Permeation enhancement

Permeation enhancers are used to improve absorption through the gastric mucosa. Eor example, oral dehvery of insulin (mol wt = 6000) has been reported from a water-in-oH- emulsion containing lecithin, nonesterified fatty acids, cholesterol [57-88-5], and the protease inhibitor aprotinin [9087-70-1] (23). 

Drug Permeation Enhancement Theory and Applications, edited by Dean S. Hsieh... 

Hwang, T.-L., Fang, C.-L., Chen, C.-H. and Fang, J.-Y. (2009) Permeation enhancer-containing water-in-oil nanoemulsions as carriers for intravesical cisplatin delivery. Pharmacological Research, 26 (10), 2314-2323. 

Encapsulation within an enteric coat (resistant to low pH values) protects the product during stomach transit. Microcapsules/spheres utilized have been made from various polymeric substances, including cellulose, polyvinyl alcohol, polymethylacrylates and polystyrene. Delivery systems based upon the use of liposomes and cyclodextrin-protective coats have also been developed. Included in some such systems also are protease inhibitors, such as aprotinin and ovomucoids. Permeation enhancers employed are usually detergent-based substances, which can enhance absorption through the gastrointestinal lining. 

Shojaei AH, Khan M, Lim G, Khosravan R (1999) Transbuccal permeation of a nucleoside analog, dideoxycytidine Effects of menthol as a permeation enhancer. IntJPharm 192 139-146... 

The ex vivo methods lend themselves easily for the performance of mechanistic investigations. In order to optimize selection of drug candidates prior to further clinical development, it is important to decipher the contributive roles of permeation, metabolism, efflux, and toxicity. This will then make it possible to properly channel the optimization process, for instance, by permeation enhancement, mucoadhesion, modification of the physicochemical characteristics of the drug, or even change in the route of administration in case the drug and/or formulation turns out to be too toxic. Regarding permeability studies, it is possible not only to quantify passive diffusion but also to identify and characterize (compound)-specific carrier-mediated transport routes. These tools have been used to identify and characterize the relative contribution of... 

The major strategies to enhance transmucosal peptide and other drug absorption include (a) coadministration with protease inhibitors, (b) the use of membrane permeation enhancers, (c) coadministration with a combination of absorption enhancers and protease inhibitors, (d) modification of peptide structure to improve metabolic stability or membrane permeation, and (e) use of nano- or microparticles [27], Some of these strategies have been investigated using the in situ rat model. 

At present, despite the advantages offered by the buccal delivery route, such as the bypass of intestinal and hepatic first-pass metabolism for systemic delivery, very few pharmaceutical products employ this route of administration. The reasons that contribute to this situation include (1) high costs associated with development, (2) lack of standardized tests to identify drug candidates suitability for this route, (3) the limited understanding of the impact of metabolism and/or transporters found in the oral cavity mucosa on buccal delivery, and (4) the relatively small number of reports describing the usefulness and safety of excipients/permeation enhancers in humans [82, 83], Therefore, the... 

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. 

Mucus also appears to be a barrier to the permeation enhancing effect of polymeric or monomeric absorption enhancers. In the above mentioned TMC studies, the enhancement effect (enhancement ratio = permeation rate of the drug in the presence... 

A buccal drug delivery system is applied to a specific area on the buccal membrane. Moreover, the delivery system ean be designed to be unidirectional in drug release so that it can be protected from the loeal environment of the oral cavity. It also permits the inclusion of a permeation enhancer/protease inhibitor or pH modifier in the formulation to modulate the membrane or the tablet-mucosal environment at that particular application site. While the irritation is limited to the well-defined area, the systemic toxicity of these enhancers/inhibitors and modifiers can be reduced. The buccal mucosa is well suited for this type of modification as it is less prone to irreversible damage [9]. In the event of drug toxicity, delivery can be terminated promptly by removal of the dosage form. 

Assessment of Membrane Damage. Several methods are commonly used to estimate the damage to biological membranes caused by various permeation enhancers. The following methods comprise a partial listing ... 

Determination of the extent of hemolysis caused by a permeation enhancer [70],... 

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... 

Catz, P. and Friend, D.R. Alkyl esters as skin permeation enhancers for indomethacin, Int. J. Pharm., 55(l) 17-23, 1989. 

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. 

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