title: Microenvironmental pH-modified solid dispersions to enhance the dissolution and bioavailability of poorly water-soluble weakly basic GT0918, a developing anti-prostate cancer drug: preparation, characterization and evaluation in vivo.
abstract: The aim of the present work was to design a pH-modified solid dispersion (pH(M)-SD) that can improve the dissolution and bioavailability of poorly water-soluble weakly basic GT0918, a developing anti-prostate cancer drug. To select the appropriate acidifiers, a solubility test was carried out first. Solid dispersions (SDs) containing GT0918 and polyvinylpyrrolidone (PVP) were prepared using a solvent evaporation method and were characterized using dissolution studies in different media. The solid states of the SDs were investigated using scanning electron microscopy (SEM), powder X-ray diffraction (PXRD), differential scanning calorimetry (DSC) and Fourier transformed infrared spectroscopy (FTIR). The in vivo pharmacokinetics of the pH(M)-SDs tablets were also studied in beagle dogs compared to the conventional tablets. The optimized pH(M)-SD (GT0918/PVP/citric acid, 1:2:2 weight ratio) exhibited a significant improvement in the dissolution behavior compared to both the physical mixture and the binary SDs. Solid-state characterization revealed that the amorphous formation of GT0918 in the SDs and the strong H-bonding were only found in the pH(M)-SDs containing citric acid. Furthermore, the GT0918-loaded pH(M)-SD tablets showed a higher AUC and a lower tmax compared to the conventional tablets. Accordingly, the pH(M)-SD might be an efficient route for enhancing the dissolution and bioavailability of poorly water-soluble GT0918.
authors.affiliation: Department of Pharmaceutics, Beijing Institute of Pharmacology and Toxicology, No. 27 Taiping Road, Beijing 100850, PR China.
authors.forename: Meiyan
authors.initials: M
authors.lastname: Yang
authors.affiliation: Department of Pharmaceutics, Beijing Institute of Pharmacology and Toxicology, No. 27 Taiping Road, Beijing 100850, PR China; School of Pharmacy, Central South University, Changsha 410013, PR China.
authors.forename: Shaolong
authors.initials: S
authors.lastname: He
authors.affiliation: School of Pharmaceutical Sciences, Peking University, Beijing 100191, PR China.
authors.forename: Yunzhou
authors.initials: Y
authors.lastname: Fan
authors.affiliation: Department of Pharmaceutics, Beijing Institute of Pharmacology and Toxicology, No. 27 Taiping Road, Beijing 100850, PR China.
authors.forename: Yuli
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Pharmaceutical College, Henan University, Kaifeng 475004, PR China.
authors.forename: Zhenzhong
authors.initials: Z
authors.lastname: Ge
authors.affiliation: Department of Pharmaceutics, Beijing Institute of Pharmacology and Toxicology, No. 27 Taiping Road, Beijing 100850, PR China.
authors.forename: Li
authors.initials: L
authors.lastname: Shan
authors.affiliation: Department of Pharmaceutics, Beijing Institute of Pharmacology and Toxicology, No. 27 Taiping Road, Beijing 100850, PR China.
authors.forename: Wei
authors.initials: W
authors.lastname: Gong
authors.affiliation: Department of Pharmaceutics, Beijing Institute of Pharmacology and Toxicology, No. 27 Taiping Road, Beijing 100850, PR China; School of Pharmacy, Central South University, Changsha 410013, PR China.
authors.forename: Xiaoli
authors.initials: X
authors.lastname: Huang
authors.affiliation: Suzhou Kintor Pharmaceutics Inc., Suzhou 215123, PR China.
authors.forename: Youzhi
authors.initials: Y
authors.lastname: Tong
authors.affiliation: Department of Pharmaceutics, Beijing Institute of Pharmacology and Toxicology, No. 27 Taiping Road, Beijing 100850, PR China. Electronic address: gaocs@bmi.ac.cn.
authors.forename: Chunsheng
authors.initials: C
authors.lastname: Gao
mesh_terms: D000818:Animals; D017849:Animals, Inbred Strains; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000032:analysis / Q000097:blood / Q000493:pharmacokinetics*; D001682:Biological Availability; D002934:Cinnamates / Q000737:chemistry; D019343:Citric Acid / Q000737:chemistry; D004285:Dogs; D004339:Drug Compounding; D015507:Drugs, Investigational / Q000008:administration & dosage / Q000032:analysis / Q000493:pharmacokinetics*; D005079:Excipients / Q000737:chemistry*; D005650:Fumarates / Q000737:chemistry; D006863:Hydrogen-Ion Concentration; D007093:Imidazoles / Q000008:administration & dosage / Q000032:analysis / Q000097:blood / Q000493:pharmacokinetics*; D008297:Male; D009570:Nitriles / Q000008:administration & dosage / Q000032:analysis / Q000097:blood / Q000493:pharmacokinetics*; D010080:Oxazoles / Q000008:administration & dosage / Q000032:analysis / Q000097:blood / Q000493:pharmacokinetics*; D011205:Povidone / Q000737:chemistry; D011471:Prostatic Neoplasms / Q000188:drug therapy; D011897:Random Allocation; D012995:Solubility; D019802:Succinic Acid / Q000737:chemistry; D013535:Suspensions; D013607:Tablets; D013867:Thiohydantoins / Q000008:administration & dosage / Q000032:analysis / Q000097:blood / Q000493:pharmacokinetics*
chemical_list: D000970:Antineoplastic Agents; D002934:Cinnamates; D015507:Drugs, Investigational; D005079:Excipients; D005650:Fumarates; D007093:Imidazoles; D009570:Nitriles; D010080:Oxazoles; D013535:Suspensions; D013607:Tablets; D013867:Thiohydantoins; C029010:cinnamic acid; D019343:Citric Acid; C032005:fumaric acid; D019802:Succinic Acid; D011205:Povidone; C000599887:proxalutamide
keywords: Acidifier; Bioavailability; Microenvironmental pH; Poorly water-soluble drug; Solid dispersion