Factors Contributing to Drug Release From Enteric-Coated Omeprazole Capsules: An In Vitro and In Vivo Pharmacokinetic Study and IVIVC Evaluation in Beagle Dogs

Abstract

This study was performed to explore factors influencing the release of the proton pump inhibitor omeprazole from entericcoated capsules in vitro and absorption in vivo in beagle dogs. Enteric-coated pellets with different enteric coating materials and coating levels were designed and prepared. All self-prepared formulations were characterized in vitro as well as in vivo and compared to the brand and generic commercial products. Evaluation of the corresponding release profiles suggested that coating material was the most critical factor. Enteric coating level determined the lag time before initiation of drug release, and subcoating level affected the drug release rate. Pharmacokinetic studies were performed in beagle dogs to further confirm the influence of formulation factors on drug absorption. Medium at pH 6.8 was a more biorelevant condition for in vitro drug release tests, although medium at pH 6.0 was better for discriminating release profiles of different formulations. A multiple level C in vitro/in vivo correlation was preliminarily established by which T max and C max of omeprazole formulations could be predicted with release parameters such as T lag and T 25 . These results may facilitate quality evaluation and potentially improve the clinical efficacy of generic omeprazole products.

A prospective, randomized, masked, placebo‐controlled crossover study for the effect of 10 mg omeprazole capsules on gastric pH in healthy dogs

“…Differences in enteric coating layer characteristics could result in differences in the drug's pharmacokinetic 6 and pharmacodynamic profile in dogs. There is no FDA, or other regulatory body, ‐approved omeprazole product for administration in dogs that would ensure consistency and quality of the product including an encapsulated formulation.…”

“…The enteric coating is designed to be degraded at a specific pH such that the drug can avoid premature degradation in the stomach and be released and absorbed in the small intestine either immediately upon entering the intestine, or over the course of small intestinal transit. The enteric‐coating characteristics, including thickness and polymer composition, determine the lag time before initiation of drug release and the subcoating characteristics affect the drug release rate 6 . In a recent study evaluating 1 branded, 1 generic, and several self‐prepared omeprazole capsules with different drug coating materials, the drug's enteric‐coated layer had a dramatic effect on in vitro drug release as well as the pharmacokinetics of PO administered omeprazole in beagle dogs 6 .…”

“…The enteric‐coating characteristics, including thickness and polymer composition, determine the lag time before initiation of drug release and the subcoating characteristics affect the drug release rate 6 . In a recent study evaluating 1 branded, 1 generic, and several self‐prepared omeprazole capsules with different drug coating materials, the drug's enteric‐coated layer had a dramatic effect on in vitro drug release as well as the pharmacokinetics of PO administered omeprazole in beagle dogs 6 . The effect of the various products on increasing intragastric pH in dogs was not assessed.…”

“…6 In a recent study evaluating 1 branded, 1 generic, and several self-prepared omeprazole capsules with different drug coating materials, the drug's entericcoated layer had a dramatic effect on in vitro drug release as well as the pharmacokinetics of PO administered omeprazole in beagle dogs. 6 The effect of the various products on increasing intragastric pH in dogs was not assessed. These results suggest a demand for further evaluation of the efficacy of encapsulated omeprazole in dogs and the need for a consistent and efficacious omeprazole product that can be easily dosed to a variety of dog sizes.…”

Impact of gastrointestinal differences in veterinary species on the oral drug solubility, in vivo dissolution, and formulation of veterinary therapeutics

“…It should also be noted that while excipients associated with enteric coating have been explored for use in dogs [ 96 , 97 ], the pH at which drug release occurs needs to be carefully evaluated to insure the ability to withstand fluctuations in canine gastric pH and the location of drug release does not compromise oral bioavailability (when considering the relatively rapid transit through the small intestine). Clearly, more work is needed on this topic, with a focus on the relationship between formulation selection and the drug molecule.…”