CN117323300A - 可经口吸入的伊曲康唑纳米晶聚集体微粒及其制备方法 - Google Patents
可经口吸入的伊曲康唑纳米晶聚集体微粒及其制备方法 Download PDFInfo
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Abstract
本发明公开了一种可经口吸入的伊曲康唑纳米晶组合物聚集体微粒及其制备方法,包含伊曲康唑、分散剂和赋形剂,通过超声波处理法、高压均质法和磁力搅拌法获得稳定的纳米晶悬浮液,使用喷雾冷冻干燥技术制备可吸入组合物聚集体微粒。所述组合物聚集体微粒具有多孔、脆性结构,载药量大于60%,质量中值空气动力学尺寸小于4μm,排空率大于90%,微细粒子分数大于60%,极细粒子分数大于30%的特点,每吸入10mg该组合物聚集体微粒,其中大于3.6mg的伊曲康唑能够进入深肺。
Description
技术领域
本发明属于药物粉体制剂领域,涉及一种可经口吸入的伊曲康唑纳米晶聚集体微粒,具体为以伊曲康唑作为活性药物成分的可经口吸入的组合物聚集体微粒及其制备方法。
背景技术
肺曲霉病是一种由曲霉菌感染导致的肺部疾病,其病灶通常处于肺泡,易扩散转移,具有极高的致死率,值得注意的是近年来新冠病毒感染引发的肺曲霉病患者数量正在逐渐增加。伊曲康唑是治疗肺曲霉病的一线用药,口服是其重要剂型,然而通过口服给药的肺部生物利用度极低,因此需要大量给药以在肺部实现有效的治疗浓度,这通常会引发严重的毒副作用,不利于实际临床应用,因此十分必要探索新剂型及给药途径以实现伊曲康唑的高效肺部递送。一项最新的临床研究表明相较于口服给药200 mg伊曲康唑,通过经口吸入20 mg伊曲康唑进肺,可以在痰液中检测到70倍的药物浓度,同时全血中的药物浓度仅为口服的1/66,这项研究展示了伊曲康唑吸入制剂的显著潜力(NCT03479411)。然而伊曲康唑的水溶性极差(1-5 ng/mL),同时受限于肺部表面有限的粘液体积,伊曲康唑在肺部粘液中通常难以溶解,这可能会导致巨噬细胞的吞噬和纤毛摆动的清除作用易将肺部表面的伊曲康唑排出肺部,不利于治疗效果。
发明内容
本发明提供一种用于经口吸入的伊曲康唑纳米晶组合物聚集体微粒,所述组合物包含伊曲康唑、分散剂和赋形剂,通过超声波处理法、高压均质法和磁力搅拌法获得稳定的前驱液,结合喷雾冷冻干燥技术制备得到。其中用于吸入的伊曲康唑纳米晶聚集体微粒具有多孔、脆性结构,载药量大于60%,质量中值空气动力学尺寸小于4 μm,排空率大于90%,微细粒子分数大于60%,极细粒子分数大于30%的特点,每吸入10mg该组合物聚集体微粒,其中大于3.6mg的伊曲康唑能够进入深肺。
本发明采用如下技术方案:
一种可经口吸入的伊曲康唑纳米晶聚集体微粒的制备方法,包括以下步骤,将伊曲康唑组合物分散处理,得到纳米晶悬浮液,然后进行喷雾冷冻干燥,得到可经口吸入的伊曲康唑纳米晶聚集体微粒;所述伊曲康唑组合物包括伊曲康唑、分散剂和赋形剂,所得产品为含伊曲康唑、分散剂和赋形剂的可吸入纳米晶聚集体微粒。
本发明中,分散处理包括超声波处理、高压均质处理、搅拌处理(比如磁力搅拌),即,本发明可经口吸入的伊曲康唑组合物聚集体微粒通过将伊曲康唑、分散剂和赋形剂以及分散介质组成的伊曲康唑组合物超声波处理、高压均质处理、磁力搅拌处理和喷雾冷冻干燥处理四个单元操作制备得到,包含大于60%质量分数的伊曲康唑,具有1-4 μm的质量中值空气动力学尺寸,具有多孔、脆性结构,具有小于5%的含水量,具有大于90%的排空率,具有大于60%的微细粒子分数,具有大于30%极细粒子分数,每吸入10mg该组合物聚集体微粒,其中大于3.6 mg的伊曲康唑能进入深肺,即每10 mg的可吸入聚集体微粒中空气动力学尺寸小于5 μm的药物绝对量大于3.6 mg,甚至大于4.6mg,可避免吞噬和清除机制,同时纳米晶可以逐渐溶解,实现更长药效。
本发明中,分散剂包括维生素E聚乙二醇琥珀酸酯(简称TPGS),赋形剂包括氨基酸、糖及其衍生物;其中,氨基酸包括甘氨酸、亮氨酸和异亮氨酸,糖及其衍生物包括乳糖、海藻糖、蔗糖和甘露醇;优选的,赋形剂为亮氨酸。
本发明中,伊曲康唑、分散剂的质量比例为(10~30)∶1,优选(15~25)∶1,比如20∶1;伊曲康唑/分散剂、赋形剂的质量比例为(1~5)∶1,优选(1.5~3)∶1,比如7∶3。伊曲康唑/分散剂是指伊曲康唑、分散剂的质量和。
本发明中,以水为分散介质,通过超声波处理、高压均质法和磁力搅拌法制备得到稳定的伊曲康唑组合物(伊曲康唑纳米晶悬浮液),可用于后续喷雾冷冻干燥;该伊曲康唑组合物具有水力学中值尺寸小于700 nm的特点,其中固形物含量为1~4 w/w%,优选2 w/w%。
本发明中,将超声波法、高压均质法和磁力搅拌法处理获得的伊曲康唑组合物进行喷雾冷冻干燥,具体的,先喷雾冷冻再冻干,使用的冷冻温度为-30~-70℃,优选-50℃。
可将伊曲康唑和表面活性剂在液相下(通常为水相)进行组装制备成伊曲康唑纳米晶,然而伊曲康唑纳米晶处于液相下的稳定性差,容易发生不可逆转的再聚集,因此通常需要低温储存、冷链运输。同时通过雾化纳米晶悬浮液给药的肺部递送效率低,依从性差、高度依赖于患者用药习惯,因此伊曲康唑纳米晶悬浮液无法直接应用。
本发明中,分散处理的伊曲康唑纳米晶悬浮液经过喷雾冷冻干燥工艺可制备多孔、脆性、低密度、流动性佳的聚集体微粒,吸入过程中,由于剪切力的作用,聚集体可以被分散成碎片,从而具有更优的可吸入性能,即更高的深肺递送效率;干粉形式可以提高伊曲康唑纳米晶的存储稳定性,降低储存、运输成本,同时以吸入粉雾剂进行给药具有更佳的依从性、递送剂量均一性和便携性。此外,聚集体碎片在肺部表面粘液中可快速崩解释放出包载的纳米颗粒,而释放的纳米颗粒具有长效释放能力,有望进一步提高其肺部生物利用度。因此,本发明中的喷雾冷冻伊曲康唑纳米晶组合物聚集体微粒用作高效肺部递送药剂具有显著的应用潜力和优势。
附图说明
图1为伊曲康唑纳米晶悬浮液的显微镜图片。
图2为冷冻温度为-50℃下制备的伊曲康唑纳米晶聚集体微粒宏观形貌的扫描电子显微镜图。
图3为对比配方伊曲康唑纳米晶聚集体微粒宏观形貌的扫描电子显微镜图。
图4为以配方5为前驱液,通过喷雾冷冻干燥和喷雾干燥工艺制备的伊曲康唑纳米晶微粒,经过吸入装置分散后,在新一代撞击器第五个收集盘中的宏观形貌图。
具体实施方式
本发明制备的可经口吸入的伊曲康唑纳米晶聚集体微粒,可经口吸入的伊曲康唑纳米晶聚集体微粒中,伊曲康唑的质量分数大于60%;具有1-4μm的质量中值空气动力学尺寸,具有大于60%的微细粒子分数(FPF)和大于30%的极细粒子分数(eFPF),其计算公式为FPF=FPD/TD,eFPF=eFPD/TD,其中FPD为单个胶囊中空气动力学尺寸小于5 μm的微粒含有的药物质量,eFPD为单个胶囊中空气动力学尺寸小于2 μm的微粒含有的药物质量,TD为单个胶囊中所有微粒含有的药物质量;每吸入10 mg所述组合物聚集体,大于3.6 mg的伊曲康唑的空气动力学尺寸小于5 μm,即每10 mg的可吸入聚集体中能够进入深肺的药物绝对量大于3.6mg。
本发明涉及以伊曲康唑作为活性药物成分,以TPGS作为分散剂、氨基酸等物质作为赋形剂的组合物聚集体微粒及其制备方法,属于药物粉体制剂领域。本发明所用原料为现有产品,具体检测及评价方法为常规技术。
本发明中,分散处理为依次进行的超声波处理、高压均质处理、磁力搅拌处理,其中超声波处理的功率为500~1000W,频率为20~40kHz,时间为5~30 min;高压均质的压力为500~700 bar,时间为10~30 min;磁力搅拌处理的转速为400~800rpm;优选的,超声波处理的功率为600~800W,频率为25~30kHz,时间为5~30 min;高压均质的压力为500~700 bar,时间为15~25 min;磁力搅拌处理的转速为400~600rpm,时间保持至喷雾冷冻干燥实验前,具体为30~360 min。
实施例一
伊曲康唑纳米晶悬浮液的制备
表1 伊曲康唑纳米晶悬浮液的配方表
按上述配方设计,将伊曲康唑和分散剂TPGS加入水中,先通过超声波处理分散,再通过高压均质机进行二次分散,然后加入赋形剂亮氨酸,通过磁力搅拌器进行混匀,得到可用于喷雾冷冻干燥的伊曲康唑纳米晶悬浮液。超声波处理的功率为700W,频率为26 kHz,时间为20 min;高压均质的压力为600 bar,时间为20 min;磁力搅拌处理速度为500 rpm,1小时。
经过超声波、高压均质和磁力搅拌处理的伊曲康唑纳米晶悬浮液的显微镜图片如图1所示,可以看到伊曲康唑纳米晶粒度分散性良好,水力学中值尺寸均小于700 nm,在限定范围内改变伊曲康唑/TPGS纳米晶和赋形剂比例或固含量均不会显著影响水力学中值尺寸,所述水力学中值尺寸通过激光衍射法测得。
实施例二
可经口吸入伊曲康唑纳米晶聚集体微粒的制备
以实施例一中制得的伊曲康唑纳米晶悬浮液作为前驱液进行喷雾冷冻干燥,制备伊曲康唑纳米晶聚集体干粉,将前驱液装载于注射器中,设定注射泵流量为5 mL/min,使用超声雾化喷嘴进行雾化,雾化后的液滴进入冷媒中进行冷冻得到冰球,冷冻温度设定为-50℃,收集后的冰球转移到真空冷冻干燥机中进行冻干,冻干参数为一次干燥温度分别-40℃、-20℃和-10℃,二次干燥温度分别为0℃、10℃和20 ℃,真空度低于10Pa。
所得的伊曲康唑纳米晶聚集体微粒的宏观形貌如图2所示,当前驱液中仅为伊曲康唑TPGS纳米晶时(配方1),样品呈现为堆积的纳米晶聚集体,随着亮氨酸含量增加,可以观察到聚集体趋近微粒“球形”结构,伊曲康唑TPGS纳米晶分散于赋形剂(亮氨酸)组成的片状基质中(配方2-4)。提高固含量后(配方5、6),“球形”聚集体的球形度和完整度得以进一步提高。对于可以观察到球形颗粒的配方,基于标尺测量的静态几何尺寸均大于60 μm(图2)。
表2 可经口吸入伊曲康唑纳米晶聚集体微粒的动态几何粒径分布表
配方 | D10(μm) | D50(μm) | D90(μm) |
1 | 1.55 | 6.33 | 41.31 |
2 | 2.12 | 8.44 | 32.50 |
3 | 3.76 | 16.74 | 45.90 |
4 | 6.07 | 29.31 | 70.74 |
5 | 4.39 | 21.88 | 61.96 |
6 | 4.73 | 24.10 | 81.84 |
通过激光衍射法,以Breezhaler®作为吸入装置,在60L/min的吸气流速下测的所得样品的动态几何粒径分布如表2所示,D10、D50和D90分别代表累积体积分布达到10%、50%和90%时对应的几何粒径。提高配方中亮氨酸的含量或提高固含量,分散状态下聚集体的几何中值粒径逐渐增大,但均明显小于原始样品静态下尺寸(如图2观察所得),这是由于通过吸入装置的气流作用,可以将伊曲康唑纳米晶聚集体进一步剪切分散,更有利于提升气溶胶性能,以实现更高的深肺递送效率。
表3 可经口吸入伊曲康唑纳米晶聚集体微粒的肺部宏观递送性能表
配方 | 冷冻温度(°C) | 排空率(%) | 微细颗粒分数(%) | 极细颗粒分数(%) | 质量中值空气动力学尺寸(μm) | 空气动力学尺寸小于5 μm的伊曲康唑绝对量(mg/10 mg微粒) |
1 | -50 | 74.57 | 32.92 | 12.15 | 4.18 | 3.14 |
2 | -50 | 86.79 | 56.37 | 17.76 | 3.34 | 4.83 |
3 | -50 | 95.07 | 69.95 | 36.17 | 2.59 | 4.66 |
4 | -50 | 94.62 | 76.53 | 50.12 | 1.91 | 3.64 |
5 | -50 | 94.21 | 69.74 | 36.87 | 2.50 | 4.65 |
6 | -50 | 92.88 | 58.94 | 27.51 | 3.16 | 3.93 |
伊曲康唑纳米晶聚集体微粒的肺部宏观递送性能如表3所示,上述性能指标均通过新一代撞击器测试得到(基于级联撞击器的测试是吸入粉雾剂体外评价的黄金标准,新一代撞击器是级联撞击器的一种类型,参考2020中国药典四部0951章节“吸入制剂微细粒子空气动力学特性测定法”进行测试),可以看到加入亮氨酸、降低固含量可以显著提高伊曲康唑纳米晶聚集体微粒的肺部宏观递送性能。
微细颗粒分数(FPF)和极细颗粒分数(eFPF)计算公式分别为FPF=FPD/TD,eFPF=eFPD/TD,其中FPD为单个胶囊中空气动力学尺寸小于5 μm的微粒含有的药物质量,TD为单个胶囊中所有微粒含有的药物质量。
载药量=每当量干粉伊曲康唑的质量,以配方1为例,每100g溶液中,伊曲康唑为0.9524g,TPGS为0.0476g,水有99g,得到干粉后,即去掉水剩下1g的干粉,其中有伊曲康唑为0.9524g,TPGS为0.0476g,载药量即0.9524g/(0.9524g+0.0476g)=95.24%。
综上所述,赋形剂为TPGS、亮氨酸的组合物,冷冻温度选用-50℃,在限定配方和工艺下,载药量可达66.67%,尤其是极细颗粒分数可达36.87%,即可相当于36.87%的药物可以被递送至深肺区域的细支气管和肺泡处,同时每吸入10 mg粉末约有高达4.65 mg的伊曲康唑进入深肺。该配方分散后在新一代撞击器第五个收集盘中状态如图3所示,可以发现与初始状态相比(图1),微粒显著发生破碎,这一方面是由于吸入撞击分散作用,另外一方面是飞行过程中微粒间相互剪切可能引发的二次破碎所致。
实施例三
将表1配方5分别在-30℃和-70℃下进行喷雾冷冻干燥造粒,其余一样,最终所得产品性能如表4所示。
将表1中配方3中的亮氨酸替换为甘露醇为配方7,替换为α-一水乳糖为配方8,在相同的工艺条件下制备纳米晶聚集体微粒,最终所得产品性能如表4所示。将表1中配方3中的TPGS替换为吐温-80为配方9,在相同的工艺条件下制备纳米晶聚集体微粒,最终所得产品性能如表4所示。
表4 可经口吸入伊曲康唑纳米晶聚集体微粒的肺部宏观递送性能表
配方 | 冷冻温度(°C) | 排空率(%) | 微细颗粒分数(%) | 极细颗粒分数(%) | 质量中值空气动力学尺寸(μm) | 空气动力学尺寸小于5 μm的伊曲康唑绝对量(mg/10 mg微粒) |
5 | -30 | 92.00 | 36.81 | 7.35 | 5.16 | 2.45 |
5 | -70 | 91.21 | 62.36 | 25.59 | 2.88 | 4.16 |
7 | -50 | 75.59 | 35.71 | 10.30 | 4.15 | 2.38 |
8 | -50 | 89.58 | 24.84 | 7.61 | 4.80 | 1.66 |
9 | -50 | 87.92 | 56.63 | 17.59 | 3.37 | 3.78 |
实施例四
将表1配方5(雾化后的液滴)在进口温度和出口温度分别为120℃和90℃下进行喷雾干燥造粒,其余一样,最终所得产品性能如表5所示。分散后在新一代撞击器第五个收集盘中状态如图4所示,可见经过分散后的喷雾干燥伊曲康唑纳米晶微粒没有发生破碎,极细颗粒占比较小。
表5 可经口吸入伊曲康唑纳米晶聚集体微粒的肺部宏观递送性能表
配方 | 进口/出口温度(°C) | 排空率(%) | 微细颗粒分数(%) | 极细颗粒分数(%) | 质量中值空气动力学尺寸(μm) | 空气动力学尺寸小于5 μm的伊曲康唑绝对量(mg/10 mg微粒) |
5 | 120/90 | 89.65 | 47.71 | 14.14 | 3.63 | 3.18 |
现有技术利用Span60或Span80作为分散剂,通过旋转蒸发法结合超声波处理制备伊曲康唑纳米晶悬浮液,并加入甘露醇作为赋形剂,通过喷雾干燥技术制备伊曲康唑纳米晶聚集体微粒,其问题在于:所得最优样品微细颗粒分数仅为37.3%,极细颗粒分数更是不足5%,进入深肺比例很低;在喉部和预分离器沉积量之和大于20%,这部分药物无法被递送到呼吸系统,可能会进入消化道被吸收,造成严重的副作用。现有技术利用分散剂,通过瞬时纳米沉淀法制备伊曲康唑纳米晶悬浮液,并通过超滤离心法除去有机溶剂,然后将纳米晶重悬于含二甲基亚砜的水溶液中,加入MC M20作为赋形剂配置前驱液,通过喷雾干燥技术制备伊曲康唑纳米晶聚集体微粒,其问题在于:一是伊曲康唑纳米晶悬浮液的制备过程反复投加再超滤去除二甲基亚砜,流程繁琐且成本较高,工业放大瓶颈明显;二是通过瞬时纳米沉淀法制备悬浮液需要加入大量的分散剂,同时在干燥过程中加入了大量赋形剂作为保护剂,导致制剂载药量极低(不足5%),无法实际应用。发明人之前公开的用于吸入的氯硝柳胺组合物微粒通过超声波处理法、高压均质法和喷雾冷冻干燥法等三个单元操作制备得到,虽然具有大于40%的微细粒子分数,但是极细颗粒分数更是不足10%,进入深肺比例很低。
Claims (10)
1.一种可经口吸入的伊曲康唑纳米晶聚集体微粒的制备方法,其特征在于,包括以下步骤,将伊曲康唑组合物分散处理,得到纳米晶悬浮液,然后进行喷雾冷冻干燥,得到可经口吸入的伊曲康唑纳米晶聚集体微粒;所述伊曲康唑组合物包括伊曲康唑、分散剂和赋形剂。
2.根据权利要求1所述可经口吸入的伊曲康唑纳米晶聚集体微粒的制备方法,其特征在于,所述分散剂包括维生素E聚乙二醇琥珀酸酯;赋形剂包括氨基酸、糖及其衍生物。
3.根据权利要求2所述可经口吸入的伊曲康唑纳米晶聚集体微粒的制备方法,其特征在于,所述氨基酸包括甘氨酸、亮氨酸和异亮氨酸,糖及其衍生物包括乳糖、海藻糖、蔗糖、甘露醇。
4.根据权利要求1所述可经口吸入的伊曲康唑纳米晶聚集体微粒的制备方法,其特征在于,伊曲康唑、分散剂的质量比例为(10~30)∶1;伊曲康唑/分散剂、赋形剂的质量比例为(1~5)∶1。
5.根据权利要求1所述可经口吸入的伊曲康唑纳米晶聚集体微粒的制备方法,其特征在于,分散处理包括超声波处理、高压均质处理、搅拌处理。
6.根据权利要求5所述可经口吸入的伊曲康唑纳米晶聚集体微粒的制备方法,其特征在于,将伊曲康唑和分散剂加入分散介质中,通过超声波处理法和高压均质法制备得到伊曲康唑纳米晶悬浮液,再加入赋形剂,磁力搅拌处理,得到纳米晶悬浮液;然后通过喷雾冷冻干燥,得到可经口吸入的伊曲康唑纳米晶聚集体微粒。
7.根据权利要求6所述可经口吸入的伊曲康唑纳米晶聚集体微粒的制备方法,其特征在于,超声波处理的功率为500~1000W,频率为20~40kHz,时间为5~30 min;高压均质的压力为500~700 bar,时间为10~30 min;磁力搅拌处理的转速为400~800rpm。
8.根据权利要求1所述可经口吸入的伊曲康唑纳米晶聚集体微粒的制备方法制备的可经口吸入的伊曲康唑纳米晶聚集体微粒。
9.权利要求8所述可经口吸入的伊曲康唑纳米晶聚集体微粒在制备经口吸入肺部用药物中的应用。
10.权利要求8所述可经口吸入的伊曲康唑纳米晶聚集体微粒在制备经口吸入药物中的应用。
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