CN1345233A - 在控制释放制剂中的预胶凝淀粉 - Google Patents
在控制释放制剂中的预胶凝淀粉 Download PDFInfo
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- CN1345233A CN1345233A CN00805541A CN00805541A CN1345233A CN 1345233 A CN1345233 A CN 1345233A CN 00805541 A CN00805541 A CN 00805541A CN 00805541 A CN00805541 A CN 00805541A CN 1345233 A CN1345233 A CN 1345233A
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- preparation
- active component
- pregelatinized starch
- hydrophilic
- sustained release
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Abstract
本发明涉及预胶凝淀粉防止来自亲水的控制释放制剂的剂量倾泄的用途。本发明也涉及亲水的控制释放制剂,更具体地说,涉及亲水的控制释放基质制剂和从它们制备的固体剂型,优选用于每天口服给药一次。所述亲水的控制释放制剂包含预胶凝淀粉、一种或多种活性成分、一种或多种粘性亲水聚合物和任选药学上可接受的配方剂。优选的亲水聚合物包括羟丙基纤维素和羟丙基甲基纤维素。
Description
本发明涉及预胶凝淀粉用于防止来自亲水控制释放制剂的剂量倾泄(dose-dumping)的用途。它也涉及亲水控制释放制剂,更详细地讲是亲水性控制释放基质制剂,和由它们制备的固体剂型,优选用于每天一次口服给药。亲水控制释放制剂包含预胶凝淀粉、一种或多种活性成分、一种或多种粘性的亲水聚合物和任选药学上可接受的配方剂。优选亲水聚合物包括羟丙基纤维素和羟丙基甲基纤维素。
WO 96/14070公开用于口服给药的延时释放制剂,它含有包埋在两种亲水的粘性聚合物基质特别是羟丙基纤维素和羟丙基甲基纤维素中的作为活性成分的西沙必利-(L)-酒石酸盐。这些亲水聚合物与水接触溶胀,由此形成活性成分从中逐渐释放的凝胶层。
WO 97/24109描述生物粘合药用组合物和由它们制备的固体剂型,其包含药学上有效量的活性成分、作为生物粘合聚合物混入组合物中的80%-98%(w/w)预胶凝淀粉和1%-10%(w/w)形成亲水基质聚合物。所述剂型具有定时和延长释放模式,用于局部作用成分或也用于全身作用药物,且它们适宜于口服、鼻、直肠和阴道给药。
EP 0299877涉及含有均匀分散在亲水基质中的沙丁胺醇或其衍生物的片剂,该亲水基质包含至少一种作为溶胀剂的高分子量的纤维素水胶体,特别是羟丙基甲基纤维素(15Pa.s)和稀释剂,其中所述稀释剂包含一种特性稀释剂和一种增稠稀释剂,尤其是预胶凝玉米淀粉。
EP 0280613描述了包含在水溶性基质中均匀分散的双氢麦角胺或它的衍生物之一,该基质包含一种或多种水溶性聚合物质,尤其是羟丙基甲基纤维素,和包含至少一种淀粉衍生物的稀释剂,尤其是预胶凝玉米淀粉。
EP 0477061要求在亲水基质中的均匀分散液中包含5-单硝酸异山梨醇酯的缓释片剂,该基质基于至少一种溶胀成分,特别是羟丙基甲基纤维素和至少一种稀释剂。后者包含至少一种特性稀释剂和一种选自聚合物例如淀粉和淀粉衍生物的增稠稀释剂。
GB 2,195,893描述包含与a)微晶纤维素和b)羟丙基甲基纤维素混合的药理活性成分的缓释药用组合物,其中a)对b)的重量比为至少1比1,条件是当活性成分不为以游离形式或盐形式存在的乙酰水杨酸时,该活性成分也与预胶凝淀粉混合。
WO 97/04752描述用于口服给予结合雌激素的药用组合物。所述结合雌激素被包上一种或多种包含羟丙基甲基纤维素和预胶凝淀粉的有机赋形剂,后者作为适宜的粘合剂存在。
控制释放药用制剂调节所掺入的一种活性成分或多种活性成分延时释放并包括具有延长释药、缓释、慢释、持续释放、阻释或延长释放的制剂,于是它们实现常规剂型例如溶液剂或迅速溶解剂型所不能提供的治疗或便利的目的。通过减少推荐的每天摄取量,活性成分的控制释放使患者的剂量方案简化并改善患者的顺应性。人们不应该低估对每天摄取一次来替代每天摄取两次或多次的患者而言所带来的积极的心理作用。
通过使所述活性成分均匀包埋在亲水基质中,可实现活性成分从药用制剂中控制释放,该亲水基质为粘性的亲水聚合物的可溶、部分可溶或不溶的网状物,它们通过物理或化学缠结、通过离子或结晶的相互作用、通过形成配合物、通过氢键或范德华力保持在一起。所述亲水基质与水接触溶胀,由此产生保护性凝胶层,通过聚合物网状物扩散、通过凝胶层溶蚀、通过聚合物溶出、或者通过所述释放机制的组合,活性成分及时从这些层中缓慢、逐渐、持续释放。通常使用的用于制备控制释放基质的亲水聚合物包括多糖、聚丙烯酸酯和聚环氧烷。
有效口服控制释放制剂,尤其是每天一次或两次的控制释放制剂,优选按照其经过的胃肠道的途径保留其药代动力学释放模式以致于避免不合乎需要的药物血浆浓度波动或完全剂量倾泄。这暗示控制释放制剂优选不得不提供控制释放模式并尤其不得不在变化的离子强度的介质中避免剂量倾泄,因为胃肠腔内容物在胃肠道不同的区域呈现变化的离子强度值。
当在进食状态下给予患者控制释放制剂时,可遇到与食物有关的剂量倾泄。在进食的患者上存在的与食物有关的剂量倾泄问题能够归结于多种因素。这些因素之一无疑是机械力,其通过胃施加在它的内容物上并因此施加在摄入的制剂上。另一个因素似乎是胃肠汁的离子强度。因为在胃肠道中遇到的离子强度值不仅随胃肠道的区域变化,而且随食物的摄取变化,控制释放制剂优选也不得不提供控制释放模式并尤其不得不避免无论患者处于禁食或进食条件下剂量倾泄。胃肠流体的离子强度可在大约0.01至大约0.2之间(Johnson等,1993,Int.J.Pharm.,151-159)。
离子强度,大部分情况下由符号μ(有时为I)表示,为溶液的特性并定义为 其中ci为第i个离子的摩尔浓度,Zi为它的电荷,且该总和包括溶液中的所有离子(Martin,A.,1993,Physical Pharmacy,Williams&wilkins,第134-135页)。因此离子强度为溶液的性质且不是溶液中任何具体离子的性质。已知在通过溶液中特定的电解质产生的离子上,离子强度的建立可良好测量由溶液的所有离子影响的非理想性。
在文献中描述了环境介质的离子强度在亲水基质的崩解作用、胶凝作用和粘度上的影响。
Mitchell等(制药技术·控制的药物释放,第2卷,Wells,J.I.,Rubinstein,M.H.(编辑),Ellis Horwood Limited,第23-33页,1991)公开电解质对羟丙基甲基纤维素(HPMC)K15M基质片崩解作用和胶凝作用的影响。在环境介质的低离子强度下,HPMC基质不受电解质影响且发生水合作用产生完整的凝胶层。然而,在中等离子强度下,基质失去形状和完整性,且它们迅速崩解。片剂停止作为控制释放基质起作用,因为在增加环境介质中的溶质浓度的情况下,通过水合作用的减少而阻碍胶凝作用。因此,存在于环境介质中的电解质能够改进药物从HPMC基质中的释放模式。药物本身也可以影响水合作用并因此影响HPMC的胶凝作用。因此,药物可在测定它们本身的释放中起积极作用(Mitchell等,Int.J.Pharm.,1993,100,165-173)。所以,药物掺合到HPMC基质中可导致无法预期的崩解模式并因此导致剂型无法预期的治疗效果。
在Int.J.Pharm.,1995,120,63-72中描述黄原酸胶基质片剂在不同离子强度的氯化钠溶液中的溶胀行为。在生理离子强度的范围内,黄原酸胶片剂的溶胀显示与盐浓度相互关联。
意想不到的是发现通过向制剂中加入预胶凝淀粉能够抵消释放介质的离子强度对亲水基质制剂控制的释放模式上的损害或者甚至破坏作用。所述离子强度对亲水基质制剂的控制释放模式的损害作用,如在上文中指出的那样,能够归结为粘性的亲水基质聚合物的水合作用的变化。所述基质聚合物不得不与组成释放介质的离子强度的溶质来竞争水合水。所以,聚合物不可水合到这样的程度以确保对崩解具有可接受的抗性的足够完整的基质形成。基质聚合物的水合可极大的或者甚至完全受到抑制以致于在释放介质中基质几乎立即崩解,例如在给药后15min的时间间隔内。通过使预胶凝淀粉掺合到制剂中,活性成分从亲水的控制释放制剂中的控制释放能够在变化离子强度的释放介质中受到保护或得以维持,特别是在具有增加的离子强度的释放介质中,更特别是在具有范围最多可达0.4的离子强度值的释放介质中,甚至更特别是在生理条件下遇到的离子强度值的释放介质中,即沿着整个胃肠道在禁食以及在进食条件下,且最特别是在大约0.01至大约0.2范围内变化的离子强度值的释放介质中受到保护或得以维持。
因此,本发明涉及预胶凝淀粉在包含一种或多种活性成分和一种或多种粘性亲水聚合物的亲水的控制释放制剂中以抵消释放介质的离子强度对活性成分从所述制剂控制释放的损害作用的用途或涉及预胶凝淀粉在包含一种或多种活性成分和一种或多种粘性的亲水聚合物的、亲水控制释放制剂中以便在具有变化的离子强度的释放介质中维持活性成分从所述制剂中控制释放的用途,特别是在具有增加的离子强度的释放介质中,更特别是在具有范围最多可达0.4的离子强度值的释放介质中,甚至更特别是在生理条件下遇到的离子强度值的释放介质中,即沿着整个胃肠道在禁食以及在进食条件下,且最特别是在大约0.01至大约0.2范围内的离子强度值的释放介质中。本发明也包括预胶凝淀粉在包含一种或多种活性成分和一种或多种粘性的亲水聚合物的、亲水的控制释放制剂中以防止在禁食以及在进食条件下沿着胃肠道从所述制剂中剂量倾泄,更特别是防止与食物有关的剂量倾泄的用途。
在上文或下文中使用的术语“释放介质”包括所有种类的液体介质,其中能够发生活性成分从亲水的控制释放制剂中的释放,即例如在体外溶解介质中,而且在体液中,更特别是在胃肠流体中的释放。
术语“维持从制剂的活性成分的控制释放”指的是活性成分及时从制剂中缓慢、逐渐释放、持续释放、延长释药、缓释或延长释放。特别是术语“从制剂的活性成分的控制释放”指的是口服给药后制剂不立即释放活性成分且制剂使给药次数减少,按照美国药典24版第2059页,延时释放的定义可与控制释放互换。在此与延长作用、持续释放或延时释放同义使用的控制释放剂型描述为使给药次数减少至少两倍或与常规剂型(例如,作为溶液或促进药物释放的常规固体剂型)相比较明显增加患者的顺应性或治疗作用的剂型。
术语“剂量倾泄”为本领域技术人员熟知且定义为在打算用作控制释放制剂的制剂中掺合的活性成分大部分或全部突然释放。代替时间延长期间的释放,全部剂量或至少其大部分短时间内释放。依活性成分和效力而定,这可引起严重的副作用或甚至死亡。
本发明也涉及亲水控制释放制剂,其包含预胶凝淀粉、一种或多种活性成分、一种或多种粘性的亲水聚合物和任选药学上可接受的配方剂,其特征在于预胶凝淀粉能够使制剂在具有变化的离子强度的释放介质中维持所掺合的活性成分控制释放,尤其是在具有增加的离子强度的释放介质中,更特别是在具有最多可达0.4的范围内的离子强度的释放介质中,甚至更特别是在生理条件下遇到的离子强度的释放介质中,即在禁食以及进食条件下沿着整个胃肠道,且最特别是在具有大约0.01至大约0.2范围内的离子强度值的释放介质中。本发明也涉及包含预胶凝淀粉、一种或多种活性成分、一种或多种粘性的亲水聚合物和任选药学上可接受的配方剂的亲水的控制释放制剂,其特征在于预胶凝淀粉防止所述制剂沿着胃肠道在禁食以及进食条件下的剂量倾泄,更特别是预胶凝淀粉防止与食物有关的剂量倾泄。
本发明制剂尤其用于给予一种或多种活性成分
(a)具有短的半衰期,以4至8小时或更短的级别,当以常规制剂给予时其不得不整天分几次剂量服用;或者
(b)具有窄的治疗指数;或者
(c)经整个胃肠道具有足够的吸收;或者
(d)具有相对小的治疗有效剂量。
适宜的活性成分为那些口服给药后发挥局部生理作用的物质以及那些发挥全身作用的物质。它们的实例为:
-止痛药和抗炎药(NSAIDs、芬太尼、吲哚美辛、布洛芬、酮洛芬、萘丁美酮、对乙酰氨基酚、吡罗昔康、曲马朵、COX-2抑制剂如塞来昔布(celecoxib)和罗非昔布(rofecoxib));
-抗心律失常药(普鲁卡因胺,奎尼丁、维拉帕米);
-抗菌和抗原生动物药(阿莫西林、氨苄西林、苄星青霉素、青霉素、头孢克洛、头孢羟氨苄、头孢丙烯、头孢呋辛axetil、头孢氨苄、氯霉素、氯喹、环丙沙星、克拉霉素、克拉维酸、克林霉素、多西环素、红霉素、氟氯西林钠、卤泛群、异烟肼、硫酸卡那霉素、林可霉素、甲氟喹、米诺环素、萘夫西林钠、萘啶酸、新霉素、诺氟沙星、氧氟沙星、苯唑西林、青霉素V钾、乙胺嘧啶-磺胺多辛、链霉素);
-抗凝药(华法林);
-抗抑郁药(阿米替林、阿莫沙平、布替林、氯米帕明、地昔帕明、度硫平、氟西汀、瑞波西汀、amineptine、司来吉兰、吉哌隆、丙米嗪、碳酸锂、米安色林、米那普仑、去甲替林、帕罗西汀、舍曲林、3-[2-[3,4-二氢苯并呋喃并[3,2-c]吡啶-2(1H)-基]乙基]-2-甲基-4H-吡啶并[1,2-a]嘧啶-4-酮);
-抗糖尿病药(格列本脲、二甲双胍);
-抗癫痫药(卡马西平、氯硝西泮、乙琥胺、加巴喷丁、拉莫三嗪、左乙拉西坦、苯巴比妥、苯妥英、扑米酮、噻加宾、托吡酯、丙戊酰胺、氨己烯酸);
-抗真菌药(两性霉素B、克霉唑、益康唑、氟康唑、氟胞嘧啶、灰黄霉素、伊曲康唑、酮康唑、硝酸咪康唑、制霉菌素、特比萘芬、voriconazole);
-抗组胺药(阿司咪唑、桂利嗪、赛庚啶、脱乙酯基氯雷他定、fexofenadine、氟桂利嗪、左卡巴斯汀、氯雷他定、norastemizole、奥沙米特、异丙嗪、特非那定);
-抗高血压药(卡托普利、依那普利、酮色林、赖诺普利、米诺地尔、哌唑嗪、雷米普利、利舍平、特拉唑嗪);
-抗毒蕈碱药(硫酸阿托品、东莨菪碱);
-抗肿瘤药和抗代谢物(铂化合物例如顺铂、卡铂;紫杉烷类例如紫杉酚、紫杉特尔(docetaxel);替康类(tecans)例如喜树碱、伊立替康、拓扑替康(topotecan);长春生物碱例如长春碱、长春地辛、长春新碱、长春瑞滨;核苷衍生物和叶酸拮抗剂例如5-氟尿嘧啶、加西他滨(capecitabine)、吉西他滨、巯嘌呤、硫鸟嘌呤、克拉屈滨、甲氨蝶呤;烷化剂例如氮芥类,如环磷酰胺、苯丁酸氮芥、氮芥、异环磷酰胺、美法仑、或亚硝基脲类,例如卡莫司汀、洛莫司汀、或者其它的烷化剂,例如白消安、达卡巴嗪、丙卡巴肼、塞替派;抗生素类例如柔红霉素、多柔比星、伊达比星、表柔比星、博来霉素、放线菌素D、丝裂霉素;HER 2抗体,例如trastuzumab;鬼臼毒素衍生物,例如依托泊苷、替诺泊苷;法呢基转移酶抑制剂;蒽醌衍生物,例如米托蒽醌);
-抗偏头痛药(alniditan、那拉曲坦、舒马普坦);
-抗帕金森病药(甲磺酸溴隐亭、左旋多巴、司来吉兰);
-精神抑制药、催眠药和镇静药(阿普唑仑、丁螺环酮、氯氮、氯丙嗪、氯氮平、地西泮、氟哌噻吨、氟奋乃静、氟西泮、9-羟基利培酮、劳拉西泮、mazapertine、奥氮平、奥沙西泮、匹莫齐特、匹泮哌隆、吡拉西坦、丙嗪、利培酮、塞福太、seroquel、舍吲哚、舒必利、替马西泮、替沃噻吨、三唑仑、三氟哌多、佐匹克隆(ziprasidone)、唑吡坦);
-抗中风药(芦贝鲁唑、芦贝鲁唑氧化物、利鲁唑、aptiganel、依利罗地、remacemide);
-镇咳药(右美沙芬、laevodropropizine);
-抗病毒药(阿昔洛韦、更昔洛韦、洛韦胺、tivirapine、齐多夫定、拉米夫定、齐多夫定+拉米夫定、去羟肌苷、扎西他滨、司他夫定(stavudine)、阿巴卡韦(abacavir)、lopinavir、安普那韦(amprenavir)、奈韦拉平、efavirenz、地拉韦啶(delavirdine)、英地那韦(indinavir)、奈非那韦(nelfinavir)、利托那韦(ritonavir)、沙奎那韦、adefovir、羟基脲);
-β-肾上腺素受体阻断剂(阿替洛尔、卡维地洛、美托洛尔、奈必洛尔、普萘洛尔(propanolol));
-强心药(氨力农、洋地黄毒苷、地高辛、米力农);
-皮质类固醇(倍氯米松二丙酸酯、倍他米松、布地奈德、地塞米松、氢化可的松、甲泼尼龙、泼尼松龙、泼尼松、曲安西龙);
-消毒剂(氯己定);
-利尿药(乙酰唑胺、呋塞米、氢氯噻嗪、异山梨醇);
-酶类;
-精油(茴香脑、茴香油、
蒿、小豆蔻、山扁豆油、桉树脑、肉桂油、丁子香油、芫荽油、薄荷油、莳萝油、桉树油、丁子香酚、姜、柠檬油、芥子油、苦橙花油、肉豆蔻油、橙油、胡椒薄荷、一串红、薄荷、萜品油、百里香);
-胃肠道药物(西咪替丁、西沙必利、氯波必利、地芬诺酯、多潘立酮、法莫替丁、兰索拉唑、洛哌丁胺、洛哌丁胺氧化物、美沙拉嗪、甲氧氯普胺、莫沙必利、尼扎替丁、norcisapride、奥沙拉嗪、奥美拉唑、泮托拉唑、吡拉唑(perprazole)、prucalopride、雷贝拉唑、雷尼替丁、利多格雷、柳氮磺吡啶);
-止血药(氨基己酸);
-脂质调节药(阿伐他汀(atorvastatin)、洛伐他汀、普伐他汀、普罗布考、辛伐他汀);
-局部麻醉药(苯佐卡因、利多卡因);
-阿片类镇痛药(丁丙诺啡、可待因、右吗拉胺、双氢可待因、二氢可待因酮、羟考酮、吗啡);
-拟副交感神经药和抗痴呆药(AIT-082、依斯的明、加兰他敏、美曲膦酯、milameline、新斯的明、毒扁豆碱、他克林、donepezil、rivastigmine、sabcomeline、talsaclidine、占诺美林、美金刚、拉扎贝胺);
-肽和蛋白质(抗体、becaplermin、环孢菌素、红细胞生成素、免疫球蛋白、胰岛素);
-性激素(雌激素:结合雌激素、炔雌醇、美雌醇、雌二醇、雌三醇、雌酮、孕激素:醋酸氯地孕酮、醋酸环丙孕酮、17-脱乙酰基诺孕酯、去氧孕烯、地诺孕素、地屈孕酮、二醋酸炔诺醇、孕二烯酮、3-酮基去氧孕烯、左炔诺孕酮、利奈孕酮、醋酸甲羟孕酮、甲地孕酮、炔诺酮(norethindrone)、醋酸炔诺酮、炔诺酮(norethisterone)、醋酸炔诺酮、异炔诺酮、诺孕酯、炔诺孕酮、诺孕烯酮、黄体酮、醋酸奎孕醇);
-兴奋剂(西地那非(sildenafil))
-血管舒张药(氨氯地平、丁咯地尔、亚硝酸异戊酯、地尔硫、双嘧达莫、硝酸甘油、硝酸异山梨酯、利多氟嗪、吗多明、尼卡地平、硝苯地平、己酮可可碱、戊四硝酯);它们的N-氧化物、它们的药学上可接受的酸或碱加成盐和它们的立体化学异构体形式。
药学上可接受的酸加成盐包括其经用适宜的有机和无机酸处理活性成分的碱形式能够便利得到的酸加成盐形式。
通过用适宜的有机和无机碱处理,可将含有酸性质子的活性成分转化为它们的非毒性金属或胺加成盐形式。
术语加成盐也包括活性成分能够形成的水合物和溶剂加合形式。这样形式的实例为例如水合物、醇化物等。
活性成分的N-氧化物形式包括那些其中一或数个氮原子被氧化为所谓N-氧化物的活性成分。
术语“立体化学异构体形式”定义为活性成分可具有的所有可能的立体异构体形式。更详细地讲,立体中心可具有R-或S-构型,且包含一或多个双键的活性成分可具有E-或Z-构型。
一组重要的活性成分为那些如在上文中描述的成分,条件是不包括沙丁胺醇、5-单硝酸异山梨醇酯、双氢麦角胺、维生素B12、结合雌激素、乙酰水杨酸、氟化物、咪康唑和曲安西龙。
另一组重要的活性成分为那些如在上文中描述的成分,条件是不包括与苯海拉明组合的沙丁胺醇、5-单硝酸异山梨醇酯、双氢麦角胺、维生素B12、结合雌激素、乙酰水杨酸、氟化物、咪康唑、曲安西龙、阿昔洛韦、拉莫三嗪和对乙酰氨基酚。
鉴于存在的一种或多种活性成分,本发明也涉及如在上文中描述的那样用作药物的亲水的控制释放制剂。
如在上文中描述的那样,预胶凝淀粉包含在本发明的制剂中。预胶凝淀粉为易于得到的产品,其能够通过预煮和干燥淀粉来制备。它广泛用于食品工业,目的是在水中复制后得到粘性糊状物。
通过以下方法,可达到预胶凝作用:
·喷雾干燥:以这种方法产生的预胶凝淀粉由空心圆球体组成,通常在中心周围围绕有气泡。它们通过先在水中煮沸所述淀粉并然后将热的糊状物喷雾到干燥室或干燥塔中制备;
·辊筒式干燥:以这种方法制备的预胶凝淀粉由表面为透明的、扁平、无规则小片状体的粒子组成。通常这些产物同时被煮沸并在加热的辊筒上干燥,使用紧密固定的一对压水辊或具有紧密固定的刮刀的单一辊。在每一种情况下,其然后磨碎至筛目大小,得到纸厚度的薄片。
·挤出或转鼓式干燥:以这种方法制备的预胶凝淀粉由各自的粒子组成,它们比辊筒式干燥产物更粗且更无规则。转鼓式干燥与辊筒式干燥相似,除了更粗的淀粉糊包衣施加于加热辊上,且然后将干燥产物磨碎至要求的粒子大小。在挤出过程中,在非常高的剪切力下,潮湿的淀粉受力通过过热室,然后爆裂并通过在大气压下排出气体同时干燥。
预胶凝淀粉的优选形式为转鼓式干燥的蜡状玉米淀粉,其能够从Cerestar Benelux BV公司(Breda,荷兰)得到。
预胶凝淀粉在本发明的亲水的控制释放制剂中的重量百分比优选在大约0.01%至小于80%(w/w)之间,更优选在大约0.01%至大约15%之间,甚至更优选在大约0.01%至大约5%之间,且最优选为大约5%。
构成控制释放基质的亲水聚合物优选逐渐、缓慢、连续释放活性成分。它们给药后与含水流体接触溶胀,生成粘性的、调节药物释放的凝胶层。聚合物的粘度优选在150至100,000mPa.s(在20℃下,2%水溶液的表观粘度)之间。这样的聚合物的实例为:
-烷基纤维素,例如甲基纤维素;
-羟烷基纤维素,例如羟甲基纤维素、羟乙基纤维素、羟丙纤维素和羟丁基纤维素;
-羟烷基烷基纤维素,例如羟乙基甲基纤维素和羟丙基甲基纤维素;
-羧烷基纤维素,例如羧甲基纤维素;
-羧烷基纤维素的碱金属盐,例如羧甲基纤维素钠;
-羧烷基烷基纤维素,例如羧甲基乙基纤维素;
-羧烷基纤维素酯;
-其它的天然的、半合成的或合成的多糖,例如藻酸、其碱金属盐和铵盐、角叉菜聚糖、半乳甘露聚糖、黄蓍胶、琼脂、阿拉伯胶、瓜尔胶、黄原胶、淀粉、果胶例如羧甲基支链淀粉钠、甲壳质衍生物例如脱乙酰壳多糖、多聚果糖、旋复花粉;
-聚丙烯酸和它们的盐;
-聚甲基丙烯酸和它们的盐、甲基丙烯酸酯共聚物;
-聚乙烯醇;
-聚乙烯吡咯烷酮、聚乙烯吡咯烷酮与乙酸乙烯酯的共聚物;
-聚乙烯醇与聚乙烯吡咯烷酮的组合物;
-聚环氧烷例如聚环氧乙烷和聚环氧丙烷和环氧乙烷与环氧丙烷的共聚物。
优选的亲水聚合物为多糖,更特别为纤维素衍生物且最特别为纤维素醚衍生物。
最优选的纤维素醚衍生物为羟丙基甲基纤维素和羟丙基纤维素。
不同粘度级别的羟丙基纤维素和羟丙基甲基纤维素为市场上可得到的。
在本发明中优选使用的羟丙基甲基纤维素具有在大约3,500mPa.s至大约100,000mPa.s之间的粘度级别,特别是在大约4,000mPa.s至大约20,000mPa.s之间,且最特别是在大约6,500mPa.s至大约15,000mPa.s(在20℃下,2%水溶液的表观粘度)之间的粘度级别,例如hypromellose 2208(DOW,Antwerp,比利时)。
具有粘度低于1,500mPa.s(在20℃下,2%水溶液的表观粘度)的羟丙基纤维素为优选,特别是在大约150至大约700mPa.s之间的粘度的羟丙基纤维素,优选在200至600mPa.s之间,例如Klucel EF(Hercules,Wilminton,USA)。
组成基质的粘性的亲水聚合物主要提供制剂的控制药代动力学释放模式。依在制剂中所具有聚合物的量而定,释放模式能够被变化。本发明制剂中粘性的亲水聚合物的量优选在大约0.01至大约80%(w/w)之间。另外,当使用聚合物的组合物时,所述聚合物的比例也影响制剂的释放模式。例如,当使用一种或多种亲水的聚合物时,优选使用纤维素衍生物,更特别使用羟丙基纤维素和羟丙基甲基纤维素,羟丙基甲基纤维素的重量百分比(%w/w)优选在0至大约16%之间;羟丙基纤维素的重量百分比优选在大约25%至大约62%之间。羟丙基纤维素与羟丙基甲基纤维素的比例优选在1∶5至5∶1之间,更优选在1∶1至5∶1之间,且最优选在3∶1至5∶1之间。
不同聚合物的组合物提供使不同的机制组合的可能性,借助这些机制从基质中释放活性成分。这样的组合有助于任意控制制剂的药代动力学释放模式。如在上文中提及的那样,存在三种主要的机制,借助这些机制可以从亲水性基质中释放活性成分:溶出、溶蚀和扩散。当它均匀分散在可溶性聚合物的基质网状物中时,活性成分将通过溶出机制释放。该网状物将逐渐溶于胃肠道,由此逐渐释放出它的载荷。基质聚合物也能够逐渐从基质表面溶蚀,同样及时释放活性成分。当活性成分在不溶性聚合物组成的基质中处理时,它将经扩散释放:胃肠道流体渗透到不溶性的、海绵样的基质中并伴随药物脱离载荷扩散出来。
通过一套组合的释放机制,一种或多种活性成分从包含羟丙基纤维素和羟丙基甲基纤维素的基质中释放。由于羟丙基甲基纤维素与羟丙基纤维素相比较具有较高的溶解性,前者将逐渐从基质中溶解和溶蚀,而后者更多是作为海绵样基质起作用,前者主要通过扩散释放活性成分。
除活性成分、亲水的聚合物和预胶凝淀粉以外,本发明制剂也可任选包含药学上可接受的配方剂,以促进制剂的制备、可压性、外观和味觉。这些配方剂包括例如稀释剂或填充剂、助流剂、粘合剂、成粒剂、抗结块剂、润滑剂、矫味剂、染料和防腐剂。
填充剂可选自可溶性填充剂,例如,蔗糖、乳糖、海藻糖、麦芽糖、甘露糖醇、山梨醇、旋复花粉,并且可选自不溶性填充剂,例如,磷酸二钙或磷酸三钙、滑石粉。重要的填充剂为乳糖,特别是乳糖单水合物。能够使用不同级别的乳糖。优选用于本发明的一类乳糖为乳糖单水合物200目(DMV,Veghel,荷兰)。也能够优选使用另一种乳糖单水合物,DCL11型的乳糖单水合物(DMV,Veghel,荷兰)。符号DCL指的是“直接压制乳糖”。编号11为制造商的参考号数。这种类型乳糖的特征在于98%(w/w)的粒子具有小于250μm的直径,30%至60%(w/w)的粒子具有100μm的直径,且最多15%(w/w)的粒子具有小于45μm的直径。
填充剂的重量百分比在大约6%至大约54%(w/w)之间。
在另外可包含在基质制剂中的任选配方剂可被提及的有例如聚乙烯吡咯烷酮(polyvidone)、淀粉、阿拉伯胶、明胶、海藻衍生物如藻酸、藻酸钠和藻酸钙、纤维素衍生物如乙基纤维素、羟丙基甲基纤维素,它们具有有用的粘合和成粒性质,助流剂如胶态二氧化硅、淀粉或滑石粉,润滑剂如硬脂酸镁和/或棕榈酸镁、硬脂酸钙、硬脂酸、聚乙二醇、液体石蜡、十二烷基硫酸钠或十二烷基硫酸镁、防粘剂如滑石粉和玉米淀粉。
除以上描述的药学上可接受的配方剂以外,在本发明的控制释放制剂中也可包含环糊精或其衍生物,以改善活性成分的溶出速率。为此目的,推荐量的环糊精或其衍生物可替代等量的填充剂。
药物从口服固体控制释放剂型中释放且随后药物从胃肠道吸收进入到血流中是依赖溶出速率的且可以是缓慢的和不规则的,特别是在美国药典24版第10页定义的略溶于水的、微溶于水的、极微溶于水的,几乎不溶于水的或不溶于水的药物的情况下。
在具有依赖pH的溶解性的药物的情况下,药物从剂型中释放且随后吸收进入到血流中,能够在剂型沿着胃肠道通过期间变化。这特别与呈现随pH增加溶解性减少的碱性药物有关。当沿着胃肠道通过时,控制释放制剂将在胃肠道(回肠和结肠)较低部位滞留相当长的一段时间,这里腔内容物的平均pH值从7.5(回肠)经6.4(右结肠)变化至7.0(左结肠)(Evans等,Gut,29,1035-1041,1988;Wilson andWashington,Physiological Pharmaceutics,Ellis Horwood Limited,WestSussex,UK,第21-36页,1989)。在胃肠道较低部位的较高pH值,当与较高部位相比较时,可引起碱性药物的溶解性减少,这导致剂型中较低的药物释放且因而导致较低的和较慢的药物吸收。
环糊精或其衍生物通常称作络合剂。通常将药物/环糊精络合物掺合到本发明的控制释放制剂中,能够改善略溶于水的、微溶于水的、极微溶于水的、几乎不溶于水的或不溶于水的药物或具有依赖pH的溶解性的药物的溶出速率且其后改善吸收性质。它特别提供更迅速或更有规律地释放所述药物;优选得到零级释放。除增强溶出速率功能以外,环糊精或其衍生物也可作为本发明制剂的溶蚀因素起作用。
用于本发明的环糊精包括本领域已知的药学上可接受的未取代的和取代的环糊精,更具体地讲,为α、β或γ环糊精或它们的药学上可接受的衍生物。
其能够在本发明中使用的取代的环糊精包括在U.S.专利3,459,731中描述的聚醚类。通常,未取代的环糊精与环氧烷反应,优选在超计大气压下且在升高的温度下,在碱催化剂存在下进行。
因为环糊精的羟基部分能够被环氧烷取代,环氧烷本身仍可与另一分子的环氧烷反应,平均摩尔取代值(MS)用作测量每葡萄糖单元取代剂的平均摩尔数。MS能够大于3且理论上没有限制。
另外的取代的环糊精为其中一或多个环糊精羟基上的氢由以下基团置换的醚类或它们的混合醚类,包括:C1-6烷基、羟基C1-6烷基、羧基C1-6烷基或C1-6烷氧基羰基C1-6烷基。这样取代的环糊精特别为其中一或多个环糊精羟基上的氢由以下基团置换的醚类,包括:C1-3烷基、羟基C2-4烷基或羧基C1-2烷基,或者更特别为由甲基、乙基、羟基乙基、羟丙基、羟基丁基、羧基甲基或羧基乙基置换的醚类。
在前述的定义中,术语“C1-2烷基”意指包括具有1或2个碳原子的饱和烃基团,例如甲基或乙基;术语“C1-3烷基”意指包括具有1至3个碳原子的直链和支链的饱和烃基团,包括对术语“C1-2烷基”描述的那些基团和1-甲基乙基、丙基;术语“C2-4烷基”意指包括具有2至4个碳原子的直链和支链的饱和烃基团,包括乙基、1-甲基乙基、1,1-二甲基乙基、丙基、2-甲基丙基、丁基等;术语“C1-6烷基”意指包括具有1至6个碳原子的直链和支链的饱和烃基团,包括对上文提及的术语描述的那些基团和戊基、己基等。
在所选择的以致可得到要求的环糊精醚的浓度下,通过使起始的环糊精与适宜的O-烷基化试剂或这样试剂的混合物反应,能够制备这样的醚类。优选在适宜的碱存在下,于适宜的溶剂中进行所述反应。用这样的醚,取代度(DS)指的是每葡萄糖单元取代的羟基官能团的平均数目,因此DS为3或更小。
在用于本发明制剂的环糊精衍生物中,DS优选处于0.125至3的范围内,特别在0.3至2的范围内,更特别在0.3至1的范围内。MS处于0.125至10的范围内,特别在0.3至3的范围内且更特别在0.3至1.5的范围内。
在本发明中特别有用的是β-环糊精醚,例如在Drugs of the Future,第9卷,第8期,第577-578页中由M.Nogradi(1984)描述的二甲基-β-环糊精和聚醚类,例如羟丙基β-环糊精和羟基乙基β-环糊精就是实例。这样的烷基醚可为具有大约0.125至3,例如大约0.3至2的取代度的甲基醚。例如,这样的羟丙基环糊精可从β-环糊精与环氧丙烷之间的反应形成且可具有大约0.125至10,例如大约0.3至3的MS值。
另一适宜类型的取代环糊精为磺基丁基环糊精。该类型也包括在本发明中。
本发明优选使用的环糊精为β-环糊精,且更特别为羟丙基β-环糊精,这是由于它的较高的水溶性。
环糊精与活性成分的比例可广泛变化。它依所使用的活性成分或环糊精、要求的溶出模式、环糊精和活性成分在用于制备如在下文中描述的环糊精-活性成分混合物的溶剂中的溶解性而定。优选可使用至少1∶1的比例,尽管不排除较低的比例。
不同类型(α、β、γ)或不同取代度(2-羟丙基或甲基)或不同取代级别的环糊精的混合物的用途也包括在本发明中。
为将环糊精或它们的衍生物掺合到本发明的控制释放制剂中,环糊精优选首先与活性成分紧密混合,随后使该紧密混合物与控制释放制剂的其余的成分混合。
能够使用以下不同技术制备环糊精和活性成分的紧密混合物,所述技术包括:
a)简单混合技术,其中在适宜的混合装置中物理混合两种成分,例如Turbula混合器(Willy A.Bachoven Machinenfabrik,巴塞尔,瑞士)。
b)球磨技术,其中将两种成分混合在一起并在适宜的球磨机(Retsch GMBH&Co,Haan,德国)上研磨。
c)干法压实技术,其中在适宜的混合装置中将环糊精和活性成分混合。然后将生成的混合物运行通过压实机,例如Polvgran 3W压实机(Gerteis,Jona,瑞士),随后使生成的附聚物,例如片状物或板状物破碎。
d)固体分散技术,在下文中使用的术语“固体分散物”定义为以固体状态(与液体或气体状态相对)存在的包含至少两种成分的体系,即活性成分和环糊精,其中一种成分在一定程度上均匀分散在其它的一种成分或多种成分(在这样的情况下,包括另外的在本领域中普遍已知的药学上可接受的配方剂,例如增塑剂、防腐剂等)中。当所述成分的分散液如此这样以致于该体系为化学上和物理上均匀或均质的或由如在热力学中定义的一相组成,这样的固体分散液将在下文中称作“固体溶液”。固体溶液为优选物理体系,因为其中的成分对它们所给予的有机体而言通常为可易于生物利用的。
这个有利条件可用以下事实易于解释,当与液体介质例如胃肠汁接触时,所述固体溶液能够形成液体溶液。易于溶出可至少部分归因于以下事实,成分从固体溶液中溶出所需要的能量要小于成分从结晶或微晶固相中溶出所需要的能量。
术语“固体分散物”也包括比固体溶液均匀性差的分散物。这样的分散物不是化学上和物理上均匀的或包含一相以上。例如,术语“固体分散物”也涉及具有区域结构或小的区域的体系,其中无定形、微晶或结晶活性成分、或无定形、微晶或结晶环糊精,或者两者皆有之在一定程度上均匀分散在另一相中,该相包含环糊精或活性成分、或包含活性成分和环糊精的固体溶液。所述区域结构为固体分散物中的区域,由一些物理特征特殊地标记,体积小,且均匀和随机分布于固体分散物中。
存在多种用于制备固体分散物的技术,包括熔体-挤出、喷雾干燥、冷冻干燥和溶液蒸发,后一技术为优选。
溶液蒸发方法包括以下步骤:
a)任选在升高的温度下,将活性成分和环糊精溶解于适宜的溶剂中,例如水或有机溶剂,例如醇如甲醇、乙醇或它们的混合物;
b)任选在真空下,将在a)点下生成的溶液的溶剂蒸发。也可将溶液倾入到大的表面上以致于形成薄膜,并从那上面蒸发溶剂。
在喷雾干燥技术中,也将两种成分溶解于适宜的溶剂中并然后经喷雾干燥器的喷嘴喷雾生成的溶液,随后在升高的温度下从生成的液滴蒸发溶剂。
在冷冻干燥技术中,将环糊精与活性成分溶解在适宜的溶剂中。然后将该混合物冷冻随后真空下和提供升华热下升华溶剂,同时连续除去形成的蒸气。在升高的温度下,生成的冷冻干燥固体可经历第二次干燥过程。
熔体-挤出方法包括以下步骤:
a)使活性成分与环糊精混合,
b)任选将添加剂与由此得到的混合物混合,
c)加热并配合由此得到的共混物直到得到均匀的熔体,
d)迫使由此得到的熔体通过一或多个喷嘴;和
e)冷却熔体直到其固化。
应广泛理解术语“熔体”和“熔化”。这些术语不仅意指从固体状态到液体状态的变化,而且也能指的是转化为玻璃状态或橡胶状态,且其中可能有混合物中的一种成分在一定程度上均匀包埋在其它的成分当中。在具体情况下,一种成分将熔化而其它的成分将溶解于熔体中,因此形成溶液,其冷却下可形成具有有利溶出性质的固体溶液。
如在上文中描述的那样,制备固体分散物后,所得到的产物能够任选研磨和筛分。
可以理解本领域技术人员能够优化制备以上描述的活性成分与环糊精的紧密混合物的技术参数,例如最适宜的溶剂、操作温度、所使用装置的类型、混合和研磨的速率、喷雾干燥的速率、冷冻的速率、升华的速率、熔体-挤出机中的物料通过量的速率等。
替代环糊精或它们的衍生物,其它的水溶性聚合物可用于与活性成分一起制备以上描述的紧密混合物。当在20℃下,以2%(w/v)溶于水溶液中时,适宜的水溶性聚合物具有1至5000mPa.s的表观粘度,更优选具有1至700mPa.s,且最优选具有1至100mPa.s的表观粘度。例如,水溶性聚合物可选自:
-烷基纤维素,例如甲基纤维素,
-羟基烷基纤维素,例如羟甲基纤维素、羟乙基纤维素、羟丙基纤维素和羟丁基纤维素,
-羟烷基烷基纤维素,例如羟乙基甲基纤维素和羟丙基甲基纤维素,
-羧烷基纤维素,例如羧甲基纤维素,
-羧烷基纤维素的碱金属盐,例如羧甲基纤维素钠,
-羧烷基烷基纤维素,例如羧甲基乙基纤维素,
-羧烷基纤维素酯,
-淀粉,
-果胶例如羧甲基支链淀粉钠,
-甲壳质衍生物例如脱乙酰壳多糖,
-二糖、寡糖和多糖,例如海藻糖、藻酸、它们的碱金属和铵盐、角叉菜聚糖、半乳甘露聚糖、黄蓍胶、琼脂、阿拉伯胶、瓜尔胶和黄原胶,
-聚丙烯酸和它们的盐,
-聚甲基丙烯酸、它们的盐和酯、甲基丙烯酸酯共聚物,
-聚乙烯醇;
-聚乙烯吡咯烷酮、聚乙烯吡咯烷酮-乙酸乙烯酯的共聚物;
-聚乙烯吡咯烷酮与聚乙烯醇的组合物,
-聚环氧烷例如聚环氧乙烷和聚环氧丙烷和环氧乙烷与环氧丙烷的共聚物。
本发明的重要制剂如下:活性成分 0.01-50%(w/w)粘性亲水聚合物 0.01-80%(w/w)预胶凝淀粉 0.01-<80%(w/w)药学上可接受的配方剂 加至100%(w/w)
或者活性成分 0.01-50%(w/w)包含羟丙基纤维素的粘性亲水聚合物 0.01-80%(w/w)预胶凝淀粉 0.01-<80%(w/w)药学上可接受的配方剂 加至100%(w/w)
本发明另一重要的制剂如下:活性成分 0.01-50%(w/w)粘性亲水聚合物 0.01-80%(w/w)预胶凝淀粉 0.01-15%(w/w)药学上可接受的配方剂 加至100%(w/w)
或者活性成分 0.01-50%(w/w)包含羟丙基纤维素的粘性亲水聚合物 0.01-80%(w/w)预胶凝淀粉 0.01-15%(w/w)药学上可接受的配方剂 加至100%(w/w)
本发明又一重要的制剂如下:活性成分 0.01-50%(w/w)粘性亲水聚合物 0.01-80%(w/w)预胶凝淀粉 0.01-5%(w/w)药学上可接受的配方剂 加至100%(w/w)
或者活性成分 0.01-50%(w/w)包含羟丙基纤维素的粘性亲水聚合物 0.01-80%(w/w)预胶凝淀粉 0.01-5%(w/w)药学上可接受的配方剂 加至100%(w/w)
本发明另外一个重要的制剂如下:活性成分 0.01-50%(w/w)羟丙基纤维素 25-62%(w/w)羟丙基甲基纤维素 0-16%(w/w)预胶凝淀粉 0.01-5%(w/w)药学上可接受的配方剂 加至100%(w/w)
按照以下方法,通常可制备本发明的控制释放基质制剂:
(1.a)将一种或多种活性成分、预胶凝淀粉、一种或多种粘性亲水聚合物和任选一些或所有的药学上可接受的配方剂混合;
(1.b)将(1.a)下制备的粉状混合物运行通过压实机,由此得到片状物;
(1.c)将生成的片状物破碎并筛分,由此得到颗粒;
(1.d)生成的颗粒与所有的或剩余的药学上可接受的配方剂任选混合直到混合均匀。
在活性成分为略溶于水的、微溶于水的、极微溶于水的、几乎不溶于水或不溶于水的药物或具有依赖pH的溶解性的药物,特别是碱性药物的情况下,如以上描述的那样,可将活性成分以与环糊精或其衍生物或另一种水溶性聚合物形成的紧密混合物的形式掺合到控制释放制剂中。在所述情况下,本发明控制释放制剂的制备包括另外的第一个步骤,即
(2.a)将一种或多种活性成分与水溶性聚合物紧密混合;
(2.b)将(2.a)下制备的紧密混合物与预胶凝淀粉、一种或多种粘性亲水聚合物和任选一些或所有的药学上可接受的配方剂混合;
(2.c)将(2.b)下制备的粉状混合物运行通过压实机,由此得到片状物;
(2.d)将生成的片状物破碎并筛分,由此得到颗粒;
(2.e)将生成的颗粒与所有的或剩余的药学上可接受的配方剂任选混合直到混合均匀。
通过如在上文中描述的方法得到的制剂可用于制备剂型,特别是控制释放剂型。优选的剂型为固体剂型,特别是口服固体剂型且更特别为片剂或胶囊剂,例如用从本发明制剂得到的颗粒填充的胶囊。通过在本领域已知的压片机械上压制从以上描述的方法中生成的最终的共混物,即在(1.d)或(2.e)方法下得到的共混物,可得到所述片剂。
如在以上描述的方法的步骤(1.b)或(2.c)中提到的压实机为一种装置,其中粉状混合物在两个辊之间运行,该辊对粉状混合物施加压力。以这种方法,压实混合物并且形成片状物或板状物。压实机为市场上可得到的,例如,从Gerteis公司(Jona,瑞士)得到,例如Polygran3W压实机。
本领域技术人员可改进以上制备控制释放制剂的常规方法,例如在其它的而不是以上指明的阶段加入某些成分。
作为以上描述的制备方法的另一种替代方法,包括压实步骤,使用直接压制也能够将以上描述的混合物压片。当使用直接压制技术时,用具有片剂组成的粉状混合物填充所要求的片剂形式的冲模或模型,然后冲压。这种压片方法的有利之处是它通常需要较少的步骤。用于直接压片的装置为市场上可得到的。当没有强制进料情况下,混合物的流变学性质不适于填充到冲模或模型中时,这些装置需要强制进料系统。
得到的片剂可具有不同类型的形状,例如椭圆形的或圆形的。由于不同的形状具有不同的表面对体积的比例的事实,本领域技术人员将意识到片剂的形状影响释放周期。因此,鉴于片剂的溶出为主要发生在片剂表面的过程的事实,不同的形状可意味着-但不是必然的-不同的溶出模式。
得到的片剂也可具有不同的标称重量且因此具有不同的大小。片剂的大小影响表面对体积的比例,从而影响如在上文中提到的释放周期。
由上文提及成分的均匀分散物制备成片剂。通过将该成分物理混合,可得到所述分散物。通过由于均匀分散的亲水聚合物溶胀形成凝胶层,确立片剂的控制释放模式。这意味着片剂是可分的且可提供适宜的片芯。当需要时,这使人们调整推荐的剂量。
以上描述的成分、比例和重量百分比适用于未包衣片剂或适用于片芯,即没有包衣的片剂。
然而,本发明片剂优选用本领域已知的薄膜包衣组合物薄膜包衣。该包衣用于改善片剂的外观和/或味觉和它们吞服的容易性。包衣本发明片剂也可用于其它的目的,例如改善稳定性和贮存期限。
适宜的包衣制剂包含形成薄膜的聚合物如羟丙基甲基纤维素,例如hypromellose 2910(5mPa.s)、增塑剂如二元醇,例如丙二醇或聚乙二醇,遮光剂如二氧化钛,和薄膜滑粉如滑石粉。
适宜的包衣溶剂为水以及有机溶剂。有机溶剂的实例为醇类,例如乙醇或异丙醇,酮类例如丙酮或卤代烃类例如二氯甲烷。
包衣中任选包含治疗有效量的一种或多种活性成分以提供所述活性成分的迅速释放并因此提供对所述活性成分治疗的症状的迅速缓解。
用以上所述方法,通过首先制备片芯,随后使用常规技术将所述片芯包衣,例如在包衣锅中包衣,制备本发明包衣片剂。
活性成分以治疗有效量存在于由本发明制剂制备的剂型中。构成治疗有效量的量依使用的成分、治疗的疾病、所述疾病的严重性、治疗的患者而变化。在本发明中使用的活性成分的量优选在大约0.01%至大约50%(w/w)之间。
以下实施例打算阐明本发明。实验部分片剂制剂片剂1西沙必利-(L)-酒石酸盐 52.92mg乳糖单水合物200目 274.83mg羟丙基甲基纤维素2208 34.2mg羟丙基纤维素 142.5mg转鼓式干燥蜡状玉米淀粉 28.5mg硬脂酸镁 2.85mg胶态无水二氧化硅 5.7mg滑石粉* 28.5mg片剂2西沙必利-(L)-酒石酸盐 52.92mg乳糖单水合物200目 149.43mg羟丙基甲基纤维素2208 74.1mg羟丙基纤维素 228.00mg转鼓式干燥蜡状玉米淀粉 28.5mg硬脂酸镁 2.85mg胶态无水二氧化硅 5.7mg滑石粉* 28.5mg片剂33-[2-[3,4-二氢苯并呋喃并[3,2-c]吡 16.00mg啶-2(1H)-基]乙基]-2-甲基-4H-吡啶并[1,2-a]嘧啶-4-酮(超细)乳糖单水合物DCL11 108.80mg羟丙基甲基纤维素2208 41.60mg羟丙基纤维素 128.00mg转鼓式干燥蜡状玉米淀粉 16.00mg硬脂酸镁 6.4mg胶态无水二氧化硅 3.20mg片剂43-[2-[3,4-二氢苯并呋喃并[3,2-c]吡 16.00mg啶-2(1H)-基]乙基]-2-甲基-4H-吡啶并[1,2-a]嘧啶-4-酮(超细)乳糖单水合物DCL11 54.20mg羟丙基甲基纤维素2208 23.40mg羟丙基纤维素 72.00mg转鼓式干燥蜡状玉米淀粉 9.00mg硬脂酸镁 3.6mg胶态无水二氧化硅 1.80mg片剂53-[2-[3,4-二氢苯并呋喃并[3,2-c]吡 21.26mg啶-2(1H)-基]乙基]-2-甲基-4H-吡啶并[1,2-a]嘧啶-4-酮丁二酸盐(1∶1)乳糖单水合物DCL11 103.54mg羟丙基甲基纤维素2208 41.60mg羟丙基纤维素 128.00mg转鼓式干燥蜡状玉米淀粉 16.00mg硬脂酸镁 6.4mg胶态无水二氧化硅 3.20mg片剂63-[2-[3,4-二氢苯并呋喃并[3,2-c]吡 16mg啶-2(1H)-基]乙基]-2-甲基-4H-吡啶并[1,2-a]嘧啶-4-酮(超细)羟丙基β-环糊精 200mg乳糖单水合物DCL11 6.3mg羟丙基甲基纤维素2208 74.1mg羟丙基纤维素 228mg转鼓式干燥蜡状玉米淀粉 28.5mg硬脂酸镁 11.4mg胶态无水二氧化硅 5.7mg乙醇96%(v/v)** 363mg
*由于技术原因,在偏向高标度端的生产过程中,可用硬脂酸镁和乳糖单水合物DCL11替代滑石粉。
**在最终产物中不出现片剂1-5的制备
在行星式混合器中,将活性成分、羟丙基甲基纤维素、羟丙基纤维素、转鼓式干燥蜡状玉米淀粉,且在使用乳糖单水合物200目(片剂1和2)情况下,乳糖填充剂混合,然后使用干燥压实机压实。将压实物破碎,筛分并在行星式混合器中与胶态无水二氧化硅混合,且在使用乳糖单水合物DCL11(片剂3、4和5)情况下,乳糖填充剂混合。加入硬脂酸镁并混合。使用偏心压片机,将得到的共混物压片。
从以上描述的片剂制备方法,能够得出结论:可在聚合物共混物干法压实之前或之后,加入乳糖填充剂。这依使用乳糖的种类而定,更特别依乳糖的粒子大小而定。片剂6的制备
在75℃下,将活性成分和羟丙基β-环糊精溶解于乙醇96%(v/v)中。真空下将生成的溶液蒸发至干。研磨生成的沉淀并筛分且随后在行星式混合器中与羟丙基甲基纤维素、羟丙基纤维素和转鼓式干燥蜡状玉米淀粉混合,然后使用干法压实机压实。将压实物破碎,筛分并在行星式混合器中与胶态无水二氧化硅和乳糖混合。加入硬脂酸镁并混合。使用偏心压片机,将生成的共混物压片。包衣制剂
通过使69.0%w/w二氯甲烷与17.30%w/w的乙醇(96%v/v)混合并向其中悬浮6.0%w/w羟丙基甲基纤维素2910(5mPa.s)、1.5%w/w聚乙二醇400、4.0%w/w滑石粉、1.5%w/w二氧化钛和0.60%w/w聚乙二醇6000,制备包衣溶液。在包衣锅中,将该包衣悬浮液施加于片剂3和4上,得到42.8mg/片的3和28.4mg/片的4的包衣厚度。任选将一种或多种活性成分掺合到所述包衣悬浮液中。体外溶出试验
a)通过将每片放置于包含400ml含有1.5%十二烷基硫酸钠的pH7.2的McIlvaine缓冲液或Eurand缓冲液的烧杯中,在37℃下,评价西沙必利-(L)-酒石酸盐体外从片剂1和片剂2中的释放。以每分钟150转,用桨式搅拌器搅拌介质。2小时后,向溶出介质中加入600ml缓冲液(McIlvaine或Eurand)且将搅拌速率减至每分钟100转。在适当的时间间隔,从释放介质中取样并借助UV光谱法分析。
pH7.2的McIlvaine缓冲液(100ml)(J.Biol.Chem.49,183(1921))由13.05ml枸橼酸溶液(0.1M)和86.95ml的Na2HPO4.2H2O溶液(0.2M)组成。该McIlvaine缓冲液具有比Eurand缓冲液更高的离子强度,其中溶出试验正常进行。在pH7.2下,McIlvaine缓冲液的离子强度为0.398。
pH7.2的Eurand缓冲液(100ml)由190ml氢氧化钠溶液(0.2N)和0.087g的KH2PO4组成。用盐酸(1N)将溶液pH调至7.2且用水稀释至100ml.该Eurand缓冲液(pH7.2)的离子强度为0.076。
表1显示对于片剂1和片剂2而言,西沙必利-(L)-酒石酸盐在McIlvaine或Eurand缓冲液中作为时间的函数的释放百分比。该数据阐明当释放介质的离子强度增加时活性成分从片剂中控制释放不受阻碍。它们也显示通过改变羟丙基纤维素和羟丙基甲基纤维素的量,能够改变释放模式。
b)通过将每片放置于包含900ml的0.1N HCl的烧杯中内的篮中,在37℃下,体外评价3-[2-[3,4-二氢苯并呋喃并[3,2-c]吡啶-2(1H)-基]乙基]-2-甲基-4H-吡啶并[1,2-a]嘧啶-4-酮从片剂3和片剂4中的释放,两种片剂如在上文“包衣制剂”中描述的那样包衣。以每分钟100转,用篮搅拌所述介质。在适当的时间间隔,从释放介质中取样并借助UV光谱法分析。
表2显示对于包衣片剂3和包衣片剂4而言,3-[2-[3,4-二氢苯并呋喃并[3,2-c]吡啶-2(1H)-基]乙基]-2-甲基-4H-比啶并[1,2-a]嘧啶-4-酮作为时间的函数的释放百分比。该数据阐明活性成分从片剂中控制释放并也显示通过改变片剂的标称重量且因此改变片剂的大小,能够改变释放模式。
c)制备具有以下组成的片剂:西沙必利-(L)-酒石酸盐 52.92mg乳糖 346.08mg羟丙基甲基纤维素2208 66.00mg羟丙基纤维素 67.95mg硬脂酸镁 2.85mg胶态无水二氧化硅 5.70mg滑石粉 28.60mg
通过将每片放置于包含400ml含有1.5%十二烷基硫酸钠的pH7.2的McIlvaine缓冲液的烧杯中的篮中,在37℃下,体外评价西沙必利-(L)-酒石酸盐的释放。以每分钟150转,用篮搅拌该介质。在适当的时间间隔,从释放介质中取样并借助UV光谱法分析。
表3显示西沙必利-(L)-酒石酸盐作为时间的函数的释放百分比。该数据阐明活性成分释放非常迅速。缺乏预胶凝淀粉的制剂不能提供活性药物物质的控制释放;该片剂在溶出介质中不能胶凝且不能形成完整的基质网状物。因而,它在浸没在溶出介质中后大约10至15min的时间间隔内崩解。
d)通过在含有300ml的pH7.5的USP缓冲液的烧杯中加入216mg所述紧密混合物,在37℃下,体外评价3-[2-[3,4-二氢苯并呋喃并[3,2-c]吡啶-2(1H)-基]乙基]-2-甲基-4H-吡啶并[1,2-a]嘧啶-4-酮从如在片剂6制备方法中描述的那样制备的与羟丙基β-环糊精的紧密混合物中的溶出。以每分钟100转,用桨式搅拌器搅拌该介质。在适当的时间间隔,从溶出介质中取样并借助UV光谱法分析。
通过在1升烧杯中加入6.805g的KH2PO4、204.5ml的0.2N NaOH溶液和700ml蒸馏水,制备USP缓冲液(pH7.5)。搅拌的同时完全溶出后,在适当的容器中,用蒸馏水将生成的混合物加至1升体积。
表4显示3-[2-[3,4-二氢苯并呋喃并[3,2-c]吡啶-2(1H)-基]乙基]-2-甲基-4H-吡啶并[1,2-a]嘧啶-4-酮作为时间的函数的溶出百分比。该数据阐明在pH7.5的介质中碱性的活性成分从与羟丙基β-环糊精的紧密混合物中溶出是迅速的。
e)通过将片剂放置于含有600ml的USP缓冲液(pH7.5)的烧杯中的篮中,在37℃下,体外评价3-[2-[3,4-二氢苯并呋喃并[3,2-c]吡啶-2(1H)-基]乙基]-2-甲基-4H-吡啶并[1,2-a]嘧啶-4-酮从片剂6中的释放。以每分钟100转,用篮搅拌该介质。在适当的时间间隔,从释放介质中取样并借助UV光谱法分析。
表5显示在USP缓冲液(pH 7.5)中3-[2-[3,4-二氢苯并呋喃并[3,2-c]吡啶-2(1H)-基]乙基]-2-甲基-4H-吡啶并[1,2-a]嘧啶-4-酮作为时间的函数的释放百分比。释放模式属于控制和有规律(零级)的释放。临床试验临床试验1
在这个实施例中描述的研究目标是评价并比较摄取以下物质后西沙必利的生物利用度和药代动力学:
·单次剂量40 mg在片剂制剂2下描述的控制释放制剂中的西沙必利(作为西沙必利-(L)-酒石酸盐给药);
·一天q.i.d.方案(每天服药四次)的普通市售10mg片剂(普瑞博思),其包含作为活性成分的西沙必利单水合物。
另外,研究伴随摄取高脂肪膳食对控制释放制剂的药代动力学的作用。
这个探索试验为20位健康志愿者中的开放3-臂试验(open 3-armtrial)。包括年龄在18至45岁之间的男性和女性健康志愿者。由至少4天的清除期,将三个治疗阶段分开。
每位志愿者以随机交叉排序服用片剂2,在禁食下服用和高脂肪膳食后直接服用,和一天q.i.d.剂量方案的普瑞博思。后者用作参比治疗组且在“市场条件”下服用片剂,即在主食和就寝时间前15分钟。
高热量、高脂肪膳食由三条小麦面包、15克奶油、一个炸鸡蛋和在5克奶油中煎过的15克腊肉、70克干酪、150ml高脂肪牛奶和150ml橙汁(大约4000KJ;70g脂肪,30g蛋白质,40g碳水化合物,350g水)组成。完成膳食后10分钟内服用西沙必利控制释放片剂。
抽取给药前和在规律的时间间隔内直至给药后48小时的血样。
通过有效的HPLC方法,测定西沙必利的血浆浓度。评价多个治疗组的心血管和实验室安全性和耐受性。
试验结果证实所有治疗是安全和良好耐受的。
详细的药代动力学结果呈现于表6中。
在禁食条件下,摄取片剂2后西沙必利的相对生物利用度与一天q.i.d.疗程的普通普瑞博思片剂相似。当摄取高脂肪膳食时,片剂2的药代动力学特性与在禁食条件下的摄取是可比拟的。临床试验2
第二种探索试验目标是评价控制释放制剂片剂2与用普瑞博思标准治疗组相比较的的相对稳态生物利用度。
在这个2-臂开放试验中,18位健康志愿者以随机交叉排序按每天一次,服用6天疗程的片剂2和市售10mg普瑞博思片剂q.i.d.。
膳食前15分钟摄取所有片剂(或在就寝时间服用q.i.d.剂量方案的第四片)。
在第6天、开始给药前并在规定的时间间隔内直至早晨摄取后48小时,抽取血样。通过有效的HPLC方法,测定西沙必利的血浆浓度。评价多个治疗组的心血管和实验室安全性和耐受性。
试验结果证实两种长期治疗是良好耐受和安全的。
详细的药代动力学结果呈现于表6中。从两治疗组中得到稳态。每天一次摄取片剂2后西沙必利的相对稳态生物利用度与用普通普瑞博思片剂q.i.d.治疗是可比拟的。
表1
西沙必利-(L)-酒石酸盐释放% | ||||
片剂1 | 片剂2 | |||
时间(分钟) | Eurand | McIlvaine | Eurand | McIlvaine |
0306090120150180210240270300330360390420450480510540570600630660690720750780810840870900 | 0.008.7415.4022.4028.4428.1529.6031.4332.8934.6336.4638.4040.3342.4644.49 | 0.0022.4637.7548.1162.6266.3474.1082.8392.2397.2898.1598.3598.3598.4498.25 | 0.004.8910.6916.2721.7420.8722.6024.2426.1628.1830.2032.4134.6236.9339.0541.1643.1845.3047.3249.3451.3653.3855.1156.8458.5760.4962.2264.0565.6967.3269.15 | 0.009.0914.2618.5223.1922.3324.1527.1231.0535.9441.2146.2951.8557.9867.5776.0083.4888.3790.9592.5894.2195.4696.4297.1897.6698.0598.2498.3398.5398.8198.91 |
表2
3-[2-[3,4-二氢苯并呋喃并[3,2-c]吡啶-2(1H)-基]乙基]-2-甲基-4H-吡啶并[1,2-a]嘧啶-4-酮释放% | ||
时间(分钟) | 包衣片剂3 | 包衣片剂4 |
0306090120150180210240270300330360390420450480510540570600630660690720750780810840870900 | 0.0012.5921.0427.7333.7239.3744.8449.7654.6359.3363.5667.4070.9874.3477.4980.4683.0585.5187.7589.7891.5493.2394.7395.6896.6397.1197.3697.4597.5897.5897.67 | 0.0015.0024.9733.4641.4448.6455.2961.2967.2472.3677.1281.6485.6689.2192.4494.8496.9298.7299.96100.84101.39101.49101.44101.53101.39101.44101.49101.58101.53101.53101.58 |
表3
时间(分钟) | 活性成分释放% |
0306090120 | 0.0089.3193.4494.1993.81 |
表4
时间(分钟) | 活性成分溶出% |
051530 | 0.00100.88101.44101.63 |
表5
时间(分钟) | 活性成分释放% |
0306090120150180240270300330360390420 | 0.007.9811.9915.3017.7420.0321.9425.8027.5329.6331.2033.2634.1335.96 |
表6片剂2的药代动力学数据
禁食 | 进食 | 稳态 | |
tmax,hCmax,ng/mlAUC24h,ng.h/mlAUC48h,ng.h/mlAUC∞,ng.h/ml | 9.6±4.559.3±18.9968±2931286±3831373±401 | 6.4±3.274.9±17.51012±2421288±3461349±363 | 4.2±3.285.9±32.91305±5411798±7831982(模拟) |
进食与禁食的生物等效性 | |||
FrelCmaxFrelAUC24hFrelAUC48hFrelAUC∞ | 1.261.051.000.98 | ||
生物等效性与参比组(普瑞博思q.i.d.) | |||
FrelCmaxFrelAUC24hFrelAUC48hFrelAUC∞ | 0.840.890.930.96 | 1.050.930.930.94 | 0.990.971.031.10 |
Claims (19)
1.在包含一种或多种活性成分和一种或多种粘性的亲水聚合物的亲水控制释放制剂中的预胶凝淀粉抵消释放介质的离子强度对活性成分从所述制剂中控制释放的损害作用的用途。
2.在包含一种或多种活性成分和一种或多种粘性的亲水聚合物的亲水控制释放制剂中的预胶凝淀粉维持在变化的离子强度的释放介质中活性成分从所述制剂中控制释放的用途。
3.权利要求1或2的预胶凝淀粉的用途,其中所述释放介质的离子强度范围最多可达0.4。
4.权利要求1或2的预胶凝淀粉的用途,其中所述释放介质的离子强度在禁食以及在进食两者条件下沿着整个胃肠道所遇到的离子强度。
5.权利要求1或2的预胶凝淀粉的用途,其中所述释放介质的离子强度范围在大约0.01至大约0.2。
6.在包含一种或多种活性成分和一种或多种粘性亲水聚合物的亲水控制释放制剂中的预胶凝淀粉防止在禁食以及在进食条件下,沿着整个胃肠道的来自所述制剂的剂量倾泄的用途。
7.权利要求1、2或6的预胶凝淀粉的用途,其中所述亲水控制释放制剂还包含药学上可接受的配方剂。
8.一种亲水控制释放制剂,其包含预胶凝淀粉、一种或多种活性成分、一种或多种粘性的亲水聚合物和任选药学上可接受的配方剂,其特征在于预胶凝淀粉能使该制剂维持在变化的离子强度的释放介质中所掺合的活性成分的控制释放。
9.一种权利要求8的制剂,其中所述预胶凝淀粉能使制剂维持在禁食以及在进食条件下沿着整个胃肠道的所掺合的活性成分的控制释放。
10.一种亲水的控制释放制剂,其包含预胶凝淀粉、一种或多种活性成分、一种或多种粘性亲水聚合物和任选药学上可接受的配方剂,其特征在于所述预胶凝淀粉防止在禁食以及在进食条件下沿着整个胃肠道的来自所述制剂的剂量倾泄。
11.一种权利要求8、9或10的制剂,其具有以下组成:活性成分 0.01-50%重量粘性亲水聚合物 0.01-80%重量预胶凝淀粉 0.01-<80%重量药学上可接受的配方剂 加至100%重量。
12.一种权利要求11的制剂,其中所述粘性亲水聚合物包括羟丙基纤维素。
13.一种权利要求8、9或10的制剂,还包含作为溶出速率促进剂的水溶性聚合物。
14.一种权利要求13的制剂,其中所述水溶性聚合物为羟丙基β-环糊精。
15.用作药物的一种权利要求8、9或10的制剂。
16.一种权利要求8、9或10的制剂用于制备一种剂型的用途。
17.一种剂型,其包含治疗有效量的一种权利要求8、9或10的制剂。
18.一种权利要求17的剂型,作为任选包衣的片剂成型。
19.一种制备权利要求8、9、10或13的制剂的方法,其特征在于:
(a)将一种或多种活性成分与水溶性聚合物任选紧密混合;
(b)将一种或多种活性成分混合,或者,如果(a)完成,将(a)下制备的紧密混合物与预胶凝淀粉、一种或多种粘性亲水聚合物和任选一些或所有的药学上可接受的配方剂混合;
(c)通过使(b)下制备的粉状混合物通过压实机,将其压实,从而得到片状物;
(d)将生成的片状物破碎并筛分,从而得到颗粒;
(e)将生成的颗粒与所有的或剩余的药学上可接受的配方剂任选混合直到混合均匀。
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CN100488376C (zh) * | 2003-07-30 | 2009-05-20 | 诺瓦提斯公司 | 适口的可塑可咀嚼兽用组合物 |
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CN102215677B (zh) * | 2008-11-17 | 2014-07-16 | 巴斯夫欧洲公司 | 含淀粉的颗粒配制剂 |
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