BR112019014180B1 - CORE-CASTING STRUCTURE, FORMULATION, TAPE PREPARATION, MEDICINE FOR EXTERNAL APPLICATION AND COSMETIC PRODUCT COMPRISING SAID CORE-CASTING STRUCTURE - Google Patents

Abstract

A core-shell structure is provided that exhibits excellent fast-acting properties in terms of percutaneous absorption of an active ingredient. A core-shell structure that is provided with a core portion containing an active ingredient and a shell portion containing a surfactant having an HLB value of 4 to 14. The core portion is a solid; and the surfactant has a saturated hydrocarbon group having from 7 to 15 carbon atoms or an unsaturated hydrocarbon group having from 7 to 17 carbon atoms.

Description

Technical Field

[0001] The present invention relates to a core-shell structure and a formulation, an external medicament, a tape preparation and a cosmetic that includes the core-shell structure.

Background Technique

[0002] In the areas of external medicines, cosmetics and the like, techniques for the transdermal absorption of an active ingredient, such as pharmaceuticals, have been developed. The processes for transdermal absorption of an active ingredient can be influenced by skin barrier function, metabolism or the like, and such influence is known to depend on the drugs.

[0003] Patent Literature 1 described below reports that a formulation including an active ingredient and sucrose erucic acid ester increased the amount of active ingredient absorbed transdermally.

[0004] Patent Literature 2 described below reports that a formulation including an active ingredient and a surfactant such as tetraglycerin-condensed ricinoleate increased the amount of transdermal absorption. Citation List Patent Literature Patent Literature 1: Japanese Patent No. 4843494 Patent Literature 2: Japanese Patent No. 5531230

Summary of the Invention Technical problem

[0005] When the formulation of Patent Literatures 1 or 2 for an external medicine or cosmetic is used, however, the transdermal absorption capacity of the active ingredient is still not sufficient. The formulations of Patent Literature 1 and 2, in particular, have a long transdermal absorption lag time for the active ingredient (lag time: time required for an active ingredient to permeate the skin), and a long time may have been required from administration to the generation of the medicinal effect. In other words, the formulations of Patent Literature 1 and 2 provided an insufficient immediate effect on transdermal absorption of the active ingredient.

[0006] It is an object of the present invention to provide a core-shell structure, a formulation, an external medicament, a tape preparation and a cosmetic that has an excellent immediate effect on transdermal absorption of an active ingredient.

Solution of the problem

[0007] The present inventors have studied intensively to solve the above problem, and as a result, they have discovered that the above problem can be solved using a core-shell structure that includes a central part containing an active ingredient and a shell part containing an active ingredient. surfactant having an HLB value of 4 to 14, the central part being solid, and the surfactant containing a saturated hydrocarbon group having from 7 to 15 carbon atoms or an unsaturated hydrocarbon group having from 7 to 17 carbon atoms. The present invention has been carried out by further attempts made on the basis of this discovery and covers the following aspects.

[0008] That is, a core-shell structure according to the present invention includes a central part containing an active ingredient and a shell part containing a surfactant having an HLB value of 4 to 14, wherein the central part is solid and the surfactant has a saturated hydrocarbon group that has 7 to 15 carbon atoms or an unsaturated hydrocarbon group that has 7 to 17 carbon atoms.

[0009] In a specific aspect of the core-shell structure according to the present invention, the surfactant is a surfactant formed by linking an alcohol with a fatty acid through the ester linkage or amide linkage, the alcohol has a molecular weight in the range of 70 g/mol to 330 g/mol.

[0010] In another specific aspect of the core-shell structure according to the present invention, the surfactant contains at least one selected from the group consisting of sorbitan fatty acid esters, glycerin fatty acid esters, fatty acid esters of propylene glycol and fatty acid alkanolamides. Preferably, the surfactant contains at least one selected from the group consisting of sorbitan fatty acid esters, glycerin fatty acid esters and propylene glycol fatty acid esters.

[0011] In another specific aspect of the core-shell structure according to the present invention, the glycerin fatty acid ether is at least one selected from monoglycerin fatty acid esters, diglycerin fatty acid esters, and diglycerin fatty acid esters. triglycerin fatty acid.

[0012] In yet another aspect of the core-shell structure according to the present invention, the mass ratio between the active ingredient and the surfactant (active ingredient: surfactant) is 1:0.5 to 1:100.

[0013] In yet another aspect of the core-shell structure according to the present invention, the mass ratio between the active ingredient and the surfactant (active ingredient: surfactant) is 1:5 to 1:100.

[0014] In yet another aspect of the core-shell structure according to the present invention, the mass ratio between the active ingredient and the surfactant (active ingredient: surfactant) is 1:0.5 to 1:5.

[0015] In yet another aspect of the core-shell structure according to the present invention, the mass ratio between the active ingredient and the surfactant (active ingredient: surfactant) is 1:0.5 to 1:2.

[0016] A formulation according to the present invention contains a core-shell structure constituted in accordance with the present invention.

[0017] An external medicament according to the present invention contains a core-shell structure constituted in accordance with the present invention.

[0018] A tape preparation according to the present invention contains a core-shell structure constituted in accordance with the present invention.

[0019] A cosmetic according to the present invention contains a core-shell structure constituted in accordance with the present invention.

Advantageous Effects of the Invention

[0020] According to the present invention, it is possible to provide a core-shell structure, a formulation, an external medicament, a tape preparation and a cosmetic that has an excellent immediate effect on transdermal absorption of active ingredients. When the surfactant contains at least one selected from the group consisting of sorbitan fatty acid esters, glycerin fatty acid esters and propylene glycol fatty acid esters, it is possible to provide a core-shell structure, a formulation, a medicament external, a tape preparation and a cosmetic that have an excellent immediate effect on transdermal absorption and additionally have reduced skin irritation. Brief Description of the Drawings Figure 1 is a schematic cross-sectional view of a core-shell structure in accordance with an embodiment of the present invention. Figure 2 is a view to illustrate the hydrophilic portion and the hydrophobic portion of a surfactant formed by an alcohol and a fatty acid linked through the ester bond. Figure 3 is a view used to illustrate the hydrophilic portion and the hydrophobic portion of a surfactant formed by an alcohol and a fatty acid linked through the amide bond. Figure 4 is a schematic cross-sectional view showing a tape preparation in accordance with an embodiment of the present invention. Figure 5 is a simplified view of a drug skin permeation test cell used in Test Example 1. Figure 6 is a schematic view used to illustrate a method of measuring delay time. Figure 7 shows the X-ray diffraction spectra of the tape preparations obtained in Example 21, Comparative Example 8 and Comparative Example 9.

Description of the modalities

[0021] Details of the present invention will be described below.

[Core-shell structure]

[0022] A core-shell structure according to the present invention includes a central part containing an active ingredient and a shell part containing a surfactant.

[0023] In the present invention, the central part and the shell part can be connected to each other through intermolecular force or the like, to form an assembly. However, from the point of view of further increasing the transdermal absorption capacity of the active ingredient, at least a part of the surface of the central part is preferably coated with the shell part.

[0024] More specifically, 30% or more of the surface of the central part is preferably coated with the casing part. More preferably 50% or more, even more preferably 70% or more, even more preferably 85% or more, particularly preferably 95% or more, and most preferably 99% or more of the surface is coated. The surface of the central part can be completely covered with the shell part. The core-shell structure, which is configured as described above, can release the active ingredient contained in the central part into the body when applied to the skin, for example.

[0025] In the present invention, the central part above is solid. Since the central part is solid, the stability on a base described below can be further enhanced. In this case, dispersion of the core-shell structure in a base phase such as an oil phase can form a formulation having an S/O (Solid in Oil) type structure.

[0026] As described in the section on a production method below, the core-shell structure of the present invention can be obtained by drying a W/O emulsion to remove the solvent (aqueous solvent and oily solvent), and thus, its central part is solid (S in the S/O (Solid in Oil) type described above). The W/O emulsion drying step preferably removes moisture substantially completely. Specifically, the water content is preferably 5% by weight or less, more preferably 2% by weight or less, even more preferably 1% by weight or less, particularly preferably 0.5% by weight or less, according to the measured by the Karl Fisher method, for example. Thus, the core-shell structure of the present invention is different from a W/O emulsion.

[0027] In the present invention, the surfactant contained in the shell part has an HLB value of 4 to 14. The surfactant includes a saturated hydrocarbon group having from 7 to 15 carbon atoms or an unsaturated hydrocarbon group having from 7 to 17 carbon atoms. Note that "aa to bb" refers to "aa or more and bb or less". For example, an HLB value of 4 to 14 is intended to refer to an HLB value of 4 or more and 14 or less.

[0028] The core-shell structure of the present invention has an excellent immediate effect on the transdermal absorption of an active ingredient because the HLB value of the surfactant contained in the shell part is in a specific range, and additionally the number of carbon atoms in the hydrocarbon group of the surfactant is in the specific range described above.

[0029] The reason for this can be explained as follows. When the HLB value of the surfactant contained in the shell part is in the specific range described above, it is possible to reduce the barrier function of the skin and thus obtain a skin barrier structure. core-shell having an excellent immediate effect on transdermal absorption.

[0030] When the number of carbon atoms in the hydrocarbon group of the surfactant is in the specific range described above, the ability to release the active ingredient from the particles in the body increases. Consequently, it is possible to obtain a core-shell structure having an excellent immediate effect on transdermal absorption.

[0031] The core-shell structure of the present invention, which has an excellent immediate effect on transdermal absorption of active ingredients, can be suitably used for formulations. Among others, the core-shell structure can be suitably used in the fields of external medicines, tape preparations, cosmetics, injections or the like.

[0032] An example of the core-shell structure of the present invention will now be described with reference to the drawings.

[0033] Figure 1 is a schematic cross-sectional view of a core-shell structure in accordance with an embodiment of the present invention.

[0034] As shown in Figure 1, a core-shell structure 10 includes a core part 11 and a shell part 12. The surface of the core part 11 is coated with the shell part 12.

[0035] The shape of the core-shell structure of the present invention is not limited to such spherical particles. The core-shell structure of the present invention may be a particle having a rod-like, cubic, lens-like, micellar, lamellar, hexagonal, bicellar, sponge-like or spiny shape or may be amorphous. As described above, the shape of the core-shell structure of the present invention is not particularly limited. As described above, at least a part of the surface of the central part is preferably coated with the casing part.

[0036] The size of the core-shell structure of the present invention is not particularly limited. From the point of view of further increasing the transdermal absorption capacity of the active ingredient, the average size of the core-shell structure can preferably be 1 nm to 100 μm.

[0037] It is observed that, in the present invention, the average size of the core-shell structure is the average diameter number calculated by the dynamic light scattering method in the case of dispersion in a solvent (for example, squalene or the like) .

[0038] Details of the central part and the casing part will now be described.

(The center, the middle part, the nucleus)

[0039] The central part contains at least one active ingredient.

[0040] Specific examples of the active ingredient include, but are not particularly limited to, dementia therapeutic agents, antiepileptic agents, antidepressants, antiparkinsonian agents, antiallergic agents, anticancer agents, antidiabetics, antihypertensive agents, drugs for respiratory diseases , drugs for erectile dysfunction, therapeutic agents for skin diseases and local analgesics. An active ingredient may be used alone or two or more active ingredients may be used in combination.

[0041] More specific examples include memantine, donepezil, diphenhydramine, vardenafil, octreotide, rivastigmine, galantamine, nitroglycerin, lidocaine, fentanyl, male hormones, female hormones, nicotine, clomipramine, nalfurafine, metoprolol, fesoterodine, tandospirone, beraprost sodium, taltirelin, lurasidone, nefazodone, rifaximin, benidipine, doxazosin, nicardipine, formoterol, lomerizine, amlodipine, teriparatide, bucladesine, cromoglycic acid, lixisenatide, exenatide, liraglutide, lanreotide, glucagon, oxytocin, calcitonin, elcatonin, glatiramer, acid risedronic, diclofenac and ascorbic acid, and their pharmaceutically acceptable salts.

[0042] The pharmaceutically acceptable salt is not particularly limited, and any of the acidic salts and basic salts can be used. Examples of the acidic salts include inorganic acid salts such as hydrochloride, hydrobromide, sulfate, nitrate and phosphate, and organic acid salts such as acetate, propionate, tartrate, fumarate, maleate, malate, citrate, methanesulfonate, bensenesulfonate and p- toluenesulfonate. Examples of the basic salts include alkali metal salts such as sodium salts and potassium salts, and alkaline earth metal salts such as calcium salts and magnesium salts. Specific examples of active ingredient salts include memantine hydrochloride, donepezil hydrochloride, rivastigmine tartrate, galantamine hydrobromide, clomipramine hydrochloride, diphenhydramine hydrochloride, nalfurafine hydrochloride, metoprolol tartrate, fesoterodine fumarate, vardenafil hydrochloride, nalfurafine hydrochloride, tandospirone citrate, beraprost sodium, lurasidone hydrochloride, nefazodone hydrochloride, benidipine hydrochloride, doxazosin mesylate, nicardipine hydrochloride, formoterol fumarate, lomerizine hydrochloride and amlodipine besylate.

[0043] An active ingredient to be formulated in a cosmetic is not particularly limited, as long as it is required to penetrate transdermally. Examples of active ingredients include vitamin ingredients such as vitamin C and vitamin E, humectant ingredients such as hyaluronic acid, ceramide and collagen, skin lightening ingredients such as tranexamic acid and arbutin, hair growth ingredients such as minoxidil, beauty ingredients such as FGF (fibroblast growth factor) and EGF (epidermal growth factor), and salts and derivatives thereof.

[0044] The active ingredient in the present invention preferably has low skin irritation. Low skin irritation means having a primary irritation index (P.I.I.) of 5 or less. Note that the primary irritation index can be measured by a method described below.

1. Formulation Preparation

[0045] An active ingredient is added to a Plastibase ointment base (manufactured by Taisho Pharmaceutical Co., Ltd.) such that its content reaches 4% by weight based on the total weight, mixed and dispersed therein to produce a formulation.

2. Assessment of Skin Irritation (Primary Irritation Index Assessment)

[0046] The dorsal skin of a rabbit is shaved with an electric clipper (with an electric shaver as required). Healthy skin at two points on each side of the dorsal midline of the dorsal skin, that is, at four points in total, is used as administration sites. Afterwards, the prepared formulation is taken with a spatula and spread evenly with pieces of gauze, each having a size of 2 cm x 2 cm, and the pieces are fixed over the administration sites. The pieces of gauze are secured by covering with a non-woven adhesive bandage (manufactured by Nichiban Co., Ltd., MESHPORE, No. 50). Afterwards, the administration sites are completely covered with gauze and then sealed through the covering with an elastic adhesive fabric bandage (manufactured by Nichiban Co., Ltd., ELASTPORE, No. 100). Sealing is completed 24 hours after the start of administration and administration specimens are removed.

[0047] Skin reaction 24 hours after administration (30 minutes after sealing is completed and administration specimens are removed) is observed with the naked eye. Thereafter, the skin reaction later at 48 hours and 72 hours after administration (30 minutes after sealing is completed and administration specimens are removed) is observed with the naked eye in the same manner. Assessment of skin reaction should be performed based on the Draize score shown in Table 1 below.Table 1

[0048] Specifically, individual skin reaction scores (sum of erythema and eschar formation and edema formation) at each rabbit's administration sites are calculated for each administration specimen at each observation time. Thereafter, the primary irritation index (Primary Irritation Index; P.I.I.) is calculated from the individual scores each at 24 hours and 72 hours after administration (the score at 48 hours after administration is not added). Specifically, the following equations (1) and (2) are used for the calculation. Average score of each administration site = (Sum of individual scores at 24 hours and 72 hours after administration) / 2 Equation (1) Primary irritation index (P.I.I.) = (Sum of average score of each administration site) / ( 3 (rabbits)) Equation (2)

[0049] The primary irritation index measured by the method described above is preferably 2 or less, more preferably 1 or less.

[0050] Examples of low skin irritation active ingredients include loxoprofen sodium dihydrate (P.I.I. = 0.3), rivastigmine (P.I.I. = 0.5), donepezil (P.I.I. = 0.5) and memantine hydrochloride ( P.I.I. = 2.5).

[0051] Such an active ingredient is preferably hydrophilic. When the active ingredient is a hydrophilic drug, a drug required to have a systemic effect or local effect is generally used.

[0052] Active ingredients, if easily absorbed transdermally, are preferable. The active ingredients are preferably, but are not particularly limited to, compounds having an octanol/water splitting coefficient of -2 to 6. In this case, the permeability of the skin to the active ingredient is further improved. From the point of view of further increasing the permeability of the skin to the active ingredient, the octanol/water partition coefficient is preferably -1 or more, more preferably 0 or more. The octanol/water partition coefficient of the active ingredient is also preferably 4 or less, more preferably 1 or less. When the octanol/water split coefficient of the active ingredient is equal to or less than the upper limit described above, the permeability of the skin to the active ingredient is further increased.

[0053] It is observed that, in the present invention, the octanol/water division coefficient is determined based on the active ingredient concentration of each phase obtained by adding an active ingredient to a vial containing octanol and an aqueous pH buffer 7, by shaking the bottle and then determining the concentration. Specifically, the splitting coefficient can be determined by calculating using an equation: octanol/water splitting coefficient = Log10 (concentration in an octanol phase/concentration in an aqueous phase).

[0054] An amount of the active ingredient contained in the core-shell structure, although depending on the type of active ingredient, is, for example, preferably from 1% by weight to 70% by weight, more preferably from 5% by weight to 70% by weight as a weight of raw material. The raw material weight is a value obtained on the basis of the total weight of all raw materials contained in the core-shell structure.

[0055] The central part may contain two or more active ingredients as active ingredients as necessary.

[0056] The molecular weight of the active ingredient is not particularly limited. The molecular weight of the active ingredient is preferably 250 g/mol or more, more preferably 300 g/mol or more, preferably 7500 g/mol or less, more preferably 6500 g/mol or less, even more preferably 1500 g/mol or less .

(Casing Part)

[0057] The shell part contains a surfactant that has an HLB value of at least 4 to 14. The shell part also contains a surfactant whose hydrocarbon group is a saturated hydrocarbon having from 7 to 15 carbon atoms or a unsaturated hydrocarbon that has 7 to 17 carbon atoms. The shell part preferably contains a surfactant whose hydrophilic portion has a molecular weight of 100 g/mol to 350 g/mol. The molecular weight of the hydrophilic portion of the surfactant is not particularly limited.

[0058] An HLB value (abbreviation for Hydrophile Lypophile Balance) in the present invention, which is an index that shows that an emulsifier is hydrophilic or lipophilic, has a value from 0 to 20. A lower HLB value indicates a greater lipophilic capacity .

[0059] In the present invention, the HLB value is calculated by the following Griffin equation. HLB value = 20 x [(Molecular weight of the hydrophilic portion) / (Total molecular weight)]

[0060] A weighted average of the HLB value can be calculated using the following calculation equation.

[0061] A calculation equation for a weighted average value when surfactants having HLB values of A, B, and C are used in weights of x, y, and z, respectively, is as follows: (xA + yB + zC) /(x + y + z).

[0062] When a surfactant contains a plurality of hydrocarbon groups, the hydrocarbon group whose content in the surfactant is the highest is taken as the hydrocarbon group of the surfactant of the present invention.

[0063] Particularly when a surfactant contains a plurality of hydrocarbon groups having different numbers of carbon atoms, the number of carbon atoms in the hydrocarbon group whose content in the surfactant is the highest is taken as the number of atoms carbon in the hydrocarbon group of the surfactant of the present invention.

[0064] For example, specifically, when a surfactant is coconut oil fatty acid ester, the surfactant contains a saturated hydrocarbon group having 11 carbon atoms in the largest amount. Therefore, the hydrocarbon group of coconut oil fatty acid ester is a saturated hydrocarbon group, and the number of carbon atoms in the hydrocarbon group is 11.

[0065] When a plurality of surfactants are contained, the number of carbon atoms in the hydrocarbon group whose content in the plurality of surfactants is the highest is taken as the number of carbon atoms in the hydrocarbon group in the surfactant of the present invention.

[0066] The HLB value of the surfactant or, when a plurality of surfactants are contained, the weighted average value of the HLB value is 4 or more and 14 or less, more preferably 5 or more and 12 or less.

[0067] The surfactant may have at least one of a saturated hydrocarbon group such as an alkyl group and an unsaturated hydrocarbon group such as an alkenyl group or an alkynyl group.

[0068] The number of carbon atoms in the saturated hydrocarbon group is 7 or more and 15 or less, preferably 7 or more and 11 or less. When the number of carbon atoms in the saturated hydrocarbon group is equal to or greater than the lower limit described above, the ability to coat the surface of the central part with the shell part will be even more pronounced. Consequently, it is possible to obtain a core-shell structure having an even more excellent immediate effect on transdermal absorption. When the number of carbon atoms in the saturated hydrocarbon group is equal to or less than the upper limit described above, the release capacity of the active ingredient from the core-shell structure in the body is further enhanced, and in this way, it is possible to obtain a core-shell structure having an even more excellent immediate effect on transdermal absorption.

[0069] The number of carbon atoms in the unsaturated hydrocarbon group is 7 or more and 17 or less, preferably 7 or more and 13 or less, more preferably 7 or more and 11 or less. When the number of carbon atoms in the unsaturated hydrocarbon group is equal to or greater than the lower limit described above, the ability to coat the surface of the central part with the shell part will be even more pronounced. Consequently, it is possible to obtain a core-shell structure having an even more excellent immediate effect on transdermal absorption. When the number of carbon atoms in the unsaturated hydrocarbon group is equal to or less than the upper limit described above, the release capacity of the active ingredient from the core-shell structure in the body is further increased, and thus, it is possible to obtain a core-shell structure having an even more excellent immediate effect on transdermal absorption.

[0070] The molecular weight of the hydrophilic portion of the surfactant is preferably 100 g/mol or more and 350 g/mol or less, more preferably 100 g/mol or more and 300 g/mol or less, even more preferably 100 g/mol or more and 200 g/mol or less. When the molecular weight of the hydrophilic portion of the surfactant is equal to or greater than the lower limit described above, the ability to coat the central part with the shell part will be further enhanced. Therefore, it is possible to obtain a core-shell structure that has a greater immediate effect on transdermal absorption. When the molecular weight of the hydrophilic portion of the surfactant is equal to or less than the upper limit described above, the ability to release the active ingredient from the particles in the body increases further. Consequently, it is possible to obtain a core-shell structure having an even more pronounced immediate effect on transdermal absorption.

[0071] It is noted that the hydrophilic portion of a surfactant refers to the part remaining after the hydrocarbon group of the constituent fatty acid is removed from the entire surfactant molecule. For example, in the case of sorbitan monooleate, the molecular weight of the hydrophilic portion is calculated to be 191.2 g/mol by subtracting the molecular weight of the hydrocarbon group of the constituent fatty acid from the molecular weight of the entire surfactant molecule, since the molecular weight of the total surfactant molecule is 428.6 g/mol and the molecular weight of the monooleic acid hydrocarbon group as the constituent fatty acid is 237.4 g/mol.

[0072] The surfactant is also, preferably, a surfactant formed by linking an alcohol with a fatty acid through the ester bond or amide bond. In this case, the molecular weight of the alcohol is preferably 70 g/mol or more, more preferably 80 g/mol or more, preferably 330 g/mol or less, more preferably 300 g/mol or less, even more preferably 250 g/mol or less, particularly preferable 200 g/mol or less.

[0073] When the molecular weight of the alcohol is equal to or greater than the lower limit described above, the coating capacity of the central part with the shell part will be further increased. In this way, it is possible to obtain a core-shell structure that has a more pronounced immediate effect on transdermal absorption. When the molecular weight of the alcohol is equal to or less than the upper limit described above, the ability to release the active ingredient from the particles in the body increases further. Consequently, it is possible to obtain a core-shell structure having an even more pronounced immediate effect on transdermal absorption. When an alcohol is linked to a fatty acid via an amide bond, an alkanolamine is said to be attached to the fatty acid via an amide bond. Therefore, in this case, the molecular weight of the alcohol means the molecular weight of the alkanolamine.

[0074] With reference to Figure 2, the hydrophilic portion and the hydrophobic portion of a surfactant formed by an alcohol and a fatty acid linked through the ester bond will be described below. As shown in Figure 2, when the alcohol is linked to the fatty acid through the ester bond, the part enclosed by a dotted line in Figure 2 is the hydrophobic portion. The number of carbon atoms in the hydrocarbon group is the number of carbon atoms contained in R in the hydrophobic portion. Accordingly, also when R in the hydrophobic portion contains an ether bond or the like, the number of carbon atoms contained in R in the hydrophobic portion is only determined. The part enclosed by a long dashed short dashed line in Figure 2 is the hydrophilic portion. The alcohol portion is R'O in the hydrophilic portion. The original alcohol is thus represented by R'OH. So, in this case, the molecular weight of the alcohol described above is the molecular weight of R'OH.

[0075] With reference to Figure 3, the hydrophilic portion and the hydrophobic portion of a surfactant formed by an alcohol and a fatty acid linked through an amide bond will now be described. As shown in Figure 3, when alcohol is linked to a fatty acid through the amide bond, the part enclosed by a dotted line in Figure 3 is the hydrophobic portion. The number of carbon atoms in the hydrocarbon group is the number of carbon atoms contained in R in the hydrophobic moiety. In this way, also when R in the hydrophobic portion contains an ether bond or similar, the number of carbon atoms contained in R in the hydrophobic portion is only determined. The part enclosed by a long dashed short dashed line in Figure 3 is the hydrophilic portion. The alcohol component is R'R"N in the hydrophilic portion. The original alcohol is thus represented by R'R"NH. So, in this case, the molecular weight of the alcohol described above is the molecular weight of R'R"NH.

[0076] The surfactant preferably contains at least one selected from the group consisting of sorbitan fatty acid esters, glycerin fatty acid esters, propylene glycol fatty acid esters and fatty acid alkanolamides. Of these, from the point of view of simultaneously achieving transdermal absorption capacity and low skin irritation at an even higher level, the surfactant preferably contains at least one selected from the group consisting of fatty acid esters of sorbitan, glycerin fatty acid esters and propylene glycol fatty acid esters.

[0077] Examples of sorbitan fatty acid esters in the present invention include, but are not particularly limited to, sorbitan esters and a fatty acid.

[0078] Examples of fatty acids include caproic acid, caprylic acid, capric acid, lauric acid, myristic acid, palmitic acid, stearic acid, behenic acid, undecylenic acid, ricinoleic acid, oleic acid, linoleic acid, linolenic acid, ricinoleic acid, erucic acid, beef tallow, lard, coconut oil, palm oil, palm kernel oil, olive oil, rapeseed oil, rice bran oil, soybean oil and castor oil.

[0079] Specifically, examples of sorbitan fatty acid esters include, from the point of view of further enhancing the immediate effect and absorption capacity of the active ingredient, preferably sorbitan monostearate (NIKKOL SO-10MV manufactured by Nippon Surfactant Industries , Co., Ltd.), sorbitan trioleate (NIKKOL SO-30V manufactured by Nippon Surfactant Industries, Co., Ltd.), sorbitan sesquiolate (NIKKOL SO-15MV manufactured by Nippon Surfactant Industries, Co., Ltd. ), sorbitan monooleate (NIKKOL SO-10V manufactured by Nippon Surfactant Industries, Co., Ltd.), sorbitan monolaurate (NIKKOL SL-10 manufactured by Nippon Surfactant Industries, Co., Ltd.), fatty acid sorbitan of coconut oil (EMALEX SPC-10 manufactured by NIHON EMULSION Co., Ltd.) and sorbitan laurate (RIKEMAL L-250A manufactured by RIKEN VITAMIN Co., Ltd.).

[0080] Examples of fatty acid esters of glycerin in the present invention include, but are not particularly limited to, esters of glycerin and a fatty acid.

[0081] Glycerin can be polyglycerin. The degree of polymerization of the polyglycerin is not particularly limited, and is preferably 5 or less, more preferably 4 or less, even more preferably 3 or less. Of these, such as glycerin, monoglycerin, diglycerin or triglycerin is preferable. Specifically, as a glycerin fatty acid ester, a monoglycerin fatty acid ester, a diglycerin fatty acid ester or a triglycerin fatty acid ester is preferred. In this case, it is possible to further increase the immediate effect on transdermal absorption of the active ingredient.

[0082] Examples of fatty acids include caproic acid, caprylic acid, capric acid, lauric acid, myristic acid, palmitic acid, stearic acid, behenic acid, undecylenic acid, ricinoleic acid, oleic acid, linoleic acid, linolenic acid, ricinoleic acid, erucic acid, beef tallow, lard, coconut oil, palm oil, palm kernel oil, olive oil, rapeseed oil, rice bran oil, soybean oil and castor oil.

[0083] Specific examples of glycerin fatty acid esters include, from the standpoint of further enhancing the immediate effect and absorption capacity of the active ingredient, preferably diglyceryl monostearate (NIKKOL DGMS manufactured by Nippon Surfactant Industries, Co. ., Ltd.), glyceryl monostearate (NIKKOL MGS-BMV manufactured by Nippon Surfactant Industries, Co., Ltd.), glyceryl monostearate (NIKKOL MGS-AMV manufactured by Nippon Surfactant Industries, Co., Ltd.), glyceryl monostearate (NIKKOL MGS-DEXV manufactured by Nippon Surfactant Industries, Co., Ltd.), glyceryl monostearate (NIKKOL MGS-ASEV manufactured by Nippon Surfactant Industries, Co., Ltd.), glyceryl monostearate (NIKKOL MGS-BSEV manufactured by Nippon Surfactant Industries, Co., Ltd.), glyceryl myristate (MGM manufactured by Nippon Surfactant Industries, Co., Ltd.), glyceryl tri(caprylate/caprate) (NIKKOL Triester F-810 manufactured by Nippon Surfactant Industries, Co., Ltd.), glyceryl monooleate (NIKKOL MGO manufactured by Nippon Surfactant Industries, Co., Ltd.), glyceryl monooleate (Capmul GMO-50 manufactured by ABITEC), glyceryl monooleate (Capmul GMO-50 manufactured by ABITEC), glyceryl (NIKKOL MGOL-70 manufactured by Nippon Surfactant Industries, Co., Ltd.), diglyceryl monooleate (NIKKOL DGMO-CV manufactured by Nippon Surfactant Industries, Co., Ltd.), diglyceryl monooleate (NIKKOL DGMO -90V manufactured by Nippon Surfactant Industries, Co., Ltd.), glyceryl monocaprylate (Sunsoft No. 700P-2-C manufactured by Taiyo Kagaku Co., Ltd.), glyceryl monocaprylate (Capmul 808G manufactured by ABITEC) , glyceryl monocaprylate (Capmul MCM C8 manufactured by ABITEC), glyceryl monocaprylate (Sunsoft No. 760-C manufactured by Taiyo Kagaku Co., Ltd.), glyceryl caprate (Capmul MCM C10 manufactured by ABITEC), glyceryl caprylate/caprate (Capmul MCM manufactured by ABITEC), glyceryl caprylate/caprate (Capmul 471 manufactured by ABITEC), mono/diglyceride caprate (Sunsoft No. 707-C manufactured by Taiyo Kagaku Co., Ltd.), diglyceride (Sunfat GDC-S manufactured by Taiyo Kagaku Co., Ltd.), glyceryl monolaurate (Sunsoft No. 750-C manufactured by Taiyo Kagaku Co., Ltd.) and glyceryl monoundecylenate (NIKKOL MGU manufactured by Nippon Surfactant Industries , Co., Ltd.).

[0084] More preferable examples of glycerin fatty acid esters include glyceryl monooleate (NIKKOL MGO, manufactured by Nippon Surfactant Industries, Co., Ltd.), glyceryl monooleate (Capmul GMO-50 manufactured by ABITEC) , glyceryl mono-olivate (NIKKOL MGOL-70 manufactured by Nippon Surfactant Industries, Co., Ltd.), diglyceryl mono-oleate (NIKKOL DGMO-CV manufactured by Nippon Surfactant Industries, Co., Ltd.), mono-oleate diglyceryl (NIK-KOL DGMO-90V manufactured by Nippon Surfactant Industries, Co., Ltd.), glyceryl monocaprylate (Sunsoft No. 700P-2-C manufactured by Taiyo Kagaku Co., Ltd.), glyceryl monocaprylate (Capmul 808G manufactured by ABITEC), glyceryl monocaprylate (Capmul MCM C8 manufactured by ABITEC), glyceryl monocaprate (Sunsoft No. 760-C manufactured by Taiyo Kagaku Co., Ltd.), glyceryl caprate (Capmul MCM C10 manufactured by ABITEC) , glyceryl caprylate/caprate (Capmul MCM manufactured by ABITEC), glyceryl caprylate/caprate (Capmul 471 manufactured by ABITEC), mono/diglyceride caprate (Sunsoft No. 707-C manufactured by Taiyo Kagaku Co., Ltd.), caprate diglyceride (Sunfat GDC-S manufactured by Taiyo Kagaku Co., Ltd.), glyceryl monolaurate (Sunsoft No. 750-C manufactured by Taiyo Kagaku Co., Ltd.) and glyceryl monoundecylenate (NIKKOL MGU manufactured by Nippon Surfactant Industries, Co., Ltd.).

[0085] Examples of propylene glycol fatty acid esters in the present invention include, but are not particularly limited to, propylene glycol esters and a fatty acid.

[0086] Examples of fatty acids include caproic acid, caprylic acid, capric acid, lauric acid, myristic acid, palmitic acid, stearic acid, behenic acid, undecylenic acid, ricinoleic acid, oleic acid, linoleic acid, linolenic acid, ricinoleic acid, erucic acid, beef tallow, lard, coconut oil, palm oil, palm kernel oil, olive oil, rapeseed oil, rice bran oil, soybean oil and castor oil.

[0087] Specific examples of propylene glycol fatty acid esters include, from the standpoint of further increasing the immediate effect and transdermal absorption capacity of the active ingredient, preferably propylene glycol monostearate (RIKEMAL PS-100 manufactured by RIKEN VITAMIN Co., Ltd.), propylene glycol monostearate (NIKKOL PMS-1CV manufactured by Nippon Surfactant Industries, Co., Ltd.), propylene glycol diisostearate (EMALEX PG-di-IS, manufactured by NIHON EMULSION Co., Ltd.), propylene glycol distearate (EMALEX PG-di-S manufactured by NIHON EMULSION Co., Ltd.), preferably propylene glycol monolaurate (RIKEMAL PL-100 manufactured by RIKEN VITAMIN Co., Ltd. ), propylene glycol monooleate (RIKEMAL PO-100 manufactured by RIKEN VITAMIN Co., Ltd.), propylene glycol dioleate (EMALEX PG-di-O manufactured by NIHON EMULSION Co., Ltd.), propylene glycol dicaprylate (NIKKOL SEFSOL-228 manufactured by Nippon Surfactant Industries, Co., Ltd.) and propylene glycol dilaurate (EMALEX PG-M-L, manufactured by NIHON EMULSION Co., Ltd.).

[0088] The fatty acid alkanolamides of the present invention refer to those that have a structure in which one R-CO group and two -CH2CH2OH groups are linked to N in the center and are represented by a chemical formula of R -CON (CH2CH2OH)2.

[0089] Specific examples of fatty acid alkanolamides include oleic acid diethanolamide, lauric acid diethanolamide, lauric acid monoisopropanolamide, stearic acid diethanolamide, stearic acid monoethanolamide, stearic acid monoisopropanolamide, lauric acid diethanolamide myristic acid, monoe - palmitic acid tananolamide, coconut oil fatty acid diethanolamide, coconut oil fatty acid monoisopropanolamide, N-methyl coconut oil fatty acid diethanolamide, coconut oil fatty acid monoethanolamide and coconut oil fatty acid diethanolamide of palm kernel. From the point of view of further increasing the permeability of the skin, the fatty acid alkanolamides are preferably diethanolamides such as oleic acid diethanolamide, lauric acid diethanolamide and coconut oil fatty acid diethanolamide.

[0090] The surfactant of the present invention may further contain surfactants other than sorbitan fatty acid esters, glycerin fatty acid esters, propylene glycol fatty acid esters and fatty acid alkanolamides, and such surfactants may be appropriately selected depending on the application. Such surfactants can be selected from a wide variety of surfactants that can be used as medicines and cosmetics. A plurality of surfactants can be used in combination.

[0091] Surfactants other than sorbitan fatty acid esters, glycerin fatty acid esters, propylene glycol fatty acid esters and fatty acid alkanolamides can be any of non-ionic surfactants, anionic surfactants, cationic surfactants and amphoteric surfactants.

[0092] Examples of nonionic surfactants include, but are not particularly limited to, fatty acid esters, fatty alcohol ethoxylates, polyoxyethylene alkyl phenyl ethers, alkyl glycosides, polyoxyethylene castor oil and hydrogenated castor oil.

[0093] Examples of fatty acid esters include, but are not particularly limited to, esters of at least one of glycerin, polyglycerin, polyoxyethylene glycerin, polyoxyethylene, sorbitan, propylene glycol and polyoxyethylene sorbitol with a fatty acid such as caproic acid, caprylic acid, capric acid, lauric acid, myristic acid, palmitic acid, stearic acid, behenic acid, undecylenic acid, ricinoleic acid, oleic acid, linoleic acid, linolenic acid, ricinoleic acid, erucic acid, beef tallow, lard , coconut oil, palm oil, palm kernel oil, olive oil, rapeseed oil, rice bran oil, soybean oil and castor oil.

[0094] Examples of anionic surfactants include alkyl sulfate salts, polyoxyethylene alkyl ether sulfate salts, alkyl benzene sulfonate salts, fatty acid salts and phosphate salts.

[0095] Examples of cationic surfactants include alkyl trimethyl ammonium salts, dialkyl dimethyl ammonium salts, alkyl dimethyl benzyl ammonium salts and amine salts.

[0096] Examples of amphoteric surfactants include alkyl amino fatty acid salts, alkyl betainese and alkyl amine oxides.

[0097] As surfactants other than sorbitan fatty acid esters, glycerin fatty acid esters, propylene glycol fatty acid esters and fatty acid alkanolamides, sucrose fatty acid esters, polyoxyethylene glycerin fatty acid esters, esters of sorbitan fatty acid, sorbitated polyoxyethylene fatty acid esters, polyoxyethylene castor oil and hydrogenated castor oil are particularly preferable.

[0098] Surfactants other than sorbitan fatty acid esters, glycerin fatty acid esters, propylene glycol fatty acid esters and fatty acid alkanolamides may be those that have a hydrocarbon chain such as an alkyl chain , alkenyl chain or alkynyl chain.

[0099] The surfactant content can be appropriately adjusted within a range where an effect of the present invention is exerted. The mass ratio for the active ingredient (active ingredient: surfactant) is preferably 1:0.5 to 1:100, more preferably 1:5 to 1:100. In this case, it is possible to further enhance the immediate effect of the active ingredient on the core-shell structure and formulations containing the core-shell structure. From the point of view of further intensifying the immediate effect of the active ingredient, the mass ratio between the active ingredient and the surfactant (active ingredient:surfactant) is preferably from 1:0.5 to 1:50, more preferably from 1:0.5 to 1:30. From the point of view of further intensifying the immediate effect of the active ingredient, the mass ratio between the active ingredient and the surfactant (active ingredient:surfactant) is preferably 1:5 to 1:50, more preferably 1:5 to 1:30.

[00100] In the present invention, the mass ratio between the active ingredient and the surfactant (active ingredient: surfactant) can also be from 1:0.5 to 1:2. Generally, in a tape preparation, a higher content of the active ingredient tends to degrade the dispersibility of the active ingredient in the tape preparation. However, in the present invention, a surfactant having the HLB value described above and a saturated hydrocarbon group or an unsaturated hydrocarbon group is used, and thus it is possible to further increase the dispersibility in tape preparation even if the content of the active ingredient is high.

(Other Additive Components)

[00101] The core-shell structure may contain at least one other component in addition to the active ingredient and surfactant. Examples of the other components include, but are not particularly limited to, a stabilizing agent, a transdermal absorption enhancer, a skin irritation reducing agent, an antiseptic and an analgesic.

[00102] The stabilizing agent has a stabilizing action on a particle structure. The stabilizing agent prevents unintentional early disintegration of the particle structure and plays a role in further enhancing a sustained release effect of the active ingredient.

[00103] Examples of stabilizing agents include, but are not particularly limited to, polysaccharides, proteins and hydrophilic polymeric materials. One or two or more stabilizing agents may be contained. The content of the stabilizing agent can be adjusted appropriately depending on its type. The stabilizing agent can be formulated so that, for example, the weight ratio between the active ingredient and the stabilizing agent (active ingredient: stabilizing agent) is 1:0.1 to 1:10.

[00104] Examples of transdermal absorption enhancers include, but are not particularly limited to, higher alcohols, N-acyl sarcosine and its salts, higher monocarboxylic acids, higher monocarboxylic acid esters, aromatic monoterpene fatty acid esters, dicarboxylic acids having 2 to 10 carbon atoms and their salts, phosphoric acid esters of polyoxyethylene alkyl ether and their salts, lactic acid, esters of lactic acid and citric acid. One or two or more transdermal absorption enhancers may be contained. The content of the transdermal absorption enhancer can be adjusted appropriately depending on its type. The transdermal absorption enhancer may be formulated so that, for example, the weight ratio between the active ingredient and the transdermal absorption enhancer (active ingredient:transdermal absorption enhancer) is 1:0.01 to 1: 50.

[00105] Examples of skin irritation reducing agents include, but are not particularly limited to, hydroquinone glycosides, pantethine, tranexamic acid, lecithin, titanium oxide, aluminum hydroxide, sodium nitrite, sodium hydrogen nitrite , soy lecithin, methionine, glycyrrhetinic acid, BHT, BHA, vitamin E and its derivatives, vitamin C and its derivatives, benzotriazole, propyl gallate and mercaptobenzimidazole. One or two or more skin irritation reducing agents may be contained. The content ratio of skin irritation reducing agent can be adjusted appropriately depending on its types. The skin irritation reducing agent can be formulated such that its content ranges from 0.1% by weight to 50% by weight, for example, with respect to the entire core-shell structure.

[00106] Examples of antiseptics include, but are not particularly limited to, methyl paraoxybenzoate, propyl paraoxybenzoate, phenoxyethanol and thymol. The antiseptic content ratio in the central part can be adjusted appropriately depending on its type. The antiseptic can be formulated such that its content ranges from 0.01% by weight to 10% by weight, for example, with respect to the entire core-shell structure. One or two or more antiseptics may be contained.

[00107] Examples of analgesics include, but are not particularly limited to, local anesthetics, such as procaine, tetracaine, lidocaine, dibucaine, prilocaine and their salts. One or two or more analgesics may be contained. The analgesic content ratio in the core-shell structure can be adjusted appropriately depending on its types. The analgesic may be formulated such that its content is from 0.1% by weight to 30% by weight, for example, relative to the entire core-shell structure.

[Formulation]

[00108] A formulation of the present invention contains at least the core-shell structure described above. The formulation of the present invention, which contains at least the core-shell structure described above, has an excellent immediate effect on transdermal absorption of the active ingredient.

[00109] The content ratio of the core-shell structure described above in the formulation is not particularly limited. In the case of an adhesive preparation, ointment, cream or gel, the content ratio of the core-shell structure is preferably 10% by weight or more and 70% by weight or less, more preferably 20% by weight or more and 50 % by weight or less.

[00110] The mass ratio between the active ingredient and the surfactant (active ingredient:surfactant) in the formulation can be appropriately adjusted within a range in which an effect of the present invention is exerted, and is preferably from 1:0.5 to 1:100, more preferably 1:5 to 1:100. In this case, it is possible to further enhance the immediate effect of the active ingredient in the core-shell structure and in formulations containing the core-shell structure. From the point of view of further enhancing the immediate effect of the active ingredient, the mass ratio between the active ingredient and the surfactant (active ingredient:surfactant) is preferably 1:0.5 to 1:50, more preferably from 1:0.5 to 1:30. From the point of view of further enhancing the immediate effect of the active ingredient, the mass ratio between the active ingredient and the surfactant (active ingredient:surfactant) is preferably 1:5 to 1:50, more preferably 1:5 to 1:30.

[00111] In the present invention, the mass ratio between the active ingredient and the surfactant (active ingredient: surfactant) is preferably 1:0.5 to 1:5, more preferably 1:0.5 to 1:2, 5, even more preferably from 1:0.5 to 1:2. Generally, in an adhesive preparation such as a tape preparation, a higher content of the active ingredient tends to degrade the dispersibility of the active ingredient in the adhesive preparation such as the tape preparation. However, in the present invention, a surfactant having the HLB value described above and a saturated hydrocarbon group or an unsaturated hydrocarbon group is used, and thus it is possible to further increase the dispersibility in the adhesive preparation such as tape preparation even if the active ingredient content is high. Therefore, it is possible to further increase the skin's permeability to the active ingredient.

[00112] The formulation of the present invention can be used in a wide variety of applications intended for transdermal adsorption or transmucosal absorption, for example, external medicines such as external skin medicines, eye drops, nasal sprays, suppositories and oral cavity medicines , cosmetics and injections, depending on the type of active ingredient.

[00113] The formulation of the present invention sustains its effect in general, but not particularly limited from 1 day to 1 week. In the preferred embodiment, the formulation is used for administration once a day to once a week.

[00114] When the formulation of the present invention is an external medicine, a target disease differs depending on the type of active ingredient.

[00115] The formulation of the present invention is not particularly limited and can be used as an adhesive preparation such as a tape preparation, e.g. a patch preparation or a tape preparation, e.g. a patch preparation (e.g. , reservoir type or matrix type), a poultice, a patch or a microneedle, an ointment, an external liquid preparation such as a liniment, or a lotion, a spray preparation such as an external aerosol or a pump spray preparation, a cream, a gel, an eye drop, an eye ointment, a nasal drop, a suppository, a semisolid formulation for rectal use, an enema formulation, oral agents, or an injection.

[00116] The formulation of the present invention preferably has a water content of 20% by mass or less, and more preferably contains substantially no water. This makes it possible to further increase the shape-retaining capacity of the core-shell structure. In combination with the intrinsic structure retention capacity of the core-shell structure, the elution of the active ingredient from the core-shell structure and the crystallization of the active ingredient can further be reduced. Consequently, the core-shell structure can further exert a transdermal absorption capacity. From this point of view, the formulation of the present invention is preferably used as a preparation whose water content is adjusted to 20% by mass or less. The formulation of the present invention is most preferably used as a preparation containing substantially no water. The formulation of the present invention is preferably used as a plaster preparation, a plaster, an ointment or a gel.

(Base Phase)

[00117] The formulation of the present invention may contain a base phase and the base phase may contain core-shell structures. In this case, such core-shell structures are preferably dispersed or dissolved in the base phase.

[00118] The base is not particularly limited and can be selected from a wide variety of bases that can be used as medicines, in particular, external medicines and cosmetics.

[00119] As described above, in the core-shell structure of the present invention, the central part is solid. Thus, when the base phase is an oil phase, an S/O (Solid in Oil) type formulation can be formed by dispersing the core-shell structure in the oil phase of the base phase. The S/O type formulation can be obtained, for example, by dispersing the particles obtained by a production method described below in the oily phase.

[00120] Once the S/O (Solid in Oil) type formulation is formed, the transparency of a coated sheet is increased when a base material is coated with the formulation. Once the S/O (Solid in Oil) type formulation is formed, in the case of X-ray diffraction measurement, for example, the diffraction pattern of the active ingredient must be different from the diffraction of the original active ingredient alone. Compared to a coated slide that is coated with only the active ingredient, the coated slide of the S/O type formulation has a diffraction pattern in which at least one of a displacement from the maximum position, a change in shape, and a decrease in maximum intensity is observed. Particularly, with respect to the decrease in maximum intensity, the maximum intensity of the active ingredient in the X-ray diffraction spectrum should be decreased below the maximum intensity of the active ingredient alone. In this case, the peak of the active ingredient may be lost due to the decrease.

[00121] The base is not particularly limited and can be appropriately selected depending on the planned use of suitable bases to disperse or dissolve the core-shell structure.

[00122] A plurality of bases can be used in combination.

[00123] Examples of bases include, but are not particularly limited to, oily bases and aqueous bases. Of these, the base is preferably an oily base. When the base is an oil base, a formulation having an S/O (Solid in Oil) type structure can be formed by dispersing the core-shell structures in the oil base. The formulation having an S/O (Solid in Oil) type structure can be produced by a method that includes a step of drying a W/O emulsion containing an active ingredient in the aqueous phase, for example, as described below.

[00124] Examples of oily bases include vegetable oils, animal oils, neutral lipids, synthetic fats and oils, sterol derivatives, waxes, hydrocarbons, monoalcohol carboxylic acid esters, oxyacid esters, polyhydric alcohol fatty acid esters, silicones, higher alcohols, higher fatty acids and fluorine-based oils. Examples of aqueous bases include water and (polyhydric) alcohols.

[00125] Examples of vegetable oils include, but are not particularly limited to, soybean oil, sesame oil, olive oil, coconut oil, palm oil, rice oil, cottonseed oil, sunflower oil, of rice bran, cocoa butter, corn oil, safflower oil, castor oil and rapeseed oil.

[00126] Examples of animal oils include, but are not particularly limited to, mink oil, turtle oil, fish oil, beef oil, horse oil, pork oil and shark squalane.

[00127] Examples of neutral lipids include, but are not particularly limited to, triolein, trilinolein, trimyristin, triestearin and triarachidonin.

[00128] Examples of synthetic oils and fats include, but are not particularly limited to, phospholipid and azone.

[00129] Examples of sterol derivatives include, but are not particularly limited to, dihydrocholesterol, lanosterol, dihydrolanosterol, phytosterol, cholic acid and cholesteryl linoleate.

[00130] Examples of the waxes include candelilla wax, carnauba wax, rice wax, Japanese wax, beeswax, montane wax, ozokerite, ceresin, paraffin wax, microcrystalline wax, petrolatum, Fischer-Tropsch wax, polyethylene and ethylene-propylene copolymers.

[00131] Examples of the hydrocarbons include liquid paraffin (mineral oil), heavy liquid isoparaffin, light liquid isoparaffin, α-olefin oligomers, polyisobutene, hydrogenated polyisobutene, polybutene, squalane, olive-derived squalane, squalene, Vaseline and solid paraffin.

[00132] Examples of carboxylic monoalcool acid esters include octyldodecil miristato, hexildecil miristatus, octyldodecyl isoteract, cetilla palmitate, octyl paddle, octano-octane, octanoate of hexildecilla, isononanone of isotridecilla Isononyl act, isononananoate octylation, isotridecyl isononanoate, isodecyl neopentanoate, isotridecyl neopentanoate, isostearyl neopentanoate, octyldodecyl neocodecanoate, oleyl oleate, octyldodecyl oleate, octyldodecyl ricinoleate, lanolin fatty acid octyldodecyl, hexyldecyl dimethyloctanoate, octyldodecyl erucate, hydrogenated castor oil isostearate, ethyl oleate, ethyl avocado oil fatty acid, isopropyl myristate, isopropyl palmitate, octyl palmitate, isopropyl isostearate, isopropyl lanolin fatty acid, sebacate diethyl, diisopropyl sebacate, dioctyl sebacate, diisopropyl adipate, dibutyl octyl sebacate, diisobutyl adipate, dioctyl succinate and triethyl citrate.

[00133] Examples of oxyacid esters include cetyl lactate, diisostearyl malate and hydrogenated castor oil monoisostearate.

[00134] Examples of polyalcohol fatty acid esters include glyceryl trioctanoate, glyceryl trioleate, glyceryl triisostearate, glyceryl diisostearate, glyceryl tri(caprylate/caprate), tri(caprylate/caprate/myristate glyceryl/stearate), hydrogenated resin triglyceride (hydrogenated ester gum), resin triglyceride (ester gum), glyceryl behenate/eicosadioate, trioctanoate trimethylolpropane, trimethylolpropane triisostearate, neopentylglycol dioctanoate, neopentylglycol dicaprate , 2-butyl-2-ethyl-1,3-propanediol dioctanoate, propylene glycol dioleate, pentaerythritol tetraoctanoate, hydrogenated pentaerythrityl rosinate, ditrimethylolpropane triethyl hexanoate, ditrimethylolpropane (isostearate/sebacate), pentaerythrityl triethyl hexanoate, dipentaerythrityl (hydroxystearate/stearate/rosinate), diglyceryl diisostearate, polyglyceryl tetraisostearate, polyglyceryl-10 nonasostearate, polyglyceryl-8 deca (erucate/isostearate/ricinoleate), (hexyldecanoic acid/sebacic acid) oligo ester diglyceryl, glycol distearate (ethylene glycol distearate), 3-methyl-1,5-pentanediol dineopentanoate and 2,4-diethyl-1,5-pentanediol dineopentanoate.

[00135] Examples of silicones include dimethicone (dimethylpolysiloxane), highly polymerized dimethicone (highly polymerized dimethylpolysiloxane), cyclomethicone (cyclodimethylsiloxane, decamethylcyclopentasiloxane), phenyl trimethicone, diphenyl dimethicone, phenyl dimethicone, stearoxypropyl dimethylamine, copolymers (aminoethylaminopropyl methicone /dimethicone), dimethiconol, dimethiconol crosspolymers, silicone resins, silicone rubber, amino-modified silicones such as aminopropyl dimethicone and amodimethicone, cation-modified silicones, polyether-modified silicones such as dimethicone copolyol, polyglycerol-modified silicones, silicones sugar modified silicones, carboxylic acid modified silicones, phosphoric acid modified silicones, sulfuric acid modified silicones, alkyl modified silicones, fatty acid modified silicones, alkyl ether modified silicones, amino acid modified silicones, peptide modified silicones, silicones fluorine-modified, cation-modified or polyether-modified silicones, amino-modified or polyether-modified silicones, alkyl-modified or polyether-modified silicones, and polysiloxane/oxyalkylene copolymers.

[00136] Examples of higher alcohols include cetanol, myristyl alcohol, oleyl alcohol, lauryl alcohol, cetostearyl alcohol, stearyl alcohol, arachidyl alcohol, behenyl alcohol, jojoba alcohol, chemyl alcohol, selakyl alcohol, bathyl alcohol, hexyldecanol, isostearyl alcohol , 2-octyldodecanol and diol dimer.

[00137] Examples of higher fatty acids include lauric acid, myristic acid, palmitic acid, stearic acid, 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, anteisoeneicosanoic acid, long chain branched fatty acid, dimeric acid and hydrogenated dimeric acid.

[00138] Examples of fluorine-based oils include perfluorodecane, perfluorooctane and perfluoropolyether.

[00139] Examples of (polyhydric) alcohols include ethanol, isopropanol, glycerin, propylene glycol, 1,3-butylene glycol and polyethylene glycol.

[00140] Furthermore, examples of the other bases include, but are not particularly limited to, bases used for adhesive preparations such as tape preparations, e.g., plaster preparations or patch preparations (e.g., reservoir type or matrix type ), poultices, bandages and microneedles, ointments, external liquid preparations (e.g. liniments and lotions), spray preparations (e.g. external aerosols and pump spray preparations), creams, gels, eye drops, eye ointments, nasal drops, suppositories, semi-solid formulations for rectal use, enema formulations, oral agents and injections.

[00141] An example of the tape preparation of the present invention will be described below with reference to Figure 4.

[00142] Figure 4 is a schematic cross-sectional view showing a tape preparation in accordance with an embodiment of the present invention.

[00143] As shown in Figure 4, the tape preparation 20 includes a base material layer 21 and a pressure-sensitive adhesive layer 22. The pressure-sensitive adhesive layer 22 is superimposed onto a surface 21a of the material layer base 21. A coating 23 is superimposed on the surface 22a of the pressure-sensitive adhesive layer 22.

[00144] The pressure-sensitive adhesive layer 22 can be superimposed on only the surface 21a on one side of the base material layer 21 or both surfaces can be superimposed according to this embodiment. The pressure-sensitive adhesive layer 22 of the tape preparation 20 contains the core-shell structure of the present invention described above. In one type of reservoir or the like, the core-shell structure may not be contained in the pressure-sensitive adhesive layer 22, but in a reservoir phase, for example.

[00145] The base material layer 21 is not particularly limited, as long as it supports the pressure-sensitive adhesive layer 22, and examples thereof include resin films, fibers and non-woven fabrics. Examples of resin films include films such as polyester and polyolefin films. The resin film is preferably a polyester film. Examples of polyesters include polyethylene terephthalate and polybutylene terephthalate, and polyethylene terephthalate is preferred.

[00146] A pressure-sensitive adhesive constituting the pressure-sensitive adhesive layer 22 is not particularly limited, and examples thereof include rubber pressure-sensitive adhesives, acrylic pressure-sensitive adhesives, and silicone pressure-sensitive adhesives. The pressure-sensitive adhesive constituting the pressure-sensitive adhesive layer 22 is preferably a rubber pressure-sensitive adhesive or an acrylic pressure-sensitive adhesive, more preferably an acrylic pressure-sensitive adhesive.

[00147] The coating 23 is not particularly limited as long as it is one that protects the pressure-sensitive adhesive layer 22 until the tape preparation 20 is applied to the skin and is coated with silicone or the like, for example, so as to be easily released. Examples of coating 23 include those produced by coating polyethylene terephthalate or polypropylene with silicone. Liner 23 may not be provided. In forming the pressure-sensitive adhesive layer 22, the pressure-sensitive adhesive may be applied to the side of the base material 21 or may be applied to the side of the coating 23.

[Production Method]

[00148] The core-shell structure of the present invention can be produced, but not particularly limited to, for example, a method that includes a step of drying a W/O emulsion containing an active ingredient in the aqueous phase.

[00149] The W/O emulsion is not particularly limited, as long as it is a so-called water-in-oil emulsion, and specifically it is an emulsion in which droplets of an aqueous solvent are dispersed in an oily solvent.

[00150] The W/O emulsion containing an active ingredient in an aqueous phase can be obtained, for example, by mixing an aqueous solvent, such as water and an aqueous buffer solution, containing an active ingredient, and an oily solvent, such as cyclohexane, hexane and toluene, containing a surfactant. The aqueous solvent containing an active ingredient may contain an additive component, such as a stabilizing agent, an absorption enhancer or an irritation reducing agent, as necessary, in addition to the active ingredient. The oily solvent containing a surfactant may contain an additive component, such as an irritation reducing agent, an analgesic, an absorption enhancer or a stabilizing agent, as necessary, in addition to a surfactant. A method for mixing is not particularly limited, as long as it can form a W/O emulsion, and examples thereof include stirring with a homogenizer or the like.

[00151] The condition under stirring with a homogenizer is, for example, from about 5000 to about 50000 rpm, preferably from about 10000 to about 30000 rpm.

[00152] The mass ratio between the active ingredient and the surfactant (active ingredient: surfactant) in the W/O emulsion described above is preferably in the range of 1:0.5 to 1:100, more preferably in the range of 1:5 to 1:100. The mass ratio (active ingredient: surfactant) is further preferably in the range of 1:0.5 to 1:50, particularly preferably in the range of 1:5 to 1:50. The mass ratio (active ingredient: surfactant) is further preferably in the range of 1:0.5 to 1:30, particularly preferably in the range of 1:5 to 1:30. The mass ratio between the active ingredient and the surfactant (active ingredient:surfactant) can be from 1:0.5 to 1:2.

[00153] A method for drying the W/O emulsion containing an active ingredient in an aqueous phase is not particularly limited, as long as it can remove the solvent (an aqueous solvent and an oily solvent) contained in the emulsion. Examples of methods for drying the W/O emulsion include freeze drying and vacuum drying, preferably freeze drying.

[00154] The method described above preferably further includes a heat treatment step of the W/O emulsion or a dry substance of the W/O emulsion from the point of view of a further reduction in the numerical average particle diameter of the core-structure. casing to be obtained. A heat treatment temperature is, for example, 30°C to 60°C, preferably 35°C to 50°C, more preferably 35°C to 45°C.

[00155] A heat treatment time is appropriately adjusted according to the heat treatment temperature, and is, for example, 1 to 30 days, preferably 2 to 15 days, more preferably 3 to 7 days.

[00156] Examples of other methods for further reducing the number average particle diameter of the core-shell structure to be obtained include methods of subjecting the W/O emulsion or a dry substance of the W/O emulsion, after dispersion in a solvent or similar, as necessary, to filtration through a filter or the like or to centrifugation. In the case of filtration through a filter, a pore diameter of the filter is, for example, 1 μm or less, preferably 0.2 μm or less, more preferably 0.1 μm or less.

[00157] The core-shell structure of the present invention can be used as such or can be used after being dispersed in the above-described base or the like.

[00158] A formulation can be produced using the core-shell structure of the present invention, for example, through a solution coating method. In the solution coating method, the desired additive components are further added, in addition to the core-shell structure of the present invention and a base, to a solvent so as to achieve a predetermined ratio. Then the mixture is stirred to prepare a homogeneous solution. Examples of the additive components described above include an absorption enhancer, a thickener and a gel-forming agent. Examples of the solvents described above include hexane, toluene and ethyl acetate. A concentration of solid content in the solution is preferably 10% to 80% by mass, more preferably 20% to 60% by mass.

[00159] Next, the solution containing each of the components described above is uniformly applied to a release liner, such as a silicone-treated polyester film, using a coating device such as a spatula, a comma coating apparatus. or a reverse coating apparatus. After application, the solution was dried to form a drug-containing layer, a support material was laminated onto the layer, and then a formulation could be obtained. Depending on the type of a support, after the drug-containing layer is formed on the support, then a release coating can be laminated to the surface of the drug-containing layer.

[00160] In another method, for example, additive components, such as a base, an absorption enhancer, a stabilizer, a thickener and a gel-forming agent, are added to the core-shell structure of the present invention as necessary, and mixed. After mixing, the mixture is retained by rolling or dipping in a natural woven member such as gauze or absorbent cotton, a woven member of synthetic fiber such as polyester or polyethylene, or a braided fabric, a nonwoven fabric or the like produced by combining suitably the materials described above, or a permeable membrane or the like, depending on the applications. Furthermore, the retained mixture can be covered with an adhesive covering material or the like and used.

[00161] The formulation thus obtained is cut into the shape of an ellipse, a circle, a square, a rectangle or the like, as necessary, depending on the purpose of use. Alternatively, a layer of pressure-sensitive adhesive or the like may be applied to the periphery of the formulation as needed.

[00162] Next, the present invention will become apparent through reference to specific examples and comparative examples of the present invention. Note that the present invention is not limited to the following examples.

(Example 1)

[00163] 0.2 g of vardenafil hydrochloride hydrate (manufactured by Atomax Chemicals Co., Ltd., octanol/water partition coefficient: 0.0, molecular weight: 579 g/mol) was dissolved in 40 g of pure water. To this solution, a solution obtained by dissolving 2.0 g of sorbitan monooleate (manufactured by Nippon Surfactant Industries, Co., Ltd., trade name "NIKKOL SO-10V", HLB value: 8.9 , number of carbon atoms in the unsaturated hydrocarbon group: 17) in 80 g of cyclohexane was added and the resulting solution was stirred with a homogenizer (25000 rpm, 2 minutes). Then, the solution was freeze-dried for 2 days to obtain a core-shell structure.

(Example 2)

[00164] A core-shell structure was obtained in the same manner as in Example 1, except that the sorbitan monooleate used in Example 1 was replaced with glyceryl monooleate (manufactured by Nippon Surfactant Industries, Co., Ltd ., trade name "NIKKOL MGO", HLB value: 6.7, number of carbon atoms in the unsaturated hydrocarbon group: 17).

(Example 3)

[00165] A core-shell structure was obtained in the same manner as in Example 1, except that the sorbitan monooleate used in Example 1 was replaced with sorbitan trioleate (manufactured by Nippon Surfactant Industries, Co., Ltd., trade name "NIKKOL SO-30V", HLB value: 5.1, number of carbon atoms in the unsaturated hydrocarbon group: 17).

(Example 4)

[00166] A core-shell structure was obtained in the same manner as in Example 1, except that the sorbitan monooleate used in Example 1 was replaced with sorbitan monolaurate (manufactured by Nippon Surfactant Industries, Co., Ltd., trade name "NIKKOL SL-10", HLB value: 11.0, number of carbon atoms in the saturated hydrocarbon group: 11).

(Example 5)

[00167] A core-shell structure was obtained in the same manner as in Example 1, except that the sorbitan monooleate used in Example 1 was replaced by glyceryl monocaprylate (manufactured by Taiyo Kagaku Co., Ltd., trade name "Sunsoft No. 700P-2-C", HLB value: 10.9, number of carbon atoms in the saturated hydrocarbon group: 7).

(Example 6)

[00168] A core-shell structure was obtained in the same manner as in Example 1, except that the sorbitan monooleate used in Example 1 was replaced by glyceryl monocaprate (manufactured by Taiyo Kagaku Co., Ltd., trade name "Sunsoft No. 760C", HLB value: 9.7, number of carbon atoms in the saturated hydrocarbon group: 9).

(Example 7)

[00169] A core-shell structure was obtained in the same manner as in Example 1, except that the sorbitan monooleate used in Example 1 was replaced by glyceryl monoundecylenate (manufactured by Nippon Surfactant Industries, Co., Ltd ., trade name "NIKKOL MGU", HLB value: 9.1, number of carbon atoms in the unsaturated hydrocarbon group: 10).

(Example 8)

[00170] A core-shell structure was prepared in the same manner as in Example 1, except that the sorbitan monooleate used in Example 1 was replaced with coconut oil fatty acid diethanolamide (manufactured by NOF CORPORATION, trade name "STAFOAM DFC", HLB value: 9.2, number of carbon atoms in the saturated hydrocarbon group: 11).

(Example 9)

[00171] A core-shell structure was prepared in the same manner as in Example 1, except that the sorbitan monooleate used in Example 1 was replaced with lauric acid diethanolamide (manufactured by NOF CORPORATION, trade name "STAFOAM DL", HLB value: 9.2, number of carbon atoms in the saturated hydrocarbon group: 11).

(Comparative Example 1)

[00172] A core-shell structure was obtained in the same manner as in Example 1, except that the sorbitan monooleate used in Example 1 was replaced by sucrose erucic acid ester (manufactured by Mitsubishi-Chemical Foods Corporation, name commercial "ER-290", HLB value: 2.0, number of carbon atoms in the unsaturated hydrocarbon group: 21).

(Comparative Example 2)

[00173] A core-shell structure was obtained in the same manner as in Example 1, except that the sorbitan monooleate used in Example 1 was replaced with sucrose lauric acid ester (manufactured by Mitsubishi-Chemical Foods Corporation, name commercial "L-195", HLB value: 1.0, number of carbon atoms in the saturated hydrocarbon group: 11).

(Comparative Example 3)

[00174] A core-shell structure was obtained in the same manner as in Example 1, except that the sorbitan monooleate used in Example 1 was replaced with sucrose oleic acid ester (manufactured by Mitsubishi-Chemical Foods Corporation, name commercial "O-170", HLB value: 1.0, number of carbon atoms in the unsaturated hydrocarbon group: 17).

(Comparative Example 4)

[00175] A core-shell structure was obtained in the same manner as in Example 1, except that the sorbitan monooleate used in Example 1 was replaced by propylene glycol monostearate (manufactured by Nippon Surfactant Industries, Co., Ltd. , trade name "NIKKOL PMS-1CV", HLB value: 6.0, number of carbon atoms in the saturated hydrocarbon group: 17).

(Comparative Example 5)

[00176] A core-shell structure was obtained in the same manner as in Example 1, except that the sorbitan monooleate used in Example 1 was replaced by glycerin monostearate (manufactured by Nippon Surfactant Industries, Co., Ltd., trade name "NIKKOL MGS-AMV", HLB value: 6.6, number of carbon atoms in the saturated hydrocarbon group: 17).

(Comparative Example 6)

[00177] A core-shell structure was obtained in the same manner as in Example 1, except that the sorbitan monooleate used in Example 1 was replaced with sorbitan monostearate (manufactured by Nippon Surfactant Industries, Co., Ltd., trade name "NIKKOL SS-10MV", HLB value: 8.9, number of carbon atoms in the saturated hydrocarbon group: 17).

(Assessment)

[00178] The core-shell structures obtained in Examples 1 to 9 and Comparative Examples 1 to 6 were evaluated with respect to skin permeability in rats without the following test.

Hairless Rat Skin Permeability Test;

[00179] A formulation was produced by adding, mixing and dispersing each of the core-shell structures of the Examples and Comparative Examples in liquid paraffin (manufactured by Wako Pure Chemical Industries, Ltd., density (20°C): 0.800 at 0.835 g/ml) such that its content reached 20% by weight in relation to the total weight of the formulation.

[00180] A piece of skin from a hairless mouse (Japan SLC, Inc., taken from 8-week-old HWY/Slc) was placed in a drug skin permeability test cell (see Figure 5). In the upper part of the device, 1.0 g (approximately 7.07 cm2) of the formulation produced by the method described above was applied. A buffer was prepared allowing distilled water to contain 5 x 10-4 M NaH2PO4, 2 x 10-4 M Na2HPO4, 1.5 x 10-4 M NaCl, and 10 ppm gentamicin sulfate (G1658, manufactured by Wako Pure Chemical Industries, Ltd.) and adjusting the pH of the solution to 7.2 with NaOH, and placed in a receiving layer at the bottom. The device was fixed in a thermostatic chamber maintained at 32oC from the beginning of the test. At a predetermined time after the start of the test, 1 ml of the liquid in the thermostatic chamber was withdrawn from the receiving layer at the bottom of the device, and immediately later, 1 ml of liquid having the same composition was added to the layer. Methanol was added to each of the collected receiver liquid samples to extract the eluted lipid or the like, and the extract was centrifuged. After centrifugation, the concentration of the active ingredient in the supernatant was quantitatively determined by high-performance liquid chromatography (HPLC). Based on the quantitatively determined amount of active ingredient, the delay time and the cumulative amount permeated through the skin over 24 hours were calculated.

[00181] As shown in Figure 6, in a graph having the cumulative amount permeated through the skin on the vertical axis and time on the horizontal axis, the delay time is the time read from a point on the horizontal axis at which the section straight line extrapolated from the steady state crosses the horizontal axis.

[00182] The results are shown in Table 2 below. Table 2 shows the molecular weight of the hydrophilic moiety (molecular weight of the hydrophilic moiety), the molecular weight of the alcohol, the HLB value, the number of carbon atoms in the hydrocarbon group and the number of double bonds in the hydrocarbon group in each of the surfactants used in Examples 1 to 9 and Comparative Examples 1 to 6, respectively. Table 2

[00183] As shown in Table 2, the core-shell structures of Comparative Examples 1 to 3 had a drug lag time (transdermal absorption delay time) of 17 hours or more. From the core-shell structures of Comparative Examples 4 to 6, no drug was absorbed transdermally. In contrast, the core-shell structures of the Examples, which had a lag time of 10 hours or less, were particles that had excellent immediate effect and high skin permeability.

(Example 10)

[00184] 0.2 g of loxoprofen sodium dihydrate (manufactured by Tokyo Chemical Industry Co., Ltd., octanol/water division coefficient: 0.8, molecular weight: 304 g/mol) was dissolved in 40 g of pure water. To this solution, a solution obtained by dissolving 1.0 g of sorbitan monooleate (manufactured by Nippon Surfactant Industries, Co., Ltd., trade name "NIKKOL SO-10V", HLB value: 8 .9, number of carbon atoms in the unsaturated hydrocarbon group: 17) in 80 g of cyclohexane was added, and the resulting solution was stirred with a homogenizer (25000 rpm, 2 minutes). Then, the solution was freeze-dried for 2 days to obtain a core-shell structure.

(Example 11)

[00185] A core-shell structure was obtained in the same manner as in Example 10, except that the sorbitan monooleate used in Example 10 was replaced by glyceryl monooleate (manufactured by Nippon Surfactant Industries, Co., Ltd ., trade name "NIKKOL MGO", HLB value: 6.7, number of carbon atoms in the unsaturated hydrocarbon group: 17).

(Example 12)

[00186] A core-shell structure was obtained in the same manner as in Example 10, except that the sorbitan monooleate used in Example 10 was replaced with sorbitan trioleate (manufactured by Nippon Surfactant Industries, Co., Ltd., trade name "NIKKOL SO-30V", HLB value: 5.1, number of carbon atoms in the unsaturated hydrocarbon group: 17).

(Example 13)

[00187] A core-shell structure was obtained in the same manner as in Example 10, except that the sorbitan monooleate used in Example 10 was replaced by sorbitan monolaurate (manufactured by Nippon Surfactant Industries, Co., Ltd., trade name "NIKKOL SL-10", HLB value: 11.0, number of carbon atoms in the saturated hydrocarbon group: 11).

(Example 14)

[00188] A core-shell structure was obtained in the same manner as in Example 10, except that the sorbitan monooleate used in Example 10 was replaced by glyceryl monocaprylate (manufactured by Taiyo Kagaku Co., Ltd., trade name "Sunsoft No. 700P-2-C", HLB value: 10.9, number of carbon atoms in the saturated hydrocarbon group: 7).

(Example 15)

[00189] A core-shell structure was obtained in the same manner as in Example 10, except that the sorbitan monooleate used in Example 10 was replaced by glyceryl monocaprate (manufactured by Taiyo Kagaku Co., Ltd., trade name "Sunsoft No. 760-C", HLB value: 9.7, number of carbon atoms in the saturated hydrocarbon group: 9).

(Example 16)

[00190] A core-shell structure was obtained in the same manner as in Example 10, except that the sorbitan monooleate used in Example 10 was replaced by glyceryl monoundecylenate (manufactured by Nippon Surfactant Industries, Co., Ltd ., trade name "NIKKOLMGU", HLB value: 9.2, number of carbon atoms in the unsaturated hydrocarbon group: 10).

(Example 17)

[00191] A core-shell structure was prepared in the same manner as in Example 10, except that the sorbitan monooleate used in Example 10 was replaced with coconut oil fatty acid diethanolamide (manufactured by NOF CORPORATION, trade name "STAFOAM DFC", HLB value: 9.2, number of carbon atoms in the saturated hydrocarbon group: 11).

(Example 18)

[00192] A core-shell structure was prepared in the same manner as in Example 10, except that the sorbitan monooleate used in Example 10 was replaced with lauric acid diethanolamide (manufactured by NOF CORPORATION, trade name "STAFO - AM DL", HLB value: 9.2, number of carbon atoms in the saturated hydrocarbon group: 11).

(Assessment)

[00193] The core-shell structures obtained in Examples 10 to 18 were evaluated for skin permeability in hairless rats and primary irritation in rabbit skin by the following tests. The results are shown in Table 3 below.

Hairless Rat Skin Permeability Test;

[00194] A formulation was produced by adding, mixing and dispersing each of the core-shell structures of Examples 10 to 18 in a Plastibase ointment base (manufactured by Taisho Pharmaceutical Co., Ltd.) such that the its content reached 20% by weight in relation to the total weight of a formulation.

[00195] A piece of skin from a hairless mouse (manufactured by Japan SLC, Inc., taken from 8-week-old HWY/Slc) was attached to a drug skin permeability test cell (see Figure 5). In the upper part of the device, 1.0 g (7.07 cm2) of the formulation produced by the method described above was applied. In a receiving layer at the bottom, a buffer was placed which was prepared by allowing distilled water to contain 5 x 10-4 M NaH2PO4, 2 x 10-4 M Na2HPO4, 1.5 x 10-4 M NaCl, and 10 ppm of gentamicin sulfate (G1658, manufactured by Wako Pure Chemical Industries, Ltd.) and adjusting the pH of the solution to 7.2 with NaOH. The device was fixed in a thermostatic chamber maintained at 32oC from the beginning of the test. At a predetermined time after the start of the test, 1 ml of the liquid in the thermostatic chamber was taken from the receiving layer at the bottom of the device, and immediately afterwards 1 ml of liquid having the same composition was added to the layer. Methanol was added to each of the collected receiver liquid samples to extract the eluted lipid or the like, and the extract was centrifuged. After centrifugation, the concentration of the active ingredient in the supernatant was quantitatively determined by high-performance liquid chromatography (HPLC). Based on the quantity of active ingredient determined quantitatively, the delay time and the cumulative amount permeated through the skin over 24 hours were calculated in the same manner as described above.

Rabbit Skin Primary Irritation Test;

[00196] The dorsal skin of a rabbit is shaved with an electric clipper (with an electric shaver as required). Healthy skin at two points on each side of the dorsal midline of the dorsal skin, that is, at four points in total, was used as administration sites. The formulation produced in the same manner as in the hairless rat permeability test was taken with a spatula and spread homogeneously with pieces of gauze having a size of 2 cm x 2 cm, and the pieces of gauze are fixed at the administration sites. The pieces of gauze are secured by covering with a non-woven adhesive bandage (manufactured by Nichiban Co., Ltd., MESHPORE, No. 50). Then, the administration sites were completely covered with gauze and then sealed through the covering with an elastic adhesive fabric bandage (manufactured by Nichiban Co., Ltd., ELASTPORE, No. 100). Sealing was completed 24 hours after the start of administration and administration specimens were removed.

[00197] Skin reaction 24 hours after administration (30 minutes after sealing is completed and administration specimens are removed) is observed with the naked eye. Thereafter, the skin reaction at 48 hours 48 hours and 72 hours after administration (30 minutes after sealing was completed and administration specimens were removed) was observed with the naked eye in the same manner. Skin reaction assessment was performed based on the Draize score shown in Table 4 below.

[00198] Specifically, individual skin reaction scores (sum of erythema and eschar formation and edema formation) at the administration sites of each rabbit were calculated for each administration specimen at each observation time. Thereafter, the primary irritation index (primary irritation index; P.I.I.) was calculated from the individual scores at 24 hours and 72 hours after administration (the score at 48 hours after administration is not added). Specifically, the following equations (1) and (2) were used for the calculation. Average score for each administration site = (Sum of individual scores at 24 hours and 72 hours after administration) / 2 Equation (1) Index of primary irritation (P.I.I.) = (Sum of the average score for each administration site) / (3 (rabbits)) Equation (2)

[00199] Based on the primary irritation index (PII) obtained, the degree of irritation of each of the administration specimens was classified according to the classification table in Table 5 below.

[00200] As can be clearly seen in Table 3, it is possible to confirm that Examples 10 to 16 have an excellent immediate effect, as well as being able to further reduce skin irritation, in transdermal absorption.

(Example 19)

[00201] 0.2 g of rivastigmine L-tartrate (manufactured by Tokyo Chemical Industry Co., Ltd., octanol/water partition coefficient: 2.3, molecular weight: 400 g/mol) was dissolved. in 10 g of pure water. To this solution, a solution obtained by dissolving 0.4 g of glyceryl monooleate (manufactured by Nippon Surfactant Industries, Co., Ltd., trade name "NIKKOL MGO", HLB value: 6.7 , number of carbon atoms in the unsaturated hydrocarbon group: 17) in 20 g of cyclohexane was added, and the resulting solution was stirred with a homogenizer (25000 rpm, 2 minutes). Then, the solution was freeze-dried for 2 days to obtain a core-shell structure.

[00202] In 60 parts by weight of the obtained core-shell structure, 40 parts by weight of an acrylic pressure-sensitive adhesive (manufactured by CosMED Pharmaceutical Co., Ltd., trade name "MAS683") were mixed, and toluene was added to the mixture in such a way that the solids concentration reached 30% by weight. Then, the resultant was mixed until homogeneity to prepare a pressure-sensitive adhesive layer solution.

[00203] Then, a release blade was provided which had been subjected to a mold release treatment by applying silicone to a surface of a release base material produced from a polyethylene terephthalate film having a thickness of 38μm. The pressure-sensitive adhesive layer solution was applied to the surface subjected to mold release treatment of this release sheet, and dried at 90°C for 20 minutes to produce a laminate having a pressure-sensitive adhesive layer having a thickness of 110 μm on the surface of the release blade subjected to mold release treatment. Then, a support produced from a polyethylene terephthalate film having a thickness of 38 μm was provided. A surface of this support and the pressure-sensitive adhesive layer of the laminate described above were superimposed so as to face each other, and the support and the laminate were superimposed and integrated by transferring the pressure-sensitive adhesive layer of the laminate onto the support to thus produce a tape preparation.

(Example 20)

[00204] A ribbon preparation was obtained in the same manner as in Example 19, except that the glyceryl monooleate used in Example 19 was replaced by sorbitan monolaurate (manufactured by Nippon Surfactant Industries, Co., Ltd., trade name "NIKKOL SL- 10", HLB value: 11.0, number of carbon atoms in the saturated hydrocarbon group: 11).

(Example 21)

[00205] A ribbon preparation was obtained in the same manner as in Example 19, except that the glyceryl monooleate used in Example 19 was replaced by 0.2 g of glyceryl monocaprylate (manufactured by Taiyo Kagaku Co., Ltd. , trade name "Sunsoft No. 700P-2-".C", HLB value: 10.9, number of carbon atoms in the saturated hydrocarbon group: 7).

(Comparative Example 7)

[00206] A ribbon preparation was obtained in the same manner as in Example 19, except that the glyceryl monooleate used in Example 19 was replaced by sucrose erucic acid ester (manufactured by Mitsubishi-Chemical Foods Corporation, trade name " ER- 290", HLB value: 2.0, number of carbon atoms in the unsaturated hydrocarbon group: 21).

(Comparative Example 8)

[00207] A tape preparation was obtained in the same manner as in Example 19, except that 40 parts by weight of an acrylic pressure-sensitive adhesive (manufactured by CosMED Pharmaceutical Co., Ltd., trade name "MAS683") were mixed as if 40 parts by weight of rivastigmine L-tartrate and 20 parts by weight of glyceryl monocaprylate, toluene was added to the mixture in such a way that the solids concentration reached 40% by weight, and then the resultant was mixed until homogeneity to thereby prepare a pressure-sensitive adhesive layer solution.

(Comparative Example 9)

[00208] A tape preparation was obtained in the same manner as in Example 19, except that 40 parts by weight of rivastigmine L-tartrate were mixed with 60 parts by weight of an acrylic pressure-sensitive adhesive (manufactured by CosMED Pharmaceutical Co., Ltd., trade name "MAS683").

(Assessment)

[00209] The tape preparations obtained in Examples 19 to 21 and in Comparative Example 7 were evaluated for skin permeability in hairless rats through the following test. Additionally, the tape preparations obtained in Example 21 and Comparative Examples 8 and 9 were evaluated with respect to X-ray diffraction measurement by the following test.

[00210] Hairless Mouse Skin Permeability Test; A piece of skin from a hairless mouse (Japan SLC, Inc., taken from 8-week-old HWY/Slc) was fixed in a hairless mouse permeability test cell. drug skin (Figure 5). In the upper part of the device, 1.33 cm2 of each of the tape preparations produced in the Examples and Comparative Examples was applied. A buffer was prepared by allowing distilled water to contain 5 x 10-4 M NaH2PO4, 2 x 10-4 M Na2HPO4, 1.5 x 10-4 M NaCl, and 10 ppm gentamicin sulfate (G1658, manufactured by Wako Pure Chemical Industries, Ltd.) and adjusting the pH of the solution to 7.2 with NaOH, and placed in a receiving layer at the bottom. The device was fixed in a thermostatic chamber maintained at 32oC from the beginning of the test. At a predetermined time after the start of the test, 1 ml of the liquid in the thermostatic chamber was withdrawn from the receiving layer at the bottom of the device, and immediately thereafter 1 ml of liquid having the same composition was added to the layer. Methanol was added to each of the collected receiver liquid samples to extract the eluted lipid or the like, and the extract was centrifuged. After centrifugation, the concentration of the active ingredient in the supernatant was quantitatively determined by high-performance liquid chromatography (HPLC). Based on the quantity of active ingredient determined quantitatively, the delay time and the cumulative amount permeated through the skin over 24 hours were calculated in the same manner as described above. The results are shown in Table 6 below.

[00211] It is observed that in Examples 19 to 21, although the content of the active ingredient was increased, it was confirmed that the coating property and dispersibility in the form of a tape preparation were increased.

[00212] Measurement of X-ray Diffraction;The tape preparations of Example 21, Comparative Example 8 and Comparative Example 9 were measured by the X-ray diffraction method.

[00213] A crystalline state of the active ingredient was measured using an X-ray diffractometer (manufactured by Rigaku Corporation, "SmartLab). An optical arrangement of the concentration method was used, and a CuKα ray (wavelength: 1.54 Â ) was used with the energy of 45 kV and 200 mA as the light source. A 5.0o Soller slit was used as the incident slit, and a 5.0o Soller slit was used as the receiving slit. every 0.02o in the scan range of 5 to 40o. The counting time was set to 5o/minute.

[00214] As shown in Figure 7, when the X-ray diffraction pattern of Comparative Example 8 was checked, the positions of the diffraction peaks corresponded to those of the diffraction peak observed in Comparative Example 9. When the X-ray diffraction pattern of Example 21 was checked, the diffraction peaks observed in Comparative Example 8 disappeared. It was confirmed that the active ingredient formed a core-shell structure also in the pressure-sensitive adhesive layer of the tape preparation.Table 6

(Example 22)

[00215] A core-shell structure was obtained in the same manner as in Example 1, except that the sorbitan monooleate used in Example 1 was replaced by diglyceride caprylate (manufactured by Taiyo Kagaku Co., Ltd., trade name "Sunfat GDC-S", HLB value: 13.2, number of carbon atoms in the saturated hydrocarbon group: 7).

(Example 23)

[00216] A core-shell structure was obtained in the same manner as in Example 1, except that the sorbitan monooleate used in Example 1 was replaced by diglyceryl monooleate (manufactured by Nippon Surfactant Industries, Co., Ltd ., trade name "NIKKOL DGMO-CV", HLB value: 9.0, number of carbon atoms in the unsaturated hydrocarbon group: 17).

(Example 24)

[00217] A core-shell structure was obtained in the same manner as in Example 1, except that the sorbitan monooleate used in Example 1 was replaced by propylene glycol dioleate (manufactured by NIHON EMULSION Co., Ltd., name commercial "EMALEX PG-di-O", HLB value: 4.3, number of carbon atoms in the unsaturated hydrocarbon group: 17).

(Example 25)

[00218] A core-shell structure was obtained in the same manner as in Example 1, except that the sorbitan monooleate used in Example 1 was replaced by propylene glycol monolaurate (manufactured by RIKEN VITAMIN Co., Ltd., name commercial "RIKEMAL PL-100", HLB value: 8.0, number of carbon atoms in the saturated hydrocarbon group: 11).

(Example 26)

[00219] 0.2 g of vardenafil hydrochloride hydrate (manufactured by Atomax Chemicals Co., Ltd., octanol/water division coefficient: 0.0, molecular weight: 579 g/mol) was dissolved in 40 g of pure water. To this solution, a solution obtained by dissolving 0.1 g of glyceryl monocaprylate (manufactured by Taiyo Kagaku Co., Ltd., trade name "Sunsoft No. 700P-2-C", HLB value: 10 .9, number of carbon atoms in the hydrocarbon group: 7) in 80 g of cyclohexane was added, and the resulting solution was stirred with a homogenizer (25000 rpm, 2 minutes). Then, the solution was freeze-dried for 2 days to obtain a core-shell structure. Therefore, the mass ratio (core-shell ratio) between the active ingredient (vardenafil hydrochloride hydrate) and the surfactant (glyceryl monocaprylate) was adjusted to 1:0.5.

(Example 27)

[00220] 0.2 g of vardenafil hydrochloride hydrate (manufactured by Atomax Chemicals Co., Ltd., octanol/water division coefficient: 0.0, molecular weight: 579 g/mol) was dissolved in 40 g of pure water. To this solution, a solution obtained by dissolving 4.0 g of glyceryl monocaprylate (manufactured by Taiyo Kagaku Co., Ltd., trade name "Sunsoft No. 700P-2-C", HLB value: 10 .9, number of carbon atoms in the hydrocarbon group: 7) in 80 g of cyclohexane was added, and the resulting solution was stirred with a homogenizer (25000 rpm, 2 minutes). Then, the solution was freeze-dried for 2 days to obtain a core-shell structure. Therefore, the mass ratio (core-shell ratio) between the active ingredient (vardenafil hydrochloride hydrate) and the surfactant (glyceryl monocaprylate) was adjusted to 1:20.

(Example 28)

[00221] A core-shell structure was obtained in the same manner as in Example 1, except that the sorbitan monooleate used in Example 1 was replaced by glycerin palmitate (manufactured by Tokyo Chemical Industry Co., Ltd., name commercial "Monopalmitin", HLB value: 7.2, number of carbon atoms in the saturated hydrocarbon group: 15).

(Example 29)

[00222] A core-shell structure was obtained in the same manner as in Example 1, except that the sorbitan monooleate used in Example 1 was replaced by sorbitan palmitate (manufactured by Nippon Surfactant Industries, Co., Ltd., trade name "NIKKOLSP-10V", HLB value: 9.5, number of carbon atoms in the saturated hydrocarbon group: 15).

(Example 30)

[00223] A core-shell structure was obtained in the same manner as in Example 1, except that the sorbitan monooleate used in Example 1 was replaced by glyceryl monolaurate (manufactured by Taiyo Kagaku Co., Ltd., trade name "Sunsoft No. 750C", HLB value: 8.7, number of carbon atoms in the saturated hydrocarbon group: 11).

(Example 31)

[00224] 0.1 g of [Arg-8]-Vasopressin (manufactured by Heat-biochem Co., Ltd., octanol/water partition coefficient: -4.8, molecular weight: 1084 g/mol) was dissolved in 40 g of pure water. To this solution, a solution obtained by dissolving 0.6 g of glyceryl monocaprate (manufactured by Taiyo Kagaku Co., Ltd., trade name "Sunsoft No. 760-C", HLB value: 9.7 , number of carbon atoms in the saturated hydrocarbon group: 9) in 80 g of cyclohexane was added, and the resulting solution was stirred with a homogenizer (25000 rpm, 2 minutes). Then, the solution was freeze-dried for 2 days to obtain a core-shell structure. It is observed that the core-to-shell ratio was fixed as 1:6.

(Example 32)

[00225] 0.1 g of Miravirsen (sequence name: antimir 122, manufactured by GeneDesign Inc., molecular weight: 4967 g/mol) was dissolved in 40 g of pure water. To this solution, a solution obtained by dissolving 0.6 g of lauric acid diethanolamide (manufactured by NOF CORPORATION, trade name "STAFOAM DL", HLB value: 9.2, number of carbon atoms in the saturated hydrocarbon group : 11) in 80 g of cyclohexane was added and the resulting solution was stirred with a homogenizer (25000 rpm, 2 minutes). Then, the solution was freeze-dried for 2 days to obtain a core-shell structure. It is observed that the core-to-shell ratio was set at 1:6.

(Example 33)

[00226] 0.1 g of K3 Et-Free (class B TLR9 ligand) (manufactured by GeneDesign Inc., molecular weight: 6349 g/mol) was dissolved in 40 g of pure water. To this solution, a solution obtained by dissolving 0.6 g of lauric acid diethanolamide (manufactured by NOF CORPORATION, trade name "STAFOAM DL", HLB value: 9.2, number of carbon atoms in the saturated hydrocarbon group : 11) in 80 g of cyclohexane was added, and the resulting solution was stirred with a homogenizer (25000 rpm, 2 minutes). Then, the solution was freeze-dried for 2 days to obtain a core-shell structure. It is observed that the core-to-shell ratio was set to 1:6.

(Comparative Example 10)

[00227] A core-shell structure was obtained in the same manner as in Example 1, except that the sorbitan monooleate used in Example 1 was replaced by tetraglyceryl monooleate (manufactured by Nippon Surfactant Industries, Co., Ltd ., trade name "NIKKOL Tetraglyn 1-OV", HLB value: 11.8, number of carbon atoms in the saturated hydrocarbon group: 17).

(Comparative Example 11)

[00228] A core-shell structure was obtained in the same manner as in Example 1, except that the sorbitan monooleate used in Example 1 was replaced by ricinoleate condensed with hexaglycerin (manufactured by Nippon Surfactant Industries, Co., Ltd. , trade name "NIKKOL Hexaglyn PR-15", HLB value: 7.5, number of carbon atoms in the unsaturated hydrocarbon group: 53).

(Comparative Example 12)

[00229] A core-shell structure was obtained in the same manner as in Example 1, except that the sorbitan monooleate used in Example 1 was replaced by ricinoleate condensed with tetraglycerin (manufactured by Sakamoto Yakuhin Kogyo Co., Ltd., trade name "CR-310", HLB value: 7.8 or less, number of carbon atoms in the unsaturated hydrocarbon group: 35 or more).

(Comparative Example 13)

[00230] A core-shell structure was obtained in the same manner as in Example 1, except that the sorbitan monooleate used in Example 1 was replaced by glycerin erucic acid ester (manufactured by Tokyo Chemical Industry Co., Ltd ., trade name "Monoerucin", HLB value: 5.8, number of carbon atoms in the unsaturated hydrocarbon group: 21).

[00231] The core-shell structures obtained in Examples 22 to 31 and Comparative Examples 10 to 13 were subjected to the skin permeability test on hairless rats in the same way as in Example 1 to obtain the delay time and the cumulative amount permeated through the skin over 24 hours. The results are shown in Table 7 below.

[00232] The core-shell structures obtained in Examples 32 to 33 were evaluated for skin permeability in hairless mice through the following test. The results are shown in Table 7 below.

[00233] Hairless mouse skin permeability test;

[00234] A formulation was produced by adding, mixing and dispersing each of the core-shell structures of Examples 32 to 33 in liquid paraffin (manufactured by Wako Pure Chemical Industries, Ltd., density (20°C): 0.800 at 0.835 g/ml) such that its content reached 20% by weight in relation to the total weight of the formulation.

[00235] A piece of skin from a hairless mouse (manufactured by Japan SLC, Inc., taken from 7-week-old Hos:HR-1) was attached to a drug skin permeability test cell ( see Figure 5). In the upper part of the device, 1.0 g (7.07 cm2) of the formulation produced by the method described above was applied. A buffer was prepared by allowing distilled water to contain 5 x 10-4 M NaH2PO4, 2 x 10-4 M Na2HPO4, 1.5 x 10-4 M NaCl, and 10 ppm gentamicin sulfate (G1658, manufactured by Wako Pure Chemical Industries, Ltd.) and adjusting the pH of the solution to 7.2 with NaOH, and placed in a receiving layer at the bottom. The device was fixed in a thermostatic chamber maintained at 32oC since the beginning of the test. At a predetermined time after the start of the test, 1 ml of the liquid in the thermostatic chamber was withdrawn from the receiving layer at the bottom of the device, and immediately thereafter, 1 ml of liquid having the same composition was added to the layer. Methanol was added to each of the collected receiver liquid samples to extract the eluted lipid or the like, and the extract was centrifuged. After centrifugation, the concentration of the active ingredient in the supernatant was quantitatively determined by high-performance liquid chromatography (HPLC). Based on the quantitatively determined amount of active ingredient, the lag time and the cumulative amount permeated through the skin over 24 hours were calculated in the same manner as described above.

(Example 34)

[00236] The core-shell structure obtained in Example 5 was subjected to the skin permeability test on hairless rats using an ointment-based Plastibase in the same way as in Example 10 to obtain the delay time and the cumulative amount permeated through the skin for 24 hours. The results are shown in Table 7 below.

(Comparative Example 14)

[00237] The core-shell structure obtained in Comparative Example 1 was subjected to the skin permeability test on hairless mice using a Plastibase ointment base in the same way as in Example 10 to obtain the delay time and the cumulative amount permeated through the skin for 24 hours. The results are shown in Table 7 below.

(Example 35)

[00238] The core-shell structure obtained in Example 5 was used to produce a tape preparation in the same way as in Example 19, and the tape preparation was subjected to the skin permeability test on hairless rats in the same way as in Example 19 to obtain the delay time and the cumulative amount permeated through the skin over 24 hours. The results are shown in Table 7 below.Table 7 List of Reference Signals 1 Parafilm 2 Skin 3 Formulation 4 Receiver liquid (phosphate buffer pH = 7.2) 5 Stirrer 10 Core-shell structure 11 Core part 12 Shell part 20 Tape preparation 21 Base material layer 21a, 22a Surface 22 Pressure-sensitive adhesive layer 23 Coating

Claims (8)

1. Core-shell structure (10), characterized in that it comprises: a central part (11) containing an active ingredient, and a shell part (12) containing a surfactant having an HLB value of 4 to 14, in which the core region (11) is solid, the surfactant is a surfactant formed by the bond of an alcohol with a fatty acid via an ester or amide bond, the alcohol has a molecular weight in the range of 70g/mol to 200 g/mol mol, the surfactant contains a saturated hydrocarbon group having 7 to 11 carbon atoms or an unsaturated hydrocarbon group having 7 to 11 carbon atoms, and the surfactant comprises at least one selected from the group consisting of sorbitan fatty acid esters, fatty acid esters of glycerin, fatty acid esters of propylene glycol and fatty acid alkanolamides. 2. Core-shell structure (10), according to claim 1, characterized by the fact that the surfactant comprises at least one selected from the group consisting of sorbitan fatty acid esters, glycerin fatty acid esters and esters propylene glycol fatty acid. 3. Core-shell structure (10) according to claim 1 or 2, characterized in that the glycerin fatty acid ester is at least one selected from monoglycerin fatty acid esters, monoglycerin fatty acid esters, diglycerin and triglycerin fatty acid esters. 4. Core-shell structure (10), according to any one of claims 1 to 3, characterized by the fact that a mass ratio between the active ingredient and the surfactant (active ingredient: surfactant) is 1:0, 5 to 1:2.5. 5. Formulation, characterized by the fact that it comprises the core-shell structure (10) as defined in any one of claims 1 to 4. 6. External medicine, characterized by the fact that it comprises the core-shell structure (10) as defined in any one of claims 1 to 4. 7. Tape preparation, characterized by the fact that it comprises the core-shell structure (10) as defined in any one of claims 1 to 4. 8. Cosmetic, characterized by the fact that it comprises the core-shell structure (10) as defined in any one of claims 1 to 4.