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Development of a Convenient In Vitro Gel Diffusion Model for Predicting the In Vivo Performance of Subcutaneous Parenteral Formulations of Large and Small Molecules

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Abstract

Parenteral delivery remains a compelling drug delivery route for both large- and small-molecule drugs and can bypass issues encountered with oral absorption. For injectable drug products, there is a strong patient preference for subcutaneous administration due to its convenience over intravenous infusion. However, in subcutaneous injection, in contrast to intravenous administration, the formulation is in contact with an extracellular matrix environment that behaves more like a gel than a fluid. This can impact the expected performance of a formulation. Since typical bulk fluid dissolution studies do not accurately simulate the subcutaneous environment, improved in vitro models to help better predict the behavior of the formulation are critical. Herein, we detail the development of a new model system consisting of a more physiologically relevant gel phase to simulate the rate of drug release and diffusion from a subcutaneous injection site using agarose hydrogels as a tissue mimic. This is coupled with continuous real-time data collection to accurately monitor drug diffusion. We show how this in vitro model can be used as an in vivo performance differentiator for different formulations of both large and small molecules. Thus, this model system can be used to improve optimization and understanding of new parenteral drug formulations in a rapid and convenient manner.

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Acknowledgements

We would like to thank Peter Wuelfing, Executive Director, Preclinical Development at Merck & Co., Inc. for his valuable comments and a thorough discussion on the findings presented in this manuscript, and Merck Research Laboratories for support.

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Author notes

  1. Dennis H. Leung

    Present address: Small Molecule Pharmaceutical Sciences, Genentech Inc., 1 DNA Way, South San Francisco, California, 94080, USA

Authors and Affiliations

  1. Discovery Pharmaceutical Sciences, Merck & Co., Inc., 126 E. Lincoln Ave., Rahway, New Jersey, 07065, USA

    Dennis H. Leung, Candice Alleyne, Erika Walsh, Andrew Leithead & Annette Bak

  2. Formulation Sciences, Merck & Co., Inc., 770 Sumneytown Pike, West Point, Pennsylvania, 19486, USA

    Yash Kapoor

  3. Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, Merck & Co., Inc., 126 E. Lincoln Ave., Rahway, New Jersey, 07065, USA

    Bahanu Habulihaz & Gino M. Salituro

  4. Preformulation Automation, Merck & Co., Inc., 126 E. Lincoln Ave., Rahway, New Jersey, 07065, USA

    Timothy Rhodes

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  1. Dennis H. Leung
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Corresponding author

Correspondence to Dennis H. Leung.

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All studies were conducted under a protocol approved by the Merck & Co. Institutional Animal Care and Use Committees (IACUC).

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Leung, D.H., Kapoor, Y., Alleyne, C. et al. Development of a Convenient In Vitro Gel Diffusion Model for Predicting the In Vivo Performance of Subcutaneous Parenteral Formulations of Large and Small Molecules. AAPS PharmSciTech 18, 2203–2213 (2017). https://doi.org/10.1208/s12249-016-0698-5

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