Other Routes of Protein and Peptide Delivery: Transdermal, Topical, Uterine, and Rectal - Challenges in Delivery of Therapeutic Genomics and Proteomics - page 639

components. Examples of commonly investigated chemical permeation enhancers
include phospholipids, surfactants, dimethylsulfoxide (DMSO), and 1-odecylazacy-
cloheptan-2-one (azone). Ideal characteristics of a permeation enhancer are that it
must be pharmacologically inert, nonirritating, nontoxic, compatible with most drugs
and excipients, and nonallergenic. However, no single agent meets all the required
qualities of an ideal enhancer. A blend of enhancers may thus be necessary [117] . In
addition to these chemical enhancers, many of the generally regarded as safe (GRAS)
parenteral vehicles that are GRAS also enhance percutaneous drug absorption. The
addition of cosolvents in transdermal and dermal delivery products is another good
approach. These cosolvents include polyethylene glycol 400, propylene glycol, iso-
propyl myristate (IPM) and palmitate (IPP), ethanol, water, and mineral oil. Because
an enhancer is delivered to the skin, its pharmacokinetic properties, such as its mech-
anism of elimination, half-life in skin, degree of absorption, and metabolism, must
be known. Also, the reversibility of skin barrier properties should be determined as
any permanent breakdown in the barrier properties of SC could result in infection
[119] . Use of a transdermal patch creates occlusive conditions on the skin, leading to
increased hydration and irritation of skin beneath the patch. Increased skin hydration
may increase the permeation of the enhancer itself, which may result in even more
irritation or toxicity. Further, the enhancer may increase the permeation of the formu-
lation ingredients along with the drug. Therefore, careful evaluation of the long-term
local and systemic toxicity of the chemical enhancers in the final transdermal dosage
form is important [114,115] .
12.1.4.2.3 Protease Inhibitors
Therapeutic proteins and peptide are becoming increasingly important. These com-
pounds are degraded by the luminally secreted and brush border membrane-bound
proteolytic enzymes. Because of their nonhydrophobic character and comparatively
large size, they are frequently taken up via the paracellular route after oral admin-
istration. Coadministration of inhibitors of proteolytic enzymes provide a practical
means to avoid the enzymatic barrier in achieving the delivery of peptide and protein
drugs. A number of inhibitors, like misleading aprotinin (trypsin/chymotrypsin inhib-
itor), amastatin, bestatin, boroleucine, and puromycin (aminopeptidase inhibitors),
have been reported for this purpose. Interestingly, these inhibitors were not effective
in skin diffusion experiments [116,117] . The drawback of using protease inhibitors
is that the inhibition may also affect the absorption of other peptides or proteins that
normally would be degraded, thereby decreasing any effect. Moreover, high doses of
inhibitor are needed, and the bioavailability of the drug is still limited by the physical
barrier of the cells.
This section of the chapter deals with the transdermal route as a delivery route. The
transdermal route has less proteolytic activity compared to the mucosal route. The
transdermal route has the potential to hydrolyze peptides. Protease inhibitors are used
to avoid or reduce the enzymatic barrier of the skin. Other potentially useful protease
inhibitors are pepstatin, leupeptin, p -chloromercuribenzoate, and phenylmethylsulfo-
nyl fluoride. A metalloprotease inhibitor, o -phenanthroline, has been shown to inhibit
degradation of delta sleep-inducing peptide and increase its transdermal iontophoretic