Proteomics - Challenges in Delivery of Therapeutic Genomics and Proteomics - page 390

�.2.1.1.2 Site of Administration
Site of administration affects the performance of penetration enhancers. Anatomical
barriers, degree of vascularization, and thickness of biological membranes act as
rate-limiting barriers for percutaneous drug absorption and constraint the penetration
enhancers also. It is well known that buccal mucosa and skin are the most resistant
biological barriers to enhancer action. Kurosaki et al. [6] investigated bile salts like
sodium taurocholate and found them to be ineffective in lowering the barrier proper-
ties of keratinized oral mucosa of hamster cheek pouch.
Similar observations can be extrapolated to various parts of the gastrointestinal
tract. Fix et al. [7] reported that medium-chain glycerides, carnitine derivatives, and
EDTA are more effective in the upper part of the gut as compared to the lower part.
This site-to-site variation may be attributed to differences in composition of the phos-
pholipids and other vital constituents in cell membranes of different mucosa. This
has also been corroborated by the role of sphingomyelin content in red blood corpus-
cles in determining the stability of erythrocytes against emulsion-induced hemolysis.
�.2.1.1.� Nature of the Vehicle
The nature of the vehicle greatly influences the efficacy of enhancers by affecting the
available concentration of permeation enhancer at the absorption site. This is evident
from the findings of Murakami [8] that cap rate lost its effectiveness in promoting
rectal absorption of human epidermal growth factor in rat on changing the vehicle
from sodium carboxy methylcellulose to methylcellulose. Similarly, Nakanishi [9]
studied the rectal absorption of sulfanilic acid formulated in the form of o/w emul-
sion, using Tween-type surfactants, by comparing it with an aqueous solution of the
same drug. The researchers reported a significant increase in rectal absorption of sul-
fanilic acid in rats, when administered in the form of o/w emulsions prepared using
Tween-type surfactants as compared to the aqueous solution of sulfanilic acid. The
probable mechanism for this significant increase in rectal absorption of sulfanilic
acid in o/w emulsion form as compared to aqueous solution may be explained by
increased distribution of hydrophilic surfactant in a small amount of water in rectal
mucosa, leading to increased partitioning of the drug in rectum.
�.2.1.1.4 Safety Concerns
Penetration enhancers have not been found to be free from toxicity and at times may
lead to irritation of mucosal tissues, extensive damage to mucous membranes, and
irritation. Investigations on transdermal products bear testimonial to this fact that
penetration enhancers are associated with potential toxicities. However, apart from
the transdermal route, the relationship between penetration enhancers and irritation
has not been much documented in literature.
8.2.1.2 Safety and Stability Aspects of Proteins
The stability of proteins in different microenvironments in a human body is a critical
issue. The presence of acidic environment and proteolytic enzymes are detrimental to
protein stability. However, there are certain exceptional proteins: for example, Human