TY - JOUR
T1 - A mechanistic model of controlled drug release from polymer millirods
T2 - Effects of excipients and complex binding
AU - Wang, Fangjing
AU - Saidel, Gerald M.
AU - Gao, Jinming
N1 - Funding Information:
The authors would like to thank Dr. Zhenghong Lee for his support during the completion of this project. We also thank Dr. David Boothman for helpful discussions. This work is supported by the National Institutes of Health (R01 CA90696 to J.G.).
PY - 2007/5/14
Y1 - 2007/5/14
N2 - The incorporation of different cyclodextrin (CD) excipients such as HPβ-CD, β-CD, γ-CD or α-CD into polymer millirods for complexing β-lapachone (β-lap), a potent anti-cancer drug, significantly improved the drug release kinetics with various drug release patterns. However, such a complex system requires a mechanistically based model in order to provide a quantitative understanding of the many molecular events and processes that are essential for the rational development of millirod implants. This study focuses on mathematical modeling of drug release from PLGA cylindrical millirods. This millirod system incorporates multiple components: a PLGA matrix; excipient in free and complex forms; drug in free, bound, and crystalline forms. The model characterizes many dynamic transport and complexation processes that include radial diffusion, excipient complexation and crystalline drug dissolution. Optimal estimates of the model parameters were obtained by minimizing the difference between model simulation and experimentally measured drug release kinetics. The effects of different drug loadings on the drug release rate were simulated and compared with other data to validate this model. Whereas our model can simulate all the experimental data, the Higuchi model can simulate only some of them. Furthermore, our model incorporates mechanisms by which the processes underlying drug release from a polymer matrix can be quantitatively analyzed. These processes include drug entrapment/dissolution in the matrix, drug recrysallization, and supersaturation. This modeling study shows that complex binding capacity, which affects drug initial conditions, drug-polymer interactions, and bound drug behavior in aqueous solution, is crucial in controlling drug release kinetics.
AB - The incorporation of different cyclodextrin (CD) excipients such as HPβ-CD, β-CD, γ-CD or α-CD into polymer millirods for complexing β-lapachone (β-lap), a potent anti-cancer drug, significantly improved the drug release kinetics with various drug release patterns. However, such a complex system requires a mechanistically based model in order to provide a quantitative understanding of the many molecular events and processes that are essential for the rational development of millirod implants. This study focuses on mathematical modeling of drug release from PLGA cylindrical millirods. This millirod system incorporates multiple components: a PLGA matrix; excipient in free and complex forms; drug in free, bound, and crystalline forms. The model characterizes many dynamic transport and complexation processes that include radial diffusion, excipient complexation and crystalline drug dissolution. Optimal estimates of the model parameters were obtained by minimizing the difference between model simulation and experimentally measured drug release kinetics. The effects of different drug loadings on the drug release rate were simulated and compared with other data to validate this model. Whereas our model can simulate all the experimental data, the Higuchi model can simulate only some of them. Furthermore, our model incorporates mechanisms by which the processes underlying drug release from a polymer matrix can be quantitatively analyzed. These processes include drug entrapment/dissolution in the matrix, drug recrysallization, and supersaturation. This modeling study shows that complex binding capacity, which affects drug initial conditions, drug-polymer interactions, and bound drug behavior in aqueous solution, is crucial in controlling drug release kinetics.
KW - Cyclodextrin inclusion complex
KW - Drug release
KW - Excipients
KW - Mathematical model
KW - PLGA millirods
KW - Parameter estimation
UR - http://www.scopus.com/inward/record.url?scp=34147115081&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=34147115081&partnerID=8YFLogxK
U2 - 10.1016/j.jconrel.2007.01.019
DO - 10.1016/j.jconrel.2007.01.019
M3 - Article
C2 - 17379347
AN - SCOPUS:34147115081
SN - 0168-3659
VL - 119
SP - 111
EP - 120
JO - Journal of Controlled Release
JF - Journal of Controlled Release
IS - 1
ER -