Epithelia penetration enhancers

Penetration enhancers are low molecular weight compounds that can increase the absorption of poorly absorbed hydrophilic drugs such as peptides and proteins from the nasal, buccal, oral, rectal, and vaginal routes of administration [186], Chelators, bile salts, surfactants, and fatty acids are some examples of penetration enhancers that have been widely tested [186], The precise mechanisms by which these enhancers increase drug penetration are largely unknown. Bile salts, for instance, have been shown to increase the transport of lipophilic cholesterol [187] as well as the pore size of the epithelium [188], indicating enhancement in both transcellular and paracellular transport. Bile salts are known to break down mucus [189], form micelles [190], extract membrane proteins [191], and chelate ions [192], While breakdown of mucus, formation of micelles, and lipid extraction may have contributed predominantly to the bile salt-induced enhancement of transcellular transport, chelation of ions possibly accounts for their effect on the paracellular pathway. In addition to their lack of specificity in enhancing mem-... 

Although the ocular absorption of peptide as well as nonpeptide drugs is poor [96,196-198], the ocular route is by far the least studied for the usefulness of penetration enhancers. This is in part due to the perceived sensitivity of ocular tissues to irritation and the fear of corneal and conjunctival damage caused by the enhancers. Whereas the rat nasal epithelium may tolerate up to 5% sodium glycocholate [199], ocular administration of sodium glycocholate at a concentration of 2% and beyond induces reddening of the eye and tear production in rabbits (Kompella and Lee, unpublished observation). 

Hoogstraate A.J., et al. 1997. Effects of the penetration enhancer glycodeoxycholate on the lipid integrity in porcine buccal epithelium in-vitro. Eur J Pharm Sci 5 189. 

Penetration enhancers are substances that can increase the absorption of a co-administered dmg, and include surfactants, bile salts, chelating agents, and fatty acids. Penetration enhancers are widely used in dmg delivery to potentiate absorption across various types of epithelia, including the epithelium of the gastrointestinal tract. However, a major limiting factor in the general acceptance of absorption enhancers for improving oral dmg absorption is the non-specific nature of their effects. 

Locally irritating or sensitizing dmgs must be used with caution in this route. Nasal epithelia, and in particular the cilia, are highly sensitive and fragile. This contrasts with, for example, the buccal epithelium which is much more robust and less prone to irritation. The fragility of the tissue also means that this route is particularly sensitive to the adverse effects of penetration enhancers. Damage to the epithelium could result in compromised mucocilary clearance which is associated with respiratory disease. 

Although, as described above, the vagina is permeable to many peptides and proteins, in most cases the bioavailability is insufficient for systemic therapy and is also highly variable. Penetration enhancers may be used to promote peptide absorption across the vaginal epithelium. However, less extensive investigations on the use of penetration enhancers for the vaginal route have been carried out in comparison to other routes, such as intranasal and transdermal (see Sections 9.7.1 and 8.6.1). 

Penetration Enhancers The transport process across the corneal tissue is the rate-limiting step in ocular drug absorption. Increasing the permeability of the corneal epithelium by penetration enhancers is likely to enhance the drug transport across the corneal tissues and therefore improve ocular bioavailability of the drug. 

Modification of the integrity of the comeal epithelium transiently by use of penetration enhancers. 

The topic of ocular bioavailability of indomethacin administered in a sub-micrometer emulsion was al.so examined by the research group led by M, J. Alon.so at the University of Santiago de Compo-stela, Spain (32). These workers tested several carriers in vivo in rabbits nanopaiticles, nanocapsules, microparticles, and a submicrometer emulsion. The latter, prepared by the method of Yu et al. (33) with poloxamer 188 and soybean lecithin and containing 0.1% w/v indomethacin, had particles of diameter 0.21 0.02 im. The submicrometer systems (nanoparticles, nanocapsules, and emulsion) increased by more than three-fold the indomethacin concentration in the cornea, aqueous humor, and iris-ciliary body at 0.S and 1.0 h post instillation. Furthermore, an increased indomethacin bioavailability of 300% was observed in comparison with the value obtained for an aqueous commercial solution. Confocal laser scanning microscopy studies indicated (hat the submtcion particles penetrated into the comeal epithelium cells by endocyiosis (he audiors further suggested that the vehicle components (lecithin in the case of emulsions) may act as penetration enhancers or as endocytotic stimulators. 

Cholinergic hypersensitivity can be tested by using pilocarpine in 0.0625%, 0.1%, 0.125%, or 0.25% solution (Table 22-5).The usefulness of the pilocarpine test in eliciting cholinergic hypersensitivity depends on the presence of a standardized concentration of dmg at the iris. Thus any clinical procedure that compromises the corneal epithelium, the use of wetting agents, or other factors that enhance corneal penetration may result in false-positive findings. 

---