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Development of a Clinically Relevant Dissolution Approach to Simulate Physiological Forces with a USP 2 Apparatus: “Peristaltic Dissolution”

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Abstract

Purpose

Gastrointestinal hydrodynamics are poorly replicated in vitro and can significantly alter the release kinetics of drug products due to compressive forces in the stomach and peristaltic movement in the intestines. In this work, we describe the development and application of a predictive in vitro dissolution device that simulates gastrointestinal forces for the testing of oral drug products. The peristaltic dissolution device developed herein is designed as an addition to the common USP Apparatus 2 that applies repetitive compressive forces via a piston during dissolution testing of a product to replicate in vivo conditions.

Methods

A dissolution testing device was designed, fabricated, and evaluated against human in vivo pharmacokinetic data to better mimic the physical forces present in the gastrointestinal tract. An optimized compression protocol to predict in vivo dissolution was developed using clinical data from two modified release carvedilol drug products. The apparatus was further evaluated using data from an additional modified release drug product. Finally, additional dissolution studies were performed to evaluate the utility of the apparatus for in vitro analysis of medicated gums, gastric retentive formulations, and long-acting injectable drug depots.

Results

The device was successfully implemented and the protocol to use the device was optimized using two initial drug products and further evaluated using an additional three drug products. The optimized protocol included a 1-h lag time (applicable in the fed state), followed by a cycle of 3 s of compression with 6 s intervals between compressions. Additional applications of the peristaltic dissolution device were also demonstrated through small exploratory studies, with continued potential for further optimization of the testing protocols following further research.

Conclusion

This simple compressive device referred to as the “peristaltic dissolution device” was successfully proven to better predict in vivo performance of modified release drug products, as gastrointestinal mechanical forces have been observed to significantly impact and occasionally cause complete dose dumping of controlled release formulations. In addition, it has proven to be easily adapted for evaluation of other drug products such as medicated gums, gastric retentive formulations, and ex vivo long-acting injectable drug depots.

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Data Availability

Clinical data used in this manuscript has been previously published and citations to the published data are included herein.

Abbreviations

API:

Active pharmaceutical ingredient

BSA:

Bovine serum albumin

CTAB:

Cetyltrimethylammonium bromide

GI:

Gastrointestinal

GSK:

GlaxoSmithKline

IVIVC:

In vitro–in vivo correlation

LOD:

Limit of detection

PBS:

Phosphate buffered saline

PEG:

Polyethylene glycol

PK:

Pharmacokinetics

QbD:

Quality by design

TNO TIM-1:

TNO [organization name] intestinal model 1

UHPLC/MS:

Ultra-high performance liquid chromatography–mass spectrometry

USP:

United States Pharmacopeia

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Acknowledgments

The authors would like to acknowledge the Jeff Seely and Distek team for continuing development work on the Peristaltic Dissolution Device, as well as David Curran, Stefania Beato, Nena Mistry, Paul Connolly, Richard Lloyd, Lihua Zhang, Philip Barish, Brian Zimmerman, Mark Coffin, Alan Parr, and David DeMagistris for their technical expertise and work in support of this project.

Funding

Research was funded and performed via GlaxoSmithKline. No external funding was received for this work.

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Authors and Affiliations

  1. GlaxoSmithKline, 1250 South Collegeville Rd, Collegeville, PA, 19426, USA

    Matthew D. Burke & Michael C. Koetting

  2. Radius Health, Inc., 550 E Swedesford Rd, Suite 370, Wayne, PA, 19087, USA

    Matthew D. Burke

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  1. Matthew D. Burke
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Correspondence to Michael C. Koetting.

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Burke, M.D., Koetting, M.C. Development of a Clinically Relevant Dissolution Approach to Simulate Physiological Forces with a USP 2 Apparatus: “Peristaltic Dissolution”. J Pharm Innov 16, 699–714 (2021). https://doi.org/10.1007/s12247-020-09485-7

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