Drug Delivery Technology

B IOAVAILABILITY
ENHANCEMENT

improved bioavailability of other currently marketed solid dispersions as well. Six et al investigated the ability to produce solid dispersions of itraconazole and several hydrophilic excipients using hot-melt extrusion, characterizing compositions for in vitro dissolution behavior and in vivo pharmacokinetic performance in healthy male volunteers. ¹¹Dissolution testing was conducted under non-sink conditions (equilibrium solubility of itraconazole = 4 to 12 µg/ml) by placing 100-mg itraconazole capsules in 500 ml of simulated gastric fluid without pepsin and conducting testing at 100 rpm. All compositions provided substantial levels of supersaturation; however, the commercial formulation exhibited the slowest dissolution rate (Figure 2).

Drug Delivery Technology October 2008 Vol 8 No 8

Surprisingly, pharmacokinetic data generated in human trials showed that HPMC-based compositions provided the greatest AUCs compared to formulations of Eudragit E 100-PVPVA and Eudragit E 100; however, substantial inter-subject variability was observed in all groups. Additionally, similar C_maxand T_maxvalues were observed in vivo, which contradicts what one would anticipate from the in vitro data. The in vivo performance of itraconazole formulations were most likely strongly affected by the solubility properties of itraconazole, which exhibits orders of magnitude lower solubility in more neutral conditions similar to those observed in the upper small intestine, making it an interesting model drug for other advanced solid dispersion technologies, such as site-specific supersaturation and stabilized supersaturation using concentration-enhancing polymers.

SITE-TARGETED
SUPERSATURATION USING
MODIFIED-RELEASE POLYMERS

While the enhancement in dissolution rate can provide improved oral bioavailability by achieving the equilibrium solubility faster or providing higher metastable equilibrium

In vitro supersaturation dissolution profiles and in vivo data for itraconazole solid dispersions. Reprinted with permission from reference 13.

solubility values, these formulations may not provide the greatest improvement in bioavailability. Weakly basic drugs may be ionized at gastric pH where hydrophilic compositions will dissolve and release the drug. Upon transition to the upper small intestine, the pH rises, and the drug may become partially or completely unionized, resulting in a rapid precipitation of dissolved drug. Furthermore, most drugs are primarily absorbed in the upper small intestine, where the substantial surface area provided by the villi and microvilli facilitate transport across the membrane. Compositions that supersaturate the gastric environment for short durations may also be subject to partial or complete precipitation, achieving only equilibrium solubility prior to entering the upper small intestine and negating the tremendous advantages provided by solid

dispersions. In these cases, it would be prudent to target supersaturation to the upper small intestine, which is commonly achieved by using pH-responsive carriers. These carrier materials are insoluble at gastric pH; however, upon entering the upper small intestine, the pH change will trigger ionization of the carboxylic acid functional groups on the polymer chain, resulting in dissolution. As with the hydrophilic solid dispersions, correct formulation and processing can produce compositions whose dissolution rate is governed by that of the polymeric material, resulting in significantly improved dissolution rates, supersaturation, and enhanced bioavailability.

Although a less commonly reported technique for the production of solid dispersions, the use of enteric carriers has been reported to improve bioavailability for at