CN101511343A - 使用多元醇来获得利福昔明的稳定的多晶型形式 - Google Patents

使用多元醇来获得利福昔明的稳定的多晶型形式 Download PDF

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CN101511343A
CN101511343A CNA2007800330052A CN200780033005A CN101511343A CN 101511343 A CN101511343 A CN 101511343A CN A2007800330052 A CNA2007800330052 A CN A2007800330052A CN 200780033005 A CN200780033005 A CN 200780033005A CN 101511343 A CN101511343 A CN 101511343A
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rifaximin
polyhydric alcohol
beta
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moisture content
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P·马费伊
M·巴凯蒂
G·博托尼
G·C·维斯科米
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Alpha sigma Co., Ltd
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Abstract

多元醇稳定利福昔明的多晶型形式，特别是β形式。当具有至少两个羟基的多元醇添加至利福昔明粉末，β多晶型物是稳定的并且不依赖于环境湿度地随时间仍然稳定。在本发明中，描述了制备由纯的且稳定的多晶型形式构成的制剂以产生药物产品的方法。

Description

使用多元醇来获得利福昔明的稳定的多晶型形式
发明背景
医药产品中含有的有效成分能以具有不同的化学物理特性，例如不同的溶解性和化学稳定性的多晶型形式获得。
对于医药产品，这些特性对于有效成分的体内吸收是关键的，并因此对人或动物施用后的产品功效和安全性是关键的。
有关这个话题，可获得大量的科学论文。一些论文是例如多沙唑嗪(doxazosin)(Sohn Y.T.等，Arch.Pharm.Res.，2005；28，730-735)；曲尼斯特(tranilast)(Vogt F.G.等，J.Pharm.Sci.，2005，94，651-65)；氯吡格雷(clopidogrel)(Koradia V等，Acta.Pharm.，2004，54(3)，193-204)；塞来昔布(celecoxib)(Chawla G.等，Pharm.Dev.Technol.，2004，9(4)，419-33)；酮咯酸(ketorolac)(Sohn Y.T.等，Arch.Pharm.Res.2004，27(3)，357-60)；氟康唑(fluconazol)(Caira M.R.等，J.Pharm.Sci.，2004，93(3)，601-11)；吡罗昔康(piroxicam)(Vrecer F.等，Int.J.Pharm.，2003，256(1-2)，3-15)；茶碱(theophylline)(Airaksinen S.等，Int.J.Pharm.，2004，276(1-2)，129-41)。
由于上述原因，负责批准医药产品上市的医药局需要固态的多晶型有效成分的特性和生产一致性(production consistency)的信息；在药物制品的生产阶段和储存的期间，避免多晶型形式的改变是重要的。为了这个目的，从所有可能的多晶型形式中选择那些随时间延长显示最高稳定性的多晶型形式是重要的，就如Rodriguez-Spong B.等在Adv.Drug Deliv.Rev.，2004，56(3)，241-74中描述的那样。
为了获得更加稳定的多晶型形式，有效成分的盐(saline activeingredients)是常用的，如Adv.Drug Del.Rev.，2006，56，231-334所述。
利福昔明(rifaximin)是一种抗生素，属于利福平(rifampicin)家族，可以片剂、颗粒剂、经口悬浮剂、和软膏剂获得，在欧洲、美国和许多其他国家销售。
利福昔明可以Viscomi G.C.等在IT MI2003 A 002144，(2003)和US7,045,620B1，(2003)中描述的多晶型形式α、β和γ存在，和以Viscomi G.C.等在EP 1698630(2005)中描述的多晶型形式δ和ε存在。这些多晶型形式非常重要，因为它们可以改变内在溶解作用约10倍，和改变利福昔明的生物利用率约600倍，就如Viscomi等在WO 2005/044823(2004)中所述的那样。这些改变会对产品的功效和安全性具有强的影响。
而且，从US7045620 B1(2003)和EP1698630(2005)中知道，根据获得水或失去水的可能性，利福昔明的多晶型形式可以容易地转变为其他形式。由于湿度和温度条件的变化，这些转变也会发生在固态。例如，环境相对湿度在约50％或50％以上时，α多晶型物转化为β多晶型物。另一例子由ε多晶型物代表，其可通过干燥δ多晶型物获得，如在EP1698630(2005)中所述，并且与δ形式比较，ε形式显示生物利用率降低20倍。
在生产含利福昔明的医药产品时，不同的利福昔明多晶型形式可以有利地以均质的和纯的产品使用，因为通过使用合适的多晶型形式能调节产品的功效和安全性。
现有技术允许了解含利福昔明的医药产品的生产条件的重要性，所述生产条件如果没有恰当地控制，会产生利福昔明多晶型形式的不希望有的转变。
而且，在药学产品生产中使用的工作状况(working phases)和涉及的水的使用，如在湿条件下的粉末粒化、用水作为溶剂的膜包衣过程、干燥，均可改变所选利福昔明的多晶型形式。由于湿度会适时改变多晶型形式，因此利福昔明和含有利福昔明的医药产品在储存中也会出现问题，因此生产过程备受关注。
如之前所述，从工业观点来看，具有在不依赖于环境湿度的条件下的利福昔明多晶型形式是有利的，以允许水去除而不改变同质多晶现象的生产。
我们吃惊地发现，也就是本发明的真正目的，添加具有至少2个羟基的化合物，以下称多元醇，能使利福昔明的多晶型形式稳定。
根据本发明，“多元醇”是指多羟基化合物(例如乙二醇、丙二醇、丁二醇、戊二醇、赤藓醇、季戊四醇等)；单糖和多糖，如果糖、右旋糖、蔗糖、淀粉、纤维素及其衍生物(羟丙基纤维素、羟乙基纤维素、羧甲基纤维素等)；麦芽糖糊精、糊精、黄原酸胶(xantan gum)等；2-羟基酸和多羟基酸(如苹果酸、酒石酸、柠檬酸等)。
式I所示的化合物是优选的：
H-[O-CH-(X)-CH2]n-OH
                 (I)
其中X为氢或低级烷基，n可以从1到20，或者是1，2，3-丙三醇和1，2-丙二醇。
特别地，当将多元醇添加至多种利福昔明多晶型物中的一种利福昔明多晶型物时，确切地说是β多晶型物时，该多晶型形式不改变其结晶形状，甚至在那些至今已知的观察到这些变化的条件下也是如此。干燥后，利福昔明的β多晶型物的含水率在US 7,045,620 B1中公开为降低至重量百分数低于4.5％，并且该多晶型物转变为α多晶型物。当将多元醇添加至利福昔明β，后者是稳定的，甚至当固体形式的残余含水率(residual watercontent)低于4.5％时也是如此；而且该多晶型物的储存不依赖于相对环境湿度。
在利福昔明的多晶型物中，β形式是非常重要的，因为它是利福昔明的所有多晶型形式中较少被吸收的多晶型形式，如Viscomi G.C.等人在WO 2005/044823(2004)和在EP 1698630(2005)中公开的。对于利福昔明而言，低吸收是非常重要的，因为它在胃肠道中对抗引起感染性腹泻的广谱微生物中起到有效的抗菌活性，由于不被人吸收而显示极佳的安全谱，如Dascombe J.J.等人在Int.J.Clin.Pharmacol.Res.，1994，14(2)，51-56中公开的那样。在WO 2005/044823和在EP 1698630(2005)中阐述了利福昔明吸收仅取决于其同质多晶现象，并且在多晶型物中吸收上可能具有约600倍的不同；因此使用较少被吸收的β多晶型物是非常有利的。事实上，诱导细菌菌株对抗生素的抗性是与使用抗生素相关的一个可能的副作用。在使用利福昔明的情况下，这是尤其重要的，因为利福昔明属于利福平家族，在治疗结核病时被主要使用，其中所述的结核病是一种具有复发的病理学，如Kremer L.等人在Expert Opin.Investig.Drugs，2002，11(2)，153-157中所述的那样。
根据本发明，在所有可获得的多元醇中，式H-IO-CH2-CH2]n-OH的化合物和它们的混合物(其中n可以在2至16之间)以及化合物1，2，3-丙三醇和1，2-丙二醇是非常重要的，因为它们都用于制备用于人和动物的药物制剂，而且它们具有增塑特性，这可使得它们用作涉及包衣的药物制品如颗粒剂和片剂中的添加剂。
已发现，并且本发明的真正目的是，式H-[O-CH2-CH2]n-OH的化合物和它们的混合物(其中n可以在2至16之间)以及化合物1，2，3-丙三醇和1，2-丙二醇能够用作β多晶型形式的稳定剂和用作制备包衣的增塑剂，通过使用浓度在5％(w/w)至50％(w/w)之间，优选地在10％(w/w)至30％(w/w)之间的多元醇水溶液，接下来去除过量的水，获得并储存β多晶型形式，其中所述包衣也是胃稳定的(gastroresistant)(通过使用纤维素或丙烯酸和甲基丙烯酸衍生物)并且能够包衣利福昔明颗粒剂和片剂。
发明描述
如之前所述，本发明的目的是使用上述的多元醇来稳定利福昔明多晶型形式，尤其是Viscomi G.C.等人在US 7,045,620B1(2003)中公开的β形式，以获得含有利福昔明的β形式的药物制品，其中有效成分利福昔明的残余含水率低于4.5％(w/w)，以及在能够直接或间接地导致利福昔明干燥的产生阶段期间维持β多晶型物未改变，也就是说，在不使用多元醇的条件下，不允许保存β形式，β形式确实会转变为利福昔明的另一种多晶型形式，这取决于所应用的干燥条件的严重性。
我们发现，通过将利福昔明β与浓度为5％(w/w)至50％(w/w)，且优选地在10％(w/w)至30％(w/w)之间的多元醇水溶液接触一段时间，通常地接触1至24小时，则获得了β形式的利福昔明，这导致稳定，甚至当固体形式中的残余含水率低于4.5％(w/w)也是稳定的。
作为本发明目的的上述多元醇或它们的混合物可添加至利福昔明β，所述添加是纯的或是与一些药学技术中已知的稀释剂混合添加，以提高平滑性和利于与多元醇或它们的混合物的相互作用。为此目的，可以使用如胶态二氧化硅的物质(例如已知为的胶态二氧化硅)并且可以以包含的在1％(w/w)至20％(w/w)之间、和优选地0.2％(w/w)至5％(w/w)之间的范围添加至有效成分。
上述这些多元醇之一或它们的混合物与利福昔明之间的相互作用工艺可以通过药学技术领域已知的允许紧密混合组分的任一操作获得。
这些多元醇之一或它们的混合物可以在合适的水稀释后应用于成粒工艺，其中将所述溶液适时地添加至含有有效成分的粉末或排他地由有效成分构成的粉末，合适地混合。所述操作可以在常规的成粒机中实施，或在具有旋转叶片和破碎器的高速成粒机中实施，以利于混合组分。
可以人工实施将一种或多种多元醇的溶液添加至所述粉末混合物，注意缓慢添加溶液至所述粉末或粉末混合物，以利于组分相互作用；或者更适当地，可以通过合适的泵系统实施；例如罗茨泵(lobs pump)、活塞泵或蠕动泵，和通过使用允许雾化溶液的喷雾器，从而利于更好的组分相互作用。
当实现了成粒后，可以将过量的水使用药学技术领域已知的常规干燥系统，通过在静电炉中干燥或通过在流化床设备中干燥而除去。干燥温度可以在30℃和90℃之间，优选地在40℃和80℃之间。干燥时间取决于所使用的设备、待干燥的粉末的量、和目的残余湿度。
含有上述多元醇之一或它们的混合物的溶液的应用也可用流化床设备实施。在这种情况下，含有有效成分的粉末或排他地由有效成分构成的粉末通过热风流维持在悬浮状态，并且同时使含有上述多元醇之一或它们的混合物的溶液细细地雾化在粉末上。在这种情况下，在干燥工艺的同时产生含有多元醇或它们的混合物的溶液与固态利福昔明的紧密混合物。
药学技术领域的熟练技术人员能够通过改变临界参数而获得具有目的残余含水率的产物，其中所述临界参数如进气温度、进气容量、和溶液的应用速度。通常设置进气温度在20℃和90℃之间，优选地在30℃和80℃之间。
溶液的应用速度与维持粉末在悬浮状态下的空气温度密切相关。为本领域技术人员熟知的该目的是在所有工艺期间维持混合物温度恒定。事实上，太快的应用速度会导致过度的湿润、粉末凝结、防止所需获得的对粉末的有效作用的混合；而太慢的应用速度会引起混合物温度增加，伴随着有效成分可能降解。
本发明可以通过提供含有上述多元醇或它们的混合物的溶液的紧密混合物并随后干燥的任一其它药学方法获得。
优选的具有式H-[O-CH2-CH2]n-OH(其中n能够在2和10之间)的化合物和它们的混合物、以及化合物1，2，3-丙三醇和1，2-丙二醇作为适用于固态经口药物制品的膜包衣的含水混合物的组分，可以以包含的浓度在5％(w/w)和50％(w/w)之间添加，优选地在10％(w/w)和30％(w/w)之间添加，能够引起受控释放或胃稳定。
在下列非限制性实施例中阐述本发明。
实施例1
残余含水率低于4.5％的利福昔明β形式的制备
在具有入口温度为80℃的流化床设备中将199克利福昔明β形式与1克
Figure A200780033005D0009160129QIETU
混合5分钟。
将由390克水和13克1，2-丙二醇组成的悬液喷雾至流化床设备中的利福昔明β形式的混合物上，在所有工艺中使用的是具有11克/分钟容量的蠕动泵，并且维持温度在恒定值80℃。将混合物在80℃干燥，并继续干燥，直至重量减轻是恒定的。测定微颗粒的残余含水率(卡尔-费休(Karl-Fisher))，并且等于2.2％。将由此获得的微颗粒进行X射线光谱学，并且在图1中报告的衍射图对应于利福昔明的β多晶型物。
当1，2-丙二醇被赤藓醇或甘露糖醇替换时获得同样的结果。
比较实施例2
该实施例显示了在不存在多元醇时，残余含水率低于4.5％的利福昔明不采取多晶型的β形式，并且添加多元醇允许获得残余含水率低于4.5％的固态利福昔明的β形式(操作与实施例1所述相同，其中被喷雾的溶液不含1，2-丙二醇)。
在具有入口温度为80℃的流化床设备中将199克利福昔明β形式与1克
Figure A200780033005D0010160151QIETU
混合5分钟。
将400克水喷雾至流化床设备中的利福昔明β形式的混合物上，在所有工艺中使用的是具有11克/分钟容量的蠕动泵，并且维持温度在恒定值80℃。将混合物在80℃干燥，并继续干燥，直至重量减轻是恒定的。测定微颗粒的残余含水率(卡尔-费休)，并且等于1.1％。将由此获得的微颗粒进行X射线光谱学，并且在图2中报告的衍射图对应于利福昔明的α多晶型物。
比较实施例3
该实施例显示了多元醇中存在的羟基对于获得残余含水率低于4.5％的利福昔明多晶型β形式是重要的。操作与实施例1所述相同，其中1，2-丙二醇被具有酯化的羟基的多元醇如三乙酸1，2，3-丙三醇酯替代。
在具有入口温度为80℃的流化床设备中将199克利福昔明与1克混合5分钟。
将由382.75克水和12.75克三乙酸1，2，3-丙三醇酯构成的悬液喷雾至流化床设备中的利福昔明的混合物上，在所有工艺中使用的是具有11克/分钟容量的蠕动泵，并且维持温度在恒定值80℃。将混合物在80℃干燥，并继续干燥，直至重量减轻是恒定的。测定微颗粒的残余含水率(卡尔-费休)，并且等于0.5％。将由此获得的微颗粒进行X射线光谱学，并且在图3中报告的衍射图对应于利福昔明的α多晶型物。
实施例4
在存在PEG400时残余含水率低于4.5％的利福昔明β的制备
在具有入口温度为80℃的流化床设备中将199克利福昔明与1克
Figure A200780033005D00111
混合5分钟。
将由360克水和40克PEG400(具有式H-[O-CH2-CH2]n-OH的聚乙二醇)组成的悬液喷雾至流化床设备中的利福昔明的混合物上，在所有工艺中使用的是具有6克/分钟容量的蠕动泵，并且维持温度在恒定值80℃。将混合物在80℃干燥，并继续干燥，直至重量减轻是恒定的。测定微颗粒的残余含水率(卡尔-费休)，并且等于0.8％。
将由此获得的微颗粒进行X射线光谱学，并且在图4中报告的衍射图对应于利福昔明的β多晶型物。使用羟乙基纤维素或酒石酸而非PEG400时获得同样的结果。
实施例5
在存在1，2-丙二醇时残余含水率低于4.5％的利福昔明β胃稳定微颗粒的制备
该实施例显示了添加至利福昔明以获得残余含水率低于4.5％的利福昔明β的多元醇1，2-丙二醇在制备覆盖颗粒的膜时，同时还可以作为增塑剂发挥作用，其中所述在制备覆盖颗粒的膜时没有添加其它具有增塑剂功能的化合物。
将25.000克利福昔明粉末和作为流化剂的125克
Figure A200780033005D0011160259QIETU
加载在流化床设备中，用于在有效成分上应用包衣的膜，其中所述流化床设备是装备有18英寸Wurster系统的膜Glatt GPC 30型。
同时，在搅拌下于混和器中制备如表1所述的悬液。
表1
Figure A200780033005D00112
使用高速Ultra Turrax均化器将固态组分均匀分散在软化水中。将均化的悬液加载在具有蠕动泵的Wurster型设备中，并在所包含的压力为1.0至1.5巴之间时通过1.8mm喷嘴雾化在利福昔明粉末混合物和
Figure A200780033005D0012160323QIETU
200上。
在如表2所述同样的条件下实施膜包衣应用。
表2
 
工艺参数 预温阶段 包衣溶液的应用 干燥
入口处气流(m3/小时) 400±100 550±100 350±50
入口处气温(℃) 60±2 60±10 80±2
产物温度(℃) 32 25-27 60±2
喷射压力(巴)(起始阶段) 1-1.5±0.1
喷射速度(g/分钟) 150-200
按照卡尔-费休确定由此获得的微颗粒上的残余空气含量(residual aircontent)，结果等于1.2％。
获得的微颗粒的X射线衍射图在图5中报告，对应于β多晶型物。
实施例6
制备在热焊接袋(thermo welded bags)中的药物制品利福昔明β
在0.5mm网筛上筛9.12Kg根据实施例5制备的胃稳定的利福昔明微颗粒、19.58Kg山梨糖醇、0.49Kg天冬甜素、0.21Kg无水柠檬酸、2.10Kg果胶、2.10Kg甘露糖醇、0.21Kg新橙皮苷DC、1.12Kg樱桃香精、和0.07Kg硅胶，然后在V混合器中混合20分钟。分配所得的混合物并置于含有对应于800mg利福昔明的5克产物的热焊接袋中。下表3中报导了在热焊接袋中含有的医药学特制品的组分。
表3
Figure A200780033005D00131
在25℃储存12个月后评估热焊接袋中含有的微颗粒的胃稳定性，如USP第28版第2417页公开的那样，与实施例1制备的微颗粒获得相同的结果，在0.1N盐酸中的溶解作用等于2.2％，在pH6.8的缓冲液中的溶解作用等于91.1％。
实施例7
含有根据实施例5制备的利福昔明β的片剂形式的药物制品
在0.5mm网筛上筛9.3Kg根据实施例1制备的胃稳定的利福昔明微颗粒、593g羟基乙酸淀粉钠、100g硬脂酸镁，然后在V混合器中混合20分钟。使用装备有Oblong、调整过的19x9mm冲压机的旋转片剂机(Fette1200)将所得的混合物制成片剂，产生718mg的最终重量，对应于400mg利福昔明。
表4报导了片剂组分。
表4
Figure A200780033005D00132
Figure A200780033005D00141
然后使用常规的锅设备，用羟丙甲基纤维素膜包衣片剂，以改善外观和获得掩味特性。在表5中报导了单元的膜组分。
表5
 
包衣组分 量(mg)
HPMC 14.07
二氧化钛 4.10
Na-EDTA 0.05
丙二醇 1.37
氧化铁红 E 172 0.41

Claims (15)

1.具有至少两个羟基的一种或多种化合物(文中称为“多元醇”)的用途，以稳定利福昔明的多晶型形式。
2.如权利要求1所述的用途，其中一种或多种多元醇选自含有两个至七个碳原子和两个至七个羟基的多元醇；单糖；二糖；多糖，如淀粉、纤维素及其衍生物；糊精；和麦芽糖糊精；黄原酸胶；2-羟基酸；和多羟基酸。
3.如权利要求1所述的用途，其中一种或多种多元醇如式I所示：
H-[O-CH-(X)-CH2]n-OH
(I)
其中X代表氢或低级烷基，且n能够在1到20之间的范围。
4.如权利要求1所述的用途，其中多元醇是1，2，3-丙三醇。
5.如权利要求2所述的用途，其中多元醇具有通式H-[O-CH2-CH2]n-OH，其中n能够在2到14之间的范围。
6.如权利要求2所述的用途，其中多元醇是1，2-丙二醇。
7.如权利要求1所述的用途，其中多元醇用于获得残余含水率低于4.5％的固态利福昔明的β多晶型形式。
8.通过使用权利要求1至6中所述的一种或多种多元醇而稳定的、不依赖于残余含水率的固态利福昔明的多晶型形式。
9.通过使用权利要求1至6中所述的一种或多种多元醇而稳定的、不依赖于残余含水率的固态利福昔明的β多晶型物。
10.经口医药学制品和局部医药学制品，其含有通过使用权利要求1至6中所述的一种或多种多元醇而稳定的、不依赖于残余含水率的利福昔明的β多晶型形式和本领域熟知的赋形剂，如稀释剂、配体、润滑剂、崩解剂、染料、香精、和甜味剂，用于治疗需要抗生素治疗的病理学。
11.胃稳定的利福昔明β的微颗粒，其中β多晶型物是用权利要求1至6中所述的一种或多种多元醇稳定的，不依赖于残余含水率。
12.在热焊接袋中的利福昔明β，其中β多晶型物是通过使用权利要求1至6中所述的一种或多种多元醇而稳定的，不依赖于残余含水率。
13.片剂形式的利福昔明β，其中β多晶型物是通过使用权利要求1至6中所述的一种或多种多元醇而稳定的，不依赖于残余含水率。
14.用于制备根据权利要求9的β多晶型形式的利福昔明的方法，其特征在于：将固态利福昔明与权利要求1至6中所述的一种或多种多元醇的浓度为5％至59％(w/w)的水溶液在30℃至90℃之间的温度接触一段时间，包括接触1至24小时之间的一段时间，以及在固体残余物分离后，在30℃至80℃之间的温度、于环境压力或真空下干燥一段时间，包括干燥2至72小时之间的一段时间。
15.用于制备根据权利要求9的β多晶型形式的利福昔明的方法，其特征在于：将含有权利要求1至6中所述的一种或多种多元醇的多元醇水溶液喷雾在流化床设备中的固态利福昔明β上，入口温度在40℃至90℃之间，并且将由此获得的混合物在气流下温度为40℃至90℃之间干燥，其中所述多元醇水溶液包含浓度为5％至50％(w/w)的多元醇水溶液。
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