期刊
PHARMACEUTICS
卷 13, 期 8, 页码 -出版社
MDPI
DOI: 10.3390/pharmaceutics13081188
关键词
pyrazoloquinolinones; nanocrystals; wet media milling; fasted; fed bioavailability
资金
- Ministry of Education, Science and Technological Development, Republic of Serbia [451-03-9/2021-14/200161, 451-03-09/2021-14/200126, 451-03-9/2021-14/200026]
- National Institutes of Health, USA [R01 NS076517, R01 MH096463]
- National Science Foundation, Division of Chemistry [CHE-1625735]
- Ministry of Education, Science and Technological Development
- University of Belgrade-Faculty of Pharmacy [451-03-9/2021-14/200161]
The study demonstrates that using nanocrystal technology can enhance the oral bioavailability of DK-I-60-3, resulting in an improved therapeutic effect of the potential drug substance.
Poor water solubility of new chemical entities is considered as one of the main obstacles in drug development, as it usually leads to low bioavailability after administration. To overcome these problems, the selection of the appropriate formulation technology needs to be based on the physicochemical properties of the drug and introduced in the early stages of drug research. One example of the new potential drug substance with poor solubility is DK-I-60-3, deuterated pyrazoloquinolinone, designed for the treatment of various neuropsychiatric disorders. In this research, based on preformulation studies, nanocrystal technology was chosen to improve the oral bioavailability of DK-I-60-3. Nanocrystal dispersions stabilized by sodium lauryl sulfate and polyvinylpyrrolidone were prepared by modified wet media milling technique, with the selection of appropriate process and formulation parameters. The nanoparticles characterization included particle size and zeta potential measurements, differential scanning calorimetry, X-ray powder diffraction, dissolution and solubility study, and in vivo pharmacokinetic experiments. Developed formulations had small uniform particle sizes and were stable for three months. Nanonization caused decreased crystallite size and induced crystal defects formation, as well as a DK-I-60-3 solubility increase. Furthermore, after oral administration of the developed formulations in rats, two to three-fold bioavailability enhancement was observed in plasma and investigated organs, including the brain.
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