CN108601745B - 口服考来烯胺制剂及其用途 - Google Patents
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- CN108601745B CN108601745B CN201780010725.0A CN201780010725A CN108601745B CN 108601745 B CN108601745 B CN 108601745B CN 201780010725 A CN201780010725 A CN 201780010725A CN 108601745 B CN108601745 B CN 108601745B
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- cholestyramine
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Abstract
本发明涉及用于将考来烯胺靶向递送至结肠的口服制剂,其包含用扩散‑控制的内包衣和肠溶外包衣涂覆的多个考来烯胺丸剂。本发明还涉及该制剂治疗胆汁酸吸收不良的用途。
Description
本发明涉及用于将考来烯胺靶向递送至结肠的口服制剂,其包含用扩散-控制的内包衣和肠溶外包衣涂覆的多个考来烯胺丸剂。本发明还涉及该制剂治疗胆汁酸吸收不良的用途。
背景技术
胆汁酸吸收不良是一种特征在于结肠中胆汁酸过量的病症,通常导致慢性腹泻。胆汁酸是在肝脏中合成和缀合的类固醇酸。从肝脏,它们通过胆道系统排出到小肠中,在那里它们参与饮食脂质和脂溶性维生素的溶解和吸收。当它们到达回肠时,胆汁酸被重新吸收到门脉循环中并返回肝脏。一小部分分泌的胆汁酸在回肠中不被重新吸收并到达结肠。在此,细菌作用导致胆汁酸的去缀合和脱羟基化,产生次级胆汁酸脱氧胆酸盐和石胆酸盐。
在结肠中,胆汁酸(特别是脱羟基胆汁酸鹅脱氧胆酸盐和脱氧胆酸盐)刺激电解质和水的分泌。这增加了结肠运动性并缩短了结肠运输时间。如果过量存在,胆汁酸会产生腹泻,伴有其他胃肠道症状,如腹胀、尿急和大便失禁。最近在理解胆汁盐或胆汁酸吸收不良或BAM的这种情况方面取得了一些进展(Pattni和Walters,Br.Med.Bull.2009,vol 92,p.79-93;Islam和Di Baise,Pract.Gastroenterol.2012,vol.36(10),p.32-44)。根据回肠末端无法吸收胆汁酸的原因,胆汁酸吸收不良可分为1型、2型和3型BAM。
在用增加胆汁酸产生和/或影响小肠对胆汁酸重吸收的药物治疗后,例如用回肠胆汁酸吸收(IBAT)抑制剂治疗,大肠中高浓度胆汁酸也可导致腹泻。
目前对胆汁酸吸收不良的治疗旨在结合胃肠道中过量的胆汁酸,从小肠的近端部分开始,从而减少胆汁酸的分泌作用。为此目的,考来烯胺通常被用作胆汁酸螯合剂。考来烯胺(或考来烯胺;CAS Number 11041-12-6)是强碱性阴离子交换树脂,其实际上不溶于水并且不从胃肠道吸收。相反,它吸收并与肠中的胆汁酸结合形成不溶性复合物。胆汁酸与树脂结合后形成的复合物在粪便中排泄。由此通过肝肠循环阻止胆汁酸的正常再吸收,导致胆固醇向胆汁酸的转化增加,以代替从再吸收中除去的胆汁酸。这种转化主要通过降低低密度脂蛋白(LDL)-胆固醇来降低血浆胆固醇浓度。
考来烯胺也可用作降血脂药,用于治疗高胆固醇血症、II型高脂蛋白血症和2型糖尿病。它还用于缓解与回肠切除术、克罗恩病、迷走神经切断术,糖尿病迷走神经病和放射有关的腹泻,以及用于治疗胆汁淤积患者的瘙痒症。
在目前的高脂血症和腹泻治疗中,口服考来烯胺剂量为每日12至24g,以单剂量或以至多4个分剂量给药。在瘙痒症的治疗中,通常4至8克的剂量就足够了。可以在3至4周内逐渐摄入考来烯胺,以最小化胃肠道效应。最常见的副作用是便秘,而其他胃肠道副作用是腹胀、腹部不适和疼痛、胃灼热、胃肠胀气和恶心/呕吐。由于胆汁中胆固醇浓度增加,胆结石的风险增加。高剂量可通过干扰脂肪的胃肠道吸收和伴随的脂溶性维生素吸收减少而导致脂肪痢。慢性给药可导致由于与维生素K缺乏相关的低凝血酶原血症导致的出血倾向增加,或者可由于钙和维生素D吸收受损而导致骨质疏松症。还偶尔有皮疹和舌头、皮肤和肛周区域瘙痒的报告。由于味道和质地差以及各种副作用,>50%的患者在12个月内停止治疗。
使用考来烯胺的当前治疗的另一个缺点是该药物减少了伴随施用的其他药物的吸收,例如雌激素、噻嗪类利尿剂、地高辛和相关生物碱、洛哌丁胺,保泰松,巴比妥酸盐、甲状腺激素、华法林和一些抗生素。因此,建议在给予考来烯胺后至少1小时之前或4至6小时之后服用其他药物。可能仍然需要对同时服用的药物进行剂量调整。
鉴于这些副作用,如果考来烯胺可以被配制成结肠释放制剂,即用于在结肠近端部分释放考来烯胺,则是理想的。这样的制剂可需要较低剂量的考来烯胺,并且应该具有更好的关于质地和味道的特性,因此可以被患者更好地耐受。更重要的是,考来烯胺的结肠释放应该避免与其他药物产生相互作用,并且不应该诱导脂肪和脂溶性维生素吸收不良的风险,同时仍然结合胆汁酸以减少结肠分泌和运动性的增加。出于患者顺应性的原因,如果要服用的药丸数量可以保持尽可能少,则也是理想的。因此,每个药丸应含有尽可能多的考来烯胺。
EP 1273307公开了用于预防胆汁酸腹泻的制剂,其包含以聚合物包衣的胆汁酸吸附剂,以允许胆汁酸吸附剂在从小肠下部到盲肠的区域周围释放。显示用HPMCAS-HF或乙基纤维素包衣的考来烯胺颗粒在模拟胃环境的条件下显示出明显的膨胀和破裂。
Jacobsen等人(Br.Med.J.1985,vol.290,p.1315-1318)描述了一项研究,其中接受回肠切除术的患者被给予500mg用邻苯二甲酸乙酸纤维素包衣的考来烯胺片剂(每日12片)。在该研究中的14名患者中有5名,片剂在所需的地方没有崩解。
尽管在该领域取得了进展,但仍需要进一步改进的考来烯胺制剂。特别是,需要将考来烯胺靶向递送至结肠的口服制剂。
附图简述
图1显示了模拟胃和小肠pH的测定中制剂A、B和C的螯合曲线。图1A显示了在pH5.5下6小时内制剂A、B和C的结果。图1B显示在pH 1下2小时,然后在pH 6.8下4小时的结果。图1C显示在pH 1下2小时,然后在pH 7.4下4小时的结果。
发明详述
已经发现可以获得小且稳定的考来烯胺丸剂,并且这些丸剂可以涂覆有防止丸剂在到达结肠之前释放的包衣层。小的考来烯胺丸剂和结肠释放丸剂的组合允许考来烯胺的剂量减少至例如每天两次,每次1.5克。据信该剂量的考来烯胺足以结合结肠中过量的胆汁酸。本发明公开的组合物进一步减少了考来烯胺与胃肠道中的其他组分(例如其他药物或营养素)的不期望的相互作用。
在一方面,本发明涉及用于将考来烯胺靶向递送至结肠的口服制剂,包含:
a)包含考来烯胺的多个丸剂;
b)围绕所述丸剂的扩散-控制的内包衣;和
c)肠溶外包衣,
且其中多于70%的考来烯胺在结肠中释放。
该包衣层基本上防止了考来烯胺在到达结肠之前从丸剂中释放。
优选地,多于75%的考来烯胺在结肠中释放,如多于80%,或如多于85%。更优选地,多于90%的考来烯胺在结肠中释放。
在另一方面,本发明涉及用于将考来烯胺靶向递送至结肠的口服制剂,包含:
a)包含考来烯胺的多个丸剂;
b)围绕所述丸剂的扩散-控制的内包衣;和
c)肠溶外包衣,
且其中少于30%的考来烯胺在小肠中释放。
优选地,少于25%的考来烯胺在小肠中释放,如少于20%,或如少于15%。更优选地,少于10%的考来烯胺在小肠中释放。
丸剂的考来烯胺含量应尽可能高。未包衣的丸剂因此优选包含至少70%w/w考来烯胺,更优选至少75%w/w考来烯胺,更优选至少80%w/w考来烯胺,还更优选至少85%w/w考来烯胺,且最优选至少90%w/w考来烯胺。
在另一方面,本发明涉及用于将考来烯胺靶向递送至结肠的口服制剂,包含:
a)多个丸剂,其包含考来烯胺和
i.至少7%w/w的基于乙烯基吡咯烷酮的聚合物;或
ii.至少6%w/w的基于乙烯基吡咯烷酮的聚合物和至少2%w/w的丙烯酸酯共聚物的组合;或
iii.至少5%w/w的基于乙烯基吡咯烷酮的聚合物和至少3%w/w的丙烯酸酯共聚物的组合;或
iv.至少6%w/w的基于乙烯基吡咯烷酮的聚合物、至少1%w/w的丙烯酸酯共聚物和至少10%w/w微晶纤维素的组合;或
v.至少5%w/w的基于乙烯基吡咯烷酮的聚合物、至少2%w/w的丙烯酸酯共聚物和至少20%w/w微晶纤维素的组合;
b)围绕所述丸剂的扩散-控制的内包衣;和
c)肠溶外包衣。
在一个实施方案中,多于70%的考来烯胺在结肠中释放,优选多于75%,如多于80%,或如多于85%。更优选地,多于90%的考来烯胺在结肠中释放。
在另一实施方案中,少于30%的考来烯胺在小肠中释放,优选少于25%,如少于20%,或如少于15%。更优选地,少于10%的考来烯胺在小肠中释放。
特定量的基于乙烯基吡咯烷酮的聚合物或基于乙烯基吡咯烷酮的聚合物和丙烯酸酯共聚物的组合在丸剂组合物中的存在使得可以具有高考来烯胺含量。所得丸剂足够稳定,能够承受将包衣层施加到丸剂上所必需的条件。
扩散-控制的内包衣和肠溶外包衣基本上防止考来烯胺从丸剂中释放,直到它们到达大肠,特别是近端结肠。另外,包衣可防止丸剂破裂。当通过包衣扩散的水被考来烯胺吸收时,考来烯胺的体积增加导致丸剂膨胀。丸剂的扩散-控制的内包衣是弹性的,因此能够承受丸剂的膨胀。因此,包衣防止了丸剂的破裂和考来烯胺的过早释放。
由于其溶解度非常低,考来烯胺不会从制剂中“释放”,因为它从制剂溶解出来并扩散到肠中。相反,考来烯胺可保留在包衣丸剂逐渐降解的结构内。因此,如本发明所用,术语考来烯胺的“释放”是指考来烯胺对肠内容物的可得性,以便结合其中的组分(即胆汁酸)。
丸剂
如本发明所述,术语“丸剂”是指挤出丸剂,即通过挤出和滚圆获得的丸剂。挤出的丸剂的制备通常包括以下步骤:将粉末与液体混合以得到湿物质,挤出湿物质,将挤出物滚圆并干燥湿丸剂。
重要的是丸剂足够稳定以在处理过程中,例如在将丸剂干燥和包衣期间,承受机械应力。丸剂的稳定性可以根据脆碎性表示,脆碎性是固体物质(例如片剂、颗粒、球体或丸剂)例如,通过磨损、破裂或变形减少到较小的碎片的能力。低程度的脆碎性意味着固体物质仅在低程度上破碎成较小的碎片。如本发明所用,脆碎性定义为当丸剂经受机械应变(例如翻滚、振动、流化等)时发生的丸剂质量的减少。用于测量脆碎性的方法是本领域已知的(例如,European Pharmacopoeia 8.0,测试2.9.7或2.9.41)。
实验已表明,与上述规定相比,加入较少量的基于乙烯基吡咯烷酮的聚合物和/或丙烯酸酯共聚物,可以使丸剂具有更低的屈服性(yield)和更高的脆碎性。尽管通常不能确定丸剂的可接受的脆碎性限度,但据报道<1.7%w/w脆碎性的脆碎性值可承受与流化床包衣、处理和其他过程相关的应力(Vertommen和Kinget,Drug Dev.Ind.Pharm.1997,vol.23,p.39-46)。对于本发明的考来烯胺丸剂,已发现2.1%的脆碎性仍是可接受的。脆碎性优选低于2.0%,更优选低于1.5%,甚至更优选低于1.0%。
丸剂中的基于乙烯基吡咯烷酮的聚合物可为聚乙烯吡咯烷酮(聚维酮)或乙烯基吡咯烷酮-乙酸乙烯酯共聚物(共聚维酮)。聚乙烯吡咯酮为由N-乙烯基吡咯烷酮制备的线性、水溶性聚合物。共聚维酮(也称为copolyvidone)为1-乙烯基-2-吡咯烷酮(聚维酮)和乙酸乙烯酯以6:4的质量比例的线性、水溶性共聚物。在一个优选实施方案中,所述基于乙烯基吡咯烷酮的聚合物为共聚维酮。
丸剂中的丙烯酸酯共聚物可为任何包含丙烯酸酯单体的药物可接受的共聚物。丙烯酸酯单体的实例包括,但不限于,丙烯酸酯(丙烯酸)、丙烯酸甲酯、丙烯酸乙酯、甲基丙烯酸(甲基丙烯酸酯)、甲基丙烯酸甲酯、甲基丙烯酸丁酯、甲基丙烯酸三甲基铵基乙基酯和甲基丙烯酸二甲基氨基乙基酯。多种丙烯酸酯共聚物作为商品名是已知的。
聚(丙烯酸乙酯-共聚-甲基丙烯酸甲酯-共聚-甲基丙烯酸三甲基铵基乙基酯氯化物)为丙烯酸乙酯、甲基丙烯酸甲酯和低含量的甲基丙烯酸三甲基铵基乙基酯氯化物(具有季铵基团的甲基丙烯酸酯)的共聚物。该共聚物也称为甲基丙烯酸铵酯共聚物。其不溶但铵盐基团的存在使得该共聚物可渗透。该共聚物可作为1:2:0.2混合物(A型)或1:2:0.1混合物(B型)获得。A型和B型的30%水性分散体分别以商品名RL 30D和RS 30D销售。
7:3:1的聚(丙烯酸甲酯-共聚-甲基丙烯酸甲酯-共聚-甲基丙烯酸)为丙烯酸甲酯、甲基丙烯酸甲酯和甲基丙烯酸的共聚物。其不溶于酸性介质但在高于pH 7.0通过形成盐而溶解。30%水性分散体以商品名FS 30D销售。
优选的丙烯酸酯共聚物为7:3:1的甲基丙烯酸铵酯共聚物、聚(丙烯酸甲酯-共聚-甲基丙烯酸甲酯-共聚-甲基丙烯酸)和1:1的聚(甲基丙烯酸-共聚-丙烯酸乙酯)。更优选地,丙烯酸酯聚合物为甲基丙烯酸铵酯共聚物,且最优选丙烯酸酯聚合物为1:2:0.2的聚(丙烯酸乙酯-共聚-甲基丙烯酸甲酯-共聚-甲基丙烯酸三甲基铵基乙基酯氯化物)。
在一个实施方案中,所述丸剂包含考来烯胺和
i.至少7%w/w的基于乙烯基吡咯烷酮的聚合物;或
ii.至少6%w/w的基于乙烯基吡咯烷酮的聚合物和至少2%w/w的丙烯酸酯共聚物的组合。
在更优选实施方案中,所述丸剂包含考来烯胺和
i.至少7%w/w共聚维酮;或
ii.至少6%w/w共聚维酮和至少2%w/w甲基丙烯酸铵酯共聚物的组合。
该丸剂可进一步包含赋形剂如微晶纤维素。在一个实施方案中,所述丸剂包含0至20%w/w微晶纤维素,如0至10%w/w微晶纤维素。在更优选实施方案中,该丸剂包含0至5%w/w微晶纤维素。
在另一实施方案中,所述丸剂不含微晶纤维素。
在一个实施方案中,所述丸剂包含70至92%w/w考来烯胺、6至12%w/w的基于乙烯基吡咯烷酮的聚合物、2至5%w/w的丙烯酸酯共聚物和0至20%w/w微晶纤维素。更优选地,该丸剂包含80至92%w/w考来烯胺、6至12%w/w的基于乙烯基吡咯烷酮的聚合物、2至5%w/w的丙烯酸酯共聚物和0至5%w/w微晶纤维素。
在另一实施方案中,所述丸剂包含70至92%w/w考来烯胺、6至12%w/w共聚维酮、2至5%w/w甲基丙烯酸铵酯共聚物和0至20%w/w微晶纤维素。更优选地,该丸剂包含80至92%w/w考来烯胺、6至12%w/w共聚维酮、2至5%w/w甲基丙烯酸铵酯共聚物和0至5%w/w微晶纤维素。
在另一实施方案中,所述丸剂包含70至93%w/w考来烯胺、7至12%w/w的基于乙烯基吡咯烷酮的聚合物和0至20%w/w微晶纤维素。更优选地,该丸剂包含70至93%w/w考来烯胺、7至12%w/w共聚维酮和0至20%w/w微晶纤维素。
在另一实施方案中,所述丸剂包含80至93%w/w考来烯胺、7至12%w/w的基于乙烯基吡咯烷酮的聚合物和0至10%w/w微晶纤维素。更优选地,该丸剂包含80至93%w/w考来烯胺、7至12%w/w共聚维酮和0至10%w/w微晶纤维素。
未包衣的丸剂在水性条件下迅速崩解。然而,它们足够稳定以承受将结肠释放包衣施加到丸剂上所需的条件。
扩散-控制的包衣
扩散控制的内包衣提供考来烯胺的改良释放,即考来烯胺不能立即获得但是在延长的时间段内可获得。该包衣包含一种或多种在任何pH值下都不溶但是对于水和溶解在其中的小分子是可渗透的聚合物。该聚合物的实例包括,但不限于,1:2:0.2的聚(丙烯酸乙酯-共聚-甲基丙烯酸甲酯-共聚-甲基丙烯酸三甲基铵基乙基酯氯化物)(RL30D)、1:2:0.1的聚(丙烯酸乙酯-共聚-甲基丙烯酸甲酯-共聚-甲基丙烯酸三甲基铵基乙基酯氯化物)(RS 30D)、2:1的聚(丙烯酸乙酯-共聚-甲基丙烯酸甲酯)(NE 30D或NM 30D)和聚乙酸乙烯酯(SR 30D)。扩散-控制的内包衣优选包含1:2:0.2的聚(丙烯酸乙酯-共聚-甲基丙烯酸甲酯-共聚-甲基丙烯酸三甲基铵基乙基酯氯化物)(RL 30D)、1:2:0.1的聚(丙烯酸乙酯-共聚-甲基丙烯酸甲酯-共聚-甲基丙烯酸三甲基铵基乙基酯氯化物)(RS 30D)或其组合,且最优选1:2:0.1的聚(丙烯酸乙酯-共聚-甲基丙烯酸甲酯-共聚-甲基丙烯酸三甲基铵基乙基酯氯化物)。
当考来烯胺吸收水时,考来烯胺的体积增加导致颗粒膨胀。因此,扩散-控制的内包衣应是弹性的(即,具有高的断裂伸长率)。由于包衣的弹性,包衣能够承受这种膨胀。由此避免了丸剂的破裂和考来烯胺的过早释放。包衣的弹性可以是有机聚合物本身的弹性的结果,或者可以通过添加增塑剂来诱导。合适的增塑剂的实例包括柠檬酸三乙酯、三乙酸甘油酯、柠檬酸三丁酯、邻苯二甲酸二乙酯、柠檬酸乙酰基三丁酯、邻苯二甲酸二丁酯和癸二酸二丁酯。
肠溶包衣
肠溶包衣包含pH-敏感性聚合物,其在胃中的酸性pH值(pH~1-3)下稳定且不溶,但在酸性较弱的pH值(例如在小肠中的pH值(pH~6至7))下迅速分解或变得可溶。这种pH-敏感性聚合物的实例包括,但不限于,邻苯二甲酸乙酸纤维素、乙酸琥珀酸纤维素、乙酸琥珀酸羟丙基甲基纤维素、邻苯二甲酸羟丙基甲基纤维素、1:1的聚(甲基丙烯酸-共聚-甲基丙烯酸甲酯)(L 100)、1:2的聚(甲基丙烯酸-共聚-甲基丙烯酸甲酯)(S100)、1:1聚(甲基丙烯酸-共聚-丙烯酸乙酯)(L 100-55)、7:3:1的聚(丙烯酸甲酯-共聚-甲基丙烯酸甲酯-共聚-甲基丙烯酸)(FS 30D)、聚乙烯基乙酸邻苯二甲酸酯、虫胶、藻酸钠和玉米蛋白、以及它们的混合物。肠溶包衣优选包含选自以下的pH-敏感性聚合物:1:1的聚(甲基丙烯酸-共聚-甲基丙烯酸甲酯)、乙酸琥珀酸羟丙基甲基纤维素和1:2的聚(甲基丙烯酸-共聚-甲基丙烯酸甲酯)。肠溶包衣最优选包括乙酸琥珀酸羟丙基甲基纤维素。
扩散控制的包衣和肠溶包衣可包括一种或多种添加剂,如酸和碱、增塑剂、助流剂和表面活性剂。合适的酸的实例包括有机酸如柠檬酸、乙酸、三氟乙酸、丙酸、琥珀酸、乙醇酸、乳酸、苹果酸、酒石酸、抗坏血酸、扑酸、马来酸、羟基马来酸、苯基乙酸、谷氨酸、苯甲酸、水杨酸、甲磺酸、乙磺酸、苯磺酸、磺胺酸、2-乙酰氧基苯甲酸、富马酸、甲苯磺酸、甲磺酸、乙二磺酸和草酸、和无机酸如盐酸、氢溴酸、硫酸、氨基磺酸、磷酸和硝酸。合适的碱的实例包括无机碱如碳酸氢钠、氢氧化钠和氢氧化铵。合适的增塑剂的实例包括柠檬酸三乙酯、三乙酸甘油酯、柠檬酸三丁酯、邻苯二甲酸二乙酯、柠檬酸乙酰基三丁酯、邻苯二甲酸二丁酯和癸二酸二丁酯。合适的助流剂的实例包括滑石、单硬脂酸甘油酯、油酸、中链甘油三酯和胶体二氧化硅。合适的表面活性剂的实例包括十二烷基硫酸钠、聚山梨酯80和单油酸脱水山梨醇酯。
为了改善包衣层在考来烯胺丸剂上的粘附性,或者为了使包衣层和丸剂中的考来烯胺之间的相互作用最小化,可以在丸剂和包衣层之间任选存在另外的屏障涂层。当两个不同的包衣层应保持彼此物理分离时,也可以存在屏障涂层。用于屏障涂层的特别合适的材料是羟丙基甲基纤维素(HPMC)。
最终可以将薄的不粘剂层施加到包衣的丸剂上。该外层防止包衣的丸剂粘在一起,例如,在储存期间。合适的不粘剂的实例包括气相二氧化硅(fumed silica)、滑石和硬脂酸镁。
所述包衣层在一起基本上防止了考来烯胺在到达大肠之前从丸剂中释放。此外,由于在扩散-控制的内包衣中聚合物的性质,考来烯胺仅在几小时的时间内缓慢地供大肠使用。优选地,在小肠中不应暴露考来烯胺,而一旦多颗粒通过回盲瓣,暴露应该很快。在一个实施方案中,少于30%的考来烯胺在小肠中释放,如少于20%,如少于10%。在更优选实施方案中,少于5%的考来烯胺在小肠中释放。在另一实施方案中,多于70%的考来烯胺在结肠中释放,如多于80%,如多于90%。在更优选实施方案中,多于95%的考来烯胺在结肠中释放。
所述包衣层进一步增加了丸剂的重量和体积。丸剂尺寸越小,包衣对最终制剂体积的影响越大。然而,出于患者顺应性的原因,希望制剂的总体积保持尽可能低。因此包衣层应尽可能薄。优选地,最终制剂中的包衣量(基于干重)小于40%w/w,更优选小于35%w/w。
丸剂的考来烯胺含量应尽可能高。未包衣的丸剂因此优选包含至少70%w/w考来烯胺,更优选至少75%w/w考来烯胺,更优选至少80%w/w考来烯胺,还更优选至少85%w/w考来烯胺,且最优选至少90%w/w考来烯胺。最终制剂的考来烯胺含量(基于干重)优选至少为50%w/w,且更优选至少55%w/w。
丸剂的尺寸最初由挤出步骤中使用的筛网的直径决定。在挤出和滚圆步骤之后,可以将丸剂过筛以获得具有窄尺寸分布的丸剂级分。未包衣的考来烯胺丸剂的直径优选为500μm至3000μm,更优选750μm至2000μm,还更优选1000至1600μm。在最优选实施方案中,丸剂的直径为1000至1400μm。
考来烯胺丸剂可通过包括以下步骤的方法制备:
i)混合该干燥的成分;
ii)添加水,且任选添加丙烯酸酯共聚物,以得到湿物质;
iii)将湿物质挤出;
iv)滚圆该挤出物;和
v)干燥所得丸剂。
干燥丸剂可被随后筛分以得到均匀尺寸的丸剂。
步骤i)中的干燥成分包括考来烯胺和基于乙烯基吡咯烷酮的聚合物,且可任选包含微晶纤维素。
由于其物理性质,考来烯胺粉末能够吸收大量的水,这导致材料相当大的膨胀。因此,为了从干燥的考来烯胺制备湿物质,需要添加比通常用于从干燥成分制备湿物质的水更多的水。优选地,将水添加到干燥成分的混合物中,其量为考来烯胺的量的至少1.5倍(w/w),更优选为考来烯胺量的至少1.75倍(w/w),还更优选考来烯胺量的至少2倍(w/w)。
可以通过本领域已知的方法将包衣施加到考来烯胺丸剂上,例如通过涉及穿孔锅和流化床的薄膜包衣。
本发明所述的口服制剂可以以不同的形式给予患者,这取决于诸如患者的年龄和一般身体状况等因素。例如,制剂可以以一种或多种胶囊的形式给药,在胶囊中含有包衣的丸剂。这种胶囊通常包含可降解材料,例如明胶、羟丙基甲基纤维素(HPMC)、支链淀粉或淀粉,它们在胃中的酸性条件下易于崩解。由此将包衣的丸剂快速释放到胃中。因此,一方面,本发明涉及包含本发明公开的口服制剂的胶囊。
或者,包衣的丸剂可以作为喷洒(sprinkle)制剂给药,其内容物可以分散在液体或软食品中。这样的制剂不需要吞咽较大的胶囊,因此特别适用于婴儿和小孩以及老年人。因此,在另一方面,本发明涉及包含本发明公开的口服制剂的喷洒制剂。在这样的制剂中,包衣的丸剂可以包含在胶囊、囊剂(sachet)或棒状包装中。
本发明公开的口服制剂提供了优于其它制剂的几个优点。根据本发明的小包衣丸剂(多颗粒)能够容易地通过胃肠道。这消除了制剂暂时滞留在胃肠道(例如胃或回盲瓣中)中的风险,如整体制剂(例如不在胃中崩解的片剂或胶囊)有时会遇到的那样。此外,只有当扩散控制的内包衣开始在下胃肠道特别是结肠中降解时,考来烯胺才对肠内容物可得。因此,胃和小肠的内容物有效地避开了考来烯胺,这是相对直接在胃或小肠中释放考来烯胺的制剂的主要改进。
考来烯胺在水性环境中的低溶解度防止考来烯胺从待直接测量的制剂中释放。相反,可以在体外测定考来烯胺对肠内容物随时间和在不同pH值下的可得性,例如通过测量在胃肠道的模拟条件下制剂的螯合能力(sequestering capacity)。这种方法包括测量代表胃肠道的液体介质中游离胆汁酸(即待螯合的化合物)的减少量。还可参见考来烯胺树脂的官方专着(USP40,第3404页)。
在另一方面,本发明涉及本发明公开的制剂,其用于治疗或预防胆汁酸吸收不良。
本发明还涉及本发明公开的制剂在制备用于治疗或预防胆汁酸吸收不良的药物中的用途。本发明进一步涉及治疗或预防胆汁酸吸收不良的方法,包括向需要该治疗或预防的哺乳动物给药治疗有效量的本发明公开的制剂。
胆汁酸吸收不良可分为三种不同类型,这取决于回肠末端吸收胆汁酸失败的原因。1型BAM是(末端)回肠疾病(如克罗恩病)或(末端)回肠切除或旁路的结果。2型BAM通常被称为特发性胆汁酸吸收不良或原发性胆汁酸腹泻(BAD),并且被认为是胆汁酸过量产生的结果或由肝胆汁酸合成的缺陷性反馈抑制引起。该反馈调节是由人体中的回肠激素成纤维细胞生长因子19(FGF19)介导。最后,3型BAM可以是胆囊切除术、迷走神经切断术、小肠细菌过度生长(SIBO)、乳糜泻、胰腺功能不全(慢性胰腺炎、囊性纤维化)、胰腺移植、放射性肠炎,胶原性结肠炎,显微镜结肠炎,淋巴细胞性结肠炎,溃疡性结肠炎或肠易激综合征(即以腹泻为主的肠易激综合征(IBS-D))。
该制剂也可以与回肠胆汁酸吸收(IBAT)抑制剂组合使用。用IBAT抑制剂治疗,例如治疗肝脏疾病、脂肪酸代谢紊乱或葡萄糖利用障碍,可导致胆汁酸水平升高和/或影响小肠对胆汁酸的重吸收,导致在大肠中高浓度的胆汁酸,且因此引起腹泻。用IBAT抑制剂治疗的这种副作用可以通过用本发明公开的制剂治疗来治疗或预防。该制剂和IBAT抑制剂可以同时、依次或分开给药。
因此,在另一方面,本发明涉及本发明公开的制剂,其用于在口服给药IBAT抑制剂后治疗或预防腹泻。
本发明还涉及本发明公开的制剂在制备用于在口服给药IBAT抑制剂后治疗或预防腹泻的药物中的用途。本发明进一步涉及在口服给药IBAT抑制剂后治疗或预防腹泻的方法,包括向需要该治疗或预防的哺乳动物给予治疗有效量的IBAT抑制剂和本发明公开的制剂。
在一个优选实施方案中,本发明涉及本发明公开的制剂,其用于在治疗肝疾病,如胆汁淤积性肝疾病后治疗或预防胆汁酸腹泻,包括口服给药IBAT抑制剂。特别是,本发明涉及本发明公开的制剂,其用于在治疗Alagilles综合征(ALGS)、进行性家族性肝内胆汁淤积(PFIC)、原发性胆汁性肝硬变(PBC)、原发性硬化性胆管炎(PSC)、自身免疫肝炎、胆汁淤积性瘙痒、非酒精性脂肪性肝疾病(NAFLD)或非酒精性脂肪性肝炎(NASH)后治疗或预防腹泻,包括口服给药IBAT抑制剂。
在另一实施方案中,本发明涉及在治疗肝疾病(包括口服给药IBAT抑制剂)后治疗或预防胆汁酸腹泻的方法,包括向需要该治疗或预防的哺乳动物给予治疗有效量的本发明公开的制剂。特别是,本发明涉及用于治疗或预防腹泻的这种方法,其中肝疾病为Alagilles综合征(ALGS)、进行性家族性肝内胆汁淤积(PFIC)、原发性胆汁性肝硬变(PBC)、原发性硬化性胆管炎(PSC)、自身免疫肝炎、胆汁淤积性瘙痒、非酒精性脂肪性肝疾病(NAFLD)或非酒精性脂肪性肝炎(NASH)。
本发明定义的肝脏疾病是肝脏和与其连接的器官中的任何胆汁酸依赖性疾病,例如胰腺、门静脉、肝实质、肝内胆道系统、肝外胆道系统和胆囊。肝病包括但不限于遗传性肝脏代谢紊乱;胆汁酸合成的先天性缺陷;先天性胆管异常;胆道闭锁;新生儿肝炎;新生儿胆汁淤积;遗传性胆汁淤积形式;脑腱黄瘤病;BA合成的次要缺陷;Zellweger综合征;囊性纤维化(肝脏中的表现);α1-抗胰蛋白酶缺乏症;Alagilles综合征(ALGS);Byler综合征;胆汁酸(BA)合成的主要缺陷;进行性家族性肝内胆汁淤积症(PFIC),包括PFIC-1、PFIC-2、PFIC-3和非特异性PFIC;良性复发性肝内胆汁淤积症(BRIC),包括BRIC1、BRIC2和非特异性BRIC;自身免疫性肝炎;原发性胆汁性肝硬化(PBC);肝纤维化;非酒精性脂肪性肝病(NAFLD);非酒精性脂肪性肝炎(NASH);门静脉高压症;一般性胆汁淤积;妊娠期黄疸;药物引起的黄疸;肝内胆汁淤积;肝外胆汁淤积;原发性硬化性胆管炎(PSC);胆结石和胆总管结石;导致胆道系统阻塞的恶性肿瘤;胆汁淤积或黄疸引起的瘙痒;胰腺炎;导致进行性胆汁淤积的慢性自身免疫性肝病;肝脏脂肪变性;酒精性肝炎;急性脂肪肝;妊娠期脂肪肝;药物诱导的肝炎;铁过载症;肝纤维化;肝硬化;淀粉样变性;病毒性肝炎;和由于肝脏、胆道和胰腺的肿瘤和赘生物引起的胆汁淤积有关的问题。
脂肪酸代谢障碍和葡萄糖利用障碍包括但不限于高胆固醇血症、血脂异常、代谢综合征、肥胖症、脂肪酸代谢障碍、葡萄糖利用障碍、涉及胰岛素抵抗的障碍、以及1型和2型糖尿病。
IBAT抑制剂通常用不同的名称来表示。如本发明所用,术语“IBAT抑制剂”应理解为还包括文献中已知的化合物,如顶端钠依赖性胆汁酸转运体抑制剂(ASBTI),胆汁酸转运体(BAT)抑制剂、回肠钠/胆汁酸协同转运蛋白系统抑制剂、顶端钠-胆汁酸协同转运体抑制剂、回肠钠依赖性胆汁酸转运体抑制剂、胆汁酸再吸收抑制剂(BARI)和胆汁酸钠转运体(SBAT)抑制剂。
可与本发明公开的胆汁酸螯合剂制剂组合使用的IBAT抑制剂包括,但不限于,苯并硫氮杂环庚三烯、苯并硫杂环庚三烯、1,4-苯并硫氮杂环庚三烯、1,5-苯并硫氮杂环庚三烯和1,2,5-苯并硫杂二氮杂环庚三烯。
可与本发明公开的胆汁酸螯合剂制剂组合使用的IBAT抑制剂的合适的实例包括,但不限于,WO 93/16055、WO 94/18183、WO 94/18184、WO 96/05188、WO 96/08484、WO 96/16051、WO 97/33882、WO 98/03818、WO 98/07449、WO 98/40375、WO 99/35135、WO 99/64409、WO 99/64410、WO 00/47568、WO00/61568、WO 00/38725、WO 00/38726、WO 00/38727、WO 00/38728、WO 00/38729、WO 01/68096、WO 02/32428、WO 03/061663、WO 2004/006899、WO 2007/009655、WO 2007/009656、DE 19825804、EP 864582、EP 489423、EP 549967、EP573848、EP 624593、EP 624594、EP 624595、EP 624596、EP 0864582、EP 1173205和EP1535913公开的化合物。
特别合适的IBAT抑制剂为WO 01/66533、WO 02/50051、WO 03/022286、WO 03/020710、WO 03/022825、WO 03/022830、WO 03/091232、WO 03/106482和WO 2004/076430公开的那些,尤其是选自以下的化合物:
1,1-二氧代-3,3-二丁基-5-苯基-7-甲基硫基-8-(N-{(R)-α-[N-(羧基甲基)氨基甲酰基]苄基}氨基甲酰基甲氧基)-2,3,4,5-四氢-1,2,5-苯并硫杂二氮杂环庚三烯;
1,1-二氧代-3,3-二丁基-5-苯基-7-甲基硫基-8-(N-{(R)-α-[N'-((S)-1-羧基乙基)氨基甲酰基]苄基}氨基甲酰基甲氧基)-2,3,4,5-四氢-1,5-苯并硫氮杂环庚三烯;
1,1-二氧代-3,3-二丁基-5-苯基-7-甲基硫基-8-(N-{(R)-α-[N-((S)-1-羧基丙基)氨基甲酰基]苄基}氨基甲酰基甲氧基)-2,3,4,5-四氢-1,2,5-苯并硫杂二氮杂环庚三烯;
1,1-二氧代-3,3-二丁基-5-苯基-7-甲基硫基-8-(N-{(R)-α-[N-((R)-1-羧基-2-甲基硫基乙基)氨基甲酰基]苄基}氨基甲酰基甲氧基)-2,3,4,5-四氢-1,2,5-苯并硫杂二氮杂环庚三烯;
1,1-二氧代-3,3-二丁基-5-苯基-7-甲基硫基-8-(N-{(R)-α-[N-((S)-1-羧基丙基)氨基甲酰基]-4-羟基苄基}氨基甲酰基甲氧基)-2,3,4,5-四氢-1,2,5-苯并硫杂二氮杂环庚三烯;
1,1-二氧代-3,3-二丁基-5-苯基-7-甲基硫基-8-(N-{(R)-α-[N-((R)-1-羧基-2-甲基硫基-乙基)氨基甲酰基]-4-羟基苄基}氨基甲酰基甲氧基)-2,3,4,5-四氢-1,2,5-苯并硫杂二氮杂环庚三烯;
1,1-二氧代-3,3-二丁基-5-苯基-7-甲基硫基-8-(N-{(R)-α-[N-((S)-1-羧基-2-甲基丙基)氨基甲酰基]苄基}氨基甲酰基甲氧基)-2,3,4,5-四氢-1,2,5-苯并硫杂二氮杂环庚三烯;
1,1-二氧代-3,3-二丁基-5-苯基-7-甲基硫基-8-(N-{(R)-α-[N-((S)-1-羧基-2-(R)-羟丙基)氨基甲酰基]-4-羟基苄基}氨基甲酰基甲氧基)-2,3,4,5-四氢-1,2,5-苯并硫杂二氮杂环庚三烯;
1,1-二氧代-3,3-二丁基-5-苯基-7-甲基硫基-8-(N-{(R)-α-[N-((S)-1-羧基丁基)氨基甲酰基]-4-羟基苄基}氨基甲酰基甲氧基)-2,3,4,5-四氢-1,2,5-苯并硫杂二氮杂环庚三烯;
1,1-二氧代-3,3-二丁基-5-苯基-7-甲基硫基-8-(N-{(R)-α-[N-((S)-1-羧基乙基)氨基甲酰基]苄基}氨基甲酰基甲氧基)-2,3,4,5-四氢-1,2,5-苯并硫杂二氮杂环庚三烯;
1,1-二氧代-3,3-二丁基-5-苯基-7-甲基硫基-8-(N-{(R)-α-[N'-((S)-1-羧基丙基)氨基甲酰基]-4-羟基苄基}氨基甲酰基甲氧基)-2,3,4,5-四氢-1,5-苯并硫氮杂环庚三烯;
1,1-二氧代-3,3-二丁基-5-苯基-7-甲基硫基-8-(N-{(R)-α-[N-((S)-1-羧基乙基)氨基甲酰基]-4-羟基苄基}氨基甲酰基甲氧基)-2,3,4,5-四氢-1,2,5-苯并硫杂二氮杂环庚三烯;
1,1-二氧代-3,3-二丁基-5-苯基-7-甲基硫基-8-(N-{(R)-α-[N-((S)-1-羧基-2-甲基丙基)氨基甲酰基]-4-羟基苄基}氨基甲酰基甲氧基)-2,3,4,5-四氢-1,2,5-苯并硫杂二氮杂环庚三烯;和
1,1-二氧代-3,3-二丁基-5-苯基-7-甲基硫基-8-(N-{(R)-1'-苯基-1'-[N'-(羧基甲基)氨基甲酰基]甲基}氨基甲酰基甲氧基)-2,3,4,5-四氢-1,5-苯并硫氮杂环庚三烯;
或其药物可接受的盐。
其它特别合适的IBAT抑制剂为公开于WO99/32478、WO00/01687、WO01/68637、WO03/022804、WO 2008/058628和WO 2008/058630中的那些,尤其是选自以下的化合物:
1-[4-[4-[(4R,5R)-3,3-二丁基-7-(二甲基氨基)-2,3,4,5-四氢-4-羟基-1,1-二氧代-1-苯并硫杂环庚三烯-5-基]苯氧基]丁基]4-氮杂-1-氮杂鎓双环[2.2.2]辛烷甲磺酸盐;
1-[[4-[[4-[3,3-二丁基-7-(二甲基氨基)-2,3,4,5-四氢-4-羟基-1,1-二氧代-1-苯并硫杂环庚三烯-5-基]苯氧基]甲基]苯基]甲基]-4-氮杂-1-氮鎓氮杂双环(azoniazabicyclo)[2.2.2]辛烷氯化物;
1-[[5-[[3-[(3S,4R,5R)-3-丁基-7-(二甲基氨基)-3-乙基-2,3,4,5-四氢-4-羟基-1,1-二氧代-1-苯并硫杂环庚三烯-5-基]苯基]氨基]-5-氧代戊基]氨基]-1-脱氧-D-葡萄糖醇;和
((2R,3R,4S,5R,6R)-4-苄基氧基-6-{3-[3-((3S,4R,5R)-3-丁基-7-二甲基氨基-3-乙基-4-羟基-1,1-二氧代-2,3,4,5-四氢-1H-苯并[b]硫杂环庚三烯-5-基)-苯基]-脲基}-3,5-二羟基-四氢-吡喃-2-基甲基)硫酸钾、乙醇合物、水合物。
根据本发明的考来烯胺制剂的有效量可为包含大于或等于约100mg考来烯胺的任何量,如大于或等于约250mg、500mg、750mg、1000mg、1250mg、1500mg、1750mg或2000mg考来烯胺。例如,考来烯胺的有效量可为100mg至5000mg,如250mg至2500mg,250mg至2000mg,500mg至2500mg,500mg至2000mg,或750mg至2000mg。
根据本发明的考来烯胺制剂的单位剂量可包括200至300mg考来烯胺,如220至280mg考来烯胺,如240至260mg考来烯胺。单位剂量优选包括约250mg考来烯胺。日剂量可以单次剂量给药或分成一个、两个、三个或更多个单位剂量。
如本发明所公开的制剂的给药频率可以是降低胆汁酸吸收不良状况而不会对患者造成任何显著不利影响或毒性的任何频率。给药频率可以从一周一次或两次变化到一天几次,例如每天一次或每天两次。在治疗期间,给药频率可以进一步保持恒定或可变。
有几个因素会影响给药频率和应用于特定用途的制剂的有效量,例如所治疗病症的严重程度、治疗的持续时间、以及正在接受治疗的患者的年龄、体重、性别、饮食和一般医疗状况。
通过以下实施例进一步说明本发明,这些实施例在任何方面都不限制本发明。所有引用的文献和参考文献都通过引用并入本发明。
缩写
HPLC 高效液相色谱
PTFE 聚四氟乙烯
RH 相对湿度
rpm 每分钟转数
UHPLC 超高效液相色谱
UV-Vis 紫外-可见光谱
实施例
实施例1
挤出实验
所有实验均以100-200g规模进行。将干燥成分(考来烯胺,基于乙烯基吡咯烷酮的聚合物和/或微晶纤维素)以下述量混合。以50-100克的份加入水,每次加入之间混合3分钟。当实验中包括丙烯酸酯共聚物时,将其作为在水中的2%w/w分散体(20g丙烯酸酯共聚物(30%水分散体)加入至多300g的水)加入。如果需要,加入最后一部分纯水。在每个实验中,加入的液体总量为固体材料量的1.7至2.3倍(w/w)。
将湿物质转移到配有1.5mm筛网的挤出机中,以25rpm(每分钟转数)操作,并将挤出物收集在不锈钢托盘上。将大约100g的挤出物在730rpm的速度下在球化器中运行1分钟。然后将球化的材料转移到不锈钢托盘中,置于干燥烘箱中并在50℃下干燥16小时。产率计算为通过1.6mm筛子但保留在1.0mm筛子上的丸剂的分数。
使用European Pharmacopoeia 8.0,测试2.9.7中描述的设备和程序进行脆碎性测试。在称重之前,将丸剂在500μm筛子上筛分以除去任何松散的灰尘。
表1
*=挤出和随后的滚圆没有得到丸剂。
表2
实施例2
丸剂的制备
具有根据表1条目8的组成的丸剂在挤出步骤中以200g的批量生产并且在滚圆步骤中以100g的批量生产。将170g考来烯胺、15g共聚维酮和9g微晶纤维素装入行星式混合器中。将混合器以中速操作,并在每次加入之间在混合下分批缓慢加入液体。首先将300g水与20gRL 30D(30%干重)分三等份加入,每次加入之间混合3分钟。最后加入40g纯水并再混合30秒。然后将湿物质转移到挤出机中。挤出机配备1.5mm筛,以25rpm操作,并将挤出物收集在不锈钢托盘上。将大约100g的挤出物在730rpm的速度下在球化器中运行1分钟。然后将球化的材料转移到不锈钢托盘中,置于干燥烘箱中并在50℃下干燥16小时。将干燥的丸剂过筛,收集1mm至1.4mm的级分。
实施例3
pH-和扩散-控制释放的制剂A-C
实施例2的考来烯胺丸剂被配制为具有结肠释放包衣,其包含基于聚(丙烯酸乙酯-共聚-甲基丙烯酸甲酯-共聚-甲基丙烯酸三甲基铵基乙基酯氯化物)的扩散控制的内包衣,和基于乙酸琥珀酸羟丙基甲基纤维素的肠溶外包衣。
三种制剂被制备为在内包衣中具有不同量的聚(丙烯酸乙酯-共聚-甲基丙烯酸甲酯-共聚-甲基丙烯酸三甲基铵基乙基酯氯化物),如下所示:
包含250mg考来烯胺的单位剂量的丸剂组合物如下所示。
内包衣
根据Evonik的一般说明书制备含有GMS、聚山梨酯80和柠檬酸三乙酯的甘油单硬脂酸酯(GMS)乳液。然后将乳液与EudragitRL30D/RS30D分散体(30%w/w)混合。基于干重,内包衣膜的组成如下所示。基于施加的分散体的干重的浓度为19.8%(w/w)。
使用Hüttlin Kugelcoater HKC005施加包衣层;批量大小为75克。包衣过程在空气入口温度为45℃下进行,得到产物温度为27-29℃。调节空气流量以在包衣期间实现丸剂的适当流化。将肠溶包衣施加到丸剂上,以获得10%的重量增加。包衣后,将丸剂在40℃下热处理24小时。
外包衣
肠溶包衣通过在<15℃的低温使用顶置式搅拌器将7%w/w乙酸琥珀酸羟丙甲纤维素、2.45%w/w柠檬酸三乙酯、2.1%w/w滑石、0.21%w/w月桂基硫酸钠和88.24%w/w水混合30分钟而制备。基于干重的外包衣膜的组成如下所示。在包衣过程中,包衣液体保持在低于15℃。
使用Hüttlin Kugelcoater HKC005施加包衣层,批量大小为75克。包衣过程在空气入口温度为55℃下进行,得到产物温度为32℃。调节空气流量以在包衣期间实现丸剂的适当流化。将肠溶包衣施加到丸剂上,以获得40%的重量增加(基于施加内包衣后包衣的丸剂的质量)。包衣后,将丸剂在40℃/75%RH下热处理48小时。
包衣的丸剂可以包封在胶囊中,例如硬明胶胶囊。最终制剂的详细信息(基于干重)如下所示:
剂量重量:452.9mg
考来烯胺:250mg(55%)
内包衣:29.4mg
外包衣:129.4mg
总包衣:158.8mg(35%)
实施例4
pH-和扩散-控制释放的制剂D
实施例2的考来烯胺丸剂被配制为具有结肠释放包衣,该包衣包含基于聚(丙烯酸乙酯-共聚-甲基丙烯酸甲酯-共聚-甲基丙烯酸三甲基铵基乙基酯氯化物)的扩散控制的内包衣、基于乙酸琥珀酸羟丙基甲基纤维素的肠溶包衣,且该丸剂最终涂覆气相二氧化硅以防止丸剂在储存过程中粘附。
包含250mg考来烯胺的单位剂量的丸剂组合物如下所示。
内包衣
根据Evonik的一般说明书制备含有GMS、聚山梨酯80和柠檬酸三乙酯的甘油单硬脂酸酯(GMS)乳液。然后将乳液与Eudragit RS30D分散体(30%w/w)混合。基于干重,内包衣膜的组成如下所示。基于施加的分散体的干重的浓度为20.0%(w/w)。
使用Vector FL-M-1装置施加包衣溶液。初始批量大小为500克。包衣过程在空气入口温度为41-43℃下进行,得到产物温度为28-30℃。调节空气流量以在包衣期间实现丸剂的适当流化。将包衣施加到考来烯胺丸剂上,以获得10%的重量增加。然后将包衣的丸剂在40℃热处理50小时30分。
肠溶包衣
肠溶包衣通过在<15℃的低温使用顶置式搅拌器将7%w/w乙酸琥珀酸羟丙甲纤维素、2.45%w/w柠檬酸三乙酯、2.1%w/w滑石、0.21%w/w月桂基硫酸钠和88.24%w/w水混合30分钟而制备。基于干重的外包衣膜的组成如下所示。在包衣过程中,包衣液体保持在低于15℃。
使用Vector FL-M-1装置施加包衣层。包衣过程在空气入口温度为35-55℃下进行,得到产物温度为28-32℃。调节空气流量以在包衣期间实现丸剂的适当流化。将肠溶包衣施加到丸剂上,以获得40%(w/w)的重量增加(基于施加内包衣后包衣的丸剂的质量)。
最终包衣
紧接在肠溶包衣后,通过将5%的200水悬浮液喷涂到丸剂上,将气相二氧化硅施加到包衣的丸剂上。使用相同的设备施加包衣,入口温度为40-41℃,得到产物温度为30℃。调节空气流量以在包衣期间实现丸剂的适当流化。将包衣施加到考来烯胺丸剂上,以获得1%(w/w)的重量增加。最终将包衣的丸剂在包衣设备中在60℃下进行过程中热处理30分钟。
包衣的丸剂可以包封在胶囊中,例如硬明胶胶囊。最终制剂的详细信息(基于干重)如下所示:
剂量重量:457.4mg
考来烯胺:250mg(55%)
内包衣:29.4mg
肠溶包衣:129.4mg
防粘包衣4.5mg
总包衣:163.3mg(36%)
实施例5
螯合测试
在简化的测试中测定制剂A、B和C的螯合能力,其中模拟胃和小肠的pH。通过测量水溶液中胆酸的减少量来确定螯合。使用USP溶出装置2(桨)Ph.Eur.2.9.3。
在pH 5.5下的螯合
将相当于250mg考来烯胺的一定量的制剂A、B或C加入到含有500mL胆酸(0.192mg/mL)的缓冲溶液(pH 5.5)的容器中,并将内容物在75rpm下搅拌6小时。在不同时间点取出溶液样品,并通过HPLC分析胆酸,其使用Thermo Hypersil Gold柱,50mm×2.1mm,粒径1.9μm;柱温60℃;流动相30:70乙腈:磷酸盐缓冲液(pH 3.0);流速0.75mL/min。对每种制剂分析5个重复样品,并计算平均值。
在pH 6.8或7.4的螯合
将对应于250mg考来烯胺的一定量的制剂A、B或C加入到含有250mL 0.1M盐酸溶液(pH 1)的容器中,并将内容物在75rpm下搅拌2小时。然后将250mL胆酸在氢氧化钾/磷酸钾缓冲溶液中的溶液加入容器中,得到pH6.8或7.4的胆酸(0.192mg/mL)缓冲溶液。混合1分钟后,取出第一份样品。然后验证pH,如果需要,通过加入适量的0.1M氢氧化钾溶液将pH调节至6.8或7.4。然后将溶液再混合6小时。在不同时间点取出溶液样品,并通过HPLC分析胆酸,其使用Thermo Hypersil Gold柱,50mm×2.1mm,粒径1.9μm;柱温60℃;流动相30:70乙腈:磷酸盐缓冲液(pH 3.0);流速0.75mL/min。对每种制剂分析5个重复样品,并计算平均值。
制剂A-C的螯合曲线显示在图1中。5.5的pH略低于十二指肠中通常观察到的pH,尽管它可能发生在一些患者和健康人中。在该pH下,所有制剂的螯合受到限制(图1A)。在pH6.8的螯合代表了回肠中的条件。在该pH下,在4小时后制剂A、B和C分别得到52%、42%和34%螯合(图1B)。在pH 7.4下,在4小时后制剂A、B和C分别得到54%、42%和36%螯合(图1C)。该pH可略高于通常在回肠末端观察到的pH。
制剂A、B和C的包衣丸剂显示没有或只有轻微的崩解。丸剂的目视检查显示,搅拌6小时后,包衣完好无损。相反,实施例2的未包衣的丸剂,当在磷酸盐缓冲液(50mM,pH6.8)中以300rpm(螺旋桨搅拌器)搅拌时,在1分25秒内完全崩解。
实施例6
体外测定制剂A-C在模拟胃肠道条件下的螯合能力
在由ProDigest(Ghent,Belgium)开发的人肠微生物生态系统模拟器中研究了制剂A、B和C的螯合能力。该模拟器适于评估在生理条件下结合胆汁盐的螯合能力,所述生理条件代表禁食的胃、小肠和近端结肠。Marzorati等人先前描述了代表禁食的胃和小肠的液体介质(LWT-Food Sci.Technol.2015,vol.60,p.544-551)。用于近端结肠的液体介质包含基质,其含有代表人结肠的稳定微生物群落。Possemiers等人描述了获得稳定的人肠微生物群落的方法(FEMS Microbiol.Ecol.2004,第49卷,第495-507页)及其中的参考文献。通过测量水溶液中胆汁酸的减少量来测定螯合。使用胆酸(CA)、鹅脱氧胆酸(CDCA)和脱氧胆酸(DCA)的40:40:20(w/w)混合物作为人胆汁盐的代表性混合物(Carulli等人,Aliment.Pharmacol.Ther.2000,vol.14,出版增补s2,p.14-18)。
进行对比实验,向其中加入纯的考来烯胺粉末。进行没有加入考来烯胺的对照实验,以监测在测定中使用的结肠条件下胆汁盐的降解。
每个实验一式三份进行以解释生物学变化。
禁食胃
将对应于91mg考来烯胺的一定量的制剂A、B和C和纯考来烯胺(91mg)加入到14mL禁食的胃液体介质(pH 1.8)中。将消化物在37℃温育1小时。
小肠
在胃温育1小时后,加入含有限定的40:40:20胆汁盐混合物(46.7mM)的5.6mL胰液(pH 6.8)。将小肠消化物在37℃温育2小时,且在0、60和120分钟后取出样品。
近端结肠
样品分析
通过HPLC评估样品中游离胆汁盐的浓度。使用校准曲线计算样品中CA、CDCA和DCA的浓度。将1mL各样品以5000g离心2分钟。将500μL上清液与500μL甲醇和磷酸盐缓冲液的80:20(v:v)混合物混合,剧烈涡旋,通过0.2μm PTFE过滤器过滤并注入配备UV-Vis检测器的Hitachi Chromaster HPLC中。通过反相C18柱(Hydro-RP,4μm,250x4.6mm,Synergi)分离三种胆汁盐。在室温下溶剂成分不变的(isocratic)条件下进行分离,使用甲醇和磷酸盐缓冲液的80:20(v:v)混合物作为流动相。在23分钟内以0.7mL/min进行分析,并在210nm处检测胆汁盐。对于胃和小肠样品,注射体积设定为20μL,对于结肠样品,注射体积设定为50μL。
用于结肠培养的完整基质含有源自BD DifcoTM Oxgall,一种来自牛的脱水新鲜胆汁提取物(目录号212820),的(降解的)胆汁盐。尽管该混合物的确切组成是未知的,但在结肠样品中可能预期有更高量的游离胆汁盐。因此,从每个样品中减去背景值(即没有加入胆汁盐混合物的空白样品),以便考虑总基质中存在的游离胆汁盐的“基线”。
下表显示了小肠孵育2小时(“SI-2”)和结肠孵育4小时(“C-4”)后的CA、CDCA和DCA的相对浓度,以及它们之间期间的成比例减少。
CA、CDCA和DCA相对于孵育时间的相对浓度(%)分别显示在图2、3和4中。该图包括在小肠(SI)孵育0小时和2小时后以及在结肠(C)孵育0、2、4、6、19和24小时后采集的样品。
该图证实了肠道中微生物盐代谢的作用和程度(例如,去缀合、脱氢和脱羟基),如通过未加入考来烯胺的对照样品中胆汁盐水平的显著降低所观察到的。
可以看出,这三种制剂在小肠孵育期间提供了对活性化合物的保护。而在小肠孵育2小时后,纯的(未包衣的)考来烯胺就可以减少59%的CA、90%的CDCA和89%的DCA(参见对比实验),制剂A、B和C在此期间导致胆汁盐减少更多。在小肠孵育期间,制剂C显示出最佳结果,CA、CDCA和DCA分别仅减少18%、17%和19%。在结肠孵育的前四个小时期间,所有三种制剂产生了大量的胆汁盐减少。制剂C显示出最佳结果,具有71%的CA螯合、68%的CDCA螯合和75%的DCA螯合,分别对应于CA、CDCA和DCA的53%、52%和57%的减少。
实施例7
稳定性测试
将包含制剂C(250mg考来烯)的硬胶囊在25℃/60%RH下储存11个月。
储存0、3、6和11个月后,分析胶囊的考来烯胺和水含量。此外,使用实施例5中描述的测定法测定制剂的螯合能力。结果显示在下表中。
Claims (26)
1.用于将考来烯胺靶向递送至结肠的口服制剂,包含:
a)多个挤出丸剂,该丸剂包含至少70%w/w考来烯胺和
i.至少7%w/w的基于乙烯基吡咯烷酮的聚合物;或
ii.至少6%w/w的基于乙烯基吡咯烷酮的聚合物和至少2%w/w的丙烯酸酯共聚物的组合;或
iii.至少5%w/w的基于乙烯基吡咯烷酮的聚合物和至少3%w/w的丙烯酸酯共聚物的组合;或
iv.至少6%w/w的基于乙烯基吡咯烷酮的聚合物、至少1%w/w的丙烯酸酯共聚物和至少10%w/w微晶纤维素的组合;
其中所述基于乙烯基吡咯烷酮的聚合物选自共聚维酮和聚维酮,所述丙烯酸酯共聚物由丙烯酸酯单体组成,所述丙烯酸酯单体选自丙烯酸、丙烯酸甲酯、丙烯酸乙酯、甲基丙烯酸、甲基丙烯酸甲酯、甲基丙烯酸丁酯、甲基丙烯酸三甲基铵基乙基酯和甲基丙烯酸二甲基氨基乙基酯;
b)围绕所述挤出丸剂的扩散-控制的内包衣;和
c)肠溶外包衣。
2.根据权利要求1的制剂,其中所述扩散-控制的内包衣为弹性的。
3.根据权利要求1的制剂,其中所述扩散-控制的内包衣包含1:2:0.2或1:2:0.1的聚(丙烯酸乙酯-共聚-甲基丙烯酸甲酯-共聚-甲基丙烯酸三甲基铵基乙基酯氯化物)或其组合。
4.根据权利要求1的制剂,其中所述肠溶外包衣包含乙酸琥珀酸羟丙基甲基纤维素。
5.根据权利要求1的制剂,其中未包衣的丸剂的直径为1000至1400μm。
6.根据权利要求1的制剂,其中未包衣的丸剂还包含微晶纤维素。
7.根据权利要求1的制剂,其中未包衣的丸剂不含微晶纤维素。
8.根据权利要求1的制剂,其中未包衣的丸剂包含至少80%w/w考来烯胺。
9.根据权利要求1的制剂,其中未包衣的丸剂包含至少85%w/w考来烯胺。
10.根据权利要求1的制剂,其中基于干重,最终制剂的考来烯胺含量至少为50%w/w。
11.根据权利要求1的制剂,其中基于干重,最终制剂的考来烯胺含量至少为55%w/w。
12.根据权利要求1的制剂,其中基于干重,最终制剂中包衣的量少于40%w/w。
13.根据权利要求1的制剂,其中基于干重,最终制剂中包衣的量少于35%w/w。
14.根据权利要求1的制剂,其中多于70%的考来烯胺在结肠中释放。
15.根据权利要求1的制剂,其中少于30%的考来烯胺在小肠中释放。
16.根据权利要求1的制剂,其中所述制剂包含在胶囊中。
17.根据权利要求1的制剂,其中所述制剂包含在囊剂中。
18.根据权利要求1的制剂在制备用于治疗或预防胆汁酸吸收不良的药物中的用途。
19.根据权利要求18的用途,其中所述胆汁酸吸收不良是回肠疾病、回肠切除或回肠旁路的结果,是胆汁酸过量产生或肝胆汁酸合成反馈抑制缺陷的结果,或是胆囊切除术、迷走神经切断术、小肠细菌过度生长(SIBO)、乳糜泻、胰腺功能不全、胰腺移植、放射性肠炎、胶原性结肠炎、显微镜结肠炎、淋巴细胞性结肠炎、溃疡性结肠炎或肠易激综合征的结果。
20.根据权利要求19所述的制剂的用途,其中所述肠易激综合症是伴有腹泻的肠易激综合征(IBS-D)。
21.根据权利要求19的用途,其中所述回肠疾病为克罗恩病。
22.根据权利要求19的用途,其中所述胰腺功能不全为慢性胰腺炎或囊性纤维化。
23.根据权利要求1的制剂在制备用于治疗或预防胆汁酸腹泻的药物中的用途。
24.根据权利要求1的制剂在制备用于在口服给药IBAT抑制剂后治疗或预防胆汁酸腹泻的药物中的用途。
25.根据权利要求1的制剂在制备用于在治疗胆汁淤积性肝疾病后治疗或预防胆汁酸腹泻的药物中的用途,所述治疗胆汁淤积性肝疾病包括口服给药IBAT抑制剂。
26.根据权利要求24或25的用途,其中所述IBAT抑制剂为
1,1-二氧代-3,3-二丁基-5-苯基-7-甲基硫基-8-(N-{(R)-α-[N-((S)-1-羧基丙基)氨基甲酰基]-4-羟基苄基}氨基甲酰基甲氧基)-2,3,4,5-四氢-1,2,5-苯并硫杂二氮杂环庚三烯;或
1,1-二氧代-3,3-二丁基-5-苯基-7-甲基硫基-8-(N-{(R)-1'-苯基-1'-[N'-(羧基甲基)氨基甲酰基]甲基}氨基甲酰基甲氧基)-2,3,4,5-四氢-1,5-苯并硫氮杂环庚三烯;
或其药物可接受的盐。
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- 2017-02-09 JP JP2018560429A patent/JP6954927B2/ja active Active
- 2017-02-09 EP EP17705975.5A patent/EP3413878B1/en active Active
- 2017-02-09 RU RU2018131259A patent/RU2750937C2/ru active
- 2017-02-09 CA CA3011619A patent/CA3011619C/en active Active
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Also Published As
Publication number | Publication date |
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CN108601745A (zh) | 2018-09-28 |
ES2874546T3 (es) | 2021-11-05 |
EP3413878A1 (en) | 2018-12-19 |
CA3011619C (en) | 2024-01-02 |
JP6954927B2 (ja) | 2021-10-27 |
EP3413878B1 (en) | 2021-04-14 |
JP2019504887A (ja) | 2019-02-21 |
CA3011619A1 (en) | 2017-08-17 |
RU2750937C2 (ru) | 2021-07-06 |
RU2018131259A3 (zh) | 2020-04-14 |
RU2018131259A (ru) | 2020-03-10 |
WO2017138878A1 (en) | 2017-08-17 |
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