Permeation Enhancement Mechanism

Microwave promotes fluidization of stratum corneum via lipid/keratin interation 

Negatively chained pectindecorated liposomes fluidize stratum corneum via rq ulsion against skin lipid 

Muo adhesive pectin increases the contact between drug and skin. 

Ahrabi S. F., Madsen G., Dyrstad K., Sande S. A., Graffner C. [2000]. Development of pectin matrix tablets for colonic delivery of model drug ropivacaine. Eur. I. Pharm. Set. 10, 43-52. 

Andrews G. R, Laverty T. R, Jones D. S. (2009). Mucoadhesive polymeric platforms for controlled drug delivery. 

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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. 

Permeation enhancement by excipients has generated some interest, but there is still much research that needs to be done to elucidate the mechanism of these excipients. PEG-400 (and many other excipients such as polyethylene glycol, poloxamers, polysorbates, and vitamin E) is known to inhibit p-glycoprotein, which may increase the bioavailability of the API, which was a substrate for this efflux pump. On the other hand, it has been demonstrated that PEG-400 can accelerate small intestinal transit, and thereby reduce the bioavailability of some drugs (e.g., ranitidine) (5). 

To understand the mechanism of action of permeation enhancers, the routes by which drugs are absorbed first need to be considered. Chapter 9 reviews the basic biopharmaceutics of buccal and sublingual drug delivery, so only a very brief discussion of this in the context of permeation enhancement will be given below. 

Fatty acid esters would be predicted to have little irritation or toxic effects. Ex vivo permeability studies conducted in porcine buccal mucosa showed significant permeation enhancement of an enkephalin from liquid crystalline phases of glycerine monooleate [32]. These were reported to enhance peptide absorption by a cotransport mechanism. Diethylene glycol monoethyl ether was reported to enhance the permeation of essential oil components of Salvia desoleana through porcine buccal mucosa from a topical microemulsion gel formulation [33]. Some sucrose fatty acid esters, namely, sucrose laurate, sucrose oleate, sucrose palmitate, and sucrose stearate, were investigated on the permeation of lidocaine hydrochloride [34], with 1.5% w/v sucrose laurate showing a 22-fold increase in the enhancement ratio. 

Godin, B., and E. Touitou. 2004. Mechanism of bacitracin permeation enhancement through the skin and cellular membranes from an ethosomal carrier. J Control Release 94 365. 

A permeation enhancer can be defined as a compound that alters the skin barrier function so that a desired drug can permeate at a faster rate. Dozens of enhancers are patented each year, and several books have been written summarizing the work and proposing mechanisms of enhancement.70-72 The permeation enhancers may be classified simply as polar and nonpolar ones. They can be used individually or in combination, such as binary mixtures. For several drugs, the flux across skin was observed to be linear with that of the most widely used enhancer, ethanol.73-75 Another polar enhancer, isopropanol, facilitated ion association of charged molecules and enhanced the transport of both neutral and ionic species across the stratum corneum.76 77 While polar enhancers traverse the skin, nonpolar enhancers are largely retained in the stratum corneum both aspects make the combination a superior enhancer to the individual enhancers.78... 

A new generation of transdermal drug delivery (TDD) system was developed to contain one or more skin permeation enhancers in the surface adhesive coating layers. This TDD system has been found, experimentally, to release the enhancers to the surface of stratum corneum to modify the skin s barrier properties, prior to the controlled delivery of the active drug. The extent of enhancement in skin permeability appears to be dependent upon the chemical structure of drug to be delivered transdermally as well as the type and the concentration of enhancer used. The mechanism of skin permeation enhancement have been explored and are analyzed in this report. 

As the surface concentration of enhancer in the adhesive coating increased, the mechanism of skin permeation enhancement showed some changes as reflected in the relative contribution of fatty matrix and protein gel pathways (Table VII ). The behavior for azone and oleic acid at high concentration was observed to be identical to that at low concentration (compare the data in... 

Tirucherai, G. S., Dias, C., and Mitra, A. K. (2002), Corneal permeation of ganciclovir Mechanism of ganciclovir permeation enhancement by acyl ester prodrug design, I. Ocul. Pharmacol. Then, 18(6), 535-548. 

The substantial contributions of calorimetry and infrared spectroscopy to our knowledge base of SC biophysics speaks for themselves. Most notably, the pivotal role of the intercellular lipid domains in SC barrier function has been elucidated and has elevated the understanding of this complex membrane to a new level. In turn, this has allowed mechanisms of permeation and mechanisms of penetration enhancement to be examined and identified. Furthermore, the opportunity to monitor the uptake and distribution of topically administered chemicals into and within the SC offers a level of detail and quantification of the permeation process, in vivo in humans, that was unimaginable a decade ago. The variety of potential applications of these findings is considerable and will form the basis of substantial further work. 

Different mechanisms of absorption enhancement for these permeation enhancers have been proposed. Most permeation enhancers are thought to disrupt the lipid bilayer, which increases membrane fluidity. Some enhancers (non-ionic and presumably ionic... 

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