期刊
JOURNAL OF CONTROLLED RELEASE
卷 329, 期 -, 页码 372-384出版社
ELSEVIER
DOI: 10.1016/j.jconrel.2020.11.055
关键词
Tacrolimus / FK506; Microsphere; Subcutaneous depot; In vitro release; IVIVC; PBPK modelling
资金
- LOEWE intitiative of the State of Hessen
- National University of Singapore [R-148-000-282-133, R-148-000-297-114]
- Astellas Pharma Inc.
In this study, two microsphere formulations were compared in terms of their in vitro release and degradation characteristics using a novel biorelevant medium. The capability of an in vitro performance assay was verified through level A in vitro-in vivo correlation analysis. The findings provide insights into the contributions of in vitro drug release, drug degradation, diffusion rate, and lymphatic transport to the drug absorption process.
Today, tacrolimus represents a cornerstone of immunosuppressive therapy for liver and kidney transplants and remains subject of preclinical and clinical investigations, aiming at the development of long-acting depot formulations for subcutaneous injection. One major challenge arises from establishing in vitro-in vivo correlations due to the absence of meaningful in vitro methods predictive for the in vivo situation, together with a strong impact of multiple kinetic processes on the plasma concentration-time profile. In the present approach, two microsphere formulations were compared with regards to their in vitro release and degradation characteristics. A novel biorelevant medium provided the physiological ion and protein background. Release was measured using the dispersion releaser technology under accelerated conditions. A release of 100% of the drug from the carrier was achieved within 7 days. The capability of the in vitro performance assay was verified by the level A in vitro-in vivo correlation analysis. The contributions of in vitro drug release, drug degradation, diffusion rate and lymphatic transport to the absorption process were quantitatively investigated by means of a mechanistic modelling approach. The degradation rate, together with release and diffusion characteristics provides an estimate of the bioavailability and therefore can be a guide to future formulation development.
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