Division of Pharmaceutical Technology, Faculty of Pharmacy, University of Helsinki, Helsinki, Finland.
School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, Kuopio, Finland; Institute of Biomedicine, Faculty of Medicine, University of Oulu, Oulu, Finland.
J Control Release. 2014 Apr 28;180:109-16. doi: 10.1016/j.jconrel.2014.02.016. Epub 2014 Feb 22.
Nanoscience holds true promise in enabling efficient formulation development and in vivo delivery of poorly water soluble drugs. The objective of this study was to formulate solid oral nanocrystal delivery systems of itraconazole, and thus enhance the oral bioavailability of the very poorly soluble drug. Nanocrystal suspensions were prepared by a rapid wet milling technique, after which the suspensions were transformed into solid dosage forms by both freeze drying and granulating. Finally, the obtained nanocrystalline powders were capsule-packed as well as compacted to tablets. After in vitro analysis, the formulations (nanocrystal suspension (NPs), freeze dried NPs, granulated NPs) were tested in vivo in a rat model, and compared with commercial itraconazole formulation (Sporanox). Importantly, the results indicated rapid dissolution of the nanocrystalline itraconazole with enhanced bioavailability compared to physical mixture. Drug dissolution in vitro was immediate from NPs and freeze dried powder, and differed significantly from the marketed product (P=0.004 and 0.002, correspondingly) until 30min. Freeze drying was detected to be especially advantageous for the solid dosage forms. It is possible to maintain the original character of the nanocrystals, e.g. rapid dissolution, even after tableting of the nanocrystalline powders. Interestingly, the marketed product out-performed the nanocrystalline formulations in vivo, even though the nanocrystals provided reasonable bioavailability of itraconazole absorption as well. The efficient in vitro dissolution enhancement of the nanocrystalline formulations compared to Sporanox® was not realized in in vivo drug absorption.
纳米科学在实现高效制剂开发和改善难溶性药物体内传递方面具有广阔的应用前景。本研究旨在开发伊曲康唑固体口服纳米晶体传递系统，从而提高该极难溶性药物的口服生物利用度。采用快速湿磨技术制备纳米晶体混悬液，然后通过冷冻干燥和造粒将混悬液转化为固体剂型。最后，将获得的纳米晶体粉末装胶囊或压片。体外分析后，将这些制剂（纳米晶体混悬液（NPs）、冷冻干燥 NPs、造粒 NPs）在大鼠模型中进行体内测试，并与市售伊曲康唑制剂（Sporanox）进行比较。重要的是，结果表明与物理混合物相比，纳米晶体伊曲康唑具有快速溶解和增强的生物利用度。NPs 和冷冻干燥粉末中的药物在体外即刻溶解，与市售产品相比差异显著（分别为 P=0.004 和 0.002），直到 30 分钟。冷冻干燥对固体剂型尤其有利。即使将纳米晶体粉末压片后，也能保持纳米晶体的原有特性，如快速溶解。有趣的是，即使纳米晶体提供了合理的伊曲康唑吸收生物利用度，市售产品在体内的表现仍优于纳米晶体制剂。与 Sporanox®相比，纳米晶体制剂在体外的高效溶解增强在体内药物吸收中并未实现。
