embodiments, the chelating agent is disodium ethylenediaminetetraacetic acid (EDTA). In some embodiments, disodium EDTA is provided at least or about 0.001% by weight, 0.005% by weight, 0.01% by weight, 0.02% by weight, 0.05% by weight, 0.10% by weight, 0.20% by weight, 0.25% by weight, 0.50% by weight, 0.75% by weight, 1.0% by weight, 1.5% by weight, 2.0% by weight, 2.5% by weight, 3.0% by weight, 3.5% by weight, 4.0% by weight, or more than 4% by weight (wt.%). In some embodiments, disodium EDTA is provided in the range of about 0.25% to about 10%, about 0.1% to about 2.5%, about 0.5% to about 8%, about 0.75% to about 6%, or about 1% to about 4% by weight. In some embodiments, disodium EDTA 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.

[0174] The carrier preferably has a pH of about 4.0 to 10.0, more preferably about 4.8 to about 7.8, more preferably about 5.0 to about 6.5. 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 composition, such as vitamin C, vitamin E, or other reducing agents known in the pharmaceutical art.

[0175] 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.

[0176] 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.

[0177] 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 (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).

[0178] In some embodiments, the composition comprises phenoxyethanol, ethylhexylglycerin, or a combination thereof. In some embodiments, phenoxyethanol is provided at least about 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 than 10% by weight (wt.%). In some embodiments, phenoxyethanol 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, ethylhexylglycerin is provided at least about 0.05%, 0.10%, 0.25%, 0.50%, 0.75%, 0.85%, 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, ethylhexylglycerin 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, phenoxyethanol and ethylhexylglycerin are provided at at least or about 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 than 10% by weight (wt.%).In some embodiments, phenoxyethanol and ethylhexylglycerin are provided in the range of about 0.25% to about 10%, about 0.1% to about 4%, about 0.5% to about 8%, about 0.75% to about 6%, or about 1% to about 4% by weight.

[0179] In some embodiments, the composition comprises polyacrylate-13, polyisobutene, polysorbate 20, or a combination thereof. In some embodiments, polyacrylate-13 is provided at at least or about 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 than 10% by weight (wt.%). In some embodiments, polyacrylate-13 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, polyisobutene is provided in at least about 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 than 10% by weight (wt.%). In some embodiments, polyisobutene 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, polyacrylate-13 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, Polysorbate 20 is provided at at least or about 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 than 10% by weight (wt.%).In some embodiments, polysorbate 20 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, polyacrylate-13, polyisobutene, and polysorbate 20 are provided at or about 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 than 10% by weight (wt.%). In some embodiments, polyacrylate-13, polyisobutene, and polysorbate 20 are provided in the range of about 0.25% to about 10% by weight, about 0.1% to about 4% 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 (wt.%).

[0180] The topical composition may contain micelles, or aggregates of surfactant molecules, dispersed in an aqueous solution. Micelles can be prepared by dispersing an oil solvent in an aqueous solution containing a surfactant, where the surfactant concentration exceeds the critical micelle concentration. The resulting composition contains micelles, i.e., spherical oil droplets.

[0181] Penetration enhancers Fatty acids and alcohols enhance the penetration of peptides and are useful in the composition, 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 6-12It 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.

[0182] How to use Described herein are compositions and methods for improving pigmentation, including hyperpigmentation. In some embodiments, the hyperpigmentation is due to post-inflammatory hyperpigmentation, melasma, or aging. In some embodiments, aging hyperpigmentation is caused by UV exposure or inflammation.

[0183] Also described herein are compositions and methods for reducing melanocyte activity, inhibiting melanin synthesis, reducing melanin transfer, increasing melanosome autophagy, reducing inflammation, or combinations thereof. In some embodiments, the reduction in melanocyte activity is due to inhibiting MITF, TYR, TRP1, TRP2, or a combination thereof. In some embodiments, the reduction in melanocyte activity is due to activating ERK signaling, JNK signaling, or a combination thereof. In some embodiments, the increased melanosome autophagy is due to increased expression, activity, or both of PAR-2, ET-1, or SCF.

[0184] The compositions described herein include peptides, silymarin, tranexamic acid, lactoferrin, cannabidiol, ashwagandha extract, gallic acid, sesamol, acteoside, oleuropein, hesperidin, sideroxylon inerme extract, parthenolide, 1,2-hexanediol, pentasodium tetracarboxymethyl dipeptide-51, pentasodium tetracarboxymethyl acetyl hydroxyprolyl dipeptide-12, niacinamide, Tremella fuciformis extract, Thermus thermophilus extract, phytoene, phytofluene, white horehound, rhubarb extract, or combinations thereof to treat pigmentation diseases or disorders.

[0185] Various pigmentation disorders or diseases can be improved using the compositions and methods described herein. In some embodiments, the pigmentation disorder or disease is hyperpigmentation. In some embodiments, the pigmentation disorder or disease is focal hypopigmentation or diffuse hypopigmentation. In some embodiments, the disorder or disease is post-inflammatory hyperpigmentation (PIH). In some embodiments, the PIH is an epidermal form of PIH. In some embodiments, the PIH is a dermal form of PIH. In some embodiments, the pigmentation disorder or disease includes, but is not limited to, acanthosis nigricans, senile lentigines, albinism, incontinentia pigmenti, lentigines, melasma, pityriasis alba, or progressive pigmented purpura.

[0186] The compositions described herein, in some embodiments, improve pigmentation by reducing melanocyte activity, inhibiting melanin synthesis, reducing melanin transfer, increasing melanosome autophagy, reducing inflammation, or a combination thereof. In some embodiments, the compositions described herein improve pigmentation by at least or about 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or more than 95%. In some embodiments, the compositions described herein improve pigmentation by at least or about 0.5x, 1.0x, 1.5x, 2.0x, 2.5x, 3.0x, 3.5x, 4.0x, 5.0x, 6.0x, 7.0x, 8.0x, 9.0x, 10x, or more than 10x.

[0187] The compositions described herein can be used in various treatment regimens. In some cases, the topical compositions described herein are administered once a day, twice a day, three times a day, or more. In some cases, the topical compositions described herein are administered twice a day. In some embodiments, the topical 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 topical compositions described herein are administered twice a day, for example, in the morning and in the evening. In some embodiments, the topical composition described herein is 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. In some embodiments, the topical composition described herein is administered twice daily for at least or about 1 week, 2 weeks, 3 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, or more. In some embodiments, the topical composition described herein is administered once daily, twice daily, three times daily, four times daily, or more than four times daily for at least or about 1 week, 2 weeks, 3 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, or more.

[0188] Stability testing Stability testing of the compositions can be carried out as follows. 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), where most products will show excellent stability. In some cases, the product is also subjected to -10°C (14°F) for 3 months.

[0189] 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.

[0190] 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.

[0191] 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.

[0192] 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.

[0193] Kits for non-invasive use Some embodiments of the methods and compositions provided herein include kits that include the peptides provided herein. In some embodiments, the kits may be provided to a physician, other medical personnel, a patient, or a caregiver to administer. In some embodiments, the kits include a container containing the peptide composition in a suitable topical composition and instructions for administering the peptide composition to a subject. The kits may also optionally contain one or more additional therapeutic or other agents. For example, a kit containing a topical form of the peptide composition may be provided with other skin care agents, such as cleansers, occlusive moisturizers, penetrating moisturizers, sunscreens, sunblocks, and the like. The kits may contain the peptide composition in bulk form, or may contain separate doses of the peptide composition for continuous or sequential administration. The kits may optionally contain one or more diagnostic tools, administration tools, and / or instructions for use. The kits may contain a suitable delivery device, such as a syringe, pump dispenser, single dose packet, and the like, along with instructions for administering the peptide composition and any other therapeutic or beneficial agents. The kit may optionally contain instructions for storage, reconstitution (if applicable), and administration of any or all of the therapeutic or beneficial agents included. The kit may contain multiple containers reflecting the number of doses to be given to a subject, or different products to be administered to a subject.

[0194] In some embodiments, the composition also works with the skin's own natural renewal process, helping to improve the appearance of the skin and the firmness of the skin. The topical composition is suitable for all skin types and post-treatment skin. The topical composition can be provided to the patient in bulk form to allow a suitable amount of peptide to be self-administered by the patient. For example, the patient can apply a sufficient amount of the composition to evenly cover the affected area, or as otherwise instructed by a physician. In certain embodiments, it may be desirable to incorporate additional therapeutic or active agents into the topical composition. Alternatively, adjunct therapies or agents can be administered separately. For example, cleansers, sunblocks, sunscreens, penetrating moisturizers, and / or occlusive moisturizers can be provided for administration before or after the topical composition of the embodiments.

[0195] Various examples of creams, ointments, lotions, solutions, gels, sprays, and patches may incorporate the peptide compositions described herein as active ingredients in combination with penetration enhancers and other active agents that act synergistically on the skin to promote wound healing or wound closure, or to treat chronic skin wounds. EXAMPLES

[0196] The following examples are provided for the purpose of illustrating various embodiments of the present disclosure and are not intended to limit the disclosure in any manner. The examples, together with the methods described herein, are representative of currently preferred embodiments and are illustrative and are not intended as limitations on the scope of the present disclosure. Modifications therein and other uses encompassed within the spirit of the invention as defined by the scope of the claims will occur to those skilled in the art.

[0197] Example 1: Exemplary Compositions and Modulation of Gene Expression Exemplary compositions are found in Table 2. Additionally, the compounds and concentrations listed in Tables 3-6 can be analyzed to assess their effect on the expression of genes important in regulating melanogenesis. Specifically, the effect of these compounds on gene expression in endothelial cells, melanocytes, fibroblasts, and keratinocytes is analyzed. Gene sequencing analysis, bioinformatics, and gene ontology analysis are performed.

[0198] Table 2: Formulation 1 TIFF2024535424000002.tif141128

[0199] Table 3: Formulation 2 TIFF2024535424000003.tif76166

[0200] Table 4: Formulation 3 TIFF2024535424000004.tif126128

[0201] Table 5: Formulation 4 TIFF2024535424000005.tif205161

[0202] Table 6: Formulation 5 TIFF2024535424000006.tif227161

[0203] Example 2: Synergistic Effects of Combining Tripeptide-1 and Hexapeptide-12-Skin Pigmentation Microphthalmia-associated transcription factor (MITF) is a master regulator of pigmentation and melanin migration and a potential new target for pigmentation and melanoma. An in vitro MITF gene expression study was performed to confirm the differences between individual peptides (tripeptide-1 and hexapeptide-12) and their combinations with respect to MITF downregulation.

[0204] Specifically, the study was carried out by culturing fibroblasts and then adding tripeptide-1, hexapeptide-12, or a combination of both. After 48 hours, MITF gene expression was analyzed. As shown in Table 7 below, MITF gene analysis showed that each peptide had limited effect on MITF downregulation. In fact, hexapeptide-12 alone showed very little MITF downregulation (-1.16), while tripeptide-1 alone showed little MITF upregulation (+1.72). However, when combined together in a blend, MITF downregulation was significantly increased (-4.17). This increased expression continued to manifest and further increased at 72 hours.

[0205] (Table 7) TIFF2024535424000007.tif26145*80ppm hexapeptide refers to the concentration of hexapeptide-12 in the carrier, 120ppm tripeptide refers to the concentration of tripeptide-1 in the carrier, and the peptide blend of 80ppm hexapeptide and 120ppm tripeptide

[0206] The data show that tripeptide-1 and hexapeptide-12 have a synergistic effect on MITF gene expression.

[0207] Example 3: Gene Expression Studies Four cell types related to the pigmentation pathway were analyzed for gene expression: melanocytes, keratinocytes, fibroblasts, and endothelial (HUVEC) cells.

[0208] method To simulate the UV-stimulated pigmentation pathway process, melanocytes were pretreated with PGE2, which is the normal direct result of UV exposure that normally occurs from exposed keratinocytes. After 48 hours of adherent culture, these melanocytes were induced with 10uM PGE2 in melanocyte medium for 24 hours. Four primary human adult dermal cell lines were cultured and seeded in triplicate in well plates, then treated with 11 different compound treatments (+DMSO control). After 48 hours of adherent culture, the remaining fibroblasts, HUVECs, and keratinocytes were treated with the test compounds listed in Table 8.

[0209] Table 8. Compounds used in gene expression studies TIFF2024535424000008.tif76128

[0210] After 24 hours of compound exposure, RNA lysate preparation was performed and samples were sent to MedGenome for RNA extraction, library construction, and sequencing on 25M paired-end 100 bp reads per sample. Library preparation and sequencing were completed at MedGenome.

[0211] result Of the four cell lines, it was possible to identify active substances with significant melanogenic activity in three cell lines, melanocytes, keratinocytes, and HUVECS. The fibroblast cell line showed various functions not related to melanogenic activity (mainly wound healing) and was not used further. The melanocyte activity pathway was found to be activated (Figures 3A-3D). Hexapeptide-12 (Hex12) and lactoferrin (lacto) were particularly prevalent in melanogenic activity. Figures 4 and 5 show the downregulation of melanogenic genes related to hexapeptide-12 (Hex12) and lactoferrin (lacto). Similarly, Figures 6A-6F show gene expression data for SCF, LIF, POMC, endothelin genes, PGE2, and NGF in keratinocyte cells in response to various compounds listed in Table 8. The data indicates hexapeptide-11 (Hex11) as the active component in melanogenesis activity, while Figure 7 shows individual Hex-11 activity. Figures 8A-8C show data in HUVEC for gene expression of EDN-1 (EDN1) (Figure 8A), SCF (Figure 8B), and TGFB1 (Figure 8C) in response to various compounds listed in Table 8. Figure 9 shows the potent activity of phosphatidylserine on EDN1 and other melanogenesis genes.

[0212] conclusion Cell line melanogenic gene activity studies identified lactoferrin, hexapeptide-11, hexapeptide-12, and phosphatidylserine as having significant effects on melanogenic activity.

[0213] Example 4: Comparative in vitro melanocyte analysis via absorbance readings The melanocyte model was designed to test agents that exhibit a direct effect on melanocyte cells and melanin production from melanocyte samples treated with the compound via absorption.

[0214] method Melanocytes were cultured in 6-well plates containing growth medium. Once confluent, two concentrations of each of the 10 compounds were added to the cells in triplicate wells for 4 days. There were a total of 11 6-well plates, one for each compound treatment and one for the vehicle control. Absorbance readings were taken on lysates prepared for each well of the 6-well plates and normalized for cell number. The model was first tested for accuracy and validated using hexapeptide-12 given the strong gene expression results in the melanocyte cell line in the initial study, giving confirmation of reduced stimulation. Additional validation was performed using MSH addition to the medium to confirm increased stimulation of melanin production. The following compounds used in this study are seen in Table 9.

[0215] Table 9: Test compounds used in the in vitro melanocyte comparative assay TIFF2024535424000009.tif46128

[0216] result Table 10 shows the results in three absorption spectra at two concentrations of selected compounds.

[0217] Table 10: Absorption spectra of selected compounds at 405 nm, 490 nm, and 492 nm TIFF2024535424000010.tif189160

[0218] This study confirmed the effectiveness of these selected agents to reduce melanogenesis in melanocytes (% reduction in absorption indicating reduced melanogenesis). Modulation of melanogenesis was observed for lactoferrin, hexapeptide-11, hexapeptide-12, and phosphatidylserine. Modulation of melanogenesis was also observed for silymarin, sesamol, tranexamic acid, and phytoene / phytofluene (Table 10).

[0219] Example 5: Gene Expression Studies The melanocyte model was designed to test agents that exhibit a direct effect on melanocyte cells and melanin production from melanocyte samples treated with the compound via absorption.

[0220] method Using the same methods as in Examples 3 and 4, the expression of PMEL, tyrosinase gene, MC1 / 4R, EDNRB, MITF, ERK1 / 2, JNK, and ANKT1 was measured.

[0221] result Figures 10A-10D show the expression of PMEL (Figure 10A), tyrosinase genes (Figure 10B), MC1 / 4R (Figure 10C), and EDNRB (Figure 10D) following treatment of endothelial cells with lactoferrin (Lacto), peptide derived from lactoferrin (TCV), hexapeptide-12 (Hex12), tripeptide-1 and hexapeptide-12 (TriHex), hexapeptide-11 (Hex11), tranexamic acid (Tran acid), octapeptide (Octa), phosphatidylserine (phos), cannabidiol (CBD), and all (All). Figures 10A-10D show that hexapeptide-12 and lactoferrin exhibited robust melanogenesis activity. Figure 11 shows data from hexapeptide-12.

[0222] MITF is regulated by phosphorylation. Specifically, the MAPK and Akt pathways are known to phosphorylate MITF at certain sites. Figures 12A-12C show the expression of ERK1 / 2 (MAPK3 / MAPK1) (Figure 12A), JNK (Figure 12B), and AKT1 (Figure 12C) after treatment of endothelial cells with lactoferrin (Lacto), a peptide derived from lactoferrin (TCV), hexapeptide-12 (Hex12), tripeptide-1 and hexapeptide-12 (TriHex), hexapeptide-11 (Hex11), octapeptide (Octa), phosphatidylserine (phos), cannabidiol (CBD), and all (all).

[0223] conclusion Taken together, the increased expression of these kinases may be associated with the decreased expression of MITF, thus contributing to reduced melanogenesis. Hexapeptide-12 and lactoferrin have a significant effect on such melanogenic activity.

[0224] Example 6: Melanocyte assay hTERT-immortalized dermal melanocytes were treated with various compounds, and the experimental materials and results are presented below.

[0225] method Primary human melanocytes were supplied by ATCC (catalog number ATCC CRL-4059). Melanocytes were first seeded in 6-well tissue culture plates (1.5x10^3 cells per well) in Melanocyte Growth Medium (Dermal Cell Basal Medium (ATCC® PCS-200-030) supplemented with Melanocyte Growth Kit (ATCC® PCS-200-041). Melanocytes were then grown in 10cm tissue culture plates at the concentration recommended by ATCC. The cells appear fully attached to the plate / dish while culturing in a spider web morphology. The cells were cultured in a 5% CO2 incubator at 37°C.

[0226] Stocks of compounds 1-10 listed below were suspended in either complete melanocyte growth medium or DMSO (indicated in parentheses). Each compound resuspension was then diluted in melanocyte growth medium to the final concentrations in Table 11.

[0227] Table 11. Compounds used in the in vitro melanocyte comparative assay TIFF2024535424000011.tif68158

[0228] Once the melanocytes were 100% confluent in the 6-well plates, the Melanocyte Growth Medium was removed and the melanocytes were treated with medium containing the compositions above, with duplicate wells for each compound / concentration listed above. Duplicate vehicle control wells received Melanocyte Growth Medium alone or Melanocyte Growth Medium containing DMSO (10 uL per 10 mL of Melanocyte Growth Medium).

[0229] Cells were fed with the appropriate medium for the next 5 days. Cells were inspected for morphology every day. All cells maintained normal morphology over the entire 5-day treatment period, except as noted below.

[0230] Melanocytes cultured in lactoferrin-containing medium (at both 500 and 1000ug / mL concentrations) developed a ring-shaped morphology rather than the usual spider web morphology 24 hours after the first treatment. Interestingly, at 48 hours after the first treatment, the melanocytes reverted to normal morphology and maintained normal morphology throughout the 5-day treatment period.

[0231] Melanocytes cultured in Ashwagandha containing medium (at both 10 and 20 ug / mL concentrations) began to die 24 hours after the first dose and continued to die until all melanocytes were dead 48 hours after the first dose.

[0232] Melanocytes in oleuropein-containing medium (at both concentrations 500 and 1000 ug / mL) began to die 24 hours after the first dose and continued to die each day until nearly all melanocytes had died 72 hours after the first dose.

[0233] Lysates were prepared for each sample. Briefly, 6.6x10^5 cells from each sample were spun down and collected in a vial. 150uL of CHAPS lysis buffer was added to each replicate sample, vortexed, placed in a dry ice / ethanol bath for 2 minutes, then left at room temperature until completely thawed. This freeze-thaw cycle was repeated one more time for a total of two freeze / thaw cycles. Lysate samples were spun at 14,800rpm for 15 minutes. The supernatant was removed, leaving the black pellet in the vial. The pellet was resuspended in 100uL of 1M NaOH / 10% DMSO solution and incubated at 80°C for 90 minutes, with pipette mixing at 30, 60, and 90 minutes.

[0234] result 100 uL of each replicate sample at each concentration was added to individual wells of a flat-bottom 96-well plate and absorbance readings were taken at 405 nm, 490 nm, and 492 nm on an Envision 2103 Multilabel Reader.

[0235] Table 12. Absorbance readings at 405 nm, 490 nm, and 492 nm TIFF2024535424000012.tif173152

[0236] Example 7: Full preparation melanocyte assay Compounds and concentrations were combined from the original stock solutions in Example 6 to make a complete formulated medium for melanocyte culture.

[0237] method The compounds and concentrations in Table 13 below were combined from the original stock solutions to make 50 mL of complete formulation medium in which melanocytes were cultured for 5 days in 6-well plates. The medium used is indicated in brackets.

[0238] Table 13: Compounds and concentrations used in Example 7 TIFF2024535424000013.tif57128

[0239] When the melanocytes were 100% confluent in the 6-well plates, the Melanocyte Growth Medium was removed and the melanocytes were treated in duplicate wells with medium containing the complete formulation medium described above. Duplicate vehicle control wells were fed with Melanocyte Growth Medium containing DMSO (20 uL per 10 mL of Melanocyte Growth Medium). The cells were fed with the appropriate medium for the next 5 days. Every day, the cells were inspected for morphology. All cells maintained normal morphology over the entire 5-day treatment period.

[0240] Lysates were prepared as in Example 6 for each replicate well sample containing melanocytes grown in complete formulation medium, and for replicate wells containing melanocytes grown in vehicle control medium.

[0241] result 100 uL of each replicate sample was added to a flat-bottom 96-well plate and absorbance readings were taken at 405 nm, 490 nm, and 492 nm on an Envision 2103 Multilabel Reader. Readings are shown in Table 14.

[0242] Table 14. Absorbance readings at 405 nm, 490 nm, and 492 nm TIFF2024535424000014.tif30156

[0243] Example 8: Double Liposomes This example demonstrates the preparation of double liposomes for use in the formulations described herein.

[0244] In the first step, 0.90 weight percent (wt.%) Pro-Lipo-NEO, 0.02 wt.% hexapeptide-11, 0.005 wt.% hexapeptide-12, and 0.10 wt.% lactoferrin were combined to form a liposome solution. 0.50 wt.% photoliposomes were added to the liposome solution to generate double liposomes.

[0245] Example 9: Clinical Trial to Evaluate the Efficacy and Safety of a Topical Product for Facial Pigmentation Disorders background Dyschromia and dyspigmentation are abnormalities in the formation of pigmentation in the skin. Hyperpigmentation is an increase in pigmentation or abnormally dark skin color. Hyperpigmentation occurs when excessive amounts of melanin are produced. Causes of hyperpigmentation include sun exposure, certain medicines, hormonal changes, PIH (post-inflammatory hyperpigmentation), or congenital pigmentation disorders. Hyperpigmentation results in uneven skin tone and a photoaged appearance.

[0246] Hydroquinone ("HQ") is accepted as the standard for efficacy against hyperpigmentation (facial pigmentation disorders). 4% HQ is considered an effective concentration for pigmentation maintenance treatment. However, long-term use of HQ is associated with side effects, tissue browning, and adverse irritant effects. Rebound is also known to occur with HQ use. Thus, a substantial equivalent to the established HQ without the side effects would be desirable for any product for treating hyperpigmentation (facial pigmentation disorders), and the ability to continue effective long-term treatment without adverse side effects that allows control of pigmentation (which is often an ongoing problem) would be a major advantage to any pigment product.

[0247] In this study, a composition according to the present disclosure ("Formulation 5" above) was compared to HQ 4%, which is representative of current use for treating pigmentation and dyschromia.

[0248] The purpose of this study was to evaluate the efficacy and safety of a topical product according to the present disclosure (the "Test Product") compared to HQ4% for the improvement of pigmentation disorders and hyperpigmentation through investigator assessment, participant assessment / questionnaires, photography, skin imaging, and reported adverse reactions. The extension portion of this study evaluated continued use of the Test Product over a 3-month extension period, during which all participants randomized to HQ4% discontinued and used only the Test Product, SPF, and moisturizer.

[0249] Study population Forty-three participants (male and female, skin types I-IV, mean age 49.2) with mild to severe facial pigmentation disorders and / or facial hyperpigmentation were enrolled. Participants provided informed consent and agreed to limit sun exposure for the duration of the study. Participants were required to follow a skin care regimen and return for follow-up visits. This study population was deemed a sufficiently large sample size for safety and efficacy. Only participants who were eligible to participate were selected. Participants who enrolled and completed the 3-month study for this protocol were eligible to participate in a 3-month extension study.

[0250] The following items represent the inclusion criteria: 1. Men and women, skin types I-V, ages 18-71 years, with mild to severe facial pigmentation disorders and / or hyperpigmentation, defined as grade 3-7 on the Dyschromic Scale at baseline. 2. Willingness to provide written informed consent and to have photographs published. 3. Willingness to not use any new skin care products on the facial area, other than the test product provided for the duration of the study, in accordance with the study design and procedures. 4. Willingness to avoid prolonged sun exposure and use of tanning beds for the duration of the study. 5. Individuals who are willing to refrain from any other treatment or procedure to the facial area for the duration of the study. 6. Participants of childbearing potential must use contraception or abstain from sexual activity during the study. Participants who use prescribed contraception must use it for at least 30 days prior to study entry.

[0251] The following items represent the exclusion criteria: 1. Known allergy to facial skin care products or allergy to any of the ingredients in the test products. 2. Individuals who are breastfeeding, pregnant, or planning to become pregnant during the study. 3. Individuals who have used any of the medicines or undergone any of the procedures outlined below: - Use of Retin-A®, Retin-A Micro®, Renova®, Evita®, Tazorac®, Soriatane®, Differin®, or more than 1% retinol within the last month Accutane® within 12 months -Prescription doses of skin lightening products (e.g., hydroquinone, tretinoin, AHA, BHA, and polyhydroxy acids, 4-hydroxyanisole alone or in combination with tretinoin) within the past month Within 2 weeks, anti-wrinkle, skin lightening products, or any other products known to affect skin aging or pigmentation disorders or topical or systemic medications (e.g., products containing alpha / beta / polyhydroxy acids, vitamin C, soy, Q-10, hydroquinone; systemic or licorice extract (topical), etc.), retinoids, or 1% or less retinol Have undergone a regimen of high-energy facial treatments, laser resurfacing, light therapy, chemical peels, or microneedling within the past two months 4. Individuals with facial skin conditions (e.g., psoriasis, rosacea, acne, eczema, seborrheic dermatitis, severe excoriation, etc.) that, in the opinion of the Investigator or designee, make them unsuitable for participation or that may interfere with the outcome of the study. 5. Individuals with uncontrolled medical conditions such as asthma, diabetes, hypertension, hyperthyroidism, or hypothyroidism. 6. Individuals who have undergone any planned surgery and / or invasive medical procedures during the course of the study. 7. Individuals currently participating in any other face-use study or who have participated in any clinical trial within 4 weeks prior to study inclusion. 8. Individuals with sunburn, sunburn irritation, scarring, birthmarks, excess hair, etc., or other facial dermal conditions that, in the opinion of the Investigator or designee, may affect the outcome. 9.Individuals who have initiated hormone replacement therapy (HRT) or contraceptive hormones within 3 months prior to study entry, or who plan to start, stop, or change the dose of HRT or contraceptive hormones during the study.

[0252] method Participants underwent a 12-week extension study that included up to eight study visits in the main study: screening, baseline, and three follow-up visits, and an additional three follow-up visits conducted over 12 weeks: a final visit at weeks 16, 20, and 24, with participants receiving the extended 12-week follow-up visit. At the initial screening visit, participants were consented prior to any study treatment. Medical / aesthetic medical history, concomitant medications, and study eligibility were collected and assessed. The following procedures were performed at baseline: investigator evaluation, photography, and optical coherence tomography (OCT) imaging of the skin (at select sites only). Participants were randomized to receive either the study product or HQ 4% along with cleanser and sunscreen for application to facial skin as directed. Participants were asked to return to the office for follow-up visits at weeks 4, 8, and 12. Then, at week 12, participants were offered the option to continue the study for an additional 12 weeks, during which participants randomized to HQ4% discontinued use of the study-provided 4% hydroquinone and used only the provided cleanser, SPF, and moisturizer. Participants randomized to the topical study products continued to use the products throughout the duration of the study, along with the study-provided cleanser and sunscreen for application to facial skin as previously instructed.

[0253] Biopsy: Two participants consented to 2-3 mm punch biopsies before and after 12 weeks of product use. Biopsies were performed on facial skin and specimens were sent to an independent dermatopathologist for analysis.

[0254] OCT skin imaging: A non-invasive imaging technique for skin assessment that uses commercially available devices and has no discernible effect on tissue.

[0255] Clinical Photography: Using a camera system with consistent placement and conditions, photographs were taken at all visits, including the 12-week extension study follow-up visit. Photographs were taken (clean, dry skin only) before any product application at all study visits. (All photographs used for publication or marketing purposes had consent for use. Participants consented to being photographed in order to participate in this study.)

[0256] Test Product All participants received a gentle cleanser, sunscreen, and either the test product or HQ4%, which was only used until week 12, at which point participants discontinued use of HQ4%.

[0257] Participants received an appropriate amount of topical product for application at home. A gentle cleanser to be used AM / PM Test product or HQ 4% (in blinded bottles) applied to face in the morning / afternoon In the morning, sunscreen is applied after application of the test product or HQ4%. Moisturizer to be used AM / PM

[0258] Study visit Visit 1: Screening / Baseline: Participants were consented and assessed for eligibility to participate in the study. The following procedures were performed: ●Facial skin evaluation by the responsible physician UPT for women of childbearing age ●Facial skin evaluation by the responsible physician Photographing clean, dry facial skin OCT imaging of the skin (only at one clinical site) ●Biopsy (2-3mm punch) before using the product Participants returned to the office for suture removal according to the investigator's standard of care. Distribute randomized testing kits with instructions for use

[0259] Visits 2-3: Participants returned for follow-up visits at weeks 4 and 8 (+ / - 5 days). The following procedures were performed: Participant assessment of facial skin Photographing clean, dry facial skin OCT imaging of the skin (only at one clinical site) Dispense additional product as needed

[0260] Visit 4: Participants returned for a follow-up visit at Week 12 (+ / - 5 days), at which point they were given the opportunity to continue participation for an additional 12 weeks or to complete study participation at the end of the Week 12 visit. Participants were consented and the following procedures were administered: ●Facial skin evaluation by the responsible physician Participant assessment of facial skin Photographing clean, dry facial skin OCT imaging of the skin (only at one clinical site) ●Biopsy (2-3mm punch) Participants returned to the office for suture removal according to the investigator's standard of care. Participants who agreed to continue in the study for an additional 12 weeks and were randomized to HQ4% returned all remaining study products. These participants were then instructed to continue using the study-supplied cleanser, SPF, and moisturizer for the remainder of the study. Participants who agreed to continue in the study for an additional 12 weeks and were randomized to the study product continued to use the study product along with the study-provided cleanser, sunscreen, and moisturizer for application to facial skin as previously instructed throughout the duration of the study. Dispensing of additional study product for these patients was permitted as needed. Collection of all study product for participants who did not agree to continue into the optional 12-week extension study.

[0261] Visits 5–6: Participants returned for follow-up visits at weeks 16 and 20 (+ / - 5 days). The following procedures were performed: ●Facial skin evaluation by the responsible physician Participant assessment of facial skin Photographing clean, dry facial skin ● Dispensing additional topical test product (only for participants who were using the product) ●Dispense additional cleanser, SPF, and moisturizer as needed.

[0262] Visit 7: Participants returned for a final follow-up visit at Week 24 (+ / - 5 days). The following procedures were performed: ●Facial skin evaluation by the responsible physician Participant assessment of facial skin Photographing clean, dry facial skin • Collection of all test products for patients using topical test products.

[0263] Randomization The test product and HQ4% were administered through stratified randomization with 22 and 21 participants with mild, moderate, or severe pigmentation disorders in the test product and HQ4% arms, respectively. The products were provided in kits with several quantities and then distributed according to the baseline grading of pigmentation disorders. Participants who agreed to participate in the 12-week extension study and were randomized to HQ4% discontinued use at week 12 and continued the same test-supplied cleanser, SPF, and moisturizer for the remainder of the study and throughout the follow-up period.

[0264] For the test product, 22 participants (20 female, 2 male) completed the study (1 withdrew consent) with the following skin types: I, n=1; II, n=7; III, n=7; IV, n=6; V, n=1. For HQ4%, 21 participants (20 female, 1 male) completed the study (1 withdrew consent, 1 LTFU) with the following skin types: I, n=2; II, n=6; III, n=6; IV, n=6; V, n=1.

[0265] Investigator assessment of facial skin severity: Baseline and Week 12 (and Weeks 16, 20, and 24) As summarized in Table 15, investigator assessment of facial skin severity was based on the following scale: 0=none, 1-3=mild, 4-6=moderate, 7-9=severe, taking into account the overall appearance of pigmentary abnormalities, skin tone (transparency and uniformity), luminance, and skin texture.

[0266] (Table 15) Physician-in-Charge Scale TIFF2024535424000015.tif55166

[0267] (Table 16) Results of the investigator's assessment of facial skin severity TIFF2024535424000016.tif131166

[0268] As shown in Table 16, the test product performed substantially as well (if not slightly better) in efficacy as HQ4% on facial pigmentation disorders. In terms of skin tone and luminosity, the test product showed similarity to HQ4%. However, in terms of skin texture, the test product showed a statistically significant improvement over HQ4%.

[0269] Investigator Assessment: mMASI Scoring - Baseline and Week 12 (and Weeks 16, 20, and 24) Investigator mMASI scoring was performed using a modified MASI scoring method as shown in Figure 13. Results of mMASI scoring assessment are shown in Table 17. As evidenced by the data, the test product demonstrated a statistically significant improvement in mMASI scoring at 12 weeks versus baseline, whereas HQ4% did not. In particular, the test product demonstrated a statistically significant improvement in the right and left cheek regions while performing in at least a statistically comparable manner to HQ4% across the entire face.

[0270] Table 17 mMASI Scoring TIFF2024535424000017.tif195166

[0271] Investigator assessment of tolerability (erythema, dryness, peeling) Results from investigator assessment of tolerability for test product versus HQ 4% are shown in Table 18.

[0272] (Table 18) Results from investigator tolerability assessment TIFF2024535424000018.tif135128

[0273] As shown in Table 18, when compared to HQ 4%, erythema, dryness, and peeling were reduced in the test product group at 4, 8, and 12 weeks.

[0274] Participant assessment of tolerability (stinging / tingling, prickling, itching) Results from participant assessment of tolerability for study product versus HQ 4% are presented in Table 19.

[0275] Table 19. Results from participant tolerability assessment TIFF2024535424000019.tif130128

[0276] As evidenced by the participant data, irritation is increased across all parameters for HQ4% relative to that observed with the test product population. In particular, the incidence of "itchiness" at weeks 4 and 12 was significantly reduced for the test product population, which is particularly important in developing treatment regimens for end users.

[0277] Participant Survey At weeks 4, 8, and 12, participants completed surveys regarding their satisfaction with the study product versus treatment with HQ 4%. Results are summarized in Table 20.

[0278] (Table 20) Results from participant survey TIFF2024535424000020.tif246152TIFF2024535424000021.tif246153TIFF2024535424000022.tif24377

[0279] As shown in Table 20, based on overall participant interpretation, the initial 4 weeks of HQ4% treatment appeared to have greater efficacy against hyperpigmentation when compared to the test product, but from the participant's perspective, the test product performed at least equally to HQ4%, and in some cases surpassed HQ4% in terms of participant's impression of efficacy against hyperpigmentation by the 8-week and 12-week visits. In addition, throughout the study, participants preferred the general appearance and health of the skin achieved with the test product.

[0280] Adverse events Adverse events assessed by the investigator are a crucial parameter for determining possible shortcomings of a therapeutic product. For the HQ4% population, a total of 5 adverse events (23.8%) were reported: 2 moderate contact dermatitis (related), 1 mild contact dermatitis (related), 1 eyelid erythema (possibly related), and 1 chin acne breakout (unlikely related). Notably, the test product population reported no adverse events (0%). Thus, the improvement in adverse events for the test product represents a significant improvement over those known to participate in the use of HQ4%.

[0281] Clinical photograph 14A-H show clinical photographs at baseline and 12 weeks of a study subject who started a clinical trial with severe hyperpigmentation and was treated with the test product (14A,B) and HQ4% (14C), a subject who started a clinical trial with moderate hyperpigmentation and was treated with the test product (14D,E) and HQ4% (14F), and a subject who started a clinical trial with mild hyperpigmentation and was treated with the test product (14G) and HQ4% (14H). The clinical photographs show that the efficacy of the test product in reducing hyperpigmentation is at least equivalent to (and in some cases exceeds) the efficacy of HQ4%.

[0282] FIG. 15 shows clinical photographs of subjects undergoing long-term treatment (up to 5 months) with the test product, demonstrating the long-term effectiveness of the test product in reducing hyperpigmentation.

[0283] While preferred embodiments of the present disclosure have been shown and described herein, it will be apparent to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, changes, and substitutions will now occur to those skilled in the art without departing from the present disclosure. It should be understood that various alternatives to the embodiments of the present disclosure described herein may be used in the practice of the present disclosure. The following claims define the scope of the present disclosure, and it is intended that methods and structures within the scope of these claims and their equivalents be covered thereby.

Claims

1. A topical composition for improving pigmentation, comprising hexapeptide-11, hexapeptide-12, and one or more dipeptides.

2. The topical composition of claim 1, further comprising one or more photosomes present in a range of about 0.1 wt. % to about 2 wt. %.

3. The topical composition of claim 2 further comprising one or more liposomes.

4. The topical composition of claim 3 , wherein the one or more photosomes encapsulate the one or more liposomes.

5. The topical composition of claim 1 , wherein the one or more dipeptides comprise dipeptide-51 or dipeptide-12.

6. 10. The topical composition of claim 1, wherein the hexapeptide-11 is present at 50 to 150 ppm.

7. The topical composition of claim 3, wherein the hexapeptide-11 or the hexapeptide-12 is encapsulated in a liposome.

8. 10. The topical composition of claim 1, wherein the hexapeptide-12 is present at 1 to 10 ppm.

9. The topical composition of claim 1, further comprising lactoferrin present at about 0.25 wt.% or less.

10. The topical composition of claim 1, further comprising phosphatidylserine present in an amount of up to 5.0 wt.%.

11. Niacinamide present in the range of about 1.0 wt. % to about 10 wt. %, or Tranexamic acid present in a range of about 0.25 wt. % to about 10 wt. % The topical composition of claim 1 , further comprising at least one of:

12. The topical composition of claim 1, further comprising milk thistle (Silybum marianum) extract, sesamol, squalane, Dunaliella salina extract, ashwagandha (Withania somnifera) extract, gallic acid, hesperidin, Pancratium maritimum, Thermus thermophilus ferment, Tremella fuciformis, or combinations thereof.

13. 10. The topical composition of claim 1, further comprising phenoxyethanol, ethylhexylglycerin, caprylyl glycol, caprylhydroxamic acid, glycerin, lecithin, carnosine, tocopherol, phenoxyethanol, betaine, 1,2-hexanediol, plankton extract, fructose, sodium acrylates copolymer, dimethicone, caprylyl methicone, propanediol, or a combination thereof.

14. A topical composition according to any one of claims 1 to 13 for improving pigmentation as a result of a pigmentation disorder or disease.

15. 15. The topical composition of claim 14, wherein the pigmentation disorder is hyperpigmentation, focal hypopigmentation, diffuse hypopigmentation, acanthosis nigricans, senile lentigo, albinism, incontinentia pigmenti, lentigo, melasma, pityriasis alba, or progressive pigmented purpura.

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