CN101052379A - 优选阿片样物质的多颗粒以及使用挤出的制造方法 - Google Patents
优选阿片样物质的多颗粒以及使用挤出的制造方法 Download PDFInfo
- Publication number
- CN101052379A CN101052379A CNA2005800377469A CN200580037746A CN101052379A CN 101052379 A CN101052379 A CN 101052379A CN A2005800377469 A CNA2005800377469 A CN A2005800377469A CN 200580037746 A CN200580037746 A CN 200580037746A CN 101052379 A CN101052379 A CN 101052379A
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- China
- Prior art keywords
- oxycodone
- many granules
- pharmaceutically active
- active agents
- unit dose
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Abstract
使用足够起增塑剂还起润滑剂作用的增塑赋形剂,可以实现含有药物活性剂的混合物的挤出,从而避免包含润滑剂的需要。本发明提供基本上不含润滑剂的具有控释性能的多颗粒。本发明优选涉及包含阿片样物质如羟考酮、甲基丙烯酸铵共聚物如EudragitRSPO、增塑赋形剂如优选硬脂醇和透水性改性剂如优选EudragitRLPO的挤出的多颗粒。所获得的多颗粒显示出与pH值无关的释放速度分布图。
Description
本发明涉及一种生产挤出的药物产品的方法,尤其是多颗粒,并且特别涉及挤出的产品,尤其是提供控释药物活性成分的多颗粒(multiparticulates)。
发明背景
发现生产控释药物制剂的挤压加工具有减少需要生产所述制剂的加工步骤以及能够在连续或半连续的基础上进行生产的优点。通常将这样包括活性剂的软化的混合物的挤出称为熔体挤出。熔体挤出技术的基础是热塑性材料的应用,所述热塑性材料起粘合剂作用用于包埋在溶液或基质内分散体形式中的药物。具有低玻璃化转变温度(Tg)的热塑性聚合物优选通过熔体挤出来加工。考虑到热敏性药物以及其它必需的赋形剂的稳定性,优选较低的加工温度。可以降低聚合物玻璃化转变温度以便于在较低的温度下通过任选加入增塑剂进行加工。
通过选择合适的聚合物和添加剂,熔体挤出技术可被用于提高水溶性差的药物的溶解度,和随后的生物利用度,以及延迟用于控释产品的中度至高度水溶性药物的药物释放。
通过这样的熔体挤出技术可以容易地生产具有改进药物释放性能的均匀大小的多颗粒。
例如WO 96 14058描述了制备适于口服给药的缓释药物挤出物的熔体挤出法。所述方法包括:
将治疗活性剂与(1)选自烷基纤维素、丙烯酸和甲基丙烯酸聚合物及共聚物、紫胶、玉米蛋白、氢化蓖麻油、氢化植物油及其混合物的物质,和(2)选自天然或合成的石蜡、脂肪酸、脂肪醇,及其混合物的易熔载体混合;所述缓释材料具有30-200℃之间的熔点并且要包含足够的量以进一步地减缓治疗活性剂的释放;
将所述混合物加热至足以软化混合物而足以挤压的温度;
将所述加热的混合物挤压成直径0.1-3mm的条形物;冷却所述的条形物;并将所述条形物分割以形成长0.1-5mm的所述挤出物的非球状多颗粒;并将所述非球状多颗粒分成包含有效量的所述治疗活性剂的单位剂量,所述单位剂量提供所述治疗活性剂从大约8至大约24小时的持续释放。
在用于描述本方法的操作实施例中,将硬脂酸用作挤压制剂的润滑剂。例如在实施例1至6中,所述制剂包含以重量计为20%的硬脂酸,控释材料是不同地乙基纤维素和Eudragit RS PO。挤压温度在85℃至105℃范围内。
然而,热塑材料的缺点是Tg可能会过高以至不能在低至足以避免所述活性成分和/或赋形剂降解的温度下进行加工。
减轻此问题的解决办法是加入赋形剂材料,其具有增塑作用并由此降低热塑性聚合物的Tg。通过提供所述聚合物的内部润滑来减少内聚。
在我们的共同待审批的PCT专利申请WO 2005/000310(2004年6月27日中请,名称为多颗粒)中,我们描述了制剂的实施例,其中将相对高浓度的增塑剂(尤其是硬脂醇)和润滑剂(即硬脂酸)与丙烯酸共聚物和作为活性成分的盐酸羟考酮一起使用。挤压这些制剂所需的温度通常在75℃至95℃范围内。在这样的温度下,发现所述挤出物在加速的贮存条件(40℃/相对湿度75%)下贮存之后具有良好的化学稳定性,但是在体外试验中发现所述活性剂从制剂中释放的速度随时间变化。最初,发现硬脂酸对在不同pH的缓冲液中的释放速度有影响,由此要寻找供替代的润滑剂。发现二十二烷酸甘油酯是有效的。
需要保持新方法和制剂的可用性并且让控释制剂的挤压在相对低至中度的温度下进行,此温度不引起制剂中的热敏性或不耐热的活性成分或其它组分降解的危险,例如在75℃至95℃的范围内,并且使制剂挤压,可以排除制剂中的导致释放速度不稳定的常规组分。
发明简述
我们已经令人惊讶地发现显示出增塑作用的赋形剂也可具有有用的润滑性能。润滑作用降低了基质材料在挤压机到挤压室(chamber)壁、孔壁和螺杆(screw)表面以及挤压机中的其它元件的粘连。这种降低的结果是使挤压所需的转矩和必需提供给发动机的动力降低。
更具体地,结合WO 2005/000310的调查研究结果,我们出乎意料地发现通过完全消除润滑剂组分和增加增塑剂浓度,可获得具有增加的pH溶出(dissolution)稳定性的挤压制剂。但是发现了一些热溶出不稳定性。减少增塑剂的浓度降低了热溶出不稳定性,但导致需要较高加工温度和增加转矩。我们令人惊讶地发现通过适当调节增塑剂的浓度,可在低至中等的温度下进行加工以生产具有良好热溶出稳定性和良好pH溶出稳定性的挤压产品。
根据本发明,我们提供大量颗粒(plurality of particles),称为多颗粒,其包含药物活性剂。此药物活性剂通常为药学上可接受的盐的形式。在不需要包含增塑剂以外的润滑剂的情况下通过挤压制备多颗粒。
一方面,本发明提供一种制备挤出的药物组合物的方法,所述方法包括选择提供增塑和润滑性能的增塑赋形剂,和挤压包括药物活性剂和所述增塑赋形剂的混合物,所述增塑赋形剂以其起所述混合物的增塑剂作用和起所述混合物的润滑剂作用的有效量使用。优选地,混合物基本上不含另外的起润滑混合物作用的赋形剂。
由此,通过本发明,可以制备包含药物活性剂和具有润滑性能的增塑赋形剂的多颗粒,其基本上不含另外的润滑剂。
本发明的多颗粒使用的增塑剂辅助起润滑剂作用。因此,例如,此多颗粒包含药物活性剂、甲基丙烯酸铵共聚物、非支配性(non-dominating)增塑剂和透水性改性剂。我们所说的非支配性增塑剂是指,当加入一定量时显著影响玻璃化转变温度(Tg)和热塑性熔体粘度,从而能够在低至中度温度经过模具头口(die-head orifice)挤压,同时具有足够的润滑性能以避免在挤压机上产生由增加的转矩和提供发动机的动力所引起的不必要的应力。
在具体方面,本发明的多颗粒包含药物活性剂、甲基丙烯酸铵共聚物、透水性改性剂和非支配性增塑剂或基本上由这些组分组成,其中药物活性剂优选是羟考酮并且其通常为药学上可接受的盐的形式。
透水性改性剂优选是与pH值无关的透水性改性剂。更具体地,我们优选的是透水性改性剂的溶解度在胃和肠环境中是基本上相同的。
本发明的多颗粒不含支配或非支配性的润滑剂,一定数量的润滑剂在加工期间至少提供显著的润滑作用。我们所说的支配性润滑剂是指显著降低了热塑性聚合物对挤压机表面的粘连而没有显著降低热塑性聚合物的Tg的材料。非支配性润滑剂将明显降低所述粘连,但也会在某种程度上降低Tg。
本发明的多颗粒可被用作胶囊填充物。因此,本发明提供适于一天给药一次或两次的胶囊。可以提供控释制剂的其它剂型。
在本发明的另一方面,在此提供一种用本发明的控释制剂治疗患者的方法。所述方法包括向需要适当治疗,尤其是羟考酮止痛治疗的患者给予本发明的剂型,优选是包含羟考酮或其盐的剂型。在相关方面,本发明提供一种向患者提供止痛的方法,所述方法包括给予有效量的包含本发明的多颗粒的控释制剂,其中药物活性剂是止痛剂。本发明进一步延伸至止痛药物活性剂在制备用于向患者提供止痛的方法的单位剂量中的用途,所述方法包括给予有效量的包含本发明的多颗粒的控释制剂,其中药物活性剂是止痛剂。
所述多颗粒优选通过挤出可挤出的混合物来获得。这样的挤出可以是WO 9614058中公开的种类并被称为熔体挤出。实际上,聚合物软化但实际上可以不熔化。
在相关方面,我们提供一种用于制备包含活性剂,优选羟考酮或其盐的多颗粒的方法,所述方法包括可挤出混合物的挤出,所述混合物包含通常为药学上可接受的盐的形式的活性剂、甲基丙烯酸铵共聚物、非支配性增塑剂和透水性改性剂。
本发明的优选方法包括使用一种或多种也起润滑剂作用的增塑剂,挤出可挤出的混合物以形成多颗粒。
本发明进一步属于一种在可挤出的混合物的挤出时避免热降解的方法,所述可挤出的混合物包含热敏性药物活性剂、甲基丙烯酸铵共聚物、增塑剂、润滑剂和透水性改性剂,所述方法包括选择足够量的也起润滑剂作用的增塑剂。在相关方面,本发明提供一种挤出包含热敏性药物活性剂的可挤出的混合物的方法,包括使用足够量的也起润滑剂作用的增塑剂并且通过充分降低内聚力和粘着力来避免在高温下挤出的需要。
发明详述
本发明优选的多颗粒包含(a)活性剂,(b)水不溶性的甲基丙烯酸铵共聚物,(c)非支配性的增塑剂,和(d)透水性改性剂。
可用于本发明的制剂和方法的活性剂优选是那些在95-100℃温度以上热敏的活性剂。这样的活性剂包括如阿片样物质、HMGCoA还原酶抑制剂(抑制素)和抗生素。
候选的阿片样物质或阿片制剂包括阿芬太尼、烯丙罗定、阿法罗定、阿尼利定、苄吗啡、贝齐米特、丁丙诺啡、布托啡诺、氯尼他秦、可待因、环佐辛、地素吗啡、右吗拉胺、地佐辛、二乙酰吗啡、地恩丙胺、双氢可待因、双氢吗啡、地美沙朵、地美庚醇、二甲噻丁、吗苯丁酯、地匹哌酮、依他佐辛、依索庚嗪、乙甲噻丁、乙基吗啡、依托尼秦、芬太尼、氢可酮、氢吗啡酮、羟哌替啶、异美沙酮、凯托米酮、左啡诺、左芬啡烷、洛芬太尼、哌替啶、美普他酚、美他佐辛、美沙酮、美托酮、吗啡、吗啡-6-葡糖苷酸、麦罗啡、纳布啡、罂粟碱(narceine)、尼可吗啡、去甲左啡诺、去甲美沙酮、去甲吗啡、诺匹哌酮、去甲羟吗啡酮(noroxymorphone)、阿片、羟考酮、羟吗啡酮、阿片全碱、喷他佐辛、苯吗庚酮、非诺啡烷、非那佐辛、苯哌利定、匹米诺定、哌腈米特、propheptazine、三甲利定、丙哌利定、丙吡兰、右丙氧芬、瑞芬太尼、舒芬太尼、替利定、曲马多,以及药学上可接受的盐。
优选的阿片样物质/阿片制剂是:丁丙诺啡、可待因、双氢可待因、双氢吗啡、芬太尼、氢可酮、氢吗啡酮、吗啡、羟考酮、羟吗啡酮和曲马多,以及药学上可接受的盐。
候选的羟甲基戊二酰辅酶A还原酶抑制剂包括阿伐他汀(atorvastatin)、6-[4,4-双(氟代苯基)-3-(1-甲基-1H-四唑-5-基)-1,3-丁二烯基]-3,4,5,6-四氢-4-羟基-2H-吡喃-2-酮、3-(12-羧基-12-甲基十三烷基)-3-羟基戊二酸、西立伐他汀、达伐他汀、3,5-二羟基-9,9-二苯基-6,8-壬二烯酸甲酯、fluindostatin、氟伐他汀、6-[2-(4′-氟-3,3′,5-三甲基-2-联苯基)乙烯基]-4-羟基-2-氧代四氢吡喃、6-[2-[4-(4-氟苯基)-2-异丙基-6-苯基-3-吡啶基]乙烯基]-3,4,5,6-四氢-4-羟基-2H-吡喃-2-酮、洛伐他汀、美伐他汀、洛伐他汀酸(mevinolinic acid)、洛伐他汀J、洛伐他汀L、匹伐他汀、普伐他汀、罗苏伐他汀(rosuvastatin)、辛伐他汀,和药学上可接受的盐。
候选的抗生素包括氨基葡糖苷类,例如阿米卡星、庆大霉素、新霉素、奈替米星、妥布霉素;碳青霉烯类,例如亚胺培南、美罗培南;头孢菌素,例如头孢克洛、头孢羟氨苄、头孢孟多、头孢克肟、头孢噻肟、头孢匹罗、头孢泊肟、头孢丙烯、头孢他啶、头孢曲松、头孢呋辛、头孢氨苄、头孢唑林、头孢霉定(cephradine);头霉素类,例如头孢西丁;叶酸抑制剂,例如甲氧苄啶;林可酰胺类抗生素,例如克林霉素;大环内酯类,例如阿奇霉素、克拉霉素、红霉素、泰利霉素;单酰胺菌素,例如氨曲南;硝基咪唑类,例如双唑泰栓、替硝唑;青霉素类,例如阿莫西林、氨苄西林、哌拉西林、青霉素G、氟氯西林、替卡西林;喹诺酮类,例如环丙沙星、左氧氟沙星、萘啶酸、氧氟沙星;链霉杀阳菌素(streptogramin),例如奎奴普丁/达福普汀;磺胺类药,例如磺胺林;和四环素类,例如地美环素、多西环素、赖甲环素、米诺环素、土霉素、四环素、金霉素,和药学上可接受的盐。
优选的活性剂是羟考酮,其为游离碱或它的药学上可接受的盐,尤其是盐酸盐。对羟考酮的更加详尽的资料,我们参见我们的共同待审批的名称为多颗粒的PCT专利申请WO 2005/000310,在此引用作为参考。另一种优选的活性剂是羟吗啡酮,其为游离碱或其药学上可接受的盐,尤其是盐酸盐。
水不溶性的甲基丙烯酸铵共聚物(也称为水不溶性的铵基甲基丙烯酸盐共聚物),适宜地是磨成细粉的Eudragit RS PO或Eudragit RS 100。它具有以下性能:
·不溶性至水溶性差,
·低水渗透性,
·已证明与各种药物以及其它添加剂具有相容性,
·在没有分解的中度温度下或较低温度下在合适的增塑剂存在下可挤出,
·对于预定的存贮时间和条件稳定,
·热稳定性。
特别地,Eudragit RS PO是低水渗透性的热塑性共聚物,其可以显著地延迟在它的基质中所包埋的羟考酮的释放。将其描述为对于基质制剂的低渗透性、与pH值无关的聚合物粉末。它是丙烯酸酯和甲基丙烯酸酯的共聚物,具有低含量的季铵基以控制渗透性,并且平均分子量大约为150,000。
非支配性的增塑剂用来软化不溶性甲基丙烯酸铵共聚物以使其更易于挤出共聚物。为此,通常的增塑剂易于与不溶性甲基丙烯酸铵共聚物混合以产生降低的拉伸强度、较低的软化温度,并且降低聚合物的玻璃化转变温度Tg。通过提供聚合物的内部润滑来减少内聚。增塑剂通常选自水不溶性的固体,如鲸蜡醇、硬脂醇和十六醇十八醇混合物;水溶性的固体,如山梨醇和蔗糖以及高分子量的聚乙二醇;水不溶性的液体,如癸二酸二丁酯和柠檬酸三丁酯以及水溶性的液体,如柠檬酸三乙酯、丙二醇和低分子量的聚乙二醇。优选在室温下为固体的增塑剂。硬脂醇是优选的增塑剂。另外优选的增塑剂是高分子量的聚乙二醇,优选具有4000-10000范围内的分子量的聚乙二醇,如PEG 6000。
更普遍地,根据本发明可使用的其它增塑剂包括可以模仿所指出的典型增塑剂之一的增塑剂。因此这类其它增塑剂具有与那些选自如下的材料相接近的增塑和润滑性能,这些材料选自鲸蜡醇、硬脂醇、十六醇十八醇混合物、山梨醇、蔗糖、高分子量的聚乙二醇(优选分子量范围为4000-10000,例如PEG 6000)、癸二酸二丁酯、柠檬酸三丁酯、柠檬酸三乙酯、丙二醇和低分子量的聚乙二醇。例如,合适的其它增塑剂具有与鲸蜡醇或硬脂醇、或十六醇十八醇混合物、或山梨醇、或蔗糖、或高分子量的聚乙二醇(优选具有4000-10000范围内的分子量,例如PEG 6000)、或癸二酸二丁酯、或柠檬酸三丁酯、或柠檬酸三乙酯、或丙二醇、或低分子量的聚乙二醇相接近的增塑和润滑性能。优选具有与硬脂醇或PEG 6000相接近的增塑和润滑性能。
具有与此类典型增塑剂接近的增塑和润滑性能的增塑剂可以通过以下标准确定:
(a)在给定浓度的Eudragit RS PO下通过差示扫描量热法对增塑作用测试时,会在由相同浓度的典型增塑剂所提供的降低作用的±50%内降低Eudragit聚合物的Tg(以℃测量);
(b)在给定浓度的Eudragit RS PO下在IKAMKD 0,6-H 60高性能测量捏和机中对润滑作用测试时,会在由相同浓度的典型增塑剂所提供的减少作用的±50%内减少转矩(以Nm测量);
其中Tg和转矩的数值是三次测试结果的平均值。
优选地,在(a)中的降低在由典型的增塑剂所达到的降低作用的±25%范围内。
优选地,在(b)中的减少在由典型的增塑剂所达到的减少作用的±25%范围内。
因此,可以使用合适的其它增塑剂来获得试验(a)的增塑作用和试验(b)的润滑作用。
透水性改性剂调节药物从剂型中的分泌。通常,透水性改性剂用来增加药物释放,特别是在溶出的后期,虽然我们还想让透水性改性剂在有些情况下起缓释作用。用于改进挤出的多颗粒的透水性的试剂的例子包括不溶性的亲水性芯吸剂、水合以形成凝胶来控制水移动的胶凝剂、高分子量的聚乙二醇(如PEG 6000),或水可渗透性的甲基丙烯酸铵共聚物,也称为铵基甲基丙烯酸盐共聚物,如磨成细粉的Eudragit RL PO或Eudragit RL 100。Eudragit RL PO被描述为对于基质制剂的高可渗透的、与pH值无关的聚合物粉末。它是丙烯酸酯和甲基丙烯酸酯的共聚物,具有达到渗透性的季铵基的含量,并且平均分子量大约为150,000。
例如,微晶纤维素、高分子量的水凝胶如高粘度羟丙基甲基纤维素和高粘度聚(环氧乙烷),和水可渗透的甲基丙烯酸铵共聚物可以用来提高活性剂的总释放量。在最后的方面,用作试剂(d)以改进透水性的甲基丙烯酸铵共聚物不同于用作成分(b)的水不溶性的甲基丙烯酸铵共聚物,后者由于被季铵基取代的程度不同因而透水性更高。
微晶纤维素改善水的扩散和交换并由此提高药物释放。微晶纤维素起不溶性但亲水性的芯吸剂的作用。微晶纤维素的替代物是交联羧甲纤维素钠、交聚维酮或淀粉乙醇酸钠。
最初将高分子量级别(高粘度)的羟丙基甲基纤维素(HPMC)水合以形成控制水移动的浓凝胶。然后将水合凝胶随时间逐渐溶解和/或侵蚀,留下多孔和高渗透性的结构。依据这种假设,据信高粘度的HPMC不能显著地增加药物在早期的释放,但增加了在后面时间点的释放。候选的其它胶凝剂包括聚环氧乙烷、果胶、刺槐豆胶或黄原胶。
Eudragit RLPO是高度透水性的类似物并可以显著地提高释放速度和总的药物释放。
下表给出成分(a)至(d)的合适的百分含量,所述百分含量基于四种成分的总重量。
通常的范围 | 优选的范围 | 最优选的范围 | |
活性剂 | 3-50 | 5-40 | 8-30 |
不溶性甲基丙烯酸铵共聚物 | 25-85 | 35-75 | 55-70 |
非支配性增塑剂 | 1-30 | 3-25 | 10-20 |
透水性改性剂 | 1-30 | 3-25 | 10-20 |
还可使用其它的添加剂以在一组预定规格内生产多颗粒。填充剂(例如乳糖和磷酸钙)广泛地用作药物赋形剂并可以用于本发明以改变释放速度和/或总释放量。也可认为其它的释放调节剂能调节释放速度和/或提高总释放量。抗氧化剂(例如丁基羟基甲苯(butylated hydroxytoluene))可通过防止或减少热敏的或不耐热的活性成分或赋形剂在较高的生产温度下的化学降解,来用于稳定本发明的制剂。
本发明的多颗粒不包括在加工期间足以提供显著的或有效量的润滑作用的一定量的支配或非支配性的润滑剂。典型的支配性和非支配性的润滑剂是固体,如硬脂酸、二十二烷酸甘油酯、硬脂酸镁,硬脂酸钙、滑石粉或硅氧烷二氧化物(silicone dioxide)(熔凝二氧化硅)。
特别优选的制剂包含7.5-9%w/w,优选大约8.3%w/w的盐酸羟考酮;55-70%w/w,优选约61.7%w/w的Eudragit RS PO;10-20%w/w,优选大约15%w/w的Eugragit RL PO;和10-20%w/w,优选大约15%w/w的硬脂醇。
此外,对于使用1号胶囊以40毫克和80毫克浓度提供一日两次的胶囊的需要导致对药物装载量的进一步地重新评价,在这方面我们已确定了下列成分(a)至(d)的合适的百分含量列于下表中,所述百分含量基于四种成分的总重量。
通常的范围 | 优选的范围 | 最优选的范围 | |
活性剂,优选盐酸羟考酮 | 25-32 | 29-31 | 大约30,如30.3 |
不溶性甲基丙烯酸铵共聚物 | 25-85 | 35-75 | 50-60 |
非支配性增塑剂 | 1-30,如1-10 | 3-25 | 5-15 |
透水性改性剂 | 1-30,如10-20 | 3-25 | 3-15 |
依据本发明,当在25℃/60%相对湿度(“RH”)或30℃/65%RH下贮存长达3个月时,优选的制剂(例如含有8.3%w/w盐酸羟考酮)在根据本文公开的方法测试时在溶出方面没有显示出或显示出可忽略的变化。在40℃/75%RH下测试时,在溶出方面有微小变化,例如在一个月的贮存期后观察到有3-5%的减少,但是在继续贮存时没有进一步地变化。
在本发明的方法中,将所述成分混合,然后挤出。此类步骤的详情在WO 9614058中给出,在此引用作为参考。
对于本发明,我们优选使用双螺杆挤出机,双螺杆挤出机可以具有一起旋转或反向旋转的螺杆。基本上,通常在相对低的温度(例如10-20℃)下,通过送料器将粉末形式的混合物送入桶的第一部分,以确保恒量的粉末流向高温的桶。送料器向挤压机提供均匀流量的混合物。所需粘度是不规则的并且不同的进料速率可以产生具有不同物理性质(如密度和孔隙率)的多颗粒。
优选的挤压机设计有用于运送、混合、压缩、加热和软化混合物的任务的双螺杆,优选反向旋转的螺杆。根据混合物的组分以及挤出条件的选择,可将所述混合物熔化和软化。进行这种挤出过程的重要部分的螺杆是由选自各种螺杆元件和捏和机元件的不同的小元件构成的。通过改变螺杆元件和可能的捏和机元件的类型、长度和结构,可以显著地改变混合和捏和的时间。短暂的停留时间和中至低度的剪切力有助于安全加工和稳定产品(甚至对于热敏药物)。可利用的挤压机的例子包括那些由Leistritz、Brabender、Randcastle和Kurimoto Co.Ltd生产的挤压机,例如Leistritz Micro18型机器。
螺杆的旋转速度可影响多颗粒生产的质量。在没有适当的混合物进料速度的补偿的情况下,高旋转速度可产生药物释放速度可变的高孔隙率的多颗粒。另一方面,减缓螺杆转动会导致不必要的长久的停留时间。需要有连接到挤压机桶的真空装置以除去软化的混合物内所夹带的空气并由此产生密集的低孔隙率的多颗粒。
通常将挤压头设计成能产生固定直径的许多条形物。可以改变孔的数量、形状和直径以适于预定的规格。
除了螺杆的速度之外,另一个主要影响参数是螺杆的转矩、单独的桶温度和挤压头的压力和温度。
根据本发明的切割程序,将挤出的条形物从传送机的模具封头(die-head)上折断。此条形物的直径受混合物进料速率、螺杆速度、桶温、模具封头的设计以及孔直径、运送速度和夹辊(nip rolls)速度的影响。运送适于将挤出的条形物传送到激光计量装置或其它测量装置以监测所要求的直径,如1.0mm。在这种运送过程中,条形物逐渐冷却下来,但基本上保持柔韧。在激光计量装置上、造粒机进料夹辊之间以及在进入造粒机期间,柔韧的条形物保持完整。取决于制剂,快速冷却的条形物可失去它们的完整性并且在经过夹辊和造粒机期间粉碎成为不均匀形状和不规则尺寸的多颗粒。
通过夹辊将条形物送入造粒机。造粒机例如使用旋转切割机将送入的条形物切割成预定的长度,例如1.0mm。条形物的送入速率和造粒机的切割速度决定多颗粒的长度。
总的来说,粉末进料器、挤压机、传送机、激光计量装置和造粒机之间的共同排列/相互作用是影响最终多颗粒产品的数量、质量和重复性的重要参数。
通过这种切割程序产生的多颗粒典型地呈圆筒状,在该切割程序中挤出的条形物从模具封头折断(carry away)。
在另一种优选的切割程序中,当挤出的混合物在压力下形成并在模板(die plate)的孔仍然柔软时,切割机切割挤出的混合物。切割机适宜地是具有一个或多个刀片的旋转切割机,其中刀片扫过模具封头的表面而经过孔。优选为两个完全相反的刀片。理想地,内外表面边界至挤出孔都涂有不粘性材料,例如聚四氟乙烯(PTFE)。随着切割的挤出颗粒膨胀并冷却,它们趋向于形成圆形的表面。通过适当的调节模具封头的挤出压力、挤出速率、模具封头的设计和孔直径以及孔的数量,以及刀片的速度,有可能获得球形或近似球形的多颗粒。或者,如果需要,可以调整该过程以产生棒条体。在一个实施方案中,将一股空气直吹到模具封头的表面,低温的空气来冷却挤出物并加速凝固,从而减少粘结。
通过这种方法产生的球形多颗粒表现出许多潜在的优点:
较好的批次间的重现性。
更容易包衣并且所需包衣重量较低。
较好的胶囊填充和较高的收率。
在升高的贮存温度下更稳定。
更多的干扰抵抗性(tamper resistant)。
减少了下游处理。
减少或消除了在运送条形物和将条形物制粒期间产生的一些问题,例如条形物粉碎成不同长度的小粒和静电。
可将多颗粒分成单位剂量,以使每个单位剂量包括足以对哺乳动物,优选人类患者提供止痛的羟考酮剂量。羟考酮的合适剂量是5-400毫克,尤其是5毫克、10毫克、20毫克、40毫克、80毫克、120毫克或160毫克单位剂量。在这方面,单位剂量含有有效量的治疗活性剂以使患者疼痛减轻和/或止痛。给予患者的羟考酮的剂量会由于许多因素而变化,包括患者的体重、疼痛的严重程度、代谢状态和耐受性、以及所给予的任何其它治疗剂的性质。
在一个优选的实施方案中,将多颗粒填充入硬胶囊,每个胶囊含有单位剂量。胶囊中的填充重量优选80至500毫克,更优选120至500毫克。在本发明的变体中,单位剂量的多颗粒可混入到其它固体药物剂型中,例如使用压缩或成形为片剂,通过填充入小药囊或通过将挤出制品形成栓剂形式。
在本发明的优选方面中和如以下的实施方案所述,根据本发明选择的成分使制备多颗粒以及含有盐酸羟考酮的胶囊成为可能,并且所述多颗粒和胶囊模拟OxyContin片剂的体外和优选在体内的释放特征。特别地,此组合能达到适当的羟考酮的初期释放(早期),同时在溶出后期保持活性成分的高总释放量。在加速条件下贮存之后,在体外试验中此类优选形式的制剂表现出良好的热化学稳定性和热物理/溶出速率稳定性。
虽然可以使用其它药学上可接受的盐,但盐酸羟考酮是优选的羟考酮形式。
指出羟考酮用于中度至严重疼痛的治疗。当连续和昼夜不停的供给需要的止痛剂一段持续时间时,控释的羟考酮产品能够控制疼痛。
例如在WO 9310765中描述了提供羟考酮控制释放的羟考酮制剂。典型地使用制粒方法。在实施例3中,由盐酸羟考酮、乳糖、聚维酮、Eudragit RS30D、三醋汀、硬脂醇、滑石粉和硬脂酸镁的混合物来制备含10毫克盐酸羟考酮的片剂。将调整了用量的相同成分应用于实施例4中以制备含20毫克盐酸羟考酮的片剂。最终产品表现出不同的药物代谢动力学和药效性能。
示例性地,10毫克和20毫克羟考酮片剂的体外释放速度在WO 9310765中给出,如下:
释放的盐酸羟考酮% | ||
小时 | 10毫克 | 20毫克 |
1 | 38.0 | 31 |
2 | 47.5 | 44 |
4 | 62.0 | 57 |
8 | 79.8 | 71 |
12 | 91.1 | 79 |
18 | 94.9 | 86 |
24 | 98.7 | 89 |
这种类型和具有这样释放速率的片剂形成商业化制品的基础。控释的羟考酮片剂以OxyContin(注册商标)片剂获得,此片剂被设计成在12小时期间提供羟考酮的控制释放。
从60%至87%的口服生物利用度的OxyContin片剂中良好地吸收羟考酮。OxyContin片剂相对于速释的口服剂型的相对口服生物利用度是100%。在正常志愿者的药物代谢动力学研究中重复给药,在24-36小时内达到了稳态水平。
根据如以下数据所示的血浆峰浓度(Cmax)和吸收程度(生物利用度)(AUC),已经将剂量比例确定为10毫克、20毫克,40毫克、80毫克和160毫克片剂浓度。
平均值[偏离系数(coefficient variation)%]
用药法 | 剂型 | AUC(ng.hr/mL)* | Cmax(ng/mL) | Tmax(hrs) | 谷浓度(ng/mL) |
单剂量 | 10mg OxyContin片剂 | 100.7[26.6] | 10.6[20.1] | 2.7[44.1] | n.a. |
20mg OxyContin片剂 | 207.5[35.9] | 21.4[36.6] | 3.2[57.9] | n.a. | |
40mg OxyContin片剂 | 423.1[33.3] | 39.3[34.0] | 3.1[77.4] | n.a. | |
80mg OxyContin片剂** | 1085.5[32.3] | 98.5[32.1] | 2.1[52.3] | n.a. | |
多剂量 | 10mg OxyContin片剂q12h | 103.6[38.6] | 15.1[31.0] | 3.2[69.5] | 7.2[48.1] |
5mg速释q6h | 99.0[36.2] | 15.5[28.8] | 1.6[49.7] | 7.4[50.9] |
*对于单剂量AUC=AUC0-inf,多剂量AUC=AUC0-T
**在志愿者接受可以增加吸收的纳曲酮时得到的数据
羟考酮主要是在尿中以结合和非结合代谢产物的形式被广泛地代谢和除去。与速释羟考酮的3.2小时相比,给予OxyContin片剂后的羟考酮的表观消除半衰期是4.5小时。
与肠胃外剂量相比,大约60%至87%的口服剂量的羟考酮到达中央室。这种高口服生物利用度是由于低预先全身性代谢和/或首过代谢。在正常的志愿者中,对于速释口服羟考酮而言,吸收的t1/2是0.4小时。相反,OxyContin片剂表现出具有0.6和6.9小时的两个表观吸收半衰期的双相性吸收图形,该图形描述了羟考酮从所述片剂中的初始释放,继之延续的释放。
根据本发明的优选方面,我们提供大量的羟考酮颗粒,称为羟考酮多颗粒。
一方面,我们提供具有羟考酮的高初始释放和高总释放量的羟考酮多颗粒。释放性能可以用在对照体外条件下羟考酮的释放来表示,所述对照体外条件例如为模拟人的胃液或人的肠环境。可以测试在生理学的pH值(例如大约1.2或大约6.8的pH值)下的释放。试验方法还可以设计成反映在通过身体期间从胃到肠的转换。
特别地,我们发现透水性改性剂的内含物(inclusion)可以允许羟考酮的多颗粒的挤出,羟考酮的多颗粒显示出与OxyContin片剂的某些生物等效性。所述多颗粒可以具有与OxyContin片剂相接近的药物代谢动力学和/或药效性能。特别地,所述多颗粒可以具有与OxyContin片剂相接近的体外释放速度。
在相关方面,我们提供了羟考酮多颗粒,其包含通常以药学上可接受的盐的形式的羟考酮、甲基丙烯酸铵共聚物、增塑剂(它还作为润滑剂)和透水性改性剂。
使用羟考酮多颗粒的剂型优选是单位剂型,并且优选显示出与OxyContin片剂的某些生物等效性。此剂型可以具有与OxyContin片剂相接近的药物代谢动力学和/或药效性能。特别地,所述剂型可以具有与OxyContin片剂相接近的体外释放速度。
本发明的羟考酮多颗粒优选具有与OxyContin片剂相接近的体外释放速度。OxyContin片剂的释放速度所值得注意的是高初始释放和高的总释放量。优选地,羟考酮的释放基本上与大约1至大约7的pH值范围内的pH值无关。为此,基本上与pH值无关的释放是指对于在pH值为6.8的模拟肠液中测试时给予的制剂,在任何给定的时间点,以制剂中羟考酮的初始量的百分比计的羟考酮的释放量基本上等于在pH值为1.2的模拟胃液中测试时的基于制剂中羟考酮的初始量的羟考酮释放量的百分比。当各个数量具有±30%,更优选±20%及最优选±15%的差异时,此释放量基本上相等。
除非另有说明,我们通过指定方法测定释放速度,此方法包括在900ml没有酶的pH值为1.2的USP模拟胃液中、在37℃、在100rpm的条件下使用Ph.Eur.篮式溶出装置(basket dissolution apparatus)。在一个变体中,溶出介质是没有酶的pH值为6.8的模拟肠液。
对于pH值为1.2的模拟胃液,本发明的羟考酮多颗粒通常在1小时后释放出至少15%的羟考酮,表现出高的初始释放。优选地,在1小时后它们释放至少20%,更优选至少25%以及最优选至少35%的羟考酮。
本发明的羟考酮多颗粒通常在2小时后释放出至少30%的羟考酮,表现出高的初始释放。优选地,在2小时后它们释放至少40%,更优选至少50%以及最优选至少55%的羟考酮。
本发明的羟考酮多颗粒通常在4小时后释放出至少60%的羟考酮,表现出高的初始释放。优选地,在4小时后它们释放至少70%,更优选至少75%以及最优选至少80%的羟考酮。
本发明的羟考酮多颗粒通常在10小时后释放出至少75%的羟考酮,表现出高的总释放量。优选地,在10小时后它们释放至少80%,更优选至少90%以及最优选至少95%的羟考酮。
此外,优选在8小时后有至少85%的羟考酮释放。本发明的羟考酮多颗粒可以在12小时后释放出100%的羟考酮,表现出高的总释放量。
优选的本发明多颗粒包含(a)羟考酮、(b)水不溶性的甲基丙烯酸铵共聚物、(c)增塑剂和(d)透水性改性剂。成分的选择使得制备多颗粒以及包含羟考酮的胶囊变成可能,所述多颗粒及胶囊模拟OxyContin片剂的体外和优选体内的释放特征。特别地,包括透水性改性剂的组合能达到足够的羟考酮的初期释放(早期),同时在溶出后期保持活性成分的高的总释放量。
优选将本发明的胶囊或其它单位剂型设计成每隔大约12小时给药。为此,当通过USP划桨方法(Paddle Method)(参见美国药典XXII,1990),在900ml缓冲水溶液(pH值在1.6至7.2之间)中,在100rpm、37℃的条件下测定时,所述单位剂型适宜地在1小时后具有12.5-42.5%(重量)的羟考酮释放,2小时后具有25-56%(重量)的羟考酮释放,4小时后具有45-75%(重量)的羟考酮释放以及6小时后具有55-85%(重量)的羟考酮释放的羟考酮的体外溶出速率。此外,我们优选在所述剂型给药后的2-4.5小时之间在体内达到羟考酮的血浆峰浓度。
对于此类羟考酮制剂的所需特征的更多信息在WO 9310765中给出,在此引用作为参考。
在pH值为1.2的模拟胃液中使用我们指定的方法,释放速度适宜地如下所述:
优选的范围
小时 | 释放的下限% | 释放的上限% |
1 | 16 | 56 |
2 | 37 | 77 |
4 | 60 | 100 |
10 | 75 | 100 |
更优选的范围
小时 | 释放的下限% | 释放的上限% |
1 | 21 | 51 |
2 | 42 | 72 |
4 | 65 | 95 |
10 | 80 | 100 |
最优选的范围
小时 | 释放的下限% | 释放的上限% |
1 | 24 | 48 |
2 | 45 | 69 |
4 | 68 | 92 |
10 | 83 | 100 |
在pH值为6.8的模拟肠液中使用我们指定的方法,释放速度适宜地如下所述:
优选的范围
小时 | 释放的下限% | 释放的上限% |
1 | 11 | 51 |
2 | 28 | 68 |
4 | 48 | 88 |
10 | 61 | 100 |
更优选的范围
小时 | 释放的下限% | 释放的上限% |
1 | 16 | 46 |
2 | 33 | 63 |
4 | 53 | 83 |
10 | 66 | 96 |
最优选的范围
小时 | 释放的下限% | 释放的上限% |
1 | 19 | 43 |
2 | 36 | 60 |
4 | 56 | 80 |
10 | 69 | 93 |
作为每隔大约12小时给药的替代方案,将本发明的胶囊或其它单位剂型设计成每隔大约24小时给药。为此,当通过USP篮式方法,在pH值为1.6至7.2之间的900ml缓冲水溶液中,在100rpm、37℃的条件下测定时,所述单位剂型适宜地具有在1小时为0%-大约40%,在4小时为大约8%-大约70%,在8小时为大约20%-大约80%,在12小时为大约30%-大约95%,在18小时为大约35%-大约95%以及在24小时为大于大约50%的羟考酮的体外溶出速率。此外,我们优选在所述剂型的稳定状态下给药后的大约2至大约17小时在体内达到羟考酮的血浆峰浓度。
对于此类羟考酮制剂的所需特征的更多信息在WO 02087512中给出,在此引用作为参考。
在变体中,本发明提供含有羟考酮和有效预防干扰的羟考酮拮抗剂的单位剂量。在这方面,参考WO 0313433,其在此全文引用作为参考。特别地,所述单位剂量可以含有羟考酮和纳曲酮。可以使用本领域已知的其它的阿片样物质拮抗剂,例如纳洛酮。
为此,本发明的另一方面提供羟考酮的挤出的多颗粒和羟考酮拮抗剂(如纳曲酮或纳洛酮)的挤出的多颗粒。纳曲酮多颗粒在常规给药,例如具有非释放包衣时不释放纳曲酮。优选两者在视觉上和物理上都是相同的。
本发明的一个重要方面是具有小于500毫克的单位剂量填充的胶囊,其包含高达大约350毫克的羟考酮多颗粒和高达大约200毫克的防干扰的羟考酮拮抗剂。例如,可以有120至300毫克羟考酮多颗粒和125至175毫克防干扰的羟考酮拮抗剂的多颗粒。
附图
参照附图,其中:
图1图式的代表实施例中所用的Leistritz Micro 18双螺杆挤出机的一个螺杆行列(screw train)。
图2至5提供所示产品的体外释放速度。
本发明的实施例
标准化条件
对于以下实验工作,为盐酸羟考酮混合物挤出确定标准化条件。除非另有说明,挤压机是以每分钟140转的螺杆速度运行的Leistritz Micro 18,其具有2.6千克/小时的进料速度,生产1毫米直径和1毫米长度的小粒。
如图1所示,所述螺杆的设计使用由分布器(Leistritz USA)的生产编码标明的部件。目的是通过增加额外的混合元件‘GGC2’或‘ZS’来优化混合以避免混合问题,并通过包括‘FD’元件来增加停留时间以避免变湿问题。
挤压机包括十个区域,在图1上区域1从0延伸至5D,在图1上区域2从5D延伸至10D,依此类推直至区域8从35D延伸至40D,之后区域9和10位于挤压机机头。
典型的分批区域温度在后面给出。
释放速度的研究
在37℃、在900ml没有酶的pH值1.2的USP模拟胃液(SGF)中每分钟100转的条件下,使用Ph.Eur.篮式溶出装置测试实施例1至7的羟考酮的挤出多颗粒的溶出。用标准HPLC方法测定。
此外,在37℃、在900ml没有酶的pH值6.8的模拟肠液(SIF)中每分钟100转的条件下,使用Ph.Eur.篮式溶出装置测试实施例2的羟考酮的挤出多颗粒的溶出。再次,用标准HPLC方法测定。
测定在体外的释放速度,并将结果绘制在附图2至5中。
实施例1至3
准备下列具有8.3%w/w载药量的试验批次,其中重量是毫克/单位剂量。
重量(quantity)(mg)/单位剂量重量(占总量的百分比) | |||
实施例1 | 实施例2 | 实施例3 | |
盐酸羟考酮 | 10.0(8.3%) | 10.0(8.3%) | 10.0(8.3%) |
Eudragit RS PO | 79.0(65.8%) | 71.0(59.2%) | 74.0(61.7%) |
Eudragit RL PO | 18.0(15.0%) | 26.0(21.7%) | 18.0(15.0%) |
硬脂醇 | 13.0(10.8%) | 13.0(10.8%) | 18.0(15.0%) |
总计 | 120mg | 120mg | 120mg |
典型的分批区域温度(℃)、用于加工实施例1至3的制剂的熔化压力和转矩如下:
实施例 | 区域温度(℃) | |||||||
1 | 2 | 3-6 | 7-8 | 9 | 10 | 熔化压力(巴) | 转矩(%) | |
1 | 14 | 40 | 125 | 115 | 120 | 125 | 74-85,如74-81,75-83或79-85 | 82-91,如82-85,83-87或86-91 |
2 | 14 | 40 | 125 | 115 | 120 | 125 | 72-90如72-79或83-90 | 85-92如88-92 |
3 | 14 | 40 | 103 | 102 | 105 | 105 | 83-90 | 87-90 |
实施例3的制剂是目前优选的8.3%w/w载药量的产品。
实施例4和5
制备具有30.3%w/w载药量的Q12Hr制剂,以使其能够填充入1号胶囊:在132毫克剂量重量中有40毫克以及在264毫克剂量重量中有80毫克。此组分含量能够达到相对低的加工温度。在加工期间将传送机和造粒机速度最优化。显示出实施例4和5的加工条件。
实施例4是优选的30.3%w/w载药量的产品。
重量(mg)/单位剂量重量(占总量的百分比)
实施例4 实施例5
盐酸羟考酮 40.0(30.3%) 40.0(30.3%)
Eudragit RS PO 68.0(51.5%) 66.0(50.0%)
Eudragit RL PO 8.0(6.1%) 7.0(5.3%)
硬脂醇 16.0(12.1%) 19.0(14.4%)
总计 132mg 132mg
实施例4:挤压机的加工条件:
挤压机: Leistritz Micro 18
螺杆结构: 参见图1中的简图
进料速度(千克/小时): 2.0
螺杆速度(rpm): 120
模板孔直径(mm): 1.0(8孔板)
小粒尺寸: 1.0mm×1.0mm(范围在0.8-1.2mm)
实施例4:
加热区域 | 1 | 2 | 3-8 | 9-10 |
温度*(℃) | 14 | 40 | 107 | 109 |
转矩(%): 94-97
熔化压力(巴): 94-101
模板孔深度(mm): 3.7
实施例5:挤压机加工条件:
挤压机: Leistritz Micro 18
螺杆结构: 参见图1中的简图
进料速度(千克/小时): 2.6
螺杆速度(rpm): 140
模板孔直径(mm): 1.0(8孔板)
小粒尺寸: 1.0mm×1.0mm(范围在0.8-1.2mm)
实施例5:
加热区域 | 1 | 2 | 3-6 | 7-8 | 9-10 |
温度*(℃) | 14 | 40 | 102-103 | 103 | 104 |
转矩(%): 81-84
熔化压力(巴): 79-83
模板孔深度(mm): 3.7
实施例6
基于实施例5的批次,调整增塑剂的含量,来制备制剂。使用孔深度为2.4毫米的挤压模板进行该批次的加工。将挤压模板深度从3.7毫米调整到2.4毫米之后,得到加工条件即熔化压力和螺杆转矩的进一步改进。所使用的温度和模板条件显示如下:
重量(mg)/单位剂量重
量(占总量的百分比)
批次 实施例6
盐酸羟考酮 40.0(30.3%)
Eudragit RSPO 70.0(53.0%)
Eudragit RLPO 4.0(3.0%)
硬脂醇 18.0(13.6%)
总计 132mg
实施例6:
加热区域 | 1 | 2 | 3-6 | 7-8 | 9-10 |
温度*(℃) | 14 | 40 | 102-103 | 102-103 | 104 |
转矩(%): 74-76
熔化压力(巴): 70-73
模板孔深度(mm): 2.4
对实施例6的胶囊(也称为F764/61)进行溶出试验。如图5中所示,该制剂的羟考酮溶出曲线良好地相比于称为PN2797(装入胶囊的产品)的目标曲线。OxyContin40mg片剂的商品化批次的曲线也在图5中给出。
实施例7
设计出另一种具有减少硬脂醇含量的制剂以确保改善的贮存稳定性并使贮存期间溶出曲线的变化降到最低。这种方法在前面就显示出在对10/20毫克剂量产品制剂(例如在120毫克胶囊填充重量中有10毫克盐酸羟考酮和在240毫克胶囊填充重量中有20毫克盐酸羟考酮)的加速贮存条件下,改善溶出速率的稳定性。
实施例7是优选的30.3%w/w载药量的产品。由于这种制剂达到最大转矩限度,因此不能在Leistritz Micro 18挤压机上确定出容许的挤压加工条件。但是,建议这种制剂在Leistritz Micro 27挤压机上进行加工,其能够操作更高的转矩水平,以产生具有改进贮存稳定性的产品。
重量(mg)/单位剂量重
量(占总量的百分比)
批次 实施例7
盐酸羟考酮 40.0(30.3%)
Eudragit RSPO 71.0(53.8%)
Eudragit RLPO 5.0(3.8%)
硬脂醇 16.0(12.1%)
总计 132mg
实施例8
挤出的羟考酮多颗粒和挤出的纳曲酮多颗粒的共同胶囊化可用于抗干扰的组合产品。
使用单或双阶段填充方法,可将如WO 03013433中所述的羟考酮多颗粒和纳曲酮多颗粒填入胶囊中。所填充的纳曲酮多颗粒的重量是150毫克,其中含有8毫克纳曲酮。达到10毫克至40毫克羟考酮剂量的羟考酮多颗粒的建议填充重量如下(参见下表):
1.120毫克和240毫克的8.3%(w/w)载药量的多颗粒分别用于10毫克和20毫克的羟考酮剂量。
2.160毫克的25%(w/w)载药量的多颗粒用于40毫克的羟考酮剂量。
3.132毫克的30.3%(w/w)载药量的多颗粒用于40毫克的羟考酮剂量。
此外,也可以考虑5毫克和80毫克的羟考酮剂量,它们分别具有如下的胶囊填充重量:
1.60毫克的8.3%(w/w)载药量的多颗粒用于5毫克的羟考酮剂量。
2.320毫克的25%(w/w)载药量的多颗粒用于80毫克的羟考酮剂量。
3.264毫克的30.3%(w/w)载药量的多颗粒用于80毫克的羟考酮剂量。
使用单阶段填充方法或者优选地使用双阶段填充方法,可达到所需比例的羟考酮和纳曲酮多颗粒的胶囊填充物。在单阶段填充方法中,将各比例的多颗粒可预先混合并通过手工或优选通过自动操作的方法填入胶囊。通过优选的双阶段填充方法,可在第一阶段通过手工或优选通过自动操作的方法填入一种类型的多颗粒。然后可在第二填充阶段再通过手工或者优选通过自动操作的方法填入第二种类型的多颗粒。
基于载药量的胶囊浓度范围的理论填充重量在下表中给出:
羟考酮mg/胶囊 | 羟考酮载药量8.3%w/w | |
羟考酮多颗粒(mg) | 羟考酮和纳曲酮多颗粒(mg) | |
10 | 120 | 270(1号胶囊) |
20 | 240 | 390(0号胶囊) |
40 | 480 | 630(不能填充) |
5+ | 60* | 210(1号胶囊) |
80+ | 960 | 1110(不能填充) |
*重量低于假定的最小可能的胶囊填充重量。
+表示可能性的注解,如果需要所述范围内较低或较高的浓度。
120毫克纳曲酮多颗粒+20%包衣。
羟考酮mg/胶囊 | 羟考酮载药量25%w/w | |
羟考酮多颗粒(mg) | 羟考酮和纳曲酮多颗粒(mg) | |
10 | 40* | 低于填充量 |
20 | 80 | 230(1号胶囊) |
40 | 160 | 310(0号胶囊) |
5+ | 20* | 低于填充量 |
80+ | 320 | 470(0E号胶囊) |
*重量低于假定的最小可能的胶囊填充重量。
+表示可能性的注解,如果需要所述范围内较低或较高的浓度。
120毫克纳曲酮多颗粒+20%包衣。
Claims (20)
1.一种制备挤出的药物组合物的方法,所述方法包括选择提供增塑和润滑性能的增塑赋形剂,和挤压包括药物活性剂和所述增塑赋形剂的混合物,所述增塑赋形剂以其起所述混合物的增塑剂作用和起所述混合物的润滑剂作用的有效量使用。
2.根据权利要求1的方法,其中所述混合物基本上不含另外的对混合物起润滑作用的赋形剂。
3.多颗粒,其含有药物活性剂和具有润滑性能的增塑赋形剂,基本上不含另外的润滑剂。
4.根据权利要求3的多颗粒,其含有药物活性剂、甲基丙烯酸铵共聚物、具有润滑性能的增塑赋形剂和透水性改性剂。
5.多颗粒,其基本上由药物活性剂、甲基丙烯酸铵共聚物、具有润滑性能的增塑赋形剂和透水性改性剂组成。
6.根据权利要求3至5中任一项的多颗粒,其中药物活性剂是阿片样物质。
7.根据权利要求6的多颗粒,其中所述药物活性剂是羟考酮游离碱或其药学上可接受的盐。
8.根据权利要求4至7中任一项的多颗粒,其中所述甲基丙烯酸铵共聚物是Eudragit RS PO。
9.根据权利要求3至8中任一项的多颗粒,其中所述增塑赋形剂选自水不溶性的固体,如鲸蜡醇、硬脂醇和十六醇十八醇混合物;水溶性的固体,如山梨醇和蔗糖和高分子量的聚乙二醇;水不溶性的液体,如癸二酸二丁酯和柠檬酸三丁酯以及水溶性的液体,如柠檬酸三乙酯、丙二醇和低分子量的聚乙二醇。
10.根据权利要求4至9中任一项的多颗粒,其中所述透水性改性剂选自不溶性亲水芯吸剂如微晶纤维素、水合以形成凝胶来控制水移动的胶凝剂、高分子量的聚乙二醇,如PEG 6000,或可渗透水的甲基丙烯酸铵共聚物,也称为铵基甲基丙烯酸盐共聚物,如Eudragit RL PO或Eudragit RL 100。
11.根据权利要求4至10中任一项的多颗粒,其含有以w/w计为3-50%的药物活性剂、25-85%的不溶性甲基丙烯酸铵共聚物、1-30%的非支配性增塑剂和1-30%的透水性改性剂。
12.由根据权利要求3至12中任一项的多颗粒所形成的单位剂量。
13.根据权利要求12的单位剂量,其含有5-400毫克的盐酸羟考酮。
14.根据权利要求12或13的单位剂量,其适于每日给药一次。
15.根据权利要求12或13的单位剂量,其适于每日给药两次。
16.根据权利要求12至15中任一项的单位剂量,其包括填充多颗粒的胶囊。
17.根据权利要求12至16中任一项的单位剂量,其中所述药物活性剂是羟考酮且所述单位剂量还包含羟考酮拮抗剂。
18.一种用于制备含有药物活性剂的多颗粒的方法,所述方法包括活性剂、甲基丙烯酸铵共聚物、还作为润滑剂的增塑剂、以及透水性改性剂的可挤压混合物的挤压。
19.止痛的药物活性剂在制备用于向患者提供止痛的方法的单位剂量中的用途,所述方法包括给药有效量的包含权利要求12至17中任一项的多颗粒的控释制剂,其中药物活性剂是止痛剂。
20.一种向患者提供止痛的方法,所述方法包括给药有效量的包含权利要求12至17中任一项的多颗粒的控释制剂,其中药物活性剂是止痛剂。
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