JP6450144B2 - Liposomes and liposome-containing cosmetics - Google Patents

Description

  The present invention relates to liposomes and liposome-containing cosmetics.

Liposomes refer to multi-layer capsule structures made of phospholipids. The water phase is included in it. It is attracting attention mainly in the fields of medicine and pharmacy as a technique for administering drugs. Liposomes, which are constituents of liposomes, have an affinity for the lamellar layer in the horny layer of the skin and release the components contained in the lamellar layer. Therefore, it has been clarified that it becomes a more effective cosmetic, and is therefore also used in the field of cosmetics.
Liposomes generally have a size of 100 to 300 nm (0.1 to 0.3 μm), and a particle size smaller than that of skin cells of 60 to 80 μm, but the spacing of human keratinocytes is about 50 nm. Therefore, in order to improve the transdermal absorbability of the liposome and exert a moisturizing effect, it is preferable to prepare a liposome having a particle diameter of 50 nm or less.
Liposomes tend to aggregate, and when the liposomes aggregate (unify), lamellar liquid crystals are formed and the liposomes are destroyed (Non-patent Document 1). For this reason, many proposals of the invention which suppresses coalescence of particles and improves the stability by reducing the particle diameter as much as possible have been made so far.

  For example, liposomes having a particle size of about 100 nm are disclosed in Patent Document 1 (Japanese Patent Laid-Open No. 3-5426), Patent Document 2 (Japanese Patent Laid-Open No. 3-181491), Patent Document 3 (Japanese Patent Laid-Open No. 3-218309), and the like. Is disclosed. An invention for preparing liposomes having a particle size of about 30 nm using maltopentaose cetylamide as a stabilizer is disclosed in Patent Document 4 (Japanese Patent Laid-Open No. 5-317677).

Patent Document 5 (Patent No. 5064717) discloses a liposome having good temporal stability, and the sterol concentration ratio (mass / mass) is 0.01 to 0.1 with respect to phospholipid 1. A liposome having a polyoxyethylene sterol ether concentration ratio (mass / mass) of HLB 12.0 to 16.0 of 0.01 to 0.5 is disclosed. Furthermore, in Patent Document 6 (Japanese Patent Application Laid-Open No. 2003-171257), a polymer having a structural unit of acrylic acid or methacrylic acid monomer having a polyethylene glycol structure in the side chain used in the present invention has a water retention function. Patent Document 7 (Japanese Patent Application Laid-Open No. 2012-31087) describes that methoxypolyethylene glycol polymethacrylate functions as a polymer emulsifier, but none of the liposomes have been studied. .
Liposomes undergo agglomeration and coalescence to become lamellar liquid crystals, destroying the capsule structure. In order to prevent this, it is known that it is important to reduce the diameter of the liposome. Moreover, in order to keep the fluidity | liquidity in the molecular film of a liposome moderate, it is employ | adopted normally to mix | blend cholesterol.

Japanese Patent Laid-Open No. 3-5426 JP-A-3-181491 JP-A-3-218309 JP-A-5-317677 Japanese Patent No. 5064717 JP 2003-171257 A JP 2012-31087 A

Supervised by Masato Suzuki, Functional Cosmetics III, pages 302-309, etc., CMC Corporation, published January 1, 2000

  An object of the present invention is to provide a liposome having polymethoxymethoxyglycol methacrylate and excellent in stability.

  The present inventors have conducted research on blending polymethoxymethoxyglycol methacrylate with moisturizing properties into cosmetics. In order to make this polymethoxymethacrylic acid glycol glycol penetrate into the skin, we tried to mix the liposome as a constituent, and the resulting liposome was refined, and the cause of instability of the liposome such as coalescence was suppressed. Have been found to form stable liposomes. Further, this discovery has been found to be more effective when used in combination with the invention of Patent Document 5, and further research has been made to complete the present invention.

The main configuration of the present invention is as follows.
(1) The concentration ratio (mass / mass) of sterol (component B) with respect to non-hydrogen added lecithin (component A) 1 is 0.1 to 10% by mass. 0.01-0.1, concentration ratio (mass / mass) of polyoxyethylene sterol ether (C component) of HLB 12-18 is 0.01-0.5, non-hydrogenated lecithin (A component), It contains sterol (B component), polyoxyethylene sterol ether (C component) of HLB 12-18, polyhydric alcohol (D component), water (E component), and poly (methacrylic acid) methoxypolyethylene glycol (F component). Liposome dispersion.
(2) The liposome dispersion liquid according to (1), which contains dipropylene glycol as a polyhydric alcohol (D component).
(3) The liposome dispersion liquid according to (1) or (2) , containing 0.02 to 20% by mass of polymethoxypolyethyleneglycol glycol (F component).
(4) A skin external preparation or cosmetic comprising the liposome dispersion liquid according to any one of (1) to ( 3) .

Stable liposomes could be prepared.
In addition, by blending this liposome into a skin lotion or a cosmetic liquid, a cosmetic having an excellent moisturizing effect and feel can be provided.
Furthermore, by blending the liposome of the present invention into a cosmetic, the liposome penetrates into the skin, and it can be expected that the moisturizing effect is further improved by polymethoxymethoxyglycol glycol contained in the liposome. Moreover, the sustained effect by the sustained-release effect of a cosmetic component can be expected by encapsulating the cosmetic component in the liposome of the present invention and applying it to the skin.

It is a graph which shows the test result which confirmed that the polymethoxy methacrylate glycol blended with the present invention reduced the particle size of the liposome depending on the concentration. It is a graph which shows the result of the test which confirmed that the particle diameter of the liposome reduced by the combination of polymethacrylic acid methoxypolyethyleneglycol and non-hydrogenated lecithin.

The present application is an invention relating to a liposome containing polymethoxymethoxyglycol glycol (F component), and more specifically, phospholipid (A component), sterol (B component), and polyoxyethylene sterol ether (C) of HLB 12-18. Component), polyhydric alcohol (D component), water (E component), and polymethacrylic acid methoxypolyethylene glycol (F component).
Examples of the phospholipid (component A) used in the present invention include natural phospholipids such as egg yolk lecithin and soybean lecithin, hydrogenated egg yolk lecithin obtained by changing unsaturated carbon chains in lecithin to saturated bonds by hydrogenation, soybean lecithin and the like. Examples include phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, phosphatidic acid, phosphatidylinositol, phosphatidylglycerol, which are purified from phospholipids, natural lecithin or synthesized. These phospholipids can be used alone or in combination. Hydrogenated lecithin or hydrogenated lecithin with an increased concentration of a specific phospholipid may be used. Particularly preferred is non-hydrogenated lecithin.

  As the phospholipid used in the present invention, one obtained by purifying natural lecithin and adjusting the phosphatidylcholine content to 55 to 85% by mass is preferable for preparing stable and minute liposomes. If the phosphatidylcholine content is less than 55% by mass, the efficiency of liposome formation decreases. When the phosphatidylcholine content exceeds 85% by mass, the liposomes easily aggregate.

As preferable commercially available hydrogenated lecithin (hydrogenated lecithin), Nikko Chemicals Co., Ltd., Resinol S-10M (phosphatidylcholine content 55-65%), Resinol S-10E (phosphatidylcholine content 75-85%), Nisshin Oilio Co., Ltd., Basis LP-60HR (phosphatidylcholine content 65-75%), NOF COATSOME NC-61 (phosphatidylcholine content 60% or more), Kewpie Inc. egg yolk lecithin PL100P (phosphatidylcholine content about 80%), etc. Can be mentioned.
Examples of the non-hydrogen-added lecithin include Phosphopon 85G manufactured by H. Holstein GmbH & Co. KG, LIPOID P100 manufactured by the same company, Basis LP-20 manufactured by Nisshin Oilio Co., Ltd., and egg yolk lecithin PL-30 manufactured by Kewpie Co., Ltd.

  The concentration of the phospholipid when preparing the liposome of the present invention is preferably 0.1 to 10% by mass, particularly preferably 1 to 2% by mass.

Examples of sterols (component B) used in the present invention include animal sterols, plant sterols (phytosterols), and fungal sterols.
Examples of animal sterols include cholesterol, cholestanol, and 7-dehydrocholesterol. Examples of plant sterols (phytosterols) include sitosterol, stigmasterol, fucosterol, spinasterol, and brush casterol. Moreover, the phytostanol which is a hydrogenated substance of a plant sterol is mentioned. Examples of fungal sterols include ergosterol.

  A commercial item can also be used as a sterol used for this invention. Examples thereof include phytosterol S (phytosterol) manufactured by Tama Seikagaku Co., Ltd., cholesterol JSCI (cholesterol) manufactured by Nippon Seika Co., Ltd., GENEROL 122N (phytosterol) manufactured by Cognis Japan Co., Ltd., and the like.

  The concentration (mass / mass) of the sterol when preparing the liposome of the present invention is preferably 0.01 to 0.1, preferably 0.01 to 0.1 when the phospholipid is 1 in terms of the concentration ratio with the phospholipid. 05 is particularly preferred. When the concentration ratio of sterol to phospholipid 1 is less than 0.01 or exceeds 0.1, the stability of the liposome is not so good.

  Examples of the polyoxyethylene sterol ether (component C) used in the present invention include polyoxyethylene cholesterol ether, polyoxyethylene cholestanol ether, polyoxyethylene phytosterol ether, polyoxyethylene phytostanol ether, and the like.

  The HLB of the polyoxyethylene sterol ether used in the present invention is 12 or more and 18 or less. When the HLB of the polyoxyethylene sterol ether is less than 12 or more than 18, the stability of the liposome is deteriorated.

  A commercial item can be used as polyoxyethylene sterol ether used for this invention. For example, GENEROL 122N E10D (polyoxyethylene (10) phytosterol) HLB12.5 manufactured by Cognis Japan Co., Ltd., NIKKOL BPS-10T (polyoxyethylene (10) phytosterol) HLB12.5, NIKKOL BPS-20T (produced by Nikko Chemicals Co., Ltd.) Polyoxyethylene (20) phytosterol) HLB15.5, NIKKOL BPSH-25 (polyoxyethylene (25) phytostanol) HLB14.5, NIKKOL BPS-30 (polyoxyethylene (30) phytosterol) HLB18, manufactured by Nippon Emulsion Co., Ltd. CS-20 (polyoxyethylene (20) cholesterol) HLB13, CS-24 (polyoxyethylene (24) cholesterol) HLB14, CS-30 (polyoxy) Ethylene (30) cholesterol) HLB15 and the like.

  The concentration (mass / mass) of the polyoxyethylene sterol ether when preparing the liposome of the present invention is preferably 0.01 to 0.5 when the phospholipid is 1 in terms of the concentration ratio to the phospholipid. 01-0.3 is particularly preferable. When the concentration ratio of polyoxyethylene sterol ether to phospholipid 1 is less than 0.01, the stability of the liposome is not so good. When the concentration ratio of polyoxyethylene sterol ether exceeds 0.5, liposomes are hardly formed due to micelle formation or the like.

Examples of the polyhydric alcohol (component D) used in the present invention include dipropylene glycol, glycerin, 1,3-butylene glycol, propylene glycol, isoprene glycol, 1,2-pentanediol and the like.
When preparing the liposome of the present invention, it is preferable to incorporate dipropylene glycol. If dipropylene glycol is not blended, it may be difficult to prevent the formation of precipitates.
In order to prepare the liposome of the present invention, it is essential to add water (E component).

  The methoxypolyethylene glycol glycol (F component) used in the present invention is obtained by homopolymerizing methoxypolyethylene glycol methacrylate.

Methoxypolyethylene glycol methacrylate can be obtained, for example, by reacting polyethylene glycol methyl ether with methacrylic acid chloride. Some are commercially available as reagents. For example, NK ester M-90G (chemical name: methoxypolyethylene glycol # 400 methacrylate) commercially available from Shin-Nakamura Chemical Co., Ltd. and Bremer PME (PME-400: n≈9) commercially available from NOF Corporation are used as monomers. Can be used as About the manufacturing method of a polymer, what is necessary is just to follow a conventional method, and a monomer is made to react in presence of a polymerization initiator in a solvent.
This manufacturing method is the method disclosed in Patent Document 6 and Patent Document 7.
Although the molecular weight of a polymer can be variously adjusted according to the intended purpose, it is 1000 or more and 100,000 or less normally in polystyrene conversion, Preferably it is 2500 or more and 100,000 or less. In the liposome of the present invention, the polymer is usually contained in the range of 0.02 to 20% by mass, preferably 0.1 to 4% by mass, particularly preferably 1 to 4% by mass.

  Furthermore, it is preferable to adjust the pH to 5 to 8 by blending a pH adjuster (G component). Water (E component) and pH adjuster (G component) can be used, for example, as a citrate buffer.

The liposome of the present invention can be prepared using a high-pressure emulsifier. Purified water of a polyhydric alcohol solution of phospholipid, sterol, polyoxyethylene sterol ether, and a pH adjuster are heated to 60 to 95 ° C. and dispersed with a homomixer. Further, methoxypolyethylene glycol polymethacrylate is added and mixed, and then high-pressure emulsified using a high-pressure emulsifier to prepare liposomes. High-pressure emulsifiers include a thin film swivel type high-speed homomixer (TK Filmix) manufactured by Primix Co., Ltd., an ultra-high pressure homogenizer manufactured by Microfluidics (microfluidizer), and an internal shear force type mixer manufactured by M Technique Co., Ltd. (Claire) Mix) or the like.
For example, when an internal shear force type mixer (CLEAMIX) manufactured by M Technique Co., Ltd. is used, (rotor No. R1, rotation speed 14,000 rpm or more), (screen No. T15.5.24, rotation speed) By applying a shearing force at 14,000 rpm or more, liposomes of 60 nm or less can be prepared. Alternatively, in the case of using a microfluidizer, the target liposome can be obtained by selecting the chamber so that the pressure is 2000 psi and passing it once.

  When preparing the liposome of the present invention, the scope of the present invention does not impair the effects of the present invention other than phospholipids, sterols, polyoxyethylene sterol ethers, polyhydric alcohols, polymethacrylic acid methoxypolyethylene glycol, purified water, and pH adjusters. Nonionic surfactants, anionic surfactants, cationic surfactants, amphoteric surfactants, oil agents, moisturizers, water-soluble polymers, antioxidants, UV absorbers, chelating agents, preservatives Antibacterial agents, coloring agents, fragrances and the like can be blended. Moreover, cosmetic ingredients such as vitamins such as ascorbic acid derivatives, tocopherols, retinol derivatives, and plant extracts can be blended, and the cosmetic ingredients can be encapsulated in liposomes.

  The dosage form of the liposome-containing cosmetic of the present invention may be any of an aqueous solution (meaning an aqueous solution in which liposomes are dispersed), an oil-in-water emulsion composition, a water-in-oil emulsion composition, a multiple emulsion composition, and a multilayer agent. Good. The prepared liposome dispersion may be used as it is. The liposome-containing cosmetic of the present invention can be a lotion, milky lotion, cream, cosmetic liquid, pack, hair restorer, sunscreen cosmetic, liquid foundation, hair treatment, hair rinse or the like.

  In order for cosmetics to contain the liposome dispersion liquid of the present invention, it is desirable that the liposome dispersion liquid is stirred and mixed at 70 ° C. or less, preferably at room temperature, in the final step of cosmetic production. If the liposomes are mixed at 70 ° C. or higher, the liposomes may be broken. The pH of the cosmetic is preferably 5 to 8 from the viewpoint of liposome stability.

[Test Example 1]
<Preparation of liposome and measurement of liposome particle size>
The liposome dispersions of Examples 1 to 5 and Comparative Example 1 were prepared with the compositions shown in Table 1 below.

A phospholipid solution (polyhydric alcohol solution of phospholipid) is heated and dissolved to 85 ° C., and a solution such as sterol heated to 85 ° C. (polyvalent of nonionic surfactants such as sterol and polyoxyethylene sterol ether) (Alcohol solution) was added, and tocopherol and cetyl polyethylene glycol hydroxyethylpartamide were further added and mixed. Next, purified water at 85 ° C. was added, and the mixture was treated with a homomixer (TK homomixer MARK II 2.5 type modified, manufactured by PRIMIX Corporation) at a rotation speed of 6000 rpm for 5 minutes. After cooling to room temperature, citrate buffer was added and mixed. Furthermore, polymethacrylic acid methoxypolyethylene glycol was added, mixed with a homomixer, and the resulting pre-treatment product was used with a microfluidics super high pressure homogenizer (microfluidizer), chamber: JF12Y, APM: H30Z, Pressure: 20000 psi Number of liquid passing: Treated under the condition of 1 time to obtain a liposome dispersion.
The pH of the citrate buffer was adjusted to 6.5.
The component F polymethacrylic acid methoxypolyethylene glycol used was that obtained in Synthesis Example 1 disclosed in JP2012-31087A.
That is, 0.0403 g of polymerization initiator AIBN was weighed into a 100 ml eggplant flask, the inside of the flask was replaced with argon gas three times, 30 ml of distilled benzene was added, and the mixture was stirred at room temperature until AIBN was dissolved. 5 ml of ether methacrylate (PEG average polymerization degree: 9) was added, and the mixture was heated at 60 ° C. for 48 hours and then at 70 ° C. for 24 hours to carry out polymerization. This compound had a number average molecular weight Mn = 15363 and a mass average molecular weight Mw = 35680 in terms of polystyrene. In the table, “FK-90BG” (manufactured by Wako Pure Chemical Industries, Ltd.) is preliminarily treated with 20% by mass of methoxypolyethylene glycol polymethacrylate glycol, 30% by mass of 1,3-butylene glycol, 50% water to improve handling. %.

The number average particle diameter of the obtained liposome was measured. The measurement method is as follows.
[Number average particle size measurement method]
Equipment: Zeta potential / particle size measurement system ELSZ-1100ZS manufactured by Otsuka Electronics Co., Ltd.
Cell used: Standard glass cell (quartz glass cell)
Measurement method: Dynamic light scattering (DLS)
Measurement conditions: measured at 25 ° C

<Test results>
The particle diameter of the obtained liposome is shown in Table 2 and FIG.

  It was confirmed that the size of the liposomes was reduced depending on the concentration of poly (methoxypolyethylene glycol) methacrylate.

  During the test of Test Example 1, since a particle size difference was observed in liposomes prepared using non-hydrogenated lecithin and hydrogenated lecithin, a comparative test between non-hydrogenated lecithin and hydrogenated lecithin was performed.

[Test Example 2]
<Measurement of change in liposome particle size by preparation of liposome and measurement of particle size>
Liposome dispersions of Comparative Examples 1 and 2 and Examples 1 to 14 prepared according to the composition of Table 1 were prepared at the polymethoxy methacrylate glycol concentration shown in Table 3.
As the hydrogenated lecithin, NIKKOL lecinol S-10M (Nikko Chemicals Co., Ltd.) was used. The particle size of the obtained liposome composition was measured in the same manner as in Test Example 1.

<Test results>
The test results are shown in Table 3 below and FIG.

  It has been found that the effect of reducing the particle size of the liposome of poly (methoxypolyethylene glycol) methacrylate is more effectively exhibited by combining with lecithin without addition of hydrogen.

[Test Example 3]
Effect of inhibiting changes in liposome particle size during storage at high temperatures <Test method>
When the structure of the lipid multilayer film is preserved at a high temperature, the liposome containing the phospholipid is united as described above to form a lamellar liquid crystal structure and loses its function as a liposome. The product of the present invention is stable even in such a high temperature storage environment, and coalescence and aggregation are suppressed.
The liposomes of Table 4 prepared in Test Example 2 (compositions of Comparative Example 1 and Examples 1 to 7) were stored in a constant temperature bath at 40 ° C. for 4 weeks, and changes in the particle size of the liposomes were observed. The particle size was measured in the same manner as in Test Examples 1 and 2.

<Result>
As shown in Table 4 below, the liposome particle diameter after 4 weeks at 40 ° C. is limited to 60 nm, which is the size of the intercellular space of the horny layer of the skin, and the polymethacrylic acid liposomes. When the acid methoxypolyethylene glycol concentration exceeded 1%, it remained on the order of 50 nm (Examples 4 and 5).

  From this test, it was revealed that methoxypolyethylene glycol polymethacrylate not only makes the liposome particles smaller, but also suppresses destabilization of the liposomes due to aggregation and coalescence occurring under high temperature conditions.

[Test Example 4]
Comparison test with other methacrylic acid polymers <Test method>
Copolymer (glyceryl amidoethyl methacrylate / stearyl methacrylate) copolymer having a structure similar to that of poly (methoxy polyethylene glycol) methacrylate used in the present invention is a skin elasticity improving agent marketed under the trade name of Seracute-L. The composition of Comparative Example 3 in which this substance was blended in place of polymethacrylic acid polyethylene glycol and the composition of Example 15 (shown in Table 5) were prepared in the same manner as in Test Example 1 and the particle size was measured.

<Result>
The measurement results at 25 ° C. are shown in Table 6 below.

The liposome particles having the composition of Comparative Example 3 had a particle size twice or more that of Example 15. Further, the liposome having the composition of Comparative Example 3 had a particle size of 84.9 nm after storage at 40 ° C. for 1 month.
From this test result, it is considered that the action of reducing and stabilizing the particle size of the liposomes of poly (methoxypolyethylene glycol) polymethacrylate is an effect peculiar to poly (methoxypolyethylene methacrylate glycol) and not derived from the structure. .

Examples of cosmetic preparations Examples of cosmetic preparations incorporating the liposomes of the present invention are shown below.

Formulation Example 1 Moisturizing lotion (blending ingredients) (mass%)
1. Liposome dispersion of Example 4 0.5
2. Glycerin 3
3. 1,3-butylene glycol 1
4). Methyl Gluces-10 0.5
5. Diglycerin 0.5
6). Dipropylene glycol 6
7. 1,2-Pentanediol 1
8). Citric acid 0.01
9. Sodium citrate 0.1
10. Purified water residue (production method)
Components 2 to 9 were stirred and dissolved in Component 10, heated and cooled, and then Component 1 was added to prepare a moisturizing lotion.
(Cosmetics effect)
The moisturizing lotion of Formulation Example 1 had a penetrating feeling and was not sticky, had a pleasant feeling to use, and was excellent in the moisturizing effect. Also, the storage stability was good.

Formulation Example 2 Moisturizing beauty emulsion (formulation component) (mass%)
1. Liposome dispersion of Example 4 10
2. Glycerin 10
3. 1,3-butylene glycol 5
4). Betaine 3
5. Dipropylene glycol 7
6). Citric acid 0.01
7). Sodium citrate 0.1
8). Xanthan gum 0.08
9. 1,2-pentanediol 1
10. Squalane 3
11. Dimethicone 1
12 Polysorbate 60 0.8
13. Sorbitan stearate 0.3
14 Purified water residue (production method)
Add component 8 heated and dispersed in component 9 to component 14, add components 2 to 7 and stir and dissolve (aqueous phase). Ingredients 10-13 were heated and dissolved, and the previously prepared aqueous phase was added to emulsify. Then, component 1 was added and stirred to prepare an emulsified composition (moisturizing cosmetic emulsion).
(Cosmetics effect)
The emulsified composition of Formulation Example 2 had a pleasant feeling of being moist and moist without stickiness, and was excellent in the moisturizing effect and its sustainability. Also, the storage stability was good.

Claims (4)

The concentration of non-hydrogen added lecithin (component A) is 0.1 to 10% by mass, and the concentration ratio (mass / mass) of sterol (component B) to non-hydrogen added lecithin (component A) 1 is 0.00. 01-0.1, concentration ratio (mass / mass) of polyoxyethylene sterol ether (C component) of HLB 12-18 is 0.01-0.5, non-hydrogenated lecithin (A component), sterol (B Component), polyoxyethylene sterol ether (component C) of HLB 12-18, polyhydric alcohol (component D), water (component E), polymethacrylic acid methoxypolyethylene glycol (component F) Dispersion.   2. The liposome dispersion liquid according to claim 1, comprising dipropylene glycol as a polyhydric alcohol (D component). The liposome dispersion liquid according to claim 1 or 2 , comprising 0.02 to 20% by mass of poly (methoxypolyethylene glycol) (F component). A skin external preparation or cosmetic comprising the liposome dispersion liquid according to any one of claims 1 to 3 .

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