JP2807840B2 - Stabilization of liposome and phospholipid dispersions - Google Patents

Description

Description: TECHNICAL FIELD The present invention relates to a method for stabilizing a liposome and a phospholipid dispersion applied to pharmaceuticals, quasi-drugs, cosmetics, and the like.

[Conventional technology]

Liposomes, which are closed vesicles of lipids, were originally widely used as biomembrane models, but in recent years, various applications directed to drug delivery systems (DDS) have been made. Phospholipids are also used in the cosmetics field for hair and
Although formulated as a skin nutritional supplement, in recent years, attempts have been made to use it as a surfactant or moisturizer.
When liposome and phospholipid dispersions are used in this way, it is important that these dispersions are stable in order to exhibit the effect as a DDS and the effects as a surfactant and a humectant.

However, liposomes and phospholipid dispersions
Under the influence of light, heat, osmotic pressure, etc., it easily undergoes chemical and physical changes.In particular, since the pH of the system tends to decrease over time, hydrolysis, aggregation, sedimentation, There has been a problem that appearance change or function deterioration due to precipitation or the like occurs.

For this reason, a method of adding an electrolyte to a dispersion and trying to suppress the pH drop by its buffering action (Japanese Patent Laid-Open No.
No. 3109), and an attempt has been made to replace the air in a closed container with nitrogen gas and store these dispersions therein.

[Problems to be solved by the invention]

However, in the method of adding an electrolyte, if a sufficient amount of electrolyte is added to suppress the decrease in pH of the system, liposome aggregation and gelation of the system will be promoted. Although it is effective in reducing the pH of a typical system, once it is opened, the effect of nitrogen gas replacement is lost, and there is a drawback that it cannot withstand long-term continuous use.

Therefore, a liposome and phospholipid dispersion liquid which does not cause a decrease in the pH of the system and have excellent long-term stability has been desired.

[Means for solving the problem]

Under such circumstances, the present inventors have conducted intensive studies. As a result, when a compound selected from cepharanthin, rutin and an oil-soluble licorice extract is blended, a decrease in pH of the system is suppressed, and a long-term stable liposome and phospholipid The inventors have found that a dispersion can be obtained, and have completed the present invention.

That is, the present invention provides a method for stabilizing a liposome or a phospholipid dispersion, which comprises mixing one or more selected from cepharanthin, rutin, and an oil-soluble licorice extract, and a liposome or phosphorus stabilized by the method. Disclosed are lipid dispersions and cosmetics containing these dispersions.

The cepharanthin, rutin, and oil-soluble licorice extract used in the present invention can be each extracted by a conventional method. These can be used alone or in combination of two or more kinds, and 0.0001 to 10% by weight (hereinafter simply referred to as%
Is preferably blended. These may be added during or after the preparation of the liposome dispersion or the phospholipid dispersion. Particularly in the case of liposomes, it is preferable to add the liposome at the time of preparing the dispersion.

Examples of the phospholipid used in the present invention include natural phospholipids such as phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, phosphatidylinositol, lysophosphatidylcholine, sphingomyelin, egg yolk lecithin, soybean lecithin, synthetic phospholipids such as dioleoyl phosphatidylcholine, and the like. Or hydrogenated lecithin in which unsaturated carbon chains of naturally occurring phospholipids are saturated with hydrogen, and other phospholipids extracted from microorganisms such as Escherichia coli, etc., and these may be used alone or in combination of two or more. Can be. In order to enhance the dispersion stability, it is desired that the complex lipid lamellar phase be charged. In this case, phosphatidylserine, dicetyl phosphate, phosphatidic acid, stearylamine and the like may be blended.

In the present invention, liposomes can be prepared by a generally known method, for example, a vortexing method (ADBangham, J. Mol. Bi).
ol., 13,238 (1965)), the sonication method (C. Huang, Bi)
ochem., 8,344 (1969)), Prevesicle method (H. Trauble,
Neurosci. Res. Prog. Bull., 9, 273, (1971)), ethanol injection method (S. Batzri, Biochem. Biophys. Acta, 298, 1015).
(1973)), French press extrusion method (Y. Barenholz, FEBS)
Lett., 99, 210 (1979)), cholic acid removal method (Y.Kagawa,
J. Biol. Chem., 246, 5477 (1971), Triton X-100 batch method (WJ Gerritsen, Eur. J. Biochem., 85, 255 (197
8)), Ca ²⁺ fusion method (D.Papahadjopoulos.Biochem.Bioph
ys. Acta, 394, 483 (1975)), ether injection method (D. Deaze
r, Biochem. Biophys. Acta, 443, 629 (1976)), annealing method (R. Lawczeck. Biochem. Biophys. Acta, 443, 313)
(1976)), freeze-thaw fusion method (M. Kasahara, J. Biol. Che
m., 252, 7384 (1977)), W / O / W emulsion method (S. Mats
umoto, J. Colloid Interface Sci., 62, 149 (1977)),
Reverse phase evaporation method (F. Szoka, Proc. Natl. Acad. Sci. USA, 75, 4194
(1978)), and a polyhydric alcohol method (Japanese Patent Application Laid-Open No. 60-7793).

The blending amount of the phospholipid is preferably in the range of 0.01 to 20% in the liposome and the phospholipid dispersion. If it is less than 0.01%, the effects of liposomes and phospholipids cannot be obtained when this dispersion is used in cosmetics and the like, and if it exceeds 20%, the system gels, which is not preferable.

Depending on the purpose, the liposome and phospholipid dispersion of the present invention may contain, for example, a lower alcohol such as ethanol, propyl alcohol, or isopropyl alcohol; or a lower alcohol such as propylene glycol, 1,3-butanediol, ethylene glycol, polyethylene glycol, or glycerin. Polyhydric alcohols; water-soluble substances such as sodium chondroitin sulfate and sodium hyaluronate; oil-soluble substances such as squalane and cholesterol; and powders such as dyes and pigments can be appropriately blended.

The liposome and phospholipid dispersion of the present invention are stable for a long period of time, and can exert the effects of liposomes and phospholipids, especially when they are added to cosmetics such as lotions, serums, emulsions, creams, and packs. It is.

The liposome and phospholipid dispersion of the present invention have a pH of
It is stable in the range of 6.5 to 8, and when it is blended in cosmetics or the like, it is stable in almost the same range.

〔Example〕

Next, the present invention will be described in more detail with reference to examples, but the present invention is not limited to these examples.

Example 1 In a 50 ml eggplant type flask, 0.15 g of egg yolk lecithin, 0.02 g of cepharanthin and 10 mg of dicetyl phosphate are dissolved in 10 ml of chloroform, and chloroform is distilled off using a rotary evaporator. This was dried in a vacuum desiccator for 2 hours, and chloroform was completely distilled off. After adding 20 ml of water thereto and hydrating at 40 ° C. for 30 minutes, the mixture was vigorously shaken with a vortex mixer to form liposomes. After cooling, adjust the pH using 1N sodium hydroxide.
It was adjusted to 7.60 ± 0.05 to obtain the target liposome solution.

Example 2 A liposome solution was produced in the same manner as in Example 1 except that 0.02 g of rutin was added.

Reference Example 1 6.3 g of concentrated glycerin was heated to 75 to 80 ° C., and 1.55 g of partially hydrogenated lecithin and 109 mg of dicetyl phosphate were added thereto, followed by stirring to uniformly swell. 200 ml of a 0.01% aqueous kojic acid solution was added thereto, and further swollen at 60 ° C. for 3 minutes. Finally, while keeping this solution at 60 ° C, use a homomixer for 3 hours.
Stir for 1 minute, return to room temperature, and adjust the pH with 1N sodium hydroxide.
It was adjusted to 7.60 ± 0.05 to obtain the target liposome solution.

Example 3 A liposome solution was produced in the same manner as in Reference Example 1, except that the oil-soluble licorice extract was mixed with concentrated glycerin together with phospholipids.

Comparative Example In place of cepharanthin in Example 1, berberine hydrochloride, which is relatively similar in structure to cepharanthin, D-
A liposome solution containing (+)-catechin or quercetin or none was prepared.

Test Example The liposome solutions prepared in Examples 1 to 3 and Comparative Example
It was stored at 40 ° C. for 2 months and evaluated for pH change and system stability. The results are shown in Table 1.

As is clear from Table 1, the liposome solution of the present invention did not cause a significant decrease in pH over time and was excellent in stability.

Example 4 Essence: (Component) (%) (1) Hydrogenated egg yolk lecithin 1.8 (2) Liquid paraffin 0.5 (3) Cepharanthin 0.1 (4) Licorice extract (oil-soluble) 0.1 (5) Flavor 0.1 (6) Glycerin 5.0 (7) Polyethylene glycol 15.0 (8) Carboxyvinyl polymer 0.1 (9) Sodium hydroxide 0.01 (10) Celtrol 0.1 (11) Purified water Remaining (Production method) A. Heat components (1) to (5) Dissolve.

B. Components (6) to (11) are mixed and stirred.

B was added to C.A and mixed uniformly to obtain a serum.

The essence of the present invention obtained as described above has a pH of 7.5 immediately after production, and after storage at 40 ° C. for 2 months, does not show a significant decrease in pH over time to pH 7.0. It was excellent.

〔The invention's effect〕

As described in detail above, according to the present invention, it is possible to obtain a liposome and a phospholipid dispersion liquid which do not cause a time-dependent decrease in pH and have excellent long-term stability. Therefore, it can be stably blended into cosmetics and the like, and the effects of liposomes and phospholipids can be sufficiently exerted.

──────────────────────────────────────────────────続 き Continuation of the front page (56) References JP-A-2-169507 (JP, A) JP-A-62-263109 (JP, A) JP-A-3-501842 (JP, A) (58) Field (Int.Cl. ⁶ , DB name) A61K 7/00-7/50 B01F 17/14 C07F 9/10

Claims (4)

(57) [Claims] 1. A method for stabilizing a liposome or phospholipid dispersion, comprising one or more selected from cepharanthin, rutin and an oil-soluble licorice extract. 2. A stabilized phospholipid dispersion comprising a phospholipid and one or more selected from cepharanthin, rutin and an oil-soluble licorice extract. 3. A stabilized liposome dispersion comprising one or more selected from cepharanthin, rutin and an oil-soluble licorice extract. 4. A cosmetic comprising the phospholipid dispersion according to claim 2 and / or the liposome dispersion according to claim 3.