Parenteral Delivery of Peptides and Proteins - Challenges in Delivery of Therapeutic Genomics and Proteomics - page 527

moieties acts at the molecular and/or cellular level, and often fails to produce the
desired therapeutic action at the specific molecular target while studying in vivo .
Protein therapeutics suffer from poor pharmacokinetic profiles due to poor oral bio-
availability, poor egress across biological membranes, short plasma half-life, immu-
nogenicity, and inadequate stability and shelf life [1,8,9] .
The oral route is the most convenient for drug delivery; however, it presents sig-
nificant barriers to the delivery of therapeutic P/P due to poor intrinsic permeability,
susceptibility to enzymatic attack, rapid postabsorptive clearance, and the chemical
instability of P/P [10] . Apart from a few low-molecular-weight peptides like adenocor-
ticotropic hormone (ACTH) and thyrotropin-releasing hormone (TRH), very limited
success has been achieved using this route [10] . Alternative routes, such as nasal, pul-
monary, buccal, rectal, vaginal, ocular, and transdermal, have also been explored for
their delivery; however, the protease enzymes in the homogenates of the nasal, buc-
cal, rectal, and vaginal mucosa of rabbits are considerable and quite similar to those in
the intestinal mucosa [9,11] , thus causing P/P degradation. Degradation of luteinizing
hormone-releasing hormone (LHRH) has been reported in buccal, liver, and nasal tis-
sues, indicating the inability of these alternative routes to deliver substantial amounts
of P/P drugs to the body to elicit the therapeutic response [12] . Hence, most of the
protein-based therapeutics are normally administered by frequent injections through
different parenteral routes such as intravenous (i.v.), intramuscular (i.m.), and subcu-
taneous (s.c.). Therefore, most marketed products of protein therapeutics are designed
for parenteral delivery. However, the parenteral P/P delivery suffers from such disad-
vantages as requiring skilled personal to ensure proper administration, frequent admin-
istration due to short half-life in vivo , a lack of site specificity precipitating various
side effects, and immunogenicity at the injection site, thus leading to poor patient com-
pliance especially in the case of chronic treatment. This results in continuous research
into developing various innovations in parenteral delivery of P/P [13-17] .
Apart from a proper delivery route, other obstacles to successful protein and peptide
delivery related to their biochemical and biological properties are their large molecular
weight, electrical charge, hydrophilic nature, relatively poor physical and chemical sta-
bility, immunogenicity, and instability in extreme pH environments. Also, while being
delivered to the desired site, they are subjected to unfavorable physiological effects
such as shear pressure during circulation, proteolysis in the plasma, low pH in endo-
somes, and digestive enzymes in lysosomes, all of which can lead to harmful modifica-
tion in the protein structure [1,17] . These factors sum up the very low bioavailability
of protein and peptide formulations. Protein and peptide drugs are very different from
small chemical entities in that the cost of active pharmaceutical ingredient (API) is gen-
erally high. Consequently, a protein formulation with a relatively low bioavailability
can be too costly to manufacture and too costly to the ultimate user, that is the patient.
Another limitation of protein drugs is their immunogenicity. This is a major con-
cern in formulation and development because it provokes undesirable host immune
responses including the formation of antibodies against the drug product. Binding
of endogenous proteins, in other words, antibodies to foreign therapeutic proteins,
accelerates their clearance from the body, resulting in a loss of efficacy, and neces-
sitating repeated administration of the drug. The factors contributing to such immune