Compositions and methods relating to pigmentation

Abstract

Disclosed herein are compositions and methods for improving pigmentation. Compositions as described herein include one or more peptides.

Description

(19) State Intellectual Property Office (12) Invention Patent Application (10) Application Publication Number (43) Application Publication Date (21) Application Number 202511945610.3 (22) Application Date 2021.03.26 (30) Priority Data 63 / 001,095 2020.03.27 US (62) Divisional Application Data 202180038830.1 2021.03.26 (71) Applicant Alastine Skin Care Products Co., Ltd. Address California, USA (72) Inventors A.D. Wadegarrou J.A. Garutto (74) Patent Agency Shanghai Bixing Law Firm 31283 Patent Attorneys Shui Wenyu Wang Weibin (51) Int.Cl. A61K 38 / 08 (2019.01) A61K 38 / 40 (2006.01) A61K 9 / 127 (2025.01) A61P 17 / 16 (2006.01) A61P 17 / 00 (2006.01) A61P 7 / 04 (2006.01) (54) Invention Title: Compositions and Methods Related to Pigmentation (57) Abstract: This document discloses compositions and methods for improving pigmentation. The compositions described herein comprise one or more peptides. Claims 1 page, Description 50 pages, Sequence Listing (electronic publication), Drawings 20 pages, CN 121570573 A 2026.02.27 CN 1 21 57 05 73 A 1. Use of a composition comprising hexapeptide-11, hexapeptide-12 and a peptide derived from lactoferrin in the preparation of a medicament for improving pigmentation caused by a pigmentation disorder or disease, wherein the composition comprises: 0.004 wt.% to 0.100 wt.% of hexapeptide-11, wherein hexapeptide-11 downregulates the expression of SCF, LIF, POMC, EDN1, PGE2 or NGF genes in human keratinocytes; and 0.001 wt.% to 0.025 wt.% of hexapeptide-12, wherein hexapeptide-12 downregulates MAPK1 in endothelial cells, 1. Expression of the MITF, JNK, EDNRB, DCT, TYR, TYRP1, or PMEL genes, or downregulation of the expression of the MAPK1, MAPK3, MAP2K1, MAP2K2, POMC, or CTNNB1 genes in melanocytes. 2. The application according to claim 1, wherein the pigmentation disorder or disease is hyperpigmentation. 3. The application according to claim 1, wherein the pigmentation disorder or disease is post-inflammatory hyperpigmentation (PIH). 4. The application according to claim 1, wherein the pigmentation disorder or disease is focal hypopigmentation or diffuse hypopigmentation.5. The application according to claim 1, wherein the pigmentation disorder or disease is acanthosis nigricans, age spots, albinism, pigmentary disorders, freckles, melasma, pityriasis alba, or progressive pigmentary purpura. Claims 1 / 1 page 2 CN 121570573 A Compositions and methods related to pigmentation

[0001] This application is a divisional application of patent application filed on March 26, 2021, with application number 202180038830.1 and entitled "Compositions and methods related to pigmentation".

[0002] Cross-reference to related applications

[0003] This application claims the benefit of U.S. Provisional Patent Application No. 63 / 001,095, filed on March 27, 2020, which is incorporated herein by reference in its entirety. Technical Field

[0004] This invention relates to the field of cosmetic technology, and more particularly to compositions and methods related to pigmentation. Background Art

[0005] The color of skin, hair, and eyes is caused by melanin produced by melanosomes. The amount of melanin produced by a particular individual varies based on a variety of genetic and environmental factors, including exposure to UV light. Excessive production of melanin in the skin can lead to hyperpigmentation, resulting in melasma, freckles, and age spots. Therefore, understanding the regulation and underlying mechanisms of melanin production is important for identifying targets for the prevention and treatment of pigmentation disorders. Summary of the Invention

[0006] Compositions and methods for regulating pigmentation are described herein. In some cases, the compositions and methods described herein can reduce melanocyte activation, inhibit melanin synthesis, reduce melanin transfer, lead to the shedding of keratinocytes containing melanosomes or melanosome autophagy, or combinations thereof.

[0007] One aspect described herein is a topical composition for improving pigmentation, the topical composition 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 the range of about 0.1 wt.% to about 2 wt.%. In one feature, the one or more photosomes are present in the range of about 0.25 wt.% to about 1 wt.%. In one feature, the one or more photosomes encapsulate the one or more liposomes. In one feature, the hexapeptide-11 is present in the range of 50-150 ppm. In one feature, the hexapeptide-11 is present in the range of about 0.004 wt.% to about 0.100 wt.%. In one feature, the hexapeptide-11 is encapsulated in a first liposome within the one or more liposomes. In one feature...In one embodiment, the hexapeptide-12 is encapsulated in a second liposome within one or more liposomes. In another embodiment, the hexapeptide-11 and the hexapeptide-12 are encapsulated in a first liposome within one or more liposomes. In another embodiment, the hexapeptide-12 comprises palmitoyl hexapeptide-12, myristoyl hexapeptide-12, or a combination thereof. In another embodiment, the hexapeptide-12 is present at a concentration of 1-10 ppm. In another embodiment, the hexapeptide-12 is present in the range of about 0.001 wt.% to about 0.025 wt.%. In another embodiment, the embodiment further comprises lactoferrin. In another embodiment, the lactoferrin is present at a concentration not exceeding about 0.25 wt.%. In another embodiment, the lactoferrin is present in the range of about 0.005 wt.% to about 0.25 wt.%. In another embodiment, the lactoferrin is encapsulated in a third liposome within one or more liposomes. In one feature, the portion further comprises lactoferrin, and wherein the lactoferrin, the hexapeptide-11, and the hexapeptide-12 are encapsulated in a first liposome within one or more liposomes. In one feature, the portion further comprises a peptide derived from lactoferrin. In one feature, the peptide derived from lactoferrin 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: Page 1 / 50, CN 121570573 A 1. In one feature, the portion further comprises phosphatidylserine. In one feature, the phosphatidylserine is present at no more than about 0.075 wt.%. In one feature, the phosphatidylserine is present in the range of about 0.005 wt.% to about 0.1 wt.%. In one feature, the phosphatidylserine is present in the range of no more than 5.0 wt.%. In one feature, the local compound further comprises silymarin. In one feature, the silymarin is present in the range of about 0.1 wt.% to about 1.0 wt.%. In one feature, the silymarin is present in the range of about 0.2 wt.% to about 3.0 wt.%. In one feature, the local compound further comprises sesamol. In one feature, the sesamol is present in the range of about 0.002 wt.% to about 0.050 wt.%. In one feature, the local compound further comprises tranexamic acid. In one feature, the tranexamic acid is present in the range of about 1 wt.% to about 10 wt.%. In one feature, the tranexamic acid is present in the range of about 0.25 wt.% to about 6.25 wt.%. In one feature, the local compound further comprises tranexamic acid.The component further comprises phytoene, phytohexene, or a combination thereof. In one feature, the phytoene, phytohexene, or combination thereof are present in the range of about 1 wt.% to about 10 wt.%. In one feature, the component further comprises Ashwagandha extract. In one feature, the Ashwagandha extract is present in the range of about 0.020 wt.% to about 0.500 wt.%. In one feature, the component further comprises gallic acid. In one feature, the gallic acid is present in the range of about 0.40 wt.% to about 10 wt.%. In one feature, the component further comprises hesperidin. In one feature, the hesperidin is present in the range of about 0.020 wt.% to about 0.50 wt.%. In one feature, the component further comprises crinoid. In one feature, the crinoid is present in the range of about 0.50 wt.% to about 5.0 wt.%. In one feature, the component further comprises nicotinamide. In one feature, the nicotinamide is present in the range of about 1 wt% to about 10 wt%. In one feature, the portion further comprises oleuropein. In one feature, the oleuropein is present in the range of about 0.030 wt% to about 0.750 wt%. In one feature, the portion further comprises thermophilic fungi enzyme. In one feature, the thermophilic fungi enzyme is present in the range of about 0.30 wt.% to about 7.5 wt.%. In one feature, the portion further comprises tremella fuciformis. In one feature, the tremella fuciformis is present in the range of about 0.20 wt.% to about 5.0 wt.%. In one feature, the portion further comprises heptasodium hexacarboxymethyl dipeptide-12. In one feature, the heptasodium hexacarboxymethyl dipeptide-12 is present in the range of about 0.1 wt.% to about 10 wt.%. In one feature, the heptasodium hexacarboxymethyl dipeptide-12 is present in the range of about 0.2 wt.% to about 5 wt.%. In one aspect, the topical composition is aqueous.

[0008] One aspect described herein is a topical composition for improving pigmentation, the topical composition comprising: hexapeptide-11; hexapeptide-12; and a peptide derived from lactoferrin; wherein the topical composition improves pigmentation. In one aspect, the hexapeptide-12 comprises palmitoyl hexapeptide-12, myristoyl hexapeptide-12, or a combination thereof. In one aspect, the hexapeptide-12 is present at 1-10 ppm. In one aspect, the hexapeptide-12 is present in the range of about 0.001 wt.% to about 0.025 wt.%. In one aspect, the hexapeptide-11 is present at 50-150 ppm. In one aspect, the hexapeptide-11 is present in the range of about 0.004 wt.% to about 0.100 wt.The range of percentages is specified. In one feature, the peptide derived from lactoferrin 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 feature, the topical composition further comprises phosphatidylserine. In one feature, the phosphatidylserine is present at no more than about 0.075% by wt.%. In one feature, the phosphatidylserine is present in the range of about 0.005 wt.% to about 0.1 wt.%. In one feature, the phosphatidylserine is present at no more than 5.0 wt%. In one feature, the topical composition further comprises lactoferrin. In one feature, the lactoferrin is present at no more than about 0.25 wt.%. In one feature, the lactoferrin is present in the range of about 0.005 wt.% to about 0.25 wt.%. In one feature, the composition further comprises photon. In one feature, the photon is present in the range of about 0.1 wt.% to about 2 wt.%. In one feature, the topical composition further comprises silymarin, sesamol, tranexamic acid, phytohexene, hexahydrolycopene, ashwagandha extract, hesperidin, crinoid, nicotinamide, oleuropein, thermophilic bacteria enzyme, tremella, heptasodium hexacarboxymethyl dipeptide-12, or combinations thereof. In one feature, the topical composition is aqueous.

[0009] One aspect described herein is a method for improving hyperpigmentation caused by a pigmentation disorder or disease, the method comprising applying the topical composition described herein. In one feature, the topical composition further comprises a pigmentation disorder or disease for hyperpigmentation. In one feature, the topical composition further comprises a pigmentation disorder or disease of post-inflammatory hyperpigmentation (PIH). In one feature, the topical composition further comprises a pigmentation disorder or disease of focal hypopigmentation or diffuse hypopigmentation. In one feature, the topical composition further comprises a pigmentation disorder or disease of acanthosis nigricans, senile lentigines, albinism, pigmentary disorders, freckles, melasma, pityriasis alba, or progressive pigmented purpura.

[0010] Incorporated by Reference

[0011] All disclosures, patents, and patent applications mentioned in this specification are incorporated herein by reference to the same extent, as specifically and individually indicated that each individual disclosure, patent, or patent application is incorporated by reference. Brief Description of the Drawings

[0012] Figure 1 illustrates factors influencing pigmentation and strategies and agents that can be used to treat pigmentation disorders or conditions.

[0013] Figure 2 illustrates the effects of external influences on different pigmentation pathways. The abbreviations listed are as follows: For surface receptors on melanocytes: EDNRB = endothelin receptor B, MC1R = melanocortin-1 receptor 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 = α-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-associated protein 2, TRP-1 = tyrosinase-associated protein 1.

[0014] Figures 3A-3D show the expression levels of lactoferrin (Lacto), lactoferrin-derived peptides (TCV), hexapeptide-12 (Hex12), tripeptide-1 and hexapeptide-12 (TriHex), hexapeptide-11 (Hex11), tranexamic acid, octapeptide, phosphatidylserine, cannabidiol (CBD), and all (total) MEK (Figure 3A), ERK (Figure 3B), POMC (Figure 3C), and CTNNB1 (Figure 3D) in melanocytes after treatment with lactoferrin (Lacto).

[0015] Figure 4 shows the expression of various genes after treatment of melanocytes with hexapeptide-12 (Hex-12).

[0016] Figure 5 shows the expression of various genes after treatment of melanocytes with lactoferrin (Lacto).

[0017] Figures 6A-6F show the expression of lactoferrin (Lacto), lactoferrin-derived peptide (TCV), tripeptide-1 (Tri), hexapeptide-12 (Hex12), tripeptide-1 and hexapeptide-12 (TriHex), hexapeptide-11 (Hex11), tranexamic acid, octapeptide (Octa), phosphatidylserine (phos), cannabidiol (CBD), and all (total) SCF (Figure 6A), LIF (Figure 6B), POMC (Figure 6C), endothelin gene (Figure 6D), PGE2 (Figure 6E), and NGF (Figure 6F) in keratinocytes after treatment.

[0018] Figure 7 shows the individual hexapeptide-11 (Hex-11) activities for different genes.

[0019] Figures 8A-8C illustrate the use of lactoferrin (Lacto), lactoferrin-derived peptides (TCV), hexapeptide-12 (Hex12), tripeptide-1 and hexapeptide-12 (TriHex), hexapeptide-11 (Hex11), tranexamic acid, octapeptide (Octa), phosphatidyl...Expression of serine (phos), cannabidiol (CBD), and all (total) EDN1 (Fig. 8A), SCF (Fig. 8B), and TGFB1 (Fig. 8C) after treatment of endothelial cells.

[0020] Fig. 9 shows the individual phosphatidylserine activities on EDN1 and other melanin-producing genes.

[0021] Figures 10A-10D show the expression of lactoferrin (Lacto), lactoferrin-derived peptide (TCV), hexapeptide-12 (Hex12), tripeptide-1 and hexapeptide-12 (TriHex), hexapeptide-11 (Hex11), tranexamic acid, octapeptide (Octa), phosphatidylserine (phos), cannabidiol (CBD), and all (total) treatments of endothelial cells, including PMEL (Figure 10A), tyrosinase gene (Figure 10B), MC1 / 4R (Figure 10C), and EDNRB (Figure 10D).

[0022] Figure 11 shows the expression of MITF in endothelial cells after treatment with lactoferrin (Lacto), lactoferrin-derived peptide (TCV), hexapeptide-12 (Hex12), tripeptide-1 and hexapeptide-12 (TriHex), hexapeptide-11 (Hex11), tranexamic acid, octapeptide (Octa), phosphatidylserine (phos), cannabidiol (CBD) and all (total).

[0023] Figures 12A-12C illustrate the expression of 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 (total) treatments of endothelial cells followed by ERK1 / 2 (MAPK3 / MAPK1) (Figure 12A), JNK (Figure 12B), and AKT1 (Figure 12C). Detailed Description

[0024] Definitions

[0025] Throughout this disclosure, various embodiments are presented in 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 of the range of any embodiment. Therefore, unless the context clearly specifies otherwise, the description of ranges should be considered as having specifically disclosed all possible subranges and individual numerical values ​​within the range up to one-tenth of the lower limit unit. For example, a description of a range such as 1 to 6 should be considered as having 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 said ranges, such as 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 intermediate ranges...It may be independently included in a smaller scope and also covered within this disclosure, subject to any expressly excluded limits in the stated scope. Where the stated scope includes one or two limits, the scope excluding any or both of those included limits is also included in this disclosure, unless the context expressly specifies otherwise.

[0026] The terminology used herein is for the purpose of describing particular embodiments only and is not intended to limit any embodiments. As used herein, unless the context clearly indicates otherwise, the singular forms “a / an” and “the” are intended to also include the plural forms. It will be further understood that, when used in this specification, the terms “comprises and / or comprising” 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.

[0027] Unless specifically stated or obvious from the context, as used herein, the term “about” when referring to numbers or ranges of numbers is understood to mean the stated number and numbers plus or minus 10%, or values ​​listed for a range that are 10% below the lower limit and 10% above the upper limit.

[0028] Compositions

[0029] Peptides

[0030] The compositions described herein comprise one or more peptides. In some embodiments, one or more peptides described herein improve hyperpigmentation including hyperpigmentation. In some embodiments, one or more peptides regulate post-inflammatory hyperpigmentation, melasma, or aging. In some embodiments, hyperpigmentation due to aging is caused by UV exposure or inflammation.

[0031] In some embodiments, one or more peptides comprise hexapeptide-11. In some embodiments, hexapeptide-11 promotes the activation of proteasomes, autophagy, molecular chaperones, and genes related to antioxidant responses. In some embodiments, one or more peptides comprise hexapeptide-11, tripeptide-1, and hexapeptide-12.

[0032] In some embodiments, hexapeptide-11, tripeptide-1, and hexapeptide-12 result in a synergistic effect on gene expression. In some cases, hexapeptide-11, tripeptide-1, and hexapeptide-12 regulate MITF gene expression. In some cases, compared to hexapeptide-11, tripeptide-1, and hexapeptide-12 alone, hexapeptide-11, tripeptide-1, and hexapeptide-12 increase MITF downregulation by at least or about 0.5-fold, 1-fold, 2-fold, 3-fold, 4-fold, 5-fold, or more than 5-fold.

[0033] The peptides described herein, in some embodiments, in combination, improve pigmentation, melanosome autophagy, and MITF.Reduce or combinations 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, in combination with one or more different peptides, such as tripeptide-1, hexapeptide-12, or combinations thereof, can stimulate autophagy and macrophage aggregation and can improve melanosome removal.

[0034] The compositions described herein comprise different concentrations of peptides. In some cases, the peptides are present at about 50 ppm or less up to 1000, 5000, 10000, 50000, 100000, 500000 ppm or more, for example, 100 ppm of peptide. In some cases, the peptide is present in concentrations of about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 50, 75, 100, 200, 300, 400, 500, 600, 700, 800, 900, 1000, or greater than 1000 ppm. In other cases, the peptide is present in concentrations ranging from 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 in concentrations 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 (ug / mL) per milliliter. In other cases, the peptide is present in concentrations 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 amounts from about 0.01 wt% to about 10 wt%, from about 0.01 wt% to about 0.02 wt%, from about 0.01 wt% to about 0.03 wt%, from about 0.01 wt% to about 0.04 wt%, from about 0.01 wt% to about 0.05 wt%, from about 0.01 wt% to about 0.1 wt%, from about 1 wt% to about 5 wt%, or from about 1 wt% to 10 wt% (wt.%).

[0035] The compositions described herein include one or more peptides in some embodiments. In some cases, the peptides of the one or more peptides are present in amounts from about 50 ppm or less to 1000, 5000, 10000, 50000, 100000, 500000 ppm or more, such as 100 ppm of peptide or any other suitable amount. In some cases, the peptides of the one or more peptides are present in amounts from about 50 ppm or less to 1000, 5000, 10000, 500000 ppm or more, such as 100 ppm of peptide or any other suitable amount.It is present in concentrations of about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 50, 75, 100, 200, 300, 400, 500, 600, 700, 800, 900, 1000, or greater than 1000 ppm. In some cases, the peptides of the one or more said peptides are present in concentrations ranging from 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 peptides of the one or more peptides are present in amounts 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 (ug / mL) per milliliter. In some cases, the peptides of the one or more peptides are present in amounts ranging from 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 amount of peptide in the one or more peptides is from about 0.01 wt% to about 10 wt%, from about 0.01 wt% to about 0.02 wt%, from about 0.01 wt% to about 0.03 wt%, from about 0.01 wt% to about 0.04 wt%, from about 0.01 wt% to about 0.05 wt%, from about 0.01 wt% to about 0.1 wt%, from about 1 wt% to about 5 wt%, or from about 1 wt% to 10 wt% (wt. %). In some embodiments, a peptide of one or more of the peptides is provided in amounts of at least or about 0.00001 wt%, 0.0003 wt%, 0.0005 wt%, 0.001 wt%, 0.001 wt%, 0.005 wt%, 0.0055 wt%, 0.01 wt%, 0.02 wt%, 0.05 wt%, 0.10 wt%, 0.25 wt%, 0.50 wt%, 0.75 wt%, 1.0 wt%, 1.5 wt%, 2.0 wt%, 2.5 wt%, 3.0 wt%, 3.5 wt%, 4.0 wt%, 4.5 wt%, 5.0 wt%, 5.5 wt%, 6.0 wt%, 6.5 wt%, 7.0 wt%, 8 wt%, 9 wt%, 10 wt%, or greater than 10 wt%. In some embodiments, the peptides of the one or more peptides are provided in the range of about 0.25% to about 10% by weight, about 0.5% to about 8% by weight, about 0.75% to about 6% by weight, or about 1% to about 4% by weight.In some embodiments, each of the one or more peptides is provided in the range of about 0.001% by weight to about 6% by weight, about 0.002% by weight to about 4% by weight, about 0.01% by weight to about 3% by weight, or about 0.02% by weight to about 2% by weight. In some embodiments, the peptide is tripeptide-1, hexapeptide-12, hexapeptide-11, octapeptide, or a combination thereof.

[0036] 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, for example, from 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, for example, from 50 ppm to 150 ppm.

[0037] In some embodiments, at least or about 0.00001 wt%, 0.0003 wt%, 0.0005 wt%, 0.001 wt%, 0.001 wt%, 0.005 wt%, 0.0055 wt%, 0.05 wt%, 0.10 wt%, 0.25 wt%, 0.50 wt%, 0.75 wt%, 1.0 wt%, 1.5 wt%, 2.0 wt%, 2.5 wt%, 3.0 wt%, 3.5 wt%, 4.0 wt%, 4.5 wt%, 5.0 wt%, 5.5 wt%, 6.0 wt%, 6.5 wt%, 7.0 wt%, 8 wt%, 9 wt%, 10 wt%, or greater than 10 wt% (wt.%) of tripeptide-1 is provided. In some embodiments, tripeptide-1 is provided in the range of about 0.25 wt% to about 10 wt%, about 0.5 wt% to about 8 wt%, about 0.75 wt% to about 6 wt%, or about 1 wt% to about 4 wt%. In some embodiments, tripeptide-1 is provided at least or about 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, or greater 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 least or about 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, or greater than 25 micrograms (ug / mL) per milliliter. 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.

[0038] In some embodiments, at least or about 0.00001% by weight, 0.0003% by weight, or 0.0005% by weight are provided.Hexapeptide-12 in the range of 0.001 wt%, 0.005 wt%, 0.0055 wt%, 0.05 wt%, 0.10 wt%, 0.25 wt%, 0.50 wt%, 0.75 wt%, 1.0 wt%, 1.5 wt%, 2.0 wt%, 2.5 wt%, 3.0 wt%, 3.5 wt%, 4.0 wt%, 4.5 wt%, 5.0 wt%, 5.5 wt%, 6.0 wt%, 6.5 wt%, 7.0 wt%, 8 wt%, 9 wt%, 10 wt%, or greater than 10 wt%. In some embodiments, hexapeptide-12 is provided in the range of about 0.00001 wt% to about 10 wt%, about 0.0003 wt% to about 9 wt%, about 0.0005 wt% to about 8 wt%, or about 0.001 wt% to about 4 wt%. In some embodiments, hexapeptide-12 is provided at least or about 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, or 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 least or about 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, or greater than 25 micrograms (ug / mL) per milliliter. 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.

[0039] In some embodiments, at least or 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) of hexapeptide-12 is provided. 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, at least or about 0.150 μg of hexapeptide-12 is provided. In some embodiments, at least or about 450 μg of hexapeptide-12 is provided.

[0040] In some embodiments, at least or about 0.00001 wt%, 0.0003 wt%, and 0.0005 wt% are provided.0.001 wt%, 0.005 wt%, 0.0055 wt%, 0.01 wt%, 0.02 wt%, 0.05 wt%, 0.10 wt%, 0.25 wt%, 0.50 wt%, 0.75 wt%, 1.0 wt%, 1.5 wt%, 2.0 wt%, 2.5 wt%, 3.0 wt%, 3.5 wt%, 4.0 wt%, 4.5 wt%, 5.0 wt%, 5.5 wt%, 6.0 wt%, 6.5 wt%, 7.0 wt%, 8 wt%, 9 wt%, 10 wt% or greater than 10 wt% (wt.%) of hexapeptide-11. In some embodiments, hexapeptide-11 is provided in the range of about 0.00001 wt% to about 10 wt%, about 0.0003 wt% to about 8 wt%, about 0.0005 wt% to about 6 wt%, or about 0.001 wt% to about 4 wt%, about 0.005 wt% to about 2 wt%, or about 0.01 wt% to about 1 wt%. In some embodiments, hexapeptide-11 is provided in the range of about 0.001% to about 6%, about 0.002% to about 4%, about 0.01% to about 3%, or about 0.02% to about 2%. In some embodiments, hexapeptide-11 is provided in the range of about 0.005 wt% to about 0.02 wt%. In some embodiments, hexapeptide-11 is provided at least or 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 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) per milliliter. 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.

[0041] In some embodiments, hexapeptide-11 is provided at least or about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 20, 30, 40, 50, 60, 70, 80, 90, or about 100 milligrams (mg). In some embodiments, hexapeptide-11 is provided in the range of about 1 to about 100 mg.Provided. In some embodiments, hexapeptide-11 is provided in the range of about 2 to about 90, about 3 to about 80, about 4 to about 70, or about 5 to about 60 mg. In some embodiments, at least or about 6 mg of hexapeptide-11 is provided. In some embodiments, at least or about 18 mg of hexapeptide-11 is provided.

[0042] In some embodiments, an octapeptide is provided in amounts of at least or about 0.00001 wt%, 0.0003 wt%, 0.0005 wt%, 0.001 wt%, 0.001 wt%, 0.005 wt%, 0.0055 wt%, 0.05 wt%, 0.10 wt%, 0.25 wt%, 0.50 wt%, 0.75 wt%, 1.0 wt%, 1.5 wt%, 2.0 wt%, 2.5 wt%, 3.0 wt%, 3.5 wt%, 4.0 wt%, 4.5 wt%, 5.0 wt%, 5.5 wt%, 6.0 wt%, 6.5 wt%, 7.0 wt%, 8 wt%, 9 wt%, 10 wt%, or greater than 10 wt%. In some embodiments, the octapeptide is provided in the range of about 0.25 wt% to about 10 wt%, about 0.5 wt% to about 8 wt%, about 0.75 wt% to about 6 wt%, or about 1 wt% to about 4 wt%. In some embodiments, the 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 ppm. In some embodiments, the octapeptide is provided at concentrations of about 10 to about 190 ppm, about 20 to about 180 ppm, about 30 to about 170 ppm, about 40 to about 160 ppm, about 50 to about 150 ppm, about 60 to about 140 ppm, about 70 to about 130 ppm, about 80 to about 120 ppm, or about 90 to about 110 ppm. In some embodiments, the octapeptide is provided at a concentration of about 100 ppm. In some embodiments, the octapeptide is provided at a concentration of at least about 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, or greater than 200 ug / mL. In some embodiments, the octapeptide is provided at a concentration of about 10 to about 190 ug / mL, about 20 to about 180 ug / mL, about 30 to about 170 ug / mL, about 40 to about 160 ug / mL, about 50 to about 150 ug / mL, about 60 to about 140 ug / mL, about 70 to about 130 ug / mL, about 80 to about 120 ug / mL, or about 90 to about 110 ug / mL. In some embodiments, the octapeptide is provided at a concentration of about 100 ug / mL.A concentration of 121570573 A ug / mL is provided.

[0043] The peptide can be functionalized. For example, the peptide can be functionalized with fatty acids such as myristoleic acid, palmitoleic acid, saponinic acid, oleic acid, transoleic acid, isoleic acid, linoleic acid, linolenic 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, ceric acid, ceric acid, etc. Examples include palmitoyl hexapeptide-12 (Pal-VGVAPG), palmitoyl tripeptide-1 (Pal-GHK), myristic hexapeptide-12 (Myr-VGVAPG), and myristic tripeptide-1 (Myr-GHK). In some examples, palmitoyl or myristic functionalization may be desired because it exhibits enhanced permeability compared to other fatty acids. In some embodiments, the peptide is functionalized with chemical groups. For example, the peptide is functionalized with acetyl groups. In some cases, the peptide is functionalized with functional groups comprising no more than 14 carbons. In some cases, the peptide is functionalized with functional groups comprising no more than 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or more than 20 carbons. In some cases, the peptide is non-palmitoylated. Where it is not desired to be limited by a particular theory, in some embodiments, incorporating the peptide into liposomes increases the lipophilicity of the functionalized or unfunctionalized peptide.

[0044] Some embodiments of the methods and compositions provided herein contain glycine-histidine-lysine (GHK) as a first peptide. GHK is a peptide sequence that is rarely found in protein classes but frequently found in extracellular matrix proteins. The small size of GHK makes it more accessible to membrane receptors than larger peptides. Furthermore, its unique copper-binding structure enhances the transport of copper both intracellularly and extracellularly, and promotes 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).

[0045] Silymarin

[0046] Silymarin is derived from the milk thistle plant, milk thistle. Silymarin, the main component of silymarin, has antioxidant and photoprotective effects by minimizing the effects of UV radiation, such as oxidative stress, inflammation, edema, erythema, and DNA damage. In some cases, silymarin inhibits melanin production and reduces the expression of tyrosinase proteins without affecting cell viability. A study of patients with melasma found that silymarin cream was more effective than intradermal tranexamic acid. In some cases, silymarin inhibits the production of white blood cells by cyclooxygenase-2 (COX-2) in keratinocytes and macrophages.The production of interleukin-1β (IL-1β) and PGE-2. In some cases, silybin reduces inducible nitric oxide synthase (iNOS) and COX-2, as well as NF-κB.

[0047] The compositions described herein include silybin in some embodiments. In some embodiments, silybin includes silybin. In some embodiments, at least or about 0.001 wt%, 0.005 wt%, 0.01 wt%, 0.02 wt%, 0.05 wt%, 0.10 wt%, 0.20 wt%, 0.25 wt%, 0.50 wt%, 0.75 wt%, 1.0 wt%, 1.5 wt%, 2.0 wt%, 2.5 wt%, 3.0 wt%, 3.5 wt%, 4.0 wt%, or greater than 4 wt%. In some embodiments, silymarin is provided in the range of about 0.25 wt% to about 10 wt%, about 0.1 wt% to about 2.5 wt%, or about 0.5 wt% to about 8 wt%. In some embodiments, silymarin is provided in the range of about 0.001 wt% to about 6 wt%, about 0.002 wt% to about 4 wt%, about 0.01 wt% to about 3 wt%, about 0.02 wt% to about 2 wt%, or about 0.2 wt% to about 3 wt%. In some embodiments, silymarin comprises about or no more than about 0.7 wt%. In some embodiments, silymarin is provided at least or about 10, 50, 100, 200, 500, 1000, 2000, 2500, 5000, 7500, 10000, 15000, 20000, 25000, 30000, 35000, 40000, or more than 40000 ppm. In some embodiments, silymarin is provided in the range of about 2500 ppm to about 100000 ppm, about 1000 ppm to about 25000 ppm, about 5000 ppm to about 80000 ppm, about 75000 ppm to about 60000 ppm, or about 1000 ppm to about 40000 ppm. In some embodiments, silymarin 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 at least or about 5, 10, 15, 20, 25, 30, 35, or 40 micrograms (ug / mL) per mL. In some embodiments, silymarin is provided in the range of about 1 to about 50, about 5 to about 45, about 10 to about 40, or about 15 to about 35 ug / mL.

[0048] In some embodiments, silymarin is provided 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 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 mg. In some embodiments, silymarin is provided in about 6 mg. In some embodiments, silymarin is provided in about 18 mg.

[0049] Tranexamic acid

[0050] Tranexamic acid (TXA) is a plasmin inhibitor used to prevent fibrinolysis to reduce blood loss. It is a synthetic derivative of lysine and functions by reversibly blocking the lysine binding site on the plasminogen molecule, thereby preventing plasminogen from binding to basal keratinocytes, inhibiting the conversion of plasminogen to plasmin, and thus reducing the production of prostaglandins (especially PGE-2). In some cases, UV exposure is associated with the pathogenesis of melasma. UV irradiation can induce plasminogen activator synthesis and increase plasmin activity in keratinocytes, thereby stimulating the release of arachidonic acid (AA) via phospholipase. Free AA can stimulate melanin production through its metabolite PGE-2. In some cases, plasmin in endothelial cells increases AA release. Increased plasmin itself can increase α-MSH, thereby activating melanin synthesis in melanocytes. Plasmin can also increase the release of basic fibroblast growth factor (bFGF), a potent melanocyte growth factor. All these processes lead to increased melanin production in the skin. In some cases, plasmin plays an important angiogenic role. Plasmin converts extracellular matrix-bound VEGF into a freely diffusing form. TXA, a plasmin inhibitor, can inhibit angiogenesis and also inhibit bFGF-induced neovascularization. Furthermore, TXA is structurally similar to tyrosine, meaning it can competitively inhibit the enzymatic activity of tyrosinase. In some cases, TXA reduces VEGF and ET-1 levels, which may be a reason for increased angiogenesis in melasma lesions.

[0051] The compositions described herein include tranexamic acid (TXA) in some embodiments. In some embodiments, at least or about 0.001 wt%, 0.005 wt%, 0.01 wt%, 0.02 wt%, 0.05 wt%, 0.10 wt%, 0.20 wt%, 0.25 wt%, 0.50 wt%, 0.75 wt%, 1.0 wt%, 1.5 wt%, 2.0 wt%, 2.5 wt%, 3.0 wt%, 3.5 wt%, 4.0 wt%, 4.5 wt%, 5.0 wt%, 5.5 wt%, 6.0 wt%, 6.5 wt%, 7.0 wt% are provided.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. 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. In some embodiments, TXA is provided in the range of about or not more than about 1.25% by weight. In some embodiments, TXA is provided 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 the range of about 2,500 ppm to about 10,000 ppm, about 1,000 ppm to about 25,000 ppm, about 5,000 ppm to about 8,000 ppm, about 7,500 ppm to about 6,000 ppm, or about 10,000 ppm to about 4,000 ppm. In some embodiments, TXA is provided in the range of about 10 ppm to about 6,000 ppm, about 20 ppm to about 4,000 ppm, about 100 ppm to about 3,000 ppm, or about 200 ppm to about 2,000 ppm. In some embodiments, TXA is about 5,000 ppm. In some embodiments, at least or about 10, 50, 100, 200, 500, 1,000, 2,000, 2,500, or 5,000 micrograms (ug / mL) of TXA is provided per milliliter. In some examples, on pages 9 / 50 of CN 121570573 A, TXA is described as being from about 10 to about 5000 ug / mL, from about 50 to about 4000 ug / mL, and from about 100 to about 3000 ug / mL.The TXA is provided in the range of about 150 to about 2000 ug / mL, or about 500 to about 1500 ug / mL.

[0052] In some embodiments, at least or about 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 mg. In some embodiments, the 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 mg. In some embodiments, the TXA is provided in about 30 mg. In some embodiments, the TXA is provided in about 90 mg.

[0053] Lactoferrin

[0054] Lactoferrin (Lf) is an 80 kDa iron-binding glycoprotein of the transferrin family, found in exocrine fluids (tears, saliva, breast milk, nasal and bronchial secretions, gastrointestinal fluids, etc.). Lactoferrin has a range of effects from antibacterial to anti-inflammatory and immunomodulatory activity with high iron-binding affinity. Lactoferrin can downregulate the production of TNFα and other cytokines (IL-1) by local skin cells and may be associated with bruise resolution and prevention of post-inflammatory hyperpigmentation. Lactoferrin also has a positive effect on wound healing. Lactoferrin is also a plasmin inhibitor and may affect endothelial cell-induced hyperpigmentation, especially melasma.

[0055] In some cases, trypsinized peptide fragments derived from lactoferrin promote receptor-mediated MITF degradation. In some cases, trypsinized peptide fragments have an inhibitory effect on hyperpigmentation.

[0056] The compositions described herein include transferrin in some embodiments. In some embodiments, transferrin is lactoferrin. In some embodiments, the composition comprises a trypsinized fragment of lactoferrin. In some embodiments, the composition comprises a peptide derived from lactoferrin. In some embodiments, the composition comprises a variant or fragment of lactoferrin. In some cases, 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. Exemplary peptides derived from lactoferrin include, but are not limited to, PRKNVRWCT (SEQ ID NO: 2), LGFLRIP (SEQ ID NO: 3), GYSGAFKC (SEQ ID NO: 4), TCVRR (SEQ ID NO: 5), TCVRRAF (SEQ ID NO: 6), WNSLKDKKSCH (SEQ ID NO: 7), and SEQ ID NO: 8.7), LFNDNTECLAKLG (SEQ ID NO: 8), TTLKNLR (SEQ ID NO: 9), QGLDKCVPNSKE (SEQ ID NO: 10), VKKANE (SEQ ID NO: 11), LAKLGGRP (SEQ ID NO: 12), GDVAFVK (SEQ ID NO: 13), NLNREDFRL (SEQ ID NO: 14), ALGFLRI (SEQ ID NO: 15), TTLKNLR (SEQ ID NO: 16), DALNLDG (SEQ ID NO: 17), LAEDV (SEQ ID NO: 18), RAFALEC (SEQ ID NO: 19), GAVAKFFS (SEQ ID NO: 20), NLRETA (SEQ ID NO: 21), EEQKKC (SEQ ID NO: 22), CVNSKEKY (SEQ ID NO: 23) and QAYPNL (SEQ ID NO: 24).

[0057] Table 1. Specification 10 / 50 pages 12 CN 121570573 A

[0058]

[0059] In some cases, lactoferrin has antibacterial activity. In some cases, lactoferrin has antimicrobial activity against bacteria, fungi, yeasts, viruses, parasites, or combinations thereof. In some cases, lactoferrin includes antibiofilm activity. In some cases, lactoferrin interacts with bacterial surfaces and destabilizes microbial membranes. In some cases, lactoferrin chelates iron to disrupt microbial membranes.

[0060] In some embodiments, lactoferrin is provided in amounts of at least or about 0.001 wt%, 0.005 wt%, 0.01 wt%, 0.02 wt%, 0.05 wt%, 0.10 wt%, 0.20 wt%, 0.25 wt%, 0.50 wt%, 0.75 wt%, 1.0 wt%, 1.5 wt%, 2.0 wt%, 2.5 wt%, 3.0 wt%, 3.5 wt%, 4.0 wt%, or greater than 4 wt%. In some embodiments, lactoferrin is provided in the range of about 0.005 wt% to about 0.1 wt%, about 0.25 wt% to about 10 wt%, about 0.5 wt% to about 8 wt%, about 0.75 wt% to about 6 wt%, or about 1 wt% to about 4 wt%. In some embodiments, lactoferrin is provided in the range of about 0.001 wt% to about 6 wt%, about 0.002 wt% to about 4 wt%, about 0.01 wt% to about 2.5 wt%, or about 0.02 wt% to about 2 wt%. In some embodiments, lactoferrin is provided in the range of about or not more than about 0.025 wt%.Lactoferrin is provided at a concentration of about 0.05% by weight (wt.%). In some embodiments, lactoferrin is provided at a concentration of about 0.10% by weight (wt.%). In some embodiments, lactoferrin is provided at a concentration of at least or about 5, 10, 20, 25, 50, 75, 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, 1000 or greater than 1000 micrograms (ug / mL) per milliliter. In some embodiments, lactoferrin is provided at a concentration 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 (ug / mL) per milliliter. In some embodiments, lactoferrin is provided at least about 1 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.

[0061] In some embodiments, lactoferrin is provided at least or about at least 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 200, 300, 400, 500, or greater than 500 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 mg. In some embodiments, lactoferrin is provided in about 30 mg. In some embodiments, lactoferrin is provided in about 90 mg.

[0062] In some embodiments, at least or about 0.001 wt%, 0.005 wt%, 0.01 wt%, 0.02 wt%, 0.05 wt%, 0.10 wt%, 0.20 wt%, 0.25 wt%, 0.50 wt%, 0.75 wt%, 1.0 wt%, 1.5 wt%, 2.0 wt%, 2.5 wt%, 3.0 wt%, 3.5 wt%, 4.0 wt%, or greater than 4 wt% (wt.%) of a peptide derived from lactoferrin. In some embodiments, the peptides derived from lactoferrin are present in amounts of about 0.005% by weight to about 0.1% by weight and about 0.25% by weight.The peptides are provided in the range of about 10% by weight, about 0.5% by weight, about 8% by weight, about 0.75% by weight, about 6% by weight, or about 1% by weight, to about 4% by weight. In some embodiments, the peptides derived from lactoferrin are provided in the range of about 0.001% by weight, about 0.002% by weight, about 4% by weight, about 0.01% by weight, about 2.5% by weight, or about 0.02% by weight, to about 2% by weight (wt.%). In some embodiments, the peptides derived from lactoferrin are provided in the range of about or not more than about 0.025% by weight (wt.%). In some embodiments, the peptides derived from lactoferrin are provided in the range of about or not more than about 0.05% by weight (wt.%). In some embodiments, the peptides derived from lactoferrin are provided in the range of about or not more than about 0.10% by weight (wt.%). In some embodiments, the lactoferrin-derived peptides are provided at a concentration of at least or 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 (ug / mL) per milliliter. In some embodiments, the lactoferrin-derived peptides are provided in the range of about 5 to about 5000, about 10 to about 4000, about 20 to about 3000, about 25 to about 2000, about 50 to about 1000, or about 75 to about 950 ug / mL. In some embodiments, the lactoferrin-derived peptides are provided at about 100 ug / mL. In some embodiments, the lactoferrin-derived peptides are provided at approximately 1000 ug / mL. In some embodiments, at least approximately 100, 200, 300, 400, 500, 600, 700, 800, 900, 1000, 1100, 1200, 1300, 1400, 1500, 1600, 1700, 1800, 1900, 2000, or greater than 2000 ppm of lactoferrin-derived peptides are provided. In some embodiments, peptides derived from lactoferrin are present in amounts ranging from 100 ppm to about 1900 ppm, from about 200 ppm to about 1800 ppm, from about 200 ppm to about 1700 ppm, from about 400 ppm to about 1600 ppm, from about 500 ppm to about 1500 ppm, from about 600 ppm to about 1400 ppm, from about 700 ppm to about 1300 ppm, from about 800 ppm to about 1200 ppm, or from about 900 ppm to about 1100 ppm.The range of ppm is provided. In some embodiments, the peptides derived from lactoferrin are provided in the range of about 10 ppm to 1000 ppm, about 50 ppm to about 1000 ppm, about 100 ppm to about 1000 ppm, or about 500 ppm to about 1000 ppm.

[0063] In some embodiments, at least or about 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 mg of peptides derived from lactoferrin are provided. In some embodiments, the peptides derived from lactoferrin are provided in the range of about 5 to about 500, about 10 to about 400, about 15 to about 300, about 20 to about 200, or about 25 to about 100 mg of peptides. In some embodiments, the peptides derived from lactoferrin are provided in the range of about 30 mg of peptides. In some embodiments, the peptide derived from lactoferrin is provided at about 90 mg.

[0064] Cannabidiol

[0065] Cannabidiol (CBD) can reduce the activity of the NF-κB pathway, which is a major pathway regulating the expression of pro-inflammatory genes. In addition, CBD upregulates the activation of the STAT3 transcription factor, which is an element of the homeostatic mechanism that induces anti-inflammatory events. NF-κB can regulate the cytokines IL-1β and IL-6. CBD can reduce ongoing pro-inflammatory processes and enhance anti-inflammatory events. In a carrageenan-induced rat inflammation model, CBD reduced the production of PGE2, nitric oxide (NO), and malondialdehyde, as well as COX activity.

[0066] The compositions described herein include cannabidiol (CBD) in some embodiments. In some embodiments, CBD is provided at least or about 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, or greater than 200 ug / mL. In some embodiments, CBD is provided in the range of about 10 to about 190 ug / mL, about 20 to about 180 ug / mL, about 30 to about 170 ug / mL, about 40 to about 160 ug / mL, about 50 to about 150 ug / mL, about 60 to about 140 ug / mL, about 70 to about 130 ug / mL, about 80 to about 120 ug / mL, or about 90 to about 110 ug / mL. In some embodiments, CBD is provided at about 100 ug / mL. In some embodiments, at least or about 0.001% by weight, 0.005% by weight are provided. (Specification 12 / 50 pages, 14 CN 121570573 A)The CBD is provided in the range of about 0.25 wt%, 0.01 wt%, 0.02 wt%, 0.05 wt%, 0.10 wt%, 0.20 wt%, 0.25 wt%, 0.50 wt%, 0.75 wt%, 1.0 wt%, 1.5 wt%, 2.0 wt%, 2.5 wt%, 3.0 wt%, 3.5 wt%, 4.0 wt%, or greater than 4 wt%. In some embodiments, the CBD is provided in the range of about 0.25 wt% to about 10 wt%, about 0.1 wt% to about 2.5 wt%, about 0.5 wt% to about 8 wt%, about 0.75 wt% to about 6 wt%, or about 1 wt% to about 4 wt%. In some embodiments, the CBD is provided in the range of about 0.001 wt% to about 6 wt%, about 0.002 wt% to about 4 wt%, about 0.01 wt% to about 3 wt%, or about 0.02 wt% to about 2 wt%. In some embodiments, CBD is provided at least or about 10, 50, 100, 200, 500, 1000, 2000, 2500, 5000, 7500, 10000, 15000, 20000, 25000, 30000, 35000, 40000, or more than 40000 ppm. In some embodiments, CBD is provided in the range of about 2500 ppm to about 100000 ppm, about 1000 ppm to about 25000 ppm, about 5000 ppm to about 80000 ppm, about 75000 ppm to about 60000 ppm, or about 1000 ppm to about 40000 ppm. In some embodiments, CBD 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.

[0067] Ashwagandha Extract

[0068] While other depigmenting agents typically inhibit tyrosinase, Ashwagandha extract (10 ug / mL) leads to downregulation of the melanocyte master transcription factor MITF by disrupting the amplification of the intracellular signaling cascade triggered by ET-1, which is mainly composed of the PKC and MAPK pathways. The reduction in MITF function can inhibit the expression and function of its downstream targets, thereby leading to reduced melanin synthesis. Ashwagandha extract can be used as a treatment tool for ET-1-related hyperpigmentation disorders such as UVB-melanosis and senile lentigines.

[0069] The compositions described herein include Ashwagandha extract in some embodiments. In some embodiments, Ashwagandha extract is present at a concentration of at least about 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, per milliliter.The extract is provided at concentrations of 19, 20, 25, 30, 35, 40, or greater than 40 micrograms (ug / mL). In some embodiments, the Ashwagandha extract is provided in the range of about 0.5 to about 20, about 1 to about 19, about 2 to about 18, about 3 to about 17, about 4 to about 16, about 5 to about 15, about 6 to about 14, about 7 to about 13, about 8 to about 12, or about 9 to about 11 ug / mL. In some embodiments, the Ashwagandha extract is provided at least about 10 ug / mL. In some embodiments, the Ashwagandha extract is provided at least about 20 ug / mL. In some embodiments, at least or about 0.001 wt%, 0.005 wt%, 0.01 wt%, 0.02 wt%, 0.05 wt%, 0.10 wt%, 0.20 wt%, 0.25 wt%, 0.50 wt%, 0.75 wt%, 1.0 wt%, 1.5 wt%, 2.0 wt%, 2.5 wt%, 3.0 wt%, 3.5 wt%, 4.0 wt%, or greater than 4 wt. % of Ashwagandha extract is provided. In some embodiments, Ashwagandha extract is provided in the range of about 0.005 wt% to about 0.1 wt%, about 0.25 wt% to about 10 wt%, about 0.5 wt% to about 8 wt%, about 0.75 wt% to about 6 wt%, or about 1 wt% to about 4 wt. % of Ashwagandha extract. In some embodiments, Ashwagandha extract is provided in the range of about 0.001 wt% to about 6 wt%, about 0.002 wt% to about 4 wt%, about 0.01 wt% to about 2.5 wt%, about 0.02 wt% to about 2 wt%, and about 0.02 wt% to about 0.5 wt%. In some embodiments, Ashwagandha extract is provided in the range of about or no more than about 0.025 wt%. In some embodiments, Ashwagandha extract is provided in the range of about or no more than about 0.05 wt%. In some embodiments, Ashwagandha extract is provided in the range of about or no more than about 0.10 wt%.

[0070] In some embodiments, at least or about 0.5, 0.75, 1.0, 1.2, 1.4, 1.6, 1.8, 2, 4, 6, 8, or greater than 10 micrograms (ug) of Ashwagandha extract is provided. In some embodiments, Ashwagandha extract is provided in the range of about 0.5 to about 2, about 0.75 to about 5, or about 1.0 to about 4 micrograms (ug).

[0071] Gallic acid

[0072] Gallic acid (GA) is a dietary phenolic compound found in plants and fruits. It can provide beneficial effects against hyperpigmentation through its antioxidant properties. Gallic acid can inhibit melanin production in melanoma cells. (Instructions for use, page 13 / 50, 15 CN 121570573 A)Phenolic compounds. Gallic acid can downregulate melanin production regulatory genes including TYR, TRP-1, and Dct expression at both the transcriptional and translational levels. In some cases, GA effectively inhibits MITF expression by downregulating cAMP-mediated PKA / CREB signaling cascade amplification. UV-B-induced hyperpigmentation in mouse skin was significantly reduced by topical application of GA for 4 weeks.

[0073] The compositions described herein include gallic acid in some embodiments. In some cases, GA is present at about 50 ppm or less up to 1000, 5000, 10000, 50000, 100000, 500000 ppm or more, for example, 100 ppm of GA. In some cases, GA is present in concentrations of about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 50, 75, 100, 200, 300, 400, 500, 600, 700, 800, 900, 1000, or greater than 1000 ppm. In some cases, GA is present in concentrations ranging from about 1 to about 100, about 1 to about 50, about 1 to about 40, about 1 to about 30, about 1 to about 20, about 1 to about 10, about 5 to about 90, about 10 to about 80, about 20 to about 60, or about 30 to about 50 ppm. In some cases, GA is present at concentrations 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 (ug / mL). In other cases, GA is present at concentrations ranging from about 1 to about 100, about 1 to about 50, about 1 to about 40, about 1 to about 30, about 1 to about 20, about 1 to about 10, about 5 to about 90, about 10 to about 80, about 20 to about 60, or about 30 to about 50 ug / mL. In some cases, GA is present in amounts from about 0.01 wt% to about 10 wt%, from about 0.01 wt% to about 0.02 wt%, from about 0.01 wt% to about 0.03 wt%, from about 0.01 wt% to about 0.04 wt%, from about 0.01 wt% to about 0.05 wt%, from about 0.01 wt% to about 0.1 wt%, from about 1 wt% to about 5 wt%, or from about 1 wt% to 10 wt% (wt.%). In some cases, GA is present at about or no more than about 2.0 wt.%.

[0074] Sesamol

[0075] Sesamol is an active lignin isolated from sesame. In melan-a cells, sesamol can inhibit melanin biosynthesis and intracellular tyrosinase activity by reducing the accumulation of cyclic adenosine monophosphate (cAMP). Sesamol can reduce the expression of melanin-related genes such as TYR, TRP-1, TRP-2, MITF, and MC1R. Sesamol can inhibit melanin biosynthesis.

[0076] The compositions described herein include sesamol in some embodiments. In some embodiments, sesamol is provided at a concentration of at least about 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, or greater than 100 µM. In some embodiments, sesamol is provided in concentration ranges of about 5 to about 100 µM, about 10 to about 90 µM, about 20 to about 80 µM, about 30 to about 70 µM, and 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 up to 1000, 5000, 10000, 50000, 100000, 500000 ppm or more, for example, 100 ppm of sesamol. In some cases, sesamol is present in concentrations of about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 50, 75, 100, 200, 300, 400, 500, 600, 700, 800, 900, 1000, or greater than 1000 ppm. In other cases, sesamol is present in concentrations ranging from 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 concentrations 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 (ug / mL) per milliliter. In some cases, sesamol is present in concentrations ranging from 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 in at least or about 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 greater than 0.5 wt%. In some cases, sesamol is present in about 0.002 wt% to about 0.05 wt%, about 0.001 wt% to about 0.5 wt%, about 0.002 wt% to about 0.4 wt%, about 0.003 wt% to about 0.3 wt%, about 0.004 wt% to about 0.2 wt%, or about 0.005 wt%. (See specification 14 / 50 pages 16 CN 121570573 A)It is present in about 0.05 wt.% by weight. In some cases, sesamol is present in at least or about 0.01 wt.%.

[0077] In some embodiments, sesamol is provided in at least or about 0.25, 0.5, 0.75, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 20, 30, 40, 50 or greater than 50 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 mg. In some embodiments, sesamol is provided in about 3 mg. In some embodiments, sesamol is provided in about 9 mg.

[0078] Ergosterol

[0079] Ergosterol is a phenylpropanoid glycoside extracted from Rehmannia glutinosa leaves. Ergosterol can inhibit tyrosinase activity and melanin synthesis in both cell-free assay systems and cultured B16F10 melanoma cells. Ergosterol can reduce TYR, TRP-1, and MITF protein levels and increase ERK phosphorylation. In some cases, ergosterol inhibits α-MSH-induced melanin production and exhibits UV absorption effects.

[0080] The compositions described herein include ergosterol in some embodiments. In some embodiments, ergosterol is provided at concentrations of at least about 50, 100, 200, 300, 400, 500, 600, 700, 800, 900, 1000, or greater than 1000 µM. In some embodiments, ergosterol is provided at concentrations ranging from about 50 to about 1000 µM, about 100 to about 900 µM, about 200 to about 800 µM, about 300 to about 700 µM, and about 400 to about 600 µM. In some embodiments, ergosterol is provided at a concentration of about 500 µM. In some cases, ergosterol is present at concentrations of about 50 ppm or less up to 1000, 5000, 10000, 50000, 100000, 500000 ppm or more, for example, 100 ppm. In some cases, ergosterol is present at concentrations of about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 50, 75, 100, 200, 300, 400, 500, 600, 700, 800, 900, 1000, or greater than 1000 ppm. In some cases, ergosterol is present at concentrations ranging from 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, ergosterol is present at concentrations of approximately 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 50, 75 mg / mL.It is present in concentrations of 100, 200, 300, 400, 500, 600, 700, 800, 900, 1000, or greater than 1000 micrograms (ug / mL). In some cases, ergosterol 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, ergosterol is present in amounts of about 0.01 wt% to about 10 wt%, about 0.01 wt% to about 0.02 wt%, about 0.01 wt% to about 0.03 wt%, about 0.01 wt% to about 0.04 wt%, about 0.01 wt% to about 0.05 wt%, about 0.01 wt% to about 0.1 wt%, about 1 wt% to about 5 wt%, or about 1 wt% to 10 wt% (wt.%).

[0081] Oleuropein

[0082] Oleuropein is a potent anti-inflammatory and antioxidant derived from olive trees, exhibiting 90% tyrosinase inhibitory activity, and the inhibition type is non-competitive.

[0083] The compositions described herein include oleuropein in some embodiments. In some cases, oleuropein is present at concentrations of about 50 ppm or less up to 1000, 5000, 10000, 50000, 100000, 500000 ppm or more, for example, 100 ppm. In some cases, oleuropein is present at concentrations of about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 50, 75, 100, 200, 300, 400, 500, 600, 700, 800, 900, 1000, or greater than 1000 ppm. In some cases, oleuropein is present at concentrations ranging from 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 concentrations 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, 1200, 1400, 1600, 1800, 2000, or greater than 2000 micrograms (ug / mL). In other cases, oleuropein is present at concentrations 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 1200 ug / mL. In some cases, the oleuropein instruction manual is on page 15 / 50, page 17, CN 121570573 A.The amount present is from about 0.01 wt.% to about 10 wt.%, from about 0.01 wt.% to about 0.02 wt.%, from about 0.01 wt.% to about 0.03 wt.%, from about 0.01 wt.% to about 0.04 wt.%, from about 0.01 wt.% to about 0.05 wt.%, from about 0.01 wt.% to about 0.1 wt.%, from about 0.03 wt.% to about 0.750 wt.%, from about 0.1 wt.% to about 5 wt.%, or from about 0.1 wt.% to about 10 wt.%. In some cases, oleuropein is present at about or not more than about 0.15 wt.%.

[0084] In some embodiments, at least or about 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 mg of oleuropein is provided. 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 mg of oleuropein. In some embodiments, oleuropein is provided in about 30 mg of oleuropein. In some embodiments, oleuropein is provided in about 90 mg of oleuropein.

[0085] Hesperidin

[0086] Hesperidin is one of the citrus flavonoids active against various oxidative stress-mediated diseases. Hesperidin can inhibit melanosome transport in melanocytes and has shown a skin-brightening effect in a pigment-reconstructed epidermal model. Rab27A, melanavitin, and myosin Va form a complex to link melanosomes to phosphatidylserine, thereby docking melanosomes to the plasma membrane. In co-culture and in vivo, dark melanocytes with significantly higher RAB27A expression can transfer more melanosomes to keratinocytes compared to light-colored melanocytes. Hesperidin has a depigmenting effect by blocking the Rab27A-melavitin interaction.

[0087] The compositions provided herein include hesperidin in some embodiments. In some cases, hesperidin is present at about 50 ppm or less up to 1000, 5000, 10000, 50000, 100000, 500000 ppm or more, for example, 100 ppm of hesperidin. In some cases, hesperidin is present at concentrations of approximately 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, hesperidin is present at concentrations of approximately 1 to...It is present in the range of 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 in the range 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 (ug / mL) per milliliter. In some cases, hesperidin is present in the range of about 1 to about 100, about 1 to about 50, about 1 to about 40, about 1 to about 30, about 1 to about 20, about 1 to about 10, about 5 to about 90, about 10 to about 80, about 20 to about 60, or about 30 to about 50 ug / mL. In some cases, hesperidin is present in amounts of about 0.01 wt.% to about 10 wt.%, about 0.01 wt.% to about 0.02 wt.%, about 0.01 wt.% to about 0.03 wt.%, about 0.01 wt.% to about 0.04 wt.%, about 0.01 wt.% to about 0.05 wt.%, about 0.01 wt.% to about 0.1 wt.%, about 0.020 to about 0.50 wt.%, about 1 wt.% to about 5 wt.%, or about 1 wt.% to about 10 wt.%. In some cases, hesperidin is present in amounts of about or not more than about 0.10 wt.%.

[0088] Sideroxylon Inerme L. Stem Bark

[0089] The compositions described herein include Sideroxylon Inerme L. Stem Bark extract in some embodiments. In some cases, the white sheath extract is present at concentrations of about 50 ppm or less up to 1000, 5000, 10000, 50000, 100000, 500000 ppm or more, for example, 100 ppm. In some cases, the white sheath extract is present at concentrations of about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 50, 75, 100, 200, 300, 400, 500, 600, 700, 800, 900, 1000, or greater than 1000 ppm. In some cases, the white sheath extract is present at concentrations ranging from 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, white milkweed extract is administered at doses of approximately 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 50, 75, 100, 200, 300 mg / mL.It is present in concentrations of 400, 500, 600, 700, 800, 900, 1000 or greater than 1000 micrograms (ug / mL). In some cases, the white milkweed extract is present in the range of about 1 to about 100, about 1 to about 50, about 1 to about 40, about 1 to about 30, about 1 to about 20, about 1 to about 10, about 5 to about 90, about 10 to about 80, about 20 to about 60 or about 30 to about 50 ug / mL. In some cases, the amount of white milkweed extract is from about 0.01% to about 10% by weight, about 0.01% to about 0.02% by weight, about 0.01% to about 0.03% by weight, about 0.01% to about 0.04% by weight, about 0.01% to about 0.05% by weight, about 0.01% to about 0.1% by weight, about 1% to about 5% by weight, or about 1% to 10% by weight (wt.%).

[0090] Parthenolide

[0091] Parthenolide is a sesquiterpene lactone compound and an active substance in the herb parthenolide (wild chamomile), which can be used for inflammation. Parthenolide is an NF-κB inhibitor that can block UVB-mediated skin changes by inhibiting NF-κB-mediated gene expression, thereby reducing the production of bFGF and MMP-1 from cells. In some cases, bFGF production is UV-induced and promotes the proliferation of keratinocytes and melanocytes in the skin.

[0092] The compositions described herein include, in some embodiments, parthenolide. In some embodiments, parthenolide is provided in amounts of at least or about 0.001 wt%, 0.005 wt%, 0.01 wt%, 0.02 wt%, 0.05 wt%, 0.10 wt%, 0.20 wt%, 0.25 wt%, 0.50 wt%, 0.75 wt%, 1.0 wt%, 1.5 wt%, 2.0 wt%, 2.5 wt%, 3.0 wt%, 3.5 wt%, 4.0 wt%, or greater than 4 wt%. In some embodiments, parthenolide is provided in the range of about 0.25 wt% to about 10 wt%, about 0.1 wt% to about 2.5 wt%, about 0.5 wt% to about 8 wt%, about 0.75 wt% to about 6 wt%, or about 1 wt% to about 4 wt%. In some embodiments, parthenolide is provided in the range of about 0.001 wt% to about 6 wt%, about 0.002 wt% to about 4 wt%, about 0.01 wt% to about 3 wt%, or about 0.02 wt% to about 2 wt%. In some embodiments, parthenolide is provided in a concentration of at least or about 10, 50, 100, 200, 500, 1000, 2000, 2500, 5000, or greater than 5000 ppm. In some embodiments, parthenolide is provided in a concentration of about 25 ppm.The concentrations are provided in the range of 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 the 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.

[0093] Sea lily

[0094] In some cases, melanin released from melanocytes to keratinocytes is stimulated by neuropeptides released from nerve fibers present in the epidermis containing substance P. Sea lily extract (PME; sea lily extract) can at least partially inhibit melanin transfer by its action on substance P receptors present on melanocyte dendrites, thereby providing an effective and original solution for treating pigmentation spots.

[0095] The compositions described herein include sea lily extract in some embodiments. In some cases, crinoid extract is present at concentrations of about 50 ppm or less up to 1000, 5000, 10000, 50000, 100000, 500000 ppm or more, for example, 100 ppm. In some cases, crinoid extract is present at concentrations of about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 50, 75, 100, 200, 300, 400, 500, 600, 700, 800, 900, 1000, or greater than 1000 ppm. In some cases, crinoid extract is present at concentrations ranging from 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, crinoid extract is present at concentrations 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 (ug / mL). In other cases, crinoid extract is present at concentrations ranging from about 1 to about 100, about 1 to about 50, about 1 to about 40, about 1 to about 30, about 1 to about 20, about 1 to about 10, about 5 to about 90, about 10 to about 80, about 20 to about 60, or about 30 to about 50 ug / mL. In some cases, the crinoid extract is present in amounts from about 0.01 wt.% to about 10 wt.%, from about 0.01 wt.% to about 0.02 wt.%, from about 0.01 wt.% to about 0.03 wt.%, from about 0.01 wt.% to about 0.04 wt.%, and from about 0.01 wt.%.% to about 0.05 wt.%, about 0.01 wt.%, about 0.1 wt.%, about 0.5 wt.% to about 5 wt.%, about 1 wt.% to about 5 wt.%, or about 1 wt.% to about 10 wt.%. In some cases, the sea lily extract is present at at least or about 1.5 wt.%.

[0096] Autophagy

[0097] In some cases, the compositions described herein include an autophagy for degrading melanosomes. In some cases, the autophagy is present at about 50 ppm or less up to 1000, 5000, 10000, 50000, 100000, 500000 ppm or more, for example, 100 ppm of autophagy. In some cases, the autophagocytic agent is present in concentrations of about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 50, 75, 100, 200, 300, 400, 500, 600, 700, 800, 900, 1000, or greater than 1000 ppm. In other cases, the autophagocytic agent is present in concentrations ranging from 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, autophagy is present at concentrations 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 (ug / mL) per milliliter. In other cases, autophagy is present at concentrations ranging from about 1 to about 100, about 1 to about 50, about 1 to about 40, about 1 to about 30, about 1 to about 20, about 1 to about 10, about 5 to about 90, about 10 to about 80, about 20 to about 60, or about 30 to about 50 micrograms per milliliter. In some cases, the autophagy agent is present in amounts from about 0.01 wt% to about 10 wt%, from about 0.01 wt% to about 0.02 wt%, from about 0.01 wt% to about 0.03 wt%, from about 0.01 wt% to about 0.04 wt%, from about 0.01 wt% to about 0.05 wt%, from about 0.01 wt% to about 0.1 wt%, from about 1 wt% to about 5 wt%, or from about 1 wt% to 10 wt% (wt.%). In some cases, the autophagy agent is Melatrepein™.

[0098] Nicotinamide

[0099] Once synthesized, melanin is packaged in melanosomes and transferred from melanocytes to their adjacent basal keratinocytes via melanocyte dendrites. To inhibit this transfer, nicotinamide can reduce dendrite formation.

[0100] The compositions described herein include nicotinamide in some embodiments. In some embodiments, nicotinamide is provided in amounts of at least about 0.25 wt%, 0.5 wt%, 1 wt%, 1.5 wt%, 2 wt%, 2.5 wt%, 3 wt%, 3.5 wt%, 4 wt%, 4.5 wt%, 5 wt%, 5.5 wt%, 6 wt%, 6.5 wt%, 7 wt%, 7.5 wt%, 8 wt%, 8.5 wt%, 9 wt%, 9.5 wt%, 10 wt%, or greater than 10 wt%. In some embodiments, nicotinamide is provided in the range of about 0.25 wt.% to about 10 wt.%, about 0.5 wt.% to about 9.5 wt.%, about 1 wt.% to about 9 wt.%, about 1.5 wt.% to about 8.5 wt.%. In some embodiments, at least or about 2.0 wt.% of nicotinamide is provided.

[0101] Tremella fuciformis

[0102] Tremella fuciformis can inhibit melanin production. The compositions described herein include, in some embodiments, a Tremella fuciformis extract. In some embodiments, the Tremella fuciformis extract is derived from edible fungi. In some embodiments, the Tremella fuciformis extract provides moisture and antioxidant properties.

[0103] In some embodiments, the Tremella fuciformis extract is provided in amounts of at least or about 0.001 wt.%, 0.005 wt.%, 0.01 wt.%, 0.02 wt.%, 0.05 wt.%, 0.10 wt.%, 0.20 wt.%, 0.25 wt.%, 0.50 wt.%, 0.75 wt.%, 1.0 wt.%, 1.5 wt.%, 2.0 wt.%, 2.5 wt.%, 3.0 wt.%, 3.5 wt.%, 4.0 wt.%, or greater than 4 wt.%. In some embodiments, the Tremella fuciformis extract is provided in the range of about 0.25 wt.% to about 10 wt.%, about 0.1 wt.% to about 2.5 wt.%, about 0.5 wt.% to about 8 wt.%, about 0.75 wt.% to about 6 wt.%, or about 1 wt.% to about 4 wt.%. In some embodiments, the Tremella fuciformis extract is provided in the range of about 0.001 wt.% to about 6 wt.%, about 0.002 wt.% to about 4 wt.%, about 0.01 wt.% to about 3 wt.%, about 0.02 wt.% to about 2 wt.%, or about 0.20 wt.% to about 5.0 wt.%. In some embodiments, at least or about 1.0 wt.% of the Tremella fuciformis extract is provided.

[0104] Thermostats extract

[0105] Thermostats enzymes can act as antioxidants, particularly against PGE2. The compositions described herein are available in the specification.Page 18 / 50 20 CN 121570573 A Some embodiments include thermophilic thermocide enzymes. In some cases, the thermophilic thermocide extract is present at about 50 ppm or less up to 1000, 5000, 10000, 50000, 100000, 500000 ppm or more, for example, 100 ppm. In some cases, the thermophilic thermocide 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 ppm. In some cases, the thermophilic bacteria extract is present in the range of about 1 to about 100, about 1 to about 50, about 1 to about 40, about 1 to about 30, about 1 to about 20, about 1 to about 10, about 5 to about 90, about 10 to about 80, about 20 to about 60, or about 30 to about 50 ppm. In some cases, the thermophilic bacteria extract is present in the range 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 (ug / mL) per milliliter. In some cases, the extract of Thermophilus thermophilus is present in the range of about 1 to about 100, about 1 to about 50, about 1 to about 40, about 1 to about 30, about 1 to about 20, about 1 to about 10, about 5 to about 90, about 10 to about 80, about 20 to about 60, or about 30 to about 50 ug / mL. In some cases, the amount of *Thermophilus thermophilus* extract is from about 0.01 wt.% to about 10 wt.%, from about 0.01 wt.% to about 0.02 wt.%, from about 0.01 wt.% to about 0.03 wt.%, from about 0.01 wt.% to about 0.04 wt.%, from about 0.01 wt.% to about 0.05 wt.%, from about 0.01 wt.% to about 0.1 wt.%, from about 0.3 wt.% to about 7.5 wt.%, from about 1 wt.% to about 5 wt.%, or from about 1 wt.% to about 10 wt.%. In some cases, the *Thermophilus thermophilus* extract is present at at least or at least about 1.5 wt.%.

[0106] Hydroxyl lycopene and hexahydrolycopene

[0107] The compositions described herein include, in some embodiments, hydroxyl lycopene, hexahydrolycopene, or a combination thereof. Hydroxyl lycopene and hexahydrolycopene are colorless carotenoids derived from saline microalgae that regulate prostaglandin E-2 (PGE-2).

[0108] In some embodiments, hydroxyl lycopene, hexahydrolycopene, or a combination thereof are present in an amount of at least or about 0.5% by weight.The lycopene is provided in the range of 1.0 wt%, 2.0 wt%, 3.0 wt%, 4.0 wt%, 5.0 wt%, 6.0 wt%, 7.0 wt%, 8.0 wt%, 9.0 wt%, 10 wt%, 11 wt%, 12 wt%, 13 wt%, 14 wt%, 15 wt%, 16 wt%, 17 wt%, 18 wt%, 19 wt%, 20 wt%, or greater than 20 wt%. In some embodiments, phytoene, lycopene, or combinations thereof are provided in the range of about 0.5 wt% to about 20 wt%, about 1.0 wt% to about 15 wt%, about 2.0 wt% to about 12 wt%, about 3.0 wt% to about 10 wt%, or about 4.0 wt% to about 8 wt%. In some cases, phytoene, lycopene, or combinations thereof are provided in the range of at least or about 5.0 wt%. In some cases, phytoene, hexahydrolycopene, or combinations thereof are present at concentrations 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 (ug / mL). In some cases, phytoene, hexahydrolycopene, or combinations thereof are present at concentrations ranging from 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.

[0109] Peppermint

[0110] Peppermint (mint bark) can lower ET-1 levels. The compositions described herein include, in some embodiments, *Eriocaulon buergerianum* extract. In some cases, *Eriocaulon buergerianum* extract is present at about 50 ppm or less up to 1000, 5000, 10000, 50000, 100000, 500000 ppm or more, for example, 100 ppm. In some cases, *Eriocaulon buergerianum* 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 ppm. In some cases, *Eriocaulon buergerianum* extract is present in the range of about 1 to about 100, about 1 to about 50, about 1 to about 40, about 1 to about 30, about 1 to about 20, about 1 to about 10, about 5 to about 90, about 10 to about 80, about 20 to about 60, or about 30 to about 50 ppm. In some cases, *Eriocaulon buergerianum* extract is present in the range of about 1 ppm per milliliter.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 the instructions on page 19 / 50, 21 CN 121570573 A, greater than 1000 micrograms (ug / mL). In some cases, *Eriocaulon buergerianum* extract is present in the range of about 1 to about 100, about 1 to about 50, about 1 to about 40, about 1 to about 30, about 1 to about 20, about 1 to about 10, about 5 to about 90, about 10 to about 80, about 20 to about 60 or about 30 to about 50 ug / mL. In some cases, the amount of *Polypodium aureum* extract is from about 0.01 wt% to about 10 wt%, from about 0.01 wt% to about 0.02 wt%, from about 0.01 wt% to about 0.03 wt%, from about 0.01 wt% to about 0.04 wt%, from about 0.01 wt% to about 0.05 wt%, from about 0.01 wt% to about 0.1 wt%, from about 1 wt% to about 5 wt%, or from about 1 wt% to 10 wt% (wt. %).

[0111] *Polypodium leucotomos*

[0112] *Polypodium leucotomos* or *Phlebodium aureum* includes compounds that can combat inflammation and prevent skin damage. The compositions described herein include *Polypodium leucotomos* extract in some embodiments. In some cases, *Polyporus hygrophila* extract is present at concentrations of about 50 ppm or less up to 1000, 5000, 10000, 50000, 100000, 500000 ppm or more, for example, 100 ppm. In other cases, *Polyporus hygrophila* extract is present at concentrations of about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 50, 75, 100, 200, 300, 400, 500, 600, 700, 800, 900, 1000 or greater than 1000 ppm. In some cases, *Polyporus hyacinthus* extract is present in the range of about 1 to about 100, about 1 to about 50, about 1 to about 40, about 1 to about 30, about 1 to about 20, about 1 to about 10, about 5 to about 90, about 10 to about 80, about 20 to about 60, or about 30 to about 50 ppm. In some cases, *Polyporus hyacinthus* extract is present in the range 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 (ug / mL) per milliliter. In some cases, *Polyporus hyacinthus* extract is present in the range of about 1 to about 100, about 1 to about 50, about 1 to about 40, about 1 to about 30, about 1 to about 50, or about 1 to about 60.The range is 20, about 1 to about 10, about 5 to about 90, about 10 to about 80, about 20 to about 60, or about 30 to about 50 ug / mL. In some cases, the amount of the extract of *Polygonum aviculare* is about 0.01 wt% to about 10 wt%, about 0.01 wt% to about 0.02 wt%, about 0.01 wt% to about 0.03 wt%, about 0.01 wt% to about 0.04 wt%, about 0.01 wt% to about 0.05 wt%, about 0.01 wt% to about 0.1 wt%, about 1 wt% to about 5 wt%, or about 1 wt% to 10 wt% (wt. %).

[0113] Phosphatidylserine

[0114] The compositions described herein include phosphatidylserine in some embodiments. In some embodiments, phosphatidylserine is provided at a concentration of at least about or no more than about 0.01 wt%, 0.02 wt%, 0.03 wt%, 0.04 wt%, 0.05 wt%, 0.06 wt%, 0.07 wt%, 0.08 wt%, 0.09 wt%, 0.10 wt%, 0.11 wt%, 0.12 wt%, 0.13 wt%, 0.14 wt%, 0.15 wt%, 0.16 wt%, 0.17 wt%, 0.18 wt%, 0.19 wt%, 0.20 wt%, or greater than 0.20% (wt.%). In some embodiments, phosphatidylserine is provided at a concentration of about 0.01 wt% to about 0.2 wt%, about 0.02 wt% to about 0.15 wt%, about 0.03 wt% to about 0.1 wt%, about 0.04 wt% to about 0.1 wt% (wt.%). In some embodiments, phosphatidylserine is present at about or no more than about 0.075% by weight (wt.%). In some embodiments, phosphatidylserine is provided at a concentration of about or no more than about 0.05% by weight (wt.%). In some embodiments, phosphatidylserine is provided at a concentration of at least about 100, 200, 300, 400, 500, 600, 700, 800, 900, 1000, 1100, 1200, 1300, 1400, 1500, 1600, 1700, 1800, 1900, 2000, or greater than 2000 ppm. In some embodiments, phosphatidylserine is provided at concentrations 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, phosphatidylserine is provided at a concentration of about 1000 ppm. In some embodiments, phosphatidylserine is provided at a concentration of at least about [missing information - likely a concentration of a specific concentration] per milliliter.Concentrations of 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 (ug / mL) are available. In some embodiments, phosphatidylserine is provided at concentrations of about 100 to about 1900 ug / mL, about 200 to about 1800 ug / mL, about 300 to about 1700 ug / mL, about 400 to about 1600 ug / mL, about 500 to about 1500 ug / mL, about 600 to about 1400 ug / mL, about 700 to about 1300 ug / mL, about 800 to about 1200 ug / mL, or about 900 to about 1100 ug / mL. In some embodiments, phosphatidylserine is provided at a concentration of about 500 to about 1000 ug / mL.

[0115] In some embodiments, at least or about 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 mg of phosphatidylserine is provided. In some embodiments, phosphatidylserine is provided in the range of about 20 to about 500, about 30 to about 400, about 40 to about 300, about 50 to about 200, about 60 to about 100, about 70 to about 95, or about 80 to about 90 mg of phosphatidylserine. In some embodiments, phosphatidylserine is provided in the range of about 15 mg of phosphatidylserine. In some embodiments, phosphatidylserine is provided in the range of about 20 mg of phosphatidylserine. In some embodiments, lactoferrin is provided in the range of about 45 mg of phosphatidylserine.

[0116] Heptasodium hexacarboxymethyl dipeptide-12 (HHD12)

[0117] HHD12 can stimulate autophagy in keratinocytes. Melanosomes are normally transferred to neighboring keratinocytes and then naturally degraded through autophagy. However, when the skin is constantly exposed to sunlight, pathogens, and hormonal changes, the autophagy process is disrupted and melanosomes cannot be degraded. The accumulation of undegraded melanosomes in keratinocytes leads to skin pigmentation. HHD12 activates autophagy to break down melanosomes in keratinocytes and simultaneously inhibits melanosome uptake into keratinocytes.

[0118] In some embodiments, HHD12 is used in amounts of about or at least about 0.01 wt.%, 0.05 wt.%, 0.1 wt.%, 0.5 wt.%, 1 wt.%, 2 wt.%, 3 wt.%, 4 wt.%, 5 wt.%, 6 wt.%, 7 wt.%, 8 wt.%, and 9 wt.%.HHD12 is present in the range of about 0.01 wt.% to about 10 wt.%, about 0.05 wt.% to about 9 wt.%, about 0.1 wt.% to about 8 wt.%, about 0.5 wt.% to about 7 wt.%, or about 1 wt.% to about 6 wt.%. In some embodiments, HHD12 is present in the range of about 0.2 wt.% to about 5 wt%. In some embodiments, HHD12 is present in the range of about or not more than about 1.0 wt.%.

[0119] Liposomes

[0120] Liposome compositions for improving distribution, efficacy, bioavailability, and / or activity are described herein. 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, improved delivery and skin penetration are due to the active ingredient being incorporated (e.g., encapsulated) in liposomes. In some cases, the active ingredient is a peptide encapsulated in liposomes. In some cases, peptides encapsulated in liposomes allow for efficient interfollicular transdermal delivery.

[0121] Liposome compositions as described herein may include peptides encapsulated in liposomes. In some embodiments, the peptide is hexapeptide-12. In some embodiments, the peptide is hexapeptide-11. In some embodiments, the peptide is palmitoyl-functionalized. In some embodiments, the peptide is acetyl-functionalized. In some embodiments, the peptide encapsulated in liposomes is lactoferrin.

[0122] In some embodiments, the peptide encapsulated in liposomes is about or about 10, 25, 50, 100, 200, 300, 400, 500, 600, 700, 800, 900, 1000, 1500, 2000, 3000, 4000, 5000, or 5000 Da or more. In some embodiments, the peptides encapsulated in the liposomes are 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 peptides encapsulated in the liposomes are about 500 to about 800 Da.

[0123] 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 present 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.

[0124] In some embodiments, the liposomes are photobodies. In some embodiments, the photon includes DNA repair technology and / or makes the specification page 21 / 50 23 CN 121570573 AUV-induced dimers damaged by the DNA repair enzyme photolyase are repaired. In some cases, the compositions described herein include one or more photosomes. In some cases, the photosomes are present in amounts of at least or about 0.01 wt%, 0.1 wt%, 0.2 wt%, 0.3 wt%, 0.4 wt%, 0.5 wt%, 0.6 wt%, 0.7 wt%, 0.8 wt%, 0.9 wt%, 1 wt%, 2 wt%, 3 wt%, 4 wt%, or 5 wt%. In some cases, the photosomes are present in amounts ranging from about 0.01 wt% to about 5 wt%, from about 0.1 wt% to about 4 wt%, from about 0.2 wt% to about 3 wt%, or from about 0.3 wt% to about 2 wt%. In some cases, the photosomes are present in amounts ranging from about 0.1 wt.% to about 2 wt.%.

[0125] The compositions described herein include one or more photosomes and one or more liposomes in some embodiments. In some embodiments, each of the one or more liposomes encapsulates at least one peptide. In some embodiments, each of the one or more liposomes encapsulates a different peptide. In some embodiments, each liposome in one or more liposomes encapsulates different peptides including hexapeptide-11, hexapeptide-12, lactoferrin, lactoferrin-derived peptides, or combinations thereof. In some embodiments, one or more liposomes encapsulate one or more peptides, wherein the one or more peptides include hexapeptide-11, hexapeptide-12, lactoferrin, lactoferrin-derived peptides, or combinations thereof.

[0126] In some embodiments, a first liposome in one or more liposomes encapsulates at least one peptide. In some embodiments, a first liposome in one or more liposomes encapsulates a non-palmitoylated hexapeptide. In some embodiments, a first liposome in one or more liposomes encapsulates hexapeptide-11. In some embodiments, a first liposome in one or more liposomes encapsulates hexapeptide-12. In some embodiments, a first liposome in one or more liposomes encapsulates lactoferrin. In some embodiments, a first liposome in one or more liposomes encapsulates a peptide derived from lactoferrin. In some embodiments, a first liposome in one or more liposomes encapsulates a non-palmitoylated hexapeptide and lactoferrin. In some embodiments, a first liposome in one or more liposomes encapsulates hexapeptide-11 and hexapeptide-12. In some embodiments, a first liposome in one or more liposomes encapsulates hexapeptide-11 and lactoferrin. In some embodiments, a first liposome in one or more liposomes encapsulates hexapeptide-11 and a peptide derived from lactoferrin. In some embodiments, a first liposome in one or more liposomes encapsulates hexapeptide-12 and lactoferrin. In some embodiments, a first liposome in one or more liposomes encapsulates hexapeptide-12 and a peptide derived from lactoferrin. In some embodiments, a first liposome in one or more liposomes encapsulates...Hexapeptide-11, hexapeptide-12, and lactoferrin. In some embodiments, a first liposome in one or more liposomes encapsulates hexapeptide-11, hexapeptide-12, and a peptide derived from lactoferrin. In some embodiments, a first liposome in one or more liposomes encapsulates hexapeptide-11, lactoferrin, and a peptide derived from lactoferrin. In some embodiments, a first liposome in one or more liposomes encapsulates hexapeptide-12, lactoferrin, and a peptide derived from lactoferrin. In some embodiments, a first liposome in one or more liposomes encapsulates hexapeptide-11, hexapeptide-12, lactoferrin, and a peptide derived from lactoferrin.

[0127] In some embodiments, a first liposome in one or more liposomes encapsulates hexapeptide-11, and a second liposome in one or more liposomes encapsulates lactoferrin. In some embodiments, a first liposome in one or more liposomes encapsulates hexapeptide-11, and a second liposome in one or more liposomes encapsulates hexapeptide-12. In some embodiments, a first liposome in one or more liposomes encapsulates hexapeptide-11, and a second liposome in one or more liposomes encapsulates a peptide derived from lactoferrin. In some embodiments, a first liposome in one or more liposomes encapsulates hexapeptide-12 and a second liposome in one or more liposomes encapsulates lactoferrin. In some embodiments, a first liposome in one or more liposomes encapsulates hexapeptide-12 and a second liposome in one or more liposomes encapsulates peptides derived from lactoferrin. In some embodiments, a first liposome in one or more liposomes encapsulates lactoferrin and a second liposome in one or more liposomes encapsulates peptides derived from lactoferrin.

[0128] In some embodiments, a first liposome in one or more liposomes encapsulates hexapeptide-11, a second liposome in one or more liposomes encapsulates hexapeptide-12, and a third liposome in one or more liposomes encapsulates lactoferrin. Specification 22 / 50 pages 24 CN 121570573 A In some embodiments, a first liposome in one or more liposomes encapsulates hexapeptide-11, a second liposome in one or more liposomes encapsulates hexapeptide-12, and a third liposome in one or more liposomes encapsulates peptides derived from lactoferrin. In some embodiments, a first liposome in one or more liposomes encapsulates hexapeptide-11, a second liposome in one or more liposomes encapsulates lactoferrin, and a third liposome in one or more liposomes encapsulates a peptide derived from lactoferrin. ...

[0129] In some embodiments, a first liposome in one or more liposomes encapsulates hexapeptide-11, a second liposome in one or more liposomes encapsulates lactoferrin, and a third liposome in one or more liposomes encapsulates a peptide derived from lactoferrin.A second liposome in a plastid encapsulates hexapeptide-12, a third liposome in one or more liposomes encapsulates lactoferrin, and a fourth liposome in one or more liposomes encapsulates a peptide derived from lactoferrin.

[0130] The compositions described herein include, in some embodiments, one or more photosomes encapsulating one or more liposomes that encapsulate one or more peptides. In some embodiments, the photosome is encapsulated with liposomes encapsulating one peptide. In some embodiments, the photosome is encapsulated with liposomes encapsulating hexapeptide-11. In some embodiments, the photosome is encapsulated with liposomes encapsulating hexapeptide-12. In some embodiments, the photosome is encapsulated with liposomes encapsulating lactoferrin. In some embodiments, the photosome is encapsulated with liposomes encapsulating peptides derived from lactoferrin. In some embodiments, the photosome is encapsulated with liposomes encapsulating two or more peptides. In some embodiments, the photosome is encapsulated with liposomes encapsulating two or more peptides, wherein the two or more peptides include hexapeptide-11, hexapeptide-12, lactoferrin, peptides derived from lactoferrin, or combinations thereof. In some embodiments, a photobody encapsulates one or more liposomes, wherein each of the one or more liposomes encapsulates a different peptide. In some embodiments, a photobody encapsulates one or more liposomes, wherein each 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.

[0131] The compositions described herein include, in some embodiments, one or more photobody encapsulates one or more liposomes. In some embodiments, one or more photobody encapsulates one or more liposomes encapsulating one or more peptides. In some embodiments, one or more photobody encapsulates one or more liposomes, wherein each 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, one or more photobody encapsulates 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.

[0132] In some embodiments, one or more photobody encapsulates one or more liposomes, wherein a first liposome encapsulates hexapeptide-11. In some embodiments, one or more photobodies encapsulate one or more liposomes, wherein a first liposome in the one or more liposomes encapsulates hexapeptide-12. In some embodiments, one or more photobodies encapsulate one or more liposomes, wherein a first liposome in the one or more liposomes encapsulates lactoferrin. In some embodiments, one or more photobodies encapsulate one or more liposomes, wherein a first liposome in the one or more liposomes encapsulates a peptide derived from lactoferrin.

[0133] In some embodiments, one or more photomolecules encapsulate one or more liposomes, wherein a first liposome encapsulates hexapeptide-11 and a second liposome encapsulates lactoferrin. In some embodiments, one or more photomolecules encapsulate one or more liposomes, wherein a first liposome encapsulates hexapeptide-11 and a second liposome encapsulates hexapeptide-12. In some embodiments, one or more photomolecules encapsulate one or more liposomes, wherein a first liposome encapsulates hexapeptide-11 and a second liposome encapsulates a peptide derived from lactoferrin. In some embodiments, one or more photomolecules encapsulate one or more liposomes, wherein a first liposome encapsulates hexapeptide-12 and a second liposome encapsulates lactoferrin. In some embodiments, one or more photomolecules encapsulate one or more liposomes, wherein a first liposome encapsulates hexapeptide-12 and a second liposome encapsulates a peptide derived from lactoferrin. In some embodiments, one or more photosomes encapsulate one or more liposomes, wherein a first liposome encapsulates lactoferrin, and a second liposome encapsulates a peptide derived from lactoferrin.

[0134] In some embodiments, one or more photosomes encapsulate one or more liposomes, wherein a first liposome encapsulates hexapeptide-11, a second liposome encapsulates hexapeptide-12, and a third liposome encapsulates lactoferrin. In some embodiments, one or more photosomes encapsulate one or more liposomes, wherein a first liposome encapsulates hexapeptide-11, a second liposome encapsulates hexapeptide-12, and a third liposome encapsulates a peptide derived from lactoferrin. In some embodiments, one or more photosomes encapsulate one or more liposomes, wherein a first liposome encapsulates hexapeptide-11, a second liposome encapsulates lactoferrin, and a third liposome encapsulates a peptide derived from lactoferrin. In some embodiments, one or more photosomes encapsulate one or more liposomes, wherein a first liposome encapsulates hexapeptide-12, a second liposome encapsulates lactoferrin, and a third liposome encapsulates a peptide derived from lactoferrin.

[0135] In some embodiments, one or more photosomes encapsulate one or more liposomes, wherein a first liposome encapsulates hexapeptide-11, a second liposome encapsulates hexapeptide-12, a third liposome encapsulates lactoferrin, and a fourth liposome encapsulates a peptide derived from lactoferrin.

[0136] In some embodiments, the average particle size of each liposome or photosome 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 liposome or photosome 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 each liposome or photosome is about 110 nm.

[0137] In some embodiments, the average particle size of each liposome in one or more liposomes or each photobody in one or more photobody 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 in one or more liposomes or each photobody in one or more photobody is in the range of about 10 to about 1000, about 20 to about 900, about 30 to about 800, about 40 to about 700, about 50 to about 600, about 60 to about 500, about 70 to about 400, or about 80 to about 300 nm. In some embodiments, the average particle size of each liposome in one or more liposomes or each photobody in one or more photobody is about or at least about 220 nm.

[0138] 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 a 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 a second step, a second liposome is added. In some embodiments, the second liposome is a photosome.

[0139] Lecithin and other phospholipids can be used to prepare liposomes containing peptide compositions as described herein. In someIn the embodiments, liposomes are used to prepare one or more peptides. In some embodiments, the peptides are functionalized with acetyl groups. When phospholipids such as lecithin are placed in water and thus form a bilayer or a series of bilayers, lipid vesicles are formed, and each bilayer is separated by water molecules once sufficient energy is provided. Liposomes can be produced by sonicating phospholipids in water. Low shear rates produce multilayer liposomes. Sustained high-shear sonication tends to form smaller monolayer liposomes. Hydrophobic chemicals can dissolve into the phospholipid bilayer membrane. The lipid bilayer of the liposomes delivers peptide compositions as described herein.

[0140] The phospholipids used to prepare the liposome compositions described herein may include a transition phase temperature of about 10°C to about 25°C. In some cases, the phospholipids include transition phase temperatures 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 above 40°C. In some cases, phospholipids include transition phase temperatures 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.

[0141] Local compositions 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 comprising a surfactant, wherein the surfactant concentration exceeds a critical micelle concentration. The resulting composition contains micelles, i.e., spherical oil droplets.

[0142] Liposome compositions 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 comprising a surfactant, wherein the surfactant concentration exceeds a critical micelle concentration. The resulting formulation contains micelles, i.e., spherical oil droplets surrounded by a film of polar surfactant molecules dispersed in an aqueous solvent.

[0143] In some embodiments, the present invention describes a method for preparing a composition comprising a peptide encapsulated in liposomes, the method comprising: combining the peptide and a solvent to form a mixture; and contacting the mixture with an aqueous solution comprising liposomes. In some cases, the contact occurs at a temperature between about 10°C and about 25°C. In some cases, the contact 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 above 40°C. In some cases, the contact occurs at a 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.

[0144] The method for preparing a composition comprising a peptide encapsulated in liposomes may include the use of a solvent. In some casesIn some cases, the solvent is water. In others, 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 ethylene glycol. In some cases, the solvent is butanediol. In some cases, the solvent is octyl glycol. In some cases, the solvent is propylene glycol (propylene glycol).

[0145] Solvents may be used in various percentages. In some cases, a solvent 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 greater than 10% is provided. The solvent may be propylene glycol, butanediol, or octyl glycol.

[0146] In some embodiments, the method as described herein includes combining the peptide and the solvent to form a mixture; and contacting the mixture with an aqueous solution comprising 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 ranging from 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 ranging from about 10% to about 80%, about 20% to about 70%, or about 30% to about 60%. The ratio of liposomes to water can be in the range of about 1:9 to about 3:7. In some cases, the ratio of liposomes to water can be at least or about 1:10, 1:9, 1:8, 1:7, 1:6, 1:5, 1:4, 1:3, or 1:2.

[0147] The method for producing the liposome composition as described herein can result in an encapsulation efficiency of no more than 100%. In some cases, the encapsulation efficiency does not exceed 50%, 60%, 70%, 80%, 90%, 95%, 99%, or 99.5%.

[0148] This document describes liposome compositions in which peptides comprise a certain percentage of the composition. In some embodiments, the peptides are at least or about 0.0001%, 0.0005%, 0.00055%, 0.001%, 0.005%, 0.01%, 0.02% of the composition.The peptide is provided in amounts of 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 in amounts of at least or about 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 22%, 24%, 26%, 28%, 30%, or more than 30% of the composition. In some embodiments, the peptide is provided in amounts ranging from about 0.001% by weight to about 6% by weight, about 0.002% by weight to about 4% by weight, about 0.01% by weight to about 5% by weight, or about 0.02% by weight to about 2% by weight. In some embodiments, the peptide is provided in amounts of about 0.03% of the composition.

[0149] This document describes liposome compositions, wherein the liposomes comprise a percentage of the composition. In some embodiments, the liposomes are provided at least or about 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 22%, 24%, 26%, 28%, 30%, or more than 30% of the composition. In some embodiments, the liposomes are provided in the range of about 5% to about 90%, about 10% to about 80%, about 20% to about 70%, about 30% to about 60%, about 10% to about 30%, or about 20% to about 40%.

[0150] In some embodiments, the liposome composition as described herein comprises an average particle size of up to 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 approximately 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.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 in the range of about 50 nm to about 500 nm, about 100 nm to about 400 nm, about 150 nm to about 220 nm, about 180 nm to about 220 nm, or about 190 nm to about 210 nm.

[0151] In some cases, the liposome composition includes an active agent with a molecular weight not exceeding about 600 Daltons (Da). In some cases, the molecular weight of the active agent is at least or about 50, 75, 100, 125, 150, 175, 200, 225, 250, 275, 300, 325, 350, 375, 400, 425, 450, 475, 500, 525, 550, 575, 600, 625, 650, 675, 700, 725, 750, 775, 800, 825, 850, 875, 900, 925, 950, 975, 1000 or greater than 1000 Daltons (Da). In some cases, the molecular weight of the active agent is at least or about 1000, 1100, 1200, 1300, 1400, 1500, 1600, 1700, 1800, 1900, 2000, 2100, 2200, 2300, 2400, 2500, 2600, 2700, 2800, 2900, 3000, 4000, 5000, 6000, or greater than 6000 Daltons (Da). In some cases, the molecular weight of the active agent is 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 liposomes. Specification 26 / 50 pages 28 CN 121570573 A

[0152] In some embodiments, the polydispersity index (PdI) of the liposome composition as described herein is in the range of 0 to about 0.2. In some cases, the polydispersity index is about 0.01, 0.025, 0.05, 0.1, 0.25, 0.3, 0.35, 0.4, 0.45, 0.5, 0.55, 0.6, 0.65, 0.7, 0.75 or 0.8. In some cases, the polydispersity index is in the range of about 0.01 to about 0.8, about 0.025 to about 0.75, about 0.05 to about 0.6 or about 0.1 to about 0.3.

[0153] In some cases, the intercept of the liposome composition as described herein is in the range of about 0.85 to about 0.95. In some cases, the intercept is an amplitude. In some cases, the intercept is at least or about 0.65, 0.70, 0.75, 0.80, 0.85, 0.90, or 0.95.

[0154] In some embodiments, the liposomes comprise propylene glycol, lecithin, or a combination thereof. In some embodiments, propylene glycol is provided in amounts of at least or about 0.001 wt%, 0.005 wt%, 0.01 wt%, 0.02 wt%, 0.05 wt%, 0.10 wt%, 0.20 wt%, 0.25 wt%, 0.50 wt%, 0.75 wt%, 1.0 wt%, 1.5 wt%, 2.0 wt%, 2.5 wt%, 3.0 wt%, 3.5 wt%, 4.0 wt%, 4.5 wt%, 5.0 wt%, 5.5 wt%, 6.0 wt%, 6.5 wt%, 7.0 wt%, 8 wt%, 9 wt%, 10 wt%, or greater than 10 wt%. In some embodiments, propylene glycol is provided in the range of about 0.001 wt% to about 6 wt%, about 0.002 wt% to about 4 wt%, about 0.01 wt% to about 3 wt%, or about 0.02 wt% to about 2 wt%. In some embodiments, lecithin is provided in amounts of at least or about 0.001 wt%, 0.005 wt%, 0.01 wt%, 0.02 wt%, 0.05 wt%, 0.10 wt%, 0.20 wt%, 0.25 wt%, 0.50 wt%, 0.75 wt%, 1.0 wt%, 1.5 wt%, 2.0 wt%, 2.5 wt%, 3.0 wt%, 3.5 wt%, 4.0 wt%, 4.5 wt%, 5.0 wt%, 5.5 wt%, 6.0 wt%, 6.5 wt%, 7.0 wt%, 8 wt%, 9 wt%, 10 wt%, or greater than 10 wt%. In some embodiments, lecithin is provided in the range of about 0.001 wt% to about 6 wt%, about 0.002 wt% to about 4 wt%, about 0.01 wt% to about 3 wt%, or about 0.02 wt% to about 2 wt%. In some embodiments, the liposomes comprise propylene glycol and lecithin. In some embodiments, at least or about 0.001 wt%, 0.005 wt%, 0.01 wt%, 0.02 wt%, 0.05 wt%, 0.10 wt%, 0.20 wt%, 0.25 wt%, 0.50 wt%, 0.75 wt%, 1.0 wt%, 1.5 wt%, 2.0 wt%, 2.5 wt%, 3.0 wt%, 3.5 wt%, 4.0 wt%, 4.5 wt%, 5.0 wt%, 5.5 wt%, 6.0 wt%, 6.5 wt%, 7.0 wt%, 8 wt%, 9 wt%, 10 wt%, or greater than 10 wt%.The propylene glycol and lecithin are provided in the range of about 0.001% by weight to about 6% by weight, about 0.002% by weight to about 4% by weight, about 0.01% by weight to about 3% by weight, or about 0.02% by weight to about 2% by weight. In some embodiments, the propylene glycol and lecithin are provided in the range of about 0.90% by weight.

[0155] The liposomal compositions described herein include improved distribution, efficacy, bioavailability, and / or activity. Compared to compositions without liposomes, the liposomal compositions may include improved distribution, efficacy, bioavailability, and / or activity. In some cases, the distribution is improved by at least or about 0.5X, 1.0X, 1.5X, 2.0X, 2.5X, 3.0X, 4.0X, 4.5X, 5X, or more than 5X compared to compositions without liposomes. In some cases, the efficacy is improved by at least or about 0.5X, 1.0X, 1.5X, 2.0X, 2.5X, 3.0X, 4.0X, 4.5X, 5X, or more than 5X compared to compositions without liposomes. In some cases, the bioavailability is improved by at least or about 0.5X, 1.0X, 1.5X, 2.0X, 2.5X, 3.0X, 4.0X, 4.5X, 5X, or more than 5X compared to compositions without liposomes. In some cases, the activity is improved by at least or about 0.5X, 1.0X, 1.5X, 2.0X, 2.5X, 3.0X, 4.0X, 4.5X, 5X, or more than 5X compared to compositions without liposomes. Compared to compositions that do not contain liposomes, the distribution, efficacy, bioavailability, and / or activity are improved by at least or about 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or greater than 90%.

[0156] The liposome compositions and methods described herein are, in some embodiments, topical compositions. In some cases, the liposome compositions are oil-free. In some cases, the liposome compositions are preservative-free. In some examples of embodiments (pages 27 / 50, CN 121570573 A), the liposome formulation is an aqueous formulation. In some embodiments, the liposome formulation is an anhydrous formulation. In some cases, the liposome composition comprises a pH in the range of about 5 to about 8. In some cases, the liposome composition comprises a pH of at least or about 2, 3, 4, 5, 6, 7, 8, 9, or 10.

[0157] The methods and compositions described herein can result in improved follicle permeability. In some cases, the follicle permeability is increased by at least or about 0.5X, 1.0X, 1.5X, 2.0X, 2.5X, 3.0X, 4.0X, 4.5X, 5X, or more than 5X.Follicle penetration can be increased 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 composition results in a follicle penetration 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 greater than 10 mm.

[0158] Other Components

[0159] Other components may include anti-inflammatory agents, antioxidants, and solubility enhancers. Exemplary antiirritants include, but are not limited to, panthenol triacetate and naringenin. Panthenol triacetate and naringenin are natural plant extracts that reduce skin redness and moisture loss. When used in a composition, the typical amount of the antiirritant is from 1% to 4% by weight (wt.%).

[0160] Exemplary antioxidants include, but are not limited to, Dunaliella salina extract and squalane. Dunaliella salina extract contains components such as β-carotene. It can exhibit antioxidant activity. When used in a composition, the typical amount of the anti-inflammatory agent is 0.1% to 2.5% by weight (wt.%). In some embodiments, at least or about 0.001% by weight, 0.005% by weight, 0.01% by weight, 0.02% by weight, 0.05% by weight, 0.10% by weight, 0.20% by weight, 0.25% by weight, 0.50% by weight, 0.75% by weight, 1.0% by weight, 1.5% by weight, 2.0% by weight, 2.5% by weight, 3.0% by weight, 3.5% by weight, 4.0% by weight, or greater than 4% by weight of Dunaliella salina extract is provided. In some embodiments, the 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 in at least or about 0.001 wt%, 0.005 wt%, 0.01 wt%, 0.02 wt%, 0.05 wt%, 0.10 wt%, 0.20 wt%, 0.25 wt%, 0.50 wt%, 0.75 wt%, 1.0 wt%, 1.5 wt%, 2.0 wt%, 2.5 wt%, 3.0 wt%, 3.5 wt%, 4.0 wt%, or greater than 4 wt%. 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, at least or about 0.001 wt%, 0.005 wt%, 0.01 wt%, 0.02 wt%, 0.05 wt%, and 0.10 wt% are provided.The extract of Dunaliella salina and squalane are present in amounts of 0.20 wt%, 0.25 wt%, 0.50 wt%, 0.75 wt%, 1.0 wt%, 1.5 wt%, 2.0 wt%, 2.5 wt%, 3.0 wt%, 3.5 wt%, 4.0 wt%, or greater than 4 wt%. In some embodiments, the Dunaliella salina squalane extract and squalane are provided in the range of about 0.001% to about 4.0%, about 0.01% to about 3.0%, about 0.1% to about 2.5%, or about 0.50% to about 1.5%.

[0161] In some embodiments, the peptide is mixed with a suitable carrier, diluent, or excipient and may contain auxiliary substances such as wetting agents or emulsifiers, pH buffers, gelling or viscosity-enhancing additives, preservatives, flavorings, colorants, etc., depending on the route of application and the desired formulation. See, for example, *Remington: The Science and Practice of Pharmacy*, Lippincott Williams & Wilkins; 20th edition (1 June 2003) and *Remington's Pharmaceutical Sciences*, Mack Pub. Co.; 18th and 19th editions (December 1985 and June 1990, respectively). Such formulations may contain chelating agents, metal ions, polymers such as polyacetic acid, polyglycolic acid, hydrogels, dextran, etc., liposomes, microemulsions, micelles, monolayer or multilayer vesicles, erythrocyte shadows, or spherocytes. Suitable lipids for use in the composition include, but are not limited to, monoglycerides, diglycerides, thioesters, lysophosphatidylcholine, phospholipids, saponins, bile acids, etc. In some embodiments, the compositions described herein comprise phosphatidylserine, phospholipids, tocopherol, ascorbyl palmitate, or combinations thereof. In some embodiments, 0.001 wt%, 0.005 wt%, 0.01 wt%, 0.02 wt%, 0.05 wt%, 0.10 wt%, 0.20 wt%, 0.25 wt%, 0.50 wt%, 0.75 wt%, 1.0 wt%, 1.5 wt%, 2.0 wt%, 2.5 wt%, 3.0 wt%, 3.5 wt%, 4.0 wt%, or greater than 4 wt% (wt.%) of phosphatidylserine, phospholipids, tocopherol, ascorbyl palmitate, or combinations thereof are provided. In some embodiments, phosphatidylserine, phospholipids, tocopherol, ascorbyl palmitate, or combinations thereof are present in amounts from about 0.25 wt% to about 10 wt%.The composition is provided in the range of 0.5 wt% to about 8 wt%, about 0.75 wt% to about 6 wt%, or about 1 wt% to about 4 wt%. In some embodiments, phosphatidylserine, phospholipids, tocopherol, ascorbyl palmitate, or combinations thereof are provided in the range of about 0.001 wt% to about 6 wt%, about 0.002 wt% to about 4 wt%, about 0.01 wt% to about 3 wt%, or about 0.02 wt% to about 5 wt%. In some embodiments, the additive is betaine. In some embodiments, betaine is provided in the range of about 0.001 wt% to about 6 wt%, about 0.002 wt% to about 4 wt%, about 0.01 wt% to about 3 wt%, or about 0.02 wt% to about 5 wt%. In some embodiments, the composition described herein includes caprylyl glycol. In some embodiments, caprylyl glycol is provided in the range of about 0.001 wt% to about 6 wt%, about 0.002 wt% to about 4 wt%, about 0.01 wt% to about 3 wt%, or about 0.02 wt% to about 5 wt%. In some embodiments, the compositions described herein include capryloyl oxime acid. In some embodiments, capryloyl oxime acid is provided in the range of about 0.001% by weight to about 6% by weight, about 0.002% by weight to about 4% by weight, about 0.01% by weight to about 3% by weight, or about 0.02% by weight to about 5% by weight. The presence of such additional components can affect the physical state, solubility, stability, release rate, clearance rate, and permeability of the active ingredient.

[0162] Compositions for topical application include the peptide compositions described herein and dermatologically acceptable mediators. Mediators may be aqueous or non-aqueous. Dermatologically acceptable mediators used in topical compositions may be in the form of lotions, gels, ointments, liquids, creams, or emulsions. If the mediator is an emulsion, the emulsion may have a continuous aqueous phase and a discontinuous non-aqueous or oil phase (oil-in-water emulsion), or a continuous non-aqueous or oil phase and a discontinuous aqueous phase (water-in-oil emulsion). When applied topically in liquid or gel form, a liquid carrier, such as water, petroleum, animal or plant-derived oils, such as peanut oil, mineral oil, soybean oil, or sesame oil, or synthetic oil, may be added to the active ingredient. Physiological saline solutions, glucose 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 may be a vegetable oil, such as olive oil or peanut oil, a mineral oil, such as liquid paraffin, or a mixture thereof. Suitable emulsifiers include naturally occurring gums, such as gum arabic and tragacanth, naturally occurring phospholipids, such as soybean lecithin, esters or metaesters derived from fatty acids and hexitan anhydrides, such as sorbitan monooleate, and condensation products of these metaesters with ethylene oxide, such as polyoxyethylene sorbitan monooleate. The emulsion may also contain colorants and flavorings.

[0163] In some embodiments, silicone elastomers (e.g., dimethylsiloxane crosslinked polymers) are used to increase peptide delivery and penetration into the skin. An alternative to increasing the molecular weight (e.g., silicone gels) or adding fillers (e.g., silicone compounds) is to partially crosslink the siloxane polymer and disperse this material in a suitable silicone carrier solution. The resulting polydimethylsiloxane crosslinked polymer (also known as silicone elastomers in the personal care industry) differs from basic polydimethylsiloxane (PDMS) because crosslinking exists between the linear polymers. These materials can be used in peptide compositions and offer benefits in scar treatment, wound peri-wound protection, and enzyme delivery. In skincare applications, the aesthetic appeal of silicone elastomers (including those with functional groups) and their ability to absorb various oils (e.g., with polydimethylsiloxane / vinyl polydimethylsiloxane crosslinked polymers, such as Dow Corning® 9506 elastomer powder) are two desirable properties of elastomers. Silicone elastomers have a skin feel unlike any silicone fluid, described as “smooth,” “velvety,” and “powder-like.” The amount of liquid phase in the formulation can be modified, and thus the degree of swelling can be controlled. Due to its film-forming properties, polydimethylsiloxane crosspolymers can be used as delivery systems for active ingredients such as peptides or other compositional components such as oil-soluble vitamins and sunscreens, as described herein. Sunscreens such as octyl methoxycinnamate can be delivered more effectively from compositions containing silicone elastomers, resulting in a higher sun protection factor (SPF). Silicone elastomer blends can be used to enhance the SPF in oil-in-water compositions containing organic sunscreens. For example, in tests of SPF, adding 4% of a silicone elastomer blend to a sunscreen composition containing organic sunscreens increased the SPF from 5.7 to 18. This property of silicone elastomers maximizes the effectiveness of the sunscreen in the composition while reducing the amount required to achieve the desired SPF. Therefore, the cost of the composition can be reduced, while also reducing potential irritation caused by the sunscreen active ingredients. Therefore, a higher SPF can be obtained with the same amount of UV absorber, resulting in enhanced performance without increasing the cost of the composition. Silicone elastomers can be produced from linear silicone polymers through various crosslinking reactions, such as hydrosilylation reactions involving the reaction of vinyl groups with silanes. The general process involves linear silicone polymers whose reaction sites react with a crosslinking agent along the polymer chain. Polydimethylpolysiloxane crosslinked polymers can be gels made from suspensions of elastomer particles swollen in a carrier liquid (e.g., mixtures of high molecular weight silicone elastomers in polysiloxane compounds, such as Dow Corning® 9040 silicone elastomer blends), or from spray-dried powders (polydimethylsiloxane / vinyl polydimethylsiloxane crosslinked polymers, such as Dow Corning®).9506 elastomer powder) is produced. The gel form with the desired properties is cyclomethicone, but low-viscosity polydimethylsiloxane and organic fluids can also be used. Examples of polydimethylsiloxane crosslinked polymers in suspension or gel form are mixtures of high molecular weight silicone elastomers (12%) in decamethylcyclopentane (e.g., Dow Corning® ST elastomer 10) and high molecular weight silicone elastomers in cyclopentane (e.g., Dow Corning® 9040 silicone elastomer blends), with elastomer content typically between 10% and 20% by weight.

[0164] In some embodiments, the composition comprises a siloxane polymer. In some embodiments, the siloxane polymer is octyl polymethylsiloxane. In some embodiments, octyl polymethylsiloxane is provided in amounts of at least or about 0.001 wt%, 0.005 wt%, 0.01 wt%, 0.02 wt%, 0.05 wt%, 0.10 wt%, 0.20 wt%, 0.25 wt%, 0.50 wt%, 0.75 wt%, 1.0 wt%, 1.5 wt%, 2.0 wt%, 2.5 wt%, 3.0 wt%, 3.5 wt%, 4.0 wt%, or greater than 4.0 wt%. In some embodiments, octyl polymethylsiloxane is provided at about 0.5 wt%. In some embodiments, octyl polymethylsiloxane is provided in the range of about 0.001 wt% to about 4.0 wt%, about 0.01 wt% to about 3.0 wt%, about 0.1 wt% to about 2.5 wt%, or about 0.50 wt% to about 1.5 wt%. In some embodiments, octyl polymethylsiloxane is provided at about 0.25 wt%. In some embodiments, octyl polymethylsiloxane is provided at about 1 wt%.

[0165] Bentonite clay can be used in combination with peptides to impart permeability and adsorption properties to the composition and to help stabilize the emulsion. Other clays, such as lithium saponite and magnesium aluminosilicates, can also be used. Bentonite or other clays can be modified to produce organically modified clay compounds. Fatty acid (e.g., hydrogenated fatty acid) salts (e.g., quaternary ammonium salts) can react with lithium saponite or other clays. As provided herein, fatty acids are referred to and described using conventional terms 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 typically cis; however, trans double bonds are also possible. The position of a double bond can be indicated by Δn, where n indicates the lower-numbered carbon atom in each pair of double-bonded carbon atoms. A simplified notation for specifying the total number of carbons: double bond number, can be Δ double bond position. For example, 20:4 Δ5, 8, 11, 14 refer to fatty acids with 20 carbon atoms and four double bonds, where the double bonds are located between carbon atoms 5 and 6, 8 and 9, 11 and 12, and 14 and 15, with carbon atom 1 being the carbon of a carboxylic acid group. Stearic acid (octadecyl ester) is a saturated fatty acid. Oleic acid (cis-Δ9-methyl oleate) is a monounsaturated fatty acid, and linolenic acid (all-cis-Δ9,12,15-octadecanoic acid) is a polyunsaturated fatty acid. Suitable fatty acids may include 5 to 30 carbon atoms, for example, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 carbon atoms. The fatty acids can be fully saturated or can contain as many double bonds as possible, provided the chain length is appropriate. Suitable for functionalized lithium soapstone or other clays. (Instructions 30 / 50 pages 32 CN 121570573 A) Fatty acids include palmitic acid and stearic acid. Dialkyl quaternary cationic modifiers include dipalmitoyl dimethyl ammonium chloride and distearyl dimethyl ammonium chloride. Amide quaternary ammonium cationic modifiers include palmitamidopropyltrimethylammonium chloride, cetearyl alcohol, and palmitamidopropyltrimethyl ammonium chloride.

[0166] Pharmaceutical excipients for topical formulations of peptide compositions may be selected from the group consisting of: solvents, emollients and / or emulsifiers, oil bases, preservatives, antioxidants, tension modifiers, penetration enhancers and solubilizers, chelating agents, buffers, surfactants, one or more polymers and combinations thereof.

[0167] Suitable solvents for aqueous or hydrophilic liposome compositions comprise: water; ethanol; isopropanol; mixtures of water and ethanol and / or isopropanol; glycerol; ethylene glycol, propylene glycol or butylene glycol; DMSO; and mixtures thereof. In some embodiments, at least or about 1 wt%, 2 wt%, 3 wt%, 4 wt%, 5 wt%, 6 wt%, 7 wt%, 8 wt%, 9 wt%, 10 wt%, 11 wt%, 12 wt%, or greater than 12 wt% (wt.%) of glycerol is provided. In some embodiments, at least or about 7% of glycerol is provided. In some embodiments, glycerol is provided in the range of about 1 wt% to about 12 wt%, about 2 wt% to about 11 wt%, or about 3 wt% to about 10 wt%. In some embodiments, at least or about 0.0025 wt%, 0.005 wt%, 0.075 wt%, 0.01 wt%, 0.025 wt%, 0.05 wt%, 0.75 wt%, 1 wt%, 2 wt%, 3 wt%, 4 wt%, 5 wt%, 6 wt%, 7 wt%, 8 wt%, 9 wt%, 10 wt%, 11 wt%, 12 wt%, or greater are provided.The butanediol is present in a concentration of 12% by weight. In some embodiments, the butanediol is provided in the range of about 0.01% by weight to about 10% by weight, about 0.025% by weight to about 5% by weight, or about 0.05% by weight to about 1.25% by weight. Suitable solvents for the hydrophobic composition include mineral oil, vegetable oil, and silicone oil. If desired, the peptide composition as described herein can be dissolved or dispersed in a hydrophobic oil phase, and the oil phase can then be emulsified in an aqueous phase comprising water, alone or in combination with lower alcohols, glycerol, and / or glycols. In some embodiments, anhydrous compositions are applied because the presence of water can cause stinging when applied to skin tissue subjected to laser treatment, chemical peels, dermabrasion, etc. Anhydrous compositions can also serve to prevent water-based irritant contact dermatitis in damaged or sensitive skin, which can produce rashes and skin irritations that can delay wound healing and improve skin quality. Tsai, T.F., Maibach, H.I. How irritating is water? Overview. Contact Dermatitis 41(6) (1999): 311-314 (describes water-induced contact dermatitis as an irritant). However, in some embodiments, it may be acceptable to provide a water-based composition or allow the presence of a limited amount of water. For example, water may be present, but in amounts below a threshold that would cause a stinging sensation when applied to damaged skin. Osmotic shock or osmotic stress is a sudden change in the concentration of solutes around cells, resulting in a rapid change in the movement of water across its cell membrane. Under conditions of high concentrations of salt, substrate, or any solute in the supernatant, water is drawn out of the cell by osmosis. This also inhibits the transport of substrates and cofactors into the cell, thus “shocking” the cell. Alternatively, under conditions of low solute concentrations, water may enter the cell in large quantities, resulting in cell swelling and rupture or apoptosis. Certain compositions as described herein can be advantageously used where it is desirable to minimize osmotic shock.

[0168] Compositions as described herein may include varying amounts of solvent. In some embodiments, the solvent is water. In some embodiments, the solvent is at least or about 10 wt%, 15 wt%, 20 wt%, 25 wt%, 30 wt%, 35 wt%, 40 wt%, 45 wt%, 50 wt%, 55 wt%, 60 wt%, 65 wt%, 70 wt%, 75 wt%, 80 wt%, 85 wt%, 90 wt%, 95 wt%, or greater than 95 wt%. In some embodiments, the solvent is in the range of about 10 wt% to about 95 wt%, about 20 wt% to about 90 wt%, about 30 wt% to about 85 wt%, about 40 wt% to about 80 wt%, or about 50 wt% to about 75 wt%.

[0169] The viscosity of the composition can be maintained at a selected level using a pharmaceutically acceptable thickener. It can be used to prepare...Suitable viscosity enhancers or thickeners for water-based adhesives or creams include sodium polyacrylate, xanthan gum, polyvinylpyrrolidone, acrylic polymers, carrageenan, hydroxyethyl cellulose, hydroxypropyl cellulose, methylcellulose, ethylcellulose, propyl cellulose, hydroxypropyl methylcellulose, polyethoxylated polyacrylamide, polyethoxylated acrylates, and polyethoxylated alkyl thiols. Methylcellulose is preferred because it is readily available, cost-effective, and readily effective. Other suitable thickeners include, for example, xanthan gum, carboxymethyl cellulose, hydroxypropyl cellulose, carbomer, etc. The preferred concentration of the thickener will depend on the thickener selected. Preferably, an amount that will achieve the selected viscosity is used. Viscous compositions are typically prepared from a solution by adding such thickeners or by using an alkali with an acceptable viscosity level.

[0170] In some embodiments, the viscosity of the composition as described herein is in the range of about 8,000 centipoise (cps) to about 30,000 cps. In some embodiments, the viscosity is at least or about 4,000; 5,000; 6,000; 7,000; 8,000; 9,000; 10,000; 11,000; 12,000; 13,000; 14,000; 15,000; 16,000; 17,000; 18,000; 19,000; 20,000; 21,000; 22,000; 23,000; 24,000; 25,000; 26,000; 27,000; 28,000; 29,000; 30,000; 31,000; 32,000; 33,000; 34,000; 35,000; 36,000; 37,000; 38,000; 39,000; 40,000; or greater than 40,000 cps. In some embodiments, the composition includes viscosities 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.

[0171] Suitable emollients comprise hydrocarbon oils and waxes, such as mineral oil, petrolatum, paraffin, mineral wax, ceresin, microcrystalline wax, polyethylene, squalene, perhydrosqualene, silicone oil, triglycerides, acetylated glycerides, such as acetylated monoglycerides; ethoxylated glycerides, such as ethoxylated monostearate; alkyl esters of fatty acids or dicarboxylic acids. In some embodiments, the emollient is caprylic / capric triglyceride.

[0172] In some embodiments, at least or about 0.0025 wt%, 0.005 wt%, 0.075 wt%, and 0.01 wt% are provided.The emollient is provided in amounts of 0.025 wt%, 0.05 wt%, 0.75 wt%, 1 wt%, 2 wt%, 3 wt%, 4 wt%, 5 wt%, 6 wt%, 7 wt%, 8 wt%, 9 wt%, 10 wt%, 11 wt%, 12 wt%, or greater than 12 wt%. In some embodiments, the emollient is provided in the range of about 0.01 wt% to about 10 wt%, about 0.01 wt% to about 2.5 wt%, about 0.025 wt% to about 5 wt%, or about 0.05 wt% to about 1.25 wt%. In some embodiments, caprylic / capric triglycerides are provided in amounts of at least or about 0.0025 wt%, 0.005 wt%, 0.075 wt%, 0.01 wt%, 0.025 wt%, 0.05 wt%, 0.75 wt%, 1 wt%, 2 wt%, 3 wt%, 4 wt%, 5 wt%, 6 wt%, 7 wt%, 8 wt%, 9 wt%, 10 wt%, 11 wt%, 12 wt%, or greater than 12 wt%. In some embodiments, caprylic / capric triglycerides are provided in the range of about 0.01 wt% to about 10 wt%, about 0.01 wt% to about 2.5 wt%, about 0.025 wt% to about 5 wt%, or about 0.05 wt% to about 1.25 wt%.

[0173] Suitable silicone oils used as emollients comprise dimethylpolysiloxane, methyl (phenyl)polysiloxane, and water-soluble and alcohol-soluble silicone glycol copolymers. Suitable triglycerides used as emollients comprise 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.

[0174] Suitable esters of carboxylic acids or diacids used as emollients comprise methyl esters, isopropyl esters, and butyl esters of fatty acids. Specific examples of alkyl esters include hexyl laurate, isohexyl laurate, isohexyl palmitate, isopropyl palmitate, decyl oleate, isodecyl oleate, hexadecyl stearate, decyl stearate, isopropyl isostearate, dilauryl lactate, myristyl lactate, and cetyl lactate; and alkenyl esters of fatty acids, such as oleyl myristate, oleyl stearate, and oleic acid. Specific examples of alkyl diacid esters include diisopropyl adipate, diisohexyl adipate, di(hexyldecyl) adipate, and diisopropyl sebacate.

[0175] Other suitable types of emollients or emulsifiers that can be used in the composition include fatty acids, fatty alcohols, fatty alcohol ethers, ethoxylated fatty alcohols, fatty acid esters of ethoxylated fatty alcohols, and waxes. Instruction manual, pages 32 / 50, CN 121570573 A

[0176] Specific examples of fatty acids used as emollients include nonanoic 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. Fats used as emollientsSpecific examples of alcohols include lauryl alcohol, myristyl alcohol, cetyl alcohol, hexadecyl alcohol, stearyl alcohol, isostearyl alcohol, hydroxystearyl alcohol, oleyl alcohol, ricinoleyl alcohol, behenyl alcohol, and garnet alcohol, as well as 2-octyldodecyl alcohol.

[0177] Specific examples of waxes suitable for use as emollients include lanolin and its derivatives, which include lanolin oil, lanolin wax, lanolin alcohol, lanolin fatty acid, isopropyl lanolinate, ethoxylated lanolin, ethoxylated lanolin alcohol, ethoxylated cholesterol, propoxylated lanolin alcohol, acetylated lanolin, acetylated lanolin alcohol, lanolin alcohol linoleate, lanolin alcohol ricinoleate, lanolin alcohol ricinoleate acetate, lanolin alcohol ricinoleate acetate, ethoxylated alcohol ester acetate, hydrogenated lanolin, hydrogenated lanolin, ethoxylated hydrogenated lanolin, ethoxylated sorbitol lanolin, and liquid and semi-solid lanolin. They can also be used as waxes, including hydrocarbon waxes, ester waxes, and amide waxes. Useful waxes include wax esters such as beeswax, cetyl, myristate, and stearate; beeswax derivatives such as polyoxyethylene sorbitan beeswax; and plant waxes containing carnauba wax and candelilla wax.

[0178] Polyols and polyether derivatives can be used as solvents and / or surfactants in the composition. Suitable polyols and polyethers include propylene glycol, dipropylene glycol, polypropylene glycol 2000 and 4000, poly(ethylene oxide-co-oxypropylene) glycol, glycerin, sorbitol, ethoxylated sorbitol, hydroxypropyl sorbitol, polyethylene glycol 200-6000, methoxylated polyethylene glycol 350, 550, 750, 2000 and 5000, poly[ethylene oxide] homopolymers (100,000-5,000,000), polyalkylene glycols and their derivatives, hexanediol, 2-methyl-2,4-pentanediol, 1,3-butanediol, 1,2,6-hexanetriol, 2-ethyl-1,3-hexanediol, diols having 15 to 18 carbon atoms, and polyoxypropylene derivatives of trimethylolpropane.

[0179] Polyol esters can be used as emulsifiers or emollients. Suitable polyol 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 acid esters, polypropylene glycol 2000 monooleate, polypropylene glycol 2000 monostearate, ethoxylated propylene glycol monostearate, glycerol mono- and di-fatty acid esters, polyglycerol poly-fatty acid esters, ethoxylated glycerol monostearate, 1,3-butanediol monostearate, 1,3-butanediol distearate, polyoxyethylene polyol fatty acid esters, sorbitol fatty acid esters, and polyoxyethylene sorbitol fatty acid esters.

[0180] Suitable emulsifiers for the composition include anionic, cationic, nonionic, and amphoteric surfactants. Preferred ionic emulsifiers include phospholipids, such as lecithin and its derivatives.

[0181] Sterols include, for example, cholesterol and cholesterol fatty acid esters; amides such as fatty acid amides, ethoxylated fatty acid amides, and fatty acid alkanolamides can also be used as emollients and / or penetration enhancers.

[0182] Pharmaceutically acceptable preservatives can be used to increase the shelf life of the composition. Other suitable preservatives and / or antioxidants used in the composition include benzalkonium chloride, benzyl alcohol, phenol, urea, parabens, butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), tocopherol, thimerosal, chlorobutanol, and mixtures thereof, all of which can be used. If a preservative, such as an antioxidant, is used, the suitable concentration of said preservative, such as an antioxidant, is generally from about 0.02% to about 2% based on the total weight of the composition, but may require larger or smaller amounts depending on the reagent chosen. As described herein, reducing agents can be advantageously used to maintain a good shelf life of the composition. The anhydrous compositions of the examples are generally observed to exhibit satisfactory stability, thus making it possible to omit preservatives from the composition.

[0183] Suitable chelating agents for the composition include ethylenediaminetetraacetic acid (EDTA), its alkali metal salt, its alkaline earth metal salt, its ammonium salt, and its tetraalkylammonium salt. In some embodiments, the chelating agent is disodium ethylenediaminetetraacetate (EDTA). In some embodiments, at least or about 0.001 wt%, 0.005 wt%, 0.01 wt%, 0.02 wt%, 0.05 wt%, 0.10 wt%, 0.20 wt%, 0.25 wt%, 0.50 wt%, 0.75 wt%, 1.0 wt%, 1.5 wt%, 2.0 wt%, 2.5 wt%, 3.0 wt%, 3.5 wt%, 4.0 wt%, or greater than 4 wt% (wt.%) of disodium EDTA. In some embodiments, disodium EDTA is provided in the range of about 0.25 wt% to about 10 wt%, about 0.1 wt% to about 2.5 wt%, about 0.5 wt% to about 8 wt%, about 0.75 wt% to about 6 wt%, or about 1 wt% to about 4 wt%. In some embodiments, disodium EDTA is provided in the range of about 0.001 wt% to about 6 wt%, about 0.002 wt% to about 4 wt%, about 0.01 wt% to about 3 wt%, or about 0.02 wt% to about 2 wt%.

[0184] The pH of the carrier is preferably between about 4.0 and 10.0, more preferably between about 4.8 and about 7.8, and even more preferably between about 5.0 and about 6.5. Buffer solutions or other pH adjusters can be used to control the pH. Suitable pH adjusters include phosphoric acid and / or phosphates, citric acid and / or citrates, hydroxide salts (i.e., calcium hydroxide, sodium hydroxide, potassium hydroxide), and amines such as triethanolamine. Suitable buffer solutions contain potassium dihydrogen phosphate and phosphorus, with the pH maintained between 5.8 and 8.Buffer solutions containing dipotassium phosphate, and buffer solutions comprising monosodium phosphate and disodium phosphate solutions maintained at a pH between 6 and 7.5. Other buffers also include citric acid / sodium citrate and disodium hydrogen phosphate / citric acid. The peptide compositions of the examples are preferably isotonic with the recipient's blood or other bodily fluids. Sodium tartrate, propylene glycol, or other inorganic or organic solutes can be used to achieve the isotonicity of the composition. Sodium chloride is particularly preferred. Buffers such as acetic acid and salts, citric acid and salts, boric acid and salts, and phosphate and salts can be used. It may be desirable to include reducing agents in the composition, such as vitamin C, vitamin E, or other reducing agents known in the pharmaceutical industry.

[0185] Surfactants can also be used as excipients, for example, anionic detergents (such as sodium dodecyl sulfate, sodium dioctyl sulfosuccinate, and sodium dioctyl sulfonate), cationic detergents (such as benzalkonium chloride or benzyl chloride), or nonionic detergents (such as polyoxyethylene hydrogenated castor oil, glyceryl monostearate, polysorbate, sucrose fatty acid esters, methylcellulose, or carboxymethyl cellulose).

[0186] In some embodiments, it may be advantageous to include additional agents with pharmacological activity. Anti-infective agents include, but are not limited to, anthelmintics (mebendazole), antibiotics containing aminoglycosides (gentamicin, neomycin, tobramycin), antifungal antibiotics (amphotericidal, fluconazole, griseofulvin, itraconazole, ketoconazole, nystatin, miconazole, tolnaftate), and cephalosporins (cefaclor, cefazolin, cefotaxime). Cefotaxime, ceftazidime, ceftriaxone sodium, cefuroxime, cefalexin, β-lactam antibiotics (cefotetan, meropenem), chloramphenicol, macrolides (azithromycin, clarithromycin, erythromycin), penicillins (penicillin G sodium, amoxicillin, ampicillin, dicloxacillin, ethoxynaphthylpenicillin)(nafcillin), piperacillin, ticarcillin, tetracycline (doxycycline, minocycline), bacitracin, clindamycin, colistimethate sodium, polymyxin B sulfate sulfate), vancomycin, antiviral drugs containing acyclovir, amantadine, didanosine, efavirenz, foscarnet, ganciclovir, indinavir, lamivudine, nelfinavir, ritonavir, saquinavir, stavudine, valacyclovir, valganciclovir, zidovudine, quinolones (Ciprofloxacin package insert, 34 / 50, page 36, CN 121570573 A) Anesthetics may include, but are not limited to, ciprofloxacin, levofloxacin, sulfonamides (sulfadiazine, sulfisoxazole), sulfones (dapsone), furazolidone, metronidazole, pentamidine, sulfanilamidum crystallinum, gatifloxacin, and sulfamethoxazole / trimethoprim. Anesthetics may include, but are not limited to, ethanol, bupivacaine, chloroprocaine, levobupivacaine, lidocaine, mepivacaine, procaine, and ropivacaine.(ropivacaine), tetracaine, desflurane, isoflurane, ketamine, propofol, sevoflurane, codeine, fentanyl, hydromorphone, marcaine, meperidine, methadone, morphine, oxycodone, remifentanil, sufentanil, butorphanol, nalbuphine, tramadol, benzocaine, dibucaine, ethyl chloride, lidocaine, and phenazopyridine. Anti-inflammatory agents include, but are not limited to, nonsteroidal anti-inflammatory drugs (NSAIDs), such as aspirin, celecoxib, choline magnesium trisalicylate, diclofenac potassium, diclofenac sodium, diflunisal, etodolac, fenoprofen, flurbiprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, melanic acid, nabumetone, naproxen, and naproxen sodium. Sodium, oxaprozin, piroxicam, rofecoxib, salsalate, sulindac, and tolmetin; and corticosteroids such as cortisone, hydrocortisone, and methylprednisolone.(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 Propionate and dexamethasone.

[0187] In some embodiments, the addition of emollients, emulsion stabilizers, humectants, excipients, and other compounds may be modified to enhance the sensory properties of the local composition, including but not limited to: skin feel (e.g., silky, light, creamy), absorbency (time required for the product to lose its moistness and no longer be perceived by the skin), consistency, firmness, spreadability (e.g., viscosity, flow initiation, shear rate), tackiness, shape integrity, gloss, hydrophilicity, or hydrophobicity. Preferably, the composition will have high spreadability and low viscosity. Compositions with such properties have been shown to have an enhanced “silky” or “lightweight” skin feel (see, for example, Bekker, M. Webber, G., Louw, N.). Rheological measurements were correlated with primary and secondary skin feeling when mineral-based and Fischer-Tropsch wax-based cosmetic emulsions and gels were applied to the skin (Relating rheological measurements to primary and secondary skin feeling when mineral-based and Fischer-Tropsch wax-based cosmetic emulsions, 35 / 50 pages, 37 CN 121570573 A and jellies).(are applied to the skin), International Journal of Cosmetic Science, 2013, 35(4), pp. 354-61.

[0188] In some embodiments, the composition comprises phenoxyethanol, ethylhexylglycerin, or a combination thereof. In some embodiments, at least or about 0.05 wt%, 0.10 wt%, 0.25 wt%, 0.50 wt%, 0.75 wt%, 1.0 wt%, 1.5 wt%, 2.0 wt%, 2.5 wt%, 3.0 wt%, 3.5 wt%, 4.0 wt%, 4.5 wt%, 5.0 wt%, 5.5 wt%, 6.0 wt%, 6.5 wt%, 7.0 wt%, 8 wt%, 9 wt%, 10 wt%, or greater than 10 wt% (wt%) of phenoxyethanol is provided. In some embodiments, phenoxyethanol is provided in the range of about 0.25 wt% to about 10 wt%, about 0.5 wt% to about 8 wt%, about 0.75 wt% to about 6 wt%, or about 1 wt% to about 4 wt%. In some embodiments, ethylhexylglycerol is provided in amounts of at least or about 0.05 wt%, 0.10 wt%, 0.25 wt%, 0.50 wt%, 0.75 wt%, 1.0 wt%, 1.5 wt%, 2.0 wt%, 2.5 wt%, 3.0 wt%, 3.5 wt%, 4.0 wt%, 4.5 wt%, 5.0 wt%, 5.5 wt%, 6.0 wt%, 6.5 wt%, 7.0 wt%, 8 wt%, 9 wt%, 10 wt%, or greater than 10 wt%. In some embodiments, ethylhexylglycerol is provided in the range of about 0.25 wt% to about 10 wt%, about 0.5 wt% to about 8 wt%, about 0.75 wt% to about 6 wt%, or about 1 wt% to about 4 wt%. In some embodiments, phenoxyethanol and ethylhexylglycerin are provided in amounts of at least or about 0.05 wt%, 0.10 wt%, 0.25 wt%, 0.50 wt%, 0.75 wt%, 1.0 wt%, 1.5 wt%, 2.0 wt%, 2.5 wt%, 3.0 wt%, 3.5 wt%, 4.0 wt%, 4.5 wt%, 5.0 wt%, 5.5 wt%, 6.0 wt%, 6.5 wt%, 7.0 wt%, 8 wt%, 9 wt%, 10 wt%, or greater than 10 wt%. In some embodiments, phenoxyethanol and ethylhexylglycerin are provided in the range of about 0.25 wt% to about 10 wt%, about 0.1 wt% to about 4 wt%, about 0.5 wt% to about 8 wt%, about 0.75 wt% to about 6 wt%, or about 1 wt% to about 4 wt%.

[0189] In some embodiments, the composition comprises polyacrylate-13, polyisobutylene, polysorbate 20, or combinations thereof. In some embodiments, polyacrylate-13 is provided in amounts of at least or about 0.05 wt%, 0.10 wt%, 0.25 wt%, 0.50 wt%, 0.75 wt%, 1.0 wt%, 1.5 wt%, 2.0 wt%, 2.5 wt%, 3.0 wt%, 3.5 wt%, 4.0 wt%, 4.5 wt%, 5.0 wt%, 5.5 wt%, 6.0 wt%, 6.5 wt%, 7.0 wt%, 8 wt%, 9 wt%, 10 wt%, or greater than 10 wt%. In some embodiments, polyacrylate-13 is provided in the range of about 0.25 wt% to about 10 wt%, about 0.5 wt% to about 8 wt%, about 0.75 wt% to about 6 wt%, or about 1 wt% to about 4 wt%. In some embodiments, polyisobutylene is provided in amounts of at least or about 0.05 wt%, 0.10 wt%, 0.25 wt%, 0.50 wt%, 0.75 wt%, 1.0 wt%, 1.5 wt%, 2.0 wt%, 2.5 wt%, 3.0 wt%, 3.5 wt%, 4.0 wt%, 4.5 wt%, 5.0 wt%, 5.5 wt%, 6.0 wt%, 6.5 wt%, 7.0 wt%, 8 wt%, 9 wt%, 10 wt%, or greater than 10 wt%. In some embodiments, polyisobutylene is provided in the range of about 0.25 wt% to about 10 wt%, about 0.5 wt% to about 8 wt%, about 0.75 wt% to about 6 wt%, or about 1 wt% to about 4 wt%. In some embodiments, polyacrylate-13 is provided in the range of about 0.25 wt% to about 10 wt%, about 0.5 wt% to about 8 wt%, about 0.75 wt% to about 6 wt%, or about 1 wt% to about 4 wt%. In some embodiments, polysorbate 20 is provided in amounts of at least or about 0.05 wt%, 0.10 wt%, 0.25 wt%, 0.50 wt%, 0.75 wt%, 1.0 wt%, 1.5 wt%, 2.0 wt%, 2.5 wt%, 3.0 wt%, 3.5 wt%, 4.0 wt%, 4.5 wt%, 5.0 wt%, 5.5 wt%, 6.0 wt%, 6.5 wt%, 7.0 wt%, 8 wt%, 9 wt%, 10 wt%, or greater than 10 wt%. In some embodiments, polysorbate 20 is provided in the range of about 0.25 wt% to about 10 wt%, about 0.5 wt% to about 8 wt%, about 0.75 wt% to about 6 wt%, or about 1 wt% to about 4 wt%. In some embodiments, at least or about 0.05 wt% is provided in the range of at least 0.05 wt%.Polyacrylate-13, polyisobutylene, and polysorbate 20 are provided in the range of about 0.10 wt%, 0.25 wt%, 0.50 wt%, 0.75 wt%, 1.0 wt%, 1.5 wt%, 2.0 wt%, 2.5 wt%, 3.0 wt%, 3.5 wt%, 4.0 wt%, 4.5 wt%, 5.0 wt%, 5.5 wt%, 6.0 wt%, 6.5 wt%, 7.0 wt%, 8 wt%, 9 wt%, 10 wt%, or greater than 10 wt% (wt%). In some embodiments, polyacrylate-13, polyisobutylene, and polysorbate 20 are provided in the range of about 0.25 wt% to about 10 wt%, about 0.1 wt% to about 4 wt%, about 0.5 wt% to about 8 wt%, about 0.75 wt% to about 6 wt%, or about 1 wt% to about 4 wt% (wt.%).

[0190] The local 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, wherein the surfactant concentration exceeds a critical micelle concentration. The resulting composition contains micelles, i.e., spherical oil droplets.

[0191] Penetration Enhancers

[0192] Fatty acids and alcohols can be used to enhance the permeability of peptides and provide a silky feel to the composition (e.g., formic acid, acetic acid, propionic acid, butyric acid, isobutyric acid, valeric acid, hexanoic acid, heptanoic acid, caprylic acid, nonanoic acid, decanoic acid, myristic acid, isovaleric acid, palmitoleic acid, saponin acid, oleic acid, transoleic acid, isoleic acid, linoleic acid, linolenic acid, α-linolenic acid, arachidonic acid, eicosapentaenoic acid, erucic acid, docosahexaenoic acid, caprylic acid, decanoic acid, lauric acid, palmitic acid, stearic acid, arachidic acid, behenic acid, lignoceric acid, ceric acid, medium-chain fatty acids, such as C6-12 fatty acids, etc. When used in the composition, the typical dosage is 1% to 4% by weight.

[0193] Method of Use

[0194] This document describes compositions and methods for improving hyperpigmentation including hyperpigmentation. In some embodiments, hyperpigmentation is due to post-inflammatory hyperpigmentation, melasma, or aging. In some embodiments, hyperpigmentation due to aging is caused by UV exposure or inflammation.

[0195] This document also describes compositions and methods for reducing melanocyte activity, inhibiting melanin synthesis, reducing melanin transfer, increasing melanosome autophagy, reducing inflammation, or combinations thereof. In some embodiments, the reduction in melanocyte activity is caused by inhibition of MITF, TYR, TRP1, TRP2, or combinations thereof. In some embodiments, the reduction in melanocyte activity is caused by activation of ERK signaling, JNK signaling, or combinations thereof. In some embodiments, the increased melanosome autophagy is caused by increased expression, activity, or both of PAR-2, ET-1, or SCF.

[0196] The compositions described herein include peptides, silymarin, tranexamic acid, lactoferrin, cannabidiol, Ashwagandha extract, gallic acid, sesamol, ergosterol, oleuropein, hesperidin, white sheath extract, ternolactone, Melatrepein™, nicotinamide, Tremella fuciformis extract, Thermophilic bacteria extract, phytorepinephrine, hexahydrolycopene, *Smilax china*, *Polygonum hydropiper* extract, or combinations thereof for the treatment of pigmentary disorders or conditions.

[0197] Various pigmentary disorders or conditions can be improved using the compositions and methods described herein. In some embodiments, a pigmentary disorder or condition is hyperpigmentation. In some embodiments, a pigmentary disorder or condition is focal hypopigmentation or diffuse hypopigmentation. In some embodiments, the condition or condition is post-inflammatory hyperpigmentation (PIH). In some embodiments, PIH is an epidermal form of PIH. In some embodiments, PIH is a defined form of PIH. In some embodiments, pigmentary disorders or diseases include, but are not limited to, acanthosis nigricans, age spots, albinism, pigmentary disorders, freckles, melasma, pityriasis alba, or progressive pigmented purpura.

[0198] In some embodiments, the compositions described herein improve pigmentation by reducing melanocyte activity, inhibiting melanin synthesis, reducing melanin transfer, increasing melanosome autophagy, reducing inflammation, or combinations 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.

[0199] The compositions described herein can be used with a variety of treatment regimens. In some cases, the topical compositions described herein are applied once daily, twice daily, three times daily, or more frequently. In some cases, the topical compositions described herein are applied twice daily. In some embodiments, the topical compositions described herein are applied daily, every other day, five days a week, once a week, every other week, two weeks a month, three weeks a month, once a month, twice a month, three times a month, or more frequently. In some embodiments, the topical compositions described herein are applied twice daily, for example, in the morning and evening. In some embodiments, the topical composition described herein is applied for at least 1 day, 2 days, 3 days, 4 days, or 5 days.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 longer. In some embodiments, the topical composition described herein is applied 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 longer. In some embodiments, the topical composition described herein is applied 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 longer.

[0200] Stability Testing

[0201] The stability of the composition may be tested as follows.

[0202] High temperature testing is now commonly used as a predictor of long-term stability. High-temperature tests can be performed at 37°C (98°F) and 45°C (113°F). If the product is stored at 45°C for three months (and exhibits acceptable stability), then it should remain stable at room temperature for two years. A good controlled temperature is 4°C (39°F), where most products exhibit good stability. Sometimes the product is also subjected to -10°C (14°F) for three months.

[0203] In some cases, the stability of the product is evaluated by three temperature test cycles from -10°C (14°F) to 25°C (77°F). In this case, the product is placed at -10°C for 24 hours and then at room temperature (25°C) for 24 hours. This completes one cycle. A more rigorous test is a five-cycle test from -10°C to 45°C. This puts the emulsion under tremendous stress.

[0204] The dispersed phase (of an oil-in-water emulsion) tends to separate and rise to the top of the emulsion, thus forming a layer of oil droplets. This phenomenon is called emulsification. Emulsification is one of the first signs of impending emulsion instability. One test to predict emulsification is centrifugation. The emulsion is heated to 50°C (122°F) and centrifuged at 3000 rpm for 30 minutes. The resulting product is then examined for signs of emulsification.

[0205] Both the formulation and packaging may be sensitive to UV radiation. The product is placed in glass and actually packaged in a lightbox with broad-spectrum output. Another glass jar completely covered with aluminum foil is used as a control. Discoloration of the product may be observed.

[0206] For all the above tests, color, odor / fragrance, viscosity, pH, and (if any) particle size uniformity and / or particle aggregation can be observed under a microscope.

[0207] Kits for non-invasive use

[0208] Some examples of the methods and compositions provided herein include kits comprising the peptides provided herein.In some embodiments, the kit may be provided to administering physicians, other healthcare professionals, patients, or caregivers. In some embodiments, the kit includes a container containing a peptide composition in a suitable topical composition, and instructions for administering the peptide composition to a subject. The kit may also optionally contain one or more additional therapeutic agents or other pharmaceutical agents. For example, a kit containing a peptide composition in a topical form may be provided with other skin care agents, such as cleansers, occlusive moisturizers, penetrating moisturizers, sunscreens, etc. The kit may contain a peptide composition in bulk form, or may contain individual doses of the peptide composition for continuous or sequential administration. The kit may optionally contain one or more diagnostic tools, administration tools, and / or instructions for use. The kit may contain a suitable delivery device, such as a syringe, pump dispenser, single-dose pack, etc., and instructions for administering the peptide composition and any other therapeutic agents or benefits. The kit may optionally contain instructions for the storage, reconstitution (if applicable), and administration of any or all of the contained therapeutic agents or benefits. The kit may contain multiple containers reflecting the number of applications to be given to the subject, or different products to be administered to the subject.

[0209] In some embodiments, the composition also works synergistically with the skin’s own natural regeneration process and helps improve the appearance and firmness of the skin. The topical composition is suitable for all skin types and postoperative skin. The topical composition may be provided to the patient in bulk form to allow the patient to self-apply an appropriate amount of peptide. For example, the patient may apply an amount sufficient to provide a uniform coating on the affected area or as directed by a physician. In some embodiments, it may be necessary to incorporate additional therapeutic agents or active agents into the topical composition. Alternatively, adjunctive therapies or agents may be applied alone. For example, cleansers, sunscreens, sunblocks, penetrating moisturizers, and / or occlusive moisturizers may be provided before or after the topical composition of the embodiments.

[0210] Various embodiments of creams, ointments, lotions, solutions, gels, sprays, and patches may combine peptide compositions as described herein as active ingredients with penetration enhancers and other active agents that synergistically act on the skin to promote wound healing or wound closure or treat chronic skin wounds.

[0211] Numbered Examples

[0212] Numbered Example 1 includes a topical composition for improving pigmentation, said topical composition comprising: one or more photosomes; one or more liposomes; hexapeptide-11; and hexapeptide-12; wherein said topical composition improves pigmentation. Numbered Example 2 includes the topical composition according to Numbered Example 1, wherein said one or more photosomes are present in an amount of about 0.1 wt.% to about 2 wt.%The content is present in the range of wt.%. Example 3, numbered, comprises the topical composition according to Examples 1-2, wherein the one or more photosomes are present in the range of about 0.25 wt.% to about 1 wt.%. Example 4, numbered, comprises the topical composition according to Examples 1-3, wherein the one or more photosomes encapsulate the one or more liposomes. Example 5, numbered, comprises the topical composition according to Examples 1-4, wherein the hexapeptide-11 is present in the range of 50-150 ppm. Example 6, numbered, comprises the topical composition according to Examples 1-5, wherein the hexapeptide-11 is present in the range of about 0.004 wt.% to about 0.100 wt.%. Example 7, numbered, comprises the topical composition according to Examples 1-6, wherein the hexapeptide-11 is encapsulated in a first liposome within the one or more liposomes. Example 8, numbered, comprises the topical composition according to Examples 1-7, wherein the hexapeptide-12 is encapsulated in a second liposome within the one or more liposomes. Example 9, numbered, comprises the topical composition according to Examples 1 through 8, wherein hexapeptide-11 and hexapeptide-12 are encapsulated in a first liposome within one or more liposomes. Example 10, numbered, comprises the topical composition according to Examples 1 through 9, wherein hexapeptide-12 comprises palmitoyl hexapeptide-12, myristoyl hexapeptide-12, or a combination thereof. Example 11, numbered, comprises the topical composition according to Examples 1 through 10, wherein hexapeptide-12 is present at 1-10 ppm. Example 12, numbered, comprises the topical composition according to Examples 1 through 11, wherein hexapeptide-12 is present in the range of about 0.001 wt.% to about 0.025 wt.%. Example 13, numbered, comprises the topical composition according to Examples 1 through 12, wherein the topical composition further comprises lactoferrin. Example 14, numbered, comprises the topical composition according to Examples 1 to 13, wherein the lactoferrin is present in an amount not exceeding about 0.25 wt.%. Example 15, numbered, comprises the topical composition according to Examples 1 to 14, wherein the lactoferrin is present in an amount ranging from about 0.005 wt.% to about 0.25 wt.%. Example 16, numbered, comprises the topical composition according to Examples 1 to 15, wherein the lactoferrin is encapsulated in a third liposome within one or more liposomes. Example 17, numbered, comprises the topical composition according to Examples 1 to 16, wherein the topical composition further comprises lactoferrin. (Specification page 39 / 50, 41 CN 121570573)A. White, wherein the lactoferrin, hexapeptide-11, and hexapeptide-12 are encapsulated in a first liposome within one or more liposomes. Example 18, numbered, comprises the topical composition according to Examples 1 through 17, wherein the topical composition further comprises a peptide derived from lactoferrin. Example 19, numbered, comprises the topical composition according to Examples 1 through 18, wherein the peptide derived from lactoferrin 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. Example 20, numbered, comprises the topical composition according to Examples 1 through 19, wherein the topical composition further comprises phosphatidylserine. Example 21, numbered, comprises the topical composition according to Examples 1 through 20, wherein the phosphatidylserine is present in an amount not exceeding about 0.075 wt.%. Example 22, numbered, comprises the topical composition according to Examples 1 through 21, wherein the phosphatidylserine is present in an amount ranging from about 0.005 wt.% to about 0.1 wt.%. Example 23, numbered, comprises the topical composition according to Examples 1 through 22, wherein the phosphatidylserine is present in an amount not exceeding 5.0 wt.%. Example 24, numbered, comprises the topical composition according to Examples 1 through 23, wherein the topical composition further comprises silymarin. Example 25, numbered, comprises the topical composition according to Examples 1 through 24, wherein the silymarin is present in an amount ranging from about 0.1 wt.% to about 1.0 wt.%. Example 26, numbered, comprises the topical composition according to Examples 1 to 25, wherein the silymarin is present in the range of about 0.2 wt.% to about 3.0 wt.%. Example 27, numbered, comprises the topical composition according to Examples 1 to 26, wherein the topical composition further comprises sesamol. Example 28, numbered, comprises the topical composition according to Examples 1 to 27, wherein the sesamol is present in the range of about 0.002 wt.% to about 0.050 wt.%. Example 29, numbered, comprises the topical composition according to Examples 1 to 28, wherein the topical composition further comprises tranexamic acid. Example 30, numbered, comprises the topical composition according to Examples 1 to 29, wherein the tranexamic acid is present in the range of about 1 wt.% to about 10 wt.%. Example 31, numbered, comprises the topical composition according to Examples 1 to 30, wherein the tranexamic acid is present in the range of about 0.25 wt.% to about 6.25 wt.%.The composition is present in the range of wt.%. Example 32, numbered, comprises the topical composition according to Examples 1 to 31, wherein the topical composition further comprises phytoene, phytohexene, or a combination thereof. Example 33, numbered, comprises the topical composition according to Examples 1 to 32, wherein the phytoene, phytohexene, or a combination thereof is present in the range of about 1 wt.% to about 10 wt.%. Example 34, numbered, comprises the topical composition according to Examples 1 to 33, wherein the topical composition further comprises Ashwagandha extract. Example 35, numbered, comprises the topical composition according to Examples 1 to 34, wherein the Ashwagandha extract is present in the range of about 0.020 wt.% to about 0.500 wt.%. Example 36, numbered, comprises the topical composition according to Examples 1 to 35, wherein the topical composition further comprises gallic acid. Example 37, numbered, comprises the topical composition according to Examples 1 to 36, wherein gallic acid is present in the range of about 0.40 wt.% to about 10 wt.%. Example 38, numbered, comprises the topical composition according to Examples 1 to 37, wherein the topical composition further comprises hesperidin. Example 39, numbered, comprises the topical composition according to Examples 1 to 38, wherein hesperidin is present in the range of about 0.020 wt.% to about 0.50 wt.%. Example 40, numbered, comprises the topical composition according to Examples 1 to 39, wherein the topical composition further comprises crinoid. Example 41, numbered, comprises the topical composition according to Examples 1 to 40, wherein crinoid is present in the range of about 0.50 wt.% to about 5.0 wt.%. Example 42, numbered, comprises the topical composition according to Examples 1 to 41, wherein the topical composition further comprises nicotinamide. Example 43, numbered, comprises the topical composition according to Examples 1 to 42, wherein the nicotinamide is present in the range of about 1 wt% to about 10 wt%. Example 44, numbered, comprises the topical composition according to Examples 1 to 43, wherein the topical composition further comprises oleuropein. Example 45, numbered, comprises the topical composition according to Examples 1 to 44, wherein the oleuropein is present in the range of about 0.030 wt% to about 0.750 wt%. Example 46, numbered, comprises the topical composition according to Examples 1 to 45, wherein the topical composition further comprises thermophilic thermocide enzymes. Example 47, numbered, comprises the topical composition according to Examples 1 to 46, wherein the thermophilic thermocide enzymes are present in the range of about 1 wt% to about 10 wt%.The fungal enzyme is present in the range of about 0.30 wt.% to about 7.5 wt.%. Example 48, numbered, comprises the topical composition according to Examples 1 to 47, wherein the topical composition further comprises *Tremella fuciformis*. Example 49, numbered, comprises the topical composition according to Examples 1 to 48, wherein the *Tremella fuciformis* is present in the range of about 0.20 wt.% to about 5.0 wt.%. Example 50, numbered, comprises the topical composition according to Examples 1 to 49, wherein the topical composition further comprises heptasodium hexacarboxymethyl dipeptide-12. Example 51, numbered, comprises the topical composition according to Examples 1 to 50, wherein the heptasodium hexacarboxymethyl dipeptide-12 is present in the range of about 0.1 wt.% to about 10 wt%. Example 52, numbered, comprises the topical composition according to Examples 1 to 51, wherein the heptasodium hexacarboxymethyl dipeptide-12 is present in the range of about 0.2 wt.% to about 5 wt%. Example 53, numbered, comprises the topical composition according to Examples 1 through 52, wherein the topical composition is aqueous. Example 54, numbered, comprises a topical composition for improving pigmentation, the topical composition comprising: hexapeptide-11; hexapeptide-12; and a peptide derived from lactoferrin; wherein the topical composition improves pigmentation. Example 55, numbered, comprises the topical composition according to Examples 1 through 54, wherein the hexapeptide-12 comprises palmitoyl hexapeptide-12, myristoyl hexapeptide-12, or a combination thereof. Example 56, numbered, comprises the topical composition according to Examples 1 through 55, wherein the hexapeptide-12 is present in a concentration of 1-10 ppm. Example 57, numbered, comprises the topical composition according to Examples 1 through 56, wherein the hexapeptide-12 is present in a concentration ranging from about 0.001 wt.% to about 0.025 wt.%. Example 58, numbered, comprises the topical composition according to Examples 1 through 57, wherein the hexapeptide-11 is present in an amount of 50-150 ppm. Example 59, numbered, comprises the topical composition according to Examples 1 through 58, wherein the hexapeptide-11 is present in an amount ranging from about 0.004 wt.% to about 0.100 wt.%. Example 60, numbered, comprises the topical composition according to Examples 1 through 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. Example 61, numbered, comprises the topical composition according to Examples 1 through 60.Compositions, wherein the topical composition further comprises phosphatidylserine. Example 62, numbered, comprises the topical composition according to Examples 1 to 61, wherein the phosphatidylserine is present at no more than about 0.075% by wt.%. Example 63, numbered, comprises the topical composition according to Examples 1 to 62, wherein the phosphatidylserine is present in the range of about 0.005 wt.% to about 0.1 wt.%. Example 64, numbered, comprises the topical composition according to Examples 1 to 63, wherein the phosphatidylserine is present at no more than 5.0 wt.%. Example 65, numbered, comprises the topical composition according to Examples 1 to 64, wherein the topical composition further comprises lactoferrin. Example 66, numbered, comprises the topical composition according to Examples 1 to 65, wherein the lactoferrin is present at no more than about 0.25 wt.%. Example 67, numbered, comprises the topical composition according to Examples 1 to 66, wherein the lactoferrin is present in the range of about 0.005 wt.% to about 0.25 wt.%. Example 68, numbered, comprises the topical composition according to Examples 1 to 67, wherein the topical composition further comprises a photon. Example 69, numbered, comprises the topical composition according to Examples 1 to 68, wherein the photon is present in the range of about 0.1 wt.% to about 2 wt.%. Example 70, numbered, comprises the topical composition according to Examples 1 to 69, wherein the topical composition further comprises silymarin, sesamol, tranexamic acid, phytohexanoic acid, hexahydrolycine, ashwagandha extract, hesperidin, crinoid, nicotinamide, oleuropein, thermophilic bacteria enzyme, tremella, heptasodium hexacarboxymethyl dipeptide-12, or combinations thereof. Example 71, numbered, comprises a topical composition according to Examples 1 through 70, wherein the topical composition is aqueous. Example 72, numbered, comprises a method for improving hyperpigmentation caused by a pigmentation disorder or disease, the method comprising applying a topical composition according to Examples 1 through 71. Example 73, numbered, comprises the method according to Examples 1 through 72, wherein the topical composition further comprises a pigmentation disorder or disease of hyperpigmentation. Example 74, numbered, comprises the method according to Examples 1 through 73, wherein the topical composition further comprises a pigmentation disorder or disease of post-inflammatory hyperpigmentation (PIH). Example 75, numbered, comprises the method according to Examples 1 through 74, wherein the topical composition further comprises a pigmentation disorder or disease of focal hypopigmentation.A pigmentary disorder or disease of diffuse hypopigmentation. Example 76, numbered, comprises the method according to Examples 1 through 75, wherein the topical composition further comprises a pigmentary disorder or disease of acanthosis nigricans, senile lentigines, albinism, pigmentary disorders, freckles, melasma, pityriasis alba, or progressive pigmented purpura.

[0213] Examples

[0214] The following examples are given for the purpose of illustrating various embodiments of the present disclosure and are not intended to limit the present disclosure in any way. The examples, together with the methods described herein, currently represent exemplary preferred embodiments and are not intended to limit the scope of the present disclosure. Variations and other uses covered within the spirit of the present disclosure as defined by the scope of the claims will be apparent to those skilled in the art.

[0215] Example 1: Exemplary Compositions and Regulation of Gene Expression

[0216] Exemplary compositions are shown in Table 2. In addition, the compounds and concentrations listed in Tables 3 and 4 can be analyzed to evaluate their effects on the expression of genes important for regulating melanin production. Specifically, the effects of these compounds on gene expression in endothelial cells, melanocytes, fibroblasts, and keratinocytes were analyzed. Gene sequencing analysis, bioinformatics, and gene ontology analysis were performed.

[0217] Table 2: Compound 1 Specification 42 / 50 pages 44 CN 121570573 A

[0218]

[0219] Table 3: Compound 2

[0220]

[0221] Table 4: Compound 3 Specification 43 / 50 pages 45 CN 121570573 A

[0222]

[0223] Example 2: Synergistic effect of combined tripeptide-1 and hexapeptide-12 - skin pigmentation

[0224] Microphthalmia-associated transcription factor (MITF) is a major regulator of pigmentation and melanin transfer (Figure 2) and a potential new target for hyperpigmentation and melanoma. In vitro MITF gene expression assays were performed to determine the differences in MITF downregulation between individual peptides (tripeptide-1 and hexapeptide-12) and their combinations.

[0225] Specifically, the assay was performed by culturing fibroblasts and then adding tripeptide-1, hexapeptide-12, or a combination of both. MITF gene expression was analyzed after 48 hours. As shown in Table 5 below, MITF gene analysis showed that individual peptides had limited effect on MITF downregulation. In fact, while hexapeptide-12 alone showed negligible MITF downregulation (-1.16), tripeptide-1 alone showed slight MITF upregulation (+1.72). However, when mixed together, MITF downregulation increased significantly (-4.17). This increased expression continued to be present at the 72-hour time point and increased further.

[0226] Table 5.

[0227]

[0228] * 80 ppm hexapeptide refers to the concentration of hexapeptide-12 in the vector; 120ppm tripeptide refers to the concentration of tripeptide-1 in the carrier; a peptide blend of 80 ppm hexapeptide and 120 ppm tripeptide

[0229] The data showed that tripeptide-1 and hexapeptide-12 had a synergistic effect on MITF gene expression.

[0230] Example 3: Gene Expression Study

[0231] Gene expression in four cell types associated with the pigmentation pathway—melanocytes, keratinocytes, fibroblasts, and endothelial (HUVEC) cells—was analyzed.

[0232] Methods

[0233] To simulate the UV-stimulated pigmentation pathway process, melanocytes were pretreated with PGE2, a normal direct consequence of UV light exposure from exposed keratinocytes (Figure 1). After 48 hours of adherent culture, these melanocytes were induced in melanocyte culture medium with 10 uM PGE2 for 24 hours. Four primary human adult dermal cell lines were cultured and seeded in three wells in a single batch (page 44 / 50, CN 121570573 A, according to the instruction manual). The cells were then treated with 11 different compounds (plus a DMSO control). After 48 hours of adherent culture, the remaining fibroblasts, HUVECs, and keratinocytes were treated with the test compounds listed in Table 6.

[0234] Table 6: Compounds used for gene expression studies

[0235]

[0236] After 24 hours of compound exposure, RNA lysate preparation was performed, and the samples were transported to MedGenome for RNA extraction, library construction, and sequencing, achieving 25M paired-end 100 bp reads per sample. Library preparation and sequencing were performed in MedGenome.

[0237] Results

[0238] Among the four cell lines, it was possible to identify active compounds with significant melanin-producing activity in three cell lines—melanocytes, keratinocytes, and HUVECS. Fibroblast cell lines exhibited various functions unrelated to melanin production activity and not further utilized (primarily wound healing). Activation of melanocyte activity pathways was found (Figs. 3A-3D). Hexapeptide-12 (Hex12) and lactoferrin (lacto) were particularly dominant in melanin production activity. Figs. 4 and 5 show the downregulation of melanin production genes associated with hexapeptide-12 (Hex12) and lactoferrin (lacto). Similarly, Figs. 6A-6F show gene expression data for SCF, LIF, POMC, endothelin genes, PGE2, and NGF in keratinocytes in response to the various compounds listed in Table 6. The data indicate that hexapeptide-11 (Hex11) is the active component in melanin production activity, while Fig. 7 shows Hex-11 activity alone. Figs. 8A-8C show the response of HUVECs to the various compounds listed in Table 6 for EDN-1 (EDN1) (Fig. 8A).Data on gene expression of SCF (Fig. 8B) and TGFB1 (Fig. 8C). Fig. 9 shows the effective activity of phosphatidylserine on EDN1 and other melanin-producing genes.

[0239] Conclusion

[0240] Cell line melanin-producing gene activity assays identified lactoferrin, hexapeptide-11, hexapeptide-12 and phosphatidylserine as having significant effects on melanin-producing activity.

[0241] Example 4: Comparative analysis of in vitro melanocytes by absorbance readings

[0242] The melanocyte model was designed to test reagents to demonstrate the direct effects of absorbance on melanocytes and melanin production from compound-treated melanocyte samples.

[0243] Methods

[0244] Melanocytes were cultured in 6-well plates containing growth medium. Once confluenced, two concentrations of each of the 10 compounds were added to the cells in triplicate wells for 4 days. Eleven 6-well plates were used, one for each compound treatment and one for the vector control. Absorbance readings were taken from the lysates prepared for each well of a 6-well plate to normalize cell counts. The model was initially tested for accuracy based on the strong gene expression results of the melanocyte line in the first study and validated using hexapeptide-12 – confirming reduced stimulation. Further validation was performed using MSH added to the culture medium using the instruction manual (pages 45 / 50, 47 CN 121570573 A) to confirm increased stimulation of melanin production. The following compounds used in this study are listed in Table 7.

[0245] Table 7: Test compounds used for comparative analysis of melanocytes in vitro

[0246]

[0247] Results

[0248] Table 8 shows the results of three absorption spectra of the selected compounds at two concentrations.

[0249] Table 8: Absorption spectra of the selected compounds at 405 nm, 490 nm, and 492 nm

[0250]

[0251] This test confirmed the efficacy of these selected reagents in reducing melanin production in melanocytes (the percentage reduction in absorption indicates a reduction in melanin formation). The regulation of melanin production by lactoferrin, hexapeptide-11, hexapeptide-12, and phosphatidylserine was observed. The regulatory effects of silymarin, sesamol, tranexamic acid, and phytoene / hexahydrolycopene on melanin production were also observed (Table 8). Specification 46 / 50 pages 48 CN 121570573 A

[0252] Example 5: Gene Expression Study

[0253] The melanocyte model was designed to test the reagents to demonstrate the direct effects of absorption on melanocytes and melanin production from melanocyte samples treated with the compounds.

[0254] Methods

[0255] The expression of PMEL, tyrosinase genes, MC1 / 4R, EDNRB, MITF, ERK1 / 2, JNK, and ANKT1 was measured using methods similar to those in Examples 3-4.

[0256] Results

[0257] Figures 10A-10D show the expression of endothelial cells after treatment with lactoferrin (Lacto), lactoferrin-derived peptide (TCV), hexapeptide-12 (Hex12), tripeptide-1 and hexapeptide-12 (TriHex), hexapeptide-11 (Hex11), tranexamic acid, octapeptide (Octa), phosphatidylserine (phos), cannabidiol (CBD), and all (total) PMEL (Figure 10A), tyrosinase genes (Figure 10B), MC1 / 4R (Figure 10C), and EDNRB (Figure 10D). Figures 10A-10D show the robust melanogenesis activity exhibited by hexapeptide-12 and lactoferrin. Figure 11 shows the data for hexapeptide-12.

[0258] MITF is regulated by phosphorylation. Specifically, the MAPK and Akt pathways are known to phosphorylate MITF at certain sites. Figures 12A-12C show the expression of lactoferrin (Lacto), lactoferrin-derived peptide (TCV), hexapeptide-12 (Hex12), tripeptide-1 and hexapeptide-12 (TriHex), hexapeptide-11 (Hex11), octapeptide (Octa), phosphatidylserine (phos), cannabidiol (CBD), and all (total) ERK1 / 2 (MAPK3 / MAPK1) (Figure 12A), JNK (Figure 12B), and AKT1 (Figure 12C) after endothelial cell treatment.

[0259] Conclusion

[0260] In summary, the increased expression of these kinases may be associated with reduced MITF expression and may therefore contribute to reduced melanin production. Hexapeptide-12 and lactoferrin have significant effects on this type of melanin-producing activity.

[0261] Example 6: Melanocyte Assay

[0262] hTERT immortalized dermal melanocytes were treated with various compounds. Experimental materials and results are presented below.

[0263] Methods

[0264] Primary human melanocytes were obtained from ATCC (catalog number ATCC CRL-4059). Melanocytes were initially seeded 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)). Melanocytes were then expanded to 10 cm tissue culture plates at the concentration recommended by ATCC. Cells appeared to adhere completely to the plate / plate and were cultured in a mesh-like morphology. Cells were cultured in a 37°C 5% CO2 incubator.

[0265] Stock of compounds 1 to 10 listed below were suspended in complete melanocyte growth medium or DMSO (indicated in parentheses). The resuspension of each compound was then diluted in melanocyte growth medium to the final concentration in Table 9.

[0266] Table 9: Compounds for comparative analysis of melanocytes in vitro 47 / 50 pages 49 CN 121570573 A

[0267]

[0268] Once the melanocytes were 100% confluent in the 6-well plate, the melanocyte growth medium was removed and the melanocytes were treated with a medium containing the above-mentioned compounds; for each compound / concentration listed above, the wells were replicated. The replicated mediator control wells were fed only to melanocyte growth medium or melanocyte growth medium with DMSO (10 uL per 10 mL of melanocyte growth medium).

[0269] Over the next 5 days, the cells were fed to the appropriate medium. Cell morphology was checked daily. All cells maintained normal morphology throughout the five-day dosing period, except as described below:

[0270] Melanocytes cultured in a medium containing lactoferrin (concentrations of 500 and 1000 ug / mL) formed a round morphology instead of the normal reticular morphology 24 hours after the initial dosing. Interestingly, melanocytes returned to their normal morphology 48 hours after initial administration and maintained this morphology during the 5-day administration period.

[0271] Melanocytes cultured in medium containing Ashwagandha (at concentrations of 10 and 20 ug / mL) began to die 24 hours after initial administration and continued to die until all melanocytes were dead 48 hours after initial administration.

[0272] Melanocytes cultured in medium containing oleuropein (at concentrations of 500 and 1000 ug / mL) began to die 24 hours after initial administration and continued to die until almost all melanocytes were dead 72 hours after initial administration.

[0273] Lysates were prepared for each sample. Briefly, 6.6 x 10^5 cells from each sample were vortexed and collected in a vial. 150 μL of CHAPS lysis buffer was added to each replicated sample, vortexed, and placed in a dry ice / ethanol bath for 2 minutes, then finely thawed at room temperature. This freeze-thaw cycle was repeated once, for a total of two freeze / thaw cycles. The lysate sample was rotated at 14,800 rpm for 15 minutes. The supernatant was removed, leaving a black precipitate in the vial. The precipitate was resuspended in 100 μL of 1 M NaOH / 10% DMSO solution and incubated at 80 °C for 90 minutes, mixed by pipette at 30, 60, and 90 minutes.

[0274] Results

[0275] 100 μL of each replicate sample of each concentration was added to the individual wells of a flat-bottomed 96-well plate, and absorbance readings were taken at 405 nm, 490 nm, and 492 nm on an Envision 2103 Multilabel reader.

[0276] Table 10: Absorbance readings at 405 nm, 490 nm, and 492 nmPages 48 / 50 50 CN 121570573 A

[0277]

[0278] Example 7: Full-Formulation Melanocyte Assay

[0279] The compounds and concentrations from the original stock solutions of Example 6 were combined to create a full-formulation medium for melanocyte culture.

[0280] Method

[0281] The compounds and concentrations from the original stock solutions in Table 11 below were combined to create a 50 mL full-formulation medium for culturing melanocytes in 6-well plates for 5 days. The mediums used are shown in parentheses.

[0282] Table 11. Compounds and concentrations used in Example 7

[0283]

[0284] Once the melanocytes were 100% confluent in the 6-well plates, the melanocyte growth medium was removed and the melanocytes were treated in replicated wells with a medium containing the full-formulation medium described above. The replicated media control wells were fed into melanocyte growth medium containing DMSO (20 μL per 10 mL of melanocyte growth medium). Over the next 5 days, the cells were fed to the appropriate culture medium. Cell morphology was checked daily. All cells maintained normal morphology throughout the five-day dosing period.

[0285] Lysates were prepared as in Example 6 for each well sample containing a replication of melanocytes grown in the full formulation medium and for each well sample containing a replication of melanocytes grown in the mediator control medium.

[0286] Results

[0287] 100 μL of each replication sample was added to a flat-bottomed 96-well plate, and absorbance readings were taken at 405 nm, 490 nm, and 492 nm on an Envision 2103 Multilabel reader. The readings are shown in Table 12.

[0288] Table 12: Absorbance readings at 405 nm, 490 nm and 492 nm

[0289]

[0290] Example 8: Dual Liposomes

[0291] This example demonstrates the preparation of dual liposomes for the formulations described herein.

[0292] In the first step, 0.90 wt.% (wt.%) of Pro-Lipo NEO, 0.02 wt.% of hexapeptide-11, 0.005 wt.% of hexapeptide-12 and 0.10 wt.% of lactoferrin were combined to form a liposome solution. 0.50 wt.% of photoliposomes were added to the liposome solution to generate dual liposomes.

[0293] While preferred embodiments of the present disclosure have been shown and described herein, it will be apparent to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, changes and substitutions will now occur to those skilled in the art without departing from the present disclosure. It should be understood that the present disclosure described herein...Various alternatives to the embodiments can be used to practice this disclosure. The intent of this invention is that the following claims define the scope of this disclosure and thus cover the methods and structures within the scope of these claims and their equivalents. Instruction manual 50 / 50 pages 52 CN 121570573 A Figure 1 Figure 2 Instruction manual drawing 1 / 20 pages 53 CN 121570573 A Figure 3A Instruction manual drawing 2 / 20 pages 54 CN 121570573 A Figure 3B Instruction manual drawing 3 / 20 pages 55 CN 121570573 A Figure 3C Instruction manual drawing 4 / 20 pages 56 CN 121570573 A Figure 3D Instruction manual drawing 5 / 20 pages 57 CN 121570573 A Figure 4 Instruction manual drawing 6 / 20 pages 58 CN 121570573 A Figure 5 Instruction manual drawing 7 / 20 pages 59 CN 121570573 A Figure 6A Figure 6B Instruction manual drawing 8 / 20 pages 60 CN 121570573 A Figure 6C Figure 6D Instruction manual drawing 9 / 20 pages 61 CN 121570573 A Figure 6E Figure 6F Instruction Manual Drawings, Page 10 / 20, 62 CN 121570573 A Figure 7 Instruction Manual Drawings, Page 11 / 20, 63 CN 121570573 A Figure 8A Figure 8B Instruction Manual Drawings, Page 12 / 20, 64 CN 121570573 A Figure 8C Instruction Manual Drawings, Page 13 / 20, 65 CN 121570573 A Figure 9 Instruction Manual Drawings, Page 14 / 20, 66 CN 121570573 A Figure 10A Instruction Manual Drawings, Page 15 / 20, 67 CN 121570573 A Figure 10B Instruction Manual Drawings, Page 16 / 20, 68 CN 121570573 A Figure 10C Instruction Manual Drawings, Page 17 / 20, 69 CN 121570573 A Figure 10D Instruction Manual Drawings, Page 18 / 20, 70 CN 121570573 A Figure 11 Figure 12A Instruction Manual Appendix Page 19 / 20 71 CN 121570573 A Figure 12B Figure 12C Instruction Manual Appendix Page 20 / 20 72 CN 121570573 A Abstract Abdominal ultrasound examination method, system and deviceDisclosed herein are compositions and methods for improving pigmentation. Compositions as described herein comprise one or more peptides.

Claims

1. The use of a composition comprising hexapeptide-11, hexapeptide-12 and a peptide derived from lactoferrin in the preparation of a medicament for improving pigmentation caused by a pigmentation disorder or disease, wherein the composition comprises: 0.004 wt.% to 0.100 wt.% of hexapeptide-11, wherein hexapeptide-11 downregulates the expression of SCF, LIF, POMC, EDN1, PGE2 or NGF genes in human keratinocytes; And, 0.001 wt.% to 0.025 wt.% of hexapeptide-12, wherein the hexapeptide-12 downregulates the expression of MAPK1, MITF, JNK, EDNRB, DCT, TYR, TYRP1 or PMEL genes in endothelial cells, or downregulates the expression of MAPK1, MAPK3, MAP2K1, MAP2K2, POMC or CTNNB1 genes in melanocytes.

2. The application according to claim 1, wherein the pigmentation disorder or disease is hyperpigmentation.

3. The application according to claim 1, wherein the pigmentation disorder or disease is post-inflammatory hyperpigmentation (PIH).

4. The application according to claim 1, wherein the pigmentation disorder or disease is focal hypopigmentation or diffuse hypopigmentation.

5. The application according to claim 1, wherein the pigmentation disorder or disease is acanthosis nigricans, age spots, albinism, pigmentary disorders, freckles, melasma, pityriasis alba, or progressive pigmentary purpura.

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