JP2006273790A - Cationic polymer micell medicinal carrier, dispersant containing the medicinal carrier, and skin care preparation and cosmetic blended with the medicinal carrier - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a cationic polymer micell medicinal carrier of which the permeability to the skin and the effect persistency of a medicinal effect component having physiological activity effect are remarkably enhanced, and a dispersant containing the medicinal carrier, a skin care preparation and a cosmetic blended with the medicinal carrier. <P>SOLUTION: The cationic polymer micell medicinal carrier is characterised by containing a cationic amphipathic polymer having a charging portion and a hydrophobic portion, a medicinal effect component, and a liquid oil agent. <P>COPYRIGHT: (C)2007,JPO&INPIT

Description

  The present invention relates to a cationic polymer micelle drug carrier, a dispersion containing the drug carrier, a skin external preparation and a cosmetic containing the drug carrier.

  When applying active ingredients such as whitening ingredients, anti-aging ingredients, cell activation ingredients, antibacterial ingredients, anti-inflammatory ingredients, etc., increase the penetration of the active ingredients into the skin and act on the target site for a long time. Is important in terms of efficacy and safety.

  A polymeric micelle is an association of amphiphilic polymers, a fine particle formed with a hydrophilic polymer chain as the outer shell and a hydrophobic polymer chain as the inner shell, and is a new DDS that demonstrates the sustained release of medicinal ingredients. It is attracting attention as a preparation. And as a technique which applies a polymer micelle to such a DDS formulation, there exists invention like the following patent document 1, for example.

JP 2005-8614 A

  However, the invention according to Patent Document 1 is intended for ophthalmic use, and there are few studies on the skin and application studies on high-functional cosmetics such as whitening cosmetics. In particular, when applied to the skin, there is a problem that the active ingredient is difficult to penetrate due to the stratum corneum barrier function, and conventional polymer micelles are insufficient in terms of skin permeability.

  On the other hand, there is also a method of improving the permeability by destroying the stratum corneum barrier function with an enhancer such as a surfactant or menthol. As such a technique, there is an invention such as Patent Document 2 below.

JP 2002-322045 A

  However, there are problems in terms of safety and side effects, and the retention and persistence in the epidermal basal layer are poor, so the actual effect of the active ingredient is not sufficient.

  The present invention has been made in order to solve such conventional problems, and is a highly safe cationic polymer micelle with significantly enhanced penetration into the skin and sustained effect of a medicinal component having a physiologically active effect. It is an object of the present invention to provide a drug carrier, a drug carrier-containing dispersion, a skin external preparation and a cosmetic containing the drug carrier.

  The inventors of the present invention provide a cationic polymer micelle drug carrier composed of a cationic amphiphilic polymer having a charged site (segment) and a hydrophobic site (segment), a medicinal component and a liquid oil agent, and has a skin barrier function. It was found that the retention of the medicinal component in the epidermis and epidermis basal layer was remarkably enhanced while increasing the amount of medicinal component penetrating into the stratum corneum without breaking the skin, and the present invention was completed.

  That is, the invention according to claim 1 relating to a cationic polymer micelle drug carrier comprises a cationic amphiphilic polymer having a charged site and a hydrophobic site, a medicinal component, and a liquid oil agent. And The invention described in claim 2 is characterized by containing a cationic amphiphilic polymer having a charged site and a hydrophobic site, a medicinal component, a liquid oil, and a polyhydric alcohol.

  Furthermore, the invention described in claim 3 is characterized by containing a cationic amphiphilic polymer having a charged portion and a hydrophobic portion, a medicinal component, a liquid oil agent, and an ionic water-soluble polymer. . Furthermore, the invention of claim 4 contains a cationic amphiphilic polymer having a charged portion and a hydrophobic portion, a medicinal component, a liquid oil agent, a polyhydric alcohol, and an ionic water-soluble polymer. It is characterized by that.

  The invention according to claim 5 is the cationic polymer micelle drug carrier according to any one of claims 1 to 4, characterized in that the zeta potential is +10 mV to +100 mV. The invention according to claim 6 is the cationic polymer micelle drug carrier according to any one of claims 1 to 5, characterized in that the drug carrier has an average particle diameter of 50 nm to 900 nm. The invention according to claim 7 is the cationic polymer micelle drug carrier according to any one of claims 1 to 6, wherein the zeta potential of the cationic amphiphilic polymer is +10 mV to +100 mV. And

  Furthermore, the invention according to claim 8 is the cationic polymer micelle drug carrier according to any one of claims 1 to 7, wherein the cationic amphiphilic polymer is partially introduced into the hydrophobic group having 4 to 20 carbon atoms. It has a site and a cationic group site. Furthermore, the invention according to claim 9 is the cationic polymer micelle drug carrier according to any one of claims 1 to 8, wherein the cationic amphiphilic polymer is partially introduced into a hydrophobic group having 4 to 20 carbon atoms. It has a site and an amino group site or a quaternary salt amino group site.

  Furthermore, the invention according to claim 10 is the cationic polymer micelle drug carrier according to any one of claims 1 to 9, wherein the cationic amphiphilic polymer is a chitin derivative or a chitosan derivative. . Furthermore, the invention described in claim 11 is characterized in that, in the cationic polymer micelle drug carrier according to any one of claims 1 to 10, the solubility of the medicinal component in water is 50 mg / ml or less. Furthermore, the invention according to claim 12 is the cationic polymer micelle drug carrier according to any one of claims 1 to 11, wherein the IOB value of the liquid oil agent is 0 to 1.0.

  The thirteenth aspect of the present invention is the cationic water-soluble polymer according to any one of the third to twelfth aspects, wherein the ionic water-soluble polymer has a zeta potential of +5 mV to +100 mV. It is a polymer. Furthermore, the invention described in claim 14 is the cationic polymer micelle drug carrier according to any one of claims 3 to 13, wherein the ionic water-soluble polymer has a phospholipid structure.

  Furthermore, the invention according to claim 15 is characterized in that, in the cationic polymer micelle drug carrier according to any one of claims 1 to 14, the medicinal component has an enzyme inhibitory action or an enzyme synthesis inhibitory action. To do. Furthermore, the invention according to claim 16 is the cationic polymer micelle drug carrier according to any one of claims 1 to 14, characterized in that the medicinal component is a whitening component having a tyrosinase inhibitory action or a tyrosinase synthesis inhibitory action. And

  Furthermore, the invention according to claim 17 relating to a dispersion containing a cationic polymer micelle drug carrier comprises the cationic polymer micelle drug carrier according to any one of claims 1 to 16. Furthermore, the invention according to claim 18 relating to the external preparation for skin contains the cationic polymer micelle drug carrier according to any one of claims 1 to 16. Furthermore, the invention according to claim 19 relating to a cosmetic is characterized by containing the cationic polymer micelle drug carrier according to any one of claims 1 to 16.

  Furthermore, the invention according to claim 20 relating to the whitening cosmetic is characterized by containing the cationic polymer micelle drug carrier according to any one of claims 1 to 16. Furthermore, the invention according to claim 21 relating to an anti-aging cosmetic is characterized by comprising the cationic polymer micelle drug carrier according to any one of claims 1 to 16.

  The cationic polymer micelle drug carrier of the present invention penetrates a large amount of the horny layer having many anion sites, and is encapsulated and held in the drug carrier after penetrating the horny layer responsible for most of the skin barrier function. The medicinal component is gradually released, and as a result, the medicinal component acts on the epidermis and the epidermis basal layer continuously. Therefore, the cationic polymer micelle drug carrier of the present invention is more in comparison with the polymer micelle drug carrier composed of anionic amphiphilic polymer and nonionic amphiphilic polymer which is nonionic. A remarkably excellent effect is obtained.

  In addition, the cationic polymeric micelle drug carrier of the present invention has excellent binding retention and sustained release of medicinal ingredients even for biological membranes and mucous membranes, so that it is inflamed skin, lips, eyes, nasal cavity, oral cavity, etc. There is also an advantage that the pharmacological effect and safety are enhanced even for the part having the mucous membrane. For example, when a whitening ingredient having a tyrosinase inhibitory action or a tyrosinase synthesis inhibitory action is used as a medicinal ingredient, it increases the amount of melanocytes existing in the epidermis basal layer, which is the target site, and at the same time the retention at the melanocyte site and the slowdown of the medicinal ingredient Since the sustainability of the effect derived from release is enhanced, the whitening action and safety when actually used are greatly improved.

  Furthermore, since the cationic polymeric micelle drug carrier of the present invention has high safety and long-lasting retention on biological membranes and mucous membranes, it can be applied to mucous membranes such as skin, eyes and lips, which are causing inflammation and damage, and external use By doing so, it can be used for a new external preparation having both higher safety and excellent efficacy.

  The cationic polymer micelle drug carrier of the present invention and the dispersion containing the same can increase or decrease the stability of a medicinal component that is inferior in stability, and thus can suppress or prevent a decrease in medicinal effect due to modification or decomposition of the medicinal component. And since the stability of the drug carrier and the dispersion itself containing the drug carrier is high, the stability and effectiveness of the cationic polymeric micelle drug carrier will not be reduced even if it is mixed with an existing pharmaceutical system.

  As described above, the cationic polymer micelle drug carrier of the present invention contains a cationic amphiphilic polymer having a charged site and a hydrophobic site, a medicinal component, and a liquid oil. Moreover, a polyhydric alcohol and ionic water-soluble polymer are contained as needed.

  Fine emulsification equipment such as a high-pressure emulsifier after homogenizing a cationic amphiphilic polymer having an electric site (segment) and a hydrophobic site (segment), a medicinal component, a liquid oil and a polyhydric alcohol in the presence of purified water By repeating the high-pressure treatment 1 to 10 times, a translucent to cloudy dispersion containing a cationic polymer micelle drug carrier encapsulating and retaining a medicinal component can be obtained. Furthermore, a cationic polymer micelle drug carrier or a concentrated dispersion can be obtained by using a freeze dryer, an ultrafiltration device, a large evaporator or the like.

  The average particle size of the cationic polymeric micelle drug carrier thus prepared is not particularly limited, but is preferably 50 nm to 10 μm, and more preferably 50 nm to 900 nm in order to exhibit the effect. desirable.

  The kind of the medicinal component is not particularly limited, but a component having a solubility of 50 mg / ml or less of the medicinal component in water is desirable from the viewpoint that the effect is more easily exhibited. In particular, those having enzyme inhibitory activity or enzyme synthesis system inhibitory activity are desirable for effectively exerting the effectiveness of the present invention, such as tyrosinase inhibitor, protease inhibitor, hyaluronidase inhibitor collagenase inhibitor, elastase inhibitor, Examples include ceramidase inhibitors. When a whitening ingredient having a tyrosinase inhibitory action or a tyrosinase synthesis inhibitory action is included with a medicinal ingredient, herbal medicines, plant-derived polyphenols, flavonoids, isoflavans, and the like can be mentioned.

  The whitening component used in the present invention is not particularly limited as long as it has a tyrosinase inhibitory action, a tyrosinase synthesis inhibitory action, a melanin production inhibitory action, a melanin decolorizing action, or an antioxidant action. Whitening action when actually used compared to the case of using only whitening ingredients to increase the amount of melanocytes existing in the epidermal basal layer, which is the target site, and the continuous action on melanocytes, while at the same time enhancing safety. And safety is greatly improved.

  For example, the following can be exemplified as components that effectively demonstrate the effectiveness of the cationic polymeric micelle drug carrier of the present invention.

  As licorice flavonoids, licorice extract containing licorice flavonoids, licorice extract, licorice flavonoids, licorice including 40% or more Extract (product name: licorice flavonoid PT-40, oil-soluble licorice extract BGSR, oil-soluble licorice extract PU, etc.), plant extract containing ellagic acid and ellagic acid, soybean extract containing soybean isoflavone and soybean isoflavone, Ferulic acid and plant extracts containing ferulic acid, glycyrrhizic acid and its derivatives, glycyrrhetinic acid and its derivatives, plant extracts containing pycnogenol and pycnogenol, placenta extract, Clara extract, Sakuhakhi extract, Yukinoshita Eki , Chamomile extract, rosemary extract, such as Ougonekisu and the like.

  Carotenoids and animal and plant extracts containing them, catechins, procyanidins, rutin, hesperidin, quercetin, plant extracts containing them, plant polyferols contained in grapes and grape seeds, acerola and acerola seeds, etc. Is mentioned. A component having an inhibitory action on the production of αMSH, which is a melanogenesis stimulating hormone, is also effective for exerting more effectively.

  In addition, hydroquinone and derivatives thereof, arbutin and derivatives thereof, plant extracts containing arbutin, glutathione and derivatives thereof, acetylcysteine, hypotaurine, thiotaurine, cysteine and derivatives thereof, sulfur-containing amino acid components such as N-acetylcysteine and cysteamine Derivatives thereof, vitamin E and derivatives thereof, vitamin A and derivatives thereof, carotenoid components such as carotene and astaxanthin and derivatives thereof, ascorbic acid and derivatives thereof, and salts thereof, panthenol and derivatives thereof, linoleic acid and linolenic acid Higher unsaturated fatty acids and derivatives thereof, and natural fats and oils containing 10% or more of these higher unsaturated fatty acids. Examples of vitamin E derivatives include tocopherol nicotinate, tocopherol linoleate, tocopherol succinate, and tocopherol acetate. Examples of vitamin A derivatives include retinol palmitate, retinol linoleate, and retinol acetate. Examples of natural fats and oils containing 10% or more of higher unsaturated fatty acids include soybean oil, rice oil, rice bran oil, evening primrose oil, wheat germ oil, olive oil and the like.

  Ascorbic acid and its derivatives and salts thereof include water-soluble ascorbic acid derivatives such as sodium ascorbate phosphate, magnesium ascorbate phosphate, magnesium ascorbyl phosphate and salts thereof such as ascorbyl phosphate and salts thereof, and Ascorbic acid alkyl ethers and ascorbic acid alkyl esters such as ascorbyl tetraisopalmitate (product name: VCIP), ascorbyl palmitate, ascorbyl isopalmitate, ascorbyl stearate, ascorbyl diisopalmitate, etc., as salts and hydrophobic ascorbic acid derivatives Etc. In addition, ascorbic acid polypeptide, ascorbic acid chitosan and the like can also be mentioned.

  The liquid oil to be included is not particularly limited, but an IOB value of 0 to 1.0 is desirable. More preferably, the IOB value is 0 to 0.5. The IOB value is an index indicating the degree of polarity of the oil component, and is a value representing the ratio of inorganic to organic (with an organic value of 20 for one carbon atom in the molecule and an inorganic value of 100 for one hydroxyl group) Based on this, it is a value calculated on the basis of an inorganic salt of another substituent (inorganic group) (Organic Conceptual Diagram-Fundamentals and Applications, P227, 1984, Sankyo Publishing). Inorganic value of the component / organic value of the component, the higher the IOB value, the higher the polarity, the lower the IOB value, the lower the polarity, the higher the polarity, the higher the IOB value, the present invention For example, an ester-based liquid oil agent is specifically mentioned.

  Specific examples include liquid paraffin (0.0), liquid isoparaffin (0.0), squalane (0.0), isononyl isononanoate (0.20), 2-ethylhexyl isononanoate (0.18), isotridecyl isononanoate (0.15), ethylhexanoic acid. Cetyl (0.13), glyceryl tri-ethylhexanoate (0.35), cetyl caprylate (0.12), ethylene glycol dilaurate (0.23), tri (capryl-capric acid) glycerin (0.33), cetyl palmitate (0.10), isostearin 2-hexyldecyl acid (0.09), stearyl stearate (0.08), propylene glycol diisostearate (0.16), ethylene glycol distearate (0.16), octyl palmitate (0.24), isostearyl myristate (0.15), di-2 -Neopentyl glycol ethylhexanoate (0.47), neopentyl glycol dicaprate (0.25), di-adipate 2-heptylundecyl (0.14), trimethylolpropane triisostearate (0.14), pentaerythritol tetra-2-ethylhexanoate (0.35), glyceryl diisostearate (0.29), propylene glycol distearate (0.15), propylene dioleate Glycol (0.16), tri (caprylic acid / capric acid / stearic acid) glyceryl (0.23), diethylene glycol diisostearate (0.25), diethylene glycol distearate (0.24), diethylene glycol dioleate (0.25), polyethylene glycol distearate (0.32), Triethylene glycol dioleate (0.33), triethylene glycol diisostearate (0.33), N-lauroyl-L-dihexyldecyl glutamate (0.33), polyglyceryl distearate (0.69), dioctyldodecyl lauroyl glutamate (0.29) Diisostearyl malate (0.33), polyglyceryl triisostearate (0.26), polyoxyethylene glyceryl triisostearate (0.20), dioctyldodecyl stearoyl glutamate (0.26), polyoxyethylene glyceryl tristearate (0.19), trioleic acid Examples include polyoxyethylene glyceryl (0.20), polyoxyethylene sorbitol tristearate (0.33), polyglyceryl tetraisostearate (0.86), octyldodecyl lactate (0.41), and polyglyceryl diisostearate (0.42).

  Also, vegetable oils such as soybean oil, rice oil, rice bran oil, evening primrose oil, wheat germ oil, olive oil, jojoba oil, grape seed oil, chamomile oil, rosemary oil, fennel oil, jojoba oil, egg yolk oil, etc. Also included are animal-based liquid oils.

  The composition ratio (weight ratio) of (a) a cationic amphiphilic polymer essential to the cationic polymer micelle drug carrier of the present invention and a dispersion thereof and (b) a liquid oil agent having an IOB value of 0 to 1.0 is ( a) :( b) = 1: 0.01-1: 100.00 is desirable. More preferably, (a) :( b) = 1: 0.1 to 1: 50.0 is good. If the weight ratio of component (b) to component (a) is less than 0.1, the medicinal component cannot be encapsulated in the cationic polymer micelle drug carrier, and sufficient effects cannot be exhibited. Further, when the weight ratio of the component (b) to the component (a) exceeds 50.0, the particle size becomes large and a sufficient effect cannot be exhibited.

  Furthermore, the presence of a polyhydric alcohol in the cationic polymer micelle drug carrier of the present invention and its dispersion allows the stability and refinement of the cationic polymer micelle drug carrier and the cationic polymer micelle drug carrier as a medicinal component. It is more desirable to make it coexist from the viewpoint of inclusion and retention. Examples of the polyhydric alcohol include 1,3-butylene glycol, dipropylene glycol, glycerin, diglycerin, pentadiol, polyethylene glycol, sorbitol, mannitol, and ethylene glycol.

It is essential that the cationic amphiphilic polymer has a hydrophobic site (segment) and a cationic group site. The zeta potential when set to a 1% aqueous solution concentration and pH 3.5 to 5 is +20 mV to +100 mV. The hydrophobic portion (segment) is preferably a hydrophobic group having 4 to 20 carbon atoms, and preferably 0.1 to 50.0% in the molecular structure.
A desirable cationic amphiphilic polymer is characterized by having an amino group or a quaternary salt amino group as a charged site (segment), and 0.1-50.0% of a hydrophobic group (segment) having 4 to 20 carbon atoms. It is characterized by being a partially introduced polyamine derivative.

Specific examples of the polyamine include polyallylamine, polyvinylamine, polyamidoamine, polylysine, protein, chitin, and chitosan.
The cationic water-soluble polymer can be prepared by containing 0.1 to 50.0% of a hydrophobic group having 4 to 20 carbon atoms in the molecular structure. For example, cationic water-soluble polymers such as cationic polyacrylate polymers, polymethacrylate polymers, cationic polyvinyl polymers, and cationic water-soluble polymers derived from natural polymers It can be prepared by containing 0.1 to 50.0% of a hydrophobic group having 4 to 20 carbon atoms in the molecular structure.

  Examples of cationic polymethacrylate polymers include vinylpyrrolidone, dimethylaminoethyl methacrylate, acrylate, PPG diacrylate copolymer, polymethacryloyloxyethyl phosphorylcholine, hydroxyacryloyloxypropyltrimethium chloride copolymer (polyquaternium- 64), polymethacryloyloxyethyl phosphorylcholine / butyl methacrylate copolymer (polyquaternium-51), and the like. These ionic water-soluble polymers, which are polymethacrylate polymers, more desirably have a polymethacryloyloxyethyl phosphorylcholine moiety having a phospholipid structure from the viewpoint of biocompatibility. These cationic polymers can be prepared by bonding 0.1 to 50.0% of the carbon number myristoyl group, stearyl group, lauryl group,.

  Examples of cationic polyvinyl polymers include dimethyldiallylammonium chloride / acrylamide copolymer (polyquaternium-7), vinylpyrrolidone / dimethylaminoethylmethacrylic acid copolymer diethyl sulfate (polyquaternium-11), and methyl chloride vinyl imidazole. Nitrogen / vinylpyrrolidone copolymer ammonium salt (polyquaternium-16), vinylpyrrolidone / methacrylic acid dimethylaminopropylamide (polyquaternium-28), vinylpyrrolidone / imidazolinium ammonium (polyquaternium-44), vinylcaprolactam / vinylpyrrolidone / methyl Examples include vinyl imidazolinium methylsulfate (polyquaternium-46), vinyl pyrrolidone, dimethylaminoethyl methacrylate, and the like.

  These cationic polymers include acyl groups such as myristoyl group having 4 to 20 carbon atoms, stearyl group, succinyl group, lauryl group and oleyl group, octyl groups having 4 to 20 carbon atoms, decyl group, dodecyl group, octadecyl group and the like. Can be prepared by bonding 0.1 to 50.0% of the alkyl group in the molecular structure, that is, partially introducing it. Here, “partial introduction” indicates how much a substituent such as a higher acyl group is introduced per monomer residue of the cationic polymer, and “0.1-50.0% partial introduction” means For example, it means that 1 to 500 substituents are introduced into 1000 residues of monomers.

  Cationic water-soluble polymers derived from natural polymers include cationized guar gum, cationized cellulose such as cationized hydroxyethyl cellulose (polyquaternium-10), polylysine, cationized soy protein that is a quaternary ammonium salt, and cationized conchiolin. Basic polysaccharides, basic polysaccharides such as cationized dextrin, cationized starch, partially hydrolyzed chitin, dicarboxymethyl chitosan, carboxybutyl chitosan, partially succinylated chitosan, ethylene glycol chitosan, succinylated carboxymethyl chitosan, succinylated chitin, Quaternary ammonium salts such as quaternary chitin chloride and quaternary chloride chitosan, chitin and chitosan pyrrolidone carboxylate, glycolate, lactate, ascorbate and other chitin and chitosan salts Chitin or chitosan derivatives thereof. Higher alkyl groups such as myristoyl groups having 4 to 20 carbon atoms, stearyl groups, lauryl groups, and oleyl groups, and octyl groups having 4 to 20 carbon atoms, decyl groups, dodecyl groups, and octadecyl groups are included in these cationic polymers. Can be prepared by attaching 0.1-50.0% of the group in the molecular structure

  The average molecular weight is not particularly limited, but is preferably about 10,000 to 5,000,000. Furthermore, 5 to 2 million is desirable. The average molecular weight in this case is, for example, GPC-HPLC coupled with a data module GPC cartridge [gel filtration chromatography column: TSK-gel-G3000WXL + TSK-gel-G2500PWXL manufactured by Tosoh Corporation, solvent: 0.4 M acetic acid-Na acetate Buffer (pH = 4.8)] determined by revealing the molecular weight distribution by analysis. As molecular weight standards, chitosan oligosaccharide (molecular weight: 413,1006), dextran sulfate (molecular weight: 5000, 8000) and pullulan molecular weight standard are used. The average molecular weight can also be determined from a viscosity measurement method or the like.

  Further desirable cationic amphiphilic polymers have an amino group or a quaternary salt amino group as a charged site (segment), and 0.1 to 50.0% of a hydrophobic group having 4 to 20 carbon atoms as a hydrophobic site (segment). It is a polyamine as partially introduced.

  Specific examples of polyamines that introduce hydrophobic sites (segments) include silk proteins such as polylysine, collagen, sericin, and proteins such as vegetable proteins such as soybean protein and their derivatives, polyvinylamine, polyethyleneimine, polyamidoamine, etc. Examples thereof include macromolecules, chitosan and chitin polysaccharides and derivatives thereof. The average molecular weight is not particularly limited, but is preferably about 1 to 5 million.

  Examples of cationic amphiphilic polymers that are particularly effective are chitin derivatives and chitosan derivatives. The cationic amphiphilic polymer is preferably a chitosan derivative or chitin derivative having an amino group site or a quaternary salt amino group site in a molecular structure and a hydrophobic group site having 4 to 20 carbon atoms and 0.1 to 50.0% partial introduction. . Chitin and chitosan derivatives such as, carboxymethyl chitosan, partially succinylated chitosan, partially hydrolyzed chitin, phosphorylated chitosan, dicarboxymethyl chitosan, carboxybutyl chitosan, ethylene glycol chitosan, succinylated carboxymethyl chitosan, succinylated chitin And quaternary ammonium salts such as quaternary chitin chloride and quaternary chloride chitosan, chitin and chitosan pyrrolidone carboxylate, glycolate, lactate, ascorbate and other chitin and chitosan salts.

  A cationic amphiphilic polymer can be obtained by partially introducing 0.1 to 50.0% of a hydrophobic group having 4 to 20 carbon atoms into the amino group or hydroxyl group of these chitin and chitosan derivatives. Although the kind of hydrophobic group is not particularly limited, a fatty acid group or an alkyl group is desirable. For example, to these chitin and chitosan derivatives thereof, acyl groups such as myristoyl group having 4 to 20 carbon atoms, stearyl group, lauryl group, oleyl group and succinyl group, octyl group having 4 to 20 carbon atoms, decyl group, dodecyl group, It can be prepared by bonding 0.1 to 50.0% of an alkyl group such as an octadecyl group in the molecular structure. Furthermore, it is possible to partially introduce 0.1 to 50.0% of a carboxyl-containing acyl group such as a succinyl group or a glutar group.

  Specifically, partially oleylated chitosan, partially myristoylated chitosan, partially myristoylated chitin, partially myristoylated quaternary chitosan chloride, partially laurylated quaternary chloride chitosan, partially stearylated chitin, partially lauroylated chitosan, partially myristoylated moiety Succinylated chitosan, partially myristoylated partially glutarylated chitosan, partially myristoylated carboxymethyl chitosan, partially lauroylated carboxymethyl chitosan, partially succinylated chitosan, partially myristoylated partially hydrolyzed chitin, partially stearylated chitosan, partially palmitoylated chitosan and the like Pyrrolidone carboxylates, glycolates, lactates, ascorbates, glutamates, salicylates and the like.

  Although it does not specifically limit as an ionic water-soluble polymer, It is desirable to show the cationic property in which zeta potential in 1% aqueous solution density | concentration shows + 5mV-+ 100mV. The zeta potential indicates the surface potential governing the electrostatic repulsion effect by the interfacial electric double layer, and the zeta potential serving as an index of the charge of the ionic polymer is preferably +5 to +100 mV which is cationic.

  For example, cationic water-soluble polymers include cationic polyacrylate polymers, polymethacrylate polymers, and cationic polyvinyl polymers. Examples of cationic polymethacrylate polymers include vinylpyrrolidone, dimethylaminoethyl methacrylate, acrylate, PPG diacrylate copolymer, polymethacryloyloxyethyl phosphorylcholine, hydroxyacryloyloxypropyltrimethium chloride copolymer (polyquaternium- 64), polymethacryloyloxyethyl phosphorylcholine / butyl methacrylate copolymer (polyquaternium-51), and the like.

  These ionic water-soluble polymers, which are polymethacrylate polymers, more desirably have a polymethacryloyloxyethyl phosphorylcholine moiety having a phospholipid structure from the viewpoint of biocompatibility.

  Examples of cationic polyvinyl polymers include dimethyldiallylammonium chloride / acrylamide copolymer (polyquaternium-7), vinylpyrrolidone / dimethylaminoethylmethacrylic acid copolymer diethyl sulfate (polyquaternium-11), and methyl chloride vinyl imidazole. Nitrogen / vinylpyrrolidone copolymer ammonium salt (polyquaternium-16), vinylpyrrolidone / methacrylic acid dimethylaminopropylamide (polyquaternium-28), vinylpyrrolidone / imidazolinium ammonium (polyquaternium-44), vinylcaprolactam / vinylpyrrolidone / methyl Examples include vinyl imidazolinium methylsulfate (polyquaternium-46), vinyl pyrrolidone, dimethylaminoethyl methacrylate, and the like.

  Cationic water-soluble polymers derived from natural polymers include cationized guar gum, cationized cellulose such as cationized hydroxyethyl cellulose (polyquaternium-10), polylysine, cationized soy protein that is a quaternary ammonium salt, and cationized conchiolin. Basic polysaccharides, basic polysaccharides such as cationized dextrin, cationized starch, partially hydrolyzed chitin, dicarboxymethyl chitosan, carboxybutyl chitosan, partially succinylated chitosan, ethylene glycol chitosan, succinylated carboxymethyl chitosan, succinylated chitin, Quaternary ammonium salts such as quaternary chitin chloride and quaternary chloride chitosan, chitin and chitosan pyrrolidone carboxylate, glycolate, lactate, ascorbate and other chitin and chitosan salts Chitin or chitosan derivatives thereof. The average molecular weight is not particularly limited, but is preferably about 10,000 to 5,000,000. Furthermore, 5 to 2 million is desirable.

  Since the stability of the cationic polymeric micelle drug carrier of the present invention and the dispersion itself is high, the stability and effectiveness of the cationic polymeric micelle drug carrier may be reduced even when mixed with an existing pharmaceutical system. Absent. By containing the cationic polymer micelle drug carrier of the present invention and a dispersion thereof, it can be used in a wide range of pharmaceutical systems such as cosmetics, external preparations and pharmaceuticals.

  For example, it can be widely applied to medicines applied to the skin, skin and hair, quasi-drugs and cosmetics applied to the oral cavity, etc., and the formulation type is gel-based, solubilized system, emulsified system, somewhat viscous It can be applied to a wide range of preparations such as sol system, essence system, liquid system, water-oil two-layer system, and powder-containing system. In order for the effects of the cationic polymeric micelle drug carrier of the present invention to be fully exerted, it is desirable to adjust the pH of the cationic polymeric micelle drug carrier and its dispersion to 2.5 to 6.5, so that it can be used in a pharmaceutical system. In this case, it is desirable to adjust the pH to 2.5 to 6.5.

  For example, lotions, O / W or W / O creams, O / W or W / O emulsions, cosmetics, gels, O / W or W / O UV sunscreens, face wash, It can be provided as a preparation of skin cosmetics such as ointments, hair cosmetics such as hair conditioners, hair tonics, hair restorers, shampoos, makeup cosmetics such as liquid foundations, lipsticks and mascaras. In that case, components generally used in external preparations, cosmetics, etc. can be widely blended as long as the effects and functionality of the present invention are not impaired. For example, higher alcohols such as cetanol and behenyl alcohol, nonpolar oils such as liquid paraffin and squalane, ester oils such as isopropyl palmitate and isopropyl myristate, vegetable oils such as wheat germ oil and olive oil, trimethylsiloxysilicate , Silicon compounds such as methylphenylpolysiloxane, and fluorine compounds such as perfluoropolyether.

  As low molecular weight surfactants, nonionic surfactants such as fatty acid monoglycerides, polyoxyethylene fatty acid esters, polyoxyethylene alkyl ethers, polyglycerin fatty acid esters, cationic surfactants such as benzalkonium chloride, amphoteric surfactants Agents and anionic surfactants. However, when these low-molecular-weight surfactants are used, the weight percentage in the preparation is desirably 0 to 5%. When the blending amount is increased, the formation of the cationic polymer micelle drug carrier of the present invention is suppressed, which is effective. This is because cannot be fully exhibited.

  In addition, moisturizing softeners, antioxidants, astringents, antibacterial agents, anti-inflammatory agents, bactericides, antiallergic agents, UV absorbers, UV scattering agents, stabilizers, vitamins, enzymes, etc. Ingredients such as ingredients standards for cosmetics, ingredients for cosmetic varieties, cosmetics ingredients standards, cosmetics separate paper standards, Japanese pharmacopoeia, official standards for food additives, and the like.

  However, when using an anionic component such as an anionic surfactant such as sodium dodecyl sulfate or an anionic polymer such as hyaluronic acid or carboxyvinyl polymer, 0 to It is desirable that the amount be 0.5, and if it exceeds this amount, the surface potential of the cationic polymeric micelle drug carrier of the present invention will be less than +10 mV, and the effect cannot be fully exhibited.

Examples of the present invention will be described below.
The cationic polymer micelle drug carriers of Examples 1 to 10 and the compositions of Comparative Examples 1 to 10 are shown below.

Example 1
Composition Blending amount (% by weight)
(1) Cetyl ethylhexanoate (IOB: 0.13) 1.0
(2) Glyceryl tri-ethylhexanoate (IOB: 0.35) 0.5
(3) Binary Recall 2.0
(4) Graphisin-containing licorice flavonoid 0.2
(Product name: Kanzo Flavonoid PT-40)
(5) Partially myristoylated chitosan 0.2
(ζ potential: + 65.2mV)
(6) Partially myristoylated chitin 0.2
(ζ potential: + 34.1mV)
(7) Purified water remaining

(Example 2)
Composition Blending amount (% by weight)
(1) Cetyl ethylhexanoate (IOB: 0.13) 1.0
(2) Glyceryl tri-ethylhexanoate (IOB: 0.35) 0.5
(3) Binary Recall 2.0
(4) Graphisin-containing licorice flavonoid 0.2
(Product name: Kanzo Flavonoid PT-40)
(5) Partially myristoylated chitosan 0.2
(ζ potential: + 65.2mV)
(6) Partially myristoylated chitin 0.2
(ζ potential: + 34.1mV)
(7) Polyquaternium-64
(ζ potential: + 58.1mV) 0.2
(8) Remaining amount of purified water

(Example 3)
Composition Blending amount (% by weight)
(1) Cetyl ethylhexanoate (IOB: 0.13) 1.0
(2) Glyceryl tri-ethylhexanoate (IOB: 0.35) 0.5
(3) Butencall recall 5.0
(4) Graphisin-containing licorice flavonoid 0.2
(Product name: Kanzo Flavonoid PT-40)
(5) Linoleic acid 0.2
(6) Partially myristoylated chitosan 0.2
(ζ potential: + 65.2mV)
(7) Partially myristoylated chitin 0.2
(ζ potential: + 34.1mV)
(8) Polyquaternium-64
(ζ potential: + 58.1mV) 0.4
(9) Purified water remaining

(Comparative Example 1)
Composition Blending amount (% by weight)
(1) Cetyl ethylhexanoate (IOB: 0.13) 1.0
(2) Glyceryl tri-ethylhexanoate (IOB: 0.35) 0.5
(3) Binary Recall 2.0
(4) Graphisin-containing licorice flavonoid 0.2
(Product name: Kanzo Flavonoid PT-40)
(5) POE monostearate sorbitan 3.0
(6) Remaining amount of purified water

(Comparative Example 2)
Composition Blending amount (% by weight)
(1) Cetyl ethylhexanoate (IOB: 0.13) 1.0
(2) Glyceryl tri-ethylhexanoate (IOB: 0.35) 0.5
(3) Binary Recall 2.0
(4) Graphisin-containing licorice flavonoid 0.2
(Product name: Kanzo Flavonoid PT-40)
(5) POE monostearate sorbitan 3.0
(6) Hensalniconium chloride 0.1
(7) Purified water remaining

Example 4
Composition Blending amount (% by weight)
(1) Cetyl ethylhexanoate (IOB: 0.13) 2.5
(2) Zipro Recall Recall 5.0
(3) Graphisin-containing licorice flavonoid solution 5.0
(Product name: Oil-soluble licorice extract BGSR)
(4) Glutathione 1.0
(5) β-Arbutin 2.0
(6) Ascorbyl tetraisopalmitate
(Product name: VCIP) 0.8
(7) dl-tocopherol acetate 0.5
(8) Astaxanthin 0.05
(9) Retinol 0.1
(10) BHT (Dibutyl human oxytoluene) 0.02
(11) Partially myristoylated partially succinylated chitosan 0.2
(ζ potential: + 55.2mV)
(12) Partially myristoylated polylysine 0.2
(ζ potential: + 45.1mV)
(13) Polyquaternium-64 (ζ potential: + 58.1mV) 0.1
(14) Quaternary chitosan chloride (ζ potential: +78.1 mV) 0.1
(15) Purified water remaining

(Example 5)
Composition Blending amount (% by weight)
(1) Cetyl ethylhexanoate (IOB: 0.13) 0.5
(2) Polyglyceryl tetraisostearate 2.5
(IOB: 0.86)
(3) Zipro Recall Recall 5.0
(4) Licorice flavonoid solution containing graphidine 5.0
(Product name: Oil-soluble licorice extract BGSR)
(5) Glutathione 1.0
(6) β-Arbutin 2.0
(7) Ascorbyl tetraisopalmitate
(Product name: VCIP) 0.8
(8) dl-tocopherol acetate 0.5
(9) Astaxanthin 0.05
(10) Retinol 0.1
(11) BHT (Dibutyl human oxytoluene) 0.02
(12) Partially myristoylated partially succinylated chitosan 0.2
(ζ potential: + 55.2mV)
(13) Partially myristoylated polylysine 0.2
(ζ potential: + 45.1mV)
(14) Partially myristoylated carboxymethyl chitosan 0.2
(ζ potential: + 25.1mV)
(15) Polyquaternium-64 (ζ potential: +58.1 mV) 0.1
(16) Polyquaternium-51 (ζ potential: + 11.1mV) 0.1
(17) Purified water remaining

(Example 6)
Composition Blending amount (% by weight)
(1) Cetyl ethylhexanoate (IOB: 0.13) 12.0
(2) Polyglyceryl tetraisostearate 5.0
(IOB: 0.86)
(3) Zipro Recall Recall 5.0
(4) Licorice flavonoid solution containing graphidine 5.0
(Product name: Oil-soluble licorice extract BGSR)
(5) Glutathione 1.0
(6) β-Arbutin 2.0
(7) Ascorbyl tetraisopalmitate
(Product name: VCIP) 0.8
(8) dl-tocopherol acetate 0.5
(9) Astaxanthin 0.05
(10) Retinol 0.1
(11) BHT (Dibutyl human oxytoluene) 0.02
(12) Partially myristoylated partially succinylated chitosan 0.2
(ζ potential: + 55.2mV)
(13) Partially myristoylated polylysine 0.2
(ζ potential: + 45.1mV)
(14) Partially myristoylated carboxymethyl chitosan 0.2
(ζ potential: + 25.1mV)
(15) Polyquaternium-64 (ζ potential: +58.1 mV) 0.1
(16) Quaternary chitosan chloride (ζ potential: +78.1 mV) 0.1
(17) Purified water remaining

(Comparative Example 3)
Composition Blending amount (% by weight)
(1) Cetyl ethylhexanoate (IOB: 0.13) 1.0
(2) Polyglyceryl tetraisostearate0.5
(IOB: 0.86)
(3) Zipro Recall Recall 5.0
(4) Licorice flavonoid solution containing graphidine 5.0
(Product name: Oil-soluble licorice extract BGSR)
(5) Glutathione 1.0
(6) β-Arbutin 2.0
(7) Ascorbyl tetraisopalmitate
(Product name: VCIP) 0.8
(8) dl-tocopherol acetate 0.5
(9) Astaxanthin 0.05
(10) Retinol 0.1
(11) BHT (Dibutyl human oxytoluene) 0.02
(12) Carboxyl-modified vinyl polymer (ζ potential: -44.1 mV) 0.3
(Product name: Hemlen, anionic polymer emulsifier)
(13) Remaining amount of purified water

(Comparative Example 4)
Composition Blending amount (% by weight)
(1) Zipro Recall Recall 5.0
(2) Licorice flavonoid solution containing graphite
(Product name: Oil-soluble licorice extract BGSR)
(3) Glutathione 1.0
(4) β-Arbutin 2.0
(5) Ascorbyl tetraisopalmitate
(Product name: VCIP) 0.8
(6) dl-tocopherol acetate 0.5
(7) Astaxanthin 0.05
(8) Retinol 0.1
(9) BHT (Dibutyl human oxytoluene) 0.02
(10) Partially myristoylated partially succinylated chitosan 0.2
(ζ potential: + 55.2mV)
(11) Partially myristoylated polylysine 0.2
(ζ potential: + 45.1mV)
(12) Remaining amount of purified water

(Example 7)
Composition Blending amount (% by weight)
(1) Butylene glycol 10.0
(2) Ethanol 5.0
(3) Hydroxypropylcellulose 2.0
(4) Cationic polymer micelle drug carrier dispersion of Example 2 20.0
(5) Purified water remaining

(Example 8)
Composition Blending amount (% by weight)
(1) Butylene glycol 10.0
(2) Ethanol 5.0
(3) Hydroxypropylcellulose 2.0
(4) Cationic polymer micelle drug carrier dispersion of Example 2 40.0
(5) Purified water remaining

(Comparative Example 5)
Composition Blending amount (% by weight)
(1) Butylene glycol 10.0
(2) Ethanol 5.0
(3) Hydroxypropylcellulose 2.0
(4) Purified water remaining

(Comparative Example 6)
Composition Blending amount (% by weight)
(1) Butylene glycol 10.0
(2) Ethanol 5.0
(3) Hydroxypropylcellulose 2.0
(4) Dispersion of Comparative Example 2 20.0
(5) Purified water remaining

(Comparative Example 7)
Composition Blending amount (% by weight)
(1) Butylene glycol 10.0
(2) Ethanol 5.0
(3) Hydroxypropylcellulose 2.0
(4) Dispersion of Comparative Example 2 40.0
(5) Purified water remaining

Example 9
Composition Blending amount (% by weight)
(1) Vaseline 5.0
(2) Behenyl alcohol 10.0
(3) Squalane 5.0
(4) POE lauryl sorbitan 2.0
(5) Hydroxypropyl cellulose 0.2
(6) Cationic polymer micelle drug carrier dispersion of Example 4 20.0
(7) Purified water remaining

(Example 10)
Composition Blending amount (% by weight)
(1) Vaseline 5.0
(2) Behenyl alcohol 10.0
(3) Squalane 5.0
(4) POE lauryl sorbitan 6.0
(5) Hydroxypropyl cellulose 0.2
(6) Cationic polymer micelle drug carrier dispersion of Example 4 20.0
(7) Purified water remaining

(Comparative Example 8)
Composition Blending amount (% by weight)
(1) Vaseline 5.0
(2) Behenyl alcohol 10.0
(3) Squalane 5.0
(4) POE lauryl sorbitan 2.0
(5) Hydroxypropyl cellulose 0.2
(6) Dispersion of Comparative Example 3
(7) Purified water remaining

(Comparative Example 9)
Composition Blending amount (% by weight)
(1) Vaseline 5.0
(2) Behenyl alcohol 10.0
(3) Squalane 5.0
(4) POE lauryl sorbitan 2.0
(5) Hydroxypropyl cellulose 0.2
(6) Dispersion of Comparative Example 3 20.0
(7) Purified water remaining

(Comparative Example 10)
Composition Blending amount (% by weight)
(1) Vaseline 5.0
(2) Behenyl alcohol 10.0
(3) Squalane 5.0
(4) POE lauryl sorbitan 2.0
(5) Hydroxypropyl cellulose 0.2
(6) Dispersion of Comparative Example 4 20.0
(7) Purified water remaining

(Test Example 1)
<Preparation of cationic polymeric micelle drug carrier using high-pressure emulsifier>
After the cationic amphiphilic polymer, the medicinal component, the liquid oil, and the polyhydric alcohol of Examples 1 to 3 are uniformly treated with a homomixer (7000 rpm, 2 minutes) in the presence of purified water, fine particles such as a high-pressure fluidizer device are used. A translucent to cloudy pH 3.5 to 5.8 dispersion containing a cationic polymeric micelle drug carrier containing a medicinal ingredient is prepared by repeating high pressure treatment (2000 to 10,000 PSI) 2 to 10 times with an emulsifier. did. The average particle size was measured by a dynamic light scattering particle size distribution measuring instrument (manufactured by HORIBA), and the ζ potential was diluted 100 times with ion-exchanged water and measured by the M3-PALS method. Comparative Examples 1 and 2 were also prepared and evaluated under the same preparation conditions. The results are shown in Table 1.

In addition, regarding the drug stability of the cationic polymer micelle drug carrier dispersion, the appearance change after 6 months at 40 ° C. and the residual ratio of the encapsulated medicinal components were quantified by HPLC method.
The release of a medicinal component from a cationic polymeric micelle drug carrier was evaluated as follows. Add 1 ml of cationic polymer micelle drug carrier dispersion to the donor site of a Franz diffusion cell equipped with a filter membrane (Millipore, pore size: 0.025 μm) and permeate the receptor site (purified water containing 30% propylene glycol) The medicinal components that were used were quantified by HPLC. The permeate was sampled every 12, 24, 36, 48, 96, and 152 hours to evaluate the release of medicinal ingredients. The results are shown in Tables 2, 3, and 4.

  As is clear from Tables 2 and 3, in Comparative Examples 1 and 2, the residual rate of the encapsulated medicinal component was about 60 to 70%, and separation of the medicinal component was observed, whereas Examples 1 to 3 Then, the residual rate of the encapsulated medicinal ingredients was very good at 95% or more, and separation of medicinal ingredients was not recognized. Further, as is clear from Table 4, in Comparative Examples 1 and 2, no release of the medicinal component was observed, whereas in Examples 1 to 3, the release of the medicinal component was observed.

(Test Example 2)
<Measurement of skin penetration of medicinal ingredients using human skin model>
The skin permeability of the medicinal component was determined by the following method. 100 μl of a sample solution containing a cationic polymer micelle drug carrier was added to the skin surface of a three-dimensional human skin model (manufactured by Toyobo, product name: TESTSKIN, LSE003High) and treated for 24 hours. After treatment, wash the skin surface with phosphate buffer and ethanol 5 times, remove unpermeated medicinal ingredients, separate into epidermis and dermis, add 5 ml medicinal ingredient extract (alcohol solution or phosphate buffer) Then, the amount of the medicinal component in the skin was extracted by sonication and quantified by HPLC. The results are shown in Table 5.

  Cytotoxicity, which is a safety indicator, was determined by measuring the production of IL-1α, a stimulating inflammatory cytokine, by ELISA. The results are shown in Table 6.

  As is apparent from Table 5, in Examples 1 to 3, the penetration amount of the medicinal component into the epidermis was remarkably better than those in Comparative Examples 1 and 2. In addition, the production amount of IL-1α was lower in Examples 1 to 3 than in Comparative Examples 1 and 2, and it was confirmed that the production was high.

(Test Example 3)
<Measurement of melanin inhibitory action using human skin model>
The melanin production inhibitory action considering skin permeability was determined by the following method. Add 50 μl of sample solution containing cationic polymeric micelle drug carrier to the skin surface of 3D human skin model (Kurabo, product name: MEL-30) with melanocytes as melanocytes in the epidermis basal layer and culture did. After culturing, the skin surface was washed 5 times with phosphate buffer and ethanol, the unpermeated medicinal components were removed, the skin surface was taken into an image, and the L * value, which is a brightness index, was measured and determined. When melanin formation is suppressed, melanin decreases and brightness increases, so the L * value increases. The melanin inhibitory action was calculated from the L * value. The results are shown in Table 7.

  As is clear from Table 7, in Examples 1 to 3, the L * value was higher than in Comparative Examples 1 and 2, and it was found that the melanin inhibitory action was superior to Comparative Examples 1 and 2.

(Test Example 4)
A lotion preparation and a cream preparation containing the cationic polymeric micelle drug carrier dispersion of Example 1 were prepared, and the whitening effect on male monitors (10 persons, average age: 36.3 years old) was determined. That is, each preparation was applied after irradiating the inside of the forearm with a 2MED amount by a UV-B ultraviolet lamp (manufactured by Toshiba). The whitening effect was determined from the L * value, which is an index of skin brightness, using a color difference meter for the degree of pigmentation after 2 weeks and 4 weeks after application. Comparative examples 1 and 2 were similarly tested.

  The cream formulation is prepared by adding an aqueous phase to an oil phase at 70 ° C., emulsifying with a homomixer, cooling, adding a cationic polymer micelle drug carrier dispersion at around 40 ° C., and homogenizing the emulsion cream. Obtained.

A cream preparation containing the cationic polymeric micelle drug carrier dispersion of Example 1 was produced, and the wrinkle improving action on female wrinkle monitors (10 persons, average age: 38.7 years) was determined. That is, the example cream was applied on the half side to a female wrinkle monitor having the same level of wrinkles on the left and right. Wrinkle-improving action was obtained by collecting replicas from the application sites 4 and 8 weeks after application, and determining the average wrinkle depth by image analysis.
Comparative examples 1 and 2 were similarly tested.

These results are shown in Table 8.

As is apparent from Table 8, in Comparative Examples 1 and 2, the L * value of the spot did not decrease even after 8 weeks of use, but in Example 1, a decrease in the L * value of the spot was observed after 4 weeks of use. It was.

(Test Example 5)
<Preparation of cationic polymeric micelle drug carrier using high-pressure emulsifier>
A translucent to cloudy dispersion containing a cationic polymer micelle drug carrier from the cationic amphiphilic polymer of Examples 4 to 6, a medicinal component, a liquid oil, and a polyhydric alcohol in the same manner as in Test Example 1. And the average particle size and ζ potential were measured. Comparative Examples 3 and 4 were also prepared and evaluated under the same preparation conditions. The results are shown in Table 9.

  Further, the drug stability of the drug carrier dispersion, the release of the medicinal component, and the like were measured in the same manner as in Test Example 1. The results are shown in Tables 10 and 11.

  As is clear from Table 10, separation of medicinal components was observed in Comparative Examples 3 and 4, whereas separation of medicinal components was not observed in Examples 4 and 5. Furthermore, as is clear from Table 11, no release of medicinal components was observed in Comparative Example 4, whereas release of medicinal components was observed in Examples 4 to 6.

(Test Example 6)
<Measurement of skin penetration of medicinal ingredients using human skin model>
For Examples 4 to 6 and Comparative Examples 1 and 2, the skin permeability and the like of the medicinal components were measured in the same manner as in Test Example 2. The results are shown in Table 12.

  Cytotoxicity was also determined in the same manner as in Test Example 6. The results are shown in Table 13.

  As is clear from Table 12, in Examples 4 to 6, the penetration amount of the medicinal component into the epidermis was better than in Comparative Examples 3 and 4. In addition, the production amount of IL-1α was lower in Examples 4 to 6 than in Comparative Examples 3 and 4, and it was confirmed that the production amount was high.

(Test Example 7)
<Measurement of melanin inhibitory action using human skin model>
About Examples 4-6 and Comparative Examples 1 and 2, the melanin production inhibitory effect was measured similarly to Test Example 3. The results are shown in Table 14.

  As is clear from Table 14, in Examples 4 to 6, it was found that the L * value was higher than in Comparative Examples 3 and 4, and the melanin inhibitory action was superior to Comparative Examples 3 and 4.

(Test Example 8)
For Examples 7 and 8, and Comparative Examples 5 to 7, a monitor test was conducted in the same manner as in Test Example 4 to confirm the presence or absence of side effects. The results are shown in Table 15.

  As is clear from Table 15, the stain reducing effect was excellent in Examples 7 and 8 as compared with Comparative Examples 5 to 7. In Comparative Example 7, two side effects were observed, whereas in Examples 7 and 8, no side effects were observed.

(Test Example 9)
Examples 9 and 10 and Comparative Examples 8 to 10 were tested for whitening effect and wrinkle improving effect. The results are shown in Table 16.

  As is clear from Table 16, both the whitening effect and the wrinkle improving effect were superior in Examples 9 and 10 as compared with Comparative Examples 8 to 10.

(Test Example 10)
A transmission electron microscope (TEM) image of the cationic polymeric micelle drug carrier of Example 1 was taken. This was performed by negative staining with uranium acetate. A sample was placed on a grid (copper) covered with a carbon support film, and then a uranium acetate solution was placed on the sample surface and allowed to dry naturally. Observation was performed with a transmission electron microscope JEOL-2010 (manufactured by JEOL Ltd.) at an acceleration voltage of 200 kV, and a CCD camera was used for photographing. The TEM photograph is shown in FIG. As is clear from FIG. 1, drug carriers having a particle diameter of about 0.5 μm (500 nm) and drug carriers having a smaller particle diameter (100 nm or less) were observed.

(Test Example 11)
Skin of a three-dimensional human skin model (manufactured by Kurabo Industries, product name: MEL-30) having 50 μl of a sample solution containing the cationic polymeric micelle drug carrier of Examples 1 and 3 having melanocytes as melanocytes in the epidermis basal layer Added to the surface and cultured. The same was done for Comparative Example 1. After culturing, the cells were washed 5 times with a phosphate buffer solution and ethanol, and after removing unpermeated medicinal components, the skin cross section was cut into slices, stained with melanin, and photographed. The photographs are shown in FIGS. As is clear from FIG. 4, in Comparative Example 1, a set of dark spots that were recognized as melanin pigments was observed near the lower part of the cut section of the skin in the photograph, that is, around the basal layer of the epidermis. On the other hand, in Examples 1 and 3, as shown in FIGS. 2 and 3, compared with Comparative Example 1, there were very few dark spots that were recognized as melanin pigments. From this, the cationic polymer micelle drug carriers of Examples 1 and 3 were confirmed to have a melanin production inhibitory effect in the skin model. In Example 3, since the cross section of the skin peeled off during the test, the state is photographed in FIG. 3, but it has no influence on the melanin production inhibitory action.

  As is clear from each of the above test examples, the cationic polymer micelle drug carrier dispersion according to the present invention has an improved skin permeation of an excellent medicinal component (whitening component) and an effective action by the medicinal component (enhancement of whitening effect). In addition, it is clear that it is excellent in safety and stability.

4 is a transmission electron microscope image of the cationic polymeric micelle drug carrier in Test Example 10. FIG. A photograph of a melanin-stained image of a human skin model in Test Example 11 (Example 1). A photograph of a melanin-stained image of a human skin model in Test Example 11 (Example 3). A photograph of a melanin-stained image of a human skin model in Test Example 11 (Comparative Example 1).

Claims (21)

  A cationic polymer micelle drug carrier comprising a cationic amphiphilic polymer having a charged site and a hydrophobic site, a medicinal component, and a liquid oil.   A cationic polymer micelle drug carrier comprising a cationic amphiphilic polymer having a charged site and a hydrophobic site, a medicinal component, a liquid oil, and a polyhydric alcohol.   A cationic polymeric micellar drug carrier comprising a cationic amphiphilic polymer having a charged site and a hydrophobic site, a medicinal component, a liquid oil, and an ionic water-soluble polymer.   A cationic polymer comprising a cationic amphiphilic polymer having a charged portion and a hydrophobic portion, a medicinal component, a liquid oil agent, a polyhydric alcohol, and an ionic water-soluble polymer. Micelle drug carrier.   The cationic polymer micelle drug carrier according to any one of claims 1 to 4, wherein the zeta potential is +10 mV to +100 mV.   The cationic polymer micelle drug carrier according to any one of claims 1 to 5, wherein the drug carrier has an average particle size of 50 nm to 900 nm.   The cationic polymer micelle drug carrier according to any one of claims 1 to 6, wherein the zeta potential of the cationic amphiphilic polymer is +10 mV to +100 mV.   The cationic polymer micelle drug carrier according to any one of claims 1 to 7, wherein the cationic amphiphilic polymer has a partially introduced hydrophobic group having 4 to 20 carbon atoms and a cationic group.   The cation according to any one of claims 1 to 8, wherein the cationic amphiphilic polymer has a partially introduced hydrophobic group having 4 to 20 carbon atoms and an amino group or a quaternary salt amino group. Type polymer micelle drug carrier.   The cationic polymer micelle drug carrier according to any one of claims 1 to 9, wherein the cationic amphiphilic polymer is a chitin derivative or a chitosan derivative.   The cationic polymeric micelle drug carrier according to any one of claims 1 to 10, wherein the solubility of the medicinal component in water is 50 mg / ml or less.   The cationic polymer micelle drug carrier according to any one of claims 1 to 11, wherein the liquid oil agent has an IOB value of 0 to 1.0.   The cationic polymer micelle drug carrier according to any one of claims 3 to 12, wherein the ionic water-soluble polymer exhibits a zeta potential of +5 mV to +100 mV.   The cationic polymer micelle drug carrier according to any one of claims 3 to 13, wherein the ionic water-soluble polymer has a phospholipid structure.   The cationic polymeric micelle drug carrier according to any one of claims 1 to 14, wherein the medicinal component has an enzyme inhibitory action or an enzyme synthesis inhibitory action.   The cationic polymeric micelle drug carrier according to any one of claims 1 to 14, wherein the medicinal component is a whitening component having a tyrosinase inhibitory action or a tyrosinase synthesis inhibitory action.   A cationic polymer micelle drug carrier-containing dispersion comprising the cationic polymer micelle drug carrier according to any one of claims 1 to 16.   An external preparation for skin comprising the cationic polymeric micelle drug carrier according to any one of claims 1 to 16.   A cosmetic comprising the cationic polymeric micelle drug carrier according to any one of claims 1 to 16.   A whitening cosmetic comprising the cationic polymeric micelle drug carrier according to any one of claims 1 to 16.   An anti-aging cosmetic comprising the cationic polymeric micelle drug carrier according to any one of claims 1 to 16.

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