TW202021622A - Liposome, composition, and liposome preparing method characterized by maintaining the transparency and the size uniformity of liposome particle, and being particularly advantageous for being used as a cosmetic composition - Google Patents

Abstract

The present invention provides a liposome, a composition, and a liposome preparing method. The liposome is a liposome internally wrapped with lipid ingredient, and the transparency and the size uniformity of liposome particle are maintained as much as possible in the composition containing aforementioned liposome. A liposome contains hydrogenated phospholipids and at least one surfactant selected form the group consisting of polyoxyethylene hardened castor oil whose average addition mole number of ethylene oxide is 40~ 95, PPG-6-Decyltetradeceth-30 and PEG-20 phytosterol, and internally wrapped with lipid ingredient.

Description

Liposome, composition and liposome manufacturing method

The present invention relates to a liposome and the like containing oil and fat components.

Liposomes are artificial capsules (capsules) composed of phospholipids, which are the main constituents of biofilms. Phospholipids have an amphiphilic structure and form a lipid bilayer (in other words, a bilayer). Oil-soluble substances can be absorbed in the bimolecular membrane, and water-soluble substances can be absorbed in the internal water phase according to the preparation method. [Prior Art Literature] [Patent Literature]

[Patent Document 1] Japanese Patent Laid-Open No. 2015-174860 [Patent Document 2] International Publication No. 2008/093848

[Problems to be solved by the invention] As described above, liposomes can absorb oil-soluble substances inside the bimolecular membrane, and therefore it is considered that they may be used to stably contain oil and fat components in an aqueous composition. In addition, in recent years, the functions of vegetable oils and fats have received attention. In particular, the need for blending vegetable oils and fats in external compositions such as cosmetics (especially external water-based compositions) has increased.

In addition, when such an aqueous composition is used in cosmetics, the appearance (transparency) is often valued, and it is particularly important that the transparency is maintained. The reason is that consumers tend to avoid compositions that become cloudy over time (especially cosmetic compositions). Generally, the smaller the liposome particle size, the more transparent the aqueous composition. Therefore, from the above viewpoint, the liposome particle size is preferably relatively small. In addition, the smaller the liposome particle size, the higher the tendency for transdermal absorbability. Therefore, it is also preferable from the above viewpoint.

In addition, furthermore, the more uniform the size of the liposome particles (that is, the more uniform), the less likely it is to cause the merging or collapse of liposomes, and the dispersion stability tends to be high over time. From the viewpoint, the size of each liposome particle is preferably as uniform as possible.

Therefore, the object of the present invention is to provide a liposome, which is a liposome encapsulating an oil and fat component and maintains transparency and liposome particle size uniformity as much as possible in a composition containing the liposome. [Technical means to solve the problem]

The inventors of the present invention found that by using a specific surfactant in the preparation of liposomes, it is possible to prepare liposome-containing compositions that maintain transparency and liposome particle size uniformity, and further Repeated improvements have been made to complete the present invention.

The present invention includes, for example, the subjects described in the following items. Item 1. A liposome comprising: hydrogenated phospholipids, and Selected from polyoxyethylene hardened castor oil with an average added molar number of ethylene oxide of 40 to 95, PPG-6 decyltetradeceth-30 (‎PPG-6-Decyltetradeceth-30), and PEG-20 At least one surfactant in the group consisting of PEG-20 Phytosterol, and It contains grease ingredients. Item 2. The liposome according to item 1, wherein the fat component is selected from rice oil, soybean oil, olive oil, meadowfoam oil, sunflower oil, hazelnut oil, and tocopherol At least one of the group consisting of. Item 3. The liposome according to item 1 or 2, wherein the hydrogenated phospholipid is hydrogenated lecithin. Item 4. A liposome comprising: hydrogenated lecithin, and Polyoxyethylene hardened castor oil with an average added molar number of ethylene oxide of 55 to 65, and It contains rice bran oil. Item 5. The liposome according to any one of items 1 to 4, wherein the average particle diameter is 82 nm or less. Item 6. The liposome according to any one of items 1 to 5, wherein the polydispersity index (PdI) is 0.26 or less. Item 7. A composition containing the liposome according to any one of items 1 to 6. Item 8. The composition according to Item 7, which is a pharmaceutical composition for external use, a composition for oral cavity, or a cosmetic composition. Item 9. The liposome according to any one of items 1 to 6, or the composition according to item 7 or 8, wherein the pH is 6 to 7.5. Item 10. A method for manufacturing liposomes, including: stirring the composition, and Process the completely stirred composition at 100 MPa to 400 MPa, and the composition contains: Hydrogenated phospholipids, At least selected from the group consisting of polyoxyethylene hardened castor oil with an average added molar number of ethylene oxide of 40 to 95, PPG-6 decyltetradeceth-30, and PEG-20 phytosterol A surfactant, Grease composition, and water. Item 11. The method according to item 10, wherein the pH of the composition is 6 to 7.5. [Effect of invention]

The present invention provides a liposome-containing composition that maintains transparency and liposome particle size uniformity, liposomes contained in the composition, and methods for producing these. The liposome-containing composition is particularly advantageous for use as a cosmetic composition.

Hereinafter, each embodiment included in the present invention will be described in further detail. The present invention preferably includes a composition containing liposomes, liposomes contained in the composition, and methods for producing these, but are not limited to these. The present invention includes those disclosed in this specification and those in the art. All the content that the technician can understand.

The liposomes contained in the present invention comprise (A) hydrogenated phospholipids, and (B) polyoxyethylene hardened castor oil with an average added molar number of 40 to 95 selected from ethylene oxide, PPG-6 decyl ten At least one surfactant in the group consisting of tetraeth-30 and PEG-20 phytosterol, and contains (C) oil and fat components. Hereinafter, the liposome contained in the present invention may be referred to as the "liposome of the present invention". Furthermore, although there is no particular limitation, it is preferable that the liposome of the present invention further contains (D) cholesterol (cholesterol).

As the phospholipids of the hydrogenated phospholipids, preferably exemplified are phospholipids such as phosphatidylcholine, phospholipid ethanolamine, phospholipid serine, phospholipid inositol, phospholipid acid, or sphingomyelin (sphingomyelin). Phospholipids. In addition, lecithin (for example, soybean lecithin, corn lecithin, cottonseed oil lecithin, egg yolk lecithin, egg white lecithin, etc.) can also be used. The lecithin is preferably lecithin having a phospholipid choline content of 60% by mass or more, more preferably 65% by mass or more, 70% by mass or more, 75% by mass or more, 80% by mass or more, 85% by mass or more, or 90% by mass or more. Lecithin above mass%. In addition, phospholipid derivatives in which polyethylene glycol or amino polysaccharides are introduced, or phospholipid choline hydroxide, lysophospholipid choline, and the like are also included in the phospholipids here.

As a hydrogenated phospholipid, the phospholipid obtained by hydrogenating the said phospholipid can be mentioned preferably. Among them, hydrogenated glycerophospholipids are preferred, and hydrogenated phospholipid ethanolamine, hydrogenated phospholipid serine, hydrogenated phospholipid inositol, hydrogenated phospholipid choline, and the like are particularly preferred. In addition, hydrogenated lecithin (for example, hydrogenated soybean lecithin, hydrogenated egg yolk lecithin, hydrogenated corn lecithin, hydrogenated cottonseed oil lecithin, etc.) can also be used.

Furthermore, the hydrogenated phospholipids may be used alone or in combination of two or more.

In the liposome of the present invention, as a surfactant, polyoxyethylene hardened castor oil having an average added molar number of ethylene oxide of 40 to 95, PPG-6 decyltetradeceth-30, and PEG-20 plant sterols. These components can be used individually by 1 type or in combination of 2 or more types.

The polyoxyethylene hardened castor oil used in the present invention has an average added molar number of ethylene oxide of 40 to 95 (40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, or 95). It is preferably about 45 to 90, more preferably about 50 to 80, still more preferably about 55 to 70, and still more preferably about 55 to 65.

PPG-6 decyltetradecyl alcohol polyether-30 has a structure formed by addition polymerization of ethylene oxide and propylene oxide on decyl tetradecyl alcohol, and the average number of ethylene oxide addition moles is 6, and propylene oxide addition A compound with an average molar number of 30.

PEG-20 phytosterol is a polyglycol ether of phytosterol (Phytosterols), and is a compound with an average addition molar number of ethylene oxide of 20.

As the oil and fat component, especially an animal oil and fat component and a vegetable oil and fat component are mentioned. The animal fats and oils components here include not only animal-derived fats and oils components but also components known as animal-derived fats and oils even if they are synthetic fats and oils components. Similarly, the vegetable fat and oil component here includes not only a vegetable-derived fat and oil component, but also a component known as a plant-derived fat and oil component even if it is a synthetic fat and oil component. For example, tocopherol is a component contained in a large amount of vegetable oil, and therefore even synthetic tocopherol is included in the vegetable oil and fat component here. As the oil and fat component, a vegetable oil and fat component is particularly preferable.

Examples of vegetable oil and fat components include rice oil, soybean oil, olive oil, white flower seed oil, sunflower oil, hazelnut oil, and tocopherols (preferably α-tocopherol, for example, including D-α-tocopherol , Dl-α-tocopherol, dl-α-tocopherol acetate, etc.). Furthermore, rice oil is preferably rice bran oil. As rice bran oil, a solvent (for example, hexane, acetone, etc.) may be used to extract rice bran oil, and it is preferably rice bran oil obtained by squeezing (preferably squeezing) rice bran. In addition, other plant-based oils and fats components can also be appropriately selected and used, and known oils that are particularly suitably formulated in cosmetics can be used. In addition, the vegetable oil and fat components can be used alone or in combination of two or more.

The content ratio of (A) hydrogenated phospholipid and (B) surfactant can be appropriately set within the range of liposomes that can obtain the effect of the present invention. For example, in terms of mass ratio, (B): (A) is preferable It is about 1:1-10, more preferably about 1:2-8 or about 1:2.5-6, and still more preferably about 1:3-5. In addition, when the liposome of the present invention contains (D) cholesterol, the total amount of (A) and (D) (A+D) and the content ratio of (B) can be appropriately set, for example, in terms of mass ratio, (B): (A+D) is preferably about 1:1-10, more preferably about 1:2-8 or about 1:2.5-6, and still more preferably about 1:3-5 or 1:4-5 about.

In addition, the form of (A), (B), and (D) contained in liposomes is not particularly limited. For example, it also includes the case where it is contained in the hydrophilic region or the hydrophobic region formed in the liposome, and attachment If it exists on the membrane surface of the outermost membrane of the liposome structure, it is preferable to coexist with the liposome membrane component (especially when it is contained in the liposome as a component of the liposome membrane).

The amount of (C) oil and fat component contained in the liposome of the present invention can be appropriately set. For example, in terms of mass ratio, (C):(A) is preferably about 1:1 to 10, and more preferably 1:2 ~8 or about 1:2.5-6, more preferably about 1:3-5. In addition, when (D) is included, it is preferably the mass ratio of (C) and (A). In terms of mass ratio, (C):(A+D) is more preferably about 1:1-10, More preferably, it is about 1:2-8 or about 1:2.5-6, and still more preferably about 1:3-5 or about 1:4-5.

Furthermore, based on the number of lipid bilayers, liposomes are classified into two types: multilamellar vesicle (MLV) and unilamellar vesicle. According to their size, unilamellar liposomes are further classified into small unilamellar vesicles (SUV), large unilamellar vesicles (LUV), giant unilamellar vesicles (GUV), etc. . As the liposome of the present invention, any of these can be suitably used. In addition, regarding the size (particle size) of the liposome of the present invention, the average particle diameter (in the case of not having a spherical particle shape, the average outer diameter) is preferably 82 nm or less, more preferably 81 nm or less, 80 nm or less, 79 nm or less, 78 nm or less, 77 nm or less, 76 nm or less, 75 nm or less, 74 nm or less, or 73 nm or less. The lower limit of the average particle diameter is not particularly limited. For example, about 10 nm or more, 15 nm or more, or 20 nm or more can be exemplified.

In addition, the polydispersity index (PdI) of the liposomes of the present invention is preferably 0.26 or less, more preferably 0.25 or less, 0.24 or less, 0.23 or less, 0.22 or less, 0.21 or less, or 0.20 or less, more preferably 0.19 or less, 0.18 or less, or 0.17 or less. In addition, the polydispersity index (PDI) is an index for evaluating the width of the particle size distribution, and takes a value in the range of 0 to 1. The closer to 0, the more uniform the dispersion.

The average particle diameter and PdI are values measured by a dynamic light scattering method. For example, a particle size distribution meter based on dynamic light scattering can be used for measurement.

In addition, the liposome of the present invention preferably has a pH of about 6 to 7.5. By being a liposome in such a pH range, the dispersion stability becomes higher with time, which is preferable. Liposomes in this pH range can be prepared, for example, by adjusting the pH of the composition used in liposome preparation to the pH range in advance. The pH value can be adjusted using a pH value adjuster. As a pH adjusting agent, sodium hydroxide, potassium hydroxide, etc. are mentioned, for example.

The present invention also includes liposome compositions containing the liposomes of the present invention. The liposome composition is preferably an aqueous composition. In addition, the composition is preferably used as, for example, a pharmaceutical composition for external use, a composition for oral cavity, and a cosmetic composition.

The liposome of the present invention and the composition containing the liposome can be prepared, for example, by stirring a composition containing the liposome-containing raw material and water, and then subjecting it to high pressure treatment.

As the raw material of liposomes, the content can be preferably applied directly. For example, it can be prepared by mixing the (A) component, (B) component, and (C) component, and optionally the (D) component or other components (for example, polyol, preferably propylene glycol), etc., with water Composition to use. Regarding various conditions such as the usage amount of each component, the above content described for the raw material of liposomes can also be applied directly and preferably. In addition, it is also preferable to adjust the pH of the composition to about 6 to 7.5 in advance. As described above, pH adjusting agents (for example, sodium hydroxide, potassium hydroxide, etc.) can be used to adjust the pH.

For the stirring treatment, a known stirring treatment used in the field of liposome preparation can be preferably used. For example, a homomixer can be used, and the rotation speed is 3000 rpm to 10000 rpm, preferably 4000 rpm to 6000 rpm, and stirring for about 2 minutes to 10 minutes. Through the stirring treatment, liposomes can usually be prepared.

In addition, the high-pressure treatment can preferably use a well-known high-pressure treatment used in the field of liposome preparation. For example, a method of high-pressure treatment of a stirred composition using a wet micronization device can be cited. As such a wet micronization device, STARBURSTmini (Sugino machine company) can be exemplified. As high-pressure treatment, for example, treatment at 100 MPa to 400 MPa (preferably 150 MPa to 300 MPa) is mentioned. Through high pressure treatment, the particle size of liposomes can generally be reduced, and the size of each particle can be made more uniform.

Furthermore, the liposome suspension thus obtained can be directly used as a liposome composition containing the liposome of the present invention.

As long as the effects of the present invention are not impaired, the liposome and liposome composition of the present invention may contain components other than the above-mentioned components. For example, oily components, lipids, water-soluble substances, physiologically active substances, etc. can be cited. Particularly, well-known ingredients used in external medicines or cosmetics can be preferably used. For example, bactericides (especially, phenolic bactericides such as isopropyl methylphenol); antioxidants such as ascorbic acid; organic acids such as lactic acid and citric acid; alkaline compounds such as potassium hydroxide and sodium hydroxide; phospholipids Lipids such as glycerol and phospholipid ethanolamine; natural polymers such as chitosan, fucoidan, and hyaluronic acid; synthetic polymers such as polyethylene glycol and carboxyvinyl polymers; Carbohydrates such as trehalose, lactulose, and maltitol; polyols such as glycerine.

In addition, the respective components used in the liposome and liposome composition of the present invention are all known components, and for example, commercially available products can be purchased and used.

Furthermore, in this specification, the term "comprising" also includes "consisting essentially of" and "consisting of" (The term "comprising" includes "consisting essentially of" and "consisting of". ). In addition, the present invention includes any combination of all the constituent elements described in this specification.

In addition, the various characteristics (property, structure, function, etc.) explained for each embodiment of the present invention may be combined arbitrarily when specifying the subjects included in the present invention. That is, the present invention includes all themes composed of all combinations of the various features described in this specification that can be combined. [Example]

Hereinafter, the present invention will be described more specifically, but the present invention is not limited to the following examples.

According to the compositions shown in Table 1 and Table 2, liposome suspensions of Examples 1 to 3 and Comparative Examples 1 to 8 were prepared. In more detail, according to the composition described in Table 1, hydrogenated lecithin (hydrogenated lecithin), rice oil (Sunbran rice oil (squeezed rice bran oil): Sanhe Oil Co., Ltd.), various surfactants ( Refer to Table 2), dissolve cholesterol and methyl paraben (heated at 80°C) in propylene glycol, add water heated to 80°C (dissolved potassium hydroxide), adjust the pH to about 7 Stirring at 5000 rpm for 5 minutes, and then performing high-pressure treatment at 200 MPa, thereby preparing liposome suspensions of the respective Examples and Comparative Examples. Furthermore, the stirring treatment is performed using a homomixer (Homomixer MARK II: PRIMIX). The high-pressure treatment is performed using a wet micronization device (STARBURSTmini: Sugino machine company). Among them, in the preparation of the liposome suspension of Comparative Example 8, a surfactant and potassium hydroxide were not used. Furthermore, in Comparative Example 8, the amount of ion-exchange water was increased corresponding to the absence of the surfactant and potassium hydroxide. In addition, the average number of added ethylene oxide of the polyoxyethylene hardened castor oil used in Comparative Example 3, Example 2, and Comparative Example 6 was 30, 60, and 100, respectively.

*PC表示磷脂醯膽鹼。[Table 1]

*PC stands for Phosphatidylcholine.

[Table 2]

In addition, for the obtained liposome suspensions of each example (excluding Comparative Example 8), a particle size distribution meter based on dynamic light scattering (Zetasizer nano: Malvern) was used to measure The average particle diameter and polydispersity index (PdI) of the contained liposomes. In addition, after the preparation, it was allowed to stand for 3 months in a dark place at normal temperature (25°C), and then the same measurement was performed. The measurement results are shown in Table 2 together. In addition, photographs of the liposome suspensions of the respective examples immediately after preparation (initial) and after 3 months of standing (3M) are shown in FIGS. 1A and 1B.

According to the above results, it is believed that when preparing liposomes containing hydrogenated phospholipids and surfactants and containing oil and fat components (especially vegetable oil and fat components: rice oil in this example), ethylene oxide is considered to be used When polyoxyethylene hardened castor oil, PPG-6 decyltetradeceth-30, and PEG-20 phytosterol with an average added molar number of 40 to 95 are used as surfactants, they will be used immediately after preparation and for a long period of time. (3 months in this example) In any case after storage, the average particle diameter is relatively small, the transparency of the composition is maintained, and the PdI is relatively small and the stability is high.

In addition, in addition to the fact that potassium hydroxide is not used and the amount of ion exchange water is increased accordingly, and the vegetable oil component uses soybean oil, olive oil, white flower seed oil, sunflower oil, hazelnut oil, or tocopherol instead of rice Except for the oil, a liposome suspension was prepared in the same manner as in Example 2 or Comparative Example 8, and the average particle diameter and polydispersity index (PdI) of the liposome were measured immediately after the preparation. The measurement results are shown in Table 3 and Table 4. In addition, photographs of the liposome suspension of each example immediately after preparation (initial stage) are shown in Fig. 2A and Fig. 2B (Fig. 2A: Example A to Example F, Fig. 2B: Comparative Example A to Comparative Example F) .

[table 3]

[Table 4]

It is found that no matter what kind of vegetable oil and fat component is used, the average particle diameter of the liposomes of the obtained liposome suspension is relatively small, the transparency of the composition is maintained, and PdI is also relatively small. The stability is also high. In addition, based on the above results, it is considered that the use of rice oil as the vegetable oil and fat component is particularly preferable.

no.

Figures 1A and 1B show the state of liposome suspensions prepared using different surfactants immediately after preparation and after 3 months of storage. Fig. 2A and Fig. 2B show the state immediately after preparation of a liposome suspension prepared using different oil and fat components (especially vegetable oil and fat components) in a suitable composition.

no.

Claims (11)

A liposome containing: Hydrotreated phospholipids; and At least selected from the group consisting of polyoxyethylene hardened castor oil with an average added molar number of ethylene oxide of 40 to 95, PPG-6 decyltetradeceth-30, and PEG-20 phytosterol A surfactant, and It contains grease ingredients. The liposome according to item 1 of the scope of patent application, wherein the oil component is selected from the group consisting of rice oil, soybean oil, olive oil, white flower seed oil, sunflower oil, hazelnut oil, and tocopherol At least one of them. The liposome according to item 1 or item 2 of the scope of patent application, wherein the hydrogenated phospholipid is hydrogenated lecithin. A liposome containing: Hydrogenated lecithin; and Polyoxyethylene hardened castor oil with an average added molar number of ethylene oxide of 55 to 65, and It contains rice bran oil. The liposome according to any one of items 1 to 4 of the scope of patent application, wherein the average particle diameter is 82 nm or less. The liposome according to any one of items 1 to 5 of the scope of patent application, wherein the polydispersity index (PdI) is 0.26 or less. A composition containing the liposome described in any one of items 1 to 6 in the scope of the patent application. The composition as described in item 7 of the scope of the patent application is a pharmaceutical composition for external use, a composition for oral cavity, or a cosmetic composition. The liposome according to any one of items 1 to 6 of the scope of patent application, or the composition according to item 7 or item 8 of the scope of patent application, wherein the pH is 6 to 7.5. A method for manufacturing liposomes, including: Stir the composition; and Process the stirred composition at 100 MPa to 400 MPa, and the composition contains: Hydrogenated phospholipids; At least selected from the group consisting of polyoxyethylene hardened castor oil with an average added molar number of ethylene oxide of 40 to 95, PPG-6 decyltetradeceth-30, and PEG-20 phytosterol A surface active agent; Fat content; and water. The method for producing liposomes as described in item 10 of the scope of patent application, wherein the pH of the composition is 6 to 7.5.

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