CN111803447B - 一种制备无定形药物的方法 - Google Patents
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Abstract
本发明公开一种制备无定形药物的方法，涉及无定形小分子药物的制备方法领域。本方法包括以下步骤：(1)将药物活性成分与球磨辅料混合，得到混合物；所述药物活性成分选自氨基酸类药物、碱基类药物、硝苯地平和塞来昔布中的一种；(2)对该混合物进行球磨处理。本发明直接将药物活性成分球磨为无定形，无须对原药物活性成分的生产过程进行调节，降低了药物生产成本，简化了操作。本发明中所用球磨辅料本身为药剂中允许成分，无须对球磨后的产物做进一步分离。本发明所涉及工艺简单成熟，适用性广，适用用于多种药物的无定形化，适合于大批量、廉价地制备无定形药物。
Description
技术领域
本发明涉及无定形小分子药物的制备方法领域，具体涉及一种辅料辅助的、通过干式球磨来制备无定形药物的方法。
背景技术
药物多晶型的研究和制备新技术的开发对于新药研制、药品质量控制以及临床疗效的提高，有着深刻的积极意义。如口服A、B型混合棕榈氯霉素后，人体血液中的B型棕榈氯霉素浓度高于A型棕榈氯霉素，产生有效的抗菌作用；而口服同剂量A型棕榈氯霉素后，达不到同样有效的抗菌效果。无定形是一种特殊的药物晶型，药物活性组分(Activepharmaceutical ingredient，API)在无定形状态下，其各种理化性质及临床药效特征常有别于一般的晶型，无定形药物通常具有稳定性低，溶解度高，生物利用率高等特点。
文献中无定形药物的制备方法包括熔化物的固化法、减小颗粒尺寸法、喷雾干燥法、冻干法、除去晶体中溶剂法、改变pH的酸碱沉淀法等。无定形药物的成功制备是药物制剂所需要的，目前工业规模的无定型药物的制备面临诸多问题。比如熔化物的固化法制备无定形必须要将API加热到熔融点以上，该过程会消耗很多能量，而且高温会不可逆地损害药物性质。冻干法同样面临成本高的问题，且不适合使用有机溶剂的无定形制备过程。喷雾干燥法经常也只限于水做溶剂。球磨法是一种常用的制备粉体材料的方法，适用于粉磨各种矿石及其它物料，被广泛用于选矿，建材及化工等行业，是一种成熟的工业方法，目前尚未形成普适的利用干式球磨法制备无定形药物的方法。
发明内容
本发明的目的是发明一种普适的干式球磨法来制备无定形药物的方法，该方法具有廉价、操作简便、球磨成分无需分离等特点。为此，本发明提供了一种辅料辅助的制备无定形药物的方法，在辅料辅助作用下实现药物活性成分的无定形化，球磨辅料无需分离，可与药物活性组分（API）一同制成片剂。本发明的技术方案如下。
一种制备无定形药物的方法，包括以下步骤：
（1）将药物活性成分与球磨辅料混合，得到混合物；所述药物活性成分选自氨基酸类药物、碱基类药物、硝苯地平和塞来昔布中的一种，但不限于此；
（2）对所述混合物进行球磨处理。
优选的，步骤（1）中的球磨辅料选自糖类、钙盐、钠盐、钾盐、聚乙烯吡咯烷酮和聚乳酸中的一种或几种。其中，糖类可以是葡萄糖、蔗糖、果糖、乳糖、淀粉和纤维素中的一种或多种。所述钙盐、钠盐和钾盐的酸根离子均可以是Cl-、NO3 -和CH3COO-中的任意一种。
进一步优选的，聚乙烯吡咯烷酮为PVP K30。K值代表相应的聚乙烯吡咯烷酮（PVP）平均分子量范围。K30的平均分子量38000左右，25℃时粘度2.4mpa.s，粘度适中，与药物活性成分结合力适中，又有利于球磨分散，能促进药物活性成分的无定型化。
优选的，所述氨基酸类药物为甘氨酸或γ-氨基丁酸。
优选的，所述碱基类药物为5-氟尿嘧啶。
优选的，步骤（1）中药物活性成分和球磨辅料的质量比是500：（1-500）。例如，当所述药物活性成分为γ-氨基丁酸时，所述辅料为氯化钙，并且γ-氨基丁酸和氯化钙的质量比是1:1。当所述药物活性成分为5-氟尿嘧啶时，所述辅料为PVP K30，并且5-氟尿嘧啶和PVP K30的质量比是1:1；
优选的，步骤（2）中球磨时间为10min到2h，球磨的温度为15~60℃。
进一步优选的，步骤（2）中球磨时间为1h，球磨的温度为20~30℃。
与现有技术相比，本发明主要具有以下有益效果：
1、本发明直接将药物活性成分球磨为无定形，无须对原药物活性成分的生产过程进行调节，降低了药物生产成本，简化了操作。
2、本发明中所用球磨辅料本身为药剂中允许成分，无须对球磨后的产物做进一步分离。
3、本发明所涉及工艺简单成熟，适用性广，适用用于多种药物的无定形化，适合于大批量、廉价地制备无定形药物。
附图说明
图1为实施例1中γ-氨基丁酸原料和球磨后无定形氨基丁酸的XRD图。
图2为实施例2中硝苯地平原料和球磨后无定形的硝苯地平的XRD图。
图3为实施例3中5-氟尿嘧啶原料和球磨后无定形5-氟尿嘧啶的XRD图。
图4为实施例4中塞来昔布原料和球磨后无定形的塞来昔布的XRD图。
具体实施方式
为使本发明实施例的目的、技术方案和优点更加清楚，下面将结合附图对本发明实施例的技术方案进行清楚、完整地描述。实施例中未注明具体条件者，按照常规条件或制造商建议的条件进行。所用试剂或仪器未注明生产厂商者，均为可以通过市售购买获得的常规产品。
实施例1：
常温25℃下，1g的γ-氨基丁酸和1g氯化钙混合，并球磨1小时。
图1是本实施例中γ-氨基丁酸原料和球磨后无定形氨基丁酸的XRD图，显示出球磨后产物的无定形化很完全。
实施例2：
1g硝苯地平和1g的PVP K30混合，在20℃室温下球磨0.5小时。
图2是本实施例中硝苯地平原料和球磨后无定形的硝苯地平的XRD图，显示出球磨后产物的无定形化很完全。
实施例3：
1g的5-氟尿嘧啶和1g的PVP K30混合，加热至45℃球磨1.5小时。
图3是本实施例中5-氟尿嘧啶原料和球磨后无定形5-氟尿嘧啶的XRD图，显示出球磨后产物的无定形化很完全。
实验过程中，5-氟尿嘧啶和PVP K30的用量均扩大20倍，结果无明显变化，一样显示出球磨后产物的无定形化很完全。
实施例4：
1g塞来昔布和1g的PVP K30混合，加热至60℃球磨2小时。
图4是本实施例中塞来昔布原料和球磨后无定形的塞来昔布的XRD图，显示出球磨产物的无定形化很完全。
实验过程中，将塞来昔布和PVP K30的用量均扩大30倍，同样显示出球磨后产物的无定形化很完全。
从以上实施例可以看出，本发明的在辅料辅助作用下，通过干法球磨来制备无定形药物的方法，高效实现了药物活性成分的无定形化，且所用球磨辅料本身为药剂中允许成分，球磨辅料无需分离，可与药物活性组分（API）一同制成片剂。本发明的方法所涉及工艺简单成熟，适用性广，适用用于多种药物的无定形化，适合于大批量、廉价地制备无定形药物。
以上实施例仅用以说明本发明的技术方案，而非对本发明要求保护的范围进行限制，基于本发明的实施例，本领域的普通技术人员对本发明的技术方案进行修改或者等同替换，而不脱离本发明的精神和范围，均属于本发明要求保护的范围。
Claims (3)
1.一种制备无定形药物的方法，其特征在于，包括以下步骤：
（1）将药物活性成分与球磨辅料混合，得到混合物；所述药物活性成分选自氨基酸类药物、碱基类药物中的一种；所述氨基酸类药物为γ-氨基丁酸；所述碱基类药物为5-氟尿嘧啶；辅料选自氯化钙或聚乙烯吡咯烷酮；所述聚乙烯吡咯烷酮为PVP K30；
当所述药物活性成分为γ-氨基丁酸时，所述辅料为氯化钙，并且γ-氨基丁酸和氯化钙的质量比是1:1；
当所述药物活性成分为5-氟尿嘧啶时，所述辅料为PVP K30，并且5-氟尿嘧啶和PVPK30的质量比是1:1；
（2）对所述混合物进行球磨处理。
2.根据权利要求1所述的制备无定形药物的方法，其特征在于，步骤（2）中球磨时间为10min到2h，球磨的温度为15~60℃。
3.根据权利要求1所述的制备无定形药物的方法，其特征在于，步骤（2）中球磨时间为1h，球磨的温度为20~30℃。
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