CN1144087A - 药物释放控制型透皮吸收制剂 - Google Patents
药物释放控制型透皮吸收制剂 Download PDFInfo
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- CN1144087A CN1144087A CN96106266A CN96106266A CN1144087A CN 1144087 A CN1144087 A CN 1144087A CN 96106266 A CN96106266 A CN 96106266A CN 96106266 A CN96106266 A CN 96106266A CN 1144087 A CN1144087 A CN 1144087A
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- rubber
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Abstract
本发明提供一种贮存稳定性优良的可以任意地控制药物的释放速度的药物释放控制型透皮吸收制剂。该透皮吸收制剂是在橡胶类粘合剂1中分散由内藏有药物的水溶性的囊壁物质形成的微囊2及淀粉与聚丙烯酸盐的接枝共聚物等水不溶性且橡胶及橡胶溶剂不溶性的吸水性树脂粉末3制成的。
Description
本发明涉及一种透皮吸收制剂，该透皮吸收制剂可根据治疗目的而任意控制药物的释放速度、贮存稳定性非常优良、且不会因为粘贴而引起斑疹等，因此安全性很高。
以天然及合成橡胶类粘合剂为主成分的粘贴剂，因药物的分解或挥发等易引起含量降低或粘合力下降等制剂方面的变化，存在贮存稳定性差的缺点。
另外，橡胶类粘合剂因不吸收水分，所以粘贴时出汗或皮肤水分高的情况下容易剥落，在密封性高的情况下会因为泡胀而形成斑疹。使用粘贴剂时当通气性差或完全没有的情况下，由于粘贴部位的角质细胞被密封，因此皮肤被水分泡涨成为过水和状态。另外，与此相反，因为干燥的表皮层的脆化，在剥离粘贴剂时，皮肤的脆弱层被剥离。此状态下如果在同一部位反复粘贴几次之后，则角质层被破坏，由于血管扩张而产生红斑进而诱发斑疹。另外，虽然对干燥的缺乏油脂的老人的皮肤很容易粘贴，但对脂肪皮肤、湿润皮肤来说，以往的透皮吸收吸收制剂存在对这些皮肤的粘合力差的缺点。
作为含有微囊的透皮吸收制剂，在特公平2-38569号公报中记载有：在粘合剂层中分散将吸收促进剂作为囊心物质的微囊，在粘贴时由于皮肤的水分使囊壁物质膨润，从而使吸收促进剂扩散，在粘合剂层中分散，由此可以促进粘合剂层中的药物的透皮吸收。在该发明中，由于皮肤的水分不向疏水性的合成橡胶类粘合剂层中吸收，所以膨润的微囊只限于在粘合剂表面的微囊，另外由于药物在粘合剂层中分散或溶解，因此药物成分间的相互作用会使贮存稳定性降低。
在特开平3-163013号公报中记载有将药物作为囊心物质内藏，使用以ホリマリン系树脂为主成分的物质作为囊壁物质制成的止痒剂。在该发明中，虽然制剂的稳定性很高，但必须从外部进行物理摩擦才能使囊壁物质破坏。
在专利申请公表平4-503810号公报中还记载有分散雌激素的微型贮药囊(reservoir)的透皮吸收制剂，但被认为囊壁物质的破坏及囊心物质的扩散不充分。
在这些现有技术中的制剂的贮存稳定性差且不能控制药物的释放速度。
优良的医疗用粘贴剂要具有如下条件：无药物的含量降低及粘合力降低，贮存稳定性优良，在粘贴时对被汗水润湿的皮肤还能维持适度的粘合力，在剥离时对皮肤没有损伤等。
作为透皮吸收制剂的最重要条件是药物的吸收性高，能够根据治疗目的在制剂上控制药物的释放速度。
本发明的目的在于开发一种能够解决在使用上述天然或合成橡胶粘合剂时粘合剂方面存在的问题，且能任意控制药物的释放量的优良的透皮吸收制剂。
本发明的透皮吸收制剂是，在使用橡胶类粘合剂的透皮吸收制剂中，通过将由内藏有药物或药物及吸收促进剂的水溶性的囊壁物质形成的微囊与橡胶类粘合剂分离，分散于橡胶粘合剂中，由此制得贮存稳定性高的粘贴剂。另外，通过混合数种具有不同壁厚及粘度分布的微囊可以得到能够任意控制药物的释放速度的制剂。另外，通过在粘合剂中分散水不溶性且橡胶及橡胶溶剂不溶性的吸水性树脂粉末和水溶性树脂粉末，粘贴时可以将由皮肤分泌的汗水吸收到粘合剂中，解决了以往的橡胶类粘合剂中存在的问题。
从分散在橡胶类粘合剂中的微囊中释放药物的释放量及释放速度取决于分散在橡胶类粘合剂中的微囊、吸水性树脂粉末及水溶性高分子粉末的浓度、微囊的囊壁物质的厚度、微囊粒子的大小等，可通过控制这些因素进行调节，特别是可以通过混合使用囊壁物质的厚度不同的微囊粒子及/或粒度分布不同的微囊粒子来控制经时药物释放量及释放速度。
本发明的第1种制剂为药物释放控制型透皮吸收制剂，其特征在于，将由内藏有药物的水溶性囊壁物质形成的微囊及水不溶性且橡胶及橡胶溶剂不溶性的吸水性树脂粉末分散在橡胶类粘合剂中。
本发明的第2种制剂为药物释放控制型透皮吸收制剂，其特征在于，将由内藏有药物的水溶性囊壁物质形成的微囊、水不溶性且橡胶及橡胶溶剂不溶性的吸水性树脂粉末和橡胶溶剂不溶性且在水分的存在下具有粘合性的水溶性高分子粉末分散在橡胶类粘合剂中。
本发明的第3种制剂为药物释放控制型透皮吸收制剂，该制剂是在上述第1及第2种制剂中，将2种或2种以上的具有不同的囊壁厚度的微囊粒子和/或具有2种或2种以上不同粒度分布的微囊粒子混合而制成的。另外，本发明还涉及使用这些制剂的胶带剂(テ-プ剂)或贴剂型(パツチ型)粘贴剂。
〔作用〕
在本发明的透皮吸收制剂中，通过将药物或药物与吸收促进剂的微囊化使任意地控制药物释放速度成为可能。
另外，在粘贴透皮吸收制剂时，粘合剂中分散的粉末状的吸水性树脂可将汗水等体液吸收至粘合剂内部，在皮肤与粘合剂的界面上不会滞留汗水等排出物，使得粘合剂难以从皮肤表面剥落的同时，通过吸收的水分破坏微囊的水溶性的囊壁物质，使内藏于微囊内的药物或药物和吸收促进剂溶出扩散至粘合剂层中。另外，由于分散在基剂中的粉末状的水溶性高分子，具有在水分的存在下赋予制剂以粘合性的作用，因此可以得到不会剥离角质层，难以形成斑疹的透皮吸收制剂。
被本发明的粘贴剂密封的部位由于贮留的水分使角质层软化、膨润，从而使屏障性降低，药物的透皮吸收显著增加。
本发明中使用的橡胶类粘合剂成分可以适当选用1种或1种以上下列各物质：天然橡胶、异戊二烯系橡胶、异丁烯系橡胶、苯乙烯-丁二烯橡胶、苯乙烯-丁二烯-苯乙烯嵌段共聚合物、苯乙烯-异戊二烯-苯乙烯嵌段共聚合物等苯乙烯共聚物系橡胶、硅酮系橡胶及丙烯酸系橡胶。
粘合附加剂成分可以适当选择石油树脂、松香、加氢松香、脂胶树脂、萜烯树脂、改性萜烯树脂、香豆酮-茚树脂、石油裂化馏分、芳香族烃树脂、苯乙烯系树脂及异戊二烯树脂中的1种或1种以上。
增塑剂成分可以适当选用聚丁烯、低分子聚异丁烯、凡士林、含水羊毛脂、液体石蜡、高级脂肪酸酯类、植物油及动物油中的1种或1种以上。
本发明的橡胶系粘合剂主要由上述橡胶系粘合剂成分、粘合附加剂成分及增塑剂成分组成，相对于100重量份的橡胶系粘合剂成分，配合40-200重量份的粘合付与剂成分，优选60-100重量份，配合增塑剂成分30-300重量份，优选75-250重量份。
另外，因为天然橡胶及合成橡胶在分子中含有不饱和键，对于氧或紫外线有劣化的危险，所以优选在橡胶系粘合剂中配合加入抗氧化剂或紫外线吸收剂，如二丁基羟基苯、4-乙基-6-丁基苯酚等稳定剂。
本发明中使药物作为微囊在橡胶类粘合剂中混合、分散所说的药物可以从油性的不溶解囊壁物质的物质中选择1种或1种以上使用，所说的物质(例如有水杨酸甲酯、乙二醇水杨酸酯、l-薄荷醇、dl-薄荷醇、dl-樟脑、冰片、薄荷油、辣椒提取物、壬酸香草酰胺、水杨酸-α-二苯甲氧基-N，N-二甲基乙胺、硝酸甘油、硝酸异山梨醇酯、氟比洛芬、酮布洛芬、吲哚美辛、ロキソプロフェン钠、布洛芬、双氯灭痛、甲灭酸、d-马来酸氯苯那敏、dl-马来酸氯苯那敏、水杨酸苯海拉明、苯海拉明、黄体酮、睾酮、雌三醇、雌二醇、炔雌醇、心得安、妥布特罗、东莨菪碱、トラニラスト、富马酸凯托替芬、丙酸倍氯米松、阿托品及利多卡因等，但并不限定于上述这些药物。
作为微囊的囊壁物质，可以将明胶、阿拉伯胶、聚乙烯醇及羧甲基纤维素等水溶性高分子物质中的1种或1种以上混合，通过变换囊心物质及囊壁物质的混合比例、微囊的硬化时间等制备条件来调节微囊的囊壁厚度，由此可以控制从制剂释放药物的速度。另外，可以通过2种或2种以上不同壁厚的微囊粒子来任意地控制药物的释放速度。
微囊的粒径如果过小则内含药物的含量变少。如果粒径过大则在粘合剂中的混合、在基布上的涂布、干燥干序时引起粒子的破坏，不能得到稳定的制剂。因此微囊的粒径优选在1-100μ左右的范围内。
对于微囊的壁厚也同样，如小于0.2μ则容易破坏，不能得到制剂的稳定性，另外，如果为2μ以上时微囊的膜变得难以被破坏，囊心物质的溶出减慢，因此壁厚优选在0.2-2μ左右的范围内。另外，微囊的囊心物质的重量比最优选为85-90％。
另外，通过将高分子物质单独或2种或2种以上混合，改变囊心物质与囊壁物质的种类、混合比例、微囊的凝胶化时间等条件，来调整微囊，可以得到具有各种粒径及壁厚的微囊。通过将2种或2种以上的具有不同粒径及壁厚的微囊混合，可以任意地控制药物的释放速度。即，壁厚薄的微囊粒子由于粘贴后的微量的吸水而容易被破坏，因此药物的释放变快，壁厚厚的粒子的药物释放变慢。因此可以根据治疗目的调节微囊的壁厚，由此可以任意地控制药物的释放速度。
作为微囊的囊心物质，除药物以外，可通过使内藏吸收促进剂而得到贮存稳定性优良且药物的吸收性非常优良的制剂。作为吸收促进剂可以从不溶解壁物质的物质，即碳原子数10-22的脂肪族醇、碳原子数9-22的脂肪族羧酸、脂肪族胺、长链脂肪族酯、N-烷基内酸胺、克罗米通、单萜烯系化合物中选择1种或1种以上。
作为本发明中使用的吸水性树脂粉末，例如有淀粉-聚丙烯酸盐接枝共聚物(商品名<サンウエツト>三洋化学工业)、交联聚丙烯酸盐(商品名<アラソ-プ>，荒川化学工业，商品名<アクアキ-プ>制铁化学工业、商品名<アクアリツク>日本触媒化学工业)、丙烯酸-乙烯醇共聚物(商品名<スミカゲルS型>住友化学工业)、聚氧化乙烯交联体(商品名<スミカグルR型>住友化学工业)、交联异丁烯-马来酸盐共聚物系(商品名<KI凝胶>クラレ等。该吸水性树脂是将水溶性的树脂适度地交联形成的三元构造树脂，由于具有分子中的羟基、羧基、羧酸盐基等亲水性基团而具有高吸水能力，优选具有作为去离子水的不低于100g/g的高吸水能力。
吸水性树脂粉末的平均粒径为1-100μ，特别优选5-30μ。
吸水性树脂可以单独使用，也或以混合使用粒径不同的2种或2种以上的树脂。吸水性树脂粉末相对于橡胶粘合剂配合使用0-30重量％，优选5-20重量％。
本发明中使用的在水的存在下具有粘性的水溶性高分子粉末例如有聚丙烯酸、聚丙烯酸盐、聚丙烯酸胺、聚氧化乙烯、聚乙烯亚胺、聚乙烯醇、聚乙烯吡咯烷酮、羧乙烯基聚合物、甲基纤维素、羧甲基纤维素、羟乙基纤维素等的粉末。这些水溶性高分子粉末的平均粒径为1-100μ，特别优选5-30μ。水溶性高分子粉末可以单独使用，也可混合使用粒径不同的2种或2种以上的树脂。水溶性高分子粉末相对于橡胶粘合剂配合使用0-30重量％，优选5-20重量％。
本发明的透皮吸收制剂可以胶带剂、贴剂型粘贴剂等任意形态使用。图1为在胶带剂中将分散物涂布在基布或脱膜纸上形成的层的说明图，图2为胶带剂的剖面图。在该图中1为粘合剂层，2为微囊，3为吸水性树脂粉末，4为基布，5为脱膜纸。
胶带剂是将由橡胶类粘合成分、粘合附加剂及增塑剂组成的橡胶类粘合剂溶于挥发性有机溶剂中，在该溶汇中分散由内藏有药物的水溶性的囊壁物质形成的微囊2及水不溶性且橡胶和橡胶不溶性的吸水性树脂粉末3，将该分散物涂布在基布4或脱膜纸5上，挥发有机溶剂，形成分散有微囊2及吸水性树脂粉末3的粘合剂层1，在其上贴合脱膜纸5或基布4而制得。
图3及图4是贴剂型粘贴剂中的一例，图5及图6表示其他的贴剂型粘贴剂的例子。在贴剂型粘贴剂中也与胶带剂同样，将由橡胶类粘合成分、粘合附加剂及增塑剂形成的橡胶类粘合剂溶于挥发性有机溶剂，在该溶液中分散由内藏有药物的水溶性的囊壁物质形成的微囊2及水不溶性且橡胶及橡胶溶剂不溶性的吸水性粉末3，制成粘合剂。该粘合剂如图3及图4所示在基布或脱膜纸5的一部分例如正中部分上涂布，形成分散有微囊2及吸水性树脂粉末3的粘合剂层1，在剩余部分例如基布4或脱膜纸5的周边部分上涂布不含有微囊的粘合剂层，或如图5及图6所示，将其与不含有微囊的粘合剂层6层叠，制成贴剂型粘贴剂。
粘合剂的涂布方法有热压法(压延涂布)、热熔融法(热熔融涂布)及溶液涂布等，可利用任一涂布方法实施，但在微囊的壁厚较薄的情况下如果使用压延涂布、热熔融涂布方法，则粒子被破坏，所以最优选溶液涂布。在溶液涂布中使用的溶剂优选使用甲苯、正己烷、异己烷、环己烷、橡胶用挥发油等对天然橡胶、合成橡胶溶解度高的溶剂。
另外，作为基底材料可以使用聚氯乙烯系膜、聚酯系膜、聚烯烃系膜、聚氯乙烯膜与聚酯膜的层叠膜、聚酯、聚丙烯、人造丝等无纺布或纺织布、在聚酯膜上将无纺布热熔粘合加工的薄膜等。
〔实施例〕
实施例1
微囊的制备
将5％聚乙烯醇水溶液250份及5％羧甲基纤维素水溶液250份，氟比洛芬80份及倍半油酸山梨糖醇酐50份搅拌混合形成o/w型乳浊液，升温至40℃，缓慢加入2.5％氯化钠250份。然后冷却至10℃，加入50％的戊二醛20份，搅拌15小时，加热至40℃再搅拌3小时。然后进行洗涤、过滤、喷雾干燥。得到的微囊的囊心物质浓度为87％，内含药物(氟比洛芬)为47.1％、平均粒径为16μ。
透皮吸收制剂的制造
将苯乙烯-异戊二烯-苯乙烯嵌段共聚物30份、聚异丁烯10份、液体石蜡20份、粘合附加剂(エスコレツツ5300)30份混合溶解于350份正己烷中，将上述的微囊3份及过100目筛的淀粉及聚丙烯酸接枝共聚物5份、过100目筛的聚丙烯酸粉末(ハイビスワコ-グル
)5份混合分散上述得到粘合剂溶液中。然后将该分散物涂布于脱膜纸上，加热使正己烷挥发后，贴合氯乙烯膜，由此制得透皮吸收制剂。
〔实施例2〕
微囊(I)的调制
将克罗他米通20份、丁二醇20份、炔雌醇10份在10％明胶水溶液30份中分散乳化形成o/w型乳浊液后，加入10％阿拉伯胶水溶液30份，混合约20分钟。然后加入40℃温水200份，用10％醋酸调节PH为4-4.3，形成溶胶后冷却至5℃，凝胶化后加入30％福尔马林1份，再滴加10％的苛性钠使PH为9，缓慢加热，在50℃下搅拌约1小时。然后进行洗涤、过滤、喷雾干燥，得到囊心物质为89％、内含药物(炔雌醇)12.7％、平均粒径为13μ的球形的微囊。
微囊(II)的制备
将克罗他米通15份、丁二醇20份、炔雌醇15份在12.5％明胶水溶液40份中分散乳化形成o/w型乳浊液后，加入10％阿拉伯胶水溶液30份，混合约20分钟。然后加入40℃温水200份，用10％醋酸调节PH为4-4.3，形成溶胶后冷却至5℃，凝胶化后加入30％福尔马林1份，再滴加10％的苛性钠使PH为9，缓慢加热，在50℃下搅拌约1小时。然后进行洗涤、过滤、喷雾干燥，得到囊心物质为76％、内含药物(炔雌醇)15.1％，平均粒径为16μ的球形的微囊。
透皮吸收制剂的制备
将苯乙烯-异戊二烯-苯乙烯嵌段共聚物25份、聚异丁烯15份、液体石蜡25份、粘合附加剂(エスコレッツ5300)25份混合溶解于340份正己烷中，在得到的粘合剂溶液中混合分散上述微囊(I)2份、上述微囊(II)3份及过100目筛的淀粉与聚丙烯酸盐的接枝共聚物(サンウエツトIM1000)7份。然后将该分散物涂布于脱膜纸上，加热使正己烷挥发后，贴合氯乙烯膜，由此制得透皮吸收制剂。
本发明的透皮吸收制剂通过将药物及吸收促进剂形成微囊使制剂的贮存稳定性极高。另外，通过粘贴在皮肤上而将体液吸收至膏体中，将微囊缓慢破坏而使药物及吸收促进剂溶出，因此可以通过混合数种壁厚不同的微囊，能够任意控制药物的释放速度。本发明的附加效果是因为将体液吸收到制剂中，所以不会因为出汗而剥离。
附图简单说明
图1为本发明的胶带剂中粘合剂层的说明图。
图2为本发明的胶带剂的剖面图。
图3为本发明的贴剂型粘贴剂中之1例的粘合剂层的说明图。
图4为本发明的贴剂型粘贴剂的断面图。
图5为本发明其他贴剂型例子的粘合剂层的说明图。
图6为本发明其他贴剂型例子的剖面图。
符号说明
1粘合剂层
2微囊
3吸水性树脂粉末
4基布
5脱膜纸
6粘合剂
Claims (11)
1.药物释放控制型透皮吸收制剂，其特征在于，在橡胶类粘合剂中分散由内藏有药物的水溶性的囊壁物质形成的微囊及水不溶性且橡胶和橡胶溶剂不溶性的吸水性树脂粉末。
2.药物释放控制型透皮吸收制剂，其特征在于，在橡胶类粘合剂中分散由内藏有药物的水溶性的囊壁物质形成的微囊、水不溶性且橡胶及橡胶溶剂不溶性的吸水性树脂粉末、橡胶及橡胶溶剂不溶性且在水分的存在下具有粘合性的水溶性高分子粉末。
3.如权利要求1或2中记载的药物释放控制型透皮吸收制剂，由橡胶类粘合剂、粘合附加剂及增塑剂形成，其中的橡胶类粘合剂是从天然橡胶、异戊二烯系橡胶、异丁烯系橡胶、苯乙烯共聚物系橡胶、硅酮系橡胶及丙烯酸系橡胶中选择的1种或1种以上的橡胶粘合成分，粘合附加剂是从石油树脂、松香、加氢松香、脂胶树脂、萜烯树脂、改性萜烯树脂、香豆酮-茚树脂、石油裂化馏分、芳香族烃树脂、苯乙烯系树脂及异戊二烯系树脂中选择的1种或1种以上的粘合附加剂，增塑剂是从聚丁烯、低分子聚异丁烯、凡士林、液体石蜡、高级脂肪酸酯类、植物油及动物油中选择的1种或1种以上的增塑剂。
4.如权利要求1或2中记载的药物释放控制型透皮吸收制剂，其中的吸水性树脂粉末是平均粒径为1-100μ的淀粉-聚丙烯酸盐接枝共聚物、交联聚丙烯酸盐、丙烯酸-乙烯醇共聚物、聚氧化乙烯交联体或交联异丁烯-马来酸盐共聚物。
5.如权利要求1或2中记载的药物释放控制型透皮吸收制剂，内藏1种或1种以上的油性的不溶解囊壁物质的药物。
6.如权利要求1或2中记载的药物释放控制型透皮吸收制剂，其中的囊壁物质是从明胶、阿拉伯胶、聚乙烯醇及羧甲基纤维素中选择的1种或1种以上。
7.如权利要求1或2中记载的药物释放控制型透皮吸收制剂，是将2种或2种以上的具有不同的囊壁厚度的微囊粒子混合形成的。
8.如权利要求1或2中记载的药物释放控制型透皮吸收制剂，其中的微囊的平均粒径为100μ以下。
9.如权利要求1或2中记载的药物释放控制型透皮吸收制剂，作为微囊的囊心物质除药物之外还含有吸收促进剂，该吸收促进剂是从碳原子数10-22的脂肪族醇、碳原子数9-22的脂肪族羧酸、脂肪族胺、长链脂肪族酯、N-烷基内酰胺、克罗他米通、单萜烯系化合物中选择的1种或1种以上。
10.一种胶带剂，是将由橡胶类粘合成分、粘合附加剂及增塑剂组成的橡胶类粘合剂溶于挥发性有机溶剂，在该溶液中分散内藏有药物的微囊及水不溶性的橡胶及橡胶溶剂不溶性的吸水性树脂粉末，将该分散物涂布于基布或脱膜纸上，挥发有机溶剂，将脱膜纸或基布贴合而制成。
11.一种贴剂型粘贴剂，是将由橡胶类粘合成分、粘合附加剂及增塑剂组成的粘合剂溶于挥发性有机溶剂，在该溶液中分散内藏有药物的微囊及水不溶性的橡胶及橡胶溶剂不溶性的吸水性树脂粉末，将该分散物涂布于基布或脱膜纸的一部分上，与橡胶类粘合剂层叠或将橡胶类粘合剂分离涂布而制成。
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-
1996
- 1996-03-15 JP JP8087646A patent/JPH0912448A/ja active Pending
- 1996-04-24 TW TW085104908A patent/TW448052B/zh not_active IP Right Cessation
- 1996-04-26 US US08/638,565 patent/US5695779A/en not_active Expired - Lifetime
- 1996-04-26 CN CNB961062665A patent/CN1174746C/zh not_active Expired - Fee Related
- 1996-04-26 CA CA002175122A patent/CA2175122C/en not_active Expired - Fee Related
- 1996-04-29 DE DE69622780T patent/DE69622780T2/de not_active Expired - Fee Related
- 1996-04-29 EP EP96106759A patent/EP0739626B1/en not_active Expired - Lifetime
- 1996-04-29 KR KR1019960013477A patent/KR100425556B1/ko not_active IP Right Cessation
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2004019920A1 (en) * | 2002-08-27 | 2004-03-11 | Carol Choi Fung Yuen | Transdermal delivery system |
| CN100420726C (zh) * | 2005-09-19 | 2008-09-24 | 上海安立霸电器有限公司 | 医用热熔压敏胶型基质及制备 |
| CN101896179B (zh) * | 2007-12-11 | 2013-06-19 | 美德阿利克斯株式会社 | 包含离子性液体形式的依托度酸的胶带制剂 |
| CN107412202A (zh) * | 2010-12-14 | 2017-12-01 | 绿叶制药股份公司 | 用于施用活性物质的经皮治疗系统 |
| CN109124862A (zh) * | 2018-07-12 | 2019-01-04 | 广州馥邦科技应用有限公司 | 一种控释长效退热贴及其制备方法 |
| CN113832747A (zh) * | 2021-09-27 | 2021-12-24 | 上海捻幅智能科技有限公司 | 一种能够定期提示纺织品更换的承载物制备方法及承载物 |
Also Published As
| Publication number | Publication date |
|---|---|
| US5695779A (en) | 1997-12-09 |
| CN1174746C (zh) | 2004-11-10 |
| EP0739626A3 (en) | 1997-05-07 |
| EP0739626B1 (en) | 2002-08-07 |
| DE69622780T2 (de) | 2003-04-03 |
| EP0739626A2 (en) | 1996-10-30 |
| DE69622780D1 (de) | 2002-09-12 |
| CA2175122C (en) | 2006-11-21 |
| TW448052B (en) | 2001-08-01 |
| JPH0912448A (ja) | 1997-01-14 |
| KR960037042A (ko) | 1996-11-19 |
| KR100425556B1 (ko) | 2004-06-18 |
| CA2175122A1 (en) | 1996-10-29 |
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