In Vitro and In Vivo Characterization of Drug Nanoparticles Prepared Using PureNano™ Continuous Crystallizer to Improve the Bioavailability of Poorly Water Soluble Drugs

• Published in: Pharmaceutical research 2016-09, Vol.33 (9), p.2259-2268
• Main Authors: Tahara, Kohei, Nishikawa, Masahiro, Matsui, Ko, Hisazumi, Koji, Onodera, Risako, Tozuka, Yuichi, Takeuchi, Hirofumi
• Format: Article
• Language: English
• Subjects: Administration, Oral; Analysis; Animals; Bioavailability; Biochemistry; Biological Availability; Biomedical and Life Sciences; Biomedical Engineering and Bioengineering; Biomedicine; Caco-2 Cells; Cell Line, Tumor; Chemistry, Pharmaceutical - methods; Crystallization; Crystallization - methods; Dissolution; Drug Carriers - chemistry; Flurbiprofen; Freeze Drying; Gastrointestinal system; Humans; Male; Medical Law; Microfluidics; Nanoparticles; Nanoparticles - chemistry; Nanoparticles - metabolism; Particle Size; Pharmaceutical Preparations - chemistry; Pharmaceutical Preparations - metabolism; Pharmaceutical sciences; Pharmacology/Toxicology; Pharmacy; Phenytoin; Polyvinyl Alcohol - chemistry; Rats; Rats, Wistar; Research Paper; Solubility; Solvents - chemistry; Suspensions - chemistry; Suspensions - metabolism; Water - chemistry
• ISSN: 0724-8741; 1573-904X
• DOI: 10.1007/s11095-016-1964-7

Purpose 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). Method 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 . Results 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. Conclusions PCC can continuously produce nanoparticle APIs and is an efficient approach for improving their oral bioavailability.