Gastrointestinal (GI) transit data were collected using pigs as animal models. Density and size effects of non-disintegrating dosage forms on GI transit were investigated. Total GI transit times range from 2 to 33 days for 22 administrations of these nondisintegrating dosage forms. Pigs are found to not be an appropriate animal model for studying bioavailability or GI transit of non-disintegrating, non-erodible oral release dosage forms. Development of controlled release dosage forms where the mechanism of drug release is diffusion through polymeric membrane formed via film coating utilizing fluid-bed technology requires optimization of several processing and formulation variables. The influence of a processing variable (nozzle orifice opening) and a few formulation variables (individual vs. combination plasticizer, or a water-insoluble additive) on dissolution of a model drug (acetaminophen) spray coated with Aquacoat® were studied. Pharmacodynamic and pharmacokinetic information for a model drug (acetaminophen) and computer simulation were used to develop a dosage form with a 12 hour sustained release for oral administration to children and adults for maximum analgesic and antipyretic effect. Simulated plasma acetaminophen concentration-time curves were similar to observed bioavailability study profiles. In vitro and preliminary in vivo results from an adult human volunteer indicate that sustained therapeutic saliva acetaminophen concentration is possible using the newly developed acetaminophen molded tablet dosage form. The bioavailability of the new, oral controlled release acetaminophen molded tablet relative to a commercially available product (Extra-Strength Tylenol® caplet) was evaluated in 8 healthy, adult volunteers. Multiple doses of these two products were administered in a two-way cross-over design. Bioavailability of the new sustained release molded tablet is comparable to that of the immediate release product. Polymer coated acetaminophen beads were effective in maintaining saliva acetaminophen concentrations of 5 μ/ml over a 12 hour dosing interval. / Graduation date: 1991

Graduation date: 1993

Acetaminophen has been safely used for analgesia for many years. Literature suggests that a plasma acetaminophen level of 5��g/ml is necessary to maintain analgesic relief in humans. Current dosing regiments are inconvenient (every 4-6 hours) and do not maintain this minimum plasma level. Simulations were conducted to examine various doses and input rates for sustained release formulations of acetaminophen. Once parameters were selected from the simulations, sample formulations were prepared and tested using standard dissolution techniques. Investigations into dose/size relationships, hydroxypropylmethylcellulose (HPMC) percentage for erosion matrix tablets, compression force, tablet shape, tablet divisibility, and granulation methods were performed for non-disintegrating hydrophilic matrix tablets. Tablets containing 5% and 7.5% HPMC were selected for pharmacokinetic study in 10 healthy human subjects. Tylenol Extra Strength and Tylenol Extended Relief tablets were administered as control formulations. Pharmacokinetic fitting of the kinetic profiles of all four formulations were performed using Win Nonlin. The formulations were best described by a 1-compartment open model with first order input and first order elimination. The 5% HPMC sustained release acetaminophen formulation was selected for Phase II clinical trials. Patients with osteoarthritis of the knee were recruited for a double blind crossover study of 5% HPMC sustained release acetaminophen formulations and immediate release acetaminophen. Patients received two tablets of study medication, four times a day for 4 weeks. After a seven day wash-out period patients were then crossed over to the other treatment. Patients were evaluated using a twelve question questionnaire and the time to walk 50 feet was measured. Thirty patients were enrolled in the study and seventeen patients completed the study. The sustained release formulations were statistically superior to the baseline treatments in reducing pain level, decreasing disability, and improving the duration of pain relief. Additional, larger scale studies are needed to confirm these findings. / Graduation date: 2000

Graduation date: 2003