Many current nanoformulations of taxanes are hampered by low drug-loading capacity and unfavorable physicochemical characteristics such as large particles size (>100 nm) and/or low size uniformity. We have previously reported on taxane nanoformulations, based on poly(2-oxazoline) polymeric micelles that display an extremely high taxane loading capacity (>40% w/w) and particle size below 50 nm. Previous work was based on a triblock copolymer having poly(2-butyl-2oxazoline) as the hydrophobic block and poly(2-methyl-2-oxazoline) as the hydrophilic blocks. This paper explores the effects of various formulation parameters such as (i) the drug and polymer structure; (ii) the drug and polymer concentration; and (iii) the composition of aqueous medium on the solubilization behavior and physicochemical properties of the resulting formulations. In addition, in vitro anticancer activity is reported. Despite numerous variations of the hydrophobicity, polarity or addition of aromatic residues in the hydrophobic core, the triblock copolymer with the poly(2-butyl-2-oxazoline) block remains the polymer with the highest drug-loading capacity. Notably, the formulation was easily scalable with uncompromised encapsulation efficacy, loading capacity, and physicochemical properties. The taxane formulations were stable upon storage (water, saline, and dextrose solution) for 1-2 weeks and could be lyophilized and re-dispersed without compromising the formulation properties. Furthermore, the micelles remained stable upon dilution. The drug-loaded poly(2-oxazoline) micelles showed high toxicity against several cancer cell lines. Taken together, these results underscore the potential of poly(2-oxazoline) micelles as formulation excipient for taxanes and possibly other hydrophobic drugs. Figure 10. Stability of 50 g/l T1 micelle formulations of (a) paclitaxel (39.7 g/l) and (b) docetaxel (40.6 g/l) in DI water, 5% dextrose solution (DEX) or phosphate buffered saline at room temperature. This figure is available in colour online at wileyonlinelibrary.com/journal/pat Y. SEO ET AL.wileyonlinelibrary.com/journal/pat

To develop sildenafil lactate, a salt form of sildenafil with improved solubility and bioavailability of poorly water-soluble sildenafil base, this salt form was prepared using a spray dryer. Its solubility and pharmacokinetics in rabbits were evaluated compared with sildenafil base and sildenafil citrate. Sildenafil lactate improved the solubility of sildenafil in various solvents including distilled water compared with sildenafil citrate. It provided higher AUC and C(max) and, shorter t(1/2) values than did the other materials, indicating that it improved the oral bioavailability of sildenafil in rabbits. Our results suggest that sildenafil lactate would be useful to deliver sildenafil in a pattern that allows fast absorption and late metabolism. Furthermore, the plasma concentration at 0.25 h in sildenafil lactate was similar to the C(max) value at T(max) (0.5 h) in sildenafil citrate. Thus, sildenafil lactate might provide a faster onset of action and immediate erection compared with sildenafil citrate, the conventional drug.

The main purpose of this study was to evaluate the effect of a mixed drug solution containing a surfactant and beta-cyclodextrin (beta-CD) on the solubility and bioavailability of a poorly water soluble drug, flurbiprofen. Solubility, dissolution and in vivo pharmacokinetics of flurbiprofen in the presence of surfactant, beta-CD or mixture of surfactant and beta-CD were investigated. Among the surfactants tested, Tween 80 produced the highest improvement in the aqueous solubility of flurbiprofen. The solubility of flurbiprofen increased linearly as a function of beta-CD, resulting in B8 type that suggested a formation of inclusion complex in a molar ratio of 1:1. The solubility of flurbiprofen increased further when Tween 80 was included in addition to beta-CD, suggesting that a micelle formation in the presence of Tween 80 was the likely reason for additional increase. Furthermore, the data suggested that Tween 80 did not interfere with the inclusion interaction between flurbiprofen and beta-CD. The solubility of flurbiprofen was the highest in the mixed system containing 1.3 mM beta-CD and 0.3% w/v Tween 80, and the maximum solubility of 160 microg/mL was achieved. Consistent with the enhanced solubility, the plasma exposure (both AUC and Cmax) of flurbiprofen when dosed as the mixed system was significantly higher (as much as 2 to 3-fold) than that without surfactant or beta-CD, with surfactant alone, or with beta-CD alone. Therefore, the mixed system consists of surfactant and beta-CD could be used as an effective oral dosage form to improve bioavailability of poorly water soluble drugs such as flurbiprofen.

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