Solid particle dispersion preparation

Abstract

The invention provides a solid particle dispersion preparation. According to the present invention, the solid particle dispersion preparation contains solid particles and an oily base agent, the solid particles containing a water-soluble molecule and a combination of a specific emulsifier and a specific emulsifier, and the solid particles are dispersed in the oily base agent.

Description

Technical Field

[0001] This invention relates to solid particle dispersion formulations. Background Technology

[0002] The stratum corneum, a layer of skin tissue, provides a non-specific physical barrier against invasion by invaders such as bacteria and viruses. However, the presence of this physical barrier also hinders the permeability of substances, making it an obstacle for transdermal drug delivery. In particular, hydrophilic molecules with a molecular weight exceeding 800 are unsuitable for transdermal drug delivery.

[0003] To enable the transdermal absorption of hydrophilic compounds, formulation techniques have been developed that disperse solid complexes of hydrophilic compounds coated with surfactants in an oil phase (Patent Documents 1 and 2).

[0004] Existing technical documents

[0005] Patent documents

[0006] Patent Document 1: WO2006 / 025583

[0007] Patent Document 2: WO2022 / 196748 Summary of the Invention

[0008] This invention provides a solid particle dispersion formulation.

[0009] According to the present invention, the usefulness and effectiveness of dispersion formulations containing particles of a solid complex composed of two specific emulsifiers and a target molecule are clarified.

[0010] According to the present invention, the following invention is provided.

[0011] (1) A dispersion formulation comprising solid particles and an oily base, wherein the solid particles comprise a complex of water-soluble molecules and an emulsifier, wherein the emulsifier comprises fatty acid glycerides, and the solid particles are dispersed in the oily base.

[0012] (2) The dispersing formulation according to (1) above, wherein the fatty acid glycerides are selected from the group consisting of polyglycerol esters of fatty acids, polyglycerol esters of monofatty acids, polyglycerol esters of monofatty acids and monoglycerol esters of monofatty acids.

[0013] (3) The dispersion formulation according to (1) or (2) above, wherein the fatty acid glyceride contains polyglycerol groups with a number-average degree of polymerization of 2 to 6.

[0014] (4) The dispersion formulation according to any one of (1) to (3) above, wherein the emulsifier further contains a nonionic surfactant (e.g., a sugar fatty acid ester).

[0015] (5) The dispersing formulation according to any one of (1) to (4) above, wherein the sugar fatty acid ester is a sucrose fatty acid ester.

[0016] (6) The dispersion formulation according to any one of (1) to (5) above, wherein the sugar fatty acid ester is sucrose erucic acid ester.

[0017] (7) The dispersion formulation according to any one of (4) to (6) above, wherein the emulsifier contains 10 to 40 mol% of sugar fatty acid ester.

[0018] (8) The dispersion formulation according to any one of (1) to (7) above, wherein the Z-average size of the particles is 500 nm or less.

[0019] (9) A cosmetic product containing any one of (1) to (7) above.

[0020] (21) The dispersible formulation according to any one of (1) to (7) above, wherein the fatty acid glycerides contain one or more selected from the group A of fatty acid glycerides: polyglycerol decaoleate, polyglycerol ricinoleate, polyglycerol diisostearate, polyglycerol tetraisostearate, polyglycerol monooleate, polyoxyethylene hydrogenated castor oil, polyglycerol pentaoleate, polyglycerol decaoleate, and glycerol monodecanoate.

[0021] (22) The dispersing formulation according to any one of (1) to (8) above, wherein the fatty acid glycerides contain one or more selected from the group B of fatty acid glycerides: polyglycerol-10 decaoleate, polyglycerol-6 polyricinoleate, polyglycerol-6 polyricinoleate, polyglycerol-2 diisostearate, polyglycerol-2 tetraisostearate, glyceryl monooleate, polyoxyethylene hydrogenated castor oil, polyglycerol-10 pentaoleate, polyglycerol-10 decaoleisostearate and glyceryl monodecanoate.

[0022] (31) The dispersion formulation according to any one of (1) to (8) above, wherein the fatty acid glyceride contains decaole polyglyceride.

[0023] (32) The dispersion formulation according to any one of (1) to (8) above, wherein the fatty acid glyceride contains polyricinoleate polyglycerol.

[0024] (33) The dispersion formulation according to any one of (1) to (8) above, wherein the fatty acid glyceride contains diisostearate polyglycerol ester.

[0025] (34) The dispersion formulation according to any one of (1) to (8) above, wherein the fatty acid glyceride contains tetraisostearate polyglycerol ester.

[0026] (35) The dispersion formulation according to any one of (1) to (8) above, wherein the fatty acid glyceride contains monooleic glyceride.

[0027] (36) The dispersion formulation according to any one of (1) to (8) above, wherein the fatty acid glyceride contains polyoxyethylene hydrogenated castor oil.

[0028] (37) The dispersion formulation according to any one of (1) to (8) above, wherein the fatty acid glyceride contains pentaole polyglycerol ester.

[0029] (38) The dispersion formulation according to any one of (1) to (8) above, wherein the fatty acid glyceride contains decaisostearic acid polyglycerol ester.

[0030] (39) The dispersing formulation according to any one of (1) to (8) above, wherein the fatty acid glyceride contains monodecanoic acid glyceride.

[0031] (41) The dispersion formulation according to (4) above, wherein the fatty acid glycerides contain decaole polyglycerides.

[0032] (42) The dispersion formulation according to (4) above, wherein the fatty acid glycerides contain polyricinoleate polyglycerol ester.

[0033] (43) The dispersion formulation according to (4) above, wherein the fatty acid glycerides contain diisostearate polyglycerol ester.

[0034] (44) The dispersion formulation according to (4) above, wherein the fatty acid glycerides contain tetraisostearate polyglycerol ester.

[0035] (45) The dispersion formulation according to (4) above, wherein the fatty acid glycerides contain monooleic glycerides.

[0036] (46) The dispersion formulation according to (4) above, wherein the fatty acid glyceride contains polyoxyethylene hydrogenated castor oil.

[0037] (47) The dispersion formulation according to (4) above, wherein the fatty acid glycerides contain pentaole polyglycerol ester.

[0038] (48) The dispersion formulation according to (4) above, wherein the fatty acid glycerides contain decaisostearic acid polyglycerol ester.

[0039] (49) The dispersion formulation according to (4) above, wherein the fatty acid glycerides contain monodecanoic acid glycerides.

[0040] (51) The dispersion formulation according to (5) above, wherein the fatty acid glycerides contain decaole polyglycerides.

[0041] (52) The dispersion formulation according to (5) above, wherein the fatty acid glycerides contain polyricinoleate polyglycerol.

[0042] (53) The dispersion formulation according to (5) above, wherein the fatty acid glycerides contain diisostearate polyglycerol ester.

[0043] (54) The dispersion formulation according to (5) above, wherein the fatty acid glycerides contain tetraisostearate polyglycerol ester.

[0044] (55) The dispersion formulation according to (5) above, wherein the fatty acid glycerides contain monooleic glycerides.

[0045] (56) The dispersion formulation according to (5) above, wherein the fatty acid glyceride contains polyoxyethylene hydrogenated castor oil.

[0046] (57) The dispersion formulation according to (5) above, wherein the fatty acid glycerides contain pentaole polyglycerol ester.

[0047] (58) The dispersion formulation according to (5) above, wherein the fatty acid glycerides contain polyglycerol decaisostearate.

[0048] (59) The dispersion formulation according to (5) above, wherein the fatty acid glycerides contain monodecanoic acid glycerides.

[0049] (71) The dispersion formulation according to (6) above, wherein the fatty acid glycerides contain decaole polyglycerides.

[0050] (72) The dispersion formulation according to (6) above, wherein the fatty acid glycerides contain polyricinoleate polyglycerol.

[0051] (73) The dispersion formulation according to (6) above, wherein the fatty acid glycerides contain diisostearate polyglycerol ester.

[0052] (74) The dispersion formulation according to (6) above, wherein the fatty acid glycerides contain tetraisostearate polyglycerol ester.

[0053] (75) The dispersion formulation according to (6) above, wherein the fatty acid glycerides contain monooleic glycerides.

[0054] (76) The dispersion formulation according to (6) above, wherein the fatty acid glyceride contains polyoxyethylene hydrogenated castor oil.

[0055] (77) The dispersion formulation according to (6) above, wherein the fatty acid glycerides contain pentaole polyglycerol ester.

[0056] (78) The dispersion formulation according to (6) above, wherein the fatty acid glycerides contain decaisostearate polyglycerol ester.

[0057] (79) The dispersion formulation according to (6) above, wherein the fatty acid glycerides contain monodecanoic acid glycerides.

[0058] (81) The dispersion formulation according to (7) above, wherein the fatty acid glycerides contain decaole polyglycerides.

[0059] (82) The dispersion formulation according to (7) above, wherein the fatty acid glycerides contain polyricinoleate polyglycerol.

[0060] (83) The dispersion formulation according to (7) above, wherein the fatty acid glycerides contain diisostearate polyglycerol ester.

[0061] (84) The dispersion formulation according to (7) above, wherein the fatty acid glycerides contain tetraisostearate polyglycerol ester.

[0062] (85) The dispersion formulation according to (7) above, wherein the fatty acid glycerides contain monooleic glycerides.

[0063] (86) The dispersion formulation according to (7) above, wherein the fatty acid glyceride contains polyoxyethylene hydrogenated castor oil.

[0064] (87) The dispersion formulation according to (7) above, wherein the fatty acid glycerides contain pentaole polyglycerol ester.

[0065] (88) The dispersion formulation according to (7) above, wherein the fatty acid glycerides contain decaisostearic acid polyglycerol ester.

[0066] (89) The dispersion formulation according to (7) above, wherein the fatty acid glycerides contain monodecanoic acid glycerides.

[0067] (101) A dispersion formulation comprising solid particles and an aqueous base, wherein the solid particles comprise water-soluble molecules and one or more emulsifiers, wherein the solid particles are dispersed in the aqueous base.

[0068] (102) The dispersion formulation according to (101) above, wherein the above one or more emulsifiers contain sucrose fatty acid esters.

[0069] (103) The dispersion formulation according to (101) or (102) above, wherein the above one or more emulsifiers contain sucrose erucic acid ester.

[0070] (104) The dispersion formulation according to any one of (101) to (103) above, wherein the Z-average size of the particles is 300 nm or less, or 200 nm or less.

[0071] (105) The dispersion formulation according to any one of (101) to (104) above, wherein the Z-average size of the particles is 50 nm or more.

[0072] (106) The dispersing formulation according to any one of (101) to (105) above, wherein the water-soluble molecule contains nicotinamide mononucleotide.

[0073] (107) The dispersing formulation according to any one of the above has a dispersibility of more than one month, preferably more than two months, at a temperature of 25°C.

[0074] (108) The dispersion formulation according to (107) above, wherein the emulsifier contains a nonionic surfactant and a fatty acid polyglycerol ester.

[0075] (109) The dispersing formulation according to (108) above, wherein the nonionic surfactant contains a sugar fatty acid ester.

[0076] (110) The dispersion formulation according to (107) above, wherein the number of glycerol polymers of the fatty acid polyglycerol ester is any one of 2 to 6.

[0077] (111) The dispersion formulation according to (108) above, wherein the number of glycerol polymers of the fatty acid polyglycerol ester is any one of 2 to 6.

[0078] (112) The dispersion formulation according to (110) above, wherein the fatty acid polyglycerol ester is selected from one or more of the group consisting of polyglycerol-6 polyricinoleate, polyglycerol-6 polyricinoleate, polyglycerol-10 decaoleate, polyglycerol-10 pentaoleate, polyglycerol-2 diisostearate and polyglycerol-10 decaisostearate.

[0079] (113) The dispersion formulation according to (111) above, wherein the fatty acid polyglycerol ester is selected from one or more of the group consisting of polyglycerol-6 polyricinoleate, polyglycerol-6 polyricinoleate, polyglycerol-10 decaoleate, polyglycerol-10 pentaoleate, polyglycerol-2 diisostearate and polyglycerol-10 decaisostearate.

[0080] (114) The dispersing formulation according to (109) above, wherein the sugar fatty acid ester contains sucrose erucic acid ester.

[0081] (115) The dispersing formulation according to (111) above, wherein the sugar fatty acid ester contains sucrose erucic acid ester.

[0082] (116) The dispersing formulation according to (112) above, wherein the sugar fatty acid ester contains sucrose erucic acid ester.

[0083] (117) The dispersing formulation according to (113) above, wherein the sugar fatty acid ester contains sucrose erucic acid ester.

[0084] (131) A dispersion formulation comprising solid particles and an aqueous base, wherein the solid particles comprise water-soluble molecules and one or more (preferably two or more) emulsifiers, wherein the solid particles are dispersed in the aqueous base.

[0085] (132) The dispersing formulation according to (131) above, wherein the above one or more emulsifiers contain sucrose fatty acid esters.

[0086] (133) The dispersion formulation according to (131) or (132) above, wherein the above one or more emulsifiers contain sucrose erucic acid ester.

[0087] (134) The dispersion formulation according to any one of (131) to (133) above, wherein the Z-average size of the particles is 200 nm or less.

[0088] (135) The dispersion formulation according to any one of (131) to (134) above, wherein the emulsifier contains two or more emulsifiers.

[0089] (136) The dispersion formulation according to any one of (131) to (135) above, wherein the emulsifier contains fatty acid polyglycerol ester.

[0090] (137) The dispersion formulation according to (136) above, wherein the fatty acid polyglycerol ester contains polyricinoleate polyglycerol ester.

[0091] (138) The dispersion formulation according to any one of (131) to (137) above, wherein the emulsifier contains sucrose fatty acid ester and fatty acid polyglycerol ester.

[0092] (139) The dispersant formulation according to any one of (131) to (138) above, wherein the water-soluble molecule contains nicotinamide mononucleotide (NMN).

[0093] According to the present invention, the following invention is provided.

[0094] (1001) A dispersion formulation comprising solid particles and an oily base agent, wherein the solid particles comprise a complex of water-soluble molecules and two or more emulsifiers, wherein the two or more emulsifiers comprise a polyglycerol ester of fatty acid with a number-average degree of polymerization of 2 to 6 having an HLB value of 5 or less and a sucrose fatty acid ester having an HLB value of 5 or less, wherein the solid particles have a Z-average particle size of 100 nm or more and 500 nm or less, wherein the solid particles are dispersed in the oily base agent, and wherein the polyglycerol ester of fatty acid with a number-average degree of polymerization of 2 to 6 and the sucrose fatty acid ester are contained in a ratio that maintains dispersibility for 2 months at a temperature of 25°C while remaining transparent or translucent.

[0095] (1002) The dispersing formulation according to (1001) above, wherein the fatty acid glyceride is polyricinoleate polyglycerol.

[0096] (1003) The dispersing formulation according to (1001) above, wherein the sugar fatty acid ester contains sucrose erucic acid ester.

[0097] (1004) The dispersing formulation according to (1002) above, wherein the sugar fatty acid ester contains sucrose erucic acid ester.

[0098] (1005) A cosmetic product containing any one of the dispersive formulations described in (1001) to (1004) above.

[0099] (1101) A dispersion formulation comprising solid particles and an oily base, said solid particles comprising a complex of water-soluble molecules and two or more emulsifiers.

[0100] (1102) According to the dispersion formulation described in (1101) above, wherein the two or more emulsifiers described above each have an HLB value of 5 or less, preferably 4 or less.

[0101] (1103) The dispersing formulation according to (1101) above, wherein the two or more emulsifiers mentioned above contain at least polyglycerol esters of fatty acids.

[0102] (1104) The dispersing formulation according to (1101) above, wherein the two or more emulsifiers mentioned above contain at least sucrose fatty acid esters.

[0103] (1105) The dispersing formulation according to (1101) above, wherein the two or more emulsifiers mentioned above contain polyglycerol esters of fatty acids and sucrose fatty acid esters.

[0104] (1106) The dispersion formulation according to (1101) above, wherein the two or more emulsifiers mentioned above contain at least a polyglycerol ester of fatty acid with a number-average degree of polymerization of 2 to 6 having an HLB value of 5 or less.

[0105] (1107) The dispersing formulation according to (1101) above, wherein the two or more emulsifiers mentioned above contain at least a sucrose fatty acid ester having an HLB value of 5 or less.

[0106] (1108) The dispersion formulation according to (1101) above, wherein the two or more emulsifiers contain polyglycerol esters of fatty acids having an HLB value of 5 or less and a number-average degree of polymerization of 2 to 6 and sucrose fatty acid esters having an HLB value of 5 or less.

[0107] (1109) The dispersion formulation according to (1101) above, wherein the two or more emulsifiers mentioned above contain at least sucrose erucic acid ester.

[0108] (1110) The dispersion formulation according to (1101) above, wherein the two or more emulsifiers mentioned above contain at least sucrose erucic acid ester having an HLB value of 5 or less.

[0109] (1111) The dispersing formulation according to (1101) above, wherein the two or more emulsifiers mentioned above contain at least polyglycerol ricinoleate.

[0110] (1112) The dispersing formulation according to (1109) above, wherein the two or more emulsifiers mentioned above contain at least polyglycerol ricinoleate.

[0111] (1113) The dispersing formulation according to (1110) above, wherein the two or more emulsifiers mentioned above contain at least polyglycerol ricinoleate.

[0112] (1114) The dispersion formulation according to (1101) above, wherein the two or more emulsifiers mentioned above contain at least polyglycerol ricinoleate having an HLB value of 5 or less.

[0113] (1115) The dispersion formulation according to (1109) above, wherein the two or more emulsifiers mentioned above contain at least polyglycerol ricinoleate having an HLB value of 5 or less.

[0114] (1116) The dispersion formulation according to (1110) above, wherein the two or more emulsifiers mentioned above contain at least polyglycerol ricinoleate having an HLB value of 5 or less.

[0115] (1117) The dispersion formulation according to any one of the above claims, wherein the two or more emulsifiers each have an aliphatic chain with 18 to 22 carbon atoms.

[0116] (1118) The dispersion formulation according to any one of the above claims, wherein the two or more emulsifiers mentioned above contain fatty acid glycerides, the fatty acid glycerides having fatty acid chains with 18 to 22 carbon atoms.

[0117] (1119) The dispersion formulation according to any one of the above claims, wherein the two or more emulsifiers mentioned above contain fatty acid esters, the fatty acid esters having fatty acid chains with 18 to 22 carbon atoms. Attached Figure Description

[0118] Figure 1A The graph shows the degree of penetration of solid particle dispersions made using ER290 and the described emulsifier into the stratum corneum. The fractions in the graph represent the ER290 / emulsifier ratio.

[0119] Figure 1B Same as above.

[0120] Figure 2A This figure shows the extent to which solid particle dispersions made using ER290 and the described emulsifier penetrate into the layers beneath the stratum corneum. The fractions in the figure represent the ER290 / emulsifier ratio.

[0121] Figure 2B Same as above.

[0122] Figure 3 The appearance of the solid particle dispersions of Examples 2-1 and 2-2 is shown.

[0123] Figure 4 The particle size distribution of the particles in the solid particle dispersions of Examples 2-1 and 2-2 is shown.

[0124] Figure 5 The solid particle dispersion formulations of Examples 2-1 and 2-2 are shown to penetrate the skin.

[0125] Figure 6 The particle size distribution of the particles in the solid particle dispersion aqueous formulation of Example 3 is shown.

[0126] Figure 7 This illustrates the penetration of the solid particle dispersion aqueous formulation of Example 3 into the stratum corneum and the layers beneath it. Detailed Implementation

[0127] Embodiments of the present invention will be described with reference to the accompanying drawings. It should be noted that the present invention is not limited to the following embodiments and drawings. It should also be noted that in the following embodiments, expressions such as "having," "comprising," or "containing" also include the meaning of "composed of" or "constituting from." The singular form refers to either the singular or the plural.

[0128] In this specification, "object" refers to mammals including humans, preferably humans. Examples of mammals include, for example, humans, chimpanzees and other primates; dogs, cats, rabbits, horses, sheep, goats, cattle, pigs, rats (including nude rats), mice (including nude mice and SCID mice), guinea pigs, and other livestock, pet animals, and laboratory animals, etc., but are not limited to these.

[0129] In this specification, "surfactant" refers to a molecule that has 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, ionic surfactants may have either a cationic or anionic moiety and a hydrophobic portion. Cationic surfactants may contain a cationic moiety and an aliphatic chain (e.g., a long-chain aliphatic chain) such as an alkyl, alkenyl, or alkynyl group. Anionic surfactants may contain an anionic moiety and fatty acids such as long-chain fatty acids, unsaturated fatty acids (e.g., monovalent or divalent), or long-chain unsaturated fatty acids (e.g., monovalent or divalent). "Long-chain" is a term used for compounds with 14 to 22 carbon atoms. Aliphatic chains can be aliphatic chains with 8 to 22 carbon atoms, i.e., C8 to C96. 22 Alkyl, C8-C 22 alkenyl or C8~C 22 Alkyne group and other C8-C 22 Fatty acid chains. Furthermore, fatty acid chains can be long-chain fatty acid chains. Saturation refers to a fatty acid chain that does not have double or triple bonds, while unsaturation refers to a fatty acid chain that has at least one double or triple bond. Examples of fatty acid chains with double bonds include cis-type and trans-type; from the viewpoint of biological compliance, the cis-type is preferred. Nonionic surfactants are surfactants that do not have ionic groups within the molecule, possessing a nonionic hydrophilic portion and a hydrophobic portion. The hydrophobic portion may contain fatty acid chains such as alkyl, alkenyl, or alkynyl groups (e.g., long-chain fatty acid chains). Fatty acid chains and long-chain fatty acid chains are as specified above.

[0130] As nonionic surfactants, ester compounds derived from fatty acids such as erucic acid and oleic acid (e.g., saturated or unsaturated fatty acids) are preferred. Examples of lipophilic nonionic surfactants include sugar fatty acid esters with high esterification (i.e., a high proportion of diesters, triesters, and polyesters relative to monoesters), preferably sucrose fatty acid esters (sucrose stearate, sucrose palmitate, sucrose myristate, sucrose oleate, sucrose laurate, sucrose erucic acid, and mixed sucrose fatty acid esters), polyglycerol condensed castor oil esters, decaglycerides, glycerol fatty acid esters, polyglycerol fatty acid esters, polyoxyethylene glycerol fatty acid esters, sorbitan fatty acid esters, polyoxyethylene sorbitol fatty acid esters, and polyoxyethylene castor oil / hydrogenated castor oil. Sucrose laurate is a preferred nonionic surfactant. A single surfactant or a mixture of two or more surfactants can be used. Preferred examples of surfactants used to prepare the complex are nonionic surfactants with an HLB (Hydrophile-Lipophile Balance) value of 10 or less that are lipophilic (hydrophobic). The HLB value of each nonionic surfactant can 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 value of the nonionic surfactant is preferably 8 or less, more preferably 5 or less, further preferably 4 or less, and particularly preferably 3 or less.

[0131] As cationic surfactants (cationic lipids), they are described in U.S. Patent Application Publications Nos. 2006 / 0083780 and 2006 / 0240554, U.S. Patents Nos. 5208036, 5264618, 5279833, 5283185, 5753613 and 5785992, and PCT Publication No. WO96 / 10390, which are incorporated herein by reference in their entirety for all purposes. As cationic lipids, they are 1,2-dilinoleoyloxy-N,N-dimethylaminopropane (DLinDMA), 1,2-dilinoleoyloxy-N,N-dimethylaminopropane (DLenDMA), 2,2-dilinoleoyl-4-(2-dimethylaminoethyl)-[1,3]-dioxolane (DLin-K-C2-DMA; "XTC2"), and 2,2-dilinoleoyl-4-(3-dimethylaminopropyl)-[1,3]-dioxolane ( DLin-K-C3-DMA), 2,2-dilinoleoyl-4-(4-dimethylaminobutyl)-[1,3]-dioxolane (DLin-K-C4-DMA), 2,2-dilinoleoyl-5-dimethylaminomethyl-[1,3]-dioxane (DLin-K6-DMA), 2,2-dilinoleoyl-4-N-methylpiperazinyl (methylpepiazino)-[1,3]-dioxolane (DLin-K-M PZ), 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-dilinoleoylthio-3-dimethylaminopropane (DLin-S-DMA), 1-linolenoyl-2-linoleoyloxy-3-dimethylaminopropane (DLin-2-DMAP), 1,2-dilinoleoyloxy-3-trimethylaminopropane hydrochloride (DLin-TMA.Cl), 1,2-dilinoleoyl-3-trimethylaminopropane hydrochloride (DLin-TAP).Cl), 1,2-dilinoleoyloxy-3-(N-methylpiperazinyl)propane (DLin-MPZ), 3-(N,N-dilinoleoylamino)-1,2-propanediol (DLinAP), 3-(N,N-dioleoylamino)-1,2-propanediol (propanedio) (DOAP), 1,2-dilinoleoyloxy-3-(2-N,N-dimethylamino)ethoxypropane (DLin-EG-DMA), N,N-dioleoyl-N,N-dimethylammonium chloride (DODAC), 1,2-dioleoyl... Oxy-N,N-dimethylaminopropane (DODMA), 1,2-distearyloxy-N,N-dimethylaminopropane (DSDMA), N-(1-(2,3-dioleoyloxy)propyl)-N,N,N-trimethylammonium 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 (D C-Chol), N-(1,2-dimyristoyloxypropyl-3-yl)-N,N-dimethyl-N-hydroxyethylammonium bromide (DMRIE), 2,3-dioleoyloxy-N-[2(spermine-formamide)ethyl]-N,N-dimethyl-1-propanetrifluoroacetate ammonium (DOSPA), bis(octadecylamide-glycyl)spermine (DOGS), 3-dimethylamino-2-(cholest-5-en-3-β-oxybutane-4-oxy)-1-(cis,cis-9,12-octadecadienoxy)propane (CLinDMA), 2 -[5'-(cholest-5-en-3-β-oxy)-3'-oxaproloxy)-3-dimethyl-1-(cis,cis-9',1-2'-octadecadienoxy)propane (CpLinDMA), N,N-dimethyl-3,4-dioleoyloxybenzylamine (DMOBA), 1,2-N,N'-dioleoylcarbamoyl-3-dimethylaminopropane (DOcarbDAP), 1,2-N,N'-dilinoleoylcarbamoyl-3-dimethylaminopropane (DLincarbDAP), or mixtures thereof. In a preferred embodiment, the cationic lipid is DLinDMA, DLin-K-C2-DMA (“XTC2”), or mixtures thereof. 1,2-Dimyristoyl-sn-glycerol-3-ethylphosphatidylcholine (EDMPC) is also preferably listed as a cationic lipid.

[0132] Phospholipids and fatty acids can be examples of anionic surfactants (anionic lipids). Examples of anionic surfactants include phosphatidylglycerol, cardiolipin, diacylphosphatidylserine, diacylphosphatidic acid, N-dodecanoylphosphatidylethanolamine, N-succinylphosphatidylethanolamine, N-glutarylphosphatidylethanolamine, lysylphosphatidylglycerol, palmitoylphosphatidylglycerol (POPG), and other anionic surfactants formed by combining anionic modifying groups with neutral lipids.

[0133] In this specification, "solid complex" refers to a complex composed of solid components. In this specification, particle-shaped solid complexes are sometimes referred to as solid particles. Solid complexes may contain water, but are complexes containing solid components. Solid complexes may have low water content; for example, in determinations using known methods, the water content may be less than 1% by mass, less than 0.9% by mass, less than 0.8% by mass, less than 0.7% by mass, less than 0.6% by mass, less than 0.5% by mass, less than 0.4% by mass, less than 0.3% by mass, less than 0.2% by mass, or less than 0.1% by mass. Solid complexes containing water-soluble molecules and surfactants may have a core-shell structure, with the core containing water-soluble molecules and the shell containing surfactants, wherein the surfactants can be arranged such that the water-soluble portion faces the core and the hydrophobic portion faces the outer surface of the solid complex. Therefore, the resulting complex or solid complex may have a hydrophilic central portion (core) but a hydrophobic outer surface (peripheral portion or shell). Such solid complexes are preferably dispersed in an oil phase. However, in this invention, such a solid complex may not be dispersed in an oil phase (or liquid). Because an oil phase is not used, the skin is prevented from becoming overly oily. Additionally, because an oil phase is not used, the application of the patch is sometimes easier.

[0134] (Dispersible formulation)

[0135] According to the present invention, a dispersion formulation is provided, comprising solid particles and an oily base, wherein the solid particles comprise a complex of water-soluble molecules and an emulsifier. In the dispersion formulation, the solid particles are dispersed in the oily base.

[0136] According to the present invention, a dispersion formulation is provided, comprising solid particles and an aqueous base, wherein the solid particles comprise a complex of water-soluble molecules and an emulsifier. In the dispersion formulation, the solid particles are dispersed in the aqueous base.

[0137] In one preferred embodiment, the emulsifier contains one or more emulsifiers. In another preferred embodiment, the emulsifier contains two or more emulsifiers.

[0138] In a preferred embodiment, the emulsifier contains a fatty acid chain having 18 to 22 carbon atoms as the emulsifier of the fatty acid chain. In another preferred embodiment, two or more emulsifiers each contain a fatty acid chain having 18 to 22 carbon atoms as the emulsifier of the fatty acid chain. If two or more emulsifiers contain two fatty acid chains having 18 to 22 carbon atoms as the emulsifier of the fatty acid chain, they may also contain any additional emulsifiers.

[0139] In a preferred embodiment, the emulsifier preferably contains a sugar fatty acid ester. In a preferred embodiment, the sugar fatty acid ester is a sucrose fatty acid ester, more preferably a sucrose erucic acid ester.

[0140] In a preferred embodiment, the emulsifier contains fatty acid glycerides. The fatty acid glycerides are selected, for example, from the group consisting of polyglycerol esters, monoglycerol esters, polymonoglycerol esters, and monoglycerol esters.

[0141] In a preferred embodiment, the fatty acid glyceride has polyglycerol groups with a degree of polymerization of 2 to 10. In another preferred embodiment, the fatty acid glyceride has polyglycerol groups with a degree of polymerization of 2 to 8, or 2 to 6, 2 to 4, 3 to 5, or 4 to 6.

[0142] In a preferred embodiment, the fatty acid glycerides are not particularly limited, and examples of fatty acid glycerides in group A include: polyglycerol decaoleate, polyglycerol ricinoleate, polyglycerol diisostearate, polyglycerol tetraisostearate, glycerol monooleate, polyoxyethylene hydrogenated castor oil, polyglycerol pentaoleate, polyglycerol decaoleate, and glycerol monodecanoate. In another preferred embodiment, the fatty acid glycerides are not particularly limited, and examples of fatty acid glycerides in group B include: polyglycerol-10 decaoleate, polyglycerol-6 polyricinoleate, polyglycerol-6 polyricinoleate, polyglycerol-2 diisostearate, polyglycerol-2 tetraisostearate, glycerol monooleate, polyoxyethylene hydrogenated castor oil, polyglycerol-10 pentaoleate, polyglycerol-10 decaoleate, and glycerol monodecanoate.

[0143] In a preferred embodiment, the emulsifier contains sugar fatty acid esters and fatty acid glycerides.

[0144] In a preferred embodiment, the emulsifier contains sucrose erucic acid ester and fatty acid glycerides. In a preferred embodiment, the fatty acid glycerides are selected from the group consisting of polyglycerol esters, monoglycerol esters, polymonoglycerol esters, and monomonoglycerol esters. In a preferred embodiment, the fatty acid glycerides are not particularly limited, and may be, for example, one or more selected from group A of fatty acid glycerides. In a preferred embodiment, the fatty acid glycerides are not particularly limited, and may be, for example, one or more selected from group B of fatty acid glycerides.

[0145] In a preferred embodiment, the emulsifier comprises sucrose erucic acid ester and polyglycerol-10 decaoleate. The molar ratio of sucrose erucic acid ester to polyglycerol-10 decaoleate can be, for example, 5:95–95:5, 10:90–90:10, 15:85–85:15, 20:80–80:20, 25:75–75:25, 30:70–70:30, 35:65–65:35, or 40:60–60:40. The ratio of sucrose erucic acid ester to polyglycerol-10 decaoleate can be, for example, 5:95–75:25, 10:90–65:35, 15:85–50:50, 20:80–40:60, 20:80–35:65, or 20:80–30:70. The ratio of sucrose erucic acid ester to polyglycerol-10 decaole ester can be, for example, 25:75-95:5, 35:65-90:10, 50:50-85:15, 60:40-80:20, 65:35-80:20 or 70:30-80:20.

[0146] In a preferred embodiment, the emulsifier comprises sucrose erucic acid ester and polyglycerol-6 polyricinoleate. The ratio of sucrose erucic acid ester to polyglycerol-6 polyricinoleate can be, for example, 5:95–95:5, 10:90–90:10, 15:85–85:15, 20:80–80:20, 25:75–75:25, 30:70–70:30, 35:65–65:35, or 40:60–60:40. The ratio of sucrose erucic acid ester to polyglycerol-6 polyricinoleate can also be, for example, 5:95–75:25, 10:90–65:35, 15:85–50:50, 20:80–40:60, 20:80–35:65, or 20:80–30:70. The ratio of sucrose erucic acid ester to polyglycerol-6 polyricinoleate can be, for example, 25:75-95:5, 35:65-90:10, 50:50-85:15, 60:40-80:20, 65:35-80:20 or 70:30-80:20.

[0147] In a preferred embodiment, the emulsifier comprises sucrose erucic acid ester and polyglycerol-6 polyricinoleate. The ratio of sucrose erucic acid ester to polyglycerol-6 polyricinoleate can be, for example, 5:95–95:5, 10:90–90:10, 15:85–85:15, 20:80–80:20, 25:75–75:25, 30:70–70:30, 35:65–65:35, or 40:60–60:40. The ratio of sucrose erucic acid ester to polyglycerol-6 polyricinoleate can also be, for example, 5:95–75:25, 10:90–65:35, 15:85–50:50, 20:80–40:60, 20:80–35:65, or 20:80–30:70. The ratio of sucrose erucic acid ester to polyglycerol-6 polyricinoleate can be, for example, 25:75-95:5, 35:65-90:10, 50:50-85:15, 60:40-80:20, 65:35-80:20 or 70:30-80:20.

[0148] In a preferred embodiment, the emulsifier comprises sucrose erucic acid ester and polyglycerol-2 diisostearate. The ratio of sucrose erucic acid ester to polyglycerol-2 diisostearate can be, for example, 5:95–95:5, 10:90–90:10, 15:85–85:15, 20:80–80:20, 25:75–75:25, 30:70–70:30, 35:65–65:35, or 40:60–60:40. The ratio of sucrose erucic acid ester to polyglycerol-2 diisostearate can also be, for example, 5:95–75:25, 10:90–65:35, 15:85–50:50, 20:80–40:60, 20:80–35:65, or 20:80–30:70. The ratio of sucrose erucic acid ester to polyglycerol-2 diisostearate can be, for example, 25:75-95:5, 35:65-90:10, 50:50-85:15, 60:40-80:20, 65:35-80:20 or 70:30-80:20.

[0149] In a preferred embodiment, the emulsifier comprises sucrose erucic acid ester and polyglycerol-2 tetraisostearate. The ratio of sucrose erucic acid ester to polyglycerol-2 tetraisostearate can be, for example, 5:95–95:5, 10:90–90:10, 15:85–85:15, 20:80–80:20, 25:75–75:25, 30:70–70:30, 35:65–65:35, or 40:60–60:40. The ratio of sucrose erucic acid ester to polyglycerol-2 tetraisostearate can also be, for example, 5:95–75:25, 10:90–65:35, 15:85–50:50, 20:80–40:60, 20:80–35:65, or 20:80–30:70. The ratio of sucrose erucic acid ester to polyglycerol-2 tetraisostearate can be, for example, 25:75-95:5, 35:65-90:10, 50:50-85:15, 60:40-80:20, 65:35-80:20 or 70:30-80:20.

[0150] In a preferred embodiment, the emulsifier comprises sucrose erucic acid ester and glyceryl monooleate. The ratio of sucrose erucic acid ester to glyceryl monooleate can be, for example, 5:95–95:5, 10:90–90:10, 15:85–85:15, 20:80–80:20, 25:75–75:25, 30:70–70:30, 35:65–65:35, or 40:60–60:40. The ratio of sucrose erucic acid ester to glyceryl monooleate can also be, for example, 5:95–75:25, 10:90–65:35, 15:85–50:50, 20:80–40:60, 20:80–35:65, or 20:80–30:70. The ratio of sucrose erucic acid ester to monooleic glyceride can be, for example, 25:75-95:5, 35:65-90:10, 50:50-85:15, 60:40-80:20, 65:35-80:20 or 70:30-80:20.

[0151] In a preferred embodiment, the emulsifier comprises sucrose erucic acid ester and polyoxyethylene hydrogenated castor oil. The ratio of sucrose erucic acid ester to polyoxyethylene hydrogenated castor oil can be, for example, 5:95–95:5, 10:90–90:10, 15:85–85:15, 20:80–80:20, 25:75–75:25, 30:70–70:30, 35:65–65:35, or 40:60–60:40. The ratio of sucrose erucic acid ester to polyoxyethylene hydrogenated castor oil can also be, for example, 5:95–75:25, 10:90–65:35, 15:85–50:50, 20:80–40:60, 20:80–35:65, or 20:80–30:70. The ratio of sucrose erucic acid ester to polyoxyethylene hydrogenated castor oil can be, for example, 25:75-95:5, 35:65-90:10, 50:50-85:15, 60:40-80:20, 65:35-80:20, or 70:30-80:20.

[0152] In a preferred embodiment, the emulsifier contains sucrose erucic acid ester and polyglycerol-10 pentaoleate. The ratio of sucrose erucic acid ester to polyglycerol-10 pentaoleate can be, for example, 5:95–95:5, 10:90–90:10, 15:85–85:15, 20:80–80:20, 25:75–75:25, 30:70–70:30, 35:65–65:35, or 40:60–60:40. The ratio of sucrose erucic acid ester to polyglycerol-10 pentaoleate can also be, for example, 5:95–75:25, 10:90–65:35, 15:85–50:50, 20:80–40:60, 20:80–35:65, or 20:80–30:70. The ratio of sucrose erucic acid ester to polyglycerol-10 pentaole ester can be, for example, 25:75-95:5, 35:65-90:10, 50:50-85:15, 60:40-80:20, 65:35-80:20 or 70:30-80:20.

[0153] In a preferred embodiment, the emulsifier comprises sucrose erucic acid ester and polyglycerol-10 decaisostearate. The ratio of sucrose erucic acid ester to polyglycerol-10 decaisostearate can be, for example, 5:95–95:5, 10:90–90:10, 15:85–85:15, 20:80–80:20, 25:75–75:25, 30:70–70:30, 35:65–65:35, or 40:60–60:40. The ratio of sucrose erucic acid ester to polyglycerol-10 decaisostearate can also be, for example, 5:95–75:25, 10:90–65:35, 15:85–50:50, 20:80–40:60, 20:80–35:65, or 20:80–30:70. The ratio of sucrose erucic acid ester to polyglycerol-10 decaisostearate can be, for example, 25:75-95:5, 35:65-90:10, 50:50-85:15, 60:40-80:20, 65:35-80:20 or 70:30-80:20.

[0154] In a preferred embodiment, the emulsifier comprises sucrose erucic acid ester and glyceryl monodecanoate. The ratio of sucrose erucic acid ester to glyceryl monodecanoate can be, for example, 5:95–95:5, 10:90–90:10, 15:85–85:15, 20:80–80:20, 25:75–75:25, 30:70–70:30, 35:65–65:35, or 40:60–60:40. The ratio of sucrose erucic acid ester to glyceryl monodecanoate can also be, for example, 5:95–75:25, 10:90–65:35, 15:85–50:50, 20:80–40:60, 20:80–35:65, or 20:80–30:70. The ratio of sucrose erucic acid ester to monodecanoic acid glyceride can be, for example, 25:75-95:5, 35:65-90:10, 50:50-85:15, 60:40-80:20, 65:35-80:20 or 70:30-80:20.

[0155] In this invention, any substance that is liquid at room temperature (e.g., 25°C), substantially insoluble in water, viscous, has a lower specific gravity than water, and is used in the cosmetics and pharmaceutical fields without causing adverse effects upon contact with the skin of animals, including humans, is acceptable; there are no particular limitations. Examples of such oily bases include: cetyl alcohol, myristyl alcohol, oleyl alcohol, lauryl alcohol, cetearyl alcohol, stearyl alcohol, behenyl alcohol, jojoba alcohol, squalene alcohol, squalene alcohol, hexyldecyl alcohol, isostearyl alcohol, 2-octyldodecyl alcohol, and other higher (poly) alcohols; aromatic alcohols and their derivatives such as benzyl alcohol; isostearic acid, behenic acid, undecenoic acid, 12-hydroxystearic acid, palmitoleic acid, oleic acid, linoleic acid, linolenic acid, erucic acid, docosahexaenoic acid, eicosapentaenoic acid, isohexadecanic acid, and transisohexaenoic acid. Long-chain fatty acids and their derivatives, such as alkyl acids, dimer acids, and hydrogenated dimer acids; hydrocarbons such as liquid paraffin (mineral oil), heavy liquid isoparaffins, light liquid isoparaffins, α-olefin oligomers, polyisobutylene, hydrogenated polyisobutylene, polybutene, squalane, squalane from olives, squalene, petrolatum, and solid paraffin; waxes such as candelilla wax, carnauba wax, rice bran wax, wood wax, beeswax, lignite wax, ceresin wax, pure ceresin wax, paraffin wax, microcrystalline wax, petrolatum, Fischer-Tropsch wax, polyethylene wax, and ethylene-propylene copolymer; and coconut oil, palm oil, and palm fiber. Vegetable oils including: sesame oil, safflower oil, olive oil, castor oil, avocado oil, sesame oil, tea oil, evening primrose oil, wheat germ oil, perilla oil, almond oil, almond oil, macadamia nut oil, hazelnut oil, kukui nut oil, rosehip oil, meadowfoam seed oil, peach kernel oil, tea tree oil, peppermint oil, corn oil, rapeseed oil, sunflower oil, wheat germ oil, flaxseed oil, cottonseed oil, soybean oil, peanut oil, rice bran oil, cocoa butter, shea butter, hydrogenated coconut oil, hydrogenated castor oil, jojoba oil, and other vegetable oils; beef tallow, milk fat, horse fat, and egg yolk. Animal fats such as oil, mink oil, and turtle oil; animal waxes such as cetearyl, lanolin, and deep-sea fish oil; lanolins such as liquid lanolin, reduced lanolin, adsorbed refined lanolin, acetylated lanolin, acetylated liquid lanolin, hydroxy lanolin, polyoxyethylene lanolin, lanolin fatty acids, hard lanolin fatty acids, lanolin alcohol, acetylated lanolin alcohol, and acetates (cetyl / lanolinyl) esters; sterols such as cholesterol, dihydrocholesterol, lanosterol, dihydrolanosterol, phytosterols, and bile acids; saponin aglycones; saponins;Cholesterol acetate, cholesterol nonanoate, cholesterol stearate, cholesterol isostearate, cholesterol oleate, di(cholesterol / behenol / octyldodecanol)N-lauroyl-L-glutamate, di(cholesterol / octyldodecanol)N-lauroyl-L-glutamate, di(phytosterol / behenol / octyldodecanol)N-lauroyl-L-glutamate, di(phytosterol / octyldodecanol)N-lauroyl-L-glutamate, cholesterol 12-hydroxystearate, cholesterol australis Nut oil fatty acid esters, phytosterol macadamia oil fatty acid esters, phytosterol isostearate, soft cholesterol lanolin fatty acid esters, hard cholesterol lanolin fatty acid esters, cholesterol long-chain branched fatty acid esters, cholesterol long-chain α-hydroxy fatty acid esters, and other sterol esters; N-lauroyl sarcosine isopropyl esters and other acyl sarcosine alkyl esters; phospholipid-cholesterol complexes, phospholipid-phytosterol complexes, and other lipid complexes; octyl dodecyl myristate, hexyl decyl myristate, octyl dodecyl isostearate. Cetyl palmitate, octyl dodecyl palmitate, cetyl octanoate, hexyl decyl octanoate, isotriacontyl isononanoate, octyl isonononanoate, isotriacontyl isonononanoate, isodecyl neopentanoate, isotriacontyl neopentanoate, isostearyl neopentanoate, octyl dodecyl neodecanoate, oleyl oleate, octyl dodecyl oleate, octyl dodecyl ricinoleate, octyl dodecyl lanolin fatty acid ester, hexyl dodecyl dimethyl octanoate, octyl dodecyl erucic acid ester, hydrogenated castor oil Long-chain fatty acid esters such as sesame oil isostearate, ethyl oleate, avocado oil fatty acid ethyl ester, isopropyl myristate, isopropyl palmitate, octyl palmitate, isopropyl isostearate, and lanolin fatty acid isopropyl ester; dicarboxylic acid esters such as diethyl sebacate, diisopropyl sebacate, dioctyl sebacate, diisopropyl adipate, dibutyl octyl sebacate, diisobutyl adipate, dioctyl succinate, and triethyl citrate; hydroxy acid esters such as cetyl lactate, diisostearyl malate, and hydrogenated castor oil monoisostearate.Tricaprylic acid glyceride (tris(2-ethylhexanoate) glyceride), trioleic acid glyceride, triisostearate glyceride, diisostearate glyceride, tri(caprylic / capric) glyceride, tri(caprylic / capric / myristic / stearic) glyceride, hydrogenated rosin triglyceride (hydrogenated ester gum), rosin triglyceride (ester gum), eicosanoic acid glyceride, trimethylolpropane tricaprylate, trimethylolpropane triisostearate, neopentyl glycol dicaprylate Neopentyl glycol didecanoate, 2-butyl-2-ethyl-1,3-propanediol dioctanoate, propylene glycol dioleate, pentaerythritol tetraoctanoate, hydrogenated rosin pentaerythritol ester, di(trimethylolpropane)triethylhexanoate, di(trimethylolpropane)(isostearic acid / sebacic acid) ester, pentaerythritol triethylhexanoate, dipentaerythritol(hydroxystearic acid / stearic acid / rosin acid) ester, diglycerol diisostearate, polyglycerol tetraisostearate, poly Glyceryl-10 nonaisostearate, polyglycerol-8 deca(erucic acid / isostearate / ricinoleic acid) ester, (hexyldecanoic acid / sebacic acid) diglyceride low polyester, ethylene glycol distearate (ethylene glycol distearate), 3-methyl-1,5-pentanediol dinepentate, 2,4-diethyl-1,5-pentanediol dinepentate and other polyol fatty acid esters; diisopropyl linoleate, diisostearyl diisooleate, di(isostearyl / vegetable) Derivatives of dimer acids or dimer alcohols, such as phytosterol (β-dioleoyl) dimer linoleate, (phytosterol / behenol) dimer linoleate, (phytosterol / isostearyl / cetearyl / stearyl / behenol) dimer linoleate, dimer linoleyl alcohol dimer linoleate, dimer linoleyl alcohol diisostearate, dimer linoleyl alcohol hydrogenated rosin condensate, hydrogenated castor oil dimer linoleate, and hydroxyalkyl dimer linoleyl ether; and 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).Polydimethylsiloxane (dimethyl polysiloxane), highly polymerized polydimethylsiloxane (highly polymerized dimethyl polysiloxane), decamethylcyclopentasiloxane (also simply cyclopentasiloxane) and other cyclic polymethylsiloxanes (cyclic dimethylsiloxanes), phenyl polytrimethylsiloxane, diphenyl polydimethylsiloxane, phenyl polydimethylsiloxane, stearoxypropyl dimethylamine, (aminoethylaminopropyl polymethylsiloxane / polydimethylsiloxane) copolymer, polydimethylsiloxane alcohol, polydimethylsiloxane alcohol crosspolymer, organosilicon resin, organosilicon rubber, aminopropyl polydimethylsiloxane and ammonia-terminated polydimethylsiloxane Organosilicones such as alkyl-modified amino-modified organosilicones, cationic-modified organosilicones, polyether-modified organosilicones such as polydimethylsiloxane copolyols, polyglycerol-modified organosilicones, sugar-modified organosilicones, carboxylic acid-modified organosilicones, phosphoric acid-modified organosilicones, sulfuric acid-modified organosilicones, alkyl-modified organosilicones, fatty acid-modified organosilicones, alkyl ether-modified organosilicones, amino acid-modified organosilicones, peptide-modified organosilicones, fluorine-modified organosilicones, cationic and polyether-modified organosilicones, amino-modified and polyether-modified organosilicones, alkyl-modified and polyether-modified organosilicones, and polysiloxane-oxidized olefin copolymers; and fluorinated oils such as perfluorodecane, perfluorooctane, and perfluoropolyether. The preferred components include long-chain fatty acids such as oleic acid, vegetable oils such as olive oil and jojoba oil, alkyl esters of fatty acids with 12 to 18 carbon atoms such as isopropyl myristate, isopropyl palmitate, octyl palmitate, and isopropyl isostearate, and hydrocarbons such as squalane. Isopropyl myristate and squalane are more preferred. Isopropyl myristate is particularly preferred as an oily base agent.

[0156] As an aqueous base, water or an aqueous solution containing pharmaceutically acceptable additives can be used. Examples of pharmaceutically acceptable additives include pharmaceutically acceptable salts, isotonic agents, pH adjusters, and thickeners. An aqueous solution containing pharmaceutically acceptable additives can be, for example, physiological saline.

[0157] Examples of water-soluble molecules include: hyaluronic acid and its salts, heparin and its similar compounds, chitosan and other polysaccharides; proteins such as ovalbumin, casein, and collagen; vitamin C and its derivatives, retinol and other vitamins; amino acids such as amino acids, tranexamic acid, and placental extracts; 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, immunoglobulins, interleukins, interferon, human glucagon, human growth hormone, erythropoietin, platelet-derived growth factor, and insulin; and peptide preparations such as cancer vaccines and allergy vaccines. Regarding the molecular weight of water-soluble molecules, a molecular weight of 500 Da or more is preferred, 1000 Da (i.e., 1 kDa) or more is preferred, and 200 kDa or less is more preferred, 100 kDa or less is more preferably 50 kDa or less.

[0158] As water-soluble molecules, they can be lipid vesicles, lipid nanoparticles, extracellular vesicles (e.g., exosomes), polyionic complex micelles, polyionic complex polymer vesicles, and other nanoparticles or nanovesicles. Nanoparticles or nanovesicles refer to substances with a submicron Z-average size. When using such nanoparticles or nanovesicles as water-soluble molecules, the manufacturing process of solid particle dispersion formulations can be applied. The nanoparticles or nanovesicles described above can be mixed with an emulsifier in a volatile oil phase (e.g., cyclohexane) to form an emulsion, and the volatile oil phase can be removed by freeze-drying.

[0159] The Z-mean size of the solid particles (polyfacial fatty acids) can be, for example, less than 700 nm, less than 600 nm, less than 500 nm, less than 400 nm, less than 300 nm, or less than 200 nm. The particle size (Z-mean size) of the solid particles can be, for example, greater than 100 nm or greater than 200 nm. The particle size (Z-mean size) of the solid particles can be, for example, 100 nm–600 nm, 100 nm–500 nm, 100 nm–400 nm, 100 nm–300 nm, 100 nm–200 nm, 200 nm–600 nm, 200 nm–500 nm, 200 nm–400 nm, or 200 nm–300 nm. The Z-mean size is specified by ISO 13321. Particles with a diameter less than 2 μm can be determined by dynamic scattering (DLS) using a Zetasizer Nano ZS 90 (Malvern Instr. Ltd.).

[0160] The polydispersity index (PDI) of the solid particles can be, for example, 0.1 to 1. Preferably, the PDI can be 0.1 to 0.5, 0.1 to 0.4, 0.1 to 0.3 or 0.1 to 0.2.

[0161] In a preferred embodiment, even after standing at 25°C under atmospheric conditions for 2 months following preparation, the Z-average particle size of the dispersion of the present invention, as measured using a Zetasizer (e.g., Zetasizer Nano Pro) at 20°C, can still be between 100 nm and 500 nm. Before measuring the Z-particle size, the dispersion of the present invention can also be diluted with an oily base such as cyclohexane (e.g., diluted 100 times).

[0162] In a preferred embodiment, the dispersion of the present invention does not have the precipitation of solid particles during preparation. In a more preferred embodiment, the dispersion of the present invention does not have the precipitation of solid particles during preparation, and the solid particles are dispersed transparently or translucently in the dispersion medium. This dispersibility can be adjusted by the mixing ratio of two or more emulsifiers. Therefore, the dispersion of the present invention preferably contains two or more emulsifiers at a ratio that maintains dispersibility in a transparent or translucent manner.

[0163] The dispersion formulation of the present invention contains two or more emulsifiers, and preferably has improved storage stability. In a preferred embodiment, the dispersion formulation of the present invention does not exhibit the precipitation of solid particles even after standing at 25°C under atmospheric conditions for a certain period of time following preparation. In a more preferred embodiment, the dispersion formulation of the present invention does not exhibit the precipitation of solid particles even after standing at 25°C under atmospheric conditions for a certain period of time following preparation, and the solid particles are dispersed transparently or translucently in the dispersion medium. This dispersibility can be adjusted by the mixing ratio of the two or more emulsifiers. Therefore, the dispersion formulation of the present invention preferably contains two or more emulsifiers at a ratio that maintains dispersibility transparently or translucently for a certain period of time at a temperature of 25°C. The aforementioned certain period of time can 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. Alternatively, the aforementioned certain period of time can be, for example, less than 3 months or less than 2 months. The aforementioned certain period of time can be, for example, about 2 months.

[0164] The dispersion formulation of the present invention contains two or more emulsifiers, and preferably has improved storage stability. In a preferred embodiment, the dispersion formulation of the present invention does not exhibit the precipitation of solid particles even after standing at 25°C under atmospheric conditions for 2 months following preparation. In a more preferred embodiment, the dispersion formulation of the present invention does not exhibit the precipitation of solid particles even after standing at 25°C under atmospheric conditions for 2 months following preparation, and the solid particles are dispersed transparently or translucently in the dispersion medium. This dispersibility can be adjusted by the mixing ratio of the two or more emulsifiers. Therefore, the dispersion formulation of the present invention preferably contains two or more emulsifiers at a ratio that maintains dispersibility transparently or translucently for 2 months at 25°C.

[0165] (Preparation method of dispersible formulation)

[0166] If target molecules such as water-soluble molecules are mixed with an emulsifier in an oil phase (preferably a volatile oil phase, such as cyclohexane), particles with a core-shell structure are formed, containing target molecules such as water-soluble molecules in the core and an emulsifier in the shell. These particles are dispersed in the oil phase. The emulsifier contains one or more emulsifiers. When the oil phase used here is a volatile oil phase (e.g., cyclohexane), the solvent can be easily evaporated and removed by drying (e.g., freeze-drying), thereby obtaining particles with a core-shell structure containing water-soluble molecules in the core and an emulsifier in the shell as solid particles (also called "solid complexes"). By dispersing these solid particles in an oily or aqueous base, solid particle dispersions in oily or aqueous formulations (also simply "solid particle dispersions") can be obtained, respectively. Such solid particle dispersions in oily formulations can penetrate deeply into the stratum corneum (non-hydrophilic), which is difficult for water-soluble molecules to penetrate, and, depending on the situation, penetrate below the stratum corneum, preferably into the bloodstream. According to embodiments, the solid particle dispersion aqueous formulation also has the ability to allow the active ingredient to penetrate under the stratum corneum, preferably into the bloodstream.

[0167] (cosmetic)

[0168] According to the present invention, cosmetics containing the dispersion formulation of the present invention are provided. The cosmetics may be ointments, creams, lotions, sprays, powders, or patches. The cosmetics may contain the dispersion formulation of the present invention and dermatologically acceptable additives (e.g., excipients, carriers, etc.).

[0169] Example

[0170] Example 1: Effect of Emulsifier

[0171] Preparation of solid particle dispersion solutions

[0172] Dissolve 10 mg of fluorescein-labeled hyaluronic acid in 2 mL of MilliQ water. Dissolve 200 mg of each of the emulsifiers listed in Table 1 in 4 mL of cyclohexane. Add the aqueous and organic phases to a glass vial and stir at 26,000 rpm for 2 minutes using a Polytron homogenizer. Flash-freeze the resulting emulsion in liquid nitrogen and freeze-dry for 24 hours.

[0173] The total amount of the dried solids was redispersed in 5 mL of olive oil to prepare a solid particle dispersion.

[0174] [Table 1]

[0175] Determination of particle size distribution

[0176] The solid particle dispersion was diluted 100 times with cyclohexane, and the particle size distribution and Z-mean particle size at 20 °C were determined using Zetasizer Nano Pro.

[0177] Yucatan miniature pig skin penetration test

[0178] Thaw the skin of 4-month-old Yucatan miniature pigs and remove the subcutaneous tissue using a scalpel. Cut into 2cm × 2cm pieces and sandwich the cuticle upwards between the feed and receiver phases in a vertical Franz diffusion cell. Fill the receiver phase with 5 mL of PBS solution (pH 7.4) at 32°C. Administer 100 μL of the solid particle dispersion to the feed phase and incubate at 32°C for 24 hours.

[0179] After 24 hours, the solid particle dispersion of the supply phase was wiped off with Kimwipes wipes, and the outermost two sheets of the stratum corneum were removed by peeling with adhesive tape. The remaining stratum corneum was then peeled off by adhesive tape, and five sheets were immersed in 1 mL of solution (PBS / methanol / acetonitrile = 2 / 1 / 1, v / v) and extracted with shaking at room temperature for 22 hours. The skin outside the stratum corneum was divided into 16 aliquots with a scalpel and extracted with 1 mL of PBS solution with shaking at room temperature for 22 hours.

[0180] The extract was diluted 10 times with PBS solution, and the fluorescence intensity was measured using an ELISA reader to quantify the amount of hyaluronic acid.

[0181] Table 2 shows the composition of the prepared solid particle dispersion. Additionally, Table 3 shows the Z-mean and polydispersity index of the particles in the solid particle dispersion prepared by mixing sucrose fatty acid ester (ER-290) and various emulsifiers. Hyalo-Oligo (trademark) was used as the hyaluronic acid.

[0182] [Table 2]

[0183] [Table 3]

[0184] ※ In the table, the symbol "S" indicates a transparent or translucent dispersion, the symbol "B" indicates precipitation, the symbol "A" indicates no precipitation but turbidity, and the symbol "C" indicates gelation or other adverse conditions. Evaluation is conducted through visual confirmation.

[0185] ※1 is a case where most of the precipitation occurs, and the number of dispersed particles is small, making it impossible to measure the value. However, there are dispersed particles that penetrate the skin.

[0186] In cases where precipitation occurs in transparent dispersions when emulsifiers are used alone, particles with small Z-mean values ​​and low polydispersity indices can also be prepared by mixing two emulsifiers. In many systems, ER-290 containing 25% of the total emulsifier showed the smallest Z-mean value. Furthermore, emulsifiers with particularly high stabilizing effects are those with large head and tail groups, such as polyglycerol-6 polyricinoleate and polyglycerol-2 diisostearate. Emulsifiers with small head and tail groups, such as glyceryl monodecanoate, tend to have low stabilizing effects. On the other hand, if it is a decaglycerol fatty acid ester, the hydrophilicity of the emulsifier increases, thus weakening the effect of stabilizing and dispersing hydrophilic drug solids. The same low stabilizing effect is observed for polyoxyethylene (10) hydrogenated castor oil. This suggests that the highest stabilizing effect is likely to be achieved when the number of polymerization units of the glycerol units in the head group of the emulsifier is in the range of 2-6. It should be noted that in Tables 3 and 4, S is the most preferred, A is preferred after S, B is preferred after A, and C is preferred after B. Furthermore, the presence of precipitation or turbidity does not necessarily mean the absence of dispersion of solid particles in the liquid. Therefore, it should be noted that the presence of precipitation or turbidity does not preclude the penetration of solid particles into the skin. Thus, even samples that have produced turbidity, precipitation, or gelation can still be used for skin penetration applications.

[0187] In addition, long-term dispersibility was evaluated. After preparing the above-mentioned solid particle dispersion formulation, the dispersibility of the formulation after storage at 25°C for 2 months was visually confirmed. The results are shown in Table 4.

[0188] [Table 4]

[0189] ※ In the table, the symbol "S" indicates a transparent or translucent dispersion, the symbol "B" indicates precipitation, and the symbol "A" indicates no precipitation but a cloudy appearance.

[0190] As shown in Table 4, the long-term dispersibility of the formulation is improved in both cases when two emulsifiers are mixed. The mixing ratio of the emulsifiers used to obtain dispersibility or long-term dispersibility can be appropriately adjusted by those skilled in the art.

[0191] Figure 1 shows the amount of drug penetrating into the skin of a solid particle dispersion prepared by mixing sucrose fatty acid ester (ER-290) with various emulsifiers when administered to the skin of a miniature pig. The Z-mean value is related to the permeability to the stratum corneum, indicating that formulations with a low Z-mean value penetrate the layer below the stratum corneum. Furthermore, the permeability to the hydrophilic regions of the skin below the stratum corneum is also high (Figure 2). The stratum corneum is a state in which keratinized cells filled with keratin are spread across a hydrophobic region composed of a ceramide bilayer, much like bricks and mortar. Therefore, it is believed that small particles can more stably permeate between keratinocytes within the highly hydrophobic stratum corneum.

[0192] Example 2: Solid particle dispersion of extracellular vesicles

[0193] ER-290 was obtained from Mitsubishi Chemical Corporation, and SY Glyster CRS-75 and S Face IS-202P were obtained from Sakamoto Pharmaceutical Co., Ltd. Milk exosomes (Cosmo Bio) were stained with a CoraLite594-labeled CD9 antibody (Proteintech Japan), and unreacted antibodies were removed using a PURE-EV column (HansaBioMed).

[0194] The obtained exosomes were mixed in cyclohexane with a mixture of ER290 and CRS-75 or a mixture of ER290 and 202P. This process is believed to form core-shell structured particles containing exosomes in the core and an emulsifier in the shell. Cyclohexane was removed by freeze-drying to obtain core-shell structured solid complex particles. These solid complex particles were then dispersed in an IPM to prepare a solid particle dispersion of exosomes.

[0195] The mixing amounts of each component used to prepare the solid particle dispersion formulation are shown in Table 5.

[0196] [Table 5]

[0197] The appearance of the resulting dispersion is as follows Figure 3 As shown, a transparent dispersion was obtained. The particle size distribution of the obtained dispersion at 25°C was determined using ZetasizerPro. The results are as follows. Figure 4 As shown in Table 6, a formulation with smaller particles below 500 nm was obtained.

[0198] [Table 6]

[0199] The obtained exosome-containing solid particle dispersion was applied to the skin of miniature pigs to confirm its permeability. Yucatan miniature pig skin (4 months old) was thawed, and subcutaneous tissue was removed using a scalpel. The skin was cut into 2cm × 2cm pieces and sandwiched between the donor and receiver phases in a vertical Franz diffusion cell, with the stratum corneum facing upwards. The receiver phase was filled with 5 mL of PBS solution (pH 7.4) at 32°C. 100 μL of the dispersion from 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 in the donor phase was wiped off with Kimwipes wipes, and the outermost two layers of the stratum corneum were peeled off using adhesive tape. The remaining skin was frozen to prepare 8 μm frozen sections. The skin tissue sections were sealed with ProLong Glass Antifade Mountant with NucBlu Stain (ThermoFisher Scientific) and observed using a fluorescence microscope. Results are as follows: Figure 5 As shown. Figure 5 As shown, the penetration of exosomes into the epidermis was confirmed through dispersion formulation.

[0200] Example 3: Aqueous Dispersion

[0201] Dissolve 4 mg of nicotinamide mononucleotide (NMN) in 2 mL of MilliQ water. Dissolve 19 mg of ER-290 and 57 mg of SY Glyster CRS-75 in 4 mL of cyclohexane. Add the aqueous and organic phases to a glass vial and stir at 26,000 rpm for 2 minutes using a Polytron homogenizer to form an emulsion. Flash-freeze the resulting emulsion in liquid nitrogen and freeze-dry for 24 hours.

[0202] The 20 mg dried liquid was dispersed in 1 mL of cyclohexane. 60 mg of Nikkol BL-25 (Nikkol Chemicals) was dissolved in 3 mL of water. 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 for 24 hours for freeze-drying. The freeze-dried liquid was dispersed in 1 mL of water to prepare a dispersion of solid particles in water (solid particle dispersion aqueous solution) (final NMN concentration: 1 mg / mL).

[0203] Determination of particle size distribution

[0204] The resulting dispersion was diluted 100-fold with water, and the particle size distribution at 25°C was determined using Zetasizer Pro. The results are as follows: Figure 6 As shown in Table 7. Figure 6 As shown in Table 7, by applying the technology of the present invention to NMN, solid particles were successfully formed and dispersed in an aqueous solution. The resulting particles have a submicron particle size distribution.

[0205] [Table 7]

[0206] Yucatan miniature pig skin penetration test

[0207] Yucatan miniature pig skin (4 months old) was thawed, and subcutaneous tissue was removed using a scalpel. The skin was cut into 2cm × 2cm pieces and sandwiched, cuticle side up, between the donor and receiver phases in a vertical Franz diffusion cell. The receiver 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. As a control, a 1 mg / mL NMN aqueous solution was used.

[0208] After 24 hours, the dispersion of the supplied phase was wiped off with Kimwipes paper, and the outermost two layers of the stratum corneum were removed by tape peeling. The remaining stratum corneum was peeled off by tape peeling 20 times and immersed in 5 mL of solution (PBS / methanol / acetonitrile = 2 / 1 / 1, v / v) and extracted with shaking at room temperature for 22 hours. The skin outside the stratum corneum was divided into 16 aliquots with a scalpel and extracted with 1 mL of PBS solution with shaking at room temperature for 22 hours.

[0209] The nuclear extract was diluted 10 times with diluent (0.1% formic acid / acetonitrile = 50 / 50, v / v), and the amount of NMN in the extract was quantified using LC-MS.

[0210] like Figure 7 As shown, solid particles dispersed in an aqueous solution can allow a large amount of NMN to penetrate into the layer beneath the stratum corneum of the skin.

Claims

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

2. The dispersing formulation according to claim 1, wherein, Fatty acid glycerides are selected from the group consisting of polyglycerol esters of fatty acids, polyglycerol esters of monofatty acids, polyglycerol esters of monofatty acids, and monoglycerol esters of monofatty acids.

3. The dispersion formulation according to claim 1 or 2, wherein, Fatty acid glycerides contain polyglycerol groups with a number-average degree of polymerization of 2 to 6.

4. The dispersing formulation according to any one of claims 1 to 3, wherein, The one or more emulsifiers mentioned above also contain sugar fatty acid esters.

5. The dispersing formulation according to any one of claims 1 to 4, wherein, Sugar fatty acid esters include sucrose fatty acid esters.

6. The dispersing formulation according to any one of claims 1 to 5, wherein, Sugar fatty acid esters contain sucrose erucic acid esters.

7. The dispersing formulation according to any one of claims 4 to 6, wherein, The one or more emulsifiers contain 10 to 40 mol% of sugar fatty acid esters.

8. The dispersing formulation according to any one of claims 1 to 7, wherein, The average Z-size of the particles is less than 500 nm.

9. A cosmetic product comprising any one of claims 1 to 8.

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

11. The dispersion formulation according to claim 10, wherein, The one or more emulsifiers mentioned above contain sucrose fatty acid esters.

12. The dispersion formulation according to claim 10 or 11, wherein, The one or more emulsifiers mentioned above contain sucrose erucic acid esters.

13. The dispersing formulation according to any one of claims 10 to 12, wherein, The average Z-size of the particles is less than 200 nm.

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