Skin care product composition and pharmaceutical composition containing sulfonated calixarene, and use of sulfonated calixarene

Abstract

A skin care product composition containing a sulfonated calixarene compound represented by formula (I) and a skin care active substance, a pharmaceutical composition for treating skin inflammatory diseases, and its novel use in the treatment of skin care and / or skin inflammatory diseases (wherein R, M and n are as defined herein). [Chemical formula 1] TIFF2025525220000016.tif46156

Description

Technical Field

[0001] The present invention belongs to the field of skin care products, and specifically relates to a skin care product composition and a pharmaceutical composition containing a sulfonated calixarene supramolecular compound as an excipient, and a novel use of the sulfonated calixarene supramolecular compound in the treatment of skin care and skin inflammatory diseases.

Background Art

[0002] Skin care products are daily used cosmetics that can supplement skin nutrition, moisturize, lock in moisture, regulate the balance of skin oil and moisture, promote healthy and moisturized skin, and achieve a beautifying effect. They also have functions such as anti-wrinkle, anti-aging, anti-acne, whitening, anti-inflammatory, and soothing of sensitive skin (Liu Zhihong et al, China Food Drug Administration, 2020, (05) 98-101+126). Medical skin care products do not have a strict definition in China. They are also called "functional cosmetics" or "medicated cosmetics" abroad. They were proposed by Albert Kligman in 1984 as a third category of products between cosmetics and pharmaceuticals (Albert Kligman et al., Dermatologic Surgery. 2005, 31(7 Pt 2):890-891). Essentially, they are cosmetics, not pharmaceuticals. Functional skin care products are becoming increasingly popular and can be classified into several categories: cleansing, moisturizing and skin barrier restoration, oil control, anti-inflammatory, soothing, sun protection, whitening, and freckle removal. In addition, the application of medical cosmetics in skin diseases such as dermatitis and eczema is also increasing (Gou Weijun et al., Fine and Specialty Chemicals, 2020, 28(09), 1-5). To achieve a good skin care effect, these active ingredients in cosmetics need to have a certain stability and should not be irritating.

[0003] In recent years, the incidence of skin diseases has been relatively high, and there are many diseases closely related to skin care products, especially acne, sensitive facial skin, hormone-dependent dermatitis, perioral dermatitis, rosacea, and chloasma (Zhao Hengguang et al., Dermatology Bulletin, 2017, 34(04), 462-467+9). Almost without exception, these diseases are faced with the current situation of the clinical use of topical medications. Under such a premise, how to select skin care products and how to coordinate the simultaneous use of skin care products and topical medications are issues that must be carefully resolved in skin care consulting (Qi Xianlong, et al., Chinese Journal of Aesthetic Medicine, 2009, 18(02):240-241; Dreno B, et al., J Eur Acad Dermatol Venereol, 2014, 28(11):1409-1417). The rational use of skin care products can not only play a role in repairing the skin barrier and alleviating inflammation, but also relieve symptoms such as skin dryness, burning sensation, and itching, reduce the dosage of medications, prevent the recurrence of skin diseases, and improve the quality of life of patients (Li Li, et al., The Chinese Journal of Dermatovenereology, 2015, 29(06):553-555; He Li, et al., Journal of Clinical Dermatology, 2009, 38(6):409-410; Willis CM, et al., Br J Dermatol, 2001, 145(2):258-263). For skin diseases such as skin barrier damage and seborrhea, skin care products with sedative, cleansing, moisturizing, and skin barrier repair effects are often selected (Zhou Xiaotong et al., Journal of Practical Dermatology, 2016, 9(03), 175-179; Loden M et al., Clin Dermatol, 2012, 30(3):286-296).

[0004] In the context of the constantly evolving needs of consumers, the development of multifunctional skincare products has become a trend. When adding multiple skincare active ingredients to the same skincare product, the problem of preventing the active ingredients from interfering with each other must be solved. Furthermore, the addition concentration and stability of the active ingredients are also very important for their effects, and the permeability and irritation of the active ingredients to the skin need to be carefully tested. In the field of skincare products, it is increasingly required to comprehensively consider the above factors, optimize the preparation process from multiple aspects, optimize the carriers and dosage forms of the active ingredients, and thereby prepare skincare products with excellent effects. Taking vitamin A, an anti-aging ingredient widely used in the market, as an example, due to its low solubility in water, it can only dissolve in an oily matrix, which can give consumers a greasy feeling and discomfort. In addition, vitamin A is unstable to light, heat, oxygen, and water, so the concentration of vitamin A used in skincare products is likely to be lower than the initial addition concentration. As another example, retinoic acid, a component medically used to treat acne, has low solubility in water, so it can only dissolve in an oily matrix, is also unstable in the presence of light, heat, and water, and furthermore, retinoic acid is irritating and can cause a painful experience for patients during use. Therefore, there is an urgent need for a suitable delivery platform for skincare active ingredients that solves the solubility and stability of these active ingredients, improves their transdermal permeability, reduces irritation, prevents multiple cosmetic ingredients from interfering with each other, and even provides a synergistic effect.

Summary of the Invention

Problems to be Solved by the Invention

[0005] An object of the present invention is to provide a molecular container platform for encapsulating skincare active substances, thereby improving the water solubility, stability, and effectiveness of skincare active substances and reducing irritation.

Means for Solving the Problems

[0006] More specifically, the present invention provides a skin care product composition comprising at least one skin care active substance and; Formula (I):

Chemical formula

[0007] In a preferred embodiment, M is at least one metal selected from the group consisting of Na, K, Mg, and Ca, more preferably Na.

[0008] In another preferred embodiment, R is selected from C 8~12 linear alkyl, more preferably dodecyl.

[0009] In a preferred embodiment, the at least one skin care active substance is one or more active substances selected from basic skin care products or functional skin care products, and in particular, an active substance having at least one function of cleansing or makeup removal, whitening, anti-aging (e.g., anti-wrinkle, antioxidant), anti-inflammatory or anti-acne, moisturizing, and sunburn prevention.

[0010] Preferably, the active substances having a cleansing or makeup removal function are selected from polyols such as butylene glycol, polyethylene glycol, and dipropylene glycol, surfactants such as sodium dodecyl sulfate, sodium lauryl sulfate, acyl sodium sulfate, decyl glucoside, cocamidopropyl betaine, and amino acids, and synthetic esters such as isopropyl myristate, isopropyl palmitate, and triglyceride.

[0011] Active substances with whitening function are selected from vitamin C and its derivatives (sodium ascorbyl phosphate / magnesium, ascorbyl glucoside, ethyl ascorbate, and ascorbyl tetrahydroxydecanoate, etc.), phenyl ethyl resorcinol, niacinamide, tranexamic acid, arbutin, ellagic acid, p-dihydroxybenzene, kojic acid, glutathione, salicylic acid, tretinoin, and hydroquinone.

[0012] Active substances with anti-aging function are selected from vitamin A, proanthocyanidins, vitamin E, resveratrol, peptides (hexapeptides, palmitoyl tripeptide-5, etc.), bifidobacterium culture lysate, astaxanthin, epidermal growth factor, glycolic acid and lactic acid, ubiquinone, caffeine, glycolic acid, lactic acid, vitamin C and its derivatives.

[0013] Active substances with anti-inflammatory or anti-acne function are selected from retinoic acid, α-hydroxy acid, salicylic acid, azelaic acid, and α-bisabolol.

[0014] Active substances with moisturizing function are selected from ceramide, sphingolipid, phospholipid, cholesterol, lecithin, squalane, hyaluronic acid, chondroitin sulfate, natural moisturizing factor, sorbitol, mannitol, glucose, trehalose, glycerin, pentylene glycol, butylene glycol, and provitamin B5.

[0015] The active substances having a sunburn prevention function are selected from benzophenone-3, octyl methoxycinnamate, ensulizole, PEG-25 p-aminobenzoic acid, ethylhexyl triazone, 2-ethylhexyl 2-cyano-3,3-diphenylacrylate, pentyl p-dimethylaminobenzoate, polyacrylamidomethyl benzylidene camphor, glyceryl p-aminobenzoate, hexyl diethylaminohydroxybenzoyl benzoate, camphor benzalkonium methosulfate, benzophenone-5, homosalate, ethylhexyl methoxycinnamate, isoamyl methoxycinnamate, and disodium phenyl dibenzimidazole tetrasulfonate.

[0016] The present inventors have found that calixarene as a macrocyclic host molecule can encapsulate skin care active substances through host-guest interactions, thereby helping to protect the aforementioned active substances. By applying calixarene in the field of skin care, new supramolecular skin care formulations can be developed to meet the requirements of more effective skin improvement. Therefore, calixarene can not only be used to enhance the stability and water solubility of skin care active substances, but also can be used to encapsulate multiple functional molecules simultaneously to prevent the functions of each molecule from interfering or affecting each other. Host-guest interaction is an important basis for applying calixarene to the development of new supramolecular skin care active ingredients. Since calixarene shows strong selective binding to various bioactive substances, it will have extensive market applications in the field of skin care.

[0017] Another object of the present invention is to provide a molecular container platform for encapsulating anti-inflammatory active substances that can be used to prepare a pharmaceutical composition for treating skin inflammatory diseases. This molecular container can improve the water solubility, stability and effectiveness of the active substance, and reduce the irritation and side effects of the anti-inflammatory active substance.

[0018] More specifically, the present invention relates to at least one active substance having a skin anti-inflammatory function and; Formula (I): [Chemical formula] (wherein n is an integer selected from 4 to 8, M is independently selected from H, an alkali metal, and an alkaline earth metal, R is independently selected from C 4~16 linear alkyl), and a sulfonated calixarene compound, to provide a pharmaceutical composition for treating skin inflammatory diseases.

[0019] In a preferred embodiment, M is at least one metal selected from the group consisting of Na, K, Mg, and Ca, more preferably Na.

[0020] In another preferred embodiment, R is selected from C 8~12 linear alkyl, more preferably dodecyl.

[0021] In a preferred embodiment, the active substance having a skin anti-inflammatory function is selected from one or more of retinoic acid, α-hydroxy acid, salicylic acid, azelaic acid, and α-bisabolol.

[0022] In an embodiment of the present invention, the skin inflammatory disease is at least one disease selected from superficial scar, hypertrophic scar, keloid, lupus vulgaris, syphilitic ulcer, tinea favosa, scalp ringworm, cutaneous cryptococcosis, impetigo, acne, and dermatitis. In a preferred embodiment, the skin inflammatory disease is at least one dermatitis selected from neurodermatitis, seborrheic dermatitis, and atopic dermatitis. Specifically, neurodermatitis is selected from eczema, lichen, psoriasis, and pruritus, etc.; seborrheic dermatitis is selected from psoriasis of the head and face, pityriasis versicolor, tinea corporis, etc.; atopic dermatitis is selected from erythema, papules, papulovesicles, exudative crusts, lichenification, skin scratches, and skin dryness, etc.

[0023] In the skin care product composition and pharmaceutical composition of the present invention, the molar ratio of the skin care active substance or the active substance having a skin anti-inflammatory function to the sulfonated calixarene compound is 1:(0.8 - 5.0), preferably 1:(0.9 - 3.0), more preferably 1:(1.0 - 1.5).

[0024] The sulfonated calixarene compound is a class of supramolecular macrocyclic compounds that can improve the solubility and stability of skin care components, have a sustained release effect on drugs, and can reduce its stimulation to normal cells.

[0025] The sulfonated calixarene compounds provided by the present invention have the characteristics of an accurate structure, a certain molecular weight, stable batch synthesis, easy derivatization, and unique cavity binding properties. They can enhance the water solubility and stability of skin care active substances, prevent the functions of each active ingredient from interfering with each other, and can be used to reduce the stimulation of drugs to inflamed skin. Therefore, another object of the present invention is to provide the use of the sulfonated calixarene compound of formula (I) in the preparation of a skin care product or a drug for the treatment of skin inflammatory diseases.

Brief Description of the Drawings

[0026]

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Figure 2A

Figure 2B

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Figure 8

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Figure 10

Mode for Carrying Out the Invention

[0027] Term The term "alkyl" refers to an aliphatic hydrocarbon group which may have a branched or straight chain. Depending on the structure, the alkyl group may be a monoradical or a diradical (i.e., an alkylene group). In the present invention, the alkyl group is preferably an alkyl having 1 to 8 carbon atoms, more preferably a "lower alkyl" having 1 to 6 carbon atoms, and still more preferably an alkyl having 1 to 4 carbon atoms. Typical alkyl groups include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, etc. It should be understood that the "alkyl" referred to herein includes all possible configurations and conformations of the alkyl group. For example, the "propyl" referred to herein includes n-propyl and isopropyl, the "butyl" includes n-butyl, isobutyl, and tert-butyl, and the "pentyl" includes n-pentyl, isopentyl, neopentyl, tert-pentyl, and pent-3-yl.

[0028] The term "alkoxy" refers to an -O-alkyl group (wherein alkyl is as defined herein). Typical alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, etc.

[0029] The term "cycloalkyl" refers to a monocyclic or polycyclic radical containing only carbon and hydrogen. Examples of cycloalkyl groups include groups having 3 to 12 ring atoms. Depending on the structure, the cycloalkyl group may be a monoradical or a diradical (e.g., a cycloalkylene group). In the present invention, the cycloalkyl group is preferably a cycloalkyl having 3 to 8 carbon atoms, more preferably a "lower cycloalkyl" having 3 to 6 carbon atoms. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, and adamantyl.

[0030] The term "aromatic" refers to a planar ring having a delocalized π - electron system with 4n + 2 (where n is an integer) π - electrons. The aromatic ring can be formed from 5, 6, 7, 8, 9, or more than 9 atoms. The aromatic may be optionally substituted. The term "aromatic" includes both carbocyclic aryl groups (e.g., phenyl) and heterocyclic aryl (or "heteroaryl" or "heteroaromatic") groups (e.g., pyridine). The term includes monocyclic groups or fused - ring polycyclic groups (i.e., rings sharing adjacent pairs of carbon atoms).

[0031] As used herein, the term "aryl" refers to an aromatic ring in which each atom forming the ring is a carbon atom. The aryl ring can be formed from 5, 6, 7, 8, 9, or more than 9 carbon atoms. The aryl group may be optionally substituted. Examples of aryl groups include, but are not limited to, phenyl, naphthalenyl, phenanthrenyl, anthracenyl, fluorenyl, and indenyl. Depending on the structure, the aryl group can be a monoradical or a diradical (i.e., an arylene group).

[0032] The term "aryloxy" refers to an - O - aryl group (where aryl is as defined herein).

[0033] The term "heteroaryl" refers to an aryl group containing one or more ring heteroatoms selected from nitrogen, oxygen, and sulfur. An N-containing "heteroaryl" moiety refers to an aromatic group in which at least one of the skeletal atoms of the ring is a nitrogen atom. Depending on the structure, a heteroaryl group can be a monoradical or a diradical (i.e., a heteroarylene group). Examples of heteroaryl groups include, but are not limited to, pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, thiadiazolyl, furyl, benzofuranyl, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl, naphthyridinyl, furopyridinyl, etc.

[0034] As used herein, the term "heteroalkyl" refers to an alkyl group as defined herein in which one or more of the skeletal chain atoms are heteroatoms, such as oxygen, nitrogen, sulfur, silicon, phosphorus, or combinations thereof. The heteroatom can be located at any position within the heteroalkyl group or at the position where the heteroalkyl group is attached to the remainder of the molecule.

[0035] As used herein, the terms "heterocycloalkyl" or "heterocyclyl" refer to non-aromatic rings in which one or more of the atoms forming the ring are heteroatoms selected from nitrogen, oxygen, and sulfur. Heterocycloalkyl rings can be formed by 3, 4, 5, 6, 7, 8, 9, or more than 9 atoms. Heterocycloalkyl rings may optionally be substituted. Examples of heterocycloalkyl include lactam, lactone, cyclic imide, cyclic thioimide, cyclic carbamate, tetrahydrothiopyran, 4H-pyran, tetrahydropyran, piperidine, 1,3-dioxin, 1,3-dioxane, 1,4-dioxin, 1,4-dioxane, piperazine, 1,3-oxathiane, 1,4-oxathiin, 1,4-oxathiane, tetrahydro-1,4-thiazine, 2H-1,2-oxazine, maleimide, succinimide, barbituric acid, thiobarbituric acid, dioxopiperazine, hydantoin, dihydrouracil, morpholine, trioxane, hexahydro-1,3,5-triazine, tetrahydrothiophene, tetrahydrofuran, pyrroline, pyrrolidine, imidazolidine, pyrrolidone, pyrazoline, pyrazolidine, imidazoline, imidazolidine, 1,3-dioxol, 1,3-dioxolane, 1,3-dithiol, 1,3-dithiolane, isoxazoline, isoxazolidine, oxazoline, oxazolidine, oxazolidinone, thiazoline, thiazolidine, and 1,3-oxathiolane, but are not limited thereto. Depending on the structure, the heterocycloalkyl group can be a monoradical or a diradical (i.e., a heterocycloalkylene group).

[0036] The term "halo" or "halogen" refers to fluorine, chlorine, bromine, and iodine.

[0037] The terms "haloalkyl", "haloalkoxy", and "haloheteroalkyl" include alkyl, alkoxy, or heteroalkyl structures in which at least one hydrogen is replaced by a halogen atom. In certain embodiments where two or more hydrogen atoms are replaced by halogen atoms, the halogen atoms may be the same or different from each other.

[0038] The term "amino" refers to the -NH2 group.

[0039] The term "hydroxy" refers to the -OH group.

[0040] The term "cyano" refers to the -CN group.

[0041] The term "ester" refers to a chemical moiety having the formula -COOR, where R is selected from alkyl, cycloalkyl, aryl, heteroaryl (bonded through a ring carbon), and heterocyclyl (bonded through a ring carbon).

[0042] The term "amide" refers to -NR-CO-R', where R and R' are each independently hydrogen or alkyl.

[0043] The term "aminoacyl" refers to the -CO-NH2 group.

[0044] The term "alkylaminoacyl" refers to the -CO-NH-R group, where R is an alkyl group as defined herein.

[0045] The term "optionally" means that one or more of the events described hereinafter may or may not occur, and includes both events that can occur and events that cannot occur. The term "optionally substituted" or "substituted" means that the group(s) mentioned are each independently optionally substituted with one or more additional groups selected from alkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, hydroxy, alkoxy, cyano, halo, amide, nitro, haloalkyl, amino, methylsulfonyl, alkylcarbonyl, alkoxycarbonyl, heteroarylalkyl, heterocycloalkylalkyl, aminoacyl, amino protecting groups, etc., and the above amino protecting groups are preferably selected from the group consisting of pivaloyl, tert-butoxycarbonyl, benzyloxycarbonyl, 9-fluorenylmethoxycarbonyl, benzyl, p-methoxybenzyl, allyloxycarbonyl, trifluoroacetyl, etc.

[0046] Unless otherwise defined, all scientific and technical terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the claimed subject matter belongs.

[0047] Unless otherwise specified, conventional methods of mass spectrometry, NMR, HPLC, protein chemistry, biochemistry, recombinant DNA technology, and pharmacology within the scope of the art are used in the present invention. Unless otherwise indicated, the nomenclature used in connection with analytical chemistry, synthetic organic chemistry, and medicinal and pharmaceutical chemistry described herein, as well as their experimental procedures and techniques, are known in the art. The aforementioned techniques and procedures are well known in the art and can be carried out by conventional methods as described in various general and more specific references cited and discussed throughout this specification.

[0048] Use of the sulfonated calixarene compound of the present invention and its encapsulation of skin care active substances The present invention provides a molecular container platform for encapsulating skin care active substances, which improves the water solubility and stability of skin care active substances and prevents the functions of various components from interfering with each other. The molecular container platform of the present invention has the formula (I): [Chemical formula] (wherein n is an integer selected from 4 to 8, M is independently selected from H, alkali metals, and alkaline earth metals, R is independently selected from C 4~16 linear alkyl) and is a sulfonated calixarene compound.

[0049] In a preferred embodiment, M is at least one metal selected from the group consisting of Na, K, Mg, and Ca, and more preferably Na.

[0050] In another preferred embodiment, R is selected from C 8~12 linear alkyl, and more preferably dodecyl.

[0051] Particularly preferably, the sulfonated calixarene compound of the present invention is the following compound: [Chemical formula] selected from.

[0052] The sulfonated calixarene compound of the present invention can form a host-guest inclusion complex with a skin care active substance through non-covalent bond interactions such as hydrogen bonds, electrostatic bonds, and hydrophobic bonds, and the binding constant is 10 3 or more, more preferably 10 4 or more, and even more preferably 10 5The above is the case. As shown in Fig. 1, the sulfonated calixarene compound of the present invention can increase the solubility of a fat-soluble active substance in water and further enhance its stability. When a fat-soluble active substance is used in water, the active substance can be more closely adapted to the skin, and the permeability of the active substance is likely to increase. Therefore, the sulfonated calixarene compound of the present invention helps to reduce the amount of skin care molecules used and enhance the effectiveness. Furthermore, the sulfonated calixarene compound of the present invention has a sustained release effect on skin care active substances. As a result, the skin care active substances are released controllably, reducing the stimulation to normal cells.

[0053] The sulfonated calixarene compound of the present invention can form a stable host-guest non-covalent bond structure with various small molecule skin care active substances and reduce the stimulation of the skin care active substances to the inflamed skin. Therefore, it can be used as a molecular container platform for enhancing the effectiveness of skin care products in the skin care field.

[0054] Novel supramolecular skin care product composition and pharmaceutical composition of the present invention The present invention also provides a skin care product composition or a pharmaceutical composition for treating skin inflammatory diseases, which contains at least one skin care active substance and a sulfonated calixarene compound of formula (I). Optionally, the skin care product composition or pharmaceutical composition of the present invention may also contain other carriers and other functional components or pharmaceutical components acceptable in the skin care industry.

[0055] In a preferred embodiment, the skin care active substances used for solubilization, stabilization and specific release using the sulfonated calixarene molecular container platform of the present invention can be used to meet one or more of the following skin care needs: cleansing or makeup removal, whitening, anti-aging (anti-wrinkle, antioxidant, etc.), anti-inflammatory or anti-acne, moisturizing, and sunburn prevention.

[0056] Preferably, the active substances having a cleansing or makeup removing function are selected from polyols such as butylene glycol, polyethylene glycol, and dipropylene glycol, surfactants such as sodium dodecyl sulfate, sodium lauryl sulfate, acyl sodium sulfate, decyl glucoside, cocamidopropyl betaine, and amino acids, and synthetic esters such as isopropyl myristate, isopropyl palmitate, and triglyceride.

[0057] The active substances having a whitening function are selected from vitamin C and its derivatives (sodium / magnesium ascorbyl phosphate, ascorbyl glucoside, ethyl ascorbate, and ascorbyl tetrahydroxydecanoate, etc.), phenyl ethyl resorcinol, niacinamide, tranexamic acid, arbutin, ellagic acid, p-dihydroxybenzene, kojic acid, glutathione, salicylic acid, tretinoin, and hydroquinone.

[0058] The active substances having an anti-aging function are selected from vitamin A, proanthocyanidins, vitamin E, resveratrol, peptides (hexapeptides, palmitoyl tripeptide-5, etc.), bifidobacterium culture lysate, astaxanthin, epidermal growth factor, glycolic acid and lactic acid, ubiquinone, caffeine, glycolic acid, lactic acid, vitamin C and its derivatives.

[0059] The active substances having an anti-inflammatory or anti-acne function are selected from retinoic acid, α-hydroxy acids, salicylic acid, azelaic acid, and α-bisabolol.

[0060] The active substances having a moisturizing function are selected from ceramides, sphingolipids, phospholipids, cholesterol, lecithin, squalane, hyaluronic acid, chondroitin sulfate, natural moisturizing factors, sorbitol, mannitol, glucose, trehalose, glycerin, pentylene glycol, butylene glycol, and provitamin B5.

[0061] The active substances having a sunburn prevention function are selected from benzophenone-3, octyl methoxycinnamate, ensulizole, PEG-25 p-aminobenzoic acid, ethylhexyl triazone, 2-ethylhexyl 2-cyano-3,3-diphenylacrylate, pentyl p-dimethylaminobenzoate, polyacrylamidomethyl benzylidene camphor, glyceryl p-aminobenzoate, hexyl diethylaminohydroxybenzoyl benzoate, camphor benzalkonium methosulfate, benzophenone-5, homosalate, ethylhexyl methoxycinnamate, isoamyl methoxycinnamate, and disodium phenyl dibenzimidazole tetrasulfonate.

[0062] In the skin care product composition and pharmaceutical composition of the present invention, the molar ratio of the skin care active substance or the active substance having a skin anti-inflammatory function to the sulfonated calixarene compound is 1:(0.8 - 5.0), preferably 1:(0.9 - 3.0), more preferably 1:(1.0 - 1.5).

[0063] In use, depending on the situation, a single skin care active substance or a combination of a plurality of skin care active substances can be used. The sulfonated calixarene molecular container platform of the present invention can be used in the following products: skin care products such as skin care creams, lotions, oils, toners, talcum powders, bath products, eye skin care products, facial masks, and facial cleansers; cosmetics such as foundations, solid powders, lipsticks, body makeups, eyebrow pencils, eye shadows, eyelid products, mascara products, eye makeup removers, lip balms, lip glosses, general color lipsticks, and lip liners.

[0064] In the embodiments of the present invention, when improving the skin quality of consumers according to the present invention, the selected skin care products are determined by many factors such as the skin type of consumers, select appropriate skin care products, and follow the correct steps for skin care. General skin care and makeup steps are as follows: 1. Facial cleansing, 2. Serum, 3. Toner, 4. Eye essence, 5. Facial essence, 6. Eye cream, 7. Lotion, 8. Face cream; Next, the makeup steps are: 1. First apply lip balm, 2. Sunscreen, 3. Base makeup, 4. Concealer, 5. Adjust makeup, 6. Draw eyebrows, 7. Brow dyeing, 8. Eyeshadow, 9. Eyeliner, 10. Eyelash curler, 11. False eyelashes, 12. Eyelash primer, 13. Mascara, 14. Contouring, 15. Highlighting, 16. Nose shadow, 17. Draw lip line, 18. Lipstick, 19. Blush, 20. Adjust makeup again. It should be noted that makeup removal, exfoliation, and facial masks are also indispensable. Those skilled in the art will understand that although the above skin care suggestions are shown, the specific operation steps and usage amounts can be appropriately adjusted according to the needs of the consumers themselves and in combination with the guidance of experts.

[0065] In addition to imparting a sustained release effect to skin care active substances and reducing the irritation of active substances to inflamed skin, the advantages of the sulfonated calixarene compound of the present invention as a molecular container platform include high solubility in aqueous solutions and the ability to further solubilize poorly soluble skin care active substances. Therefore, when used as an active substance delivery platform, the use concentration of the active substance is not limited by the solubility limit, and greater flexibility is imparted in the selection of the use concentration. In addition, it avoids the greasy feeling associated with the lipid matrix and improves the user experience.

[0066] The solubility of the skin care active substance in the solution can be enhanced by various methods, such as co-grinding the active substance with the sulfonated calixarene compound of the present invention and then dissolving it, or subjecting them together to ultrasonic treatment, shaking or reflux in the solution. Preferably, when the skin care product composition and the pharmaceutical composition of the present invention are in solution form, the concentration of the sulfonated calixarene compound in the solution is 0.5 - 5 mM.

[0067] Preparation of sulfonated calixarene compounds The compounds of formula (I) can be synthesized using standard synthetic techniques known to those skilled in the art or by combining methods known in the art with the methods described herein. In addition, the solvents, temperatures and other reaction conditions shown herein can be varied according to the practice in the art. As a further guide, the following synthetic methods can also be utilized.

[0068] The reactions described can be used sequentially to provide the compounds described herein; or can be used to synthesize fragments that are added later by the methods described herein and / or methods known in the art.

[0069] The compounds can be synthesized using methods similar to those described below using appropriate alternative starting materials. The starting materials used to synthesize the compounds described herein can be synthesized or obtained from commercial suppliers. The compounds described herein, and other related compounds having various substituents, can be synthesized using techniques and starting materials known to those skilled in the art. The general methods for preparing the compounds disclosed herein can be derived from reactions known in the art, and these reactions can be modified by reagents and conditions considered appropriate by those skilled in the art for introducing various moieties into the molecules shown herein.

[0070] If necessary, the reaction product can be separated and purified using conventional techniques including, but not limited to, filtration, distillation, crystallization, chromatography, etc. These products can be characterized using conventional methods including physical constants and spectral data.

[0071] Taking the sulfonated calixarene compound where R is dodecyl as an example, its synthetic route is as follows.

Chemical formula

[0072] SC4A-12C: Calix[4]arene (calix[n]arene where n = 4 - 8, for the synthesis process, see Org. Synth. 1990, 68, 238; J. Am. Chem. Soc. 1982, 104, 2652; J. Org. Chem. 1998, 63, 489) (2.00 g, 4.71 mmol) was added to a round-bottom flask. 12 mL of concentrated sulfuric acid was gradually added, and the reaction was carried out at 90 °C for 4 hours. A small amount of the reaction solution was taken and added to water. If no insoluble substances were observed, heating was stopped and the reaction solution was cooled to room temperature. Then, the reaction solution was dropped into 400 mL of rapidly stirred ethyl ether, stirred overnight, and subjected to suction filtration to obtain an off-white solid. The solid was dissolved in a small amount of water, and sodium hydroxide (0.77 g, 19.25 mmol) was added. Then, a large amount of ethanol was added to induce recrystallization. Sulfonated calix[4]arene (SC4A) was obtained by suction filtration. SC4A (3.00 g, 3.60 mmol) and sodium hydroxide (2.35 g, 58.8 mmol) were dissolved in 15 mL of water and stirred for 3 hours. Then, dodecyl bromide (15.40 g, 61.8 mmol) dissolved in 60 mL of DMSO was added, and the mixture was reacted at 100 °C for 5 days. After cooling to room temperature, a large amount of methanol was added with stirring, and the mixture was placed in a refrigerator and left to freeze. The mixture was subjected to suction filtration, the obtained solid was dissolved in water, and the insoluble substances were filtered off. A large amount of ethanol was added with stirring, and the mixture was placed in a refrigerator and left to freeze. After suction filtration and drying, 4.99 g of the product, sulfonated calix[4]arene compound (SC4A-12C), was obtained in a 92% yield. 1H NMR (400 MHz, DMSO-d6) δ 7.08 (s, 8H, ArH), 4.32 (d, 4H, Ar-CH2-Ar), 3.86 (t, 8H, Ar-O-CH2), 3.22 (d, 4H, Ar-CH2-Ar), 1.92 (m, 8H, -O-CH2-CH2), 1.37 - 1.24 (m, 72H, alkyl chain), 0.85 (t, 12H, CH3).

[0073] SC6A-12C: Calix[6]arene (2.00 g, 3.14 mmol) was added to a round-bottom flask. 12 mL of concentrated sulfuric acid was gradually added, and the reaction was carried out at 90 °C for 4 hours. A small amount of the reaction solution was taken and added to water. If no insoluble substances were observed, heating was stopped and the reaction solution was cooled to room temperature. Then, the reaction solution was dropped into 400 mL of rapidly stirred ethyl ether, stirred overnight, and subjected to suction filtration to obtain an off-white solid. The solid was dissolved in a small amount of water, and sodium hydroxide (0.77 g, 19.25 mmol) was added. Then, a large amount of ethanol was added to induce recrystallization. Sulfonated calix[6]arene (SC6A) was obtained by suction filtration. SC6A (3.00 g, 2.40 mmol) and sodium hydroxide (2.35 g, 58.8 mmol) were dissolved in 15 mL of water and stirred for 3 hours. Then, dodecyl bromide (15.40 g, 61.8 mmol) dissolved in 60 mL of DMSO was added, and the mixture was reacted at 100 °C for 5 days. After cooling to room temperature, a large amount of methanol was added with stirring, and the mixture was placed in a refrigerator and left to freeze. The mixture was subjected to suction filtration, and the obtained solid was dissolved in water, and the insoluble substances were filtered off. A large amount of ethanol was added with stirring, and the mixture was placed in a refrigerator and left to freeze. After suction filtration and drying, 5.20 g of the product, sulfonated calix[6]arene compound (SC6A-12C), was obtained in a 96% yield. 1H NMR (400 MHz, DMSO-d6) δ 7.37 (s, 12H, ArH), 4.54 (d, 6H, Ar-CH2-Ar), 3.67 (t, 12H, Ar-O-CH2), 3.43 (d, 6H, Ar-CH2-Ar), 1.82 (m, 12H, -O-CH2-CH2), 1.31 - 1.22 (m, 108H, alkyl chain), 0.85 (t, 18H, CH3).

[0074] SC8A-12C: Calix[8]arene (2.00 g, 2.36 mmol) was added to a round-bottom flask. 12 mL of concentrated sulfuric acid was added gradually, and the reaction was carried out at 90 °C for 4 hours. A small amount of the reaction solution was taken and added to water. If no insoluble substances were observed, heating was stopped and the reaction solution was cooled to room temperature. Then, the reaction solution was added dropwise to 400 mL of vigorously stirred ethyl ether, stirred overnight, and subjected to suction filtration to obtain an off-white solid. The solid was dissolved in a small amount of water, and sodium hydroxide (0.77 g, 19.25 mmol) was added. Then, a large amount of ethanol was added to induce recrystallization. Sulfonated calix[8]arene (SC8A) was obtained by suction filtration. SC8A (3.00 g, 1.80 mmol) and sodium hydroxide (2.35 g, 58.8 mmol) were dissolved in 15 mL of water and stirred for 3 hours. Then, dodecyl bromide (15.40 g, 61.8 mmol) dissolved in 60 mL of DMSO was added, and the mixture was reacted at 100 °C for 5 days. After cooling to room temperature, a large amount of methanol was added with stirring, and the mixture was placed in a refrigerator and left to freeze. The mixture was subjected to suction filtration, the obtained solid was dissolved in water, and the insoluble substances were filtered off. A large amount of ethanol was added with stirring, and the mixture was placed in a refrigerator and left to freeze. After suction filtration and drying, 4.89 g of the product, sulfonated calix[8]arene compound (SC8A-12C), was obtained in a 90% yield. 1H NMR (400 MHz, DMSO-d6) δ 7.27 (s, 16H, ArH), 4.32 (d, 8H, Ar-CH2-Ar), 3.66 - 3.56 (m, 24H, Ar-CH2-Ar, Ar-O-CH2), 1.63 (m, 16H, -O-CH2-CH2), 1.37 - 1.24 (m, 144H, alkyl chain), 0.84 (t, 24H, CH3).

[0075] Test example Example 1: Determination of the binding constant between a sulfonated calixarene compound and a skin care active substance Test method: UV titration Test apparatus: A Shimadzu Corporation (Japan)-manufactured UV-3600 UV-visible spectrophotometer equipped with a temperature control module (model: PTC-348WI) was used. The samples were tested using a Shimadzu Corporation-made quartz cuvette with an optical path length of 10 mm. Reagents: Vitamin A (Va) was purchased from Shanghai Macklin Biochemical Technology Co., Ltd, retinoic acid was purchased from Heowns Biochem Technologies, LLC (Tianjin), and the other skin care active substances were commercially available products.

[0076] The UV titration experiments of SC8A-12C and the active substances were carried out at room temperature (25 °C). To titrate the binding constant between SC8A-12C and Va, first, an SC8A-12C stock solution and a Va stock solution were prepared. SC8A-12C was dissolved in deionized water to a prepared concentration of 4 mM. Va was dissolved in methanol to a concentration of 2 mM. During the test, the Va stock solution was added to the cuvette and adjusted to a volume of 3 mL with deionized water to obtain a concentration of 10 μM. Subsequently, the SC8A-12C stock solution was added to the cuvette in multiple portions with a predetermined volume so that the final concentration of SC8A-12C increased sequentially (the final concentration of SC8A-12C is shown in Figure 2A). The change in UV absorption intensity was recorded after each addition of the SC8A-12C stock solution. The UV titration data were fitted using a 1:1 host-guest direct binding model (host: SC8A-12C, guest: Va) at a wavelength of 317 nm. The binding constant K α for host-guest inclusion was determined. The results are shown in Figure 2A and Figure 2B. The binding constant K α of SC8A-12C for Va was (4.0 ± 0.5) × 10 5 M -1 .

[0077] The binding constant between SC8A-12C and retinoic acid was determined using the same method. Specifically, a UV titration experiment of SC8A-12C and retinoic acid was carried out at room temperature (25 °C). First, a SC8A-12C stock solution and a retinoic acid stock solution were prepared. SC8A-12C was dissolved in deionized water to a prepared concentration of 4 mM, and retinoic acid was dissolved in methanol to a prepared concentration of 2 mM. During the test, the retinoic acid stock solution was added to a cuvette, adjusted to a volume of 3 mL with deionized water to obtain a concentration of 15 μM. Subsequently, the SC8A-12C stock solution was added to the cuvette in predetermined volumes in multiple portions so that the final concentration of SC8A-12C increased sequentially. The change in UV absorption intensity was recorded after each addition of the SC8A-12C stock solution. The binding constant K α for SC8A-12C with respect to retinoic acid was (1.0 ± 0.3) × 10 5 M -1 .

[0078] The binding constants between SC8A-12C and various active substances were determined using the same method. Specifically, a UV titration experiment of SC8A-12C and the active substance was carried out at room temperature (25 °C). First, a stock solution of SC8A-12C and a stock solution of the active substance were prepared respectively. SC8A-12C was dissolved in deionized water to a prepared concentration of 2 mM, and the active substance was dissolved in methanol or water to a prepared concentration of 2 mM. During the test, the stock solution of the active substance was added to a cuvette, adjusted to a volume of 3 mL with deionized water to obtain a concentration of 15 μM. Subsequently, the SC8A-12C stock solution was added to the cuvette in predetermined volumes in multiple portions so that the final concentration of SC8A-12C increased sequentially. The change in UV absorption intensity was recorded after each addition of the SC8A-12C stock solution. The UV titration data was fitted using a 1:1 host-guest direct binding model to determine the binding constant K α for host-guest inclusion. The test results of the binding constants between various active substances and SC8A-12C are shown in Table 1.

Table 1

[0079] The higher binding constant of the host-guest complex indicates a stronger inclusion ability of SC8A-12C for the active substance and a higher stability of the formed inclusion complex, making it difficult for the skin care active substance to leak out.

[0080] As shown in the experimental results, the sulfonated calixarene compound of the present invention exhibits a strong inclusion strength for the skin care active substance, and the binding constant is 10 3 or more, preferably 10 4 or more, more preferably 10 5 or more. Therefore, the sulfonated calixarene compound of the present invention can form a stable non-covalent host-guest bond with the active substance.

[0081] Example 2: Experiment on the interference of Ca 2+ and Mg 2+ on host-guest inclusion Test method: Fluorescence spectroscopy Test apparatus: A quartz cuvette with an optical path length of 10 mm was used as the sample cell. The type of the instrument was Cary Eclipse manufactured by Varian equipped with a Cary Single-cuvette Peltier cuvette temperature control unit.

[0082] First, lucigenin (LCG) (purchased from Beijing Oaknas Biotechnology Co., Ltd.) was dissolved in water to a prepared concentration of 1 mM to prepare a stock solution of lucigenin. Then, SC8A-12C was dissolved in deionized water to a prepared concentration of 1 mM to prepare a stock solution of SC8A-12C. The LCG stock solution was added to the cuvette and adjusted to a volume of 3 mL with deionized water to obtain a concentration of 10 μM. The excitation wavelength was set to 365 nm and the emission wavelength was set to 505 nm. First, the fluorescence intensity of 10 μM LCG at 505 nm was measured. Subsequently, the SC8A-12C stock solution was added so that the concentration of SC8A-12C became 10 μM, and the fluorescence intensity of 10 μM SC8A-12C-LCG at 505 nm was measured. Next, 10 μM SC8A-12C-LCG and 2.5 mM Ca2+ A solution containing and a solution containing 10 μM SC8A-12C-LCG and 0.8 mM Mg 2+ were prepared, and the fluorescence intensities at 505 nm of these two solutions were measured. The test results are shown in Figure 3.

[0083] The results indicate that the addition of a large amount of Ca 2+ and Mg 2+ to the inclusion complex SC8A-12C-LCG has no effect on the binding. This suggests that even when the metal ions on the head group of SC8A-12C are replaced by Ca 2+ , Mg 2+ , or other ions, the calixarene can still encapsulate guest molecules via host-guest interactions.

[0084] Example 3: Experiment on the solubilization of phenylethyl resorcinol by sulfonated calixarene Test method: UV absorption spectroscopy Test apparatus: A UV-3600 UV-visible spectrophotometer manufactured by Shimadzu Corporation (Japan) equipped with a temperature control module (model: PTC-348WI) was used. Samples were tested using a quartz cuvette manufactured by Shimadzu Corporation with an optical path length of 10 mm.

[0085] Standard solutions of phenylethyl resorcinol with concentrations of 100, 80, 60, 40, and 20 μg / mL were prepared with deionized water. The UV absorption intensity was measured to create a standard calibration curve. 10 mg of phenylethyl resorcinol was added to 1 mL of deionized water and 1 mL of 2 mM SC8A-12C solution, respectively. The mixtures were shaken overnight and then centrifuged to recover the supernatant for UV absorption curve detection. The supernatant of the phenylethyl resorcinol aqueous solution was diluted to an appropriate concentration (to fit the standard calibration curve) for UV absorption intensity measurement (Figure 4).

[0086] Figure 4 shows that a clear and transparent solution was obtained by completely dissolving 10 mg of phenyl ethyl resorcinol in 1 mL of 2 mM SC8A-12C solution, while 1 mL of deionized water could not completely dissolve 10 mg of phenyl ethyl resorcinol, and white precipitates of phenyl ethyl resorcinol remained at the bottom of the container.

[0087] According to the standard calibration curve, the solubility of phenyl ethyl resorcinol in water was calculated to be 4.9 mg / mL, while the solubility of phenyl ethyl resorcinol in water enhanced by the sulfonated calixarene of the present invention exceeded at least 10 mg / mL (completely dissolved).

[0088] Example 4: Experiment on solubilization of vitamin A by sulfonated calixarene Test method: UV absorption spectrophotometry Test apparatus: A UV-3600 UV-visible spectrophotometer manufactured by Shimadzu Corporation (Japan) equipped with a temperature control module (model: PTC-348WI) was used. The samples were tested using a quartz cuvette manufactured by Shimadzu Corporation with an optical path length of 10 mm.

[0089] 5 mg (excess amount) of vitamin A was added to 3 mL of deionized water, and the mixture was shaken overnight. Then, the mixture was centrifuged to collect the supernatant, and the UV absorption curve of the supernatant was measured (Figure 5).

[0090] Solutions of SC4A, SC8A, and SC8A-12C were each prepared at a concentration of 500 μM in deionized water. An excess of Va was added to each of these three solutions at a concentration of 5 mg / mL, and the mixture was shaken with a shaker to enhance the solubility of Va. After 24 hours, each solution group was diluted 40-fold for UV absorption wavelength measurement. On the other hand, Va was dissolved in a methanol solution to prepare a 4 mM Va methanol stock solution. Then, the Va methanol stock solution was diluted with water to prepare a 5 μM Va standard solution containing methanol as a co-solvent, which was used for UV absorption wavelength measurement. The results are shown in Figure 5.

[0091] Figure 5 shows that the supernatant obtained by dissolving vitamin A only in deionized water did not have the characteristic absorption peak of Va (maximum absorption wavelength of 317 nm). Instead, the UV absorption curve of the supernatant had a maximum absorption peak at 290 nm, which is highly likely to be due to the dissolved impurities. This result indicates that Va is hardly soluble in water. In contrast, the newly prepared Va standard solution (containing methanol as a co-solvent) had a characteristic absorption peak of Va at 320 nm, indicating that Va is soluble in water with the help of methanol.

[0092] Compared with the Va standard solution containing methanol as a co-solvent (maximum absorption wavelength at 317 nm), the characteristic absorption peak of Va was not observed in the solutions of the SC4A group and the SC8A group, indicating that they could not solubilize Va. The UV absorption curves of these two solution groups had a maximum absorption peak near 280 nm, which is the inherent absorption peak of the calixarene itself. SC8A-12C exhibited a good solubilizing effect on Va.

[0093] Subsequently, solutions of SC8A-12C with concentrations of 250, 500, 1000, 2000, and 4000 μM were each prepared with deionized water. An excess amount of Va was added to each of these solutions at 5 mg / mL, and the solutions were stirred on a shaker to enhance the solubility of Va. After 24 hours, each solution group was diluted by an appropriate multiple (to conform to the following standard calibration curve) and used for the measurement of UV absorption intensity.

[0094] A standard calibration curve of Va was created. A methanol solution containing 4 mM of Va was prepared. A specific volume of the Va methanol solution was diluted into a solution containing 100 μM of SC8A-12C to obtain Va concentrations of 40, 30, 20, 10, 5, and 2.5 μM in the diluted solution, respectively. The addition of 100 μM of SC8A-12C was to exclude the influence of SC8A-12C on the UV absorption of Va. Subsequently, the UV absorption intensities of these six solution groups with various Va concentrations were measured, and a standard calibration curve was created.

[0095] Based on the standard calibration curve, the solubilized amount of Va in SC8A-12C solutions of various concentrations was calculated from the UV absorption intensity. The results are shown in Table 2.

Table 2

[0096] The results indicate that the sulfonated calixarene compound SC8A-12C of the present invention has a remarkable solubilizing effect on Va which is poorly soluble in water. Therefore, it can solubilize insoluble skin care molecules and enhance the overall utilization efficiency of active substances.

[0097] Example 5: Experiment on Solubilization of Skin Care Active Substances by Sulfonated Calixarene Test method: UV-visible spectrophotometry Test apparatus: A UV-3600 UV-visible spectrophotometer manufactured by Shimadzu Corporation (Japan) equipped with a temperature control module (model: PTC-348WI) was used. Samples were tested using a quartz cuvette manufactured by Shimadzu Corporation with an optical path length of 10 mm.

[0098] An experiment on the stabilization of Va by SC8A-12C was conducted as follows. A solution of SC8A-12C with a concentration of 2000 μM was prepared, and an excess of Va was added thereto at 5 mg / mL. After shaking for 12 hours to dissolve Va, the supernatant of the SC8A-12C solution was collected, diluted (so that the concentration of SC8A-12C in the diluted supernatant became 15 μM), and then subjected to UV absorption detection. After the 2000 μM SC8A-12C solution was allowed to stand at room temperature for 30 days, the supernatant was collected, diluted to a solution with an SC8A-12C concentration of 15 μM, and then subjected to UV detection. The results are shown in Figure 6.

[0099] Va was dissolved in methanol to prepare a Va methanol solution with a concentration of 4 mM, and then it was stored in the dark for 2 days. The UV absorption of both the newly prepared Va methanol solution and the Va methanol solution stored for 2 days was tested. During the test, first, the Va methanol solution was added to a cuvette, and the volume was adjusted to 3 mL with deionized water to make the final concentration of Va 10 μM. The UV absorption curve was detected (shown in Figure 6).

[0100] From Figure 6, it can be seen that the newly prepared aqueous Va solution (containing methanol as a cosolvent) showed an absorption peak characteristic of 317 nm. However, after storage for 2 days, the UV absorption of the aqueous Va solution (containing methanol as a cosolvent) decreased significantly, indicating that most of the free Va in water had decomposed, suggesting poor stability of Va in water. After storing the SC8A-12C solution for 30 days, the amount of solubilized Va actually increased. This is because there was an excess of Va monomers in the solution, and over time, more Va dissolved. In addition, SC8A-12C has a good stabilizing effect on Va, enabling the concentration of solubilized Va to continuously increase over time rather than decrease.

[0101] Example 6: Experiment on Solubilization of Retinoic Acid by Sulfonated Calixarene Test Method: UV Absorption Spectrophotometry Test Apparatus: A UV-3600 UV-visible spectrophotometer manufactured by Shimadzu Corporation (Japan) equipped with a temperature control module (Model: PTC-348WI) was used. Samples were tested using a quartz cuvette manufactured by Shimadzu Corporation with an optical path length of 10 mm.

[0102] Solutions of SC4A, SC8A, and SC8A-12C were each prepared at a concentration of 2000 μM with deionized water. Excess retinoic acid was added to each of the three solution groups at a concentration of 5 mg / mL, and then ultrasonic treatment was performed to enhance the solubility of retinoic acid. After 20 minutes, each solution group was diluted 10-fold for UV absorption wavelength measurement. At the same time, 5 mg (excess amount) of retinoic acid was added to 3 mL of deionized water, the mixture was shaken overnight, and centrifuged to obtain the supernatant. The UV absorption curve of the supernatant was measured (Figure 7). Retinoic acid was dissolved in a methanol solution to prepare a methanol stock solution of 4 mM retinoic acid. After 20 minutes, the methanol stock solution of retinoic acid was diluted with water to prepare a retinoic acid standard solution with an appropriate concentration for UV absorption wavelength detection. The results are shown in Figure 7.

[0103] Figure 7 shows that the supernatant obtained by dissolving retinoic acid only in deionized water did not have an absorption peak of retinoic acid (maximum absorption wavelength of 360 nm), demonstrating that retinoic acid is almost insoluble in water. The retinoic acid standard solution (containing methanol as a solubilizing agent) had a characteristic absorption peak of retinoic acid at 360 nm, demonstrating that retinoic acid can be dissolved in water with the help of methanol. In contrast to the retinoic acid standard solution, neither the SC4A group nor the SC8A group had a characteristic absorption peak of retinoic acid, indicating that they could not effectively solubilize retinoic acid. On the other hand, SC8A-12C exhibited a better solubilizing effect on retinoic acid.

[0104] Thereafter, solutions of SC8A-12C with concentrations of 250, 500, 1000, 2000, and 4000 μM were each prepared with deionized water. An excess amount of retinoic acid was added to the above solutions at 5 mg / mL, and then ultrasonic treatment was performed to enhance the solubility of retinoic acid. After 20 minutes, each solution group was diluted by an appropriate multiple (to conform to the standard calibration curve below) and used for the measurement of UV absorption intensity.

[0105] A standard calibration curve of retinoic acid was prepared. A methanol solution containing 4 mM retinoic acid was prepared. A specific volume of the retinoic acid methanol solution was diluted into a solution containing 100 μM SC8A-12C to obtain concentrations of 25, 20, 15, 10, 5, and 2.5 μM retinoic acid, respectively. The addition of 100 μM SC8A-12C was to eliminate the influence of SC8A-12C on the UV absorption of retinoic acid. Subsequently, the UV absorption intensities of these six groups of solutions with various retinoic acid concentrations were measured to create a standard calibration curve.

[0106] Based on the standard calibration curve, the amount of solubilized retinoic acid in SC8A-12C solutions with various concentrations was calculated as shown in Table 3.

Table 3

[0107] The results show that the sulfonated calixarene compound of the present invention exhibits a remarkable solubilizing effect on retinoic acid, which is poorly soluble in water. The poorly soluble skin care active substance can be solubilized so that it can be used in the aqueous phase, thereby improving the water solubility of the skin care active substance.

[0108] Example 7: Release profile of Va from the inclusion complex SC8A-12C-Va Test method: UV absorption spectroscopy Test apparatus: A UV-3600 UV-visible spectrophotometer manufactured by Shimadzu Corporation (Japan) equipped with a temperature control module (model: PTC-348WI) was used. The samples were tested using a quartz cuvette manufactured by Shimadzu Corporation with an optical path length of 10 mm.

[0109] 700 μL of SC8A-12C-Va solution with a Va concentration of 4 mM was placed in a dialysis bag with a molecular weight cut-off of 500 kDa. After tying both ends of the dialysis bag, it was placed in a centrifuge tube containing 30 mL of deionized water. The centrifuge tube was placed in a shaker, and the solution in the centrifuge tube was sampled for UV absorption detection after 2, 4, 6, and 8 hours. After each detection, the solution was recovered into the centrifuge tube. Finally, according to the standard calibration curve of Va obtained in Example 4, the content of Va released into the centrifuge tube was calculated as shown in Figure 8.

[0110] The results show that sustained release of Va is achieved after inclusion of Va by SC8A-12C, which is beneficial for reducing the irritation of Va and extending its effective duration.

[0111] Example 8: Release profile of retinoic acid from the inclusion complex SC8A-12C-retinoic acid Test method: UV absorption spectroscopy Test apparatus: A UV-3600 UV-visible spectrophotometer manufactured by Shimadzu Corporation (Japan) equipped with a temperature control module (model: PTC-348WI) was used. Samples were tested using a quartz cuvette manufactured by Shimadzu Corporation with an optical path length of 10 mm.

[0112] 700 μL of SC8A-12C-retinoic acid solution with a retinoic acid concentration of 664 μM was placed in a dialysis bag with a molecular weight cut-off of 500 kDa. After tying both ends of the dialysis bag, it was placed in a centrifuge tube containing 15 mL of deionized water. The centrifuge tube was placed in a shaker, and the solution in the centrifuge tube was sampled for UV absorption detection after 2, 4, 6, 8, 21, and 31 hours. After each detection, the solution was recovered into the centrifuge tube. Finally, according to the standard calibration curve of retinoic acid obtained in Example 6, the content of retinoic acid released into the centrifuge tube was calculated as shown in Figure 9.

[0113] The results show that sustained release of retinoic acid is achieved after inclusion of retinoic acid by SC8A-12C, which is beneficial for reducing the irritation of retinoic acid and extending its effective duration.

[0114] Example 9: Experiment on Promoting Transdermal Permeability of Skin-Care Active Substance (Va) by Sulfonated Calixarene Test Method: Skin Permeability Test Test Apparatus: TP-6 Intelligent Transdermal Diffusion Apparatus (Tianjin Jingtuo Instrument Technology Co., Ltd.)

[0115] An experiment was conducted as follows to evaluate the promotion of transdermal permeability of Va by SC8A-12C. Fresh pig skin obtained immediately after slaughter was depilated, and intact skin was carefully excised. Undamaged sections were cut into small pieces of uniform thickness about 2 cm × 2 cm in size, wrapped with plastic wrap, and stored at -20 °C for later use.

[0116] 0.8 mg of Va and 200 mg of skin-care cream (ointment base) were weighed and added to a mortar. The mixture was thoroughly pulverized to dissolve Va in the skin-care cream, obtaining a Va concentration of 0.4% (w / w). Subsequently, 0.8 mg of Va was weighed, shaken well, and dispersed in 200 μL of water to prepare an aqueous Va suspension with a Va concentration of 0.4% (w / w). Next, 8.41 mg of SC8A-12C and 183.6 μL of water were weighed into a centrifuge tube and heated to dissolve. After SC8A-12C was dissolved, 0.8 mg of Va was added to prepare an inclusion complex. The concentration of Va in the inclusion complex was also 0.4% (w / w).

[0117] After thawing the skin, it was placed between the diffusion chamber and the receptor chamber. The receptor chamber was filled with receptor solution (deionized water), and all air bubbles were discharged. The receptor chamber was maintained at 37 °C in a circulating water bath throughout the experiment. The magnetic stirring speed was set at 300 r·min -1 and the transdermal diffusion apparatus was operated. After 55 hours, the solution from the receptor chamber of each group was collected for UV detection.

[0118] The detection results indicated that Va was not detected in the receptor chamber of the ointment base group, suggesting that Va dissolved in the ointment base hardly penetrated into the pig skin. Va dissolved in the aqueous base existed in water as a large amount of undissolved Va oil due to its poor solubility, and thus its permeability was not sufficiently good. However, compared with the group where Va was dissolved in the ointment base, the aqueous base was more favorable for the permeation of Va. The Va content detected in the receptor chamber of the SC8A-12C-Va group was 3.5 times that of the aqueous base group, indicating that Va solubilized by SC8A-12C showed better permeation.

[0119] Example 10: Experiment on the promotion of percutaneous permeability of a skin care active substance (retinoic acid) by sulfonated calixarene Test method: Skin permeability test Test apparatus: TP-6 Intelligent Transdermal Diffusion Apparatus (Tianjin Jingtuo Instrument Technology Co., Ltd.)

[0120] An experiment was conducted as follows to evaluate the promotion of percutaneous permeability of retinoic acid by SC8A-12C. Fresh pig skin obtained immediately after slaughter was depilated, and intact skin was carefully excised. The undamaged sections were cut into small pieces of uniform thickness of about 2 cm × 2 cm, wrapped with plastic wrap, and stored at -20 °C for later use.

[0121] An excessive amount of retinoic acid (5 mg / mL) was added to a 4 mM SC8A-12C solution. After sonication for 30 minutes, the mixture was centrifuged to obtain the supernatant, which was designated as the SC8A-12C-retinoic acid inclusion complex group. The concentration of retinoic acid in the inclusion complex was determined by UV detection and subsequently diluted to 0.1% (w / w). In addition, 3 mg of retinoic acid was weighed and mixed with 297 mg of cream in a mortar. The mixture was completely pulverized to dissolve retinoic acid in the cream, and a 1% (w / w) retinoic acid concentration was obtained.

[0122] After thawing the skin, it was placed between the diffusion chamber and the receptor chamber. The receptor chamber was filled with receptor solution (deionized water), and all air bubbles were removed. The receptor chamber was maintained at 37 °C in a circulating water bath throughout the experiment. The magnetic stirring speed was set to 300 r·min -1 and the transdermal diffusion device was operated. After 24 hours, the solution from the receptor chamber of each group was collected for UV detection. The results are shown in Figure 10.

[0123] As shown in Figure 10, no absorption peak of retinoic acid was detected in the receptor chamber of the ointment base group, indicating that retinoic acid dissolved in the ointment base hardly penetrated into the porcine skin. In contrast, a distinct absorption peak of retinoic acid was detected in the receptor chamber of the SC8A-12C-retinoic acid inclusion complex group, demonstrating that solubilization of retinoic acid by SC8A-12C facilitated its permeation.

[0124] Overall, the sulfonated calixarene compound of the present invention improves the water solubility and stability of the active substance and achieves sustained release of the active substance. When used in the aqueous phase, the sulfonated calixarene compound improves the permeability of the active substance and reduces its effective concentration. Furthermore, in the case of irritant skin care active substances, strong inclusion complex formation and sustained release can reduce the irritation of the skin care active substance to normal skin. In addition, the improvement of the stability of the active substance enables a reduction in the usage amount, which further contributes to the reduction of irritation.

Industrial Applicability

[0125] The present invention provides a skin care product composition and a pharmaceutical composition that utilize a sulfonated calixarene supramolecular compound as an auxiliary material. The sulfonated calixarene supramolecular compound can encapsulate various skin care active substances to produce corresponding multifunctional skin care products, and exhibits the effects of solubilization, stabilization, permeability improvement, and irritation reduction on various skin care active substances, making it suitable for industrial applications.

Claims

1. at least one skin care active substance; Formula (I): 【Chemical 1】 (wherein, n is an integer selected from 4 to 8, M is independently selected from H, alkali metals, and alkaline earth metals, R is independently C ４～１６ and a sulfonated calixarene compound selected from (linear alkyl). The at least one skin care active substance is selected from active substances having at least one of the functions of cleansing or makeup removal, whitening, anti-aging, anti-inflammatory or anti-acne, moisturizing, and sunburn prevention, a skin care product composition.

2. The skin care product composition according to claim 1, wherein M is at least one metal selected from the group consisting of Na, K, Mg, and Ca.

3. R is C ８～１２ The skin care product composition according to claim 1 or 2, wherein R is selected from linear alkyls, more preferably dodecyl.

4. The sulfonated calixarene compound of the above formula (I) is 【Chemical 2】 selected from, the skin care product composition according to any one of claims 1 to 3.

5. The skin care active substance is Active substances having a cleansing or makeup removal function selected from butylene glycol, polyethylene glycol, dipropylene glycol, sodium dodecyl sulfate, sodium lauryl sulfate, sodium acyl sulfate, decyl glucoside, cocamidopropyl betaine, amino acids, isopropyl myristate, isopropyl palmitate, and triglycerides; Active substances having a whitening function selected from vitamin C and its derivatives, phenyl ethyl resorcinol, niacinamide, tranexamic acid, arbutin, ellagic acid, p-dihydroxybenzene, kojic acid, glutathione, salicylic acid, tretinoin, and hydroquinone; Active substances having an anti-aging function selected from vitamin A, proanthocyanidins, vitamin E, resveratrol, hexapeptides, palmitoyl tripeptide-5, bifidobacterium culture lysate, astaxanthin, epidermal growth factor, glycolic acid, lactic acid, ubiquinone, caffeine, glycolic acid, lactic acid, vitamin C and its derivatives; Active substances having an anti-inflammatory or anti-acne function selected from retinoic acid, α-hydroxy acids, salicylic acid, azelaic acid, and α-bisabolol; An active substance having a moisturizing function selected from ceramide, sphingolipid, phospholipid, cholesterol, lecithin, squalane, hyaluronic acid, chondroitin sulfate, natural moisturizing factor, sorbitol, mannitol, glucose, trehalose, glycerin, pentylene glycol, butylene glycol, and provitamin B5; An active substance having a sun protection function selected from benzophenone-3, octyl methoxycinnamate, ensulizole, PEG-25 p-aminobenzoic acid, ethylhexyl triazone, 2-cyano-3,3-diphenylacrylic acid 2-ethylhexyl, pentyl p-dimethylaminobenzoate, polyacrylamide methyl benzylidene camphor, glyceryl p-aminobenzoate, diethylamino hydroxybenzoyl hexyl benzoate, camphor benzalkonium methosulfate, benzophenone-5, homosalate, ethylhexyl methoxycinnamate, isoamyl methoxycinnamate, and disodium phenyl dibenzimidazole tetrasulfonate; The skin care product composition according to any one of claims 1 to 4, selected from one or more of the above.

6. The skin care product composition according to any one of claims 1 to 5, wherein the molar ratio of the skin care active substance to the sulfonated calixarene compound is 1: (0.8 to 5.0), preferably 1: (0.9 to 3.0), more preferably 1: (1.0 to 1.5).

7. At least one active substance having a skin anti-inflammatory function; Formula (I): [Chemical Formula 3] (In the formula, n is an integer selected from 4 to 8, M is independently selected from H, alkali metals, and alkaline earth metals, R is independently C ４～１６ A pharmaceutical composition for treating skin inflammatory diseases, comprising a sulfonated calixarene compound (selected from linear alkyl).

8. The pharmaceutical composition according to claim 7, wherein the active substance having a skin anti-inflammatory function is selected from one or more of retinoic acid, α-hydroxy acid, salicylic acid, azelaic acid, and α-bisabolol.

9. The pharmaceutical composition according to claim 7 or 8, wherein M is at least one metal selected from the group consisting of Na, K, Mg, and Ca.

10. R is C ８～１２ The pharmaceutical composition according to any one of claims 7 to 9, wherein R is selected from linear alkyls, more preferably dodecyl.

11. The sulfonated calixarene compound of the above formula (I) is 【Chemical Formula 4】 Selected from the above, the pharmaceutical composition according to any one of claims 7 to 10.

12. The pharmaceutical composition according to any one of claims 7 to 11, wherein the skin inflammatory disease is at least one disease selected from superficial scar, hypertrophic scar, keloid, lupus vulgaris, syphilitic ulcer, tinea favosa, ringworm, cutaneous cryptococcosis, impetigo, acne, and dermatitis.

13. The pharmaceutical composition according to any one of claims 7 to 11, wherein the skin inflammatory disease is neurodermatitis selected from eczema, lichen, psoriasis, and pruritus; seborrheic dermatitis selected from psoriasis of the head and face, pityriasis versicolor, and tinea corporis; and atopic dermatitis selected from at least one disease selected from erythema, papule, papulovesicle, exudative crust, lichenification, skin scratch injury, and skin dryness.

14. The pharmaceutical composition according to any one of claims 7 to 13, wherein the molar ratio of the active substance having the skin anti-inflammatory function to the sulfonated calixarene compound is 1:(0.8 to 5.0), preferably 1:(0.9 to 3.0), more preferably 1:(1.0 to 1.5).

15. Use of a sulfonated calixarene compound of formula (I) for skin care or treatment of skin inflammatory diseases. 【Chemical Formula 5】 (In the formula, n is an integer selected from 4 to 8, M is independently selected from H, alkali metals, and alkaline earth metals, R is independently selected from C ４～１６ a straight-chain alkyl. )

16. The use of the compound according to claim 15, wherein M is at least one metal selected from the group consisting of Na, K, Mg, and Ca.

17. R is C ８～１２ Use of a compound according to claim 15 or 16, wherein R is selected from a straight-chain alkyl, more preferably dodecyl.

18. The sulfonated calixarene compound of formula (I) is 【Chemical Formula 6】 selected from The use of the compound according to any one of claims 15 to 17.

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