Topical Compositions and Methods for Treating Dermatoporosis

Abstract

Disclosed herein are topical compositions comprising Centella asiatica (Centella asiatica) extract and mandelic acid, wherein the composition has a pH of less than 5, and methods of using the compositions to reduce cellular senescence in the skin and treat dermatoporosis. The topical composition comprising Centella asiatica extract and mandelic acid is effective in reducing the number of senescent cells in mammalian dermis, reducing the senescence-associated secretory phenotype (SASP), downregulating at least one SASP-related gene, increasing the expression of at least one cell cycle-related gene in dermal fibroblasts, downregulating at least one gene associated with skin inflammation, and increasing fibroblast turnover.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority under 35 U.S.C. §119(e) to U.S. Provisional Application No. 63 / 442,424, filed January 31, 2023, the entire contents of which are incorporated herein by reference. [Background technology]

[0002] The present disclosure relates generally to the field of topical compositions and methods of using the same. Specifically, the disclosure relates to topical compositions for treating and / or reducing the effects of dermatoporosis. Dermatoporosis is a term referring to chronic skin failure and fragility leading to loss of function, ultimately resulting in the breakdown of human skin's protective mechanisms. People with dermatoporosis exhibit atrophic, thinning skin that becomes fragile, exhibits purpura and white pseudoscars on the extremities, has a tendency to tear, and can lead to deep dissecting hematomas. See G. Kaya, et al., "Dermatoporosis, a Prevalent Skin Condition Affecting the Elderly: Current Situation and Potential Treatments," 37 Clinics Dermatol. 346-50 (2019) (Non-Patent Document 1). The progression of dermatoporosis can lead to skin cracking, delayed healing, bleeding, skin infections, and ultimately, medical emergencies.

[0003] Dermatoporosis first appears between the ages of 40 and 60, with the disease reaching full onset between the ages of 70 and 90 (a potential 50-year span). As members of the post-World War II "baby boom" generation continue to age and the population shifts toward a higher proportion of people aged 65 and over, the prevalence of dermatoporosis is likely to increase. Among this generation, full-on dermatoporosis is fairly common, with two French studies placing prevalence rates at 32% and 37.5%. See JH Saurat, et al., "A Simple Self-Diagnosis Tool to Assess the Prevalence of Dermatoporosis in France," 31 J. Eur. Acad. Dermatol. Venereol. 1380-86 (2017) (Non-Patent Document 2); V. Mengeaud, et al., "Prevalence of Dermatoporosis in Elderly French Hospital In-Patients: A Cross-Sectional Study," 166 Br. J. Dermatol. 442-43 (2012) (Non-Patent Document 3). Thus, improved compositions and methods for treating and / or reducing the effects of dermatoporosis would be of great benefit. [Prior art documents] [Non-patent literature]

[0004] [Non-Patent Document 1] G. Kaya, et al., “Dermatoporosis, a Prevalent Skin Condition Affecting the Elderly:Current Situation and Potential Treatments,” 37 Clinics Dermatol.346-50(2019) [Non-patent document 2] JHSaurat,et al.,“A Simple Self-Diagnosis Tool to Assess the Prevalence of Dermatoporosis in France,”31 J.Eur.Acad.Dermatol.Venereol.1380-86(2017) [Non-patent document 3] V. Mengeaud, et al., “Prevalence of Dermatoporosis in Elderly French Hospital In-Patients:A Cross-Sectional Study,” 166 Br.J.Dermatol.442-43(2012) Summary of the Invention

[0005] In one aspect, which may be combined with any other aspect or embodiment, the present disclosure relates to a topical composition comprising a liposomally encapsulated Centella asiatica extract and an alpha hydroxy acid (AHA), wherein the composition has a pH of less than 5. In some embodiments, the composition is in the form of an emulsion. In some embodiments, the emulsion is an oil-in-water (O / W) emulsion.

[0006] In some embodiments, the pH of the composition is greater than or equal to 4 and less than 5. In some embodiments, the Centella asiatica extract is present at a concentration of at least about 0.01% and less than 0.2% by weight, based on the total weight of the composition. In some embodiments, the Centella asiatica extract is present at a concentration of about 0.01% to about 0.1% by weight, based on the total weight of the composition.

[0007] In some embodiments, the Centella asiatica extract comprises a triterpene. In some embodiments, the triterpene is one or more selected from the group consisting of madecassoside, asiaticoside, madecassic acid, and asiatic acid. In some embodiments, the triterpene is present in the Centella asiatica extract at a concentration of at least about 70% by weight, based on the total weight of the Centella asiatica extract. In some embodiments, the triterpene is present in the composition at a concentration of at least about 0.005% by weight and less than 0.2% by weight, based on the total weight of the composition. In some embodiments, the triterpene is present in the Centella asiatica extract at a concentration of at least about 0.01% to about 0.05% by weight, based on the total weight of the composition.

[0008] In some embodiments, the AHA comprises mandelic acid. In some embodiments, the AHA is present at a concentration of at least about 0.01% and less than 0.5% by weight based on the total weight of the composition. In some embodiments, the AHA is present at a concentration of about 0.05% to about 0.3% by weight based on the total weight of the composition.

[0009] In some embodiments, the liposomes are present at a concentration of about 0.03% to about 4% by weight, based on the total weight of the composition. In some embodiments, the liposomes comprise lecithin, propanediol, or a combination thereof. In some embodiments, the liposomes comprise an antioxidant. In some embodiments, the antioxidant is tocopherol, tocopheryl acetate, or a combination thereof. In some embodiments, the liposomes have an average particle size of 100 nm to 300 nm. In some embodiments, the liposomes have an average particle size of about 250 nm.

[0010] In some embodiments, the Centella asiatica extract is present in an active solution. In some embodiments, the liposomes and active solution are present in a weight ratio of about 1:1 to about 1:20. In some embodiments, the liposomes and active solution are present in a weight ratio of about 1:2 to about 1:10.

[0011] In some embodiments, the Centella asiatica extract and the AHA are present in a weight ratio of about 1:5 to 1:15.

[0012] In some embodiments, the topical composition further comprises an antioxidant separate from any antioxidant in the liposome, hi some embodiments, the antioxidant separate from any antioxidant in the liposome is tocopheryl acetate, tocopherol, or a combination thereof.

[0013] In some embodiments, the topical composition further comprises at least one of a moisturizer, an emollient, or a humectant, hi some embodiments, the topical composition further comprises glycerin.

[0014] In some embodiments, the topical composition is a cream or lotion.

[0015] In another aspect that may be combined with any other aspect or embodiment, the present disclosure relates to a topical composition comprising a Centella asiatica extract, wherein the Centella asiatica extract is encapsulated in liposomes, and an alpha hydroxy acid (AHA), wherein the composition is an emulsion, and wherein the composition has a pH of 4 to 5, and wherein the composition reduces biomarkers of skin inflammation in mammalian skin cells.

[0016] In another aspect that may be combined with any other aspect or embodiment, the present disclosure relates to a topical composition comprising an alpha hydroxy acid (AHA) and a triterpene selected from the group consisting of madecassoside, asiaticoside, madecassic acid, and asiatic acid, wherein the triterpene is encapsulated in a liposome, and the composition has a pH of 4 to 5. In some embodiments, the AHA comprises mandelic acid.

[0017] In some embodiments, the AHA is present in the composition at a concentration of at least about 0.01% and less than 0.5% by weight, based on the total weight of the composition.

[0018] In some embodiments, the triterpene is present in the composition at a concentration of at least about 0.005% by weight and less than 0.2% by weight, based on the total weight of the composition.

[0019] In some embodiments, the composition is an emulsion.

[0020] In some embodiments, the topical compositions of the present disclosure are effective in reducing the number of senescent cells in the dermis of a mammal.

[0021] In some embodiments, the topical compositions of the present disclosure are effective in reducing the senescence-associated secretory phenotype (SASP) in mammalian epidermal cells.

[0022] In some embodiments, the topical compositions of the present disclosure are effective in downregulating at least one SASP-associated gene selected from the group consisting of IL8, IL1B, HIST1H2BG, and UBE2C.

[0023] In some embodiments, the topical composition of the present disclosure is effective in increasing the expression of at least one cell cycle gene in mammalian dermal fibroblasts. In some embodiments, the at least one cell cycle gene in mammalian fibroblasts is selected from the group consisting of TK1, NDC80, HMMR, KIF2C, UBEC, LMNB1, CABLES1, MCM10, H2AFX, CASC5, ESCO2, ERCC6L, BUB1, BIRC5, CCNE2, GTSE1, CDCA8, WEE1, CDC45, CDK1, CCNB2, CLSPN, BUB1B, PKMYT1, KIF23, TPX2, KIF20A, and NCAPH.

[0024] In some embodiments, the topical compositions of the present disclosure are effective in downregulating at least one gene associated with skin inflammation selected from the group consisting of MMP2, HSPA8, CSF2RA, CXCL1, IL2RB, NFKBIA, and PTGS2.

[0025] In some embodiments, the topical compositions of the present disclosure are effective in downregulating at least one transcription factor of the AP-1 complex, in some embodiments, the transcription factor of the AP-1 complex is at least one selected from JunB and FosL2.

[0026] In some embodiments, the topical compositions of the present disclosure are effective in activating cell cycle progression by upregulating CCNE2, CCNB1, or a combination thereof.

[0027] In some embodiments, in the topical compositions of the present disclosure, the Centella asiatica extract and AHA are present at concentrations effective to synergistically down-regulate at least one SASP-related gene selected from the group consisting of IL8, IL1B, HIST1H2BG, and UBE2C.

[0028] In some embodiments, in the topical compositions of the present disclosure, the Centella asiatica extract and the AHA are present at concentrations effective to synergistically upregulate at least one cell cycle gene in mammalian dermal fibroblasts selected from the group consisting of TK1, NDC80, HMMR, KIF2C, UBEC, LMNB1, CABLES1, MCM10, H2AFX, CASC5, ESCO2, ERCC6L, BUB1, BIRC5, CCNE2, GTSE1, CDCA8, WEE1, CDC45, CDK1, CCNB2, CLSPN, BUB1B, PKMYT1, KIF23, TPX2, KIF20A, and NCAPH.

[0029] In some embodiments, in the topical compositions of the present disclosure, the Centella asiatica extract and AHA are present at concentrations effective to synergistically down-regulate at least one SASP-related gene selected from the group consisting of IL8, IL1B, HIST1H2BG, and UBE2C.

[0030] In some embodiments, in the topical compositions of the present disclosure, the Centella asiatica extract and AHA are present at concentrations effective to synergistically down-regulate at least one transcription factor of the AP-1 complex. In some embodiments, the transcription factor of the AP-1 complex is at least one selected from JunB and FosL2.

[0031] In some embodiments, in the topical compositions of the present disclosure, the Centella asiatica extract and AHA are present at concentrations effective to synergistically activate cell cycle progression by upregulating CCNE2, CCNB1, or a combination thereof.

[0032] In some embodiments, in the topical compositions of the present disclosure, the triterpene and AHA are present at concentrations effective to synergistically down-regulate at least one SASP-related gene selected from the group consisting of IL8, IL1B, HIST1H2BG, and UBE2C.

[0033] In some embodiments, in the topical compositions of the present disclosure, the triterpene and AHA are present at concentrations effective to synergistically upregulate at least one cell cycle gene in mammalian dermal fibroblasts selected from the group consisting of TK1, NDC80, HMMR, KIF2C, UBEC, LMNB1, CABLES1, MCM10, H2AFX, CASC5, ESCO2, ERCC6L, BUB1, BIRC5, CCNE2, GTSE1, CDCA8, WEE1, CDC45, CDK1, CCNB2, CLSPN, BUB1B, PKMYT1, KIF23, TPX2, KIF20A, and NCAPH.

[0034] In some embodiments, in the topical compositions of the present disclosure, the triterpene and AHA are present at concentrations effective to synergistically down-regulate at least one SASP-related gene selected from the group consisting of IL8, IL1B, HIST1H2BG, and UBE2C.

[0035] In some embodiments, in the topical compositions of the present disclosure, the triterpene and AHA are present at concentrations effective to synergistically down-regulate at least one transcription factor of the AP-1 complex. In some embodiments, the transcription factor of the AP-1 complex is at least one selected from JunB and FosL2.

[0036] In some embodiments, in the topical compositions of the present disclosure, the triterpene and AHA are present at concentrations effective to synergistically activate cell cycle progression by upregulating CCNE2, CCNB1, or a combination thereof.

[0037] In another aspect, which may be combined with any other aspect or embodiment, the present disclosure relates to a method of treating skin affected by dermatoporosis, the method comprising administering to the affected skin a topical composition of the present disclosure.

[0038] In another aspect that may be combined with any other aspect or embodiment, the present disclosure relates to a method of increasing fibroblast turnover in mammalian skin, the method comprising administering to the mammalian skin a topical composition of any one of claims 1-47.

[0039] In another aspect, which may be combined with any other aspect or embodiment, the present disclosure relates to a method of reducing the number of senescent cells in the dermis of a mammal, the method comprising administering to the skin of the mammal a topical composition of the present disclosure.

[0040] In another aspect, which may be combined with any other aspect or embodiment, the present disclosure relates to a method of reducing senescence-associated secretory phenotype (SASP) in epidermal cells of a mammal, the method comprising administering to the skin of the mammal a topical composition of the present disclosure.

[0041] In another aspect that may be combined with any other aspect or embodiment, the present disclosure relates to a method for downregulating at least one SASP-related gene in mammalian skin, the method comprising administering a topical composition of the present disclosure to the mammalian skin, wherein the at least one SASP-related gene is selected from the group consisting of IL8, IL1B, HIST1H2BG, and UBE2C.

[0042] In another aspect that may be combined with any other aspect or embodiment, the present disclosure relates to a method of increasing expression of at least one cell cycle gene in mammalian dermal fibroblasts, the method comprising administering to mammalian skin a topical composition of the present disclosure, wherein the at least one cell cycle gene in the mammalian fibroblasts is selected from the group consisting of TK1, NDC80, HMMR, KIF2C, UBEC, LMNB1, CABLES1, MCM10, H2AFX, CASC5, ESCO2, ERCC6L, BUB1, BIRC5, CCNE2, GTSE1, CDCA8, WEE1, CDC45, CDK1, CCNB2, CLSPN, BUB1B, PKMYT1, KIF23, TPX2, KIF20A, and NCAPH.

[0043] In another aspect that may be combined with any other aspect or embodiment, the present disclosure relates to a method of downregulating at least one gene associated with skin inflammation, the method comprising administering to the skin of a mammal a topical composition of the present disclosure, wherein the at least one gene associated with skin inflammation is selected from the group consisting of MMP2, HSPA8, CSF2RA, CXCL1, IL2RB, NFKBIA, and PTGS2.

[0044] In another aspect that may be combined with any other aspect or embodiment, the present disclosure relates to a method for downregulating at least one transcription factor of the AP-1 complex, the method comprising administering to mammalian skin a topical composition of the present disclosure. In some embodiments, the transcription factor of the AP-1 complex is at least one selected from JunB and FosL2.

[0045] In another aspect that may be combined with any other aspect or embodiment, the present disclosure relates to a method of activating cell cycle progression, the method comprising administering to mammalian skin a topical composition of the present disclosure, wherein the composition upregulates CCNE2, CCNB1, or a combination thereof.

[0046] Additional aspects and / or embodiments of the present invention are provided in the detailed description of the technology set forth below, which is illustrative and explanatory but not intended to be limiting. [Brief explanation of the drawings]

[0047] Various objects, aspects, features and advantages will become more apparent and be better understood by reference to the detailed description taken in conjunction with the accompanying drawings.

[0048] [Figure 1A] 1 is a plot of fluorescence emission (590 nm) versus concentration of Centella asiatica extract in human dermal fibroblasts in an Alamar Blue assay. [Figure 1B] 1 is a plot of fluorescence emission (590 nm) versus concentration of Centella asiatica extract in human skin keratinocytes in an Alamar Blue assay. [Figure 1C] 1 is a plot of fluorescence emission (590 nm) versus concentration of mandelic acid in human dermal fibroblasts in an Alamar Blue assay. [Figure 1D] 1 is a plot of fluorescence emission (590 nm) versus concentration of mandelic acid in human skin keratinocytes in an Alamar Blue assay. [Figure 2] FIG. 1 is a schematic diagram of biomarkers associated with senescence in dermal cells. [Figure 3A] 1 is a plot of IL8 gene expression in human keratinocytes grown to confluence and treated with a composition comprising Centella asiatica extract, mandelic acid, or a combination of Centella asiatica extract and mandelic acid. [Figure 3B]1 is a plot of IL1B gene expression in human keratinocytes grown to confluence and treated with a composition comprising Centella asiatica extract, mandelic acid, or a combination of Centella asiatica extract and mandelic acid. [Figure 3C] 1 is a plot of HIST1H2BG gene expression in human keratinocytes grown to confluence and treated with a composition comprising Centella asiatica extract, mandelic acid, or a combination of Centella asiatica extract and mandelic acid. [Figure 3D] 1 is a plot of UBE2C gene expression in human keratinocytes grown to confluence and treated with a composition comprising Centella asiatica extract, mandelic acid, or a combination of Centella asiatica extract and mandelic acid. [Figure 4A] 1 is a plot of MMP2 gene expression (fold change) in human keratinocytes grown to confluence and treated with a composition comprising Centella asiatica extract, mandelic acid, or a combination of Centella asiatica extract and mandelic acid. [Figure 4B] Plot of HSPA8 gene expression (fold change) in human keratinocytes grown to confluence and treated with a composition containing Centella asiatica extract, mandelic acid, or a combination of Centella asiatica extract and mandelic acid. [Figure 4C] 1 is a plot of CSF2RA (fold change) gene expression in human keratinocytes grown to confluence and treated with a composition comprising Centella asiatica extract, mandelic acid, or a combination of Centella asiatica extract and mandelic acid. [Figure 4D] 1 is a plot of CXCL1 (fold change) gene expression in human keratinocytes grown to confluence and treated with a composition comprising Centella asiatica extract, mandelic acid, or a combination of Centella asiatica extract and mandelic acid. [Figure 4E] 1 is a plot of IL2RB (fold change) gene expression in human keratinocytes grown to confluence and treated with a composition comprising Centella asiatica extract, mandelic acid, or a combination of Centella asiatica extract and mandelic acid. [Figure 4F]1 is a plot of NFKBIA gene expression (fold change) in human keratinocytes grown to confluence and treated with a composition comprising Centella asiatica extract, mandelic acid, or a combination of Centella asiatica extract and mandelic acid. [Figure 4G] 1 is a plot of PTGS2 (fold change) gene expression in human keratinocytes grown to confluence and treated with a composition comprising Centella asiatica extract, mandelic acid, or a combination of Centella asiatica extract and mandelic acid. [Figure 5] 1 is a plot of CDKN2B gene expression (fold change) in human keratinocytes grown to confluence and treated with a composition comprising Centella asiatica extract, mandelic acid, or a combination of Centella asiatica extract and mandelic acid. [Figure 6] 1 is a plot of gene expression (fold change) in cell cycle-related genes that were upregulated in human dermal fibroblasts grown to confluence and treated with a composition comprising Centella asiatica extract, mandelic acid, or a combination of Centella asiatica extract and mandelic acid. [Figure 7A] 1 is a plot of WEE1 gene expression (fold change) in human dermal fibroblasts grown to confluence and treated with a composition comprising Centella asiatica extract, mandelic acid, or a combination of Centella asiatica extract and mandelic acid. [Figure 7B] 1 is a plot of H2AFX (fold change) gene expression in human dermal fibroblasts grown to confluence and treated with a composition comprising Centella asiatica extract, mandelic acid, or a combination of Centella asiatica extract and mandelic acid. [Figure 7C] 1 is a plot of LMNB1 (fold change) gene expression in human dermal fibroblasts grown to confluence and treated with a composition comprising Centella asiatica extract, mandelic acid, or a combination of Centella asiatica extract and mandelic acid. [Figure 7D]1 is a plot of CCNB2 (fold change) gene expression in human dermal fibroblasts grown to confluence and treated with a composition comprising Centella asiatica extract, mandelic acid, or a combination of Centella asiatica extract and mandelic acid. [Figure 7E] 1 is a plot of BUB1 (fold change) gene expression in human dermal fibroblasts grown to confluence and treated with a composition comprising Centella asiatica extract, mandelic acid, or a combination of Centella asiatica extract and mandelic acid. [Figure 7F] 1 is a plot of CDC45 (fold change) gene expression in human dermal fibroblasts grown to confluence and treated with a composition comprising Centella asiatica extract, mandelic acid, or a combination of Centella asiatica extract and mandelic acid. [Figure 7G] 1 is a plot of CDK1 (fold change) gene expression in human dermal fibroblasts grown to confluence and treated with a composition comprising Centella asiatica extract, mandelic acid, or a combination of Centella asiatica extract and mandelic acid. [Figure 7H] 1 is a plot of BIRC5 (fold change) gene expression in human dermal fibroblasts grown to confluence and treated with a composition comprising Centella asiatica extract, mandelic acid, or a combination of Centella asiatica extract and mandelic acid. [Figure 7I] 1 is a plot of MCM10 (fold change) gene expression in human dermal fibroblasts grown to confluence and treated with a composition comprising Centella asiatica extract, mandelic acid, or a combination of Centella asiatica extract and mandelic acid. [Figure 7J] 1 is a plot of CCNE2 (fold change) gene expression in human dermal fibroblasts grown to confluence and treated with a composition comprising Centella asiatica extract, mandelic acid, or a combination of Centella asiatica extract and mandelic acid. [Figure 8] 1 shows a plot of gene expression (fold change relative to untreated group) for JunB and related proteins in human dermal fibroblasts grown to confluence and treated with a composition comprising a combination of Centella asiatica extract and mandelic acid. [Figure 9A] Shown is a p16 stained (yellow) human skin sample treated with a topical composition according to the present disclosure compared to an untreated cell sample. Nuclei are blue. The circled areas indicate the presence of senescent cells in the dermis (untreated) and migration of senescent cells into the epidermis (test composition). [Figure 9B] A p16 stained (yellow) human skin sample treated with a topical composition according to the present disclosure is shown compared to an untreated cell sample. Nuclei are blue. The circled areas indicate the presence of senescent cells in the dermis (untreated) and migration of senescent cells into the epidermis (test composition). The senescent cells in the center of the image in the untreated sample are located in hair follicles, where the cells undergo natural aging as part of the hair cycle. [Figure 9C] A p16 stained (yellow) human skin sample treated with a topical composition according to the present disclosure is shown compared to an untreated cell sample. Nuclei are blue. The circled areas indicate the presence of senescent cells in the dermis (untreated) and migration of senescent cells into the epidermis (test composition). Senescent cells on the right side of the image for the untreated sample and in the lower left-center of the image for the treated sample are present in hair follicles, where the cells undergo natural aging as part of the hair cycle. [Figure 9D] A p16 stained (yellow) human skin sample treated with a topical composition according to the present disclosure is shown compared to an untreated cell sample. Nuclei are blue. The circled areas indicate the presence of senescent cells in the dermis (untreated) and migration of senescent cells into the epidermis (test composition). Senescent cells at the bottom of the image for the untreated sample and at the center to top of the image for the treated sample are present in hair follicles, where the cells undergo natural aging as part of the hair cycle. DETAILED DESCRIPTION OF THE INVENTION

[0049] In the following description, numerous specific details are set forth in order to provide a thorough understanding of the present technology. Certain exemplary embodiments of the present technology may be practiced without some or all of these specific details. In other instances, well-known process operations have not been described in detail in order to not unnecessarily obscure the present technology.

[0050] Topical Compositions Centella asiatica extract The topical composition according to the present disclosure includes Centella asiatica extract. Centella asiatica is a traditional herb widely used in Asia and is becoming more widely used in Western countries. Centella asiatica extract is used as a natural therapy with a wide range of uses in wound healing, strengthening the skin barrier, maintaining moisture in the skin, reducing wrinkles, and alleviating skin conditions such as acne, atopic dermatitis, and burns. In wound healing, it is used because it has the activity of improving collagen synthesis and microcirculatory function. It is also believed to regulate cellular aging and have anti-hyaluronidase activity. In general, for example, E. Arribas-Lopez, et al., “A Systematic Review of the Effect of Centella Asiatica on Wound Healing,” 19 Int'l J. Envtl. Res. Pub. Health 3266 (2022), S. Saeidinia, et al., “Partial Thickness Burn Wound Healing by Topical Treatment: A Randomized Controlled Comparison Between Silver Sulfadiazine and Centiderm,”96 Medicine 103(2017), NKNema,et al. Dermal Fibroblasts,”20 See Exptl. Dermatol. 998-1003 (2011).

[0051] Centella asiatica extracts are available as aqueous or organic extracts, and their therapeutic properties are attributed to the presence of triterpenes (triterpenes): madecassoside, asiaticoside, madecassic acid, and asiatic acid. Centella asiatica extracts may contain high concentrations of triterpenes. For example, commercially available Centella asiatica extracts (e.g., Heterosides available from Seppic) may contain more than 70% by weight of triterpenes. In some embodiments, the Centella asiatica extract includes Heterosides (Seppic). In some embodiments, the Centella asiatica extract includes a triterpene selected from the group consisting of madecassoside, asiaticoside, madecassic acid, and asiatic acid.

[0052] Centella asiatica extract contains triterpenes at any suitable concentration to achieve therapeutic benefits (for example, reducing cellular aging).In some embodiments, triterpenes are present in Centella asiatica extract at a concentration of about 5 wt% or more, about 8 wt% or more, about 10 wt% or more, about 15 wt% or more, about 20 wt% or more, about 25 wt% or more, about 30 wt% or more, about 35 wt% or more, about 40 wt% or more, about 45 wt% or more, about 50 wt% or more, about 55 wt% or more, about 60 wt% or more, about 65 wt% or more, about 70 wt% or more, about 75 wt% or more, about 80 wt% or more, about 85 wt% or more, about 90 wt% or more, about 95 wt% or more, or any range or value therein, based on the total weight of Centella asiatica extract.In some embodiments, Centella asiatica extract contains triterpenes at a concentration of 70 wt% or more by weight based on the total weight of Centella asiatica extract.

[0053] The Centella asiatica extract (including triterpenes and any solvent, including water) is present in the topical composition at any suitable concentration suitable for achieving a therapeutic benefit (e.g., reducing cellular aging). In some embodiments, the Centella asiatica extract is present in the topical composition at a concentration of at least about 0.01 wt.%, at least about 0.02 wt.%, at least about 0.03 wt.%, at least about 0.04 wt.%, at least about 0.05 wt.%, at least about 0.06 wt.%, at least about 0.07 wt.%, at least about 0.08 wt.%, at least about 0.09 wt.%, at least about 0.10 wt.%, at least about 0.15 wt.%, at least about 0.20 wt.%, at least about 0.25 wt.%, at least about 0.30 wt.%, at least about 0.35 wt.%, at least about 0.40 wt.%, at least about 0.45 wt.%, at least about 0.50 wt.%, or any range or value therebetween, based on the total weight of the topical composition.

[0054] In some embodiments, the Centella asiatica extract is present in the topical composition at a concentration of about 0.5 wt % or less, about 0.45 wt % or less, about 0.40 wt % or less, about 0.35 wt % or less, about 0.30 wt % or less, about 0.25 wt % or less, about 0.20 wt % or less, about 0.15 wt % or less, about 0.10 wt % or less, about 0.09 wt % or less, about 0.08 wt % or less, about 0.07 wt % or less, about 0.06 wt % or less, about 0.05 wt % or less, or any range or value therebetween, by weight based on the total weight of the topical composition.

[0055] In some embodiments, the Centella asiatica extract is present in the topical composition at a concentration of at least about 0.01 wt.% and less than 0.2 wt.%, about 0.01 wt.% to about 0.15 wt.%, about 0.01 wt.% to about 0.10 wt.%, about 0.01 wt.% to about 0.08 wt.%, about 0.01 wt.% to about 0.05 wt.%, or any range or value therein, by weight based on the total weight of the topical composition.

[0056] The embodiments provided above include exemplary concentration amounts in Centella asiatica extracts based on high concentrations of triterpenes (e.g., greater than 70% triterpenes available from Seppic). In those cases where lower triterpene amounts are present in the Centella asiatica extract, the concentration of the example Centella asiatica extract can be increased to ensure that the minimum triterpene concentrations disclosed herein are present in the formulation.

[0057] In some embodiments, the Centella asiatica extract is present in an active solution. As used herein, the term "active solution" refers to a solution containing a Centella asiatica extract (including any terpenes) and a solvent. In some embodiments, the Centella asiatica extract is present in the composition at a concentration lower than the concentration recommended for formulating Centella asiatica extract into a topical composition (e.g., about 0.2% to 0.5% by weight is recommended). Thus, in some embodiments, the Centella asiatica extract is present as an active solution at a concentration of 0.01% to less than 0.2% by weight (e.g., 0.01% to 0.15% by weight, 0.01% to 0.10% by weight, 0.01% to 0.08% by weight, or 0.01% to 0.05% by weight) based on the total weight of the composition. The inventors have surprisingly discovered that low concentrations (e.g., less than 0.2% by weight) of Centella asiatica extract provide numerous therapeutic benefits, as discussed below (see Methods of Use). In some embodiments, low concentrations of Centella asiatica extract achieve synergistic therapeutic activity with low concentrations of alpha hydroxy acids (AHAs).

[0058] Considering the concentration range of Centella asiatica extract in the total composition (e.g., at least about 0.01% by weight and less than 0.2% by weight), and the concentration of triterpenes in Centella asiatica extract relative to the total weight of the Centella asiatica extract (e.g., at least about 5% by weight to about 95% by weight), it is clear that triterpenes, whether or not part of the Centella asiatica extract, can be present in concentrations appropriate to achieve a therapeutic benefit (e.g., in reducing cellular aging). In some embodiments, the triterpene is present in the topical composition in an amount by weight based on the total weight of the topical composition of at least about 0.0005 wt.%, at least about 0.001 wt.%, at least about 0.002 wt.%, at least about 0.003 wt.%, at least about 0.004 wt.%, at least about 0.005 wt.%, at least about 0.006 wt.%, at least about 0.007 wt.%, at least about 0.008 wt.%, at least about 0.009 wt.%, at least about 0.01 wt.%, at least about 0.02 wt.%, at least about 0.03 wt.%, at least about It may be present at a concentration of 0.04% by weight, at least about 0.05% by weight, at least about 0.06% by weight, at least about 0.07% by weight, at least about 0.08% by weight, at least about 0.09% by weight, at least about 0.10% by weight, at least about 0.11% by weight, at least about 0.12% by weight, at least about 0.13% by weight, at least about 0.14% by weight, at least about 0.15% by weight, at least about 0.16% by weight, at least about 0.17% by weight, at least about 0.18% by weight, at least about 0.19% by weight, or any range of values ​​therein.

[0059] In some embodiments, the triterpene is present in the topical composition at less than about 0.2 wt.%, about 0.19 wt.% or less, about 0.18 wt.% or less, about 0.17 wt.% or less, about 0.16 wt.% or less, about 0.15 wt.% or less, about 0.14 wt.% or less, about 0.13 wt.% or less, about 0.12 wt.% or less, about 0.11 wt.% or less, about 0.10 wt.% or less, about 0.15 wt.% or less, about 0.16 wt.% or less, about 0.17 ... 0.09% by weight or less, about 0.08% by weight or less, about 0.09% by weight or less, about 0.08% by weight or less, about 0.07% by weight or less, about 0.06% by weight or less, about 0.05% by weight or less, about 0.04% by weight or less, about 0.05% by weight or less, about 0.04% by weight or less, about 0.03% by weight or less, about 0.02% by weight or less, about 0.01% by weight or less, or any range or value therebetween.

[0060] In some embodiments, the triterpene may be present in the topical composition at a concentration of at least about 0.0005% and less than 0.2% by weight, 0.001% and less than 0.2% by weight, about 0.001% and less than 0.2% by weight, about 0.001% and about 0.15% by weight, about 0.001% and about 0.1% by weight, about 0.001% and about 0.05% by weight, about 0.001% and about 0.01% by weight, at least about 0.005% and less than 0.2% by weight, about 0.005% and about 0.15% by weight, about 0.005% and about 0.10% by weight, about 0.005% and about 0.05% by weight, about 0.005% and about 0.01% by weight, or any range or value therein, based on the total weight of the topical composition.

[0061] Liposomes The triterpenes present in Centella asiatica extract have high molecular weights and are chemically unstable, inhibiting skin adsorption after topical administration.Therefore, in some embodiments, Centella asiatica extract (and the triterpenes therein) are encapsulated in a delivery vehicle (for example, liposome, lipid nanoparticle, or a combination thereof) to improve the stability of triterpenes and improve the delivery of Centella asiatica extract to the skin by improving the penetration of epidermis and dermis.In some embodiments, Centella asiatica extract is encapsulated in liposome.The liposome composition 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 occur as a result of the active ingredient being encapsulated in liposome.

[0062] Lecithin and other phospholipids can be used to prepare liposomes that encapsulate Centella asiatica extract. Liposome formation occurs when phospholipids such as lecithin are placed in water, and as a result, when sufficient energy is supplied, they form a bilayer or a series of bilayers, each separated by water molecules. Liposomes can be formed by sonicating phospholipids in water. Low shear rates create multilayer liposomes. Continuous high-shear sonication tends to form smaller unilamellar liposomes. Hydrophobic compounds (e.g., triterpenes, antioxidants such as tocopherol and / or tocopheryl acetate, and oils such as sunflower seed oil) can be dissolved in the phospholipid bilayer membrane. The lipid bilayer of the liposome delivers the Centella asiatica extract described herein.

[0063] The phospholipids used to prepare the liposomes described herein can have a transition phase temperature of about 10°C to about 25°C. In some embodiments, the phospholipids have a transition phase temperature of about 10°C, 12°C, 14°C, 16°C, 18°C, 20°C, 22°C, 24°C, 26°C, 28°C, 30°C, 32°C, 34°C, 36°C, 38°C, 40°C, or greater than 40°C. In some embodiments, the phospholipids have a transition phase temperature in the range of about 10°C to about 40°C, about 12°C to about 36°C, about 14°C to about 32°C, about 16°C to about 20°C, or about 21°C to about 25°C.

[0064] In some embodiments, liposomes encapsulating Centella asiatica extract are prepared by a method comprising combining an "active solution," a solution containing Centella asiatica extract, with a solvent (e.g., water) to form a mixture, and contacting the active solution with an aqueous solution containing liposomes. In some cases, the contacting occurs at a temperature of about 10°C to about 25°C. In some cases, the contacting occurs at a temperature of about 10°C, 12°C, 14°C, 16°C, 18°C, 20°C, 22°C, 24°C, 26°C, 28°C, 30°C, 32°C, 34°C, 36°C, 38°C, 40°C, or greater than 40°C. In some cases, the contacting occurs at a temperature ranging from about 10°C to about 40°C, from about 12°C to about 36°C, from about 14°C to about 32°C, from about 16°C to about 20°C, or from about 21°C to about 25°C.

[0065] In some embodiments, the solvent is water. In some embodiments, the solvent is an organic solvent. Exemplary organic solvents include, but are not limited to, petroleum ether, cyclohexane, toluene, carbon tetrachloride, dichloromethane, chloroform, diethyl ether, diisopropyl ether, ethyl acetate, butanol, n-propanol, ethanol, methanol, polyethylene glycol, propylene glycol, and pyridine. In some cases, the solvent is glycol. In some cases, the solvent is butylene glycol. In some cases, the solvent is caprylyl glycol. In some cases, the solvent is propanediol (propylene glycol).

[0066] The solvent may be used at any suitable concentration to form stable liposomes. In some embodiments, the solvent (e.g., propanediol) is present in an amount by weight relative to the total weight of the liposomes of about 0.001% by weight or more, about 0.005% by weight or more, about 0.01% by weight or more, about 0.02% by weight or more, about 0.05% by weight or more, about 0.10% by weight or more, about 0.20% by weight or more, about 0.25% by weight or more, about 0.50% by weight or more, about 0.75% by weight or more, about 1.0 ... The solvent may be provided at a concentration of 0.5% by weight or greater, about 2.0% by weight or greater, about 2.5% by weight or greater, about 3.0% by weight or greater, about 3.5% by weight or greater, about 4.0% by weight or greater, about 4.5% by weight or greater, about 5.0% by weight or greater, about 5.5% by weight or greater, about 6.0% by weight or greater, about 6.5% by weight or greater, about 7.0% by weight or greater, about 8% by weight or greater, about 9% by weight or greater, about 10% by weight or greater, or any range or value therebetween. In some embodiments, the solvent is selected from propanediol, butylene glycol, caprylyl glycol, or a combination thereof. In some embodiments, the solvent is propanediol.

[0067] In some embodiments, forming liposomes encapsulating the Centella asiatica extract includes combining the Centella asiatica extract with a solvent (e.g., water) to form an active solution and contacting the active solution with an aqueous solution containing liposomes, the aqueous solution containing water and liposomes at any suitable concentration to form stable liposomes and encapsulate the Centella asiatica extract within the liposomes. In some embodiments, the aqueous solution contains water at about 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or more by weight, based on the total weight of the liposomes, water, and Centella asiatica extract. In some embodiments, the aqueous solution contains water in an amount ranging from about 10% to about 95%, from about 20% to about 90%, from about 30% to about 85%, from about 40% to about 80%, or from about 50% to about 60% by weight, based on the total weight of the liposomes, water, and Centella asiatica extract.

[0068] In some embodiments, the aqueous solution contains liposomes at a concentration of at least about 10 wt%, at least about 20 wt%, at least about 30 wt%, at least about 40 wt%, at least about 50 wt%, at least about 60 wt%, or any range or value therebetween, based on the total weight of the liposomes, water, and Centella asiatica extract. In some embodiments, the aqueous solution contains liposomes at a concentration of about 10 wt% to about 80 wt%, about 20 wt% to about 70 wt%, or about 30 wt% to about 60 wt%, based on the total weight of the liposomes, water, and Centella asiatica extract. The liposome-to-water ratio (w / w) can be in the range of about 1:9 to about 3:7. In some embodiments, the liposome to water ratio (w / w) can be about 1:10 or greater, about 1:9 or greater, about 1:8 or greater, about 1:7 or greater, about 1:6 or greater, about 1:5 or greater, about 1:4 or greater, about 1:3 or greater, about 1:2 or greater.

[0069] Methods for producing liposomes that encapsulate Centella asiatica extract may result in an entrapment efficiency of 100% or less, hi some embodiments, the entrapment efficiency is 50%, 60%, 70%, 80%, 90%, 95%, 99%, or 99.5% or less.

[0070] The liposomes can be present in the topical composition at any suitable concentration that improves delivery of the Centella asiatica extract to the extracellular matrix of the epidermal or dermal layer of the skin. In some embodiments, the liposomes are present in the topical composition at about 0.01 wt. % or more, about 0.02 wt. % or more, about 0.03 wt. % or more, about 0.04 wt. % or more, about 0.05 wt. % or more, about 0.06 wt. % or more, about 0.07 wt. % or more, about 0.08 wt. % or more, about 0.09 wt. % or more, about 0.10 wt. % or more, about 0.15 wt. % or more, about 0.20 wt. % or more, about 0.25 wt. % or more, about 0.30 wt. % or more, by weight based on the total weight of the composition. or greater, about 0.35% by weight or greater, about 0.40% by weight or greater, about 0.50% by weight or greater, about 0.6% by weight or greater, about 0.7% by weight or greater, about 0.8% by weight or greater, about 0.9% by weight or greater, about 1.0% by weight or greater, about 1.5% by weight or greater, about 2.0% by weight or greater, about 2.5% by weight or greater, about 3.0% by weight or greater, about 3.5% by weight or greater, about 4.0% by weight or greater, about 4.5% by weight or greater, about 5.0% by weight or greater, or any range or value therebetween.

[0071] In some embodiments, the liposomes are present in the topical composition at a concentration of about 0.01 wt.% to about 5 wt.%, about 0.05 wt.% to about 5 wt.%, about 0.1 wt.% to about 5 wt.%, about 0.03 wt.% to about 4 wt.%, about 0.05 wt.% to about 4 wt.%, about 0.05 wt.% to about 3 wt.%, about 0.05 wt.% to about 2 wt.%, about 0.05 wt.% to about 1 wt.%, about 0.05 wt.% to about 0.5 wt.%, about 0.05 wt.% to about 0.1 wt.%, about 0.1 wt.% to about 2 wt.%, about 0.1 wt.% to about 1 wt.%, about 0.2 wt.% to about 0.8 wt.%, about 0.3 wt.% to about 0.7 wt.%, or any range or value therebetween, by weight based on the total weight of the composition.

[0072] In some embodiments, the liposomes have any suitable size that improves delivery of the Centella asiatica extract to the skin. In some embodiments, the liposomes have a size of about 50 nm or more, about 60 nm or more, about 70 nm or more, about 80 nm or more, about 90 nm or more, about 100 nm or more, about 110 nm or more, about 120 nm or more, about 130 nm or more, about 140 nm or more, about 150 nm or more, about 160 nm or more, about 170 nm or more, about 180 nm or more, about 190 nm or more, about 200 nm or more, about 210 nm or more, about 220 nm or more, about 230 nm or more, about 240 nm or more, about 250 nm or more, about 260 nm or more, about 270 nm or more, about 280 nm or more, about 290 nm or more, about 300 nm or more, about 310 nm or more, about 320 nm or more, about 330 nm or more, about 340 nm or more, about 350 nm or more, about 360 nm or more, about 370 nm or more, about 380 nm or more, about 390 nm or more, about 400 nm or more, about 410 nm or more, about 420 nm or more, about 430 nm or more, about 440 nm or more, about 450 nm or more, about 460 nm or more, about 470 nm or more, about 480 nm or more, about 490 nm or more, about 500 nm or more, about 510 nm or more, about 520 nm or more, about 530 nm or more, about 540 nm or more, about 550 nm or more, about 560 nm or more, about 570 nm and / or greater than about 200 nm, about 280 nm or greater, about 290 nm or greater, about 300 nm or greater, about 310 nm or greater, about 320 nm or greater, about 330 nm or greater, about 340 nm or greater, about 350 nm or greater, about 360 nm or greater, about 370 nm or greater, about 380 nm or greater, about 390 nm or greater, about 400 nm or greater, about 410 nm or greater, about 420 nm or greater, about 430 nm or greater, about 440 nm or greater, about 450 nm or greater, about 500 nm or greater, about 500 nm or greater, or any range or value therebetween.

[0073] In some embodiments, the liposomes have an average diameter of about 50 nm to about 500 nm, about 50 nm to about 400 nm, about 50 nm to about 300 nm, about 50 nm to about 250 nm, about 100 nm to about 500 nm, about 100 nm to about 400 nm, about 100 nm to about 300 nm, 100 nm to about 250 nm, about 200 nm to about 500 nm, about 200 nm to about 400 nm, about 200 nm to about 300 nm, or any range or value therein. In some embodiments, the liposomes have an average diameter of about 250 nm.

[0074] In some embodiments, the liposomes have a polydispersity index (PdI) of 0 to about 0.2. In some embodiments, 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.

[0075] In some embodiments, the liposomes comprise propanediol, lecithin, or a combination thereof. In some embodiments, the propanediol is present in the liposomes at about 0.001% by weight or more, about 0.005% by weight or more, about 0.01% by weight or more, about 0.02% by weight or more, about 0.05% by weight or more, about 0.10% by weight or more, about 0.20% by weight or more, about 0.25% by weight or more, about 0.50% by weight or more, about 0.75% by weight or more, about 1.0% by weight or more, about 1.5% by weight or more, about 2.0% by weight or more, about 2.5% by weight or more, about 3.0% by weight or more, about 4.0% by weight or more, about 4.0% by weight or more, about 5.0% by weight or more, about 6.0% by weight or more, about 7.0% by weight or more, about 8.0% by weight or more, about 9.0% by weight or more, about 10.0% by weight or more, about 11.0% by weight or more, about 12.0% by weight or more, about 13.0% by weight or more, about 14.0% by weight or more, about 15.0% by weight or more, about 16.0% by weight or more, about 17.0% by weight or more, about 18.0% by weight or more, about 19.0% by weight or more, about 20.0% by weight or more, about 21.0% by weight or more, about 22.0% by weight or more, about 23.0% by weight or more, about 24.0% by weight or more, about 25.0% by weight or more, about 26.0% by weight or more, about 27.0% by weight or more 0.5% by weight or more, about 2.0% by weight or more, about 2.5% by weight or more, about 3.0% by weight or more, about 3.5% by weight or more, about 4.0% by weight or more, about 4.5% by weight or more, about 5.0% by weight or more, about 5.5% by weight or more, about 6.0% by weight or more, about 6.5% by weight or more, about 7.0% by weight or more, about 8% by weight or more, about 9% by weight or more, about 10% by weight or more, or any range or value therebetween.

[0076] In some embodiments, propanediol is present in the liposomes at a concentration of about 0.001% to about 6%, about 0.002% to about 4%, about 0.01% to about 3%, or about 0.02% to about 2% by weight based on the total weight of the liposomes or based on the total weight of the topical composition.

[0077] In some embodiments, lecithin is present in the liposome at about 0.001% by weight or more, about 0.005% by weight or more, about 0.01% by weight or more, about 0.02% by weight or more, about 0.05% by weight or more, about 0.10% by weight or more, about 0.20% by weight or more, about 0.25% by weight or more, about 0.50% by weight or more, about 0.75% by weight or more, about 1.0% by weight or more, about 1.5% by weight or more, by weight based on the total weight of the liposome. % or more by weight, about 2.0% or more by weight, about 2.5% or more by weight, about 3.0% or more by weight, about 3.5% or more by weight, about 4.0% or more by weight, about 4.5% or more by weight, about 5.0% or more by weight, about 5.5% or more by weight, about 6.0% or more by weight, about 6.5% or more by weight, about 7.0% or more by weight, about 8% or more by weight, about 9% or more by weight, about 10% or more by weight, or any range or value therebetween.

[0078] In some embodiments, lecithin is present in the liposomes at a concentration of about 0.001% to about 6%, about 0.002% to about 4%, about 0.01% to about 3%, or about 0.02% to about 2% by weight, based on the total weight of the liposomes or based on the total weight of the topical composition.

[0079] In some embodiments, the liposomes are commercially available (e.g., PRO-LIPO™ NEO). In some embodiments, the liposomes comprise propanediol, lecithin, sunflower seed oil, and tocopherol.

[0080] Alpha Hydroxy Acids (AHAs) The topical compositions according to the present disclosure comprise one or more alpha hydroxy acids (AHAs). In some embodiments, the one or more AHAs are selected from the group consisting of mandelic acid, glycolic acid, lactic acid, citric acid, malic acid, hydroxycaprylic acid, and hydroxycapric acid. In some embodiments, the one or more AHAs comprise mandelic acid. In some embodiments, the mandelic acid comprises (S)-mandelic acid. In some embodiments, the mandelic acid comprises (R)-mandelic acid. In some embodiments, the mandelic acid comprises (S)-mandelic acid and (R)-mandelic acid (e.g., paramandelic acid).

[0081] Mandelic acid, derived from almonds, is a larger molecule than other AHAs used in skin care (e.g., glycolic acid). Therefore, it tends to penetrate the skin more slowly, causing less skin irritation than other AHAs. At low concentrations (e.g., 6% by weight or less), it does not cause visible peeling, is safe for home use, and is well tolerated by patients with all skin types. Therefore, mandelic acid is a viable option for topical application to improve skin quality. See, for example, SW Jacobs, et al., "Effects of Topical Mandelic Acid Treatment on Facial Skin Viscoelasticity," 34 Facial Plast. Surg. 651-56 (2018) for general information.

[0082] The one or more AHAs (e.g., mandelic acid) are present in the topical composition at any suitable concentration suitable for achieving a therapeutic benefit (e.g., reducing cellular aging). In some embodiments, the one or more AHAs (e.g., mandelic acid) are present in the topical composition at a concentration of at least about 0.01 wt.%, at least about 0.02 wt.%, at least about 0.03 wt.%, at least about 0.04 wt.%, at least about 0.05 wt.%, at least about 0.06 wt.%, at least about 0.07 wt.%, at least about 0.08 wt.%, at least about 0.09 wt.%, at least about 0.10 wt.%, at least about 0.15 wt.%, at least about 0.20 wt.%, at least about 0.25 wt.%, at least about 0.30 wt.%, at least about 0.35 wt.%, at least about 0.40 wt.%, at least about 0.45 wt.%, and less than 0.50 wt.%, or any range or value therebetween, based on the total weight of the topical composition.

[0083] In some embodiments, the one or more AHAs (e.g., mandelic acid) are present in the topical composition at a concentration of less than 0.50 wt.%, about 0.45 wt.% or less, about 0.40 wt.% or less, about 0.35 wt.% or less, about 0.30 wt.% or less, about 0.25 wt.% or less, about 0.20 wt.% or less, about 0.15 wt.% or less, about 0.10 wt.% or less, about 0.09 wt.% or less, about 0.08 wt.% or less, about 0.07 wt.% or less, about 0.06 wt.% or less, about 0.05 wt.% or less, or any range or value therebetween, based on the total weight of the topical composition.

[0084] In some embodiments, the one or more AHAs (e.g., mandelic acid) are present in the topical composition at a concentration of at least about 0.01 wt.% and less than 0.5 wt.%, about 0.01 wt.% to about 0.4 wt.%, about 0.01 wt.% to about 0.3 wt.%, about 0.01 wt.% to about 0.2 wt.%, about 0.01 wt.% to about 0.1 wt.%, about 0.01 wt.% to about 0.05 wt.%, about 0.01 wt.% to about 0.04 wt.%, about 0.01 wt.% to about 0.03 wt.%, 0.05 wt.% to about 0.5 wt.%, about 0.05 wt.% to about 0.4 wt.%, about 0.05 wt.% to about 0.3 wt.%, about 0.05 wt.% to about 0.2 wt.%, about 0.05 wt.% to about 0.1 wt.%, or any range or value therein, based on the total weight of the topical composition.

[0085] In some embodiments, one or more AHAs (e.g., mandelic acid) are present in the topical composition at a concentration lower than the concentration recommended for formulating one or more AHAs into a topical composition (e.g., a recommended concentration of about 0.5% to 6% by weight of mandelic acid for skin brightening). The inventors have surprisingly discovered that low concentrations of AHAs, particularly mandelic acid, e.g., less than 0.5% by weight, provide numerous therapeutic benefits discussed below (see Methods of Use). At the same time, the low concentration of AHA achieves a desirable acidic pH value (e.g., 4 to 6, 3 to 5, or 4 to 5) for the topical composition while reducing or eliminating undesirable effects, such as inflammation and skin irritation, associated with the use of higher doses.

[0086] The present inventors also surprisingly discovered that low doses of AHA (e.g., mandelic acid) achieve synergistic activity with low doses of Centella asiatica extract, such as synergistic protection from senescent cell products and reduced inflammation in the epidermis due to increased cell cycle activity in the dermis. This activity represents a synergistic effect in reducing cellular aging, which was unexpected and unknown in the art at the time.

[0087] The Centella asiatica extract and AHA are present in any weight ratio suitable for achieving the synergistic activity described above. In some embodiments, the Centella asiatica extract and AHA are present in a weight ratio of about 1:2 to 1:20, about 1:5 to 1:15, about 1:6 to 1:14, about 1:7 to about 1:13, about 1:8 to about 1:12, or any range or value therein. In some embodiments, the Centella asiatica extract and AHA are present in a weight ratio of about 1:2, about 1:3, about 1:4, about 1:5, about 1:6, about 1:7, about 1:8, about 1:9, about 1:10, about 1:11, about 1:12, about 1:13, about 1:14, about 1:15, about 1:16, about 1:17, about 1:18, about 1:19, about 1:20, or less.

[0088] In some embodiments, the triterpene and AHA are present in a weight ratio of about 1:2 to 1:400, about 1:5 to 1:200, about 1:6 to 1:100, about 1:7 to about 1:50, about 1:8 to about 1:20, about 1:10 to 1:15, or any range or value therein. In some embodiments, the triterpene and the AHA are present in a weight ratio of about 1:2, about 1:3, about 1:4, about 1:5, about 1:6, about 1:7, about 1:8, about 1:9, about 1:10, about 1:11, about 1:12, about 1:13, about 1:14, about 1:15, about 1:16, about 1:17, about 1:18, about 1:19, about 1:20, about 1:25, about 1:30, about 1:35, about 1:40, about 1:45, about 1:50, about 1:60, about 1:70, about 1:80, about 1:90, about 1:100, about 1:150, about 1:200, about 1:300, about 1:400 or less.

[0089] antioxidants UV irradiation causes oxidative stress, which can be detrimental to cellular function and negatively impact cell survival. Antioxidants can mitigate these oxidative processes by acting against the formation or proliferation of reactive oxygen species, improving cell function and survival.

[0090] In some embodiments, a topical composition according to the present disclosure comprises one or more antioxidants. In some embodiments, the one or more antioxidants comprise tocopherol, tocopheryl acetate, hydroxyacetophenone, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), t-butylhydroquinone (TBHQ), propyl gallate, tocotrienol, ascorbyl palmitate, rosemary (Rosmarinus officinalis) leaf extract, or a combination thereof. In some embodiments, the one or more antioxidants comprise tocopherol, tocopheryl acetate, or a combination thereof. In some embodiments, the one or more antioxidants comprise tocopherol. In some embodiments, the one or more antioxidants comprise tocopheryl acetate. In some embodiments, the one or more antioxidants are present separately (e.g., in addition to) any antioxidants that may be present in one or more liposomes that may be present in the composition. In some embodiments, the one or more antioxidants are present in an oil phase that is prepared separately from one or more liposomes that may be present in the composition.

[0091] In some embodiments, the one or more antioxidants, individually or collectively, comprise at least about 0.001 wt. %, at least about 0.002 wt. %, at least about 0.003 wt. %, at least about 0.004 wt. %, at least about 0.005 wt. %, at least about 0.006 wt. %, at least about 0.007 wt. %, at least about 0.008 wt. %, at least about 0.009 wt. %, at least about 0.01 wt. %, at least about 0.02 wt. %, at least about 0.03 wt. %, at least about 0.04 wt. %, at least about 0.05 wt. %, at least about 0.06 wt. %, at least about 0.07 wt. %, at least about 0.08 wt. %, at least about 0.09 wt. %, at least about 0.1 wt. %, at least about 0.2 wt. %, at least about 0.3 wt. %, at least about 0.4 wt. %, or less by weight based on the total weight of the composition. %. The present invention may be present in a concentration of at least about 0.5 wt.%, at least about 0.6 wt.%, at least about 0.7 wt.%, at least about 0.8 wt.%, at least about 0.9 wt.%, at least about 1.0 wt.%, at least about 1.2 wt.%, at least about 1.5 wt.%, at least about 1.8 wt.%, at least about 2.0 wt.%, at least about 2.5 wt.%, at least about 3.0 wt.%, at least about 3.5 wt.%, at least about 4.0 wt.%, at least about 4.5 wt.%, at least about 5.0 wt.%, at least about 5.5 wt.%, at least about 6.0 wt.%, at least about 6.5 wt.%, at least about 7.0 wt.%, at least about 7.5 wt.%, at least about 8.0 wt.%, at least about 8.5 wt.%, at least about 9.0 wt.%, at least about 9.5 wt.%, at least about 10 wt.%, or any range or value therebetween. In some embodiments, the one or more antioxidants are present at these concentrations separate from (e.g., in addition to) any antioxidants that may be present in one or more liposomes present in the composition.

[0092] In some embodiments, the one or more antioxidants, individually or collectively, are present in an amount by weight relative to the total weight of the composition of about 10.0 wt. % or less, about 9.5 wt. % or less, about 9.0 wt. % or less, about 8.5 wt. % or less, about 8.0 wt. % or less, about 7.5 wt. % or less, about 7.0 wt. % or less, about 6.5 wt. % or less, about 6.0 wt. % or less, about 5.5 wt. % or less, about 5.0 wt. % or less, about 4.5 wt. % or less, about 4.0 wt. % or less, about 3.5 wt. % or less, about 3.0 wt. % or less, about 2.5 wt. % or less, about 2.0 wt. % or less, about 1.5 wt. % or less , about 1.0% by weight or less, about 0.9% by weight or less, about 0.8% by weight or less, about 0.7% by weight or less, about 0.6% by weight or less, about 0.5% by weight or less, about 0.4% by weight or less, about 0.3% by weight or less, about 0.2% by weight or less, about 0.1% by weight or less, about 0.09% by weight or less, about 0.08% by weight or less, about 0.07% by weight or less, about 0.06% by weight or less, about 0.05% by weight or less, about 0.04% by weight or less, about 0.03% by weight or less, about 0.02% by weight or less, about 0.01% by weight or less, or any range or value therebetween. In some embodiments, the one or more antioxidants are present at these concentrations separately from (e.g., in addition to) any antioxidants that may be present in one or more liposomes present in the composition.

[0093] In some embodiments, the one or more antioxidants, individually or collectively, by weight, based on the total weight of the composition, are about 0.001 wt.%, about 0.002 wt.%, about 0.005 wt.%, about 0.008 wt.%, about 0.01 wt.%, about 0.02 wt.%, about 0.05 wt.%, about 0.08 wt.%, about 0.1 wt.%, about 0.2 wt.%, about 0.5 wt.%, about 0.8 wt.%, about 1.0 wt.%, about 1.2 wt.%, about 1.5 wt.%, about 1.8 wt.%, about 2.0 wt.%, about 2.2 wt.%, about 3.0 wt.%, about 3.2 wt.%, about 3.4 wt.%, about 3.6 wt.%, about 3.8 wt.%, about 3.9 ... %, about 2.5 wt%, about 2.8 wt%, about 3.0 wt%, about 3.2 wt%, about 3.5 wt%, about 3.8 wt%, about 4.0 wt%, about 4.2 wt%, about 4.5 wt%, about 4.8 wt%, about 5.0 wt%, about 5.5 wt%, about 6.0 wt%, about 6.5 wt%, about 7.0 wt%, about 7.5 wt%, about 8.0 wt%, about 8.5 wt%, about 9.0 wt%, about 9.5 wt%, about 10.0 wt%, or any range or value therebetween. In some embodiments, the one or more antioxidants are present at these concentrations separately from (e.g., in addition to) any antioxidants that may be present in a delivery vehicle (e.g., liposome) present in the composition.

[0094] In some embodiments, one or more antioxidants are present in the composition, individually or collectively, in an amount by weight relative to the total weight of the composition of about 0.001 wt % to about 10 wt %, about 0.01 wt % to about 10 wt %, about 0.1 wt % to about 10 wt %, about 1 wt % to about 10 wt %, about 0.001 wt % to about 1 wt %, about 0.01 wt % to about 1 wt %, about 0.1 wt % to about 1 wt %, about 0.001 wt % to about 0.1 wt %, about 0.01 wt % to about 0.1 wt %, about 0.01 wt % to about 10 wt %, about 0.01 wt % to about 1 wt %, about 0.01 wt % to about 0.1 wt %, about 0.1 wt % to about 1 wt %, or any range or value therebetween. In some embodiments, the one or more antioxidants are present at these concentrations separate from (e.g., in addition to) any antioxidants that may be present in a delivery vehicle (e.g., a liposome) present in the composition.

[0095] Wetting Agents / Softeners In some embodiments, topical compositions according to the present disclosure include one or more humectants and / or emollients. By way of non-limiting example, in some embodiments, the one or more humectants and / or emollients may include polyols such as polyols having 2 to 20 carbon atoms, including glycerol (glycerin), glycol derivatives (e.g., propylene glycol, butylene glycol, pentylene glycol, hexylene glycol, dipropylene glycol, diethylene glycol, caprylyl glycol), and mixtures thereof. In some embodiments, the humectant and / or emollient may include glycerin sorbitol, sugars (e.g., glucose, lactose, etc.), alkoxylated glucose derivatives, glucose ethers, panthenol (e.g., D-panthenol, DL-panthenol), polyethylene glycol (PEG), urea, sodium hyaluronate, caprylyl glycol, pantolactone, caprylic / capric triglyceride, coco-caprylate / caprate, pantolactone, squalane, soluble chitosan, hexanetriol, amino acids (e.g., serine, citrulline, arginine, asparagine, or alanine), alpha-hydroxy acids, salicylic acid, hyaluronic acid (HA), sodium lactate, sodium pyroglutamate (sodium PCA), aloe vera gel, or combinations thereof.

[0096] In some embodiments, the one or more humectants and / or emollients, individually or collectively, comprise at least about 0.1 wt.%, at least about 0.2 wt.%, at least about 0.3 wt.%, at least about 0.4 wt.%, at least about 0.5 wt.%, at least about 0.6 wt.%, at least about 0.7 wt.%, at least about 0.8 wt.%, at least about 0.9 wt.%, at least about 1.0 wt.%, at least about 1.2 wt.%, at least about 1.5 wt.%, at least about 1.8 wt.%, at least about 2.0 wt.%, based on the total weight of the composition. It may be present in a concentration of at least about 2.5% by weight, at least about 3.0% by weight, at least about 3.5% by weight, at least about 4.0% by weight, at least about 4.5% by weight, at least about 5.0% by weight, at least about 5.5% by weight, at least about 6.0% by weight, at least about 6.5% by weight, at least about 7.0% by weight, at least about 7.5% by weight, at least about 8.0% by weight, at least about 8.5% by weight, at least about 9.0% by weight, at least about 9.5% by weight, at least about 10% by weight, or any range or value therebetween.

[0097] In some embodiments, one or more humectants and / or emollients, individually or collectively, may be present at a concentration of about 30% by weight or less, about 25% by weight or less, about 20% by weight or less, about 15% by weight or less, about 14% by weight or less, about 13% by weight or less, about 12% by weight or less, about 11% by weight or less, about 10.0% by weight or less, about 9.5% by weight or less, about 9.0% by weight or less, about 8.5% by weight or less, about 8.0% by weight or less, about 7.5% by weight or less, about 7.0% by weight or less, about 6.5% by weight or less, about 6.0% by weight or less, about 5.5% by weight or less, about 5.0% by weight or less, about 4.5% by weight or less, about 4.0% by weight or less, about 3.5% by weight or less, about 3.0% by weight or less, or any range or value therebetween, based on the total weight of the composition.

[0098] In some embodiments, the one or more humectants and / or emollients, individually or collectively, comprise about 0.1 wt.%, about 0.2 wt.%, about 0.5 wt.%, about 0.8 wt.%, about 1.0 wt.%, about 1.2 wt.%, about 1.5 wt.%, about 1.8 wt.%, about 2.0 wt.%, about 2.2 wt.%, about 2.5 wt.%, about 2.8 wt.%, about 3.0 wt.%, about 3.2 wt.%, about 3.5 wt.%, about 3.8 ... %, about 4.0 wt%, about 4.2 wt%, about 4.5 wt%, about 4.8 wt%, about 5.0 wt%, about 5.5 wt%, about 6.0 wt%, about 6.5 wt%, about 7.0 wt%, about 7.5 wt%, about 8.0 wt%, about 8.5 wt%, about 9.0 wt%, about 9.5 wt%, about 10.0 wt%, about 15 wt%, about 20 wt%, about 25 wt%, about 30 wt%, or any range or value therebetween.

[0099] In some embodiments, the one or more humectants and / or emollients, individually or collectively, comprise from about 0.1% to about 30%, from about 0.1% to about 25%, from about 0.1% to about 20%, from about 0.1% to about 15%, from about 0.1% to about 14%, from about 0.1% to about 13%, from about 0.1% to about 12%, from about 0.1% to about 11%, from about 0.1% to about 10.0% by weight of the total weight of the composition. Weight%, about 0.1% to about 8% by weight, about 0.1% to about 5% by weight, about 0.1 to about 4% by weight, about 0.1% to about 3% by weight, about 0.1% to about 2% by weight, about 0.1% to about 1% by weight, about 0.5% by weight About 30% by weight, about 0.5% to about 25% by weight, about 0.5% to about 20% by weight, about 0.5% to about 15% by weight, about 0.5% to about 10.0% by weight, about 0.5% to about 8% by weight, about 0.5% to about 5% by weight Amount%, about 0.5 to about 4% by weight, about 0.5 to about 3% by weight, about 0.5 to about 2% by weight, about 0.5 to about 1% by weight, about 1% to about 30% by weight, about 1% to about 25% by weight, about 1% to about 20% by weight, about 1% to about 15% by weight, about 1% to about 10% by weight, about 1% to about 8% by weight, about 1% to about 5% by weight, about 1% to about 4% by weight, about 1% to about 3% by weight, about 1% to about 2% by weight, about 3% to about 30% by weight %, about 3% to about 25% by weight, about 3% to about 20% by weight, about 3% to about 15% by weight, about 1% to about 10% by weight, about 3% to about 8% by weight, about 3% to about 5% by weight, about 5% to about 30% by weight, about 5% to about 25% by weight, about 5% to about 20% by weight, about 5% to about 15% by weight, about 5% to about 10% by weight, about 5% to about 8% by weight, or any range or value therein.

[0100] emulsifier Topical compositions according to the present disclosure may include one or more emulsifiers to stabilize the aqueous and / or oil phases of the emulsion. Emulsifiers suitable for use in topical compositions include anionic, cationic, nonionic, and zwitterionic surfactants.

[0101] In some embodiments, the emulsifier comprises a polyhydric alcohol ester, which can be used as an emulsifier or emollient. Suitable polyhydric alcohol esters include ethylene glycol mono- and di-fatty acid esters, diethylene glycol mono- and di-fatty acid esters, polyethylene glycol (200-6000) mono- and di-fatty acid esters, propylene glycol mono- and di-fatty esters, polypropylene glycol 2000 monooleate, polypropylene glycol 2000 monostearate, ethoxylated propylene glycol monostearate, glyceryl mono- and di-fatty acid esters, polyglycerol polyfatty acid esters, ethoxylated glyceryl monostearate, 1,3-butylene glycol monostearate, 1,3-butylene glycol distearate, polyoxyethylene polyol fatty acid esters, sorbitan fatty acid esters, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene ethers of higher saturated fatty alcohols, and alkyl polyglucoside emulsifiers. In some embodiments, the emulsifier comprises an acrylic acid polymer (e.g., an acrylates / C10-30 alkyl acrylate crosspolymer, such as that sold under the name PEMULEN™ EZ-4U). In some embodiments, the emulsifier comprises potassium cetyl phosphate. In some embodiments, the emulsifier comprises methyl glucose sesquistearate.

[0102] In some embodiments, the emulsifiers, individually or collectively, comprise at least about 0.1 wt.%, at least about 0.2 wt.%, at least about 0.3 wt.%, at least about 0.4 wt.%, at least about 0.5 wt.%, at least about 0.6 wt.%, at least about 0.7 wt.%, at least about 0.8 wt.%, at least about 0.9 wt.%, at least about 1.0 wt.%, at least about 1.2 wt.%, at least about 1.5 wt.%, at least about 1.8 wt.%, at least about 2.0 wt.%, at least about 2.2 wt.%, at least about 2.5 wt.%, at least about 2.8 wt.%, at least about 3.0 wt.%, based on the total weight of the composition. 0 wt.%, at least about 3.2 wt.%, at least about 3.5 wt.%, at least about 3.8 wt.%, at least about 4.0 wt.%, at least about 4.2 wt.%, at least about 4.5 wt.%, at least about 4.8 wt.%, at least about 5.0 wt.%, at least about 5.5 wt.%, at least about 6.0 wt.%, at least about 6.5 wt.%, at least about 7.0 wt.%, at least about 7.5 wt.%, at least about 8.0 wt.%, at least about 8.5 wt.%, at least about 9.0 wt.%, at least about 9.5 wt.%, at least about 10.0 wt.%, or any range or value therebetween.

[0103] In some embodiments, the emulsifiers, individually or collectively, may be present at a concentration of about 10.0% by weight or less, about 9.5% by weight or less, about 9.0% by weight or less, about 8.5% by weight or less, about 8.0% by weight or less, about 7.5% by weight or less, about 7.0% by weight or less, about 6.5% by weight or less, about 6.0% by weight or less, about 5.5% by weight or less, about 5.0% by weight or less, about 4.5% by weight or less, about 4.0% by weight or less, about 3.5% by weight or less, about 3.0% by weight or less, or any range or value therebetween, relative to the total weight of the composition.

[0104] In some embodiments, the emulsifiers, individually or collectively, are present in an amount of about 0.1 wt.%, about 0.2 wt.%, about 0.3 wt.%, about 0.4 wt.%, about 0.5 wt.%, about 0.6 wt.%, about 0.7 wt.%, about 0.8 wt.%, about 0.9 wt.%, about 1.0 wt.%, about 1.2 wt.%, about 1.5 wt.%, about 1.8 wt.%, about 2.0 wt.%, about 2.2 wt.%, about 2.5 wt.%, about 2.8 wt.%, about 3.0 wt.%, about 4.0 wt.%, about 5.0 wt.%, about 6.0 wt.%, about 7.0 wt.%, about 8.0 wt.%, about 9.0 wt.%, about 10.0 wt.%, about 11.0 wt.%, about 12.0 wt.%, about 13.0 wt.%, about 14.0 wt.%, about 15.0 wt.%, about 16.0 wt.%, about 17.0 wt.%, about 18.0 wt.%, about 19.0 wt.%, about 20.0 wt.%, about 21.0 wt.%, about 22.0 wt.%, about 23.0 wt.%, about 24.0 wt.%, about 25.0 wt.%, about 26.0 wt.%, about 27.0 wt.%, about 28.0 wt.%, about 29.0 wt.%, about 30.0 wt.%, about 31.0 wt.%, about 32.0 wt.%, about 33.0 wt.%, about 34.0 wt.%, about 35.0 wt.%, about 36.0 wt.%, about 3 %, about 3.2%, about 3.5%, about 3.8%, about 4.0%, about 4.2%, about 4.5%, about 4.8%, about 5.0%, about 5.5%, about 6.0%, about 6.5%, about 7.0%, about 7.5%, about 8.0%, about 8.5%, about 9.0%, about 9.5%, about 10.0% by weight, or any range or value therein.

[0105] In some embodiments, the emulsifiers, individually or collectively, are present in an amount of from about 0.1% to about 10% by weight, from about 0.1% to about 5% by weight, from about 0.1% to about 4% by weight, from about 0.1% to about 3% by weight, from about 0.1% to about 2% by weight, from about 0.1% to about 1% by weight, from 0.1% to about 0.5% by weight, from about 0.5% to about 10% by weight, from about 0.5% to about 5% by weight, from about 0.5% to about 4% by weight, or about 0.5% by weight, based on the total weight of the composition. It may be present in a concentration of about 3% by weight, about 0.5% by weight to about 2% by weight, about 0.5% by weight to about 1% by weight, about 1% by weight to about 10% by weight, about 1% by weight to about 5% by weight, about 1% by weight to about 4% by weight, about 1% by weight to about 3% by weight, about 1% by weight to about 2% by weight, about 2% by weight to about 10% by weight, about 2% by weight to about 5% by weight, about 3% by weight to about 10% by weight, about 3% by weight to about 5% by weight, about 5% by weight to about 10% by weight, or any range or value therein.

[0106] oil In some embodiments, the topical composition according to the present disclosure comprises one or more oils. In some embodiments (e.g., when the composition is in the form of an emulsion, such as an oil-in-water or water-in-oil emulsion), the composition comprises an oil phase comprising one or more oils. By way of non-limiting example, the one or more oils may comprise vegetable oils, mineral oils, animal oils, or synthetic waxes, oils, or butters, and mixtures thereof. In some embodiments, the oil is one or more mineral oils (e.g., PRIMOL 352®, MARCOL 82®, and MARCOL 152® sold by Esso), one or more vegetable oils (e.g., almond oil, sweet almond oil, palm oil, soybean oil, sesame oil, sunflower oil, olive oil, etc.), hydrogenated vegetable oils, one or more animal oils or vegetable-derived substitutes (e.g., lanolin, squalene, or fish oil, and derivatives thereof, e.g., perhydrosqualene sold by Sophim as SOPHIDERM®), one or more synthetic oils (e.g., cetearyl isononanoate such as CETIOL SN PH® by Cognis France, isononyl isononanoate such as DUB ININ® sold by Stearinerie Dubois, diisopropyl adipate such as CRODAMOL DA® by Croda, hydroxypropyl methylcellulose ... isopropyl palmitate such as IPP®, caprylic / capric triglyceride such as MIGLYOL 812® sold by Univar, hydrogenated polyisobutene such as the PARLEAM® products by Rossow), one or more silicone oils (e.g., dimethicone such as Q7-9120 Silicone Fluid® having a viscosity of 20 cSt to 12,500 cSt by Dow Corning, cyclomethicone such as ST-Cyclomethicone 5NF® by Dow Corning, or DC9045 Elastomer Blend® by Dow Corning), or any combination thereof.

[0107] In some embodiments, the one or more oils, individually or collectively, are present in an amount of at least about 0.5 wt.%, at least about 0.6 wt.%, at least about 0.7 wt.%, at least about 0.8 wt.%, at least about 0.9 wt.%, at least about 1.0 wt.%, at least about 1.2 wt.%, at least about 1.5 wt.%, at least about 1.8 wt.%, at least about 2.0 wt.%, at least about 2.5 wt.%, at least about 3.0 wt.%, at least about 3.5 wt.%, at least about 4.0% by weight, at least about 4.5% by weight, at least about 5.0% by weight, at least about 5.5% by weight, at least about 6.0% by weight, at least about 6.5% by weight, at least about 7.0% by weight, at least about 7.5% by weight, at least about 8.0% by weight, at least about 8.5% by weight, at least about 9.0% by weight, at least about 9.5% by weight, at least about 10% by weight, at least about 15.0% by weight, at least about 20.0% by weight, or any range or value therebetween.

[0108] In some embodiments, the one or more oils, individually or collectively, may be present at a concentration of about 35.0 wt. % or less, about 30 wt. % or less, about 25 wt. % or less, about 20 wt. % or less, about 19 wt. % or less, about 18 wt. % or less, about 17 wt. % or less, about 16 wt. % or less, about 15 wt. % or less, about 14 wt. % or less, about 13 wt. % or less, about 12 wt. % or less, about 11 wt. % or less, about 10.0 wt. % or less, about 9.5 wt. % or less, about 9.0 wt. % or less, about 8.5 wt. % or less, about 8.0 wt. % or less, about 7.5 wt. % or less, about 7.0 wt. % or less, about 6.5 wt. % or less, about 6.0 wt. % or less, about 5.5 wt. % or less, about 5.0 wt. % or less, about 4.5 wt. % or less, about 4.0 wt. % or less, about 3.5 wt. % or less, about 3.0 wt. % or less, or any range or value therebetween, relative to the total weight of the composition.

[0109] In some embodiments, the one or more oils, individually or collectively, comprise about 0.5 wt%, about 0.8 wt%, about 1.0 wt%, about 1.2 wt%, about 1.5 wt%, about 1.8 wt%, about 2.0 wt%, about 2.2 wt%, about 2.5 wt%, about 2.8 wt%, about 3.0 wt%, about 3.2 wt%, about 3.5 wt%, about 3.8 wt%, about 4.0 wt%, about 4.2 wt%, about 4.5 wt%, about 4.8 wt%, about 5.0 wt%, about 5.5 wt%, about 6.0 wt%, about 6.5 wt%, about 7.0 wt%, about 7.5 wt%, about 8.0 wt%, about 8.5 wt%, about 9.0 wt%, about 9.5 wt%, about 10.0 wt%, about 10.5 ... 0%, about 9.5%, about 10.0%, about 10.5%, about 11.0%, about 11.5%, about 12.0%, about 12.5%, about 13.0%, about 13.5%, about 14.0%, about 14.5%, about 15.0%, about 16%, about 17%, about 18%, about 19%, about 20%, about 21%, about 22%, about 23%, about 24%, about 25%, about 26%, about 27%, about 28%, about 29%, about 30%, about 35% by weight, or any range or value therebetween.

[0110] In some embodiments, the one or more oils, individually or collectively, comprise from about 0.5% to about 35% by weight, from about 0.5% to about 30% by weight, from about 0.5% to about 25% by weight, from about 0.5% to about 20% by weight, from about 0.5% to about 15% by weight, from about 0.5% to about 10.0% by weight, from about 0.5% to about 5% by weight, from about 0.5% to about 4% by weight, from about 0.5% to about 3% by weight, from about 0.5% to about 2% by weight, from about 0.5 to about 1% by weight, from about 1% to about 30% by weight, from about 1% to about 25% by weight, or from about It may be present in a concentration of 1% to about 20% by weight, about 1% to about 15% by weight, about 1% to about 10% by weight, about 1% to about 8% by weight, about 1% to about 5% by weight, about 1% to about 4% by weight, about 1% to about 3% by weight, about 1% to about 2% by weight, about 3% to about 30% by weight, about 3% to about 20% by weight, about 3% to about 15% by weight, about 3% to about 10% by weight, about 3% to about 8% by weight, about 3% to about 5% by weight, about 5% to about 10% by weight, about 5% to about 8% by weight, or any range or value therein.

[0111] Additional Fat Phase Ingredients Compositions according to the present disclosure may include an oily or fatty phase. In some embodiments, the oily or fatty phase includes an oil and additional components (e.g., wax, fatty alcohol, fatty acid, ester of a carboxylic acid or diacid, alkyl ester of a fatty acid or diacid, alkenyl ester of a fatty acid or diacid, mineral oil, petrolatum, etc.).

[0112] In some embodiments, topical compositions according to the present disclosure comprise one or more waxes, in some embodiments, the wax is selected from lanolin and its derivatives, including lanolin oil, lanolin wax, lanolin alcohol, lanolin fatty acids, isopropyl lanolate, ethoxylated lanolin, ethoxylated lanolin alcohol, ethoxylated cholesterol, propoxylated lanolin alcohol, acetylated lanolin, acetylated lanolin alcohol, lanolin alcohol linoleate, lanolin alcohol resinoleate, acetate of lanolin alcohol resinoleate, acetate of lanolin alcohol resinoleate, acetate of ethoxylated alcohol esters, hydrogenolysates of lanolin, hydrogenated lanolin, ethoxylated hydrogenated lanolin, ethoxylated sorbitol lanolin, and liquid and semi-solid lanolins. Waxes that can be used also include hydrocarbon waxes, ester waxes, amide waxes, microcrystalline waxes, hydrogenated vegetable oils, rice (Oryz sativa) bran wax, sunflower (Helianthus annuus) seed wax, paraffin, ceresin, and combinations thereof. Waxes that can be used also include beeswax (e.g., synthetic beeswax), spermaceti, wax esters such as myristyl myristate and stearyl stearate, beeswax derivatives such as polyoxyethylene sorbitol beeswax, and vegetable waxes including carnauba and candela wax.

[0113] In some embodiments, topical compositions according to the present disclosure include one or more fatty acids (e.g., pelargonic acid, lauric acid, myristic acid, palmitic acid, stearic acid, isostearic acid, hydroxystearic acid, oleic acid, linoleic acid, ricinoleic acid, arachidic acid, behenic acid, erucic acid, and combinations thereof). In some embodiments, topical compositions according to the present disclosure include one or more fatty alcohols (e.g., combinations thereof, such as lauryl alcohol, myristyl alcohol, cetyl alcohol, hexadecyl alcohol, stearyl alcohol, isostearyl alcohol, hydroxystearyl alcohol, oleyl alcohol, ricinoleyl alcohol, behenyl alcohol, erucyl alcohol, and cetostearyl alcohol (i.e., cetearyl alcohol)), and 2-octyldodecanol.

[0114] In some embodiments, topical compositions according to the present disclosure include esters of carboxylic acids or diacids (e.g., methyl, isopropyl, and butyl esters of fatty acids). In some embodiments, topical compositions according to the present disclosure include alkyl esters (e.g., 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). In some embodiments, topical compositions according to the present disclosure include alkenyl esters of fatty acids, such as oleyl myristate, oleyl stearate, and oleyl oleate. In some embodiments, topical compositions according to the present disclosure include alkyl esters of diacids (e.g., diisopropyl adipate, diisohexyl adipate, bis(hexyldecyl) adipate, and diisopropyl sebacate).

[0115] In some embodiments, the additional fatty phase components (e.g., waxes, fatty alcohols, fatty acids, esters of carboxylic acids or diacids, alkyl esters of fatty acids or diacids, alkenyl esters of fatty acids or diacids) individually or collectively comprise at least about 0.1 wt.%, at least about 0.2 wt.%, at least about 0.3 wt.%, at least about 0.4 wt.%, at least about 0.5 wt.%, at least about 0.6 wt.%, at least about 0.7 wt.%, at least about 0.8 wt.%, at least about 0.9 wt.%, at least about 1.0 wt.%, at least about 1.2 wt.%, at least about 1.5 wt.%, at least about 1.8 wt.%, at least about 2.0 wt.%, at least about 2 ... 0.2% by weight, at least about 2.5% by weight, at least about 2.8% by weight, at least about 3.0% by weight, at least about 3.2% by weight, at least about 3.5% by weight, at least about 3.8% by weight, at least about 4.0% by weight, at least about 4.2% by weight, at least about 4.5% by weight, at least about 4.8% by weight, at least about 5.0% by weight, at least about 5.5% by weight, at least about 6.0% by weight, at least about 6.5% by weight, at least about 7.0% by weight, at least about 7.5% by weight, at least about 8.0% by weight, at least about 8.5% by weight, at least about 9.0% by weight, at least about 9.5% by weight, at least about 10.0% by weight, or any range or value therebetween.

[0116] In some embodiments, the additional fatty phase components (e.g., waxes, fatty acids, fatty alcohols, esters of carboxylic acids or diacids, alkyl esters of fatty acids or diacids, alkenyl esters of fatty acids or diacids) may be present individually or collectively at a concentration of about 10.0 wt. % or less, about 9.5 wt. % or less, about 9.0 wt. % or less, about 8.5 wt. % or less, about 8.0 wt. % or less, about 7.5 wt. % or less, about 7.0 wt. % or less, about 6.5 wt. % or less, about 6.0 wt. % or less, about 5.5 wt. % or less, about 5.0 wt. % or less, about 4.5 wt. % or less, about 4.0 wt. % or less, about 3.5 wt. % or less, about 3.0 wt. % or less, or any range or value therebetween, based on the total weight of the composition.

[0117] In some embodiments, the additional fatty phase components (e.g., waxes, fatty alcohols, fatty acids, esters of carboxylic acids or diacids, alkyl esters of fatty acids or diacids, alkenyl esters of fatty acids or diacids) are individually or collectively present in an amount of about 0.1 wt.%, about 0.2 wt.%, about 0.3 wt.%, about 0.4 wt.%, about 0.5 wt.%, about 0.6 wt.%, about 0.7 wt.%, about 0.8 wt.%, about 0.9 wt.%, about 1.0 wt.%, about 1.2 wt.%, about 1.5 wt.%, about 1 ... 0.8%, about 2.0%, about 2.2%, about 2.5%, about 2.8%, about 3.0%, about 3.2%, about 3.5%, about 3.8%, about 4.0%, about 4.2%, about 4.5%, about 4.8%, about 5.0%, about 5.5%, about 6.0%, about 6.5%, about 7.0%, about 7.5%, about 8.0%, about 8.5%, about 9.0%, about 9.5%, about 10.0% by weight, or any range or value therein.

[0118] In some embodiments, the additional fatty phase components (e.g., waxes, fatty alcohols, esters of fatty acids, carboxylic acids or di-salts, alkyl esters of fatty acids or di-acids, alkenyl esters of fatty acids or di-acids) are individually or collectively present in an amount of from about 0.1 wt. % to about 10 wt. %, from about 0.1 wt. % to about 5 wt. %, from about 0.1 wt. % to about 4 wt. %, from about 0.1 wt. % to about 3 wt. %, from about 0.1 wt. % to about 2 wt. %, from about 0.1 wt. % to about 1 wt. %, from 0.1 wt. % to about 0.5 wt. %, from about 0.5 wt. % to about 1 wt. %, based on the total weight of the composition. It may be present in a concentration of 0% by weight, about 0.5% to about 5% by weight, about 0.5% to about 4% by weight, about 0.5% to about 3% by weight, about 0.5% to about 2% by weight, about 0.5% to about 1% by weight, about 1% to about 10% by weight, about 1% to about 5% by weight, about 1% to about 4% by weight, about 1% to about 3% by weight, about 1% to about 2% by weight, about 2% to about 10% by weight, about 2% to about 5% by weight, about 3% to about 10% by weight, about 3% to about 5% by weight, about 5% to about 10% by weight, or any range or value therein.

[0119] Gelling agent In some embodiments, topical compositions according to the present disclosure include one or more gelling agents (also known as suspending agents or thickening agents). By way of non-limiting example, the one or more gelling agents may be selected from ready-to-use blends (e.g., polyacrylate-13 / polyisobutene / polysorbate 20 sold by Seppic under the name SEPIPLUS 400®, or the ammonium acrylate / acrylamide copolymer / polyisobutene / polysorbate 20 blend sold by Seppic under the name SEPIPLUS 265®, or the acrylamide / sodium acryloyldimethyltaurate copolymer / isohexadecane / polysorbate 80 sold by Seppic under the name SIMULGEL™ 600), acrylic acid polymers (e.g., acrylate / C10-30 alkyl acrylate crosspolymers such as those sold under the name PEMULEN™ EZ-4U), carbomers (e.g., ULTREZ 20®, ULTREZ 10®, CARBOPOL®, sold by Lubrizol), and the like. 1382®, CARBOPOL ETD2020NF®, or AQUA SF1®), polysaccharides (for example, xanthan gum (such as XANTURAL 180® sold by Kelco), gellan gum (for example, KELCOGEL® sold by Kelco), sclerotium gum (for example, AMIGEL® by Alban Muller Industrie), guar gum and its derivatives (such as hydroxypropyl guar gum sold under the name JAGUAR HP-105® by Rhodia), cationic guar gum, pullulan, cellulose and cellulose derivatives (microcrystalline cellulose and sodium carboxymethylcellulose, for example, sold under the name BLANOSE CMC 7H4XF® by Hercules, hydroxypropyl methylcellulose, for example, METHOCEL® by Dow Chemical). Hydroxyethylcellulose, sold under the name E4M® Premium, e.g. NATROSOL by AqualonHHX250®), magnesium aluminum silicate (e.g., VEEGUM K®, VEEGUM Plus®, or VEEGUM Ultra® sold by Vanderbilt), bentonite, modified starch (e.g., STRUCTURE modified potato starch sold under the name SOLANACE®), carrageenan (e.g., the kappa, lambda, beta, and omega families, such as the VISCARIN® and GELCARIN® products sold by IMCD), polyvinyl alcohol (PVA) (e.g., Polyvinyl Alcohol 40-88® sold by Merck), polyvinylpyrrolidone, carboxyvinyl polymers, acrylic acid / ethyl acrylate copolymers (e.g., CARBOPOLS®), polyacrylic acid polymers, polymethacrylic acid polymers, polyvinyl acetate polymers, polyvinyl chloride polymers, polyvinylidene chloride polymers, mixtures of polyethylene glycol and polyethylene glycol stearate or distearate, oleogels (e.g., trihydroxystearin or aluminum magnesium hydroxystearate), non-ionic polymers, and combinations of any of the above.

[0120] In some embodiments, the one or more gelling agents, individually or collectively, comprise at least about 0.1 wt.%, at least about 0.2 wt.%, at least about 0.3 wt.%, at least about 0.4 wt.%, at least about 0.5 wt.%, at least about 0.6 wt.%, at least about 0.7 wt.%, at least about 0.8 wt.%, at least about 0.9 wt.%, at least about 1.0 wt.%, at least about 1.2 wt.%, at least about 1.5 wt.%, at least about 1.8 wt.%, at least about 2.0 wt.%, at least about 2.2 wt.%, at least about 2.5 wt.%, at least about 2.8 wt.%, at least about 2.9 wt.%, at least about 3.0 wt.%, at least about 3.1 wt.%, at least about 3.2 wt.%, at least about 3.4 wt.%, at least about 3.5 wt.%, at least about 3.6 wt.%, at least about 3.7 wt.%, at least about 3.8 wt.%, at least about 3.9 wt.%, at least about 4.0 wt.%, at least about 4.1 wt.%, at least about 4.2 wt.%, at least about 4.5 wt.%, at least about 4.6 wt.%, at least about 4.7 wt.%, at least about 4.8 wt.%, at least about 4.9 wt.%, at least about 5.0 wt.%, at least about 5.1 wt.%, at least about 5.2 wt.%, at least about 5.3 wt.%, at least about 5.4 wt.%, at least about 5.5 wt.%, at least about 5.6 wt.%, at least about 5.7 wt.%, at least about 5.8 wt.%, at least about 5.9 wt It may be present in a concentration of about 3.0% by weight, at least about 3.2% by weight, at least about 3.5% by weight, at least about 3.8% by weight, at least about 4.0% by weight, at least about 4.2% by weight, at least about 4.5% by weight, at least about 4.8% by weight, at least about 5.0% by weight, at least about 5.5% by weight, at least about 6.0% by weight, at least about 6.5% by weight, at least about 7.0% by weight, at least about 7.5% by weight, at least about 8.0% by weight, at least about 8.5% by weight, at least about 9.0% by weight, at least about 9.5% by weight, at least about 10.0% by weight, or any range or value therebetween.

[0121] In some embodiments, the one or more gelling agents, individually or collectively, may be present at a concentration of about 10.0 wt % or less, about 9.5 wt % or less, about 9.0 wt % or less, about 8.5 wt % or less, about 8.0 wt % or less, about 7.5 wt % or less, about 7.0 wt % or less, about 6.5 wt % or less, about 6.0 wt % or less, about 5.5 wt % or less, about 5.0 wt % or less, about 4.5 wt % or less, about 4.0 wt % or less, about 3.5 wt % or less, about 3.0 wt % or less, or any range or value therebetween, relative to the total weight of the composition.

[0122] In some embodiments, the one or more gelling agents, individually or collectively, are present in an amount of about 0.1 wt %, about 0.2 wt %, about 0.3 wt %, about 0.4 wt %, about 0.5 wt %, about 0.6 wt %, about 0.7 wt %, about 0.8 wt %, about 0.9 wt %, about 1.0 wt %, about 1.2 wt %, about 1.5 wt %, about 1.8 wt %, about 2.0 wt %, about 2.2 wt %, about 2.5 wt %, about 2.8 wt %, about It may be present in a concentration of 3.0% by weight, about 3.2% by weight, about 3.5% by weight, about 3.8% by weight, about 4.0% by weight, about 4.2% by weight, about 4.5% by weight, about 4.8% by weight, about 5.0% by weight, about 5.5% by weight, about 6.0% by weight, about 6.5% by weight, about 7.0% by weight, about 7.5% by weight, about 8.0% by weight, about 8.5% by weight, about 9.0% by weight, about 9.5% by weight, about 10.0% by weight, or any range or value therein.

[0123] In some embodiments, the one or more gelling agents, individually or collectively, comprise from about 0.1% to about 10% by weight, from about 0.1% to about 5% by weight, from about 0.1% to about 4% by weight, from about 0.1% to about 3% by weight, from about 0.1% to about 2% by weight, from about 0.1% to about 1% by weight, from 0.1% to about 0.5% by weight, from about 0.5% to about 10% by weight, from about 0.5% to about 5% by weight, from about 0.5% to about 4% by weight, or from about 0.5% to about 10% by weight, based on the total weight of the composition. It may be present in a concentration of about 10% to about 3% by weight, about 0.5% to about 2% by weight, about 0.5% to about 1% by weight, about 1% to about 10% by weight, about 1% to about 5% by weight, about 1% to about 4% by weight, about 1% to about 3% by weight, about 1% to about 2% by weight, about 2% to about 10% by weight, about 2% to about 5% by weight, about 3% to about 10% by weight, about 3% to about 5% by weight, about 5% to about 10% by weight, or any range or value therein.

[0124] Composition pH Topical compositions according to the present disclosure may have any suitable pH to ensure chemical and physical stability of the composition and any active ingredients contained therein, non-irritation to the skin, and prevention of dry skin.

[0125] In some embodiments, the anti-inflammatory topical composition according to the present disclosure has a saturation of about 3.0 to about 9.0, about 3.0 to about 8.5, about 3.0 to about 8.0, about 3.0 to about 7.5, about 3.0 to about 7.0, about 3.0 to about 6.5, about 3.0 to about 6.0, about 3.0 to about 5.5, about 3.0 to about 5.0, about 3.0 to about 4.5, about 3.5 to about 9.0, about 3.5 to about 8.5, about 3.5 to about 8.0, about 3.5 to about 7.5, about 3.5 to about 7.0, about 3.5 to about 6.5, about 3.5 to about 6.0, about 3.5 to about 5.5, about 3.5 to about 5.0, about 3.5 The pH range is from about 4.5 to about 9.0, from about 4.0 to about 8.5, from about 4.0 to about 8.0, from about 4.0 to about 7.5, from about 4.0 to about 7.0, from about 4.0 to about 6.5, from about 4.0 to about 6.0, from about 4.0 to about 5.5, from about 4.0 to about 5.0, from about 4.5 to about 9.0, from about 4.5 to about 8.5, from about 4.5 to about 8.0, from about 4.5 to about 7.5, from about 4.5 to about 7.0, from about 4.5 to about 6.5, from about 4.5 to about 6.0, from about 4.5 to about 5.5, from about 4.5 to about 5.0, or any range or value therein.

[0126] In some embodiments, the anti-inflammatory topical composition according to the present application has a saturation of about 3.0, about 3.1, about 3.2, about 3.3, about 3.4, about 3.5, about 3.6, about 3.7, about 3.8, about 3.9, about 4.0, about 4.1, about 4.2, about 4.3, about 4.4, about 4.5, about 4.6, about 4.7, about 4.8, about 4.9, about 5.0, about 5.1, about 5.2, about 5.3, about 5.4, about 5.5, about 5.6, about 5.7, about 5.8, about 5.9, about 6.0, about 6.1, about 6.2, about 6.3, about 6.4, about 6.5, about 6.6, about 6.7, about 6.8, about 6.9, about 7.0, about 7.1, about 7.2, about 7.3, about 7.4, about 7.5, about 7.6, about 7.7, about 7.8, about 7.9, about 8.0, about 8.1, about 8.2, about 8.3, about 8.4, about 8.5, about 8.6, about 8.7, about 8.8, about 8.9, about 9.0, about 9.1, about 9.2, about 9.3, about 9.4, about 9.5, about 9.6, about 9.7, about 9.8, about 9.9, about 10.0, about 10.1, about 10.2, about 10.3, about 10.4, about 10.5, about 10.6, about 10.7, about 10.8, about 10. The pH may be about 0.0, about 6.1, about 6.2, about 6.3, about 6.4, about 6.5, about 6.6, about 6.7, about 6.8, about 6.9, about 7.0, about 7.1, about 7.2, about 7.3, about 7.4, about 7.5, about 7.6, about 7.7, about 7.8, about 7.9, about 8.0, about 8.1, about 8.2, about 8.3, about 8.4, about 8.5, about 8.6, about 8.7, about 8.8, about 8.9, about 9.0, or any range or value therebetween.

[0127] In some embodiments, the topical composition has an acidic pH, for example, less than about 7, less than about 6.5, less than about 6.0, less than about 5.5, less than about 5.0, less than about 4.5, or any range or value therebetween.

[0128] In particular, acidic topical compositions may be advantageous for treating elderly patients with dermatoporosis or atopic dermatitis. Skin treated with an acidic emulsion (e.g., pH 4) exhibits resistance to oxidative damage, increased barrier integrity, and reduced roughness and scaling of the skin surface after several weeks of treatment. See, for example, M. Lukic, et al., "Towards Optimal pH of the Skin and Topical Formulations: From the Current State of the Art to Tailored Products," 8 Cosmetics 69 (2021); A. Kilic, et al., "Skin Acidification With a Water-in-Oil Emulsion (pH 4) Restores Disrupted Epidermal Barrier and Improves Structure of Lipid Lamellae in the Elderly," 46 J. Dermatol. 457-65 (2019).

[0129] pH adjuster In some embodiments, the topical composition may contain one or more pH adjusters suitable for adjusting the pH of the composition to any of the ranges discussed above. In some embodiments, the pH adjuster may include one or more suitable inorganic acids (e.g., hydrochloric acid, nitric acid, phosphoric acid, phosphorous acid, sulfuric acid, etc.), carboxylic acids (e.g., citric acid, glycolic acid, lactic acid, maleic acid, malic acid, succinic acid, glutaric acid, benzoic acid, malonic acid, salicylic acid, gluconic acid, etc.), polymeric acids (e.g., linear poly(acrylic) acid and its copolymers, such as maleic acid-acrylic acid, sulfonic acid-acrylic acid, and styrene-acrylic acid copolymers), crosslinked polyacrylic acid, poly(methacrylic) acid, carrageenic acid, alginic acid, etc.), and any combination thereof.

[0130] The pH can be increased or made more alkaline by the addition of any suitable alkaline pH adjuster (e.g., sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, etc.). In some embodiments, the one or more pH adjusters can include ammonia; mono-, di-, and tri-alkylamines (e.g., trimethylamine); mono-, di-, and tri-alkanolamines (e.g., monoethanolamine, diethanolamine, triethanolamine, isopropanolamine, diisopropanolamine, and triisopropanolamine); alkali metal and alkaline earth metal hydroxides (e.g., sodium hydroxide, potassium hydroxide, lithium hydroxide, etc.); alkali metal and alkaline earth metal silicates; and other pH adjusters (e.g., aminomethylpropanol (AMP-95), tetrahydroxypropylethylenediamine, ETHOMEEN® C-25 (PEG-15 cocoamine), etc.).

[0131] In some embodiments, the one or more pH adjusting agents comprise a buffering agent. A buffering agent is one or more chemical compounds added to a solution that allow the solution to resist changes in pH, either as a result of dilution or the addition of small amounts of acid or base. An effective buffer system employs a solution containing a large amount and approximately equal concentrations of a conjugate acid-base pair (or buffering agent). The buffering agent used herein can be any such chemical compound(s) that is pharmaceutically acceptable, including, but not limited to, salts of phosphate and citrate (conjugate acid and / or base). In some aspects, the buffering agent comprises phosphate-buffered saline (PBS) or an alternative phosphate buffer.

[0132] Additional ingredients Topical compositions according to the present disclosure may include a wide range of optional ingredients or additives. The CTFA International Cosmetic Ingredient Dictionary, Fifteenth Edition, 2014, which is incorporated herein by reference in its entirety, describes a wide variety of non-limiting cosmetic and pharmaceutical ingredients commonly used in the skin care industry that are suitable for use in the topical compositions of the present disclosure. Non-limiting examples of such ingredient types include abrasives, anti-acne agents, anti-caking agents (e.g., silica, starch phosphate, etc.), binders, biological additives, bulking agents, chelating agents (e.g., disodium EDTA), chemical additives, colorants, cosmetic astringents, cosmetic biocides, denaturants, drug astringents, topical analgesics, film formers, fragrance ingredients, opacifying agents, plasticizers, preservatives (e.g., phenoxyethanol, ethylhexylglycerin, etc.), propellants, reducing agents, skin bleaching agents, skin conditioning agents, skin protectants, solvents (e.g., ethanol, 1,2-hexanediol, etc.), phosphatidylcholine, hydroxybenzoates ... Examples of suitable surfactants include boosters, hydrotropes, solubilizers, suspending agents (non-surfactants), sunscreens, UV absorbers, and thickeners (aqueous and non-aqueous), solubilizers, sequestering agents, and keratolytic agents, plant extracts, dipeptides, tripeptides (e.g., tripeptide-1) and derivatives thereof, tetrapeptides (e.g., tetrapeptide-2 and derivatives), hexapeptides (e.g., hexapeptide-11, hexapeptide-12, hexapeptide-38, and derivatives thereof), octapeptides (e.g., octapeptide-45 and derivatives), and any combination thereof.

[0133] If present, such additional components are preferably present at relatively low concentrations, such as from about 0.001% to about 5% by weight, from about 0.001% to about 1% by weight, from about 0.001% to about 0.5% by weight, from about 0.001% to about 0.1% by weight, from about 0.001% to about 0.05% by weight, from about 0.001% to about 0.01% by weight, or any range or value therebetween.

[0134] water Topical compositions according to the present disclosure may contain water at a concentration of about 0% to about 98% by weight, about 5% to about 95% by weight, about 10% to about 90% by weight, about 15% to about 85% by weight, about 20% to about 80% by weight, about 25% to about 75% by weight, about 30% to about 70% by weight, about 35% to about 65% by weight, or about 40% to about 60% by weight, based on the total weight of the composition, or any range or value therein. In some embodiments, water is present at a concentration of about 5 wt%, about 10 wt%, about 15 wt%, about 20 wt%, about 25 wt%, about 30 wt%, about 35 wt%, about 40 wt%, about 45 wt%, about 50 wt%, about 55 wt%, about 60 wt%, about 65 wt%, about 70 wt%, about 75 wt%, about 80 wt%, about 85 wt%, about 90 wt%, about 95 wt%, about 96 wt%, about 97 wt%, about 98 wt%, about 99 wt%, or any range or value therebetween, based on the total weight of the composition.

[0135] Composition form Topical compositions according to the present disclosure can be in any galenic form that ensures that the composition is stable, non-irritating to the skin, non-drying to the skin, and / or pleasant and easy to apply. In some embodiments, the topical composition is an emulsion (e.g., an oil-in-water emulsion or a water-in-oil emulsion), a gel, a cream, a cream-gel, a solution, a suspension, a lotion, an emulsion, an ointment, a salve, a foam (e.g., an aerosol or a self-foaming composition), a balm, a paste, or a sachet. In some embodiments, the topical composition is an emulsion. In some embodiments, the topical composition is a gel. In some embodiments, the topical composition is a cream. In some embodiments, the topical composition is in a galenic form suitable for a pump dispenser. In some embodiments, the anti-inflammatory composition is formulated for leave-on application (as opposed to "wash-off"). In some embodiments, the topical composition is an oil-in-water (O / W) emulsion.

[0136] How to use In some aspects, the present disclosure relates to a method of treating skin affected by dermatoporosis, the method comprising administering to the affected skin a topical composition according to the present disclosure.

[0137] In some aspects, the present disclosure relates to a method of increasing fibroblast turnover in mammalian skin, the method comprising administering to the mammalian skin a topical composition according to the present disclosure. In any of the embodiments described herein, the mammalian skin may include human skin.

[0138] In some aspects, the present disclosure relates to a method of reducing the number of senescent cells in the dermis of a mammal, the method comprising administering to the skin of the mammal a topical composition according to the present disclosure. In some embodiments, the method comprises reducing the number of senescent cells in the dermis and removing the senescent cells from the dermis to the epidermis.

[0139] In some aspects, the present disclosure relates to a method of reducing senescent cell activity in mammalian skin, the method comprising administering to the mammalian skin a topical composition according to the present disclosure. In some embodiments, the method comprises reducing p16 expression and / or activity in the mammalian skin.

[0140] In certain aspects, the present disclosure relates to a method for reducing senescence-associated secretory phenotype (SASP) in mammalian epidermal cells, the method comprising administering to the mammalian skin a topical composition according to the present disclosure. In some aspects, the present disclosure relates to a method for modulating at least one SASP-related gene in mammalian skin, the method comprising administering to the mammalian skin a topical composition according to the present disclosure, wherein the at least one SASP-related gene is selected from the group consisting of IL8, IL1B, HIST1H2BG, and UBE2C. In some embodiments, modulating comprises downregulating one or more genes and / or upregulating one or more genes. In some embodiments, modulating comprises downregulating one or more genes selected from the group consisting of IL8, IL1B, HIST1H2BG, and UBE2C. In some embodiments, modulating comprises downregulating IL8. In some embodiments, modulating comprises downregulating IL1B. In some embodiments, modulating comprises downregulating HIST1H2BG. In some embodiments, the modulating comprises downregulating UBE2C. In some embodiments, the modulating is in keratinocytes.

[0141] In certain aspects, the present disclosure relates to a method of modulating one or more inflammation-related genes in mammalian skin, the method comprising administering to the mammalian skin a topical composition according to the present disclosure, wherein the at least one inflammation-related gene is selected from the group consisting of MMP2, HSPA8, CSF2RA, CXCL1, IL2RB, NFKBIA, and PTGS2. In some embodiments, modulating comprises downregulating one or more genes and / or upregulating one or more genes. In some embodiments, modulating comprises downregulating one or more genes selected from the group consisting of MMP2, HSPA8, CSF2RA, CXCL1, IL2RB, NFKBIA, and PTGS2. In some embodiments, modulating comprises downregulating MMP2. In some embodiments, modulating comprises downregulating HSPA8. In some embodiments, modulating comprises downregulating CSF2RA. In some embodiments, modulating comprises downregulating CXCL1. In some embodiments, modulating comprises downregulating IL2RB. In some embodiments, modulating comprises downregulating NFKBIA. In some embodiments, the modulating comprises downregulating PTGS2. In some embodiments, the gene is associated with skin inflammation. In some embodiments, the modulating is in keratinocytes.

[0142] In some aspects, the present disclosure relates to a method of modulating expression of one or more genes associated with p15 activity in mammalian skin, the method comprising administering to the mammalian skin a topical composition according to the present disclosure, wherein the one or more genes associated with p15 activity comprise CDKN2B. In some embodiments, the modulating is upregulating. In some embodiments, the method comprises upregulating expression of CDKN2B in the mammalian skin. In some embodiments, the modulating is in keratinocytes.

[0143] In some aspects, the present disclosure relates to a method of modulating expression of at least one cell cycle gene in mammalian dermal fibroblasts, the method comprising administering to mammalian skin a topical composition according to the present disclosure, wherein the at least one cell cycle gene in the mammalian fibroblasts is selected from the group consisting of TK1, NDC80, HMMR, KIF2C, UBEC, LMNB1, CABLES1, MCM10, H2AFX, CASC5, ESCO2, ERCC6L, BUB1, BIRC5, CCNE2, GTSE1, CDCA8, WEE1, CDC45, CDK1, CCNB2, CLSPN, BUB1B, PKMYT1, KIF23, TPX2, KIF20A, and NCAPH. In some embodiments, modulating comprises downregulating one or more genes and / or upregulating one or more genes. In some embodiments, modulating comprises upregulating one or more genes selected from TK1, NDC80, HMMR, KIF2C, UBEC, LMNBl, CABLES1, MCM10, H2AFX, CASC5, ESCO2, ERCC6L, BUB1, BIRC5, CCNE2, GTSE1, CDCA8, WEE1, CDC45, CDK1, CCNB2, CLSPN, BUB1B, PKMYT1, KIF23, TPX2, KIF20A, and NCAPH. In some embodiments, modulating comprises upregulating TK1. In some embodiments, modulating comprises upregulating NDC80. In some embodiments, modulating comprises upregulating HMMR. In some embodiments, modulating comprises upregulating KIF2C. In some embodiments, modulating comprises upregulating UBEC. In some embodiments, modulating comprises upregulating LMNBl. In some embodiments, the modulating comprises upregulating CABLES1. In some embodiments, the modulating comprises upregulating MCM10. In some embodiments, the modulating comprises upregulating H2AFX. In some embodiments, the modulating comprises upregulating CASC5.In some embodiments, modulating comprises upregulating ESCO2. In some embodiments, modulating comprises upregulating ERCC6L. In some embodiments, modulating comprises upregulating BUB1. In some embodiments, modulating comprises upregulating BIRC5. In some embodiments, modulating comprises upregulating CCNE2. In some embodiments, modulating comprises upregulating GTSE1. In some embodiments, modulating comprises upregulating CDCA8. In some embodiments, modulating comprises upregulating WEE1. In some embodiments, modulating comprises upregulating CDC45. In some embodiments, modulating comprises upregulating CDK1. In some embodiments, modulating comprises upregulating CCNB2. In some embodiments, modulating comprises upregulating CLSPN. In some embodiments, modulating comprises upregulating BUB1B. In some embodiments, modulating comprises upregulating PKMYT1. In some embodiments, modulating comprises upregulating KIF23. In some embodiments, the modulating comprises upregulating TPX2. In some embodiments, the modulating comprises upregulating KIF20A. In some embodiments, the modulating comprises upregulating NCAPH.

[0144] In some aspects, the present disclosure relates to a method for downregulating at least one transcription factor of the AP-1 complex, the method comprising administering to mammalian skin a disclosed topical composition. In some embodiments, the transcription factor of the AP-1 complex is at least one selected from JunB and FosL2.

[0145] In one aspect, which may be combined with any other aspect or embodiment, the present disclosure relates to a method of activating cell cycle progression, the method comprising administering to mammalian skin a topical composition of the present disclosure, wherein the composition upregulates CCNE2, CCNB1, or a combination thereof.

[0146] In some aspects, the present disclosure relates to a method of increasing dermal fibroblast turnover in mammalian skin, the method comprising administering to affected skin a topical composition according to the present disclosure.

[0147] In some aspects, the present disclosure relates to a method of stimulating collagen production in mammalian skin, the method comprising administering to the affected skin a topical composition according to the present disclosure.

[0148] In any aspect or embodiment, modulation (upregulation or downregulation) of gene expression can be measured in terms of fold change relative to baseline expression or expression in untreated cells. In some embodiments, upregulating means an increase of at least 1.1 fold, at least 1.2 fold, at least 1.3 fold, at least 1.4 fold, at least 1.5 fold, at least 1.6 fold, at least 1.7 fold, at least 1.8 fold, at least 1.9 fold, at least 2.0 fold, at least 2.1 fold, at least 2.2 fold, at least 2.3 fold, at least 2.4 fold, at least 2.5 fold, at least 2.6 fold, at least 2.7 fold, at least 2.8 fold, at least 2.9 fold, at least 3.0 fold, at least 3.1 fold, at least 3.2 fold, at least 3.3 fold, at least 3.4 fold, at least 3.5 fold, at least 3.6 fold, at least 3.7 fold, at least 3.8 fold, at least 3.9 fold, at least 4.0 fold, at least 4.1 fold, at least 4.2 fold, at least 4.3 fold, at least 4.4 fold, at least 4.5 fold, at least 4.6 fold, at least 4.7 fold, at least 4.8 fold, at least 4.9 fold, at least 5.0 fold, at least 5.1 fold, at least 5.2 fold, at least 5.3 fold, at least 5.4 fold, at least 5.5 fold, at least 5.6 fold, at least 5.7 fold, at least 5.8 fold, at least 5.9 fold, at least 6.0 fold, at least 6.1 fold, at least or at least 3.7 times, at least 3.8 times, at least 3.9 times, at least 4.0 times, at least 4.1 times, at least 4.2 times, at least 4.3 times, at least 4.4 times, at least 4.5 times, at least 4.6 times, at least 4.7 times, at least 4.8 times, at least 4.9 times, at least 5.0 times, at least 5.5 times, at least 6.0 times, at least 6.5 times, at least 7.0 times, at least 7.5 times, at least 8.0 times, at least 8.5 times, at least 9.0 times, at least 9.5 times, at least 10.0 times, at least 15 times, at least 20 times, or more, or any range or value therebetween.

[0149] In some embodiments, downregulating is by at least -0.1 fold, at least -0.2 fold, at least -0.3 fold, at least -0.4 fold, at least -0.5 fold, at least -0.6 fold, at least -0.7 fold, at least -0.8 fold, at least -0.9 fold, at least -1.0 fold, at least -1.1 fold, at least -1.2 fold, at least -1.3 fold, at least -1.4 fold, at least -1.5 fold, at least -1.6 fold, at least -1.7 fold, at least -1.8 fold, at least -1.9 fold, at least -2.0 fold, at least -2.1 fold, at least -2.2 fold, at least -2.3 fold, at least -2.4 fold, at least -2.5 fold, at least -2.6 fold, at least -2.7 fold, at least -2.8 fold, at least -2.9 fold, at least -3.0 fold, at least -3.1 fold, at least -3.2 fold, at least -3.4 fold, at least -3.5 fold, at least -3.6 fold, at least -3.7 fold, at least -3.8 fold, at least -3.9 fold, at least -4.0 fold, at least -4.1 fold, at least -4.2 fold, at least -4.3 fold, at least -4.4 fold, at least -4.5 fold, at least -4.6 fold, at least -4.7 fold, at least -4.8 fold, at least -4.9 fold, at least -5.0 fold, at least -5.1 fold, at least -5.2 fold, at least -5.3 fold, at least -5.4 fold, at least -5.5 fold, at least -5.6 fold, at least -5.7 or -3.2 times, at least -3.3 times, at least -3.4 times, at least -3.5 times, at least -3.6 times, at least -3.7 times, at least -3.8 times, at least -3.9 times, at least -4.0 times, at least -4.1 times, at least -4.2 times, at least -4.3 times, at least -4.4 times, at least -4.5 times, at least -4.6 times, at least -4.7 times, at least -4.8 times, at least -4.9 times, at least -5.0 times, at least -5.5 times, at least -6.0 times, at least -6.5 times, at least -7.0 times, at least -7.5 times, at least -8.0 times, at least -8.5 times, at least -9.0 times, at least -9.5 times, at least -10.0 times, at least -15 times, at least -20 times, or more, or any range or value therebetween.

[0150] The topical composition according to the present disclosure can be used with various treatment regimens.In some cases, the topical composition described herein is administered once a day, twice a day, three times a day, or more.In some cases, the topical composition described herein is administered twice a day.In some embodiments, the topical composition described herein is administered daily, every day, every other day, five days a week, once a week, every other week, two weeks a month, three weeks a month, once a month, twice a month, three times a month, or more.In some embodiments, the topical composition described herein is administered twice a day (for example, morning and evening).

[0151] In some embodiments, the topical compositions described herein are administered for at least 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 1 week, 2 weeks, 3 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, 18 months, 2 years, 3 years, 4 years, 5 years, 10 years or more.In some embodiments, the topical compositions described herein are administered twice daily for at least or about 1 week, 2 weeks, 3 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months or more.In some embodiments, the topical compositions described herein are administered once daily, twice daily, three times daily, four times daily, or more than four times daily for at least or about 1 week, 2 weeks, 3 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months or more. [Example]

[0152] Example 1. Preparation of a topical composition Exemplary topical compositions according to the present disclosure are shown in Table 1 below.

[0153] Table 1. Exemplary Topical Compositions TIFF2026503317000002.tif167140

[0154] Topical compositions according to Table 1 are prepared according to the following general procedure.

[0155] The gelling phase (Phase A) is prepared in a main tank by adding a gelling agent (e.g., acrylates / C10-30 alkyl acrylate crosspolymer), disodium EDTA, glycerin, and water under agitation until completely dispersed. The oil phase (Phase B) is prepared in a first auxiliary tank by adding an oil (e.g., sunflower seed oil, hydrogenated vegetable oil) and a non-liquid fatty substance (e.g., cetearyl alcohol, synthetic beeswax) under agitation, followed by an emulsifier (e.g., methyl glucose sesquistearate) and an antioxidant (e.g., tocopheryl acetate) and stirring until completely dispersed. Phase B is added to Phase A under agitation, followed by Phase C (potassium cetyl phosphate), the emulsifying phase, until an oil-in-water emulsion is observed. The acrylate is then neutralized (e.g., to a pH of approximately 5-6) by adding sodium hydroxide solution. The reserve phase, Phase F (eg, phenoxyethanol, ethylhexylglycerin), is then added under agitation until completely dispersed.

[0156] The active liposome phase (Phase G) is prepared in a second auxiliary tank by stirring the liposome mixture (e.g., PRO-LIPO™ NEO), water, and Centella asiatica leaf extract (e.g., HETEROSIDES) until the Centella asiatica leaf extract is completely dispersed in the liposome mixture. Phase G is then added to the pH-adjusted emulsion in the main tank with stirring until completely dispersed. Finally, the AHA phase (Phase H) containing mandelic acid is added to the main tank with stirring until completely dispersed and the pH is between 4 and 5, resulting in an oil-in-water emulsion containing liposome-encapsulated Centella asiatica leaf extract and mandelic acid.

[0157] Example 2. Cytotoxicity test of mandelic acid and Centella asiatica extract To determine the appropriate dosage of Centella asiatica extract and mandelic acid, human primary adult dermal fibroblasts and human primary adult skin keratinocytes were purchased from ZenBio (https: / / www.zen-bio.com / , Durham, NC) and seeded in the recommended medium from ZenBio according to the provided ZenBio protocol.

[0158] Approximately 10,000 cells were seeded per well in a 96-well plate. A 12-point dilution series of Centella asiatica extract or mandelic acid was performed in triplicate wells. Centella asiatica extract concentrations ranged from 0.00025% to 0.25% in 2× steps. Mandelic acid concentrations ranged from 0.00004% to 0.08% in 2× steps. After 24 hours of treatment, an Alamar Blue assay was performed. The plates were then read using an Envision plate reader with 560 nm excitation and 590 nm emission filters to determine cell viability. Fluorescence intensity values ​​are plotted and shown in Figure 1A (Centella asiatica, fibroblasts), Figure 1B (Centella asiatica, keratinocytes), Figure 1C (mandelic acid, fibroblasts), and Figure 1D (mandelic acid, keratinocytes). The arrow indicates the highest concentration at which no cytotoxicity was observed in the Alamar Blue assay, where cells were directly exposed to each component in the absence of other topical formulation components. Based on the surprising cellular responses at the tested concentrations, we investigated whether using Centella asiatica extract and mandelic acid at concentrations lower than those traditionally recommended for their topical use (0.2-0.5 wt% and 0.5-6 wt%, respectively) could reduce negative effects (e.g., inflammation) while still providing therapeutic benefits (e.g., reducing cellular senescence and increasing cell turnover).

[0159] Example 3. In vitro analysis of gene expression in human keratinocytes and dermal fibroblasts A series of in vitro gene expression analyses were performed to evaluate the effects of topical compositions according to the present disclosure on inflammation, cell turnover, and aging. (See Figure 2 for a schematic diagram of biomarkers associated with inflammation, cell turnover, and aging.) Modulation of gene expression in the presence of Centella asiatica extract, mandelic acid, and a combination of Centella asiatica extract and mandelic acid was examined to assess the effect on genes involved in the senescence-associated secretory phenotype (SASP), a phenotype associated with senescent cells. These cells secrete high levels of inflammatory cytokines, immunomodulatory factors, growth factors, and proteases. Human dermal fibroblasts and keratinocytes were grown to confluence and treated with Centella asiatica extract (0.005%), mandelic acid (0.05%), or a combination of the two active substances (at the same concentration) for 72 hours. (The selected concentrations of mandelic acid and Centella asiatica extract were determined as the highest concentrations that did not cause cytotoxicity, as discussed in Example 2.) RNA was extracted and subjected to RNA sequencing. Differentially expressed genes were determined compared to untreated cells and were annotated using the Reactome database.

[0160] As shown in Figures 3A-3D, multiple SASP-related genes that increase inflammation were downregulated by Centella asiatica extract, demonstrating a protective effect against senescent cells. Furthermore, the combination of Centella asiatica extract and mandelic acid synergistically downregulated the SASP-related genes IL8 (Figure 3A), IL1B (Figure 3B), HIST1H2BG (Figure 3C), and UBE2C (Figure 3D).

[0161] Furthermore, as shown in Figures 4A-4G, pro-inflammatory gene expression was significantly down-regulated by Centella asiatica extract and by mandelic acid, individually and in combination, particularly for MMP2 (Figure 4A), HSPA8 (Figure 4B), CSF2RA (Figure 4C), CXCL1 (Figure 4D), IL2RB (Figure 4E), NFKBIA (Figure 4F), and PTG52 (Figure 4G). Furthermore, the combination of Centella asiatica extract and mandelic acid synergistically down-regulated the expression of genes related to systemic inflammation, which may be related to the down-regulation of SASP-related genes. These data are summarized in Table 2.

[0162] Table 2. Regulation of gene expression (fold change) by Centella asiatica extract, mandelic acid, and the combination of Centella asiatica extract and mandelic acid TIFF2026503317000003.tif91128

[0163] As shown in Figure 5, Centella asiatica extract and mandelic acid, individually and in combination, upregulate the expression of p15(CDKN2B), which is involved in avoiding oxidative stress-induced senescence due to defective p16INK4A binding to CDK4. Thus, treatment with a composition according to the present disclosure could prevent cellular senescence in keratinocytes and reduce the presence of senescent cells in the dermis.

[0164] Referring now to Figure 6, the combination of Centella asiatica extract and mandelic acid significantly synergistically up-regulates the expression of cell cycle-related genes TK1, UBEC, H2AFX, BUB1, CDCA8, CCNB2, KIF23, NDC80, LMNB1, CASC5, BIRC5, WEE1, CLSPN, TPX2, HMMR, CABLES1, ESCO2, CCNE2, CDC45, BUB1B, KIF20A, KIF2C, MCM10, ERCC6L, GTSE1, CDK1, PKMYT1, and NCAPH in dermal fibroblasts. Notably, only the combination of Centella asiatica extract and mandelic acid significantly up-regulates all of the genes shown (y-axis indicates log2 fold change). The data indicate improved cell turnover and thereby reduced cellular senescence.

[0165] In addition, referring now to Figures 7A-7J, the combination of Centella asiatica extract and mandelic acid synergistically upregulated the expression of p16-interacting genes WEE1 (Figure 7A), H2AFX (Figure 7B), LMNB1 (Figure 7C), CCNB2 (Figure 7D), BUB1 (Figure 7E), CDC45 (Figure 7F), CDK1 (Figure 7G), BIRC5 (Figure 7H), MCM10 (Figure 7I), and CCNE2 (Figure 7J), indicating that the combination counteracts p16 and reverses cellular senescence in fibroblasts.

[0166] Dermatoporosis is associated with the loss of extracellular matrix (ECM) (e.g., collagen, elastin, and GAGs), leading to skin thinning, fragility, and vascular leakage. This degradation is associated with ROS generation, which stimulates the activation of transcription factors (e.g., AP-1) and the synthesis of matrix metalloproteinases (MMPs). JunB is a major component of the transcription factor AP-1. Therefore, downregulating this factor reduces or limits ECM degradation. Referring now to Figure 8, fibroblasts treated with a combination of Centella asiatica extract (0.005%) and mandelic acid (0.05%) show significant downregulation of JunB and FosL2, both transcription factors and members of the AP-1 complex. This downregulation blocks the ability of p21 (CDKN1A) to inhibit cell cycle progression, which in turn activates cell cycle progression, as indicated by the upregulation of CyclinE2 (CCNE2) and CyclinB1d (CCNB1). (All fold changes were significant with p-values ​​<0.05.)

[0167] Taken together, the gene expression data indicate that the combination of Centella asiatica extract and mandelic acid induces robust and synergistic effects in (i) significantly reducing the senescent cell inflammatory secretome (SASP), thus avoiding senolytic activity in keratinocytes, (ii) increasing dermal fibroblast turnover, and (iii) reducing p16 (a senescent cell marker, cell cycle blocker), indicating an overall decreased cellular senescence in fibroblasts.

[0168] Example 4. Ex vivo analysis of cellular senescence activity To investigate the effect of topical compositions according to the present disclosure on senescent cell responses when applied topically to skin, test compositions were prepared according to Example 1 and tested ex vivo on discarded human skin samples. Biopsies were made from discarded human skin samples, and the tissue was placed in a 24-well plate for culture. After acclimation, the skin samples were treated with the test compositions once daily for 10 days. The samples were stained with p16 to assess anti-aging activity, and untreated skin samples were used as a baseline.

[0169] Figures 9A-9D show images of p16-stained skin samples comparing untreated skin (left) with skin treated with the test composition (right). Cell nuclei appear blue, while p16 appears yellow. Untreated skin shows evidence of p16 (senescent cells) in the dermis. In contrast, samples treated with the test composition show a loss of senescent cells in the dermis and evidence of senescent cells in the epidermis. In some images, high concentrations of senescent cells are observed in hair follicles, where cells undergo natural aging as part of the hair cycle. These senescent cells are expected to be present and are not considered in this analysis.

[0170] The ex vivo results confirm the gene expression data related to p16 senescence activity (Example 2), and the test composition containing Centella asiatica extract and mandelic acid appears to reduce and even inhibit p16 activity. The ex vivo results also show increased dermal cell turnover, as evidenced by a reduced senescent cell population in the treated dermis compared to untreated skin.

[0171] Furthermore, the compositions according to the present disclosure surprisingly appear to promote the clearance of dermal senescent cells from the dermis and into the epidermis. Without being bound by any particular theory, the test compositions appear to potentially promote the clearance of senescent cells through a signaling mechanism that initiates in the epidermis: signaling dermal senescent cells (possibly due to the collagen-stimulating effect of Centella asiatica extract), reversing senescence in the dermis, and then promoting epidermal turnover through increased epidermal senescent cells (and protection from these cells) and terminally differentiated cells emerging in the upper epidermis. This suggests a form of senescent cell clearance and cellular recovery, which would be highly advantageous for the management of dermatoporosis.

[0172] While the foregoing terms are believed to be well understood by those of ordinary skill in the art, the following definitions are provided herein to facilitate description of the subject matter of the present disclosure.

[0173] The term "a" or "an" can refer to one or more of that entity, i.e., to a plurality of referents. Thus, the terms "a" or "an," "one or more," and "at least one" are used interchangeably herein. In addition, reference to an "element" by the indefinite article "a" or "an" does not exclude the possibility that more than one of the element is present, unless the context clearly requires that only one of the element is present.

[0174] References throughout this specification to "one embodiment," "an embodiment," "one aspect," or "an aspect" mean that a particular feature, structure, or characteristic described in connection with that embodiment is included in at least one embodiment of the present disclosure. Thus, the appearances of the phrases "in one embodiment" or "in an embodiment" in various places throughout this specification are not necessarily all referring to the same embodiment. Furthermore, particular features, structures, or characteristics may be combined in any suitable manner in one or more embodiments.

[0175] As used herein, the terms "about" or "approximately," when preceding a numerical value, indicate a range of plus or minus 10% of that value.

[0176] As will be understood by those skilled in the art, for any and all purposes, particularly in terms of providing a written description, all ranges disclosed herein also encompass any and all possible subranges and combinations of those subranges. Any recited range can be readily recognized as fully descriptive and allowing for the same range to be broken down into at least equal halves, thirds, quarters, fifths, tenths, etc. As a non-limiting example, each range discussed herein can be readily broken down into lower, middle, and upper thirds, etc. As will be understood by those skilled in the art, all terms such as "up to," "at least," "greater than," and "less than" refer to ranges that are inclusive of the recited numbers and can subsequently be broken down into subranges, as discussed above. Finally, as will be understood by those skilled in the art, a range includes each individual member. Thus, for example, a group having 1 to 3 cells refers to a group having 1, 2, or 3 cells. Similarly, a group having 1 to 5 cells refers to a group having 1, 2, 3, 4, or 5 cells, etc.

[0177] Unless otherwise defined, all terms (including technical and scientific terms) used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Terms as defined in commonly used dictionaries should be interpreted to have a meaning consistent with their meaning in the context of this application and related art, and it will be further understood that they should not be interpreted in an idealized or overly formal sense unless explicitly defined herein. Unless explicitly defined below, such terms should be interpreted according to their common meaning.

[0178] Additionally, when features or aspects of the disclosure are described in terms of a Markush group, those skilled in the art will recognize that the disclosure is thereby also described in terms of any individual member or subgroup of members of the Markush group.

[0179] It is specifically contemplated that the various features of the invention described herein can be used in any combination, unless the context dictates otherwise. Furthermore, the present disclosure also contemplates that, in some embodiments, any feature or combination of features described herein may be excluded or omitted. To illustrate, if the specification states that a composite comprises components A, B, and C, it is specifically contemplated that any of A, B, or C, or combinations thereof, alone or in any combination, may be omitted or eliminated.

[0180] Unless expressly stated otherwise, all particular embodiments, features, and terms are intended to include both the recited embodiment, feature, or term and their equivalents.

[0181] All patents, patent applications, provisional applications, and publications mentioned or cited herein are incorporated by reference in their entirety, including all figures and tables, to the extent they do not contradict the explicit teachings of this specification.

[0182] Reference will now be made in detail to some specific embodiments contemplated by the present disclosure. While various embodiments are described herein, it will be understood that it is not intended to limit the technology of the present invention to the described embodiments. On the contrary, it is intended to cover alternatives, modifications, and equivalents that may be included within the spirit and scope of the technology as defined by the appended claims.

Claims

1. a liposome-encapsulated Centella asiatica extract; Alpha hydroxy acids (AHAs) A topical composition comprising: The topical composition, wherein the composition has a pH of less than 5.

2. The topical composition of claim 1 , wherein the composition is in the form of an emulsion.

3. The topical composition of claim 2 , wherein the emulsion is an oil-in-water (O / W) emulsion.

4. The topical composition of any one of claims 1 to 3, wherein the pH of the composition is greater than or equal to 4 and less than 5.

5. 5. The topical composition of any one of claims 1 to 4, wherein the Centella asiatica extract is present at a concentration of at least about 0.01% and less than 0.2% by weight, based on the total weight of the composition.

6. 6. The topical composition of any one of claims 1 to 5, wherein the Centella asiatica extract is present in a concentration of about 0.01% to about 0.1% by weight, based on the total weight of the composition.

7. The topical composition of any one of claims 1 to 6, wherein the Centella asiatica extract comprises triterpenes.

8. 8. The topical composition of claim 7, wherein the triterpene is one or more selected from the group consisting of madecassoside, asiaticoside, madecassic acid, and asiatic acid.

9. 9. The topical composition of claim 7 or 8, wherein the triterpenes are present in the Centella asiatica extract at a concentration of at least about 70% by weight, based on the total weight of the Centella asiatica extract.

10. 10. The topical composition of any one of claims 7 to 9, wherein the triterpene is present in the composition at a concentration of at least about 0.005% by weight and less than 0.2% by weight, based on the total weight of the composition.

11. 11. The topical composition of any one of claims 7 to 10, wherein the triterpene is present in the Centella asiatica extract at a concentration of at least about 0.01% to about 0.05% by weight, based on the total weight of the composition.

12. The topical composition of any one of claims 1 to 11, wherein the AHA comprises mandelic acid.

13. The topical composition of any one of claims 1 to 12, wherein the AHA is present at a concentration of at least about 0.01% and less than 0.5% by weight, based on the total weight of the composition.

14. 14. The topical composition of any one of claims 1 to 13, wherein the AHA is present at a concentration of about 0.05% to about 0.3% by weight, based on the total weight of the composition.

15. 15. The topical composition of any one of claims 1 to 14, wherein the liposomes are present in a concentration of about 0.03% to about 4% by weight based on the total weight of the composition.

16. The topical composition of any one of claims 1 to 15, wherein the liposome comprises lecithin, propanediol, or a combination thereof.

17. The topical composition of any one of claims 1 to 16, wherein the liposomes comprise an antioxidant.

18. 18. The topical composition of claim 17, wherein the antioxidant is tocopherol, tocopheryl acetate, or a combination thereof.

19. 19. The topical composition of any one of claims 1 to 18, wherein the liposomes have an average particle size of 100 nm to 300 nm.

20. 20. The topical composition of any one of claims 1 to 19, wherein the liposomes have an average particle size of about 250 nm.

21. The topical composition of any one of claims 1 to 20, wherein the Centella asiatica extract is present in an active solution.

22. 22. The topical composition of claim 21, wherein the liposomes and the active solution are present in a weight ratio of about 1:1 to about 1:

20.

23. 23. The topical composition of claim 21 or 22, wherein the liposomes and the active solution are present in a weight ratio of about 1:2 to about 1:

10.

24. 24. The topical composition of any one of claims 1 to 23, wherein the Centella asiatica extract and the AHA are present in a weight ratio of about 1:5 to 1:

15.

25. 25. The topical composition of any one of claims 1 to 24, further comprising an antioxidant separate from any antioxidant in the liposome.

26. 26. The topical composition of any one of claims 1 to 25, wherein the antioxidant, separate from any antioxidant in the liposome, is tocopheryl acetate, tocopherol, or a combination thereof.

27. The topical composition of any one of claims 1 to 26, further comprising at least one of a humectant, an emollient, or a moisturizer.

28. The topical composition of any one of claims 1 to 27, further comprising glycerin.

29. The topical composition of any one of claims 1 to 28, wherein the composition is a cream or lotion.

30. Centella asiatica extract encapsulated in liposomes; Alpha hydroxy acids (AHAs) A topical composition comprising: the composition is an emulsion, the composition has a pH of 4 to 5; and the composition reduces biomarkers of skin inflammation in mammalian skin cells; The topical composition.

31. Alpha hydroxy acids (AHAs), a triterpene selected from the group consisting of madecassoside, asiaticoside, madecassic acid, and asiatic acid, encapsulated in liposomes; A topical composition comprising: The topical composition, wherein the composition has a pH of 4 to 5.

32. 32. The topical composition of claim 31, wherein the AHA comprises mandelic acid.

33. 33. The topical composition of claim 31 or 32, wherein the AHA is present in the composition at a concentration of at least about 0.01% by weight and less than 0.5% by weight, based on the total weight of the composition.

34. 34. The topical composition of any one of claims 31 to 33, wherein the triterpene is present in the composition at a concentration of at least about 0.005% by weight and less than 0.2% by weight, based on the total weight of the composition.

35. The topical composition of any one of claims 31 to 34, wherein the composition is an emulsion.

36. 36. The topical composition of any one of claims 1 to 35, wherein the composition is effective in reducing the number of senescent cells in the dermis of a mammal.

37. 37. The topical composition of any one of claims 1 to 36, wherein the composition is effective in reducing senescence-associated secretory phenotype (SASP) in mammalian epidermal cells.

38. 38. The topical composition of any one of claims 1 to 37, wherein the composition is effective to downregulate at least one SASP-associated gene selected from the group consisting of IL8, IL1B, HIST1H2BG, and UBE2C.

39. 39. The topical composition of any one of claims 1 to 38, wherein the composition is effective to increase the expression of at least one cell cycle gene in mammalian dermal fibroblasts.

40. 40. The topical composition of claim 39, wherein the at least one cell cycle gene in mammalian fibroblasts is selected from the group consisting of TK1, NDC80, HMMR, KIF2C, UBEC, LMNB1, CABLES1, MCM10, H2AFX, CASC5, ESCO2, ERCC6L, BUBl, BIRC5, CCNE2, GTSE1, CDCA8, WEE1, CDC45, CDK1, CCNB2, CLSPN, BUBlB, PKMYT1, KIF23, TPX2, KIF20A, and NCAPH.

41. 41. The topical composition of any one of claims 1 to 40, wherein the composition is effective to downregulate at least one gene associated with skin inflammation selected from the group consisting of MMP2, HSPA8, CSF2RA, CXCL1, IL2RB, NFKBIA, and PTGS2.

42. 42. The topical composition of any one of claims 1 to 41, wherein the composition is effective to downregulate transcription factors of the AP-1 complex.

43. 43. The topical composition of claim 42, wherein the transcription factor of the AP-1 complex is at least one selected from JunB and FosL2.

44. 44. The topical composition of any one of claims 1 to 43, wherein the composition is effective to activate cell cycle progression by upregulating CCNE2, CCNB1, or a combination thereof.

45. 31. The topical composition of any one of claims 1 to 30, wherein the Centella asiatica extract and the AHA are present at concentrations effective to synergistically down-regulate at least one SASP-related gene selected from the group consisting of IL8, IL1B, HIST1H2BG, and UBE2C.

46. The Centella asiatica extract and the AHA are at least one cell cycle gene in mammalian dermal fibroblasts selected from the group consisting of TK1, NDC80, HMMR, KIF2C, UBEC, LMNB1, CABLES1, MCM10, H2AFX, CASC5, ESCO2, ERCC6L, BUB1, BIRC5, CCNE2, GTSE1, CDCA8, WEE1, CDC45, CDK1, CCNB2, CLSPN, BUB1B, PKMYT1, KIF23, TPX2, KIF20A, and NCAPH; 46. ​​The topical composition of any one of claims 1 to 30 or 45, wherein the composition is present in a concentration effective to synergistically upregulate

47. At least one SASP-related gene selected from the group consisting of IL8, IL1B, HIST1H2BG, and UBE2C, and the topical composition of any one of claims 1-30 or 45-46.

48. 48. The topical composition of any one of claims 1-30 or 45-47, wherein the Centella asiatica extract and the AHA are present in concentrations effective to synergistically downregulate transcription factors of the AP-1 complex.

49. 49. The topical composition of claim 48, wherein the transcription factor of the AP-1 complex is at least one selected from JunB and FosL2.

50. 50. The topical composition of any one of claims 1-30 or 45-49, wherein the Centella asiatica extract and the AHA are present in concentrations effective to synergistically activate cell cycle progression by upregulating CCNE2, CCNB1, or a combination thereof.

51. 35. The topical composition of any one of claims 31 to 34, wherein the triterpene and the AHA are present at concentrations effective to synergistically down-regulate at least one SASP-associated gene selected from the group consisting of IL8, IL1B, HIST1H2BG, and UBE2C.

52. The triterpene and the AHA are at least one cell cycle gene in mammalian dermal fibroblasts selected from the group consisting of TK1, NDC80, HMMR, KIF2C, UBEC, LMNB1, CABLES1, MCM10, H2AFX, CASC5, ESCO2, ERCC6L, BUB1, BIRC5, CCNE2, GTSE1, CDCA8, WEE1, CDC45, CDK1, CCNB2, CLSPN, BUB1B, PKMYT1, KIF23, TPX2, KIF20A, and NCAPH; 52. The topical composition of any one of claims 31-34 or 51, present in a concentration effective to synergistically upregulate

53. 53. The topical composition of any one of claims 31-34 or 51-52, wherein the triterpene and the AHA are present at concentrations effective to synergistically downregulate at least one SASP-associated gene selected from the group consisting of IL8, IL1B, HIST1H2BG, and UBE2C.

54. 54. The topical composition of any one of claims 31-34 or 51-53, wherein the triterpene and the AHA are present in concentrations effective to synergistically downregulate transcription factors of the AP-1 complex.

55. 55. The topical composition of claim 54, wherein the transcription factor of the AP-1 complex is at least one selected from JunB and FosL2.

56. 56. The topical composition of any one of claims 31-34 or 51-55, wherein the triterpene and the AHA are present in concentrations effective to synergistically activate cell cycle progression by upregulating CCNE2, CCNB1, or a combination thereof.

57. 1. A method of treating skin affected by dermatoporosis, comprising: administering to the affected skin a topical composition according to any one of claims 1 to 56. The method comprising:

58. 1. A method for increasing fibroblast turnover in mammalian skin, comprising: administering to the skin of the mammal a topical composition according to any one of claims 1 to 56. The method comprising:

59. 1. A method for reducing the number of senescent cells in the dermis of a mammal, comprising: administering to the skin of a mammal a topical composition according to any one of claims 1 to 56. The method comprising:

60. 1. A method for reducing senescence-associated secretory phenotype (SASP) in mammalian epidermal cells, comprising: administering to the skin of a mammal a topical composition according to any one of claims 1 to 56. The method comprising:

61. 1. A method for downregulating at least one SASP-related gene in mammalian skin, comprising: administering to the skin of a mammal a topical composition according to any one of claims 1 to 56. Including, The method, wherein the at least one SASP-associated gene is selected from the group consisting of IL8, IL1B, HIST1H2BG, and UBE2C.

62. 1. A method for increasing expression of at least one cell cycle gene in mammalian dermal fibroblasts, comprising: administering to the skin of a mammal a topical composition according to any one of claims 1 to 56. Including, the at least one cell cycle gene in mammalian fibroblasts is selected from the group consisting of TK1, NDC80, HMMR, KIF2C, UBEC, LMNB1, CABLES1, MCM10, H2AFX, CASC5, ESCO2, ERCC6L, BUB1, BIRC5, CCNE2, GTSE1, CDCA8, WEE1, CDC45, CDK1, CCNB2, CLSPN, BUB1B, PKMYT1, KIF23, TPX2, KIF20A, and NCAPH; The method.

63. 1. A method for downregulating at least one gene associated with skin inflammation, comprising: Administering to the skin of a mammal a composition according to any one of claims 1 to 56. Including, The at least one gene associated with skin inflammation is selected from the group consisting of MMP2, HSPA8, CSF2RA, CXCL1, IL2RB, NFKBIA, and PTGS2; The method.

64. 1. A method of downregulating at least one transcription factor of the AP-1 complex, comprising: administering to the skin of a mammal a topical composition according to any one of claims 1 to 56. The method comprising:

65. 65. The method of claim 64, wherein the transcription factor of the AP-1 complex is at least one selected from JunB and FosL2.

67. 1. A method of activating cell cycle progression, comprising: administering to the skin of a mammal a topical composition according to any one of claims 1 to 56. wherein the topical composition upregulates CCNE2, CCNB1, or a combination thereof.

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