Blonanserin-containing patch and method for producing same

Abstract

To provide a blonanserin-containing patch having high skin permeability and a method for producing the same.SOLUTION: A patch comprising a support and an adhesive layer on the support, wherein the adhesive layer contains blonanserin or a salt thereof, a thermoplastic elastomer, a nonvolatile hydrocarbon oil, and an aliphatic dicarboxylic acid ester, and does not contain lactic acid.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to a patch containing blonanserin and a method for producing the same, and more particularly to a patch containing blonanserin with high skin permeability and a method for producing the same. [Background technology]

[0002] In the treatment of schizophrenia, relapse and recurrence due to poor adherence to oral schizophrenia medications have become a problem. LONASEN® Tape, which was launched in September 2019, is a patch containing the schizophrenia medication blonanserin as its active ingredient. Unlike conventional oral medications, the administration status can be visually confirmed, making it easy for caregivers and nurses to manage medication administration, and is therefore expected to improve medication adherence.

[0003] Lonasen (registered trademark) tape uses the formulation technology described in Patent Documents 1 and 2. Patent Document 1 describes a patch that uses an acrylic adhesive as the adhesive base, and discloses a technology in which the addition of lactic acid as a permeation enhancer dramatically improves the amount of blonanserin permeated in a rat skin permeation test. Furthermore, Patent Document 2 discloses a technology that, by making the addition of lactic acid essential, can achieve an unprecedentedly high permeation rate of blonanserin for all adhesive bases, including silicone-based adhesives, rubber-based (styrene-isoprene-styrene block copolymer) adhesives, and acrylic-based adhesives.

[0004] However, the drug availability of Lonasen® Tape is low (Non-Patent Document 1), and the size of the formulation needed to be large in order to allow a sufficient amount of drug to be absorbed through the skin and achieve the blood drug concentration required for treatment. Considering that the application site of Lonasen® Tape must be changed every day, the large size of the formulation is extremely inconvenient for patients, and it can be said that the formulation is extremely difficult to use.

[0005] Therefore, no blonanserin-containing patch with high skin permeability and a method for producing the same are known, and there is a strong demand for providing them. [Prior art documents] [Patent documents]

[0006] [Patent Document 1] Patent No. 5001271 [Patent Document 2] Patent No. 5837518 [Non-patent literature]

[0007] [Non-Patent Document 1] Pharmaceutical Interview Form LONASEN (registered trademark) Tape (1st edition, created in June 2019) Summary of the Invention [Problem to be solved by the invention]

[0008] The present invention aims to solve the above-mentioned conventional problems and achieve the following object: That is, the present invention aims to provide a blonanserin-containing patch with high skin permeability, and a method for producing the same. [Means for solving the problem]

[0009] As a result of extensive research by the present inventors to achieve the above-mentioned object, they have found that a blonanserin-containing patch with high skin permeability can be provided by a patch having a support and an adhesive layer on the support, wherein the adhesive layer contains blonanserin or a salt thereof, a thermoplastic elastomer, and a non-volatile hydrocarbon oil, and wherein the amount of lactic acid in the adhesive layer is 1.5 molar equivalents or less relative to the blonanserin contained in the adhesive layer.

[0010] The present invention is based on the above findings by the present inventors, and the means for solving the above problems are as follows: <1> The patch comprises a support and an adhesive layer on the support, wherein the adhesive layer contains blonanserin or a salt thereof, a thermoplastic elastomer, lactic acid, and a non-volatile hydrocarbon oil, and the amount of lactic acid in the adhesive layer is more than 0 molar equivalents and not more than 1.5 molar equivalents relative to the blonanserin contained in the adhesive layer. <2> The patch comprises a support and an adhesive layer on the support, wherein the adhesive layer contains blonanserin or a salt thereof, a thermoplastic elastomer, and a non-volatile hydrocarbon oil, and is free of lactic acid. <3> The aforementioned <1> or <2> The method for producing the patch according to claim 1, further comprising the step of laminating the support and the adhesive layer. [Effects of the Invention]

[0011] According to the present invention, the above-mentioned conventional problems can be solved, the above-mentioned objects can be achieved, and a blonanserin-containing patch with high skin permeability and a method for producing the same can be provided. DETAILED DESCRIPTION OF THE INVENTION

[0012] (patch) The patch comprises a backing and an adhesive layer on the backing, and may further comprise other elements.

[0013] <Support> The support is not particularly limited and can be appropriately selected depending on the purpose. For example, adhesive sheets for skin application or those generally used for transdermal absorption preparations can be used. The material of the support is not particularly limited and can be appropriately selected depending on the purpose. Examples include polyesters such as polyethylene terephthalate, polyolefins such as polyethylene and polypropylene, polyurethane, ethylene-vinyl acetate copolymer, and polyvinyl chloride. The support may have a single layer structure or a multilayer structure, and may be in the form of a knitted fabric, a woven fabric, a nonwoven fabric, a film, a foam, a porous material, a mesh structure, a sheet, or a flat plate.

[0014] Furthermore, in order to prevent static electricity from accumulating on the support, an antistatic agent may be contained in the woven fabric, nonwoven fabric, film, etc. constituting the support. In order to obtain good anchoring properties with the PSA layer, a nonwoven fabric or woven fabric, or a laminate of these with a film, can be used as the support.

[0015] The thickness of the support is not particularly limited and can be appropriately selected depending on the purpose, but for films, it is preferably 10 μm to 100 μm, more preferably 15 μm to 50 μm, and for porous sheets such as woven fabrics, nonwoven fabrics, and foamable supports, it is preferably 50 μm to 2,000 μm, more preferably 100 μm to 1,000 μm.

[0016] <Adhesive layer> The adhesive layer contains (a) blonanserin or a salt thereof, (b) a thermoplastic elastomer, and (c) a non-volatile hydrocarbon oil, and the amount of lactic acid in the adhesive layer is 1.5 molar equivalents or less relative to the blonanserin contained in the adhesive layer, and may further contain other components.

[0017] (a) Blonanserin or a salt thereof The aforementioned "blonanserin" is a compound whose chemical name is 2-(4-ethyl-1-piperanidyl)-4-(4-fluorophenyl)-5,6,7,8,9,10-hexahydroxychloroocta[b]pyridine, and is classified as an SDA (serotonin-dopamine antagonist) and is commercially available as an antipsychotic (atypical antipsychotic). The blonanserin contained in the adhesive layer may be in the free form or a pharmaceutically acceptable salt thereof, and is not particularly limited.

[0018] The pharmaceutically acceptable salt is not particularly limited and can be appropriately selected depending on the purpose. Examples thereof include pharmaceutically acceptable acid addition salts, which may be inorganic salts or organic salts. The pharmaceutically acceptable salts may be used alone or in combination of two or more thereof. Furthermore, a mixture of the free form and a salt may be used.

[0019] The inorganic salt is not particularly limited and can be appropriately selected depending on the purpose. Examples thereof include hydrochlorides, hydrobromides, nitrates, sulfates, and phosphates. Examples of the organic acid salts include formates, acetates, trifluoroacetates, propionates, lactates, tartrates, oxalates, fumarates, maleates, citrates, malonates, methanesulfonates, etc. From the viewpoint of availability, the free form or hydrochlorides is preferred, and from the viewpoint of skin permeability, it is more preferred to use the free form.

[0020] The content of blonanserin or a salt thereof in the adhesive layer, i.e., the proportion of blonanserin or a salt thereof in a total of 100% by mass of the components of the adhesive layer, is not particularly limited and can be selected appropriately depending on the purpose, but from the viewpoint of ensuring dispersibility in the adhesive layer and good skin permeability, the lower limit is preferably 0.5% by mass or more, more preferably 0.75% by mass or more, even more preferably 1% by mass or more, and particularly preferably 1.5% by mass or more, and the upper limit is preferably 30% by mass or less, more preferably 25% by mass or less, even more preferably 20% by mass or less, and particularly preferably 15% by mass or more.

[0021] (b) Thermoplastic elastomer The "thermoplastic elastomer" according to the present invention is an elastomer that exhibits thermoplasticity, softening and exhibiting fluidity when heated, and returning to a rubber-like elastic body when cooled. The thermoplastic elastomer is not particularly limited and can be appropriately selected depending on the purpose, and examples thereof include various thermoplastic elastomers such as urethane-based, acrylic-based, styrene-based, olefin-based, etc. In particular, from the viewpoint of achieving both sufficient skin adhesion and low skin irritation, styrene-based thermoplastic elastomers, particularly styrene-based block copolymers, are preferred.

[0022] The styrene-based block copolymer is not particularly limited and can be appropriately selected depending on the purpose. Examples include styrene-butadiene block copolymer, styrene-butadiene-styrene block copolymer, styrene-isoprene block copolymer, styrene-isoprene-styrene block copolymer, 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. The term "ethylene / butylene" refers to a copolymer block of ethylene and butylene, and the term "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.

[0023] Of the styrene-based block copolymers, one or more selected from the group consisting of styrene-isoprene-styrene block copolymers and styrene-isoprene block copolymers are preferred, from the viewpoints of availability and ease of handling, as well as the compatibility of sufficient skin adhesion of the pressure-sensitive adhesive layer with reduced adhesive residue due to improved cohesive strength, and a mixture of a styrene-isoprene block copolymer and a styrene-isoprene-styrene block copolymer is particularly preferred.

[0024] The lower limit of the proportion of the styrene-isoprene block copolymer in the mixture is not particularly limited and can be selected appropriately depending on the purpose, but is preferably 10% by mass or more, more preferably 15% by mass or more, even more preferably 20% by mass or more, particularly preferably 40% by mass or more, and most preferably 50% by mass or more. The upper limit of the proportion of the styrene-isoprene block copolymer in the mixture is not particularly limited and can be selected appropriately depending on the purpose, but is preferably 95% by mass or less, more preferably 90% by mass or less, even more preferably 85% by mass or less, and particularly preferably 80% by mass or less.

[0025] The styrene content in the styrene-isoprene-styrene block copolymer is not particularly limited and can be appropriately selected depending on the purpose, but the styrene content in the copolymer is preferably 5% by mass or more and 60% by mass or less, and more preferably 10% by mass or more and 50% by mass or less.

[0026] The molecular weight of the styrene-isoprene-styrene block copolymer is not particularly limited and can be appropriately selected depending on the purpose. However, the weight average molecular weight measured by gel permeation chromatography (GPC) is preferably 20,000 or more and 500,000 or less, and more preferably 30,000 or more and 300,000 or less.

[0027] The styrene content in the styrene-isoprene block copolymer is not particularly limited and can be appropriately selected depending on the purpose. However, the styrene content in the copolymer is preferably 5% by mass or more and 50% by mass or less, and more preferably 10% by mass or more and 40% by mass or less.

[0028] The molecular weight of the styrene-isoprene block copolymer is not particularly limited and can be selected appropriately depending on the purpose, but the weight average molecular weight measured by GPC is preferably 10,000 to 500,000, more preferably 20,000 to 300,000.

[0029] The viscosity of the styrene-based block copolymer is not particularly limited and can be selected appropriately depending on the purpose. However, from the viewpoint of achieving a good balance of adhesive properties, the lower limit of the solution viscosity of a 25% by mass toluene solution at 25°C is preferably 500 mPa·s or more, more preferably 900 mPa·s or more, and the upper limit is preferably 2000 mPa·s or less, more preferably 1800 mPa·s or less. The "solution viscosity of a 25% by mass toluene solution at 25°C" is a value measured based on the viscosity measurement method for styrene-isoprene-styrene block copolymers described on page 395 of "Pharmaceutical Additives Standards 2013" (published by Yakuji Nipposha).

[0030] The styrene-isoprene-styrene block copolymer and the styrene-isoprene block copolymer can each be a copolymer produced by a known method. Alternatively, the styrene-isoprene-styrene block copolymer and the styrene-isoprene block copolymer can each be a commercially available product that satisfies the above-mentioned properties. Mixtures of the styrene-isoprene-styrene block copolymer and the styrene-isoprene block copolymer are also commercially available, and commercially available mixtures of the styrene-isoprene-styrene block copolymer and the styrene-isoprene block copolymer in the above-mentioned mixing ratio that satisfy the above-mentioned properties can be preferably used.

[0031] Commercially available styrene-based block copolymers include, for example, "KRATON (registered trademark) D1111," "KRATON (registered trademark) D1163," "KRATON (registered trademark) D1113," and "KRATON (registered trademark) D1119" manufactured by KRATON POLYMERS; "JSR (registered trademark) SIS5229," "JSR (registered trademark) SIS5002," "JSR (registered trademark) SIS5403," and "JSR (registered trademark) SIS5505" manufactured by JSR Corporation; and "Quintac (registered trademark) 3421," "Quintac (registered trademark) 3433N," "Quintac (registered trademark) 3520," "Quintac (registered trademark) 3450," and "Quintac (registered trademark) 3270" manufactured by Zeon Corporation.

[0032] Among these, in terms of the blending ratio of the styrene-isoprene-styrene block copolymer and the styrene-isoprene block copolymer and the solution viscosity, "KRATON (registered trademark) D1163," "KRATON (registered trademark) D1113," "JSR (registered trademark) SIS5403," "JSR (registered trademark) SIS5505," "Quintac (registered trademark) 3433N," and / or "Quintac (registered trademark) 3520" are preferred, with "JSR (registered trademark) SIS5505" and / or "Quintac (registered trademark) 3520" being particularly preferred.

[0033] The content of the thermoplastic elastomer in the pressure-sensitive adhesive layer, i.e., the proportion of the thermoplastic elastomer in a total of 100% by mass of the constituent components of the pressure-sensitive adhesive layer, is not particularly limited and can be appropriately selected depending on the purpose, but the lower limit is preferably 10% by mass or more, more preferably 15% by mass or more, and even more preferably 20% by mass or more, and the upper limit is preferably 70% by mass or less, more preferably 65% ​​by mass or less, and even more preferably 60% by mass or less. If the proportion is 10% by mass or more, the shape of the pressure-sensitive adhesive layer can be more reliably maintained, and if it is 70% by mass or less, the pressure-sensitive adhesive layer can more reliably exhibit its adhesiveness to the skin.

[0034] (c) non-volatile hydrocarbon oil The non-volatile hydrocarbon oil is not particularly limited and can be appropriately selected depending on the purpose, but is preferably a substance that is liquid at room temperature and consists of a saturated hydrocarbon having about 10 to 200 carbon atoms or an unsaturated hydrocarbon having about 10 to 200 carbon atoms, such as liquid paraffin, squalene, squalane, pristane, etc. Among these, liquid paraffin is more preferred from the viewpoint of ease of availability. Here, room temperature refers to the range of 15° C. to 25° C. as defined in the general rules of the Japanese Pharmacopoeia. The same applies to the following descriptions. The liquid paraffin is a colorless, odorless, liquid mixture of saturated hydrocarbons, and in the present invention, it is preferable to use one that conforms to the standards prescribed in the Japanese Pharmacopoeia, the United States Pharmacopoeia, etc. The non-volatile hydrocarbon oil is preferably one with a high viscosity, and it is particularly preferable to use liquid paraffin with a high viscosity from the viewpoint of adhesion.

[0035] Specifically, the non-volatile hydrocarbon oil has a kinematic viscosity of 60 mm at 40°C. 2 / s or more is preferable, and 70 mm 2 / s or more, more preferably 80 mm 2 The upper limit of the kinematic viscosity is not particularly limited, but from the viewpoint of ease of handling and availability, for example, 500 mm 2 / s or less is preferable, 250 mm 2 / s or less is more preferable. The "kinematic viscosity" referred to here is the value obtained by converting the viscosity (mPa·s) measured in accordance with "Method 2, Rotational Viscometer Method (2.12 Single Cylindrical Rotational Viscometer (Brookfield Viscometer)" in "2.53 Viscosity Measurement Method" of the General Test Methods of the "Japanese Pharmacopoeia, Seventeenth Edition" into kinematic viscosity.

[0036] The content of the non-volatile hydrocarbon oil in the pressure-sensitive adhesive layer is not particularly limited and can be selected appropriately depending on the purpose, but is preferably more than 50 parts by weight and not more than 800 parts by weight per 100 parts by weight of thermoplastic elastomer. If the content of non-volatile hydrocarbon oil per 100 parts by weight of thermoplastic elastomer exceeds 800 parts by weight, it becomes difficult to maintain the shape of the pressure-sensitive adhesive layer. On the other hand, if the content of non-volatile hydrocarbon oil is less than 50 parts by weight, the pressure-sensitive adhesive tends to become too hard and not achieve sufficient skin adhesion, particularly, the pressure-sensitive adhesive may become poorly responsive to skin movement during application, resulting in detachment during application. From this perspective, the lower limit of the content of non-volatile hydrocarbon oil in the pressure-sensitive adhesive layer is preferably 50 parts by weight or more, more preferably 60 parts by weight or more, and particularly preferably 70 parts by weight or more, per 100 parts by weight of thermoplastic elastomer. The upper limit is preferably 800 parts by weight or less, more preferably 600 parts by weight or less, and particularly preferably 500 parts by weight or less. Furthermore, even within this range, if the content of non-volatile hydrocarbon oil is high, the peel stress, which is one of the adhesive properties, tends to decrease, and the adhesive may extrude during storage or application, resulting in problems such as adhesion to packaging materials or clothing. On the other hand, if the content of non-volatile hydrocarbon oil is low, the skin adhesion may decrease, particularly during sweating or bathing, and the patch may fall off. From this perspective, the content of non-volatile hydrocarbon oil in the adhesive layer is preferably 80 to 400 parts by weight, more preferably 90 to 350 parts by weight, and particularly preferably 100 to 300 parts by weight, per 100 parts by weight of thermoplastic elastomer.

[0037] -Amount of lactic acid- The amount of lactic acid in the adhesive layer is not particularly limited as long as it is within a range that does not reduce the skin permeability of the drug, and can be appropriately selected depending on the purpose as long as it is 1.5 molar equivalents or less relative to the blonanserin contained in the adhesive layer; however, 1.4 molar equivalents or less is preferred, 1.25 molar equivalents or less is more preferred, 1 molar equivalents or less is even more preferred, 0.75 molar equivalents or less is particularly preferred, and 0 molar equivalents is most preferred. The amount of lactic acid in the pressure-sensitive adhesive layer is measured according to the method described in JIS K 8726:2014.

[0038] -Other ingredients- The pressure-sensitive adhesive layer may contain, as necessary, other components such as (d) polyisobutylene, (e) aliphatic dicarboxylic acid ester, (f) glycerin monoether, (g) liquid organic acid excluding lactic acid, (h1) fatty acid monoester of polyhydric alcohol, (h2) higher alcohol, (h3) alcohol-based solvent, (h4) amide-based solvent, (h5) ester-based solvent, (h6) carboxylate, (h7) lactone, (h8) surfactant, (h9) filler, (h10) crystal precipitation inhibitor, (i) tackifier, etc.

[0039] (d) Polyisobutylene Polyisobutylene can be added to adjust adhesive properties. The "polyisobutylene" used in the adhesive layer of the present invention is a polymer of isobutylene, and is an elastic, rubbery, semi-solid or viscous substance, which is added in the present invention to impart sufficient skin adhesion.

[0040] The polyisobutylene may be a low-molecular-weight polyisobutylene having a viscosity-average molecular weight of 30,000 to 100,000, a medium-molecular-weight polyisobutylene having a viscosity-average molecular weight of 100,000 to 500,000, or a high-molecular-weight polyisobutylene having a viscosity-average molecular weight of 500,000 to 5,000,000, either alone or in combination. In particular, a mixture of the low-molecular-weight polyisobutylene and the high-molecular-weight polyisobutylene, or the medium-molecular-weight polyisobutylene alone, is preferred in terms of achieving a balance between low skin irritation and high skin adhesion.

[0041] The polyisobutylene may be an isobutylene polymer produced by a method known per se. In particular, in the adhesive layer of the present invention, which is for application to the skin, it is preferable to use one that complies with the standards prescribed in the Pharmaceutical Excipients Standards and the United States Pharmacopoeia. In addition, commercially available polyisobutylenes that satisfy the above-mentioned viscosity-average molecular weights may be used.

[0042] Examples of commercially available low molecular weight polyisobutylenes include "Oppanol (registered trademark) B10SFN," "Oppanol (registered trademark) B10N," "Oppanol (registered trademark) B12SFN," "Oppanol (registered trademark) B15SFN," and "Oppanol (registered trademark) B15N," all manufactured by BASF. Examples of medium molecular weight polyisobutylenes include "Oppanol (registered trademark) N50SF" and "Oppanol (registered trademark) N50," all manufactured by BASF. Examples of high molecular weight polyisobutylenes include "Oppanol (registered trademark) N80," "Oppanol (registered trademark) N100," and "Oppanol (registered trademark) N150," all manufactured by BASF.

[0043] Among these, from the viewpoint of solubility when prepared as a coating liquid and the balance of adhesive properties of the obtained patch, "Oppanol (registered trademark) B15SFN" and "Oppanol (registered trademark) B15N" having a viscosity average molecular weight of 50,000 to 100,000 are particularly preferred as the low molecular weight polyisobutylene, "Oppanol (registered trademark) N50SF" and "Oppanol (registered trademark) N50" as the medium molecular weight polyisobutylene, and "Oppanol (registered trademark) N80" as the high molecular weight polyisobutylene.

[0044] The content of polyisobutylene in the pressure-sensitive adhesive layer is not particularly limited and can be appropriately selected depending on the purpose, but if the content of polyisobutylene in the pressure-sensitive adhesive layer is too low, the skin adhesion will not be sufficiently enhanced, and if the content is too high, excessive skin adhesion may result in problems such as increased skin irritation, adhesive residue upon peeling, poor drug solubility, etc. Therefore, the lower limit of the content of polyisobutylene in the pressure-sensitive adhesive layer is 0.1 parts by weight or more, preferably 0.3 parts by weight or more, more preferably 0.5 parts by weight or more, and even more preferably 1 part by weight or more, per 100 parts by weight of the thermoplastic elastomer, and the upper limit of the content of polyisobutylene in the pressure-sensitive adhesive layer is 300 parts by weight or less, preferably 200 parts by weight or less, more preferably 150 parts by weight or less, and even more preferably 100 parts by weight or less, per 100 parts by weight of the thermoplastic elastomer.

[0045] In a more specific preferred embodiment, the polyisobutylene content in the pressure-sensitive adhesive layer is 0.1% by mass to 50% by mass, more preferably 0.2% by mass to 40% by mass, even more preferably 0.3% by mass to 30% by mass, and particularly preferably 0.5% by mass to 25% by mass.

[0046] (e) Aliphatic dicarboxylic acid ester The aliphatic dicarboxylic acid ester is not particularly limited and can be appropriately selected depending on the purpose, and examples thereof include diesters of dicarboxylic acids having from 2 to 12 carbon atoms and monohydric aliphatic alcohols having from 1 to 20 carbon atoms that are liquid at room temperature, such as adipic acid diesters that are liquid at room temperature, such as diethyl adipate, diisopropyl adipate, and diisobutyl adipate, and sebacate diesters that are liquid at room temperature, such as diethyl sebacate, diisopropyl sebacate, and dioctyldodecyl sebacate. Of these, diisopropyl adipate and diisobutyl adipate are preferred from the viewpoint of improving the solubility and absorption-promoting effect of the drug.

[0047] The lower limit of the content of the aliphatic dicarboxylic acid ester relative to the total 100% by mass of the components of the pressure-sensitive adhesive layer is not particularly limited and can be selected appropriately depending on the purpose, but is preferably 0.2% by mass or more, more preferably 0.5% by mass or more, even more preferably 0.7% by mass or more, and particularly preferably 1% by mass or more. The upper limit of the content of the aliphatic dicarboxylic acid ester relative to the total of 100% by mass of the components of the pressure-sensitive adhesive layer is not particularly limited and can be selected appropriately depending on the purpose, but is preferably 20% by mass or less, more preferably 10% by mass or less, even more preferably 5% by mass or less, and particularly preferably 3% by mass or less.

[0048] (f) Glycerin monoether The glycerin monoether is not particularly limited and can be appropriately selected depending on the purpose. Examples thereof include α-monoisostearyl glyceryl ether.

[0049] The lower limit of the content of the glycerin monoether relative to the total 100% by mass of the components of the pressure-sensitive adhesive layer is not particularly limited and can be selected appropriately depending on the purpose, but is preferably 0.01% by mass or more, more preferably 0.03% by mass or more, even more preferably 0.05% by mass or more, and particularly preferably 0.07% by mass or more. The upper limit of the content of the glycerin monoether relative to the total 100% by mass of the components of the adhesive layer is not particularly limited and can be selected appropriately depending on the purpose, but is preferably 10% by mass or less, more preferably 5% by mass or less, even more preferably 1.5% by mass or less, and particularly preferably 1.0% by mass or less.

[0050] (g) Liquid organic acids, excluding lactic acid The liquid organic acid excluding lactic acid is not particularly limited as long as it is an organic acid that is liquid at room temperature, and can be appropriately selected depending on the purpose. Examples include aliphatic monocarboxylic acids such as acetic acid, propionic acid, butyric acid, valeric acid, isovaleric acid, caproic acid, isostearic acid, enanthic acid (heptanoic acid), caprylic acid, and pelargonic acid (nonanoic acid); aliphatic unsaturated monocarboxylic acids such as oleic acid, linoleic acid, arachidonic acid, and docosahexaenoic acid; liquid carboxylic acids substituted with an alkoxy group such as methoxyacetic acid; carboxylic acids having a carbonyl group such as levulinic acid; and sulfonic acids such as methanesulfonic acid. These liquid organic acids have the function of assisting the dissolution of a basic drug, allowing the basic drug to be contained at a high concentration in the adhesive layer, and also improving dispersibility, and further having the effect of improving transdermal absorbability. From these viewpoints, of these liquid organic acids, oleic acid, isostearic acid, and levulinic acid are preferred.

[0051] In the present invention, one or more liquid organic acids other than lactic acid may be selected and added as needed. Preferred combinations of the organic acids include levulinic acid and isostearic acid, levulinic acid and oleic acid, and isostearic acid and oleic acid. The content of the liquid organic acid excluding lactic acid is not particularly limited and can be selected appropriately depending on the purpose, but is preferably 0.1% by mass or more and 20% by weight or less, more preferably 0.3% by mass or more and 15% by weight or less, even more preferably 0.5% by mass or more and 10% by weight or less, and particularly preferably 1% by mass or more and 5% by weight or less, relative to the total amount of the adhesive layer. Furthermore, the amount is preferably more than 0 molar equivalents and not more than 10 molar equivalents, more preferably not less than 0.3 molar equivalents and not more than 5 molar equivalents, and even more preferably not less than 0.5 molar equivalents and not more than 3 molar equivalents, relative to the blonanserin contained in the adhesive layer.

[0052] (h1) Fatty acid monoester of polyhydric alcohol In the present invention, "fatty acid monoester of polyhydric alcohol" refers to a compound in which one hydroxyl group of a polyhydric alcohol such as ethylene glycol, propylene glycol, glycerin, etc. is ester-bonded to a fatty acid. Fatty acid monoester of polyhydric alcohol contributes to improving drug solubility and has an absorption-promoting effect without significantly reducing the cohesive strength of the adhesive base.

[0053] The polyhydric alcohol constituting the fatty acid monoester of polyhydric alcohol is not particularly limited and can be appropriately selected depending on the purpose. Examples thereof include ethylene glycol, propylene glycol, butylene glycol, and glycerin. The fatty acid constituting the fatty acid monoester of the polyhydric alcohol is not particularly limited and can be appropriately selected depending on the purpose, but fatty acids having 8 to 18 carbon atoms are preferred, such as capric acid, caprylic acid, myristic acid, palmitic acid, stearic acid, isostearic acid, oleic acid, and linoleic acid.

[0054] Specific preferred examples of the polyhydric alcohol fatty acid monoester include propylene glycol monocaprylate and propylene glycol monolaurate. In order to enhance the drug solubility and absorption-promoting effect, the content of the polyhydric alcohol fatty acid monoester is preferably 1% by mass or more, more preferably 2% by mass or more, and particularly preferably 5% by mass or more, based on the total amount of the adhesive components. On the other hand, since adding a large amount of the polyhydric alcohol fatty acid monoester reduces the cohesive strength and adhesive strength of the adhesive, the content of the polyhydric alcohol fatty acid monoester is preferably 30% by mass or less, more preferably 20% by mass or less, and particularly preferably 10% by mass or less, based on the total amount of the adhesive components.

[0055] (h2) Higher alcohol The higher alcohol is not particularly limited and can be appropriately selected depending on the purpose. Examples include higher saturated aliphatic alcohols having from about 12 to about 20 carbon atoms that are liquid at room temperature, such as lauryl alcohol and isostearyl alcohol; and higher unsaturated aliphatic alcohols having from about 12 to about 20 carbon atoms that are liquid at room temperature, such as oleyl alcohol. Among these, lauryl alcohol and oleyl alcohol are preferred from the viewpoint of enhancing the solubility and absorption-promoting effect of the drug.

[0056] (h3) Alcohol-based solvents The alcohol-based solvent is not particularly limited and can be appropriately selected depending on the purpose. Examples thereof include polyhydric alcohols that are liquid at room temperature, such as ethylene glycol, propylene glycol, glycerin, 1,3-butanediol, and polyethylene glycols having a molecular weight of approximately 100 to 600; monoalkyl ethers of polyhydric alcohols, such as diethylene glycol monoethyl ether; and mono-fatty acid esters of polyhydric alcohols, such as glycerol monolinoleate and glycerol monooleate. Among these, ethylene glycol, propylene glycol, glycerin, 1,3-butanediol, and diethylene glycol monoethyl ether are preferred from the viewpoint of improving the solubility of the drug.

[0057] (h4) Amide solvents The amide solvent is not particularly limited and can be appropriately selected depending on the purpose. Examples thereof include pyrrolidones such as N-methyl-2-pyrrolidone and 2-pyrrolidone; imidazolidinones such as 1,3-dimethyl-2-imidazolidinone; N-substituted toluidines such as crotamiton; and alkanamides such as formamide, N-methylformamide, N,N-dimethylformamide, N-methylacetamide, N,N-dimethylacetamide, and N-methylpropanamide. Among the amide solvents, from the viewpoint of improving the solubility, dispersibility and transdermal absorbability of the drug, N-methyl-2-pyrrolidone, crotamiton, N,N-dimethylformamide and N,N-dimethylacetamide are preferred, and N-methyl-2-pyrrolidone and crotamiton are more preferred.

[0058] (h5) Ester-based solvents The ester-based solvent is not particularly limited and can be appropriately selected depending on the purpose. Examples thereof include diesters of dihydric alcohols and carboxylic acids, medium-chain fatty acid triglycerides, esters of polycarboxylic acids and monohydric aliphatic alcohols, and carbonate esters.

[0059] The diester of a dihydric alcohol and a carboxylic acid is not particularly limited and can be appropriately selected depending on the purpose. Examples thereof include diesters composed of propylene glycol and caprylic acid, capric acid, lauric acid, oleic acid, etc.

[0060] The medium-chain fatty acid triglyceride is a triglyceride composed of glycerin and a fatty acid having approximately 6 to 12 carbon atoms, such as caproic acid, caprylic acid, capric acid, or lauric acid. In the present invention, caprylic acid triglyceride, a mixture of triglycerides of caprylic acid and capric acid, or a mixture of triglycerides of caprylic acid, capric acid, and lauric acid, which are liquid at room temperature, can be used. Oils and fats that contain a large amount of these and are liquid at room temperature can also be used. Examples of such oils and fats include olive oil, almond oil, safflower oil, soybean oil, corn oil, sesame oil, coconut oil, orange oil, ginger oil, spruce oil, rapeseed oil, castor oil, sunflower oil, cottonseed oil, and peanut oil. In the present invention, commercially available products for pharmaceutical use can also be used as medium-chain fatty acid triglycerides that are liquid at room temperature or medium-chain fatty acid triglyceride-containing oils and fats that are liquid at room temperature.

[0061] The carbonate ester is not particularly limited and can be appropriately selected depending on the purpose. Examples of the carbonate ester include cyclic carbonate esters of carbonic acid and diols having from 2 to 10 carbon atoms, such as ethylene carbonate, propylene carbonate, and vinylene carbonate, with propylene carbonate being preferred.

[0062] Among the above ester solvents, a medium-chain fatty acid triglyceride mixture and a carbonate ester are preferred, and a triglyceride mixture of caprylic acid and capric acid and propylene carbonate are more preferred.

[0063] In the present invention, one or more of the alcohol-based solvents, the amide-based solvents, and the ester-based solvents can be selected and used as needed. The content of these solvents is not particularly limited and can be selected appropriately depending on the purpose, but is preferably 0.1% by mass or more and 20% by mass or less, and more preferably 0.5% by mass or more and 15% by mass or less, relative to the total amount of the adhesive layer.

[0064] (h6) Carboxylate The carboxylate is not particularly limited and can be appropriately selected depending on the purpose. Examples thereof include salts of aliphatic monocarboxylic acids, alicyclic monocarboxylic acids, and aliphatic dicarboxylic acids. The aliphatic monocarboxylic acid is not particularly limited and can be appropriately selected depending on the purpose. Examples thereof include short-chain fatty acids having from 2 to 7 carbon atoms, such as acetic acid, butyric acid, and hexanoic acid; medium-chain fatty acids having from 8 to 11 carbon atoms, such as octanoic acid and decanoic acid; long-chain fatty acids having 12 or more carbon atoms, such as lauric acid, myristic acid, stearic acid, isostearic acid, and oleic acid; hydroxymonocarboxylic acids, such as glycolic acid, lactic acid, 3-hydroxybutyric acid, and mandelic acid; monocarboxylic acids substituted with an alkoxy group, such as methoxyacetic acid; and ketomonocarboxylic acids, such as levulinic acid. The alicyclic monocarboxylic acid is not particularly limited and can be appropriately selected depending on the purpose. Examples thereof include alicyclic monocarboxylic acids having 6 to 8 carbon atoms, such as cyclohexanecarboxylic acid. The aliphatic dicarboxylic acid is not particularly limited and can be appropriately selected depending on the purpose. Examples thereof include sebacic acid, adipic acid, malic acid, maleic acid, and fumaric acid.

[0065] Preferred carboxylic acids include long-chain fatty acids having 12 or more carbon atoms and hydroxymonocarboxylic acids, such as myristic acid, stearic acid, isostearic acid, lauric acid, oleic acid, etc. Lauric acid and oleic acid are more preferred. The salt of the carboxylic acid is not particularly limited and can be appropriately selected depending on the purpose. Examples thereof include alkali metal salts such as sodium salts and potassium salts, alkaline earth metal salts such as calcium salts, and amine salts. From the viewpoints of availability and the effect of improving transdermal absorbability, sodium salts are preferred.

[0066] (h7) Lactone The lactone is not particularly limited and can be appropriately selected depending on the purpose. Examples thereof include five-membered ring lactones such as ascorbic acid and isoascorbic acid. In the patch of the present invention, in consideration of the effect of improving the stability or transdermal absorbability of the drug, the carboxylate or lactone is preferably sodium oleate, sodium lactate, ascorbic acid, or isoascorbic acid.

[0067] When a carboxylate or lactone is contained in the patch of the present invention, the content in the adhesive layer is not particularly limited and can be selected appropriately depending on the purpose, but is preferably 0.1 to 5 mol, more preferably 0.2 to 3 mol, per mol of drug. If the amount added is less than 0.1 mol per mol of drug, a sufficient effect of improving transdermal absorbability may not be obtained, and if the amount added is more than 5 mol per mol of drug, the physical properties of the preparation, such as adhesive properties, may deteriorate.

[0068] (h8) Surfactants The surfactant is not particularly limited and can be appropriately selected depending on the purpose. Examples of the surfactant include polyoxyethylene fatty acid esters such as polyoxyethylene monolaurate, polyoxyethylene sorbit fatty acid esters such as polyoxyethylene sorbit tetraoleate, polyoxyethylene sorbitan fatty acid esters such as polyoxyethylene sorbitan monooleate, polyoxyethylene sorbitan monolaurate, and polyoxyethylene sorbitan monopalmitate, sorbitan fatty acid esters such as sorbitan monolaurate, sorbitan monooleate, sorbitan sesquioleate, and sorbitan trioleate, glycerin fatty acid esters such as glycerin monooleate, polyoxyethylene castor oil derivatives, and polyoxyethylene hydrogenated castor oil, polyoxyethylene lauryl ether, and polyoxyethylene Examples of surfactants that can be used include polyoxyethylene higher aliphatic alcohol ethers such as polyoxyethylene oleyl ether, polyoxyethylene alkylphenyl ethers such as polyoxyethylene nonylphenyl ether, polyoxyethylene alkylamino ethers such as polyoxyethylene laurylamine and polyoxyethylene oleylamine, nonionic surfactants such as polyoxyethylene polyoxypropylene copolymers such as Pluronic (registered trademark) L-31 and Pluronic (registered trademark) L-44, anionic surfactants such as sodium alkyl sulfates such as sodium lauryl sulfate, cationic surfactants such as alkyltrimethylammonium salts and alkyldimethylammonium salts, and amphoteric surfactants such as alkyldimethylamine oxide and alkylcarboxybetaine, and one or more of these can be selected and used.

[0069] Among the surfactants, nonionic surfactants that are liquid at room temperature are preferred in order to enhance transdermal absorbability, polyoxyethylene higher aliphatic alcohol ethers and sorbitan fatty acid esters that are liquid at room temperature are more preferred, and polyoxyethylene lauryl ether and sorbitan monolaurate are particularly preferred. In the patch of the present invention, when a surfactant is contained, the content in the adhesive layer is not particularly limited and can be selected appropriately depending on the purpose, but is preferably 0.01% by mass or more and 10% by mass or less, more preferably 0.1% by mass or more and 5% by mass or less.

[0070] (h9) Filler A filler may be contained in order to control the flexibility of the pressure-sensitive adhesive layer. The filler is not particularly limited and can be appropriately selected depending on the purpose, and examples thereof include silicon compounds such as silicic acid anhydride, light silicic acid anhydride, and hydrous silicic acid, cellulose derivatives such as ethyl cellulose, methyl cellulose, hydroxypropyl cellulose, and hydroxypropylmethyl cellulose, water-soluble polymers such as polyvinyl alcohol, aluminum compounds such as dried aluminum hydroxide gel and hydrous aluminum silicate, kaolin, titanium oxide, etc. The fillers may be used alone or in combination of two or more. The content of the filler is not particularly limited and can be appropriately selected depending on the purpose, and can be contained within a range that maintains high skin permeability and sufficient cohesive strength and adhesive strength as a patch. Among these, it is preferably 10% by mass or less, more preferably 5% by mass or less, and most preferably 2% by mass or less, based on the total amount of the adhesive component.

[0071] (h10) Crystallization inhibitor A crystal precipitation inhibitor may be contained in the adhesive layer to inhibit crystal precipitation of the drug. The crystal precipitation inhibitor is not particularly limited and can be appropriately selected depending on the purpose, and examples thereof include polyvinylpyrrolidone, vinyl acetate-vinylpyrrolidone copolymer, polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, aminoalkyl methacrylate copolymer, methacrylic acid copolymer, ammonioalkyl methacrylate copolymer, etc. The crystal precipitation inhibitor may be used alone or in combination of two or more.

[0072] The content of the crystal precipitation inhibitor is not particularly limited and can be appropriately selected depending on the purpose, and can be contained within a range that maintains the adhesive strength of the patch, preferably from 0.01% by mass to 10% by mass, more preferably from 0.1% by mass to 5% by mass, based on the total amount of the adhesive components.

[0073] (i) Tackifier The patch may contain a tackifier from the viewpoint of increasing the adhesive strength of the adhesive layer. In the present invention, the "tackifier" refers to a tackifier that is generally used in the field of patches, and is not particularly limited and can be appropriately selected depending on the purpose. Examples include rosin-based resins, polyterpene-based resins, coumarone-indene resins, petroleum-based resins, terpene resins, terpene-phenol resins, and alicyclic saturated hydrocarbon resins.

[0074] In order to achieve the adhesive strength required to obtain sufficient medicinal efficacy, the tackifier may be added, but adding a large amount of tackifier may reduce drug release or increase skin irritation, so the content of tackifier is preferably 50% by mass or less of the total amount of adhesive components, more preferably 30% by mass or less, even more preferably 20% by mass or less, still more preferably 10% by mass or less, particularly preferably 5% by mass or less, and most preferably no tackifier is included.

[0075] <Other elements> The patch may also be provided with a release liner that is common in the art. That is, the patch of the present invention may be one in which a backing, an adhesive layer, and a release liner are laminated in this order. The release liner is not particularly limited and can be appropriately selected depending on the purpose, and examples that can be used include glassine paper, polyolefins such as polyethylene and polypropylene, polyesters such as polyethylene terephthalate, and resin films such as polystyrene; aluminum films; foamed polyethylene films or foamed polypropylene films; laminates of two or more of the above; and the release liner can also be silicone-treated, fluororesin-treated, embossed, hydrophilically treated, hydrophobically treated, or the like.

[0076] The thickness of the release liner is not particularly limited and can be appropriately selected depending on the purpose, but is preferably 10 μm or more and 200 μm or less, and more preferably 15 μm or more and 150 μm or less.

[0077] (Method of manufacturing patch) The method for producing the patch includes a step of laminating the support and the pressure-sensitive adhesive layer, and may further include other steps. The pressure-sensitive adhesive layer and the support are as described above.

[0078] <Laminating process of support and adhesive layer> The step of laminating the support and the pressure-sensitive adhesive layer is not particularly limited and can be appropriately selected depending on the purpose. For example, a method of laminating the support and the pressure-sensitive adhesive layer by pressure bonding can be mentioned.

[0079] <Other processes> The other steps are not particularly limited and can be appropriately selected depending on the purpose, and examples thereof include a step of laminating a release liner. The release liner is as described above.

[0080] -Lamination process of release liner- The step of laminating the release liner is not particularly limited and can be appropriately selected depending on the purpose. Examples include a step of spreading the coating liquid for forming the pressure-sensitive adhesive layer onto a release liner before the step of laminating the support and the pressure-sensitive adhesive layer, drying the solvent in the coating liquid, and laminating the pressure-sensitive adhesive layer on the surface of the release liner (spreading and drying step), and a step of pressing the release liner onto the pressure-sensitive adhesive layer after the step of laminating the support and the pressure-sensitive adhesive layer.

[0081] --Spreading and drying process-- The spreading and drying step is not particularly limited and can be appropriately selected depending on the purpose. For example, there can be mentioned a method in which (a) blonanserin or a salt thereof, (b) a thermoplastic elastomer, and (c) a non-volatile hydrocarbon oil are each dissolved or dispersed in a solvent such as toluene to prepare a coating liquid for forming a pressure-sensitive adhesive layer, and the obtained coating liquid is applied to a release liner and then dried.

[0082] The coating method is not particularly limited and can be appropriately selected depending on the purpose. For example, the coating can be carried out using a conventional coater such as a roll coater, a die coater, a gravure roll coater, a reverse roll coater, a kiss roll coater, a dip roll coater, a bar coater, a knife coater, or a spray coater.

[0083] The solvent used in the coating liquid is not particularly limited and can be appropriately selected depending on the purpose. However, a solvent that can uniformly dissolve or disperse the components (a), (b), and (c) is preferred. Examples of the solvent include aromatic hydrocarbons such as toluene, alicyclic hydrocarbons such as cyclohexane and methylcyclohexane, aliphatic hydrocarbons such as hexane and heptane, ethers such as tetrahydrofuran, diethyl ether, and t-butyl methyl ether, ketones such as acetone, methyl ethyl ketone, and methyl isobutyl ketone, alcohols such as ethanol, propanol, and butanol, and acetates such as ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate, and isobutyl acetate. These solvents can be used alone or in combination of two or more. Because they have good solubility for the components constituting the pressure-sensitive adhesive layer, it is preferable to use aromatic hydrocarbons such as toluene, alicyclic hydrocarbons such as cyclohexane and methylcyclohexane, and aliphatic hydrocarbons such as hexane and heptane alone or in combination, or to use aromatic hydrocarbons such as toluene, and aliphatic hydrocarbons such as hexane and heptane in combination with acetate esters such as ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate, and isobutyl acetate.

[0084] The drying method is not particularly limited and can be appropriately selected depending on the purpose. However, it is preferable to perform the drying under heating, for example, at a temperature of about 40°C or higher and 150°C or lower. The drying temperature, drying time, and drying method may be adjusted depending on the solvent used and its amount. The weight per unit area of ​​the dried adhesive layer may be adjusted depending on the required skin adhesion and transdermal absorption performance. The range within which the adhesive layer can be produced while still obtaining skin adhesion is not particularly limited and can be appropriately selected depending on the purpose. However, the adhesive layer preferably has a weight per unit area of ​​10 g / m after drying. 2 More than 1,000g / m 2 or less, more preferably 20 g / m 2 More than 800g / m 2 or less, more preferably 30 g / m 2 More than 600g / m 2 The following is the result. [Example]

[0085] Examples of the present invention will be described below, but the present invention is not limited to these examples in any way.

[0086] <Example 1: Production of patch> Each component constituting the pressure-sensitive adhesive layer was weighed out according to the formulation shown in Table 1. The numerical values ​​for each component in Table 1 are in mass %. First, the styrene-based block copolymer was dissolved in toluene, and then blonanserin and liquid paraffin were added, followed by mixing and stirring to prepare a coating liquid for forming the pressure-sensitive adhesive layer. The coating liquid was applied to a silicone-treated polyethylene terephthalate (PET) film release liner. After drying for 60 minutes in an oven at 50°C, a PET film (support) was laminated onto the surface of the adhesive layer, and the resulting adhesive layer was cut into a size of 15 cm x 30 cm to obtain a patch.

[0087] [Table 1]

[0088] <Test Example 1: Evaluation of skin permeability> The abdominal skin of shaved male hairless rats (HWY / Slc, SPF, 5 weeks old) was punched out into 2.5 cm diameter circles. The patches prepared in the examples were punched out into 1.3 cm diameter circles and applied to the rat skin. The patches were then placed in a vertical diffusion cell, and the test was initiated using an automatic percutaneous absorption test sampling device (manufactured by Cosmedy). A buffer solution was used as the receptor fluid, and the test was conducted at a liquid temperature of 32°C. A portion of the receptor fluid was sampled 24 hours after the start of the test, and the amount of drug in the receptor fluid that had permeated the rat skin was quantified by HPLC. Lonasen® Tape (a conventional formulation) was used as a control formulation containing blonanserin. Measurements were performed on 3 to 6 samples for each patch, and the average value was calculated. Drug skin permeability was evaluated by the number of times the average value was compared to the Lonasen® Tape value. The results are shown in Table 1.

[0089] <Test Example 2: Evaluation of cohesive strength> The cohesive strength of the adhesive layer of the patch was evaluated using a finger tack test on a four-point scale according to the following criteria. The results are shown in Table 1. 3: No adhesive residue was observed. 2: Almost no adhesive residue was observed, and it was within the range of no problem. 1: The cohesion is slightly insufficient, but within the range of no problems. 0: Adhesive residue, deformation, etc. were observed, and the cohesive strength was significantly insufficient.

[0090] <Test Example 3: Evaluation of Adhesion> The adhesiveness of the adhesive layer of the patch was evaluated on a four-point scale by finger tack (finger touch test) according to the following criteria. The results are shown in Table 1. 3: The adhesiveness was the same as that of Lonasen (registered trademark) tape. 2: Slightly less adhesive than Lonasen® tape. 1: The adhesive was weak and could be easily removed with a finger. 0: No adhesion at all, with noticeable peeling.

[0091] <Example 2: Production of patch> A patch was produced in the same manner as in Example 1, except that the components constituting the adhesive layer were changed to the formulation shown in Table 1. The skin permeability, cohesive strength, and adhesiveness were evaluated in the same manner as in Example 1. The results are shown in Table 1.

[0092] <Example 3: Production of patch> A patch was produced in the same manner as in Example 1, except that the components constituting the adhesive layer were changed to the formulation shown in Table 1. The skin permeability, cohesive strength, and adhesiveness were evaluated in the same manner as in Example 1. The results are shown in Table 1.

[0093] <Example 4: Production of patch> A patch was produced in the same manner as in Example 1, except that the components constituting the adhesive layer were changed to the formulation shown in Table 1. The skin permeability, cohesive strength, and adhesiveness were evaluated in the same manner as in Example 1. The results are shown in Table 1.

[0094] <Example 5: Production of patch> A patch was produced in the same manner as in Example 1, except that the components constituting the adhesive layer were changed to the formulation shown in Table 1. The skin permeability, cohesive strength, and adhesiveness were evaluated in the same manner as in Example 1. The results are shown in Table 1.

[0095] <Example 6: Production of patch> A patch was produced in the same manner as in Example 1, except that the components constituting the adhesive layer were changed to the formulation shown in Table 1. The skin permeability, cohesive strength, and adhesiveness were evaluated in the same manner as in Example 1. The results are shown in Table 1.

[0096] <Example 7: Production of patch> A patch was produced in the same manner as in Comparative Example 2, except that the components constituting the adhesive layer were changed to the formulation shown in Table 1. The skin permeability, cohesive strength, and adhesiveness were evaluated in the same manner as in Example 1. The results are shown in Table 1.

[0097] <Example 8: Production of patch> A patch was produced in the same manner as in Example 1, except that the components constituting the adhesive layer were replaced with those shown in Table 1, and that the styrene block copolymer and polyisobutylene were dissolved in toluene, and then blonanserin, liquid paraffin, and each additive were added. The skin permeability, cohesive strength, and adhesiveness were evaluated in the same manner as in Example 1. The results are shown in Table 1.

[0098] <Comparative Example 1: Production of Patch> A patch was produced in the same manner as in Example 1, except that the components constituting the adhesive layer were changed to those shown in Table 1, and that blonanserin was added after mixing the acrylic adhesive and ethyl acetate. The skin permeability, cohesive strength, and adhesiveness were evaluated in the same manner as in Example 1. The results are shown in Table 1.

[0099] Comparative Example 2: Production of Patches A patch was produced in the same manner as in Example 1, except that the components constituting the adhesive layer were changed to the formulation shown in Table 1. The skin permeability, cohesive strength, and adhesiveness were evaluated in the same manner as in Example 1. The results are shown in Table 1.

[0100] Comparative Example 3: Production of Patches A patch was produced in the same manner as in Example 1, except that the components constituting the adhesive layer were changed to the formulation shown in Table 1. The skin permeability, cohesive strength, and adhesiveness were evaluated in the same manner as in Example 1. The results are shown in Table 1.

[0101] Comparative Example 4: Production of Patches A patch was produced in the same manner as in Example 1, except that the components constituting the adhesive layer were changed to the formulation shown in Table 1 and the adhesive layer was coated so that the thickness after drying would be approximately 60 μm. The skin permeability, cohesive strength, and adhesiveness were evaluated in the same manner as in Example 1. The results are shown in Table 1.

[0102] As shown in the results in Table 1, it was found that Example 1, which used a styrene-isoprene-styrene block copolymer as the adhesive base polymer, exhibited higher permeability than Comparative Example 1, which used an acrylic adhesive base using the formulation technology of Patent Document 1. Furthermore, compared to Comparative Example 4, which used the formulation technology of Patent Document 2, Example 7, which did not contain lactic acid, exhibited higher permeability, and it was observed that adding a large amount of lactic acid tended to decrease skin permeability. The patches of Examples 2 and 8, which contained additives added to Example 1, exhibited skin permeability three times higher than that of the existing preparation. On the other hand, Comparative Examples 2 to 4 contained more than 1.5 molar equivalents of lactic acid added, and therefore exhibited lower skin permeability than the patch of Example 2. Furthermore, there was a tendency for the skin permeability to decrease depending on the amount of lactic acid added, and crystals were observed to precipitate in the adhesive layer of the preparations stored after production.

[0103] <Example 9: Production of patch> A patch was produced in the same manner as in Example 1, except that the components constituting the adhesive layer were changed to the formulation shown in Table 2. The skin permeability, cohesive strength, and adhesiveness were evaluated in the same manner as in Example 1. The results are shown in Table 2.

[0104] [Table 2]

[0105] Example 10: Preparation of a patch A patch was produced in the same manner as in Example 1, except that the components constituting the adhesive layer were changed to the formulation shown in Table 2. The skin permeability, cohesive strength, and adhesiveness were evaluated in the same manner as in Example 1. The results are shown in Table 2.

[0106] <Example 11: Production of patch> A patch was produced in the same manner as in Example 1, except that the components constituting the adhesive layer were changed to the formulation shown in Table 2. The skin permeability, cohesive strength, and adhesiveness were evaluated in the same manner as in Example 1. The results are shown in Table 2.

[0107] <Example 12: Production of patch> A patch was produced in the same manner as in Example 1, except that the components constituting the adhesive layer were changed to the formulation shown in Table 2. The skin permeability, cohesive strength, and adhesiveness were evaluated in the same manner as in Example 1. The results are shown in Table 2.

[0108] <Example 13: Production of patch> A patch was produced in the same manner as in Example 1, except that the components constituting the adhesive layer were changed to the formulation shown in Table 2. The skin permeability, cohesive strength, and adhesiveness were evaluated in the same manner as in Example 1. The results are shown in Table 2.

[0109] Example 14: Preparation of a patch A patch was produced in the same manner as in Example 1, except that the components constituting the adhesive layer were changed to the formulation shown in Table 2. The skin permeability, cohesive strength, and adhesiveness were evaluated in the same manner as in Example 1. The results are shown in Table 2.

[0110] Example 15: Preparation of a patch A patch was produced in the same manner as in Example 1, except that the components constituting the adhesive layer were changed to the formulation shown in Table 2. The skin permeability, cohesive strength, and adhesiveness were evaluated in the same manner as in Example 1. The results are shown in Table 2.

[0111] Example 16: Preparation of a patch A patch was produced in the same manner as in Example 1, except that the components constituting the adhesive layer were changed to the formulation shown in Table 2. The skin permeability, cohesive strength, and adhesiveness were evaluated in the same manner as in Example 1. The results are shown in Table 2.

[0112] As shown in the results in Table 2, it was found that diisopropyl adipate exhibited a high absorption-enhancing effect in Examples 1 and 9 to 12. Furthermore, the patches of Examples 13 to 16 exhibited skin permeability six times higher than that of existing preparations, and it was found that α-monoisostearyl glyceryl ether exhibited a high absorption-enhancing effect.

[0113] Example 17: Preparation of a patch A patch was produced in the same manner as in Example 1, except that the components constituting the adhesive layer were changed to the formulation shown in Table 3. The skin permeability, cohesive strength, and adhesiveness were evaluated in the same manner as in Example 1. The results are shown in Table 3.

[0114] [Table 3]

[0115] <Example 18: Production of patch> A patch was produced in the same manner as in Example 1, except that the components constituting the adhesive layer were changed to the formulation shown in Table 3. The skin permeability, cohesive strength, and adhesiveness were evaluated in the same manner as in Example 1. The results are shown in Table 3.

[0116] <Example 19: Production of patch> A patch was produced in the same manner as in Example 1, except that the components constituting the adhesive layer were changed to the formulation shown in Table 3. The skin permeability, cohesive strength, and adhesiveness were evaluated in the same manner as in Example 1. The results are shown in Table 3.

[0117] As shown in the results in Table 3, all of the patches of Examples 17 to 19 containing various aliphatic dicarboxylic acid esters exhibited skin permeability that was four times or more higher than that of existing preparations.

[0118] <Example 20: Production of patch> A patch was produced in the same manner as in Example 1, except that the components constituting the adhesive layer were changed to the formulation shown in Table 4. The skin permeability, cohesive strength, and adhesiveness were evaluated in the same manner as in Example 1. The results are shown in Table 4.

[0119] [Table 4]

[0120] <Example 21: Production of patch> A patch was produced in the same manner as in Example 1, except that the components constituting the adhesive layer were changed to the formulation shown in Table 4. The skin permeability, cohesive strength, and adhesiveness were evaluated in the same manner as in Example 1. The results are shown in Table 4.

[0121] <Example 22: Production of patch> A patch was produced in the same manner as in Example 1, except that the components constituting the adhesive layer were changed to the formulation shown in Table 4. The skin permeability, cohesive strength, and adhesiveness were evaluated in the same manner as in Example 1. The results are shown in Table 4.

[0122] As the results shown in Table 4 show, Examples 20 to 22, in which a liquid organic acid other than lactic acid was added, exhibited permeability equivalent to that of Example 5, in which lactic acid was added, and also demonstrated a phenomenon in which crystal precipitation of blonanserin was suppressed.

[0123] <Example 23: Production of patch> A patch was produced in the same manner as in Example 1, except that the components constituting the adhesive layer were changed to the formulation shown in Table 5. The skin permeability, cohesive strength, and adhesiveness were evaluated in the same manner as in Example 1. The results are shown in Table 5.

[0124] [Table 5]

[0125] Example 24: Preparation of a patch A patch was produced in the same manner as in Example 1, except that the components constituting the adhesive layer were changed to the formulation shown in Table 5. The skin permeability, cohesive strength, and adhesiveness were evaluated in the same manner as in Example 1. The results are shown in Table 5.

[0126] Example 25: Preparation of a patch A patch was produced in the same manner as in Example 1, except that the components constituting the adhesive layer were changed to the formulation shown in Table 5. The skin permeability, cohesive strength, and adhesiveness were evaluated in the same manner as in Example 1. The results are shown in Table 5.

[0127] <Example 26: Production of patch> A patch was produced in the same manner as in Example 8, except that the components constituting the adhesive layer were changed to the formulation shown in Table 5. The skin permeability, cohesive strength, and adhesiveness were evaluated in the same manner as in Example 1. The results are shown in Table 5.

[0128] <Example 27: Production of patch> A patch was produced in the same manner as in Example 8, except that the components constituting the adhesive layer were changed to the formulation shown in Table 5. The skin permeability, cohesive strength, and adhesiveness were evaluated in the same manner as in Example 1. The results are shown in Table 5.

[0129] <Example 28: Production of patch> A patch was produced in the same manner as in Example 8, except that the components constituting the adhesive layer were changed to the formulation shown in Table 5. The skin permeability, cohesive strength, and adhesiveness were evaluated in the same manner as in Example 1. The results are shown in Table 5.

[0130] <Example 29: Production of patch> A patch was produced in the same manner as in Example 8, except that the components constituting the adhesive layer were changed to the formulation shown in Table 5. The skin permeability, cohesive strength, and adhesiveness were evaluated in the same manner as in Example 1. The results are shown in Table 5.

[0131] Example 30: Preparation of a patch A patch was produced in the same manner as in Example 8, except that the components constituting the adhesive layer were changed to the formulation shown in Table 5. The skin permeability, cohesive strength, and adhesiveness were evaluated in the same manner as in Example 1. The results are shown in Table 5.

[0132] As shown in the results in Table 5, the patches of Examples 24 to 30, which contained aliphatic dicarboxylic acid esters, glycerin monoethers, and liquid organic acids other than polyoxyethylene lauryl ether or lactic acid, all showed skin permeability that was four times higher than that of existing formulations.

[0133] The present invention includes, for example, the following aspects. <1> The patch comprises a support and an adhesive layer on the support, wherein the adhesive layer contains blonanserin or a salt thereof, a thermoplastic elastomer, lactic acid, and a non-volatile hydrocarbon oil, and the amount of lactic acid in the adhesive layer is more than 0 molar equivalents and not more than 1.5 molar equivalents relative to the blonanserin contained in the adhesive layer. <2> The patch comprises a support and an adhesive layer on the support, wherein the adhesive layer contains blonanserin or a salt thereof, a thermoplastic elastomer, and a non-volatile hydrocarbon oil, and is free of lactic acid. <3> The thermoplastic elastomer includes a styrene-based block copolymer. <1> or <2> The patch described in 1. <4> The styrene-based block copolymer is a mixture of a styrene-isoprene-styrene block copolymer and a styrene-isoprene block copolymer. <3> The patch described in 1. <5> The pressure-sensitive adhesive layer contains polyisobutylene. <1> from <4> The patch according to any one of the above items. <6> The pressure-sensitive adhesive layer contains an aliphatic dicarboxylic acid ester. <1> from <5> The patch according to any one of the above items. <7> The pressure-sensitive adhesive layer contains glycerin monoether. <1> from <6> The patch according to any one of the above items. <8> the adhesive layer contains a liquid organic acid other than lactic acid. <1> from <7> The patch according to any one of the above items. <9> The aforementioned <1> from <8> The method for producing the patch according to any one of the above items 1 to 4, which comprises a step of laminating the support and the pressure-sensitive adhesive layer.

Claims

1. A support; a pressure-sensitive adhesive layer on the support, A patch, wherein the adhesive layer contains blonanserin or a salt thereof, a thermoplastic elastomer, a non-volatile hydrocarbon oil, and an aliphatic dicarboxylic acid ester, and does not contain lactic acid.

2. The patch according to claim 1 , wherein the thermoplastic elastomer comprises a styrene-based block copolymer.

3. The patch according to claim 2, wherein the styrene-based block copolymer is a mixture of a styrene-isoprene-styrene block copolymer and a styrene-isoprene block copolymer.

4. The proportion of the styrene-isoprene block copolymer in the mixture is 40% by mass or more. The patch according to claim 3.

5. The patch according to claim 1 , wherein the adhesive layer comprises polyisobutylene.

6. The patch according to claim 1 , wherein the adhesive layer comprises glycerin monoether.

7. The patch according to claim 1 , wherein the adhesive layer comprises a liquid organic acid other than lactic acid.

8. The patch according to claim 1 , wherein the content of the thermoplastic elastomer in the pressure-sensitive adhesive layer is 35% by mass or more and 70% by mass or less.

9. 9. The patch according to claim 1, wherein the content of the non-volatile hydrocarbon oil in the adhesive layer is 100 parts by weight or more and 300 parts by weight or less per 100 parts by weight of the thermoplastic elastomer.

10. The patch according to claim 1 , wherein the adhesive layer comprises a fatty acid monoester of a polyhydric alcohol.

11. The patch according to claim 1 , wherein the adhesive layer comprises benzyl alcohol.

12. A method for producing the patch according to any one of claims 1 to 11, comprising: A method for producing a patch, comprising the step of laminating the support and the pressure-sensitive adhesive layer.

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