de la Torre-Iglesias Paloma Marina, García-Rodriguez Juan José, Torrado Guillermo, Torrado Susana, Torrado-Santiago Santiago, Bolás-Fernández Francisco
Department of Pharmaceutical Technology, Faculty of Pharmacy, Complutense University, Madrid, Spain ; Institute of Industrial Pharmacy, Complutense University, Madrid, Spain.
Department of Parasitology, Faculty of Pharmacy, Complutense University, Madrid, Spain.
Drug Des Devel Ther. 2014 Sep 18;8:1467-79. doi: 10.2147/DDDT.S65561. eCollection 2014.
Mebendazole (MBZ) is an extremely insoluble and therefore poorly absorbed drug and the variable clinical results may correlate with blood concentrations. The necessity of a prolonged high dose treatment of this drug increases the risk of adverse effects.
In the present study we prepared redispersible microparticles (RDM) containing MBZ, an oral, poorly water-soluble drug, in different proportions of low-substituted hydroxypropylcellulose (L-HPC). We investigated the microparticulate structures that emerge spontaneously upon dispersion of an RDM in aqueous medium and elucidated their influence on dissolution, and also on their oral bioavailability and therapeutic efficiency using a murine model of infection with the nematode parasite Trichinella spiralis.
Elevated percentages of dissolved drug were obtained with RDM at 1:2.5 and 1:5 ratios of MBZ: L-HPC. Thermal analysis showed an amorphization of MBZ in the RDM by the absence of a clear MBZ melting peak in formulations. The rapid dissolution behavior could be due to the decreased drug crystallinity, the fast dissolution time of carriers as L-HPC, together with its superior dispersibility and excellent wetting properties. RDM-1:2.5 and RDM-1:5 resulted in increased maximum plasma concentration and area(s) under the curve (AUC)0-∞ values. Likewise, after oral administration of the RDM-1:2.5 and RDM-1:5 the AUC0-∞ were 2.67- and 2.97-fold higher, respectively, compared to those of pure MBZ. Therapeutic activity, assessed on the Trichinella spiralis life cycle, showed that RDM-1:5 was the most effective in reducing the number of parasites (4.56-fold) as compared to pure MBZ, on the encysted stage.
THE MBZ: L-HPC RDM might be an effective way of improving oral bioavailability and therapeutic activity using low doses of MBZ (5 mg/kg), which implies a low degree of toxicity for humans.
甲苯咪唑（MBZ）极难溶解，因此吸收不佳，其临床效果的差异可能与血药浓度相关。延长该药物高剂量治疗的必要性增加了不良反应的风险。
在本研究中，我们制备了含MBZ（一种口服的难溶性药物）与不同比例低取代羟丙基纤维素（L-HPC）的可再分散微粒（RDM）。我们研究了RDM在水性介质中分散时自发形成的微粒结构，并阐明了它们对溶解的影响，以及使用线虫寄生虫旋毛虫感染的小鼠模型对其口服生物利用度和治疗效果的影响。
MBZ与L-HPC比例为1:2.5和1:5的RDM获得了更高的药物溶解百分比。热分析表明，由于制剂中没有明显的MBZ熔点峰，RDM中的MBZ发生了非晶化。快速溶解行为可能是由于药物结晶度降低、载体L-HPC的快速溶解时间，以及其优异的分散性和良好的润湿性。RDM-1:2.5和RDM-1:5导致最大血浆浓度和曲线下面积（AUC）0至∞值增加。同样，口服RDM-1:2.5和RDM-1:5后，AUC0至∞分别比纯MBZ高2.67倍和2.97倍。在旋毛虫生命周期上评估的治疗活性表明，与纯MBZ相比，RDM-1:5在包囊阶段减少寄生虫数量方面最有效（4.56倍）。
MBZ:L-HPC RDM可能是一种使用低剂量MBZ（5mg/kg）提高口服生物利用度和治疗活性的有效方法，这意味着对人类的毒性较低。
