Solubility and bioavailability improvement of pazopanib hydrochloride

• Published in: International journal of pharmaceutics Vol. 544; no. 1; pp. 181 - 190
• Main Authors: Herbrink, Maikel, Groenland, Stefanie L., Huitema, Alwin D.R., Schellens, Jan H.M., Beijnen, Jos H., Steeghs, Neeltje, Nuijen, Bastiaan
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 10.06.2018
• Subjects: Bioavailability; Formulation; Pazopanib; Pharmaceutics; Solubility; Pharmaceutics; Bioavailability; Formulation; Pazopanib; Solubility
• ISSN: 0378-5173; 1873-3476; 1873-3476
• DOI: 10.1016/j.ijpharm.2018.04.037

[Display omitted] The anti-cancer drug pazopanib hydrochloride (PZH) has a very low aqueous solubility and a variable oral bioavailability. A new pharmaceutical formulation with an improved solubility may enhance the bioavailability and reduce the variability. A broad selection of polymer excipients was tested for their compatibility and solubilizing properties by conventional microscopic, thermal and spectrometric techniques. A wet milling and mixing technique was used to produce homogenous powder mixtures. The dissolution properties of the formulation were tested by a pH-switch dissolution model. The final formulation was tested in vivo in cancer patient following a dose escalation design. Of the tested mixture formulations, the one containing the co-block polymer Soluplus® in a 8:1 ratio with PZH performed best in terms of in vitro dissolution properties. The in vivo results indicated that 300 mg of the developed formulation yields similar exposure and a lower variability (379 μg/mL∗h (36.7% CV)) than previously reported values for the standard PZH formulation (Votrient®) at the approved dose of 800 mg. Furthermore, the expected plasma-Cthrough levels (27.2 μg/mL) exceeds the defined therapeutic efficacy threshold of 20 μg/mL.