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 

Additional advantages associated with the pulmonary route include  

Although obviously occurring in practice, macromolecules absorbed via the pulmonary route must cross a number of biological barriers to get into the blood. These are  

Although no biopharmaceutical product delivered to the bloodstream via the pulmonary route has been approved to date, several companies continue to pursue active research and development programmes in the area. Amongst the leading product candidates is Exubera , an inhalable dry powder insulin formulation currently being evaluated by Pfizer and Aventis Pharma in Phase III clinical studies. The inhaled insulin is actually more rapidly absorbed than if administered subcutaneously and appears to achieve equivalent glycaemic control. While promising, final approval or otherwise of this product also depends upon additional safety studies which are currently under way. 

A nasal-based biopharmaceutical delivery route is considered potentially attractive as  

However, the route does display some disadvantages, including  

The pressurized metered dose inhalers in the use of environmentally friendly propellants means the choice of hydrofluoroalkanes, wherein the dosage form can be a suspension of the solution form. The problems of formulating suspensions, as discussed earlier, apply here as well, but particularly with respect to interactions with the formulation components specific to pressurized inhaler systems. 

Nebulizer formulations are normally solutions, but suspensions (particle size of less than 2 (jim) are also used. Important preformulation considerations include stability, solubility, viscosity, and surface tension of the solution of suspension. 

---

Several groups investigated the use of liposomes for the intra-pulmonary delivery. Farr et al. (1985) showed that the deposition of aerosolized liposomes in the human lung depends on the aerosol particle size. Short-term retention profiles for MLVs and SUVs deposited in the lung were indicative of clearance via the mucociliary transport mechanism. 

A Adjei, J Garren. Pulmonary delivery of peptide drugs effect of particle size on bioavailability of... 

J. S. Patton and R. M. Platz, Routes of drug delivery case studies (2) pulmonary delivery of peptides and proteins for systemic action, Adv. Drug Deliv. Rev, 8, 179 (1992). 

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

Taljanski W, Pierzynowski SG, Lundin PD, Westrom BR, Eirefelt S, Podlesny J, Dahlback M, Siwinska Golebiowska H, Karlsson BW (1997) Pulmonary delivery of intratracheally instilled and aerosolized cyclosporine A to young and adult rats. Drug Metab Dispos 25 917-920. 

The AERx pulmonary delivery system [40,41] can be regarded as a combination of a MDI and a nebulizer. This system forms an aerosol by extrusion of an aqueous drug-containing solution through a disposable nozzle containing an array of precisely micromachined holes. The droplets are entrained by the airflow passing over the blister. Control over the size distribution of the holes enables the formation of droplets having a narrow size distribution. 

Dry powder inhalers have initially found their application in inhalation therapy as a CFC-free alternative for the older MDIs. However, nowadays they seem to have a much larger potential [14,53], because of the high lung deposition that can be attained and also because they are suitable for the pulmonary delivery of therapeutic peptides and proteins [2,10,16]. 

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

Therapeutics/ EHD pulmonary delivery or liquid aqueous/ nonaqueous formulation device design Sterile barrier Chemical inertness, especially for high liquid doses Clear barrier offers QA check for both producer and end user... 

---