Development of an oral dosage form of capecitabine with modified release characteristics

Abstract

Capecitabine is an orally-administered chemotherapeutic agent used in the treatment of a.o. metastatic breast, gastric and colorectal cancer and is commercially available as an immediate release tablet (Xeloda®, Roche). Capecitabine is a pre-pro-drug that is enzymatically converted into 5-fluorouracil (5-FU) in the liver and the tumor. In tumor it inhibits DNA synthesis and slows tumor growth. To form 5-FU, the activation of capecitabine follows a three-step enzymatic pathway with two intermediary metabolites, 5'-deoxy-5-fluorocytidine (DFCR) and 5'-deoxy-5-fuorouridine (DFUR). The metabolism of capecitabine to 5-FU is fast (Cmax in 90 minutes) and follows the pharmacokinetic profile of capecitabine. Subsequently, 5-FU is cleared rapidly and is undetectable in plasma after approximately six hours. Therefore, it is argued that the approved twice daily dosing (morning-evening) schedule of Xeloda® results in an in-between dosing capecitabine-exposure gap of approximately six hours. Clinical studies have shown that, as a consequence of the prolonged exposure and reduction of the 5-FU peak plasma concentration, a continuous infusion instead of a bolus injection of 5-FU increases the anti-cancer response rate and decreases toxicity in terms of a reduced recurrence and grade of some adverse events. The translation of this concept to an oral dosing scheme requires the development of an extended release oral dosage form. In this thesis, steps towards an extended release oral dosage form of capecitabine are described. The extended release dosageform was developed making use of spray dried amorphous capecitabine. Spray dried amorphous capecitabine shows an unexpected and slower dissolution behaviour than its crystalline form. Due to the intrinsic slow dissolution behaviour of the amorphous capecitabine only minor percentages of additional extended release excipients were needed to obtain reasonable and highly reproducible slow release. Stability profiling proofed the amorphous capecitabine to be chemically and physically stable. In addition Thermodynamic analysis capecitabine and doxifluridine revealed that the carbamate carbon chain of capecitabine is responsible for its non-crystalizing behaviour compared to the rapid crystalizing of its structure analogue doxifluridine. The developed extended release formulation making use of amorphous capecitabine and the release-modifier Kollidon® SR is currently tested in a clinical proof-of-concept study.