CN105534923B - 应用超临界抗溶剂技术制备厄贝沙坦超细颗粒的方法 - Google Patents
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Abstract
本发明公开一种应用超临界抗溶剂技术制备厄贝沙坦超细颗粒的工艺，属于药物剂型和超临界技术领域。厄贝沙坦溶液经超临界流体抗溶剂设备体系喷入结晶釜中，在结晶釜内结晶析出“砖型”和无定形态的厄贝沙坦超细颗粒。该工艺通过改变溶剂种类、溶液浓度、溶液进样速率、结晶压力和结晶温度等参数，控制药物的形貌及粒径。通过本发明制备得到的厄贝沙坦超细颗粒粒径较小、粒度分布较窄，并且药物微粒的溶出度和平衡溶解度得到了显著的提升。
Description
技术领域
本发明涉及的是制备厄贝沙坦超细颗粒的工艺，具体而言，本发明涉及应用超临界CO2压缩抗溶剂沉淀法(PCA)制备厄贝沙坦超细颗粒的工艺，属于药物剂型和超临界技术领域。
技术背景
近年来，超细药物颗粒特别是纳米微粒的研制，已成为药物传递系统(drugdelivery systems DDS)领域中的一个热点。静脉注射给药的药物粒径通常在0.1～0.3μm之间，吸入式给药为1～5μm，口服给药为0.1～100μm。对于传统的药物微粒化技术，包括研磨法、喷雾干燥法、抗溶剂法，冷冻干燥法等得到的微粒粒度分布通常较宽，并且存在有机溶剂残留、产品易失活等缺陷，很难满足现今的药物微粒化需求。
超临界流体结晶技术是近十几年来国内外积极研发的一项药物微粒制备新技术，其原理是利用超临界流体与药物溶液在超临界状态下相互接触，药物迅速分散并形成微米甚至纳米级微粒。按照超临界流体在制粒过程中起的作用，大致可分为溶剂、反溶剂和溶质三大类，其中超临界流体作为反溶剂的应用最为广泛。根据装置不同，超临界抗溶剂技术又包括气体抗溶剂法(gas antisolvent recrystallization，GAS)、超临界抗溶剂压缩沉淀法(precipitation with a compressed anti-solvent method，PCA)、气溶胶溶剂萃取体系法(aerosol solvent extraction systems，ASES)、超临界流体强化溶液分散法(solution enhanced dispersion by supercritical fluids，SEDS)等。超临界流体结晶技术与传统的药物微粒化技术相比，制备得到的微粒具有粒径较小，粒度分布较窄、溶剂残留较少、可控且可一步到位生产等优点。因此，超临界流体结晶技术在药物微粒化方面具有良好的应用前景。
厄贝沙坦是血管紧张素II受体拮抗剂，与氯沙坦有相似的活性，用于高血压的治疗，包括高血压糖尿病患者并发肾疾病的治疗。厄贝沙坦可通过胃肠道迅速吸收，口服生物利用度为60％～80％。口服厄贝沙坦1.5～2h后可达最高血药浓度，最终清除半衰期为11～15h。1997年，FDA批准商品名为“Avapro”的厄贝沙坦片剂的上市。在国内市场上，厄贝沙坦的剂型多为片剂和胶囊。按照生物药剂学分类系统划分，厄贝沙坦属于BCS II类(低溶解性、高渗透性)，因此可通过改变药物粒径和形貌以提高其溶出度和平衡溶解度。目前，在中国发明专利CN95118711中公开了厄贝沙坦具有A型和B型两种晶型。两种晶型不会发生自发转变，但是通过控制重结晶溶质条件可以实现A晶型和B晶型的相互转变。在中国发明专利CN99807707中公开了A晶型存在“针型”和“砖型”两种形态。处于“针型”的A晶型呈现不吸湿的稳定状态，但难于过滤和干燥，流动性差；而处于“砖型”的A晶型堆密度和流动指数相对较大，易于干燥操作。
目前人们十分渴望出现一种将厄贝沙坦药物制成专一形态的超细颗粒，以提高该药物溶出度和平衡溶解度的工艺。
发明内容
本发明目的在于提供一种应用超临界抗溶剂技术制备厄贝沙坦超细颗粒的工艺，以提高该药物的溶出度和平衡溶解度。
本发明的目的是通过下述技术方案实现的：
一种应用超临界CO2压缩抗溶剂沉淀法(PCA)制备厄贝沙坦超细颗粒的工艺，该工艺在超临界流体抗溶剂设备中包括下列四个步骤：
(1)配制厄贝沙坦溶液：溶质为厄贝沙坦，溶剂为能够溶解厄贝沙坦的混合有机溶剂，溶解温度为10～30℃，50～80Hz超声3～10min以保证溶质完全溶解；
(2)二氧化碳进料：将CO2钢瓶内的CO2通过压力调节阀输入超临界流体抗溶剂设备体系中的结晶釜中；
(3)厄贝沙坦结晶析出：将上述配制的厄贝沙坦溶液通过高效液相泵经超临界流体抗溶剂设备体系中的喷嘴以较高压状态喷入结晶釜中，操作时间为10～40min，进样结束后，维持超临界CO2通入与通出状态30～90min，在结晶釜内收集厄贝沙坦超细颗粒；
(4)检验：采用扫描电子显微镜(SEM)分析超细颗粒的粒径及形貌，通过恒温振荡仪测量超细颗粒在纯水中的溶解度，使用智能溶出仪检测超细颗粒的体外溶出度。
所述步骤(1)的混合有机溶剂，包括丙酮、二氯甲烷、乙醇中的一种与二甲基亚砜的混合溶剂，混合比例为7∶1～10∶1，溶液浓度范围为5～20mg/mL。
所述步骤(2)的结晶釜内超临界CO2压力为8～18MPa，结晶温度为35～55℃。
所述步骤(3)的药物溶液进样流速为0.5～2mL/min，超临界CO2的进出流量为3～7L/min。
本发明制备的厄贝沙坦超细颗粒肉眼观察为蓬松絮状，不同溶剂下制备得到的超细颗粒在SEM下观测呈现两种形貌，一种是处于“砖型”的A晶型，粒径为0.3～3μm，粒度分布均匀，另一种为无定型态；而厄贝沙坦原料药为存在“针型”和“砖型”两种的A晶型，粒径为5～20μm，粒度分布极不均匀。处理前厄贝沙坦在纯水中的平衡溶解度极低，为17.89μg/mL，优化工艺得到的超细颗粒的平衡溶解度为71.33μg/mL，提高了近五倍。同时相较于原料药，超细颗粒的溶出度有了明显提高，具体表现为，通过溶出度检测，经过2h，超细颗粒的累积溶出度达到85％以上，而原料药为40％左右。
附图说明
附图1是使用本发明方法的设备流程图；
《附图中序号说明》
1：CO2钢瓶，2：低温恒温水槽，3：高压泵，4：CO2预热装置，5：储液槽，6：高效液相泵，7：结晶釜，8：溶剂回收装置
附图2显示(a)厄贝沙坦原料药，(b)本发明实例一中厄贝沙坦超细颗粒的SEM图像；
附图3为厄贝沙坦原料药和本发明实例二中厄贝沙坦超细颗粒的XRD谱图；
附图4是厄贝沙坦原料药和PCA法制备的厄贝沙坦超细微粒的溶出度对比曲线图。
具体实施方式
下面结合实施例进一步解释本发明的内容。给出这些实施例仅为更好地理解本发明，而非限制本发明的范围。
一种应用超临界抗溶剂技术制备厄贝沙坦超细颗粒的工艺，所述工艺在超临界流体抗溶剂设备中按照如下步骤依次进行：
(1)配制厄贝沙坦溶液：溶质为厄贝沙坦，溶剂为能够溶解厄贝沙坦的混合有机溶剂，溶解温度为10～30℃，50～80Hz超声3～10min以保证溶质完全溶解；
(2)二氧化碳进料：将CO2钢瓶内的CO2通过压力调节阀输入超临界流体抗溶剂设备体系中的结晶釜中；
(3)厄贝沙坦结晶析出：将上述配制的厄贝沙坦溶液通过高效液相泵经超临界流体抗溶剂设备体系中的喷嘴以较高压状态喷入结晶釜中，操作时间为10～40min，进样结束后，维持超临界CO2通入与通出状态30～90min，在结晶釜内收集厄贝沙坦超细颗粒；
(4)检验：采用扫描电子显微镜(SEM)分析超细颗粒的粒径及形貌，通过恒温振荡仪测量超细颗粒在纯水中的溶解度，使用智能溶出仪检测超细颗粒的体外溶出度。
所述步骤(1)的混合有机溶剂，包括丙酮、二氯甲烷、乙醇中的一种与二甲基亚砜的混合溶剂，混合比例为7∶1～10∶1，溶液浓度范围为5～20mg/mL。
所述步骤(2)的结晶釜内超临界CO2压力为8～18MPa，结晶温度为35～55℃。
所述步骤(3)的药物溶液进样流速为0.5～2mL/min，超临界CO2的通出流量为3～7L/min。
实施例一：
精确称量厄贝沙坦原料药240mg，加到乙醇∶二甲基亚砜＝13mL∶2mL的混合溶剂中，25℃下溶解，并在70Hz超声5min以确保溶质溶解完全；设置超临界抗溶剂设备体系中的结晶压力为13.5MPa，结晶温度为48℃；通过HPLC泵将药物溶液以0.8mL/min的进样速率喷入结晶釜中，保持超临界CO2的通入与通出以控制体系内压力为13.5MPa，其中超临界CO2的通出速率控制在5.0～6.0L/min之间；进样量达10mL后，停止进样，维持超临界CO2的通入与通出状态80min后，停止CO2的通入；待体系内的压力降为大气压后，从结晶釜中取出样品检测分析；所得厄贝沙坦超细颗粒肉眼观测为蓬松絮状，在SEM下观测呈处于“砖型”的A晶型及部分无定型态，粒径为0.5～5μm，粒度分布均匀，通过恒温振荡仪测量得到超细颗粒在纯水中的溶解度为76.75μg/mL。
实施例二：
精确称量厄贝沙坦原料药225mg，加到二氯甲烷∶二甲基亚砜＝13.5mL∶1.5mL的混合溶剂中，25℃下溶解，并在70Hz超声5min以确保溶质溶解完全；设置超临界抗溶剂设备体系中的结晶压力为15MPa，结晶温度为45℃；通过HPLC泵将药物溶液以0.8mL/min的进样速率喷入结晶釜中，保持超临界CO2的通入与通出以控制体系内压力为15MPa，其中超临界CO2的通出速率控制在5.0～6.0L/min之间；进样量达10mL后，停止进样，维持超临界CO2的通入与通出状态70min后，停止CO2的通入；待体系内的压力降为大气压后，从结晶釜中取出样品检测分析；所得厄贝沙坦超细颗粒肉眼观测为蓬松絮状，在SEM下观测呈处于“砖型”的A晶型，粒径为0.3～3μm，粒度分布均匀，通过恒温振荡仪测量得到超细颗粒在纯水中的溶解度为71.33μg/mL。
Claims (1)
1.一种应用超临界抗溶剂技术制备厄贝沙坦超细颗粒的方法，其特征在于，包括步骤：
（1）配制厄贝沙坦溶液：溶质为厄贝沙坦，溶剂为体积比为13:2的乙醇/二甲基亚砜混合溶剂或体积比为27:3的二氯甲烷/二甲基亚砜混合溶剂，溶解温度为25℃，70Hz超声5min以保证溶质完全溶解，溶液浓度范围为5~20mg/mL；
（2）二氧化碳进料：将CO2钢瓶内的CO2通过压力调节阀输入超临界流体抗溶剂设备体系中的结晶釜中，超临界CO2的通出速率控制在5.0~6.0L/min之间，以保证结晶釜内超临界CO2压力为13.5~15MPa；结晶釜内的温度为45~48℃；
（3）厄贝沙坦结晶析出：将上述配制的厄贝沙坦溶液通过高效液相泵经超临界流体抗溶剂设备体系中的喷嘴以流速0.8mL/min喷入结晶釜中，进样量达10mL后停止进样，维持超临界CO2通入与通出状态70~80min；最后停止CO2的通入，待体系内的压力降为大气压后，在结晶釜内收集厄贝沙坦超细颗粒。
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