Pulmonary delivery of insulin

Kawashima, Y., Yamamoto, H., Takeuchi, H., Fujioka, S., and Hino, T. (1999). Pulmonary delivery of insulin with nebulized DL-lactide/glycolide copolymer (PLGA) nanospheres to prolong hypoglycemic effect. J. Controlled Release, 62, 279-287. 

One of the main drivers for the development of new pulmonary drug delivery systems has been the potential for noninvasive systemic delivery of protein and peptide compounds. The systemic delivery of macromolecules via the airways would overcome the inconvenience and cost associated with current methods of administration (injection), and appears likely given the large surface area of the airways and the thin pulmonary epithelium. Most research has concentrated on pulmonary delivery of insulin for the treatment of diabetes. Recently, one insulin product has completed phase three studies and is now undergoing review by European regulatory agencies for marketing approval. 

Figure 8.10 PDS device developed by Nektar Therapeutics for pulmonary delivery of insulin.

Huang, Y.-Y. and C.-H. Wang (2006) Pulmonary delivery of insulin by liposomal carriers. Journal of Controlled Release, 113 p. 9-14. 

White, S., Bennett, D. B., and Cheu, S., et al. (2005), EXUBERA Pharmaceutical development of a novel product for pulmonary delivery of insulin, Diabetes Technol. Ther.,1, 896-906. 

Pulmonary delivery of insulin for systemic absorption in the treatment of diabetes has been studied extensively since the early days of insulin discovery almost a century ago. Colthorpe et al. and Pillai et al. demonstrated in rabbit and monkey models, respectively, that the deeper into limg the dose of insulin was delivered, the higher was the bioavailability. The work of Laube, Benedict, and Dobs showed the need to achieve deep pulmonary deposition of this molecule for efficient absorption in humans. Handheld liquid and dry powder delivery systems have been developed to generate insulin-containing aerosols with the majority of the particles in the aerodynamic size range 1-3 pm. The relative bioavailability compared with subcutaneous injection based on the insulin contained in the dosage form was 110/ [52] powder system and for the aqueous-based... 

Mitra R, et al. Enhanced pulmonary delivery of insulin by lung lavage fluid and phospholipids. Int J Pharm 217(1 —2) 25—31, 2001. 

H. Hamishehkar, J. Emami, A. Rouholamini Najafabadi, K. Gilani, M. Minaiyan, H. Mahdavi, A. Nokhodchi. Effect of carrier morphology and surface characteristics on the development of respirable PLGA microcapsules for sustained-release pulmonary delivery of insulin. Int J Pharm 389, 74-85, 2010. 

The active inhaler made by Nektar Therapeutics (formerly Inhale Therapeutic Systems, United States), called Pulmonary Delivery System (PDS), mechanically compresses a fixed volume of air required for delivery and dispersion of a premetered dry-powder unit dose by a spring-loaded pump (Fig. 8.10). Generation of the respirable aerosol cloud thus is independent of the inspiration effort exerted by the patient. The aerosol is generated in a transparent holding chamber that acts as a spacer from which the patient inhales the standing cloud of particles (Patton 1997). The PDS device is actually close to market for inhaled delivery of insulin under the trade name Exubera. 

In conclusion, the pulmonary delivery of insuhn offers an efficient and convenient therapy for diabetic patients. The feasibility of inhaled insuhn is based mainly on the lungs large absorption area of alveoli and their extremely thin walls full of intercellular spaces that make them more permeable than other mucosal sites to large proteins. Generally, inhaled insuhn showed a more rapid absorption than insulin administered by SC injection [59]. One major concern for pulmonary insuhn delivery is the unknown long-term effects of inhaled insuhn within the respiratory tract. Thus, possible long-term problems should be considered when insuhn is administered in this manner [66]. 

With the exception of a few approved products for nasal administration of peptides and the very recent regulatory approvals of delivery systems for both pulmonary and buccal delivery of insulin, there is relatively little precedence with the worldwide regulatory approval process for non-invasive delivery systems incorporating protein or peptide pharmaceuticals. Consequently, there is limited specific information... 

Brown LR, Mcgeehan JK, Yuanxi Q, Rashba SJ, Scott TL. Pulmonary delivery of spherical insulin microparticles. WO 20080026068, 2008. 

Pulmonary delivery currently represents the most promising alternative to parenteral delivery systems for biopharmaceuticals. Delivery via the pulmonary route moved from concept to reality in 2006 with the approval of Exubera, an inhalable insulin product (Chapter 11). Although the lung is not particularly permeable to solutes of low molecular mass (e.g. sucrose or urea), macromolecules can be absorbed into the blood via the lungs surprisingly well. In fact, pulmonary... 

Not only will the charge of a lipid and the composition of lipids affect the delivery of biomacromolecules, but the size of the liposome may alter the transport. Mixtures of insulin with three different diameter (1.98 pm, 0.4 pm, and 0.1 pm) neutral liposomes (DPPC Choi) resulted in similar overall hypoglycemic effects to insulin alone. Contrary to this finding is the fact that pulmonary absorption of liposomal [3H] terbutaline, a small molecule, has been reported to be dependent on both composition and size of the liposomes used (Abra et al. 1990). Differences in the absorption mechanism may be the explanation for this contradictory evidence further studies are needed to clarify this and other uncertainties about the uptake mechanism of macromolecules (Patton 1996). 

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