WO2023085282A1 - セレキシパグを有効成分とする貼付剤 - Google Patents
セレキシパグを有効成分とする貼付剤 Download PDFInfo
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- WO2023085282A1 WO2023085282A1 PCT/JP2022/041600 JP2022041600W WO2023085282A1 WO 2023085282 A1 WO2023085282 A1 WO 2023085282A1 JP 2022041600 W JP2022041600 W JP 2022041600W WO 2023085282 A1 WO2023085282 A1 WO 2023085282A1
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- WIPO (PCT)
- Prior art keywords
- mass
- selexipag
- acrylate
- meth
- adhesive layer
- Prior art date
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- QXWZQTURMXZVHJ-UHFFFAOYSA-N selexipag Chemical compound C=1C=CC=CC=1C1=NC(N(CCCCOCC(=O)NS(C)(=O)=O)C(C)C)=CN=C1C1=CC=CC=C1 QXWZQTURMXZVHJ-UHFFFAOYSA-N 0.000 title claims abstract description 121
- 229960003841 selexipag Drugs 0.000 title claims abstract description 119
- 239000000853 adhesive Substances 0.000 title claims abstract description 23
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- NIXOWILDQLNWCW-UHFFFAOYSA-N acrylic acid group Chemical group C(C=C)(=O)O NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 claims description 12
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical group C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 claims description 11
- 239000004820 Pressure-sensitive adhesive Substances 0.000 claims description 11
- OMNKZBIFPJNNIO-UHFFFAOYSA-N n-(2-methyl-4-oxopentan-2-yl)prop-2-enamide Chemical group CC(=O)CC(C)(C)NC(=O)C=C OMNKZBIFPJNNIO-UHFFFAOYSA-N 0.000 claims description 5
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- NIXOWILDQLNWCW-UHFFFAOYSA-M Acrylate Chemical compound [O-]C(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-M 0.000 description 79
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- 125000004106 butoxy group Chemical group [*]OC([H])([H])C([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 1
- 229910000019 calcium carbonate Inorganic materials 0.000 description 1
- CREMABGTGYGIQB-UHFFFAOYSA-N carbon carbon Chemical compound C.C CREMABGTGYGIQB-UHFFFAOYSA-N 0.000 description 1
- 238000003763 carbonization Methods 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
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- 229960000541 cetyl alcohol Drugs 0.000 description 1
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- 229940114081 cinnamate Drugs 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- 238000005520 cutting process Methods 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 210000004207 dermis Anatomy 0.000 description 1
- LSXWFXONGKSEMY-UHFFFAOYSA-N di-tert-butyl peroxide Chemical compound CC(C)(C)OOC(C)(C)C LSXWFXONGKSEMY-UHFFFAOYSA-N 0.000 description 1
- 229910001873 dinitrogen Inorganic materials 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 125000006232 ethoxy propyl group Chemical group [H]C([H])([H])C([H])([H])OC([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000005448 ethoxyethyl group Chemical group [H]C([H])([H])C([H])([H])OC([H])([H])C([H])([H])* 0.000 description 1
- 125000005745 ethoxymethyl group Chemical group [H]C([H])([H])C([H])([H])OC([H])([H])* 0.000 description 1
- IIEWJVIFRVWJOD-UHFFFAOYSA-N ethyl cyclohexane Natural products CCC1CCCCC1 IIEWJVIFRVWJOD-UHFFFAOYSA-N 0.000 description 1
- 239000004744 fabric Substances 0.000 description 1
- 150000004665 fatty acids Chemical class 0.000 description 1
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- 238000009472 formulation Methods 0.000 description 1
- 229930195712 glutamate Natural products 0.000 description 1
- JFCQEDHGNNZCLN-UHFFFAOYSA-N glutaric acid Chemical compound OC(=O)CCCC(O)=O JFCQEDHGNNZCLN-UHFFFAOYSA-N 0.000 description 1
- VOZRXNHHFUQHIL-UHFFFAOYSA-N glycidyl methacrylate Chemical group CC(=C)C(=O)OCC1CO1 VOZRXNHHFUQHIL-UHFFFAOYSA-N 0.000 description 1
- 230000005986 heart dysfunction Effects 0.000 description 1
- 125000003187 heptyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- BXWNKGSJHAJOGX-UHFFFAOYSA-N hexadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCO BXWNKGSJHAJOGX-UHFFFAOYSA-N 0.000 description 1
- PXDJXZJSCPSGGI-UHFFFAOYSA-N hexadecanoic acid hexadecyl ester Natural products CCCCCCCCCCCCCCCCOC(=O)CCCCCCCCCCCCCCC PXDJXZJSCPSGGI-UHFFFAOYSA-N 0.000 description 1
- 229940100463 hexyl laurate Drugs 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 229920006270 hydrocarbon resin Polymers 0.000 description 1
- 150000003840 hydrochlorides Chemical class 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000011256 inorganic filler Substances 0.000 description 1
- 229910003475 inorganic filler Inorganic materials 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000006229 isopropoxyethyl group Chemical group [H]C([H])([H])C([H])(OC([H])([H])C([H])([H])*)C([H])([H])[H] 0.000 description 1
- 229940074928 isopropyl myristate Drugs 0.000 description 1
- 229940075495 isopropyl palmitate Drugs 0.000 description 1
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical class CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 1
- 229940031957 lauric acid diethanolamide Drugs 0.000 description 1
- 229940049918 linoleate Drugs 0.000 description 1
- DTOSIQBPPRVQHS-PDBXOOCHSA-M linolenate Chemical compound CC\C=C/C\C=C/C\C=C/CCCCCCCC([O-])=O DTOSIQBPPRVQHS-PDBXOOCHSA-M 0.000 description 1
- 229940040452 linolenate Drugs 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 230000005980 lung dysfunction Effects 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 229940049920 malate Drugs 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N malic acid Chemical compound OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- IWYDHOAUDWTVEP-UHFFFAOYSA-M mandelate Chemical compound [O-]C(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-M 0.000 description 1
- 235000012054 meals Nutrition 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 description 1
- 229940043348 myristyl alcohol Drugs 0.000 description 1
- 229940078812 myristyl myristate Drugs 0.000 description 1
- QRWZCJXEAOZAAW-UHFFFAOYSA-N n,n,2-trimethylprop-2-enamide Chemical compound CN(C)C(=O)C(C)=C QRWZCJXEAOZAAW-UHFFFAOYSA-N 0.000 description 1
- 229940088644 n,n-dimethylacrylamide Drugs 0.000 description 1
- YLGYACDQVQQZSW-UHFFFAOYSA-N n,n-dimethylprop-2-enamide Chemical compound CN(C)C(=O)C=C YLGYACDQVQQZSW-UHFFFAOYSA-N 0.000 description 1
- KCTMTGOHHMRJHZ-UHFFFAOYSA-N n-(2-methylpropoxymethyl)prop-2-enamide Chemical compound CC(C)COCNC(=O)C=C KCTMTGOHHMRJHZ-UHFFFAOYSA-N 0.000 description 1
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 1
- GOQYKNQRPGWPLP-UHFFFAOYSA-N n-heptadecyl alcohol Natural products CCCCCCCCCCCCCCCCCO GOQYKNQRPGWPLP-UHFFFAOYSA-N 0.000 description 1
- AWGZKFQMWZYCHF-UHFFFAOYSA-N n-octylprop-2-enamide Chemical compound CCCCCCCCNC(=O)C=C AWGZKFQMWZYCHF-UHFFFAOYSA-N 0.000 description 1
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 150000002823 nitrates Chemical class 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- 125000001400 nonyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OEIJHBUUFURJLI-UHFFFAOYSA-N octane-1,8-diol Chemical compound OCCCCCCCCO OEIJHBUUFURJLI-UHFFFAOYSA-N 0.000 description 1
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 229940073665 octyldodecyl myristate Drugs 0.000 description 1
- 239000005022 packaging material Substances 0.000 description 1
- 125000000913 palmityl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 150000002978 peroxides Chemical class 0.000 description 1
- 235000021317 phosphate Nutrition 0.000 description 1
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 1
- XNGIFLGASWRNHJ-UHFFFAOYSA-L phthalate(2-) Chemical compound [O-]C(=O)C1=CC=CC=C1C([O-])=O XNGIFLGASWRNHJ-UHFFFAOYSA-L 0.000 description 1
- 229920001200 poly(ethylene-vinyl acetate) Polymers 0.000 description 1
- 230000000379 polymerizing effect Effects 0.000 description 1
- 229920002635 polyurethane Polymers 0.000 description 1
- 239000004814 polyurethane Substances 0.000 description 1
- 229920000915 polyvinyl chloride Polymers 0.000 description 1
- 239000004800 polyvinyl chloride Substances 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 238000010837 poor prognosis Methods 0.000 description 1
- 208000037821 progressive disease Diseases 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 125000006225 propoxyethyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])OC([H])([H])C([H])([H])* 0.000 description 1
- 125000005767 propoxymethyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])[#8]C([H])([H])* 0.000 description 1
- 210000001147 pulmonary artery Anatomy 0.000 description 1
- 230000002040 relaxant effect Effects 0.000 description 1
- 239000013557 residual solvent Substances 0.000 description 1
- YGSDEFSMJLZEOE-UHFFFAOYSA-M salicylate Chemical compound OC1=CC=CC=C1C([O-])=O YGSDEFSMJLZEOE-UHFFFAOYSA-M 0.000 description 1
- 229960001860 salicylate Drugs 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 229930195734 saturated hydrocarbon Natural products 0.000 description 1
- RMAQACBXLXPBSY-UHFFFAOYSA-N silicic acid Chemical compound O[Si](O)(O)O RMAQACBXLXPBSY-UHFFFAOYSA-N 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- 239000002356 single layer Substances 0.000 description 1
- 229940075554 sorbate Drugs 0.000 description 1
- 230000000087 stabilizing effect Effects 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 210000000434 stratum corneum Anatomy 0.000 description 1
- 229920001935 styrene-ethylene-butadiene-styrene Polymers 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 150000003467 sulfuric acid derivatives Chemical class 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- DZKXJUASMGQEMA-UHFFFAOYSA-N tetradecyl tetradecanoate Chemical compound CCCCCCCCCCCCCCOC(=O)CCCCCCCCCCCCC DZKXJUASMGQEMA-UHFFFAOYSA-N 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- OGIDPMRJRNCKJF-UHFFFAOYSA-N titanium oxide Inorganic materials [Ti]=O OGIDPMRJRNCKJF-UHFFFAOYSA-N 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical class CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 125000005490 tosylate group Chemical group 0.000 description 1
- WBYWAXJHAXSJNI-VOTSOKGWSA-M trans-cinnamate Chemical compound [O-]C(=O)\C=C\C1=CC=CC=C1 WBYWAXJHAXSJNI-VOTSOKGWSA-M 0.000 description 1
- 125000002889 tridecyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000002948 undecyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000002759 woven fabric Substances 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
- 239000011787 zinc oxide Substances 0.000 description 1
- 239000004711 α-olefin Substances 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/4965—Non-condensed pyrazines
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
Definitions
- the present invention relates to a patch for transdermal administration of selexipag as a drug.
- Pulmonary hypertension is a progressive disease with a poor prognosis that causes heart and lung dysfunction due to increased blood pressure in the pulmonary arteries that carry blood from the heart to the lungs.
- Selexipag (2- ⁇ 4-[(5,6-diphenylpyrazin-2-yl)(propan-2-yl)amino]butoxy ⁇ -N-methanesulfonylacetamide) is known as a therapeutic agent for pulmonary hypertension. .
- Selexipag is already in clinical use as an injection and oral formulation.
- Patent Document 1 discloses a patch containing riociguat.
- selexipag has low transdermal absorbability, and therefore no patches containing selexipag have been put to practical use.
- an object of the present invention is to provide a patch that has excellent transdermal absorbability of selexipag.
- the patch of the present invention is characterized by comprising a backing and an adhesive layer laminated on one surface of the backing and containing selexipag and an acrylic adhesive.
- the patch of the present invention comprises a backing and an adhesive layer laminated on one surface of the backing.
- the adhesive layer contains selexipag and an acrylic adhesive.
- the adhesive layer may contain at least one of the free base form of selexipag and the acid addition salt form of selexipag. Among them, free base type (free form) selexipag is preferred.
- the free base form of selexipag is selexipag (2- ⁇ 4-[(5,6-diphenylpyrazin-2-yl)(propan-2-yl)amino]butoxy ⁇ -N- methanesulfonylacetamide) itself. According to the free base form of selexipag, it is possible to provide a patch in which the transdermal absorbability of selexipag is superior.
- the adhesive layer may contain only one of the free base form of selexipag and the acid addition salt form of selexipag, or may contain both the free base form of selexipag and the acid addition salt form of selexipag.
- the acid addition salt form of selexipag is a physiologically acceptable acid addition salt of the free base form of selexipag.
- Physiologically acceptable acid addition salts include, but are not limited to, inorganic acid salts such as hydrochlorides, hydrobromides, nitrates, sulfates, phosphates; formates, acetates, trifluoro Acetate, Ascorbate, Benzoate, Cinnamate, Citrate, Fumarate, Glutamate, Tartrate, Oxalate, Glutarate, Camphorate, Adipate, Sorbate, Lactic Acid Salt, Maleate, Linoleate, Linolenate, Malate, Malonate, Mandelate, Methanesulfonate (Mesylate), Phthalate, Salicylate, Stearate, Isostearate, Succinate and organic acid salts such as acid salts, propionates, butyrates, pamoates, p-toluenesul
- the content ratio of selexipag in the adhesive layer is preferably 0.5% by mass or more, more preferably 1% by mass or more, more preferably 2% by mass or more, and 3% by mass in the total amount of 100% by mass of selexipag and acrylic adhesive. % or more is more preferable, 4% by mass or more is more preferable, and 5% by mass or more is more preferable. In addition, the content ratio of selexipag in the adhesive layer is more preferably 30% by mass or less, more preferably 20% by mass or less, more preferably 15% by mass or less, in 100% by mass of the total amount of selexipag and acrylic adhesive.
- % by mass or less is more preferable, 8% by mass or less is more preferable, and 6% by mass or less is more preferable.
- the content ratio of selexipag in the adhesive layer is 0.5% by mass or more, the blood concentration of selexipag can be rapidly increased to a desired range.
- the content of selexipag in the adhesive layer is 30% by mass or less, excessive precipitation of selexipag as crystals in the adhesive layer is reduced, and the percutaneous absorbability and storage stability of selexipag are maintained at a high level. can do.
- the mass of selexipag obtained by converting the acid addition salt form of selexipag to the free base form is used as the mass of the acid addition salt form of selexipag.
- the mass of selexipag obtained by converting the acid addition salt form of selexipag into the free base form is the mass of the free base form of selexipag in an equimolar amount to the acid addition salt form of selexipag.
- the adhesive layer contains an acrylic adhesive.
- an acrylic adhesive By using a combination of selexipag and an acrylic adhesive in the adhesive layer, it is possible to provide a patch with improved percutaneous absorbability of selexipag.
- the acrylic pressure-sensitive adhesive preferably contains an acrylic polymer.
- the acrylic polymer is not particularly limited, and those used as acrylic pressure-sensitive adhesives in conventional patches can be used.
- An acrylic polymer may be used individually by 1 type, or 2 or more types may be used together.
- the acrylic polymer is preferably a polymer containing (meth)acrylate monomer units.
- (Meth)acrylate-based monomers are not particularly limited, and examples thereof include alkyl (meth)acrylates, hydroxyalkyl (meth)acrylates, and glycidyl (meth)acrylates. Among them, alkyl (meth)acrylates are preferred.
- the (meth)acrylate-based monomer preferably does not have an amide structure represented by formula (1) described later.
- (Meth)acrylate means acrylate or methacrylate.
- the acrylic polymer preferably contains alkyl (meth)acrylate units.
- Alkyl (meth)acrylate units have a moderate affinity for selexipag and can dissolve some or all of the formulated selexipag, thereby promoting the transfer of selexipag to the skin. . Therefore, an acrylic polymer containing an alkyl (meth)acrylate unit can provide a patch with improved percutaneous absorbability of selexipag.
- the alkyl group of the alkyl (meth)acrylate is preferably a linear or branched alkyl group.
- the number of carbon atoms in the alkyl group of the alkyl (meth)acrylate is preferably 1-16, more preferably 1-14, more preferably 2-12, and particularly preferably 2-10.
- alkyl (meth)acrylates examples include methyl (meth)acrylate, ethyl (meth)acrylate, n-propyl (meth)acrylate, isopropyl (meth)acrylate, n-butyl (meth)acrylate, isobutyl (meth)acrylate, Hexyl (meth)acrylate, n-octyl (meth)acrylate, isooctyl (meth)acrylate, 2-ethylhexyl (meth)acrylate, decyl (meth)acrylate, dodecyl (meth)acrylate, tridecyl (meth)acrylate, hexadecyl (meth)acrylate acrylate, cyclododecyl (meth)acrylate, cyclohexyl (meth)acrylate, and the like.
- ethyl (meth)acrylate, n-butyl (meth)acrylate, n-octyl (meth)acrylate, and 2-ethylhexyl (meth)acrylate are preferable, and ethyl (meth)acrylate, n-octyl (meth)acrylate, and 2-ethylhexyl (meth)acrylate are more preferred, and ethyl acrylate, n-octyl acrylate, and 2-ethylhexyl acrylate are more preferred.
- An alkyl (meth)acrylate may be used individually by 1 type, or may use 2 or more types together.
- the acrylic polymer may be a homopolymer of (meth)acrylate monomers.
- the acrylic polymer is preferably an alkyl (meth)acrylate homopolymer.
- An alkyl (meth)acrylate homopolymer can provide an adhesive patch with excellent percutaneous absorbability of selexipag.
- the alkyl (meth)acrylate may contain a combination of two or more alkyl (meth)acrylates.
- Combinations of two or more alkyl (meth)acrylates include a combination of 2-ethylhexyl (meth)acrylate and ethyl (meth)acrylate, a combination of ethyl (meth)acrylate and n-octyl (meth)acrylate, and A combination of 2-ethylhexyl (meth)acrylate, ethyl (meth)acrylate and n-butyl (meth)acrylate is preferred.
- the acrylic polymer may be a copolymer of a (meth)acrylate monomer and another vinyl monomer.
- the vinyl-based monomer means a monomer having an ethylenically unsaturated double bond.
- the acrylic polymer preferably contains vinyl monomer (I) units having an amide structure represented by the following formula (1).
- the amide structure represented by formula (1) above is a monovalent, divalent, or trivalent atomic group.
- the valence of an atomic group means the number (valence) of other atoms or atomic groups to which this atomic group can be bonded.
- the amide structure represented by formula (1) above is a monovalent atomic group, the amide structure can be bonded to one other atom or atomic group.
- bonds *1 to *3 in the amide structure represented by the above formula (1) are single bonds, and at least one bond among the bonds *1 to *3 is that of the vinyl monomer (I). It is bonded directly or through multiple atoms to carbon atoms forming ethylenically unsaturated double bonds (carbon-carbon double bonds).
- bonds *1 to *3 in the amide structure represented by the above formula (1) one or two bonds are ethylenically unsaturated double bonds (carbon-carbon divalent heavy bond), the remaining bond is a monovalent atom such as a hydrogen atom or a monovalent atomic group such as an alkyl group. may be connected to
- Two of the bonds *1 to *3 in the amide structure represented by the above formula (1) may be bonded to each other via an atom or atomic group to form a ring structure.
- bond *1 and bond *2 or *3 are preferably bonded to each other to form a ring structure.
- the storage temperature may change during storage of the patch, but even if the storage temperature of the patch changes, the dissolution state and precipitation state of selexipag in the adhesive layer are maintained unchanged before and after storage. is preferred. This is because if the dissolution and precipitation states of selexipag change, the percutaneous absorbability of selexipag will also change, and there is a possibility that the intended efficacy will not be obtained and the treatment will be affected. In particular, if selexipag crystals are excessively precipitated due to changes in the storage temperature of the patch, there is a possibility that the percutaneous absorbability of the drug may become non-uniform or deteriorate.
- the vinyl-based monomer (I) having an amide structure represented by the above formula (1) has a high affinity for selexipag and has the effect of stabilizing the dissolved state of selexipag.
- the acrylic polymer containing the vinyl monomer (I) unit by using the acrylic polymer containing the vinyl monomer (I) unit, the state of selexipag can be stably maintained in the adhesive layer. Therefore, even if the storage temperature of the patch changes, it is possible to reduce changes in the dissolution state and precipitation state of selexipag in the adhesive layer, thereby reducing changes in the percutaneous absorbability of selexipag. can.
- the acrylic polymer containing the vinyl-based monomer (I) unit as described above, it is possible to provide a patch that not only has excellent percutaneous absorbability of selexipag but also excellent storage stability of selexipag. becomes.
- the acrylic polymer preferably contains vinyl monomer (I) units having an amide structure represented by formula (1) above. That is, the acrylic polymer is preferably a polymer of monomers containing vinyl monomer (I) having an amide structure represented by formula (1) above.
- Examples of the vinyl-based monomer (I) include vinyl-based monomers represented by the following formula (2).
- R 1 represents a hydrogen atom or a methyl group
- R 2 and R 3 are alkyl groups which may be the same or different
- R 2 and R 3 are may be combined to form a ring structure.
- R 2 and R 3 are alkyl groups that may be the same or different.
- Alkyl groups may be linear or branched. The number of carbon atoms in the alkyl group is preferably 1-5.
- alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl groups. Among them, a methyl group, an ethyl group and an n-propyl group are preferred, and a methyl group and an ethyl group are more preferred.
- R 2 and R 3 are preferably bonded to each other to form a ring structure together with the nitrogen and carbon atoms to which they are bonded.
- vinyl-based monomers represented by formula (2) include N-vinyl-2-pyrrolidone, N-vinylpiperidone, and N-vinyl- ⁇ -caprolactam.
- the vinyl-based monomers represented by formula (2) may be used singly or in combination of two or more.
- Examples of the vinyl-based monomer (I) include vinyl-based monomers represented by the following formula (3).
- R 4 represents a hydrogen atom or a methyl group
- R 5 represents a hydrogen atom or a methyl group
- R 6 represents an alkyl group, an alkoxyalkyl group, or the following formula (4) denoting the indicated group
- *4 is a bond (single bond), R7 represents an alkylene group, and R8 represents an alkyl group.
- the alkyl group represented by R 6 in the above formula (3) may be linear or branched.
- the number of carbon atoms in the alkyl group is preferably 1-15, more preferably 1-10.
- Alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl and heptyl groups. group, octyl group, nonyl group, decyl group, undecyl group, dodecyl group, isooctyl group and the like.
- the alkoxyalkyl group represented by R 6 in formula (3) above may be linear or branched.
- the number of carbon atoms in the alkoxyalkyl group is preferably 2-5.
- alkoxyalkyl groups include methoxymethyl group, methoxyethyl group, methoxypropyl group, ethoxymethyl group, ethoxyethyl group, ethoxypropyl group, propoxymethyl group, propoxyethyl group, isopropoxymethyl group, isopropoxyethyl group, butoxy Examples include methyl, sec-butoxymethyl, isobutoxymethyl, and tert-butoxymethyl groups.
- R 6 in the above formula (3) is a group represented by the above formula (4)
- the bond *4 is a single bond
- R 7 is linear or branched and R 8 preferably represents a linear or branched alkyl group.
- R 6 in the formula (3) is a group represented by the formula (4)
- the bond *4 in the group represented by the formula (4) is the vinyl monomer represented by the formula (3). It is directly attached to the nitrogen atom forming an amide structure.
- R 7 is preferably a linear or branched alkylene group.
- the number of carbon atoms in the alkylene group is preferably 1-10, more preferably 1-6.
- Alkylene groups include methylene, ethylene, methylmethylene, ethylmethylene, dimethylmethylene, ethylmethylmethylene, isopropylmethylene, trimethylene, propylene, 1-methyltrimethylene, and 2-methyltrimethylene. group, tetramethylene group, dimethylethylene group, ethylethylene group, and the like. Among them, a dimethylethylene group is preferred.
- R 8 is preferably a linear or branched alkyl group.
- the number of carbon atoms in the alkyl group is preferably 1-5.
- alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl groups. Among them, a methyl group, an ethyl group and an n-propyl group are preferred, and a methyl group and an ethyl group are more preferred.
- vinyl-based monomers represented by the above formula (3) include diacetoneacrylamide, N-(isobutoxymethyl)acrylamide, N,N-dimethylacrylamide, N,N-dimethylmethacrylamide, and N-octylacrylamide. , N-isopropyl methacrylamide.
- the vinyl-based monomers represented by the above formula (3) may be used singly or in combination of two or more.
- the vinyl-based monomer (I) preferably includes the vinyl-based monomer represented by formula (2) and the vinyl-based monomer represented by formula (3). Among them, N-vinyl-2-pyrrolidone and diacetoneacrylamide are more preferable, and N-vinyl-2-pyrrolidone is more preferable.
- the vinyl monomer (I) may be used singly or in combination of two or more.
- the content of vinyl monomer (I) units in the acrylic polymer is preferably 1% by mass or more, more preferably 5% by mass or more.
- the content of vinyl-based monomer (I) units in the acrylic polymer is preferably 40% by mass or less, more preferably 35% by mass or less, and more preferably 30% by mass or less.
- the acrylic polymer preferably contains vinyl-based monomer (I) units having an amide structure represented by formula (1) above and alkyl (meth)acrylate units. That is, the acrylic polymer is preferably a copolymer of a vinyl monomer (I) having an amide structure represented by the above formula (1) and a monomer containing an alkyl (meth)acrylate. According to such an acrylic polymer, it is possible to provide a patch having excellent percutaneous absorbability and storage stability of selexipag.
- the acrylic polymer contains a vinyl-based monomer (I) unit having an amide structure represented by the formula (1) and an alkyl (meth)acrylate unit
- the alkyl (meth)acrylate in the acrylic polymer The unit content is preferably 60% by mass or more, more preferably 65% by mass or more, and more preferably 70% by mass or more.
- the acrylic polymer contains vinyl monomer (I) units having an amide structure represented by the above formula (1) and alkyl (meth)acrylate units, alkyl (meth)acrylate units in the acrylic polymer )
- the content of acrylate units is preferably 99% by mass or less, more preferably 95% by mass or less.
- the percutaneous absorbability of selexipag can be improved.
- the content of the alkyl (meth)acrylate unit By setting the content of the alkyl (meth)acrylate unit to 99% by mass or less, a sufficient amount of the vinyl monomer (I) unit can be included in the acrylic polymer.
- the acrylic polymer preferably contains N-vinyl-2-pyrrolidone units as vinyl monomer (I) units and 2-ethylhexyl (meth)acrylate units as alkyl (meth)acrylate units. Further, the acrylic polymer contains N-vinyl-2-pyrrolidone units as the vinyl monomer (I) units, and ethyl (meth)acrylate units and n-octyl (meth)acrylate units as the alkyl (meth)acrylate units. It preferably contains units.
- the acrylic polymer contains diacetone acrylamide units as the vinyl monomer (I) units, and 2-ethylhexyl (meth)acrylate units and n-butyl (meth)acrylate units as the alkyl (meth)acrylate units. preferably included.
- the ratio of the content of selexipag to the content of vinyl-based monomer (I) units in the adhesive layer is
- the mass ratio [selexipag content (parts by mass)/vinyl-based monomer (I) unit content (parts by mass)] is preferably 0.1 or more, more preferably 0.2 or more, and more preferably 0.3 or more. preferable. By setting the mass ratio to 0.1 or more, it is possible to provide an adhesive patch having excellent percutaneous absorbability of selexipag.
- the ratio of the content of selexipag to the content of vinyl-based monomer (I) units in the adhesive layer is
- the mass ratio [selexipag content (parts by mass)/vinyl-based monomer (I) unit content (parts by mass)] is preferably 1.3 or less, more preferably 1.1 or less, and more preferably 0.8 or less. Preferably, 0.7 or less is more preferable.
- the mass ratio to 1.1 or less, the amount of selexipag remaining in the patch at the end of administration can be kept low, thereby preventing excessive administration of selexipag when the patch is forgotten to be removed, A patch with high safety can be provided.
- the content (parts by mass) of vinyl-based monomer (I) units in the adhesive layer is, for example, a value calculated based on the following formula.
- Content of vinyl-based monomer (I) units in the adhesive layer (parts by mass) [ W1 * C1 + W2 * C2 +...+ Wn * Cn ]/100 (Wherein, n is an integer representing the number of types of acrylic polymers contained in the adhesive layer, and W n is the content (parts by mass) of the n-type acrylic polymer in the adhesive layer.
- C n is the content (% by mass) of the vinyl-based monomer (I) unit in the n-type acrylic polymer.)
- the acrylic polymer is preferably a polymer containing (meth)acrylate-based monomer units, and the (meth)acrylate-based monomers include alkyl (meth)acrylates, hydroxyalkyl (meth) Also included are acrylates and glycidyl (meth)acrylates.
- the acrylic polymer may contain (meth)acrylate monomer units other than alkyl (meth)acrylate units, such as hydroxyalkyl (meth)acrylate units and glycidyl (meth)acrylate units.
- the (meth)acrylate-based monomer units other than the alkyl (meth)acrylate units may be used singly or in combination of two or more.
- Hydroxyalkyl (meth)acrylates include hydroxyethyl (meth)acrylate, hydroxypropyl (meth)acrylate, and hydroxybutyl (meth)acrylate.
- a hydroxyalkyl (meth)acrylate may be used individually by 1 type, or may use 2 or more types together.
- the acrylic polymer may contain other vinyl-based monomer units in addition to the (meth)acrylate-based monomer units and vinyl-based monomer (I) units described above.
- Other vinyl monomers include (meth)acrylic acid, acrylonitrile, vinyl acetate, vinyl chloride, ⁇ -olefins, and styrene.
- Other vinyl-based monomers may be used singly or in combination of two or more.
- (meth)acrylic acid is preferred.
- (Meth)acrylic acid means acrylic acid or methacrylic acid.
- the content of (meth)acrylic acid units in the acrylic polymer is preferably 10% by mass or less, more preferably 5% by mass or less, and more preferably 3% by mass or less.
- the content of (meth)acrylic acid units in the acrylic polymer is preferably 0.1% by mass or more.
- a conventionally known method may be used as a method for forming an acrylic polymer.
- a method of polymerizing the above-described monomers such as (meth)acrylate-based monomers or vinyl-based monomers (I) in the presence of a polymerization initiator can be used.
- predetermined amounts of monomers, a polymerization initiator, and a polymerization solvent are supplied to a reactor and heated at a temperature of 60 to 80° C. for 4 to 48 hours to radically polymerize the monomers.
- polymerization initiators examples include 2,2′-azobisisobutyronitrile (AIBN), 1,1′-azobis(cyclohexane-1-carbonitrile), 2,2′-azobis-(2,4′ -dimethylvaleronitrile); and peroxide polymerization initiators such as benzoyl peroxide (BPO), lauroyl peroxide (LPO) and di-tert-butyl peroxide.
- BPO benzoyl peroxide
- LPO lauroyl peroxide
- di-tert-butyl peroxide examples include ethyl acetate, cyclohexane and toluene.
- the polymerization reaction is preferably carried out under a nitrogen gas atmosphere.
- the content of the acrylic polymer in the acrylic pressure-sensitive adhesive is preferably 80% by mass or more, more preferably 90% by mass or more, more preferably 95% by mass or more, more preferably 98% by mass or more, and 100% by mass. Especially preferred. That is, it is particularly preferable that the acrylic pressure-sensitive adhesive consists of only an acrylic polymer. By setting the content of the acrylic polymer to 80% by mass or more, it is possible to provide a patch having excellent percutaneous absorbability of selexipag.
- the content ratio of the acrylic adhesive in the adhesive layer is more preferably 70% by mass or more, more preferably 80% by mass or more, more preferably 85% by mass or more, based on the total amount of 100% by mass of the selexipag and the acrylic adhesive. 90 mass % or more is more preferable, 92 mass % or more is more preferable, and 94 mass % or more is more preferable.
- the content ratio of the acrylic adhesive in the adhesive layer is preferably 99.5% by mass or less, more preferably 99% by mass or less, and 98% by mass or less in the total amount of 100% by mass of the selexipag and the acrylic adhesive.
- the pressure-sensitive adhesive layer can contain selexipag in a necessary amount.
- the adhesive layer preferably contains a plasticizer.
- Plasticizers can be used to modify the diffusibility of selexipag and control the release.
- Plasticizers include fatty acid esters such as methyl laurate, hexyl laurate, isopropyl myristate, myristyl myristate, octyldodecyl myristate, isopropyl palmitate, and cetyl palmitate; myristyl alcohol, cetanol, octyldodecanol, isostearyl alcohols and fatty alcohols such as monohydric fatty alcohols such as stearyl alcohol and dihydric fatty alcohols such as octanediol; petroleum oils such as liquid paraffin, paraffinic process oils, naphthenic process oils, and aromatic process oils and fatty acid amides such as lauric acid diethanolamide.
- fatty acid esters such as methyl laurate, hexyl laurate, isopropyl myristate, myristyl myristate, octyldodecyl myristate
- fatty acid esters and petroleum oils are preferred, isopropyl myristate, isopropyl palmitate and liquid paraffin are more preferred, and isopropyl myristate and isopropyl palmitate are more preferred.
- a plasticizer may be used individually by 1 type, or 2 or more types may be used together.
- the content of the plasticizer in the adhesive layer is preferably 1 part by mass or more, more preferably 5 parts by mass or more, and more preferably 10 parts by mass or more with respect to 100 parts by mass of the acrylic adhesive.
- the content of the plasticizer in the adhesive layer is preferably 30 parts by mass or less, more preferably 20 parts by mass or less, and more preferably 15 parts by mass or less with respect to 100 parts by mass of the acrylic pressure-sensitive adhesive.
- the content of the plasticizer is 1 part by mass or more, it is possible to change the diffusibility of selexipag and adjust the release property.
- the content of the plasticizer is 30 parts by mass or less, the sticking property of the pressure-sensitive adhesive layer can be maintained satisfactorily, so that an easy-to-handle patch can be provided.
- the adhesive layer may contain other additives such as tackifiers and fillers.
- Tackifiers include terpene resins, modified terpene resins, hydrogenated terpene resins, terpene phenolic resins, rosin, hydrogenated rosin, rosin esters, petroleum resins, coumarone-indene resins, phenolic resins, xylene resins, alicyclic saturated carbonization Hydrogen resin etc. are mentioned.
- the tackifier may be used singly or in combination of two or more.
- the content of the tackifier in the adhesive layer is preferably 15 to 80 parts by mass, more preferably 20 to 70 parts by mass, based on 100 parts by mass of the acrylic adhesive.
- filler is used to adjust the shape retention of the adhesive layer.
- fillers include inorganic fillers such as light anhydrous silicic acid, titanium oxide and zinc oxide; organic metal salts such as calcium carbonate and magnesium stearate; Cellulose derivatives; crosslinked polyvinylpyrrolidone and the like.
- a filler may be used individually by 1 type, or 2 or more types may be used together.
- the content of the filler in the adhesive layer is preferably 5 parts by mass or less, more preferably 0.1 to 2 parts by mass with respect to 100 parts by mass of the acrylic adhesive.
- the thickness of the adhesive layer is preferably 20-200 ⁇ m, more preferably 30-150 ⁇ m, and particularly preferably 50-120 ⁇ m.
- the adhesive layer can contain the amount of selexipag necessary for obtaining the desired efficacy.
- the thickness of the adhesive layer is 200 ⁇ m or less, strong drying conditions are not required during production to reduce the residual solvent in the adhesive layer, so volatilization or decomposition of selexipag in the adhesive layer can be suppressed.
- an adhesive layer is integrally laminated on one surface of the backing.
- the support is required to have strength to prevent loss of the drug in the adhesive layer and to impart self-retaining properties to the patch.
- supports include resin films, nonwoven fabrics, woven fabrics, knitted fabrics, and aluminum sheets.
- Examples of the resin constituting the resin film include cellulose acetate, rayon, polyethylene terephthalate, plasticized vinyl acetate-vinyl chloride copolymer, nylon, ethylene-vinyl acetate copolymer, plasticized polyvinyl chloride, polyurethane, polyethylene, Examples include polypropylene and polyvinylidene chloride. Among them, polyethylene terephthalate is preferred.
- Nonwoven fabric Materials constituting the nonwoven fabric include, for example, polyethylene, polypropylene, ethylene-vinyl acetate copolymer, ethylene-methyl (meth)acrylate copolymer, nylon, polyester, vinylon, SIS copolymer, SEBS copolymer, Rayon, cotton and the like can be mentioned, and polyester is preferred.
- these materials may be used individually by 1 type, or 2 or more types may be used together.
- the support may be a single layer or a laminated sheet in which multiple layers are laminated and integrated.
- the laminated sheet include a laminated sheet obtained by laminating and integrating a polyethylene terephthalate sheet and a nonwoven fabric or a flexible resin film.
- the thickness of the support is not particularly limited, it is preferably 2 to 200 ⁇ m, more preferably 2 to 100 ⁇ m.
- a release liner in the adhesive patch of the present invention, a release liner may be releasably laminated on one surface of the adhesive layer.
- a release liner is used to prevent loss of the drug in the adhesive layer and to protect the adhesive layer.
- release liners include paper and resin films.
- the resin constituting the resin film include polyethylene terephthalate, polyethylene, polypropylene, polyvinyl chloride, and polyvinylidene chloride. It is preferable that the surface of the release liner facing the adhesive layer is subjected to a release treatment.
- Method for producing patch for example, (1) an adhesive layer-forming solution containing selexipag, an acrylic adhesive, and a solvent is coated on one surface of a support, and then dried to obtain a coating of the support. A method of laminating and integrating an adhesive layer on one side, and optionally laminating a release liner on the adhesive layer so that the release-treated surface of the release liner faces the adhesive layer, (2) A method of forming an adhesive layer on the release liner by applying the above adhesive layer-forming solution onto the release-treated surface of the release liner and drying it, and laminating and integrating a support on the adhesive layer. etc.
- the adhesive layer-forming solution is obtained by uniformly stirring the selexipag, acrylic adhesive, solvent, and, if necessary, other additives.
- solvents include toluene, normal hexane, cyclohexane, normal heptane, and ethyl acetate.
- a solvent may be used individually by 1 type, or 2 or more types may be used together.
- the adhesive patch of the present invention has the above-described configuration, and is therefore excellent in percutaneous absorbability of selexipag.
- ⁇ Acrylic polymer (A10) (Acrylic polymer containing 68.15% by mass of 2-ethylhexyl acrylate units, 26.5% by mass of vinyl acetate units, 5.2% by mass of hydroxyethyl acrylate units, and 0.15% by mass of glycidyl methacrylate units, product manufactured by Henkel Name "DURO-TAK 387-2287”)
- Examples 1 to 10 In a solution containing 83.6 parts by weight of each of the acrylic polymers (A1) to (A10), 4.4 parts by weight of free-base selexipag was added so as to obtain an adhesive layer containing each component in the amount shown in Table 1. and 12.0 parts by mass of isopropyl myristate to prepare an adhesive layer forming solution.
- a polyethylene terephthalate film with a thickness of 75 ⁇ m and subjected to silicone release treatment was prepared as a release liner.
- An adhesive layer-forming solution was applied to the silicone release-treated surface of the polyethylene terephthalate film and dried at 60° C. for 30 minutes to form an adhesive layer having a thickness of 70 ⁇ m on the silicone release-treated surface of the polyethylene terephthalate film.
- a laminate was produced.
- a polyethylene terephthalate film having a thickness of 38 ⁇ m is prepared as a support, and one surface of this support and the adhesive layer of the laminate are superposed so as to face each other, and the adhesive layer of the laminate is transferred to the support.
- a patch was manufactured by laminating and integrating the layers, and various performances were evaluated according to the methods described later.
- the free-base selexipag content in the obtained adhesive layer was 4.4% by mass.
- Example 11 Comparative Examples 1 and 2
- the free-base selexipag, the following acrylic polymer (A11), the following rubber-based adhesives (B1) and (B2), and isopropyl myristate were added so as to obtain an adhesive layer containing the respective components in the amounts shown in Table 2.
- an adhesive layer-forming solution containing the following tackifier was prepared, a patch was produced in the same manner as in Example 1, and various performances were evaluated according to the methods described later.
- Example 12-13 In order to obtain an adhesive layer containing each component in the amount shown in Table 3, the amount of the acrylic polymer (A4) and the type and amount of the plasticizer were added to 4.4 parts by mass of the free base type selexipag. was changed, a patch was produced in the same manner as in Example 1, and various properties were evaluated according to the methods described later.
- Example 14-18 In order to obtain an adhesive layer containing each component in the amount shown in Table 4, the amount of isopropyl myristate was set to 12.0 parts by mass, and the amount of free base selexipag and the acrylic polymer (A4) were blended. Patches were produced in the same manner as in Example 1 with varying amounts, and various properties were evaluated according to the methods described later.
- Example 19-22 In order to obtain an adhesive layer containing each component in the amount shown in Table 5, the amount of the acrylic polymer (A4) and the amount of isopropyl myristate were adjusted to 4.4 parts by mass of the free base type selexipag. Instead, a patch was produced in the same manner as in Example 1, and various properties were evaluated according to the methods described later.
- the adhesive patch was cut to obtain a flat circular test piece with a diameter of 1 cm and an area of 0.8 cm 2 .
- hairless mouse skin was fixed to the Franz-type diffusion cell, and the dermis side of the skin was brought into contact with the receptor liquid.
- a test piece from which the release liner was peeled off was attached to the stratum corneum side of the skin using an adhesive layer.
- the receptor liquid contained phosphate-buffered saline adjusted to pH 7.4 and polyethylene glycol 400 at a volume ratio of 6:4 (phosphate-buffered saline: polyethylene glycol 400).
- the free-base selexipag permeation amount was calculated from the free-base selexipag concentration and the receptor fluid volume.
- the calculated free base selexipag permeation amount was divided by the area of the test piece (0.8 cm 2 ) and the obtained value was defined as the 24-hour cumulative skin permeation amount ( ⁇ g/cm 2 ) of the free base selexipag.
- the obtained results are shown in the column of "24h Cumulative Skin Permeation Amount" in Tables 1 to 5.
- the theoretical amount Q T ( ⁇ g/cm 2 ) of the free-base selexipag contained in the adhesive layer of the test piece was a value calculated as follows. First, for a test piece obtained by cutting the adhesive patch immediately after production, the mass ( ⁇ g) of the adhesive layer in the test piece was divided by the area (0.8 cm 2 ) of the test piece. The mass W T ( ⁇ g/cm 2 ) of the adhesive layer per unit area of the piece was determined. In addition, the content (% by mass) of the free-base selexipag in the adhesive layer contained in the patch immediately after production was defined as Cs .
- the 24-hour cumulative skin permeation rate of the free-base selexipag patch immediately after production is Y0
- the 24-h cumulative skin permeation rate of the free-base selexipag patch after storage at 40°C for 1 month is Y1
- test piece After sealing the observed test piece in an aluminum packaging material, it was stored under a temperature atmosphere of 40°C for 1 month, and then further stored under a temperature atmosphere of 25°C for 24 hours. After storage, the test piece was taken out, and the state of precipitation of free base selexipag crystals was observed and evaluated in the same manner as immediately after production.
- Medium crystals Crystals with a crystal diameter of 110 ⁇ m or more and less than 1000 ⁇ m
- Large crystals Crystals with a crystal diameter of 1000 ⁇ m or more
- the crystal diameter means the diameter of the smallest perfect circle that can surround the crystal on the photograph.
- (A, A, A) means that the entire amount of free base selexipag was dissolved and no crystals of free base selexipag were precipitated.
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Abstract
Description
本発明の貼付剤は、支持体と、上記支持体の一面に積層一体化された粘着層とを含む。粘着層は、セレキシパグ、及びアクリル系粘着剤を含む。
セレキシパグには、遊離塩基型と酸付加塩型が含まれる。粘着層は、遊離塩基型のセレキシパグ及び酸付加塩型のセレキシパグのうち少なくとも一方を含んでいればよい。なかでも、遊離塩基型(フリー体)のセレキシパグが好ましい。遊離塩基型のセレキシパグとは、塩の形態となっていない、セレキシパグ(2-{4-[(5,6-ジフェニルピラジン-2-イル)(プロパン-2-イル)アミノ]ブトキシ}-N-メタンスルホニルアセトアミド)そのものを意味する。遊離塩基型のセレキシパグによれば、セレキシパグの経皮吸収性がより優れる貼付剤を提供することができる。粘着層は、遊離塩基型のセレキシパグ及び酸付加塩型のセレキシパグいずれか一方のみを含んでいてもよく、遊離塩基型のセレキシパグ及び酸付加塩型のセレキシパグの双方を含んでいてもよい。
粘着層は、アクリル系粘着剤を含む。粘着層において、セレキシパグ及びアクリル系粘着剤を組み合わせて用いることにより、セレキシパグの経皮吸収性が向上された貼付剤を提供することができる。
粘着層中におけるビニル系モノマー(I)単位の含有量(質量部)
=[W1×C1+W2×C2+・・・+Wn×Cn]/100
(式中、nは、粘着層中に含まれるアクリル系重合体の種類数を表す整数であり、Wnは、粘着層中におけるn種目のアクリル系重合体の含有量(質量部)であり、Cnは、上記n種目のアクリル系重合体中におけるビニル系モノマー(I)単位の含有量(質量%)である。)
粘着層は、可塑剤を含んでいることが好ましい。可塑剤を用いることにより、セレキシパグの拡散性を変化させ、放出性を調整することができる。
粘着付与剤としては、テルペン樹脂、変性テルペン樹脂、水素添加テルペン樹脂、テルペンフェノール樹脂、ロジン、水素添加ロジン、ロジンエステル、石油樹脂、クマロン・インデン樹脂、フェノール樹脂、キシレン樹脂、脂環族飽和炭化水素樹脂などが挙げられる。粘着付与剤は、一種単独で用いられても、2種以上が併用されてもよい。粘着層中における粘着付与剤の含有量は、アクリル系粘着剤100質量部に対して、15~80質量部が好ましく、20~70質量部がより好ましい。
充填剤は、粘着層の形状保持性を調整するために用いられる。充填剤としては、例えば、軽質無水ケイ酸、酸化チタン、酸化亜鉛などの無機充填剤;炭酸カルシウム、ステアリン酸マグネシウムなどの有機金属塩類;乳糖、結晶セルロース、エチルセルロース、低置換度ヒドロキシプロピルセルロースなどのセルロース誘導体;架橋ポリビニルピロリドンなどが挙げられる。充填剤は、一種単独で用いられても、2種以上が併用されてもよい。粘着層中における充填剤の含有量は、アクリル系粘着剤100質量部に対して、5質量部以下が好ましく、0.1~2質量部がより好ましい。
本発明の貼付剤では、支持体の一面に粘着層が積層一体化される。支持体は、粘着層中の薬物の損失を防ぎ、貼付剤に自己保持性を付与するための強度を有することが求められる。このような支持体としては、樹脂フィルム、不織布、織布、編布、アルミニウムシートなどが挙げられる。
本発明の貼付剤では、粘着層の一面に、剥離ライナーが剥離可能に積層されていてもよい。剥離ライナーは、粘着層中の薬物の損失防止や粘着層を保護するために用いられる。
本発明の貼付剤の製造方法としては、例えば、(1)セレキシパグ、アクリル系粘着剤、及び溶媒を含む粘着層形成溶液を、支持体の一面に塗工した後に乾燥させることにより、支持体の一面に粘着層を積層一体化し、必要に応じて、粘着層に剥離ライナーを、剥離ライナーの離型処理が施された面が粘着層に対向した状態となるように積層する方法、(2)上記粘着層形成溶液を剥離ライナーの離型処理が施された面上に塗工し、乾燥させることにより、剥離ライナー上に粘着層を形成し、この粘着層に支持体を積層一体化させる方法などが挙げられる。
2-エチルヘキシルアクリレート65質量部、及びN-ビニル-2-ピロリドン35質量部を含むモノマー、並びに酢酸エチル185質量部からなる反応液を重合機に供給して重合機内を80℃の窒素雰囲気とした。そして、上記反応液にラウロイルパーオキサイド0.6質量部を酢酸エチル16質量部に溶解させてなる重合開始剤溶液を14時間かけて加えながら上記モノマーを共重合させ、重合完了後に上記反応液に更に酢酸エチルを加えて、アクリル系重合体(A1)の含有量が30質量%のアクリル系重合体(A1)溶液を得た。
2-エチルヘキシルアクリレート75質量部、及びN-ビニル-2-ピロリドン25質量部を含むモノマー、並びに酢酸エチル50質量部からなる反応液を重合機に供給して重合機内を80℃の窒素雰囲気とした。そして、上記反応液にラウロイルパーオキサイド1.2質量部を酢酸エチル30質量部及びシクロヘキサン20質量部に溶解させてなる重合開始剤溶液を24時間かけて加えながら上記モノマーを共重合させ、重合完了後に上記反応液に更に酢酸エチルを加えて、アクリル系重合体(A2)の含有量が30質量%のアクリル系重合体(A2)溶液を得た。
2-エチルヘキシルアクリレート75質量部、N-ビニル-2-ピロリドン22質量部、及びアクリル酸3質量部を含むモノマー、並びに酢酸エチル150質量部からなる反応液を重合機に供給して重合機内を80℃の窒素雰囲気とした。そして、上記反応液にラウロイルパーオキサイド0.6質量部を酢酸エチル17質量部に溶解させてなる重合開始剤溶液を24時間かけて加えながら上記モノマーを共重合させ、重合完了後に上記反応液に更に酢酸エチルを加えて、アクリル系重合体(A3)の含有量が30質量%のアクリル系重合体(A3)溶液を得た。
N-ビニル-2-ピロリドン10質量部、エチルアクリレート50質量部、及びn-オクチルアクリレート40質量部を含むモノマー、並びに酢酸エチル50質量部からなる反応液を重合機に供給して重合機内を80℃の窒素雰囲気とした。そして、上記反応液にラウロイルパーオキサイド1質量部を酢酸エチル30質量部及びシクロヘキサン20質量部に溶解させてなる重合開始剤溶液を24時間かけて加えながら上記モノマーを共重合させ、重合完了後に上記反応液に更に酢酸エチルを加えて、アクリル系重合体(A4)の含有量が30質量%のアクリル系重合体(A4)溶液を得た。
N-ビニル-2-ピロリドン5質量部、エチルアクリレート50質量部、及びn-オクチルアクリレート45質量部を含むモノマー、並びに酢酸エチル140質量部からなる反応液を重合機に供給して重合機内を80℃の窒素雰囲気とした。そして、上記反応液にラウロイルパーオキサイド0.4質量部を酢酸エチル20質量部に溶解させてなる重合開始剤溶液を14時間かけて加えながら上記モノマーを共重合させ、重合完了後に上記反応液に更に酢酸エチルを加えて、アクリル系重合体(A5)の含有量が30質量%のアクリル系重合体(A5)溶液を得た。
2-エチルヘキシルアクリレート57質量部、n-ブチルアクリレート29質量部、ジアセトンアクリルアミド14質量部を含むモノマー、並びに酢酸エチル150質量部からなる反応液を重合機に供給して重合機内を80℃の窒素雰囲気とした。そして、上記反応液にラウロイルパーオキサイド0.6質量部を酢酸エチル17質量部に溶解させてなる重合開始剤溶液を14時間かけて加えながら上記モノマーを共重合させ、重合完了後に上記反応液に更に酢酸エチルを加えて、アクリル系重合体(A6)の含有量が30質量%のアクリル系重合体(A6)溶液を得た。
2-エチルヘキシルアクリレート75質量部、及びエチルアクリレート25質量部を含むモノマー、並びに酢酸エチル75質量部からなる反応液を重合機に供給して重合機内を80℃の窒素雰囲気とした。そして、上記反応液にラウロイルパーオキサイド0.6質量部を酢酸エチル17質量部に溶解させてなる重合開始剤溶液を14時間かけて加えながら上記モノマーを共重合させ、重合完了後に上記反応液に更に酢酸エチルを加えて、アクリル系重合体(A7)の含有量が30質量%のアクリル系重合体(A7)溶液を得た。
エチルアクリレート56質量部、及びn-オクチルアクリレート44質量部を含むモノマー、並びに酢酸エチル122質量部からなる反応液を重合機に供給して重合機内を80℃の窒素雰囲気とした。そして、上記反応液にラウロイルパーオキサイド0.431質量部を酢酸エチル20質量部に溶解させてなる重合開始剤溶液を14時間かけて加えながら上記モノマーを共重合させ、重合完了後に上記反応液に更に酢酸エチルを加えて、アクリル系重合体(A8)の含有量が30質量%のアクリル系重合体(A8)溶液を得た。
2-エチルヘキシルアクリレート57質量部、エチルアクリレート14質量部、n-ブチルアクリレート29質量部を含むモノマー、並びに酢酸エチル75質量部からなる反応液を重合機に供給して重合機内を80℃の窒素雰囲気とした。そして、上記反応液にラウロイルパーオキサイド0.6質量部を酢酸エチル17質量部に溶解させてなる重合開始剤溶液を14時間かけて加えながら上記モノマーを共重合させ、重合完了後に上記反応液に更に酢酸エチルを加えて、アクリル系重合体(A9)の含有量が30質量%のアクリル系重合体(A9)溶液を得た。
(2-エチルヘキシルアクリレート単位68.15質量%、酢酸ビニル単位26.5質量%、ヒドロキシエチルアクリレート単位5.2質量%、及びグリシジルメタクリレート単位0.15質量を含むアクリル系重合体、Henkel社製 商品名「DURO-TAK 387-2287」)
各成分を表1に示す配合量で含む粘着層が得られるように、アクリル系重合体(A1)~(A10)をそれぞれ83.6質量部含む溶液に、遊離塩基型セレキシパグを4.4質量部、およびミリスチン酸イソプロピルを12.0質量部配合し、粘着層形成溶液を作製した。
各成分を表2に示す配合量で含む粘着層が得られるように、遊離塩基型セレキシパグ、下記アクリル系重合体(A11)、下記ゴム系粘着剤(B1)及び(B2)、並びにミリスチン酸イソプロピル及び下記粘着付与剤を含む粘着層形成溶液を作製し、実施例1と同様にして貼付剤を製造し、後述する方法に従って各種性能を評価した。
・ゴム系粘着剤(B1)(スチレン-イソプレン-スチレンブロック共重合体(SIS)、Kraton社製 商品名「クレイトンD DX401」および、商品名「クレイトンD D1117PT」の質量比1:1.54混合物)
・ゴム系粘着剤(B2)(ポリイソブチレン(PIB)、BASF社製 商品名「OPPANOL B100」、商品名「OPPANOL B30」および商品名「OPPANOL B12」の質量比1:1:1混合物)
・粘着付与剤:脂環族飽和炭化水素樹脂(荒川化学工業社製 商品名「アルコン P-90」)
各成分を表3に示す配合量で含む粘着層が得られるように、遊離塩基型セレキシパグ4.4質量部に対し、アクリル系重合体(A4)の配合量、および可塑剤の種類と配合量を変え、実施例1と同様にして貼付剤を製造し、後述する方法に従って各種性能を評価した。
各成分を表4に示す配合量で含む粘着層が得られるように、ミリスチン酸イソプロピルの配合量を12.0質量部とし、遊離塩基型セレキシパグの配合量とアクリル系重合体(A4)の配合量を変え、実施例1と同様にして貼付剤を製造し、後述する方法に従って各種性能を評価した。
各成分を表5に示す配合量で含む粘着層が得られるように、遊離塩基型セレキシパグ4.4質量部に対し、アクリル系重合体(A4)の配合量、およびミリスチン酸イソプロピルの配合量を変え、実施例1と同様にして貼付剤を製造し、後述する方法に従って各種性能を評価した。
実施例及び比較例の貼付剤について、下記手順に従って、皮膚透過性、及び遊離塩基型セレキシパグの溶解状態を評価した。
貼付剤について、製造直後及び40℃にて1カ月保存後、皮膚透過性を評価するために、以下の方法でヘアレスマウス皮膚透過性試験を行った。なお、貼付剤の保存は、貼付剤を遮光したアルミ袋中に密封し、40℃の温度雰囲気下で1カ月に亘って保存することにより行った。
24h累積皮膚透過率(%)=(QE/QT)×100
QT(μg/cm2)=WT×Cs/100
遊離塩基型セレキシパグの24h累積皮膚透過率の変化率=100×(Y1-Y0)/Y0
貼付剤の製造直後において、貼付剤から面積が5cm2の平面正方形状の試験片を打ち抜いた。次に、試験片から剥離ライナーを剥離除去し、偏光顕微鏡を用いて倍率40倍で試験片のほぼ中央部の1cm2の範囲の粘着層表面を観察し、写真撮影を行った。得られた写真を観察し、遊離塩基型セレキシパグの結晶の析出状態を観察し、結晶径の大きさによって各結晶を以下に示す「小結晶・中結晶・大結晶」のいずれかに分類し、さらに各大きさの結晶の個数を以下に示す「A・B・C」のいずれかに分類し、評価した。
小結晶:結晶径が10μm以上で且つ110μm未満であった結晶
中結晶:結晶径が110μm以上で且つ1000μm未満であった結晶
大結晶:結晶径が1000μm以上であった結晶
A:結晶の個数が、0個であった。
B:結晶の個数が、1個以上で且つ100個未満であった。
C:結晶の個数が、100個以上であった。
小結晶が0個、中結晶が0個、大結晶が0個の場合は(A、A、A)、
小結晶が0個、中結晶が3個、大結晶が0個の場合は(A、B、A)、
小結晶が100個以上、中結晶が0個、大結晶が0個の場合は(C、A、A)のように表記した。
本出願は、2021年11月15日に出願された日本国特許出願第2021-185910号に基づく優先権を主張し、この出願の開示はこれらの全体を参照することにより本明細書に組み込まれる。
Claims (4)
- 支持体と、上記支持体の一面に積層一体化され、セレキシパグ、及びアクリル系粘着剤を含む粘着層とを含むことを特徴とする貼付剤。
- ビニル系モノマー(I)単位が、N-ビニル-2-ピロリドン単位、及びジアセトンアクリルアミド単位のうち少なくとも一方を含むことを特徴とする請求項2に記載の貼付剤。
- 粘着層中における、ビニル系モノマー(I)単位の含有量に対するセレキシパグの含有量の質量比[上記セレキシパグの含有量(質量部)/上記ビニル系モノマー(I)単位の含有量(質量部)]が、0.2以上且つ1.1以下であることを特徴とする請求項2又は3に記載の貼付剤。
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JP6459148B2 (ja) | 2015-09-29 | 2019-01-30 | 王子ホールディングス株式会社 | 経皮吸収型製剤 |
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