Molecular 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-... 

Diffusion of small molecular penetrants in polymers often assumes Fickian characteristics at temperatures above Tg of the system. As such, classical diffusion theory is sufficient for describing the mass transport, and a mutual diffusion coefficient can be determined unambiguously by sorption and permeation methods. For a penetrant molecule of a size comparable to that of the monomeric unit of a polymer, diffusion requires cooperative movement of several monomeric units. The mobility of the polymer chains thus controls the rate of diffusion, and factors affecting the chain mobility will also influence the diffusion coefficient. The key factors here are temperature and concentration. Increasing temperature enhances the Brownian motion of the polymer segments the effect is to weaken the interaction between chains and thus increase the interchain distance. A similar effect can be expected upon the addition of a small molecular penetrant. 

Figure 8 (A) In vitro permeability of candidate drug molecules in the presence of synergistic combinations of penetration enhancers (SCOPE) formulations. Open circles indicate passive skin permeability and closed circles indicate skin permeability in the presence of SCOPE formulations as a function of the molecular weight of the solute. (B) In vivo delivery of leuprolide acetate, a synthetic analogue of LHRH in hairless rat model, y-axis shows blood plasma concentration of leuprolide acetate as a function of time for control formulation (open circles) and SCOPE formulation (closed circles). Abbreviation-. LHRH, luteinizing hormone-releasing hormone.

It is difficult to select rationally a penetration enhancer for a given permeant. Accelerant potencies appear to be drug specific, or at best may be predictive for a series of permeants with similar physicochemical properties (such as similar partition coefficients, molecular weights, and solubilities). Some broad trends are apparent, such as the use of hydrocarbon monoterpenes for lipophilic permeants, but the level of enhancement expected for these agents is unpredictable. 

Penetration enhancers have been used to facilitate the absorption of higher molecular weight molecules. The mode of action of the surfactant enhancers is often attributed to membrane damage [37]. However, studies in epithelial cell monolayers suggest that some surfactant-based absorption enhancers act primarily by increasing the permeability of tight junctions [38]. Nevertheless, except for the chelators and nonsurfactants, which exert their... 

Liaw, J., and J.R. Robinson. 1992. The effect of polyethylene glycol molecular weight on corneal transport and related influence of penetration enhancers. Int J Pharm 88 125. 

Infrared microscopic imaging provides the significant advantages of direct spatially resolved concentration and molecular structure information for sample constituents. Raman microscopy (not further discussed in this chapter) possesses the additional benefit of confocal acquisition of this information and a 10-fold increase in spatial resolution at the expense of reduced signal-to-noise ratios compared with IR. The interested reader is urged to check the seminal studies of the Puppels group in Rotterdam,38 0 as well as our own initial efforts in this direction.41 The current section describes the initial applications of IR microspectroscopic imaging to monitor the permeation and tissue distribution of the dermal penetration enhancer, DMSO, in porcine skin as well as to track the extent of permeation of phospholipid vesicles. 

Most compounds of interest for nasal delivery have a molecular weight in excess of 1,000 Da and until recently were thought to cross the cells endocytically. However, a recent study in rats has shown the transport of fluoroscein isothiocyanate (FITC)-labeled dextran (M. Wt. = 3,000 Da) to be via the paracellular pathway, with only a proportion moving endocytically. Hardly any transport of FITC-labeled dextran with a molecular weight of 10,000 Da was observed unless a penetration enhancer was coadministered, but the penetration enhancer, sodium taurodihydrofusidate (STDHF), caused cell swelling and extrusion of mucus. 

It is therefore of importance to determine how diffusing molecules and potential penetration enhancers interact with the stractured lipids. This can be achieved using a number of spectroscopic techniques, which is the subject of other chapters in this book. Here the use of monolayers and neutron scattering is considered as techniques that can probe the molecular features of ordered lipids and how the ordering may be affected by the presence of enhancers. 

The studies just outlined indicate that neutron reflectometry has considerable potential for studying the mode of actions of skin penetration enhancers at a molecular level. Of particular interest in the field of percutaneous absorption... 

The objective of this book is to provide an up-to-date and critical evaluation of the application of biophysical tools and analysis for the determination of molecular transport across the skin. Both the nature of the passive permeability barrier and the impact of diverse penetration enhancement strategies are considered and discussed. 

Brain, K.R. Walters, K.A. Molecular modeling of skin permeation enhancement by chemical agents. In Pharmaceutical Skin Penetration Enhancement Walters, K.A., Hadgraft, J., Eds. Marcel Dekker, Inc. New York, 1993 389 16. 

Second, because of their molecular size and hydrophilic nature, peptide and protein drugs are poorly absorbed through the intestinal membrane, and absorption has to be improved. This may be accomplished by coadministration of penetration enhancers or by chemical modifications such as increasing lipo-philicity. 

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