WO2024021544A1 - 维生素c乳酸酯及其类似物在制备皮肤组织用制品中的用途及其相关制品 - Google Patents

维生素c乳酸酯及其类似物在制备皮肤组织用制品中的用途及其相关制品 Download PDF

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WO2024021544A1
WO2024021544A1 PCT/CN2023/072684 CN2023072684W WO2024021544A1 WO 2024021544 A1 WO2024021544 A1 WO 2024021544A1 CN 2023072684 W CN2023072684 W CN 2023072684W WO 2024021544 A1 WO2024021544 A1 WO 2024021544A1
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vitamin
lactate
skin
skin tissue
analogs
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PCT/CN2023/072684
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English (en)
French (fr)
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王晋岳
郑茜
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长春圣博玛生物材料有限公司
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Publication of WO2024021544A1 publication Critical patent/WO2024021544A1/zh

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    • 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
    • A61K8/67—Vitamins
    • A61K8/676—Ascorbic acid, i.e. vitamin C
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A23L33/15—Vitamins
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/365—Lactones
    • A61K31/375—Ascorbic acid, i.e. vitamin C; Salts thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L27/54—Biologically active materials, e.g. therapeutic substances
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L27/60—Materials for use in artificial skin
    • 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
    • A61P17/18—Antioxidants, e.g. antiradicals
    • 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
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
    • A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2800/00—Properties of cosmetic compositions or active ingredients thereof or formulation aids used therein and process related aspects
    • A61K2800/10—General cosmetic use
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
    • A61L2300/412—Tissue-regenerating or healing or proliferative agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
    • A61L2300/428—Vitamins, e.g. tocopherol, riboflavin

Definitions

  • the present invention relates to the field of medical technology, specifically, to the use of vitamin C lactate and its analogs in preparing skin tissue products, and skin tissue products containing vitamin C lactate and its analogs.
  • Vitamins are a type of trace organic matter necessary for the growth and development of animals and plants. However, they are extremely unstable, easily oxidized and denatured, and have limited solubility. However, when vitamins are esterified, their stability is significantly improved in various solvent systems, and they have the functions and activities of the original and new functional groups.
  • Modified vitamin C ester is a new and safe food additive with multiple functional properties such as anti-tumor, anti-aging, anti-oxidation, scavenging free radicals in the body, etc.
  • Vitamin E ester can be widely used as a substitute for vitamin E. In medicine, food and cosmetics, etc.; vitamin A ester is an important medicine and feed additive.
  • the object of the present invention is to provide new uses of vitamin C lactate and its analogs.
  • the research of the present invention has found that vitamin C lactate and its analogues can effectively prevent, improve and/or treat problematic skin such as aging, wrinkles, depressions, pigmentation, spots, irritation, inflammation or Skin that is in a less than ideal state of health.
  • the vitamin C lactate and its analogs of the present invention can participate in the repair and regeneration of skin tissue, participate in cell activities, and preferably promote the secretion of collagen by cells when used in skin tissue products.
  • the present invention provides the use of vitamin C lactate and its analogs in the preparation of skin tissue products.
  • the preparation for skin tissue may be used to prevent, improve and/or treat problematic skin.
  • the present invention provides the use of vitamin C lactate and its analogs in the preparation of skin tissue preparations for preventing, improving and/or treating problematic skin.
  • the skin tissue preparation is selected from one or more of drugs, cosmetics, kits, health products, and medical devices.
  • the drug is selected from the group consisting of ointments, patches, emulsions, solutions, suspensions, injections and other forms.
  • the dosage form of the cosmetic product may be in any form.
  • the dosage form of the cosmetics may be, for example, at least one of creams, facial masks, emulsions, solutions, suspensions, essential oils, lotions, foundations, and make-up foundations.
  • the cosmetic product further includes adjuvants known in the art.
  • the vitamin C lactate and its analogs are used as active ingredients.
  • the vitamin C lactate and its analogs are the only active ingredient.
  • the vitamin C lactate and its analogs are made from vitamin C and lactic acid and their derivatives through chemical synthesis (esterification reaction, transesterification reaction), biosynthesis or enzyme catalyzed synthesis. get.
  • vitamin C lactate is obtained from vitamin C and lactic acid through chemical synthesis (esterification reaction), biosynthesis or enzyme-catalyzed synthesis.
  • the vitamin C lactate analogue is obtained from vitamin C and lactic acid derivatives through chemical synthesis (esterification reaction, transesterification reaction), biosynthesis or enzymatic synthesis.
  • the lactic acid derivative is selected from one or more of polylactic acid degradable polymers, lactic acid oligomers, lactates, lactic acid and complexes of the above substances and other compounds, preferably Lactic acid.
  • the polylactic acid degradable polymer is, for example, polylactic acid, glycolide-lactide copolymer, lactide-caprolactone copolymer, and polylactic acid-polyethylene glycol copolymer.
  • the lactate is a chemical derivative of lactic acid, which is a salt formed when the carboxyl group on lactic acid releases hydrogen ions and is combined with a positively charged substance.
  • the lactate includes but is not limited to sodium lactate, potassium lactate, lithium lactate, calcium lactate, magnesium lactate, ferrous lactate, zinc lactate, aluminum lactate, chitosan lactate, oftenanone lactate, methyl lactate, Trioxazole lactate, 1-ethyl-3-methylimidazole L-(+)-lactate, 2-hydroxyethyl-trimethylammonium L-(+)-lactate, L-lactic acid One or more tetrabutylammonium salts.
  • the vitamin C lactate and its analogs have a structural formula represented by any one of the following formulas (1)-(4):
  • R is selected from * is the connection site; n is 1 to 30, preferably 1 to 20, further preferably 1 to 10; R 1 is selected from H.
  • the R is provided by the above-mentioned lactic acid and its derivatives.
  • the vitamin C lactate ester has a structural formula represented by the following formula (1'):
  • the vitamin C lactate and its analogues can be antioxidant, anti-allergic, reduce irritation, anti-aging, remove wrinkles, moisturize, whiten, enhance skin elasticity, etc., and can also effectively prevent and Treats problem skin such as aging, wrinkles, dimpling, pigmentation, blemishes, skin that is irritated, inflamed or in a less than ideal state of health.
  • the dosage of vitamin C lactate and its analogues is 0.01mmol/L to 1mol/L, for example, 0.01mmol/L to 0.5mol/L, for example It is 0.01mmol/L ⁇ 1mmol/L, and for example, it is 0.02 ⁇ 0.5mol/L.
  • the preparation for skin tissue is selected from injections.
  • vitamin C lactate and its analogs are used as active ingredients.
  • the vitamin C lactate and its analogs are used as the active ingredient. The only active ingredient.
  • the present invention also provides a product for skin tissue, which contains the above-mentioned vitamin C lactate and its analogs, and the vitamin C lactate and its analogs have the meanings as described above.
  • the vitamin C lactate and its analogs are used as active ingredients.
  • the vitamin C lactate and its analogs are the only active ingredient.
  • the skin tissue preparation is selected from one or more of drugs, cosmetics, kits, health products, and medical devices.
  • the drug is selected from the group consisting of ointments, patches, emulsions, solutions, suspensions, injections and other forms.
  • the dosage form of the cosmetic product may be in any form.
  • the dosage form of the cosmetics may be, for example, at least one of creams, facial masks, emulsions, solutions, suspensions, essential oils, lotions, foundations, and make-up foundations.
  • the cosmetic product further includes adjuvants known in the art.
  • the preparation for skin tissue is an injection, wherein the dosage of the vitamin C lactate and its analogues is 0.01mmol/L to 1mmol/L, for example, 0.01mmol/L to 0.5mol/ L is another example of 0.02 to 0.5 mol/L.
  • the present invention also provides the use of the above skin tissue preparation in preventing problem skin, improving problem skin and/or treating problem skin.
  • the present invention also provides the use of the above-mentioned preparation for skin tissue in preparing a medicament for preventing problem skin, improving problem skin, and/or treating problem skin.
  • the drug can be used to improve wrinkles, increase skin elasticity or moisturize.
  • the problem skin refers to skin that is aged, dry, allergic, pigmented, irritated, inflamed or in a less than ideal health state, such as at least facial skin, body skin, lip skin, etc. A sort of.
  • the treatment of problematic skin includes skin regeneration, improvement of wrinkles, improvement of skin elasticity, freckle removal, skin whitening, moisturizing, anti-allergy, anti-inflammation, etc.
  • the skin regeneration means that the skin tissue product can promote the proliferation of dermal fibroblasts and have a skin regeneration effect.
  • the improvement of wrinkles and improvement of skin elasticity refers to the effect of improving wrinkles by promoting the synthesis of collagen and elastin.
  • the skin whitening has a whitening effect due to inhibiting the synthesis of melanin in melanocytes.
  • the prevention of problematic skin includes anti-oxidation, anti-allergy, reducing irritation, anti-aging, moisturizing, reducing pigmentation, enhancing skin elasticity, slowing down wrinkles and depressions, etc.
  • vitamin C lactate and its analogues can effectively prevent and treat problematic skin, such as skin that is irritated, inflamed or in a less than ideal health state, and can be antioxidant, anti-allergic, reduce irritation, Anti-aging, removing freckles, removing wrinkles, moisturizing, and enhancing skin elasticity, it has broad medicinal value.
  • the vitamin C lactate and its analogues of the present invention can participate in the repair and regeneration of skin tissue and participate in cell activities when used in skin tissue products. Preferably, they can promote cells to secrete collagen, smooth wrinkles, and increase skin elasticity. .
  • Solution 1 Prepare an aqueous solution of 0.01mmol/L vitamin C lactate
  • Solution 2 Prepare an aqueous solution of 1mmol/L vitamin C lactate
  • Comparative solution 1 Configure an aqueous solution of 0.01mmol/L vitamin C;
  • Comparative solution 2 configure an aqueous solution of 0.01mmol/L lactic acid
  • Comparative solution 3 Prepare an aqueous solution containing 0.01mmol/L lactic acid and 0.01mmol/L vitamin C.
  • the present invention conducts animal experiments by injecting the solution 1-2 prepared in Preparation Example 1, the comparative solution 1-3 and the blank solution.
  • the specific experimental methods are as follows:
  • the experimental animal was a male mouse, weighing (23 ⁇ 4) g, and the experimental site was the neck skin.
  • the injection dose 0.1ml at a single point.
  • the sampling time points were: 7th day, 14th day and 21st day after the injection.
  • the left neck skin of the experimental mice used the above solution 1 as the test group 1, and the right neck skin used the above blank solution as the blank control group 1.
  • the corresponding solution Stop injections from the 8th day.
  • the experimental animals were sacrificed at the time point, and the observed skin tissues were cut out. After the tissue was fixed, Sirius red staining was performed to observe the impact of the injected solution on the tissues of various parts of the mouse. Analysis of the effect of vitamin C lactate solution on collagen synthesis in mouse skin.
  • the base peptide was made into a 10 mg/mL aqueous solution as a positive drug
  • mice The experimental nude mice were divided into 8 equal groups, with 6 mice in each group (blank control group, model group, positive administration group, 5 mg/mL administration group, 25 mg/mL administration group, 50 mg/mL administration group, 80 mg/ mL dosing group, 100 mg/mL dosing group), and were adaptively raised for 1 week at 25°C and 65% humidity with a 12-hour light-dark cycle.
  • Nude mice in the non-blank control group were irradiated with UV light (100mJ/cm 2 ) starting from the 2nd week, for 4 consecutive weeks, twice a week, for 1 hour each time.
  • nude mice were dissected, and skin tissue and serum were collected for observation and measurement of microscopic indicators.
  • the nude mice in the model group only received ultraviolet radiation without any medication. Compared with the nude mice in the blank control group, the skin was dry, rough, peeling, with spots and ulcers, showing common symptoms of photoaging. The model was successful and suitable for further testing.
  • the positive drug was given to the nude mice in the positive drug group after irradiation. Compared with the model group, the skin condition was significantly improved, with a small number of ulcer spots.
  • the nude mice in the vitamin C lactate group were injected with vitamin C lactate injection after irradiation.
  • vitamin C lactate can inhibit the formation of ulcers. Based on the apparent characteristics of the skin of nude mice, it can be preliminarily determined that the concentration is 5 mg/mL ⁇ 100 mg/mL. Injectable administration of vitamin C lactate can repair photoaging induced by ultraviolet radiation.
  • the present invention has proved through animal experiments that the injection containing the vitamin C lactate ester and its analogues of the present invention has a significant promoting effect on the skin tissue of animals, especially the growth and healing of skin tissue, and can effectively prevent, Treats and repairs skin tissue damaging diseases.

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Abstract

本发明提供维生素C乳酸酯及其类似物在制备皮肤组织用制品中的应用及其相关制品。本发明的维生素C乳酸酯及其类似物可以有效预防、改善和/或治疗问题皮肤。本发明的维生素C乳酸酯及其类似物用于皮肤组织用制品中可以参与皮肤组织的修复和再生，参与细胞活动，具有广阔的应用前景。

Description

维生素C乳酸酯及其类似物在制备皮肤组织用制品中的用途及其相关制品
本申请要求享有2022年7月26日向中国国家知识产权局提交的，专利申请号为202210887810.8，发明名称为“维生素C乳酸酯及其类似物在制备皮肤组织用制品中的用途及其相关制品”的在先申请的优先权权益。所述在先申请的全文通过引用的方式结合于本申请中。
技术领域
本发明涉及医药技术领域，具体地说，是维生素C乳酸酯及其类似物在制备皮肤组织用制品中的用途、含有维生素C乳酸酯及其类似物的皮肤组织用制品。
背景技术
维生素是参与动植物生长发育所必须的一类微量有机物，然而其极不稳定，容易氧化变性，且溶解能力有限。然而，当维生素经酯化后，在多种溶剂体系下其稳定性显著提高，同时具备原有和新增功能基团的功能和活性。
目前，已有多种经过结构修饰的维生素衍生物实现商品化，可广泛用作食品添加剂、药品或保健品。改性后的维生素C酯是一种兼具抗肿瘤、抗衰老、抗生物氧化、清除体内自由基等多种功能特性、安全的新型食品添加剂；维生素E酯可作为维生素E替代品而广泛用于医药、食品和化妆品等方面；维生素A酯是重要药品和饲料添加剂。
然而，尚未发现维生素C乳酸酯及其类似物在治疗问题皮肤的制品等方面中的应用。
发明内容
本发明的目的是提供维生素C乳酸酯及其类似物的新用途。本发明研究发现，维生素C乳酸酯及其类似物应用于皮肤组织用制品中，可以有效预防、改善和/或治疗问题皮肤例如老化、皱纹、凹陷、色素沉淀、斑点、受刺激、发炎或处于不太理想健康状态的皮肤。本发明的维生素C乳酸酯及其类似物用于皮肤组织用制品中可以参与皮肤组织的修复和再生，参与细胞活动，优选可以促进细胞分泌胶原。
本发明提供维生素C乳酸酯及其类似物在制备皮肤组织用制品中的应用。
根据本发明的实施方案，所述皮肤组织用制品可以用于预防、改善和/或治疗问题皮肤。
本发明提供维生素C乳酸酯及其类似物在制备用于预防、改善和/或治疗问题皮肤的皮肤组织用制品中的应用。
根据本发明的实施方案，所述皮肤组织用制品选自药物、化妆品、试剂盒、保健品、医疗器械中的一个或多个。
根据本发明的实施方案，所述药物选自膏剂、贴剂、乳液、溶液、悬浮液、注射剂等形式。
根据本发明的实施方案，所述化妆品的剂型可以为任意形态。
优选地，所述化妆品的剂型例如可以为霜剂类、面膜类、乳液类、溶液类、悬浮液类、精油类、化妆水类、粉底类以及彩妆粉底类等中的至少一种。
根据本发明的实施方案，所述化妆品还包括本领域已知的辅剂。
根据本发明的实施方案，所述皮肤组织用制品中，所述维生素C乳酸酯及其类似物作为活性成分，优选，所述维生素C乳酸酯及其类似物作为唯一活性成分。
根据本发明的实施方案，所述维生素C乳酸酯及其类似物是由维生素C和乳酸及其衍生物经过化学合成法(酯化反应、酯交换反应)、生物合成法或酶催化合成法得到。
优选地，由维生素C和乳酸经过化学合成法(酯化反应)、生物合成法或酶催化合成法得到维生素C乳酸酯。
优选地，由维生素C和乳酸衍生物经过化学合成法(酯化反应、酯交换反应)、生物合成法或酶催化合成法得到维生素C乳酸酯类似物。
根据本发明的实施方案，所述乳酸衍生物选自聚乳酸类可降解聚合物、乳酸低聚物、乳酸盐、乳酸及上述物质与其他化合物的复合物中的一个或多个，优选为乳酸。
优选地，所述聚乳酸类可降解聚合物例如为聚乳酸、乙交酯丙交酯共聚物、丙交酯己内酯共聚物、聚乳酸聚乙二醇共聚物。
优选地，所述乳酸盐是乳酸的一种化学衍生物，是当乳酸上的羧基释放出氢离子后，同带正电的物质相结合所形成的盐。进一步地，所述乳酸盐包括但不限于乳酸钠、乳酸钾、乳酸锂、乳酸钙、乳酸镁、乳酸亚铁、乳酸锌、乳酸铝、壳聚糖乳酸盐、常山酮乳酸盐、甲氧苄啶乳酸盐、1-乙基-3-甲基咪唑L-(+)-乳酸盐、2-羟乙基-三甲基铵L-(+)-乳酸盐、L-乳酸四丁基铵盐中的一种或多种。
根据本发明的实施方案，所述维生素C乳酸酯及其类似物具有如下式(1)-(4)任一所示的结构式：

其中，R选自*为连接位点；n为1～30，优选为1～20，还优选为1～10；R1选自H。
优选地，所述R由上述乳酸及其衍生物提供。
根据本发明示例性的方案，所述维生素C乳酸酯具有如下式(1’)所示的结构式：
根据本发明的实施方案，所述维生素C乳酸酯及其类似物能够抗氧化、抗过敏、降低刺激性、抗衰老、祛皱、保湿、美白、增强皮肤弹性等作用，还能够有效预防和治疗问题皮肤，例如老化、皱纹、凹陷、色素沉积、斑点、受刺激、发炎或处于不太理想健康状态的皮肤。
根据本发明的实施方案，所述皮肤组织用制品中，所述维生素C乳酸酯及其类似物的用量为0.01mmol/L～1mol/L，例如0.01mmol/L～0.5mol/L，例如为0.01mmol/L～1mmol/L，又例如为0.02～0.5mol/L。
根据本发明示例性的方案，所述皮肤组织用制品选自注射剂，所述注射剂中，维生素C乳酸酯及其类似物作为活性成分，优选，所述维生素C乳酸酯及其类似物作为唯一活性成分。
本发明还提供一种皮肤组织用制品，所述皮肤组织用制品含有上述维生素C乳酸酯及其类似物，所述维生素C乳酸酯及其类似物具有如上文所述含义。
根据本发明的实施方案，所述皮肤组织用制品中，所述维生素C乳酸酯及其类似物作为活性成分，优选，所述维生素C乳酸酯及其类似物作为唯一活性成分。
根据本发明的实施方案，所述皮肤组织用制品选自药物、化妆品、试剂盒、保健品、医疗器械中的一个或多个。
根据本发明的实施方案，所述药物选自膏剂、贴剂、乳液、溶液、悬浮液、注射剂等形式。
根据本发明的实施方案，所述化妆品的剂型可以为任意形态。
优选地，所述化妆品的剂型例如可以为霜剂类、面膜类、乳液类、溶液类、悬浮液类、精油类、化妆水类、粉底类以及彩妆粉底类等中的至少一种。
根据本发明的实施方案，所述化妆品还包括本领域已知的辅剂。
根据本发明优选的方案，所述皮肤组织用制品为注射剂，其中，所述维生素C乳酸酯及其类似物的用量为0.01mmol/L～1mmol/L，例如0.01mmol/L～0.5mol/L，又例如为0.02～0.5mol/L。
本发明还提供上述皮肤组织用制品在预防问题皮肤、改善问题皮肤和/或治疗问题皮肤的用途。
本发明还提供上述皮肤组织用制品在制备预防问题皮肤、改善问题皮肤和/或治疗问题皮肤的药物中的用途。
优选地，所述药物可以用于改善皱纹、增进皮肤弹性或保湿。
根据本发明的实施方案，所述问题皮肤是指受老化、干燥、过敏、色素沉积、刺激、发炎或处于不太理想健康状态的皮肤，例如为面部皮肤、身体皮肤、嘴唇皮肤等中的至少一种。
根据本发明的实施方案，所述治疗问题皮肤包括皮肤再生、改善皱纹及增进皮肤弹性、祛斑、皮肤美白、保湿、抗过敏、消炎等。
根据本发明的实施方案，所述皮肤再生是指所述皮肤组织用制品能促进真皮成纤维细胞的增殖而具有皮肤再生的效果。
根据本发明的实施方案，所述改善皱纹及增进皮肤弹性是指因促进胶原蛋白和弹性蛋白的合成而具有改善皱纹的效果。
根据本发明的实施方案，所述皮肤美白因抑制黑色素细胞中黑色素的合成而具有美白效果。
根据本发明的实施方案，所述预防问题皮肤包括抗氧化、抗过敏、降低刺激性、抗衰老、保湿、减少色素沉淀、增强皮肤弹性、减缓皱纹凹陷等。
有益效果
本发明通过动物实验发现，维生素C乳酸酯及其类似物能够有效预防和治疗问题皮肤例如受刺激、发炎或处于不太理想健康状态的皮肤，例如能够抗氧化、抗过敏、降低刺激性、抗衰老、祛斑、祛皱、保湿、增强皮肤弹性，具有广阔的药用价值。
本发明的维生素C乳酸酯及其类似物用于皮肤组织用制品中可以参与皮肤组织的修复和再生，参与细胞活动，优选可以促进细胞分泌胶原，用于抚平皱纹，增加皮肤弹性的作用。
具体实施方式
下文将结合具体实施例对本发明的技术方案做更进一步的详细说明。应当理解，下列实施例仅为示例性地说明和解释本发明，而不应被解释为对本发明保护范围的限制。凡基于本发明上述内容所实现的技术均涵盖在本发明旨在保护的范围内。
制备例1
取具有如式(1’)所示结构的维生素C乳酸酯制备下述溶液作为注射剂：
溶液1：配置0.01mmol/L维生素C乳酸酯的水溶液；
溶液2：配置1mmol/L维生素C乳酸酯的水溶液；
空白溶液：不含维生素C乳酸酯的水溶剂；
对比溶液1：配置0.01mmol/L维生素C的水溶液；
对比溶液2：配置0.01mmol/L乳酸的水溶液；
对比溶液3：配置含有0.01mmol/L乳酸和0.01mmol/L维生素C的水溶液。
实施例1
1.实验设计：胶原蛋白测定
为验证维生素C乳酸酯具有刺激皮肤产生胶原蛋白的作用。本发明以注射制备例1制得的溶液1-2、对比溶液1-3和空白溶液进行动物实验。具体实验方法如下：
实验动物为雄性小鼠，重量(23±4)g，实验部位为颈部皮肤，注射剂量：单点注射0.1ml，取样时间节点：注射结束后第7天、14天和21天。
2.检测方法：
(1)实验小鼠左侧颈部皮肤为采用上述溶液1作为试验组1，右侧颈部皮肤采用上述空白溶液作为空白对照组1，前7日每天在颈部皮肤两侧注射对应溶液、 从第8日起停止注射。在时间节点时处死实验动物，切取观察的皮肤组织。组织固定后进行天狼星红染色，观察注射溶液对小鼠各部位组织产生的影响。分析维生素C乳酸酯溶液对小鼠皮肤中胶原蛋白合成的作用。
将试验组1和空白对照组1在各时间点的组织切片的偏振光显微镜照片，经Image J软件统计其新生Ⅲ型胶原纤维的量占总量的百分比，结果见表1。
表1新生Ⅲ型胶原纤维的量占总量的百分比
由表1中结果可知：试验组1注射后7天、14天和21天的组织切片比空白对照组1注射后7天、14天和21天的组织切片中新生Ⅲ型胶原纤维的含量明显增多。
(2)另取一组实验小鼠，在实验小鼠的左侧颈部皮肤为采用上述溶液2作为试验组2，右侧颈部皮肤采用上述空白溶液作为空白对照组2，前7日每天在颈部皮肤两侧注射对应溶液，从第8日起停止注射。在时间节点时处死实验动物，切取观察的皮肤组织。组织固定后进行天狼星红染色，观察注射溶液对小鼠各部位组织产生的影响。分析维生素C乳酸酯溶液对小鼠皮肤中胶原蛋白合成的作用。
将试验组2和空白对照组2在各时间点的组织切片的偏振光显微镜照片，经Image J软件统计其新生Ⅲ型胶原纤维的量占总量的百分比，结果见表2。
表2新生Ⅲ型胶原纤维的量占总量的百分比
(3)另取3组实验小鼠，在实验小鼠的左侧颈部皮肤分别采用上述对比溶液1-3作为对比试验组1-3，右侧颈部皮肤采用上述空白溶液作为空白组1-3，前7日每天在颈部皮肤两侧注射对应溶液，从第8日起停止在颈部皮肤两侧注射对应溶液。在时间节点时处死实验动物，切取观察的皮肤组织。观察注射溶液对小鼠各部位组织产生的影响。
通过上述实验结果可知，连续注射7天后，对比实验组1-3小鼠颈部皮肤有红肿、发炎现象。
3.结论
由上述实验结果可以看出，实验组1-2的效果最好，具有明显的促进胶原产生的作用。由此可知，本发明的维生素C乳酸酯对于小鼠颈部皮肤合成胶原蛋白有显著的，甚至是极显著的促进作用。
制备例2
取具有如式(1’)所示结构的维生素C乳酸酯制备下述溶液作为注射剂：
配制0.02mmol/mL(5mg/mL)、0.1mmol/mL(25mg/mL)、0.2mmol/mL(50mg/mL)、0.32mmol/mL(80mg/mL)、0.4mmol/mL(100mg/mL)维生素C乳酸酯的水溶液。
实施例2
2.1实验材料：
七周龄BALB/c裸鼠(来源：北京维通利华实验动物有限公司)；
注射剂：选用制备例2的注射剂；
基肽制成10mg/mL水溶液作为阳性药；
2.2实验方法：光老化模型造模方法
试验裸鼠分成数量相等的8组，每组6只(空白对照组、模型组、阳性给药组、5mg/mL给药组、25mg/mL给药组、50mg/mL给药组、80mg/mL给药组、100mg/mL给药组)，于25℃、65％湿度12小时光暗周期适应性饲养1周。
非空白对照组裸鼠从第2周开始照射紫外灯(100mJ/cm2)，连续4周，每周2次，每次1h。
从第5周开始停止照射开始注射给药，连续六周，每周4次。观察并记录裸鼠皮肤表观。第11周给药结束解剖裸鼠，收集皮肤组织和血清用于微观指标观察及测定。
2.3结果分析
由实验结果可知，空白对照组裸鼠不照射不给药，皮肤出现干燥、溃疡点。模型组裸鼠只接受紫外辐射不给药，与空白对照组裸鼠相比，皮肤干燥、粗糙、起皮、长斑及溃疡点，表现出光老化的普遍症状，模型成功，适用于进一步试验。阳性给药组裸鼠照射之后给阳性药，其皮肤与模型组相比，状态明显改善，出现少量的溃疡点；维生素C乳酸酯给药组裸鼠照射之后注射维生素C乳酸酯注射剂给药，其皮肤未出现干燥、粗糙、起皮、长斑、溃疡点等症状。对皮肤水分及溃疡点进行量化，可明显观察到紫外线照射之后的裸鼠皮肤含水量降低，这种紫外照射引起的皮肤失水可以被上述维生素C乳酸酯的注射剂改善，实验浓度下的注射剂对裸鼠皮肤具有一定的保湿作用。由于裸鼠的抵抗力较低，在实验的后期阳性给药组裸鼠皮肤出现了溃疡点，紫外照射使溃疡点数量增多，阳性药能够降低溃疡点的形成。而维生素C乳酸酯给药组裸鼠皮肤均未出现溃疡点，说明维生素C乳酸酯能够抑制溃疡点的生成，由裸鼠皮肤表观特征可初步判断浓度为5mg/mL～100mg/mL的维生素C乳酸酯经注射给药能够修复由紫外照射诱导的光老化。
2.4裸鼠皮肤组织切片观察
如图1所示，紫外照射使模型组裸鼠皮肤角质层加厚、皮脂腺增生、皮下细胞及胶原蛋白纤维紊乱，导致皮肤出现松弛、干燥等症状，这与目前的研究是 一致的。与模型组裸鼠相比，维生素C乳酸酯给药组裸鼠皮肤状态有明显的改善，随给药浓度升高，其角质层厚度逐渐回归正常、增生的皮脂腺减少、皮下细胞和胶原蛋白纤维更为规整，高浓度效果接近阳性对照组。对皮肤增生的皮脂腺和表皮厚度进行量化，显示紫外照射能够引发皮脂腺增生，而这种皮脂腺的增生可以被维生素C乳酸酯抑制，且呈剂量依赖关系，浓度越高，其抑制作用越明显；紫外照射增加皮肤角质层的厚度，维生素C乳酸酯能够改善紫外辐射诱导的表皮增厚，其改善作用与阳性药效果相似。
综上，本发明通过动物实验证明了含有本发明的维生素C乳酸酯及其类似物的注射剂对于动物的皮肤组织，特别是皮肤组织的增长与愈合均有显著的促进作用，能够有效预防、治疗和修复皮肤组织损伤疾病。
以上，对本发明的实施方式进行了说明。但是，本发明不限定于上述实施方式。凡在本发明的精神和原则之内，所做的任何修改、等同替换、改进等，均应包含在本发明的保护范围之内。

Claims (10)

  1. 维生素C乳酸酯及其类似物在制备皮肤组织用制品中的应用，其特征在于，所述皮肤组织用制品用于预防、改善和/或治疗问题皮肤。
  2. 根据权利要求1所述的应用，其特征在于，所述皮肤组织用制品选自药物、化妆品、试剂盒、保健品、医疗器械中的一个或多个。
    优选地，所述药物选自膏剂、贴剂、乳液、溶液、悬浮液、注射剂等形式。
    优选地，所述化妆品的剂型例如可以为霜剂类、面膜类、乳液类、溶液类、悬浮液类、精油类、化妆水类、粉底类以及彩妆粉底类等中的至少一种。
    优选地，所述皮肤组织用制品选自注射剂，所述注射剂中，维生素C乳酸酯及其类似物作为活性成分，优选，所述维生素C乳酸酯及其类似物作为唯一活性成分。
  3. 根据权利要求1或2所述的应用，其特征在于，所述维生素C乳酸酯及其类似物是由维生素C和乳酸及其衍生物经过化学合成法、生物合成法或酶催化合成法得到。
    优选地，由维生素C和乳酸经过化学合成法、生物合成法或酶催化合成法得到维生素C乳酸酯。
    优选地，由维生素C和乳酸衍生物经过化学合成法、生物合成法或酶催化合成法得到维生素C乳酸酯类似物。
    优选地，所述乳酸衍生物选自聚乳酸类可降解聚合物、乳酸低聚物、乳酸盐、乳酸及上述物质与其他化合物的复合物中的一个或多个。
  4. 根据权利要求1-3任一项所述的应用，其特征在于，所述维生素C乳酸酯及其类似物具有如下式(1)-(4)任一所示的结构式：
    其中，R选自*为连接位点；n为1～30，优选为1～20，还优选为1～10；R1选自H。
    优选地，所述R由上述乳酸及其衍生物提供。
  5. 根据权利要求1-4任一项所述的应用，其特征在于，所述维生素C乳酸酯具有如下式(1’)所示的结构式：
  6. 根据权利要求1所述的应用，其特征在于，所述皮肤组织用制品中，所述维生素C乳酸酯及其类似物的用量为0.01mmol/L～1mol/L，例如0.01mmol/L～0.5mol/L，例如为0.01mmol/L～1mmol/L，又例如为0.02～0.5mol/L。
  7. 一种皮肤组织用制品，其特征在于，所述皮肤组织用制品含有权利要求3-5任一项所述的维生素C乳酸酯及其类似物。
    优选地，所述皮肤组织用制品中，所述维生素C乳酸酯及其类似物作为活性成分。
    优选地，所述维生素C乳酸酯及其类似物作为唯一活性成分。
  8. 根据权利要求7所述的皮肤组织用制品，其特征在于，所述皮肤组织用制品选自药物、化妆品、试剂盒、保健品、医疗器械中的一个或多个。
    所述药物选自膏剂、贴剂、乳液、溶液、悬浮液、注射剂等形式。
    所述化妆品选自霜剂类、面膜类、乳液类、溶液类、悬浮液类、精油类、化妆水类、粉底类以及彩妆粉底类等中的至少一种。
  9. 根据权利要求7或8所述的皮肤组织用制品，其特征在于，所述皮肤组织用制品为注射剂，其中，所述维生素C乳酸酯及其类似物的用量为0.01mmol/L～1mol/L，例如0.01mmol/L～0.5mol/L，例如为0.01mmol/L～1mmol/L， 又例如为0.02～0.5mol/L。
  10. 权利要求7-9任一项所述皮肤组织用制品在制备预防问题皮肤、改善问题皮肤和/或治疗问题皮肤的药物中的用途。
    优选地，所述药物可以用于改善皱纹、增进皮肤弹性或保湿。
PCT/CN2023/072684 2022-07-26 2023-01-17 维生素c乳酸酯及其类似物在制备皮肤组织用制品中的用途及其相关制品 WO2024021544A1 (zh)

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