CN1507918A - 透皮促进剂甘油三醋酸酯 - Google Patents
透皮促进剂甘油三醋酸酯 Download PDFInfo
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- CN1507918A CN1507918A CNA2004100392112A CN200410039211A CN1507918A CN 1507918 A CN1507918 A CN 1507918A CN A2004100392112 A CNA2004100392112 A CN A2004100392112A CN 200410039211 A CN200410039211 A CN 200410039211A CN 1507918 A CN1507918 A CN 1507918A
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- Prior art keywords
- matrix patch
- triacetin
- binding agent
- medicine
- described method
- Prior art date
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Abstract
描述了用于碱性药物经皮渗透的组合物和方法。该组合物含有基质贴剂,所述基质贴剂含有有效量的碱性药物,优选pKa为约8.0或更大;有效量的基本由甘油三醋酸酯组成的渗透促进剂;和优选含有压敏型粘合剂的聚合物层。优选的碱性药物是奥昔布宁及其酸加成盐。促进经皮渗透的方法包括向选定的皮肤部位应用所述基质贴剂。
Description
发明领域
本发明总的涉及促进生物活性物质经生物膜释放的组合物和方法,所述生物膜包括皮肤和粘膜。更具体地讲,本发明涉及甘油三醋酸酯促进pKa为约8.0或更大的碱性药物如奥昔布宁经膜或经粘膜释放的用途。
发明背景
目前应用的药物口服给药方式因许多原因而不能令人满意。首先,半衰期短的药物需要频繁地服药(每日2至4次),这将导致患者的依从性不好。第二,药物血浆半衰期短和频繁服药将形成血浆浓度曲线的“峰”和“谷”,这将导致伴随峰浓度的副作用可能性的增加,以及在接近给药间隔的终点时治疗效果的丧失。第三,伴随口服给药的肝脏首过代谢作用将导致药物的生物利用度不好。因此,克服了这些缺点的有效、持续的释药系统将比目前的口服方案优越的多。
药物的经皮释放比起常规的口服给药有许多优点。经皮系统的优点包括方便、不间断的治疗、增加患者的依从性、治疗的可逆性(从皮肤上除去该系统)、无“肝脏首过”效应、对血药浓度的高度控制以及整体治疗的改善。
尽管经皮系统有许多优点,但由于众所周知的皮肤的屏障特性,大多数药物并不适于这种形式的给药。分子从周围环境中进入并穿过完整的皮肤必需首先渗透角质层(皮肤的外部角层)及其上面的所有物质。然后,分子在透过毛细血管壁进入机体循环之前必需渗透活的表皮和真皮乳头层。在此过程中,上述各组织将对同一分子表现出不同的渗透阻力。然而,角质层构成了局部给药的组合物或经皮给药的药物吸收的最大屏障,所述角质层是从细胞外脂质区分离出的紧密的角质化细胞残余物的复合结构。与口腔或胃粘膜相比,角质层对外界分子的通透性要低得多。
可以通过(a)改变阻力(扩散系数),或(b)改变驱动力(药物在角质层中的溶解度以及随后的扩散梯度)来促进药物通过皮肤的吸收量。已经开发出了多种促进剂组合物以改变上述的一种或两种因素。例如,美国专利4006218、3551154和3472931分别记载了二甲基亚砜(DMSO)、二甲基甲酰胺(DMF)和N,N-二甲基乙酰胺(DMA)促进局部给药的药物通过角质层吸收的用途。在美国专利4973468中公开了用于促进类固醇如孕激素和雌激素经皮释放的由二甘醇单乙醚或二甘醇单甲醚与丙二醇单月桂酸酯和月桂酸甲酯组成的促进剂组合物。在美国专利4820720中公开了用于药物经皮释放的由甘油单月桂酸酯和乙醇组成的二元促进剂。美国专利5006342列举了大量用于经皮给药的促进剂,所述促进剂由C2-C4链烷二醇的脂肪酸酯或脂肪醇醚组成,其中酯/醚中的脂肪酸/醇部分为大约8-22个碳原子。美国专利4863970公开了用于局部应用的渗透促进组合物,该组合物含有包含在渗透促进载体中的活性渗透剂,所述载体中含有特定量的一种或多种破坏细胞被膜功能的化合物如油酸、油醇、油酸甘油酯;C2或C3烷醇;和惰性稀释剂如水。
甘油三醋酸酯是已知的用于溶解或稀释药物释放系统中的药物和/或其它成分的溶剂。例如,美国专利4879297(Mahjour等)公开了甘油三醋酸酯在丙二醇和亚油酸组成的促进剂系统中用作溶剂。增加促进剂配方中甘油三醋酸酯的量并相应地减少亚油酸的量将会降低吸收量并延长药物羟氢吗啡酮的渗透滞后时间,这表明甘油三醋酸酯在促进剂配方中的重要性相对较低。另一个例子是WO 9325168-A1(Ebert等),它公开了将甘油三醋酸酯作为溶剂(同时还列举了许多其它的溶剂)与破坏细胞被膜功能的化合物一起使用,用于释放氯压定、孕酮、睾酮及其它药物。其它记载了将甘油三醋酸酯作为溶剂的专利文献包括美国专利4908389;美国专利5019395;美国专利4666926;美国专利4857313;美国专利4789547;美国专利4814173;美国专利4783450;EP-387647-A;JP63255227-A;JP62215537-A。
已知甘油三醋酸酯还可作为增塑剂。例如,美国专利5160743(Edgren等)公开了将甘油三醋酸酯作为常规的增塑剂与乳化剂一起用于片剂、胶囊、粉末剂等用于在胃肠道释放药物。其它公开了将甘油三醋酸酯用作增塑剂的专利文献和出版物包括Lin等,药物研究1137(1991);WO9313753;EP 509335-A1以及JP3083917。
还有记载甘油三醋酸酯可起到抗菌剂的作用。美国专利4895727(Allen)公开了甘油三醋酸酯具有抗真菌剂的活性。
还有记载甘油三醋酸酯具有吸收促进剂的活性。WO 9309783-A1(Ikeda等)公开了含有炎痛喜康的硬膏剂,该硬膏剂可通过炎痛喜康的经皮吸收而达到抗炎和镇痛效果,并指出了甘油三醋酸酯可促进炎痛喜康的经皮吸收。该硬膏剂由以下物质组成:水溶性聚合物粘合剂;甘醇化合物如甘油或丙二醇;交联剂;水;无机粉末;以及表面活性剂,例如聚氧乙烯山梨醇单油酸酯、聚氧乙烯单油酸酯、山梨醇单油酸酯或聚氧乙烯蓖麻油。该文献还进一步指出,如需要,还可在配方中加入渗透促进剂、防腐剂、抗氧剂、矫味剂和着色剂。甘醇和表面活性剂是渗透促进领域已知的常规溶剂和破坏细胞被膜功能的化合物(例如美国专利4855294),因此所观察到的效果似乎是由于甘醇、表面活性剂和甘油三醋酸酯的组合引起的。
日本专利文献JP 05148141-A记载了一种两层的经皮吸收制剂,该制剂含有粘合剂、异山梨醇二硝酸酯和吸收促进剂。所述的吸收促进剂是甘油三酯,其中脂肪酸酯的链长为1-4个碳原子,优选甘油三醋酸酯。应当注意到,异山梨醇二硝酸酯本身即具有加溶特性,即它是中性的“可起溶剂作用的药物(solvent-acting drugs)”,Sablotsky等,美国专利5186938。其它的血管扩张剂,如特征为碳-氧-氮顺序的硝酸酯类(-C-O-NO2)和特征为(-C-O-NO)顺序的亚硝酸酯类也属于这类可起溶剂作用的药物,其中包括甘油三硝酸酯(根据其通俗和官方的命名,被误称为硝酸甘油)、甘露醇六硝酸酯、赤藓醇四硝酸酯、季四戊醇四硝酸酯。因此,JP05148141-A中所报道的甘油三醋酸酯的渗透促进效果仅在与中性的可起溶剂作用的药物一起使用时才表现出来。
以前所没有发现的是,甘油三醋酸酯本身即是促进无溶剂作用的药物(non-solvent-acting drugs)、特别是pKa为约8.0或更大的碱性药物或其酸加成盐经皮释放的有效的渗透促进剂。根据上述内容可以理解,促进这些碱性药物及其酸加成盐渗透的组合物和方法将是本领域的显著进步。
发明目的和概述
本发明的目的是提供促进碱性药物通过皮肤或粘膜进行经皮释放的组合物和方法。
本发明的另一个目的是提供促进碱性药物奥昔布宁或其酸加成盐通过皮肤或粘膜进行经皮释放的组合物和方法。
本发明的又一个目的是提供促进pKa为约8.0或更大的碱性药物,如奥昔布宁或其酸加成盐经皮释放的组合物和方法,其中使用甘油三醋酸酯作为渗透促进剂以促进药物渗透皮肤或粘膜。
这些和其它的目的是通过提供用于促进pKa为约8.0或更大的碱性药物的经皮渗透速率的基质贴剂来完成的,所述基质贴剂含有:
(a)生物相容性聚合物层;
(b)有效量的可经皮吸收的pKa为约8.0或更大的碱性药物;和
(c)有效量的基本由甘油三醋酸酯组成的渗透促进剂。
优选的pKa为约8.0或更大的碱性药物包括奥昔布宁、东莨菪碱、氟苯氧苯胺、肾上腺素、吗啡、二氢吗啡酮、阿托品、可卡因、叔丁啡、氯丙嗪、丙咪嗪、去甲丙咪嗪、哌醋甲酯、去氧麻黄碱、利多卡因、普鲁卡因、吲哚心安、萘羟心安、异丙安宁以及它们的酸加成盐。特别优选奥昔布宁及其酸加成盐。该基质贴剂优选含有约0.1%-约50%重的甘油三醋酸酯,更优选约1%-约40%重的甘油三醋酸酯,最优选约2%-约20%重的甘油三醋酸酯。聚合物层优选为粘合剂,但也可以将其覆盖在粘合剂层上或将其与涂覆层粘合剂一起使用。适宜的聚合物包括丙烯酸类、乙酸乙烯基酯类、天然和合成橡胶、乙烯乙酸乙烯酯共聚物、聚硅氧烷、聚丙烯酸酯、聚氨基甲酸乙酯、增塑量的聚醚嵌段酰胺共聚物、增塑的聚苯乙烯橡胶嵌段共聚物,以及它们的混合物。优选丙烯酸共聚物粘合剂。该基质贴剂还可含有稀释剂、赋性剂、乳化剂、增塑剂、降低对皮肤刺激性的试剂、载体,以及它们的混合物,条件是这些添加剂不会改变基质贴剂的基本的及新的特征。
促进碱性药物经皮渗透的方法包括对选定的应用部位应用上述基质贴剂。
发明详述
在公开并描述本发明促进碱性药物如奥昔布宁及其酸加成盐经皮释放的组合物和方法之前,应当理解本发明并不仅限于本文所公开的具体的方法步骤和材料,因为可以对这些方法步骤和材料进行一定程度的改变。还应当理解,本文所用的术语仅仅是用来描述具体实施方案的,并非想要对本发明的范围进行限定,本发明的范围仅由所附的权利要求和其等同物进行限定。
必需注意,在说明书和权利要求书中使用的单数形式“一个”、“一种”等均包括复数的情况,除非从上下文中可以清楚地看出不是这样。因此,例如对于含有“药物”的药物释放装置的解释包括两种或多种药物的混合物,对“粘合剂”的解释包括一种或多种这样的粘合剂,对“赋形剂”的解释包括两种或多种这样的赋形剂的混合物。
在本发明的说明书和权利要求书中,下列术语具有以下所定义的意义。
本文所用的术语“促进”、“通透促进”或“渗透促进”是指生物膜(即皮肤或粘膜)对药物通透性的增加,从而增加药物通过该膜渗透的速率。“通透促进剂”、“促进剂”、“渗透促进剂”或类似的术语是指可以产生渗透促进的材料,促进剂的“有效量”是指足以将选定的试剂对皮肤或粘膜的通透性提高到所选程度的量。使用这些促进剂所引起的通透性增强可以观察到,例如使用扩散池测定药物通过动物或人皮肤扩散的速率进行观察。所述扩散池的描述参见Merritt等,用于皮肤通透性的扩散装置,1控释杂志61(1984),该文献引入本文作为参考。
本文使用的术语“经皮肤”或“经皮”释放是指通过进入并透过皮肤或粘膜组织的途径来释放药物。在此,除非另有具体说明,术语“经皮肤”或“经皮”可以互换使用。同样,除非另有具体说明,术语“皮肤”、“皮”、“表皮”、“粘膜”等均可以互换使用。
术语“渗透剂”或“药物”是指任何适用于经皮或经粘膜给药的化学物质或化合物,它以适宜的游离碱或酸加成盐的形成存在,可以通过经皮释放产生所需的生理学或药理学效果。所述物质包括一大类通常通过身体表面如皮肤进行释放的化合物。通常包括所有主要治疗领域中的治疗剂,包括但不仅限于抗感染剂如抗菌剂和抗病毒剂、镇痛剂和镇痛联合剂、减食欲剂、止泻剂、抗组胺剂、抗炎剂、抗偏头痛制剂、抗运动恶心剂、止恶心剂、抗肿瘤剂、抗帕金森氏病的药物、止痒剂、抗精神病药物、解热剂、解痉剂(包括胃肠道和泌尿系)、抗胆碱能药物、拟交感神经药、黄嘌呤衍生物、心血管制剂(包括钙通道阻滞剂、β-受体阻滞剂、抗心律失常药、抗高血压药、利尿药)、血管扩张剂(包括主冠脉、外周和脑血管)、中枢神经系统兴奋药(包括咳嗽和感冒制剂)、减轻充血剂、诊断制剂、激素、免疫抑制剂、肌肉松弛剂、抗副交感神经药、拟副交感神经药、精神兴奋药、镇静药和安定药。术语“渗透剂”或“药物”还包括混合物。混合物是指不同类型的渗透剂的联合、同一类型的渗透剂的混合物、以及相同或不同类型的同种或不同种渗透剂的游离碱和盐形式的混合物。
“碱性药物”是指游离碱或其酸加成盐形式的药物或渗透剂。优选的碱性药物含有使药物具有碱性特征的氨基。更优选pKa为约8.0或更大的强碱性药物。优选的可以通过本发明的渗透促进系统释放的碱性药物例子包括奥昔布宁、东莨菪碱、氟苯氧苯胺、肾上腺素、吗啡、二氢吗啡酮、阿托品、可卡因、叔丁啡、氯丙嗪、丙咪嗪、去甲丙咪嗪、哌醋甲酯、去氧麻黄碱、利多卡因、普鲁卡因、吲哚心安、萘羟心安、异丙安宁以及它们的酸加成盐。更优选奥昔布宁及其酸加成盐。
药物或渗透剂的“有效量”是指无毒但足以提供所需的局部或全身效果的化合物量。本文使用的渗透促进剂的“有效量”是指所选定的用于产生所需的膜通透性的增加以及相应的所需渗透深度、给药速率以及药物量的渗透促进剂的量。
“药物释放系统”、“药物/促进剂组合物”或任何类似的术语是指所配制的含有需经皮释放的药物以及渗透促进剂的组合物。在所述药物/促进剂组合物中还可有其它可药用的材料或添加剂,例如稀释剂、降低对皮肤刺激性的试剂、载体、赋形剂、增塑剂、乳化剂、或其它添加剂以及它们的混合物,条件是这些添加剂不会影响基质贴剂的基本的及新的特征。
术语“基质”、“基质系统”或“基质贴剂”是指溶于或悬浮在生物相容性聚合物相中的渗透剂或药物,优选压敏型的粘合剂,其中还可含有其它成分或溶解或悬浮在其中的促进剂。该定义包括聚合物相被压合在压敏型粘合剂上或与涂覆层粘合剂一起使用的实施方案。基质系统通常并优选包括一层粘合剂层,该粘合剂层在其外表面上压合有一层无渗透性的薄膜被衬,并在经皮施用前,在粘合剂的内表面上有一层释放内衬。薄膜被衬包含基质贴剂的聚合物相并防止药物和/或促进剂向环境中释放。释放内衬的功能与无渗透性被衬相似,但在贴剂施用于应用部位前将其从基质贴剂上除去。基质贴剂是经皮药物释放领域已知的,通常含有被衬和释放内衬,本发明的基质贴剂应理解为含有所述被衬和释放内衬或其功能等同物。美国专利5122383描述了所述被衬和释放内衬,在此将其引入本文作为参考。因此,基质系统是在聚合物载体中的药物组合物的单位剂量形式,所述组合物中还含有促进剂以及掺入用于维持聚合物层中的药物组合物与皮肤(即皮肤或粘膜)之间的药物转运关系的其它成分。基质贴剂与“液体储库贴剂”不同,后者是将活性渗透剂或药物溶于凝胶化的液体并将该液体装入密闭的装置中,所述装置有一个无渗透性的背面,其另一面通过用于经皮给药的可渗透膜和粘合剂成形,例如美国专利4983395。
本文所用的术语“应用部位”是指适于局部应用的部位如耳后、胳膊、背、胸、腹部、腿、脚面等,所述局部应用可以使用或不用机械缓释装置、贴剂或绷带的方式。
如上所述,本发明包括用于促进pKa为约8.0或更大的碱性药物经皮释放的基质贴剂,所述基质贴剂含有:
(a)生物相容性聚合物层;
(b)有效量的可经皮吸收的pKa为约8.0或更大的碱性药物;和
(c)有效量的基本由甘油三醋酸酯组成的渗透促进剂。
出人意料的是,甘油三醋酸酯对于促进碱性药物,尤其是pKa为约8.0或更大的碱性药物的经皮制剂有效,而对中性或酸性药物无效。在这些可被甘油三醋酸酯促进其渗透性的碱性药物中,奥昔布宁游离碱及其酸加成盐为优选。仍然令人惊奇的是,虽然甘油三醋酸酯在基质贴剂制剂中是碱性药物如奥昔布宁游离碱的有效的渗透促进剂,但对于含有凝胶化药物制剂的液体储库贴剂,却没有观察到对碱性药物(包括奥昔布宁)或其它药物的渗透促进作用。
可用于基质贴剂的生物相容性聚合物层的适宜聚合物包括适于和皮肤长期接触的压敏型粘合剂。所述粘合剂必需与药物和促进剂、以及掺入药物/促进剂组合物中的任何载体或其它添加剂是物理和化学相容性的。用于基质贴剂的适宜粘合剂包括丙烯酸粘合剂,包括交联和非交联的丙烯酸共聚物;乙酸乙烯基酯粘合剂;天然和合成橡胶,包括聚异丁烯、氯丁橡胶、聚丁二烯、和聚异戊二烯;乙烯乙酸乙烯酯共聚物;聚硅氧烷;聚丙烯酸酯;聚氨基甲酸乙酯;增塑量的聚醚嵌段酰胺共聚物;增塑的聚苯乙烯橡胶嵌段共聚物。用于本文基质贴剂的优选的接触粘合剂是丙烯酸粘合剂如TSR(Sekisui Chemical Co.,Osaka,Japan)和DuroTak粘合剂(National Starch & Chemical Co.Bridgewater,N.J.),和聚异丁烯粘合剂如ARcareTMMA-24(Adhesive Research,Glen Rock,Pennsyvania)。
在使用时,基质贴剂包含一层压合在聚合物层上的外侧被衬。该外侧被衬是基质贴剂朝向外界环境的一侧,即远离皮肤或粘膜的一侧。被衬层的功能是保护基质聚合物层和药物/促进剂组合物,并提供无渗透性的层,从而防止药物向外界环境的流失。因此,所选用于被衬的材料应与聚合物层、药物和促进剂是相容性的,并且对基质贴剂中任意组分的渗透性最小。被衬最好是不透明的,以防止基质贴剂中的组分由于接触紫外线而降解。此外,该被衬应能粘合并支持聚合物层并应是柔韧的,从而使用该基质贴剂的人仍可以运动。用于被衬的适宜材料包括金属箔、金属化的聚合箔(Dolyfoils)、复合箔或薄膜,所述复合箔或薄膜含有聚酯如对苯二酸酯聚酯、聚酯或铝化聚酯、聚四氟乙烯、聚醚嵌段酰胺共聚物、聚乙烯异丁烯酸甲酯嵌段共聚物、聚氨基甲酸乙酯、聚偏二氯乙烯、尼龙、硅氧烷弹性体、橡胶基质的聚异丁烯、苯乙烯、苯乙烯-丁二烯和苯乙烯异戊二烯共聚物、聚乙烯和聚丙烯。优选大约0.0005-0.01英寸的厚度。释放内衬可以用与被衬相同的原料制成,或用其它合适的涂覆有适宜释放表面的膜制成。
除聚合物层、碱性药物、含有甘油三醋酸酯的渗透促进剂这些经皮药物释放系统的基本成分外,该基质贴剂还可含有各种添加剂。这些添加剂通常是药物释放领域、特别是经皮药物释放领域已知的可药用成分,条件是这些添加剂成分不会改变所述基质贴剂的基本的及新的特征。例如,适宜的稀释剂可以包括矿物油、低分子量聚合物、增塑剂等。许多经皮药物释放制剂与皮肤接触较长时间后都易产生皮肤刺激性,因此,添加降低对皮肤刺激性的试剂将有助于得到皮肤更易忍受的组合物。优选的降低对皮肤刺激性的试剂是甘油,美国专利4855294。还应注意,本发明无需加入所谓的加速促进剂或渗透促进剂成分,如溶剂和破坏细胞被膜功能的化合物。
根据本发明,为了释放碱性药物,将含有聚合物层、碱性药物如奥昔布宁以及含有甘油三醋酸酯的渗透促进剂的基质贴剂在限定的应用部位与皮肤或粘膜接触,并用适宜的压敏型粘合剂固定。基质贴剂的聚合物层优选为粘合剂,但也可将聚合物层压合在粘合剂上或将其与涂覆层粘合剂一起使用。
应当理解,尽管通过优选的具体实施方案对本发明进行了描述,但这些实施方案仅是用来说明而并非限定本发明的范围。本发明的其它方面对于本发明相关领域的技术人员是显而易见的。
实验
皮肤吸收量研究
人尸体皮肤吸收量的体外研究用改性的Franz无夹套渗透池进行。通过将渗透池放置在置于搅拌装置上的循环水浴中将池的温度保持在32℃。通过Kligman和Christopher的热分离方法〔88 Arch.Dermatol.702(1963),该文献引入本文作为参考〕从人尸体的完整皮肤上分离表皮膜,该方法包括将整个厚皮肤在60℃处理60秒,然后将角质层和表皮(表皮膜)从皮肤上轻轻剥离。
为了对基质装置进行皮肤吸收量研究,将表皮膜切割成四方形的块,并将基质装置切割成0.96cm2的圆片。从圆片上剥离释放内衬,将圆片压合到表皮膜角质层的表面上以形成皮肤-基质叠层。然后将皮肤-基质叠层放置在扩散池的供给室和接受室之间,并使表皮侧朝向接受室。将叠层用夹子固定,然后向接受室中注满用于选定药物的适宜接受溶液。选择接受溶液的条件是:药物在该溶液中稳定,对随后进行的药物分析没有干扰,并且对药物有足够的溶解度以确保在整个实验过程中保持汇集条件(sinkcondition)。然后将扩散池置于循环水浴中,并对该循环水浴进行校准以便将皮肤表面的温度维持在32±1℃。按照预定的取样间隔,收集接受室内的全部内容物进行药物定量,并向接受室内充满新的接受溶液,并注意清除皮肤/溶液界面上的所有气泡。
为了对凝胶制剂进行皮肤吸收量研究(即,为了液体储库贴剂设计),切下表皮膜并将其置于渗透池的中间,角质层朝向供给室。将皮肤用0.02%(w/v)叠氮化钠溶液于32℃下在接受室内水合过夜。第二天早晨,将聚四氟乙烯垫圈放置在角质层表面形成空腔并将75μl凝胶化的制剂放置在空腔内。然后在垫圈和凝胶上固定一闭合衬垫将空腔封闭。然后向接受室中放置用于选定药物的适宜接受溶液并与表皮的真皮侧接触。选择接受室溶液的条件是:药物在该溶液中稳定,对随后进行的药物分析没有干扰,并且对药物有足够的溶解度以确保在整个实验过程中保持汇集条件。按照预定的取样间隔,收集接受室内的全部内容物进行药物定量,并向接受室内充满新的接受溶液,并注意清除皮肤/溶液界面上的所有气泡。
在任意时间点t,透过表皮膜的药物累加量Qt(μg/cm2)用下式计算:
其中Cn是在相应的取样时间,接受室样品中的药物浓度(μg/ml),V是接受室中的液体体积(6.3cm3),A是池的扩散面积(0.64cm2)。Qt对t图的最佳拟合线的斜率给出了稳定状态的吸收量(Jss,μg/cm2/小时);该线在时间轴上的交点给出了延迟时间(tL,h)。
实施例1
奥昔布宁游离碱(pKa=10.3)是经皮给药用于解痉和抗胆碱能治疗的强碱性药物。制备含不同量的奥昔布宁游离碱和渗透促进剂的基质贴剂并按上述方法进行实验。基质系统由包含在药物级丙烯酸共聚物粘合剂中的5-20%(重)奥昔布宁游离碱和0-20%(重)促进剂组成。
按如下制备基质制剂。首先,通过称重在称重过的铝盘中的少量粘合剂溶液来确定粘合剂的固体含量。通过在80℃的对流烤箱中干燥过夜来蒸发溶剂,确定残留物(干粘合剂)的重量和溶液中固体粘合剂的百分含量。在确定了固体含量后,在玻璃瓶中称量已知重量的丙烯酸共聚物粘合剂溶液。从粘合剂溶液的重量和固体粘合剂的百分含量计算出溶液中粘合剂的量。将奥昔布宁游离碱和促进剂以可得到所选最终组合物的比例加到瓶中。然后将瓶子盖紧,用实验室薄膜密封并旋转过夜,直到所有的成分完全溶解并且肉眼观察所得溶液是透明的。
然后将约8ml溶液分散到硅烷化的聚酯释放层上,然后用10mil缺口的成模刀成型。然后将模型在70℃的对流烤箱中干燥15分钟以蒸发掉溶剂并得到约0.002英寸厚的干燥膜。用橡胶滚柱将0.003英寸厚的聚乙烯被衬膜压合到干燥的粘合剂膜上。然后用这些基质叠层按上述方法完成体外皮肤吸收量研究。皮肤吸收量实验的结果列于表1-3。
表1 | ||
配方aA/D/E(%W/W) | Qt(t=24小时)(μg/cm2/t)b | Jss(μg/cm2/hr)b |
80/20/0 | 47.05±21.01 | 2.03±0.95 |
75/20/5 | 63.90±23.45 | 3.07±1.06 |
70/20/10 | 125.75±56.00 | 6.08±2.62 |
60/20/20 | 155.08±74.55 | 7.46±3.44 |
a A=粘合剂=TSR;D=药物=奥昔布宁;E=促进剂=甘油三醋酸酯
b 平均值±SD
表2 | ||
配方aA/D/E(%W/W) | Qt(t=24小时)(μg/cm2/t)b | Jss(μg/cm2/hr)b |
80/20/0 | 28.12±13.74 | 1.13±0.52 |
75/20/10 | 84.41±30.72 | 3.64±1.23 |
60/20/20 | 132.31±42.61 | 5.92±1.85 |
a A=粘合剂=DuroTak 87-2196;D=药物=游离碱;E=促进剂=甘油三醋酸酯
b 平均值±SD
表3 | ||
配方aA/D/E(%W/W) | Qt(t=24小时)(μg/cm2/t)b | Jss(μg/cm2/hr)b |
80/15/0 | 61.57±33.19 | 2.58±1.39 |
75/15/10 | 13 5.36±23.85 | 5.80±0.90 |
a A=粘合剂=Arcre MA-24;D=药物=奥昔布宁游离碱;E=促进剂=甘油三醋酸酯
b 平均值±SD
这些结果表明,与不含甘油三醋酸酯的粘合剂/奥昔布宁对照相比,甘油三醋酸酯可显著增加奥昔布宁游离碱的皮肤吸收量。在这些基质制剂中测试的所有三种粘合剂中,均观察到了甘油三醋酸酯的促进效果。对于TSR粘合剂,在20%上药量的条件下,与对照相比,5%(w/w)甘油三醋酸酯引起的增加为大约50%,10%(w/w)甘油三醋酸酯为3倍,20%(w/w)甘油三醋酸酯为近乎4倍。对于DuroTak87-2196粘合剂,在20%上药量的条件下,与对照相比,10%(w/w)甘油三醋酸酯引起的皮肤吸收量的增加为大约3倍,20%(w/w)甘油三醋酸酯为5倍。对于ArcareMA-24粘合剂,在15%上药量的条件下,与对照相比在10%(w/w)甘油三醋酸酯中观察到皮肤的吸收量增加2倍。
实施例2
根据实施例1的方法,对多种已知的促进剂促进奥昔布宁游离碱经皮吸收量的活性进行了评估,所不同的是用这些促进剂代替甘油三醋酸酯。体外皮肤吸收量实验的结果列于表4。
表4 | |||
促进剂 | 配方aA/D/E(%W/W) | Qt(t=2 4小时)(μg/cm2/t)b | Jss(μg/cm2/hr)b |
无 | 80/20/0 | 47.05±21.01 | 2.03±0.95 |
脱水山梨醇单油酸酯 | 70/20/10 | 42.47±21.63 | 1.92±0.98 |
N-甲基吡咯烷酮 | 60/20/20 | 54.36±1.98 | 2.42±0.97 |
月桂醇 | 70/20/10 | 24.29±8.73 | 1.25±0.41 |
肉豆蔻酸异丙酯 | 70/20/10 | 48.26±13.08 | 2.05±0.54 |
单油酸甘油酯 | 70/20/10 | 52.78±8.25 | 2.25±0.32 |
a A=粘合剂=TSR;D=药物=奥昔布宁游离碱;E=促进剂=甘油三醋酸酯
b 平均值±SD
这些结果表明,在所实验的熟知的渗透促进剂脱水山梨醇单油酸酯(ARLANCEL 80,ICI Americas,Wilmington,Delaware)、N-甲基吡咯烷酮(Pharmasolve,International Specialty Chemicals,Wayne,NJ)、月桂醇、肉豆蔻酸异丙酯或单油酸甘油酯中,没有一种表现出增加基质系统中碱性药物(奥昔布宁游离碱)的经皮皮肤吸收量的活性。
实施例3
炎痛喜康是一种弱碱性抗炎、镇痛、解热剂,其pKa为6.3。根据实施例1的方法对甘油三醋酸酯促进炎痛喜康经皮吸收量的活性进行评估,所不同的是用炎痛喜康代替奥昔布宁。结果列于表5。
表5 | ||
实施例号 | 配方aA/D/E(%W/W) | Qt(t=24小时)(μg/cm2/t)b |
1 | 99.75/0.25/0 | 0.56±0.30 |
99.25/0.25/0.5 | 0.58±0.07 | |
97.75/0.25/2.0 | 0.32±0.08 | |
95.75/0.25/4.0 | 0.45±0.17 | |
2 | 99.75/0.25/0 | 0.55±0.31 |
99.25/0.25/0.5 | 0.27±0.15 | |
97.75/0.25/2.0 | 0.03±0.02 | |
95.75/0.25/4.0 | 0.18±0.04 | |
3 | 99.75/0.25/0 | 0.60±0.20 |
99.25/0.25/0.5 | 0.36±0.14 |
97.75/0.25/2.0 | 0.42±0.09 | |
95.75/0.25/4.0 | 0.31±0.14 |
a A=粘合剂=TSR;D=药物=炎痛喜康游离碱;E=促进剂=甘油三醋酸酯
b 平均值±SD
这些结果表明甘油三醋酸酯降低了炎痛喜康的皮肤吸收量。这些结果明显说明,WO 9309783-A1(Ikeda等)中所指出的凝胶中炎痛喜康的吸收量增加并不仅仅是由于甘油三醋酸酯,而似乎是甘醇和表面活性剂联合的结果。
实施例4
按照上述方法对含有奥昔布宁游离碱和甘油三醋酸酯的液体储库凝胶制剂进行实验。所述液体储库凝胶制剂以10ml的量进行制备。将乙醇、水、甘油和甘油三醋酸酯以选定的比例在带盖的瓶中混合。然后,将400mg奥昔布宁游离碱加入瓶中,将瓶子盖紧并超声以使药物完全溶解。然后向该混合物中加入0.3g改性的羟乙基纤维素(NATROSOL PLUS 330CS,Aqualon,Wilmington,Delaware)作为胶凝剂,将全部内容物充分混合并轻轻旋转过夜以使胶凝剂完全溶解。然后将得到的凝胶由于皮肤吸收量研究,结果列于表6。
表6 | |||
实施例号 | 配方Et/W/G/E(%W/W)a | Qt(t=24hr)(μg/cm2/t)b | Jss(μg/cm2/hr)b |
1 | 30/60/10/0 | 178.41±24.02 | 7.40±0.98 |
30/58/10/2 | 191.54±35.48 | 7.91±1.48 | |
30/50/10/10 | 110.58±20.06 | 4.49±0.83 | |
2 | 30/60/10/0 | 172.41±45.51 | 7.16±1.89 |
30/58/10/2 | 144.05±40.63 | 5.94±1.68 | |
30/50/10/10 | 155.74±61.53 | 6.43±2.60 |
3 | 30/60/10/0 | 118.23±52.30 | 4.86±2.15 |
30/58/10/2 | 65.27±10.81 | 2.65±0.44 | |
30/50/10/10 | 54.75±12.91 | 2.22±0.52 |
a Et=乙醇;W=水;G=甘油;E=促进剂=甘油三醋酸酯
b 平均值±SD
这些结果表明甘油三醋酸酯不能提高凝胶制剂(例如可用于液体储库装置的凝胶制剂)中奥昔布宁的吸收量。在含有甘油三醋酸酯的系统中,吸收量确实降低,这与美国专利4879297(Mahjour等)相一致。因此,即使甘油三醋酸酯可以非常有效地在基质制剂中促进奥昔布宁的渗透,却不能在储库制剂中促进同种药物的渗透。
实施例5
下列配方是本发明范围内的其它组合物的例子,这些组合物在基质贴剂中含有甘油三醋酸酯和其它强碱性活性渗透剂。所述基质贴剂可根据实施例1的方法制备。可以使用多种不同类型的压敏型的可与皮肤接触的药物级粘合剂,例如丙烯酸共聚物粘合剂或“丙烯酸粘合剂”(例如DuroTak80-1196,National Starch;Gelva 737,Monsato Co.,St.Louis,Missouri)、橡胶基质的粘合剂或“橡胶粘合剂”如聚异丁烯或“PIB粘合剂”(例如Adhesive Research MA-24)、以及硅氧烷基质的粘合剂或“硅氧烷粘合剂”如Dow Bio-PSA。所有组合物用以重量百分比所表示的范围给出。
配方5-A
吗啡 0.1-2.5%
丙烯酸粘合剂 82.5-94.9%
甘油三醋酸酯 5.0-15.0%
配方5-B
二氢吗啡酮 30.0-40.0%
PIB粘合剂 55.0-68.0%
甘油三醋酸酯 2.0-20.0%
配方5-C
东莨菪碱 2.0-10.0%
PIB粘合剂 75.0-93.0%
甘油三醋酸酯 5.0-15.0%
配方5-D
阿托品 1.0-10.0%
硅氧烷粘合剂 85.0-98.0%
甘油三醋酸酯 1.0-5.0%
配方5-E
可卡因 0.5-5.0%
丙烯酸粘合剂 80.0-94.5%
甘油三醋酸酯 5.0-15.0%
配方5-F
叔丁啡 0.5-5.0%
PIB粘合剂 85.0-97.5%
甘油三醋酸酯 2.5-10.0%
配方5-G
东莨菪碱 0.1-5.0%
丙烯酸粘合剂 90.0-96.4%
甘油三醋酸酯 1.0-5.0%
配方5-H
氯丙嗪 0.5-7.5%
丙烯酸粘合剂 78.5-94.5%
甘油三醋酸酯 1.0-20.0%
配方5-I
丙咪嗪 0.5-5.0%
丙烯酸粘合剂 85.0-97.0%
甘油三醋酸酯 2.5-10.0%
配方5-J
去甲丙咪嗪 0.5-5.0%
丙烯酸粘合剂 87.5-94.0%
甘油三醋酸酯 2.5-7.5%
配方5-K
哌醋甲酯 0.1-1.0%
硅氧烷粘合剂 94.0-97.4%
甘油三醋酸酯 2.5-5.0%
配方5-L
去甲麻黄碱 2.5-10.0%
丙烯酸粘合剂 82.5-95.0%
甘油三醋酸酯 2.5-7.5%
配方5-M
利多卡因 0.1-5.0%
丙烯酸粘合剂 90.0-98.9%
甘油三醋酸酯 1.0-5.0%
配方5-N
普鲁卡因 0.1-5.0%
PIB粘合剂 80.0-97.4%
甘油三醋酸酯 1.0-5.0%
配方5-0
吲哚心安 0.1-10.0%
丙烯酸粘合剂 65.0-94.9%
甘油三醋酸酯 5.0-25.0%
配方5-P
萘羟心安 0.1-10.5%
丙烯酸粘合剂 74.5-94.9%
甘油三醋酸酯 5.0-15.0%
配方5-Q
氟苯氧苯胺 5.0-40.0%
丙烯酸粘合剂 35.0-84.9%
甘油三醋酸酯 5.0-25.0%
配方5-R
氟苯氧苯胺 5.0-40.5%
PIB粘合剂 55.5-90.0%
甘油三醋酸酯 5.0-15.0%
配方5-S
氟苯氧苯胺 5.0-40.5%
硅氧烷粘合剂 55.5-89.5%
甘油三醋酸酯 5.0-15.0%
配方5-T
氟苯氧苯胺 5.0-40.5%
EVA共聚物 55.5-89.5%
甘油三醋酸酯 5.0-15.0%
配方5-U
氟苯氧苯胺 5.0-40.5%
苯乙烯-橡胶嵌段共聚物 55.5-89.5%
甘油三醋酸酯 5.0-15.0%
配方5-V
异丙安宁 5.0-40.5%
苯乙烯-橡胶嵌段共聚物(PIB粘合剂) 55.5-89.5%
甘油三醋酸酯 5.0-15.0%
Claims (28)
1.促进pKa为约8.0或更大的碱性药物的经皮渗透速率的方法,包括向选定的应用部位施用基质贴剂,所述基质贴剂含有:
(a)生物相容性聚合物层;
(b)有效量的可经皮吸收的pKa为约8.0或更大的碱性药物;和
(c)有效量的基本由甘油三醋酸酯组成的渗透促进剂。
2.权利要求1所述的方法,其中所述的碱性药物选自奥昔布宁、东莨菪碱、氟苯氧苯胺、肾上腺素、吗啡、二氢吗啡酮、阿托品、可卡因、叔丁啡、氯丙嗪、丙咪嗪、去甲丙咪嗪、哌醋甲酯、去氧麻黄碱、利多卡因、普鲁卡因、吲哚心安、萘羟心安、异丙安宁以及它们的酸加成盐。
3.权利要求2所述的方法,其中所述的渗透促进剂的有效量包括约0.1%-约50%重的甘油三醋酸酯。
4.权利要求3所述的方法,其中所述的聚合物层含有粘合剂。
5.权利要求4所述的方法,其中所述的粘合剂选自丙烯酸类、乙烯基乙酸酯类、天然和合成橡胶、乙烯乙酸乙烯酯共聚物、聚硅氧烷、聚丙烯酸酯、聚氨基甲酸乙酯、增塑量的聚醚嵌段酰胺共聚物、增塑的聚苯乙烯橡胶嵌段共聚物,以及它们的混合物。
6.权利要求5所述的方法,其中所述的碱性药物选自奥昔布宁及其酸加成盐。
7.权利要求6所述的方法,其中所述的渗透促进剂的有效量包括约0.1%-约40%重的甘油三醋酸酯。
8.权利要求7所述的方法,其中的基质贴剂还含有选自如下组成的成分:稀释剂、赋形剂、乳化剂、增塑剂、降低对皮肤刺激性的试剂、载体、及其混合物。
9.权利要求8所述的方法,其中所述的碱性药物是奥昔布宁。
10.权利要求9所述的方法,其中所述的粘合剂是丙烯酸共聚物。
11.权利要求10所述的方法,其中的渗促进剂含有约2%-约20%重的甘油三醋酸酯。
12.权利要求11所述的方法,其中所述的基质贴剂含有降低对皮肤刺激性的试剂,其中所述的降低对皮肤刺激性的试剂是甘油。
13.权利要求3所述的方法,其中所述的聚合物层压合在粘合剂上。
14.权利要求3所述的方法,其中所述的聚合物层用粘合剂涂覆。
15.用于对pKa为约8.0或更大的碱性药物进行经皮给药的基质贴剂,其含有:
(a)生物相容性聚合物层;
(b)有效量的可经皮吸收的pKa为约8.0或更大的碱性药物;和
(c)有效量的基本由甘油三醋酸酯组成的渗透促进剂。
16.权利要求15所述的基质贴剂,其中所述的碱性药物选自奥昔布宁、东莨菪碱、氟苯氧苯胺、肾上腺素、吗啡、二氢吗啡酮、阿托品、可卡因、叔丁啡、氯丙嗪、丙咪嗪、去甲丙咪嗪、哌醋甲酯、去氧麻黄碱、利多卡因、普鲁卡因、吲哚心安、萘羟心安、异丙安宁以及它们的酸加成盐。
17.权利要求16所述的基质贴剂,其中所述的渗透促进剂的有效量包括约0.1%-约50%重的甘油三醋酸酯。
18.权利要求17所述的基质贴剂,其中所述的聚合物层含有粘合剂。
19.权利要求18所述的基质贴剂,其中所述的粘合剂选自丙烯酸类、乙烯基乙酸酯类、天然和合成橡胶、乙烯乙酸乙烯酯共聚物、聚硅氧烷、聚丙烯酸酯、聚氨基甲酸乙酯、增塑量的聚醚嵌段酰胺共聚物、增塑的聚苯乙烯橡胶嵌段共聚物,以及它们的混合物。
20.权利要求19所述的基质贴剂,其中所述的碱性药物选自奥昔布宁及其酸加成盐。
21.权利要求20所述的基质贴剂,其中所述的渗透促进剂的有效量包括约0.1%-约40%重的甘油三醋酸酯。
22.权利要求21所述的基质贴剂,其中的基质贴剂还含有选自如下组成的成分:稀释剂、赋形剂、乳化剂、增塑剂、降低对皮肤刺激性的试剂、载体、及其混合物。
23.权利要求22所述的基质贴剂,其中所述的碱性药物是奥昔布宁。
24.权利要求23所述的基质贴剂,其中所述的粘合剂是丙烯酸共聚物。
25.权利要求24所述的基质贴剂,其中的渗促进剂含有约2%-约20%重的甘油三醋酸酯。
26.权利要求25所述的基质贴剂,其中所述的基质贴剂含有降低对皮肤刺激性的试剂,其中所述的降低对皮肤刺激性的试剂是甘油。
27.权利要求17所述的基质贴剂,其中所述的聚合物层压合在粘合剂上。
28.权利要求17所述的基质贴剂,其中所述的聚合物层用粘合剂涂覆。
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US08/429,757 | 1995-04-26 | ||
US08/429,757 US5601839A (en) | 1995-04-26 | 1995-04-26 | Triacetin as a penetration enhancer for transdermal delivery of a basic drug |
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CNB961934565A Division CN1143688C (zh) | 1995-04-26 | 1996-04-08 | 透皮促进剂甘油三醋酸酯 |
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CNA2004100392112A Pending CN1507918A (zh) | 1995-04-26 | 1996-04-08 | 透皮促进剂甘油三醋酸酯 |
CNB961934565A Expired - Lifetime CN1143688C (zh) | 1995-04-26 | 1996-04-08 | 透皮促进剂甘油三醋酸酯 |
CNB2005100719966A Expired - Lifetime CN100374161C (zh) | 1995-04-26 | 1996-04-08 | 透皮促进剂甘油三醋酸酯 |
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CNB961934565A Expired - Lifetime CN1143688C (zh) | 1995-04-26 | 1996-04-08 | 透皮促进剂甘油三醋酸酯 |
CNB2005100719966A Expired - Lifetime CN100374161C (zh) | 1995-04-26 | 1996-04-08 | 透皮促进剂甘油三醋酸酯 |
Country Status (19)
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US (2) | US5601839A (zh) |
EP (1) | EP0871420B1 (zh) |
JP (2) | JP3228341B2 (zh) |
KR (1) | KR100275593B1 (zh) |
CN (3) | CN1507918A (zh) |
AR (1) | AR001721A1 (zh) |
AT (1) | ATE205694T1 (zh) |
AU (1) | AU696777B2 (zh) |
CA (1) | CA2217888C (zh) |
DE (2) | DE69615399T2 (zh) |
DK (1) | DK0871420T3 (zh) |
ES (1) | ES2163012T3 (zh) |
FR (1) | FR05C0008I2 (zh) |
HK (1) | HK1084320A1 (zh) |
NL (1) | NL300200I1 (zh) |
NZ (1) | NZ306249A (zh) |
PT (1) | PT871420E (zh) |
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Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN103919754A (zh) * | 2013-01-15 | 2014-07-16 | 江苏康倍得药业有限公司 | 奥昔布宁药物组合物及其应用 |
Families Citing this family (126)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5474783A (en) * | 1988-03-04 | 1995-12-12 | Noven Pharmaceuticals, Inc. | Solubility parameter based drug delivery system and method for altering drug saturation concentration |
US5633000A (en) * | 1994-06-23 | 1997-05-27 | Axxia Technologies | Subcutaneous implant |
US5785991A (en) * | 1995-06-07 | 1998-07-28 | Alza Corporation | Skin permeation enhancer compositions comprising glycerol monolaurate and lauryl acetate |
US6512010B1 (en) | 1996-07-15 | 2003-01-28 | Alza Corporation | Formulations for the administration of fluoxetine |
WO1998002169A2 (en) * | 1996-07-15 | 1998-01-22 | Alza Corporation | Novel formulations for the administration of fluoxetine |
US6572880B2 (en) | 1996-10-24 | 2003-06-03 | Pharmaceutical Applications Associates Llc | Methods and transdermal compositions for pain relief |
US6290986B1 (en) | 1996-10-24 | 2001-09-18 | Pharmaceutical Applications Associates, Llc | Method and composition for transdermal administration of pharmacologic agents |
US6479074B2 (en) | 1996-10-24 | 2002-11-12 | Pharmaceutical Applications Associates Llc | Methods and transdermal compositions for pain relief |
CA2263334A1 (en) * | 1996-10-30 | 1998-05-07 | Sonal R. Patel | Fatty acid esters of lactic acid salts as permeation enhancers |
US20060002949A1 (en) | 1996-11-14 | 2006-01-05 | Army Govt. Of The Usa, As Rep. By Secretary Of The Office Of The Command Judge Advocate, Hq Usamrmc. | Transcutaneous immunization without heterologous adjuvant |
US6797276B1 (en) | 1996-11-14 | 2004-09-28 | The United States Of America As Represented By The Secretary Of The Army | Use of penetration enhancers and barrier disruption agents to enhance the transcutaneous immune response |
US5980898A (en) * | 1996-11-14 | 1999-11-09 | The United States Of America As Represented By The U.S. Army Medical Research & Material Command | Adjuvant for transcutaneous immunization |
US6203817B1 (en) | 1997-02-19 | 2001-03-20 | Alza Corporation | Reduction of skin reactions caused by transdermal drug delivery |
DE19706824C1 (de) * | 1997-02-21 | 1998-03-26 | Lohmann Therapie Syst Lts | Transdermales oder topisches Plastersystem mit Polyacrylatmatrix mit verbesserten physikalischen Eigenschaften |
US5968547A (en) | 1997-02-24 | 1999-10-19 | Euro-Celtique, S.A. | Method of providing sustained analgesia with buprenorphine |
CN1172674C (zh) * | 1997-11-10 | 2004-10-27 | 赛勒吉药物股份有限公司 | 促进渗透和减少刺激的系统 |
TW492882B (en) * | 1997-11-28 | 2002-07-01 | Caleb Pharmaceuticals Inc | Cholinergic antagonist plaster composition |
EP1459741A1 (en) * | 1997-12-15 | 2004-09-22 | Noven Pharmaceuticals, Inc. | Compositions and methods for treatment of attention deficit disorder and attention deficit/hyperactivity disorder with menthylphenidate |
US20020102291A1 (en) * | 1997-12-15 | 2002-08-01 | Noven Pharmaceuticals, Inc. | Compositions and method for treatment of attention deficit disorder and attention deficit/hyperactivity disorder with methylphenidate |
US6210705B1 (en) * | 1997-12-15 | 2001-04-03 | Noven Pharmaceuticals, Nc. | Compositions and methods for treatment of attention deficit disorder and attention deficit/hyperactivity disorder with methylphenidate |
US6727401B1 (en) * | 1998-02-12 | 2004-04-27 | Watson Pharmaceuticals, Inc. | Pressure sensitive adhesive matrix patch for the treatment of onychomycosis |
DE19812413C1 (de) * | 1998-03-20 | 1999-06-10 | Sanol Arznei Schwarz Gmbh | Transdermales Therapeutisches System (TTS) Oxybutynin enthaltend |
DE19814084B4 (de) * | 1998-03-30 | 2005-12-22 | Lts Lohmann Therapie-Systeme Ag | D2-Agonist enthaltendes transdermales therapeutisches System zur Behandlung des Parkinson-Syndroms und Verfahren zu seiner Herstellung |
US6475514B1 (en) | 1998-12-03 | 2002-11-05 | Andrew Blitzer | Athletic patch |
KR100383252B1 (ko) * | 1998-12-17 | 2003-07-16 | 주식회사 삼양사 | 부프레놀핀을함유하는경피투여조성물및이를포함하는패취 |
AU3536799A (en) * | 1999-04-26 | 2000-11-10 | Lead Chemical Co., Ltd. | Percutaneous preparations containing oxybutynin |
AU6403600A (en) * | 1999-06-10 | 2001-01-02 | Sepracor, Inc. | Methods and compositions for treating urinary frequency and urgency using optically pure (s)-oxybutynin |
WO2001000139A1 (en) | 1999-06-25 | 2001-01-04 | Durham Pharmaceuticals Ltd. | Topical formulations comprising skin penetration agents and the use thereof |
GB9918735D0 (en) * | 1999-08-09 | 1999-10-13 | Straken Limited | Transdermal patches |
US20010049546A1 (en) * | 2000-02-08 | 2001-12-06 | Israel Dvoretzky | Multi-purpose drug and heat therapy treatment system |
US6436428B1 (en) | 2000-03-21 | 2002-08-20 | Enhance Pharmaceuticals, Inc. | Device and method for treating urinary incontinence in females |
US20030124177A1 (en) * | 2000-04-26 | 2003-07-03 | Watson Pharmaceuticals, Inc. | Compositions and methods for transdermal oxybutynin therapy |
US7179483B2 (en) * | 2000-04-26 | 2007-02-20 | Watson Pharmaceuticals, Inc. | Compositions and methods for transdermal oxybutynin therapy |
US7029694B2 (en) * | 2000-04-26 | 2006-04-18 | Watson Laboratories, Inc. | Compositions and methods for transdermal oxybutynin therapy |
MXPA02010542A (es) * | 2000-04-26 | 2003-10-14 | Watson Pharmaceuticals Inc | Minimizacion de experiencias adversas asociadas con la terapia con oxibutinina. |
ATE485837T1 (de) * | 2000-08-03 | 2010-11-15 | Antares Pharma Ipl Ag | Zusammensetzung zur transdermalen und/oder transmukosalen verabreichung von wirkstoffen, die ausreichende therapeutische spiegel garantiert |
US7198801B2 (en) * | 2000-08-03 | 2007-04-03 | Antares Pharma Ipl Ag | Formulations for transdermal or transmucosal application |
US8980290B2 (en) | 2000-08-03 | 2015-03-17 | Antares Pharma Ipl Ag | Transdermal compositions for anticholinergic agents |
US20070225379A1 (en) * | 2001-08-03 | 2007-09-27 | Carrara Dario Norberto R | Transdermal delivery of systemically active central nervous system drugs |
DE10041478A1 (de) * | 2000-08-24 | 2002-03-14 | Sanol Arznei Schwarz Gmbh | Neue pharmazeutische Zusammensetzung |
DE10060550C1 (de) * | 2000-12-06 | 2002-04-18 | Lohmann Therapie Syst Lts | Transdermales therapeutisches System mit dem Wirkstoff Oxybutynin und Verfahren zur Herstellung Oxybutynin enthaltender Wirkstoffschichten |
US6585963B1 (en) * | 2001-02-15 | 2003-07-01 | Watson Pharmaceuticals, Inc. | Nail compositions and methods of administering same |
US20030026830A1 (en) * | 2001-05-08 | 2003-02-06 | Thomas Lauterback | Transdermal therapeutic system for parkinson's disease inducing high plasma levels of rotigotine |
US20030027793A1 (en) * | 2001-05-08 | 2003-02-06 | Thomas Lauterback | Transdermal treatment of parkinson's disease |
CA2446619C (en) * | 2001-05-11 | 2011-04-26 | Elan Corporation, Plc | Permeation enhancers |
US6913760B2 (en) * | 2001-08-06 | 2005-07-05 | New England Medical Hospitals, Inc. | Drug delivery composition |
US20030175329A1 (en) * | 2001-10-04 | 2003-09-18 | Cellegy Pharmaceuticals, Inc. | Semisolid topical hormonal compositions and methods for treatment |
US7921999B1 (en) * | 2001-12-20 | 2011-04-12 | Watson Laboratories, Inc. | Peelable pouch for transdermal patch and method for packaging |
JP4295467B2 (ja) * | 2002-04-12 | 2009-07-15 | 日東電工株式会社 | 貼付剤およびその製造方法 |
KR100469995B1 (ko) * | 2002-05-20 | 2005-02-05 | 안국약품 주식회사 | 천식치료제를 함유한 매트릭스형 패취 |
JP4323138B2 (ja) * | 2002-06-05 | 2009-09-02 | 日東電工株式会社 | 経皮吸収型製剤およびその製造方法 |
DE10234673B4 (de) * | 2002-07-30 | 2007-08-16 | Schwarz Pharma Ag | Heißschmelz-TTS zur Verabreichung von Rotigotin und Verfahren zu seiner Herstellung sowie Verwendung von Rotigotin bei der Herstellung eines TTS im Heißschmelzverfahren |
US8246979B2 (en) | 2002-07-30 | 2012-08-21 | Ucb Pharma Gmbh | Transdermal delivery system for the administration of rotigotine |
EP1386604A1 (en) * | 2002-07-30 | 2004-02-04 | Schwarz Pharma Ag | Improved transdermal delivery system |
US8211462B2 (en) * | 2002-07-30 | 2012-07-03 | Ucb Pharma Gmbh | Hot-melt TTS for administering rotigotine |
US8246980B2 (en) * | 2002-07-30 | 2012-08-21 | Ucb Pharma Gmbh | Transdermal delivery system |
US20040197397A1 (en) * | 2002-08-30 | 2004-10-07 | Watson Pharmaceuticals, Inc. | Drug delivery system for treatment of urinary incontinence |
DE10251256A1 (de) * | 2002-11-04 | 2004-05-13 | Novosis Ag | Transdermales Wirkstoffabgabesystem für Oxybutynin |
EP1426049B1 (en) * | 2002-12-02 | 2005-05-18 | Schwarz Pharma Ag | Iontophoretic delivery of rotigotine for the treatment of Parkinson's disease |
DE10261696A1 (de) | 2002-12-30 | 2004-07-15 | Schwarz Pharma Ag | Vorrichtung zur transdermalen Verabreichung von Rotigotin-Base |
ATE461681T1 (de) * | 2003-04-29 | 2010-04-15 | Gen Hospital Corp | Verfahren und vorrichtungen für die verzögerte freisetzung von mehreren arzneimitteln |
DE10338174A1 (de) * | 2003-08-20 | 2005-03-24 | Lts Lohmann Therapie-Systeme Ag | Transdermale Arzneimittelzubereitungen mit Wirkstoffkombinationen zur Behandlung der Parkinson-Krankheit |
MXPA06003316A (es) * | 2003-10-10 | 2006-06-08 | Antares Pharma Ipl Ag | Formulacion farmaceutica transdermica para minimizar los residuos en la piel. |
WO2005077364A1 (ja) * | 2004-02-18 | 2005-08-25 | Yamanouchi Pharmaceutical Co., Ltd. | ソリフェナシンの経皮投与製剤およびその経皮透過改善方法 |
US7425340B2 (en) * | 2004-05-07 | 2008-09-16 | Antares Pharma Ipl Ag | Permeation enhancing compositions for anticholinergic agents |
EP1611882B1 (en) * | 2004-06-01 | 2010-04-07 | Hisamitsu Pharmaceutical Co., Inc. | Adhesive patch |
EP1802258A4 (en) | 2004-09-13 | 2015-09-23 | Chrono Therapeutics Inc | BIOSYNCHRONE TRANSDERMAL MEDICINES |
US8252321B2 (en) | 2004-09-13 | 2012-08-28 | Chrono Therapeutics, Inc. | Biosynchronous transdermal drug delivery for longevity, anti-aging, fatigue management, obesity, weight loss, weight management, delivery of nutraceuticals, and the treatment of hyperglycemia, alzheimer's disease, sleep disorders, parkinson's disease, aids, epilepsy, attention deficit disorder, nicotine addiction, cancer, headache and pain control, asthma, angina, hypertension, depression, cold, flu and the like |
NZ582975A (en) | 2004-10-21 | 2011-07-29 | Durect Corp | Transdermal delivery systems delivering sufentanil |
US8252320B2 (en) | 2004-10-21 | 2012-08-28 | Durect Corporation | Transdermal delivery system for sufentanil |
US20070053965A1 (en) * | 2005-02-25 | 2007-03-08 | Gruenenthal Gmbh | Kit comprising a plaster, optionally containing an active substance, and an agent that at least partially reduces skin irritation |
WO2007124250A2 (en) | 2006-04-21 | 2007-11-01 | Antares Pharma Ipl Ag | Methods of treating hot flashes with formulations for transdermal or transmucosal application |
US8372040B2 (en) | 2005-05-24 | 2013-02-12 | Chrono Therapeutics, Inc. | Portable drug delivery device including a detachable and replaceable administration or dosing element |
US8067399B2 (en) | 2005-05-27 | 2011-11-29 | Antares Pharma Ipl Ag | Method and apparatus for transdermal or transmucosal application of testosterone |
US20070065494A1 (en) * | 2005-08-03 | 2007-03-22 | Watson Laboratories, Inc. | Formulations and Methods for Enhancing the Transdermal Penetration of a Drug |
US10137135B2 (en) * | 2005-08-15 | 2018-11-27 | Allergan Sales, Llc | Formulations and methods for providing progestin-only contraception while minimizing adverse side effects associated therewith |
JP5037831B2 (ja) * | 2006-02-15 | 2012-10-03 | 久光製薬株式会社 | 凝集力向上及び徐放化の外用貼付剤 |
CN101431988A (zh) * | 2006-02-27 | 2009-05-13 | 诺芬药品公司 | 包含东莨菪碱的透皮治疗系统 |
TW200817049A (en) * | 2006-06-05 | 2008-04-16 | Verus Pharmaceuticals Inc | Epinephrine dosing regimens comprising buccal, lingual or sublingual and injectable dosage forms |
TW200815048A (en) * | 2006-06-05 | 2008-04-01 | Verus Pharmaceuticals Inc | Methods for buccal, lingual or sublingual dosing regimens of epinephrine for the treatment of allergic emergencies |
WO2008067991A2 (en) * | 2006-12-08 | 2008-06-12 | Antares Pharma Ipl Ag | Skin-friendly drug complexes for transdermal administration |
ATE482703T1 (de) * | 2006-12-28 | 2010-10-15 | Kaken Pharma Co Ltd | Gelzusammensetzung zur behandlung von mykose |
NZ552816A (en) * | 2007-01-24 | 2009-05-31 | Bomac Research Ltd | Formulation for transdermal administration of antihyperthyroid drug comprising a penetration enhancer selected from oleic acid, d-limonene, pyrrolidones, a C2-C8 alcohol, glycol ethers, triacetin and combinations thereof |
RU2428186C2 (ru) | 2007-03-02 | 2011-09-10 | Теика Фармасьютикал Ко., Лтд. | Лекарственная композиция для чрескожной абсорбции, изделие, сохраняющее лекарственную композицию, и содержащий ее препарат для чрескожной абсорбции |
US20080226698A1 (en) * | 2007-03-16 | 2008-09-18 | Mylan Technologies, Inc. | Amorphous drug transdermal systems, manufacturing methods, and stabilization |
US10183001B1 (en) * | 2007-05-22 | 2019-01-22 | Pisgah Laboratories, Inc. | Opioid and attention deficit hyperactivity disorder medications possessing abuse deterrent and anti-dose dumping safety features |
EP2182987A4 (en) * | 2007-07-30 | 2011-11-02 | Medacure International Inc | FORMULATION FOR IMMUNE SYSTEM MODULATOR |
US20090098191A1 (en) * | 2007-10-16 | 2009-04-16 | Anderson Christopher G | Use of bases to stabilize transdermal formulations |
WO2009075324A1 (ja) * | 2007-12-12 | 2009-06-18 | Teikoku Seiyaku Co., Ltd. | ロキソプロフェン含有水性貼付剤 |
US20090297591A1 (en) * | 2008-05-30 | 2009-12-03 | Orient Pharma Co., Ltd. | Compositions And Methods For The Transdermal Delivery Of Pharmaceutical Compounds |
US8404255B2 (en) * | 2008-07-29 | 2013-03-26 | Matt Gibson | System and method for transdermal drug delivery |
KR101258336B1 (ko) * | 2008-10-02 | 2013-04-25 | 밀란 인크. | 다층 접착제 라미네이트를 제조하는 방법 |
JP5155128B2 (ja) * | 2008-12-11 | 2013-02-27 | 日東電工株式会社 | メチルフェニデート貼付製剤 |
US8920392B2 (en) | 2009-05-05 | 2014-12-30 | Watson Laboratories, Inc. | Method for treating overactive bladders and a device for storage and administration of topical oxybutynin compositions |
CA2778103C (en) * | 2009-10-21 | 2017-11-07 | Teikoku Seiyaku Co., Ltd. | Donepezil-containing transdermal absorption formulation |
TW201129397A (en) | 2009-12-15 | 2011-09-01 | Teikoku Seiyaku Kk | Dermal absorption agent comprising alkali anti-inflammatory analgesic agent |
KR101955175B1 (ko) | 2010-04-13 | 2019-03-06 | 나지브 바불 | 1-메틸-2'-6'-피페콜옥실리디드의 피부 약제학적 조성물 및 사용 방법 |
CA2796877A1 (en) | 2010-04-30 | 2011-11-03 | Merck Sharp & Dohme Corp. | Novel beta 3 adrenergic receptor agonists |
FR2972923B1 (fr) * | 2011-03-25 | 2013-08-23 | Urgo Lab | Composition filmogene contenant un filtre solaire, son utilisation pour le traitement des cicatrices |
US11786455B2 (en) | 2011-05-10 | 2023-10-17 | Itochu Chemical Frontier Corporation | Non-aqueous patch |
WO2012153396A1 (ja) | 2011-05-10 | 2012-11-15 | 伊藤忠ケミカルフロンティア株式会社 | 非水性貼付剤 |
US9925264B2 (en) | 2011-05-10 | 2018-03-27 | Itochu Chemical Frontier Corporation | Non-aqueous patch |
CN103781478A (zh) * | 2011-06-24 | 2014-05-07 | 艾森达制药有限公司 | 用以改善酯类前药吸收率的方法与改良的药学组合物 |
US20130017259A1 (en) | 2011-07-06 | 2013-01-17 | The Parkinson's Institute | Compositions and Methods for Treatment of Symptoms in Parkinson's Disease Patients |
PL2823815T3 (pl) | 2011-09-27 | 2018-10-31 | Itochu Chemical Frontier Corporation | Niewodny plaster |
ES2786504T3 (es) * | 2011-10-26 | 2020-10-13 | Hisamitsu Pharmaceutical Co | Preparación de absorción transdérmica que contiene oxibutinina |
US20130266643A1 (en) * | 2012-04-10 | 2013-10-10 | Hpo Life Sciences, Inc. | Compositions comprising glyceryl-triacetate (GTA) and uses in human performance optimization and thermogenesis |
JP6129184B2 (ja) * | 2012-09-03 | 2017-05-17 | 第一三共株式会社 | ヒドロモルフォン塩酸塩含有の経口用徐放性医薬組成物 |
RU2657749C2 (ru) | 2012-09-21 | 2018-06-15 | Интенсити Терапьютикс, Инк | Способы лечения рака |
US9072682B2 (en) | 2012-12-31 | 2015-07-07 | Mylan Inc. | Transdermal dosage form for low-melting point active agent |
US10105487B2 (en) | 2013-01-24 | 2018-10-23 | Chrono Therapeutics Inc. | Optimized bio-synchronous bioactive agent delivery system |
AR095258A1 (es) * | 2013-03-14 | 2015-09-30 | Noven Pharma | Composiciones transdérmicas de metilfenidato con adhesivos a base de goma |
US20170217976A1 (en) * | 2014-03-21 | 2017-08-03 | Chironwells Gmbh | 6-(amino acid)-morphinan derivatives in combination with permeation enhancers for use as an orally, rectally, transdermally or nasally administered medicament |
US10149828B2 (en) | 2015-01-09 | 2018-12-11 | Chase Pharmaceuticals Corporation | Oxybutynin transdermal therapeutic system combination |
US10213586B2 (en) | 2015-01-28 | 2019-02-26 | Chrono Therapeutics Inc. | Drug delivery methods and systems |
CA2977814A1 (en) | 2015-03-12 | 2016-09-15 | Chrono Therapeutics Inc. | Craving input and support system |
CA3049529A1 (en) | 2017-01-06 | 2018-07-12 | Chrono Therapeutics Inc. | Transdermal drug delivery devices and methods |
JP2019034905A (ja) * | 2017-08-17 | 2019-03-07 | コスメディ製薬株式会社 | デヒドロ酢酸含有経皮吸収製剤 |
WO2019089523A1 (en) * | 2017-10-30 | 2019-05-09 | Theracaine Llc | Hydrophobic acid addition salts and pharmaceutical formulations thereof |
KR101975677B1 (ko) | 2017-11-20 | 2019-05-07 | 양진석 | 환편기용 보풀 제거장치 |
CA3101966A1 (en) | 2018-05-29 | 2019-12-05 | Morningside Venture Investments Limited | Drug delivery methods and systems |
WO2020085879A1 (ko) | 2018-10-26 | 2020-04-30 | 경상대학교산학협력단 | 아세틴 화합물의 생물학적 제조 방법 |
CN113384558A (zh) * | 2021-02-01 | 2021-09-14 | 深圳普洛美康材料有限公司 | 一种递送大麻活性物质的透皮贴剂 |
JP2022122784A (ja) | 2021-02-10 | 2022-08-23 | コスメディ製薬株式会社 | 酸化防止剤含有経皮吸収製剤 |
KR20230026232A (ko) | 2021-08-17 | 2023-02-24 | 신신제약 주식회사 | 옥시부티닌을 함유하는 경피흡수제제 |
CN113749968A (zh) * | 2021-10-26 | 2021-12-07 | 奥易生物科技(杭州)有限公司 | 一种快速透皮吸收的化妆品及其制备方法 |
Family Cites Families (20)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US466926A (en) * | 1892-01-12 | Advertising device | ||
US4336262A (en) * | 1973-02-23 | 1982-06-22 | Fisons Ltd. | Pour-on veterinary anthelmintic |
JPS61502760A (ja) * | 1984-07-24 | 1986-11-27 | キイ・フア−マシユ−テイカルズ・インコ−ポレイテツド | 粘着性経皮投与層 |
US4895727A (en) * | 1985-05-03 | 1990-01-23 | Chemex Pharmaceuticals, Inc. | Pharmaceutical vehicles for exhancing penetration and retention in the skin |
US4666926A (en) * | 1986-02-27 | 1987-05-19 | Warner-Lambert Company | Transdermal formulations |
US4908389A (en) * | 1986-08-27 | 1990-03-13 | Warner-Lambert Company | Penetration enhancement system |
JPH0676327B2 (ja) * | 1987-04-14 | 1994-09-28 | 株式会社大塚製薬工場 | ステロイド軟膏製剤 |
US4857313A (en) * | 1987-05-28 | 1989-08-15 | Warner-Lambert Company | Transdermal drug delivery device comprising copolymers of N-morpholinoethyl methacrylate and 2-hydroxylmethacrylate |
US4879297A (en) * | 1987-06-01 | 1989-11-07 | Warner-Lambert Company | Fatty acids and their small chain esters as penetration enhancers in aqueous systems |
US4789547A (en) * | 1987-06-17 | 1988-12-06 | Warner-Lambert Company | Transdermal matrix system |
US4814173A (en) * | 1987-09-08 | 1989-03-21 | Warner-Lambert Company | Silicone elastomer transdermal matrix system |
JP2526256B2 (ja) * | 1987-11-17 | 1996-08-21 | 清水建設株式会社 | 構造物の振動抑制装置 |
US5019395A (en) * | 1988-03-08 | 1991-05-28 | Warner-Lambert Company | Compositions with enhanced penetration |
DE3913954A1 (de) * | 1989-04-27 | 1990-10-31 | Stief Georg | Arzneimittel zur behandlung erektiler dysfunktionen |
EP0612526A4 (en) * | 1991-11-15 | 1995-08-02 | Ss Pharmaceutical Co | ANTI-INFLAMMATORY AND ANALGESIC PLATTER. |
JP3130350B2 (ja) * | 1991-11-28 | 2001-01-31 | 積水化学工業株式会社 | 経皮吸収製剤 |
TW224048B (zh) * | 1992-03-30 | 1994-05-21 | Hoechst Roussel Pharma | |
WO1993025168A1 (en) * | 1992-06-11 | 1993-12-23 | Theratech, Inc. | The use of glycerin in moderating transdermal drug delivery |
JPH08245377A (ja) * | 1995-03-15 | 1996-09-24 | Yamanouchi Pharmaceut Co Ltd | 経皮吸収用製剤 |
JPH09309783A (ja) * | 1996-05-20 | 1997-12-02 | Chisso Corp | 改良された土中崩壊型被覆粒状肥料 |
-
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Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN103919754A (zh) * | 2013-01-15 | 2014-07-16 | 江苏康倍得药业有限公司 | 奥昔布宁药物组合物及其应用 |
CN103919754B (zh) * | 2013-01-15 | 2018-11-06 | 江苏康倍得药业股份有限公司 | 奥昔布宁药物组合物及其应用 |
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