In Vitro and In Vivo Characterization of Drug Nanoparticles Prepared Using PureNano™ Continuous Crystallizer to Improve the Bioavailability of Poorly Water Soluble Drugs.
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.
Laboratory of Pharmaceutical Engineering, Gifu Pharmaceutical University, 1-25-4 Daigaku-nishi, Gifu, 501-1196, Japan.
Kohei
K
Tahara
Laboratory of Pharmaceutical Engineering, Gifu Pharmaceutical University, 1-25-4 Daigaku-nishi, Gifu, 501-1196, Japan.
Masahiro
M
Nishikawa
Powrex Corporation, 121-1-8 Kita-Itami, Itami, Hyogo, 664-0831, Japan.
Ko
K
Matsui
Powrex Corporation, 121-1-8 Kita-Itami, Itami, Hyogo, 664-0831, Japan.
Koji
K
Hisazumi
Laboratory of Pharmaceutical Engineering, Gifu Pharmaceutical University, 1-25-4 Daigaku-nishi, Gifu, 501-1196, Japan.
Risako
R
Onodera
Laboratory of Formulation Design and Pharmaceutical Technology, Osaka University of Pharmaceutical Sciences, 4-20-1 Nasahara, Takatsuki, Osaka, 569-1094, Japan.
Yuichi
Y
Tozuka
Laboratory of Pharmaceutical Engineering, Gifu Pharmaceutical University, 1-25-4 Daigaku-nishi, Gifu, 501-1196, Japan. takeuchi@gifu-pu.ac.jp.
Hirofumi
H
Takeuchi
D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D018938:Caco-2 Cells; D045744:Cell Line, Tumor; D002626:Chemistry, Pharmaceutical / Q000379:methods; D003460:Crystallization / Q000379:methods; D004337:Drug Carriers / Q000737:chemistry; D005612:Freeze Drying; D006801:Humans; D008297:Male; D053758:Nanoparticles / Q000737:chemistry* / Q000378:metabolism; D010316:Particle Size; D004364:Pharmaceutical Preparations / Q000737:chemistry* / Q000378:metabolism*; D011142:Polyvinyl Alcohol / Q000737:chemistry; D051381:Rats; D017208:Rats, Wistar; D012995:Solubility; D012997:Solvents / Q000737:chemistry; D013535:Suspensions / Q000737:chemistry / Q000378:metabolism; D014867:Water / Q000737:chemistry*
D004337:Drug Carriers; D004364:Pharmaceutical Preparations; D012997:Solvents; D013535:Suspensions; D014867:Water; D011142:Polyvinyl Alcohol
PureNano; crystallization; nanoparticles