Hydrotropic polymer micelles containing acrylic acid moieties for oral delivery of paclitaxel

Abstract

Hydrotropic polymers (HPs) and their micelles have been recently developed as vehicles for delivery of poorly water-soluble drugs, such as paclitaxel (PTX), by oral administration. The release of PTX from HP micelles, however, was slow and it took more than a day for complete release of the loaded PTX. Since the gastrointestinal (GI) transit time is known to be only several hours, pH-sensitive HP micelles were prepared for fast release of the loaded PTX responding to pH changes along the GI tract. Acrylic acid (AA) was introduced, as a release modulator, into HPs by copolymerization with 4-(2-vinylbenzyloxy)-N,N-(diethylnicotinamide) (VBODENA). The AA content was varied from 0% to 50% (in the molar ratio to VBODENA). HPs spontaneously produced micelles in water, and their critical micelle concentrations (CMCs) ranged from 31 microg/mL to 86 microg/mL. Fluorescence probe study using pyrene showed that blank HP micelles possessed a good pH sensitivity, which was clearly observed at relatively high AA contents and pH>6. The pH sensitivity also affected the PTX loading property. Above pH 5, the PTX loading content and loading efficiency in HP micelles were significantly reduced. Although this may be primarily due to the AA moieties, other factors may include PTX degradation and polymer aggregation. The PTX release from HP micelles with more than 20% (mol) AA contents was completed within 12 h in a simulated intestinal fluid (SIF, pH=6.5). The HP micelles without any AA moiety showed very slow release profiles. In the simulated gastric fluid (SGF, pH=1.6), severe degradation of the released PTX was observed. The pH-dependent release of PTX from HP micelles can be used to increase the bioavailability of PTX upon oral delivery.

Fig. 1

Synthetic scheme of hydrotropic block copolymers by varying molar ratios of VBODENA to AA.

Fig. 2

Acid-base titration curves for blank (methanol:water=1:1) and six hydrotropic polymers (HPs) (a), and the pyrene study monitoring the pH-sensitivity of HP micelles (b). The low value of I₃₃₉/I₃₃₄ represents the micelle destabilization. (n = 3).

Fig. 3

PTX loading content (a) and loading efficiency (b) as a function of pH. The PTX loading content (%, w/w) was calculated by [PTX weight/ (PTX + polymer) weight)] × 100. The PTX loading efficiency (%, w/w) was determined by [(measured PTX weight)/(initially fed PTX weight)] × 100. (n=3 for both experiments).

Fig. 4

Optical transmittance at 500 nm as a function of pH. The optical transmittance was changed by adding 1 N NaOH solution into each HP micelle dispersion (10 mM phosphate buffer, pH 1.0, μ = 154 mM). Left insert shows the HP micelles in the acidic buffer (pH 1.0) and right insert presents their optical transparency at pH 8.0.

Fig. 5

Cumulative amount of the released PTX as a function of time in SIF (a) and in SGF (b). (n = 3). The amounts of PTX release in SGF (0-1 h) and in SIF (1-2 h) are compared to determine the difference of release rate in both solutions (c). The asterisk indicates that there exists statistical significance (one-way ANOVA P < 0.05, c)

Fig. 6

Cumulative amount of released PTX as a function of time in 0.8 M sodium salicylate aqueous solution at pH 6.5 (a) and in 10 mM MES buffer containing 1 % (v/v) Tween 80 at pH 6 and ionic strength of 154 mM (b). (n=3 for a, and n=4 for b).