"Novel, highly sustainable compounds for altering gene expression in human skin and production methods"

Abstract

The expression of genes and metabolism associated with extracellular matrix degradation, inflammation, stress, pigmentation, anti-aging elasticity, barrier function, hyaluronic acid synthesis, and epidermal turnover in human skin can be modulated by formulations containing highly purified, bio-based R-mevalonolactone. Highly purified, bio-based R-mevalonolactone can be applied topically or ingested to modify metabolism and gene expression. It can also be used as an ingredient in food, pharmaceutical, and cosmetic products.

Claims

[1] A gene modulation formulation for modulating the expression of one or more genes, the composition comprising mevalonolactone; wherein the mevalonolactone (a) is at least 97.5 percent pure in an aqueous solution, as measured by HPLC, (b) contains less than 1% by weight of fermentation by-products, ethyl acetate, dichloromethane, tetrahydrofuran, isopropanol, petrochemicals or combinations thereof, based on the total weight of the mevalonolactone, and (c) contains less than 10,000 ppm of odour-causing substances as measured by gas chromatography (GC). [2] The gene modulation formulation of claim 1, wherein the mevalonolactone in an aqueous solution is at least 98.5 or 99.5 percent pure as measured by HPLC. [3] The gene modulation formulation of claim 1, wherein the gene modulation formulation comprises 0.1 to 10% by weight of the mevalonolactone. [4] The gene modulation formulation of claim 1, wherein the mevalonolactone is in the form of an aqueous solution containing the mevalonolactone. [5] The gene modulation formulation of claim 1, wherein the gene modulation formulation increases the expression of at least two genes selected from the group consisting of: COL1A1, COL1A2, COL4A1, ELN, EMILIN1, EMILIN2, MFAP5, FN1, LAMA1, TIMP1, TIMP2, TIMP3, TIMP4, HAS1, HAS2, HAS3, HABP4, HAPLN1, EGF, FGF7, HBEGF, KRT1, KRT2, KRT4 and DEFA1 by at least 10 percent as measured 24 hours after application. [6] The gene modulation formulation of claim 1, wherein the gene modulation formulation increases the expression of at least two genes selected from the group consisting of: MMP1, MMP2, MMP3, MMP7, MMP9, NFATC1, IL1A, IL1B, TNFA, SELE, SELL, EDN1, EDN2, EDN3, PTGS2 (COX2) and POMC by at least 10 percent as measured 24 hours after application. [7] The gene modulation formulation of claim 1, wherein the gene modulation formulation reduces the production of cortisol in human epithelial skin cells by at least 10 percent as measured 24 hours after application. [8] The gene modulation formulation of claim 1, wherein the mevalonolactone comprises at least 95% by weight of R-mevalonolactone based on the total weight of the mevalonolactone. [9] The gene modulation formulation of claim 1, wherein the gene modulation formulation is a topical skin care composition in the form of a mist, lotion, emulsion, gel, cream or ointment. [10] The gene modulation formulation of claim 1, wherein the mevalonolactone comprises less than 1, 0.5, 0.1, 0.05, 0.01, 0.005, 0.001, 0.0005, 0.001, 0.0005, 0.0001, 0.00005, or 0.00001 weight percent of fermentation by-products, ethyl acetate, dichloromethane, tetrahydrofuran, isopropanol, petrochemicals, or combinations thereof, based on the total weight of the mevalonolactone. [11] The gene modulation formulation of claim 1, wherein the mevalonolactone has a cation, anion and / or metal content of less than 10,000 ppm, 5,000 ppm, 1,000 ppm, 500 ppm, 400 ppm, 300 ppm, 200 ppm, 100 ppm or 10 ppm as measured by ICP-OES. [12] The gene modulation formulation of claim 1, wherein the composition comprises at least 0.5, 1, 1.5, 2, 3, 4, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85 or 90 and / or less than 99, 90, 80, 70, 60, 50, 40, 30, 25, 20, 15, 10, 9 or 8 weight percent of mevalonolactone, mevalonic acid and / or a salt of mevalonic acid, based on the total weight of the composition. [13] The gene modulation formulation of claim 1, wherein the mevalonolactone has an APHA color of less than 500, 450, 400, 350, 300, 250, 200, 150, 100, 90, 80, 70, 60, 50, 40, 30, 20, 10, 1, 0.1, or 0.01 units of parts per million platinum-cobalt to water as measured by ASTM D1209. [14] The gene modulation formulation of claim 1, wherein the composition comprises bakuchiol, lactic acid, or a combination thereof. [15] The gene modulation formulation of claim 1, wherein the composition contains less than 5,000 ppm, 1,000 ppm, 500 ppm, 400 ppm, 300 ppm, 200 ppm, 100 ppm, or 10 ppm of odor-causing body as measured by gas chromatography (GC). [16] The gene modulation formulation according to claim 1, wherein the mevalonolactone is purified in a wiped film evaporator, a rotary evaporator and / or a falling film evaporator. [17] A process for preparing a dermatological composition, the process comprising: (a) providing an aqueous solution of mevalonolactone, wherein the mevalonolactone (i) is at least 97.5 percent pure in an aqueous solution as measured by HPLC, (ii) contains less than 1% by weight of fermentation by-products, ethyl acetate, dichloromethane, tetrahydrofuran, isopropanol, petrochemicals or combinations thereof, based on the total weight of the mevalonolactone, and (iii) contains less than 10,000 ppm of odor-causing substances as measured by gas chromatography (GC); and (b) combining the aqueous solution with at least one additive to thereby form the dermatological composition. [18] The method of claim 17, wherein the mevalonolactone in an aqueous solution is at least 98.5 or 99.5 percent pure as measured by HPLC. [19] The method of claim 17, wherein the dermatological composition contains 0.1 to 10% by weight of the mevalonolactone. [20] The method of claim 17, wherein the mevalonolactone is in the form of an aqueous solution containing the mevalonolactone. [21] The method of claim 17, wherein the dermatological composition increases the expression of at least two genes selected from the group consisting of: COL1A1, COL1A2, COL4A1, ELN, EMILIN1, EMILIN2, MFAP5, FN1, LAMA1, TIMP1, TIMP2, TIMP3, TIMP4, HAS1, HAS2, HAS3, HABP4, HAPLN1, EGF, FGF7, HBEGF, KRT1, KRT2, KRT4 and DEFA1 by at least 10 percent as measured 24 hours after application. [22] The method of claim 17, wherein the dermatological composition reduces the expression of at least two genes selected from a group consisting of: MMP1, MMP2, MMP3, MMP7, MMP9, NFATC1, IL1A, IL1B, TNFA, SELE, SELL, EDN1, EDN2, EDN3, PTGS2 (COX2) and POMC by at least 10 percent as measured 24 hours after application. [23] The method of claim 17, wherein the dermatological composition reduces the production of cortisol in human epithelial skin cells by at least 10 percent as measured 24 hours after application. [24] The method of claim 17, wherein the mevalonolactone comprises at least 95% by weight of R-mevalonolactone based on the total weight of the mevalonolactone. [25] The method of claim 17, wherein the dermatological composition is a topical skin care composition in the form of a mist, lotion, emulsion, gel, cream or ointment. [26] The process of claim 17, wherein the mevalonolactone contains less than 1, 0.5, 0.1, 0.05, 0.01, 0.005, 0.001, 0.0005, 0.0001, 0.00005, or 0.00001 weight percent of fermentation by-products, ethyl acetate, dichloromethane, tetrahydrofuran, isopropanol, petrochemicals, or combinations thereof, based on the total weight of the mevalonolactone. [27] The method of claim 17, wherein the mevalonolactone has a cation, anion and / or metal content of less than 10,000 ppm, 5,000 ppm, 1,000 ppm, 500 ppm, 400 ppm, 300 ppm, 200 ppm, 100 ppm or 10 ppm as measured by ICP-OES. [28] The method of claim 17, wherein the dermatological composition comprises at least 0.5, 1, 1, 2, 3, 4, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85 or 90 and / or less than 99, 90, 80, 70, 60, 50, 40, 30, 25, 20, 15, 10, 9 or 8% by weight of mevalonolactone, mevalonic acid and / or a salt of mevalonic acid, based on the total weight of the composition. [29] The method of claim 17, wherein the mevalonolactone has an APHA color of less than 500, 450, 400, 350, 300, 250, 200, 150, 100, 90, 80, 70, 60, 50, 40, 30, 20, 10, 1, 0.1 or 0.01 units of parts per million platinum-cobalt to water as measured by ASTM D1209. [30] The method of claim 17, wherein the dermatological composition comprises bakuchiol, lactic acid, or a combination thereof. [31] The method of claim 17, wherein the dermatological composition contains less than 5,000 ppm, 1,000 ppm, 500 ppm, 400 ppm, 300 ppm, 200 ppm, 100 ppm or 10 ppm of odor-causing substances as measured by gas chromatography (GC). [32] The process according to claim 17, wherein the mevalonolactone is purified in a wiped film evaporator, a rotary evaporator and / or a falling film evaporator. [33] The method of claim 17, wherein providing comprises: Fermenting a starting material to thereby form an unpurified solution comprising mevalonolactone, mevalonic acid and / or a salt of mevalonic acid; contacting the unpurified solution with an acid to thereby form an acidic mixture; and Purifying the acidic mixture with a wiped film evaporator, a falling film evaporator, a rotary evaporator, an electrodialysis device and / or an electrodeionization device to thereby form a purified solution containing mevalonolactone, mevalonic acid and / or a salt of mevalonic acid. [34] The method of claim 17, wherein providing comprises: Fermenting a starting material to thereby form an unpurified solution comprising mevalonolactone, mevalonic acid and / or a salt of mevalonic acid; Purifying the acidic mixture with a falling film evaporator and / or a rotary evaporator to form a purified solution; and If necessary, further purification of the purified solution in a falling film evaporator. [35] The method of claim 17, wherein providing comprises: Fermenting a starting material to thereby form an unpurified solution comprising mevalonolactone, mevalonic acid and / or a salt of mevalonic acid; Purifying the acidic mixture with a falling film evaporator and / or a rotary evaporator to form a purified solution; and [36] (a) Mevalonolactone, where the mevalonolactone: (i) is at least 97.5 percent pure in an aqueous solution as measured by HPLC, (i) is at least 97.5 percent pure in an aqueous solution as measured by HPLC, (ii) contains less than 1% by weight of fermentation by-products, ethyl acetate, dichloromethane, tetrahydrofuran, isopropanol, petrochemicals or combinations thereof, based on the total weight of the mevalonolactone, and (iii) contains less than 10,000 ppm of odor-causing substances as measured by gas chromatography (GC); and (b) Water. [37] The purified mevalonolactone process of claim 36, wherein the mevalonolactone in an aqueous solution is at least 99 or 99.5 percent pure as measured by HPLC. [38] The purified mevalonolactone method of claim 36, wherein the solution reduces the expression of at least two genes selected from the group consisting of: COL1A1, COL1A2, COL4A1, ELN, EMILIN1, EMILIN2, MFAP5, FN1, LAMA1, TIMP1, TIMP2, TIMP3, TIMP4, HAS1, HAS2, HAS3, HABP4, HAPLN1, EGF, FGF7, HBEGF, KRT1, KRT2, KRT4 and DEFA1 by at least 10 percent as measured 24 hours after application. [39] The purified mevalonolactone method of claim 36, wherein the solution is the expression of at least two genes selected from the group consisting of: MMP1, MMP2, MMP3, MMP7, MMP9, NFATC1, IL1A, IL1B, TNFA, SELE, SELL, EDN1, EDN2, EDN3, PTGS2 (COX2) and POMC by at least 10 percent measured 24 hours after application. [40] The purified mevalonolactone method of claim 36, wherein the solution reduces the production of cortisol in human epithelial skin cells by at least 10 percent as measured 24 hours after application. [41] The purified mevalonolactone process of claim 36, wherein the mevalonolactone comprises at least 95% by weight of R-mevalonolactone based on the total weight of the mevalonolactone. [42] The purified mevalonolactone process of claim 36, wherein the mevalonolactone comprises less than 1, 0.5, 0.1, 0.05, 0.01, 0.005, 0.001, 0.0005, 0.0001, 0.00005, or 0.00001 weight percent of fermentation by-products, ethyl acetate, dichloromethane, tetrahydrofuran, isopropanol, petrochemicals, or combinations thereof, based on the total weight of the mevalonolactone. [43] The purified mevalonolactone process of claim 36, wherein the mevalonolactone has a cation, anion and / or metal content of less than 10,000 ppm, 5,000 ppm, 1,000 ppm, 500 ppm, 400 ppm, 300 ppm, 200 ppm, 100 ppm or 10 ppm as measured by ICP-OES. [44] The purified mevalonolactone process according to claim 36, wherein the solution contains at least 0.5, 1, 1, 2, 3, 4, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85 or 90 and / or less than 99, 90, 80, 70, 60, 50, 40, 30, 25, 20, 15, 10, 9 or 8 weight percent of mevalonolactone, mevalonic acid and / or a salt of mevalonic acid, based on the total weight of the composition. [45] The purified mevalonolactone process of claim 36, wherein the mevalonolactone has an APHA color of less than 500, 450, 400, 350, 300, 250, 200, 150, 100, 90, 80, 70, 60, 50, 40, 30, 20, 10, 1, 0.1, or 0.01 units of parts per million platinum-cobalt to water as measured by ASTM D1209. [46] The purified mevalonolactone process of claim 36, wherein the composition contains less than 5,000 ppm, 1,000 ppm, 500 ppm, 400 ppm, 300 ppm, 200 ppm, 100 ppm, or 10 ppm of odor-causing bodies as measured by gas chromatography (GC). [47] A process for purifying mevalonolactone according to claim 36, wherein the mevalonolactone is purified in a wiped film evaporator, a rotary evaporator and / or a falling film evaporator.

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