WO2023237004A1

WO2023237004A1 - Ternary freeze-dry composition and use thereof in freeze-dry formulation

Info

Publication number: WO2023237004A1
Application number: PCT/CN2023/098898
Authority: WO
Inventors: 吴冬; 侯丽丽; 梁乾宝
Original assignee: 吴冬
Priority date: 2022-06-07
Filing date: 2023-06-07
Publication date: 2023-12-14
Also published as: CN114886785B; CN114886785A

Abstract

A ternary freeze-dry composition and a use thereof in a freeze-dry formulation, which relate to the technical field of freeze-dry formulations. The ternary freeze-dry composition comprises the following components: scaffold molecules, a liposome encapsulation, and macromolecular carriers; by controlling the specific components and the mass ratio of the scaffold molecules, the liposome encapsulation, and the macromolecular carriers, the composition can achieve freeze-drying of a fat or oil-type component, allowing the loading capacity of the fat or oil-type component to reach 75%, and causing rehydration after freeze-drying to form an emulsified state. Consequently, a a freeze-dry formulation compatible with both oil-based and water-based components is provided, and the prepared freeze-dry formulation does not need any added preservatives.

Description

一种三元冻干组合物及其在冻干制剂中的应用A ternary freeze-dried composition and its application in freeze-dried preparations

技术领域Technical field

本发明涉及冻干制剂技术领域，具体涉及一种三元冻干组合物及其在冻干制剂中的应用。The invention relates to the technical field of freeze-dried preparations, and in particular to a ternary freeze-dried composition and its application in freeze-dried preparations.

背景技术Background technique

面部护肤品是一种用于面部的化妆品，其中含有比较珍贵的功效成分，如植物提取物等，从而使得面部护肤品具有防衰老、抗皱、保湿、美白、祛斑等功效。传统面部护肤品中通常含有不稳定的活性物，从而影响产品的长期保存，并且由于皮肤的亲脂性而需要有乳化才能更好的保存和递送活性物，因此需要添加大量的乳化剂、肤感调节剂等用于提高产品稳定性，并且传统面部护肤品多为瓶装液体，为了防止细菌的滋生，需要添加防腐剂，并且存在携带不方便的问题，且多次开关具有交叉污染的风险，会对皮肤造成损伤，因此化妆品超低温真空冷冻干燥技术应运而生。Facial skin care products are a kind of cosmetics used on the face, which contain relatively precious functional ingredients, such as plant extracts, etc., so that facial skin care products have anti-aging, anti-wrinkle, moisturizing, whitening, freckle removal and other effects. Traditional facial skin care products usually contain unstable active substances, which affects the long-term storage of the product. Due to the lipophilicity of the skin, emulsification is required to better preserve and deliver the active substances. Therefore, a large amount of emulsifiers and skin feel need to be added. Conditioners are used to improve product stability, and traditional facial skin care products are mostly bottled liquids. In order to prevent the growth of bacteria, preservatives need to be added, which is inconvenient to carry, and multiple switching on and off has the risk of cross-contamination, which will It causes damage to the skin, so cosmetics ultra-low temperature vacuum freeze-drying technology came into being.

超低温真空冷冻干燥技术就是把含有大量水分的物质，预先进行降温冻结成固体，然后在真空的条件下使固态水直接升华出来，而物质本身剩留在冻结时的冰架中，因此它干燥后体积不变。冻干技术可有效防止物料理化及生物特性的改变，对热敏性物质及活性成分有很好的保护，并且可以使一些易氧化的物质(如油脂类)也能得到保护，冷冻干燥技术在化妆品行业应用能够充分保存生物物质的活性成分，能延长保存时间，复水性好，因为化妆品冻干加工处理后含水量均在1％以下，采用真空密封包装，有效抑制微生物的生长，不用添加防腐剂。通过冷冻干燥技术将化妆品制备成冻干粉，不仅加工过程简单，无污染物产生，绿色环保，而且其配方中不含防腐剂，对皮肤无刺激性，适用于任何肤质。Ultra-low temperature vacuum freeze-drying technology is to freeze substances containing a large amount of moisture into solids in advance, and then directly sublimate the solid water under vacuum conditions, while the substance itself remains in the ice shelf during freezing, so it is dried The volume remains unchanged. Freeze-drying technology can effectively prevent changes in the physical, chemical and biological properties of materials, has good protection for heat-sensitive substances and active ingredients, and can also protect some easily oxidized substances (such as oils and fats). Freeze-drying technology is widely used in cosmetics. Industrial applications can fully preserve the active ingredients of biological substances, extend the storage time, and have good rehydration properties, because the moisture content of cosmetics after freeze-drying is less than 1%, and they are packaged in vacuum seals to effectively inhibit the growth of microorganisms without adding preservatives. . Cosmetics are prepared into freeze-dried powder through freeze-drying technology. Not only is the processing process simple, no pollutants are produced, and it is green and environmentally friendly, but the formula does not contain preservatives, is non-irritating to the skin, and is suitable for any skin type.

但是市场上常见的冻干精华或冻干面膜液等由于技术原因，无法更好的对油脂类成分进行冻干，从而使体系中只有水性物，肤感不足，并且无法复水乳化，导致产品功能和应用受到很大限制。However, due to technical reasons, common freeze-dried essences or freeze-dried facial masks on the market cannot freeze-dry oils and fats. As a result, there are only water-based substances in the system, which lacks skin feel and cannot be rehydrated and emulsified, resulting in product Functions and applications are greatly limited.

如中国专利申请201410187505.3中公开了一种抗皱、美白冻干速溶化妆品及其制备方法。所述化妆品，包括下述组分：赋形剂，2-16重量份；透明质酸钠，0.1-10重量份；EGF，0.0002-0.008重量份；VC，0-5重量份；胶原蛋白，0-0.5重量份；α-熊果苷，0-3重量份；D-泛醇，0-0.5重量份；α-硫辛酸，0-0.3重量份。该化妆品的性状稳定，抗皱及美白的效果好其制备方法简单，易于操作。 For example, Chinese patent application 201410187505.3 discloses an anti-wrinkle, whitening freeze-dried instant cosmetic and its preparation method. The cosmetics include the following components: excipient, 2-16 parts by weight; sodium hyaluronate, 0.1-10 parts by weight; EGF, 0.0002-0.008 parts by weight; VC, 0-5 parts by weight; collagen, 0-0.5 parts by weight; α-arbutin, 0-3 parts by weight; D-panthenol, 0-0.5 parts by weight; α-lipoic acid, 0-0.3 parts by weight. The cosmetic has stable properties, good anti-wrinkle and whitening effects, and its preparation method is simple and easy to operate.

再如中国专利申请201911209367.3及一种美容护肤化妆品冻干粉制剂及其在溶液剂上的应用由以下质量百分比的原料组分制作而成：透明质酸：1％-5％、抗菌肽：0.001％-0.005％、赋形剂：5％-15％、水：79.995％-93.999％以上原料经搅拌加热完全溶解后，经过冻干技术升华得到冻干粉制剂。该美容护肤化妆品冻干粉制剂可应用在原液、精华液、溶酶液或液体敷料上。Another example is Chinese patent application 201911209367.3 and a freeze-dried powder preparation for beauty and skin care cosmetics and its application in a solution. It is made of the following raw material components with mass percentages: hyaluronic acid: 1%-5%, antimicrobial peptide: 0.001 %-0.005%, excipients: 5%-15%, water: 79.995%-93.999%. After the above raw materials are completely dissolved by stirring and heating, the freeze-dried powder preparation is obtained by sublimation through freeze-drying technology. The freeze-dried powder preparation of beauty and skin care cosmetics can be applied to original solution, essence, enzyme solution or liquid dressing.

但是上述现有的冻干制剂中加载植物源油脂类和动物源油脂类成分少，完全无法复水乳化，因此难以实现肤感更多维度，使体验感降低，功效受限，因此需要提供一种高载量、高兼容性，功效好、肤感好，且无添加防腐剂的冻干组合物及其应用。However, the above-mentioned existing freeze-dried preparations contain few plant-derived oils and animal-derived oils and ingredients, and cannot be rehydrated and emulsified at all. Therefore, it is difficult to achieve more dimensions of skin feel, which reduces the experience and limits the efficacy. Therefore, it is necessary to provide a A freeze-dried composition with high loading capacity, high compatibility, good efficacy, good skin feel, and no added preservatives and its application.

发明内容Contents of the invention

针对现有技术的不足，本发明旨在提供一种三元冻干组合物及其应用，通过各组分相互配合协同增效，组成的冻干体系可以实现高载量、高兼容性，能够冻干油脂类、多元醇类、易分解不稳定活性物以及干燥后易成胶糖类等常规冻干难度较大的组分，并且复水后直接乳化。In view of the shortcomings of the existing technology, the present invention aims to provide a ternary freeze-drying composition and its application. Through the synergy of each component, the composed freeze-drying system can achieve high loading capacity, high compatibility, and can Freeze-dried oils, polyols, easily decomposed and unstable active substances, and other components that are difficult to freeze-dry after drying, such as gums, can be directly emulsified after rehydration.

为实现上述发明目的，本发明技术方案如下：In order to achieve the above-mentioned object of the invention, the technical solutions of the present invention are as follows:

一种三元冻干组合物，按重量百分含量计包括如下组分：骨架分子50-80％、脂质体包埋15-30％和大分子载体5-20％。A ternary freeze-dried composition includes the following components in terms of weight percentage: 50-80% skeleton molecules, 15-30% liposome embedding and 5-20% macromolecular carriers.

优选地，所述的三元冻干组合物，按重量百分含量计包括如下组分：骨架分子50-65％、脂质体包埋20-25％和大分子载体10-20％。。Preferably, the ternary freeze-dried composition includes the following components in terms of weight percentage: 50-65% skeleton molecules, 20-25% liposome embedding, and 10-20% macromolecular carrier. .

进一步优选地，所述的三元冻干组合物，按重量百分含量计包括如下组分：骨架分子65％、脂质体包埋25％和大分子载体10％。Further preferably, the ternary freeze-dried composition includes the following components in terms of weight percentage: 65% framework molecules, 25% liposome encapsulation and 10% macromolecular carrier.

其中，所述的骨架分子包括氨基酸；Wherein, the skeleton molecule includes amino acids;

所述的氨基酸选自脯氨酸、色氨酸、谷氨酸钠、丙氨酸、甘氨酸、赖氨酸盐酸盐、肌氨酸、L-酪氨酸、苯丙氨酸和精氨酸中的一种或几种；The amino acid is selected from the group consisting of proline, tryptophan, monosodium glutamate, alanine, glycine, lysine hydrochloride, sarcosine, L-tyrosine, phenylalanine and arginine one or more of;

优选地，所述的氨基酸为甘氨酸。Preferably, the amino acid is glycine.

氨基酸具有酸、碱两性，因此能够在生物制品的低温保存和冷冻干燥过程中能保持溶液的pH稳定，从而达到保护活性组分的目的；结晶型甘氨酸能升高成品的塌陷温度，阻止因塌陷而引起的蛋白质药物的破坏。Amino acids have both acidic and alkaline properties, so they can keep the pH of the solution stable during low-temperature storage and freeze-drying of biological products, thereby protecting the active components; crystalline glycine can increase the collapse temperature of the finished product and prevent collapse due to And cause the destruction of protein drugs.

所述的骨架分子还包括海藻糖、水解木聚糖、甘露醇和鼠李糖中的两种或两种以上的组合； The skeleton molecules also include a combination of two or more of trehalose, hydrolyzed xylan, mannitol and rhamnose;

其中海藻糖为葡萄糖的二聚体，为稳定的非还原性双糖，广泛用于冻干保存，作为保护剂冻干的样品生物性能比较稳定，保存时间长，是低温生物领域最佳的保护剂，它分子量较小，易于填充到大分子内部的空隙中，有效限制大分子内部的结构变化，避免活性物失活，玻璃化温度高，可有效防止崩解和塌陷。甘露醇是一种多羟基化合物，作为载体可以形成疏松结实的均匀骨架，还能兼作渗透性调节剂及蛋白质的冻干保护剂，在生物制品的冷冻干燥过程中，甘露醇一般用作填充剂，在慢速冻结时会结晶，从而为活性组分提供支撑结构，同时甘露醇也不会与活性组分发生反应。水解木聚糖、鼠李糖等糖类是最常见的、使用最广泛的一类冻干保护剂，在冻干的各阶段对活性物起到保护作用。Among them, trehalose is a dimer of glucose and a stable non-reducing disaccharide. It is widely used for freeze-drying and preservation. As a protective agent, the biological properties of freeze-dried samples are relatively stable and the storage time is long. It is the best protection in the field of low-temperature biology. The agent has a small molecular weight and is easy to fill into the gaps inside the macromolecules, effectively limiting the structural changes inside the macromolecules and avoiding the deactivation of active substances. It has a high glass transition temperature, which can effectively prevent disintegration and collapse. Mannitol is a polyhydroxy compound that can be used as a carrier to form a loose, strong and uniform skeleton. It can also serve as a permeability regulator and a freeze-drying protectant for proteins. In the freeze-drying process of biological products, mannitol is generally used as a filler. , crystallizes during slow freezing, providing a supporting structure for the active ingredients while mannitol does not react with the active ingredients. Hydrolyzed xylan, rhamnose and other sugars are the most common and widely used freeze-drying protective agents, which protect active substances at various stages of freeze-drying.

优选地，所述的骨架分子为甘氨酸、海藻糖、水解木聚糖、甘露醇和鼠李糖的混合物；Preferably, the skeleton molecule is a mixture of glycine, trehalose, hydrolyzed xylan, mannitol and rhamnose;

优选地，所述的甘氨酸、海藻糖、水解木聚糖、甘露醇和鼠李糖的质量比为3:3:3:3:1；Preferably, the mass ratio of glycine, trehalose, hydrolyzed xylan, mannitol and rhamnose is 3:3:3:3:1;

所述的脂质体包埋为卵磷脂；优选地，所述的卵磷脂为大豆卵磷脂和/或氢化卵磷脂；再优选地，所述的卵磷脂为大豆卵磷脂和氢化卵磷脂的混合物；再优选地，所述的大豆卵磷脂和氢化卵磷脂的质量比为1:3-5；优选为1:4。The liposomes are embedded with lecithin; preferably, the lecithin is soybean lecithin and/or hydrogenated lecithin; further preferably, the lecithin is a mixture of soybean lecithin and hydrogenated lecithin ;More preferably, the mass ratio of the soybean lecithin and hydrogenated lecithin is 1:3-5; preferably 1:4.

卵磷脂的胆碱基是亲脂基团，具有能使互不相溶的两相(油相和水相)中的一相分散在另一相中的作用，本发明采用质量比为1:3-5的大豆卵磷脂和氢化卵磷脂作为脂质体包埋的原料，能够使油相和水相更好的分散，形成稳定的乳浊液。The choline group of lecithin is a lipophilic group, which has the function of dispersing one of the two mutually immiscible phases (oil phase and water phase) in the other phase. The mass ratio used in the present invention is 1: 3-5 soy lecithin and hydrogenated lecithin are used as raw materials for liposome embedding, which can better disperse the oil phase and water phase and form a stable emulsion.

但是现有的冻干制剂在仅含有骨架分子和脂质体包埋的条件下对油脂类组分进行冻干时油脂的负载量较少，不能更好的满足需求，因此需要在此基础上增加其他组分，从而提高对油脂类组分的冻干效果；本申请在实施过程中发现在组分中加入大分子载体，利用大分子载体相对分子质量较大，分子链较长，分子结构复杂的特性，能够通过吸附作用或电荷作用等，实现高载量多元醇类、油脂类等不同极性的物质。However, the existing freeze-dried preparations only contain skeleton molecules and liposomes to lyophilize the lipid components. The loading capacity of the lipids is small and cannot better meet the needs. Therefore, it is necessary to build on this basis. Add other components to improve the freeze-drying effect on oils and fats components; during the implementation process of this application, it was found that adding macromolecular carriers to the components can make use of the macromolecular carriers' larger relative molecular mass, longer molecular chain, and better molecular structure. The complex characteristics can achieve high loading of substances of different polarities such as polyols and oils through adsorption or charge effects.

其中，所述的大分子载体选自丝心蛋白、酪蛋白酸钠、硬脂酸甘油酯、胶原蛋白和乳清蛋白中的一种或几种。Wherein, the macromolecular carrier is selected from one or more of silk fibroin, sodium caseinate, glyceryl stearate, collagen and whey protein.

优选地，所述的大分子载体为丝心蛋白、酪蛋白酸钠、硬脂酸甘油酯、胶原蛋白和乳清蛋白的混合物，所述的丝心蛋白、酪蛋白酸钠、硬脂酸甘油酯、胶原蛋白和乳清蛋白的质量比为1:4:4:0.5:0.5。 Preferably, the macromolecular carrier is a mixture of silk fibroin, sodium caseinate, glyceryl stearate, collagen and whey protein. The mass ratio of ester, collagen and whey protein is 1:4:4:0.5:0.5.

丝心蛋白是以脱胶蚕丝为原料制成的纤维蛋白质，由1条H链和1条L链通过S-S键结合而成，主要由甘氨酸、丙氨酸和丝氨酸组成，具有良好的生物降解性、生物相容性；Silk fibroin is a fibrous protein made from degummed silk. It consists of 1 H chain and 1 L chain combined through S-S bonds. It is mainly composed of glycine, alanine and serine. It has good biodegradability and biocompatibility;

酪蛋白酸钠和硬脂酸甘油酯为常用的乳化剂及表面活性剂，本发明实施过程中发现将丝心蛋白、酪蛋白酸钠和硬脂酸甘油酯按照一定的配比混合，并与骨架分子和脂质体包埋混合后能够高载量吸附油脂类组分等，从而使冻干体系中增加油脂成分，形成水油混合体系，从而提高肤感维度和体验感。Sodium caseinate and glyceryl stearate are commonly used emulsifiers and surfactants. During the implementation of the present invention, it was found that fibroin, sodium caseinate and glyceryl stearate are mixed according to a certain ratio and mixed with After being embedded and mixed with the liposomes, the framework molecules can adsorb oil components at a high capacity, thereby adding oil components to the freeze-drying system and forming a water-oil mixed system, thereby improving the dimension and experience of skin feel.

作为一个优选地实施方案，所述的三元冻干组合物，按重量百分含量计包括如下组分：甘氨酸15％、海藻糖15％、水解木聚糖15％、甘露醇15％、鼠李糖5％、大豆卵磷脂5％、氢化卵磷脂20％、丝心蛋白1％、酪蛋白酸钠4％、硬脂酸甘油酯4％、胶原蛋白0.5％、乳清蛋白0.5％。As a preferred embodiment, the ternary freeze-dried composition includes the following components in terms of weight percentage: glycine 15%, trehalose 15%, hydrolyzed xylan 15%, mannitol 15%, rat 5% plum sugar, 5% soy lecithin, 20% hydrogenated lecithin, 1% silk fibroin, 4% sodium caseinate, 4% glyceryl stearate, 0.5% collagen, 0.5% whey protein.

本发明的另一个目的是还提供了上述三元冻干组合物在制备冻干制剂中的应用，所述的冻干制剂为化妆品冻干制剂。Another object of the present invention is to provide the use of the above-mentioned ternary freeze-dried composition in preparing freeze-dried preparations, and the freeze-dried preparations are cosmetic freeze-dried preparations.

一种化妆品冻干制剂，包括上述三元冻干组合物，还包括油脂类组分、多元醇类组分、不稳定易分解组分、干燥后易成胶组分、维生素、增稠剂和活性成分中的一种或几种；A cosmetic freeze-dried preparation, including the above-mentioned ternary freeze-dried composition, also includes oil components, polyol components, unstable and easy-to-decompose components, easy-to-gel-forming components after drying, vitamins, thickeners and One or more active ingredients;

所述的油脂类组分选自动物源油脂和植物源油脂；The oil and fat components are selected from animal-derived oils and plant-derived oils;

所述的动物源油脂选自黄油、水貂油、蛋黄油、羊毛脂油和角鲨烷中的一种或几种；The animal-derived fats and oils are selected from one or more of butter, mink oil, egg yolk oil, lanolin oil and squalane;

所述的植物源油脂选自乳木果油、夏威夷果油、霍霍巴籽油、橄榄油、椰子油、蓖麻油、棉籽油、大豆油、芝麻油、杏仁油、花生油、玉米油、米糠油、茶籽油、沙棘油、鳄梨油、石栗子油、胡桃油和可可油中的一种或几种。The vegetable oils and fats are selected from the group consisting of shea butter, macadamia nut oil, jojoba seed oil, olive oil, coconut oil, castor oil, cottonseed oil, soybean oil, sesame oil, almond oil, peanut oil, corn oil, rice bran oil, One or more of tea seed oil, sea buckthorn oil, avocado oil, chestnut oil, walnut oil and cocoa butter.

所述的多元醇类组分选自甘油或/和丙二醇。The polyol component is selected from glycerin or/and propylene glycol.

所述的不稳定易分解组分选自视黄醇棕榈酸酯和/或羟基频哪酮视磺酸酯。The unstable and easily decomposable component is selected from retinyl palmitate and/or hydroxypinacolone retinate.

所述的干燥后易成胶组分选自玻色因。The component that is easy to gel after drying is selected from Bose.

所述的维生素为维生素C及其盐；所述的增稠剂选自微生物胶、黄原胶和小核菌胶中的一种或几种；所述的活性成分为腺苷、生育酚乙酸酯、超氧化物歧化酶、透明质酸钠、花青素、水解人参皂苷类、积雪草提取物和赤芝提取物中的一种或几种。The vitamins are vitamin C and its salts; the thickening agent is selected from one or more of microbial gum, xanthan gum and sclerotinia gum; the active ingredients are adenosine, tocopherol B One or more of acid esters, superoxide dismutase, sodium hyaluronate, anthocyanins, hydrolyzed ginsenosides, centella asiatica extract and red ganoderma extract.

本发明还提供了上述冻干制剂的制备方法，包括以下步骤： The invention also provides a preparation method for the above freeze-dried preparation, which includes the following steps:

(1)取配方用量的骨架分子、大分子载体以及维生素、增稠剂或活性成分，混合均匀过筛，得到混合物；(1) Take the formula dosage of skeleton molecules, macromolecular carriers, vitamins, thickeners or active ingredients, mix them evenly and sieve to obtain a mixture;

(2)取配方用量的脂质体包埋加水溶解，得混合液；并将步骤(1)中的混合物加入混合液中，搅拌，得到冻干体系；(2) Take the prescribed amount of liposomes for embedding and dissolve in water to obtain a mixed solution; add the mixture in step (1) to the mixed solution and stir to obtain a freeze-dried system;

(3)将油脂类组分、多元醇类组分、不稳定易分解组分或干燥后易成胶组分加入步骤(2)的冻干体系中，超声(40℃，300W，30min)乳化，得到载有油脂的冻干体系；(3) Add oil components, polyol components, unstable and easy-to-decompose components or components that are easy to gel after drying into the freeze-drying system of step (2), and emulsify by ultrasonic (40°C, 300W, 30min) , to obtain a freeze-dried system containing oil;

(4)将步骤(3)中得到的载有油脂的冻干体系进行塑型，冻干处理后得到所述的冻干制剂；(4) Shape the freeze-dried system containing grease obtained in step (3), and obtain the freeze-dried preparation after freeze-drying;

所述的冻干包括预冻、升华和解析干燥三个步骤；The freeze-drying includes three steps: pre-freezing, sublimation and analytical drying;

所述的预冻操作为：开启冻干设备，使冷井温度由室温开始在40分钟左右达到-45℃以下，保持2小时；The described pre-freezing operation is: turn on the freeze-drying equipment, make the cold well temperature reach below -45°C from room temperature in about 40 minutes, and maintain it for 2 hours;

所述的升华分为三个阶段，具体操作为：The sublimation described is divided into three stages, and the specific operations are:

阶段一：冻干仓内温度在1小时内缓慢升温达到-30℃左右，真空度保持在1帕以下，保持3-5小时；Stage 1: The temperature in the freeze-drying chamber slowly rises to about -30°C within 1 hour, and the vacuum degree is kept below 1 Pa for 3-5 hours;

阶段二、冻干仓内温度在1小时内缓慢升温达到-10℃左右，真空度25-35帕，保持4-8小时；Stage 2: The temperature in the freeze-drying warehouse slowly rises to about -10°C within 1 hour, and the vacuum degree is 25-35 Pa, maintained for 4-8 hours;

阶段三、冻干仓内在1小时内缓慢升达到0℃左右，真空度35-45帕，保持1-2小时。Stage 3: The freeze-drying chamber slowly rises to about 0°C within 1 hour, with a vacuum degree of 35-45 Pa and maintained for 1-2 hours.

所述的解析干燥分为两个阶段，具体操作为：The analytical drying is divided into two stages, and the specific operations are:

阶段一：冻干仓内温度在1小时内达到5-15℃，真空度45-55帕，保持2-3小时；Stage 1: The temperature in the freeze-drying chamber reaches 5-15°C within 1 hour, and the vacuum degree is 45-55 Pa, maintained for 2-3 hours;

阶段二：冻干仓内温度在1小时内达到15-25℃，真空度下降至35-45帕，保持1-2小时。Stage 2: The temperature in the freeze-drying chamber reaches 15-25°C within 1 hour, and the vacuum degree drops to 35-45 Pa, and is maintained for 1-2 hours.

与现有技术相比，本发明的有益效果在于：Compared with the prior art, the beneficial effects of the present invention are:

(1)本发明提供了一种三元冻干组合物，该组合物能够实现对油脂类组分、多元醇类组分、不稳定易分解组分、干燥后易成胶组分的冻干，能够使油脂类组分的负载量最高达到75％，多元醇类的负载量最高达到15％，不稳定易分解物的负载量最高达到20％，干燥后易成胶类的负载量最高达到50％。(1) The present invention provides a ternary freeze-drying composition, which can freeze-dry oil components, polyol components, unstable and easily decomposed components, and components that are easy to form gel after drying. , it can make the loading capacity of grease components reach up to 75%, the loading capacity of polyols reach up to 15%, the loading capacity of unstable and easily decomposable substances reaches up to 20%, and the loading capacity of easily decomposed substances after drying can reach up to 20%. 50%.

(2)本发明采用骨架分子、大分子载体和脂质体包埋对有效成分进行冻干，不需要添加防腐剂，因此减少了因防腐剂引起的皮肤过敏等问题；并且本发明提供的冻干制剂稳定性好，整体水分含量少，重量减轻，便于携带及长途运输；(2) The present invention uses framework molecules, macromolecular carriers and liposomes to lyophilize the active ingredients. There is no need to add preservatives, thus reducing problems such as skin allergies caused by preservatives; and the freeze-dried preparation provided by the invention has good stability, low overall moisture content, reduced weight, and is easy to carry and long-distance transportation;

(3)本发明公开的冻干制剂可以根据需要进行个性化定制，市场接受度更广泛；使用时加入清水即可，冷冻干燥后溶解性更快，几秒内速溶，单次使用量设计，用完即抛，无交叉污染，使用更便捷的冻干产品(3) The freeze-dried preparation disclosed in the present invention can be customized according to needs, and has wider market acceptance; just add water when using it, the solubility is faster after freeze-drying, and it dissolves quickly within a few seconds. The single use amount is designed. Disposable after use, no cross-contamination, more convenient freeze-dried products to use

附图说明Description of drawings

图1为应用实施例1.1-1.8制备的冻干制剂，刀切面状态以及复溶状态图；Figure 1 is a diagram showing the freeze-dried preparation prepared in Examples 1.1-1.8, the cut surface state and the reconstituted state;

图2为应用实施例1.1-1.8制备的冻干制剂40℃高温放置以及室温放置2周后效果图；Figure 2 is a diagram showing the effect of the freeze-dried preparation prepared in Example 1.1-1.8 after being placed at high temperature at 40°C and at room temperature for 2 weeks;

图3为应用实施例2.1-2.8制备的冻干制剂，刀切面状态以及复溶状态图；Figure 3 is a diagram of the freeze-dried preparation prepared in Examples 2.1-2.8, the cut surface state and the reconstituted state;

图4为应用实施例3.1-3.8制备的冻干制剂，刀切面状态以及复溶状态图；Figure 4 is a diagram of the freeze-dried preparation prepared in Examples 3.1-3.8, the cut surface state and the reconstituted state;

图5为应用实施例4.1-4.8制备的冻干制剂，刀切面状态以及复溶状态图；Figure 5 is a diagram of the freeze-dried preparation prepared in Examples 4.1-4.8, the cut surface state and the reconstituted state;

图6为应用实施例5.1-5.8制备的冻干制剂，刀切面状态以及复溶状态图；Figure 6 is a diagram of the freeze-dried preparation prepared in Examples 5.1-5.8, the cut surface state and the reconstituted state;

图7为应用实施例6.1-6.8制备的冻干制剂，刀切面状态以及复溶状态图；Figure 7 is a diagram of the freeze-dried preparation prepared in Examples 6.1-6.8, the cut surface state and the reconstituted state;

图8为应用实施例1-6制备的冻干制剂中各组分最大负载量比较图；Figure 8 is a comparison chart of the maximum loading capacity of each component in the freeze-dried preparations prepared in Examples 1-6;

图9为应用实施例1.7制备的冻干制剂冷冻干燥前后羟基频哪酮视黄酸酯(HPR)HPLC图谱；Figure 9 is the HPLC spectrum of hydroxypinacolone retinoate (HPR) before and after freeze-drying of the freeze-dried preparation prepared in Example 1.7;

其中A为HPR标准品HPLC图谱，B为制剂冻干前的HPLC图谱，C为冻干制剂的HPLC图谱；Among them, A is the HPLC spectrum of the HPR standard, B is the HPLC spectrum of the preparation before freeze-drying, and C is the HPLC spectrum of the freeze-dried preparation;

图10为应用实施例1.6制备的冻干制剂冷冻干燥后及冷冻干燥后40℃高温处理2周后视黄醇棕榈酸酯含量HPLC图；Figure 10 is an HPLC chart of the content of retinyl palmitate in the freeze-dried preparation prepared in Example 1.6 after freeze-drying and high-temperature treatment at 40°C for 2 weeks after freeze-drying;

其中，A为视黄醇棕榈酸酯标准品HPLC图谱，B为冻干制剂的HPLC图谱，C为冻干制剂40℃高温处理2周后的HPLC图谱；Among them, A is the HPLC spectrum of the retinyl palmitate standard, B is the HPLC spectrum of the freeze-dried preparation, and C is the HPLC spectrum of the freeze-dried preparation after high temperature treatment at 40°C for 2 weeks;

图11为应用实施例7制备的冻干面膜制剂以及复溶后的状态图；Figure 11 is a diagram of the freeze-dried facial mask preparation prepared in Example 7 and its state after reconstitution;

图12为应用对比例1所述制剂溶解状态图及制备的冻干制剂；Figure 12 is a diagram showing the dissolution state of the preparation described in Comparative Example 1 and the prepared freeze-dried preparation;

图13为应用对比例2所述制剂溶解状态图；Figure 13 is a diagram showing the dissolution state of the preparation described in Comparative Example 2;

图14为应用对比例3所述制剂溶解状态图。Figure 14 is a diagram showing the dissolution state of the preparation described in Comparative Example 3.

具体实施方式Detailed ways

本发明中提到的上述特征，或实施例提到的特征可以任意组合。本案说明书所解释的所有特征可与任意方法形式并用，说明书中揭示的各个特征，可被任何可提供相同、均等或相似目的的取代性特征取代。因此除有特殊说明，所揭示的特征仅为均等或相似特征的一般性例子。The above-mentioned features mentioned in the present invention or the features mentioned in the embodiments may be combined in any combination. All the features explained in the description of this case can be used with any method form, and each feature disclosed in the description can be used by any method. Substitute features may be substituted that serve the same, equivalent or similar purpose. Therefore, unless otherwise stated, the disclosed features are only general examples of equivalent or similar features.

下面结合具体实施例，进一步阐述本发明。这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中为注明具体条件的实施方法，通常按照常规条件或按照制造厂商所建议的条件。除非特殊说明，否则所有的百分比和分数按重量计。The present invention will be further described below in conjunction with specific embodiments. These examples are only used to illustrate the invention and are not intended to limit the scope of the invention. The following examples indicate implementation methods under specific conditions, usually in accordance with conventional conditions or conditions recommended by the manufacturer. All percentages and fractions are by weight unless otherwise stated.

除非另行定义，文中所使用的所有专业与科学用语与本领域技术人员所熟知的意义相同。此外，任何与所记载内容相似或均等的方法及材料皆可应用于本发明方法中。文中所述的优选实施方法与材料仅做示范作用。Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. In addition, any methods and materials similar or equivalent to those described can be used in the method of the present invention. The preferred implementation methods and materials described herein are for exemplary purposes only.

本申请实验过程中使用的原料以及仪器的购买厂家以及型号如下：

The purchasing manufacturers and models of the raw materials and instruments used in the experiment of this application are as follows:

实施例1-6一种三元冻干组合物Example 1-6 A ternary freeze-dried composition

按重量百分含量计，包括如下组分：
In terms of weight percentage, it includes the following components:

应用实施例1.1-1.8一种冻干制剂及其制备方法Application Examples 1.1-1.8 A freeze-dried preparation and its preparation method

按重量份数计，包括以下组分：
In parts by weight, it includes the following components:

应用实施例1.1所述的冻干制剂的制备方法：(1)取配方用量的甘氨酸、丝心蛋白、酪蛋白酸钠、黄原胶和花青素，混合均匀过150目筛，得到混合物；The preparation method of the freeze-dried preparation described in Application Example 1.1: (1) Take the formula amount of glycine, Silk fibroin, sodium caseinate, xanthan gum and anthocyanins are evenly mixed and passed through a 150 mesh sieve to obtain a mixture;

(2)取配方用量的大豆卵磷脂加水溶解，得混合液；并将步骤(1)中的混合物加入混合液中，搅拌，得到冻干体系；(2) Take the formula amount of soy lecithin and dissolve it in water to obtain a mixed solution; add the mixture in step (1) to the mixed solution and stir to obtain a freeze-dried system;

(3)将动物源黄油加热融化后加入步骤(2)的冻干体系中，超声(40℃，300W)乳化30min，得到载有黄油的冻干体系；(3) Heat and melt the animal-derived butter, add it to the freeze-drying system in step (2), and emulsify with ultrasonic (40°C, 300W) for 30 minutes to obtain a butter-loaded freeze-drying system;

(4)将步骤(3)中得到的载有黄油的冻干体系倒入模具中，进行塑型，然后冻干处理后得到所述的冻干制剂。(4) Pour the freeze-dried system containing butter obtained in step (3) into a mold, perform shaping, and then freeze-dry to obtain the freeze-dried preparation.

阶段一：冻干仓内温度在1小时内缓慢升温达到-30℃，真空度保持在1帕以下，保持5小时；Stage 1: The temperature in the freeze-drying chamber slowly rises to -30°C within 1 hour, and the vacuum degree is kept below 1 Pa for 5 hours;

阶段二、冻干仓内温度在1小时内缓慢升温达到-10℃，真空度25-35帕，保持8小时；Stage 2: The temperature in the freeze-drying chamber slowly rises to -10°C within 1 hour, and the vacuum degree is 25-35 Pa, maintained for 8 hours;

阶段三、冻干仓内在1小时内缓慢升达到0℃，真空度35-45帕，保持2小时。Stage 3: The freeze-drying chamber slowly rises to 0°C within 1 hour, with a vacuum degree of 35-45 Pa and maintained for 2 hours.

阶段一：冻干仓内温度在1小时内达到5-15℃，真空度45-55帕，保持3小时；Stage 1: The temperature in the freeze-drying chamber reaches 5-15°C within 1 hour, and the vacuum degree is 45-55 Pa, maintained for 3 hours;

阶段二：冻干仓内温度在1小时内达到15-25℃，真空度下降至35-45帕，保持2小时。Stage 2: The temperature in the freeze-drying chamber reaches 15-25°C within 1 hour, and the vacuum degree drops to 35-45 Pa and is maintained for 2 hours.

应用实施例1.2-1.8所述的制备方法除步骤(3)中所加入组分不同外，其他操作均与应用实施例1.1制备方法相同。Except for the different components added in step (3), the preparation methods described in Application Examples 1.2-1.8 are the same as the preparation methods in Application Example 1.1.

如附图1所示，针对上述应用实施例1.1-1.8制备了冻干样品，得到的冻干球成型好，形态完整，表面光滑；刀切面层呈叠片状；复水较快，2分钟内可溶解，呈乳化效果较好的乳浊液。As shown in Figure 1, freeze-dried samples were prepared for the above-mentioned application examples 1.1-1.8. The obtained freeze-dried balls were well formed, complete in shape, and smooth in surface; the knife-cut surface layers were in the shape of laminated sheets; the rehydration was fast, 2 It can dissolve within minutes and form an emulsion with good emulsification effect.

试验例1-1乳化值OD500检测Test Example 1-1 Emulsification value OD500 detection

根据蛋白质乳液乳化稳定性的评价检测方法-乳化活力指数，检测样品在500nm处的吸光值，可关联评定其乳化性及稳定性；应用实施例1.1-1.8中制备的冻干制剂及冷冻干燥后复溶于水检测其OD500值，其结果如下表1所示。According to the evaluation and detection method of protein emulsion emulsification stability - emulsification activity index, the absorbance value of the sample at 500nm can be detected to evaluate its emulsification and stability; prepared in Application Examples 1.1-1.8 The freeze-dried preparation was re-dissolved in water after freeze-drying to detect its OD500 value. The results are shown in Table 1 below.

表1
Table 1

结论：应用实施例1.1-1.8中制备的冻干制剂及冷冻干燥后复溶于水的OD500值，变化范围在±5％之内，说明复水后乳化效果较好，乳化稳定性较好。Conclusion: The OD500 value of the freeze-dried preparation prepared in Examples 1.1-1.8 and reconstituted in water after freeze-drying was within ±5%, indicating that the emulsification effect and emulsification stability after rehydration were better.

试验例1-2高温稳定性试验Test Example 1-2 High Temperature Stability Test

参见附图2，应用实施例1.1-1.8制备的冻干制剂，冷冻干燥后每种取3瓶放入40℃高温处理2周，2周后取出，与室温放置2周后的样品进行对比，颜色形态无变化，说明具有高温稳定性。Referring to Figure 2, use the freeze-dried preparations prepared in Examples 1.1-1.8. After freeze-drying, take 3 bottles of each type and place them in a high temperature treatment of 40°C for 2 weeks. Take them out after 2 weeks and compare them with the samples left at room temperature for 2 weeks. There is no change in color and form, indicating high temperature stability.

试验例1-3最高负载量检测Test Example 1-3 Maximum load detection

最大负载量的判定标准是：冻干球成型好，表面光滑无液态物；复水后为乳浊液，无油滴，不分层。The criterion for determining the maximum loading capacity is: the freeze-dried spheres are well formed, with a smooth surface and no liquid matter; after rehydration, they become emulsions with no oil droplets and no stratification.

针对实施例1中记载的冻干组合物的最高负载量进行了检测，实施例1制备的冻干组合物针对动物源黄油的最大负载量是20％；针对乳木果油的最大负载量是1％；针对夏威夷果油的最大负载量是20％；针对甘油的最大负载量是3％；针对丙二醇的最大负载量是3％；针对视黄醇棕榈酸酯的最大负载量是1％；针对HPR的最大负载量是1％；针对玻色因的最大负载量是10％。The maximum loading capacity of the freeze-dried composition recorded in Example 1 was tested. The maximum loading capacity of the freeze-dried composition prepared in Example 1 for animal-derived butter was 20%; the maximum loading capacity for shea butter was 1%; maximum loading for macadamia oil is 20%; maximum loading for glycerin is 3%; maximum loading for propylene glycol is 3%; maximum loading for retinyl palmitate is 1%; The maximum loading for HPR is 1%; the maximum loading for Bose is 10%.

应用实施例2.1-2.8一种冻干制剂及其制备方法Application Examples 2.1-2.8 A freeze-dried preparation and its preparation method

应用实施例2.1所述的冻干制剂的制备方法：(1)取配方用量的甘氨酸、甘露醇、丝心蛋白、硬脂酸甘油酯、胶原蛋白、黄原胶和花青素，混合均匀过150目筛，得到混合物；The preparation method of the freeze-dried preparation described in Example 2.1: (1) Take the formula amount of glycine, mannitol, fibroin, glyceryl stearate, collagen, xanthan gum and anthocyanins, mix them evenly and Sieve with 150 mesh to obtain the mixture;

(2)取配方用量的大豆卵磷脂和氢化卵磷脂加水溶解，得混合液；并将步骤(1)中的混合物加入混合液中，搅拌，得到冻干体系；(2) Dissolve the formula amount of soybean lecithin and hydrogenated lecithin in water to obtain a mixed solution; add the mixture in step (1) to the mixed solution and stir to obtain a freeze-dried system;

(3)将动物源黄油隔水加热融化后加入步骤(2)的冻干体系中，超声(40℃，300W)乳化30min，，得到载有黄油的冻干体系；(3) Heat and melt the animal-derived butter in water, add it to the freeze-drying system in step (2), and emulsify with ultrasonic (40°C, 300W) for 30 minutes to obtain a freeze-drying system containing butter;

阶段一：冻干仓内温度在1小时内缓慢升温达到-30℃，真空度保持在1帕以下，保持3小时；Stage 1: The temperature in the freeze-drying chamber slowly rises to -30°C within 1 hour, and the vacuum degree is kept below 1 Pa for 3 hours;

阶段二、冻干仓内温度在1小时内缓慢升温达到-10℃，真空度25-35帕，保持4小时；Stage 2: The temperature in the freeze-drying chamber slowly rises to -10°C within 1 hour, and the vacuum degree is 25-35 Pa, maintained for 4 hours;

阶段三、冻干仓内在1小时内缓慢升达到0℃，真空度35-45帕，保持1小时。Stage 3: The freeze-drying chamber slowly rises to 0°C within 1 hour, and the vacuum degree is 35-45 Pa, maintained for 1 hour.

阶段一：冻干仓内温度在1小时内达到5-15℃，真空度45-55帕，保持2小时； Stage 1: The temperature in the freeze-drying chamber reaches 5-15°C within 1 hour, and the vacuum degree is 45-55 Pa, maintained for 2 hours;

阶段二：冻干仓内温度在1小时内达到15-25℃，真空度下降至35-45帕，保持1小时。Stage 2: The temperature in the freeze-drying chamber reaches 15-25°C within 1 hour, and the vacuum degree drops to 35-45 Pa and is maintained for 1 hour.

应用实施例2.2-2.8所述的制备方法除步骤(3)中所加入组分不同外，其他操作均与应用实施例2.1制备方法相同。The preparation method described in Application Examples 2.2-2.8 is the same as the preparation method in Application Example 2.1 except that the components added in step (3) are different.

如附图3所示，针对上述应用实施例2.1-2.8制备了冻干样品，得到的冻干球成型好，形态完整，表面光滑；刀切面层呈叠片状；复水较快，2分钟内可溶解，呈乳化效果较好的乳浊液。As shown in Figure 3, freeze-dried samples were prepared for the above application examples 2.1-2.8. The obtained freeze-dried balls were well formed, complete in shape, and smooth on the surface; the knife-cut surface layers were in the shape of laminated sheets; the rehydration was fast, 2 It can dissolve within minutes and form an emulsion with good emulsification effect.

试验例2-1乳化值OD500检测Test Example 2-1 Emulsification value OD500 detection

根据蛋白质乳液乳化稳定性的评价检测方法-乳化活力指数，检测样品在500nm处的吸光值，可关联评定其乳化性及稳定性；应用实施例2.1-2.8中制备的冻干制剂及冷冻干燥后复溶于水检测其OD500值，其结果如下表2所示。According to the evaluation and detection method of protein emulsion emulsification stability - emulsification activity index, the absorbance value of the sample at 500 nm can be detected to evaluate its emulsification and stability; after applying the freeze-dried preparation prepared in Examples 2.1-2.8 and freeze-drying Re-dissolve in water and detect its OD500 value. The results are shown in Table 2 below.

表2
Table 2

结论：应用实施例2.1-2.8中制备的冻干制剂及冷冻干燥后复溶于水的OD500值，变化范围在±5％之内，说明复水后乳化效果较好，乳化稳定性较好。Conclusion: The OD500 value of the freeze-dried preparation prepared in Examples 2.1-2.8 and reconstituted in water after freeze-drying was within ±5%, indicating that the emulsification effect and emulsification stability after rehydration were better.

试验例2-2最大负载量检测Test Example 2-2 Maximum load detection

针对实施例2中记载的冻干组合物的最高负载量进行了检测，实施例2中所述的冻干组合物针对动物源黄油的最大负载量是30％；针对乳木果油的最大负载量是5％；针对夏威夷果油的最大负载量是30％；针对甘油的最大负载量是5％；针对丙二醇的最大负载量是5％；针对视黄醇棕榈酸酯的最大负载量是3％；针对HPR的最大负载量是3％；针对玻色因的最大负载量是20％。The maximum loading capacity of the freeze-dried composition described in Example 2 was tested. The maximum loading capacity of the freeze-dried composition described in Example 2 for animal-derived butter was 30%; the maximum loading capacity for shea butter was Amount is 5%; maximum loading for macadamia oil is 30%; maximum loading for glycerin is 5%; maximum loading for propylene glycol is 5%; maximum loading for retinyl palmitate is 3 %; the maximum loading for HPR is 3%; the maximum loading for Boseine is 20%.

应用实施例3.1-3.8一种冻干制剂及其制备方法 Application Examples 3.1-3.8 A freeze-dried preparation and its preparation method

应用实施例3.1所述的冻干制剂的制备方法：(1)取配方用量的甘氨酸、海藻糖、甘露醇、鼠李糖、丝心蛋白、酪蛋白酸钠、硬脂酸甘油酯、乳清蛋白、黄原胶和花青素，混合均匀过150目筛，得到混合物；The preparation method of the freeze-dried preparation described in Example 3.1: (1) Take the formula dosage of glycine, trehalose, mannitol, rhamnose, fibroin, sodium caseinate, glyceryl stearate, and whey Mix egg whites, xanthan gum and anthocyanins evenly and pass through a 150 mesh sieve to obtain a mixture;

(3)将动物源黄油隔水加热融化后加入步骤(2)的冻干体系中，超声(40℃，300W)乳化30min，得到载有黄油的冻干体系；(3) Heat and melt the animal-derived butter in water, add it to the freeze-drying system in step (2), and emulsify with ultrasonic (40°C, 300W) for 30 minutes to obtain a freeze-drying system containing butter;

阶段二、冻干仓内温度在1小时内缓慢升温达到-10℃，真空度25-35帕，保持4小时； Stage 2: The temperature in the freeze-drying chamber slowly rises to -10°C within 1 hour, and the vacuum degree is 25-35 Pa, maintained for 4 hours;

阶段一：冻干仓内温度在1小时内达到5-15℃，真空度45-55帕，保持2小时；Stage 1: The temperature in the freeze-drying chamber reaches 5-15°C within 1 hour, and the vacuum degree is 45-55 Pa, maintained for 2 hours;

应用实施例3.2-3.8所述的制备方法除步骤(3)中所加入组分不同外，其他操作均与应用实施例3.1制备方法相同。Except for the different components added in step (3), the preparation methods described in Application Examples 3.2-3.8 are the same as the preparation methods in Application Example 3.1.

如附图4所示，针对上述应用实施例3.1-3.8制备了冻干样品，得到的冻干球成型好，形态完整，表面光滑；刀切面层呈叠片状；复水较快，2分钟内可溶解，呈乳化效果较好的乳浊液。As shown in Figure 4, freeze-dried samples were prepared for the above-mentioned application examples 3.1-3.8. The obtained freeze-dried balls were well formed, complete in shape, and smooth in surface; the knife-cut surface layers were in the shape of laminated sheets; the rehydration was fast, 2 It can dissolve within minutes and form an emulsion with good emulsification effect.

试验例3-1乳化值OD500检测Test Example 3-1 Emulsification value OD500 detection

根据蛋白质乳液乳化稳定性的评价检测方法-乳化活力指数，检测样品在500nm处的吸光值，可关联评定其乳化性及稳定性；应用实施例3.1-3.8中制备的冻干制剂及冷冻干燥后复溶于水检测其OD500值，其结果如下表3所示。According to the evaluation and detection method of protein emulsion emulsification stability - emulsification activity index, the absorbance value of the sample at 500nm can be detected to evaluate its emulsification and stability; after applying the freeze-dried preparation prepared in Examples 3.1-3.8 and freeze-drying Re-dissolve in water and detect its OD500 value. The results are shown in Table 3 below.

表3
table 3

结论：应用实施例3.1-3.8中制备的冻干制剂及冷冻干燥后复溶于水的OD500值，变化范围在±5％之内，说明复水后乳化效果较好，乳化稳定性较好。Conclusion: The OD500 value of the freeze-dried preparation prepared in Examples 3.1-3.8 and reconstituted in water after freeze-drying was within ±5%, indicating that the emulsification effect and emulsification stability were better after rehydration.

试验例3-2最大负载量检测Test Example 3-2 Maximum load detection

实施例3中记载的冻干组合物针对动物源黄油的最大负载量是50％；针对乳木果油的最大负载量是5％；针对夏威夷果油的最大负载量是50％；针对甘油的最大负载量是10％；针对丙二醇的最大负载量是10％；针对视黄醇棕榈酸酯的最大负载量是5％；针对HPR的最大负载量是5％；针对玻色因的最大负载量是20％。The maximum loading capacity of the freeze-dried composition described in Example 3 for animal-derived butter is 50%; for milk Maximum loading for Aroma Oil is 5%; Maximum loading for Macadamia Nut Oil is 50%; Maximum loading for Glycerin is 10%; Maximum loading for Propylene Glycol is 10%; Maximum loading for Retinyl Palmitate The maximum loading for HPR is 5%; for Boseine the maximum loading is 20%.

应用实施例4.1-4.8一种冻干制剂及其制备方法Application Examples 4.1-4.8 A freeze-dried preparation and its preparation method

应用实施例4.1所述的冻干制剂的制备方法：(1)取配方用量的甘氨酸、海藻糖、水解木聚糖、甘露醇、丝心蛋白、酪蛋白酸钠、硬脂酸甘油酯、胶原蛋白、乳清蛋白、黄原胶和花青素，混合均匀过150目筛，得到混合物；The preparation method of the freeze-dried preparation described in Example 4.1: (1) Take the formula dosage of glycine, trehalose, hydrolyzed xylan, mannitol, fibroin, sodium caseinate, glyceryl stearate, collagen Mix egg white, whey protein, xanthan gum and anthocyanins evenly and pass through a 150 mesh sieve to obtain a mixture;

所述的预冻操作为：开启冻干设备，使冷井温度由室温开始在40分钟左右达到-45℃以下，保持2小时；The described pre-freezing operation is: turn on the freeze-drying equipment and make the cold well temperature start from room temperature for about 40 minutes. Reach below -45℃ and keep for 2 hours;

应用实施例4.2-4.8所述的制备方法除步骤(3)中所加入组分不同外，其他操作均与应用实施例4.1制备方法相同。Except for the different components added in step (3), the preparation methods described in Application Examples 4.2-4.8 are the same as the preparation methods in Application Example 4.1.

如附图5所示，针对上述应用实施例4.1-4.8制备了冻干样品，得到的冻干球成型好，形态完整，表面光滑；刀切面层呈叠片状；复水较快，2分钟内可溶解，呈乳化效果较好的乳浊液。As shown in Figure 5, freeze-dried samples were prepared for the above-mentioned application examples 4.1-4.8. The obtained freeze-dried balls were well formed, complete in shape, and smooth in surface; the knife-cut surface layers were in the shape of laminated sheets; the rehydration was fast, 2 It can dissolve within minutes and form an emulsion with good emulsification effect.

试验例4-1乳化值OD500检测Test Example 4-1 Emulsification value OD500 detection

根据蛋白质乳液乳化稳定性的评价检测方法-乳化活力指数，检测样品在500nm处的吸光值，可关联评定其乳化性及稳定性；应用实施例4.1-4.8中制备的冻干制剂及冷冻干燥后复溶于水检测其OD500值，其结果如下表4所示。According to the evaluation and detection method of protein emulsion emulsification stability - emulsification activity index, the absorbance value of the sample at 500nm can be detected to evaluate its emulsification and stability; after applying the freeze-dried preparation prepared in Examples 4.1-4.8 and freeze-drying Re-dissolve in water and detect its OD500 value. The results are shown in Table 4 below.

表4
Table 4

结论：应用实施例4.1-4.8中制备的冻干制剂及冷冻干燥后复溶于水的OD500值，变化范围在±5％之内，说明复水后乳化效果较好，乳化稳定性较好。Conclusion: The OD500 value of the freeze-dried preparations prepared in Examples 4.1-4.8 and reconstituted in water after freeze-drying was within ±5%, indicating that the emulsification effect and emulsification stability were better after rehydration.

试验例4-2最大负载量检测Test Example 4-2 Maximum load detection

实施例4中所述的冻干组合物针对动物源黄油的最大负载量是50％；针对乳木果油的最大负载量是5％；针对夏威夷果油的最大负载量是50％；针对甘油的最大负载量是10％；针对丙二醇的最大负载量是10％；针对视黄醇棕榈酸酯的最大负载量是5％；针对HPR的最大负载量是5％；针对玻色因的最大负载量是30％。The maximum loading capacity of the freeze-dried composition described in Example 4 is 50% for animal-derived butter; the maximum loading capacity for shea butter is 5%; the maximum loading capacity for macadamia nut oil is 50%; and the maximum loading capacity for glycerin The maximum loading is 10%; the maximum loading for propylene glycol is 10%; the maximum loading for retinyl palmitate is 5%; the maximum loading for HPR is 5%; the maximum loading for Bosein The amount is 30%.

应用实施例5.1-5.8一种冻干制剂及其制备方法Application Examples 5.1-5.8 A freeze-dried preparation and its preparation method

应用实施例5.1所述的冻干制剂的制备方法：(1)取配方用量的甘氨酸、海藻糖、水解木聚糖、甘露醇、鼠李糖、丝心蛋白、酪蛋白酸钠、硬脂酸甘油酯、胶原蛋白、乳清蛋白、黄原胶和花青素，混合均匀过150目筛，得到混合物；The preparation method of the freeze-dried preparation described in Example 5.1: (1) Take the formula dosage of glycine, trehalose, hydrolyzed xylan, mannitol, rhamnose, fibroin, sodium caseinate, and stearic acid Glycerides, collagen, whey protein, xanthan gum and anthocyanins are mixed evenly and passed through a 150 mesh sieve to obtain a mixture;

(2)取配方用量的大豆卵磷脂和氢化卵磷脂加水溶解，得混合液；并将步骤(1)中的混合物加入混合液中，搅拌，得到冻干体系； (2) Dissolve the formula amount of soybean lecithin and hydrogenated lecithin in water to obtain a mixed solution; add the mixture in step (1) to the mixed solution and stir to obtain a freeze-dried system;

应用实施例5.2-5.8所述的制备方法除步骤(3)中所加入组分不同外，其他操作均与应用实施例5.1制备方法相同。Except for the different components added in step (3), the preparation methods described in Application Examples 5.2-5.8 are the same as the preparation methods in Application Example 5.1.

如附图6所示，针对上述应用实施例5.1-5.8制备了冻干样品，得到的冻干球成型好，形态完整，表面光滑；刀切面层呈叠片状；复水较快，2分钟内可溶解，呈乳化效果较好的乳浊液。As shown in Figure 6, freeze-dried samples were prepared for the above-mentioned application examples 5.1-5.8. The obtained freeze-dried balls were well formed, complete in shape, and smooth in surface; the knife-cut surface layers were in the shape of laminated sheets; the rehydration was fast, 2 It can dissolve within minutes and form an emulsion with good emulsification effect.

试验例5-1乳化值OD500检测Test Example 5-1 Emulsification value OD500 detection

根据蛋白质乳液乳化稳定性的评价检测方法-乳化活力指数，检测样品在500nm处的吸光值，可关联评定其乳化性及稳定性；应用实施例5.1-5.8中制备的冻干制剂及冷冻干燥后复溶于水检测其OD500值，其结果如下表5所示。According to the evaluation and detection method of protein emulsion emulsification stability - emulsification activity index, the absorbance value of the sample at 500 nm can be detected to evaluate its emulsification and stability; after applying the freeze-dried preparation prepared in Examples 5.1-5.8 and freeze-drying Re-dissolve in water and detect its OD500 value. The results are shown in Table 5 below.

表5

table 5

结论：应用实施例5.1-5.8中制备的冻干制剂及冷冻干燥后复溶于水的OD500值，变化范围在±5％之内，说明复水后乳化效果较好，乳化稳定性较好。Conclusion: The OD500 value of the freeze-dried preparation prepared in Examples 5.1-5.8 and reconstituted in water after freeze-drying was within ±5%, indicating that the emulsification effect after rehydration is better and the emulsion stability is better.

试验例5-2最大负载量检测Test Example 5-2 Maximum load detection

实施例5中所述的冻干组合物针对动物源黄油的最大负载量是75％；针对乳木果油的最大负载量是10％；针对夏威夷果油的最大负载量是75％；针对甘油的最大负载量是15％；针对丙二醇的最大负载量是15％；针对视黄醇棕榈酸酯的最大负载量是20％；针对HPR的最大负载量是20％；针对玻色因的最大负载量是50％。The maximum loading capacity of the freeze-dried composition described in Example 5 is 75% for animal-derived butter; the maximum loading capacity for shea butter is 10%; the maximum loading capacity for macadamia nut oil is 75%; and the maximum loading capacity for glycerin The maximum loading is 15% for propylene glycol; the maximum loading for retinyl palmitate is 20%; the maximum loading for HPR is 20%; the maximum loading for Bosein The amount is 50%.

应用实施例6.1-6.8一种冻干制剂及其制备方法Application Examples 6.1-6.8 A freeze-dried preparation and its preparation method

应用实施例6.1所述的冻干制剂的制备方法：(1)取配方用量的甘氨酸、海藻糖、水解木聚糖、甘露醇、鼠李糖、丝心蛋白、酪蛋白酸钠、硬脂酸甘油酯、胶原蛋白、乳清蛋白、黄原胶和花青素，混合均匀过150目筛，得到混合物；The preparation method of the freeze-dried preparation described in Example 6.1: (1) Take the formula dosage of glycine, trehalose, hydrolyzed xylan, mannitol, rhamnose, fibroin, sodium caseinate, and stearic acid Glycerides, collagen, whey protein, xanthan gum and anthocyanins are mixed evenly and passed through a 150 mesh sieve to obtain a mixture;

应用实施例6.2-6.8所述的制备方法除步骤(3)中所加入组分不同外，其他操作均与应用实施例6.1制备方法相同。Except for the different components added in step (3), the preparation methods described in Application Examples 6.2-6.8 are the same as the preparation methods in Application Example 6.1.

如附图7所示，针对上述应用实施例6.1-6.8制备了冻干样品，得到的冻干球成型好，形态完整，表面光滑；刀切面层呈叠片状；复水较快，2分钟内可溶解，呈乳化效果较好的乳浊液。 As shown in Figure 7, freeze-dried samples were prepared for the above-mentioned application examples 6.1-6.8. The obtained freeze-dried balls were well formed, complete in shape, and smooth in surface; the knife-cut surface layers were in the shape of laminated sheets; the rehydration was fast, 2 It can dissolve within minutes and form an emulsion with good emulsification effect.

试验例6-1乳化值OD500检测Test Example 6-1 Emulsification value OD500 detection

根据蛋白质乳液乳化稳定性的评价检测方法-乳化活力指数，检测样品在500nm处的吸光值，可关联评定其乳化性及稳定性；应用实施例6.1-6.8中制备的冻干制剂及冷冻干燥后复溶于水检测其OD500值，其结果如下表6所示。According to the evaluation and detection method of protein emulsion emulsification stability - emulsification activity index, the absorbance value of the sample at 500 nm can be detected to evaluate its emulsification and stability; after applying the freeze-dried preparation prepared in Examples 6.1-6.8 and freeze-drying Re-dissolve in water and detect its OD500 value. The results are shown in Table 6 below.

表6
Table 6

结论：应用实施例6.1-6.8中制备的冻干制剂及冷冻干燥后复溶于水的OD500值，变化范围在±5％之内，说明复水后乳化效果较好，乳化稳定性较好。Conclusion: The OD500 value of the freeze-dried preparations prepared in Examples 6.1-6.8 and reconstituted in water after freeze-drying was within ±5%, indicating that the emulsification effect and emulsification stability after rehydration were better.

试验例6-2最大负载量检测Test Example 6-2 Maximum load detection

实施例6中所述的冻干组合物针对动物源黄油的最大负载量是50％；针对乳木果油的最大负载量是5％；针对夏威夷果油的最大负载量是50％；针对甘油的最大负载量是10％；针对丙二醇的最大负载量是10％；针对视黄醇棕榈酸酯的最大负载量是10％；针对HPR的最大负载量是10％；针对玻色因的最大负载量是30％。The maximum loading capacity of the freeze-dried composition described in Example 6 is 50% for animal-derived butter; the maximum loading capacity for shea butter is 5%; the maximum loading capacity for macadamia nut oil is 50%; and the maximum loading capacity for glycerin The maximum loading is 10% for Propylene Glycol; the maximum loading for Retinyl Palmitate is 10%; the maximum loading for HPR is 10%; the maximum loading for Bosein The amount is 30%.

为了进一步验证，本申请其他应用实施例制备的冻干制剂具有较好的高温稳定性，针对应用实施例2.1-6.8制备的冻干制剂进行了高温稳定性测试，将应用实施例2.1-6.8制备的冻干制剂冷冻干燥后每种取3瓶放入40℃高温处理2周，2周后取出，与室温放置2周后的样品进行对比，与应用实施例1.1-1.8状态相同，颜色形态无变化，说明冻干制剂具有高温稳定性。In order to further verify that the freeze-dried preparations prepared in other application examples of this application have good high-temperature stability, a high-temperature stability test was conducted on the freeze-dried preparations prepared in application examples 2.1-6.8. After freeze-drying, 3 bottles of each kind of freeze-dried preparation were taken and treated at 40°C for 2 weeks. After 2 weeks, they were taken out and compared with the samples left at room temperature for 2 weeks. The state was the same as that of Application Examples 1.1-1.8, but the color and shape were the same. changes, indicating that the freeze-dried preparation has high temperature stability.

根据附图8可以看出，骨架分子、脂质体包埋和大分子载体的具体组分对油脂类组分、多元醇类组分、不稳定易分解组分、干燥后易成胶组分的负载量具有较大影响，实施例1中以甘氨酸为骨架分子，大豆卵磷脂为脂质体包埋，以丝心蛋白和酪蛋白酸钠为大分子载体，得到的冻干组合物对于油脂类组分、多元醇类组分、不稳定易分解组分、干燥后易成胶组分的负载量较少；实施例2以甘氨酸和甘露醇为骨架分子，大豆卵磷脂和氢化卵磷脂为脂质体包埋，以丝心蛋白、硬脂酸酐油脂和胶原蛋白为大分子载体，得到的冻干组合物对于油脂类组分、多元醇类组分、不稳定易分解组分、干燥后易成胶组分的负载量较实施例1有所提高，但是依然比较低；实施例3和实施例4，增加了多种组分，得到的冻干组合物油脂类组分、多元醇类组分、不稳定易分解组分、干燥后易成胶组分的负载量实施例1-2明显提高；实施例5通过控制骨架分子为质量比为3:3:3:3:1的甘氨酸、海藻糖、水解木聚糖、甘露醇和鼠李糖；脂质体包埋为质量比1:4大豆卵磷脂和氢化卵磷脂；大分子载体为质量比1:4:4:0.5:0.5丝心蛋白、酪蛋白酸钠、硬脂酸甘油酯、胶原蛋白和乳清蛋白得到的冻干组合物，能够明显提高油脂类组分、多元醇类组分、不稳定易分解组分和干燥后易成胶组分的负载量；实施例6中公开的冻干组合物的组分与实施例5相同，且骨架分子、脂质体包埋和大分子载体的含量与实施例5相同，但是由于各组分之间的配比不同，明显降低了对油脂类组分、多元醇类组分、不稳定易分解组分和干燥后易成胶组分的负载量。According to Figure 8, it can be seen that the specific components of skeleton molecules, liposome encapsulation and macromolecular carriers have a significant impact on oil components, polyol components, unstable components that are easily decomposed, and components that are prone to gelation after drying. The loading amount has a greater impact. In Example 1, glycine is used as the backbone molecule, soy lecithin is embedded in liposomes, and silk core Protein and sodium caseinate are macromolecular carriers, and the obtained freeze-dried composition has less loading capacity for oil components, polyol components, unstable components that are easily decomposed, and components that are prone to gelation after drying; Implementation Example 2: Glycine and mannitol are used as skeleton molecules, soy lecithin and hydrogenated lecithin are embedded in liposomes, and fibroin, stearic anhydride oil and collagen are used as macromolecular carriers. The resulting freeze-dried composition The loading of components, polyol components, unstable and easily decomposed components, and components that are easy to gel after drying has increased compared with Example 1, but is still relatively low; Examples 3 and 4 have increased With a variety of components, the obtained freeze-dried composition has a significantly higher loading capacity of grease components, polyol components, unstable components that are easily decomposed, and components that are prone to gelation after drying. Examples 1-2; Example 5 By controlling the backbone molecules to be glycine, trehalose, hydrolyzed xylan, mannitol and rhamnose with a mass ratio of 3:3:3:3:1; the liposomes are embedded with soy lecithin and hydrogenated with a mass ratio of 1:4 Lecithin; the macromolecular carrier is a freeze-dried composition obtained by fibroin, sodium caseinate, glyceryl stearate, collagen and whey protein in a mass ratio of 1:4:4:0.5:0.5, which can significantly increase the oil content The loading amount of components, polyol components, unstable and easily decomposed components and components that are easy to gel after drying; the components of the freeze-dried composition disclosed in Example 6 are the same as those in Example 5, and the skeleton molecules , the content of liposome encapsulation and macromolecular carrier is the same as that in Example 5, but due to the different ratios between the components, the impact on oil components, polyol components, unstable and easily decomposed components is significantly reduced. The loading amount of components that are likely to form gel after separation and drying.

为了进一步证明本申请制备的冻干制剂具有较高的稳定性，针对应用实施例1.7、2.7、3.7、4.7、5.7和6.7制备的冻干制剂样品，每组制备3个样品分别对冷冻前后HPR的含量进行了检测。In order to further prove that the freeze-dried preparations prepared in this application have high stability, for the freeze-dried preparation samples prepared in Examples 1.7, 2.7, 3.7, 4.7, 5.7 and 6.7, three samples were prepared in each group to conduct HPR analysis before and after freezing. The content was tested.

检测方法为：The detection method is:

将制备的载有HPR的冻干制剂，分别在冻干前和冻干后进行HPR的HPLC检测，HPR色谱条件：色谱柱：C18柱(4.6mm×250mm，5μm)；柱温：30℃，检测波长：358nm，流动相：98％乙腈+2％水，流速：1.0mL/min；程序：等梯度洗脱。The prepared freeze-dried preparations containing HPR were subjected to HPLC detection of HPR before and after freeze-drying. HPR chromatography conditions: chromatographic column: C18 column (4.6mm×250mm, 5μm); column temperature: 30°C. Detection wavelength: 358nm, mobile phase: 98% acetonitrile + 2% water, flow rate: 1.0mL/min; program: isotropic elution.

样品处理：冻干前和冷冻干燥后分别取样，用流动相98％乙腈+2％水溶解超声提取30min，0.22um过滤，上样检测，检测结果见下表7。Sample processing: Take samples before and after freeze-drying, use mobile phase 98% acetonitrile + 2% water to dissolve and extract with ultrasonic for 30 minutes, filter with 0.22um, and load the sample for testing. The test results are shown in Table 7 below.

表7冷冻干燥前后羟基频哪酮视黄酸酯含量HPLC检测结果

Table 7 HPLC detection results of hydroxypinacolone retinoate content before and after freeze-drying

根据上表7和附图9可以看出，本申请制备的冻干制剂，具有较高的稳定性，应用实施例1.7制备的冻干制剂冻干前和冻干后HPR的保留率可以达到98.58％，由于应用实施例2.7、3.7、4.7、5.7和6.7制备的冻干制剂均为最大负载范围内的冻干制剂，因此冻干前和冻干后HPR的保留率与应用实施例1.7的数值相当，均在95％以上，说明本申请制备的冻干制剂冻干前后有效成分稳定性好。According to Table 7 and Figure 9 above, it can be seen that the freeze-dried preparation prepared in this application has high stability. The HPR retention rate of the freeze-dried preparation prepared in Example 1.7 before and after freeze-drying can reach 98.58. %, since the freeze-dried preparations prepared in Application Examples 2.7, 3.7, 4.7, 5.7 and 6.7 are all freeze-dried preparations within the maximum load range, the retention rate of HPR before and after freeze-drying is the same as the value in Application Example 1.7 Comparable, both above 95%, indicating that the active ingredients of the freeze-dried preparation prepared in this application have good stability before and after freeze-drying.

另外，针对应用实施例1.6、2.6、3.6、4.6、5.6和6.6制备的冻干制剂样品，每组制备3个样品分别对冷冻前后视黄醇棕榈酸酯的含量进行了检测。In addition, for the freeze-dried preparation samples prepared in Examples 1.6, 2.6, 3.6, 4.6, 5.6 and 6.6, three samples were prepared in each group to detect the content of retinyl palmitate before and after freezing.

检测方法为：The detection method is:

将制备的载有载有视黄醇棕榈酸酯的冻干体系，分别在冷冻干燥后及冷冻干燥后在40℃高温处理2周后进行视黄醇棕榈酸酯的HPLC检测，视黄醇棕榈酸酯色谱条件：色谱柱：C18柱(4.6mm×250mm，5μm)；柱温：30℃，检测波长：325nm，流动相：45％异丙醇+55％甲醇，流速：1.0mL/min；程序：等梯度洗脱。The prepared freeze-dried system containing retinyl palmitate was subjected to HPLC detection of retinyl palmitate after freeze-drying and freeze-drying at 40°C for 2 weeks. Acid ester chromatography conditions: Chromatographic column: C18 column (4.6mm×250mm, 5μm); column temperature: 30°C, detection wavelength: 325nm, mobile phase: 45% isopropyl alcohol + 55% methanol, flow rate: 1.0mL/min; Procedure: Isogradient elution.

样品处理：冷冻干燥后和冷冻干燥后40℃高温处理2周后取样进行HPLC检测，用流动相45％异丙醇+55％甲醇溶解超声提取30min，0.22um过滤，上样检测检测结果见下表8。Sample processing: After freeze-drying and high temperature treatment at 40°C for 2 weeks, samples were taken for HPLC testing. Use mobile phase 45% isopropyl alcohol + 55% methanol to dissolve and extract with ultrasonic for 30 minutes. Filter with 0.22um. The sample loading test results are shown below. Table 8.

表8：冷冻干燥后及冷冻干燥后40℃高温处理2周后视黄醇棕榈酸酯含量HPLC检测结果
Table 8: HPLC detection results of retinyl palmitate content after freeze-drying and after freeze-drying and high temperature treatment at 40°C for 2 weeks

根据上表8和附图10可以看出，本申请制备的冻干制剂，具有较高的稳定性，应用实施例1.6制备的冻干制剂冷冻干燥后及冷冻干燥后在40℃高温处理2周后进行视黄醇棕榈酸酯的保留率可以达到97.99％，由于应用实施例2.6、3.6、4.6、5.6和6.6制备的冻干制剂均为最大负载范围内的冻干制剂，因此冷冻干燥后及冷冻干燥后在40℃高温处理2周后进行视黄醇棕榈酸酯的保留率与应用实施例1.6的数值相当，说明本申请制备的冻干制剂高温稳定性好，适合长期保存。It can be seen from Table 8 and Figure 10 above that the freeze-dried preparation prepared in the present application has high stability. The freeze-dried preparation prepared in Example 1.6 is subjected to high temperature treatment at 40°C for 2 weeks after freeze-drying and freeze-drying. The retention rate of retinyl palmitate can reach 97.99%. Since the freeze-dried preparations prepared in Application Examples 2.6, 3.6, 4.6, 5.6 and 6.6 are all freeze-dried preparations within the maximum load range, after freeze-drying and After freeze-drying and high-temperature treatment at 40°C for 2 weeks, the retention rate of retinyl palmitate is equivalent to the value in Application Example 1.6, indicating that the freeze-dried preparation prepared in this application has good high-temperature stability and is suitable for long-term storage.

应用实施例7一种冻干面膜制剂及其制备方法Application Example 7 A freeze-dried facial mask preparation and its preparation method

所述的冻干制剂的制备方法：(1)取配方用量的甘氨酸、海藻糖、水解木聚糖、甘露醇、鼠李糖、丝心蛋白、酪蛋白酸钠、硬脂酸甘油酯、胶原蛋白、乳清蛋白、黄原胶和花青素，混合均匀过150目筛，得到混合物；The preparation method of the freeze-dried preparation: (1) Take the formula dosage of glycine, trehalose, hydrolyzed xylan, mannitol, rhamnose, fibroin, sodium caseinate, glyceryl stearate, and collagen Mix egg white, whey protein, xanthan gum and anthocyanins evenly and pass through a 150 mesh sieve to obtain a mixture;

(3)将剩余其他组分加热融化后加入步骤(2)的冻干体系中，超声(40℃，300W)乳化30min，得到载有其他组分的冻干体系；(3) Heat and melt the remaining other components and then add them to the freeze-drying system in step (2), and emulsify with ultrasonic (40°C, 300W) for 30 minutes to obtain a freeze-drying system containing other components;

(4)将步骤(3)中得到的载有其他组分的冻干体系中浸入蚕丝膜布，直至膜布吸满液体，然后冻干处理后得到所述的冻干面膜制剂。(4) Dip the freeze-dried system containing other components obtained in step (3) into the silk film cloth until the film cloth is filled with liquid, and then freeze-dry it to obtain the freeze-dried facial mask preparation.

阶段二：冻干仓内温度在1小时内达到15-25℃，真空度下降至35-45帕，保持1小时。Stage 2: The temperature in the freeze-drying chamber reaches 15-25°C within 1 hour, and the vacuum degree drops to 35-45 Pa. Leave on for 1 hour.

该应用实施例使用实施例5的冻干组合物可以实现多种组分的冻干，如附图11所示，将得到的载有其他组分的冻干体系中浸入蚕丝膜布基材，可以实现冻干，添加20-25mL水，几秒内即可复水，使用方便。In this application example, the freeze-drying composition of Example 5 can be used to achieve freeze-drying of multiple components. As shown in Figure 11, the obtained freeze-drying system containing other components is immersed in the silk film cloth base material, Freeze-drying can be achieved by adding 20-25mL of water and it can be rehydrated within a few seconds, making it easy to use.

应用对比例1.1-1.8一种冻干制剂及其制备方法Application Comparative Examples 1.1-1.8 A freeze-dried preparation and its preparation method

应用对比例1.1所述的冻干制剂的制备方法：(1)取配方用量的甘露醇、黄原胶和花青素，混合均匀过150目筛，得到混合物；The preparation method of the freeze-dried preparation described in Comparative Example 1.1 is applied: (1) Take the formula amounts of mannitol, xanthan gum and anthocyanins, mix them evenly and pass through a 150-mesh sieve to obtain a mixture;

(2)将动物源黄油隔水加热融化后加入步骤(1)的混合物中，超声(40℃，300W)乳化30min，得到载有黄油的混合物；(2) Heat and melt the animal-derived butter in water, then add it to the mixture in step (1), and emulsify with ultrasonic (40°C, 300W) for 30 minutes to obtain a mixture containing butter;

(3)将步骤(2)中得到的载有黄油的混合物倒入模具中，进行塑型，然后冻干处理后得到所述的冻干制剂。(3) Pour the butter-laden mixture obtained in step (2) into a mold, perform shaping, and then freeze-dry to obtain the freeze-dried preparation.

阶段一：冻干仓内温度在1小时内缓慢升温达到-30℃，真空度保持在1帕以下，保持3小时； Stage 1: The temperature in the freeze-drying chamber slowly rises to -30°C within 1 hour, and the vacuum degree is kept below 1 Pa for 3 hours;

应用对比例1.2-1.8所述的制备方法除步骤(2)中所加入组分不同外，其他操作均与应用对比例1.1制备方法相同。The preparation method described in Comparative Examples 1.2-1.8 is the same as the preparation method in Comparative Example 1.1 except that the components added in step (2) are different.

效果验证：根据图12B可看出，应用对比例1.1、1.2、1.3、1.6、1.7，在分别载入黄油、乳木果油、夏威夷果油、视黄醇棕榈酸酯、HPR时，不能载入，经超声乳化后，呈小颗粒油滴状漂浮于液体表面，不能呈乳化状态，呈分散的两相，故后续未冷冻干燥。Effect verification: According to Figure 12B, it can be seen that when applying comparative examples 1.1, 1.2, 1.3, 1.6, and 1.7, butter, shea butter, macadamia nut oil, retinyl palmitate, and HPR cannot be loaded respectively. After ultrasonic emulsification, it appears as small oil droplets floating on the surface of the liquid. It cannot be in an emulsified state and is in a dispersed two-phase state, so it is not subsequently freeze-dried.

根据图12A可看出，应用对比例1.4、1.5、1.8溶解完全，呈澄清透亮的紫色溶液，进行冷冻干燥，在冷冻干燥过程中，冻干球皱缩塌陷，不能成型。It can be seen from Figure 12A that when Comparative Examples 1.4, 1.5, and 1.8 were completely dissolved and turned into a clear and translucent purple solution, they were freeze-dried. During the freeze-drying process, the freeze-dried balls shrank and collapsed and could not be formed.

应用对比例2Application comparison example 2

采用中国专利申请201410187505.3中实施例1公开的配方，然后步骤(2)中载入固体成分10％的黄油，即1.01g黄油，但是根据图13可看出，载入10％黄油后，油滴漂浮于表面，未能乳化，无法进行冻干处理。The formula disclosed in Example 1 of Chinese patent application 201410187505.3 is used, and then in step (2), butter with a solid content of 10% is loaded, that is, 1.01g butter. However, it can be seen from Figure 13 that after loading 10% butter, the oil droplets Floats on the surface, fails to emulsify, and cannot be freeze-dried.

应用对比例3Application comparison example 3

采用中国专利申请201911209367.3中实施例1公开的配方：透明质酸：3％、抗菌肽F：0.003％、赋形剂：10％、水：86.997％，以上原料经搅拌加热完全溶解后，载入固体成分10％的夏威夷果油，但是根据图14可看出，载入10％夏威夷果油后，油滴漂浮于表面，未能乳化，无法进行冻干处理。The formula disclosed in Example 1 of Chinese patent application 201911209367.3 is adopted: hyaluronic acid: 3%, antimicrobial peptide F: 0.003%, excipient: 10%, water: 86.997%. After the above raw materials are completely dissolved by stirring and heating, load Macadamia nut oil with a solid content of 10%, however, as shown in Figure 14, after loading 10% macadamia nut oil, the oil droplets floated on the surface and failed to be emulsified, making it impossible to freeze-dry.

对于本领域技术人员而言，显然本发明不限于上述示范性实施例的细节，而且在不背离本发明的精神或基本特征的情况下，能够以其他的具体形式实现本发明。It will be obvious to those skilled in the art that the present invention is not limited to the details of the above-described exemplary embodiments, but And the present invention can be implemented in other specific forms without departing from the spirit or essential characteristics of the present invention.

因此，无论从哪一点来看，均应将实施例看作是示范性的，而且是非限制性的，本发明的范围由所附权利要求而不是上述说明限定，因此旨在将落在权利要求的等同要件的含义和范围内的所有变化囊括在本发明内。不应将权利要求中的任何附图标记视为限制所涉及的权利要求。Therefore, the embodiments should be regarded as illustrative and non-restrictive from any point of view, and the scope of the present invention is defined by the appended claims rather than the above description, and it is therefore intended that all claims falling within the claims All changes within the meaning and scope of equivalent elements are included in the present invention. Any reference signs in the claims shall not be construed as limiting the claim in question.

此外，应当理解，虽然本说明书按照实施方式加以描述，但并非每个实施方式仅包含一个独立的技术方案，说明书的这种叙述方式仅仅是为清楚起见，本领域技术人员应当将说明书作为一个整体，各实施例中的技术方案也可以经适当组合，形成本领域技术人员可以理解的其他实施方式。 In addition, it should be understood that although this specification is described in terms of implementations, not each implementation only contains an independent technical solution. This description of the specification is only for the sake of clarity, and those skilled in the art should take the specification as a whole. , the technical solutions in each embodiment can also be appropriately combined to form other implementations that can be understood by those skilled in the art.

Claims

一种三元冻干组合物，其特征在于：按重量百分含量计包括如下组分：骨架分子50-80％、脂质体包埋15-30％和大分子载体5-20％。A ternary freeze-dried composition is characterized in that it includes the following components in terms of weight percentage: 50-80% skeleton molecules, 15-30% liposome embedding and 5-20% macromolecular carriers.
根据权利要求1所述的三元冻干组合物，其特征在于：按重量百分含量计包括如下组分：骨架分子50-65％、脂质体包埋20-25％和大分子载体10-20％。The ternary freeze-dried composition according to claim 1, characterized in that: it includes the following components in terms of weight percentage: 50-65% skeleton molecules, 20-25% liposome embedding and 10 macromolecular carriers -20%.
根据权利要求2所述的三元冻干组合物，其特征在于：按重量百分含量计包括如下组分：骨架分子65％、脂质体包埋25％和大分子载体10％。The ternary freeze-dried composition according to claim 2, characterized in that it includes the following components in terms of weight percentage: 65% skeleton molecules, 25% liposome embedding and 10% macromolecular carrier.
根据权利要求3所述的三元冻干组合物，其特征在于：所述的骨架分子选自氨基酸、海藻糖、水解木聚糖、甘露醇和鼠李糖中的一种或几种；The ternary freeze-dried composition according to claim 3, characterized in that: the skeleton molecule is selected from one or more of amino acids, trehalose, hydrolyzed xylan, mannitol and rhamnose;

所述的脂质体包埋为卵磷脂；The liposomes are embedded in lecithin;

所述的大分子载体选自丝心蛋白、酪蛋白酸钠、硬脂酸甘油酯、胶原蛋白和乳清蛋白中的一种或几种。The macromolecular carrier is selected from one or more of silk fibroin, sodium caseinate, glyceryl stearate, collagen and whey protein.
根据权利要求4所述的三元冻干组合物，其特征在于：所述的骨架分子为甘氨酸、海藻糖、水解木聚糖、甘露醇和鼠李糖的混合物；The ternary freeze-dried composition according to claim 4, characterized in that: the skeleton molecule is a mixture of glycine, trehalose, hydrolyzed xylan, mannitol and rhamnose;

所述的脂质体包埋为大豆卵磷脂和氢化卵磷脂的混合物；The liposomes are embedded in a mixture of soybean lecithin and hydrogenated lecithin;

所述的大分子载体选自丝心蛋白、酪蛋白酸钠、硬脂酸甘油酯、胶原蛋白和乳清蛋白的混合物。The macromolecular carrier is selected from a mixture of silk fibroin, sodium caseinate, glyceryl stearate, collagen and whey protein.
根据权利要求5所述的三元冻干组合物，其特征在于：所述的甘氨酸、海藻糖、水解木聚糖、甘露醇和鼠李糖的质量比为3:3:3:3:1；The ternary freeze-dried composition according to claim 5, characterized in that: the mass ratio of the glycine, trehalose, hydrolyzed xylan, mannitol and rhamnose is 3:3:3:3:1;

所述的大豆卵磷脂和氢化卵磷脂的质量比为1:3-5；The mass ratio of the soybean lecithin and hydrogenated lecithin is 1:3-5;

所述的丝心蛋白、酪蛋白酸钠、硬脂酸甘油酯、胶原蛋白和乳清蛋白的质量比为1:4:4:0.5:0.5。The mass ratio of the fibroin, sodium caseinate, glyceryl stearate, collagen and whey protein is 1:4:4:0.5:0.5.
根据权利要求1-6任一项所述的三元冻干组合物在制备冻干制剂中的应用，所述的冻干制剂为化妆品冻干制剂。The application of the ternary freeze-dried composition according to any one of claims 1 to 6 in preparing a freeze-dried preparation, wherein the freeze-dried preparation is a cosmetic freeze-dried preparation.
一种化妆品冻干制剂，其特征在于：包括权利要求1-6任一项所述的三元冻干组合物以及油脂类组分、多元醇类组分、不稳定易分解组分、干燥后易成胶组分、维生素、增稠剂和活性成分中的一种或几种。A cosmetic freeze-dried preparation, characterized by: comprising the ternary freeze-dried composition described in any one of claims 1-6, oil components, polyol components, unstable and easily decomposable components, and dried components. One or more of gel-forming components, vitamins, thickeners and active ingredients.
根据权利要求8所述的化妆品冻干制剂，其特征在于：所述的油脂类组分选自动物源油脂和植物源油脂；所述的动物源油脂选自黄油、水貂油、蛋黄油、羊毛脂油和角鲨烷中的一种或几种；所述的植物源油脂选自乳木果油、夏威夷果油、霍霍巴籽油、橄榄油、椰子油、蓖麻油、棉籽油、大豆油、芝麻油、杏仁油、花生油、玉米油、米糠油、茶籽油、沙棘油、鳄梨油、石栗子油、胡桃油和可可油中的一种或几种；所述的多元醇类组分选自甘油或/和丙二醇；所述的不稳定易分解组分选自视黄醇棕榈酸酯和/或羟基频哪酮视磺酸酯；所述的干燥后易成胶组分选自玻色因。The cosmetic freeze-dried preparation according to claim 8, characterized in that: the oil component is selected from animal-derived oils and vegetable-derived oils; the animal-derived oils and fats are selected from butter, mink oil, egg yolk oil, and wool. One or more of fat and squalane; the vegetable oil is selected from shea butter, macadamia nut oil, jojoba seed oil, olive oil, coconut oil, castor oil, cottonseed oil, soybean oil, sesame oil, almond oil, One or more of peanut oil, corn oil, rice bran oil, tea seed oil, sea buckthorn oil, avocado oil, chestnut oil, walnut oil and cocoa butter; the polyol component is selected from glycerin or/and Propylene glycol; the unstable and easily decomposable component is selected from retinol palmitate and/or hydroxypinacolone retinosulfonate; the component that is easily gelled after drying is selected from Boseine.
根据权利要求8-9任一项所述的冻干制剂的制备方法，其特征在于：包括以下步骤：The preparation method of the freeze-dried preparation according to any one of claims 8-9, characterized in that: comprising the following steps:

(1)取配方用量的骨架分子、大分子载体以及维生素、增稠剂或活性成分，混合均匀过筛，得到混合物；(1) Take the formula dosage of skeleton molecules, macromolecular carriers, vitamins, thickeners or active ingredients, mix them evenly and sieve to obtain a mixture;

(2)取配方用量的脂质体包埋加水溶解，得混合液；并将步骤(1)中的混合物加入混合液中，搅拌，得到冻干体系；(2) Take the prescribed amount of liposomes for embedding and dissolve in water to obtain a mixed solution; add the mixture in step (1) to the mixed solution and stir to obtain a freeze-dried system;

(3)将油脂类组分、多元醇类组分、不稳定易分解组分或干燥后易成胶组分融化后加入步骤(2)的冻干体系中，超声乳化，得到载有油脂的冻干体系；(3) Melt the grease components, polyol components, unstable components that easily decompose or components that easily form gel after drying, then add them to the freeze-drying system of step (2), and perform ultrasonic emulsification to obtain grease-loaded components. Freeze-drying system;

(4)将步骤(3)中得到的载有油脂类组分、多元醇类组分、不稳定易分解组分或干燥后易成胶组分的冻干体系进行塑型，冻干处理后得到所述的冻干制剂；(4) Shape the freeze-dried system obtained in step (3) containing oil components, polyol components, unstable and easily decomposed components, or components that easily form gel after drying. After freeze-drying Obtain the freeze-dried preparation;

所述的冻干包括预冻、升华和解析干燥三个步骤；The freeze-drying includes three steps: pre-freezing, sublimation and analytical drying;

所述的预冻操作为：开启冻干设备，使冷井温度由室温开始在40分钟左右达到-45℃以下，保持2小时；The described pre-freezing operation is: turn on the freeze-drying equipment, make the cold well temperature reach below -45°C from room temperature in about 40 minutes, and maintain it for 2 hours;

所述的升华分为三个阶段，具体操作为：The sublimation described is divided into three stages, and the specific operations are:

阶段一：冻干仓内温度在1小时内缓慢升温达到-30℃左右，真空度保持在1帕以下，保持3-5小时；Stage 1: The temperature in the freeze-drying chamber slowly rises to about -30°C within 1 hour, and the vacuum degree is kept below 1 Pa for 3-5 hours;

阶段二、冻干仓内温度在1小时内缓慢升温达到-10℃左右，真空度25-35帕，保持4-8小时；Stage 2: The temperature in the freeze-drying warehouse slowly rises to about -10°C within 1 hour, and the vacuum degree is 25-35 Pa, maintained for 4-8 hours;

阶段三、冻干仓内在1小时内缓慢升达到0℃左右，真空度35-45帕，保持1-2小时；Stage 3: The freeze-drying chamber slowly rises to about 0°C within 1 hour, and the vacuum degree is 35-45 Pa, maintained for 1-2 hours;

所述的解析干燥分为两个阶段，具体操作为：The analytical drying is divided into two stages, and the specific operations are:

阶段一：冻干仓内温度在1小时内达到5-15℃，真空度45-55帕，保持2-3小时；Stage 1: The temperature in the freeze-drying chamber reaches 5-15°C within 1 hour, and the vacuum degree is 45-55 Pa, maintained for 2-3 hours;

阶段二：冻干仓内温度在1小时内达到15-25℃，真空度下降至35-45帕，保持1-2小时。 Stage 2: The temperature in the freeze-drying chamber reaches 15-25°C within 1 hour, and the vacuum degree drops to 35-45 Pa, and is maintained for 1-2 hours.