title: Improving cabazitaxel chemical stability in parenteral lipid emulsions using cholesterol.
abstract: Intravenous lipid emulsions of cabazitaxel (CLEs) with a high stability were prepared by adding cholesterol (CH) to provide a new and more suitable delivery system for its administration. The factors affecting CLEs, such as the solubility of cabazitaxel in various oils, different kinds of lecithin, pH, different types of oil phases, and different concentrations of lipoid E80®, CH and poloxamer 188 were investigated systematically. The degradation of cabazitaxel in aqueous solution and lipid emulsion both followed pseudo first-order kinetics. A degradation mechanism was suggested by the U-shaped pH-rate profile of cabazitaxel. A formulation containing 0.5% (w/v) CH and another formulation without CH were made to investigate the protective influence of CH on the chemical stability of CLEs. The activation energy of the two formulations was calculated to be 65.74±6.88 and 54.24±1.43 kJ/mol (n=3), respectively. Compared with the untreated CH, the shelf-life of cabazitaxel with added CH was longer, namely 134.0±23.4 days versus 831.4±204.4 days (n=3) at 4 °C. This indicates that the addition of CH significantly improved the lifetime of cabazitaxel in intravenous lipid emulsions. The hydrogen bonding that takes place between cabazitaxel and CH accounts for the protective effect of CH on the chemical stability of CLEs in two ways: preventing cabazitaxel from leaking and hydrolyzing in aqueous solution and hindering hydrolysis in the oil phase. Finally, the hypothesis was confirmed by LC/TOFMS and Fourier-transform infrared-spectroscopy. As a result, CLEs were obtained successfully by the addition of CH and were stable enough to allow further research.
authors.affiliation: School of Pharmacy, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang 110016, China.
authors.forename: Yanjie
authors.initials: Y
authors.lastname: Shao
authors.affiliation: School of Pharmacy, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang 110016, China.
authors.forename: Chungang
authors.initials: C
authors.lastname: Zhang
authors.affiliation: School of Pharmacy, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang 110016, China.
authors.forename: Qing
authors.initials: Q
authors.lastname: Yao
authors.affiliation: School of Pharmacy, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang 110016, China.
authors.forename: Yueqi
authors.initials: Y
authors.lastname: Wang
authors.affiliation: School of Pharmacy, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang 110016, China.
authors.forename: Bin
authors.initials: B
authors.lastname: Tian
authors.affiliation: School of Pharmacy, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang 110016, China.
authors.forename: Xing
authors.initials: X
authors.lastname: Tang
authors.affiliation: School of Pharmacy, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang 110016, China. Electronic address: tangpharma@gmail.com.
authors.forename: Yanjiao
authors.initials: Y
authors.lastname: Wang
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry*; D002784:Cholesterol / Q000737:chemistry; D004355:Drug Stability; D005217:Fat Emulsions, Intravenous / Q000737:chemistry*; D005990:Glycerol / Q000737:chemistry; D006863:Hydrogen-Ion Concentration; D054709:Lecithins / Q000737:chemistry; D010713:Phosphatidylcholines / Q000737:chemistry; D010714:Phosphatidylethanolamines / Q000737:chemistry; D020442:Poloxamer / Q000737:chemistry; D012995:Solubility; D013024:Soybean Oil / Q000737:chemistry; D013109:Sphingomyelins / Q000737:chemistry; D043823:Taxoids / Q000737:chemistry*; D014280:Triglycerides / Q000737:chemistry
chemical_list: D000970:Antineoplastic Agents; D005217:Fat Emulsions, Intravenous; D054709:Lecithins; D010713:Phosphatidylcholines; D010714:Phosphatidylethanolamines; D013109:Sphingomyelins; D043823:Taxoids; D014280:Triglycerides; D020442:Poloxamer; C483858:phosphatidylethanolamine; C552428:cabazitaxel; D013024:Soybean Oil; D002784:Cholesterol; D005990:Glycerol
keywords: Acetonitrile; Alcohol; Cabazitaxel; Chemical stability; Cholesterol; Degradation kinetics; Formulation; Intravenous lipid emulsion; Phosphatidylcholine; Phosphatidylethanolamine; Poloxamer 188; Sphingomyelin; Triglyceride