Preclinical evaluation of new formulation concepts for abiraterone acetate bioavailability enhancement based on the inhibition of pH-induced precipitation
Language English Country Netherlands Media print-electronic
Document type Journal Article
PubMed
32298757
DOI
10.1016/j.ejpb.2020.04.005
PII: S0939-6411(20)30098-9
Knihovny.cz E-resources
- Keywords
- Abiraterone acetate, Bioavailability, Food effect, Precipitation, Solid dispersion, Spray drying,
- MeSH
- Abiraterone Acetate chemistry metabolism MeSH
- Biological Availability MeSH
- Food-Drug Interactions physiology MeSH
- Hydrogen-Ion Concentration MeSH
- Rats MeSH
- Fasting metabolism MeSH
- Polymers chemistry MeSH
- Excipients chemistry MeSH
- Rats, Wistar MeSH
- Drug Evaluation, Preclinical MeSH
- Therapeutic Equivalency MeSH
- Drug Liberation physiology MeSH
- Animals MeSH
- Check Tag
- Rats MeSH
- Male MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Names of Substances
- Abiraterone Acetate MeSH
- Polymers MeSH
- Excipients MeSH
Abiraterone acetate is a potent drug used for the treatment of metastatic castration resistant prostate cancer. However, currently marketed product containing crystalline abiraterone acetate exhibits strong positive food effect which results in strict dosing regimen. In the present work, a rational approach towards design of novel abiraterone acetate formulations that would allow increased bioavailability on a fasting stomach and thus decreased food effect is presented. Precipitation experiments in biorelevant media were designed to assess pH induced precipitation of the drug and a pool of polymeric excipients was then screened for their potential to inhibit precipitation. The best performing polymeric excipients were subsequently used as carriers for the preparation of amorphous solid dispersions. Two main approaches were followed in order to formulate the drug. The first approach relies on the suppression of precipitation from a supersaturated solution whereas the second one is based on the hypothesis that when the release of the drug is tuned, optimal uptake of the drug can be reached. Optimized formulation prototypes were tested in a rat animal model in an incomplete block, randomized bioequivalence study to assess their relative bioavailability under fasting conditions. We show that both formulation approaches lead to increased bioavailability of abiraterone acetate on a fasting stomach with bioavailability in rats being enhanced up to 250% compared to the original drug product containing crystalline drug.
Department of Analytical Chemistry Faculty of Science Charles University Prague Czech Republic
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