Abstract
The ability of sodium caprylate and l-menthol to fluidize phospholipid bilayers composed of lipids simulating the buccal epithelium was investigated using electron spin resonance (ESR) to evaluate the action of these agents as permeation enhancers. 5-Doxyl stearic acid (5-DSA) and 16-doxyl stearic acid (16-DSA) were used as spin labels to identify alterations in membrane fluidity near the polar head groups or inner acyl regions of the lipid bilayer, respectively. The molecular motion of both 5-DSA and 16-DSA showed increased disorder near the polar and inner hydrophobic regions of the bilayer in the presence of sodium caprylate suggesting fluidization in both the regions, which contributes to its permeation enhancing effects. L-menthol decreased the order parameter for 16-DSA, showing membrane fluidization only in the inner acyl regions of the bilayer, which also corresponded to its weaker permeation enhancing effects. The rapid evaluation of changes in fluidity of the bilayer in the presence of potential permeation enhancers using ESR enables improved selection of effective permeation enhancers and enhancer combinations based on their effect on membrane fluidization.
Highlights
Buccal drug delivery is an alternative to oral and parenteral administration due to the potential for rapid absorption and the lower enzymatic activity present in the buccal tissues compared to the GI lumen, mucosa, and liver [1,2,3]
These results suggest that 5% sodium caprylate alone and in combination with 1% l-menthol can increase the bilayer fluidity in the region close to the polar head groups, but l-menthol failed to generate any change in fluidity in that region
The electron spin resonance (ESR) studies investigating model buccal lipid bilayers were conducted at room temperature, and it is likely that the fluidity of these lipids would be increased at physiologic temperatures, similar to the results reported by Ogiso et al where the fluidity of stratum corneum lipids was increased with an increase in temperature (25–50 ◦C) [52]
Summary
Buccal drug delivery is an alternative to oral and parenteral administration due to the potential for rapid absorption and the lower enzymatic activity present in the buccal tissues compared to the GI lumen, mucosa, and liver [1,2,3]. Mona et al investigated the suitability of mucoadhesive, hybridized nanovesicles loaded with ciclopiroxolamine (antimycotic agent) along with permeation enhancers (LabrafacTM or Labrasol), and their results showed excellent permeation enhancement resulting in superior therapy for buccal candidiasis [16] Despite their frequent incorporation into buccal delivery systems, the mechanisms by which most enhancers increase the permeation of drugs are not well understood. Several techniques, including differential scanning calorimetry (DSC) [19], infrared spectroscopy (FTIR) [20], small-angle X-ray diffraction [21], Raman spectroscopy [22], and electron spin resonance (ESR) [23] have been used to investigate the interaction of permeation enhancers with cell membrane components, both in the skin and in the buccal mucosa These techniques have been used to investigate physical or chemical changes or interactions in membranes following exposure to permeation enhancers in efforts to identify the molecular-level alterations that result in increased barrier permeability. These unexpected complimentary actions warranted further investigation to determine how the enhancers were interacting with the buccal barrier in order to design improved delivery systems containing single or synergistic combinations of permeation enhancers
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