Abstract
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.
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Abbreviations
- AE:
-
Adverse Events
- ArgHCl:
-
Arginine hydrochloride
- ASIC:
-
Acid sensing ion channels
- BD:
-
Beckton Dickinson
- GCP:
-
Good Clinical Practice
- ICH:
-
International Council for Harmonization
- IM:
-
Intramuscular
- ISP:
-
Injection Site Pain
- IV:
-
Intravenous
- mAb:
-
Monoclonal Antibody
- MCSD:
-
Minimal Clinically Significant Difference
- NaCl:
-
Sodium Chloride
- PsA:
-
Psoriatic Arthritis
- RA:
-
Rheumatoid Arthritis
- SC:
-
Subcutaneous
- SE:
-
Standard Error
- SF-MPQ:
-
Short-form McGill Pain Questionnaire
- T0:
-
Initial/ time zero
- TRP:
-
Transient receptor potential
- VAS:
-
Visual Analog Scale
- WFI:
-
Water for Injection
References
Bittner B, Richter W, Schmidt J. Subcutaneous Administration of Biotherapeutics: an overview of current challenges and opportunities. BioDrugs. 2018;32(5):425–40.
Collins DS, Sanchez-Felix M, Badkar AV, Mrsny R. Accelerating the development of novel technologies and tools for the subcutaneous delivery of biotherapeutics. J Control Release. 2020;321:475–82.
Stoner KL, Harder H, Fallowfield LJ, Jenkins VA. Intravenous versus subcutaneous drug administration. Which do patients prefer? a systematic review. Patient. 2014.
Turner MR, Balu-Iyer SV. Challenges and opportunities for the subcutaneous delivery of therapeutic proteins. J Pharm Sci. 2018;107(5):1247–60.
Matucci A, Vultaggio A, Danesi R. The use of intravenous versus subcutaneous monoclonal antibodies in the treatment of severe asthma: a review. Respir Res. 2018;19(1):154.
Usmani SZ, Nahi H, Mateos MV, van de Donk N, Chari A, Kaufman JL, et al. Subcutaneous delivery of daratumumab in relapsed or refractory multiple myeloma. Blood. 2019;134(8):668–77.
Hedayati E, Fracheboud L, Srikant V, Greber D, Wallberg S, Linder Stragliotto C. Economic benefits of subcutaneous trastuzumab administration: a single institutional study from Karolinska University hospital in Sweden. PLoS One. 2019;14(2):e0211783.
Martin A, Lavoie L, Goetghebeur M, Schellenberg R. Economic benefits of subcutaneous rapid push versus intravenous immunoglobulin infusion therapy in adult patients with primary immune deficiency. Transfus Med. 2013;23(1):55–60.
Papadmitriou K, Trinh XB, Altintas S, Van Dam PA, Huizing MT, Tjalma WA. The socio-economical impact of intravenous (IV) versus subcutaneous (SC) administration of trastuzumab: future prospectives. Facts Views Vis Obgyn. 2015;7(3):176–80.
Spain CV, Wright JJ, Hahn RM, Wivel A, Martin AA. Self-reported barriers to adherence and persistence to treatment with injectable medications for type 2 diabetes. Clin Ther. 2016;38(7):1653–64 e1.
Gandell DL, Bienen EJ, Gudeman J. Mode of injection and treatment adherence: results of a survey characterizing the perspectives of health care providers and US women 18-45 years old. Patient Prefer Adherence. 2019;13:351–61.
Bolge SC, Goren A, Tandon N. Reasons for discontinuation of subcutaneous biologic therapy in the treatment of rheumatoid arthritis: a patient perspective. Patient Prefer Adherence. 2015;9:121–31.
Raja SN, Carr DB, Cohen M, Finnerup NB, Flor H, Gibson S, et al. The revised International Association for the Study of Pain definition of pain: concepts, challenges, and compromises. PAIN. 2020;161(9):1976–82.
Brazeau GA, Cooper B, Svetic KA, Smith CL, Gupta P. Current perspectives on pain upon injection of drugs. J Pharm Sci. 1998;87(6):667–77.
Fernandez JM, Madsen S, Krase JM, Shi VY. Classification and mitigation of negative injection experiences with biologic medications. Dermatol Ther. 2020;33(2):e13240.
Usach I, Martinez R, Festini T, Peris JE. Subcutaneous injection of drugs: literature review of factors influencing pain sensation at the injection site. Adv Ther. 2019;36(11):2986–96.
Frenken LA, van Lier HJ, Jordans JG, Leunissen KM, van Leusen R, Verstappen VM, et al. Identification of the component part in an epoetin alfa preparation that causes pain after subcutaneous injection. Am J Kidney Dis. 1993;22(4):553–6.
Laursen T, Hansen B, Fisker S. Pain perception after subcutaneous injections of media containing different buffers. Basic Clin Pharmacol Toxicol. 2006;98(2):218–21.
Veys N, Dhondt A, Lameire N. Pain at the injection site of subcutaneously administered erythropoietin: phosphate-buffered epoetin alpha compared to citrate-buffered epoetin alpha and epoetin beta. Clin Nephrol. 1998;49(1):41–4.
Yu AW, Leung CB, Li PK, Lui SF, Lai KN. Pain perception following subcutaneous injections of citrate-buffered and phosphate-buffered epoetin alpha. Int J Artif Organs. 1998;21(6):341–3.
Nash P, Vanhoof J, Hall S, Arulmani U, Tarzynski-Potempa R, Unnebrink K, et al. Randomized crossover comparison of injection site pain with 40 mg/0.4 or 0.8 mL formulations of Adalimumab in patients with rheumatoid arthritis. Rheumatol Ther. 2016;3(2):257–70.
Cohen S, Samad A, Karis E, Stolshek BS, Trivedi M, Zhang H, et al. Decreased injection site pain associated with phosphate-free Etanercept formulation in rheumatoid arthritis or psoriatic arthritis patients: a randomized controlled trial. Rheumatol Ther. 2019;6(2):245–54.
Fransson J, Espander-Jansson A. Local tolerance of subcutaneous injections. J Pharm Pharmacol. 1996;48(10):1012–5.
Palmon SC, Lloyd AT, Kirsch JR. The effect of needle gauge and lidocaine pH on pain during intradermal injection. Anesth Analg. 1998;86(2):379–81.
Parham SM, Pasieka JL. Effect of pH modification by bicarbonate on pain after subcutaneous lidocaine injection. Can J Surg. 1996;39(1):31–5.
Karges B, Muche R, Riegger I, Moritz M, Heinze E, Debatin KM, et al. Injection of acidic or neutral insulin and pain: a single-center, prospective, controlled, noninterventional study in pediatric patients with type 1 diabetes mellitus. Clin Ther. 2006;28(12):2094–101.
Kappelgaard AM, Bojesen A, Skydsgaard K, Sjogren I, Laursen T. Liquid growth hormone: preservatives and buffers. Horm Res. 2004;62(Suppl 3):98–103.
Huskisson EC. Measurement of pain. J Rheumatol. 1982;9(5):768–9.
Langley GB, Sheppeard H. The visual analogue scale: its use in pain measurement. Rheumatol Int. 1985;5(4):145–8.
Bodian CA, Freedman G, Hossain S, Eisenkraft JB, Beilin Y. The visual analog scale for pain: clinical significance in postoperative patients. Anesthesiology. 2001;95(6):1356–61.
Kelly AM. The minimum clinically significant difference in visual analogue scale pain score does not differ with severity of pain. Emerg Med J. 2001;18(3):205–7.
Melzack R. The McGill pain questionnaire: major properties and scoring methods. Pain. 1975;1(3):277–99.
Pattison LA, Callejo G, St John Smith E. Evolution of acid nociception: ion channels and receptors for detecting acid. Philos Trans R Soc Lond B Biol Sci. 2019;374(1785):20190291.
Hill RZ, Bautista DM. Getting in touch with mechanical pain mechanisms. Trends Neurosci. 2020;43(5):311–25.
Doenicke AW, Roizen MF, Hoernecke R, Lorenz W, Ostwald P. Solvent for etomidate may cause pain and adverse effects. Br J Anaesth. 1999;83(3):464–6.
Tan CH, Onsiong MK. Pain on injection of propofol. Anaesthesia. 1998;53(5):468–76.
Wang W. Tolerability of hypertonic injectables. Int J Pharm. 2015;490(1–2):308–15.
Woolf CJ. Central sensitization: implications for the diagnosis and treatment of pain. PAIN. 2011;152(3):S2–S15.
Funding
Funding for the clinical studies was provided by Eli Lilly and Company.
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Shi, G.H., Pisupati, K., Parker, J.G. et al. Subcutaneous Injection Site Pain of Formulation Matrices. Pharm Res 38, 779–793 (2021). https://doi.org/10.1007/s11095-021-03047-3
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DOI: https://doi.org/10.1007/s11095-021-03047-3