Solid particle dispersion formulation

Abstract

To provide a solid particle dispersion formulation with enhanced transdermal absorption. [Solution] A dispersion formulation comprising solid particles containing a complex of a water-soluble molecule and one or more emulsifiers, and an oily base or an aqueous base, wherein the emulsifier contains fatty acid glyceryl or sugar fatty acid ester, and the solid particles are dispersed in the oily base or aqueous base.

Description

TECHNICAL FIELD

[0001] The present disclosure relates to a solid particle dispersion formulation. BACKGROUND ART

[0002] Skin tissue has a stratum corneum, which provides a physical barrier that non-specifically prevents invasion by intruders such as bacteria and viruses. Due to the presence of the aforementioned physical barrier, the stratum corneum has poor substance permeability, and acts as an obstacle for transdermal administration of drugs. In particular, hydrophilic molecules with a molecular weight exceeding 800 are not suitable for transdermal administration.

[0003] For the transdermal absorption of hydrophilic compounds, formulation techniques have 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). PRIOR ART DOCUMENTS PATENT DOCUMENTS

[0004] PATENT DOCUMENT 1 WO2006 / 025583 PATENT DOCUMENT 2 WO2022 / 196748 SUMMARY OF THE INVENTION

[0005] The present disclosure provides a solid particle dispersion formulation.

[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 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 solid particles containing a complex of a water-soluble molecule and an emulsifier, and an oily base, wherein the emulsifier comprises glyceryl fatty acid, 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 polyfatty acids, polyglyceryl monofatty acids, polyglyceryl monofatty acids, and monoglyceryl monofatty acids. (3) The dispersion formulation according to (1) or (2) above, wherein the fatty acid glyceryl contains polyglyceryl having a number average degree of polymerization of 2 to 6. (4) The dispersion formulation according to any one of (1) to (3) above, wherein the emulsifier further comprises a nonionic surfactant (e.g., sugar fatty acid ester). (5) A dispersion formulation according to any of (1) to (4) above, wherein the sugar fatty acid ester is a sucrose fatty acid ester. (6) A dispersion formulation according to any of (1) to (5) above, wherein the sugar fatty acid ester is sucrose erucate ester. (7) A dispersion formulation according to any one of (4) to (6) above, wherein the emulsifier contains 10 to 40 mol% of a sugar fatty acid ester. (8) A dispersion formulation according to any of (1) to (7) above, wherein the Z-average size of the particles is 500 nm or less. (9) Cosmetics comprising any of the dispersion formulations described in (1) to (8) above.

[0008] (21) A dispersion formulation according to any one of (1) to (8) above, 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) A dispersion formulation according to any one of (1) to (8) above, 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) A dispersion formulation according to any one of (1) to (7) above, wherein the fatty acid glyceryl contains polyglyceryl decaoleate. (32) A dispersion formulation according to any one of (1) to (7) above, wherein the fatty acid glyceryl contains polyglyceryl polyricinoleate. (33) A dispersion formulation according to any one of (1) to (7) above, wherein the fatty acid glyceryl contains polyglyceryl diisostearate. (34) A dispersion formulation according to any one of (1) to (7) above, wherein the fatty acid glyceryl contains polyglyceryl tetraisostearate. (35) A dispersion formulation according to any one of (1) to (7) above, wherein the fatty acid glyceryl contains glyceryl monooleate. (36) A dispersion formulation according to any one of (1) to (7) above, wherein the fatty acid glyceryl contains polyoxyethylene hydrogenated castor oil. (37) A dispersion formulation according to any one of (1) to (7) above, wherein the fatty acid glyceryl contains polyglyceryl pentaoleate. (38) A dispersion formulation according to any one of (1) to (7) above, wherein the fatty acid glyceryl contains polyglyceryl decaisostearate. (39) A dispersion formulation according to any one of (1) to (7) above, wherein the fatty acid glyceryl contains monocaprate glyceryl.

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

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

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

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

[0014] (101) A dispersion formulation comprising solid particles containing a water-soluble molecule and one or more emulsifiers and an aqueous base, wherein the solid particles are dispersed in the aqueous base. (102) The dispersion formulation according to (101) above, wherein one or more emulsifiers contain a sucrose fatty acid ester. (103) The dispersion formulation according to (101) or (102) above, comprising one or more emulsifiers, wherein the dispersion formulation comprises sucrose erucate ester. (104) A dispersion formulation according to any of (101) to (103) above, wherein the Z-average size of the particles is 300 nm or less, or 200 nm or less. (105) A dispersion formulation according to any of (101) to (104) above, wherein the Z-average size of the particles is 50 nm or more. (106) A dispersion formulation according to any one of (101) to (105) above, wherein the water-soluble molecule contains nicotinamide mononucleotide. (107) A dispersion formulation according to any of the above, which exhibits dispersibility for one month or more, preferably two months or more, under a temperature condition of 25°C. (108) The dispersion formulation according to (107) above, wherein the emulsifier comprises a nonionic surfactant and a fatty acid polyglyceryl. (109) The dispersion formulation according to (108) above, wherein the nonionic surfactant contains a sugar fatty acid ester. (110) The dispersion formulation according to (107) above, wherein the number of glycerol polymerization units of the fatty acid polyglyceryl is any of 2 to 6. (111) The dispersion formulation according to (108) above, wherein the number of glycerol polymerization units of the fatty acid polyglyceryl is any 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 contains sucrose erucate ester. (115) The dispersion formulation according to (111) above, wherein the sugar fatty acid ester contains sucrose erucate ester. (116) The dispersion formulation according to (112) above, wherein the sugar fatty acid ester contains sucrose erucate ester. (117) The dispersion formulation according to (113) above, wherein the sugar fatty acid ester contains sucrose erucate ester.

[0015] (131) A dispersion formulation comprising solid particles containing a water-soluble molecule 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 formulation according to (131) above, wherein one or more emulsifiers contain a sucrose fatty acid ester. (133) The dispersion formulation according to (131) or (132) above, comprising one or more emulsifiers, wherein the emulsifier comprises sucrose erucate ester. (134) A dispersion formulation according to any of (131) to (133) above, wherein the Z-average size of the particles is 200 nm or less. (135) A dispersion formulation according to any of (131) to (134) above, wherein the emulsifier contains two or more emulsifiers. (136) A dispersion formulation according to any one of (131) to (135) above, wherein the emulsifier contains fatty acid polyglyceryl. (137) The dispersion formulation according to (136) above, wherein the fatty acid polyglyceryl contains polyglyceryl polyricinoleate. (138) A 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) A dispersion formulation according to any one of (131) to (138) above, wherein the water-soluble molecule contains nicotinamide mononucleotide (NMN). [Brief explanation of the drawing]

[0016] [Figure 1A] This figure shows the degree of penetration into the stratum corneum of a solid particle dispersion formulation prepared using an emulsifier labeled ER290. The fractions in the figure represent the ER290 / emulsifier ratio. [Figure 1B] Same as above [Figure 2A] This figure shows the degree of penetration of a solid particle dispersion formulation prepared using an emulsifier labeled ER290 into layers below the stratum corneum. The fractions in the figure represent the ER290 / emulsifier ratio. [Figure 2B] Same as above [Figure 3] The appearance of the solid particle dispersion formulations of Examples 2-1 and 2-2 is shown. [Figure 4] The particle size distribution in the solid particle dispersion formulations of Examples 2-1 and 2-2 is shown. [Figure 5] Examples 2-1 and 2-2 demonstrate the penetration of the solid particle dispersion formulations into the skin. [Figure 6] The particle size distribution of the solid particle dispersion aqueous formulation of Example 3 is shown. [Figure 7] This shows the penetration of the solid particle dispersion aqueous formulation of Example 3 into the stratum corneum and the layers below the stratum corneum. [Modes for carrying out the invention]

[0017] Embodiments of the present invention will be described with reference to the drawings. However, the present invention is not limited to the embodiments and drawings described below. In the embodiments described below, expressions such as “having,” “including,” or “containing” also include the meaning of “consisting of” or “composed of.” The singular form means singular or plural.

[0018] In this specification, “subject” refers to mammals, including humans, and preferably humans. Examples of mammals include, but are not limited to, humans, chimpanzees and other primates; domestic animals such as dogs, cats, rabbits, horses, sheep, goats, cattle, pigs, rats (including nude rats), mice (including nude mice and skid mice), guinea pigs, pets and laboratory animals.

[0019] In this specification, "surfactant" refers to a molecule having a relatively hydrophilic portion and a relatively hydrophobic portion within its molecule. Surfactants are broadly classified into ionic surfactants and nonionic surfactants. Examples of ionic surfactants include cationic surfactants and anionic surfactants. Typically, ionic surfactants may have either a cationic or anionic portion and a hydrophobic portion. Cationic surfactants may contain a cationic portion and fatty acid chains such as alkyl, alkenyl, or alkynyl (e.g., long-chain fatty acid chains). Anionic surfactants may contain an anionic portion 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 applied to compounds with 14 to 22 carbon atoms. Fatty acid chains are fatty acid chains with 8 to 22 carbon atoms, i.e., C8 to C22. 22 Alkyl, C8~C 22 Alkenyl, or C8~C 22 C8~C such as Alkinyl 22It may be a fatty acid chain. Furthermore, the fatty acid chain may be a long-chain fatty acid chain. Saturated means that the fatty acid chain does not have double or triple bonds, and unsaturated means that the fatty acid chain has at least one double or triple bond. Examples of fatty acid chains having double bonds include cis and trans forms, but the cis form is preferred from the viewpoint of biocompatibility. Nonionic surfactants are surfactants that do not have ionic groups in their molecules and have a nonionic hydrophilic part and a hydrophobic part. The hydrophobic part may contain fatty acid chains such as alkyl, alkenyl, or alkynyl (e.g., long-chain fatty acid chains). Fatty acid chains and long-chain fatty acid chains are as defined above.

[0020] As nonionic surfactants, ester compounds derived from fatty acids (e.g., saturated or unsaturated fatty acids) such as erucic acid and oleic acid are preferred. Examples of lipophilic nonionic surfactants include sugar fatty acid esters with a high degree of esterification (i.e., a high proportion of di, tri, and polyester relative to monoesters), preferably sucrose fatty acid esters (sucrose stearate, sucrose palmitate, sucrose myristicate, sucrose oleate, sucrose laurate, sucrose erucate, sucrose mixed fatty acid ester), polyglycerin condensed ricinoleate, decaglycerin ester, glycerin fatty acid ester, polyglycerin fatty acid ester, polyoxyethylene glycerin fatty acid ester, sorbitan fatty acid ester, polyoxyethylene sorbitan fatty acid ester, and polyoxyethylene castor oil / hydrogenated castor oil. Preferably, the nonionic surfactant is sucrose laurate. Surfactants may be used individually or in mixtures of two or more. A preferred example of a surfactant used for preparing the complex is a lipophilic (hydrophobic) nonionic surfactant with an HLB (Hydrophile-Lipophile Balance) value of 10 or less. The HLB of the nonionic surfactant is preferably 8 or less, more preferably 5 or less, and particularly preferably 3 or less.

[0021] Cationic surfactants (cationic lipids) are described in U.S. Patent Applications Publications 2006 / 0083780 and 2006 / 0240554, U.S. Patents 5,208,036, 5,264,618, 5,279,833, 5,283,185, 5,753,613, and 5,785,992, and PCT Publication No. WO96 / 10390, the disclosures thereof being incorporated herein by reference in their entirety for all purposes. Examples of 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), and 2,2-dilinoleyl-4-(4-dimethylaminopropyl) Minobutyl)-[1,3]-dioxolane (DLin-K-C4-DMA), 2,2-dilinoleyl-5-dimethylaminomethyl-[1,3]-dioxane (DLin-K6-DMA), 2,2-dilinoleyl-4-N-methylpepiazino (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-dilinoleyoxy-3-(dimethylamino)acetoxypropane (DLin-DAC), 1,2-dilinoleyoxy-3-morpholinopropane (DLin-MA), 1,2-dilinoleoyl-3-dimethylaminopropane (DLinDAP), 1,2-dilinoleythio-3-dimethylaminopropane (DLin-S-DMA), 1-linoleoyl-2-linoleyloxy-3-dimethylaminopropane (DLin-2-DMAP), 1,2-dilinoleyoxy-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 (propanedio) (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 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-dimyristyloxypropane-3-yl)-N,N-dimethyl-N-hydroxyethylammonium bromide (DMRIE), 2,3-dioleyloxy-N-[2(spermine-carboxamide)ethyl]-N,N-dimethyl-1-propaneaminium trifluoroacetate (DOSPA), dioctadecylamideglycylspermine (DOGS), 3-dimethylamino-2-(cholesta-5-en-3-β-oxybutane-4-oxy)-1-(cis,cis-9,12- Octadecadienoxy)propane (CLinDMA), 2-[5'-(cholesta-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 one preferred embodiment, the cationic lipid is DLinDMA, DLin-K-C2-DMA ("XTC2"), or a mixture thereof. Preferably, the cationic lipid is 1,2-dimyristoyl-sn-glycero-3-ethyl-phosphatidylcholine (EDMPC).

[0022] Examples of anionic surfactants (anionic lipids) include phospholipids and fatty acids. Examples of anionic surfactants include phosphatidylglycerol, cardiolipin, diacylphosphatidylserine, diacylphosphatidic acid, N-dodecanoylphosphatidylethanolamine, N-succinylphosphatidylethanolamine, N-glutarylphosphatidylethanolamine, lysylphosphatidylglycerol, palmitoyloleoylphosphatidylglycerol (POPG), and other anionic modifying groups bonded to neutral lipids.

[0023] In this specification, "solid composite" refers to a composite consisting of solid components. In this specification, a solid composite in particulate form may be referred to as a solid particle. A solid composite may contain water, but is a composite containing solid components. A solid composite may have a low water content; for example, by measurement using known methods, 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. A solid composite containing a water-soluble molecule and a surfactant may have a core-shell structure, where the core contains the water-soluble molecule and the shell contains the surfactant, and the surfactant may orient its water-soluble portion toward the core and its hydrophobic portion toward the outer surface of the solid composite. Therefore, the resulting composite or solid composite may have a hydrophilic center (core) but a hydrophobic outer surface (periphery or shell). Such a solid composite can be preferably dispersed in an oil phase. However, in this disclosure, such solid composites do not necessarily 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. Also, by not using an oil phase, the handling of the patch may be easier.

[0024] (Dispersed formulation) This disclosure provides a dispersion formulation comprising solid particles containing a complex of a water-soluble molecule and an emulsifier, and an oily base. In the dispersion formulation, the solid particles are dispersed in the oily base.

[0025] This disclosure provides a dispersion formulation comprising solid particles containing a complex of a water-soluble molecule and an emulsifier, and an aqueous base. In the dispersion formulation, the solid particles are dispersed in the aqueous base.

[0026] In one preferred embodiment, the emulsifier comprises one or more emulsifiers.

[0027] In one preferred embodiment, the emulsifier preferably comprises a sugar fatty acid ester. In one preferred embodiment, the sugar fatty acid ester is a sucrose fatty acid ester, and more preferably a sucrose erucate ester.

[0028] In one preferred embodiment, the emulsifier includes fatty acid glyceryl. The fatty acid glyceryl is selected from the group consisting of, for example, polyglyceryl polyfatty acids, polyglyceryl monofatty acids, polyglyceryl monofatty acids, and monoglyceryl monofatty acids.

[0029] In one preferred embodiment, the fatty acid glyceryl has polyglyceryl groups with a degree of polymerization of 2 to 10. In one preferred embodiment, the fatty acid glyceryl has polyglyceryl groups with a degree of polymerization of 2 to 8, or 2 to 6, 2 to 4, 3 to 5, or 4 to 6.

[0030] In one preferred embodiment, the fatty acid glyceryl is not particularly limited, but examples include 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 one preferred embodiment, fatty acid glyceryls are not particularly limited, but examples include 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.

[0031] In one preferred embodiment, the emulsifier comprises a sugar fatty acid ester and a fatty acid glyceryl.

[0032] In a particular preferred embodiment, the emulsifier comprises sucrose erucate and fatty acid glyceryl. In a preferred embodiment, the fatty acid glyceryl is selected from the group consisting of polyglyceryl polyfatty acids, polyglyceryl monofatty acids, polyglyceryl monofatty acids, and monoglyceryl monofatty acids. In a preferred embodiment, the fatty acid glyceryl may be one or more selected from fatty acid glyceryl group A, for example, although not particularly limited. In a preferred embodiment, the fatty acid glyceryl may be one or more selected from fatty acid glyceryl group B, for example, although not particularly limited.

[0033] In a particular preferred embodiment, the emulsifier comprises sucrose erucate and polyglyceryl-10 decaoleate. The molar ratio of sucrose erucate to polyglyceryl-10 decaoleate may 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 erucate to polyglyceryl-10 decaoleate may 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 erucate to polyglyceryl-10 decaoleate may 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.

[0034] In a particular preferred embodiment, the emulsifier comprises sucrose erucate and polyglyceryl-6 polyricinoleate. The ratio of sucrose erucate to polyglyceryl-6 polyricinoleate may 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 erucate to polyglyceryl-6 polyricinoleate may 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 erucate to polyglyceryl-6 polyricinoleate may 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.

[0035] In one preferred embodiment, the emulsifier comprises sucrose erucate and polyglyceryl-6 polyricinoleate. The ratio of sucrose erucate to polyglyceryl-6 polyricinoleate may 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 erucate to polyglyceryl-6 polyricinoleate may 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 erucate to polyglyceryl-6 polyricinoleate may 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.

[0036] In one preferred embodiment, the emulsifier comprises sucrose erucate and polyglyceryl-2 diisostearate, the ratio of sucrose erucate to polyglyceryl-2 diisostearate may 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 erucate to polyglyceryl-2 diisostearate may 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 erucate to polyglyceryl-2 diisostearate may 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.

[0037] In one preferred embodiment, the emulsifier comprises sucrose erucate and polyglyceryl-2 tetraisostearate, where the ratio of sucrose erucate to polyglyceryl-2 tetraisostearate may 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 erucate to polyglyceryl-2 tetraisostearate may 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 erucate to polyglyceryl-2 tetraisostearate may 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.

[0038] In one preferred embodiment, the emulsifier comprises sucrose erucate and glyceryl monooleate, where the ratio of sucrose erucate to glyceryl monooleate may 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 erucate to glyceryl monooleate may 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 erucate to glyceryl monooleate may 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 one preferred embodiment, the emulsifier comprises sucrose erucate and polyoxyethylene hydrogenated castor oil, the ratio of sucrose erucate to polyoxyethylene hydrogenated castor oil may 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 erucate to polyoxyethylene hydrogenated castor oil may 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 erucate to polyoxyethylene hydrogenated castor oil may 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 one preferred embodiment, the emulsifier comprises sucrose erucate and polyglyceryl-10 pentaoleate, where the ratio of sucrose erucate to polyglyceryl-10 pentaoleate may 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 erucate to polyglyceryl-10 pentaoleate may 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 erucate to polyglyceryl-10 pentaoleate may 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.

[0041] In one preferred embodiment, the emulsifier comprises sucrose erucate and polyglyceryl-10 decaisostearate, where the ratio of sucrose erucate to polyglyceryl-10 decaisostearate may 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 erucate to polyglyceryl-10 decaisostearate may 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 erucate to polyglyceryl-10 decaisostearate may 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.

[0042] In one preferred embodiment, the emulsifier comprises sucrose erucate and glyceryl monocaprate, the ratio of sucrose erucate to glyceryl monocaprate may 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 erucate to glyceryl monocaprate may 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 erucate to glyceryl monocaprate may 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.

[0043] In this 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 water, is used in the cosmetics and pharmaceutical fields, and does not adversely affect the skin of animals, including humans, when in contact with it. 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, chymyl alcohol, ceracyl alcohol, batyl alcohol, hexyldecanol, isostearyl alcohol, 2-octyldodecanol, and dimer ol; aralkyl alcohols such as benzyl alcohol and their derivatives; long-chain fatty acids and their derivatives 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; liquid paraffin (mineral oil), heavy liquid isoparaffin, light liquid isoparaffin, α-olefin oligomer, polyisobutene, hydrogenated polyisobutene Hydrocarbons such as tene, polybutene, squalane, olive-derived squalane, squalene, petrolatum, and solid paraffin; waxes such as candelilla wax, carnauba wax, rice wax, wood 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, safflower Vegetable oils such as 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, peach kernel 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, etc.Animal fats and oils such as beef tallow, milk fat, horse fat, egg yolk oil, mink oil, turtle oil; animal waxes such as whale wax, lanolin, orange roughy oil; lanolins such as liquid lanolin, reduced lanolin, adsorbed and purified lanolin, lanolin acetate, liquid lanolin acetate, hydroxylanolin, polyoxyethylene lanolin, lanolin fatty acid, hard lanolin fatty acid, lanolin alcohol, lanolin acetate alcohol, (cetyl lanolyl) acetate; sterols such as cholesterol, dihydrocholesterol, lanosterol, dihydrolanosterol, phytosterol, cholic acid; sapogenins; saponins; cholesteryl acetate, cholesteryl nonanoate, cholesteryl stearate, cholesteryl isostearate, cholesteryl oleate, N-lauroyl-L-glutamic acid di(cholesteryl / behenyl / Sterol esters such as octyldodecyl, 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, isostearate phytosteryl, soft lanolin fatty acid cholesteryl, hard lanolin fatty acid cholesteryl, long-chain branched fatty acid cholesteryl, long-chain α-hydroxy fatty acid cholesteryl; acylsarcosinate alkyl esters such as N-lauroyl sarcosinate isopropyl; lipid complexes such as phospholipid-cholesterol complex and phospholipid-phytosterol complex;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 ocate, hydrogenated castor oil isostearate, ethyl oleate, ethyl avocado oil fatty acid, isopropyl myristate, isopropyl palmitate, octyl palmitate, isopropyl isostearate, isopropyl lanolinate; dicarboxylic acid esters such as diethyl sebacate, diisopropyl sebacate, dioctyl sebacate, diisopropyl adipate, dibutyloctyl sebacate, diisobutyl adipate, dioctyl succinate, triethyl citrate; oxy acid esters such as cetyl lactate, diisostearyl malate, 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 eicosanedioate behenate, trimethylolpropane trioctanoate, trimethylolpropane triisostearate, dio Neopentyl glycol ctanoate, neopentyl glycol dicaprate, 2-butyl-2-ethyl-1,3-propanediol dioctanoate, propylene glycol dioleate, pentaerythrityl tetraoctanoate, hydrogenated rosin pentaerythrityl, ditrimethylolpropane triethylhexanoate, (isostearate / sebacate) ditrimethylolpropane, pentaerythrityl triethylhexanoate, (hydroxystearate / stearate / rosinate) dipentaerythrityl, dig diisostearate Polyglyceryl dimer dilinoleate, polyglyceryl-10 nonaisostearate, polyglyceryl-8 erucate / isostearate / ricinoleate, diglyceryl oligoesters (hexyldecanoate / sebacate), glycol distearate (ethylene glycol distearate), polyhydric alcohol fatty acid esters such as 3-methyl-1,5-pentanediol dieopentanoate and 2,4-diethyl-1,5-pentanediol dieopentanoate; diisopropyl dimer dilinoleate, dimer dimer dilinoleate Dimer acids or dimer ol derivatives such as diisostearyl dilinoleate, di(isostearyl / phytosteryl) dimer dilinoleate, (phytosteryl / behenyl) dimer dilinoleate, (phytosteryl / isostearyl / cetyl / stearyl / behenyl) dimer dilinoleate, dimer dilinoleyl diisostearate, hydrogenated rosin condensate of dimer dilinoleate, hydrogenated castor oil of dimer dilinoleate, 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), coconut oil fatty acid methylethanolamide (cocamide methyl MEA); cyclomethicone (cyclic dimethylsiloxane) such as dimethicone (dimethylpolysiloxane), highly polymerized dimethicone (highly polymerized dimethylpolysiloxane), decamethylcyclopentasiloxane (also simply called cyclopentasiloxane), phenyl trimethicone, diphenyl dimethicone, phenyl dimethicone, stearoxypropyl dimethicone Silicones such as sylamine, (aminoethylaminopropylmethicone / dimethicone) copolymer, dimethiconol, dimethiconol crosspolymer, silicone resins, silicone rubber, amino-modified silicones such as aminopropyldimethicone and amodimethicone, cationic-modified silicones, polyether-modified silicones such as dimethicone copolyol, polyglycerin-modified silicones, sugar-modified silicones, carboxylic acid-modified silicones, phosphate-modified silicones, sulfuric acid-modified silicones, alkyl-modified silicones, fatty acid-modified silicones, alkyl ether-modified silicones, amino acid-modified silicones, peptide-modified silicones, fluorine-modified silicones, cationic-modified and polyether-modified silicones, amino-modified and polyether-modified silicones, alkyl-modified and polyether-modified silicones, and polysiloxane-oxyalkylene copolymers;Examples include fluorinated oils such as perfluorodecane, perfluorooctane, and perfluoropolyether. Among these, long-chain fatty acids such as oleic acid, vegetable oils such as olive oil and jojoba oil, alkyl esters of C12 to C18 fatty acids such as isopropyl myristate, isopropyl palmitate, octyl palmitate, and isopropyl isostearate, and hydrocarbons such as squalane are preferred, with isopropyl myristate and squalane being more preferred. Particularly preferred isopropyl myristate as the oily base.

[0044] As the 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 may be, for example, physiological saline.

[0045] Examples of water-soluble molecules include polysaccharides such as hyaluronic acid and its salts, heparin and its analogues, and chitosan; proteins such as ovalbumin, casein, and collagen; vitamins such as vitamin C and its derivatives, and retinol; amino acids such as 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 molecules is preferably 500 Da or more, more preferably 1000 Da (i.e., 1 kDa) or more, preferably 200 kDa or less, more preferably 100 kDa or less, and particularly preferably 50 kDa or less.

[0046] 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 polymerosomes. Nanoparticles or nanovesicles are defined as having a Z-average size of sub-μm. When such nanoparticles or nanovesicles are used as water-soluble molecules, the manufacturing process for solid particle dispersion formulations can also be applied. Such nanoparticles or nanovesicles 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.

[0047] The particle size (Z-average size) of solid particles may 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 solid particles may be, for example, 100 nm or more, or 200 nm or more. The particle size (Z-average size) of solid particles may 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 specified in ISO 13321. Particles with a diameter smaller than 2 μm can be measured by dynamic scattering (DLS) using Zetasizer Nano ZS 90 (Malvern Instr. Ltd.).

[0048] The polydispersity index (PDI) of the solid particles may be, for example, 0.1 to 1. Preferably, the PDI may be 0.1 to 0.5, 0.1 to 0.4, 0.1 to 0.3, or 0.1 to 0.2.

[0049] (Method for preparing dispersed formulations) When a target molecule, such as a water-soluble molecule, is mixed with an emulsifier in an oil phase (preferably a volatile oil phase, such as cyclohexane), particles having a core-shell structure are formed, with the target molecule, such as the water-soluble molecule, in the core and the emulsifier in the shell. These particles are dispersed in the oil phase. The emulsifier contains one or more emulsifiers. If the oil phase used here is a volatile oil phase (e.g., cyclohexane), the solvent can be easily evaporated thereafter, and by removing the solvent by drying (e.g., freeze-drying), particles having a core-shell structure with a water-soluble molecule in the core and an emulsifier in the shell can be obtained as solid particles (also called "solid composites"). By dispersing these solid particles in an oily substrate or an aqueous base, a solid particle-dispersed oily formulation or a solid particle-dispersed aqueous formulation (also simply called "solid particle-dispersed formulation") can be obtained, respectively. Such a solid particle-dispersed oily formulation can penetrate deeply into the stratum corneum (which is non-hydrophilic), where water-soluble molecules have difficulty penetrating, and in some cases penetrate below the stratum corneum, preferably into the bloodstream. According to the examples, the solid particle dispersion aqueous formulation also has the ability to penetrate the stratum corneum with the active ingredient, and preferably penetrates into the bloodstream.

[0050] (cosmetics) This disclosure provides cosmetics comprising the dispersion formulation of the Disclosure. The cosmetics may be ointments, creams, lotions, sprays, powders, or patches. The cosmetics may comprise the dispersion formulation of the Disclosure and dermatologically acceptable additives (e.g., excipients, carriers, etc.). [Examples]

[0051] Example 1: Effect of emulsifier Preparation of solid particle dispersion solutions Ten mg of fluorescein-labeled hyaluronic acid was dissolved in 2 mL of Milli-Q water. Two hundred mg of each emulsifier shown in Table 1 were dissolved in 4 mL of cyclohexane. The aqueous and organic phases were added to glass vials and stirred at 26,000 rpm for 2 minutes using a Polytron homogenizer. The resulting emulsions were flash-frozen in liquid nitrogen and freeze-dried for 24 hours. The entire amount of the solid obtained after drying was redispersed in 5 mL of olive oil to obtain a solid particle dispersion.

[0052] [Table 1]

[0053] Measurement of particle size distribution The solid particle dispersion was diluted 100-fold with cyclohexane, and the particle size distribution and Z-average particle size at 20°C were measured using a Zetasizer NanoPro.

[0054] Yucatan Micropig Skin Penetration Test Yucatan micropig skin (4 months old) was thawed, and subcutaneous tissue was removed using a scalpel. It was cut into 2 cm x 2 cm pieces, and the stratum corneum was placed facing upwards between the donor and acceptor phases of a longitudinal Franz cell. The receptor phase was filled with 5 mL of PBS solution (pH 7.4) at 32°C. 100 μL of solid particle dispersion solution was administered to the donor phase, and the cells were incubated at 32°C for 24 hours. After 24 hours, the donor phase solid particle dispersion was wiped off with a Kimwipe, and the two outermost layers of the stratum corneum were removed by tape stripping. The remaining stratum corneum was peeled off by tape stripping, and every five layers were immersed in 1 mL of solution (PBS / methanol / acetonitrile = 2 / 1 / 1, v / v) and extracted by shaking at room temperature for 22 hours. The skin other than the stratum corneum was divided into 16 sections with a scalpel, and similarly extracted by shaking at room temperature for 22 hours using 1 mL of PBS solution. The extract was diluted 10-fold with PBS solution, and the amount of hyaluronic acid was quantified by measuring the fluorescence intensity using a microplate reader.

[0055] Table 2 shows the composition of the prepared solid particle dispersion formulations. Table 3 shows the Z-mean value and polydispersity index of particles in the solid particle dispersion formulations prepared by mixing sucrose fatty acid ester (ER-290) with various emulsifiers. Hyalo-Oligo™ was used as the hyaluronic acid.

[0056] [Table 2]

[0057] [Table 3] JPEG2026174717000004.jpg187158

[0058] Even in cases where a clear dispersion precipitated when using an emulsifier alone, mixing two types of emulsifiers made it possible to prepare particles with a small Z-mean value and low polydispersity index. In many systems, the smallest Z-mean value was observed when ER-290 was included at 25% of the total emulsifier. Furthermore, emulsifiers that showed particularly high stabilization effects were those with large and 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 low stabilization effects. On the other hand, when using decaglycerin fatty acid esters, the hydrophilicity of the emulsifier increased, weakening its effect in stably dispersing hydrophilic drug solids. Polyoxyethylene(10) hydrogenated castor oil also showed similar low stabilization effects. From this, it is suggested that the highest stabilization effect may be obtained when the polymerization number of glycerin units in the head group of the emulsifier is in the range of 2-6. In Tables 3 and 4, S is the most preferred, A is the second most preferred, B is the second most preferred, and C is the second most preferred. Furthermore, the presence of precipitate or turbidity does not mean that there is no dispersion of solid particles in the liquid. Therefore, it should be noted that even if precipitate or turbidity is present, skin penetration of solid particles is not ruled out. Thus, even samples that exhibit turbidity, precipitate, or gelation can be used for skin penetration applications.

[0059] Furthermore, the long-term dispersibility was evaluated. After preparing the solid particle dispersion formulation described above, the dispersibility of the formulation was visually confirmed after storage at 25°C for two months. The results are shown in Table 4.

[0060] [Table 4]

[0061] As shown in Table 4, in both cases, the long-term dispersibility of the formulation was improved when the two emulsifiers were mixed. The mixing ratio of the emulsifiers to obtain dispersibility or long-term dispersibility can be appropriately adjusted by those skilled in the art.

[0062] Figure 1 shows the amount of solid particle dispersion formulations prepared by mixing sucrose fatty acid ester (ER-290) and various emulsifiers that penetrated the skin of Yucatan micropig after administration. The Z-mean value correlated with penetration below the stratum corneum, and formulations with lower Z-mean values ​​showed that the drug penetrated further into the layers below the stratum corneum. Furthermore, penetration into the hydrophilic regions of the skin below the stratum corneum was also high (Figure 2). The stratum corneum can be likened to brick and mortar, with keratin-filled keratinocytes laid out within hydrophobic regions consisting of a ceramide bilayer. Therefore, it is thought that smaller particles were able to penetrate more stably between keratinocytes within the highly hydrophobic stratum corneum.

[0063] Example 2: Solid particle dispersion formulation of extracellular vesicles ER-290 was obtained from Mitsubishi Chemical Corporation, and SY Glister CRS-75 and S Face IS-202P were obtained from Sakamoto Pharmaceutical Co., Ltd. Milk exosomes (Cosmo Bio) were stained with CoraLite594-labeled CD9 antibody (Protein Tech Japan), and unreacted antibody was removed using a PURE-EV column (HansaBioMed).

[0064] 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 thought to have formed particles with a core-shell structure, containing exosomes in the core and an emulsifier in the shell. Cyclohexane was removed by freeze-drying to obtain solid complex particles with a core-shell structure. The solid complex particles were dispersed in IPM to prepare a solid particle dispersion formulation of exosomes.

[0065] The mixing amounts of each component used to prepare the solid particle dispersion formulation are shown in Table 5.

[0066] [Table 5]

[0067] As shown in Figure 3, the obtained dispersion formulation was transparent. The particle size distribution of the obtained 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 with relatively small particles of 500 nm or less was obtained.

[0068] [Table 6]

[0069] The obtained solid particle dispersion formulation containing exosomes was applied to the skin of micropig, and its permeability was confirmed. Yucatan micropig skin (4 months old) was thawed, and subcutaneous tissue was removed using a scalpel. It was cut into 2 cm × 2 cm sections, and the stratum corneum was placed facing upward between the donor and acceptor phases of a longitudinal Franz cell. The receptor phase was filled with 5 mL of PBS solution (pH 7.4) at 32°C. 100 μL of the dispersion formulation 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 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 frozen sections were prepared. The skin tissue sections were mounted in ProLong Glass Antifade Mountant with NucBlu Stain (Thermo Fisher Scientific), and the tissue was observed using a fluorescence microscope. The results are shown in Figure 5. As shown in Figure 5, dispersion formulation enabled the penetration of exosomes into the epidermis.

[0070] Example 3: Aqueous dispersion Nicotinamide mononucleotide (NMN) 4 mg was dissolved in 2 mL of Milli-Q water. ER-290 19 mg and SY Glister CRS-75 57 mg were dissolved in 4 mL of cyclohexane. The aqueous and organic phases were placed in glass vials 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 freeze-dried for 24 hours.

[0071] 20 mg of the liquid obtained after drying was dispersed in 1 mL of cyclohexane. 60 mg of Nikkor BL-25 (Nikko Chemicals) was dissolved in 3 mL of water. The aqueous phase and organic phase were placed in glass vials 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 in which solid particles were dispersed in water (solid particle dispersion aqueous solution) (final NMN concentration: 1 mg / mL).

[0072] Measurement of particle size distribution The obtained dispersion was diluted 100-fold 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 this disclosure to NMN, we succeeded in solidifying it into particles and dispersing them in an aqueous solution. The obtained particles had a sub-μm particle size distribution.

[0073] [Table 7]

[0074] Yucatan Micropig Skin Penetration Test Yucatan micropig skin (4 months old) was thawed, and subcutaneous tissue was removed using a scalpel. The skin was cut into 2 cm × 2 cm sections, and the stratum corneum was placed facing upwards between the donor and acceptor phases of a longitudinal Franz cell. 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.

[0075] After 24 hours, the donor phase dispersion was wiped off with a Kimwipe, and the two outermost layers of the stratum corneum were removed by tape stripping. The remaining stratum corneum was removed by tape stripping 20 times, immersed in 5 mL of solution (PBS / methanol / acetonitrile = 2 / 1 / 1, v / v), and extracted by shaking at room temperature for 22 hours. The skin other than the stratum corneum was divided into 16 sections with a scalpel, and extracted by shaking at room temperature for 22 hours using 1 mL of PBS solution.

[0076] 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.

[0077] As shown in Figure 7, the solid particle dispersion aqueous solution was able to penetrate a large amount of NMN into the layers of the skin below the stratum corneum.

Claims

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

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

3. The dispersion formulation according to claim 1 or 2, wherein the fatty acid glyceryl comprises 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, further comprising one or more emulsifiers, a sugar fatty acid ester.

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

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

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

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 comprising a dispersion formulation according to any one of claims 1 to 8.

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

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

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

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

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