A Novel Dantrolene Sodium-Loaded Mixed Micelle Containing a Small Amount of Cremophor EL: Characterization, Stability, Safety and Pharmacokinetics
Wenzhen Jin,
Xiaochuan Tan,
Jin Wen,
Ya Meng,
Yujia Zhang,
He Li,
Dong Jiang,
Hui Song,
Wensheng Zheng
Affiliations
Wenzhen Jin
State Key Laboratory of Bioactive Substance and Function of Natural Medicines & Beijing Key laboratory of Drug Delivery Technology and Novel Formulation, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China
Xiaochuan Tan
State Key Laboratory of Bioactive Substance and Function of Natural Medicines & Beijing Key laboratory of Drug Delivery Technology and Novel Formulation, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China
Jin Wen
Chinese Pharmaceutical Association, Beijing 100022, China
Ya Meng
State Key Laboratory of Bioactive Substance and Function of Natural Medicines & Beijing Key laboratory of Drug Delivery Technology and Novel Formulation, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China
Yujia Zhang
State Key Laboratory of Bioactive Substance and Function of Natural Medicines & Beijing Key laboratory of Drug Delivery Technology and Novel Formulation, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China
He Li
State Key Laboratory of Bioactive Substance and Function of Natural Medicines & Beijing Key laboratory of Drug Delivery Technology and Novel Formulation, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China
Dong Jiang
State Key Laboratory of Bioactive Substance and Function of Natural Medicines & Beijing Key laboratory of Drug Delivery Technology and Novel Formulation, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China
Hui Song
State Key Laboratory of Bioactive Substance and Function of Natural Medicines & Beijing Key laboratory of Drug Delivery Technology and Novel Formulation, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China
Wensheng Zheng
State Key Laboratory of Bioactive Substance and Function of Natural Medicines & Beijing Key laboratory of Drug Delivery Technology and Novel Formulation, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China
Dantrolene sodium (DS) is the only drug specifically used for the treatment of malignant hyperthermia. Nevertheless, its clinical application is significantly restricted due to its aqueous insolubility and the limited formulations available in clinical practice. In order to solve these problems, a novel mixed micelle composed of phospholipid and Cremophor EL was designed and evaluated. The mixed micelle was prepared using a stirring- ultrasonic method. The Dynamic Light Scattering (DLS) results showed that the micelle was small in size (12.14 nm) and narrowly distributed (PdI = 0.073). Transmission Electron Microscopy (TEM) images showed that the micelle was homogeneous and spherical. The stability study indicated that the system was stable for storage and dilution with distilled water, while the safety testing showed that the micelle was safe for intravenous administration with low hemolysis rates and low allergic reaction rates. In the pharmaceutics study, the Cmax and AUC0-t of the DS-loaded micelle were 4- and 4.5- folds higher than that of the DS. Therefore, the constructed phospholipid-Cremophor EL mixed micelle is a promising drug delivery system for DS.
