CN114652685B - 一种高生物利用度的伊曲康唑胶囊剂 - Google Patents
一种高生物利用度的伊曲康唑胶囊剂 Download PDFInfo
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Abstract
本发明属于药物制剂技术领域，公开了一种高生物利用度的伊曲康唑胶囊剂。该胶囊剂是将伊曲康唑、共聚维酮和结晶抑制剂用热熔挤出机在140‑155℃加热熔融挤出，再将挤出物粉碎后与填充剂、崩解剂、助流剂和润滑剂混合并充填胶囊壳而成。该胶囊剂中脂溶性主药伊曲康唑溶出快速，药物生物利用度提高，个体差异减小，稳定性和工艺重现性均较好，适合于规模化生产。
Description
技术领域
本发明属于西药制剂技术领域，具体而言，涉及一种高生物利用度的伊曲康唑固体分散体及其胶囊剂。
背景技术
伊曲康唑(Itraconazole)为新一代三氮唑类衍生物抗真菌药，其作用原理是能够破坏真菌细胞膜的重要组成部分——麦角甾醇的合成。伊曲康唑为广谱抗真菌药物，对类球孢子菌病、着色真菌病、球孢子菌病、组织胞浆菌病等深部真菌所引起的系统感染，以及对手足体癣、真菌性角膜炎、花斑糠疹、外阴阴道念珠菌病等浅表真菌所引起的系统感染具有良好的治疗效果。其结构式为：
伊曲康唑为BCS二类弱碱性难溶药物，pKa为3.70，具有强亲脂性，极难溶于水，生物利用度低。其溶解度具有pH依赖性，在中性pH条件下其水溶液的饱和溶解度约为1ng/ml；在pH＝1的盐酸溶液中，饱和溶解度约为5μg/ml。由于伊曲康唑的难溶性，导致其在胃肠道中的溶出速率很小，口服绝对生物利用度低，约为55％左右，限制了伊曲康唑药效的发挥。为改善伊曲康唑的溶解度和溶出度，提高伊曲康唑口服生物利用度，现有技术中已进行了诸多的研究。
伊曲康唑的原研胶囊制剂
由比利时杨森制药公司生产。1992年9月，获美国食品药品管理局(FDA)批准在美国上市，次年在我国获准进口。
是内装微丸的胶囊(美国专利：US5633015)，其工艺过程为在流化床造粒机内，将药物和羟丙甲纤维素以二氯甲烷和无水乙醇为溶液(1.5:l)在流化床内喷雾至600～700μm粒径的蔗糖丸芯表面，真空干燥后，用聚乙二醇20000、二氯甲烷溶液包衣，制得微丸后装入胶囊。工艺中多次用到二氯甲烷，不利于车间安全生产和工人的劳动保护。流化床设备要求高，需要防爆，工艺过程复杂。蔗糖丸芯的使用，对高血糖患者不适用。
专利CN106619521B公开了一种伊曲康唑肠溶性固体分散体及其制备方法，所述固体分散体由作为活性成分的伊曲康唑、肠溶性高分子载体和表面活性剂通过热熔挤出技术制备而成。该专利中的伊曲康唑在胃液中不溶出，从而有效抑制药物在到达肠道之前的重结晶。然而伊曲康唑在肠液的pH环境中下溶解度很低，即便保持无定型状态，溶解度依然有限，导致溶出度低。因此该药物在人体中的生物利用度并不理想。另外，表面活性剂存在，对胃肠道的刺激较大。
专利CN110898015A公开了一种伊曲康唑制剂的制备方法，包括以下具体步骤：将伊曲康唑溶于醇性溶剂中，将环糊精与水配成溶液，然后将伊曲康唑溶液倒入环糊精水溶液中，形成环糊精包合伊曲康唑的包合物，作为粘合剂；将填充剂和崩解剂充分混匀，加入所述粘合剂经湿法制粒得到颗粒。虽然该制备方法能有效提高伊曲康唑的溶解度和溶出度，然而有报道指出，环糊精主要经过肾脏消除，所以对于严重肾功能障碍的患者，其消除时间会大幅延长，可能导致蓄积中毒。另外，制粒过程使用了有机溶剂，不利于劳动保护。
专利CN103622918B公开了一种伊曲康唑微丸及其制备方法，通过在微丸丸芯表面处依次包覆伊曲康唑含药层及隔离保护层制得；所述伊曲康唑含药层由伊曲康唑、固体分散体、粘合剂、抗黏剂、有机溶剂制得。虽然该技术制备的伊曲康唑微丸可实现迅速溶出，然而制剂中表面活性剂用量大，且用到有机试剂二氯甲烷，胃肠道刺激明显，不利于劳动保护且工艺过程复杂。
伊曲康唑在胃液中溶出快，从而使其在胃中形成热力学不稳定的过饱和溶液。关于伊曲康唑固体分散体形式的胶囊制剂，现已报道的技术中，由于不能避免药物向肠道转运过程以及肠道环境下过饱和溶液重结晶量大的问题，因此造成伊曲康唑的实际生物利用度并不理想。另外溶剂法制备固体分散体，存在残留溶剂问题，长期储存后容易导致制剂的杂质升高。
发明内容
鉴于现有技术的不足，本发明的目的在于提供一种高生物利用度的伊曲康唑固体分散体及其胶囊剂，制备过程中不使用有机溶剂，得到的伊曲康唑胶囊溶出快，胃肠道内过饱和浓度维持时间久，生物利用度高。
为了实现上述技术目的，发明人结合多年来的制剂研发经验，通过大量试验研究并不懈探索，最终获得了如下技术方案：一种伊曲康唑固体分散体，所述伊曲康唑固体分散体是将伊曲康唑、共聚维酮和结晶抑制剂混匀后用热熔挤出机在140-155℃加热熔融挤出而得，所述的结晶抑制剂为羟丙甲纤维素。
进一步优选地，如上所述的伊曲康唑固体分散体，其中伊曲康唑、共聚维酮和结晶抑制剂的重量比为1：(2.5-6.5)：(0.05-0.5)。
再进一步优选地，如上所述的伊曲康唑固体分散体，其中伊曲康唑、共聚维酮和结晶抑制剂的重量比为1：(3-6)：(0.1-0.3)。
进一步优选地，如上所述的伊曲康唑固体分散体，其中的共聚维酮为共聚维酮VA64或共聚维酮S630。
进一步优选地，如上所述的伊曲康唑固体分散体，其中的结晶抑制剂羟丙甲纤维素的型号选自E5 LV、E6 LV、E15 LV、E4M中的一种。
一种伊曲康唑胶囊剂，该胶囊剂包含上述的伊曲康唑固体分散体，以及填充剂、崩解剂、助流剂和润滑剂。进一步优选地，所述胶囊剂具有含有如下重量份的组份：固体分散体100份，填充剂10～30份，崩解剂5～20份，助流剂1～2.5份，润滑剂0.3～1.2份。
再进一步优选地，如上所述的伊曲康唑胶囊剂，其中：所述填充剂选自微晶纤维素、硅化微晶纤维素、喷雾干燥甘露醇、纤维素乳糖、预胶化淀粉和乳糖中的一种或两种以上；所述崩解剂选自羧甲基淀粉钠、交联羧甲基纤维素钠、交联聚维酮、低取代羟丙纤维素和部分α淀粉中的一种或两种以上；所述助流剂选自胶态二氧化硅和滑石粉中的一种或两种；所述润滑剂选自硬脂酸镁、硬脂酸锌、硬脂酸富马酸钠和氢化蓖麻油中的一种或两种以上。
另外，本发明还提供了一种上述伊曲康唑胶囊剂的制备方法，该方法包括以下步骤：
(1)将伊曲康唑、共聚维酮和结晶抑制剂混匀，用热熔挤出机在140-155℃加热熔融后挤出，冷却至室温；
(2)将冷却后的挤出物通过锤式粉碎机粉碎，得到伊曲康唑固体分散体；
(3)将伊曲康唑固体分散体与填充剂、崩解剂、助流剂和润滑剂混合均匀后，充填明胶空心胶囊壳。
与现有技术相比，本发明制备的伊曲康唑胶囊剂具有如下优点和显著进步：
(1)药物溶出快，且伊曲康唑在胃肠道内维持过饱和浓度时间长。结晶抑制剂的引入，有效抑制了药物在肠道内重结晶，从而大幅度提高了生物利用度。
(2)制剂中无表面活性剂，避免了表面活性剂对胃肠道的刺激。
(3)制备过程不使用任何有机试剂，环境友好，胶囊的稳定性提高。
(4)制备工艺相对简单，可连续化生产。
附图说明
图1为本发明伊曲康唑胶囊与原研胶囊
在pH1.0介质中的溶出曲线。
具体实施方式
下面通过具体制备例和试验例对本发明的技术方案和技术效果作进一步详细说明。但本领域技术人员将会理解，下列实施例仅用于说明本发明，而不应视为限定本发明的范围。另外，实施例中未注明具体技术操作步骤或条件者，均按照本领域内的文献所描述的技术或条件或者按照产品说明书进行。所用试剂或仪器未注明生产厂商者，均为可以通过市购获得的常规产品。
实施例1
1)处方
2)制备工艺
(a)将处方量的伊曲康唑、共聚维酮VA64和羟丙甲纤维素E4M混粉，用热熔挤出机在155℃加热熔融挤出，冷却至室温。
(b)将冷却后挤出物通过锤式粉碎机粉碎，过筛。
(c)将粉碎后的热熔挤出物与微晶纤维素PH102、交联羧甲基纤维素钠、胶态二氧化硅和硬脂酸镁混合均匀后，充填明胶空心胶囊即得。
实施例2
1)处方
2)制备工艺
(a)将处方量的伊曲康唑、共聚维酮VA64和羟丙甲纤维素E4M混粉用热熔挤出机在140℃加热熔融挤出，冷却至室温。
(b)将冷却后挤出物通过锤式粉碎机粉碎，过筛。
(c)将粉碎后的热熔挤出物与纤维素乳糖、交联聚维酮、胶态二氧化硅和硬脂酸锌混合均匀后，充填明胶空心胶囊即得。
实施例3
1)处方
2)制备工艺
(a)将处方量的伊曲康唑、共聚维酮VA64和羟丙甲纤维素E6 LV混粉用热熔挤出机在145℃加热熔融挤出，冷却至室温。
(b)将冷却后挤出物通过锤式粉碎机粉碎，过筛。
(c)将粉碎后热熔挤出物与喷雾干燥甘露醇、羧甲淀粉钠、滑石粉和硬脂酸镁混合均匀后，充填明胶空心胶囊即得。
实施例4
1)处方
2)制备工艺
(a)将处方量的伊曲康唑、共聚维酮S630和羟丙甲纤维素E15 LV混粉用热熔挤出机在150℃加热熔融挤出，冷却至室温。
(b)将冷却后挤出物通过锤式粉碎机粉碎，过筛。
(c)将粉碎后的热熔挤出物与硅化微晶纤维素、羧甲淀粉钠、低取代羟丙纤维素、滑石粉和硬脂酸镁混合均匀后，充填明胶空心胶囊即得。
实施例5
1)处方
2)制备工艺
(a)将处方量的伊曲康唑、共聚维酮S630和羟丙甲纤维素E4M混粉用热熔挤出机在147℃加热熔融挤出，冷却至室温。
(b)将冷却后挤出物通过锤式粉碎机粉碎，过筛。
(c)将粉碎后的热熔挤出物与预胶化淀粉、部分α淀粉、低取代羟丙纤维素、滑石粉和氢化蓖麻油混合均匀后，充填明胶空心胶囊即得。
实施例6
1)处方
2)制备工艺
(a)将处方量的伊曲康唑、共聚维酮VA64和羟丙甲纤维素E5 LV混粉用热熔挤出机在152℃加热熔融挤出。
(b)将冷却后挤出物通过锤式粉碎机粉碎，过筛。
(c)将粉碎后的热熔挤出物与乳糖、羧甲淀粉钠、胶态二氧化硅和硬脂酸镁混合均匀后，充填明胶空心胶囊即得。
对比实施例1
1)处方
2)制备工艺
(a)将处方量的伊曲康唑、共聚维酮VA64混粉用热熔挤出机在135℃加热熔融挤出，冷却至室温。
(b)将冷却后挤出物通过锤式粉碎机粉碎，过筛。
(c)将粉碎后的热熔挤出物与微晶纤维素PH102、交联羧甲基纤维素钠、胶态二氧化硅和硬脂酸镁混合均匀后，充填明胶空心胶囊即得。
对比实施例2
该对比实施例为西安杨森制药有限公司生产的
胶囊，规格100mg。
对比实施例3
1)处方
2)制备工艺
称取处方量的伊曲康唑、肠溶性高分子载体材料和表面活性剂，研磨使混合均匀，制成物理混合物；加入双螺杆热熔挤出机中，挤出物理混合物，挤出温度165℃，冷却后粉碎过80目筛，即得所述伊曲康唑的固体分散体。
将伊曲康唑的固体分散体与交联羧甲基纤维素钠、微晶纤维素和硬脂酸镁混合均匀，充填明胶胶囊即得。
对比实施例4
1)处方
2)制备工艺
(a)将处方量的伊曲康唑、共聚维酮VA64和羟丙甲纤维素E5 LV混粉用80％乙醇湿法制粒，20目筛网整粒，55℃烘箱中烘干。
(b)将干燥后颗粒与微晶纤维素PH102、羧甲淀粉钠、胶态二氧化硅和硬脂酸镁混合均匀后，充填明胶空心胶囊即得。
实施例7：伊曲康唑胶囊剂的溶出度、稳定性及生物等效性实验
1.溶出度试验
实施例1-6及对比实施例1-4所得的伊曲康唑胶囊采用如下方法测定溶出度。
取本品，照中国药典2020版溶出度与释放度测定法(通则0931第二法)。以盐酸溶液(9→1000)1000ml为溶出介质，转速为每分钟75转，依法操作，经60分钟时取样。取溶出液适量，滤过，精密量取续滤液5ml，置25ml量瓶中，用甲醇－溶出介质(5:95)稀释至刻度，摇匀，作为供试品溶液。另取伊曲康唑对照品约20mg，精密称定，置200ml量瓶中，加甲醇40ml，置40℃水浴中加热振摇使溶解，放冷，用溶出介质稀释至刻度，摇匀，精密量取5ml，置25ml的量瓶中，用溶出介质稀释至刻度，摇匀。取供试品溶液与对照品溶液，照紫外-可见分光光度法(通则0401)，在255nm的波长处分别测定吸光度，计算每粒的溶出度。限度标示量的80％，应符合规定。
表1.溶出度试验结果
2.溶出曲线测定
依照溶出度试验项下的溶出方法和紫外－可见分光光度法测定条件，对实施例1和实施例5及对比实施例2
所得的伊曲康唑胶囊分别在10min、20min、30min、45min、60min取样测定吸光度，计算溶出度并绘制溶出曲线，见附图。
表2.溶出曲线试验结果
3.长期稳定性试验
对本发明实施例中所得产品在25±2℃、60％±5％RH条件中存放12个月，依据2020版中国药典二部伊曲康唑胶囊有关物质项下的测定方法，分别于0月、3月、6月、9月、12月对保留样品的有关物质进行测定，总杂限度为1.5％。具体数据如下表所示。
表3.伊曲康唑胶囊长期稳定性试验结果
4.生物等效性模拟
通过PION公司的药物生物等效性及体内外相关性预测仪光纤药物溶出度与渗透测定仪，模拟自制胶囊和原研制剂
在人体内空腹状态下的渗透吸收情况，对比吸收速率的差别，来预测体内外相关性。对照组胶囊
规格为100mg，生产厂家为西安杨森制药有限公司。体内渗透吸收结果如下表：
表4.伊曲康唑胶囊模拟空腹渗透吸收结果对比统计表
| 样品 | AUC90％置信区间(％) | Cmax90％置信区间(％) |
| 实施例1 | 110.31～130.55 | 103.68～131.75 |
| 实施例2 | 112.69～138.74 | 109.23～142.21 |
| 实施例3 | 106.45～125.53 | 105.38～126.47 |
| 实施例4 | 109.23～134.57 | 106.77～136.53 |
| 实施例5 | 115.64～141.39 | 109.85～144.12 |
| 实施例6 | 103.61～121.76 | 101.62～128.43 |
| 对比实施例1 | 10.35～41.62 | 14.68～46.29 |
| 对比实施例3 | 57.13～75.64 | 54.36～76.83 |
| 对比实施例4 | 37.36～68.25 | 37.03～61.15 |
由上表实验结果可知，本发明制备的伊曲康唑胶囊在模拟空腹条件下的吸收效果优于原研制剂。
Claims (6)
1.一种伊曲康唑固体分散体，其特征在于，所述伊曲康唑固体分散体是将伊曲康唑、共聚维酮和结晶抑制剂混匀后用热熔挤出机在140-155℃加热熔融挤出而得，所述的结晶抑制剂为羟丙甲纤维素；
所述伊曲康唑固体分散体中伊曲康唑、共聚维酮和结晶抑制剂的重量比为1：（3-6）：（0.1-0.3）；
所述的共聚维酮为共聚维酮VA64或共聚维酮S630；
所述结晶抑制剂羟丙甲纤维素的型号选自E6 LV、E15 LV、E4M中的一种。
2.一种伊曲康唑胶囊剂，其特征在于，该胶囊剂包含权利要求1所述的伊曲康唑固体分散体，以及填充剂、崩解剂、助流剂和润滑剂。
3.根据权利要求2所述的伊曲康唑胶囊剂，其特征在于，所述胶囊剂具有含有如下重量份的组份：固体分散体100份，填充剂10~30份，崩解剂5~20份，助流剂1~2.5份，润滑剂0.3~1.2份。
4.根据权利要求2所述的伊曲康唑胶囊剂，其特征在于，所述填充剂选自微晶纤维素、硅化微晶纤维素、喷雾干燥甘露醇、纤维素乳糖、预胶化淀粉和乳糖中的一种或两种以上；所述崩解剂选自羧甲基淀粉钠、交联羧甲基纤维素钠、交联聚维酮、低取代羟丙纤维素和部分α淀粉中的一种或两种以上；所述助流剂选自胶态二氧化硅和滑石粉中的一种或两种；所述润滑剂选自硬脂酸镁、硬脂酸锌、硬脂酸富马酸钠和氢化蓖麻油中的一种或两种以上。
5.一种根据权利要求2所述伊曲康唑胶囊剂的制备方法，其特征在于，该方法包括以下步骤：
(1) 将伊曲康唑、共聚维酮和结晶抑制剂混匀，用热熔挤出机在140-155℃加热熔融后挤出，冷却至室温；
(2) 将冷却后的挤出物通过锤式粉碎机粉碎，得到伊曲康唑固体分散体；
(3) 将伊曲康唑固体分散体与填充剂、崩解剂、助流剂和润滑剂混合均匀后，充填明胶空心胶囊壳。
6.根据权利要求5所述伊曲康唑胶囊剂的制备方法，其特征在于，所述填充剂选自微晶纤维素、硅化微晶纤维素、喷雾干燥甘露醇、纤维素乳糖、预胶化淀粉和乳糖中的一种或两种以上；所述崩解剂选自羧甲基淀粉钠、交联羧甲基纤维素钠、交联聚维酮、低取代羟丙纤维素和部分α淀粉中的一种或两种以上；所述助流剂选自胶态二氧化硅和滑石粉中的一种或两种；所述润滑剂选自硬脂酸镁、硬脂酸锌、硬脂酸富马酸钠和氢化蓖麻油中的一种或两种以上。
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