WO2018214915A1 - 乳化脂质体组合物及其制备方法 - Google Patents

乳化脂质体组合物及其制备方法 Download PDF

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WO2018214915A1
WO2018214915A1 PCT/CN2018/088051 CN2018088051W WO2018214915A1 WO 2018214915 A1 WO2018214915 A1 WO 2018214915A1 CN 2018088051 W CN2018088051 W CN 2018088051W WO 2018214915 A1 WO2018214915 A1 WO 2018214915A1
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weight
liposome composition
emulsified
solution
liposome
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PCT/CN2018/088051
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English (en)
French (fr)
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林咏翔
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大江生医股份有限公司
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Priority to BR112019024505-7A priority Critical patent/BR112019024505A2/pt
Priority to RU2019138555A priority patent/RU2746414C1/ru
Priority to EP18805652.7A priority patent/EP3632403A4/en
Priority to AU2018272337A priority patent/AU2018272337B2/en
Priority to CN202311188409.6A priority patent/CN117205094A/zh
Priority to CN201880026604.XA priority patent/CN110536674A/zh
Priority to US16/611,508 priority patent/US20200107999A1/en
Publication of WO2018214915A1 publication Critical patent/WO2018214915A1/zh
Priority to US17/177,226 priority patent/US20210169805A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/02—Cosmetics or similar toiletry preparations characterised by special physical form
    • A61K8/14—Liposomes; Vesicles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/02—Cosmetics or similar toiletry preparations characterised by special physical form
    • A61K8/04—Dispersions; Emulsions
    • A61K8/06—Emulsions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/19—Cosmetics or similar toiletry preparations characterised by the composition containing inorganic ingredients
    • A61K8/24—Phosphorous; Compounds thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/55—Phosphorus compounds
    • A61K8/553—Phospholipids, e.g. lecithin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q19/00—Preparations for care of the skin
    • A61Q19/007—Preparations for dry skin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2800/00—Properties of cosmetic compositions or active ingredients thereof or formulation aids used therein and process related aspects
    • A61K2800/40—Chemical, physico-chemical or functional or structural properties of particular ingredients
    • A61K2800/41—Particular ingredients further characterized by their size
    • A61K2800/412—Microsized, i.e. having sizes between 0.1 and 100 microns
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2800/00—Properties of cosmetic compositions or active ingredients thereof or formulation aids used therein and process related aspects
    • A61K2800/40—Chemical, physico-chemical or functional or structural properties of particular ingredients
    • A61K2800/52—Stabilizers
    • A61K2800/522—Antioxidants; Radical scavengers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2800/00—Properties of cosmetic compositions or active ingredients thereof or formulation aids used therein and process related aspects
    • A61K2800/80—Process related aspects concerning the preparation of the cosmetic composition or the storage or application thereof
    • A61K2800/805—Corresponding aspects not provided for by any of codes A61K2800/81 - A61K2800/95

Definitions

  • This invention relates to a liposome solution, and more particularly to an emulsified liposome composition and a process for its preparation.
  • Liposomes are mainly made of phospholipids and are spherical vesicles formed by a lipid bilayer structure including an exposed hydrophilic layer and an internal hydrophobic layer. Since liposome has a lipid structure similar to that of an organism's cell membrane, it has good biocompatible and biodegradable and can be widely used as a carrier for drug administration, release or delivery of related components.
  • the active ingredient is encapsulated in a liposome carrier and applied, which not only has the advantages of increasing the stability of the active ingredient, reducing toxicity and transporting various components, but also reducing the occurrence of allergic conditions through its lipid characteristics and size. Accelerates the metabolism of the body and enhances the penetration of drugs or active ingredients.
  • liposomes In addition to its application to drug delivery, liposomes have been increasingly used in skin care products or cosmetics in recent years. Especially in the skin care products, since the absorption directly affects the action and effect of the active ingredients therein, the characteristics of easy absorption or penetration have always been an important consideration for manufacturers or consumers. In particular, since skin care products or cosmetics are applied to the skin, and the skin is the first shielding important to foreign substances, it cannot be easily penetrated. Therefore, the maintenance-related solutions affect the permeability and penetration rate of the skin. The effect of maintenance ingredients on the skin or deeper tissues. Therefore, if the characteristics of the liposome can be passed to the deep layer of the skin, the maintenance or promotion of the skin care product or the cosmetic can be more effectively exerted.
  • the liposome prepared in the general preparation process is too large in particle size, which is not conducive to the penetration and absorption of the skin; and because the body is relatively large, the stability of the carrier is insufficient, and the composition is easily affected by the liposome. It breaks and leaks, greatly reducing the effect of liposome transfer and action.
  • Another object of the present invention is to provide an emulsified liposome composition having excellent moisturizing effect and antioxidant activity, which enhances the skin by combining the active ingredients of moisturizing and anti-oxidizing effects with the penetration of liposomes. Moisturizing ability and antioxidant capacity.
  • Still another object of the present invention is to provide a liposome composition having high temperature sterilization treatment characteristics, wherein the liposome can maintain a stable structure after high temperature treatment, so as to be applicable to various products. Process the sterilization process.
  • Still another object of the present invention is to provide a method for preparing an emulsified liposome composition which is subjected to emulsification homogenization at a high pressure and an appropriate temperature to prepare an emulsified liposome composition containing a liposome having a small particle diameter.
  • the emulsified liposome composition may include a phospholipid, and the weight ratio of phosphatidyl ethanol amine to Phosphatidylcholine contained in the phospholipid may be 3 ⁇ 6:1, preferably 4:1.
  • the liposomes formed from the emulsified liposome composition retain their intact structure after 30 minutes of treatment at 95 °C.
  • the phospholipid may be present in an amount of from about 0.1% to about 2% by weight based on 100% by weight of the emulsified liposome composition.
  • the emulsified liposome composition may comprise from 3% by weight to 7% by weight of 1,3-butanediol (Butane-1,3-diol), 0.4% by weight to 0.7% 1% by weight of hydroxyacetophenone (Hydroxyacetophenone) and 0.4% by weight to 0.7% by weight of hexylene glycol (Hexane-1,6-diol); from 1% by weight to 5% by weight of glycerol (Glycerol a second component group consisting of 0.01% by weight to 0.3% by weight of Xantham Gum and 0.1% by weight to 0.3% by weight of Hydrolyzed sclerotium gum; 0.5% by weight to 10% by weight a third component group consisting of 0.1% active ingredient and 0.1% by weight to 2% by weight of lecithin; and water.
  • 1,3-butanediol butane-1,3-diol
  • Hydroxyacetophenone hydroxyacetophenone
  • the active ingredient in the emulsified liposome composition may be selected from the group consisting of red peony extract, coconut oil, anti-sensitive plant complex, water-locking magnet, Glycosyl trehalose, and A group consisting of their combinations.
  • the active ingredient may be 0.1% by weight to 2% by weight of red peony extract, 0.1% by weight to 2% by weight of coconut oil, and 0.1% by weight to 2% by weight of anti-sensitive plant compound.
  • the composition is composed of 0.1% by weight to 2% by weight of the lock water magnet and 0.1% by weight to 2% by weight of the sugar-based trehalose.
  • the liposome formed in the emulsified liposome composition may have a particle diameter of from 10 nm to 1000 nm, preferably from 300 nm to 400 nm, more preferably about 350 nm.
  • a process for the preparation of an emulsified liposome composition comprising the steps of: preparing a first solution to provide 3% by weight to 7% by weight of 1,3-butanediol, 0.4 5% by weight to 0.7% by weight of hydroxyacetophenone and 0.4% by weight to 0.7% by weight of hexanediol, which are uniformly mixed and dispersed, and then heated at 60 ° C to 80 ° C until the solution becomes transparent and Undissolved particles, cooled to 25 ° C ⁇ 30 ° C; prepare a second solution, provide 1% by weight to 5% by weight of glycerin, 0.01% to 0.3% by weight of xanthan gum and 0.1% to 0.3% by weight of small hydrolysis After the nuclear gelatin is uniformly mixed and dispersed, 74% by weight to 94.4% by weight of water is added.
  • the heating can be carried out at 60 ° C to 80 ° C until the colloid has no agglomeration, and the temperature is lowered to 25 ° C to 30 ° C for use; the third solution is prepared to provide 0.5% by weight to 10% by weight of the active ingredient and 0.1% by weight to 2
  • the weight% of lecithin is added to the second solution and stirred well.
  • Stirring can be carried out at a speed of 1500 rpm to 3500 rpm for 5 minutes to 15 minutes;
  • preparing a fourth solution the third solution is homogenized at a pressure of 300 bar to 600 bar and a temperature of 25 ° C to 30 ° C;
  • the fourth solution is added to the first solution and stirred well.
  • the stirring can be carried out at a rotation speed of 1,500 rpm to 3,500 rpm for 5 minutes to 15 minutes.
  • the active ingredient in the preparation method of the emulsified liposome composition may be selected from the group consisting of red peony extract, coconut oil, anti-sensitive plant complex, water-locking magnet, sugar-based trehalose and The combination consists of groups, but is not limited to this.
  • the active ingredient in the method for preparing the emulsified liposome composition, may be from 0.1% by weight to 2% by weight of red peony extract, 0.1% by weight to 2% by weight of coconut oil, 0.1%.
  • the anti-sensitive plant complex is composed by weight% to 2% by weight, the lock water magnet of 0.1% by weight to 2% by weight, and the sugar-based trehalose of 0.1% by weight to 2% by weight.
  • the liposome formed by the emulsified liposome composition prepared by the aforementioned preparation method may have a particle diameter of 10 nm to 1000 nm, preferably 300 nm to 400 nm, more preferably about 350 nm. .
  • Example 1 is a comparison result of particle size distribution analysis of a liposome solution prepared in an example of the present invention, wherein (A) is the emulsified liposome composition prepared in Example 1, and (B) is the general preparation of Example 2. Liposomal solution.
  • Example 2 is an image of a liposome observed under an atomic force microscope of an emulsified liposome composition prepared in Example 1 of the present invention.
  • Fig. 3 is a graph showing the results of comparison of liposome solutions prepared in Example 1 (test group) and Example 2 (control group) in the skin moisturizing test of the arm.
  • Fig. 4 is a graph showing the results of comparison of the liposome structural stability test of the liposome solution prepared in Example 1 (test group) and different lecithin (comparative group) of the present invention.
  • Fig. 5 is an analysis chart for preparing components (A and B) contained in lecithin used in Example 1 (test group) of the present invention, and components of lecithin of the test group (C) and the comparison group (D).
  • Fig. 6 is a graph showing the results of comparison of liposome solutions prepared in Example 1 (test group) and Example 2 (control group) in the skin moisturizing test of the face.
  • Fig. 7 is a graph showing the results of comparison of liposome solutions prepared in Example 1 (test group) and Example 2 (control group) in the effect of melanin index.
  • Fig. 8 is a graph showing the results of comparison of the effect of ultraviolet spot number on the liposome solution prepared in Example 1 (test group) and Example 2 (control group) of the present invention.
  • Fig. 9 is a graph showing the results of comparison of the effects of liposome solutions prepared in Example 1 (test group) and Example 2 (control group) on the degree of skin redness.
  • Fig. 10 is a graph showing the results of comparison of the effect of the liposome solution prepared in Example 1 (test group) and Example 2 (control group) on the reduction ratio of wrinkles.
  • hydroxyacetophenone (trade name: SymSave) is purchased from Fulissa Co., Ltd.; xanthan gum (trade name: Rhodicare T) Purchased from Dingyun Industrial Co., Ltd.; hydrolyzed nucleocapsid gum (trade name: BioNest-Chcogum HG) was purchased from Jiacheng Chemical Co., Ltd.; red peony extract was purchased from Dajiangsheng Medical Co., Ltd.; coconut oil was purchased from Bodan Co., Ltd.; anti-sensitive plant complex (trade name: BIOPHYTEXTM LS 9832) was purchased from Baimao Co., Ltd.; lock water magnet was purchased from Gawei Industrial Co., Ltd.; sugar-based trehalose (trade name: Tornare) was purchased from Xianglin Enterprise Co., Ltd.; and lecithin (trade name: SOLEC) are available from Sol
  • each component of the second component group consisting of 1% by weight to 5% by weight of glycerin, 0.01% by weight to 0.3% by weight of xanthan gum, and 0.1% by weight to 0.3% by weight of hydrolyzed sclerotin is prepared. Firstly, the mixture is uniformly mixed and dispersed, and then 74% by weight to 94.4% by weight of deionized water is added, and heated at 60 ° C to 80 ° C until the colloid has no agglomeration, and the temperature is lowered to 25 ° C to 30 ° C for use. It is called the second solution.
  • the third solution is homogenized by a high pressure homogenizer at a pressure of 300 to 600 bar and a temperature of 25 to 30 ° C, and the solution treated as the fourth solution is referred to as a fourth solution.
  • the fourth solution is added to the first solution prepared as described above, and stirred at a rotational speed of 1,500 rpm to 3,500 rpm for 5 minutes to 15 minutes to complete the preparation of the emulsified liposome composition.
  • the source of the components required for preparing the general essence solution may be the same as in the foregoing Example 1.
  • the preparation please refer to the components listed in Table 2 below, and prepare 3% by weight to 7% by weight of 1,3-butanediol and 0.4% by weight to 0.7% by weight of hydroxyl groups based on 100% by weight of the liposome composition.
  • Each component of the first component group consisting of acetophenone and 0.4% by weight to 0.7% by weight of hexanediol is uniformly mixed and dispersed, and then heated at 60 ° C to 80 ° C until the solution becomes transparent and There is no undissolved granules, and the temperature is lowered to 25 ° C to 30 ° C for use.
  • the solution prepared at this time is referred to as a first solution.
  • each component of the second component group consisting of 1% by weight to 5% by weight of glycerin, 0.01% by weight to 0.3% by weight of xanthan gum, and 0.1% by weight to 0.3% by weight of hydrolyzed sclerotin is prepared. Firstly, the mixture is uniformly mixed and dispersed, and then 76% by weight to 94.5% by weight of deionized water is added, and heated at 60 ° C to 80 ° C until the colloid has no agglomeration, and the temperature is lowered to 25 ° C to 30 ° C for use. It is called the second solution.
  • the components of the comparative third component group composed of the water magnet and 0.1% by weight to 2% by weight of the sugar-based trehalose are sequentially added to the second solution, and then stirred at a speed of 1500 to 3500 rpm for 5 minutes to 15 minutes until The solution prepared at this time is referred to as a comparative third solution. Thereafter, the comparative third solution is added to the first solution prepared as described above, and stirred at a rotational speed of 1500 rpm to 3500 rpm for 5 minutes to 15 minutes to complete the preparation of a general liposome solution.
  • the emulsified liposome composition prepared in Example 1 was used as a test group, and the general liposome composition prepared in Example 2 was used as a control group, and the following particle size distribution analysis was performed.
  • 2 ml of the emulsified liposome composition prepared in Example 1 was diluted with 1:1 (v/v) deionized water, and similarly, 2 ml of the liposome composition prepared in Example 2 was taken out, 1 : 1 (v/v) diluted with deionized water. Then, 2 ml of the diluted solution was taken out separately for particle size analysis by Dynamic Light Scattering (DLS), and the results of the particle size distribution were shown by the detected intensity, as shown in FIG.
  • DLS Dynamic Light Scattering
  • the emulsified liposome composition (test group) prepared by the special component of the present invention and the preparation method has a particle size ranging from 100 nm to 1000 nm and from 40 nm to 200 nm. There is a large distribution between 200 nm and 1000 nm, and the average particle size is 350 nm, and the liposome solution (control group) obtained by the general preparation method of Fig. 1 (B) has an average particle size of 4716 nm. The particle size is obviously much larger than the test group. Therefore, the emulsified liposome composition prepared by the components of the embodiments of the present invention and the preparation method can effectively assist the penetration and absorption of the skin because of having a small particle size distribution.
  • the emulsified liposome composition prepared in Example 1 of the present invention was placed on a mica substrate, and observed by an atomic force microscope (Atomic Force Microscope System with Scan Asyst, Dimension Icon). The results are shown in Fig. 2 . From the results of Fig. 2, it was found that the emulsified liposome composition prepared by the present invention allows the liposome to have a two-layer structure. Basically, the components of the third component group are encapsulated on the bilayer membrane formed by the liposome, and the first component group, the two component group and the slightly third group are encapsulated in the liposome core cavity. The composition of the group.
  • the liposome solutions prepared in the foregoing Examples 1 and 2 were also prepared as the test group and the control group, respectively.
  • An appropriate amount of the liposome composition is uniformly mixed with 0.1 ⁇ g to 1 ⁇ g of Dil fluorescent dye (DiTC 18 (3)), and then applied to the treated pig ear skin at 0 minutes, 5 minutes, and 15 minutes after administration, respectively. After 8 hours, the results were observed and photographed using a conjugated bifocal microscope.
  • the test group observed a significant red fluorescence infiltration under the skin within 5 minutes, and after 15 minutes of application, the penetration depth was already about 200 ⁇ m.
  • the control group showed a penetration depth of only about 30 ⁇ m after 15 minutes of application, showing that the emulsified liposome composition prepared by the present invention has excellent penetration and can rapidly penetrate into the skin.
  • the liposome compositions prepared in the foregoing Examples 1 and 2 were also prepared as test groups and control groups, respectively. Apply appropriate amount of liposome composition to the inside of the test subject's arm, at 0 hours, 0.5 hours, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours and 8 hours after administration.
  • the moisture content of the skin was measured by a skin moisture measuring probe (Courage+Khazaka electronic GmbH), and the results are shown in Fig. 3. From the results of Fig. 3, when the emulsified liposome composition of the test group was applied, the average skin water content was about 14% to 20% higher than that of the control group at any measurement time point, and after 8 hours, the test was performed.
  • the average skin moisture content of the group was still 26% higher than that before use, showing that the emulsified liposome composition prepared by the present invention not only has an excellent moisturizing effect, but also has a long-lasting moisturizing property.
  • the liposome composition prepared in the foregoing Example 1 was prepared as a test group, and the same components and methods as in Example 1 were also used, except that lecithin was replaced with other commercially available lecithin (EMULMETIK 900, Lucas Neyer Cosmetics).
  • the liposome composition was used as a comparison group.
  • the test group and the comparison group were respectively heated at 95 ° C for 30 minutes under heating conditions equivalent to sterilization, and then the particle size and concentration thereof were measured, and the structure of the liposome was observed, and the results are shown in Fig. 4 . As is apparent from the results of Fig.
  • the structure of the emulsified liposome composition prepared by the present invention was still intact after heating at a high temperature, that is, its structural stability was higher than that of the comparative group.
  • the high temperature resistance is used in products that must be sterilized, which will greatly improve the stability of the product.
  • the lecithin used in the above Example 1 and the lecithin used in the above Example 6 were subjected to NMR spectral alignment, and the results are shown in (C) and (D) of Fig. 5, respectively.
  • (A) and (B) in Fig. 5 are the chemical structural formulas of phosphatidylcholine and phosphatidylethanolamine contained in lecithin, respectively.
  • From (C) the phospholipids contained in the lecithin used in the test group of Example 1 are known.
  • the ratio of acylethanolamine to phosphatidylcholine was approximately 4:1, while (D) showed a ratio of approximately 1:1 for the comparative group. It is speculated that it may be because the phosphatidylcholine has more amine groups, resulting in instability of the liposome structure in the comparative group.
  • the liposome compositions prepared in the foregoing Examples 1 and 2 were prepared as the test group and the control group, respectively, after appropriate dilution. Thereafter, the mask which was dried without adding any ingredients was cut into two left and right pieces for use. One of the tablets was soaked in a dilution of 10 ml of the test group, and the other was soaked with a dilution of 10 ml of the control group. Thereafter, the left and right masks were spread on the left and right faces of 10 subjects for about 15 minutes. Apply 3 times a week, and observe or test the following skin moisturizing, melanin index, ultraviolet spot number, skin redness and wrinkle reduction ratio on the 0th, 1st, 2nd, and 4th week, respectively. 6 to 10 are shown.
  • the melanin index can be detected by a melanin detection probe (Courage+Khazaka electronic GmbH), and the rest is quantified by image statistics.
  • FIG. 6 is a graph showing the comparison results of the liposome compositions prepared in Example 1 (test group) and Example 2 (control group) in the skin moisturizing test of the face. From the results of Fig. 6, it was found that when the emulsified liposome composition of the test group was administered, the moisture content of the facial skin was about 22.4% higher than that of the control group after the fourth week of administration, showing that the emulsified fat prepared by the present invention
  • the plastid composition not only has an excellent moisturizing effect on the face but also on the face.
  • FIG. 7 is a graph showing the results of comparison of the effect of the melanin index on the liposome compositions prepared in Example 1 (test group) and Example 2 (control group) of the present invention. From the results of Fig. 7, it was found that when the emulsified liposome composition of the test group was administered, the melanin index was significantly lowered by 5.9% after the fourth week of administration, showing that the emulsified liposome composition prepared by the present invention has excellent properties. Whitening effect.
  • Fig. 8 is a graph showing the results of comparison of the effects of ultraviolet spot number on the liposome compositions prepared in Example 1 (test group) and Example 2 (control group) of the present invention. From the results of Fig. 8, it was found that when the emulsified liposome composition of the test group was applied, the ultraviolet ray spot was also significantly reduced by 6.3% after the fourth week of application, showing that the emulsified liposome composition prepared by the present invention It has a good effect on skin repair after sunburn.
  • Fig. 9 is a graph showing the results of comparison of the effects of liposome compositions prepared in Example 1 (test group) and Example 2 (control group) on skin redness ratio.
  • the emulsified liposome composition of the test group was administered, the redness and inflammation of the skin was significantly reduced by 5.9% after the fourth week of administration, showing that the emulsified lipid prepared by the present invention showed The body composition has a good effect on the anti-inflammatory of the skin.
  • Fig. 10 is a graph showing the results of comparison of the effects of the liposome composition prepared in Example 1 (test group) and Example 2 (control group) of the present invention on the wrinkle reduction ratio.
  • the emulsified liposome composition of the test group was applied, the reduction of wrinkles by up to 23% after the fourth week of application showed that the emulsified liposome composition prepared by the present invention was applied to the skin wrinkles.
  • the flat has an excellent effect.
  • the emulsified liposome composition of the embodiment of the present invention can effectively exert the effective effect by rapidly transmitting the encapsulated active ingredient to the deep layer of the skin due to the small particle size, the better penetration force and the permeation rate.
  • the emulsified liposome composition of the embodiment of the present invention can be further applied to moisturizers, moisturizers, essences, lotions, make-up removers, aftershaves, mascara or eyeliner, creams, and even Shampoo and conditioner, as well as sun care products, anti-aging or anti-wrinkle, whitening and other care products.

Abstract

本发明是关于一种乳化脂质体组合物及其制备方法，该乳化脂质体组合物包括磷脂质，该磷脂质中所包含的磷脂酰乙醇胺与磷脂酰胆碱的重量比为3～6∶1。通过本发明制备的乳化脂质体组合物，其中的脂质体粒径小，因此可迅速且深入地渗透到皮肤的深层，且通过其所包裹的保湿或抗氧化有效成分，达到皮肤保湿与抗氧化的效果，并可广泛应用于保养、彩妆、抗晒等产品中。

Description

乳化脂质体组合物及其制备方法
相关申请的交叉引用
本申请主张在2017年05月23日在美国提交的美国专利申请号No.62/510,216的优先权，其全部内容通过引用包含于此。
技术领域
本发明是关于一种脂质体溶液，尤其是关于一种乳化脂质体组合物及其制备方法。
背景技术
脂质体(Liposome)主要是以磷脂质所制成，是由包括外露的亲水层以及内部的疏水层的脂双层结构所形成的球形囊泡。由于脂质体有着与生物体细胞膜相似的脂质结构，因此具有良好的生物兼容性(biocompatible)及生物降解性(biodegradable)，可广泛用作药物施用、释放或相关成分传递的载体。例如将有效成分包裹在脂质体载体中后施用，不但具有增加活性成分稳定度、减少毒性与适用多种成分运输等优点，也可通过其脂质特性与尺寸大小，减少过敏情形的产生、加速身体的代谢，并加强药物或有效成分的穿透性。
除了应用于药物传递，近年来脂质体已逐渐应用于保养品或化妆品中。特别是保养品部分，由于吸收性直接影响其中有效成分的作用与效果，所以是否容易吸收或渗透的特性一直是各制造商或消费者选择的重要考虑。特别的是，由于保养品或化妆品涂抹在皮肤上，而皮肤是人体对于外来物质重要的第一道屏蔽，无法轻易渗透，因此该些保养相关溶液对于皮肤的渗透性、渗透速率，就会影响其中保养成分对皮肤或更深层组织的作用。因此，若能通过脂质体的特性，让包裹其中的有效成分传递至皮肤深层，将能更有效发挥保养品或化妆品的保养或促进作用。然而一般制备过程中制备出的脂质体，其粒径过于庞大，并不利于皮肤的渗透与吸收；且因为体较较大，在载体的稳定度上较为不足，其成分容易因脂质体破裂而外漏，大幅降低脂质体传递 与作用的效果。
发明内容
本发明的一个目的在于提供一种乳化脂质体组合物，通过乳化后的脂质体溶液中较小粒径的脂质体，促进所包裹有效成分的渗透与吸收。
本发明的另一个目的在于提供一种具有优良保湿效果、抗氧化力的乳化脂质体组合物，通过数种具保湿与抗氧化效果的有效成分，结合脂质体的渗透作用，提升皮肤的保湿能力与抗氧化能力。
本发明的又一个目的在于提供一种具有耐高温灭菌处理特性的脂质体组合物，使其中的脂质体在高温处理后仍能维持稳定的结构，以能适用于各种产品的前处理灭菌流程。
本发明的再一个目的在于提供一种乳化脂质体组合物的制备方法，在高压与适当温度下进行乳化均质作用，制备出含有粒径较小脂质体的乳化脂质体组合物。
在本发明的一个实施例中，该乳化脂质体组合物可包括磷脂质，该磷脂质中所包含的磷脂酰乙醇胺(phosphatidyl ethanol amine)与磷脂酰胆碱(Phosphatidylcholine)的重量比可为3～6∶1，较佳为4∶1。
在本发明的一个实施例中，该乳化脂质体组合物形成的脂质体在95℃下处理30分钟后仍可维持完整结构。
在本发明的一个实施例中，以该乳化脂质体组合物为100重量％计，该磷脂质的含量可为约0.1重量％～2重量％。
在本发明的一个实施例中，该乳化脂质体组合物可包括：由3重量％～7重量％的1，3-丁二醇(Butane-1，3-diol)、0.4重量％～0.7重量％的羟基苯乙酮(Hydroxyacetophenone)与0.4重量％～0.7重量％的己二醇(Hexane-1，6-diol)组成的第一组分群；由1重量％～5重量％的甘油(Glycerol)、0.01重量％～0.3重量％的黄原胶(Xantham Gum)与0.1重量％～0.3重量％的水解小核菌胶(Hydrolyzed sclerotium gum)组成的第二组分群；由0.5重量％～10重量％的有效成分与0.1重量％～2重量％的卵磷脂(Lecithin)组成的第三组分群；以及水。
在本发明的一个实施例中，该乳化脂质体组合物中的有效成分可选自由红藜萃取物、椰子油、抗敏感植物复合物、锁水磁石、糖基海藻糖(Glycosyl trehalose)以及它们的组合组成的组。
在本发明的另一个实施例中，该有效成分可由0.1重量％～2重量％的红藜萃取物、0.1重量％～2重量％的椰子油、0.1重量％～2重量％的抗敏感植物复合物、0.1重量％～2重量％的锁水磁石与0.1重量％～2重量％的糖基海藻糖组成。
在本发明的再一个实施例中，该乳化脂质体组合物中所形成的脂质体的粒径可为10nm～1000nm，较佳为300nm～400nm，更佳为约350nm。
在本发明的另一实施例中，提供一种乳化脂质体组合物的制备方法，包括以下步骤：制备第一溶液，提供3重量％～7重量％的1，3-丁二醇、0.4重量％～0.7重量％的羟基苯乙酮以及0.4重量％～0.7重量％的己二醇，将其均匀混合分散后，可在60℃～80℃下进行加热，直到溶液变成透明状且无未溶解颗粒，降温至25℃～30℃；制备第二溶液，提供1重量％～5重量％的甘油、0.01重量％～0.3重量％的黄原胶以及0.1重量％～0.3重量％的水解小核菌胶，均匀混合分散后，加入74重量％～94.4重量％水。之后可在60℃～80℃下进行加热，直到胶体无结块现象，降温至25℃～30℃备用；制备第三溶液，提供0.5重量％～10重量％的有效成分以及0.1重量％～2重量％的卵磷脂，加入该第二溶液中后，搅拌均匀。搅拌时可在1500rpm～3500rpm的转速下进行5分钟～15分钟；制备第四溶液，将该第三溶液在300bar～600bar的压力以及25℃～30℃的温度下进行均质化处理；以及将该第四溶液加入该第一溶液中，搅拌均匀。搅拌时可以在1500rpm～3500rpm的转速下进行5分钟～15分钟。
在本发明的一个实施例中，该乳化脂质体组合物的制备方法中该有效成分可选自由红藜萃取物、椰子油、抗敏感植物复合物、锁水磁石、糖基海藻糖以及它们的组合组成的组，但并不仅限于此。
在本发明的另一个实施例中，该乳化脂质体组合物的制备方法中该有效成分可由0.1重量％～2重量％的红藜萃取物、0.1重量％～2重量％的椰子油、0.1重量％～2重量％的抗敏感植物复合物、0.1重量％～2重量％的锁水磁石与0.1重量％～2重量％的糖基海藻糖组成。
在本发明的再一个实施例中，通过前述制备方法制备的乳化脂质体组合物中所形成的脂质体的粒径可为10nm～1000nm，较佳为300nm～400nm，更佳为约350nm。
附图说明
图1是本发明实施例制备的脂质体溶液的粒径分布分析的比较结果图，其中(A)为实施例1制备的乳化脂质体组合物，(B)为实施例2制备的一般脂质体溶液。
图2是本发明实施例1制备的乳化脂质体组合物在原子力显微镜下所观察的脂质体的图像。
图3是本发明实施例1(试验组)与实施例2(对照组)制备的脂质体溶液在手臂皮肤保湿性测试中的比较结果图。
图4是本发明实施例1(试验组)与利用不同卵磷脂(比较组)制备的脂质体溶液的脂质体结构稳定性测试的比较结果图。
图5是制备本发明实施例1(试验组)使用的卵磷脂所含成分(A与B)以及试验组(C)与比较组(D)的卵磷脂所含成分的分析图。
图6是本发明实施例1(试验组)与实施例2(对照组)制备的脂质体溶液在脸部皮肤保湿性测试中的比较结果图。
图7是本发明实施例1(试验组)与实施例2(对照组)制备的脂质体溶液对在黑色素指数影响中的比较结果图。
图8是本发明实施例1(试验组)与实施例2(对照组)制备的脂质体溶液在紫外线斑点数影响中的比较结果图。
图9是本发明实施例1(试验组)与实施例2(对照组)制备的脂质体溶液在皮肤发红程度影响中的比较结果图。
图10是本发明实施例1(试验组)与实施例2(对照组)制备的脂质体溶液在皱纹减少比例的影响中的比较结果图。
具体实施方式
以下将进一步说明本发明的实施方式，下述所列举的实施例是用于阐明 本发明，而非用以限定本发明的范围，对于本领域普通技术人员来说，在不脱离本发明的精神和范围内，应当可做若干改进与润饰，因此本发明的保护范围应当以权利要求书所界定的范围为准。
首先准备适当量的用于制备乳化脂质体组合物所需的组分，其中，羟基苯乙酮(商品名：SymSave)购自富莉萨有限公司；黄原胶(商品名：Rhodicare T)购自顶韵实业有限公司；水解小核菌胶(商品名：BioNest-Chcogum HG)购自嘉诚化学股份有限公司；红藜萃取物购自大江生医股份有限公司；椰子油购自博丹有限公司；抗敏感植物复合物(商品名：BIOPHYTEXTM LS 9832)购自百贸股份有限公司；锁水磁石购自迦威实业股份有限公司；糖基海藻糖(商品名：Tornare)购自香林企业股份有限公司；以及卵磷脂(商品名：SOLEC)购自美国Solae，LLC公司，其可为大豆卵磷脂等。前述组分并不限于所购买的来源，具有相同或近似的组分均可使用。其余用于制备的化合物或溶液也不限于所购买的来源，只要组分相同即可。
实施例1 乳化脂质体组合物的制备
请参照以下表1所列组分，以乳化脂质体组合物为100％重量计，准备3重量％～7重量％的1，3-丁二醇、0.4重量％～0.7重量％的羟基苯乙酮以及0.4重量％～0.7重量％的己二醇组成的第一组分群的各组分，将它们均匀混合分散后，在60℃～80℃下进行加热，直到溶液变成透明状且无未溶解颗粒，降温至25℃～30℃备用，此时制备的溶液被称为第一溶液。另外准备由1重量％～5重量％的甘油、0.01重量％～0.3重量％的黄原胶以及0.1重量％～0.3重量％的水解小核菌胶组成的第二组分群的各组分，同样先均匀混合分散，后加入74重量％～94.4重量％的去离子水，在60℃～80℃下进行加热，直到胶体无结块现象，降温至25℃～30℃备用，此时制备的溶液被称为第二溶液。接着，将由0.1重量％～2重量％的红藜萃取物、0.1重量％～2重量％的椰子油、0.1重量％～2重量％的抗敏感植物复合物、0.1重量％～2重量％的锁水磁石、0.1重量％～2重量％的糖基海藻糖以及0.1重量％～2重量％的卵磷脂组成的第三组分群的各组分，依序加入第二溶液中，再以1500rpm～3500rpm的转速搅拌5分钟～15分钟，直到均匀为止，此时制备的溶液被称为第三溶液。之后，用高压均质乳化机将第三溶液在300bar～600bar的压力以及25℃～30℃温度下 进行均质化处理，经此处理的溶液被称为第四溶液。最后，将第四溶液加入前述制备的第一溶液中，在1500rpm～3500rpm的转速下搅拌5分钟～15分钟，即完成乳化脂质体组合物的制备。
表1
Figure PCTCN2018088051-appb-000001
实施例2 一般精华液溶液的制备
本实施例中，制备一般精华液溶液所需的组分来源可与前述实施例1相同。制备时请参照以下表2所列组分，以脂质体组合物为100％重量计，准备3重量％～7重量％的1，3-丁二醇、0.4重量％～0.7重量％的羟基苯乙酮以及0.4重量％～0.7重量％的己二醇组成的第一组分群的各组分，将其均匀混合分散后，在60℃～80℃下进行加热，直到溶液变成透明状且无未溶解颗粒，降温至25℃～30℃备用，此时制备的溶液被称为第一溶液。另外准备由1重量％～5重量％的甘油、0.01重量％～0.3重量％的黄原胶以及0.1重量％～0.3重量％的水解小核菌胶组成的第二组分群的各组分，同样先均匀混合分散，后加入76重量％～94.5重量％的去离子水，在60℃～80℃下进行加热，直到胶体无结块现 象，降温至25℃～30℃备用，此时制备的溶液被称为第二溶液。接着，将由0.1重量％～2重量％的红藜萃取物、0.1重量％～2重量％的椰子油、0.1重量％～2重量％的抗敏感植物复合物、0.1重量％～2重量％的锁水磁石以及0.1重量％～2重量％的糖基海藻糖组成的对比第三组分群的各组分，依序加入第二溶液中，再以1500～3500rpm的转速搅拌5分钟～15分钟，直到均匀为止，此时制备的溶液被称为对比第三溶液。之后，将对比第三溶液加入前述制备的第一溶液中，在1500rpm～3500rpm的转速下搅拌5分钟～15分钟，即完成一般脂质体溶液的制备。
表2
Figure PCTCN2018088051-appb-000002
实施例3 脂质体组合物中脂质体的粒径分布分析
将实施例1制备的乳化脂质体组合物作为试验组，而以实施例2制备的一般脂质体组合物作为对照组，进行以下粒径分布的分析。首先，取2ml实施例1制备的乳化脂质体组合物，以1∶1(v/v)的去离子水稀释，同样地，也取出2ml实施例2制备的脂质体组合物，以1∶1(v/v)的去离子水稀释。再分别取出2ml稀释后的溶液以动态光散射法(Dynamic light scattering， DLS)进行粒径分析，其粒径分布情形的结果以检测强度显示，如图1所示。
由图1中(A)的结果可知，通过本发明特殊组分与制备方法制备的乳化脂质体组合物(试验组)，粒径大小范围在100nm～1000nm之间，而在40nm～200nm以及200nm～1000nm之间有较多的分布，其平均粒径大小为350nm，而由图1(B)以一般制备方式所获得的脂质体溶液(对照组)，其平均粒径大小则为4716nm，粒径显然比试验组大出很多。因此，通过本发明实施例的组分以及制备方法制备的乳化脂质体组合物，因为具有较小的粒径分布，可有效帮助皮肤的渗透与吸收。
进一步，将本发明实施例1制备的乳化脂质体组合物置于云母基片上，利用原子力显微镜(Atomic Force Microscope System with ScanAsyst，Dimension Icon公司)进行观察，其结果如图2所示。由图2的结果可发现，通过本发明制备的乳化脂质体组合物，可使脂质体具有双层结构。基本上，所述第三组分群的成分会包裹在脂质体所形成的双层膜上，而在脂质体核心空腔中则会包裹第一组分群、二组分群与稍许第三组分群的成分。
实施例4 乳化脂质体组合物的经皮吸收测试
同样准备前述实施例1与2制备的脂质体溶液分别作为试验组与对照组。取适量脂质体组合物与0.1μg～1μg的Dil荧光染剂(DiTC 18(3))均匀混合后，涂抹在处理后的猪耳朵皮肤上，分别在施用后0分钟、5分钟、15分钟以及8小时后，利用共轭双焦显微镜观察并拍摄结果。
由观察结果可知，试验组在5分钟内即可观察到皮下有明显红色荧光渗透，并在施用15分钟后，渗透深度即已达约200μm。相较之下，对照组在施用15分钟后，渗透深度仅约30μm，显示出：通过本发明制备的乳化脂质体组合物，具有极佳的渗透力，并能迅速渗透至皮肤内。
实施例5 脂质体组合物的手臂皮肤保湿性测试
同样准备前述实施例1与2制备的脂质体组合物分别作为试验组与对照组。分别取适量脂质体组合物涂抹在受测者手臂内侧，在施用后第0小时、0.5小时、1小时、2小时、3小时、4小时、5小时、6小时、7小时与8小时，以肌肤含水率测量探头(Courage+Khazaka electronic GmbH公司)进行肌肤含水率的测定，其结果如图3所示。由图3结果可知，施用试验组的乳 化脂质体组合物时，在任何测量时间点处，其平均肌肤含水量均比对照组高出约14％～20％，且经过8小时后，试验组的平均肌肤含水量仍然较使用前高出26％，显示出：通过本发明制备的乳化脂质体组合物不但具有优异的保湿效果，且具有持久保湿的特性。
实施例6 脂质体组合物中脂质体的结构完整性测试
准备前述实施例1制备的脂质体组合物作为试验组，同样以实施例1相同的组分以及方法，但将卵磷脂替换以其他市售的卵磷脂(EMULMETIK 900，Lucas Neyer Cosmetics公司)制备的脂质体组合物作为比较组。分别将试验组与比较组以相当于灭菌的加热条件下，在95℃下加热30分钟，而后测量其粒径、浓度，并观察其脂质体的结构，其结果如图4所示。由图4结果可知，通过本发明制备的乳化脂质体组合物在高温加热后其结构依然完整，即其结构稳定性比比较组高。有耐高温的特性，则用于须灭菌的产品中，将可大幅提升产品的稳定度。
实施例7 脂质体组合物中卵磷脂的差异性比对
将前述实施例1所使用的卵磷脂以及前述实施例6所使用的卵磷脂进行NMR光谱比对，其结果分别如图5中的(C)与(D)所示。图5中的(A)与(B)分别是卵磷脂中所含磷脂酰胆碱以及磷脂酰乙醇胺的化学结构式，由(C)可知，实施例1试验组中所使用卵磷脂中所含磷脂酰乙醇胺与磷脂酰胆碱的比例大约为4∶1，而(D)则显示比较组的比例约为1∶1。经推测，可能是因为磷脂酰胆碱的胺基较多，造成比较组中脂质体结构的不稳定。
实施例8 脂质体组合物的脸部临床测试
准备前述实施例1与2制备的脂质体组合物在适当稀释后分别作为试验组与对照组。之后，将干燥未添加任何成分的面膜切割分成左右二片备用。其中一片以10ml试验组的稀释液浸湿，另一片则以10ml对照组的稀释液浸湿，之后，将此左右二片面膜铺覆在10位受试者的左右脸上作用约15分钟。每周施用3次，并分别在第0、1、2、4周，观察或测试以下脸部皮肤保湿性、黑色素指数、紫外线斑点数、皮肤发红程度与皱纹减少比例等效果，其结果如图6～图10所示。关于脸部肌肤保湿性的测试，可利用前述实施例5的测试方法。黑色素指数则可以黑色素侦测探头(Courage+Khazaka electronic  GmbH公司)进行检测，其余则以影像统计进行量化分析。
请参阅图6，图6是关于本发明实施例1(试验组)与实施例2(对照组)制备的脂质体组合物在脸部皮肤保湿性测试中的比较结果图。由图6结果可知，施用试验组的乳化脂质体组合物时，在施用第4周后，脸部肌肤含水量已比对照组高出约22.4％，显示出：通过本发明制备的乳化脂质体组合物不但在手臂上，对于脸部肌肤也具有优异的保湿效果。
请参阅图7，图7是关于本发明实施例1(试验组)与实施例2(对照组)制备的脂质体组合物在黑色素指数影响中的比较结果图。由图7结果可知，施用试验组的乳化脂质体组合物时，在施用第4周后，可将黑色素指数显著降低5.9％，显示出：通过本发明制备的乳化脂质体组合物具有优秀的美白效果。
请参阅图8，图8是关于本发明实施例1(试验组)与实施例2(对照组)制备的脂质体组合物在紫外线斑点数影响中的比较结果图。由图8结果可知，施用试验组的乳化脂质体组合物时，在施用第4周后，同样也可将紫外线斑点显著降低6.3％，显示出：通过本发明制备的乳化脂质体组合物对于晒伤后的皮肤修复具有不错的效果。
请参阅图9，图9是关于本发明实施例1(试验组)与实施例2(对照组)制备的脂质体组合物在皮肤发红比例影响中的比较结果图。由图9结果可知，施用试验组的乳化脂质体组合物时，在施用第4周后，对于皮肤的发红、发炎现象可显著降低5.9％，显示出：通过本发明制备的乳化脂质体组合物对于皮肤的消炎具有不错效果。
请参阅图10，图10是关于本发明实施例1(试验组)与实施例2(对照组)制备的脂质体组合物在皱纹减少比例的影响中的比较结果图。由图10结果可知，施用试验组的乳化脂质体组合物时，在施用第4周后，对于皱纹的减少可高达23％显示通过本发明制备的乳化脂质体组合物对于皮肤皱纹的抚平具有极佳的效果。
通过上述试验可知，本发明实施例的乳化脂质体组合物，由于粒径小，有较佳渗透力以及渗透速率，能将所包裹的有效成分迅速传递皮肤深层，因此能有效发挥该些有效成分的作用。
因此，本发明实施例的乳化脂质体组合物，也可进一步应用于保湿霜、润肤霜、精华液、化妆水、卸妆液、须后水、睫毛膏或眼线液、隔离霜，甚至是洗发精和护发乳，以及防晒产品、抗老化或抗皱、美白等护理产品中。

Claims (10)

  1. 一种乳化脂质体组合物，包括磷脂质，该磷脂质中所包含的磷脂酰乙醇胺与磷脂酰胆碱的重量比为3～6∶1。
  2. 如权利要求1所述的乳化脂质体组合物，其中该磷脂酰乙醇胺与该磷脂酰胆碱的重量比为4∶1。
  3. 如权利要求1所述的乳化脂质体组合物，其中该乳化脂质体组合物所形成的脂质体在95℃下处理30分钟后仍可维持完整结构。
  4. 如权利要求1所述的乳化脂质体组合物，其中该乳化脂质体组合物所形成的脂质体的粒径为10nm～1000nm。
  5. 如申权利要求4所述的乳化脂质体组合物，其中该脂质体的粒径为300nm～400nm。
  6. 如权利要求1所述的乳化脂质体组合物，其中以该乳化脂质体组合物为100重量％计，该磷脂质为0.1重量％～2重量％。
  7. 一种乳化脂质体组合物的制备方法，包括以下步骤：
    制备第一溶液，提供3重量％～7重量％的1，3-丁二醇、0.4重量％～0.7重量％的羟基苯乙酮以及0.4重量％～0.7重量％的己二醇，将它们均匀混合分散；
    制备第二溶液，提供1重量％～5重量％的甘油、0.01重量％～0.3重量％的黄原胶以及0.1重量％～0.3重量％的水解小核菌胶，均匀混合分散后，加入74重量％～94.4重量％的水，加热直到胶体无结块现象，降温备用；
    制备第三溶液，提供0.5重量％～10重量％的有效成分以及0.1重量％～2重量％的卵磷脂，加入该第二溶液中后，搅拌均匀；
    制备第四溶液，将该第三溶液在300bar～600bar的压力以及25℃～30℃的温度下进行均质化处理；以及
    将该第四溶液加入该第一溶液中后，搅拌均匀。
  8. 如权利要求7所述的乳化脂质体组合物的制备方法，其中该磷脂质中所包含的磷脂酰乙醇胺与磷脂酰胆碱的重量比为3～6∶1。
  9. 如权利要求7所述的乳化脂质体组合物的制备方法，其中乳化脂质体组合物所形成的脂质体的粒径为10nm～1000nm。
  10. 如权利要求9所述的乳化脂质体组合物的制备方法，其中该脂质体的粒径为300nm～400nm。
PCT/CN2018/088051 2017-05-23 2018-05-23 乳化脂质体组合物及其制备方法 WO2018214915A1 (zh)

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