title: Development of a Convenient In Vitro Gel Diffusion Model for Predicting the In Vivo Performance of Subcutaneous Parenteral Formulations of Large and Small Molecules.
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.
authors.affiliation: Discovery Pharmaceutical Sciences, Merck & Co., Inc., 126 E. Lincoln Ave., Rahway, New Jersey, 07065, USA. leung.dennis@gene.com.|Small Molecule Pharmaceutical Sciences, Genentech Inc., 1 DNA Way, South San Francisco, California, 94080, USA. leung.dennis@gene.com.
authors.forename: Dennis H
authors.initials: DH
authors.lastname: Leung
authors.affiliation: Formulation Sciences, Merck & Co., Inc., 770 Sumneytown Pike, West Point, Pennsylvania, 19486, USA.
authors.forename: Yash
authors.initials: Y
authors.lastname: Kapoor
authors.affiliation: Discovery Pharmaceutical Sciences, Merck & Co., Inc., 126 E. Lincoln Ave., Rahway, New Jersey, 07065, USA.
authors.forename: Candice
authors.initials: C
authors.lastname: Alleyne
authors.affiliation: Discovery Pharmaceutical Sciences, Merck & Co., Inc., 126 E. Lincoln Ave., Rahway, New Jersey, 07065, USA.
authors.forename: Erika
authors.initials: E
authors.lastname: Walsh
authors.affiliation: Discovery Pharmaceutical Sciences, Merck & Co., Inc., 126 E. Lincoln Ave., Rahway, New Jersey, 07065, USA.
authors.forename: Andrew
authors.initials: A
authors.lastname: Leithead
authors.affiliation: Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, Merck & Co., Inc., 126 E. Lincoln Ave., Rahway, New Jersey, 07065, USA.
authors.forename: Bahanu
authors.initials: B
authors.lastname: Habulihaz
authors.affiliation: Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, Merck & Co., Inc., 126 E. Lincoln Ave., Rahway, New Jersey, 07065, USA.
authors.forename: Gino M
authors.initials: GM
authors.lastname: Salituro
authors.affiliation: Discovery Pharmaceutical Sciences, Merck & Co., Inc., 126 E. Lincoln Ave., Rahway, New Jersey, 07065, USA.
authors.forename: Annette
authors.initials: A
authors.lastname: Bak
authors.affiliation: Preformulation Automation, Merck & Co., Inc., 126 E. Lincoln Ave., Rahway, New Jersey, 07065, USA.
authors.forename: Timothy
authors.initials: T
authors.lastname: Rhodes
mesh_terms: D003692:Delayed-Action Preparations; D004058:Diffusion; D004339:Drug Compounding / Q000379:methods; D016503:Drug Delivery Systems; D065546:Drug Liberation; D006801:Humans; D020100:Hydrogels / Q000737:chemistry / Q000494:pharmacology; D007279:Injections, Subcutaneous / Q000379:methods; D008954:Models, Biological; D004364:Pharmaceutical Preparations / Q000008:administration & dosage; D012685:Sepharose / Q000737:chemistry / Q000494:pharmacology
chemical_list: D003692:Delayed-Action Preparations; D020100:Hydrogels; D004364:Pharmaceutical Preparations; D012685:Sepharose
keywords: agarose gel; diffusion; formulation; model; subcutaneous