Drug Delivery Technology

B IOAVAILABILITY
ENHANCEMENT

FIGURE 5

In vitro supersaturation dissolution profiles and in vivo plasma profiles for paclitaxel formulations developed by Gao et al. Reprinted with permission from reference 15.

least 20 years. In the development of HO-221, a novel anticancer agent, Kondo et al reported the use of micronization technology to enhance the oral bioavailability of the drug in mice, dogs, and monkeys. ¹²Their results showed that the production of submicron particles provided modest improvement in bioavailability (~20% BA), although still incomplete. Additionally, a substantial food effect was observed indicating a potential partial solubilization due to bile salts. This group further investigated the use of solid dispersions of hydrophilic and enteric polymers produced by a coprecipitation process for enhanced oral bioavailability (Figure 3). Using hydroxypropylmethylcellulose phthalate (HP- 55), in vitro supersaturated dissolution testing conducted at pH 6. 5 and with a modified pH-change method showed significant levels of supersaturation. Compositions produced using hydrophilic excipients also achieved substantial levels of supersaturation; however, these systems exhibited precipitation after 60 minutes, which reduced levels of drug in solution during the later stages of testing. In vivo studies in beagle dogs revealed a substantial improvement in bioavailability of the solid dispersions compared to micronized drug, with hydrophilic compositions providing approximately 60% bioavailability and enteric compositions providing nearly complete

bioavailability. The researchers hypothesized that the improvement in oral bioavailability of the enteric compositions was due to the site-targeting of drug release to the upper small intestine, where the drug had been previously shown to be primarily absorbed.

Using a similar approach, Miller and co-workers formulated solid dispersions of itraconazole with Eudragit L100-55 and Carbopol 974P, a mucoadhesive agent. ¹³Because itraconazole is a weakly basic agent having a pKa of 3. 7, it is ionized at acidic pH but exhibits a rapid decrease in apparent solubility at pH values representative of the upper small intestine. By formulating compositions capable of site-specific supersaturation with high-viscosity stabilizers, it was hypothesized that in vivo bioavailability could be improved over traditional hydrophilic solid dispersions of itraconazole. Analytical characterization showed that the amorphous enteric compositions were capable of supersaturation; however, the maximum concentration achieved in vitro decreased with increasing levels of Carbopol (Figure 4). This was attributed to the high viscosity of the polymer, acting to slow the dissolution rate upon pH change. Incorporation of Carbopol 974P at a 20% polymer loading also exhibited the longest duration of in vitro supersaturation via a combination of hydrogen-bonding interactions and high-viscosity stabilization.

In vivo testing in Sprague-Dawley rats demonstrated that the composition containing 20% Carbopol 974P also provided the greatest AUC, suggesting that the maximum concentration achieved was secondary to the ability to maintain supersaturation for physiologically relevant time scales. Furthermore, the high variability of the itraconazole:L100-55 composition observed in vivo was attributed to the inability to stabilize supersaturation, highlighting the importance of maintaining supersaturation for enhanced performance.

CONCENTRATION-ENHANCING
POLYMERS FOR PROLONGED
DURATIONS OF
SUPERSATURATION

The importance of maintaining levels of supersaturation has been clearly illustrated in the previous examples in which decreasing levels of solubilized drug can result in incomplete and highly variable bioavailability. By developing formulations with materials capable of inhibiting precipitation from supersaturation, termed concentration enhancing polymers, it is possible to improve the bioavailability of poorly water-soluble compounds. Concentration-enhancing polymers provide increased levels of drug in solution in excess of the normal equilibrium solubility through either physical, chemical, or a combination thereof of interactions with drug molecules that inhibits precipitation. ¹⁴Using these materials, several formulations have demonstrated substantial improvements in oral bioavailability.

Although not studied for solid dispersions, Gao and co-workers developed supersaturatable self-emulsifying drug delivery systems (s-SEDDS) utilizing concentration-enhancing polymers for the delivery of paclitaxel and an experimental compound PNU-91325.^{15, 16}In these studies, s-SEDDS compositions containing HPMC E5