Developing the Subcutaneous Drug Delivery Route
Main Article Content
Abstract
Biopharmaceuticals and biosimilars now represent the majority of the top 10 selling drugs. High development costs and requirement for most to be administered intravenously are noted drawbacks. Recent advances in subcutaneous drug delivery methods offer a viable alternative route for parenteral drug administration. Comparison studies have highlighted equivalent drug efficacies coupled with substantial cost savings. Allied to these developments are new closed-loop drug delivery systems which have the potential to revolutionize the biopharmaceutical sector through active patient engagement. First demonstrated in the insulin marketplace, these efforts represent formal embodiments of the precision medicine approach to disease management. This review will highlight key considerations for subcutaneous drug delivery, including patient preferences, drug formulation and needle and device design. We also provide an overview of the market evolution of subcutaneously administered drugs, highlighting those currently in clinical development, and predict areas for future innovation.
Keywords:
Subcutaneous, closed loop, interstitial matrix, hyaluronidase, biologics, drug development, personalized medicine, syringe and needle technology
Article Details
How to Cite
WRIGHT, J. M.; JONES, Graham B..
Developing the Subcutaneous Drug Delivery Route.
Medical Research Archives, [S.l.], v. 5, n. 12, dec. 2017.
ISSN 2375-1924.
Available at: <https://esmed.org/MRA/mra/article/view/1652>. Date accessed: 22 dec. 2024.
doi: https://doi.org/10.18103/mra.v5i12.1652.
Section
Research Articles
The Medical Research Archives grants authors the right to publish and reproduce the unrevised contribution in whole or in part at any time and in any form for any scholarly non-commercial purpose with the condition that all publications of the contribution include a full citation to the journal as published by the Medical Research Archives.
References
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1. Mullard A. Robust Biotech Sector Increases R&D Spend. Nature Reviews Drug Discovery 14, 449 (2015).
2. Collins FS, Varmus H. A New Initiative on Precision Medicine. N. Engl. J. Med. 372, 793-795 (2015).
3. McCabe C, Claxton, K, Culyer AJ. The NICE Cost-Effectiveness Threshold What it is and What that Means, Pharma-coeconomics 26, 733-744 (2008).
4. Brinckerhoff CC, Schorr K. Patent Watch: Have The Biosimilar Floodgates Been Opened in the United States? Nature Reviews Drug Discovery 14, 303–304 (2015).
5. Tetteh EK, Morris S. Evaluating the administration costs of biologic drugs: development of a cost algorithm. Health Economics Review 4, 26 (2014).
6. Jin J, Zhu LL, Chen M, Xu HM, Wang HF, Feng XQ, Zhou XP. The Optimal Choice of Medication Administration Route Regarding Intravenous, Intramuscular, and Subcutaneous Injection. Patient Preference and Adherence 9, 923–942 (2015).
7. Rejinold NS, Shin JH, Seok HY, Kim YC. Biomedical Applications of Microneedles in Therapeutics: Recent Advancements and Implications in Drug Delivery. Expert Opinion on Drug Delivery 13, 109-131 (2016).
8. Trevaskis NL, Kaminskas LM, Porter CJ. From Sewer to Saviour -Targeting the Lymphatic System to Promote Drug Exposure and Activity. Nat. Rev. Drug. Disc. 14, 781 (2015).
9. Berteau C, Filipe-Santos O, Wang T, Rojas HE, Granger C, Schwarzenbach F. Evaluation of the Impact of Viscosity, Injection Volume and Injection Flow Rate on Subcutaneous Injection Tolerance. Medical Devices:Evidence and Research 8 473–484 (2015).
10. Harvey AJ, Kaestner SA, Sutter DE, Harvey NG, Mikszta JA, Pettis RJ.
Microneedle-Based Intradermal Delivery Enables Rapid Lymphatic Uptake and Distribution of Protein Drugs. Pharm. Res. 28, 107-116 (2011).
11: Wright JM, Thyagarajapuram NR, Sirkar R, Kapur S, Harrison MW, Collins DS, Bryan DJ, Jones GB. Optimizing the bioavailability of subcutaneously administered therapeutics through mechanochemical drivers Pharm. Res, 2017, 34(10), 2000-2011.
12: Sawinski VJ, Loiselle RJ, Goldberg AF. Histologic evaluation of injection site edema. Oral Surg Oral Med Oral Pathol. 1966, 22(1):125-6.
13: Kurtin S, Knop CS, Milliron T. Subcutaneous Administration of Bortezomib: Strategies to Reduce Injection Site Reactions, J Adv Pract Oncol. 2012, 3(6): 406–410.
14. Shapiro R. Subcutaneous Immunoglobulin Therapy by Rapid Push is Preferred to Infusion by Pump: A Retrospective Analysis. J. Clin. Immunol. 30, 301-30 (2010).
15. Yang MX, Shenoy B, Disttler M, Patel R, McGrath M, Pechenov S, Margolin AL. Crystalline Monoclonal Antibodies for Subcutaneous Delivery. Proc. Natl. Acad. Sci. USA, 100, 6934–6939 (2003).
16. Schoellhammer CM, Schroeder A, Maa R, Lauwers GY, Swiston A, Zervas M, Barman R, DiCiccio AM, Brugge WR, Anderson DG, Blankschtein D, Langer R, Traverso G. Ultrasound-Mediated Gastrointestinal Drug Delivery. Sci. Transl. Med. 7 310ra168 (2015).
17. Fathallah AM, Turner MR, Mager DE, Balu-Iyer SV. Effects of Hypertonic Buffer Composition on Lymph Node Uptake and Bioavailability of
Rituximab, After Subcutaneous Administration. Biopharm Drug Dispos. 36, 115–125 (2015).
18. Bocci V, Muscettola M, Grasso G, Magyar Z, Naldini A, Szabo G.The lymphatic route. 1) Albumin and hyaluronidase modify the normal distribution of interferon in lymph and plasma. Experientia, 42 (4) 432–433 (1986).
19. Fathallah AM, Balu-Iyer SV. Anatomical, Physiological, and Experimental Factors Affecting the Bioavailability of sc-Administered Large Biotherapeutics. J. Pharm. Sci. 104, 301–306 (2015). Deng R, Meng YG, Hoyte K, Lutman J, Lu Y, SuhasiniIyer I, DeForge LE, Theil F-P, Fielder PJ, Prabhu S. Subcutaneous Bioavailability of Therapeutic Antibodies as a Function of FcRn Binding Affinity in Mice, mAbs 4, 101-109 (2012).
20. Richter WF, Jacobsen B. Subcutaneous Absorption of Biotherapeutics: Knowns and Unknowns. Drug Metab Dispos. 42, 1881-1889 (2014).
21. Kang DW, Jadin LM, Nekoroski TA, Zepeda ML. Recombinant Human Hyaluronidase (rHuPH20) Facilitates Subcutaneous Infusion of Immunoglobulin, Increases Local Fluid Dispersion, and Reduces Induration in a Porcine Model. J. Allerg. Clin.Immunol. 129(2) AB85 (2012).
22. Kang DW, Jadin L, Nekoroski T, Drake FH, Zepeda ML. Recombinant Human Hyaluronidase PH20 (rHuPH20) Facilitates Subcutaneous Infusions of Large Volumes of Immunoglobulin in a Swine Model. Drug Deliv. Transl. Res 2, 254-264 (2012); Bookbinder LH et al. A recombinant human enzyme for enhanced interstitial transport of therapeutics. J Control Release 114(2), 230-41 (2006).
23. Zheng Y. et al. Minipig as a Potential Translatable Model for Monoclonal Antibody Pharmacokinetics After Intravenous and Subcutaneous Administration. mAbs 4, 243-255 (2012).
24. Ismael G, et al. Subcutaneous Versus Intravenous Administration of (neo) Adjuvant Trastuzumab in Patients with HER2-Positive, Clinical Stage I–III Breast Cancer (HannaH study): A Phase 3, Open-Label, Multicentre, Randomised Trial. Lancet Oncol. 13, 869–78 (2012); Pivot X. et al. Preference for Subcutaneous or Intravenous Administration of Trastuzumab in Patients with HER2-Positive Early breast cancer (PrefHer): An Open-Label Randomised Study. Lancet Oncol. 14(10), 962-970 (2013).
25. Salar A. et al. Comparison of Subcutaneous Versus Intravenous Administration of Rituximab As Maintenance Treatment for Follicular Lymphoma: Results From a Two-Stage, Phase IB Study. J Clin Oncol. 32, 1782-1791 (2014).
26. Spandorfer PR. et al. A Randomized Clinical Trial of Recombinant Human Hyaluronidase-Facilitated Subcutaneous Versus Intravenous Rehydration in Mild to Moderately Dehydrated Children in the Emergency Department, Clinical Therapeutics, 34 (11), 2232-2245 (2012).
27: Jain M, Doughty D, Clawson C, Li X, White N, Agoram B, van der Merwe R. Tralokinumab pharmacokinetics and tolerability when administered by different subcutaneous injection methods and rates, International Journal of Clinical Pharmacology and Therapeutics, 2017, 55(7):606-618.
28. Comley K, Fleck NA. Deep penetration and liquid injection into adipose tissue, J. Mech. Mater. Struct. 6, 127-140 (2011).
29. Thomsen M, Hernandez-Garcia A, Mathiesen J, Poulsen M, Sørensen DN, Tarnow L, Feidenhans R. Model Study of the Pressure Build-Up during Subcutaneous Injection. PLOS One 9(8) e104054 (2014).
30: Kim H, Park H, Lee SJ. Effective method for drug injection into subcutaneous tissue, Scientific Reports 2017, 7, # 9613 doi:10.1038/s41598-017-10110-w
31. Videira MA, Botelho MF, Santos AC, Gouveia LF, Pedroso de Lima JJ, Almeida AJ. Lymphatic Uptake of Pulmonary Delivered Radiolabelled Solid Lipid Nanoparticles. J. Drug Target. 10 (8), 607–613 (2002).
32. Zhang F, Niu G, Lu G, Chen X. Preclinical Lymphatic Imaging. Mol Imaging Biol. 13(4) 599–612 (2011).
33. Eberlin LS. et al. Visualizing Dermal Permeation of Sodium Channel Modulators by Mass Spectrometric Imaging. J. Am. Chem. Soc. 136, 6401-6405 (2014).
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