Effect of surfactants and pH on naltrexone (NTX) permeation across buccal mucosa

The objective of this pre-formulation study was to systematically investigate the effects of two surfactants (Brij 58® and Tween 80®) and change in solution pH on in vitro permeation of naltrexone HCl (NTX-HCl) across tissue engineered human buccal mucosa. For the study, 10 mg/ml solutions of Tween 80® (0.1 and 1%, w/v) and Brij 58® (1%, w/v) were prepared in standard artificial saliva buffer solution (pH 6.8). For studying pH effects, solution pH was adjusted to either 7.5 or 8.2. As controls, three concentrations of NTX-HCl (2.5, 10 and 25 mg/ml) were prepared. Using NTX standard solution (10 mg/ml; pH 6.8), the permeation was observed between in vitro human and ex vivo porcine mucosa. It was observed that Brij 58® increased the permeation rates of NTX significantly. The flux of 10 mg/ml solution (pH 6.8) increased from 1.9 ± 0.6 (×102) to 13.9 ± 2.2 (×102) μg/(cm2 h) (approximately 6-fold) in presence of 1% Brij 58®. Increasing pH of NTX-HCl solution was found to increase the drug flux from 1.9 ± 0.6 (×102) (pH 6.8) to 3.0 ± 0.6 (×102) (pH 7.4) and 8.0 ± 3.5 (×102) (pH 8.2) μg/(cm2 h), respectively. Histological analyses exhibited no tissue damage due to exposure of buccal tissue to Brij 58®. The mean permeability coefficients (Kp) for 2.5, 10 and 25 mg/ml solutions of NTX-HCl (pH 6.8) were 5.0 (×10−2), 1.8 (×10−2) and 3.2 (×10−2) cm/h, respectively, consistent with data from published literature sources. Increase of NTX flux observed with 1% Brij 58® solution may be due to the effects of ATP. Increase in flux and the shortening of lag time observed by increasing in solution pH confirmed earlier finding that distribution coefficient (log D) of NTX is significantly affected by small increments in pH value and therefore plays an important role in NTX permeation by allowing faster diffusion across tissue engineered human buccal tissue.

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