Solid particle dispersion preparation

Abstract

To provide a solid particle dispersion preparation.SOLUTION: A dispersion preparation contains solid particles containing a combination of a water-soluble molecule and two or more emulsifiers, and an oil base. The two or more emulsifiers include a glycerol fatty acid ester with an HLB value of 5 or less and a sugar fatty acid ester with an HLB value of 5 or less. The solid particles have a Z average particle size of 500 nm or less. The solid particles are dispersed in the oil base and retain their dispersibility for two months under temperature conditions of 25°C.SELECTED DRAWING: None

Description

[Technical Field]

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

[0002] The skin tissue contains a stratum corneum, which acts as a non-specific barrier against the invasion of invaders such as bacteria and viruses. The stratum corneum provides a physical barrier that prevents the The poor permeability of the substance is an obstacle to transdermal drug administration. More hydrophilic molecules are not suitable for transdermal administration.

[0003] A solid in which a hydrophilic compound is coated with a surfactant in order to allow the hydrophilic compound to be absorbed transdermally. A formulation technique has been developed in which the complex 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 solid particle dispersion formulations.

[0006] According to the present disclosure, particles of a solid complex composed of two specific emulsifiers and a target molecule are separated. The usefulness and effectiveness of the dispersed formulation were 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. The emulsifier contains a fatty acid glyceryl, and the solid particles are dispersed in the oil base. Dispersed formulation. (2) The fatty acid glyceryl may be polyglyceryl fatty acid, monoglyceryl fatty acid, polyglyceryl fatty acid, or polyglyceryl fatty acid. monoglycerides of fatty acids, and monoglycerides of fatty acids, The dispersion formulation described in (1) above. (3) The fatty acid glyceryl includes polyglyceryl having a number average degree of polymerization of 2 to 6, or (2). (4) The above emulsifier further comprises a nonionic surfactant (e.g., a sugar fatty acid ester). The dispersion formulation according to any one of (1) to (3) above. (5) Any of the above (1) to (4), wherein the sugar fatty acid ester is a sucrose fatty acid ester. The dispersion formulation described above. (6) Any of the above (1) to (5), wherein the sugar fatty acid ester is sucrose erucate. The dispersion formulation described above. (7) Any one of the above (4) to (6), wherein the emulsifier contains 10 to 40 mol % of a sugar fatty acid ester. 2. The dispersion formulation according to claim 1 , (8) Any of the above (1) to (7), wherein the Z-average particle size is 500 nm or less. The dispersion formulation described. (9) A cosmetic comprising the dispersion preparation according to any one of (1) to (8) above.

[0008] (21) The fatty acid glyceryl is fatty acid glyceryl group A: polyglyceryl decaoleate, Polyglyceryl polyricinoleate, Polyglyceryl diisostearate, Tetraisostearate Polyglyceryl tearic acid, glyceryl monooleate, polyoxyethylene hydrogenated castor Oil, Polyglyceryl Pentaoleate, Polyglyceryl Decaisostearate, and Mono glyceryl nocaprate, The dispersion formulation described in any one of the above. (22) Fatty acid glyceryl is fatty acid glyceryl group B: polyglyceryl decaoleate 10. Polyglyceryl-6 Polyricinoleate, Polyglyceryl-6 Polyricinoleate , Polyglyceryl-2 diisostearate, Polyglyceryl-2 tetraisostearate , Glyceryl Monooleate, Polyoxyethylene Hydrogenated Castor Oil, Polypentaoleate Glyceryl-10, Polyglyceryl-10 Decaisostearate, and Monocapric Acid glyceryl Dispersion formulation as described above.

[0009] (31) The fatty acid glyceryl includes polyglyceryl decaoleate, ) The dispersion formulation according to any one of the preceding claims. (32) The fatty acid glyceryl may be polyglyceryl polyricinoleate, (7) A dispersion formulation according to any one of the above. (33) The fatty acid glyceryl may be polyglyceryl diisostearate, (7) A dispersion formulation according to any one of the above. (34) The fatty acid glyceryl includes polyglyceryl tetraisostearate, 10. The dispersion formulation according to any one of (1) to (7). (35) The fatty acid glyceryl of any one of (1) to (7) above, wherein the fatty acid glyceryl includes glyceryl monooleate. The dispersion formulation described in any one of the above. (36) The fatty acid glyceryl of (1) to ( 7) A dispersion formulation according to any one of the above. (37) The fatty acid glyceryl may be polyglyceryl pentaoleate, 7) A dispersion formulation according to any one of the above. (38) The above (1), wherein the fatty acid glyceryl includes polyglyceryl decaisostearate. The dispersion formulation according to any one of (1) to (7). (39) The fatty acid glyceryl of any one of (1) to (7) above, wherein the fatty acid glyceryl includes glyceryl monocaprate. The dispersion formulation described in any one of the above.

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

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

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

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

[0014] (101) A dispersion formulation comprising solid particles containing water-soluble molecules and one or more emulsifiers and an aqueous base. wherein the solid particles are dispersed in the aqueous base. (102) The method according to (101), wherein the one or more emulsifiers include a sucrose fatty acid ester. Dispersion formulation as described above. (103) The one or more emulsifiers include sucrose erucate. or (102). (104) The above, wherein the Z-average size of the particles is 300 nm or less, or 200 nm or less. The dispersion formulation according to any one of (101) to (103). (105) The above (101) to (104), wherein the Z-average particle size is 50 nm or more. The dispersion formulation described in any one of the above. (106) The water-soluble molecule includes nicotinamide mononucleotide. 105). A dispersion formulation according to any one of claims 1 to 105. (107) At a temperature of 25°C for at least one month, preferably at least two months. Any of the above dispersion preparations exhibiting dispersibility. (108) The emulsifier according to (10), wherein the emulsifier comprises a nonionic surfactant and a fatty acid polyglyceryl. 7) A dispersion formulation according to the present invention. (109) The nonionic surfactant according to (108), wherein the nonionic surfactant comprises a sugar fatty acid ester. Dispersion formulation. (110) The above, wherein the glycerin polymerization number of the fatty acid polyglyceryl is 2 to 6. (107) A dispersion formulation according to (107). (111) The above, wherein the glycerin polymerization number of the fatty acid polyglyceryl is 2 to 6. (108) A dispersion formulation according to (108). (112) Fatty acid polyglyceryl is polyglyceryl-6 polyricinoleate, polyricinoleate Polyglyceryl-6 oleate, Polyglyceryl-10 decaoleate, Polyglyceryl-10 pentaoleate Glyceryl-10, Polyglyceryl-2 Diisostearate, and Polydecalisostearate The dispersion medium according to (110), wherein the dispersion medium is one or more selected from the group consisting of triglyceride-10 and triglyceride-11. formulation. (113) Fatty acid polyglyceryl is polyglyceryl-6 polyricinoleate, polyricinoleate Polyglyceryl-6 oleate, Polyglyceryl-10 decaoleate, Polyglyceryl-10 pentaoleate Glyceryl-10, Polyglyceryl-2 Diisostearate, and Polydecalisostearate The dispersion medium according to (111), wherein the dispersion medium is one or more selected from the group consisting of triglyceride-10 and triglyceride-11. formulation. (114) The sugar fatty acid ester according to (109), wherein the sugar fatty acid ester includes sucrose erucate. Dispersion formulation. (115) The sugar fatty acid ester according to (111), wherein the sugar fatty acid ester includes sucrose erucate. Dispersion formulation. (116) The sugar fatty acid ester according to (112), wherein the sugar fatty acid ester comprises sucrose erucate. Dispersion formulation. (117) The sugar fatty acid ester according to (113), wherein the sugar fatty acid ester includes sucrose erucate. Dispersion formulation.

[0015] (131) Solid particles containing water-soluble molecules and one or more (preferably two or more) emulsifiers; A dispersion formulation comprising an aqueous base, wherein the solid particles are dispersed in the aqueous base. Powder formulation. (132) The method according to (131), wherein the one or more emulsifiers include sucrose fatty acid esters. Dispersion formulation as described above. (133) The one or more emulsifiers include sucrose erucate. or (132). (134) The above (131) to (133), wherein the Z-average particle size is 200 nm or less. The dispersion formulation according to any one of the preceding claims. (135) Any of the above (131) to (134), wherein the emulsifier contains two or more kinds of emulsifiers. The dispersion formulation described in (136) Any of the above (131) to (135), wherein the emulsifier contains a fatty acid polyglyceryl. The dispersion formulation described above. (137) The above ( 136). A dispersion formulation according to claim 136. (138) The emulsifier comprises a sucrose fatty acid ester and a fatty acid polyglyceryl. The dispersion formulation according to any one of 1) to (137). (139) The method of any one of the above (1) wherein the water-soluble molecule comprises nicotinamide mononucleotide (NMN). A dispersion formulation according to any one of items 31) to (138). [Brief explanation of the drawings]

[0016] [Figure 1A] 1 shows the degree of penetration into the stratum corneum of a solid particle dispersion formulation made using an emulsifier designated ER290. The fractions in the figure indicate the ER290 / emulsifier ratio. [Figure 1B] Same as above [Figure 2A] 1 shows the degree of penetration into the substratum corneum of a solid particle dispersion formulation made with an emulsifier designated ER290. The fractions in the figure indicate the ER290 / emulsifier ratio. [Figure 2B] Same as above [Figure 3] 1 shows the appearance of the solid particle dispersion formulations of Examples 2-1 and 2-2. [Figure 4] 1 shows particle size distributions of particles in the solid particle dispersion formulations of Examples 2-1 and 2-2. [Figure 5] 1 shows the skin penetration of the solid particle dispersion formulations of Examples 2-1 and 2-2. [Figure 6]1 shows the particle size distribution of particles in the aqueous solid particle dispersion formulation of Example 3. [Figure 7] 1 shows the penetration of the aqueous solid particle dispersion formulation of Example 3 into the stratum corneum and layers below the stratum corneum. DETAILED DESCRIPTION OF THE INVENTION

[0017] The embodiments of the present invention will be described with reference to the drawings. The present invention is not limited to the embodiments and drawings. The words "have," "include," or "contain" are used interchangeably with "consisting of" or "composed of." The singular form "a," "an," or "an" means singular or plural.

[0018] As used herein, a "subject" is a mammal, including a human, and preferably a human. Examples of mammals include humans, chimpanzees, and other primates; dogs, cats, and rabbits. , horses, sheep, goats, cattle, pigs, rats (including nude rats), mice (gnu (including domestic mice and skid mice), guinea pigs and other livestock, pets and experimental animals These include, but are not limited to, animals used in agriculture.

[0019] As used herein, a "surfactant" refers to a substance that has a relatively hydrophilic portion and a relatively hydrophobic portion in the molecule. Surfactants are molecules that contain ionic moieties. Surfactants are classified into ionic surfactants and nonionic surfactants. Ionic surfactants are broadly classified into cationic surfactants and anionic surfactants. Typically, ionic surfactants include both cationic and anionic surfactants. Cationic surfactants can have either a cationic moiety or an alkyl group. The alkyl group may contain a fatty chain (e.g., a long fatty chain), such as an alkyl, alkenyl, or alkynyl. Anionic surfactants consist of an anionic moiety and long-chain fatty acids, unsaturated fatty acids (e.g., monobasic or dibasic) or long chain unsaturated fatty acids (e.g., monobasic or dibasic). "Long chain" is a term given to compounds with 14 to 22 carbon atoms. The chain is a fatty chain with 8 to 22 carbon atoms, i.e., C8 to C 22 Alkyl, C8-C 22 alkenyl, or C8~C 22 C8-C such as alkynyl 22 The fatty chain may be a long chain fatty acid. Saturated means that the fatty chain has no double or triple bonds, and Saturated means that the fatty chain has at least one double or triple bond. Fatty acid chains with double bonds include cis and trans configurations. Therefore, the cis-type is preferred. Nonionic surfactants have ionic groups in the molecule. It is a surfactant that does not have a hydrophilic portion and a hydrophobic portion. The moiety may have a fatty chain (e.g., a long fatty chain) such as an alkyl, alkenyl, or alkynyl. The fatty chains and long fatty chains are as defined above.

[0020] Nonionic surfactants include fatty acids such as erucic acid and oleic acid (e.g., saturated fatty acids Ester compounds made from fatty acids or unsaturated fatty acids are preferred. Examples of surfactants include those with a high degree of esterification (i.e., di-, tri-, or monoesters). High proportion of polyester), sugar fatty acid ester, preferably sucrose fatty acid ester Terephthalate (sucrose stearate, sucrose palmitate, sucrose myristate) Esters, sucrose oleate, sucrose laurate, sucrose erucate ester, sucrose mixed fatty acid ester), polyglycerin condensed ricinoleate, deca Glycerin esters, glycerin fatty acid esters, polyglycerin fatty acid esters, poly Oxyethylene glycerin fatty acid ester, sorbitan fatty acid ester, polyoxyethylene These include lenthorbit fatty acid esters and polyoxyethylene castor oil / hydrogenated castor oil. Preferably, the nonionic surfactant is sucrose laurate. One species may be used alone, or two or more species may be used in combination. Suitable examples of surfactants include HLB (Hydrophile-Lipophile Barium Biphenyls). It is a lipophilic (hydrophobic) nonionic surfactant with a lance value of 10 or less. The HLB of the ionic surfactant is preferably 8 or less, more preferably 5 or less, and particularly preferably is less than or equal to 3.

[0021] Examples of cationic surfactants (cationic lipids) include U.S. Patent Application Publication No. 2006 / 0 Nos. 083780 and 2006 / 0240554, U.S. Pat. No. 5,208,036 , No. 5,264,618, No. 5,279,833, No. 5,283,185, No. 5, 753,613, and 5,785,992, and PCT Publication No. WO96 / 10390, the disclosures of which are incorporated herein in their entirety for all purposes. The cationic lipids include 1,2-dilinoleyloxy- N,N-Dimethylaminopropane (DLinDMA), 1,2-Dilinolenyloxy-N ,N-Dimethylaminopropane (DLenDMA), 2,2-Dilinoleyl-4-(2- Dimethylaminoethyl)-[1,3]-dioxolane (DLin-K-C2-DMA; XTC2), 2,2-dilinoleyl-4-(3-dimethylaminopropyl)-[1,3 ]-dioxolane (DLin-K-C3-DMA), 2,2-dilinoleyl-4-(4- Dimethylaminobutyl)-[1,3]-dioxolane (DLin-K-C4-DMA), 2,2-Dilinoleyl-5-dimethylaminomethyl-[1,3]-dioxane (DLin -K6-DMA), 2,2-dilinoleyl-4-N-methylpepiazino (methylp epiazino)-[1,3]-dioxolane (DLin-K-MPZ), 2,2-di Linoleyl-4-dimethylaminomethyl-[1,3]-dioxolane (DLin-KD MA), 1,2-Dilinoleylcarbamoyloxy-3-dimethylaminopropane (D Lin-C-DAP), 1,2-dilinoleyloxy-3 -(Dimethylamino)acetoxypropane (DLin-DAC), 1,2-Dilinoleyl Oxy-3-morpholinopropane (DLin-MA), 1,2-dilinoleoyl-3-di Methylaminopropane (DLinDAP), 1,2-dilinoleylthio-3-dimethylaminopropane Minopropane (DLin-S-DMA), 1-linoleoyl-2-linoleyloxy- 3-Dimethylaminopropane (DLin-2-DMAP), 1,2-Dilinoleyloxy -3-trimethylaminopropane chloride salt (DLin-TMA.Cl), 1,2-dimethylaminopropane chloride salt DLin-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-propanedio (DOAP), 1,2-dilinoleyloxo-3-(2-N,N-dimethylamino)ethoxy Dimethylpropane (DLin-EG-DMA), N,N-dioleyl-N,N-dimethylane Monomethanol chloride (DODAC), 1,2-dioleyloxy-N,N-dimethylamino Propane (DODMA), 1,2-distearyloxy-N,N-dimethylaminopropane N-(1-(2,3-dioleyloxy)propyl)-N,N,N- Trimethylammonium chloride (DOTMA), N,N-distearyl-N,N-dimethyl Diethylammonium bromide (DDAB), N-(1-(2,3-dioleoyloxy)propanol) propyl)-N,N,N-trimethylammonium chloride (DOTAP), 3-(N-( N',N'-dimethylaminoethane)-carbamoyl)cholesterol (DC-Chol ), N-(1,2-dimyristyloxyprop-3-yl)-N,N-dimethyl-N-hydroxypropane Dihydroxyethylammonium bromide (DMRIE), 2,3-dioleyloxy-N- [2(Spermine-carboxamido)ethyl]-N,N-dimethyl-1-propanamin Trifluoroacetate (DOSPA), Dioctadecylamidoglycylspermine (DOGS), 3-dimethylamino-2-(cholest-5-ene-3-β-oxybutane -4-oxy)-1-(cis,cis-9,12-octadecadienoxy)propane (CLinDMA), 2-[5'-(cholest-5-ene-3-β-oxy)-3'- oxapentoxy)-3-dimethyl-1-(cis,cis-9',1-2'-octyl (Tadecadienoxy)propane (CpLinDMA), N,N-dimethyl-3,4-diole 1,2-N,N'-Dioleylcarbamyl- 3-Dimethylaminopropane (DOcarbDAP), 1,2-N,N'-Dilinoleyl Carbamyl-3-dimethylaminopropane (DLincarbDAP), or In a preferred embodiment, the cationic lipid is DLinDMA, DLin- K-C2-DMA ("XTC2"), or a mixture thereof. Preferably, 1,2-dimyristoyl-sn-glycero-3-ethyl-phosphatidylinositol is used. Examples include diethyl methyl cellulose (EDMPC).

[0022] Anionic surfactants (anionic lipids) include phospholipids and fatty acids. Examples of anionic surfactants include phosphatidylglycerol, cardiolipin, and the like. pine, diacylphosphatidylserine, diacylphosphatidic acid, N-dodecanoylphosphatidylcholine Phosphatidylethanolamine, N-succinylphosphatidylethanolamine, N- Glutaryl phosphatidylethanolamine, lysyl phosphatidylglycerol, palm Mitoyloleoylphosphatidylglycerol (POPG), and other anionic modifiers Examples include those in which a decorative group is bound to a neutral lipid.

[0023] As used herein, a "solid composite" is a composite made of solid matter. The solid composite in the form of a polymer may be called a solid particle. The solid composite may contain water. The solid composite may have a low moisture content, e.g. When measured by a known method, the moisture content is 1% by mass or less, 0.9% by mass or less, 0.8% by mass or less Bottom, 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. It may be 3% by weight or less, 0.2% by weight or less, or 0.1% by weight or less. The solid composite containing the surfactant may have a core-shell structure, the core being a water-soluble component. The shell contains a surfactant, which directs the water-soluble portion toward the core and the hydrophobic portion toward the The moiety may be directed to the outer surface of the solid composite. Thus, the resulting composite or solid composite may be , may have a hydrophilic center (core) but a hydrophobic outer surface (periphery or shell). Such a solid complex can be preferably dispersed in an oil phase. In the illustration, such solid complexes may not be dispersed in an oil phase (or liquid). By not using an oil phase, it is possible to prevent the skin from becoming excessively oily due to oil. Furthermore, by not using an oil phase, the patch may become easier to handle.

[0024] (dispersion formulation) According to the present disclosure, a method for producing a pharmaceutical composition comprising: ... Dispersion formulations are provided in which solid particles are dispersed in an oily base.

[0025] According to the present disclosure, a method for producing a pharmaceutical composition comprising: a solid particle comprising a complex of a water-soluble molecule and an emulsifier; and an aqueous base. Dispersion formulations are provided in which solid particles are dispersed in an aqueous base.

[0026] In some preferred embodiments, 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 ester is a sucrose fatty acid ester, more preferably a sucrose fatty acid ester. It is a sugar erucate ester.

[0028] In a preferred embodiment, the emulsifier comprises a glyceryl fatty acid. For example, polyglyceryl fatty acids, monoglyceryl fatty acids, polyglyceryl fatty acids, monoglyceryl fatty acids and monoglyceryl mono-fatty acids.

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

[0030] In a preferred embodiment, the fatty acid glyceryl may be, but is not limited to, a fatty acid Glyceryl Acid Group A: Polyglyceryl decaoleate, Polyglyceryl polyricinoleate , Polyglyceryl Polyricinoleate, Polyglyceryl Diisostearate, Tetraisostearate Polyglyceryl stearate, glyceryl monooleate, polyoxyethylene hydrogenated castor oil Sheep Oil, Polyglyceryl Pentaoleate, Polyglyceryl Decaisostearate, and In a preferred embodiment, the fatty acid glyceryl is Examples of fatty acid glyceryl group B include, but are not limited to, polyglyceryl decaoleate. Polyglyceryl-10, Polyglyceryl-6 Polyricinoleate, Polyglyceryl Polyricinoleate -6, Polyglyceryl-2 Diisostearate, Polyglyceryl Tetraisostearate -2, glyceryl monooleate, polyoxyethylene hydrogenated castor oil, pentaoleic acid Polyglyceryl-10, Polyglyceryl-10 Decaisostearate, and Monocaprylate Examples include glyceryl phosphate.

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

[0032] In certain preferred embodiments, the emulsifier is a mixture of sucrose erucate and glyceryl fatty acid ester. In a preferred embodiment, the glyceryl fatty acid comprises a polyglyceryl fatty acid, a monoglyceryl fatty acid, Polyglyceryl fatty acids, polymonoglyceryl fatty acids, and monomonoglyceryl fatty acids In a preferred embodiment, the fatty acid glyceryl is selected from the group consisting of, but not limited to, However, for example, it may be one or more selected from fatty acid glyceryl group A. The fatty acid glyceryl is not particularly limited, but may be selected from fatty acid glyceryl group B, for example. There can be one or more.

[0033] In certain preferred embodiments, the emulsifier is a mixture of sucrose erucate and polydecanoate. Contains sucrose erucate and polyglyceryl-10 decaoleate. The molar ratio of 10 is, for example, 5:95 to 95:5, 10:90 to 90:10, 15:85 to 85:15, 20:80~80:20, 25:75~75:25, 30:70~70:3 It can be 0, 35:65 to 65:35, or 40:60 to 60:40. The ratio of the acid ester to polyglyceryl-10 decaoleate is, for example, 5:95 to 75: 25, 10:90~65:35, 15:85~50:50, 20:80~40:60, 2 It can be 0:80 to 35:65, or 20:80 to 30:70. The ratio of ester to polyglyceryl-10 decaoleate is, for example, 25:75 to 95:5, 35:65~90:10, 50:50~85:15, 60:40~80:20, 65:3 It can be 5 to 80:20, or 70:30 to 80:20.

[0034] In certain preferred embodiments, the emulsifier is sucrose erucate and polyricinolein. Contains polyglyceryl-6 ester of sucrose erucate and polyglyceryl polyricinoleate The ratio of aryl-6 is, for example, 5:95 to 95:5, 10:90 to 90:10, 15:85 ~85:15, 20:80~80:20, 25:75~75:25, 30:70~70: It can be 30, 35:65 to 65:35, or 40:60 to 60:40. The ratio of the carboxylic acid ester to polyglyceryl-6 polyricinoleate is, for example, 5:95 to 7:95. 5:25, 10:90~6:35, 15:85~50:50, 20:80~40:60 , 20:80 to 35:65, or 20:80 to 30:70. The ratio of the ester to polyglyceryl-6 polyricinoleate is, for example, 25:75 to 95. :5, 35:65~90:10, 50:50~85:15, 60:40~80:20, 6 It can be 5:35 to 80:20, or 70:30 to 80:20.

[0035] In one preferred embodiment, the emulsifier is a mixture of sucrose erucate and polyricinoleate. Contains glyceryl-6. Sucrose erucate and polyglyceryl-6 polyricinoleate. The ratio is, for example, 5:95 to 95:5, 10:90 to 90:10, 15:85 to 85:1 5, 20:80~80:20, 25:75~75:25, 30:70~70:30, 35 :65 to 65:35, or 40:60 to 60:40. The ratio of polyglyceryl-6 polyricinoleate to polyglyceryl-6 polyricinoleate is, for example, 5:95 to 75:25, 0:90~65:35, 15:85~50:50, 20:80~40:60, 20:80 The ratio can be 35:65, or 20:80 to 30:70. The ratio of polyglyceryl-6 ricinoleate is, for example, 25:75 to 95:5, 35:6 5~90:10, 50:50~85:15, 60:40~80:20, 65:35~80 :20, or it can be 70:30 to 80:20.

[0036] In a preferred embodiment, the emulsifier is a mixture of sucrose erucate and polydiisostearate. Contains glyceryl-2, sucrose erucate and polyglyceryl diisostearate The ratio of 2 is, 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, It can be 35:65 to 65:35, or 40:60 to 60:40. The ratio of ester to polyglyceryl-2 diisostearate is, for example, 5:95 to 75:2 5, 10:90~65:35, 15:85~50:50, 20:80~40:60, 20 The ratio can be 20:80 to 35:65, or 20:80 to 30:70. The ratio of the glyceryl ester to polyglyceryl-2 diisostearate is, for example, 25:75 to 95:5. 35:65~90:10, 50:50~85:15, 60:40~80:20, 65:3 It can be 5 to 80:20, or 70:30 to 80:20.

[0037] In one preferred embodiment, the emulsifier is a mixture of sucrose erucate and tetraisostearate. Contains polyglyceryl-2, sucrose erucate and polyglyceryl tetraisostearate The ratio of rile-2 is, for example, 5:95 to 95:5, 10:90 to 90:10, 15:85 to 85:15, 20:80~80:20, 25:75~75:25, 30:70~70:3 It can be 0, 35:65 to 65:35, or 40:60 to 60:40. The ratio of the acid ester to polyglyceryl-2 tetraisostearate is, for example, 5:95 to 7:95. 5:25, 10:90~6:35, 15:85~50:50, 20:80~40:60 , 20:80 to 35:65, or 20:80 to 30:70. The ratio of the ester to polyglyceryl-2 tetraisostearate is, for example, 25:75 to 9: 5:5, 35:65~90:10, 50:50~85:15, 60:40~80:20, It can be 65:35 to 80:20, or 70:30 to 80:20.

[0038] In one preferred embodiment, the emulsifier is a mixture of sucrose erucate and glyceryl monooleate. The ratio of sucrose erucate to glyceryl monooleate, including glyceryl monooleate, is, 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 it can be 40:60 to 60:40. Sucrose erucate and monooleate glycerol The ratio of lyceryl is, for example, 5:95 to 75:25, 10:90 to 65:35, 15:8 5~50:50, 20:80~40:60, 20:80~35:65, or 20:80 The ratio of sucrose erucate to glyceryl monooleate can be ∼30:70. 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 It is possible.

[0039] In a preferred embodiment, the emulsifier is a mixture of sucrose erucate and polyoxyethylene ester. The ratio of sucrose erucate to polyoxyethylene hydrogenated castor oil, including castor oil, is 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~ It can be 65:35, or 40:60 to 60:40. The ratio of oxyethylene hydrogenated castor oil to hydroxyethylene hydrogenated castor oil is, for example, 5:95 to 75:25, 10:90 to 6 5:35, 15:85~50:50, 20:80~40:60, 20:80~35:65 or 20:80 to 30:70. The ratio of linseed oil to hydrogenated castor oil is, for example, 25:75 to 95:5, 35:65 to 90:10, 50:50~85:15, 60:40~80:20, 65:35~80:20, or 7 It can be 0:30 to 80:20.

[0040] In one preferred embodiment, the emulsifier is a mixture of sucrose erucate and polyglycerol pentaoleate. Sucrose erucate and polyglyceryl-10 pentaoleate, including glyceryl-10 The ratio may be, for example, 5:95 to 95:5, 10:90 to 90:10, or 15:85 to 85:15. , 20:80~80:20, 25:75~75:25, 30:70~70:30, 35: It can be 65 to 65:35, or 40:60 to 60:40. and polyglyceryl-10 pentaoleate ratio is, for example, 5:95 to 75:25, 10 :90~65:35, 15:85~50:50, 20:80~40:60, 20:80~ It can be 35:65, or 20:80 to 30:70. The ratio of polyglyceryl-10 oleate to polyglyceryl-10 oleate is, for example, 25:75 to 95:5, 35:65 ~90:10, 50:50~85:15, 60:40~80:20, 65:35~80: 20, or 70:30 to 80:20.

[0041] In one preferred embodiment, the emulsifier is a mixture of sucrose erucate and polydecaisostearate. Sucrose erucate and decaisostearate polyglycerides containing diglyceryl-10 The ratio of 10:10 to 15:85 is, for example, 5:95 to 95:5, 10:90 to 90:10, 15:85 to 85:15, 20:80~80:20, 25:75~75:25, 30:70~70:3 It can be 0, 35:65 to 65:35, or 40:60 to 60:40. The ratio of the acid ester to polyglyceryl-10 decaisostearate is, for example, 5:95 to 7:95. 5:25, 10:90~6:35, 15:85~50:50, 20:80~40:60 , 20:80 to 35:65, or 20:80 to 30:70. The ratio of the ester to polyglyceryl-10 decaisostearate is, for example, 25:75 to 9: 5:5, 35:65~90:10, 50:50~85:15, 60:40~80:20, It can be 65:35 to 80:20, or 70:30 to 80:20.

[0042] In one preferred embodiment, the emulsifier is a mixture of sucrose erucate and glyceryl monocaprate. The ratio of sucrose erucate to glyceryl monocaprate, including glyceryl monocaprate, is, 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 it can be 40:60 to 60:40. Sucrose erucate and monocapric acid glycerol The ratio of lyceryl is, for example, 5:95 to 75:25, 10:90 to 65:35, 15:8 5~50:50, 20:80~40:60, 20:80~35:65, or 20:80 The ratio of sucrose erucate to glyceryl monocaprate can be ∼30:70. 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 It is possible.

[0043] In the present disclosure, the oily base is a base that is liquid at room temperature (e.g., 25°C) and is substantially water-soluble. It is insoluble, viscous, and has a specific gravity lower than that of water, and is used in the cosmetics and pharmaceutical fields. There are no particular restrictions as long as the substance does not cause any adverse effects when it comes into contact with the skin of animals, including humans. Examples of such oily bases include cetanol, myristyl alcohol, and oleyl Alcohol, lauryl alcohol, cetostearyl alcohol, stearyl alcohol, Behenyl alcohol, jojoba alcohol, chimyl alcohol, selachyl alcohol, basil Alcohol, Hexyldecanol, Isostearyl Alcohol, 2-Octyldodecanoic Acid higher (polyhydric) alcohols such as dimer diol and dimer diol; Alcohol and its derivatives; 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, ante Long-chain fatty acids such as isoheneicosanoic acid, dimer acid, hydrogenated dimer acid, and their derivatives Liquid paraffin (mineral oil), heavy liquid isoparaffin, light liquid isoparaffin α-olefin oligomer, polyisobutene, hydrogenated polyisobutene, polybutene, Carbonated water such as quaran, olive-derived squalane, squalene, petrolatum, and solid paraffin Materials: Candelilla wax, carnauba wax, rice wax, Japan wax, beeswax , montan wax, ozokerite, ceresin, paraffin wax, microcrystalline Phosphorus wax, petrolatum, Fischer-Tropsch wax, polyethylene wax Waxes such as ethylene-propylene copolymers; coconut oil, palm oil, palm kernel oil, Flower oil, olive oil, castor oil, avocado oil, sesame oil, tea oil, evening primrose oil, wheat germ oil , perilla oil, apricot kernel oil, almond oil, macadamia nut oil, hazelnut oil, kukui nut Tea oil, rosehip oil, meadowfoam oil, persic oil, tea tree oil, peppermint oil, Corn oil, rapeseed oil, sunflower oil, wheat germ oil, linseed oil, cottonseed oil, soybean oil, peanut oil Raw oil, rice bran oil, cocoa butter, shea butter, hydrogenated coconut oil, hydrogenated castor oil, jojoba oil, Vegetable oils and fats such as hydrogenated jojoba oil; beef tallow, milk fat, horse fat, egg yolk oil, mink oil, turtle oil Animal fats and oils such as whale wax, lanolin, orange roughy oil, and other animal waxes; liquid lanolin Lanolin, reduced lanolin, adsorbed purified lanolin, acetic acid lanolin, acetic acid liquid lanolin, hydroxy Silanolin, Polyoxyethylene Lanolin, Lanolin Fatty Acids, Hard Lanolin Fatty Acids, Lanolin Lanolin alcohol, lanolin alcohol acetate, cetyl lanol acetate, etc. Phosphorus; cholesterol, dihydrocholesterol, lanosterol, dihydrolanosterol sterols such as cholesterols, phytosterols, and cholic acid; sapogenins; saponins; vinegar Cholesteryl nonanoate, cholesteryl stearate, isostearic acid Cholesteryl, Cholesteryl Oleate, N-Lauroyl-L-Glutamic Acid Di(cholesterol) Triethyl / Behenyl / Octyldodecyl), N-Lauroyl-L-Glutamic Acid Di(cholesteryl) Phytosteryl / Octyldodecyl), N-Lauroyl-L-Glutamic Acid Di(Phytosteryl / Behenyl / Octyldodecyl), N-Lauroyl-L-Glutamic Acid Di(Phytosteryl) / Octyldodecyl), 12-hydroxystearate cholesteryl, macadamia nuts Cholesteryl oil fatty acid, phytosteryl macadamia nut oil fatty acid, phytosteryl isostearate Lanolin fatty acid cholesteryl, soft lanolin fatty acid cholesteryl, hard lanolin fatty acid cholesteryl, Sterol esters such as branched chain fatty acid cholesteryl and long chain α-hydroxy fatty acid cholesteryl Acyl sarcosine alkyl esters such as N-lauroyl sarcosine isopropyl esters Lipid complexes such as phospholipid-cholesterol complexes and phospholipid-phytosterol complexes Body: Octyldodecyl myristate, hexyldecyl myristate, isostearic acid octyldodecyl Cetyldodecyl, Cetyl Palmitate, Octyldodecyl Palmitate, Cetyl Octanoate Hexyldecyl octanoate, isotridecyl isononanoate, isononyl isononanoate , octyl isononanoate, isotridecyl isononanoate, isodecyl neopentanoate, Isotridecyl neopentanoate, Isostearyl neopentanoate, Octyl neodecanoate Decyl, Oleyl Oleate, Octyldodecyl Oleate, Octyldodecyl Ricinoleate Decyl, Lanolin Fatty Acid Octyldodecyl, Dimethyloctanoic Acid Hexyldecyl, Eruca Octyldodecyl ester, hydrogenated castor oil isostearate, ethyl oleate, avocado oil Ethyl fatty acid, isopropyl myristate, isopropyl palmitate, octyl palmitate Long-chain fatty acid esters such as ethyl acrylate, isostearate isopropyl, and lanolin fatty acid isopropyl Sebacates: diethyl sebacate, diisopropyl sebacate, dioctyl sebacate, azide Diisopropyl adipate, dibutyl octyl sebacate, diisobutyl adipate, amber dicarboxylic acid esters such as dioctyl citrate and triethyl citrate; cetyl lactate, malic acid Oxy acid esters such as diisostearyl, hydrogenated castor oil monoisostearate; trio Glyceryl hexanoate (glyceryl tri-2-ethylhexanoate), glyceryl trioleate Glyceryl Triisostearate, Glyceryl Diisostearate, Caprylic / Capric Triisostearate Caprylic / Capric / Myristic / Stearic Triglyceride, Glyceryl Stearate, Caprylic / Capric / Myristic Triglyceride Glyceryl Phosphate, Hydrogenated Rosin Triglyceride (Hydrogenated Ester Gum), Rosin Triglyceride Glycerides (ester gum), glyceryl behenate eicosanedioate, trime trioctanoate Tyrolpropane, trimethylolpropane triisostearate, neopentanoic acid dioctanoate Neopentyl glycol, dicaprylic acid neopentyl glycol, dioctanoic acid 2-butyl-2 -Ethyl-1,3-propanediol, propylene glycol dioleate, tetraoctyl Pentaerythrityl tanoate, hydrogenated rosin pentaerythrityl, triethylhexanoate Ditrimethylolpropane, (Isostearic acid / Sebacic acid) ditrimethylolpropane Pentaerythrityl Triethylhexanoate, (Hydroxystearic Acid / Stearin Dipentaerythrityl Diisostearate / Rosin Acid, Diglyceryl Diisostearate, Tetraisostearate Polyglyceryl stearate, Polyglyceryl-10 nonaisostearate, Deca (Eruka Polyglyceryl-8 Hexyldecanoate / Isostearate / Ricinoleate, Polyglyceryl-8 Hexyldecanoate / Ceteareth-3 Diglyceryl Oligoester of Distearate, Glycol Distearate (Ethyl Distearate), ethylene glycol), 3-methyl-1,5-pentanediol dineopentanoate, dineo Polyhydric alcohol fatty acid esters such as 2,4-diethyl-1,5-pentanediol pentanoate Diisopropyl dimer dilinoleate, diisostearyl dimer dilinoleate , Dimer Dilinoleate Di(isostearyl / phytosteryl), Dimer Dilinoleate (Phytosteryl / Behenyl), Dimer Dilinoleic Acid (Phytosteryl / Isostearyl) (Cetyl / Cetyl / Stearyl / Behenyl), Dimer Dilinoleyl Dimer Dilinoleate, Dimer Dilinoleyl Dimer dilinoleyl isostearate, Dimer dilinoleyl hydrogenated rosin condensate, Dimer dilinoleyl Hydrogenated castor oil dilinoleate, hydroxyalkyl dimer dilinoleyl ether, etc. Derivatives of dimer acid or dimer diol; coconut oil fatty acid monoethanolamide (coconut oil fatty acid monoethanolamide) Cocamide MEA), coconut oil fatty acid diethanolamide (cocamide DEA), lauric acid mono Ethanolamide (Lauramide MEA), Lauric Acid Diethanolamide (Lauramide D EA), lauric acid monoisopropanolamide (lauramide MIPA), palmitic acid Monoethanolamide (Paltamide MEA), Palmitic acid diethanolamide (Palta Fat such as coconut oil fatty acid methylethanolamide (cocamidomethyl DEA), coconut oil fatty acid methylethanolamide (cocamidomethyl MEA) Acid alkanolamides; Dimethicone (dimethylpolysiloxane), Highly polymerized dimethicone ( Highly polymerized dimethylpolysiloxane), decamethylcyclopentasiloxane (simply cyclopentasiloxane) Cyclomethicone (cyclic dimethylsiloxane), phenyl trimethylsiloxane, etc. Methicone, Diphenyl Dimethicone, Phenyl Dimethicone, Stearoxypropyl Dimethyl Amine, (Aminoethylaminopropylmethicone / Dimethicone) Copolymer, Dimethicone dimethiconol crosspolymer, silicone resin, silicone rubber, aminopropyl Amino-modified silicones such as rudimethicone and amodimethicone, and cation-modified silicones , polyether-modified silicones such as dimethicone copolyol, polyglycerin-modified silicones sugar-modified silicone, carboxylic acid-modified silicone, phosphate-modified silicone, sulfate-modified Silicone, alkyl-modified silicone, fatty acid-modified silicone, alkyl ether-modified silicone Silicone, amino acid modified silicone, peptide modified silicone, fluorine modified silicone, Cation-modified and polyether-modified silicones, amino-modified and polyether-modified silicones Silicone, alkyl-modified and polyether-modified silicone, polysiloxane oxysilane silicones such as alkylene copolymers; perfluorodecane, perfluorooctane, perfluorooctane; Fluorine-based oils such as fluoropolyether are also included. Among these, long-lasting oils such as oleic acid are preferred. Chain fatty acids, vegetable oils such as olive oil and jojoba oil, isopropyl myristate, palmitoyl palmitate Carbon numbers of isopropyl tungstate, octyl palmitate, isopropyl isostearate, etc. C1-8 alkyl esters of 12-18 fatty acids, hydrocarbons such as squalane isopropyl myristate and squalane are more preferred. The oily base may be isopropyl myristate.

[0044] The aqueous base may be water or an aqueous solution containing a pharmaceutically acceptable additive. Pharmaceutically acceptable additives include pharmaceutically acceptable salts, isotonicity agents, pH adjusters, etc. Aqueous solutions containing pharmaceutically acceptable additives can be used in, for example, biodegradable liquids. It may be saline.

[0045] Examples of water-soluble molecules include hyaluronic acid and its salts, heparin and its analogs. Polysaccharides such as chitosan; proteins such as egg albumin, casein, and collagen; Vitamins such as vitamin C and its derivatives, retinol, amino acids, tranexamic acid, Placenta extract and other amino acids; arbutin and other glycosides; coenzyme Q10 and other supplements Enzymes; nucleotides such as nicotinamide mononucleotide (NMN); cholera toxin Subunit B, epidermal growth factor, serum albumin, immunoglobulin, interleukin, Interferon, human glucagon, human growth hormone, erythropoietin, platelet-derived Protein preparations such as insulin and long-acting factors; cancer vaccines, allergy vaccines, etc. The molecular weight of the water-soluble molecule is preferably 500 Da or more. and more preferably 1000 Da (i.e., 1 kDa) or more, and preferably is 200 kDa or less, more preferably 100 kDa or less, and particularly preferably 5 It is less than 0 kDa.

[0046] Water-soluble molecules include lipid vesicles, lipid nanoparticles, and extracellular vesicles (e.g., exosomes). , polyion complex micelles, polyion complex polymersomes, etc. The nanoparticles or nanovesicles may have a Z-average size of sub-μm. When such nanoparticles or nanovesicles are used as water-soluble molecules, In this case, the manufacturing process of the solid particle dispersion formulation can be applied. or nanovesicles are mixed with an emulsifier in a volatile oil phase (e.g., cyclohexane) to form an emulsion. The volatile oil phase can be removed by freeze-drying.

[0047] The particle size (Z-average size) of the solid particles is, for example, 700 nm or less, 600 nm or less, 50 It can be 0 nm or less, 400 nm or less, 300 nm or less, or 200 nm or less. The particle size (Z-average size) can be, for example, 100 nm or more or 200 nm or more. The particle size (Z-average size) of the solid particles is, for example, 100 nm to 600 nm, 100 nm ~500nm, 100nm~400nm, 100nm~300nm, 100nm~200 nm, 200nm~600nm, 200nm~500nm, 200nm~400nm, The Z-average size is specified in ISO 13321. Particles smaller than 2 μm in diameter are collected using a Zetasizer Nano ZS 90 (M can be measured by dynamic light scattering (DLS) using a .

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

[0049] (Method for preparing dispersion formulation) The target molecule, such as a water-soluble molecule, is placed in an oil phase (preferably a volatile oil phase, e.g., cyclohexane). When mixed with an emulsifier in a solvent (solvent), the core contains target molecules, such as water-soluble molecules, and the shell is emulsified. Particles having a core-shell structure containing the agent are formed. The particles are dispersed in an oil phase. The emulsifier includes one or more emulsifiers. When the oil phase used herein is a volatile oil phase (e.g., silane, If the solvent is hexane, it is easy to evaporate the solvent and dry it (e.g. By removing the solvent through freeze-drying (freeze drying), the core contains water-soluble molecules and the shell contains emulsifiers. and obtaining particles having a core-shell structure containing the above-mentioned hydroxyl group as solid particles (also called "solid composites"). The solid particles can be dispersed in an oily or aqueous base, respectively. These are solid particle dispersion oil-based formulations or solid particle dispersion aqueous formulations (also simply referred to as "solid particle dispersion formulations"). Such solid particle dispersed oil-based preparations are difficult for water-soluble molecules to penetrate. It can penetrate deep into the stratum corneum (which is non-hydrophilic), and in some cases penetrate below the stratum corneum, and preferably penetrates into the bloodstream. According to the examples, the aqueous solid particle dispersion preparation also allows the active ingredient to penetrate into the stratum corneum. The drug has the ability to penetrate into the bloodstream and preferably does so.

[0050] (cosmetics) According to the present disclosure, a cosmetic product containing the dispersion formulation of the present disclosure is provided. The cosmetic product may be a cream, lotion, spray, powder, or patch. It contains the dispersion formulation shown and dermatologically acceptable additives (e.g., excipients, carriers, etc.). Good too. [Example]

[0051] Example 1: Effect of emulsifiers Preparation of solid particle dispersion solution 10 mg of fluorescein-labeled hyaluronic acid was dissolved in 2 mL of MilliQ water. 200 mg of each emulsifier was dissolved in 4 mL of cyclohexane. The aqueous and organic phases were placed in glass vials. The mixture was added to the mixture and stirred at 26,000 rpm for 2 minutes using a Polytron homogenizer. The mixture was flash frozen in liquid nitrogen and lyophilized for 24 hours. The total amount of the solid obtained after drying was redispersed in 5 mL of olive oil to obtain a solid particle dispersion. The solution was made into a liquid.

[0052] [Table 1]

[0053] Particle size distribution measurement The solid particle dispersion was diluted 100 times with cyclohexane and measured at 20°C using a Zetasizer Nano Pro. The particle size distribution and Z-average particle size were measured.

[0054] Yucatan Micropig Skin Permeability Test Yucatan micropig skin (4 months old) was thawed and the subcutaneous tissue was removed using a scalpel. The donor and acceptor layers of the vertical Franz cell were placed on the stratum corneum facing up. The receptor phase was filled with 5 mL of PBS solution (pH 7.4) at 32°C. 100 μL of the solid particle dispersion solution was added to the first phase and incubated at 32°C for 24 hours. After 24 hours, the solid particle dispersion solution of the donor phase was wiped off with Kimwipes, and the outermost two layers of the stratum corneum were The remaining stratum corneum was removed by tape stripping. Every 5 pieces were immersed in 1 mL of a solution (PBS / methanol / acetonitrile = 2 / 1 / 1, v / v). The skin other than the stratum corneum was divided into 16 sections with a scalpel, and 1 mL of PBS solution was added to each section. Similarly, extraction was carried out at room temperature for 22 hours with shaking. The extract was diluted 10 times with PBS solution, and the fluorescence intensity was measured using a microplate reader. The amount of hydroxylase was determined.

[0055] Table 2 shows the composition of the prepared solid particle dispersion formulation. Table 3 shows the composition of the sucrose fatty acid ester. The particle size distribution in solid particle dispersion formulations prepared by mixing ester (ER-290) with various emulsifiers The Z-average value and polydispersity index are shown. Hyaluronic acid was used as Hyalo Oligo (trademark). .

[0056] [Table 2]

[0057] [Table 3] JPEG2025022745000004.jpg187158

[0058] Even in cases where a transparent dispersion precipitated when using only one emulsifier, mixing two types of emulsifiers resulted in a Z- It is now possible to prepare particles with small average particle size and low polydispersity index. The smallest Z-average value was observed when the emulsifier was 25% of the total emulsifier. The emulsifiers that were expensive were polyglyceryl-6 polyricinoleate and polyglyceryl diisostearate. Like Lyceryl-2, both the head group and the tail group were large and bulky emulsifiers. Emulsifiers with small emulsifiers, such as glyceryl monocaprate, tend to have a lower stabilizing effect. On the other hand, when decaglycerin fatty acid ester is used, the hydrophilicity of the emulsifier increases. Therefore, the effect of stably dispersing hydrophilic drug solids was weakened. The stabilizing effect of castor oil was also low. It was suggested that the highest stabilization effect could be obtained when the number of polymerization glycerin units was in the range of 2-6. In Tables 3 and 4, S is the most preferred, A is the next most preferred, and B is the most preferred. The second most preferable is C, and the second most preferable is B. The presence of precipitates or cloudiness indicates the separation of solid particles in the liquid. Therefore, even if sediment or cloudiness is present, it does not mean that there is no solid particle. Please note that the penetration of the drug into the skin is not denied. Even such samples can be used for skin penetration applications.

[0059] In addition, long-term dispersibility was evaluated. After preparing the solid particle dispersion formulation, it was left at 25°C for 2 months. The dispersibility of the preparation after storage was checked visually, and the results are shown in Table 4.

[0060] [Table 4]

[0061] As shown in Table 4, when the two emulsifiers were mixed, the long-term production The mixing ratio of emulsifiers to obtain dispersibility or long-term dispersibility is A professional may be able to adjust accordingly.

[0062] Figure 1 shows the solids prepared by mixing sucrose fatty acid ester (ER-290) with various emulsifiers. The figure shows the amount of permeation into the skin when the body particle dispersion formulation was administered to Yucatan micropig skin. There is a correlation between the Z-average value and penetration into the substratum corneum, and formulations with lower Z-average values ​​are more effective. It was revealed that the drug penetrated into the layer below the stratum corneum. It also had high penetration into the hydrophilic areas of the skin below the stratum corneum (Figure 2). For example, keratin-filled keratinocytes are composed of hydrophobic regions of ceramide bilayers. Therefore, small particles are spread out in the highly hydrophobic stratum corneum. It is thought that the hydroxybenzoate was able to penetrate between the keratinocytes more stably.

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

[0064] The obtained exosomes were mixed with a mixture of ER290 and CRS-75 in cyclohexane, Or, it was mixed with a mixture of ER290 and 202P. This procedure resulted in exosomes in the core. It is believed that particles having a core-shell structure containing an emulsifier in the shell are formed. The cyclohexane is removed by freeze-drying to form solid composite particles with a core-shell structure. The solid complex particles were dispersed in IPM to prepare a solid particle dispersion formulation of exosomes. Made.

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

[0066] [Table 5]

[0067] The appearance of the obtained dispersion preparation is shown in Figure 3, and a transparent dispersion preparation was obtained. The particle size distribution of the dispersion formulation was measured at 25°C using a Thetasizer Pro. The results were as follows: As shown in Figure 4 and Table 6, as shown in Table 6, the comparison of It was found that a formulation having relatively small particles was obtained.

[0068] [Table 6]

[0069] The obtained solid particle dispersion formulation containing exosomes was applied to the skin of micropigs, and the resulting immersion The skin of a Yucatan micro pig (4 months old) was thawed, and the subcutaneous tissue was cut using a scalpel. The tissue was cut into 2 cm x 2 cm pieces and placed in a vertical Franz cell donor with the stratum corneum facing up. The receptor phase was sandwiched between the receptor phase and the acceptor phase. The receptor phase was filled with 5 mL of PBS solution (pH 7.4) at 32°C. 100 μL of the dispersion formulation of Example 2-1 or 2-2 was administered to the donor phase, and the mixture was incubated at 32° C. for 24 hours. After 24 hours, the donor phase dispersion was wiped off with Kimwipes. The two outermost layers were removed by tape stripping. The remaining skin was frozen and an 8 μm cryostat was applied. The skin tissue sections were prepared using ProLong Glass Antifade Mountant with NucBlu St. The tissue was then mounted in PET (Thermo Fisher Scientific) and observed using a fluorescence microscope. The results are shown in Figure 5. As shown in Figure 5, by dispersing the , penetration of exosomes into the epidermis was observed.

[0070] Example 3: Aqueous dispersion 4 mg of nicotinamide mononucleotide (NMN) was dissolved in 2 mL of MilliQ water. ER-290 19 57 mg of SY Glystar CRS-75 was dissolved in 4 mL of cyclohexane. Place in a glass vial and homogenize at 26°C using a Polytron homogenizer to form an emulsion. The emulsion was stirred at 100 rpm for 2 minutes. The resulting emulsion was flash frozen in liquid nitrogen and kept frozen for 24 hours. Drying was carried out.

[0071] After drying, 20 mg of the liquid obtained was dispersed in 1 mL of cyclohexane. 60 mg of Nikko Chemicals was dissolved in 3 mL of water. The aqueous and organic phases were placed in a glass vial. The mixture was stirred at 26,000 rpm for 2 minutes using a Polytron homogenizer. The sample was flash frozen in liquid nitrogen and freeze-dried for 24 hours. The freeze-dried liquid was then dissolved in 1 mL of water. By dispersing the solid particles in water, a dispersion liquid (aqueous solid particle dispersion) was obtained. Final NMN concentration; 1 mg / mL).

[0072] Particle size distribution measurement The resulting dispersion was diluted 100 times with water and analyzed for particle size at 25°C using a Zetasizer Pro. The fabric was measured, and the results are shown in Figure 6 and Table 7. By applying the technology of the present disclosure to NMN, it can be converted into solid particles and dispersed in an aqueous solution. The resulting particles had a sub-micron particle size distribution.

[0073] [Table 7]

[0074] Yucatan Micropig Skin Permeability Test Yucatan micropig skin (4 months old) was thawed and the subcutaneous tissue was removed using a scalpel. The donor and acceptor layers of the vertical Franz cell were placed on the stratum corneum facing up. The receptor phase was filled with 5 mL of PBS solution (pH 7.4) at 32°C. 150 μL of the resulting dispersion was added to the first phase and incubated at 32°C for 24 hours. A 1 mg / mL NMN aqueous solution was used.

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

[0076] The nuclear extract was diluted 10-fold with diluent (0.1% formic acid / acetonitrile = 50 / 50, v / v) and analyzed using LC-MS. The amount of NMN in the extract was quantified.

[0077] As shown in Figure 7, the solid particle dispersion solution exerted a N It was possible to penetrate a large amount of MN.

Claims

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

2. The fatty acid glyceryl may be polyglyceryl fatty acid, monoglyceryl fatty acid, poly ... and monoglyceryl fatty acids, and monoglyceryl fatty acids. Item 2. The dispersion formulation according to item 1.

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

4. 4. The method according to claim 1, wherein the one or more emulsifiers further comprise a sugar fatty acid ester. Item 3. The dispersion formulation according to item 1.

5. The method according to any one of claims 1 to 4, wherein the sugar fatty acid ester comprises a sucrose fatty acid ester. Dispersed formulation as described above.

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

7. Claims 4 to 6, wherein the one or more emulsifiers comprise 10 to 40 mole % of a sugar fatty acid ester. The dispersion formulation according to any one of claims 1 to 4.

8. 8. The method according to claim 1, wherein the Z-average size of the particles is less than or equal to 500 nm. Dispersion formulation.

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

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

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

12. 12. The method according to claim 10 or 11, wherein the one or more emulsifiers include sucrose erucate. Dispersed formulation as described above.

13. 13. The method according to claim 10, wherein the Z-average size of the particles is less than or equal to 200 nm. Dispersed formulation as described above.

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