Pharmacokinetic modeling and simulations of gastrointestinal transit effects on drug pharmacokinetics from enteric-coated pellet formulations and their applications Public Deposited

http://ir.library.oregonstate.edu/concern/graduate_thesis_or_dissertations/2227mr78x

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  • Effects of gastrointestinal transit on plasma concentrations of drugs from enteric-coated pellet formulations were demonstrated using pharmacokinetic models describing plasma concentrations of drugs from various enteric-coated pellet formulations. Gastric emptying time, lag time of emptying, and drug release rate from pellets in the small intestine, along with other pharmacokinetic parameters of drugs, were used to construct pharmacokinetic models. The models were then evaluated by comparing simulated plasma concentrations of model drugs from Monte Carlo simulations to observed plasma concentrations of these drugs from the literature. Results showed that the models described plasma concentrations of drugs from enteric-coated pellet formulations very well. Pharmacokinetic models describing plasma concentrations of drug from mixed immediate-release and enteric-coated pellet formulations were also used in simulations of bioequivalence studies. Results from the research are very useful in designing generic products of mixed pellet formulation and in refining or selecting the final product for actual bioequivalence study. Development of crushable enteric-coated formulations was presented. Nonpareil sugar pellets were spray-loaded with mixed amphetamine salts. Drug-loaded pellets were subsequently spray-coated with enteric polymer, hydrophilic gel-forming polymer, enteric polymer and/or mixture of insoluble polymer and hydrophilic polymer. The resulting pellets were then spray-coated with disintegrant and compressed to form crushable tablets. Dissolution testing of both non-compacted crushable enteric-coated tablets and crushed tablets showed that the intact crushable tablet formulations and the crushed tablet formulations were able to prevent the majority of the drug from being released in a simulated gastric dissolution medium within first 2 hours. Concept and formulations of "leaky" enteric-coated pellets were presented. "Leaky enteric-coated pellets" formulation is defined as enteric-coated pellets that allow some of the drug to be released from the formulation in acidic dissolution medium. Different approaches of making leaky enteric-coated pellets using spray-coating techniques were presented. Plasma concentrations of drug from leaky enteric-coated pellet formulations were simulated using computer simulations. The present research was based on the hypothesis that leaky enteric-coated pellets formulations were able to provide sustained-release effect on plasma concentration profiles of drugs that have the absorption window without jeopardizing their bioavailability or with improved bioavailability.
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