CN112618490A - 一种伊曲康唑自微乳制剂及其制备方法 - Google Patents
一种伊曲康唑自微乳制剂及其制备方法 Download PDFInfo
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Abstract
本发明提供了一种伊曲康唑自微乳制剂及其制备方法,该制剂包括伊曲康唑、油相、表面活性剂、助表面活性剂和稳定剂,各组分的质量百分数为:伊曲康唑5%‑10%,油相10%‑30%,表面活性剂20%‑50%,助表面活性剂20%‑60%,稳定剂0‑3%。本发明制剂在遇到胃肠道的水性环境时可迅速乳化,在胃肠道中快速且均匀的分布,减少了药物与胃肠道长时间接触后产生的刺激性,同时可以改善药物的溶出度,又可提高药物吸收速率,从而提高药物的生物利用度。
Description
技术领域
本发明属于药物制剂技术领域,具体而言,涉及一种新型自微乳制剂,尤其涉及一种伊曲康唑自微乳制剂和软胶囊及其制备方法。
背景技术
伊曲康唑是一种由人工合成的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。伊曲康唑作为广谱抗真菌药物,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,同样具有良好的治疗效果。
伊曲康唑的化学名为(±)-顺式-4[4-[4-[4[2-(2,4-二氯苯基)-2-(1H1,2,4-三唑-1-甲基)-1,3-二氯戊环基]甲氧基]]苯基]-1-哌嗪苯基]-2,4-二氢(1-甲基丙基)-3H-1,2,4-三唑-3-酮。其结构式为:
伊曲康唑极难溶于水,其在pH1.0-12.7的水溶液中的溶解度小于4mg/L,因此采用一般制剂方法,如普通湿法制粒工艺或直混工艺,制备出的伊曲康唑成品,口服后不能及时起效。已报道的能够提高伊曲康唑溶解度或溶出速率的制剂有CN1262682A、CN1660841A、CN101002938A、CN1853634A等,以上制剂类型溶解度略有增加,但由于伊曲康唑本身性质及与其他组分不能很好结合,导致得到的制剂溶出达不到中国药典中45分钟溶出80%的要求。
由于伊曲康唑在水中的溶解度极低,一般片剂、丸剂口服生物利用度较低,从而影响了伊曲康唑药效的发挥。因此,进一步研究快速有效的新剂型和技术来提高伊曲康唑的口服生物利用度是非常必要的。
自微乳化给药系统是由油相、表面活性剂、助表面活性剂和药物组成的一种均一透明的油状浓缩液,是难溶性药物的优良载体。药物被包裹在自微乳滴中,口服遇到消化液后,在胃肠道蠕动下会自发形成粒径小于100nm的水包油型纳米乳,进而在胃肠道中快速且均匀的分布,减少了药物与胃肠道长时间接触后产生的刺激性,既可以改善药物的溶出度,又可提高药物吸收的速率和程度,从而提高药物的生物利用度。
通过检索国内外现有技术,目前尚未有伊曲康唑自微乳制剂的文献报道。
发明内容
鉴于现有技术的不足,本发明的目的在于通过自微乳技术制备伊曲康唑自微乳软胶囊,从而提供一种伊曲康唑自微乳制剂,以提高伊曲康唑肠道溶解度,进而提高其生物利用度。
为了实现上述技术目的,本发明人结合多年来对自微乳技术的研究经验,并通过大量试验研究探索,最终获得了如下技术方案:一种伊曲康唑自微乳制剂,该制剂由如下质量百分数的组分组成:
所述油相为油酸聚乙二醇甘油酯、中链甘油三酯或油酸乙酯中的一种;
所述表面活性剂为辛酸癸酸聚乙二醇甘油酯、聚乙二醇-7-硬脂酸酯、吐温80、聚氧乙烯醚35蓖麻油、聚氧乙烯醚40氢化蓖麻油中的一种或多种;
所述助表面活性剂为甘油或聚乙二醇200;
所述稳定剂为聚维酮K90。
进一步优选地,如上所述的伊曲康唑自微乳制剂,其由如下质量百分数的组分组成:
所述油相为油酸聚乙二醇甘油酯;
所述表面活性剂为辛酸癸酸聚乙二醇甘油酯和聚氧乙烯醚35蓖麻油的混合物;
所述助表面活性剂为甘油;
所述稳定剂为聚维酮K90。
再进一步优选地,如上所述的伊曲康唑自微乳制剂,其中的表面活性剂为辛酸癸酸聚乙二醇甘油酯和聚氧乙烯醚35蓖麻油按照(4~5):1的质量比组成的混合物。
再进一步优选地,如上所述的伊曲康唑自微乳制剂,其由如下质量百分数的组分组成:
所述各组分的质量百分数之和为100%。
另外,本发明提供的上述自微乳制剂制成的伊曲康唑软胶囊,包括所述伊曲康唑自微乳制剂和软胶囊壳,所述伊曲康唑自微乳制剂以液体的形式密封在软胶囊壳中。该伊曲康唑软胶囊的制备方法,包括以下步骤:
(1)将伊曲康唑溶解于助表面活性剂中,然后加入表面活性剂和油相,混合均匀;
(2)加入或不加入稳定剂,得到伊曲康唑自微乳制剂,备用;
(3)将伊曲康唑自微乳制剂灌装于软胶囊壳中,密封,得伊曲康唑软胶囊;
所述的伊曲康唑自微乳制剂中,各组分的质量百分数为:伊曲康唑5%-10%,油相10%-30%,表面活性剂20%-50%,助表面活性剂20%-60%,稳定剂0-3%;所述油相为油酸聚乙二醇甘油酯、中链甘油三酯或油酸乙酯中的一种;所述表面活性剂为辛酸癸酸聚乙二醇甘油酯、聚乙二醇-7-硬脂酸酯、吐温80、聚氧乙烯醚35蓖麻油、聚氧乙烯醚40氢化蓖麻油中的一种或多种;所述助表面活性剂为甘油或聚乙二醇200;所述稳定剂为聚维酮K90。
进一步优选地,所述的伊曲康唑自微乳制剂中,各组分的质量百分数为:伊曲康唑5%-10%,油相12%-24%,表面活性剂21%-48%,助表面活性剂26%-50%,稳定剂2-3%;所述油相为油酸聚乙二醇甘油酯;所述表面活性剂为辛酸癸酸聚乙二醇甘油酯和聚氧乙烯醚35蓖麻油的混合物;所述助表面活性剂为甘油;所述稳定剂为聚维酮K90。
再进一步优选地,所述表面活性剂为辛酸癸酸聚乙二醇甘油酯和聚氧乙烯醚35蓖麻油按照(4~5):1的质量比组成的混合物。
再进一步优选地,所述的伊曲康唑自微乳制剂中,各组分的质量百分数为:伊曲康唑5%-7%,油酸聚乙二醇甘油酯15%-24%,辛酸癸酸聚乙二醇甘油酯35%-40%,聚氧乙烯醚35蓖麻油6%-9%,甘油26%-28%,聚维酮K902-3%,所述各组分的质量百分数之和为100%。
在本发明最优选的一个实施例中,所述的伊曲康唑自微乳制剂各组分的质量百分数为:伊曲康唑5%,油酸聚乙二醇甘油酯19.8%,辛酸癸酸聚乙二醇甘油酯37.6%,聚氧乙烯醚35蓖麻油7.8%,甘油26.8%,聚维酮K903%。
与现有技术相比,本发明研制出伊曲康唑自微乳制剂和合理的生产工艺流程,伊曲康唑自微乳制剂在遇到胃肠道的水性环境时可迅速乳化,细小的油滴可从胃中迅速排空,使药物在整个胃肠道广泛分布,从而减少了药物与胃肠道长时间接触后产生的刺激性。另外,本发明制备的伊曲康唑自微乳制剂既可改善药物的溶出度,又可提高药物吸收的速率和程度,从而提高药物的生物利用度。
附图说明
图1伊曲康唑自微乳软胶囊和参比制剂的溶出曲线图。
图2伊曲康唑自微乳软胶囊实施例4与实施例5的溶出曲线图。
图3伊曲康唑的血药浓度-时间曲线图。
具体实施方式
下面通过具体制备例和实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
处方:
制备方法:
将处方量的伊曲康唑溶解于处方量的助表面活性剂中,加入处方量的表面活性剂和油相,混合均匀,即得伊曲康唑自微乳制剂;将得到的伊曲康唑自微乳制剂灌装于软胶囊壳中,即得伊曲康唑自微乳软胶囊。
实施例2
处方:
制备方法:
将处方量的伊曲康唑溶解于处方量的助表面活性剂中,加入处方量的表面活性剂和油相,混合均匀,即得伊曲康唑自微乳制剂;将得到的伊曲康唑自微乳制剂灌装于软胶囊壳中,即得伊曲康唑自微乳软胶囊。
实施例3
处方:
制备方法:
将处方量的伊曲康唑溶解于处方量的助表面活性剂中,加入处方量的表面活性剂、油相和稳定剂,混合均匀,即得伊曲康唑自微乳制剂;将得到的伊曲康唑自微乳制剂灌装于软胶囊壳中,即得伊曲康唑自微乳软胶囊。
实施例4
处方:
制备方法:
将处方量的伊曲康唑溶解于处方量的助表面活性剂中,加入处方量的表面活性剂、油相和稳定剂,混合均匀,即得伊曲康唑自微乳制剂;将得到的伊曲康唑自微乳制剂灌装于软胶囊壳中,即得伊曲康唑自微乳软胶囊。
实施例5
处方:
制备方法:
将处方量的伊曲康唑溶解于处方量的助表面活性剂中,加入处方量的表面活性剂和油相,混合均匀,即得伊曲康唑自微乳制剂;将得到的伊曲康唑自微乳制剂灌装于软胶囊壳中,即得伊曲康唑自微乳软胶囊。
实施例6
处方:
制备方法:
将处方量的伊曲康唑溶解于处方量的助表面活性剂中,加入处方量的表面活性剂和油相,混合均匀,即得伊曲康唑自微乳制剂;将得到的伊曲康唑自微乳制剂灌装于软胶囊壳中,即得伊曲康唑自微乳软胶囊。
实施例7
处方:
制备方法:
将处方量的伊曲康唑溶解于处方量的助表面活性剂中,加入处方量的表面活性剂和油相,混合均匀,即得伊曲康唑自微乳制剂;将得到的伊曲康唑自微乳制剂灌装于软胶囊壳中,即得伊曲康唑自微乳软胶囊。
对比实施例1
处方:
制备方法:
将处方量的伊曲康唑溶解于处方量的助表面活性剂中,加入处方量的表面活性剂和油相,混合均匀,即得伊曲康唑自微乳制剂;将得到的伊曲康唑自微乳制剂灌装于软胶囊壳中,即得伊曲康唑自微乳软胶囊。
对比实施例2
处方:
制备方法:
将处方量的伊曲康唑溶解于处方量的助表面活性剂中,加入处方量的表面活性剂、油相和稳定剂,混合均匀,即得伊曲康唑自微乳制剂;将得到的伊曲康唑自微乳制剂灌装于软胶囊壳中,即得伊曲康唑自微乳软胶囊。
对比实施例3
处方:
制备方法:
将处方量的伊曲康唑溶解于处方量的表面活性剂中,加入处方量的助表面活性剂和油相中,混合均匀,即得伊曲康唑自微乳制剂;将得到的伊曲康唑自微乳制剂灌装于软胶囊壳中,即得伊曲康唑自微乳软胶囊。
对比实施例4
处方:
制备方法:
将处方量的伊曲康唑溶解于处方量的表面活性剂中,加入处方量的助表面活性剂和油相中,混合均匀,即得伊曲康唑自微乳制剂;将得到的伊曲康唑自微乳制剂灌装于软胶囊壳中,即得伊曲康唑自微乳软胶囊。
对比实施例5
处方:
制备方法:
将处方量的伊曲康唑溶解于处方量的表面活性剂中,加入处方量的助表面活性剂和油相中,混合均匀,即得伊曲康唑自微乳制剂;将得到的伊曲康唑自微乳制剂灌装于软胶囊壳中,即得伊曲康唑自微乳软胶囊。
实施例8:伊曲康唑自微乳软胶囊的外观、粒径、乳化时间、稳定性和药物动力学评价
(1)取制备的伊曲康唑自微乳制剂,用水稀释100倍,测定粒径。
(2)取伊曲康唑自微乳制剂5ml,在50r·min-1搅拌下加入10倍量37℃的水,测定乳化时间。
(3)在50r·min-1搅拌下8h后考察自微乳稳定性。
样品 | 外观 | 粒径(nm) | 乳化时间 | 稳定性 |
实施例1 | 无色均一透明液体 | 21.8 | 1min内 | 均一稳定,无晶体析出 |
实施例2 | 无色均一透明液体 | 21.1 | 1min内 | 均一稳定,无晶体析出 |
实施例3 | 无色均一透明液体 | 22.6 | 1min内 | 均一稳定,无晶体析出 |
实施例4 | 无色均一透明液体 | 18.3 | 1min内 | 均一稳定,无晶体析出 |
实施例5 | 无色均一透明液体 | 23.5 | 1min内 | 均一稳定,无晶体析出 |
实施例6 | 无色均一透明液体 | 25.1 | 1min内 | 均一稳定,无晶体析出 |
实施例7 | 无色均一透明液体 | 22.4 | 1min内 | 均一稳定,无晶体析出 |
对比实施例1 | 无色均一透明液体 | >100 | >10min | 油水分离 |
对比实施例2 | 白色均一液体 | >200 | >10min | 油水分离 |
对比实施例3 | 白色均一液体 | >100 | >10min | 油水分离 |
对比实施例4 | 白色均一液体 | >100 | >10min | 油水分离 |
对比实施例5 | 白色均一液体 | >200 | >10min | 油水分离 |
(4)伊曲康唑自微乳软胶囊的溶出度评价
伊曲康唑软胶囊按照中国药典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原研厂的伊曲康唑胶囊作为参比制剂,在pH1.0的水溶液中测定其溶出度,并绘制溶出曲线。
色谱条件:HPLC-UV测定,色谱柱:色谱柱(C18,100A,150×4.6mm,5μm);流动相:乙腈-12.5mM磷酸盐缓冲液,梯度洗脱:0-10min,50%乙腈-60%乙腈,10-17min,60%乙腈,17-32min50%乙腈;检测波长:262nm;流速:1.0ml/min;柱温:40℃;进样量:50μL。
实验结果如图1和图2所示。从图中可以看出自制的自微乳软胶囊与市售的原研胶囊相比,溶出更快。
(5)比格犬体内药物动力学实验
6条健康成年比格犬,雌雄各半,体重范围9kg-18kg。在试验前两周及试验期间不得服用其他药物,试验前禁食12小时,随机分为两组,于后肢静脉采血。采用单剂量自身交叉试验,给药剂量为100mg伊曲康唑。分别吞服实施例6制备的伊曲康唑胶囊(受试制剂)和市售胶囊(参比制剂),间隔清洗期为两周。服药后,于0.5、1、2、3、4、6、8、10、12、24h分别采血0.6mL于肝素钠真空采血管中。向50.0μL含药血浆中分别加入500μL内标溶液,涡流1min,离心5min(12000rpm),取2μL上清液进行LC-MS/MS分析。
实验结果:伊曲康唑的血药浓度-时间曲线如图3所示,本发明的伊曲康唑自微乳软胶囊在比格犬体内的血药浓度高于市售参比制剂,证明本发明中的伊曲康唑自微乳软胶囊能更好地维持伊曲康唑在胃肠道中的过饱和浓度,从而提高生物利用度。
Claims (10)
3.根据权利要求2所述的伊曲康唑自微乳制剂,其特征在于,所述表面活性剂为辛酸癸酸聚乙二醇甘油酯和聚氧乙烯醚35蓖麻油按照(4~5):1的质量比组成的混合物。
5.一种根据权利要求1所述自微乳制剂制成的伊曲康唑软胶囊,其特征在于,包括所述伊曲康唑自微乳制剂和软胶囊壳,所述伊曲康唑自微乳制剂以液体的形式密封在软胶囊壳中。
6.一种伊曲康唑软胶囊的制备方法,其特征在于,该方法包括以下步骤:
(1)将伊曲康唑溶解于助表面活性剂中,然后加入表面活性剂和油相,混合均匀;
(2)加入或不加入稳定剂,得到伊曲康唑自微乳制剂,备用;
(3)将伊曲康唑自微乳制剂灌装于软胶囊壳中,密封,得伊曲康唑软胶囊;
所述的伊曲康唑自微乳制剂中,各组分的质量百分数为:伊曲康唑5%-10%,油相10%-30%,表面活性剂20%-50%,助表面活性剂20%-60%,稳定剂0-3%;所述油相为油酸聚乙二醇甘油酯、中链甘油三酯或油酸乙酯中的一种;所述表面活性剂为辛酸癸酸聚乙二醇甘油酯、聚乙二醇-7-硬脂酸酯、吐温80、聚氧乙烯醚35蓖麻油、聚氧乙烯醚40氢化蓖麻油中的一种或多种;所述助表面活性剂为甘油或聚乙二醇200;所述稳定剂为聚维酮K90。
7.根据权利要求6所述伊曲康唑软胶囊的制备方法,其特征在于,所述的伊曲康唑自微乳制剂中,各组分的质量百分数为:伊曲康唑5%-10%,油相12%-24%,表面活性剂21%-48%,助表面活性剂26%-50%,稳定剂2-3%;所述油相为油酸聚乙二醇甘油酯;所述表面活性剂为辛酸癸酸聚乙二醇甘油酯和聚氧乙烯醚35蓖麻油的混合物;所述助表面活性剂为甘油;所述稳定剂为聚维酮K90。
8.根据权利要求7所述伊曲康唑软胶囊的制备方法,其特征在于,所述表面活性剂为辛酸癸酸聚乙二醇甘油酯和聚氧乙烯醚35蓖麻油按照(4~5):1的质量比组成的混合物。
9.根据权利要求6所述伊曲康唑软胶囊的制备方法,其特征在于,所述的伊曲康唑自微乳制剂中,各组分的质量百分数为:伊曲康唑5%-7%,油酸聚乙二醇甘油酯15%-24%,辛酸癸酸聚乙二醇甘油酯35%-40%,聚氧乙烯醚35蓖麻油6%-9%,甘油26%-28%,聚维酮K902-3%,所述各组分的质量百分数之和为100%。
10.根据权利要求9所述伊曲康唑软胶囊的制备方法,其特征在于,所述的伊曲康唑自微乳制剂中,各组分的质量百分数为:伊曲康唑5%,油酸聚乙二醇甘油酯19.8%,辛酸癸酸聚乙二醇甘油酯37.6%,聚氧乙烯醚35蓖麻油7.8%,甘油26.8%,聚维酮K903%。
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