Albumin is a versatile drug carrier in anti-cancer drug delivery system and it also has an actively targeting capacity to tumors. Recently, nanoparticle albumin-bound (nab) paclitaxel (nab-paclitaxel; Abraxane) has been approved in 2006 for use in patients with metastatic breast cancer who have failed in the combination chemotherapy, and so the nab-technology has attracted much interest in the anti-cancer drug delivery system. The details about the preparation, characterization and evaluation of nab-paclitaxel (ABI-007) are discussed. The pharmacokinetics, pharmacodynamics and the clinical trials of ABI-007 are also reviewed. Furthermore, the recent applications of nab-technology in the anti-cancer drug delivery systems are summarized by virtue of the patents pertaining to nab-technology. To sum up, nab-technology has a great potential of being applied extensively in the field of anti-cancer agents delivery in the future in order to acquire the good safety and better therapeutical effect.

The objective of this study is to compare two different dissolution-enhancing strategies, solid dispersion (SD) and micronized techniques, for improving oral absorption of poorly soluble glimepiride, and to decide which strategy is suitable for its solubilization. The formulation of glimepiride SD was prepared by a solvent-evaporation process with povidone k-30 (PVPk30) at a weight ratio of 1:9 (drug:carrier). The other was prepared via a modified micronization technique, where glimepiride was premilled together with lactose and Lutrol F68 until the milled material passes through a 500 mesh ASTM sieve (30 μm). The dissolution results indicated that the two techniques were both capable of enhancing the dissolution rate and extent of glimepiride. The release profiles of the two prepared products were similar to the marketed product (Amaryl®) in various types of dissolution media. Furthermore, the oral bioavailability was evaluated for the three formulations in fasted beagle dogs. Statistical analysis indicated that there were no significant differences in pharmacokinetic parameters among the two prepared formulations and a marketed product, especially for AUC₀₋₃₆, C(max), and T(max). The dissolution parameters (D₁₀ and AUC₀₋₂₀) in Tris buffer demonstrated the good in vitro/in vivo relationship with T(max) values for the three formulations. In conclusion, our studies confirmed that both SD and micronization techniques were capable of improving dissolution and oral absorption of glimepiride tablets to a similar extent as the marketed product, and the three glimepiride tablets were bioequivalent in the case of the rate and extent of absorption in dogs.

Five peptidomimetic prodrugs of didanosine (DDI) were synthesized and designed to improve bioavailability of DDI following oral administration via targeting intestinal oligopeptide transporter (PepT1) and enhancing chemical stability. The permeability of prodrugs was screened in Caco-2 cells grown on permeable supports. 5'-O-L-valyl ester prodrug of DDI (compound 4a) demonstrated the highest membrane permeability and was selected as the optimal target prodrug for further studies. The uptake of glycylsarcosine (Gly-Sar, a typical substrate of PepT1) by Caco-2 cells could be inhibited by compound 4a in a concentration-dependent manner. The Caco-2 cells were treated with 0.2 nM leptin for enhanced PepT1 expression. The uptake of compound 4a was markedly increased in the leptin-treated Caco-2 cells compared with the control Caco-2 cells, both of which were obviously inhibited by 20 mM Gly-Sar. The K(m) and V(max) values of kinetic study of compound 4a transported by PepT1 in Caco-2 cells were 0.91 mM and 11.94 nmol/mg of protein/10 min, respectively. The chemical stability studies were performed in simulated gastric fluid (SGF), phosphate buffers under various pH conditions, rat tissue homogenates and plasma at 37 °C. The concentrations of DDI could not be detected in the two minutes in SGF. But compound 4a could significantly increase DDI acidic stability, and its t(½) was extended to as long as 36 min in SGF. Compound 4a was stable in pH 6.0 phosphate buffer but could be quickly transformed into DDI in plasma and tissue homogenates. The oral absolute bioavailability of DDI was 47.2% and 7.9% after compound 4a and DDI were orally administered to rats at a dose of 15 mg/kg, respectively. The coadministration with antiacid agent could also suggest that compound 4a was more stable under harsh acidic conditions compared with DDI. Compound 4a bioavailability in rats was reduced to 33.9% when orally co-administered with Gly-Sar (100 mg/kg). The In Vivo bioactivation mechanism of compound 4a was investigated by comparing the levels of DDI and compound 4a in the jugular and portal veins in rats. The plasma concentration of intact compound 4a was very low in portal veins and could hardly be detected in the jugular vein. In conclusion, compound 4a could significantly improve the oral bioavailability of DDI in rats through PepT1-mediated absorption and enhanced acidic stability, followed by rapid and mostly intracellular bioactivation, the majority in the intestinal cells but the minority in the liver. Additionally, the prodrug strategy targeted to intestinal PepT1 could offer a promising strategy to improve oral bioavailability of poorly absorbed didanosine.

Abstract. For the accurate prediction of in vivo hepatic clearance or drug-drug interaction potential through in vitro microsomal metabolic data, it is essential to evaluate the fraction unbound in hepatic microsomal incubation media. Here, a structure-based in silico predictive model of the nonspecific binding (fu mic , fraction unbound in hepatic microsomes) for 86 drugs was successfully developed based on seven selected molecular descriptors. The R 2 of the predicted and observed log((1−fu mic )/fu mic ) for the training set (n=64) and test set (n=22) were 0.82 and 0.85, respectively. The average fold error (AFE, calculated by fu mic rather than log((1−fu mic )/fu mic )) of the in silico model was 1.33 (n=86). The predictive capability of fu mic for neutral drugs compared well to that for basic compounds (R 2 =0.82, AFE=1.18 and fold error values were all below 2, except for felodipine and progesterone) in our model. This model appears to perform better for neutral compounds when compared to models previously published in the literature. Therefore, this in silico model may be used as an additional tool to estimate fu mic and for predicting in vivo hepatic clearance and inhibition potential from in vitro hepatic microsomal studies.

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