Jiake He1,2,3, Ge Zhang2, Qiuyang Zhang2, Jiayin Chen2, Yongjie Zhang2, Xiaoxia An2, Pan Wang2, Shan Xie2, Fang Fang2, Jianheng Zheng2, Yue Tang4, Jiabi Zhu4, Yang Yu3, Xijing Chen2, Yang Lu2. 1. Department of Cardiovascular Medicine, The Second Affiliated Hospital of Nanchang University, Nanchang, China. 2. Clinical Pharmacokinetics Laboratory, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, China. 3. Department of Pharmacy, The Second Affiliated Hospital of Nanchang University, Nanchang, China. 4. Department of Pharmaceutics, School of Pharmacy, China Pharmaceutical University, Nanjing, China.
Abstract
OBJECTIVES: The present study was designed to assess the pharmacokinetic and pharmacodynamic performance of inhaled recombinant human insulin (rh-insulin) dry powders together with their safety profiles after 14-day inhalation. METHODS: In the pharmacokinetic and pharmacodynamic study, pulmonary surfactant (PS)-loaded and phospholipid hexadecanol tyloxapol (PHT)-loaded rh-insulin dry powders were intratracheally administered to male rats at the dose of 20 U/kg. Novolin R was used as control. Serum glucose and rh-insulin concentrations were determined by glucose oxidase method and human rh-insulin CLIA kit, respectively. For the safety study, rats were exposed to rh-insulin dry powders or air for 14-day by nose-only inhalation chambers. Bronchoalveolar lavage and histopathology examinations were performed after inhalation. KEY FINDINGS: There were no significant differences in the major pharmacokinetic and pharmacodynamic parameters between PS-loaded and PHT-loaded rh-insulin dry powders. The relative bioavailabilities and pharmacodynamic availabilities were 39.9%, 25.6% for PS-loaded dry powders and 30.1%, 23% for PHT-loaded dry powders, respectively. Total protein was the only injury marker that was significantly altered. Histopathology examinations showed the ranking of irritations (from slight to severe) were PHT-loaded rh-insulin, negative air control and PS-loaded rh-insulin. CONCLUSIONS: Both PS- and PHT-loaded rh-insulin dry powders were able to deliver rh-insulin systemically with appropriate pharmacokinetic, pharmacodynamic and safety profiles.
OBJECTIVES: The present study was designed to assess the pharmacokinetic and pharmacodynamic performance of inhaled recombinant humaninsulin (rh-insulin) dry powders together with their safety profiles after 14-day inhalation. METHODS: In the pharmacokinetic and pharmacodynamic study, pulmonary surfactant (PS)-loaded and phospholipid hexadecanol tyloxapol (PHT)-loaded rh-insulin dry powders were intratracheally administered to male rats at the dose of 20 U/kg. Novolin R was used as control. Serum glucose and rh-insulin concentrations were determined by glucose oxidase method and humanrh-insulin CLIA kit, respectively. For the safety study, rats were exposed to rh-insulin dry powders or air for 14-day by nose-only inhalation chambers. Bronchoalveolar lavage and histopathology examinations were performed after inhalation. KEY FINDINGS: There were no significant differences in the major pharmacokinetic and pharmacodynamic parameters between PS-loaded and PHT-loaded rh-insulin dry powders. The relative bioavailabilities and pharmacodynamic availabilities were 39.9%, 25.6% for PS-loaded dry powders and 30.1%, 23% for PHT-loaded dry powders, respectively. Total protein was the only injury marker that was significantly altered. Histopathology examinations showed the ranking of irritations (from slight to severe) were PHT-loaded rh-insulin, negative air control and PS-loaded rh-insulin. CONCLUSIONS: Both PS- and PHT-loaded rh-insulin dry powders were able to deliver rh-insulin systemically with appropriate pharmacokinetic, pharmacodynamic and safety profiles.