Transdermal patch

Abstract

A transdermal absorption-type patch (10) comprises a support body (1) and an adhesive layer (2) layered on the support body (1). The adhesive layer (2) contains: a solid composite body (2a) in which an active ingredient having a molecular weight of 800 or more is covered with a surfactant; an oil phase; and an acrylic elastomer. The content of the acrylic elastomer is 30 to 70 mass% with respect to the combined mass of the acrylic elastomer and the oil phase. The composite body (2a) constitutes solid-in-oil type particles dispersed in the oil phase.

Description

[Technical field]

[0001] The present invention relates to a transdermal patch. [Background technology]

[0002] Skin tissue contains a stratum corneum that has a physicochemical barrier function that can nonspecifically prevent the invasion of various infectious agents including bacteria and viruses. Therefore, it is extremely difficult to permeate drugs into the body through the skin. In particular, it is known that hydrophilic polymers (e.g., proteins) with a molecular weight of more than 800 are not absorbed by themselves through the skin.

[0003] The inventors have previously developed liquid solid-in-oil (S / O) type topical preparations (see, for example, Patent Document 1) and transdermal immune agents (see, for example, Patent Document 2) in order to allow hydrophilic compounds to penetrate into the body through the skin. [Prior art documents] [Patent documents]

[0004] [Patent Document 1] International Publication No. 2006 / 025583 [Patent Document 2] JP 2008-179561 A [Patent Document 3] JP 2014-172840 A Summary of the Invention [Problem to be solved by the invention]

[0005] However, it is difficult to regulate the dosage per administration for liquid S / O type topical preparations, and for practical application in clinical practice, a tape- or sealed S / O type preparation is required. In addition, there are no transdermal patches that can penetrate proteins with a molecular weight of over 800 through the skin.

[0006] Patent Document 3 discloses a patch having an adhesive layer containing an adhesive composition containing S / O type microparticles containing loxoprofen sodium dihydrate and an acrylic polymer. Since the molecular weight of loxoprofen sodium dihydrate is about 300, the composition of the adhesive layer disclosed in Patent Document 3 is not optimized for the polymer S / O type particles.

[0007] The present invention has been made in view of the above circumstances, and has an object to provide a transdermal patch capable of increasing the skin permeability of polymeric S / O type particles. [Means for solving the problem]

[0008] The transdermal patch according to the first aspect of the present invention comprises: A support; A pressure-sensitive adhesive layer laminated on the support; Equipped with the pressure-sensitive adhesive layer comprises a solid complex in which an active ingredient having a molecular weight of 800 or more is coated with a surfactant, an oil phase, and a pressure-sensitive adhesive comprising an acrylic elastomer; The acrylic elastomer is The ester moiety of the alkyl group has 6 to 14 carbon atoms. The content of the acrylic elastomer is 30 to 70% by mass based on the total mass of the acrylic elastomer and the oil phase, The complex forms solid-in-oil type particles dispersed in the oil phase.

[0009] In this case, the content of the acrylic elastomer is 40 to 50% by mass based on the total mass of the acrylic elastomer and the oil phase. This may also be the case.

[0010] The support contains an acrylic resin. This may also be the case.

[0011] In addition, the transdermal patch according to the first aspect of the present invention is Further comprising a liner layer covering the pressure-sensitive adhesive layer on the pressure-sensitive adhesive layer. This may also be the case.

[0012] In addition, the active ingredient is a protein having a molecular weight of more than 10,000. This may also be the case.

[0013] In addition, the active ingredient is a protein having a molecular weight of 30,000 or more. This may also be the case.

[0014] In addition, the active ingredient is a physiologically active peptide, an antibody or an antigen. This may also be the case.

[0015] In addition, the transdermal patch according to the first aspect of the present invention is A promoter layer containing a percutaneous absorption promoter is further provided between the support and the pressure-sensitive adhesive layer, The active ingredient is an antigen. This may also be the case.

[0016] In addition, the transdermal patch according to the first aspect of the present invention is The active ingredient is an antigen, Used as a vaccine This may also be the case.

[0017] In addition, the active ingredient is leuprorelin, octreotide, or a salt thereof. This may also be the case. The transdermal patch according to the second aspect of the present invention comprises: A support; A pressure-sensitive adhesive layer laminated on the support; an enhancer layer between the support and the pressure-sensitive adhesive layer, the enhancer layer containing a percutaneous absorption enhancer; Equipped with the pressure-sensitive adhesive layer comprises a solid complex in which an antigen having a molecular weight of 800 or more is coated with a surfactant, an oil phase, and a pressure-sensitive adhesive comprising an acrylic elastomer; The content of the acrylic elastomer is 30 to 70% by mass based on the total mass of the acrylic elastomer and the oil phase, The complex forms solid-in-oil type particles dispersed in the oil phase. Effect of the Invention

[0018] According to the present invention, the skin permeability of polymeric S / O type particles can be increased. [Brief description of the drawings]

[0019] [Figure 1] FIG. 1 is a cross-sectional view showing a schematic diagram of a transdermal patch according to a first embodiment of the present invention. [Diagram 2] FIG. 2 is a cross-sectional view showing a schematic diagram of a transdermal patch according to another embodiment 1 of the present invention. [Diagram 3] FIG. 2 is a cross-sectional view showing a schematic diagram of a transdermal patch according to another embodiment 1 of the present invention. [Figure 4] FIG. 2 is a cross-sectional view showing a schematic diagram of a transdermal patch according to another embodiment 1 of the present invention. [Diagram 5] FIG. 2 is a schematic diagram showing a transdermal absorption agent according to a second embodiment of the present invention. [Figure 6] FIG. 1 is a cross-sectional view showing a schematic diagram of a percutaneous absorption test system in Test Example 1. [Figure 7] FIG. 1 shows the results of a transdermal absorption test using an S / O seal encapsulating FITC-OVA in Test Example 1. [Figure 8] FIG. 1 shows the results of a transdermal absorption test using an S / O seal containing FITC-IgG in Test Example 2. [Figure 9] FIG. 13 is a diagram showing the results of a transdermal absorption test using an OCT-encapsulated S / O seal in Test Example 2. [Figure 10] FIG. 1 shows the schedule of the animal immunity test in Test Example 3. [Figure 11] FIG. 1 shows the results of an animal immunity test using an S / O seal encapsulating OVA in Test Example 3. [Figure 12] FIG. 1 shows the results of an animal immunity test using an OVA-encapsulated S / O seal in Test Example 4. [Figure 13] FIG. 13 is a graph showing the particle size distribution of a leuprorelin-surfactant complex in an S / O formulation in Example 4. [Figure 14]FIG. 1 is a cross-sectional view showing a schematic diagram of a percutaneous absorption test system in Test Example 5. [Figure 15] FIG. 1 shows the results of a percutaneous absorption test using an S / O type preparation in Test Example 5. [Figure 16] FIG. 1 shows the results of a percutaneous absorption test using an S / O type preparation in Test Example 5. [Figure 17] FIG. 1 shows the results of an administration test to mice using an S / O type formulation in Test Example 6. [Figure 18] FIG. 13 is a diagram showing the particle size distribution of the octreotide acetate-surfactant complex in the S / O type formulation of Example 6. [Figure 19] FIG. 13 is a schematic cross-sectional view of a percutaneous absorption test system in Test Example 7. [Figure 20] FIG. 1 shows the skin permeation amounts of an S / O type preparation in Test Example 7 and Comparative Example 1. [Figure 21] 1 shows the change in plasma octreotide acetate concentration over time in Test Example 8. (A) shows the octreotide acetate concentration from 0 to 24 hours, and (B) shows the octreotide acetate concentration from 0 to 96 hours. [Figure 22] 1 shows the change in plasma octreotide acetate concentration over time in Test Example 9. (A) shows the octreotide acetate concentration from 0 to 24 hours, and (B) shows the octreotide acetate concentration from 0 to 96 hours. [Diagram 23] FIG. 13 is a graph showing blood glucose levels measured in Test Example 9. [Figure 24] FIG. 13 shows the results of a transdermal absorption test using an S / O seal encapsulating FITC-K-TRP-2 in Test Example 10. [Diagram 25] FIG. 13 shows the results of a transdermal absorption test using an S / O seal encapsulating FITC-OVA in Test Example 11. [Figure 26] 1 shows the schedule and results of an animal immunity test using an OVA-encapsulated S / O seal and an OVA-encapsulated MGO seal in Test Example 12. (A) shows the schedule of the animal immunity test. (B) shows the antibody titer on day 35. (C) shows the antibody titer on day 56. [Figure 27] FIG. 13 shows the results of a transdermal absorption test using an MGO seal encapsulating FITC-OVA in Test Example 13. [Figure 28] FIG. 13 shows the results of a transdermal absorption test using a two-layer S / O seal encapsulating FITC-OVA in Test Example 14. [Figure 29] 1 shows the schedule and results of an animal immunity test using a two-layer S / O seal encapsulating FITC-OVA in Test Example 15. (A) shows the schedule of the animal immunity test, and (B) shows the amount of anti-OVA antibody. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0020] The transdermal patch according to the embodiment will be described in detail below.

[0021] First embodiment <Transdermal patch> The transdermal patch of this embodiment comprises a support and an adhesive layer laminated on the support. The adhesive layer contains a solid complex (active ingredient-surfactant complex) in which an active ingredient having a molecular weight of 800 or more is coated with a surfactant, an oil phase, and an adhesive. The complex forms solid-in-oil (S / O) type particles dispersed in the oil phase.

[0022] As shown in the examples below, the transdermal patch has an adhesive layer containing solid-in-oil type particles in which a solid complex is dispersed in an oil phase, and thus allows an active ingredient with a molecular weight of 800 or more, which is usually unable to penetrate the skin, to penetrate into the body through the skin. In addition, since the form is a patch, the dose of the active ingredient administered per time can be specified. Furthermore, since the form is a patch, it can be fixed to the skin, and as shown in the examples below, the active ingredient can penetrate into the body through the skin more efficiently than a liquid S / O type preparation.

[0023] 1 is a cross-sectional view showing a transdermal patch 10 as an example of the transdermal patch according to the present embodiment. The transdermal patch 10 comprises a support 1 and an adhesive layer 2. The transdermal patch 10 has a rectangular planar shape when viewed from the direction of the adhesive layer 2 of the transdermal patch 10. The transdermal patch 10 comprises the support 1 and the adhesive layer 2, so that the transdermal patch 10 can be fixed to the skin.

[0024] The adhesive layer 2 is laminated on one side of the support 1. The adhesive layer 2 contains a solid complex 2a. The complex 2a is configured such that an active ingredient having a molecular weight of 800 or more is coated with a surfactant. In the adhesive layer 2, the oil phase remains without evaporating, and in the mixture of the components of the adhesive layer 2, the complex 2a is in a state of being dispersed in the oil phase.

[0025] FIG. 2 is a cross-sectional view showing a transdermal patch 20, which is another example of the transdermal patch according to the present embodiment. In FIG. 2 and subsequent figures, the same components as those shown in the figures already described are given the same reference numerals as those in the figures already described, and detailed description thereof will be omitted. The transdermal patch 20 is the same as the transdermal patch 10 shown in FIG. 1, except that the adhesive layer 2 has one or more protrusions on the surface of the adhesive layer 2 that contacts the skin. The adhesive layer 2 has one or more protrusions on the surface of the adhesive layer 2 that contacts the skin, so that the active ingredient can penetrate more effectively into the body from the skin. The shape of the protrusions is not particularly limited, but examples include pyramidal and conical shapes. The size of each protrusion is not particularly limited, but from the viewpoint of enhancing the penetration effect of the active ingredient into the body, the height, width and depth can be micro-order, for example, 1 μm or more and less than 1000 μm.

[0026] Fig. 3 is a cross-sectional view showing a transdermal patch 30, which is another example of the transdermal patch according to the present embodiment. The transdermal patch 30 is the same as the transdermal patch 10 shown in Fig. 1, except that the adhesive layer 2 is covered with a liner layer 3 disposed on the adhesive layer 2. That is, the transdermal patch 30 has a support 1, an adhesive layer 2, and a liner layer 3 laminated in this order. Since the transdermal patch 30 has the liner layer 3, it can be stored while protecting the adhesive layer 2 until it is applied to the skin.

[0027] The transdermal patch according to the present embodiment is not limited to that shown in Figs. 1 to 3, and may be one in which some of the configurations shown in Figs. 1 to 3 have been modified, or other configurations have been added to those described above, within the scope that does not impair the effects of the transdermal patch.

[0028] For example, the transdermal patches 10, 20, and 30 shown in Figures 1 to 3 have a rectangular planar shape, but may have other shapes. Planar shapes of the transdermal patches 10, 20, and 30 include, but are not limited to, polygons (including regular polygons), semicircles, ellipses, approximate circles, and perfect circles.

[0029] 3, in order to easily peel the liner layer 3 from the upper surface of the adhesive layer 2, the liner layer 3 may further have an easily peelable layer on the surface thereof in contact with the adhesive layer 2. The easily peelable layer can be prepared, for example, by disposing a known release agent such as a silicone-based resin or a fluorine-based resin on the surface of the liner layer 3 in contact with the adhesive layer 2.

[0030] Next, each component constituting the transdermal patch will be described in detail below.

[0031] [Adhesive layer] The adhesive layer is formed from an adhesive composition containing a solid complex, an oil phase, and an adhesive. In the adhesive composition, the solid complex forms S / O type particles dispersed in the oil phase.

[0032] The thickness of the adhesive layer can be, for example, 1 μm or more and 5000 μm or less. By setting the thickness of the adhesive layer within the above range, a more sufficient amount of S / O type particles can be contained. Note that the "thickness of the adhesive layer" referred to here means the thickness of the entire adhesive layer, and for example, the thickness of an adhesive layer consisting of multiple layers means the total thickness of all layers constituting the adhesive layer.

[0033] (S / O type particle) In the S / O type particles, the dispersed phase is a solid phase (S) that is a solid, and the continuous phase is an oil phase (O) that is based on an oily substance. The solid phase contains an active ingredient. The active ingredient is not particularly limited as long as it has a molecular weight of 800 or more and has some function in the living body. Preferably, the active ingredient is hydrophilic. The active ingredient is, for example, a protein, an antibody, an antigen, leuprorelin, octreotide, or a salt thereof.

[0034] Examples of hydrophilic active ingredients include antigens, dementia treatment drugs, nucleic acid medicines, antibiotic preparations, antineoplastic agents, antifungal agents, antibacterial agents, antibody preparations, enzyme preparations, antiestrogens, immunosuppressants, antischizophrenia drugs, antiepileptic drugs, antidepressants, antiParkinson's disease drugs, antiallergic drugs, anticancer drugs, diabetes treatment drugs, antihypertensive drugs, osteoporosis treatment drugs, ED (Erectile Dysfunction) treatment drugs, skin disease drugs, local anesthetics, and pharma- ceutical acceptable salts thereof. There are no particular limitations on the pharma-ceutical acceptable salts of the active ingredient, and both acid salts and basic salts can be used. More specifically, examples of hydrophilic active ingredients include octreotide acetate, leuprorelin acetate, teriparatide acetate, glatiramer acetate, insulin, growth hormone (somatropin), somatomedin, glucagon, urokinase, prourokinase, erythropoietin, G-CSF, IL-2, INF (α, β, γ), tPA, factor VIII, antibodies, recombinant forms thereof, and pharma- ceutical acceptable analogs thereof.

[0035] The protein as an active ingredient contained in the S / O type particle has a molecular weight of 800 or more, preferably more than 10000, more preferably 30000 or more. The upper limit of the molecular weight is not particularly limited, but can be, for example, 2000000 or less, 1000000 or less, 500000 or less, or 300000 or less. The transdermal patch can penetrate a protein having a molecular weight within the above range into the body by forming an S / O type particle in which the complex is dispersed in the oil phase in the adhesive layer. In this specification, the term "molecular weight" refers to a weight average molecular weight, which can be measured, for example, by gel permeation chromatography (GPC).

[0036] Such proteins include, for example, physiologically active peptides, antibodies, antigens, etc. Physiologically active peptides include, for example, hormones such as insulin, and neuropeptides, etc.

[0037] The antigen is not particularly limited as long as it is soluble or dispersible in an aqueous phase, is a substance that induces an immune response, and induces immunogenicity, and antigens used in conventional immunization, vaccine antigens, immunogenic substances, and cancer antigens are used. Specific examples include proteins and peptides such as physiologically active substances (e.g., lysozyme derived from chicken egg white and antigenic region peptides of Japanese cedar pollen allergy, etc.), haptenized substances bound to proteins or peptides, live or inactivated (killed) bacteria and viruses (whole) or partial decomposition products thereof, inactivated (killed) cancer cells (whole) or partial decomposition products thereof, and nucleic acids. In addition, substances that lack antigenicity (e.g., carbohydrates, lipids, inorganic substances, etc.) that have been given antigenicity by means of haptenization or the like are also used as antigens. The antigen may be derived from either animals or plants. For example, the antigen may be an antigen for poultry and livestock or an antigen for pet animals, an antigen for cattle, an antigen for chickens, an antigen for pigs, or an antigen for arthropods such as mites and insects. The antigen may also be of food origin.

[0038] These antigens may be single molecules, or may be hydrophilic water-soluble nanocarriers such as nanogels (cholesterol-modified pullulan) encapsulating hydrophobic antigens, etc. These antigens may be mixed with water-soluble hydrophilic adjuvants such as CpG oligodeoxynucleotides, which will be described later. Preferably, the antigens described above are hydrophilic antigens.

[0039] Examples of proteins other than those mentioned above include collagen, as well as quasi-drug ingredients such as growth factors, such as epidermal growth factor, insulin-like growth factor, fibroblast growth factor, and brain-derived neurotrophic factor, as well as cosmetic ingredients, etc. The S / O type particles may contain one type of these proteins alone or two or more types in combination.

[0040] In the S / O type particles, the solid phase is typically formed as a complex. There is no particular limitation on the production of the complex, and various methods for preparing the complex can be applied. Typically, to produce the complex, an aqueous solution of the active ingredient is emulsified and dispersed in an organic solvent containing a surfactant to prepare a W / O type emulsion, and then the resulting W / O type emulsion is freeze-dried by a standard method to prepare the complex. There is no particular limitation on the organic solvent as long as it can dissolve the lipophilic surfactant and can be removed by freeze-drying, but lower alcohols such as ethanol and low-boiling point hydrocarbons such as hexane are usually used. Emulsification and dispersion can be performed with conventional devices such as a stirrer, a high-speed rotating shear stirrer (such as a propeller mixer), a colloid mill, a homogenizer, a flow jet mixer, an ultrasonic emulsifier, and a vacuum emulsifier. The particle size of the dispersed droplets can be controlled by adjusting the stirring intensity (=power x time). For detailed techniques, refer to JP 2004-43355 A (Reference 1).

[0041] The surfactant used for preparing the complex is a surfactant that can be added to a pharmaceutical preparation, preferably a surfactant that can be added to a pharmaceutical preparation for transdermal delivery, and that can stably disperse the solid phase in the oil phase. Examples of the surfactant include nonionic surfactants, anionic surfactants, cationic surfactants, amphoteric surfactants, and bile salts.

[0042] A suitable example of a surfactant used for preparing the complex is a lipophilic (hydrophobic) nonionic surfactant having an HLB (Hydrophile-Lipophile Balance) value of 10 or less. The HLB of the nonionic surfactant is preferably 8 or less, more preferably 5 or less, and particularly preferably 3 or less. As the nonionic surfactant, an ester compound made from an unsaturated fatty acid such as erucic acid or oleic acid is preferred. Examples of lipophilic nonionic surfactants include sucrose fatty acid esters (sucrose stearate, sucrose palmitate, sucrose myristic acid, sucrose oleate, sucrose laurate, sucrose erucate, sucrose mixed fatty acid esters) with a high degree of esterification (i.e., a high ratio of di-, tri-, and polyester to monoester), polyglycerol condensed ricinoleate, decaglycerol ester, glycerol fatty acid ester, polyglycerol fatty acid ester, polyoxyethylene glycerol fatty acid ester, sorbitan fatty acid ester, polyoxyethylene sorbitol fatty acid ester, and polyoxyethylene castor oil / hydrogenated castor oil. Preferably, the nonionic surfactant is sucrose laurate. The surfactant may be used alone or in combination of two or more.

[0043] From the viewpoint that the transdermal patch is intended exclusively for transdermal delivery, it is preferable that the surfactant further has effects such as promoting absorption, reducing irritation, and moisturizing.

[0044] The complex is preferably dispersed in an oil phase to form S / O type particles before being mixed with an adhesive and the like to prepare an adhesive composition. The concentration of the complex in the oil phase is not particularly limited as long as it is a dispersible concentration, but can be, for example, 0.6% by mass or more and 60% by mass or less with respect to the total mass of the dispersion or suspension.

[0045] The oil phase may be liquid, or may be a solid having flowability or developability. The base material of the oil phase is not particularly limited as long as it is an oil-based base acceptable for use in pharmaceutical preparations, preferably an acceptable for use in pharmaceutical preparations for transdermal delivery. As the oil phase, any oil that is liquid at room temperature (25°C) or fat that is solid at room temperature can be used. There is no limitation on the origin of the raw material, and for example, any natural product or synthetic product can be used, and it may be vegetable (e.g., soybean oil, cottonseed oil, rapeseed oil, sesame oil, corn oil, peanut oil, safflower oil, sunflower oil, olive oil, rapeseed oil, perilla oil, fennel oil, cacao oil, cinnamon oil, peppermint oil, bergamot oil) or animal (beef tallow, lard oil, fish oil). In addition, the surfactant may be a neutral lipid (e.g., glyceride, triolein, trilinolein, tripalmitin, tristearin, trimyristin, triarachidonin), a synthetic lipid, a sterol derivative (e.g., cholesteryl oleate, cholesteryl linoleate, cholesteryl myristate, cholesteryl palmitate, cholesteryl arachidate), a long-chain fatty acid ester (e.g., isopropyl myristate, octyldodecyl myristate, cetyl myristate, ethyl oleate, ethyl linoleate, isopropyl linoleate, isopropyl palmitate, butyl stearate), a carboxylic acid ester (ethyl lactate, cetyl lactate, triethyl citrate, diisopropyl adipate, diethyl sebacate, diisopropyl sebacate, cetyl 2-ethylhexanoate), a hydrocarbon (e.g., petrolatum, paraffin squalane, vegetable squalane), or a silicone. The oil-based base material may be used alone or in combination of two or more kinds.

[0046] The oil phase can be made of triglyceride or edible oils mainly composed of triglyceride. For practical purposes, soybean oil is preferred, and highly refined soybean oil is more preferred. In addition, neutral lipids or long-chain fatty acid esters can also be suitably used as the oil phase, and long-chain fatty acid esters are more preferred, with isopropyl myristate being even more preferred.

[0047] (Adhesive) The adhesive may be any adhesive that is not toxic to living organisms, and the type of adhesive may be appropriately selected depending on the material of the support.

[0048] Examples of adhesives include, but are not limited to, adhesives made of synthetic compounds and adhesives made of natural compounds. Examples of adhesives made of synthetic compounds include urethane-based elastomers, acrylic-based elastomers, olefin-based elastomers, silicone-based elastomers, rubber-based adhesives, calcium phosphate-based adhesives, and resin-based cements. Examples of rubber-based adhesives include styrene-based elastomers, polyisobutylene (PIB), polyisoprene, polybutadiene, and raw rubber. Among these, silicone-based elastomers, rubber-based adhesives, and acrylic-based elastomers are preferred, and acrylic-based elastomers are more preferred from the viewpoint of further improving permeability.

[0049] Preferably, the adhesive contained in the adhesive layer includes an acrylic elastomer. The acrylic elastomer preferably contains a structural unit derived from a (meth)acrylic acid alkyl ester in which the carbon number of the alkyl group in the ester portion is 6 to 14. Specific examples of the (meth)acrylic acid alkyl ester include hexyl (meth)acrylate, n-octyl (meth)acrylate, isooctyl (meth)acrylate, 2-ethylhexyl (meth)acrylate, dodecyl (meth)acrylate, decyl (meth)acrylate, isodecyl (meth)acrylate, lauryl (meth)acrylate, and myristyl (meth)acrylate. These may be used alone or in combination of two or more.

[0050] The acrylic elastomer may further contain a structural unit derived from a vinyl monomer containing a reactive functional group in addition to the structural unit derived from the (meth)acrylic acid alkyl ester. This can facilitate the reaction with other structural units, and in particular, when a crosslinking agent is contained, can facilitate the reaction with the crosslinking agent. Examples of the reactive functional group include a hydroxyl group, an amino group, a carboxyl group, and a thiol group. Such reactive functional groups may be contained alone or in combination of two or more. Among these reactive functional groups, a hydroxyl group, an amino group, or a carboxyl group is preferred. When the acrylic elastomer contains a structural unit derived from a vinyl monomer having a reactive functional group, the cohesive force of the pressure-sensitive adhesive composition for forming the pressure-sensitive adhesive layer can be controlled.

[0051] Examples of the vinyl monomer containing the reactive functional group include hydroxyl group-containing (meth)acrylates such as hydroxyethyl (meth)acrylate, hydroxypropyl (meth)acrylate, and hydroxybutyl (meth)acrylate; carboxy group-containing (meth)acrylates such as 1,4-di(meth)acryloxyethylpyromellitic acid, 4-(meth)acryloxyethyltrimellitic acid, N-(meth)acryloyl-p-aminobenzoic acid, 2-(meth)acryloyloxybenzoic acid, N-(meth)acryloyl-5-aminosalicylic acid, acrylic acid, and methacrylic acid; primary to secondary amino group-containing (meth)acrylates such as aminoethyl (meth)acrylate, ethylaminoethyl (meth)acrylate, aminopropyl (meth)acrylate, and ethylaminopropyl (meth)acrylate; and thiol group-containing (meth)acrylates such as 2-(methylthio)ethyl methacrylate. These may be used alone or in combination of two or more.

[0052] The acrylic elastomer may contain a structural unit derived from a monomer having a plurality of polymerizable unsaturated groups in addition to the structural unit derived from the (meth)acrylic acid alkyl ester. That is, the acrylic elastomer may be a copolymer of a monomer composition containing a (meth)acrylic acid alkyl ester having an alkyl group of the ester moiety having 6 to 14 carbon atoms and a monomer having a plurality of polymerizable unsaturated groups.

[0053] Examples of the monomer having a plurality of polymerizable unsaturated groups include alkylene glycols such as (poly)ethylene glycol, (poly)propylene glycol, (poly)butylene glycol, (poly)pentamethylene glycol, and (poly)hexamethylene glycol, trimethylolpropane, glycerin polyoxyethylene glycol, polyoxypropylene glycol, and (poly)glycerin, di- or tri(meth)acrylic acid esters of polyols, diallyl phthalate, and divinylbenzene, and one or more of these can be used in combination. Among the above, alkylene glycol diacrylate is preferred because it has excellent reactivity with other monomers and can suitably increase the cohesive force of the acrylic elastomer.

[0054] The method for producing the acrylic elastomer is not particularly limited, and the acrylic elastomer can be obtained by polymerizing raw material monomers corresponding to each structural unit by solution polymerization, etc. In addition, commercially available products can be used as the acrylic elastomer.

[0055] Examples of commercially available acrylic elastomers include "DURO TAK 87-4098", "DURO TAK 87-2052", "DURO TAK 87-9301", "DURO TAK 87-235A", "DURO TAK 87-4287", and "DURO TAK 87-2516" manufactured by Henkel Corporation, and "MAS 811B", "MAS 683", "MAS43", "MASCOS10", and "HiPAS10" manufactured by Cosmedi Pharmaceutical Co., Ltd.

[0056] As the styrene-based elastomer, a styrene-based block copolymer can be preferably used. Specific examples of the styrene-based block copolymer include styrene-butadiene block copolymer, styrene-butadiene-styrene block copolymer, styrene-isoprene block copolymer, styrene-isoprene-styrene block copolymer (SIS), styrene-ethylene / butylene block copolymer, styrene-ethylene / butylene-styrene block copolymer, styrene-ethylene / propylene block copolymer, styrene-ethylene / propylene-styrene block copolymer, styrene-isobutylene block copolymer, and styrene-isobutylene-styrene block copolymer. In the above, "ethylene / butylene" refers to a copolymer block of ethylene and butylene, and "ethylene / propylene" refers to a copolymer block of ethylene and propylene. These styrene-based block copolymers may be used alone or in combination of two or more.

[0057] The styrene-isoprene-styrene block copolymer and the styrene-isoprene block copolymer may each be a copolymer produced by a method known per se. In addition, the styrene-isoprene-styrene block copolymer and the styrene-isoprene block copolymer may each be a commercially available product. In addition, mixtures of styrene-isoprene-styrene block copolymers and styrene-isoprene block copolymers are also commercially available, and a commercially available mixture of styrene-isoprene-styrene block copolymers and styrene-isoprene block copolymers may be preferably used.

[0058] Examples of commercially available styrene-based block copolymers include "KRATON D1163", "KRATON D1113", and "KRATON D1119" manufactured by KRATON POLYMERS, "JSR SIS5229", "JSR SIS5403", and "JSR SIS5505" manufactured by JSR Corporation, and "Quintac 3421", "Quintac 3433N", "Quintac 3520", "Quintac 3450", and "Quintac 3270" manufactured by Zeon Corporation.

[0059] Examples of adhesives made of natural compounds include fibrin glue and gelatin glue.

[0060] (Other ingredients) The adhesive composition for forming the adhesive layer may further contain other components such as a crosslinking agent and a transdermal absorption enhancer.

[0061] Examples of the crosslinking agent include polyfunctional amino compounds, polyfunctional isocyanate compounds, polyfunctional epoxy compounds, polyfunctional aziridine compounds, polyfunctional oxazoline compounds, polyfunctional metal compounds, etc. These crosslinking agents may be used alone or in combination of two or more.

[0062] The percutaneous absorption enhancer may be any compound that has been recognized to have an absorption enhancing effect in the skin, such as fatty acids having 6 to 20 carbon atoms, aliphatic alcohols, fatty acid amides, fatty acid ethers, aromatic organic acids, aromatic alcohols, aromatic organic acid esters or ethers, lactates, acetates, monoterpene compounds, sesquiterpene compounds, glycerin fatty acid esters, propylene glycol fatty acid esters, sorbitan fatty acid esters, polysorbates, polyethylene glycol fatty acid esters, polyoxyethylene hydrogenated castor oils, polyoxyethylene alkyl ethers, sucrose fatty acid esters, and vegetable oils. The percutaneous absorption enhancer is preferably glyceryl monooleate (MGO), and more preferably glyceryl oleate such as MGOL-70, which improves the skin permeability of active ingredients by temporarily destroying the lamellar structure of the stratum corneum.

[0063] Furthermore, when the S / O type particles contain an antigen, the adhesive composition may further contain a hydrophobic adjuvant. The hydrophobic adjuvant is not particularly limited as long as it is one that is normally used in vaccines, and examples thereof include ligands for innate immune receptors. The term "ligand" as used herein refers to a substance that specifically binds to a receptor, and in particular, a substance that specifically binds to a receptor and exhibits various physiological actions can be used. Such a substance is also called an "agonist."

[0064] Examples of innate immune receptors include toll-like receptors (TLR), RIG-I-like receptors (RLR), NOD-like receptors (NLR), and C-type lectin receptors (CLR). Among them, ligands for TLRs (hereinafter sometimes referred to as "TLR ligands") or ligands for CLRs (hereinafter sometimes referred to as "CLR ligands") are preferred, and ligands for TLRs present on the cell membrane of antigen-presenting cells are more preferred because they are known to contribute greatly to the activation of antigen-presenting cells.

[0065] As the TLR ligand, for example, one that interacts with at least one TLR selected from the group consisting of TLR-2, TLR-3, TLR-4, TLR-5, TLR-6, ​​TLR-7, TLR-8 and TLR-9 may be appropriately selected. As the TLR-2 ligand, for example, Pam3CSK4, etc. are included. As the TLR-3 ligand, for example, polyICLC, polyinosinic:polycytidylic acid (polyI:C), etc. are included. As the TLR-4 ligand, for example, R-type lipopolysaccharide, S-type lipopolysaccharide, paclitaxel, lipid A, monophosphoryl lipid A, etc. are included. As the TLR-5 ligand, for example, flagellin, etc. are included.

[0066] Examples of TLR-2 and TLR-6 ligands include MALP-2, etc. Examples of TLR-7 and TLR-8 ligands include resiquimod (R848), imiquimod (R837), gardiquimod, and loxoribine, etc. Examples of TLR-9 ligands include CpG oligodeoxynucleotides, etc. Among them, resiquimod (R848) is preferred as a hydrophobic adjuvant because its safety and immune-activating effect in humans and mice have been confirmed.

[0067] The CLR ligand may be appropriately selected from those that interact with at least one CLR selected from the group consisting of macrophage inducible c-type lectin (Mincle) receptor, macrophage c-type lectin (MCL) receptor, dendritic cell-associated c-type lectin-2 (Dectin-2) receptor, and dendritic cell immunoactivating receptor (DCAR).

[0068] Examples of Mincle receptor ligands and MCL receptor ligands include trehalose dimycolic acid, etc. Examples of Dectin-2 receptor ligands include lipoarabinomannan, etc. Examples of DCAR ligands include phosphatidylinositol mannoside, etc.

[0069] The adhesive composition for forming the adhesive can be produced by mixing the components constituting the composition. In producing the adhesive composition, the blending ratio of the S / O type particles (a solution or suspension in which the complex is dispersed in an oil phase) (solid content concentration of 0.6% by mass to 60% by mass) to the adhesive (solid content concentration of 20% by mass to 80% by mass) can be 5:1 to 1:5 by mass, preferably 3:1 to 1:3, more preferably 2:1 to 1:2, further preferably 1.25:1 to 1:1.25, and particularly preferably 1:1.

[0070] When the adhesive contained in the adhesive layer contains an acrylic elastomer, the content of the acrylic elastomer in the adhesive layer is suitably 30 to 70 mass %, preferably 40 to 50 mass %, relative to the total mass of the acrylic elastomer and the oil phase.

[0071] [Support] The support preferably has flexibility (pliability), can conform to curved surfaces when applied, and is suitable for cutting, punching, or the like when processed.

[0072] Such a support is not particularly limited, but examples thereof include plastic films, woven fabrics, knitted fabrics, nonwoven fabrics, etc., made of polyesters such as polyethylene terephthalate (PET), polybutylene terephthalate (PBT), and polyethylene naphthalate (PEN), polyolefins such as polyethylene (PE) and polypropylene (PP), polyarylates, polyurethanes, polycarbonates, polyamides, polyimides, ethylene-vinyl acetate copolymers, polyvinyl chloride, polytetrafluoroethylene, silicones, polysulfones, nylons, polylactic acid, rayon, and acrylic resins. Furthermore, laminate sheets of two or more layers of plastic films and plastic films, woven fabrics, knitted fabrics, nonwoven fabrics, paper, etc., can be used. Among these, plastic films made of acrylic resins are preferred.

[0073] The thickness of the support can be, for example, 1 μm or more and 5000 μm or less. Note that the "thickness of the support" means the thickness of the entire support, and for example, the thickness of a support consisting of multiple layers means the total thickness of all layers constituting the support.

[0074] [Liner layer] Examples of the liner layer that can be used include laminated papers such as polyethylene laminated paper and polypropylene laminated paper, polyester films such as polyethylene terephthalate, and synthetic resin films such as polyolefin films such as polyethylene and polypropylene. Furthermore, the liner layer may be subjected to a release treatment with a release agent such as a silicone resin or a fluorine resin on one or both sides of these materials as necessary.

[0075] The thickness of the liner layer can be, for example, 10 μm to 1000 μm. Note that the "thickness of the liner layer" here means the thickness of the entire liner layer, and for example, the thickness of a liner layer consisting of multiple layers means the total thickness of all layers that make up the liner layer.

[0076] <Manufacturing method of transdermal patch> In the case of the transdermal patch 10 shown in FIG. 1 or the transdermal patch 20 shown in FIG. 2, it can be produced, for example, by applying an adhesive composition onto a support 1 and drying it to form an adhesive layer 2.

[0077] The transdermal patch 30 shown in FIG. 3 can be produced by the following two methods. (A) A method for producing a transdermal patch 30 by applying an adhesive composition onto a support 1 and drying it to form an adhesive layer 2, and then attaching a liner layer 3 to the surface of the adhesive layer 2 opposite to the surface in contact with the support 1. (B) A method of producing a transdermal patch 30 by applying an adhesive composition to a liner layer 3 and drying the same to form an adhesive layer 2, and then attaching a support 1 to the surface of the adhesive layer 2 opposite to the surface in contact with the liner layer 3.

[0078] The adhesive composition can be prepared in advance using the method described above in "Adhesive Layer." In addition, in the transdermal patch, the content of the active ingredient can be appropriately adjusted by changing the content of the S / O type particles according to the therapeutically effective amount of the active ingredient.

[0079] <Usage> The transdermal patch according to this embodiment can be used as a vaccine, for example, when the active ingredient contained in the S / O type particles is an antigen. That is, in one embodiment, a transdermal patch for inducing immunity (for a vaccine) comprises a support and an adhesive layer laminated on the support, the adhesive layer contains a solid complex in which an antigen having a molecular weight of 800 or more is coated with a surfactant, an oil phase, and an adhesive, and the solid complex forms S / O type particles dispersed in the oil phase.

[0080] For example, when the active ingredient contained in the S / O type particles is an antibody, the transdermal patch can be used as a pharmaceutical composition (antibody drug) for treating various diseases depending on the type of the antibody. Specifically, when the active ingredient contained in the S / O type particles is a PD-1 antibody, the transdermal patch can be used as an anticancer drug.

[0081] For example, when the active ingredient contained in the S / O type particle is a physiologically active peptide, the transdermal patch can be used as a pharmaceutical composition for treating various diseases. Specifically, when the active ingredient contained in the S / O type particle is insulin, the transdermal patch can be used as a pharmaceutical composition for treating diabetes.

[0082] When the active ingredient contained in the S / O type particles is collagen, for example, the transdermal patch can be used as a quasi-drug composition or a cosmetic composition.

[0083] The subject of application of the transdermal patch is preferably a vertebrate, more preferably a mammal.The mammal includes, but is not limited to, human, chimpanzee and other primates; dog, cat, rabbit, horse, sheep, goat, cow, pig, rat (including nude rat), mouse (including nude mouse and skid mouse), guinea pig and other livestock animals, pet animals and experimental animals.Among them, the mammal is preferably human.

[0084] When the active ingredient is an antigen, the transdermal patch according to a preferred embodiment may further comprise an enhancer layer containing a percutaneous absorption enhancer between the support and the adhesive layer. Fig. 4 is a cross-sectional view showing a transdermal patch 40 as an example of the transdermal patch. The transdermal patch 40 comprises an enhancer layer 4 containing a percutaneous absorption enhancer. The enhancer layer 4 is interposed between the support 1 and the adhesive layer 2.

[0085] The transdermal patch 40 can be produced, for example, by applying a transdermal absorption enhancer composition containing a transdermal absorption enhancer onto a support 1, drying the composition to form an enhancer layer 4, and then applying an adhesive composition onto the enhancer layer 4, drying the composition to form an adhesive layer 2. The enhancer layer 4 is formed from a transdermal absorption enhancer composition containing a transdermal absorption enhancer. The transdermal absorption enhancer composition may contain a transdermal absorption enhancer dissolved in a solvent. The solvent is not limited as long as it dissolves the transdermal absorption enhancer, and is preferably an oil phase. The oil phase may be the same as that described above. The oil phase contained in the transdermal absorption enhancer composition is preferably the same as the oil phase contained in the adhesive composition. The content of the transdermal absorption enhancer in the transdermal absorption enhancer composition is, for example, 1 to 30% by mass, 3 to 25% by mass, 5 to 20% by mass, or 8 to 15% by mass, and preferably 10% by mass.

[0086] The percutaneous absorption enhancer composition may contain the above-mentioned adhesive. When the percutaneous absorption enhancer composition contains an adhesive, the mixing ratio of the solvent containing the percutaneous absorption enhancer to the adhesive is not particularly limited, and is, for example, 1:1.

[0087] The transdermal patch 40 may have a liner layer 3 disposed on the adhesive layer 2 to cover the adhesive layer 2, similar to the transdermal patch 30. In this case, the transdermal patch 40 can be produced by applying a transdermal absorption enhancer composition containing a transdermal absorption enhancer onto a support 1, drying the composition to form an enhancer layer 4, applying an adhesive composition onto the enhancer layer 4, drying the composition to form an adhesive layer 2, and then attaching a liner layer 3 to the surface of the adhesive layer 2 opposite to the surface in contact with the enhancer layer 4. The transdermal patch 40 can also be produced by applying an adhesive composition onto the liner layer 3, drying the composition to form an adhesive layer 2, applying a transdermal absorption enhancer composition onto the adhesive layer 2, drying the composition to form an enhancer layer 4, and then attaching a support 1 to the surface of the enhancer layer 4 opposite to the surface in contact with the adhesive layer 2.

[0088] The transdermal patch has an enhancer layer containing a transdermal absorption enhancer between the support and the adhesive layer, which allows the antigen to penetrate into the body through the skin more efficiently and improves sustained release, thereby allowing the antibody titer to be maintained over time after immunization with the antigen, as shown in the following examples.

[0089] Embodiment 2 Next, a description will be given of a transdermal absorption agent according to embodiment 2. The transdermal absorption agent according to this embodiment contains leuprorelin as an active ingredient.

[0090] Leuprorelin is an agonist for the pituitary gonadotropin-releasing hormone (GnRH) receptor, and has the effect of suppressing the secretion of the gonadotropic hormones luteinizing hormone (LH) and follicle-stimulating hormone (FSH). In 1992, a sustained-release formulation of leuprorelin was approved as a treatment for prostate cancer, and it has since been approved for use in estrogen-dependent diseases (endometriosis, uterine fibroids, etc.), central precocious puberty, and premenopausal breast cancer. Leuprorelin is a hydrophilic compound, and is currently only available in the form of an injection.

[0091] It has been pointed out that the administration of drugs by injection has a problem in that side effects such as anaphylaxis occur due to an initial increase in drug concentration in the blood. From the viewpoint of suppressing side effects and improving the duration of medicinal efficacy, it is desirable to use a transdermal formulation. However, since leuprorelin is a hydrophilic compound, its skin permeability is extremely low, and its medicinal efficacy cannot be fully demonstrated when used as a transdermal formulation. Therefore, there is a demand for the development of a leuprorelin transdermal formulation with high skin permeability and improved duration of medicinal efficacy.

[0092] <Transdermal absorption agent> The transdermal absorption preparation according to this embodiment contains a solid leuprorelin-surfactant complex (hereinafter simply referred to as the "complex") in which leuprorelin or a salt thereof (hereinafter collectively referred to as "leuprorelin") is coated with a surfactant, and an oil phase. The complex forms solid-in-oil type particles dispersed in the oil phase.

[0093] The transdermal formulation forms S / O type particles in which the complex is dispersed in an oil phase, and as shown in the Examples below, it allows leuprorelin, which normally cannot penetrate the skin, to penetrate into the body through the skin. In addition, as shown in the Examples below, the transdermal formulation has superior sustained release properties to conventional injections.

[0094] 5 is a schematic diagram of a transdermal absorption agent 50 as an example of the transdermal absorption agent according to this embodiment. The complex 5 is configured such that the hydrophilic portion of the surfactant 5b associates with leuprorelin 5a, and the periphery of the leuprorelin 5a is coated with the surfactant 5b. In the transdermal absorption agent 50, the complex 5 is dispersed in the oil phase 6, forming S / O type particles.

[0095] The transdermal absorption agent according to this embodiment is not limited to that shown in FIG. 5, and may be one in which some of the components shown in FIG. 5 have been modified or removed, or other components may be added to those described above, provided that the effect of the transdermal absorption agent is not impaired.

[0096] For example, in the transdermal absorption agent 50 shown in FIG. 5, a transdermal absorption enhancer may be dispersed in the oil phase 6 in order to enhance permeability into the skin.

[0097] Next, each component constituting the transdermal absorption agent will be described in detail below.

[0098] [Solid Leuprorelin-surfactant complex] The solid complex is composed of leuprorelin and a surfactant. The complex may consist of only leuprorelin and a surfactant to prevent the particles from becoming too large, or may contain a stabilizer as described below.

[0099] The average particle size of the complex dispersed in the oil phase may be any size that allows the complex to remain dispersed in the oil phase and does not impair skin permeability, and may be, for example, 1 nm or more and 1000 nm or less, preferably 10 nm or more and 900 nm or less, more preferably 50 nm or more and 700 nm or less, and even more preferably 100 nm or more and 500 nm or less.

[0100] (Leuprorelin) Leuprorelin is usually used in the form of acetate, and is distributed in the form of an injection under the trade name "Leuprorelin (registered trademark)". Leuprorelin acetate is a peptide compound represented by the following formula (I).

[0101] [ka]

[0102] Leuprorelin is a white to yellowish white powder, very soluble in water or acetic acid, soluble in methanol, and slightly soluble in ethanol. Leuprorelin is hygroscopic. In addition, since the molecular weight of leuprorelin is 1209.42 (1269.45 in the case of leuprorelin acetate), which is more than 1000, and since it is a hydrophilic compound, it cannot usually be permeated through the skin by itself. However, in the transdermal absorption agent of this embodiment, leuprorelin is made into S / O type particles, thereby achieving permeation through the skin.

[0103] The salt of leuprorelin contained in the transdermal absorbent is not limited as long as it is a pharma- ceutically acceptable salt. The salt of leuprorelin is preferably an acid addition salt, and may be an inorganic acid salt or an organic acid salt. Examples of inorganic acid salts include salts of inorganic acids such as hydrohalic acids such as hydrochloric acid and hydrobromic acid, perchloric acid, nitric acid, and sulfuric acid. Examples of organic acid salts include salts of organic acids such as formic acid, acetic acid, propionic acid, lactic acid, thermophilic acid, oxalic acid, malonic acid, and succinic acid. Among them, the leuprorelin contained in the transdermal absorbent is preferably leuprorelin acetate (also called leuprorelin acetate).

[0104] (Surfactant) The surfactant may be the surfactant in the above embodiment 1. In the complex, the mass ratio of leuprorelin to the surfactant is preferably 1 / 100 or more and 1 / 10 or less, more preferably 1 / 50 or more and 1 / 10 or less, even more preferably 1 / 50 or more and 1 / 20 or less, and particularly preferably 1 / 50 or more and 1 / 30 or less. When the mass ratio of leuprorelin to the surfactant is equal to or more than the lower limit, the particles can be more effectively prevented from becoming too large. On the other hand, when the mass ratio is equal to or less than the upper limit, the complex can be more effectively penetrated into the skin.

[0105] The content of the complex in the transdermal absorption agent is not particularly limited as long as it is a dispersible concentration, but can be, for example, 0.6 w / v % or more and 60 w / v % or less.

[0106] (Stabilizer) The complex may contain a stabilizer. The stabilizer is preferably a hydrophilic protein or polysaccharide having a molecular weight of 10,000 or more. The stabilizer improves the stability of the complex by being coated with a surfactant together with leuprorelin, and can prevent leakage of leuprorelin to the outside of the complex in the transdermal absorption agent.

[0107] Examples of proteins that can be used as stabilizers include serum albumin (molecular weight: about 67,000), ovalbumin (molecular weight: about 45,000), casein (molecular weight: about 19,000 or more), lysozyme (molecular weight: about 14,000 or more), and lipase (molecular weight: about 45,000). These proteins may be used alone or in combination of two or more. Among them, serum albumin, ovalbumin, or casein are preferred.

[0108] Examples of polysaccharides include LM pectin, HM pectin, hydroxypropyl methylcellulose phthalate, heparin, alginic acid, and carboxymethylcellulose. These polysaccharides may be used alone or in combination of two or more. Among them, LM pectin, HM pectin, and hydroxypropyl methylcellulose phthalate are preferred.

[0109] The molecular weight of the protein or polysaccharide used as a stabilizer varies depending on its origin, etc. For example, the general molecular weight of pectin is 50,000 or more and 150,000 or less, but the molecular weight of pectin may be 20,000 or more and 40,000 or less. The molecular weight of the proteins and polysaccharides exemplified above can generally be said to be 10,000 or more. The molecular weight here can be determined by referring to the catalog values ​​of the protein and polysaccharide used, or if it is unknown, it can be measured as a number average molecular weight, etc.

[0110] In the complex, the mass ratio of the stabilizer to leuprorelin is preferably from 0.01 to 100, more preferably from 0.1 to 10, and even more preferably from 0.5 to 5. When the mass ratio of the stabilizer to leuprorelin is equal to or more than the above lower limit, the effect can be exerted more sufficiently, while when it is equal to or less than the above upper limit, the amount of leuprorelin in the complex can be made sufficient, and the inherent effect of the drug can be exerted more sufficiently.

[0111] (Oil phase) The oil phase may be the same as that in the above-mentioned embodiment 1. The content of the oil phase in the transdermal absorption agent varies depending on the type of oil component and other constituents, but is preferably 50 w / v% or more and 99.5 w / v% or less, and more preferably 60 w / v% or more and 90 w / v% or less.

[0112] [Other ingredients] The transdermal absorption agent of this embodiment may further contain other components such as the above-mentioned transdermal absorption enhancer.

[0113] <Manufacturing method of transdermal absorption agent> The transdermal absorption agent can be produced, for example, by a method including the following steps (1) to (3). (1) a step of mixing leuprorelin with a surfactant and, if necessary, with an organic solvent solution containing a stabilizer to prepare a W / O type emulsion (hereinafter, sometimes referred to as "step (1)"); (2) A step of drying the W / O type emulsion to prepare a complex (hereinafter, sometimes referred to as "step (2)"); (3) Step of dispersing the complex in an oil phase (hereinafter, sometimes referred to as "step (3)")

[0114] [Process (1)] In step (1), first, an aqueous solution of leuprorelin is prepared. If necessary, a stabilizer is also added. Examples of the water used here include pure water, purified water, distilled water, physiological saline, and buffer solutions. If necessary, a small amount of a water-miscible organic solvent such as ethanol may be added. However, care must be taken because adding too much alcohol or the like may make it difficult to form an emulsion. The concentrations of leuprorelin and stabilizer in the aqueous solution are not particularly limited as long as they can be substantially completely dissolved, but can be, for example, about 0.1 mg / mL to 30 mg / mL. Separately, an organic solvent solution of a surfactant is prepared. The organic solvent used here is not particularly limited as long as it can dissolve the surfactant and can be diffused and removed in the next step, but can be, for example, aliphatic hydrocarbons such as hexane and cyclohexane, aromatic hydrocarbons such as toluene, and the like. The concentration is also not particularly limited, but can be, for example, about 0.1 mg / mL to 50 mg / mL.

[0115] Next, the aqueous solution of leuprorelin and a stabilizer is mixed with an organic solvent solution of a surfactant, and emulsified and dispersed according to a conventional method to prepare a W / O type emulsion. The emulsification and dispersion can be performed using a conventional device, as in the first embodiment. The particle size of the dispersed droplets can also be controlled, as in the first embodiment.

[0116] [Process (2)] In step (2), the W / O type emulsion obtained in step (1) is dried to obtain a complex. The drying method is not particularly limited, and examples thereof include freeze-drying and drying under reduced pressure, but freeze-drying is preferred. Specific conditions may be those of the ordinary method. In step (2), it is preferable to substantially completely remove water and organic solvent. Water may cause leakage of leuprorelin from the preparation, and organic solvents may have adverse effects on the living body. Specifically, for example, the water content may be adjusted to 1% by mass or less as measured by the Karl Fischer method.

[0117] [Process (3)] In step (3), the complex obtained in step (2) and, if necessary, other components such as a transdermal absorption enhancer are dispersed in an oil phase to obtain the transdermal absorption agent of this embodiment as an S / O type solution or suspension. Specifically, the same dispersion method as the emulsification and dispersion method in embodiment 1 can be used. The amount of the oil phase used in step (3) depends on the compatibility between the surfactant and the type of oil phase, and may be, for example, about 4 mL to 200 mL per 1 g of the complex.

[0118] <Dosage and Administration> The transdermal absorption agent according to the present embodiment may be applied directly to the affected area, or may be formulated by adding other additives. Examples of the other additives include excipients (e.g., sugars such as sucrose; starch derivatives such as dextrin; cellulose derivatives such as carmellose sodium; water-soluble polymers such as xanthan gum, etc.), colorants, lubricants (e.g., metal stearates such as calcium stearate and magnesium stearate; lauryl sulfates such as sodium lauryl sulfate and magnesium lauryl sulfate; starch derivatives in the excipients, etc.), binders (e.g., the excipients and macrogol, etc.), emulsifiers, thickeners, wetting agents (e.g., glycerin, etc.), stabilizers (e.g., methylparaben, , parahydroxybenzoic acid esters such as propylparaben; alcohols such as chlorobutanol, benzyl alcohol, phenylethyl alcohol, etc.; benzalkonium chloride; phenols such as phenol and cresol; thimerosal; acetic anhydride; sorbic acid, etc.), preservatives, solvents (e.g., water, ethanol, glycerin, etc.), solubilizing agents, suspending agents (e.g., sodium carmellose, etc.), buffers, pH adjusters and bases (e.g., polyethylene glycol, crotamiton, diethyl sebacate, petrolatum, etc.), and these can be blended in normal amounts.

[0119] The S / O type solution or suspension obtained by the above-mentioned manufacturing method can be mixed with other additive ingredients in a conventional manner appropriate for each dosage form to produce topical preparations such as ointments, lotions, aerosols, plasters, aqueous poultices, creams, gels, plasters, reservoir-type patches, matrix-type patches, and tapes, but are not limited to these.

[0120] The dosage of the transdermal agent according to this embodiment can be adjusted depending on the age and symptoms of the patient, the type of the applicable disease, etc. For example, it can usually be administered at least twice over a period of several weeks to several months so that the amount of leuprorelin per administration per adult is about 1 μg to 5000 μg, preferably about 10 μg to 4000 μg, and more preferably about 30 μg to 3000 μg.

[0121] <Method for improving percutaneous absorption of leuprorelin> The method for improving the transdermal absorbability of leuprorelin according to one embodiment (hereinafter sometimes abbreviated as "the method of the present embodiment") comprises coating leuprorelin with a surfactant to form a solid complex, dispersing the complex in an oil phase, and preparing an external preparation. For specific implementation conditions of the method of the present embodiment, refer to those described above in "Transdermal Absorption Agent". The method of the present embodiment can improve the transdermal absorbability of leuprorelin, which has previously been difficult to use as an external preparation due to its low transdermal absorbability, and which has not been able to fully exert its effects as an external preparation.

[0122] In another embodiment, a transdermal patch is provided in which the active ingredient in the above-mentioned embodiment 1 is leuprorelin. The configuration of this transdermal patch is the same as that of the above-mentioned embodiment 1 in which the active ingredient is leuprorelin. Therefore, for the transdermal patch containing leuprorelin, the explanation of the transdermal patch in the above-mentioned embodiment 1 can be referred to by substituting leuprorelin for the active ingredient.

[0123] <Treatment method> The above-mentioned transdermal absorption agent and the above-mentioned transdermal patch containing leuprorelin can be used for the treatment of diseases for which leuprorelin is used, such as prostate cancer, premenopausal breast cancer, estrogen-dependent diseases (such as endometriosis and uterine fibroids), and central precocious puberty.

[0124] In another embodiment, a method for treating prostate cancer is provided, which comprises administering the above-mentioned transdermal absorbent or the above-mentioned transdermal patch containing a therapeutically effective amount of leuprorelin to a patient or animal patient in need of treatment. In another embodiment, a method for treating premenopausal breast cancer is provided, which comprises administering the above-mentioned transdermal absorbent or the above-mentioned transdermal patch containing a therapeutically effective amount of leuprorelin to a patient or animal patient in need of treatment. In another embodiment, a method for treating estrogen-dependent diseases is provided, which comprises administering the above-mentioned transdermal absorbent or the above-mentioned transdermal patch containing a therapeutically effective amount of leuprorelin to a patient or animal patient in need of treatment.

[0125] One embodiment is a method for treating central precocious puberty, comprising administering to a patient or animal patient in need of treatment the above-mentioned transdermal absorption agent or the above-mentioned transdermal patch containing a therapeutically effective amount of leuprorelin. Note that the "therapeutically effective amount of leuprorelin" referred to here is the amount shown as the dosage of leuprorelin in the above-mentioned transdermal absorption agent, and is the dosage according to the type of disease.

[0126] In one embodiment, the transdermal agent or the transdermal patch is provided for the treatment of prostate cancer. In one embodiment, the transdermal agent or the transdermal patch is provided for the treatment of premenopausal breast cancer. In one embodiment, the transdermal agent or the transdermal patch is provided for the treatment of estrogen-dependent diseases. In one embodiment, the transdermal agent or the transdermal patch is provided for the treatment of central precocious puberty.

[0127] The animals to which the above-mentioned transdermal absorption agent and the above-mentioned transdermal patch containing leuprorelin are applied are the same as those in the first embodiment, and are preferably vertebrates, and more preferably mammals.

[0128] Third embodiment Next, a description will be given of a transdermal agent according to embodiment 3. The transdermal agent according to this embodiment contains octreotide or a salt thereof (hereinafter collectively referred to as "octreotide") as an active ingredient.

[0129] Octreotide is a drug used to treat gastrointestinal hormone-producing tumors and acromegaly. Currently, only injections are used to administer octreotide in clinical practice. Subcutaneous injections of octreotide require multiple daily administrations. Administration by injection is painful, and especially multiple daily administrations impose an excessive burden on patients.

[0130] In order to reduce the number of injections to patients, microsphere-type preparations that can impart sustained release to preparations containing octreotide have been developed. JP2017-509661A discloses a method for preparing poly(D,L-lactide-co-glycolide) polymer microspheres of octreotide acetate. Microsphere-type preparations of octreotide are used in clinical practice as Sandostatin LAR (registered trademark).

[0131] Microsphere-type sustained-release formulations of octreotide are administered intramuscularly once a month, but the drug concentration does not reach a sufficient level for two weeks after the first administration. For this reason, it is necessary to administer the same dose of an injection containing octreotide in combination with gastrointestinal hormone-producing tumors. This still places a heavy burden on patients, and there is a need for the development of an octreotide formulation that improves the quality of life of patients.

[0132] To avoid administration by injection, it is possible to apply a topical preparation. JP2019-516709A suggests administering octreotide transdermally. However, since octreotide is a hydrophilic compound, its skin permeability is extremely low. If octreotide is administered as a transdermal agent, its efficacy cannot be fully obtained.

[0133] Regarding octreotide, a formulation that enhances skin permeability and provides excellent sustained release has not yet been investigated.

[0134] The transdermal absorption agent according to this embodiment can enhance the skin permeability of octreotide and provide excellent sustained release properties.

[0135] <Transdermal absorption agent> The configuration of the transdermal absorption agent according to this embodiment is the same as that of the transdermal absorption agent according to the above-mentioned embodiment 2, except that the active ingredient is octreotide instead of leuprorelin. Therefore, for the transdermal absorption agent containing octreotide, reference can be made to the explanation of the transdermal absorption agent according to the above-mentioned embodiment 2 by substituting octreotide for leuprorelin. The following mainly describes the points of difference between the transdermal absorption agent according to this embodiment and the transdermal absorption agent according to the above-mentioned embodiment 2.

[0136] The transdermal absorption agent according to this embodiment contains a solid complex in which octreotide or a salt thereof (hereinafter collectively referred to as "octreotide") is coated with a surfactant, and an oil phase. The hydrophilic portion of the surfactant associates with octreotide, and octreotide is coated with the surfactant, forming a complex of octreotide and the surfactant. In the transdermal absorption agent, the complex forms S / O type particles dispersed in the oil phase.

[0137] Octreotide is a peptidic compound represented by the following formula (I): Octreotide is usually used in the form of an acetate salt.

[0138] [ka]

[0139] Octreotide acetate is a white to slightly yellowish white powder with a slight odor of acetic acid. It is highly soluble in water, and is easily soluble in ethanol, acetic acid, or N-methylpyrrolidone. The molecular weights of octreotide and octreotide acetate are 1019.24 and 1139.34, respectively, which are greater than 1000, and are hydrophilic compounds. For this reason, they generally cannot penetrate the skin by themselves. In the transdermal absorption agent according to the present embodiment, the skin permeability of octreotide is enhanced by forming S / O type particles.

[0140] The salt of octreotide is not limited as long as it is a pharma- ceutically acceptable salt. The salt is preferably an acid addition salt, and may be an inorganic acid salt or an organic acid salt. Examples of inorganic acid salts include salts of inorganic acids such as hydrohalic acids such as hydrochloric acid and hydrobromic acid, perchloric acid, nitric acid, and sulfuric acid. Examples of organic acid salts include salts of organic acids such as formic acid, acetic acid, propionic acid, lactic acid, thermophilic acid, oxalic acid, malonic acid, and succinic acid. The octreotide contained in the transdermal absorption agent according to the present embodiment is preferably octreotide acetate.

[0141] The ratio of the mass of octreotide to the mass of the surfactant in the complex (parts by mass of octreotide to 1 part by mass of surfactant) is preferably 0.01 to 0.2, more preferably 0.012 to 0.1, even more preferably 0.015 to 0.05, and particularly preferably 0.017 to 0.03. The ratio of the mass of octreotide to the mass of the surfactant is preferably 0.018 to 0.025 or 0.02.

[0142] The method for producing the transdermal absorption agent according to this embodiment has the same configuration as the transdermal absorption agent according to the second embodiment, except that the active ingredient is octreotide instead of leuprorelin.

[0143] The concentration of octreotide in the aqueous solution of octreotide in step (1) is not particularly limited as long as it can be substantially completely dissolved, and is, for example, 0.1 mg / mL to 30 mg / mL. The concentration of the surfactant in the organic solvent solution is not particularly limited, and is, for example, 1 mg / mL to 100 mg / mL, 20 mg / mL to 90 mg / mL, or 40 mg / mL to 80 mg / mL.

[0144] The dosage of the transdermal agent according to the present embodiment can be adjusted depending on the age and symptoms of the patient, the type of the disease to be treated, etc. For example, the agent can be administered over a period of several weeks to several months so that the amount of octreotide per administration for an adult is usually 1 μg to 30 mg, preferably 10 μg to 10 mg, and more preferably 30 μg to 3 mg.

[0145] The transdermal absorption agent according to the present embodiment forms S / O type particles in which a solid octreotide-surfactant complex is dispersed in an oil phase, and as shown in the following examples, it allows octreotide, which hardly permeates the skin, to penetrate into the body through the skin. Furthermore, as shown in the following examples, the transdermal absorption agent has superior sustained release properties to conventional injections.

[0146] Furthermore, the transdermal absorption preparation according to this embodiment has pharmacokinetic properties that provide sustained release, and as shown in the examples below, it is able to suppress transient hypoglycemia, which has been reported as a side effect of octreotide.

[0147] In another embodiment, a method for improving the transdermal absorbability of octreotide is provided. The method includes coating octreotide with a surfactant to form a solid octreotide-surfactant complex, and dispersing the complex in an oil phase to prepare an external preparation. The method can improve the transdermal absorbability of octreotide, which is difficult to use as an external preparation due to its low transdermal absorbability and cannot fully exert its effect when used as an external preparation.

[0148] <Method for improving transdermal absorption of octreotide> A method for improving the transdermal absorbability of octreotide in one embodiment includes coating octreotide with a surfactant to form a solid complex, and dispersing the complex in an oil phase to prepare an external preparation.

[0149] In another embodiment, a transdermal patch is provided in which the active ingredient in the above-mentioned embodiment 1 is octreotide. The configuration of this transdermal patch is the same as that of the above-mentioned embodiment 1 in which the active ingredient is octreotide. Therefore, for the transdermal patch containing octreotide, the active ingredient can be replaced with octreotide in the description of the above-mentioned embodiment 1.

[0150] <Treatment method> The above-mentioned transdermal absorption agent and the above-mentioned transdermal absorption patch containing octreotide can be used for the treatment of diseases for which octreotide is applied, such as VIP-producing tumor, carcinoid tumor, gastrin-producing tumor, gastrointestinal hormone-producing tumor, acromegaly, pituitary gigantism, gastrointestinal neuroendocrine tumor, gastrointestinal symptoms associated with gastrointestinal obstruction in palliative care of patients with advanced or recurrent cancer, thyroid-stimulating hormone-producing pituitary tumor, diarrhea and flushing due to carcinoid syndrome, and diarrhea due to vasoactive intestinal peptide-producing tumor.

[0151] In another embodiment, there is provided a method for treating a disease such as the VIP-producing tumor, comprising administering to a subject in need of treatment the transdermal absorption agent or the transdermal patch containing a therapeutically effective amount of octreotide. The therapeutically effective amount of octreotide is the amount shown as the dosage of octreotide in the transdermal absorption agent, and is a dosage set according to the disease.

[0152] In another embodiment, the above-mentioned transdermal absorption agent or the above-mentioned transdermal absorption patch is provided for the treatment of diseases such as the above-mentioned VIP-producing tumor. EXAMPLES

[0153] The present invention will be described below with reference to examples, but the present invention is not limited to the following examples.

[0154] [Example 1] (Sealing of FITC-OVA-encapsulated S / O formulation) 1. Preparation of S / O formulation First, an S / O type formulation was prepared. Specifically, a solution prepared by dissolving 0.5 mg / mL FITC-labeled ovalbumin (OVA, weight-average molecular weight about 45000) (hereinafter sometimes abbreviated as "FITC-OVA") in distilled water was mixed with a cyclohexane solution containing sucrose laurate L-195 (RYOTO SUGAR ESTER, manufactured by Mitsubishi Chemical Foods Co., Ltd.) in a volume ratio of 1:2. Next, the mixture was stirred at 26,000 rpm for 2 minutes using a Polytron homogenizer (manufactured by KINEMATICA Co., Ltd.) to prepare a W / O type emulsion. After preparation, the obtained W / O type emulsion was freeze-dried to obtain a solid of the L195-FITC-OVA complex. Next, isopropyl myristate (manufactured by Fujifilm Wako Pure Chemical Industries, Ltd.) was added to the L195-FITC-OVA complex to obtain a FITC-OVA encapsulated S / O type preparation (solid content concentration: 30% by mass).

[0155] 2. Sealing of S / O type preparations The FITC-OVA encapsulated S / O type formulation obtained in "1." was mixed with DURO-TAK 87-4098 (Henkel, acrylic copolymer, solid content concentration 38.5 mass%) as an adhesive component at a mass ratio of 1:1. The mixture was then stirred until homogenous using a vortex mixer (VORTEX-GENIE 2 Mixer, MS Kiki Co., Ltd.) to prepare an adhesive solution containing the S / O type formulation. After preparation, the adhesive solution containing the S / O type formulation obtained was applied to a liner layer (liner OPP 40 μm) and dried at 60°C for about 30 minutes to form an adhesive layer on the liner layer. Next, a support (acrylic resin sheet, thickness 50 μm) was attached to the surface of the adhesive layer that was not attached to the liner layer to obtain a sealed S / O type formulation (hereinafter sometimes abbreviated as "FITC-OVA encapsulated S / O seal") (FITC-OVA content per sheet: 14.2 μg).

[0156] [Test Example 1] (S / O seal permeability test into pig skin) Using the percutaneous absorption test system shown in Figure 6, a test was conducted to confirm the permeability of the FITC-OVA-encapsulated S / O seal into pig skin. Specifically, pig skin was placed on the top opening of a water-filled, jacketed, static Franz diffusion cell (manufactured by Cosmedy) for membrane permeation tests, and the FITC-OVA-encapsulated S / O seal was placed on top of the pig skin so that the adhesive layer was attached to the pig skin, and the test was left to stand at room temperature for about 24 hours. The surface of the pig skin was washed several times with ethanol and phosphate-buffered saline (PBS), then shredded and immersed in 500 μL of extraction solution (PBS:acetonitrile:methanol=2:1:1 by volume). After shaking for 24 hours, the FITC-OVA concentration in the extraction solution filtered through a 0.2 μm filter was quantified using a fluorometer (LS-55, manufactured by PerkinElmer), and the amount of penetration into the pig skin was calculated from the results. As a control, a PBS solution containing 14.2 μg of FITC-OVA, the same amount as in the FITC-OVA-encapsulated S / O seal, was applied to pig skin to perform a permeability test. The results are shown in Figure 7. The permeation rate (amount of permeated FITC-OVA / total amount of FITC-OVA in seal × 100) was 17.2%.

[0157] Figure 7 confirms that the FITC-OVA-encapsulated S / O seal had a greater amount of permeation into the pig skin than the PBS solution.

[0158] [Examples 2 to 3] (Sealing of S / O-type preparations encapsulating antibodies or peptides) A sealed FITC-IgG encapsulated S / O type preparation (hereinafter, sometimes abbreviated as "FITC-IgG encapsulated S / O seal") (content of FITC-IgG per sheet: 43.9 μg) or a sealed OCT encapsulated S / O type preparation (hereinafter, sometimes abbreviated as "OCT encapsulated S / O seal") (content of OCT per sheet: 100 μg) was obtained using the same method as in Example 1, except that 0.5 mg / mL FITC-labeled goat anti-mouse IgG (ab97022, manufactured by Abcam, weight-average molecular weight approximately 150,000) (hereinafter, sometimes abbreviated as "FITC-IgG") or 0.5 mg / mL octreotide (OCT, manufactured by Fujifilm Wako Pure Chemical Industries, Ltd., weight-average molecular weight approximately 1080) was used.

[0159] [Test Example 2] (S / O seal permeability confirmation test into pig skin and mouse skin) Using the sealed FITC-IgG encapsulated S / O type preparation obtained in Example 2, a test to confirm the permeability into pig skin was conducted in the same manner as in Test Example 1. As a control, a PBS solution containing 43.9 μg of FITC-IgG, the same amount as the FITC-IgG encapsulated S / O seal, was applied to pig skin to conduct a test to confirm the permeability into pig skin. The results are shown in FIG. 8. The permeation rate (amount of FITC-IgG permeated / total amount of FITC-IgG in seal×100) was 21.7%.

[0160] In addition, a permeability confirmation test for the sealed OCT-encapsulated S / O formulation obtained in Example 3 was performed using a transdermal absorption test system. Specifically, mouse skin was placed on the upper opening of a water-filled, jacketed, membrane permeation test stationary Franz diffusion cell (manufactured by Cosmedy), and an OCT-encapsulated S / O seal was placed on the mouse skin so that the adhesive layer adhered to the mouse skin, and left to stand at room temperature for about 24 hours. Thereafter, a part of the solution in the stationary Franz diffusion cell was extracted, and the amount of OCT in the solution was quantified by liquid chromatography (HPLC, manufactured by Shimadzu Corporation), and the amount of permeation through the mouse skin was calculated from the result. As a control, a PBS solution containing 100 μg of OCT, the same amount as that of the OCT-encapsulated S / O seal, was applied to the mouse skin to perform a permeability confirmation test for the mouse skin. The results are shown in FIG. 9. The transmittance (amount of permeated OCT / total amount of OCT in seal×100) was 0.8%.

[0161] Figure 8 confirms that the FITC-IgG-encapsulated S / O seal also had a higher permeation rate into pig skin than the PBS solution, and Figure 9 confirms that the OCT-encapsulated S / O seal also had a higher permeation rate into mouse skin than the PBS solution.

[0162] [Test Example 3] (Animal immunity test using S / O seal) The animal immunity test was carried out according to the schedule shown in FIG. 10. Specifically, first, the backs of the mice were shaved with clippers three days before the immunity test. Next, blood was collected from the tail vein the day before the immunity test. Next, the OVA-encapsulated S / O seal obtained in Example 1 was attached to the shaved back the next day. The OVA-encapsulated S / O seal was fixed with kinesiology tape (manufactured by Nichiban Co., Ltd.). After the start of the immunity test, the OVA-encapsulated S / O seal was replaced with a new one on the 7th and 14th days, and a total of three administrations were performed. On the 21st day after the start of the immunity test, blood was collected from the tail vein of the mice. As a control group 1, a PBS solution containing 30 μg of OVA, the same amount as the S / O seal, was subcutaneously injected. The administration was performed three times according to the same schedule as the OVA-encapsulated S / O seal. Furthermore, as control group 2, the OVA-encapsulated S / O formulation (liquid) prepared in "1." of Example 1 was applied to the shaved backs of mice so that the OVA content was 30 μg, the same amount as in the S / O seal. The administration was carried out three times according to the same schedule as for the OVA-encapsulated S / O seal. The amount of anti-OVA antibodies in the blood was examined by ELISA. Specifically, the procedure was as follows.

[0163] First, 100μL / well of 5.0mg / mL OVA-containing Milli Q aqueous solution was added to a 96-well microplate (maxisorp nunc-immuno plate, Thermo Fisher Scientific) and incubated overnight at 4℃. Next, to prevent non-specific adsorption to the plate, 200μL / well of 2% by mass BSA-containing PBS solution was added, incubated at 37℃ for 2 hours, and blocked. Serum diluted to an appropriate ratio with 2% by mass BSA-containing PBS solution was added to the plate at 20μL / well and incubated at 37℃ for 2 hours. Next, horseradish peroxidase (HRP)-labeled secondary antibody (Anti-Mouse IgG-HRP, Rockland Immunochemicals) solution (1mg / mL) was diluted 20000 times with 2% by mass BSA-containing PBS solution, added at 100μL / well, and incubated at 37℃ for 2 hours. Next, 3,3',5,5'-tetramethylbenzidine (TMB, Thermo Fisher Scientific) was added at 100 μL / well and incubated at 37° C. for 30 minutes. Next, 1 M HCl was added at 50 μL / well, and the OD value at 450 nm was measured to calculate the antibody titer. The results are shown in FIG.

[0164] Figure 11 shows that the amount of anti-OVA antibodies induced by the OVA-encapsulated S / O seal was higher than that of the mouse group that received the OVA-encapsulated S / O type formulation (liquid), and was similar to that of the mouse group that received a subcutaneous injection of a PBS solution containing 30 μg of OVA, the same amount as the S / O seal.

[0165] [Test Example 4] (Animal immunity test using S / O seal) A sealed S / O type preparation (hereinafter sometimes abbreviated as "OVA-encapsulated S / O seal") (OVA content per sheet: 20 μg) was obtained in the same manner as in Example 1, except that 0.5 mg / mL OVA was used. An immunity test was performed in the same manner as in Test Example 3, except that the obtained OVA-encapsulated S / O seal (OVA content per sheet: 20 μg) was used. As a control group, a PBS solution containing 20 μg of OVA, the same amount as in the OVA-encapsulated S / O seal, was applied to the backs of shaved mice. Blood was collected on the 7th and 14th days after the final administration, and the amount of anti-OVA antibody in the blood was examined using the same method as in Test Example 3. The results are shown in FIG. 12.

[0166] FIG. 12 clearly shows that the amount of anti-OVA antibodies induced by the OVA-encapsulated S / O seal was higher than that of the mouse group that received the PBS solution.

[0167] [Example 4] (Preparation of S / O formulation) A leuprorelin acetate solution in which 1 mg of leuprorelin acetate was dissolved in 2 mL of distilled water was added with 4 mL of a cyclohexane solution containing sucrose laurate (Mitsubishi Chemical Foods Corporation, L-195, lauric acid: 99% by mass, HLB: 1) at a concentration of 12.5 mg / mL or 2.5 mg / mL so that the mass ratio of leuprorelin acetate to the surfactant was 1 / 50 or 1 / 10, and the mixture was stirred at high speed at 26,000 rpm for 2 minutes using a homogenizer to prepare a W / O type emulsion. This emulsion was freeze-dried overnight to obtain a leuprorelin acetate-surfactant complex.

[0168] This complex was dispersed in 1 mL of isopropyl myristate (Tokyo Chemical Industry Co., Ltd.) to obtain two types of S / O type preparations with different surfactant contents. Each S / O type preparation contained leuprorelin acetate at a concentration of 1 mg / mL.

[0169] Figure 13 shows the particle size distribution (frequency distribution) of the leuprorelin acetate-surfactant complex in each S / O type preparation obtained by the above method. Table 1 shows the average particle size and polydispersity index (PDI) of the leuprorelin acetate-surfactant complex in each S / O type preparation. The particle size distribution and average particle size were measured by a laser scattering method (using a Nano ZS device manufactured by Sysmex Corporation).

[0170] [Table 1]

[0171] As shown in FIG. 13 and Table 1, two types of S / O type preparations were obtained in which leuprorelin acetate-surfactant complexes having uniform particle sizes of 231 nm or more and 880 nm or less were dispersed.

[0172] [Example 5] (Preparation of S / O formulation) A leuprorelin acetate solution was prepared by dissolving 1 mg of leuprorelin acetate in 2 mL of distilled water, and 4 mL of a cyclohexane solution containing 12.5 mg / mL of sucrose laurate (Mitsubishi Chemical Foods Corporation, L-195, lauric acid: 99% by mass, HLB: 1) was added so that the mass ratio of leuprorelin acetate to surfactant was 1 / 50. The mixture was stirred at high speed at 26,000 rpm for 2 minutes using a homogenizer to prepare a W / O type emulsion. This emulsion was freeze-dried overnight to obtain a leuprorelin acetate-surfactant complex.

[0173] 0.9 mL of isopropyl myristate (Tokyo Chemical Industry Co., Ltd.) and 0.1 mL of glyceryl monooleate (MGO) were added to this complex and dispersed to obtain an S / O type formulation, which contained leuprorelin acetate at a concentration of 1 mg / mL.

[0174] [Test Example 5] (S / O formulation permeability test into mouse skin) For the S / O type preparations obtained in Examples 4 and 5, a permeability confirmation test into mouse skin was performed using the percutaneous absorption test system shown in FIG. 14. Specifically, mouse skin was placed on the upper opening of a static type Franz diffusion cell (manufactured by Cosmedy) with a jacket for membrane permeation test filled with water, and 0.2 mL of the S / O type preparation was placed on the mouse skin and left to stand at room temperature for about 24 hours. Thereafter, a part of the solution in the static type Franz diffusion cell was extracted, and the leuprorelin (LEU) concentration in the solution was quantified using a liquid chromatograph mass spectrometer (LC-MS, manufactured by Shimadzu Corporation). As a control, 0.2 mL of PBS solution was placed, and a permeability confirmation test into mouse skin was similarly performed. FIG. 15 shows the test results for two types of S / O type preparations with different surfactant contents, and FIG. 16 shows the test results for two types of S / O type preparations with different MGO contents.

[0175] Figure 15 confirms the permeability of the S / O formulation into mouse skin. The S / O formulation, in which the mass ratio of leuprorelin acetate to surfactant is 1 / 50, showed particularly good permeability of leuprorelin into mouse skin. Figure 16 shows that the incorporation of MGO into the S / O formulation increased the amount of leuprorelin permeated by about 5 times, promoting the permeability of leuprorelin into mouse skin.

[0176] [Test Example 6] (Pharmacokinetic study of leuprorelin) Three days before the test, the backs of the mice were shaved with clippers. Next, the S / O formulation obtained in Example 5 was applied to a patch (1.5 cm x 3 cm) so that the dose of leuprorelin acetate was 2 mg, and the patch was attached to the shaved back. Blood was collected from the fundus of the mice 0.25, 0.5, 1, 2, 6, 12, 24, 48, 72, and 96 hours after the start of administration. As a control group, a PBS solution in which 2 mg of leuprorelin acetate was dissolved was subcutaneously injected. The leuprorelin concentration (ng / mL) in the plasma was quantified by LC-MS (Shimadzu Corporation). The results are shown in Figure 17. In addition, pharmacokinetic analysis was performed on the collected blood using Phoenix (registered trademark) WinNonlin (registered trademark) (manufactured by CERTARA, compliant with the U.S. Food and Drug Administration (FDA)). The analysis results are shown in Table 2.

[0177] [Table 2]

[0178] As shown in Figure 17 and Table 2, 12 hours after the start of administration, the plasma leuprorelin concentration became dominant in mice administered the S / O formulation, confirming that the S / O formulation had a longer duration of efficacy (sustained release) than the injection.

[0179] [Example 6] (Preparation of S / O formulation) 1 mg of octreotide acetate was dissolved in 2 mL of distilled water to prepare an octreotide acetate solution, to which 4 mL of a 12.5 mg / mL cyclohexane solution of sucrose laurate (Mitsubishi Chemical Foods Corporation, L-195, lauric acid: 99% by mass, HLB: 1) was added so that the ratio of the mass of octreotide acetate to the mass of the surfactant was 1 / 50, and the mixture was stirred at 26,000 rpm for 2 minutes using a homogenizer. The resulting W / O type emulsion was freeze-dried overnight to obtain an octreotide acetate-surfactant complex.

[0180] The complex was dispersed in 1 mL of isopropyl myristate (Tokyo Chemical Industry Co., Ltd.) to obtain an S / O formulation. The S / O formulation contained octreotide acetate at a concentration of 1 mg / mL. The particle size distribution (frequency distribution) and average particle size of the octreotide acetate-surfactant complex in the S / O formulation were measured by dynamic light scattering (Zetasizer Nano ZS, Marvern).

[0181] (result) The particle size distribution of the octreotide acetate-surfactant complex in the S / O formulation is shown in Figure 18. The average particle size of the octreotide acetate-surfactant complex in the S / O formulation was 145.0 nm, and the polydispersity index (PDI) was 0.235 to 0.283.

[0182] In this example, it was shown that an S / O type preparation was obtained in which octreotide acetate-surfactant complexes having a low polydispersity index and a mean particle size of 145.0 nm were dispersed.

[0183] [Test Example 7] (S / O formulation permeability test into mouse skin) For the S / O formulation obtained in Example 6, a permeability confirmation test of octreotide acetate through mouse skin (Laboskin, manufactured by Hoshino Laboratory Animal Breeding Center) was carried out using the percutaneous absorption test system shown in FIG. 19. Mouse skin was placed on the upper opening of a stationary jacketed Franz diffusion cell (manufactured by Cosmedy) for membrane permeability tests filled with phosphate buffered saline (PBS), and 0.2 mL of the S / O formulation was placed on top of it. After leaving the cell to stand at 32.5°C for 24 hours while stirring the PBS with a stirrer, a portion of the PBS was extracted from the receiver phase of the Franz diffusion cell, and the concentration of octreotide acetate in the PBS was quantified using a liquid chromatograph mass spectrometer (LC-MS, manufactured by Shimadzu Corporation). As a control, a predetermined amount of octreotide acetate was dissolved in phosphate buffered saline (PBS) to a final concentration of 1 mg / mL, and 0.2 mL of an octreotide acetate aqueous solution (Comparative Example 1) was placed thereon, and a permeability confirmation test through mouse skin was carried out in the same manner. FIG. 20 shows the skin permeation amounts of the S / O preparation and Comparative Example 1 after 24 hours.

[0184] (result) 20, it was confirmed that the S / O type preparation had a significantly higher (p<0.01) octreotide acetate permeation amount than Comparative Example 1.

[0185] [Example 7] (Preparation of S / O formulation) To an octreotide acetate solution prepared by dissolving 10 mg of octreotide acetate in 4 mL of distilled water, 8 mL of a 62.5 mg / mL cyclohexane solution of sucrose laurate (Mitsubishi Chemical Foods Corporation, L-195, lauric acid: 99% by mass, HLB: 1) was added so that the ratio of the mass of octreotide acetate to the mass of the surfactant was 1 / 50, and an octreotide acetate-surfactant complex was obtained by the same procedure as in Example 6.

[0186] The complex was dispersed in 1 mL of isopropyl myristate (Tokyo Chemical Industry Co., Ltd.) to obtain an S / O formulation, which contained octreotide acetate at a concentration of 10 mg / mL.

[0187] [Test Example 8] (Pharmacokinetic study of octreotide acetate) Six-week-old mice (BALB / c, female) were housed for one week in an environment with free access to water and food to acclimate them, and then three days before the test, the hair on the backs of the mice was completely removed using clippers and hair removal cream. The mice were divided into the following three test groups (three mice per group), and each mouse was administered 2 mg of octreotide acetate.

[0188] In the group administered the S / O formulation transdermally, a patch was made by impregnating three layers of gauze (20 mm long, 20 mm wide) with 200 μL of the S / O formulation prepared in Example 7, which was then attached to the back of the mouse and secured in place with vinyl tape. The patch was then removed after 24 hours.

[0189] In the PBS solution injection group, 100 μL of octreotide acetate in PBS (20 mg / mL) was subcutaneously injected, and in the sustained release formulation injection group, 2 mg of Sandostatin LAR (registered trademark, Novartis Pharma) was intramuscularly injected into the right hind thigh.

[0190] Blood samples were taken from the fundus of the mice 0.25, 0.5, 1, 2, 6, 12, 24, 48, and 96 hours after the start of administration. The concentration of octreotide acetate in plasma was quantified by LC-MS (Shimadzu Corporation).

[0191] The obtained changes in blood drug concentration over time were analyzed for pharmacokinetics using Phoenix (registered trademark) WinNonlin (registered trademark) (manufactured by CERTARA, compliant with the US Food and Drug Administration).

[0192] (result) The time course of the plasma octreotide acetate concentration from 0 to 24 hours and from 0 to 96 hours is shown in Figure 21(A) and Figure 21(B), respectively. The plasma octreotide acetate concentration in mice administered the S / O formulation transdermally exceeded that of the PBS solution injection group 6 hours after the start of administration, and the plasma concentration remained high thereafter. The results of the pharmacokinetic analysis are shown in Table 3.

[0193] [Table 3]

[0194] The S / O formulation showed pharmacokinetics similar to that of the sustained-release formulation Sandostatin LAR (registered trademark), and was shown to have excellent prolonged efficacy (sustained release).

[0195] [Example 8] (Preparation of S / O type patch) To an octreotide acetate solution prepared by dissolving 10 mg of octreotide acetate in 4 mL of distilled water, 8 mL of a 62.5 mg / mL cyclohexane solution of sucrose laurate (Mitsubishi Chemical Foods Corporation, L-195, lauric acid: 99% by mass, HLB: 1) was added so that the ratio of the mass of octreotide acetate to the mass of the surfactant was 1 / 50, and an octreotide acetate-surfactant complex was obtained by the same procedure as in Example 6.

[0196] The complex was dispersed with 1 mL of isopropyl myristate (Tokyo Chemical Industry Co., Ltd.) to obtain an S / O type preparation. The S / O type preparation and DURO-TAK 87-4098 (Henkel, acrylic copolymer, solid content concentration 38.5 mass%) as an adhesive component were mixed in a mass ratio of 1:1. The resulting mixture was stirred until homogeneous using a vortex mixer (VORTEX-GENIE 2 Mixer, MS Equipment Co., Ltd.) to prepare an adhesive solution containing the S / O type preparation. The adhesive solution was applied to a liner layer (liner OPP 40 μm) and dried at 60 °C for about 30 minutes to form an adhesive layer on the liner layer. Next, a support (acrylic resin sheet, thickness 50 μm) was attached to the surface of the adhesive layer opposite to the surface in contact with the liner layer to obtain an S / O type patch.

[0197] [Test Example 9] (Pharmacokinetic study of octreotide acetate in S / O type patch) Six-week-old mice (BALB / c, female) were housed for one week in an environment with free access to water and food to acclimate them, and then three days before the test, the hair on the backs of the mice was completely removed using clippers and hair removal cream. The mice were divided into the following three test groups (three mice per group), and each mouse was administered 0.6 mg of octreotide acetate.

[0198] In the S / O type patch transdermal administration group, the S / O type patch (20 mm long, 30 mm wide) prepared in Example 8 was attached to the back of the mouse and fixed with vinyl tape, and then removed after 24 hours. In the PBS solution injection administration group, 100 μL of octreotide acetate in PBS (6 mg / mL) was subcutaneously injected. In the sustained release formulation injection administration group, 0.6 mg of Sandostatin LAR (registered trademark, Novartis Pharma) was intramuscularly injected into the right hind thigh.

[0199] Blood samples were taken from the fundus of the mice 0.25, 0.5, 1, 2, 6, 12, 24, 48, and 96 hours after the start of administration. Plasma octreotide acetate concentrations were quantified using LC-MS (Shimadzu Corporation). Blood glucose levels were measured before administration and 1 and 24 hours after the start of administration using a One Touch VerioView (LifeScan Japan).

[0200] (result) The time course of the plasma octreotide acetate concentration from 0 to 24 hours and from 0 to 96 hours is shown in Figure 22(A) and Figure 22(B), respectively. The plasma octreotide acetate concentration in mice administered the S / O patch transdermally exceeded that of the sustained release formulation injection group 6 hours after the start of administration, and thereafter remained at a higher plasma concentration than the sustained release formulation injection group. The results of the pharmacokinetic analysis are shown in Table 4.

[0201] [Table 4]

[0202] In addition, as shown in Figure 23, a significant drop in blood glucose level was observed 1 hour after the start of administration in the PBS solution injection group. On the other hand, the change in blood glucose level in the S / O type patch transdermal administration group was similar to that in the commercially available sustained release formulation injection administration group, confirming the effect of reducing side effects due to the sustained release characteristics.

[0203] [Example 9] (Preparation of S / O type patch) FITC-K-TRP-2 solution was prepared by dissolving 1 mg of FITC-labeled tyrosinase-related protein epitope peptide (FITC-KKKGSVYDFFVWL (SEQ ID NO: 1), hereinafter referred to as "FITC-K-TRP-2") in 2 mL of 10% by volume ethanol. 4 mL of 12.5 mg / mL cyclohexane solution of sucrose laurate (Mitsubishi Chemical Foods Corporation, L-195, lauric acid: 99% by mass, HLB: 1) was added so that the ratio of the mass of FITC-K-TRP-2 to the mass of the surfactant was 1 / 50, and the mixture was stirred at 26,000 rpm for 2 minutes with a homogenizer. The obtained W / O type emulsion was freeze-dried overnight to obtain a FITC-K-TRP-2-surfactant complex.

[0204] The complex was dispersed with 1 mL of isopropyl myristate (Tokyo Chemical Industry Co., Ltd.) to obtain an S / O formulation. The S / O formulation was mixed with DURO-TAK 87-4098 (Henkel, acrylic copolymer, solid content 38.5% by mass) as an adhesive component in a mass ratio of 1:1. The resulting mixture was stirred until homogeneous using a vortex mixer (VORTEX-GENIE 2 Mixer, MS Equipment Co., Ltd.) to prepare an adhesive solution containing the S / O formulation. The adhesive solution was applied to a liner layer (liner OPP 40 μm) and dried at 60 °C for about 30 minutes to form an adhesive layer on the liner layer. Next, a support (acrylic resin sheet, thickness 50 μm) was adhered to the surface of the adhesive layer opposite the surface in contact with the liner layer to obtain an S / O type patch (hereinafter sometimes abbreviated as "FITC-K-TRP-2-encapsulated S / O seal").

[0205] [Test Example 10] (Test to confirm the permeability of FITC-K-TRP-2-encapsulated S / O seal into pig skin) Using the percutaneous absorption test system shown in FIG. 6, a test was conducted to confirm the permeability of the FITC-K-TRP-2-encapsulated S / O seal into pig skin. Specifically, pig skin was placed on the top opening of a water-filled, jacketed, static Franz diffusion cell (manufactured by Cosmedy) for membrane permeation tests, and an FITC-K-TRP-2-encapsulated S / O seal was placed on the pig skin so that the adhesive layer would adhere to the pig skin, and the test was left to stand at room temperature for about 24 hours. The pig skin surface was washed several times with ethanol and PBS, then shredded and immersed in 500 μL of extraction solution (PBS:acetonitrile:methanol=2:1:1 by volume). After shaking for 24 hours, the amount of FITC-K-TRP-2 in the extraction solution filtered through a 0.2 μm filter was quantified using a fluorometer (LS-55, manufactured by PerkinElmer), and the amount of FITC-K-TRP-2 permeated into the pig skin was calculated from the results. As a control, a PBS solution containing 10% ethanol and containing 21.4 μg of FITC-K-TRP-2, the same amount as the FITC-K-TRP-2-encapsulated S / O seal, was applied to pig skin to perform a permeability confirmation test.

[0206] (result) As shown in Figure 24, it was confirmed that the amount of FITC-K-TRP-2 permeated into the pig skin was greater in the S / O sealant containing FITC-K-TRP-2 than in the PBS solution, and the permeation rate (amount of FITC-K-TRP-2 permeated / total amount of FITC-K-TRP-2 in the sealant × 100) was 1.9%.

[0207] [Example 10] (Preparation of S / O type patch) FITC-OVA solution was prepared by dissolving 1 mg of FITC-OVA in 2 mL of distilled water, to which 4 mL of 12.5 mg / mL cyclohexane solution of sucrose laurate (Mitsubishi Chemical Foods Corporation, L-195, lauric acid: 99% by mass, HLB: 1) was added so that the ratio of the mass of FITC-OVA to the mass of the surfactant was 1 / 50, and the mixture was stirred at 26,000 rpm for 2 minutes using a homogenizer. The resulting W / O type emulsion was freeze-dried overnight to obtain a FITC-OVA-surfactant complex.

[0208] The complex was dispersed with 1 mL of isopropyl myristate (Tokyo Chemical Industry Co., Ltd.) to obtain an S / O formulation. The S / O formulation was mixed with DURO-TAK 87-4098 (Henkel, acrylic copolymer, solid content concentration 38.5 mass%) as an adhesive component in a mass ratio of 1:0.41, 1:1, or 1:1.62. The resulting mixture was stirred until homogeneous using a vortex mixer (VORTEX-GENIE 2 Mixer, MS Equipment Co., Ltd.) to prepare an adhesive solution containing the S / O formulation. The adhesive solution was applied to a liner layer (liner OPP 40 μm) and dried at 60 °C for about 30 minutes to form an adhesive layer on the liner layer. Next, a support (acrylic resin sheet, thickness 50 μm) was adhered to the side of the adhesive layer opposite the side in contact with the liner layer to obtain S / O type patches (hereinafter sometimes abbreviated as "FITC-OVA-encapsulated S / O seal") in which the adhesive component content relative to the total mass of the adhesive component and isopropyl myristate was 20%, 38%, and 50%, respectively.

[0209] [Test Example 11] (Test to confirm the permeability of FITC-OVA-encapsulated S / O seal into pig skin) Using the percutaneous absorption test system shown in Figure 6, a test was conducted to confirm the permeability of the FITC-OVA-encapsulated S / O seal into pig skin. Specifically, pig skin was placed on the top opening of a water-filled, jacketed, static Franz diffusion cell (manufactured by Cosmedy) for membrane permeation tests, and the FITC-OVA-encapsulated S / O seal was placed on top of the pig skin so that the adhesive layer would adhere to the pig skin, and the test was left to stand at room temperature for about 24 hours. The surface of the pig skin was washed several times with ethanol and PBS, then shredded and immersed in 500 μL of extraction solution (PBS:acetonitrile:methanol=2:1:1 by volume). After shaking for 24 hours, the FITC-OVA concentration in the extraction solution filtered through a 0.2 μm filter was quantified using a fluorometer (LS-55, manufactured by PerkinElmer), and the amount of penetration into the pig skin was calculated from the results.

[0210] (result) As shown in Figure 25, the adhesive layer of the FITC-OVA encapsulated S / O seal with an adhesive component content of 20% was low in viscosity, and part of the adhesive layer was observed to adhere to the liner layer when the liner layer was peeled off. The FITC-OVA encapsulated S / O seal with an adhesive component content of 20% had extremely poor adhesion and was not suitable for application to the skin. It was also confirmed that the FITC-OVA encapsulated S / O seal with an adhesive component content of 38% had a greater penetration amount into pig skin than the FITC-OVA encapsulated S / O seal with an adhesive component content of 50%.

[0211] [Example 11] (Preparation of S / O type patch) OVA solution was prepared by dissolving 10 mg of OVA in 4 mL of distilled water, and 8 mL of 62.5 mg / mL cyclohexane solution of sucrose laurate (Mitsubishi Chemical Foods Corporation, L-195, lauric acid: 99% by mass, HLB: 1) was added so that the ratio of OVA mass to surfactant mass was 1 / 50, and the mixture was stirred at 26,000 rpm for 2 minutes with a homogenizer. The obtained W / O type emulsion was freeze-dried overnight to obtain an OVA-surfactant complex.

[0212] The complex was dispersed with 1.67 mL of isopropyl myristate (Tokyo Chemical Industry Co., Ltd.) to obtain an S / O type preparation. The S / O type preparation was mixed with DURO-TAK 87-4098 (Henkel, acrylic copolymer, solid content concentration 38.5 mass%) as an adhesive component in a mass ratio of 1:1. The resulting mixture was stirred until homogeneous using a vortex mixer (VORTEX-GENIE 2 Mixer, MS Equipment Co., Ltd.) to prepare an adhesive solution containing the S / O type preparation. The adhesive solution was applied to a liner layer (liner OPP 40 μm) and dried at 60 °C for about 30 minutes to form an adhesive layer on the liner layer. Next, a support (acrylic resin sheet, thickness 50 μm) was attached to the surface of the adhesive layer opposite to the surface in contact with the liner layer to obtain an S / O type patch (hereinafter sometimes abbreviated as "OVA-encapsulated S / O seal").

[0213] In addition, 0.9 mL of isopropyl myristate (Tokyo Chemical Industry Co., Ltd.) and 0.1 mL of glyceryl monooleate (MGO) were added to and dispersed in the OVA-surfactant complex to obtain an MGO-containing S / O type preparation. This was sealed in the same manner as the OVA-encapsulated S / O seal to obtain an MGO-containing S / O type preparation patch (hereinafter sometimes abbreviated as "OVA-encapsulated MGO seal").

[0214] [Test Example 12] (Animal immunity test using OVA-encapsulated S / O seal and OVA-encapsulated MGO seal) The miniature pig immunization test was carried out according to the schedule shown in FIG. 26(A). Specifically, first, the root of the ear of the crown-type miniature pig was shaved. Next, blood was collected from the anterior aortic sinus and the external jugular vein on the day before the immunization test. Next, the OVA-encapsulated S / O seal obtained in Example 11 was attached to the shaved root of the ear on the following day. The OVA-encapsulated S / O seal was protected with a Derm Smooth Film Roll and a Corban self-adhesive elastic bandage kinesiology tape (manufactured by Nichiban Co., Ltd.), fixed with a stockinette, and occluded for three days. After the start of the immunization test, a new OVA-encapsulated S / O seal was attached on the 8th and 15th days, and administered three times in total. On the 35th and 56th days after the start of the immunization test, blood was collected from the anterior aortic sinus and the external jugular vein. As a control group 1, a PBS solution containing 3 mg of OVA, the same amount as the S / O seal, was subcutaneously injected. The administration was carried out three times according to the same schedule as the OVA-encapsulated S / O seal. Furthermore, as control group 2, OVA-encapsulated MGO stickers were attached to the shaved backs of mice in the same manner as the OVA-encapsulated S / O stickers so that the OVA content was 3 mg, the same amount as the OVA-encapsulated S / O stickers. Administration was carried out three times on the same schedule as the OVA-encapsulated S / O stickers. The amount of anti-OVA antibodies in the blood was quantified by the ELISA method according to the following procedure.

[0215] First, 100 μL / well of 5.0 mg / mL OVA-containing Milli-Q aqueous solution was added to a 96-well microplate (maxisorp nunc-immuno plate, Thermo Fisher Scientific) and incubated overnight at 4 ° C. Then, in order to prevent non-specific adsorption to the plate, 200 μL / well of 2% by mass BSA-containing PBS solution was added, incubated at 37 ° C. for 2 hours, and blocked. Serum diluted to an appropriate ratio with 2% by mass BSA-containing PBS solution was added to the plate at 20 μL / well and incubated at 37 ° C. for 2 hours. Next, a horseradish peroxidase (HRP)-labeled secondary antibody (Anti-swine IgG-HRP, Rockland Immunochemicals) solution (1 mg / mL) was diluted 20,000 times with 2% by mass BSA-containing PBS solution, added at 100 μL / well, and incubated at 37 ° C. for 2 hours. Next, 3,3',5,5'-tetramethylbenzidine (TMB, Thermo Fisher Scientific) was added at 100 μL / well and incubated for 30 minutes at 37° C. Next, 1 M HCl was added at 50 μL / well, the OD value at 450 nm was measured, and the antibody titer was calculated.

[0216] (result) The antibody titers on days 35 and 56 are shown in Figures 26(B) and 26(C), respectively. The amount of anti-OVA antibodies induced by percutaneous administration of the OVA-encapsulated S / O seal was significantly higher than that of control group 1, which was administered subcutaneously in PBS with an OVA content of 3 mg, the same amount as in the OVA-encapsulated S / O seal, and was comparable to that of control group 2, which was administered percutaneously with an OVA-encapsulated MGO seal on day 56.

[0217] [Example 12] (Preparation of MGO-containing S / O type patch) FITC-OVA solution was prepared by dissolving 10 mg of FITC-OVA in 4 mL of distilled water, to which was added 8 mL of 62.5 mg / mL cyclohexane solution of sucrose laurate (Mitsubishi Chemical Foods Corporation, L-195, lauric acid: 99% by mass, HLB: 1) so that the ratio of the mass of FITC-OVA to the mass of the surfactant was 1 / 50, and the mixture was stirred at 26,000 rpm for 2 minutes using a homogenizer. The resulting W / O type emulsion was freeze-dried overnight to obtain a FITC-OVA-surfactant complex.

[0218] MGO was dissolved in isopropyl myristate to give an MGO concentration of 0, 1, 10, or 25% by mass. 1 mL of this solution was added to and dispersed in the FITC-OVA-surfactant complex to obtain MGO-containing S / O type formulations with different MGO contents.

[0219] The MGO-containing S / O-type formulation was mixed with DURO-TAK 87-4098 (Henkel, acrylic copolymer, solid content 38.5% by mass) as an adhesive component in a 1:1 mass ratio. The resulting mixture was stirred until homogeneous using a vortex mixer (VORTEX-GENIE 2 Mixer, MS Kiki Co., Ltd.) to prepare an adhesive solution containing the S / O-type formulation. The adhesive solution was applied to a liner layer (liner OPP 40 μm) and dried at 60 °C for about 30 minutes to form an adhesive layer on the liner layer. Next, a support (acrylic resin sheet, thickness 50 μm) was attached to the surface of the adhesive layer opposite to the surface in contact with the liner layer, and FITC-OVA-encapsulated MGO seals with different MGO contents were obtained.

[0220] [Test Example 13] (Test to confirm the permeability of FITC-OVA-encapsulated MGO seal into pig skin) Using the percutaneous absorption test system shown in Figure 6, a test was conducted to confirm the permeability of FITC-OVA-encapsulated MGO seals with different MGO contents into pig skin. Specifically, pig skin was placed on the upper opening of a water-filled, jacketed, static Franz diffusion cell (manufactured by Cosmedy) for membrane permeation tests, and an FITC-OVA-encapsulated MGO seal was placed on top of the pig skin so that the adhesive layer would adhere to the pig skin, and the test was left to stand at room temperature for about 24 hours. The pig skin surface was washed several times with ethanol and PBS, then shredded and immersed in 500 μL of extraction solution (PBS:acetonitrile:methanol=2:1:1 by volume). After shaking for 24 hours, the FITC-OVA concentration in the extraction solution filtered through a 0.2 μm filter was quantified using a fluorometer (LS-55, manufactured by PerkinElmer), and the amount of penetration into the pig skin was calculated from the results.

[0221] (result) As shown in Figure 27, the amount of FITC-OVA permeated into pig skin increased by adding MGO, a skin permeation enhancer. Furthermore, it was confirmed that the amount of FITC-OVA permeated increased as the MGO content increased. In the case of an MGO sticker containing FITC-OVA with an MGO content of 25% by mass, a small amount of the adhesive layer adhered to the liner layer when peeled off from the adhesive layer. This demonstrated that an appropriate MGO content is 10 to 20% by mass.

[0222] [Example 13] (Preparation of two-layer S / O type patch) FITC-OVA solution was prepared by dissolving 10 mg of FITC-OVA in 4 mL of distilled water, and 8 mL of 62.5 mg / mL cyclohexane solution of sucrose laurate (Mitsubishi Chemical Foods, L-195, lauric acid: 99% by mass, HLB: 1) was added so that the mass ratio of FITC-OVA to the mass of the surfactant was 1 / 50, and the mixture was stirred for 2 minutes at 26,000 rpm with a homogenizer. The obtained W / O type emulsion was freeze-dried overnight to obtain a FITC-OVA-surfactant complex. 1 mL of isopropyl myristate (Tokyo Chemical Industry) was added to this complex and dispersed to obtain an S / O type formulation. The S / O type formulation was mixed with DURO-TAK 87-4098 as an adhesive component in a mass ratio of 1:1. The resulting mixture was stirred using a vortex mixer (VORTEX-GENIE 2 Mixer, MS Kiki Co., Ltd.) until it became homogeneous, to prepare an adhesive solution containing the S / O formulation.

[0223] Next, a two-layered S / O seal containing FITC-OVA was prepared, consisting of an adhesive layer and an accelerator layer, according to the following procedure. An adhesive solution containing an S / O formulation was used for the adhesive layer. For the accelerator layer, a solution was used in which 10% by mass of MGO was dissolved in isopropyl myristate and mixed with DURO-TAK 87-4098 in a 1:1 mass ratio (hereinafter sometimes abbreviated as "accelerator solution").

[0224] (Preparation of FITC-OVA encapsulated two-layer S / O seal A) The adhesive solution was applied to a liner layer (liner OPP 40 μm) and dried at 60° C. for about 30 minutes to form an adhesive layer on the liner layer. Next, an accelerator solution was applied thereon and dried at 60° C. for about 30 minutes to form an accelerator layer on the adhesive layer. A support (acrylic resin sheet, thickness 50 μm) was adhered to the surface of the accelerator layer opposite to the surface in contact with the liner layer to obtain a two-layered S / O seal A encapsulating FITC-OVA.

[0225] (Preparation of FITC-OVA encapsulated two-layer S / O seal B) The accelerator solution was applied to a liner layer (liner OPP 40 μm) and dried at 60° C. for about 30 minutes to form an accelerator layer on the liner layer. Next, the adhesive solution was applied thereon and dried at 60° C. for about 30 minutes to form an adhesive layer on the accelerator layer. A support (acrylic resin sheet, thickness 50 μm) was adhered to the surface of the adhesive layer opposite to the surface in contact with the liner layer to obtain a FITC-OVA two-layer type S / O seal B.

[0226] [Test Example 14] (Confirmation test of the permeability of two-layer S / O type patches into pig skin) Using the percutaneous absorption test system shown in Figure 6, a test was conducted to confirm the permeability of the FITC-OVA-encapsulated two-layer S / O seal into pig skin. Specifically, pig skin was placed on the top opening of a water-filled, jacketed, static Franz diffusion cell (manufactured by Cosmedy) for membrane permeation tests, and a FITC-OVA two-layer S / O seal was placed on top of the pig skin so that the layer on the side where the liner layer was attached was attached to the pig skin, and the test was left to stand at room temperature for about 24 hours. The pig skin surface was washed several times with ethanol and PBS, then shredded and immersed in 500 μL of extraction solution (PBS:acetonitrile:methanol=2:1:1 by volume). After shaking for 24 hours, the FITC-OVA concentration in the extraction solution filtered through a 0.2 μm filter was quantified using a fluorometer (LS-55, manufactured by PerkinElmer), and the amount of penetration into the pig skin was calculated from the results. As controls, a permeability confirmation test was performed using an S / O seal containing FITC-OVA and an MGO seal containing FITC-OVA, the MGO content of which was 10% by mass relative to isopropyl myristate.

[0227] (result) As shown in Figure 28, it was confirmed that FITC-OVA encapsulated two-layered S / O seal A, which has an adhesive layer on the skin side, had a greater amount of permeation into pig skin than FITC-OVA encapsulated S / O seal B, which has an accelerator layer on the skin side, whereas a decreased amount of permeation was observed in FITC-OVA encapsulated two-layered S / O seal B, which has an accelerator layer on the skin side.

[0228] [Test Example 15] (Animal immunity test using two-layer S / O type patch) Using OVA (unmodified with FITC) instead of FITC-OVA in the FITC-OVA-encapsulated two-layered S / O seal A of Example 13, an animal immunization test was performed on the OVA-encapsulated two-layered S / O seal A obtained in the same manner as the FITC-OVA-encapsulated two-layered S / O seal A according to the schedule shown in FIG. 29(A). Specifically, first, the backs of the mice were shaved with clippers three days before the immunization test. Then, blood was collected from the tail vein the day before the immunization test. Then, the two-layered S / O seal A containing OVA was attached to the shaved back the next day. The two-layered S / O seal A containing OVA was fixed with kinesiology tape (manufactured by Nichiban Co., Ltd.). After the start of the immunization test, the two-layered S / O seal A containing OVA was replaced with a new one on the 7th and 14th days, and the drug was administered three times in total. Blood was collected from the tail vein of the mice on the 21st and 35th days after the start of the immunization test.

[0229] In control group 1, an S / O type preparation containing OVA (S / O solution) was administered transdermally. In control group 2, an S / O type preparation containing OVA containing 10% by mass of MGO relative to isopropyl myristate (MGO-containing S / O solution) was administered transdermally. In control group 3, an MGO seal containing FITC-OVA was administered transdermally. In control group 4, a PBS solution containing OVA was injected subcutaneously. In all control groups, the OVA content was 30 μg, the same amount as in the two-layer type S / O seal A containing OVA, and administration was performed three times in total according to the same schedule. The amount of anti-OVA antibodies in the blood was examined by ELISA as in Test Example 3.

[0230] (result) As shown in FIG. 29(B), the OVA-specific IgG antibody titer after 35 days was highest in the OVA-encapsulated two-layer S / O seal A, exceeding that in the group that received a subcutaneous injection of a PBS solution containing OVA.

[0231] The above-described embodiment is for explaining the present invention, and does not limit the scope of the present invention. That is, the scope of the present invention is indicated by the claims, not by the embodiment. Various modifications made within the scope of the claims and within the scope of the meaning of the invention equivalent thereto are considered to be within the scope of the present invention.

[0232] This application is based on Japanese Patent Application No. 2019-189199 filed on October 16, 2019, Japanese Patent Application No. 2020-056321 filed on March 26, 2020, and Japanese Patent Application No. 2020-140563 filed on August 24, 2020. The entire specifications, claims, and drawings of Japanese Patent Application No. 2019-189199, Japanese Patent Application No. 2020-056321, and Japanese Patent Application No. 2020-140563 are incorporated herein by reference. [Industrial Applicability]

[0233] According to the transdermal patch of this embodiment, a protein having a molecular weight of more than 1000 can be absorbed into the body by permeating the skin. [Explanation of symbols]

[0234] 1...support, 2...adhesive layer, 2a, 5...complex, 3...liner layer, 4...accelerator layer, 5a...leuprorelin, 5b...surfactant, 6...oil phase, 10, 20, 30, 40...transdermal patch, 50...transdermal agent

Claims

1. A support; A pressure-sensitive adhesive layer laminated on the support; Equipped with the pressure-sensitive adhesive layer comprises a solid complex in which an active ingredient having a molecular weight of 800 or more is coated with a surfactant, an oil phase, and a pressure-sensitive adhesive comprising an acrylic elastomer; The acrylic elastomer is The ester moiety of the alkyl group has 6 to 14 carbon atoms. The content of the acrylic elastomer is 30 to 70% by mass based on the total mass of the acrylic elastomer and the oil phase, The complex forms solid-in-oil type particles dispersed in the oil phase. Transdermal patch.

2. The content of the acrylic elastomer is 40 to 50% by mass based on the total mass of the acrylic elastomer and the oil phase. The transdermal patch according to claim 1.

3. The support contains an acrylic resin. The transdermal patch according to claim 1 or 2.

4. Further comprising a liner layer covering the pressure-sensitive adhesive layer on the pressure-sensitive adhesive layer. The transdermal patch according to any one of claims 1 to 3.

5. The active ingredient is a protein having a molecular weight of more than 10,000. The transdermal patch according to any one of claims 1 to 4.

6. The active ingredient is a protein having a molecular weight of 30,000 or more. The transdermal patch according to any one of claims 1 to 5.

7. The active ingredient is a physiologically active peptide, an antibody, or an antigen. The transdermal patch according to any one of claims 1 to 6.

8. A promoter layer containing a percutaneous absorption promoter is further provided between the support and the pressure-sensitive adhesive layer, The active ingredient is an antigen. The transdermal patch according to any one of claims 1 to 7.

9. The active ingredient is an antigen, Used as a vaccine The transdermal patch according to any one of claims 1 to 8.

10. The active ingredient is leuprorelin, octreotide or a salt thereof. The transdermal patch according to any one of claims 1 to 4.

11. A support, A pressure-sensitive adhesive layer laminated on the support; an enhancer layer between the support and the pressure-sensitive adhesive layer, the enhancer layer containing a percutaneous absorption enhancer; Equipped with the pressure-sensitive adhesive layer comprises a solid complex in which an antigen having a molecular weight of 800 or more is coated with a surfactant, an oil phase, and a pressure-sensitive adhesive comprising an acrylic elastomer; The content of the acrylic elastomer is 30 to 70% by mass based on the total mass of the acrylic elastomer and the oil phase, The complex forms solid-in-oil type particles dispersed in the oil phase. Transdermal patch.

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