CN110711176A - 一种西尼地平纳米混悬液及其制备方法 - Google Patents
一种西尼地平纳米混悬液及其制备方法 Download PDFInfo
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- CN110711176A CN110711176A CN201911174266.7A CN201911174266A CN110711176A CN 110711176 A CN110711176 A CN 110711176A CN 201911174266 A CN201911174266 A CN 201911174266A CN 110711176 A CN110711176 A CN 110711176A
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- cilnidipine
- nanosuspension
- stabilizer
- sinetipin
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Abstract
本发明涉及一种西尼地平纳米混悬液及其制备方法，该西尼地平纳米混悬液是由西尼地平和稳定剂水溶液经纳米化处理所得，其中所述稳定剂为空间稳定剂、电荷稳定剂或两者的组合。通过本发明制备的西尼地平混悬液具有溶出度高，生物利用度高的特点，将其作为制剂成品或作为制剂中间体制备固体或液体状态的西尼地平制剂，均可保证药物的吸收和药效稳定；且本发明工艺技术可行、稳定可靠，为西尼地平制剂的开发提供一种易于产业化的技术手段以及制剂中间体制备技术，并由此制得一种具有良好口服吸收和应用前景的西尼地平制剂。
Description
技术领域
本发明属于医药技术领域，特别是涉及一种西尼地平纳米混悬液及其制备方法。
背景技术
高血压是以体循环动脉血压增高为主并伴有心、脑、血管和肾脏等器官功能或器质性损坏的系统性疾病。高血压的并发症主要有冠心病、心肌梗死、脑卒、眼部疾病和肾病等。由于高血压及其并发症的严重危害性，其已成为国内外最常见的心血管疾病和主要致死性疾病之一。
西尼地平是一种新型二氢吡啶类Ca2 +拮抗剂，能有效抑制交感神经元血管平滑肌L型Ca2 +通道和N型Ca2 +通道，已被成功应用于高血压和心绞痛的临床治疗且疗效显著。但是，西尼地平属于生物药剂学分类系统（BCS）中的II类，即溶解性低，渗透性高。西尼地平极低的溶解度使其制成的药物制剂，如片剂、胶囊等溶出度速率慢，体内的生物利用度低，这严重影响了其临床治疗效果。因此，需要开发能够提高其溶解度、溶出速率和生物利用度的西尼地平新剂型或中间体。
纳米混悬液（纳米晶）是近几十年里开发的纳米给药系统，由药物和适宜稳定剂通过相应技术制成的稳定的新剂型，具有避免使用有机试剂、高载药量、低毒副作用和高安全性的特点。将难溶性药物制成纳米混悬液（纳米晶）可以获得高表面积的纳米颗粒，提高了溶解度和溶出速率，改善药物动力学，增强其生物利用度。
目前，尚未有关于西尼地平纳米混悬液/纳米晶的相关报道。
发明内容
本发明的目的在于克服上述现有技术的缺陷，提供一种有效改善西尼地平的溶解度、溶出度和生物利用度，保证药物吸收和药效稳定，且技术可行、稳定可靠的西尼地平纳米混悬液。
本发明的另一目的是提供上述西尼地平纳米混悬液的制备方法。
为实现上述发明目的所采取的技术方案为：
一种西尼地平纳米混悬液，其特征在于该西尼地平纳米混悬液是由西尼地平和稳定剂水溶液经纳米化处理所得，其中所述稳定剂为空间稳定剂、电荷稳定剂或两者的组合。
所述西尼地平纳米混悬液的药物浓度为5mg/ml～100mg/ml，粒径为100～800nm，zeta电位为0±60mV。
所述空间稳定剂为聚乙烯比咯烷酮（PVP）、羟丙甲纤维素（HPMC）、聚乙烯吡咯烷酮醋酸乙烯共聚物（PVP VA64）、羟丙基纤维素（HPC）、泊洛沙姆、聚乙二醇（PEG）、维生素E聚乙二醇1000琥珀酸酯（TPGS）、羧甲基淀粉钠（SSG）、交联羧甲基纤维素钠（CCS）、交联聚维酮（PVPP）和羧甲基纤维素钠（CMC）中的一种或多种，其用量为西尼地平原料药质量的0.1～0.5倍。
所述电荷稳定剂为聚山梨酯-80、十二烷基硫酸钠（SDS）、多库酯钠（DOSS）和海藻酸钠中的一种或多种，其用量为西尼地平原料药质量的0.01～0.1倍。
将西尼地平纳米混悬液经冷冻干燥或喷雾干燥进行固化即可得到西尼地平纳米晶体，其中固化保护剂为乳糖、蔗糖、葡萄糖、海藻糖、甘露醇或山梨醇中的一种或几种，其用量占该纳米混悬液质量的2～10%。
所述西尼地平纳米晶体进一步制成药剂学上可接受的片剂、胶囊剂、颗粒剂或混悬剂。
所述西尼地平纳米晶体中西尼地平以晶型、无定型或晶型-无定型共存的形式存在，其中药物晶型占75%以上；西尼地平和辅料之间没有相互作用，相容性良好。
所述西尼地平纳米晶体在不同pH溶出介质中相比于西尼地平原料药能显著提高体外溶出度；同时，相比于原料药和市售制剂，所制备的西尼地平纳米混悬液能显著提高其体内口服生物利用度。
上述西尼地平纳米混悬液的制备方法，其特征在于采用介质研磨法、高压均质法或高压均质-超声波法制备西尼地平纳米混悬液。
所述介质研磨法的具体工艺步骤为：
1)将稳定剂加入到水介质中，磁力搅拌均匀得稳定剂水溶液；
2)将西尼地平原料药加入到上述稳定剂水溶液中，磁力搅拌均匀得粗混悬液；
3)将步骤2)所得西尼地平粗混悬液置于纳米研磨机的研磨室中，以适宜转速研磨，即可得到西尼地平纳米混悬液。
步骤3）中所用研磨珠材质为玻璃、钇稳定的氧化锆或聚苯乙烯衍生物的聚合物，其粒径为0.2～0.8mm。
步骤3）中所述西尼地平纳米混悬液与研磨珠的体积比为1:2～1:5。
步骤3）中所述研磨机转速为1000～4000rpm，研磨时间0.25～4h，研磨温度控制在10～30℃。
本发明通过湿法研磨成功地制备西尼地平纳米悬浮液，其表现出良好的物理稳定性并且比单独使用西尼地平的溶出速率更高。
本发明制备的纳米晶体中西尼地平以晶型、无定型或晶型-无定型共存的形式存在；西尼地平和辅料之间没有相互作用，相容性良好。
本发明将西尼地平和不同稳定剂溶液混合后经纳米化处理使药物粒径降至纳米级别，所构建的西尼地平纳米混悬液具有以下技术优势：
1）本发明采用湿介质研磨技术对西尼地平进行处理，通过将药物与稳定剂共研磨改善了难溶性药物西尼地平的体外溶出特性，并能充分的防止药物粒子的聚集，保证了纳米混悬液的稳定性；红外光谱（图3）和拉曼光谱（图4）表征确定了西尼地平原料药和辅料之间没有氢键形成，表明原辅料相容性良好。从体外溶出度实验来看，原料药在pH 1.2～pH 4.0溶液中的60min时溶出度小于10%，在pH 4.0～ pH 8.0溶液中60min时溶出度小于30%，但是纳米晶在pH 1.2～pH 8.0溶液中5min时溶出度约70%，60min时大于90%（见图7）。结果表明本发明的西尼地平纳米混悬液在pH 1.2～pH 4.0溶液中60min内的体外溶出度比原料药提高了10～15倍，在pH 4.0～ pH 8.0溶液中60min内的体外溶出度比原料药提高了3～8倍。
2）本发明所用制备方法工艺简单，制得的纳米混悬液/晶体载药量高，可达到5mg/ml～100mg/ml；稳定性好，在4°C和室温条件下放置3个月，粒径、电位（见图6）初始相比未见明显变化。图2/图3 的DSC/PXRD图谱显示，西尼地平原料药的熔点峰和特征衍射峰在西尼地平纳米晶中均存在，表明其物理稳定性良好（主要是由于该纳米混悬液中静电稳定剂和空间稳定剂产生了协同稳定作用），可实现规模化生产。
3）本发明通过减小药物的粒径、改善药物粒子润湿性等作用促进药物的溶出，制备的西尼地平纳米混悬液的口服生物利用度显著提高。特别的，西尼地平纳米混悬液在体内药动学实验中，分别采用西尼地平原料药、某市售西尼地平胶囊组作为对照，评价各给药组口服24h内的体内药动学参数。结果表明，本发明纳米混悬液经动物给药后，体内最大血药浓度（Cmax）比原料药提高了1～5倍，AUC比原料药提高了的1～3倍。即西尼地平纳米混悬液相比于原料药有着更高的最大血药浓度（Cmax）和AUC，即体内生物利用度更高。
综上所述，通过本发明制备的西尼地平混悬液具有溶出度高，生物利用度高的特点，将其作为制剂成品或作为制剂中间体制备固体或液体状态的西尼地平制剂，均可保证药物的吸收和药效稳定；且本发明工艺技术可行、稳定可靠，为西尼地平制剂的开发提供一种易于产业化的技术手段以及制剂中间体制备技术，并由此制得一种具有良好口服吸收和应用前景的西尼地平制剂。
本发明的西尼地平纳米晶体可口服给药，也可以注射给药，优选口服给药；该纳米晶体还可进一步制成药剂学上可接受的各种剂型，如片剂、胶囊剂、颗粒剂和混悬剂等固体或液体制剂等。
附图说明
图1为本发明西尼地平纳米混悬液/纳米晶的粒径、电位图和扫描电镜图。
图2为本发明西尼地平纳米混悬液/纳米晶的差示扫描量热图（e为纳米晶体）。
图3为本发明西尼地平纳米混悬液/纳米晶的粉末X射线衍射图（e为纳米晶体）。
图4为本发明西尼地平纳米混悬液/纳米晶的红外光谱图（e为纳米晶体）。
图5为本发明西尼地平纳米混悬液/纳米晶的拉曼光谱图（e为纳米晶体）。
图6为本发明西尼地平纳米混悬液/纳米晶的稳定性考察分析。
图7为本发明西尼地平纳米混悬液/纳米晶的体外溶出曲线图。
图8为本发明西尼地平纳米混悬液/纳米晶的体内药动学曲线图。
具体实施方式
为使本发明的目的、技术方案和优点更加清晰，下面结合附图对本发明实施例作进一步的详细说明，实施例仅用作对解释本发明，并不作为对本发明的限定。
下述实施例1-5中，纳米研磨机为循环式纳米研磨机，其中所用研磨珠材质为玻璃、钇稳定的氧化锆或聚苯乙烯衍生物的聚合物，其粒径为0.2～0.8mm；所述西尼地平纳米混悬液与研磨珠的体积比为1:2～1:5；所述研磨机转速为1000～4000rpm，研磨时间0.25～4min；研磨机搅拌轴的转速为1000～4000 rpm；研磨温度控制在10～30℃。
实施例1：西尼地平纳米混悬液的制备
称取泊洛沙姆407 （P407）0.20g，加入到50mL蒸馏水中，磁力搅拌使溶解；然后加入1.00g 西尼地平原料药，磁力搅拌15分钟，得粗混悬液。然后将此粗混悬液转移至纳米研磨机中进行研磨。研磨条件为：钇稳定的氧化锆研磨珠粒径为0.6-0.8mm，搅拌轴转速为2000rpm。60分钟后取样，测粒径为435nm，PDI为0.190。
实施例2：西尼地平纳米混悬液的制备
称取十二烷基硫酸钠0.05g，聚乙烯吡咯烷酮醋酸乙烯共聚物（PVP VA64）0.30g，加入到50mL蒸馏水中，磁力搅拌使溶解；然后加入1.00g 西尼地平原料药，磁力搅拌15分钟，得粗混悬液。然后将此粗混悬液转移至纳米研磨机中进行研磨。研磨条件为：钇稳定的氧化锆研磨珠粒径为0.6-0.8mm，搅拌轴转速为2500rpm。45分钟后取样，测粒径为312nm，电位为-33.6mV，结果见图1a和图1b。
实施例3：西尼地平纳米混悬液的制备
称取十二烷基硫酸钠0.10g，羟丙基纤维素（HPC-SSL）0.30g，加入50mL蒸馏水中，磁力搅拌使溶解，加入1.00g 西尼地平原料药，磁力搅拌15分钟，得粗混悬液。然后将此粗混悬液转移至纳米研磨机中进行研磨。研磨条件为：钇稳定的氧化锆研磨珠粒径为0.6-0.8mm,搅拌轴转速为2500rpm。45分钟后取样,测粒径为357nm,电位为-32.3mV。
实施例4：西尼地平纳米混悬液的制备
称取1.00g 西尼地平原料药1.00g分散在50ml纯化水中，8000转高压均质5min；称取聚乙烯比咯烷酮（PVP K30）0.3g，加入到10mL纯化水中磁力搅拌使溶解，然后将PVP K30水溶液在搅拌状态下转移到西尼地平分散液得粗混悬液。将粗混悬液在高压均质机（800bar）均质10个循环，得西尼地平纳米混悬液，测粒径为216nm，PDI为0.145。
实施例5：西尼地平纳米晶的制备
取实施例1或实施例2制备的西尼地平纳米混悬液新鲜样品，加入甘露醇作为冻干保护剂，其浓度为1%（m/v），然后在-80℃预冻12小时，然后转移至冷冻干燥机中进行冻干，得其冻干粉，即为西尼地平纳米晶体。
溶出度测定：
对西尼地平原料药和实施例1中的物理混合物（西尼地平、PVP VA64和SLS）及制得的西尼地平纳米悬浮液冷冻干燥粉末进行溶出度测定，方法如下：
参考《中国药典》2015版及日本橙皮书关于本品溶出度测定要求，分别以900 mLpH 1.2盐酸溶液（含0.1%吐温-80）、纯化水（含0.1%吐温-80）、pH 6.8磷酸盐缓冲液（含0.1%吐温-80）作为溶出介质。溶出条件和实验操作如下：桨法，转速为75 rpm，温度为（37±0.5）℃。量取相应溶出介质900mL，注入1000mL 溶出杯中，待温度稳定后，分别向各溶出杯中投入样品，分别于0，5，10，15，30，45，60 min 取样 5 mL，用 0.45 μm的滤膜过滤，同时补加 5 mL新介质，取续滤液作为供试品溶液。另精密称定西尼地平对照品1.0 mg，溶于10 mL甲醇制成100 μg/mL，以溶出介质定量稀释成10μg/mL，作为对照品溶液。采用紫外可见分光光度法在242 nm波长下进行含量测定，计算西尼地平原料药、物理混合物和西尼地平纳米混悬液冻干粉末的溶出度。如图8所示，在上述三中溶出介质中，西尼地平原料药和物理混合物在60min内的累积溶出度均＜30%，纳米晶5min的累积溶出度均＞70%，60min内的累积溶出度＞90%。
Claims (13)
1.一种西尼地平纳米混悬液，其特征在于该西尼地平纳米混悬液是由西尼地平和稳定剂水溶液经纳米化处理所得，其中所述稳定剂为空间稳定剂、电荷稳定剂或两者的组合。
2.按照权利要求1所述的西尼地平纳米混悬液，其特征在于所述西尼地平纳米混悬液的药物浓度为5mg/ml～100mg/ml，粒径为100～800nm，zeta电位为0±60mV。
3.按照权利要求1所述的西尼地平纳米混悬液，其特征在于所述空间稳定剂为聚乙烯比咯烷酮、羟丙甲纤维素、聚乙烯吡咯烷酮醋酸乙烯共聚物、羟丙基纤维素、泊洛沙姆、聚乙二醇、维生素E聚乙二醇1000琥珀酸酯、羧甲基淀粉钠、交联羧甲基纤维素钠、交联聚维酮和羧甲基纤维素钠中的一种或多种，其用量为西尼地平原料药质量的0.1～0.5倍。
4.按照权利要求1所述的西尼地平纳米混悬液，其特征在于所述电荷稳定剂为聚山梨酯-80、十二烷基硫酸钠、多库酯钠和海藻酸钠中的一种或多种，其用量为西尼地平原料药质量的0.01～0.1倍。
5.按照权利要求1至4任意一项所述的西尼地平纳米混悬液，其特征在于，将西尼地平纳米混悬液经冷冻干燥或喷雾干燥进行固化即可得到西尼地平纳米晶体，其中固化保护剂为乳糖、蔗糖、葡萄糖、海藻糖、甘露醇或山梨醇中的一种或几种，其用量占该纳米混悬液质量的2～10%。
6.按照权利要求5所述的西尼地平纳米混悬液，其特征在于所述西尼地平纳米晶体进一步制成药剂学上可接受的片剂、胶囊剂、颗粒剂或混悬剂。
7.按照权利要求5所述的西尼地平纳米混悬液，其特征在于所述西尼地平纳米晶体中西尼地平以晶型、无定型或晶型-无定型共存的形式存在，其中药物晶型占75%以上；西尼地平和辅料之间没有相互作用，相容性良好。
8.按照权利要求5所述的西尼地平纳米混悬液，其特征在于所述西尼地平纳米晶体在不同pH溶出介质中明显提高了体外溶出度；尤其是相比于原料药及市售制剂，所制备的西尼地平纳米混悬液能显著提高其体内口服生物利用度。
9.一种如权利要求1至4所述的西尼地平纳米混悬液的制备方法，其特征在于采用介质研磨法、高压均质法或高压均质-超声波法制备西尼地平纳米混悬液。
10.按照权利要求8所述的西尼地平纳米混悬液的制备方法，其特征在于所述介质研磨法的具体工艺步骤为：
1)将稳定剂加入到水介质中，磁力搅拌均匀得稳定剂水溶液；
2)将西尼地平原料药加入到上述稳定剂水溶液中，磁力搅拌均匀得粗混悬液；
3)将步骤2)所得西尼地平粗混悬液置于纳米研磨机的研磨室中，以适宜转速研磨，即可得到西尼地平纳米混悬液。
11.按照权利要求9所述的西尼地平纳米混悬液的制备方法，其特征在于，步骤3）中所用研磨珠材质为玻璃、钇稳定的氧化锆或聚苯乙烯衍生物的聚合物，其粒径为0.2～0.8mm。
12.按照权利要求10所述的西尼地平纳米混悬液的制备方法，其特征在于，步骤3）中所述西尼地平纳米混悬液与研磨珠的体积比为1:2～1:5。
13.按照权利要求9所述的西尼地平纳米混悬液的制备方法，其特征在于，步骤3）中所述研磨机转速为1000～4000rpm，研磨时间0.25～4h，研磨温度控制在10～30℃。
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| CN113616592A (zh) * | 2021-09-10 | 2021-11-09 | 宁夏医科大学 | 一种二氢吡啶类药物纳米混悬液及其制备方法 |
| CN114948869A (zh) * | 2022-05-26 | 2022-08-30 | 中国药科大学 | 一种染料木素纳米混悬液的制备方法及该方法制备的染料木素纳米混悬液 |
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| CN113616592A (zh) * | 2021-09-10 | 2021-11-09 | 宁夏医科大学 | 一种二氢吡啶类药物纳米混悬液及其制备方法 |
| CN114948869A (zh) * | 2022-05-26 | 2022-08-30 | 中国药科大学 | 一种染料木素纳米混悬液的制备方法及该方法制备的染料木素纳米混悬液 |
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