Tissue Resistance during Large-Volume Injections in Subcutaneous Tissue of Minipigs
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RESEARCH PAPER
T i s s u e R e s i s t a n c e d u r i n g L a r g e -Vo l u m e I n j e c t i o n s in Subcutaneous Tissue of Minipigs Andrea Allmendinger 1
&
Stefan Fischer 1
Received: 27 May 2020 / Accepted: 6 August 2020 # Springer Science+Business Media, LLC, part of Springer Nature 2020
ABSTRACT Purpose Injection devices for administration of biopharmaceuticals enable subcutaneous self-administration by patients. To meet patient specific capabilities, injection forces need to be characterized. We address the open question of whether tissue resistance significantly contributes to overall injection forces, especially for large injection volumes. Methods Subcutaneous tissue resistance was systematically quantified for injection volumes up to 11 mL depending on viscosity (1–20 mPa·s) and injection rates (0.025–0.2 mL/s) using Göttingen Minipigs as the animal model. The contribution of an artificially applied external force at the injection site simulating autoinjector needle cover depression was tested between 2.5–7.5 N. Results Tissue resistance reached average values of ~120 mbar for injection volumes up to 11 mL independent of viscosity and injection rate, and maximum values of 300 mbar were determined. Artificially applied external forces led to higher values, independent of the absolute applied force — maximum values of 1 bar were obtained when injecting 4.5 mL of the 20 mPa·s solution at an injection rate of 0.1 mL/s with the application of an artificial 5 N force, corresponding to ~450 mbar. All conditions yield defined injection sites suggesting tissue resistance is defined by mechanical properties of the subcutaneous tissue.
Electronic supplementary material The online version of this article (https://doi.org/10.1007/s11095-020-02906-9) contains supplementary material, which is available to authorized users. * Andrea Allmendinger [email protected]
1
Pharmaceutical Development & Supplies Biologics Europe, F. Hoffmann-La Roche Ltd, Grenzacherstrasse 124, 4070 Basel, Switzerland
Conclusions We set our results in relation to overall injection forces, concluding that maximum values in tissue resistance may cause challenges during subcutaneous injection when using injection devices.
KEY WORDS auto-injector . highly concentrated protein formulations . injection device . injection force . prefilled syringe . subcutaneous drug administration
ABBREVIATIONS EFG i.m. s.c. SD w/v
External force generator Intramuscular Subcutaneous Standard deviation Weight per volume
INTRODUCTION Subcutaneous (s.c.) injection of highly concentrated protein formulations presents a technical challenge in the development of biotherapeutic agents (1,2). Careful matching of injection device configurations and the rheological behavior of the formulated protein are needed to minimize the required force and duration of injection (1,3). Injection forces are comprised of a hydrodynamic portion, a frictional portion arising between plunger and barrel, and the contribution of the tissue, which is the subject of the p
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