Pharmacokinetics of nano- and microcrystal formulations of low solubility compounds after intramuscular injection to mice.
| Autor: | Aluri KC; Drug Metabolism and Pharmacokinetics, Oncology R&D, AstraZeneca, 35 Gatehouse Park Drive, Waltham, MA 02451, United States., Sigfridsson K; Advanced Drug Delivery, Pharmaceutical Sciences, R&D, AstraZeneca, 431 83 Mölndal, Sweden., Xue A; Animal Sciences and Technologies, Clinical Pharmacology and Safety Sciences, AstraZeneca, 35 Gatehouse Drive, Waltham, MA 02451, United States., Ramsden D; Drug Metabolism and Pharmacokinetics, Oncology R&D, AstraZeneca, 35 Gatehouse Park Drive, Waltham, MA 02451, United States. |
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| Jazyk: | angličtina |
| Zdroj: | The Journal of pharmacy and pharmacology [J Pharm Pharmacol] 2024 Sep 14. Date of Electronic Publication: 2024 Sep 14. |
| DOI: | 10.1093/jpp/rgae118 |
| Abstrakt: | Objectives: The aim of this study was to investigate the pharmacokinetics (PK) of poorly soluble compounds when administered intramuscularly (i.m.) as crystalline particles of different sizes. Methods: Three uncharged compounds (griseofulvin, AZ'72, and AZ'07) with varying aqueous solubility were dosed to mice at 10 and 50 mg/kg as nano- and microparticle formulations. The PK of the compounds was evaluated. Key Findings: The smaller particles of the drugs resulted in higher maximum plasma concentration (Cmax) and area under the plasma concentration-time profile (AUC) at 50 mg/kg. There was a dose-proportional increase in AUC but less than dose dose-proportional increase in Cmax. The evaluation at 10 mg/kg was more complex as increased exposure for nanoparticles was only observed for griseofulvin which has the highest solubility. In addition, there was an increase in half-life with an increase in dose. Conclusions: This study highlights that general expectations based on in vitro dissolution (i.e. that smaller particles dissolve faster than larger particles when surrounded by liquid) do not always translate to in vivo and demonstrates the importance of understanding the physicochemical properties of the drug, the characteristics of the formulations and the microphysiology at the delivery site. (© The Author(s) 2024. Published by Oxford University Press on behalf of the Royal Pharmaceutical Society. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.) |
| Databáze: | MEDLINE |
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