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Lovastatin shows low bioavailability (lower than 5%) after oral administration because of the poor aqueous solubility and widely metabolized by CYP3A4. Lovastatin solid dispersion was designed to enhance the dissolution. The in vitro intestinal absorption study indicated an increase in the apparent permeability of different intestinal segments compared with crude lovastatin. In the range of 12.5–50 μg/ml, the absorption of both lovastatin and lovastatin solid dispersion were found to be a passive process in rat's jejunum and ileum, but not endocytosis process. CYP3A4 inhibitor (ketoconazole) significantly increased the intestinal absorption of lovastatin and lovastatin solid dispersion. However, P-glycoprotein efflux inhibitor (verapamil) had little effect on them. The absolute bioavailability of lovastatin and lovastatin acid after oral administration of lovastatin solid dispersion were increased by about 2.01-fold and 1.40-fold than that of lovastatin suspension. The oral bioavailability of lovastatin and lovastatin acid after oral administration of lovastatin solid dispersion with 10 mg/kg kaempferol (CYP3A4 inhibitor) were increased about 3.79-fold and 2.51-fold than that of lovastatin suspension, and the absolute bioavailability of lovastatin was up to 33.0%. As a result, co-administration of lovastatin solid dispersion with kaempferol could be a promising delivery system to improve the oral bioavailability of lovastatin. [ABSTRACT FROM AUTHOR]

Objective: To preliminarily develop a surfactant-free, polymeric solid dispersion (PSD) of paclitaxel suitable for oral administration. Methods: A co-solvent quench method was applied to screen the proper polymer matrix of the PSD which were prepared in a liquid system using a quasi-emulsion solvent diffusion method (QESDM). Three dissolution experiments and twoin vivotests in rats were used to explain the differences among the formulations. Results: The theoretical solubility ratio of amorphous/crystalline PTX was 92.6 (37 °C). Hydroxypropyl methylcellulose acetate succinate (HPMCAS) was chosen as the polymer carrier of the PSD and a porous silicon dioxide [called white carbon black (WCB)] was selectable to be used to further adjust the dissolution rate. The absolute oral bioavailability (AOB, 20 mg/kg) of the three formulas [HPMCAS/paclitaxel/WCB = 4/1/0 (F1), 8/1/0 (F2) and 4/1/4 (F3), w/w/w] were 11.8, 13.6 and 25.6%, respectively. The AOB of F3 is nearly seven times higher than that (3.8%) of paclitaxel material (a control). The advantage of higher HPMCAS/paclitaxel ratio of F2 in a dissolution test was not reflected in the firstin vivotest due to the relatively higher dose of polymer which could not be effectively dissolved under the limitation of intestinal environment. This was deduced from the dissolution tests and was finally validated when the oral dose of PTX (and thus polymer) was reduced. The relevant AOBs (10 mg/kg) were 10.4, 20.8 and 19.6%, respectively. Conclusion: The PSD is a promising formulation strategy and the QESDM is a practical preparation method to implement such formulation design. [ABSTRACT FROM AUTHOR]

Purpose: To develop an osmotically-driven pellet coated with polymeric film for sustained release of oxymatrine (OMT), a freely water soluble drug. Methods: Pellet containing OMT and sodium chloride (NaCl), an osmotically active agent, were prepared by extrusion/spheronization and then coated with acrylic copolymers (Eudragit® RS 30 D) by the fluidized bed coating process. In vitro release and swelling behavior studies were employed to optimize and to evaluate the sustained-release behavior from the osmotically-driven pellets with film coated. Finally, in vivo evaluation in rabbits was employed to investigate the sustained plasma level of OMT and its active metabolite matrine. Results: It was found that the F3 formulation, prepared with 20% NaCl and an 8% coating level, showed a continuous NaCl-induced water influx into the pellets providing a gradual sustained release of OMT for over 12 h. Finally, we confirmed that oral OMT with sustained release led to a gradual sustained plasma profile of both OMT, with a reduction in its bioavailability, and MT with an increase in the bioavailability compared with that of oral OMT with immediate release. Conclusions: The pharmaceutical parameters obtained suggested the potential usefulness of oral OMT with sustained release for the treatment of stress ulcers, as well as reducing the risk of MT-induced side effects. [ABSTRACT FROM AUTHOR]

7-Ethyl-10-hydroxycamptothecin (SN38), an active metabolite of irinotecan (CPT-11), is a remarkably potent antitumor agent. The clinical application of SN38 has been extremely restricted by its insolubility in water. In this study, we successfully synthesized two macromolecular prodrugs of SN38 with different conjugate positions (chitosan-(C10-OH)SN38 and chitosan-(C20-OH)SN38) to improve the water solubility and antitumor activity of SN38. These prodrugs can self-assemble into micelles in aqueous medium. The particle size, morphology, zeta potential, and in vitro drug release of SN38 and its derivatives, as well as their cytotoxicity, pharmacokinetics, and in vivo antitumor activity in a xenograft BALB/c mouse model were studied. In vitro, chitosan-(C10-OH)SN38 (CS-(10s)SN38) and chitosan-(C20-OH) SN38 (CS-(20s)SN38) were 13.3- and 25.9-fold more potent than CPT-11 in the murine colon adenocarcinoma cell line CT26, respectively. The area under the curve (AUC)0-24 of SN38 after intravenously administering CS-(10s)SN38 and CS-(20s)SN38 to Sprague Dawley rats was greatly improved when compared with CPT-11 (both P<0.01). A larger AUC0-24 of CS-(20s)SN38 was observed when compared to CS-(10s)SN38 (P<0.05). Both of the novel self-assembled chitosan-SN38 prodrugs demonstrated superior anticancer activity to CPT-11 in the CT26 xenograft BALB/c mouse model. We have also investigated the differences between these macromolecular prodrug micelles with regards to enhancing the antitumor activity of SN38. CS-(20s)SN38 exhibited better in vivo antitumor activity than CS-(10s)SN38 at a dose of 2.5 mg/kg (P<0.05). In conclusion, both macromolecular prodrug micelles improved the in vivo conversion rate and antitumor activity of SN38, but the prodrug in which C20-OH was conjugated to macromolecular materials could be a more promising platform for SN38 delivery.