Skip to main content
SpringerLink
Log in

Sublingual Diffusion of Epinephrine Microcrystals from Rapidly Disintegrating Tablets for the Potential First-Aid Treatment of Anaphylaxis: In Vitro and Ex Vivo Study

  • Research Article
  • Published:
AAPS PharmSciTech Aims and scope Submit manuscript

Abstract

For the first-aid treatment of anaphylaxis, epinephrine (Epi) 0.3 mg intramuscular (IM) injection in the thigh is the drug of choice. Epi auto-injectors are widely recommended for anaphylaxis treatment in community settings but not necessarily carried or used as prescribed when anaphylaxis occurs. We therefore developed rapidly disintegrating sublingual tablets (RDSTs) as an alternative noninvasive dosage form. Our objective in this study was to evaluate the effect of reducing Epi particle size on its in vitro and ex vivo diffusion, with the goal of enhancing Epi sublingual absorption from Epi RDSTs. Epi particle size was reduced by top-bottom technique using a microfluidizer for one pass at 30,000 Psi. The micronized Epi crystals (Epi-MC) were characterized using Zetasizer, Fourier transform infrared (FT-IR), differential scanning calorimetry (DSC), and scanning electron microscopy (SEM). Epi RDSTs were formulated and manufactured using our previously developed method. In vitro and ex vivo diffusion of Epi 10, 20, and 40 mg RDSTs and Epi-MC 10 and 20 mg RDSTs (n = 4) were evaluated using Franz cells. Epi 10 mg solution was used as a control. Mean (±standard deviation (SD)) Epi particle size was successfully reduced from 131.8 ± 10.5 to 2.5 ± 0.4 μm. Cumulative Epi diffused and influx from 40 mg Epi RDSTs and 20 mg Epi-MC RDSTs were not significantly different from each other in vitro and ex vivo (p > 0.05). Also, Epi permeability from 20 mg Epi-MC RDSTs was significantly higher than from the rest (p < 0.05). Epi-MC RDSTs improved Epi diffusion twofold and might have the potential to reduce the Epi dose needed in RDSTs by 50%.

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
Fig. 6
Fig. 7

Similar content being viewed by others

REFERENCES

  1. Kemp SF, Lockey RF, Simons FE. Epinephrine: the drug of choice for anaphylaxis. A statement of the World Allergy Organization. Allergy. 2008;63(8):1061–70. doi:10.1111/j.1398-9995.2008.01733.x.

    Article  CAS  PubMed  Google Scholar 

  2. Simons FER, Sheikh A. Anaphylaxis: the acute episode and beyond. BMJ. 2013;346:f602. doi:10.1136/bmj.f602.

    Article  PubMed  Google Scholar 

  3. Simons KJ, Simons FE. Epinephrine and its use in anaphylaxis: current issues. Curr Opin Allergy Clin Immunol. 2010;10(4):354–61. doi:10.1097/ACI.0b013e32833bc670.

    Article  CAS  PubMed  Google Scholar 

  4. Soar J, Pumphrey R, Cant A, Clarke S, Corbett A, Dawson P, et al. Emergency treatment of anaphylactic reactions—guidelines for healthcare providers. Resuscitation. 2008;77(2):157–69. doi:10.1016/j.resuscitation.2008.02.001.

    Article  PubMed  Google Scholar 

  5. Rachid O, Rawas-Qalaji MM, Simons FE, Simons KJ. Epinephrine (adrenaline) absorption from new-generation, taste-masked sublingual tablets: a preclinical study. J Allergy Clin Immunol. 2013;131(1):236–8. doi:10.1016/j.jaci.2012.10.016.

    Article  CAS  PubMed  Google Scholar 

  6. Rawas-Qalaji M, Rachid O, Mendez BA, Losada A, Simons FE, Simons KJ. Adrenaline (epinephrine) microcrystal sublingual tablet formulation: enhanced absorption in a preclinical model. J Pharm Pharmacol. 2015;67(1):20–5. doi:10.1111/jphp.12312.

    Article  CAS  PubMed  Google Scholar 

  7. Rawas-Qalaji MM, Simons FE, Simons KJ. Sublingual epinephrine tablets versus intramuscular injection of epinephrine: dose equivalence for potential treatment of anaphylaxis. J Allergy Clin Immunol. 2006;117(2):398–403. doi:10.1016/j.jaci.2005.12.1310.

    Article  CAS  PubMed  Google Scholar 

  8. Rawas-Qalaji MM, Simons FE, Simons KJ. Epinephrine for the treatment of anaphylaxis: do all 40 mg sublingual epinephrine tablet formulations with similar in vitro characteristics have the same bioavailability? Biopharm Drug Dispos. 2006;27(9):427–35. doi:10.1002/bdd.519.

    Article  CAS  PubMed  Google Scholar 

  9. Rawas-Qalaji MM, Rachid O, Simons FE, Simons KJ. Long-term stability of epinephrine sublingual tablets for the potential first-aid treatment of anaphylaxis. Ann Allergy Asthma Immunol. 2013;111(6):568–70. doi:10.1016/j.anai.2013.09.005.

    Article  CAS  PubMed  Google Scholar 

  10. Rolan P, Lim S, Sunderland V, Liu Y, Molnar V. The absolute bioavailability of racemic ketamine from a novel sublingual formulation. Br J Clin Pharmacol. 2014;77(6):1011–6.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  11. Hoffman BB, Taylor P. Neurotransmission: the autonomic and somatic motor nervous systems. In: Hardman JG, Limbird LE, Gilman AG, editors. Goodman & Gilman’s the pharmacological basis of therapeutics. 9th ed. New York: McGraw-Hill Companies, Inc; 2001. p. 115–53.

    Google Scholar 

  12. Rachid O, Rawas-Qalaji M, Simons FER, Simons KJ. Dissolution testing of sublingual tablets: a novel in vitro method. AAPS PharmSciTech. 2011;12(2):544–52. doi:10.1208/s12249-011-9615-0.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  13. Rachid O, Rawas-Qalaji M, Simons FER, Simons KJ. Rapidly-disintegrating sublingual tablets of epinephrine: role of non-medicinal ingredients in formulation development. Eur J Pharm Biopharm. 2012;82(3):598–604. doi:10.1016/j.ejpb.2012.05.020.

    Article  CAS  PubMed  Google Scholar 

  14. Rachid O, Simons FE, Rawas-Qalaji M, Simons KJ. An electronic tongue: evaluation of the masking efficacy of sweetening and/or flavoring agents on the bitter taste of epinephrine. AAPS PharmSciTech. 2010;11(2):550–7. doi:10.1208/s12249-010-9402-3.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  15. Rawas-Qalaji MM, Simons FE, Simons KJ. Fast-disintegrating sublingual epinephrine tablets: effect of tablet dimensions on tablet characteristics. Drug Dev Ind Pharm. 2007;33(5):523–30. doi:10.1080/03639040600897150.

    Article  CAS  PubMed  Google Scholar 

  16. Rawas-Qalaji MM, Simons FER, Simons KJ. Fast-disintegrating sublingual tablets: effect of epinephrine load on tablet characteristics. AAPS PharmSciTech. 2006;7(2):E72–8. doi:10.1208/pt070241.

    Article  PubMed Central  Google Scholar 

  17. Muller RH, Gohla S, Keck CM. State of the art of nanocrystals—special features, production, nanotoxicology aspects and intracellular delivery. Eur J Pharm Biopharm. 2011;78(1):1–9. doi:10.1016/j.ejpb.2011.01.007.

    Article  PubMed  Google Scholar 

  18. USP/NF. Physical tests: <905> uniformity of dosage units. United States Pharmacopeia 3. 37/32nd ed. Rockville: Pharmacopeial Convention, Inc; 2014. p. 491–4.

    Google Scholar 

  19. USP/NF. General chapters: <1216> tablet friability. United States Pharmacopeia 6. 37/32nd ed. Rockville: Pharmacopeial Convention, Inc; 2014. p. 1145–6.

    Google Scholar 

  20. USP/NF. Official monograph: epinephrine bitartrate. 31/26th ed. Rockville: United States Pharmacopeial Convention, Inc; 2008.

    Google Scholar 

  21. USP/NF. Official monograph: epinephrine injection. 31/26 ed. Rockville: United States Pharmacopeial Convention, Inc; 2008.

  22. Liu Y, Sun C, Hao Y, Jiang T, Zheng L, Wang S. Mechanism of dissolution enhancement and bioavailability of poorly water soluble celecoxib by preparing stable amorphous nanoparticles. J Pharm Pharm Sci. 2010;13(4):589–606.

    CAS  PubMed  Google Scholar 

  23. Ma Q, Sun H, Che E, Zheng X, Jiang T, Sun C, et al. Uniform nano-sized valsartan for dissolution and bioavailability enhancement: influence of particle size and crystalline state. Int J Pharm. 2013;441(1–2):75–81. doi:10.1016/j.ijpharm.2012.12.025.

    Article  CAS  PubMed  Google Scholar 

  24. Dali MM, Moench PA, Mathias NR, Stetsko PI, Heran CL, Smith RL. A rabbit model for sublingual drug delivery: comparison with human pharmacokinetic studies of propranolol, verapamil and captopril. J Pharm Sci. 2006;95(1):37–44. doi:10.1002/jps.20312.

    Article  CAS  PubMed  Google Scholar 

  25. Ong CM, Heard CM. Permeation of quinine across sublingual mucosa, in vitro. Int J Pharm. 2009;366(1–2):58–64. doi:10.1016/j.ijpharm.2008.08.048.

    Article  CAS  PubMed  Google Scholar 

Download references

ACKNOWLEDGMENTS

Dr. Rawas-Qalaji would like to acknowledge the financial support received from the President’s Faculty Research & Development Grant (PFRDG) at Nova Southeastern University. No financial or in-kind support for this study was provided by any corporate sponsor.

Conflict of Interest

Mutasem Rawas-Qalaji reports no declarations of interest.

Shima Werdy reports no declarations of interest.

Ousama Rachid reports no declarations of interest.

F. Estelle R. Simons reports no declarations of interest.

Keith J. Simons reports no declarations of interest.

Author information

Authors and Affiliations

  1. College of Pharmacy, Nova Southeastern University, 3200 South University Drive, Fort Lauderdale, Florida, 33328, USA

    Mutasem M. Rawas-Qalaji & Shima Werdy

  2. Faculty of Pharmacy, University of Manitoba, Winnipeg, Manitoba, Canada

    Ousama Rachid & Keith J. Simons

  3. Faculty of Medicine, University of Manitoba, Winnipeg, Manitoba, Canada

    F. Estelle R. Simons & Keith J. Simons

Authors
  1. Mutasem M. Rawas-Qalaji
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Shima Werdy
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ousama Rachid
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. F. Estelle R. Simons
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Keith J. Simons
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Mutasem M. Rawas-Qalaji.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Rawas-Qalaji, M.M., Werdy, S., Rachid, O. et al. Sublingual Diffusion of Epinephrine Microcrystals from Rapidly Disintegrating Tablets for the Potential First-Aid Treatment of Anaphylaxis: In Vitro and Ex Vivo Study. AAPS PharmSciTech 16, 1203–1212 (2015). https://doi.org/10.1208/s12249-015-0306-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1208/s12249-015-0306-0

KEY WORDS

Search

Navigation