Other Routes of Protein and Peptide Delivery: Transdermal, Topical, Uterine, and Rectal - Challenges in Delivery of Therapeutic Genomics and Proteomics - page 638

permanent chemical changes in the parent molecule [102-107] . There seems to be
no consistency in the usage, but in general the chemically modified drug molecule
is defined by the degree of peptide backbone structure left after derivatization. Thus,
analogues have more peptide-like structure left after chemical change than pepti-
domimetics [106,107] . In recent past several types of analogues of various biologi-
cally active peptides and proteins have been explored. Possible strategies used in the
development of analogue include N- and C-terminal modifications (e.g., conversion
of the C-terminal carboxylic acid residue to an amide); amino acid manipulations
(e.g., systematic replacement of L-amino acids with D-amino acids); peptide back-
bone modifications, where the use of amide isosters is common (e.g., N-methylation
of the peptide amide bond); and replacement of larger structural moieties in a com-
pound with dipeptide or tripeptide analogue structures or analogues of the secondary
structure [108-112] .
12.1.4.2.1 Prodrug Approach
A prodrug is by definition a pharmacological inactive derivative of a drug molecule
that is capable of releasing the parent molecule quantitatively, due to enzymatic or
spontaneous reaction in the body. The chemical group used for derivatization of the
parent drug molecule, called the progroup, should be nontoxic. The use of prodrug
suggests a promising biochemical approach for improving the skin permeation of
drug molecules [108] . As we all know that the low skin permeability of peptides is
partly because of their hydrophilic nature. The synthesis of lipophilic prodrugs of
such peptides is expected to improve transdermal transport. After diffusing into or
through the skin, the prodrug undergoes conversion into the original active drug
molecule. Such an approach was found feasible for TRH. The prodrugs studied are
N -isobutyloxycarbonyl and N -octyloxycarbonyl derivatives of TRH. Results of dif-
fusion experiments using excised human skin indicate that the N -octyloxycarbonyl
derivative demonstrated better permeability. The prodrug penetrated into the receptor
phase was found to exist primarily as TRH. The authors showed that the quantities
equivalent to those given by infusion or injection of TRH can be delivered in this
manner [103] . The prodrug approach was introduced by Albert in 1958, but focus
was not directed to this specialized area until later. Research in the design of pro-
drugs of various chemical functional groups and of well-known drug substances, as
well as types of usable progroups, intensified, and today several drugs are used clini-
cally as prodrug derivatives of a parent drug molecule [104-109] . In the late 1980s,
attention to the use of the prodrug approach to improve the delivery of peptides and
proteins increased [107,108,112-114] .
12.1.4.2.2 Permeation Enhancers
Several chemical compounds have the capacity to increase the permeation of drugs
across biomembranes, mostly by altering the barrier properties of skin [115-118] .
These are the substances that speed up the transfer across skin by altering the intercel-
lular lipid or intracellular protein domains of the SC. Their interaction with intercellular
lipids may disorder the highly ordered lamellar structure, thus increasing the diffu-
sivity of drugs across skin. In addition, they may solubilize or plasticize skin-tissue