Abstract
Aim:
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 (γmin) 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-α-phosphatidyl-DL-glycerol sodium salt (PG), DPPC/Tyl] were prepared by thin-film sonication method and direct sonication. The γmin 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 γmin of all APS dispersions were below 10 mN/m. There was no significant difference (P> 0.05) between the γmin 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 INS-APS 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.
Conclusion:
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 γmin and relative bioavailability of INS-APS, suggesting a possible effect of the γmin 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 γmin, enhancing insulin absorption, and decreasing lung injury.
Similar content being viewed by others
Article PDF
References
Agu RU, Ugwoke MI, Armand M, Kinget R, Verbeke N . The lung as a route for systemic delivery of therapeutic proteins and peptides. Respir Res 2001; 2: 198–209.
Merrill JD, Ballard RA . Pulmonary surfactant for neonatal respiratory disorders. Curr Opin Pediatr 2003; 15: 149–54.
Erpenbeck VJ, Hagenberg A, Dulkys Y, Elsner D, Balder R, Krentel H, et al. Natural porcine surfactant augments airway inflammation after allergen challenge in patients with asthma. Am J Respir Crit Care Med 2004; 169: 578–86.
Van't Veen A, Gommers D, Mouton JW, Kluytmans JA, Krijt EJ, Lachmann B . Exogenous pulmonary surfactant as a drug delivering agent: influence of antibiotics on surfactant activity. Br J Pharmacol 1996; 118: 593–8.
Katkin JP, Husser RC, Langston C, Welty SE . Exogenous surfactant enhances the delivery of recombinant adenoviral vectors to the lung. Hum Gene Ther 1997; 8: 171–6.
Jiang ZQ, Sun GM, Ma YM . Artificial reconstituted pulmonary surfactant in prevention and treatment of respiratory distress syndrome in neonates. Acta Pharmacol Sin 1997; 18: 182–4.
Mitra R, Pezron I, Li Y, Mitra AK . Enhanced pulmonary delivery of insulin by lung lavage fluid and phospholipids. Int J Pharm 2001; 217: 25–31.
Enhorning G . Pulsating bubble technique for evaluating pulmonary surfactant. J Appl Physiol 1977; 43: 198–203.
Ji Y, Pei YY . Primary study of artificial pulmonary surfactant as carrier of insulin pulmonary delivery. Chin Pharm J 2006; 41: 766–8.
Paddy JF . Surface tension. Part III. Tables relating the size and shape of liquid drops to the surface tension. In Matijevic E, editor. Surface and colloid science. New York: Wiley-Interscience; 1969. p 151–97.
Pan Y, Li YJ, Zhao HY, Zheng JM, Xu H, Wei G, et al. Bioadhesive polysaccharide in protein delivery system: chitosan nanoparticles improve the intestinal absorption of insulin in vivo. Int J Pharm 2002; 249: 139–47.
Lu J, Ji Y, Jiang ZQ . Study on the bioavailability and initial investigation on the rat following pulmonary delivery of insulin lipid suspension. Chin J Biochem Pharm 2002; 23: 271–4.
Zhang Q, Shen ZC, Tsuneji N . Prolonged hypoglycemic effect of insulin-loaded polybutylcyanoacrylate nanoparticles after pulmonary administration to normal rats. Int J Pharm 2001; 218: 75–80.
Kharasch VS, Sweeney TD, Fredberg J, Lehr J, Damokosh AI, Avery ME, et al. Pulmonary surfactant as a vehicle for intratracheal delivery of technetium sulfur colloid and pentamidine in hamster lungs. Am Rev Respir Dis 1991; 144: 909–13.
Enhorning G . Pulmonary surfactant function studied with the pulsating bubble surfactometer (PBS) and the capillary surfactometer (CS). Comp Biochem Physiol A Mol Integr Physiol 2001; 129: 221–6.
Tanaka Y, Takei T, Aiba T, Masuda K, Kiuchi A, Fujiwara T . Development of synthetic lung surfactants. J Lipid Res 1986; 27: 475–85.
Latallo JFK, Chen CL, Eichman J, Bielinska AU, Baker JR . Enhancement of endrimer–mediated transfection using synthetic lung surfactant exosurf neonatal in vitro. Biochem Biophys Res Commun 1999; 264: 253–61.
Lewis JF, Brackenbury A . Role of exogenous surfactant in acute lung damage. Crit Care Med 2003; 31: S324–8.
Palmblad M, Gustafsson M, Curstedt T, Johansson J, Schurch S . Surface activity and film formation from the surface associated material of artificial surfactant preparations. Biochim Biophys Acta 2001; 1510: 106–17.
Park SY, Hannemann RE, Franses EI . Dynamic tension and adsorption behavior of aqueous lung surfactants. Colloids Surf B Biointerfaces 1999; 15: 325–38.
Author information
Authors and Affiliations
Corresponding author
Additional information
Project supported by the Ministry of Education Grant of China (2001) and a grant from the Department of Public Health of Shanghai (2001).
Rights and permissions
About this article
Cite this article
Ji, Y., Liu, C. & Pei, Yy. Artificial pulmonary surfactant as a carrier for intratracheally instilled insulin. Acta Pharmacol Sin 28, 744–750 (2007). https://doi.org/10.1111/j.1745-7254.2007.00513.x
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1111/j.1745-7254.2007.00513.x