Low molecular mass permeation enhancers

Low Molecular Mass Permeation Enhancers in Oral Delivery of Macromolecular Drugs... 

Generally, low molecular mass permeation enhancers can be divided into transcellular and paracellular permeation enhancers. On the one hand the potential of permeation enhancers to open the paracellular route of uptake can be determined by the reduction in the transepithelial electrical resistance (TEER) (enhancement potential = EP). On the other hand the potential of permeation enhancers to open the transcellular route of uptake can be determined by the lactate dehydrogenase (LDH) assay (LDH potential = LP). The parameter K = (EP—LP)/EP represents the relative contribution of the paracellular pathway. Consequently, a K value of 0 means predominantly transcellular and a K value of 1 means predominantly paracellular. Based on this classification system Whitehead and Mitragotri classified over 50 low molecular mass permeation enhancers showing that most of them are paracellular and only a few of them are transcellular permeation enhancers (2008). 

Low molecular mass permeation enhancers include numerous classes of compounds with diverse chemical properties including detergents, surfactants, N-acetylated x-amino acids, N-acetylated non-a-amino acids, fatty acids, medium-chain mono- and diglycerides, acyl carnitine, alkanoyl cholines, Ca2 + chelating agents, zonula occludens toxins and NO donors. 

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... 

Oral Macromolecular Drug Delivery Systems Containing Low Molecular Mass Permeation Enhancers... 

Within the last decades strong evidence has been provided on the potential of various types of low molecular mass permeation enhancers to improve the oral uptake of macromolecular drugs. Nevertheless, so far no oral macromolecular drug delivery system comprising a low molecular mass permeation enhancer has entered the market indicating that the permeation-enhancing properties of these enhancers are still associated with too high toxic risks. 

Having the great potential of low molecular mass permeation enhancers in mind and taking all the opportunities ahead into consideration, this class of permeation enhancers will certainly further alter the landscape of drug delivery towards more efficient therapeutic systems. This chapter should encourage and motivate scientists in academia and industry to move on or intensify their activities in this challenging research field. 

Strategies to overcome the absorption barrier focus on the other hand on low molecular mass permeation enhancers (Chapter 5) such as medium chain fatty acids, which can still be regarded as a kind of gold standard. As low molecular mass permeation enhancers are per se rapidly uptaken from the gastrointestinal mucosa, however, the macromolecular drug is to a considerable high extent left alone behind in the gastrointestinal tract. In addition, local and systemic toxic side effects of low molecular mass permeation enhancers cannot be excluded. In contrast, polymeric permeation enhancers (Chapter 6) are simply too big to be absorbed from the GI tract. Consequently, systemic toxic side effects can be excluded. More recently various excipients could be identified as potent efflux pump inhibitors which can be subdivided into low molecular mass efflux pump inhibitors and polymeric efflux pump inhibitors (Chapter 7). Certain polymeric... 

Low molecular mass permeation enhancer 1376 Lower limit of quantification (LLOQ) 1575 Lowhepa 457 Lowmorin 457 Luciferase 1224 Luciferin 1224 Lufa cylindrica 484 Lugol s iodine 502 Lung... 

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