Salivary Flow Induction by Buccal Permucosal Pilocarpine in Anesthetized Beagle Dogs

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Abstract
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.

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