Pulmonary delivery development

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. 

One particular feature of plant-derived cannabinoids is their high lipid solubility, which indicates that limited gastrointestinal absorption and bioavailability are significant barriers to their development as therapeutics. For this reason cannabis is traditionally smoked, providing the most predictable and titratable route for administration. For therapeutic development pulmonary deliveries of cannabinoid aerosols are under investigation as an alternative. 

Powder injection applies many of the principles of pulmonary delivery of dry powders to the lungs The drug has to be in the form of very small particles, is dispensed from a reservoir, and is delivered as an aerosol i.e., particles are dispersed in a gas. Liquid or dissolved drug can be delivered by precipitation or adsorption onto carrier particles. The big difference with pulmonary delivery is the momentum at which the particles are delivered. Driven by a high-pressure helium gas stream, the particles travel fast enough to penetrate the outer layer of the skin, the stratum corneum. The design of devices to deliver needle-free injection of solids was pioneered by researchers at the University of Oxford who founded PowderJect Pharmaceuticals PLC in 1993 (now PowderMed Ltd.) to develop the only powder-based technology so far. Since that... 

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

Delivery devices play a major role in the efficiency of pulmonary delivery, and major advances have been made in the development of new devices in recent years. The most commonly used devices for pulmonary drug delivery include nebulizers, metered-dose inhalers (MDIs) and dry-powder inhalers (DPIs). These de-... 

The application of pulmonary delivery of nanoparticles (<1 um) for pharmaceuticals remains to be developed [187-189]. 

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. 

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... 

Some companies are focusing on the development of a new generation of liquid systems that are portable, more efficient, more gentle on the macromolecule and that can deliver the medicine in far fewer puffs than the old fashioned nebulizer. Two companies who are developing advanced pulmonary delivery liquid systems are Aradigm Corporation, Hayward, CA, and AeroGen, Inc., Sunnyvale, CA. 

Those involved with the pulmonary delivery of therapeutic agents are challenged in all three areas, especially the first two. We can now develop new therapies, but we must be certain that we can reproducibly deliver those therapeutic agents to the desired site, in the dosage and form in which they will be most effective. 

Quantitatively, the appropriateness of particles for pulmonary delivery is assessed by the aerodynamic diameter, a term developed by aerosol physicists which takes into account size, shape, and density, and is typically determined by an inertial sampling device such as a cascade impactor. The aerodynamic diameter, >aer (pm), for particlcs greater than 500 nm can be approximated by ... 

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... 

Around 1990, the pulmonary delivery of liposomes was largely an academic exercise [43-46] and at best at an early stage of commercial development [47]. However, these and earlier efforts demonstrated the utility of liposomes, and interest has continued to flourish. This has been reinforced by greater acceptance of the dosage form, since there are now several injectable liposomal products on the market [e.g., Ambisome , Fungisome , Myocet ]. The specific use of lipid-based vehicles to deliver plasmid-based DN A has attracted much attention [48-51]. These developments have indirectly helped improve the quality and variety of... 

At the start of the 1990s the only available aqueous solution-based pulmonary delivery systems were the nebulizers that had their routes in technology developed at the turn of the nineteenth century. From a patient perspective, nebulizer therapy is time consuming, equipment costs are high, and cleaning and maintenance can be problematic from a pharmaceutical perspective, nebulizers exhibit poor delivery efficiency and high variability [22], However, nebulizers... 

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. 

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