Tahara Kohei, Nishikawa Masahiro, Matsui Ko, Hisazumi Koji, Onodera Risako, Tozuka Yuichi, Takeuchi Hirofumi
Laboratory of Pharmaceutical Engineering, Gifu Pharmaceutical University, 1-25-4 Daigaku-nishi, Gifu, 501-1196, Japan.
Powrex Corporation, 121-1-8 Kita-Itami, Itami, Hyogo, 664-0831, Japan.
Pharm Res. 2016 Sep;33(9):2259-68. doi: 10.1007/s11095-016-1964-7. Epub 2016 Jun 14.
The aim of this study was to enhance the dissolution and oral absorption of poorly water-soluble active pharmaceutical ingredients (APIs) using nanoparticle suspensions prepared with a PureNano™ continuous crystallizer (PCC).
Nanoparticle suspensions were prepared with a PCC, which is based on microfluidics reaction technology and solvent-antisolvent crystallization. Phenytoin, bezafibrate, flurbiprofen, and miconazole were used as model APIs. These APIs were dissolved in ethanol and precipitated by the addition of water and polyvinyl alcohol. Batch crystallization (BC) using a beaker was also performed to prepare the suspensions. Both PCC and BC formulations were freeze-dried before being characterized in vitro and in vivo.
The particle sizes of the nanoparticle suspensions prepared with the PCC were smaller than those prepared by BC. The dissolution rate of each API in vitro significantly increased after crystallization. Reducing the particle size of either the BC or PCC formulation led to increased API flux across Caco-2 cell monolayers. PCC preparations showed higher plasma concentrations after oral administration, demonstrating the advantages of a fast dissolution rate and increased interaction with the gastrointestinal tract owing to the smaller particle size.
PCC can continuously produce nanoparticle APIs and is an efficient approach for improving their oral bioavailability.
本研究的目的是使用由PureNano™连续结晶器（PCC）制备的纳米颗粒悬浮液来提高难溶性活性药物成分（API）的溶出度和口服吸收。
使用基于微流控反应技术和溶剂-反溶剂结晶的PCC制备纳米颗粒悬浮液。苯妥英、苯扎贝特、氟比洛芬和咪康唑用作模型API。将这些API溶解在乙醇中，通过加入水和聚乙烯醇使其沉淀。还使用烧杯进行批量结晶（BC）以制备悬浮液。PCC和BC制剂在进行体外和体内表征之前均进行冷冻干燥。
用PCC制备的纳米颗粒悬浮液的粒径小于用BC制备的粒径。结晶后，每种API的体外溶出速率显著提高。减小BC或PCC制剂的粒径会导致API通过Caco-2细胞单层的通量增加。口服给药后，PCC制剂显示出更高的血浆浓度，这证明了由于粒径较小而具有快速溶出速率和与胃肠道相互作用增加的优势。
PCC可以连续生产纳米颗粒API，是提高其口服生物利用度的有效方法。
