CN104688536A - 一种伊曲康唑制剂的制备方法 - Google Patents
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Abstract
本发明属于药物制剂领域，具体涉及一种伊曲康唑制剂的制备方法。采用超临界流体结晶技术增加伊曲康唑在体外的溶解度和体内的生物利用度。该方法通过调节设备的压力、温度、流量、浓度等参数，控制药物粒度、晶型。因此本发明提供了一种高效、低毒、生物利用度高的伊曲康唑高效制剂，为广大患者提供了更安全有效的选择，避免了伊曲康唑在体内不起效的弊端，是伊曲康唑制剂的一个重大革新。
Description
技术领域
本发明涉及一种伊曲康唑高效制剂的制备方法，属于药物制剂领域。
背景技术
伊曲康唑为三唑类的抗真菌药，1988年上市，既可抗真菌，又可抗细菌和某些原虫，对念珠菌、曲霉菌、隐球菌、组织细胞质菌、芽生菌都有效。伊曲康唑具有强亲脂性，极难溶于水，在中性pH值下其水溶液的饱和溶解度＜1ng/mL，在pH＝1的盐酸溶液中饱和溶解度为6μg/mL。根据生物药剂学分类系统，伊曲康唑属于典型的II类药物，其口服生物利用度由药物在胃肠道中的溶解速率决定。由于伊曲康唑难溶于水，使得其在胃肠道中的溶解速率小，口服生物利用度低；同时难以做成药物含量高的注射液，用药量大。
斯皮仁诺(SPORANOX，主要成分为伊曲康唑)注射液、口服液和胶囊是目前商品化的伊曲康唑制剂。注射液和口服液通过将伊曲康唑与2-羟丙基-β-环糊精络合增加其溶解性，但是2-羟丙基-β-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，据报道，尽管临床相关性尚不清楚，但是在2-羟丙基-β-环糊精的大鼠致癌研究中发现，2-羟丙基-β-环糊精可导致胰腺癌。对斯皮仁诺胶囊的研究则发现其口服生物利用度个体差异大，受服用者胃酸分泌状况和饮食状况影响明显。因此，寻求一种高效、低毒、生物利用度高且稳定的制剂已成为伊曲康唑制剂研发的热点。
为了克服伊曲康唑的难溶性、生物利用度低以及市售制剂存在的问题，国内外研究机构从制剂的方式入手，运用现代给药技术做了一系列尝试，将伊曲康唑制成静脉乳剂、自乳化剂以及聚合物胶束，达到增溶效果。但是各种剂型还存在一些问题，例如自乳化剂处方中含有一定量的浓盐酸，直接服用会对消化道产生损伤，需要进一步借助制剂手段固态化将其包裹以后才能口服使用；对于聚合物胶束使用的高分子聚合物及其在体内降解后的产物是否安全也未见文献报道。
通过减小粒度可以改进非水溶性药物的溶解性。超临界流体结晶技术是制备微米药物的新方法，其原理是利用超临界流体如二氧化碳等与药物溶液在超临界状态下混合从喷嘴喷出，在几十微秒内形成微米级微粒，通过调节压力、温度、流量、浓度等参数，可以控制药物粒度、晶型。超临界流体结晶技术还能使药物与高分子辅料形成微米级复合微粒，保证了药物的溶解度，从而保证了药物的疗效，且复合颗粒具有较好的晶体稳定性。
发明内容
本发明的目的是通过运用超临界流体结晶技术来制备伊曲康唑高效制剂，从而提高药物的生物利用度和疗效，避免使用表面活性剂，减小药物的毒副作用。
本发明提供了一种伊曲康唑制剂的制备方法，包括下列四个步骤：
1)混合溶液的配制：在伊曲康唑和L-抗坏血酸的混合物中加入甲醇和二氯甲烷的混合溶剂，溶解后，加入羟丙甲纤维素及普朗尼克F-127，再加入二氯甲烷，使完全溶解；
2)二氧化碳进料：将钢瓶内的二氧化碳通过压力调节阀输入超临界流体结晶设备体系的高压结晶釜内；
3)复合微粒析出：将步骤1)得到的溶液经超临界流体结晶设备体系的喷嘴喷入高压结晶釜内，复合微粒从溶液中析出并收集于高压结晶釜的底部；
4)将得到的复合微粒装胶囊。
所述步骤1)中伊曲康唑占胶囊内容物的重量百分比为30-55％。
所述步骤1)中甲醇和二氯甲烷的体积比为1∶1-9。
所述步骤2)中二氧化碳流速为10-50ml/min。
所述步骤2)中压力为50-130Bar。
所述步骤3)中溶液流速为0.1-3ml/min。
本发明的有益效果：(1)本发明的制备方法制得的伊曲康唑制剂从X-粉末衍射和电子显微镜扫描数据、体外溶出度试验数据以及动物体内的药动学试验数据都优于市售的斯皮仁诺胶囊。(2)本发明避免使用表面活性剂，减小药物的毒副作用。(3)本发明提供了一种高效、低毒、生物利用度高的伊曲康唑高效制剂，为广大患者提供了更安全有效的选择，避免了伊曲康唑在体内不起效的弊端，是伊曲康唑制剂的一个重大革新。
附图说明
图1为超临界流体结晶设备的示意图；
图2为伊曲康唑原料药和高效制剂的X-粉末衍射和电子显微镜扫描图谱；
图3为市售斯皮仁诺胶囊和高效制剂在PH值1.0的溶液中溶出曲线；
图4为市售斯皮仁诺胶囊和高效制剂在狗体内的药时曲线。
具体实施方式
下面结合实施例进一步解释或理解本发明的内容。
按照本发明的制备方法制得的伊曲康唑胶囊，取其内容物进行了X-粉末衍射和电子显微镜扫描，结果如图2所示，其中a和c为伊曲康唑原料药的X-粉末衍射和电子显微镜扫描图谱，b和d为高效制剂中的伊曲康唑复合微粒X-粉末衍射和电子显微镜扫描图谱，从图2中看出，高效制剂中伊曲康唑复合微粒的粒径更小、更均匀，这就意味着自制制剂在体内有可能发挥更好的效果。
自制的胶囊(自制制剂)按照中国药典2010版附录X的方法2(桨法)，以转速75转/分钟，进行了体外溶出实验，采用相同剂量的市售的原研厂的伊曲康唑胶囊(商品名：斯皮仁诺，西安杨森制药有限公司)作为对照药物，在PH值1.0的水溶液中测定其溶出曲线，试验结果如图3所示。从图中可以看出我们的高效制剂与市售的斯皮仁诺胶囊相比，溶出更快。
以制得的伊曲康唑高效制剂(Test)，进行狗的体内试验，以市售的斯皮仁诺胶囊为对照药物(Reference)，采用液质联用进行测定，药时曲线如图4所示，体内药动学数据如下表所示。从图及数据可知，自制制剂比市售的斯皮仁诺胶囊具有更快的吸收速度，并且自制制剂比斯皮仁诺有更高的最大血药浓度Cmax(自制制剂的Cmax为423±61ng/mL，而市售的斯皮仁诺Cmax为305±11ng/mL)。另外，自制制剂相对于斯皮仁诺的生物利用度为120％，即自制制剂有更好的生物利用度。
自制制剂的药代动力学数据：
对照制剂的药代动力学数据：
实施例1
| 成分 | 百分比％ |
| 伊曲康唑 | 35 |
| L-抗坏血酸 | 15 |
| 羟丙甲纤维素 | 40 |
| 普朗尼克F-127 | 10 |
(1)在伊曲康唑(0.63g)和L-抗坏血酸(0.27g)的混合物中加入甲醇和二氯甲烷的混合溶剂12ml(1/1，v/v)，超声溶解，加入羟丙甲纤维素(0.72g)及普朗尼克F-127(0.18g)，再加入二氯甲烷48ml，使完全溶解；
(2)将钢瓶内的二氧化碳通过压力调节阀输入超临界流体结晶设备体系的高压结晶釜内，二氧化碳流速为10ml/min，压力为50Bar；
(3)将步骤1)得到的溶液经超临界流体结晶设备体系的喷嘴喷入高压结晶釜内，复合微粒从溶液中析出并收集于高压结晶釜的底部，溶液流速为0.1ml/min；
(4)将得到的复合微粒装胶囊(制剂规格：50mg/粒、100mg/粒)。
实施例2
| 成分 | 百分比％ |
| 伊曲康唑 | 40 |
| L-抗坏血酸 | 10 |
| 羟丙甲纤维素 | 40 |
| 普朗尼克F-127 | 10 |
(7)在伊曲康唑(0.72g)和L-抗坏血酸(0.18g)的混合物中加入甲醇和二氯甲烷的混合溶剂12ml(1/1，v/v)，超声溶解，加入羟丙甲纤维素(0.72g)及普朗尼克F-127(0.18g)，再加入二氯甲烷12ml，使完全溶解；
(2)将钢瓶内的二氧化碳通过压力调节阀输入超临界流体结晶设备体系的高压结晶釜内，二氧化碳流速为20ml/min，压力为95Bar；
(3)将步骤1)得到的溶液经超临界流体结晶设备体系的喷嘴喷入高压结晶釜内，复合微粒从溶液中析出并收集于高压结晶釜的底部，溶液流速为0.4ml/min；
(4)将得到的复合微粒装胶囊(制剂规格：50mg/粒、100mg/粒)。
实施例3
| 成分 | 百分比％ |
| 伊曲康唑 | 55 |
| L-抗坏血酸 | 10 |
| 羟丙甲纤维素 | 30 |
| 普朗尼克F-127 | 5 |
(1)在伊曲康唑(0.99g)和L-抗坏血酸(0.18g)的混合物中加入甲醇和二氯甲烷的混合溶剂24ml(1/1，v/v)，超声溶解，加入羟丙甲纤维素(0.54g)及普朗尼克F-127(0.09g)，再加入二氯甲烷12ml，使完全溶解；
(2)将钢瓶内的二氧化碳通过压力调节阀输入超临界流体结晶设备体系的高压结晶釜内，二氧化碳流速为30ml/min，压力为100Bar；
(3)将步骤1)得到的溶液经超临界流体结晶设备体系的喷嘴喷入高压结晶釜内，复合微粒从溶液中析出并收集于高压结晶釜的底部，溶液流速为1ml/min；
(4)将得到的复合微粒装胶囊(制剂规格：50mg/粒、100mg/粒)。
实施例4
| 成分 | 百分比％ |
| 伊曲康唑 | 30 |
| L-抗坏血酸 | 15 |
| 羟丙甲纤维素 | 50 |
| 普朗尼克F-127 | 5 |
(1)在伊曲康唑(0.54g)和L-抗坏血酸(0.27g)的混合物中加入甲醇和二氯甲烷的混合溶剂36ml(2/1，v/v)，超声溶解，加入羟丙甲纤维素(0.9g)及普朗尼克F-127(0.09g)，再加入二氯甲烷12ml，使完全溶解；
(2)将钢瓶内的二氧化碳通过压力调节阀输入超临界流体结晶设备体系的高压结晶釜内，二氧化碳流速为50ml/min，压力为130Bar；
(3)将步骤1)得到的溶液经超临界流体结晶设备体系的喷嘴喷入高压结晶釜内，复合微粒从溶液中析出并收集于高压结晶釜的底部，溶液流速为3ml/min；
(4)将得到的复合微粒装胶囊(制剂规格：50mg/粒、100mg/粒)。
Claims (6)
1.一种伊曲康唑制剂的制备方法，其特征在于，包括下列四个步骤：
1）混合溶液的配制：在伊曲康唑和L-抗坏血酸的混合物中加入甲醇和二氯甲烷的混合溶剂，溶解后，加入羟丙甲纤维素及普朗尼克F-127，再加入二氯甲烷，使完全溶解；
2）二氧化碳进料：将钢瓶内的二氧化碳通过压力调节阀输入超临界流体结晶设备体系的高压结晶釜内；
3）复合微粒析出：将步骤1）得到的溶液经超临界流体结晶设备体系的喷嘴喷入高压结晶釜内，复合微粒从溶液中析出并收集于高压结晶釜的底部；
4）将得到的复合微粒装胶囊。
2.按照权利要求1所述的一种伊曲康唑制剂的制备方法，其特征在于，所述步骤1）中伊曲康唑占胶囊内容物的重量百分比为30-55%。
3.按照权利要求1所述的一种伊曲康唑制剂的制备方法，其特征在于，所述步骤1）中甲醇和二氯甲烷的体积比为1:1-9。
4.按照权利要求1所述的一种伊曲康唑制剂的制备方法，其特征在于，所述步骤2）中二氧化碳流速为10-50ml/min。
5.按照权利要求1所述的一种伊曲康唑制剂的制备方法，其特征在于，所述步骤2）中压力为50-130Bar。
6.按照权利要求1所述的一种伊曲康唑制剂的制备方法，其特征在于，所述步骤3）中溶液流速为0.1-3ml/min。
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| PCT/CN2015/089129 WO2016123973A1 (zh) | 2015-02-03 | 2015-09-08 | 伊曲康唑制剂的制备方法 |
| GB1714060.9A GB2551672A (en) | 2015-02-03 | 2015-09-08 | Method for preparing itraconazole preparation |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2016123973A1 (zh) * | 2015-02-03 | 2016-08-11 | 常州制药厂有限公司 | 伊曲康唑制剂的制备方法 |
| WO2016123982A1 (zh) * | 2015-02-06 | 2016-08-11 | 京东方科技集团股份有限公司 | 薄膜晶体管的制备方法及薄膜晶体管、阵列基板 |
| CN109381432A (zh) * | 2017-08-03 | 2019-02-26 | 康芝药业股份有限公司 | 一种伊曲康唑复合微粒的制备方法 |
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| CA3160807A1 (en) * | 2019-12-05 | 2021-06-10 | Antons SIZOVS | Stabilized drug formulations and methods of loading drug delivery implants |
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| CN104027299A (zh) * | 2014-06-13 | 2014-09-10 | 暨南大学 | 一种伊曲康唑温度敏感型凝胶制剂及其制备方法和应用 |
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| US6673373B2 (en) * | 2001-02-01 | 2004-01-06 | Carlsbad Technology Inc. | Antifungal formulation and the methods for manufacturing and using the same |
| US20060062848A1 (en) * | 2004-09-17 | 2006-03-23 | Nektar Therapeutics Uk Limited | Formulation comprising itraconazole |
| CN104688536B (zh) * | 2015-02-03 | 2016-06-08 | 常州制药厂有限公司 | 一种伊曲康唑制剂的制备方法 |
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- 2015-09-08 WO PCT/CN2015/089129 patent/WO2016123973A1/zh active Application Filing
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| CN1285746A (zh) * | 1997-12-31 | 2001-02-28 | 中外制药株式会社 | 制备依曲康唑口服制剂的方法及组合物 |
| CN1849123A (zh) * | 2003-09-09 | 2006-10-18 | 韩美药品株式会社 | 不受所摄入的食物影响的口服依曲康唑组合物及其制备方法 |
| CN101961313A (zh) * | 2009-09-04 | 2011-02-02 | 华中科技大学 | 一种伊曲康唑纳米结晶及其制备方法和应用 |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2016123973A1 (zh) * | 2015-02-03 | 2016-08-11 | 常州制药厂有限公司 | 伊曲康唑制剂的制备方法 |
| GB2551672A (en) * | 2015-02-03 | 2017-12-27 | Changzhou pharmaceutical factory co ltd | Method for preparing itraconazole preparation |
| WO2016123982A1 (zh) * | 2015-02-06 | 2016-08-11 | 京东方科技集团股份有限公司 | 薄膜晶体管的制备方法及薄膜晶体管、阵列基板 |
| CN109381432A (zh) * | 2017-08-03 | 2019-02-26 | 康芝药业股份有限公司 | 一种伊曲康唑复合微粒的制备方法 |
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| CN104688536B (zh) | 2016-06-08 |
| US20180263912A1 (en) | 2018-09-20 |
| GB2551672A (en) | 2017-12-27 |
| GB201714060D0 (en) | 2017-10-18 |
| US10258574B2 (en) | 2019-04-16 |
| WO2016123973A1 (zh) | 2016-08-11 |
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