Insulin pulmonary delivery

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... 

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. 

Steiner, S., Pfutzner, A., Wilson, B.R., Harzer, O., Heinemann, L., and Rave, K. (2002). Technosphere (TM)/Insulin - proof of concept study with a new insulin formulation for pulmonary delivery. Exp. Clin. Endocrinol. Diabetes, 110, 17-21. 

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. 

Protein-based drugs have been formulated mainly as stable liquids or in cases where liquid stability is limiting as lyophilized dosage forms to be reconstituted with a suitable diluent prior to injection. This is because their delivery has been limited primarily to the parenteral routes of intravenous (IV), subcutaneous (SC), or intramuscular (IM) administration. There are a few drugs that have been developed for pulmonary delivery, such as rhDNase (Pulmozyme ) and an inhalable formulation of insulin (e.g., Exubra ). However, even such drugs have been formulated as either liquid or lyophilized or spray-dried powders. This chapter will focus only on excipients that are applicable to liquid and lyophilized protein formulations. 

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. 

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

Compared with insulin aqueous solution, low-viscosity insulin containing hyalur-onate (0.1-0.2%) greatly enhanced the pharmacological availability of insulin via pulmonary delivery routes to rats [57]. Morimoto et al. [57] subsequently examined the effects of intratracheal administration of different concentrations and pH va-... 

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]. 

In the aerosol solvent extraction system (ASES), the protein is dissolved in a compatible solvent (i.e., water or DMSO) and then introduced by atomization into supercritical CO2 (12,13). The solvent is extracted from the droplet, and the protein precipitates to form particles with appropriate sizes for pulmonary delivery (see Note 3). CO2 is then removed by venting off and the particles are collected. Insulin powders (see Note 4) made by this method possess a mean geometric diameter of 9.6 xm, and 22% of the powder was in the respirable range (0.5-6 p,m) (12). 

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. 

Boyd, B., Noymer, R, Liu, K., et al. (2004), Effect of gender and device mouthpiece shape on bolus insulin aerosol delivery using the AERx pulmonary delivery system, Pharm. Res., 21,1776-1782. 

Although routine oral delivery of proteins has not been realized, some protein formulations have been developed for pulmonary delivery. Pulmonary delivery can result in either parenteral or local administration of the drug and, like oral delivery, is considered non-invasive. As with other routes of delivery, the size of the protein may limit its ability to be delivered systemi-cally via the pulmonary route of administration. Pulmozyme , a DNase-based formulation approved for the treatment of cystic fibrosis (CF), is delivered to the lungs by a nebulizer to clear blockage of the airways in the CF patient.Formulations for insulin to be administered by inhalation for systemic delivery of... 

While the PK profile reported for inhaled insulin seems appropriate to meet prandial insulin requirements, it will not address basal insulin needs. In certain treatment regimes, an injection of a long-acting (basal) insulin preparation will be required unless a pulmonary delivery system capable of producing a sustained release profile is developed. Moreover, if the pharmacological characteristics of inhaled insulin prove... 

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... 

Farr, S.J. Gonda, 1. Licko, V. Physicochemical and physiological factors influencing the effectiveness of inhaled insulin, pulmonary absorption of therapeutic peptides and proteins. In Respiratory Drug Delivery VP, Dalby, R.N., Byron, P.R., Farr, S.J., Eds. Interpharm Press, Inc. Buffalo Grove, IL, 1998 25-33. 

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

Finally, pulmonary protein delivery has advanced tremendously since 1990. One local therapy has been approved and a number of others, including insulin, are in the later stages of clinical development. The device platforms that have been developed for these macromolecules have also exhibited higher delivery efficiencies and greater reproducibility than the old technologies, and these attributes may well have application in other areas of pulmonary delivery. For example, they may facilitate delivery of small molecules though the lung for a faster onset of action. 

Garcia-Contreras, L., Morcol, T, Bell, S. J. D., Hickey, A. J. (2003) Evaluation of novel particles as pulmonary delivery systems for insulin in rats. AAPS PharmSci. 5(2), Article 9. 

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