Salivary Flow Induction by Buccal Permucosal Pilocarpine in Anesthetized Beagle Dogs

We tested whether permucosal delivery of pilocarpine nitrate could be used to elicit significant salivary secretion. Pilocarpine (pKa 6.6 at 37°C) was applied as solutions (pHs 5.6, 6.6, 7.6; 15 mg/mL) to the buccal mucosa (2.8 cm2) of 6 anesthetized dogs. Saliva was collected continuously from cannulated submandibular and parotid ducts and blood sampled during and after drug administration. Plasma pilocarpine levels were determined by reversed-phase HPLC. Absorption rates were determined by use of data from separate zero-order intravenous infusions to the same dogs. Pilocarpine was buccally absorbed at a constant rate of 72.9 ± 38.5 μg/kg/h following its application at pH 7.6. At this pH of the drug solution, the time to appearance of pilocarpine in blood plasma was 0.31 ± 0.08 h, and the time to appearance of salivary flow was 0.86 ± 0.32 h. A threshold dose of 32.9 ± 7.5 ug/kg was required to induce secretion with the pH 7.6 drug, the steady-state plasma concentration was 28.9 ± 19.3 ng/mL, and the steady-state submandibular flow rate was 0.14 ± 0.11 mL/ min/gland pair. Salivary flow induction was symmetrical and reached levels as high as 0.35 mL/min/submandibular gland pair without apparent tachyphylaxis. Results at pHs 5.6, 6.6, and 7.6 were consistent with the hypothesis that pilocarpine is primarily absorbed as un-ionized drug. The data indicate that transmucosal delivery of pilocarpine, avoiding "first pass" hepatic loss, may hold promise for the treatment of xerostomia.