WO2024027193A1 - 含磺化杯芳烃的护肤品组合物、药用组合物、及磺化杯芳烃的用途 - Google Patents

含磺化杯芳烃的护肤品组合物、药用组合物、及磺化杯芳烃的用途 Download PDF

Info

Publication number
WO2024027193A1
WO2024027193A1 PCT/CN2023/087475 CN2023087475W WO2024027193A1 WO 2024027193 A1 WO2024027193 A1 WO 2024027193A1 CN 2023087475 W CN2023087475 W CN 2023087475W WO 2024027193 A1 WO2024027193 A1 WO 2024027193A1
Authority
WO
WIPO (PCT)
Prior art keywords
skin
acid
skin care
sc8a
active substances
Prior art date
Application number
PCT/CN2023/087475
Other languages
English (en)
French (fr)
Inventor
郭东升
李诗慧
王宏磊
Original Assignee
苏州隽德生物科技有限公司
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 苏州隽德生物科技有限公司 filed Critical 苏州隽德生物科技有限公司
Publication of WO2024027193A1 publication Critical patent/WO2024027193A1/zh

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/46—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing sulfur
    • A61K8/466—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing sulfur containing sulfonic acid derivatives; Salts
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/46—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing sulfur
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/04—Antipruritics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/10—Anti-acne agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/10—Antimycotics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q17/00—Barrier preparations; Preparations brought into direct contact with the skin for affording protection against external influences, e.g. sunlight, X-rays or other harmful rays, corrosive materials, bacteria or insect stings
    • A61Q17/04—Topical preparations for affording protection against sunlight or other radiation; Topical sun tanning preparations
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q19/00—Preparations for care of the skin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q19/00—Preparations for care of the skin
    • A61Q19/02—Preparations for care of the skin for chemically bleaching or whitening the skin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q19/00—Preparations for care of the skin
    • A61Q19/08—Anti-ageing preparations
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q19/00—Preparations for care of the skin
    • A61Q19/10—Washing or bathing preparations

Definitions

  • the invention belongs to the field of skin care products, and specifically relates to a skin care composition and a pharmaceutical composition containing a sulfonated calixarene supramolecular compound as an auxiliary material, as well as the use of the sulfonated calixarene supramolecular compound in skin care and treatment of skin inflammatory diseases. New uses.
  • Skin care products are daily cosmetics that can replenish skin nutrients, moisturize and lock in water, adjust the oil and water balance of the skin, promote healthy and moist skin, and achieve the purpose of beauty. It also has anti-wrinkle, anti-aging, anti-acne, whitening, anti-inflammatory and soothing properties. Allergy and other effects (Liu Zhihong et al., China Food and Drug Supervision 2020, (05), 98-101+126). Medical skin care products do not have a strict definition in my country. They are also called “functional cosmetics” or "Cosmeceuticals” abroad. They were proposed by Albert Kligman in 1984 and are the third category between cosmetics and drugs.
  • the product (Albert Kligman et al., Dermatologic Surgery.2005,31(7 Pt 2):890-891) is essentially a cosmetic rather than a drug.
  • Functional skin care products are increasingly favored by people and can be divided into the following categories: cleansing, moisturizing and restoring skin barrier, oil control, anti-inflammatory, soothing, sunscreen, whitening and freckle removal.
  • medical skin care products are increasingly used in skin diseases such as dermatitis and eczema (Gou Weijun et al., Fine and Specialty Chemicals, 2020, 28(09), 1-5). To achieve good skin care effects, these active ingredients are required to have a certain degree of stability in skin care products and not be irritating.
  • Rational use of skin care products can not only repair the skin barrier and relieve inflammation, but also relieve symptoms such as dry skin, burning, itching, reduce drug dosage, prevent recurrence of skin diseases, and improve patients' quality of life (Li Li et al., China skin Journal of Venereology, 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).
  • Vitamin A is unstable to light, heat, oxygen, and water, so the concentration of vitamin A used in skin care products is likely to be lower than the initial concentration.
  • retinoic acid is a medical ingredient used to treat acne. Retinoic acid has poor solubility in water, so it can only be dissolved with an oily base; retinoic acid is also unstable to light, heat, and water; in addition, Tretinoin is irritating and brings painful use experience to patients.
  • One object of the present invention is to provide a molecular container platform for enclosing skin care active substances, thereby improving the water solubility, stability and effectiveness of skin care active substances, and reducing irritation.
  • the present invention provides a skin care composition
  • a skin care composition comprising at least one skin care active substance and a sulfonated calixarene compound of formula (I):
  • 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.
  • M is selected from at least one metal selected from Na, K, Mg and Ca, and is more preferably Na.
  • R is selected from C 8-12 linear alkyl, more preferably dodecyl.
  • At least one skin care active substance is one or more active substances selected from basic skin care products or functional skin care products, especially those with cleaning or makeup removal, whitening, anti-aging (such as anti-wrinkle, An active substance with at least one function among antioxidants), anti-inflammatory or anti-acne, moisturizing, and sun protection.
  • the active substance with cleaning or makeup removal function is selected from polyols such as butylene glycol, polyethylene glycol, and dipropylene glycol, sodium lauryl sulfate, sodium laureth sulfate, and acyl sulfonic acid.
  • polyols such as butylene glycol, polyethylene glycol, and dipropylene glycol, sodium lauryl sulfate, sodium laureth sulfate, and acyl sulfonic acid.
  • Surfactants such as sodium, sunflower glycoside, cocamidopropyl betaine, amino acids, and artificial synthetic esters such as isopropyl myristate, isopropyl hexadecanoate, and triglycerides.
  • Active substances with whitening function are selected from: vitamin C and its derivatives (such as sodium/magnesium ascorbyl phosphate, ascorbic acid glucoside, ethyl ascorbic acid and ascorbic acid tetraisopalmitate), phenylethylresorcinol, nicotinamide, Tranexamic acid, arbutin, ellagic acid, hydroquinone, kojic acid, glutathione, salicylic acid, retinoic acid, and hydroquinone.
  • vitamin C and its derivatives such as sodium/magnesium ascorbyl phosphate, ascorbic acid glucoside, ethyl ascorbic acid and ascorbic acid tetraisopalmitate
  • phenylethylresorcinol such as sodium/magnesium ascorbyl phosphate, ascorbic acid glucoside, ethyl ascorbic acid and ascorbic acid tetraisopalmitate
  • Active substances with anti-aging functions are selected from: vitamin A, proanthocyanidins, vitamin E, resveratrol, peptides (hexapeptide, palmitoyl tripeptide-5), bifid yeast, astaxanthin, epidermal growth factor , glycolic acid and lactic acid, ubiquinone, caffeine, glycolic acid, lactic acid, vitamin C and its derivatives.
  • Active substances with anti-inflammatory or anti-acne functions are selected from: retinoic acid, fruit acid, salicylic acid Acid, azelaic acid and alpha-bisabolol.
  • Active substances with moisturizing function are selected from: ceramide, sphingolipids, phospholipids, cholesterol, lecithin, squalane, hyaluronic acid, chondroitin sulfate, natural moisturizing factors, sorbitol, mannitol, glucose, trehalose, Glycerin, Pentylene Glycol, Butylene Glycol and Provitamin B5.
  • Active substances with sunscreen function are selected from: benzophenone-3, octyl methoxycinnamate, Ensulizole, PEG-25 p-aminobenzoic acid, ethylhexyltriazinone, 2-cyano- 3,3-Isooctyl diphenyl acrylate, pentyl dimethyl p-aminobenzoic acid, polyacrylamide methyl benzylidene camphor, glyceryl p-aminobenzoate, diethylaminohydroxybenzoylbenzoate Hexyl formate, camphorbenzalkonium methyl sulfate, benzophenone-5, methyl salicyl alcohol, ethylhexyl methoxycinnamate, isoamyl methoxycinnamate, and phenyldibenzimidazole Disodium tetrasulfonate.
  • calixarene as a macrocyclic receptor molecule, can protect the above-mentioned active substances through host-guest inclusion of skin care active substances.
  • new supramolecular skin care dosage forms can be developed to meet the need for more effective improvement of skin quality. Therefore, not only can calixarene be used to enhance the stability and water solubility of active substances in skin care products; further, calixarene can also be used to include multiple functional molecules at the same time to protect the functions of each molecule from interfering with or affecting each other. .
  • Host-guest interaction is an important basis for the application of calixarene in the development of new supramolecular skin care active ingredients.
  • Calixarenes have strong selective binding to a variety of biologically active substances and will have a broad application market in the field of skin care.
  • Another object of the present invention is to provide a molecular container platform containing anti-inflammatory active substances, which can be used to prepare pharmaceutical compositions for treating skin inflammatory diseases.
  • the molecular container increases the water solubility, stability and effectiveness of actives and reduces the irritation and side effects of anti-inflammatory actives.
  • the present invention provides a pharmaceutical composition for treating inflammatory skin diseases, including at least one active substance with skin anti-inflammatory function and a sulfonated calixarene compound of formula (I):
  • 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.
  • M is selected from at least one metal selected from Na, K, Mg and Ca, and is more preferably Na.
  • R is selected from C 8-12 linear alkyl, more preferably dodecyl.
  • the active substance with skin anti-inflammatory function is selected from one or more of the following: retinoic acid, fruit acid, salicylic acid, azelaic acid and ⁇ -bisabolol.
  • the skin inflammatory disease is selected from at least one of the following diseases: superficial scars, hypertrophic scars, keloids, lupus vulgaris, leprosy ulcers, psoriasis, cutaneous cryptococcosis, and ulcers. , acne and dermatitis.
  • the skin inflammatory disease is at least one dermatitis selected from the group consisting of neurodermatitis, seborrheic dermatitis, and atopic dermatitis.
  • neurodermatitis is selected from eczema, lichen, psoriasis, pruritus, etc.
  • seborrheic dermatitis is selected from psoriasis of the head and face, pityriasis rosea, tinea corporis, etc.
  • atopic dermatitis is selected from erythema, papule, Papular herpes, oozing scabs, lichenification, skin scratches and dry skin, etc.
  • the molar ratio of the skin care active substance or the active substance with 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).
  • Sulfonated calixarenes are a class of supramolecular macrocyclic compounds that can improve the solubility and stability of skin care ingredients, have a sustained-release effect on drugs, and reduce their irritation to normal cells.
  • the sulfonated calixarene compound provided by the invention has the characteristics of accurate structure, fixed molecular weight, stable batch synthesis, easy derivatization and unique cavity bonding properties, and can be used to enhance the water solubility and stability of skin care active substances and protect various The active ingredients do not interfere with each other and reduce the irritation of the drug on inflammatory 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 skin care products or medicaments for treating skin inflammatory diseases.
  • Figure 1 is a diagram showing the combination of the sulfonated calixarene compound SC8A-12C of the present invention with vitamin A or Schematic diagram of the formation of host-guest inclusion complexes with retinoic acid.
  • Figure 2b shows the relationship between Rh B and The bonding constant fitting curve of SC8A-12C is fitted by the host-guest (the host is SC8A-12C and the guest is vitamin A) 1:1 direct bonding model.
  • Figure 3 shows the fluorescence intensity comparison of the inclusion complex SC8A-12C-LCG and after introducing a large amount of Ca 2+ and Mg 2+ into the inclusion complex.
  • Figure 4 shows the dissolution of phenethylresorcinol in water and the photos of the dissolution in water when SC8A-12C is solubilized.
  • Figure 5 shows the UV absorption curves of vitamin A aqueous solutions, methanol-assisted vitamin A aqueous solutions, SC4A, SC8A and SC8A-12C solutions after solubilization of vitamin A.
  • Figure 6 shows the stabilizing effect of SC8A-12C on solubilized vitamin A.
  • Figure 7 shows the UV absorption curves of tretinoin aqueous solution, methanol-assisted tretinoin aqueous solution, SC4A, SC8A and SC8A-12C for the solution solubilized by tretinoin.
  • Figure 8 shows the release profile of vitamin A from SC8A-12C-vitamin A (inclusion complex).
  • Figure 9 shows the release profile of tretinoin from SC8A-12C-retinoic acid (inclusion complex).
  • Figure 10 shows the UV absorption curves of the solution in the receiving pool in the free retinoic acid group and SC8A-12C-retinoic acid (inclusion compound) group after 24 hours of testing with an intelligent transdermal instrument.
  • alkyl refers to an aliphatic hydrocarbon group, which may be branched or straight chain. Depending on the structure, an alkyl group can be a monovalent group or a bivalent group (i.e., an alkylene group). In the present invention, the alkyl group is preferably an alkyl group having 1 to 8 carbon atoms, more preferably a “lower alkyl group” having 1 to 6 carbon atoms, and even more preferably an alkyl group having 1 to 4 carbon atoms. Typical alkyl groups include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, etc.
  • alkyl includes all possible configurations and conformations of the alkyl group.
  • the "propyl” mentioned herein includes n-propyl and isopropyl
  • the "butyl” includes n-butyl. base, isobutyl and tert-butyl
  • "pentyl” includes n-pentyl, isopentyl, neopentyl, tert-pentyl, and pentyl-3-yl, etc.
  • alkoxy refers to -O-alkyl, where alkyl is as defined herein.
  • Typical alkanes Oxy groups include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, etc.
  • cycloalkyl refers to a monocyclic or polycyclic group containing only carbon and hydrogen. Cycloalkyl groups include groups having 3 to 12 ring atoms. Depending on the structure, a cycloalkyl group can be a monovalent group or a bivalent group (eg, cycloalkylene). In the present invention, the cycloalkyl group is preferably a cycloalkyl group having 3 to 8 carbon atoms, and more preferably a “lower cycloalkyl group” having 3 to 6 carbon atoms.
  • cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, and adamantane base.
  • aryl refers to a planar ring having a delocalized pi electron system and containing 4n+2 pi electrons, where n is an integer.
  • Aryl rings may be composed of five, six, seven, eight, nine, or more than nine atoms.
  • Aryl groups may be optionally substituted.
  • aryl includes carbocyclic aryl (eg, phenyl) and heterocyclic aryl (or “heteroaryl” or “heteroaryl”) groups (eg, pyridine).
  • the term includes monocyclic or fused polycyclic (ie, rings that share adjacent pairs of carbon atoms) groups.
  • aryl means an aryl ring in which each ring-constituting atom is a carbon atom.
  • Aryl rings can be composed of five, six, seven, eight, nine, or more than nine atoms.
  • Aryl groups may be optionally substituted. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, phenanthrenyl, anthracenyl, fluorenyl, and indenyl.
  • an aryl group can be a monovalent group or a bivalent group (i.e., arylene group).
  • aryloxy refers to -O-aryl, where aryl is as defined herein.
  • heteroaryl refers to an aryl group that includes one or more ring heteroatoms selected from nitrogen, oxygen, and sulfur.
  • the N-containing “heteroaryl” part refers to an aromatic group in which at least one skeleton atom in the ring is a nitrogen atom.
  • a heteroaryl group can be a monovalent group or a bivalent group (i.e., a heteroarylene group).
  • heteroaryl groups include, but are not limited to, pyridyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazole base, isothiazolyl, pyrrolyl, quinolyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, isoindole Indolyl, pteridinyl, purinyl, oxadiazolyl, thiadiazolyl, furazyl, benzofuranyl, benzothienyl, benzothiazolyl, benzoxazolyl, quinazolinyl , naphthyridinyl and furopyr
  • heteroalkyl as used herein means an alkyl group as defined herein in which one or more of the backbone chain atoms are heteroatoms, such as oxygen, nitrogen, sulfur, silicon, phosphorus, or combinations thereof. described The heteroatom(s) may be located anywhere within the heteroalkyl group or at the position where the heteroalkyl group is attached to the rest of the molecule.
  • heterocycloalkyl or “heterocyclyl” as used herein refers to a non-aromatic ring in which one or more of the ring-constituting atoms is a heteroatom selected from the group consisting of nitrogen, oxygen and sulfur.
  • Heterocycloalkyl rings can be composed of three, four, five, six, seven, eight, nine or more than nine atoms. Heterocycloalkyl rings may be optionally substituted.
  • heterocycloalkyl groups include, but are not limited to, lactams, lactones, cyclic imines, cyclic thioimines, cyclic carbamates, tetrahydrothiopyran, 4H-pyran, tetrahydropyran, piperidine, 1,3-dioxin, 1,3-dioxane, 1,4-dioxin, 1,4-dioxane, piperazine, 1,3-oxathiane, 1,4- Oxathiane, 1,4-oxathiane, tetrahydro-1,4-thiazine, 2H-1,2-oxazine, maleimide, succinimide, apeloline Bituric acid, thiobarbituric acid, dioxopiperazine, hydantoin, dihydrouracil, morpholine, trioxane, hexahydro-1,3,5-triazine, tetrahydrothiophene, Te
  • halogen refers to fluorine, chlorine, bromine and iodine.
  • haloalkyl examples include alkyl, alkoxy or heteroalkyl structures in which at least one hydrogen is replaced by a halogen atom. In certain embodiments, if two or more hydrogen atoms are replaced by halogen atoms, the halogen atoms may be the same as or different from each other.
  • amino refers to the -NH group.
  • hydroxy refers to the -OH group.
  • cyano refers to the -CN group.
  • ester group refers to a chemical moiety having the formula -COOR, wherein R is selected from the group consisting of alkyl, cycloalkyl, aryl, heteroaryl (attached through a ring carbon) and heterocyclyl (attached through a ring carbon).
  • amide or “amido” refers to -NR-CO-R', where R and R' are each independently hydrogen or alkyl.
  • aminoacyl or “aminoacyl” refers to the -CO- NH2 group.
  • alkylaminoacyl or “alkylaminoacyl” refers to the group -CO-NH-R, where R is alkyl as defined herein.
  • optional means that one or more of the events described below may or may not occur, and includes both events that occur and events that do not occur.
  • optionally substituted or “substituted” means that the mentioned group may be substituted by one or more additional groups each and independently selected from alkyl, cycloalkyl , aryl, heteroaryl, heterocyclyl, hydroxyl, alkoxy, cyano, halogen, amide, nitro, haloalkyl, amino, methanesulfonyl, alkylcarbonyl, alkoxycarbonyl, heteroaryl Alkyl, heterocycloalkylalkyl, aminoacyl, amino protecting group, etc.
  • the amino protecting group is preferably selected from pivaloyl, tert-butoxycarbonyl, benzyloxycarbonyl, 9-fluorenemethoxycarbonyl, benzyl, p-methoxybenzyl, allyloxycarbonyl, trifluoroacetyl, and the like.
  • the present invention adopts conventional methods such as mass spectrometry, NMR, HPLC, protein chemistry, biochemistry, recombinant DNA technology and pharmacology within the technical scope of the art.
  • mass spectrometry NMR, HPLC, protein chemistry, biochemistry, recombinant DNA technology and pharmacology
  • specific definitions are provided, the nomenclature and laboratory procedures and techniques chemically relevant to the analytical chemistry, synthetic organic chemistry, and medical and medicinal chemistry described herein are known to those skilled in the art.
  • the foregoing techniques and steps may be carried out by conventional methods that are well known in the art and described in various general and more specific documents, which are cited and discussed in this specification.
  • the sulfonated calixarene compound of the present invention and its use in containing skin care active substances
  • the invention provides a molecular container platform that encloses skin care active substances, improves the water solubility and stability of skin care active substances, and protects the functions of each component from interfering with each other.
  • the molecular container platform of the present invention is a sulfonated calixarene compound of formula (I):
  • 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.
  • M is selected from at least one metal selected from Na, K, Mg and Ca, and is more preferably Na.
  • R is selected from C 8-12 linear alkyl, more preferably dodecyl.
  • the sulfonated calixarene compounds of the present invention are selected from the following compounds:
  • the sulfonated calixarene compound of the present invention can form a host-guest inclusion complex with skin care active substances through non-covalent interactions such as hydrogen bonding, electrostatics, and hydrophobicity.
  • the bonding constant is 10 3 or more, more preferably 10 4 or more, and even more preferably 10 +5 .
  • the sulfonated calixarene compound of the present invention can improve the solubility of fat-soluble active substances in water and also enhance their stability. The use of fat-soluble active substances in water makes the active substances closer and more consistent with the skin, which is beneficial to improving the permeability of the active substances.
  • the sulfonated calixarene compound of the present invention is beneficial to reducing the usage amount of skin care molecules and improving the efficacy.
  • the sulfonated calixarene compound of the present invention has a sustained-release effect on skin care active substances, allowing the skin care active substances to be released controllably and reducing the irritation to normal cells.
  • the sulfonated calixarene compound of the present invention can form a stable host-guest non-covalent binding structure with various small molecule skin care active substances, and reduce the irritation of skin care active substances to inflammatory skin, it can be used to improve the efficacy of skin care products.
  • the molecular container platform is used in the field of skin care.
  • Novel supramolecular skin care product composition and pharmaceutical composition of the present invention are Novel supramolecular skin care product composition and pharmaceutical composition of the present invention.
  • the present application also provides a skin care composition or a pharmaceutical composition for treating inflammatory skin diseases, which includes at least one skin care active substance and a sulfonated calixarene compound of formula (I).
  • the skin care composition or pharmaceutical composition of the present invention may also include other carriers acceptable in the skin care industry and other functional ingredients or pharmaceutical ingredients.
  • 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 (such as anti-wrinkle, antioxidant), anti-inflammatory or acne removal, moisturizing, and sun protection.
  • the active substance with cleaning or makeup removal function is selected from polyols such as butylene glycol, polyethylene glycol, and dipropylene glycol, sodium lauryl sulfate, sodium laureth sulfate, and acyl sulfonic acid.
  • polyols such as butylene glycol, polyethylene glycol, and dipropylene glycol, sodium lauryl sulfate, sodium laureth sulfate, and acyl sulfonic acid.
  • Surfactants such as sodium, sunflower glycoside, cocamidopropyl betaine, and amino acids, artificial synthetic esters such as isopropyl myristate, isopropyl hexadecanoate, and triglyceride, etc.
  • Active substances with whitening function are selected from: vitamin C and its derivatives (such as sodium/magnesium ascorbyl phosphate, ascorbic acid glucoside, ethyl ascorbic acid and ascorbic acid tetraisopalmitate), phenylethylresorcinol, nicotinamide, Tranexamic acid, arbutin, ellagic acid, hydroquinone, kojic acid, glutathione, salicylic acid, retinoic acid, and hydroquinone.
  • vitamin C and its derivatives such as sodium/magnesium ascorbyl phosphate, ascorbic acid glucoside, ethyl ascorbic acid and ascorbic acid tetraisopalmitate
  • phenylethylresorcinol such as sodium/magnesium ascorbyl phosphate, ascorbic acid glucoside, ethyl ascorbic acid and ascorbic acid tetraisopalmitate
  • Active substances with anti-aging functions are selected from: vitamin A, proanthocyanidins, vitamin E, resveratrol, peptides (hexapeptide, palmitoyl tripeptide-5), bifid yeast, astaxanthin, epidermal growth factor , glycolic acid and lactic acid, ubiquinone, caffeine, glycolic acid, lactic acid, vitamin C and its derivatives, etc.
  • the active substance with anti-inflammatory or anti-acne function is selected from the group consisting of retinoic acid, fruit acid, salicylic acid, azelaic acid and ⁇ -bisabolol.
  • Active substances with moisturizing function are selected from: ceramide, sphingolipids, phospholipids, cholesterol, lecithin, squalane, hyaluronic acid, chondroitin sulfate, natural moisturizing factors, sorbitol, mannitol, glucose, trehalose, Glycerin, Pentylene Glycol, Butylene Glycol and Provitamin B5.
  • Active substances with sunscreen function are selected from: benzophenone-3, octyl methoxycinnamate, ensolizole, PEG-25 p-aminobenzoic acid, ethylhexyltriazone, 2-cyano-3,3 -Isooctyl diphenyl acrylate, pentyl dimethyl para-aminobenzoic acid, polyacrylamide methyl benzylidene camphor, glyceryl para-aminobenzoate, diethylaminohydroxybenzoyl hexyl benzoate , camphor benzalkonium methyl sulfate, benzophenone-5, methyl salicyl alcohol, ethylhexyl methoxycinnamate, isoamyl methoxycinnamate and phenyldibenzimidazole tetrasulfonic acid Disodium ester.
  • the molar ratio of the skin care active substance or the active substance with 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).
  • the sulfonated calixarene molecular container platform of the present invention can be used in the following products: such as skin care creams, lotions, oils, lotions, body washes, showers, eye skin care, facial masks, and face washes. and other skin care products; such as foundation, powder, rouge, body makeup, eyebrow painting, eye shadow, eyelids, eyelashes, eye makeup remover, lip balm, lip gloss oil , general color lipsticks, lip liners and other cosmetics.
  • the skin care products selected depend on many factors, such as selecting appropriate skin care products according to the skin quality of the consumer, and following the correct steps.
  • the general skin care and makeup steps are as follows: 1. Cleanse the face, 2. Body serum, 3. Toner, 4. Eye essence, 5. Facial essence, 6. Eye cream, 7. Lotion, 8. Face cream; next is makeup Steps: 1. Apply lip balm first, 2. Sunscreen, 3. Base makeup, 4. Concealer, 5. Set makeup, 6. Draw eyebrows, 7. Eyebrow tint, 8. Eye shadow, 9. Eyeliner, 10. Clamp Eyelashes, 11. False eyelashes, 12. Eyelash primer, 13. Mascara, 14. Contouring, 15. Highlight, 16. Nose shadow, 17.
  • the sulfonated calixarene compound of the present invention also has the advantage of being a molecular container platform: it has high solubility in aqueous solution, and It has an additional solubilizing effect for poorly soluble skin care active substances. Therefore, when used as an active substance delivery platform, it will not limit the concentration of active substances due to solubility limitations, and can provide a higher degree of freedom in selecting the concentration. In addition, it also avoids the greasy feeling caused by the lipid matrix and improves the use feeling.
  • the concentration of the sulfonated calixarene compound in the solution is 0.5-5 mM.
  • the reactions can be used sequentially to provide the compounds described herein; or they can be used to synthesize fragments that are added subsequently by methods described herein and/or methods known in the art.
  • reaction product can be isolated and purified using conventional techniques, including but not limited to filtration, distillation, crystallization, chromatography and other methods. These products can be characterized using conventional methods, including physical constants and spectral data.
  • SC4A-12C Calix[4]arene (calix[n]arene, n is 4-8, the synthesis process refers to the text Add Org.Synth.1990,68,238; J.Am.Chem.Soc.1982,104,2652; J.Org.Chem.1998,63,489) (2.00g, 4.71mmol) into the round bottom flask, slowly add 12mL of concentrated Sulfuric acid, react at 90°C for 4 hours. Take a small amount of the reaction solution in water. If there is no insoluble matter, stop heating and cool to room temperature. Add it dropwise to 400 mL of rapidly stirring diethyl ether. Stir overnight. Filter to obtain an off-white solid.
  • SC6A-12C Add calix[6]arene (2.00g, 3.14mmol) into a round-bottomed flask, slowly add 12mL of concentrated sulfuric acid, and react at 90°C for 4 hours. Take a small amount of the reaction solution in water. If there is no insoluble matter, stop heating and cool to room temperature. Add it dropwise to 400 mL of rapidly stirring diethyl ether. Stir overnight. Filter to obtain an off-white solid. Dissolve the solid in a small amount of water and add hydroxide. Sodium (0.77g, 19.25mmol), then adding a large amount of ethanol to recrystallize, and suction filtration to obtain sulfonated calix[6]arene (SC6A).
  • SC8A-12C Add calix[8]arene (2.00g, 2.36mmol) into a round-bottomed flask, slowly add 12mL of concentrated sulfuric acid, and react at 90°C for 4 hours. Take a small amount of reaction solution in water, if If there is no insoluble matter, stop heating and cool to room temperature. Add it dropwise to 400 mL of rapidly stirring diethyl ether. Stir overnight. Filter to obtain an off-white solid. Dissolve the solid in a small amount of water. Add sodium hydroxide (0.77g, 19.25mmol). Then a large amount of ethanol is added for recrystallization, and sulfonated calix[8]arene (SC8A) is obtained by suction filtration.
  • Example 1 Determination of bonding constants between sulfonated calixarene compounds and skin care active substances
  • Test method UV titration method.
  • Test tool Japan's Shimadzu UV-3600 UV-visible spectrophotometer, equipped with a temperature control module (model: PTC-348WI).
  • the test sample uses Shimadzu's own quartz cuvette, with an optical path of 10mm.
  • Vitamin A was purchased from Shanghai McLean Biochemical Technology Co., Ltd.
  • tretinoin was purchased from Tianjin Xiensi Biochemical Technology Co., Ltd.
  • other skin care active substances were commercially available products.
  • the UV titration experiments of SC8A-12C and active substances were performed at room temperature (25°C).
  • To titrate the bonding constants of SC8A-12C and Va first prepare SC8A-12C mother liquor and Va mother liquor. Dissolve SC8A-12C in deionized water to prepare a concentration of 4mM. Dissolve Va in methanol and prepare a concentration of 2mM. During the test, first add the Va mother solution to the cuvette, dilute it to a volume of 3 mL with deionized water, and make the concentration 10 ⁇ M.
  • the sulfonated calixarene compound of the present invention and the skin care active substance have strong inclusion strength, and the bonding constant reaches more than 10 3 , preferably more than 10 4 , and more preferably more than 10 5 . Therefore, the sulfonated calixarene compound of the present invention can form a stable host-guest non-covalent combination with the active material.
  • Example 2 Inclusion interference experiment of Ca 2+ and Mg 2+ on host and guest
  • Test method Fluorescence spectroscopy.
  • Test tools The quartz cuvette is used as the sample cell for the test, the test light path is 10mm, the instrument model is Varian Cary Eclipse, and it is equipped with a Cary Single-cuvette Peltier cuvette temperature control device.
  • SC8A-12C stock solution was added so that the concentration of SC8A-12C was 10 ⁇ M, and the fluorescence intensity of 10 ⁇ M SC8A-12C-LCG at 505 nm was measured.
  • solutions containing 10 ⁇ M SC8A-12C-LCG and 2.5 mM Ca 2+ were prepared, as well as solutions containing 10 ⁇ M SC8A-12C-LCG and 0.8mM Mg 2+ solutions, respectively measure the fluorescence intensity of these two solutions at 505nm.
  • the test results are shown in Figure 3.
  • Example 3 Solubilization experiment of phenethylresorcinol by sulfonated calixarenes
  • Test method UV absorption spectrometry.
  • Test tool Japan's Shimadzu UV-3600 UV-visible spectrophotometer, equipped with a temperature control module (model: PTC-348WI).
  • the test sample uses Shimadzu's own quartz cuvette, with an optical path of 10mm.
  • Figure 4 shows that 1mL of 2mM SC8A-12C solution can completely dissolve 10mg of phenethylresorcinol, and the solution is clear and transparent; 1mL of deionized water cannot completely dissolve 10mg of phenethylresorcinol, and there is phenethylresorcinol at the bottom of the container. White precipitate of resorcinol.
  • the solubility of phenethylresorcinol in water calculated from the ultraviolet absorption intensity is 4.9 mg/mL; while the solubility of phenethylresorcinol in water solubilized by the sulfonated calixarene of the present invention
  • the solubility is at least higher than 10mg/mL (all dissolved).
  • Test method UV absorption spectrometry.
  • Test tool Japan's Shimadzu UV-3600 UV-visible spectrophotometer, equipped with a temperature control module (model: PTC-348WI).
  • the test sample uses Shimadzu's own quartz cuvette, with an optical path of 10mm.
  • Figure 5 shows that there is no characteristic absorption peak of Va (maximum absorption wavelength is 317nm) in the supernatant in which only deionized water is used to dissolve vitamin A.
  • the maximum absorption peak of the ultraviolet absorption curve of the supernatant is at 290nm, which should be Peaks of dissolved impurities.
  • This result shows that Va is almost insoluble in water.
  • the freshly prepared Va standard solution (added with methanol to help dissolve) has the characteristic absorption peak of Va at 320nm, indicating that Va can be dissolved in water with methanol as the help.
  • SC8A-12C solutions with concentrations of 250, 500, 1000, 2000, and 4000 ⁇ M were prepared in deionized water. Add excess Va to the above solution at 5 mg/mL, and shake on a shaker to solubilize Va. After 24 hours, each group of solutions was diluted to an appropriate multiple (to fit the standard working curve described below) for detection of UV absorption intensity.
  • the sulfonated calixarene compound SC8A-12C of the present invention has a significant solubilizing effect on Va that is poorly soluble in water. Therefore, it can solubilize poorly soluble skin care molecules and improve the overall use efficiency of active substances.
  • Example 5 Stabilization experiment of sulfonated calixarenes on skin care active substances
  • Test method UV-visible spectrometry.
  • Test tool Japan's Shimadzu UV-3600 UV-visible spectrophotometer, equipped with a temperature control module (model: PTC-348WI).
  • the test sample uses Shimadzu's own quartz cuvette, with an optical path of 10mm.
  • the stabilization experiment of SC8A-12C on Va was tested as follows: prepare SC8A-12C solution with a concentration of 2000 ⁇ M, add excess Va at 5 mg/mL, shake to solubilize for 12 hours, take the supernatant of the SC8A-12C solution, and dilute (The concentration of SC8A-12C in the diluted supernatant is 15 ⁇ M) and the UV absorption is detected. After the 2000 ⁇ M SC8A-12C solution was left at room temperature for 30 days, the supernatant of the SC8A-12C solution was diluted into a solution with an SC8A-12C concentration of 15 ⁇ M for UV detection, as shown in Figure 6.
  • Va methanol solution with a concentration of 4mM
  • the UV absorption of freshly prepared and two-day-old Va methanol solutions was tested respectively. During the test, first add the Va methanol solution to the cuvette, dilute it with deionized water to a volume of 3 mL, so that the final concentration of Va is 10 ⁇ M, and detect the UV absorption curve (see Figure 6).
  • Test method UV absorption spectrometry.
  • Test tool Japan Shimadzu UV-3600 UV-visible spectrophotometer, equipped with temperature control module (model: PTC-348WI).
  • the test sample uses Shimadzu’s own quartz cuvette, and the optical path 10mm.
  • Figure 7 shows that there is no absorption peak of tretinoin (maximum absorption wavelength is 360 nm) in the supernatant in which only deionized water is used to dissolve tretinoin. This result shows that tretinoin is almost insoluble in water.
  • the tretinoin standard solution (added with methanol to help dissolve) has the characteristic absorption peak of tretinoin at 360nm, indicating that tretinoin can be dissolved in water with methanol to help dissolve.
  • SC8A-12C solutions with concentrations of 250, 500, 1000, 1500, and 2000 ⁇ M were prepared in deionized water. Add excess tretinoin at 5 mg/mL to the above solution and sonicate to solubilize the tretinoin. After 20 minutes, each group of solutions was diluted to an appropriate multiple (to adapt to the standard working curve described below) for detection of UV absorption intensity.
  • retinoic acid Prepares a standard working curve for retinoic acid.
  • Prepare a 4mM methanol solution containing retinoic acid Take a certain volume of retinoic acid methanol solution and dilute it into a solution containing 100 ⁇ M SC8A-12C.
  • the retinoic acid concentrations are 25, 20, 15, 10, 5, and 2.5 ⁇ M respectively.
  • 100 ⁇ M SC8A-12C was added to eliminate the effect of SC8A-12C on the UV absorption of retinoic acid.
  • the UV absorption intensities of these six groups of retinoic acid solutions with different concentrations were then tested, and a standard working curve was prepared.
  • the sulfonated calixarene compound of the present invention is effective against retinoic acid that is poorly soluble in water. It has significant solubilizing effect. Insoluble skin care active substances can be solubilized so that they can be applied in the water phase, thereby improving the water solubility of the skin care active substances.
  • Test method UV absorption spectrometry.
  • Test tool Japan's Shimadzu UV-3600 UV-visible spectrophotometer, equipped with a temperature control module (model: PTC-348WI).
  • the test sample uses Shimadzu's own quartz cuvette, with an optical path of 10mm.
  • a dialysis bag with a molecular weight cutoff of 500 kDa was filled with 700 ⁇ L of SC8A-12C-Va solution, in which the Va concentration was 4 mM. Tie both ends of the dialysis bag tightly and place it into a centrifuge tube filled with 30 mL of deionized water. Place the centrifuge tube in a shaker, and take the solution in the centrifuge tube for UV absorption detection after 2, 4, 6, and 8 hours. After each test, the solution was recovered into the centrifuge tube. Finally, according to the standard working curve of Va obtained in Example 4, the content of Va released in the centrifuge tube was calculated. See Figure 8.
  • Example 8 Release curve of tretinoin in inclusion compound SC8A-12C-tretinoin
  • Test method UV absorption spectrometry.
  • Test tool Japan's Shimadzu UV-3600 UV-visible spectrophotometer, equipped with a temperature control module (model: PTC-348WI).
  • the test sample uses Shimadzu's own quartz cuvette, with an optical path of 10mm.
  • Example 9 Experiment on promoting the transdermal permeability of sulfonated calixarenes on skin care active substance (Va)
  • Test method Skin permeability test
  • Test tool TP-6 intelligent transdermal tester (Tianjin Jingtuo Instrument Technology Co., Ltd.)
  • the skin After the skin is thawed, it is placed between the diffusion pool and the receiving pool.
  • the receiving pool is filled with receiving liquid (deionized water) and all air bubbles are drained.
  • the receiving pool is placed in a circulating water bath at 37°C throughout the process. Turn on the transdermal diffusion tester and set the magnetic stirring speed to 300r ⁇ min -1 . After 55 hours, take the solution in the receiving pool of each group for UV detection.
  • the test results showed that Va was not detected in the receiving pool of the cream matrix group, indicating that Va dissolved in the cream matrix had hardly penetrated the pig skin. Because the solubility of Va dissolved in the water matrix is not good enough, a large amount of undissolved Va oil still exists in the water, so the permeability is not good enough. However, compared to the Va group dissolved in the cream matrix, the water matrix was beneficial to the penetration of Va.
  • the Va content detected in the receiving pool of the SC8A-12C-Va group was 3.5 times that of the water matrix group, indicating that Va solubilized by SC8A-12C has better penetration.
  • Example 10 Experiment on promoting the transdermal permeability of sulfonated calixarenes on skin care active substances (retinoic acid)
  • Test method Skin permeability test
  • Test tool TP-6 intelligent transdermal tester (Tianjin Jingtuo Instrument Technology Co., Ltd.)
  • the SC8A-12C test on the promotion of retinoic acid permeability was carried out as follows: take fresh pig skin after slaughter, remove the hair, and carefully remove the intact skin. Cut the undamaged parts into uniformly thick pieces with an area of about 2cm ⁇ 2cm, wrap them in plastic wrap and freeze them at -20°C for later use.
  • retinoic acid added an excess of 5 mg/mL retinoic acid to the 4mM SC8A-12C solution. After ultrasonic for 30 minutes, centrifuge and take the supernatant, which is the inclusion compound SC8A-12C-retinoic acid group. After ultraviolet detection of the concentration of retinoic acid in the inclusion compound group, the concentration of retinoic acid in the inclusion compound group was diluted to 0.1% (w/w). Weigh 3 mg of tretinoin and 297 mg of cream respectively into a mortar and grind them thoroughly to dissolve the tretinoin in the cream. The concentration of tretinoin is 1% (w/w).
  • the skin After the skin is thawed, it is placed between the diffusion pool and the receiving pool.
  • the receiving pool is filled with receiving liquid (deionized water) and all air bubbles are drained.
  • the receiving pool is placed in a circulating water bath at 37°C throughout the process. Turn on the transdermal diffusion tester and set the magnetic stirring speed to 300r ⁇ min -1 . After 24 hours, take the solution in the receiving pool of each group for UV detection. See Figure 10.
  • the sulfonated calixarene compound of the present invention can enhance the water solubility and stability of active substances and achieve sustained release of active substances.
  • the use of sulfonated calixarene compounds in the aqueous phase can increase the permeability of active substances and reduce the active concentration.
  • the irritation of skin care active substances to normal skin can be reduced through strong encapsulation and sustained release effects; on the other hand, the stability of skin care active substances is improved, which reduces the usage amount. It is also helpful in reducing irritation.
  • the present invention provides a skin care composition and a pharmaceutical composition in which a sulfonated calixarene supramolecular compound is used as an auxiliary material, which can contain a variety of skin care active substances and make corresponding multifunctional skin care products, which can react with a variety of skin care active substances. It has the functions of solubilizing, stabilizing, improving permeability and reducing irritation, so it is suitable for industrial applications.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Dermatology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Medicinal Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Epidemiology (AREA)
  • Birds (AREA)
  • Gerontology & Geriatric Medicine (AREA)
  • Communicable Diseases (AREA)
  • Oncology (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

一种护肤品组合物和用于治疗皮肤炎性疾病的药用组合物，包括式(I)的磺化杯芳烃化合物和护肤活性物质，及其在护肤和/或治疗皮肤炎性疾病的新用途，其中R、M和n如说明书所定义。

Description

含磺化杯芳烃的护肤品组合物、药用组合物、及磺化杯芳烃的用途 技术领域
本发明属于护肤品领域，具体涉及一种包含磺化杯芳烃超分子化合物作为辅料的护肤品组合物和药用组合物，以及磺化杯芳烃超分子化合物在护肤和治疗皮肤炎性疾病中的新用途。
背景技术
护肤品是一种能补充皮肤养分、保湿锁水、调节肌肤油水平衡、促使皮肤健康润泽、达到美颜目的的日用化妆品，同时它还具有抗皱、防衰老、祛痘、美白、抗炎舒敏等功效(刘志红等人，中国食品药品监管2020,(05),98-101+126)。医学护肤品在我国尚无严格的定义，在国外又称为“功效性化妆品”或“药妆(Cosmeceuticals)”，是由Albert Kligman于1984年提出，介于化妆品和药品之间的第三类产品(Albert Kligman等人，Dermatologic Surgery.2005,31(7 Pt 2):890-891)，本质是化妆品而不是药品。具有功能性的护肤品越来越多地受到人们的青睐，可分为以下几类：清洁类，保湿和恢复皮肤屏障类，控油类，抗炎、舒缓类，防晒类，美白祛斑类。另外，医学护肤品在皮炎湿疹等皮肤性疾病的应用也越来越多(缑卫军等人，精细与专用化学品，2020,28(09),1-5)。要想达到好的护肤效果，要求这些活性成分在护肤品中具有一定的稳定性，且不能有刺激性。
近年来，皮肤疾病发病率较高，特别是与护肤品密切相关的疾病，如痤疮、面部敏感皮肤、激素依赖皮炎、口周皮炎、酒渣鼻、黄褐斑等均较常见(赵恒光等人，皮肤科学通报，2017,34(04),462-467+9)。这些疾病几乎都无一例外的面临临床使用外用药物的现状。在此前提下，如何选择护肤品、如何协调好护肤品和外用药物同时使用的情况，均是护肤品咨询中必须用心解决的问题(齐显龙等人，中国美容医学,2009,18(02):240-241；Dreno B等人，J Eur Acad Dermatol Venereol,2014,28(11):1409-1417)。合理使用护肤品不仅能够发挥修复皮肤屏障和缓解炎症等作用，还能减轻皮肤干燥、灼热、瘙痒等症状，减少药物用量，预防皮肤病复发，可提高患者的生活质量(李利等人，中国皮肤 性病学杂志,2015,29(06):553-555；何黎等人，临床皮肤科杂志,2009,38(6):409-410；Willis CM等人，Br J Dermatol,2001,145(2):258-263)。像皮肤屏障受损性的皮肤病，和皮脂溢出性皮肤病等，多选择舒缓类、清洁类、保湿和皮肤屏障修复类的护肤品(周笑同等人，实用皮肤病学杂志2016,9(03),175-179；Lodén M等人，Clin Dermatol,2012,30(3):286-296)。
随着不断升级的消费需求，集多种功能护肤品的开发已成为趋势。而将多种护肤活性成分都集中加入到同一种护肤品中，就要解决各活性成分之间互不干扰的问题。进一步地，活性成分的添加浓度以及稳定性对功效的影响也很重要，活性成分在皮肤上的渗透性和对皮肤的刺激性也需要慎重考察。要综合考虑上述多种因素，从多方面来优化制备工艺，优化活性成分的载体和剂型，从而制备出效果优异的护肤品产品，成为护肤品领域中日益增长的需求。以市场上广泛使用的抗衰老成分维生素A为例，由于其在水中的溶解性差，故只能用油性基质来溶解，这会给消费者带来油腻、不清爽等不良的使用感；另外，维生素A对光、热、氧气、水都具有不稳定性，所以护肤品中维生素A的使用浓度很可能低于初始的添加浓度。作为另外的例子，维A酸是治疗痤疮的医用成分，维A酸在水中的溶解性差，故只能用油性基质来溶解；维A酸对光、热、水也具有不稳定性；另外，维A酸具有刺激性，给患者带来了痛苦的使用体验。所以，目前亟需一种合适的护肤活性成分的递送平台，在解决这些活性成分的溶解性、稳定性的同时，还能提高活性成分的经皮渗透性、降低刺激性，以及保证多种护肤成分互不干扰，甚至提供协同增效的效果。
发明内容
本发明的一个目的在于提供一种包合护肤活性物质的分子容器平台，从而提高护肤活性物质的水溶性、稳定性和有效性，并减少刺激性。
更具体地，本发明提供一种护肤品组合物，包括至少一种护肤活性物质和式(I)的磺化杯芳烃化合物：
其中，
n为选自4至8的整数，
M独立地选自H、碱金属和碱土金属，
R独立地选自C4-16直链烷基。
在优选的实施方式中，M选自Na、K、Mg和Ca中的至少一种金属，更优选为Na。
在其他优选的实施方式中，R选自C8-12直链烷基，更优选为十二烷基。
在优选的实施方式中，至少一种护肤活性物质是选自基础型护肤品或功能型护肤品中的一种或多种活性物质，特别是具有清洁或卸妆、美白、抗衰老(如抗皱、抗氧化)、消炎或祛痘、保湿、和防晒中的至少一种功能的活性物质。
优选地，具有清洁或卸妆功能的活性物质选自：丁二醇、聚乙二醇、双丙甘醇等多元醇类，十二烷基硫酸钠、月桂醇聚醚硫酸酯钠、酰基磺酸钠、葵基葡萄糖苷、椰油酰胺丙基甜菜碱、氨基酸等表面活性剂，十四酸异丙酯、十六酸异丙酯、三酸甘油脂等人工合成酯。
具有美白功能的活性物质选自：维生素C及其衍生物(如抗坏血酸磷酸钠/镁，抗坏血酸葡萄糖苷，抗坏血酸乙酯和抗坏血酸四异棕榈酸酯)、苯乙基间苯二酚、烟酰胺、传明酸、熊果苷、鞣花酸、对苯二酚、曲酸、谷胱甘肽、水杨酸、维甲酸、以及氢醌。
具有抗衰老功能的活性物质选自：维生素A、原花青素、维生素E、白藜芦醇、胜肽类(六胜肽、棕榈酰三肽-5)、二裂酵母、虾青素、表皮生长因子、甘醇酸和乳酸、泛醌、咖啡因、甘醇酸、乳酸、维生素C及其衍生物。
具有消炎或祛痘功能的活性物质选自：选自维A酸、果酸、水杨 酸、壬二酸和α-红没药醇。
具有保湿功能的活性物质选自：神经酰胺、鞘脂、磷脂、胆固醇、卵磷脂、角鲨烷、透明质酸、硫酸软骨素、天然保湿因子、山梨糖醇、甘露醇、葡萄糖、海藻糖、甘油、戊二醇、丁二醇和维生素原B5。
具有防晒功能的活性物质选自：二苯酮-3、甲氧基肉桂酸辛酯、恩索利唑(Ensulizole)、PEG-25对氨基苯甲酸、乙基己基三嗪酮、2-氰基-3,3-二苯基丙烯酸异辛酯、戊烷基二甲对胺基苯甲酸、聚丙烯酰胺甲基亚苄基樟脑、甘油对氨基苯甲酸酯、二乙基氨基羟基苯甲酰苯甲酸己酯、樟脑苯扎铵甲基硫酸盐、二苯酮-5、甲基水杨醇、甲氧基肉桂酸乙基己酯、甲氧基肉桂酸异戊酯和苯基二苯并咪唑四磺酸酯二钠。
本发明人发现，杯芳烃作为大环受体分子，通过主客体包合护肤活性物质，能起到保护上述活性物质的作用。将其应用到护肤领域中，可开发新型超分子护肤剂型，用于满足更有效地改善肤质的需求。因此，不仅可以利用杯芳烃来增强护肤品活性物质的稳定性和水溶性；进一步地，还可以利用杯芳烃同时包合多个功能分子，保护各分子之间的功能互不干扰、互不影响。主客体相互作用是将杯芳烃应用于开发新型超分子护肤活性成分的重要依托。杯芳烃对于多种生物活性物质的选择性强键合，将在护肤领域有广阔的应用市场。
本发明的另一个目的是提供一种包合消炎活性物质的分子容器平台，可用于制备用于治疗皮肤炎性疾病的药用组合物。该分子容器可提高活性物质的水溶性、稳定性和有效性，并降低消炎活性物质的刺激性和副作用。
更具体地，本发明提供一种用于治疗皮肤炎性疾病的药用组合物，包括至少一种具有皮肤消炎功能的活性物质和式(I)的磺化杯芳烃化合物：
其中，
n为选自4至8的整数，
M独立地选自H、碱金属和碱土金属，
R独立地选自C4-16直链烷基。
在优选的实施方式中，M选自Na、K、Mg和Ca中的至少一种金属，更优选为Na。
在其他优选的实施方式中，R选自C8-12直链烷基，更优选为十二烷基。
在优选的实施方式中，具有皮肤消炎功能的活性物质选自以下一种或多种：维A酸、果酸、水杨酸、壬二酸和α-红没药醇。
在本发明的实施方式中，皮肤炎性疾病选自以下至少一种疾病：表浅性瘢痕、增生性瘢痕、瘢痕疙瘩、寻常狼疮、麻风溃疡、黄癣脓癣、皮肤隐球菌病、膨疮、痤疮和皮炎。在优选的实施方式中，皮肤炎性疾病是选自神经性皮炎、脂溢性皮炎和异位性皮炎中的至少一种的皮炎。特别地，神经性皮炎选自湿疹、苔藓、银屑病、瘙痒症等；脂溢性皮炎选自头面部银屑病、玫瑰糠疹、体癣等；异位性皮炎选自红斑、丘疹、丘疱疹、渗出结痂、苔藓样变、皮肤抓痕和皮肤干燥等。
在本发明的护肤品组合物和药用组合物中，护肤活性物质或具有皮肤消炎功能的活性物质与磺化杯芳烃化合物的摩尔比为1：(0.8-5.0)，优选为1：(0.9-3.0)，更优选为1：(1.0-1.5)。
磺化杯芳烃化合物是一类超分子大环化合物，可以改善护肤成分的溶解性和稳定性，对药物有缓释作用，降低其对正常细胞的刺激性。
本发明提供的磺化杯芳烃化合物，具有结构准确、分子量固定、批合成稳定、易于衍生化且具有独特空腔键合性质的特点，可用于增强护肤活性物质的水溶性和稳定性、保护各活性成分间互不干扰，和降低药物对炎性皮肤的刺激性。因此，本发明的再一个目的是提供式(I)的磺化杯芳烃化合物在制备护肤品或用于治疗皮肤炎性疾病的药物中的用途。
附图说明
图1是显示本发明的磺化杯芳烃化合物SC8A-12C与维生素A或 维A酸形成主客体包合物的示意图。
图2a显示维生素A与SC8A-12C的紫外滴定曲线(λ＝317nm)，图中的箭头表示317nm处由上至下的曲线依次对应浓度由大到小的SC8A-12C；图2b显示Rh B与SC8A-12C的键合常数拟合曲线，由主客体(主体是SC8A-12C，客体是维生素A)1:1直接键合模型进行拟合。
图3显示包合物SC8A-12C-LCG以及在该包合物中引入大量的Ca2+和Mg2+后，荧光强度对比图。
图4显示苯乙基间苯二酚分别在水中的溶解情况及在SC8A-12C增溶情况下水中的溶解情况照片。
图5显示维生素A水溶液、甲醇助溶的维生素A水溶液、SC4A、SC8A以及SC8A-12C对维生素A的增溶后溶液的紫外吸收曲线。
图6显示SC8A-12C对增溶后维生素A的稳定作用。
图7显示维A酸水溶液、甲醇助溶的维A酸水溶液、SC4A、SC8A以及SC8A-12C对维A酸增溶后溶液的紫外吸收曲线。
图8显示SC8A-12C-维生素A(包合物)中维生素A的释放曲线。
图9显示SC8A-12C-维A酸(包合物)中维A酸的释放曲线。
图10显示用智能透皮仪测试24小时后，游离维A酸组和SC8A-12C-维A酸(包合物)组中接收池内溶液的紫外吸收曲线。
具体实施方式
术语
术语“烷基”是指脂肪族烃基团，可以是支链或直链的烷基。根据结构，烷基可以是单价基团或双价基团(即亚烷基)。在本发明中，烷基优选是具有1-8个碳原子的烷基，更优选具有1-6个碳原子的“低级烷基”，甚至更优选具有1-4个碳原子的烷基。典型的烷基包括但不限于甲基、乙基、丙基、丁基、戊基、己基等。应理解，本文提到的“烷基”包括可能存在的所有构型和构象的该烷基，例如本文提到的“丙基”包括正丙基和异丙基，“丁基”包括正丁基、异丁基和叔丁基，“戊基”包括正戊基、异戊基、新戊基、叔戊基、和戊-3-基等。
术语“烷氧基”是指-O-烷基，其中烷基如本文中定义。典型的烷 氧基包括但不限于甲氧基、乙氧基、丙氧基、丁氧基、戊氧基、己氧基等。
术语“环烷基”是指单环或多环基，其仅含有碳和氢。环烷基包括具有3-12个环原子的基团。根据结构，环烷基可以是单价基团或双价基团(例如亚环烷基)。在本发明中，环烷基优选是具有3-8个碳原子的环烷基，更优选具有3-6个碳原子的“低级环烷基”。环烷基的例子包括但不限于，环丙基、环丁基、环戊基、环己基、环庚基、环辛基、环戊烯基、环己烯基、环庚烯基和金刚烷基。
术语“芳香基”是指平面环具有离域的π电子系统并且含有4n+2个π电子，其中n是整数。芳香基环可以由五、六、七、八、九或多于九个原子构成。芳香基可以是任选取代的。术语“芳香基”包括碳环芳基(例如苯基)和杂环芳基(或“杂芳基”或“杂芳香基”)基团(例如吡啶)。该术语包括单环或稠环多环(即共用相邻的碳原子对的环)基团。
本文使用的术语“芳基”是指芳香基环中每一个构成环的原子都是碳原子。芳基环可以由五、六、七、八、九或多于九个原子构成。芳基可以是任选取代的。芳基的实例包括但不限于苯基、萘基、菲基、蒽基、芴基和茚基。根据结构，芳基可以是单价基团或双价基团(即亚芳基)。
术语“芳氧基”是指-O-芳基，其中芳基如本文中定义。
术语“杂芳基”是指芳基中包括一个或多个选自氮、氧和硫的环杂原子。含N“杂芳基”部分是指芳香基中环上至少有一个骨架原子是氮原子。根据结构，杂芳基可以是单价基团或双价基团(即亚杂芳基)。杂芳基的实例包括但不限于吡啶基、咪唑基、嘧啶基、吡唑基、三唑基、吡嗪基、四唑基、呋喃基、噻吩基、异噁唑基、噻唑基、噁唑基、异噻唑基、吡咯基、喹啉基、异喹啉基、吲哚基、苯并咪唑基、苯并呋喃基、吲唑基、吲嗪基、酞嗪基、哒嗪基、异吲哚基、蝶啶基、嘌呤基、噁二唑基、噻二唑基、呋咱基、苯并呋咱基、苯并噻吩基、苯并噻唑基、苯并噁唑基、喹唑啉基、萘啶基和呋喃并吡啶基等。
本文使用的术语“杂烷基”是指本文定义的烷基中的一个或多个骨架链原子是杂原子，例如氧、氮、硫、硅、磷或它们的组合。所述 杂原子(一个或多个)可以位于杂烷基内部的任意位置或在杂烷基与分子的其余部分相连的位置。
本文使用的术语“杂环烷基”或“杂环基”是指非芳香基环中一个或多个构成环的原子是选自氮、氧和硫的杂原子。杂环烷基环可以由三、四、五、六、七、八、九或多于九个原子构成。杂环烷基环可以是任选取代的。杂环烷基的实例包括但不限于内酰胺、内酯、环亚胺、环硫代亚胺、环氨基甲酸酯、四氢噻喃、4H-吡喃、四氢吡喃、哌啶、1,3-二噁英、1,3-二噁烷、1,4-二噁英、1,4-二噁烷、哌嗪、1,3-氧硫杂环己烷、1,4-氧硫杂环己二烯、1,4-氧硫杂环己烷、四氢-1,4-噻嗪、2H-1,2-噁嗪、马来酰亚胺、琥珀酰亚胺、巴比妥酸、硫代巴比妥酸、二氧代哌嗪、乙内酰脲、二氢尿嘧啶、吗啉、三噁烷、六氢-1,3,5-三嗪、四氢噻吩、四氢呋喃、吡咯啉、吡咯烷、咪唑烷，吡咯烷酮、吡唑啉、吡唑烷、咪唑啉、咪唑烷、1,3-二氧杂环戊烯、1,3-二氧杂环戊烷、1,3-二硫杂环戊烯、1,3-二硫杂环戊烷、异噁唑啉、异噁唑烷、噁唑啉、噁唑烷、噁唑烷酮、噻唑啉、噻唑烷和1,3-氧硫杂环戊烷。根据结构，杂环烷基可以是单价基团或双价基团(即亚杂环烷基)。
术语“卤”或“卤素”是指氟、氯、溴和碘。
术语“卤代烷基”、“卤代烷氧基”和“卤代杂烷基”包括烷基、烷氧基或杂烷基的结构，其中至少一个氢被卤原子置换。在某些实施方式中，如果两个或更多氢原子被卤原子置换，所述卤原子彼此相同或不同。
术语“氨基”是指-NH2基团。
术语“羟基”是指-OH基团。
术语“氰基”是指-CN基团。
术语“酯基”是指具有式-COOR的化学部分，其中R选自烷基、环烷基、芳基、杂芳基(通过环碳连接)和杂环基(通过环碳连接)。
术语“酰胺基”或“酰氨基”是指-NR-CO-R’，其中R和R’各自独立地为氢或烷基。
术语“氨酰基”或“胺酰基”是指-CO-NH2基团。
术语“烷基氨酰基”或“烷基胺酰基”是指-CO-NH-R基团，其中R为本文定义的烷基。
术语“任选”指后面描述的一个或多个事件可以发生或可以不发生，并且包括发生的事件和不发生的事件两者。术语“任选取代的”或“取代的”是指所提及的基团可以被一个或多个额外的基团取代，所述额外的基团各自并且独立地选自烷基、环烷基、芳基、杂芳基、杂环基、羟基、烷氧基、氰基、卤素、酰胺基、硝基、卤代烷基、氨基、甲磺酰基、烷基羰基、烷氧基羰基、杂芳基烷基、杂环烷基烷基、氨酰基、氨基保护基等。其中，氨基保护基优选选自新戊酰基、叔丁氧羰基、苄氧羰基、9-芴甲氧羰基、苄基、对甲氧苄基、烯丙氧羰基、和三氟乙酰基等。
除非另外定义，所有本文使用的科技术语都具有与要求保护的主题所属领域的技术人员一般理解相同的含义。
除非另有说明，本发明采用本领域技术范围内的质谱、NMR、HPLC、蛋白质化学、生物化学、重组DNA技术和药理学等常规方法。除非提供具体的定义，否则与本文描述的分析化学、合成有机化学、以及医学和药物化学等化学上相关的命名和实验室操作和技术，是本领域技术人员已知的。一般而言，前述技术和步骤可以通过本领域众所周知的和在各种一般文献和更具体文献中描述的常规方法来实施，这些文献在本说明书中被引用和讨论。
本发明的磺化杯芳烃化合物及其包合护肤活性物质的用途
本发明提供一种包合护肤活性物质的分子容器平台，提高护肤活性物质的水溶性、稳定性，并且保护各成分间的功能互不干扰。本发明的分子容器平台为式(I)的磺化杯芳烃化合物：
其中，
n为选自4至8的整数，
M独立地选自H、碱金属和碱土金属，
R独立地选自C4-16直链烷基。
在优选的实施方式中，M选自Na、K、Mg和Ca中的至少一种金属，更优选为Na。
在其他优选的实施方式中，R选自C8-12直链烷基，更优选为十二烷基。
特别优选地，本发明的磺化杯芳烃化合物选自以下化合物：
本发明的磺化杯芳烃化合物能够与护肤活性物质通过氢键、静电、疏水等非共价相互作用形成主客体包合物，键合常数为103以上，更优选104以上，再更优选105以上。如图1所示例，本发明的磺化杯芳烃化合物可以提高脂溶性活性物质在水中的溶解度，同时也增强其稳定性。在水中使用脂溶性活性物质使得活性物质与皮肤更密切更贴合，有利于提高活性物质的渗透性。因此，本发明的磺化杯芳烃化合物有有利于降低护肤分子的使用量，提升功效。另一方面，本发明的磺化杯芳烃化合物对护肤活性物质有缓释作用，使得护肤活性物质被可控地释放出来，降低对正常细胞的刺激性。
由于本发明的磺化杯芳烃化合物能够与各种小分子护肤活性物质形成稳定的主客体非共价结合结构，以及降低护肤活性物质对炎性皮肤的刺激性，可被用作提升护肤品功效的分子容器平台在护肤领域中应用。
本发明的新型超分子护肤品组合物和药用组合物
本申请还提供一种护肤品组合物或用于治疗皮肤炎性疾病的药用组合物，其包括至少一种护肤活性物质和式(I)的磺化杯芳烃化合物。任选地，本发明的护肤品组合物或药用组合物还可以包括其它护肤品行业可接受的载体以及其它功能性成分或药用成分。
在优选的实施方式中，用于使用本发明的磺化杯芳烃分子容器平台进行增溶、增稳、特异性释放的护肤活性物质，可用于满足以下一种或多种护肤需求：清洁或卸妆、美白、抗衰老(如抗皱、抗氧化)、消炎或祛痘、保湿、防晒。
优选地，具有清洁或卸妆功能的活性物质选自：丁二醇、聚乙二醇、双丙甘醇等多元醇类，十二烷基硫酸钠、月桂醇聚醚硫酸酯钠、酰基磺酸钠、葵基葡萄糖苷、椰油酰胺丙基甜菜碱、氨基酸等表面活性剂，十四酸异丙酯、十六酸异丙酯、三酸甘油脂等人工合成酯等。
具有美白功能的活性物质选自：维生素C及其衍生物(如抗坏血酸磷酸钠/镁，抗坏血酸葡萄糖苷，抗坏血酸乙酯和抗坏血酸四异棕榈酸酯)、苯乙基间苯二酚、烟酰胺、传明酸、熊果苷、鞣花酸、对苯二酚、曲酸、谷胱甘肽、水杨酸、维甲酸、和氢醌。
具有抗衰老功能的活性物质选自：维生素A、原花青素、维生素E、白藜芦醇、胜肽类(六胜肽、棕榈酰三肽-5)、二裂酵母、虾青素、表皮生长因子、甘醇酸和乳酸、泛醌、咖啡因、甘醇酸、乳酸、维生素C及其衍生物等。
具有消炎或祛痘功能的活性物质选自：选自维A酸、果酸、水杨酸、壬二酸和α-红没药醇。
具有保湿功能的活性物质选自：神经酰胺、鞘脂、磷脂、胆固醇、卵磷脂、角鲨烷、透明质酸、硫酸软骨素、天然保湿因子、山梨糖醇、甘露醇、葡萄糖、海藻糖、甘油、戊二醇、丁二醇和维生素原B5。
具有防晒功能的活性物质选自：二苯酮-3、甲氧基肉桂酸辛酯、恩索利唑、PEG-25对氨基苯甲酸、乙基己基三嗪酮、2-氰基-3,3-二苯基丙烯酸异辛酯、戊烷基二甲对胺基苯甲酸、聚丙烯酰胺甲基亚苄基樟脑、甘油对氨基苯甲酸酯、二乙基氨基羟基苯甲酰苯甲酸己酯、樟脑苯扎铵甲基硫酸盐、二苯酮-5、甲基水杨醇、甲氧基肉桂酸乙基己酯、甲氧基肉桂酸异戊酯和苯基二苯并咪唑四磺酸酯二钠。
在本发明的护肤品组合物和药用组合物中，护肤活性物质或具有皮肤消炎功能的活性物质与磺化杯芳烃化合物的摩尔比为1：(0.8-5.0)，优选为1：(0.9-3.0)，更优选为1：(1.0-1.5)。
在使用过程中，可以根据情况单独使用一种护肤活性物质或将多种护肤活性物质组合使用。本发明的磺化杯芳烃分子容器平台可用于以下多种产品中：如护肤膏霜类、乳液类、油类、化妆水类、爽身类、沐浴类、眼周护肤类、面膜类、洗面类等多种护肤品中；如粉底类、粉饼类、胭脂类、涂身彩妆类、描眉类、眼影类、眼睑类、眼睫毛类、眼部彩妆卸除剂、护唇膏类、亮唇油类、普色唇膏类、唇线笔等彩妆品中。
在本发明的实施方式中，在根据本发明对消费者进行肤质改善时，选用的护肤品取决于诸多因素，如根据消费者的肤质，然后选用合适的护肤产品，并按照正确的步骤进行护肤。一般的护肤、化妆步骤如下：1.清洁面部、2.肌底液、3.爽肤水、4.眼部精华、5.面部精华、6.眼霜、7.乳液、8.面霜；接下来是化妆步骤：1.先涂上润唇膏、2.防晒霜、3.底妆、4.遮瑕、5.定妆、6.画眉毛、7.染眉膏、8.眼影、9.眼线、10.夹睫毛、11.假睫毛、12.睫毛打底、13.睫毛膏、14.修容、15.高光、16.鼻影、17.画唇线、18.口红、19.腮红、20.再次定妆。值得注意的是，卸妆、去角质、敷面膜也是必不可少的。本领域技术人员可以理解的是，尽管给出了上述护肤建议，但具体的操作步骤和使用量可根据消费者的自身需求并结合专业人员的指导而进行适当地调节。
除了能够对护活性物质有缓释作用，降低活性物质对炎性皮肤的刺激性之外，本发明的磺化杯芳烃化合物作为分子容器平台的优势还在于：其在水溶液中具有高溶解度，并且对于难溶的护肤活性物质具备额外的增溶效果，因此在用作活性物质递送平台时不会由于溶解度的限制而束缚活性物质的使用浓度，能够为使用浓度的选择提供更高的自由度。另外也避免了脂质基质带来的油腻感，提高使用感。
为了增加护肤活性物质在溶液中的溶解度，可以通过将活性物质与本发明的磺化杯芳烃化合物共研磨后溶解、或在溶液中共同超声、震荡、回流等方式而实现。优选地，当本发明的护肤品组合物和药用组合物为溶液剂型时，磺化杯芳烃化合物在溶液中的使用浓度为0.5-5 mM。
磺化杯芳烃化合物的制备
使用本领域技术人员已知的标准合成技术或使用本领域已知的方法与本文描述的方法组合，可以合成式(I)的化合物。另外，本文给出的溶剂、温度和其它反应条件可以根据本领域技术而改变。作为进一步的指导，也可以利用以下的合成方法。
所述反应可以按顺序使用，以提供本文描述的化合物；或它们可以用于合成片段，所述片段通过本文描述的方法和/或本领域已知的方法随后加入。
可以使用与下述类似的方法，通过使用适当的可选择的起始原料，合成化合物。用于合成本文描述的化合物的起始原料可以被合成或可以从商业来源获得。本文描述的化合物和其它相关具有不同取代基的化合物可以使用本领域技术人员已知的技术和原料合成。制备本文公开的化合物的一般方法可以来自本领域已知的反应，并且该反应可以通过由本领域技术人员所认为适当的试剂和条件修改，以引入本文提供的分子中的各种部分。
如果需要，反应产物可以使用常规技术分离和纯化，包括但不限于过滤、蒸馏、结晶、色谱等方法。这些产物可以使用常规方法表征，包括物理常数和图谱数据。
以R为十二烷基的磺化杯芳烃化合物为例，其合成路线如下。
SC4A-12C：将杯[4]芳烃(杯[n]芳烃，n为4-8，合成过程参考文 献Org.Synth.1990,68,238；J.Am.Chem.Soc.1982,104,2652；J.Org.Chem.1998,63,489)(2.00g，4.71mmol)加入圆底烧瓶中，缓慢加入12mL浓硫酸，90℃反应4小时。取少量反应液于水中，若无不溶物，停止加热，冷却至室温，将其滴加至快速搅拌的400mL乙醚中，搅拌过夜，抽滤得灰白色固体，将固体溶于少量水中，加入氢氧化钠(0.77g，19.25mmol)，然后加入大量乙醇重结晶，抽滤得磺化杯[4]芳烃(SC4A)。将SC4A(3.00g，3.60mmol)和氢氧化钠(2.35g，58.8mmol)溶于15mL水中，搅拌3小时，加入溶于60mL DMSO的溴代十二烷(15.40g，61.8mmol)，100摄氏度反应5天。冷却至室温，搅拌下加入大量甲醇，放入冰箱冷冻静置。抽滤，将固体溶于水中，滤去不溶物，搅拌下加入大量乙醇，放入冰箱冷冻静置。抽滤，干燥得到产物磺化杯[4]芳烃化合物(SC4A-12C)4.99g，产率92％。1H NMR(400MHz,DMSO-d6)δ7.08(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)。
SC6A-12C：将杯[6]芳烃(2.00g，3.14mmol)加入圆底烧瓶中，缓慢加入12mL浓硫酸，90℃反应4小时。取少量反应液于水中，若无不溶物，停止加热，冷却至室温，将其滴加至快速搅拌的400mL乙醚中，搅拌过夜，抽滤得灰白色固体，将固体溶于少量水中，加入氢氧化钠(0.77g，19.25mmol)，然后加入大量乙醇重结晶，抽滤得磺化杯[6]芳烃(SC6A)。将SC6A(3.00g，2.40mmol)和氢氧化钠(2.35g，58.8mmol)溶于15mL水中，搅拌3小时，加入溶于60mL DMSO的溴代十二烷(15.40g，61.8mmol)，100摄氏度反应5天。冷却至室温，搅拌下加入大量甲醇，放入冰箱冷冻静置。抽滤，将固体溶于水中，滤去不溶物，搅拌下加入大量乙醇，放入冰箱冷冻静置。抽滤，干燥得到产物磺化杯[6]芳烃化合物(SC6A-12C)5.20g，产率96％。1H NMR(400MHz,DMSO-d6)δ7.37(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)。
SC8A-12C：将杯[8]芳烃(2.00g，2.36mmol)加入圆底烧瓶中，缓慢加入12mL浓硫酸，90℃反应4小时。取少量反应液于水中，若 无不溶物，停止加热，冷却室温，将其滴加至快速搅拌的400mL乙醚中，搅拌过夜，抽滤得灰白色固体，将固体溶于少量水中，加入氢氧化钠(0.77g，19.25mmol)，然后加入大量乙醇重结晶，抽滤得磺化杯[8]芳烃(SC8A)。将SC8A(3.00g，1.80mmol)和氢氧化钠(2.35g，58.8mmol)溶于15mL水中，搅拌3小时，加入溶于60mL DMSO的溴代十二烷(15.40g，61.8mmol)，100摄氏度反应5天。冷却至室温，搅拌下加入大量甲醇，放入冰箱冷冻静置。抽滤，将固体溶于水中，滤去不溶物，搅拌下加入大量乙醇，放入冰箱冷冻静置。抽滤，干燥得到产物磺化杯[8]芳烃化合物(SC8A-12C)4.89g，产率90％。1H NMR(400MHz,DMSO-d6)δ7.27(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)。
测试实施例
实施例1：磺化杯芳烃化合物与护肤活性物质键合常数的测定
测试方法：紫外滴定法。
测试工具：日本岛津UV-3600紫外-可见分光光度计，配有控温模块(型号：PTC-348WI)，测试样品选用岛津自带石英比色皿，光程10mm。
试剂：维生素A(Va)购自上海麦克林生化科技有限公司，维A酸购自天津希恩思生化科技有限公司，其他护肤活性物质均为市售产品。
SC8A-12C和活性物质的紫外滴定实验均在室温(25℃)进行。滴定SC8A-12C与Va的键合常数，首先配制SC8A-12C母液与Va母液。将SC8A-12C溶于去离子水中，配制浓度为4mM。将Va溶于甲醇，配制浓度为2mM。测试时先将Va母液加入到比色皿中，用去离子水定容到体积为3mL，使其浓度为10μM。随后分次将SC8A-12C母液以预定体积加入比色皿内，使SC8A-12C的终浓度依次递增(SC8A-12C的终浓度见图2a)，每次加入SC8A-12C母液后均记录紫外吸收强度的变化。紫外滴定数据由主客体(主体是SC8A-12C，客体是Va)1:1直接键合模型进行拟合，拟合波长317nm，测定主客体包合的键合常 数Ka。结果见图2a和图2b，SC8A-12C对Va的键合常数Ka为(4.0±0.5)×105M-1。
采用同样的方法检测SC8A-12C与维A酸的键合常数。具体而言，SC8A-12C与维A酸的紫外滴定实验均在室温(25℃)进行。首先配制SC8A-12C母液与维A酸母液。将SC8A-12C溶于去离子水中，配制浓度为4mM。将维A酸溶于甲醇，配制浓度为2mM。测试时先将维A酸母液加入到比色皿中，用去离子水定容到体积为3mL，使其浓度为15μM。随后分次将SC8A-12C母液以预定体积加入比色皿内，使SC8A-12C的终浓度依次递增，每次加入SC8A-12C母液后均记录紫外吸收强度的变化。SC8A-12C对维A酸的键合常数Ka为1.0±0.3×105M-1。
采用同样的方法检测SC8A-12C与各类活性物质的键合常数。具体而言，SC8A-12C和活性物质的紫外滴定实验均在室温(25℃)进行。首先配制SC8A-12C母液与活性物质母液。将SC8A-12C溶于去离子水中，配制浓度为2mM。将活性物质溶于甲醇或是水中，配制浓度为2mM。测试时先将活性物质母液加入到比色皿中，用去离子水定容到体积为3mL，使其浓度为15μM。随后分次将SC8A-12C母液以预定体积加入比色皿内，使SC8A-12C的终浓度依次递增，每次加入SC8A-12C母液后均记录紫外吸收强度的变化。紫外滴定数据由主客体1:1直接键合模型进行拟合，测定主客体包合的键合常数Ka。各种活性物质与SC8A-12C的键合常数测试结果如下表1所示。
表1.SC8A-12C与护肤活性物质的键合常数Ka

主客体的键合常数越大，说明SC8A-12C与活性物质的包合能力越强，形成的包合物越稳定，护肤活性物质越不容易泄露。
如实验结果所示，本发明的磺化杯芳烃化合物与护肤活性物质具有较强的包合强度，键合常数达到103以上，优选104以上，更优选105以上。因此，本发明的磺化杯芳烃化合物能够与活性物质形成稳定的主客体非共价结合。
实施例2：Ca2+和Mg2+对主客体的包合干扰实验
测试方法：荧光光谱法。
测试工具：测试选用石英比色皿为样品池，测试光路10mm，仪器型号为Varian Cary Eclipse，配有型号为Cary Single-cuvette Peltier的比色皿控温装置。
首先配制光泽精(Lucigenin,LCG)(购自北京欧凯纳斯生化科技有限公司)母液，将其溶于水中，配制浓度为1mM。再配制SC8A-12C母液，将其溶于去离子水中，配制浓度为1mM。取LCG母液加入到比色皿中，用去离子水定容到体积为3mL，使其浓度为10μM。激发波长为365nm，发射波长为505nm。先测试10μM LCG在505nm处的荧光强度。随后加入SC8A-12C母液，使得SC8A-12C浓度为10μM，测定10μM SC8A-12C-LCG在505nm处的荧光强度。然后分别配制含10μM SC8A-12C-LCG和2.5mM Ca2+的溶液，以及含10μM  SC8A-12C-LCG和0.8mM Mg2+的溶液，分别测定这两份溶液在505nm处的荧光强度。测试结果如图3所示。
结果显示，向包合物SC8A-12C-LCG中加入大量的Ca2+和Mg2+后，对键合没有影响。说明SC8A-12C头基上的金属离子被替换成Ca2+、Mg2+或者是其他离子后，杯芳烃依然可以通过主客体相互作用对客体进行包合。
实施例3：磺化杯芳烃对苯乙基间苯二酚的增溶实验
测试方法：紫外吸收光谱法。
测试工具：日本岛津UV-3600紫外-可见分光光度计，配有控温模块(型号：PTC-348WI)，测试样品选用岛津自带石英比色皿，光程10mm。
在去离子水中分别配制浓度为100、80、60、40、20μg/mL的苯乙基间苯二酚的标准溶液，测定紫外吸收强度，并制备标准工作曲线。在1mL去离子水与1mL 2mM SC8A-12C溶液中分别加入10mg苯乙基间苯二酚，震荡过夜，离心取上清液，用于紫外吸收曲线的检测；将苯乙基间苯二酚水溶液的上清液稀释合适倍数后(以适配标准工作曲线)用于紫外吸收强度的检测(见图4)。
图4显示，1mL的2mM SC8A-12C溶液能完全溶解10mg苯乙基间苯二酚，溶液澄清透明；1mL的去离子水不能完全溶解10mg苯乙基间苯二酚，容器底部有苯乙基间苯二酚的白色沉淀。
根据标准工作曲线，由紫外吸收强度计算出苯乙基间苯二酚在水中的溶解度为4.9mg/mL；而通过本发明的磺化杯芳烃增溶的苯乙基间苯二酚在水中的溶解度至少高于10mg/mL(全部溶解)。
实施例4：磺化杯芳烃对维生素A的增溶实验
测试方法：紫外吸收光谱法。
测试工具：日本岛津UV-3600紫外-可见分光光度计，配有控温模块(型号：PTC-348WI)，测试样品选用岛津自带石英比色皿，光程10mm。
在3mL去离子水中加入5mg(过量)维生素A，震荡过夜，离心 取上清液，检测上清液的紫外吸收曲线(见图5)。
在去离子水中分别配制浓度为500μM SC4A、SC8A与SC8A-12C溶液。在三组溶液中按5mg/mL分别加过量Va，在摇床上摇晃以增溶Va。24h后，将各组溶液分别稀释40倍后用于紫外吸收波长的检测。同时将Va溶于甲醇溶液中，制成浓度为4mM的Va甲醇母液，将Va甲醇母液稀释到水中，制成5μM甲醇助溶的Va标准品溶液，用于紫外吸收波长的检测。结果见图5。
图5显示，仅用去离子水溶解维生素A的上清液中未见Va的特征吸收峰(最大吸收波长为317nm)，该上清液的紫外吸收曲线的最大吸收峰在290nm处，应该是溶解的杂质的峰。该结果说明Va在水中几乎不溶解。新鲜配制的Va标准品溶液(加甲醇助溶)在320nm处有Va的特征吸收峰，说明Va在甲醇助溶下可溶解于水中。
与甲醇助溶的Va标准品溶液对比(最大吸收波长317nm)，SC4A与SC8A组中未见Va的特征吸收峰，说明无法增溶Va，这两组溶液的紫外吸收曲线的最大吸收峰280nm左右，是杯芳烃自身的吸收峰。SC8A-12C对Va有较好的增溶作用。
接着，在去离子水中分别配制浓度为250、500、1000、2000、4000μM的SC8A-12C溶液。在上述溶液中按5mg/mL分别加过量Va，在摇床上摇晃以增溶Va。24h后，将各组溶液分别稀释合适倍数后(以适配下文所述的标准工作曲线)用于紫外吸收强度的检测。
制作Va的标准工作曲线。配制4mM含Va的甲醇溶液。分别取一定体积的Va甲醇溶液稀释到含有100μM SC8A-12C的溶液中，稀释得到的Va溶液的浓度分别为40、30、20、10、5、2.5μM。加入100μM SC8A-12C是为了消除SC8A-12C对Va紫外吸收的影响。随后检测这六组不同浓度的Va溶液的紫外吸收强度，并制备标准工作曲线。
根据标准工作曲线，由紫外吸收强度计算出不同浓度的SC8A-12C溶液中溶解的Va的量，见表2。
表2不同浓度SC8A-12C对维生素A的增溶能力
结果显示，本发明的磺化杯芳烃化合物SC8A-12C对于难溶于水的Va具有显著的增溶效果，因此对于难溶性护肤分子可进行增溶，提升活性物质的整体使用效率。
实施例5：磺化杯芳烃对护肤活性物质的增稳实验
测试方法：紫外-可见分光光谱法。
测试工具：日本岛津UV-3600紫外-可见分光光度计，配有控温模块(型号：PTC-348WI)，测试样品选用岛津自带石英比色皿，光程10mm。
SC8A-12C对Va的增稳实验按下述方法进行检测：配制浓度为2000μM的SC8A-12C溶液，按5mg/mL加入过量Va，震荡增溶12h后取SC8A-12C溶液的上清液，稀释(稀释后的上清液中SC8A-12C的浓度为15μM)并进行紫外吸收的检测。将2000μM的SC8A-12C溶液在室温下放置30天后，取SC8A-12C溶液的上清液稀释为SC8A-12C浓度为15μM的溶液进行紫外检测，得图6。
将Va溶于甲醇，配制得到浓度为4mM的Va甲醇溶液，避光放置两天。分别测试新鲜配制和放置两天的Va甲醇溶液的紫外吸收。测试时先将Va甲醇溶液加入到比色皿中，用去离子水定容到体积为3mL，使Va的终浓度为10μM，检测紫外吸收曲线(见图6)。
从图6可以看出，新鲜配制的Va水溶液(加甲醇助溶)在317nm处有Va的特征吸收峰。而放置两天后，Va水溶液(加甲醇助溶)紫外吸收明显下降，说明大部分游离在水中的Va已经降解，Va在水中的稳定性很差。SC8A-12C溶液放置30天后，增溶的Va反而增多，这是因为溶液中有过量的Va单质，随着时间的延长，溶解的Va增多。也是因为SC8A-12C对Va有较好的稳定作用，所以随着时间的延长，增溶的Va浓度能持续增多而没有降低。
实施例6：磺化杯芳烃对维A酸的增溶实验
测试方法：紫外吸收光谱法。
测试工具：日本岛津UV-3600紫外-可见分光光度计，配有控温模块(型号：PTC-348WI)，测试样品选用岛津自带石英比色皿，光程 10mm。
在去离子水中分别配制浓度为2000μM SC4A、SC8A与SC8A-12C溶液。在三组溶液中按5mg/mL分别加过量维A酸，超声以增溶维A酸。20min后，将各组溶液分别稀释10倍后用于紫外吸收波长的检测。同时在3mL去离子水中加入5mg(过量)维A酸，震荡过夜，离心取上清液，检测上清液的紫外吸收曲线(见图7)。将维A酸溶于甲醇溶液中，制成浓度为4mM的维A酸甲醇母液，20min后将维A酸甲醇母液稀释到水中，制成浓度合适的维A酸标准品溶液，用于紫外吸收波长的检测。结果见图7。
图7显示，仅用去离子水溶解维A酸的上清液中未见维A酸的吸收峰(最大吸收波长为360nm)。该结果说明维A酸在水中几乎不溶解。维A酸标准品溶液(加甲醇助溶)在360nm处有维A酸的特征吸收峰，说明维A酸在甲醇助溶下可溶解于水中。与维A酸标准品溶液对比，SC4A与SC8A组中未见维A酸的特征吸收峰，说明不能增溶维A酸，SC8A-12C对维A酸有较好的增溶作用。
接着，在去离子水中分别配制浓度为250、500、1000、1500、2000μM的SC8A-12C溶液。在上述溶液中按5mg/mL加入过量维A酸，超声以增溶维A酸。20min后，将各组溶液分别稀释合适倍数后(以适配下文所述的标准工作曲线)用于紫外吸收强度的检测。
制作维A酸的标准工作曲线。配制4mM含维A酸的甲醇溶液。取一定体积的维A酸甲醇溶液稀释到含有100μM SC8A-12C的溶液中，维A酸浓度分别为25、20、15、10、5、2.5μM。加入100μM SC8A-12C是为了消除SC8A-12C对维A酸紫外吸收的影响。随后检测这六组不同浓度的维A酸溶液的紫外吸收强度，并制备标准工作曲线。
根据标准工作曲线，计算出不同浓度的SC8A-12C溶液中增溶的维A酸的量，见表3。
表3不同浓度SC8A-12C对维A酸的增溶能力
结果显示，本发明的磺化杯芳烃化合物对于难溶于水的维A酸具 有显著的增溶效果。对于难溶性护肤活性物质可进行增溶使其能在水相中得到应用，提高了护肤活性物质的水溶性。
实施例7：包合物SC8A-12C-Va中Va的释放曲线
测试方法：紫外吸收光谱法。
测试工具：日本岛津UV-3600紫外-可见分光光度计，配有控温模块(型号：PTC-348WI)，测试样品选用岛津自带石英比色皿，光程10mm。
在截留分子量为500kDa的透析袋中装入700μL的SC8A-12C-Va溶液，其中Va浓度为4mM。将透析袋两端绑紧后，放入装有30mL去离子水的离心管里。将离心管置于摇床中，分别在2、4、6、8小时后取离心管中的溶液进行紫外吸收检测。每次检测完后，将溶液回收至离心管中。最后，根据实施例4得到的Va的标准工作曲线，计算出离心管中释放的Va的含量。见图8。
结果显示：SC8A-12C对Va进行包合后，实现了Va的缓释，有利于降低Va的刺激性，以及延长Va的作用时间。
实施例8：包合物SC8A-12C-维A酸中维A酸的释放曲线
测试方法：紫外吸收光谱法。
测试工具：日本岛津UV-3600紫外-可见分光光度计，配有控温模块(型号：PTC-348WI)，测试样品选用岛津自带石英比色皿，光程10mm。
在截留分子量为500kDa的透析袋中装入700μL的SC8A-12C-维A酸溶液，其中维A酸浓度为664μM。将透析袋两端绑紧后，放入装有15mL去离子水的离心管里。将离心管置于摇床中，分别在2、4、6、8、21、31小时后取离心管中的溶液进行紫外吸收检测。每次检测完后，将溶液回收至离心管中。最后，根据实施例6得到的维A酸的标准工作曲线，计算出离心管中释放的维A酸的含量。见图9。
结果显示：SC8A-12C对维A酸进行包合后，实现了维A酸的缓释，有利于降低维A酸的刺激性，以及延长维A酸的作用时间。
实施例9：磺化杯芳烃对护肤活性物质(Va)的透皮性促进实验
测试方法：皮肤渗透性测试
测试工具：TP-6智能透皮试验仪(天津市精拓仪器科技有限公司)
SC8A-12C对Va的促进透皮性实验按下述方法进行检测：取屠宰后新鲜猪皮，剔除毛发，小心地取下完整皮肤。将无破损的部分切割成厚薄均匀的、面积约为2cm×2cm大小的块状，用保鲜膜包好并于-20℃的温度下冷冻保存，备用。
分别称取0.8mg Va与200mg护肤霜(乳膏基质)于研钵中，充分研磨使Va溶解在护肤霜中，Va浓度为0.4％(w/w)。然后称取0.8mg Va于200μL水中，充分震荡，制备Va的悬浊液(水基质)，Va浓度为0.4％(w/w)。再称取8.41mg SC8A-12C和183.6μL水于离心管中，加热溶解。SC8A-12C溶解后，加入0.8mg Va制备包合物。包合物中Va浓度也为0.4％(w/w)。
皮肤解冻后，置于扩散池和接收池之间，接收池加满接收液(去离子水)，并排尽气泡，接收池全程置于37℃的循环水浴中。打开透皮扩散试验仪，磁力搅拌速度为300r·min-1。在55小时后，取各组接收池内的溶液进行紫外检测。
检测结果显示，乳膏基质组的接收池内没有检测到Va，说明溶解在乳膏基质中的Va几乎没有渗透过猪皮。溶解在水基质中的Va由于溶解度不够好，在水中还是以大量未溶解的Va油状物存在，所以渗透性也不够好。但是对比溶解在乳膏基质中的Va组，水基质有利于Va的渗透。而SC8A-12C-Va组接收池内检测到的Va含量是水基质组的3.5倍，说明被SC8A-12C增溶的Va有较好的渗透作用。
实施例10：磺化杯芳烃对护肤活性物质(维A酸)的透皮性促进实验
测试方法：皮肤渗透性测试
测试工具：TP-6智能透皮试验仪(天津市精拓仪器科技有限公司)
SC8A-12C对维A酸的促进透皮性实验按下述方法进行检测：取屠宰后的新鲜猪皮，剔除毛发，小心地取下完整皮肤。将无破损的部分切割成厚薄均匀的、面积约为2cm×2cm大小的块状，用保鲜膜包好并于-20℃的温度下冷冻保存，备用。
在4mM SC8A-12C溶液中按5mg/mL加入过量的维A酸，超声30min后，离心取上清液，为包合物SC8A-12C-维A酸组。紫外检测包合物组中维A酸浓度后将包合物组中维A酸浓度稀释至0.1％(w/w)。再分别称取3mg维A酸与297mg乳膏于研钵中，充分研磨使维A酸溶解在乳膏中，维A酸浓度为1％(w/w)。
皮肤解冻后，置于扩散池和接收池之间，接收池加满接收液(去离子水)，并排尽气泡，接收池全程置于37℃的循环水浴中。打开透皮扩散试验仪，磁力搅拌速度为300r·min-1。在24小时后，取各组接收池内的溶液进行紫外检测。见图10。
由图10可知，维A酸乳膏基质组的接收池里没有检测到维A酸的吸收峰，说明溶解在乳膏基质中的维A酸几乎没有渗透过猪皮。而包合物SC8A-12C-维A酸组的接收池里检测到明显的维A酸的吸收峰，说明SC8A-12C对维A酸的助溶有利于促进维A酸的渗透。
综合来看，本发明的磺化杯芳烃化合物可增强活性物质的水溶性、稳定性，并实现活性物质的缓释。在水相中使用磺化杯芳烃化合物可以提高活性物质的渗透性，降低作用浓度。进一步地，对于有刺激性的护肤活性物质通过强包合作用，以及缓释作用可以降低护肤活性物质对正常皮肤的刺激性；另一方面，护肤活性物质的稳定性得到提高使得使用量减少，也有利于降低刺激性。
工业应用性
本发明提供一种磺化杯芳烃超分子化合物作为辅料的护肤品组合物和药用组合物，可以包合多种护肤活性物质并制成相应的多功能护肤品，其对多种护肤活性物质具有增溶、增稳、提高渗透性、降低刺激性的作用，因此适于工业应用。

Claims (18)

  1. 一种护肤品组合物，包括至少一种护肤活性物质和式(I)的磺化杯芳烃化合物：
    其中，
    n为选自4至8的整数，
    M独立地选自H、碱金属和碱土金属，
    R独立地选自C4-16直链烷基，
    所述至少一种护肤活性物质是选自具有清洁或卸妆、美白、抗衰老、消炎或祛痘、保湿、和防晒中的至少一种功能的活性物质。
  2. 如权利要求1所述的护肤品组合物，其中M选自Na、K、Mg和Ca中的至少一种金属。
  3. 如权利要求1或2所述的护肤品组合物，其中R选自C8-12直链烷基，更优选为十二烷基。
  4. 如权利要求1-3中任一项所述的护肤品组合物，其中所述式(I)的磺化杯芳烃化合物选自：
  5. 如权利要求1-4中任一项所述的护肤品组合物，其中所述护肤活性物质选自以下一种或多种：选自丁二醇、聚乙二醇、双丙甘醇、十二烷基硫酸钠、月桂醇聚醚硫酸酯钠、酰基磺酸钠、葵基葡萄糖苷、椰油酰胺丙基甜菜碱、氨基酸、十四酸异丙酯、十六酸异丙酯、和三酸甘油脂的具有清洁或卸妆功能的活性物质；选自维生素C及其衍生物、苯乙基间苯二酚、烟酰胺、传明酸、熊果苷、鞣花酸、对苯二酚、曲酸、谷胱甘肽、水杨酸、维甲酸、和氢醌的具有美白功能的活性物质；选自维生素A、原花青素、维生素E、白藜芦醇、六胜肽、棕榈酰三肽-5、二裂酵母、虾青素、表皮生长因子、甘醇酸、乳酸、泛醌、咖啡因、甘醇酸、乳酸、维生素C及其衍生物的具有抗衰老功能的活性物质；选自维A酸、果酸、水杨酸、壬二酸和α-红没药醇的具有消炎或祛痘功能的活性物质；选自神经酰胺、鞘脂、磷脂、胆固醇、卵磷脂、角鲨烷、透明质酸、硫酸软骨素、天然保湿因子、山梨糖醇、甘露醇、葡萄糖、海藻糖、甘油、戊二醇、丁二醇和维生素原B5的具有保湿功能的活性物质；选自二苯酮-3、甲氧基肉桂酸辛酯、恩索利唑、PEG-25对氨基苯甲酸、乙基己基三嗪酮、2-氰基-3,3-二苯基丙烯酸异辛酯、戊烷基二甲对胺基苯甲酸、聚丙烯酰胺甲基亚苄基樟脑、甘油对氨基苯甲酸酯、二乙基氨基羟基苯甲酰苯甲酸己酯、樟脑苯扎铵甲基硫酸盐、二苯酮-5、甲基水杨醇、甲氧基肉桂酸乙基己酯、甲氧基肉桂酸异戊酯和苯基二苯并咪唑四磺酸酯二钠的具有防晒功能的活性物质。
  6. 如权利要求1-5中任一项所述的护肤品组合物，其中所述护肤活性物质与所述磺化杯芳烃化合物的摩尔比为1：(0.8-5.0)，优选为1：(0.9-3.0)，更优选为1：(1.0-1.5)。
  7. 一种用于治疗皮肤炎性疾病的药用组合物，包括至少一种具有皮肤消炎功能的活性物质和式(I)的磺化杯芳烃化合物：
    其中，
    n为选自4至8的整数，
    M独立地选自H、碱金属和碱土金属，
    R独立地选自C4-16直链烷基。
  8. 如权利要求7所述的药用组合物，其中所述具有皮肤消炎功能的活性物质选自以下一种或多种：维A酸、果酸、水杨酸、壬二酸和α-红没药醇。
  9. 如权利要求7或8所述的药用组合物，其中M选自Na、K、Mg和Ca中的至少一种金属。
  10. 如权利要求7-9中任一项所述的药用组合物，其中R选自C8-12直链烷基，更优选为十二烷基。
  11. 如权利要求7-10中任一项所述的药用组合物，其中所述式(I)的磺化杯芳烃化合物选自：
  12. 如权利要求7-11中任一项所述的药用组合物，其中所述皮肤炎性疾病选自以下至少一种疾病：表浅性瘢痕、增生性瘢痕、瘢痕疙瘩、寻常狼疮、麻风溃疡、黄癣脓癣、皮肤隐球菌病、膨疮、痤疮和皮炎。
  13. 如权利要求7-11中任一项所述的药用组合物，其中所述皮肤炎性疾病选自以下至少一种疾病：选自湿疹、苔藓、银屑病、和瘙痒症的神经性皮炎；选自头面部银屑病、玫瑰糠疹、和体癣的脂溢性皮炎；选自红斑、丘疹、丘疱疹、渗出结痂、苔藓样变、皮肤抓痕和皮肤干燥的异位性皮炎。
  14. 如权利要求7-13中任一项所述的药用组合物，其中所述具有皮肤消炎功能的活性物质与所述磺化杯芳烃化合物的摩尔比为1：(0.8-5.0)，优选为1：(0.9-3.0)，更优选为1：(1.0-1.5)。
  15. 式(I)的磺化杯芳烃化合物用于护肤或用于治疗皮肤炎性疾病的用途，
    其中，
    n为选自4至8的整数，
    M独立地选自H、碱金属和碱土金属，
    R独立地选自C4-16直链烷基。
  16. 如权利要求15所述的化合物的用途，其中M选自Na、K、Mg和Ca中的至少一种金属。
  17. 如权利要求15或16所述的化合物的用途，其中R选自C8-12直链烷基，更优选为十二烷基。
  18. 如权利要求15-17中任一项所述的化合物的用途，其中所述式(I)的磺化杯芳烃化合物选自：
PCT/CN2023/087475 2022-08-03 2023-04-11 含磺化杯芳烃的护肤品组合物、药用组合物、及磺化杯芳烃的用途 WO2024027193A1 (zh)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN202210928325.0A CN117547474A (zh) 2022-08-03 2022-08-03 含磺化杯芳烃的护肤品组合物、药用组合物、及磺化杯芳烃的用途
CN202210928325.0 2022-08-03

Publications (1)

Publication Number Publication Date
WO2024027193A1 true WO2024027193A1 (zh) 2024-02-08

Family

ID=89819087

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2023/087475 WO2024027193A1 (zh) 2022-08-03 2023-04-11 含磺化杯芳烃的护肤品组合物、药用组合物、及磺化杯芳烃的用途

Country Status (2)

Country Link
CN (1) CN117547474A (zh)
WO (1) WO2024027193A1 (zh)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN118005529A (zh) * 2024-04-09 2024-05-10 深圳杉海创新技术有限公司 一种超分子泛醇红没药醇及其制备方法与应用

Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1265024A (zh) * 1997-06-12 2000-08-30 普罗克特和甘保尔公司 化妆品组合物
US20100292272A1 (en) * 2006-08-11 2010-11-18 Anthony William Coleman Supramolecular co-colloids produced using macrocyclic polyanionic systems
CN102697666A (zh) * 2012-05-30 2012-10-03 复旦大学 一种环糊精水杨酸包合物水溶液及其制备方法和应用
CN104211970A (zh) * 2014-09-11 2014-12-17 南开大学 一种由杯芳烃构筑的超分子水凝胶材料及其制备方法
WO2016152954A1 (ja) * 2015-03-25 2016-09-29 国立研究開発法人理化学研究所 カリックスアレーン誘導体
US20170145351A1 (en) * 2014-07-17 2017-05-25 Henkel Ag & Co. Kgaa Active ingredients which improve primary detergent power
CN114302885A (zh) * 2019-06-18 2022-04-08 维也纳大学 杯芳烃化合物及其用途

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1265024A (zh) * 1997-06-12 2000-08-30 普罗克特和甘保尔公司 化妆品组合物
US20100292272A1 (en) * 2006-08-11 2010-11-18 Anthony William Coleman Supramolecular co-colloids produced using macrocyclic polyanionic systems
CN102697666A (zh) * 2012-05-30 2012-10-03 复旦大学 一种环糊精水杨酸包合物水溶液及其制备方法和应用
US20170145351A1 (en) * 2014-07-17 2017-05-25 Henkel Ag & Co. Kgaa Active ingredients which improve primary detergent power
CN104211970A (zh) * 2014-09-11 2014-12-17 南开大学 一种由杯芳烃构筑的超分子水凝胶材料及其制备方法
WO2016152954A1 (ja) * 2015-03-25 2016-09-29 国立研究開発法人理化学研究所 カリックスアレーン誘導体
CN114302885A (zh) * 2019-06-18 2022-04-08 维也纳大学 杯芳烃化合物及其用途

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
HALL, IRIS H. ET AL.: "Anti-inflammatory Activity of (Polyphenolic)-Sulfonates and Their Sodium Salts in Rodents", METAL-BASED DRUGS, vol. 5, no. 2, 1 January 1998 (1998-01-01), XP055841878, ISSN: 0793-0291, DOI: 10.1155/MBD.1998.67 *
ZHOU YUNYOU, DING XUEPING, FANG XIAOLI, LI TAO, TANG DONGBAO, LU QIN: "Studies on the Inclusion Behavior of Amphiphilic p-Sulfonatocalix[4]arene with Ascorbic Acid by Spectrofluorometric Titrations", OPTICS AND PHOTONICS JOURNAL, vol. 01, no. 02, 1 January 2011 (2011-01-01), pages 59 - 64, XP093136594, ISSN: 2160-8881, DOI: 10.4236/opj.2011.12009 *

Also Published As

Publication number Publication date
CN117547474A (zh) 2024-02-13

Similar Documents

Publication Publication Date Title
US9308157B2 (en) Whitening cosmetic
JP5439849B2 (ja) システイン誘導体
JP2002522366A (ja) エクトインまたはエクトイン誘導体の化粧品製剤における使用
WO2024027193A1 (zh) 含磺化杯芳烃的护肤品组合物、药用组合物、及磺化杯芳烃的用途
ES2258443T3 (es) Formulacion galenica que contiene biotina.
ES2604104T3 (es) Agente preventivo o mejorador para la pigmentación
JP5671483B2 (ja) 色素沈着予防又は改善剤
ES2453148T3 (es) Derivado de carnitina, sal del mismo, preparación externa para la piel y preparación cosmética
JP5898310B2 (ja) オキサゼチジン誘導体、それらの調製方法並びにヒト医療及び化粧品におけるそれらの使用
JP3623548B2 (ja) 化粧料
JP4541699B2 (ja) カルボキシレート−ゲート−ニトロキシド（ｃｇｎ）化合物および組成物ならびにその使用方法
KR101194337B1 (ko) 레티노이드 유도체 및 그를 포함하는 화장료 조성물
WO2013081146A1 (ja) シワ防止化粧料
KR20080001603A (ko) 5-아미노레불린산의 불포화 알킬 에스터 및 약학적으로허용되는 그의 염, 이의 제조방법 및 이의 용도
JP2003327523A (ja) 皮膚外用剤
WO2022076262A1 (en) Topical agents for dermatological applications
EP2221040A1 (en) Composition for external application to skin
CZ2013330A3 (cs) Způsob přípravy esteru 2-oxoglutarové, přípravek obsahující ester 2-oxoglutarátu a jeho použití
RU2626954C2 (ru) Комплексные соединения германия с аминокислотами и липоевой кислотой
AU2014223236A1 (en) Glycyrrhetinimidyl hydroxyproline alkyl esters and protected derivatives thereof
KR101451401B1 (ko) 비타민 c와 비타민 e의 컨쥬게이트 및 그를 포함하는 항산화제
JP6254808B2 (ja) ベンジリデンアゾリジン誘導体またはその塩を含む美白剤および抗光老化剤
CN115737480A (zh) 含偶氮杯芳烃的护肤品组合物、药用组合物、及偶氮杯芳烃的用途
JP5328254B2 (ja) セラミド産生促進剤
TW201601763A (zh) 皮膚外用組成物

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 23848132

Country of ref document: EP

Kind code of ref document: A1