Parenteral Delivery of Peptides and Proteins - Challenges in Delivery of Therapeutic Genomics and Proteomics - page 528

incompatibility include (1) proteins of nonhuman origin (e.g., bacterial toxins and
enzymes), (2) the presence of impurities or aggregates, and (3) the immune status
or genetic makeup of individual patients [18,19] . Though the individual patient's
traits cannot be modified, the immunogenicity of protein pharmaceuticals may be
reduced by improving manufacturing processes to obtain chemically-intact, pure, and
nonaggregated protein formulations [1] .
In spite of all such obstacles, the typical delivery method of a therapeutic protein
is still the subcutaneous or intravenous administration of a solution or suspension.
Frequently, the product is a lyophilized form of the protein along with either some
excipient or any of the particulate or carrier systems that have to be reconstituted before
administration because an appropriate shelf life cannot be achieved with a ready-to-use
protein solution. This combination of a lyophilized protein or proteins along with the
carrier system and the subcutaneous route seems at present to be the most robust and
successful design [2] .
The present chapter focuses on various developments in injectables for P/P deli-
very for improving their therapeutic response with reducing side effects and immuno-
genicity, and the relevant aspects of formulating the therapeutic protein in a suitable
delivery system.
11.2 Pharmacological Considerations of P/P Drugs
11.2.1 Pharmacokinetic Considerations of P/P Drugs
To formulate an effective parenteral delivery system for proteins and peptides, the phar-
macokinetic profile of the P/P drug must be considered [20] . In P/P drugs, the bioavail-
ability is reduced from subcutaneous injection due to proteolytic degradation at the site
of injection. Also, bioavailability from intravenous injection is not 100% because nor-
mally degradation by proteolytic enzymes may start in the blood itself [20] . The bio-
availability might differ between administration sites like the thigh or abdomen. Other
factors that might be considered in relation to their effect on the bioavailability are depth
of the injection, delivery system, concentration of the solution for injection, volume of
the injection, formulation-related factors, and patient-specific factors. Absorption of P/P
drugs in body cells may follow different mechanisms that are attributable to their size,
shape, linearity, lipophilicity, and so on. Various mechanisms are nonionic passive dif-
fusion (e.g., cyclosporine), carrier-mediated transport (e.g., rennin, cholecystokinin-8),
and energy dependent carrier-mediated transport (e.g., receptor-mediated transport for
insulin, EFG, and IgG). There is an inverse correlation between the steady-state volume
of distribution (Vss) and molecular weight [21-23] . A comparable relationship is seen
also for permeability and molecular weight [21-23] . For larger proteins, Vss is simi-
lar to the distribution of albumin (approximately 0.1 l/kg) [21-23] . Small proteins of
MW  50,000 Da are eliminated through renal filtration followed by tubular reabsorp-
tion and subsequent metabolic catabolism. For larger protein molecules, elimination in
other tissues and/or in target cells through receptor-mediated endocytosis followed by
catabolism is more important relative to renal filtration. Glomerular filteration of P/P