JP2019210253A - Patch containing fentanyl - Google Patents
Patch containing fentanyl Download PDFInfo
- Publication number
- JP2019210253A JP2019210253A JP2018108939A JP2018108939A JP2019210253A JP 2019210253 A JP2019210253 A JP 2019210253A JP 2018108939 A JP2018108939 A JP 2018108939A JP 2018108939 A JP2018108939 A JP 2018108939A JP 2019210253 A JP2019210253 A JP 2019210253A
- Authority
- JP
- Japan
- Prior art keywords
- fentanyl
- acid
- adhesive layer
- patch
- salt
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 229960002428 fentanyl Drugs 0.000 title claims abstract description 53
- PJMPHNIQZUBGLI-UHFFFAOYSA-N fentanyl Chemical compound C=1C=CC=CC=1N(C(=O)CC)C(CC1)CCN1CCC1=CC=CC=C1 PJMPHNIQZUBGLI-UHFFFAOYSA-N 0.000 title 1
- IVLVTNPOHDFFCJ-UHFFFAOYSA-N fentanyl citrate Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O.C=1C=CC=CC=1N(C(=O)CC)C(CC1)CCN1CCC1=CC=CC=C1 IVLVTNPOHDFFCJ-UHFFFAOYSA-N 0.000 claims abstract description 85
- 150000003839 salts Chemical class 0.000 claims abstract description 50
- 229960004207 fentanyl citrate Drugs 0.000 claims abstract description 33
- 239000012790 adhesive layer Substances 0.000 claims abstract description 19
- 239000000853 adhesive Substances 0.000 claims abstract description 14
- 230000001070 adhesive effect Effects 0.000 claims abstract description 14
- 239000004820 Pressure-sensitive adhesive Substances 0.000 claims description 50
- 239000010410 layer Substances 0.000 claims description 37
- 229920005989 resin Polymers 0.000 claims description 12
- 239000011347 resin Substances 0.000 claims description 12
- -1 2-ethylhexyl Chemical group 0.000 description 40
- 235000014113 dietary fatty acids Nutrition 0.000 description 18
- 239000000194 fatty acid Substances 0.000 description 18
- 229930195729 fatty acid Natural products 0.000 description 18
- 238000002360 preparation method Methods 0.000 description 16
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 9
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 9
- 239000007788 liquid Substances 0.000 description 9
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 8
- 229920001971 elastomer Polymers 0.000 description 8
- RSWGJHLUYNHPMX-UHFFFAOYSA-N Abietic-Saeure Natural products C12CCC(C(C)C)=CC2=CCC2C1(C)CCCC2(C)C(O)=O RSWGJHLUYNHPMX-UHFFFAOYSA-N 0.000 description 7
- 229920002367 Polyisobutene Polymers 0.000 description 7
- KHPCPRHQVVSZAH-HUOMCSJISA-N Rosin Natural products O(C/C=C/c1ccccc1)[C@H]1[C@H](O)[C@@H](O)[C@@H](O)[C@@H](CO)O1 KHPCPRHQVVSZAH-HUOMCSJISA-N 0.000 description 7
- 239000002253 acid Substances 0.000 description 7
- 239000003795 chemical substances by application Substances 0.000 description 7
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- 239000005060 rubber Substances 0.000 description 7
- 238000012360 testing method Methods 0.000 description 7
- KHPCPRHQVVSZAH-UHFFFAOYSA-N trans-cinnamyl beta-D-glucopyranoside Natural products OC1C(O)C(O)C(CO)OC1OCC=CC1=CC=CC=C1 KHPCPRHQVVSZAH-UHFFFAOYSA-N 0.000 description 7
- NIXOWILDQLNWCW-UHFFFAOYSA-M Acrylate Chemical compound [O-]C(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-M 0.000 description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 6
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 6
- 238000010521 absorption reaction Methods 0.000 description 6
- 150000004665 fatty acids Chemical class 0.000 description 6
- 239000002202 Polyethylene glycol Substances 0.000 description 5
- NIXOWILDQLNWCW-UHFFFAOYSA-N acrylic acid group Chemical group C(C=C)(=O)O NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 description 5
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- 239000003381 stabilizer Substances 0.000 description 5
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- HIQIXEFWDLTDED-UHFFFAOYSA-N 4-hydroxy-1-piperidin-4-ylpyrrolidin-2-one Chemical compound O=C1CC(O)CN1C1CCNCC1 HIQIXEFWDLTDED-UHFFFAOYSA-N 0.000 description 4
- GLZPCOQZEFWAFX-UHFFFAOYSA-N Geraniol Chemical compound CC(C)=CCCC(C)=CCO GLZPCOQZEFWAFX-UHFFFAOYSA-N 0.000 description 4
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- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 4
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 4
- 239000000945 filler Substances 0.000 description 4
- 235000011187 glycerol Nutrition 0.000 description 4
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 4
- GHBFNMLVSPCDGN-UHFFFAOYSA-N rac-1-monooctanoylglycerol Chemical compound CCCCCCCC(=O)OCC(O)CO GHBFNMLVSPCDGN-UHFFFAOYSA-N 0.000 description 4
- 238000013112 stability test Methods 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 4
- WBYWAXJHAXSJNI-VOTSOKGWSA-M .beta-Phenylacrylic acid Natural products [O-]C(=O)\C=C\C1=CC=CC=C1 WBYWAXJHAXSJNI-VOTSOKGWSA-M 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- CMBYOWLFQAFZCP-UHFFFAOYSA-N Hexyl dodecanoate Chemical compound CCCCCCCCCCCC(=O)OCCCCCC CMBYOWLFQAFZCP-UHFFFAOYSA-N 0.000 description 3
- 239000013032 Hydrocarbon resin Substances 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 239000004698 Polyethylene Substances 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 235000011054 acetic acid Nutrition 0.000 description 3
- 125000002723 alicyclic group Chemical group 0.000 description 3
- 150000005215 alkyl ethers Chemical class 0.000 description 3
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 3
- 239000008280 blood Substances 0.000 description 3
- 210000004369 blood Anatomy 0.000 description 3
- 235000013985 cinnamic acid Nutrition 0.000 description 3
- 229930016911 cinnamic acid Natural products 0.000 description 3
- 229920001577 copolymer Polymers 0.000 description 3
- MTHSVFCYNBDYFN-UHFFFAOYSA-N diethylene glycol Chemical compound OCCOCCO MTHSVFCYNBDYFN-UHFFFAOYSA-N 0.000 description 3
- 150000002191 fatty alcohols Chemical class 0.000 description 3
- 229940093915 gynecological organic acid Drugs 0.000 description 3
- 229940100463 hexyl laurate Drugs 0.000 description 3
- 229920006270 hydrocarbon resin Polymers 0.000 description 3
- 229940057995 liquid paraffin Drugs 0.000 description 3
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 3
- 238000000034 method Methods 0.000 description 3
- WBYWAXJHAXSJNI-UHFFFAOYSA-N methyl p-hydroxycinnamate Natural products OC(=O)C=CC1=CC=CC=C1 WBYWAXJHAXSJNI-UHFFFAOYSA-N 0.000 description 3
- 235000005985 organic acids Nutrition 0.000 description 3
- 230000002093 peripheral effect Effects 0.000 description 3
- 239000011505 plaster Substances 0.000 description 3
- 229920001083 polybutene Polymers 0.000 description 3
- 229920000573 polyethylene Polymers 0.000 description 3
- 239000010734 process oil Substances 0.000 description 3
- 239000004576 sand Substances 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- PRAKJMSDJKAYCZ-UHFFFAOYSA-N squalane Chemical compound CC(C)CCCC(C)CCCC(C)CCCCC(C)CCCC(C)CCCC(C)C PRAKJMSDJKAYCZ-UHFFFAOYSA-N 0.000 description 3
- XMGQYMWWDOXHJM-JTQLQIEISA-N (+)-α-limonene Chemical compound CC(=C)[C@@H]1CCC(C)=CC1 XMGQYMWWDOXHJM-JTQLQIEISA-N 0.000 description 2
- ALSTYHKOOCGGFT-KTKRTIGZSA-N (9Z)-octadecen-1-ol Chemical compound CCCCCCCC\C=C/CCCCCCCCO ALSTYHKOOCGGFT-KTKRTIGZSA-N 0.000 description 2
- WRIDQFICGBMAFQ-UHFFFAOYSA-N (E)-8-Octadecenoic acid Natural products CCCCCCCCCC=CCCCCCCC(O)=O WRIDQFICGBMAFQ-UHFFFAOYSA-N 0.000 description 2
- DSSYKIVIOFKYAU-XCBNKYQSSA-N (R)-camphor Chemical compound C1C[C@@]2(C)C(=O)C[C@@H]1C2(C)C DSSYKIVIOFKYAU-XCBNKYQSSA-N 0.000 description 2
- AXTGDCSMTYGJND-UHFFFAOYSA-N 1-dodecylazepan-2-one Chemical compound CCCCCCCCCCCCN1CCCCCC1=O AXTGDCSMTYGJND-UHFFFAOYSA-N 0.000 description 2
- RZRNAYUHWVFMIP-KTKRTIGZSA-N 1-oleoylglycerol Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OCC(O)CO RZRNAYUHWVFMIP-KTKRTIGZSA-N 0.000 description 2
- XDOFQFKRPWOURC-UHFFFAOYSA-N 16-methylheptadecanoic acid Chemical compound CC(C)CCCCCCCCCCCCCCC(O)=O XDOFQFKRPWOURC-UHFFFAOYSA-N 0.000 description 2
- BHIZVZJETFVJMJ-UHFFFAOYSA-N 2-hydroxypropyl dodecanoate Chemical compound CCCCCCCCCCCC(=O)OCC(C)O BHIZVZJETFVJMJ-UHFFFAOYSA-N 0.000 description 2
- LQJBNNIYVWPHFW-UHFFFAOYSA-N 20:1omega9c fatty acid Natural products CCCCCCCCCCC=CCCCCCCCC(O)=O LQJBNNIYVWPHFW-UHFFFAOYSA-N 0.000 description 2
- XZIIFPSPUDAGJM-UHFFFAOYSA-N 6-chloro-2-n,2-n-diethylpyrimidine-2,4-diamine Chemical compound CCN(CC)C1=NC(N)=CC(Cl)=N1 XZIIFPSPUDAGJM-UHFFFAOYSA-N 0.000 description 2
- QSBYPNXLFMSGKH-UHFFFAOYSA-N 9-Heptadecensaeure Natural products CCCCCCCC=CCCCCCCCC(O)=O QSBYPNXLFMSGKH-UHFFFAOYSA-N 0.000 description 2
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 description 2
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 2
- LKUNXBRZDFMZOK-GFCCVEGCSA-N Capric acid monoglyceride Natural products CCCCCCCCCC(=O)OC[C@H](O)CO LKUNXBRZDFMZOK-GFCCVEGCSA-N 0.000 description 2
- WBYWAXJHAXSJNI-SREVYHEPSA-N Cinnamic acid Chemical compound OC(=O)\C=C/C1=CC=CC=C1 WBYWAXJHAXSJNI-SREVYHEPSA-N 0.000 description 2
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- AOMUHOFOVNGZAN-UHFFFAOYSA-N N,N-bis(2-hydroxyethyl)dodecanamide Chemical compound CCCCCCCCCCCC(=O)N(CCO)CCO AOMUHOFOVNGZAN-UHFFFAOYSA-N 0.000 description 2
- 229920000459 Nitrile rubber Polymers 0.000 description 2
- 239000005642 Oleic acid Substances 0.000 description 2
- ZQPPMHVWECSIRJ-UHFFFAOYSA-N Oleic acid Natural products CCCCCCCCC=CCCCCCCCC(O)=O ZQPPMHVWECSIRJ-UHFFFAOYSA-N 0.000 description 2
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- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
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- DOIRQSBPFJWKBE-UHFFFAOYSA-N dibutyl phthalate Chemical compound CCCCOC(=O)C1=CC=CC=C1C(=O)OCCCC DOIRQSBPFJWKBE-UHFFFAOYSA-N 0.000 description 2
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Abstract
Description
本発明は、フェンタニル含有貼付剤に関する。 The present invention relates to a fentanyl-containing patch.
フェンタニルは、合成オピオイドに分類される化合物であり、μオピオイド受容体に対して高選択的に完全作動薬として作用し、中等度から高度の癌性疼痛又は慢性疼痛、術後疼痛の緩和を目的として使用される。フェンタニルの塩としては、クエン酸塩の状態で利用される。 Fentanyl is a compound classified as a synthetic opioid and acts as a full agonist with high selectivity to the μ opioid receptor, aiming to alleviate moderate to severe cancer pain or chronic pain and postoperative pain Used as. As a salt of fentanyl, it is used in the state of citrate.
フェンタニル含有貼付剤は、その着脱により、フェンタニルの血中濃度を管理しやすいという利点を期待され、皮膚刺激性や皮膚透過性の観点から多くの検討が行われている（例えば、特許文献１〜３）。また、１日１回投与用フェンタニル含有貼付剤としては、フェントス（登録商標）テープ、ワンデュロ（登録商標）パッチ等が販売されている（例えば、非特許文献１〜２）。 The fentanyl-containing patch is expected to have an advantage of easy management of the blood concentration of fentanyl by its attachment and detachment, and many studies have been made from the viewpoint of skin irritation and skin permeability (for example, Patent Documents 1 to 3). 3). In addition, as a fentanyl-containing patch for once-daily administration, Fentos (registered trademark) tape, Wanduro (registered trademark) patch, etc. are sold (for example, Non-Patent Documents 1 and 2).
フェンタニルは、通常、中等度から高度の疼痛患者に投与されるため、その患者の病態に合わせた細かな血中濃度の管理が要求されることがある。しかし、フェンタニル含有貼付剤は、貼付面積１ｃｍ２あたりフェンタニルクエン酸塩を０．２ｍｇ以上含有しており、細かな血中濃度の調節をすることが困難な場合がある。 Since fentanyl is usually administered to patients with moderate to severe pain, it may be required to control the blood concentration in detail according to the pathology of the patient. However, the fentanyl-containing patch contains 0.2 mg or more of fentanyl citrate per 1 cm 2 of the patch area, and it may be difficult to finely adjust the blood concentration.
本発明者らは、貼付面積が２．５ｃｍ２であり、フェンタニルクエン酸塩０．５ｍｇを含有する貼付剤を調製したところ、予想外にもフェンタニルクエン酸塩の保存安定性が低下することを見出した。 The present inventors prepared a patch containing 0.5 mg of fentanyl citrate having an area of 2.5 cm 2 and unexpectedly reducing the storage stability of fentanyl citrate. I found it.
そこで、本発明の目的は、フェンタニル又はその塩の含有量が低くても、保存安定性に優れた貼付剤を提供することにある。 Therefore, an object of the present invention is to provide a patch excellent in storage stability even when the content of fentanyl or a salt thereof is low.
本発明は、以下の［１］〜［１４］を提供する。
［１］支持体上に粘着剤層を備える貼付剤であって、上記粘着剤層が、フェンタニル又はその塩、及び、粘着剤を含有し、上記粘着剤層におけるフェンタニル又はその塩の含有量が、貼付面積１ｃｍ２あたり、フェンタニルクエン酸塩に換算した場合に０．０１〜０．１８ｍｇである、貼付剤。
［２］テープ剤である、［１］に記載の貼付剤。
［３］粘着剤層におけるフェンタニル又はその塩の含有量が、フェンタニルクエン酸塩に換算した場合に０．１〜０．８ｍｇである、［１］又は［２］に記載の貼付剤。
［４］貼付面積が３〜１０ｃｍ２である、［１］〜［３］のいずれかに記載の貼付剤。
［５］フェンタニルまたはその塩の濃度が、粘着剤層全体の質量を基準として０．５〜３．８％である、［１］〜［４］のいずれかに記載の貼付剤。
［６］粘着剤層が、可塑剤をさらに含む、［１］〜［５］のいずれかに記載の貼付剤。
［７］粘着剤層が、粘着付与樹脂をさらに含む、［１］〜［６］のいずれかに記載の貼付剤。
［８］支持体上に粘着剤層を備える貼付剤であって、上記粘着剤層が、フェンタニル又はその塩、及び、粘着剤を含有し、上記粘着剤層におけるフェンタニル又はその塩の濃度が、フェンタニルクエン酸塩の質量に換算した場合に、０．５〜３．８％である、貼付剤。
［９］テープ剤である、［８］に記載の貼付剤。
［１０］粘着剤層におけるフェンタニル又はその塩の含有量が、フェンタニルクエン酸塩に換算した場合に０．１〜０．８ｍｇである、［８］又は［９］に記載の貼付剤。
［１１］貼付面積が３〜１０ｃｍ２である、［８］〜［１０］のいずれかに記載の貼付剤。
［１２］フェンタニルまたはその塩の濃度が、粘着剤層全体の質量を基準として０．５〜３．８％である、［８］〜［１１］のいずれかに記載の貼付剤。
［１３］粘着剤層が、可塑剤をさらに含む、［８］〜［１２］のいずれかに記載の貼付剤。
［１４］粘着剤層が、粘着付与樹脂をさらに含む、［８］〜［１３］のいずれかに記載の貼付剤。
The present invention provides the following [1] to [14].
[1] A patch comprising a pressure-sensitive adhesive layer on a support, wherein the pressure-sensitive adhesive layer contains fentanyl or a salt thereof and a pressure-sensitive adhesive, and the content of fentanyl or a salt thereof in the pressure-sensitive adhesive layer is The patch, which is 0.01 to 0.18 mg when converted to fentanyl citrate per 1 cm 2 of the application area.
[2] The patch according to [1], which is a tape.
[3] The patch according to [1] or [2], wherein the content of fentanyl or a salt thereof in the pressure-sensitive adhesive layer is 0.1 to 0.8 mg when converted to fentanyl citrate.
[4] The patch according to any one of [1] to [3], wherein the patch area is 3 to 10 cm 2 .
[5] The patch according to any one of [1] to [4], wherein the concentration of fentanyl or a salt thereof is 0.5 to 3.8% based on the mass of the entire pressure-sensitive adhesive layer.
[6] The patch according to any one of [1] to [5], wherein the pressure-sensitive adhesive layer further contains a plasticizer.
[7] The patch according to any one of [1] to [6], wherein the pressure-sensitive adhesive layer further contains a tackifier resin.
[8] A patch comprising an adhesive layer on a support, wherein the adhesive layer contains fentanyl or a salt thereof, and an adhesive, and the concentration of fentanyl or the salt thereof in the adhesive layer is A patch, which is 0.5 to 3.8% when converted to the mass of fentanyl citrate.
[9] The patch according to [8], which is a tape.
[10] The patch according to [8] or [9], wherein the content of fentanyl or a salt thereof in the pressure-sensitive adhesive layer is 0.1 to 0.8 mg when converted to fentanyl citrate.
[11] The adhesive patch according to any one of [8] to [10], wherein the adhesive area is 3 to 10 cm 2 .
[12] The patch according to any one of [8] to [11], wherein the concentration of fentanyl or a salt thereof is 0.5 to 3.8% based on the mass of the entire pressure-sensitive adhesive layer.
[13] The patch according to any one of [8] to [12], wherein the pressure-sensitive adhesive layer further contains a plasticizer.
[14] The patch according to any one of [8] to [13], wherein the pressure-sensitive adhesive layer further contains a tackifier resin.
本発明によれば、フェンタニル又はその塩の含有量が低くても（例えば、フェンタニル又はその塩の含有量が、フェンタニルクエン酸塩に換算した場合に０．１〜０．８ｍｇであっても）、フェンタニル又はその塩の保存安定性に優れる貼付剤を提供することができる。 According to the present invention, even if the content of fentanyl or a salt thereof is low (for example, even if the content of fentanyl or a salt thereof is 0.1 to 0.8 mg when converted to fentanyl citrate) Further, it is possible to provide a patch excellent in the storage stability of fentanyl or a salt thereof.
本明細書において、「保存安定性」とは、フェンタニル又はその塩を含有する貼付剤を、一定期間保存した後にフェンタニル又はその塩が当初の形態のまま９５％以上残存していることを意味する。「保存安定性に優れる」とは、例えば、フェンタニルクエン酸塩を含有する貼付剤を、６０℃にて１ヶ月間保存した（苛酷試験）後に、フェンタニルクエン酸塩が保存前の含有量に基づいて、少なくとも９５％の量で残存していることを意味する。 In the present specification, “storage stability” means that fentanyl or a salt thereof remains at 95% or more in its original form after the patch containing fentanyl or a salt thereof is stored for a certain period of time. . “Excellent storage stability” means, for example, that a patch containing fentanyl citrate is stored at 60 ° C. for 1 month (severe test), and then fentanyl citrate is based on the content before storage. Meaning that it remains in an amount of at least 95%.
本発明について、以下に詳細に述べる。 The present invention is described in detail below.
本発明の一実施形態は、支持体上に粘着剤層を備える貼付剤であって、粘着剤層が、フェンタニル又はその塩、及び、粘着剤を含有し、粘着剤層におけるフェンタニル又はその塩の含有量が、貼付面積１ｃｍ２あたり、フェンタニルクエン酸塩に換算した場合に０．０１〜０．１８ｍｇである、貼付剤である。 One embodiment of the present invention is a patch comprising a pressure-sensitive adhesive layer on a support, the pressure-sensitive adhesive layer contains fentanyl or a salt thereof, and a pressure-sensitive adhesive, and fentanyl or a salt thereof in the pressure-sensitive adhesive layer. The patch has a content of 0.01 to 0.18 mg when converted to fentanyl citrate per 1 cm 2 of the patch area.
本実施形態に係る貼付剤では、粘着剤層にフェンタニル又はその塩、及び、粘着剤を含有する。 In the patch according to this embodiment, fentanyl or a salt thereof and an adhesive are contained in the adhesive layer.
フェンタニルは、Ｎ−（１−フェネチルポペリジン−４−イル）−Ｎ−フェニルプロパンアミドとも呼ばれる。フェンタニルの塩とは、フェンタニルの酸付加塩を意味し、具体的にはフェンタニルと有機酸又は無機酸との塩である。有機酸としては、例えば、酢酸、乳酸、クエン酸、シュウ酸、マレイン酸、フマル酸、グルタミン酸、アスパラギン酸、メタンスルホン酸、エタンスルホン酸、ベンゼンスルホン酸、トルエンスルホン酸が挙げられる。無機酸としては、例えば、塩酸、臭化水素酸、硫酸、硝酸、リン酸が挙げられる。好ましいフェンタニル又はその塩は、フェンタニルクエン酸塩である。 Fentanyl is also called N- (1-phenethylpoperidin-4-yl) -N-phenylpropanamide. The salt of fentanyl means an acid addition salt of fentanyl, specifically, a salt of fentanyl and an organic acid or an inorganic acid. Examples of the organic acid include acetic acid, lactic acid, citric acid, oxalic acid, maleic acid, fumaric acid, glutamic acid, aspartic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, and toluenesulfonic acid. Examples of the inorganic acid include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid. A preferred fentanyl or salt thereof is fentanyl citrate.
本明細書において、フェンタニル又はその塩の含有量又は濃度を計算するときは、フェンタニルクエン酸塩に換算して考慮される。フェンタニルクエン酸塩は、化学式（１）で表されるフェンタニルのモノクエン酸塩であり、その分子量は５２８．５９である。
本明細書において、「粘着剤層におけるフェンタニル又はその塩の含有量」とは、貼付剤の粘着剤層全体に含有されるフェンタニル又はその塩の含有量を意味し、本発明においては、フェンタニルクエン酸塩の質量に換算して考慮される。 In the present specification, “content of fentanyl or a salt thereof in the adhesive layer” means the content of fentanyl or a salt thereof contained in the entire adhesive layer of the patch. Considered in terms of the mass of the acid salt.
本実施形態に係る貼付剤では、粘着剤層におけるフェンタニル又はその塩の含有量は、フェンタニルクエン酸塩の質量に換算した場合に、０．１〜０．８ｍｇであることが好ましく、０．２〜０．７ｍｇであることがより好ましく、０．４〜０．６５ｍｇであることが特に好ましい。 In the patch according to the present embodiment, the content of fentanyl or a salt thereof in the pressure-sensitive adhesive layer is preferably 0.1 to 0.8 mg when converted to the mass of fentanyl citrate, 0.2 -0.7 mg is more preferable, and 0.4-0.65 mg is particularly preferable.
また、「貼付面積」とは、貼付剤を皮膚に貼付する際に皮膚に接する面積を意味する。本実施形態に係る貼付剤では、貼付面積は３〜１０ｃｍ２であることが好ましく、４〜８ｃｍ２であることがより好ましい。貼付面積が３ｃｍ２以上であると、取り扱い性がより向上し、貼付しやすい。貼付面積が１０ｃｍ２以下であると、衣服の着脱時等において貼付剤の周縁部がひっかかりにくくなる。 The “applied area” means an area in contact with the skin when the patch is applied to the skin. In the patch according to the present embodiment, the adhesion area is preferably from 3 to 10 cm 2, more preferably 4~8cm 2. When the application area is 3 cm 2 or more, the handleability is further improved and the application is easy. When the sticking area is 10 cm 2 or less, the peripheral edge of the patch becomes difficult to catch when attaching or detaching clothes.
「貼付面積１ｃｍ２あたりのフェンタニル又はその塩の含有量」とは、当該皮膚に接する面積１ｃｍ２に相当する粘着剤層におけるフェンタニル又はその塩の含有量を意味し、本発明においては、フェンタニルクエン酸塩の質量に換算して考慮される。すなわち、当該フェンタニル又はその塩の含有量とは、粘着剤層中に含有されるフェンタニル又はその塩の含有量をフェンタニルクエン酸塩の質量に換算した後、貼付面積で除した値であり得る。 “Content of fentanyl or a salt thereof per 1 cm 2 of application area” means a content of fentanyl or a salt thereof in an adhesive layer corresponding to an area of 1 cm 2 in contact with the skin. Considered in terms of the mass of the acid salt. That is, the content of the fentanyl or a salt thereof can be a value obtained by converting the content of fentanyl or a salt thereof contained in the pressure-sensitive adhesive layer into the mass of fentanyl citrate and then dividing the mass by the sticking area.
本実施形態に係る貼付剤では、貼付面積１ｃｍ２あたりのフェンタニル又はその塩の含有量が０．０１〜０．１８ｍｇであることが好ましく、０．０１〜０．０９ｍｇであることがより好ましく、０．０２〜０．０８ｍｇであることが更に好ましく、０．０３〜０．０７ｍｇであることが特に好ましい。 In the patch according to the present embodiment, the content of fentanyl or a salt thereof per 1 cm 2 of the application area is preferably 0.01 to 0.18 mg, more preferably 0.01 to 0.09 mg. It is more preferable that it is 0.02-0.08 mg, and it is especially preferable that it is 0.03-0.07 mg.
本明細書において、「フェンタニル又はその塩の濃度」とは、粘着剤層全体の質量を基準とした場合のフェンタニル又はその塩の質量を意味し、本発明においては、フェンタニルクエン酸塩の質量に換算して考慮される。 In the present specification, the “concentration of fentanyl or a salt thereof” means the mass of fentanyl or a salt thereof based on the mass of the entire pressure-sensitive adhesive layer. Considered in terms of conversion.
本実施形態に係る貼付剤では、粘着剤層におけるフェンタニル又はその塩の濃度は、フェンタニルクエン酸塩の質量に換算した場合に、０．５〜３．８％であることが好ましく、０．５〜３．５％であることがより好ましく、１〜２．５％であることが特に好ましい。 In the patch according to the present embodiment, the concentration of fentanyl or a salt thereof in the pressure-sensitive adhesive layer is preferably 0.5 to 3.8% when converted to the mass of fentanyl citrate, -3.5% is more preferable, and 1-2.5% is particularly preferable.
粘着剤は、貼付剤に一般的に使用されているものであればよく、例えば、アクリル系粘着剤、ゴム系粘着剤、シリコーン系粘着剤が挙げられる。好ましい粘着剤は、ゴム系粘着剤である。 The pressure-sensitive adhesive is not particularly limited as long as it is generally used for patches, and examples thereof include acrylic pressure-sensitive adhesives, rubber-based pressure-sensitive adhesives, and silicone-based pressure-sensitive adhesives. A preferred pressure-sensitive adhesive is a rubber-based pressure-sensitive adhesive.
アクリル系粘着剤として、例えば、（メタ）アクリル酸アルキルエステルの重合体又は（メタ）アクリル酸アルキルエステルとコモノマーとの共重合体が挙げられる。ここで、（メタ）アクリル酸アルキルエステルとは、アクリル酸アルキルエステル及びメタクリル酸アルキルエステルを意味する。（メタ）アクリル酸アルキルエステルとして、例えば、（メタ）アクリル酸ブチル、（メタ）アクリル酸イソブチル、（メタ）アクリル酸ヘキシル、（メタ）アクリル酸オクチル、（メタ）アクリル酸２−エチルヘキシル、及び（メタ）アクリル酸デシルが挙げられる。（メタ）アクリル酸アルキルエステルは単独で又は２種以上を組み合わせて用いてよい。コモノマーとしては、例えば、（メタ）アクリル酸ヒドロキシアルキル、エチレン、プロピレン、スチレン、酢酸ビニル、Ｎ−ビニルピロリドン、及び（メタ）アクリル酸アミドが挙げられる。コモノマーは、単独で又は２種以上を組み合わせて用いてよい。アクリル系粘着剤の具体例としては、ブチルアクリレート、２−エチルヘキシルアクリレート、酢酸ビニル、メタクリル酸、ヒドロキシエチルアクリレート、グリシジルメタクリレート、メトキシエチルアクリレート、及びアクリル酸から選ばれる少なくとも２種類を含む共重合体からなるものが挙げられ、より具体的には、ＤＵＲＯ−ＴＡＫ ８７−２０９７、８７−２１９４、８７−２１９６、８７−２２８７、８７−２５１６、８７−２８５２、８７−４２８７、及び８７−９００Ａ（商品名、ヘンケル社製）、並びにニッセツＫＰ−７７及びＡＳ−３７０（商品名、日本カーバイド工業（株）製）が挙げられる。 Examples of the acrylic pressure-sensitive adhesive include a polymer of (meth) acrylic acid alkyl ester or a copolymer of (meth) acrylic acid alkyl ester and a comonomer. Here, the (meth) acrylic acid alkyl ester means an acrylic acid alkyl ester and a methacrylic acid alkyl ester. Examples of (meth) acrylic acid alkyl esters include, for example, butyl (meth) acrylate, isobutyl (meth) acrylate, hexyl (meth) acrylate, octyl (meth) acrylate, 2-ethylhexyl (meth) acrylate, and ( Meth) decyl acrylate. The (meth) acrylic acid alkyl ester may be used alone or in combination of two or more. Examples of the comonomer include hydroxyalkyl (meth) acrylate, ethylene, propylene, styrene, vinyl acetate, N-vinylpyrrolidone, and (meth) acrylic amide. Comonomers may be used alone or in combination of two or more. Specific examples of the acrylic pressure-sensitive adhesive include a copolymer containing at least two kinds selected from butyl acrylate, 2-ethylhexyl acrylate, vinyl acetate, methacrylic acid, hydroxyethyl acrylate, glycidyl methacrylate, methoxyethyl acrylate, and acrylic acid. More specifically, DURO-TAK 87-2097, 87-2194, 87-2196, 87-2287, 87-2516, 87-2852, 87-4287, and 87-900A (trade names) And Nisset KP-77 and AS-370 (trade name, manufactured by Nippon Carbide Industries Co., Ltd.).
ゴム系粘着剤としては、例えば、スチレン−イソプレン−スチレン共重合体（ＳＩＳ）、イソプレンゴム、ポリイソブチレン（ＰＩＢ）、スチレン−ブタジエン−スチレンブロック共重合体（ＳＢＳ）、スチレン−ブタジエンゴム（ＳＢＲ）、ポリシロキサン等が挙げられる。これらのゴム系粘着剤は、１種単独で用いてもよく、２種以上を組み合わせて用いてもよい。好ましいゴム系粘着剤は、スチレン−イソプレン−スチレン共重合体（ＳＩＳ）又はポリイソブチレン（ＰＩＢ）である。ゴム系粘着剤の具体例としては、オパノールＢ１２、Ｂ１５、Ｂ５０、Ｂ８０、Ｂ１００、Ｂ１２０、Ｂ１５０、Ｂ２２０（商品名、ＢＡＳＦ社製）、ＪＳＲブチル０６５、２６８、３６５（商品名、ＪＳＲ社製）、ビスタネックスＬＭ−ＭＳ、ＭＨ、Ｈ、ＭＭＬ−８０、１００、１２０、１４０（商品名、エクソン・ケミカル社製）、ＨＹＣＡＲ（商品名、グッドリッチ社製）、Ｑｕｉｎｔａｃ ３５７０Ｃ（商品名、日本ゼオン社製）、ＳＩＳ５００２（商品名、ジェイエスアールクレイトンエラストマー社製）、ＳＩＢＳＴＡＲ Ｔ１０２（商品名、カネカ社製）等が挙げられる。 Examples of the rubber-based adhesive include styrene-isoprene-styrene copolymer (SIS), isoprene rubber, polyisobutylene (PIB), styrene-butadiene-styrene block copolymer (SBS), and styrene-butadiene rubber (SBR). And polysiloxane. These rubber-based pressure-sensitive adhesives may be used alone or in combination of two or more. A preferred rubber-based pressure-sensitive adhesive is styrene-isoprene-styrene copolymer (SIS) or polyisobutylene (PIB). Specific examples of rubber adhesives include Opanol B12, B15, B50, B80, B100, B120, B150, B220 (trade names, manufactured by BASF), JSR butyl 065, 268, 365 (trade names, manufactured by JSR) , Vistanex LM-MS, MH, H, MML-80, 100, 120, 140 (trade name, manufactured by Exxon Chemical), HYCAR (trade name, manufactured by Goodrich), Quintac 3570C (trade name, Nippon Zeon) SIS5002 (trade name, manufactured by GS Kraton Elastomer Co., Ltd.), SIBSTAR T102 (trade name, manufactured by Kaneka Corp.), and the like.
シリコーン系粘着剤として、例えば、ジメチルポリシロキサン、ジメチルポリシロキサンとシリケート樹脂との縮合反応物等のオルガノポリシロキサンが挙げられる。シリコーン系粘着剤の具体例としては、ＢＩＯ−ＰＳＡ Ｘ７−４２０１、ＢＩＯ−ＰＳＡ ７−４１０２、ＢＩＯ−ＰＳＡ ７−４２０２、ＢＩＯ−ＰＳＡ ７−４３０２、ＢＩＯ−ＰＳＡ Ｑ７−４５０１、３６０Ｍｅｄｉｃａｌ ｆｌｕｉｄ １０００ＣＳ、及びＭＤＸ４−４２１０（商品名、ダウ・コーニング社製）が挙げられる。 Examples of the silicone-based pressure-sensitive adhesive include organopolysiloxane such as dimethylpolysiloxane and a condensation reaction product of dimethylpolysiloxane and silicate resin. Specific examples of the silicone-based adhesive include BIO-PSA X7-4201, BIO-PSA 7-4102, BIO-PSA 7-4202, BIO-PSA 7-4302, BIO-PSA Q7-4501, 360 Medical fluid 1000CS, and MDX4-2410 (trade name, manufactured by Dow Corning) can be mentioned.
粘着剤の含有量は、粘着剤層全体の質量に対して、１０〜９５質量％であることが好ましく、１０〜８０質量％であることがより好ましい。 It is preferable that content of an adhesive is 10-95 mass% with respect to the mass of the whole adhesive layer, and it is more preferable that it is 10-80 mass%.
粘着剤層は、その他の成分として、粘着付与樹脂、可塑剤、経皮吸収促進剤、安定化剤、充填剤、香料等をさらに含有してもよい。 The pressure-sensitive adhesive layer may further contain a tackifier resin, a plasticizer, a transdermal absorption accelerator, a stabilizer, a filler, a fragrance and the like as other components.
粘着付与樹脂としては、例えば、ロジン、ロジンのグリセリンエステル、水添ロジン、水添ロジンのグリセリンエステル及びロジンのペンタエリストールエステルなどのロジン誘導体、アルコンＰ１００（商品名、荒川化学工業社製）などの脂環族飽和炭化水素樹脂、クイントンＢ１７０（商品名、日本ゼオン社製）などの脂肪族炭化水素樹脂、クリアロンＰ−１２５（商品名、ヤスハラケミカル社製）などのテルペン樹脂、マレイン酸レジンなどが挙げられる。これらの中でも、水添ロジンのグリセリンエステル、脂環族飽和炭化水素樹脂、脂肪族炭化水素樹脂又はテルペン樹脂が好ましく、脂環族炭化水素樹脂がより好ましい。これら粘着付与樹脂は２種以上組み合わせてもよい。粘着付与樹脂を含むことにより、粘着剤層の接着性を向上させ、他の物性を安定に維持することができる。 Examples of tackifying resins include rosin, rosin glycerin ester, hydrogenated rosin, hydrogenated rosin glycerin ester, rosin derivatives such as rosin pentaerythrester, Alcon P100 (trade name, manufactured by Arakawa Chemical Industries, Ltd.), etc. Alicyclic saturated hydrocarbon resin, aliphatic hydrocarbon resin such as Quinton B170 (trade name, manufactured by Nippon Zeon Co., Ltd.), terpene resin such as Clearon P-125 (trade name, manufactured by Yashara Chemical Co., Ltd.), resin maleate, etc. Can be mentioned. Among these, glycerin ester of hydrogenated rosin, alicyclic saturated hydrocarbon resin, aliphatic hydrocarbon resin or terpene resin is preferable, and alicyclic hydrocarbon resin is more preferable. Two or more of these tackifying resins may be combined. By including the tackifier resin, the adhesiveness of the pressure-sensitive adhesive layer can be improved and other physical properties can be stably maintained.
粘着付与樹脂の含有量は、粘着剤層の全質量を基準として、０〜８０質量％であることが好ましく、１０〜７０質量％であることがより好ましい。 The content of the tackifier resin is preferably 0 to 80% by mass and more preferably 10 to 70% by mass based on the total mass of the adhesive layer.
可塑剤としては、例えば、パラフィン系プロセスオイル、ナフテン系プロセスオイル及び芳香族系プロセスオイルなどの石油系オイル；スクワラン；スクワレン；オリーブ油、ツバキ油、ひまし油、トール油及びラッカセイ油などの植物系オイル；シリコンオイル；ジブチルフタレート及びジオクチルフタレートなどの二塩基酸エステル；ポリブテン及び液状イソプレンゴムなどの液状ゴム；ミリスチン酸イソプロピル、ラウリン酸ヘキシル、セバシン酸ジエチル及びセバシン酸ジイソプロピルなどの液状脂肪酸エステル類；ジエチレングリコール；ポリエチレングリコール；サリチル酸グリコール；プロピレングリコール；ジプロピレングリコール；トリアセチン；クエン酸トリエチル；クロタミトンなどが挙げられる。これらの中でも、流動パラフィン、液状ポリブテン、ミリスチン酸イソプロピル、セバシン酸ジエチル及びラウリン酸ヘキシルが好ましく、液状ポリブテン、ミリスチン酸イソプロピル及び流動パラフィンがより好ましく、流動パラフィンが特に好ましい。これらの可塑剤は２種以上組み合わせてもよい。 Examples of the plasticizer include petroleum oils such as paraffinic process oil, naphthenic process oil, and aromatic process oil; squalane; squalene; vegetable oils such as olive oil, camellia oil, castor oil, tall oil, and peanut oil; Silicon oils; dibasic acid esters such as dibutyl phthalate and dioctyl phthalate; liquid rubbers such as polybutene and liquid isoprene rubber; liquid fatty acid esters such as isopropyl myristate, hexyl laurate, diethyl sebacate and diisopropyl sebacate; diethylene glycol; polyethylene Glycol; salicylate glycol; propylene glycol; dipropylene glycol; triacetin; triethyl citrate; crotamiton and the like. Among these, liquid paraffin, liquid polybutene, isopropyl myristate, diethyl sebacate and hexyl laurate are preferable, liquid polybutene, isopropyl myristate and liquid paraffin are more preferable, and liquid paraffin is particularly preferable. Two or more of these plasticizers may be combined.
経皮吸収促進剤は、従来、皮膚での経皮吸収促進作用を有することが知られている化合物であればよい。経皮吸収促進剤としては、例えば、有機酸及びその塩（例えば、炭素原子数６〜２０の脂肪族カルボン酸（以下、「脂肪酸」ともいう。）及びその塩、ケイ皮酸及びその塩）、有機酸エステル（例えば、脂肪酸エステル、ケイ皮酸エステル）、有機酸アミド（例えば、脂肪酸アミド）、脂肪アルコール、多価アルコール、エーテル（例えば、脂肪エーテル、ポリオキシエチレンアルキルエーテル）などが挙げられる。これらの吸収促進剤は、不飽和結合を有していてもよく、環状、直鎖状又は分枝状の化学構造であってもよい。また、経皮吸収促進剤は、モノテルペン系化合物、セスキテルペン系化合物、及び植物油（例えば、オリーブ油）であってもよい。これらの経皮吸収促進剤は２種以上組み合わせてもよい。 The percutaneous absorption enhancer may be any compound that has been conventionally known to have a skin percutaneous absorption promoting action. Examples of the transdermal absorption enhancer include organic acids and salts thereof (for example, aliphatic carboxylic acids having 6 to 20 carbon atoms (hereinafter also referred to as “fatty acids”) and salts thereof, cinnamic acid and salts thereof). Organic acid esters (for example, fatty acid esters, cinnamic acid esters), organic acid amides (for example, fatty acid amides), fatty alcohols, polyhydric alcohols, ethers (for example, fatty ethers, polyoxyethylene alkyl ethers) and the like. . These absorption enhancers may have an unsaturated bond, and may have a cyclic, linear or branched chemical structure. Further, the transdermal absorption enhancer may be a monoterpene compound, a sesquiterpene compound, and a vegetable oil (for example, olive oil). Two or more of these percutaneous absorption enhancers may be combined.
かかる有機酸としては、脂肪族（モノ、ジ又はトリ）カルボン酸（例えば、酢酸、プロピオン酸、クエン酸（無水クエン酸を含む）、イソ酪酸、カプロン酸、カプリル酸、脂肪酸、乳酸、マレイン酸、ピルビン酸、シュウ酸、コハク酸、酒石酸等）、芳香族カルボン酸（例えば、フタル酸、サリチル酸、安息香酸、アセチルサリチル酸等）、ケイ皮酸、アルカンスルホン酸（例えば、メタンスルホン酸、エタンスルホン酸、プロパンスルホン酸、ブタンスルホン酸）、アルキルスルホン酸誘導体（例えば、ポリオキシエチレンアルキルエーテルスルホン酸、Ｎ−２−ヒドロキシエチルピペラジン−Ｎ’−２−エタンスルホン酸）、コール酸誘導体（例えば、デヒドロコール酸等）が挙げられる。これらの有機酸は、ナトリウム塩等のアルカリ金属塩であってもよい。中でも、脂肪族カルボン酸、芳香族カルボン酸又はこれらの塩が好ましく、酢酸、酢酸ナトリウム又はクエン酸が特に好ましい。 Such organic acids include aliphatic (mono, di or tri) carboxylic acids (eg acetic acid, propionic acid, citric acid (including citric anhydride), isobutyric acid, caproic acid, caprylic acid, fatty acid, lactic acid, maleic acid. , Pyruvic acid, oxalic acid, succinic acid, tartaric acid, etc.), aromatic carboxylic acid (eg, phthalic acid, salicylic acid, benzoic acid, acetylsalicylic acid, etc.), cinnamic acid, alkane sulfonic acid (eg, methane sulfonic acid, ethane sulfone) Acid, propanesulfonic acid, butanesulfonic acid), alkylsulfonic acid derivatives (eg, polyoxyethylene alkyl ether sulfonic acid, N-2-hydroxyethylpiperazine-N′-2-ethanesulfonic acid), cholic acid derivatives (eg, Dehydrocholic acid and the like). These organic acids may be alkali metal salts such as sodium salts. Among these, aliphatic carboxylic acids, aromatic carboxylic acids or salts thereof are preferable, and acetic acid, sodium acetate or citric acid is particularly preferable.
脂肪酸としては、例えば、ラウリン酸、ミリスチン酸、パルミチン酸、ステアリン酸、イソステアリン酸、オレイン酸、リノ−ル酸、リノレン酸が挙げられる。 Examples of the fatty acid include lauric acid, myristic acid, palmitic acid, stearic acid, isostearic acid, oleic acid, linoleic acid, and linolenic acid.
有機酸エステルとしては、例えば、酢酸エチル、酢酸プロピル、乳酸セチル、乳酸ラウリル、サリチル酸メチル、サリチル酸エチレングリコール、ケイ皮酸メチル、脂肪酸エステルが挙げられる。脂肪酸エステルとしては、例えば、ラウリン酸メチル、ラウリン酸ヘキシル、ミリスチン酸イソプロピル、ミリスチン酸ミリスチル、ミリスチン酸オクチルドデシル、パルミチン酸セチルが挙げられる。脂肪酸エステルは、グリセリン脂肪酸エステル、プロピレングリコール脂肪酸エステル、ソルビタン脂肪酸エステル、ポリエチレングリコールソルビタン脂肪酸エステル、ポリエチレングリコール脂肪酸エステル、ショ糖脂肪酸エステル、又はポリオキシエチレン硬化ヒマシ油であってもよい。脂肪酸エステルの具体例としては、グリセリンモノカプリレート、グリセリンモノカプレート、グリセリンモノラウレート、グリセリンモノオレエー卜、ソルビタンモノラウレート、ショ糖モノラウレート、ポリソルベート２０（商品名）、プロピレングリコールモノラウレート、ポリエチレングリコールモノラウレート、ポリエチレングリコールモノステアレート、Ｓｐａｎ２０、Ｓｐａｎ４０、Ｓｐａｎ６０、Ｓｐａｎ８０、Ｓｐａｎ１２０（商品名）、Ｔｗｅｅｎ２０、Ｔｗｅｅｎ２１、Ｔｗｅｅｎ４０、Ｔｗｅｅｎ６０、Ｔｗｅｅｎ８０（商品名）、ＮＩＫＫＯＬ ＨＣＯ−６０（商品名、日光ケミカルズ（株）製）が挙げられる。 Examples of the organic acid ester include ethyl acetate, propyl acetate, cetyl lactate, lauryl lactate, methyl salicylate, ethylene glycol salicylate, methyl cinnamate, and fatty acid ester. Examples of fatty acid esters include methyl laurate, hexyl laurate, isopropyl myristate, myristyl myristate, octyldodecyl myristate, and cetyl palmitate. The fatty acid ester may be glycerin fatty acid ester, propylene glycol fatty acid ester, sorbitan fatty acid ester, polyethylene glycol sorbitan fatty acid ester, polyethylene glycol fatty acid ester, sucrose fatty acid ester, or polyoxyethylene hydrogenated castor oil. Specific examples of fatty acid esters include glycerol monocaprylate, glycerol monocaprate, glycerol monolaurate, glycerol monooleate, sorbitan monolaurate, sucrose monolaurate, polysorbate 20 (trade name), propylene glycol monolaur Rate, polyethylene glycol monolaurate, polyethylene glycol monostearate, Span 20, Span 40, Span 60, Span 80, Span 120 (trade name), Tween 20, Tween 21, Tween 40, Tween 60, Tween 80 (trade name), NIKKOL HCO-60 (trade name, Nikko Chemicals Co., Ltd.).
有機酸アミドとしては、例えば、脂肪酸アミド（例えば、ラウリン酸ジエタノールアミド）、ヘキサヒドロ−１−ドデシル−２Ｈ−アゼピン−２−オン（Ａｚｏｎｅともいう。）及びその誘導体、ピロチオデカンが挙げられる。 Examples of the organic acid amide include fatty acid amide (for example, lauric acid diethanolamide), hexahydro-1-dodecyl-2H-azepin-2-one (also referred to as Azone), a derivative thereof, and pyrothiodecane.
脂肪アルコールとは、炭素原子数６〜２０の脂肪族アルコールを意味する。脂肪アルコールとしては、例えば、ラウリルアルコール、ミリスチルアルコール、オレイルアルコール、イソステアリルアルコール、セチルアルコールが挙げられる。多価アルコールとしては、例えば、プロピレングリコールが挙げられる。 The fatty alcohol means an aliphatic alcohol having 6 to 20 carbon atoms. Examples of the fatty alcohol include lauryl alcohol, myristyl alcohol, oleyl alcohol, isostearyl alcohol, and cetyl alcohol. Examples of the polyhydric alcohol include propylene glycol.
ポリオキシエチレンアルキルエーテルとしては、例えば、ポリオキシエチレンラウリルエーテルが挙げられる。 Examples of the polyoxyethylene alkyl ether include polyoxyethylene lauryl ether.
モノテルペン系化合物としては、例えば、ゲラニオール、チモール、オイゲノール、テルピネオール、ｌ−メントール、ボルネオロール、ｄ−リモネン、イソオイゲノール、イソボルネオール、ネロール、ｄｌ−カンフルが挙げられる。 Examples of the monoterpene compound include geraniol, thymol, eugenol, terpineol, l-menthol, borneolol, d-limonene, isoeugenol, isoborneol, nerol, and dl-camphor.
オレイルアルコール、ラウリルアルコール、イソステアリルアルコール、ラウリン酸ジエタノールアミド、グリセリンモノカプリレート、グリセリンモノカプレート、グリセリンモノオレエー卜、ソルビタンモノラウレート、プロピレングリコールモノラウレート、ポリオキシエチレンラウリルエーテル又はピロチオデカンがより好ましい。脂肪酸が好ましく、オレイン酸が特に好ましい。 More oleyl alcohol, lauryl alcohol, isostearyl alcohol, lauric acid diethanolamide, glycerol monocaprylate, glycerol monocaprate, glycerol monooleate, sorbitan monolaurate, propylene glycol monolaurate, polyoxyethylene lauryl ether or pyrothiodecane preferable. Fatty acids are preferred and oleic acid is particularly preferred.
経皮吸収促進剤の含有量は、粘着剤層の全質量を基準として、０〜２０質量％であることが好ましく、０〜１０質量％であることがより好ましい。 The content of the transdermal absorption promoter is preferably 0 to 20% by mass, more preferably 0 to 10% by mass based on the total mass of the pressure-sensitive adhesive layer.
安定化剤は、酸化防止剤（トコフェロール誘導体、アスコルビン酸誘導体、エリソルビン酸誘導体、ノルジヒドログアヤレチン酸、没食子酸誘導体、ジブチルヒドロキシトルエン（ＢＨＴ）、ブチルヒドロキシアニソール、ピロ亜硫酸ナトリウム、亜硫酸ナトリウム、２−メルカプトベンズイミダゾール等）、紫外線吸収剤（イミダゾール誘導体、ベンゾトリアゾール誘導体、ｐ−アミノ安息香酸誘導体、アントラニル酸誘導体、サリチル酸誘導体、ケイヒ酸誘導体、ベンゾフェノン誘導体、クマリン酸誘導体、カンファー誘導体等）などを挙げることができる。これらの安定化剤は２種以上組み合わせてもよい。 Stabilizers include antioxidants (tocopherol derivatives, ascorbic acid derivatives, erythorbic acid derivatives, nordihydroguaiaretic acid, gallic acid derivatives, dibutylhydroxytoluene (BHT), butylhydroxyanisole, sodium pyrosulfite, sodium sulfite, 2 -Mercaptobenzimidazole, etc.), UV absorbers (imidazole derivatives, benzotriazole derivatives, p-aminobenzoic acid derivatives, anthranilic acid derivatives, salicylic acid derivatives, cinnamic acid derivatives, benzophenone derivatives, coumaric acid derivatives, camphor derivatives, etc.) be able to. Two or more of these stabilizers may be combined.
安定化剤の含有量は、粘着剤層の全質量を基準として、０〜５質量％であることが好ましく、０〜２質量％であることがより好ましい。粘着剤層が安定化剤を含有することにより、フェンタニル又はその塩の安定性がより向上し得る。 The content of the stabilizer is preferably 0 to 5% by mass and more preferably 0 to 2% by mass based on the total mass of the pressure-sensitive adhesive layer. When the pressure-sensitive adhesive layer contains a stabilizer, the stability of fentanyl or a salt thereof can be further improved.
充填剤は、金属酸化物（酸化亜鉛、酸化チタン等）、金属塩（炭酸カルシウム、炭酸マグネシウム、ステアリン酸亜鉛等）、ケイ酸化合物（カオリン、タルク、ベントナイト、アエロジル、含水シリカ、ケイ酸アルミニウム、ケイ酸マグネシウム、メタケイ酸アルミン酸マグネシウム等）、金属水酸化物（水酸化アルミニウム等）などを挙げることができる。これらの充填剤は２種以上組み合わせてもよい。 Fillers include metal oxides (zinc oxide, titanium oxide, etc.), metal salts (calcium carbonate, magnesium carbonate, zinc stearate, etc.), silicate compounds (kaolin, talc, bentonite, aerosil, hydrous silica, aluminum silicate, Examples thereof include magnesium silicate and magnesium aluminate metasilicate) and metal hydroxides (such as aluminum hydroxide). Two or more of these fillers may be combined.
充填剤の含有量は、粘着剤層の全質量を基準として、０〜１０質量％であることが好ましく、０〜５質量％であることがより好ましい。 The content of the filler is preferably 0 to 10% by mass and more preferably 0 to 5% by mass based on the total mass of the pressure-sensitive adhesive layer.
粘着剤層は、溶剤を含んでいてもよい。溶剤としては、例えば、メタノール、エタノール、アセトン、酢酸エチル、トルエン、テトラヒドロフラン、アセトニトリル等が挙げられる。これらの溶剤は２種以上組み合わせてもよい。 The pressure-sensitive adhesive layer may contain a solvent. Examples of the solvent include methanol, ethanol, acetone, ethyl acetate, toluene, tetrahydrofuran, acetonitrile, and the like. Two or more of these solvents may be combined.
粘着剤層（膏体）の単位面積（１ｍ２）あたりの質量は、２５〜７５ｇ／ｍ２であってもよく、３０〜７０ｇ／ｍ２であることが好ましく、３５〜６０ｇ／ｍ２であることがより好ましい。 Mass per unit area (1 m 2) of pressure-sensitive adhesive layer (plaster) may be a 25~75g / m 2, is preferably 30~70g / m 2, in 35~60g / m 2 More preferably.
支持体としては、粘着剤層を支持するのに適したものであれば特に限定はされず、伸縮性又は非伸縮性のものを用いることができる。支持体の材質としては、ポリエチレン（ＰＥ）、ポリプロピレン（ＰＰ）、ポリブタジエン、エチレン酢酸ビニル共重合体、ポリ塩化ビニル、ポリエステル、ナイロン、ポリウレタン、ポリアクリロニトリル（ＰＡＮ）などのフィルム、シート、これらの積層体、多孔体、発泡体、布及び不織布、並びにこれらのラミネート品などが使用できる。また、好ましい支持体の材質は、ポリエチレンテレフタレート（ＰＥＴ）又はポリエチレンである。好ましい支持体の具体例としては、Ｓｃｏｔｃｈｐａｋ（登録商標）９７２３、９７３２等のＳｃｏｔｃｈｐａｋシリーズ（スリーエム社製）が挙げられる。 The support is not particularly limited as long as it is suitable for supporting the pressure-sensitive adhesive layer, and a stretchable or non-stretchable one can be used. Materials for the support include polyethylene (PE), polypropylene (PP), polybutadiene, ethylene vinyl acetate copolymer, polyvinyl chloride, polyester, nylon, polyurethane, polyacrylonitrile (PAN) and other films, sheets, and laminates thereof. Bodies, porous bodies, foams, cloths and nonwoven fabrics, and laminates thereof can be used. A preferred support material is polyethylene terephthalate (PET) or polyethylene. Specific examples of the preferred support include Scotchpak series (manufactured by 3M) such as Scotchpak (registered trademark) 9723, 9732.
支持体は、その粘着剤層と接する面に、サンドマット処理を施してもよい。支持体にサンドマット処理を施すことにより、投錨性がより向上する。サンドマット処理の方法としては、当業者に周知の方法により行うことができる。 The support may be subjected to a sand mat treatment on the surface in contact with the pressure-sensitive adhesive layer. By subjecting the support to a sand mat treatment, the anchoring property is further improved. As a method of sand mat treatment, a method well known to those skilled in the art can be used.
本実施形態に係る貼付剤は、粘着剤層の貼付面を覆うように剥離ライナーを備えていてもよい。すなわち、貼付剤が剥離ライナーを備える場合、貼付剤は、粘着剤層が支持体と剥離ライナーで挟まれた三層構造となる。 The patch according to the present embodiment may include a release liner so as to cover the sticking surface of the pressure-sensitive adhesive layer. That is, when the patch includes a release liner, the patch has a three-layer structure in which the pressure-sensitive adhesive layer is sandwiched between the support and the release liner.
本実施形態に係る貼付剤は、フェンタニル又はその塩、粘着剤、及び、任意にその他の成分を混合して得られる膏体液を支持体上に展延し、剥離ライナーをその上に積層することにより、得ることができる。また、上記膏体液を剥離ライナー上に展延し、支持体をその上に積層してもよい。 The patch according to the present embodiment comprises spreading a plaster liquid obtained by mixing fentanyl or a salt thereof, an adhesive, and optionally other components on a support, and laminating a release liner thereon. Can be obtained. Further, the plaster liquid may be spread on a release liner, and a support may be laminated thereon.
本実施形態に係る貼付剤は、パウチ内に入れて保存することが好ましい。 The patch according to the present embodiment is preferably stored in a pouch.
以下に、実施例と比較例を用いて、本発明をより詳細に説明する。 Hereinafter, the present invention will be described in more detail with reference to Examples and Comparative Examples.
試験例１：保存安定性試験１
表１の記載にしたがい、フェンタニルクエン酸塩を含有するテープ剤（比較例１、２）を調製した。具体的には、各成分を混合して得られた膏体液を、成形される粘着剤層の質量が５０ｇ／ｍ２となるように支持体上に展延し、剥離ライナーをその上に積層することにより、テープ剤を得た。比較例１のテープ剤は、貼付面積が５ｃｍ２であり、粘着剤層中にフェンタニルクエン酸塩１ｍｇを含有するテープ剤である。一方、比較例２のテープ剤は、貼付面積が２．５ｃｍ２であり、粘着剤層中にフェンタニルクエン酸塩０．５ｍｇを含有するテープ剤である。
Test Example 1: Storage stability test 1
According to the description in Table 1, tape preparations (Comparative Examples 1 and 2) containing fentanyl citrate were prepared. Specifically, the paste liquid obtained by mixing each component is spread on a support so that the mass of the pressure-sensitive adhesive layer to be molded is 50 g / m 2, and a release liner is laminated thereon. By doing so, a tape agent was obtained. The tape preparation of Comparative Example 1 has a sticking area of 5 cm 2 and contains 1 mg of fentanyl citrate in the adhesive layer. On the other hand, the tape preparation of Comparative Example 2 has a sticking area of 2.5 cm 2 and contains 0.5 mg of fentanyl citrate in the adhesive layer.
得られた各テープ剤におけるフェンタニルクエン酸塩の含有量を測定した。その後、テープ剤をアルミニウム製パウチに入れ、６０℃にて１か月間保管した後、粘着剤層に含まれるフェンタニルクエン酸塩の含有量を高速液体クロマトグラフ法にて測定した。テープ剤を調製した時のフェンタニルクエン酸塩の含有量（初期値）に対する、保管後のフェンタニルクエン酸塩の含有量を算出した。 The content of fentanyl citrate in each obtained tape was measured. Thereafter, the tape agent was put in an aluminum pouch and stored at 60 ° C. for 1 month, and then the content of fentanyl citrate contained in the adhesive layer was measured by a high performance liquid chromatograph method. The content of fentanyl citrate after storage was calculated with respect to the content (initial value) of fentanyl citrate when the tape preparation was prepared.
結果を表１に示す。比較例２のテープ剤では、比較例１のテープ剤と比べて保存後のフェンタニルクエン酸塩の含有量が低下した。 The results are shown in Table 1. In the tape preparation of Comparative Example 2, the content of fentanyl citrate after storage was lower than that of the tape preparation of Comparative Example 1.
試験例２：保存安定性試験２
表２の記載にしたがい、試験例１と同様に、フェンタニルクエン酸塩を含有するテープ剤（実施例１〜３）を調製した。実施例１〜３のテープ剤は、比較例１のテープ剤と比較して、粘着剤層におけるフェンタニルクエン酸塩の濃度を低くして、貼付面積を大きくしたテープ剤である。試験例１と同様にして、実施例１〜３のテープ剤の保存安定性を評価した。
Test Example 2: Storage stability test 2
According to the description in Table 2, in the same manner as in Test Example 1, tape preparations (Examples 1 to 3) containing fentanyl citrate were prepared. The tape agent of Examples 1-3 is a tape agent which made the sticking area large by making the density | concentration of the fentanyl citrate in an adhesive layer low compared with the tape agent of the comparative example 1. FIG. In the same manner as in Test Example 1, the storage stability of the tape preparations of Examples 1 to 3 was evaluated.
結果を表２に示す。実施例１〜３のテープ剤では、６０℃、１ヶ月保存後のフェンタニルクエン酸塩の含有量は９５％以上であり、特に実施例２、３のテープ剤では約９６％であった。 The results are shown in Table 2. In the tape preparations of Examples 1 to 3, the content of fentanyl citrate after storage at 60 ° C. for 1 month was 95% or more, and in particular, the tape preparations of Examples 2 and 3 were about 96%.
また、ＳＩＳとＰＩＢの組み合わせに代えて、粘着剤としてＳＩＳのみを含有する以外は実施例１〜３と同様にしてテープ剤（実施例４〜６）をそれぞれ調製した。さらに、ＳＩＳとＰＩＢの組み合わせに代えて、粘着剤としてＰＩＢのみを含有する以外は実施例１〜３と同様にしてテープ剤（実施例７〜９）をそれぞれ調製した。実施例４〜９のテープ剤を用いて保存安定性試験を実施したところ、実施例１〜３と同等の結果を示した。 Moreover, it replaced with the combination of SIS and PIB, and prepared the tape agent (Examples 4-6) like Example 1-3, respectively except containing only SIS as an adhesive. Furthermore, it replaced with the combination of SIS and PIB, and prepared the tape agent (Examples 7-9) similarly to Examples 1-3 except containing only PIB as an adhesive. When the storage stability test was carried out using the tape preparations of Examples 4 to 9, the results equivalent to those of Examples 1 to 3 were shown.
試験例３：保存安定性試験３
表３の記載にしたがい、実施例２と同一の組成を有し、貼付面の形状の異なるテープ剤（実施例１０〜１４）を調製した。実施例２、１０〜１４のテープ剤は、その形状の違いにより、貼付面積は互いに同一であるが、外周の長さは異なる。試験例１と同様にして、実施例１０〜１４のテープ剤の保存安定性を評価した。
Test Example 3: Storage stability test 3
According to the description in Table 3, tape preparations (Examples 10 to 14) having the same composition as in Example 2 and having different shapes of the pasting surfaces were prepared. The tapes of Examples 2 and 10 to 14 have the same sticking area due to the difference in shape, but the outer circumferences are different. In the same manner as in Test Example 1, the storage stability of the tape preparations of Examples 10 to 14 was evaluated.
結果を表３に示す。実施例１１〜１４の貼付面の形状は、表３に記載の縦横比を有する長方形である。貼付面の外周長さが長くなるにつれて、フェンタニルクエン酸塩の含有量が低下する傾向が見られた。貼付面積が同一であるテープ剤を比較する場合、粘着剤層の表面積は貼付面の外周長さに依存する。したがって、粘着剤層の表面積がより小さい実施例２、１０〜１２のテープ剤は、実施例１３、１４のテープ剤よりもフェンタニルクエン酸塩の保存安定性が更に高い結果となった。
The results are shown in Table 3. The shape of the sticking surface of Examples 11 to 14 is a rectangle having the aspect ratio described in Table 3. There was a tendency for the content of fentanyl citrate to decrease as the outer peripheral length of the application surface increased. When comparing tape preparations having the same application area, the surface area of the adhesive layer depends on the outer peripheral length of the application surface. Therefore, the tape preparations of Examples 2 and 10 to 12 having a smaller surface area of the pressure-sensitive adhesive layer resulted in higher storage stability of fentanyl citrate than the tape preparations of Examples 13 and 14.
Claims (6)
前記粘着剤層が、フェンタニル又はその塩、及び、粘着剤を含有し、
前記粘着剤層におけるフェンタニル又はその塩の含有量が、貼付面積１ｃｍ２あたり、フェンタニルクエン酸塩に換算した場合に０．０１〜０．１８ｍｇである、貼付剤。 A patch comprising an adhesive layer on a support,
The pressure-sensitive adhesive layer contains fentanyl or a salt thereof, and a pressure-sensitive adhesive,
The patch, wherein the content of fentanyl or a salt thereof in the pressure-sensitive adhesive layer is 0.01 to 0.18 mg when converted to fentanyl citrate per 1 cm 2 of the patch area.
The patch according to any one of claims 1 to 5, wherein the pressure-sensitive adhesive layer further contains a tackifier resin.
Priority Applications (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2018108939A JP7179501B2 (en) | 2018-06-06 | 2018-06-06 | Patches containing fentanyl |
| JP2022182452A JP7216867B2 (en) | 2018-06-06 | 2022-11-15 | Patches containing fentanyl |
| JP2023006872A JP7253126B2 (en) | 2018-06-06 | 2023-01-19 | Patches containing fentanyl |
| JP2023011150A JP7253127B2 (en) | 2018-06-06 | 2023-01-27 | Patches containing fentanyl |
| JP2023029532A JP7260726B1 (en) | 2018-06-06 | 2023-02-28 | Patches containing fentanyl |
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| Application Number | Priority Date | Filing Date | Title |
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| JP2018108939A JP7179501B2 (en) | 2018-06-06 | 2018-06-06 | Patches containing fentanyl |
Related Child Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP2022182452A Division JP7216867B2 (en) | 2018-06-06 | 2022-11-15 | Patches containing fentanyl |
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| Publication Number | Publication Date |
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| JP2019210253A true JP2019210253A (en) | 2019-12-12 |
| JP7179501B2 JP7179501B2 (en) | 2022-11-29 |
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| JP2018108939A Active JP7179501B2 (en) | 2018-06-06 | 2018-06-06 | Patches containing fentanyl |
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH1045570A (en) * | 1996-05-13 | 1998-02-17 | Hisamitsu Pharmaceut Co Inc | Fentanyl-containing percutaneous administration tape pharmaceutical preparation |
| WO2009051217A1 (en) * | 2007-10-17 | 2009-04-23 | Hisamitsu Pharmaceutical Co., Inc. | Fentanyl-containing percutaneous absorption preparation |
-
2018
- 2018-06-06 JP JP2018108939A patent/JP7179501B2/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH1045570A (en) * | 1996-05-13 | 1998-02-17 | Hisamitsu Pharmaceut Co Inc | Fentanyl-containing percutaneous administration tape pharmaceutical preparation |
| WO2009051217A1 (en) * | 2007-10-17 | 2009-04-23 | Hisamitsu Pharmaceutical Co., Inc. | Fentanyl-containing percutaneous absorption preparation |
Non-Patent Citations (1)
| Title |
|---|
| フェントステープ、添付文書, JPN6022022141, 2014, ISSN: 0004791907 * |
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