Purpose

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.

Methods

Two randomized, blinded, crossover studies in healthy subjects were conducted at a single site, where subjects received 1 mL SC injections of the buffer matrices. ISP intensity was measured using a 100 mm visual analogue scale (VAS), which was then analyzed via heatmap, categorical grouping, subgroup analysis, and paired delta analysis.

Results

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 20 mM citrate buffer was more painful than 10 or 5 mM 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 150 mM > 75 mM > 25 mM > 0 mM NaCl, while histidine buffers containing Arginine-HCl at 0, 50, or 150 mM all showed very low ISP. Histidine buffer at pH 6.5 showed a lower ISP than pH 5.7.

Conclusions

This systematic study via orthogonal analyses demonstrated that subcutaneous ISP is significantly influenced by solution composition.

中文翻译：

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制剂基质的皮下注射部位疼痛

目的

这项工作的目的是使用包含常见药物赋形剂的基质系统地评估制剂组合物对皮下注射部位疼痛 (ISP) 的影响。

方法

在一个地点对健康受试者进行了两项随机、盲法、交叉研究，受试者接受了 1 mL 缓冲基质的皮下注射。ISP 强度使用 100 mm 视觉模拟量表 (VAS) 测量，然后通过热图、分类分组、亚组分析和配对 delta 分析进行分析。

结果

缓冲液类型、缓冲液浓度和张力剂对 ISP 有显着影响。柠檬酸盐缓冲液表现出比醋酸盐缓​​冲液或盐水更高的 ISP）。20 mM 柠檬酸盐缓冲液比 10 或 5 mM 柠檬酸盐缓冲液更痛。NaCl 和丙二醇明显比糖醇（甘露醇、蔗糖、海藻糖或甘油）更痛。组氨酸缓冲液以 150 mM > 75 mM > 25 mM > 0 mM NaCl 的降序显示 ISP，而含有 0、50 或 150 mM 精氨酸-HCl 的组氨酸缓冲液都显示出非常低的 ISP。pH 6.5 的组氨酸缓冲液显示出比 pH 5.7 更低的 ISP。

结论

这项通过正交分析的系统研究表明，皮下 ISP 受溶液成分的显着影响。