title: Improving Oral Bioavailability of Sorafenib by Optimizing the "Spring" and "Parachute" Based on Molecular Interaction Mechanisms.
abstract: Sorafenib is a clinically important oral tyrosine kinase inhibitor for the treatment of various cancers. However, the oral bioavailability of sorafenib tablet (Nexavar) is merely 38-49% relative to the oral solution, due to the low aqueous solubility of sorafenib and its relatively high daily dose. It is desirable to improve the oral bioavailability of sorafenib to expand the therapeutic window, reduce the drug resistance, and enhance patient compliance. In this study, we observed that the solubility of sorafenib could be increased ∼50-fold in the coexistence of poly(vinylpyrrolidone-vinyl acetate) (PVP-VA) and sodium lauryl sulfate (SLS), due to the formation of PVP-VA/SLS complexes at a lower critical aggregation concentration. The enhanced solubility provided a faster initial sorafenib dissolution rate, analogous to a forceful "spring" to release drug into solution, from tablets containing both PVP-VA and SLS. However, SLS appears to impair the ability of PVP-VA to act as an efficient "parachute" to keep the drug in solution and maintain drug supersaturation. Using 2D (1)H NMR, (13)C NMR, and FT-IR analysis, we concluded that the solubility enhancement and supersaturation of sorafenib were achieved by PVP-VA/SLS complexes and PVP-VA/sorafenib interaction, respectively, both through molecular interactions hinged on the PVP-VA VA groups. Therefore, a balance between "spring" and "parachute" must be carefully considered in formulation design. To confirm the in vivo relevance of these molecular interaction mechanisms, we prepared three tablet formulations containing PVP-VA alone, SLS alone, and PVP-VA/SLS in combination. The USP II in vitro dissolution and dog pharmacokinetic in vivo evaluation showed clear differentiation between these three formulations, and also good in vitro-in vivo correlation. The formulation containing PVP-VA alone demonstrated the best bioavailability with 1.85-fold and 1.79-fold increases in Cmax and AUC, respectively, compared with the formulation containing SLS only, the poorest performing one. Despite its forceful "spring", the formulation containing both PVP-VA and SLS showed a moderate bioavailability enhancement, due to the lack of an efficient "parachute".
authors.affiliation: School of Pharmaceutical Sciences and Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Tsinghua University , Beijing 100084, China.
authors.forename: Chengyu
authors.initials: C
authors.lastname: Liu
authors.affiliation: School of Pharmaceutical Sciences and Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Tsinghua University , Beijing 100084, China.
authors.forename: Zhen
authors.initials: Z
authors.lastname: Chen
authors.affiliation: School of Pharmaceutical Sciences and Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Tsinghua University , Beijing 100084, China.
authors.forename: Yuejie
authors.initials: Y
authors.lastname: Chen
authors.affiliation: College of Pharmaceutical Sciences, Soochow University , Suzhou 215006, China.
authors.forename: Jia
authors.initials: J
authors.lastname: Lu
authors.affiliation: College of Pharmaceutical Sciences, Soochow University , Suzhou 215006, China.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Li
authors.affiliation: School of Pharmaceutical Sciences and Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Tsinghua University , Beijing 100084, China.
authors.forename: Shujing
authors.initials: S
authors.lastname: Wang
authors.affiliation: School of Pharmaceutical Sciences and Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Tsinghua University , Beijing 100084, China.
authors.forename: Guoliang
authors.initials: G
authors.lastname: Wu
authors.affiliation: School of Pharmaceutical Sciences and Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Tsinghua University , Beijing 100084, China.
authors.forename: Feng
authors.initials: F
authors.lastname: Qian
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics; D001682:Biological Availability; D002626:Chemistry, Pharmaceutical; D004285:Dogs; D008297:Male; D009536:Niacinamide / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D010671:Phenylurea Compounds / Q000008:administration & dosage* / Q000493:pharmacokinetics; D011108:Polymers / Q000737:chemistry*; D012995:Solubility; D000077157:Sorafenib; D017550:Spectroscopy, Fourier Transform Infrared; D013607:Tablets / Q000737:chemistry*; D014018:Tissue Distribution
chemical_list: D000970:Antineoplastic Agents; D010671:Phenylurea Compounds; D011108:Polymers; D013607:Tablets; D009536:Niacinamide; D000077157:Sorafenib
keywords: bioavailability; molecular interaction; polymer−surfactant complex; poorly water-soluble drugs; sorafenib