Pre-liposome preparation capable of being used for entrapping water-soluble functional substances as well as preparation method and application of pre-liposome preparation

Abstract

The invention relates to a pre-liposome preparation for entrapping a water-soluble functional substance as well as a preparation method and application of the pre-liposome preparation. The pre-liposome preparation is mainly prepared from the following raw materials in percentage by mass: 20.0%-27.0% of phospholipid; 20.0% to 27.0% of ethanol; 0.6%-1.0% of cholesterol; 8.0%-11.0% of an emulsifier; 0.2%-0.4% of an antioxidant; and 33.6% to 51.2% of a polyol; the emulsifying agent is prepared from beheneth-25. The pre-liposome preparation has universality and can be used for entrapping various water-soluble functional substances and improving the water solubility, stability and transdermal property of various water-soluble functional raw materials, the liposome entrapping the water-soluble functional raw materials is further obtained, and both the pre-liposome preparation and the liposome can be applied to cosmetics.

Description

Technical Field

[0001] The present invention belongs to the technical field of cosmetics, and particularly relates to a pre-liposome preparation capable of encapsulating water-soluble active substances, a preparation method thereof, and an application thereof. Background Art

[0002] Water-soluble cosmetic active ingredients such as hydroxyproline, ergothioneine, ectoin, asiaticoside, various peptides, lactic acid, tranexamic acid, nicotinamide, and collagen have good physiological effects on the skin. However, due to their irritancy at high concentrations, instability, and difficulty in absorption of macromolecules, the application of these active ingredients in cosmetics is limited. There is an urgent need in the industry for a method to improve the water solubility, stability, and transdermal permeability of these active ingredients. Summary of the Invention

[0003] Aiming at the above problems, the purpose of the present invention is to provide a pre-liposome preparation that can improve the irritancy, stability, and transdermal permeability of various water-soluble active ingredients, and further obtain liposomes encapsulating water-soluble active ingredients. Both the pre-liposome preparation and the liposomes can be applied in cosmetics.

[0004] The technical solution is as follows:

[0005] A pre-liposome preparation capable of encapsulating water-soluble active substances is mainly made of the following raw materials in mass percentages:

[0006]

[0007] The emulsifier includes behenyl alcohol polyether-25.

[0008] In one embodiment, the sum of the masses of the phospholipid, ethanol, cholesterol, emulsifier, and antioxidant is A, and the mass of the polyol is B. The ratio of A / B is (1.5 - 2.0):1.

[0009] In one embodiment, the phospholipid is soy lecithin PC60.

[0010] In one embodiment, the mass ratio of the phospholipid to cholesterol is (28 - 32):1.

[0011] In one embodiment, the polyol includes one or a mixture of two of glycerol and pentylene glycol.

[0012] In one embodiment, the pre-liposome preparation is mainly made of the following raw materials in mass percentages:

[0013]

[0014] In one embodiment, the antioxidant is pentaerythritol tetra(bis-tert-butyl hydroxyhydrocinnamate).

[0015] In one embodiment, the raw materials further include one or more of a preservative and a pH regulator.

[0016] In one embodiment, based on the total mass percentage of the raw materials, the raw materials further include:

[0017] preservative 0.05% - 1.05%; and

[0018] pH regulator 0.5% - 1.5%.

[0019] In one embodiment, the pH regulator is NaOH.

[0020] In one embodiment, the preservative is p-hydroxyacetophenone.

[0021] In one embodiment, the particle size of the pre-liposome preparation is 100 nm - 250 nm, the PDI is 0.3 - 0.6, and the pH is 6.2 - 6.7.

[0022] The present invention also provides a method for preparing the pre-liposome preparation as described above that can be used to encapsulate water-soluble active substances, including the following steps:

[0023] Mix the phospholipid, the cholesterol, the emulsifier, and the antioxidant in the ethanol to prepare an oil-phase mixture;

[0024] Mix the polyol and the oil-phase mixture to prepare a primary emulsion;

[0025] Perform heat treatment on the primary emulsion to remove the ethanol therein.

[0026] In one embodiment, the process parameters for preparing the oil-phase mixture include: the temperature of the system is 40°C - 50°C.

[0027] In one embodiment, the process parameters for heat treatment include: vacuum concentration, the temperature is 40°C - 60°C, and the time is 30 min - 90 min.

[0028] The present invention also provides the application of the pre-liposome preparation as described above that can be used to encapsulate water-soluble active substances. The technical solution is as follows:

[0029] A liposome encapsulating a water-soluble active substance, including water, a water-soluble active substance, and the pre-liposome preparation as described above that can be used to encapsulate a water-soluble active substance.

[0030] In one embodiment, the liposome encapsulating a water-soluble active substance is mainly made of raw materials in the following mass percentages:

[0031] Water 50% - 79%;

[0032] Water-soluble active substance 0.9% - 10%; and

[0033] Pre-liposome preparation 20.1% - 40%.

[0034] The present invention also provides a cosmetic, comprising a pre-liposome preparation capable of encapsulating a water-soluble active substance, or a liposome encapsulating a water-soluble active substance as described above.

[0035] In one embodiment, the cosmetic is selected from at least one of a facial mask, eye cream, facial cream, primer, essence, lotion, and skin softener.

[0036] The present invention has at least the following beneficial effects:

[0037] The pre-liposome preparation provided by the present invention for encapsulating a water-soluble active substance comprises phospholipids, cholesterol, an emulsifier, an antioxidant, and a polyol in specific mass percentages, and the emulsifier comprises behenyl alcohol polyether-25. This pre-liposome preparation can improve the irritation, stability, and transdermal permeability of various water-soluble active raw materials, showing universality, and can be used as a cosmetic matrix. The preparation method of this pre-liposome preparation is simple, has high repeatability, short preparation time, no harmful substance residues, high encapsulation efficiency. After being diluted 10 times, the encapsulation still reaches more than 60%. The preparation method of this pre-liposome preparation does not require complex mechanical processes and equipment, and can make the product quality and process have good reproducibility and stability, and is easy for industrial production.

[0038] Furthermore, by mixing the pre-liposome preparation and an aqueous solution of the active substance, the present invention can simply and quickly obtain a liposome with good encapsulation effect on the active substance after stirring and mixing evenly. This method is applicable to different water-soluble active substances, can be used to prepare liposomes encapsulating one or more different active substances, and the liposomes have the advantages of small particle size, high homogeneity, high stability, being gentle to the human body, and having a sustained-release effect. It has been confirmed that the liposome encapsulating a water-soluble active substance shows excellent stability under 7 different harsh environments including normal temperature, refrigeration, freezing, heating, freeze-thaw, light, and darkness. In addition, the loading amount of the liposome encapsulating a water-soluble active substance is easily controllable, the preparation does not require complex equipment, is fast and simple, the method is economical and simple, has broad application potential, and can be well applied to cosmetics. BRIEF DESCRIPTION OF THE DRAWINGS

[0039] Figure 1Trend charts of the particle size, PDI, and zeta potential of the pre-liposome preparation obtained in Example 1 under 7 different environments;

[0040] Figure 2 Trend charts of the particle size, PDI, and zeta potential of the pre-liposome preparation obtained in Example 8 after being diluted 10-fold under 7 different environments;

[0041] Figure 3 Trend charts of the particle size, PDI, and zeta potential of the pre-liposome preparation obtained in Example 8 after being diluted 100-fold under 7 different environments;

[0042] Figure 4 Trend charts of the particle size, PDI, and zeta potential of the pre-liposome preparation obtained in Example 9 after encapsulating niacinamide under 7 different environments;

[0043] Figure 5 Trend charts of the particle size, PDI, and zeta potential of the pre-liposome preparation obtained in Example 9 after encapsulating ectoin under 7 different environments;

[0044] Figure 6 Stability analysis chart of the pre-liposome preparation obtained in Example 1 on a Turbiscan stability analyzer;

[0045] Figure 7 Stability analysis chart of the pre-liposome essence obtained in Example 10 on a Turbiscan stability analyzer;

[0046] Figure 8 Stability analysis chart of the pre-liposome preparation obtained in Example 8 after being diluted 10-fold on a Turbiscan stability analyzer;

[0047] Figure 9 Stability analysis chart of the pre-liposome preparation obtained in Example 8 after being diluted 100-fold on a Turbiscan stability analyzer;

[0048] Figure 10 Stability analysis chart of the pre-liposome preparation encapsulated with niacinamide liposome essence obtained in Example 11 on a Turbiscan stability analyzer. Detailed implementation manners

[0049] The present invention will be further described in detail below with reference to specific embodiments. The present invention can be implemented in many different forms and is not limited to the embodiments described herein. On the contrary, these embodiments are provided to make the disclosure of the present invention more thorough and comprehensive.

[0050] 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 to which this invention belongs. The terms used in the description of the present invention herein are for the purpose of describing specific embodiments only and are not intended to limit the present invention. The term "and / or" as used herein includes any and all combinations of one or more of the associated listed items.

[0051] The terms "preferably", "more preferably", "more preferably", "even more preferably", etc. in the present invention refer to embodiments of the present invention that can provide certain beneficial effects in certain cases. However, in the same or other cases, other embodiments may also be preferred. In addition, the description of one or more preferred embodiments does not imply that other embodiments are not available, nor is it intended to exclude other embodiments from the scope of the present invention. That is, in the present invention, "preferably", "more preferably", "more preferably", "even more preferably", etc. are only used to describe embodiments or examples with better effects, but do not constitute a limitation on the protection scope of the present invention.

[0052] In the present invention, "further", "even further", "especially", etc. are used for descriptive purposes and indicate differences in content, but should not be construed as a limitation on the protection scope of the present invention.

[0053] In the present invention, "above" and "below" both include the number itself. For example, "below 1" means ≥1.

[0054] In the present invention, the meaning of "at least one" is more than one, such as one, two or more. The meaning of "multiple" or "several" is at least two, such as two, three, etc. The meaning of "multiple layers" is at least two layers, such as two layers, three layers, etc., unless otherwise specifically defined. In the description of the present invention, the meaning of "several" is at least one, such as one, two, etc., unless otherwise specifically defined.

[0055] When a numerical range is disclosed in the present invention, the above range is considered continuous and includes the minimum and maximum values of the range, as well as every value between such minimum and maximum values. Further, when the range refers to integers, it includes every integer between the minimum and maximum values of the range. In addition, when multiple ranges are provided to describe features or characteristics, the ranges can be combined. In other words, unless otherwise specified, all ranges disclosed herein should be understood to include any and all sub-ranges subsumed therein.

[0056] Unless otherwise specified, all steps of the present invention can be carried out sequentially or randomly. For example, the method includes steps (a) and (b), which means that the method may include steps (a) and (b) carried out sequentially, or may also include steps (b) and (a) carried out sequentially. For example, it is mentioned that the method may further include step (c), which means that step (c) can be added to the method in any order. For example, the method may include steps (a), (b) and (c) in sequence, or may also include steps (a), (c) and (b), or may include steps (c), (a) and (b), etc.

[0057] In the present invention, the terms "first" and "second" are only used for descriptive purposes and cannot be construed as indicating or implying relative importance or implicitly specifying the quantity of the indicated technical features. Thus, the features defined with "first" and "second" may explicitly or implicitly include at least one of such features.

[0058] In the present invention, "comprising", "including", "containing", "having" or other variants are intended to cover non-closed inclusion, and no distinction is made between these terms. The term "including" means that other steps and components can be added without affecting the final result. The compositions and methods / processes of the present invention comprise, consist of, and consist essentially of the essential elements and limitations described herein, as well as any additional or optional components, ingredients, steps or limitations described herein.

[0059] In the present invention, no distinction is made between the terms "efficacy", "performance", "effect" and "function".

[0060] In the description of the embodiments of the present invention, the weight of the relevant components mentioned not only can refer to the specific content of each component, but also can represent the proportional relationship of the weights between the components. Therefore, as long as the content of the relevant components in the description of the embodiments of the present invention is scaled up or down in proportion, it is within the scope disclosed in the description of the embodiments of the present invention. Specifically, the weight described in the description of the embodiments of the present invention can be mass units well-known in the chemical industry such as μg, mg, g, kg, etc.

[0061] In the present invention, for temperature parameters, unless otherwise specified, both constant temperature treatment and treatment within a certain temperature range are allowed. The constant temperature treatment allows the temperature to fluctuate within the accuracy range controlled by the instrument. The room temperature referred to in the present invention means 0 to 40 °C, preferably 10 °C to 35 °C, and more preferably 20 °C to 30 °C.

[0062] Unless otherwise mentioned, terms in the singular form may include the plural form and should not be construed as having a quantity of one.

[0063] In addition, the drawings of the present invention are not drawn to a scale of 1:1, and the relative sizes of the components are only drawn by way of example in the drawings for the convenience of understanding the present invention, but are not necessarily drawn to the actual scale, and the scale in the drawings does not constitute a limitation to the present invention.

[0064] Water-soluble cosmetic efficacy raw materials with good skin physiological effects, such as hydroxyproline, ergothioneine, ectoin, asiaticoside, various peptides, lactic acid, tranexamic acid, niacinamide, collagen, etc., are restricted in their application in cosmetics due to their poor water solubility, instability and poor absorption.

[0065] Liposomes are closed bilayer vesicles formed by amphiphilic substances such as phospholipids, with an internal aqueous phase and a cell membrane-like structure. They can encapsulate lipophilic active substances and water-soluble active substances in the lipid bilayer membrane and the internal aqueous phase respectively, and have a wide range of applications in improving the water solubility and stability of substances. At present, the preparation methods of liposomes loaded with water-soluble substances on the market are all added during the preparation process, and the preparation process of water-soluble liposomes is complex.

[0066] Aiming at the above problems, the purpose of the present invention is to provide a universal pre-liposome preparation that can improve the water solubility, stability and transdermal permeability of various water-soluble efficacy raw materials, and further obtain liposomes loaded with water-soluble efficacy raw materials, which can be applied to cosmetics.

[0067] The technical solution is as follows:

[0068] A pre-liposome preparation for encapsulating water-soluble efficacy substances, which is mainly made of raw materials with the following mass percentages:

[0069]

[0070] The emulsifier includes behenyl alcohol polyether-25.

[0071] In the present invention, calculated by the total mass percentage of the raw materials used for preparing the pre-liposome preparation, the dosage of phospholipid is 20.0% - 27.0%, including but not limited to 20.0%, 20.5%, 20.7%, 20.8%, 20.9%, 21.0%, 21.6%, 21.7%, 21.8%, 22.0%, 22.6%, 22.7%, 22.8%, 23.0%, 24.0%, 24.6%, 25.0%, 25.7%, 26.0%, 26.8% or 27.0%. Preferably, the dosage of phospholipid is 26.0%.

[0072] In one embodiment, the phospholipid is soy lecithin PC60.

[0073] In the present invention, based on the total mass percentage of the raw materials used for preparing the pre-liposome preparation, the dosage of ethanol is 20.0% to 27.0%, including but not limited to 20.0%, 20.5%, 20.7%, 20.8%, 20.9%, 21.0%, 21.6%, 21.7%, 21.8%, 22.0%, 22.6%, 22.7%, 22.8%, 23.0%, 24.0%, 24.6%, 25.0%, 25.7%, 26.0%, 26.8% or 27.0%.

[0074] In the present invention, based on the total mass percentage of the raw materials used for preparing the pre-liposome preparation, the dosage of cholesterol is 0.6% to 1.0%, including but not limited to 0.6%, 0.7%, 0.8%, 0.86%, 0.9% or 1.0%. Preferably, the dosage of cholesterol is 0.86%.

[0075] In one embodiment, the mass ratio of the phospholipid to cholesterol is (28 - 32):1, which is beneficial to enhancing the stability of the vesicles and reducing the permeability of the lipid membrane to solutes. It can be understood that the mass ratio of the lecithin to cholesterol includes but not limited to 28:1, 28.5:1, 29:1, 29.5:1, 30:1, 30.5:1, 31:1, 31.5:1 or 32:1. Preferably, the mass ratio of the lecithin to cholesterol is (28 - 32):1. Further preferably, the mass ratio of the lecithin to cholesterol is 30:1.

[0076] In the present invention, based on the total mass percentage of the raw materials used for preparing the pre-liposome preparation, the dosage of the emulsifier is 8.0% to 11.0%, including but not limited to 8%, 8.1%, 8.18%, 8.2%, 8.28%, 9%, 9.1%, 9.18%, 9.2%, 9.28%, 10%, 10.1%, 10.18%, 10.2%, 10.28% or 11%.

[0077] In the present invention, the emulsifier includes behenyl alcohol polyether - 25. In one embodiment, the emulsifier is behenyl alcohol polyether - 25.

[0078] In the present invention, an antioxidant is added to further enhance the antioxidant property and stability of the pre-liposome preparation and improve the stability problem of the encapsulated water-soluble active substances.

[0079] In the present invention, based on the total mass percentage of the raw materials used for preparing the pre-liposome preparation, the dosage of the antioxidant is 0.2% to 0.4%, including but not limited to 0.20%, 0.25%, 0.30%, 0.35% or 0.40%. Preferably, the dosage of the antioxidant is 0.33%.

[0080] In one embodiment, the antioxidant is pentaerythritol tetra(bis-tert-butylhydroxyhydrocinnamate).

[0081] In the present invention, based on the total mass percentage of the raw materials used for preparing the pre-liposome preparation, the dosage of the polyol is 33.6% to 51.2%, including but not limited to 33.6%, 34.6%, 35.6%, 37.6%, 38.6%, 39.35%, 40.0%, 42.0%, 44.0%, 46.0%, 46.26%, 47.65%, 48.0%, 49.0%, 50.0% or 51.2%.

[0082] In one embodiment, the polyol includes one or a mixture of two of glycerol and pentanediol. Glycerol mainly plays the role of a stabilizer, and pentanediol mainly plays the roles of a stabilizer and a preservative.

[0083] In one embodiment, the pre-liposome preparation is mainly made from the following raw materials in mass percentages:

[0084]

[0085] In the present invention, based on the total mass percentage of the raw materials used for preparing the pre-liposome preparation, the dosage of glycerol is 20.0% to 27.0%, including but not limited to 20.0%, 20.5%, 20.7%, 20.8%, 20.9%, 21.0%, 21.6%, 21.7%, 21.8%, 22.0%, 22.6%, 22.7%, 22.8%, 23.0%, 24.0%, 24.6%, 25.0%, 25.7%, 26.0%, 26.8% or 27.0%.

[0086] In the present invention, based on the total mass percentage of the raw materials used for preparing the pre-liposome preparation, the dosage of pentanediol is 6.6% to 31.2%, including but not limited to 6.6%, 10.0%, 15.0%, 20.0%, 20.5%, 20.7%, 20.8%, 20.9%, 21.0%, 21.6%, 21.7%, 21.8%, 22.0%, 22.6%, 22.7%, 22.8%, 23.0%, 24.0%, 24.6%, 25.0%, 25.7%, 26.0%, 26.8%, 27.0% or 31.2%.

[0087] In one embodiment, the sum of the masses of the phospholipid, ethanol, cholesterol, emulsifier and antioxidant is A, the mass of the polyol is B, and A / B is (1.5 - 2.0):1. It can be understood that the mass ratio of the oil phase to the polyol includes but is not limited to 1.50:1, 1.55:1, 1.60:1, 1.65:1, 1.70:1, 1.75:1, 1.80:1, 1.85:1, 1.90:1, 1.95:1 or 2.0:1.

[0088] In one embodiment, the raw materials further include one or more of a preservative and a pH regulator.

[0089] In one embodiment, based on the total mass percentage of the raw materials used for preparing the pre - liposome preparation, the raw materials further include:

[0090] preservative 0.05% - 1.05%; and

[0091] pH regulator 0.5% - 1.5%.

[0092] It can be understood that the preservative mainly plays a role in preventing the preparation from spoiling in the present invention. Based on the total mass percentage of the raw materials used for preparing the pre - liposome preparation, the dosage of the preservative is 0.05% - 1.05%, including but not limited to 0.05%, 0.06%, 0.07%, 0.075%, 0.08%, 0.09%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1% or 1.05%.

[0093] In one embodiment, the preservative is p - hydroxyacetophenone.

[0094] It can be understood that the pH regulator mainly plays a role in adjusting the pH of the system and reducing the particle size and distribution of the pre - liposome preparation. Based on the total mass percentage of the raw materials used for preparing the pre - liposome preparation, the dosage of the pH regulator is 0.5% - 1.5%, including but not limited to 0.5%, 0.55%, 0.6%, 0.65%, 0.7%, 0.75%, 0.8%, 0.85%, 0.9%, 0.95%, 1%, 1.1%, 1.2%, 1.3%, 1.4% or 1.5%.

[0095] In one embodiment, the pH regulator is NaOH, including but not limited to 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1.0%, 1.1%, 1.18%, 1.2%, 1.28%, 1.3%, 1.31%, 1.4% or 1.5%. Further, the concentration of NaOH is 1 mol / L.

[0096] In one embodiment, the pre-liposome preparation is mainly made of raw materials in the following mass percentages:

[0097]

[0098]

[0099] In one embodiment, the particle size of the pre-liposome preparation is 100 nm to 250 nm, the PDI is 0.3 to 0.6, and the pH is 4.5 to 7.5, including but not limited to 4.5, 4.9, 5.0, 5.5, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0 or 7.5. Further, the particle size of the pre-liposome preparation is 100 nm to 250 nm, the PDI is 0.3 to 0.6, and the pH is 6.2 to 6.7.

[0100] In one embodiment, the particle size of the pre-liposome preparation is 130 nm to 250 nm, the PDI is 0.3 to 0.6, and the encapsulation efficiency is ≥90%. Further, the particle size of the pre-liposome preparation with universality and capable of encapsulating water-soluble active substances is 100 nm to 250 nm, the PDI is 0.2 to 0.6, and the encapsulation efficiency for water-soluble active substances is ≥90%.

[0101] The present invention also provides a preparation method of the pre-liposome preparation capable of encapsulating water-soluble active substances as described above, comprising the following steps:

[0102] Mix the phospholipid, the cholesterol, the emulsifier and the antioxidant in the ethanol to prepare an oil-phase mixture;

[0103] Mix the polyol and the oil-phase mixture to prepare a primary emulsion;

[0104] Perform heat treatment on the primary emulsion to remove the ethanol therein.

[0105] The phospholipid, cholesterol, emulsifier and antioxidant are arranged in the oil-phase mixture, and the lipidosome preparation membrane material is completely dissolved in advance so as to form a closed vesicle structure when encountering water and encapsulate water-soluble active substances. The emulsifier can well adhere to the surface of the vesicle to enhance the interaction force between particles in the solution and enhance the stability of the solution.

[0106] The present invention prepares the pre-liposome preparation by the ethanol injection method. The preparation method is simple, rapid, and the process is simple, which is suitable for large-scale industrial production.

[0107] In one embodiment, the process parameters for preparing the first mixture include: the temperature of the system is 40°C to 50°C.

[0108] In one embodiment, the process parameters of the heat treatment include: reduced-pressure concentration, with a temperature of 40°C to 60°C and a time of 30 min to 90 min.

[0109] It can be understood that for embodiments where the system pH needs to be adjusted during the preparation process, the method for preparing the pre-liposome preparation that can be used to encapsulate water-soluble active substances includes the following steps:

[0110] Mix the phospholipid, cholesterol, emulsifier, and antioxidant in the ethanol to prepare a first mixture.

[0111] Mix the polyol and the first mixture to prepare a second mixture.

[0112] Mix the second mixture and a pH regulator to prepare a primary emulsion.

[0113] Perform heat treatment on the primary emulsion to remove the ethanol therein.

[0114] The present invention also provides the application of the pre-liposome preparation for encapsulating water-soluble active substances as described above. The technical solution is as follows:

[0115] A liposome encapsulating a water-soluble active substance, comprising water, a water-soluble active substance, and the pre-liposome preparation that can be used to encapsulate water-soluble active substances as described above.

[0116] In one embodiment, by mass percentage, the liposome encapsulating a water-soluble active substance is mainly made of raw materials with the following mass percentages:

[0117] Water 50% - 79%;

[0118] Water-soluble active substance 0.9% - 10%; and

[0119] Pre-liposome preparation 20.1% - 40%.

[0120] The present invention also provides a method for preparing the liposome encapsulating a water-soluble active substance as described above, including the following steps:

[0121] Mix water, a water-soluble active substance, and a pre-liposome preparation.

[0122] In one embodiment, the mixing temperature is 30°C to 60°C.

[0123] In one embodiment, the method for preparing the liposome encapsulating a water-soluble active substance as described above includes the following steps:

[0124] Preheat the pre-liposome, add the water-soluble active substance and mix well, then add the preheated water and stir to mix well.

[0125] In one embodiment, the method for preparing the liposome encapsulating a water-soluble active substance as described above comprises the following steps:

[0126] Add the water-soluble active substance to water to form an aqueous phase;

[0127] Preheat the proliposome;

[0128] Add the aqueous phase to the proliposome and stir to mix evenly.

[0129] The present invention also provides a cosmetic, comprising a proliposome preparation capable of encapsulating a water-soluble active substance, or a liposome encapsulating a water-soluble active substance as described above.

[0130] In one embodiment, the cosmetic is selected from at least one of a facial mask, eye cream, facial cream, primer, essence, lotion and skin softener.

[0131] In one embodiment, the cosmetic is an essence. By mass percentage, it comprises 20% - 60% of a proliposome preparation capable of encapsulating a water-soluble active substance and 40% - 80% of common cosmetic auxiliaries.

[0132] In one embodiment, by mass percentage, the essence comprises the following components:

[0133] 20% - 60% of a proliposome preparation capable of encapsulating a water-soluble active substance, 3% - 5% of glycerol, 3% - 5% of butanediol, 0.5% - 2% of pentanediol, 0.02% - 0.05% of EDTA-2Na, 0.3% - 0.6% of AVC (ammonium acryloyldimethyltaurate / VP copolymer), 0.5% - 2% of polyglyceryl-10 myristate, 0.1% - 0.3% of p-hydroxyacetophenone, and the balance being deionized water.

[0134] In one embodiment, the cosmetic is an essence. By mass percentage, it comprises 20% - 60% of a liposome encapsulating a water-soluble active substance and 40% - 80% of common cosmetic auxiliaries.

[0135] In one embodiment, by mass percentage, the essence comprises the following components:

[0136] 20% - 60% of a liposome encapsulating a water-soluble active substance, 3% - 5% of glycerol, 3% - 5% of butanediol, 0.5% - 2% of pentanediol, 0.02% - 0.05% of EDTA-2Na, 0.3% - 0.6% of AVC (ammonium acryloyldimethyltaurate / VP copolymer), 0.5% - 2% of polyglyceryl-10 myristate, 0.1% - 0.3% of p-hydroxyacetophenone, and the balance being deionized water.

[0137] The following is the specific embodiment part.

[0138] Unless otherwise specified, all raw materials are commercially available products.

[0139] The room temperature mentioned in the following embodiments is 20°C to 30°C, and the sum of the raw material dosages in the embodiments is 100%.

[0140] Embodiment 1

[0141] This embodiment provides a pre-liposome preparation that can be used to encapsulate water-soluble active substances, which is composed of the following raw material components in mass percentage: phospholipid 26.47%, cholesterol 0.86%, ceteth-25 10.63%, absolute ethanol 26.47%, pentaerythrityl tetra(bis-tert-butyl hydroxyhydrocinnamate) 0.33%, glycerol 26.47%, p-hydroxyacetophenone 0.05%, pentylene glycol 8.2%, pH regulator 0.52%, and the mass percentage ratio of phospholipid to cholesterol is 30:1.

[0142] This embodiment also provides a preparation method of the above liposome, which specifically includes the following steps: adding phospholipid to absolute ethanol and stirring at 45°C until completely dissolved; after the solution is clear and transparent, adding cholesterol, ceteth-25, and pentaerythrityl tetra(bis-tert-butyl hydroxyhydrocinnamate), and stirring until the solution is clear and transparent and completely dissolved; then adding glycerol and pentylene glycol and stirring to dissolve; adding 1 mol / L NaOH solution to adjust the pH to 6.5 to obtain the primary emulsion; rotating and evaporating the primary emulsion with a rotary evaporator at 50°C and 40 rpm for 60 min to remove absolute ethanol, adding 0.05% p-hydroxyethyl phenylacetate as a preservative and mixing evenly to obtain the sample.

[0143] Embodiment 2

[0144] Comparing pre-liposomes prepared at different pH values

[0145] Prepare samples according to the ratios in Table 1. Add phospholipid to absolute ethanol and stir at 45°C until completely dissolved; after the solution is clear and transparent, add cholesterol, ceteth-25, and pentaerythrityl tetra(bis-tert-butyl hydroxyhydrocinnamate), and stir until the solution is clear and transparent and completely dissolved; then add glycerol and pentylene glycol and stir to dissolve; respectively add 1 mol / L NaOH solution to adjust the pH to 6.2 - 6.7, or do not add NaOH solution, and the pH of the system is 4.9 to obtain primary emulsions with different pH values; then add preservatives and mix evenly to obtain two samples.

[0146] Place the two samples in a room temperature environment without direct sunlight, visually observe their appearance properties, measure their particle sizes with a Malvern laser particle size analyzer, and detect the encapsulation efficiency with a UV spectrophotometer. The results are shown in Table 1.

[0147] Table 1

[0148]

[0149] The experimental results show that: the prepared samples in the examples of the present invention have no stratification, no leakage, no agglomeration, and no flocculation phenomena. The results show that after adjusting the pH, the particle size of the proliposomes and DPI are smaller, and the particle size is more uniform. It shows that the proliposomes prepared according to the component contents and preparation methods used in the present invention have good properties.

[0150] Example 3

[0151] Compare proliposomes prepared with different glycerol addition amounts

[0152] Prepare samples according to the ratios in Table 2. Add phospholipids to absolute ethanol and stir at 45 °C until completely dissolved; after the solution is clear and transparent, add cholesterol, polyoxyethylene 25 stearyl ether, and pentaerythrityl tetrakis(bis-tert-butylhydroxyhydrocinnamate), and stir until the solution is clear and transparent and completely dissolved; then add glycerol with different mass percentages and stir and dissolve with pentanediol; add 1 mol / L NaOH solution to adjust the pH to 6.2 - 6.7 to obtain the primary emulsion; rotate and evaporate the primary emulsion with a rotary evaporator at 50 °C and 40 rpm for 60 min to remove absolute ethanol, and add 0.05% p-hydroxybenzyl alcohol as a preservative and mix well to obtain the sample.

[0153] Place the two samples in an environment at room temperature without direct sunlight, visually observe their appearance properties, measure their particle sizes with a Malvern laser particle size analyzer, and detect the entrapment efficiency with an ultraviolet spectrophotometer. The results are shown in Table 2.

[0154] Table 2

[0155]

[0156] The experimental results show that: when the glycerol addition amount used in the present invention is 26%, it has the effect of maintaining the stability of the liposome properties. The liposomes prepared at this ratio have no stratification, no leakage, no agglomeration, and no flocculation phenomena, and have the highest entrapment efficiency. Their appearance, properties, and particle size meet the actual application requirements.

[0157] Example 4

[0158] Compare proliposomes prepared with different ethanol contents

[0159] Prepare samples according to the ratios in Table 3. Add phospholipids to absolute ethanol and stir at 45 °C until completely dissolved; after the solution becomes clear and transparent, add cholesterol, behenyl alcohol polyether-25, and pentaerythrityl tetra(bis-tert-butyl hydroxyhydrocinnamate), and stir until the solution becomes clear and transparent and completely dissolved; then add glycerol and pentylene glycol and stir to dissolve; add 1 mol / L NaOH solution (adjust the pH to 6.2 - 6.7) to obtain the primary emulsion; respectively evaporate the primary emulsion with a rotary evaporator at 50 °C and 40 rpm for 60 min to remove absolute ethanol, add 0.05% p-hydroxybenzyl alcohol as a preservative and mix well to obtain two samples.

[0160] Place the samples in an environment at room temperature without direct sunlight, visually observe their appearance properties, measure their particle sizes with a Malvern laser particle size analyzer, and detect the encapsulation efficiency with a UV spectrophotometer. The results are shown in Table 3.

[0161] Table 3

[0162]

[0163] The experimental results show that: the samples prepared by the present invention have no phenomena of stratification, leakage, aggregation, and flocculation. The experimental results show that after removing the irritating component absolute ethanol from the formula, the encapsulation efficiency of the active substance loading is not reduced, indicating that the pre-liposomes prepared according to the component contents and preparation methods used in the present invention have good properties.

[0164] Example 5

[0165] Prepare samples according to the ratios in Table 4. Add phospholipids to absolute ethanol and stir at 45 °C until completely dissolved; after the solution becomes clear and transparent, add the first oil-phase emulsifier shown in Table 4, behenyl alcohol polyether-25, and pentaerythrityl tetra(bis-tert-butyl hydroxyhydrocinnamate), and stir until the solution becomes clear and transparent and completely dissolved; then add glycerol with different mass percentages and stir to dissolve with pentylene glycol; add 1 mol / L NaOH solution and adjust the pH to 6.2 - 6.7 to obtain the primary emulsion; evaporate the primary emulsion with a rotary evaporator at 50 °C and 40 rpm for 60 min to remove absolute ethanol, add 0.05% p-hydroxybenzyl alcohol as a preservative and mix well to obtain the samples.

[0166] Table 4

[0167]

[0168]

[0169] The experimental results show that: compared with sodium cholate or polyoxyethylene 21 stearyl ether, cholesterol is used as the first oil-phase emulsifier in the present invention, and it cooperates with other components. The prepared samples have no layering or leakage phenomena, and the appearance is transparent, the color is lighter, the properties are better, and it is more easily applied to actual formula applications.

[0170] Example 6

[0171] Prepare the sample according to the ratio in Table 5. Add phospholipids to absolute ethanol and stir at 45 °C until completely dissolved; after the solution is clear and transparent, add cholesterol, the second oil-phase emulsifier, and pentaerythritol tetrakis(bis-tert-butylhydroxyhydrocinnamate), and stir until the solution is clear and transparent and completely dissolved; then add glycerol with different mass percentages and stir and dissolve with pentylene glycol; add 1 mol / L NaOH solution and adjust the pH to 6.2 - 6.7 to obtain the primary emulsion; rotate and evaporate the primary emulsion with a rotary evaporator at 50 °C and 40 rpm for 60 min to remove absolute ethanol, add 0.05% p-hydroxybenzyl alcohol as a preservative and mix well to obtain the sample.

[0172] Table 5

[0173]

[0174]

[0175] The experimental results show that: compared with triglyceride caprylate / caprate and monoglyceride, behenyl alcohol polyether-25 is used as the second oil-phase emulsifier in the present invention, and it cooperates with other components. The prepared samples have no layering or leakage phenomena, and the appearance is transparent, the color is lighter, the properties are better, and it is more easily applied to actual formula applications.

[0176] Example 7

[0177] Compare liposomes with different usage methods

[0178] This example provides a pre-liposome preparation containing water-soluble active substances. Prepare the pre-liposome according to the preparation method of Example 1, and prepare liposomes encapsulating niacinamide according to different preparation methods in Table 6. Place the sample in an environment at room temperature and out of direct sunlight, visually observe its appearance and properties, measure its particle size with a Malvern laser particle size analyzer, and detect the encapsulation efficiency with a UV spectrophotometer. The results are shown in Table 6.

[0179] Table 6

[0180]

[0181]

[0182] The experimental results show that: after dissolving the water-soluble substance in pure water and then adding it to the proliposome, the resulting liposome is more uniform and has a higher encapsulation efficiency.

[0183] Example 8

[0184] Comparing proliposomes diluted by different multiples

[0185] This example provides a general and rapid method for preparing proliposome formulations of water-soluble active substances. After preparing the proliposome according to the preparation method of Example 1, it was diluted 2, 4, 5, 8, 10, and 100 times. The samples were placed in a room-temperature environment without direct sunlight, and their appearance was visually observed. The particle size was measured using a Malvern laser particle size analyzer, and the encapsulation efficiency was detected using an ultraviolet spectrophotometer. The results are shown in Table 7.

[0186] Table 7

[0187]

[0188] The experimental results show that: after diluting the proliposome formulation of water-soluble active substances prepared by the present invention by 10 times, the encapsulation efficiency still reaches more than 60%.

[0189] Example 9

[0190] Comparing liposomes encapsulating different water-soluble active substances

[0191] This example provides a general and rapid method for preparing proliposome formulations of water-soluble active substances. After preparing the proliposome according to the preparation method of Example 1, the proliposome was preheated at 40°C and mixed well by magnetic stirring; different water-soluble active substances were added to pure water as the aqueous phase and preheated; the aqueous phase was slowly added to the proliposome and mixed well by magnetic stirring for 30 min. The samples were placed in a room-temperature environment without direct sunlight, and their appearance was visually observed. The particle size was measured using a Malvern laser particle size analyzer, and the encapsulation efficiency was detected using an ultraviolet spectrophotometer. The results are shown in Table 8.

[0192] Among them, a. The encapsulation efficiency of the liposome encapsulating nicotinamide prepared in Example 9 was tested.

[0193] The content of nicotinamide in the prepared nicotinamide liposome was measured using an ultraviolet spectrophotometer at a wavelength of 262 nm.

[0194] First, prepare a 300 μg / mL niacinamide solution, and perform serial dilutions with phosphate buffer solution (PBS) to obtain the proportional relationship between the niacinamide concentration and the absorbance value at a wavelength of 262 nm, and plot the standard curve. The regression equation of the standard curve is y = 0.02224x - 0.00609, where X is the concentration of the niacinamide solution in μg / mL, y is the absorbance value of the niacinamide solution at 262 nm, and the regression coefficient is 0.99991.

[0195] Using a 10KD ultrafiltration tube, take 0.5 mL of niacinamide liposomes in the inner tube, and centrifuge for 15 min at a centrifugal force of 14000 rpm to separate the niacinamide liposomes and free niacinamide. Collect the filtrate and record the volume of the collected filtrate, which is the volume of free niacinamide. Mix the niacinamide liposomes and 0.2% surfactant polyethylene glycol octylphenyl ether (Triton x-100) in a ratio of 1:1, let it stand for half an hour to rupture the membrane, take an appropriate amount of the ruptured niacinamide liposomes and the ultrafiltration filtrate, after appropriate dilution, use a UV spectrophotometer to measure the absorbance value at 262 nm, and calculate the total concentration of niacinamide and the concentration of free niacinamide in the niacinamide liposomes.

[0196] Entrapment efficiency = (total niacinamide concentration * 0.5 mL - free niacinamide concentration * filtrate volume) / (total niacinamide concentration * 0.5 mL) * 100%.

[0197] b. Perform an entrapment efficiency test on ectoine encapsulated in the pre-liposome preparation for the rapid preparation of water-soluble active substances prepared in Example 9.

[0198] Accurately weigh 0.1 g (accurate to 0.0001 g) of ectoine reference substance and place it in a 50 mL volumetric flask, dissolve it with methanol and make up to the mark to obtain the standard stock solution. Take different volumes of the standard stock solution and dilute it with 50% methanol aqueous solution to prepare ectoine standard series solutions with mass concentrations of 5, 20, 50, 100, 150, and 200 mg / L respectively. According to the chromatographic method: mobile phase: phase A, methanol; phase B, sodium dihydrogen phosphate buffer solution (40 mmol sodium dihydrogen phosphate + 10 mmol 1-heptanesulfonic acid sodium, dissolved in 1000 mL of water, adjusted to pH 3.0 with phosphoric acid), flow rate: 0.8 mL / min, retention time 10 min, injection volume 10 μL, column temperature 30 °C; detection wavelength: 210 nm; chromatographic column C 18 to measure the peak area. Taking the peak area as the ordinate Y and the standard product concentration as the abscissa X (mg / L), the regression equation of the standard curve is y = 15.445x + 79.6867, and the regression coefficient is 0.99905.

[0199] Using a 3KD ultrafiltration tube, take 0.5 mL of ectoine liposome in the inner tube, centrifuge for 15 min at a centrifugal force of 10000 rpm to separate the ectoine liposome and free ectoine, collect the filtrate and record the volume of the collected filtrate, which is the volume of free ectoine. Mix the ectoine liposome and methanol in a ratio of 1:1, let it stand for half an hour to break the membrane, take an appropriate amount of the broken membrane ectoine liposome and ultrafiltration filtrate, after appropriate dilution, measure its peak area by high performance liquid chromatography, and calculate the total concentration of ectoine and the concentration of free ectoine in the ectoine liposome.

[0200] Entrapment efficiency = (total ectoine concentration * 0.5 mL - free ectoine concentration * filtrate volume) / (total ectoine concentration * 0.5 mL) * 100%.

[0201] c. Perform an entrapment efficiency test on ergothioneine encapsulated in the pre-liposome preparation for the universal and rapid preparation of water-soluble active substances prepared in Example 9.

[0202] Use an ultraviolet spectrophotometer to measure the content of ergothioneine in the prepared ergothioneine liposome at a wavelength of 257 nm.

[0203] First, prepare a 0.1 mg / mL ergothioneine solution and perform a series of dilutions with pure water to obtain the proportional relationship between the ergothioneine concentration and the absorbance value at a wavelength of 257 nm, and draw a standard curve. The regression equation of the standard curve is y = 68.76x + 0.00125, where X is the concentration of the ergothioneine solution in mg / mL, y is the absorbance value of the ergothioneine solution at 257 nm, and the regression coefficient is 0.99974.

[0204] Using a 3KD ultrafiltration tube, take 0.5 mL of ergothioneine liposome in the inner tube, centrifuge for 15 min at a centrifugal force of 10000 xg to separate the ergothioneine liposome and free ergothione, collect the filtrate and record the volume of the collected filtrate, which is the volume of free ergothione. Mix the ergothioneine liposome and methanol in a ratio of 1:1, let it stand for half an hour to break the membrane, take an appropriate amount of the broken membrane ergothioneine liposome and ultrafiltration filtrate, after appropriate dilution, measure its absorbance value at 257 nm by ultraviolet spectrophotometer, and calculate the total concentration of ergothione and the concentration of free ergothione in the ergothioneine liposome.

[0205] Entrapment efficiency = (total ergothione concentration * 0.5 mL - free ergothione concentration * filtrate volume) / (total ergothione concentration * 0.5 mL) * 100%.

[0206] d. Perform an entrapment efficiency test on heptapeptide-1 encapsulated in the pre-liposome preparation for the universal and rapid preparation of water-soluble active substances prepared in Example 9.

[0207] The content of heptapeptide-1 in the prepared heptapeptide-1 liposome was measured using an ultraviolet spectrophotometer at a wavelength of 280 nm.

[0208] First, a 0.1 mg / mL heptapeptide-1 solution was prepared and serially diluted with pure water to obtain the proportional relationship between the concentration of heptapeptide-1 and the absorbance value at a wavelength of 280 nm, and a standard curve was plotted. The regression equation of the standard curve was y = 68.76x + 0.00125, where X was the concentration of the heptapeptide-1 solution in mg / mL and y was the absorbance value of the heptapeptide-1 solution at 257 nm, and the regression coefficient was 0.99974.

[0209] Using a 3KD ultrafiltration tube, 0.5 mL of heptapeptide-1 liposome was placed in the inner tube, and centrifuged for 15 min at a centrifugal force of 10000 xg to separate the heptapeptide-1 liposome and free heptapeptide-1. The filtrate was collected and the volume of the collected filtrate was recorded, which was the volume of free heptapeptide-1. The heptapeptide-1 liposome and methanol were mixed in a ratio of 1:1, and after standing for half an hour, the membrane was disrupted. An appropriate amount of the disrupted heptapeptide-1 liposome and ultrafiltration filtrate were taken, appropriately diluted, and the absorbance value at 257 nm was measured using an ultraviolet spectrophotometer to calculate the total concentration of heptapeptide-1 in the heptapeptide-1 liposome and the concentration of free heptapeptide-1.

[0210] Entrapment efficiency = (total heptapeptide-1 concentration * 0.5 mL - free heptapeptide-1 concentration * filtrate volume) / (total heptapeptide-1 concentration * 0.5 mL) * 100%

[0211] e. The entrapment efficiency of tranexamic acid encapsulated in the pre-liposome preparation for the universal and rapid preparation of water-soluble active substances prepared in Example 9 was tested.

[0212] The content of lactobionic acid in the prepared lactobionic acid liposome was measured using an ultraviolet spectrophotometer at a wavelength of 261 nm.

[0213] First, an 80 mg / mL tranexamic acid solution was prepared and serially diluted with pure water to obtain the proportional relationship between the concentration of tranexamic acid and the absorbance value at a wavelength of 261 nm, and a standard curve was plotted. The regression equation of the standard curve was y = 0.00231x - 0.00118, where X was the concentration of the tranexamic acid solution in mg / mL and y was the absorbance value of the tranexamic acid solution at 261 nm, and the regression coefficient was 0.99485.

[0214] Using a 3KD ultrafiltration tube, take 0.5 mL of tranexamic acid liposomes in the inner tube, centrifuge for 15 min under the condition of a centrifugal force of 10,000 xg to separate tranexamic acid liposomes and free tranexamic acid, collect the filtrate and record the volume of the collected filtrate, which is the volume of free tranexamic acid. Mix the tranexamic acid liposomes and methanol in a ratio of 1:1, let it stand for half an hour to rupture the membrane, take an appropriate amount of the ruptured tranexamic acid liposomes and ultrafiltration filtrate, after appropriate dilution, use a UV spectrophotometer to measure the absorbance value at 294 nm, and calculate the total concentration of tranexamic acid and the concentration of free tranexamic acid in the tranexamic acid liposomes.

[0215] Entrapment efficiency = (total tranexamic acid concentration * 0.5 mL - free tranexamic acid concentration * filtrate volume) / (total tranexamic acid concentration * 0.5 mL) * 100%.

[0216] f. Perform an entrapment efficiency test on the lactic acid encapsulated in the universal rapid preparation of water-soluble active ingredient pre-liposome preparation obtained in Example 9.

[0217] Use a UV spectrophotometer to measure the lactic acid content in the prepared lactic acid liposomes at a wavelength of 294 nm.

[0218] First, prepare a 150 mg / mL lactic acid solution and perform a series of dilutions with pure water to obtain the proportional relationship between the lactic acid concentration and the absorbance value at a wavelength of 294 nm, and draw a standard curve. The regression equation of the standard curve is y = 0.00192x - 0.00128, where X is the concentration of the lactic acid solution in mg / mL and y is the absorbance value of the lactic acid solution at 294 nm, and the regression coefficient is 0.9994.

[0219] Using a 3KD ultrafiltration tube, take 0.5 mL of lactic acid liposomes in the inner tube, centrifuge for 15 min under the condition of a centrifugal force of 10,000 xg to separate lactic acid liposomes and free lactic acid, collect the filtrate and record the volume of the collected filtrate, which is the volume of free lactic acid. Mix the lactic acid liposomes and methanol in a ratio of 1:1, let it stand for half an hour to rupture the membrane, take an appropriate amount of the ruptured lactic acid liposomes and ultrafiltration filtrate, after appropriate dilution, use a UV spectrophotometer to measure the absorbance value at 294 nm, and calculate the total concentration of lactic acid and the concentration of free lactic acid in the lactic acid liposomes.

[0220] Entrapment efficiency = (total lactic acid concentration * 0.5 mL - free lactic acid concentration * filtrate volume) / (total lactic acid concentration * 0.5 mL) * 100%.

[0221] Table 8

[0222]

[0223] The experimental results show that: the pre-liposome preparation for encapsulating water-soluble active substances prepared in Example 1 of the present invention has an encapsulation efficiency of over 90% for various water-soluble active substances.

[0224] Example 10

[0225] This example provides an essence containing a pre-liposome preparation for encapsulating water-soluble active substances, which contains the pre-liposome prepared in Example 1. Specifically, it consists of the following raw material components by mass percentage: 30% of the pre-liposome in Example 1, 3% of glycerol, 5% of propylene glycol, 5% of butylene glycol, 1% of pentylene glycol, 1% of polyglyceryl-10 myristate, 0.03% of EDTA-2Na, 0.4% of AVC (acryloyldimethyltaurine / VP copolymer), 0.2% of hydroxyacetophenone, and the balance is deionized water.

[0226] This example also provides a preparation method for the above essence, which specifically includes the following steps: First, stir AVC evenly in glycerol, propylene glycol, butylene glycol, and pentylene glycol, add polyglyceryl-10 myristate, hydroxyacetophenone, EDTA-2 sodium, and pure water, heat to 85°C, and keep warm for 30 min; cool to 40°C, and then add a pre-liposome preparation in Example 1 and mix evenly.

[0227] Example 11

[0228] This example provides an essence containing the liposome encapsulating niacinamide prepared in Example 9, and the component ratio is shown in Table 9.

[0229] Table 9

[0230]

[0231]

[0232] The preparation method is as follows:

[0233] First, disperse AVC well in 50% water, then add glycerol, butylene glycol, pentylene glycol, hydroxyacetophenone, EDTA-2Na, and polyglyceryl-10 myristate, heat to 85°C and keep warm for 30 min; after cooling to room temperature, add the liposome encapsulating niacinamide prepared in Example 10, mix evenly, and make up the water to 100%.

[0234] Stability investigation

[0235] For the pre-liposome preparation for universally and rapidly preparing water-soluble active substances prepared in Example 1 ( Figure 1 ), the pre-liposome preparation for universally and rapidly preparing water-soluble active substances obtained in Example 8 diluted 10 times ( Figure 2 ) and 100 times ( Figure 3) The nicotinamide liposomes ([ Figure 4 ) and ectoin liposomes ([ Figure 5 ) prepared in Example 9 were respectively filled into 7 vials and sealed, and stored in environments of normal temperature, refrigeration (4°C), freezing (-15°C), heating (45°C), freeze-thawing (alternating between -15°C and 45°C), light avoidance, and light exposure (28°C). Particle size, PDI, and zeta potential were measured at 7, 14, 30, 60, and 90 days. The results are as Figures 1 to 5 shown. It can be seen from Figures 1 to 5 that the pre-liposome formulations for the universal and rapid preparation of water-soluble active substances, the pre-liposome formulations for the universal and rapid preparation of water-soluble active substances diluted 10 times and 100 times, and the liposomes prepared by encapsulating nicotinamide and ectoin in the pre-liposome formulations for the universal and rapid preparation of water-soluble active substances have good stability in terms of particle size, PDI, and zeta potential in seven different environments within 90 days.

[0236] (3) Stability test of pre-liposomes and pre-liposomes encapsulating nicotinamide in essence

[0237] The pre-liposome formulations for the universal and rapid preparation of water-soluble active substances prepared in Example 1 ([ Figure 6 ), the essence of the pre-liposome formulations for water-soluble active substances prepared in Example 10 ([ Figure 7 ), the pre-liposome formulations for the universal and rapid preparation of water-soluble active substances prepared in Example 8 diluted 10 times ([ Figure 8 ) and 100 times ([ Figure 9 ), and the essence of the liposomes prepared by encapsulating nicotinamide in the pre-liposomes for water-soluble active substances prepared in Example 11 ([ Figure 10 ) were subjected to stability investigation. It can be seen from Figures 6 to 10 that each reference spectrum is relatively close, with ΔBS less than 0.5, indicating a relatively stable state. It can be seen that the pre-liposome formulations for the universal and rapid preparation of water-soluble active substances and their essence applied to the essence matrix have good stability and can be simply and stably applied to cosmetic formulations.

[0238] The technical features of the above-described embodiments can be combined arbitrarily. For the sake of brevity of description, not all possible combinations of the technical features in the above embodiments are described. However, as long as there is no contradiction in the combination of these technical features, it should be considered as the scope described in this specification.

[0239] The above-described embodiments merely represent several implementation manners of the present invention. The description thereof is relatively specific and detailed, but it should not be construed as a limitation on the scope of the invention patent. It should be noted that for those of ordinary skill in the art, without departing from the concept of the present invention, several modifications and improvements can still be made, and these all fall within the protection scope of the present invention. Therefore, the protection scope of the present invention patent shall be subject to the appended claims.

Claims

1. A pre-liposome preparation that can be used to encapsulate water-soluble active substances, characterized in that, It is mainly made of raw materials with the following mass percentages: The emulsifier includes behenyl alcohol polyether-25.

2. The pre-liposome preparation according to claim 1, wherein The sum of the masses of the phospholipid, ethanol, cholesterol, emulsifier and antioxidant is A, and the mass of the polyol is B. The ratio of A to B is (1.5 to 2.0):

1.

3. The pre-liposome preparation according to claim 1, wherein, It satisfies at least one of the following (1) to (2): (1) The phospholipid is soy lecithin PC60; (2) The mass ratio of the phospholipid to cholesterol is (28 to 32):

1.

4. The pre-liposome preparation according to claim 1, characterized in that, The polyol includes one or a mixture of two of glycerol and pentylene glycol.

5. The pre-liposomal preparation according to claim 4, characterized in that, It is mainly made of raw materials with the following mass percentages:

6. The pre-liposomal preparation according to any one of claims 1 to 5, characterized in that, The antioxidant is pentaerythritol tetra(bis-tert-butylhydroxyhydrocinnamate).

7. The proliposomal preparation according to any one of claims 1 to 5, characterized in that, The raw materials also include one or more of a preservative and a pH regulator.

8. The pre-liposome preparation according to claim 7, characterized in that, The preservative is p-hydroxyacetophenone, and the pH regulator is NaOH.

9. The pre-liposome preparation according to any one of claims 1 to 5, characterized in that, The particle size of the pre-liposome preparation is 100 nm to 250 nm, the PDI is 0.3 to 0.6, and the pH is 6.2 to 6.

7.

10. A method for preparing a pre-liposome preparation according to any one of claims 1 to 9, which is used for encapsulating water-soluble active substances, characterized in that, It includes the following steps: Mix the phospholipid, cholesterol, emulsifier and antioxidant in ethanol to prepare an oil-phase mixture; Mix the polyol and the oil-phase mixture to prepare a primary emulsion; Perform heat treatment on the primary emulsion to remove the ethanol therein.

11. The preparation method according to claim 10, characterized in that, It satisfies at least one of the following (1) to (2): (1) The process parameters for preparing the oil-phase mixture include: the temperature of the system is 40 °C to 50 °C; (2) The process parameters for heat treatment include: vacuum concentration, the temperature is 40 °C to 60 °C, and the time is 30 min to 90 min.

12. A liposome encapsulating a water-soluble active substance, characterized in that, It includes water, a water-soluble active substance, and the pre-liposome preparation according to any one of claims 1 to 9 that can be used to encapsulate the water-soluble active substance.

13. The liposome encapsulating a water-soluble active substance according to claim 12, wherein, In terms of mass percentage, it is mainly made of raw materials with the following mass percentages: Water 50% to 79%; Water-soluble active substance 0.9% to 10%; and Pre-liposome preparation 20.1% to 40%.

14. A cosmetic, characterized in that, It includes the pre-liposome preparation according to any one of claims 1 to 9 that can be used to encapsulate the water-soluble active substance, or the liposome encapsulating the water-soluble active substance according to claim 12 or 13.

15. The cosmetic according to claim 14, characterized in that, The cosmetic is selected from at least one of a facial mask, eye cream, face cream, primer, essence, lotion and skin softener.

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