Measuring tissue back-pressure--in vivo injection forces during subcutaneous injection.

PURPOSE: Limited information is available on injection forces of parenterals representing the in vivo situation. Scope of the present study was to investigate the contribution of the subcutaneous (sc) tissue layer to injection forces during in vivo injection. METHODS: Göttingen minipigs received injections of isotonic dextran solutions (1-100 mPas) into the plica inguinalis using different injection rates and volumes (0.025-0.2 mL/s and 2.5 vs. 4.5 mL). RESULTS: The contribution of the sc back-pressure to injection forces was found to increase linearly with viscosity and injection rate ranging from 0.6 ± 0.5 N to 1.0 ± 0.4 N (1 mPas), 0.7 ± 0.2 N to 2.4 ± 1.9 N (10 mPas), and 1.8 ± 0.6 N to 4.7 ± 3.3 N (20 mPas) for injection rates of 0.025 to 0.2 mL/s, respectively. Variability increased with viscosity and injection rate. Values are average values from 10 randomized injections. A maximum of 12.9 N was reached for 20 mPas at 0.2 mL/s; 6.9 ± 0.3 N was determined for 100 mPas at 0.025 mL/s. No difference was found between injection volumes of 2.5 and 4.5 mL. The contribution of the tissue was differentiated from the contribution of the injection device and a local temperature effect. This effect was leading to warming of the (equilibrated) sample in the needle, therefore smaller injection forces than expected compensating tissue resistance to some parts. CONCLUSIONS: When estimating injection forces representative for the in vivo situation, the contribution of the tissue has to be considered as well as local warming of the sample in the needle during injection.

Rheological characterization and injection forces of concentrated protein formulations: an alternative predictive model for non-Newtonian solutions.

Development of injection devices for subcutaneous drug administration requires a detailed understanding of user capability and forces occurring during the drug administration process. Injection forces of concentrated protein therapeutics are influenced by syringe properties (e.g., needle diameter) and injection speed, and are driven by solution properties such as rheology. In the present study, it is demonstrated that concentrated protein therapeutics may show significantly reduced injection forces because of shear-thinning (non-Newtonian) behavior. A mathematical model was thus established to predict/correlate injection forces of Newtonian and non-Newtonian solutions with viscosity data from plate/cone rheometry. The model was verified experimentally by glide-force measurements of reference and surrogate solutions. Application of the suggested model was demonstrated for injection force measurements of concentrated protein solutions to determine viscosity data at high shear rates (3 × 10(4)-1.6 × 10(5)s(-1)). By combining these data with viscosity data obtained by different viscosity methods (plate/cone and capillary rheometry), a viscosity-shear rate profile of the protein solution between 10(2) and 1.6 × 10(5)s(-1) was obtained, which was mathematically described by the Carreau model. Characterization of rheological properties allows to accurately predict injection forces for different syringe-needle combinations as well as injection rates, thus supporting the development of injection devices for combination products.