Abstract
Purpose. To determine if tetradecyl-β-maltoside (TDM) and dimethyl-β-cyclodextrin (DMβCD) enhance pulmonary absorption of insulin and to investigate if they do so by a reversible action on respiratory epithelium.
Methods. Insulin formulated with saline, TDM, or DMβCD was administered intratracheally, after laryngoscopic visualization, as a spray to anesthetized rats. Reversibility studies were conducted in intact rats by administering insulin at different time points after administration of TDM or DMβCD. The pharmacodynamics and pharmacokinetics of insulin formulations were assessed by measuring plasma glucose and plasma insulin concentrations.
Results. When insulin formulated with increasing concentrations (0.06-0.25%) of TDM or DMβCD were administered to anesthetized rats, there was a concentration-dependent decrease in plasma glucose and increase in plasma insulin concentrations. The relative bioavailability of insulin formulations containing TDM was higher (0.34-0.84%) than that of formulations containing DMβCD (0.19-0.48%). When insulin was administered 120 min after an agent was administered, in the reversibility study, no significant change in plasma glucose and insulin levels occurred compared to control.
Conclusions. Both TDM and DMBCD enhance pulmonary absorption of insulin, with TDM being more efficacious than DMβCD in enhancing insulin absorption via pulmonary administration. The effects of TDM and DMβCD on respiratory epithelium are reversible, and the epithelium reestablishes its normal physiologic barrier 120 min after exposure to these agents.
Similar content being viewed by others
References
W. T. Cefalu, J. Rosenstock, and S. Bindra. Inhaled insulin: a novel route for insulin delivery. Expert. Opin. Investig. Drugs 11:687-691 (2002).
J. S. Patton, J. Bukar, and S. Nagarajan. Inhaled insulin. Adv. Drug Del. Rev. 35:235-247 (1999).
F. M. Wigley, J. H. Londono, S. H. Wood, J. C. Shipp, and R. H. Waldman. Insulin across respiratory mucosae by aerosol delivery. Diabetes 20:552-556 (1971).
R. U. Agu, M. I. Ugwoke, M. Armand, R. Kinget, and N. Verbeke. The lung as a route for systemic delivery of therapeutic proteins and peptides. Respir. Res. 2:198-209 (2001).
J. Yu and Y. W. Chien. Pulmonary drug delivery: physiologic and mechanistic aspects. Crit. Rev. Ther. Drug Carrier Syst. 14:395-453 (1997).
F. Komada, S. Iwakawa, N. Yamamoto, H. Sakakibara, and K. Okumura. Intratracheal delivery of peptide and protein agents: absorption from solution and dry powder by rat lung. J. Pharm. Sci. 83:863-867 (1994).
R. D. DiMarchi, R. E. Chance, H. B. Long, J. E. Shields, and L. J. Slieker. Preparation of insulin with improved pharmacokinetics relative to human insulin through consideration of structural homology with insulin-like growth factor I. Horm. Res. 41:93-96 (1994).
M. E. Trautmann. Effect of insulin analogue [Lys(B28), Pro(B29)] on blood glucose control. Horm. Metab. Res. 26:588-590 (1994).
A. Yamamoto, S. Umemori, and S. Muranishi. Absorption enhancement of intrapulmonary administered insulin by various absorption enhancers and protease inhibitors in rats. J. Pharm. Pharmacol. 46:14-18 (1994).
K. Okumura, S. Iwakawa, Y. Tsuguchika, S. Toshimitsu, and F. Komada. Intratracheal delivery of insulin absorption from solution and aerosol by rat lung. Int. J. Pharm. 88:63-73 (1992).
S. Saurez, L. Garcia-Contreras, D. Sarubbi, E. Flanders, D. O'Toole, J. Smart, and A. J. Hickey. Facilitation of pulmonary insulin absorption by H-MAP: Phamacokinetics and pharmacodynamics in rats. Pharm. Res. 18:1677-1684 (2001).
D. J. Pillion, J. A. Atchison, C. Gargiulo, R. X. Wang, P. Wang, and E. Meezan. Insulin delivery in nosedrops: New formulations containing alkylglycosides. Endocrinology 135:1386-1391 (1994).
F. Ahsan, J. Arnold, E. Meezan, and D. J. Pillion. Enhanced bioavailability of calcitonin formulated with alkylglycosides following nasal and ocular administration in rats. Pharm. Res. 18:1742-1746 (2001).
D. J. Pillion, P. Wang, J. Yorks, P. McCann, and E. Meezan. Systemic absorption of insulin and glucagon applied topically to the eyes of rats and a diabetic dog. J. Ocul. Pharmacol. Ther. 11:283-295 (1995).
D. J. Pillion, F. Ahsan, J. Arnold, B. M. Balasubramaniam, O. Piraner, and E. Meezan. Synthetic long chain alkyl maltosides and alkyl sucrose esters as enhancers of nasal insulin absorption. J. Pharm. Sci. 91:1456-1462 (2002).
D. J. Pillion, J. A. Atchison, R. X. Wang, and E. Meezan. Alkylglycosides enhance systemic absorption of insulin applied topically to the rat eye. J. Pharmacol. Exp. Ther. 271:1274-1280 (1994).
T. Irie and K. Uekama. Cyclodextrins in peptide and protein delivery. Adv. Drug Del. Rev 36:101-123 (1999).
F. W. H. M. Merkus, J. C. Verhoef, S. G. Romeijn, and N. G. M. Schipper. Absorption enhancing effect of cyclodextrins on intranasally administered insulin in rats. Pharm. Res. 8:588-592 (1991).
S. A. Francis, J. M. Kelly, J. McCormack, R. A. Rogers, J. Lai, E. E. Schneeberger, and R. D. Lynch. Rapid reduction of MDCK cell cholesterol by methyl-β-cyclodextrin alters steady-state transepithelial electrical resistance. Eur. J. Cell Biol. 78:473-484 (1991).
M. A. Bagger, H. W. Nielson, and E. Bechgaard. Nasal bioavailability of peptide T in rabbits: Absorption enhancement by sodium glycocholate and glycofurol. Eur. J. Pharm. Sci. 14:69-74 (2001).
J. Arnold, F. Ahsan, E. Meezan, and D. J. Pillion. Nasal administration of low molecular weight heparin. J. Pharm. Sci. 91:1707-1714 (2002).
D. J. Pillion, J. D. Bartlett, E. Meezan, M. Yang, J. R. Crain, and W. F. Grizzle. Systemic absorption of insulin delivered topically to the rat eye. Invest. Ophthalmol. Vis. Sci. 32:3021-3027 (1991).
J. L. Izzo, A. M. Roncone, D. L. Helton, and M. J. Izzo. Deposition of 131I proinsulin in the rat. Comparisons with 131I insulin. Diabetes 27:400-410 (1978).
J. C. Soddy, F. R. Sodoyez-Goffaux, and Y. M. Morris. 125I-Insulin: Kinetics of interaction with its receptors and rate of degradation in vivo. Am. J. Physiol. 239:E3-E11 (1980).
S. P. Newman. Therapeutic aerosols. In S. W. Clarke and D. Pavia (eds.), Aerosol and the Lung: Clinical and the Experimental Aspect, Butterworths, London, 1984, pp. 197-224.
R. A. Rajewski and V. J. Stella. Pharmaceutical applications of cyclodextrins. 2. In Vivo Drug delivery. J. Pharm. Sci. 85:1142-1169 (1996).
S. Kobayashi, S. Konda, and K. Juni. Pulmonary delivery of salmon calcitonin dry powders containing absorption enhancers in rats. Pharm. Res. 13:80-83 (1996).
M. Lovatt, A. Cooper, and P. Camilleri. Energetics of cyclodextrin induced dissociation of insulin. Eur. Biophys. J. 24:354-357 (1996).
K. Tokihiro, T. Irie, and K. Uekama. Varying effects of cyclodextrin derivatives on aggregation and thermal behavior of insulin in aqueous solution. Chem. Pharm. Bull. 45:525-531 (1997).
Z. Shao, R. Krishnamoorty, and A. K. Mitra. Cyclodextrins as nasal absorption promoters of insulin: Mechanistic evaluations. Pharm. Res. 9:1157-1163 (1992).
M. Eljamal, S. Nagarajan, and J. S. Patton. In situ and in vivo methods for pulmonary delivery. In R. T. Borchardt, P. L. Smith, and G. Wilson (eds.), Models for Assessing Drug Absorption and Metabolism, Plenum, New York, 1996, pp. 361-374.
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Hussain, A., Yang, T., Zaghloul, AA. et al. Pulmonary Absorption of Insulin Mediated by Tetradecyl-β-Maltoside and Dimethyl-β-Cyclodextrin. Pharm Res 20, 1551–1557 (2003). https://doi.org/10.1023/A:1026118813943
Issue Date:
DOI: https://doi.org/10.1023/A:1026118813943