Skip to main content

Advertisement

SpringerLink
Log in

Primaquine Loaded Solid Lipid Nanoparticles (SLN), Nanostructured Lipid Carriers (NLC), and Nanoemulsion (NE): Effect of Lipid Matrix and Surfactant on Drug Entrapment, in vitro Release, and ex vivo Hemolysis

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

A Correction to this article was published on 20 December 2021

This article has been updated

Abstract

Primaquine (PQ), an 8-aminoquinoline antimalarial drug, has been widely used for the eradication of hypnozoites from the liver and, therefore, recognized as the radical cure of malaria. However, the clinical applications of PQ are restricted to patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency due to severe dose-related hemolytic side effects. Nanoparticle carriers have shown great potential in achieving higher PQ concentrations in the target site, thereby reducing dose-related systemic toxicity caused by non-specific exposure. This work aims to develop, compare, and evaluate three PQ-loaded lipid-based drug carriers including solid lipid nanoparticles (SLN), nanostructured lipid carriers (NLC), and nano-emulsions (NE). The optimized PQ-SLN, PQ-NLC, and PQ-NE had a particle size of 250 nm, a PDI range of 0.1 to 0.3, a zeta potential of − 30 mV, and entrapment efficiency of ~ 90%. All lipid formulations showed sustained release in both simulated gastric and intestinal fluids over 6 h. Four empirical models — including zero-order, Higuchi, Korsmeyer-Peppas, and Hixson-Crowell models — were tested to understand the drug release mechanisms of PQ-SLN, PQ-NLC, and PQ-NE. The model fitness was found to be the highest in the Korsmeyer-Peppas model for all the PQ-loaded lipid formulations (R2: 0.88–0.94). No significant changes were observed in the entrapment efficiency, particle size, and PDI of lipid formulations throughout 1 month of storage at 4 °C and 25 °C. PQ-SLN and PQ-NLC can be further lyophilized with cryoprotectants to improve long-term stability. Finally, the treatment of erythrocytes with PQ-SLN, PQ-NLC, and PQ-NE reduced erythrocyte hemolysis by approximately 4.5-fold compared to the free drug solution.

Graphical abstract

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.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

Change history

References

  1. World malaria report 2020: 20 years of global progress and challenges. World Health Organization; 2020.

  2. Baird JK, Hoffman SL. Primaquine therapy for malaria. Clin Infect Dis. 2004;39(9):1336–45.

    Article  CAS  PubMed  Google Scholar 

  3. Baird JK, Rieckmann KH. Can primaquine therapy for vivax malaria be improved? Trends Parasitol. 2003;19(3):115–20.

    Article  CAS  PubMed  Google Scholar 

  4. Fernando D, Rodrigo C, Rajapakse S. Primaquine in vivax malaria: an update and review on management issues. Malar J. 2011;10(1):351.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Camarda G, Jirawatcharadech P, Priestley RS, Saif A, March S, Wong MHL, et al. Antimalarial activity of primaquine operates via a two-step biochemical relay. Nat Commun. 2019;10(1):3226.

    Article  PubMed  PubMed Central  Google Scholar 

  6. Fasinu PS, Nanayakkara NPD, Wang YH, Chaurasiya ND, Herath HMB, McChesney JD, et al. Formation primaquine-5,6-orthoquinone, the putative active and toxic metabolite of primaquine via direct oxidation in human erythrocytes. Malar J. 2019;18(1):30.

    Article  PubMed  PubMed Central  Google Scholar 

  7. Hill DR, Baird JK, Parise ME, Lewis LS, Ryan ET, Magill AJ. Primaquine: report from CDC expert meeting on malaria chemoprophylaxis I. Am J Trop Med Hyg. 2006;75(3):402–15.

    Article  CAS  PubMed  Google Scholar 

  8. Das S, Chaudhury A. Recent advances in lipid nanoparticle formulations with solid matrix for oral drug delivery. AAPS PharmSciTech. 2011;12(1):62–76.

    Article  CAS  PubMed  Google Scholar 

  9. Hauss DJ. Oral lipid-based formulations. Adv Drug Deliv Rev. 2007;59(7):667–76.

    Article  CAS  PubMed  Google Scholar 

  10. Rahman A, Harwansh R, Mirza A, Hussain S, Hussain A. Oral lipid based drug delivery system (LBDDS): formulation, characterization and application: a review. Curr Drug Deliv. 2011;8(4):330–45.

    Article  CAS  PubMed  Google Scholar 

  11. Pirson P, Steiger R, Trouet A. The disposition of free and liposomally encapsulated antimalarial primaquine in mice. Biochem Pharmacol. 1982;31(21):3501–7.

    Article  CAS  PubMed  Google Scholar 

  12. Bhadra D, Yadav A, Bhadra S, Jain N. Glycodendrimeric nanoparticulate carriers of primaquine phosphate for liver targeting. Int J Pharm. 2005;295(1–2):221–33.

    Article  CAS  PubMed  Google Scholar 

  13. Dierling AM, Cui Z. Targeting primaquine into liver using chylomicron emulsions for potential vivax malaria therapy. Int J Pharm. 2005;303(1–2):143–52.

    Article  CAS  PubMed  Google Scholar 

  14. Singh KK, Vingkar SK. Formulation, antimalarial activity and biodistribution of oral lipid nanoemulsion of primaquine. Int J Pharm. 2008;347(1–2):136–43.

    Article  CAS  PubMed  Google Scholar 

  15. Omwoyo WN, Ogutu B, Oloo F, Swai H, Kalombo L, Melariri P, et al. Preparation, characterization, and optimization of primaquine-loaded solid lipid nanoparticles. Int J Nanomedicine. 2014;9:3865–74.

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Zoubari G, Staufenbiel S, Volz P, Alexiev U, Bodmeier R. Effect of drug solubility and lipid carrier on drug release from lipid nanoparticles for dermal delivery. Eur J Pharm Biopharm. 2017;110:39–46.

    Article  CAS  PubMed  Google Scholar 

  17. Azeem A, Rizwan M, Ahmad FJ, Iqbal Z, Khar RK, Aqil M, et al. Nanoemulsion components screening and selection: a technical note. AAPS PharmSciTech. 2009;10(1):69–76.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Muller RH, Mader K, Gohla S. Solid lipid nanoparticles (SLN) for controlled drug delivery - a review of the state of the art. Eur J Pharm Biopharm. 2000;50(1):161–77.

    Article  CAS  PubMed  Google Scholar 

  19. Li S, Ji Z, Zou M, Nie X, Shi Y, Cheng G. Preparation, characterization, pharmacokinetics and tissue distribution of solid lipid nanoparticles loaded with tetrandrine. AAPS PharmSciTech. 2011;12(3):1011–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Costa P, Sousa Lobo JM. Modeling and comparison of dissolution profiles. Eur J Pharm Sci. 2001;13(2):123–33.

    Article  CAS  PubMed  Google Scholar 

  21. Dash S, Murthy PN, Nath L, Chowdhury P. Kinetic modeling on drug release from controlled drug delivery systems. Acta Pol Pharm. 2010;67(3):217–23.

    CAS  PubMed  Google Scholar 

  22. Evans BC, Nelson CE, Yu SS, Beavers KR, Kim AJ, Li H, et al. Ex vivo red blood cell hemolysis assay for the evaluation of pH-responsive endosomolytic agents for cytosolic delivery of biomacromolecular drugs. J Vis Exp. 2013(73):e50166.

  23. Chong W-T, Tan C-P, Cheah Y-K, B. Lajis AF, Habi Mat Dian NL, Kanagaratnam S, et al. Optimization of process parameters in preparation of tocotrienol-rich red palm oil-based nanoemulsion stabilized by Tween80-Span 80 using response surface methodology. PloS one. 2018;13(8):e0202771.

  24. Lv G, Wang F, Cai W, Zhang X. Characterization of the addition of lipophilic Span 80 to the hydrophilic Tween 80-stabilized emulsions. Colloids Surf, A. 2014;447:8–13.

    Article  CAS  Google Scholar 

  25. Athas JC, Jun K, McCafferty C, Owoseni O, John VT, Raghavan SR. An effective dispersant for oil spills based on food-grade amphiphiles. Langmuir. 2014;30(31):9285–94.

    Article  CAS  PubMed  Google Scholar 

  26. Muller RH, Shegokar R, Keck CM. 20 years of lipid nanoparticles (SLN and NLC): present state of development and industrial applications. Curr Drug Discov Technol. 2011;8(3):207–27.

    Article  PubMed  Google Scholar 

  27. Win KY, Feng SS. Effects of particle size and surface coating on cellular uptake of polymeric nanoparticles for oral delivery of anticancer drugs. Biomaterials. 2005;26(15):2713–22.

    Article  CAS  PubMed  Google Scholar 

  28. Ritger PL, Peppas NA. A simple equation for description of solute release II. Fickian and anomalous release from swellable devices. Journal of controlled release. 1987;5(1):37–42.

  29. Siepmann J, Peppas NA. Modeling of drug release from delivery systems based on hydroxypropyl methylcellulose (HPMC). Adv Drug Deliv Rev. 2012;64:163–74.

    Article  Google Scholar 

  30. Schwarz C, Mehnert W. Freeze-drying of drug-free and drug-loaded solid lipid nanoparticles (SLN). Int J Pharm. 1997;157(2):171–9.

    Article  CAS  PubMed  Google Scholar 

  31. Kumar H, Gothwal A, Khan I, Nakhate KT, Alexander A, Singh V, et al. Galactose-anchored gelatin nanoparticles for primaquine delivery and improved pharmacokinetics: a biodegradable and safe approach for effective antiplasmodial activity against p. Falciparum 3d7 and in vivo hepatocyte targeting. Molecular pharmaceutics. 2017;14(10):3356–69.

Download references

Acknowledgements

The authors acknowledge the Chemistry and Drug Metabolism and Pharmacokinetics core, Center of Biomedical Research Excellence (COBRE), (P30GM122733-01A1) funded by the National Institute of General Medical Sciences (NIGMS) a component of the National Institutes of Health (NIH). Scanning electron microscopy images presented in this study were generated using the instruments and services at the Microscopy and Image Center, the University of Mississippi. This facility is supported in part by the National Science Foundation (Grant # 1726880).

Funding

This work was supported by the National Institute of Allergy and Infectious Disease (NIAID), National Institute of Health (NIH; Grant# 1R01AI132579). The contents are the sole responsibility of the authors and do not necessarily represent the official views of the NIH.

Author information

Authors and Affiliations

  1. Department of Pharmaceutics and Drug Delivery, The University of Mississippi, 111 Faser Hall, University, MA, 38677, USA

    Kai-Wei Wu, Corinne Sweeney, Narendar Dudhipala, Prit Lakhani & Soumyajit Majumdar

  2. Department of Infectious Diseases, Division of Drug Discovery, Southern Research, 2000 Ninth Avenue South, Birmingham, AL, 35205, USA

    Narayan D. Chaurasiya & Babu L. Tekwani

  3. Research Institute of Pharmaceutical Sciences, University of Mississippi, University, MA, 38677, USA

    Soumyajit Majumdar

Authors
  1. Kai-Wei Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Corinne Sweeney
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Narendar Dudhipala
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Prit Lakhani
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Narayan D. Chaurasiya
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Babu L. Tekwani
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Soumyajit Majumdar
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Soumyajit Majumdar.

Ethics declarations

Conflict of interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

The original online version of this article was revised to add additional corrections.

Supplementary Information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Wu, KW., Sweeney, C., Dudhipala, N. et al. Primaquine Loaded Solid Lipid Nanoparticles (SLN), Nanostructured Lipid Carriers (NLC), and Nanoemulsion (NE): Effect of Lipid Matrix and Surfactant on Drug Entrapment, in vitro Release, and ex vivo Hemolysis. AAPS PharmSciTech 22, 240 (2021). https://doi.org/10.1208/s12249-021-02108-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1208/s12249-021-02108-5

Keywords

Search

Navigation