Cell permeation enhancers

Although the objective of most absorption enhancers is to avoid direct interaction with the mucosal membrane, cell permeation enhancers use this as a means to increase drug absorption. One form of enhancer currently of interest consists of glycosylated molecules, or facial amphiphiles. It is claimed that these compounds temporarily increase membrane permeability. Molecules are designed to self-assemble in membranes to form transient pores that permit hydrophilic com-poimds to cross the membrane. This technology has considerable potential for absorption enhancement. No adverse effects have been reported to date. ... 

Extent of Damage to Mucosal Cells. Permeation enhancement implies possible alteration of the protective permeability barrier either by 1) an increase in the fludity of intercellular lipids (relatively non-toxic) and/ or 2) extraction of intercellular lipids or denaturation of cellular proteins (much more damaging/toxic). Therefore, it is imperative that the permeation enhancer 1) exert a reversible effect 2) not be systemically absorbed and 3) not cause cumulative toxicity or permanent changes in the barrier properties. Application of up to 1% sodium lauryl sulfate or cetylpyridinium chloride to the ventral surface of the tongue of dogs resulted in desquamation, widening and separation of keratin.f The buccal mucosa of rabbits treated with... 

Caco-2 cells have been valuable in the estimation of drug absorption potential, transport mechanisms, and effect of permeation enhancers on transepithelial transport.35,39,53,67-69,78-81 Owing to the sensitivity of the cells and the limited solubility of new molecular entities, Caco-2 permeability studies are routinely done with relatively low concentration of compounds. One way to increase the solubility of these compounds is to use organic solvents. The low tolerability of Caco-2 cells to organic solvents limits the use of this approach in permeability studies. 

In recent studies both in vitro (Caco-2 cells) and in vivo in rats, TMC with a degree of trimethylation of 60% was proven to be an excellent intestinal absorption enhancer of the peptide drugs buserelin and octreotide. The observed absolute bioavailability values were 13 and 16% for buserelin and octreotide, respectively [83] (impublished data Fig. 5). Permeation enhancing effects were more responsible for these increased bioavailabilities, rather than the mucoadhesive properties of the TMC polymers. Nevertheless, mucoadhesion is a prerequisite for these polymers in order to further act as absorption enhancers. 

Other Toxicity Concerns. Additional toxicity concerns include interference with normal metabolism and function of mucosal cells, for example, water absorption by these cells [80]. The unconjugated bile acids are known to block amino acid metabolism [81] and glucose transport [82]. There is a possibility of biotransformation of these enhancers to toxic or carcinogenic substances by hepatic monooxygenases [83]. Absorption of permeation enhancers into the systemic circulation can also cause toxicity, for example, azone [84] and hexamethylene lauramide [85] which are absorbed... 

To achieve a reasonable degree of absorption, peptide and protein pharmaceuticals may need permeation enhancers to promote passage across mucosal cells. Another concern is that studies of insulin and enkephalin in animals suggest that protease activity may be high, especially in the rectal cavity [5,6]. On the other hand, the density of lymphatic vessels and drainage therein at these sites may be advantageous compared with other routes of administration. 

Pharmaceutical scientists assess and express drug permeation across membrane barriers in terms of flux. Flux measures the molar unit of a drug that permeates a resistant barrier (e.g., skin or gastrointestinal epithelial cells) per unit time and surface area (Box 13.1). Permeation enhancers, such as alcohols and surfactants, increase flux by modulating resistance factors that counteract drug diffusion across barriers at the site of administration. 

Receptor-mediated transporters are excipients that serve as substrates to exploit specific receptors present on cell membranes. Examples of various receptors that have been explored for permeation enhancement include bile acids (45), vitamin Bi2 (46), amino acids (47), and folic acid (48). Most of the work in receptor-mediated transporters is conducted via the use of prodrugs. For example, a prodrug of acyclovir conjugated to bile acids was seen to have higher permeability as compared to the original drug, because of receptor-mediated transport of the prodrug via bile acid transporters (49). 

Burgalassi, S., et al. 2001. Cytotoxicity of potential ocular permeation enhancers evaluated on rabbit and human corneal epithelial cell lines. Toxicol Lett 122 1. 

The dead cells on the surface of skin offer a formidable barrier to drugs. The use of permeation enhancers in controlled delivery patches and techniques such as iontophoresis, electroporation, and ultrasound are applied to enhance the permeation of drugs across skin.131... 

Some of these low molecular mass permeation enhancers act as surfactants/ detergents to increase the transcelluar transport of more lipophilic drugs by disrupting the structure of the lipid bilayer and rendering the cell membrane... 

In orientating toxicity studies palmitoyl-DL-carnitine chloride and lauroyl choline were shown to cause only slight alterations of the mucosal cell structure of jejunum and colon under prolonged exposure when being tested in permeation-enhancing concentrations (LeCluyse et al. 1993 Fix et al. 1996). In another study on Caco-2 monolayers, however, palmitoyl-DL-carnitine chloride caused LDH release, increased uptake of propidium iodide and reduced neutral red retention, in concentrations needed to provide an improved uptake of PEG 4000 (Duizer et al. 1998). 

Furthermore, the permeation-enhancing effects of NO donors seem to be strongly dose-dependent. Utoguchi et al. (1998) reported that the absorptionenhancing effect of S-nitroso-A-acetyl-penicillamine for rectal insulin absorption was dose-dependent over the range of 0.25-4.0 mg in rats. Similarly, Salzman et al. (1995) demonstrated that incubation with sodium nitroprusside resulted in a concentration-dependent increase in the transepithelial transport of fluorescein sulphonic acid in Caco-2 cells. To our knowledge the potential of NO donors for oral macromolecular delivery, however, has so far not been tested in a valid animal model. 

Another aspect from the drug delivery point of view is the combined use of different types of permeation enhancers in the same formulation. Whitehead et al. (2008), for instance, could show a synergistic effect of binary combinations of hexylamine and chembetaine and ternary combinations of sodium laureth sulphate, decyltrimethyl ammonium bromide and chembetaine on the uptake of 70 kDa dextran from Caco-2 monolayer while inducing very little toxicity in Caco-2 cells. 

Sadeghi, A.M.M., Dorkoosh, F.A., Avadi, M.R., Bayat, A., Delie, F., Gurny, R., Rafieeh-Tehrani, M. and Junginger, H.E. (2008a) Permeation enhancer effect of chit-osan and chitosan derivatives comparison of formulations as soluble polymers and nanoparticulate systems on insulin absorption in Caco-2 cells. Eur. J. Pharm. Bio-pharm. 70 270-278. 

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