Peptides aerosolized

Specific formulation strategies need to be employed for macromolecule compounds. An excellent review of protein stability in aqueous solutions has been published by Chi et al. (92). In addition to solution stability of proteins and peptides, aerosolization may result in significant surface interfacial destabilization of these compounds if no additional stabilization excipients are added. This is due to the fact that protein molecules are also surface active and adsorb at interfaces. The surface tension forces at interfaces perturb protein structure and often result in aggregation (92). Surfactants inhibit interface-induced aggregation by limiting the extent of protein adsorption (92). 

The lungs large, permeable surface makes systemic deUvery possible. For example, an inhaler deUvers 360 )Tg per dose of aerosolized ergotamine tartrate [379-79-3] for migraine (54), and inhalant systems deUver anesthetic gases. Research is under way on the systemic deUvery of proteins and peptides through the lungs (57,58). 

Folkesson HG, Westrom BR, Dahlback M, Lundin S, Karlsson BW (1992) Passage of aerosolized BSA and the nona-peptide dDAVP via the respiratory tract in young and adult rats. Exp Lung Res 18 595-614. 

Tronde A, Krondahl E, von Euler-Chelpin H, Brunmark P, Bengtsson UH, Ekstrom G, Lennernas H (2002) High airway-to-blood transport of an opioid tetrapeptide in the isolated rat lung after aerosol delivery. Peptides 23 469-478. 

PMIO fraction of ambient aerosols " major histocompatibihty complex (MHC)-associated peptides proteolytic digest of glycoproteins ... 

Evans and Farr [314] patented a process for preparation of aerosol inhalants containing proteins and peptides (with particular reference to insulin) solubilized in RMs. 

A small number of biopharmaceuticals are delivered by nonparenteral means. Recombinant DNase is given by inhalation aerosol to reduce the viscosity of mucus in the lungs of patients with cystic hbrosis. A platelet-derived growth factor in the form of a gel is administered topically for wound healing. Several hormones and peptides are administered in solution by the intranasal route. A solution of an antisense drug used for the treatment of cytomegalovirus retinitis is injected directly into the eye. 

Several portable inhalation devices have been developed and are being tested to determine whether they improve protein and peptide delivery via the airways. Aerosolized DNase has been shown in patients with cystic flbrosis to significantly reduce the buildup of mucus in the lung and the incidence of infections. Devices for delivery of therapeutic proteins to deep-lung alveoli to achieve systemic effects are also in development. These products are formulated so that the device aerosolizes the protein in a defined particle size range that cannot be easily achieved by means of conventional metered dose inhalers. 

ITABLE 13.12. Aerosolized proteins and peptides tested in humans with portable devices for pulmonary delivery... 

Pulmonary administration of PNAs has great potential for the same reasons that pulmonary protein and peptide delivery have been successful. Predominantly, the distance for transport and ease of administration of agents are the advantages of pulmonary delivery, but the formulation of labile molecules for eventual pulmonary administration as lipid-based aerosols may be problematic. 

Evans, R. M., and S. J. Farr. 1993. Aerosol formulations including proteins and peptides solubilized in reverse micelles and process for making the aerosol formulations. US Patent 5,230,884. 

In a mouse model of aerosol sensitization to birch pollen we previously demonstrated that intranasal as well as oral administration of the major birch pollen allergen Bet v 1 prevented allergic sensitization, airway inflammation and airway hyperresponsiveness [28], Similar effects were achieved using hypoallergenic derivates of Bet v 1, containing the immunodominant T cell peptides but not the anaphylactogenic B cell epitopes, for intranasal tolerance induction [60],... 

Peptides and proteins can be delivered to the lung for localized or systemic effects by either intratracheal instillation or aerosol inhalation. 

Hoover et al. [47] assessed the absorption of a series of model D-phenylalanine analogues that were resistant towards enzymatic hydrolysis, after intrapulmonary administration of aerosolized peptide solution into the rat lung. Compared to oral administration, all peptides showed better absorption from the lung than from the gut, with pulmonary absorption ranging from 55.1 to 68.5% for the methylated series of these model peptides. However, some members of the non-methy-lated peptide series were metabolized during the absorption process, which was not observed in the intestinal absorption studies. Therefore, the advantage of pulmonary over oral administration must be examined on a case-by-case basis. 

Shoyele, S. A., and Slowey, A. (2006), Prospects of formulating proteins/peptides as aerosols for pulmonary drug delivery, Int. J. Pharm., 314,1-8. 

Kawashima, Y. (1995). Aerosolization oflactide/glycolide copolymer (PLGA) nanospheres for pulmonary delivery of peptide-drugs. Yakugaku Zasshi 115, 732-741. 

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