CN116406262A - 含有阿塞那平的贴剂 - Google Patents
含有阿塞那平的贴剂 Download PDFInfo
- Publication number
- CN116406262A CN116406262A CN202180076338.3A CN202180076338A CN116406262A CN 116406262 A CN116406262 A CN 116406262A CN 202180076338 A CN202180076338 A CN 202180076338A CN 116406262 A CN116406262 A CN 116406262A
- Authority
- CN
- China
- Prior art keywords
- acid
- adhesive layer
- asenapine
- pharmaceutically acceptable
- acceptable 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.)
- Pending
Links
- 229960005245 asenapine Drugs 0.000 title claims abstract description 46
- VSWBSWWIRNCQIJ-GJZGRUSLSA-N (R,R)-asenapine Chemical compound O1C2=CC=CC=C2[C@@H]2CN(C)C[C@H]2C2=CC(Cl)=CC=C21 VSWBSWWIRNCQIJ-GJZGRUSLSA-N 0.000 title claims abstract description 45
- 230000001070 adhesive effect Effects 0.000 title claims abstract description 43
- 239000000853 adhesive Substances 0.000 title claims abstract description 42
- 239000012790 adhesive layer Substances 0.000 claims abstract description 54
- 150000003839 salts Chemical class 0.000 claims abstract description 44
- 150000001413 amino acids Chemical class 0.000 claims abstract description 19
- 239000004475 Arginine Substances 0.000 claims abstract description 9
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 claims abstract description 9
- HNDVDQJCIGZPNO-YFKPBYRVSA-N L-histidine Chemical compound OC(=O)[C@@H](N)CC1=CN=CN1 HNDVDQJCIGZPNO-YFKPBYRVSA-N 0.000 claims abstract description 9
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 claims abstract description 9
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 claims abstract description 9
- 239000004472 Lysine Substances 0.000 claims abstract description 9
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 claims abstract description 9
- 238000000354 decomposition reaction Methods 0.000 claims abstract description 9
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 claims abstract description 9
- 230000002401 inhibitory effect Effects 0.000 claims abstract description 5
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- 238000000034 method Methods 0.000 claims description 9
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- 229940024606 amino acid Drugs 0.000 description 14
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- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 7
- 238000010521 absorption reaction Methods 0.000 description 7
- 229920001577 copolymer Polymers 0.000 description 7
- WNWHHMBRJJOGFJ-UHFFFAOYSA-N 16-methylheptadecan-1-ol Chemical compound CC(C)CCCCCCCCCCCCCCCO WNWHHMBRJJOGFJ-UHFFFAOYSA-N 0.000 description 6
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 6
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- 229960003121 arginine Drugs 0.000 description 6
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- 238000004128 high performance liquid chromatography Methods 0.000 description 6
- 229960003646 lysine Drugs 0.000 description 6
- 238000004519 manufacturing process Methods 0.000 description 6
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 6
- 235000011054 acetic acid Nutrition 0.000 description 5
- 125000000217 alkyl group Chemical group 0.000 description 5
- 239000003795 chemical substances by application Substances 0.000 description 5
- 150000004665 fatty acids Chemical class 0.000 description 5
- 229960002885 histidine Drugs 0.000 description 5
- 239000007788 liquid Substances 0.000 description 5
- 239000004014 plasticizer Substances 0.000 description 5
- 238000012360 testing method Methods 0.000 description 5
- 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 4
- GLZPCOQZEFWAFX-UHFFFAOYSA-N Geraniol Chemical compound CC(C)=CCCC(C)=CCO GLZPCOQZEFWAFX-UHFFFAOYSA-N 0.000 description 4
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- 150000007524 organic acids Chemical class 0.000 description 4
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- 229920005862 polyol Polymers 0.000 description 4
- GHBFNMLVSPCDGN-UHFFFAOYSA-N rac-1-monooctanoylglycerol Chemical compound CCCCCCCC(=O)OCC(O)CO GHBFNMLVSPCDGN-UHFFFAOYSA-N 0.000 description 4
- DCKVNWZUADLDEH-UHFFFAOYSA-N sec-butyl acetate Chemical class CCC(C)OC(C)=O DCKVNWZUADLDEH-UHFFFAOYSA-N 0.000 description 4
- 238000003860 storage Methods 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 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 4
- ALSTYHKOOCGGFT-KTKRTIGZSA-N (9Z)-octadecen-1-ol Chemical compound CCCCCCCC\C=C/CCCCCCCCO ALSTYHKOOCGGFT-KTKRTIGZSA-N 0.000 description 3
- WRIDQFICGBMAFQ-UHFFFAOYSA-N (E)-8-Octadecenoic acid Natural products CCCCCCCCCC=CCCCCCCC(O)=O WRIDQFICGBMAFQ-UHFFFAOYSA-N 0.000 description 3
- GMDCDXMAFMEDAG-CHHFXETESA-N (S,S)-asenapine maleate Chemical compound OC(=O)\C=C/C(O)=O.O1C2=CC=CC=C2[C@H]2CN(C)C[C@@H]2C2=CC(Cl)=CC=C21 GMDCDXMAFMEDAG-CHHFXETESA-N 0.000 description 3
- RZRNAYUHWVFMIP-KTKRTIGZSA-N 1-oleoylglycerol Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OCC(O)CO RZRNAYUHWVFMIP-KTKRTIGZSA-N 0.000 description 3
- BHIZVZJETFVJMJ-UHFFFAOYSA-N 2-hydroxypropyl dodecanoate Chemical compound CCCCCCCCCCCC(=O)OCC(C)O BHIZVZJETFVJMJ-UHFFFAOYSA-N 0.000 description 3
- LQJBNNIYVWPHFW-UHFFFAOYSA-N 20:1omega9c fatty acid Natural products CCCCCCCCCCC=CCCCCCCCC(O)=O LQJBNNIYVWPHFW-UHFFFAOYSA-N 0.000 description 3
- 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 3
- QSBYPNXLFMSGKH-UHFFFAOYSA-N 9-Heptadecensaeure Natural products CCCCCCCC=CCCCCCCCC(O)=O QSBYPNXLFMSGKH-UHFFFAOYSA-N 0.000 description 3
- 239000005711 Benzoic acid Substances 0.000 description 3
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
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- AOMUHOFOVNGZAN-UHFFFAOYSA-N N,N-bis(2-hydroxyethyl)dodecanamide Chemical compound CCCCCCCCCCCC(=O)N(CCO)CCO AOMUHOFOVNGZAN-UHFFFAOYSA-N 0.000 description 3
- 239000005642 Oleic acid Substances 0.000 description 3
- ZQPPMHVWECSIRJ-UHFFFAOYSA-N Oleic acid Natural products CCCCCCCCC=CCCCCCCCC(O)=O ZQPPMHVWECSIRJ-UHFFFAOYSA-N 0.000 description 3
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- 125000004432 carbon atom Chemical group C* 0.000 description 3
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- RZRNAYUHWVFMIP-HXUWFJFHSA-N glycerol monolinoleate Natural products CCCCCCCCC=CCCCCCCCC(=O)OC[C@H](O)CO RZRNAYUHWVFMIP-HXUWFJFHSA-N 0.000 description 3
- 229940093915 gynecological organic acid Drugs 0.000 description 3
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Abstract
本发明公开了一种抑制阿塞那平或其药学上可接受的盐的分解的贴剂。上述贴剂在支持体上具备粘合剂层，上述粘合剂层含有粘合基剂、阿塞那平或其药学上可接受的盐、以及选自赖氨酸、精氨酸和组氨酸中的至少1种碱性氨基酸或其药学上可接受的盐。
Description
技术领域
本发明涉及含有阿塞那平或其药学上可接受的盐的贴剂。
背景技术
阿塞那平已知是作为中枢神经系统疾病、特别是精神分裂症的治疗药的化合物。在日本，作为含有阿塞那平的药品，销售了马来酸阿塞那平舌下含片(商品名：Sycrest(注册商标)舌下含片)。舌下给药通常已知被认为是不易受首过效应影响的给药途径。因此，即使是代谢稳定性较低的化合物，通过舌下给药，也能够期待发挥充分的药理效果。近年来，作为新的制剂，研究了含阿塞那平的贴剂的开发。例如，专利文献1中公开了一种在粘合剂层中含有低分子胺的贴剂，其即使在粘合剂层吸湿的情况下，也能抑制粘合剂层的粘合力降低。
现有技术文献
专利文献
专利文献1：国际公开第2017/018322号
发明内容
发明要解决的课题
本发明人等发现，在制造和/或保存贴剂时，阿塞那平会分解，从而产生阿塞那平的N-氧化物和四脱氢物。本发明的目的在于，提供一种抑制阿塞那平或其药学上可接受的盐的分解的贴剂。另外，本发明的目的在于，提供一种抑制贴剂中的阿塞那平或其药学上可接受的盐的分解的方法。
解决课题的手段
本发明人等进行了深入研究，结果发现，通过在粘合剂层中配合碱性氨基酸或其药学上可接受的盐，能够抑制阿塞那平的分解，从而完成了本发明。
即，本发明的贴剂在支持体上具备粘合剂层，上述粘合剂层含有粘合基剂、阿塞那平或其药学上可接受的盐、以及选自赖氨酸、精氨酸和组氨酸中的至少1种碱性氨基酸或其药学上可接受的盐。
另外，本发明是一种抑制在支持体上具备粘合剂层的贴剂中的阿塞那平或其药学上可接受的盐的分解的方法，上述粘合剂层含有粘合基剂和阿塞那平或其药学上可接受的盐，通过使上述粘合剂层中含有选自赖氨酸、精氨酸和组氨酸中的至少1种碱性氨基酸或其药学上可接受的盐，从而抑制阿塞那平或其药学上可接受的盐的分解。
发明效果
根据本发明，可提供一种稳定性优异的含有阿塞那平或其药学上可接受的盐的贴剂。
具体实施方式
以下，示出本发明的实施方式，详细说明本发明。
本发明的一实施方式的贴剂在支持体上具备粘合剂层，上述粘合剂层含有粘合基剂、阿塞那平或其药学上可接受的盐、以及选自赖氨酸、精氨酸和组氨酸中的至少1种碱性氨基酸或其药学上可接受的盐。
本发明的一实施方式的方法为抑制在支持体上具备粘合剂层的贴剂中的阿塞那平或其药学上可接受的盐的分解的方法，上述粘合剂层含有粘合基剂和阿塞那平或其药学上可接受的盐，通过使上述粘合剂层中含有选自赖氨酸、精氨酸和组氨酸中的至少1种碱性氨基酸或其药学上可接受的盐，由此抑制阿塞那平或其药学上可接受的盐的分解。
支持体只要是能维持贴剂、尤其是粘合剂层的形状即可。作为支持体的材质，例如可举出：聚乙烯、聚丙烯、聚丁二烯、乙烯-氯乙烯共聚物、聚氯乙烯、尼龙等聚酰胺、聚酯、纤维素衍生物、聚氨酯等合成树脂。支持体的性状例如为膜、片、片状多孔体、片状发泡体、织物、编织物、无纺布等布帛、以及它们的层叠体等。支持体的厚度没有特殊限制，通常优选为2μm～3000μm左右。
粘合剂层由将粘合基剂、阿塞那平或其药学上可接受的盐、选自赖氨酸、精氨酸和组氨酸中的至少1种碱性氨基酸或其药学上可接受的盐、和后述的任意成分混合而得到的粘合剂组合物形成。粘合剂层的每单位面积的质量没有特别限制，可以为30g/m2～400g/m2，也可以为40g/m2～300g/m2、50g/m2～200g/m2或70g/m2～120g/m2。当粘合剂层的每单位面积的质量超过400g/m2时，在穿脱衣服时等贴剂容易脱落。
阿塞那平是也被称为(3aRS,12bRS)-5-氯-2-甲基-2,3,3a,12b-四氢-1H-二苯并[2,3:6,7]氧杂
并[4,5-c]吡咯的化合物，由以下式(1)表示。
[化1]
阿塞那平的药学上可接受的盐是指可药用的阿塞那平的酸加成盐。作为酸，例如可举出：盐酸、氢溴酸、氢碘酸、磷酸、醋酸、丙酸、乙醇酸、马来酸、丙二酸、琥珀酸、酒石酸、柠檬酸、抗坏血酸、水杨酸、苯甲酸等。例如，阿塞那平马来酸盐作为精神分裂症的治疗药而市售。
阿塞那平具有多种光学异构体，可以为任意光学异构体，也可以为外消旋体等光学异构体的混合物。作为加成到阿塞那平上的酸，只要是药学上可接受的酸，就没有特殊限制。阿塞那平的酸加成盐可以是无水物或水合物。
阿塞那平或其药学上可接受的盐的含量以粘合剂层的总质量为基准，可以为1～30质量％，也可以为5质量％～25质量％、7质量％～22质量％或10质量％～20质量％。
粘合基剂是向粘合剂层赋予粘合性的成分，例如可举出：橡胶系粘合基剂、丙烯酸系粘合基剂、有机硅系粘合基剂等。粘合基剂优选为选自橡胶系粘合基剂、丙烯酸系粘合基剂、和有机硅系粘合基剂中的1种以上。粘合基剂优选不含水(即，非水系粘合基剂)。粘合基剂既可以是橡胶系粘合基剂、丙烯酸系粘合基剂和有机硅系粘合基剂中的任一种，也可以是它们的组合。粘合基剂的总含量以粘合剂层的总质量为基准，可以为10质量％～90质量％，也可以为20质量％～90质量％、20质量％～60质量％、20质量％～40质量％。
作为橡胶系粘合基剂，例如可举出：天然橡胶、聚异丁烯、烷基乙烯基醚(共)聚合物、聚异戊二烯、聚丁二烯、苯乙烯-丁二烯共聚物、苯乙烯-异戊二烯共聚物、苯乙烯-异戊二烯-苯乙烯嵌段共聚物(SIS)等。橡胶系粘合基剂可以单独使用它们中的1种，也可以组合使用2种以上。其中，作为本实施方式的橡胶系粘合基剂，从具有能够发挥粘合剂层的更充分的粘合力的倾向的观点考虑，优选为选自苯乙烯-异戊二烯-苯乙烯嵌段共聚物和聚异丁烯中的1种以上。
作为橡胶系粘合剂的具体例，可举出：Quintac(注册商标)3570C(商品名，日本瑞翁株式会社制)、SIS5002(商品名，JSR公司制)、Oppanol(注册商标)N50、N80、N100、N150、B11、B12、B50、B80、B100、B120、B150、B220(商品名，BASF公司制)、JSR butyl 065、268、365(商品名，JSR公司制)、SIBSTAR(注册商标)T102(商品名，Kaneka公司制)等。
橡胶系粘合基剂的含量以粘合剂层的总质量为基准，可以为10质量％～90质量％，也可以为20质量％～90质量％、20质量％～60质量％、20质量％～40质量％。
丙烯酸系粘合基剂是向粘合剂层赋予粘合性的成分，例如为1种或2种以上的(甲基)丙烯酸烷基酯的(共)聚合物。作为(甲基)丙烯酸烷基酯，例如可举出：(甲基)丙烯酸丁酯、(甲基)丙烯酸异丁酯、(甲基)丙烯酸己酯、(甲基)丙烯酸辛酯、(甲基)丙烯酸2-乙基己酯、(甲基)丙烯酸癸酯等。予以说明，本说明书中，术语“(甲基)丙烯酸”是指丙烯酸和甲基丙烯酸中的任一者或两者，类似的表述也具有相同的含义。
丙烯酸系粘合基剂也可以是由(甲基)丙烯酸烷基酯(主要单体)和共聚单体形成的共聚物。作为主要单体，例如可举出：(甲基)丙烯酸甲酯、(甲基)丙烯酸乙酯、(甲基)丙烯酸丁酯、(甲基)丙烯酸己酯、(甲基)丙烯酸庚酯、(甲基)丙烯酸辛酯、(甲基)丙烯酸2-乙基己酯等，可以单独使用它们中的1种，也可以组合使用2种以上。共聚单体只要是可与(甲基)丙烯酸烷基酯共聚的成分即可。作为共聚单体，例如可举出：(甲基)丙烯酸羟基烷基酯、乙烯、丙烯、苯乙烯、乙酸乙烯酯、N-乙烯基吡咯烷酮、(甲基)丙烯酸、(甲基)丙烯酰胺等。共聚单体可以单独使用它们中的1种或组合使用2种以上。
作为丙烯酸系粘合基剂的具体例，可举出：丙烯酸-丙烯酸辛酯共聚物、丙烯酸2-乙基己酯-乙烯基吡咯烷酮共聚物溶液、丙烯酸酯-乙酸乙烯酯共聚物、丙烯酸2-乙基己酯-甲基丙烯酸2-乙基己酯-甲基丙烯酸十二烷基酯共聚物、丙烯酸甲酯-丙烯酸2-乙基己酯共聚树脂乳液、丙烯酸树脂烷醇胺液体中所含的丙烯酸系高分子等。作为这样的丙烯酸系粘合剂，作为具体例，可举出：DURO-TAK(注册商标)387-2510、DURO-TAK(注册商标)87-2510、DURO-TAK(注册商标)387-2287、DURO-TAK(注册商标)87-2287、DURO-TAK(注册商标)87-4287、DURO-TAK(注册商标)387-2516、DURO-TAK(注册商标)87-2516、DURO-TAK(注册商标)87-2074、DURO-TAK(注册商标)87-900A、DURO-TAK(注册商标)87-901A、DURO-TAK(注册商标)87-9301、DURO-TAK(注册商标)87-4098等DURO-TAK系列(Henkel公司制)；GELVA(注册商标)GMS 788、GELVA(注册商标)GMS 3083、GELVA(注册商标)GMS 3253等GELVA系列(Henkel公司制)；MAS811(商品名)、MAS683(商品名)等MAS系列(Cosmedy制药公司制)；Eudragit(注册商标)系列(Evonik公司制)、Nikasol(注册商标)系列(日本电石工业株式会社制)、ウルトラゾール(注册商标)系列(Aica工业公司制)。
丙烯酸系粘合基剂的含量以粘合剂层的总质量为基准，可以为10质量％～90质量％，也可以为20质量％～90质量％、20质量％～60质量％、20质量％～40质量％。
有机硅系粘合基剂是具有有机聚硅氧烷骨架的化合物。作为有机硅系粘合基剂，例如可举出：二甲基聚硅氧烷、聚甲基乙烯基硅氧烷、聚甲基苯基硅氧烷。作为具体的有机硅系粘合基剂，例如可举出：MD7-4502有机硅粘合剂、MD7-4602有机硅粘合剂等MD系列(DuPont Toray Specialty Materials公司制)；Liveo(注册商标)BIO-PSA 7-4301有机硅粘合剂、Liveo(注册商标)BIO-PSA 7-4302有机硅粘合剂、Liveo(注册商标)BIO-PSA 7-4201有机硅粘合剂、Liveo(注册商标)BIO-PSA 7-4202有机硅粘合剂、Liveo(注册商标)BIO-PSA 7-4101有机硅粘合剂、Liveo(注册商标)BIO-PSA 7-4102有机硅粘合剂、Liveo(注册商标)BIO-PSA 7-4601有机硅粘合剂、Liveo(注册商标)BIO-PSA 7-4602有机硅粘合剂、Liveo(注册商标)BIO-PSA 7-4501有机硅粘合剂、Liveo(注册商标)BIO-PSA 7-4502有机硅粘合剂、Liveo(注册商标)BIO-PSA 7-4401有机硅粘合剂、Liveo(注册商标)BIO-PSA 7-4402有机硅粘合剂等BIO-PSA系列(DuPont Toray Specialty Materials公司制)、DowCorning(注册商标)7-9800A、Dow Corning(注册商标)7-9800B、Dow Corning(注册商标)7-9700A、Dow Corning(注册商标)7-9700B。
有机硅系粘合基剂的含量以粘合剂层的总质量为基准，可以为10质量％～90质量％，也可以为20质量％～90质量％、20质量％～60质量％、20质量％～40质量％。
通过使粘合剂层中含有选自赖氨酸、精氨酸和组氨酸中的至少1种碱性氨基酸或其药学上可接受的盐，可抑制在制造和/或保存贴剂时的阿塞那平的N-氧化物和四脱氢物的生成。碱性氨基酸的药学上可接受的盐是指可药用的碱性氨基酸的酸加成盐。作为酸，例如可举出：盐酸、氢溴酸、氢碘酸、磷酸、醋酸、丙酸、乙醇酸、马来酸、丙二酸、琥珀酸、酒石酸、柠檬酸、抗坏血酸、水杨酸、苯甲酸等。优选的酸加成盐为盐酸盐(赖氨酸盐酸盐、精氨酸盐酸盐和组氨酸盐酸盐)。
碱性氨基酸或其药学上可接受的盐的含量以粘合剂层的总质量为基准，可以为0.01质量％～7质量％，也可以为0.05质量％～7质量％、0.01质量％～3质量％、0.01质量％～1质量％、0.05％质量％～1质量％或0.1质量％～0.5质量％。
粘合剂层还可以任选含有其他添加剂作为其他添加剂，例如可举出：粘合赋予树脂、增塑剂、吸收促进剂、溶解剂、其他辅助性稳定剂、填充剂、香料等。
增粘树脂是调整粘合剂层的粘合性的成分。作为增粘树脂，例如可举出：脂环族饱和烃树脂；松香、松香的甘油酯、氢化松香、氢化松香的甘油酯、松香的季戊四醇酯、马来松香等松香衍生物；萜烯系增粘树脂；石油系增粘树脂等。增粘树脂可单独使用1种或组合使用2种以上。当粘合剂层含有增粘树脂时，增粘树脂的含量以粘合剂层的总质量为基准，可以为20质量％～80质量％，也可以为30质量％～70质量％。
作为增塑剂，例如可举出：石蜡油(液体石蜡等)；角鲨烷、角鲨烯、植物油类(橄榄油、山茶油、蓖麻油、妥尔油、花生油、薄荷油、桉油、荷荷芭油、白樟油、葵花籽油、橙油等)；油脂类(邻苯二甲酸二丁酯、邻苯二甲酸二辛酯等)；和液态橡胶(液态聚丁烯、液态异戊二烯橡胶等)。优选的增塑剂为液体石蜡或液态聚丁烯。当粘合剂层含有增塑剂时，增塑剂的含量相对于粘合剂层的总质量，例如为3质量％～50质量％、5质量％～30质量％、或7质量％～20质量％。
吸收促进剂只要是以往已知具有经皮吸收促进作用的化合物即可。作为吸收促进剂，例如可举出：有机酸及其盐(例如，碳数6～20的脂族羧酸(以下，也称为“脂肪酸”)及其盐、肉桂酸及其盐)、有机酸酯(例如，脂肪酸酯、肉桂酸酯)、有机酰胺(例如，脂肪酰胺)、脂肪醇、多元醇、醚(例如，脂肪醚、聚氧乙烯烷基醚)等。这些吸收促进剂可具有不饱和键，也可以为环状、直链状或支链状的化学结构。另外，吸收促进剂可以为单萜系化合物、倍半萜系化合物、和植物油(例如，橄榄油)。这些吸收促进剂可以单独使用1种或组合使用2种以上。
作为上述有机酸，可举出：脂族(单、二或三)羧酸(例如，乙酸、丙酸、柠檬酸(包括柠檬酸酐)、异丁酸、己酸、辛酸、脂肪酸、乳酸、马来酸、丙酮酸、草酸、琥珀酸、酒石酸等)、芳族羧酸(例如，邻苯二甲酸、水杨酸、苯甲酸、乙酰水杨酸等)、肉桂酸、链烷磺酸(例如，甲磺酸、乙磺酸、丙磺酸、丁磺酸)、烷基磺酸衍生物(例如，聚氧乙烯烷基醚磺酸、N-2-羟乙基哌嗪-N'-2-乙磺酸)、胆酸衍生物(例如，去氢胆酸等)。这些有机酸也可以是钠盐等碱金属盐。其中，优选为脂族羧酸、芳族羧酸或它们的盐，特别优选为乙酸、乙酸钠或柠檬酸。作为脂肪酸，例如可举出：月桂酸、肉豆蔻酸、棕榈酸、硬脂酸、异硬脂酸、油酸、亚油酸、亚麻酸。
作为有机酸酯，例如可举出：乙酸乙酯、乙酸丙酯、乳酸鲸蜡酯、乳酸月桂酯、水杨酸甲酯、水杨酸乙二醇酯、肉桂酸甲酯、脂肪酸酯。作为脂肪酸酯，例如可举出：月桂酸甲酯、月桂酸己酯、肉豆蔻酸异丙酯、肉豆蔻酸肉豆蔻酯、肉豆蔻酸辛基十二烷基酯、棕榈酸异丙酯、棕榈酸鲸蜡基酯。脂肪酸酯可以是甘油脂肪酸酯、丙二醇脂肪酸酯、山梨糖醇酐脂肪酸酯、聚乙二醇山梨糖醇酐脂肪酸酯、聚乙二醇脂肪酸酯、蔗糖脂肪酸酯、或聚氧乙烯氢化蓖麻油。作为脂肪酸酯的具体例，可举出：单辛酸甘油酯、单癸酸甘油酯、单月桂酸甘油酯、单油酸甘油酯、山梨糖醇酐单月桂酸酯、蔗糖单月桂酸酯、聚山梨酯20(商品名)、丙二醇单月桂酸酯、聚乙二醇单月桂酸酯、聚乙二醇单硬脂酸酯、司盘40、司盘60、司盘80、司盘120(商品名，Croda Japan公司制)、吐温20、吐温21、吐温40、吐温60、吐温80、NIKKOL HCO-60(商品名，日光化学株式会社制)。
作为有机酰胺，例如可举出：脂肪酰胺(例如，月桂酸二乙醇酰胺)、六氢-1-十二烷基-2H-氮杂
-2-酮(也称为“氮酮”)及其衍生物、焦性硫代癸烷(pyrothiodecane)。
脂肪醇是指碳数6～20的脂族醇。作为脂肪醇，例如可举出：月桂醇、肉豆蔻醇、油醇、异硬脂醇、鲸蜡醇。作为多元醇，例如可举出：丙二醇。
脂肪醚是指具有碳数6～20的脂族基(例如烷基、烯基)的醚。作为聚氧乙烯烷基醚，例如可举出：聚氧乙烯月桂基醚。
作为单萜系化合物，例如可举出：香叶醇、百里香酚、松油醇、l-薄荷醇、冰片、d-柠檬烯、异冰片、橙花醇、dl-樟脑。作为单萜系化合物，也可以使用薄荷油。
作为吸收促进剂，更优选脂肪酸(特别是油酸)、棕榈酸异丙酯、油醇、月桂醇、异硬脂醇、月桂酸二乙醇酰胺、甘油单辛酸酯、甘油单癸酸酯、甘油单油酸酯、山梨糖醇酐单月桂酸酯、丙二醇单月桂酸酯、聚氧乙烯月桂基醚或焦性硫代癸烷(pyrothiodecane)。
当粘合剂层含有吸收促进剂时，吸收促进剂的含量以粘合剂层的总质量为基准，可以为2质量％～40质量％。
溶解剂是使阿塞那平或其药学上可接受的盐易溶于粘合剂组合物的成分。作为溶解剂，例如可举出：脂肪酸(例如，癸酸、油酸、亚油酸)、脂肪酸烷基酯(例如，肉豆蔻酸异丙酯、棕榈酸异丙酯)、脂肪酸多元醇酯(例如，单月桂酸丙二醇酯、单月桂酸甘油酯、单油酸甘油酯、山梨糖醇酐单月桂酸酯)、脂肪酰胺(例如，月桂酸二乙醇酰胺)、脂族醇(例如，辛基十二烷醇、异硬脂醇、油醇)、多元醇(例如，丙二醇、二丙二醇、聚乙二醇)、吡咯烷酮衍生物(例如N-甲基-2-吡咯烷酮)、有机酸或其盐(例如，乙酸、乳酸、乙酸钠、乳酸钠)、氢氧化钠。当粘合剂层含有溶解剂时，溶解剂的含量以粘合剂层的总质量为基准，可以为2质量％～40质量％。
其他辅助性的稳定剂只要是能够抑制由紫外线等光线、热或活性化学物质的作用而产生的自由基的生成及其连锁反应的进行的物质即可。通过任选地含有稳定剂，可进一步提高制造贴剂时的阿塞那平的稳定性。作为稳定剂，例如可举出：生育酚及其酯衍生物、抗坏血酸及其酯衍生物、2,6-二丁羟基甲苯(BHT)、2,6-二丁羟基苯甲醚(BHA)、2-巯基苯并咪唑等。稳定剂可以单独使用1种，也可以组合使用2种以上。当粘合剂层含有稳定剂时，稳定剂的含量以粘合剂层的总质量为基准，可以为0.05质量％～3质量％，也可以为0.05质量％～1质量％、0.05质量％～0.25质量％、或0.1质量％～0.25质量％。当稳定剂的含量为0.05质量％～3质量％时，存在贴剂中的各成分的稳定性优异的倾向。
作为填充剂，例如可举出：金属化合物(氧化铝、氢氧化铝、氧化锌、氧化钛、碳酸钙等)、陶瓷(滑石、粘土、高岭土、二氧化硅、羟基磷灰石、合成硅酸铝、偏硅酸铝镁等)或有机化合物(纤维素粉末、硬脂酸盐等)的粉末或含有它们的树脂的短纤维。当粘合剂层含有填充剂时，填充剂的含量以粘合剂层的总质量为基准，可以为0.1质量％～20质量％。
贴剂还可以具备剥离衬垫。剥离衬垫层叠在粘合剂层的与支持体相反一侧的表面。当具备剥离衬垫时，存在可减少储存期间污物等附着在粘合剂层上的倾向。剥离衬垫的与粘合剂层接触的面优选通过有机硅或氟化聚烯烃等进行了脱模处理。
作为剥离衬垫的材料，没有特别限定，可使用本领域技术人员公知的衬垫。作为剥离衬垫，例如可举出：聚对苯二甲酸乙二醇酯、聚萘二甲酸乙二酯等聚酯；聚乙烯、聚丙烯等聚烯烃；聚氯乙烯、聚偏二氯乙烯、尼龙、铝等的膜。剥离衬垫可以是优质纸与聚烯烃的层压膜。作为剥离衬垫的材质，优选聚丙烯或聚对苯二甲酸乙二醇酯制的膜。
贴剂例如可以通过如下方法制造，但并不限定于此，可以使用公知的方法。首先，将构成粘合剂层的各成分以规定比例混合而得到均匀的溶解物(粘合剂组合物)。接着，将粘合剂组合物以规定厚度延展在可剥离膜(剥离衬垫)上而形成粘合剂层。进而，以粘合剂层夹在剥离衬垫与支持体之间的方式将支持体压接在粘合剂层上。最后，通过剪切成期望的形状和尺寸，可得到贴剂。此时，剥离衬垫在施用贴剂时被除去。贴剂的形状和尺寸例如可以是短边为3～14cm且长边为7～20cm的矩形、或直径为1～10cm的圆形。
实施例
试验例1：含有碱性氨基酸的贴剂的稳定性评价
贴剂的制备
根据下述表1～表2，混合各成分，得到粘合剂组合物。以每单位面积的质量为100g/m2的方式，将得到的粘合剂组合物延展在剥离衬垫(实施了脱模处理的聚对苯二甲酸乙二醇酯制膜)上，干燥除去溶剂，形成粘合剂层。在所得粘合剂层的与上述相反的面上层压支持体层(聚对苯二甲酸乙二醇酯制膜)，得到以支持体层/粘合剂层/剥离衬垫的顺序层压而成的贴剂。
含量试验
通过上述制造方法制造出贴剂后，立即通过HPLC(高效液相色谱法)测定产生的阿塞那平的N-氧化物和四脱氢物的量；将贴剂在60℃在包装袋内保存1个月后，同样通过HPLC测定产生的阿塞那平的N-氧化物和四脱氢物的量。
更详细而言，取出贴剂的粘合剂层，浸渍在5mL四氢呋喃(高效液相色谱用等级)中，提取有机物，向其中加入稀释溶液(0.1％磷酸水溶液/甲醇＝50/50(v/v))45mL，使总量为50mL，过滤出不溶物后，通过在以下分析条件下的高效液相色谱法，得到阿塞那平、其N-氧化物及其四脱氢物的峰分离的色谱图。N-氧化物和四脱氢物的含量是将阿塞那平的理论量设为100，由N-氧化物和四脱氢物所对应的峰的曲线下面积的值计算。予以说明，N-氧化物相对于阿塞那平的相对保留时间(RRT)为0.24，四脱氢物相对于阿塞那平的RRT为1.10。
＜分析条件＞
色谱柱：CAPCELLPAKC18 MGII 5μm(4.6mm I.D×150mm)
流动相：甲醇/磷酸缓冲液(pH6.8)＝70/30
测定波长：230nm
流速：1.0mL/min
样品注入量：15μL
柱温：50℃
[表1]
[表2]
确认在含有碱性氨基酸的贴剂中能够充分抑制阿塞那平的N-氧化物和四脱氢物的产生。
试验例2：含有碱性氨基酸的贴剂的稳定性评价
根据下述表3～表4，混合各成分，得到粘合剂组合物。与试验例1同样操作，得到贴剂。与试验例1同样操作，通过HPLC，对刚制造出的贴剂和在60℃在包装袋内保存1个月后的贴剂中产生的阿塞那平的N-氧化物和四脱氢物的量进行定量。
[表3]
[表4]
确认在含有碱性氨基酸的贴剂中能够充分抑制阿塞那平的N-氧化物和四脱氢物的产生。
Claims (6)
1.贴剂，其是在支持体上具备粘合剂层的贴剂，其中，
上述粘合剂层含有粘合基剂、阿塞那平或其药学上可接受的盐、以及选自赖氨酸、精氨酸和组氨酸中的至少1种碱性氨基酸或其药学上可接受的盐。
2.如权利要求1所述的贴剂，其中，上述粘合基剂为选自橡胶系粘合基剂、丙烯酸系粘合基剂和有机硅系粘合基剂中的至少1种。
3.如权利要求1或2所述的贴剂，其中，上述碱性氨基酸或其药学上可接受的盐的含量以粘合剂层的总质量为基准，为0.01质量％～7质量％。
4.抑制贴剂中的阿塞那平或其药学上可接受的盐的分解的方法，
其中，上述贴剂是在支持体上具备粘合剂层、且上述粘合剂层含有粘合基剂和阿塞那平或其药学上可接受的盐的贴剂；
上述方法包括使上述粘合剂层中含有选自赖氨酸、精氨酸和组氨酸中的至少1种碱性氨基酸或其药学上可接受的盐。
5.如权利要求4所述的方法，其中，上述粘合基剂为选自橡胶系粘合基剂、丙烯酸系粘合基剂和有机硅系粘合基剂中的至少1种。
6.如权利要求4或5所述的方法，其中，上述碱性氨基酸或其药学上可接受的盐的含量以粘合剂层的总质量为基准，为0.01质量％～7质量％。
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