Sublingual Absorption

Abstract: Eight healthy male volunteers received 16 doses of sublingual nitroglycerin tablets (0.4 mg). After 8 minutes, each subject rinsed out his mouth to halt the drug absorption process. The mouth rinses were assayed by high-performance liquid chromatography for residual nitroglycerin content. Each subject also received intravenous infusions of nitroglycerin so that the absolute bioavailability could be evaluated. Plasma nitroglycerin concentrations were determined using a specific and sensitive capillary gas chromatographic method capable of quantifying 25 pg/ml of nitroglycerin. The mean bioavailability (+/- standard deviation) of sublingual nitroglycerin, estimated from plasma concentrations, was 36.2 +/- 24.9% (range 2.6 to 113%). The amount of drug not absorbed after 8 minutes, as determined from the analysis of the mouth rinses, varied from 2.7 to 65.8% (mean 31.4 +/- 18.9%) of the administered sublingual dose. Mean nitroglycerin peak concentrations of 1.89 +/- 1.64 ng/ml were obtained at a mean peak time of 5.3 +/- 2.3 minutes. Thus, sublingual absorption is not instantaneous and can be relatively slow, with peak times of as long as 10 minutes. These data indicate that nitroglycerin pharmacokinetic values should not be estimated only from sublingual doses. Additionally, attempts to correlate pharmacodynamic measurements to sublingual doses must take into account the low and variable bioavailability and the potentially long peak times after sublingual nitroglycerin administration to patients.

Abstract: The present invention encompasses oral formulations of a PDE5 inhibitor which provide rapid disintegration after introduction to the oral cavity, followed by buccal and/or sublingual absorption. The orally disintegrating formulations can be in a variety of dosage forms including lingual strip, sublingual strip, oral mist, rapidly disintegrating tablet, lyophilized wafer, granulated particles and gum. The formulations can include an extended release component that allows the PDE5 inhibitor to be swallowed for gastrointestinal absorption. Combination therapies with a second pharmaceutical agent known to cause a PDE5-treatable condition as a side effect, such as erectile dysfunction, are also described. The PDE5 inhibitor of the following chemical structure is particularly favored for these formulations: formula (I).

Abstract: Isosorbide dinitrate (ISDN) kinetics and dynamics were examined after various routes of administration for angina. Given intravenously, ISDN kinetics were apparently linear over the range of infusion rate (0.083 and 0.133 mg /min) and duration (15 min and 1 and 2 hr) studied. Mean ± SD systemic clearance of ISDN was 3.4 ± 1.4 l/min and volume of distribution (Vdss or Vdarea) about 100 l. These data are consistent with the presence of extensive extrahepatic metabolism. In six patients, sublingual ISDN (5 mg) was also given and mean bioavailability of 59% (19% to 93%) for this route was determined. For this group, sublingual absorption of intact ISDN was incomplete and variable. The presence of a longer disappearance t½ after sublingual dosing suggested that the input process may be rate limiting. After percutaneous application of a topical formulation (100 mg over an area of 400 cm2), steady-state plasma concentrations at about 7 ng/ml were maintained from 6 to 24 hr. The bioavailability of the topical application was estimated at 30%. At the doses given, intravenous ISDN had no apparent effect on heart rate but induced significant reduction in standing systolic blood pressure. The effect vs the ISDN concentration profile was described by a hysteresis loop, indicating that changes in blood pressure response lag behind changes in plasma ISDN concentration. After intravenous dosing, peak plasma ISDN concentration and peak effect (maximum change in standing systolic blood pressure). At the doses used, both sublingual and percutaneous ISDN induced less distinct circulatory changes than the intravenous infusion. Clinical Pharmacology and Therapeutics (1983) 33, 747–756; doi:10.1038/clpt.1983.102