CN1226834A - 使用(甲基)丙烯酸共聚物增加粘膜的渗透性 - Google Patents
使用(甲基)丙烯酸共聚物增加粘膜的渗透性 Download PDFInfo
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- CN1226834A CN1226834A CN97196964A CN97196964A CN1226834A CN 1226834 A CN1226834 A CN 1226834A CN 97196964 A CN97196964 A CN 97196964A CN 97196964 A CN97196964 A CN 97196964A CN 1226834 A CN1226834 A CN 1226834A
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- methyl
- pharmaceutical composition
- copolymer
- acrylic acid
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- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 9
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- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 3
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Abstract
本发明涉及(甲基)丙烯酸共聚物对增加粘膜渗透性的应用,其中共聚用单体是甲基丙烯酸酯和/或其他能够进行自由基聚合的单体,(甲基)丙烯酸:共聚用单体的摩尔比率为99∶1至1∶99。
Description
本发明涉及用(甲基)丙烯酸共聚物增加粘膜的渗透性。
上皮组织形成了对亲水活性物质特别是那些高分子量的物质的旁细胞(parazellulr)输送的重要渗透屏障,所谓的“紧密连接”(在质膜直接接触的相邻上皮细胞之间的胞间连接点)保证了官器的内部环境与外部环境的隔离。胞间连接点的紧密性决定了这些上皮细胞的旁细胞的被动可渗透性。加宽“紧密连接”使吸收性得到改善,因而提高活性物质的生物利用率。
所以,过去曾进行了许多研究以打开胞间接触点的方法。从而显示使用表面活性成分和Ca2+-螯合物是有希望的方法。
然而,J.Controlled Rel.,29(1994)253提出,使用表面活性物质具有细胞溶解的危险和与此有关的毒性副作用。
许多出版物,特别是,J.Controlled Rel.,36(1995)25;化学药品公报(Chem.Pharm.Bull)33(1985)4600;细胞生物学杂志(Journal of Cell Biology)87(1980)736和国际药物学杂志(Int.J.Pharm.),90(1993)229叙述了EDTA或EGTA对各种细胞体系的渗透性的影响,例如对Caco-2细胞的影响。据此,Ca2+-螯合物质的存在导致紧密连接的快速而常常是不可逆地打开。另外,在EDTA的情况下,为了在中性pH下观测效果(降低跨上皮阻力),需要比较高的浓度。另外,分子量≤20kDa的配位剂伴随着被全身吸收的危险,因此可以导致不希望的毒性副作用。
在J.Controlled Rel.,29(1994)329中指出,基于交联的聚丙烯酸酯如Polycarbophil(NoveonAAl,B.F.Goodrich)的不可吸收高分子化合物也能够打开紧密连接。由于其特别高的分子量(>1000kDa)以及在低浓度(≥0.5%(重量))下的高粘度,所以在应用技术方面有缺点。
此外,已知具有生物粘合性的聚合物能够改善活性物质的生物利用率。例如,EP-A-587047叙述了由(甲基)丙烯酸酯与各种不饱和羧酸的共聚物作为基于孕激素的药物组合物。
EP-B-410422公开了增加难溶活性物质的生物利用率的方法,方法中通过加入(甲基)丙烯酸/(甲基)丙烯酸酯共聚物,配制之后,它们以无定形存在,并由此呈较好的可溶性。
本发明的目的是寻找一种聚合物,它能够可逆地增加上皮细胞的渗透性、同时又没有上述应用技术方面的缺点,或者不会引起毒性问题。
意外地发现,通过使用(甲基)丙烯酸共聚物,达到了增加粘膜渗透性以及由此提高了活性物质的渗透。
按照本发明的共聚物包含,作为单体的丙烯酸或甲基丙烯酸,它们能够以其游离酸、其盐和/或其酐的形式使用。
如果将单体以其盐的形式应用于聚合,那末所优选的是碱土金属-、碱金属-或铵盐或者有机胺盐,特别优选的是碱金属-或铵盐。
作为其他共聚用单体是(甲基)丙烯酸酯和/或其他能够进行自由基聚合的单体。使用饱和的、直链的或支链的C1~C40醇的(甲基)丙烯酸酯。例如丙烯酸的甲酯、乙酯、正丙酯、异丙酯、正丁酯、异丁酯、叔丁酯、正己酯、正辛酯、异壬酯、正癸酯、正十二烷酯、正十四烷酯、正十六烷酯、正十七烷酯、正十八烷酯、正十九烷酯、正二十烷酯、正二十二烷酯、正二十四烷酯、2-乙基己酯、异冰片酯,或丙烯酸环己酯,或相应的甲基丙烯酸酯。优选使用丙烯酸或甲基丙烯酸的C1~C6和/或C6~C30烷基酯。特别优选的具有C1~C6链的代表物是甲基丙烯酸甲酯、丙烯酸乙酯和丙烯酸丁酯,以及具有C6~C30链的代表物(甲基)丙烯酸的C8~C22烷基酯。
此外,也能使用苯乙烯和/或饱和C1~C30羧酸的乙烯基酯作单体单元。其优选的实例是乙酸乙烯酯和/或丙酸乙烯酯。
本发明的共聚物中的(甲基)丙烯酸:共聚用单体的摩尔比率能够在大范围内变化。例如,其范围为99∶1-1∶99,优选为70∶30-30∶70。
通常共聚物以药物组合物的形式与活性物质一起服用。适宜的药物形式是片剂、压出物、颗粒、丸、粉末、胶囊、栓剂、软膏、悬浮物或乳剂,根据应用可经口、舌下、颊、直肠、肺、鼻或眼粘膜进行给药。所优选的药物形式是:(a)基质片剂,(b)层状片剂和(c)涂膜片剂。特别是按照本发明将聚合物和活性物充分混合再压制在一起的基质片剂是具有高活性潜力的给药形式。在这些给药形式中,所使用的本发明的共聚物的含量一般为该给药形式总量的50%以上,特别是60-99%,最好为75~99%。然而,也可以先用增加渗透性的共聚物处理诸如肠-、咽-或眼粘膜,然后再供给活性药物。
通常,上述给药形式是采用加入填充剂、粘结剂、分裂剂、润滑剂或其他辅助物质生产的。应用于片剂的填充剂和干粘结剂特别是乳糖、蔗糖、甘露糖醇、山梨糖醇、微晶纤维素、淀粉、磷酸二钙和聚乙二醇。适于造粒的粘结剂例如是淀粉、藻酸盐、聚乙烯吡咯烷酮和羧甲基纤维素。适宜的流动调节剂例如是淀粉、滑石和二氧化硅。在机械生产片剂中能够使用的润滑剂是硬脂酸镁和其他金属皂。常规片剂分裂剂包括淀粉、纤维素衍生物和交联聚乙烯吡咯烷酮。
根据应用领域和活性物质,本发明的共聚物最好以中和的、部分中和的或未中和的形式使用。如果共聚物是未中和的形式,那末或者由其他辅助物质和/或直接由活性物质组成的碱或质子接受体的存在常常是有利的。
如果活性物质是碱性的,那未它能够全部地或部分地与本发明的共聚物呈盐的形式。
共聚物可按文献中公开的方法制备,例如:溶剂聚合法、悬浮聚合法或乳液聚合法,所优选的是乳液聚合法。
乳液聚合法使用诸如过氧-或偶氮化合物的引发剂以常规方法进行,引发剂的实例有二苯甲酰氧化物、过新戊酸叔丁酯、过2-乙基己酸叔丁酯、二叔丁基过氧化物、叔丁基氢过氧化物、碱金属-或铵过硫酸盐、偶氮二异丁腈、2,2′-偶氮二(2-甲基丁腈)、2,2′-偶氮二(2,4-二甲基戊腈)、1,1′-偶氮二(1-环己烷腈)、2,2′-偶氮二(2-脒基丙烷)盐、4,4′-偶氮双(4-氰基戊酸)或2-(氨基甲酰基偶氮)异丁腈等,也可用过氧化氢或氧化还原引发剂。引发剂的用量按聚合单体重量计通常为高达10%,优选0.02~5%。
聚合作用在有为此目的的常规乳化剂和/或保护胶体存在下进行。适宜的保护胶体的实例是聚乙烯醇、纤维素衍生物或聚乙烯吡咯烷酮。乳化剂能够是阴离子性的、阳离子性的或非离子性的。适宜的乳化剂的实例是乙氧基化的单-、二-和三烷基酚、乙氧基化的脂肪醇或脱水山梨糖醇酯,烷基硫酸或烷基醚硫酸的、烷基磺酸的、木素磺酸的和烷基芳基磺酸的或烷基二苯醚磺酸的碱金属-和铵盐。
乳液聚合法通常在隔绝氧的条件下在20~200℃下进行。能够间歇或连续进行聚合反应。
最好在聚合作用期间以恒定速度计量地向反应器加入的物料包括:至少单体部分、引发剂和需要时加调节剂如醛、卤化合物或硫化合物,例如甲醛、乙醛、溴三氯甲烷、巯基乙醇、巯基乙酸或十二烷硫醇。然而,单体和引发剂也可以最初就存在于反应器中,并进行聚合,需要时必须冷却。
这样得到重均分子量为50,000~2,000,000的共聚物。平均分子量为20,000~1,500,000,特别是120,000~400,000的共聚物特别适用于本发明的应用。
所有常规工艺均可用于干燥聚合物分散体,例如薄膜干燥、流化床干燥、喷雾干燥或冷冻干燥。
按照本发明所使用的聚合物的渗透性能的增加,在以实例Caco-2细胞培养物(ATCC公司,Pockville,美国马里兰州)的生物体外的试验系统中得到了证明。该细胞系在聚碳酸酯膜上形成组织集聚,在外观和蛋白质组成方面与小肠内皮非常相似。在Transwell系统中(Costar公司出品,德国Bodenheim),这种人造内皮组织把用介质充填的两个腔分成顶区室和基底外侧区室。这种结构使得通过Caco-2组织层的物质的渗透可被测定。其中,上皮渗透阻力(TEER)和荧光示踪化合物[例如,荧光素-异硫氰酸盐-葡聚糖(FITC-dextran-4400;FITC-dextran-11000);荧光素-生物素=(生物素-酰氨基己酰基酰氨基)-(戊基硫脲基)-荧光素]渗透过细胞单层表明了紧密连接开或关闭到什么程度。通过紧密连接的可逆性打开表明渗透性得到改善。
实验性实例:
1.细胞培养
Caco-2细胞在DMEM(Dulbeccos Modified Eagle介质,GibcoBRL公司出品,德国Eggenstein)中采用10%FCS(胎儿腓肠浆液)、1%L-谷氨酰胺和4.5mg/ml(毫克/毫升)葡萄糖在37℃下及5%CO2和95%相对湿度进行培养。在胰蛋白酶消化之后,细胞在Transwell聚碳酸酯过滤器上散开,密度为3×105细胞/厘米2。用第30传代细胞和第50传代细胞之间的细胞形成单层。在细胞散开之后的15~21天(每3天更换介质一次)后对单层进行实验。
2.渗透速度测定
在实验之前,将在Transwell过滤器滤芯中的Caco-2细胞组织用PBS(磷酸缓冲盐水)洗涤。然后,用EBSS(Earl缓冲盐溶液,pH6)填充顶区室,用DMEM填充底外侧区室。将中和至pH为7的试验聚合物[KollicoatMAE30D(丙烯酸乙酯/甲基丙烯酸1∶1,BASF)、EudragitL100(甲基丙烯酸/甲基丙烯酸甲酯l∶1,Rhm)、Eudragit S100(甲基丙烯酸/甲基丙烯酸甲酯1∶2,Rhm)]和示踪化合物加入顶区室,聚合物浓度为0.5~3%(重量),此后,样品再经24小时,测定示踪化合物的渗透速度。
试验采用荧光分光度法(Spex Fluorolog 1680:激发波长488nm,发射波长513nm)进行分析,在C22H32N6O4的情况下,采用HPLC(高压液相色谱法(柱材料Vidac C-18;流动相:水/乙腈/0.1%三氟乙酸;检测:240nm),实验结果汇编于表1。未进行测定者以“-”表示。表1:
C22H32N6O4=HOOC-CH2-(D)-Cha-Pro-NH-3-(6-Am)-Pico
对照 | KollicoatMAE 30D | ||||
0.5% | 1.0% | 1.5% | 3.0% | ||
渗透速度[(cm/sec)*10-8] | |||||
试验物质 | |||||
荧光素-生物素 | 2.3 | 2.3 | 5.8 | 20 | - |
Dextran-FITC4400 | 0.8 | - | 9.6 | - | 935 |
Dextran-FITC11000 | 2.3 | - | 17.0 | - | 769 |
C22H32N6O4 | 56 | 79 | 94 | 280 | - |
对照 | Eudragit L100 | ||||
2.0% | |||||
渗透速度[(cm/sec)*10-8] | |||||
试验物质 | |||||
荧光素-生物素 | 2.3 | 4.8 | |||
C22H32N6O4 | 56 | 104 | |||
对照 | Eudragit S100 | ||||
2.0% | |||||
渗透速度[(cm/sec)*10-8] | |||||
试验物质 | |||||
荧光素-生物素 | 2.3 | 7.1 | |||
C22H32N6O4 | 56 | 103 | |||
从表1显而易见,所有三个试验聚合物均显示提高渗透性的性能。与对照试验比较,使用KollicoatMAE 30D即使浓度为1%和1%以上也使渗透明显提高。
3.跨上皮阻力(TEER)的测定
本发明聚合物对组织紧密度(紧密连接的打开)的影响是通过测量跨上皮电阻测定的。在Caco-2细胞组织用PBS洗涤之后,顶区室用EBSS(pH6)填充,底外侧区室用DMEM填充。在将中和至pH7的聚合物以不同浓度(0.1-2%)加入到顶区室之前和之后的不同时刻,测定TEER(图1:Kollicoat MAE 30D;图2:Eudragit L100;图3:Eudragit S100)。在150分钟之后,用pH为6的EBSS置换该溶液,并基于TEER以研究组织再生。
EudragitS和L100两者以及特别是Kollicoat MAE 30D导致测量时的Caco-2细胞单层的跨上皮明显的下降。
4.给药形式的实例
Atenolol(阿替洛尔)涂膜片剂
Atenolol | 50mg |
Ludipress | 50mg |
甲基丙烯酸-丙烯酸乙酯共聚物(1∶1),中和至pH7 | 146.5mg |
Aerosil 200 | 2mg |
硬脂酸镁 | 1.5mg |
片重 | 250mg |
1000g(克)atenolol、1000g Ludipress(BASF)、2930g中和至pH7的甲基丙烯酸/丙烯酸乙酯共聚物、40g Aerosil200(Degussa)和30g硬脂酸镁经0.8mm筛子过筛,并在Turbula混合器中混合5分钟。然后以旋转压片机上在20kN压力下制出直径9mm的两面凸的片剂。
用甲基丙烯酸-丙烯酸乙酯共聚物对两面凸的片剂薄膜,涂膜是在引入50℃空气的Accela-Cota型卧式转鼓涂布器(Manesty出品)中进行。涂膜分散体含有如下组分:
二氧化钛 | 0.5%(重量) |
滑石 | 2%(重量) |
Sicovit Rot30 | 0.5%(重量) |
Kollidon30 | 0.5%(重量) |
甲基丙烯酸-丙烯酸乙酯共聚物(1∶1),中和至pH7 | 15%(重量) |
柠檬酸三乙酯 | 1.5%(重量) |
水 | 80%(重量) |
施加到5000g两面凸的片剂上的涂覆量为1680.8g涂膜分散体。
b.Propranolol(普萘洛尔)片剂
Propranolol-HCl | 160mg |
甲基丙烯酸-丙烯酸乙酯共聚物(1∶1),中和至pH7 | 190mg |
Aerosil 200 | 3,4mg |
硬脂酸镁 | 1,6mg |
片重 | 355mg |
1600g Propranolol-HCl、1900g中和至pH7的甲基丙烯酸/丙烯酸乙酯共聚物、34g Aerosil 200和16g硬脂酸镁经0.8mm筛子过筛,再在Turbula混合器中混合5分钟。混合物经Korsch型PH106旋转压片机在20kN压力下以30转/分钟速度压制,生产出直径10mm,重量355mg的双面磨平的片剂。
c.Furosemide(呋塞米)微型片剂
Furosemid | 1mg |
甲基丙烯酸-丙烯酸乙酯共聚物(1∶1),中和至pH7 | 5.95mg |
硬脂酸镁 | 0.05mg |
片重 | 7mg |
使100g furosemide和595g中和至pH7的甲基丙烯酸/丙烯酸乙酯共聚物在Stephan混合器中混合,并在搅拌的同时,用133g异丙醇增湿。将湿物料挤压过网眼为0.6mm的筛子,以薄层置于盘中在室温下干燥24小时。干燥颗粒通过0.8mm筛子,并在Turbula混合器中与同样过筛过的硬脂酸镁混合5分钟,再经过0.8mm筛子。然后在Korsch EKO型偏心压制机中制出直径2mm高约2mm的双面凸的微型片剂。为达40mg剂量,每次将40片微型片剂装入两片明胶形成的胶囊之中。
d.Methyldopa(甲基多巴)片剂
Methyldopa | 250mg |
甲基丙烯酸-丙烯酸乙酯共聚物(1∶1),中和至pH7 | 347.5mg |
Aerosil 200 | 3,5mg |
Kollidon CL | 6mg |
硬脂酸镁 | 3mg |
片重 | 610mg |
2500g methyldopa、3475g甲基丙烯酸/丙烯酸乙酯共聚物、35gAerosil200、60g Kollidon CL(BASF)和30g硬脂酸镁经0.8mm筛子过筛,再在Turbula混合器中混合5分钟。接着该粉末混合物在旋转片剂压制机中于30kN压力及30转/分钟速度下压制成直径12mm的双平磨面片剂。
e.S-Adenosylmethionin(S-腺苷甲硫氨酸)锭剂
S-Adenosylmethionin | 100mg |
甲基丙烯酸-丙烯酸乙酯共聚物(1∶1),中和至pH7 | 700mg |
甘露糖醇 | 200mg |
天冬苯丙二酞酯 | 3mg |
橙香料 | 5mg |
Kollidon VA64 | 37mg |
Aerosil 200 | 5mg |
硬脂酸镁 | 5mg |
片重 | 1055mg |
500g S-Adenosylmethionin、3500g中和至pH7的甲基丙烯酸/丙烯酸乙酯共聚物、1000g甘露糖醇、15g天冬苯丙二酞酯、25g橙香料25g Aerosil200和185g Kollidon VA64经0.8mm筛子过筛,再在Turbula混合器中混合5分钟。然后,加入25g经0.5mm筛子过筛过的硬脂酸镁,并在其中混合2.5分钟。在旋转压片机中于35kN压力及30转/分钟的速度下压制出双平磨面的重1055mg的片剂。
f.Cefuroxim(头孢呋辛钠)颗粒
Cefuroximaxetil(相当250mg Cefuroxin) | 300.7mg |
甲基丙烯酸-丙烯酸乙酯共聚物(1∶1),中和至pH7 | 1250mg |
甲基丙烯酸-甲基丙烯酸甲酯共聚物(1∶1) | 150mg |
蔗糖 | 482,3mg |
橙香料 | 5mg |
天冬苯丙二酞酯 | 2mg |
Kollidon CL | 30mg |
Kollidon VA64 | 30mg |
片重 | 2250mg |
将300.7g cefuroximaxetil(相当于250g cefuroxim)、1250g中和至pH7的甲基丙烯酸/丙烯酸乙酯共聚物(1∶1)、150g甲基丙烯酸/甲基丙烯酸甲酯共聚物(1∶1)、482.3g蔗糖、5g橙香料、2g天冬苯丙二酞酯和30g Kollidon CL在Stephan混合器中混合,再在搅拌的同时,用30g Kollidon VA64在390g异丙醇中的溶液增湿。该湿物料挤压过网眼为1.2mm的筛子,并置于盘上于室温下缓缓干燥24小时。以2250mg剂量将干燥颗粒包装在密封袋中。
Claims (9)
1.(甲基)丙烯酸共聚物对增加粘膜渗透性的应用。
2.权利要求1的应用,其中共聚用单体是(甲基)丙烯酸酯和/或其他能够进行自由基聚合的单体,(甲基)丙烯酸:共聚用单体的摩尔比率为99∶1-1∶99。
3.权利要求1的应用,其中共聚用单体是(甲基)丙烯酸的C1~C6烷基酯、苯乙烯、乙酸乙烯酯和/或丙酸乙烯酯。
4.一种改善粘膜渗透性的药物组合物,它包含权利要求1~3中所述的(甲基)丙烯酸共聚物的量占总重量的50%(重量)以上。
5.权利要求4的药物组合物,包含的(甲基)丙烯酸共聚物的量占总重量的60-99%(重量)。
6.权利要求4和5的药物组合物,其形式为片剂、压出物、颗粒、丸、粉末、胶囊、栓剂、软膏、悬浮物或乳剂。
7.权利要求4~6的药物组合物,其中共聚物以未中和的、部分中和的或中和的形式存在,在未中和的形式情况下,给药形式可另外包含碱或质子接受体。
8.权利要求4~7的药物组合物,其中碱性活性物质全部或部分呈与(甲基)丙烯酸共聚物的盐的形式存在。
9.权利要求4~8的药物组合物经口、舌下、颊、直肠、肺或鼻给药,或者经眼粘膜给药的应用。
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
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DE19631084A DE19631084A1 (de) | 1996-08-01 | 1996-08-01 | Verwendung von (Meth)acrylsäure-Copolymeren zur Erhöhung der Permeabilität der Schleimhaut |
DE19631084.9 | 1996-08-01 |
Publications (2)
Publication Number | Publication Date |
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CN1226834A true CN1226834A (zh) | 1999-08-25 |
CN1182872C CN1182872C (zh) | 2005-01-05 |
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CNB971969647A Expired - Fee Related CN1182872C (zh) | 1996-08-01 | 1997-07-21 | 使用(甲基)丙烯酸共聚物增加粘膜的渗透性 |
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US (1) | US6555124B1 (zh) |
EP (1) | EP0918542B1 (zh) |
JP (1) | JP2000515159A (zh) |
KR (1) | KR20000029736A (zh) |
CN (1) | CN1182872C (zh) |
AU (1) | AU3769197A (zh) |
BR (1) | BR9710889A (zh) |
DE (2) | DE19631084A1 (zh) |
ES (1) | ES2221060T3 (zh) |
WO (1) | WO1998005360A2 (zh) |
ZA (1) | ZA976846B (zh) |
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-
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- 1996-08-01 DE DE19631084A patent/DE19631084A1/de not_active Withdrawn
-
1997
- 1997-07-21 WO PCT/EP1997/003899 patent/WO1998005360A2/de not_active Application Discontinuation
- 1997-07-21 BR BR9710889A patent/BR9710889A/pt not_active Application Discontinuation
- 1997-07-21 EP EP97934501A patent/EP0918542B1/de not_active Expired - Lifetime
- 1997-07-21 US US09/230,741 patent/US6555124B1/en not_active Expired - Fee Related
- 1997-07-21 DE DE59711600T patent/DE59711600D1/de not_active Expired - Lifetime
- 1997-07-21 JP JP10507524A patent/JP2000515159A/ja not_active Withdrawn
- 1997-07-21 ES ES97934501T patent/ES2221060T3/es not_active Expired - Lifetime
- 1997-07-21 CN CNB971969647A patent/CN1182872C/zh not_active Expired - Fee Related
- 1997-07-21 AU AU37691/97A patent/AU3769197A/en not_active Abandoned
- 1997-07-21 KR KR1019997000840A patent/KR20000029736A/ko not_active Application Discontinuation
- 1997-07-31 ZA ZA976846A patent/ZA976846B/xx unknown
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Publication number | Priority date | Publication date | Assignee | Title |
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CN1735435B (zh) * | 2003-01-14 | 2012-08-29 | 辻彰 | 由质子驱动的运载体介导的消化道吸收促进剂及其制备方法 |
US8871818B2 (en) | 2003-01-14 | 2014-10-28 | Otsuka Pharmaceutical Co., Ltd. | Gastrointestinal absorption enhancer mediated by proton-coupled transporter and its preparing method |
Also Published As
Publication number | Publication date |
---|---|
DE19631084A1 (de) | 1998-02-05 |
AU3769197A (en) | 1998-02-25 |
US6555124B1 (en) | 2003-04-29 |
ES2221060T3 (es) | 2004-12-16 |
WO1998005360A2 (de) | 1998-02-12 |
WO1998005360A3 (de) | 1998-05-07 |
CN1182872C (zh) | 2005-01-05 |
EP0918542A2 (de) | 1999-06-02 |
EP0918542B1 (de) | 2004-05-06 |
JP2000515159A (ja) | 2000-11-14 |
KR20000029736A (ko) | 2000-05-25 |
DE59711600D1 (de) | 2004-06-09 |
ZA976846B (en) | 1999-02-01 |
BR9710889A (pt) | 1999-08-17 |
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