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Subcutaneous Injection Site Pain of Formulation Matrices

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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

  1. Bittner B, Richter W, Schmidt J. Subcutaneous Administration of Biotherapeutics: an overview of current challenges and opportunities. BioDrugs. 2018;32(5):425–40.

    Article  Google Scholar 

  2. 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.

    Article  CAS  Google Scholar 

  3. Stoner KL, Harder H, Fallowfield LJ, Jenkins VA. Intravenous versus subcutaneous drug administration. Which do patients prefer? a systematic review. Patient. 2014.

  4. Turner MR, Balu-Iyer SV. Challenges and opportunities for the subcutaneous delivery of therapeutic proteins. J Pharm Sci. 2018;107(5):1247–60.

    Article  CAS  Google Scholar 

  5. 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.

    Article  Google Scholar 

  6. 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.

    Article  CAS  Google Scholar 

  7. 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.

    Article  CAS  Google Scholar 

  8. 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.

    Article  CAS  Google Scholar 

  9. 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.

    CAS  PubMed  PubMed Central  Google Scholar 

  10. 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.

    Article  Google Scholar 

  11. 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.

    Article  Google Scholar 

  12. 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.

    Article  Google Scholar 

  13. 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.

    Article  Google Scholar 

  14. 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.

    Article  CAS  Google Scholar 

  15. Fernandez JM, Madsen S, Krase JM, Shi VY. Classification and mitigation of negative injection experiences with biologic medications. Dermatol Ther. 2020;33(2):e13240.

    Article  Google Scholar 

  16. 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.

    Article  CAS  Google Scholar 

  17. 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.

    Article  CAS  Google Scholar 

  18. 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.

    Article  CAS  Google Scholar 

  19. 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.

    CAS  PubMed  Google Scholar 

  20. 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.

    Article  CAS  Google Scholar 

  21. 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.

    Article  Google Scholar 

  22. 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.

    Article  Google Scholar 

  23. Fransson J, Espander-Jansson A. Local tolerance of subcutaneous injections. J Pharm Pharmacol. 1996;48(10):1012–5.

    Article  CAS  Google Scholar 

  24. 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.

    CAS  PubMed  Google Scholar 

  25. Parham SM, Pasieka JL. Effect of pH modification by bicarbonate on pain after subcutaneous lidocaine injection. Can J Surg. 1996;39(1):31–5.

    CAS  PubMed  PubMed Central  Google Scholar 

  26. 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.

    Article  CAS  Google Scholar 

  27. Kappelgaard AM, Bojesen A, Skydsgaard K, Sjogren I, Laursen T. Liquid growth hormone: preservatives and buffers. Horm Res. 2004;62(Suppl 3):98–103.

    CAS  PubMed  Google Scholar 

  28. Huskisson EC. Measurement of pain. J Rheumatol. 1982;9(5):768–9.

    CAS  PubMed  Google Scholar 

  29. Langley GB, Sheppeard H. The visual analogue scale: its use in pain measurement. Rheumatol Int. 1985;5(4):145–8.

    Article  CAS  Google Scholar 

  30. 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.

    Article  CAS  Google Scholar 

  31. 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.

    Article  CAS  Google Scholar 

  32. Melzack R. The McGill pain questionnaire: major properties and scoring methods. Pain. 1975;1(3):277–99.

    Article  Google Scholar 

  33. 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.

    Article  CAS  Google Scholar 

  34. Hill RZ, Bautista DM. Getting in touch with mechanical pain mechanisms. Trends Neurosci. 2020;43(5):311–25.

    Article  CAS  Google Scholar 

  35. 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.

    Article  CAS  Google Scholar 

  36. Tan CH, Onsiong MK. Pain on injection of propofol. Anaesthesia. 1998;53(5):468–76.

    Article  CAS  Google Scholar 

  37. Wang W. Tolerability of hypertonic injectables. Int J Pharm. 2015;490(1–2):308–15.

    Article  CAS  Google Scholar 

  38. Woolf CJ. Central sensitization: implications for the diagnosis and treatment of pain. PAIN. 2011;152(3):S2–S15.

    Article  Google Scholar 

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Funding

Funding for the clinical studies was provided by Eli Lilly and Company.

Author information

Author notes

  1. Galen H. Shi and Karthik Pisupati contributed equally to this work.

Authors and Affiliations

  1. Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana, 46285, USA

    Galen H. Shi, Karthik Pisupati, Jonathan G. Parker, Vincent J. Corvari, Christopher D. Payne, Wen Xu, David S. Collins & Michael R. De Felippis

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  1. Galen H. Shi
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  2. Karthik Pisupati
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  4. Vincent J. Corvari
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  8. Michael R. De Felippis
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Correspondence to Vincent J. Corvari.

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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

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