Clinical evaluation of large volume subcutaneous injection tissue effects, pain, and acceptability in healthy adults

Abstract

Determining feasibility and tolerability of large volume viscous subcutaneous injection may enable optimized, intuitive delivery system design. A translational early feasibility clinical study examined large volume subcutaneous injection viability, tolerability, acceptability, tissue effects and depot location for ~1, 8, and 20 cP injections at volumes up to 10 ml in the abdomen and 5 ml in the thigh in 32 healthy adult subjects. A commercial syringe pump system delivered 192 randomized, constant rate (20 µl/s) injections (6/subject) with in-line injection pressure captured versus time. Deposition location was qualified via ultrasound. Tissue effects and pain tolerability were monitored through 2 hours post-injection with corresponding Likert acceptability questionnaires administered through 72 hours. All injection conditions were feasible and well-tolerated with ≥79.3% favorable subject responses for injection site appearance and sensation immediately post-injection, increasing to ≥96.8% at 24 hours. Mean subject pain measured via 100 mm visual analog scale increased at needle insertion (6.9 mm, SD 10.8), peaked during injection (26.9 mm, SD 21.7) and diminished within 10 minutes post-removal (1.9 mm, SD 4.2). Immediate injection site wheal (90.9%) and erythema (92.6%) formation was observed with progressive although incomplete resolution through 2 hours (44.6% and 11.4% remaining, respectively). Wheal resolution occurred more rapidly at lower viscosities. Most subjects (64.5%) had no preference between abdomen and thigh. Correlations between tissue effects, injection pressure and pain were weak (Pearson's rho ± 0-0.4). The large volume injections tested, 1-20 cP viscosities up to 10 ml in the abdomen and 5 ml in the thigh, are feasible with good subject acceptability and rapid resolution of tissue effects and pain.

FIGURE 1

Frequency (%) of measurable wheals with 95% confidence interval (CI; calculated using Wilson’s score method, left) and corresponding wheal area (cm², right) mean and 95% CI (calculated using bootstrap) per injection condition and time post‐injection. The wheal area represents the entire footprint (spread) of wheal formation and is calculated from the measured wheal length (major axis) and width (minor axis) dimensions using theoretical elliptical geometry. Connecting lines between data points are solid for abdominal injections (A 5 ml 1.1 cP, B 5 ml 8 cP, C 5 ml 20 cP, and D 10 ml 20 cP) and dashed for thigh injections (E 5 ml 1.1 cP, F 5 ml 20 cP)

FIGURE 2

Pain scores (visual analog scale [VAS] mm) over time for each injection condition. Boxplot displays median within first and third quartiles; the whiskers are 1.5 times the interquartile range (IQR). Dots are the individual data points. 0 hour = pump stop plus 10 min (device removal)

FIGURE 3

Top: Percentage of depot locations in tissue layers (intradermal, subcutaneous, intramuscular, or combination) per injection condition and sex determined by qualitative assessment of ultrasound images. Bottom: Representative ultrasound images of subcutaneous (SC; entirely localized in subcutaneous), intradermal and subcutaneous (ID/SC; predominantly subcutaneous with minor intradermal infiltration), and intramuscular (IM) depots

FIGURE 4

In‐line injection pressure curves for constant rate 20 µl/s injections into the human abdomen (red) or thigh (black). Each curve is the mean value of all included injections (Table 1) per delivery condition (solid line) with the ±95% confidence interval (CI) indicated by the dotted line. The blue arrows denote the time point at which the pump stopped: 4.1 min for 5 ml and 8.2 min for 10 ml. Three phases observed across the curves: (1) initial rise, (2) plateau‐like region (gradual slope), and (3) decline after injection ceases