Formulations and methods for skin care or hyaluronic acid synthesis

Abstract

Cosmetic and pharmaceutical formulations containing specific amino acid blends are described herein. These formulations strengthen and enhance the barrier function of skin epithelial cells, thereby reducing water loss from the skin and restoring and / or maintaining the structural integrity of the skin, epithelial differentiation, cell-cell adhesion, and intracellular signaling. The formulations described herein contain a therapeutically effective amount of a free amino acid or a peptide combination of amino acids, and a therapeutically effective amount of a plant extract for skin barrier repair or a therapeutically effective amount of a retinoid for improving skin moisture. Also provided are injectable formulations described herein for treating subjects suffering from osteoarthritis or its symptoms. Methods for administering these formulations for cosmetic and / or therapeutic purposes, and their uses for the same, such as in the preparation of pharmaceuticals, are also described herein.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of priority to International Application No. PCT / US22 / 82663, filed December 30, 2022, and U.S. Provisional Application No. 63 / 296,033, filed January 3, 2022, both of which are incorporated by reference in their entireties.

[0002] Field of the Disclosure The present disclosure is directed to formulations and methods of their use in improving skin barrier integrity, skin barrier repair, and skin moisture, as well as methods of treating osteoarthritis or symptoms thereof. [Background technology]

[0003] Skin diseases and conditions can cause considerable physical discomfort and psychological distress to patients suffering from such diseases and conditions. Common skin diseases and conditions include atopic dermatitis, psoriasis, and ichthyosis. Xeroderma (dry skin) is a very common skin disease that afflicts a significant subset of the population. The skin diseases, conditions, and disorders that afflict patients often vary with age and are influenced by lifestyle and geographic region. Despite the high prevalence of skin diseases, conditions, and disorders in the population and their adverse impact on people's quality of life and the associated economic burden, few effective treatments are available. There is an unmet need for effective formulations to address cosmetic skin care goals and for the treatment of skin diseases, conditions, and disorders. Summary of the Invention

[0004] Cosmetic and pharmaceutical formulations are described herein. Such formulations strengthen and enhance the barrier function of skin epithelial cells, thereby reducing water loss from the skin and restoring and / or promoting the maintenance of the skin's structural integrity, cell-cell adhesion, and biochemistry. Described herein are formulations comprising, consisting essentially of, or consisting of therapeutically effective amounts of the free amino acids or peptide combinations thereof of alanine, glutamine, glycine, and serine, and, optionally, a therapeutically effective amount of at least one additional free amino acid or peptide combination of amino acids of valine, isoleucine, arginine, threonine, or tryptophan, or any combination thereof. Also included herein are methods for maintaining and / or improving the barrier integrity of skin cells in a subject in need thereof or for improving the cosmetic skin condition of a human, comprising administering a formulation described herein to the subject. Also included herein are uses of the formulations described herein for maintaining and / or improving the barrier integrity of skin cells in a subject in need thereof or for improving the cosmetic skin condition of a human, comprising administering a formulation described herein to the subject or human. The formulations described herein may be used in the preparation of dermatological medicaments for treating cosmetic skin conditions in subjects in need thereof. Other formulations described herein may be used in the preparation of medicaments for treating osteoarthritis or its symptoms. Such methods, uses, and dermatological medicaments or medicaments are administered or used to improve cosmetic skin conditions or diseases or disorders, such as osteoarthritis. In some embodiments, the cosmetic skin condition is associated with skin aging. The cosmetic skin condition may be associated with at least one visual characteristic, at least one tactile characteristic, or a combination of visual and tactile characteristics of the skin. Thus, improving at least one visual characteristic, at least one tactile characteristic, or a combination of visual and tactile characteristics of the skin reduces the length, depth, and / or other size of lines and / or wrinkles on the skin.Also encompassed herein are methods for treating and / or preventing skin diseases, conditions, or disorders in a subject in need thereof, comprising administering a formulation described herein to the subject. Also encompassed herein are uses of the formulations described herein for treating and / or preventing skin diseases, conditions, or disorders in a subject in need thereof, comprising administering a formulation described herein to the subject. The formulations described herein may also be used in the preparation of medicaments for treating and / or preventing skin diseases, conditions, or disorders or other diseases, conditions, or disorders, such as osteoarthritis, in a subject in need thereof.

[0005] Embodiment 1. A formulation for administration to the skin comprising, as free amino acids or peptide combinations of amino acids, a therapeutically effective amount of alanine, glutamine, glycine, and serine, or salts thereof, and optionally a therapeutically effective amount of at least one additional free amino acid or peptide combination of amino acids valine, isoleucine, arginine, threonine, or tryptophan, or salts thereof, or any combination thereof, wherein said therapeutically effective amount of glutamine, glycine, alanine, and serine, or salts thereof, and said therapeutically effective amount of glutamine, glycine, alanine, and serine, or salts thereof, and The formulation, wherein an effective amount of the at least one additional free amino acid or salt thereof improves the barrier integrity of skin cells, optionally comprising a dermatologically acceptable carrier or vehicle, wherein the formulation improves the barrier integrity of skin cells when tested by a method that detects expression of a barrier marker gene (e.g., CPT2, EGF, FGF2, FLG, MKI67, PDGF, PPARD, TGM4) and determines that the barrier marker gene is regulated with an average fold change of 1.5 to 7 for amino acid-treated skin compared to amino acid-untreated skin.

[0006] Embodiment 2. The formulation of embodiment 1, wherein the free amino acids or peptide combinations of amino acids comprise, consist essentially of, or consist of glutamine, glycine, alanine, serine, and valine, or salts thereof, and at least one additional amino acid isoleucine, arginine, threonine, or tryptophan, or salts thereof, or any combination thereof.

[0007] Embodiment 3. The formulation of embodiment 1 or embodiment 2, wherein the free amino acids or peptide combinations of amino acids comprise, consist essentially of, or consist of glutamine, glycine, alanine, serine, valine, and isoleucine, or salts thereof, and at least one additional amino acid arginine, or threonine, or salts thereof, or any combination thereof.

[0008] Embodiment 4. The formulation of embodiment 1 or embodiment 2, wherein the free amino acid or peptide combination of amino acids comprises, consists essentially of, or consists of glutamine, glycine, alanine, serine, and valine, or salts thereof.

[0009] Embodiment 5. The formulation of embodiment 1 or embodiment 2, wherein the free amino acid or peptide combination of amino acids comprises, consists essentially of, or consists of glutamine, glycine, alanine, serine, valine, and isoleucine, or salts thereof.

[0010] Embodiment 6. The formulation of any one of embodiments 1-3, wherein the free amino acid or peptide combination of amino acids comprises, consists essentially of, or consists of glutamine, glycine, alanine, serine, valine, isoleucine, and arginine, or salts thereof.

[0011] Embodiment 7. The formulation of any one of embodiments 1-3, wherein the free amino acid or peptide combination of amino acids comprises, consists essentially of, or consists of glutamine, glycine, alanine, serine, valine, isoleucine, and threonine, or salts thereof.

[0012] Embodiment 8. The formulation of embodiment 1, wherein the free amino acids or peptide combinations of amino acids comprise, consist essentially of, or consist of glutamine, glycine, alanine, and serine, or salts thereof, and at least one additional amino acid isoleucine, arginine, threonine, or tryptophan, or salts thereof, or any combination thereof.

[0013] Embodiment 9. The formulation of embodiment 8, wherein the free amino acid or peptide combination of amino acids comprises, consists essentially of, or consists of glutamine, glycine, alanine, serine, and isoleucine, or salts thereof.

[0014] Embodiment 10. The formulation of embodiment 8, wherein the free amino acid or peptide combination of amino acids comprises, consists essentially of, or consists of glutamine, glycine, alanine, serine, and arginine, or salts thereof.

[0015] Embodiment 11. The formulation of embodiment 8, wherein the free amino acid or peptide combination of amino acids comprises, consists essentially of, or consists of glutamine, glycine, alanine, serine, and threonine, or salts thereof.

[0016] Embodiment 15. The formulation of embodiment 8, wherein the free amino acid or peptide combination of amino acids comprises, consists essentially of, or consists of glutamine, glycine, alanine, serine, and tryptophan, or salts thereof.

[0017] Embodiment 16. The formulation of embodiment 8, wherein the free amino acids or peptide combinations of amino acids comprise, consist essentially of, or consist of glutamine, glycine, alanine, serine, and isoleucine, or salts thereof, and at least one additional amino acid arginine, or threonine, or tryptophan, or salts thereof, or any combination thereof.

[0018] Embodiment 17. The formulation of embodiment 16, wherein the free amino acid or peptide combination of amino acids comprises, consists essentially of, or consists of glutamine, glycine, alanine, serine, isoleucine, and arginine, or salts thereof.

[0019] Embodiment 18. The formulation of embodiment 16, wherein the free amino acid or peptide combination of amino acids comprises, consists essentially of, or consists of glutamine, glycine, alanine, serine, isoleucine, and threonine, or salts thereof.

[0020] Embodiment 19. The formulation of embodiment 16, wherein the free amino acid or peptide combination of amino acids comprises, consists essentially of, or consists of glutamine, glycine, alanine, serine, isoleucine, and tryptophan, or salts thereof.

[0021] Embodiment 20. The formulation of embodiment 16, wherein the free amino acid or peptide combination of amino acids comprises, consists essentially of, or consists of glutamine, glycine, alanine, serine, isoleucine, arginine, and threonine, or salts thereof.

[0022] Embodiment 21. The formulation of embodiment 16, wherein the free amino acid or peptide combination of amino acids comprises, consists essentially of, or consists of glutamine, glycine, alanine, serine, isoleucine, arginine, and tryptophan, or salts thereof.

[0023] Embodiment 22. The formulation of embodiment 16, wherein the free amino acid or peptide combination of amino acids comprises, consists essentially of, or consists of glutamine, glycine, alanine, serine, isoleucine, threonine, and tryptophan, or salts thereof.

[0024] Embodiment 23. The formulation of embodiment 16, wherein the free amino acid or peptide combination of amino acids comprises, consists essentially of, or consists of glutamine, glycine, alanine, serine, isoleucine, arginine, threonine, and tryptophan, or salts thereof.

[0025] Embodiment 24. The formulation of embodiment 8, wherein the free amino acids or peptide combinations of amino acids comprise, consist essentially of, or consist of glutamine, glycine, alanine, serine, and arginine, or salts thereof, and at least one additional amino acid isoleucine, threonine, or tryptophan, or salts thereof, or any combination thereof.

[0026] Embodiment 25. The formulation of embodiment 8, wherein the free amino acids or peptide combinations of amino acids comprise, consist essentially of, or consist of glutamine, glycine, alanine, serine, and threonine, or salts thereof, and at least one additional amino acid isoleucine, arginine, or tryptophan, or salts thereof, or any combination thereof.

[0027] Embodiment 26. The formulation of embodiment 8, wherein the free amino acids or peptide combinations of amino acids comprise, consist essentially of, or consist of glutamine, glycine, alanine, serine, and tryptophan, or salts thereof, and at least one additional amino acid isoleucine, arginine, or threonine, or salts thereof, or any combination thereof.

[0028] Embodiment 27. A formulation according to any one of embodiments 1 to 26, wherein each of the free amino acids, or each of the amino acids in the peptide combination of amino acids, or a salt thereof, is present at a concentration ranging from 0.05 mM to 20 mM.

[0029] Embodiment 28. A formulation according to any one of embodiments 1 to 27, wherein each of the free amino acids, or each of the amino acids in the peptide combination of amino acids, or a salt thereof, is present at a concentration ranging from 0.05 mM to 10 mM.

[0030] Embodiment 29. A formulation according to any one of embodiments 1 to 28, wherein each of the free amino acids, or each of the amino acids in the peptide combination of amino acids, or a salt thereof, is present at a concentration ranging from 0.05 mM to 5 mM.

[0031] Embodiment 30. A formulation according to any one of embodiments 1 to 26, wherein each of the free amino acids, or each of the amino acids in the peptide combination of amino acids, or a salt thereof, is present at a concentration ranging from 0.1 mM to 10 mM.

[0032] Embodiment 31. A formulation according to any one of embodiments 1 to 26, wherein each of the free amino acids, or each of the amino acids in the peptide combination of amino acids, or a salt thereof, is present at a concentration ranging from 0.1 mM to 5 mM.

[0033] Embodiment 32. A formulation according to any one of embodiments 1 to 11, wherein each of the free amino acids, or each of the amino acids in a peptide combination of amino acids, or a salt thereof, is present at a concentration ranging from 0.1 mM to 4 mM or less.

[0034] Embodiment 33. A formulation according to any one of embodiments 1 to 26, wherein each of the free amino acids, or each of the amino acids in the peptide combination of amino acids, or a salt thereof, is present at a concentration ranging from 0.5 mM to 4 mM.

[0035] Embodiment 34. A formulation of any one of embodiments 1 to 33, wherein, if present, the amino acid cysteine, or a salt thereof, is present at a concentration of 1 mM or less; if present, the amino acid histidine, or a salt thereof, is present at a concentration of 0.5 mM or less; if present, the amino acid tyrosine, or a salt thereof, is present at a concentration of 1 mM or less; if present, the amino acid leucine, or a salt thereof, is present at a concentration of 4 mM or less; or if present, the amino acid aspartic acid, or a salt thereof, is present at a concentration of 2 mM or less; or any combination thereof.

[0036] Embodiment 35. A formulation of any one of embodiments 1 to 34, wherein the formulation does not comprise the amino acids cysteine, histidine, tyrosine, leucine, aspartic acid, taurine, taurate, or glutamic acid, or salts thereof, or any combination thereof.

[0037] Embodiment 36. The formulation of any one of embodiments 1 to 35, wherein the formulation is administered to the skin or is administrable by transdermal, subcutaneous, or topical administration.

[0038] Embodiment 37. A method for maintaining and / or improving skin cell barrier integrity in a subject in need thereof, comprising administering to the skin of the subject a formulation of any one of embodiments 1 to 36.

[0039] Embodiment 38. The method of embodiment 37, wherein the formulation is administered to improve a cosmetic skin condition.

[0040] Embodiment 39. The method of embodiment 38, wherein the cosmetic skin condition is associated with skin aging.

[0041] Embodiment 40. The method of any one of embodiments 37-39, wherein the formulation is administered to improve at least one visual characteristic, or at least one tactile characteristic, or a combination of visual and tactile characteristics of the skin.

[0042] Embodiment 41. The method of embodiment 40, wherein improving at least one visual characteristic, or at least one tactile characteristic, or a combination of visual and tactile characteristics of the skin reduces the length, depth, and / or other size of skin lines and / or wrinkles.

[0043] Embodiment 42. The method of embodiment 37, wherein the subject in need thereof is suffering from a skin condition.

[0044] Embodiment 43. The method of embodiment 42, wherein the skin condition comprises atopic dermatitis, dermatitis, psoriasis, pruritus, eczema, a wound, or a burn.

[0045] Embodiment 44. The method of any one of embodiments 37 to 43, wherein the subject is a human.

[0046] Embodiment 45. A method for improving the cosmetic skin condition of a human, comprising administering to the skin of the human a formulation according to any one of embodiments 1 to 36 in an amount effective to improve at least one visual characteristic, or at least one tactile characteristic, or a combination of visual and tactile characteristics of the skin.

[0047] Embodiment 46. The method of embodiment 45, wherein the cosmetic skin condition is associated with skin aging.

[0048] Embodiment 47. The method of embodiment 45 or embodiment 46, wherein improving at least one visual characteristic, or at least one tactile characteristic, or a combination of visual and tactile characteristics of the skin reduces the length, depth, and / or other size of skin lines and / or wrinkles.

[0049] Embodiment 48. Use of a formulation according to any one of embodiments 1 to 36 for the treatment of a cosmetic skin condition.

[0050] Embodiment 49. The use of embodiment 48, wherein the cosmetic skin condition is associated with skin aging.

[0051] Embodiment 50. The use of embodiment 48 or embodiment 49, wherein the formulation is administered to improve at least one visual characteristic, or at least one tactile characteristic, or a combination of visual and tactile characteristics of the skin.

[0052] Embodiment 51. The method of embodiment 50, wherein improving at least one visual characteristic, or at least one tactile characteristic, or a combination of visual and tactile characteristics of the skin reduces the length, depth, and / or other size of skin lines and / or wrinkles.

[0053] Embodiment 52. Use of a formulation according to any one of embodiments 1 to 36 for the treatment of a skin condition.

[0054] Embodiment 53. The use of embodiment 52, wherein the skin condition comprises atopic dermatitis, dermatitis, psoriasis, pruritus, eczema, a wound, or a burn.

[0055] Embodiment 58. Use of a formulation according to any one of embodiments 1 to 36 in the preparation of a dermatological medication for treating a cosmetic skin condition in a subject in need thereof.

[0056] Embodiment 59. The dermatological agent of embodiment 58, wherein the cosmetic skin condition is associated with skin aging.

[0057] Embodiment 60. The dermatological agent of embodiment 58 or embodiment 59, wherein the dermatological agent is capable of being administered to improve at least one visual characteristic, or at least one tactile characteristic, or a combination of visual and tactile characteristics of the skin.

[0058] Embodiment 61. A dermatological agent according to embodiment 60, wherein the length, depth, and / or other size of lines and / or wrinkles on the skin is reduced by improving at least one visual characteristic, or at least one tactile characteristic, or a combination of visual and tactile characteristics of the skin.

[0059] Embodiment 62. Use of a formulation according to any one of embodiments 1 to 36 in the preparation of a medicament for treating a skin condition in a subject in need thereof.

[0060] Embodiment 63. The pharmaceutical composition of embodiment 62, wherein the skin condition comprises atopic dermatitis, dermatitis, psoriasis, pruritus, eczema, a wound, or a burn.

[0061] In some embodiments, the topical formulation comprises (or consists essentially of, or consists of) a therapeutically effective amount of a formulation comprising (or consisting essentially of, or consisting of) at least one of alanine, glutamine, glycine, and serine as free amino acids or peptide combinations thereof, or salts thereof; a therapeutically effective amount of a plant extract comprising (or consisting essentially of, or consisting of) a Boswellia extract (e.g., Boswellia serrata; Burseraceae family; Olibanum; Frankincense); and, optionally, a dermatologically acceptable carrier or vehicle and / or additive.

[0062] In additional embodiments, topical formulations are provided comprising (or consisting essentially of, or consisting of) a therapeutically effective amount of a formulation comprising (or consisting essentially of, or consisting of) alanine, glutamine, glycine, and serine, or salts thereof, as free amino acids or peptide combinations of amino acids; a therapeutically effective amount of a plant extract formulation (e.g., Boswellia serrata resin extract, cellulose (microcrystalline), lecithin, silica), comprising Boswellia extract (e.g., Boswellia serrata; Burseraceae family; olibanum; frankincense); texturing agents and / or fillers (e.g., cellulose (microcrystalline)); phospholipids (e.g., lecithin or phosphatidylcholine, ceramide); and anti-caking agents (e.g., silica, to adsorb water in hygroscopic applications); and optionally, a dermatologically acceptable carrier or vehicle and / or additives.

[0063] In further embodiments, the formulation for administration to the skin comprises a therapeutically effective amount of a blend of free amino acids or peptide combinations thereof comprising (or consisting essentially of, or consisting of) alanine, glutamine, glycine, and serine, or salts thereof; a therapeutically effective amount of a plant extract blend (e.g., Boswellia serrata resin extract, cellulose (microcrystalline), lecithin, silica), comprising a Boswellia extract (e.g., Boswellia serrata; Burseraceae family; olibanum; frankincense); texturing agents and / or fillers (e.g., cellulose (microcrystalline); phospholipids (e.g., lecithin); and anti-caking agents (e.g., silica, to adsorb water in hygroscopic applications); and optionally, a dermatologically acceptable carrier or vehicle, comprising (or consisting essentially of, or consisting of) a plant extract formulation, wherein a therapeutically effective amount of a formulation of free amino acids or peptide combinations thereof and a therapeutically effective amount of the plant extract formulation is effective in improving the skin barrier when tested by a method that detects expression of a barrier marker gene (e.g., EGF) and determines that the barrier marker gene is increased by an average fold change of 1.5 to 40 for amino acid-treated skin compared to amino acid-untreated skin. and (iii) improving skin barrier repair (e.g., skin barrier repair, skin barrier strengthening, skin barrier preservation, wound healing; growth, stimulation, proliferation, differentiation, and migration of epidermal cells, keratinocytes, endothelial cells, and fibroblasts; promotion of dermal regeneration) (see, e.g., Figures 8-14), where such formulations improve skin barrier repair (e.g., skin barrier repair, skin barrier strengthening, skin barrier preservation, wound healing; growth, stimulation, proliferation, differentiation, and migration of epidermal cells, keratinocytes, endothelial cells, and fibroblasts; promotion of dermal regeneration). and fibroblast growth, stimulation, proliferation, differentiation, and migration; promotion of dermal regeneration), and improvement of skin barrier repair is 1.5 or higher (e.g., 1.7, 1.9, 2.1, 2.3, 2.5, 2.7, 2.9, 3.1, 3.3, 3.5, 3.7, 3.9, 4.1, 4.3, 4.5, 4.7, 4.9, 5.1, 5.3, 5.5, 5.7, 5.9, 6.1, 6.3, 6.5, 6.7, 6.9, 7.1, 7.3, 7.5, 7.7, 7.9, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.9, 9.8, 9.9, 9.1, 9.2, 9.3, 9.5, 9.7, 9.9, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.9, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9, 9.1, 9.2, 9.3, 9.4, 9.5, 9.7, 9.9, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9, 9.1, 9.2, 9.3, 9.43, 8.5, 8.7, 8.9, 9.1, 9.3, 9.5, 9.7, 9.9, 10.1, 10.3, 10.5, 10.7, 10.9, 11.1, 11.3, 11.5, 11.7, 11.9, 12.1, 12.3, 12.5, 12.7, 12.9, 13.1, 13.3, 13.5, 1 3.7, 13.9, 14.1, 14.3, 14.5, 14.7, 14.9, 15.1, 15.3, 15.5, 15.7, 15.9, 16.1, 16.3, 16.5, 16.7, 16.9, 17.1, 17.3, 17.5, 17.7, 17.9, 18.1, 18.3, 18.5, 1 8.7, 18.9, 19.1, 19.3, 19.5, 19.7, 19.9, 20.1, 20.3, 20.5, 20.7, 20.9, 21.1, 21.3, 21.5, 21.7, 21.9, 22.1, 22.3, 22.5, 22.7, 22.9, 23.1, 23.3, 23.5, 2 3.7, 23.9, 23.1, 23.3, 23.5, 23.7, 23.9, 24.1, 24.3, 24.5, 24.7, 24.9, 25.1, 25.3, 25.5, 25.7, 25.9, 26.1, 26.3, 26.5, 26.7, 26.9, 27.1, 27.3, 27.5, 2 7.7, 27.9, 28.1, 28.3, 28.5, 28.7, 28.9, 29.1, 29.3, 29.5, 29.7, 29.9, 30.1, 30.3, 30.5, 30.7, 30.9, 31.1, 31.3, 31.5, 31.7, 31.9, 32.1, 32.3, 32.5, 3 2.7, 32.9, 33.1, 33.3, 33.5, 33.7, 33.9, 34.1, 34.3, 34.5, 34.7, 34.9, 35.1, 35.3, 35.5, 35.7, 35.9, 36.1, 36.3, 36.5, 36.7, 36.9, 37.1, 37.3, 37.5, 3 7.7, 37.9, 38.1, 38.3, 38.5, 38.7, 38.9, 39.1, 39.3, 39.5, 39.7, 39.9, 40.1, 40.3, 40.5, 40.7, 40.9, 41.1, 41.3, 41.5); 40 or less (e.g., 39.8, 39.6, 39.4, 39.6) 9.2, 39, 38.8, 38.6, 38.4, 38.2, 38, 37.8, 37.6, 37.4, 37.2, 37, 36.8, 36.6, 36.4, 36.2, 36, 35.8, 35.6, 35.4, 35.2, 35, 34.8, 34.6, 34.4, 34.2, 34, 33.8, 33.6, 33.4, 33.2, 33, 32.8, 32.6, 32.4, 32.2, 32, 31.8, 31.6, 31.4, 31.2, 31, 30.8, 30.6, 30.4, 30.2, 30, 29.8, 29.6, 29.4, 29.2, 29, 28.8, 28.6, 28 .4, 28.2, 28, 27.8, 27.6, 27.4, 27.2, 27, 26.8, 26.6, 26.4, 26.2, 26, 25.8, 25.6, 25.4, 25.2, 25, 24.8, 24.6, 24.4, 24.2, 24, 23.8, 23.6, 23.4, 23.2, 23 , 22.8, 22.6, 22.4, 22.2, 22, 21.8, 21.6, 21.4, 21.2, 21, 20.8, 20.6, 20.4, 20.2, 20, 19.8, 19.6, 19.4, 19.2, 19, 18.8, 18.6, 18.4, 18.2, 18, 17.8, 17.6 , 17.4, 17.2, 17.2, 17, 16.8, 16.6, 16.4, 16.2, 16, 15.8, 15.6, 15.4, 15.2, 15, 14.8, 14.6, 14.4, 14.2, 14, 13.8, 13.6, 13.4, 13.2, 13, 12.8, 12.6, 12.4 ,12.2,12,11.8,11.6,11.4,11.2,11,10.8,10.6,10.4,10.2,10,9.8,9.6,9.4,9.2,9,8.8,8.6,8.4,8.2,8,7.8,7.6,7.4,7.2,7,6.8,6.6,6.4,6.2, 6, 5.8, 5.6, 5.4, 5.2, 5, 4.8, 4.6, 4.4, 4.2, 4, 3.8, 3.6, 3.4, 3.2, 3, 2.8, 2.6, 2.4, 2.2, 2, 1.8, 1.6, 1.4, 1.2, 1, 0.8, 0.6); or 1.5 to 40 (e.g., 1.6 to 39.9, 1 .7~39.8, 1.8~39.7, 1.9~39.6, 2~39.5, 2.1~39.4, 2.2~39.3, 2.3~39.2, 2.4~39.1, 2.5~39, 2.6~38.9, 2.7~38.8, 2.8~38.7, 2.9~38.6, 3~38.5, 3.1~38 .4, 3.2~38.3, 3.3~38.2, 3.4~38.1, 3.5~38, 3.6~37.9, 3.7~37.8, 3.8~37.7, 3.9~37.6, 4~37.5, 4.1~37.4, 4.2~37.3, 4.3~37.2, 4.4~37.1, 4.5~37, 4.6~36.9、4.7~36.8、4.8~36.7、4.9~36.6、5~36.5、5.1~36.4、5.2~36.3、5.3~36.2、5.4~36.1、5.5~36、5.6~35.9、5.7~35.8、5.8~35.7、5.9~35.6、6~35.5、6.1~35.4、6.2~35.3、6.3~35.2、6.4~35.1、6.5~35、6.6~34.9、6.7~34.8、6.8~34.7、6.9~34.6、7~34.5、7.1~34.4、7.2~34.3、7.3~34.2、7.4~34.1、7.5~34、7.6~33.9、7.7~33.8、7.8~33.7、7.9~33.6、8~33.5、8.1~33.4、8.2~33.3、8.3~33.2、8.4~33.1、8.5~33、8.6~32.9、8.7~32.8、8.8~32.7、8.9~32.6、9~32.5、9.1~32.4、9.2~32.3、9.3~32.2、9.4~32.1、9.5~32、9.6~31.9、9.7~31.8、9.8~31.7、9.9~31.6、10~31.5、10.1~31.4、10.2~31.3、10.3~31.2、10.4~31.1、10.5~31、10.6~30.9、10.7~30.8、10.8~30.7、10.9~30.6、11~30.5、11.1~30.4、11.2~30.3、11.3~30.2、11.4~30.1、11.5~30、11.6~29.9、11.7~29.8、11.8~29.7、11.9~29.6、12~29.5、12.1~29.4、12.2~29.3、12.3~29.2、12.4~29.1、12.5~29、12.6~28.9、12.7~28.8、12.8~28.7、12.9~28.6、13~28.5、13.1~28.4、13.2~28.3、13.3~28.2、13.4~28.1、13.5~28、13.6~27.9、13.7~27.8、13.8~27.7、13.9~27.6、14~27.5、14.1~27.4、14.2~27.3、14.3~27.2、14.4~27.1、14.5~27、14.6~26.9、14.7~26.8、14.8~26.7、14.9~26.6、15~26.5、15.1~26.4、15.2~26.3、15.3~26.2、15.4~26.1、15.5~26, 15.6~25.9, 15.7~25.8, 15.8~25.7, 15.9~25.6, 16~25.5, 16.1~25.4, 16.2~25.3, 16.3~25.2, 16.4~25.1, 16.5~25, 16.6~24.9, 16.7~24.8, 16.8~24.7, 16.9~25.2 4.6, 17~24.5, 17.1~24.4, 17.2~24.3, 17.3~24.2, 17.4~24.1, 17.5~24, 17.6~23.9, 17.7~23.8, 17.8~23.7, 17.9~23.6, 18~23.5, 18.1~23.4, 18.2~23.3, 18.3~23.2 , 18.4~23.1, 18.5~23, 18.6~22.9, 18.7~22.8, 18.8~22.7, 18.9~22.6, 19~22.5, 19.1~22.4, 19.2~22.3, 19.3~22.2, 19.4~22.1, 19.5~22, 19.6~21.9, 19.7~21.8, 19 These findings are indicated by a mean fold increase in the expression of skin barrier marker genes (e.g., EGR) in the following groups: 19.8–21.7, 19.9–21.6, 20–21.5, 20.1–21.4, 20.2–21.3, 20.3–21.2, 20.4–21.1, 20.5–21, 20.6–20.9; 20.7–20.8).

[0064]

[0033] In some embodiments, a method of improving skin barrier repair in the skin of a subject is provided, comprising: a topical formulation (as described in any preceding formulation or in any one of embodiments 64-66) comprising a therapeutically effective amount of a blend of free amino acids or peptide combinations thereof comprising (or consisting essentially of, or consisting of) at least one of alanine, glutamine, glycine, and serine, or salts thereof; and a therapeutically effective amount of a plant extract blend (e.g., Boswellia serrata resin extract, cellulose (microcrystalline), lecithin, silica), wherein the Boswellia extract (e.g., Boswellia serrata; Burseraceae family; olibanum; frankincense), alone or optionally in combination with at least one of a texturing agent and / or filler (e.g., cellulose (microcrystalline)); a phospholipid (e.g., lecithin or phosphatidylcholine); and an anti-caking agent (e.g., silica, which adsorbs water in hygroscopic applications), a plant extract blend; and optionally a dermatologically acceptable carrier or vehicle and / or additive, wherein the topical formulation comprises (or consists essentially of, or consists of) a plant extract blend comprising: ...

[0065] In some embodiments, formulations such as topical formulations comprise (or consist essentially of, or consist of) a therapeutically effective amount of a formulation comprising (or consisting essentially of, or consisting of) at least one of alanine, glutamine, glycine, and serine as free amino acids or peptide combinations thereof or salts thereof; a therapeutically effective amount of a retinoid or at least one retinoid, wherein the retinoid is a retinoid precursor, a retinoid, or a retinoid derivative, or the retinoid is selected from the group consisting of a retinyl ester (e.g., retinyl palmitate, retinyl oleate, retinyl stearate, retinyl linoleate, retinyl palmitoleate), retinol or vitamin A, retinaldehyde, or retinal; retinoic acid; and any combination thereof; and, optionally, a dermatologically acceptable vehicle and / or additive.

[0066] In an additional aspect, there is provided a formulation, such as a topical formulation, comprising (or consisting essentially of, or consisting of) a therapeutically effective amount of a blend of amino acids, as free amino acids or peptide combinations of amino acids, comprising (or consisting essentially of, or consisting of) alanine, glutamine, glycine, and serine, or salts thereof; a therapeutically effective amount of a retinoid, comprising (or consisting essentially of, or consisting of) at least one of a retinyl ester (e.g., retinyl palmitate, retinyl oleate, retinyl stearate, retinyl linoleate, retinyl palmitoleate); retinol or vitamin A; retinaldehyde or retinal; retinoic acid; or combinations thereof; and optionally, a dermatologically acceptable vehicle and / or additive for improving skin hydration (e.g., increasing skin hydration, decreasing water loss, increasing hyaluronic acid (HA), increasing hyaluronan synthase (HAS)). Hyaluronic acid can be found primarily in the synovial fluid of joints. This fluid contributes to the viscoelasticity and lubrication of cartilage, which is degraded or worn away in people with osteoarthritis. Approximately 2-3 mg / ml of hyaluronic acid is found in the human knee joint, and may be slightly higher in young adults than in older adults.Hyaluronic acid or hyaluronic acid synthase content in biological fluids and tissues can be measured using commonly used techniques, including, but not limited to, ELISA, ELISA, ELISA-like assays, radioassays, etc. (See, e.g., Cowman et al. Front Immunol. 6:261, 2015; Dahl et al. Ann Rheum Dis 44:817-22, 1985; Balazs EA, Watson D, Duff IF, Roseman S. Hyaluronic acid in synovial fluid: I. Molecular parameters of hyaluronic acid in normal and arthritis human fluids. Arthritis Rheum. 10:357-76, 1967; Balazs EA. Univ Mich Med Cent J. 255-9, 1968, all of which are incorporated by reference herein for their teachings regarding hyaluronic acid and its quantification.)

[0067] In further embodiments, formulations for administration to the skin include a therapeutically effective amount of a blend of free amino acids or peptide combinations thereof comprising (or consisting essentially of, or consisting of) alanine, glutamine, glycine, and serine, or salts thereof; a therapeutically effective amount of a retinoid, including retinyl esters (e.g., retinyl palmitate, retinyl oleate, retinyl stearate, retinyl linoleate, retinyl palmitoleate); retinol or vitamin A; retinaldehyde or retinal; retinoic acid; or and optionally, (or) consisting essentially of, or consisting of) a dermatologically acceptable vehicle(s) and / or additive(s), wherein such a therapeutically effective amount of a combination of free amino acids or peptide combinations thereof and a therapeutically effective amount of a retinoid detects the expression of a skin moisture marker gene or an HA marker gene (e.g., HAS1, HAS2, HAS3, or EGF) to detect the expression of a skin moisture marker. and improves skin moisture (e.g., increases skin moisture, decreases water loss, increases hyaluronic acid (HA), increases hyaluronic acid synthase (HAS)), when tested by a method that determines that a 1.4 to 450 fold increase in a HA marker gene or HA marker gene is increased in amino acid-treated skin or skin cells compared to amino acid-untreated skin or skin cells (see, e.g., Figures 17 to 22, and Figures 24 to 27 (parts)), and improves skin moisture (e.g., increases skin moisture, decreases water loss, increases hyaluronic acid (HA), increases hyaluronic acid synthase (HAS)), wherein such formulations improve skin moisture (e.g., increases skin moisture, Decreased water loss, increased hyaluronic acid (HA), increased hyaluronan synthase (HAS; e.g., HAS1 (in fibroblasts), HAS2, and HAS3 (in keratinocytes)), and improved skin moisture are reported as ≥1.4 (e.g., 1.5, 1.7, 1.9, 2.1, 2.3, 2.5, 2.7, 2.9, 3.1, 3.3, 3.5, 3.7, 3.9, 4.1, 4.3, 4.5, 4.7, 4.9, 5.1, 5.3, 5.5, 5.7, 5.9, 6.1, 6.3, 6.5, 6.7, 6.9, 7.1, 7.3, 7.5, 7.7, 7.9, 8.1, 8.3, 8.4).5、8.7、8.9、9.1、9.3、9.5、9.7、9.9、10.1、10.3、10.5、10.7、10.9、11.1、11.3、11.5、11.7、11.9、12.1、12.3、12.5、12.7、12.9、13.1、13.3、13.5、13.7、13.9、14.1、14.3、14.5、14.7、14.9、15.1、15.3、15.5、15.7、15.9、16.1、16.3、16.5、16.7、16.9、17.1、17.3、17.5、17.7、17.9、18.1、18.3、18.5、18.7、18.9、19.1、19.3、19.5、19.7、19.9、20.1、20.3、20.5、20.7、20.9、21.1、21.3、21.5、21.7、21.9、22.1、22.3、22.5、22.7、22.9、23.1、23.3、23.5、23.7、23.9、23.1、23.3、23.5、23.7、23.9、24.1、24.3、24.5、24.7、24.9、25.1、25.3、25.5、25.7、25.9、26.1、26.3、26.5、26.7、26.9、27.1、27.3、27.5、27.7、27.9、28.1、28.3、28.5、28.7、28.9、29.1、29.3、29.5、29.7、29.9、30.1、30.3、30.5、30.7、30.9、31.1、31.3、31.5、31.7、31.9、32.1、32.3、32.5、32.7、32.9、33.1、33.3、33.5、33.7、33.9、34.1、34.3、34.5、34.7、34.9、35.1、35.3、35.5、35.7、35.9、36.1、36.3、36.5、36.7、36.9、37.1、37.3、37.5、37.7、37.9、38.1、38.3、38.5、38.7、38.9、39.1、39.3、39.5、39.7、39.9、40.1、40.3、40.5、40.7、40.9、41.1、41.3、41.5, 55, 70, 90, 105, 120, 170, 195, 205, 255, 270, 295, 305, 320, 355, 370, 405, 420, 455); 450 or less (e.g., 425, 405, 400, 375, 350, 325, 300, 290, 275, 250, 225) , 200, 190, 175, 150, 125, 100, 95, 75, 50, 39.8, 39.6, 39.4, 39.2, 39, 38.8, 38.6, 38.4, 38.2, 38, 37.8, 37.6, 37.4, 37.2, 37, 36.8, 36.6, 36.4, 36.2, 36 , 35.8, 35.6, 35.4, 35.2, 35, 34.8, 34.6, 34.4, 34.2, 34, 33.8, 33.6, 33.4, 33.2, 33, 32.8, 32.6, 32.4, 32.2, 32, 31.8, 31.6, 31.4, 31.2, 31, 30.8, 30.6 , 30.4, 30.2, 30, 29.8, 29.6, 29.4, 29.2, 29, 28.8, 28.6, 28.4, 28.2, 28, 27.8, 27.6, 27.4, 27.2, 27, 26.8, 26.6, 26.4, 26.2, 26, 25.8, 25.6, 25.4, 25.2 ,25,24.8,24.6,24.4,24.2,24,23.8,23.6,23.4,23.2,23,22.8,22.6,22.4,22.2,22,21.8,21.6,21.4,21.2,21,20.8,20.6,20.4,20.2,20,19.8,1 9.6, 19.4, 19.2, 19, 18.8, 18.6, 18.4, 18.2, 18, 17.8, 17.6, 17.4, 17.2, 17.2, 17, 16.8, 16.6, 16.4, 16.2, 16, 15.8, 15.6, 15.4, 15.2, 15, 14.8, 14.6, 1 4.4, 14.2, 14, 13.8, 13.6, 13.4, 13.2, 13, 12.8, 12.6, 12.4, 12.2, 12, 11.8, 11.6, 11.4, 11.2, 11, 10.8, 10.6, 10.4, 10.2, 10, 9.8, 9.6, 9.4, 9.2, 9, 8.8 ,8.6,8.4,8.2,8,7.8,7.6,7.4,7.2,7,6.8,6.6,6.4,6.2,6,5.8,5.6,5.4,5.2,5,4.8,4.6,4.4,4.2,4,3.8,3.6,3.4,3.2,3,2.8,2.6,2.4,2.2,2,1.8, 1.6, 1.4, 1.2, 1, 0.8, 0.6); or 1.4 to 450 (e.g., 1.5 to 440, 1.6 to 445, 1.7 to 430, 1.8 to 420, 1.9 to 410, 2 to 400, 2.1 to 390, 2.2 to 380, 2.3 to 370, 2.4 to 360, 2.5 to 350, 2.6 to 340, 2.7 to 330, 2.8 to 320, 2.9 to 310, 3 to 300, 3.1 to 290, 3.2 to 280, 3.3 to 270, 3.4 to 260, 3.5 to 250, 3.6 to 240, 3.7 to 230, 3.8 to 220, 3.9 to 210, 4 to 200, 4.1 to 190 , 4.2~180, 4.3~170, 4.4~160, 4.5~150, 4.6~140, 4.7~130, 4.8~120, 4.9~110, 5~100, 5.1~90, 5.2~80, 5.3~70, 5.4~60, 5.5~50, 5.6~40, 5.7~35.8, 5.8 ~35.7, 5.9~35.6, 6~35.5, 6.1~35.4, 6.2~35.3, 6.3~35.2, 6.4~35.1, 6.5~35, 6.6~34.9, 6.7~34.8, 6.8~34.7, 6.9~34.6, 7~34.5, 7.1~34.4, 7.2~34.3 , 7.3~34.2, 7.4~34.1, 7.5~34, 7.6~33.9, 7.7~33.8, 7.8~33.7, 7.9~33.6, 8~33.5, 8.1~33.4, 8.2~33.3, 8.3~33.2, 8.4~33.1, 8.5~33, 8.6~32.9, 8.7~ 32.8, 8.8-32.7, 8.9-32.6, 9-32.5, 9.1-32.4, 9.2-32.3, 9.3-32.2, 9.4-32.1, 9.5-32, 9.6-31.9, 9.7-31.8, 9.8-31.7, 9.9-31.6, 10-31.5, 10.1-31. 4, 10.2~31.3, 10.3~31.2, 10.4~31.1, 10.5~31, 10.6~30.9, 10.7~30.8, 10.8~30.7, 10.9~30.6, 11~30.5, 11.1~30.4, 11.2~30.3, 11.3~30.2, 11.4~30 .1, 11.5~30, 11.6~29.9, 11.7~29.8, 11.8~29.7, 11.9~29.6, 12~29.5, 12.1~29.4, 12.2~29.3, 12.3~29.2, 12.4~29.1, 12.5~29, 12.6~28.9, 12.7~28.8, 12.8-28.7, 12.9-28.6, 13-28.5, 13.1-28.4, 13.2-28.3, 13.3-28.2, 13.4-28.1, 13.5-28, 13.6-27.9, 13.7-27.8, 13.8-27.7, 13.9-27.6, 14-27.5, 14.1-27.4, 14.2-27.3, 14.3-27.2, 14.4-27.1, 14.5-27, 14.6-26.9, 14.7-26.8, 14.8-26.7, 14.9-26. 6, 15~26.5, 15.1~26.4, 15.2~26.3, 15.3~26.2, 15.4~26.1, 15.5~26, 15.6~25.9, 15.7~25.8, 15.8~25.7, 15.9~25.6, 16~25.5, 16.1~25.4, 16.2~25.3, 16.3~25.2, 16.4~25.1, 16.5~25, 16.6~24.9, 16.7~24.8, 16.8~24.7, 16.9~24.6, 17~24.5, 17.1~24.4, 17.2~24.3, 17.3~24.2, 17.4~24.1, 17.5~24, 17.6~23.9, 17.7~23.8, 17.8~23.7, 17.9~23.6, 18~23.5, 18.1~23.4, 18.2~23.3, 18.3~23.2, 18.4~23.1, 18.5~23, 18.6~22.9, 18.7~22.8, 18.8~22.7, 18.9~22.6, 19~22.5, 19.1~22.4, 19.2~22.3, 19.3~22.2, These are indicated by fold changes or fold increases in the expression of skin moisture marker genes or HA marker genes (e.g., HAS1, HAS2, HAS3, or EGF) in the following ranges: 19.4-22.1, 19.5-22, 19.6-21.9, 19.7-21.8, 19.8-21.7, 19.9-21.6, 20-21.5, 20.1-21.4, 20.2-21.3, 20.3-21.2, 20.4-21.1, 20.5-21, 20.6-20.9, 20.7-20.8).

[0068] In another aspect of the present disclosure, there is provided an injectable formulation for treating a subject suffering from osteoarthritis or symptoms thereof, the injectable formulation comprising a therapeutically effective amount of a formulation, as free amino acids or peptide combinations, of a therapeutically effective amount of a combination of: (a) alanine, glutamine, glycine, and serine, or salts thereof; and optionally, a therapeutically effective amount of at least one of arginine, isoleucine, threonine, tryptophan, or valine (e.g., alanine, glutamine, glycine, and serine, and arginine or isoleucine). leucine or threonine or tryptophan or valine;arginine and isoleucine;arginine and threonine;arginine and tryptophan;arginine and valine;isoleucine and threonine;isoleucine and tryptophan;isoleucine and valine;threonine and tryptophan;threonine and valine;tryptophan and valine;arginine, isoleucine, and threonine;arginine, isoleucine, and tryptophan;arginine, isoleucine, and valine;arginine, threonine, and tryptophan;arginine arginine, threonine, and valine; arginine, tryptophan, and valine; isoleucine, threonine, and tryptophan; isoleucine, threonine, and valine; isoleucine, tryptophan, and valine; threonine, tryptophan, and valine; arginine, isoleucine, threonine, and tryptophan; arginine, isoleucine, threonine, and valine; arginine, threonine, tryptophan, and valine; isoleucine, threonine, tryptophan, and valine; arginine, isoleucine, tryptophan, and valine arginine, isoleucine, threonine, tryptophan, and valine), or any combination thereof; or (b) at least one of alanine, glutamine, glycine, and serine (e.g., alanine; glutamine; glycine; serine; alanine and glutamine; alanine and glycine; alanine and serine; glutamine and glycine; glutamine and serine; glycine and serine; alanine and glutamine and glycine; glutamine and glycine and serine; alanine and glycine and serine; alanine and glutamine and serine;and alanine and glutamine and glycine and serine), or a salt thereof; or (c)(i) at least one of alanine, glutamine, glycine, and serine (e.g., alanine; glutamine; glycine; serine; alanine and glutamine; alanine and glycine; alanine and serine; glutamine and glycine; glutamine and serine; glutamine and glycine and serine; alanine and glycine and serine; alanine and glutamine and serine; and alanine and glutamine and glycine and serine), or a salt thereof. and (c)(ii) a formulation comprising (or consisting essentially of, or consisting of) a therapeutically effective amount of a retinoid, the formulation comprising (or consisting essentially of, or consisting of) a retinoid, comprising (or consisting essentially of, or consisting of) at least one of a retinyl ester (e.g., retinyl palmitate, retinyl oleate, retinyl stearate, retinyl linoleate, retinyl palmitoleate); retinol or vitamin A; retinaldehyde or retinal; retinoic acid; or combinations thereof. Some embodiments are directed to such injectable formulations, optionally further comprising a pharmaceutically acceptable vehicle and / or additive.

[0069] In some aspects, provided are methods of improving skin moisture in the skin or skin cells of a subject, such methods comprising: a topical formulation (according to any one of the described formulations or embodiments) comprising a therapeutically effective amount of a blend of free amino acids or peptide combinations thereof comprising (or consisting essentially of, or consisting of) at least one of alanine, glutamine, glycine, and serine, or salts thereof; and a therapeutically effective amount of a retinoid (e.g., a retinyl ester (e.g., retinyl palmitate, retinyl oleate, retinyl stearate, retinyl linoleate, retinyl palmitoleate); retinol or vitamin A; retinaldehyde or retinal; retinoic acid; or a combination thereof); and optionally a topical formulation comprising (or consisting essentially of, or consisting of) a dermatologically acceptable vehicle and / or additive, and wherein, when tested by a method detecting expression of a skin moisture marker gene or an HA marker gene, e.g., HAS1, HAS2, HAS3, or EGF, expression is increased by a fold change of 1.4 to 450 in amino acid-treated skin compared to amino acid-untreated skin, thereby improving skin moisture (e.g., increasing skin moisture, decreasing water loss, increasing hyaluronic acid (HA), increasing hyaluronan synthase (HAS; e.g., HAS1 (in fibroblasts), HAS2 and HAS3 (in keratinocytes))).

[0070] A further aspect is directed to a method of treating a subject suffering from osteoarthritis, such method comprising (or consisting essentially of, or consisting of) administering by injection to a joint of the subject (e.g., a hand joint, a hip joint, or a knee joint) in a subject suffering from osteoarthritis, a therapeutically effective amount of a formulation, wherein the therapeutically effective amount of the formulation is a therapeutically effective amount of a compound, as free amino acids or peptide combinations, of: (a) alanine, glutamine, glycine, and serine, or salts thereof; and optionally, a therapeutically effective amount of arginine, isoleucine, at least one of threonine, tryptophan, or valine (e.g., alanine, glutamine, glycine, and serine, and arginine or isoleucine or threonine or tryptophan or valine; arginine and isoleucine; arginine and threonine; arginine and tryptophan; arginine and valine; isoleucine and threonine; isoleucine and tryptophan; isoleucine and valine; threonine and tryptophan; threonine and valine; tryptophan and valine; arginine, isoleucine, and threonine; arginine, isoleucine, and tryptophan; arginine, isoleucine, and valine; arginine, threonine, and tryptophan; arginine, threonine, and valine; arginine, tryptophan, and valine; isoleucine, threonine, and tryptophan; isoleucine, threonine, and valine; isoleucine, tryptophan, and valine; threonine, tryptophan, and valine; arginine, isoleucine, threonine, and tryptophan; arginine, isoleucine, threonine, and valine; or (b) at least one of alanine, glutamine, glycine, and serine (e.g., alanine; glutamine; glycine; serine; alanine and glutamine; alanine and glycine; alanine and serine; glutamine and glycine; glutamine and serine; glutamine and glycine; glutamine and serine;glycine and serine; alanine and glutamine and glycine; glutamine and glycine and serine; alanine and glycine and serine; alanine and glutamine and serine; and alanine and glutamine and glycine and serine), or salts thereof; or (c) (i) at least one of alanine, glutamine, glycine, and serine (e.g., alanine; glutamine; glycine; serine; alanine and glutamine; alanine and glycine; alanine and serine; glutamine and glycine; glutamine and serine; glycine and serine; alanine and glutamine and glycine; glutamine and glycine and serine; alanine and glycine and serine; alanine and glutamine and serine; and alanine and glutamine and glycine and serine), or salts thereof; and (ii) a therapeutically effective amount of a retinoid, comprising (or consisting essentially of, or consisting of) at least one of retinyl esters (e.g., retinyl palmitate, retinyl oleate, retinyl stearate, retinyl linoleate, retinyl palmitoleate); retinol or vitamin A; retinaldehyde or retinal; retinoic acid; or a combination thereof. In some embodiments, such injectable formulations optionally include a pharmaceutically acceptable vehicle and / or additive. In an additional aspect, such an injectable formulation is provided for treating a subject suffering from osteoarthritis or symptoms thereof, wherein a subject treated with an injectable formulation of the present disclosure has one or more of decreased pain, increased hyaluronic acid synthesis, increased proliferation of elastin and / or collagen, or a combination thereof, compared to a control or untreated subject (a healthy subject or a subject not suffering from osteoarthritis);

[0071] Use of an injectable formulation described herein in the preparation of a medicament for treating osteoarthritis in a subject in need thereof.

[0072] In another aspect of the methods or uses of the formulations described in various embodiments herein, the formulations are sterile.

[0073] In certain embodiments, the formulations described herein are in the form of a single unit dose. In one aspect, the formulations described herein have a pH of about 2.0 to about 8.5. According to one embodiment, the formulations described herein are formulated for topical (e.g., transdermal, epicutaneous) or parenteral (e.g., subcutaneous, intradermal, intraarticular, intrasynovial, periarticular, intramuscular, intravenous) administration.

[0074] In further aspects of the methods or uses, the formulations described in various embodiments herein are administered on a daily dosing schedule (e.g., once daily, twice daily, three, four, or five times daily, or as needed), on an alternate day schedule, every two days, every three days, or as needed. In some aspects, the injectable formulation is provided in a unit dosage form, and the unit dosage form is a liquid.

[0075] Also described herein are kits that include a formulation described herein and instructions for administering the formulation described herein to a subject or contacting a biological sample with the formulation described herein. In other aspects, the kits can further include one or more additional reagents, pharmaceutical agents, or other agents for administration of any one of the formulations described herein.

[0076] definition All terms used herein are intended to have their ordinary meaning in the art unless otherwise specified. All concentrations are in terms of weight percent of the particular ingredient based on the total weight of the topical composition unless otherwise defined.

[0077] As used herein, "a" or "an" means one or more. When used herein in conjunction with the word "comprising," the words "a" or "an" means one or more. As used herein, "another" means at least a second or more instances.

[0078] As used herein, any numerical range includes the endpoints and all possible values ​​disclosed between the disclosed values. All half-integer exact values ​​are also contemplated as specific disclosures and limits for all subsets of the disclosed ranges. For example, the range 0.1% to 3% specifically discloses percentages of 0.1%, 1%, 1.5%, 2.0%, 2.5%, and 3%. Furthermore, the range 0.1% to 3% includes subsets of the original range, such as 0.5% to 2.5%, 1% to 3%, and 0.1% to 2.5%. It is understood that the sum of all weight percentages of individual components does not exceed 100%.

[0079] The terms "improving cosmetic skin condition," "improving skin condition," or "treating a skin condition" include treating a cosmetic skin condition or therapeutically treating a skin condition, which may involve at least one of the following benefits: improved moisture retention, reduced permeability of the skin's epithelial cell barrier, skin thickening (increasing the depth of the skin's epithelial layer), restoring skin elasticity, preventing loss of skin elasticity, reduced skin cell scaling, improved smoother skin texture, reduced physical appearance of lines or wrinkles (e.g., as determined by appearance or tactile perception), and any combination thereof.

[0080] The skin comprises three distinct layers: the stratum corneum (outermost layer), the epidermis, and the dermis.

[0081] The term "skin cell barrier integrity," as used herein, refers to the ability of the epidermis, particularly the stratum corneum (SC), to function as a selective permeability barrier, limiting transepidermal water loss and enabling survival in a dry external environment. The SC is a multilayered tissue composed of flat, anucleated keratinocytes, surrounded by multiple planar lamellar sheets, rich in ceramides, cholesterol, and free fatty acids (FFA), which hold the entire matrix together. These components, along with tight junction proteins and antimicrobial peptides, contribute to the skin's ability to act as a permeability barrier. Tight junction proteins contribute to the cell-cell adhesion interface, essentially acting as a seal between cells. Unregulated intercellular leakage from the outermost layer of the skin can, for example, result in water loss from the inner layers of the skin. Barrier integrity can be measured using a variety of assays, such as transepidermal water loss (TEWL) at the surface of the skin (in situ); transepithelial / transendothelial electrical resistance (TEER) (also a widely accepted quantitative method for measuring tight junction integrity in cell culture models of endothelial and epithelial monolayers); methods monitoring the diffusion of dyes (X-Gal or Lucifer Yellow, Toluidine Blue) through the upper epidermis (also used in skin explants and / or in situ skin); two-dimensional or three-dimensional keratinocyte cell cultures (used to assess epidermal differentiation processes directly related to skin barrier permeability); upregulation of proteins that promote skin barrier function and / or downregulation of genes that reduce skin barrier function; and immunohistochemistry, microscopy, and / or other imaging methods.

[0082] The term "improving" when used in relation to improving "skin cell barrier integrity" refers to an increase in the skin's permeability barrier, for example, due to an increase in the strength of adhesion between skin cells, as indicated by the ability of the intercellular adhesion interface to prevent uncontrolled leakage between cells. Barrier integrity may be detected using assays such as those described for barrier integrity. The term "improving" may be used to describe an increase of 1%, 2%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 97%, 98%, 99%, or 100% or more compared to the starting measurement value before contact with the amino acid formulations described herein.

[0083] The term "maintaining" when used in relation to maintaining "skin cell barrier integrity" refers to preserving the strength of the skin's permeability barrier, for example, by preserving the strength of adhesion between skin cells, as indicated by the ability of the intercellular adhesion interface to prevent uncontrolled leakage between cells. For maintaining "skin cell barrier integrity," to determine the baseline intercellular adhesion strength, for example, measurements can be performed on healthy skin to establish the desired target intercellular adhesion level to be maintained. Then, a sample of healthy skin can be exposed to a stressor, such as airborne pollution (e.g., cigarette smoke, harmful smoke, airborne irritants) or physical stressor (e.g., abrasion, harsh detergent, or chemicals), in the presence or absence of the formulations described herein. The amino acid formulations described herein that at least partially prevent the deterioration of intercellular adhesion even when stimulated by a stressor are characterized as being able to maintain a determined level of barrier integrity. In such context, the term "maintaining" may be used to describe the preservation of baseline intercellular strength at 100% of pre-stressor levels, or at 99% or more, 98% or more, 97% or more, 95% or more, 90% or more, 85% or more, 80% or more, 75% or more, 70% or more, 65% or more, 60% or more, 55% or more, 50% or more, 45% or more, 40% or more, 35% or more, 30% or more, 25% or more, 20% or more, 15% or more, 10% or more, 5% or more, 2% or more, or 1% or more of pre-stressor levels due to the presence of an amino acid formulation described herein that attenuates the adverse effects of such stressor.

[0084] The term "topical application," as used herein, means applying or painting the formulations described herein onto the surface of the epidermal tissue.

[0085] The term "dermatologically acceptable," as used herein, means that the formulation or components thereof so described are suitable for use in contact with the epidermal tissue of mammals without undue toxicity, incompatibility, instability, allergic response, and the like.

[0086] The term "therapeutically effective amount," as used herein, refers to an amount of a compound or formulation sufficient to induce a beneficial benefit, an improvement in the appearance and / or texture of the skin, and in some embodiments, the beneficial benefit of amino acid-treated skin can be an increase of 1% or more, 2% or more, 5% or more, 10% or more, 15% or more, 20% or more, 25% or more, 30% or more, 35% or more, 40% or more, 45% or more, 50% or more, 55% or more, 60% or more, 65% or more, 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, 95% or more, 97% or more, 98% or more, 99% or more, or 100% or more compared to a starting measurement prior to contact with an amino acid formulation described herein; an increase of 1-fold or more (e.g., 3-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 9-fold, 10 ... , 7x, 9x, 11x, 13x, 15x, 17x, 19x, 21x, 23x, 25x, 27x, 29x, 31x, 33x, 35x, 37x, 39x, 41x); 40x or less (e.g., 38x, 36x, 34x, 32x, 30x, 28x, 26x, 24x, 22x, 20x, 18x, 16x, 14x, 12x, 10x, 8x, 6x, 4x, 2x, 0.8x, 0.6-fold); or 1-40-fold (e.g., 2-39-fold, 3-38-fold, 4-37-fold, 5-36-fold, 6-35-fold, 7-34-fold, 8-33-fold, 9-32-fold, 10-31-fold, 11-30-fold, 12-29-fold, 13-28-fold, 14-27-fold, 15-26-fold, 16-25-fold, 17-24-fold, 18-23-fold, 19-22-fold, 20-21-fold) better. According to the present disclosure, a therapeutically effective amount is the amount of a formulation of free amino acids or peptide combinations thereof, alone or in combination with other agents, that physically and / or visually regulates and / or improves skin.

[0087] The term "amelioration" or any grammatical variations thereof (e.g., ameliorate, ameliorating, and amelioration, etc.), as used herein, includes, but is not limited to, delaying the onset or reducing the severity of a disease or condition. Amelioration, as used herein, does not require the complete absence of symptoms.

[0088] The term "effective amount" or "substantial amount," as used herein, refers to an amount that can treat or ameliorate a disease, condition, or disorder or otherwise produce the intended therapeutic effect.

[0089] The term "healthy functional food" refers to food that has been prepared or processed into tablets, capsules, powders, granules, liquids, pills, or any other form using raw materials or ingredients that have functions that are beneficial to the human body.

[0090] The term "functional" refers to an effect beneficial to human health, such as regulation of structure or function of nutrients, the immune system, inflammation, fluid balance, physiological actions, etc.

[0091] The term "carrier" or "vehicle" refers to a compound or active ingredient, such as, but not limited to, free amino acids or peptide combinations thereof (e.g., at least one of alanine, glutamine, glycine, and serine, or salts thereof, or any combination thereof), plant extracts (e.g., Boswellia extract, including Boswellia serrata, Burseraceae, olibanum, or frankincense), or plant extract formulations (e.g., Boswellia extract (e.g., Boswellia serrata; Burseraceae; olibanum; frankincense; texturing agents and / or fillers (e.g., cellulose (microcrystalline); phospholipids (e.g., lecithin or phosphatidylcholine); and anti-caking agents (e.g., silica, which adsorbs water in hygroscopic applications)), or diluents, adjuvants, or excipients used in formulating and administering the retinoids described herein (e.g., retinyl esters (e.g., retinyl palmitate, retinyl oleate, retinyl stearate, retinyl linoleate, retinyl palmitoleate); retinol or vitamin A; retinaldehyde or retinal; retinoic acid; or combinations thereof). Examples of suitable pharmaceutical carriers are described in "Remington's Pharmaceutical Sciences" by E.W. Martin (23rd edition), which is incorporated herein by reference.

[0092] The term "treatment" or any grammatical variations thereof (e.g., treat, treating, and treatment, etc.), as used herein, includes, but is not limited to, alleviating the symptoms of a disease, condition, or disorder; and / or reducing, suppressing, inhibiting, reducing, or affecting the progression, severity, and / or extent of a disease, condition, or disorder.

[0093] The term "consisting essentially of," as used herein, limits the scope of ingredients and steps to those that do not substantially affect the specific materials or steps and the basic and novel feature(s) of this embodiment of the invention, i.e., formulations and methods for promoting at least one of skin integrity, function, texture, moisture, or appearance, or any combination thereof, or for repairing and strengthening the skin barrier, or for improving skin barrier integrity.

[0094] The term "amino acid" encompasses all known amino acids containing an amine (-NH) functional group, a carboxyl (-COOH) functional group, and / or a side chain ("R") group specific to each amino acid. "Amino acid" encompasses the 21 amino acids encoded by the human genome (i.e., proteinogenic amino acids), amino acids encoded or produced by bacteria or unicellular organisms, and naturally occurring amino acids. For purposes of this disclosure, the conjugate acid form of an amino acid with a basic side chain (arginine, lysine, and histidine) or the conjugate base form of an amino acid with an acidic side chain (aspartic acid and glutamic acid) are essentially the same unless otherwise specified. "Amino acid" also encompasses derivatives and analogs thereof that retain substantially the same activity in improving skin cell barrier integrity, e.g., in a TEER assay or TEWL assay, as described above. Derivatives and analogs may be, for example, mirror images, including both D- and L-forms. In some embodiments, at least one or more of the free amino acids is in the D-form. In other embodiments, at least one or more of the free amino acids is in the L-form. The "peptide combinations" of amino acids described herein (two or more amino acids; typically, 2 to 50 amino acids) can include one or more amino acids in the D-form, the L-form, or a mixture of the D- and L-forms linked by peptide bonds. As used herein, "amino acid blends" can refer to free amino acids or peptide combinations of amino acids. Derivatives and analogs can be derivatives of "natural" or "unnatural" amino acids (e.g., β-amino acids, homoamino acids, proline derivatives, pyruvate derivatives, 3-substituted alanine derivatives, glycine derivatives, ring-substituted cysteine ​​derivatives, ring-substituted phenylalanine derivatives, linear core amino acids, and N-methyl amino acids), such as selenocysteine, pyrrolysine, iodocysteine, norleucine, or norvaline. Derivatives and analogs can include protecting groups (α-amino groups, α-carboxylic acid groups, or suitable R groups, where R contains NH, OH, SH, COOH, or other reactive functionality).Other amino acid derivatives include, but are not limited to, those synthesized by acylation, methylation, glycosylation, and / or halogenation of amino acids. These include, for example, β-methyl amino acids, C-methyl amino acids, and N-methyl amino acids. The amino acids described herein can exist as free amino acids. The term "free amino acid" refers to an amino acid that is not part of a peptide or polypeptide (e.g., not connected to another amino acid via a peptide bond). A free amino acid is free in solution (as opposed to being linked to at least one other amino acid, e.g., via a dipeptide bond), but may be associated with salts or other components in the solution.

[0095] As used herein, the term "salt" refers to all salts or salt forms of a compound, including pharmaceutically acceptable salts. For example, embodiments of the present disclosure are directed to amino acids or their salts.

[0096] Exemplary salts for inclusion in the formulations described herein include sodium chloride, potassium chloride, calcium chloride, magnesium chloride, or phosphate buffers of trisodium citrate, sodium bicarbonate, sodium gluconate, using monosodium phosphate, disodium phosphate, or trisodium phosphate, or any combination thereof.

[0097] Exemplary diluents include calcium carbonate, sodium carbonate, calcium phosphate, dicalcium phosphate, calcium sulfate, calcium hydrogen phosphate, cellulose, microcrystalline cellulose, kaolin, sodium chloride, and mixtures thereof.

[0098] Pharmaceutically acceptable excipients used in the manufacture of the pharmaceutical formulations described herein include inert diluents, dispersing and / or granulating agents, surfactants and / or emulsifying agents or phospholipids; in some embodiments, phospholipids are used as emulsifiers (e.g., lecithin or phosphatidylcholine), disintegrating agents, binders, preservatives, buffers, lubricants, and / or oils. Excipients such as cocoa butter and suppository waxes, colorants, coating agents, and flavoring agents may also be present in the compositions.

[0099] Abbreviations used: Amino acids: Ala-alanine, Arg-arginine, Cys-cysteine, Gln-glutamine, Gly-glycine, His-histidine, Ile-isoleucine, Ser-serine, Thr-threonine, Tyr-tyrosine, Val-valine.Gene / Product: CPT2 - carnitine palmitoyltransferase 2; CASP8 - caspase 8; EGF - epidermal growth factor; FGF - fibroblast growth factor; MKI67 - marker of proliferation Ki-67; PDGF - platelet-derived growth factor; PPAR - peroxisome proliferator-activated receptors; SMAD - acronym for the fusion of the Caenorhabditis elegans Sma gene and the Drosophila Mad, Mothers against decapentaplegic gene; TGFB1 - transforming grown factor beta 1; TGM - transglutaminase, TNFRSF10D - TNF Receptor Superfamily Member 10d (TNF receptor superfamily member 10d); Other: FAA-free amino acids, NMF-natural moisturizing factor, NHEK-normal human epidermal keratinocytes, pPCR-quantitative polymerase chain reaction; TJ-tight junctions, SC-stratum corneum. [Brief explanation of the drawings]

[0100] [Figure 1]Figure 1 shows the effect of amino acid formulation treatment on mRNA expression of barrier marker genes in differentiated normal human epidermal keratinocyte (NHEK) cells from five donors. Treatment time: 4 hours. All graphed data represent mean ± SE. *: p<0.05, **: p<0.01, ***: p<0.001 (compared to untreated cells (CTR) in a two-tailed t-test). Data from two independent experiments. Exemplary barrier marker genes examined were epidermal growth factor (EGF); fibroblast growth factor 2 (FGF2); platelet-derived growth factor (PDGF); carnitine palmitoyltransferase 2 (CPT2); transglutaminase 4 (TGM4); peroxisome proliferator-activated receptor delta (PPARD); and TNF receptor superfamily member 10d (TNFRSF10D). [Figure 2] A table listing the amino acid combinations is shown. Amino acids #1, #2, #4, #6, and #7 in the combo were used at a concentration of 4 mM for each amino acid. Amino acids #3 and #4 in the combo were used at the lower indicated concentrations (mM) because toxic effects were detected at 4 mM. [Figure 3] Table showing transcript analysis of skin barrier integrity marker genes in primary keratinocytes. Differentiation genes are designated with * and proliferation genes with +. EGF contributes to both differentiation and proliferation. Scoring system developed: number of points awarded for relative expression. (Mean relative expression >1.5 (50% increase); untreated = 1). [Figure 4] Table showing transcript analysis of skin barrier integrity marker genes in primary keratinocytes. Differentiation genes are designated with * and proliferation genes with +. EGF contributes to both differentiation and proliferation. Scoring system developed: number of points awarded for relative expression. (mean relative expression >1.5 (50% increase); untreated = 1) (n = 5). [Figure 5]Quantification of involucrin (INV) expression by Western blot analysis at 24 hours after treatment. Combo #1: Gln, Gly, Ala, Ser; Combo #2: Gln, Gly, Ala, Ser, Ile, Val; Combo #5: Cys, His, Leu, Asp. Quantitative analysis of involucrin expression determined based on results from two donor samples. [Figure 6] Quantification of Western blot analysis of filaggrin (FLG) expression at 4 and 24 hours of treatment is shown. Combo #1: Gln, Gly, Ala, Ser; Combo #2: Gln, Gly, Ala, Ser, Ile, Val; Combo #3: Cys, His, Tyr; Combo #5: Cys, His, Leu, Asp. [Figure 7] Figures A-D show graphs of EGF expression comparing a four amino acid blend (Ala, Gln, Gly, Ser; 4GAA) and a Boswellia plant extract blend (BSW = BSXL), alone or in combination. Figure A shows EGF expression in donor O cells with 4GAA alone (4 mM); BSW (1%) alone; and a combination of 4GAA (4 mM) and BSW (1%). Figure B shows EGF expression in donor O cells with 4GAA alone (1 mM); BSW (0.25%) alone; and a combination of 4GAA (1 mM) and BSW (0.25%). Figure C shows EGF expression in donor G cells with 4GAA alone (4 mM); BSW (0.5%) alone; and a combination of 4GAA (4 mM) and BSW (0.5%). D shows EGF expression in donor G keratinocyte cells treated with 4GAA alone (1 mM); BSW (0.25%) alone; and a combination of 4GAA (1 mM) and BSW (0.25%). *p-value=0.05; **p-value=0.01. "CTR" or "CTR untr" refers to untreated controls. n=3 [Figure 8]A and B show the fold change in EGF mRNA in donor G keratinocyte cells compared with 1 mM or 4 mM of a 4-amino acid blend (Ala, Gln, Gly, Ser; 4GAA) and / or a plant extract blend containing, for example, Boswellia (BSXL), alone (0.1%, 0.25%, 0.5%) or in combination at different concentrations. Data are shown in graphical (A) and tabular (B) formats. *p<0.05, **p<0.01, ***p<0.001, ****p<0.0001 vs. untreated control (ctr). n=3 [Figure 9] A and B show the fold change in EGF mRNA comparing a 4 amino acid blend (Ala, Gln, Gly, Ser; 4GAA) and a Boswellia plant extract blend (BSXL; Bosexil®), alone or in combination at different concentrations, using donor O keratinocyte cells. Data are shown in graphical (A) and tabular (B) formats. **p<0.01, ***p≦0.001 (vs. untreated CTR control). n=2 or n=3. [Figure 10] A and B show the fold change in EGF mRNA comparing a 4-amino acid formula (Ala, Gln, Gly, Ser; 4GAA; 4 mM), a 3-amino acid formula (Cys 1 mM, His 0.5 mM, Tyr 1 mM; 3BAA), a 0.5% Boswellia plant extract formula (BSXL), and piperonylic acid (100 μM; PA), alone or in combination, using donor G keratinocyte cells. Data are presented in graphical (A) and tabular (B) formats. *p<0.05, **p≦0.01, ***p≦0.001 (vs. untreated CTR control). n=3 [Figure 11]A and B show the fold change in EGF mRNA comparing a 4-amino acid formulation (Ala, Gln, Gly, Ser; 4GAA; 4 mM), a 3-amino acid formulation (Cys 1 mM, His 0.5 mM, Tyr 1 mM; 3BAA), a Boswellia plant extract formulation (BSXL), and piperonylic acid (100 μM; PA), alone or in combination, using donor T keratinocyte cells. Data are presented in graphical (A) and tabular (B) formats. *p<0.05, **p<0.01, ****p<0.001 (vs. untreated CTR control). n=3 [Figure 12] A and B show the fold change in EGF mRNA in donor O keratinocytes comparing a 4-amino acid blend (Ala, Gln, Gly, Ser; 4GAA; 4 mM), a Boswellia plant extract blend (BSXL), and a boswellic acid extract (BA) alone or in combination at various concentrations or weight percent (wt / wt%). Data are shown in graphical (A) and tabular (B) formats. *p<0.05, **p≦0.01, ***p≦0.001 (vs. untreated CTR control). n=2 or n=3. [Figure 13] A and B show the fold change in EGF mRNA comparing a 4-amino acid formulation (Ala, Gln, Gly, Ser; 4GAA; 4 mM), an alternative 4-amino acid formulation (Asp, Ile, Tyr, Val; 4OAA; 4 mM), and a Boswellia plant extract formulation (BSXL; combined at 0.5% or 0.5 w / w%) alone or in combination at various concentrations or weight percent (wt / wt%) using donor A keratinocytes. Data are presented in graphical (A) and tabular (B) formats. ***p≦0.001 vs. untreated CTR control. n=3 [Figure 14A] Figure 1 shows the fold change in EGF mRNA comparing a 4 amino acid formula (Ala, Gln, Gly, Ser; 4GAA; 4 mM) and a Boswellia plant extract formula (BSXL; 0.5% w / w), alone or in combination, using keratinocytes from donors A, G, and T. Data are presented in tabular format (donor A (n=1), donor G (n=3), and donor T (n=2)). [Figure 14B] Figure 1 shows the fold change in EGF mRNA comparing a 4 amino acid formula (Ala, Gln, Gly, Ser; 4GAA; 4 mM) and a Boswellia plant extract formula (BSXL; 0.5% w / w), alone or in combination, using keratinocytes from donors A, G, and T. Data are presented in tabular format (donor A (n=3), donor G (n=9), and donor T (n=6)). [Figure 14C] Figure 14 shows the fold change in EGF mRNA in keratinocytes from donors A, G, and T, comparing a 4-amino acid formulation (Ala, Gln, Gly, Ser; 4GAA; 4 mM) and a Boswellia plant extract formulation (BSXL; 0.5% w / w), alone or in combination. The data from Figure 14B are presented in graphical form. Shown are CTR; 4GAA; BSXL; and 4GAA + BSXL formulations: Donor G (top three), Donor T (middle), and Donor A (bottom three). *p<0.05 vs. untreated CTR control; #p<0.05 vs. 4GAA and BSXL. Analysis was performed using repeated measures analysis of variance (RMANOVA) with Tukey's post-hoc test. [Figure 15] A and B show the change in transepidermal water loss (TEWL) in 12 subjects after 10 days of application of the test article (active (4GAA), left bar; placebo, right bar) dissolved in an oil / water (O / W) vehicle followed by repeated tape stripping (15 tape strips). A shows the change in TEWL from baseline immediately after tape stripping on Day 1, while Days 2, 3, and 5 (X-axis) are after twice-daily treatment with the test article. B shows the relative increase in TEWL after tape stripping; all values ​​are normalized to baseline Day 1, which represents TEWL immediately after tape stripping. Active (left bar); Placebo (right bar). Mean + / - 95% confidence interval (CI). [Figure 16]This figure shows skin barrier improvement, measured by skin moisture content (y-axis), after 10 days of test article application followed by repeated tape stripping (25 times) in 25 subjects. Control represents no treatment (top line on day 3; left bar in inset), placebo represents a water / oil / water (W / O / W) vehicle without active treatment (middle line on day 3; middle bar in inset), and amino acids represent a 4-amino acid blend (Ala (4%), Gln (4%), Gly (4%), Ser (4%)) dissolved in a W / O / W vehicle (bottom line on day 3; right bar in inset). *, p-value = 0.05. Inset: control (left), placebo (center), amino acids (right). [Figure 17] Figures 17A-C show fold changes in mRNA of specific genes using human-derived epidermal keratinocytes (NHEKs) from donors E, G, O, R, and T treated for 4 hours in amino acid (AA)-deficient medium with a 4-amino acid formulation (Ala, Gln, Gly, Ser; 4GAA; 4 mM) and retinol (ROL; 10 μM), alone or in combination, compared to the control (CTR; untreated control without amino acids or retinol). Data are shown in graph format, showing the combinations CTR; 4GAA (4 mM); ROL (10 μM); and 4GAA (4 mM) + ROL (10 μM). Figure 17A shows the fold change in EGF mRNA (n = 3). Figure 17B shows the fold change in TGFB mRNA (n = 3). Figure 17C shows the fold change in COL1A1 mRNA (n = 3). [Figure 18A] Data showing the fold change in mRNA of specific genes using human-derived epidermal keratinocytes (NHEKs) from donors E, G, O, R, and T treated for 4 hours in amino acid (AA)-deficient medium with a 4-amino acid formulation (Ala, Gln, Gly, Ser; 4GAA; 4 mM), and retinol (ROL; 10 μM), alone or in combination, compared to control (CTR; untreated control without amino acids or retinol), are shown in graph format. The combination of CTR; 4GAA (4 mM); ROL (10 μM); and 4GAA (4 mM) + ROL (10 μM) shows the fold change in HAS1 mRNA. [Figure 18B]Human-derived epidermal keratinocytes (NHEKs) from donors E, G, O, R, and T were treated for 4 hours in amino acid (AA)-deficient medium with a 4-amino acid formulation (Ala, Gln, Gly, Ser; 4GAA; 4 mM), and retinol (ROL; 10 μM), alone or in combination, compared to the control (CTR; untreated control without amino acids or retinol). Data are presented in graph format showing the combination of CTR; 4GAA (4 mM); ROL (10 μM); and 4GAA (4 mM) + ROL (10 μM). The fold change in HAS2 mRNA is shown. [Figure 18C] Human-derived epidermal keratinocytes (NHEKs) from donors E, G, O, R, and T were treated for 4 hours in amino acid (AA)-deficient medium with a 4-amino acid formulation (Ala, Gln, Gly, Ser; 4GAA; 4 mM) and retinol (ROL; 10 μM), alone or in combination, compared to the control (CTR; untreated control without amino acids or retinol). Data are presented in graph format showing the combination of CTR; 4GAA (4 mM); ROL (10 μM); and 4GAA (4 mM) + ROL (10 μM). The fold change in HAS3 mRNA is shown. [Figure 18D] Tabular data for fold change of HAS1 mRNA, HAS2 mRNA, and HAS3 mRNA, respectively (Donor E (n=3), Donor G (n=3), Donor O (n=3), Donor R (n=3), and Donor T (n=3)) are shown, along with tabular data showing the fold change for each specific condition in each respective graphical format. [Figure 18E] Tabular data for fold change of HAS1 mRNA, HAS2 mRNA, and HAS3 mRNA, respectively (Donor E (n=3), Donor G (n=3), Donor O (n=3), Donor R (n=3), and Donor T (n=3)) are shown, along with tabular data showing the fold change for each specific condition in each respective graphical format. [Figure 18F]Tabular data for fold change of HAS1 mRNA, HAS2 mRNA, and HAS3 mRNA, respectively (Donor E (n=3), Donor G (n=3), Donor O (n=3), Donor R (n=3), and Donor T (n=3)) are shown, along with tabular data showing the fold change for each specific condition in each respective graphical format. [Figure 19] Figures A-D show the fold change in mRNA of specific genes using donor O human-derived epidermal keratinocytes (NHEK) treated for 24 hours in complete medium with a 4-amino acid formulation (Ala, Gln, Gly, Ser; 4GAA; 4 mM), and retinol (ROL; 10 μM), alone or in combination, compared to the control (CTR; untreated control without amino acids or retinol). Data A-D are shown in graph format, showing the combinations CTR; 4GAA (4 mM); ROL (10 μM); and 4GAA (4 mM) + ROL (10 μM). A shows the fold change in EGF mRNA. B shows the fold change in HAS1 mRNA. C shows the fold change in HAS2 mRNA. D shows the fold change in HAS3 mRNA. Figure 21 shows the data from donor O in tabular format for the fold change in EGF, HAS1, HAS2, and HAS3 mRNA under specified conditions. [Figure 20] Figures 20A-D show the fold change in mRNA of specific genes using donor R human-derived epidermal keratinocytes (NHEK) treated for 24 hours in complete medium with a 4-amino acid formulation (Ala, Gln, Gly, Ser; 4GAA; 4 mM), and retinol (ROL; 10 μM), alone or in combination, compared to the control (CTR; untreated control without amino acids or retinol). Data from Figures 20A-20D are presented in graph format showing the combinations CTR; 4GAA (4 mM); ROL (10 μM); and 4GAA (4 mM) + ROL (10 μM). A shows the fold change in EGF mRNA. B shows the fold change in HAS1 mRNA. C shows the fold change in HAS2 mRNA. D shows the fold change in HAS3 mRNA. FIG. 21 shows the donor R data in tabular form for fold change of EGF mRNA, HAS1 mRNA, HAS2 mRNA, and HAS3 mRNA under specified conditions. [Figure 21] Donor O and donor R data are presented in tabular form as fold changes in EGF mRNA, HAS1 mRNA, HAS2 mRNA, and HAS3 mRNA under specified conditions. [Figure 22] (A) and (B) show the fold change in mRNA of specific genes using 3-dimensional skin equivalents (normal human-derived epidermal keratinocytes (NHEK); EpiDerm™; MatTek Corp., Ashland, MA) cultured at an air-liquid interface (ALI) on tissue culture inserts and treated twice for 24 hours in complete medium with a 4-amino acid blend (Ala, Gln, Gly, Ser; 4GAA; 4 mM), and retinol (ROL; 5 μM), alone or in combination (4GAA + ROL), compared to a control (CTR; untreated control without amino acids or retinol). Data in (A) and (B) are shown in graph form, showing the combinations of CTR; 4GAA (4 mM); ROL (5 μM); and 4GAA (4 mM) + ROL (5 μM), and in table form, showing the fold change for each specific condition in each respective graph form. (A) shows the fold change in HAS2 mRNA. (B) shows the fold change in HAS3 mRNA. [Figure 23] Panels A and B show the fold change in mRNA of specific genes in fibroblasts (adult human dermal fibroblasts (HDFa)) treated for 4 hours in EBS medium with a 4-amino acid formulation (Ala, Gln, Gly, Ser; 4GAA; 4 mM), and retinol (ROL; 10 μM), alone or in combination, compared to the control (CTR; untreated control without amino acids or retinol). Data in A and B are shown in graph format, showing the combinations CTR; 4GAA (4 mM); ROL (10 μM); and 4GAA (4 mM) + ROL (10 μM). Panel A shows the fold change in fibroblast collagen, COL1A1 mRNA (n = 3). Panel B shows the fold change in fibroblast elastin, ELN mRNA (n = 3). [Figure 24]Figures A-C show the fold change in mRNA of specific genes using fibroblasts (adult human dermal fibroblasts (HDFa)) treated for 4 hours in complete medium with a 4-amino acid formulation (Ala, Gln, Gly, Ser; 4GAA; 4 mM) and retinol (ROL; 10 μM), alone or in combination, compared to the control (CTR; untreated control without amino acids or retinol). Data for A-C are shown in graph form, showing CTR; 4GAA (4 mM); ROL (10 μM); and the combination of 4GAA (4 mM) + ROL (10 μM), and in table form, showing the fold change for each specific condition in each graph form. Figure A shows the fold change of HAS1 mRNA (n = 3). Figure B shows the fold change of HAS2 mRNA (n = 3). Figure C shows the fold change of HAS3 mRNA (n = 3). [Figure 25A] Figure 1 shows the fold change in HAS1 mRNA in fibroblasts (adult human dermal fibroblasts (HDFa)) treated with a four-amino acid blend (Ala, Gln, Gly, Ser; 4GAA; 4 mM) and retinol (ROL; 10 μM), alone or in combination, compared to the control (CTR; untreated control without amino acids or retinol) after 4 hours of treatment in amino acid (AA)-deficient and complete media. Data are presented in graph form showing CTR; 4GAA (4 mM); ROL (10 μM); and the combination of 4GAA (4 mM) + ROL (10 μM), and in table form showing the fold change in HAS1 mRNA for each specific condition in each graph format. The fold change in HAS1 mRNA (n = 3) after 4 hours of treatment in AA-deficient and complete media is shown. [Figure 25B]Figure 25B shows the fold change in HAS1 mRNA in fibroblasts (adult human dermal fibroblasts (HDFa)) treated with a four-amino acid blend (Ala, Gln, Gly, Ser; 4GAA; 4 mM) and retinol (ROL; 10 μM), alone or in combination, compared to the control (CTR; untreated control without amino acids or retinol) in complete medium for 24 hours. Data are presented in graph form showing CTR; 4GAA (4 mM); ROL (10 μM); and the combination of 4GAA (4 mM) + ROL (10 μM), and in table form showing the fold change in HAS1 mRNA for each specific condition in each graph form. The fold change in HAS1 mRNA (n = 3) after 24 hours of treatment in complete medium is shown. [Figure 26] Fibroblast data are tabulated as fold changes in EGF mRNA, HAS1 mRNA, HAS2 mRNA, and HAS3 mRNA relative to control (CTR; fibroblasts in complete medium) under the specified conditions: control (CTR; untreated control without amino acids or retinol; 4GAA (4 mM); ROL (10 μM); combination of 4GAA (4 mM) + ROL (10 μM)) treated for 24 hours in complete medium. [Figure 27A] Table 1 shows the CT of endogenous expression of HAS2 mRNA in human epidermal keratinocytes (NHEK) from donor E (cycle threshold, CT = 35) under specific conditions: control (CTR; untreated control containing no amino acids or retinol; 4GAA (4 mM); ROL (10 μM); and combinations of 4GAA (4 mM) and ROL (10 μM). [Figure 27B] Table 1 shows the CT of endogenous expression of HAS2 mRNA in human epidermal keratinocytes (NHEK) from donor G (cycle threshold, CT = 35) under specified conditions: control (CTR; untreated control containing no amino acids or retinol; 4GAA (4 mM); ROL (10 μM); and combinations of 4GAA (4 mM) and ROL (10 μM). [Figure 27C]Table 1 shows the CT of endogenous expression of HAS2 mRNA in human epidermal keratinocytes (NHEK) from donor O (cycle threshold, CT = 35) under specific conditions: control (CTR; untreated control containing no amino acids or retinol; 4GAA (4 mM); ROL (10 μM); and combinations of 4GAA (4 mM) and ROL (10 μM). [Figure 27D] The data (cycle threshold, CT = 35) for the CT of endogenous expression of HAS2 mRNA in human epidermal keratinocytes (NHEK) from donor R under specified conditions, i.e., control (CTR; untreated control containing neither amino acids nor retinol; 4GAA (4 mM); ROL (10 μM); and combinations of 4GAA (4 mM) and ROL (10 μM), are shown in tabular form. [Figure 27E] Table 1 shows the data (cycle threshold, CT = 35) for the CT of endogenous expression of HAS2 mRNA in human epidermal keratinocytes (NHEK) from donor T under specified conditions: control (CTR; untreated control containing neither amino acids nor retinol; 4GAA (4 mM); ROL (10 μM); and combinations of 4GAA (4 mM) and ROL (10 μM). DETAILED DESCRIPTION OF THE INVENTION

[0101] Although detailed embodiments of the present disclosure are disclosed herein, it should be understood that the disclosed embodiments are merely exemplary of the present disclosure, which may be embodied in various forms. Moreover, each of the examples given in connection with various embodiments of the present disclosure are intended to be illustrative, not limiting.

[0102] Skin functions as a physical barrier that isolates organisms from their surrounding environment but also serves as an interactive interface with that environment. Skin comprises three distinct layers: the stratum corneum, epidermis, and dermis. The stratum corneum (outermost layer) contains keratinocytes and provides a physical barrier from the external environment. Environmental stressors vary, for example, depending on climate and / or lifestyle, and can include xenobiotics, UV radiation, pollution (e.g., cigarette smoke or engine exhaust), and pathogens. In addition to acting as a shield to protect the underlying skin layers from such external stimuli, the stratum corneum also reduces water loss from the skin. Skin keratinocytes are connected via tight junction (TJ) proteins, such as zona occludin (ZO). TJ proteins play a critical role in barrier function and also contribute to keratinocyte proliferation and differentiation. The integrity of the barrier function prevents excessive water loss from the skin, a key feature of skin, and thereby plays a key role in maintaining healthy skin.

[0103] Dysregulation of the skin barrier is involved in a wide variety of common skin diseases, such as atopic dermatitis, psoriasis, and ichthyosis. Dysregulation of the skin barrier also contributes to xerosis (dry skin), a common skin disease that is exacerbated by low humidity, repeated washing, and exposure to harsh chemicals. Such external stressors promote moisture loss from the skin. Dry skin can result in or be accompanied by itching and / or skin irritation. Dry skin can be considered a symptom of impaired skin barrier function. Dry skin is also a common feature of aging skin.

[0104] Optimal management of many skin diseases, conditions, or disorders involves proper skin care. The incorporation of a properly designed moisturizing / barrier repair formulation may help reduce disease-related signs and symptoms, thereby improving the disease. Described herein is an effective moisturizing / barrier repair formulation for treating dry skin that enhances skin regeneration and strengthens skin barrier function. The formulation contains a specific amino acid blend that provides cosmetic and / or therapeutic benefits in connection with the treatment of a wide variety of cosmetic skin conditions and skin diseases, conditions, and disorders (e.g., dry skin).

[0105] Described herein are formulations of specific combinations of amino acids for maintaining healthy skin, treating cosmetic skin conditions, and treating skin conditions, disorders, and diseases. In one aspect, described herein are formulations and methods for improving skin barrier integrity and promoting cell proliferation and / or development. As used herein, reference to "development" may include, for example, skin cell migration, maturation, and / or differentiation. The present disclosure also provides formulations and methods for treating and / or preventing cosmetic skin conditions or skin conditions associated with skin diseases or disorders. Such skin conditions include, but are not limited to, atopic dermatitis, psoriasis, conditions associated with skin aging, pruritus, eczema, and / or cosmetic conditions. The present disclosure also provides formulations and methods for treating wounds or burns.

[0106] For example, atopic dermatitis (AD) is the most common chronic inflammatory skin disease, affecting up to 15 million Americans (17% of children and 6% of adults). Despite its high prevalence, impact on quality of life, and economic burden, there are still no effective treatments for AD, and most treatments generally focus on suppressing inflammation. AD is thought to develop in part as a result of acquired or genetic abnormalities in the skin barrier. The epidermis of AD subjects exhibits alterations in tight junctions (TJs), which are associated with reduced expression of select TJ components (e.g., claudins). TJs seal the intercellular spaces between epithelial cells, and the "tightness" of this structure is dynamically regulated by endogenous or environmental factors. Regulation of TJ sealing is important for various reasons, including proper transport patterns of ions, proteins, and water, as well as immune cell permeability.

[0107] The integrity of tight junction dynamics between endothelial and epithelial cells, which regulates diffusion and maintains homeostasis in organs protected by physiological barriers, can be measured in vitro using transepithelial / transendothelial electrical resistance (TEER). TEER can be used to identify agents that improve physiological barriers and, therefore, may have beneficial effects on conditions associated with increased levels of physiological barrier permeability compared to normal, healthy conditions. Conditions associated with increased levels of physiological barrier permeability include, for example, atopic dermatitis and dry skin. The results presented herein demonstrate that specific amino acid formulations improve / enhance skin cell barrier integrity. Improved skin cell barrier integrity is believed to be mediated, at least in part, by tight junction dynamics and reflects reduced tight junction permeability. See, for example, Figures 1-6.

[0108] The subject may be a patient in need of improving skin barrier integrity. The patient may have such a need due to, for example, exposure to chemical or physical irritants, age-related predisposition, genetic predisposition, or skin inflammation. In one embodiment, the patient is asymptomatic. The subject may be any animal, including, for example, a human. In addition to humans, the animal may be, for example, a mammal, such as a rabbit, cow, horse, sheep, pig, goat, dog, or cat.

[0109] As noted above, skin barrier dysfunction is involved in common skin disorders such as atopic dermatitis, psoriasis, and ichthyosis, as well as the very common skin disorder xeroderma (dry skin). Dry skin is a condition that most people experience at some point in their lives. Seasonal xeroderma is common during the cold, dry winter months, and the frequency of xeroderma increases with age. Optimal management of many skin disorders involves proper skin care. Incorporating a properly designed moisturizer / barrier repair formulation into a skin care regimen may contribute to the improvement or alleviation of symptoms associated with the condition or disease.

[0110] Effective moisturizer / barrier repair formulations for dry, dehydrated skin that enhance the skin's own ability to regenerate, restore, and strengthen its barrier function are desirable, and such formulations employ amino acid-based technology. These formulations offer new treatment options for dry, scaly skin, benefiting the large number of people who suffer from dry, scaly skin and are at risk of developing more serious conditions resulting from neglected dry skin.

[0111] Physiologically, amino acids and their derivatives are important components of the skin because they are components of the natural moisturizing factors (NMFs) of the stratum corneum (SC), the outermost layer of the skin. Free amino acids (FAAs) are produced by the hydrolysis of keratinocyte proteins filaggrin, corneodesmosomes, and SC keratin during the normal physiological processes of epidermal maturation and terminal differentiation. NMFs contribute to maintaining adequate skin moisture. Some amino acids can effectively bind water and may therefore play a role in regulating skin moisture. Therefore, supplementation of the skin with specific amino acids is proposed herein to ensure adequate levels of NMFs and protein synthesis or the production of certain key amino acid metabolites [pyrrolidone carboxylic acid (PCA) and trans-urocanic acid (t-UCA)] for regulation, nutrition, and / or protein supplementation in normal and dry skin, as well as in other skin conditions where the epidermal barrier is impaired.

[0112] Without being bound by theory, by delivering specific amino acid blends to the skin, the skin's natural ability to form an adequate barrier may be "fertilized." The problem of how to maintain / restore skin barrier function is solved by developing amino acid formulations that target specific intracellular pathways involved in skin barrier function and repair, thereby converting amino acids from simple building blocks into small molecules that can trigger signaling pathways that promote skin barrier function.

[0113] The results presented herein demonstrate that supplementation with specific amino acid formulations can regulate the transcription of key regulators of differentiation and proliferation, such as the EGF and PDGF genes, in normal primary human keratinocytes. Specific combinations of amino acids that demonstrate this functional ability were determined by analyzing their effects on skin barrier markers. Notably, certain combinations of amino acids exhibit beneficial effects on skin barrier function (e.g., Ser, Ala, Gly, and Gln), while other amino acid combinations (e.g., Cys, His, and Tyr) have no effect or even a negative impact on skin barrier function. Additional screening assays to identify the most effective combination(s) of amino acids for improving the barrier integrity of skin / skin barrier function will be conducted, tested, and validated in preclinical studies using different skin models and different administration methods (e.g., systemic and / or topical).

[0114] Specific goals include defining effective amino acid formulations that promote skin barrier function (see Figures 1-6) and further evaluating and developing such amino acid formulations using 2D monolayer cultures (human differentiated keratinocytes) and 3D models (skin equivalents of human epidermis). The effects of adding several amino acid formulations (e.g., the four major amino acid formulations of Ser, Ala, Gly, and Gln described above, with and without Ile, Trp, and / or Arg) to culture media will be determined on the mRNA and protein levels of the identified skin barrier marker panel based on replicate analyses. See, e.g., Example 1.

[0115] In brief, genes and proteins related to epidermal differentiation, proliferation, and lipid regulation in skin were repeatedly evaluated and weighted for their structural / functional impact on skin barrier integrity.The panel of markers used herein that reflects skin barrier integrity was determined through a series of multivariate iterative analyses.The complexity of this task is highlighted by the vast array of potential genes that are suggested to be involved in, for example, barrier function, proliferation, differentiation, and inflammation, and each of these biological processes contributes to skin barrier integrity to some extent.In fact, hundreds of genes have been suggested to be involved in these processes.Therefore, the starting point for determining a suitable panel of markers that reflects skin barrier integrity is given an unpredictable number of different potential skin barrier marker panels.Selecting a panel from this countless options required experiments using multiple sample sources to avoid sample bias, repeated analyses to study different endpoints, weighted importance of different genes in the skin barrier marker panel, and careful analysis of all variables in these analytical methods. The panel of skin barrier markers selected to reflect skin barrier integrity is the result of the analytical methodology described above and was therefore determined according to a mathematical and biological method involving experimental results, their statistical analysis, and algorithmic analysis of all collected inputs.

[0116] After identifying the skin barrier marker panel, a scoring system was developed to evaluate the different amino acid formulations under investigation. The scoring system was developed to address the many variables that arise from experimental results. Such variables include, for example, the degree of transcriptional upregulation, the number of different genes that are up- or down-regulated in response to the amino acid formulations being investigated, and the variability of the readouts observed between different sample sources. See, for example, Figures 3 and 4.

[0117] Specific goals include evaluating the effects of topical administration of the most promising amino acid formulations on epithelial barrier markers in in vitro and ex vivo models of normal and hypodermal skin. Briefly, amino acid formulations identified based on their superior ability to improve barrier function will be used for topical treatment of normal and hypodermal skin equivalents, as well as normal skin tissue cultures (skin explants). To generate an inflammatory skin phenotype, immature epidermal skin equivalents will be pretreated with helper T cell (Th-2)-derived cytokines in combination with TNFα, and the skin explants will be delipidated using tape stripping. The effects of treatment on barrier function and tight junction (TJ) dynamics will be examined using a combination of gene expression, biochemical, morphological, and functional analyses (e.g., transepithelial / transendothelial electrical resistance (TEER)). See, for example, Examples 4 and 5.

[0118] Therefore, identifying effective amino acid formulations and using them in barrier repair formulations / moisturizers provides a solution to the problem of how to maintain and restore healthy skin as people age and under stress and / or disease conditions.Therefore, the formulations identified herein fulfill the long-standing need for scientifically validated barrier repair formulations / moisturizers that address the underlying biological causes of skin conditions (e.g., dry skin), rather than simply the symptoms.Proof-of-concept tests are conducted on human subjects using the most promising amino acid-based cosmetic formulations.

[0119] Formulations and methods for treating cosmetic or other skin conditions Dry, sensitive, and dehydrated skin (also known as xerosis, dry skin, or asteatosis) is the most common skin disorder affecting approximately 50% of the world's population. The severity of this disorder increases with age. It affects patients' quality of life and, due to impaired skin barrier function, is a risk factor for the development of atopic or allergic dermatitis and other skin disorders.

[0120] Dry skin is associated with the development of skin cracks and pressure ulcers, which can be avoided with proper skin care. Many skin care products used to manage dry skin mimic various components of the skin barrier. They are designed to incorporate lipophilic (lipid-replenishing, film-forming) and hydrophilic (remoisturizing) ingredients into the skin. While such products can improve the moisture content of the SC, thereby attenuating inflammation, they do not address the underlying biochemical abnormalities in dry skin. Furthermore, many commercially available skin care products do not provide scientifically proven benefits.

[0121] Therefore, there is a need for topical skin care products that are effective against dry skin, which not only mimic skin barrier components but also enhance the skin's own ability to maintain and / or repair the strength of its barrier. The protective barrier thus formed at least partially restores the structural and functional properties of healthy skin. Therefore, topical skin care products that enhance the skin's ability to maintain and / or repair barrier integrity address the underlying causes of dry skin, rather than simply addressing the symptoms. A formulation has been developed that aims to address this objective.

[0122] For example, dry aging skin has reduced levels of profilaggrin and filaggrin, which are the main sources of free amino acids (FAA) in SC, and therefore the reduced levels of these proteins cause a decrease in the available FAA pool.The results presented herein show that the specific amino acid formulations described herein target-specifically supplement the FAA pool that is reduced with age.The results presented herein further show that specific combinations of amino acids act synergistically to benefit the structural / functional properties of skin barrier integrity, and surprisingly, certain amino acids can also be harmful to skin barrier integrity.

[0123] The data presented herein also show that treatment with specific amino acid formulations upregulates a panel of skin barrier marker genes (e.g., EGF, PDGF, CPT2, TGM4) in normal human keratinocytes that play important roles in skin development and homeostasis.

[0124] Described herein are mechanism(s) by which amino acids strengthen skin barrier integrity, focusing on their effects on TJs and / or improving skin barrier repair. To the extent that they are known, these mechanisms have not previously been scientifically rigorously explored in skin.

[0125] As highlighted above, not all amino acids have the same beneficial effect on skin barrier integrity.In fact, some amino acids, either alone or in combination, are contraindicated for skin barrier integrity.Therefore, a targeted approach is needed to identify the most effective amino acids for promoting skin barrier health.This paper proposes a new, scientifically proven amino acid-based technology that targets hypofunctional epithelial skin, to provide a better solution for people suffering from dry and sensitive skin.

[0126] Thus, in certain embodiments, the present disclosure provides a method for treating and / or preventing a skin condition in a subject in need thereof, the method comprising administering to the subject a formulation described herein. In certain aspects, the skin condition is dry skin, atopic dermatitis, dermatitis, radiation dermatitis, ichthyosis, psoriasis, skin aging, a condition associated with skin aging (e.g., wrinkles, loss of flexibility, increased roughness), pruritus, or eczema. In a further aspect, the skin condition is a cosmetic skin condition.

[0127] In certain aspects, a formulation for treating and / or preventing a cosmetic skin condition or a skin condition comprises a therapeutically effective amount of a combination of glutamine, glycine, alanine, and serine as free amino acids or peptide combinations of amino acids, and optionally a therapeutically effective amount of at least one additional free amino acid or peptide combination of amino acids, such as valine, isoleucine, arginine, threonine, or tryptophan, or any combination thereof, wherein the therapeutically effective amount of a combination of glutamine, glycine, alanine, and serine and the therapeutically effective amount of at least one additional free amino acid or peptide combination of amino acids improves the barrier integrity of skin cells, and the formulation optionally includes a dermatologically acceptable carrier and improves the barrier integrity of the skin. In certain embodiments, the free amino acids or peptide combination of amino acids comprises, consists essentially of, or consists of glutamine, glycine, alanine, serine, and valine, and at least one additional amino acid, such as isoleucine, arginine, threonine, or tryptophan, or any combination thereof. In more particular embodiments, the free amino acids or peptide combinations of amino acids comprise, consist essentially of, or consist of glutamine, glycine, alanine, serine, valine, and isoleucine, and at least one additional amino acid, arginine, or threonine, or any combination thereof. In more particular embodiments, the free amino acids or peptide combinations of amino acids comprise, consist essentially of, or consist of glutamine, glycine, alanine, serine, and valine; the free amino acids or peptide combinations of amino acids comprise, consist essentially of, or consist of glutamine, glycine, alanine, serine, valine, and isoleucine; the free amino acids or peptide combinations of amino acids comprise, consist essentially of, or consist of glutamine, glycine, alanine, serine, valine, isoleucine, and arginine;The free amino acids or peptide combinations of amino acids comprise, consist essentially of, or consist of glutamine, glycine, alanine, serine, valine, isoleucine, and threonine; the free amino acids or peptide combinations of amino acids comprise, consist essentially of, or consist of glutamine, glycine, alanine, and serine, and at least one additional amino acid isoleucine, arginine, threonine, or tryptophan, or any combination thereof; the free amino acids or peptide combinations of amino acids comprise, consist essentially of, or consist of glutamine, glycine, alanine, serine, and isoleucine; the free amino acids or peptide combinations of amino acids comprise, consist essentially of, or consist of glutamine, glycine, alanine, serine, and arginine; the free amino acids or peptide combinations of amino acids comprise, consist essentially of, or consist of glutamine, glycine, alanine, serine, and threonine; the free amino acids or peptide combinations of amino acids comprise, consist essentially of, or consist of glutamine, glycine, alanine, serine, and threonine; the free amino acids or peptide combinations of amino acids the peptide combination of amino acids comprises, consists essentially of, or consists of glutamine, glycine, alanine, serine, and tryptophan; the free amino acids or peptide combination of amino acids comprises, consists essentially of, or consists of glutamine, glycine, alanine, serine, and isoleucine, and at least one additional amino acid arginine, or threonine, or tryptophan, or any combination thereof; the free amino acids or peptide combination of amino acids comprises, consists essentially of, or consists of glutamine, glycine, alanine, serine, isoleucine, and arginine; the free amino acids or peptide combination of amino acids comprises, consists essentially of, or consists of glutamine, glycine, alanine, serine, isoleucine, and threonine; the free amino acids or peptide combination of amino acids comprises, consists essentially of, or consists of glutamine, glycine, alanine, serine, isoleucine, and tryptophan;The free amino acids or peptide combinations of amino acids comprise, consist essentially of, or consist of glutamine, glycine, alanine, serine, isoleucine, arginine, and threonine; the free amino acids or peptide combinations of amino acids comprise, consist essentially of, or consist of glutamine, glycine, alanine, serine, isoleucine, arginine, and tryptophan; the free amino acids or peptide combinations of amino acids comprise, consist essentially of, or consist of glutamine, glycine, alanine, serine, isoleucine, arginine, threonine, and tryptophan; the free amino acids or peptide combinations of amino acids comprise, consist essentially of, or consist of glutamine, glycine, alanine, serine, isoleucine, arginine, threonine, and tryptophan; the free amino acids or peptide combinations of amino acids comprise, consist essentially of, or consist of glutamine, glycine, alanine, serine, isoleucine, arginine, threonine, and tryptophan The free amino acids or peptide combinations of amino acids comprise, consist essentially of, or consist of glutamine, glycine, alanine, serine, and arginine, and at least one additional amino acid isoleucine, threonine, or tryptophan, or any combination thereof; the free amino acids or peptide combinations of amino acids comprise, consist essentially of, or consist of glutamine, glycine, alanine, serine, and threonine, and at least one additional amino acid isoleucine, arginine, or tryptophan, or any combination thereof; or the free amino acids or peptide combinations of amino acids comprise, consist essentially of, or consist of glutamine, glycine, alanine, serine, and tryptophan, and at least one additional amino acid isoleucine, arginine, or threonine, or any combination thereof. Some aspects of the present disclosure are directed to such formulations for treating and / or preventing skin conditions, administered topically or by injection (e.g., intradermally, subcutaneously, intramuscularly).

[0128] In one embodiment, the formulation optionally includes, for example, a pharmaceutically acceptable carrier, adjuvants, other active agents, and additives (eg, sugars, electrolytes, vitamins, minerals, etc.).

[0129] In some embodiments of the formulations described herein, the amino acid cysteine, if present, is present at a concentration of 1 mM or less; the amino acid histidine, if present, is present at a concentration of 0.5 mM or less; the amino acid tyrosine, if present, is present at a concentration of 1 mM or less; the amino acid leucine, if present, is present at a concentration of 4 mM or less; or the amino acid aspartic acid, if present, is present at a concentration of 2 mM or less; or any combination thereof. In some embodiments of the formulations, the formulation does not include the amino acids cysteine, histidine, tyrosine, leucine, aspartic acid, taurate, taurine, or glutamic acid, or any combination thereof.

[0130] In some embodiments of the formulations described herein, if present, the amino acid alanine is present in an amount of 4% or less (e.g., 3.8, 3.6, 3.4, 3.2, 2.8, 2.6, 2.4, 2.2, 2, 1.8, 1.6, 1.4, 1.2, 0.8, 0.6, 0.4, 0.2, 0.18, 0.16, 0.14, 0.12, 0.08, 0.06, 0.058, 0.056, 0.054, 0.052, 0.05, 0.048, 0.046, 0.044, 0.042, 0.04, 0.038, 0.036, 0.034, 0.032, 0.03, 0.02, 0.018, 0.016 , 0.014, 0.012); 0.01% or more (e.g., 0.011, 0.013, 0.015, 0.017, 0.019, 0.021, 0.023, 0.025, 0.027, 0.029, 0.03, 0.031, 0.033, 0.035, 0.037, 0.039, 0. 041, 0.043, 0.045, 0.047, 0.049, 0.05, 0.051, 0.053, 0.055, 0.057, 0.059, 0.07, 0.09, 0.1, 0.11, 0.13, 0.15, 0.17, 0.19, 0.3, 0.5, 0.7, 0.9, 1, 1.1, 1 0.3, 1.5, 1.7, 1.9, 2.1, 2.3, 2.5, 2.7, 2.9, 3, 3.1, 3.3, 3.5, 3.7, 3.9, 4.1, 4.3, 4.5, 4.7, 4.9, 5); if present, the amino acid glutamine should be present at concentrations of 4% or less (e.g., 3.8, 3.6, 3.4, 3.2, 2.8, 2.6, 2.4, 2.2, 2.8, 1.8, 1.6, 1.4, 1.2, 0.8, 0.6, 0.4, 0.2, 0.18, 0.16, 0.14, 0.12, 0.08, 0.06, 0.058, 0.056, 0.054, 0.052, 0.05, 0.048, 0. 0.046, 0.044, 0.042, 0.04, 0.038, 0.036, 0.034, 0.032, 0.03, 0.02, 0.018, 0.016, 0.014, 0.012); 0.01% or more (e.g., 0.011, 0.013, 0.015, 0.017, 0.019, 0 .021, 0.023, 0.025, 0.027, 0.029, 0.03, 0.031, 0.033, 0.035, 0.037, 0.039, 0.041, 0.043, 0.045, 0.047, 0.049, 0.05, 0.051, 0.053, 0.055, 0.057, 0.0.59, 0.07, 0.09, 0.1, 0.11, 0.13, 0.15, 0.17, 0.19, 0.3, 0.5, 0.7, 0.9, 1, 1.1, 1.3, 1.5, 1.7, 1.9, 2.1, 2.3, 2.5, 2.7, 2.9, 3, 3.1, 3.3, 3.5, 3.7, 3.9, 4.1, 4.3, 4.5, 4.7, 4.9, 5); if present, the amino acid glycine is present at 4% or less (e.g., 3.8, 3.6, 3.4, 3.2, 2.8, 2.6, 2.4, 2.2, 2.0, 1.8, 1.6, 1.4, 1.2, 0.8, 0.6, 0.4, 0.2, 0.1 8, 0.16, 0.14, 0.12, 0.08, 0.06, 0.058, 0.056, 0.054, 0.052, 0.05, 0.048, 0.046, 0.044, 0.042, 0.04, 0.038, 0.036, 0.034, 0.032, 0.03, 0.02, 0.018, 0.016, 0.014, 0.012); 0.01% or more (e.g., 0.011, 0.013, 0.015, 0.017, 0.019, 0.021, 0.023, 0.025, 0.027, 0.029, 0.03, 0.031, 0.033, 0.035, 0.037, 0.03 9, 0.041, 0.043, 0.045, 0.047, 0.049, 0.05, 0.051, 0.053, 0.055, 0.057, 0.059, 0.07, 0.09, 0.1, 0.11, 0.13, 0.15, 0.17, 0.19, 0.3, 0.5, 0.7, 0.9, 1, 1.1, 1.3, 1.5, 1.7, 1.9, 2.1, 2.3, 2.5, 2.7, 2.9, 3, 3.1, 3.3, 3.5, 3.7, 3.9, 4.1, 4.3, 4.5, 4.7, 4.9, 5); if present, the amino acid serine is present at a concentration of 4% or less (e.g., 3.8, 3.6 ,3.4,3.2,2.8,2.6,2.4,2.2,2,1.8,1.6,1.4,1.2,0.8,0.6,0.4,0.2,0.18,0.16,0.14,0.12,0.08,0.06,0.058,0.056,0.054,0.052,0.05,0.048,0 0.046, 0.044, 0.042, 0.04, 0.038, 0.036, 0.034, 0.032, 0.03, 0.02, 0.018, 0.016, 0.014, 0.012); 0.01% or more (e.g., 0.011, 0.013, 0.015, 0.017, 0.019, 0.021, 0.023, 0.025, 0.027, 0.029, 0.03, 0.031, 0.033, 0.035, 0.037, 0.039, 0.041, 0.043, 0.045, 0.047, 0.049, 0.05, 0.051, 0.053, 0.055, 0.057, 0.059, 0.07, 0.09, 0.1, 0.11, 0 0.13, 0.15, 0.17, 0.19, 0.3, 0.5, 0.7, 0.9, 1, 1.1, 1.3, 1.5, 1.7, 1.9, 2.1, 2.3, 2.5, 2.7, 2.9, 3, 3.1, 3.3, 3.5, 3.7, 3.9, 4.1, 4.3, 4.5, 4.7, 4.9, 5); or any combination thereof.

[0131] Or, in certain embodiments, even if these amino acids are present in the formulation, they are not present in such an amount that they affect the skin barrier integrity. " Negligible " means that the specific amino acids present do not have any effect on the skin barrier integrity. " Negligible " means that the specific amino acids present do not have any effect on the skin barrier integrity-related disease or condition, for example, do not have any effect on wound healing, the treatment of skin conditions (for example, atopic dermatitis, psoriasis, or skin aging-related conditions) in the subject who needs it.

[0132] When present in the formulations described herein, amino acids can be present at concentrations of, for example, 0.5 mM, about 1 mM, about 2 mM, about 3 mM, about 4 mM, about 5 mM, about 6 mM, about 7 mM, about 8 mM, about 9 mM, or about 10 mM. For example, 4 mM of each amino acid contains 0.0356% alanine, 0.0584% glutamine, 0.03% glycine, and 0.042% serine. In some embodiments, each of the amino acids in the formulations described herein (4% or 4 mM) is about 100-fold higher than the concentration used in tissue culture (TC) experiments.

[0133] In one embodiment, the total osmolality of the formulation is from about 10 mosm to about 280 mosm, from 50 mosm to about 280 mosm, from 100 mosm to about 280 mosm, or from about 150 to about 260 mosm.

[0134] In some embodiments, the formulation has a pH of, for example, about 2.5 to about 8.5. In some embodiments, the formulation has a pH of about 2.5 to about 6.5, about 2.5 to about 6.0, about 3.0 to about 6.0, about 3.5 to about 6.0, about 3.9 to about 6.0, about 4.2 to about 6.0, about 3.5 to about 5.5, about 3.9 to about 5.0, or about 4.2 to about 4.6. In some embodiments, the pH is about 4.0 to about 6.0 or about 4.5 to about 5.7.

[0135] In some embodiments, the formulation is administered systemically or locally. In some embodiments, the formulation is used to treat a disease or condition associated with skin barrier integrity, such as treating dry skin, wound healing, treating a skin condition (e.g., atopic dermatitis, dermatitis, psoriasis, skin aging, conditions associated with skin aging, pruritus, or eczema), and / or improving skin barrier integrity. Therapeutic formulations can be administered enterally, parenterally, topically, or by inhalation. In certain embodiments, the formulation is for therapeutic, cosmetic, or nutritional purposes.

[0136] In some embodiments, the formulation is a solution. The formulation can be administered together with other therapeutic agents.

[0137] Formulations and uses thereof for treating and / or preventing conditions associated with dry skin, atopic dermatitis, dermatitis, radiation dermatitis, psoriasis, pruritus, eczema, wounds, burns, or skin aging In certain embodiments, the present disclosure provides methods for treating and / or preventing conditions associated with dry skin, atopic dermatitis, dermatitis, radiation dermatitis, psoriasis, pruritus, eczema, wounds, burns, or skin aging, the methods comprising administering to a subject a formulation described herein.

[0138] In certain aspects, a formulation for use in the treatment and / or prevention of conditions associated with dry skin, atopic dermatitis, dermatitis, psoriasis, pruritus, eczema, wounds, burns, or skin aging comprises, as free amino acids or peptide combinations of amino acids, a therapeutically effective amount of a blend of glutamine, glycine, alanine, and serine, and optionally a therapeutically effective amount of at least one additional free amino acid or peptide combination of amino acids valine, isoleucine, arginine, threonine, or tryptophan, or any combination thereof, wherein the therapeutically effective amount of the blend of glutamine, glycine, alanine, and serine and the therapeutically effective amount of at least one additional free amino acid or peptide combination of amino acids improves the barrier integrity of skin cells, and the formulation optionally comprises a dermatologically acceptable carrier and improves the barrier integrity of the skin. In certain embodiments, the free amino acids or peptide combinations of amino acids comprise, consist essentially of, or consist of glutamine, glycine, alanine, serine, and valine, and at least one additional amino acid isoleucine, arginine, threonine, or tryptophan, or any combination thereof. In more particular embodiments, the free amino acids or peptide combinations of amino acids comprise, consist essentially of, or consist of glutamine, glycine, alanine, serine, valine, and isoleucine, and at least one additional amino acid arginine or threonine, or any combination thereof. In more particular embodiments, the free amino acids or peptide combinations of amino acids comprise, consist essentially of, or consist of glutamine, glycine, alanine, serine, and valine; the free amino acids or peptide combinations of amino acids comprise, consist essentially of, or consist of glutamine, glycine, alanine, serine, valine, and isoleucine; the free amino acids or peptide combinations of amino acids comprise, consist essentially of, or consist of glutamine, glycine, alanine, serine, valine, isoleucine, and arginine;The free amino acids or peptide combinations of amino acids comprise, consist essentially of, or consist of glutamine, glycine, alanine, serine, valine, isoleucine, and threonine; the free amino acids or peptide combinations of amino acids comprise, consist essentially of, or consist of glutamine, glycine, alanine, and serine, and at least one additional amino acid isoleucine, arginine, threonine, or tryptophan, or any combination thereof; the free amino acids or peptide combinations of amino acids comprise, consist essentially of, or consist of glutamine, glycine, alanine, serine, and isoleucine; the free amino acids or peptide combinations of amino acids comprise, consist essentially of, or consist of glutamine, glycine, alanine, serine, and arginine; the free amino acids or peptide combinations of amino acids comprise, consist essentially of, or consist of glutamine, glycine, alanine, serine, and threonine; the free amino acids or peptide combinations of amino acids comprise, consist essentially of, or consist of glutamine, glycine, alanine, serine, and threonine; the free amino acids or peptide combinations of amino acids the peptide combination of amino acids comprises, consists essentially of, or consists of glutamine, glycine, alanine, serine, and tryptophan; the free amino acids or peptide combination of amino acids comprises, consists essentially of, or consists of glutamine, glycine, alanine, serine, and isoleucine, and at least one additional amino acid arginine, or threonine, or tryptophan, or any combination thereof; the free amino acids or peptide combination of amino acids comprises, consists essentially of, or consists of glutamine, glycine, alanine, serine, isoleucine, and arginine; the free amino acids or peptide combination of amino acids comprises, consists essentially of, or consists of glutamine, glycine, alanine, serine, isoleucine, and threonine; the free amino acids or peptide combination of amino acids comprises, consists essentially of, or consists of glutamine, glycine, alanine, serine, isoleucine, and tryptophan;The free amino acids or peptide combinations of amino acids comprise, consist essentially of, or consist of glutamine, glycine, alanine, serine, isoleucine, arginine, and threonine; the free amino acids or peptide combinations of amino acids comprise, consist essentially of, or consist of glutamine, glycine, alanine, serine, isoleucine, arginine, and tryptophan; the free amino acids or peptide combinations of amino acids comprise, consist essentially of, or consist of glutamine, glycine, alanine, serine, isoleucine, arginine, threonine, and tryptophan; the free amino acids or peptide combinations of amino acids comprise, consist essentially of, or consist of glutamine, glycine, alanine, serine, isoleucine, arginine, threonine, and tryptophan; the free amino acids or peptide combinations of amino acids comprise, consist essentially of, or consist of glutamine, glycine, alanine, serine, isoleucine, arginine, threonine, and tryptophan the free amino acids or peptide combinations of amino acids comprise, consist essentially of, or consist of glutamine, glycine, alanine, serine, and arginine, and at least one additional amino acid isoleucine, arginine, or tryptophan, or any combination thereof; the free amino acids or peptide combinations of amino acids comprise, consist essentially of, or consist of glutamine, glycine, alanine, serine, and threonine, and at least one additional amino acid isoleucine, arginine, or tryptophan, or any combination thereof; or the free amino acids or peptide combinations of amino acids comprise, consist essentially of, or consist of glutamine, glycine, alanine, serine, and tryptophan, and at least one additional amino acid isoleucine, arginine, or threonine, or any combination thereof. Some aspects of the present disclosure are directed to such formulations administered topically or by injection (e.g., intradermally, subcutaneously, intramuscularly) for treating and / or preventing conditions associated with dry skin, atopic dermatitis, dermatitis, radiation dermatitis, psoriasis, pruritus, eczema, wounds, burns, or skin aging;

[0139] In one embodiment, the formulation optionally includes, for example, a pharmaceutically acceptable carrier, adjuvants, other active agents, and additives (e.g., sugars, electrolytes, vitamins, minerals, etc.) The formulation may further include, for example, a prebiotic or probiotic substance.

[0140] In some embodiments of the formulations described herein, the amino acid cysteine, if present, is present at a concentration of 1 mM or less; the amino acid histidine, if present, is present at a concentration of 0.5 mM or less; the amino acid tyrosine, if present, is present at a concentration of 1 mM or less; the amino acid leucine, if present, is present at a concentration of 4 mM or less; or the amino acid aspartic acid, if present, is present at a concentration of 2 mM or less; or any combination thereof. In some embodiments of the formulations, the formulation does not include the amino acids cysteine, histidine, tyrosine, leucine, aspartic acid, taurate, taurine, or glutamic acid, or any combination thereof.

[0141] Or, in certain embodiments, even if these amino acids are present in the formulation, they are not present in such an amount that they affect the skin barrier integrity. " Negligible " means that the specific amino acids present do not have any effect on the skin barrier integrity. " Negligible " means that the specific amino acids present do not have any effect on the skin barrier integrity-related disease or condition, for example, do not have any effect on wound healing, the treatment of skin conditions (for example, atopic dermatitis, psoriasis, or skin aging-related conditions) in the subject who needs it.

[0142] When present in the formulations described herein, the amino acid may be present at a concentration of, for example, about 0.5 mM, about 1 mM, about 2 mM, about 3 mM, about 4 mM, about 5 mM, about 6 mM, about 7 mM, about 8 mM, about 9 mM or about 10 mM.

[0143] In one embodiment, the total osmolality of the formulation is from about 10 mosm to about 280 mosm, from 50 mosm to about 280 mosm, from 100 mosm to about 280 mosm, or from about 150 to about 260 mosm.

[0144] In some embodiments, the formulation has a pH of, for example, about 2.5 to about 8.5. In some embodiments, the formulation has a pH of about 2.5 to about 6.5, about 2.5 to about 6.0, about 3.0 to about 6.0, about 3.5 to about 6.0, about 3.9 to about 6.0, about 4.2 to about 6.0, about 3.5 to about 5.5, about 3.9 to about 5.0, or about 4.2 to about 4.6. In some embodiments, the pH is about 4.0 to about 6.0 or about 4.5 to about 5.7.

[0145] In some embodiments, the formulation is administered systemically or locally. In some embodiments, the formulation is used to treat a disease or condition associated with skin barrier integrity, such as treating dry skin, wound healing, treating a skin condition (e.g., atopic dermatitis, dermatitis, psoriasis, skin aging, conditions associated with skin aging, pruritus, or eczema), and / or improving skin barrier integrity. Therapeutic formulations can be administered enterally, parenterally, topically, by inhalation, or any combination thereof. In certain embodiments, the formulation is for therapeutic, cosmetic, or nutritional purposes.

[0146] In some embodiments, the formulation is a solution. The formulation can be administered together with other therapeutic agents.

[0147] In some embodiments, the formulation is administered systemically or locally. Therapeutic formulations can be administered enterally, parenterally, topically, or by inhalation. In certain embodiments, the formulation is therapeutic, cosmetic, or nutritional.

[0148] In certain embodiments, the formulation may include a natural amino acid or a derivative thereof that retains substantially the same or better activity in improving skin barrier integrity. In certain embodiments, the formulation may include a natural amino acid or a derivative thereof that retains substantially the same or better activity in treating dry skin, wound healing, and / or treating a skin condition (e.g., atopic dermatitis, psoriasis, or a condition related to skin aging) in a subject in need thereof. The derivative may be, for example, an enantiomer, including both the D- and L-forms of an amino acid. The derivative may be, for example, iodotyrosine or norvaline. Other amino acid derivatives include, for example, norleucine, ornithine, penicillamine, pyroglutamine derivatives, or other alanine derivatives, asparagine, aspartic acid, cysteine, glutamic acid, glycine, isoleucine, leucine, lysine, methionine, proline, phenylalanine, serine, threonine, tryptophan, or valine. In certain embodiments, the amino acid derivative is at least one derivative of glutamine, glycine, alanine, serine, valine, isoleucine, arginine, threonine, or tryptophan, or any combination thereof. Other amino acid derivatives include, but are not limited to, those synthesized by acylation, methylation, and / or halogenation of amino acids. These include, for example, β-methyl amino acids, C-methyl amino acids, and N-methyl amino acids.

[0149] In certain embodiments, the formulation also includes additives (e.g., nutrients, electrolytes, vitamins, minerals, etc.). In certain embodiments, the formulation includes iron or zinc. In certain embodiments, the therapeutic formulation includes, for example, Na + ;K + ;HCO3-;CO3 2- ;Ca 2+ ;Mg 2+ ;Fe2;Cl - ;H2PO4 - , HPO4 2- , and PO4 3In an alternative embodiment, the formulation comprises one or more electrolytes selected from phosphate ions such as zinc, iodine, copper, iron, selenium, chromium, and molybdenum. - CO3 2- In another alternative embodiment, the formulation does not contain HCO3 - and CO3 2- at a total concentration of less than 5 mg / L or at a concentration lower than 5 mg / L. In certain embodiments, the formulation does not contain electrolytes. For example, in certain embodiments, the formulation contains Na + ;K + ;HCO3 - ;CO3 2- ;Ca 2+ ;Mg 2+ ;Fe2;Cl - ;H2PO4 - , HPO4 2- , and PO4 3- and the like; zinc; iodine; copper; iron; selenium; chromium; and molybdenum, or none of them.

[0150] In one embodiment, H2PO4-, HPO4 2- , and PO4 3- Phosphate ions such as HCl, ... - or CO3 2- In another embodiment, the therapeutic formulation contains HCO3 - or CO3 2- is not used as a buffer.

[0151] In some embodiments, the formulations and methods described herein are useful, for example, in cosmetic applications where rejuvenation of various layers of the skin and / or underlying tissues is desired, which rejuvenation can be facilitated, for example, by improving the barrier integrity of the skin.

[0152] In this embodiment, the disclosed methods generally include the step of topically applying a formulation to the skin (e.g., epidermis) of a patient in need of such treatment, wherein such formulation is applied in a therapeutically effective amount. In one embodiment, the formulation is applied to the face.

[0153] Advantageously, the present invention provides formulations and methods for combating skin aging, which may include, for example, treating the appearance of wrinkles, fine lines, and other forms of undesirable skin texture. By providing the formulations to the dermis and / or epidermis layer(s) of the skin, the skin's form, strength, and function are enhanced. In certain embodiments, the formulations and methods described herein are useful for aesthetic applications, for example, where rejuvenation of various layers of the skin and / or underlying tissues is desired.

[0154] In some embodiments, the formulations of the present disclosure include, in addition to amino acids, substances useful for delaying, minimizing, or eliminating skin aging, wrinkling, and / or other histological changes typically associated with intrinsic conditions (e.g., aging, menopause, etc.) and extrinsic conditions (e.g., environmental pollution (e.g., cigarette smoke), wind, heat, sunlight, radiation, low humidity, harsh surfactants, etc.).

[0155] The present invention is useful for therapeutically and / or prophylactically improving the visible and / or tactile characteristics of the skin, for example, in one embodiment, reducing the length, depth, and / or other size of lines and / or wrinkles.

[0156] In one embodiment, the formulation applied to the skin or other tissues can further comprise collagen, hyaluronic acid (HA), and / or ceramide. In one embodiment, the HA is cross-linked HA. The formulation can further comprise ingredients and / or additives such as, but not limited to, a dermatologically acceptable carrier, exfoliants, anti-acne agents, anti-wrinkle / anti-atrophy agents, vitamin B3 compounds, retinoids, hydroxyl acids, antioxidants / radical scavengers, chelating agents, flavonoids, anti-inflammatory agents, anti-cellulite agents, topical anesthetics, tanning agents, skin lightening agents, skin soothing and healing agents, antibacterial and antifungal agents, sunscreens, conditioning agents, structuring agents, thickening agents (including thickeners and gelling agents), formulation modifiers, and preservatives. In this regard, International PCT Application Publication No. WO 2008 / 089408 is incorporated herein by reference in its entirety.

[0157] In another aspect, the present disclosure provides methods of treating and / or preventing a skin condition (e.g., atopic dermatitis, radiation dermatitis, psoriasis, or a condition associated with skin aging) in a subject in need thereof, comprising administering to the subject a formulation described herein. In certain embodiments, the skin condition is atopic dermatitis, radiation dermatitis, psoriasis, skin aging, or a condition associated with skin aging. In some embodiments, the skin condition is pruritus (itching), psoriasis, eczema, burns, or dermatitis. In certain embodiments, the skin condition is psoriasis. In certain embodiments, the skin condition is pruritus.

[0158] The formulations of the present disclosure can also be administered at the site of surgery, such as the site of minimally invasive surgery, to improve healing and surgical outcomes.

[0159] Formulations for repairing and strengthening the skin barrier and uses thereof In some embodiments, the formulations or topical preparations of the present disclosure comprise a therapeutically effective amount of a formulation comprising (or consisting essentially of, or consisting of) at least one of alanine, glutamine, glycine, and serine (e.g., alanine; glutamine; glycine; serine; alanine and glutamine; alanine and glycine; alanine and serine; glutamine and glycine; glutamine and glycine and serine; alanine and glycine and serine; alanine and glycine and serine; alanine and glutamine and serine; and alanine and glutamine and glycine and serine), or salts thereof, as free amino acids (including amino acid blends) or peptide combinations of amino acids; a therapeutically effective amount of a plant extract, such as Boswellia extract (e.g., Boswellia serrata; Burseraceae family; olibanum; frankincense), or a therapeutically effective amount of a plant extract blend (e.g., BOSEXIL® (INDENA SpA) or Boswellia serrata resin extract, cellulose (microcrystalline), lecithin, silica) comprising (or consisting essentially of, or consisting of) a Boswellia extract (e.g., Boswellia serrata; Burseraceae family; olibanum; frankincense); a texturing agent and / or filler (e.g., cellulose (microcrystalline)); an emulsifier or phospholipid (in some embodiments, a phospholipid is used as an emulsifier) ​​(e.g., lecithin or phosphatidylcholine); and an anti-caking agent (e.g., silica, to adsorb water in hygroscopic applications); and, optionally, a dermatologically acceptable vehicle and / or additive. In additional embodiments of formulations or topical preparations comprising, consisting essentially of, or consisting of a therapeutically effective amount of an amino acid or amino acid blend (of free amino acids or peptide combinations of amino acids), the therapeutically effective amount of the amino acid or amino acid blend in such formulation is:Comprising, consisting essentially of, or consisting of alanine; glutamine; glycine; serine; alanine and glutamine; glycine and serine; alanine and glycine; alanine and serine; glutamine and glycine; glutamine and serine; alanine, glutamine, and glycine; glutamine, glycine, and serine; alanine, glutamine, and serine; alanine, glycine, and serine; or alanine, glutamine, glycine, and serine, or salts thereof. In further embodiments of the formulations described herein, the mean fold increase in expression of the barrier marker gene EGR is 1.5 or more (e.g., 1.7, 1.9, 2.1, 2.3, 2.5, 2.7, 2.9, 3.1, 3.3, 3.5, 3.7, 3.9, 4.1, 4.3, 4.5, 4.7, 4.9, 5.1, 5.3, 5.5, 5.7, 5.9, 6.1, 6.3, 6.5, 6.7, 6.9, 7.1, 7.3, 7.5, 7.7, 7.9, 8.1, 8.3, 8.5, 8.6, 8.7, 8.8, 8.9, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.9, 10.1, 10.2, 10.3, 10.4, 10.5, 10.6, 10.7, 10.8, 10.9, 11.1, 11.2, 11.3, 11.4, 11.5, 11.6, 11.7, 11.8, 11.9, 12.1, 12.3, 12.5, 12.7, 12.9, 13.1, 13.3, 13.5, 13.7, 13.9, 14.1, 14.3, 14.5, 14.7, 14.9, 15.1, 15.3, 15.5, 15.7, 15.9, 16.1, 16. , 8.7, 8.9, 9.1, 9.3, 9.5, 9.7, 9.9, 10.1, 10.3, 10.5, 10.7, 10.9, 11.1, 11.3, 11.5, 11.7, 11.9, 12.1, 12.3, 12.5, 12.7, 12.9, 13.1, 13.3, 13.5, 13.7, 13.9, 14.1, 14.3, 14.5, 14.7, 14.9, 15.1, 15.3, 15.5, 15.7, 15.9, 16.1, 16.3, 16.5, 16.6, 16.7, 16.8, 16.9, 16.1, 16.2, 16.3, 16.4 ...9, 16.1, 16.3, 16.5, 16.9, 16.1, 16.4, 16.6, 16.7, 16.9, 16.1, 16.2, 16.3, 16.4, 16.5, 16.6, 16.7, 16.8, 16.9, 16.1, 16.2, 16.3, 16.4, 16.5, 16.9, 16.1, 16.3, 16.5, .7, 16.9, 17.1, 17.3, 17.5, 17.7, 17.9, 18.1, 18.3, 18.5, 18.7, 18.9, 19.1, 19.3, 19.5, 19.7, 19.9, 20.1, 20.3, 20.5, 20.7, 20.9, 21.1, 21.3, 21.5, 21.7, 21.9, 22.1, 22.3, 22.5, 22.7, 22.9, 23.1, 23.3, 23.5, 23.7, 23.9, 23.1, 23.3, 23. 5, 23.7, 23.9, 24.1, 24.3, 24.5, 24.7, 24.9, 25.1, 25.3, 25.5, 25.7, 25.9, 26.1, 26.3, 26.5, 26.7, 26.9, 27.1, 27.3, 27.5, 27.7, 27.9, 28.1, 28.3, 28.5, 28.7, 28.9, 29.1, 29.3, 29.5, 29.7, 29.9, 30.1, 30.3, 30.5, 30.7, 30.9, 31.1, 31.3,31.5, 31.7, 31.9, 32.1, 32.3, 32.5, 32.7, 32.9, 33.1, 33.3, 33.5, 33.7, 33.9, 34.1, 34.3, 34.5, 34.7, 34.9, 35.1, 35.3, 35.5, 35.7, 35.9, 36.1, 36.3, 36.5, 36.7, 36.9, 37.1, 37.3, 37.5, 37.7, 37.9, 38.1, 38.3, 38.5, 38.7, 38.9, 39.1, 39.3, 39.5, 39.7, 39.9, 40.1, 40.3, 40.5, 40.7, 40.9, 41.1, 41.3, 41.5); 40 or less (e.g., 39.8, 39.6, 39.4, 39.2, 39, 38.8, 38.6, 38.4, 38.2, 38, 37.8, 37.6, 37.4, 37.2, 37, 36.8, 36.6, 36.4, 36.2, 36, 35.8, 35.6, 35.4, 35. 2, 35, 34.8, 34.6, 34.4, 34.2, 34, 33.8, 33.6, 33.4, 33.2, 33, 32.8, 32.6, 32.4, 32.2, 32, 31.8, 31.6, 31.4, 31.2, 31, 30.8, 30.6, 30.4, 30.2, 30, 29.8, 29.6, 29.4, 29.2, 29, 28.8, 28.6, 28.4, 28.2, 28, 27.8, 27.6, 27.4, 27.2, 27, 26.8, 26.6, 26.4, 26.2, 26, 25.8, 25.6, 25.4, 25.2, 25, 24.8, 24.6, 24.4, 24.2, 24, 23.8, 23.6, 23.4, 23.2, 23, 22.8, 22.6, 22.4, 22.2, 22, 21.8, 21.6, 21.4, 21.2, 21, 20.8, 20.6, 20.4, 20.2, 20, 19.8, 19.6, 19.4, 19.2, 19, 18 .8, 18.6, 18.4, 18.2, 18, 17.8, 17.6, 17.4, 17.2, 17.2, 17, 16.8, 16.6, 16.4, 16.2, 16, 15.8, 15.6, 15.4, 15.2, 15, 14.8, 14.6, 14.4, 14.2, 14, 13.8, 13 .6, 13.4, 13.2, 13, 12.8, 12.6, 12.4, 12.2, 12, 11.8, 11.6, 11.4, 11.2, 11, 10.8, 10.6, 10.4, 10.2, 10, 9.8, 9.6, 9.4, 9.2, 9, 8.8, 8.6, 8.4, 8.2, 8, 7.8,7.6, 7.4, 7.2, 7, 6.8, 6.6, 6.4, 6.2, 6, 5.8, 5.6, 5.4, 5.2, 5, 4.8, 4.6, 4.4, 4.2, 4, 3.8, 3.6, 3.4, 3.2, 3, 2.8, 2.6, 2.4, 2.2, 2, 1.8, 1.6, 1.4, 1.2, 1, 0.8, 0.6); or 1.5 to 40 (e.g., 1.6 to 39.9, 1.7 to 39.8, 1.8 to 39.7, 1.9 to 39.6, 2 to 39.5, 2.1 to 39.4, 2.2 to 39.3, 2.3 to 39.2, 2.4 to 39.1, 2.5 to 39, 2.6 to 38.9, 2.7 to 38.8) , 2.8~38.7, 2.9~38.6, 3~38.5, 3.1~38.4, 3.2~38.3, 3.3~38.2, 3.4~38.1, 3.5~38, 3.6~37.9, 3.7~37.8, 3.8~37.7, 3.9~37.6, 4~37.5, 4.1~37.4, 4.2 ~37.3, 4.3~37.2, 4.4~37.1, 4.5~37, 4.6~36.9, 4.7~36.8, 4.8~36.7, 4.9~36.6, 5~36.5, 5.1~36.4, 5.2~36.3, 5.3~36.2, 5.4~36.1, 5.5~36, 5.6~35. 9, 5.7~35.8, 5.8~35.7, 5.9~35.6, 6~35.5, 6.1~35.4, 6.2~35.3, 6.3~35.2, 6.4~35.1, 6.5~35, 6.6~34.9, 6.7~34.8, 6.8~34.7, 6.9~34.6, 7~34.5, 7. 1~34.4, 7.2~34.3, 7.3~34.2, 7.4~34.1, 7.5~34, 7.6~33.9, 7.7~33.8, 7.8~33.7, 7.9~33.6, 8~33.5, 8.1~33.4, 8.2~33.3, 8.3~33.2, 8.4~33.1, 8.5~ 33, 8.6~32.9, 8.7~32.8, 8.8~32.7, 8.9~32.6, 9~32.5, 9.1~32.4, 9.2~32.3, 9.3~32.2, 9.4~32.1, 9.5~32, 9.6~31.9, 9.7~31.8, 9.8~31.7, 9.9~31.6 , 10~31.5, 10.1~31.4, 10.2~31.3, 10.3~31.2, 10.4~31.1, 10.5~31, 10.6~30.9, 10.7~30.8, 10.8~30.7, 10.9~30.6, 11~30.5, 11.1~30.4, 11.2~30.3,11.3~30.2, 11.4~30.1, 11.5~30, 11.6~29.9, 11.7~29.8, 11.8~29.7, 11.9~29.6, 12~29.5, 12.1~29.4, 12.2~29.3, 12.3~29.2, 12.4~29.1, 12.5~29, 1 2.6~28.9, 12.7~28.8, 12.8~28.7, 12.9~28.6, 13~28.5, 13.1~28.4, 13.2~28.3, 13.3~28.2, 13.4~28.1, 13.5~28, 13.6~27.9, 13.7~27.8, 13.8~27.7, 13.9~27.6, 14~27.5, 14.1~27.4, 14.2~27.3, 14.3~27.2, 14.4~27.1, 14.5~27, 14.6~26.9, 14.7~26.8, 14.8~26.7, 14.9~26.6, 15~26.5, 15.1~26.4, 1 5.2~26.3, 15.3~26.2, 15.4~26.1, 15.5~26, 15.6~25.9, 15.7~25.8, 15.8~25.7, 15.9~25.6, 16~25.5, 16.1~25.4, 16.2~25.3, 16.3~25.2, 16.4~25.1, 16.5~25, 16.6~24.9, 16.7~24.8, 16.8~24.7, 16.9~24.6, 17~24.5, 17.1~24.4, 17.2~24.3, 17.3~24.2, 17.4~24.1, 17.5~24, 17.6~23.9, 17.7~23.8, 1 7.8~23.7, 17.9~23.6, 18~23.5, 18.1~23.4, 18.2~23.3, 18.3~23.2, 18.4~23.1, 18.5~23, 18.6~22.9, 18.7~22.8, 18.8~22.7, 18.9~22.6, 19~22.5, 19 Skin barrier repair (e.g., skin barrier repair, skin barrier strengthening, skin barrier preservation, wound healing; epidermal cells, keratinocytes, endothelial cells, and fibroblasts), as indicated by:The present invention provides a therapeutically effective amount of an amino acid or amino acid blend and / or a therapeutically effective amount of a plant extract (e.g., Boswellia extract) sufficient to improve the growth, stimulation, proliferation, differentiation, and migration of the dermis (e.g., promoting dermal regeneration). See, e.g., Figures 8-14.

[0160] In other embodiments, a formulation or topical preparation is provided, comprising a therapeutically effective amount of a formulation comprising (or consisting essentially of, or consisting of) alanine, glutamine, glycine, and serine, or salts thereof, as free amino acids or peptide combinations of amino acids; a therapeutically effective amount of a plant extract (e.g., Boswellia extract (e.g., Boswellia serrata; Burseraceae family; Olibanum; Frankincense) or a plant extract blend (e.g., BOSEXIL® (INDENA SpA) or Boswellia serrata resin extract, cellulose (microcrystalline), lecithin, silica), comprising a Boswellia extract (e.g., Boswellia serrata; Burseraceae family; olibanum; frankincense); texturing agents and / or fillers (e.g., cellulose (microcrystalline)); emulsifiers or phospholipids (in some embodiments, phospholipids are used as emulsifiers) (e.g., lecithin or phosphatidylcholine); and anti-caking agents (e.g., silica, which adsorbs water in hygroscopic applications); and optionally, comprising (or consisting essentially of, or consisting of) a plant extract or plant extract blend, comprising (or consisting essentially of, or consisting of) a dermatologically acceptable vehicle and / or additive.

[0161] In additional embodiments, the formulation or topical preparation for administration to the skin of a subject comprises a therapeutically effective amount of a blend of free amino acids or peptide combinations thereof comprising (or consisting essentially of, or consisting of) alanine, glutamine, glycine, and serine, or salts thereof; a therapeutically effective amount of a plant extract (e.g., Boswellia extract (e.g., Boswellia serrata; Burseraceae family; Olibanum; Frankincense) or a plant extract blend (e.g., BOSEXIL™ or Boswellia serrata resin extract, cellulose (microcrystalline), lecithin, silica), wherein the Boswellia extract (e.g., Boswellia serrata; Burseraceae family; olibanum; frankincense); texturing agents and / or fillers (e.g., cellulose (microcrystalline); emulsifiers or phospholipids (in some embodiments, phospholipids are used as emulsifiers) (e.g., lecithin or phosphatidylcholine, soy lecithin); and anti-caking agents (e.g., silica, to adsorb water in hygroscopic applications); and optionally, a plant extract or plant extract blend, comprising (consisting essentially of, or consisting of) a dermatologically acceptable vehicle and / or additive. wherein a therapeutically effective amount of a blend of free amino acids or peptide combinations thereof and a therapeutically effective amount of a plant extract or plant extract blend improves skin barrier repair (e.g., skin barrier repair, skin barrier strengthening, skin barrier preservation, wound healing; growth, stimulation, proliferation, differentiation, and migration of epidermal cells, keratinocytes, endothelial cells, and fibroblasts; promotion of dermal regeneration), and the formulation or topical preparation detects expression of a barrier marker gene, EGF, to determine whether the barrier marker gene is 1 or higher in amino acid-treated skin compared to amino acid-untreated skin.Improves skin barrier repair (e.g., skin barrier correction, skin barrier strengthening, skin barrier preservation, wound healing; growth, stimulation, proliferation, differentiation, and migration of epidermal cells, keratinocytes, endothelial cells, and fibroblasts; promotion of dermal regeneration) when tested by a method determining an increase in mean fold change of 5 to 40 (see, e.g., Figures 8 to 14). Without being bound by theory, formulations or topical formulations comprising the free amino acids and / or peptide combinations of amino acids described herein not only increase the expression of barrier marker genes, e.g., EGF, but also increase the synthesis of such barrier marker genes, e.g., EGF, which is a precursor of downstream responses for proliferation, which may be specific for EGF and diseases or conditions such as, but not limited to, those requiring improvement of skin barrier repair (e.g., skin barrier correction, skin barrier strengthening, skin barrier preservation, wound healing; growth, stimulation, proliferation, differentiation, and migration of epidermal cells, keratinocytes, endothelial cells, and fibroblasts; promotion of dermal regeneration); ichthyosis, psoriasis, dermatitis, atopic dermatitis, radiation dermatitis, etc. Skin barrier disorders can be caused by genetic factors, aging, environmental factors (e.g., solar radiation (e.g., ultraviolet radiation, visible light, infrared radiation); air pollution; chemical pollutants (e.g., detergents, cosmetics, alcohol-containing skin products, synthetic fragrances); smoking); excessive use of acids or abrasives; and health factors (e.g., poor nutrition; poor sleep; stress; dehydration).

[0162] In additional embodiments, the formulations or topical preparations described herein comprise a therapeutically effective amount of a free amino acid or a peptide combination of amino acids; a plant extract (e.g., a Boswellia extract (e.g., Boswellia serrata; Burseraceae family; Olibanum; Frankincense) or a plant extract blend (e.g., BOSEXIL® (INDENA SpA) or Boswellia serrata resin extract, cellulose (microcrystalline), lecithin, silica), comprising a Boswellia extract (e.g., Boswellia serrata; Burseraceae; Olibanum; Frankincense); or retinoids (e.g., retinyl esters (e.g., retinyl palmitate, retinyl oleate, retinyl stearate, retinyl linoleate, retinyl palmitoleate); retinol or vitamin A; retinaldehyde or retinal; retinoic acid; or combinations thereof); optionally, texturing agents and / or fillers (e.g., cellulose (microcrystalline)); emulsifiers or phospholipids (in some embodiments, phospholipids are used as emulsifiers) (e.g., lecithin or phosphatidylcholine); and anti-caking agents (e.g., silica, to adsorb water in hygroscopic applications); and optionally, comprising (or consisting essentially of, or consisting of) dermatologically acceptable carriers and / or additives. , 0.011, 0.013, 0.015, 0.017, 0.019, 0.021, 0.023, 0.025, 0.027, 0.029, 0.031, 0.033, 0.035, 0.037, 0.039, 0.041, 0.043, 0.045, 0.046, 0.047, 0.048, 0.049, 0.050, 0.051, 0.052, 0.053, 0.054, 0.055, 0.056, 0.057, 0.058, 0.059, 0.060, 0.061, 0.062, 0.063, 0.064, 0.065, 0.066, 0.067, 0.068, 0.069, 0.070, 0.071, 0.072, 0.073, 0.074, 0.075, 0.076, 0.077, 0.078, 0.079, 0.080, 0.081, 0.082, 0.083, 0.084, 0.085, 0.086, 0.087, 0.088, 0.089, 0.090, 0.091, 0.092, 0.093, 0.094, 0.095, 0.096, 0.097, 0.098, 0.099, 1000 7, 0.049, 0.051, 0.053, 0.055, 0.057, 0.059, 0.061, 0.063, 0.065, 0.067, 0.069, 0.071, 0.073, 0.075, 0.077, 0.079, 0.081, 0.083, 0.085, 0.087, 0.089, 0.091, 0.093, 0.095, 0.097, 0.099, 0.1, 0.15, 0.3, 0.35, 0.5, 0.55, 0.7, 0.75, 0.9, 0.95, 1.1, 1.3, 1.5, 1.7, 1.9, 2.1, 2.3, 2.5, 2.7, 2.9, 3.1, 3.3, 3.5, 3.7, 3.9, 4.1, 4.3, 4.5, 4.7, 4.9, 5.1, 5.3); 5 w / w% or less (e.g., 4.8, 4.6, 4.4, 4.2, 4, 3.8, 3.6, 3.4, 3.2, 3, 2.8, 2.6, 2.4, 2.2, 2, 1.8, 1.6, 1.4, 1.2, 1, 0.85, 0.8, 0.65, 0.6, 0.45, 0.4, 0.25, 0.2, 0.098, 0.096, 0.094, 0.092, 0 .09, 0.088, 0.086, 0.084, 0.082, 0.08, 0.078, 0.076, 0.074, 0.072, 0.07, 0.068, 0.066, 0.064, 0.062, 0.06, 0.058, 0.056, 0.054, 0.052, 0.05, 0.048 ,0.046,0.044,0.042,0.04,0.038,0.036,0.034,0.032,0.03,0.028,0.026,0.024,0.022,0.02,0.018,0.016,0.014,0.012,0.01,0.008,0.006,0. 004); or 0.01 w / w% to 5 w / w% (e.g., 0.011 w / w% to 4.9 w / w%, 0.012 w / w% to 4.8 w / w%, 0.013 w / w% to 4.7 w / w%, 0.014 w / w% to 4.6 w / w%, 0.015 w / w% to 4.5 w / w%, 0.016 w / w %~4.4w / w%, 0.017w / w%~4.3w / w%, 0.018w / w%~4.2w / w%, 0.019w / w%~4.1w / w %, 0.02w / w%~4w / w%, 0.021w / w%~3.9w / w%, 0.022w / w%~3.8w / w%, 0.023w / w%~ 3.7w / w%, 0.024w / w%~3.6w / w%, 0.025w / w%~3.5w / w%, 0.026w / w%~3.4w / w%, 0.027w / w%~3.3w / w%, 0.028w / w%~3.2w / w%, 0.029w / w%~3.1w / w%, 0.03w / w%~ 3w / w%, 0.031w / w%~2.9w / w%, 0.032w / w%~2.8w / w%, 0.033w / w%~2.7w / w%, 0.0 34w / w%~2.6w / w%, 0.035w / w%~2.5w / w%, 0.036w / w%~2.4w / w%, 0.037w / w%~2.3w / w%, 0.038w / w%~2.2w / w%, 0.039w / w%~2.1w / w%, 0.04w / w%~2w / w%, 0.041w / w%~1.9w / w%, 0.042w / w%~1.8w / w%, 0.043w / w%~1.7w / w%, 0.044w / w%~1.6 w / w%、0.045w / w%~1.5w / w%、0.046w / w%~1.4w / w%、0.047w / w%~1.3w / w%、0.0 48w / w%~1.2w / w%、0.049w / w%~1.1w / w%、0.05w / w%~1w / w%、0.051w / w%~0.99w / w%、0.052w / w%~0.98w / w%、0.053w / w%~0.97w / w%、0.054w / w%~0.96w / w%、0.055w / w%~0.95w / w%、0.056w / w%~0.94w / w%、0.057w / w%~0.93w / w%、0.058w / w%~0.92w / w%、0.059w / w%~0.91w / w%、0.06w / w%~0.9w / w%、0.061w / w%~0.89 w / w%、0.062w / w%~0.88w / w%、0.063w / w%~0.87w / w%、0.064w / w%~0.86w / w%、0 0.065w / w%~0.85w / w%、0.066w / w%~0.84w / w%、0.067w / w%~0.83w / w%、0.068w / w%~0.82w / w%、0.069w / w%~0.81w / w%、0.07w / w%~0.8w / w%、0.071w / w%~0.7 9w / w%、0.072w / w%~0.78w / w%、0.073w / w%~0.77w / w%、0.074w / w%~0.76w / w% 、0.075w / w%~0.75w / w%、0.076w / w%~0.74w / w%、0.077w / w%~0.73w / w%、0.078 w / w%~0.72w / w%、0.079w / w%~0.71w / w%、0.08w / w%~0.7w / w%、0.081w / w%~0. 69w / w%、0.082w / w%~0.68w / w%、0.083w / w%~0.67w / w%、0.084w / w%~0.66w / w% 、0.085w / w%~0.65w / w%、0.086w / w%~0.64w / w%、0.087w / w%~0.63w / w%、0.08 8w / w%~0.62w / w%、0.089w / w%~0.61w / w%、0.09w / w%~0.6w / w%、0.091w / w%~0.59w / w%、0.092w / w%~0.58w / w%、0.093w / w%~0.57w / w%、0.094w / w%~0.56w / w%、0.095w / w%~0.55w / w%、0.096w / w%~0.54w / w%、0.097w / w%~0.53w / w%、0.098w / w%~0.52w / w%、0.099w / w%~0.51w / w%、0.1w / w%~0.5w / w%、0.101w / w%~0.49w / w%、0.102w / w%~0.48w / w%、0.103w / w%~0.47w / w%、0.104w / w%~0.46w / w%、0.105w / w%~0.45w / w%、0.106w / w%~0.44w / w%、0.107w / w%~0.43w / w%、0.108w / w%~0.42w / w%、0.109w / w%~0.41w / w%、0.110w / w%~0.4w / w%、0.111w / w%~0.39w / w%、0.112w / w%~0.38w / w%、0.113w / w%~0.37w / w%、0.114w / w%~0.36w / w%、0.115w / w%~0.35w / w%、0.116w / w%~0.34w / w%、0.117w / w%~0.33w / w%、0.118w / w%~0.32w / w%、0.119w / w%~0.31w / w%、0.120w / w%~0.3w / w%、0.121w / w%~0.29w / w%、0.122w / w%~0.28w / w%、0.123w / w%~0.27w / w%、0.124w / w%~0.26w / w%、0.125w / w%~0.25w / w%、0.126w / w%~0.24w / w%、0.127w / w%~0.23w / w%、0.128w / w%~0.22w / w%、0.129w / w%~0.21w / w%、0.130w / w%~0.2w / w%、0.0131w / w%~0.19w / w%、0.132w / w%~0.18w / w%、0.133w / w%~0.17w / w%、0.134w / w%~0.16w / w%、0.135w / w%~0.15w / w%、0.136w / w%~0.14w / w%、0.137w / w%~0.The plant extract is present in a weight percent (w / w%) of 139%. In some embodiments, the plant extract comprises, consists essentially of, or consists of Boswellia extract, including Boswellia serrata, Burseraceae, olibanum, or frankincense. Other embodiments are directed to plant extract formulations comprising, consisting essentially of, or consisting of Boswellia extract (e.g., Boswellia serrata; Burseraceae; olibanum; frankincense); texturing agents and / or fillers (e.g., cellulose (microcrystalline); phospholipids (e.g., lecithin or phosphatidylcholine); and anti-caking agents (e.g., silica, which adsorbs water in hygroscopic applications). In additional embodiments, the plant extract formulation comprises, consists essentially of, or consists of Boswellia serrata resin extract, cellulose (microcrystalline), lecithin, and silica.

[0163] In further embodiments, there is provided a formulation or topical preparation as described herein, wherein a therapeutically effective amount of a combination of free amino acids or peptide combinations thereof and a therapeutically effective amount of a plant extract or plant extract combination inhibits 5-lipoxygenase (an inflammation-inducing enzyme); reduces calcium ion mobilization; and reduces MAP kinase activation. Without wishing to be bound by theory, a plant extract or plant extract combination containing Boswellia extract may have anti-inflammatory properties, which, for example, may reduce inflammation induced by 5-lipoxygenase. See, e.g., D. Poeckel and O. Werz (e.g., Curr Med Chem. 13(28):3359-3369, 2006; Singh et al. Phytomedicine. 15(6-7):400-407, 2008).

[0164] In some embodiments, the formulation or topical preparation comprises a therapeutically effective amount of a combination comprising (or consisting essentially of, or consisting of) alanine, glutamine, glycine, and serine as free amino acids or peptide combinations of amino acids; a therapeutically effective amount of a plant extract comprising (or consisting essentially of, or consisting of) Boswellia extract (e.g., Boswellia serrata; Burseraceae family; olibanum; frankincense); and optionally, a dermatologically acceptable vehicle and / or additive, such as, but not limited to, lecithin, microcrystalline cellulose, and silica.

[0165] In some embodiments, the formulations or topical formulations of the present disclosure comprise a therapeutically effective amount of a combination of at least one of alanine, glutamine, glycine, and serine (e.g., alanine; glutamine; glycine; serine; alanine and glutamine; alanine and glycine; alanine and serine; glutamine and glycine; glutamine and serine; glutamine and glycine and serine; alanine and glycine and serine; alanine and glycine and serine; alanine and glutamine and serine; and alanine and glutamine and a therapeutically effective amount of a plant extract or plant extract blend; a texturing agent and / or filler (e.g., cellulose (microcrystalline)); a phospholipid (in some embodiments, a phospholipid is used as an emulsifier) ​​(e.g., lecithin or phosphatidylcholine); and an anti-caking agent (e.g., silica, to adsorb water in hygroscopic applications); and, optionally, a dermatologically acceptable vehicle and / or additive.Non-limiting examples of at least one phospholipid useful in the formulations of the present disclosure include any phospholipid containing two fatty acids per phosphate backbone, including phosphatidic acid (phosphatidate) (PA); phosphatidylethanolamine (cephalin) (PE); phosphatidylcholine (lecithin) (PC); phosphatidylserine (PS); phosphatidylinositol (PI); phosphatidylinositol phosphate (PIP); phosphatidylinositol diphosphate (PIP2); and phosphatidylinositol triphosphate (PIP3); ceramides containing a phosphate group; ceramide phosphorylcholine (sphingomyelin) (SPH); ceramide phosphorylethanolamine (sphingomelin) (Cer-PE); phospholipids containing saturated fatty acids (e.g., butyric acid, lauric acid, myristic acid, palmitic acid, stearic acid, Acids); unsaturated fatty acids (e.g., myristoleic acid (cis-9-tetradecenoic acid); sapienic acid (cis-6-hexadecenoic acid); palmitoleic acid (cis-9-hexadecenoic acid); oleic acid (cis-9-octadecenoic acid); petroselinic acid (cis-octadec-6-enoic acid); cis-vaccenic acid (cis-11-octadecenoic acid); vaccenic acid (trans-11-octadecenoic acid); elaidic acid (trans-9-octadecenoic acid) phospholipids comprising a fatty acid selected from the group consisting of: linoleic acid; linolenic acid; paulic acid (cis-13-eicosenoic acid); gadoleic acid (cis-9-eicosenoic acid); gondoic acid (cis-11-eicosenoic acid); erucic acid (cis-15-docosenoic acid); brassidic acid (trans-15-docosenoic acid); nervonic acid (cis-15-tetracosenoic acid); arachidonic acid; and combinations thereof.

[0166] In other embodiments, a formulation or topical formulation is provided that comprises (or consists essentially of, or consists of) a therapeutically effective amount of a formulation comprising, as free amino acids or peptide combinations of amino acids, at least one of alanine, glutamine, glycine, and serine (e.g., alanine; glutamine; glycine; serine; alanine and glutamine; alanine and glycine; alanine and serine; glutamine and glycine; glutamine and serine; glutamine and glycine and serine; alanine and glycine and serine; alanine and glycine and serine; alanine and glutamine and serine; and alanine and glutamine and glycine and serine); and (a) a therapeutically effective amount of a plant extract or plant extract formulation, comprising Boswellia extract (e.g., Boswellia serrata; Burseraceae family; olibanum; frankincense), alone or in combination with at least one of a texturing agent and / or filler (e.g., cellulose (microcrystalline); phospholipids (e.g., lecithin); and an anti-caking agent (e.g., silica, which adsorbs water in hygroscopic applications), or (b) a plant extract or plant extract blend comprising (or consisting essentially of, or consisting of) a therapeutically effective amount of a retinoid (e.g., retinyl esters (e.g., retinyl palmitate, retinyl oleate, retinyl stearate, retinyl linoleate, retinyl palmitoleate); retinol or vitamin A; retinaldehyde or retinal; retinoic acid;or a combination thereof), wherein the free amino acid or peptide combination of amino acids and (a) a plant extract or plant extract blend, or (b) a retinoid are present in a ratio of 1:100 or more (e.g., 2:100, 4:100, 6:100, 8:100, 10:100, 12:100, 14:100, 16:100, 18:100, 20:100, 22:100, 24:100, 26:100, 28:100, 30:100, 31:100, 32:100, 33:100, 34:100, 35:100, 36:100, 37:100, 38:100, 39:100, 40:100, 41:100, 42:100, 43:100, 44:100, 45:100, 46:100, 47:100, 48:100, 49:100, 50:100, 51:100, 52:100, 53:100, 54:100, 55:100, 56:100, 57:100, 58:100, 59:100, 60:100, 61:100, 62:100, 63:100, 64:100, 65:100, 66:100, 67:100, 68:100, 69:100, 70:100, 71:100, 72:100, 73 100, 30:100, 32:100, 34:100, 36:100, 38:100, 40:100, 42:100, 44:100, 46:100, 48:100, 50:100, 52:100, 54:100, 56:100, 58:100, 60:100, 62:100, 64:100, 66:100, 68:100, 70:100, 72:100, 74:100, 76:100, 78:100, 80:100, 82:100, 84:100, 86:10 0, 88:100, 90:100, 92:100, 94:100, 96:100, 98:100, 100:100); 100:1 or less (e.g., 99:100, 97:100, 95:100, 93:100, 91:100, 89:100, 87:100, 85:100, 83:100, 81:100, 79:100, 77:100, 75:100, 73:100, 71:100, 69:100, 67:100, 65:100, 63:100, 61:100, 59:100, 57:100, 55:100, 53:100, 51:100, 49:100, 47:100, 45:100, 43:100, 41:100, 39:100, 37:100, 35:100, 33:100, 31:100, 29:100, 27:100, 25:100, 23:100, 21:100, 19:100, 17:100, 15:100, 13:100, 11:100, 9:100, 7:100, 5:100, 3:100, 1:100);1:100-100:1 (e.g., 1:99-99:1, 1:98-98:1, 1:97-97:1, 1:96-96:1, 1:95-95:1, 1:94-94:1, 1:93-93:1, 1:92-92:1, 1:91-91:1, 1:90-90:1, 1:89-89 :1, 1:88~88:1, 1:87~87:1, 1:86~86:1, 1:85~85:1, 1:84~84:1, 1:83~83:1, 1:82~82:1, 1:81~81:1, 1:80~80:1, 1:79~79:1, 1:78~78:1, 1:77~77:1, 1 :76~76:1, 1:75~75:1, 1:74~74:1, 1:73~73:1, 1:72~72:1, 1:71~71:1, 1:70~70:1, 1:69~69:1, 1:68~68:1, 1:67~67:1, 1:66~66:1, 1:65~65:1, 1:64 ~64:1, 1:63~63:1, 1:62~62:1, 1:61~61:1, 1:60~60:1, 1:59~59:1, 1:58~58:1, 1:57~57:1, 1:56~56:1, 1:55~55:1, 1:54~54:1, 1:53~53:1, 1:52~52: 1, 1:51~51:1, 1:50~50:1, 1:49~49:1, 1:48~48:1, 1:47~47:1, 1:46~46:1, 1:45~45:1, 1:44~44:1, 1:43~43:1, 1:42~42:1, 1:41~41:1, 1:40~40:1, 1 :39~39:1, 1:38~38:1, 1:37~37:1, 1:36~36:1, 1:35~35:1, 1:34~34:1, 1:33~33:1, 1:32~32:1, 1:31~31:1, 1:30~30:1, 1:29~29:1, 1:28~28:1, 1:27~ It is present in the following ratios: 1:27:1, 1:26-26:1, 1:25-25:1, 1:24-24:1, 1:23-23:1, 1:22-22:1, 1:21-21:1, 1:20-20:1, 1:19-19:1, 1:18-18:1, 1:17-17:1, 1:16-16:1, 1:15-15:1, 1:14-14:1, 1:13-13:1, 1:12-12:1, 1:11-11:1, 1:10-10:1, 1:9-9:1, 1:8-8:1, 1:7-7:1, 1:6-6:1, 1:5-5:1, 1:4-4:1, 1:3-3:1, 1:2-2:1). ;

[0167] In additional embodiments, the formulations or topical preparations described herein comprise (a) a therapeutically effective amount of a blend of free amino acids or peptide combinations thereof, comprising, consisting essentially of, at least one of alanine, glutamine, glycine, and serine (e.g., alanine; glutamine; glycine; serine; alanine and glutamine; alanine and glycine; alanine and serine; glutamine and glycine; glutamine and serine; glutamine and glycine and serine; alanine and glycine and serine; alanine and glycine and serine; alanine and glutamine and serine; and alanine and glutamine and glycine and serine); (b) a therapeutically effective amount of a plant extract or plant extract blend, comprising a Boswellia extract (e.g., Boswellia serrata; Burseraceae; olibanum; frankincense); and optionally (c) a dermatologically acceptable vehicle and / or additives.The mixture of (a), (b), and optionally (c) is heated to a temperature sufficient to thoroughly mix, homogenize, or emulsify (a), (b), and optionally (c), and is not less than 20°C (e.g., 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 42, 44, 46, 48, 50, 52, 54, 56, 58, 60, 62, 64, 66, 68, 70, 72, 74, 76, 78, 80, 82, 84, 86, 88, 90, 92, 94, 96, 98, 100, 102, 104, 106, 108, 110); not more than 100°C (e.g., 99, 97, 95, 93, 91, 89, 87, 85, 83, 81, 79, 77, 75, 73, 71, 69, 67, 65, 63, 61, 59, 57, 55, 53, 51, 49, 47, 45, 43, 41, 39, 37, 35, 33, 31, 29, 27, 25, 23, 21, 19, 17); or 20°C to 100°C (e.g., 21°C to 99°C, 22°C to 98°C, 23°C to 97°C, 24°C to 96°C, 25°C to 95°C, 26°C to 94°C, 27°C to 93°C, 28°C to 92°C, 29°C to 91°C, 30°C to 90°C, 31°C to 89°C, 32°C to 88°C, 33°C to 99°C, 34°C to 99°C, 35°C to 99°C, 36°C to 99°C, 37°C to 99°C, 38°C to 99°C, 39°C to 99°C, 40°C to 40°C, 41°C to 41°C, 42°C to 42°C, 43°C to 43°C, 44°C to 44°C, 45°C to 45°C, 46°C to 46°C, 47°C to 47°C, 48° ℃~87℃, 34℃~86℃, 35℃~85℃, 36℃~84℃, 37℃~83℃, 38℃~82℃, 39℃~81℃, 40℃~80℃, 41℃~79℃, 42℃~78℃, 43℃~77℃, 44℃~76℃, 45℃~75℃, 46℃~74℃, 47℃~73℃, 48℃~72℃, 49℃~71℃, 50℃~70℃, 51℃~69℃, 52℃~68℃, 53℃~67℃, 54℃~66℃, 55℃~65℃, 56℃~64℃, 57℃~63℃, 58℃~62℃, 59℃~61℃. The plant extracts can be heated (together or separately) for a time (e.g., a few seconds to a few minutes) sufficient to solidify the emulsion. In some embodiments, the plant extract blends of the formulations or topical formulations described herein further comprise (or consist essentially of, or consist of) texturing agents and / or fillers (e.g., cellulose (microcrystalline)); phospholipids (e.g., lecithin or phosphatidylcholine); and anti-caking agents (e.g., silica, which adsorbs water in hygroscopic applications). See, e.g., Example 7.

[0168] Formulations for improving skin moisture and uses thereof Aging skin exhibits wrinkles, elastosis, abnormal pigmentation formation and / or distribution, loss of skin firmness, and decreased moisture content. Hyaluronic acid (HA; also known as hyaluronan or hyaluronate, used interchangeably herein), a major component of the extracellular matrix (ECM), is a glycosaminoglycan (GAG). Due to its water-binding ability, it is known to be an important molecule in matrix formation, cell proliferation, cell migration, tissue development, and skin moisture retention. HA is a polymer of disaccharides (D-glucuronic acid; N-acetyl-D-glucosamine) linked alternately by β-(1→4) and β-(1→3) glycosidic bonds. The carboxyl groups make HA negatively charged, enabling it to bind water. Skin HA concentration decreases with age, contributing to the loss of moisture and / or firmness in aging skin. Hyaluronan synthases (HAS1, HAS2, and HAS3) are enzymes involved in the synthesis of HA at the cell membrane, which is then released into the extracellular space. HAS1, HAS2, and HAS3 are three mammalian isoforms of HAS, which have different enzymatic properties and can synthesize HA chains of different lengths. Therefore, the presence of HA is desirable for improving skin hydration (e.g., increased skin moisture, reduced water loss, increased hyaluronic acid (HA), and increased hyaluronan synthase (HAS)). HA induction is associated with skin moisturization and anti-aging, and aging is associated with ECM breakdown and water loss. Without being bound by theory, upregulation of HA increases water content and the healthy structure of the ECM, thereby supporting the skin dermis and reducing depressions, wrinkles, or tissue breakdown or herniation.

[0169] In various embodiments of the present disclosure, the formulations, such as topical formulations, described herein comprise a therapeutically effective amount of a compound comprising or consisting of at least one of alanine, glutamine, glycine, and serine (e.g., alanine; glutamine; glycine; serine; alanine and glutamine; alanine and glycine; alanine and serine; glutamine and glycine; glutamine and serine; glutamine and glycine and serine; alanine and glycine and serine; alanine and glycine and serine; alanine and glutamine and serine; and alanine and glutamine and glycine and serine), or salts thereof. and retinoids (e.g., retinoids, retinoid derivatives, retinoid precursors, or combinations thereof), including, but not limited to, retinyl esters (e.g., retinyl palmitate, retinyl oleate, retinyl stearate, retinyl linoleate, retinyl palmitoleate); retinol or vitamin A; retinaldehyde or retinal; retinoic acid; or combinations thereof, and, optionally, a dermatologically acceptable vehicle and / or additives. Some embodiments are formulations or topical formulations of the present disclosure, comprising a therapeutically effective amount of a formulation of free amino acids or peptide combinations of amino acids, comprising, consisting essentially of, or consisting of at least one of alanine, glutamine, glycine, and serine (e.g., alanine; glutamine; glycine; serine; alanine and glutamine; alanine and glycine; alanine and serine; glutamine and glycine; glutamine and serine; glutamine and glycine and serine; alanine and glycine and serine; alanine and glutamine and serine; and alanine and glutamine and glycine and serine), or salts thereof, or any combination thereof; and a therapeutically effective amount of retinol or vitamin A; or a combination thereof; and optionally,Further embodiments of the formulations described herein are directed to formulations or topical preparations comprising a dermatologically acceptable vehicle and / or excipient. In further embodiments of the formulations described herein, for example, a fold increase or fold change in expression of a skin moisture marker or HA marker gene, e.g., HAS1, HAS2, HAS3, or EGF, is 1.4 or more (e.g., 1.5, 1.7, 1.9, 2.1, 2.3, 2.5, 2.7, 2.9, 3.1, 3.3, 3.5, 3.7, 3.9, 4.1, 4.3, 4.5, 4.7, 4.9, 5.1, 5.3, 5.5, 5.7, 5.9, 6.1, 6.3, 6.5, 6.7, 6.9, 7.1, 7.3, 7.5, 7.7, 7.9, 8.1, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.9, 10.1, 10.2, 10.3, 10.4, 10.5, 10.6, 10.7, 10.8, 10.9, 11.1, 11.2, 11.3, 11.4, 11.5, 11.6, 11.7, 11.9, 2.1, 2.3, 2.5, 2.7, 2.9, 3.1, 3.3, 3.5, 3.7, 3.9, 4.1, 4.3, .5, 8.7, 8.9, 9.1, 9.3, 9.5, 9.7, 9.9, 10.1, 10.3, 10.5, 10.7, 10.9, 11.1, 11.3, 11.5, 11.7, 11.9, 12.1, 12.3, 12.5, 12.7, 12.9, 13.1, 13.3, 13.5, 13.7, 13.9, 14.1, 14.3, 14.5, 14.7, 14.9, 15.1, 15.3, 15.5, 15.7, 15.9, 16.1, 16.3, 16.5, 16.7, 16.9, 17.1, 17.3, 17.5, 17.7, 17.9, 18.1, 18. 3, 18.5, 18.7, 18.9, 19.1, 19.3, 19.5, 19.7, 19.9, 20.1, 20.3, 20.5, 20.7, 20.9, 21.1, 21.3, 21.5, 21.7, 21.9, 22.1, 22.3, 22.5, 22.7, 22.9, 23.1, 23.3, 23.5, 23.7, 23.9, 23.1, 23.3, 23.5, 23.7, 23.9, 24.1, 24.3, 24.5, 24.7, 24.9, 25.1, 25.3, 25.5, 25.7, 25.9, 26.1, 26.3, 26.5, 26.7, 26.8 6.9, 27.1, 27.3, 27.5, 27.7, 27.9, 28.1, 28.3, 28.5, 28.7, 28.9, 29.1, 29.3, 29.5, 29.7, 29.9, 30.1, 30.3, 30.5, 30.7, 30.9, 31.1, 31.3, 31.5, 31.7, 31.9, 32.1, 32.3, 32.5, 32.7, 32.9, 33.1, 33.3, 33.5, 33.7, 33.9, 34.1, 34.3, 34.5, 34.7, 34.9, 35.1, 35.3, 35.5, 35.7, 35.9, 36.1, 36.3,36.5, 36.7, 36.9, 37.1, 37.3, 37.5, 37.7, 37.9, 38.1, 38.3, 38.5, 38.7, 38.9, 39.1, 39.3, 39.5, 39.7, 39.9, 40.1, 40.3, 40.5, 40.7, 40.9, 41.1, 41.3, 41.5, 55, 70, 90, 105, 120, 170, 195, 205, 255, 270, 295, 305, 320, 355, 370, 405, 420, 455); 450 or less (e.g., 425, 405, 400, 375, 350, 325, 300, 290, 275, 250, 225, 200, 190, 175, 150, 125, 100, 95, 75, 50, 39.8, 39.6, 39.4, 39.2, 39, 38.8, 38.6, 38.4, 38.2, 38, 37.8, 37.6, 37.4, 37.2, 37, 36.8, 36.6, 36.4, 36.2 , 36, 35.8, 35.6, 35.4, 35.2, 35, 34.8, 34.6, 34.4, 34.2, 34, 33.8, 33.6, 33.4, 33.2, 33, 32.8, 32.6, 32.4, 32.2, 32, 31.8, 31.6, 31.4, 31.2, 31, 30.8, 3 0.6, 30.4, 30.2, 30, 29.8, 29.6, 29.4, 29.2, 29, 28.8, 28.6, 28.4, 28.2, 28, 27.8, 27.6, 27.4, 27.2, 27, 26.8, 26.6, 26.4, 26.2, 26, 25.8, 25.6, 25.4, 2 5.2, 25, 24.8, 24.6, 24.4, 24.2, 24, 23.8, 23.6, 23.4, 23.2, 23, 22.8, 22.6, 22.4, 22.2, 22, 21.8, 21.6, 21.4, 21.2, 21, 20.8, 20.6, 20.4, 20.2, 20, 19. 8, 19.6, 19.4, 19.2, 19, 18.8, 18.6, 18.4, 18.2, 18, 17.8, 17.6, 17.4, 17.2, 17.2, 17, 16.8, 16.6, 16.4, 16.2, 16, 15.8, 15.6, 15.4, 15.2, 15, 14.8, 14. 6, 14.4, 14.2, 14, 13.8, 13.6, 13.4, 13.2, 13, 12.8, 12.6, 12.4, 12.2, 12, 11.8, 11.6, 11.4, 11.2, 11, 10.8, 10.6, 10.4, 10.2, 10, 9.8, 9.6, 9.4, 9.2, 9,8.8, 8.6, 8.4, 8.2, 8, 7.8, 7.6, 7.4, 7.2, 7, 6.8, 6.6, 6.4, 6.2, 6, 5.8, 5.6, 5.4, 5.2, 5, 4.8, 4.6, 4.4, 4.2, 4, 3.8, 3.6, 3.4, 3.2, 3, 2.8, 2.6, 2.4, 2.2, 2, 1.8, 1.6, 1.4, 1.2, 1, 0.8, 0.6); or 1.4 to 450 (e.g., 1.5 to 440, 1.6 to 445, 1.7 to 430, 1.8 to 420, 1.9 to 410, 2.4 to 400, 2.1 to 390, 2.2 to 380, 2.3 to 370, 2.4 to 360, 2. 5~350, 2.6~340, 2.7~330, 2.8~320, 2.9~310, 3~300, 3.1~290, 3.2~280, 3.3~270, 3.4~260, 3.5~250, 3.6~240, 3.7~230, 3.8~220, 3.9~210, 4~200, 4. 1~190, 4.2~180, 4.3~170, 4.4~160, 4.5~150, 4.6~140, 4.7~130, 4.8~120, 4.9~110, 5~100, 5.1~90, 5.2~80, 5.3~70, 5.4~60, 5.5~50, 5.6~40, 5.7~35. 8, 5.8~35.7, 5.9~35.6, 6~35.5, 6.1~35.4, 6.2~35.3, 6.3~35.2, 6.4~35.1, 6.5~35, 6.6~34.9, 6.7~34.8, 6.8~34.7, 6.9~34.6, 7~34.5, 7.1~34.4, 7. 2~34.3, 7.3~34.2, 7.4~34.1, 7.5~34, 7.6~33.9, 7.7~33.8, 7.8~33.7, 7.9~33.6, 8~33.5, 8.1~33.4, 8.2~33.3, 8.3~33.2, 8.4~33.1, 8.5~33, 8.6~32. 9, 8.7~32.8, 8.8~32.7, 8.9~32.6, 9~32.5, 9.1~32.4, 9.2~32.3, 9.3~32.2, 9.4~32.1, 9.5~32, 9.6~31.9, 9.7~31.8, 9.8~31.7, 9.9~31.6, 10~31.5, 1 0.1~31.4, 10.2~31.3, 10.3~31.2, 10.4~31.1, 10.5~31, 10.6~30.9, 10.7~30.8, 10.8~30.7, 10.9~30.6, 11~30.5, 11.1~30.4, 11.2~30.3, 11.3~30.2,11.4~30.1, 11.5~30, 11.6~29.9, 11.7~29.8, 11.8~29.7, 11.9~29.6, 12~29.5, 12.1~29.4, 12.2~29.3, 12.3~29.2, 12.4~29.1, 12.5~29, 12.6~28.9 , 12.7~28.8, 12.8~28.7, 12.9~28.6, 13~28.5, 13.1~28.4, 13.2~28.3, 13.3~28.2, 13.4~28.1, 13.5~28, 13.6~27.9, 13.7~27.8, 13.8~27.7, 13.9~27 .6, 14~27.5, 14.1~27.4, 14.2~27.3, 14.3~27.2, 14.4~27.1, 14.5~27, 14.6~26.9, 14.7~26.8, 14.8~26.7, 14.9~26.6, 15~26.5, 15.1~26.4, 15.2~26 .3, 15.3~26.2, 15.4~26.1, 15.5~26, 15.6~25.9, 15.7~25.8, 15.8~25.7, 15.9~25.6, 16~25.5, 16.1~25.4, 16.2~25.3, 16.3~25.2, 16.4~25.1, 16.5~ 25, 16.6~24.9, 16.7~24.8, 16.8~24.7, 16.9~24.6, 17~24.5, 17.1~24.4, 17.2~24.3, 17.3~24.2, 17.4~24.1, 17.5~24, 17.6~23.9, 17.7~23.8, 17.8~ 23.7, 17.9~23.6, 18~23.5, 18.1~23.4, 18.2~23.3, 18.3~23.2, 18.4~23.1, 18.5~23, 18.6~22.9, 18.7~22.8, 18.8~22.7, 18.9~22.6, 19~22.5, 19.1~ 22.4, 19.2–22.3, 19.3–22.2, 19.4–22.1, 19.5–22, 19.6–21.9, 19.7–21.8, 19.8–21.7, 19.9–21.6, 20–21.5, 20.1–21.4, 20.2–21.3, 20.3–21.2, 20.4–21.1, 20.5–21, 20.6–20.9, 20.7–20.8), improving skin hydration (e.g., increasing skin hydration, decreasing water loss, increasing hyaluronic acid (HA), hyaluronan synthase (HAS; e.g.,a therapeutically effective amount of a free amino acid or peptide combination of amino acids and a therapeutically effective amount of a retinoid, retinoid derivative, retinoid precursor, or combination thereof (e.g., a retinyl ester (e.g., retinyl palmitate, oleic acid, retinyl leate, retinyl stearate, retinyl linoleate, retinyl palmitoleate; retinol or vitamin A; retinaldehyde or retinal; retinoic acid; or combinations thereof), and optionally, a dermatologically acceptable vehicle and / or additives. See, e.g., Figures 17-22 and 24-27 (parts).

[0170] Further embodiments described herein are formulations or topical formulations of the present disclosure, comprising a therapeutically effective amount of a formulation comprising, consisting essentially of, or consisting of at least one of alanine, glutamine, glycine, and serine (e.g., alanine; glutamine; glycine; serine; alanine and glutamine; alanine and glycine; alanine and serine; glutamine and glycine; glutamine and serine; glutamine and glycine and serine; alanine and glycine and serine; alanine and glutamine and serine; and alanine and glutamine and glycine and serine), or salts thereof, as free amino acids or peptide combinations of amino acids; and (a) a therapeutically effective amount of a plant extract (e.g., Boswellia oleracea L.) for repairing and strengthening the skin barrier. serrata; Burseraceae family; olibanum; frankincense; or combinations thereof) or a plant extract blend (e.g., Boswellia extract (e.g., Boswellia serrata; Burseraceae family; olibanum; frankincense); texturing agents and / or fillers (e.g., cellulose (microcrystalline); phospholipids (e.g., lecithin or phosphatidylcholine); and anti-caking agents (e.g., silica, to adsorb water in hygroscopic applications)); or (b) improving skin moisture (e.g., increasing skin moisture, decreasing water loss, increasing hyaluronic acid (HA), increasing hyaluronan synthases (HAS; e.g., HAS1 (in fibroblasts), HAS2, and HAS3 (in keratinocytes)). The present invention provides a formulation or topical preparation comprising a therapeutically effective amount of a retinoid, retinoid derivative, or retinoid precursor (e.g., a retinyl ester (e.g., retinyl palmitate, retinyl oleate, retinyl stearate, retinyl linoleate, retinyl palmitoleate); retinol or vitamin A; retinaldehyde or retinal; retinoic acid; or a combination thereof) for treating or improving the skin's condition, wherein each of the free amino acids or peptide combinations of amino acids (at least one of alanine, glutamine, glycine, and serine, or salts thereof) is 0.05 to 0.1% by weight.Concentrations of 1 mM or higher (e.g., 0.3, 0.5, 0.7, 0.9, 1.1, 1.3, 1.5, 1.7, 1.9, 2.1, 2.3, 2.5, 2.7, 2.9, 3.1, 3.3, 3.5, 3.7, 3.9, 4.1, 4.3, 4.5, 4.7, 4.9, 5.1, 5.3, 5.5, 5.7, 5.9, 6.1, 6.3, 6.5, 6.7, 6.9, 7.1, 7.3, 7.5, 7.7, 7.9, 8.1, 8.3, 8.5, 8.7, 8.9, 9.1, 9.3, 9.5, 9.7, 9.9, 10.1, 10.3, 10.5); and 10 mM or lower (e.g., 9.8, 9.6, 9.4, 9.6). 2, 9, 8.8, 8.6, 8.4, 8.2, 8, 7.8, 7.6, 7.4, 7.2, 7, 6.8, 6.6, 6.4, 6.2, 6, 5.8, 5.6, 5.4, 5.2, 5, 4.8, 4.6, 4.4, 4.2, 4, 3.8, 3.6, 3.4, 3.2, 3, 2.8, 2.6, 2.4, 2 Concentrations of 0.2, 0.2, 1.8, 1.6, 1.4, 1.2, 1, 0.8, 0.6, 0.4, 0.2, 0.08, 0.06, 0.04, 0.02; or 0.1 mM to 10 mM (e.g., 0.2 mM to 9.9 mM, 0.3 mM to 9.8 mM, 0.4 mM to 9.7 mM, 0.5 mM to 9.9 mM). 6mM, 0.6mM~9.5mM, 0.7mM~9.4mM, 0.8mM~9.3mM, 0.9mM~9.2mM, 1mM~9.1mM, 1.1mM~9mM, 1.2mM~8.9mM, 1.3mM~8.8mM, 1.4mM~8.7mM, 1.5mM~8.6mM, 1.6mM ~8.5mM, 1.7mM~8.4mM, 1.8mM~8.3mM, 1.9mM~8.2mM, 2mM~8.1mM, 2.1mM~8mM , 2.2mM~7.9mM, 2.3mM~7.8mM, 2.4mM~7.7mM, 2.5mM~7.6mM, 2.6mM~7.5mM, 2. 7mM~7.4mM, 2.8mM~7.3mM, 2.9mM~7.2mM, 3mM~7.1mM, 3.1mM~7mM, 3.2mM~6. 9mM, 3.3mM~6.8mM, 3.4mM~6.7mM, 3.5mM~6.6mM, 3.6mM~6.5mM, 3.7mM~6.4mM , 3.8mM~6.3mM, 3.9mM~6.2mM, 4mM~6.1mM, 4.1mM~6mM, 4.2mM~5.9mM, 4.3mM ~5.8mM, 4.4mM~5.7mM, 4.5mM~5.6mM, 4.6mM~5.5mM, 4.7mM~5.4mM, 4.8mM~5.It is present in concentrations ranging from 3mM, 4.9mM-5.2mM, and 5mM-5.1mM.

[0171] In some embodiments described herein, a formulation or topical formulation of the present disclosure (therapeutically effective amount of free amino acids or peptide combinations thereof) is provided, wherein each of the free amino acids or peptide combinations thereof (at least one of alanine, glutamine, glycine, and serine, or salts thereof) is present in an amount of 0.001% or more by weight of the formulation (e.g., 0.002, 0.003, 0.004, 0.005, 0.006, 0.007, 0.008, 0.009, 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 10.001, 10.002, 10.003, 10.004, 10.005, 10.006, 10.007, 10.008, 10.0 ... 9, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1); 1% by weight or less (e.g., 0.95, 0.85, 0.75, 0.65, 0.55, 0.45, 0.35, 0.25, 0.15, 0.095, 0.085, 0.075, 0.065, 0.055, 0.045, 0.035, 0.025, 0.015, 0.0095, 0.0085, 0.0075, 0.0065, 0.0055, 0.0045, 0.0035, 0.0025, 0.0015); or 0.001% by weight to 1% by weight (e.g., 0.0012% by weight to 0.9 9wt%, 0.0014wt%~0.97wt%, 0.0016wt%~0.95wt%, 0.0018wt%~0.93wt%, 0.002wt%~0.91wt%, 0.0022wt%~0.89wt%, 0.0024wt%~0.87wt%, 0.0026wt%~0. 85wt%, 0.0028wt%~0.83wt%, 0.003wt%~0.81wt%, 0.0032wt%~0.79wt%, 0.0034wt%~0.77wt%, 0.0036wt%~0.75wt%, 0.0038wt%~0.73wt%, 0.004wt%~0.7 1wt%, 0.0042wt%~0.69wt%, 0.0044wt%~0.67wt%, 0.0046wt%~0.65wt%, 0.0048wt%~0.63wt%, 0.005wt%~0.61wt%, 0.0052wt%~0.59wt%, 0.0054wt%~0. 57wt%, 0.0056wt%~0.55wt%, 0.0058wt%~0.53wt%, 0.006wt%~0.51wt%, 0.0062wt%~0.49wt%, 0.0064wt%~0.47wt%, 0.0066wt%~0.45wt%, 0.0068wt%~0.43 wt%, 0.007 wt%~0.41 wt%, 0.0072 wt%~0.39 wt%, 0.0074 wt%~0.37 wt%, 0.0076 wt%~0.35 wt%, 0.0078 wt%~0.33 wt%, 0.008 wt%~0.31 wt%, 0.0082 wt%~0.29 wt%, 0.0084 wt%~0.27 wt%, 0.0086 wt%~0.25 wt%, 0.0088 wt% ~0.23 wt%, 0.009 wt% ~0.21 wt%, 0.0092 wt% ~0.19 wt%, 0.0094 wt% ~0.17 wt%, 0.0096 wt% ~0.15 wt%, 0.0098 wt% ~0.13 wt%, 0.01 wt% ~0.11 wt%, 0.012 wt% ~0.099 wt%, 0.014 wt% ~0.097 wt%, 0.016 wt% ~0.095 wt%, 0.018 wt% ~0.093 wt%, 0.02 wt% ~0.091 wt%, 0.022 wt% ~0.089 wt%, 0.024 wt% ~0.087 wt%, 0.026 wt% ~0.085 wt%, 0.028 wt% ~0.083 wt%, 0.03 wt% ~0.081 wt%, 0.032 wt% ~0.079 wt%, 0.034 wt% ~0.077 wt%, 0.036 wt% ~0.075 wt%, 0.038 wt% Amount%~0.073% by weight, 0.04% by weight~0.071% by weight, 0.042% by weight~0.069% by weight, 0.044% by weight~0.067% by weight, 0.046% by weight~0.065% by weight, 0.048 Weight% ~ 0.063% by weight, 0.05% by weight ~ 0.061% by weight, 0.052% by weight ~ 0.059% by weight, 0.054% by weight ~ 0.057% by weight) does not exist. .

[0172]

[0037] In other embodiments, there is provided a formulation or topical formulation described herein, wherein the amino acid alanine is present in an amount of 0.0035% or more by weight of the formulation (e.g., 0.00352, 0.00354, 0.00356, 0.00358, 0.0036, 0.00362, 0.00364, 0.00366, 0.00368, 0.0037, 0.00372, 0.00374, 0.00376, 0.00378, 0.0038, 0.00382, 0.00384, 0.00386, 0.00388, 0.004, 0.0042, 0.0044, 0.0046, 0.0048, 0.005, 0.0052, 0.0054, 0.0056, 0.0058, 0.006, 0.0062, 0.0064, 0.0066, 0.0068, 0.007, 0.0072, 0.0074, 0.0076, 0.0078, 0.008, 0.0082, 0.0084, 0.0 086, 0.0088, 0.009, 0.0092, 0.0094, 0.0096, 0.0098, 0.01, 0.012, 0.014, 0.016, 0.018, 0.02, 0.022, 0.024, 0.026, 0.028, 0.03, 0.032, 0.034, 0.036 ,0.038,0.04,0.042,0.044,0.046,0.048,0.05,0.052,0.054,0.056,0.058,0.06,0.062,0.064,0.066,0.068,0.07,0.072,0.074,0.076,0.078,0. 08, 0.082, 0.084, 0.086, 0.088, 0.09, 0.092, 0.094, 0.096, 0.098, 0.1, 0.102, 0.104, 0.106, 0.108, 0.11, 0.112, 0.114, 0.116, 0.118, 0.12, 0.122, 0 .124, 0.126, 0.128, 0.13, 0.132, 0.134, 0.136, 0.138, 0.14, 0.142, 0.144, 0.146, 0.148, 0.15, 0.152, 0.154, 0.156, 0.158, 0.16, 0.162, 0.164, 0.16 6, 0.168, 0.17, 0.172, 0.174, 0.176, 0.178, 0.18, 0.182, 0.184, 0.186, 0.188, 0.19, 0.192, 0.194, 0.196, 0.198, 0.2, 0.202, 0.204, 0.206, 0.208, 0.21、0.212、0.214、0.216、0.218、0.22、0.222、0.224、0.226、0.228、0.23、0.232、0.234、0.236、0.238、0.24、0.242、0.244、0.246、0.248、0.25、0.252、0.254、0.256、0.258、0.26、0.262、0.264、0.266、0.268、0.27、0.272、0.274、0.276、0.278、0.28、0.282、0.284、0.286、0.288、0.19、0.192、0.194、0.196、0.198、0.2、0.202、0.204、0.206、0.208、0.21、0.212、0.214、0.216、0.218、0.22、0.222、0.224、0.226、0.228、0.23、0.232、0.234、0.236、0.238、0.24、0.242、0.244、0.246、0.248、0.25、0.252、0.254、0.256、0.258、0.26、0.262、0.264、0.266、0.268、0.27、0.272、0.274、0.276、0.278、0.28、0.282、0.284、0.286、0.288、0.3、0.302、0.304、0.306、0.308、0.31、0.312、0.314、0.316、0.318、0.32、0.322、0.324、0.326、0.328、0.33、0.332、0.334、0.336、0.338、0.34、0.342、0.344、0.346、0.348、0.35、0.352、0.354、0.356、0.358、0.36、0.362、0.364、0.366、0.368、0.37、0.372、0.374、0.376、0.378、0.38、0.382、0.384、0.386、0.388、0.39、0.392、0.394、0.396、0.398、0.4、0.402、0.404、0.406、0.408、0.41、0.412、0.414、0.416、0.418、0.42、0.422、0.424、0.426、0.428、0.43、0.432、0.434、0.436、0.438、0.44、0.442、0.444、0.446、0.448、0.45、0.452、0.454、0.456、0.458、0.46、0.462、0.464、0.466, 0.468, 0.47, 0.472, 0.474, 0.476, 0.478, 0.48, 0.482, 0.484, 0.486, 0.488, 0.5); 0.4% by weight or less (e.g., 0.399, 0.397, 0.395, 0.393, 0.391, 0.389, 0.3 87, 0.385, 0.383, 0.381, 0.379, 0.377, 0.375, 0.373, 0.371, 0.369, 0.367, 0.365, 0.363, 0.361, 0.359, 0.357, 0.355, 0.353, 0.351, 0.349, 0.347, 0. 345, 0.343, 0.341, 0.339, 0.337, 0.335, 0.333, 0.331, 0.329, 0.327, 0.325, 0.323, 0.321, 0.319, 0.317, 0.315, 0.313, 0.311, 0.309, 0.307, 0.305, 0 .303, 0.301, 0.299, 0.297, 0.295, 0.293, 0.291, 0.289, 0.287, 0.285, 0.283, 0.281, 0.279, 0.277, 0.275, 0.273, 0.271, 0.269, 0.267, 0.265, 0.263, 0.261, 0.259, 0.257, 0.255, 0.253, 0.251, 0.249, 0.247, 0.245, 0.243, 0.241, 0.239, 0.237, 0.235, 0.233, 0.231, 0.229, 0.227, 0.225, 0.223, 0.221 ,0.219,0.217,0.215,0.213,0.211,0.209,0.207,0.205,0.203,0.201,0.199,0.197,0.195,0.193,0.191,0.189,0.187,0.185,0.183,0.181,0.17 9, 0.177, 0.175, 0.173, 0.171, 0.169, 0.167, 0.165, 0.163, 0.161, 0.159, 0.157, 0.155, 0.153, 0.151, 0.149, 0.147, 0.145, 0.143, 0.141, 0.139, 0.1 37, 0.135, 0.133, 0.131, 0.129, 0.127, 0.125, 0.123, 0.121, 0.119, 0.117, 0.115, 0.113, 0.111, 0.109, 0.107, 0.105, 0.103, 0.101, 0.099, 0.097, 0.095, 0.093, 0.091, 0.089, 0.087, 0.085, 0.083, 0.081, 0.079, 0.077, 0.075, 0.073, 0.071, 0.069, 0.067, 0.065, 0.063, 0.061, 0.059, 0.057, 0.055, 0.053, 0.051, 0.049, 0.047, 0.045, 0.043, 0.041, 0.039, 0.037, 0.035, 0.033, 0.031, 0.029, 0.027, 0.025, 0.023, 0.021, 0.019, 0.017, 0.015, 0.013 , 0.011, 0.009, 0.007, 0.005, 0.003, 0.002); or 0.0035 wt% to 0.36 wt% (e.g., 0.00351 wt% to 0.359 wt%, 0.00352 wt% to 0.358 wt%, 0.00353 wt% to 0.357 wt%, 0.00354 wt% to 0.356 wt%, 0.00355 wt% to 0.355 wt%, 0.00356 wt% to 0.354 wt%, 0.00357 wt% to 0.353 wt%, 0.00358 wt% to 0.352 wt%, 0.00359 wt% to 0.351 wt%, 0.0036 wt% Amount%~0.35wt%, 0.00361wt%~0.349wt%, 0.00362wt%~0.348wt%, 0.00363wt%~0.347wt%, 0.00364wt%~0.346wt%, 0.00365wt%~0.345wt%, 0.00366wt%~0.3 44wt%, 0.00367wt%~0.343wt%, 0.00368wt%~0.342wt%, 0.00369wt%~0.341wt%, 0.0037wt%~0.34wt%, 0.00371wt%~0.339wt%, 0.00372wt%~0.338wt%, 0 .00373wt%~0.337wt%, 0.00374wt%~0.336wt%, 0.00375wt%~0.335wt%, 0.00376wt%~0.334wt%, 0.00377wt%~0.333wt%, 0.00378wt%~0.332wt%, 0.0037 9wt%~0.331wt%, 0.0038wt%~0.33wt%, 0.00381wt%~0.329wt%, 0.00382wt%~0.328wt%, 0.00383wt%~0.327wt%, 0.00384wt%~0.326wt%, 0.00385wt%~0.325 wt%, 0.00386 wt%~0.324 wt%, 0.00387 wt%~0.323 wt%, 0.00388 wt%~0.322 wt%, 0.00389 wt%~0.321 wt%, 0.0039 wt%~0.32 wt%, 0.00391 wt%~0.319 wt%, 0.00392 wt%~0.318 wt%, 0.00393 wt%~0.317 wt%, 0.00394 wt%~0.316 wt%, 0.00395 wt%~0.315 wt%, 0.00396 wt%~0.314 wt%, 0.00397 wt%~0.313 wt%, 0.00 398 wt%~0.312 wt%, 0.00399 wt%~0.311 wt%, 0.004 wt%~0.31 wt%, 0.00401 wt%~0.309 wt%, 0.00402 wt%~0.308 wt%, 0.00403 wt%~0.307 wt%, 0.00404 wt%~0.306 wt%, 0.00405 wt%~0.305 wt%, 0.00406 wt%~0.304 wt%, 0.00407 wt%~0.303 wt%, 0.00408 wt%~0.302 wt%, 0.00409 wt%~0.301 wt%, 0.0041 wt%~0.3 wt% 0.00411 wt%~0.299 wt%, 0.00412 wt%~0.298 wt%, 0.00413 wt%~0.297 wt%, 0.00414 wt%~0.296 wt%, 0.00415 wt%~0.295 wt%, 0.00416 wt%~0.294 wt%, 0.00417 wt%~0.293 wt%, 0.00418 wt%~0.292 wt%, 0.00419 wt%~0.291 wt%, 0.00422 wt%~0.299 wt%, 0.00421 wt%~0.289 wt%, 0.00422 wt%~0.288 wt%, 0.00423 wt% ~0.287 wt%, 0.00424 wt%~0.286 wt%, 0.00425 wt%~0.285 wt%, 0.00426 wt%~0.284 wt%, 0.00427 wt%~0.283 wt%, 0.00428 wt%~0.282 wt%, 0.00429 wt%~0.281 wt%, 0.0043 wt%~0.28 wt%, 0.00431 wt%~0.279 wt%, 0.00432 wt%~0.278 wt%, 0.00433 wt%~0.277 wt%, 0.00434 wt%~0.276 wt%, 0.00435 wt%~0.275 wt%, 0.0.00436 wt%~0.274 wt%, 0.00437 wt%~0.273 wt%, 0.00438 wt%~0.272 wt%, 0.00439 wt%~0.271 wt%, 0.0044 wt%~0.27 wt%, 0.00441 wt%~0.269 wt%, 0.00442 wt%. %~0.268 wt%, 0.00443 wt%~0.267 wt%, 0.00444 wt%~0.266 wt%, 0.00445 wt%~0.265 wt%, 0.00446 wt%~0.264 wt%, 0.00447 wt%~0.263 wt%, 0.00448 wt%~0.262 wt%, 0.00449 wt%~0.261 wt%, 0.00455 wt%~0.26 wt%, 0.00451 wt%~0.259 wt%, 0.00452 wt%~0.258 wt%, 0.00453 wt%~0.257 wt%, 0.00454 wt%~0.256 wt% 0.00455 wt%~0.255 wt%, 0.00456 wt%~0.254 wt%, 0.00457 wt%~0.253 wt%, 0.00458 wt%~0.252 wt%, 0.00459 wt%~0.251 wt%, 0.0046 wt%~0.25 wt%, 0.00461 wt%~0.249 wt%, 0.00462 wt%~0.248 wt%, 0.00463 wt%~0.247 wt%, 0.00464 wt%~0.246 wt%, 0.00465 wt%~0.245 wt%, 0.00466 wt%~0.244 wt%, 0.00467 wt% ~0.243 wt%, 0.00468 wt%~0.242 wt%, 0.00469 wt%~0.241 wt%, 0.0047 wt%~0.24 wt%, 0.00471 wt%~0.239 wt%, 0.00472 wt%~0.238 wt%, 0.00473 wt%~0.237 wt%, 0.00474 wt%~0.236 wt%, 0.00475 wt%~0.235 wt%, 0.00476 wt%~0.234 wt%, 0.00477 wt%~0.233 wt%, 0.00478 wt%~0.232 wt%, 0.00479 wt%~0.231 wt%. 0.0048 wt%~0.23 wt%, 0.00481 wt%~0.229 wt%, 0.00482 wt%~0.228 wt%, 0.00483 wt%~0.227 wt%, 0.00484 wt%~0.226 wt%, 0.00485 wt%~0.225 wt%, 0.00486 wt%~0.224 wt%, 0.00487 wt%~0.223 wt%, 0.00488 wt%~0.222 wt%, 0.00489 wt%~0.221 wt%, 0.00499 wt%~0.22 wt%, 0.00491 wt%~0.219 wt%, 0.00492 wt%~0.218 wt%, 0.00493 wt%~0.217 wt%, 0.00494 wt%~0.216 wt%, 0.00495 wt%~0.215 wt%, 0.00496 wt%~0.214 wt%, 0.00497 wt%~0.213 wt%, 0.00498 wt%~0.212 wt%, 0.00499 wt%~0.211 wt%, 0.005 wt%~0.21 wt%, 0.00501 wt%~0.209 wt%, 0.00502 wt%~0.208 wt%, 0.00503 wt%~0.207 wt%, 0.00504 wt%~0.206 wt%, 0.005 0.05%~0.205% by weight, 0.00506%~0.204% by weight, 0.00507%~0.203% by weight, 0.00508%~0.202% by weight, 0.00509%~0.201% by weight, 0.0051%~0.2% by weight, 0.00511%~0.199% by weight, 0.00512%~0.198% by weight, 0.00513%~0.197% by weight, 0.00514%~0.196% by weight, 0.00515%~0.195% by weight, 0.00516%~0.194% by weight, 0.00517%~0.193% by weight Weight%, 0.00518 wt%~0.192 wt%, 0.00519 wt%~0.191 wt%, 0.0052 wt%~0.19 wt%, 0.00521 wt%~0.189 wt%, 0.00522 wt%~0.188 wt%, 0.00523 wt%~0.187 wt%, 0.00524 wt%~0.186 wt%, 0.00525 wt%~0.185 wt%, 0.00526 wt%~0.184 wt%, 0.00527 wt%~0.183 wt%, 0.00528 wt%~0.182 wt%, 0.00529 wt%~0.181 wt%, 0.0053 wt% %~0.18 wt%, 0.00531 wt%~0.179 wt%, 0.00532 wt%~0.178 wt%, 0.00533 wt%~0.177 wt%, 0.00534 wt%~0.176 wt%, 0.00535 wt%~0.175 wt%, 0.00536 wt%~0.174 wt%, 0.00537 wt%~0.173 wt%, 0.00538 wt%~0.172 wt%, 0.00539 wt%~0.171 wt%, 0.0054 wt%~0.17 wt%, 0.00541 wt%~0.169 wt%, 0.00542 wt%~0.168 wt%, 0.0.00543 wt%~0.167 wt%, 0.00544 wt%~0.166 wt%, 0.00545 wt%~0.165 wt%, 0.00546 wt%~0.164 wt%, 0.00547 wt%~0.163 wt%, 0.00548 wt%~0.162 wt%, 0.00549 wt%~0.161 wt%, 0.0055 wt%~0.16 wt%, 0.00551 wt%~0.159 wt%, 0.00552 wt%~0.158 wt%, 0.00553 wt%~0.157 wt%, 0.00554 wt%~0.156 wt%, 0.00555 wt%~0.1 55% by weight, 0.00556% by weight to 0.154% by weight, 0.00557% by weight to 0.153% by weight, 0.00558% by weight to 0.152% by weight, 0.00559% by weight to 0.151% by weight, 0.0056% by weight to 0.15% by weight, 0.00561% by weight to 0.149% by weight, 0.00562% by weight to 0.148% by weight, 0.00563% by weight to 0.147% by weight, 0.00564% by weight to 0.146% by weight, 0.00565% by weight to 0.145% by weight, 0.00566% by weight to 0.144% by weight, 0.00567% by weight to 0.143% by weight, 0.0056 8% by weight ~ 0.142% by weight, 0.00569% by weight ~ 0.141% by weight, 0.0057% by weight ~ 0.14% by weight, 0.00571% by weight ~ 0.139% by weight, 0.00572% by weight ~ 0.138% by weight, 0.00573% by weight ~ 0.137% by weight, 0.00574% by weight ~ 0.136% by weight, 0.00575% by weight ~ 0.135% by weight, 0.00576% by weight ~ 0.134% by weight, 0.00577% by weight ~ 0.133% by weight, 0.00578% by weight ~ 0.132% by weight, 0.00579% by weight ~ 0.131% by weight, 0.0058% by weight ~ 0.13% by weight 0.00581 wt%~0.129 wt%, 0.00582 wt%~0.128 wt%, 0.00583 wt%~0.127 wt%, 0.00584 wt%~0.126 wt%, 0.00585 wt%~0.125 wt%, 0.00586 wt%~0.124 wt%, 0.00587 wt%~0.123 wt%, 0.00588 wt%~0.122 wt%, 0.00589 wt%~0.121 wt%, 0.0059 wt%~0.12 wt%, 0.00591 wt%~0.119 wt%, 0.00592 wt%~0.118 wt%, 0.00593 wt%~0.117 wt%, 0.00594 wt%~0.116 wt%, 0.00595 wt%~0.115 wt%, 0.00596 wt%~0.114 wt%, 0.00597 wt%~0.113 wt%, 0.00598 wt%~0.112 wt%, 0.00599 wt%~0.111 wt%, 0.0056 wt%~0.11 wt%, 0.00561 wt%~0.109 wt%, 0.00562 wt%~0.108 wt%, 0.00563 wt%~0.107 wt%, 0.00564 wt%~0.106 wt%, 0.00565 wt%~0.105 wt%, 0.00 566 wt%~0.104 wt%, 0.00567 wt%~0.103 wt%, 0.00568 wt%~0.102 wt%, 0.00569 wt%~0.101 wt%, 0.0057 wt%~0.1 wt%, 0.00571 wt%~0.099 wt%, 0.00572 wt%~0.098 wt%, 0.00573 wt%~0.097 wt%, 0.00574 wt%~0.096 wt%, 0.00575 wt%~0.095 wt%, 0.00576 wt%~0.094 wt%, 0.00577 wt%~0.093 wt%, 0.00578 wt%~0.092 % by weight, 0.00579%~0.091% by weight, 0.0058%~0.09% by weight, 0.00581%~0.089% by weight, 0.00582%~0.088% by weight, 0.00583%~0.087% by weight, 0.00584%~0.086% by weight, 0.00585%~0.085% by weight, 0.00586%~0.084% by weight, 0.00587%~0.083% by weight, 0.00588%~0.082% by weight, 0.00589%~0.081% by weight, 0.0059%~0.08% by weight, 0.00591% by weight %~0.079 wt%, 0.00592 wt%~0.078 wt%, 0.00593 wt%~0.077 wt%, 0.00594 wt%~0.076 wt%, 0.00595 wt%~0.075 wt%, 0.00596 wt%~0.074 wt%, 0.00597 wt%~0.073 wt%, 0.00598 wt%~0.072 wt%, 0.00599 wt%~0.071 wt%, 0.006 wt%~0.07 wt%, 0.00601 wt%~0.069 wt%, 0.00602 wt%~0.068 wt%, 0.00603 wt%~0.067 wt%, 0.0.0604 wt%~0.066 wt%, 0.00605 wt%~0.065 wt%, 0.00606 wt%~0.064 wt%, 0.00607 wt%~0.063 wt%, 0.00608 wt%~0.062 wt%, 0.00609 wt%~0.061 wt%, 0.0061 wt%~0.06 wt%, 0.00611 wt%~0.059 wt%, 0.00612 wt%~0.058 wt%, 0.00613 wt%~0.057 wt%, 0.00614 wt%~0.056 wt%, 0.00615 wt%~0.055 wt%, 0.00616 wt%~0 0.054 wt%, 0.00617 wt%~0.053 wt%, 0.00618 wt%~0.052 wt%, 0.00619 wt%~0.051 wt%, 0.0062 wt%~0.05 wt%, 0.00621 wt%~0.049 wt%, 0.00622 wt%~0.048 wt%, 0.00623 wt%~0.047 wt%, 0.00624 wt%~0.046 wt%, 0.00625 wt%~0.045 wt%, 0.00626 wt%~0.044 wt%, 0.00627 wt%~0.043 wt%, 0.00628 wt%~0.042 wt%, 0. 0.00629 wt%~0.041 wt%, 0.0063 wt%~0.04 wt%, 0.00631 wt%~0.0399 wt%, 0.00632 wt%~0.0398 wt%, 0.00633 wt%~0.0397 wt%, 0.00534 wt%~0.0396 wt%, 0.00535 wt%~0.0395 wt%, 0.00536 wt%~0.0394 wt%, 0.00537 wt%~0.0393 wt%, 0.00538 wt%~0.0392 wt%, 0.00539 wt%~0.0391 wt%, 0.0054 wt%~0.039 wt%, 0.00 541 wt%~0.0389 wt%, 0.00542 wt%~0.0388 wt%, 0.00543 wt%~0.0387 wt%, 0.00544 wt%~0.0386 wt%, 0.00545 wt%~0.0385 wt%, 0.00546 wt%~0.0384 wt%, 0.00547 wt%~0.0383 wt%, 0.00548 wt%~0.0382 wt%, 0.00549 wt%~0.0381 wt%, 0.0055 wt%~0.038 wt%, 0.00551 wt%~0.0379 wt%, 0.00552 wt%~0.0378 wt%, 0.0.00553 wt%~0.0377 wt%, 0.00554 wt%~0.0376 wt%, 0.00555 wt%~0.0375 wt%, 0.00556 wt%~0.0374 wt%, 0.00557 wt%~0.0373 wt%, 0.00558 wt%~0.0372 wt%, 0.00559 wt%~0.037. 1 wt%, 0.0056 wt%~0.037 wt%, 0.00561 wt%~0.0369 wt%, 0.00562 wt%~0.0368 wt%, 0.00563 wt%~0.0367 wt%, 0.00564 wt%~0.0366 wt%, 0.00565 wt%~0.0365 wt%, 0.00566 wt%~0.0364 wt%, 0.00567 wt%~0.0363 wt%, 0.00568 wt%~0.0362 wt%, 0.00569 wt%~0.0361 wt%, 0.0057 wt%~0.036 wt%, 0.00571 wt%~0.035 9% by weight, 0.00572% by weight to 0.0358% by weight, 0.00573% by weight to 0.0357% by weight, 0.00574% by weight to 0.0356% by weight, 0.00575% by weight to 0.0355% by weight, 0.00576% by weight to 0.0354% by weight, 0.00577% by weight to 0.0353% by weight, 0.00578% by weight to 0.0352% by weight, 0.00579% by weight to 0.0351% by weight, 0.0058% by weight to 0.0355% by weight, 0.00581% by weight to 0.0349% by weight, 0.00582% by weight to 0.0348% by weight, 0.00583% by weight to 0.03 47 wt%, 0.00584 wt%~0.0346 wt%, 0.00585 wt%~0.0345 wt%, 0.00586 wt%~0.0344 wt%, 0.00587 wt%~0.0343 wt%, 0.00588 wt%~0.0342 wt%, 0.00589 wt%~0.0341 wt%, 0.0059 wt%~0.034 wt%, 0.00591 wt%~0.0339 wt%, 0.00592 wt%~0.0338 wt%, 0.00593 wt%~0.0337 wt%, 0.00594 wt%~0.0336 wt%, 0.00595 wt%~0.0 335 wt%, 0.00596 wt%~0.0334 wt%, 0.00597 wt%~0.0333 wt%, 0.00598 wt%~0.0332 wt%, 0.00599 wt%~0.0331 wt%, 0.0056 wt%~0.033 wt%, 0.00561 wt%~0.0329 wt%, 0.00562 wt%~0.0328 wt%, 0.00563 wt%~0.0327 wt%, 0.00564 wt%~0.0326 wt%, 0.00565 wt%~0.0325 wt%, 0.00566 wt%~0.0324 wt%, 0.00567 wt%~0.0.0323 wt%, 0.00568 wt%~0.0322 wt%, 0.00569 wt%~0.0321 wt%, 0.0057 wt%~0.032 wt%, 0.00571 wt%~0.0319 wt%, 0.00572 wt%~0.0318 wt%, 0.00573 wt%~0.0317 wt%, 0.00574 wt%~0.0316 wt%, 0.00575 wt%~0.0315 wt%, 0.00576 wt%~0.0314 wt%, 0.00577 wt%~0.0313 wt%, 0.00578 wt%~0.0312 wt%, 0.00579 wt%~0 0.0311 wt%, 0.0058 wt%~0.031 wt%, 0.00581 wt%~0.0309 wt%, 0.00582 wt%~0.0308 wt%, 0.00583 wt%~0.0307 wt%, 0.00584 wt%~0.0306 wt%, 0.00585 wt%~0.0305 wt%, 0.00586 wt%~0.0304 wt%, 0.00587 wt%~0.0303 wt%, 0.00588 wt%~0.0302 wt%, 0.00589 wt%~0.0301 wt%, 0.0059 wt%~0.03 wt%, 0.00591 wt%~0.0 299 wt%, 0.00592 wt%~0.0298 wt%, 0.00593 wt%~0.0297 wt%, 0.00594 wt%~0.0296 wt%, 0.00595 wt%~0.0295 wt%, 0.00596 wt%~0.0294 wt%, 0.00597 wt%~0.0293 wt%, 0.00598 wt%~0.0292 wt%, 0.00599 wt%~0.0291 wt%, 0.006 wt%~0.029 wt%, 0.00601 wt%~0.0289 wt%, 0.00602 wt%~0.0288 wt%, 0.00603 wt%~0.0 287 wt%, 0.00604 wt%~0.0286 wt%, 0.00605 wt%~0.0285 wt%, 0.00606 wt%~0.0284 wt%, 0.00607 wt%~0.0283 wt%, 0.00608 wt%~0.0282 wt%, 0.00609 wt%~0.0281 wt%, 0.0061 wt%~0.028 wt%, 0.00611 wt%~0.0279 wt%, 0.00612 wt%~0.0278 wt%, 0.00613 wt%~0.0277 wt%, 0.00614 wt%~0.0276 wt%, 0.00615 wt%~0.0275 weight%, 0.00616 weight%~0.0274 weight%, 0.00617 weight%~0.0273 weight%, 0.00618 weight%~0.0272 weight%, 0.00619 weight%~0.0271 weight% %, 0.0062wt%~0.027wt%, 0.00621wt%~0.0269wt%, 0.00622wt%~0.0268wt%, 0.00623wt%~0.0267wt%, 0.00624 Present in weight percent (wt / wt%) of 0.0266 wt%, 0.00625 wt% to 0.0265 wt%, 0.00626 wt% to 0.0264 wt%, 0.00627 wt% to 0.0263 wt%, 0.00628 wt% to 0.0262 wt%, 0.00629 wt% to 0.0261 wt%, 0.0063 wt% to 0.026 wt%, and 0.00631 wt% to 0.0259 wt%.

[0173] In additional embodiments, the formulations or topical formulations described herein comprise 0.00584% or more (e.g., 0.0059, 0.006, 0.007, 0.008, 0.009, 0.01, 0.011, 0.012, 0.013, 0.014, 0.015, 0.016, 0.017, 0.018, 0.019, 0.02, 0.021, 0.022, 0.023, 0.024, 0.025, 0.026, 0.027, 0.028, 0.029, 0.03, 0.031, 0.032, 0.033, 0.034, 0.035, 0.036, 0.037, 0.038, 0.040, 0.041, 0.042, 0.043, 0.044, 0.045, 0.046, 0.047, 0.048, 0.049, 0.050, 0.051, 0.052, 0.053, 0.054, 0.055, 0.056, 0.057, 0.058, 0.059, 0.060, 0.061, 0.062, 0.063, 0.064, 0.065, 0.066, 0.067, 0.068, 0.069, 0.070, 0.071, 0.072, 0.073, 0.07 .038, 0.039, 0.04, 0.041, 0.042, 0.043, 0.044, 0.045, 0.046, 0.047, 0.048, 0.049, 0.05, 0.051, 0.052, 0.053, 0.054, 0.055, 0.056, 0.057, 0.058, 0. 059, 0.06, 0.061, 0.062, 0.063, 0.064, 0.065, 0.066, 0.067, 0.068, 0.069, 0.07, 0.071, 0.072, 0.073, 0.074, 0.075, 0.076, 0.077, 0.078, 0.079, 0.0 8, 0.081, 0.082, 0.083, 0.084, 0.085, 0.086, 0.087, 0.088, 0.089, 0.09, 0.091, 0.092, 0.093, 0.094, 0.095, 0.096, 0.097, 0.098, 0.099, 0.1, 0.11, 0 .12, 0.13, 0.14, 0.15, 0.16, 0.17, 0.18, 0.19, 0.2, 0.21, 0.22, 0.23, 0.24, 0.25, 0.26, 0.27, 0.28, 0.29, 0.3, 0.31, 0.32, 0.33, 0.34, 0.35, 0.36, 0.3 7, 0.38, 0.39, 0.4, 0.41, 0.42, 0.43, 0.44, 0.45, 0.46, 0.47, 0.48, 0.49, 0 0.584% by weight or less (e.g., 0.583, 0.582, 0.581, 0.58, 0.579, 0.578, 0.577, 0.576, 0.575, 0.574, 0.573, 0.572, 0.571, 0.57, 0.569, 0.568, 0.567, 0.566, 0.565, 0.564, 0.563、0.562、0.561、0.56、0.559、0.558、0.557、0.556、0.554、0.553、0.552、0.551、0.55、0.549、0.548、0.547、0.546、0.545、0.544、0.543、0.542、0.541、0.54、0.539、0.538、0.537、0.536、0.535、0.534、0.533、0.532、0.531、0.53、0.529、0.528、0.527、0.526、0.525、0.524、0.523、0.522、0.521、0.52、0.519、0.518、0.517、0.516、0.515、0.514、0.513、0.512、0.511、0.51、0.509、0.508、0.507、0.506、0.505、0.504、0.503、0.502、0.501、0.5、0.499、0.498、0.497、0.496、0.495、0.494、0.493、0.492、0.491、0.49、0.489、0.488、0.487、0.486、0.485、0.484、0.483、0.482、0.481、0.48、0.479、0.478、0.477、0.476、0.475、0.474、0.473、0.472、0.471、0.47、0.469、0.468、0.467、0.466、0.465、0.464、0.463、0.462、0.461、0.46、0.459、0.458、0.457、0.456、0.455、0.454、0.453、0.452、0.451、0.45、0.449、0.448、0.447、0.446、0.445、0.444、0.443、0.442、0.441、0.44、0.439、0.438、0.437、0.436、0.435、0.434、0.433、0.432、0.431、0.43、0.429、0.428、0.427、0.426、0.425、0.424、0.423、0.422、0.421、0.42、0.419、0.418、0.417、0.416、0.415、0.414、0.413、0.412、0.411、0.41、0.409、0.408、0.407、0.406、0.405、0.404、0.403、0.402、0.401、0.4、0.3、0.2、0.1、0.09、0.08、0.07、0.06、0.05、0.04、0.0.03, 0.02, 0.01, 0.009, 0.008, 0.007, 0.006, 0.005, 0.004, 0.003, 0.002, 0.001); or 0.00584 wt% to 0.584 wt% (e.g., 0.00585 wt% to 0.582 wt%, 0.0059 wt% to 0.58 wt%, 0.0065 wt% to 0.578 wt%, 0.007 wt% to 0.576 wt%, 0.0075 wt% to 0.574 wt% , 0.008wt%~0.572wt%, 0.0085wt%~0.57wt%, 0.009wt%~0.568wt%, 0.0095wt%~0.566wt%, 0.01wt%~0.564wt%, 0.0 15wt%~0.562wt%, 0.02wt%~0.56wt%, 0.025wt%~0.558wt%, 0.03wt%~0.556wt%, 0.035wt%~0.554wt%, 0.04wt%~0.5 52wt%, 0.045wt%~0.55wt%, 0.05wt%~0.548wt%, 0.055wt%~0.546wt%, 0.06wt%~0.544wt%, 0.065wt%~0.542wt%, 0 .07wt%~0.54wt%, 0.075wt%~0.538wt%, 0.08wt%~0.536wt%, 0.085wt%~0.534wt%, 0.09wt%~0.532wt%, 0.095wt%~ and glutamine, an amino acid present in weight percent (wt%) of 0.53 wt%, 0.1 wt% to 0.528 wt%, 0.15 wt% to 0.526 wt%, 0.2 wt% to 0.524 wt%, 0.25 wt% to 0.522 wt%, 0.3 wt% to 0.52 wt%, 0.35 wt% to 0.518 wt%, 0.4 wt% to 0.516 wt%, 0.45 wt% to 0.514 wt%, and 0.5 wt% to 0.512 wt%.

[0174] In further embodiments described herein, there is provided a formulation or topical formulation as described herein, wherein the amino acid glycine is present in an amount of 0.003% or more (e.g., 0.004, 0.005, 0.006, 0.007, 0.008, 0.009, 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.1, 0.11, 0.12, 0.13, 0.14, 0.15, 0.16, 0.17, 0.18, 0.19, 0.2, 0.21, 0.22, 0.23, 0.24, 0.25, 0.26, 0.27, 0.28, 0.29, 100% or more) by weight of the formulation. 0.29, 0.3, 0.31, 0.32, 0.33, 0.34, 0.35, 0.36, 0.37, 0.38, 0.39, 0.4); 0.3% by weight or less (e.g., 0.298, 0.296, 0.294, 0.292, 0.29, 0.288, 0.286, 0.284, 0.282, 0 .28, 0.278, 0.276, 0.274, 0.272, 0.27, 0.268, 0.266, 0.264, 0.262, 0.26, 0.258, 0.256, 0.254, 0.252, 0.25, 0.248, 0.246, 0.244, 0.242, 0.24, 0.238 ,0.236,0.234,0.232,0.23,0.228,0.226,0.224,0.222,0.22,0.218,0.216,0.214,0.212,0.21,0.208,0.206,0.204,0.202,0.2,0.198,0.196,0.1 94, 0.192, 0.19, 0.188, 0.186, 0.184, 0.182, 0.18, 0.178, 0.176, 0.174, 0.172, 0.17, 0.168, 0.166, 0.164, 0.162, 0.16, 0.158, 0.156, 0.154, 0.152, 0.15, 0.148, 0.146, 0.144, 0.142, 0.14, 0.138, 0.136, 0.134, 0.132, 0.13, 0.128, 0.126, 0.124, 0.122, 0.12, 0.118, 0.116, 0.114, 0.112, 0.11, 0.10 8, 0.106, 0.104, 0.102, 0.1, 0.098, 0.096, 0.094, 0.092, 0.09, 0.088, 0.086, 0.084, 0.082, 0.08, 0.078, 0.076, 0.074, 0.072, 0.07, 0.068, 0.066, 0.064, 0.062, 0.06, 0.058, 0.056, 0.054, 0.052, 0.05, 0.048, 0.046, 0.044, 0.042, 0.04, 0.038, 0.036, 0.034, 0.032, 0.03, 0.028, 0.026, 0.024, 0.022, 0.02, 0.018, 0.016, 0.014, 0.012, 0.01, 0.008, 0 0.006, 0.004, 0.002); or 0.003 wt% to 0.3 wt% (e.g., 0.0035 wt% to 0.29 wt%, 0.004 wt% to 0.27 wt%, 0.0045 wt% to 0.25 wt%, 0.005 wt% to 0.23 wt%, 0.0055 wt% to 0.21 wt%, 0.006 wt% to 0.19 wt%, 0.0065 wt% to 0.17 wt%, 0.0 07wt%~0.15wt%, 0.0075wt%~0.13wt%, 0.008wt%~0.11wt%, 0.0085wt%~0.099wt%, 0.009wt%~0.097wt Amount%, 0.0095wt%~0.095wt%, 0.01wt%~0.093wt%, 0.015wt%~0.091wt%, 0.02wt%~0.089wt%, 0.025wt%~0 Present in weight percents (wt%) of 0.087 wt%, 0.03 wt% to 0.085 wt%, 0.035 wt% to 0.083 wt%, 0.04 wt% to 0.081 wt%, 0.045 wt% to 0.079 wt%, 0.05 wt% to 0.077 wt%, 0.055 wt% to 0.075 wt%, 0.06 wt% to 0.073 wt%, and 0.065 wt% to 0.071 wt%.

[0175] In some embodiments, the formulations or topical formulations of the present disclosure contain 0.0042% or more by weight of the formulation (e.g., 0.0044, 0.0046, 0.0048, 0.005, 0.0052, 0.0054, 0.0056, 0.0058, 0.006, 0.0062, 0.0064, 0.0066, 0.0068, 0.007, 0.0072, 0.0074, 0.0076, 0.0078, 0.008, 0.0082, 0.0084, 0.0086, 0.0088, 0.009, 0.0092, 0.0094, 0.0096, 0.0098, 0.01, 0.01 02, 0.0104, 0.0106, 0.0108, 0.011, 0.0112, 0.0114, 0.0116, 0.0118, 0.012, 0.0122, 0.0124, 0.0126, 0.0128, 0.013, 0.0132, 0.0134, 0.0136, 0.0138 ,0.014,0.0142,0.0144,0.0146,0.0148,0.015,0.0152,0.0154,0.0156,0.0158,0.016,0.0162,0.0164,0.0166,0.0168,0.017,0.0172,0.0174,0. 0176, 0.0178, 0.018, 0.0182, 0.0184, 0.0186, 0.0188, 0.019, 0.0192, 0.0194, 0.0196, 0.0198, 0.02, 0.0202, 0.0204, 0.0206, 0.208, 0.021, 0.0212, 0.0214, 0.0216, 0.0218, 0.022, 0.0222, 0.0224, 0.0226, 0.0228, 0.023, 0.0232, 0.0234, 0.0236, 0.0238, 0.024, 0.0242, 0.0244, 0.0246, 0.0248, 0. 025, 0.0252, 0.0254, 0.0256, 0.0258, 0.026, 0.0262, 0.0264, 0.0266, 0.0268, 0.027, 0.0272, 0.0274, 0.0276, 0.0278, 0.028, 0.0282, 0.0284, 0.028 6, 0.0288, 0.029, 0.0292, 0.0294, 0.0296, 0.0298, 0.03, 0.0302, 0.0304, 0.0306, 0.0308, 0.031, 0.0312, 0.0314, 0.0316, 0.0318, 0.032, 0.0322, 0.0324、0.0326、0.0328、0.033、0.0332、0.0334、0.0336、0.0338、0.034、0.0342、0.0344、0.0346、0.0348、0.035、0.0352、0.0354、0.0356、0.0358、0.036、0.0362、0.0364、0.0366、0.0368、0.037、0.0372、0.0374、0.0376、0.0378、0.038、0.0382、0.0384、0.0386、0.0388、0.039、0.0392、0.0394、0.0396、0.0398、0.04、0.0402、0.0404、0.0406、0.0408、0.041、0.0412、0.0414、0.0416、0.0418、0.042、0.0422、0.0424、0.0426、0.0428、0.043、0.0432、0.0434、0.0436、0.0438、0.044、0.0442、0.0444、0.0446、0.0448、0.045、0.0452、0.0454、0.0456、0.0458、0.046、0.0462、0.0464、0.0466、0.0468、0.047、0.0472、0.0474、0.0476、0.0478、0.048、0.0482、0.0484、0.0486、0.0488、0.049、0.0492、0.0494、0.0496、0.0498、0.05、0.0502、0.0504、0.0506、0.0508、0.051、0.0512、0.0514、0.0516、0.0518、0.052、0.0522、0.0524、0.0526、0.0528、0.053、0.0532、0.0534、0.0536、0.0538、0.054、0.0542、0.0544、0.0546、0.0548、0.055、0.0552、0.0554、0.0556、0.0558、0.056、0.0562、0.0564、0.0566、0.0568、0.057、0.0572、0.0574、0.0576、0.0578、0.058、0.0582、0.0584、0.0586、0.0588、0.059、0.0592、0.0594、0.0596、0.0598、0.06、0.0602、0.0604、0.0606、0.0608、0.061、0.0612、0.0614、0.0616、0.0618、0.062、0.0622、0.0624、0.0626、0.0628、0.063、0.0632、0.0634、0.0636、0.0638、0.064、0.0642、0.0644、0.0646、0.0648、0.065、0.0652、0.0654、0.0656、0.0658、0.066、0.0662、0.0664、0.0666、0.0668、0.067、0.0672、0.0674、0.0676、0.0678、0.068、0.0682、0.0684、0.0686、0.0688、0.069、0.0692、0.0694、0.0696、0.0698、0.07、0.0702、0.0704、0.0706、0.0708、0.071、0.0712、0.0714、0.0716、0.0718、0.072、0.0722、0.0724、0.0726、0.0728、0.073、0.0732、0.0734、0.0736、0.0738、0.074、0.0742、0.0744、0.0746、0.0748、0.075、0.0752、0.0754、0.0756、0.0758、0.076、0.0762、0.0764、0.0766、0.0768、0.077、0.0772、0.0774、0.0776、0.0778、0.078、0.0782、0.0784、0.0786、0.0788、0.079、0.0792、0.0794、0.0796、0.0798、0.08、0.0802、0.0804、0.0806、0.0808、0.081、0.0812、0.0814、0.0816、0.0818、0.082、0.0822、0.0824、0.0826、0.0828、0.083、0.0832、0.0834、0.0836、0.0838、0.084、0.0842、0.0844、0.0846、0.0848、0.085、0.0852、0.0854、0.0856、0.0858、0.086、0.0862、0.0864、0.0866、0.0868、0.087、0.0872、0.0874、0.0876、0.0878、0.088、0.0882、0.0884、0.0886、0.0888、0.089、0.0892、0.0894、0.0896、0.0898、0.09、0.0902、0.0904、0.0906、0.0908、0.091、0.0912, 0.0914, 0.0916, 0.0918, 0.092, 0.0922, 0.0924, 0.0926, 0.0928, 0.093, 0.0932, 0.0934, 0.0936, 0.0938, 0.094, 0.0942, 0.0944, 0.0946, 0.0 948, 0.095, 0.0952, 0.0954, 0.0956, 0.0958, 0.096, 0.0962, 0.0964, 0.0966, 0.0968, 0.097, 0.0972, 0.0974, 0.0976, 0.0978, 0.098, 0.0982, 0.0984 ,0.0986,0.0988,0.099,0.0992,0.0994,0.0996,0.0998,0.1,0.102,0.104,0.106,0.108,0.11,0.112,0.114,0.116,0.118,0.12,0.122,0.124,0 .126, 0.128, 0.13, 0.132, 0.134, 0.136, 0.138, 0.14, 0.142, 0.144, 0.146, 0.148, 0.15, 0.152, 0.154, 0.156, 0.158, 0.16, 0.162, 0.164, 0.166, 0.16 8, 0.17, 0.172, 0.174, 0.176, 0.178, 0.18, 0.182, 0.184, 0.186, 0.188, 0.19, 0.192, 0.194, 0.196, 0.198, 0.2, 0.22, 0.24, 0.26, 0.28, 0.3, 0.32, 0.34, 0.36, 0.38, 0.4, 0.42, 0.44, 0.46, 0.48, 0.5); 0.42% by weight or less (e.g., 0.418, 0.416, 0.414, 0.412, 0.41, 0.408, 0.406, 0.404, 0.402, 0.4, 0.398, 0.396, 0.394, 0.392, 0.39, 0.388, 0.386, 0.384, 0.382, 0.38, 0.378, 0.376, 0.374, 0.372, 0.37, 0.368, 0.366, 0.364, 0.362, 0.36, 0.358, 0.356, 0.354, 0.3 52, 0.35, 0.348, 0.346, 0.344, .342, 0.34, 0.338, 0.336, 0.334, 0.332, 0.33, 0.328, 0.326, 0.324, 0.322, 0.32, 0.318, 0.316, 0.314, 0.312, 0.31, 0.308、0.306、0.304、0.302、0.3、0.298、0.296、0.294、0.292、0.294、0.292、0.29、0.288、0.286、0.284、0.282、0.28、0.278、0.276、0.274、0.272、0.27、0.268、0.266、0.264、0.262、0.26、0.258、0.256、0.254、0.252、0.25、0.248、0.246、0.244、0.242、0.24、0.238、0.236、0.234、0.232、0.23、0.228、0.226、0.224、0.222、0.22、0.218、0.216、0.214、0.212、0.21、0.208、0.206、0.204、0.202、0.2、0.198、0.196、0.194、0.192、0.19、0.188、0.186、0.184、0.182、0.18、0.178、0.176、0.174、0.172、0.17、0.168、0.166、0.164、0.162、0.16、0.158、0.156、0.154、0.152、0.15、0.148、0.146、0.144、0.142、0.14、0.138、0.136、0.134、0.132、0.13、0.128、0.126、0.124、0.122、0.12、0.118、0.116、0.114、0.112、0.11、0.108、0.106、0.104、0.102、0.1、0.098、0.096、0.094、0.092、0.09、0.088、0.086、0.084、0.082、0.08、0.078、0.076、0.074、0.072、0.07、0.068、0.066、0.064、0.062、0.06、0.058、0.056、0.054、0.052、0.05、0.048、0.046、0.044、0.042、0.04、0.038、0.036、0.034、0.032、0.03、0.028、0.026、0.024、0.022、0.02、0.018、0.016、0.014、0.012、0.01、0.0088、0.0086、0.0084、0.0082、0.008、0.0078、0.0076、0.0074、0.0072、0.007、0.0068、0.0066、0.0064、0.0062、0.006、0.0058、0.0056、0.0.0054, 0.0052, 0.005, 0.0048, 0.0046, 0.0044, 0.0042, 0.004); or 0.0042 wt% to 0.42 wt% (e.g., 0.0043 wt% to 0.415 wt%, 0.0045 wt% to 0.41 wt%, 0.0047 wt% to 0.405 wt%, 0. 0.0049 wt%~0.4 wt%, 0.0051 wt%~0.395 wt%, 0.0053 wt%~0.39 wt%, 0.0055 wt%~0.385 wt%, 0.0057 wt%~0.38 wt%, 0.0059 wt%~0.375 wt%, 0.0061 wt%~0.37 wt%, 0.0063 wt%~0.365 wt%, 0.0065 wt%~0.36 wt%, 0.0067 wt%~0.355 wt%, 0.0069 wt%~0.35 wt%, 0.0061 wt%~0.345 wt%, 0.0063 wt%~0.34 wt%, 0.0065 wt%~0. 335 wt%, 0.0067 wt%~0.33 wt%, 0.0069 wt%~0.325 wt%, 0.0071 wt%~0.32 wt%, 0.0073 wt%~0.315 wt%, 0.0075 wt%~0.31 wt%, 0.0077 wt%~0.305 wt%, 0.0079 wt%~0.3 wt%, 0.0081 wt%~0.295 wt%, 0.0083 wt%~0.29 wt%, 0.0085 wt%~0.285 wt%, 0.0087 wt%~0.28 wt%, 0.0089 wt%~0.275 wt%, 0.0091 wt%~0.27 wt%, 0.0 0.93 wt%~0.265 wt%, 0.0095 wt%~0.26 wt%, 0.0097 wt%~0.255 wt%, 0.0099 wt%~0.35 wt%, 0.0101 wt%~0.345 wt%, 0.0103 wt%~0.34 wt%, 0.0105 wt%~0.335 wt%, 0.0107 wt%~0.33 wt%, 0.0109 wt%~0.325 wt%, 0.0111 wt%~0.32 wt%, 0.0113 wt%~0.315 wt%, 0.0115 wt%~0.31 wt%, 0.0117 wt%~0.305 wt%, 0.0119 wt%~0 0.3 wt%, 0.0121 wt%~0.295 wt%, 0.0123 wt%~0.29 wt%, 0.0125 wt%~0.285 wt%, 0.0127 wt%~0.28 wt%, 0.0129 wt%~0.275 wt%, 0.0131 wt%~0.27 wt%, 0.0133 wt%~0.265 wt%, 0.0135 wt%~0.26 wt%, 0.0137 wt%~0.255 wt%, 0.0139 wt%~0.25 wt%, 0.0141 wt%~0.245 wt%, 0.0143 wt%~0.24 wt%, 0.0145 wt%~0.235 wt%, 0.0147wt%~0.23wt%, 0.0149wt%~0.225wt%, 0.0151wt%~0.22wt%, 0.0153wt%~0.215wt%, 0.0155wt%~0.21wt%, 0.0157wt%~ 0.205wt%, 0.0159wt%~0.2wt%, 0.0161wt%~0.195wt%, 0.0163wt%~0.19wt%, 0.0165wt%~0.185wt%, 0.0167wt%~0.18wt%, 0 .0169wt%~0.175wt%, 0.0171wt%~0.17wt%, 0.0173wt%~0.165wt%, 0.0175wt%~0.16wt%, 0.0177wt%~0.155wt%, 0.0179wt %~0.15wt%, 0.0181wt%~0.145wt%, 0.0183wt%~0.14wt%, 0.0185wt%~0.135wt%, 0.0187wt%~0.13wt%, 0.0189wt%~0.125wt %, 0.0191wt%~0.12wt%, 0.0193wt%~0.115wt%, 0.0195wt%~0.11wt%, 0.0197wt%~0.105wt%, 0.0199wt%~0.1wt%, 0.0201wt Amount%~0.095wt%, 0.0203wt%~0.09wt%, 0.0205wt%~0.085wt%, 0.0207wt%~0.08wt%, 0.0209wt%~0.075wt%, 0.0211wt%~0.07wt The amino acid serine is present in weight percents (wt%) of 0.0213 wt% to 0.065 wt%, 0.0215 wt% to 0.06 wt%, 0.0217 wt% to 0.055 wt%, 0.0219 wt% to 0.05 wt%, 0.0221 wt% to 0.045 wt%, 0.0223 wt% to 0.04 wt%, 0.0225 wt% to 0.035 wt%, 0.0227 wt% to 0.03 wt%, and 0.0229 wt% to 0.025 wt%.

[0176] Additional embodiments described herein provide a formulation or topical formulation as disclosed herein, wherein the therapeutically effective amount of the amino acid blend comprises, consists essentially of, or consists of 0.0356% alanine (4 mM), 0.0584% glutamine (4 mM), 0.03% glycine (4 mM), and 0.042% serine (4 mM). In some embodiments where the formulation or topical formulation disclosed herein comprises a therapeutically effective amount of free amino acids or peptide combinations thereof, the free amino acids or peptide combinations comprise, consist essentially of, or consist of 0.0356% alanine (4 mM), 0.0584% glutamine (4 mM), 0.03% glycine (4 mM), and 0.042% serine (4 mM), further comprising a therapeutically effective amount of a plant extract or plant extract blend for skin barrier repair and strengthening, the plant extract being a Boswellia extract (e.g., Boswellia serrata; Burseraceae family; olibanum; frankincense), or the plant extract blend is combined with at least one of a texturing agent and / or filler (e.g., cellulose (microcrystalline); phospholipid (e.g., lecithin); and an anti-caking agent (e.g., silica, which adsorbs water in hygroscopic applications) as described herein), or a plant extract or plant extract blend that improves skin moisture (e.g., increases skin moisture) The composition comprises a therapeutically effective amount of a retinoid or at least one retinoid (e.g., a retinyl ester (e.g., retinyl palmitate, retinyl oleate, retinyl stearate, retinyl linoleate, retinyl palmitoleate); retinol or vitamin A; retinaldehyde or retinal; retinoic acid; or a combination thereof) to reduce water loss, increase hyaluronic acid (HA), or increase hyaluronic acid synthases (HAS; e.g., HAS1 (in fibroblasts), HAS2, and HAS3 (in keratinocytes)).

[0177] In other embodiments described herein, there is provided a formulation or topical formulation as disclosed herein, wherein the therapeutically effective amount of the blend of free amino acids or peptide combinations of amino acids comprises (or consists essentially of, or consists of) alanine (Ala), glutamine (Gln), glycine (Gly), and serine (Ser), each amino acid being in the following ratio relative to each of the other amino acids: 1:100 [0.1 to 10] or greater (e.g., 1 (Ala):100 (Gln):100 (Gly):100 (Ser) [0.1 to 10]). , 100(Ala):1(Gln):100(Gly):100(Ser) [0.1 vs. 10], 100(Ala):100(Gln):1(Gly):100(Ser) [0.1 vs. 10], 100(Ala):100(Gln):100(Gly):1(Ser) [0.1 vs. 10], 1(Ala):90(Gln):90(Gly):90(Ser) [0.1 vs. 9], 90(Ala):1(Gln):90(Gly):90(Ser) [0.1 vs. 9], 90(Ala):90(Gln):1(Gly):90(Ser) [0.1 vs. 9], 90 (Ala):90(Gln):90(Gly):1(Ser) [0.1 to 9], 1(Ala):80(Gln):80(Gly):80(Ser) [0.1 to 8], 80(Ala):1(Gln):80(Gly):80(Ser) [0.1 to 8], 80(Ala):80(Gln):1(Gly):80(Ser) [0.1 to 8], 80(Ala):80(Gln):80(Gly):1(Ser) [0.1 to 8], 1(Ala):70(Gln):70(Gly):70(Ser) [0.1 to 7], 70(Ala):1(Gln):70 (Gly):70(Ser) [0.1 vs. 7], 70(Ala):70(Gln):1(Gly):70(Ser) [0.1 vs. 7], 70(Ala):70(Gln):70(Gly):1(Ser) [0.1 vs. 7], 1(Ala):60(Gln):60(Gly):60(Ser) [0.1 vs. 6], 60(Ala):1(Gln):60(Gly):60(Ser) [0.1 vs. 6], 60(Ala):60(Gln):1(Gly):60(Ser) [0.1 vs. 6], 60(Ala):60(Gln):60(Gly):1(Ser) [0.1 to 6], 1(Ala):50(Gln):50(Gly):50(Ser) [0.1 to 5], 50(Ala):1(Gln):50(Gly):50(Ser) [0.1 to 5], 50(Ala):50(Gln):1(Gly):50(Ser) [0.1 to 5], 50(Ala):50(Gln):50(Gly):1(Ser) [0.1 to 5], 1(Ala):40(Gln):40(Gly):40(Ser) [0.1 to 4], 40(Ala):1(Gln):40(Gly):40(Ser) [0.1 to 4], 40(Ala):40(Gln n):1(Gly):40(Ser) [0.1 vs. 4], 40(Ala):40(Gln):40(Gly):1(Ser) [0.1 vs. 4], 1(Ala):30(Gln):30(Gly):30(Ser) [0.1 vs. 3], 30(Ala):1(Gln):30(Gly):30(Ser) [0.1 vs. 3], 30(Ala):30(Gln):1(Gly):30(Ser) [0.1 vs. 3], 30(Ala):30(Gln):30(Gly):1(Ser) [0.1 vs. 3], 1(Ala):20(Gln):20(Gly):20(Ser) 0.1 to 2], 20(Ala):1(Gln):20(Gly):20(Ser) [0.1 to 2], 20(Ala):20(Gln):1(Gly):20(Ser) [0.1 to 2], 20(Ala):20(Gln):20(Gly):1(Ser) [0.1 to 2], 1(Ala):10(Gln):10(Gly):10(Ser) [0.1 to 1], 10(Ala):1(Gln):10(Gly):10(Ser) [0.1 to 1], 10(Ala):10( Gln):10(Gly):1(Ser) [0.1 vs. 1], 1(Ala):5(Gln):5(Gly):5(Ser) [0.1 vs. 0.5], 5(Ala):1(Gln):5(Gly):5(Ser) [0.1 vs. 0.5], 5(Ala):5(Gln):1(Gly):5(Ser) [0.1 vs. 0.5], 5(Ala):5(Gln):5(Gly):1(Ser) [0.1 vs. 0.5], 2(Ala):5(Gln):5(Gly):5(Ser) [0.1 vs. 0.25], 5(Ala):2(Gln):5(Gly):5(Ser) [0.1 vs. 0.25].25], 5(Ala):5(Gln):2(Gly):5(Ser) [0.1 vs. 0.25], 5(Ala):5(Gln):5(Gly):2(Ser) [0.1 vs. 0.25], 1(Ala):1(Gln):1(Gly):1(Ser) [0.1 vs. 0.1], 2(Ala):1(Gln):1(Gly):1(Ser) [0.2 vs. 0.1], 1(Ala):2(Gln):1(Gly):1(Ser) [0.2 vs. 0.1], 1(Ala):1(Gln):2(Gly):1(Ser) [0.2 vs. 0.1], 1(Ala):1(Gln):1(Gly): 2(Ser) [0.2 vs. 0.1], 3(Ala):1(Gln):1(Gly):1(Ser) [0.3 vs. 0.1], 1(Ala):3(Gln):1(Gly):1(Ser) [0.3 vs. 0.1], 1(Ala):1(Gln):3(Gly):1(Ser) [0.3 vs. 0.1], 1(Ala):1(Gln):1(Gly):3(Ser) [0.3 vs. 0.1], 4(Ala):1(Gln):1(Gly):1(Ser) [0.4 vs. 0.1], 1(Ala):4(Gln):1(Gly):1(Ser) [0.4 vs. 0.1], 1(Ala):1(Gln ):4(Gly):1(Ser) [0.4 vs. 0.1], 1(Ala):1(Gln):1(Gly):4(Ser) [0.4 vs. 0.1], 1(Ala):5(Gln):5(Gly):5(Ser) [0.5 vs. 0.1], 1(Ala):5(Gln):1(Gly):1(Ser) [0.5 vs. 0.1], 1(Ala):1(Gln):5(Gly):1(Ser) [0.5 vs. 0.1], 1(Ala):1(Gln):1(Gly):5(Ser) [0.5 vs. 0.1], 6(Ala):1(Gln):1(Gly):1(Ser) [0.6 vs. 0.1], 1( Ala):6(Gln):1(Gly):1(Ser) [0.6 vs. 0.1], 1(Ala):1(Gln):6(Gly):1(Ser) [0.6 vs. 0.1], 1(Ala):1(Gln):1(Gly):6(Ser) [0.6 vs. 0.1], 7(Ala):1(Gln):1(Gly):1(Ser) [0.7 vs. 0.1], 1(Ala):7(Gln):1(Gly):1(Ser) [0.7 vs. 0.1], 1(Ala):1(Gln):7(Gly):1(Ser) [0.7 vs. 0.1], 1(Ala):1(Gln):1(Gly):7(Ser) [0.7 vs. 0.1], 8(Ala):1(Gln):1(Gly):1(Ser) [0.8 vs. 0.1], 1(Ala):8(Gln):1(Gly):1(Ser) [0.8 vs. 0.1], 1(Ala):1(Gln):8(Gly):1(Ser) [0.8 vs. 0.1], 1(Ala):1(Gln):1(Gly):8(Ser) [0.8 vs. 0.1], 9(Ala):1(Gln):1(Gly):1(Ser) [0.9 vs. 0.1], 1(Ala):9(Gln):1(Gly):1(Ser) [0.9 vs. 0.1], 1(Ala):1(Gln):9(G ly):1(Ser) [0.9 vs. 0.1], 1(Ala):1(Gln):1(Gly):9(Ser) [0.9 vs. 0.1], 10(Ala):1(Gln):1(Gly):1(Ser) [1 vs. 0.1], 1(Ala):10(Gln):1(Gly):1(Ser) [1 vs. 0.1], 1(Ala):1(Gln):10(Gly):1(Ser) [1 vs. 0.1], 1(Ala):1(Gln):1(Gly):10(Ser) [1 vs. 0.1], 20(Ala):1(Gln):1(Gly):1(Ser) [2 vs. 0.1], 1(Ala):20 (Gln):1(Gly):1(Ser) [2 to 0.1], 1(Ala):1(Gln):20(Gly):1(Ser) [2 to 0.1], 1(Ala):1(Gln):1(Gly):20(Ser) [2 to 0.1], 30(Ala):1(Gln):1(Gly):1(Ser) [3 to 0.1], 1(Ala):30(Gln):1(Gly):1(Ser) [3 to 0.1], 1(Ala):1(Gln):30(Gly):1(Ser) [3 to 0.1], 1(Ala):1(Gln):1(Gly):30(Ser) [3 to 0.1], 40( Ala):1(Gln):1(Gly):1(Ser) [4 vs. 0.1], 1(Ala):40(Gln):1(Gly):1(Ser) [4 vs. 0.1], 1(Ala):1(Gln):40(Gly):1(Ser) [4 vs. 0.1], 1(Ala):1(Gln):1(Gly):40(Ser) [4 vs. 0.1], 50(Ala):1(Gln):1(Gly):1(Ser) [5 vs. 0.1], 1(Ala):50(Gln):1(Gly):1(Ser) [5 vs. 0.1], 1(Ala):1(Gln):50(Gly):1(Ser) [5 vs. 0.1].1], 1(Ala):1(Gln):1(Gly):50(Ser) [5 to 0.1], 60(Ala):1(Gln):1(Gly):1(Ser) [6 to 0.1], 1(Ala):60(Gln):1(Gly):1(Ser) [6 to 0.1], 1(Ala):1(Gln):60(Gly):1(Ser) [6 to 0.1], 1(Ala):1(Gln):1(Gly):60(Ser) [6 to 0.1], 70(Ala):1(Gln):1(Gly):1(Ser) [7 to 0.1], 1(Ala):70(Gln):1(Gly):1( Ser) [7 to 0.1], 1(Ala):1(Gln):70(Gly):1(Ser) [7 to 0.1], 1(Ala):1(Gln):1(Gly):70(Ser) [7 to 0.1], 80(Ala):1(Gln):1(Gly):1(Ser) [8 to 0.1], 1(Ala):80(Gln):1(Gly):1(Ser) [8 to 0.1], 1(Ala):1(Gln):80(Gly):1(Ser) [8 to 0.1], 1(Ala):1(Gln):1(Gly):80(Ser) [8 to 0.1], 90(Ala):1(Gln):1 (Gly):1(Ser) [9 to 0.1], 1(Ala):90(Gln):1(Gly):1(Ser) [9 to 0.1], 1(Ala):1(Gln):90(Gly):1(Ser) [9 to 0.1], 1(Ala):1(Gln):1(Gly):90(Ser) [9 to 0.1], 100(Ala):1(Gln):1(Gly):1(Ser) [10 to 0.1], 1(Ala):100(Gln):1(Gly):1(Ser) [10 to 0.1], 1(Ala):1(Gln):100(Gly):1(Ser) [10 to 0.1], 1( Ala):1(Gln):1(Gly):100(Ser) [10 to 0.1]; 100:1 [10 to 0.1] or less (e.g., 95(Ala):1(Gln):1(Gly):1(Ser) [9.5 to 0.1], 1(Ala):95(Gln):1(Gly):1(Ser) [9.5 to 0.1], 1(Ala):1(Gln):95(Gly):1(Ser) [9.5 to 0.1], 1(Ala):1(Gln):1(Gly):95(Ser) [9.5 to 0.1], 85(Ala):1(Gln):1(Gly):1(Ser) [8.5 to 0.1]).1], 1(Ala):85(Gln):1(Gly):1(Ser) [8.5 vs. 0.1], 1(Ala):1(Gln):85(Gly):1(Ser) [8.5 vs. 0.1], 1(Ala):1(Gln):1(Gly):85(Ser) [8.5 vs. 0.1], 75(Ala):1(Gln):1(Gly):1(Ser) [7.5 vs. 0.1], 1(Ala):75(Gln):1(Gly):1(Ser) [7.5 vs. 0.1], 1(Ala):1(Gln. ):75(Gly):1(Ser) [5.5 vs. 0.1], 1(Ala):1(Gln):1(Gly):55(Ser) [5.5 vs. 0.1], 65(Ala):1(Gln):1(Gly):1(Ser) [6.5 vs. 0.1], 1(Ala):65(Gln):1(Gly):1(Ser) [6.5 vs. 0.1], 1(Ala):1(Gln):65(Gly):1(Ser) [6.5 vs. 0.1], 1(Ala):1(Gln):1(Gly):65(Ser) [6.5 vs. 0.1], 55(Ala):1(Gln):1(Gly):1(Ser ) [5.5 vs. 0.1], 1(Ala):55(Gln):1(Gly):1(Ser) [5.5 vs. 0.1], 1(Ala):1(Gln):55(Gly):1(Ser) [5.5 vs. 0.1], 1(Ala):1(Gln):1(Gly):55(Ser) [5.5 vs. 0.1], 45(Ala):1(Gln):1(Gly):1(Ser) [4.5 vs. 0.1], 1(Ala):45(Gln):1(Gly):1(Ser) [4.5 vs. 0.1], 1(Ala):1(Gln):45(Gly):1(Ser) [4.5 vs. 0.1], 1(Al a):1(Gln):1(Gly):45(Ser) [4.5 vs. 0.1], 35(Ala):1(Gln):1(Gly):1(Ser) [3.5 vs. 0.1], 1(Ala):35(Gln):1(Gly):1(Ser) [3.5 vs. 0.1], 1(Ala):1(Gln):35(Gly):1(Ser) [3.5 vs. 0.1], 1(Ala):1(Gln):1(Gly):35(Ser) [3.5 vs. 0.1], 25(Ala):1(Gln):1(Gly):1(Ser) [2.5 vs. 0.1], 1(Ala):25(Gln):1(Gl y):1(Ser) [2.5 vs. 0.1], 1(Ala):1(Gln):25(Gly):1(Ser) [2.5 vs. 0.1], 1(Ala):1(Gln):1(Gly):25(Ser) [0.1 vs. 0.5], 15(Ala):1(Gln):1(Gly):1(Ser) [1.5 vs. 0.1], 1(Ala):15(Gln):1(Gly):1(Ser) [1.5 vs. 0.1], 1(Ala):1(Gln):15(Gly):1(Ser) [1.5 vs. 0.1], 1(Ala):1(Gln):1(Gly):15(Ser) [1.5 vs. 0.1].1], 14(Ala):1(Gln):1(Gly):1(Ser) [1.4 vs. 0.1], 1(Ala):14(Gln):1(Gly):1(Ser) [1.4 vs. 0.1], 1(Ala):1(Gln):14(Gly):1(Ser) [1.4 vs. 0.1], 1(Ala):1(Gln):1(Gly):14(Ser) [1.4 vs. 0.1], 13(Ala):1(Gln):1(Gly):1(Ser) [1.3 vs. 0.1], 1(Ala):13(Gln):1(Gly):1(Ser) [1.3 vs. 0.1], 1(Ala):1(Gln):1 3(Gly):1(Ser) [1.3 vs. 0.1], 1(Ala):1(Gln):1(Gly):13(Ser) [1.3 vs. 0.1], 12(Ala):1(Gln):1(Gly):1(Ser) [1.2 vs. 0.1], 1(Ala):12(Gln):1(Gly):1(Ser) [1.2 vs. 0.1], 1(Ala):1(Gln):12(Gly):1(Ser) [1.2 vs. 0.1], 1(Ala):1(Gln):1(Gly):12(Ser) [1.2 vs. 0.1], 11(Ala):1(Gln):1(Gly):1(Ser) [1.1 vs. 0.1] .1], 1(Ala):11(Gln):1(Gly):1(Ser) [1.1 vs. 0.1], 1(Ala):1(Gln):11(Gly):1(Ser) [1.1 vs. 0.1], 1(Ala):1(Gln):1(Gly):11(Ser) [1.1 vs. 0.1], 10(Ala):1(Gln):1(Gly):1(Ser) [1 vs. 0.1], 1(Ala):10(Gln):1(Gly):1(Ser) [1 vs. 0.1], 1(Ala):1(Gln):10(Gly):1(Ser) [1 vs. 0.1], 1(Ala):1(Gln):1(Gly) :10(Ser) [1 vs. 0.1], 19(Ala):2(Gln):2(Gly):2(Ser) [0.95 vs. 0.1], 2(Ala):19(Gln):2(Gly):2(Ser) [0.95 vs. 0.1], 2(Ala):2(Gln):19(Gly):2(Ser) [0.95 vs. 0.1], 2(Ala):2(Gln):2(Gly):19(Ser) [0.95 vs. 0.1], 17(Ala):2(Gln):2(Gly):2(Ser) [0.85 vs. 0.1], 2(Ala):17(Gln):2(Gly):2(Ser) [0.85 vs. 0.1], 2(Ala):2(Gln):17(Gly):2(Ser) [0.85 vs. 0.1], 2(Ala):2(Gln):2(Gly):17(Ser) [0.85 vs. 0.1], 15(Ala):2(Gln):2(Gly):2(Ser) [0.75 vs. 0.1], 2(Ala):15(Gln):2(Gly):2(Ser) [0.75 vs. 0.1], 2(Ala):2(Gln):15(Gly):2(Ser) [0.75 vs. 0.1], 2(Ala):2(Gln):2(Gly):15(Ser) [0.75 vs. 0.1], 13(Ala):2(Gl n):2(Gly):2(Ser) [0.65 vs. 0.1], 2(Ala):13(Gln):2(Gly):2(Ser) [0.65 vs. 0.1], 2(Ala):2(Gln):13(Gly):2(Ser) [0.65 vs. 0.1], 2(Ala):2(Gln):2(Gly):13(Ser) [0.65 vs. 0.1], 11(Ala):2(Gln):2(Gly):2(Ser) [0.55 vs. 0.1], 2(Ala):11(Gln):2(Gly):2(Ser) [0.55 vs. 0.1], 2(Ala):2(Gln):11(Gly):2(Ser ) [0.55 vs. 0.1], 2(Ala):2(Gln):2(Gly):11(Ser) [0.55 vs. 0.1], 9(Ala):2(Gln):2(Gly):2(Ser) [0.45 vs. 0.1], 2(Ala):9(Gln):2(Gly):2(Ser) [0.45 vs. 0.1], 2(Ala):2(Gln):9(Gly):2(Ser) [0.45 vs. 0.1], 2(Ala):2(Gln):2(Gly):9(Ser) [0.45 vs. 0.1], 7(Ala):2(Gln):2(Gly):2(Ser) [0.35 vs. 0.1], 2(Ala):7 (Gln):2(Gly):2(Ser) [0.35 vs. 0.1], 2(Ala):2(Gln):7(Gly):2(Ser) [0.35 vs. 0.1], 2(Ala):2(Gln):2(Gly):7(Ser) [0.35 vs. 0.1], 5(Ala):2(Gln):2(Gly):2(Ser) [0.25 vs. 0.1], 2(Ala):5(Gln):2(Gly):2(Ser) [0.25 vs. 0.1], 2(Ala):2(Gln):5(Gly):2(Ser) [0.25 vs. 0.1], 2(Ala):2(Gln):2(Gly):5(Ser) [0.25 vs. 0.1], 3(Ala):2(Gln):2(Gly):2(Ser) [0.15 vs. 0.1], 2(Ala):3(Gln):2(Gly):2(Ser) [0.15 vs. 0.1], 2(Ala):2(Gln):3(Gly):2(Ser) [0.15 vs. 0.1], 2(Ala):2(Gln):2(Gly):3(Ser) [0.15 vs. 0.1], 2(Ala):3(Gln):3(Gly):3(Ser) [0.1 vs. 0.15], 3(Ala):2(Gln):3(Gly):3(Ser) [0.1 vs. 0.15], 3(Ala) :3(Gln):2(Gly):3(Ser) [0.1 vs. 0.15], 3(Ala):3(Gln):3(Gly):2(Ser) [0.1 vs. 0.15], 2(Ala):5(Gln):5(Gly):5(Ser) [0.1 vs. 0.25], 5(Ala):2(Gln):5(Gly):5(Ser) [0.1 vs. 0.25], 5(Ala):5(Gln):2(Gly):5(Ser) [0.1 vs. 0.25], 5(Ala):5(Gln):5(Gly):2(Ser) [0.1 vs. 0.25], 2(Ala):7(Gln):7(Gly) :7(Ser) [0.1 vs. 0.35], 7(Ala):2(Gln):7(Gly):7(Ser) [0.1 vs. 0.35], 7(Ala):7(Gln):2(Gly):7(Ser) [0.1 vs. 0.35], 7(Ala):7(Gln):7(Gly):2(Ser) [0.1 vs. 0.35], 2(Ala):9(Gln):9(Gly):9(Ser) [0.1 vs. 0.45], 9(Ala):2(Gln):9(Gly):9(Ser) [0.1 vs. 0.45], 9(Ala):9(Gln):2(Gly):9(Ser) [0.1 vs. 0. 45], 9(Ala):9(Gln):9(Gly):2(Ser) [0.1 vs. 0.45], 2(Ala):11(Gln):11(Gly):11(Ser) [0.1 vs. 0.55], 11(Ala):2(Gln):11(Gly):11(Ser) [0.1 vs. 0.55], 11(Ala):11(Gln):2(Gly):11(Ser) [0.1 vs. 0.55], 11(Ala):11(Gln):11(Gly):2(Ser) [0.1 vs. 0.55], 2(Ala):13(Gln):13(Gly):13(Ser) [0.1 vs. 0.65], 13(Ala):2(Gln):13(Gly):13(Ser) [0.1 vs. 0.65], 13(Ala):13(Gln):2(Gly):13(Ser) [0.1 vs. 0.65], 13(Ala):13(Gln):13(Gly):2(Ser) [0.1 vs. 0.65], 2(Ala):15(Gln):15(Gly):15(Ser) [0.1 vs. 0.75], 15(Ala):2(Gln):15(Gly):15(Ser) [0.1 vs. 0.75], 15(Ala):15(Gln):2(Gly):15(Ser) 0.1 vs. 0.75], 15(Ala):15(Gln):15(Gly):2(Ser) [0.1 vs. 0.75], 2(Ala):17(Gln):17(Gly):17(Ser) [0.1 vs. 0.85], 17(Ala):2(Gln):17(Gly):17(Ser) [0.1 vs. 0.85], 17(Ala):17(Gln):2(Gly):17(Ser) [0.1 vs. 0.85], 17(Ala):17(Gln):17(Gly):2(Ser) [0.1 vs. 0.85], 2(Ala):19(Gln):19(Gly):19 (Ser) [0.1 vs. 0.95], 19(Ala):2(Gln):19(Gly):19(Ser) [0.1 vs. 0.95], 19(Ala):19(Gln):2(Gly):19(Ser) [0.1 vs. 0.95], 19(Ala):19(Gln):19(Gly):2(Ser) [0.1 vs. 0.95]; or 1:100–100:1 (e.g., 1(Ala):100(Gln):100(Gly):100(Ser) [0.1 vs. 10]–100(Ala):1(Gln):1(Gly):1(Ser) [10 vs. 0.1], 1 00(Ala):1(Gln):100(Gly):100(Ser) [0.1 to 10] to 1(Ala):100(Gln):1(Gly):1(Ser) [10 to 0.1], 100(Ala):100(Gln):1(Gly):100(Ser) [0.1 to 10] to 1(Ala):1(Gln):100(Gly):1(Ser) [10 to 0.1], 100(Ala):100(Gln):100(Gly):1(Ser) [0.1 to 10] to 1(Ala):1(Gln):1(Gly):100(Ser) [10 to 0.1]).

[0178] In some embodiments, the formulations (or topical formulations) described herein comprise a therapeutically effective amount of a blend of free amino acids or peptide combinations thereof, comprising, consisting essentially of, or consisting of at least one of alanine, glutamine, glycine, and serine, or salts thereof; and a therapeutically effective amount of a plant extract (e.g., Boswellia serrata; Burseraceae family; olibanum; frankincense; or combinations thereof) or a plant extract blend (e.g., Boswellia extract (e.g., Boswellia serrata; Burseraceae family; olibanum; frankincense); texturing agents and / or fillers (e.g., cellulose (microcrystalline); phospholipids (e.g., lecithin or phosphatidylcholine); and anti-caking agents (e.g., silica, which adsorbs water in hygroscopic applications)), or a therapeutically effective amount of a retinoid or at least one retinoid (e.g., retinyl esters (e.g., retinyl palmitate, retinyl oleate, retinyl stearate, retinyl linoleate, retinyl palmitoleate); retinol or vitamin A; retinaldehyde or retinal; retinoic acid; or combinations thereof).

[0179] Formulations for treating osteoarthritis and uses thereof In some embodiments, a formulation for treating or ameliorating the symptoms of osteoarthritis is provided. Such formulations include, as free amino acids or peptide combinations of amino acids, (a) alanine, glutamine, glycine, and serine, or salts thereof, and, optionally, a therapeutically effective amount of at least one of arginine, isoleucine, threonine, tryptophan, or valine (e.g., alanine, glutamine, glycine, and serine, and arginine or isoleucine or threonine or tryptophan or valine; arginine and isoleucine; arginine and threonine; arginine and tryptophan; arginine and valine; isoleucine and threonine; isoleucine and tryptophan; isoleucine and valine; threonine and tryptophan; threonine and valine; tryptophan and valine; arginine, isoleucine, and threonine; arginine, isoleucine, and tryptophan; arginine). , isoleucine, and valine; arginine, threonine, and tryptophan; arginine, threonine, and valine; arginine, tryptophan, and valine; isoleucine, threonine, and tryptophan; isoleucine, threonine, and valine; isoleucine, tryptophan, and valine; threonine, tryptophan, and valine; arginine, isoleucine, threonine, and tryptophan; arginine, isoleucine, threonine, and valine; arginine, threonine, tryptophan, and valine; isoleucine, threonine, tryptophan, and valine; arginine, isoleucine, threonine, and valine; isoleucine, threonine, tryptophan, and valine; arginine, isoleucine, tryptophan, and valine; arginine, isoleucine, threon ...), or salts thereof, or combinations thereof, in a therapeutically effective amount. Another aspect of such embodiments is directed to such formulations for treating or ameliorating the symptoms of osteoarthritis, wherein such formulations comprise, as free amino acids or peptide combinations of amino acids, (b) at least one of alanine, glutamine, glycine, and serine (e.g., alanine; glutamine; glycine; serine; alanine and glutamine; alanine and glycine; alanine and serine;The composition may comprise (or consist essentially of, or consist of) a therapeutically effective amount of glutamine and glycine; glutamine and serine; glycine and serine; alanine and glutamine and glycine; glutamine and glycine and serine; alanine and glycine and serine; alanine and glutamine and serine; and alanine and glutamine and glycine and serine), or a salt thereof, or a combination thereof; and a therapeutically effective amount of a retinoid (e.g., retinyl esters (e.g., retinyl palmitate, retinyl oleate, retinyl stearate, retinyl linoleate, retinyl palmitoleate); retinol or vitamin A; retinaldehyde or retinal; retinoic acid; or a combination thereof). Additional embodiments of such formulations include formulations that optionally contain pharmaceutically acceptable vehicles and / or additives. Such formulations for treating or ameliorating the symptoms of osteoarthritis described herein may be in the form of an injectable formulation. In a further aspect, the use of such a formulation for treating or ameliorating the symptoms of osteoarthritis is also provided, wherein the formulation is injected into the affected area of ​​a subject suffering from osteoarthritis. For example, osteoarthritis occurs in joints such as the wrist, hip, knee, ankle, and foot, among other sites. The formulation for treating or ameliorating the symptoms of osteoarthritis may contain 0.05 mM or more (e.g., 0.07, 0.09, 0.11, 0.13, 0.15, 0.17, 0.19, 0.21, 0.23, 0.25, 0.27, 0.29, 0.31, 0.33, 0.35, 0.37, 0.39, 0.41, 0.43, 0.45, 0.47, 0.49, 0.51, 0.53, 0.55, 0.57, 0.59, 0.61, 0.63, 0.65, 0.67, 0.69, 0.71, 0.73, 0.75, 0.77, 0.79, 0.81, 0.83, 0.85, 0.87, 0.89, 0.91, 0.93, 0.95, 0.97, 0.99, 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25);20 mM or less (e.g., 18, 16, 14, 12, 10, 8, 6, 4, 2, 0.98, 0.96, 0.94, 0.92, 0.9, 0.88, 0.86, 0.84, 0.82, 0.8, 0.78, 0.76, 0.74, 0.72, 0.7, 0.68, 0.66, 0.64, 0.62, 0.6, 0.58, 0.56, 0.54, 0.52, 0.5, 0.48, 0.46, 0.44, 0.42, 0.4, 0.38, 0.36, 0.34, 0.32, 0.3, 0.28, 0.26, 0. 24, 0.22, 0.2, 0.18, 0.16, 0.14, 0.12, 0.1, 0.08, 0.06, 0.04, 0.02); or 0.05 mM to 20 mM (e.g., 0.06 to 19, 0.07 to 18, 0.08 to 17, 0.09 to 16, 0.1 to 15, 0.11 to 14, 0.12 to 13, 0.13 to 12, 0.14 to 11, 0.15 to 10, 0.16 to 9, 0.17 to 8, 0.18 to 7, 0.19 to 6, 0.2 to 5, 0.21 to 4, 0.22 to 3, 0.23 to 2, 0.24 to 5, 0.25 to 4, 0.26 to 3, 0.27 to 2, 0.28 to 3, 0.29 to 4, 0.30 to 3, 0.31 to 3, 0.32 to 3, 0.33 to 2, 0.34 to 3, 0.35 to 3, 0.36 to 3, 0.37 to 3, 0.38 to 3, 0.39 to 4, 0.40 to 4, 0.41 to 4, 0.42 to 3, 0.43 to 2, 0.44 to 3, 0.45 to 3, 0.46 to 3, 0.47 to 3, 0.48 to 3, 0.49 to 4, 0.50 to 5, 0.51 to 5, 0. 1, 0.25~0.99, 0.26~0.98, 0.27~0.97, 0.28~0.96, 0.29~0.95, 0.3~0.94, 0.31~0.93, 0.32~0.92, 0.33~0.91, 0.34~0.9, 0.35~0.89, 0.36~0.88, 0.37~0.87, 0.38~0.86, 0.39~0.85, 0.4~0.84, 0.41~0.83, 0.42~0.82, 0.43~0.81, 0.44~0.8, 0.45~0.79, 0.46~0. 0.78, 0.47-0.77, 0.48-0.76, 0.49-0.75, 0.5-0.74, 0.51-0.73, 0.52-0.72, 0.53-0.71, 0.54-0.7, 0.55-0.69, 0.56-0.68, 0.57-0.67, 0.58-0.66, 0.59-0.65, 0.6-0.64, 0.61-0.63) in a therapeutically effective amount as a free amino acid or peptide combination of amino acids. In some embodiments, the formulation comprises a retinoid (e.g., a retinyl ester (e.g., retinyl palmitate, retinyl oleate, retinyl stearate, retinyl linoleate, retinyl palmitoleate); retinol or vitamin A; retinaldehyde or retinal; retinoic acid;or a combination thereof), wherein the retinoid is present in an amount of 0.01% or more by weight of the formulation (e.g., 0.03, 0.05, 0.07, 0.09, 0.11, 0.13, 0.15, 0.17, 0.19, 0.21, 0.23, 0.25, 0.27, 0.29, 0.31, 0.33, 0.35, 0.37, 0.39, 0.41, 0.43, 0.45, 0.47, 0.49, 0.51, 0.53, 0.55, 0.57, 0.59, 0.61, 0.63, 0.65, 0.67, 0.69, 0.71, 0.73, 0.75, 0.77, 0.79, 0.81, 0.83, 0.85, 0.87, 0.89, 0.91, 0.93, 0.95, 0.97, 0.99, 1.1, 1.3, 1.5, 1.7, 1.9, 2.1, 2.3, 2.5, 2.7, 2.9, 3.1, 3.3, 3.5, 3.7, 3.9, 4.1, 4.3, 4.5, 4.7, 4.9, 5.1, 5.3, 5.5, 5.7, 5.9, 6.1, 6.3, 6.5, 6.7, 6.9, 7.1, 7.3, 7.5, 7.7, 7.9, 8.1, 8.3, 8.5, 8.7, 8.9, 9.1, 9.3, 9.5, 9.7, 9.9, 10.1, 10.3, 10.5, 10.7, 10.9, 11.1); 10% by weight or less of the formulation (e.g., 9.8, 9.6, 9.4, 9.2, 9.8, 8.6, 8.4, 8.2, 8.7, 9.8, 9.9, 10.1, 10.3, 10.5, 10.7, 10.9, 11.1); 8, 7.6, 7.4, 7.2, 7, 6.8, 6.6, 6.4, 6.2, 6, 5.8, 5.6, 5.4, 5.2, 5, 4.8, 4.6, 4.4, 4.2, 4, 3.8, 3.6, 3.4, 3.2, 3, 2.8, 2.6, 2.4, 2.2, 2, 1.8, 1.6, 1.4, 1.2, 1, 0.8, 0.6, 0.4, 0.2, 0.08, 0.06, 0.04, 0.02, 0.008, 0.006, 0.004, 0.002);or 0.01% to 10% by weight of the formulation (e.g., 0.02% to 9.9%, 0.03% to 9.8%, 0.04% to 9.7%, 0.05% to 9.6%, 0.06% to 9.5%, 0.07% to 9.4%, 0.08% to 9.3%, 0.09% to 9.2%, 0.1% to 9.1%, 0.2% to 9%, 0.3% to 8.9%, 0.4% ~8.8%, 0.5%~8.7%, 0.6%~8.6%, 0.7%~8.5%, 0.8%~8.4%, 0.9%~8.3%, 1%~8.2%, 1.1%~8.1%, 1.2%~8%, 1.3%~7.9%, 1.4%~7.8%, 1.5%~7.7%, 1.6%~7.6%, 1.7%~7.5%, 1.8%~7.4%, 1. 9%~7.3%, 2%~7.2%, 2.1%~7.1%, 2.2%~7%, 2.3%~6.9%, 2.4%~6.8%, 2.5%~6.7%, 2.6%~6.6%, 2.7%~6.5%, 2.8%~6.4%, 2.9%~6.3%, 3%~6.2%, 3.1%~6.1%, 3.2%~6%, 3.3%~5.9%, 3.4% ~5.8%, 3.5%~5.7%, 3.6%~5.6%, 3.7%~5.5%, 3.8%~5.4%, 3.9%~5.3%, 4%~5.2%, 4.1%~5.1%, 4.2%~5%, 4.3%~4.9%, 4.4%~4.8%, 4.5%~4.7%) contained in (or essentially consisting of or consisting of);

[0180] In some embodiments, provided herein are methods of treating a subject suffering from osteoarthritis, such methods comprising (or consisting essentially of, or consisting of) administering by injection to a joint of the subject (e.g., a hand joint, a hip joint, or a knee joint) in a subject suffering from osteoarthritis, wherein such therapeutically effective amount of the formulation is a therapeutically effective amount of a compound, as free amino acids or peptide combinations, comprising: (a) alanine, glutamine, glycine, and serine, or salts thereof; and optionally, a therapeutically effective amount of arginine. at least one of alanine, glutamine, glycine, and serine, and arginine or isoleucine or threonine or tryptophan or valine; arginine and isoleucine; arginine and threonine; arginine and tryptophan; arginine and valine; isoleucine and threonine; isoleucine and tryptophan; isoleucine and valine; threonine and tryptophan; threonine and valine; tryptophan and valine; arginine leucine, isoleucine, and threonine; arginine, isoleucine, and tryptophan; arginine, isoleucine, and valine; arginine, threonine, and tryptophan; arginine, threonine, and valine; arginine, tryptophan, and valine; isoleucine, threonine, and tryptophan; isoleucine, threonine, and valine; isoleucine, tryptophan, and valine; threonine, tryptophan, and valine; arginine, isoleucine, threonine, and tryptophan ... leucine, and valine; arginine, threonine, tryptophan, and valine; isoleucine, threonine, tryptophan, and valine; arginine, isoleucine, tryptophan, and valine; arginine, isoleucine, threonine, tryptophan, and valine; arginine, isoleucine, threonine, tryptophan, and valine), or any combination thereof; or (b) at least one of alanine, glutamine, glycine, and serine (e.g., alanine; glutamine; glycine; serine; alanine and glutamine; alanine and glycine; alanine and serine; glutamine and glycine;or alanine and glutamine and glycine; glutamine and serine; glycine and serine; alanine and glycine and serine; alanine and glutamine and serine; and alanine and glutamine and glycine and serine), or a salt thereof; or (c) (i) at least one of alanine, glutamine, glycine, and serine (e.g., alanine; glutamine; glycine; serine; alanine and glutamine; alanine and glycine; alanine and serine; glutamine and glycine; glutamine and serine; glycine alanine and glutamine and glycine; alanine and glutamine and glycine; glutamine and glycine and serine; alanine and glycine and serine; alanine and glutamine and serine; and alanine and glutamine and glycine and serine), or salts thereof; and (c)(ii) a therapeutically effective amount of a retinoid, including retinyl esters (e.g., retinyl palmitate, retinyl oleate, retinyl stearate, retinyl linoleate, retinyl palmitoleate); retinol or vitamin A; retinaldehyde or retinal; retinoic acid;or a combination thereof. Some embodiments are directed to formulations further optionally comprising a pharmaceutically acceptable vehicle and / or additives. In one embodiment, the pharmaceutically acceptable vehicle and / or additives are sterile. Such methods of treating a subject suffering from osteoarthritis or its symptoms by administering these injectable formulations comprising a therapeutically effective amount of an amino acid described herein, either alone or in combination with a therapeutically effective amount of a retinoid described herein, result in one or more of: decreased pain, increased hyaluronic acid synthesis, increased proliferation of elastin and / or collagen, or a combination thereof, compared to a control or untreated subject (healthy subject or subject not suffering from osteoarthritis). In some embodiments, such formulations as described herein, including, but not limited to, therapeutically effective amounts of formulations, including, as free amino acids or peptide combinations, a therapeutically effective amount of a formulation comprising (or consisting essentially of, or consisting of) alanine, glutamine, glycine, and serine, or salts thereof, and optionally a therapeutically effective amount of at least one of arginine, isoleucine, threonine, tryptophan, or valine; and a therapeutically effective amount of a retinoid comprising (or consisting essentially of, or consisting of) at least one of a retinyl ester (e.g., retinyl palmitate, retinyl oleate, retinyl stearate, retinyl linoleate, retinyl palmitoleate); retinol or vitamin A; retinaldehyde or retinal; retinoic acid; or combinations thereof;And optionally, formulations comprising (or consisting essentially of, or consisting of) pharmaceutically acceptable vehicles and / or additives increase hyaluronic acid synthesis in subjects treated with such formulations compared to controls or untreated subjects, thereby increasing hyaluronic acid lubrication and hydration, and increasing elastin and / or collagen proliferation. Administration of such injectable formulations is performed daily, weekly, or monthly. In some embodiments, a single injection or multiple injections (e.g., 2, 3, 4, 5, 6) are provided daily, weekly, or monthly. In additional embodiments, therapeutically effective amounts of amino acids (free amino acids or peptide combinations thereof), either alone or in combination with the retinoids described herein, can be administered simultaneously or sequentially, and / or together or separately. Further embodiments provide single or multiple unit dosage forms of the injectable formulations described herein.

[0181] Exemplary Vehicles and Additives Other embodiments directed to any of the formulations described herein further optionally comprise, consist essentially of, or consist of dermatologically acceptable vehicles and / or additives. Non-limiting examples of vehicles and additives useful in any of the formulations or topical formulations described herein may be selected from the group consisting of: water, sodium phytate, xanthan gum, kaolin, glycerin, polyglycerides (e.g., oleic acid polyglyceride, linoleic acid polyglyceride, linoleic acid polyglyceride), triglycerides (e.g., caprylic acid triglyceride, capric acid triglyceride), sucrose (e.g., sucrose stearate, sucrose distearate), alcohols (e.g., behenyl alcohol, benzoic alcohol, benzyl alcohol, cetearyl alcohol, oleyl alcohol), cetearyl glucoside, sodium stearoyl lactylate, Cera Alba (beeswax), Butyrospermum parkii (shea butter), Prunus amigdalus sulcis (sweet almond oil), Simmondsia chinensis (Jojoba) seed oil, Jojoba (Jojoba) Oil, Phenoxyethanol, Lecithin, Tocopherol, Tocopheryl Acetate, Ascorbyl Palmitate, Citric Acid, Potassium Sorbate, Lactic Acid, UV Protection Agents, Hydrogenated Olive Oil Decyl Ester, Decyl Cocoate, Astrocaryum Murumuru (Astrocaryum) Seed Butter, Zanthoxylum Bungeanum (Zanthoxylum Bungeanum) Fruit Extract, Squalene, Pentylene Glycol, Dehydroacetic Acid, Tamarinds Indica (Tamarind) Seed Polysaccharide, Sodium Benzoate, Curcumin, Zanthoxylum Bungeanume (Zanthoxylum Bungeanume) Fruit Extract, Passiflora edulis seed oil, cetearyl ethylhexanoate, dimethicone, isopropyl myristate, acrylates / C10-C30 alkyl acrylate crosspolymer, allantoin, sodium phytate, PEG-90 stearate / glyceryl stearate; menthol, sodium hydroxide, sodium benzoate, dehydroacetic acid, benzoic alcohol, hexyldecanol, cetaryl ethylhexanoate, dimethicone, cetearyl ethylhexanoatePEG-90 Stearate / Glyceryl Stearate, Ascorbyl Palmitate, Citric Acid, Zanthoxylum bungeanum Fruit Extract, Allantoin, Disodium EDTA, Phenoxyethanol, Dehydroacetic Acid, Allantoin, XILOGEL®, Vaccinium Myrtillus Fruit Extract, Oryza Sativa (e.g., Rice Bran Oil), Isoamyl Laurate, Polymethyl Methacrylate, Fragrance, Nutrients, Antioxidants, Water, or combinations thereof. Additional formulation embodiments described herein can further include at least one dermatologically acceptable additive, such as an inactive ingredient useful for delivering the active ingredient, preserving, providing feel and / or scent to the formulation, providing other benefits to the skin, and the like, or combinations thereof, including, but not limited to, carriers, diluents, excipients, anti-aging ingredients (e.g., collagen stimulators), antioxidants (e.g., butylhydroxytoluene (BHT), ascorbic acid, sodium ascorbate, ascorbyl palmitate, beta-carotene, glycolic acid, hyaluronic acid), antibacterial agents, antifungal agents, antihistamines, anti-inflammatory agents, anti-irritants, antimycobacterial agents, preservatives, analgesics, colorants, emollients (dimethicone oil, ester oil, or hydrocarbon oil), natural fragrances, and the like. The composition may include, but is not limited to, synthetic fragrances, humectants (e.g., polyols such as propylene glycol and glycerin), beta-hydroxy acids (e.g., salicylic acid), depigments (e.g., kojic acid, thiodipropionic acid (TDPA), nicotinamide), emulsifiers, film formers, bulking agents, such as those that impart bulk, texture, or lubricity (e.g., silica, talc, zinc stearate, mica, kaolin, nylon powder), gelling agents, humectants, minerals, moisturizers, plant extracts or oils, viscosity or rheology modifiers (e.g., thickeners), skin protectants, skin penetration enhancers, stabilizers, structurants, sunscreens, surfactants, vitamins (e.g., tocopherol, tocopheryl acetate), and the like, and combinations or mixtures thereof. The formulator must ensure that the vehicle, carrier, excipient, diluent, or combination thereof serves primarily to deliver a safe and stable formulation, and that the formulation contains (a) a therapeutically effective amount of, as free amino acids or peptide combinations of amino acids,(b) a formulation of free amino acids or peptide combinations of amino acids comprising, consisting essentially of, or consisting of alanine, glutamine, glycine, and serine, and optionally a therapeutically effective amount of at least one additional free amino acid or peptide combination of amino acids valine, isoleucine, arginine, threonine, or tryptophan, or any combination thereof; (c) a formulation of free amino acids or peptide combinations of amino acids comprising, as free amino acids or peptide combinations of amino acids, a therapeutically effective amount of at least one additional free amino acid or peptide combination of amino acids valine, isoleucine, arginine, threonine, or tryptophan, or any combination thereof; and alanine and glutamine and glycine and serine; alanine and glutamine and glycine; alanine and serine; glutamine and glycine; glutamine and serine; glycine and serine; alanine and glutamine and glycine; glutamine and glycine and serine; alanine and glutamine and serine; alanine and glycine and serine; and alanine and glutamine and glycine and serine); and a therapeutically effective amount of a plant extract or plant extract formulation, wherein the plant extract is Boswellia extract (e.g., Boswellia serrata; Burseraceae family; olibanum; frankincense), or a plant extract blend (e.g., BOSEXIL® (INDENA SpA) or Boswellia serrata resin extract, cellulose (microcrystalline), lecithin, silica) comprising (or consisting essentially of, or consisting of) Boswellia extract (e.g., Boswellia serrata; Burseraceae family; olibanum; frankincense); texturing agents and / or fillers (e.g., cellulose (microcrystalline)); emulsifiers or phospholipids (in some embodiments, phospholipids are used as emulsifiers) (e.g., lecithin or phosphatidylcholine); and anti-caking agents (e.g., silica, which adsorbs water in hygroscopic applications),(c) a therapeutically effective amount of a blend of free amino acids or peptide combinations of amino acids, comprising or consisting essentially of at least one of alanine, glutamine, glycine, and serine (e.g., alanine; glutamine; glycine; serine; alanine and glutamine; alanine and glycine; alanine and serine; glutamine and glycine; glutamine and serine; glutamine and glycine and serine; alanine and glycine and serine; alanine and glycine and serine; alanine and glutamine and serine; and alanine and glutamine and glycine and serine), or salts thereof, as free amino acids or peptide combinations of amino acids. and a therapeutically effective amount of a retinoid, retinoid derivative, or retinoid precursor (e.g., a retinyl ester (e.g., retinyl palmitate, retinyl oleate, retinyl stearate, retinyl linoleate, retinyl palmitoleate); retinol or vitamin A; retinaldehyde or retinal; retinoic acid; or combinations thereof), wherein the formulations of (a), (b), or (c) optionally comprise, consist essentially of, or consist of dermatologically or pharmaceutically acceptable vehicles and / or additives, can contain additional inactive ingredients.

[0182] Use of formulations for repairing and strengthening the skin barrier In some embodiments of the present disclosure, there is provided a formulation or topical formulation as described herein, comprising a therapeutically effective amount of a blend of free amino acids or peptide combinations thereof, comprising, consisting essentially of, or consisting of at least one of alanine, glutamine, glycine, and serine, or salts thereof; and a therapeutically effective amount of a plant extract (e.g., Boswellia serrata; Burseraceae family; olibanum; frankincense; or combinations thereof) or a plant extract blend (e.g., Boswellia extract (e.g., Boswellia serrata; Burseraceae family; olibanum; frankincense); texturing agents and / or fillers (e.g., cellulose (microcrystalline); phospholipids (e.g., lecithin or phosphatidylcholine); and anti-caking agents (e.g., silica, to adsorb water in hygroscopic applications)). In additional aspects, a therapeutically effective amount of a blend of free amino acids or peptide combinations thereof and a therapeutically effective amount of a plant extract or plant extract blend improves skin barrier repair. Improvements in skin barrier repair include skin barrier correction, skin barrier strengthening, skin barrier preservation, skin barrier integrity, wound healing, and the like. These include, but are not limited to, wound healing; growth, stimulation, proliferation, differentiation, and migration of epidermal cells, keratinocytes, endothelial cells, and fibroblasts; promotion of dermal regeneration, and combinations thereof. A further aspect is directed to the modulation of epidermal growth factor (EGF) using a therapeutically effective amount of an amino acid combination or formulation comprising (or consisting essentially of, or consisting of) an amino acid combination described herein, such amino acid combination comprising, consisting essentially of, or consisting of at least one of alanine, glutamine, glycine, and serine, or salts thereof, for example, in a 1:1:1:1 ratio.

[0183] In additional embodiments, a method for improving skin barrier repair in a subject's skin includes a topical formulation comprising a therapeutically effective amount of a blend of free amino acids or peptide combinations thereof, comprising (or consisting essentially of, or consisting of) at least one of alanine, glutamine, glycine, and serine, or salts thereof; and a therapeutically effective amount of a plant extract blend (e.g., Boswellia serrata resin extract, cellulose (microcrystalline), lecithin, silica), comprising a Boswellia extract (e.g., Boswellia serrata; Burseraceae family; olibanum; frankincense), alone or optionally in combination with at least one of a texturing agent and / or filler (e.g., cellulose (microcrystalline)); a phospholipid (e.g., lecithin or phosphatidylcholine); and an anti-caking agent (e.g., silica, which adsorbs water in hygroscopic applications); and optionally a dermatologically acceptable vehicle and / or additive; and when tested by a method for detecting expression of a barrier marker gene (such as, but not limited to, EGF), it is determined that the barrier marker gene is increased by an average fold change of 1.5 to 40 in amino acid-treated skin compared to amino acid-untreated skin (see, e.g., Figures 8-14). Improved skin barrier repair is measured or indicated by an average fold increase in skin barrier marker gene expression, such as EGF, of 1.5 to 40 when comparing skin treated with any of the formulations described herein to untreated skin, when barrier marker gene expression is tested by expression detection methods.Methods of improving skin barrier repair include, but are not limited to, correcting the skin barrier, strengthening the skin barrier, preserving the skin barrier, improving skin barrier integrity, wound healing; growth, stimulation, proliferation, differentiation, and migration of epidermal cells, keratinocytes, endothelial cells, and fibroblasts; promoting dermal regeneration, and any combination thereof.

[0184] Use of formulations for improving skin cell barrier integrity The present disclosure provides therapeutic or pharmaceutical formulations comprising a therapeutically effective amount of the formulation and, optionally, one or more pharmaceutically acceptable carriers. The present disclosure provides therapeutic, pharmaceutical, cosmetic, or nutritional formulations comprising a therapeutically effective amount of the formulation and, optionally, one or more pharmaceutically acceptable carriers. Such pharmaceutical carriers may be liquids, such as water. The therapeutic formulation may also include excipients, adjuvants, flavoring agents, etc., that facilitate processing of the active compound into a pharmaceutically usable preparation. Suitable formulations vary depending on the route of administration selected. In one embodiment, the therapeutic formulation and all components contained therein are sterile. Examples of suitable pharmaceutical carriers are described in "Remington's Pharmaceutical Sciences" by E.W. Martin. Such formulations contain a therapeutically effective amount of the therapeutic formulation together with a suitable amount of carrier to provide a form for proper administration to a patient. The formulation should be suitable for enteral administration.

[0185] In one embodiment, administration of the formulation may be systemic. Oral, intravenous, intraarterial, subcutaneous, intraperitoneal, intramuscular, intracerebroventricular, intranasal, transmucosal, subcutaneous, topical, rectal, and other modes of administration are all contemplated, as are any combinations thereof. In certain embodiments, the formulations described herein are administered to the skin (e.g., topically, transdermally, and / or subcutaneously, or any combination thereof). The formulations described herein may be incorporated into gauze, pads (adhesive or non-adhesive), bandages, and / or dressings for chronic application to the skin. In certain embodiments, the formulations described herein are administered to the skin in combination with oral administration of the formulations described herein. In certain such embodiments, oral administration of the formulations described herein is performed before, during, or after administration of the formulation to the skin. As described herein, administration to the skin may be achieved by topical, transdermal, and / or subcutaneous administration.

[0186] In one embodiment, for injection, the active ingredient can be formulated in an aqueous solution, for example, in a physiologically compatible buffer solution.For transmucosal administration, a penetrant appropriate to the barrier to be permeated is used in the formulation.For oral administration, the active ingredient can be combined with a suitable carrier for inclusion in tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions, etc.The formulation can also be prepared for use in inhalation therapy.For administration by inhalation, the formulation can be delivered in the form of an aerosol spray from a pressurized pack or nebulizer using a suitable propellant.The formulation can also be administered as a powder by inhalation or other routes.

[0187] The therapeutically effective dose of the formulations described herein can be determined by those skilled in the art to achieve the desired strength of intercellular adhesion, which reflects healthy skin barrier integrity. Increased expression of marker genes indicative of skin cell proliferation, skin cell differentiation, and / or intercellular adhesion can be assessed using the assays described herein. Immunohistochemical staining, behavioral assessment, and / or electrophysiological techniques can also be used to assess skin barrier integrity.

[0188] In some embodiments, the methods of the present disclosure include administering the therapeutic formulation via a sustained-release system. Examples of suitable sustained-release systems include suitable polymeric materials (semipermeable polymer matrices in the form of shaped articles, e.g., films, or microcapsules), suitable hydrophobic materials (e.g., as an emulsion in an acceptable oil) or ion exchange resins, and sparingly soluble derivatives (e.g., as a sparingly soluble salt). Sustained-release formulations can be administered orally, parenterally, intracisternally, intraperitoneally, topically (as a powder, ointment, gel, drop, or transdermal patch), or as a buccal or nasal spray. Sustained-release matrices include polylactic acid, copolymers of L-glutamic acid and gamma-ethyl-L-glutamate, poly(2-hydroxyethyl methacrylate), ethylene vinyl acetate, or poly-D-(-)-3-hydroxybutyric acid.

[0189] In one embodiment, implantable drug infusion devices may be used to provide a patient with a constant, long-term dose or infusion of a therapeutic formulation. Such devices may be classified as either active or passive.

[0190] In one embodiment, polymers can be used for ion-controlled release. A variety of degradable and non-degradable polymer matrices can be used for controlled drug delivery, such as block copolymers, polaxamer 407, hydroxyapatite, and liposomes.

[0191] The pharmaceutical formulation of the present invention may be used alone or in combination with one or more drugs to be effective in treating diseases.The formulation may also be formulated in combination with at least one other agent, such as a stabilizing compound or a buffering compound, and may be dissolved and administered in any sterile biocompatible pharmaceutical carrier, including, but not limited to, saline, buffered saline, dextrose, and water.In addition to the key components, cells, or influencing factors of the formulation discussed herein, the formulation may contain suitable pharmaceutically acceptable carriers, including excipients and auxiliary agents, that facilitate the processing of the active compound into a pharmaceutically usable preparation.The formulation may be prepared as a single dosage form using a pharmaceutically acceptable carrier or excipient, or may be contained in a multi-dose container.

[0192] In one embodiment, the formulation may further contain other growth and / or differentiation inducers, examples of which include fibroblast growth factor (FGF), epidermal growth factor (EGF), and retinoic acid.

[0193] The preparation may further contain other commonly used additives such as antioxidants, buffers, bacteriostatic agents, etc., and may be formulated into injection preparations such as aqueous solutions, suspensions, emulsions, etc., or into pills, capsules, granules, tablets, etc. by further adding diluents, dispersants, surfactants, binders, lubricants, etc.

[0194] The food preparation of the present invention can be contained in a health functional food.The health functional food can be prepared according to a method commonly used in the art, and commonly used raw materials and ingredients can be added when preparing the health functional food.When the preparation described herein is included in a health functional food, the preparation can be added alone or together with another health functional food or other food ingredient(s) according to a commonly used method.The amount of active ingredient can be appropriately determined depending on the purpose of use (e.g., prevention, health improvement, or therapeutic intervention).The food preparation can further include, for example, a prebiotic substance or a probiotic substance.

[0195] The type of food is not limited. Examples of foods to which the formulation can be added include meat, sausage, bread, chocolate, candy, snacks, confectionery, pizza, ramen, other noodles, gum, dairy products such as ice cream, soup, beverages, tea, drinks, alcoholic beverages, multivitamin supplements, etc.

[0196] kit Kits (e.g., pharmaceutical, therapeutic, cosmetic, or nutritional packs) are also encompassed by the present disclosure. The provided kits may include a formulation or pharmaceutical formulation described herein and a container (e.g., a vial, ampoule, bottle, syringe, and / or dispenser package, or other suitable container). In some embodiments, the provided kits optionally further include a second container containing a pharmaceutical excipient for diluting or suspending the pharmaceutical formulation or compound described herein. In some embodiments, the pharmaceutical formulation or compound described herein provided in the first container and the second container together form a single unit dosage form.

[0197] Thus, in one aspect, a kit is provided that includes a first container containing the formulation described herein. In certain embodiments, the kit is useful for treating a disorder (e.g., a skin disorder) or a symptom thereof in a subject in need thereof. In certain embodiments, the kit is useful for preventing a disorder (e.g., a skin disorder (e.g., xeroderma, atopic dermatitis, dermatitis, radiation dermatitis, psoriasis, pruritus, eczema, wounds, burns, or conditions associated with skin aging; repairing and strengthening the skin barrier; or improving skin moisture); osteoarthritis) or a symptom thereof in a subject in need thereof.

[0198] In certain embodiments, the kits described herein further include instructions for using the formulations included in the kit. The kits described herein may also include information required by regulatory authorities, such as the US Food and Drug Administration (FDA). In certain embodiments, the information included in the kit is prescribing information. In certain embodiments, the kit and instructions provide for the treatment and / or prevention of a disorder (e.g., a skin disorder) in a subject in need thereof. The kits described herein may include one or more additional pharmaceutical or other agents described herein in separate formulations.

[0199] Administration method The formulations can be administered by any of a number of routes, including, but not limited to, oral, intravenous, intramuscular, intra-arterial, intramedullary, intrathecal, intraventricular, intradermal, intra-articular, intrasynovial, peri-articular, intramuscular, intravenous, intralesional, topical (e.g., transdermal, epidermal), subcutaneous, intraperitoneal, intranasal, parenteral, topical, sublingual, or rectal means.

[0200] For example, by using "essentially consisting," the therapeutic formulation does not contain any unspecified ingredients, including, but not limited to, free amino acids, dipeptides, oligopeptides, or polypeptides or proteins; and monosaccharides, disaccharides, oligosaccharides, polysaccharides, and carbohydrates, that have a direct beneficial or detrimental therapeutic effect on improving skin cell barrier integrity. Also, by using the term "essentially consisting," the formulation may include substances that do not have a therapeutic effect on improving skin cell barrier integrity, such as vehicles, carriers, excipients, adjuvants, flavorings, etc., that do not adversely affect skin cell barrier integrity.

[0201] In some embodiments, the formulations (e.g., topical formulations) described herein can be applied topically to the skin of a subject in need of (a) skin barrier repair, skin barrier strengthening, or improved skin barrier integrity; (b) improved skin hydration (e.g., increased skin hydration, decreased water loss, increased hyaluronic acid (HA), increased hyaluronic acid synthase (HAS)), or a combination thereof, and such formulations comprise a therapeutically effective amount of a combination of free amino acids or peptide combinations of amino acids, the combination comprising at least one of alanine, glutamine, glycine, and serine (e.g., alanine, and (a) a therapeutically effective amount of a plant extract (e.g., a plant extract formulation), comprising a Boswellia extract (e.g., Boswellia japonica), or a salt thereof; and (b) a therapeutically effective amount of a plant extract (e.g., a plant extract formulation), comprising a Boswellia extract (e.g., Boswellia japonica), or a salt thereof; and (c) a therapeutically effective amount of a plant extract (e.g., a plant extract formulation), comprising a Boswellia extract (e.g., Boswellia japonica), or a salt thereof; and (d) a therapeutically effective amount of a plant extract (e.g., a plant extract formulation), comprising a Boswellia extract (e.g., Boswellia japonica), or a salt thereof; and (e) a therapeutically effective amount of a plant extract (e.g., a plant extract formulation), comprising a Boswellia extract (e.g., Boswellia japonica), or a salt thereof; and (e) a therapeutically effective amount of a plant extract (e.g., a plant extract formulation), comprising a Boswellia extract (e.g., Boswellia japonica), or a salt thereof; and (f) a therapeutically effective amount of a plant extract (e.g., a plant extract formulation), comprising a Boswellia extract (e.g., Boswellia japonica), or a salt thereof; and (g ... serrata; Burseraceae family; olibanum; frankincense), alone or in combination with at least one of a texturing agent and / or filler (e.g., cellulose (microcrystalline)); a phospholipid (e.g., lecithin or phosphatidylcholine); and an anti-caking agent (e.g., silica, which adsorbs water in hygroscopic applications), or alternatively, (b) a therapeutically effective amount of a retinoid, including retinyl esters (e.g., retinyl palmitate, retinyl oleate, retinyl stearate, retinyl linoleate, retinyl palmitoleate); retinol or vitamin A; retinaldehyde or retinal; retinoic acid;or a combination thereof, wherein such formulations optionally contain a dermatologically acceptable vehicle and / or additive, and the concentration of the therapeutically effective amount of amino acid is 0.1 mM or more (e.g., 0.3, 0.5, 0.7, 0.9, 1.1, 1.3, 1.5, 1.7, 1.9, 2.1, 2.3, 2.5, 2.7, 2.9, 3.1, 3.3, 3.5, 3.7, 3.9, 4.1, 4.3, 4.5, 4.7, 4.9, 5.1, 5.3, 5.5, 5.7, 5.9, 6.1, 6.3, 6.5, 6.7, 6.9, 7.1, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.9, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9, 10.1, 10.2, 10.3, 10.4, 10.5, 10.6, 10.7, 10.8, 10.9, 11.1, 11.2, 11.4, 11.5, 11.6, 11.7, 11.9, 12.1, 12.3, 12.5, 12.7, 12.9, 13.1, 13.3, 13.5, 13.7, 13.9, 14.1, 14. 0.5, 7.7, 7.9, 8.1, 8.3, 8.5, 8.7, 8.9, 9.1, 9.3, 9.5, 9.7, 9.9, 10.1, 10.3, 10.5); 10 mM or less (e.g., 9.8, 9.6, 9.4, 9.2, 9, 8.8, 8.6, 8.4, 8.2, 8, 7.8, 7.6, 7.4, 7.2, 7, 6.8, 6. 6, 6.4, 6.2, 6, 5.8, 5.6, 5.4, 5.2, 5, 4.8, 4.6, 4.4, 4.2, 4, 3.8, 3.6, 3.4, 3.2, 3, 2.8, 2.6, 2.4, 2.2, 2, 1.8, 1.6, 1.4, 1.2, 1, 0.8, 0.6, 0.4, 0.2, 0.08, 0.06, 0.04, 0.02);or 0.1mM~10mM (e.g. 0.2mM~9.9mM, 0.3mM~9.8mM, 0.4mM~9.7mM, 0.5mM~9.6mM, 0.6mM~9.5mM, 0.7mM~9.4mM, 0.8mM~ 9.3mM, 0.9mM~9.2mM, 1mM~9.1mM), 1.1mM~9mM, 1.2mM~8.9mM, 1.3mM~8.8mM, 1.4mM~8.7mM, 1.5mM~8.6mM, 1.6mM~8.5m M, 1.7mM~8.4mM, 1.8mM~8.3mM, 1.9mM~8.2mM, 2mM~8.1mM, 2.1mM~8mM, 2.2mM~7.9mM, 2.3mM~7.8mM, 2.4mM~7.7mM, 2. 5mM~7.6mM, 2.6mM~7.5mM, 2.7mM~7.4mM, 2.8mM~7.3mM, 2.9mM~7.2mM, 3mM~7.1mM, 3.1mM~7mM, 3.2mM~6.9mM, 3.3mM~6 .8mM, 3.4mM~6.7mM, 3.5mM~6.6mM, 3.6mM~6.5mM, 3.7mM~6.4mM, 3.8mM~6.3mM, 3.9mM~6.2mM, 4mM~6.1mM, 4.1mM~6mM , 4.2mM~5.9mM, 4.3mM~5.8mM, 4.4mM~5.7mM, 4.5mM~5.6mM, 4.6mM~5.5mM, 4.7mM~5.4mM, 4.8mM~5.3mM, 4.9mM~5.2mM, 5 mM to 5.1 mM) containing (or consisting essentially of, or consisting of) a therapeutically effective amount of (a) a plant extract (or plant extract concentration) or (b) a retinoid (e.g., a retinyl ester (e.g., retinyl palmitate, retinyl oleate, retinyl stearate, retinyl linoleate, retinyl palmitoleate); retinol or vitamin A; retinaldehyde or retinal; retinoic acid;or a combination thereof) is present in an amount of 0.01% by weight or more of the formulation (e.g., 0.03, 0.05, 0.07, 0.09, 0.11, 0.13, 0.15, 0.17, 0.19, 0.21, 0.23, 0.25, 0.27, 0.29, 0.31, 0.33, 0.35, 0.37, 0.39, 0.41, 0.43, 0.45, 0.47, 0.49, 0.51, 0.53, 0.55, 0.57, 0.59, 0.60, 0.61, 0.62, 0.63, 0.64, 0.65, 0.66, 0.67, 0.68, 0.69, 0.70, 0.71, 0.72, 0.73, 0.74, 0.75, 0.76, 0.77, 0.78, 0.79, 0.80, 0.81, 0.82, 0.83, 0.84, 0.85, 0.86, 0.87, 0.88, 0.89, 0.90, 0.91, 0.92, 0.93, 0.94, 0.95, 0.96, 0.97, 0.98, 0.99, 100, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 1 1, 0.63, 0.65, 0.67, 0.69, 0.71, 0.73, 0.75, 0.77, 0.79, 0.81, 0.83, 0.85, 0.87, 0.89, 0.91, 0.93, 0.95, 0.97, 0.99, 1.1, 1.3, 1.5, 1.7, 1.9, 2.1, 2.3, 2.5, 2.7, 2.9, 3.1, 3.3, 3.5, 3.7, 3.9, 4.1, 4.3, 4.5, 4.7, 4.9, 5.1 , 5.3, 5.5, 5.7, 5.9, 6.1, 6.3, 6.5, 6.7, 6.9, 7.1, 7.3, 7.5, 7.7, 7.9, 8.1, 8.3, 8.5, 8.7, 8.9, 9.1, 9.3, 9.5, 9.7, 9.9, 10.1, 10.3, 10.5, 10.7, 10.9, 11.1); 10% or less (e.g., 9.8, 9.6, 9.4, 9.2, 9.8, 8.6, 8.4, 8.2, 8.7, 7.8, 7. 6, 7.4, 7.2, 7, 6.8, 6.6, 6.4, 6.2, 6, 5.8, 5.6, 5.4, 5.2, 5, 4.8, 4.6, 4.4, 4.2, 4, 3.8, 3.6, 3.4, 3.2, 3, 2.8, 2.6, 2.4, 2.2, 2, 1.8, 1.6, 1.4, 1.2, 1, 0.8, 0.6, 0.4, 0.2, 0.08, 0.06, 0.04, 0.02, 0.008, 0.006, 0.004, 0.002);or 0.01% to 10% (e.g., 0.02% to 9.9%, 0.03% to 9.8%, 0.04% to 9.7%, 0.05% to 9.6%, 0.06% to 9.5%, 0.07% to 9.4%, 0.08% to 9.3%, 0.09% to 9.2%, 0.1% to 9.1%, 0.2% to 9%, 0.3% to 8.9%, 0.4% to 8.8%) , 0.5%~8.7%, 0.6%~8.6%, 0.7%~8.5%, 0.8%~8.4%, 0.9%~8.3%, 1%~8.2%, 1.1%~8.1%, 1.2%~8%, 1.3%~7.9%, 1.4%~7.8%, 1.5%~7.7%, 1.6%~7.6%, 1.7%~7.5%, 1.8%~7.4%, 1.9%~7. .3%, 2%~7.2%, 2.1%~7.1%, 2.2%~7%, 2.3%~6.9%, 2.4%~6.8%, 2.5%~6.7%, 2.6%~6.6%, 2.7%~6.5%, 2.8%~6.4%, 2.9%~6.3%, 3%~6.2%, 3.1%~6.1%, 3.2%~6%, 3.3%~5.9%, 3.4%~5. .8%, 3.5% to 5.7%, 3.6% to 5.6%, 3.7% to 5.5%, 3.8% to 5.4%, 3.9% to 5.3%, 4% to 5.2%, 4.1% to 5.1%, 4.2% to 5%, 4.3% to 4.9%, 4.4% to 4.8%, 4.5% to 4.7%);

[0202] In some embodiments, the formulations for treating cosmetic or other skin conditions; treating and / or preventing dry skin, atopic dermatitis, dermatitis, radiation dermatitis, psoriasis, pruritus, eczema, wounds, burns, or conditions associated with skin aging; repairing and strengthening the skin barrier; or improving skin moisture are administered topically to the skin of a subject suffering from one of such skin conditions or in need of repairing and strengthening the skin barrier or in need of improved skin moisture at the area where the subject is suffering from one of such skin conditions or in need of repairing and strengthening the skin barrier or improving skin moisture.

[0203] Other embodiments are directed to methods comprising (or consisting essentially of, or consisting of) administering a topical formulation, the topical formulation being a therapeutically effective amount of a formulation, as free amino acids or peptide combinations of amino acids, of (a) alanine, glutamine, glycine, and serine, or salts thereof, and optionally a therapeutically effective amount of at least one additional free amino acid or peptide combination of amino acids arginine, isoleucine, threonine, tryptophan, or valine, or salts thereof, or any combination thereof; or (b) at least one of alanine, glutamine, glycine, and serine (e.g., alanine; glutamine; glycine; serine; alanine and glutamine; alanine and glutamine; alanine and glutamine). and alanine and glutamine and serine; and alanine and glutamine and glycine and serine), or salts thereof, or any combination thereof, and include formulations comprising (or consisting essentially of, or consisting of) a therapeutically effective amount of (a) or (b), either alone or in combination with a therapeutically effective amount of (b), including (i) a therapeutically effective amount of a plant extract (e.g., a plant extract formulation), comprising a Boswellia extract (e.g., Boswellia serrata; Burseraceae family; olibanum; frankincense) alone or in combination with at least one of a texturing agent and / or filler (e.g., cellulose (microcrystalline)); a phospholipid (e.g., lecithin or phosphatidylcholine); and an anti-caking agent (e.g., silica, which adsorbs water in hygroscopic applications); or (ii) a therapeutically effective amount of a retinoid, such as a retinyl ester (e.g., retinyl palmitate, retinyl oleate, retinyl stearate, retinyl linoleate, retinyl palmitoleate); retinol or vitamin A;The formulations are formulated with a retinoid comprising (or consisting essentially of, or consisting of) at least one of retinaldehyde or retinal; retinoic acid; or a combination thereof, and such formulations optionally include a dermatologically acceptable vehicle and / or additives. In some embodiments, provided herein is (b)(i) (a therapeutically effective amount of at least one of alanine, glutamine, glycine, and serine, as free amino acids or peptide combinations of amino acids (e.g., alanine; glutamine; glycine; serine; alanine and glutamine; alanine and glycine; alanine and serine; glutamine and glycine; glutamine and serine; glycine and serine; alanine and glutamine and glycine; glutamine and glycine and serine; alanine and glycine and serine; alanine and glutamine and serine; and alanine and glutamine and glycine and serine), or a salt thereof, or a combination thereof; and a therapeutically effective amount of a plant extract (e.g., a plant extract blend), Boswellia extract (e.g., Boswellia serrata; Burseraceae family; olibanum; frankincense) alone or in combination with at least one of a texturing agent and / or filler (e.g., cellulose (microcrystalline)); a phospholipid (e.g., lecithin or phosphatidylcholine); and an anti-caking agent (e.g., silica, which adsorbs water in hygroscopic applications), wherein the method detects an increase in a barrier marker gene (e.g., EGF) in skin treated with formulation (b)(i) compared to untreated skin by an average fold change of 1.5 to 40, thereby indicating improved skin barrier repair. Another aspect of the present disclosure is directed to a method of improving skin moisture in the skin of a subject, such method comprising administering a therapeutically effective amount of (b)(ii) (a therapeutically effective amount of at least one of alanine, glutamine, glycine, and serine, as a free amino acid or a peptide combination of amino acids (e.g., alanine; glutamine; glycine; serine;alanine and glutamine; alanine and glycine; alanine and serine; glutamine and glycine; glutamine and serine; glycine and serine; alanine and glutamine and glycine; glutamine and glycine and serine; alanine and glycine and serine; alanine and glutamine and serine; and alanine and glutamine and glycine and serine), or salts thereof; and a therapeutically effective amount of a retinoid, including retinyl esters (e.g., retinyl palmitate, retinyl oleate, retinyl stearate, retinyl linoleate, retinyl palmitoleate); retinol or vitamin A; retinaldehyde or retinal; retinoic acid or a combination thereof, wherein the method detects an increase in a skin moisture marker gene or a hyaluronic acid (HA) marker gene (e.g., HAS1, HAS2, HAS3, or EGF) by a fold change of 1.4 to 450 in skin treated with formulation (b)(ii) compared to untreated skin, thereby indicating improved skin moisture (e.g., increased skin moisture, decreased water loss, increased hyaluronic acid (HA), hyaluronan synthase (HAS);For example, HAS1 (in fibroblasts), HAS2 and HAS3 (in keratinocytes) are increased. In a further aspect, there is provided a method of treating a subject suffering from osteoarthritis or a symptom thereof, the method comprising administering to a site of osteoarthritis in a subject suffering from osteoarthritis, for example, a joint (e.g., a hand joint, a hip joint, or a knee joint) of the subject suffering from osteoarthritis, by injecting the subject with a therapeutically effective amount of a formulation, wherein the therapeutically effective amount of the formulation is a therapeutically effective amount of a combination of, as free amino acids or peptide combinations, (a) alanine, glutamine, glycine, and serine, or salts thereof, and optionally, a therapeutically effective amount of at least one of arginine, isoleucine, threonine, tryptophan, or valine (e.g., alanine, glutamine, glycine, and serine, and arginine or isoleucine or threonine or tryptophan or valine; arginine and isoleucine; arginine and threonine; arginine and tryptophan; arginine and valine; isoleucine and threonine; isoleucine arginine and tryptophan; isoleucine and valine; threonine and tryptophan; threonine and valine; tryptophan and valine; arginine, isoleucine, and threonine; arginine, isoleucine, and tryptophan; arginine, isoleucine, and valine; arginine, threonine, and tryptophan; arginine, threonine, and valine; arginine, tryptophan, and valine; isoleucine, threonine, and tryptophan; isoleucine, threonine, and valine; isoleucine isoleucine, tryptophan, and valine; threonine, tryptophan, and valine; arginine, isoleucine, threonine, and tryptophan; arginine, isoleucine, threonine, and valine; arginine, threonine, tryptophan, and valine; isoleucine, threonine, tryptophan, and valine; arginine, isoleucine, tryptophan, and valine; arginine, isoleucine, threonine, tryptophan, and valine; or a salt thereof, or any combination thereof;or (b) at least one of alanine, glutamine, glycine, serine, or a salt thereof, or any combination thereof (e.g., alanine; glutamine; glycine; serine; alanine and glutamine; alanine and glycine; alanine and serine; glutamine and glycine; glutamine and serine; glycine and serine; alanine and glutamine and glycine; glutamine and glycine and serine; alanine and glycine and serine; alanine and glutamine and serine; and alanine and glutamine and glycine and serine; or a salt thereof, or any combination thereof); or (b)(ii) alanine, glutamine, glycine, serine, or a salt thereof, or any combination thereof (e.g., alanine; glutamine; glycine; serine; alanine and and glutamine; alanine and glycine; alanine and serine; glutamine and glycine; glutamine and serine; glycine and serine; alanine and glutamine and glycine; glutamine and glycine and serine; alanine and glycine and serine; alanine and glutamine and serine; and alanine and glutamine and glycine and serine; or salts thereof, or any combination thereof); and a therapeutically effective amount of a retinoid, including retinyl esters (e.g., retinyl palmitate, retinyl oleate, retinyl stearate, retinyl linoleate, retinyl palmitoleate); retinol or vitamin A; retinaldehyde or retinal; retinoic acid;or any combination thereof, wherein each of the formulations of (a), (b), or (b)(ii) optionally comprises a dermatologically acceptable vehicle and / or additive, thereby treating a subject suffering from osteoarthritis. One aspect is directed to a method of treating a subject suffering from osteoarthritis or its symptoms, wherein such injectable formulation comprises, as free amino acids or peptide combinations of amino acids, at least one of alanine, glutamine, glycine, and serine (e.g., alanine; glutamine; glycine; serine; alanine and glutamine; alanine and glycine; alanine and serine; glutamine and glycine; glutamine and serine; glycine and serine; alanine and glutamine and glycine; glutamine and glycine and serine; alanine and glycine and and alanine and glutamine and glycine and serine), or a salt thereof, or a combination thereof; and a therapeutically effective amount of a retinoid (e.g., a retinyl ester (e.g., retinyl palmitate, retinyl oleate, retinyl stearate, retinyl linoleate, retinyl palmitoleate); retinol or vitamin A; retinaldehyde or retinal; retinoic acid; or a combination thereof). In some embodiments, such methods of treating a subject suffering from osteoarthritis or a symptom thereof, the formulation is administered by injection into or around a joint (e.g., hand joint, hip joint, knee joint, ankle joint, foot joint) of a subject suffering from osteoarthritis. Additional embodiments are directed to the formulation in unit dosage form (e.g., single or multiple unit dosage forms). Some embodiments are directed to the use of the formulation in accordance with the notes herein for osteoarthritis; The present invention relates to the administration of an injection formulation, which is injected into a subject suffering from osteoarthritis and results in one or more of decreased pain, increased hyaluronic acid synthesis, increased proliferation of elastin and / or collagen, or a combination thereof, compared to an untreated subject.

[0204] In some embodiments of the present disclosure, a therapeutically effective amount of a free amino acid or peptide combination of amino acids, alone or with a therapeutically effective amount of a plant extract or plant extract blend, or with a therapeutically effective amount of a retinoid as described herein, is administered simultaneously or sequentially, and / or together or separately. Other embodiments provide single or multiple unit doses of the formulations described herein. The amount of topical formulation for administration comprises an amount sufficient to provide a layer of the formulation over the affected area. [Example]

[0205] The following examples illustrate certain aspects of the present description. The examples and embodiments described herein are for illustrative purposes only, and various modifications or changes in light thereof will be suggested to those skilled in the art and are within the spirit and scope of the present application. Furthermore, any element or limitation of any of the embodiments disclosed herein may be combined (individually or in any combination) with any and / or all other elements or limitations disclosed herein or with any other embodiment thereof, and all such combinations are contemplated with the scope of the embodiments described herein without limitation thereto. The examples should not be construed as limiting, as they merely provide a specific understanding and implementation of the embodiments and various aspects thereof.

[0206] Example 1: Amino acid testing To test the effects of amino acid treatment on the epithelial skin barrier, a cell model of differentiated normal human epidermal keratinocytes (NHEK) was used. Commercially available NHEK (ATCC) derived from three different healthy donors were used. Based on multivariate analysis, three amino acids were selected for treatment: Ser, Gln, and Gly.

[0207] Using microarray gene expression and RNA sequencing (RNA-seq) analysis, the transcriptomes of a panel of differentiated NHEKs were evaluated, focusing on a specific set of marker genes whose upregulation or downregulation (depending on the marker gene) reflects a tendency toward improved skin barrier function. For example, upregulation of marker genes that promote keratinocyte differentiation and / or proliferation and downregulation of marker genes that promote, for example, apoptosis / cell death and / or inflammation reflects a tendency toward improved skin barrier function. In contrast, downregulation of marker genes that promote, for example, keratinocyte differentiation and / or proliferation and upregulation of marker genes that promote, for example, apoptosis / cell death and / or inflammation reflects a tendency toward impaired skin barrier function.

[0208] Using gene arrays, comparative analysis of the two datasets was performed in three different donors, focusing on genes that were consistently differentially expressed (filter criteria: fold change 1.5 (positive or negative) and p-value <0.05) after treatment with various amino acids and their combinations. qPCR was used to evaluate mRNA expression results. qPCR results confirmed the array results associated with differential expression, thereby validating the gene panel.

[0209] The marker genes: EGF, FGF, CPT2, TGFB1, SMAD1, MKI67, PPARGC1B, CASP8, and TNFRSF10D. PPARA and PPARD were also included in the marker gene panel investigated, in part because the transcription factor PPARGC1B encodes the coactivators PPARα, PPARδ, and PPARγ. The significant upregulation of CPT2, which is a major target of PPARα, solidified the inclusion of PPARA and PPARD in the panel.

[0210] Each of the amino acids was also adjusted to reach a suitable concentration for use in the amino acid blend, and thus the suitable (e.g., non-toxic, non-transforming, therapeutically effective) concentration for each single amino acid was determined during the course of developing the suitable amino acid blend.

[0211] Comparative analysis of qPCR data from two donors, including the scoring system (as described above), consistently identified two sets of most effective (Gly, Gln, Ser, Ala) and least effective (Asp, Thr, Cys, Pro, Tyr) amino acid combinations. See, e.g., Figure 2.

[0212] The two most effective amino acid combinations were tested in five different donors as an initial set of ingredients for a skin formulation [Combo #1 (Gln, Gly, Ala, Ser) and Combo #2 (Gln, Gly, Ala, Ser, Ile, Val)], and their effects on 10 genes, namely, EGF, FGF2, PDGF, CPT2, TGM4, PPARD, TGFB1, FLG, MKI67, and TNFRSF10D, were evaluated. For comparison, the least effective set of amino acids (Combo #3) was used in qPCR analysis. See, for example, Figure 1.

[0213] The conclusion from the experiment was that the most effective amino acid combinations (Combo #1 and Combo #2) significantly increased gene expression of 6 out of 10 tested genes (Figure 1), whereas Combo #3 had no effect on the transcripts of the majority of genes or even downregulated them, as in the case of EGF. In contrast, mRNA expression of TNFRSF10D, which encodes a member of the TNF receptor superfamily, was significantly downregulated by Combo #1, suggesting its anti-inflammatory / anti-apoptotic functionality. The most significant effect of Combo #1 and #2 was detected on the upregulation of EGF transcription. Together, these results indicate that specific combinations of specific amino acid combinations, rather than all or random amino acid combinations, upregulate keratinocyte genes important for normal barrier function.

[0214] These results further demonstrate that careful testing of amino acid formulations, taking into account multivariate and interdependent data points, is necessary to achieve optimal beneficial effects. It is noteworthy that, in the context of healthy skin, as provided by keratinocytes from three different healthy donors, Combo #1 and Combo #2 each conferred a statistically significant increase in the expression of many of the identified marker genes compared to the control. Results determined in the context of damaged / compromised skin may provide even more meaningful results demonstrating the effectiveness of Combo #1 and Combo #2, as well as other amino acid formulations described herein. The results presented herein clearly demonstrate the efficacy of Combo #1 and Combo #2 and are reasonably predictive of their potential for skin barrier enhancement, particularly in the context of damaged / compromised skin.

[0215] The results presented herein also show that proteins are upregulated to provide beneficial contributions to skin barrier integrity.For example, involucrin is upregulated to a statistically significant extent 24 hours after treatment with either Combo #1 or Combo #2 compared to control.See, for example, Figure 5.Filaggrin is also upregulated to a statistically significant extent 24 hours after treatment with either Combo #1 or Combo #2 compared to control.See, for example, Figure 6.

[0216] Specific combinations of amino acids in suitable ratios have synergistic effects and the ability to modulate to improve and / or restore skin barrier integrity. Specific amino acid blends trigger several intracellular pathways that collectively provide the desired synergistic effect.

[0217] Example 2: Experimental Method Amino acids are mixed in water at previously established concentrations and added to the amino acid-deficient medium.

[0218] Gene Expression: mRNA was extracted, converted to cDNA, and analyzed by qPCR using a custom TaqMan array 384-well plate (Thermo Fisher Scientific) containing 34 of the above genes. Four control housekeeping genes, GAPDH, POLR2A, YWHAZ, and PGK1, were included to normalize mRNA expression. The array plate contained a total of 38 genes, allowing analysis of 10 samples in a single qPCR run.

[0219] Protein analysis: Western Blot. Keratinocytes or epidermal skin equivalents were homogenized in lysis buffer, proteins were extracted, and Western blots were performed according to standard protocols using the following commercially available antibodies: filaggrin (#sc-66192, Santa Cruz Bio), loricrin (#ab183646), involucrin (#ab68), TGM2 (#ab2386) (all from Abcam), and β-actin (#SAB3500350, Sigma).

[0220] Because Western blot analysis is labor-intensive and not a high-throughput assay, ELISA was used instead for some proteins, using previously published and validated assays for protein ELISA. ANGPTL4 and involucrin immunoassays were performed on the Luminex xMAP platform using Milliplex MapHuman Liver Protein Magnetic Bead Panel hANGPTL4-MAG and Milliplex MapHuman Skin Magnetic Bead INVOL-MAG (EMD Millipore, Billerica, MA).

[0221] statistics: Differences between control and treatment groups are assessed by one-way ANOVA. Statistically, significant variation is defined as a 20% or greater variation from control for protein analysis and a positive or negative fold change threshold of 1.5 for gene expression with a p-value of p<0.05.

[0222] Example 3: Experimental design and methods to define additional effective combinations of amino acids that promote skin barrier function In addition to the amino acid combinations described above, several other combinations, such as those containing Trp and / or Arg, will be tested to determine whether the inclusion of these amino acids provides additional dermatological benefits. These two amino acids have shown positive effects in preliminary screening, making them attractive candidates for inclusion in the amino acid formulations described herein. Initially, the following amino acid combinations will be tested: Ala, Gln, Gly, Ser (Combo #1); Ala, Gln, Gly, Ser, Val, Ile (Combo #2); Ala, Gln, Gly, Ser, Val; Ala, Gln, Gly, Ser, Ile; Ala, Gln, Gly, Ser, Ile, Val, Trp; Ala, Gln, Gly, Ser, Ile, Val, Arg; and Ala, Gln, Gly, Ser, Ile, Val, Trp, Arg.

[0223] Experiments were performed using differentiated normal primary keratinocytes from the five different donors described above, as well as commercially available epidermal skin equivalents (3D models) (EPI-200, MatTech, Ashland, MA). Such 3D cultures closely resemble human epidermis and are commonly used in skin research. To ensure appropriate experimental conditions, experiments were performed in amino acid-deficient medium during treatment with specific amino acid formulations. Because amino acids constitute important components of the formulations described herein, the presence of amino acids normally present in the medium could obscure the results, leading to the selection of amino acid-deficient medium as a control. Cells or equivalents were treated with the amino acid combinations for 4 or 24 hours. Keratinocyte differentiation was induced by culturing them in the presence of 1.2 mM CaCl2 for 48 hours before treatment in FBS-free medium (amino acid-deficient medium).

[0224] First, we investigated a set of classic skin barrier-related genes, including those from a panel previously tested. The following genes encoding key components of the barrier or barrier formation process were included in the array: growth factors EGF, TGFB1, FGF2, and PDGF; terminal differentiation markers such as filaggrin (FLG), loricrin (LOR), TGM4, CORIN, KRT6, KRT16, SFN, SPRR2H, and late cornified envelope genes (LCE1, LCE3, S100A8 / A9); lipid metabolism regulators such as PPARA, PPARD, CPT2, PNPLA1, FASN, UGCG, HMGCR, PLA2G5, and ELOVL; adhesion structures (CLDN4, CLND7, DSC1, DSC2, OCLN, TJP1, and TJP2); water channel AQP3; and skin barrier integrity genes: SPINK5, KLK5, and KLK7. High-throughput analysis of mRNA expression of the above genes is performed using custom TaqMan array plates (Thermo Fisher Scientific). The percentage of co-expressed genes after treatment with different amino acid formulations is determined. The expression levels of cross-linking proteins such as involucrin, loricrin, TGM2, and ANGPTL are assessed by Western blot analysis or ELISA using standard protocols.

[0225] The method is carried out as described in Example 2.

[0226] Example 4: Another model system for evaluating and identifying effective amino acid formulations To evaluate the effects of the amino acid formulations described herein, alternative models of keratinocytes with immature or affected barriers are tested. Such model systems include, for example, undifferentiated keratinocytes (cultured in a low calcium concentration (0.03 mM)). These cells have an immature epithelial barrier, and differentiated keratinocytes are switched to a low Ca2+-containing medium (0.03 mM) for 24 hours before treatment. It has been shown that Ca2+ deficiency in epithelial cells opens TJs, thereby disrupting the permeability barrier. This process is restored by Ca2+ replenishment, and the expression of filaggrin is downregulated in differentiated keratinocytes treated with Th2 cytokines, namely IL-4 (50 ng / mL) and IL-13 (50 ng / mL) for 24 hours.

[0227] Example 5: Experimental design and methods to evaluate the efficacy of topical administration of amino acid formulations on skin barrier repair in in vitro and ex vivo models of normal and compromised skin The next step in evaluating the efficacy of the amino acid formulations described herein will be tested topically, achieved by direct application to the stratum corneum surface. Normal and immature epidermal skin equivalents (EPI-200 and EPI-20, MatTek Corporation, Ashland, MA) and normal and delipidated (tape-stripped) skin explants will be used as normal and impaired skin models. Full-thickness human skin obtained from normal adult humans undergoing abdominoplasty is commercially available for research and will be obtained from Zen Bio (Durham, NC). In addition to evaluating the expression of key barrier markers, such as those described in Example 1, TJ proteins will also be investigated. TJ proteins are involved in normal barrier function, preventing transepidermal water loss (TEWL) in healthy skin. Therefore, the expression of TJ proteins will be evaluated by Western blot analysis and immunohistochemistry. Transepithelial electrical resistance (TEER) measurements will also be included as an indicator of barrier integrity and TJ dynamics. Expression of filaggrin, involucrin, and loricrin is also performed as in Example 1.

[0228] method: Ex vivo model: Ex vivo studies are performed using human skin explants. Subcutaneous fat is removed from abdominal skin (Zen Bio) and 0.93 cm 2 Skin biopsies are prepared under sterile conditions and placed in keratinocyte growth medium in a 5% CO2 humidified atmosphere. To artificially induce scaly delipidated skin, abdominal skin is first tape-stripped according to standard protocols, and then biopsies are prepared. After 24 hours of acclimation, an amino acid formulation is applied topically every 24 hours for a total of 7 days. Skin explants are analyzed for gene and protein expression levels at 24 hours, 48 ​​hours, 72 hours, and the end of the experiment.

[0229] Measurement of transepithelial electrical resistance (TEER) in a three-dimensional model. For TEER, immature epidermal skin equivalents (EPI-20, MatTek Corporation, Ashland, MA) are transferred to medium containing 100 ng / ml IL-4, 100 ng / ml IL-13, 50 ng / ml IL-31, and 30 ng / ml TNFα (R&D Systems, Minneapolis, MN) as previously described. Amino acid formulations are applied topically every 24 hours, 4 hours after cytokine pretreatment. TEER is measured at 0, 24, and 48 hours using a Millicell ERS-2 Epithelial Volt-Ohm Meter (Milipore). The percent change in TEER between time 0 (100%) and time 24 hours is expressed as follows: (TEER 24 hours / TEER 0 hours) x 100. At the end of the experiment, the skin equivalents are used for mRNA and protein expression analysis.

[0230] qPCR analysis. Expression of the 38 gene array is performed as described in Examples 1 and 2 using custom TaqMan array plates.

[0231] Protein analysis: Western Blot: Expression of filaggrin, involucrin, loricrin, ANGPTL4 and TGM-2 is performed as described in Examples 1 and 2.

[0232] Immunohistochemical staining. Skin explants treated with topical amino acid formulations were incubated for 7 days, re-treated every 24 hours, and harvested for staining at the end of the experiment. Tissues were fixed in 10% buffered neutral formalin solution. Fixed tissues were embedded and 5-μm-thick sections were prepared. Immunohistochemical analysis was performed using standard protocols. Sections were deparaffinized in xylene, hydrated in ethanol, and washed in water. Nonspecific binding was blocked with mouse IG blocking reagent. The following primary antibodies were used: claudin-1 (JAY.8), occludin (OC-3F10), ZO-1 (ZO1-1A12) (all from Zymed), or the indicated isotype controls. Tissue sections were then incubated with the appropriate biotinylated secondary antibody, and antibody binding was visualized using a DAB Peroxidase Substrate Kit (Vector Laboratories). Staining was assessed by microscopy.

[0233] Example 6: Materials and Methods Cell culture and therapeutic agents To prepare experimental samples for RNA analysis, human primary keratinocytes were treated with a panel of amino acid(s), either single amino acids and / or amino acid combinations.

[0234] Primary normal human adult keratinocytes (ATCC, Catalog No. PCS-200-011) were cultured in dermal cell basal medium (ATCC, Catalog No. PCS-200-030) containing growth supplements (Keratinocyte Growth Kit, ATCC Catalog No. PCS-200-040). The medium was changed three times weekly for cell growth. For experiments, cells were seeded at a density of 20,000 cells / well in 6-well plates. When cells reached 100% confluence, CaCl2 was added to a final concentration of 1.8 mM for 24 hours to induce differentiation. All treatments were performed for 4 hours in amino acid-deficient medium (choline chloride 0.0285 mM, calcium D-pantothenate 0.00838 mM, folic acid 0.009 mM, nicotinamide 0.03 mM, pyridoxine hydrochloride 0.02 mM, riboflavin 0.001 mM, thiamine hydrochloride 0.01 mM, myo-inositol 0.04 mM, calcium chloride 1.8 mM, ferric nitrate 2.47E-4 mM, magnesium sulfate 0.8 mM, potassium chloride 5.3 mM, sodium bicarbonate 44 mM, sodium chloride 110.3 mM, monosodium phosphate 0.9 mM, D-glucose 25 mM, sodium pyruvate 1 mM) in the presence of 1.8 mM CaCl. The 4GAA formulation contained glycine, glutamine, serine, and alanine and was used at a total concentration of 4 mM (1:1:1:1). The 3BAA formulation contained cysteine ​​(1 mM), histidine (0.5 mM), and tyrosine (1 mM). A plant extract formulation containing Boswellia serrata resin extract, lecithin, microcrystalline cellulose, and silica was dissolved in amino acid-deficient medium, filtered, and used at concentrations of 0.1% to 1% w / w of the formulation.

[0235] Real-time RT-PCR analysis: Cellular RNA was isolated using the NucleoSpin RNA Plus Kit (Macherey Nagel). cDNA synthesis was performed using 1 μg of total RNA with the High-Capacity cDNA Reverse Transcription Kit (Thermo Fisher Scientific). RT products were amplified using TaqMan Gene Expression Assays for EGF, MYC, GAPDH, and YWHAZ (Thermo Fisher Scientific). Detection was performed using the StepOne Real-Time PCR System (Applied Biosystems). Differences in gene expression levels were determined by relative quantification using the delta Ct method.

[0236] Equipment, materials, reagents, and consumables Confluent differentiated primary human keratinocytes were used in 6-well plates. The following were used in the experiments described herein:

[0237] Sterile RNase-free microcentrifuge tubes (1.7 mL) and conical (50 mL and 15 mL) tubes.

[0238] Pipettes, multichannel pipettes, pipette controllers (Aid), serological pipettes and pipette tips, aspirating pipettes.

[0239] Sterile isopropyl alcohol (SIPA, 70%).

[0240] Dulbecco's medium.

[0241] Amino acids: serine, glycine, glutamine, histidine, valine, tyrosine, threonine, aspartic acid, or other amino acids based on experimental needs.

[0242] Vacuum lines / vacuum pump and pump waste collection container.

[0243] Syringe (30 mL), syringe filter (25 mm PES; 0.22 micron), syringe needle (18 G).

[0244] Weighing consumables: paper, spatula, etc.

[0245] Experimental equipment: Biosafety cabinet (BSC), water bath (37 °C), 5% CO2 incubator (37 °C), refrigerator (4 °C), analytical balance, heating / stir plate. [Table 1]

[0246] Preparation of Amino Acid Therapeutics Treatments were prepared within one week of the start of the experiment. A water bath was preheated to 37°C. DMEM was removed and aseptically transferred to the BSC. The required volume of DMEM (2 ml / well) was pipetted into a 50 mL conical tube, which was then prewarmed in a heated water bath for 30 minutes. Other necessary materials, including a 50 mL conical tube, a 30 mL syringe, an 18G needle, and a 25 mm (0.22 micron) micron syringe filter, were aseptically transferred to the BSC. The 50 mL conical tubes were labeled as either single amino acids (4 mM, 20 mM), a 4-amino acid blend (4 mM, 20 mM), or ENTERADE™, and the amino acids required for treatment were prepared (see Table 2).

[0247] The appropriate amount of each amino acid (see Table 2) was weighed out and then transferred to its respective conical tube. The amino acids for the 4AA formulation and ENTERADE® should be weighed out individually and then transferred into designated tubes and labeled together. All conical tubes (50 mL) containing dry amino acids and pre-warmed DMEM were aseptically transferred to the BSC. A serological pipette was used to transfer the DMEM into the tubes according to Table 2.

[0248] All tubes were vortexed until the mixture was debris-free and homogenous, after which the homogenous mixture was aseptically returned to the BSC.

[0249] If the mixture does not completely dissolve by vortexing alone, place a small stir bar into a conical tube (50 mL), then place the conical tube into a beaker half-filled with water and use a heating / stir plate (50 °C / 800 rpm) for approximately 10 minutes until the solution is homogenous.

[0250] In a separate rack, a new set of conical tubes (50 mL) was labeled with the AA name, concentration, and date for each amino acid or amino acid blend.

[0251] An 18G needle was attached to a 10 mL syringe, and the entire contents of one of the AA "media" tubes were aspirated. The needle was removed, and a 13 mm, 0.22 micron syringe filter was attached to the 10 mL syringe. A 25 mm, 0.22 micron syringe filter was placed over the tube labeled "treatment" for the corresponding amino acid (AA), and the mixture was pushed through the syringe and into the filter, which was then immediately capped. This was repeated as necessary, changing the filter after every 100 mL filtration or between samples of each amino acid.

[0252] The syringe filtration step was repeated for each AA or AA formulation, and syringes, needles, and filters were changed between each AA or AA formulation to avoid cross-contamination. [Table 2]

[0253] Amino acid therapy PBS and AA treatments were pre-warmed in a water bath (37°C) for 30 minutes. Six-well plates containing "differentiated keratinocytes" were aseptically transferred from a 5% CO2 incubator (37°C) to a BSC. The lids of the six-well plates were labeled with the date, initials, passage number, cell family, and target treatment. The wells on the plate lids were labeled T# ​​(treated wells) or C# (PBS-only wells).

[0254] The medium from each well was aspirated and washed with 2.0 mL of PBS.

[0255] The PBS from each well was aspirated and 2.0 mL of AA treatment was added to the well, ensuring that the treatment added corresponded to the label on the plate (the serine treatment was only added to wells on the plate labeled serine).

[0256] The remaining control wells were filled with 2 mL of DMEM in each plate, and the 6-well plate in the secondary container was transferred to a 5% CO 2 incubator (37° C.) and incubated according to the experiment.

[0257] Once the incubation period was complete, the "treated" cells were removed and transferred to a BSC for RNA / protein extraction.

[0258] Example 7: Preparation of formulations An exemplary method for preparing the formulations or topical formulations disclosed herein included the following steps:

[0259] Xanthan gum was dispersed in glycerin.

[0260] Mix until uniform, then add water.

[0261] Mix until uniform.

[0262] The ingredients of Step A in Table 3 were heated to a temperature of 80°C.

[0263] The ingredients of Step B in Table 3 were heated separately to a temperature of 80°C.

[0264] With both stages at 80°C, add Stage B to Stage A with vigorous mixing, then remove from heat to form a Stage A and Stage B batch.

[0265] Once the batch temperature was below 40°C, the ingredients from Step C of Table 3 were added to the batch.

[0266] The batch is then brought to 100% with deionized water. The various amino acids tested here are combined with the formulations prepared here, including alanine, glutamine, glycine, and serine. [Table 3]

[0267] Example 8: Comparison of EGF expression in amino acid and plant extract formulations, alone or together Keratinocytes from different donors were cultured in amino acid-free medium for 4 hours after full differentiation and treated in parallel with 1 mM or 4 mM of an amino acid blend (4GAA; alanine, glutamine, glycine, serine) and / or 0.25%, 0.5%, or 1% (w / w%) of a Boswellia plant extract blend (BSW or BSXL) (the combinations were 4GAA 4 mM / 1% BSW (Figure 7A); 4GAA 1 mM / 0.25% BSW (Figure 7B); 4GAA 4 mM / 0.5% BSW (Figure 7C); and 4GAA 1 mM / 0.5% BSW (Figure 7D)).

[0268] Cells were harvested, RNA (EGF mRNA) was extracted, and qPCR analysis was performed using GAPDH as a housekeeping gene (see Figures 7A-7D). * p<0.05, ** p<0.01 compared to untreated controls (CTR or CTR untr).

[0269] Example 9: Comparison of EGF mRNA fold change of donor G's amino acid and plant extract formulations, alone or together Keratinocytes from donor G were cultured in amino acid-free medium for 4 hours after full differentiation and treated in parallel with 1 mM or 4 mM of an amino acid blend (4GAA; alanine, glutamine, glycine, serine) and / or a plant extract blend (BSXL) at concentrations of 0.1%, 0.25%, or 0.5% (w / w%) (in which case the combinations were 4GAA 1 mM / 0.25% BSXL and 4GAA 4 mM / 0.5% BSXL).

[0270] Cells were harvested, RNA (EGF mRNA) was extracted, and qPCR analysis was performed using GAPDH as a housekeeping gene (see Figures 8A and 8B). * p<0.05, ** p<0.01, *** p<0.001, **** p<0.0001 compared to untreated control (ctr).

[0271] Example 10: Comparison of EGF mRNA fold change for amino acid and plant extract formulations, alone or together, for Donor O Keratinocytes from donor O were cultured in amino acid-free medium for 4 hours after full differentiation and treated in parallel with 1 mM or 4 mM of an amino acid blend (4GAA; alanine, glutamine, glycine, serine) and / or a plant extract blend (BSXL) at a concentration of 0.25% or 1% (w / w%) (in that case, the combinations were BSXL 0.25% / 1 mM 4GAA and BSXL 1% / 4 mM 4GAA).

[0272] Cells were harvested, RNA (EGF mRNA) was extracted, and qPCR analysis was performed using GAPDH as a housekeeping gene (see Figures 9A and 9B). ** p<0.01, *** p≦0.001 (vs. untreated control (CTR untr)).

[0273] Example 11: Comparison of EGF mRNA fold change of amino acid and plant extract formulations alone or together Keratinocytes from donor G were cultured for 4 hours in amino acid-free medium after full differentiation and treated in parallel with an amino acid formulation (4 mM 4GAA: alanine, glutamine, glycine, serine; 3BAA: cysteine ​​(Cys), histidine (His), tyrosine (Tyr): Cys 1 mM, His 0.5 mM, Tyr 1 mM) and / or 0.5% plant extract formulation (BSXL) and / or piperonylic acid (100 μM; PA) (in that case, the combinations were 4GAA 4 mM / 0.5% BSXL; 3BAA 2.5 mM / 0.5% BSXL; 4GAA 4 mM / 100 μM PA; 3BAA 2.5 mM / 100 μM PA).

[0274] The same experiment was performed using similar cells and different amino acid combinations, as well as a compound (PA) that upregulates EGFR (EGF receptor).

[0275] Cells were harve...

Claims

1. It is a topical preparation, (a) A therapeutically effective amount of a combination of free amino acids or amino acid peptides comprising alanine, glutamine, glycine, and serine, or salts thereof, wherein each free amino acid is present in a ratio of 1:100 or more to each of the other free amino acids, (b) The therapeutically effective dose of retinoids, Includes, When tested by a method that detects the expression of epidermal growth factor (EGF) or hyaluronic acid (HA) marker genes and determines that the expression of the EGF marker gene or the HA marker gene is 1.4 to 450 times higher in skin cells treated with the formulation compared to untreated skin cells, the therapeutically effective dose of the combination and the therapeutically effective dose of the retinoid improve skin moisture, The therapeutically effective amount of the above combination and the therapeutically effective amount of the retinoid improves skin moisture, The amino acids present in the aforementioned topical preparation are alanine, glutamine, glycine, and serine, or their salts only. Topical preparation.

2. The topical formulation according to claim 1, wherein each of the aforementioned amino acids is present at a concentration of 0.1 mM or more; 10 mM or less; or 0.1 mM to 10 mM.

3. The topical formulation according to claim 1, wherein each of the amino acids is present in the formulation in a weight percentage (wt / wt%) of 0.001% by weight or more; 1% by weight or less; or 0.001% by weight to 1% by weight.

4. The topical formulation according to claim 1, wherein the therapeutically effective amount of the retinoid is present in the formulation in a weight percentage (w / w%) of 0.01 w / w% or more; 5 w / w% or less; or 0.01 w / w% to 5 w / w%.

5. The topical formulation according to claim 1, wherein the retinoid is selected from the group consisting of retinyl, retinol, or vitamin A, retinaldehyde, or retinal, retinoic acid, or any combination thereof.

6. The topical formulation according to claim 1, wherein the therapeutically effective amount of the combination of (a) and the therapeutically effective amount of the retinoid of (b) is such that the therapeutically effective amount increases skin moisture; decreases water loss; increases hyaluronic acid (HA); increases hyaluronic acid synthase (HAS); or a combination thereof.

7. The topical formulation according to claim 6, wherein increasing HAS comprises increasing HAS1 in fibroblasts; increasing HAS2 and / or HAS3 in keratinocytes; or a combination thereof.

8. Texture imparting agent and / or filler; Phospholipids; Anti-caking agent; Dermatologically acceptable vehicles and / or additives; or Those combinations; The topical formulation according to claim 1, further comprising:

9. The topical formulation according to claim 8, wherein the filler comprises cellulose, microcrystalline cellulose, or a combination thereof.

10. The topical formulation according to claim 8, wherein the phospholipid comprises lecithin, phosphatidylcholine, or a combination thereof.

11. The topical formulation according to claim 8, wherein the anticaking agent comprises silica.

12. The topical formulation according to claim 8, wherein the additive is selected from the group consisting of vitamins, minerals, preservatives, exfoliating agents, anti-acne agents, anti-wrinkle / anti-atrophy agents, hydroxyl acids, antioxidants / radical scavengers, chelating agents, flavonoids, anti-inflammatory agents, anti-cellulite agents, local anesthetics, tanning agents, skin whitening agents, skin sedatives and skin healing agents, antibacterial and antifungal agents, sunscreens, conditioning agents, structuring agents, thickening agents, and preservatives, or any combination thereof.

13. The topical formulation according to claim 1, wherein at least one amino acid is L-type.

14. A method comprising administering the topical preparation described in Claim 1 to the skin of a subject suffering from a skin condition, wherein the method is: Improves skin moisture; Increases HAS1 expression in fibroblasts; To increase the expression of HAS2 and / or HAS3 in keratinocytes; or It is a combination of those; method.

15. The administration of the topical formulation improves at least one visual property of the skin, or at least one tactile property, or a combination of a visual property and a tactile property, The aforementioned skin condition includes cosmetic skin conditions, atopic dermatitis, dermatitis, psoriasis, pruritus, eczema, wounds, or burns. The method according to claim 14.

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