CN102070992B - 贴片和贴片制剂 - Google Patents
贴片和贴片制剂 Download PDFInfo
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- CN102070992B CN102070992B CN201010557610.3A CN201010557610A CN102070992B CN 102070992 B CN102070992 B CN 102070992B CN 201010557610 A CN201010557610 A CN 201010557610A CN 102070992 B CN102070992 B CN 102070992B
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Abstract
贴片和贴片制剂,根据本发明的实施方式的贴片包括支撑体和上述支撑体的至少一个表面上的粘接剂层,其中:上述粘接剂层含有丙烯酸类共聚物,上述丙烯酸类共聚物通过将含有(a)至少一种(甲基)丙烯酸烷基酯单体和(b)至少一种N-羟基烷基(甲基)丙烯酰胺单体的单体组分共聚得到;上述(甲基)丙烯酸烷基酯单体(a)的含量相对于上述单体组分的总量为50重量%~90重量%并且上述N-羟基烷基(甲基)丙烯酰胺单体(b)的含量相对于上述总量为1重量%~20重量%,并且上述单体组分实质上不含有带羧基的单体。
Description
本申请根据35 U.S.C.第119章要求于2009年11月20日申请的日本专利申请号2009-265713的优先权,该申请通过引用合并入本文中。
技术领域
本发明涉及用于皮肤的保护、药物的经皮给药等的贴片和贴片制剂。
背景技术
贴片和贴片制剂均要求具有如下特征,上述贴片和贴片制剂均通过贴附在皮肤上,以实现例如保护皮肤、固定各种医疗装置和经皮施用药物的目的。即,贴片和贴片制剂在贴附于皮肤时显示充分的粘接性,并且可以在其使用后在不污染皮肤表面(导致例如粘接剂残余物或粘性)的前提下剥离和移除。另外,需要贴片和贴片制剂均对皮肤的刺激性低。
日本公开的专利公开号平成4-150865公开了一种贴片,在其粘接剂层中含有如下共聚物的交联产物:(甲基)丙烯酸烷基酯或该酯和(甲基)丙烯酸烷氧基烷基酯的混合物;和含有羧基和/或羟基的单体。但是,由于上述贴片中的粘接剂层含有带羧基的共聚物,必需考虑活性组分例如药物和羧基之间的反应性。
另外,日本公开的专利公开号2003-313122公开了一种使用丙烯酸类粘接剂的贴片,其通过将(甲基)丙烯酸烷基酯和可与(甲基)丙烯酸烷基酯共聚合且不带羧基和磺基的单体聚合而得到。此外,该文件中贴片的粘接剂层含有有机液体组分并且可以交联。该文件描述该贴片显示对皮肤的刺激性小同时具有充分的粘结强度,使得在其剥离时没有粘接剂残余物。但是,由于该贴片当长时间贴附于皮肤表面或贴附于大幅度移动的皮肤表面时可能从皮肤上脱离,日本公开的专利公开号2003-313122中公开的不含羧基和磺基的粘接剂的粘结性能需要额外的改进。
发明内容
鉴于上述原因,本发明的目的在于提供具有下列特征的贴片或贴片制剂:
(A)即使当在粘接剂层中含有药物等时,由于与上述组分的反应而导致的变性等也可以被抑制;
(B)贴片或贴片制剂具有充分的粘结强度并且在剥离时不引起粘接剂残留;
(C)贴片或贴片制剂显示对皮肤良好的粘接性,但显示对皮肤的刺激性小并且具有柔软的贴附感;和
(D)贴片或贴片制剂特别适合于例如保护皮肤和经皮施用药物的目的。
本发明的发明人为解决上述问题进行了广泛的研究。结果,本发明人发现使用含有通过将下列单体组分共聚得到的丙烯酸类共聚物的粘接剂作为用于形成贴片或类似物的粘接剂层的组合物,提供了满足上述所有特征(A)~(D)的贴片或类似物。即,上述单体组分含有一种或两种或多种(甲基)丙烯酸烷基酯单体和一种或两种或多种N-羟基烷基(甲基)丙烯酰胺单体,并且实质上不含带羧基的单体。
根据本发明的实施方式的贴片包括支撑体和上述支撑体的至少一个表面上的粘接剂层,其中:上述粘接剂层含有丙烯酸类共聚物,上述丙烯酸类共聚物通过将含有(a)至少一种(甲基)丙烯酸烷基酯单体和(b)至少一种N-羟基烷基(甲基)丙烯酰胺单体的单体组分共聚而得到;上述(甲基)丙烯酸烷基酯单体(a)的含量相对于上述单体组分的总量为50重量%~90重量%并且上述N-羟基烷基(甲基)丙烯酰胺单体(b)的含量相对于上述总量为1重量%~20重量%,并且上述单体组分实质上不含有带羧基的单体。
在本发明的优选实施方式中,丙烯酸类共聚物通过将还含有(c)乙烯类单体的上述单体组分共聚而得到。
在本发明的优选实施方式中,乙烯类单体(c)的含量相对于上述单体组分的总量为1重量%~40重量%。
在本发明的优选实施方式中,粘接剂层还含有有机液体组分。
在本发明的优选实施方式中,粘接剂层是交联的。
根据本发明的另一个方面,提供了一种贴片制剂。该贴片制剂通过在根据本发明的贴片中的粘接剂层中含有能够经皮给药的药物而得到。
当例如在本发明的贴片和贴片制剂的粘接剂层中含有例如药物的活性组分时,由上述活性组分和粘接剂层中的官能团之间的反应所引起的上述活性组分的变性、上述活性组分在粘接剂层中的移动受限等可以被抑制。另外,本发明的贴片和贴片制剂均具有充分的粘结强度,在剥离时不引起粘接剂残留,并且显示对皮肤良好的贴附性,但显示对皮肤的刺激性小并且具有柔软的贴附感。因此,贴片和贴片制剂特别适合分别用作用于例如保护皮肤的贴片和用于药物的经皮给药的贴片制剂。
附图说明
图1是表示本发明的实施例3和比较例4的每种贴片制剂对普拉克索的皮肤渗透性的图。
具体实施方式
本发明的贴片包括支撑体的至少一个表面上的粘接剂层,其中上述粘接剂层包括含有丙烯酸类共聚物的粘接剂,上述丙烯酸类共聚物通过将含有(a)一种或两种或多种(甲基)丙烯酸烷基酯单体和(b)一种或两种或多种N-羟基烷基(甲基)丙烯酰胺单体的单体组分共聚而得到。
上述(甲基)丙烯酸烷基酯(单体(a))典型地如通式(I)所示。
在该式中,R1代表氢原子或甲基,R2代表烷基。烷基优选碳原子数为4~18的烷基。为了可以得到足以用于贴片或类似物中的良好的粘接性(粘性),必须得到具有低玻璃化转变温度的粘接剂。当烷基具有4~18个碳原子时,容易得到具有充分低的玻璃化转变温度的粘接剂。
上述(甲基)丙烯酸烷基酯的例子包括具有下列基团:直链烷基,例如正丁基、正戊基、正己基、正庚基、正辛基、正壬基、正癸基、正十一烷基、正十二烷基或正十三烷基;支链烷基,例如异丁基、异戊基、异己基、异辛基或2-乙基己基;或环状烷基,例如环戊基、环己基或环庚基。它们可以单独使用或组合使用。
在上述酯中,优选地使用降低玻璃化转变温度的单体组分,以便在正常温度下可以得到粘接性。更优选其中式(I)中R2代表的烷基具有4~12个碳原子的(甲基)丙烯酸烷基酯。具体而言,优选丙烯酸丁酯、甲基丙烯酸丁酯、丙烯酸2-乙基己酯、甲基丙烯酸2-乙基己酯、丙烯酸环己酯、甲基丙烯酸环己酯等,且最优选丙烯酸2-乙基己酯。原因如下。即,当该酯被聚合时得到具有充分低的玻璃化转变温度(-70℃)的聚合物。另外,该酯是容易得到的。
在本发明中使用的上述单体(a)优选以由该单体构成的均聚物可以具有优选-80℃~-40℃并和特别优选-70℃~-50℃的玻璃化转变温度的方式选择。
上述单体(a)的含量相对于单体组分的总量为50重量%或更多。当单体(a)的含量为50重量%或更多时,作为粘接剂使用时的粘接性(粘性)是良好的。另外,单体(a)的含量为优选60重量%或更多,以便可以得到更良好粘性。另一方面,当上述单体组分中单体(a)的含量过大时,所得的共聚物的性能接近上述单体(a)的均聚物,并且因此往往难以得到适合于粘接剂的性能。因此,单体(a)的含量相对于单体组分的总量为90重量%或更少,优选80重量%或更少,且更优选75重量%或更少。
N-羟基烷基(甲基)丙烯酰胺(单体(b))典型地如通式(II)所示。
在该式中,R3代表氢原子或甲基,R4代表羟基烷基。
作为上述式(II)中的羟基烷基,优选含有碳原子数为2~4的羟基烷基。上述羟基烷基中的烷基可以是直链的或支链的。如通式(II)所示的N-羟基烷基(甲基)丙烯酰胺的例子包括N-(2-羟基乙基)丙烯酰胺、N-(2-羟基乙基)甲基丙烯酰胺、N-(2-羟基丙基)丙烯酰胺、N-(2-羟基丙基)甲基丙烯酰胺、N-(1-羟基丙基)丙烯酰胺、N-(1-羟基丙基)甲基丙烯酰胺、N-(3-羟基丙基)丙烯酰胺、N-(3-羟基丙基)甲基丙烯酰胺、N-(2-羟基丁基)丙烯酰胺、N-(2-羟基丁基)甲基丙烯酰胺、N-(3-羟基丁基)丙烯酰胺、N-(3-羟基丁基)甲基丙烯酰胺、N-(4-羟基丁基)丙烯酰胺、和N-(4-羟基丁基)甲基丙烯酰胺。它们可以单独使用或组合使用。本发明中的单体(b)的优选例子包括N-(2-羟基乙基)丙烯酰胺和N-(2-羟基乙基)甲基丙烯酰胺。单体(b)的特别优选的例子为N-(2-羟基乙基)丙烯酰胺(HEAA)。这是因为能够形成具有良好的亲水和疏水平衡并且具有优异的粘接性平衡的粘接剂层。例如,优选HEAA占单体(b)的50重量%或更多,更优选70重量%或更多,还更优选实质上其为所有的单体(b)。
单体(b)可以通过它们的分子之间的相互作用而促进粘接剂的粘着性的改善。在本发明中,单体(b)的含量相对于单体组分的总量为1重量%~20重量%。当单体(b)的含量为1重量%以上时,则可以对粘接剂赋予充分的粘结强度,并且因此可以避免如下风险。即,由于皮肤的移动引起粘接剂朝向外侧离开贴片的端面从而导致衣服等的污染,或在去除贴片时在皮肤上出现粘接剂残余物。另一方面,当单体(b)的含量超过20重量%时,粘性可能降低从而导致例如在粘接体例如皮肤具有粗糙的表面和拉伸性的情况下贴片的端部的浮起或脱离。
在本发明的优选实施方式中,单体(b)的含量相对于单体组分的总量为2重量%~20重量%,更优选3重量%~15重量%,还更优选3重量%~12重量%。采用含有通过将含有此比例的单体(b)的单体组分共聚合而得到的丙烯酸类共聚物的粘接剂组合物,甚至在例如单体组分除单体(b)以外实质上不含有带氧以外的杂原子(例如氮或硫)的单体的情况下,当该组合物粘接在皮肤表面上时粘结强度和粘接强度可以被进一步改善。如在本说明书中使用的短语“实质上不含有带杂原子的单体”不仅包括其中带杂原子的单体的含量为0的情况,还包括其中该含量相对于单体组分的总量为0.1重量%或更少的情况。
单体组分中单体(a)和单体(b)之间的质量比(a∶b)例如为99.9∶0.1~71∶29,优选99∶1~75∶25,更优选98∶2~80∶20,还更优选97∶3~85∶15。只要该质量比(a∶b)落在此范围内,甚至在例如用于共聚的单体组分是除单体(b)以外实质上不含有带氧以外的杂原子(例如氮或硫)的单体的组合物的单体组分的情况下(即,该单体组分实质上由单体(a)和(b)构成),则可以得到当与皮肤表面粘接时具有更加良好的粘结强度和更加良好的粘接强度的贴片或类似物。
单体(a)和(b)的总量相对于单体组分的总量为优选约60重量%或更多,更优选约80重量%或更多,还更优选约90重量%或更多,特别优选约95重量%或更多。在本发明的优选实施方式中,用于形成粘接剂层的粘接剂含有实质上仅将单体(a)和(b)共聚而得到的丙烯酸类共聚物(即,单体(a)和(b)的总含量实质上占所有单体组分的100重量%)。采用此粘接剂组合物,可以得到当与皮肤表面粘接时具有良好的粘结强度和良好的粘接强度的贴片,即使该粘接剂由简单的组合物构成。
在本发明中,上述用于共聚的单体组分的特征在于实质上不含有带羧基的单体。如本文使用的术语“带羧基的单体”一般指例如在其分子中带至少一个羧基的烯属不饱和单体(羧基可以是酸酐的形式)(典型地为乙烯类单体)。带羧基的此类单体的例子包括:烯属不饱和单羧酸例如(甲基)丙烯酸和巴豆酸;烯属不饱和二羧酸例如马来酸、衣康酸和柠康酸;以及烯属不饱和二羧酸的酸酐类例如马来酸酐和衣康酸酐。应该注意的是,如本说明书中使用的短语“单体组分实质上不含有带羧基的单体”不仅包括其中进行共聚合的单体组分完全不含有带羧基的单体的情况,还包括其中该单体的含量相对于单体组分的总量为0.1重量%或更少的情况。
此外,在本发明中,优选上述用于共聚的单体组分不仅实质上不含有带羧基的单体,而且还实质上不含有带除羧基以外的酸性基团的单体(例如磺基或磷酸基)。即,优选上述单体组分完全不含有带羧基的单体和带任何其它酸性基团的单体或以相对于其总量的0.1重量%或更少的含量含有这些单体。当在通过使用粘接剂(其含有通过将上述单体共聚得到的共聚物)形成的粘接剂层中含有例如药物的医疗活性组分时,可以抑制例如由于与上述羧基等的反应所引起的上述活性组分的变性和活性组分在粘接剂层中的移动受限。
在本发明中,在上述用于构成丙烯酸类共聚物的单体组分中,除了上述单体(a)和(b),还可以含有可以与这些单体共聚的乙烯类单体(c)。单体(c)的加入可以调节贴片和贴片制剂的粘接强度和粘结强度以及药物的溶解度和释放特性。
当在本发明中用于共聚的单体组分中含有单体(c)时,其含量相对于单体组分的总量为优选40重量%或更少,更优选1重量%~40重量%,还更优选1重量%~35重量%,特别优选5重量%~30重量%。当单体(c)的含量为1重量%或更多时,含有单体(c)的作用被充分地发挥。另外,当单体(c)的含量超过40重量%时,所得到的贴片和贴片制剂的粘性或粘接强度可能下降。
例如甲基乙烯醚和乙基乙烯醚的乙烯醚,和含有带氮原子的杂环的乙烯类单体,例如N-乙烯基-2-吡咯烷酮、1-乙烯基己内酰胺、2-乙烯基-2-哌啶酮和1-乙烯基咪唑,可以用作乙烯类单体(c)。它们可以单独使用或组合使用。应当注意的是在上述乙烯类单体中优选使用带含氮原子的杂环的乙烯类单体。
在本发明中,用于从上述单体组分得到丙烯酸类共聚物的聚合方法不特别地受限制,并且可以采用任何适当的聚合方法。例如,可以采用包括使用热聚合引发剂的聚合方法(热聚合方法例如溶液聚合法、乳液聚合法或本体聚合法),或包括应用活化能射线(也称为“高能射线”)例如光或放射线的聚合方法。
在上述聚合方法中,可以优选地采用溶液聚合方法,因为该方法例如在可操作性和质量稳定性方面是优异的。溶液聚合的方式不特别地受限制,并且可以采用任何适当的方式。具体地,可以采用任何适当的单体供料方法、聚合条件(例如聚合温度、聚合时间和聚合压力)和待使用的物质(例如聚合引发剂和表面活性剂)。例如,包括将单体组分的总量以一次供给至反应容器的批量加载系统,连续供料(滴料)系统和分路供料(split supply)(滴料)系统的任一种可以用作上述单体供料方法。优选方式是例如这样的方式,即通过将单体组分和引发剂的全部量溶解在溶剂中制备的溶液供给至反应容器,然后将单体组分共同聚合(分批聚合)。由于聚合操作和过程控制容易,因此优选这样的分批聚合。另一优选方式是在反应容器中制备引发剂(典型地通过将引发剂溶解在溶剂中制备的溶液),然后将单体组分溶解在溶剂中制备的溶液滴入反应容器中,发生聚合(滴液聚合(dropping polymerization)或连续聚合)。部分单体组分(部分组分和/或部分量)可以典型地与溶剂一起加载至反应容器中,且剩余的单体组分可以滴入反应容器中。当含有15重量%或更多的单体(b)的单体组分聚合时,从易于均一地进行聚合反应的角度出发更优选采用滴液聚合。
上述热聚合引发剂的例子包括:偶氮类化合物(偶氮类引发剂),例如2,2′-偶氮二异丁腈、2,2′-偶氮二-2-甲基丁腈、二甲基2,2′-偶氮二(2-甲基丙酸酯)、4,4′-偶氮二-4-氰基戊酸、偶氮二异戊腈、2,2′-偶氮二(2-脒基丙烷)二盐酸盐、2,2′-偶氮二[2-(5-甲基-2-咪唑啉-2-基)丙烷]二盐酸盐、2,2′-偶氮二(2-甲基丙基脒)二硫酸盐、2,2′-偶氮二(N,N′-二亚甲基异丁脒)二盐酸盐、和2,2′-偶氮二[N-(2-羧乙基)-2-甲基丙基脒]水合物;过硫酸盐,例如过硫酸钾和过硫酸铵;过氧化物(过氧化物类引发剂),例如过氧化二苯甲酰、过氧化马来酸叔丁酯、过氧化叔丁醇和过氧化氢;取代的乙烷类引发剂,例如苯取代的乙烷;和氧化还原型引发剂,例如过硫酸盐和亚硫酸氢钠的混合剂,以及过氧化物和抗坏血酸钠的混合剂。当单体组分通过热聚合法聚合时,聚合温度为优选约20℃~约100℃,更优选约40℃~约80℃。
包括应用光(典型地为UV光)的聚合方法典型地通过使用光致聚合引发剂进行。光致聚合引发剂不特别地受限制,并且例如可以使用缩酮类光致聚合引发剂、苯乙酮类光致聚合引发剂、安息香醚类光致聚合引发剂、酰基膦氧化物类光致聚合引发剂、α-酮醇类光致聚合引发剂、芳族磺酰氯类光致聚合引发剂、旋光活性肟类光致聚合引发剂、安息香类光致聚合引发剂、苄基类光致聚合引发剂、二苯甲酮类光致聚合引发剂或噻吨酮类光致聚合引发剂。这些光致聚合引发剂可以单独使用或组合使用。
缩酮类光致聚合引发剂的例子包括2,2-二甲氧基-1,2-二苯基乙-1-酮[例如商品名为″Irgacure 651″的光致聚合引发剂(由Ciba Japan KK制造)]。苯乙酮类光致聚合引发剂的例子包括1-羟基环己基苯基甲酮[例如商品名为″Irgacure 184″的光致聚合引发剂(由Ciba Japan KK制造)]、2,2-二乙氧基苯乙酮、2,2-二甲氧基-2-苯基苯乙酮、4-苯氧基二氯苯乙酮和4-(叔丁基)二氯苯乙酮。安息香醚类光致聚合引发剂的例子包括安息香甲醚、安息香乙醚、安息香丙醚、安息香异丙醚和安息香异丁醚。酰基膦氧化物类光致聚合引发剂的例子包括商品名为″Lucirin TPO″的光致聚合引发剂(由BASF制造)。α-酮醇类光致聚合引发剂的例子包括2-甲基-2-羟基苯丙酮和1-[4-(2-羟基乙基)苯基]-2-甲基丙-1-酮。芳族磺酰氯类光致聚合引发剂的例子包括2-萘磺酰氯。旋光活性肟类光致聚合引发剂的例子包括1-苯基-1,1-丙二酮-2-(o-乙氧羰基)-肟。安息香类光致聚合引发剂的例子包括安息香。苄基类光致聚合引发剂的例子包括苄基。二苯甲酮类光致聚合引发剂的例子包括二苯甲酮、苯甲酰苯甲酸、3,3′-二甲基-4-甲氧基二苯甲酮、聚乙烯基二苯甲酮和α-羟基环己基苯基甲酮。噻吨酮类光致聚合引发剂的例子包括噻吨酮、2-氯噻吨酮、2-甲基噻吨酮、2,4-二甲基噻吨酮、异丙基噻吨酮、2,4-二异丙基噻吨酮和十二烷基噻吨酮。
上述聚合引发剂的使用不特别地受限制。例如,聚合引发剂的使用为相对于100重量份的单体组分的总量优选为约0.01重量份至约2重量份,更优选约0.01重量份至约1重量份。
在本发明中,如下所述地制备贴片。即,将含有上述丙烯酸类共聚物的组合物(此后可以称为“用于形成粘接剂层的组合物”或“粘接剂”)在支撑体的至少一个表面上形成为粘接剂层。
在本发明中,含有上述丙烯酸类共聚物的用于形成粘接剂层的组合物可以基于例如应用射线例如应用紫外光或应用电子束而进行物理交联处理,或根据需要使用多种交联剂的任一种进行化学交联处理。任何适当的交联剂可以适当地被选择作为上述交联剂之一。例如,可以使用异氰酸酯类化合物(异氰酸酯类交联剂)环氧类交联剂、氮丙啶类交联剂、三聚氰胺类交联剂、过氧化物类交联剂、噁唑啉类交联剂、尿素类交联剂、氨基类交联剂、碳二亚胺类交联剂或偶联剂类交联剂(例如硅烷偶联剂)。它们可以单独使用或组合使用。使用任何这样的交联剂交联(固化)粘接剂层不仅可以赋予粘接剂层以适度的粘结强度和适度的粘接强度,而且在从皮肤上剥离粘接剂层时还减少粘接剂残留物。在本发明中,用于交联粘接剂层的交联剂相对于100重量份的丙烯酸类共聚物以优选约0.01重量份~约5重量份,更优选约0.01重量份~约2重量份的含量加入。
与上述交联剂交联的粘接剂层具有优选50重量%~95重量%,更优选60重量%~92重量%的凝胶分数。当粘接剂层的凝胶分数为50重量%~95重量%时,粘接剂层被赋予充分的粘结强度,并且在剥离贴片时不可能出现粘接剂残留物或由于粘接失败所引起的强烈的皮肤刺激。应当注意的是,当粘接剂层的凝胶分数超过95重量%时,粘接剂层的粘结强度增加但可能不能得到充分的皮肤粘接强度。
应当注意的是,上述术语“凝胶分数”是指当粘接剂层浸泡在有机溶剂例如乙酸乙酯中时得到的不溶物质的重量相对于与参与粘接剂层的交联的组分的总重量的比率。凝胶分数可以由通过在常温(23℃)下将粘接剂层在有机溶剂例如乙酸乙酯中浸泡预定的时间段而得到的不溶物质的重量通过使用下列的方程确定:
凝胶分数(wt%)=(W2×100)/(W1×A/B)
其中A代表聚合物和交联剂的重量,B代表粘接剂层的组成组分的总重量,W1代表作为样品的粘接剂层的重量,W2代表通过将作为样品的粘接剂层浸泡在有机溶剂中得到的不溶物质的重量。
在用于形成本发明的贴片的粘接剂层的组合物可以含有与上述丙烯酸类共聚物相溶的有机液体组分。有机液体组分可以使粘接剂组合物形成可素体以提供柔软的感觉。结果,当本发明的粘接剂组合物用作粘接剂层时,可以减小在从皮肤上剥离贴片或贴片制剂例如粘接带或可经皮吸收制剂时由皮肤粘接强度所引起的疼痛或皮肤刺激。因此,只要该组分具有可塑性即可,可以使用任何组分作为有机液体组分而没有任何特殊的限制。应该注意的是,当在粘接剂层中含有药物时,优选使用具有促吸收作用的组分,以改善经皮吸收性。
上述有机液体组分的例子包括:植物油脂,例如橄榄油,蓖麻油和棕榈油;动物油脂,例如羊毛脂;有机溶剂,例如如二甲基癸亚砜,甲基辛基亚砜,二甲基亚砜,二甲基甲酰胺,二甲基乙酰胺,二甲基月桂酰胺,甲基吡咯烷酮和十二烷基吡咯烷酮;液体表面活性剂,例如聚氧乙烯失水山梨醇酐脂肪酸酯,山梨糖醇酐脂肪酸酯,聚氧乙烯脂肪酸酯;增塑剂,例如己二酸二异丙酯、邻苯二甲酸酯和癸二酸二乙酯;烃类,例如角鲨烷和液体石蜡;脂肪酸烷基酯,例如油酸乙酯,棕榈酸异丙酯,棕榈酸辛酯,肉豆蔻酸异丙酯,肉豆蔻酸异十三酯和月桂酸乙酯;多元醇的脂肪酸酯,例如甘油脂肪酸酯和丙二醇脂肪酸酯;乙氧化的硬脂醇;和吡咯烷酮羧酸脂肪酸酯。它们可以单独使用或组合使用。
在本发明中,上述有机液体组分可以优选以“丙烯酸类共聚物:有机液体组分”为1∶0.1~2的重量比在丙烯酸类共聚物中含有。从皮肤刺激性的角度出发,该重量比更优选地为1∶0.4~2。应当注意的是有机液体组分优选以尽可能大的量含有,该量大至不损害粘接剂性能的程度。
另外,只要本发明的特征不受损害,用于形成本发明的粘接剂层的组合物可以进一步含有任何其它组分。这些组分的例子包括抗氧化剂例如抗坏血酸,生育酚乙酸酯,天然维生素E,二丁基羟基甲苯和丁基羟基茴香醚;胺-酮类抗衰老剂,例如2,6-叔丁基-4-甲酚;芳族仲胺类抗衰老剂,例如N,N′-二-2-萘基对苯二胺;一元酚类抗衰老剂,例如2,2,4-三甲基-1,2二氢喹啉聚合物;双酚类抗衰老剂,例如2,2′-亚甲基双(4-乙基-6-叔丁基苯酚);多酚类抗衰老剂,例如2,5-叔丁基对苯二酚;填料,例如高岭土,含水二氧化硅,氧化锌和淀粉丙烯酸酯1000;软化剂,例如丙二醇,聚丁烯和聚乙二醇1500;防腐剂,例如苯甲酸,苯甲酸钠,盐酸洗必泰,山梨酸,对羟基苯甲酸甲酯和对羟基苯甲酸丁酯;着色剂,例如黄色氧化铁,黄铁(III)氧化物,铁(III)氧化物,黑氧化铁,炭黑,洋红,β-胡萝卜素,叶绿素铜,食品蓝1号,食品黄4号,食品红2号和甘草提取物;冷却剂例如茴香油,d-樟脑和dl-樟脑,薄荷油,d-冰片,和l-薄荷醇;和香料例如薄荷油,丁香油,香草醛,香柠檬油和薰衣草油。
在本发明中,贴片通过将含有丙烯酸类共聚物的粘接剂在支撑体的至少一个表面上形成为粘接剂层而得到。本发明的贴片可以以以下方式提供,例如,片状、膜状、或垫状的医用或保健用贴片,并且可以用于例如保护皮肤的病变部位或受伤部位的应用中,包括石膏中纱布的替代品和伤口覆盖敷料中无纺织物的替代品。另外,本发明的贴片可以通过在其粘接剂层中含有药物而形成贴片制剂。本发明的贴片制剂以可经皮吸收制剂例如基质型贴片制剂和储备型贴片制剂的方式提供,并且特别地以用于经皮吸收的胶带药物的方式提供。应该注意的是上述粘接剂层不限于连续形成的层且可以是形成为具有规则或随机图案例如点状或条状的粘接剂层。
在本发明的贴片和贴片制剂中使用的支撑体不特别地受限制。支撑体优选由不会由于组分通过支撑体渗透导致该组分从支撑体的背面丢失而引起粘接剂层中该组分(例如,例如药物的活性组分,或添加剂)的含量降低的材料组成。即,支撑体优选地由不允许粘接剂层中的组分渗透的材料组成。
在贴片和贴片制剂中使用的支撑体的例子包括:聚酯树脂,例如聚对苯二甲酸乙二醇酯;聚酰胺类树脂,例如尼龙;烯烃类树脂,例如Saran(注册商标),聚乙烯,聚丙烯和Surlyn(注册商标);乙烯类树脂,例如乙烯-乙酸乙烯酯共聚物,聚氯乙烯和聚偏二氯乙烯;丙烯酸类树脂,例如乙烯-丙烯酸乙酯共聚物;氟化碳树脂,例如聚四氟乙烯;金属箔的单层膜等及其层压膜。应该注意的是支撑体的厚度典型地为10μm~500μm,优选10μm~200μm。
上述支撑体优选地是由任一种上述材料形成的无孔塑料片和多孔片的层压片。这样的结构可以改善支撑体和粘接剂层之间的粘接性(锚固性能)。在此情况下,只要该片可以改善支撑体和粘接剂层之间的锚固性能即可,粘接剂层优选地形成在多孔片的一侧上。上述多孔片不特别地受限制。多孔片的具体例子包括纸、机织织物、无纺织物和机械穿孔片。在这些中,特别优选纸、机织织物、或无纺织物。多孔片优选具有10μm~500μm的厚度。采用这种厚度,锚固性能提高,并且粘接剂层的柔韧性是优异的。另外,当机织织物或无纺织物用作多孔片时,多孔片的单位面积质量为优选5g/m2~30g/m2和更优选8g/m2~20g/m2。这是因为锚固性能可以改善。应当注意当支撑体是上述层压片时,无孔片优选具有1μm~25μm的厚度。
在上述支撑体中,特别适合的支撑体是具有1.5μm-6μm的厚度的聚酯膜(优选聚对苯二甲酸乙二醇酯膜)和由聚酯(优选聚对苯二甲酸乙二醇酯)制成的单位面积质量为8g/m2-20g/m2的无纺织物的层压膜。
本发明的贴片制剂中,适当根据所需目的选择选择可以在粘接剂层中含有并且可以经皮给药的药物。含有的此类药物的例子包括可以经皮给药的皮质类固醇药物、非甾体抗炎药、抗风湿药、安眠药丸、抗精神病药物、抗抑郁药、情绪稳定剂、精神兴奋剂、抗焦虑药、抗癫痫药、偏头痛治疗药、帕金森氏病治疗药、脑循环/代谢改良剂、抗老年痴呆药、植物神经药物、肌肉松弛药、降压药、利尿药、降糖药、高血脂症治疗药物、治痛风药、全身麻醉药、局部麻醉药、抗菌药物、抗真菌药、抗病毒药物、抗寄生虫药、维生素药物、心绞痛治疗药物、血管扩张剂、抗心律失常药物、抗组胺药、介质释放抑制剂、白三烯拮抗剂、雌性激素药物、甲状腺激素药物、抗甲状腺药、止吐药、防眩晕药、支气管扩张剂、镇咳药、祛痰药和戒烟辅剂。在这些中,在本发明的贴片制剂中,就用于形成粘接剂层的粘接剂的特性而言,在含有羧基的粘接剂层中可以适当含有其稳定性显著降低的药物。
在本发明中,从得到具有高皮肤渗透性的贴片制剂的角度出发,使用碱性药物作为上述药物是有利的。碱性药物是指在其分子中具有碱性基团的药物。在本发明的医用粘接剂组合物含有实质上不含羧基的丙烯酸类共聚物的情况下,例如,由碱性药物的碱性基团和羧基之间的反应所引起的碱性药物在粘接剂层中的移动受限可以被消除。从这样的角度出发,碱性药物优选是具有碱性氮原子的碱性药物,更优选具有伯氨基、仲氨基或叔氨基的药物。
上述药物在本发明的贴片制剂中的含量含量可以适当根据例如药物的种类和其给药目的以及患者的年龄、性别和症状适当设置。上述药物的含量优选为约0.1重量%~约40重量%,更优选约0.5重量%~约30重量%。通常,当该含量小于0.1重量%时,可能预期不能达到有效用于治疗的药物释放量,并且当该含量超过40重量%时,疗效达到其限度且从经济上来说是不利的,但是由于该含量的变化取决于所选择的药物,优选的含量不可能唯一地确定。
制备本发明的贴片和贴片制剂的方法不特别地受限制,并且可以采用本领域中采用的常规方式。接着,通过将经皮吸收胶带制剂作为本发明的贴片制剂的实施方式而作为实施例给出具体的描述。首先,丙烯酸类共聚物,有机液体组分等和上述药物以说明的顺序溶解或分散在溶剂中,接着,根据需要将交联剂加入至上述溶液或分散液中。因此,得到用于形成粘接剂层的组合物。通过将该组合物涂敷在支撑体的至少一个表面上并且将涂敷的组合物干燥而形成粘接剂层。此外,将在下面描述的离型衬底可以进行层压。可选地,胶带制剂可以如下制备:在离型衬底上涂敷上述加入交联剂的溶液或分散液;干燥涂敷的溶液或分散液,从而在离型衬底的表面上形成粘接剂层;并将支撑体贴附在粘接剂层上。
上述离型衬底的例子包括:玻璃纸、聚乙烯、聚丙烯、聚酯、聚对苯二甲酸乙二醇酯、聚苯乙烯、铝膜、发泡聚乙烯膜和发泡聚丙烯膜;以及选自它们的两种或多种的层压产品和通过将它们进行硅酮加工和压花加工得到的产品。离型衬底的厚度优选为10μm~200μm,更优选25μm~100μm。
就阻透性和价格而言,上述离型衬底优选是由聚酯(尤其是聚对苯二甲酸乙二醇酯)树脂制成的离型衬底。此外,在此情况下,就操作性能而言,其厚度为优选约25μm~100μm。
用于形成粘接剂层的组合物的涂敷可以采用任何常规使用的涂布机进行,上述涂布机例如凹版辊筒涂布机(gravure roll coater)、逆转辊筒涂布机(reverse roll coater)、滚压涂布机(kiss-roll coater)、浸渍辊涂布机(dip roll coater)、刮棒涂布机(bar coater)、刮刀涂布机(knife coater)或喷涂机(spray coater)。从例如加速交联反应和改进生产效率的角度出发,粘接剂组合物优选在加热下进行干燥。尽管干燥温度的变化取决于该组合物涂敷的支撑体的种类,干燥温度为例如约40℃~约150℃。
在本发明的贴片和贴片制剂中在支撑体的至少一个表面上形成的粘接剂层的厚度为优选10μm~400μm,更优选20μm~200μm,还更优选30μm~100μm。
另外,在通过如上所述的方法制备贴片或贴片制剂后,为了使交联反应结束和改善粘接剂层和支撑体之间的锚固性能,可以在等于或高于室温的温度下进行老化。老化温度为优选25℃~80℃,且更优选40℃~70℃。
接着,本发明通过实施例详细地进行描述,但本发明不限于这些实施例。
[实施例1]贴片
(1)首先,70重量份作为单体(a)的2-丙烯酸乙基己酯(此后可以称为″2-EHA″),10重量份作为单体(b)的N-羟基乙基丙烯酰胺(此后可以称为″HEAA″),20重量份作为单体(c)的N-乙烯基-2-吡咯烷酮(此后可以称为″N-VP″),和333.3重量份的作为溶剂的乙酸乙酯装入设置有冷却管、氮气引导管、温度计、滴液漏斗和搅拌器的反应容器中,然后将内容物在室温下搅拌1小时同时进行氮气鼓泡(100mL/min)。之后,将反应容器中的内容物加热,并当内容物的温度达到60℃时加入0.2重量份作为聚合引发剂的2,2′-偶氮二异丁腈(AIBN)。控制内容物的温度以保持在60℃,然后在氮气流中进行聚合持续6小时。接着,将温度保持在76℃持续15小时。基于上述系统通过溶液聚合得到丙烯酸类共聚物溶液(2-EHA/HEAA/N-VP=70/10/20)。
(2)肉豆蔻酸异丙酯(IPM)作为有机液体组分,相对于100重量份(固体含量)的丙烯酸类共聚物以42.9重量份的量加入上述得到的丙烯酸类共聚物溶液中。此外,三羟甲基丙烷(Coronate HL)的六亚甲基二异氰酸酯加合物作为异氰酸酯类交联剂,相对于100重量份(固体含量)的丙烯酸类共聚物以0.5重量份的量加入该混合物中。由此制备用于形成粘接剂层的组合物。
(3)用敷料器在由厚度为75μm的聚对苯二甲酸乙二醇酯(PET)膜制成的离型衬底的剥离面上涂敷上述组合物,然后以100℃干燥3分钟。由此形成粘接剂层。接着,将支撑体的无纺织物表面贴附在上述粘接剂层上。由此制备贴片。应当注意的是使用厚度为2μm的PET膜和单位面积质量为14g/m2的PET无纺织物的层压体作为支撑体。
[实施例2]贴片
使用50重量份的丙烯酸2-乙基己酯作为单体(a)、10重量份的N-羟基乙基丙烯酰胺作为单体(b)和40重量份的N-乙烯基-2-吡咯烷酮作为单体(c),除此以外,以与实施例1相同的方式得到丙烯酸类共聚物(2-EHA/HEAA/N-VP=50/10/40)。以与实施例1中相同的方式以丙烯酸类共聚物制备用于形成粘接剂层的组合物,然后制备贴片。
[比较例1]贴片
除了使用丙烯酸羟乙酯(此后可以称为″HEA″)代替实施例1中作为单体(b)的N-羟基乙基丙烯酰胺得到丙烯酸类共聚物(2-EHA/HEA/N-VP=70/10/20)以外,以与实施例1相同的方式以丙烯酸类共聚物制备用于形成粘接剂层的组合物,然后制备贴片。
[比较例2]贴片
使用50重量份的丙烯酸2-乙基己酯作为单体(a)、30重量份的N-羟基乙基丙烯酰胺作为单体(b)和20重量份的N-乙烯基-2-吡咯烷酮作为单体(c);并且以异丙醇作为溶剂,除此之外以与实施例1相同的方式得到丙烯酸类共聚物(2-EHA/HEAA/N-VP=50/30/20)。除了使用0.5重量份的铝螯合剂交联剂(ALCH)作为交联剂以外,以与实施例1中相同的方式以丙烯酸类共聚物制备用于形成粘接剂层的组合物,然后制备贴片。
[比较例3]贴片
使用72重量份的丙烯酸2-乙基己酯作为单体(a)、3重量份的丙烯酸(此后称为″AA″)用于代替单体(b)和25重量份的N-乙烯基-2-吡咯烷酮作为单体(c),除此以外,以与实施例1相同的方式制备丙烯酸类共聚物(2-EHA/AA/N-VP=72/3/25)。以与实施例1中相同的方式以丙烯酸类共聚物制备用于形成粘接剂层的组合物,然后制备贴片。
测定上面提到的实施例1和2以及比较例1-3的每种贴片的粘接剂层的凝胶分数。另外,测量每种贴片的粘接强度、保持强度、滚球粘性值(ball tack value)和恒定负荷剥离强度(constant-load releasingstrength),并且对贴片进行管可固定性测试。应当注意的是测量“保持强度”作为粘接剂的粘结强度的指标,且“滚球粘性值”用作在贴片开始贴附于皮肤时,当外部负荷施加于支撑体的暴露表面时贴片是否难以从皮肤上脱落的指标。另外,测量“恒定负荷剥离强度”作为贴附性能的指标。上述评价被认为是当固定医用管等时固定强度的替代评价,当贴片贴附于皮肤时可固定性的替代评价,等等。当评价的结果较好时,该贴片比例如医用胶带的贴片更为优异。下面描述了测量上述凝胶分数的方法,测量和评价粘接强度等的方法,和用于管可固定性测试的方法。
<凝胶分数>
(1)实施例和比较例的每种贴片切成具有9cm2的面积的样品,然后测量其粘接剂层的重量(W1)。接着,上述样品贴附于四氟乙烯树脂(PTFE)多孔膜(由NITTO DENKO CORPORATION制造,商品名:″TEMISH″),然后所得物浸泡在100mL乙酸乙酯中72小时。
(2)将样品从乙酸乙酯中取出并干燥,然后测量其粘接剂层的重量(W2)。接着,由下列的方程计算凝胶分数:
凝胶分数(wt%)=(W2×100)/(W1×A/B)
其中A代表丙烯酸类共聚物和交联剂的重量,和B代表丙烯酸类共聚物、增塑剂和交联剂的重量。
<粘接强度>
(1)实施例和比较例的每种贴片切成具有12mm的宽度。由此,制备测试片。使用以注入丙酮的干净废液洗涤的干净胶木板作为粘附体。
(2)将每种上述测试片轻轻地贴附于上述粘附体,然后通过用2kg滚筒从上方滚压测试片两次而贴附于上述粘附体。所得物在23℃下保存30分钟。
(3)在温度为23℃和相对湿度为65%的测量环境中使用拉力测试机在拉伸速度为300mm/min和剥离角为180°的条件下测量剥离强度[N/12mm]。
(4)为了证实每张测试片的粘接剂具有充分的粘结强度,在测量剥离强度后观察粘附体上存在或不存在粘接剂残余物。
<保持强度>
(1)将实施例和比较例的每种贴片切成测量为10mm宽×50mm长的尺寸制备测试片。使用以注入丙酮的干净废液洗涤的干净胶木板作为粘附体。
(2)将离型衬底从上述每张测试片上剥离,然后通过使2kg滚筒以往复运动的方式滚动一次而使剩余物贴附在上述粘附体上,从而具有测量为10mm宽×20mm长的粘附面积。所得物在40℃下保存20分钟。
(3)将上述粘附体在温度为40℃的环境中垂下,并且将300g的负荷施加在上述测试片的游离端,然后使所得物静置。在施加上述负荷后,测量测试片从粘附体上脱落所需的时间。
<滚球粘性值(Ball tack value)>
(1)根据日本工业标准(JIS)Z0237测量滚球粘性值,在此测试中,为了样品方便起见,通过将实施例和比较例的每种贴片冲裁成测量为50mm宽×50mm长的尺寸而得到的产品用作测试片。
(2)在温度为23℃和相对湿度为65%的条件下以暴露其粘接剂表面的方式将测试片置于倾斜角为30°的滚球装置上。然后,固定测试片使得在测试片和入口部之间没有步长差异(step difference)。接着,具有不同直径的球在测试片上滚动,然后将停止5秒以上时的最大直径(球编号)规定为该测试片的滚球粘性值。
<恒定负荷剥离强度>
(1)将实施例和比较例的每种贴片切成测量为12mm宽×70mm长制备测试片。使用通过在带有双面胶带的以注入丙酮的干净废液洗涤的干净胶木板上贴附脱脂的拉伸的胶原膜得到的板作为粘附体。
(2)将离型衬底从上述测试片上剥离,然后通过使2kg滚筒以往复运动的方式滚动一次而使剩余物贴附在上述粘附体上。剥离贴附的测试片的一个末端使其具有20mm的长度,然后将用于悬挂负荷的夹具贴附在剥离的测试片的中央(离该末端10mm远的位置)。以夹具为弯曲线折叠剥离的测试片,然后将所得的各部分粘接剂层彼此贴附。在所得物以23℃保存30分钟后,以粘附体与底面水平的方式将粘附体放置在测量装置中,并将测试片置于粘附体下方。将15g的负荷施加于用于悬挂上述测试片的负荷的夹具上。从施加负荷开始经过1小时后,测量移动距离,然后计算移动速度[mm/min]。
<管可固定性测试>
(1)实施例和比较例的每种贴片冲裁成测量为12mm宽×55mm长的样品。直径为5mm,壁厚度为1mm和长度为70mm的橡胶管弯曲成U形,然后固定在志愿者的上臂部上,同时上述样品之一覆盖该管以便与该管的两个部位相交。固定后,测量橡胶管从皮肤上脱落所需的时间。
(2)橡胶管从皮肤上脱落所需的时间为8小时以上的情况评价为○,时间为1小时以上且小于8小时的评价为△,并且时间小于1小时的评价为×。
在表1中表示述测量和评价的结果。
[表1]
如表1中所示,与在其粘接剂层中含有由含有代替HEAA的HEA的单体组分得到的丙烯酸类共聚物的比较例1或在其粘接剂层中含有由含有大量HEAA的单体组分得到的丙烯酸类共聚物比较例2的贴片相比,在其粘接剂层中含有由含有特定量的2-EHA和HEAA的单体组分得到的丙烯酸类共聚物的实施例1和实施例2的贴片具有高粘接强度,高保持强度和高滚球粘性值,并且在恒定负荷剥离强度和管可固定性方面是优异的。那些特征接近于在其粘接剂层中含有由含有3重量份的AA的单体组分得到的丙烯酸类共聚物的比较例3的贴片的特征。
[实施例3]贴片制剂
(1)普拉克索作为药物,相对于100重量份(固体含量)的丙烯酸类共聚物以5.3重量份的量加入实施例1的贴片的制备中使用的丙烯酸类共聚物溶液中。此外,棕榈酸异丙酯(IPP)作为有机液体组分,相对于100重量份(固体含量)的丙烯酸类共聚物以72.7重量份的量加入该混合物中。由此制备用于形成粘接剂层的组合物。应该注意的是,如下式(III)中所示,普拉克索在其分子中具有一个伯氨基和一个仲氨基。
(2)用敷料器在由厚度为75μm的聚对苯二甲酸乙二醇酯(PET)膜制成的离型衬底的剥离表面上涂敷上述用于形成粘接剂层的组合物,然后以80℃干燥5分钟。之后,将厚度为25μm的PET膜作为支撑体贴附在所得物上。由此制备贴片制剂(未交联的)。
[比较例4]贴片制剂
(1)在惰性气体气氛中,在乙酸乙酯中加入72重量份的丙烯酸2-乙基己酯、25重量份N-乙烯基-2-吡咯烷酮、3重量份的丙烯酸和0.2份的偶氮二异丁腈,然后将内容物混合。混合物以60℃进行溶液聚合。由此,得到丙烯酸类共聚物(2-EHA/AA/N-VP=72/3/25)的溶液(固体含量:28重量%)。
(2)与在实施例3中一样,使用上述丙烯酸类共聚物(未交联的)的溶液制备含有普拉克索作为药物的贴片制剂。
<药物渗透性的评价>
对实施例3和比较例4贴片制剂评价其药物渗透性。即,从无毛小鼠切除的皮肤安放在垂直扩散池中,每种上述贴片制剂置于供池中,生理盐水置于受池中。一部分受池液体以预定的时间间隔回收,然后通过高效液相色谱(HPLC)测定已经渗透的普拉克索的量。HPLC在下列的条件下进行。
(HPLC测量条件)
柱:TSK-凝胶ODS-80Ts QA(5μm,150×4.6mm I.D.;TOSOH)
流动相:1%三乙胺水溶液(pH 7.0)/甲醇(80∶20)
柱温度:40℃
流速:0.7mL/min
检测器:UV吸收计(测量波长为262nm)
图1表示药物渗透性评价的结果。如从图1中可得,在实施例3的贴片制剂中观察到普拉克索充分地渗经皮肤。相反,在其粘接剂层中含有由含有3重量份的AA的单体组分得到的丙烯酸类共聚物的比较例4的贴片制剂中,普拉克索的皮肤渗透性差,并且在48小时后的累积渗透量约为实施例3的贴片制剂的累积渗透量的一半。
如上所述,本发明提供了下列的贴片和贴片制剂。即,每种贴片和贴片制剂具有充分的粘结强度,并且在剥离时不引起粘接剂残留,显示对皮肤良好的粘接性,和对皮肤的刺激性小,并且具有柔软的贴附感。另外,当含有药物等时,其变性等可以被抑制。因此,本发明的贴片和贴片制剂特别适合于例如保护皮肤和经皮施用药物的目的。
在不背离本发明的范围和精神的前提下,许多其他的变型对于本领域技术人员是显而易见的并且是容易实施的。因此应当理解附带的权利要求的范围不应受到本说明书的内容的限制而应该广义地得到解释。
Claims (4)
1.一种贴片制剂,包括支撑体和所述支撑体的至少一个表面上的粘接剂层,其特征在于:
所述粘接剂层含有能够经皮给药的药物和丙烯酸类共聚物,所述丙烯酸类共聚物通过将含有(a)至少一种(甲基)丙烯酸烷基酯单体、(b)至少一种N-羟基烷基(甲基)丙烯酰胺单体和(c)至少一种选自乙烯醚单体和含有带氮原子的杂环的乙烯基单体中的乙烯类单体的单体组分共聚得到;
所述(甲基)丙烯酸烷基酯单体(a)的含量相对于所述单体组分的总量为50重量%~90重量%,所述N-羟基烷基(甲基)丙烯酰胺单体(b)的含量相对于所述总量为1重量%~20重量%,并且所述乙烯类单体(c)的含量相对于所述单体组分的总量为1重量%~40重量%;并且
所述单体组分实质上不含有带羧基的单体。
2.如权利要求1所述的贴片制剂,其特征在于:
所述粘接剂层还含有有机液体组分。
3.如权利要求1所述的贴片制剂,其特征在于:
所述粘接剂层是交联的。
4.如权利要求1~3中任一项所述的贴片制剂,其特征在于:
所述(甲基)丙烯酸烷基酯单体中,至少一个单体选自丙烯酸丁酯、甲基丙烯酸丁酯、丙烯酸2-乙基己酯、甲基丙烯酸2-乙基己酯、丙烯酸环己酯和甲基丙烯酸环己酯,并且,
所述乙烯醚单体和乙烯基单体中的至少一种中,至少一个单体选自甲基乙烯醚、乙基乙烯醚、N-乙烯基-2-吡咯烷酮、1-乙烯基己内酰胺、2-乙烯基-2-哌啶酮和1-乙烯基咪唑。
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- 2010-11-22 CN CN201010557610.3A patent/CN102070992B/zh active Active
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Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
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US6465004B1 (en) * | 1999-06-05 | 2002-10-15 | Noven Pharmaceuticals, Inc. | Solubility enhancement of drugs in transdermal drug delivery systems and methods of use |
CN1950474A (zh) * | 2004-04-27 | 2007-04-18 | 昭和电工株式会社 | 用于皮肤贴片的粘合剂及其制备方法 |
WO2009054106A1 (ja) * | 2007-10-22 | 2009-04-30 | Nitto Denko Corporation | 加熱発泡型再剥離性アクリル系粘着テープ又はシート |
Also Published As
Publication number | Publication date |
---|---|
CN102070992A (zh) | 2011-05-25 |
US20110123598A1 (en) | 2011-05-26 |
KR101860288B1 (ko) | 2018-05-21 |
JP5665116B2 (ja) | 2015-02-04 |
EP2324859A3 (en) | 2014-07-23 |
JP2011126865A (ja) | 2011-06-30 |
CA2721866C (en) | 2018-01-02 |
ES2572758T3 (es) | 2016-06-02 |
CA2721866A1 (en) | 2011-05-20 |
KR20110056250A (ko) | 2011-05-26 |
EP2324859A2 (en) | 2011-05-25 |
KR20180019012A (ko) | 2018-02-22 |
RU2010147422A (ru) | 2012-05-27 |
EP2324859B1 (en) | 2016-03-02 |
US8361493B2 (en) | 2013-01-29 |
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