CN102970978A - 活性药物成分的颗粒加工方法 - Google Patents
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Abstract
一种减小活性药物成分(API)的粒径同时维持其多晶型形式的方法，所述方法包括通过在升高的压力下空蚀来加工所述活性药物成分的步骤。所述方法优选包括分离粉末形式的加工的活性成分的步骤，其中所述分离步骤包括过滤或喷雾干燥。通过本发明的方法制备的颗粒通常具有低于2.5的跨度值。
Description
本发明涉及一种用于活性药物成分的颗粒加工和减小粒径(sizereduction)的方法。所述方法包括湿磨，特别是通过在升高的压力下空蚀，并且优选随后进行喷雾干燥。这种方法使得能够控制粒径和大小分布而不改变活性药物成分的多晶型形式。
本发明涉及一种用于活性药物成分的颗粒减小粒径的新方法，所述方法包括湿磨，特别是通过在升高的压力下空蚀，其中优选将产物悬浮于其不溶解的水或其他溶剂中，优选随后将该悬浮液喷雾干燥以获得干粉状产物。
根据本发明的一方面，提供一种用于减小活性药物成分的粒径同时维持其多晶型形式的方法，所述方法包括通过在升高的压力下空蚀来加工所述活性药物成分的步骤。在一优选方面，随后将加工的活性成分喷雾干燥。
本发明的方法优选地对不存在任何赋形剂的分离的活性药物成分进行，除了加工所需的任何悬浮溶剂。
本发明还涵盖通过本发明的方法可获得或者获得的活性药物成分(API)。
本发明还提供在升高的压力下空蚀以减小活性药物成分的粒径同时维持其多晶型形式的用途。优选地，空蚀之后通过喷雾干燥分离活性成分。
本发明的具体特征是本文公开的方法不改变活性药物成分的晶体或多晶型形式。例如，众所周知通过传统方法(例如：空气喷射研磨)减小一些活性药物成分如糠酸莫米松一水合物的粒径部分或完全地将活性成分的晶体形式改变为无水(形式I)或无定形形式。本发明的目的在于解决这种和其他活性药物成分存在的问题，所述活性药物成分进行传统颗粒减小方法时晶体形式发生改变。
根据本发明加工或处理之后，对于晶体的晶体形式或多晶型形式，API的颗粒与加工之前的API的颗粒优选95%(以重量计)或更多相同，更优选99%(以重量计)或更多相同。如果使用晶体起始材料，优选地，加工后的颗粒包含2%(以重量计)或更少、更优选1%(以重量计)或更少的无定形材料。换句话说，优选地，加工后的颗粒包含98%(以重量计)或更多、更优选99%或更多的结晶材料。
此外，本文描述的发明使得能够通过调整操作参数如压力、浓度以及循环数目或再循环时间来精确地控制颗粒减小粒径，并且具有非常狭窄的分布。本发明还提供高重复性以及干粉状活性成分的分离。这是一种创新特征，其提供相对于传统颗粒减小粒径方法的显著优势，允许分离可以用于其中粒径很重要的不同制剂的稳定活性药物成分，所述制剂包括但不限于递送至气道的粉末或混悬剂、可注射混悬剂或者用于皮肤病学用途的制剂。
本发明的另一具体特征是制备粉末，所述粉末的特征在于它们呈现药物递送至呼吸系统所必需的高精细颗粒部分而无需稳定添加剂，使得这种方法特别适合制备可用于肺和鼻递送的制剂。
本发明的另一方面是本文描述的微粒化和分离粉末形式的材料的方法容易地放大，并且可以在工业规模应用。具体地，大规模的高压空蚀设备(例如MFIC或Bee International提供的高压空蚀设备)和喷雾干燥器(例如Niro提供的喷雾干燥器)的用途可以如本发明所述实现。
活性药物成分的颗粒减小粒径是制药工业中的关键单元操作。这个过程的最终目的是通过优化药物颗粒的空气动力特性来增加递送至肺和鼻的药物的沉积。最常见的颗粒减小粒径技术(例如喷射研磨、球磨)涉及晶体表面的高热应力，这可以诱导晶体结构一定程度的紊乱，这在某些情况下产生微粒化粉末中高水平的无定形含量或多晶型形式的变化。
尽管在升高的压力下空蚀和喷雾干燥是在许多不同应用的文献中相对很好描述的方法，但是它们并未因此描述为这样的产物的解决方法，所述产物通过其他颗粒减小粒径方法而发生多晶型转换。美国专利申请US20070178051描述一种方法，其包括喷雾干燥以前加工的包含表面稳定剂的制剂，这是为了更好地混合活性成分-赋形剂的混合物以及分离稳定的纳米颗粒。
此外，对于大多数活性药物成分，具有非常狭窄的分布的颗粒减小粒径的精确控制、高重复性和粉末形式的活性成分的分离、呈现用于肺递送的高精细颗粒部分而无需稳定添加剂尚有待于在工业规模实现。
例如，在丙酸氟替卡松的情况下，文献中描述的颗粒减小粒径方法为空气喷射研磨。然而通过这种方法难以控制粒径分布，并且最终产物呈现高水平的无定形含量。这需要微粒化的药物成分的老化以降低无定形含量的水平，这是增加制备循环时间的又一加工步骤。现有技术中没有指明本文描述的方法可以用来减小粒径而没有不期望的多晶型变化。
在糠酸莫米松一水合物的情况下，已知传统颗粒减小粒径技术如空气喷射研磨和球磨引起结合水的损失，产生无水或甚至无定形形式。US6,187,765公开使用糠酸莫米松一水合物的悬浮液与其他赋形剂的微流化以减小活性药物成分的粒径分布。然而，其并未描述获得粉末形式的微粒化的糠酸莫米松一水合物的任何方法。
在一优选方面，本发明提供一种用于活性药物成分(API)的颗粒减小粒径的方法，所述方法包括湿磨，特别是在升高的压力下空蚀，其中将产物悬浮于其不溶解的水或其他溶剂中，随后将该悬浮液喷雾干燥以获得干粉形式的产物。
可以将化合物悬浮于任何合适溶剂中，例如水或者任何其他无机或有机溶剂，其中所述化合物是不溶的。悬浮液浓度通常为2-60%w/v，优选10-50%w/v。采用的浓度的限制受加工材料的高压空蚀设备的性能的限制。
通过非溶剂中的悬浮的材料在升高的压力下空蚀来完成颗粒减小粒径。本领域技术人员应当理解，所述方法由对悬浮液施用高压，然后通过喷嘴突然扩张，由此产生强到足以破碎颗粒的空蚀力组成。微流化是有时本领域中用来描述这种方法的替代术语。对于本发明的目的，术语“在升高的压力下空蚀”与术语微流化基本上同义。一些空蚀设备的附加特征是通过逆流液体流促进颗粒-颗粒碰撞以进一步减小悬浮的材料的粒径。施用的压力仅由设备限制来限定。
“升高的压力”应当理解为压力适合地为约300巴或以上。通常，压力为300-3100巴或300-3500，虽然如果期望，可以使用更高的压力(例如高达5000或以上)，这取决于设备设定的限制。
悬浮液可以通过高压空蚀设备几次，直至达到期望的粒径和大小分布。这样的“再循环”是本发明的优选特征。例如，再循环可以进行2-30次(或循环)，这取决于API。优选循环范围包括5-25和15-25。值得注意的是，当与颗粒减小粒径的其他传统方法比较时，这种颗粒减小粒径技术提供紧密的粒径分布，并且可以特别适合于递送至肺或鼻的局部药物递送。所述方法使得能够制备具有低跨度(span)值的颗粒，并且适合地，跨度值为2.5或更少。更优选地，跨度值为2.0或更少，或者1.8或更少。本领域技术人员应当清楚，跨度通过比率((Dv90-Dv10)/Dv50)来定义，其中Dv为给定百分比的颗粒(例如方程中的10%、50%或90%)的直径等于或小于Dv值时的直径值。利用能够递送一定剂量的包含根据本发明方法制备的颗粒的药物的装置来实现药物递送，并且这些装置会通过嘴或鼻，在患者的吸气努力下递送剂量，或者通过剂量的加压来递送剂量。
根据用于空蚀过程的压力，可以将悬浮液加热至接近溶剂的沸点的温度。可以将冷却系统安装在设备的出口中，并且还可以应用背压以避免达到溶剂的沸点。
然后可以将如本发明所述的微粒化的悬浮液过滤，或者考虑到过滤具有这样小的粒径的悬浮液的难度，优选地注入喷雾干燥器，以便去除溶剂并获得干粉状产物。可以利用标准操作条件进行喷雾干燥过程。可以使用雾化装置如双流体喷嘴或压力喷嘴。可以适当地选择干燥温度以及进料速度，干燥温度取决于加工溶剂以及最终产物中的残余溶剂水平目标。
本文所述的方法可以用市场中可获得的任何合适类型的标准高压空蚀和喷雾干燥设备来完成，使得其特别适合放大至工业生产。这样的设备是技术人员公知的。
在一优选方面，喷雾干燥(SD)步骤在空蚀步骤后立即进行。“立即”表示喷雾干燥步骤在空蚀步骤完成的1小时内进行，优选在30分钟内进行。
可以应用这种方法以防止多晶型转换并实现粒径的精确控制的活性药物成分的实例包括但不限于在使用传统颗粒减小粒径技术时倾向于发生多晶型转换的活性药物成分及其药学可接受的盐的无定形、晶体、水合或溶剂化形式，例如大多数皮质类固醇和其他活性药物成分。这类化合物的实例为：莫米松及其酯(例如糠酸莫米松、糠酸莫米松一水合物)、氟替卡松及其酯(例如丙酸氟替卡松、糠酸氟替卡松)、tiotropium(例如噻托溴铵、噻托溴铵一水合物)、环索奈德、布地奈德、福莫特罗、沙美特罗、沙丁胺醇、倍氯米松及其酯(例如丙酸倍氯米松)、倍他米松及其酯(例如醋酸倍他米松)、异丙阿托品(ipratropium)、特布他林、氢化可的松及其酯(例如氢化可的松17-丙酸酯21-乙酸酯)以及这些活性药物成分中的两种或更多种的组合。
本领域技术人员应当清楚，可以将按照本发明的方法制备的API加入治疗上可用的药物组合物，所述药物组合物必要时包括适当的赋形剂。例如，粉末制剂可以通过将通过本发明制备的API粉末的颗粒与合适的微粒赋形剂如乳糖或者任何其他适当的赋形剂(甘露醇、葡萄糖、海藻糖等)混合来制备以递送至肺或鼻。本发明的颗粒还可以配制为用于递送装置的混悬剂，例如具有基于阀的剂量计量机制的加压罐。
以下实施例仅作为说明给出，并不限制本发明的范围。
实施例1
1)将糠酸莫米松一水合物(130g)悬浮于水(867g)中，并搅拌30min以形成均匀的悬浮液，并且注入实验室级高压空蚀(HPC)设备，在10kPsi(689巴)下以再循环模式操作，即将HPC的排放物返回搅拌的容器入口。空蚀步骤之后，将悬浮液转移至盛放容器以用于下一步骤。将HPC设备用水漂洗，并且将洗涤物加入悬浮液的主要部分。
2)在搅拌的同时将悬浮液注入实验室级喷雾干燥器，进料速度为5ml/min，并且干燥温度为66°C。在玻璃烧瓶中收集产物，产生72g。
3)分离的产物呈现与US6180781B1中要求保护的基本上相同的XRPD图1.1。通过动态气相吸附(DVS)测定的无定形含量低于1.1%，并且通过近红外光谱学未检测到无水形式。TGA值为3.0%。制备的粉末的粒径分布为Dv10=1.91μm；Dv50=3.97μm；Dv90=7.47μm；跨度=1.4。参见图1。
实施例2
1)将丙酸氟替卡松(30g)悬浮于水(100g)中并搅拌直至获得均匀的悬浮液，并且注入实验室级HPC，在40kPsi(2758巴)的压力下操作20个循环。空蚀步骤之后，将悬浮液转移至盛放容器以用于下一步骤。将HPC设备用水漂洗，并且将漂洗液加入悬浮液的主要部分。
2)在搅拌的同时将悬浮液注入实验室级喷雾干燥器，进料速度为5ml/min，并且干燥温度为70°C。在玻璃烧瓶中收集产物，产生21g。
3)分离的产物呈现与起始材料基本上相同的XRPD，粒径分布为Dv10=1.20μm；Dv50=2.45μm；Dv90=4.68μm；跨度=1.4。参见图2。
实施例3
1)将糠酸氟替卡松(9g)悬浮于水(100g)中并搅拌直至获得均匀的悬浮液，并且注入实验室级HPC，在30kPsi(2068巴)的压力下操作20个循环。空蚀步骤之后，将悬浮液转移至盛放容器以用于下一步骤。将HPC设备用水漂洗，并且将漂洗液加入悬浮液的主要部分。
2)在搅拌的同时将悬浮液注入实验室级喷雾干燥器，进料速度为5ml/min，并且干燥温度为50°C。在玻璃烧瓶中收集产物，产生6.7g。
3)分离的产物呈现与起始材料基本上相同的XRPD，粒径分布为Dv10=0.89μm；Dv50=1.95μm；Dv90=3.78μm；跨度=1.5。参见图3。
实施例4
1)将沙美特罗昔萘酸酯(140g)悬浮于庚烷(1400g)中并搅拌直至获得均匀的悬浮液。然后将其注入实验室级HPC，在15kPsi(1034巴)的压力下操作7个循环。空蚀步骤之后，将悬浮液转移至使用庚烷的盛放容器，并且将漂洗液加入悬浮液的主要部分。
2)在搅拌的同时将悬浮液注入实验室级喷雾干燥器，进料速度为12ml/min-17ml/min，干燥温度为40°C。在玻璃烧瓶中收集产物，产生104g。
3)分离的产物呈现与起始材料基本上相同的XRPD，粒径分布为Dv10=0.33μm；Dv50=1.37μm；Dv90=3.09μm；跨度=2.0。参见图4。
实施例5
1)将噻托溴铵(20g)悬浮于丙酮(200g)中并搅拌直至获得均匀的悬浮液。然后将其注入实验室级HPC，在20kPsi(1379巴)的压力下操作21个循环。空蚀步骤之后，将悬浮液转移至盛放容器。
2)在搅拌的同时将悬浮液注入实验室级喷雾干燥器，进料速度为6ml/min，干燥温度为45°C。在玻璃烧瓶中收集产物，产生13g。
3)分离的产物呈现的粒径分布为Dv10=0.74μm；Dv50=2.90μm；Dv90=5.58μm；跨度=1.7。
Claims (19)
1.一种用于减小活性药物成分(API)的粒径同时维持其多晶型形式的方法，所述方法包括通过在升高的压力下空蚀来加工所述活性药物成分的步骤。
2.如权利要求1所述的方法，其中将所述活性成分悬浮于其不溶解的溶剂中。
3.如权利要求1或2所述的方法，其中所述溶剂为水、庚烷、醇、酮或烷烃，或者上述溶剂中的两种或更多种的混合物。
4.如权利要求1、2或3所述的方法，其特征在于空蚀压力为300-3500巴。
5.如前述权利要求中任一项所述的方法，其还包括分离粉末形式的加工的活性成分的步骤。
6.如权利要求5所述的方法，其中所述分离步骤包括过滤或喷雾干燥。
7.如权利要求6所述的方法，其中所述分离步骤包括喷雾干燥。
8.如权利要求7所述的方法，其中所述喷雾干燥步骤在所述空蚀步骤之后立即进行。
9.如前述权利要求中任一项所述的方法，其中所述活性药物成分适合局部递送至肺或鼻。
10.如前述权利要求中任一项所述的方法，其中所述活性成分为莫米松、氟替卡松、tiotropium、环索奈德、布地奈德、福莫特罗、沙美特罗、沙丁胺醇、倍氯米松、倍他米松、异丙阿托品、特布他林或氢化可的松，或者上述活性成分之一的药学可接受的盐或酯，或者上述活性药物成分或它们的药学可接受的盐或酯中的两种或更多种的组合。
11.如权利要求10所述的方法，其中所述活性成分为糠酸莫米松或糠酸莫米松一水合物、丙酸氟替卡松或糠酸氟替卡松、噻托溴铵或噻托溴铵一水合物、环索奈德、布地奈德、福莫特罗、沙美特罗、沙丁胺醇、丙酸倍氯米松、醋酸倍他米松、异丙阿托品、特布他林、或氢化可的松17-丙酸酯21-乙酸酯，或者这些活性药物成分中的两种或更多种的组合。
12.如前述权利要求中任一项所述的方法，其中所述活性成分为糠酸莫米松一水合物、丙酸氟替卡松、糠酸氟替卡松、沙美特罗昔萘酸酯或噻托溴铵。
13.如前述权利要求中任一项所述的方法，其中所述活性药物成分的粒径分布包括低于2.5的跨度。
14.如权利要求13所述的方法，其中所述跨度低于2.0。
15.如权利要求13或14所述的方法，其中所述跨度低于1.8。
16.一种用于制备药物组合物的方法，所述方法包括进行前述权利要求中任一项所述的方法，然后将所述活性药物成分与一种或多种药学可接受的赋形剂组合。
17.如权利要求16所述的方法，其中所述药物组合物为用于局部递送至鼻或肺的粉末。
18.可通过权利要求1-15中任一项所述的方法获得的活性药物成分(API)。
19.一种包含权利要求18所述的活性药物成分(API)的药物组合物。
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| JP6857467B2 (ja) | 2021-04-14 |
| WO2011131947A3 (en) | 2012-01-05 |
| MX2012012215A (es) | 2013-05-09 |
| US9956144B2 (en) | 2018-05-01 |
| MX338594B (es) | 2016-04-25 |
| BR112012026941A2 (pt) | 2016-07-12 |
| CN102970978B (zh) | 2017-05-10 |
| CA2796978A1 (en) | 2011-10-27 |
| WO2011131947A2 (en) | 2011-10-27 |
| IL222596B (en) | 2019-03-31 |
| RU2012149459A (ru) | 2014-05-27 |
| PT105058B (pt) | 2013-04-17 |
| SG185003A1 (en) | 2012-11-29 |
| CA2796978C (en) | 2019-07-02 |
| US20130203717A1 (en) | 2013-08-08 |
| PT105058A (pt) | 2011-10-21 |
| EP2560620B1 (en) | 2020-09-16 |
| JP6347608B2 (ja) | 2018-06-27 |
| JP2017019845A (ja) | 2017-01-26 |
| PL2560620T3 (pl) | 2021-04-06 |
| RU2597790C2 (ru) | 2016-09-20 |
| EP2560620A2 (en) | 2013-02-27 |
| IL222596A0 (en) | 2012-12-31 |
| JP2013525338A (ja) | 2013-06-20 |
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