Development and evaluation of a novel dissolution apparatus for medicated chewing gum products.

A novel dissolution apparatus was developed for medicated chewing gum products. A prototype gum product containing phenylpropanolamine hydrochloride (PPA) was used to evaluate the apparatus. The apparatus consists of a conical Teflon base and a rotating, ribbed Teflon plunger suspended in a dissolution vessel. Parameters evaluated were rotation speed, plunger frequency, medium volume, medium type, medium sampling location, number of plunger ribs, and number of gum pieces. Samples were taken over a 20-min period and samples were analyzed by HPLC. Cumulative percentage released-versus-time profiles were obtained for each parameter evaluated. Statistical analysis of the gum product indicated that the only significant differences occurred at the lowest rotation speed and lowest plunger frequencies. A Level A correlation was found between the in vitro release profile for the 20-rpm and 30-cycles/min plunger frequency and the in vivo chew-out study.

Rectal bioavailability of delta-9-tetrahydrocannabinol from the hemisuccinate ester in monkeys.

Oral administration of delta-9-tetrahydrocannabinal (delta 9-THC) was shown to result in low and erratic bioavailability, while the drug showed no bioavailability from various suppository formulations. delta 9-THC-Hemisuccinate was formulated as a prodrug for delta 9-THC in suppositories using Witepsol H15 base. The bioavailability of delta 9-THC from this formulation was evaluated in monkeys. The plasma levels of delta 9-THC and its metabolite 11-nor-delta 9-THC-9-COOH were determined using GC/MS analysis. The calculated bioavailability of delta 9-THC from this formulation was found to be 13.5%. Non-compartmental analysis of the plasma concentration data using statistical moments showed the mean residence time (MRT) for delta 9-THC in the body to be 3 h following iv administration of delta 9-THC or its hemisuccinate ester (3.4 and 2.7 h, respectively), as compared with 5.8 h following rectal administration of the delta 9-THC hemisuccinate. The observed rectal bioavailability of delta 9-THC from suppositories containing the hemisuccinate ester as a prodrug is of significant importance in developing an alternative approach to oral administration of the drug.

Renal function during onset of carbachol-induced hypertension in conscious rats.

This study evaluated the changes in renal function that occur during the early phases of chronic infusion of carbachol into the lateral ventricle in conscious rats. Infusion of 1.0 micrograms/h of carbachol i.c.v. resulted in a prompt pressor response with mean arterial pressure rising 20 mm Hg within 15 min. The pressure remained elevated for the duration of a 2-hour infusion. Carbachol infusion at 0.5 micrograms/h induced a similar elevation in blood pressure, but the onset was delayed, reaching significance only after 30-60 min. The higher dose of carbachol was associated with a marked and sustained natriuresis, with sodium excretion increasing from 2.1 +/- 0.3 to 5.3 +/- 1.0 microEq/100 g min after 2 h, compared to 2.0 +/- 0.5 and 1.8 +/- 0.3 microEq/100 g min in vehicle-infused control animals. Sodium excretion did not change significantly in animals infused with carbachol at 0.5 microgram/h. There were no significant changes in glomerular filtration rate in any of the groups. Plasma levels of atrial natriuretic peptide (ANP) were not altered significantly by ventricular infusion of carbachol (188 +/- 99 before vs. 83 +/- 17 pg/ml after infusion). It is concluded that the pressor response to central carbachol infusion is not dependent on retention of sodium and water. The natriuresis observed with carbachol infusion can be dissociated from the pressor response, and is not mediated by ANP.