Final Product

Figure 1 Schematic overview of protein purification from microbial and mammalian sources.

Release from dosage form

Protein

Enzymes

Mucus

Capillary

Figure 2 Major biological barriers for transmembrane delivery of biotechnology-based pharmaceuticals.

Enzymes

Mucus

Capillary

Figure 2 Major biological barriers for transmembrane delivery of biotechnology-based pharmaceuticals.

parenteral or nonparenteral route of delivery or aimed for local or systemic effects. Ways to overcome biological barriers are illustrated in Figure 2.

Briefly, upon release of the macromolecular drug from the delivery system, the drug should withstand hydrolysis and enzymatic activity in the extracellular milieu at the site of absorption. In the case of nonparenteral delivery, the unstirred water layer and especially the viscous mucin layer in particular, both present at the surface of epithelia constitute a barrier for absorption of biotechnology-based pharmaceuticals and must be permeated for the biomacromolecule to reach the surface of the epithelial membrane. A

barrier of mucus cell layer does not cover endothelia. Irrespective of the delivery route, the cell layer must be permeated to reach the underlying capillaries. Permeation occurs sporadically by different mechanisms, for example, passive para- or transcellular diffusion or endocytotic transport mechanisms such as macropinocytosis. For macro-molecular drugs such as proteins, the mechanism is believed to be dependent on the size, as its uptake and transport are expected to occur mainly by endocytosis (3,5). During the permeation of the epithelial or endothelial cell layer, the stability of the biomacromo-lecule is further challenged by the intra- and extracellular enzyme activity before the site of action is reached. The general principles of drug absorption and different routes of administration are discussed elsewhere in this book.

Both parenteral and nonparenteral local administration of macromolecular drugs are obviously advantageous for treatment of diseases such as cystic fibrosis and bone regeneration, and the primary biological barriers to overcome upon administration are thus elimination, that is, avoiding washout and enzymatic degradation.

However, when aiming at nonparenteral administration of biotechnology-based pharmaceuticals for systemic delivery, the barrier characteristics of the biological barrier to be permeated should also be taken into account. In Table 1, the properties of different barriers are compared, and the ranges of expected bioavailability are listed.

The formulation strategies ought to ensure that the drug is applied appropriately and released sufficiently from the formulation. Also, the formulation strategy ought to ensure

Table 1 Properties of Nonparenteral Routes of Administration with Respect to Systemic Delivery of Biotechnology-Based Pharmaceuticals

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