Particle size reduction to the nanometer range: a promising approach to improve buccal absorption of poorly water-soluble drugs

Abstract

Poorly water-soluble drugs, such as phenylephrine, offer challenging problems for buccal drug delivery. In order to overcome these problems, particle size reduction (to the nanometer range) and cyclodextrin complexation were investigated for permeability enhancement. The apparent solubility in water and the buccal permeation of the original phenylephrine coarse powder, a phenylephrine-cyclodextrin complex and phenylephrine nanosuspensions were characterized. The particle size and particle surface properties of phenylephrine nanosuspensions were used to optimize the size reduction process. The optimized phenylephrine nanosuspension was then freeze dried and incorporated into a multi-layered buccal patch, consisting of a small tablet adhered to a mucoadhesive film, yielding a phenylephrine buccal product with good dosage accuracy and improved mucosal permeability. The design of the buccal patch allows for drug incorporation without the need to change the mucoadhesive component, and is potentially suited to a range of poorly water-soluble compounds.

Keywords: buccal drug delivery; mucoadhesion; nanosuspension; permeation enhancement; solubility.

Figure 1

Phenylephrine-containing buccal patch.

Figure 2

Transmucosal flux of phenylephrine through the porcine buccal mucosa versus the concentration of phenylephrine solution.

Figure 3

Permeation of phenylephrine through the porcine buccal mucosa, as a function of time. Results are shown for phenylephrine solution (9.91 mg/mL), phenylephrine-hydroxypropyl-β-cyclodextrin complex (PE-HPβCD) and phenylephrine nanosuspensions. In all cases, the dose that was applied was 2 mg of phenylephrine. Abbreviations: NPE1, nanosuspension prepared by milling in a mannitol aqueous solution; NPE2, nanosuspension prepared by high pressure homogenization of NPE1; DNPE, phenylephrine dry nanosuspension.

Figure 4

Permeation of phenylephrine through the porcine buccal mucosa, as a function of time. Results are shown for the buccal patch containing coarse phenylephrine powder in the microtablet (PMT1), and the buccal patch containing phenylephrine dry nanosuspension in the microtablet (PMT2).