A novel cyclodextrin-containing glass thermoplastic system (GTS) for formulating poorly water soluble drug candidates: Preclinical and clinical results

We present a novel solid solution/dispersion technology with glass thermoplastic properties that provide good dissolution rates and oral bioavailabilities for poorly water-soluble weak bases. In this process, a thermoplastic gum was prepared by mixing a polyhydroxy acid such as citric acid or tartaric acid with a weakly basic drug, hydroxypropyl-beta-cyclodextrin (HP-beta-CD) and a cellulose polymer such as hydroxypropylmethylcellulose (HPMC) in a protic solvent. Removal of the solvent gave a material which could be loaded into hard gelatin capsules. Several model compounds were processed in this manner including methylene blue and itraconazole. The resulting data indicated that dissolution properties of GTS's based on methylene blue was pH independent and rapid with similar to80% dissolved within 30 min. Three GTS formulations of itraconazole containing 100 mg of the drug and 500 mg of citric acid as well as various concentrations of HP-beta-CD and HMPC were found to dissolve rapidly (similar to100% in 45 min). One of these formulations was selected for human pharmacokinetic evaluation and demonstrated significant oral bioavailability relative to unmanipulated drug. The studies suggest that the components of the GTS provide for solubilization through complexation and reduced pH and that the cellulose polymer acts to inhibit recrystallization of the supersaturated solution formed. The rational development of the GTS dosage form can be useful for generating acceptable formulations for poorly water-soluble drug candidates.