CN114786652A - 用于治疗或预防疾病的剂型 - Google Patents
用于治疗或预防疾病的剂型 Download PDFInfo
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- CN114786652A CN114786652A CN202080085419.5A CN202080085419A CN114786652A CN 114786652 A CN114786652 A CN 114786652A CN 202080085419 A CN202080085419 A CN 202080085419A CN 114786652 A CN114786652 A CN 114786652A
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Abstract
本发明涉及一种剂型,其包含用于治疗或预防动物或人体疾病的生物活性成分,所述治疗或预防需要在小肠中在pH 3至pH 5.5范围内释放50%或更多的所述生物活性成分,其中所述剂型包括:a)包含所述生物活性成分的核芯,b)在所述核芯之上或上面的中间包衣层(ICL),该中间包衣层包含碱剂,和c)在所述中间包衣层之上或上面的肠溶包衣层(ECL),该溶包衣层包含肠溶性聚合物,其中所述碱剂与所述肠溶性聚合物的关系当通过下式(I)计算时为5%至95%,且其中作为属于取代的苯并咪唑化合物类别的质子泵抑制剂的生物活性成分除外。
Description
技术领域
本发明属于药物和营养品领域,尤其是包含生物活性成分的剂型领域,用于治疗或预防动物或人体疾病。
背景技术
US 4,786,505描述了一种口服药物制剂,其包含(a)核芯区域,该核芯区域包含有效量的选自以下组的材料:奥美拉唑(omeprazole)加上碱性反应化合物,碱性奥美拉唑盐加上碱性化合物,及单独的碱性奥美拉唑盐,(b)惰性底包衣,其在置于所述核芯上的水中是可溶的或迅速崩解,所述底包衣包含一层或多层选自片剂赋形剂和聚合成膜化合物的材料;及(c)置于在所述底包衣上包括肠溶包衣的外层。所述底包衣也用作pH缓冲区。底包衣层的pH缓冲性能可以通过引入选自通常用于抗酸剂制剂的一组化合物的物质而得到进一步增强,所述物质例如是镁的氧化物、氢氧化物或碳酸盐,铝或钙的氢氧化物、碳酸盐或硅酸盐;复合的铝/镁化合物,例如[Al2O3.6MgO.CO2.12H2O或MgO.AlO3.2SiO2.n-H2O],其中n不是整数且小于2。US 4,786,505的目的是提供奥美拉唑肠溶包衣剂型,其耐受在酸性介质中的溶解,在中性至碱性介质中快速溶解,且具有良好的长期储存稳定性。在US 4,786,505的实施例1和6中,底包衣层中碱性物质(氧化镁或氢氧化铝/碳酸镁)以肠溶包衣层中碱剂和肠溶性聚合物(邻苯二甲酸羟丙基甲基纤维素)的重量计算的百分比分别为约4.1重量%或6.6重量%。
US 2005/0214371A1描述了一种酸不稳定药物的稳定组合物,其包含a)含有所述酸不稳定药物的内核芯;b)不含碱性稳定剂和所述酸不稳定药物的第一中间包衣;c)包含碱性稳定剂的第二中间包衣;以及d)外肠溶层,其中所述酸不稳定药物可在pH 3下降解。术语“酸不稳定药物”是指在pH 3下会降解的任何药物或药剂或活性药物成分(API)。“酸不稳定药物”包括药学活性的取代的苯并咪唑化合物、他汀类药物(例如普伐他汀(pravastatin)、氟伐他汀(fluvastatin)和阿托伐他汀(atorvastatin))、抗生素(例如青霉素G、氨苄青霉素、链霉素、克拉霉素和阿奇霉素)、双脱氧胞嘧啶(ddC)、地高辛、胰酶(pancreatin)、安非他酮(bupropion)及其药学上其可接受的盐,例如盐酸安非他酮。术语“药学活性的取代的苯并咪唑化合物”是指任何药学活性的取代的2-(2-吡啶基甲基)-亚磺酰基-1H-苯并咪唑化合物(例如兰索拉唑(lansoprazole)、奥美拉唑、羟基奥美拉唑、泮托拉唑(pantoprazole)、雷贝拉唑(rabeprazole)、埃索美拉唑(esomeprazole)、吡帕拉唑(preprazole)、帕立拉唑(pariprazole)、雷贝拉唑和泰妥拉唑(tenatoprazole))及药学活性的取代的2-(苯甲基)-亚磺酰基-1H-苯并咪唑化合物(例如来明拉唑(leminoprazole))。US 2005/0214371A1没有提及或暗示所述酸不稳定药物在低pH值下的意外释放。
US 2005/0214371A1还提供了一种治疗选自胃或十二指肠溃疡、严重糜烂性食管炎、Zolinger-Elison综合征、胃食管反流和幽门螺杆菌感染的疾病的方法,其包括将有效量的该发明的稳定药物组合物给予患有所述疾病的个体,优选需要治疗的个体,其中所述稳定的药物组合物中的酸不稳定药物选自兰索拉唑、奥美拉唑、泮托拉唑、雷贝拉唑、羟基奥美拉唑、埃索美拉唑、帕立拉唑、吡帕拉唑、替那拉唑、来明拉唑、及其可接受的盐类。
IPCOM 000009757D(IP.com Prior Art Database Technical DisclosureIP.com Number IPCOM 000009757D,IP.com electronic publication date September17,2002,Authors et al.:Disclosed Anonymously)描述了“酸不稳定的苯并咪唑化合物的稳定药物制剂及其制备”。一般公开IPCOM 000009757D与US 2005/0214371A1的公开非常相似,除了没有提及“b)没有碱性稳定剂和所述酸不稳定药物的第一中间包衣”。IPCOM000009757D未提及所包含的活性药物成分的任何意外提前释放。
US 7,932,258 B2描述了使用部分中和的(甲基)丙烯酸酯共聚物作为包衣用于制备在降低的pH值下释放活性物质的药物剂型。
WO 2008/135090A1描述了包含两个单独包衣的剂型,其可包括内包衣和外包衣,所述内包衣包含与C2-C16羧酸组合的部分中和的阴离子(甲基)丙烯酸酯共聚物或水溶性中性聚合物,而所述外包衣包含阴离子(甲基)丙烯酸酯共聚物,其较所述内包衣的材料的中和化程度低,或者根本未中和化。预期效果是所述固体剂型在体内“较早地”释放其活性物质,即在肠道入口处已经释放。此处的术语“较早地”是指根据该发明的固体剂型在与肠道正常pH值相比较低的pH值下已经开始释放活性物质,即当所述固体剂型从具有低pH值的胃转移时进入与胃相比具有较高pH值、但未高如肠道更远端部分的pH值的肠道(例如pH5.6)时即释放活性物质。与标准L100-55包衣(其在pH 5.6时几乎没有活性成分释放)相比,所述双包衣系统在相同的pH值下在45分钟内释放约30%的活性成分。
发明内容
US 4,786,505、US 2005/0214371A1和IPCOM 000009757D提供了用于酸不稳定物质例如取代的苯并咪唑化合物、尤其是奥美拉唑或泮托拉唑物质家族的稳定药物组合物。为了提供在储存条件期间的pH稳定性,中间包衣中包含缓冲的碱性物质。外肠溶包衣层应保护所述物质不与胃酸接触。在US 4,786,505、US 2005/0214371A1和IPCOM 000009757D中没有关于在经过胃后存在的pH值下释放生物活性成分的数据。这可以通过关于所选物质的酸不稳定特性的教导推断,因此尝试在3和5.5之间的pH值下释放已经没有太大意义。
WO 2008/135090A1描述了包含两个单独包衣的剂型,其可包括内包衣和外包衣,所述内包衣包含与C2-C16羧酸组合的部分中和的阴离子(甲基)丙烯酸酯共聚物或水溶性中性聚合物,而所述外包衣包含阴离子(甲基)丙烯酸酯共聚物,其较所述内包衣的材料的中和化程度低,或者根本未中和化。预期效果是固体剂型在体内“较早地”释放其活性物质,即在肠道入口处已经释放。所述效果似乎仅限于不低于约pH 5.6的pH值。
US 7,932,258 B2描述了使用部分中和的(甲基)丙烯酸酯共聚物作为制备在降低的pH值下释放活性物质的药物剂型的包衣。然而,在实践中,当所述组合物首先在pH 1.2的酸性介质中试验2小时、然后接着在3和5.5之间的低pH介质中试验时,所述单一包衣系统的报道效果似乎减缓。
需要用于治疗或预防动物或人体疾病的剂型,所述治疗或预防需要在pH值在3至5.5范围的小肠中释放50%或更多的生物活性成分。本发明的目的如权利要求中所述的那样得到解决。
具体实施方式
剂型
本发明涉及用于治疗或预防动物或人体疾病的包含生物活性成分的剂型,所述治疗或预防提供在pH值为3直至5.5的小肠中释放50%或更多的所述生物活性成分,其中所述剂型包含:
a)包含所述生物活性成分的核芯,
b)在所述核芯之上或上面的中间包衣层(ICL),该中间包衣层包含碱剂,和
c)在所述中间包衣层之上或上面的肠溶包衣层(ECL),该肠溶包衣层包含肠溶性聚合物,
其中所述剂型中碱剂与所述肠溶性聚合物的关系当以下式计算时为5%至95%:
其中作为属于取代的苯并咪唑化合物类的质子泵抑制剂的生物活性成分除外。
所述剂型通常可以具有核芯的形式,然而如所公开的是用中间包衣层和肠溶包衣层进行另外包衣的核芯的形式,例如(包衣的)丸(核芯)的形式。此外,一些单一剂型可以作为多单元剂型的一部分包含在多个剂型中,例如包含在胶囊或片剂中,其中包含多个本发明的剂型,例如以(包衣的)丸(核芯)的形式。
所述剂型可以具有例如片剂、小片剂(minitablet)、丸剂、小丸剂、颗粒剂、小袋剂或胶囊剂的形式。所述剂型也可以被包含,优选包含在多单元中,例如包含在片剂、小袋或胶囊中。
生物活性成分的释放
优选地,所述生物活性成分的释放在pH 1.2进行120分钟时为10%或更少,而在pH3至pH 5.5、优选pH 3.2至pH 5.0进行45分钟为50%或更多(50-100%)、优选60%至100%。pH 1.2的测试介质根据USP(例如USP 42)可以是0.1N HCl,pH 3至pH 5.5的介质根据USP(例如USP 42(2019))可以是缓冲介质。
核芯
所述剂型的核芯包含生物活性成分。
所述剂型的核芯可以包含生物活性成分,其分布在基质结构中或结合在内核芯结构上的包衣中的粘合剂或封装在胶囊中。
所述核芯可以通过诸如造粒、挤出、滚圆或热熔挤出的方法制备。
所述核芯可以是小丸(pellet)、丸剂(pill)、颗粒剂、片剂或胶囊。所述核芯可以是含活性成分的片剂、含小丸的压缩片剂、小片剂或胶囊,其可以填充有含活性成分的小丸或颗粒、药物溶液或分散体、小片剂或粉末或其组合。
所述核芯可以包含例如未包衣的小丸、中性载体小丸,例如糖球或空白丸芯,在其顶部上生物活性成分结合在粘合剂中,所述粘合剂例如是乳糖、聚乙烯吡咯烷酮或中性纤维素衍生物(如HPC或HPMC)。具有生物活性成分的粘合剂-包衣层在本文中被认为是所述核芯的一部分。与所述中间包衣层和肠溶包衣层相比,所述核芯的粘合剂-包衣层对生物活性成分的控释基本上没有影响。所述核芯也可以包含由结晶的生物活性成分组成的未包衣的小丸。
所述核芯可包含以重量计1%至100%、2%至90%、5%至85%、10%至70%、15%至50%的生物活性成分。所述核芯可包含以重量计0%至99%、10%至98%、15%至95%、30%至90%或50%至85%的药学或营养学可接受的赋形剂。所述生物活性成分和药学或营养学可接受的赋形剂加起来可直至100%。
所述生物活性成分可以包含于所述剂型的核芯中,其包含量以所述核芯重量计为0.1%至100%。
生物活性成分
所述生物活性成分可以包括生物活性药物成分和生物活性营养成分。
属于取代的苯并咪唑化合物类的质子泵抑制剂的生物活性成分不在本发明的范围内。术语质子泵抑制剂对于药学领域的技术人员来说是众所周知的。质子泵抑制剂的主要药物作用是显著且持久地减少胃酸的产生。因此,属于药物活性成分类别的术语质子泵抑制剂是指具有药物质子泵抑制剂活性的取代的苯并咪唑化合物。尤其是属于药学活性的取代的苯并咪唑类化合物的术语质子泵抑制剂是指药学活性的取代的2-(2-吡啶基甲基)-亚磺酰基-1H-苯并咪唑化合物(例如兰索拉唑、奥美拉唑、羟基奥美拉唑、泮托拉唑、雷贝拉唑、埃索美拉唑、吡帕拉唑、帕立拉唑、雷贝拉唑和泰妥拉唑)和药学活性的取代的2-(苯基甲基)-亚磺酰基-1H-苯并咪唑化合物(例如来明拉唑)。
疾病
疾病与用于治疗或预防疾病相关的生物活性成分可以选自胃肠道灌洗与轻泻药,炎症性肠病与皮质类固醇,高胆固醇血症或高甘油三酯血症与他汀类药物,CHF与糖苷类,心律失常与奎尼丁的立体异构体,癌症与植物生物碱类,细菌感染与抗生素,HIV与核苷类,胰腺功能不全与脂肪酶,重度抑郁症(MDD)或季节性情感障碍(SAD)或辅助戒烟与去甲肾上腺素/多巴胺再摄取抑制剂(NDRI),疼痛或炎症与NSAID,类风湿性关节炎、骨关节炎或强直性脊柱炎与NSAID,帕金森病与多巴胺前体,疟疾与抗疟药,高血压与β受体阻滞剂,糖尿病与双胍类药物,水肿或慢性肾功能不全与苯甲酸磺胺呋喃类药物,轻度至重度心力衰竭、心室射血分数≤40%的心肌梗死后左心室功能不全与β肾上腺素受体阻滞剂,全身性真菌感染与抗真菌药,高脂蛋白血症或高甘油三酯血症与贝特类(fibrate)抗血脂药,心力衰竭与盐皮质激素,癌症与蒽环类抗生素,高血压、心绞痛或丛集性头痛预防与钙通道阻滞剂,以及心房颤动与β受体阻滞剂。
疾病与用于治疗或预防疾病相关的生物活性成分可以选自胃肠道灌洗与比沙可啶(bisacodyl),炎症性肠病与布地奈德(budesonide),高胆固醇血症或高甘油三酯血症与氟伐他汀(fluvastatin),CHF与地高辛,心律失常与奎尼丁,癌症与依托泊苷(etoposide),溃疡和胃食管反流病(GERD)与奥美拉唑、兰索拉唑、泮托拉唑或雷贝拉唑,细菌感染与红霉素、青霉素G、氨苄青霉素、链霉素、克拉霉素或阿奇霉素,HIV与双脱氧肌苷(ddI或地达诺新(didanosine))、双脱氧腺苷(ddA)或双脱氧胞嘧啶(ddC),胰腺功能不全与脂肪酶,重度抑郁症(MDD)或季节性情感障碍(SAD)或辅助戒烟与安非他酮(bupropion),疼痛和炎症、类风湿性关节炎、骨关节炎或强直性脊柱炎与乙酰水杨酸()、双氯芬酸(diclofenac)或吲哚美辛(indomethacin),帕金森病与左旋多巴(levodopa),疟疾与硫酸羟氯喹,高血压和阿替洛尔(atenolol),糖尿病与盐酸二甲双胍,水肿或慢性肾功能不全与苯甲酸磺胺呋喃类药物,轻度至重度心力衰竭、心室射血分数≤40%的心肌梗死后左心室功能不全与呋塞米(furosemide),全身真菌感染与酮康唑(ketoconazole),高脂蛋白血症或高甘油三酯血症与非诺贝特(fenofibrate),心力衰竭与醛固酮,癌症与多柔比星(doxorubicin),高血压、心绞痛或丛集性头痛预防与维拉帕米(verapamil),以及心房颤动与索他洛尔(sotalol)。
优选地,所述疾病可以是心房颤动并且与治疗或预防心房颤动相关的生物活性成分是索他洛尔。
根据本申请的进一步的生物活性成分可以是生物技术衍生产物或微生物衍生产物,并且可以选自例如酶、激素、液体或固体天然提取物、寡核苷酸、DNA、RNA、mRNA、siRNA、Protacs(蛋白酶解靶向嵌合体)、肽激素、治疗性细菌、益生元、益生菌、肽、蛋白质、泌尿科药物、ω-3-脂肪酸、例如来自越橘、蓝莓或黑醋栗作为抗氧化剂的花青素、维生素和疫苗。
中间包衣层
中间包衣层(ICL)位于内核之上或上面并且包含碱剂。所述中间包衣层可包含以重量计5%至75%、优选10%至50%的碱剂。所述中间层可包含以重量计25%至95%、优选90%至50%的其它药物或营养学可接受的赋形剂,例如聚合粘合剂,如中性水溶性纤维素,例如羟丙基甲基纤维素(HPMC)或羟丙基纤维素(HPC),或聚乙烯吡咯烷酮(PVP),或增塑剂或防结块剂(anti tacking agent)或其组合。所述聚合粘合剂也可以是中性或阴离子(甲基)丙烯酸酯共聚物。优选地,所述中间层在所述核芯之上,之间没有其它包衣。所述中间包衣层的存在量基于所述核芯的重量计算可以为5%至100%、优选7.5%至50%。
碱剂
所述碱剂可以是碱金属盐或碱土金属盐。例如,所述碱剂可以选自氧化钙、碳酸钙、碳酸镁、氧化镁、碳酸钠、碳酸氢钠和氢氧化钠或其任何混合物。优选的碱剂是氧化镁或碳酸镁。中间包衣层(ICL)中的碱剂与肠溶包衣层(ECL)中的肠溶性聚合物的关系当以下式计算时为5%至95%,优选7%至80%:
增塑剂
增塑剂可以定义为其通过与聚合物的物理相互作用实现玻璃态转变温度和最低成膜温度的降低并促进膜形成,这取决于加入量。合适的物质通常具有100至20,000的分子量并且在分子中包含一个或多个亲水基团,例如羟基酯或氨基。
所述中间包衣层或肠溶包衣层可包含增塑剂,其可选自柠檬酸烷基酯、甘油酯、邻苯二甲酸烷基酯、癸二酸烷基酯、蔗糖酯、脱水山梨糖醇酯和聚乙二醇。所述中间包衣层可包含增塑剂,优选以重量计约2%至50%、优选5%至25%,其可选自例如柠檬酸三乙酯(TEC)、乙酰基柠檬酸三乙酯(ATEC)、癸二酸二乙酯和癸二酸二丁酯(DBS)、甘油、丙二醇、聚乙二醇200至12,000和蓖麻油。用于中间包衣层的优选增塑剂可以是甘油或柠檬酸三乙酯。用于肠溶包衣层的优选增塑剂可以是柠檬酸三乙酯。
肠溶包衣层
所述肠溶包衣层在中间包衣层之上或上面,包含肠溶性聚合物和任选存在的药学或营养学上可接受的赋形剂。所述肠溶包衣层可包含以重量计10%至100%、优选20%至80%的肠溶性聚合物。所述肠溶包衣层可包含以重量计90%至0%、优选80%至20%的药学或营养学可接受的赋形剂,例如增塑剂。优选所述肠溶包衣层在所述中间包衣层上,中间没有其它包衣层。以所述核芯和中间层的重量计算,肠溶包衣层的存在量可以为5至50重量%。
肠溶性聚合物
在所述中间包衣层之上或上面的进一步的包衣层中的肠溶性聚合物可以选自阴离子(甲基)丙烯酸酯共聚物、阴离子纤维素、阴离子多糖和聚醋酸乙烯邻苯二甲酸酯或其任何混合物。以所述核芯和中间层的重量计算,所述肠溶包衣层的存在量可以为10至50重量%。
阴离子(甲基)丙烯酸酯共聚物
所述肠溶包衣层可包含(甲基)丙烯酸酯共聚物,选自包含甲基丙烯酸和丙烯酸乙酯的聚合单元的共聚物、包含甲基丙烯酸和甲基丙烯酸甲酯的聚合单元的共聚物、包含丙烯酸乙酯和甲基丙烯酸甲酯的聚合单元的共聚物、或包含甲基丙烯酸、丙烯酸甲酯和甲基丙烯酸甲酯的聚合单元的共聚物,选自包含甲基丙烯酸和丙烯酸乙酯的聚合单元的共聚物与包含甲基丙烯酸甲酯和丙烯酸乙酯的聚合单元的共聚物的混合物,以及选自包含甲基丙烯酸、丙烯酸甲酯和甲基丙烯酸甲酯的聚合单元的共聚物与包含甲基丙烯酸甲酯和丙烯酸乙酯的共聚物的混合物,或其任何混合物。
所述包衣层可包含(甲基)丙烯酸酯共聚物,该共聚物包含以重量计40至60%的甲基丙烯酸和以重量计60至40%的丙烯酸乙酯(L 100-55类型)的聚合单元。合适的第二聚合物是L 100-55(Evonik Nutrition&Care GmbH,Darmstadt,Germany),这是包含50重量%的甲基丙烯酸和50重量%的丙烯酸乙酯的聚合单元的共聚物。L 30D-55是L 100-55的30重量%的水分散体。L 100-55的玻璃化转变温度Tgm约为110℃。
所述包衣层可包含(甲基)丙烯酸酯共聚物,该共聚物包含以重量计5%至15%的甲基丙烯酸、以重量计60%至70%的丙烯酸甲酯和以重量计20%至30%的甲基丙烯酸甲酯的聚合单元(FS类型)。合适的共聚物是FS,其是由25重量%的甲基丙烯酸甲酯、65重量%的丙烯酸甲酯和10重量%的甲基丙烯酸聚合而成的共聚物。FS 30D是一种包含30重量%的FS的分散体。FS的玻璃化转变温度Tgm约为45℃。
所述包衣层可包含(甲基)丙烯酸酯共聚物,该共聚物包含以重量计40%至60%的甲基丙烯酸和以重量计60%至40%的甲基丙烯酸甲酯(L 100类型)的聚合单元。L 100是由50重量%的甲基丙烯酸甲酯和50重量%的甲基丙烯酸聚合而成的共聚物。L 100的玻璃化转变温度Tgm约为或略高于150℃。
所述包衣层可包含(甲基)丙烯酸酯共聚物,其包含以重量计20%至40%的甲基丙烯酸和以重量计60%至80%的甲基丙烯酸甲酯的聚合单元(S 100类型)。S 100是由70重量%的甲基丙烯酸甲酯和30重量%的甲基丙烯酸聚合而成的共聚物。S 100的玻璃化转变温度Tgm约为或略高于160℃。
所述包衣层还可以包含由两种(甲基)丙烯酸酯共聚物形成的核-壳聚合物形式的阴离子(甲基)丙烯酸酯共聚物。所述包衣层可包含是核-壳聚合物的(甲基)丙烯酸酯共聚物,包含以重量计50%至90%、优选70%至80%的核芯,其包含以重量计60%至80%、优选65%至75%丙烯酸乙酯和以重量计40%至20%、优选35%至25%的甲基丙烯酸甲酯的聚合单元,以及以重量计50%至10%、优选30%至20%的壳,其包含以重量计40%至60%、优选45%至55%丙烯酸乙酯和以重量计60%至40%、优选55%至45%的甲基丙烯酸的聚合单元。
合适的核-壳聚合物是FL 30D-55(Evonik Nutrition&Care GmbH,Darmstadt,Germany),这是一种市售的来自两阶段乳液聚合工艺的共聚物的30重量%的水分散体,核芯为约75重量%,其包含约70重量%的丙烯酸乙酯和30重量%的甲基丙烯酸甲酯的聚合单元,以及壳为约25重量%,其包含50重量%的丙烯酸乙酯和50重量%的甲基丙烯酸的聚合单元。FL 30D-55聚合物的玻璃化转变温度Tgm约为8℃。
阴离子纤维素
阴离子纤维素(化学改性纤维素)可选自羧甲基乙基纤维素及其盐、乙酸邻苯二甲酸纤维素、乙酸琥珀酸纤维素、乙酸偏苯三酸纤维素、邻苯二甲酸羟丙基甲基纤维素和醋酸琥珀酸羟丙基甲基纤维素、或其任何混合物。
阴离子多糖
具有肠溶特性的阴离子多糖(不基于纤维素)可以选自聚合物,例如虫胶、壳聚糖、藻酸和藻酸盐,例如藻酸钠、钾或铵。
药学或营养学可接受的赋形剂
所述中间层或肠溶包衣层中的核芯可任选地包含药学或营养学上可接受的赋形剂。所述药学或营养学可接受的赋形剂可选自抗氧化剂、增白剂、诸如乳糖、聚乙烯吡咯烷酮或中性纤维素的粘合剂、调味剂、流动助剂、助流剂、渗透促进剂、颜料、增塑剂、其它聚合物、成孔剂和稳定剂或其任何组合。
条目
本发明的特征可以在于以下条目:
1.剂型,包含用于治疗或预防动物或人体疾病的生物活性成分,所述治疗或预防需要在小肠中在pH 3至pH 5.5范围释放50%或更多的所述生物活性成分,其中所述剂型包含:
a)包含所述生物活性成分的核芯,
b)在核芯之上或上面的中间包衣层(ICL),其包含碱剂,和
c)在所述中间包衣层之上或上面的肠溶包衣层(ECL),其包含肠溶性聚合物,
其中所述碱剂与肠溶性聚合物的关系当通过下式计算时为5%至95%:
其中属于取代的苯并咪唑化合物的质子泵抑制剂的生物活性成分除外。
2.根据条目1的剂型,其中所述生物活性成分的释放在pH 1.2下120分钟为10%或更少,在pH 3至pH 5.5下45分钟为50%或更多。
3.根据条目1或2的剂型,其中所述疾病与用于治疗或预防所述疾病的生物活性成分的类别选自如下:胃肠道灌洗剂与轻泻药,炎性肠病与皮质类固醇,高胆固醇血症或高甘油三酯血症与他汀类药物,CHF与糖苷类,心律失常与奎尼丁的立体异构体,癌症与植物生物碱类,细菌感染与抗生素,HIV与核苷类,胰腺功能不全与脂肪酶,重度抑郁症(MDD)或季节性情感障碍(SAD)或辅助戒烟与去甲肾上腺素/多巴胺再摄取抑制剂(NDRI),疼痛或炎症与NSAID,类风湿性关节炎、骨关节炎或强直性脊柱炎与NSAID,帕金森病与多巴胺前体,疟疾与抗疟药,高血压与β受体阻滞剂,糖尿病与双胍类药物,水肿或慢性肾功能不全与苯甲酸磺胺呋喃类药物,轻度至重度心力衰竭、心室射血分数≤40%的心肌梗死后左心室功能不全与β肾上腺素受体阻滞剂,全身性真菌感染与抗真菌药,高脂蛋白血症或高甘油三酯血症与贝特类(fibrate)抗血脂药,心力衰竭与盐皮质激素,癌症与蒽环类抗生素,高血压、心绞痛或丛集性头痛预防与钙通道阻滞剂,以及心房颤动与β受体阻滞剂。
4.根据条目1至3中任一项的剂型,其中所述疾病与用于治疗或预防所述疾病相关的生物活性成分选自:胃肠道灌洗液和比沙可啶(bisacodyl),炎性肠病和布地奈德(budesonide),高胆固醇血症或高甘油三酯血症和氟伐他汀(fluvastatin)、CHF和地高辛(digoxin),心律失常和奎尼丁(quinidine),癌症和依托泊苷(etoposide),细菌感染和红霉素、青霉素G、氨苄青霉素、链霉素、克拉霉素或阿奇霉素,HIV和双脱氧肌苷(ddI或去羟肌苷(didanosine))、双脱氧腺苷(ddA)或双脱氧胞嘧啶(ddC)),胰腺功能不全和脂肪酶,重度抑郁症(MDD)或季节性情感障碍(SAD)或辅助戒烟和安非他酮(bupropion),疼痛和炎症、类风湿性关节炎、骨关节炎或强直性脊柱炎和乙酰水杨酸()、双氯芬酸(diclofenac)或吲哚美辛(indomethacin),帕金森病和左旋多巴(levodopa),疟疾和硫酸羟氯喹,高血压和阿替洛尔(atenolol),糖尿病和盐酸二甲双胍,水肿或慢性肾功能不全和苯甲酸磺胺呋喃类药物,轻度至重度心力衰竭、心室射血分数≤40%的心肌梗死后左心室功能不全和呋塞米(furosemide),全身真菌感染和酮康唑(ketoconazole),高脂蛋白血症或高甘油三酯血症和非诺贝特(fenofibrate),心力衰竭和醛固酮,癌症和多柔比星(doxorubicin),高血压、心绞痛或丛集性头痛预防和维拉帕米(verapamil),以及心房颤动和索他洛尔(sotalol)。
5.根据条目1至4中任一项的剂型,其中所述疾病是心房颤动并且用于治疗或预防所述疾病的生物活性成分是索他洛尔。
6.根据条目1至5中的一项或多项的剂型,其中所述核芯包含分布在基质结构中或结合在内核包衣中的粘合剂中的生物活性成分。
7.根据条目1至6中的一项或多项的剂型,其中所述碱剂是碱金属盐或碱土金属盐。
8.根据条目1至7中的一项或多项的剂型,其中所述碱剂选自氧化钙、碳酸钙、碳酸镁、氧化镁、碳酸钠、碳酸氢钠和氢氧化钠或其任何组合。
9.根据条目1至8中的一项或多项的剂型,其中所述碱剂是碳酸镁或氧化镁。
10.根据条目1至9中的一项或多项的剂型,其中所述中间包衣层进一步包含增塑剂和/或聚合物粘合剂。
11.根据条目1至10中的一项或多项的剂型,其中所述肠溶包衣层中的肠溶性聚合物选自阴离子(甲基)丙烯酸酯共聚物、阴离子纤维素、阴离子多糖和聚醋酸乙烯邻苯二甲酸酯或其任何混合物。
12.根据条目1至11中的一项或多项的剂型,其中所述阴离子(甲基)丙烯酸酯共聚物选自包含甲基丙烯酸和丙烯酸乙酯的聚合单元的共聚物、甲基丙烯酸和甲基丙烯酸甲酯的聚合单元的共聚物、以及甲基丙烯酸、丙烯酸甲酯和甲基丙烯酸甲酯的聚合单元的共聚物或其任何混合物。
13.根据条目1至12中的一项或多项的剂型,其中所述阴离子纤维素选自羧甲基乙基纤维素及其盐,醋酸邻苯二甲酸纤维素,醋酸琥珀酸纤维素,醋酸偏苯三酸纤维素,邻苯二甲酸羟丙基甲基纤维素和醋酸琥珀酸羟丙基甲基纤维素,或其任何混合物。
14.根据条目1至13中的一项或多项的剂型,其中所述碱剂与肠溶性聚合物的比例为7%至80%。
15.根据前述条目中的一项或多项的剂型,其中所述生物活性成分的释放在pH1.2下120分钟为10%或更少,在pH 3.2至pH 5.0下45分钟为60%至100%。
16.根据前述条目的一项或多项的剂型,其中所述核芯包含以重量计0.1%至100%、1%至100%、2%至90%、5%至85%、10%至70%或15%至50%的所述生物活性成分。
17.根据前述条目中的一项或多项的剂型,其中所述核芯包含以重量计0%至99.9%、0%至99%、10%至98%、15%至95%、30%至90%或50%至85%的药学或营养学可接受的赋形剂.
18.根据前述条目中的一项或多项的剂型,其中所述生物活性成分选自乙酰水杨酸、苯那普利(benazepril)、比沙可啶(bisascodyl)、布地奈德、卡维地洛(carvediol)、依托泊苷(etopside)、奎尼丁、酮康唑或索他洛尔、酶、激素、液体或固体天然提取物、寡核苷酸、DNA、RNA、mRNA、siRNA、Protacs(蛋白水解靶向嵌合体)、肽激素、治疗性细菌、益生元、益生菌、肽、蛋白质、泌尿科药物、ω-3-脂肪酸及其盐、例如来自越橘、蓝莓或黑醋栗的花青素、维生素和疫苗。
19.根据前述条目中的一项或多项的剂型,其中所述中间包衣层(ICL)的存在量基于所述核芯的重量计算为5至100重量%。
20.根据前述条目中的一项或多项的剂型,其中所述中间包衣层(ICL)的存在量基于所述核芯的重量计算为7.5至50重量%。
21.根据前述条目中的一项或多项的剂型,其中所述中间包衣层(ICL)包含5至75重量%的所述碱剂。
22.根据前述条目中的一项或多项的剂型,其中所述中间包衣层(ICL)包含10至50重量%的所述碱剂。
23.根据前述条目中的一项或多项的剂型,其中所述肠溶包衣层(ECL)的存在量基于所述核芯和所述中间层的重量计算为10至50重量%。
24.根据前述条目中的一项或多项的剂型,其中所述肠溶包衣层(ECL)包含10至100重量%的所述肠溶性聚合物。
25.根据前述条目中的一项或多项的剂型,其中所述肠溶包衣层(ECL)包含20至80重量%的所述肠溶性聚合物。
26.根据前述条目中的一项或多项的剂型,其中所述肠溶性聚合物包括(甲基)丙烯酸酯共聚物,所述(甲基)丙烯酸酯共聚物包含40至60重量%的甲基丙烯酸和60至40重量%的丙烯酸乙酯的聚合单元。
实施例
A.核芯制备
1.苯那普利(核芯)片剂
1.1苯那普利片剂的组成
表3:苯那普利片剂的组成
*q.s.:足量至制粒终点
*注释:实验I1的组成也以mg表示,用于说明计算的碱在碱与肠溶性聚合物中的百分比。随后实验中成分的量也可以同样计算。
缩写:HPMC:羟丙基甲基纤维素
1.2苯那普利片剂的制备方法
I.称重所述配方中指定的所有成分。
II.将盐酸苯那普利和乳糖一水合物混合均匀,过#40目筛。
III.将微晶纤维素PH101和半量的HPMC 6cps过#40目筛,加入步骤II溶液中。
IV.将步骤III的粉末混合物加入快速混合制粒机中,然后以慢速混合5分钟。
V.在单独的烧杯中,在持续搅拌下将剩余的半量HPMC 6cps缓慢加入纯化水中,以获得澄清的粘合剂溶液。
VI.然后将步骤V的粘合剂溶液用于将步骤IV的干混合物制粒。
VII.制粒后,将湿物料过10#(2.0mm)筛。
VIII.将颗粒在盘式干燥器中在50℃下干燥,直到LOD达到低于5%w/w。
IX.将干燥的颗粒过30#(595μm)筛。
X.精确称重所有颗粒外材料。
XI.将MCC PH 102、交联羧甲基纤维素钠和Aerosil 200在塑料袋中混合并过#40目筛。
XII.将步骤IX的苯那普利颗粒和步骤XI的筛分材料在双锥混合器中以15RPM混合15分钟。
XIII.将筛分的硬脂酸镁(60#)加入步骤XII混合物中,在双锥混合器中以15RPM将混合物润滑3分钟。
XIV.将润滑的混合物用于压片。
表4:苯那普利片剂制备的通用工艺参数
2.索他洛尔(核芯)片剂
2.1索他洛尔片剂的组成
表5:索他洛尔片剂的组成
*足量至制粒终点
2.2索他洛尔片剂的制备方法
I.称重所述配方中指定的所有成分。
III.将步骤II的粉末混合物加入快速混合制粒机中,然后以慢速混合3分钟。
IV.在单独的烧杯中,在持续搅拌下将HPMC 3cps缓慢加入纯化水中以获得澄清溶液。
V.然后将步骤IV溶液用于将步骤III的干混合物制粒。
VI.将颗粒在盘式干燥机中在60℃干燥2小时,然后过30#筛,接着在60℃进一步干燥4小时,直至LOD低于5%w/w。
VII.将干燥的颗粒过30#(595μm)筛。
VIII.精确称重所有颗粒外材料。
X.将步骤VII的索他洛尔颗粒和步骤IX的筛分材料在双锥混合器中以15RPM混合15分钟。
XI.将硬脂酸镁(过60#筛)加入步骤X的混合物中,并在双锥混合器中以15RPM润滑5分钟。
XII.将润滑的混合物用于压片。
表6:索他洛尔片剂制备的通用工艺参数
B.包衣
1.本发明实验的包衣组成
表9:本发明实验的中间包衣和肠溶包衣的包衣组成
*注释:实验I1的成分也以克(g)表示,用于说明计算的碱在碱与肠溶聚合物中的百分比。后续实验中成分的量可以同样计算。
缩写:PP:泮托拉唑小丸;BT:苯那普利片;ST:索他洛尔片;PT:泮托拉唑片;HPMC:羟丙基甲基纤维素;TEC:柠檬酸三乙酯;w.r.t.:关于
2.本发明实验的包衣制备方法
2.1中间包衣
2.1.1实验I1和I3的中间包衣
I.将所有成分称重所需数量。
II.使用顶置式搅拌器将HPMC[3cps]溶解在含有甘油的水中,直到获得澄清溶液。
III.在搅拌下将氧化镁缓慢加入上述溶液中,然后将所得悬浮液混合30分钟。
IV.将悬浮液过100#筛,用于中间包衣。
2.1.2实验I2的中间包衣
I.将所有成分称重所需数量。
II.使用顶置式搅拌器将HPMC[3cps]溶解在含有甘油的水中,直至获得澄清溶液。
III.在搅拌下将碳酸镁缓慢加入上述溶液中,然后将所得悬浮液混合30分钟。
IV.将悬浮液过40#筛,用于中间包衣。
表10:本发明实验I1 to I3的中间包衣的通用工艺参数
2.2肠溶包衣
2.2.1实验I1至I3的肠溶包衣
I.将所有成分称重所需数量。
III.将悬浮液过40#筛,然后用于肠溶包衣。
表11:本发明实验I1至I3的肠溶包衣的通用工艺参数
C.肠溶包衣的小丸/片剂
分析方法学
1.苯那普利片剂
A)溶解条件
1)溶解参数
仪器:USP II型
溶解介质:酸性阶段介质2小时,然后是缓冲阶段介质(1小时)
介质体积:酸性阶段750mL,缓冲阶段1000mL
速度:50rpm
温度:37℃±0.5℃
取液量:10ml
2)溶解介质
I.酸性阶段介质:0.1N HCl;缓冲阶段介质:pH 5.5缓冲液
II.酸性阶段介质:0.1N HCl;缓冲阶段介质:pH 4.5缓冲液
III.酸性阶段介质:0.1N HCl;缓冲阶段介质:pH 3.0缓冲液
3)溶解介质的组成
1)缓冲液pH 5.5
称取1g磷酸二氢钾、2g磷酸氢二钾和8.5g氯化钠并移至1L烧杯中。向其中加入500mL水,溶解盐,用水定容至1000mL。使用正磷酸将pH值调节至pH 5.5(±0.05)。
2)缓冲液pH 4.5-
称取1g磷酸二氢钾、2g磷酸氢二钾和8.5g氯化钠并移至1L烧杯中。向其中加入500mL水,溶解盐,用水定容至1000mL。使用正磷酸将pH值调节至pH 4.5(±0.05)。
3)缓冲液pH 3.0-
称取1g磷酸二氢钾、2g磷酸氢二钾和8.5g氯化钠并移至1L烧杯中。向其中加入500mL水,溶解盐,用水定容至1000mL。使用正磷酸将pH值调节至pH 3.0(±0.05)。
4)溶解步骤
酸性阶段:将精确称重的盐酸苯那普利片剂移至不同的溶解罐中,然后按照上述方法中给出的参数进行溶解试验(酸性阶段)。2小时后,取出10mL等分试样并作为酸性阶段样品溶液进行分析。
缓冲阶段:将在酸性阶段后的片剂移至缓冲阶段介质中。根据上述方法中给出的参数继续进行溶解试验(缓冲阶段)。将每个间隔的等分试样通过0.45μm尼龙膜注射器过滤器过滤,丢弃前几毫升滤液并作为缓冲阶段样品溶液进行分析。
B)色谱分析条件
色谱柱:Agilent Zorbax Eclipse XDB C18色谱柱,150×4.6mm,5μm或同等尺寸
流动相:缓冲液:MeOH(36:64)
波长:240nm
柱温:25℃
进样量:20μL
流速:1mL/min
流动相缓冲液的制备:
将精确称重的2.25g四丁基溴化铵移至500mL水中并溶解。向其中加入0.55mL冰醋酸,用水定容至1000mL。将该缓冲液通过0.45μm尼龙膜过滤器过滤。
2.索他洛尔片剂
A)溶解条件
1)溶解参数
仪器:USP II型
溶解介质:酸性阶段介质2小时,然后是缓冲阶段介质(1小时)
介质体积:酸性阶段750mL,缓冲阶段1000mL
速度:50rpm
温度:37℃±0.5℃
取液量:10ml
2)溶解介质
IV.酸性阶段介质:0.1N HCl;缓冲阶段介质:pH 5.5缓冲液
V.酸性阶段介质:0.1N HCl;缓冲阶段介质:pH 4.5缓冲液
VI.酸性阶段介质:0.1N HCl;缓冲阶段介质:pH 3.0缓冲液
3)溶解介质的组成
1)缓冲液pH 5.5
称取1g磷酸二氢钾、2g磷酸氢二钾和8.5g氯化钠并移至1L烧杯中。向其中加入500mL水,溶解盐,用水定容至1000mL。使用正磷酸将pH值调节至pH 5.5(±0.05)。
2)缓冲液pH 4.5
称取1g磷酸二氢钾、2g磷酸氢二钾和8.5g氯化钠并移至1L烧杯中。向其中加入500mL水,溶解盐,用水定容至1000mL。使用正磷酸将pH值调节至pH 4.5(±0.05)。
3)缓冲液pH 3.0
称取1g磷酸二氢钾、2g磷酸氢二钾和8.5g氯化钠并移至1L烧杯中。向其中加入500mL水,溶解盐,用水定容至1000mL。使用正磷酸将pH值调节至pH 3.0(±0.05)。
4)溶解步骤
酸性阶段:将精确称重的索他洛尔片剂移至不同的溶解罐中,然后按照上述方法中给出的参数进行溶解试验(酸性阶段)。2小时后,取出10mL等分试样并作为酸性阶段样品溶液进行分析。
缓冲阶段:将酸性阶段后的片剂移至缓冲阶段介质中。根据上述方法中给出的参数继续进行溶解试验(缓冲阶段)。每个间隔的等分试样通过0.45μm尼龙膜注射器过滤器过滤,丢弃前几毫升滤液并作为缓冲阶段样品溶液进行分析。
B)色谱分析条件
色谱柱:Agilent Zorbax Eclipse XDB C 18色谱柱,150×4.6mm,5μm或同等尺寸
流动相:缓冲液:ACN(90:10)
波长:238nm
柱温:25℃
进样量:20μL
流速:1.5mL/min
流动相缓冲液的制备:
将精确称重的6.8g正磷酸二氢钾溶于1000mL水中。将该缓冲液通过0.45μm尼龙膜过滤器过滤。
D.总结
表12:本发明实验的性能
#在暴露于0.1N HCl后2小时肠溶保护作用;*45分钟之后药物释放;
缩写:BT:苯那普利片剂;ST:索他洛尔片剂;MgO:氧化镁;MgCO3:碳酸镁;TEC:三乙基柠檬酸盐;cps:厘泊;Qty:量;gm:克
E.核芯制备
1.索他洛尔片剂
实验C1和C2的索他洛尔片剂的组成和制备方法:参照实验I3的核芯制备
2.泮托拉唑小丸
2.1泮托拉唑小丸的组成(药物分层方法)
表13:泮托拉唑小丸的组成
实验编号 | C3 |
成分 | 组成(%w/w) |
NPS 20/25#(707-841μm) | 73.42 |
泮托拉唑钠倍半水合物,等于20%泮托拉唑 | 22.58 |
HPMC 6cps | 4.00 |
水(足量至%w/w固体) | 足量至20.0% |
总计 | 100 |
2.2泮托拉唑小丸制备方法
I.按所需量称重所有成分。
II.使用顶置式搅拌器将HPMC[6cps]溶解在水中,直到获得澄清溶液。
III.将泮托拉唑钠倍半水合物通过40#(400μm)筛过筛,并在持续搅拌期间加入步骤II的溶液中。继续搅拌直至获得澄清溶液。
IV.将步骤III的药物溶液过40#筛,并用于在NPS 20/25#上的药物分层。
表14:泮托拉唑小丸药物分层的通用工艺参数
3.苯那普利小丸
3.1苯那普利(核芯)小丸的组成
表15:实验C4和C5的苯那普利小丸的组成
配方→ | 苯那普利小丸 | 苯那普利小丸 |
实验编号 | C4 | C5 |
成分 | 组成(%w/w) | 组成(%w/w) |
NPS 18/20#(850-1000μm) | 64.05 | .. |
NPS 20/25#(707-841μm) | .. | 64.78 |
苯那普利 | 20.52 | 20.11 |
HPMC[3cps] | 10.33 | 10.12 |
乳糖 | 2.55 | 2.50 |
Aerosil 200 | 2.55 | 2.50 |
水(足量至%w/w固体) | 足量至20% | 足量至25% |
总计 | 100 | 100 |
缩写:
NPS:空白丸芯;HPMC:羟丙基甲基纤维素;cps:厘泊
3.2实验C4和C5的苯那普利小丸制备方法
I.精确称重所有成分。
II.将盐酸苯那普利和乳糖一水合物溶解在足量的纯化水中,持续搅拌。
III.在单独的烧杯中,将HPMC 3cps在搅拌下溶解在纯化水中。
V.将步骤II溶液在搅拌下加入步骤III溶液中。
VI.在搅拌下将步骤IV分散液添加到步骤V溶液中。
VII.将步骤VI悬浮液通过#60目过滤,然后将其用于在NPS上的药物分层。
表16:对比实验C4和C5的苯那普利小丸(核芯)的通用工艺参数
F.包衣
1.对比实验的密封包衣、中间包衣和肠溶包衣的包衣组成
表17:对比实验C1至C5的密封包衣、中间包衣和肠溶包衣的包衣组成
#30%中和;@以1N NaOH溶液的形式使用缩写:ST:索他洛尔片;PP:泮托拉唑小丸;BP:苯那普利小丸;NA:不适用;w.r.t.:关于
2.密封包衣、中间包衣和肠溶包衣的制备方法
2.1密封包衣
2.1.1实验C3的密封包衣制备方法
I.按所需量称重所有成分。
II.使用顶置式搅拌器将HPMC[6cps]溶解在水中,直至获得澄清溶液。
III.在搅拌的同时将滑石缓慢加入到步骤II溶液中,然后使所得悬浮液混合30分钟。
IV.将悬浮液通过40#筛,并用于密封包衣。
表18:对比实验C3的密封包衣的通用工艺参数
2.2中间包衣
2.2.1实验C2的中间包衣制备方法
I.精确称重所有成分。
II.将称重量的滑石在均质器中在纯化水中分散30分钟。
III.将单独制备的柠檬酸溶液加入步骤II分散液中。
V.在单独的玻璃烧杯中,将TEC和Tween 80加入温热的纯化水中直至形成澄清溶液。
VI.然后将步骤V溶液加入步骤II分散液中,在顶置式搅拌器下搅拌10至15分钟。
VIII.在连续搅拌下用步骤IV的溶液将步骤VII的分散液中和以形成具有所需pH的澄清分散液。
IX.将悬浮液通过40#筛,并用于中间包衣。
表19:对比实验C2的中间包衣的通用工艺参数
2.2.2实验C3的中间包衣制备方法
I.按所需量称重所有成分。
II.使用顶置式搅拌器将Pharmacoat 606溶解在纯化水中。
III.将碳酸镁缓慢加入上述溶液中,同时搅拌,然后将所得悬浮液混合30分钟。
IV.将悬浮液通过40#筛,然后用于中间包衣。
表20:对比实验C3的中间包衣的通用工艺参数
2.2.3实验C5中间包衣的制备方法
I.按所需量称重所有成分。
II.将甘油溶解在纯化水中。
III.使用顶置式搅拌器将HPMC(3cps)溶解在步骤II溶液中,直至获得澄清溶液。
IV.在搅拌的同时将氧化镁缓慢添加到上述溶液中,然后使所得悬浮液混合30分钟。
V.将悬浮液过40#筛,并用于药物分层小丸的中间包衣。
2.3肠溶包衣
2.3.1实验C1和C2的肠溶包衣的制备方法
I.称量配方中指定的所有成分。
II.将称重量的滑石在均质器下分散在纯化水中30分钟。
III.在单独的玻璃烧杯中,将TEC加入温热的纯化水中直至形成澄清溶液。
IV.在顶置式搅拌器搅拌下将步骤III溶液加入步骤II分散体中15分钟。
VI.将制备的分散体过40#筛,并用于肠溶包衣。
2.3.2实验C3的肠溶包衣制备方法
I.按所需量称重所有成分。
III.将悬浮液过40#筛,并用于肠溶包衣。
2.3.3实验C4的肠溶包衣制备方法
I.按所需量称重所有成分。
II.将EUDRAGIT L30D-55在搅拌下加入60%量的水中。
III.用部分剩余量的水制备1N氢氧化钠溶液。
IV.在搅拌下将步骤III溶液缓慢加入步骤II溶液中。
V.在剩余量的水中加入TEC和滑石,均化30分钟。
VI.在搅拌下将步骤V分散液加入步骤IV溶液中并继续搅拌20分钟。
VII.将悬浮液过40#筛,并用于中间包衣小丸上的肠溶包衣。
2.3.4实验C5的肠溶包衣的制备方法
I.按所需量称重所有成分。
III.将悬浮液过40#筛,并用于中间包衣小丸的肠溶包衣。
表21(a):对比实验C1和C2的肠溶包衣的通用工艺参数
表21(b):对比实验C3和C4的肠溶包衣的通用工艺参数
G.肠溶包衣的片剂/小丸的分析
分析方法学
1.索他洛尔片剂:参照步骤D(2)中的分析方法学
2.泮托拉唑小丸
A)溶解条件
1)溶解参数
仪器:USP II型
溶解介质:酸性阶段介质2小时,随后缓冲阶段介质(1小时)
介质体积:酸性阶段1000mL,缓冲阶段1000mL
速度:50rpm
温度:37℃±0.5℃
取液量:10ml
样品稀释:立即用2mL 0.5N氢氧化钠溶液稀释10mL等分试样。
2)溶解介质
I.酸性阶段介质:0.1N HCl;缓冲阶段介质:pH 5.5缓冲液
II.酸性阶段介质:0.1N HCl;缓冲阶段介质:pH 4.5缓冲液
3)溶解介质的组成
1)缓冲液pH 5.5
称重1g磷酸二氢钾、2g磷酸氢二钾和8.5g氯化钠并移至1L杯中。向其中加入500mL水,溶解盐,用水定容至1000mL。使用正磷酸将pH值调节至pH 5.5(±0.05)。
2)缓冲液pH 4.5
精确称重2.99g三水合醋酸钠并将其移至1L烧杯中。向其中加入水以溶解并定容至1000mL。使用冰醋酸将pH值调节至pH 4.5(±0.05)。
3)缓冲液pH 3.0
精确称重8.98g无水柠檬酸和2.13g柠檬酸三钠二水合物并移至1000ml水中。进行超声处理以溶解。使用稀释的NaOH将其调节至pH 3.5(±0.05)。
4)溶解步骤
酸性阶段:将精确称重的泮托拉唑小丸移至不同的溶解罐中,然后按照上述方法中给出的参数进行溶解试验(酸性阶段)。2小时后,取出10mL等分试样,通过0.45μm PVDF膜注射器过滤器过滤。将1mL立即用1mL 0.5N氢氧化钠溶液稀释并作为酸性阶段样品溶液进行分析。
缓冲阶段:将酸性阶段后的小丸移至缓冲阶段介质中。根据上述方法中给出的参数继续进行溶解试验(缓冲阶段)。每个间隔的等分试样通过0.45μm PVDF膜注射器过滤器过滤,丢弃前几毫升滤液。将1mL立即用1mL 0.5N氢氧化钠溶液稀释并作为缓冲阶段样品溶液进行分析。
B)色谱分析条件
色谱分析条件
色谱柱:Agilent Zorbax XDB Eclipse C8色谱柱,150×4.6mm,5μm
流动相:水:乙腈:三乙胺(60:40:1),用正磷酸将pH值调节为pH 7.0(±0.05)
波长:290nm
柱温:30℃
进样量:10μL
流速:1.0mL/min
3.苯那普利小丸
A)溶解条件
1)溶解参数
仪器:USP II型
溶解介质:酸性阶段介质2小时,随后缓冲阶段介质(1小时)
介质体积:酸性阶段750mL,缓冲阶段1000mL
速度:50rpm
温度:37℃±0.5℃
取液量:10ml
2)溶解介质
I.酸性阶段介质:0.1N HCl;缓冲阶段介质:pH 5.5缓冲液
II.酸性阶段介质:0.1N HCl;缓冲阶段介质:pH 4.5缓冲液
III.酸性阶段介质:0.1N HCl;缓冲阶段介质:pH 3.0缓冲液
3)溶解介质的组成
1)缓冲液pH 5.5
称重1g磷酸二氢钾、2g磷酸氢二钾和8.5g氯化钠并移至1L杯中。向其中加入500mL水,溶解盐,用水定容至1000mL。使用正磷酸将pH值调节至pH 5.5(±0.05)。
2)缓冲液pH 4.5
称重1g磷酸二氢钾、2g磷酸氢二钾和8.5g氯化钠并移至1L烧杯中。向其中加入500mL水,溶解盐,用水定容至1000mL。使用正磷酸将pH值调节至pH 4.5(±0.05)。
3)缓冲液pH 3.0
称重1g磷酸二氢钾、2g磷酸氢二钾和8.5g氯化钠并移至1L烧杯中。向其中加入500mL水,溶解盐,用水定容至1000mL。使用正磷酸将pH值调节至pH 3.0(±0.05)。
4)溶解步骤
酸性阶段:将精确称重的盐酸苯那普利小丸移至不同的溶解罐中,然后按照上述方法中给出的参数进行溶解试验(酸性阶段)。2小时后,取出10mL等分试样,并作为酸性阶段样品溶液进行分析。
缓冲阶段:将酸性阶段后的小丸移至缓冲阶段介质中。根据上述方法中给出的参数继续进行溶解试验(缓冲阶段)。每个间隔的等分试样通过0.45μm尼龙膜注射器过滤器过滤,丢弃前几毫升滤液,然后作为缓冲阶段样品溶液进行分析。
B)色谱分析条件
色谱柱:Agilent Zorbax XDB Eclipse C8色谱柱,150×4.6mm,5μm或同等尺寸
流动相:缓冲液:MeOH(36:64)
波长:240nm
柱温:25℃
进样量:20μL
流速:1mL/min
流动相缓冲液的制备:
精确称重2.25g四丁基溴化铵,移至500mL水中并溶解。向其中加入0.55mL冰醋酸,用水定容至1000mL。将所述缓冲液通过0.45μm尼龙膜过滤器过滤。
H.总结
表22(a):对比实验C1至C3的性能
#暴露于0.1N HCl后2小时的肠溶保护作用;$暴露于0.1N HCl后1小时的肠溶保护作用;*45分钟后药物释放;@30分钟后药物释放
由于兰索拉唑在pH 5.5、pH 4.5和pH 3.0等较低pH条件下会快速降解,因此在实施例中使用泮托拉唑作为API。
!在肠溶性聚合物构建11.85%(与US 2005214371实施例1类似的构建)时,未获得2小时的肠溶保护作用(在暴露于酸性介质2小时后观察到降解,使用反向测定法评估),因此进一步进行肠溶包衣以达到20%的肠溶性聚合物构建,其在酸暴露2小时后通过肠溶保护作用。
缩写:ST:索他洛尔片;HPMC:羟丙基甲基纤维素;TEC:柠檬酸三乙酯;TiO2:二氧化钛;Qty.:量;gm:克(g)
表22(b):对比实验C4和C5的性能
#暴露于0.1N HCl后2小时的肠溶保护作用;*45分钟后药物释放;
缩写:BP:苯那普利小丸;TEC:柠檬酸三乙酯;NA:不适用;Qty.:数量;gm:克(g)。
Claims (15)
2.根据权利要求1所述的剂型,其中所述生物活性成分的释放在pH 1.2下120分钟为10%或更少,而在pH 3至pH 5.5下45分钟为50%或更多。
3.根据权利要求1或2所述的剂型,其中所述疾病与用于治疗或预防所述疾病的生物活性成分的类别选自如下:胃肠道灌洗剂与轻泻药,炎性肠病与皮质类固醇,高胆固醇血症或高甘油三酯血症与他汀类药物,CHF与糖苷类,心律失常与奎尼丁的立体异构体,癌症与植物生物碱类,细菌感染与抗生素,HIV与核苷类,胰腺功能不全与脂肪酶,重度抑郁症(MDD)或季节性情感障碍(SAD)或辅助戒烟与去甲肾上腺素/多巴胺再摄取抑制剂(NDRI),疼痛或炎症与NSAID,类风湿性关节炎、骨关节炎或强直性脊柱炎与NSAID,帕金森病与多巴胺前体,疟疾与抗疟药,高血压与β受体阻滞剂,糖尿病与双胍类药物,水肿或慢性肾功能不全与苯甲酸磺胺呋喃类药物,轻度至重度心力衰竭、心室射血分数≤40%的心肌梗死后左心室功能不全与β肾上腺素受体阻滞剂,全身性真菌感染与抗真菌药,高脂蛋白血症或高甘油三酯血症与贝特类抗血脂药,心力衰竭与盐皮质激素,癌症与蒽环类抗生素,高血压、心绞痛或丛集性头痛预防与钙通道阻滞剂,以及心房颤动与β受体阻滞剂。
4.根据权利要求1至3中任一项所述的剂型,其中所述疾病与用于治疗或预防所述疾病相关的生物活性成分选自:胃肠道灌洗液和比沙可啶,炎性肠病和布地奈德,高胆固醇血症或高甘油三酯血症和氟伐他汀,CHF和地高辛(digoxin),心律失常和奎尼丁,癌症和依托泊苷,细菌感染和红霉素、青霉素G、氨苄青霉素、链霉素、克拉霉素或阿奇霉素,HIV和双脱氧肌苷(ddI或去羟肌苷)、双脱氧腺苷(ddA)或双脱氧胞嘧啶(ddC)),胰腺功能不全和脂肪酶,重度抑郁症(MDD)或季节性情感障碍(SAD)或辅助戒烟和安非他酮,疼痛和炎症、类风湿性关节炎、骨关节炎或强直性脊柱炎和乙酰水杨酸双氯芬酸或吲哚美辛,帕金森病和左旋多巴,疟疾和硫酸羟氯喹,高血压和阿替洛尔,糖尿病和盐酸二甲双胍,水肿或慢性肾功能不全和苯甲酸磺胺呋喃类药物,轻度至重度心力衰竭、心室射血分数≤40%的心肌梗死后左心室功能不全和呋塞米,全身真菌感染和酮康唑,高脂蛋白血症或高甘油三酯血症和非诺贝特,心力衰竭和醛固酮,癌症和多柔比星,高血压、心绞痛或丛集性头痛预防和维拉帕米,以及心房颤动和索他洛尔。
5.根据权利要求1至4中任一项所述的剂型,其中所述疾病是心房颤动,而用于治疗或预防所述疾病的生物活性成分是索他洛尔。
6.根据权利要求1至5中的一项或多项所述的剂型,其中所述核芯包含分布在基质结构中或结合在内核上的包衣中的粘合剂中的所述生物活性成分。
7.根据权利要求1至6中的一项或多项所述的剂型,其中所述碱剂是碱金属盐或碱土金属盐。
8.根据权利要求1至7中的一项或多项所述的剂型,其中所述碱剂选自氧化钙、碳酸钙、碳酸镁、氧化镁、碳酸钠、碳酸氢钠和氢氧化钠、或其任何组合。
9.根据权利要求1至8中的一项或多项所述的剂型,其中所述碱剂是碳酸镁或氧化镁。
10.根据权利要求1至9中的一项或多项所述的剂型,其中所述中间包衣层进一步包含增塑剂和/或聚合物粘合剂。
11.根据权利要求1至10中的一项或多项所述的剂型,其中所述肠溶包衣层中的肠溶性聚合物选自阴离子(甲基)丙烯酸酯共聚物、阴离子纤维素、阴离子多糖和聚醋酸乙烯邻苯二甲酸酯、或其任何混合物。
12.根据权利要求1至11中的一项或多项所述的剂型,其中所述阴离子(甲基)丙烯酸酯共聚物选自包含甲基丙烯酸和丙烯酸乙酯的聚合单元的共聚物,包含甲基丙烯酸和甲基丙烯酸甲酯的聚合单元的共聚物,以及包含甲基丙烯酸、丙烯酸甲酯和甲基丙烯酸甲酯的聚合单元的共聚物,或其任何混合物。
13.根据权利要求1至12中的一项或多项所述的剂型,其中所述阴离子纤维素选自羧甲基乙基纤维素及其盐,醋酸邻苯二甲酸纤维素,醋酸琥珀酸纤维素,醋酸偏苯三酸纤维素,邻苯二甲酸羟丙基甲基纤维素和醋酸琥珀酸羟丙基甲基纤维素,或其任何混合物。
14.根据权利要求1至13中的一项或多项所述的剂型,其中所述中间包衣层的存在量基于所述核芯的重量计算为5至100重量%,优选7.5至50重量%。
15.根据权利要求1至14中的一项或多项所述的剂型,其中所述肠溶包衣层的存在量基于所述核芯和所述中间层的重量计算为5至50重量%。
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- 2020-09-17 KR KR1020227019198A patent/KR20220113698A/ko unknown
- 2020-09-17 CN CN202080085419.5A patent/CN114786652A/zh active Pending
- 2020-09-17 CA CA3160869A patent/CA3160869A1/en active Pending
- 2020-09-17 WO PCT/EP2020/075962 patent/WO2021115650A1/en unknown
- 2020-09-17 BR BR112022011055A patent/BR112022011055A2/pt unknown
- 2020-09-17 EP EP20774964.9A patent/EP4072532B1/en active Active
- 2020-09-17 JP JP2022535763A patent/JP2023505882A/ja active Pending
- 2020-09-17 US US17/757,043 patent/US11730708B2/en active Active
- 2020-09-17 MX MX2022007161A patent/MX2022007161A/es unknown
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KR20220113698A (ko) | 2022-08-16 |
EP4072532A1 (en) | 2022-10-19 |
EP4072532B1 (en) | 2024-01-24 |
WO2021115650A1 (en) | 2021-06-17 |
MX2022007161A (es) | 2022-07-12 |
BR112022011055A2 (pt) | 2022-08-23 |
JP2023505882A (ja) | 2023-02-13 |
IL293648A (en) | 2022-08-01 |
US20230012981A1 (en) | 2023-01-19 |
CA3160869A1 (en) | 2021-06-17 |
US11730708B2 (en) | 2023-08-22 |
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