CN115697306A - 用于在胃肠道中变时性给药活性成分的包含复合整体式骨架的固体口服组合物 - Google Patents
用于在胃肠道中变时性给药活性成分的包含复合整体式骨架的固体口服组合物 Download PDFInfo
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Abstract
本发明涉及具有活性成分控释的固体口服组合物,其包含由整体式骨架组成的核芯和所述核芯的外部包衣,所述整体式骨架包含低粘度、中等粘度或高粘度羟丙基甲基纤维素或其混合物、羟丙基纤维素(HPC)和一种或多种超崩解剂聚合物,所述外部包衣由包含羟丙基甲基纤维素和/或乙基纤维素的层组成,或由耐胃液层或包含乙基纤维素然后又用耐胃液聚合物包衣的层组成。
Description
本发明涉及具有活性成分控释的固体口服组合物,其包含由整体式骨架组成的核芯和所述核芯的外部包衣,所述整体式骨架包含低粘度、中等粘度或高粘度羟丙基甲基纤维素或其混合物、羟丙基纤维素(HPC)和一种或多种超崩解剂聚合物,所述外部包衣由包含羟丙基甲基纤维素和/或乙基纤维素的层组成,或由耐胃液层或包含乙基纤维素然后又用耐胃液聚合物包衣的层组成。
现有技术
使用具有药理活性的活性成分,无论是真正的药物还是膳食补充剂、保健营养品或植物产品,都需要在体内达到预先确定的活性成分浓度,该浓度必须在所需的时间、在吸收或功能性的特定位点是可以获得的,并且还要考虑身体的昼夜节律。具有特定昼夜节律周期的病症在一天中显示出明显的症状变化,出现高峰和低谷。
能够以适合确保对涉及昼夜节律变化的症状进行最佳治疗的时机释放药物或保健营养品的组合物的设计需要充分理解药物或保健营养品的吸收、分布、代谢和消除。通过利用pH的变化和/或药物/保健营养品在胃肠道中的不同通过时间来实现时间特异性和位点特异性释放。
胃的排空时间可能是高度可变的,这取决于所食用的食物的类型和量,并且空腹pH平均保持在1.2和3.0之间。通过时间为几分钟至几小时。
在小肠中,pH趋于接近中性,并且通过时间更恒定(约3±1小时),而在结肠中,pH值可以在5.5至中性(pH 7.0-7.5)的范围内,并且通过时间在个体与个体之间显著不同,从几小时至24-48小时。
已经描述了基于整体、多颗粒或多单元骨架或储库系统的各种控释制剂。所用技术包括耐胃液延迟系统;缓释系统(简单骨架);单独的pH依赖性释放系统;单独的pH-非依赖性释放系统;脉冲释放系统(立即释放部分与具有简单骨架的缓慢、逐渐控制释放部分组合);延长释放系统(简单的延长释放骨架);以及涉及使用起半透膜作用的包封聚合物的储库系统。
例如,在WO200610640、WO2003101421、WO2009125981和WO2011106416中描述的已知制剂的主要特征在于单组分体系,其中释放控制效果由单一类型的赋形剂决定。这可能导致活性成分在释放位点和随时间推移的释放的精度低,以及体外和体内释放的高度可变性。
常见的延迟形式(耐胃液和/或滞后时间)还可能在胃肠道中在回肠的远端部分和/或结肠的初始部分表现出不稳定的释放,快速释放活性成分而不是在胃肠道、回肠结肠和结肠管道中均匀分布。
WO200400280、WO2010100657、WO200658059和WO200658059报道了含有羟丙基甲基纤维素和丙烯酸聚合物的骨架的实例。US20100285125泛泛地指出了获得含有不同类型的羟丙基甲基纤维素与一种或多种肠溶聚合物的混合物的复合骨架的可能性。然而,其实际上举例说明的制剂的特征却是未与丙烯酸聚合物/共聚物和/或虫胶混合的羟丙基甲基纤维素乙酸酯、琥珀酸酯和邻苯二甲酸酯骨架。
WO2011069076公开了包含片芯的缓释片剂,所述片芯包含两种不同的羟丙基纤维素、羟丙基甲基纤维素、超崩解剂聚合物和甲基丙烯酸聚合物的耐胃液包衣。
EP2468264公开了控释片剂,其包含pH依赖性包衣和由含有两种不同的羟丙基甲基纤维素的亲水性骨架组成的片芯。
发明详述
现已发现,使用由具有不同特性的聚合物/材料的组合组成的复合骨架,通过降低活性成分的施用频率并控制其在胃肠道的特定部位的释放,可以有效地调节活性成分、包括保健营养品的活性。
具体地讲,已经发现使用具有低、中或高粘度的羟丙基甲基纤维素(优选至少两种具有不同粘度的羟丙基甲基纤维素)与羟丙基纤维素(HPC)和超崩解剂共聚物(例如交联羧甲基纤维素钠、羧甲基淀粉钠和交联聚乙烯吡咯烷酮)组合,使得制备克服先前已知制剂的局限性的制剂成为可能。
根据本发明的固体口服控释保健营养品组合物在核芯和所述核芯的外部包衣中包含一种或多种活性成分,其中:
a)核芯由以下组成:
(i)一种整体式骨架,其含有一种或多种活性成分、在20℃下的2%H2O溶液粘度为3至5000mPa.s的羟丙基甲基纤维素和在20℃下的2% H2O溶液粘度为13500至280000mPa.s的羟丙基甲基纤维素,
羟丙基纤维素(HPC)和至少一种或多种超崩解剂聚合物/共聚物,或
(ii)与速释层相邻的如(i)中所定义的整体式骨架,所述速释层包含与所述整体式骨架中所含的活性成分相同的活性成分;
b)包衣由包含羟丙基甲基纤维素和/或乙基纤维素的层组成,或由耐胃液层或包含羟丙基甲基纤维素和/或乙基纤维素然后又用耐胃液聚合物包衣的层组成。
核芯可以由复合整体式骨架(i)组成,或者由与速释层相邻的复合整体式骨架(i)组成的双层系统组成,所述速释层包含与整体式骨架中相同的一种或多种活性成分。
在本发明的另一个实施方案中,包衣b)由包含羟丙基甲基纤维素和/或乙基纤维素的层组成,或由用耐胃液聚合物包衣的包含羟丙基甲基纤维素和/或乙基纤维素的层组成。
骨架中的超崩解剂聚合物优选选自交联羧甲基纤维素钠、羧甲基淀粉钠和交联聚维酮。优选使用两种不同的超崩解剂。所述耐胃液包衣可以是常规类型,并且通常包含在pH≥5.5、pH≥6.0或pH≥7.0下可溶的甲基丙烯酸共聚物,其可在市场上获得(Eudragit,Eudraguard)。优选的组合是聚甲基丙烯酸酯L100与聚甲基丙烯酸酯S100的比例为1:10-10:1(优选1:1)的组合,其在pH≥6.0和pH≥7.0时可溶;或在pH≥5.5时可溶的聚甲基丙烯酸酯L 100/55;或Eudraguard或虫胶;或纤维素乙酰邻苯二甲酸酯/琥珀酸酯。
在本发明的组合物中,羟丙基甲基纤维素占核芯重量的1-40%,羟丙基纤维素占核芯重量的1-30%,超崩解剂的聚合物/共聚物和/或混合物占核芯重量的0.1-20%。超崩解剂聚合物优选选自交联聚维酮、交联羧甲基纤维素和羧甲基淀粉钠。
具有低、中和高粘度的羟丙基甲基纤维素可以不同的商品名(例如Methocel或Hypromellose)K3LV、K100 LV、K250、K750、K1500、K4M、K15M、K35M、K100M、K200M在市场上获得。
所述核芯含有两种具有不同粘度的羟丙基甲基纤维素,更优选在20℃下的2%H2O溶液粘度为3至5000mPa.s的羟丙基甲基纤维素和在20℃下的2%H2O溶液粘度为13500至280000mPa.s的羟丙基甲基纤维素,其百分比范围为所述核芯重量的1%至30%,优选5%。
乙基纤维素以核芯重量的1%至20%的百分比存在于核芯-包衣层中;优选3-10%。
骨架核芯可包含常规赋形剂,例如稀释剂(微晶纤维素、淀粉、糖)、粘合剂(PVP、淀粉、纤维素、糊精、麦芽糖糊精、低粘度纤维素)、助流剂(胶体二氧化硅、滑石)、润滑剂(硬脂酸镁、富马酰硬脂酸酯、硬脂酸)和其它功能赋形剂(蜡、聚卡波非、卡波姆、甘油酯)。
该骨架经分割直接压片、干法制粒、压制、湿法制粒、熔融挤出工艺制备而成。
然后可以用含有pH依赖性聚合物的耐胃液性膜包衣所得骨架/迷你骨架,所述pH依赖性聚合物在<1.2-5.5的pH条件下防止释放至少2小时。以下可用于此目的:在pH≥5.5下可溶的pH依赖性甲基丙烯酸共聚物(L 100-55/L 30D-55);在pH 6.0-7.0下可溶的pH依赖性甲基丙烯酸共聚物(L 100/L 12.5);在pH≥7.0下可溶的pH依赖性甲基丙烯酸共聚物(S 100/S 12.5/FS 30D);虫胶;邻苯二甲酸乙酸纤维素;琥珀酸纤维素、甲基丙烯酸共聚物和淀粉(Eudraguard Control,Protect,Natural,GRS,Biotic)。
在第三阶段,可以用非pH依赖性聚合物(具有不同粘度的乙基纤维素或羟丙基甲基纤维素)进行核芯包衣,该核芯包衣可替代和/或附加于并且位于耐胃液包衣之下,所述非pH依赖性聚合物在与生物流体接触后起到延迟加载到骨架/迷你骨架核芯中的成分通过的膜的作用(Nutrateric,Surelease,NS Enteric)。
用足够量的聚合物包衣骨架,以保证在活性成分从核芯释放之前,骨架在胃和肠液中保持完整至少2-4小时(滞后时间)。为了减少可变的胃排空时间的影响,可以在(非pH依赖性)骨架核芯外部和(非pH依赖性)纤维素膜包衣外部应用另外的(pH依赖性)耐胃液包衣,以进一步延迟生物流体与调控释放核芯之间的接触(延长释放)。
通过这种方式,该系统防止了在胃-空肠通过期间的过早释放,启动持续长达24小时的调控释放程序,并确保活性成分在十二指肠、回肠和远端回肠中以及在大肠的上升、横向和下降通道中的均匀分布。
羟丙基纤维素(HPC)和/或具有不同流变/功能特性(粘度/溶胀性质)的超崩解剂聚合物与羟丙基甲基纤维素的组合使用可以调控释放4至24小时。如果需要,调节的、控释的核芯可以与速释层组合(双层和/或三层骨架/迷你骨架);这样设计的系统给出“治疗等效”或不同水平的治疗功效的结果。
可根据本发明有利地配制的通常被认为是营养保健品的活性成分的实例包括硫酸软骨素、乳铁蛋白、泛醇、槲皮素、白藜芦醇、α-硫辛酸、S-腺苷甲硫氨酸(SAMe)、葡糖胺、绿茶、辅酶Q10、植物甾醇、黄酮类化合物、肌酸、N-乙酰半胱氨酸、谷胱甘肽、牛磺酸、番茄红素、叶黄素、玉米黄质、虾青素、维生素D、维生素E、维生素A、维生素K、谷维素、异黄酮和褪黑激素。也可使用常用的药物如抗炎药、镇痛药、抗生素、对中枢神经系统有活性的药物、抗病毒药、抗糖尿病药、降血糖药、免疫药、肠胃药、肿瘤药和心血管药、抗组胺药、抗抑郁药、单克隆抗体、支气管扩张药、抗真菌药和抗风湿药等。
本发明的制剂特别适合于优化由于大量每日给药和副作用而在依从性方面具有不利特征的营养保健品的吸收、释放位点和效果。
在以下实施例中详细描述本发明。
实施例1
将16.65Kg硫酸软骨素与3Kg羟丙基纤维素(HPC)和7.5Kg微晶纤维素一起装入制粒机中。
用5% PVP溶液(200g)将混合物制粒。干燥颗粒,然后依次加入8.3Kg羟丙基甲基纤维素(HPMC K100lv)、8.3Kg羟丙基甲基纤维素(HPMC K4M)和1.1Kg羟丙基甲基纤维素(HPMC K100M)。
混合这些成分,直至获得活性成分在骨架中的均匀分散体;然后依次加入100g硬脂酸镁、100g滑石、100g交联PVP和100g交联羧甲基纤维素。
然后将混合物均化至少15分钟。该混合物将形成片剂的第一控释层部分。
第二台制粒机中装入硫酸软骨素16.65g,加入磷酸钙2.5Kg、微晶纤维素1Kg、交联聚维酮1.16Kg、硬脂酸镁100g、滑石粉100g。
然后将混合物均化至少15分钟。该混合物将形成片剂的第二速释层部分。然后将两种单独的混合物压制得到重量为681.2mg的双层片剂。
然后用基于1.7Kg HPMC 5Premium、800g滑石、230g二氧化钛和150g柠檬酸三乙酯的溶液/混悬液对所得片剂进行膜包衣,得到平均重量为710mg的片剂。
当在pH≥6.4的条件下进行崩解和溶出试验时,片剂表现出以下释放曲线:60分钟后不超过60%,在pH为7.2时,240分钟后不超过70%,480分钟后不超过80%;24小时后该值必须>80%。
实施例2
将20Kg乳铁蛋白与5Kg羟丙基纤维素(HPC)、5Kg微晶纤维素、100g交联PVP和100g交联羧甲基纤维素一起装入制粒机中。
用5% PVP溶液(200g)将混合物制粒。干燥颗粒,然后依次加入8Kg羟丙基甲基纤维素(HPMC K4M)。
混合这些成分,直至获得活性成分在骨架中的均匀分散体;然后依次加入150g硬脂酸镁和200g滑石。然后将混合物压片得到重量为386.5mg的片剂。然后用含有3.2Kg虫胶(总计800g 25%溶液)、650g滑石、300g二氧化钛、150g柠檬酸三乙酯和1.45Kg HPMC E5Premium的耐胃液溶液/混悬液对所得片剂进行膜包衣,得到平均重量为420mg的片剂。
当在pH 1下进行崩解和溶出试验时,片剂保持完整至少2小时,释放低于1%;当在pH≥6.4进行溶出试验时,它们的释放低于10%;当在pH≥7.2下进行溶出试验时,它们表现出以下释放曲线:60分钟后不超过20%,240分钟后不超过60%,480分钟后不超过80%;24小时后该值必须≥90%。
实施例3
将20Kg泛醇与6.65Kg羟丙基纤维素(HPC)、22Kg微晶纤维素、150g交联PVP和150g交联羧甲基纤维素一起装入制粒机中。然后依次加入10Kg羟丙基甲基纤维素(HPMC K4M)和1Kg羟丙基甲基纤维素(HPMC K100M)。
混合这些成分,直至获得活性成分在骨架中的均匀分散体,然后依次加入150g硬脂酸镁和250g滑石。然后将混合物均化至少15分钟。
将混合物均化至少20分钟,然后压片,得到重量为603.5mg的片剂。
然后用基于750g聚甲基丙烯酸酯(Eudraguard Biotic)、500g滑石、200g二氧化钛和200g柠檬酸三乙酯的耐胃液溶液/混悬液对所得片剂进行膜包衣,得到平均重量为620mg的片剂。
当在pH 1.2下进行崩解和溶出试验时,片剂保持完整至少2小时,释放低于1%;当在pH≥6.4进行溶出试验时,它们的释放低于1%;当在pH≥7.2下进行溶出试验时,它们表现出以下释放曲线:60分钟后不超过60%,240分钟后不超过75%,480分钟后不超过85%;24小时后该值必须>90%。
实施例4
将20Kg槲皮素与6.65Kg羟丙基纤维素(HPC)、22Kg微晶纤维素、150g交联PVP和150g交联羧甲基纤维素一起装入制粒机中。
然后依次加入4Kg羟丙基甲基纤维素(HPMC K15M)和4Kg羟丙基甲基纤维素(HPMCK100M)。
混合这些成分,直至获得活性成分在骨架中的均匀分散体,然后依次加入150g硬脂酸镁和250g滑石。
将混合物均化至少20分钟,然后压片,得到重量为573.5mg的片剂。
然后用基于750g聚甲基丙烯酸酯(Eudraguard Biotic)、500g滑石、200g二氧化钛和200g柠檬酸三乙酯的耐胃液溶液/混悬液对所得片剂进行膜包衣,得到平均重量为590mg的片剂。
当在pH 1.2下进行崩解和溶出试验时,片剂保持完整至少2小时,释放低于1%;当在pH≥6.4进行溶出试验时,它们的释放≤1%;当在pH≥7.2下进行溶出试验时,它们表现出以下释放曲线:60分钟后不超过60%,240分钟后不超过75%,480分钟后不超过85%;24小时后该值必须>90%。
实施例5
将12.5Kg白藜芦醇与3.55Kg羟丙基纤维素(HPC)和12Kg微晶纤维素一起装入制粒机中。
然后依次加入10Kg羟丙基甲基纤维素(HPMC K 4M)和2.5Kg羟丙基甲基纤维素(HPMC K100M)。
混合这些成分,直至获得活性成分在骨架中的均匀分散体;然后依次加入150g硬脂酸镁、250g滑石、125g交联聚维酮(交联的PVP)和125g交联羧甲基纤维素。
然后将混合物均化至少25分钟。该混合物将形成片剂的第一控释层部分,重412mg。
将12.5Kg白藜芦醇装入第二个制粒机中,加入5.25Kg磷酸钙、750g微晶纤维素、1.25Kg交联聚维酮、1.25Kg交联羧甲基纤维素、150g硬脂酸镁和250g滑石。然后将混合物均化至少15分钟。该混合物将形成片剂的第二速释层部分,重214mg。然后将两种单独的混合物压制,得到重量为650mg的双层片剂。
然后用基于1.5Kg聚甲基丙烯酸酯(Eudraguard Control)、500g滑石、200g二氧化钛和200g柠檬酸三乙酯的溶液/混悬液对所得片剂进行膜包衣,得到平均重量为649.5mg的片剂。
对片剂进行崩解和溶出试验;当在pH≥6.4下进行溶出试验时,它们表现出以下释放曲线:60分钟后不超过60%,在pH为7.2时240分钟后不超过70%,480分钟后不超过80%;24小时后该值必须>80%。
实施例6
将3.75Kgα-硫辛酸与200g微晶纤维素和125g羟丙基纤维素(HPC)一起装入制粒机中。
然后依次加入250g羟丙基甲基纤维素(HPMC K4M)、125g羟丙基甲基纤维素(HPMCK15M)、30g交联聚维酮和30g交联羧甲基纤维素。
混合这些成分,直至获得活性成分在骨架中的均匀分散体,然后将混合物用含有150g聚乙烯吡咯烷酮(5%)的水溶液制粒。
干燥后,依次加入10g胶体二氧化硅、30g硬脂酸镁和15g滑石。然后将混合物均化至少15分钟。
该混合物将形成迷你片的第一控释层部分。
将3.75Kgα-硫辛酸与200g微晶纤维素、335g交联聚维酮、335g交联羧甲基纤维素、30g硬脂酸镁和75g滑石一起加入第二个制粒机中,并均匀混合。
然后将混合物均化至少20分钟。该混合物将形成迷你片的第二速释层部分。
然后将两种单独的混合物压制,得到重量为94.5mg的5mm双层迷你片。
然后用含有750g HPMC E5 Premium、200g滑石和100g柠檬酸三乙酯的溶液/混悬液对所得迷你片进行膜包衣,得到平均重量为105mg的迷你片。
当在pH 1下进行崩解和溶出试验时,片剂保持完整至少2小时,释放≤1%;当在pH≥6.4进行溶出试验时,片剂在60分钟后释放不超过50%;当在pH≥7.2下进行溶出试验时,它们表现出以下释放曲线:60分钟后不超过70%;240分钟后不超过80%,480分钟后不超过90%;24小时后该值必须>90%。
实施例7
将1.56Kg S-腺苷-甲硫氨酸(SAMe)与1.225Kg微晶纤维素和500g羟丙基纤维素(HPC)一起装入制粒机中。
然后依次加入225g羟丙基甲基纤维素(HPMC K4M)、225g羟丙基甲基纤维素(HPMCK15M)、20g交联聚维酮和20g氨基乙醇酸钠。混合这些成分,直至获得活性成分在骨架中的均匀分散体。然后依次加入13g硬脂酸镁和22.5g滑石。然后将混合物均化至少15分钟。
该混合物将形成迷你片的第一控释层部分。
将1.56Kg SAMe装入第二制粒机。
加入500g微晶纤维素、225g磷酸钙、225g交联聚维酮、225g交联羧甲基纤维素、13g硬脂酸镁和27g滑石并均匀混合。
然后将混合物均化至少20分钟。该混合物将形成迷你片的第二速释层部分。
然后将两种单独的混合物压制,得到重量为65.9mg的4mm双层迷你片。
然后用14.9g HPMC 5Premium、165.6g滑石、29g柠檬酸三乙酯和200g虫胶(25%)的溶液对所得迷你片进行膜包衣,得到平均重量为70mg的迷你片。
当在pH 1进行溶出试验和在pH≥6.0进行溶出试验时,片剂表现出以下释放曲线:60分钟后不超过60%,240分钟后不超过75%,480分钟后不超过85%;24小时后该值必须≥90%。
实施例8
将3.125Kg葡糖胺与1.225Kg微晶纤维素和500g羟丙基纤维素(HPC)一起装入制粒机中。
然后依次加入225g羟丙基甲基纤维素(HPMC K4M)、225g羟丙基甲基纤维素(HPMCK 200M)、20g交联聚维酮和20g交联羧甲基纤维素。混合这些成分,直至获得活性成分在骨架中的均匀分散体。然后依次加入13g硬脂酸镁和22.5g滑石。然后将混合物均化至少15分钟。
该混合物将形成迷你片的第一控释层部分。
将3.125Kg葡糖胺加入第二个制粒机中。
加入500g微晶纤维素、225g磷酸二钙、225g交联聚维酮、225g交联羧甲基纤维素、13g硬脂酸镁和27g滑石并均匀混合。然后将混合物均化至少20分钟。
该混合物将形成迷你片的第二速释层部分。
然后将两种单独的混合物压片以获得重量为97.155mg的4mm双层迷你片。
然后用15.5g HPMC 5Premium、40g滑石、29g柠檬酸三乙酯、200g聚甲基丙烯酸酯(Eudraguard Biotic)和虫胶(25%)的溶液对所得迷你片进行膜包衣,得到平均重量为100mg的迷你片。
当在pH 1进行溶出试验和在pH≥6.0进行溶出试验时,片剂表现出以下释放曲线:60分钟后不超过60%,240分钟后不超过75%,480分钟后不超过85%;24小时后该值必须≥90%。
实施例9
将15Kg绿茶与4.65Kg羟丙基纤维素(HPC)和7.5Kg微晶纤维素一起装入制粒机中
然后依次加入1.1Kg羟丙基甲基纤维素(HPMC K 100lv)、1.1Kg羟丙基甲基纤维素(HPMC K 200M),10g交联聚维酮和10g交联羧甲基纤维素。
混合这些成分,直至获得活性成分在骨架中的均匀分散体,然后依次加入100g硬脂酸镁和100g滑石。然后将混合物均化至少20分钟。该混合物将形成片剂的第一控释层部分。
将15Kg绿茶装入第二制粒机中,并加入2.5Kg磷酸二钙、1Kg微晶纤维素、1.16Kg交联聚维酮、1.16Kg交联羧甲基纤维素、100g硬脂酸镁和100g滑石。
然后将混合物均化至少15分钟。该混合物将形成片剂的第二速释层部分。
然后将两种单独的混合物压片得到重量为522.4mg的双层片剂。
然后用含有1.66Kg HPMC E5 Premium、800g滑石、200g二氧化钛和100g柠檬酸三乙酯的溶液/混悬液对所得片剂进行膜包衣,得到平均重量为550mg的片剂。
当在pH 1下进行崩解和溶出试验时,片剂保持完整至少2小时,释放低于1%;在pH≥6.4时,它们在60分钟后释放≤10%;在pH 7.2下,60分钟后释放≤50%;240分钟后释放≤60%,480分钟后释放不超过80%;18小时后该值必须>90%。
实施例10
将20Kg辅酶Q10与4Kg羟丙基纤维素(HPC)、10Kg微晶纤维素一起装入制粒机中。
然后依次加入1.1Kg羟丙基甲基纤维素(HPMC K 100lv)、1.1Kg羟丙基甲基纤维素(HPMC K 200M),10g交联羧甲基纤维素和10g交联聚维酮。
混合这些成分,直至获得活性成分在骨架中的均匀分散体,然后依次加入150g硬脂酸镁和200g滑石。然后将混合物均化至少15分钟。然后将混合物压制得到重量为379mg的片剂。
然后用含有700g Nutrateric、280g滑石、300g二氧化钛和150g柠檬酸三乙酯的溶液/混悬液对所得片剂进行膜包衣,得到平均重量为380mg的片剂。
当在pH 1下进行崩解和溶出试验时,片剂保持完整至少2小时,释放低于1%;在pH≥6.4时,它们显示出低于10%的释放;当在pH≥7.2下进行溶出试验时,它们表现出以下释放曲线:60分钟后不超过20%,240分钟后不超过60%,480分钟后不超过80%;18小时后该值必须≥90%。
实施例11
将20Kg植物甾醇与2.25Kg羟丙基纤维素(HPC)和7.425Kg微晶纤维素一起装入制粒机中。
然后依次加入4.5Kg羟丙基甲基纤维素(HPMC K 100lv)、4.5Kg羟丙基甲基纤维素(HPMC K200M)、10g交联聚维酮和10g交联羧甲基纤维素。
混合这些成分,直至获得活性成分在骨架中的均匀分散体,然后依次加入150g硬脂酸镁和250g滑石。
将混合物均化至少20分钟,然后将混合物压片得到重量为390.95mg的片剂。
然后用含有700g Nutrateric、305g滑石、200g二氧化钛和200g柠檬酸三乙酯的溶液/混悬液对所得片剂进行膜包衣,得到平均重量为405mg的片剂。
当在pH 1下进行崩解和溶出试验时,片剂保持完整至少2小时,释放低于1%;在pH≥6.4时,它们在60分钟后释放≤10%;在pH 7.2下,60分钟后释放≤60%;240分钟后释放≤60%,480分钟后释放不超过80%;18小时后该值必须>90%。
实施例12
将20Kg黄酮类化合物与2.25Kg羟丙基纤维素(HPC)和7.425Kg微晶纤维素一起装入制粒机中。向同一体系中依次加入5.5Kg羟丙基甲基纤维素(HPMC K 100lv)、3.5Kg羟丙基甲基纤维素(HPMC K200M)、10g交联聚维酮和10g交联羧甲基纤维素。
混合这些成分,直至获得活性成分在骨架中的均匀分散体,然后依次加入150g硬脂酸镁和250g滑石。
将混合物均化至少20分钟,然后将混合物压片得到重量为390.95mg的片剂。然后用含有840g Nutrateric、200g滑石、200g二氧化钛和200g柠檬酸三乙酯的溶液/混悬液对所得片剂进行膜包衣,得到平均重量为405mg的片剂。
当在pH 1下进行崩解和溶出试验时,片剂保持完整至少2小时,释放低于1%;在pH≥6.4时,它们在60分钟后释放≤10%;在pH 7.2下,60分钟后释放≤60%;240分钟后释放≤60%,480分钟后释放不超过80%;18小时后该值必须>90%。
实施例13
将13.75Kg肌酸与2.25Kg羟丙基纤维素(HPC)和12Kg微晶纤维素一起装入制粒机中。
然后依次加入5Kg羟丙基甲基纤维素(HPMC K 100lv)、5Kg羟丙基甲基纤维素(HPMC K 200M)、10g交联羧甲基纤维素和10g羧甲基淀粉钠。
混合这些成分,直至获得活性成分在骨架中的均匀分散体,然后依次加入150g硬脂酸镁和250g滑石。然后将混合物均化至少15分钟。
该混合物将形成片剂的第一控释层部分。
将13.75Kg肌酸装入第二个制粒机中,并加入4Kg磷酸二钙、750g微晶纤维素、1.25Kg交联聚维酮、1.25Kg交联羧甲基纤维素、150g硬脂酸镁和250g滑石。
然后将混合物均化至少20分钟。该混合物将形成片剂的第二速释层部分。
然后将两种单独的混合物压片得到重量为598.2mg的双层片剂。
然后用含有2.4Kg聚甲基丙烯酸酯(Eudraguard Control)、350g滑石、200g二氧化钛和200g柠檬酸三乙酯的溶液/混悬液对所得片剂进行膜包衣,得到平均重量为630mg的片剂。
当在pH 1下进行崩解和溶出试验时,片剂保持完整至少2小时,释放低于1%;在pH≥6.4时,它们在60分钟后释放≤5%;在pH 7.2下,60分钟后释放≤45%;240分钟后释放≤60%,480分钟后释放不超过85%;18小时后该值必须>90%。
实施例14
将7.5Kg N-乙酰半胱氨酸与1.225Kg微晶纤维素一起装入制粒机中。
然后依次加入325g羟丙基纤维素(HPC)、250g羟丙基甲基纤维素(HPMC K100lv)、125g羟丙基甲基纤维素(HPMC K15M)、30g交联聚维酮和30g交联羧甲基纤维素。
混合这些成分,直至获得活性成分在骨架中的均匀分散体,然后将混合物用含有150g聚乙烯吡咯烷酮(5%)的水溶液制粒。
干燥后,依次加入30g硬脂酸镁、10g滑石和10g胶体二氧化硅。将混合物均化至少15分钟,然后将混合物压片以获得重96.9mg的5mm迷你片。
然后用含有630g HPMC E5 Premium、20g滑石、100g二氧化钛和60g柠檬酸三乙酯的溶液/混悬液对所得迷你片进行膜包衣,得到平均重量为105mg的迷你片。
当在pH 1下进行崩解和溶出试验时,迷你片保持完整至少2小时,释放低于1%;在pH≥6.4时,它们在60分钟后释放≤10%;在pH 7.2下,60分钟后释放≤60%;240分钟后释放≤70%,480分钟后释放不超过85%;18小时后该值必须>90%。
实施例15
将3.125Kg谷胱甘肽与1.3Kg微晶纤维素一起装入制粒机中。
然后依次加入325g羟丙基纤维素(HPC)、225g羟丙基甲基纤维素(HPMC K100lv)、225g羟丙基甲基纤维素(HPMC K15M)、20g交联聚维酮和20g羧甲基淀粉钠。
混合这些成分,直至获得活性成分在骨架中的均匀分散体。
然后依次加入13g硬脂酸镁和47g滑石。将混合物均化至少15分钟,然后将混合物压片,得到4mm直径的重91mg的迷你片。
然后用含有710mg聚甲基丙烯酸酯(Eudraguard Control)、10g滑石、75g二氧化钛和15g柠檬酸三乙酯的溶液/混悬液对所得片剂进行膜包衣,得到平均重量为100mg的迷你片。
当在pH 1下进行崩解和溶出试验时,迷你片保持完整至少2小时,释放低于1%;在pH≥6.4时,它们在60分钟后释放≤10%;在pH 7.2下,60分钟后释放≤60%;240分钟后释放≤70%,480分钟后释放不超过85%;18小时后该值必须>90%。
实施例16
将6.250Kg牛磺酸与1.225Kg微晶纤维素一起装入制粒机中。
然后依次加入500g羟丙基纤维素(HPC)、225g羟丙基甲基纤维素(HPMC K100lv)、225g羟丙基甲基纤维素(HPMC K15M)、20g交联聚维酮和20g交联羧甲基纤维素。
混合这些成分,直至获得活性成分在骨架中的均匀分散体。
然后依次加入13g硬脂酸镁和47g滑石。将混合物均化至少15分钟,然后将混合物压片,得到4mm直径的重91mg的迷你片。
然后用含有834mg聚甲基丙烯酸酯(Eudraguard Control)、90g滑石、75g二氧化钛和15g柠檬酸三乙酯的溶液/混悬液对所得迷你片进行膜包衣,得到平均重量为90mg的迷你片。
当在pH 1下进行崩解和溶出试验时,迷你片保持完整至少2小时,释放低于1%;在pH≥6.4时,它们在60分钟后释放≤10%;在pH 7.2下,60分钟后释放≤60%;240分钟后释放≤70%,480分钟后释放不超过85%;18小时后该值必须>90%。
下表总结了实施例1-16的定性和定量组成。
表1-实施例1-5的片剂
表2-实施例6-8的迷你片
α-硫辛酸8迷你片5mm=600mg
SAMe 8迷你片4mm=250mg
葡糖胺8迷你片5mm=500mg
表3-实施例9-13的片剂
表4-实施例14-16的迷你片
N-乙酰半胱氨酸8迷你片5mm=600mg
谷胱甘肽8迷你片4mm=250mg
牛磺酸8迷你片5mm=500mg
比较例1-与WO 2011069076的制剂的比较
图1和2显示了代表根据WO 2011069076的实施例7-16、19-21、23、25和27的多奈哌齐制剂的溶出曲线,其中根据本发明的制剂的特征在于存在两种不同的超崩解剂:交联羧甲基纤维素钠和交联聚维酮,每片的量为0.5或1mg。从图1和2中可以推导出的结果表明,与WO 2011069076制剂相比,两种超崩解剂的存在产生无突释效应的释放和在溶出曲线中更相似的行为。
比较例2-与根据EP2468264的制剂的比较
图3和4显示了代表根据EP2468264的实施例1-3的美沙拉嗪制剂的溶出曲线,其中根据本发明的制剂的特征在于存在两种不同的超崩解剂:交联羧甲基纤维素钠和交联聚维酮,每片的量为6、8或10mg。从图3和4中可以推导出的结果表明,与EP2468264的制剂相比,两种超崩解剂的存在产生明显更小的可变性(RSD值)和行为的线性。
Claims (14)
1.一种控释固体口服药物组合物,其在核芯和所述核芯的外包衣中包含一种或多种活性成分,其特征在于:
a)核芯由以下组成:
(i)包含一种或多种活性成分的整体式骨架、在20℃下的2%H2O溶液粘度为3至5000mPa.s的羟丙基甲基纤维素和在20℃下的2%H2O溶液粘度为13500至280000mPa.s的羟丙基甲基纤维素,
羟丙基纤维素(HPC)和至少两种超崩解剂聚合物/共聚物;
或
与速释层相邻的如(i)中所定义的整体式骨架,所述速释层包含与所述整体式骨架中所含的活性成分相同的活性成分;
(ii)包衣由包含羟丙基甲基纤维素和/或乙基纤维素的层组成,或由耐胃液层或包含羟丙基甲基纤维素和/或乙基纤维素然后又用耐
胃液聚合物包衣的层组成。
2.根据权利要求1所述的组合物,其中的核芯由权利要求1的(i)中所定义的整体式骨架组成。
3.根据权利要求1所述的组合物,其中所述核芯由与速释层相邻的如权利要求1中所定义的整体式骨架组成,所述速释层包含与所述整体式骨架中包含的活性成分相同的活性成分。
4.根据权利要求1至3中任一项所述的组合物,其中所述包衣由包含乙基纤维素的层组成。
5.根据权利要求1至3中任一项所述的组合物,其中所述包衣由用耐胃液聚合物包衣的包含羟丙基甲基纤维素和/或乙基纤维素的层组成。
6.根据权利要求1至3中任一项所述的组合物,其中所述包衣由耐胃液层组成。
7.根据权利要求1至6中一项或多项所述的组合物,其中所述丙烯酸/甲基丙烯酸聚合物或共聚物选自非pH依赖性甲基丙烯酸酯共聚物、非pH依赖性铵烷基甲基丙烯酸酯共聚物;在pH最高为5.0时可溶的氨基烷基甲基丙烯酸酯共聚物、在pH≥5.5下可溶的甲基丙烯酸共聚物、在pH 6.0-7.0下可溶的甲基丙烯酸共聚物;在pH≥7.0下可溶的pH依赖性甲基丙烯酸共聚物。
8.根据权利要求1至7中一项或多项所述的组合物,其中所述耐胃液包衣包含在pH≥5.5下可溶的pH依赖性甲基丙烯酸共聚物;在pH 6.0-7.0下可溶的pH依赖性甲基丙烯酸共聚物;在pH≥7.0下可溶的pH依赖性甲基丙烯酸共聚物;甲基丙烯酸聚合物和淀粉、虫胶;乙酰邻苯二甲酸纤维素;纤维素琥珀酸酯。
9.根据权利要求1至8中一项或多项所述的组合物,其中羟丙基甲基纤维素占核芯重量的1至40%。
10.根据权利要求1至9中一项或多项所述的组合物,其中羟丙基纤维素占核芯重量的0.1至30%。
11.根据权利要求1至10中一项或多项所述的组合物,其含有两种超崩解剂聚合物,所述超崩解剂聚合物选自交联聚维酮、交联羧甲基纤维素和羧甲基淀粉钠。
12.根据权利要求11所述的组合物,其中超崩解剂聚合物以核芯重量的0.1至20%的百分比存在。
13.根据前述权利要求中一项或多项所述的组合物,其中羟丙基甲基纤维素和/或乙基纤维素以核芯重量的1至20%的百分比存在。
14.根据权利要求1至13中一项或多项所述的组合物,其中所述活性成分选自硫酸软骨素、乳铁蛋白、泛醇、槲皮素、白藜芦醇、α-硫辛酸、S-腺苷甲硫氨酸(SAMe)、葡糖胺、绿茶、辅酶Q10、植物甾醇、黄酮类化合物、肌酸、N-乙酰半胱氨酸、谷胱甘肽、牛磺酸、番茄红素、叶黄素、玉米黄质、虾青素、维生素D、维生素E、维生素A、维生素K、谷维素、异黄酮和褪黑激素。
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PCT/IB2021/053983 WO2021229419A1 (en) | 2020-05-14 | 2021-05-11 | Solid oral compositions comprising composite monolithic matrices for chronotropic administration of active ingredients in the gastrointestinal tract |
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