Development and clinical application of oral dosage forms of taxanes

Abstract

Cancer is still one of the leading causes of death in the Western World. Despite the development and introduction of new anti-cancer agents, docetaxel and paclitaxel remain the cornerstone of adjuvant and metastatic chemotherapy against solid tumors. Taxanes belong to the class of anti-mitotic agents and block the disassembly of microtubules, thereby inhibiting vital mitotic functions and cell proliferation. Because of their mechanism of action continuous exposure to docetaxel and paclitaxel could improve their effectiveness against cancer. However, continuous exposure using the current registered IV formulations is costly and inconvenient for patients. The oral administration route is preferred because of its ease of use, lower costs and the possibility to administer oral dosage forms on an outpatient basis or at home. Unfortunately, docetaxel’s and paclitaxel’s oral bioavailability is very limited due to their very low solubility and very low permeability. We were able to overcome the low permeability of docetaxel and paclitaxel by concomitant administration of the IV premix solutions and the pharmacokinetic (PK) booster ritonavir, a strong CYP3A4 inhibitor. However, further development of oral docetaxel and paclitaxel chemotherapy was hampered by the lack of a stable, easy to use, patient convenient oral formulation. Although a typical solid oral dosage form could fulfill these demands, the very low solubilities of both docetaxel and paclitaxel posed major pharmaceutical development challenges. In this thesis we describe the pharmaceutical development, stability and initial clinical testing of freeze-dried solid dispersion of docetaxel and paclitaxel with the polymeric carrier polyvinylpyrrolidone K30 (PVP-K30) and the surfactant sodium lauryl sulfate (SLS). Various polymers, surfactants, and weight ratios were evaluated to optimize the solid dispersion formulations. Hanssen solubility parameters, X-ray powder diffraction (XRD), modulated differential scanning caolorimetry (MDSC), Fourier transform infrared spectroscopy (FT-IR) were used to characterize the solid dispersion formulation. The encapsulated freeze-dried solid dispersion formulations of docetaxel (ModraDoc001) and paclitaxel (ModraPac001) were compared to the orally administered IV premix solutions in phase I clinical studies and showed clinically relevant exposures in combination with ritonavir. We subsequently improved the formulation of docetaxel using spray-drying as manufacturing method and by combining docetaxel and ritonavir in a fixed dose combination (FDC) tablet. We showed that in-vitro release rates of docetaxel and ritonavir from single agent tablets and FDC tablets were comparable and depended on the release of PVP-K30. In a phase I cross over study we found that the single agent formulations of docetaxel, the ModraDoc003 10 mg tablet and the ModraDoc001 10 mg capsule, gave a comparable exposure to docetaxel after oral administration in combination with ritonavir. Furthermore, we showed that the FDC tablet of docetaxel and ritonavir, the ModraDoc004 10/50 mg tablet, gave exposures to docetaxel and ritonavir comparable to single agent formulations. In addition to this, a tendency towards a higher and less variable docetaxel/ritonavir exposure ratio found for the FDC tablet, this was hypothesized to be the result of a simultaneous release of docetaxel and ritonavir in the gastrointestinal tract. In conclusion we developed oral solid dispersion formulations of docetaxel, paclitaxel, and docetaxel/ritonavir using freeze-drying and spray drying as preparation methods. Analysis of the solid dispersion formulations by XRD, mDSC, FT-IR, and dissolution testing showed a good stability profile which could be further improved by limiting the absorption of water. The solid dispersion formulations increased the solubilities and dissolution rates of the active ingredients which resulted in clinically relevant exposures to docetaxel and paclitaxel. In general, the capsules were well tolerated and were considered easy to use. Moreover, based on our studies it can be concluded that we developed clinically feasible oral formulations of paclitaxel, docetaxel and docetaxel/ritonavir which made way for development of oral chronic anti-cancer treatment with taxanes.