CN115066233A - 含有双氯芬酸钠的贴剂 - Google Patents
含有双氯芬酸钠的贴剂 Download PDFInfo
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- CN115066233A CN115066233A CN202180013529.5A CN202180013529A CN115066233A CN 115066233 A CN115066233 A CN 115066233A CN 202180013529 A CN202180013529 A CN 202180013529A CN 115066233 A CN115066233 A CN 115066233A
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- Prior art keywords
- patch
- adhesive layer
- diclofenac sodium
- acid
- time
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Abstract
本发明涉及一种贴剂，其是用于缓解癌症疼痛的贴剂，具备支持体层和层叠在支持体层上的粘合剂层，其中，粘合剂层含有粘合基剂和双氯芬酸钠，所述贴剂的使用方式为：每天贴附1次，每次的双氯芬酸钠的给药量为150mg～225mg。
Description
技术领域
本发明涉及含有双氯芬酸钠的贴剂。
背景技术
专利文献1中公开了配合有非甾体抗炎药的贴剂。
现有技术文献
专利文献
专利文献1：国际公开2018/124089号
发明内容
发明要解决的课题
期望提供一种在给予癌症患者时能够充分缓解癌症疼痛的贴剂。但是，市场上还没有缓解癌症疼痛的含有双氯芬酸钠的贴剂产品，因此，也不知道这样的贴剂的理想的用法和用量。
解决课题的手段
为了解决上述课题，本发明人等进行了深入的研究，结果发现，通过每天1次，每次2片或3片，施用(给药)含有75mg双氯芬酸钠的贴剂，能够得到充分的癌症疼痛缓解效果，从而完成了本发明。
本发明的用于缓解癌症疼痛的贴剂具备支持体层和层叠在支持体层上的粘合剂层，粘合剂层含有粘合基剂和双氯芬酸钠，使用方式为：每天贴附1次，每次的双氯芬酸钠的给药量为150mg～225mg。
发明效果
本发明的贴剂具有充分的癌症疼痛缓解效果。
附图说明
图1是表示双氯芬酸钠75mg给药组的Kaplan-Meier曲线的图。
图2是表示双氯芬酸钠150mg给药组的Kaplan-Meier曲线的图。
图3是表示双氯芬酸钠225mg给药组的Kaplan-Meier曲线的图。
图4是表示双氯芬酸钠150mg或225mg给药组的Kaplan-Meier曲线的图。
具体实施方式
本发明的贴剂具备支持体层和层叠在支持体层上的粘合剂层。粘合剂层通常层叠在支持体层的一个表面上，根据需要，在粘合剂层的另一个表面上层叠可剥离膜。
首先，说明粘合剂层。粘合剂层是在应用贴剂时与皮肤压接的部位，含有粘合基剂和双氯芬酸钠。
双氯芬酸钠是非甾体抗炎药，是缓解癌症疼痛的成分。优选每1片贴剂含有75mg双氯芬酸钠。
粘合基剂可以含有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种粘合基剂。橡胶系粘合基剂例如为聚异戊二烯、聚异丁烯(PIB)、聚丁二烯、苯乙烯-丁二烯-苯乙烯嵌段共聚物、苯乙烯-异戊二烯-苯乙烯(SIS)嵌段共聚物、苯乙烯-丁二烯橡胶、苯乙烯-异戊二烯橡胶、或它们的组合。其中，从提高双氯芬酸钠的皮肤透过性、并且进一步提高贴剂的粘合性的观点考虑，优选SIS嵌段共聚物、PIB、或它们的组合，更优选SIS嵌段共聚物与PIB的混合物。丙烯酸系粘合基剂例如为使(甲基)丙烯酸、(甲基)丙烯酸2-乙基己酯、(甲基)丙烯酸甲酯、(甲基)丙烯酸丁酯、(甲基)丙烯酸羟乙酯等(甲基)丙烯酸系单体中的至少1种聚合或共聚而成的粘合剂。有机硅系粘合基剂例如以聚二甲基硅氧烷、聚甲基乙烯基硅氧烷和聚甲基苯基硅氧烷等硅橡胶为主成分。
在橡胶系粘合基剂的情况下，从贴剂的粘合性的观点考虑，粘合基剂的含量相对于粘合剂层的总质量，可以为10～70质量％、20～50质量％、23～40质量％、或25～30质量％。作为橡胶系粘合基剂，在使用SIS嵌段共聚物和PIB的混合物的情况下，两者的质量比优选为4：1～1：4、3：1～1：1、或3：1～2：1。在丙烯酸系粘合基剂或有机硅系粘合基剂的情况下，粘合基剂的含量相对于粘合剂层的总质量，优选为50质量％～90质量％。
为了溶解双氯芬酸钠、提高其皮肤透过性等目的，粘合剂层还可以含有二甲亚砜(DMSO)。DMSO的含量相对于粘合剂层的总质量，优选为1质量％～20质量％、2质量％～10质量％、3质量％～10质量％、或5质量％～9质量％。
从提高双氯芬酸钠的皮肤透过性的观点以及防止双氯芬酸钠的结晶(晶体)析出的观点考虑，双氯芬酸钠与DMSO的比优选为1：0.3～1：4、1：0.4～1：3、1：0.6～1：3、或1：0.72～1：3。
为了促进双氯芬酸钠的经皮吸收或者为了防止双氯芬酸钠的结晶经时析出等目的，粘合剂层还可以含有有机酸。作为有机酸，可例示：脂族单羧酸(甲酸、乙酸、丙酸、丁酸、异丁酸、戊酸、己酸、庚酸、辛酸、壬酸、癸酸、月桂酸、油酸、亚油酸、亚麻酸、异硬脂酸、山梨酸、丙酮酸等)、脂族二羧酸(草酸、丙二酸、琥珀酸、戊二酸、己二酸、癸二酸、马来酸、富马酸、草酰乙酸等)、及脂族三羧酸(乌头酸、丙烷三羧酸等)等脂族羧酸；羟酸(乙醇酸、乳酸、羟基丙二酸、甘油酸、羟基丁酸、苹果酸、酒石酸、柠檬酸、异柠檬酸、糖酸、葡糖酸、葡糖醛酸、抗坏血酸、异抗坏血酸等)、芳族羧酸(苯甲酸、没食子酸、水杨酸、乙酰水杨酸、邻苯二甲酸等)、其他有机酸(甲磺酸、苯磺酸等)、或它们的盐(例如，钠盐等碱金属盐)。这些有机酸可以单独使用1种，也可以组合使用2种以上。在这些有机酸中，从促进双氯芬酸钠的经皮吸收并防止双氯芬酸钠的结晶经时析出的观点考虑，特别优选柠檬酸、油酸、甲磺酸、或它们的碱金属盐，更优选油酸。从提高双氯芬酸钠的皮肤透过性且防止双氯芬酸钠的结晶经时析出的观点考虑，有机酸的含量相对于粘合剂层的总质量，优选为0.1～20质量％、0.5～10质量％、1～8质量％、或2～7质量％。
粘合剂层还可以含有增粘剂(粘着赋予剂)、增塑剂、溶解剂、稳定剂、填充剂等其他添加剂。
增粘剂例如可举出：松香、松香的甘油酯、氢化松香、氢化松香甘油酯及松香的季戊四醇酯等松香衍生物、アルコンP100(商品名，荒川化学工业株式会社制)等脂环族饱和烃树脂、クイントンB170(商品名，日本Zeon公司制)等脂族烃树脂、クリアロンP-125(商品名，日本Yasuhara Chemical公司制)等萜烯树脂、马来酸树脂等。其中，优选氢化松香甘油酯、脂环族饱和烃树脂、脂族烃树脂或萜烯树脂，更优选脂环族烃树脂。这些增粘树脂可以组合2种以上。通过含有增粘树脂，能够提高粘合剂层的粘合性，稳定地维持其他物性。增粘树脂的含量以粘合剂层的总质量为标准，例如优选为5～60质量％、10～50质量％、30～45质量％、或35～40质量％。作为增粘剂，更优选脂环族饱和烃树脂和氢化松香甘油酯的组合。脂环族饱和烃树脂与氢化松香甘油酯的质量比优选为4：1～1：4、4：1～2：3或3：1～2：1。
作为增塑剂，例如可举出：石蜡系加工油、环烷烃系加工油和芳族系加工油等石油系油；角鲨烷；角鲨烯；橄榄油、山茶油、蓖麻油、妥尔油和花生油等植物系油；硅油；邻苯二甲酸二丁酯和邻苯二甲酸二辛酯等二元酸酯；聚丁烯和液态异戊二烯橡胶等液态橡胶；肉豆蔻酸异丙酯、月桂酸己酯、癸二酸二乙酯和癸二酸二异丙酯等液态脂肪酸酯类；二甘醇；聚乙二醇；水杨酸乙二醇；丙二醇；二丙二醇；三醋汀；柠檬酸三乙酯；克罗米通等。其中，优选液体石蜡、液态聚丁烯、肉豆蔻酸异丙酯、癸二酸二乙酯和月桂酸己酯，更优选液态聚丁烯、肉豆蔻酸异丙酯和液体石蜡，特别优选液体石蜡。这些增塑剂可以组合2种以上。增塑剂的含量相对于粘合剂层的总质量，例如优选为7～70质量％、8～40质量％、10～20质量％、或12～15质量％。
溶解剂例如可举出：液态脂肪酸酯类(肉豆蔻酸异丙酯、月桂酸己酯、癸二酸二乙酯、癸二酸二异丙酯等)、二甘醇、三甘醇、聚乙二醇、丙二醇、二丙二醇、三醋汀、柠檬酸三乙酯、克罗米通等。其中，优选二甘醇、三甘醇、聚乙二醇、丙二醇、二丙二醇，更优选聚乙二醇。当溶解剂为聚乙二醇时，聚乙二醇的数均分子量可以为200～20000，优选为400～6000，更优选为1000～6000。这些溶解剂可以组合2种以上。以粘合剂层的总质量为标准，溶解剂的含量例如为0.1～10质量％、或0.5～5质量％。
稳定剂可举出：脂肪酸金属盐(硬脂酸镁等)、抗氧化剂(生育酚衍生物、抗坏血酸衍生物、异抗坏血酸衍生物、去甲二氢愈创木酸、没食子酸衍生物、二丁羟基甲苯(BHT)、丁羟基苯甲醚、2-巯基苯并咪唑等)、紫外线吸收剂(咪唑衍生物、苯并三唑衍生物、对氨基苯甲酸衍生物、邻氨基苯甲酸衍生物、水杨酸衍生物、肉桂酸衍生物、二苯甲酮衍生物、香豆酸衍生物、樟脑衍生物等)等。这些稳定剂可以组合2种以上。以粘合剂层的总质量为标准，稳定剂的含量优选为0～5质量％，更优选为0～2质量％。通过使粘合剂层含有稳定剂，可进一步提高双氯芬酸钠的稳定性。
填充剂可举出：金属氧化物(氧化锌、氧化钛等)、金属盐(碳酸钙、碳酸镁、硬脂酸锌等)、硅酸化合物(高岭土、滑石、膨润土、气相二氧化硅、水合二氧化硅、硅酸铝、硅酸镁、硅酸铝镁等)、金属氢氧化物(氢氧化铝等)等。这些填充剂可以组合2种以上。以粘合剂层的总质量为标准，填充剂的含量优选为0～10质量％，更优选为0～5质量％。
粘合剂层可以是由1种组成构成的单层，也可以是由组成不同的多个层层叠而成的多层。从使贴剂适当粘着在皮肤上的观点考虑，粘合剂层整体的膏体质量优选为10～1000g/m2，更优选为30～300g/m2，进一步优选为150～250g/m2。
接着，说明支持体层。支持体层保持粘合剂层。支持体层优选将纤维制成布状(织布、无纺布、或编织布)而得，或者是无孔性或多孔性的膜(片)的单层体或层叠体。支持体层的材质优选为选自聚酯(聚对苯二甲酸乙二醇酯(PET)、聚间苯二甲酸乙二醇酯、聚对苯二甲酸丙二醇酯、聚间苯二甲酸丙二醇酯、聚对苯二甲酸丁二醇酯、或聚萘二甲酸乙二醇酯等)、聚烯烃(乙烯、丙烯、乙酸乙烯酯、或丙烯腈等乙烯基系单体的聚合物或共聚物)、聚酰胺(尼龙或丝绸等)、聚氨酯(PU)或纤维素(木棉或麻等)中的1种以上的材质。也可以在布(织布、无纺布或编织布)上涂布橡胶组合物。橡胶组合物包含橡胶系粘合剂。橡胶系粘合剂例如为聚异戊二烯、PIB、聚丁二烯、苯乙烯-丁二烯-苯乙烯嵌段共聚物、SIS嵌段共聚物、苯乙烯-丁二烯橡胶、苯乙烯-异戊二烯橡胶、或它们的组合。橡胶组合物可以含有增粘剂。增粘剂例如为脂环族饱和烃树脂、氢化松香酯、萜烯树脂、或它们的组合。另外，橡胶组合物还可以含有增塑剂、填充剂等添加剂。支持体层的厚度例如为0.1～2mm。支持体层的单位面积重量例如为30～200g/m2。本说明书中，支持体层的厚度和单位面积重量按照JIS L 1906：2000的标准进行测定。
支持体层的透湿度优选为1000g/m2·24小时以上。当使用这样高透湿度的支持体层时，DMSO会从应用于皮肤的贴剂中缓慢地挥发，因此贴剂的粘合性提高，即使长时间使用贴剂，也不易剥落。透湿度的上限值可以为20000g/m2·24小时。当支持体层的透湿度处于这样的范围时，DMSO更容易从粘合剂层中挥发，因此更有效地提高贴剂的粘合性。予以说明，支持体层的透湿度是指在JIS Z0208：1976的标准(防湿包装材料的透湿度试验方法(杯法))中定义的40℃下的透湿度。
当支持体层为布状时，支持体层的纵向(材料流动方向)和横向(材料宽度方向)的任一方向的50％模量(JIS L 1018：1999)均优选为1N/50mm～12N/50mm。当50％模量为12N/50mm以下时，贴剂因皮肤伸缩而受到的应力更小，因此对皮肤的附着性变得良好。
当支持体层为膜时，材质优选为聚氨酯那样的高透湿性(高DMSO透过性)。包含聚氨酯的膜的伸缩性优异，因此从提高贴剂对皮肤的附着性和伸缩追随性的观点考虑是优选的。
支持体层例如优选为包含聚氨酯的无纺布或膜、包含聚对苯二甲酸乙二醇酯的编织布、涂布有橡胶组合物的聚酯布或它们的组合。更具体地，支持体层优选为包含聚氨酯的膜与包含聚氨酯纤维的无纺布的层叠体、包含PET纤维的无纺布、或涂布有橡胶组合物的聚酯布。
为了确保充分的粘合力且确保充分的双氯芬酸钠的皮肤透过量，贴剂的贴附面积优选为30～300cm2，更优选为50～150cm2。
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。接着，将溶解物以规定厚度延展在可剥离膜(剥离膜、剥离衬垫)或支持体层上而形成粘合剂层。接着，以粘合剂层夹在可剥离膜与支持体层之间的方式将支持体层压接在粘合剂层或可剥离膜上。最后，通过剪切成期望的形状，可得到贴剂。这种情况下，剥离衬垫在应用贴剂时被除去。另外，同样地，也可以将溶解物以规定厚度延展在支持体层上而形成粘合剂层，然后将支持体层压接在可剥离膜(剥离膜、剥离衬垫)上。
将贴剂贴附在成年人的胸部、腹部、腰部、背部、上臂部或大腿部等处，每天1次，每天(约24小时)更换贴附。为了避免皮肤刺激，优选每次改变贴附部位。每次的双氯芬酸钠的给药量为150～225mg。给药量是指贴附的贴剂中含有的双氯芬酸钠。在使用含有75mg双氯芬酸钠的贴剂的情况下，每次的贴附片数为2片或3片，例如，在贴附片数为2片不能充分得到癌症疼痛缓解效果的情况下，可以将贴附片数设为3片。
以下说明本发明的其他实施方式。
[1]一种方法，其是用于缓解癌症疼痛的方法，包括对患者给予贴剂的步骤，其中，所述贴剂具备支持体层和层叠在支持体层上的粘合剂层，所述粘合剂层含有粘合基剂和双氯芬酸钠，所述贴剂每天贴附1次，每次的双氯芬酸钠的给药量为150mg～225mg。
[2]根据[1]所述的方法，其中，所述贴剂是在粘合剂层中含有75mg双氯芬酸钠的贴剂，所述贴剂每天贴附1次，每次2片或3片。
[3]根据[1]或[2]所述的方法，其中，所述贴剂是包含选自苯乙烯-异戊二烯-苯乙烯嵌段共聚物和聚异丁烯中的至少1种作为粘合基剂的贴剂。
[4]根据[1]或[2]所述的方法，其中，所述贴剂是包含苯乙烯-异戊二烯-苯乙烯嵌段共聚物和聚异丁烯作为粘合基剂的贴剂。
[5]根据[1]～[4]任一项所述的方法，其中，所述贴剂是在粘合剂层中含有二甲亚砜的贴剂。
[6]根据[1]～[5]任一项所述的方法，其中，所述贴剂是在粘合剂层中含有有机酸的贴剂。
[7]根据[6]所述的方法，其中，所述贴剂是包含油酸作为有机酸的贴剂。
[8]根据[1]～[7]任一项所述的方法，其中，所述贴剂是在粘合剂层中含有增粘剂的贴剂。
[9]根据[8]所述的方法，其中，所述贴剂是包含脂环族饱和烃树脂和氢化松香甘油酯作为增粘剂的贴剂。
[10]根据[1]～[9]任一项所述的方法，其中，所述贴剂是在粘合剂层中含有增塑剂的贴剂。
[11]根据[10]所述的方法，其中，所述贴剂是包含液体石蜡作为增塑剂的贴剂。
[12]根据[1]～[11]任一项所述的方法，其中，所述贴剂是以透湿度为1000g/m2·24小时以上的聚对苯二甲酸乙二醇酯编织布作为支持体的贴剂。
[13]根据[1]～[12]任一项所述的方法，其中，所述贴剂是贴附面积为50～150cm2的贴剂。
[14]贴剂，其是在用于缓解癌症疼痛的方法中使用的贴剂，所述贴剂具备支持体层和层叠在支持体层上的粘合剂层，粘合剂层含有粘合基剂和双氯芬酸钠，所述贴剂每天贴附1次，每次的双氯芬酸钠的给药量为150mg～225mg。
[15]根据[14]所述的贴剂，其中，所述贴剂是在粘合剂层中含有75mg双氯芬酸钠的贴剂，所述贴剂每天贴附1次，每次2片或3片。
[16]根据[14]或[15]所述的贴剂，其中，所述贴剂是包含选自苯乙烯-异戊二烯-苯乙烯嵌段共聚物和聚异丁烯中的至少1种作为粘合基剂的贴剂。
[17]根据[14]或[15]所述的贴剂，其中，所述贴剂是包含苯乙烯-异戊二烯-苯乙烯嵌段共聚物和聚异丁烯作为粘合基剂的贴剂。
[18]根据[14]～[17]任一项所述的贴剂，其中，所述贴剂是在粘合剂层中包含二甲亚砜的贴剂。
[19]根据[14]～[18]任一项所述的贴剂，其中，所述贴剂是在粘合剂层中包含有机酸的贴剂。
[20]根据[19]所述的贴剂，其中，所述贴剂是包含油酸作为有机酸的贴剂。
[21]根据[14]～[20]任一项所述的贴剂，其中，所述贴剂是在粘合剂层中包含增粘剂的贴剂。
[22]根据[21]所述的贴剂，其中，所述贴剂是包含脂环族饱和烃树脂和氢化松香甘油酯作为增粘剂的贴剂。
[23]根据[14]～[22]任一项所述的贴剂，其中，所述贴剂是在粘合剂层中含有增塑剂的贴剂。
[24]根据[23]所述的贴剂，其中，所述贴剂是包含液体石蜡作为增塑剂的贴剂。
[25]根据[14]～[24]任一项所述的贴剂，其中，所述贴剂是以透湿度为1000g/m2·24小时以上的聚对苯二甲酸乙二醇酯编织布作为支持体的贴剂。
[26]根据[14]～[25]任一项所述的贴剂，其中，所述贴剂是贴附面积为50～150cm2的贴剂。
实施例
(含有双氯芬酸钠的贴剂的制备1)
通过以下方法制备含有双氯芬酸钠的贴剂。混合粘合剂层的各成分(下表所示的组成)，以膏体质量成为214g/m2的方式延展在剥离衬垫(进行了脱模处理的PET膜)上。在延展的粘合剂层上层叠支持体层，得到贴剂。将贴剂剪裁成7cm×10cm的大小。支持体层使用透湿度为5667g/m2·24小时的PET编织布。
[表1]
(安慰贴剂的制备)
除了不含双氯芬酸钠以外，采用与上述方法同样的方法制备相同组成的安慰贴剂(安慰剂贴剂)。
(镇痛效果的评价1)
在剂量(用量)调节期，将含有双氯芬酸钠的贴剂贴附在伴有疼痛的癌症患者的胸部、腹部、腰部、背部、上臂部或大腿部等上，每天1次，每次1片，每天更换贴附。当镇痛效果不足时，贴附的片数依次增加为2片、3片。本评价期为6～22天。只有在此期间满足下列所有标准的患者才能转移至随后的双盲试验期。
(1)转移判定日的前3天的VAS(视觉模拟评分法(Visual Analogue Scale))值的平均值与事先检查时(剂量调节期开始前)的VAS值相比，改善了15mm以上。VAS值在睡前测定。
(2)在包括转移判定日在内的最近3天内，未采取救济(rescue)措施。
(3)转移判定日的患者的疼痛改善度的评价为“完全改善”、“显著改善”或“中度改善”。予以说明，疼痛改善度的评价基于医生的问诊，采用“完全改善”、“显著改善”、“中度改善”、“轻度改善”、“不变”和“恶化”这6个等级来评价。
接着，将患者分为含有双氯芬酸钠的贴剂给药组(76例)和安慰贴剂给药组(79例)，通过双盲试验评价镇痛效果。双氯芬酸钠的给药量为75mg(40例，安慰贴剂为34例)，150mg(22例，安慰贴剂为32例)或225mg(14例，安慰贴剂为13例)。图1～图3示出了直至患者因镇痛效果不足而申请中止治疗的期间的累积效果持续率(％)。图1表示75mg给药组的Kaplan-Meier曲线，图2表示150mg给药组的Kaplan-Meier曲线，图3表示225mg给药组的Kaplan-Meier曲线。患者的中止治疗申请的频率如下：75mg给药组为8/40、安慰贴剂组为9/34(Log-rank检验，p＝0.5034)；150mg给药组为6/22、安慰贴剂组为14/32(Log-rank检验，p＝0.1325)；225mg给药组为2/14、安慰贴剂组为6/13(Log-rank检验，p＝0.0625)。由这些结果可知，双氯芬酸钠的给药量为75mg时镇痛效果不足，与此相比，当双氯芬酸钠的给药量为150mg或225mg时，镇痛效果充分。
(镇痛效果的评价2)
在剂量调节期，将含有双氯芬酸钠的贴剂贴附在伴有疼痛的癌症患者的胸部、腹部、腰部、背部、上臂部或大腿部等处，每天1次，每次2片，每天更换贴附。当镇痛效果不足时，将贴附片数增加到3片。本评价期为2～4周。只有在此期间满足下列所有标准的患者才能转移至随后的双盲试验期。
(1)与事先检查时的VAS值相比，转移判定日的前3天的VAS值均改善了15mm以上。
(2)转移判定日的患者的疼痛改善度的评价为“完全改善”、“显著改善”或“中度改善”。
(3)转移判定前10天内，未改变剂量调节期用治疗药的剂量。
接着，将患者分为含有双氯芬酸钠的贴剂给药组(120例)和安慰贴剂给药组(118例)，通过双盲试验评价镇痛效果。双氯芬酸钠的给药量为150mg(55例，安慰贴剂为53例)或225mg(65例，安慰贴剂为65例)。将患者因镇痛效果不足而决定申请中止治疗的时间点的VAS值超过15mm的恶化的情况设为镇痛效果不足。将直到镇痛效果不足为止的期间的累积效果持续率(％)用Kaplan-Meier曲线表示，示于图4。由图4所示的结果可知，当双氯芬酸钠的给药量为150mg或225mg时，镇痛效果充分。
(单次给药时的药代动力学)
将按照表1的记载制备的贴剂(贴附面积：70cm2)2片贴附在14名健康成年男性的背部，24小时后剥离。从临贴附前至贴附开始后36小时采血，测定血药浓度。由得到的各时间点的血药浓度，判定最大血药浓度(Cmax)及其时间(Tmax)。另外，制作以时间为横轴、以血药浓度为纵轴的曲线图，求出其曲线下面积(AUC)及药物的半衰期。
结果示于表2。
[表2]
(重复给药时的药代动力学)
将按照表1的记载制备的贴剂(贴附面积：70cm2)1片贴附在14名健康成年男性的背部，每24小时剥离并更换贴附新的贴剂。重复14次该操作，在第15天剥离贴剂。从临贴附前至贴附开始后360小时为止采血，测定血药浓度。由得到的各时间点的血药浓度，判定最大血药浓度(Cmax)及其时间(Tmax)。另外，制作以时间为横轴、以血药浓度为纵轴的曲线图，求出其曲线下面积(AUC)及药物的半衰期。
结果示于表3。
[表3]
Claims (13)
1.贴剂，其是用于缓解癌症疼痛的贴剂，具备支持体层和层叠在支持体层上的粘合剂层，
其中，粘合剂层含有粘合基剂和双氯芬酸钠，
贴剂的使用方式为：每天贴附1次，每次的双氯芬酸钠的给药量为150mg～225mg。
2.权利要求1所述的贴剂，其中，粘合剂层含有75mg双氯芬酸钠，贴剂的使用方式为：每天贴附1次，每次2片或3片。
3.权利要求1或2所述的贴剂，其中，粘合基剂包含选自苯乙烯-异戊二烯-苯乙烯嵌段共聚物和聚异丁烯中的至少1种。
4.权利要求1或2所述的贴剂，其中，粘合基剂包含苯乙烯-异戊二烯-苯乙烯嵌段共聚物和聚异丁烯。
5.权利要求1～4任一项所述的贴剂，其中，粘合剂层包含二甲亚砜。
6.权利要求1～5任一项所述的贴剂，其中，粘合剂层包含有机酸。
7.权利要求6所述的贴剂，其中，有机酸为油酸。
8.权利要求1～7任一项所述的贴剂，其中，粘合剂层包含增粘剂。
9.权利要求8所述的贴剂，其中，所述增粘剂为脂环族饱和烃树脂和氢化松香甘油酯。
10.权利要求1～9任一项所述的贴剂，其中，粘合剂层包含增塑剂。
11.权利要求10所述的贴剂，其中，增塑剂为液体石蜡。
12.权利要求1～11任一项所述的贴剂，其中，支持体是透湿度为1000g/m2·24小时以上的聚对苯二甲酸乙二醇酯编织布。
13.权利要求1～12任一项所述的贴剂，其中，贴附面积为50～150cm2。
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| JPH06219940A (ja) * | 1993-01-27 | 1994-08-09 | Shiseido Co Ltd | 貼付剤 |
| CN104379139A (zh) * | 2012-06-20 | 2015-02-25 | 久光制药株式会社 | 贴附剂 |
| CN110114064A (zh) * | 2016-12-28 | 2019-08-09 | 久光制药株式会社 | 贴剂 |
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| ES2343168T3 (es) * | 2001-05-31 | 2010-07-26 | Hisamitsu Pharmaceutical Co., Inc. | Parches de absorcion por via percutanea. |
| WO2010137699A1 (ja) * | 2009-05-29 | 2010-12-02 | 株式会社イノアック技術研究所 | 貼付材 |
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| CN108780868A (zh) | 2016-03-17 | 2018-11-09 | 3M创新有限公司 | 膜组件、电极组件、膜电极组件以及由这些组件制成的电化学电池和液流蓄电池 |
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| JPH06219940A (ja) * | 1993-01-27 | 1994-08-09 | Shiseido Co Ltd | 貼付剤 |
| CN104379139A (zh) * | 2012-06-20 | 2015-02-25 | 久光制药株式会社 | 贴附剂 |
| CN110114064A (zh) * | 2016-12-28 | 2019-08-09 | 久光制药株式会社 | 贴剂 |
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