CN110913907A - 超压缩药物制剂 - Google Patents
超压缩药物制剂 Download PDFInfo
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- CN110913907A CN110913907A CN201880046341.9A CN201880046341A CN110913907A CN 110913907 A CN110913907 A CN 110913907A CN 201880046341 A CN201880046341 A CN 201880046341A CN 110913907 A CN110913907 A CN 110913907A
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- lactide
- glycolide
- dosage form
- polymer
- pharmaceutical dosage
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Abstract
一种药物剂型，其包含与肽或蛋白质治疗剂组合的丙交酯、乙交酯或丙交酯‑乙交酯聚合物，聚乙交酯、三亚甲基碳酸酯、聚己内酯和聚氧化乙烯的嵌段聚合物，所述剂型呈使用50,000至350,000 psi的压力压缩的微颗粒的形式。
Description
发明领域
本发明涉及利用生物相容性聚合物的超压缩制造的多肽和蛋白质控释药物。
发明背景
生物技术领域中许多难题中的一个是获得长期持续递送蛋白质的技术上可行的方法。这经常是由于观察到蛋白质可被容易地水解和变性。已广泛研究了将蛋白质包封在可再吸收的聚合物微颗粒中以实现延长释放。配置大分子的持续释放（例如可容易注射的施用方式）的问题归因于微颗粒的高孔隙率，从而导致尚未完全解决的两个关键问题：1)将蛋白质有效负载暴露于其周围的水，从而导致水解，2)由聚合物降解所产生的酸性造成变性。
含有药物的超压缩聚合物和共聚物是已知的。然而，当高分子量肽或蛋白质被制成控释药物时，先前尚未测定肽和蛋白质对超压缩的稳定性。
影响载体聚合物与降解的肽和蛋白质的反应性物质之间相互作用的一个重要因素是它们相互间的接近。因为超压缩使反应性物质相互更接近，超压缩实际上能促进进一步降解，从而导致具有更短货架期的更不稳定的产品。
美国和欧洲当前存在的药物法规限制了药物中涉及活性药物成分的物质的量不多于1.0重量%或5 μg TDI (总日摄取量) (任何较低的一者)，最大日剂量1.0 mg。这些要求对控释产品的配制者提出挑战。
已知某些肽和重组蛋白质具有短生物半衰期和低口服生物利用率，这已迫使药物制造商仅提供可注射制剂，这使得这些物质被显示适用的疗法复杂化。这在基于蛋白质的药物被施用于眼部时特别具有意义，所述情况有时需要频繁地眼内注射蛋白质，这使患者不悦并且还伴有感染和其他并发症的风险。
已制备了制剂，其中蛋白质与酯封端的聚(DL乳酸-共聚-乙醇酸) (封端PLGA)结合，作为提供蛋白质的控释制剂的技术，该制剂可通过植入或避免了需要直接注射的其他技术来施用。未受到超压缩的这些制剂的控释是通过选择负载蛋白质的PLGA颗粒的不同大小颗粒和不同的乳酸与乙醇酸重量比来调节。已发现使用更小颗粒(0.3 μm)的PLGA负载蛋白质颗粒比使用具有相同组成的更大颗粒(1.0-20 μm)导致蛋白质的更缓慢释放(在PBS中，pH 7.4)。使用更小和更大颗粒的封端的PLGA负载蛋白质的颗粒均产生在测试控释性质时具有明显突释效应的控释产品。在增加一段时间内的持续递送的尝试中，进行了蛋白质的物理/化学修饰或分散于介质(水凝胶)中。
已发现如果蛋白质分散于PLGA聚合物中的组合物通过超压缩而致密化，则PLGA聚合物制剂中所见的突释效应(这可能造成毒性，或药物过度浪费而折损持续时间)得以减弱或避免。突释效应的减少也导致比未压缩的产品将在更长时间段内递送疗效的制剂。
发明内容
本发明提供一种制造具有与丙交酯聚合物、乙交酯聚合物或丙交酯-乙交酯共聚物组合超压缩的肽或蛋白质的控释药物产品的方法。优选的聚合物和共聚物是酯封端的聚合物和共聚物，其中末端酸基团与诸如醇、优选无毒脂族醇的酯形成剂反应。
本发明的目的在于提供一种改进的丙交酯、乙交酯或乙丙交酯聚合物的控释制剂，所述聚合物是酸或酯封端的聚合物或共聚物，所述制剂具有分散的肽或蛋白质治疗剂，具有减少的突释效应和更长有用的控释时段，这能允许施用基于肽或蛋白质的药物之间延长的间隔。
本发明的目的还在于提供一种改进的丙交酯、乙交酯或乙丙交酯聚合物的控释制剂，所述聚合物是酸或酯封端的聚合物或共聚物，所述制剂具有分散的肽或蛋白质治疗剂，具有减少的突释效应和相对于药物负载量减小的尺寸，以便使由引入控释制剂与粘膜接触造成的任何创伤减到最少。
本发明的目的也在于通过将与酯封端的丙交酯聚合物、乙交酯聚合物或丙交酯-乙交酯共聚物组合的肽或蛋白质超压缩来提供改进的肽或蛋白质的超压缩控释制剂，所述肽或蛋白质对电子束辐射灭菌稳定。
本发明的目的还在于提供改进的控释制剂和施用眼治疗剂的方法，其包括丙交酯、乙交酯或丙交酯-乙交酯聚合物(其是酸或酯封端的聚合物或共聚物)的超压缩眼插入物，具有分散的肽或蛋白质治疗剂，所述治疗剂具有肽重均分子量，最小分子量至高达250,000或对于复杂大分子则更高。优选重均分子量应介于10,000与250,000之间。
附图简述
图1是实施例1 (55 Kpsi)和实施例3 (135 Kpsi)的贝伐单抗压缩制剂的释放率的图表，对照具有相同的配方，不同之处是对照是以估计1 Kpsi人工压制的。
发明详述
生物可降解的聚合物，诸如聚(L-丙交酯) (PLLA)和聚(丙交酯-共聚-乙交酯) (PLGA)是众所周知的。由于它们极佳的毒理学特性和可调的生物降解性，它们已被配制为纳米颗粒、微米颗粒、可注射储库、薄膜、支架和用于药物递送的整体植入物。受控药物递送体系是重要的，因为它们改进了治疗和患者顺应性，提供了在延长时段内位点处优化的药物浓度，并且降低了不希望的药物副作用。
由PLGA和PLA和其他聚合物配制的药物递送器件已被研究用于治疗眼以及其他部位的疾病，它们的水解降解、药物释放特性和机械完整性被优化以适应各种应用。
本发明利用酸封端和/或酯封端的丙交酯或乙交酯或丙交酯-乙交酯聚合物或共聚物。这些是化学文献中描述的已知材料。酯封端的聚合物是优选的，并且它们可通过使用诸如醇的酯形成前体使PLA或PGLA聚合物或共聚物酯化或转酯化来制备，所述前体将与PLA、PLGA或PG的酸末端基反应以形成酯封端的聚合物或共聚物。酯基包括具有1-20个碳原子的烷基诸如直链和支链烷基的那些，但也可采用芳族酯，诸如苄基和苯基。优选的酯封端剂是月桂醇。
本发明的超压缩组合物包含酯封端的丙交酯、乙交酯聚合物或丙交酯-乙交酯聚合物或共聚物，所述聚合物或共聚物与肽或蛋白质治疗剂结合以形成控释分配单元。可与聚合物或共聚物混合的治疗剂包括：重组蛋白质，包括第VIII因子、胰岛素、促红细胞生成素、血管内皮生长因子、成纤维细胞生长因子、葡糖脑苷脂酶；治疗用抗体，包括阿昔单抗、贝伐单抗、普托木单抗、奥瑞利珠单抗、英夫利昔单抗和萨瑞鲁单抗；免疫毒素，包括地尼白介素-毒素连接物、莫塞妥莫单抗-帕舒托(moxetumomab pasudotox)、LMB-2、奥珀妥珠单抗-蒙托(oportuzumab monatox)、HuM195-白树毒素、A-dmDT390和bisFv (UCHT1)；细胞因子，包括粒细胞集落刺激因子、干扰素、肿瘤坏死因子、白细胞介素和转化生长因子-β；ECM蛋白，包括弹性蛋白、胶原、纤连蛋白和皮卡丘素。
在超压缩前，酸或酯封端的丙交酯或乙交酯聚合物或共聚物和活性药物可形成为被称为微球体或微胶囊的微颗粒，所述微颗粒的大小范围通常为直径在约2微米至约50微米、优选约2至约25微米且更优选约5至约20微米以实践本发明。术语“微球体”被用来描述大致上均匀的结构，其通过将活性药物与合适的溶剂和聚合物混合来获得，使得成品包含均匀分散于被成形为微球体的聚合物基体中的药物。取决于所选的微颗粒的大小范围，术语“纳米颗粒”被用来描述1至1000纳米大小的结构。一纳米(nm)是一米的十亿分之一，或约10个氢原子的大小。目前，纳米颗粒药物载体主要由大小范围为50-500 nm的生物可降解固体颗粒组成。一般而言，应选择颗粒大小以使得必要时颗粒可被容易地测量并转移，目的是将颗粒置于合适的压机中以施加超压缩力来形成压缩剂型。压缩的颗粒被命名为基体，其在置于水中或者与诸如真皮、肺或肠的水性体液接触时将使压缩的颗粒解聚并形成为(曾被压缩形成基体的)单独的颗粒。
本发明的附加方面是一旦这些微球体被超压缩，则它们产生改变的或扭曲的颗粒形状，因施加超压缩力所致而在延伸度、圆形度和凸度或表面粗糙度方面变化。超压缩的颗粒可被再分散于合适的水性载剂中以注射。无菌生理盐水或其他等渗溶液可用于该目的。因为超压缩的单个微球体的颗粒大小已被减小，使用相同的微球体体积可递送远远更多的药物。
纳米颗粒可例如通过使用超声波仪(Misonix XL-2020，功率输出50-55 W)在选定的治疗剂的存在下对氯仿中的聚合物或共聚物的溶液进行超声处理10分钟来形成，所述溶液含有2% (重量/重量)的聚乙烯醇溶液。此后，4℃下过夜搅拌该乳液以蒸发氯仿并获得聚合物和治疗剂的纳米颗粒。
微胶囊优选被用来形成本发明的压缩剂型。术语“微胶囊”被用来描述剂型，其优选为非球形，并具有设置在含有活性药物和任何添加的赋形剂的核心周围的聚合物壳，其大小范围如上文所述的。一般而言，微胶囊可通过使用以下技术中的一种来制造：
(1)相分离法，包括水相和有机相分离过程、熔体分散和喷雾干燥；
(2)界面反应，包括界面聚合、原位聚合和化学汽相沉积；
(3)物理方法，包括流化床喷涂、静电包衣和物理汽相沉积；以及
(4)溶剂蒸发法，或使用具有反溶剂的乳液。
大体而言，微颗粒包含，每100重量份的治疗剂和聚合物的总重量，约0.00001至约50重量份的治疗剂，并且还包含约50至约99.99999重量份的聚合物。优选范围是1至50、5至40和5至20重量份的治疗剂，剩余部分由聚合物组成。需要时，1至5重量%的诸如聚乙烯吡咯烷酮的粘合剂可在压缩步骤前与微颗粒均匀混合。
植入的超压缩剂型中存在的药物的量可变化，但一般可采用药物的通常口服或静脉内剂量的0.5-20重量%或优选约3-5重量%，但是可根据可溶性、植入区域、待治疗的患者和病状而有大的变化。微胶囊中药物的总重量可变化，但将占微球体总重量的约1-5%。微球体可通过如本文所述的典型乳液中溶剂蒸发技术来形成。
为了向适合放置在可释放治疗剂以治疗病状的位置的控释剂型提供生物可降解聚合物基体，优选聚合物选自酸封端或酯封端的聚(l-丙交酯)，聚(dl-丙交酯)，聚乙交酯，聚(乙交酯-共聚-丙交酯)，聚(乙交酯-共聚-dl-丙交酯)，聚乙交酯和三亚甲基碳酸酯的嵌段聚合物，以及聚己内酯和三亚甲基碳酸酯或聚氧化乙烯的嵌段聚合物，或前述任何的混合物。合成聚合物可为具有任意MW (重均分子量)或MW多分散性、所有乳酸(LA)与乙醇酸(GA)之间的比率和所有结晶度的聚丙交酯或聚(丙交酯-共聚-乙交酯)。一般而言，MW的范围为约500至约10,000,000 Da，优选约2,000至约1,000,000 Da，且更优选约500至约5,000Da。可使用具有约75:25至约85:15(摩尔:摩尔)LA:GA比率和约5,000至约500,000的MW的p(LGA)。丙交酯/乙交酯聚合物是整体腐蚀聚合物(非表面腐蚀聚合物)，并且当形成为微颗粒基体时聚合物将水解，因为水进入基体并且聚合物分子量减小。通过增大聚合物分子量，使用L-聚合物和降低表面积(增大微颗粒的尺寸或剂型的尺寸)，可能使再吸收曲线移动至更长的时间。可得到具有高达6.5 dl/g和低至0.15 dl/g的固有粘度的丙交酯/乙交酯共聚物。对于本发明，优选较低分子量的共聚物。已发现，50:50的乙交酯与丙交酯的摩尔比率导致最迅速的降解和对应的药物释放。通过将聚合物骨架中丙交酯的比率从约50摩尔%提高至100%，可降低释放速率以由单一剂量单位提供延长的疗效。
优选形成胶囊的聚合物是用月桂醇封端的聚(乙交酯-共聚-dl-丙交酯)，其充当分配器件的优选控释递送体系。聚合物载体充当治疗剂的持续释放递送体系。聚合物通过借此其酯键被水解以形成正常代谢化合物、乳酸和乙醇酸的过程经历生物降解并允许释放治疗剂。
已研究了由不同比率的乳酸和乙醇酸组成的共聚物的降解速率的差异。已知生物降解速率取决于共聚物中乳酸与乙醇酸的比率，并且50:50共聚物降解最迅速。选择生物可降解的聚合物体系避免了从眼部或其他组织移除耗尽的非生物可降解结构的需要和伴发的创伤。
在制备微球体后，以非常高的力压缩微球体以形成本发明的分配器件。超压缩可在能够或容许将50,000至350,000 psi (此后使用K来代替1,000)，或者100 Kpsi至300Kpsi，或者200 Kpsi至300 Kpsi，或者50或60 Kpsi至160或170 Kpsi，或者尤其是60 Kpsi至170 Kpsi的压力施加于微颗粒或纳米颗粒的装置中进行。术语“psi (磅/平方英寸)”通过获取施加于特定剂型的以磅计的力并且测量或计算以平方英寸计的剂型或模具的顶部面积来确定，使得可进行换算以便以psi来表示施加于剂型的压力。
超压缩分配器件可为完美的球体，但优选变形的球体，诸如扁平盘、棒、具有圆或光滑边缘的粒，其足够小以被置于皮肤下某一位置，诸如骨和其关节，包括指关节、脚趾、膝盖、髋部和肩部；腺体，例如脑垂体、甲状腺、前列腺、卵巢或胰腺；或器官，例如肝、脑、心脏和肾。更具体而言，通过将器件植入病理位点处或附近，或以将影响病理，诸如包括人或动物或鱼或其他活物种的身体的任何部分的方式，可利用本发明的分配器件来治疗病状。这类部分可包括细胞的内容，头、颈、背、胸、腹、会阴、上肢或下肢的任何部分。骨骼的任何部分，包括但不限于脊柱；颅骨；胸部骨，包括胸骨或肋骨；面骨；上肢骨，诸如锁骨、肩胛骨或肱骨；手骨，诸如腕骨；下肢骨，诸如髂骨或股骨；脚骨，诸如跗骨；关节或韧带；肌肉和筋膜；心血管系统，诸如心脏、动脉、静脉，或者毛细血管或血液；淋巴系统，诸如胸导管、胸腺或脾脏；中枢或周围神经系统；感觉器官，诸如眼、耳、鼻；皮肤；呼吸系统，诸如肺、喉、气管和支气管；消化系统，诸如食道、胃或肝；泌尿生殖系统，诸如膀胱、前列腺或卵巢；内分泌腺，诸如甲状腺、甲状旁腺或肾上腺。
实施例1
将2 ml小份的含有50 mg贝伐单抗的可商购形式的贝伐单抗(Avastin®)溶液(固体的总重量为约186 mg，包括稀释剂/添加剂)冻干。用刮铲将饼形冻干产物减小成粉末。将1.25g酸封端的PLGA (Purasorb PDLG7507，在25℃下在氯仿中为0.1重量%时具有0.56-0.84dl/g的固有粘度，且丙交酯与乙交酯重量比为75:25)溶解于二氯甲烷中以制备PLGA/MeCl2溶液(总共5 ml)。将粉末状冻干Avastin®加入PLGA/MeCl2溶液并温和地分散于其中。耦接至均化器的发生器的尖端被浸于冻干的Avastin®粉末和PLGA/MeCl2分散体中；以7200rpm运行均化器60秒以形成s/o悬浮液。然后，将20 ml1%聚乙烯醇水溶液加入Avastin®和PLGA/MeCl2油包固体(s/o)悬浮液。均化器以7200 rpm运行60秒以形成水包油包固体(s/o/w)乳液，然后，将其快速倾倒入300 ml0.1%聚乙烯醇水溶液中，同时以650 rpm在磁性搅拌器上搅拌，30分钟后搅拌速度降至600 rpm。3小时后，悬浮液以2500 rpm离心5分钟，并且形成的微球体被浓缩并分散于50 ml双蒸水中。悬浮液以2500 rpm离心以回收微球体，并且再重复两次该步骤。最后，将微球体分散于5 ml双蒸水中，在-70℃冷冻并冻干。
在室温下，使用55,000 psi的压力，使用具有7.8 mm的直径和15.87 mm的深度的圆柱形模具将这些微球体超压缩以形成超压缩粒。然后，将超压缩的粒存放在含有2 ml磷酸盐缓冲盐水的5 ml Eppendorf管中。从该管中周期性吸取1.5 ml等份试样(并用等体积磷酸盐缓冲盐水装满)，并且分析这些等份试样所存在的总贝伐单抗。对最低程度压制的微球体进行单独的对照。该数据被用来制得标记为55 Kpsi的图1中的曲线，其示出贝伐单抗从酸封端的PLGA中释放的速率和持续时间。
实施例2
将2 ml小份的含有50 mg贝伐单抗的可商购形式的贝伐单抗(Avastin®)溶液(固体的总重量为约186 mg，包括稀释剂/添加剂)冻干。用刮铲将饼形冻干产物减小成粉末。将1.1g酯封端的PLGAe (Resomer RG755S，在25℃下在氯仿中的浓度为0.1重量%时具有0.5-0.7dl/g的固有粘度，且丙交酯与乙交酯重量比为75:25)溶解于二氯甲烷中以制得PLGAe/MeCl2溶液(总共约5 ml)。将粉末状冻干的Avastin®加入PLGAe/MeCl2溶液并温和地分散于其中。耦接至均化器的发生器的尖端被浸于冻干的Avastin®粉末和PLGAe/MeCl2分散体中；以10000 rpm运行均化器60秒以形成油包固体(s/o)悬浮液。然后，将20 ml含水1%聚乙烯醇加入Avastin®和PLGAe/MeCl2 s/o悬浮液。均化器以10000 rpm运行60秒以形成水包油包固体(s/o/w)乳液，然后，将其快速倾倒入300 ml0.1%聚乙烯醇水溶液中，同时以600rpm在磁性搅拌器上搅拌。2.5小时后，悬浮液以3000 rpm离心5分钟，并且形成的微球体被浓缩并分散于50 ml双蒸水中。悬浮液以3000 rpm离心以回收微球体，并且再重复一次或两次该步骤。最后，将微球体分散于双蒸水中，在-70℃冷冻并冻干。
在室温下，使用163000 psi的压力，使用具有7.8 mm的直径和15.875的深度的圆柱形模具将这些微球体超压缩以形成超压缩粒。然后，将超压缩粒存放在含有2 ml磷酸盐缓冲盐水的5 ml Eppendorf管中。从管中周期性吸取1.5 mL等份试样(并用等体积磷酸盐缓冲盐水装满)，并且分析这些等份试样所存在的总贝伐单抗。对同样制备的微球体进行单独的对照，该微球体在室温下使用估计1 Kpsi人工压制，目的在于制成离散的和粘结的对照粒。
实施例3
使用实施例2的程序制造另一个样品，不同之处在于使用135,000 psi的压力来形成超压缩微球体。
Claims (10)
1.一种药物剂型，其包含与肽或蛋白质治疗剂结合的丙交酯、乙交酯或丙交酯-乙交酯聚合物，聚乙交酯和三亚甲基碳酸酯的嵌段聚合物或聚己内酯和三亚甲基碳酸酯或聚氧化乙烯的嵌段聚合物，所述剂型呈使用50,000至350,000 psi的压力压缩的微颗粒的形式。
2.如权利要求1中所定义的药物剂型，其中所述治疗剂选自由重组蛋白质、治疗用抗体、免疫毒素、细胞因子和ECM蛋白组成的组。
3.如权利要求1中所定义的药物剂型，其中所述聚合物选自由聚(dl-丙交酯)、聚乙交酯、聚(乙交酯-共聚-丙交酯)、聚(乙交酯-共聚-dl-丙交酯)或前述任何的混合物组成的组。
4.如权利要求1中所定义的药物剂型，其中所述丙交酯、乙交酯或丙交酯-乙交酯或聚己内酯聚合物是酸封端的。
5.如权利要求1中所定义的药物剂型，其中所述丙交酯、乙交酯或丙交酯-乙交酯或聚己内酯聚合物是酯封端的。
6.如权利要求4中所定义的药物剂型，其中已通过施加50 Kpsi至170 Kpsi来压缩所述微颗粒。
7.如权利要求4中所定义的药物剂型，其中已通过施加100 Kpsi至300 Kpsi来压缩所述微颗粒。
8.如权利要求4中所定义的药物剂型，其中已通过施加60 Kpsi至170 Kpsi来压缩所述微颗粒。
9.如权利要求1中所定义的药物剂型，其中所述治疗剂是重组蛋白质。
10.如权利要求7所定义的药物剂型，其为贝伐单抗。
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| JP4475891B2 (ja) | 2003-06-20 | 2010-06-09 | ホソカワミクロン株式会社 | 経肺製剤の製造方法 |
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