Abstract
The objective of this work was to systematically evaluate the effects of formulation composition on subcutaneous injection site pain (ISP) using matrices comprising of common pharmaceutical excipients. Two randomized, blinded, crossover studies in healthy subjects were conducted at a single site, where subjects received 1mL SC injections of the buffer matrices. ISP intensity was measured using a 100mm visual analogue scale (VAS), which was then analyzed via heatmap, categorical grouping, subgroup analysis, and paired delta analysis. Buffer type, buffer concentration and tonicity agent showed a substantial impact on ISP. Citrate buffer demonstrated a higher ISP than acetate buffer or saline). The 20mM citrate buffer was more painful than 10 or 5mM citrate buffers. NaCl and propylene glycol were significantly more painful than sugar alcohols (mannitol, sucrose, trehalose or glycerol). Histidine buffers exhibited ISP in the descending order of 150mM > 75mM > 25mM > 0mM NaCl, while histidine buffers containing Arginine-HCl at 0, 50, or 150mM all showed very low ISP. Histidine buffer at pH6.5 showed a lower ISP than pH5.7. This systematic study via orthogonal analyses demonstrated that subcutaneous ISP is significantly influenced by solution composition.
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