Other Drug Treatments

In a study by Vaughn et al. the bioavailability of danazol, a drug used in the treatment of endometriosis, was found to be enhanced in correspondence with in vitro supersaturation from solid dispersion nanoparticles (67). Specifically, high potency, high surface area particles of amorphous danazol dispersions in PVP K15 were prepared by two novel nanoparticle production methods known as evaporative precipitation into aqueous solution (EPAS) (68) and spray freezing into liquid (SFL) (4). The danazol nanoparticles produced by SFL were determined to be completely amorphous with a primary particle size of 30 nm, whereas the EPAS nanoparticles were found to be partially crystalline with a primary particle size of 500 nm. Dissolution testing revealed that the SFL particles produced 33% supersaturation relative to the physical mixture at peak concentration and remained supersaturated for 90 min. The EPAS particles exhibited 27%

Table 6 Pharmacokinetic Parameters of CyA after Oral Administration of CyA Solid Dispersion and Sandimmun Neoral® to Wistar Rats

Pharmacokinetic parameter CyA solid dispersion Sandimmun Neoral®

1.71 - 0.67 41021.10 - 6239.87 1.54 - 0.44 0.085 - 0.020 21.84 - 6.78 17.97 -1.29

supersaturation relative to the physical mixture at peak concentration and remained above saturation for 60 min. The reason for the discrepancy in the level and duration of supersaturation between the SFL and EPAS particles was explained by the differences in the drug morphology. As the EPAS formulation was partially crystalline, there is not only less amorphous drug content to drive supersaturation, but also the crystalline particles would act as nucleation sites to promote precipitation of danazol from supersaturated solution. These particle compositions along with the physical mixture and a commercial danazol formulation were evaluated in vivo using mice. The two nanoparticle formulations exhibited greater Cmax values than the physical mixture and the commercial dosage form with the EPAS formulation having a slightly greater Cmax than the SFL formulation. The SFL particles showed substantially greater AUC than the other formulations with the EPAS formulation showing similar AUC to the commercial product followed by the physical mixture. A plot of the danazol serum concentrations versus time for each formulation is shown in Figure 11. These results demonstrated the direct correlation between the extent of supersaturation of danazol in vitro and in vivo drug absorption. Therefore, by formulating danazol in a highly soluble form such as amorphous nanoparticles, the oral bioavailability and thus therapeutic efficacy can be substantially improved.

Solid dispersion systems have been demonstrated to improve the oral absorption of several other drugs used to treat a variety of conditions. Due to the similarity of the solid dispersion technologies used to produce the delivery systems for these drugs to those already described, the studies will be only briefly discussed. Yakou et al. produced solid dispersions of phenytoin, an anticonvulsant drug, in PEG 4000 by a fusion method (69). Phenytoin was determined to be amorphous in the dispersions and the in vitro dissolution rate i= 500 -,

1 300-

o 250 " " 200 -g 150 -| 1008 50 -

10 15

Figure 11 Oral bioavailability of Danazol in a mouse model for the SFL composition (Danazol:PVP-K15 1:1) (■), EPAS composition (Danazol:PVP-K15 1:1) (♦), physical mixture (Danazol:PVP-K15 1:1) (*), and commercially available Danazol (s).

10 15

Figure 11 Oral bioavailability of Danazol in a mouse model for the SFL composition (Danazol:PVP-K15 1:1) (■), EPAS composition (Danazol:PVP-K15 1:1) (♦), physical mixture (Danazol:PVP-K15 1:1) (*), and commercially available Danazol (s).

was substantially improved over the crystalline drug powder and the physical mixture. Bioavailability assessment of the solid dispersion formulation was conducted in human volunteers along with phenytoin crystals and a physical mixture. The mean AUC and peak plasma concentration of the solid dispersion formulation were both found to be greater than the physical mixture and crystalline drug. Thus, from this study it was determined that a solid dispersion system offers clinical advantages of rapid drug release and excellent bioavailability that may provide improved efficacy of oral phenytoin.

Doherty et al. produced amorphous solid dispersions of a poorly water soluble diuretic drug, frusemide by solvent evaporation with PVP (70). The amorphous solid dispersion formulation showed marked dissolution improvement over crystalline frusemide in a variety of media. This in vitro dissolution performance correlated well to the in vivo performance ofthe solid dispersion formulation as a significant reduction in the time to maximum effect was found relative to the crystalline drug in human subjects. Thus, the solid dispersion formulation was found to enhance the therapeutic effect of frusemide by decreasing the time to onset of action.

Glibenclamide (Glyburide) is a hypoglycemic agent used in the treatment of diabetes mellitus. As glibenclamide is only slightly soluble in water, its dissolution characteristics limit oral absorption and lead to high variability. Tashtoush et al. examined solid dispersion formulations with Gelucire 44/14 and PEG 6000 produced by the fusion method for enhancing dissolution rate and bioavailability of glibenclamide (71). The results of these studies revealed more rapid and extensive in vitro drug release from the solid dispersion formulations than the commercial product Daonil® with the PEG formulation performing slightly better than the formulation with Gelucire. In vivo testing in human volunteers revealed that the greatest bioavailability was achieved with the solid dispersion formulation with PEG (AUC0_œ= 1035.7 ng-hr/mL) followed by the Gelucire (AUC0_œ= 680.8 ng-hr/mL) and Daonil (AUC0_œ= 432.1 ng-hr/mL). Therefore, it was demonstrated that the oral bioavailability and hence efficacy of glibenclamide can be substantially improved by formulation as a solid dispersion in a hydrophilic carrier.

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