Solid particle dispersion preparation

Abstract

The present disclosure provides a solid particle dispersion preparation. According to the present disclosure, this solid particle dispersion preparation contains a combination of a specific emulsifier and a specific emulsifier and a water-soluble molecule in solid particles and an oil base, wherein the solid particles are dispersed in the oil base.

Description

solid particle dispersion formulation

[0001] The present disclosure relates to solid particle dispersion formulations.

[0002] The stratum corneum exists in skin tissue, providing a physical barrier that nonspecifically prevents the invasion of invaders such as bacteria and viruses. Due to the presence of this physical barrier, the stratum corneum has poor permeability to substances, making it an obstacle to transdermal administration of drugs. In particular, hydrophilic molecules with a molecular weight of more than 800 are not suitable for transdermal administration.

[0003] In order to achieve transdermal absorption of a hydrophilic compound, a formulation technique has been developed in which a solid complex formed by coating a hydrophilic compound with a surfactant is dispersed in an oil phase (Patent Documents 1 and 2).

[0004] WO2006 / 025583WO2022 / 196748

[0005] The present disclosure provides solid particle dispersion formulations.

[0006] According to the present disclosure, the usefulness and effectiveness of a dispersion formulation in which particles of a solid complex composed of two specific types of emulsifiers and a target molecule are dispersed have been clarified.

[0007] According to the present disclosure, the following inventions are provided: (1) A dispersion formulation comprising an oily base and solid particles comprising a complex of a water-soluble molecule and an emulsifier, wherein the emulsifier comprises a fatty acid glyceryl, and the solid particles are dispersed in the oily base. (2) The dispersion formulation according to (1) above, wherein the fatty acid glyceryl is selected from the group consisting of polyglyceryl fatty acids, monoglyceryl fatty acid polyglyceryls, polyglyceryl fatty acids, and monoglyceryl fatty acids. (3) The dispersion formulation according to (1) or (2) above, wherein the fatty acid glyceryl comprises a polyglyceryl having a number average degree of polymerization of 2 to 6. (4) The dispersion formulation according to any of (1) to (3) above, wherein the emulsifier further comprises a nonionic surfactant (e.g., a sugar fatty acid ester). (5) The dispersion formulation according to any of (1) to (4) above, wherein the sugar fatty acid ester is a sucrose fatty acid ester. (6) The dispersion formulation according to any of (1) to (5) above, wherein the sugar fatty acid ester is sucrose erucate. (7) The dispersion formulation according to any one of (4) to (6) above, wherein the emulsifier comprises 10 to 40 mol % of a sugar fatty acid ester. (8) The dispersion formulation according to any one of (1) to (7) above, wherein the Z-average particle size is 500 nm or less. (9) A cosmetic comprising the dispersion formulation according to any one of (1) to (7) above.

[0008] (21) The dispersion formulation according to any one of (1) to (7), wherein the fatty acid glyceryl comprises one or more selected from the group consisting of fatty acid glyceryl group A: polyglyceryl decaoleate, polyglyceryl polyricinoleate, polyglyceryl diisostearate, polyglyceryl tetraisostearate, glyceryl monooleate, polyoxyethylene hydrogenated castor oil, polyglyceryl pentaoleate, polyglyceryl decaisostearate, and glyceryl monocaprate. (22) The dispersion formulation according to any one of (1) to (8), wherein the fatty acid glyceryl comprises one or more selected from the group consisting of fatty acid glyceryl group B: polyglyceryl-10 decaoleate, polyglyceryl-6 polyricinoleate, polyglyceryl-6 polyricinoleate, polyglyceryl-2 diisostearate, polyglyceryl-2 tetraisostearate, glyceryl monooleate, polyoxyethylene hydrogenated castor oil, polyglyceryl-10 pentaoleate, polyglyceryl-10 decaisostearate, and glyceryl monocaprate.

[0009] (31) The dispersion formulation according to any one of (1) to (8) above, wherein the fatty acid glyceryl comprises polyglyceryl decaoleate. (32) The dispersion formulation according to any one of (1) to (8) above, wherein the fatty acid glyceryl comprises polyglyceryl polyricinoleate. (33) The dispersion formulation according to any one of (1) to (8) above, wherein the fatty acid glyceryl comprises polyglyceryl diisostearate. (34) The dispersion formulation according to any one of (1) to (8) above, wherein the fatty acid glyceryl comprises polyglyceryl tetraisostearate. (35) The dispersion formulation according to any one of (1) to (8) above, wherein the fatty acid glyceryl comprises glyceryl monooleate. (36) The dispersion formulation according to any one of (1) to (8) above, wherein the fatty acid glyceryl comprises polyoxyethylene hydrogenated castor oil. (37) The dispersion formulation according to any one of (1) to (8) above, wherein the fatty acid glyceryl comprises polyglyceryl pentaoleate. (38) The dispersion formulation according to any one of (1) to (8) above, wherein the fatty acid glyceryl comprises polyglyceryl decaisostearate. (39) The dispersion formulation according to any one of (1) to (8) above, wherein the fatty acid glyceryl comprises glyceryl monocaprate.

[0010] (41) The dispersion formulation according to (4) above, wherein the fatty acid glyceryl comprises polyglyceryl decaoleate. (42) The dispersion formulation according to (4) above, wherein the fatty acid glyceryl comprises polyglyceryl polyricinoleate. (43) The dispersion formulation according to (4) above, wherein the fatty acid glyceryl comprises polyglyceryl diisostearate. (44) The dispersion formulation according to (4) above, wherein the fatty acid glyceryl comprises polyglyceryl tetraisostearate. (45) The dispersion formulation according to (4) above, wherein the fatty acid glyceryl comprises glyceryl monooleate. (46) The dispersion formulation according to (4) above, wherein the fatty acid glyceryl comprises polyoxyethylene hydrogenated castor oil. (47) The dispersion formulation according to (4) above, wherein the fatty acid glyceryl comprises polyglyceryl pentaoleate. (48) The dispersion formulation according to (4) above, wherein the fatty acid glyceryl comprises polyglyceryl decaisostearate. (49) The dispersion formulation according to (4) above, wherein the fatty acid glyceryl includes glyceryl monocaprate.

[0011] (51) The dispersion formulation according to (5) above, wherein the fatty acid glyceryl comprises polyglyceryl decaoleate. (52) The dispersion formulation according to (5) above, wherein the fatty acid glyceryl comprises polyglyceryl polyricinoleate. (53) The dispersion formulation according to (5) above, wherein the fatty acid glyceryl comprises polyglyceryl diisostearate. (54) The dispersion formulation according to (5) above, wherein the fatty acid glyceryl comprises polyglyceryl tetraisostearate. (55) The dispersion formulation according to (5) above, wherein the fatty acid glyceryl comprises glyceryl monooleate. (56) The dispersion formulation according to (5) above, wherein the fatty acid glyceryl comprises polyoxyethylene hydrogenated castor oil. (57) The dispersion formulation according to (5) above, wherein the fatty acid glyceryl comprises polyglyceryl pentaoleate. (58) The dispersion formulation according to (5) above, wherein the fatty acid glyceryl comprises polyglyceryl decaisostearate. (59) The dispersion formulation according to (5) above, wherein the fatty acid glyceryl includes glyceryl monocaprate.

[0012] (71) The dispersion formulation according to (6) above, wherein the glyceryl fatty acid comprises polyglyceryl decaoleate. (72) The dispersion formulation according to (6) above, wherein the glyceryl fatty acid comprises polyglyceryl polyricinoleate. (73) The dispersion formulation according to (6) above, wherein the glyceryl fatty acid comprises polyglyceryl diisostearate. (74) The dispersion formulation according to (6) above, wherein the glyceryl fatty acid comprises polyglyceryl tetraisostearate. (75) The dispersion formulation according to (6) above, wherein the glyceryl fatty acid comprises glyceryl monooleate. (76) The dispersion formulation according to (6) above, wherein the glyceryl fatty acid comprises polyoxyethylene hydrogenated castor oil. (77) The dispersion formulation according to (6) above, wherein the glyceryl fatty acid comprises polyglyceryl pentaoleate. (78) The dispersion formulation according to (6) above, wherein the glyceryl fatty acid comprises polyglyceryl decaisostearate. (79) The dispersion formulation according to (6) above, wherein the fatty acid glyceryl includes glyceryl monocaprate.

[0013] (81) The dispersion formulation according to (7) above, wherein the glyceryl fatty acid comprises polyglyceryl decaoleate. (82) The dispersion formulation according to (7) above, wherein the glyceryl fatty acid comprises polyglyceryl polyricinoleate. (83) The dispersion formulation according to (7) above, wherein the glyceryl fatty acid comprises polyglyceryl diisostearate. (84) The dispersion formulation according to (7) above, wherein the glyceryl fatty acid comprises polyglyceryl tetraisostearate. (85) The dispersion formulation according to (7) above, wherein the glyceryl fatty acid comprises glyceryl monooleate. (86) The dispersion formulation according to (7) above, wherein the glyceryl fatty acid comprises polyoxyethylene hydrogenated castor oil. (87) The dispersion formulation according to (7) above, wherein the glyceryl fatty acid comprises polyglyceryl pentaoleate. (88) The dispersion formulation according to (7) above, wherein the glyceryl fatty acid comprises polyglyceryl decaisostearate. (89) The dispersion formulation according to (7) above, wherein the fatty acid glyceryl includes glyceryl monocaprate.

[0014] (101) A dispersion formulation comprising an aqueous base and solid particles comprising water-soluble molecules and one or more emulsifiers, wherein the solid particles are dispersed in the aqueous base. (102) The dispersion formulation according to (101) above, wherein the one or more emulsifiers comprise a sucrose fatty acid ester. (103) The dispersion formulation according to (101) or (102) above, wherein the one or more emulsifiers comprise a sucrose erucate ester. (104) The dispersion formulation according to any one of (101) to (103) above, wherein the Z-average particle size is 300 nm or less, or 200 nm or less. (105) The dispersion formulation according to any one of (101) to (104) above, wherein the Z-average particle size is 50 nm or more. (106) The dispersion formulation according to any one of (101) to (105) above, wherein the water-soluble molecules comprise nicotinamide mononucleotide. (107) Any of the above-mentioned dispersion preparations, which exhibit dispersibility for one month or more, preferably two months or more, under a temperature condition of 25°C. (108) The above-mentioned dispersion preparation (107), wherein the emulsifier comprises a nonionic surfactant and a fatty acid polyglyceryl. (109) The above-mentioned dispersion preparation (108), wherein the nonionic surfactant comprises a sugar fatty acid ester. (110) The above-mentioned dispersion preparation (107), wherein the glycerin polymerization number of the fatty acid polyglyceryl is any one of 2 to 6. (111) The above-mentioned dispersion preparation (108), wherein the glycerin polymerization number of the fatty acid polyglyceryl is any one of 2 to 6. (112) The dispersion formulation according to (110) above, wherein the fatty acid polyglyceryl is one or more selected from the group consisting of polyglyceryl-6 polyricinoleate, polyglyceryl-6 polyricinoleate, polyglyceryl-10 decaoleate, polyglyceryl-10 pentaoleate, polyglyceryl-2 diisostearate, and polyglyceryl-10 decaisostearate. (113) The dispersion formulation according to (111) above, wherein the fatty acid polyglyceryl is one or more selected from the group consisting of polyglyceryl-6 polyricinoleate, polyglyceryl-6 polyricinoleate, polyglyceryl-10 decaoleate, polyglyceryl-10 pentaoleate, polyglyceryl-2 diisostearate, and polyglyceryl-10 decaisostearate.(114) The dispersion formulation according to (109) above, wherein the sugar fatty acid ester comprises sucrose erucate. (115) The dispersion formulation according to (111) above, wherein the sugar fatty acid ester comprises sucrose erucate. (116) The dispersion formulation according to (112) above, wherein the sugar fatty acid ester comprises sucrose erucate. (117) The dispersion formulation according to (113) above, wherein the sugar fatty acid ester comprises sucrose erucate.

[0015] (131) A dispersion preparation comprising solid particles comprising water-soluble molecules and one or more (preferably two or more) emulsifiers and an aqueous base, wherein the solid particles are dispersed in the aqueous base. (132) The dispersion preparation according to (131) above, wherein the one or more emulsifiers comprise a sucrose fatty acid ester. (133) The dispersion preparation according to (131) or (132) above, wherein the one or more emulsifiers comprise a sucrose erucate ester. (134) The dispersion preparation according to any one of (131) to (133) above, wherein the Z-average particle size is 200 nm or less. (135) The dispersion preparation according to any one of (131) to (134) above, wherein the emulsifier comprises two or more emulsifiers. (136) The dispersion preparation according to any one of (131) to (135) above, wherein the emulsifier comprises a fatty acid polyglyceryl. (137) The dispersion formulation according to (136) above, wherein the fatty acid polyglyceryl comprises polyglyceryl polyricinoleate. (138) The dispersion formulation according to any one of (131) to (137) above, wherein the emulsifier comprises a sucrose fatty acid ester and a fatty acid polyglyceryl. (139) The dispersion formulation according to any one of (131) to (138) above, wherein the water-soluble molecule comprises nicotinamide mononucleotide (NMN).

[0016] According to the present disclosure, the following inventions are provided: (1001) A dispersion formulation comprising an oily base and solid particles comprising a complex of a water-soluble molecule and two or more emulsifiers, wherein the two or more emulsifiers comprise a polyglyceryl fatty acid having a number-average degree of polymerization of 2 to 6 and an HLB value of 5 or less, and a sucrose fatty acid ester having an HLB value of 5 or less, the solid particles having a Z-average particle size of 100 nm to 500 nm, the solid particles being dispersed in the oily base, and the polyglyceryl fatty acid having a number-average degree of polymerization of 2 to 6 and the sucrose fatty acid ester being contained in a ratio such that the solid particles maintain a transparent or translucent dispersibility for two months at a temperature of 25°C. (1002) The dispersion formulation according to (1001) above, wherein the glyceryl fatty acid is polyglyceryl polyricinoleate. (1003) The dispersion formulation according to (1001) above, wherein the sugar fatty acid ester comprises sucrose erucate. (1004) The dispersion preparation according to (1002) above, wherein the sugar fatty acid ester comprises sucrose erucate. (1005) A cosmetic comprising the dispersion preparation according to any one of (1001) to (1004) above.

[0017] (1101) A dispersion formulation comprising an oily base and solid particles comprising a complex of a water-soluble molecule and two or more emulsifiers. (1102) The dispersion formulation according to (1101) above, wherein the two or more emulsifiers each have an HLB value of 5 or less, preferably 4 or less. (1103) The dispersion formulation according to (1101) above, wherein the two or more emulsifiers comprise at least a polyglyceryl fatty acid. (1104) The dispersion formulation according to (1101) above, wherein the two or more emulsifiers comprise at least a sucrose fatty acid ester. (1105) The dispersion formulation according to (1101) above, wherein the two or more emulsifiers comprise a polyglyceryl fatty acid and a sucrose fatty acid ester. (1106) The dispersion formulation according to (1101) above, wherein the two or more emulsifiers comprise a polyglyceryl fatty acid having a number average degree of polymerization of 2 to 6 and having an HLB value of at least 5 or less. (1107) The dispersion formulation according to (1101) above, wherein the two or more emulsifiers comprise a sucrose fatty acid ester having an HLB value of at least 5 or less. (1108) The dispersion formulation according to (1101) above, wherein the two or more emulsifiers comprise a polyglyceryl fatty acid having a number average degree of polymerization of 2 to 6 and having an HLB value of 5 or less, and a sucrose fatty acid ester having an HLB value of 5 or less. (1109) The dispersion formulation according to (1101) above, wherein the two or more emulsifiers comprise at least a sucrose erucate ester. (1110) The dispersion formulation according to (1101) above, wherein the two or more emulsifiers comprise at least a sucrose erucate ester having an HLB value of at least 5 or less. (1111) The dispersion formulation according to (1101) above, wherein the two or more emulsifiers comprise at least a polyglyceryl polyricinoleate. (1112) The dispersion formulation according to (1109) above, wherein the two or more emulsifiers comprise at least polyglyceryl polyricinoleate. (1113) The dispersion formulation according to (1110) above, wherein the two or more emulsifiers comprise at least polyglyceryl polyricinoleate. (1114) The dispersion formulation according to (1101) above, wherein the two or more emulsifiers comprise at least polyglyceryl polyricinoleate having an HLB value of 5 or less. (1115) The dispersion formulation according to (1109) above, wherein the two or more emulsifiers comprise at least polyglyceryl polyricinoleate having an HLB value of 5 or less.(1116) The dispersion formulation according to (1110) above, wherein the two or more emulsifiers comprise polyglyceryl polyricinoleate having an HLB value of at least 5. (1117) Any of the dispersion formulations above, wherein the two or more emulsifiers each have a fatty chain having 18 to 22 carbon atoms. (1118) Any of the dispersion formulations above, wherein the two or more emulsifiers comprise a fatty acid glyceryl, wherein the fatty acid glyceryl has a fatty chain having 18 to 22 carbon atoms. (1119) Any of the dispersion formulations above, wherein the two or more emulsifiers comprise a fatty acid ester, wherein the fatty acid ester has a fatty chain having 18 to 22 carbon atoms.

[0018] 1 shows the degree of penetration into the stratum corneum of a solid particle dispersion preparation prepared using an emulsifier designated ER290. The fractions in the figure indicate the ER290 / emulsifier ratio. 1 shows the degree of penetration into layers below the stratum corneum of a solid particle dispersion preparation prepared using an emulsifier designated ER290. The fractions in the figure indicate the ER290 / emulsifier ratio. 1 shows the appearance of the solid particle dispersion preparations of Examples 2-1 and 2-2. 1 shows the particle size distribution of particles in the solid particle dispersion preparations of Examples 2-1 and 2-2. 1 shows the penetration into the skin of the solid particle dispersion preparations of Examples 2-1 and 2-2. 1 shows the particle size distribution of particles in the aqueous solid particle dispersion preparation of Example 3. 1 shows the degree of penetration into the stratum corneum and layers below the stratum corneum of the aqueous solid particle dispersion preparation of Example 3.

[0019] Embodiments of the present invention will be described with reference to the drawings. The present invention is not limited to the following embodiments and drawings. In the following embodiments, the terms "have," "include," or "contain" also include the meaning of "consisting of" or "consisting of." The singular form means singular or plural.

[0020] As used herein, the term "subject" refers to a mammal, including humans, and preferably humans. Examples of mammals include, but are not limited to, humans, chimpanzees, and other primates; dogs, cats, rabbits, horses, sheep, goats, cows, pigs, rats (including nude rats), mice (including nude mice and squirrel mice), guinea pigs, and other livestock, pets, and laboratory animals.

[0021] As used herein, a "surfactant" is a molecule having a relatively hydrophilic portion and a relatively hydrophobic portion. Surfactants are broadly classified into ionic surfactants and nonionic surfactants. Ionic surfactants include cationic surfactants and anionic surfactants. Typically, an ionic surfactant may have either a cation or an anion and a hydrophobic portion. Cationic surfactants may contain a cationic portion and a fatty chain (e.g., a long-chain fatty chain) such as an alkyl, alkenyl, or alkynyl. Anionic surfactants may contain an anionic portion and a fatty acid such as a long-chain fatty acid, an unsaturated fatty acid (e.g., monovalent or divalent), or a long-chain unsaturated fatty acid (e.g., monovalent or divalent). The term "long chain" is used to refer to compounds having 14 to 22 carbon atoms. The fatty chain is preferably a fatty chain having 8 to 22 carbon atoms, i.e., C ８ ~C ２２ Alkyl, C ８ ~C ２２ alkenyl, or C ８ ~C ２２ C such as alkynyl ８ ~C ２２ The fatty chain may be a fatty chain. The fatty chain may also be a long-chain fatty chain. Saturated means that the fatty chain has no double or triple bonds, and unsaturated means that the fatty chain has at least one double or triple bond. Fatty chains with double bonds include cis- and trans-types, with the cis-type being preferred from the viewpoint of biocompatibility. Nonionic surfactants are surfactants that do not have ionic groups in their molecules and have a nonionic hydrophilic portion and a hydrophobic portion. The hydrophobic portion may contain a fatty chain such as an alkyl, alkenyl, or alkynyl (e.g., a long-chain fatty chain). The fatty chain and the long-chain fatty chain are as defined above.

[0022] Preferred nonionic surfactants are ester compounds derived from fatty acids such as erucic acid and oleic acid (e.g., saturated or unsaturated fatty acids). Examples of lipophilic nonionic surfactants include sugar fatty acid esters with a high degree of esterification (i.e., a high ratio of di-, tri-, or polyester esters relative to monoesters), preferably sucrose fatty acid esters (sucrose stearate, sucrose palmitate, sucrose myristate, sucrose oleate, sucrose laurate, sucrose erucate, and sucrose mixed fatty acid esters), polyglycerol condensed ricinoleate, decaglycerol ester, glycerol fatty acid ester, polyglycerol fatty acid ester, polyoxyethylene glycerol fatty acid ester, sorbitan fatty acid ester, polyoxyethylene sorbit fatty acid ester, and polyoxyethylene castor oil / hydrogenated castor oil. Preferably, the nonionic surfactant is sucrose laurate. Surfactants may be used alone or in combination. A suitable example of a surfactant used for preparing the complex is a lipophilic (hydrophobic) nonionic surfactant having an HLB (Hydrophile-Lipophile Balance) value of 10 or less. The HLB of each nonionic surfactant may be, for example, 8 or less, 7 or less, 6 or less, 5 or less, 4.9 or less, 4.8 or less, 4.7 or less, 4.6 or less, 4.5 or less, 4.4 or less, 4.3 or less, 4.2 or less, 4.1 or less, 4.0 or less, 3.9 or less, 3.8 or less, 3.7 or less, 3.6 or less, 3.5 or less, 3.4 or less, 3.3 or less, 3.2 or less, 3.1 or less, or 3 or less. The HLB of the nonionic surfactant is preferably 8 or less, more preferably 5 or less, even more preferably 4 or less, and particularly preferably 3 or less.

[0023] Cationic surfactants (cationic lipids) are described in U.S. Patent Application Publication Nos. 2006 / 0083780 and 2006 / 0240554, U.S. Patent Nos. 5,208,036, 5,264,618, 5,279,833, 5,283,185, 5,753,613, and 5,785,992, and PCT Publication No. WO 96 / 10390, the disclosures of which are incorporated by reference herein in their entirety for all purposes. Cationic lipids include 1,2-dilinoleyloxy-N,N-dimethylaminopropane (DLinDMA), 1,2-dilinolenyloxy-N,N-dimethylaminopropane (DLenDMA), 2,2-dilinoleyl-4-(2-dimethylaminoethyl)-[1,3]-dioxolane (DLin-K-C2-DMA; "XTC2"), 2,2-dilinoleyl-4-(3-dimethylaminopropyl)-[1,3]-dioxolane (DLin-K-C3-DMA), 2,2-dilinoleyl-4-(4-dimethylaminopropyl)-[1,3]-dioxolane (DLin-K-C3-DMA), and 2,2-dilinoleyl-4-(4-dimethylaminopropyl)-[1,3]-dioxolane (DLin-K-C3-DMA). 2,2-Dilinoleyl-5-dimethylaminomethyl-[1,3]-dioxolane (DLin-K-C4-DMA), 2,2-Dilinoleyl-5-dimethylaminomethyl-[1,3]-dioxane (DLin-K6-DMA), 2,2-Dilinoleyl-4-N-methylpepiazino-[1,3]-dioxolane (DLin-K-MPZ), 2,2-Dilinoleyl-4-dimethylaminomethyl-[1,3]-dioxolane (DLin-K-DMA), 1,2-Dilinoleylcarbamoyloxy-3-dimethylaminopropane (DLin-C-DAP), 1,2-dilinoleyloxy-3-(dimethylamino)acetoxypropane (DLin-DAC), 1,2-dilinoleyloxy-3-morpholinopropane (DLin-MA), 1,2-dilinoleoyl-3-dimethylaminopropane (DLinDAP), 1,2-dilinoleylthio-3-dimethylaminopropane (DLin-S-DMA), 1-linoleoyl-2-linoleyloxy-3-dimethylaminopropane (DLin-2-DMAP), 1,2-dilinoleyloxy-3-trimethylaminopropane chloride salt (DLin-TMA.Cl), 1,2-Dilinoleoyl-3-trimethylaminopropane chloride salt (DLin-TAP.Cl), 1,2-dilinoleyloxy-3-(N-methylpiperazino)propane (DLin-MPZ), 3-(N,N-dilinoleylamino)-1,2-propanediol (DLinAP), 3-(N,N-dioleylamino)-1,2-propanediol (DOAP), 1,2-dilinoleyloxo-3- (2-N,N-dimethylamino)ethoxypropane (DLin-EG-DMA), N,N-dioleyl-N,N-dimethylammonium chloride (DODAC), 1,2-dioleyloxy-N,N-dimethylaminopropane (DODMA), 1,2-distearyloxy-N,N-dimethylaminopropane (DSDMA), N-(1-(2,3-dioleyloxy)propyl)-N,N,N-trimethylammonium N-(1,2-dimyristyloxyprop-3-yl)-N,N-dimethyl-ammonium chloride (DOTMA), N,N-distearyl-N,N-dimethylammonium bromide (DDAB), N-(1-(2,3-dioleoyloxy)propyl)-N,N,N-trimethylammonium chloride (DOTAP), 3-(N-(N',N'-dimethylaminoethane)-carbamoyl)cholesterol (DC-Chol), N-(1,2-dimyristyloxyprop-3-yl)-N,N-dimethyl- N-hydroxyethylammonium bromide (DMRIE), 2,3-dioleyloxy-N-[2(spermine-carboxamido)ethyl]-N,N-dimethyl-1-propanaminium trifluoroacetate (DOSPA), dioctadecylamidoglycylspermine (DOGS), 3-dimethylamino-2-(cholest-5-ene-3-β-oxybutane-4-oxy)-1-(cis,cis-9,12- octadecadienoxy)propane (CLinDMA), 2-[5'-(cholest-5-ene-3-β-oxy)-3'-oxapentoxy)-3-dimethyl-1-(cis,cis-9',1-2'-octadecadienoxy)propane (CpLinDMA), N,N-dimethyl-3,4-dioleyloxybenzylamine (DMOBA), 1,2-N,N'-dioleylcarbamyl-3-dimethylaminopropane (DOcarbDAP), 1,2-N,N'-Dilinoleylcarbamyl-3-dimethylaminopropane (DLincarbDAP), or a mixture thereof. In a preferred embodiment, the cationic lipid is DLinDMA, DLin-K-C2-DMA ("XTC2"), or a mixture thereof. The cationic lipid preferably includes 1,2-dimyristoyl-sn-glycero-3-ethyl-phosphatidylcholine (EDMPC).

[0024] Anionic surfactants (anionic lipids) include phospholipids and fatty acids, such as phosphatidylglycerol, cardiolipin, diacylphosphatidylserine, diacylphosphatidic acid, N-dodecanoylphosphatidylethanolamine, N-succinylphosphatidylethanolamine, N-glutarylphosphatidylethanolamine, lysylphosphatidylglycerol, palmitoyloleoylphosphatidylglycerol (POPG), and other anionic modifying groups attached to neutral lipids.

[0025] As used herein, a "solid composite" refers to a composite consisting of solid components. In this specification, a particulate solid composite may be referred to as a "solid particle." A solid composite may contain water, but is a composite containing solid components. The solid composite may have a low water content. For example, the water content may be 1% by mass or less, 0.9% by mass or less, 0.8% by mass or less, 0.7% by mass or less, 0.6% by mass or less, 0.5% by mass or less, 0.4% by mass or less, 0.3% by mass or less, 0.2% by mass or less, or 0.1% by mass or less, as measured by a known method. A solid composite containing a water-soluble molecule and a surfactant may have a core-shell structure, in which the core contains the water-soluble molecule and the shell contains the surfactant, with the water-soluble portion of the surfactant facing the core and the hydrophobic portion facing the outer surface of the solid composite. Therefore, the resulting composite or solid composite may have a hydrophilic central portion (core) but a hydrophobic outer surface (periphery or shell). Such a solid composite can be suitably dispersed in an oil phase. However, in the present disclosure, such a solid complex does not have to be dispersed in an oil phase (or liquid). By not using an oil phase, it is possible to prevent the skin from becoming excessively oily due to oil. Furthermore, by not using an oil phase, it may be easier to handle the patch.

[0026] (Dispersion formulation) According to the present disclosure, there is provided a dispersion formulation comprising an oily base and solid particles comprising a complex of a water-soluble molecule and an emulsifier. In the dispersion formulation, the solid particles are dispersed in the oily base.

[0027] According to the present disclosure, there is provided a dispersion formulation comprising an aqueous base and solid particles comprising a complex of a water-soluble molecule and an emulsifier, wherein the solid particles are dispersed in the aqueous base.

[0028] In some preferred embodiments, the emulsifier comprises one or more emulsifiers. In some preferred embodiments, the emulsifier comprises two or more emulsifiers.

[0029] In a preferred embodiment, the emulsifier includes an emulsifier having a fatty chain with 18 to 22 carbon atoms. In a preferred embodiment, each of the two or more emulsifiers includes an emulsifier having a fatty chain with 18 to 22 carbon atoms. The two or more emulsifiers may further include any additional emulsifier, as long as they include two emulsifiers having a fatty chain with 18 to 22 carbon atoms.

[0030] In one preferred embodiment, the emulsifier preferably comprises a sugar fatty acid ester, which in one preferred embodiment is a sucrose fatty acid ester, more preferably sucrose erucate.

[0031] In one preferred embodiment, the emulsifier comprises a glyceryl fatty acid, for example, the glyceryl fatty acid selected from the group consisting of polyglyceryl fatty acids, polyglyceryl monoglyceryl fatty acids, polyglyceryl monoglyceryl fatty acids, and monoglyceryl monoglyceryl fatty acids.

[0032] In some preferred embodiments, the glyceryl fatty acid has a polyglyceryl group with a degree of polymerization of 2 to 10. In some preferred embodiments, the glyceryl fatty acid has a polyglyceryl group with a degree of polymerization of 2 to 8, or 2 to 6, 2 to 4, 3 to 5, or 4 to 6.

[0033] In a preferred embodiment, the fatty acid glyceryl includes, but is not limited to, fatty acid glyceryl group A: polyglyceryl decaoleate, polyglyceryl polyricinoleate, polyglyceryl polyricinoleate, polyglyceryl diisostearate, polyglyceryl tetraisostearate, glyceryl monooleate, polyoxyethylene hydrogenated castor oil, polyglyceryl pentaoleate, polyglyceryl decaisostearate, and glyceryl monocaprate. In a preferred embodiment, the fatty acid glyceryl includes, but is not limited to, fatty acid glyceryl group B: polyglyceryl-10 decaoleate, polyglyceryl-6 polyricinoleate, polyglyceryl-6 polyricinoleate, polyglyceryl-2 diisostearate, polyglyceryl-2 tetraisostearate, glyceryl monooleate, polyoxyethylene hydrogenated castor oil, polyglyceryl-10 pentaoleate, polyglyceryl-10 decaisostearate, and glyceryl monocaprate.

[0034] In one preferred embodiment, the emulsifier comprises a sugar fatty acid ester and a glyceryl fatty acid.

[0035] In a preferred specific embodiment, the emulsifier comprises sucrose erucate and a glyceryl fatty acid. In a preferred embodiment, the glyceryl fatty acid is selected from the group consisting of polyglyceryl fatty acids, monoglyceryl fatty acid polyglyceryls, polyglyceryl fatty acids monoglyceryls, and monoglyceryl fatty acids monoglyceryls. In a preferred embodiment, the glyceryl fatty acid may be, but is not limited to, one or more selected from glyceryl fatty acid group A. In a preferred embodiment, the glyceryl fatty acid may be, but is not limited to, one or more selected from glyceryl fatty acid group B.

[0036] In certain preferred embodiments, the emulsifier comprises sucrose erucate and polyglyceryl-10 decaoleate. The molar ratio of sucrose erucate to polyglyceryl-10 decaoleate can be, for example, 5:95 to 95:5, 10:90 to 90:10, 15:85 to 85:15, 20:80 to 80:20, 25:75 to 75:25, 30:70 to 70:30, 35:65 to 65:35, or 40:60 to 60:40. The ratio of sucrose erucate to polyglyceryl-10 decaoleate can be, for example, 5:95 to 75:25, 10:90 to 65:35, 15:85 to 50:50, 20:80 to 40:60, 20:80 to 35:65, or 20:80 to 30:70. The ratio of sucrose erucate to polyglyceryl-10 decaoleate can be, for example, 25:75 to 95:5, 35:65 to 90:10, 50:50 to 85:15, 60:40 to 80:20, 65:35 to 80:20, or 70:30 to 80:20.

[0037] In certain preferred embodiments, the emulsifier comprises sucrose erucate and polyglyceryl-6 polyricinoleate. The ratio of sucrose erucate to polyglyceryl-6 polyricinoleate can be, for example, 5:95 to 95:5, 10:90 to 90:10, 15:85 to 85:15, 20:80 to 80:20, 25:75 to 75:25, 30:70 to 70:30, 35:65 to 65:35, or 40:60 to 60:40. The ratio of sucrose erucate to polyglyceryl-6 polyricinoleate can be, for example, 5:95 to 75:25, 10:90 to 65:35, 15:85 to 50:50, 20:80 to 40:60, 20:80 to 35:65, or 20:80 to 30:70. The ratio of sucrose erucate to polyglyceryl-6 polyricinoleate can be, for example, 25:75 to 95:5, 35:65 to 90:10, 50:50 to 85:15, 60:40 to 80:20, 65:35 to 80:20, or 70:30 to 80:20.

[0038] In some preferred embodiments, the emulsifier comprises sucrose erucate and polyglyceryl-6 polyricinoleate. The ratio of sucrose erucate to polyglyceryl-6 polyricinoleate can be, for example, 5:95 to 95:5, 10:90 to 90:10, 15:85 to 85:15, 20:80 to 80:20, 25:75 to 75:25, 30:70 to 70:30, 35:65 to 65:35, or 40:60 to 60:40. The ratio of sucrose erucate to polyglyceryl-6 polyricinoleate can be, for example, 5:95 to 75:25, 10:90 to 65:35, 15:85 to 50:50, 20:80 to 40:60, 20:80 to 35:65, or 20:80 to 30:70. The ratio of sucrose erucate to polyglyceryl-6 polyricinoleate can be, for example, 25:75 to 95:5, 35:65 to 90:10, 50:50 to 85:15, 60:40 to 80:20, 65:35 to 80:20, or 70:30 to 80:20.

[0039] In a preferred embodiment, the emulsifier comprises sucrose erucate and polyglyceryl-2 diisostearate, and the ratio of sucrose erucate to polyglyceryl-2 diisostearate can be, for example, 5:95 to 95:5, 10:90 to 90:10, 15:85 to 85:15, 20:80 to 80:20, 25:75 to 75:25, 30:70 to 70:30, 35:65 to 65:35, or 40:60 to 60:40. The ratio of sucrose erucate to polyglyceryl-2 diisostearate can be, for example, 5:95 to 75:25, 10:90 to 65:35, 15:85 to 50:50, 20:80 to 40:60, 20:80 to 35:65, or 20:80 to 30:70. The ratio of sucrose erucate to polyglyceryl-2 diisostearate can be, for example, 25:75 to 95:5, 35:65 to 90:10, 50:50 to 85:15, 60:40 to 80:20, 65:35 to 80:20, or 70:30 to 80:20.

[0040] In some preferred embodiments, the emulsifier comprises sucrose erucate and polyglyceryl-2 tetraisostearate, and the ratio of sucrose erucate to polyglyceryl-2 tetraisostearate can be, for example, 5:95 to 95:5, 10:90 to 90:10, 15:85 to 85:15, 20:80 to 80:20, 25:75 to 75:25, 30:70 to 70:30, 35:65 to 65:35, or 40:60 to 60:40. The ratio of sucrose erucate to polyglyceryl-2 tetraisostearate can be, for example, 5:95 to 75:25, 10:90 to 65:35, 15:85 to 50:50, 20:80 to 40:60, 20:80 to 35:65, or 20:80 to 30:70. The ratio of sucrose erucate to polyglyceryl-2 tetraisostearate can be, for example, 25:75 to 95:5, 35:65 to 90:10, 50:50 to 85:15, 60:40 to 80:20, 65:35 to 80:20, or 70:30 to 80:20.

[0041] In some preferred embodiments, the emulsifier comprises sucrose erucate and glyceryl monooleate, and the ratio of sucrose erucate to glyceryl monooleate can be, for example, 5:95 to 95:5, 10:90 to 90:10, 15:85 to 85:15, 20:80 to 80:20, 25:75 to 75:25, 30:70 to 70:30, 35:65 to 65:35, or 40:60 to 60:40. The ratio of sucrose erucate to glyceryl monooleate can be, for example, 5:95 to 75:25, 10:90 to 65:35, 15:85 to 50:50, 20:80 to 40:60, 20:80 to 35:65, or 20:80 to 30:70. The ratio of sucrose erucate to glyceryl monooleate can be, for example, 25:75 to 95:5, 35:65 to 90:10, 50:50 to 85:15, 60:40 to 80:20, 65:35 to 80:20, or 70:30 to 80:20.

[0042] In a preferred embodiment, the emulsifier comprises sucrose erucate and polyoxyethylene hydrogenated castor oil, and the ratio of sucrose erucate to polyoxyethylene hydrogenated castor oil can be, for example, 5:95 to 95:5, 10:90 to 90:10, 15:85 to 85:15, 20:80 to 80:20, 25:75 to 75:25, 30:70 to 70:30, 35:65 to 65:35, or 40:60 to 60:40. The ratio of sucrose erucate to polyoxyethylene hydrogenated castor oil can be, for example, 5:95 to 75:25, 10:90 to 65:35, 15:85 to 50:50, 20:80 to 40:60, 20:80 to 35:65, or 20:80 to 30:70. The ratio of sucrose erucate to polyoxyethylene hydrogenated castor oil can be, for example, 25:75 to 95:5, 35:65 to 90:10, 50:50 to 85:15, 60:40 to 80:20, 65:35 to 80:20, or 70:30 to 80:20.

[0043] In some preferred embodiments, the emulsifier comprises sucrose erucate and polyglyceryl-10 pentaoleate, and the ratio of sucrose erucate to polyglyceryl-10 pentaoleate can be, for example, 5:95 to 95:5, 10:90 to 90:10, 15:85 to 85:15, 20:80 to 80:20, 25:75 to 75:25, 30:70 to 70:30, 35:65 to 65:35, or 40:60 to 60:40. The ratio of sucrose erucate to polyglyceryl-10 pentaoleate can be, for example, 5:95 to 75:25, 10:90 to 65:35, 15:85 to 50:50, 20:80 to 40:60, 20:80 to 35:65, or 20:80 to 30:70. The ratio of sucrose erucate to polyglyceryl-10 pentaoleate can be, for example, 25:75 to 95:5, 35:65 to 90:10, 50:50 to 85:15, 60:40 to 80:20, 65:35 to 80:20, or 70:30 to 80:20.

[0044] In some preferred embodiments, the emulsifier comprises sucrose erucate and polyglyceryl-10 decaisostearate, and the ratio of sucrose erucate to polyglyceryl-10 decaisostearate can be, for example, 5:95 to 95:5, 10:90 to 90:10, 15:85 to 85:15, 20:80 to 80:20, 25:75 to 75:25, 30:70 to 70:30, 35:65 to 65:35, or 40:60 to 60:40. The ratio of sucrose erucate to polyglyceryl-10 decaisostearate can be, for example, 5:95 to 75:25, 10:90 to 65:35, 15:85 to 50:50, 20:80 to 40:60, 20:80 to 35:65, or 20:80 to 30:70. The ratio of sucrose erucate to polyglyceryl-10 decaisostearate can be, for example, 25:75 to 95:5, 35:65 to 90:10, 50:50 to 85:15, 60:40 to 80:20, 65:35 to 80:20, or 70:30 to 80:20.

[0045] In some preferred embodiments, the emulsifier comprises sucrose erucate and glyceryl monocaprate, and the ratio of sucrose erucate to glyceryl monocaprate can be, for example, 5:95 to 95:5, 10:90 to 90:10, 15:85 to 85:15, 20:80 to 80:20, 25:75 to 75:25, 30:70 to 70:30, 35:65 to 65:35, or 40:60 to 60:40. The ratio of sucrose erucate to glyceryl monocaprate can be, for example, 5:95 to 75:25, 10:90 to 65:35, 15:85 to 50:50, 20:80 to 40:60, 20:80 to 35:65, or 20:80 to 30:70. The ratio of sucrose erucate to glyceryl monocaprate can be, for example, 25:75 to 95:5, 35:65 to 90:10, 50:50 to 85:15, 60:40 to 80:20, 65:35 to 80:20, or 70:30 to 80:20.

[0046] In the present disclosure, the oily base is not particularly limited as long as it is liquid at room temperature (e.g., 25°C), substantially insoluble in water, viscous, has a specific gravity lower than that of water, is used in the fields of cosmetics and pharmaceuticals, and does not have adverse effects when it comes into contact with the skin of animals, including humans. Examples of such oily bases include higher (polyhydric) alcohols such as cetanol, myristyl alcohol, oleyl alcohol, lauryl alcohol, cetostearyl alcohol, stearyl alcohol, behenyl alcohol, jojoba alcohol, chimyl alcohol, selachyl alcohol, batyl alcohol, hexyldecanol, isostearyl alcohol, 2-octyldodecanol, and dimer diol; aralkyl alcohols such as benzyl alcohol and derivatives thereof; long-chain fatty acids such as isostearic acid, behenic acid, undecylenic acid, 12-hydroxystearic acid, palmitoleic acid, oleic acid, linoleic acid, linolenic acid, erucic acid, docosahexaenoic acid, eicosapentaenoic acid, isohexadecanoic acid, anteisohenicosanoic acid, dimer acid, and hydrogenated dimer acid and derivatives thereof; liquid paraffin (mineral oil), heavy liquid isoparaffin, light liquid isoparaffin, α-olefin oligomer, polyisobutene, hydrogenated polyisobutene, Hydrocarbons such as propylene glycol, polybutene, squalane, olive-derived squalane, squalene, petrolatum, and solid paraffin; waxes such as candelilla wax, carnauba wax, rice wax, Japan wax, beeswax, montan wax, ozokerite, ceresin, paraffin wax, microcrystalline wax, petrolatum, Fischer-Tropsch wax, polyethylene wax, and ethylene-propylene copolymer; coconut oil, palm oil, palm kernel oil, and safflower vegetable oils and fats such as coconut oil, olive oil, castor oil, avocado oil, sesame oil, tea oil, evening primrose oil, wheat germ oil, perilla oil, apricot kernel oil, almond oil, macadamia nut oil, hazelnut oil, kukui nut oil, rosehip oil, meadowfoam oil, persic oil, tea tree oil, peppermint oil, corn oil, rapeseed oil, sunflower oil, wheat germ oil, linseed oil, cottonseed oil, soybean oil, peanut oil, rice bran oil, cocoa butter, shea butter, hydrogenated coconut oil, hydrogenated castor oil, jojoba oil, hydrogenated jojoba oil;Animal fats and oils such as beef tallow, milk fat, horse fat, egg yolk oil, mink oil, and turtle oil; animal waxes such as spermaceti, lanolin, and orange roughy oil; lanolins such as liquid lanolin, reduced lanolin, adsorption-refined lanolin, acetated lanolin, acetated liquid lanolin, hydroxylanolin, polyoxyethylene lanolin, lanolin fatty acids, hard lanolin fatty acids, lanolin alcohol, acetated lanolin alcohol, and cetyl lanolyl acetate esters; sterols such as cholesterol, dihydrocholesterol, lanosterol, dihydrolanosterol, phytosterol, and cholic acid; sapogenins; saponins; cholesteryl acetate, cholesteryl nonanoate, cholesteryl stearate, cholesteryl isostearate, cholesteryl oleate, di(cholesteryl / behenyl / N-lauroyl-L-glutamate) sterol esters such as N-lauroyl-L-glutamic acid di(cholesteryl / octyldodecyl), N-lauroyl-L-glutamic acid di(phytosteryl / behenyl / octyldodecyl), N-lauroyl-L-glutamic acid di(phytosteryl / octyldodecyl), 12-hydroxystearate cholesteryl, macadamia nut oil fatty acid cholesteryl, macadamia nut oil fatty acid phytosteryl, phytosteryl isostearate, soft lanolin fatty acid cholesteryl, hard lanolin fatty acid cholesteryl, long-chain branched fatty acid cholesteryl, and long-chain α-hydroxy fatty acid cholesteryl; acyl sarcosine alkyl esters such as N-lauroyl sarcosine isopropyl; lipid complexes such as phospholipid-cholesterol complexes and phospholipid-phytosterol complexes;Octyldodecyl myristate, hexyldecyl myristate, octyldodecyl isostearate, cetyl palmitate, octyldodecyl palmitate, cetyl octanoate, hexyldecyl octanoate, isotridecyl isononanoate, isononyl isononanoate, octyl isononanoate, isotridecyl isononanoate, isodecyl neopentanoate, isotridecyl neopentanoate, isostearyl neopentanoate, octyldodecyl neodecanoate, oleyl oleate, octyldodecyl oleate, octyldodecyl ricinoleate, octyldodecyl lanolinate, hexyldecyl dimethyloctanoate, el Long-chain fatty acid esters such as octyldodecyl carbonate, hydrogenated castor oil isostearate, ethyl oleate, avocado oil fatty acid ethyl, isopropyl myristate, isopropyl palmitate, octyl palmitate, isopropyl isostearate, and lanolin fatty acid isopropyl; dicarboxylic acid esters such as diethyl sebacate, diisopropyl sebacate, dioctyl sebacate, diisopropyl adipate, dibutyloctyl sebacate, diisobutyl adipate, dioctyl succinate, and triethyl citrate; oxyacid esters such as cetyl lactate, diisostearyl malate, and hydrogenated castor oil monoisostearate;Glyceryl trioctanoate (glyceryl tri-2-ethylhexanoate), glyceryl trioleate, glyceryl triisostearate, glyceryl diisostearate, caprylic / capric triglyceride, caprylic / capric / myristic / stearic triglyceride, hydrogenated rosin triglyceride (hydrogenated ester gum), rosin triglyceride (ester gum), glyceryl behenate eicosandioate, trimethylolpropane trioctanoate, trimethylolpropane triisostearate, diisostearate Neopentyl glycol octanoate, neopentyl glycol dicaprate, 2-butyl-2-ethyl-1,3-propanediol dioctanoate, propylene glycol dioleate, pentaerythrityl tetraoctanoate, pentaerythrityl hydrogenated rosin, ditrimethylolpropane triethylhexanoate, ditrimethylolpropane isostearate / sebacic acid, pentaerythrityl triethylhexanoate, dipentaerythrityl hydroxystearate / stearic acid / rosin acid, diglyceride diisostearate Polyhydric alcohol fatty acid esters such as lyceryl, polyglyceryl tetraisostearate, polyglyceryl-10 nonaisostearate, deca(erucic acid / isostearate / ricinoleic acid)polyglyceryl-8, (hexyldecanoic acid / sebacic acid) diglyceryl oligoester, glycol distearate (ethylene glycol distearate), 3-methyl-1,5-pentanediol dineopentanoate, 2,4-diethyl-1,5-pentanediol dineopentanoate; diisopropyl dimer dilinoleate, dimer Derivatives of dimer acid or dimer diol such as diisostearyl dimer dilinoleate, di(isostearyl / phytosteryl) dimer dilinoleate, (phytosteryl / behenyl) dimer dilinoleate, (phytosteryl / isostearyl / cetyl / stearyl / behenyl) dimer dilinoleate, dimer dilinoleyl diisostearate, dimer dilinoleyl hydrogenated rosin condensate, dimer dilinoleic acid hydrogenated castor oil, and hydroxyalkyl dimer dilinoleyl ether;Fatty acid alkanolamides such as coconut oil fatty acid monoethanolamide (cocamide MEA), coconut oil fatty acid diethanolamide (cocamide DEA), lauric acid monoethanolamide (lauramide MEA), lauric acid diethanolamide (lauramide DEA), lauric acid monoisopropanolamide (lauramide MIPA), palmitic acid monoethanolamide (palmitamide MEA), palmitic acid diethanolamide (palmitamide DEA), and coconut oil fatty acid methylethanolamide (cocamide methyl MEA); dimethicone (dimethylpolysiloxane), highly polymerized dimethicone (highly polymerized dimethylpolysiloxane), cyclomethicone (cyclic dimethylsiloxane) such as decamethylcyclopentasiloxane (also simply called cyclopentasiloxane), phenyl trimethicone, diphenyl dimethicone, phenyl dimethicone, stearoxypropyl dimethicone silicones such as methylaminopropyl methicone, (aminoethylaminopropyl methicone / dimethicone) copolymer, dimethiconol, dimethiconol crosspolymer, silicone resin, silicone rubber, amino-modified silicones such as aminopropyl dimethicone and amodimethicone, cation-modified silicone, polyether-modified silicones such as dimethicone copolyol, polyglycerin-modified silicone, sugar-modified silicone, carboxylic acid-modified silicone, phosphate-modified silicone, sulfate-modified silicone, alkyl-modified silicone, fatty acid-modified silicone, alkyl ether-modified silicone, amino acid-modified silicone, peptide-modified silicone, fluorine-modified silicone, cation-modified and polyether-modified silicone, amino-modified and polyether-modified silicone, alkyl-modified and polyether-modified silicone, and polysiloxane-oxyalkylene copolymer;Examples of suitable oil bases include fluorine-based oils such as perfluorodecane, perfluorooctane, and perfluoropolyether. Among these, preferred are long-chain fatty acids such as oleic acid, vegetable oils such as olive oil and jojoba oil, alkyl esters of fatty acids having 1 to 8 carbon atoms such as isopropyl myristate, isopropyl palmitate, octyl palmitate, and isopropyl isostearate, and hydrocarbons such as squalane, with isopropyl myristate and squalane being more preferred. Particularly preferred is isopropyl myristate as the oil base.

[0047] The aqueous base can be water or an aqueous solution containing pharmaceutically acceptable additives. Examples of the pharmaceutically acceptable additives include pharmaceutically acceptable salts, isotonicity agents, pH adjusters, thickeners, etc. The aqueous solution containing the pharmaceutically acceptable additives can be, for example, physiological saline.

[0048] Examples of water-soluble molecules include polysaccharides such as hyaluronic acid and its salts, heparin and its analogs, and chitosan; proteins such as ovalbumin, casein, and collagen; vitamins such as vitamin C and its derivatives and retinol; amino acids such as amino acids, tranexamic acid, and placenta extract; glycosides such as arbutin; coenzymes such as coenzyme Q10; nucleotides such as nicotinamide mononucleotide (NMN); protein preparations such as cholera toxin subunit B, epidermal growth factor, serum albumin, immunoglobulin, interleukin, interferon, human glucagon, human growth hormone, erythropoietin, platelet-derived growth factor, and insulin; and peptide preparations such as cancer vaccines and allergy vaccines. The molecular weight of the water-soluble molecule is preferably 500 Da or more, more preferably 1000 Da (i.e., 1 kDa) or more, and preferably 200 kDa or less, more preferably 100 kDa or less, and particularly preferably 50 kDa or less.

[0049] The water-soluble molecules may be nanoparticles or nanovesicles, such as lipid vesicles, lipid nanoparticles, extracellular vesicles (e.g., exosomes), polyion complex micelles, and polyion complex polymersomes. Nanoparticles or nanovesicles have a Z-average size of sub-micrometers. Even when such nanoparticles or nanovesicles are used as water-soluble molecules, the manufacturing process for solid particle dispersion formulations can be applied. Such nanoparticles or nanovesicles can be emulsified by mixing them with an emulsifier in a volatile oil phase (e.g., cyclohexane), and the volatile oil phase can be removed by lyophilization.

[0050] The solid particles of polyfatty acids (Z-average size) can be, for example, 700 nm or less, 600 nm or less, 500 nm or less, 400 nm or less, 300 nm or less, or 200 nm or less. The particle size (Z-average size) of the solid particles can be, for example, 100 nm or more or 200 nm or more. The particle size (Z-average size) of the solid particles can be, for example, 100 nm to 600 nm, 100 nm to 500 nm, 100 nm to 400 nm, 100 nm to 300 nm, 100 nm to 200 nm, 200 nm to 600 nm, 200 nm to 500 nm, 200 nm to 400 nm, or 200 nm to 300 nm. The Z-average size is defined in ISO 13321. Particles smaller than 2 μm in diameter can be measured by dynamic scattering (DLS) using a Zetasizer Nano ZS 90 (Malvern Instr. Ltd.).

[0051] The polydispersity index (PDI) of the solid particles can be, for example, from 0.1 to 1. The PDI can preferably be from 0.1 to 0.5, from 0.1 to 0.4, from 0.1 to 0.3, or from 0.1 to 0.2.

[0052] In a preferred embodiment, the dispersion formulation of the present disclosure can have a Z-average particle size of 100 nm or more and 500 nm or less at 20°C measured using a Zetasizer (e.g., Zetasizer Nano Pro) even after standing in air at 25°C for two months after preparation. Prior to measuring the Z-particle size, the dispersion formulation of the present disclosure may be diluted (e.g., 100-fold) with an oily base such as cyclohexane.

[0053] In a preferred embodiment, the dispersion formulation of the present disclosure does not exhibit precipitation of solid particles during preparation. In a more preferred embodiment, the dispersion formulation of the present disclosure does not exhibit precipitation of solid particles during preparation, and the solid particles are dispersed in the dispersion medium in a transparent or translucent manner. This dispersibility can be adjusted by the mixing ratio of two or more emulsifiers. Therefore, it is preferred that the dispersion formulation of the present disclosure contains two or more emulsifiers in a ratio that maintains a transparent or translucent dispersibility.

[0054] The dispersion formulation of the present disclosure contains two or more emulsifiers and preferably has improved storage stability. In a preferred embodiment, the dispersion formulation of the present disclosure does not exhibit solid particle precipitation even when left standing at 25°C in the atmosphere for a certain period of time after preparation. In a more preferred embodiment, the dispersion formulation of the present disclosure does not exhibit solid particle precipitation even when left standing at 25°C in the atmosphere for a certain period of time after preparation, and the solid particles are transparently or semitransparently dispersed in the dispersion medium. This dispersibility can be adjusted by the mixing ratio of two or more emulsifiers. Therefore, the dispersion formulation of the present disclosure preferably contains two or more emulsifiers in a ratio that maintains a transparent or semitransparent dispersibility for a certain period of time at a temperature of 25°C. The certain period of time may be 10 days or more, 20 days or more, 1 month or more, 40 days or more, 50 days or more, or 2 months or more. The certain period of time may also be, for example, 3 months or less or 2 months or less. The certain period of time may be, for example, about 2 months.

[0055] The dispersion formulation of the present disclosure contains two or more emulsifiers and may preferably have improved storage stability. In a preferred embodiment, the dispersion formulation of the present disclosure does not exhibit precipitation of solid particles even when left standing at 25°C in the atmosphere for two months after preparation. In a more preferred embodiment, the dispersion formulation of the present disclosure does not exhibit precipitation of solid particles even when left standing at 25°C in the atmosphere for two months after preparation, and the solid particles are transparently or semitransparently dispersed in the dispersion medium. This dispersibility can be adjusted by the mixing ratio of two or more emulsifiers. Therefore, it is preferred that the dispersion formulation of the present disclosure contains two or more emulsifiers in a ratio that maintains a transparent or semitransparent dispersibility for two months at a temperature of 25°C.

[0056] (Method for Preparing Dispersion Formulations) When target molecules, such as water-soluble molecules, are mixed with an emulsifier in an oil phase (preferably a volatile oil phase, for example, cyclohexane), particles having a core-shell structure are formed, with the target molecules, such as water-soluble molecules, in the core and the emulsifier in the shell. The particles are dispersed in the oil phase. The emulsifier comprises one or more emulsifiers. When the oil phase used here is a volatile oil phase (for example, cyclohexane), the solvent can be easily evaporated thereafter, and by removing the solvent by drying (for example, freeze-drying), particles having a core-shell structure, with the water-soluble molecules in the core and the emulsifier in the shell, can be obtained as solid particles (also referred to as "solid composites"). By dispersing the solid particles in an oily base or an aqueous base, a solid particle dispersion oil-based formulation or a solid particle dispersion aqueous formulation (also simply referred to as "solid particle dispersion formulation") can be obtained, respectively. Such solid particle-dispersed oil-based formulations can penetrate deeply into the stratum corneum (which is non-hydrophilic), which is difficult for water-soluble molecules to penetrate, and in some cases penetrate below the stratum corneum, preferably into the bloodstream. According to the examples, solid particle-dispersed aqueous formulations also have the ability to allow the active ingredient to penetrate below the stratum corneum, preferably into the bloodstream.

[0057] (Cosmetics) According to the present disclosure, a cosmetic product is provided that includes the dispersion formulation of the present disclosure. The cosmetic product may be an ointment, cream, lotion, spray, powder, or patch. The cosmetic product may include the dispersion formulation of the present disclosure and dermatologically acceptable additives (e.g., excipients, carriers, etc.).

[0058] Example 1: Effect of Emulsifiers on Solid Particle Dispersion Solution Preparation: 10 mg of fluorescein-labeled hyaluronic acid was dissolved in 2 mL of MilliQ water. 200 mg of each emulsifier listed in Table 1 was dissolved in 4 mL of cyclohexane. The aqueous and organic phases were added to a glass vial and stirred at 26,000 rpm for 2 minutes using a Polytron homogenizer. The resulting emulsion was flash-frozen in liquid nitrogen and lyophilized for 24 hours. After drying, the entire solid obtained was redispersed in 5 mL of olive oil to produce a solid particle dispersion.

[0059]

[0060] Measurement of particle size distribution The solid particle dispersion was diluted 100 times with cyclohexane, and the particle size distribution and Z-average particle size at 20°C were measured using a Zetasizer Nano Pro.

[0061] Yucatan micropig skin permeability test. Yucatan micropig skin (4 months old) was thawed and the subcutaneous tissue removed using a scalpel. It was cut into 2 cm x 2 cm pieces and sandwiched between the donor and acceptor phases of a vertical Franz cell with the stratum corneum facing up. The receptor phase was filled with 5 mL of PBS solution (pH 7.4) at 32°C. 100 μL of solid particle dispersion was administered to the donor phase and incubated at 32°C for 24 hours. After 24 hours, the solid particle dispersion in the donor phase was wiped off with a Kimwipe, and the outermost two layers of the stratum corneum were removed by tape stripping. The remaining stratum corneum was then removed by tape stripping. Five pieces were immersed in 1 mL of a solution (PBS / methanol / acetonitrile = 2 / 1 / 1, v / v) and extracted with shaking at room temperature for 22 hours. The skin other than the stratum corneum was divided into 16 sections using a scalpel, and similarly, 1 mL of PBS solution was used for shaking extraction at room temperature for 22 hours. The extract was diluted 10 times with PBS solution, and the fluorescence intensity was measured using a microplate reader to quantify the amount of hyaluronic acid.

[0062] Table 2 shows the compositions of the prepared solid particle dispersion formulations. Table 3 shows the Z-average values ​​and polydispersity indexes of particles in solid particle dispersion formulations prepared by mixing sucrose fatty acid ester (ER-290) with various emulsifiers. Hyalo-oligo (trademark) was used as the hyaluronic acid.

[0063]

[0064] *In the table, the symbol "S" indicates that the dispersion is transparent or translucent, the symbol "B" indicates that precipitation has occurred, the symbol "A" indicates that the product is cloudy but there is no precipitation, and the symbol "C" indicates that gelation or other problems have occurred. Evaluation was performed by visual inspection. *1 This is a case where the majority of the product precipitated and there were few dispersed particles, making it impossible to measure the numerical value. However, dispersed particles are present, and these particles penetrate the skin.

[0065] Even in cases where a clear dispersion precipitated when an emulsifier was used alone, mixing two types of emulsifiers enabled the preparation of particles with a small Z-average value and a low polydispersity index. In many systems, the smallest Z-average value was obtained when ER-290 accounted for 25% of the total emulsifier. Furthermore, emulsifiers with particularly high stabilizing effects were those with large, bulky head and tail groups, such as polyglyceryl-6 polyricinoleate and polyglyceryl-2 diisostearate. Emulsifiers with small head and tail groups, such as glyceryl monocaprate, tended to have a low stabilizing effect. On the other hand, the hydrophilicity of decaglycerol fatty acid esters increased, weakening their ability to stably disperse hydrophilic drug solids. Polyoxyethylene (10) hydrogenated castor oil also had a low stabilizing effect. This suggests that the highest stabilizing effect may be achieved when the number of polymerization units of the glycerol unit in the head group of the emulsifier is between 2 and 6. In Tables 3 and 4, S is the most preferred, A is the next most preferred, B is the next most preferred, and C is the next most preferred. The presence of precipitation or cloudiness does not necessarily mean that solid particles are not dispersed in the liquid. Therefore, it should be noted that the presence of precipitation or cloudiness does not negate the penetration of solid particles into the skin. Therefore, even samples that have cloudiness, precipitation, or gelation can still be used for skin penetration applications.

[0066] Furthermore, long-term dispersibility was evaluated. After preparing the solid particle dispersion formulation, the formulation was stored at 25°C for 2 months, and then the dispersibility of the formulation was visually confirmed. The results are shown in Table 4.

[0067] *In the table, the symbol "S" indicates a transparent or translucent dispersion, the symbol "B" indicates that a precipitate has formed, and the symbol "A" indicates that there is no precipitate but the solution is cloudy.

[0068] As shown in Table 4, mixing two emulsifiers improved the long-term dispersibility of the formulation in both cases. Those skilled in the art would be able to adjust the mixing ratio of the emulsifiers appropriately to obtain dispersibility or long-term dispersibility.

[0069] Figure 1 shows the skin permeation of solid particle dispersion formulations prepared by mixing sucrose fatty acid ester (ER-290) with various emulsifiers when administered to Yucatan micropig skin. The Z-average value correlated with permeability below the stratum corneum, revealing that formulations with lower Z-average values ​​had greater drug penetration into the layers below the stratum corneum. Furthermore, permeation into the hydrophilic regions of the skin below the stratum corneum was also higher (Figure 2). The stratum corneum can be likened to bricks and mortar, with keratin-filled keratinocytes packed within a hydrophobic region consisting of a ceramide bilayer. Therefore, it is thought that smaller particles were able to more stably penetrate between keratinocytes within the highly hydrophobic stratum corneum.

[0070] Example 2: Solid particle dispersion formulation of extracellular vesicles ER-290 was obtained from Mitsubishi Chemical Corporation, and SY Glystar CRS-75 and S Face IS-202P were obtained from Sakamoto Pharmaceutical Co., Ltd. Milk exosomes (Cosmo Bio) were stained with CoraLite 594-labeled CD9 antibody (Proteintech Japan), and unreacted antibody was removed using a PURE-EV column (HansaBioMed).

[0071] The obtained exosomes were mixed in cyclohexane with a mixture of ER290 and CRS-75, or a mixture of ER290 and 202P. This procedure is believed to have resulted in the formation of particles with a core-shell structure, with exosomes in the core and an emulsifier in the shell. The cyclohexane was removed by lyophilization to obtain solid composite particles with a core-shell structure. The solid composite particles were dispersed in IPM to prepare a solid particle dispersion formulation of exosomes.

[0072] The amounts of each component used to prepare the solid particle dispersion formulations are shown in Table 5.

[0073]

[0074] The appearance of the resulting dispersion formulation is shown in Figure 3, and a transparent dispersion formulation was obtained. The particle size distribution of the resulting dispersion formulation was measured at 25°C using a Thetasizer Pro. The results are shown in Figure 4 and Table 6. As shown in Table 6, it was clear that a formulation containing relatively small particles of 500 nm or less was obtained.

[0075]

[0076] The resulting solid particle dispersion formulation containing exosomes was applied to micropig skin to confirm its permeability. Yucatan micropig skin (4 months old) was thawed, and the subcutaneous tissue was removed using a scalpel. Sections of 2 cm x 2 cm were cut and sandwiched between the donor and acceptor phases of a vertical Franz cell with the stratum corneum facing up. The receptor phase was filled with 5 mL of PBS solution (pH 7.4) at 32°C. 100 μL of the dispersion formulation of Example 2-1 or 2-2 was administered to the donor phase and incubated at 32°C for 24 hours. After 24 hours, the dispersion formulation in the donor phase was wiped off with a Kimwipe, and the two outermost layers of the stratum corneum were removed by tape stripping. The remaining skin was frozen and 8 μm cryosections were prepared. Skin tissue sections were mounted in ProLong Glass Antifade Mountant with NucBlu Stain (Thermo Fisher Scientific) and observed under a fluorescence microscope. The results are shown in Figure 5. As shown in Figure 5, the exosomes were found to penetrate into the epidermis by being formulated as a dispersed formulation.

[0077] Example 3: Aqueous Dispersion. Nicotinamide mononucleotide (NMN) (4 mg) was dissolved in 2 mL of MilliQ water. ER-290 (19 mg) and SY Glystar CRS-75 (57 mg) were dissolved in 4 mL of cyclohexane. The aqueous and organic phases were placed in a glass vial and stirred at 26,000 rpm for 2 minutes using a Polytron homogenizer to form an emulsion. The resulting emulsion was flash-frozen in liquid nitrogen and lyophilized for 24 hours.

[0078] After drying, 20 mg of the liquid obtained was dispersed in 1 mL of cyclohexane. 60 mg of Nikkol BL-25 (Nikko Chemicals) was dissolved in 3 mL of water. The aqueous and organic phases were placed in a glass vial and stirred at 26,000 rpm for 2 minutes using a Polytron homogenizer. The resulting emulsion was flash-frozen in liquid nitrogen and freeze-dried for 24 hours. The freeze-dried liquid was dispersed in 1 mL of water to obtain a dispersion of solid particles in water (aqueous solid particle dispersion) (final NMN concentration: 1 mg / mL).

[0079] Measurement of particle size distribution The obtained dispersion was diluted 100 times with water, and the particle size distribution at 25°C was measured using a Zetasizer Pro. The results are shown in Figure 6 and Table 7. As shown in Figure 6 and Table 7, by applying the technology of the present disclosure to NMN, it was possible to successfully form solid particles and disperse them in an aqueous solution. The obtained particles had a particle size distribution of sub-micron.

[0080]

[0081] Yucatan micropig skin permeability test: Yucatan micropig skin (4 months old) was thawed and the subcutaneous tissue was removed using a scalpel. It was cut into 2 cm x 2 cm pieces and sandwiched between the donor and acceptor phases of a vertical Franz cell with the stratum corneum facing up. The receptor phase was filled with 5 mL of PBS solution (pH 7.4) at 32°C. 150 μL of the resulting dispersion was administered to the donor phase and incubated at 32°C for 24 hours. A 1 mg / mL NMN aqueous solution was used as a control.

[0082] After 24 hours, the resulting donor phase dispersion was wiped off with Kimwipes, and the two outermost layers of the stratum corneum were removed by tape stripping. The remaining stratum corneum was peeled off by tape stripping 20 times and immersed in 5 mL of a solution (PBS / methanol / acetonitrile = 2 / 1 / 1, v / v) for 22 hours of shaking extraction at room temperature. The skin excluding the stratum corneum was divided into 16 sections with a scalpel, and 1 mL of PBS solution was used for shaking extraction at room temperature for 22 hours.

[0083] The nuclear extract was diluted 10-fold with a diluent (0.1% formic acid / acetonitrile = 50 / 50, v / v), and the amount of NMN in the extract was quantified using LC-MS.

[0084] As shown in FIG. 7, the solid particle dispersion solution was able to allow a large amount of NMN to penetrate into layers below the stratum corneum of the skin.

Claims

1. A dispersion formulation comprising solid particles comprising a complex of a water-soluble molecule and one or more emulsifiers and an oil base, wherein the one or more emulsifiers comprise a glyceryl fatty acid, and the solid particles are dispersed in the oil base.

2. The dispersion formulation according to claim 1, wherein the fatty acid glyceryl is selected from the group consisting of polyglyceryl fatty acids, polyglyceryl mono fatty acids, polyglyceryl mono fatty acids, and monoglyceryl mono fatty acids.

3. The dispersion preparation according to claim 1 or 2, wherein the fatty acid glyceryl comprises a polyglyceryl having a number average degree of polymerization of 2 to 6.

4. The dispersion formulation according to any one of claims 1 to 3, wherein the one or more emulsifiers further comprise a sugar fatty acid ester.

5. The dispersion formulation according to any one of claims 1 to 4, wherein the sugar fatty acid ester comprises a sucrose fatty acid ester.

6. The dispersion formulation according to any one of claims 1 to 5, wherein the sugar fatty acid ester comprises sucrose erucate.

7. A dispersion formulation according to any one of claims 4 to 6, wherein the one or more emulsifiers comprise 10 to 40 mole % of a sugar fatty acid ester.

8. A dispersion formulation according to any one of claims 1 to 7, wherein the Z-average size of the particles is 500 nm or less.

9. A cosmetic product comprising the dispersion preparation according to any one of claims 1 to 8.

10. A dispersion formulation comprising solid particles comprising water-soluble molecules and one or more emulsifiers and an aqueous base, wherein the solid particles are dispersed in the aqueous base.

11. The dispersion formulation of claim 10, wherein the one or more emulsifiers include a sucrose fatty acid ester.

12. The dispersion formulation of claim 10 or 11, wherein the one or more emulsifiers include sucrose erucate.

13. The dispersion formulation according to any one of claims 10 to 12, wherein the particles have a Z-average size of 200 nm or less.

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