Artificial pulmonary surfactant as a carrier for intratracheally instilled insulin.
OBJECTIVE
The relative bioavailabilities and effects on lung injury alleviation of 4 insulin- artificial pulmonary surfactant (INS-APS) preparations were studied in normal rats. The relationship between the minimal surface tension (Gamma(min )) of INS-APS and the absorption of insulin was also investigated.


METHODS
Four formulations of APS [1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC)/lecithin/palmitic acid (PA), DPPC/1-hexadecanol (Hex)/tyloxapol (Tyl), DPPC/L-alpha-phosphatidyl-DL-glycerol sodium salt (PG), DPPC/Tyl] were prepared by thin-film sonication method and direct sonication. The Gamma(min ) of 4 APS dispersions was examined with and without INS by pulsating with a bubble surface tensiometer. In vivo experiments were performed in which serum glucose change and the insulin level were measured by an enzymatic glucose reagent kit and a radioimmunology assay kit after IT to rats. The reduction in lung injury by INS-APS following 7 d of consecutive administration was evaluated by the pulmonary edema index (the weight ratio of wet lung to dry lung) and histopathology examination.


RESULTS
The Gamma(min ) of all APS dispersions were below 10 mN/m. There was no significant difference (P> 0.05) between the Gamma(min ) of APS and the corresponding INS-APS. In vivo experiments showed a significant glucose level decrease and insulin absorption increase (P< 0.05) in the presence of APS, compared to the insulin solution alone. From the results, we found that the pulmonary edema index values of all the INSAPS groups were significant lower (P< 0.05) than that of the insulin solution group, and there were no significant differences (P> 0.05) between INS/DPPC/Tyl, INS/ DPPC/PG, and the control group. The pulmonary edema indices and histopathological observation indicated that INS-APS could alleviate lung injury.


CONCLUSIONS
The most potent hypoglycemic effect and insulin absorption increase in this study were obtained with INS/DPPC/Tyl. According to the results, there was a linear correlation between the Gamma(min ) and relative bioavailability of INS-APS, suggesting a possible effect of the Gamma(min ) of carriers on the in vivo absorption of insulin. APS, DPPC/Tyl, and DPPC/PG dispersions might be the most efficient insulin pulmonary delivery carriers in achieving a lower Gamma(min ), enhancing insulin absorption, and decreasing lung injury.
Ji
Ying
Y
Department of Pharmaceutics, School of Pharmacy, Fudan University, Shanghai 200032, China.
Liu
Chen
C
Pei
Yuan-Ying
YY
D000818:Animals; D019540:Area Under Curve; D001786:Blood Glucose / Q000378:metabolism; D004337:Drug Carriers / Q000737:chemistry / Q000378:metabolism*; D007328:Insulin / Q000008:administration & dosage* / Q000378:metabolism* / Q000494:pharmacology / Q000627:therapeutic use; D008168:Lung / Q000166:cytology / Q000187:drug effects / Q000473:pathology; D010316:Particle Size; D011654:Pulmonary Edema / Q000188:drug therapy; D011663:Pulmonary Surfactants / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology / Q000627:therapeutic use; D051381:Rats; D017208:Rats, Wistar
D001786:Blood Glucose; D004337:Drug Carriers; D007328:Insulin; D011663:Pulmonary Surfactants