CN1089469A - 用于持续释放药物的传送装置的二相基材 - Google Patents
用于持续释放药物的传送装置的二相基材 Download PDFInfo
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Abstract
一种用于含亲水药物的透过皮肤药物传送膏剂
的二相基材,其中一相是连续的疏水聚合物相,它任
意地包括用作皮肤渗透增强剂的疏水溶剂,另一相是
分散的颗粒化水合无机硅酸盐,药物溶解在其吸收的
水相中。
Description
本发明涉及控释和持续释放的药物配方,具体地涉及可用于作透过皮肤膏剂的组分的一种二相含药基材。
通常有二种透过皮肤膏剂设计:一种是“贮库”型,另一种是“基材”型。在贮库型中药物典型地是液态的,它系被包容在封闭的贮库中,其基部表面对药物是有渗透性的。在基材型中药物被分散在一种高分子层中,它典型地是一种粘合剂,并且该基材与皮肤直接触触。这二种装置均典型地包括一个背衬层及一种内侧的在使用前可被除去的释放衬垫层。
本发明涉及一种基材型装置,其中该基材包括一种含药的细颗粒水合亲水材料,并且确定至少部分基材基部的表面积。
有几个以前的专利述及了用于透过皮肤药物装置的二相基材。但所有的均与本发明的基材不同。
美国专利4,668,232叙述了一种用于透过皮肤膏剂的基材,其中包括一种不溶于水的粘合剂,溶于该粘合剂的药物,以及遇水溶胀的聚合物。据称包含入遇水溶胀的聚合物能增加药物从基材中的释放速率。
欧洲专利0391172叙述了具有一种由包含在水溶性/溶胀性聚合物的固体药物溶液所组成的孤立区域的水不溶性材料,以及用于能控制经由皮肤至基材的水蒸汽量的底层(underlayer)所组成的基材的一种透过皮肤膏剂。
美国专利4,559,222说明了一种透皮基材型膏剂,其中该基材由矿物油,聚异丁烯(一种粘合剂)和二氧化硅胶体所组成。据称二氧化硅的加入可影响矿物油-聚异丁烯混合物的流动性质。
美国专利5,071,657叙述了分散于交联聚硅氧烷的含药凝胶的透皮膏剂基材。由于该专利中使用了在其周围有分离的粘合层以将该膏药粘于皮肤,该基材显然不具有粘性。
欧洲专利0452837A2叙述了一种由疏水性的聚合物,亲水性的药物,亲水而可溶胀性聚合物,水,及渗透增强剂所组成的粘性基材。据说水是用作药物的增溶剂,而亲水可溶胀性聚合物的作用是便于各组分的混合及改善基材的稳定性。
本发明提供了一种新颖的基材,它由一连续的疏水区域及一分散的用于使亲水性药物持续释放的颗粒化水合硅酸盐所组成的区域。本发明允许亲水性药物在疏水相中有效地分散,保持药物与疏水相隔开以减少潜在的两者相互作用,并增强亲水药物从由连续疏水基材组成的区域中释放。
本发明的一个方面是含有以下部分所组成的基材的持续释药配方:
(a)一个连续的疏水聚合物相;
(b)分散于连续聚合物相的一个颗粒化相,它包括
(ⅰ)水合无机硅酸盐;
(ⅱ)至少部分溶于(ⅰ)的水相中的水可增溶性药物;以及
(c)用于将(b)分散于(a)的分散剂;
其中,颗粒化相确定了至少基材表面积的一部分,以提供基材中药物的扩散通道。
本发明的另一方面是一种含有层压复合材料的透皮膏剂:
(a)背衬层;及
(b)上述的基材层,其中连续的疏水聚合物相是压敏性的粘合剂。
本发明的再一个方面是一种基材,包括
(a)一连续的疏水聚合物相;
(b)一个分散于连续聚合物相的颗粒化相,它包括水合无机硅酸盐和水相;以及
(c)用于将(b)分散于(a)的分散剂
其中,颗粒化相确定了至少部分基材的表面积,以提供基材中能被水增溶的活性组分的扩散通道。
附图是包含有本发明基材配方的透皮膏剂的纵向剖示图(不按尺寸比例)。
关于连续相,在此所用的术语“疏水的”表明该材料在32℃经24小时在水中溶解少于20%(重量)。
在此所用的术语“基本不溶的”表明其溶解度低于约1%(重量),更通常是低于约0.5%(重量)。
在此所用的术语“连续的”表明该相是内部连接的且未分成截然不同的区域,节段,或颗粒。
关于药物,在此所用的术语“亲水的”和“水溶性的”其含义相当于或提示该药物的水溶解度在32℃至少约0.1mg/L,优选至少约1mg/L。
术语“水合的”表明分散的颗粒化材料其吸收的水相(即水相和/或极性溶剂相)占了所有吸收能力的全部或一部分。
术语“持续释放”表明了一种能够在一段时间(1-7天)中释放治疗有效量药物的配方。
组成基材的连续相或疏水区域的材料是能够被与基材的其它组分相混合并形成层或膜的疏水性聚合物。当将该基材用于透皮膏剂的含药基材时,要优选该疏水聚合物具有压敏粘着性质,以使基材粘于活人皮肤经过一段持续时间,即通常至少约1-7天。因为该聚合物是疏水性的,所以在聚合物中药物是基本上不溶解并不混溶的。可用作基材连续相的具体聚合物实例有聚硅氧烷类,聚异丁烯,溶剂基础的疏水性聚丙酸酯类,聚氨基甲酸酯类,增塑的乙烯-乙酸乙烯酯共聚物,低分子量的聚醚嵌段酰胺共聚物,苯乙烯-丁二烯聚合物,以及乙酸乙烯酯为基础的粘合剂。正常地,疏水性基质约占基材重量的30-95%,更通常为重量的40-60%。其它的疏水材料如溶剂或渗透增强剂也可包含在基材的疏水区域中。这些材料的实例有脂肪酸(油酸及硬脂酸),肉豆蔻酸异丙酸(IPM),脂肪酸酯(如,单月桂酸丙二醇酯,聚单月桂酸乙二醇酯(PEGML),油酸甲酯,油酸油酯),脂肪醇(如,油醇),以及萜类化合物(苎烯,薄荷醇,β-蒎烯,及牦牛儿醇)。
被分散的无机硅酸盐以颗粒形式,典型地该颗粒的非胶体大小范围为0.001-0.1mm(最大直径),更通常地是0.01-0.05mm。该材料在其水合态正常地吸收有其本身重量15%-600%的水,更通常地为吸收本身重量的100-500%(25℃下测量)。其它的亲水极性溶剂如乙醇,丙二醇,低分子量(200-400mw)聚乙二醇,异丙醇,正丁二醇,m-pyrol及苄基醇,可用于代替水或包含在基质的亲水区域中。这些溶剂可用以增加药物在被吸收的水相中的溶解性。水合的硅酸盐应在基材其它组分的存在下保持稳定并不与其发生不良的相互作用。硅酸盐相的填充量及粒径应足以使由相的水性组分所确定的扩散通道,它系被从基材中扩散出来的药物面能达到基材的表面。换言之,在分散相中,基本上是颗粒对颗粒地接触。未水合的硅酸盐正常地约占基质重量的2-20%,更通常地为重量的4-10%。该硅酸盐可是合成的,纯化而得的,或以自然形式(即粘土或滑石粉)。优选的是硅酸钙、镁和铝,及其混合物。具有高的水和油吸收性能的硅酸钙(即,>400%(重量))是特别优选的。
颗粒化的水合硅酸盐被均一地分散于整个基材中,并确定了基材表面积的一部分。该部分应足够大以提供药物从基材中的理想地流出。当该基材是粘性的并设计为粘附于皮肤,则该部分不应太大以避免基材对皮肤缺乏足够的粘性。通常由水合硅酸盐所确定的表面积部分其范围为约0.1-20%,更通常地为0.5-10%。
可在本发明的基材中使用的药物是亲水性的,并能溶于水合硅酸盐的水性组分中。相应地,药物基本不溶于基材的疏水性聚合物组分中,因此没有显著量的药物溶于那种聚合物中。本发明基材中药物的量将决定于本发明基材中水性组分的量及在那种组分中药物的溶解度。正常地可有基质重量的1-20%。在基材的水性组分中药物的浓度应处于或低于其饱和度。
可在本发明基材中使用的亲水性药物例如是但不限于,尼卡地平盐酸盐,甲基水杨酸,硝酸甘油,亲水的5-羟色胺5-HT3受体拮抗剂如ondansetron(商品名为20FRAN)及granisetron,氨基1,2,3,4-四氢化萘如S(-)-2-(正丙基-N-2-噻吩基乙氨基)-5-羟基-1,2,3,4-四氢化萘,以及公开于欧洲专利申请公报No.0452837A2(申请号No.91105933,5)中第4-6页的那些药物。
基材也可含有助于保持颗粒化相分散于连续相中的分散剂。阳离子型、阴离子型、两性的或非离子型分散均可使用。优选地,该分散剂是一种非离子型表面活性剂。这些分散剂例如是聚乙烯-聚氧丙二醇共聚物(商品名为Pluronic),聚氧乙烯脱水山梨醇酯(商品名为吐温(Tween))如聚氧乙烯脱水山梨醇单月桂酸酯,聚氧乙烯脱水山梨醇单棕榈酸酯,聚氧乙烯脱水山梨醇单硬脂酸酯,以及聚氧乙烯脱水山梨醇单油酸酯,和脱水山梨醇酯(商品名为Span)如单月桂酸脱水山梨醇酯,单硬脂酸脱水山梨醇酯,及单油酸脱水山梨醇酯。正常地分散剂约占基质重量的0.5-10%,更通常地占基质重量的3-6%。
本发明基材的制备可以通过将药物溶于水或任意其它的亲水极性溶剂中,然后将亲水性颗粒化材料与生成的溶液相接触,以使水溶液被颗粒化材料吸收。该混合物典型地具有糊剂的结构。将基材的疏水组分和分散剂,优选以混合形式,加入至糊剂中并伴有剧烈混合以形成一粘滞的悬浮液。可将该分散物形成适宜的外形并除去过量的溶剂。当该基材是透过皮肤或面颊吸收膏剂的组成部分,疏水区域通常地具有压敏粘性,该基材被以薄层或膜形式浇铸于背衬层上。用于背衬层的材料在透过皮肤膏剂行业技术领域是被熟知的,并在有关透过皮肤膏剂的专利文献中可得到充分地说明。典型的,该膏剂包括一层在使用前除去支暴露基材的基部释放衬垫层。一种简单且典型的透过皮肤膏剂结构,通常在图1中,10所示,其中11示意为背衬层,12为基材层,13为释放衬垫层。
除了在透过皮肤及面颊吸收膏剂中用作一种组分,本发明的基材也可制成含药的片剂用于口服或插入体内腔道或植入组织内以释放药物。
本发明将通过下列实施例而得到进一步说明。这些实施例未以任何形式限定本发明。除非有相反的说明,百分比均以重量计。
实施例1
药物配方
一种由在聚二甲基硅氧烷粘合剂(Dow Corning Silicone 2920)中4%亲水性药物(R)-(-)-N-(1-甲基-4-(3-甲苄基)六氢-1H-1,4-二氮杂草-6-基)-1H-吲唑-3-甲酰胺二盐酸盐,10%丙二醇单月桂酸酯(PGML),20%丙二醇,20%蒸馏水,7%硅酸钙粉末(Micro-Cel E)和2%非离子型表面活性剂(Pluronic L-121)所组成的基材,其制备是通过将药物溶于PG和水中,将该溶液与硅酸钙粉末混合以生成一糊剂,并将该粘剂与含粘合剂、PGML和表面活性剂的混合物剧烈混合,生成一粘稠的悬浮液。
将该悬浮液例在25微米厚的聚酯膜(购于ICI的涂有聚硅氧烷的Melinex 329)上,并用Gardener刮刀使其厚度达到250微米,然后在70℃的炉上将该组合物干燥30分钟以除去过量的溶剂。冷却后,将该组合物层压于75微米厚的聚酯背衬(3M,1022)上。
为了比较,将药物配方于不同的单相基材并制成上述的层压组合物。
皮肤流出试验
从在分离前预先冰冻的完整厚度皮肤上分离人类表皮。在真皮/表皮结合处分离表皮,其方法是通过将皮肤浸于60℃水中2分钟,然后撕去真皮。将热分离后的表皮贮于20℃待用。
使用具有扩散面积0.71cm2及接受液8.0ml的垂直调整好的扩散室。选用pH5.0磷酸盐缓冲液作为接受液以保证维持无限的沉降条件,因为该缓冲液对药物显示了相当的可溶性。在30小时的一段时间内进行皮肤流出的研究。
将一块1 3/4 cm直径的分离表皮冲压并固定在扩散室中,使其角质层面向给予单元。将层压后的组合物冲压成1 3/4 cm直径圆形。从聚酯膜的释放一侧剥离后,然后将药物基材固定在扩散室的二单元之间。
经过一预定时间后,用微量移液管从给定的扩散室的接受单元中取出1ml样品。在接受室中加入相当量的接受液以维持其体积恒定。在处理渗透数据时将接受介质的稀释考虑在内。下表1报告了这些皮肤流出试验的结果。所报告的流出是30小时间的平均流出。
表1
配方 皮肤流出(μg/cm/hr)
单相对照
2%药物于聚硅氧烷2920粘合剂中 0
2%药物于Morstix 6071粘合剂中 0
2%药物于Gelva 7892粘合剂中 0
2%药物,10% PGML,10% m-Pyrol 0.5
于聚硅氧烷2920粘合剂中
2%药物,10% PGML,10% m-Pyrol 0
于Morstix 607粘合剂中
4%药物,20%PGML,20% m-Pyrol 0.8
于Kraton 36-61721粘合剂中
二相
4%药物,10% PGML,20% PG 17.1
20%蒸馏水,7%硅酸钙
2% Pluronic L-121于聚硅氧烷2920粘
合剂中
1 Morstik 607是一种丙烯酸酯粘合剂。
2 Galva 788是一种丙烯酸酯粘合剂。
3 Kraton 36-6172是苯乙烯-丁二烯共聚物粘合剂。
如表1所示,从本发明的二相基材中的药物到肤流出大大超过从测试的任何对照单相基材中的皮肤流出。
实施例2-6
这些实施例所说明的是实施例1二相基材配方的变化形式。这些基材的制备与测试与实施例1相同。下表2具体提供了这些基材的组成及其皮肤流出试验的结果。
表2
实施例 配方 皮肤流出
(μg/cm/hr)
2 4%药物,10% PGML,30% PG 15.7
20%蒸馏水,7%硅酸钙,3%
Pluronic L-121于聚硅氧烷2920
中
3 4%药物中,15% PGML, 9.1
20% PG,10%蒸馏水,7%硅酸
钙,3% Pluronic L-121于药物
2920中
4 6%药物,6% PGML,30% PG, 20.4
20%蒸馏水,7%硅酸钙,3%
Pluronic L-121于聚硅氧烷2920
中
5 6%药物,6% PGML,50% PG, 23.9
20%药物,8%硅酸钙,3% Pluronic
L-121于聚硅氧烷2920中
6 6%药物,12% PGML,30% PG, 25.7
26%药物,8%硅酸钙 E,3%
Pluronic L-121聚硅氧烷2920中
实施例7-8
这些实施例说明了与实施例1-6相似的二相基材配方但使用不同的硅氧烷粘合剂(Dow Corning 4201)。该基材的制备和测试与实施例1相同。下表3具体提供了这些基材的配方及其流出试验的结果。
表3实施例 配方 皮肤流出
(μg/cm2/hr)
7 4%药物,15% PGML,30% PG 12.0
10%蒸馏水,7%硅酸钙,3%
Pluronic L-121于聚硅氧烷4201
中
8 2%药物,5% PGML,30% PG 5.4
20%蒸馏水,7%硅酸钙,3%吐温
于聚硅氧烷4201中
实施例9-12
这些实施例说明的基材与实施例1相似但其疏水溶剂不是PGML。该基材配方由在聚二甲基硅氧烷粘合剂中4%药物、20%PG、15%蒸馏水、7%硅酸钙、2%吐温80表面活性剂及指定%量的疏水溶剂组成。基材的制备与测试与实施例1相同。下表4具体提供了组分及疏水溶剂的量,及其皮肤流出试验结果。
表4实施例 疏水 皮肤流出
溶剂 (μg/cm2/hr)
9 12% PEGML,3% IPM 6.4
10 10% 油酸油酯 2.1
11 10% 油酸 2.0
12 10% 油醇 9.6
实施例13-14
这些实施例说明的基材与实施例1相似,但使用的硅酸盐不是硅酸钙(Mico-cellE)。这些基材的制备和测试实施例1相同。下表5具体提供了这些基材的组份及其皮肤流出试验结果。
表5实施例 配方 皮肤流出
(μg/cm/hr)
13 2%药物,5%油醇,20% PG,15% 2.1
蒸馏水,1%滑石粉,3%吐温80,
于聚硅氧烷4201中
14 2%药物,5%油醇,20% PG,15% 1.2
蒸馏水,1%高岭土,3%吐温80于
聚硅氧烷4201中
实施例15
S(-)-2-(N-丙基-N-2-噻吩乙氨基)-5-羟基1,2,3,4-四氢化萘是用于治疗帕金森氏病的选择性D2拮抗剂。估计治疗帕金森氏病的有效剂量是约1-3μg/kg/hr。相应地,当透皮使用时,该药物应达到的流出量估计约在3-10μg/cm2/hr范围内(根处传送面积为20cm2)
从不同液态配方的药物皮肤流出研究表明,有效范围内或更高的流出可以从药物在pH6.0缓冲液或PGML中的饱和溶液得到。该药物从简单的基材系统,即药物和PGML被配方于不同的粘合剂中(聚硅氧烷,聚异丁烯,或Morstic 607丙烯酸酯)中,相似的流出研究表明它们不能提供有效的流出水平。
形成对照的是,按本发明制备一系列5个二相基材配方。下表6列出了这些基材的组分及其流出试验结果。
表6基材 1 2 3 4 5 6 7 8 皮肤流出
(μg/cm2/hr)
A 2 10 5 5 10 4 3 61 6.41±0.13
B 4 10 5 5 10 4 3 59 14.2±0.6
C 4 0 5 5 10 4 6 66 8.66±0.19
D 4 5 5 5 10 4 5 62 15.5±0.19
E 4 10 5 5 10 2 3 61 13.7±1.2
1=药物(%)
2=PGML(%)
3=苄醇(%)
4=PG(%)
5=pH6.0磷酸缓冲液(%)
6=硅酸钙(%)
7=Span 60乳化剂(%)
8=聚硅氧烷4101粘合剂(%)
如上指明,这5个二相基材所提供的流出量均处于或高于需达到的水平。
实施例16
基于实施例15的结果,进一步完善了二个S(-)-2-(N-丙基-N-噻吩乙氨基)-5-羟基1,2,3,4-四氢化萘的配方。这些配方中没有PGML,苄醇或PG。一个在聚硅氧烷4201粘合剂中含有4%药物,20%磷酸缓冲液(pH6.0),4%硅酸钙(Micro-Cell E,4%山梨糖醇酯(Span)60乳化剂,及4%聚硅氧烷药用流体360(Dow Coming)。另一个是在聚硅氧烷4201粘合剂中含有5%药物,18%缓冲液,5%硅酸钙,4%山梨糖醇酯60乳化剂,及4%聚硅氧烷药用流体360。从这些配方中的流出量与从实施例15的基材B、D、E中的是相当的。
凡是在完成本发明时对上述模式作出对那种药剂、持续释放配方、透皮药物传送、聚合物、压敏粘合剂、及相关领域的技术人员显而易见的修改,均被认为属于下列权利要求的范围之内。
Claims (16)
1、一种持续释放药物配方,其特征在于:它包含具有下列组成的一种基团:
(a)一种连续的疏水聚合物相;
(b)一种分散于连续聚合物相的颗粒化相,包括
(i)水合的无机硅酸盐;
(ii)至少部分溶于(i)的水相的水增溶性药物;及
(c)用于将(b)分散于(a)的分散剂;
其中,颗粒化相确定了至少一部分的基材表面积,并为基材中的药物提供了扩散通道。
2、如权利要求1所述的持续释放药物配方,其特征在于:其中,药物占基材重量的1-20%,无机硅酸盐(未水合)占基材重量的2-20%,疏水聚合物相占基材重量的30%至约95%。
3、如权利要求1或2所述的持续释放药物配方,其特征在于:其中水合的无机硅酸盐在其吸收的水相中含有其本身重量的15-600%。
4、如权利要求2所述的持续释放药物配方,其特征在于:其中水合的无机硅酸盐在其吸收的水相中含有其本身重量的100-500%。
5、如权利要求1所述的持续释放药物配方,其特征在于:其中水合的无机硅酸盐是硅酸钙,硅酸镁,硅酸铝,或其混合物。
6、如权利要求1-5之一所述的持续释放药物配方,其特征在于:其中所述的表面积部分为基材表面积的0.1-20%。
7、如权利要求1或2所述的持续释放药物配方,其特征在于:其中的疏水聚合物相包括疏水溶剂。
8、如权利要求7所述的持续释放药物配方,其特征在于:其中疏水溶剂是皮肤渗透增强剂。
9、如权利要求7或8所述的持续释放药物配方,其特征在于:其中疏水溶剂是脂肪酸,脂肪酸酯,脂肪醇,或萜类。
10、如权利要求1-5之一所述的持续药物释放配方,其特征在于:其中水合的无机硅酸盐包括吸收有一种能增进药物的水溶解度的极性溶剂。
11、如权利要求10所述的持续药物释放配方,其特征在于:其中极性溶剂是乙醇,丙二醇,低分子量的聚乙二醇,异丙醇,正丁二醇,m-pyrol,或苄醇。
12、如权利要求1或2所述的持续药物释放配方,其特征在于:其中药物是(R)-(-)-N-(1-甲基-4-(3-甲苄基)六氢-1H-1,4-二氮杂草-6-基)-1H-吲唑-3-甲酰胺二盐酸盐,ondansteron,granisetron,或S(-)-2-(N-丙基-N-2-噻吩乙氨基)-5-羟基1,2,3,4-四氢化萘。
13、如权利要求2-5之一所述的持续释放药物配方,其特征在于:其中水合无机硅酸盐是硅酸钙,疏水聚合物是聚硅氧烷,配方中包括丙二醇和单月桂酸丙二醇酯,药物是(R)-(-)-N-(1-甲基-4-(3-甲苄基)六氢-1H-,4-二氮杂草-6-基)-1H-吲唑-3-甲酰胺二盐酸盐或S(-)-2-(N-丙基-N-2-噻吩乙氨基)-5-羟基1,2,3,4-四氢化萘。
14、一种透皮膏剂,其特征在于:它含有具下列组成的层压复合物:
(a)背衬层和
(b)一层如前述权利要求(1-13)之一的配方物层,其中连续的疏水聚合物相是压敏粘合剂。
15、一种基材,其特征在于:它包括
(a)一连续的疏水聚合物相;
(b)一分散于连续聚合物相的颗粒化相,它包括水合的无机硅酸盐和水相;以及
(c)用于将(b)分散于(a)的分散剂;
其中颗粒化相确定了至少部分的基材表面积,并为基材中水增溶性的活性组分提供了扩散通道。
16、一种如权利要求15所述基材的用途,其特征在于:它被用于制备持续释放药物配方中。
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US08/056,076 US5989586A (en) | 1992-10-05 | 1993-04-30 | Two-phase matrix for sustained release drug delivery device |
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- 1993-10-05 JP JP6509398A patent/JPH08504757A/ja active Pending
- 1993-10-05 AT AT93923258T patent/ATE198420T1/de not_active IP Right Cessation
- 1993-10-05 ES ES93923258T patent/ES2155073T3/es not_active Expired - Lifetime
- 1993-10-05 CN CN93118244A patent/CN1089469A/zh active Pending
- 1993-10-05 DK DK93923258T patent/DK0662822T3/da active
- 1993-10-05 AU AU53211/94A patent/AU5321194A/en not_active Abandoned
- 1993-10-05 CA CA002145631A patent/CA2145631C/en not_active Expired - Lifetime
- 1993-10-05 DE DE69329825T patent/DE69329825T2/de not_active Expired - Lifetime
- 1993-10-05 WO PCT/US1993/009510 patent/WO1994007468A1/en active IP Right Grant
- 1993-10-05 PT PT93923258T patent/PT662822E/pt unknown
- 1993-10-05 EP EP93923258A patent/EP0662822B1/en not_active Expired - Lifetime
- 1993-10-27 TW TW082108949A patent/TW252919B/zh active
-
1995
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2001
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Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
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CN100457095C (zh) * | 2001-05-08 | 2009-02-04 | 施瓦茨制药有限公司 | 用于治疗帕金森氏病的改良经皮治疗系统 |
CN102172351B (zh) * | 2001-05-08 | 2013-07-17 | 优时比制药有限公司 | 引起高罗替高汀血浆水平的用于治疗帕金森氏病的透皮治疗系统 |
Also Published As
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GR3035626T3 (en) | 2001-06-29 |
AU5321194A (en) | 1994-04-26 |
US5840336A (en) | 1998-11-24 |
CA2145631A1 (en) | 1994-04-14 |
US5989586A (en) | 1999-11-23 |
PT662822E (pt) | 2001-04-30 |
JPH08504757A (ja) | 1996-05-21 |
DK0662822T3 (da) | 2001-01-29 |
EP0662822A4 (en) | 1996-08-07 |
DE69329825T2 (de) | 2001-06-13 |
TW252919B (zh) | 1995-08-01 |
CA2145631C (en) | 2004-02-10 |
WO1994007468A1 (en) | 1994-04-14 |
DE69329825D1 (de) | 2001-02-08 |
EP0662822B1 (en) | 2001-01-03 |
ATE198420T1 (de) | 2001-01-15 |
EP0662822A1 (en) | 1995-07-19 |
ES2155073T3 (es) | 2001-05-01 |
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