CN1194672C - 包括有效精神安定性药物的穿皮治疗系统 - Google Patents
包括有效精神安定性药物的穿皮治疗系统 Download PDFInfo
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- CN1194672C CN1194672C CNB008065683A CN00806568A CN1194672C CN 1194672 C CN1194672 C CN 1194672C CN B008065683 A CNB008065683 A CN B008065683A CN 00806568 A CN00806568 A CN 00806568A CN 1194672 C CN1194672 C CN 1194672C
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- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
一种穿皮治疗系统，其包括一衬背层；含至少一活性物质的基质层，其可同时含有压力敏感性粘着性质；以及一可脱除的保护层；该系统的特征在于含有精神安定性药物，至少一种渗透增强剂以及一面对皮肤侧的压力敏感性粘着性且以纯烃类聚合物为基质的层。
Description
羟哌氟丙嗪(Fluphenazine)是一种三环，非常强效性羟哌氯丙嗪(perphenazines)族中的精神安定剂。这些物质拥有抗精神病作用-特别是在精神分裂性精神病的情况中-而不会实地影响到知觉与智慧功能。其典型的每日口服剂量为3-6毫克，在医院治疗情况下则高达24毫克(参看MutschlerE.“Arzneimittelwirkungen”，6th edition，Wissenschaftliche VerlagsgesellschaftStuttgart 1991)。
其在血浆中的半衷期为15小时。对于静脉内治疗，可用酯形式，如癸酸酯和庚酸酯，各具有显著延长的半衷期。于口服治疗中系使用羟哌氟丙嗪的二盐酸盐(参看Rote Liste Win 1997/II Vers.2.4，ROTE LISTE Service GmbH，ECV Editio Cantor Verlag)。
患有精神分裂性精神病的病人的治疗性处理典型地需要长期，常为终生的恰当药物的给药。时常地，病人只有部分地或短暂地敏感的，使得经常不能达成在治疗中的主动配合。其结果，患者的独立摄入很不确定性。
本发明的目的因而为提出一种含羟哌氟丙嗪的穿皮治疗系统(TTS)，其可对人类皮肤释出至少1微克/平方公分·天之活性剂，因而将每日口服一次甚或数次改成一星期使用1至3次。
该问题可依下述而解决，亦即TTS包括一增强剂且具有一以纯烃聚合物为主的贴皮压力敏感性粘着层。
至今为止阻碍在相应的穿皮治疗系统发展者为羟哌氟丙嗪且特别是其盐的穿皮性非常低的事实。对于羟哌氟丙嗪二盐酸盐因而预期会因其盐构造及与其相连的疏水性部分而有对人皮肤的不良渗透性。就化合物本身而言，其有437,53Da的相当高分子量以及在分子中的立体固定三环。
在最大50平方公分的可接受的施用表面上达到每天数毫克的穿皮吸收因而可符合某些限制条件。
其结果在文献中不能找到有关符合实用需要且具有系统性作用的穿皮系统的说明。
反而，专利文献涉及羟哌氟丙嗪的TTS只述及具有某些物理化学性质(美国专利第5,474,783号)或添加剂(美国专利第5,120,545号)者，而没有对此种活性物质的具体实施例确立相关性。这些专利说明书只将羟哌氟丙嗪视为选自可能的活性剂的纯理论说明中的一种可能活性剂。
对于口服后的羟哌氟丙嗪药物代谢动力学的最近研究已发表(KoytchevR et al.：“Absolute Biovailability of oral immoaiate ana slow releasefluphenazine in healthy volunteers”，Eur，J.Clin.Pharmacol.1996；51：183-187)。其结果显示只有口服剂量2.5至3.5％的羟哌氟丙嗪可在血液中测得。
对于避开消化道及肝中的首通效应而直接给药到血流中的情况，如透过穿皮途径可做到者，因而使用典型采用的口服剂量的一部分是足够的。
典型穿皮每日剂量应可预期为90至180微克，于住院情况下则高达840微克。
所有的研究都是用羟哌氟丙嗪二盐酸盐(ICN Biorne-dicals Inc.Ohio，USA)来进行。此种物质形式为全世界正用于治疗目的，因而，与其游离碱形式相异者，可取得大量的毒物学和一般的相关文件。皮肤渗透性系使用完整厚度母牛乳房表皮及人类表皮在体外研究，后者系用热分离法从人类全厚度皮肤分离。
这些检验系在32℃下于适当的渗透装置中(改进型Franz小匣)进行，并使用适当的HPLC法测量所得样品中的羟哌氟丙嗪。所有显示出的值都是以n＝3个样品为基础。
在基质或粘着剂包药物(drug-in-adhesive)技术的架构内，于最初用以聚(甲基)丙烯酸酯为基的压力敏感性粘着剂膜作为基质来研究。
市售产品有Durotak 387-2051，Durotak 387-2287与Durotak 387-2353(National Starch and Chemical Co.)。
由于它们都具有良好的皮肤耐受性及低潜在的过敏化，这些压力敏感性粘着剂广泛地用于医疗产品中。
二盐酸盐几乎是不溶于所述聚合物中或加工所需的有机溶剂中。因此在所有情况中都要添加Eudragit E100(Rohm Phavma GmbH)。这种中性甲基丙烯酸酯和甲基丙烯酸二甲基氨基乙基酯的(甲基)丙烯酸酯共聚物在其侧链中具有三烷基氨基且能够起离子交换树脂的作用。于此方式中，羟哌氟丙二盐酸盐的氯离子系经结合到Eudragit E100而其质子同时被接受，而以某种平衡形式形成羟哌氟丙嗪的自由碱。有利者为至少有等摩尔比例的Endragit E100与羟哌氟丙嗪二盐酸酸，亦即，具有以氢氯化钾形式计算的相同当量的重量。聚合物的碱性添加剂如Eudragit E100的较佳含量相当于所含活性物质量的当量重量的0.5-1.5倍，以氢氧化钾表示。
使用此种方法，发现羟哌氟丙嗪二盐酸盐在Durotak 287-2051中有至少15重量％的惊人高溶解度；而对于Durotak 387-2287则仍然有至少10重量％。
即使如此，在母牛乳房皮肤上的渗透速率仍非常地低(实施例Flu1-Flu5，参看图1，比较表1)。
然而，不含羧基的Durotak 387-2287(参见实施例Flu5)经证明显著地优于含羧基的387-2051(参见实施例Flu3和Flu5)。由于它们所具有与羟哌氟丙嗪碱形成盐的能力，羧基明显地不利于羟哌氟丙嗪的释出。这种假设可经由在其他条件相同之下，用等摩尔量的氢氧化钾中和Durotak 387-2051予以证明(参见实施例Flu2与Flu4)。如此导致增加的渗透值，不过其仍然不能达到中性Durotak 387-2287的值。
整体而言，对于以聚(甲基)丙烯酸酯为基础的粘着剂基质所得结果显示出有高的羟哌氟丙嗪溶解度但同时有不良的释出。
因此，特别是所含活性物质的定量潜在效率非常地差。此项可经由添加剂而惊人地改良。通过添加脂肪醇2-辛基十二烷醇(Eutanol G)及添加脂肪酸油酸两者都可以显著地增加透过牛乳房皮肤的渗透性(参看图2，表2)。尤其是脂肪酸，其清楚地显示出正面效应，可能是其与羟哌氟丙嗪形成离子配对所致。这种离子配对复合物的良好皮肤渗透性对本技术领域熟练的人员是已知的。
因此在使用碱性辅助物质例如Eudragir E100同时使用酸性辅助物质例如油酸可得到明显优点，以聚(甲基)丙烯酸酯为基础的压力敏感性粘着剂显然不适用作为基质。
因而改进的原则可应用其它可能的粘着性基质。令人讶异地发现以纯烃为基础的聚合物基质(Oppanol B10与B100)可导致非常高度改良的透过母牛乳房皮肤的渗透率(参看图3，表3)。特别是在实验的早期阶度，于24和32小时后，相对于比较基质的显著优点即变得明显。因此以纯烃聚合物为基础的压力敏感性粘着剂调配物显示出较聚(甲基)丙烯酸酯且令人讶异地也较聚硅氧烷粘着剂(BioPSA Q7-4301，Dow Corning Chem.Co.)有明显的优点。
向皮肤侧的压力敏感粘着剂层优选基本由聚异丁烯或聚异戊二烯类的聚合物组成。一个具体实施方案提供由二至三层具有相同分子结构而只有平均分子量不同的聚合物组成的层。
特别是活性物质装载量(目前只有基质中活性剂量的5重量％，优选为0.5-5重量％)对活性物质渗透量比例和其潜在效率都有明显地改良。
于另一实验中，最后系在人类表皮上检测经最适化的调配物。所得数据显示出优良的渗透过程，具有短滞后时间(lagtime)及几乎线性特性(参看图4)。用等摩尔比的羟哌氟丙嗪，Eudragit E100与油酸(相对于以氢氧化钾计算的相应的当量重量)可达到最佳结果。增加油酸和Eudragit E100的两者比例都导致在各情况中更差的结果(参看图4，表4)。
可达到2.9微克/小时·平方分公的羟哌氟丙嗪碱最大流量。因此可以使用只有2至4平方公分尺寸的TTS即达到预期的90至180微克羟哌氟丙嗪的穿皮每日剂量(参阅上文)。即使是住院治疗所需的840微克/日的量也可以用小于20平方公分的系统穿皮地达到。
根据这些数据用羟哌氟丙嗪的穿皮治疗即变成可能。于本发明架构内也可能用到甚至惊人地小量TTSs。
本发明可促成以远低于口服所需量的剂量进行的羟哌氟丙嗪穿皮治疗。用羟哌氟丙嗪穿皮治疗不仅是一种可选用的给药形式，而且因为其所具较大的剂量相关效率，也提供较一般口服长期治疗的优点。
由于具有大化学相似性，等效药效作用，相类似的所需治疗剂量，及预期的药物代谢动力学相似性，本发明也应用于下列其它活性物质：
三氟丙嗪 与 三氟噻吨
于三氟噻吨的情况中，顺式异构体(α-三氟噻吨)因为具有较大的药物代谢动力学效力而为较佳者。
所含有的活性物质也可以是医药上可接受的盐，较佳为盐酸盐或二盐酸盐。
因此本发明特别有关于穿皮治疗系统，其包括一背层；含至少一种活性物质的基质层，其可同时具有压力敏感性粘着性质；以及一可脱除的保护层；利用这些系统可对人类皮肤达到至少1微克/平方公分·天选自羟哌氟丙嗪，三氟噻吨和三氟丙嗪的精神安定剂的释放速率。
本发明还有关于给需要用高效力精神安定剂治疗的患者施用该活性物质的方法，其中该活性物质为羟哌氟丙嗪且以至少1微克/平方公分·天的速率释放到人类皮肤。以对应的方式及所述速率下也可以使用这种方法来将活性物质三氟噻吨或三氟丙嗪释放到人类皮肤。
本发明的穿皮治疗系统因而可用来将选自羟哌氟丙嗪，三氟噻吨和三氟丙嗪的强效力精神安定剂给药需要用这种活性物质治疗的人。
根据本发明用于给药上述精神安定剂的方法及根据本发明的TTSs对于给药这些精神安定剂的用途皆可特别有利地用来治疗患有精神病或精神分裂性精神病的病人。如在本文开头所提及者，大部分需要长期药物治疗的病人，口服药物是不利的。
于下文中，要指出对TTS的进一步要求：
因为吩噻嗪骨架的已知光反应性。可能需要使用安定性添加剂。除了UV辐射-吸收性物质或色素之外，还有特别的抗氧化剂。较佳的抗氧化剂为棕榈酸抗坏血酸酯，维生素E及其医药可接受的酯例如丁基羟基茴香醚(BHA)和丁基羟基甲苯(BHT)。此外，也需要含硫安定剂例如甲硫胺酸或无机亚硫酸盐。也可以使用六亚甲基四胺(乌洛托品作为吩噻嗪的特异性安定剂(参看单行本“phenothiazine”，The Merck Index，12th Edition 1996)。
这些物质典型地以低于1重量％的浓度加到TTS的含活性物质基质中。
从光敏感性的观点看来，使用经着色，上漆或金属处理变成光可透性的膜或片材，或用对应的材料复合物，可能有用。
根据其它实施方案，还提供含有作为添加剂的增粘剂的TTSs，较佳选自矿物油和天然或合成树脂。
上述渗透性增强剂为一种通式分别的H2x+1Cx-COOH和H2x-1Cx-COOH的饱和或不饱和脂肪酸，其中x＝5至17，尤其是十一碳烯酸，月桂酸，肉豆蔻酸或油酸，所述肪酸加入量较佳者为以氢氧化钾计算的所含活性物质含量当量重量的0.5至1.5倍。
渗透增强剂也可以是通式分别为H2x+1Cx-CH2-OH和H2x-1Cx-CH2OH的饱和或不饱和脂肪醇，其中x＝5至17，特别者为1-癸醇，1-十二烷醇，油醇或支链醇2-辛基十二烷醇，所述增强剂的含量较佳者为相对于含活性物质基质层的1至20重量％。
另外，最好考虑选自下列的化合物作为渗透增强剂：脂肪醇聚氧乙基醚，脂肪酸甲酯，脂肪酸乙酯，脂肪酸异丙酯，脂肪酸乳酸酯或脂肪醇脂肪酸酯，在各种情况下在含有活性物质的基质层中含有的所述增强剂的含量较佳为1-20重量％。
实施例1至13：
实施例调配物Flu2至Flu13系在下文所述通用条件下制备：
各种Durotak粘着剂与聚硅氧烷粘着剂系以制造商送来的在有机溶剂内的溶液形式使用。
Eudragit E100系以在乙酸乙酯中的溶液形式(60重量％)处理。
75重量份数Oppnaol B10与25重量份酸Oppanol B100的混合物系以在特定沸点汽油80-110中的溶液(31重量％)使用。
含羧基聚丙烯酸酯粘着剂(Durorak 387-2051和387-2353)的中和系经由将这些粘着剂的溶液与氢氧化钾/甲醇溶液(10重量％)反应而完成。氢氧化钾的用量系对应于制造商对有关产品所载明的氢氧化钾价数的下限值(毫克KOH/克聚合物)。
先用所示量的羟哌氟丙嗪二盐酸盐在压力敏感性粘着剂溶液之前与Eudragit溶液混合，且于最后，在需要时掺入其它成分。在有需要将物质稀释到适当粘度时，系用乙酸乙酸来完成。采用束型涂布器单元(beam applicatorunit)将经均匀搅拌的物质涂覆在100微米厚的经聚硅氧烷处理的聚对苯二甲酸乙二醇酯(PET)膜上，并随后置于80℃抽掉空气的烘箱内干燥5分钟。用-PET膜(15微米厚)作为保护膜覆盖经干燥后的粘着剂膜。
于所有情况下系经由恰当选择涂层厚度将每单位面积的粘着剂基质重量调整为80克/平方米。
下面诸表中所列实施例调配物的组成皆关联于TTS的含活性物质层(表1至4)。
表1：压力敏感性粘着剂基质层的组成，重量％：
| 成分 | 实施例Flu1 | 实施例Flu2 | 实施例Flu3 | 实施例Flu4 | 实施例Flu5 |
| 羟哌氟丙嗪2HCl | 11.7 | 11.7 | 17.6 | 17.6 | 11.7 |
| Eudragit E100 | 14.3 | 14.3 | 21.5 | 21.5 | 14.3 |
| Durotak 387-2051 | 74.0 | --- | 39.1 | --- | --- |
| Durotak 387-2051钾盐 | --- | 74.0 | --- | 39.1 | --- |
| Durotak 387-2287 | --- | --- | --- | --- | 74.0 |
| 合计 | 100.0 | 100.0 | 100.0 | 100.0 | 100.0 |
表2：压力敏感性粘着剂基质层的组成，重量％：
| 成分 | 实施例Flu6 | 实施例Flu7 |
| 羟哌氟丙嗪2HCl | 11.7 | 11.7 |
| Eudragit E100 | 14.3 | 14.3 |
| 油酸 | 6.5 | --- |
| Eutanol G | --- | 5.0 |
| Durotak 387-2051钾盐 | 67.5 | 69.0 |
| 合计 | 100.0 | 100.0 |
表3：压力敏感性粘着剂基质层的组成，重量％：
| 成分 | 实施例Flu8 | 实施例Flu9 | 实施例Flu10 | 实施例Flu11 |
| 羟哌氟丙嗪2HCl | 5.83 | 5.83 | 5.83 | 5.83 |
| Eudragit E100 | 7.15 | 7.15 | 7.15 | 7.15 |
| 油酸 | 3.22 | 3.22 | 3.22 | 3.22 |
| Eutanol G | --- | --- | 20.0 | --- |
| Bio PSA Q 7-4301 | 83.8 | --- | --- | --- |
| Durotak 387-2287 | --- | 83.8 | 63.8 | --- |
| Durotak 387-2353钾盐* | --- | --- | --- | --- |
| OppanolB10/B10075+25* | --- | --- | --- | 83.3 |
| 合计 | 100.0 | 100.0 | 100.0 | 100.0 |
表4：压力敏感性粘着剂基质层的组成，重量％：
| 成分 | 实施例Flu12 | 实施例Flu13 |
| 羟哌氟丙嗪2HCl | 5.83 | 5.83 |
| Eudragit E100 | 10.7 | 7.15 |
| 油酸 | 3.22 | 4.83 |
| Oppanol B10/B10075+25* | 80.3 | 82.2 |
| 合计 | 100.0 | 100.0 |
Claims (18)
1.一种穿皮治疗系统，其包括一衬背层；一含活性物质的、朝向皮肤的压力敏感性粘着剂基质层；以及一可脱除的保护层；该系统的特征在于所述基质层以纯烃聚合物为基础，并且所述基质层含有精神安定剂和至少一种渗透增进剂，其中所述精神安定剂选自羟哌氟丙嗪、三氟噻吨和三氟丙嗪，并且所述纯烃聚合物选自聚异丁烯或聚异戊二烯。
2.根据权利要求1所述的穿皮治疗系统，其特征在于该基质层中的活性物质浓度为0.5至5.83重量％。
3.根据权利要求1所述的穿皮治疗系统，其特征在于该精神安定剂的释放速率至少为1微克/平方公分·天。
4.根据权利要求1所述的穿皮治疗系统，其特征在于活性物质系医药可接受盐形式。
5.根据权利要求4的穿皮治疗系统，其特征在于活性物质以盐酸盐或二盐酸盐形式存在。
6.根据权利要求1所述的穿皮治疗系统，其特征在于在所述系统中包含一种碱性反应性添加剂，所述碱性反应性添加剂为甲基丙烯酸二甲氨基乙酯和甲基丙烯酸酯单元的共聚物。
7.根据权利要求6所述的穿皮治疗系统，其特征在于所含碱性反应性添加剂的量为该活性物质含量的当量重量的0.5至1.5倍，以氢氧化钾表出。
8.根据权利要求1所述的穿皮治疗系统，其特征在于该渗透性增进剂为一种通式分别为H2x+1Cx-COOH和H2x-1Cx-COOH的饱和或单不饱和脂肪酸，其中x＝5至17。
9.根据权利要求8所述的穿皮治疗系统，其特征在于该渗透性增进剂选自十一碳烯酸，月桂酸，肉豆蔻酸或油酸。
10.根据权利要求8或9所述的穿皮治疗系统，其特征在于该渗透性增进剂的存在量为以氢氧化钾计算的该活性物质含量当量重量的0.5至1.5倍。
11.根据权利要求1所述的穿皮治疗系统，其特征在于该渗透性增进剂为通式分别为H2x+1Cx-CH2-OH和H2x-1Cx-CH2OH的饱和或单不饱和脂肪醇，其中x＝5至17。
12.根据权利要求11所述的穿皮治疗系统，其特征在于该渗透性增进剂选自1-癸醇，1-十二烷醇，油醇或支链醇2-辛基十二烷醇。
13.根据权利要求1所述的穿皮治疗系统，其特征在于该渗透性增进剂含量为相对于含活性物质基质层的1至20重量％。
14.根据权利要求1所述的穿皮治疗系统，其特征在于朝皮肤侧上的压力敏感性粘着剂层系由二至三种具有相同分子构造而只有平均分子量不同的聚合物所制成。
15.根据权利要求1所述的穿皮治疗系统，其特征在于在该系统中含有增粘剂。
16.根据权利要求15所述的穿皮治疗系统，其特征在于所述增粘剂选自矿物油及天然或合成树脂。
17.根据权利要求1所述的穿皮治疗系统，其特征在于在该压力敏感性粘着剂层中含有安定化添加剂，其中所述安定化添加剂选自棕榈酸抗坏血酸酯、维生素E、丁基羟基茴香醚、丁基羟基甲苯和六亚甲基四胺。
18.根据权利要求17所述的穿皮治疗系统，其特征在于在该压力敏感性粘着剂层中含有其量为0.01至1.0重量％的安定化添加剂。
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19918105.5 | 1999-04-22 | ||
| DE19918105A DE19918105C1 (de) | 1999-04-22 | 1999-04-22 | Transdermales therapeutisches System mit einem stark wirksamen Neuroleptikum |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1348366A CN1348366A (zh) | 2002-05-08 |
| CN1194672C true CN1194672C (zh) | 2005-03-30 |
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| CNB008065683A Expired - Lifetime CN1194672C (zh) | 1999-04-22 | 2000-04-07 | 包括有效精神安定性药物的穿皮治疗系统 |
Country Status (16)
| Country | Link |
|---|---|
| US (1) | US7560121B1 (zh) |
| EP (1) | EP1171105B1 (zh) |
| JP (1) | JP4163859B2 (zh) |
| KR (1) | KR100610626B1 (zh) |
| CN (1) | CN1194672C (zh) |
| AR (1) | AR025521A1 (zh) |
| AT (1) | ATE270881T1 (zh) |
| AU (1) | AU773905B2 (zh) |
| BR (1) | BRPI0011135B8 (zh) |
| CA (1) | CA2370023C (zh) |
| DE (2) | DE19918105C1 (zh) |
| ES (1) | ES2225126T3 (zh) |
| MX (1) | MXPA01010503A (zh) |
| TR (1) | TR200102915T2 (zh) |
| WO (1) | WO2000064419A1 (zh) |
| ZA (1) | ZA200108512B (zh) |
Families Citing this family (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE10027258C1 (de) * | 2000-05-31 | 2001-10-31 | Lohmann Therapie Syst Lts | Transdermales therapeutisches System mit okklusiver wirkstoffhaltiger Schicht und nicht-okklusiver Rückschicht |
| DE10035891A1 (de) | 2000-07-24 | 2002-02-14 | Lohmann Therapie Syst Lts | Medizinischer Haftkleber mit einer zweiphasigen Klebermatrix aus Polyacrylaten und Polyaminsalzen |
| DE10110953A1 (de) * | 2001-03-07 | 2002-09-19 | Lohmann Therapie Syst Lts | Transdermales therapeutisches System zur Verabreichung von partiellen Dopamin-D2-Agonisten |
| DE102006054732B4 (de) * | 2006-11-21 | 2010-12-30 | Lts Lohmann Therapie-Systeme Ag | Transdermales therapeutisches System mit Ionenpaar-Mikroreservoiren |
| DE102008034453A1 (de) * | 2008-07-24 | 2010-02-11 | Lts Lohmann Therapie-Systeme Ag | Verfahren zum Herstellen eines Mehrschichtenverbundes auf einer CIP-fähigen Beschichtungsanlage und Verwendung des damit hergestellten Mehrschichtenverbundes für die transdermale Applikation oder die Applikation in Körperhöhlen |
| EP2594261A1 (en) * | 2011-11-18 | 2013-05-22 | Labtec GmbH | Composition for transdermal administration of rivastigmine |
| EP3206673B1 (en) * | 2014-10-17 | 2024-08-21 | Fidia Farmaceutici S.p.A. | Dermal therapeutic system with high adhesivity |
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| ATE42901T1 (de) * | 1984-03-05 | 1989-05-15 | Nitto Denko Corp | Haftendes arzneimittelpraeparat fuer perkutane absorption. |
| JPH01265021A (ja) * | 1987-10-29 | 1989-10-23 | Hercon Lab Corp | 薬理学的活性物質を含有する組成物を動物組織に制御放出および供給するための物品 |
| US5474783A (en) | 1988-03-04 | 1995-12-12 | Noven Pharmaceuticals, Inc. | Solubility parameter based drug delivery system and method for altering drug saturation concentration |
| DE3910543A1 (de) * | 1989-04-01 | 1990-10-11 | Lohmann Therapie Syst Lts | Transdermales therapeutisches system mit erhoehtem wirkstofffluss und verfahren zu seiner herstellung |
| JP2849937B2 (ja) * | 1990-04-18 | 1999-01-27 | 日東電工株式会社 | 医療用貼付剤 |
| US5120545A (en) | 1990-08-03 | 1992-06-09 | Alza Corporation | Reduction or prevention of sensitization to drugs |
| US5882676A (en) * | 1995-05-26 | 1999-03-16 | Alza Corporation | Skin permeation enhancer compositions using acyl lactylates |
| US5891461A (en) * | 1995-09-14 | 1999-04-06 | Cygnus, Inc. | Transdermal administration of olanzapine |
| AUPN814496A0 (en) * | 1996-02-19 | 1996-03-14 | Monash University | Dermal penetration enhancer |
| AU765603C (en) * | 1998-04-14 | 2004-08-05 | General Hospital Corporation, The | Methods for treating neuropsychiatric disorders |
-
1999
- 1999-04-22 DE DE19918105A patent/DE19918105C1/de not_active Expired - Fee Related
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2000
- 2000-04-07 MX MXPA01010503A patent/MXPA01010503A/es active IP Right Grant
- 2000-04-07 US US09/959,201 patent/US7560121B1/en not_active Expired - Fee Related
- 2000-04-07 ES ES00925177T patent/ES2225126T3/es not_active Expired - Lifetime
- 2000-04-07 KR KR1020017013508A patent/KR100610626B1/ko active IP Right Grant
- 2000-04-07 EP EP00925177A patent/EP1171105B1/de not_active Expired - Lifetime
- 2000-04-07 CA CA002370023A patent/CA2370023C/en not_active Expired - Lifetime
- 2000-04-07 BR BRPI0011135A patent/BRPI0011135B8/pt not_active IP Right Cessation
- 2000-04-07 WO PCT/EP2000/003113 patent/WO2000064419A1/de active IP Right Grant
- 2000-04-07 JP JP2000613410A patent/JP4163859B2/ja not_active Expired - Lifetime
- 2000-04-07 DE DE50007077T patent/DE50007077D1/de not_active Expired - Lifetime
- 2000-04-07 AU AU43986/00A patent/AU773905B2/en not_active Expired
- 2000-04-07 CN CNB008065683A patent/CN1194672C/zh not_active Expired - Lifetime
- 2000-04-07 TR TR2001/02915T patent/TR200102915T2/xx unknown
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- 2000-04-19 AR ARP000101846A patent/AR025521A1/es active IP Right Grant
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Also Published As
| Publication number | Publication date |
|---|---|
| TR200102915T2 (tr) | 2002-01-21 |
| EP1171105B1 (de) | 2004-07-14 |
| EP1171105A1 (de) | 2002-01-16 |
| BRPI0011135B1 (pt) | 2016-09-27 |
| US7560121B1 (en) | 2009-07-14 |
| WO2000064419A1 (de) | 2000-11-02 |
| AU4398600A (en) | 2000-11-10 |
| AU773905B2 (en) | 2004-06-10 |
| MXPA01010503A (es) | 2002-05-14 |
| AR025521A1 (es) | 2002-12-04 |
| JP2002542278A (ja) | 2002-12-10 |
| CN1348366A (zh) | 2002-05-08 |
| ZA200108512B (en) | 2002-08-06 |
| ES2225126T3 (es) | 2005-03-16 |
| JP4163859B2 (ja) | 2008-10-08 |
| DE19918105C1 (de) | 2000-09-21 |
| CA2370023A1 (en) | 2000-11-02 |
| KR20010112453A (ko) | 2001-12-20 |
| DE50007077D1 (de) | 2004-08-19 |
| BR0011135A (pt) | 2003-07-29 |
| BRPI0011135B8 (pt) | 2021-05-25 |
| KR100610626B1 (ko) | 2006-08-09 |
| CA2370023C (en) | 2009-06-23 |
| ATE270881T1 (de) | 2004-07-15 |
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