Skip to main content

Advertisement

SpringerLink
Log in

Microneedle-Based Intradermal Delivery Enables Rapid Lymphatic Uptake and Distribution of Protein Drugs

  • Research Paper
  • Published:
Pharmaceutical Research Aims and scope Submit manuscript

ABSTRACT

Purpose

The purpose of this research was to examine the pharmacokinetics (PK) of drug uptake for microneedle-based intradermal (ID) delivery of several classes of protein drugs compared to standard subcutaneous (SC) administration.

Methods

Systemic absorption kinetics of various proteins were analyzed following microneedle-based ID delivery and standard injection methods in the swine model. Comparative PK data were determined using standard non-compartmental techniques based on blood serum levels.

Results

Delivery of proteins using microneedles resulted in faster systemic availability, measured via tmax, and increased maximal drug concentration, Cmax, over SC delivery for all proteins tested. Some agents also exhibited increased bioavailability for the ID route. Imaging studies using reporter dyes showed rapid lymphatic-mediated uptake.

Conclusions

Microneedle delivery is applicable to a wide variety of protein drugs and is capable of effective parenteral administration of therapeutic drug dosages. This delivery route alters absorption kinetics via targeting a tissue bed better perfused with lymphatic and blood vessels than the SC space. Microneedle delivery may afford various advantages, including a robust method to increase the absorption rate and bioavailability of proteins that have been challenging to deliver at therapeutic levels or with physiologically relevant profiles.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

Abbreviations

AAALAC:

Association for Assessment and Accreditation of Laboratory Animal Care

BG:

Blood glucose

Cmax :

Maximum blood concentration

IACUC:

Institutional Animal Care and Use Committee

ICG:

Intracardiac green dye

ID:

Intradermal

IM:

Intramuscular

IV:

Intravenous

NIH:

National Institutes of Health

NIR:

Near infrared

PD:

Pharmacodynamics

PK:

Pharmacokinetics

rhGH:

Recombinant human growth hormone

SC:

Subcutaneous

SD:

Standard deviation

SEM:

Standard error of the mean

SWFI:

Sterile water for injection

t1/2λz :

Terminal half life

TB:

Tuberculosis

tmax :

Time to max blood concentration

TNFα:

Tumor necrosis factor alpha

USDA:

United States Department of Agriculture

VAP:

Vascular access port

REFERENCES

  1. Kang JS, Deluca PP, Lee KC. Emerging PEGylated drugs. Expert Opin Emerg Drugs. 2009;14(2):363–80.

    Article  CAS  PubMed  Google Scholar 

  2. Nieri P, Donadio E, Rossi S, Adinolfi B, Podestà A. Antibodies for therapeutic uses and the evolution of biotechniques. Curr Med Chem. 2009;16(6):753–79.

    Article  CAS  PubMed  Google Scholar 

  3. Wurch T, Lowe P, Caussanel V, Bes C, Beck A, Corvaia N. Development of novel protein scaffolds as alternatives to whole antibodies for imaging and therapy: status on discovery research and clinical validation. Curr Pharm Biotechnol. 2008;9(6):502–9.

    Article  CAS  PubMed  Google Scholar 

  4. Simon L, Goyal A. Dynamics and control of percutaneous drug absorption in the presence of epidermal turnover. J Pharm Sci. 2009;98(1):187–204.

    Article  CAS  PubMed  Google Scholar 

  5. Martanto W, Moore JS, Couse T, Prausnitz MR. Mechanism of fluid infusion during microneedle insertion and retraction. J Control Release. 2006;112(3):357–61.

    Article  CAS  PubMed  Google Scholar 

  6. Prausnitz MR. Microneedles for transdermal drug delivery. Adv Drug Deliv Rev. 2004;56(5):581–7.

    Article  CAS  PubMed  Google Scholar 

  7. Garg SK, Mathieu C, Rais N, Gao H, Tobian JA, Gates JR et al. Two-year efficacy and safety of AIR inhaled insulin in patients with type 1 diabetes: an open-label randomized controlled trial. Diabetes Technol Ther. 2009;11 Suppl 2:S5–S16.

    CAS  PubMed  Google Scholar 

  8. Shoyele SA, Slowey A. Prospects of formulating proteins/peptides as aerosols for pulmonary drug delivery. Int J Pharm. 2006;314(1):1–8.

    Article  CAS  PubMed  Google Scholar 

  9. Costantino HR, Illum L, Brandt G, Johnson PH, Quay SC. Intranasal delivery: physicochemical and therapeutic aspects. Int J Pharm. 2007;337(1–2):1–24.

    Article  CAS  PubMed  Google Scholar 

  10. Haus E. Chronobiology in the endocrine system. Adv Drug Deliv Rev. 2007;59(9–10):985–1014.

    Article  CAS  PubMed  Google Scholar 

  11. Guerci B, Sauvanet JP. Subcutaneous insulin: pharmacokinetic variability and glycemic variability. Diabetes Metab. 2005;31(4 Part 2):4S7–4S24.

    Article  CAS  PubMed  Google Scholar 

  12. Hamilton H. Complications associated with venous access devices: part one. Nurs Stand. 2006;20(41):67.

    Google Scholar 

  13. Hamilton H. Complications associated with venous access devices: part two. Nurs Stand. 2006;20(27):59–65.

    PubMed  Google Scholar 

  14. Brunton S. Insulin delivery systems: reducing barriers to insulin therapy and advancing diabetes mellitus treatment. Am J Med. 2008;121(6 Suppl):S35–41.

    Article  CAS  PubMed  Google Scholar 

  15. Gin H, Hanaire-Broutin H. Reproducibility and variability in the action of injected insulin. Diabetes Metab. 2005;31(1):7–13.

    Article  CAS  PubMed  Google Scholar 

  16. Laurent PE, Bonnet S, Alchas P, Regolini P, Mikszta JA, Pettis R et al. Evaluation of the clinical performance of a new intradermal vaccine administration technique and associated delivery system. Vaccine. 2007;25(52):8833–42.

    Article  CAS  PubMed  Google Scholar 

  17. Mikszta JA, Laurent PE. Cutaneous delivery of prophylactic and therapeutic vaccines: historical perspective and future outlook. Expert Rev Vaccines. 2008;7(9):1329–39.

    Article  PubMed  Google Scholar 

  18. Lambert PH, Laurent PE. Intradermal vaccine delivery: will new delivery systems transform vaccine administration? Vaccine. 2008;26(26):3197–208.

    Article  CAS  PubMed  Google Scholar 

  19. Haq MI, Smith E, John DN, Kalavala M, Edwards C, Anstey A et al. Clinical administration of microneedles: skin puncture, pain and sensation. Biomed Microdev. 2009;11(1):35–47.

    Article  CAS  Google Scholar 

  20. Gupta J, Felner EI, Prausnitz MR. Minimally invasive insulin delivery in subjects with type 1 diabetes using hollow microneedles. Diabetes Technol Ther. 2009;11(6):329–37. Erratum in: Diabetes Technol Ther. 11(7):471 (2009).

    Article  CAS  PubMed  Google Scholar 

  21. Huang J, D’Souza AJ, Alarcon JB, Mikszta JA, Ford BM, Ferriter MS et al. Protective immunity in mice achieved with dry powder formulation and alternative delivery of plague F1-V vaccine. Clin Vaccine Immunol. 2009;16(5):719–25.

    Article  CAS  PubMed  Google Scholar 

  22. Morefield GL, Tammariello RF, Purcell BK, Worsham PL, Chapman J, Smith LA et al. An alternative approach to combination vaccines: intradermal administration of isolated components for control of anthrax, botulism, plague and staphylococcal toxic shock. J Immune Based Ther Vaccines. 2008;6:5.

    Article  PubMed  Google Scholar 

  23. Alarcon JB, Hartley AW, Harvey NG, Mikszta JA. Preclinical evaluation of microneedle technology for intradermal delivery of influenza vaccines. Clin Vaccine Immunol. 2007;14(4):375–81.

    Article  CAS  PubMed  Google Scholar 

  24. Dean CH, Alarcon JB, Waterston AM, Draper K, Early R, Guirakhoo F et al. Cutaneous delivery of a live, attenuated chimeric flavivirus vaccine against Japanese encephalitis (ChimeriVax)-JE) in non-human primates. Hum Vaccin. 2005;1(3):106–11.

    Article  CAS  PubMed  Google Scholar 

  25. Mikszta JA, Sullivan VJ, Dean C, Waterston AW, Alarcon JB, Dekker JP et al. Protective immunization against inhalational anthrax: a comparison of minimally-invasive delivery platforms. J Infect Dis. 2005;191:278.

    Article  CAS  PubMed  Google Scholar 

  26. Mikszta JA, Dekker JP, Dean CH, Brittingham JM, Huang J, Sullivan VJ et al. Microneedle-based intradermal delivery of the anthrax recombinant protective antigen vaccine. Infect Immun. 2006;74:6806.

    Article  CAS  PubMed  Google Scholar 

  27. Beran J, Ambrozaitis A, Laiskonis A, Mickuviene N, Bacart P, Calozet Y et al. Intradermal influenza vaccination of healthy adults using a new microinjection system: a 3-year randomised controlled safety and immunogenicity trial. BMC Med. 2009;7:13.

    Article  PubMed  Google Scholar 

  28. Holland D, Booy R, De Looze F, Eizenberg P, McDonald J, Karrasch J et al. Intradermal influenza vaccine administered using a new microinjection system produces superior immunogenicity in elderly adults: a randomized controlled trial. J Infect Dis. 2008;198(5):650–8.

    Article  PubMed  Google Scholar 

  29. Leroux-Roels I, Vets E, Freese R, Seiberling M, Weber F, Salamand C et al. Seasonal influenza vaccine delivered by intradermal microinjection: a randomised controlled safety and immunogenicity trial in adults. Vaccine. 2008;26(51):6614–9.

    Article  CAS  PubMed  Google Scholar 

  30. Saville M, Marsh G, Hoffenbach A. Improving seasonal and pandemic influenza vaccines. Influenza Other Respi Viruses. 2008;2(6):229–35.

    Article  PubMed  Google Scholar 

  31. Intanza(R), The First Intradermal Influenza Vaccine, Receives The European Marketing Authorisation. http://www.medicalnewstoday.com/articles/140580.php (accessed 11/30/09), part of Medical News Today. http://www.medicalnewstoday.com/ (accessed 11/30/09).

  32. Prausnitz MR, Mikszta JA, Raeder-Devens J. Microneedles. In: Smith EW, Maibach HI, editors. Percutaneous penetration enhancers. Boca Raton: CRC; 2006. p. 239–55.

    Google Scholar 

  33. Autret E, Guilloteau D, Corbel D, Jonville AP, Peyron R, Garrigue MA et al. Comparison of plasma concentration and tolerance of a single dose of human calcitonin by intradermal and subcutaneous administration. Therapie. 1991;46(1):5–8.

    CAS  PubMed  Google Scholar 

  34. Kretsos K, Kasting GB. Dermal capillary clearance: physiology and modeling. Skin Pharmacol Physiol. 2005;18(2):55–74.

    Article  CAS  PubMed  Google Scholar 

  35. Bollinger A. Microlymphatics of human skin. Int J Microcirc Clin Exp. 1993;12(1):1–15.

    CAS  PubMed  Google Scholar 

  36. Tripp CH, Haid B, Flacher V, Sixt M, Peter H, Farkas J et al. The lymph vessel network in mouse skin visualised with antibodies against the hyaluronan receptor LYVE-1. Immunobiology. 2008;213(9–10):715–28.

    Article  CAS  PubMed  Google Scholar 

  37. Segura E, Villadangos JA. Antigen presentation by dendritic cells in vivo. Curr Opin Immunol. 2009;21(1):105–10.

    Article  CAS  PubMed  Google Scholar 

  38. Zaba LC, Krueger JG, Lowes MA. Resident and “inflammatory” dendritic cells in human skin. J Invest Dermatol. 2009;129(2):302–8.

    Article  CAS  PubMed  Google Scholar 

  39. Laurent PE, Pettis R, Easterbrook W, Berube J. Evaluating new hypodermic and intradermal injection devices. Med Device Technol. 2006;17(2):16–9.

    CAS  PubMed  Google Scholar 

  40. Lin S, Chen LL, Chien YW. Comparative pharmacokinetic and pharmacodynamics studies of human insulin and analogues in chronic diabetic Yucatan minipigs. J Pharmacol Exp Ther. 1998;286(2):959–66.

    CAS  PubMed  Google Scholar 

  41. Naik A, Kalia YN, Guy RH. Transdermal drug delivery: overcoming the skin’s barrier function. Pharm Sci Technol Today. 2000;3(9):318–26.

    Article  CAS  PubMed  Google Scholar 

  42. McAllister DV, Wang PM, Davis SP, Park JH, Canatella PJ, Allen MG et al. Microfabricated needles for transdermal delivery of macromolecules and nanoparticles: fabrication methods and transport studies. Proc Natl Acad Sci. 2003;100(24):13755–60.

    Article  CAS  PubMed  Google Scholar 

  43. Gin H, Hanaire-Broutin H. Reproducibility and variability in the action of injected insulin. Diabetes Metab. 2005;31(1):7–13.

    Article  CAS  PubMed  Google Scholar 

  44. Sindelka G, Heinemann L, Berger M, Frenck W, Chantelau E. Effect of insulin concentration, subcutaneous fat thickness and skin temperature on subcutaneous insulin absorption in healthy subjects. Diabetologia. 1994;37(4):377–80.

    Article  CAS  PubMed  Google Scholar 

  45. White HD, Ahmad AM, Vora JP. Effects of adult growth hormone deficiency and growth hormone replacement on circadian rhythmicity. Minerva Endocrinol. 2003;28(1):13–25.

    CAS  PubMed  Google Scholar 

  46. Laursen T, Gravholt CH, Heickendorff L, Drustrup J, Kappelgaard AM, Jørgensen JO et al. Long-term effects of continuous subcutaneous infusion versus daily subcutaneous injections of growth hormone (GH) on the insulin-like growth factor system, insulin sensitivity, body composition, and bone and lipoprotein metabolism in GH-deficient adults. J Clin Endocrinol Metab. 2001;86(3):1222–8.

    Article  CAS  PubMed  Google Scholar 

  47. Kagan L, Gershkovich P, Mendelman A, Amsili S, Ezov N, Hoffman A. The role of the lymphatic system in subcutaneous absorption of macromolecules in the rat model. Eur J Pharm Biopharm. 2007;67(3):759–65.

    Article  CAS  PubMed  Google Scholar 

  48. Charman SA, McLennan DN, Edwards GA, Porter CJ. Lymphatic absorption is a significant contributor to the subcutaneous bioavailability of insulin in a sheep model. Pharm Res. 2001;18(11):1620–6.

    Article  CAS  PubMed  Google Scholar 

  49. McLennan DN, Porter CJ, Charman SA. Subcutaneous drug delivery and the role of the lymphatics. Drug Discovery Today: Technologies. 2005;2(1):89–96.

    Article  CAS  Google Scholar 

  50. Sharma R, Wang W, Rasmussen JC, Joshi A, Houston JP, Adams KE et al. Quantitative imaging of lymph function. Am J Physiol Heart Circ Physiol. 2007;292(6):H3109–3118.

    Article  CAS  PubMed  Google Scholar 

  51. Sevick-Muraca EM, Sharma R, Rasmussen JC, Marshall MV, Wendt JA, Pham HQ et al. Imaging of lymph flow in breast cancer patients after microdose administration of a near-infrared fluorophore: feasibility study. Radiology. 2008;246(3):734–41.

    Article  PubMed  Google Scholar 

  52. Søeborg T, Rasmussen CH, Mosekilde E, Colding-Jørgensen M. Absorption kinetics of insulin after subcutaneous administration. Eur J Pharm Sci. 2009;36(1):78–90.

    Article  PubMed  Google Scholar 

  53. Swartz M, Boardman K. The role of interstitial stress in lymphatic function and lymphangiogenesis. Ann NY Acad Sci. 2002;979:197–210.

    Article  PubMed  Google Scholar 

Download references

ACKNOWLEDGEMENTS

This work was funded by BD. We wish to thank Immunex and Pharmacia for providing etanercept and rhGH, respectively, PK support, and partial funding. From BD Technologies, Steven Keith for his PK work on insulin, Colleen Nycz for her work with lymphatic imaging, and Tommy Robinson, Frank Martin, and Scott O’Connor for their microdevice manufacturing effort are also gratefully acknowledged.

Author information

Authors and Affiliations

  1. BD Technologies, 21 Davis Drive, Research Triangle Park, North Carolina, 27709, USA

    Alfred J. Harvey, Scott A. Kaestner, Diane E. Sutter, Noel G. Harvey, John A. Mikszta & Ronald J. Pettis

Authors
  1. Alfred J. Harvey
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Scott A. Kaestner
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Diane E. Sutter
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Noel G. Harvey
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. John A. Mikszta
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Ronald J. Pettis
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Ronald J. Pettis.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Harvey, A.J., Kaestner, S.A., Sutter, D.E. et al. Microneedle-Based Intradermal Delivery Enables Rapid Lymphatic Uptake and Distribution of Protein Drugs. Pharm Res 28, 107–116 (2011). https://doi.org/10.1007/s11095-010-0123-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11095-010-0123-9

KEY WORDS

Search

Navigation