CN107847488A - 含有阿塞那平的贴剂的制造方法 - Google Patents
含有阿塞那平的贴剂的制造方法 Download PDFInfo
- Publication number
- CN107847488A CN107847488A CN201680043642.7A CN201680043642A CN107847488A CN 107847488 A CN107847488 A CN 107847488A CN 201680043642 A CN201680043642 A CN 201680043642A CN 107847488 A CN107847488 A CN 107847488A
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- China
- Prior art keywords
- acid
- asenapine
- patch
- adhesive composition
- methyl
- 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
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- 238000000034 method Methods 0.000 title claims abstract description 38
- 238000004519 manufacturing process Methods 0.000 title claims abstract description 27
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- 239000000853 adhesive Substances 0.000 claims abstract description 78
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- 150000003839 salts Chemical class 0.000 claims abstract description 23
- BAPJBEWLBFYGME-UHFFFAOYSA-N Methyl acrylate Chemical compound COC(=O)C=C BAPJBEWLBFYGME-UHFFFAOYSA-N 0.000 claims abstract description 19
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- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 claims description 8
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- 239000011630 iodine Substances 0.000 claims 1
- VSWBSWWIRNCQIJ-HUUCEWRRSA-N (S,S)-asenapine Chemical compound O1C2=CC=CC=C2[C@H]2CN(C)C[C@@H]2C2=CC(Cl)=CC=C21 VSWBSWWIRNCQIJ-HUUCEWRRSA-N 0.000 description 61
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Abstract
本发明提供一种具备支持体、和层叠在支持体上的粘合剂层的贴剂的制造方法,所述方法包括:混合阿塞那平的酸加成盐、(甲基)丙烯酸酯(共)聚合物和脱盐剂,得到粘合剂组合物的工序;和将粘合剂组合物成形而得到粘合剂层的工序。
Description
技术领域
本发明涉及一种含有阿塞那平的贴剂的制造方法。
背景技术
阿塞那平是作为中枢神经系统疾病、特别是精神分裂症的治疗药已知的化合物。含有阿塞那平的贴剂例如记载于专利文献1~4中。已知含有阿塞那平游离碱的贴剂的阿塞那平的透皮性优异。
现有技术文献
专利文献
专利文献1:国际公开第2010/127674号
专利文献2:国际公开第2014/017593号
专利文献3:国际公开第2014/017594号
专利文献4:国际公开第2014/017595号
发明内容
发明要解决的课题
另一方面,在贴剂具备含有(甲基)丙烯酸酯(共)聚合物的粘合剂层的情况下,当在制造贴剂时使用阿塞那平游离碱时,有时阿塞那平容易分解。因此,本发明的目的在于,提供一种阿塞那平难以被分解的贴剂的制造方法。
解决课题的手段
本发明人等在研究制造贴剂时阿塞那平难以被分解的方法的过程中发现,通过使粘合剂层中含有马来酸金属盐,能减少阿塞那平的分解。进而发现,在制造贴剂时,与使用含有阿塞那平游离碱和马来酸金属盐的粘合剂组合物的情况相比,在使用含有阿塞那平的酸加成盐和脱盐剂的粘合剂组合物的情况下,更能减少阿塞那平的分解物的生成量。
另一方面,根据本发明人等的研究,在具备含有橡胶系粘合剂的粘合剂层的贴剂的制造中,在制造贴剂时几乎未观察到阿塞那平的分解。本发明人等推测,制造贴剂时的阿塞那平的分解可能由于与粘合剂组合物中的其他成分的接触、暴露于加热或紫外线等光下而容易发生。
因此,本发明提供一种具备支持体和层叠在支持体上的粘合剂层的贴剂的制造方法,其包括:混合阿塞那平的酸加成盐、(甲基)丙烯酸酯(共)聚合物和脱盐剂,得到粘合剂组合物的工序;和将粘合剂组合物成形而得到粘合剂层的工序。
阿塞那平的酸加成盐中的酸优选选自盐酸、氢溴酸、氢碘酸、磷酸、乙酸、丙酸、乙醇酸、马来酸、丙二酸、琥珀酸、酒石酸、柠檬酸、抗坏血酸、水杨酸和苯甲酸。另外,脱盐剂优选选自碱金属氢氧化物、碱金属盐、碱土金属氢氧化物、碱土金属盐和低分子胺。
本发明还提供一种使含有(甲基)丙烯酸酯(共)聚合物的粘合剂组合物中的阿塞那平稳定化的方法,其包括:混合阿塞那平的酸加成盐、(甲基)丙烯酸酯(共)聚合物和脱盐剂,得到粘合剂组合物的工序。
本发明提供一种在具备含有阿塞那平的粘合剂层的贴剂的制造过程中抑制阿塞那平的分解的方法,其包括:混合阿塞那平的酸加成盐、(甲基)丙烯酸酯(共)聚合物和脱盐剂,得到粘合剂组合物的工序;和将粘合剂组合物成形而得到粘合剂层的工序。
发明效果
根据本发明的贴剂的制造方法,可以减少制造贴剂时阿塞那平的分解物的生成量。
附图说明
图1表示阿塞那平的分解物的生成量的图。
图2表示阿塞那平的分解物的生成量的图。
图3表示阿塞那平的分解物的生成量的图。
具体实施方式
本说明书中,“(甲基)丙烯酸”的用语是指丙烯酸和甲基丙烯酸的任一者或两者,类似表述也具有同样的定义。
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为具备支持体、和层叠在支持体上的粘合剂层的贴剂。贴剂可通过包括如下工序的方法制造:混合阿塞那平的酸加成盐、(甲基)丙烯酸酯(共)聚合物和脱盐剂,得到粘合剂组合物的工序;和将粘合剂组合物成形而得到粘合剂层的工序。
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、片材、片状多孔体、片状发泡体、织物、编织布、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2~3000μm左右。
粘合剂层由混合阿塞那平的酸加成盐、(甲基)丙烯酸酯(共)聚合物和脱盐剂而得到的粘合剂组合物形成。粘合剂层优选不含橡胶系粘合剂。作为橡胶系粘合剂,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、有机硅橡胶等。
粘合剂层的厚度没有特殊限制,可以为30~300μm。如果粘合剂层的厚度超过300μm,则在穿脱衣服时等情况下,贴剂容易脱落。
阿塞那平是也称为(3aRS,12bRS)-5-氯-2-甲基-2,3,3a,12b-四氢-1H-二苯并[2,3:6,7]氧杂[4,5-c]吡咯的化合物,由以下化学式表示。阿塞那平具有多种光学异构体,可以为任一光学异构体,也可以为外消旋体等光学异构体的混合物。作为加成于阿塞那平上的酸,只要为药学上可接受的酸,就没有特殊限制。阿塞那平的酸加成盐可以为酐,也可以为水合物。
作为酸,例如可举出:盐酸、氢溴酸、氢碘酸、磷酸、乙酸、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。
[化1]
脱盐剂只要是可通过与阿塞那平的酸加成盐的盐交换反应将阿塞那平的酸加成盐转换为阿塞那平游离碱的脱盐剂即可。即,“脱盐剂”是指将阿塞那平的酸加成盐转换为阿塞那平游离碱的成分。作为脱盐剂,例如可举出:碱金属氢氧化物、碱金属盐、碱土金属氢氧化物、碱土金属盐、低分子胺等。作为碱金属氢氧化物,可举出:氢氧化锂、氢氧化钠、氢氧化钾。作为碱金属盐,可举出:碳酸钠、碳酸钾、碳酸氢钠、磷酸三钠、磷酸氢二钠、磷酸二氢钠、磷酸三钾、磷酸氢二钾、磷酸二氢钾、乳酸钠、柠檬酸钠、酒石酸二钠、酒石酸氢钠、油酸钠等。低分子胺是分子量为30~300的胺,例如可举出:单乙醇胺、二乙醇胺、三乙醇胺、异丙醇胺、二异丙醇胺等。脱盐剂只要考虑加成于阿塞那平上的酸的pKa来选择即可。当脱盐剂为氢氧化钠时,则在制造贴剂时药物的分解更少。
(甲基)丙烯酸酯(共)聚合物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。
(甲基)丙烯酸酯(共)聚合物也可以为由(甲基)丙烯酸烷基酯(主要单体)与共聚单体形成的(共)聚合物。共聚单体只要为可与(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)丙烯酰胺等。共聚单体可以为单独1种或2种以上的组合物。
具体的(甲基)丙烯酸酯(共)聚合物的例子可例示:DURO-TAK(注册商标)87-900A、DURO-TAK 87-2510、DURO-TAK 87-4287、DURO-TAK87-2194(商品名,Henkel公司制)等。DURO-TAK 87-2510和DURO-TAK87-4287在其化学结构中具有羟基,DURO-TAK 87-2194在其化学结构中具有羧基。
(甲基)丙烯酸酯(共)聚合物的含量以粘合剂层的总质量为基准,为50~98质量%,优选为70~96质量%。(甲基)丙烯酸酯(共)聚合物的含量基于固体成分的质量来计算。
粘合剂层还可以含有其他添加剂。作为其他添加剂,例如可举出:增粘树脂、增塑剂、吸收促进剂、溶解剂、稳定剂、填充剂、香料等。
增粘树脂是调节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,也可以组合2种以上使用。
吸收促进剂为调节阿塞那平或阿塞那平的酸加成盐的透皮性的成分。只要为以往认为具有对皮肤的吸收促进作用的化合物,就没有特殊限定,例如可举出:碳数6~20的脂族醇、碳数6~20的脂族醚、碳数6~20的脂肪酸、碳数6~20的脂肪酸酯、碳数6~20的脂肪酰胺、甘油、甘油脂肪酸酯类、丙二醇类、丙二醇脂肪酸酯类、聚乙二醇及聚乙二醇脂肪酸酯类、芳族系有机酸、芳族系醇、芳族系有机酸酯、芳族系有机醚(以上化合物可以为饱和和不饱和的任一种,可以为直链状和支链状的任一种,也可以包含环状结构)、乳酸酯类、乙酸酯类、单萜烯系化合物、倍半萜烯系化合物、1-十二烷基氮杂环庚烷-2-酮(Azone(商品名))及其衍生物、山梨糖醇酐脂肪酸酯类(Span(注册商标)系)、聚山梨酯系(Tween(注册商标)系)、聚氧乙烯氢化蓖麻油类、聚氧乙烯烷基醚类、蔗糖脂肪酸酯类、植物油。作为吸收促进剂的具体例,可举出:亚油酸、亚麻酸、月桂醇、肉豆蔻醇、油醇、异硬脂醇、鲸蜡醇、月桂酸甲酯、月桂酸己酯、月桂酸二乙醇酰胺、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、棕榈酸鲸蜡酯、棕榈酸异丙酯、水杨酸、水杨酸甲酯、水杨酸乙二醇酯、肉桂酸、肉桂酸甲酯、甲酚、乳酸鲸蜡酯、乳酸月桂酯、乙酸乙酯、乙酸丙酯、香叶醇、百里香酚、丁香酚、萜品醇、l-薄荷醇、冰片、d-柠檬烯、异丁香酚、异冰片、橙花醇、dl-樟脑、甘油单辛酸酯、甘油单癸酸酯、甘油单月桂酸酯、甘油单油酸酯、山梨糖醇酐单月桂酸酯、蔗糖单月桂酸酯、聚山梨酯20、丙二醇、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、聚氧乙烯月桂基醚、ニッコール(注册商标)HCO-60、吡咯并硫代癸烷(注册商标)、橄榄油及山梨糖醇酐单油酸酯。作为吸收促进剂,从显著提高阿塞那平的透皮性的观点考虑,优选为丙二醇单月桂酸酯、棕榈酸异丙酯,更优选为棕榈酸异丙酯。吸收促进剂可单独使用1种,也可以组合2种以上使用。
在粘合剂层含有吸收促进剂的情况下,吸收促进剂的含量以粘合剂层的总质量为基准,优选为2~40质量%。当吸收促进剂的含量为2质量%以上时,有阿塞那平的透皮性更高而显示出充分的药理作用的倾向。另外,当吸收促进剂的含量为40质量%以下时,有不显示皮肤刺激性的倾向。
溶解剂为使阿塞那平及其酸加成盐容易溶解在粘合剂组合物中的成分。
稳定剂只要为可抑制因紫外线等光线、热或活性化学物种的作用而产生的自由基生成及其连锁反应的进行的物质即可。通过含有稳定剂,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:维生素E及其酯衍生物、抗坏血酸及其酯衍生物、二丁羟基甲苯、丁基羟基苯甲醚、2-巯基苯并咪唑等。稳定剂可单独使用1种,也可以组合2种以上使用。作为稳定剂,从作为贴剂的物性(成形性、外观等)适当的观点、以及使阿塞那平更稳定的观点考虑,优选为二丁羟基甲苯。
在粘合剂层含有稳定剂的情况下,稳定剂的含量以粘合剂层的总质量为基准,优选为0.1~3质量%。当稳定剂的含量为0.1~3质量%时,存在贴剂中的各成分的稳定性优异的倾向。
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侧的面上。当具备剥离衬垫时,存在可减少保管时垃圾等在粘合剂层上的附着的倾向。
作为剥离衬垫的材料,没有特殊限定,可使用本领域技术人员通常已知的衬垫。作为剥离衬垫的材质,例如可举出:聚对苯二甲酸乙二醇酯、聚萘二甲酸乙二醇酯等聚酯;聚乙烯、聚丙烯等聚烯烃;聚氯乙烯、聚偏二氯乙烯等的膜;优质纸与聚烯烃的层压膜;尼龙(注册商标)、铝等的膜等。作为剥离衬垫的材质,优选为聚丙烯或聚对苯二甲酸乙二醇酯。
<贴剂的制造方法>
本发明的贴剂例如可通过以下方法制造。首先,将阿塞那平或其药学上可接受的盐、(甲基)丙烯酸酯(共)聚合物和脱盐剂混合,根据需要添加溶剂、其他添加剂等进行混合,得到均匀的粘合剂组合物。接着,将得到的粘合组合物以规定厚度涂布在支持体的单面上,然后根据需要加温,干燥除去溶剂,裁剪成期望大小,由此得到贴剂。予以说明,作为加温条件,可根据上述溶剂而适当选择,作为温度条件,优选为60~120℃,加温时间例如为2~30分钟。
在制造具备剥离衬垫的贴剂的情况下,可以在支持体上涂布粘合组合物,干燥除去溶剂,然后层叠剥离衬垫。另外,在制造具备剥离衬垫的贴剂的情况下,也可以在剥离衬垫的单面上以规定厚度涂布粘合组合物,然后根据需要加温,干燥除去溶剂,层叠支持体,剪裁成期望大小,由此得到贴剂。
在上述制造方法中使用的粘合剂组合物含有阿塞那平的酸加成盐、(甲基)丙烯酸酯(共)聚合物和脱盐剂,根据需要还含有溶剂、其他添加剂等。
溶剂只要为不与粘合组合物中含有的其他成分反应的溶剂即可,是为了调节粘合组合物的粘性而添加。作为溶剂,例如可举出:甲苯、乙醇、甲醇、乙酸乙酯等。溶剂可单独使用1种,也可以组合2种以上使用。溶剂的含量考虑粘合组合物的粘性来调节即可。
粘合剂组合物中的阿塞那平的酸加成盐的含量以粘合剂组合物的总质量为基准,优选为0.5~50质量%,更优选为4.2~21质量%。
粘合剂组合物中的(甲基)丙烯酸酯(共)聚合物的含量以粘合剂组合物的总质量为基准,优选为50~98质量%,更优选为70~96质量%。如果(甲基)丙烯酸酯(共)聚合物的含量为50质量%以上,则有凝聚力不下降、粘合力也不下降的倾向。
粘合剂组合物中的脱盐剂的含量以粘合剂组合物的总质量为基准,优选为0.05~20质量%,更优选为0.1~10质量%。
实施例
以下示出实施例和比较例,更详细地说明本发明。予以说明,DURO-TAK 87-2516、DURO-TAK 87-4287、DURO-TAK 87-2194、DURO-TAK87-900A及DURO-TAK 87-2510是基于固体成分的质量进行计算。
(1)贴剂的制造
分别称取表1中记载的成分,根据需要添加溶剂进行混合,得到粘合剂组合物。将所得粘合组合物涂布在聚酯制的剥离衬垫上,干燥除去溶剂,由此形成粘合剂层。在得到的粘合剂层上层叠聚酯膜(支持体),进行适当剪裁,得到期望的贴剂。予以说明,表1中的数字是指质量%。
[表1]
(2)分解物的生成量测定
将所得贴剂的粘合剂层浸渍于四氢呋喃(高效液相色谱用等级)10mL中进行提取,添加下述作为流动相记载的溶剂40mL,过滤后,在以下分析条件下通过高效液相色谱测定阿塞那平的分解物的生成量。阿塞那平的分解物的生成量在得到的色谱图中,由与阿塞那平的分解物对应的峰的曲线下面积相对于与阿塞那平对应的峰的曲线下面积的值表示。阿塞那平的分解物的生成量是将与阿塞那平对应的峰的曲线下面积设为100来计算。
<分析条件>
色谱柱:TSK-gel ODS-80Ts
流动相:甲醇:0.1%磷酸(添加10mM十二烷基硫酸钠)=75:25
测定波长:210nm
流速:1.0mL/分钟
柱温:40℃
试样注入量:10μL
将具有比阿塞那平的保留时间短的保留时间的峰称为“阿塞那平的分解物1”,将具有比阿塞那平的保留时间长的保留时间的峰称为“阿塞那平的分解物2”。
结果示于表2和图1。实施例1和2的贴剂与比较例1~5的贴剂相比,阿塞那平的分解物显著减少。
[表2]
比较例1 | 比较例2 | 比较例3 | 比较例4 | 比较例5 | 实施例1 | 实施例2 | |
阿塞那平 | 100 | 100 | 100 | 100 | 100 | 100 | 100 |
分解物1 | 2.09 | 0.65 | 0.72 | 0.65 | 0.78 | 0.51 | 0.34 |
分解物2 | 0.40 | 0.41 | 0.36 | 0.36 | 0.35 | 0.20 | 0.18 |
分解物的合计 | 2.49 | 1.06 | 1.08 | 1.01 | 1.13 | 0.71 | 0.52 |
(3)贴剂的制造
分别称取表3中记载的成分,根据需要添加溶剂进行混合,得到粘合组合物。将得到的粘合组合物涂布在聚酯制的剥离衬垫上,干燥除去溶剂,由此形成厚度为约100μm的粘合剂层。在得到的粘合剂层上层叠聚酯膜(支持体),进行适当剪裁,得到期望的贴剂。予以说明,表3中的数字是指质量%。
[表3]
(4)分解物的生成量测定
将得到的贴剂的粘合剂层浸渍于四氢呋喃(高效液相色谱用等级)10mL中进行提取,添加上述作为流动相记载的溶剂40mL,过滤后,在上述分析条件下,通过高效液相色谱,测定阿塞那平的分解物的生成量
结果示于表4和图2。实施例3和4的贴剂与比较例6~11的贴剂相比,阿塞那平的分解物显著减少。
[表4]
(5)贴剂的制造
分别称取表5中记载的成分,根据需要添加溶剂进行混合,得到粘合剂组合物。将得到的粘合剂组合物涂布在聚酯制的剥离衬垫上,干燥除去溶剂,由此形成粘合剂层。在得到的粘合剂层上层叠聚酯膜(支持体),进行适当剪裁,得到期望的贴剂。予以说明,表5中的数字是指质量%。
[表5]
(6)分解物的生成量测定
将得到的贴剂的粘合剂层浸渍于四氢呋喃(高效液相色谱用等级)10mL中进行提取,添加上述作为流动相记载的溶剂40mL,过滤后,在上述分析条件下,通过高效液相色谱,测定阿塞那平的分解物的生成量。
结果示于表6和图3。实施例5和6的贴剂与比较例12~17的贴剂相比,阿塞那平的分解物显著减少。
[表6]
(7)脱盐剂的研究
制备在实施例1的贴剂中使用等摩尔量的氢氧化钾代替氢氧化钠的贴剂(实施例7)。对实施例7的贴剂测定阿塞那平的分解物的生成量,结果,分解物的生成量降低。进而,制备在实施例1的贴剂中代替氢氧化钠而使用等摩尔量的碳酸钠(实施例8)、碳酸氢钠(实施例9)、碳酸钾(实施例10)、碳酸氢钾(实施例11)的贴剂。
(8)贴剂的制造
分别称取表7中记载的成分,根据需要添加溶剂进行混合,得到粘合剂组合物。将得到的粘合剂组合物涂布在聚酯制的剥离衬垫上,干燥除去溶剂,形成厚度为约100μm的粘合剂层。在得到的粘合剂层上层叠聚酯膜(支持体),进行适当剪裁,得到期望的贴剂。予以说明,表7中的数字是指质量%。
[表7]
实施例12 | 实施例13 | 实施例14 | 比较例18 | |
阿塞那平 | - | - | - | 8.5 |
阿塞那平马来酸盐 | 12 | 12 | 12 | - |
DURO-TAK 87-2516 | 79.09 | 82.98 | 68.86 | 91.5 |
三乙醇胺 | 8.91 | - | - | - |
碳酸氢钠 | - | 5.02 | - | - |
油酸钠 | - | - | 19.14 | - |
合计 | 100 | 100 | 100 | 100 |
(9)分解物的生成量测定
结果示于表8。实施例12~14的贴剂与比较例18的贴剂相比,阿塞那平的分解物显著减少。表8中,“N.D.”是指未到检测限。
[表8]
实施例12 | 实施例13 | 实施例14 | 比较例18 | |
分解物1 | N.D. | N.D. | 0.16 | 1.22 |
分解物2 | 0.10 | 0.12 | 0.10 | 0.31 |
分解物的合计 | 0.10 | 0.12 | 0.26 | 1.53 |
(10)贴剂的制造
分别称取表9中记载的成分,根据需要添加溶剂进行混合,得到粘合剂组合物。将得到的粘合剂组合物涂布在聚酯制的剥离衬垫上,干燥除去溶剂,形成厚度为约100μm的粘合剂层。在得到的粘合剂层上层叠聚酯膜(支持体),进行适当剪裁,得到期望的贴剂。予以说明,表9中的数字是指质量%。
[表9]
实施例15 | 实施例16 | 实施例17 | 实施例18 | 实施例19 | 实施例20 | |
阿塞那平马来酸盐 | 0.50 | 4.22 | 8.44 | 21 | 35 | 50 |
DURO-TAK 87-2516 | 99.40 | 94.94 | 89.88 | 74.82 | 58.03 | 40.05 |
氢氧化钠 | 0.10 | 0.84 | 1.68 | 4.18 | 6.97 | 9.95 |
合计 | 100 | 100 | 100 | 100 | 100 | 100 |
(11)分解物的生成量测定
结果示于表10。在实施例15~20的贴剂中,阿塞那平的分解物显著减少。
[表10]
实施例15 | 实施例16 | 实施例17 | 实施例18 | 实施例19 | 实施例20 | |
分解物1 | 0.34 | 0.27 | 0.45 | 0.51 | 0.35 | 0.06 |
分解物2 | 0.08 | 0.23 | 0.24 | 0.20 | 0.12 | 0.00 |
分解物的合计 | 0.42 | 0.50 | 0.69 | 0.71 | 0.47 | 0.06 |
Claims (5)
1.贴剂的制造方法,其中,所述贴剂具备支持体、和层叠在支持体上的粘合剂层,所述方法包括:
混合阿塞那平的酸加成盐、(甲基)丙烯酸酯(共)聚合物和脱盐剂,得到粘合剂组合物的工序;和
将粘合剂组合物成形而得到粘合剂层的工序。
2.权利要求1所述的方法,其中,阿塞那平的酸加成盐中的酸选自盐酸、氢溴酸、氢碘酸、磷酸、乙酸、丙酸、乙醇酸、马来酸、丙二酸、琥珀酸、酒石酸、柠檬酸、抗坏血酸、水杨酸和苯甲酸。
3.权利要求1或2所述的方法,其中,脱盐剂选自碱金属氢氧化物、碱金属盐、碱土金属氢氧化物、碱土金属盐和低分子胺。
4.使含有(甲基)丙烯酸酯(共)聚合物的粘合剂组合物中的阿塞那平稳定化的方法,所述方法包括:
混合阿塞那平的酸加成盐、(甲基)丙烯酸酯(共)聚合物和脱盐剂,得到粘合剂组合物的工序。
5.在具备含有阿塞那平的粘合剂层的贴剂的制造过程中抑制阿塞那平的分解的方法,所述方法包括:
混合阿塞那平的酸加成盐、(甲基)丙烯酸酯(共)聚合物和脱盐剂,得到粘合剂组合物的工序;和
将粘合剂组合物成形而得到粘合剂层的工序。
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CN110958876A (zh) * | 2018-06-20 | 2020-04-03 | 罗曼治疗系统股份公司 | 含有阿塞那平的透皮治疗系统 |
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CN114302716A (zh) * | 2019-10-28 | 2022-04-08 | 久光制药株式会社 | 抑制阿塞那平-n-氧化物的生成的方法 |
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CN107847487B (zh) * | 2015-07-27 | 2021-11-02 | 久光制药株式会社 | 含有阿塞那平的贴剂 |
WO2017223402A1 (en) | 2016-06-23 | 2017-12-28 | Corium International, Inc. | Adhesive matrix with hydrophilic and hydrophobic domains and a therapeutic agent |
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KR102302583B1 (ko) | 2017-02-24 | 2021-09-14 | 히사미쓰 세이야꾸 가부시키가이샤 | 첩부제 및 그 포장체 |
US11173132B2 (en) | 2017-12-20 | 2021-11-16 | Corium, Inc. | Transdermal adhesive composition comprising a volatile liquid therapeutic agent having low melting point |
CN113226308A (zh) | 2018-10-01 | 2021-08-06 | 久光制药株式会社 | 含有阿塞那平的贴剂 |
WO2020071207A1 (ja) | 2018-10-01 | 2020-04-09 | 久光製薬株式会社 | アセナピン含有貼付剤 |
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