CN1208343A - 胃肠内释药体系 - Google Patents
胃肠内释药体系 Download PDFInfo
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- CN1208343A CN1208343A CN97191743A CN97191743A CN1208343A CN 1208343 A CN1208343 A CN 1208343A CN 97191743 A CN97191743 A CN 97191743A CN 97191743 A CN97191743 A CN 97191743A CN 1208343 A CN1208343 A CN 1208343A
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Abstract
本发明涉及胃肠释药体系。该体系包括与内芯材料结合的药物、由嵌有水溶性颗粒材料的非水溶性或相对非水溶性包衣材料包封的内芯。当释药体系进入胃肠道内时,颗粒物吸收液体并由此形成将含药内芯与体系外层相连的通道。上述通道是药物进入胃肠道内的途径。通过控制体系参数例如内芯材料、包衣载体物和颗粒物可精细调控药物的局部释放。因此,本发明还涉及用上述释药体系治疗疾病的方法,以局部给药或控时给药的方式来达到胃肠道内的药物释放。
Description
发明领域
本发明涉及一种释药体系，该体系能够将肠用药物释放到肠胃道特定部位。
发明背景
将药物组合物释放到胃肠道内特定部位以治疗多种疾病的方法极其重要。仅作用于胃肠道内特定区域的靶向药物使疾病局部治疗成为可能，并且避免药物全身性副作用或直接给药造成的不便和不适。此外，仅在胃肠道吸收靶位释放药物的需求也日益增加。这种特定释药方式能够提高药效并减小最低有效剂量。
经小肠淋巴系统吸收的药物应在小肠内释放(Ritchel,E.A.，临床药理试验方法的发现13(5):313-336(1991))。大分子物质例如肽由派伊尔淋巴集结吸收到淋巴系统内，该淋巴集结均匀地分布在整个小肠的各节内。由于派伊尔淋巴集结在未成年个体中占有很高的比例，并且具有随年龄增长而减少的特征(Cornes,J.，内脏6:230(1965))，因此该淋巴集结可作为药物吸收靶位直至中年。以小肠某节内的派伊尔淋巴集结作为药物作用靶位的方法可防止药物产生损伤性副作用。
小肠淋巴液是药物吸收途径，而释药体系的设计应以此为据。(Norimoto等人，国际药理学杂志。14:149-157(1983))。
结肠内吸收药物同样应在结肠内释放，例如甾类化合物、黄嘌呤及其他药物。这样能够提高药效并减少最低有效剂量(Godbillon.J.等人，英国临床药理学杂志19:113S(1985)；Antonin,K.等人，英国临床药理学杂志19:137S(1985)；Fara,J,W.，第三界国际药物吸收研讨会，Edinburgh(1988))。心得安、氧烯洛尔、美托洛尔、噻吗心安和贝那普利主要在空肠内吸收，而甲氰咪胍、速尿、双氢氯噻嗪和羟氨苄青霉素主要在十二指肠内吸收。Rubinstein.A.，生物药物配置(Biopharm.DrugDispos.)11:465-475(1990)上发表的文章可作为上述内容的综述性参考文献。
使活性药物仅作用于胃、小肠和结肠局部疾病的靶向治疗是另一个在食道内定位释放药物的目的。
研究小肠靶向药物和结肠靶向药物的目的是为避免胃内酸性条件和胃酶对药物造成的破坏作用。另一目的也是为避免胃受到局部刺激。
最后，开发胃内靶向药物也是必需的。
然而，设计仅作用于食道内选定部位的靶向药物是十分复杂的工作。
当研究在食道靶位释放药物时一定要考虑多种因素的影响。食道各节都具有截然不同的性质，这些不同的特性可能会妨碍或促进药物通透(肠)膜。下列是应予以考虑的影响因素：1．解剖学特性-表面区域、上皮、存在的粘液细胞、静脉血流、淋巴液；2．生理学特性-吸收途径、pH、随机性和转运时间、酶；3．生化特性-内分泌、pH、肠内悬浮物、酶；4．机械特性-粘液和水的覆盖层及其更新速率；5．免疫学特性-上皮面的抗原性刺激；
本领域现有的药物控释体系中，药物穿过肠胃道时以扩散和浸蚀方式进行释放。当到达靶位时大部分药物业已流失，仅余下少量供局部释放的药物，或者是经过非释药部位时的药量过高。
常规胃内靶向药物的技术是基于口服的缓释和控释药物的持续时间随药物在胃肠内转运时间而变化，该胃肠内转运时间主要取决于胃排空速率。延长药物在胃内保留时间的方法包括：加入脂肪酸以减缓生理性胃排空(Groning R.等人，药物开发工业制药(Drug Dev.Ind.Pharm),ID-527-39(1984))和利用生物粘合聚合物(Smart,J.D.，等人，药物药理学杂志36:195(1984))。
另一胃内靶向药物体系是可防止胃排空的流体平衡体系。该体系的作用原理是使胶囊或片剂具有低于胃液的堆积密度。由此，该类制剂悬浮并停留在胃内。这类剂型通常包含20-75％的一种或多种氢化胶体(hydrocolloid)(例如，羟乙基纤维素和羟丙基甲基纤维素)(Sheth,P.R.,药物开发工业制药(Drug Dev.Ind.Pharm.)10:313-39(1983)；Chien.Y.W.，药物开发工业制药9:1291-330(1983)；Desai,S.&Bolton,S.，药物研究(Pharm.Res.)10:1321-5(1993))。
Banakar(美国药学27:39-48(1987))公开了胃充气释药体系。该体系包含一个或数个在体温下能够容纳气体的展开气室(例如，气化液体或可生成气体的固体，例如碳酸氢钠或碳酸钠)。展开气室含有塑性基质并被包封在明胶内。明胶包衣的溶解将使释药体系充气并使药物扩散。
部分上述释药体系中还包括渗透压分室，分室内含有调节渗透压的活性盐。活性盐遇胃液溶解并释放出药物。其他的此类释药体系是基于体系包含可悬浮的双层压缩基质。(Ugani,H.M.,等人，国际药学杂志。35:157-64(1987))。其中一层包含亲水性聚合物和可产生二氧化碳的组合物。二氧化碳产生飘浮力并使另一亲水基质层中的药物自基质中释放出来。
胃靶向药物另一作用方式涉及药物的胃内滞留形态，该形态由聚乙烯或聚乙烯混合物组成(Cargill,R.，等人。药物研究(Pharm.Res.)5:533-536(1988)；Cargill,R.，等人，药物研究(Pharm.Res.)5:506-509(1989))。
靶向药物的胃内释药机理同样适用于小肠。然而，小肠其他区域给药也可利用一些附加释药体系。肠溶包衣可抵抗胃内低pH值和胃酶，并保护胃粘膜不受药物刺激。肠溶包衣由选择性不溶物组成，它能够使药物不被胃酶和/或胃内低pH值减活。
最常用肠溶包衣是甲基丙烯酸共聚物(EudragitTM)、乙酸邻苯二甲酸纤维素、乙酸琥珀酸纤维素、苯乙烯马来酸共聚物(Ritschel,W.A.应用生物药物，斯图加特(1973)396-402页；Agyilirah,G.A.等人，“聚合物在肠溶包衣中应用”，《聚合物在药物控释体系中的应用》，Tarcha,P.J.编.,CRC出版，(1991)Boca Raton，第39-66页)。但肠溶包衣的最大缺陷是其胃内排空时间的不确定性。该缺陷导致血药浓度不稳定。
小肠靶向药物的另一摄入方式是淋巴系统吸收途径。毛细管和淋巴管允许脂溶性化合物和小分子基团通透(Magersohn,M.，现代药物，MarcelDekker,New York(1979)，第23-85页)。
大分子物质(例如肽)由派伊尔淋巴集结吸收入淋巴系统。以派伊尔淋巴集结吸收途径为靶向时，同样要考虑到在自身免疫疾病中会有含组织抗原的蛋白质或肽被吸收。派伊尔淋巴集结中的抗原能够调节T细胞。激活的T细胞易向炎性组织迁移，在该组织内，细胞因子抑制剂能够中和T细胞及其他任何炎性细胞。这种释药方法是在实践中发现的(Ermak,T.H.，等人，“口服免疫接种和胃免疫性诱导的方法”，控制释放的生物作用材料国际大会论文集22:334(1995))。
派伊尔淋巴集结靶向药物/肽的主要缺陷是其吸收量将自中年始减少。(Andreasen,微生物学大观(Act patrol.Microbiol.Scan.)49(增刊):81(1943))。
小肠靶向药物的另一作用方法中利用了肠内吸附启动子。研究采用了长链脂肪酸，其中包括油酸、酰基肉碱和棕榈酰肉碱(Morimoto,K.,等人，国际药学杂志(Int.J.Pharmaceru.)14:49-57(1983)；Fix,J.A.，等人，航空生理学杂志(Aires J.Physiol.)14:G-332-40(1986))。
口服释药体系中，生物粘合剂用于延长肠内物质转运时间。肠粘膜内的粘合剂作用机制既可以是机械性粘连，也可以是其他的作用机制(Longer,M.A.等人，国际药学(Pharm.Int.)7:114-7(1986))。
赋形剂也可延长GI(胃肠)转运时间。肉豆蔻酸三乙醇胺盐能够延缓胃肠转运时间并提高核黄素的吸收率(Gronig,r.和Heun,G.,药物开发，工业制药(Drug Dev.Ind.Pharm.)10:527-539(1984)；Palin,K.J.等人，国际药理学杂志19:107-127(1984))。
多数小肠靶向释药体系仍在研制开发之中，但其中并不包括肠溶包衣片剂。据上所述，肠溶包衣不能使血药水平保持稳定。
由于位于食道末端，结肠是极其不易进入的部位。肠溶包衣可在胃内吸收，同时将药物释放至小肠内。释放作用依赖于食道内两个部位之间的pH差(Ritchel,W.A.应用生物药物，斯图加特，Wissensec.出版社(1973)，396-402页；Agyilirah,G.A.&Banker,G.S.，“聚合物在肠溶包衣中应用”，《聚合物在药物控释体系中的应用》，Tarcha,P.J.编.,CRC出版，(1991)Boca Raton，第39-66页)。然而，现已证明，肠溶制剂的血药浓度随胃排空速率改变和漂移。同时，肠溶包衣使药物在小肠特定部位的释放无法重现(Kenyon,C.J.,等人，国际药学杂志(Int.J.pharm.)112:207-213(1994)；Ashford,M.等人，国际药学杂志(Int.J.Pharm.)91:241-245(1993))。因此，多种释药机制的释药体系将是需要的。
常规结肠靶向药物中，待释药物分子的固体制剂都用耐pH聚合物包衣。此类制剂与可将药物释放至回肠内的肠溶包衣制剂类似。肠溶包衣含有易被生物浸蚀的聚合物，例如紫胶和乙酸邻苯二甲酸纤维素(Levine等人，胃肠病学，92:1037-1044(1987))。
与肠溶包衣制剂相比，以结肠为靶位的释药制剂却能耐受酸性或弱碱性(接近pH7)环境达数小时。在此期间，该制剂可穿过小肠到达大肠并在其中崩解及启动药物释放。以此方式，药物例如5-氨基水杨酸(5-ASA)和某些甾类化合物可被释放至结肠内。符合这种制剂要求的聚合物通常为丙烯酸衍生物或纤维素衍生物，例如乙酸邻苯二甲酸纤维素、或乙基纤维素(Rasmussen,S.N.等人，胃肠病学，83:1062(1982)；Levine,D.S.等人，胃肠病学，92:1037(1987)；mardini H，等人，内脏18:1084-1089(1987))。
但是，上述制剂的主要缺陷是其包衣开始降解的位置和环境都无法确定。由于肠胃内存在随患者个体差异及疾病不同而变化的随机因素，则包衣既可以到达结肠后才开始降解，也可以仅至小肠就发生降解。
结肠会因短链脂肪酸、二氧化碳、其他发酵产物和胆汁酸残留物的存在而使其pH值降至近6(Stevens,C.E.，美国临床营养学杂志31:S161(1978)；mcneil,N.I.，等人，内脏28:707(1987))。该pH变化被怀疑是由结肠高pH值引发。
美国专利4,627,850(Deters等人)公开了一种控速释药渗透胶囊，该胶囊包括由不同聚合材料组成的外壁和内壁，内壁构成一个容纳药物的空间，在内外壁之间有通道将外壁外层与内壁内层相连。
美国专利4,904,474(Theeuwes等人)公开了一种结肠释药体系，该体系既能延缓药物本身的释放，也延迟药物在小肠内的释放，同时该体系还采用了仅在结肠内释放药物的技术。此释药体系还利用渗透方式迫使包含在储药室内的活性药物通过储药室出口进入到结肠内。耐酸包衣用于减缓药物在胃或小肠内释放。释药体系的缓释作用随时间变化。该制剂结构如此设计是为使内载药物在到达胃肠道选定靶位前不发生释放。
另一结肠释药体系利用了结肠悬浮物具有的对小肠无法消化物质的降解作用。该释药方式可用来释放轻泻药、番泻叶苷主成分及相应化合物(Fairbairn,J.W.，药物药理学杂志1:683(1949)；Hardcastle,J.D..等人，内脏11:758(1974))。
治疗炎性肠内疾病的传统药物是柳氮磺胺吡啶。柳氮磺胺吡啶是通过偶氮键与抗炎剂5-ASA相连的抗菌性磺胺吡啶药物。5-ASA具有临床治疗效果(Khan,A.K.等人，手术刀2:892(1977))。该柳氮磺胺吡啶是前体药物，它能够将5-ASA携带至结肠内并在结肠细菌偶氮还原作用下释放出5-ASA，以发挥其治疗功效(Klitz,U.临床药物动力学10:285(1985))。
对于5-ASA的前体药物(柳氮磺胺吡啶、偶氮二水杨酸盐(azosalicylate)和柳氮苯甲酸(salicylazobenzoic acid))，母体药物的释放是由靶器官内细菌酶而并非是靶组织内的酶完成。结肠寄生微生物的酶能够将前体药物和其他药物分子转化为治疗活性剂，从而使那些由微生物调控的结肠释药体系在所到达的区域内发挥更高的活性。
虽然某些蛋白质和肽例如白细胞介素-Ⅱ、干扰素、结肠刺激因子、肿瘤坏死因子和促黑激素都对至今仍难以控制的疾病具有新的和有效的治疗作用，但这些药物的应用通常受限于释药方式。结肠释药体系为上述药物及其他新的蛋白质和肽类药物的优选给药途径。
结肠释药体系对于炎性肠内疾病和溃疡性结肠炎治疗药物而言同样重要。但是，专供结肠释药的现有肠内给药制剂并不适合人体长时间使用，部分原因是由于偶氮化合物的潜在毒性。因此，人们希望研制出改良的结肠释药体系以供多种药物和生物活性化合物利用。
在共同未决专利申请08/193,775和08/481,148(申请日期分别是1994.2.10和1995.6.7)中公开了一种释药体系，该体系所含药物与基质相结合，该基质由含糖聚合物组成。这类聚合物能够耐受胃内化学降解和酶促降解，但对结肠细菌的酶促降解很敏感。无论基质是否能够耐受胃内化学降解和酶促降解，该结肠释药体系的作用机制却基于由结肠细菌作用的基质降解，并且结肠细菌对基质的酶促降解使包埋于基质内的药物得以释放。上述共同未决申请在本文中作为参考文献，其全部说明、用途指南和结肠释药体系制备方法都可作为参考内容。
于1992年5月20日申请的欧洲专利485840(Rhm GmbH)公开了一种肠胃释药体系，该体系包括作为包衣材料的多糖和EudragitTM的混合物。但是，液体可迅速进入制剂并将其中的药物快速放出，因此该制剂无法达到本申请所取得的药物控释效果。此外，多糖也不是颗粒状。
本发明中，上述问题都得以解决，这是由于本发明所述包衣能够防止药物在预定时间之前释放，预定时间后的包衣内含颗粒物已经充分溶胀并使药物得以释放。
发明概述
本发明涉及一种将药物靶向释放到食道选定部位的释药体系或系统，该体系包括内芯和包衣。内芯包含有与载体材料结合的药物。优选方案中的载体材料具有遇含水介质即可溶胀的特性，而其中的含水介质例如可是那些存在于食道内的液体。
内芯剂型包括片剂、胶囊和丸剂，优选压制片剂和基质片剂。
包衣包含有不溶于或微溶于水溶液的材料，该材料内包埋有亲水的非水溶性颗粒物。
这种设计使水或含水流体例如胃肠道内液体能够缓慢进入释药体系。当水分与颗粒物接触时，颗粒物开始溶胀。最终在体系外部和含药内芯之间形成通道。在实施例中，可溶胀内芯发生溶胀后，药物以控释方式穿过颗粒的内嵌通道。
对于非水溶性药物，优选可溶胀内芯。对于水溶性药物，优选非溶胀内芯。当然，可根据具体药物来设计具有不同溶胀度的内芯。
通过改变特定参数来控制药物释放位置，例如改变外包衣厚度、包衣内颗粒的包埋量、包衣内嵌颗粒的类型、包衣内嵌颗粒的颗粒大小分布、及内芯载体。同时，本发明释药体系还进一步提供了一种将药物或其他活性化合物给予需此药治疗患者的肠内给药方法，需要时，可将上述药物送到胃肠道的选定靶位。
优选的治疗靶位包括但不限于回肠和结肠。
本发明释药体系还提供了将有效量的一种或多种选定药物释放到食道特定部位、以治疗局部疾病的方法。这些疾病包括但不限于节段性回肠炎、结肠炎、过敏性肠综合症(IBS)、息肉、癌、囊肿、感染性功能失调症及寄生性功能紊乱症。本发明释药体系还提供了一种通过派伊尔淋巴集结或结肠达到免疫接种目的的方法(Cardenas,L.&Clements,J.D.临床微生物研究5/3:328-342(1992))。本发明释药体系也使局部释放光动力治疗剂成为可能。
本发明释药体系还提供一种将有效量药物经食道靶位运达全身的药物释放方法。在食道远端部位易于吸收和/或副作用较低的药物都可以食道远端部位为释药靶位。本发明释药体系以十二指肠、空肠、回肠、升结肠、横结肠和降结肠作为药物全身性释放靶位。
本发明进一步提供了上述释药体系的制备方法。优选的制备方法是制备一种亲水的非水溶性颗粒于含疏水聚合物的乙醇溶液中的悬浮液。该悬浮液可用常规锅式包衣技术喷涂，并覆盖在内芯片剂或胶囊外。
附图简介附图1：水杨酸钠在200μEudragit ETM和Eudragit ETM/果胶(pectinate)钙(1∶1)膜中的扩散作用。附图2：由Eudragit ETM包衣的果胶钙/果胶内芯中的水杨酸钠释放图示。附图3：由Eudragit ETM/果胶钙(7∶3)膜包衣的果胶钙/果胶内芯中的水杨酸钠释放图示。附图4：由Eudragit ETM/果胶钙(1∶1)膜包衣的果胶钙/果胶内芯中的水杨酸钠释放图示。附图5：由Eudragit ETM/果胶钙(3∶7)膜包衣的果胶钙/果胶内芯中的水杨酸钠释放图示。附图6：由A级Eudragit ETM/果胶钙(3∶7)膜包衣的果胶钙/果胶内芯中的水杨酸钠释放图示。附图7：由B级Eudragit ETM/果胶钙(3∶7)膜包衣的果胶钙/果胶内芯中的水杨酸钠释放图示。附图8：由C级Eudragit ETM/果胶钙(3∶7)膜包衣的果胶钙/果胶内芯中的水杨酸钠释放图示。附图9：由A、B和C级Eudragit ETM/果胶钙(3∶7)膜包衣的果胶钙/果胶内芯中的水杨酸钠释放图示。附图10：由Eudragit ETM/果胶钙(3∶7)膜和Eudragit ETM/果胶膜包衣的果胶钙/果胶内芯中的水杨酸钠释放图示。附图11：由Eudragit ETM/果胶钙(3∶7)包衣的微晶纤维素内芯中的水杨酸钠释放图示。附图12：由乙基纤维素/果胶钙(3∶7)包衣的果胶钙/果胶内芯中的水杨酸钠释放图示。附图13：无包衣果胶钙/果胶内芯中的水杨酸钠释放图示。附图14：由乙基纤维素/果胶钙(3∶7)或乙基纤维素/果胶钙(2；8)包衣的果胶钙/果胶内芯中的水杨酸钠释放图示。附图15：由Eudragit RSTM/果胶钙(3∶7)包衣的果胶钙/果胶内芯中的水杨酸钠释放图示。附图16：由Eudragit ETM/交联Byco(3∶7)包衣的果胶钙/果胶内芯中的水杨酸钠释放图示。附图17：由Eudragit ETM/Crospocidone(3∶7)包衣的果胶钙/果胶内芯中的水杨酸钠释放图示。附图18：由Eudragit ETM/交联吡咯烷酮(1∶1)包衣的果胶钙/果胶内芯中的水杨酸钠释放图示。附图19：由Eudragit ETM/交联吡咯烷酮(7∶3)包衣的果胶钙/果胶内芯中的水杨酸钠释放图示。附图20：由EudragitETM/微晶纤维素(7∶3)包衣的果胶钙/果胶内芯中的水杨酸钠释放图示。附图21：由Eudragit ETM/微晶纤维素(3∶7)包衣的果胶钙/果胶内芯中的水杨酸钠释放图示。附图21a：由Eudragit ETM/微晶纤维素(1∶1)包衣的果胶钙/果胶内芯中的水杨酸钠释放图示。附图22：由Eudragit ETM/果胶钙(3∶7)膜包衣果胶钙/果胶内芯中的双氯芬酸钠释放图示。附图23：本文实施例1中的包衣喷头示意图。
优选实施方案详述定义
本申请下文中多处引用一些药理学术语，这些术语使说明书和权利要求及保护范围清楚一致，下面将给出具体定义。除非另有说明，本文专业术语应理解成惯用的和/或所属领域常规的含义。
例如，所谓“结肠”、“大肠”、“小肠”、“胃”、“直肠”和“回肠”依然是其常规医用含义。
所谓“药物”是指任何用于疾病的诊断、治疗、缓解、处理或预防以及其他医疗用途的可药用或生理用试剂、组合物、生物活性化合物或它们的结合物。术语“药物”应是广义的而不能仅理解为化学组合物或生物活性物。
所谓“内芯”，即广义的核心部分，就本发明而言，是指释药体系中的、在其外部包有含颗粒包衣而内部含有待释药物的核心部分。药物既可嵌入内芯也可与之结合，例如通过干混法或湿法研磨。内芯是基质片剂或含药胶囊或纯药丸或覆盖有药丸层的内芯材料或含有原料药物的微囊。总之，内芯能够有效地释放药物。
内芯材料包括但不限于：果胶、果胶钙(calcium pectinate)、微晶淀粉、羟丙基甲基纤维素、乳糖、淀粉、聚乙烯吡咯烷酮、微晶纤维素、磷酸钙、瓜耳胶和常规药用添加剂和赋形剂(参考药用赋形剂手册，第2版，Wade,A,和Weller,P.J.,编辑，美国药学会(1994))。
在优选实施方案中，内芯材料包括果胶钙、羟基丙基甲基、微晶纤维素、淀粉或微晶淀粉或它们的结合物。其他内芯材料包括但不限于羧甲基纤维素，乳糖、聚乙烯吡咯烷酮、瓜耳胶、藻酸、藻酸钠、角叉菜胶(carrageenan)、或任何本领域已知的常规片剂赋形剂(参考药用赋形剂手册，第2版，Wade,A，和Weller,P.J.,编辑，美国药学会(1994))。
术语“颗粒”是指由分立的微粒组成的组合物。本发明中，这些分立的微粒包埋于内芯外的包衣材料中。颗粒吸收液体并形成通道、孔或网，以释放出体系内芯中的药物。释放出的药物需通过上述通道。
本发明中，“包衣”、“包衣层”、“膜”、“层”、“覆盖物”及类似词语可彼此通用。
颗粒物质包括但不限于：多糖，该多糖包括但不仅是果胶钙、藻酸钙、黄原酸钙；任何含有酸基团并使多糖不溶于水的多糖金属盐；微晶淀粉、不溶性淀粉、所有非水溶性多糖(例如纤维素或微晶纤维素)、任何与聚阳离子或聚阴离子反应后呈不溶性的多糖、及任何交联但不溶于水的共价交联多糖。上述交联剂包括但不限于是戊二醛、甲醛、表氯醇、二元酸酰氯、二异氰酸酯、二酸酐和二胺。
包衣材料可按本领域的常规方式选择性地含有增塑剂以改善其性能。包衣材料还可选择性地包封有常规肠溶包衣外层，如本领域已知的肠溶包衣外层，但前提是包衣材料或颗粒受到胃里酸性条件的影响。
附加外包衣还包括但不限于是易吞咽的包衣和矫味的包衣。
在优选实施例中，包衣材料包括果胶钙和EudragitETM、交联吡咯烷酮和Eudragit ETM、或果胶钙和乙基纤维素。在同一实施例中，EudragitETM或乙基纤维素含有非水溶性载体时的颗粒物质包含果胶钙或交联吡咯烷酮。
非水溶性载体可根据本领域普通技术人员所知的膜的常规性能而含有或不含增塑剂。
在另一实施例中，包衣包括但不限于由非水溶性多糖、非水溶性交联多糖、非水溶性多糖金属盐、非水溶性交联蛋白或肽、干粉型的作为颗粒的非水溶性交联亲水聚合物与任何已知可作为非水溶性载体的疏水聚合物包衣所组成的任意结合物。颗粒材料的具体例子包含但不限于非水溶性淀粉、微晶淀粉、微晶纤维素、脱乙酰壳多糖、藻酸钙或锌、黄原酸钙、瓜耳胶硼砂复合物、戊二醛或甲醛交联瓜耳胶、戊二醛或甲醛交联葡聚糖、氯甲代环丙烷交联葡聚糖、可溶性戊二醛或甲基交联淀粉、戊二醛或甲醛交联明胶、戊二醛或甲醛交联氢化明胶、戊二醛或甲醛交联胶原蛋白、多糖与蛋白或肽的任意可溶性复合物、戊二醛或甲醛交联羟丙基纤维素、或所有交联丙烯酸聚合物。非水溶性载体的具有例子包括但不仅是EudragitETM、Eudragit NETM、Eudragit RLTM、Eudragit RSTM、乙基纤维素、紫胶片、玉米醇溶蛋白和蜡。
所谓“非水溶性”是指不易溶解于水。非水溶性对于本发明含义很重要。疏水膜和亲水颗粒都不溶于水和肠液。此特性对于疏水膜的重要性表现在能够防止该包衣膜过早溶解以及由此导致的释药失控。该特性对于亲水颗粒的重要性还在于保持其所形成通道的完整性并可连续控释药物。颗粒溶解于通道内将导致不利的释药加速。
相反地，所谓“水溶性”是指易溶于水。描述膜时所用的“疏水性”是指除其常规含义外的、对于水及水溶性化合物的相对不通透性。形容膜的术语“亲水性”是指除其常规意义外的、对于水和水溶性化合物的相对通透性。
术语“包埋”或“嵌入”表示异物紧密固定于介质内。本发明内容中的该术语含义是指颗粒物固着于包衣介质内。
所谓“微囊”、“微颗粒”和“微球”是描述球状或部分球状的亚微结构近似为1000微米左右的颗粒的常用术语。优选颗粒大小介于1-200微米，更优选介于2-100微米。
术语“通道”表示任何物质可流经的途径。本文中，通道是由包衣内颗粒吸水溶胀而成，溶胀颗粒中出现不间断地连接、以允许释药体系外的含水介质通过并且使其进入释药内芯材料的通路。
术语“给药”是指将本发明释药体系施用给所需对象。治疗目的时的给药可以是预防性的或治疗性的，而用于预防目的时的给药须在任何症状显露前即实施。预防性给药旨在预防或缓解任何继发病症。治疗目的给药中的药物应于病症始发作时(或刚开始后)施用。治疗用药物可缓解任何急性病症。
所谓“动物”是指任何本发明释药体系可有效作用的含细胞活生物。其中最优选人体；然而，本发明并不局限于此，本发明组合物还可用于所有能够受益于本发明的动物。因此，本发明释药体系和方法并不限于人体，还尤其适用于任何种类动物的兽医学给药。其中包括但不仅是家畜，例如狗、猫、马、鱼和鸟，观赏动物、野生动物的预防和治疗；还包括重要的食用和乳品业动物，例如牛、乳牛、猪和家禽。
本发明涉及一种包括非水溶性或相对非水溶性的、覆盖于含药内芯、尤其是溶胀内芯外的包衣的释药体系。此包衣是一种非水溶性的亲水颗粒包埋并分散于非水溶性材料中形成的混合物。但包衣可能并非完全不溶于水。允许水或其他含水流体例如胃肠道内液体缓慢进入是膜的重要特性。包埋的亲水性颗粒与水接触后即发生溶胀。溶胀颗粒最终形成自体系外层至含药内芯的通道。药物以受控方式经通道释放。实施例中的内芯可溶胀，内芯溶胀后，药物以受控方式经通道自包埋颗粒中放出。
在本发明的一个优选实施例中，释药体系是含有内芯材料的原本不崩解片剂。片剂以标准研磨和压片方法制备，并利用锅式包衣工艺进行包衣。颗粒材料的悬浮溶液或研磨聚合物包衣材料的悬浮液可代替溶液喷涂在片剂上。搅拌悬浮液以使其相对均匀。热气流或冷气流经过片剂表面，使膜形成并干燥片剂。上述聚合物溶液或悬浮液的适宜溶剂是已知的常规喷涂包衣用溶剂，并包括但不限于是水、乙醇、丙酮和异丙醇。优选溶剂是乙醇。
本发明另一优选实施例中，释药体系为包衣片剂型。体系其他剂型可以是包衣胶囊、包衣微囊、包衣丸剂或微丸剂、包含于胶囊内的包衣丸剂或微丸剂、包含于包衣胶囊内的包衣丸剂或微丸剂、压制成片剂的包表丸剂、微丸剂或微囊剂、压制成片剂并进一步包衣的包衣丸剂、微丸剂或微囊剂。
任何材料及任何溶胀材料都应被视为可使用的内芯材料。对材料功能的要求仅是：当依次与胃肠道含水物和已吸水颗粒内通道接触后，内芯材料可释放出所含药物。释药体系的通道为释药途径。在溶胀内芯实施例中可根据所需溶胀量来采用任何常规材料。
任何材料都被视为可用作包埋颗粒。其功能条件是，该材料能够吸收胃肠道内含水物并随即形成供含水物流经药物释放的通道或网络。
改变下列参数来控释药物：(1)颗粒大小；(2)包衣厚度；(3)成颗粒材料的类型；(4)颗粒比例；及(5)非水溶性成膜材料。
在更优选的实施例中，释药体系是大小为9mm的、包含了药物(例如，水杨酸钠或双氯芬酸)及由7份果胶钙和3份Eudragit ETM的25-30份乙醇组成的悬浮液包衣的赋形剂(例如，果胶钙、果胶和羟丙基甲基纤维素)的片剂。果胶钙颗粒＜149μ且膜厚度近似为200微米时可获得最佳效果。该实施例中能够将可溶性药物释放至结肠，这是由于在美国药典肠道试液(TS)(美国药典ⅩⅩⅡ，国内汇编ⅩⅤⅡ,1789页(1990))及溶解装置2(美国药典ⅩⅩⅡ，国内汇编ⅩⅤⅡ,1579页(1990))中进行的体外试验中，药物延迟释放近4小时。
优选释药体系还可用Eudragit LTM作为肠溶包衣，以保护EudragitETM和果胶钙不受胃内酸性pH影响。肠溶包衣溶解于小肠上端。果胶钙颗粒自肠液进入包衣后开始溶胀。4小时后通道形成而可溶药物开始释放出体系。该体系所载可溶性药物在到达结肠后以控释方式经溶胀果胶钙通道扩散。薄包衣将削弱释药延缓作用并使药物释放于小肠末端。
设计结肠给药制剂是为防止药物在胃和小肠环境内释放并使药物不受胃酶和小肠酶影响。以结肠为靶位的优选释药体系具有确保所载药物释放的优越性，此应归因于大部分在胃内和小肠内不降解的包衣物(70％果胶钙)和内芯(果胶钙和果胶)将在结肠内被酶促降解。
通过结肠内的流经溶胀颗粒通道的扩散作用及结肠细菌作用，制剂释放出药物。细菌降解颗粒材料以进一步打开通道，随后自通道进入内芯并降解内芯材料以释放结肠药物。
因此，释药体系可用于胃肠道不同区域的靶向肠用药物给药。因而对于需用选定药物治疗的对象可通过口服本发明组合物达到常规医治效果。
适于结肠给药的治疗剂例包括：非甾类抗炎剂(NSAID)，例如双氯芬酸、氟比洛芬和阿斯匹林；甾类药物，例如地塞米松、布地萘德、倍氯米松、fluticasone、tioxocortol和氢化可的松；避孕-或类固醇激素，例如雌激素、雌二醇和睾酮；免疫抑制剂，例如环孢菌素；支气管扩张药，例如茶碱和沙丁胺醇；抗心绞痛和抗高血压药，例如硝酸异山梨醇酯、单硝酸异山梨醇酯、硝酸甘油、硝苯地平、氧烯洛尔、地尔硫、卡托普利、阿替洛尔、贝那普利、美托洛尔和vasopril；解痉剂，例如西托溴铵；抗结肠炎剂，例如5-氨基水杨酸；抗心律失常药，例如奎尼丁、维拉帕米、普鲁卡因胺和利多卡因；抗肿瘤药，例如甲氨蝶啶、他莫昔芬、环磷酰胺、巯嘌呤和依托泊甙；蛋白质或肽类药物，例如胰岛素、人生长激素、白介素-Ⅱ、干扰素、降钙素、亮丙瑞林、肿瘤坏死因子、骨生长因子、促黑素、卡托普利、抑生长素、抑生长素八肽类似物(octapeptide analog.)、环孢菌素、过氧化物歧化酶、其他激素和疫苗；抗凝血剂，例如肝素或短链肝素；抗偏头疼药，例如麦角胺(ergotamine)；格列苯脲；5-羟色胺1A型受体拮抗剂吉吡隆；5HT3拮抗剂枢复宁；美克法胺；薄荷脑；抗生素，例如新霉素、β-青霉素如氨苄青霉素和阿莫西林、头孢菌素如头孢氨苄和氯唑西林、大环内酯如红霉素；防止十二指肠粘膜NSAID损伤的PGE1类似物，例如米索前列醇。蛋白质药物例如促黄体素释放激素(LHRH)和胰岛素在结肠比小肠吸收更好且存活期长。其他可在结肠内吸收的药物例如是双氯芬酸、奎尼丁、茶碱、硝酸异山梨醇酯、硝苯地平、氧烯洛尔、美托洛尔、格列苯脲、5-羟色胺1A型受体拮抗剂吉吡隆、5HT3拮抗剂枢复宁、美克法胺、薄荷脑、贝那普利(ACE抑制剂)。
用于治疗食道其他不同靶位的药物例子如下：胃食道反流病症(Gastro Esphagal Reflux Disease)-H2受体拮抗剂(例如甲氰咪胍、盐酸雷尼替丁)、质子泵抑制剂(例如奥美拉唑)；念珠菌食道炎-制霉菌素和克霉唑；十二指肠溃疡-H2受体拮抗剂、前列腺素(例如米索前列醇、前列腺素)、质子泵抑制剂(例如Prilosec、奥美拉唑、硫糖铝)；病理性分泌过多症(Pathological Hypersecretory Conditions)、佐林格-埃利森综合征-H2受体拮抗剂；防止十二指肠粘膜NSAID损伤的PGE1类似物例如米索前列醇；治疗胰腺炎的GHR-IH药物例如抑生长素；以及治疗局部痉挛的解痉药例如西托溴铵。
释药体系通过将有效量药物释放至胃肠道靶位达到治疗功效。因此，可局部治疗的疾病包括但不限于是溃疡性结肠炎、节段性回肠炎、结肠癌、食道炎、念珠菌食道炎、十二指肠溃疡、胃溃疡、佐林格-埃尔森综合征、胃炎、习惯性便秘、胰腺炎、局部痉挛、局部感染、寄生虫和其他由于全身功能紊乱(例如心血管炎症、感染和肿瘤)引起的胃肠道病变。
直接作用靶位的释药体系能够提高靶位药物吸收量及与靶位细胞接触的药量。直接释药体系或靶向药物还可减少药物全身性分布以减轻不利的和基本的毒副作用。
释药体系也可用于诊断目的，例如可定位释放X射线造影剂(例如硫酸钡、泛影钠、其他含碘造影剂)、超声造影剂(例如充气微球)、磁共振成像和X线断层术的造影剂和增效剂、或正电子发射剂。体系还可将单克隆抗体标记物释放至肿瘤内。
本发明组合物制剂实例包括：例如，基质-药物片剂，优选压片；基质-药物丸剂，散装或装于明胶胶囊内或其他口服给药形式；基质-药物毫微颗粒，散装或装于明胶胶囊内或其他口服给药形式；以及多层片剂、包衣胶囊、包衣微囊、包衣丸剂或微丸剂、装于胶囊内的包衣丸剂或微丸剂、储存在包衣胶囊内的包衣丸剂或微丸剂、压成片剂的包衣丸剂、微丸剂或微囊、以及压片并被包衣的包衣丸剂、微丸剂或微囊。上述制剂可通过已知技术制备。
用药量随所用药物有效释放的需要而改变并应考虑患者年龄、性别、身体状况、疾病、和其他医学指标。此外，本发明体系所释药量将取决于相对药效。在本发明释药体系和方法中，见效所需的特定药量可由本领域技术人员通过常规技术确定。例如，常规中的推荐剂量(例如，参见内科医生手册，(E.R.Barnhart，出版商)，Merck索引，Merck&Co.,NewJersey，和治疗药物药理学基础，A.G.Goodman等人，Pergamon出版社,New York)可作为发挥有效活性所需的初步估算药量的基础。
以上述方式通过本发明体系达到有效量释放的药物实例包括：抗炎剂，包含非甾类和甾类抗炎剂，例如吲哚美辛、双氯芬酸、氟比洛芬、阿斯匹林、地塞米松、布地萘德、倍氯米松、flucticasone、tioxocortol、和氢化可的松；免疫抑制剂，例如环孢菌素；支气管扩张药，例如沙丁胺醇和茶碱；抗绞痛药和抗高血压药，例如地尔硫草、卡托普利、硝苯地平、硝酸异山梨醇酯、氧烯洛尔；解痉剂，例如西托溴铵；抗肿瘤药，例如甲氨蝶啶、他莫昔芬、环磷酰胺、巯嘌呤和依托泊甙；抗结肠炎剂，例如5-氨基水杨酸；抗心律失常药，例如奎尼丁、维拉帕米、普鲁卡因胺和利多卡因；蛋白质或肽类药物，例如胰岛素、人生长激素、白介素-Ⅱ、干扰素、降钙素、亮丙瑞林(leuorolide)、肿瘤坏死因子、骨生长因子、促黑素、卡托普利、抑生长素、抑生长素八肽类似物、环孢菌素、过氧化物歧化酶、其他激素和疫苗；抗凝血剂，例如肝素或短链肝素；抗偏头疼药，例如麦角胺。
片剂和胶囊可用已知方法制备和试验，例如，如Remington氏的药物科学，Mack出版公司，尤其是其中第89章中所述的“片剂、胶囊和丸剂”药物的制备和生产。在所有实施例中，根据需要可将同样基质内不止一种的药物给予患者。
在例如片剂实施例中的本发明组合物可释放出的药量范围很宽，例如释药量介于0.01-95％重量。
在另一实施例中，压片剂包含有效量的与片剂实施例相同的选定药物或药用化合物，以及一定量的可使片剂崩解并随后使片剂与结肠内一种或多种微生物相接触的本发明组分。其他适宜的实施方式将是常规的。
下列实施例可进一步描述完成本发明所需的材料和方法。但实施例不以任何方式对本发明构成限定。
实施例1
材料和方法
Eudragit ETM 100和Eudragit RSTM购自于Rohm Pharma(德国)，乙基纤维素为Hercules(美国)产品。水杨酸钠粉末(英国药典(BP)，美国药典(USP))由Merck公司提供(德国)。双氯芬酸钠购自Prosintex(英国)。乙醇为USP级纯。含4％和2％钙的果胶钙粉是由氯化钙加入到低碳甲氧果胶(Copenhagen Pectin)在水/异丙醇混合液的悬浮液中制备。重量约300mg、含30mg水杨酸钠的果胶/果胶钙芯片是由标准干粒法制备。重量约250mg、含30mg水杨酸钠的微晶纤维素芯片采用干粒法制备。重量约300mg、含100mg双氯芬酸钠的的果胶/果胶钙可用标准干粒法制备。交联吡咯烷酮购自于GAF(美国)。交联Byco明胶由Byco氢化明胶(Croda(英国))与戊二醛(Merck(美国))交联反应而成。微晶纤维素购自于FMC(比利时)。包衣用的果胶钙/Eudragit TM悬浮液是通过溶解Eudragit ETM(10％W/V(22.5gEudragit TM/200g溶液)于乙醇并随后在该Eudragit TM溶液中加入果胶钙粉末，以达到预定为70、50和30％重量比(g果胶钙/gEudragit TM+果胶钙)。悬浮液在包衣过程中不间断地剧烈搅拌，以避免果胶钙沉淀。其他聚合物-颗粒结合物也以类似的将聚合物(Eudragit RSTM或乙基纤维素)先溶解于乙醇并再加入颗粒(果胶钙、交联吡咯烷酮、微晶纤维素或交联Byco蛋白质)的方法制备。
喷涂包衣100片片剂(果胶/果胶钙片剂或果胶/果胶钙片和微晶纤维素片的混合物)。包衣设备由包衣锅(直径约12cm)、Erweka或Heidolph(RZR 2051，电动)传动电机、蠕动泵(Masterflex，数字控制驱动，Cole-Palmer仪器公司)和由丫型管和吸移管口构成的喷口按附图23所示组装成。
配有#16型硅氧烷管的蠕动泵能够泵出连续的悬浮液流。喷涂气压介于5-10磅/平方英寸(psi)。微晶纤维素和果胶钙/果胶片剂的取样和包衣厚度测定都在喷涂50ml悬浮液后以及每喷50ml悬浮液的间隔后进行，直至所喷悬浮液达250ml。溶解性试验是在肠液TS中利用Vankel VK7000溶解试验器完成。各片剂置于900ml肠液TS中，并以50RPM(转/分)的转速进行叶片式搅拌。肠液TS按USP ⅩⅩⅡ,1789页(不含胰酶)所述方法制备。用Vankel VK650A加热器/循环泵保存溶液于37℃下。在各试验的不同时间间隔的指定时刻，用Vankel VK8000自动取样器取样(3ml)。包衣片剂释放的水杨酸钠用HP 8452A Diode-Array分光光度计在296nm下定量测定。双氯芬酸钠的定量分析试验在波长276nm下进行。
对水杨酸钠透过自固(free-standing)喷膜的扩散作用的检测是在扩散池内厚200μ的Eudragit ETM/果胶钙和Eudragit ETM膜上进行。扩散的有效膜面积为2.27cm2。
将TS肠液(9ml)置于容器池内，并将100ppm水杨酸钠的TS肠液溶液放置在膜的另一端。膜用水/乙醇混合物(4/1 v/v)预湿5分钟。将上述装置整个放置在37℃的振荡浴中，并以每分钟70冲程的频率振摇。在预定时间间隔时用注射器取1ml样品，利用UV分光仪在296nm下测定水杨酸钠含量，随后再将样品放回池中。
Eudragit TM类物质已在Rhm药用工艺材料中公开。它们的特征在于：(1)游离羧基与酯基比例近似为1∶1的异丁烯酸和异丁烯酸甲酯的阴离子共聚物，(2)其中的游离羧基与酯基比例近似为1∶2的异丁烯酸和异丁烯酸甲酯的阴离子共聚物，(3)丙烯酸和含少量季铵基团的异丁烯酸酯的共聚物且其中铵基与其余中性异丁烯酸酯的摩尔比例为1∶20，和(4)丙烯酸和含少量季铵基团的异丁烯酸酯的共聚物，其中铵基与其余中性异丁烯酸酯的摩尔比为1∶40，该类共聚物的市售商标分别为“Eudragit L”、“Eudragit S”、“Eudragit RL”和“EudragitRS”。Emcocel和Avicel是微晶纤维素的商标。Eudragit ETM为异丁烯酸二乙基氨基乙酯和中性异丁烯酸酯的阳离子共聚物。Eudragit NETM为聚(甲基)丙烯酸酯的中性共聚物。二者在Rhm药用商品手册中已被公开。
结果
水杨酸钠(SS)透过自由膜的扩散作用
水杨酸钠通透Eudragit ETM和Eudragit ETM/果胶钙(1∶1)自由膜的扩散结果如附图1所示。各试验中的膜厚度都为200μ。在Eudragit ETM膜试验中，药物基本没有扩散。Eudragit ETM/果胶钙膜使水杨酸钠以可控速率运动。50％水杨酸钠扩散过膜的所需时间是2小时。5小时后扩散作用基本完全。
果胶钙含量对片剂中水杨酸钠扩散的影响
将果胶钙/果胶基质中含30mg水杨酸钠的片剂用含不同比例果胶钙/Eudragit ETM的、不同厚度的Eudragit ETM/果胶钙膜包衣。结果如附图2-5所示。
附图2表示仅以Eudragit ETM包衣的片剂内的水杨酸钠释放结果。包衣厚度大于等于74μ的Eudragit ETM膜包衣片剂在10小时内未被通透。用薄Eudragit ETM膜包衣的片剂能够使水杨酸钠经过一个短时滞后期后得到扩散。滞后期后，释放曲线与未包衣片剂相同。
附图3表示以Eudragit ETM/果胶钙(7∶3)包衣的片剂内水杨酸钠的释放结果。当包衣厚度超过105μ时的包衣片剂不能使其中的药物扩散。60μ后的包衣能够使药物缓慢渗出。6小时后可扩散出近10％的药物。
附图4表示以Eudragit ETM/果胶钙(1∶1)包衣的片剂内水杨酸钠的释放结果。44μ厚的膜通透完全，而厚67μ的膜需经过1小时的滞后期后才开始释药。随后的药物释放与无包衣的情况相同。厚度为93μ和115μ的膜能够分别阻止片剂释放达2小时和4小时，并因此延缓释药。
附图5表示以Eudragit ETM/果胶钙(3∶7)包衣的片剂内水杨酸钠的释放结果。48μ厚度的膜不产生滞后期，而67μ的膜导致1小时的滞后期。其后的扩散作用与无包衣时相同。厚度为125μ、169μ、185μ和290μ的膜的滞后期分别为1、2、3和6小时。与未包衣片剂相比，随后的释药因此被延缓。
表1表示果胶钙对相同厚度膜中水杨酸钠的作用数据及作用百分率的汇总
表1果胶钙(％果胶钙)对水杨酸钠释放的作用
| 膜厚度(μ) | ％果胶钙 | 释放％2小时 | 释放％4小时 | 释放％6小时 |
| 74 | 0 | 0 | 0 | 0 |
| 60 | 30 | 1 | 3 | 10 |
| 67 | 50 | 18 | 40 | 60 |
| 65 | 70 | 25 | 48 | 65 |
| 115 | 0 | 0 | 0 | 0 |
| 118 | 50 | 0 | 2 | 10 |
| 125 | 70 | 3 | 28 | 40 |
| 290 | 70 | 0 | 0 | 3 |
表中数据清楚地表明，果胶钙的增加可使可溶性药物通过膜的释放速率提高。
果胶钙颗粒大小对Eudragit ETM/果胶钙膜中水杨酸钠释放的影响
制备Eudragit ETM/果胶钙膜的果胶钙粉末经过分筛，分成4级：＜44μ、44-74μ、74-149μ、和＞149μ。它们被分别定义为A、B、C和D级。包含各级颗粒的Eudragit ETM/果胶钙(3∶7)膜分别作为含在果胶钙/果胶基质中水杨酸钠的片剂包衣。这些体系中水杨酸钠的释放结果在附图6-9中说明。
附图6图示说明以A级(＜44μ)颗粒包衣的水杨酸钠片剂的释放结果。370-460μ厚度的膜产生2小时的滞后期，并由此使水杨酸钠释放延缓。
附图7图示说明用B级包衣的结果。450μ厚的膜的滞后期为3小时，而250μ厚的膜的滞后期是2小时。
附图8图示说明用C级Eudragit ETM/果胶钙包衣的水杨酸钠片剂的释放结果。250μ厚的膜使药物延迟5小时释放，350μ厚的膜能够阻止药物扩散达8小时。
附图9图示说明用含有A、B和C级颗粒混合物(按原合成比例)包衣的水杨酸片剂释放结果。所得数据结果介于上述图示结果之间。270μ厚的膜产生约2小时的滞后期。
表2是附图6-8中的数据集合。它可说明颗粒大小级别对不同膜厚度时水杨酸钠从基质片剂中释放的影响。颗粒越小，可溶性药物释放越快。表2果胶钙颗粒大小对Eudragit ETM/果胶钙(3∶7)
包衣的片剂中水杨酸钠释放的影响
| 膜厚度(μ) | (颗粒)级别 | ％释放2小时 | ％释放4小时 | ％释放6小时 |
| 250 | 44-74μ | 0 | 15 | 40 |
| 250 | 74-149μ | 0 | 0 | 4 |
| 370 | ＜44μ | 3 | 35 | 60 |
| 350 | 74-149μ | 0 | 0 | 0 |
| 460 | ＜44μ | 1 | 12 | 40 |
| 450 | 44-74μ | 0 | 4 | 20 |
试验例2
Eudragit ETM/果胶钙膜与Eudragit ETM/果胶膜的对比
将果胶钙膜与分布有同样大小果胶颗粒膜进行了对比。结果如附图10所示。300μ厚的Eudragit ETM/果胶(3∶7)膜使药物延迟释放1小时，而其后的释药曲线与无包衣片剂的相同。厚230μ的Eudragit ETM/果胶钙(3∶7)膜却使药物延迟释放3小时，而此后的释药速率低于无包衣片剂。
试验例3Eudragit ETM/果胶钙膜对崩解片剂的作用
用Eudragit ETM/果胶钙(3∶7)膜包封由微晶纤维素(Emcocel)组成的快释片剂。直径为9mm的片剂中含30mg水杨酸钠且总重量为250mg。不同厚度的膜能够防止不同时间间隔内的片剂崩解。仅含EudragitETM单组分的包衣膜使片剂崩解滞后6小时(未标明数据)。厚达300μ时Eudragit ETM/果胶钙(3∶7)膜最多能使崩解启动时间延迟3小时。附图11图示说明上述包衣片剂的溶解数据。
试验例4
乙基纤维素作为疏水膜-果胶钙作为亲水颗粒
于果胶钙/果胶基质中含有30mg水杨酸钠的片剂用乙基纤维素包衣。厚40μ的包衣足以将片剂全部封锁以使释药被延迟10小时以上。用不同厚度的乙基纤维素/果胶钙(3∶7)膜包衣同样的片剂。附图12图示说明厚100μ-300μ的包衣膜所得的试验结果。115μ的包衣可阻止药物释放达2小时，而随后的水杨酸钠以零级方式的缓慢受控速率释放。无包衣内芯在附图13中作为对比。无包衣内芯在第一个2小时内即可释放出30％的水杨酸钠，而其后的5小时内为50％。
上述果胶钙/果胶片剂用含80％而非70％果胶钙的乙基纤维素/果胶钙膜包衣。附图14表明，通过增加亲水性颗粒百分含量可调控该体系阻止药物释放的滞后时间。含70％果胶钙(280μ)时可使药物在7小时内无释放。含80％果胶钙时，5小时后药物即可发生扩散。
试验例5
Eudragit RSTM作为疏水膜-果胶钙作为亲水颗粒
以相同于Eudragit ETM和乙基纤维素的包衣方法，用Eudragit RSTM/果胶钙(3∶7)包封果胶钙/果胶基质中含30mg水杨酸钠的片剂。附图15图示说明不同厚度包衣的溶解试验结果。厚度为440μ时，聚合物可使药物释放延缓2小时。而包衣厚340μ和220μ时，延迟时间分别为1.5和0.5小时。虽绝对包衣厚度随疏水聚合物不同而改变，本试验及上述各试验都表明，通过改变疏水聚合物可达到药物控释的效果。
试验例6
Eudragit ETM作为疏水膜-交联Byco作为亲水颗粒
以上述相同的包衣方法，用Eudragit ETM/交联Byco(3∶7)包封果胶钙/果胶基质中含30mg水杨酸钠的片剂。仅含Eudragit ETM的膜可在至少7小时内完全阻止药物扩散出片剂。附图16表明以一种交联的蛋白质(水解的明胶与戊二醛交联并磨成粉末)作为亲水水溶性颗粒时的释放结果。厚200μ的膜阻止药物释放达约1小时。厚360μ的膜则阻止药物释放达3小时。
实施例7Eudragit ETM作为疏水膜-交联吡咯烷酮(Crospovidone)作为亲水颗粒
果胶钙/果胶基质中含有30mg水杨酸钠的片剂以上述方式、用其比率分别为3∶7、1∶1和7∶3的Eudragit ETM/交联吡咯烷酮包衣。附图17-19图示说明溶解试验中的释药结果。含70％和50％交联吡咯烷酮时，药物在第一个小时内即开始释出。释放曲线与无包衣片剂相比十分迟缓。仅含30％交联吡咯烷酮的包衣显示出1-4小时的滞后时间。
试验例8
Eudragit ETM作为疏水膜-微晶纤维素作为亲水颗粒
果胶钙/果胶基质中含有30mg水杨酸钠的片剂用在Eudragit ETM中分别含有30％和70％微晶纤维素(Avicel)作为亲水的、非水溶性颗粒的包衣来包封。附图20表示包衣为Eudragit ETM/Avicel(7∶3)的片剂在溶解试验中的结果。
仅含30％Avicel的包衣(膜厚70μ)在9小时后才释放出药物，附图21图示了以Eudragit ETM/微晶纤维素(3∶7)膜包衣的相同片剂的溶解试验结果。当膜内含有70％亲水颗粒时，药物释放加快。厚260μ的膜的延迟时间为1小时，并且此后的释放是控释过程。如同其它试验中所述，颗粒含量为中间值(介于30％-70％)时，药物释放也介于中间程度。附图21a图示说明Eudragit ETM/微晶纤维素(1∶1)膜包衣的试验结果。当50％重量份的膜(330μ)为亲水颗粒时，药物被延迟释放2小时，并且此后的释放速率为常数。
实施例9Eudragit ETM作为疏水膜-果胶钙作为亲水颗粒，用100mg双氯芬酸钠作
为标识药物
可制备含有100mg双氯芬酸钠的果胶钙/果胶基质缓释制剂。无包衣片剂在TS肠液的近16小时中，药物以接近零级缓释的方式释放。用厚度介于150μ-290μ之间的Eudragit ETM/果胶钙(3∶7)膜包衣的片剂在4-6小时内的药物释放被延迟。该滞后期足以使药物通过小肠进入结肠。附图22图示说明这些制剂的溶解试验结果。
试验材料讨论
以Eudragit ETM膜包衣的果胶钙颗粒能够显著改变Eudragit ETM屏障膜的特性，并使基质内的可溶性药物以不同的速率控释。水凝胶基质和可崩解片剂都不能完全保护和靶向释放经溶胀水凝胶扩散的可溶性药物。以水杨酸钠作为可溶性药物标识物时，在肠TS液中的果胶钙/果胶基质能够允许高达50％的药物在4小时内扩散出来。
为达到可溶性药物的靶向释放，扩散屏障是必需的。该屏障须将可溶性药物的释放控制在某一时间点，从而少量或没有药物在这之前被释放。非水溶性但却亲水的颗粒与疏水包衣的结合物能够调控进入片剂中的水及片剂内药物的外扩散。已发现通过调控某些参数(颗粒百分含量、颗粒大小、膜厚度、结合物同一性和颗粒材料相似性)可以调控在控释水凝胶片剂和中间释放崩解片剂内的可溶性药物的释放时间和过程。总的结论如下：1.颗粒百分量：包埋于疏水结合物内的亲水的非水溶性颗粒的百分含量越高，药物释放越早。这可解释为增加了供可溶性药物扩散的通道数量。2.颗粒大小：颗粒的百分含量一定时，颗粒越小药物释放越快。颗粒小意味着指定颗粒含量时，颗粒的数量越多。还由于颗粒具有较大的表面积，因此在嵌于膜内颗粒物中的相互反应越多，从而形成了更多的释药通道。3.膜厚度：膜越厚时药物释放越缓慢。较厚的膜使亲水非水溶性颗粒跨经整个疏水屏障膜的溶胀过程的时间延长。4.聚合物和颗粒的同一性：当其他参数保持不变时，聚合物疏水性越强，药物释放时间越长。聚合物疏水性较强时，亲水通道形成就需要较长的时间。当其他参数保持不变时，颗粒亲水性和溶胀性越强，药物释放越快，这是由于药物以溶胀亲水颗粒为释放途径。颗粒溶胀程度高，通道就越大。颗粒亲水性越强，形成通道越快，且允许药物扩散经过的作用越强。
很多参数都对控释药物很重要，这是由于各药物-基质结合物的药物溶解性曲线和基质的扩散曲线都不同。本发明中设计的膜适合任何释药体系的需要。
以疏水膜内包埋的非水溶性亲水颗粒为基础的本释药体系可依据具体需要来由多种不同材料组成。非水溶性亲水颗粒可以是果胶钙(多糖果胶的不溶性金属盐)、戊二醛交联氢化明胶(Byco)(不溶性蛋白质衍生物)、微晶纤维素(不溶性多糖)和交联吡咯烷酮(不溶性的交联合成亲水聚合物)。疏水膜可以是Eudragit ETM(氨基聚异丁烯酸)、Eudragit RSTM(季铵聚异丁烯酸)、或乙基纤维素(多糖纤维素衍生物)。体系适合于含有10％药物的水凝胶内芯(果胶钙/果胶)、含33％药物(水杨酸钠和双氯芬酸钠)的水凝胶内芯和崩解内芯(微晶纤维素)。上述试验例可说明释药体系的多方面适应性。
通过本发明的全面描述，本领域技术人员可以理解到，本发明能够在广泛且等效的条件、参数及类似情况下完成，同时并不影响本发明或任何实施例的要旨和范围。所有在本文中引用的参考文献在此将它们的全部相关内容并入本发明。
Claims (21)
1．一种在动物胃肠道内局部用药的释药体系，该体系包括：
a．含有药物和芯材的内芯，和
b．具有一种外表面的、围绕内芯的包衣，
其中，该包衣包括嵌入非水溶性载体内的非水溶性亲水颗粒，当体系进入胃肠道时，该颗粒物可吸收液体并形成通道，以连接内芯与包衣外表层，所含药物可通过这些通道自内芯释放至胃肠道内。
2．根据权利要求1所述的释药体系，其中的内芯选自片剂、胶囊和丸剂。
3．根据权利要求1所述的释药体系，其中，包衣的非水溶性载体选自Eudragit ETM、Eudragit NETM、Eudragit LRTM、Eudragit RSTM、乙基纤维素、紫胶、玉米醇溶淀粉和蜡。
4．根据权利要求1所述的释药体系，其中该包衣(b)进一步被肠溶包衣包封。
5．根据权利要求1所述的释药体系，其中该内芯包含溶胀材料。
6．根据权利要求5所述的释药体系，其中的溶胀材料选自多糖、交联丙烯酸和改性纤维素。
7．根据权利要求6所述的释药体系，其中的多糖选自藻酸盐、果胶、呫吨胶、瓜尔胶、角叉菜胶(carrageenan)、黄耆胶、刺槐豆胶、淀粉、微晶淀粉、微晶纤维素、它们的金属盐、以及它们的共价交联衍生物。
8．根据权利要求6所述的释药体系，其中的改性纤维素选自羟丙基纤维素、羟乙基纤维素、羟丙基甲基纤维素和羧甲基纤维素。
9．根据权利要求1所述的释药体系，其中，颗粒物包含的聚合物选自：非水溶性多糖、非水溶性交联多糖、非水溶性多糖金属盐、非水溶性交联蛋白质、非水溶性交联肽，非水溶性蛋白：多糖复合物、水溶性肽：多糖复合物、经与聚阳离子或聚阴离子相互反应而为不溶性的多糖或蛋白或肽、以及干粉型的非水溶性交联亲水聚合物。
10．根据权利要求9所述的释药体系，其中的多糖选自：果胶的、呫吨胶的、角叉菜胶(carrageenan)的、黄耆胶的、刺槐豆胶的、和藻酸的不溶性金属盐；呫吨胶的、瓜尔胶的、葡聚糖的、角叉菜胶(carrageenan)的、黄耆胶的、刺槐豆胶的、果胶的、淀粉的、羟丙基纤维素的、羟乙基纤维素的、羟丙基甲基纤维素的、羧甲基纤维素与藻酸的、纤维素的、微晶纤维素的、不溶性淀粉的和微晶淀粉的不溶性交联衍生物。
11．根据权利要求10所述的释药体系，其中的不溶性藻酸金属盐选自藻酸钙、藻酸锌、藻酸铝、藻酸铁、藻酸亚铁。
12．根据权利要求10所述的释药体系，其中的不溶性果胶金属盐选自果胶钙、果胶锌、果胶铝、果胶铁、果胶亚铁。
13．根据权利要求9所述的释药体系，其中所说的交联是以选自甲醛、戊二醛、表氯醇、二酸酰氯、二酸酐、二异氰酸酯、二胺和硼砂的物质作为交联剂而进行的。
14．根据权利要求9所述的释药体系，其中的不溶性交联蛋白质选自：戊二醛交联的水解明胶、甲醛交联的水解明胶、戊二醛交联的明胶、甲醛交联的明胶、戊二醛交联的胶原蛋白和甲醛交联的胶原蛋白。
15．根据权利要求9所述的释药体系，其中的非水溶性的交联的亲水聚合物选自一组由丙烯酸聚合物(carbomers)组成的物质。
16．根据权利要求9所述的释药体系，其中的非水溶性的交联的亲水聚合物选自一组由交联吡咯烷酮组成的物质。
17．根据权利要求1所述的释药体系，其中，非水溶性载体为EudragitETM，非水溶性的亲水颗粒为果胶钙、且肠溶包衣为Eudragit LTM。
18．一种将药物释放到需要该药物治疗的患者胃肠道内的方法，其中，该方法包括口服给予权利要求1-7中的任一释药体系。
19．根据权利要求18所述的方法，其中，该药物选自一组由诊断剂和治疗剂组成的物质。
20．根据权利要求18所述的方法，其中，胃肠道中的释药部位选自胃、小肠、结肠和直肠。
21．根据权利要求18所述的方法，其中，待治疗患者的疾病选自：结肠炎、节段性回肠炎、过敏性胃综合征、胃炎、胰腺炎、高血压、绞痛、关节炎、风湿性关节炎、气喘、心律不齐、局部痉挛、粘膜溃疡、腹泻、便秘、息肉、癌、囊肿、感染性功能紊乱和寄生虫致功能紊乱。
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US08/588,247 | 1996-01-18 | ||
| US08/588,247 US5840332A (en) | 1996-01-18 | 1996-01-18 | Gastrointestinal drug delivery system |
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| CN1208343A true CN1208343A (zh) | 1999-02-17 |
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
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| CN97191743A Pending CN1208343A (zh) | 1996-01-18 | 1997-01-17 | 胃肠内释药体系 |
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|---|---|
| US (1) | US5840332A (zh) |
| EP (1) | EP0877604B1 (zh) |
| JP (1) | JP4165905B2 (zh) |
| CN (1) | CN1208343A (zh) |
| AR (1) | AR005451A1 (zh) |
| AT (1) | ATE291417T1 (zh) |
| AU (1) | AU713722B2 (zh) |
| CZ (1) | CZ295932B6 (zh) |
| DE (1) | DE69732830T2 (zh) |
| ES (1) | ES2241031T3 (zh) |
| IL (1) | IL125042A (zh) |
| MY (1) | MY133883A (zh) |
| NZ (1) | NZ324808A (zh) |
| WO (1) | WO1997025979A1 (zh) |
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- 1997-01-17 ES ES97900086T patent/ES2241031T3/es not_active Expired - Lifetime
- 1997-01-17 YU YU1497A patent/YU1497A/sh unknown
- 1997-01-17 AU AU12065/97A patent/AU713722B2/en not_active Ceased
- 1997-01-17 JP JP52583497A patent/JP4165905B2/ja not_active Expired - Fee Related
- 1997-01-17 ZA ZA97405A patent/ZA97405B/xx unknown
- 1997-01-17 IL IL12504297A patent/IL125042A/xx not_active IP Right Cessation
- 1997-01-17 MY MYPI97000180A patent/MY133883A/en unknown
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2002039982A1 (fr) * | 2000-06-07 | 2002-05-23 | Zhang, Hao | Composition pharmaceutique a administration orale liberee au niveau colique et son procede de preparation |
| CN1322865C (zh) * | 2002-11-14 | 2007-06-27 | 北京东方凯恩医药科技有限公司 | 用于治疗菌痢的口服结肠定位给药组合物 |
| CN109562069A (zh) * | 2016-04-25 | 2019-04-02 | 吉莱斯公司 | 治疗便秘的方法 |
| CN114224860A (zh) * | 2021-11-06 | 2022-03-25 | 山东润德生物科技有限公司 | 氨基葡萄糖钙片制剂及其制备方法与应用 |
Also Published As
| Publication number | Publication date |
|---|---|
| IL125042A (en) | 2005-03-20 |
| US5840332A (en) | 1998-11-24 |
| DE69732830T2 (de) | 2006-04-13 |
| ZA97405B (en) | 1997-07-30 |
| YU1497A (sh) | 1999-09-27 |
| JP2000503316A (ja) | 2000-03-21 |
| AU713722B2 (en) | 1999-12-09 |
| WO1997025979A1 (en) | 1997-07-24 |
| CZ295932B6 (cs) | 2005-12-14 |
| JP4165905B2 (ja) | 2008-10-15 |
| MY133883A (en) | 2007-11-30 |
| CZ219898A3 (cs) | 1998-12-16 |
| AR005451A1 (es) | 1999-06-23 |
| ATE291417T1 (de) | 2005-04-15 |
| NZ324808A (en) | 1999-10-28 |
| EP0877604A1 (en) | 1998-11-18 |
| AU1206597A (en) | 1997-08-11 |
| EP0877604B1 (en) | 2005-03-23 |
| DE69732830D1 (de) | 2005-04-28 |
| IL125042A0 (en) | 1999-01-26 |
| ES2241031T3 (es) | 2005-10-16 |
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