Pigmentation Compositions and Methods

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 This application claims the benefit of U.S. Provisional Patent Application No. 63 / 001,095, filed March 27, 2020, which is incorporated herein by reference in its entirety. [Background technology]

[0002] background Skin, hair, and eye color are due to melanin produced within melanosomes. The amount of melanin produced in a given individual varies based on multiple genetic and environmental factors, including exposure to ultraviolet light. Excessive production of melanin in the skin can cause hyperpigmentation, resulting in melasma, freckles, and age spots. Therefore, understanding the regulation of melanin production and its underlying mechanisms is important for 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 transport, induce melanosome-containing keratinocyte exfoliation or melanosome autophagy, or a combination thereof.

[0004] An embodiment described herein is a topical composition for improving pigmentation, comprising one or more photosomes, one or more liposomes, hexapeptide-11, and hexapeptide-12, wherein the topical composition improves pigmentation. In one feature, the one or more photosomes are present in a range of about 0.1% to about 2% by weight. In one feature, the one or more photosomes are present in a range of about 0.25% to about 1% by weight. In one feature, the one or more photosomes encapsulate one or more liposomes. In one feature, the hexapeptide-11 is present at 50 to 150 ppm. In one feature, the hexapeptide-11 is present in a range of about 0.004% (wt%) to about 0.100% by weight. In one feature, the hexapeptide-11 is encapsulated in a first liposome of the one or more liposomes. In one aspect, hexapeptide-12 is encapsulated in a second liposome of the one or more liposomes. In one aspect, hexapeptide-11 and hexapeptide-12 are encapsulated in a first liposome of the one or more liposomes. In one aspect, hexapeptide-12 includes palmitoyl hexapeptide-12, myristoyl hexapeptide-12, or a combination thereof. In one aspect, hexapeptide-12 is present at 1 to 10 ppm. In one aspect, hexapeptide-12 is present in a range of about 0.001% (wt%) to about 0.025% wt. In one aspect, the topical agent further includes lactoferrin. In one aspect, lactoferrin is present at about 0.25% wt. or less. In one aspect, lactoferrin is present in a range of about 0.005% to about 0.25% by weight. In one aspect, lactoferrin is encapsulated in a third liposome of the one or more liposomes. In one aspect, the topical agent further comprises lactoferrin, and lactoferrin, hexapeptide-11, and hexapeptide-12 are encapsulated in a first liposome of the one or more liposomes. In one aspect, the topical agent further comprises a peptide derived from lactoferrin.In one aspect, the lactoferrin-derived peptide comprises 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. In one aspect, the topical agent further comprises phosphatidylserine. In one aspect, the phosphatidylserine is present at about 0.075% by weight or less. In one aspect, the phosphatidylserine is present in the range of about 0.005% to about 0.1% by weight. In one aspect, the phosphatidylserine is present at 5.0% by weight or less. In one aspect, the topical agent further comprises silymarin. In one aspect, the silymarin is present in the range of about 0.1% to about 1.0% by weight. In one feature, silymarin is present in the range of about 0.2% to about 3.0% by weight. In one feature, the topical medication further comprises sesamol. In one feature, sesamol is present in the range of about 0.002% to about 0.050% by weight. In one feature, the topical medication further comprises tranexamic acid. In one feature, tranexamic acid is present in the range of about 1% to about 10% by weight. In one feature, tranexamic acid is present in the range of about 0.25% to about 6.25% by weight. In one feature, the topical medication further comprises phytoene, phytofluene, or a combination thereof. In one feature, phytoene, phytofluene, or a combination thereof is present in the range of about 1% to about 10% by weight. In one feature, the topical medication further comprises ashwagandha (Withania somnifera) extract. In one aspect, the Ashwagandha extract is present in a range of about 0.020% to about 0.500% by weight. In one aspect, the topical agent further comprises gallic acid. In one aspect, the gallic acid is present in a range of about 0.40% to about 10% by weight. In one aspect, the topical agent further comprises hesperidin. In one aspect, the hesperidin is present in a range of about 0.020% to about 0.50% by weight. In one aspect, the topical agent further comprises Pancratium maritimum. In one aspect, the Pancratium maritimum is present in a range of about 0.50% to about 5.0% by weight.In one aspect, the topical agent further comprises niacinamide. In one aspect, the niacinamide is present in a range of about 1% to about 10% by weight. In one aspect, the topical agent further comprises oleuropein. In one aspect, the oleuropein is present in a range of about 0.030% to about 0.750% by weight. In one aspect, the topical agent further comprises Thermus thermophilus fermentate. In one aspect, the Thermus thermophilus fermentate is present in a range of about 0.30% to about 7.5% by weight. In one aspect, the topical agent further comprises Tremella fuciformis. In one aspect, the Tremella fuciformis is present in a range of about 0.20% to about 5.0% by weight. In one aspect, the topical agent further comprises heptasodium hexacarboxymethyldipeptide-12. In one aspect, the heptasodium hexacarboxymethyldipeptide-12 is present in a range of about 0.1% to about 10% by weight. In one aspect, the heptasodium hexacarboxymethyldipeptide-12 is present in a range of about 0.2% to about 5% by weight. In one aspect, the topical composition is water-soluble.

[0005] An embodiment described herein is a topical composition for improving pigmentation, comprising hexapeptide-11, hexapeptide-12, and a lactoferrin-derived peptide, wherein the topical composition improves pigmentation. In one feature, the hexapeptide-12 comprises palmitoyl hexapeptide-12, myristoyl hexapeptide-12, or a combination thereof. In one feature, the hexapeptide-12 is present at 1 to 10 ppm. In one feature, the hexapeptide-12 is present in a range of about 0.001% by weight (wt%) to about 0.025% by weight. In one feature, the hexapeptide-11 is present at 50 to 150 ppm. In one feature, the hexapeptide-11 is present in a range of about 0.004% by weight (wt%) to about 0.100% by weight. In one aspect, the lactoferrin-derived peptide comprises 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. In one aspect, the topical composition further comprises phosphatidylserine. In one aspect, the phosphatidylserine is present at about 0.075% by weight or less. In one aspect, the phosphatidylserine is present in the range of about 0.005% to about 0.1% by weight. In one aspect, the phosphatidylserine is present at 5.0% by weight or less. In one aspect, the topical composition further comprises lactoferrin. In one aspect, the lactoferrin is present at about 0.25% by weight or less. In one aspect, lactoferrin is present in a range of about 0.005% to about 0.25% by weight. In one aspect, the topical composition further comprises photosomes. In one aspect, the photosomes are present in a range of about 0.1% to about 2% by weight. In one aspect, the topical composition further comprises silymarin, sesamol, tranexamic acid, phytoene, phytofluene, ashwagandha extract, hesperidin, pancratium malium, niacinamide, oleuropein, Thermus thermophilus ferment, tremella fuciformis, heptasodium hexacarboxymethyl dipeptide-12, or a combination thereof. In one aspect, the topical composition is water-soluble.

[0006] 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 topical composition further comprises the pigmentation disorder or disease being hyperpigmentation. In one aspect, the topical composition further comprises the pigmentation disorder or disease being post-inflammatory hyperpigmentation (PIH). In one aspect, the topical composition further comprises the pigmentation disorder or disease being focal hypopigmentation or diffuse hypopigmentation. In one aspect, the topical composition further comprises the pigmentation disorder or disease being acanthosis nigricans, age spots, albinism, incontinentia pigmenti, lentigines, melasma, pityriasis alba, or progressive pigmented purpura.

[0007] Incorporation by Reference All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference. [The present invention 1001] 1. A topical composition for improving pigmentation, comprising: one or more photosomes; one or more liposomes; Hexapeptide-11 and Hexapeptide-12 and Including, A topical composition that improves pigmentation. [The present invention 1002] 1001. The topical composition of claim 1001, wherein said one or more photosomes are present in a range of about 0.1% to about 2% by weight. [The present invention 1003] 1001. The topical composition of claim 1001, wherein said one or more photosomes are present in a range of about 0.25% to about 1% by weight. [The present invention 1004] 1001. The topical composition of claim 1001, wherein said one or more photosomes encapsulate said one or more liposomes. [The present invention 1005] 1001. The topical composition of the present invention, wherein said hexapeptide-11 is present at 50 to 150 ppm. [The present invention 1006] 1001. A topical composition according to the present invention, wherein said hexapeptide-11 is present in an amount ranging from about 0.004 (wt%) to about 0.100 wt%. [The present invention 1007] 1001. The topical composition of claim 1001, wherein said hexapeptide-11 is encapsulated in a first liposome of said one or more liposomes. [The present invention 1008] 1007. The topical composition of claim 1007, wherein said hexapeptide-12 is encapsulated in a second liposome of said one or more liposomes. [The present invention 1009] 1001. The topical composition of claim 1001, wherein said hexapeptide-11 and said hexapeptide-12 are encapsulated in a first liposome of said one or more liposomes. [The present invention 1010] 1001. The topical composition of claim 1001, wherein the hexapeptide-12 comprises palmitoyl hexapeptide-12, myristoyl hexapeptide-12, or a combination thereof. [The present invention 1011] 1001. The topical composition of claim 1001, wherein said hexapeptide-12 is present at 1 to 10 ppm. [The present invention 1012] 1001. The topical composition of the present invention, wherein said hexapeptide-12 is present in a range of about 0.001 (wt%) to about 0.025 wt% by weight. [The present invention 1013] 1001. The topical composition of this invention, further comprising lactoferrin. [The present invention 1014] 1013. The topical composition of claim 1013, wherein said lactoferrin is present in an amount of about 0.25% by weight or less. [The present invention 1015] 1013. The topical composition of claim 1013, wherein said lactoferrin is present in a range of about 0.005% by weight to about 0.25% by weight. [The present invention 1016] 1008. The topical composition of claim 10, wherein said lactoferrin is encapsulated in a third liposome of said one or more liposomes. [The present invention 1017] 1001. The topical composition of claim 1001, further comprising lactoferrin, wherein said lactoferrin, hexapeptide-11, and hexapeptide-12 are encapsulated in a first liposome of said one or more liposomes. [The present invention 1018] 1001. A topical composition according to claim 10, further comprising a peptide derived from lactoferrin. [The present invention 1019] 1013. The topical composition of the present invention, wherein the lactoferrin-derived peptide comprises 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. [The present invention 1020] 1001. The topical composition of claim 1001, further comprising phosphatidylserine. [The present invention 1021] The topical composition of claim 1020, wherein said phosphatidylserine is present in an amount of about 0.075% by weight or less. [The present invention 1022] 1020. The topical composition of claim 1020, wherein said phosphatidylserine is present in the range of about 0.005% to about 0.1% by weight. [The present invention 1023] 1020. The topical composition of claim 1020, wherein said phosphatidylserine is present at 5.0% by weight or less. [The present invention 1024] The topical composition of this invention 1001 further comprising silymarin. [The present invention 1025] 1024. The topical composition of claim 1024, wherein said silymarin is present in the range of about 0.1% to about 1.0% by weight. [The present invention 1026] 1024. The topical composition of claim 1024, wherein said silymarin is present in the range of about 0.2% by weight to about 3.0% by weight. [The present invention 1027] 1001. A topical composition according to claim 10, further comprising sesamol. [The present invention 1028] 1027. The topical composition of claim 1027, wherein said sesamol is present in a range of about 0.002% by weight to about 0.050% by weight. [The present invention 1029] 1001. The topical composition of claim 1001, further comprising tranexamic acid. [The present invention 1030] 1029. The topical composition of claim 1029, wherein said tranexamic acid is present in the range of about 1% to about 10% by weight. [The present invention 1031] 1029. The topical composition of claim 1029, wherein said tranexamic acid is present in a range of about 0.25% to about 6.25% by weight. [The present invention 1032] The topical composition of this invention 1001 further comprising phytoene, phytofluene, or a combination thereof. [The present invention 1033] The topical composition of claim 1032, wherein the phytoene, phytofluene, or a combination thereof is present in a range of about 1% to about 10% by weight. [The present invention 1034] 1001. A topical composition according to claim 1001, further comprising an extract of Ashwagandha (Withania somnifera). [This invention 1035] 1034. The topical composition of claim 1034, wherein the Ashwagandha extract is present in the range of about 0.020% to about 0.500% by weight. [The present invention 1036] 1001. The topical composition of claim 1001, further comprising gallic acid. [This invention 1037] 1036. The topical composition of claim 1036, wherein said gallic acid is present in a range of about 0.40% to about 10% by weight. [The present invention 1038] 1001. The topical composition of this invention, further comprising hesperidin. [This invention 1039] 1038. The topical composition of claim 1038, wherein said hesperidin is present in a range of about 0.020% to about 0.50% by weight. [The present invention 1040] 1001. A topical composition according to claim 1001, further comprising Pancratium maritimum. [This invention 1041] The topical composition of the present invention 1040, wherein the pancratium maritium is present in a range of about 0.50% by weight to about 5.0% by weight. [The present invention 1042] The topical composition of this invention 1001 further comprising niacinamide. [This invention 1043] 1042. The topical composition of claim 1042, wherein the niacinamide is present in a range of about 1% to about 10% by weight. [This invention 1044] The topical composition of the present invention 1001, further comprising oleuropein. [This invention 1045] The topical composition of claim 1044, wherein said oleuropein is present in a range of about 0.030% to about 0.750% by weight. [The present invention 1046] The topical composition of this invention 1001 further comprising Thermus thermophilus ferment. [This invention 1047] The topical composition of claim 1046, wherein the Thermus thermophilus ferment is present in an amount ranging from about 0.30% to about 7.5% by weight. [This invention 1048] 1001. The topical composition of claim 1001, further comprising Tremella fuciformis. [This invention 1049] 1048. The topical composition of claim 1048, wherein said Tremella fuciformis is present in a range of about 0.20% to about 5.0% by weight. [The present invention 1050] 1001. A topical composition according to claim 1001, further comprising heptasodium hexacarboxymethyldipeptide-12. [This invention 1051] 1050. The topical composition of claim 10, wherein the heptasodium hexacarboxymethyldipeptide-12 is present in the range of about 0.1% to about 10% by weight. [This invention 1052] 1050. The topical composition of claim 10, wherein the heptasodium hexacarboxymethyldipeptide-12 is present in the range of about 0.2% to about 5% by weight. [This invention 1053] The topical composition of any one of claims 1001 to 1052, wherein the topical composition is water-soluble. [This invention 1054] 1. A topical composition for improving pigmentation, comprising: Hexapeptide-11 and Hexapeptide-12, Peptides derived from lactoferrin Including, A topical composition that improves pigmentation. [This invention 1055] 1054. The topical composition of claim 1054, wherein the hexapeptide-12 comprises palmitoyl hexapeptide-12, myristoyl hexapeptide-12, or a combination thereof. [This invention 1056] 1054. The topical composition of claim 1054, wherein said hexapeptide-12 is present at 1 to 10 ppm. [This invention 1057] 1054. The topical composition of claim 1054, wherein said hexapeptide-12 is present in an amount ranging from about 0.001 (wt%) to about 0.025 wt% by weight. [This invention 1058] 1054. The topical composition of claim 1054, wherein said hexapeptide-11 is present at 50 to 150 ppm. [This invention 1059] 1054. The topical composition of claim 10, wherein said hexapeptide-11 is present in an amount ranging from about 0.004 (wt%) to about 0.100 wt% by weight. [The present invention 1060] 1054. The topical composition of claim 1054, wherein the lactoferrin-derived peptide comprises 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. [This invention 1061] The topical composition of invention 1054, further comprising phosphatidylserine. [This invention 1062] A topical composition according to claim 1061, wherein the phosphatidylserine is present in an amount by weight of about 0.075% or less. [This invention 1063] 1061. The topical composition of claim 1061, wherein said phosphatidylserine is present in the range of about 0.005% by weight to about 0.1% by weight. [This invention 1064] 1061. The topical composition of claim 1061, wherein the phosphatidylserine is present in an amount of 5.0% by weight or less. [This invention 1065] The topical composition of invention 1054, further comprising lactoferrin. [The present invention 1066] 1065. The topical composition of claim 1065, wherein said lactoferrin is present in an amount of about 0.25% by weight or less. [This invention 1067] 1065. The topical composition of claim 1065, wherein said lactoferrin is present in an amount ranging from about 0.005% to about 0.25% by weight. [The present invention 1068] The topical composition of invention 1054 further comprising a photosome. [The present invention 1069] 1068. The topical composition of claim 1068, wherein said photosomes are present in a range of about 0.1% by weight to about 2% by weight. [The present invention 1070] The topical composition of any of claims 1054 to 1069, further comprising silymarin, sesamol, tranexamic acid, phytoene, phytofluene, ashwagandha extract, hesperidin, pancratium maltium, niacinamide, oleuropein, Thermus thermophilus ferment, tremella fuciformis, heptasodium hexacarboxymethyl dipeptide-12, or a combination thereof. [This invention 1071] The topical composition of any one of claims 1054 to 1070, which is water-soluble. [This invention 1072] A method for improving pigmentation as a result of a pigmentation disorder or disease, comprising administering a topical composition according to any one of claims 1001 to 1071. [This invention 1073] 1072. The method of claim 1072, wherein said pigmentation disorder or disease is hyperpigmentation. [This invention 1074] 1072. The method of claim 1072, wherein said pigmentation disorder or disease is post-inflammatory hyperpigmentation (PIH). [This invention 1075] 1073. The method of claim 1072, wherein said pigmentation disorder or disease is focal hypopigmentation or diffuse hypopigmentation. [This invention 1076] 1073. The method of claim 1072, wherein said pigmentation disorder or disease is acanthosis nigricans, age spots, albinism, incontinentia pigmenti, lentigines, melasma, pityriasis alba, or progressive pigmented purpura. [Brief explanation of the drawings]

[0008] [Figure 1] Illustrates factors that influence pigmentation, as well as strategies and agents that can be used to treat pigmentation diseases or disorders. [Figure 2]The effect of exogenous influences on different pigmentation pathways is illustrated. The abbreviations listed are as follows: for surface receptors on melanocytes: EDNRB = endothelin receptor B, MC1R = melanocortin-1 receptor - the agonist is 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] Figures 3A-3D illustrate the expression levels of MEK (Figure 3A), ERK (Figure 3B), POMC (Figure 3C), and CTNNB1 (Figure 3D) in melanocytes after treatment with lactoferrin (Lacto), lactoferrin-derived peptide (TCV), hexapeptide-12 (Hex12), tripeptide-1 and hexapeptide-12 (TriHex), hexapeptide-11 (Hex11), tranexamic acid (Tran), octapeptide (Octa), phosphatidylserine (Phos), cannabidiol (CBD), and all (All). [Figure 3B] See legend to Figure 3A. [Figure 3C] See legend to Figure 3A. [Figure 3D] See legend to Figure 3A. [Figure 4] Illustrates the expression of various genes after treatment of melanocytes with hexapeptide-12 (Hex-12). [Figure 5] Illustrates the expression of various genes after treatment of melanocytes with lactoferrin (Lacto). [Figure 6-1]Figures 6A-6F illustrate the expression of SCF (Figure 6A), LIF (Figure 6B), POMC (Figure 6C), endothelin genes (Figure 6D), PGE2 (Figure 6E), and NGF (Figure 6F) 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), octapeptide (Octa), phosphatidylserine (Phos), cannabidiol (CBD), and all (All). [Figure 6-2] See description of Figure 6-1. [Figure 6-3] See description of Figure 6-1. [Figure 7] Illustrates individual hexapeptide-11 (Hex-11) activities for various genes. [Figure 8A] Figures 8A-8C illustrate the expression of EDN1 (Figure 8A), SCF (Figure 8B), and TGFB1 (Figure 8C) after treatment of endothelial cells with lactoferrin (Lacto), lactoferrin-derived peptide (TCV), hexapeptide-12 (Hex12), tripeptide-1 and hexapeptide-12 (TriHex), hexapeptide-11 (Hex11), tranexamic acid (Tran), octapeptide (Octa), phosphatidylserine (Phos), cannabidiol (CBD), and all (All). [Figure 8B] See legend to Figure 8A. [Figure 8C] See legend to Figure 8A. [Figure 9] Illustrates the individual phosphatidylserine activities of EDN1 and other melanogenic genes. [Figure 10A]Figures 10A-10D illustrate the expression of PMEL (Figure 10A), tyrosinase genes (Figure 10B), MC1 / 4R (Figure 10C), and EDNRB (Figure 10D) after treatment of endothelial cells with lactoferrin (Lacto), lactoferrin-derived peptides (TCV), hexapeptide-12 (Hex12), tripeptide-1 and hexapeptide-12 (TriHex), hexapeptide-11 (Hex11), tranexamic acid (Tran), octapeptide (Octa), phosphatidylserine (Phos), cannabidiol (CBD), and all (All). [Figure 10B] See legend to Figure 10A. [Figure 10C] See legend to Figure 10A. [Figure 10D] See legend to Figure 10A. [Figure 11] Illustrates the expression of MITF after treatment of endothelial cells with lactoferrin (Lacto), lactoferrin-derived peptide (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] Figures 12A-12C illustrate the expression of ERK1 / 2 (MAPK3 / MAPK1) (Figure 12A), JNK (Figure 12B), and AKT1 (Figure 12C) after treatment of endothelial cells with lactoferrin (Lacto), lactoferrin-derived peptides (TCV), hexapeptide-12 (Hex12), tripeptide-1 and hexapeptide-12 (TriHex), hexapeptide-11 (Hex11), octapeptide (Octa), phosphatidylserine (Phos), cannabidiol (CBD), and all (All). [Figure 12B] See legend to Figure 12A. [Figure 12C] See legend to Figure 12A. DETAILED DESCRIPTION OF THE INVENTION

[0009] 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. Accordingly, the description of a range should be considered to have specifically disclosed all possible subranges and individual numerical values ​​within that range to one-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, e.g., 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.

[0010] The terminology used herein is for the purpose of describing particular embodiments only 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 exclude 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.

[0011] 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 for values ​​recited for a range, 10% below the recited lower limit and 10% above the recited upper limit.

[0012] composition peptide The compositions described herein comprise 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, age-related hyperpigmentation is caused by UV exposure or inflammation.

[0013] In some embodiments, the one or more peptides comprise 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 comprise hexapeptide 11, tripeptide-1, and hexapeptide-12.

[0014] In some embodiments, hexapeptide-11, tripeptide-1, and hexapeptide-12 have 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 individually 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.

[0015] In some embodiments, the peptides described herein can be combined to improve pigmentation, melanosome autophagy, MITF reduction, 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 can be combined with one or more different peptides, such as tripeptide-1, hexapeptide-12, or a combination thereof, to stimulate autophagy and macrophage clustering and improve melanosome removal.

[0016] The compositions described herein include peptides at various concentrations. In some cases, the peptide is present at about 50 ppm or less to 1,000, 5,000, 10,000, 50,000, 100,000, 500,000 ppm or more, e.g., 100 ppm peptide. 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, 1,000, or greater than 1,000 ppm. In some cases, the peptide 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 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%, about 0.01% to about 0.02%, about 0.01% to about 0.03%, about 0.01% to about 0.04%, about 0.01% to about 0.05%, about 0.01% to about 0.1%, about 1% to about 5%, or about 1% to about 10% (wt %).

[0017] In some embodiments, the compositions described herein include one or more peptides. In some cases, a peptide of the one or more peptides is present at about 50 ppm or less to 1,000, 5,000, 10,000, 50,000, 100,000, 500,000 ppm or more, e.g., 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, 1,000, or more than 1,000 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 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, a peptide of the one or more peptides is present in a range of about 0.01% to about 10%, about 0.01% to about 0.02%, about 0.01% to about 0.03%, about 0.01% to about 0.04%, about 0.01% to about 0.05%, about 0.01% to about 0.1%, about 1% to about 5%, or about 1% to about 10% (wt %).In some embodiments, a peptide of the one or more peptides is provided at 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). In some embodiments, a peptide of the one or more peptides 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, each peptide of the one or more peptides 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 2% by weight. In some embodiments, the peptide is tripeptide-1, hexapeptide-12, hexapeptide-11, octapeptide, or a combination thereof.

[0018] 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.

[0019] In some embodiments, tripeptide-1 is provided 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% (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 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 more 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.

[0020] In some embodiments, hexapeptide-12 is provided 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% (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 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 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.

[0021] In some embodiments, hexapeptide-12 is provided at at least about 30, 40, 50, 60, 70, 80, 90, 100, 200, 300, 400, 500, 600, 700, 800, 900, 1000, 2000, or greater than 2000 micrograms (µg). In some embodiments, hexapeptide-12 is provided in the range of about 30 to about 2000 µg. 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 500 µg. In some embodiments, hexapeptide-12 is provided at at least about 150 µg. In some embodiments, hexapeptide-12 is provided at at least about 450 µg.

[0022] In some embodiments, hexapeptide-11 is provided 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% (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% by weight. 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 1,000 ppm, about 50 ppm to about 1,500 ppm, or about 500 ppm to about 5,000 ppm. In some embodiments, hexapeptide-11 is provided at about 1,000 ppm. In some embodiments, hexapeptide-11 is provided at least or about 5, 10, 20, 25, 50, 75, 100, 150, 200, 250, 300, 350, 400, 450, 500, or greater than 500 micrograms (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.

[0023] In some embodiments, hexapeptide-11 is provided in an amount of 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 a range of about 1 to about 100 mg. In some embodiments, hexapeptide-11 is provided in a 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 in an amount of at least or about 6 mg. In some embodiments, hexapeptide-11 is provided in an amount of at least or about 18 mg.

[0024] In some embodiments, the octapeptide is provided 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% (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 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 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 μg / mL. In some embodiments, the octapeptide is provided at a concentration of about 10 to about 190 μg / mL, about 20 to about 180 μg / mL, about 30 to about 170 μg / mL, about 40 to about 160 μg / mL, about 50 to about 150 μg / mL, about 60 to about 140 μg / mL, about 70 to about 130 μg / mL, about 80 to about 120 μg / mL, or about 90 to about 110 μg / mL. In some embodiments, the octapeptide is provided at a concentration of about 100 μg / mL.

[0025] Peptides can be functionalized. For example, 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, 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, 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 because it exhibits enhanced permeation 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 or fewer carbons. 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 20 or fewer carbons. In some cases, the peptide is non-palmitoylated. Without being limited to a particular theory, in some embodiments, incorporating the peptide into a liposome increases the lipophilicity of the functionalized or unfunctionalized peptide.

[0026] 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 general protein classes but is frequently found in extracellular matrix proteins. GHK's small size 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).

[0027] 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 the effects of UV radiation, such as oxidative stress, inflammation, edema, erythema, and DNA damage. In some cases, silibinin prevents melanin production and reduces tyrosinase protein expression without affecting cell viability. Silymarin cream has been shown to be more effective than intradermal tranexamic acid in studies of patients with melasma. In some cases, silymarin inhibited the production of interleukin-1 beta (IL-1β) and PGE-2, which are produced by cyclooxygenase-2 (COX-2), in keratinocytes and macrophages. In some cases, silibinin reduces inducible nitric oxide synthase (iNOS), COX-2, and NF-κB.

[0028] In some embodiments, the compositions described herein include silymarin. In some embodiments, the silymarin includes silibinin. In some embodiments, silymarin is provided at 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, silymarin is 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. In some embodiments, silymarin is 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 is provided at about 0.7% or less by weight. In some embodiments, silymarin is provided at at least about 10, 50, 100, 200, 500, 1000, 2000, 2500, 5000, 7500, 10,000, 15,000, 20,000, 25,000, 30,000, 35,000, 40,000, or greater than 40,000 ppm. In some embodiments, silymarin is provided in the range of about 2,500 ppm to about 100,000 ppm, about 1,000 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, silymarin is provided in the 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. In some embodiments, silymarin is provided in an amount of at least or about 5, 10, 15, 20, 25, 30, 35, or 40 micrograms per mL (ug / mL). In some embodiments, silymarin is provided in a 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.

[0029] In some embodiments, silymarin is provided in 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 is 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 is provided in about 6 milligrams (mg). In some embodiments, silymarin is provided in about 18 milligrams (mg).

[0030] Tranexamic acid Tranexamic acid (TXA) is a plasmin inhibitor used to prevent fibrinolysis and reduce blood loss. It is a synthetic derivative of lysine that reversibly blocks 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 sometimes implicated in the pathogenesis of melasma. UV irradiation can induce the synthesis of plasminogen activators 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, AA release is increased by plasmin in endothelial cells. Increased 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 may lead to increased 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 also inhibits bFGF-induced neovascularization. In addition, TXA is similar in structure to tyrosine, which means that TXA 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 vasculature in melasma lesions.

[0031] In some embodiments, the compositions described herein include tranexamic acid (TXA). In some embodiments, TXA is provided in an amount of 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%, 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% (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. In some embodiments, TXA is provided at at least or 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 greater than 10000 ppm. In some embodiments, TXA is provided in a 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 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.

[0032] In some embodiments, TXA 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 greater 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).

[0033] Lactoferrin Lactoferrin (Lf) is an 80 kDa iron-binding glycoprotein of the transferrin family found in exocrine secretions (tears, saliva, milk, nasal and bronchial secretions, gastrointestinal fluids, etc.). Lactoferrin's effects range from antibacterial activity to anti-inflammatory and immunomodulatory activity, and it has a 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, particularly melasma.

[0034] In some cases, tryptic peptide fragments derived from lactoferrin facilitate receptor-mediated MITF degradation. In some cases, tryptic peptide fragments have an inhibitory effect on pigmentation.

[0035] In some embodiments, the compositions described herein comprise transferrin. In some embodiments, the transferrin is lactoferrin. In some embodiments, the compositions comprise tryptic fragments of lactoferrin. In some embodiments, the compositions comprise peptides derived from lactoferrin. In some embodiments, the compositions comprise variants or fragments of lactoferrin. In some cases, the lactoferrin-derived peptides comprise 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 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), G These include, but are not limited to, DVAFVK (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).

[0036] (Table 1) TIFF0007783825000001.tif84166

[0037] In some cases, lactoferrin has antibacterial activity. In some cases, lactoferrin has antibacterial activity against bacteria, fungi, yeast, viruses, parasites, or a combination 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.

[0038] In some embodiments, lactoferrin is provided at or above 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%). 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 or above 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 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.

[0039] 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 greater 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).

[0040] In some embodiments, lactoferrin-derived peptides are provided at or above 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% (by weight). In some embodiments, lactoferrin-derived peptides 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, lactoferrin-derived peptides are provided in the range of about 0.001% to about 6%, about 0.002% to about 4%, about 0.01% to about 2.5%, or about 0.02% to about 2% (wt%) by weight. In some embodiments, lactoferrin-derived peptides are provided at about 0.025% or less. In some embodiments, lactoferrin-derived peptides are provided at about 0.05% or less. In some embodiments, lactoferrin-derived peptides are provided at about 0.10% or less. In some embodiments, 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 greater than 5000 micrograms per milliliter (ug / mL). In some embodiments, 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, lactoferrin-derived peptides are provided at about 100 ug / mL.In some embodiments, lactoferrin-derived peptides are provided at about 1000 μg / mL, hi some embodiments, lactoferrin-derived peptides 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 than 2000 ppm. In some embodiments, lactoferrin-derived peptides are provided in the range of 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, lactoferrin-derived peptides are 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.

[0041] In some embodiments, lactoferrin-derived peptides are provided in amounts of 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 greater than 500 milligrams (mg). In some embodiments, lactoferrin-derived peptides are provided in amounts ranging from 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-derived peptides are provided in amounts of about 30 milligrams (mg). In some embodiments, lactoferrin-derived peptides are provided in amounts of about 90 milligrams (mg).

[0042] Cannabidiol Cannabidiol (CBD) can reduce the activity of the NF-κB pathway, a primary pathway that regulates the expression of pro-inflammatory genes. Furthermore, CBD upregulates the activation of the STAT3 transcription factor, a component of the homeostatic mechanism that induces 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 COX activity as well as PGE2, nitric oxide (NO), and malondialdehyde production.

[0043] 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 μg / mL. In some embodiments, CBD is provided in the range of about 10 to about 190 μg / mL, about 20 to about 180 μg / mL, about 30 to about 170 μg / mL, about 40 to about 160 μg / mL, about 50 to about 150 μg / mL, about 60 to about 140 μg / mL, about 70 to about 130 μg / mL, about 80 to about 120 μg / mL, or about 90 to about 110 μg / mL. In some embodiments, CBD is provided at about 100 μg / mL. In some embodiments, CBD is provided at or above 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%). In some embodiments, CBD is provided in a 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 or above about 10, 50, 100, 200, 500, 1000, 2000, 2500, 5000, 7500, 10,000, 15,000, 20,000, 25,000, 30,000, 35,000, 40,000, or 40,000 ppm. In some embodiments, CBD is provided in a range of about 2,500 ppm to about 100,000 ppm, about 1,000 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.

[0044] Ashwagandha extract While other depigmenting agents generally inhibit tyrosinase, Ashwagandha extract (10 μg / mL) functions by disrupting the ET-1-induced intracellular signaling cascade, primarily consisting of the PKC and MAPK pathways, which leads to downregulation of the melanocyte master transcription factor MITF. The reduction in MITF function can then suppress the expression and function of its downstream targets, resulting in attenuation of melanin synthesis. Ashwagandha extract can serve as a therapeutic tool for ET-1-associated hyperpigmentary disorders, such as UVB-melanosis and age spots.

[0045] In some embodiments, the compositions described herein include an Ashwagandha extract. In some embodiments, the Ashwagandha extract 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 (µg / 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 µg / mL. In some embodiments, the Ashwagandha extract is provided at at least about 10 µg / mL. In some embodiments, the Ashwagandha extract is provided at a concentration of at least about 20 μg / mL. In some embodiments, the Ashwagandha extract 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% by weight. In some embodiments, the Ashwagandha extract is provided in a 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 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% by weight or less. In some embodiments, the Ashwagandha extract is provided at about 0.05% by weight or less. In some embodiments, the Ashwagandha extract is provided at about 0.10% by weight or less.

[0046] In some embodiments, the Ashwagandha extract is provided in an amount of at least or greater than about at least 0.5, 0.75, 1.0, 1.2, 1.4, 1.6, 1.8, 2, 4, 6, 8, or 10 micrograms (µg). In some embodiments, the Ashwagandha extract is provided in a range of about 0.5 to about 2, about 0.75 to about 5, or about 1.0 to about 4 µg.

[0047] Gallic Acid Gallic acid (GA), a dietary phenolic present in plants and fruits, may have beneficial effects on hyperpigmentation, likely 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 eliminated by topical application of GA for 4 weeks.

[0048] In some embodiments, the compositions described herein include gallic acid. In some cases, GA is present at about 50 ppm or less to 1,000, 5,000, 10,000, 50,000, 100,000, 500,000 ppm or more, for example, 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, 1,000, or more than 1,000 ppm. In some cases, the GA 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 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 μg / mL. In some cases, GA is present at about 0.01% to about 10%, about 0.01% to about 0.02%, about 0.01% to about 0.03%, about 0.01% to about 0.04%, about 0.01% to about 0.05%, about 0.01% to about 0.1%, about 1% to about 5%, or about 1% to about 10% by weight (wt%). In some cases, GA is present at about 2.0% by weight or less.

[0049] Sesamol Sesamol 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 reducing cyclic adenosine monophosphate (cAMP) accumulation. Sesamol can reduce the expression of melanogenesis-related genes such as TYR, TRP-1, TRP-2, MITF, and MC1R. Sesamol can inhibit melanin biosynthesis.

[0050] In some embodiments, the compositions described herein include sesamol. 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 1,000, 5,000, 10,000, 50,000, 100,000, 500,000 ppm or more, e.g., 100 ppm 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 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 embodiments, sesamol is provided at about 100 ug / mL. In some cases, sesamol is present at at least or about at least 0.001 wt%, 0.002 wt%, 0.003 wt%, 0.004 wt%, 0.005 wt%, 0.01 wt%, 0.05 wt%, 0.1 wt%, 0.2 wt%, 0.3 wt%, 0.4 wt%, 0.5 wt%, or more than 0.5 wt% (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% (wt %). In some cases, sesamol is present at at least or about 0.01% wt %.

[0051] In some embodiments, sesamol is provided in 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 in about 3 milligrams (mg). In some embodiments, sesamol is provided in about 9 milligrams (mg).

[0052] 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 reduce the levels of TYR, TRP-1, and MITF proteins and increase ERK phosphorylation. In some cases, acteoside suppressed α-MSH-induced melanin formation and exhibited UV-absorbing effects.

[0053] In some embodiments, the compositions described herein 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 greater than 1000 μM. In some embodiments, acteoside is provided at a concentration ranging from about 50 to about 1000 μM, from about 100 to about 900 μM, from about 200 to about 800 μM, from about 300 to about 700 μM, or from 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, for example, 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%, about 0.01% to about 0.02%, about 0.01% to about 0.03%, about 0.01% to about 0.04%, about 0.01% to about 0.05%, about 0.01% to about 0.1%, about 1% to about 5%, or about 1% to about 10% (wt%).

[0054] oleuropein Oleuropein, a potent anti-inflammatory antioxidant derived from olive trees, exhibited 90% tyrosinase inhibitory activity, with the inhibitory pattern being non-competitive competitive.

[0055] In some embodiments, the compositions described herein include oleuropein. In some cases, the oleuropein is present at about 50 ppm or less to 1,000, 5,000, 10,000, 50,000, 100,000, 500,000 ppm or more, such as 100 ppm oleuropein. In some cases, the 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, 1,000, or more than 1,000 ppm. In some cases, oleuropein 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, 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 a 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% 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 0.03% to about 0.750% by weight, about 0.1% to about 5% by weight, or about 0.1% to about 10% by weight. In some cases, oleuropein is present at about 0.15% by weight or less.

[0056] In some embodiments, oleuropein is provided in 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 greater 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 in about 30 milligrams (mg). In some embodiments, oleuropein is provided in about 90 milligrams (mg).

[0057] 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 has shown whitening effects in a pigmented reconstituted epidermis model. Rab27A, melanophilin, and myosin Va form a complex that links melanosomes to phosphatidylserine, thereby binding melanosomes to the 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 a depigmenting effect by blocking Rab27A-melanophilin interaction.

[0058] In some embodiments, the compositions provided herein include hesperidin. In some cases, the hesperidin is present at about 50 ppm or less to 1,000, 5,000, 10,000, 50,000, 100,000, 500,000 ppm or more, e.g., 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, 1,000, or more than 1,000 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 μg / mL. In some cases, hesperidin 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 0.020% to about 0.50% by weight, about 1% to about 5% by weight, or about 1% to about 10% by weight. In some cases, hesperidin is present at about 0.10% by weight or less.

[0059] Sideroxylon Inerme L. stem bark In some embodiments, the compositions described herein include a Sideroxylon inerme extract. In some cases, the Sideroxylon inerme extract is present at about 50 ppm or less to 1,000, 5,000, 10,000, 50,000, 100,000, 500,000 ppm or more, e.g., 100 ppm. 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, 1,000, or greater than 1,000 ppm. In some cases, the Sideroxylon inerme 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 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 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 μg / mL. In some cases, the Sideroxylon inerme extract is present in a range of about 0.01% to about 10%, about 0.01% to about 0.02%, about 0.01% to about 0.03%, about 0.01% to about 0.04%, about 0.01% to about 0.05%, about 0.01% to about 0.1%, about 1% to about 5%, or about 1% to about 10% (wt %).

[0060] Parthenolide Parthenolide is a sesquiterpene lactone compound and the active substance of feverfew (Tanacetum parthenium), a medicinal herb that can be used to treat inflammation. Parthenolide is an NF-κB inhibitor and can block UVB-mediated skin changes by inhibiting NF-κB-mediated gene expression and reducing the production of bFGF and MMP-1 from cells. In some cases, bFGF production is induced by UV rays and promotes the proliferation of skin keratinocytes and melanocytes.

[0061] The compositions described herein, in some embodiments, include parthenolide. In some embodiments, parthenolide is provided at or above 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%). 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 at least about 10, 50, 100, 200, 500, 1000, 2000, 2500, 5000, or greater than 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.

[0062] Pancratium malitium 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. Pancratum malitum extract (PME; a sea lily extract) can 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.

[0063] In some embodiments, the compositions described herein include a Pancratum malitum extract. In some cases, the Pancratum malitum extract is present at about 50 ppm or less to 1,000, 5,000, 10,000, 50,000, 100,000, 500,000 ppm or more, e.g., 100 ppm. In some cases, the Pancratum malitum 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, 1,000, or greater than 1,000 ppm. In some cases, the Pancratium malitium 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 ppm. In some cases, the Pancratium malitium 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 maltium 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 μg / mL. In some cases, the Pancratium maltium extract is present in a range of about 0.01% to about 10% by weight, about 0.01% to about 0.02%, about 0.01% to about 0.03%, about 0.01% to about 0.04%, about 0.01% to about 0.05%, about 0.01% to about 0.1%, about 0.5% to about 5%, about 1% to about 5%, or about 1% to about 10% by weight. In some cases, the Pancratium maritima extract is present at at least or about at least 1.5% by weight.

[0064] 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 1,000, 5,000, 10,000, 50,000, 100,000, 500,000 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, 1,000, or more than 1,000 ppm. In some cases, the autophagy agent 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 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 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 is present at about 0.01% to about 10%, about 0.01% to about 0.02%, about 0.01% to about 0.03%, about 0.01% to about 0.04%, about 0.01% to about 0.05%, about 0.01% to about 0.1%, about 1% to about 5%, or about 1% to about 10% by weight (wt%). In some cases, the autophagy agent is Melatrepein™.

[0065] Niacinamide Once synthesized, melanin pigment is packaged into melanosomes and transported from melanocytes to adjacent basal keratinocytes via melanocyte dendrites. To inhibit this transport, niacinamide can reduce the formation of dendrites.

[0066] In some embodiments, the compositions described herein contain niacinamide. In some embodiments, niacinamide is provided at at least about 0.25%, 0.5%, 1%, 1.5%, 2%, 2.5%, 3%, 3.5%, 4%, 4.5%, 5%, 5.5%, 6%, 6.5%, 7%, 7.5%, 8%, 8.5%, 9%, 9.5%, 10%, or greater than 10% by weight (wt%). In some embodiments, niacinamide is provided in the range of about 0.25% to about 10%, about 0.5% to about 9.5%, about 1% to about 9%, or about 1.5% to about 8.5% by weight. In some embodiments, niacinamide is provided at at least or about at least 2.0% by weight.

[0067] White fungus Tremella fuciformis can inhibit melanin production. In some embodiments, the compositions described herein include a Tremella fuciformis 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.

[0068] In some embodiments, Tremella fuciformis extract is provided at or above about 0.001% (wt%), 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% by weight. In some embodiments, Tremella fuciformis extract 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, Tremella fuciformis extract 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, about 0.02% to about 2% by weight, or about 0.20% to about 5.0% by weight. In some embodiments, Tremella fuciformis extract is provided at or about at least 1.0% by weight.

[0069] Thermus thermophilus extract Thermus thermophilus fermentation products may act as antioxidants, particularly for PGE2. In some embodiments, the compositions described herein include Thermus thermophilus fermentation products. In some cases, the Thermus thermophilus extract is present at about 50 ppm or less to 1,000, 5,000, 10,000, 50,000, 100,000, 500,000 ppm or more, e.g., 100 ppm Thermus thermophilus extract. 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, 1,000, or greater than 1,000 ppm. 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 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 μg / mL. In some cases, the Thermus thermophilus extract is present in an amount of about 0.01% by weight (wt%) 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 0.3% to about 7.5% by weight, about 1% to about 5% by weight, or about 1% to about 10% by weight. In some cases, the Thermus thermophilus extract is present at at least or at least about 1.5% by weight.

[0070] Phytoene and phytofluene In some embodiments, the compositions described herein comprise phytoene, phytofluene, or a combination thereof. Phytoene and phytofluene are colorless carotenoids derived from marine microalgae that regulate prostaglandin E-2 (PGE-2).

[0071] In some embodiments, phytoene, phytofluene, or a combination thereof is provided at 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 more than 20% by weight. In some embodiments, phytoene, phytofluene, or a combination thereof is provided in the 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. In some cases, phytoene, phytofluene, or a combination thereof is provided at at least or about 5.0% by weight. In some cases, phytoene, phytofluene, 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 greater than 1000 micrograms per milliliter (ug / mL). In some cases, phytoene, phytofluene, or a 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 ug / mL.

[0072] White Horehound White horehound (Marrubium vulgare) may reduce ET-1 levels. 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 1,000, 5,000, 10,000, 50,000, 100,000, 500,000 ppm or more, e.g., 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, 1,000, or greater than 1,000 ppm. In some cases, the White Horehound 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 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 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 μg / mL. In some cases, the White Horehound extract is present in a range of about 0.01% to about 10%, about 0.01% to about 0.02%, about 0.01% to about 0.03%, about 0.01% to about 0.04%, about 0.01% to about 0.05%, about 0.01% to about 0.1%, about 1% to about 5%, or about 1% to about 10% (wt %).

[0073] Giant Polypodium (Polypodium Leucotomos) Rhubarb (Polypodium leucotomos or Phlebodium aureum) contains compounds that can combat inflammation and prevent skin damage. In some embodiments, the compositions described herein include a Rhubarb extract. In some cases, the Rhubarb extract is present at about 50 ppm or less to 1,000, 5,000, 10,000, 50,000, 100,000, 500,000 ppm or more, e.g., 100 ppm Rhubarb extract. In some cases, the Rhubarb 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, 1,000, or greater than 1,000 ppm. In some cases, the Rhubarb 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 ppm. In some cases, the Rhubarb 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 Rhubarb 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 μg / mL. In some cases, the Rhubarb extract is present in a range of about 0.01% to about 10%, about 0.01% to about 0.02%, about 0.01% to about 0.03%, about 0.01% to about 0.04%, about 0.01% to about 0.05%, about 0.01% to about 0.1%, about 1% to about 5%, or about 1% to about 10% by weight.

[0074] Phosphatidylserine In some embodiments, the compositions described herein comprise phosphatidylserine. In some embodiments, the phosphatidylserine is 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%, or 0.25% by weight. 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% by weight (wt%). In some embodiments, phosphatidylserine is present at about 0.075% by weight or less. In some embodiments, phosphatidylserine is provided at a concentration of about 0.05% by weight or less. 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). In some embodiments, 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, hi some embodiments, the 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, phosphatidylserine is provided at a concentration of about 100 to about 1900 μg / mL, about 200 to about 1800 μg / mL, about 300 to about 1700 μg / mL, about 400 to about 1600 μg / mL, about 500 to about 1500 μg / mL, about 600 to about 1400 μg / mL, about 700 to about 1300 μg / mL, about 800 to about 1200 μg / mL, or about 900 to about 1100 μg / mL. In some embodiments, phosphatidylserine is provided at a concentration of about 500 to about 1000 μg / mL.

[0075] In some embodiments, phosphatidylserine is provided in an amount of 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 greater than 500 milligrams (mg). In some embodiments, phosphatidylserine is provided in an amount ranging from 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, phosphatidylserine is provided in an amount of about 15 milligrams (mg). In some embodiments, phosphatidylserine is provided in an amount of about 20 milligrams (mg). In some embodiments, lactoferrin is provided in about 45 milligrams (mg).

[0076] Heptasodium hexacarboxymethyl dipeptide-12 (HHD12) HHD12 can stimulate autophagy in keratinocytes. Melanosomes normally migrate to neighboring keratinocytes and are then naturally degraded by autophagy. However, constant exposure of skin to sunlight, pathogens, and hormonal changes disrupts the autophagy process, preventing melanosome degradation. The accumulation of undegraded melanosomes in keratinocytes leads to skin pigmentation. HHD12 activates autophagy to degrade melanosomes within keratinocytes and simultaneously inhibits melanosome uptake into keratinocytes.

[0077] In some embodiments, HHD12 is present at about or at least about 0.01% by weight (wt%), 0.05%, 0.1%, 0.5%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, or 10%. In some embodiments, HHD12 is present in a range of about 0.01% to about 10%, about 0.05% to about 9%, about 0.1% to about 8%, about 0.5% to about 7%, or about 1% to about 6% by weight. In some embodiments, HHD12 is present in a range of about 0.2% to about 5% by weight. In some embodiments, HHD12 is present at about 1.0% by weight or less.

[0078] Liposomes Described herein are liposome compositions for improved distribution, efficacy, bioavailability, and / or activity. The liposome 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 enables efficient interfollicular transdermal delivery.

[0079] 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.

[0080] 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 present 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.

[0081] 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.

[0082] In some embodiments, the liposome is a photosome. In some embodiments, the photosome includes DNA repair techniques and / or repairing broken UV-induced dimers using a DNA repair enzyme photolytic enzyme. In some cases, the compositions described herein include one or more photosomes. In some cases, the photosomes are present at at least 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% by weight.

[0083] In some embodiments, the compositions described herein comprise 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.

[0084] 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 hexapeptide-11 and a peptide derived from 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 hexapeptide-12 and a peptide derived from 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 hexapeptide-11, hexapeptide-12, and lactoferrin. In some embodiments, a first liposome of the one or more liposomes encapsulates hexapeptide-11, hexapeptide-12, and a peptide derived from 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, hi some embodiments, a first liposome of the one or more liposomes encapsulates hexapeptide-11, hexapeptide-12, lactoferrin, and a peptide derived from lactoferrin.

[0085] 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.

[0086] 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.

[0087] 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.

[0088] In some embodiments, the compositions described herein comprise 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, wherein the two or more peptides include 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.

[0089] In some embodiments, the compositions described herein comprise one or more photosomes encapsulating one or more liposomes. In some embodiments, the one or more photosomes encapsulate one or more liposomes encapsulating one or more peptides. In some embodiments, the one or more photosomes encapsulate 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. In some embodiments, the one or more photosomes encapsulate one or more liposomes encapsulating one or more peptides, wherein the one or more peptides include hexapeptide-11, hexapeptide-12, lactoferrin, a peptide derived from lactoferrin, or a combination thereof.

[0090] 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.

[0091] In some embodiments, the one or more photosomes encapsulate one or more liposomes, wherein 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, wherein 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, wherein 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, one or more photosomes encapsulate one or more liposomes, wherein 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, one or more photosomes encapsulate one or more liposomes, wherein 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, one or more photosomes encapsulate one or more liposomes, wherein 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.

[0092] In some embodiments, the one or more photosomes encapsulate one or more liposomes, wherein 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, wherein 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, wherein 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, wherein 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.

[0093] In some embodiments, the one or more photosomes encapsulate one or more liposomes, wherein 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.

[0094] 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.

[0095] In some embodiments, the average particle size of each liposome of one or more liposomes, or each photosome of 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 liposome of one or more liposomes, or each photosome of 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, each of the liposomes of the one or more liposomes, or each photosome of the one or more photosomes, has an average particle size of about or at least about 220 nm.

[0096] In some embodiments, the compositions described herein comprising 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, the one or more peptides are hexapeptide-11. In some embodiments, the one or more peptides are hexapeptide-12. In some embodiments, the 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.

[0097] Lecithin and other phospholipids may 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. Lipid vesicles are formed when phospholipids such as lecithin are placed in water and, as a result, when sufficient energy is supplied, form a bilayer or a series of bilayers, each separated by water molecules. Liposomes can be prepared by sonicating phospholipids in water. Low shear rates produce multilamellar 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.

[0098] The phospholipids used to prepare the liposome compositions described herein can have a transition phase temperature of about 10° C. to about 25° C. In some cases, the phospholipids have 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 have 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.

[0099] 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.

[0100] 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.

[0101] In some embodiments, methods of preparing compositions comprising a peptide encapsulated in liposomes are described herein, including 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 occurs at a temperature of about 10°C to about 25°C. In some cases, the contacting occurs 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 occurs 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.

[0102] The method for preparing a composition comprising a liposome-encapsulated peptide 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).

[0103] The solvent may be used in various proportions. In some cases, the solvent 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%, 4.5%, 5.0%, 5.5%, 6.0%, 6.5%, 7.0%, 8%, 9%, 10%, or more than 10%. The solvent may be propanediol, butylene glycol, or caprylyl glycol.

[0104] In some embodiments, the methods described herein include combining a peptide and a solvent to form a mixture and contacting the mixture with an aqueous solution containing liposomes, wherein the aqueous solution comprises 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 water in a 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%. 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 comprises liposomes in a range of about 10% to about 80%, about 20% to about 70%, or about 30% to about 60%. The liposome to water ratio can be in the range of about 1:9 to about 3:7. In some cases, the liposome to water ratio 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.

[0105] The methods for producing liposome 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.

[0106] Liposome compositions are described herein, wherein the peptide comprises a percentage of the composition. In some embodiments, the peptide is provided at least 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 a 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.

[0107] Liposome compositions are described herein, wherein liposomes constitute a certain percentage of the composition. In some embodiments, liposomes are provided 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, liposomes are provided in a 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%.

[0108] In some embodiments, the liposome compositions described herein comprise an average particle size of at most 220 nanometers (nm). In some cases, the average particle size is at most 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.

[0109] In some cases, the liposome composition includes an active agent having a molecular weight of about 600 Daltons (Da) or less, hi some cases, the active agent has a molecular weight of at least or greater than 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 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 greater 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.

[0110] 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 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.

[0111] 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 about 0.65, 0.70, 0.75, 0.80, 0.85, 0.90, or 0.95.

[0112] In some embodiments, the liposomes comprise propanediol, lecithin, or a combination thereof. In some embodiments, propanediol is provided in an amount of 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). In some embodiments, propanediol 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 2% by weight. In some embodiments, lecithin 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% (wt%). 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 2% by weight. In some embodiments, the liposome comprises propanediol and lecithin. In some embodiments, propanediol and lecithin are provided in an amount of 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% (wt%).In some embodiments, 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, propanediol and lecithin are provided at about 0.90% by weight.

[0113] Described herein are liposome compositions with improved distribution, efficacy, bioavailability, and / or activity. The liposome compositions may have improved distribution, efficacy, bioavailability, and / or activity compared to compositions that do not contain liposomes. In some cases, 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, 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 a composition not containing 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 a composition not containing 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 a composition not containing liposomes.

[0114] In some embodiments, the liposome compositions and methods described herein are topical compositions. In some cases, the liposome compositions are oil-free. In some cases, the liposome compositions are preservative-free. In some embodiments, the liposome formulations are aqueous formulations. In some embodiments, the liposome formulations are anhydrous formulations. In some cases, the liposome compositions have a pH ranging from about 5 to about 8. In some cases, the liposome compositions have a pH of at least or about 2, 3, 4, 5, 6, 7, 8, 9, or 10.

[0115] 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-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. 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.

[0116] Other components Other ingredients may include anti-inflammatory agents, antioxidants, and solubility enhancers. Exemplary anti-irritants include, but are not limited to, panthenyl triacetate and naringenin, which are natural plant extracts that reduce redness and moisture loss from the skin. Typical amounts of anti-irritants when used in the composition are 1% to 4% by weight (wt %).

[0117] Exemplary antioxidants include, but are not limited to, Dunaliella salina extract and squalane. Dunaliella salina extract contains constituents such as beta-carotene, which may exhibit antioxidant properties. Typical amounts of anti-inflammatory agents used in compositions are 0.1% to 2.5% by weight (wt%). In some embodiments, Dunaliella salina extract 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 4% or more by weight. In some embodiments, Dunaliella salina 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, squalane 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% 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, Dunaliella salina extract and squalane are 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 4% or more by weight. In some embodiments, the Dunaliella salina extract and squalane are provided in a 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%.

[0118] In some embodiments, the peptide is 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 desired preparation. 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 contain complexing agents, metal ions, polymeric compounds such as polylactic acid, polyglycolic acid, hydrogels, dextran, liposomes, microemulsions, micelles, unilamellar or multilamellar vesicles, erythrocyte ghosts, or spheroblasts. Suitable lipids for the compositions include, but are not limited to, monoglycerides, diglycerides, sulfatides, lysolecithin, phospholipids, saponins, bile acids, etc. In some embodiments, the compositions described herein comprise 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 greater than 4% (wt%). In some embodiments, the phosphatidylserine, phospholipid, tocopherol, ascorbyl palmitate, or combinations thereof are 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, phosphatidylserine, phospholipids, tocopherol, ascorbyl palmitate, 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 additive is betaine. In some embodiments, betaine 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 compositions described herein include caprylyl glycol. In some embodiments, caprylyl glycol 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 5% by weight. 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% 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. The presence of such additional components may affect the physical state, solubility, stability, release rate, clearance rate, and penetration of the active ingredient.

[0119] Compositions for topical administration include the peptide composition described herein and a dermatologically acceptable vehicle. The vehicle may be aqueous or non-aqueous. The dermatologically acceptable vehicle used in topical compositions 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 plant origin (e.g., peanut oil, mineral oil, soybean oil, or sesame oil), or synthetic oils may be added to the active ingredient. Saline, dextrose, or other sugar solutions, or glycols such as ethylene glycol, propylene glycol, or polyethylene glycol are also suitable liquid carriers. The pharmaceutical composition may also be in the form of an oil-in-water emulsion. The oil phase can be vegetable oil, such as olive oil or peanut oil, 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 condensation products of these partial esters with ethylene oxide, such as polyoxyethylene sorbitan monooleate.The emulsion can also contain colorants and flavoring agents.

[0120] In certain embodiments, silicone elastomers (e.g., dimethicone crosspolymers) are used to enhance peptide delivery and penetration into the skin. An alternative to increasing molecular weight (as with silicone gums) or adding fillers (as with silicone compounds) is to partially crosslink the siloxane polymer and disperse this material in an appropriate silicone-carrying fluid. The resulting dimethicone crosspolymers (also known as silicone elastomers in the personal care industry) differ from basic polydimethylsiloxane (PDMS) due to the crosslinking between linear polymers. These materials can be used in peptide compositions and also offer benefits 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., via dimethicone / vinyl dimethicone crosspolymers such as Dow Corning® 9506 Elastomer Powder) are two of the elastomers' desirable properties. Silicone elastomers have a skin feel that is distinct from silicone fluids, described as "smooth," "soft," and "liquid." This can be altered by controlling the amount of liquid phase in the formulation, and therefore the degree of swelling. Due to their film-forming properties, dimethicone crosspolymers can be used as a delivery system for active ingredients, such as the peptides described herein, or other composition components, such as oil-soluble vitamins and sunscreens. Sunscreens, such as octyl methoxycinnamate, can be delivered more efficiently from compositions containing silicone elastomers, resulting in higher sun protection factors (SPFs). 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, adding 4% silicone elastomer blend to a suncare composition containing an organic sunscreen increased the SPF from 5.7 to 18. This property of silicone elastomers allows for maximizing the effectiveness of sunscreens in a composition while reducing the amount required to achieve the desired SPF.As a result, the cost of the composition can be reduced, along with potential irritation caused by sunscreen actives. Therefore, a higher SPF can be achieved with the same amount of UV absorber, resulting in improved performance without adding to the cost of the composition. Silicone elastomers can be produced from linear silicone polymers by various crosslinking reactions, such as hydrosilylation, in which vinyl groups react with silicon hydrides. A common process involves a linear silicone polymer possessing 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 swollen elastomer particles in a carrier fluid (e.g., a mixture of high molecular weight silicone elastomers in cyclopentasiloxane, such as Dow Corning® 9040 Silicone Elastomer Blend) or as 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 dimethicone and organic fluids can also be used. Examples of dimethicone crosspolymers in suspension or gel form are high molecular weight silicone elastomer (12%) in decamethylcyclopentasiloxane (e.g., Dow Corning® ST-Elastomer 10) and mixtures of high molecular weight silicone elastomer in cyclopentasiloxane (e.g., Dow Corning® 9040 Silicone Elastomer Blend), which typically have an elastomer content in the range of 10% to 20% by weight.

[0121] 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 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 4.0% 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 1% by weight.

[0122] Bentonite clay can be used in conjunction with peptides to impart penetration and adsorption properties to the composition and aid in emulsion stabilization. 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 skilled 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 also possible. The position of the double bond can be indicated by Δn, where n indicates the lower-numbered carbon in each pair of double-bonded carbon atoms. A shorthand notation for designating the total number of carbons is: # double bonds, Δ 二重結合位置For example, 20:4Δ 5,8,11,14 refers to a fatty acid having 20 carbon atoms and four double bonds, with the double bonds located between carbon atoms 5 and 6, carbon atoms 8 and 9, carbon atoms 11 and 12, and carbon atoms 14 and 15, and 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, e.g., 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 can be fully saturated or contain as many double bonds as practical relative to 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.

[0123] Pharmaceutical excipients used in topical preparations of 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.

[0124] 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 at least about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, or more than 12% (wt%). In some embodiments, glycerin is provided at at least 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 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, butylene glycol is provided in the range of about 0.01% to about 10%, about 0.025% to about 5%, or about 0.05% to about 1.25% by weight. Suitable solvents for the hydrophobic composition include mineral oil, vegetable oil, and silicone oil. If desired, 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 a lower alcohol, glycerin, and / or glycol. In some embodiments, anhydrous compositions are applied because the presence of water can cause irritation upon administration to skin tissues undergoing laser treatment, chemical peeling, skin ablation, etc. Anhydrous compositions may also act to prevent the occurrence 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 a limited amount of water to be present. For example, water may be present, but in an amount below the threshold that may cause irritation when applied to damaged skin. Osmotic shock or osmotic stress is a sudden change in the solute concentration around a cell, causing a rapid change in the movement of water across the cell membrane. Under conditions of high concentrations of either 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.

[0125] The compositions described herein may contain various amounts of solvent. In some embodiments, the solvent is water. In some embodiments, the solvent is at least about 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or more than 95% by weight. In some embodiments, the solvent is 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 75% by weight.

[0126] The viscosity of the composition can be maintained at a selected level using a pharmaceutically acceptable thickener. Suitable viscosity enhancers or thickeners that can be used to prepare viscous gels or creams using an aqueous base include sodium polyacrylate, xanthan gum, polyvinylpyrrolidone, acrylic acid polymers, carrageenan, hydroxyethyl cellulose, hydroxypropyl cellulose, methylcellulose, ethylcellulose, propylcellulose, hydroxypropylmethylcellulose, polyethoxylated polyacrylamides, polyethoxylated acrylates, and polyethoxylated alkanethiols. Methylcellulose is preferred because it is readily and economically available and easy to handle. Other suitable thickeners include, for example, xanthan gum, carboxymethylcellulose, hydroxypropyl cellulose, carbomer, etc. The preferred concentration of the thickener depends on the selected thickener. An amount that achieves the selected viscosity is preferably used. Viscous compositions are usually prepared from solutions by adding such thickeners or by using a base with an acceptable level of viscosity.

[0127] 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 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, 41,000, 42,000, 43,000, 44,000, 45,000, 46,000, 47,000, 48,000, 49,000, 50,000, 51,000, 52,000, 53,000, 54,000, 55,000, 56,000, 57,000, 58,000, 59,000, 60,000, 61,000, 2,000, 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 more than 40,000 cps. In some embodiments, the composition has 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.

[0128] Suitable emollients include hydrocarbon oils and waxes such as mineral oil, petrolatum, paraffin, ceresin, ozokerite, microcrystalline wax, polyethylene, squalene, perhydrosqualene, silicone oil, 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.

[0129] 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 more 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 more 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.

[0130] 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, palm oil, sesame oil, and soybean oil.

[0131] Suitable carboxylic acid or diacid esters for use as softeners 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, as well as alkenyl esters of fatty acids, such as oleyl myristate, oleyl stearate, and oleyl oleate.Specific examples of alkyl esters of diacids include diisopropyl adipate, diisohexyl adipate, bis(hexyldecyl) adipate, and diisopropyl sebacate.

[0132] 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.

[0133] 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.

[0134] 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 resinoleate, acetate of lanolin alcohol resinoleate, acetate of lanolin alcohol resinoleate, acetate of ethoxylated alcohol ester, hydrogenated lanolin lysates, hydrogenated lanolin, ethoxylated hydrogenated lanolin, ethoxylated sorbitol lanolin, and liquid and semi-solid lanolin. Also usable as waxes include hydrocarbon waxes, ester waxes, and amide waxes. Useful waxes include beeswax, spermaceti, wax esters such as myristyl myristate and stearyl stearate, beeswax derivatives such as polyoxyethylene sorbitol beeswax, and vegetable waxes including carnauba and candela wax.

[0135] Polyhydric alcohols and polyether derivatives can 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 having 15-18 carbon atoms, and polyoxypropylene derivatives of trimethylolpropane.

[0136] 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.

[0137] Suitable emulsifiers for use in the compositions include anionic, cationic, nonionic, and zwitterionic surfactants. Preferred ionic emulsifiers include phospholipids such as lecithin and derivatives.

[0138] For example, sterols, including cholesterol and cholesterol fatty acid esters, fatty acid amides, ethoxylated fatty acid amides, and fatty acid alkanolamides may also be used as emollients and / or penetration enhancers.

[0139] Pharmaceutically acceptable preservatives can be used to increase the shelf life of the compositions. Other suitable preservatives and / or antioxidants for use in the compositions include 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 a good shelf life of the compositions. Generally, anhydrous compositions of the embodiments are observed to exhibit sufficient stability, allowing preservatives to be omitted from the compositions.

[0140] Suitable chelating agents for use in the compositions include ethylenediaminetetraacetic acid, its alkali metal salts, its alkaline earth metal salts, its ammonium salts, and its tetraalkylammonium salts. In some embodiments, the chelating agent is disodium ethylenediaminetetraacetic acid (EDTA). In some embodiments, disodium EDTA is provided in an amount of 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 greater than 4% (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, or 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.

[0141] The carrier preferably has a pH of about 4.0 to 10.0, more preferably about 4.8 to about 7.8, and more preferably about 5.0 to about 6.5. The pH can be controlled using a buffer or other pH adjuster. Suitable pH adjusters 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 solutions of monopotassium phosphate and dipotassium phosphate, which maintain a pH of 5.8 to 8, and solutions of monosodium phosphate and disodium phosphate, which 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 recipient's blood or other bodily fluids. Isotonicity of the composition can be achieved using sodium tartrate, propylene glycol, or other inorganic or organic solutes. Sodium chloride is particularly preferred. Buffers such as acetic acid and salts, citric acid and salts, boric acid and salts, and phosphoric acid and salts can be used. 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 arts.

[0142] 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.

[0143] In certain embodiments, it may be advantageous to include additional pharmacologically active agents. Anti-infective agents include anthelmintics (mebendazole), antibiotics, including aminoglycosides (gentamicin, neomycin, tobramycin), antifungal antibiotics (amphotericin b, fluconazole, griseofulvin, itraconazole, ketoconazole, nystatin, micatin, tolnaftate), cephalosporins (cefaclor, 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, thiamin), and the like. 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.Anesthetic agents 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. For example, 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.

[0144] In certain embodiments, the addition of emollients, emulsion stabilizers, moisturizers, excipients, and other compounds may be tailored to enhance the sensory properties of the topical composition, including, but not limited to, skin feel (silky softness, lightness, creaminess), absorbency (the time required for the product to lose its moist feel and become imperceptible on the skin), consistency, hardness, spreadability (e.g., viscosity, onset of flow, shear rate), tackiness, 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).

[0145] In some embodiments, the composition comprises phenoxyethanol, ethylhexylglycerin, or a combination thereof. In some embodiments, the phenoxyethanol is provided in an amount of 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 greater than 10% by weight. In some embodiments, the phenoxyethanol 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, ethylhexylglycerin is provided in an amount of 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 greater than 10% by weight. In some embodiments, ethylhexylglycerin is provided in an amount ranging from about 0.25% to about 10%, from about 0.5% to about 8%, from about 0.75% to about 6%, or from about 1% to about 4% by weight. In some embodiments, phenoxyethanol and ethylhexylglycerin are provided in an amount of 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 greater than 10% by weight. In some embodiments, phenoxyethanol and ethylhexylglycerin are provided in an amount ranging from about 0.25% to about 10%, from about 0.1% to about 4%, from about 0.5% to about 8%, from about 0.75% to about 6%, or from about 1% to about 4% by weight.

[0146] In some embodiments, the composition comprises polyacrylate-13, polyisobutene, polysorbate 20, or a combination thereof. In some embodiments, polyacrylate-13 is provided in an amount of 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% (wt%). In some embodiments, polyacrylate-13 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, polyisobutene is provided in an amount of 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 greater than 10% by weight. 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, and 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% (wt%).In some embodiments, polyacrylate 20 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, polyacrylate-13, polyisobutene, and polysorbate 20 are provided in an amount of 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 greater than 10% (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 %).

[0147] 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.

[0148] penetration enhancers Fatty acids and alcohols are used to enhance the penetration of peptides and compositions, such as 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, such as C 6-12Fatty acids and the like can provide a silky feel. Typical amounts when used in compositions are 1% to 4% by weight.

[0149] 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, age-related hyperpigmentation is caused by UV exposure or inflammation.

[0150] Also described herein are compositions and methods for reducing melanocyte activity, inhibiting melanin synthesis, reducing melanin transport, increasing melanosome autophagy, reducing inflammation, or a combination thereof. In some embodiments, the reduction in melanocyte activity is due to inhibition of MITF, TYR, TRP1, TRP2, or a combination thereof. In some embodiments, the reduction in melanocyte activity is due to activation of ERK signaling, JNK signaling, or a combination thereof. In some embodiments, the increase in melanosome autophagy is due to increased expression, activity, or both of PAR-2, ET-1, or SCF.

[0151] The compositions described herein include peptides, silymarin, tranexamic acid, lactoferrin, cannabidiol, ashwagandha extract, gallic acid, sesamol, acteoside, oleuropein, hesperidin, Sideroxylon inerme extract, parthenolide, Melatrepein™, niacinamide, Tremella fuciformis extract, Thermus thermophilus extract, phytoene, phytofluene, White Horehound, Rhubarb extract, or combinations thereof to treat pigmentation diseases or disorders.

[0152] 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 the epidermal form of PIH. In some embodiments, the PIH is the dermal form of PIH. In some embodiments, the pigmentation disorder or disease includes, but is not limited to, acanthosis nigricans, age spots, albinism, incontinentia pigmenti, lentigines, melasma, pityriasis alba, or progressive pigmented purpura.

[0153] In some embodiments, the compositions described herein improve pigmentation by reducing melanocyte activity, inhibiting melanin synthesis, reducing melanin transport, 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.

[0154] The compositions described herein can be used with various treatment regimens. In some cases, the topical compositions described herein are administered once a day, twice a day, three or more times a day. 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, once every two weeks, two weeks a month, three weeks a month, once a month, twice a month, three or more times a month. In some embodiments, the topical compositions described herein are administered twice a day, for example, in the morning and evening. In some embodiments, the topical compositions described herein are administered for at least 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 1 week, 2 weeks, 3 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, 18 months, 2 years, 3 years, 4 years, 5 years, 10 years or more. In some embodiments, the topical compositions described herein are 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 compositions described herein are 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.

[0155] Stability testing Stability testing of the composition can be performed as follows.

[0156] 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 a product is stored at 45°C for 3 months (and shows acceptable stability), it should be stable at room temperature for 2 years. A good controlled temperature is 4°C (39°F), with most products showing excellent stability. Occasionally, products are also exposed to -10°C (14°F) for 3 months.

[0157] In some cases, product stability is evaluated by undergoing three temperature cycles from -10°C (14°F) to 25°C (77°F). In such cases, the product is placed at -10°C for 24 hours, followed by 24 hours at room temperature (25°C). This completes one cycle. A more stringent test is a five-cycle test from -10°C to 45°C, which places a great deal of stress on the emulsion.

[0158] 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.

[0159] 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 broad spectrum light box. Another glass bottle completely covered in aluminum foil acts as a control. Discoloration of the product may be observed.

[0160] For all the above tests, color, odor / scent, viscosity, pH value, and, if available, particle size uniformity and / or particle aggregation under a microscope may be observed.

[0161] Kits for non-invasive use Some embodiments of the methods and compositions provided herein include kits containing the peptides provided herein. In some embodiments, the kits can be provided to an administering physician, other healthcare professional, patient, or caregiver. 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 can optionally also include one or more additional therapeutic or other agents. For example, a kit containing a topical peptide composition can be provided with other skin care agents, such as a cleanser, an occlusive moisturizer, a penetrating moisturizer, a sunscreen, or a sunblock. The kits can include the peptide composition in bulk form or can include separate doses of the peptide composition for continuous or sequential administration. The kits can optionally include one or more diagnostic tools, administration tools, and / or instructions for use. The kits can include a suitable delivery device, such as a syringe, pump dispenser, or single-dose packet, along with instructions for administering the peptide composition and any other therapeutic or beneficial agent. The kit may optionally include instructions for storage, reconstitution (if applicable), and administration of any or all of the therapeutic or beneficial agents included. The kit may include multiple containers reflecting the number of doses to be given to a subject or different products to be administered to a subject.

[0162] In some embodiments, the composition also works with the skin's own natural renewal process, helping to improve the appearance and firmness of the skin. The topical composition is suitable for all skin types and post-surgical skin. The topical composition can be provided to the patient in bulk form to allow the patient to self-administer an appropriate amount of peptide. For example, the patient can apply a sufficient amount of the composition to evenly cover the affected area, or as otherwise directed by a physician. In certain embodiments, it may be desirable to incorporate additional therapeutic or active agents into the topical composition. Alternatively, adjunctive therapies or medications can be administered separately. For example, cleansers, sunscreens, sunscreens, penetrating moisturizers, and / or occlusive moisturizers can be provided for administration before or after the topical composition of the embodiments.

[0163] Various examples of creams, ointments, lotions, solutions, gels, sprays, and patches can 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.

[0164] Numbered Embodiments Numbered Embodiment 1 includes a topical composition for improving pigmentation, comprising one or more photosomes, one or more liposomes, hexapeptide-11, and hexapeptide-12, wherein the topical composition improves pigmentation. Numbered Embodiment 2 includes the topical composition of numbered embodiment 1, wherein the one or more photosomes are present in a range of about 0.1% to about 2% by weight. Numbered Embodiment 3 includes the topical composition of numbered embodiment 1 or 2, wherein the one or more photosomes are present in a range of about 0.25% to about 1% by weight. Numbered Embodiment 4 includes the topical composition of numbered embodiments 1-3, wherein the one or more photosomes encapsulate one or more liposomes. Numbered Embodiment 5 includes the topical composition of numbered embodiments 1-4, wherein the hexapeptide-11 is present at 50-150 ppm. Numbered Embodiment 6 includes the topical composition of numbered embodiments 1-5, wherein hexapeptide-11 is present in the range of about 0.004% (wt%) to about 0.100% wt. Numbered Embodiment 7 includes the topical composition of numbered embodiments 1-6, wherein hexapeptide-11 is encapsulated in a first liposome of the one or more liposomes. Numbered Embodiment 8 includes the topical composition of numbered embodiments 1-7, wherein hexapeptide-12 is encapsulated in a second liposome of the one or more liposomes. Numbered Embodiment 9 includes the topical composition of numbered embodiments 1-8, wherein hexapeptide-11 and hexapeptide-12 are encapsulated in a first liposome of the one or more liposomes. Numbered Embodiment 10 includes the topical composition of numbered embodiments 1-9, wherein the hexapeptide-12 comprises palmitoyl hexapeptide-12, myristoyl hexapeptide-12, or a combination thereof. Numbered Embodiment 11 includes the topical composition of numbered embodiments 1-10, wherein the hexapeptide-12 is present at 1-10 ppm. Numbered Embodiment 12 includes the topical composition of numbered embodiments 1-11, wherein the hexapeptide-12 is present in a range of about 0.001% (wt%) to about 0.025% wt. Numbered Embodiment 13 includes the topical composition of numbered embodiments 1-12, wherein the topical agent further comprises lactoferrin.Numbered embodiment 14 includes the topical composition of numbered embodiments 1-13, wherein lactoferrin is present at about 0.25% by weight or less. Numbered embodiment 15 includes the topical composition of numbered embodiments 1-14, wherein lactoferrin is present in the range of about 0.005% by weight to about 0.25% by weight. Numbered embodiment 16 includes the topical composition of numbered embodiments 1-15, wherein lactoferrin is encapsulated in a third liposome of the one or more liposomes. Numbered embodiment 17 includes the topical composition of numbered embodiments 1-16, wherein the topical agent further comprises lactoferrin, and lactoferrin, hexapeptide-11, and hexapeptide-12 are encapsulated in a first liposome of the one or more liposomes. Numbered embodiment 18 includes the topical composition of numbered embodiments 1-17, wherein the topical agent further comprises a peptide derived from lactoferrin. Numbered embodiment 19 includes the topical composition of numbered embodiments 1-18, wherein the lactoferrin-derived peptide comprises 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. Numbered embodiment 20 includes the topical composition of numbered embodiments 1-19, wherein the topical agent further comprises phosphatidylserine. Numbered embodiment 21 includes the topical composition of numbered embodiments 1-20, wherein the phosphatidylserine is present at about 0.075% by weight or less. Numbered embodiment 22 includes the topical composition of numbered embodiments 1-21, wherein the phosphatidylserine is present in the range of about 0.005% by weight to about 0.1% by weight. Numbered embodiment 23 includes the topical composition of numbered embodiments 1-22, wherein phosphatidylserine is present at 5.0% by weight or less. Numbered embodiment 24 includes the topical composition of numbered embodiments 1-23, wherein the topical agent further comprises silymarin. Numbered embodiment 25 includes the topical composition of numbered embodiments 1-24, wherein silymarin is present in the range of about 0.1% by weight to about 1.0% by weight. Numbered embodiment 26 includes the topical composition of numbered embodiments 1-25, wherein silymarin is present in the range of about 0.2% by weight to about 3.0% by weight.Numbered embodiment 27 includes the topical composition of numbered embodiments 1-26, wherein the topical agent further comprises sesamol. Numbered embodiment 28 includes the topical composition of numbered embodiments 1-27, wherein sesamol is present in the range of about 0.002% to about 0.050% by weight. Numbered embodiment 29 includes the topical composition of numbered embodiments 1-28, wherein the topical agent further comprises tranexamic acid. Numbered embodiment 30 includes the topical composition of numbered embodiments 1-29, wherein tranexamic acid is present in the range of about 1% to about 10% by weight. Numbered embodiment 31 includes the topical composition of numbered embodiments 1-30, wherein tranexamic acid is present in the range of about 0.25% to about 6.25% by weight. Numbered embodiment 32 includes the topical composition of numbered embodiments 1-31, wherein the topical agent further comprises phytoene, phytofluene, or a combination thereof. Numbered embodiment 33 includes the topical composition of numbered embodiments 1-32, wherein phytoene, phytofluene, or a combination thereof is present in the range of about 1% to about 10% by weight. Numbered embodiment 34 includes the topical composition of numbered embodiments 1-33, wherein the topical agent further comprises ashwagandha extract. Numbered embodiment 35 includes the topical composition of numbered embodiments 1-34, wherein the ashwagandha extract is present in the range of about 0.020% to about 0.500% by weight. Numbered embodiment 36 includes the topical composition of numbered embodiments 1-35, wherein the topical agent further comprises gallic acid. Numbered embodiment 37 includes the topical composition of numbered embodiments 1-36, wherein the gallic acid is present in the range of about 0.40% to about 10% by weight. Numbered embodiment 38 includes the topical composition of numbered embodiments 1-37, wherein the topical agent further comprises hesperidin. Numbered embodiment 39 includes the topical composition of numbered embodiments 1-38, wherein hesperidin is present in the range of about 0.020% to about 0.50% by weight. Numbered embodiment 40 includes the topical composition of numbered embodiments 1-39, wherein the topical agent further comprises pancratium maritimum.Numbered embodiment 41 includes the topical composition of numbered embodiments 1-40, wherein pancratium maltium is present in the range of about 0.50% to about 5.0% by weight. Numbered embodiment 42 includes the topical composition of numbered embodiments 1-41, wherein the topical agent further comprises niacinamide. Numbered embodiment 43 includes the topical composition of numbered embodiments 1-42, wherein the niacinamide is present in the range of about 1% to about 10% by weight. Numbered embodiment 44 includes the topical composition of numbered embodiments 1-43, wherein the topical agent further comprises oleuropein. Numbered embodiment 45 includes the topical composition of numbered embodiments 1-44, wherein the oleuropein is present in the range of about 0.030% to about 0.750% by weight. Numbered embodiment 46 includes the topical composition of numbered embodiments 1-45, wherein the topical agent further comprises Thermus thermophilus ferment. Numbered embodiment 47 includes the topical composition of numbered embodiments 1-46, wherein the Thermus thermophilus ferment is present in the range of about 0.30% to about 7.5% by weight. Numbered embodiment 48 includes a topical composition according to any one of numbered embodiments 1-47, wherein the topical agent further comprises Tremella fuciformis. Numbered embodiment 49 includes a topical composition according to any one of numbered embodiments 1-48, wherein the Tremella fuciformis is present in an amount ranging from about 0.20% to about 5.0% by weight. Numbered embodiment 50 includes a topical composition according to any one of numbered embodiments 1-49, wherein the topical agent further comprises heptasodium hexacarboxymethyl dipeptide-12. Numbered embodiment 51 includes a topical composition according to any one of numbered embodiments 1-50, wherein the heptasodium hexacarboxymethyl dipeptide-12 is present in an amount ranging from about 0.1% to about 10% by weight. Numbered embodiment 52 includes a topical composition according to any one of numbered embodiments 1-51, wherein the heptasodium hexacarboxymethyl dipeptide-12 is present in an amount ranging from about 0.2% to about 5% by weight. Numbered embodiment 53 includes a topical composition according to any one of numbered embodiments 1-52, wherein the topical agent is water-soluble. Numbered embodiment 54 includes a topical composition for improving pigmentation, comprising hexapeptide-11, hexapeptide-12, and a peptide derived from lactoferrin, wherein the topical composition improves pigmentation. Numbered embodiment 55 includes a topical composition according to any one of numbered embodiments 1-54, wherein the hexapeptide-12 comprises palmitoyl hexapeptide-12, myristoyl hexapeptide-12, or a combination thereof. Numbered embodiment 56 includes a topical composition according to any one of numbered embodiments 1-55, wherein the hexapeptide-12 is present at 1-10 ppm. Numbered embodiment 57 includes a topical composition according to any one of numbered embodiments 1-56, wherein the hexapeptide-12 is present in a range of about 0.001% (wt %) to about 0.025% wt %. Numbered embodiment 58 includes the topical compositions of numbered embodiments 1-57, wherein hexapeptide-11 is present at 50-150 ppm. Numbered embodiment 59 includes the topical compositions of numbered embodiments 1-58, wherein hexapeptide-11 is present in the range of about 0.004% (wt %) to about 0.100% wt %.Numbered embodiment 60 includes the topical composition of numbered embodiments 1-59, wherein the lactoferrin-derived peptide comprises 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. Numbered embodiment 61 includes the topical composition of numbered embodiments 1-60, wherein the topical agent further comprises phosphatidylserine. Numbered embodiment 62 includes the topical composition of numbered embodiments 1-61, wherein the phosphatidylserine is present at about 0.075% wt% or less. Numbered embodiment 63 includes the topical composition of numbered embodiments 1-62, wherein the phosphatidylserine is present in the range of about 0.005% wt% to about 0.1% wt%. Numbered embodiment 64 includes the topical composition of numbered embodiments 1-63, wherein the phosphatidylserine is present at 5.0% by weight or less. Numbered embodiment 65 includes the topical composition of numbered embodiments 1-64, wherein the topical agent further comprises lactoferrin. Numbered embodiment 66 includes the topical composition of numbered embodiments 1-65, wherein the lactoferrin is present at about 0.25% by weight or less. Numbered embodiment 67 includes the topical composition of numbered embodiments 1-66, wherein the lactoferrin is present in the range of about 0.005% by weight to about 0.25% by weight. Numbered embodiment 68 includes the topical composition of numbered embodiments 1-67, wherein the topical agent further comprises photosomes. Numbered embodiment 69 includes the topical composition of numbered embodiments 1-68, wherein the photosomes are present in the range of about 0.1% by weight to about 2% by weight. Numbered embodiment 70 includes the topical composition of numbered embodiments 1-69, wherein the topical composition further comprises silymarin, sesamol, tranexamic acid, phytoene, phytofluene, ashwagandha extract, hesperidin, pancratium maltium, niacinamide, oleuropein, Thermus thermophilus ferment, Tremella fuciformis, heptasodium hexacarboxymethyl dipeptide-12, or a combination thereof. Numbered embodiment 71 includes the topical composition of numbered embodiments 1-70, wherein the topical agent is water soluble.Numbered embodiment 72 includes methods of improving pigmentation as a result of a pigmentation disorder or disease, comprising administering a topical composition as described in numbered embodiments 1-71. Numbered embodiment 73 includes methods of numbered embodiments 1-72, wherein the topical composition further comprises wherein the pigmentation disorder or disease is hyperpigmentation. Numbered embodiment 74 includes methods of numbered embodiments 1-73, wherein the topical composition further comprises wherein the pigmentation disorder or disease is post-inflammatory hyperpigmentation (PIH). Numbered embodiment 75 includes methods of numbered embodiments 1-74, wherein the topical composition further comprises wherein the pigmentation disorder or disease is focal hypopigmentation or diffuse hypopigmentation. Numbered embodiment 76 includes the methods of numbered embodiments 1-75, wherein the topical composition further includes wherein the pigmentation disorder or disease is acanthosis nigricans, age spots, albinism, incontinentia pigmenti, lentigines, melasma, pityriasis alba, or progressive pigmented purpura. [Example]

[0165] The following examples are given for the purpose of illustrating various embodiments of the present disclosure and are not meant to limit the disclosure in any way. The examples, along with the methods described herein, are presently representative of preferred embodiments and are exemplary and are not intended as limitations on the scope of the disclosure. Modifications and other uses encompassed within the spirit of the disclosure as defined by the scope of the claims will occur to those skilled in the art.

[0166] Example 1: Exemplary Compositions and Regulation of Gene Expression Exemplary compositions are shown in Table 2. Additionally, the compounds and concentrations listed in Tables 3 and 4 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 was analyzed. Gene sequencing analysis, bioinformatics, and gene ontology analysis were performed.

[0167] Table 2: Formulation 1 TIFF0007783825000002.tif127128

[0168] Table 3: Formulation 2 TIFF0007783825000003.tif76166

[0169] Table 4: Formulation 3 TIFF0007783825000004.tif111128

[0170] Example 2: Synergistic Effect of Tripeptide-1 in Combination with Hexapeptide-12 - Skin Pigmentation Microphthalmia-associated transcription factor (MITF) is a key regulator of pigmentation and melanin migration and a potential new target for pigmentation and melanoma. In vitro MITF gene expression studies were performed to identify differences between individual peptides (tripeptide-1 and hexapeptide-12) and their combination with respect to MITF downregulation.

[0171] Specifically, fibroblasts were cultured and then treated with tripeptide-1, hexapeptide-12, or a combination of both. After 48 hours, MITF gene expression was analyzed. As shown in Table 5 below, MITF gene analysis indicated that each peptide had a limited effect on MITF downregulation. Indeed, hexapeptide-12 alone showed a slight MITF downregulation (-1.16), while tripeptide-1 alone showed a slight MITF upregulation (+1.72). However, when combined together in a blend, MITF downregulation increased significantly (-4.17). This increase in expression continued to be evident and further increased at 72 hours.

[0172] (Table 5) TIFF0007783825000005.tif25146*80 ppm hexapeptide refers to the concentration of hexapeptide-12 in the carrier, 120 ppm tripeptide refers to the concentration of tripeptide-1 in the carrier, and a peptide blend of 80 ppm hexapeptide and 120 ppm tripeptide.

[0173] The data show that tripeptide-1 and hexapeptide-12 have a synergistic effect on MITF gene expression.

[0174] Example 3: Gene Expression Studies Four cell types involved in the pigmentation pathway, namely melanocytes, keratinocytes, fibroblasts, and endothelial (HUVEC) cells, were analyzed for gene expression.

[0175] method To simulate the UV-stimulated pigmentation pathway process, which is a normal direct result of UV exposure that normally occurs from exposed keratinocytes, melanocytes were pretreated with PGE2. After 48 hours of adherent culture, these melanocytes were induced with 10 μM PGE2 in melanocyte medium for 24 hours. Four primary human adult skin cell lines were cultured and plated in triplicate in well plates, then treated with 11 different compounds (plus DMSO control). After 48 hours of adherent culture, the remaining fibroblasts, HUVECs, and keratinocytes were treated with the test compounds listed in Table 6.

[0176] Table 6. Compounds used in gene expression studies TIFF0007783825000006.tif76128

[0177] 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.

[0178] result Of the four cell lines, it was possible to identify three cell lines with significant melanogenic activity: melanocytes, keratinocytes, and HUVECS. The fibroblast cell line exhibited various functions unrelated to melanogenic activity (mainly wound healing) and was not further used. The melanocyte activation pathway was found to be activated (Figures 3A-3D). Hexapeptide-12 (Hex12) and lactoferrin (lacto) were particularly prominent in melanogenic activity. Figures 4 and 5 show the downregulation of melanogenic genes associated with 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 6. The data indicate hexapeptide-11 (Hex11) as the active component in melanogenesis, while Figure 7 shows individual Hex-11 activities. Figures 8A-8C show HUVEC data for gene expression of EDN-1 (EDN1) (Figure 8A), SCF (Figure 8B), and TGFB1 (Figure 8C) in response to various compounds listed in Table 6. Figure 9 shows the potent activity of phosphatidylserine on EDN1 and other melanogenesis genes.

[0179] conclusion Cell line melanogenic gene activity studies identified that lactoferrin, hexapeptide-11, hexapeptide-12, and phosphatidylserine had significant effects on melanogenic activity.

[0180] Example 4: Comparative in vitro melanocyte analysis with absorbance readings The melanocyte model was designed to test agents that exhibit a direct effect on melanocyte cells and melanin production from compound-treated melanocyte samples via absorption.

[0181] method Melanocytes were cultured in six-well plates containing growth medium. Once confluent, two concentrations of each of the ten compounds were added to the cells in triplicate wells for four days. There were eleven six-well plates in total, one for each compound treatment and one for the vehicle control. Absorbance readings were taken from lysates prepared for each well of the six-well plates and normalized to cell number. Given the strong gene expression results using a melanocyte cell line in the initial study, this model was first tested for accuracy and validated using hexapeptide-12, which confirmed reduced stimulation. Further validation was performed using MSH addition to the culture medium to confirm increased stimulation of melanin production. The following compounds used in this study are listed in Table 7.

[0182] Table 7. Test compounds used in the in vitro melanocyte comparative assay TIFF0007783825000007.tif46128

[0183] result

[0184] Table 8 shows the results for three absorption spectra at two concentrations of selected compounds. Table 8. Absorption spectra of selected compounds at 405 nm, 490 nm, and 492 nm TIFF0007783825000008.tif189160

[0185] This study confirmed the effectiveness of these selected agents in reducing 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 8).

[0186] 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 compound-treated melanocyte samples via absorption.

[0187] 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.

[0188] result Figures 10A-10D show the expression of PMEL (Figure 10A), tyrosinase (Figure 10B), MC1 / 4R (Figure 10C), and EDNRB (Figure 10D) genes after treatment of endothelial cells with lactoferrin (Lacto), lactoferrin-derived peptides (TCV), hexapeptide-12 (Hex12), tripeptide-1 and hexapeptide-12 (TriHex), hexapeptide-11 (Hex11), tranexamic acid (Tran), octapeptide (Octa), phosphatidylserine (Phos), cannabidiol (CBD), and all (All). Figures 10A-10D show that hexapeptide-12 and lactoferrin exhibited strong melanogenesis activity. Figure 11 shows data from hexapeptide-12.

[0189] MITF is regulated by phosphorylation. Specifically, the MAPK and Akt pathways are known to phosphorylate MITF at specific sites. Figures 12A-12C illustrate the expression of ERK1 / 2 (MAPK3 / MAPK1) (Figure 12A), JNK (Figure 12B), and AKT1 (Figure 12C) after treatment of endothelial cells with lactoferrin (Lacto), lactoferrin-derived peptides (TCV), hexapeptide-12 (Hex12), tripeptide-1 and hexapeptide-12 (TriHex), hexapeptide-11 (Hex11), octapeptide (Octa), phosphatidylserine (Phos), cannabidiol (CBD), and all (All).

[0190] conclusion Taken together, increased expression of these kinases may be associated with decreased expression of MITF and therefore contribute to reduced melanogenesis. Hexapeptide-12 and lactoferrin have a significant effect on such melanogenic activity.

[0191] Example 6: Melanocyte assay hTERT-immortalized skin melanocytes were treated with various compounds. The experimental materials and results are presented below.

[0192] method Primary human melanocytes were obtained from ATCC (catalog number ATCC CRL-4059). First, melanocytes were plated in 6-well tissue culture plates (1.5 x 10^3 cells per well) in Melanocyte Growth Medium (Dermal Cell Basal Medium (ATCC® PCS-200-030 supplemented with Melanocyte Growth Kit (ATCC® PCS-200-041)). Then, melanocytes were expanded to 10 cm tissue culture plates at the density recommended by ATCC. While culturing in a web morphology, the cells appear completely attached to the plate / dish. Cells were cultured in a 37°C, 5% CO2 incubator.

[0193] Stocks of compounds 1-10 listed below were suspended in either complete melanocyte growth medium or DMSO (indicated in parentheses). The resuspension of each compound was then diluted in melanocyte growth medium to the final concentrations listed in Table 9.

[0194] Table 9. Compounds used in the in vitro melanocyte comparative assay TIFF0007783825000009.tif68158

[0195] Once melanocytes reached 100% confluence in the 6-well plates, the melanocyte growth medium was removed and the melanocytes were treated with medium containing the compounds listed above. Duplicate wells were used for each compound / concentration listed above. Duplicate vehicle control wells received melanocyte growth medium alone or melanocyte growth medium containing DMSO (10 μL per 10 mL of melanocyte growth medium).

[0196] Cells were fed with the appropriate medium for the next 5 days. Cells were inspected daily for morphology. All cells maintained normal morphology throughout the entire 5-day treatment period, except as noted below.

[0197] Melanocytes cultured in lactoferrin-containing medium (at both 500 and 1000 μg / mL concentrations) developed a ring-shaped morphology, rather than the usual web morphology, 24 hours after the first treatment. Interestingly, 48 hours after the first treatment, the melanocytes returned to normal morphology and maintained this morphology throughout the 5-day treatment period.

[0198] Melanocytes cultured in Ashwagandha-containing medium (at both 10 and 20 μg / 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.

[0199] Melanocytes in oleuropein-containing medium (at both 500 and 1000 ug / mL concentrations) began to die 24 hours after the first dose and continued to die each day until nearly all melanocytes were dead 72 hours after the first dose.

[0200] Lysates were prepared for each sample. Briefly, 6.6 x 10^5 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, and then left at room temperature until completely thawed. This freeze-thaw cycle was repeated once more for a total of two freeze / thaw cycles. Lysate samples were spun at 14,800 rpm 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.

[0201] 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.

[0202] Table 10. Absorbance readings at 405 nm, 490 nm, and 492 nm TIFF0007783825000010.tif173152

[0203] 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.

[0204] method The compounds and concentrations in Table 11 below were combined from the original stock solutions to make 50 mL of complete formulation medium in which melanocytes were cultured in 6-well plates for 5 days, the medium used being indicated in parentheses.

[0205] Table 11: Compounds and concentrations used in Example 7 TIFF0007783825000011.tif57128

[0206] When melanocytes reached 100% confluence in the 6-well plates, the melanocyte growth medium was removed, and duplicate wells were treated 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). Cells were fed with the appropriate medium for the next 5 days. Cells were inspected daily for morphology. All cells maintained normal morphology throughout the entire 5-day treatment period.

[0207] 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.

[0208] 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 12.

[0209] Table 12. Absorbance readings at 405 nm, 490 nm, and 492 nm TIFF0007783825000012.tif31156

[0210] Example 8: Double Liposomes This example demonstrates the preparation of double liposomes for use in the formulations described herein.

[0211] In the first step, 0.90 wt% (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.

[0212] 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 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 employed in practicing the disclosure. The following claims define the scope of the disclosure, and it is intended that methods and structures within the scope of these claims and their equivalents be covered thereby.

Claims

1. 1. A topical composition for improving pigmentation, comprising: a first liposome containing a photolytic enzyme; a second liposome; and 0.004% to 0.100% by weight of hexapeptide-11; 0.001% to 0.025% by weight of hexapeptide-12; Including, The hexapeptide-11 down-regulates gene expression of SCF, LIF, POMC, EDN1, PGE2, or NGF in human keratinocytes; the hexapeptide-12 down-regulates the expression of MAPK1, MITF, JNK, EDNRB, DCT, TYR, TYRP1, or PMEL in endothelial cells, or down-regulates the expression of MAPK1, MAPK3, MAP2K1, MAP2K2, POMC, or CTNNB1 in melanocytes; Topical compositions.

2. 10. The topical composition of claim 1, wherein the first liposome is present in a range of about 0.1% to about 2% by weight.

3. The topical composition of claim 1 or 2, wherein the first liposome encapsulates the second liposome.

4. 4. The topical composition of claim 1, further comprising lactoferrin present at about 0.25% by weight or less.

5. The topical composition of any one of claims 1 to 4, further comprising a peptide derived from lactoferrin.

6. 6. The topical composition of claim 1, further comprising phosphatidylserine present at about 0.075% by weight or less.

7. 7. The topical composition of claim 1, further comprising silymarin present in the range of about 0.1% to about 1.0% by weight.

8. 8. The topical composition of claim 1, further comprising sesamol present in the range of about 0.002% to about 0.050% by weight.

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

10. 10. The topical composition of any one of claims 1 to 9, further comprising phytoene, phytofluene, or a combination thereof present in the range of about 1% to about 10% by weight.

11. A topical composition described in any one of claims 1 to 10, wherein the first liposome or the second liposome comprises lecithin, propanediol, or a combination thereof.

12. the hexapeptide-12 is encapsulated in the second liposome; or the hexapeptide-11 is encapsulated in a third liposome; or the hexapeptide-12 and the hexapeptide-11 are encapsulated in the second liposome; A topical composition according to any one of claims 1 to 11.

13. 13. A topical composition according to any one of claims 1 to 12 for improving pigmentation caused by a pigmentation disorder or disease, wherein the pigmentation disorder or disease is: hyperpigmentation, Post-inflammatory hyperpigmentation (PIH), focal or diffuse hypopigmentation, acanthosis nigricans, age spots, albinism, incontinentia pigmenti, Kuroko, Melasma, Pityriasis alba, and Progressive pigmented purpura At least one selected from administered to the skin of a subject; Topical compositions.

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