Salts of tranexamic acid ester

Abstract

Salts of various tranexamic acid ester compounds are described, as are compositions comprising such compounds. Methods for treating external surfaces (e.g., skin) and methods of preparing the compounds and compositions are also described.

Description

Field of the Invention

[0001] The present invention relates to salts of various tranexamic acid esters, and compositions comprising such compounds. The present invention also includes methods of using these compounds and compositions, such as for treating an external surface of an individual (e.g., skin), and methods of preparing the compounds and compositions.

[0002] background

[0003] Salts of various tranexamic acid esters have been used to treat external skin conditions, such as melasma, UV-induced hyperpigmentation, erythema, age spots, moles and melaninized wrinkles. For example, see Japanese Patent Application Publication H04-46144, which describes an external composition containing tranexamic acid ester hydrochloride as an anti-pigmentation agent. Although tranexamic acid ester salts are useful in external compositions, common technical problems arise because the salts of various tranexamic acid esters are only slightly soluble in water or oil and are difficult to disperse in either. Poor solubility can lead to crystallization and aggregation in cosmetic compositions, which subsequently lead to product instability and poor texture and feel.

[0004] Composite compositions containing salts of certain tranexamic acid esters have been developed to overcome poor stability and produce improved skin feel. For example, U.S. Patent No. 9,345,651 describes a composite emulsion in which the oil phase comprises a combination of tranexamic acid ester hydrochloride and an amphiphilic substance, with the oil phase stabilizing the salt. The oil phase also comprises water. The oil phase is dispersed in a larger aqueous phase. Therefore, these composite compositions can be considered as three-phase emulsions (i.e., water-in-oil-in-water emulsions, U.S. Patent No. 9,833,401 discloses a dispersion of tranexamic acid ester hydrochloride and an amphiphilic polymer (i.e., 2-methacryloyloxyethyl phosphorylcholine / methacrylic acid stearyl ester copolymer). In addition, U.S. Patent No. 8,647,650 describes a method for preparing a dispersion of tranexamic acid ester hydrochloride by using a salting-out agent to produce microscopic particles less than 100 microns. The method includes multiple steps, starting with dissolving tranexamic acid ester hydrochloride in a solvent, and then helping it to precipitate into micron particles by a salting-out agent.

[0005] These compositions require multiple multi-step processes or multiple auxiliary materials to produce stable tranexamic acid ester hydrochloride formulations. The multi-step processes and auxiliary materials require added expense when preparing these compositions. In addition, the auxiliary materials are typically petrochemically derived polymers, which are often not favored by consumers seeking more natural and simple personal care products.

[0006] Therefore, there remains a need for salts of tranexamic acid esters that readily form stable and / or uniform aqueous dispersions without requiring additional processing steps and without requiring auxiliary materials to stabilize the salts. There is also a need for stable and effective compositions comprising salts of tranexamic acid esters, and methods of using and preparing such compounds and compositions. SUMMARY OF THE INVENTION

[0008] Various aspects of the present invention relate to salts of certain tranexamic acid esters. In various embodiments, the salt of tranexamic acid ester is a compound of formula (I):

[0009]

[0010] wherein R1 is a saturated or unsaturated, substituted or unsubstituted aliphatic hydrocarbon group, and A - is a counter ion with a sulfonic acid moiety.

[0011] Additional aspects of the invention include compositions comprising one or more salts of a tranexamic acid ester (eg, a compound of formula (I) as shown above and described herein) and water.

[0012] Additional aspects include methods for treating an external surface of an individual. In various embodiments, the method includes applying to an external surface of the individual an effective amount of (a) a compound of formula (I) as shown above and described herein, or (b) a composition comprising a compound of formula (I) and water.

[0013] Other aspects include methods of making a composition comprising a compound of formula (I) as shown above and described herein and water. In various embodiments, the method comprises combining water with a compound of formula (I).

[0014] Other aspects include methods of synthesizing compounds of formula (I) as shown above and described herein. In various embodiments, the method comprises reacting tranexamic acid with a 1 Part of the alcohol and contains A - ionic sulfonic acid to form the compound.

[0015] Other objects and features will be in part apparent and in part pointed out hereinafter. BRIEF DESCRIPTION OF THE DRAWINGS

[0017] Figure 1 A series of images of compositions containing different salts of tranexamate are shown.

[0018] Figure 2 Graph showing the viscosity of compositions containing salts of tranexamic acid esters. DETAILED DESCRIPTION OF THE INVENTION

[0020] Various compounds, compositions and related methods for treating the external surface (e.g., skin) of an individual are described herein. Methods for preparing the compounds and compositions are also described herein. Applicants have found that the compounds of the present invention can provide surprisingly stable and / or uniform compositions that do not form aggregates or precipitate crystals. Various compositions show a smooth and refreshing feel of use and have a texture without adverse granularity, stickiness, or greasy feeling or afterfeel.

[0021] Salts of tranexamic acid ester

[0022] Various aspects of the present invention relate to salts of tranexamic acid esters. In various embodiments, the salts of tranexamic acid esters are compounds of formula (I):

[0023]

[0024] wherein R1 is a saturated or unsaturated, substituted or unsubstituted aliphatic hydrocarbon group, and A - is a counter ion with a sulfonic acid moiety.

[0025] In various embodiments, R1 is a saturated or unsaturated aliphatic hydrocarbon group substituted with one or more alkyl, alkenyl, hydroxy, oxo, alkoxy and / or cycloalkyl moieties.

[0026] In various embodiments, R1 is alkyl. In certain embodiments, R1 is C1 to C 22 , C2 to C 22 , C3 to C 22 , C4 to C 22 , C8 to C 22 , C8 to C 20 , C8 to C 18 , C8 to C16 , C8 to C 14 , C8 to C 12 , C8 to C 10 , C 10 To C 22 , C 10 To C 20 , C 10 To C 18 , C 10 to C16 , C 10 To C 14 , C 10 To C 12 , C 12 To C 22 , C 12 To C 20 , C 12 To C 18 , C 12 toC16 , C 12 To C 14 , C 14 To C 22 , C 14 To C 20 , C 14 To C 18 , C 14 to C16 , C 16 To C 22 , C 16 To C 20 , C 16 To C 18 , C 18 To C 22 , C 18 To C 20 or C 20 To C 22 For example, in certain embodiments, R1 is C8 to C 22 In another embodiment, R1 is a straight chain C 12 , C 14 , C 16 or C 18 alkyl.

[0027] In various embodiments, R1 is alkenyl. In certain embodiments, R1 is C1 to C 22 , C2 to C 22 , C3 to C 22 , C4 to C 22 , C8 to C 22 , C8 to C 20 , C8 to C 18 , C8 to C 16 , C8 to C 14 , C8 to C 12 , C8 to C 10 , C 10 To C 22 , C 10 To C 20 , C 10 To C 18 , C 10 To C 16 , C 10 To C 14 , C 10 To C 12 , C 12 To C 22 , C 12 To C 20 , C 12 To C 18 , C 12 To C16 , C 12 To C 14 , C 14 To C 22 , C 14 To C 20 , C 14 To C 18 , C 14 To C 16 , C 16 To C 22 , C 16 To C 20 , C 16 To C 18 , C 18 To C 22 , C 18 To C 20 or C 20 To C 22 For example, in certain embodiments, R1 is C8 to C 22 In another embodiment, R1 is a straight chain C 12 , C 14 , C 16 or C 18 Alkenyl.

[0028] In various embodiments, R1 is derived from a fatty alcohol or a polyol.

[0029] As described, in formula (I), A - is a counterion having a sulfonic acid moiety. In some embodiments, the counterion having a sulfonic acid moiety has the formula R2SO3 - , wherein R2 is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted aryl, substituted or unsubstituted alkaryl, or substituted or unsubstituted heterocycle. In certain embodiments, R2 is alkyl, alkenyl, aryl, alkaryl, or heterocycle, which is substituted with one or more alkyl, alkenyl, hydroxy, oxo, alkoxy, and / or cycloalkyl moieties.

[0030] In various embodiments, R2 is alkyl. In certain embodiments, R2 is C1 to C 20 , C1 to C 12 , C1 to C 10 , C1 to C8, C1 to C6, C1 to C5, C1 to C4, C1 to C3, C1 to C2, C2 to C 12 , C2 to C 20 , C2 to C 10 , C2 to C8, C2 to C6, C2 to C5, C2 to C4 or C2 to C3 alkyl. In some embodiments, R2 is C 12 , C10 In some embodiments, R2 is methyl or ethyl.

[0031] In various embodiments, R2 is alkenyl. In certain embodiments, R2 is C1 to C 12 , C1 to C 10 , C1 to C8, C1 to C6, C1 to C5, C1 to C4, C1 to C3, C1 to C2, C2 to C 12 , C2 to C 10 , C2 to C8, C2 to C6, C2 to C5, C2 to C4 or C2 to C3 alkenyl. In some embodiments, R2 is C 12 , C 10 , C8, C6, C5, C4, C3, C2 or C1 alkenyl.

[0032] In various embodiments, R2 is aryl or alkaryl. For example, in some embodiments, R2 is phenyl or methylphenyl.

[0033] In certain embodiments, the counterion of formula (I) having a sulfonic acid moiety is mesylate, ethanesulfonate, benzenesulfonate, or tosylate.

[0034] In certain embodiments, the compound of formula (I) is lauryl tranexamic acid methanesulfonate, lauryl tranexamic acid ethanesulfonate, lauryl tranexamic acid benzenesulfonate, lauryl tranexamic acid toluenesulfonate, myristyl tranexamic acid methanesulfonate, myristyl tranexamic acid ethanesulfonate, myristyl tranexamic acid benzenesulfonate, myristyl tranexamic acid toluenesulfonate, cetyl tranexamic acid methanesulfonate, cetyl tranexamic acid ethanesulfonate, cetyl tranexamic acid benzenesulfonate, cetyl tranexamic acid toluenesulfonate, stearyl tranexamic acid methanesulfonate, stearyl tranexamic acid ethanesulfonate, stearyl tranexamic acid benzenesulfonate, or stearyl tranexamic acid toluenesulfonate.

[0035] Other aspects include methods for synthesizing compounds of formula (I), as described herein. In various embodiments, the method comprises reacting tranexamic acid with a 1 Part of the alcohol and contains A - The method is carried out under certain conditions to remove the water generated by esterification. In addition, in some embodiments, the alcohol includes a fatty alcohol.

[0036] Formula (I) compound can be synthesized by batch or continuous esterification method known in the art. For example, raw materials can be added to a glass reaction vessel with a steam column and a total condenser, and preferably purged with nitrogen, and the raw materials are heated to initiate the reaction, and the water produced by the reaction is evaporated. Tranexamic acid and alcohol (such as long-chain alcohol or fatty alcohol) can be added to the reaction vessel, heated to 80 ° C, and then the sulfonic acid solution can be slowly added over a period of several minutes. However, the reactants can be added in any order. The mixture can then be further heated to, for example, 140 ° C and kept for 12-24 hours to complete the reaction, and all water is evaporated. Post-treatment can include neutralizing any excess acid, further drying, flakes, and washing any excess residual raw materials with solvents such as ethanol or methanol. The reaction can be carried out with three reactants in equal molar ratios: tranexamic acid, ethanol and sulfonic acid. The reaction efficiency can also be improved by using a slightly molar excess of alcohol. For example, the reaction can be carried out with a molar ratio of alcohol to tranexamic acid of 1.01:1 to 1:1.6.

[0037] Composition

[0038] Additional aspects of the invention include compositions comprising one or more salts of tranexamic acid esters, such as compounds of formula (I) described herein. In some embodiments, the composition is a topical skin care composition.

[0039] In various embodiments, the present invention relates to a composition comprising a compound of formula (I) as described herein and water. In some embodiments, the composition is uniformly dissolved or dispersed in water. The water can be distilled water, purified water, spring water, coconut water, hot water, alkaline water, infused water and / or drinking water.

[0040] In various embodiments, the composition has a water concentration of about 10 wt.% or more, about 20 wt.% or more, about 30 wt.% or more, about 40 wt.% or more, about 50 wt.% or more, about 60 wt.% or more, about 70 wt.% or more, about 80 wt.% or more, or about 90 wt.% or more. In various embodiments, the composition has from about 10 wt.% to about 95 wt.%, from about 10 wt.% to about 90 wt.%, from about 10 wt.% to about 80 wt.%, from about 10 wt.% to about 70 wt.%, from about 10 wt.% to about 60 wt.%, from about 10 wt.% to about 50 wt.%, from about 10 wt.% to about 40 wt.%, from about 10 wt.% to about 30 wt.%, from about 10 wt.% to about 20 wt.%, from about 20 wt.% to about 95 wt.%, from about 20 wt.% to about 90 wt.%, from about 20 wt.% to about 80 %, about 20 wt.% to about 70 wt.%, about 20 wt.% to about 60 wt.%, about 20 wt.% to about 50 wt.%, about 20 wt.% to about 40 wt.%, about 20 wt.% to about 30 wt.%, about 30 wt.% to about 95 wt.%, about 30 wt.% to about 90 wt.%, about 30 wt.% to about 80 wt.%, about 30 wt.% to about 70 wt.%, about 30 wt.% to about 60 wt.%, about 30 wt.% to about 50 wt.%, or about 30 wt.% to about 40 wt.% water concentration.

[0041] In various embodiments, the composition has a concentration of the compound (i.e., compound of formula (I)) of about 50 wt.% or less, about 40 wt.% or less, about 30 wt.% or less, about 20 wt.% or less, about 10 wt.% or less, about 5 wt.% or less, or about 1 wt.% or less. In some embodiments, the composition has about 0.001 wt.% to about 50 wt.%, about 0.001 wt.% to about 40 wt.%, about 0.001 wt.% to about 30 wt.%, about 0.001 wt.% to about 20 wt.%, about 0.001 wt.% to about 10 wt.%, about 0.001 wt.% to about 5 wt.%, about 0.01 wt.% to about 50 wt.%, about 0.01 wt.% to about 40 wt.%, about 0.01 wt.% to about 30 wt.%, about 0.01 wt.% to about 20 wt.%, about 0.1 wt.% to about 10 wt. %, about 0.1wt.% to about 5wt.%, about 0.1wt.% to about 50wt.%, about 0.1wt.% to about 40wt.%, about 0.1wt.% to about 30wt.%, about 0.1wt.% to about 20wt.%, about 0.1wt.% to about 10wt.%, about 0.1wt.% to about 5wt.%, about 1wt.% to about 50wt.%, about 1wt.% to about 40wt.%, about 1wt.% to about 30wt.%, about 1wt.% to about 20wt.%, about 1wt.% to about 10wt.% or about 1wt.% to about 5wt.% of the compound concentration. For example, the composition can have a compound concentration of about 0.001wt.% to about 11wt.% or about 0.5wt.% to about 6wt.%.

[0042] In various embodiments, the composition has a concentration of the compound that is at or near the solubility limit of the compound in the composition at 25°C.

[0043] In some embodiments, the composition has a pH of about 6.5 or less, about 6 or less, about 5 or less, about 4 or less, or about 3 or less. In various embodiments, the composition has a pH of about 2 to about 6, about 2 to about 5, about 2 to about 4, about 3 to about 6, about 3 to about 5, about 3 to about 4, about 4 to about 6, or about 4 to about 5.

[0044] In a number of embodiments, the composition further comprises one or more additional ingredients. One or more additional ingredients can be one or more cosmetically acceptable ingredients. Examples of cosmetically acceptable ingredients are those listed in the International Cosmetic Ingredient Dictionary and Handbook or the U.S. Pharmacopoeia.

[0045] In some embodiments, the one or more additional ingredients may include an organic acid and / or a derivative thereof. For example, the one or more additional ingredients may include at least one organic acid and / or a derivative thereof selected from ascorbic acid, 3-o-ethyl ascorbic acid, azelaic acid, ellagic acid, kojic acid, mandelic acid, alpha-hydroxy acid, beta-hydroxy acid, fruit acid, and combinations thereof.

[0046] In some embodiments, one or more additional ingredients may include a tyrosinase inhibitor.

[0047] In various embodiments, the one or more additional ingredients may include gluconolactone, heparan sulfate, arbutin, niacinamide, resveratrol, hydroquinone, and / or peroxide.

[0048] In further embodiments, the one or more additional ingredients may include an exfoliant.

[0049] In certain embodiments, the one or more additional ingredients may include coal tar, aloe vera gel, keratolytics, plant extracts, marine extracts, fermented extracts, isoflavones, peptides, retinol, other retinoids, and / or combinations thereof.

[0050] In various embodiments, the one or more additional ingredients may include an alcohol. For example, the one or more additional ingredients may include at least one alcohol selected from glycerin, ethylhexylglycerin, propylene glycol, phenoxyethanol, and combinations thereof.

[0051] In certain embodiments, one or more additional ingredients may include polysaccharides and / or natural gums.

[0052] In some embodiments, one or more additional ingredients may include a preservative.

[0053] In further embodiments, one or more additional ingredients may include lipids. For example, one or more additional ingredients may include glycolipids. For example, one or more additional ingredients may include sophorolipids (e.g., ACSSOPHOR).

[0054] In some embodiments, the one or more additional ingredients may include starch. For example, the one or more additional ingredients may include potato starch.

[0055] In certain embodiments, the one or more additional ingredients may include polyglyceryl-6 esters.

[0056] In various embodiments, the one or more additional ingredients include a penetration enhancer. Examples of penetration enhancers include isosorbide esters, monoglycerides, C3 to C 10 Glycols and compounds such as capryloyl salicylic acid.

[0057] In a plurality of embodiments, the composition comprises an aqueous phase containing the compound and an oil phase containing at least one lipophilic component. The lipophilic component can comprise monoglycerides, diglycerides, triglycerides and / or fatty alcohols. For example, the lipophilic component can comprise stearin, cetearyl alcohol and / or capric triglyceride.

[0058] Further aspects include methods of preparing a composition comprising a compound of formula (I) as described herein and water. In various embodiments, the method comprises combining water with a compound of formula (I).

[0059] In various embodiments, the method further comprises adjusting the pH of the composition to about 6.5 or less, about 6 or less, about 5 or less, about 4 or less, or about 3 or less. For example, the method can include adjusting the pH of the composition to within a range of about 2 to about 6, about 2 to about 5, about 2 to about 4, about 3 to about 6, about 3 to about 5, about 3 to about 4, about 4 to about 6, or about 4 to about 5. For example, the method can include adjusting the pH of the composition to about 5.

[0060] In a number of embodiments, the method further comprises heating the compound and water. In some embodiments, the compound and water can be heated to a temperature of about 70°C or higher, about 75°C or higher, about 80°C or higher, about 85°C or higher, or about 90°C or higher. In other embodiments, the compound and water are heated to a temperature of about 70°C to about 95°C, about 70°C to about 90°C, about 70°C to about 85°C, about 75°C to about 95°C, about 75°C to about 90°C, about 75°C to about 85°C, about 77°C to about 95°C, about 77°C to about 92°C, about 77°C to about 90°C, or about 75°C to about 85°C. For example, the compound and water can be heated to the melting temperature of about the compound.

[0061] Additional ingredients may be combined with the compound, water, or any mixture thereof.

[0062] How to use

[0063] Further aspects include methods of treating an external surface of an individual (e.g., skin, hair, nails, etc.) using the compounds and compositions described herein. In various embodiments, the method of treating an external surface of an individual comprises applying to the external surface of the individual an effective amount of (a) a compound of formula (I) as described herein or (b) a composition comprising a compound of formula (I) and water as described herein.

[0064] In some embodiments, the external surface comprises skin.In various embodiments, the method can be used to treat or reduce hyperpigmentation, age spots, discoloration, redness, blemishes, fine lines, and / or wrinkles of the skin.

[0065] In further embodiments of the method, the compound or a composition comprising the compound is applied to an external surface of the individual at least once a day, at least twice a day, at least three times a day, at least four times a day, about one to three times a day, about one to two times a day, or once a day.

[0066] definition

[0067] As used herein, the term "substituted" refers to a chemically acceptable functional substituent, preferably a portion that does not invalidate the activity of the compound. Such substituents include, but are not limited to, alkyl, alkenyl, hydroxyl, oxo, alkoxy and / or cycloalkyl.

[0068] Unless otherwise indicated, the term "alkyl" as used herein refers to an alkyl moiety, preferably containing 1 to about 50 carbon atoms, preferably 1 to about 30 carbon atoms, and even more preferably 1 to about 18 carbon atoms, including branched or unbranched, and saturated or unsaturated species. The alkyl group can be selected from alkyl, alkenyl, alkoxy, alkylamino, thioalkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, N-heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, N-heteroaryl, heteroarylalkyl, etc. The alkyl group can be an optionally substituted alkyl group. Therefore, a variety of alkyl groups can be further selected from substituted alkyl (e.g., cyano), substituted cycloalkyl, etc.

[0069] As used herein, the term "alkenyl" refers to a straight or branched chain hydrocarbon group, preferably having 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 39, 30, 31 or 32 carbons, and having one or more carbon-carbon double bonds. Alkenyl includes, but is not limited to, vinyl, 1-propenyl, 2-propenyl (allyl), isopropenyl, 2-methyl-1-propenyl, 1-butenyl and 2-butenyl. Alkenyl can be unsubstituted or substituted with one or more suitable substituents as defined above.

[0070] As used herein, the term "alkyl" refers to a straight or branched chain hydrocarbon group, preferably having 1 to 32 carbon atoms (i.e., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 39, 30, 31 or 32 carbons). Alkyl includes, but is not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl. Alkyl can be unsubstituted or substituted with one or more suitable substituents as defined above.

[0071] The term "alkoxy" as used herein, means an alkyl group, as defined herein, appended to the parent molecular moiety through an oxygen atom.

[0072] As used herein, the term "aryl" refers to a monocyclic, bicyclic or tricyclic aromatic group, such as phenyl, naphthyl, tetrahydronaphthyl, indanyl, etc.; which is optionally substituted by one or more suitable substituents as defined above, preferably 1-5 suitable substituents.

[0073] As used herein, the term "alkylaryl" or "alkaryl" refers to an aryl group substituted by one or more alkyl groups, and optionally substituted by one or more suitable substituents as defined above.

[0074] As used herein, the term "cycloalkyl" refers to a monocyclic, bicyclic or tricyclic carbocyclic group (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclopentenyl, cyclohexenyl, bicyclo[2.2.1]heptyl, bicyclo[3.2.1]octyl and bicyclo[5.2.0]nonyl, etc.); which optionally contains 1 or 2 double bonds. The cycloalkyl group may be unsubstituted or substituted with one or more suitable substituents as defined above, preferably 1 to 5 suitable substituents.

[0075] As used herein, the term "heterocycle" refers to a monocyclic, bicyclic or tricyclic group containing 1-4 heteroatoms selected from N, O, S(O)n, P(O)n, PRz, NH or NRz, wherein Rz is a suitable substituent. The heterocyclic group optionally contains 1 or 2 double bonds. Heterocyclic groups include, but are not limited to, azetidinyl, tetrahydrofuranyl, imidazolidinyl, pyrrolidinyl, piperidinyl, piperazinyl, oxazolidinyl, thiazolidinyl, pyrazolidinyl, thiomorpholinyl, tetrahydrothiazinyl, tetrahydro-thiadiazinyl, morpholinyl, oxetanyl, tetrahydrodiazinyl, Azine Thiazino, indolinyl, isoindolinyl, quinuclidine, chromanyl, isochromanyl and benzo Examples of monocyclic saturated or partially saturated ring systems are tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, imidazolidin-1-yl, imidazolidin-2-yl, imidazolidin-4-yl, pyrrolidin-1-yl, pyrrolidin-2-yl, pyrrolidin-3-yl, piperidin-1-yl, piperidin-2-yl, piperidin-3-yl, piperazin-1-yl, piperazin-2-yl, piperazin-3-yl, 1,3- oxazolidin-3-yl, isothiazolidine, 1,3-thiazolidin-3-yl, 1,2-pyrazolidin-2-yl, 1,3-pyrazolidin-1-yl, thiomorpholin-yl, 1,2-tetrahydrothiazin-2-yl, 1,3-tetrahydrothiazin-3-yl, tetrahydrothiadiazin-yl, morpholin-yl, 1,2-tetrahydrodiazin-2-yl, 1,3-tetrahydrodiazin-1-yl, 1,4- Oxazine-2-yl and 1,2,5- Thiazin-4-yl. The heterocyclyl group may be unsubstituted or substituted by one or more suitable substituents as defined above, preferably 1 to 3 suitable substituents.

[0076] As used herein, the term "hydroxy" refers to an -OH group.

[0077] As used herein, the term "oxo" refers to a double-bonded oxygen (═O) group in which the bond partner is a carbon atom. Such groups may also be considered carbonyl groups.

[0078] Having described the invention in detail, it will be apparent that modifications and variations are possible without departing from the scope of the invention as defined in the appended claims. Example

[0079] The following non-limiting examples are provided to further illustrate the present invention.

[0080] Examples 1-6. Freeze stability of tranexamic acid ester salt compositions with different counterions

[0081] Cetyl tranexamic acid methanesulfonate was prepared as follows: Cetyl alcohol and tranexamic acid were added to a glass reaction vessel at a molar ratio of 1.1:1, heated to 80°C, and further methanesulfonic acid (anhydrous) was slowly added in an amount equimolar to the amount of tranexamic acid over 30 minutes. The mixture was heated to 140°C and the temperature was maintained to remove water generated during the reaction.

[0082] Compositions of different tranexamic acid ester salts with different counterions as shown in Table 1 were prepared as follows: 1) Ingredients A to D were combined based on the weight ratios in Table 1. 2) The mixture was heated to 80±5° C. with stirring until all solids were dissolved. 3) The homogeneous mixture was removed from the heat and allowed to cool to room temperature (25±5° C.). 4) The pH of Examples 3-6 was adjusted to 5.0±0.3 at room temperature with 10 wt.% NaOH or HCl aqueous solution.

[0083] Table 1

[0084]

[0085] Examples 1-6 were placed in freezing temperature for 12 hours (-9 ± 5 ° C), then thawed and stored at room temperature. Stability was investigated by visual inspection at 24 hours, 7 days, 14 days and 30 days. The results are summarized in Table 2. Examples 1, 3 and 5 were unstable and floating brown particles were unevenly dispersed. See Figure 1 Examples 2, 4 and 6 were stable and uniform throughout and did not form aggregates or precipitated crystals ( Figure 1). In addition, Examples 2, 4 and 6 do not require any additional stabilizer ingredients. Examples 2, 4 and 6 provide a smooth and refreshing feel upon use and have a texture without an undesirable grainy, sticky or greasy feel or afterfeel.

[0086] Table 2

[0087]

[0088] Examples 7-12. Stability of tranexamic acid ester sulfonate compositions

[0089] The compositions of tranexamate sulfonate shown in Table 3 were prepared as follows to test their shelf life stability at room temperature and 45±5°C. 1) Combine ingredients A and B based on the weight ratios in Table 3. 2) Heat the mixture to 80±5°C with stirring until all solids are dissolved. 3) Remove the homogenous mixture from heat and allow to cool to room temperature (25±5°C).

[0090] Table 3

[0091]

[0092] After storage at room temperature for 24 hours, Examples 10-12 were transferred to a laboratory oven at 45±5°C, while Examples 7-9 were kept at room temperature. After additional storage at room temperature or in an oven for 24 hours, 7 days, 14 days, 30 days, and 60 days, stability was studied by visual inspection. The results are summarized in Table 4. Examples 7-12 were always stable and uniform, and did not form aggregates or precipitated crystals. In addition, Examples 7-12 did not require any additional stabilizer ingredients. Examples 7-12 were all equally uniform. The composition was more opaque when the concentration of tranexamic acid sulfonate was higher. Examples 7-12 provided a smooth and refreshing feel when used, and had a texture that had no unfavorable granular, sticky or greasy feel or afterfeel.

[0093] Table 4

[0094]

[0095] Examples 13-16. Viscosity of tranexamic acid ester salt compositions with different counterions

[0096] Compositions of tranexamic acid ester salts with different counterions as shown in Table 5 were prepared as follows. 1) Combine ingredients A to C based on the weight ratios in Table 5. 2) Heat the mixture to 80±5°C with stirring until all solids are dissolved. 3) Remove the homogeneous mixture from heat and allow to cool to room temperature (25±5°C).

[0097] Table 5

[0098]

[0099] The viscosity of Examples 13-16 at room temperature (25±1°C) was determined by the vertical falling ball method using the equation μ = [2(ρ s -ρ l ) 2 ] / 9v, where μ = dynamic viscosity, ρ s = density of the sphere, ρ l = density of the test material (Examples 13-16), g = standard gravity, a = radius of the ball, and v = velocity of the ball.

[0100] The results are shown in Figure 2 In the present invention, tranexamate sulfonate produces higher viscosity with increasing concentration compared to tranexamate hydrochloride. In addition, tranexamate sulfonate gives stable and uniform compositions not observed with tranexamate hydrochloride (see Examples 1 to 12). Viscosity may be one of the forces contributing to higher stability, but surprisingly, viscosity does not fully explain this phenomenon, because tranexamate sulfonate also produces stable compositions at low viscosities.

[0101] Example 17. Lightening serum containing tranexamic acid sulfonate

[0102] The brightening essence of Example 17 shown in Table 6 was prepared as follows. 1) Ingredients 1 and 2 were combined based on the weight ratio of Table 6. 2) The mixture was mixed and heated to 80±5°C until all solids were dissolved. 3) Ingredients 3-6 were combined with each other, and ingredient 7 was dispersed therein, and ingredients 3-7 were added to ingredients 1-2 with stirring at 80±5°C. 4) Oil phase ingredients 8-10 were combined with each other, heated to 80±5°C until melted, and added to ingredients 1-7 with high speed (600-1200 rpm) mixing at 80±5°C. 5) The composition was removed from the heat and kept mixing at a low speed (<500 rpm) while it was allowed to cool to room temperature.

[0103] Example 17 provides a smooth and refreshing feel in use, and has a moisturizing, shiny slurry texture without an undesirable grainy, sticky or greasy feel or afterfeel. It can be used to moisturize and inhibit hyperpigmentation of the skin, as well as reduce age spots, discoloration, redness, blemishes, fine lines and wrinkles. Stability was visually inspected, and the results are summarized in Table 9. Example 17 showed no signs of deterioration or separation after 60 days.

[0104] Table 6

[0105]

[0106] Example 18. Aqueous Toner Containing Tranexamate Sulfonate

[0107] The aqueous toner of Example 18 shown in Table 7 was prepared as follows. 1) Combine ingredients 1-2 based on the weight ratio of Table 7. 2) Heat the mixture to 80±5°C with stirring until all solids are dissolved. 3) Remove the homogeneous mixture from the heat, keep stirring, and allow to cool to room temperature. 4) Add ingredients 3-6 to ingredients 1-2 with stirring at room temperature. 5) Add ingredients 7-8 with stirring at room temperature. 6) Adjust the pH to 4.5±0.3 with ingredient 9.

[0108] Example 18 provides a smooth and refreshing feel in use, and has a moisturizing, shiny slurry texture, without undesirable graininess, stickiness or greasiness or after-feel. It can be used to gently cleanse and moisturize the skin, promote an even skin tone, and inhibit skin pigmentation, as well as reduce age spots, discoloration, redness, blemishes, fine lines and wrinkles. Stability was visually inspected, and the results are summarized in Table 9, showing no signs of deterioration or separation after 60 days.

[0109] Table 7

[0110]

[0111]

[0112] Example 19. Aqueous Facial Spray Containing Tranexamate Sulfonate

[0113] Prepare an aqueous facial spray as shown in Table 8 as follows. 1) Combine ingredients 1-2 based on the weight ratio of Table 8. 2) Heat the mixture to 80±5°C with stirring until all solids are dissolved. 3) Remove the homogenous mixture from heat, keep stirring, and allow to cool to room temperature. 4) Add ingredients 3-6 to ingredients 1-2 and mix at room temperature. 5) Add ingredient 7 at room temperature. 6) Adjust pH to 5.0±0.3 with ingredient 8. 7) Fill the aqueous facial spray into a spray bottle.

[0114] Example 19 provides a smooth and refreshing feel in use, and has a moisturizing, shiny slurry texture, without an undesirable grainy, sticky or greasy feel or afterfeel. It can be used to moisturize, and inhibit skin pigmentation, and reduce age spots, discoloration, redness, blemishes, fine lines and wrinkles. The stability of Example 19 was visually inspected, and the results are summarized in Table 9, showing no signs of deterioration or separation after 60 days.

[0115] Table 8

[0116]

[0117]

[0118] In summary, Examples 17 to 19 are consistently stable and homogeneous, and do not aggregate, precipitate, or crystallize at room temperature or at 45±5° C. Examples 17 to 19 also demonstrate that the tranexamate sulfonates described herein can be effectively used to prepare stable compositions with a refreshing smooth feel and afterfeel.

[0119] Table 9

[0120]

[0121]

[0122] When introducing elements of the present invention or the preferred embodiments thereof, the articles "a," "an," "the," and "said" are intended to mean that there are one or more of the elements. The terms "comprising," "including," and "having" are intended to be inclusive and mean that there may be additional elements other than the listed elements.

[0123] In view of the above, it will be seen that the several objects of the invention are achieved and other advantageous results attained.

[0124] As various changes could be made in the above compositions, methods and processes without departing from the scope of the invention, it is intended that all matter contained in the above description and shown in the accompanying drawings shall be interpreted as illustrative and not in a limiting sense.

Claims

1. A compound, which is cetyl tranexamic acid mesylate.

2. A composition comprising the compound of claim 1 and water.

3. The composition of claim 2, wherein the composition is a topical skin care composition.

4. The composition of claim 2, wherein cetyl tranexamic acid mesylate is uniformly dissolved or dispersed in water.

5. The composition of claim 2, wherein the water is purified water, spring water and / or coconut water.

6. The composition of claim 2, wherein the composition has a water concentration of 80 wt.% or more.

7. The composition of claim 2, wherein the composition has a water concentration of 10 wt.% to 95 wt.%.

8. The composition of claim 2, wherein the composition has a cetyl tranexamic acid mesylate concentration of 20 wt.% or less.

9. The composition of claim 2, wherein the composition has a concentration of cetyl tranexamic acid mesylate of 1 wt.% to 10 wt.%.

10. The composition of claim 2, wherein the composition has a concentration of cetyl tranexamic acid mesylate of 0.001 wt.% to 11 wt.%.

11. The composition of claim 2, wherein the composition has a concentration of cetyl tranexamic acid mesylate of 0.5 wt.% to 6 wt.%.

12. The composition of claim 2, wherein the composition has a pH of 6.5 or less.

13. The composition of claim 2, wherein the composition has a pH of 2 to 6.

14. A composition according to any one of claims 2 to 13 further comprising one or more additional ingredients.

15. The composition of claim 14, wherein the one or more additional ingredients comprises one or more cosmetically acceptable ingredients.

16. The composition of claim 14, wherein the one or more additional ingredients comprises an organic acid.

17. The composition of claim 14, wherein the one or more additional ingredients comprises at least one organic acid selected from the group consisting of ascorbic acid, 3-o-ethylascorbic acid, azelaic acid, ellagic acid, kojic acid, alpha-hydroxy acids, beta-hydroxy acids, fruit acids, and combinations thereof.

18. The composition of claim 14, wherein the one or more additional ingredients comprises gluconolactone, heparan sulfate, arbutin, niacinamide, resveratrol, hydroquinone and / or peroxide.

19. The composition of claim 14, wherein the one or more additional ingredients comprises an exfoliant.

20. The composition of claim 14, wherein the one or more additional ingredients comprises a tyrosinase inhibitor.

21. The composition of claim 14, wherein the one or more additional ingredients comprises coal tar, aloe vera gel, keratolytics, isoflavones, peptides, retinoids, and / or combinations thereof.

22. The composition of claim 14, wherein the one or more additional ingredients comprises an alcohol.

23. The composition of claim 14, wherein the one or more additional ingredients comprises at least one alcohol selected from the group consisting of glycerin, ethylhexylglycerin, propylene glycol, phenoxyethanol, and combinations thereof.

24. The composition of claim 14, wherein the one or more additional ingredients comprises a polysaccharide and / or a natural gum.

25. The composition of claim 14, wherein the one or more additional ingredients comprises a preservative.

26. The composition of claim 14, wherein the one or more additional ingredients comprises a penetration enhancer.

27. The composition of claim 14, wherein the one or more additional ingredients comprises a lipid.

28. The composition of any one of claims 2 to 13, wherein the composition comprises an aqueous phase comprising cetyl tranexamic acid mesylate and an oil phase comprising at least one lipophilic component.

29. The composition of claim 28, wherein the lipophilic component comprises monoglycerides, diglycerides, triglycerides and / or fatty alcohols.

30. Use of a compound of claim 1 or a composition of any one of claims 2 to 13 in the preparation of a topical skin care composition for treating an external surface of an individual.

31. The use of claim 30, wherein the external surface comprises skin.

32. The use of claim 31, wherein the treatment of the external surface of the individual is for treating or reducing age spots, discoloration, redness and wrinkles of the skin.

33. The use of claim 31, wherein the topical skin care composition is applied to the skin of the individual at least once a day.

34. A method for preparing the composition of claim 2, the method comprising: Combine water and cetyl tranexamic acid mesylate.

35. The method of claim 34, further comprising adjusting the pH of the composition to 6.5 or less.

36. The method of claim 34, further comprising adjusting the pH of the composition to within the range of 2 to 6.

37. The method of claim 34, wherein the pH of the mixture is adjusted to 5.

38. The method of claim 34, further comprising heating the cetyl tranexamic acid mesylate and the water.

39. The method of claim 38, wherein the cetyl tranexamic acid mesylate and water are heated to a temperature of 70°C or greater.

40. The method of claim 38, wherein the cetyl tranexamic acid mesylate and water are heated to a temperature of 70°C to 95°C.

41. The method of claim 38, wherein the cetyl tranexamate mesylate and water are heated to the melting temperature of cetyl tranexamate mesylate.

42. The method of claim 34, further comprising combining one or more additional ingredients with the water, cetyl tranexamate mesylate, or a combination thereof.

43. A method of synthesizing the compound of claim 1 comprising contacting tranexamic acid with cetyl alcohol and adding methanesulfonic acid to form cetyl tranexamic acid mesylate and water.

44. The process of claim 43, wherein the process is carried out under conditions to remove water produced by esterification.

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