Slow-release, Controlled Release Formulations Pharmacokinetic Theory And Its Use In The Macrolides Biological Research Applications

Aims To establish systematic pharmacokinetic (P1<) theories of the controlled/sustained release (CSR) dosage forms, and to apply the principles and methods to the macrolides with poor bioavailabilities (BA).Methods 1. The in viva release kinetics of a CSR dosage form was processed by Kalman Filter method.2.The PK of the non-parenteral zero-order release and the first-order release was analyzed mainly by means of the Laplace Transform.3.A new tool of the P1< of the CSR dosage forms, the Zhang抯 Dose-Division method, was proposed based on the basis that any drug release profile can be simulated by a series of zero-order release doses administered by the same way.4.A novel kinetic tool for evaluation of the CSR dosage forms was proposed as the Zhang抯 Release-Division method by the hypothesis that all the CSR dosage forms are all formed by and therefore can be divided into the classical releases.5.The P1< of the CSR dosage forms administered with repeating doses, in vivo release kinetics, and in vitro absorption kinetics were methodologically established by the Dose-Division method and the Release-Division method.6.The methodology study was processed by the Dose-Division method and the Release-Division method to propose five categories of in vitro versus in vivo Level A correlation methods, namely, the correlation of the in vitro release versus the in vivo release, the in vitro absorption expectance versus the in viva absorption, the in vitro plasma drug level expectance versus the in viva plasma concentration, the in vitro Sustained Release Index versus the in viva Sustained Release Index, and the in vitro Controlled Release Index versus the in viva Controlled Release Index.7.Two single-parameter method to evaluate the release of the CSR dosage forms were established, one by the Similarity method, and the other by the Release Division method. The release profiles of the CSR dosage4Abstractsforms can be simply evaluated by the Controlled Release Index (CSI) or the Sustained Release Index (55/) respectively by the Similarity method; or by the Controlled Release Index (CRD) or the Sustained Release Index (SRD) respectively by Release-Division method. The single parameter evaluation method makes it possible to control the release quality and evaluate the release stability of the CSR dosage forms quantitatively and statistically. The CSI and SSI, or CRD and SRD are correlated with the PK behaviors of the CSR dosage forms.8. The PK profiles of non-typical releases, such as Higuchi release, double exponential release, and pulse-style release, were predicted by the Dose-Division method and the Release-Division method.9. The poor BA of macrolides were analyzed by the Pk theory of the CSR dosage forms to reveal the role the in vivo release and in vivo absorption of the macrolides played in the BA. That the poor stability in an acid solution, and the slow release in a neutralized solution after agglomeration in the stomach decreased the BA of the macrolides.10. The dosage form design should be targeted on overcoming the BA influencing parameters. The BA validation test was processed in dogs by the microbiological test of antibiotics.Results 1. The kalman Filter was able to process the in vivo release profile of the CSR dosage forms, but the method was too abstract to be accepted and not easy to control for it is a totally computerized process.2.The releases (non-parenterai zero-order release, and the first-order release) were elucidated. The residue in the absorption site after the release finished plays an important role for understand the Pk of CSR dosage forms and behaves as an immediate release.The residue dose of non-parenteral zero-order release is:X~The residue dose of non-parenteral first-order release is:k_Dekt)~I鐥k,?It is possible the first time to report the PK of the repeating doses of the first-order release, the peak plasma concentration time (tmax) formula of the same release.The formula wa...