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), mac-romolecules can be absorbed into the blood via the lungs surprisingly well. In fact, pulmonary macromolecular absorption generally appears to be inversely related to molecular mass, up to a mass of about 500 kDa. Many peptides/proteins delivered to the deep lung are detected in the blood within minutes, and bioavailabilities approaching/exceeding 50 per cent (relative to s.c. injection) have been reported for therapeutic proteins such as colony-stimulating factors and some interferons. Although not completely understood, such high pulmonary bioavailability may stem from:

• the lung's very large surface area;

• their low surface fluid volume;

• thin diffusional layer;

• relatively slow cell surface clearance;

• the presence of proteolytic inhibitors.

Additional advantages associated with the pulmonary route include:

• the avoidance of first-pass metabolism;

• the availability of reliable, metered nebulizer-based delivery systems capable of accurate dosage delivery, either in powder or liquid form;

• levels of absorption achieved without the need to include penetration enhancers which are generally too irritating for long-term use.

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:

• a protective monolayer of insoluble phospholipid, termed 'lung surfactant', and its underlying surface lining fluid, which lies immediately above the lung epithelial cells;

• the epithelial cells lining the lung;

• the interstitium (an extracellular space), and the basement membrane, composed of a layer of interstitial fibrous material;

• the vascular endothelium, i.e. the monolayer of cells that constitute the walls of the blood vessels.

Passage through the epithelium and endothelial cellular barriers likely represents the greatest challenge to absorption. Although the molecular details remain unclear, this absorption process appears to occur via one of two possible means: transcytosis or paracellular transport (Figure 4.6).

Figure 4.6 Likely mechanisms by which macromolecules cross cellular barriers in order to reach the bloodstream from (in this case) the lung. Transcytosis entails direct uptake of the macromolecule at one surface via endocytosis, travel of the endosome vesicle across the cell, with subsequent release on the opposite cell face via exocytosis. Paracellular transport entails the passage of the macromolecules through 'leaky' tight junctions found between some cells

Figure 4.6 Likely mechanisms by which macromolecules cross cellular barriers in order to reach the bloodstream from (in this case) the lung. Transcytosis entails direct uptake of the macromolecule at one surface via endocytosis, travel of the endosome vesicle across the cell, with subsequent release on the opposite cell face via exocytosis. Paracellular transport entails the passage of the macromolecules through 'leaky' tight junctions found between some cells

Diabetes 2

Diabetes 2

Diabetes is a disease that affects the way your body uses food. Normally, your body converts sugars, starches and other foods into a form of sugar called glucose. Your body uses glucose for fuel. The cells receive the glucose through the bloodstream. They then use insulin a hormone made by the pancreas to absorb the glucose, convert it into energy, and either use it or store it for later use. Learn more...

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