Oral Delivery of Proteins and Peptides: Concepts and Applications - Challenges in Delivery of Therapeutic Genomics and Proteomics - page 494

amount of carbon showed improved permeability due to increased lipophilicity with
increased chain length and inhibition of insulin self-union [130,141] . Research has
also been done on the modification of peptides, for example, TRH, LHRH, neuro-
tensin, pepsin, gastrin, fibrinopeptides, and collagen (peptides containing the pyro-
glutamyl group). These studies conclude that lipophilic alteration of these peptides
resulted in a significant increase in their absorption, by overcoming poor perme-
ability and enzymatic insecurity [142] . Buccal absorption of TRH tripeptide from
the buccal patch has been enhanced when chemically modified to its lauryl deriva-
tive [143,144] . However, an increase in the lipophilic nature of the peptide does not
ensure increased permeability across the mucosa. This can be explained by the devel-
oping myristoylated TRH tripeptide, which, having a high lipophilic nature, is unable
to cross the mucosa and is retained in the epithelium [145] .
10.6.2.2 Prodrug Approach
A prodrug itself has no pharmacological activity but elicits activity only after conver-
sion to the parent drug. Before reaching the systemic circulation, prodrugs must retain
their structure to avoid enzymatic degradation and to increase absorption. After reach-
ing the systemic circulation, they must be transformed to their dynamic form to have
a pharmacological effect [146] . This approach can be understood with the example
of lauryl-TRH, which is a prodrug of TRH and is gradually converted to TRH in the
plasma [132,133] , as is demonstrated in the study conducted by Tanaka et al.
10.6.2.3 Methylation of Peptides and Proteins
Peptides are often methylated to improve lipophilicity and to reduce their potential to
form hydrogen bonds. Methylation changes the conformation of peptides and makes
them permeable across the cell membrane. Conradi et al. studied methylation of
AcPhe 3 NH 2 peptide and its effect on penetration and concluded that methylation
of AcPhe 3 NH 2 peptide at four different places significantly increases its penetration
through the CACO-2 cell membrane [110] . The modified peptides must be demethyl-
ated enzymatically in the blood after absorption, to liberate the active peptide so that
its pharmacological action can take place [142,147] .
10.6.2.4 Polymeric Conjugates
This approach involving covalent conjugation of peptides to polymers may be useful
to increase peptide stability and plasma half-life. It has also showed its usefulness for
decreasing the immunogenicity of peptides, because it involves partially or totally
covering the immunogenic sites of the peptides with polymers [65] . Prerequisites for
these types of modifications are that these polymers must be water soluble, biocom-
patible, and nonimmunogenic. Lipophilicity is also increased by coupling the peptide
with lipophilic polymers [148] . Research has already been done on the conjugation
of peptides with polystyrene- co -maleic acid/anhydride, PEG, poly(styrene maleic
acid), copolymer (SM), albumin, and dextrans [149] , and the usefulness of these
approaches has been demonstrated.