CN103895961A - 包装材料及使用该包装材料的包装结构 - Google Patents
包装材料及使用该包装材料的包装结构 Download PDFInfo
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- CN103895961A CN103895961A CN201310430064.0A CN201310430064A CN103895961A CN 103895961 A CN103895961 A CN 103895961A CN 201310430064 A CN201310430064 A CN 201310430064A CN 103895961 A CN103895961 A CN 103895961A
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Abstract
本发明的目的在于提供一种包装材料,其能够防止贴附剂的粘着剂中所含的易氧化性成分及油状成分吸附或转移到包装材料上,同时还能够防止由氧化导致的变色、药效降低,能够长期保存。本发明提供一种包装材料,其为贴附剂用包装材料,其具有内层、氧吸收层及作为外层的阻氧层,所述内层由具有热封性的聚对苯二甲酸乙二醇酯构成;所述氧吸收层含有氧吸收性树脂,其具有不饱和脂环结构作为氧吸收部位;所述阻氧层由铝箔构成。
Description
技术领域
本发明涉及一种贴附剂用包装材料,尤其涉及一种粘着剂中含有易氧化性成分及油状成分,且易受氧影响的贴附剂用包装材料。
背景技术
贴附剂,尤其是粘着剂层中含有药物的经皮吸收用贴附剂,从保存过程中的品质保持等观点考虑,目前使用密闭性包装材料进行密封包装。但是,将粘着剂中含有易氧化性成分及油状成分的贴附剂用包装材料进行包装的情况下,贴附剂与包装材料的内表面接触,从而使易氧化性成分及油状成分吸附或转移至包装材料上,粘着剂中的易氧化性成分及油状成分的含量发生变化,致使粘结特性发生变化。并且,本领域中已经指出,在经皮吸收用贴附剂的情况下,由于所含有的药物的经皮吸收性降低、或含有的药物本身的吸附,会导致药理效果降低等问题。
对于上述问题,现有技术中已提出由乙烯/乙烯醇共聚物或丙烯腈/丙烯酸甲酯共聚物形成包装材料的内表面的方案(日本专利特开平5-305108号公报)。并且,作为易受氧等影响的药效成分的稳定性优异的贴附剂以及贴附剂的药效成分稳定性优异的保存方法,已提出封入具有脱氧性能的包装容器内的贴附剂,以及以封入具有脱氧性能的包装容器内为特征的贴附剂的保存方法(日本专利特开平11-47233号公报)。
但是,能够同时满足防止贴附剂中的易氧化性成分及油状成分向包装材料转移的要求及贴附剂中易受氧影响的药效成分的稳定性的包装材料是非常难以实现的。
现有技术文件
专利文件
专利文献1:日本专利特开平5-305108号公报
专利文件2:日本专利特开平11-47233号公报
发明内容
[发明需要解决的技术问题]
本发明的目的是提供一种包装材料,其能够防止贴附剂的粘着剂中所含的易氧化性成分和油状成分吸附或转移至包装材料上,同时能够防止由氧化导致的变色、药效降低,并能够长期保存。
[解决技术问题的手段]
本发明提供一种包装材料,其为贴附剂用包装材料,具有内层、氧吸收层及作为外层的阻氧层;所述内层由具有热封性的聚对苯二甲酸乙二醇酯构成;所述氧吸收层含有氧吸收性树脂,其具有不饱和脂环结构作为氧吸收部位;所述阻氧层由铝箔构成。
本发明的包装材料中,优选:
(1)氧吸收层为由具有不饱和脂环结构作为氧吸收部位的氧吸收性聚酯多元醇与异氰酸酯类固化剂构成的氧吸收性粘接剂层;
(2)氧吸收性聚酯多元醇为含有来自于四氢苯二甲酸或其衍生物的结构单元的聚酯多元醇;
(3)贴附剂为在支持物的一面上形成含有经皮吸收性药物的粘着剂层而成的经皮吸收制剂。
进而,本发明的包装结构中,优选:
(4)所述包装结构为用上述包装材料包装贴附剂而成的包装结构;
(5)贴附剂为通过在支持物的一面上形成含有经皮吸收性药物的粘着剂层而成的经皮吸收制剂。
[发明的效果]
根据本发明可实现下述包装材料,其能够在防止贴附剂的粘着剂中所含的易氧化性成分和油状成分吸附或转移至包装材料上的同时,防止由氧化导致的变色、药效降低,并能够长期保存。
附图说明
图1为本发明的包装材料的截面图。
附图标记说明
1 包装材料,2 内层,3 氧吸收性中间层,4 阻氧层。
具体实施方式
本发明的贴附剂用包装材料具有内层、氧吸收层和作为外层的阻氧层;所述内层由具有热封性的聚对苯二甲酸乙二醇酯构成;所述氧吸收层含有氧吸收性树脂,其具有不饱和脂环结构作为氧吸收部位;所述阻氧层由铝箔构成。
作为具有热封性的聚对苯二甲酸乙二醇酯树脂,优选共聚的聚对苯二甲酸乙二醇酯树脂。所述聚对苯二甲酸乙二醇酯树脂,由于油状成分的非吸附性优异,同时具有适度的透气性,因此不会妨碍氧吸收性中间层对容器内的脱氧功能。因此,所述聚对苯二甲酸乙二醇酯树脂作为能够同时满足防止贴附剂中的油状成分向包装材料转移的要求以及贴附剂中易受氧影响的药效成分的稳定性的包装材料的内层是优异的。所述聚对苯二甲酸乙二醇酯树脂更优选用间苯二甲酸或己二酸改性的共聚的聚对苯二甲酸乙二醇酯树脂。该树脂由于结晶性低,因此热封性优异。
此外,由聚对苯二甲酸乙二醇酯构成的内层优选无延伸或以低倍率延伸的状态。以高倍率延伸的聚对苯二甲酸乙二醇酯因定向结晶化而丧失热封性,因此不优选。
氧吸收层含有氧吸收性树脂,其具有不饱和脂环结构作为氧吸收部位。具有不饱和脂环结构作为氧吸收部位的氧吸收性树脂,随着自发氧化反应、即氧吸收反应产生的分解气体少,因此与由分解气体产生量多的不饱和脂肪酸或具有不饱和基团的链烃聚合物构成的氧吸收剂相比,在作为贴附剂用包装材料的用途方面优异。通过抑制醛、酮、羧酸、醇等产生分解气体,能够抑制因分解气体与贴附剂成分间的化学反应导致的贴附剂的品质降低,从而能够长期稳定保存。
作为具有不饱和脂环结构作为氧吸收部位的氧吸收性树脂,可例举具有环己烯环的聚合物,例如乙烯-丙烯酸甲酯-环己基丙烯酸甲酯共聚物或以四氢邻苯二甲酸酐衍生物为原料的缩聚物。此外,也可以使用共轭二烯类聚合物的环化反应物。
作为优选的具有不饱和脂环结构作为氧吸收部位的氧吸收性树脂,可例举将含有从下述单体(i)及单体(ii)组成的组中选择的单体的原料聚合而成的树脂:
(i)不饱和脂环结构中含有连接至下述结构(a)及(b)的两基团、且与一个或两个氢原子相连的碳原子的单体;
(a)不饱和脂环结构内的碳-碳双键基团;
(b)从含有杂原子的官能团、由该官能团衍生出的连接基团、碳-碳双键基团及芳香环组成的组中选择的基团;
(ii)与不饱和脂环结构内的碳-碳双键邻接的碳原子与给电子性取代基及氢原子相连,且与该碳原子邻接的另外的碳原子与含有杂原子的官能团或由该官能团衍生出的连接基团相连,该给电子性取代基与含有杂原子的官能团或由该官能团衍生出的连接基团位于顺位上的单体。
可通过将含有单体(i)及单体(ii)的原料聚合得到的氧吸收性树脂,优选为含有来自四氢苯二甲酸或其衍生物(如四氢邻苯二甲酸酐等)的结构单元的聚酯。
作为具有(i)结构的酸成分,可例举Δ2-四氢苯二甲酸或其衍生物、Δ3-四氢苯二甲酸或其衍生物、Δ2-四氢邻苯二甲酸酐或其衍生物、Δ3-四氢邻苯二甲酸酐或其衍生物。优选为Δ3-四氢苯二甲酸或其衍生物、Δ3-四氢邻苯二甲酸酐或其衍生物,尤其优选4-甲基-Δ3-四氢苯二甲酸或其衍生物,或者4-甲基-Δ3-四氢邻苯二甲酸酐或其衍生物。4-甲基-Δ3-四氢邻苯二甲酸酐可以通过例如将以异戊二烯为主要成分的石脑油的C5馏分与马来酸酐反应而成的、含有4-甲基-Δ4-四氢邻苯二甲酸酐的异构体混合物进行结构异构化得到,已经在进行工业制备。
作为具有(ii)结构的酸成分,尤其优选顺-3-甲基-Δ4-四氢苯二甲酸或其衍生物,或者顺-3-甲基-Δ4-四氢邻苯二甲酸酐或其衍生物。顺-3-甲基-Δ4-四氢邻苯二甲酸酐可以通过例如将以反式-戊间二烯为主要成分的石脑油的C5馏分与马来酸酐反应得到,已经在进行工业制备。
此外,氧吸收层优选为使用氧吸收性粘接剂的层。作为氧吸收性粘接剂层,优选含有由具有不饱和脂环结构作为氧吸收部位的氧吸收性聚酯多元醇构成的主剂和异氰酸酯类固化剂。
作为异氰酸酯类固化剂,可以使用芳香族、脂肪族或脂环族的各种公知的异氰酸酯类。作为芳香族二异氰酸酯类,可例举如4,4’-二苯基甲烷二异氰酸酯、甲苯二异氰酸酯等。作为脂肪族二异氰酸酯类,可例举如六亚甲基二异氰酸酯、苯二亚甲基二异氰酸酯、赖氨酸二异氰酸酯等。作为脂环族二异氰酸酯类,可例举如环己烷-1,4-二异氰酸酯、异佛尔酮二异氰酸酯、二环己基甲烷-4,4’-二异氰酸酯、将二聚酸的羧基转变为异氰酸酯基的二聚二异氰酸酯等。进而,也可以将这些异氰酸酯类作为三羟甲基丙烷加合物或异氰脲酸酯、缩二脲化合物(ビュレット体)等使用。上述异氰酸酯类及异氰酸酯类衍生物可以单独使用,并且,也可以两种以上组合使用。
相对于作为主剂的氧吸收性树脂,异氰酸酯类固化剂以固体成分重量份计,优选添加3phr~30phr,更优选为5phr~20phr,进一步优选为7phr~15phr。当添加量过少时,粘接性及内聚力不充分;当过多时,树脂单位重量中所含的氧吸收成分的加入量减少,氧吸收性能不充分。此外,在因固化导致树脂的运动性显著降低的情况下,难以进行氧吸收反应,氧吸收能力降低。
氧吸收性粘接剂层中使用的具有不饱和脂环结构作为氧吸收部位的氧吸收性聚酯多元醇优选为含有来自四氢苯二甲酸或其衍生物的结构单元的聚酯多元醇。
作为阻氧层可使用铝箔,铝箔不仅阻氧,对水分、光的阻挡性也优异,能够适用。
在包装材料的制备中,可以使用其本身公知的挤出成型法。例如,使用与树脂种类相应数量的挤出机,用多层多重模具进行挤出成型,从而能够成型为层压体。进而,可以使用挤出涂布法、夹心层压法,此外,通过预先形成的膜的干式层压法,也能够制备层压体。
层压体可以通过制袋形成常见的三边或四边密封的平袋类、角撑袋类(ガセット付パウチ類)、自立袋类、枕形包装袋类等,由此可以制成包装袋。制袋可以用公知的制袋方法进行。
用上述包装材料包装的贴附剂,由支持物层与粘着剂层构成,粘着剂层中混有药物,使药物经皮吸收来进行各种疾病的治疗或预防。这里所称的药物没有特别限定,全身性作用药、局部作用药均可以使用。作为这样的药物,可例举如肾上腺皮质类固醇、非类固醇抗炎药、抗风湿药、催眠剂、抗精神病剂、抗抑郁剂、心境稳定剂、精神刺激剂、抗焦虑剂、抗癫痫剂、偏头痛治疗剂、帕金森病治疗剂、毒蕈碱受体拮抗剂、多动腿综合征治疗剂、脑循环代谢改善剂、抗认知障碍剂、自律神经作用剂、肌肉松弛剂、降压剂、利尿剂、降糖剂、高脂血症治疗剂、痛风治疗剂、全身麻醉剂、局部麻醉剂、抗菌剂、抗真菌剂、抗病毒剂、抗寄生虫剂、维生素剂、心绞痛治疗剂、血管扩张剂、抗心律失常剂、抗组胺剂、介质游离抑制剂、白三烯拮抗剂性激素剂、甲状腺激素剂、抗甲状腺剂、抗肿瘤剂、止吐剂、抗运动病剂、支气管扩张剂、止咳剂、祛痰剂、戒烟辅助剂、抗骨质疏松剂等。这些药物可以以游离体形式使用,也可以以盐的形式使用。此外,这些药物可以单独使用,也可以两种以上混合使用。
本发明中所使用的贴附剂含有易受氧影响的易氧化性成分,具体地,为分子中含有氨基、苄基、巯基及羰基中的至少一种的化合物。例如,其包括具有胺、酰胺、环胺、内酯、羧酸结构的化合物。
作为支持体层只要在贴附时没有显著的不适感即可,没有特别限定。具体地,可例举由聚酯、聚乙烯或聚丙烯等聚烯烃、聚氯乙烯、可塑化的聚氯乙烯、可塑化的乙酸乙烯酯-氯乙烯共聚物、聚偏二氯乙烯、乙烯-乙酸乙烯酯共聚物、乙酸纤维素、乙基纤维素、乙烯-丙烯酸乙酯共聚物、聚四氟乙烯、聚氨酯、离子交联聚合物树脂等合成树脂构成的单膜或它们的层压膜,或者由橡胶、上述合成树脂、聚对苯二甲酸乙二醇酯等聚酯或尼龙等聚酰胺制成的多孔性膜或片材、无纺布、织物或它们与上述合成树脂膜的层压物等。
贴附剂为经皮吸收制剂,优选通过在支持体的一面上形成含有经皮吸收性药物的粘着剂层而成。此外,还可以具有层压在该粘着剂层的另一面上的、经剥离处理的离型膜。
贴附剂的形态为平面状的扁平形态,平面形状除大致为矩形之外,还可例举三角形、五角形等多边形、即以大致的直线构成轮廓的形状,以椭圆、圆形等曲线构成轮廓的形状、或它们的组合等,但并不限于这些。
贴附剂的大小可根据贴附剂的用途或使用位置等进行适当选择。例如,贴附剂的形状大致为矩形的情况下,一般地,其一边的长度为15mm~90mm,另一边长度也为15mm~90mm。
贴附剂的总厚度通常为50μm~2000μm,优选100μm~1000μm的范围。此外,贴附剂由支持层与粘着剂层构成,支持体层的厚度通常为1μm~1000μm,粘着剂层通常为10μm~200μm,优选为15μm~150μm。
粘着剂层中还可以含有油状成分。含有的油状成分用来使粘着剂层增塑,赋予柔软感,降低皮肤刺激性,并调节药物的经皮吸收性。油状成分优选在室温(25℃)下为液体的物质,或在两种以上混合使用的情况下,最终的混合物在室温下(25℃)下为液体。作为这样的油状成分,可例举如油醇、辛基十二烷醇等高级醇;甘油、乙二醇、聚丙二醇等多元醇;辛酸、油酸等高级脂肪酸;肉豆蔻酸异丙酯、棕榈酸异丙酯、油酸乙酯等脂肪酸酯;癸二酸二乙酯、己二酸二异丙酯等多元酸酯;三异硬脂酸二甘油脂、脱水山梨糖醇单油酸酯、二辛酸丙二醇酯、聚乙二醇单月桂酸酯、聚氧乙烯山梨醇四油酸酯等多元醇脂肪酸酯;聚氧乙烯月桂醚等聚氧乙烯烷基醚;角鲨烷、液体石蜡等烃;橄榄油、蓖麻油等植物油;硅油;N-甲基吡咯烷酮、N-十二烷基吡咯烷酮等吡咯烷酮类;癸基甲基亚砜等亚砜类等。这些油状成分可以单独使用,或两种以上混合使用。
本发明的贴附剂用包装体的形状只要能够包装贴附剂即可,没有特别限定,例如,除正方形、长方形等大致矩形之外,还可例举三角形、五角形等多边形,圆形、椭圆形、其他图形等。此外,贴附剂用包装体的形状和被包装的贴附剂的形状只要能够将贴附剂分别包装(密封)即可,可以相同也可以不同。
[实施例]
1.含有不饱和脂环结构的聚酯多元醇的配制
向具备搅拌装置、氮气导入管、迪恩-斯塔克(Dean-Stark)型分水器的3L分体式烧瓶中,加入898g含有45mol% 4-甲基-Δ3-四氢邻苯二甲酸酐和21mol% 顺-3-甲基-Δ4-四氢邻苯二甲酸酐的甲基四氢邻苯二甲酸酐异构体混合物(日立化成公司制,HN-2200)、60g琥珀酸酐(和光纯药公司制)、702g 1,4-丁二醇(和光纯药公司制)、300ppm作为聚合催化剂的异丙醇钛,以及20ml甲苯,在氮气气氛中150℃~200℃下,边除去生成的水边进行约5小时反应。然后从反应体系中除去甲苯,之后在0.7kPa的减压下,在200~220℃下进行约6小时聚合,得到聚酯多元醇。得到的聚酯多元醇的Mn约3400、Mw为27100。
2. 氧吸收性粘接剂溶液的配制
将得到的聚酯多元醇以20wt%的浓度溶解在乙酸乙酯中,以换算为固体成分后为10phr的量添加异氰酸酯类固化剂(三井化学公司制,A-50),振荡,配制氧吸收性粘接剂溶液。
3. 贴附剂用包装材料的制作
将配制好的粘接剂溶液用#18涂布棒涂布在由12μm双轴延伸PET膜和7μm铝箔构成的干式层压膜基材的铝箔面侧。立刻用100℃的电烤箱处理1分钟,以使粘接剂中含有的溶剂飞散,之后,使干式层压膜基材的粘接剂涂布面与20μm无延伸的间苯二甲酸改性PET膜相对,用70℃的热辊进行压接,在35℃氮气气氛下固化5天,从而得到由双轴延伸PET膜/铝箔/氧吸收性粘接剂(膜厚4μm)/无延伸PET膜构成的氧吸收性层压膜。
4.氧吸收性能的评价
将切成2cm×10cm的氧吸收性层压膜试验片与由甘油溶液构成的调湿液一起加入容积为85cm3的不透氧性钢箔层压杯中,用铝箔层压膜盖热封密封,在22℃环境下保存。通过调湿液控制杯内湿度为50%RH。用微型气相色谱装置(安捷伦科技公司制,M200)测定保存7天、30天后的杯内氧浓度,计算出每1m2膜的氧吸收量。结果,7天后及30天后的氧吸收量分别为170ml/m2、450ml/m2。
5.贴附剂的制备
将丙烯酸2-乙基己酯、N-乙烯基吡咯烷酮及丙烯酸以74:22:4的聚合比(换算为重量)共聚,配制绝对分子量为1.8×106的聚合物。将41.5重量份(固体成分)该聚合物、50.9重量份肉豆蔻酸异丙酯(IPM)、7.4重量份普萘洛尔及0.2重量份乙酰乙酸乙基铝二异丙酯边用乙酸乙酯调节粘度,边充分混合,得到粘着剂溶液。
将该粘着剂溶液涂布在经有机硅塑料处理的双轴延伸PET膜上,使干燥后的厚度为60μm,干燥后,贴合作为支持体的双轴延伸PET膜。将其在氮气气氛、70℃下加热48小时后,裁成10cm2大小,得到贴附剂。
[实施例1]
将得到的氧吸收性层压膜切成两张7cm×7cm的正方形,将它们的无延伸PET膜层相对,从而使两张氧吸收性层压膜重叠,在内部填充制得的一张贴附剂,以5mm的密封宽度热封四边,制成容积为2ml的装入贴附剂的包装结构。
根据下述方法评价贴附剂的品质变化。结果表示在表1中。
[比较例1]
使用由不具有氧吸收性能的双轴延伸PET膜/铝箔/无延伸PET膜构成的干式层压膜代替氧吸收性层压膜作为包装材料,除此以外,与实施例1相同,制得装入贴附剂的包装结构,进行评价。结果表示在表1中。
[比较例2]
使用通过将30μm LDPE膜代替20μm无延伸间苯二甲酸改性PET膜进行层压制得的、由双轴延伸PET膜/铝箔/氧吸收性粘接剂(膜厚4μm)/LDPE膜构成的氧吸收性层压膜作为包装材料,除此以外,与实施例1相同,制得装入贴附剂的包装结构,进行评价。结果表示在表1中。
[试验例]
将实施例1、比较例1、比较例2的包装结构在50℃下保存三个月后,测定各贴附剂的药物(普萘洛尔)含量、杂质生成率、色彩、IPM含量,与保存开始前(初始)的值进行比较。
药物含量是用液相色谱(HPLC)对贴附剂的甲醇提取液进行分析而求得的,以保存后相对于初始的比例进行评价。
杂质生成率是以在测定药物含量时的HPLC色谱中,保存后与初始时除药物以外的峰面积的总和相对于药物峰面积的比例的差(保存后的增加量)来进行评价。
色彩用色彩色差计进行测定,以L*a*b*表色系统中的、初始与保存后的色差ΔE*进行评价。
IPM含量是用气相色谱对贴附剂的己烷提取液进行分析而求得的,以保存后相对于初始的比例进行评价。
表1
药物含量 | 杂质生成率 | 色彩 | IPM含量 | |
实施例1 | 95% | 1.5% | 0.0 | 98% |
比较例1 | 87% | 4.1% | 5.0 | 98% |
比较例2 | 80% | 1.9% | 0.3 | 58% |
由表1可见,实施例1中,各评价项目均能得到良好结果。与此相对,可见比较例1中,药物含量降低、杂质生成率增加、色彩变化较大、药物分解显著。此外,比较例2中,虽然杂质生成率与色彩变化较小,可认为实现了氧吸收性粘接剂的效果,但IPM含量和药物含量大幅下降,这是因为其吸附到了包装材料的内层上。
Claims (6)
1.一种包装材料,其为贴附剂用包装材料,其特征在于,所述包装材料具有内层、氧吸收层及作为外层的阻氧层;所述内层由具有热封性的聚对苯二甲酸乙二醇酯构成;所述氧吸收层含有氧吸收性树脂,所述氧吸收性树脂具有不饱和脂环结构作为氧吸收部位;所述阻氧层由铝箔构成。
2.根据权利要求1所述的包装材料,其特征在于,所述氧吸收层为由具有不饱和脂环结构作为氧吸收部位的氧吸收性聚酯多元醇与异氰酸酯类固化剂构成的氧吸收性粘接剂层。
3.根据权利要求2所述的包装材料,其特征在于,所述氧吸收性聚酯多元醇为含有来自四氢苯二甲酸或其衍生物的结构单元的聚酯多元醇。
4.根据权利要求1~3中任意一项所述的包装材料,其特征在于,所述贴附剂是通过在支持物的一面上形成含有经皮吸收性药物的粘着剂层而构成的经皮吸收制剂。
5.一种包装结构,其用根据权利要求1~4中任意一项所述的包装材料包装贴附剂而成。
6.根据权利要求5所述的包装结构,其特征在于,所述贴附剂是通过在支持物的一面上形成含有经皮吸收性药物的粘着剂层而构成的经皮吸收制剂。
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JP2016202290A (ja) * | 2015-04-16 | 2016-12-08 | 三菱瓦斯化学株式会社 | 貼付剤包装体、及び貼付剤の保存方法 |
CN106166871A (zh) * | 2016-08-26 | 2016-11-30 | 南通惠得成包装材料有限公司 | 一种预涂型药品包装用铝箔 |
WO2018231219A1 (en) * | 2017-06-14 | 2018-12-20 | Bemis Company, Inc. | Transdermal patch packaging film |
JP2019107220A (ja) * | 2017-12-18 | 2019-07-04 | ニプロ株式会社 | 貼付剤用包装袋及び貼付剤製品 |
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US20140083890A1 (en) | 2014-03-27 |
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CA2827568A1 (en) | 2014-03-21 |
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