Formulations for pulmonary delivery

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. 

Malcolmson RJ, Embleton JK. Dry powder formulations for pulmonary delivery. Pharm Sci Technol Today 1998 1 394-398. 

An aerosol dosage form developed by suspending zinc insulin crystals in a propellant together with oleyl alcohol to improve the wetting of the crystals was stated to be chemically stable (Lee and Sciarra, 1976), but as this conclusion was based on immunoassay results, it does not necessarily reflect reality. When insulin is formulated for pulmonary delivery by dry-powder generators (Byron, 1990), it is important to remember that insulin in the dry state, in an amorphous as well as a crystalline form, is hygroscopic, even when it contains 10-20% water, depending on the relative humidity. 

T. Sou, L. Orlando, M.P. McIntosh, L.M. Kaminskas, D.A.V. Morton, Investigating the interactions of amino acid components on a mcumitol-based spray-dried powder formulation for pulmonary delivery A design of experiment approach. International Journal of Pharmaceutics, 421, 220-229, 2011. 

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. 

Later, Lizio et al. [78] used a new aerosol delivery system (ASTA-ADS) to investigate the pulmonary absorption and tolerability of four different cetrorelix formulations delivered as nebulized aerosols to orotracheally cannulated rats. After only 5 min exposure to the cetrorelix aerosol, serum testosterone concentrations were reduced to subnormal levels over a 24-h period. After dose adjustment (dose delivered minus exhaled amount), the bioavailabilities for pulmonary delivery ranged from 48.4 27.0% to 77.4 44.0% compared to IV administration. In addition, the lung function parameters did not reveal any formulation-related changes. Overall, the results of cetrorelix aerosol administration compared well with those obtained with intratracheal instillation of cetrorelix solution [77]. 

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... 

Clark, AR. Shire, S.J. Formulation of Proteins for Pulmonary Delivery Protein and Formulation Delivery, McNahy, E.J., Ed. Marcel Dekker, Inc. New York, 2000 201-234. O Riordan, T.G. Formulations and nebulizer performance. Respir. Care 2002, 47 (11), 1305-1313. 

Clark, A.R. Shire, S.J. Formulation of proteins for pulmonary delivery. In Protein Formulation and Delivery ... 

Another issue is reproducibility. The formulation may work perfectly in an in vitro test system, but the dosage form requires aerosolization, and lung deposition is a function of the characteristics of the aerosol (dose, mass concentration, droplet/particle size, etc.) and the nature of the inspiratory maneuver, a factor that the patient has control over. These factors can influence performance to a far greater extent than can be built into a particle, and thus the term controlled does not seem a defensible objective for pulmonary delivery. The vagaries of the deposition profile and of the amount that will deposit also imply that sustaining a certain drug concentration is a difficult proposition, but the loosest definition extended release, seems an acceptable goal within the boundaries set by the clearance mechanisms. 

Microcapsules, produced at ideal size for inhalation (1-5 jm), can be used in formulating drugs for pulmonary delivery, both for local delivery and for systemic absorption. 

Particle-based formulations for pulmonary protein delivery request novel types of powder inhalers, which combine several attributes Kke the ability to apply rather high dosages of up to the milligram range. They need to exhibit high dose accuracy as well as to be even less dependent on the breath rate of the patient. 

There are several oil-based formulations for the delivery of hydrophilic and lipophilic drugs, which maj orly include emulsions and gels (Figure 58.2). Apart from these, various other novel formulations may also be named under this category such as micelles, reverse micelles, solid lipid nanoparticles, and liposomes. - Based on the physicochemical properties of the drug and patient requirements, the vegetable oil-based formulations may be delivered by various routes like oral, parenteral, topical, transdermal, pulmonary, or ocular, etc., - ... 

Bivas-Benita et al. (2004) has proposed chitosan-DNA nanoparticles for pulmonary delivery of a DNA vaccine for Mycobacterium tuberculosis. The authors used an HLA-A2 transgenic mouse model to investigate the effect of pulmonary delivery of a new pDNA encoding eight HLA-A 0201-restricted T cell epitopes from M. tuberculosis formulated in chitosan nanoparticles. Pulmonary administration of these nanoparticles was shown to induce the maturation of dendritic cells as well as induce increased levels of IFN-y secretion compared to pulmonary delivery of plasmids in solution or the intramuscular immunization route (Bivas-Benita et al. 2004). 

Overall, these studies showed that formulating two drags intended for pulmonary delivery into amorphous composites can result in better particle characteristics, a higher respirable fraction, reduced demixing, and thus better drag performance. 

Klyashchitsky, B. A., Owen, A. J., Nebulizer-compatible liquid formulations for aerosol pulmonary delivery of hydrophobic drugs glucocorticoids and cyclosporine,... 

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