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Permeation-Enhancing Nanoparticle Formulation to Enable Oral Absorption of Enoxaparin

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Abstract

This study tests the hypothesis that association complexes formed between enoxaparin and cetyltrimethylammonium bromide (CTAB) augment permeation across the gastrointestinal mucosa due to improved encapsulation of this hydrophilic macromolecule within biocompatible poly (lactide-co-glycolide, PLGA RG 503) nanoparticles. When compared with free enoxaparin, association with CTAB increased drug encapsulation efficiency within PLGA nanoparticles from 40.3 ± 3.4 to 99.1 ± 1.0%. Drug release from enoxaparin/CTAB PLGA nanoparticles was assessed in HBSS, pH 7.4 and FASSIFV2, pH 6.5, suggesting effective protection of PLGA-encapsulated enoxaparin from unfavorable intestinal conditions. The stability of the enoxaparin/CTAB ion pair complex was pH-dependent, resulting in more rapid dissociation under simulated plasma conditions (i.e., pH 7.4) than in the presence of a mild acidic gastrointestinal environment (i.e., pH 6.5). The intestinal flux of enoxaparin complexes across in vitro Caco-2 cell monolayers was greater when encapsulated within PLGA nanoparticles. Limited changes in transepithelial transport of PLGA-encapsulated enoxaparin complexes in the presence of increasing CTAB concentrations suggest a significant contribution of size-dependent passive diffusion as the predominant transport mechanism facilitating intestinal absorption.

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References

  1. Caputo HE, Straub JE, Grinstaff MW. Design, synthesis, and biomedical applications of synthetic sulphated polysaccharides. Chem Soc Rev. 2019;48(8):2338–65.

  2. Zhou J, Fang R, Yan Q, Li C, Zhou Y, Nur AA, Liu T, Wang W. Low-molecular-weight heparin followed by rivaroxaban or not for the prevention of deep venous thromboembolism after total knee arthroplasty. Blood Coagul Fibrinolysis. 2019;30(1):29–33.

  3. Dong W, Wang X, Liu C, Zhang X, Zhang X, Chen X, Kou Y, Mao S. Chitosan based polymer-lipid hybrid nanoparticles for oral delivery of enoxaparin. Int J Pharm. 2018;547(1–2):499–505.

  4. Hayes PY, Ross BP, Thomas BG, Toth I. Polycationic lipophilic-core dendrons as penetration enhancers for the oral administration of low molecular weight heparin. Bioorg Med Chem. 2006;14(1):143–52.

    CAS  PubMed  Google Scholar 

  5. Twarog C, Fattah S, Heade J, Maher S, Fattal E, Brayden DJ. Intestinal permeation enhancers for oral delivery of macromolecules: a comparison between salcaprozate sodium (SNAC) and sodium caprate (C10). Pharmaceutics. 2019;11(2):78.

    CAS  PubMed Central  Google Scholar 

  6. He H, Lu Y, Qi J, Zhu Q, Chen Z, Wu W. Adapting liposomes for oral drug delivery. Acta Pharm Sin B. 2019;9(1):36–48.

  7. Maher S, Brayden DJ, Casettari L, Illum L. Application of permeation enhancers in oral delivery of macromolecules: an update. Pharmaceutics. 2019;11(1):41.

    CAS  PubMed Central  Google Scholar 

  8. Bernkop-Schnürch A. The use of inhibitory agents to overcome the enzymatic barrier to perorally administered therapeutic peptides and proteins. J Control Release. 1998;52(1–2):1–16.

    PubMed  Google Scholar 

  9. Colzani B, Pandolfi L, Hoti A, Iovene PA, Natalello A, Avvakumova S, Colombo M, Prosperi D. Investigation of antitumor activities of trastuzumab delivered by PLGA nanoparticles. Int J Nanomedicine. 2018;13:957.

  10. Pereverzeva E, Treschalin I, Treschalin M, Arantseva D, Ermolenko Y, Kumskova N, Maksimenko O, Balabanyan V, Kreuter J, Gelperina S. Toxicological study of doxorubicin-loaded PLGA nanoparticles for the treatment of glioblastoma. Int J Pharm. 2019;554:161–78.

  11. Sah E, Sah H. Recent trends in preparation of poly (lactide-co-glycolide) nanoparticles by mixing polymeric organic solution with antisolvent. J Nanomater. 2015;2015:61.

    Google Scholar 

  12. Zaichik S, Steinbring C, Caliskan C, Bernkop-Schnürch A. Development and in vitro evaluation of a self-emulsifying drug delivery system (SEDDS) for oral vancomycin administration. Int J Pharm. 2019;554:125–33.

    CAS  PubMed  Google Scholar 

  13. Phan TNQ, Le-Vinh B, Efiana NA, Bernkop-Schnürch A. Oral self-emulsifying delivery systems for systemic administration of therapeutic proteins: science fiction? Journal of Drug Targeting. 2019;27(9):1017–24.

  14. Lozoya-Agullo I, Planelles M, Merino-Sanjuán M, Bermejo M, Sarmento B, González-Álvarez I, González-Álvarez M. Ion-pair approach coupled with nanoparticle formation to increase bioavailability of a low permeability charged drug. Int J Pharm. 2019;557:36–42.

  15. Nazir I, Asim MH, Dizdarević A, Bernkop-Schnürch A. Self-emulsifying drug delivery systems: impact of stability of hydrophobic ion pairs on drug release. Int J Pharm. 2019;561:197–205.

  16. Eleraky NE, Mohamed DF, Attia MA, Pauletti GM. Hydrophobic ion-pairing of low molecular weight heparin with cetyltrimethylammonium bromide. Int J Pharm Sci Res. 2015;6:558–65.

  17. Cadène M, Boudier C, de Marcillac GD, Bieth JG. Influence of low molecular mass heparin on the kinetics of neutrophil elastase inhibition by mucus proteinase inhibitor (*). J Biol Chem. 1995;270(22):13204–9.

    PubMed  Google Scholar 

  18. Fessi H, Puisieux F, Devissaguet JP, Ammoury N, Benita S. Nanocapsule formation by interfacial polymer deposition following solvent displacement. Int J Pharm. 1989;55(1):R1–4.

    CAS  Google Scholar 

  19. D’souza SS, DeLuca PP. Methods to assess in vitro drug release from injectable polymeric particulate systems. Pharm Res. 2006;23(3):460–74.

    PubMed  Google Scholar 

  20. Pauletti GM, Gangwar S, Okumu FW, Siahaan TJ, Stella VJ, Borchardt RT. Esterase-sensitive cyclic prodrugs of peptides: evaluation of an acyloxyalkoxy promoiety in a model hexapeptide. Pharm Res. 1996;13(11):1615–23.

    CAS  PubMed  Google Scholar 

  21. Souza VMD, Shertzer HG, Menon AG, Pauletti GM. High glucose concentration in isotonic media alters Caco-2 cell permeability. AAPS PharmSci. 2015;5(3):17.

    Google Scholar 

  22. Kotzé AR, Lueβen HL, de Leeuw BJ, de Boer BG, Verhoef JC, Junginger HE. N-trimethyl chitosan chloride as a potential absorption enhancer across mucosal surfaces: in vitro evaluation in intestinal epithelial cells (Caco-2). Pharm Res. 1997;14(9):1197–202.

    PubMed  Google Scholar 

  23. Haas S. The role of low molecular weight heparins for venous thromboembolism prevention in medical patients—what is new in 2019? Hämostaseologie. 2019;39 (01):062–6.

  24. Zupančič O, Grieβinger JA, Rohrer J, de Sousa IP, Danninger L, Partenhauser A, Sündermann NE, Laffleur F, Bernkop-Schnürch A. Development, in vitro and in vivo evaluation of a self-emulsifying drug delivery system (SEDDS) for oral enoxaparin administration. Eur J Pharm Biopharm. 2016;109:113–21.

  25. Holmkvist AD, Friberg A, Nilsson UJ, Schouenborg J. Hydrophobic ion pairing of a minocycline/Ca2+/AOT complex for preparation of drug-loaded PLGA nanoparticles with improved sustained release. Int J Pharm. 2016;499(1–2):351–7.

    CAS  PubMed  Google Scholar 

  26. Banerjee A, Qi J, Gogoi R, Wong J, Mitragotri S. Role of nanoparticle size, shape and surface chemistry in oral drug delivery. J Control Release. 2016;238:176–85.

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Caldorera-Moore M, Guimard N, Shi L, Roy K. Designer nanoparticles: incorporating size, shape and triggered release into nanoscale drug carriers. Expert Opinion on Drug Delivery. 2010;7(4):479–95.

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Sun S, Liang N, Kawashima Y, Xia D, Cui F. Hydrophobic ion pairing of an insulin-sodium deoxycholate complex for oral delivery of insulin. Int J Nanomedicine. 2011;6:3049.

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Kalaria D, Sharma G, Beniwal V, Kumar MR. Design of biodegradable nanoparticles for oral delivery of doxorubicin: in vivo pharmacokinetics and toxicity studies in rats. Pharm Res. 2009;26(3):492–501.

    CAS  PubMed  Google Scholar 

  30. Jain AK, Swarnakar NK, Godugu C, Singh RP, Jain S. The effect of the oral administration of polymeric nanoparticles on the efficacy and toxicity of tamoxifen. Biomaterials. 2011;32(2):503–15.

    CAS  PubMed  Google Scholar 

  31. Fredenberg S, Wahlgren M, Reslow M, Axelsson A. The mechanisms of drug release in poly (lactic-co-glycolic acid)-based drug delivery systems—a review. Int J Pharm. 2011;415(1):34–52.

    CAS  PubMed  Google Scholar 

  32. Wang J, Wang BM, Schwendeman SP. Characterization of the initial burst release of a model peptide from poly (D, L-lactide-co-glycolide) microspheres. J Control Release. 2002;82(2):289–307.

    CAS  PubMed  Google Scholar 

  33. Jiao Y, Ubrich N, Marchand-Arvier M, Vigneron C, Hoffman M, Lecompte T, Maincent P. In vitro and in vivo evaluation of oral heparin–loaded polymeric nanoparticles in rabbits. Circulation. 2002;105(2):230–5.

  34. Makino K, Mogi T, Ohtake N, Yoshida M, Ando S, Nakajima T, Ohshima H. Pulsatile drug release from poly (lactide-co-glycolide) microspheres: how does the composition of the polymer matrices affect the time interval between the initial burst and the pulsatile release of drugs? Colloids Surf B: Biointerfaces. 2000;19(2):173–9.

  35. Lewis R. Hawley’s condensed chemical dictionary. 15 e éd. A John Wiley & Sons. Inc, New York. 2007.

  36. Sang Yoo H, Gwan PT. Biodegradable nanoparticles containing protein-fatty acid complexes for oral delivery of salmon calcitonin. J Pharm Sci. 2004;93(2):488–95.

    PubMed  Google Scholar 

  37. Motlekar NA, Srivenugopal KS, Wachtel MS, Youan BBC. Modulation of gastrointestinal permeability of low-molecular-weight heparin by L-arginine: in-vivo and in-vitro evaluation. J Pharm Pharmacol. 2006;58(5):591–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Artursson P. Epithelial transport of drugs in cell culture. I: a model for studying the passive diffusion of drugs over intestinal absorbtive (Caco-2) cells. J Pharm Sci. 1990;79(6):476–82.

    CAS  PubMed  Google Scholar 

  39. He C, Hu Y, Yin L, Tang C, Yin C. Effects of particle size and surface charge on cellular uptake and biodistribution of polymeric nanoparticles. Biomaterials. 2010;31(13):3657–66.

    CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This research was supported in part by a predoctoral fellowship from the Egyptian Ministry of Higher Education awarded to Nermin E. Eleraky.

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Authors and Affiliations

  1. James L. Winkle College of Pharmacy, University of Cincinnati, Cincinnati, Ohio, USA

    Nermin E. Eleraky, Nitin K. Swarnakar & Giovanni M. Pauletti

  2. Pharmaceutics Dept., Faculty of Pharmacy, Assiut University, Assiut, 71526, Egypt

    Nermin E. Eleraky, Dina F. Mohamed & Mohamed A. Attia

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  1. Nermin E. Eleraky
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  2. Nitin K. Swarnakar
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  3. Dina F. Mohamed
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  4. Mohamed A. Attia
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  5. Giovanni M. Pauletti
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Contributions

Nermin E. Eleraky executed preparation and characterization of enoxaparin/CTAB complexes and enoxaparin/CTAB loaded PLGA nanoparticles, in vitro release of enoxaparin, enoxaparin/CTAB complex stability study using ITC, Caco-2 cell permeation study and manuscript preparation. Nitin K. Swarnakar helped with Caco-2 cell permeation studies. Dina F. Mohamed and Mohamed A. Attia participated in the experimental design and manuscript review. Giovanni M. Pauletti collaborated with experimental designs and aid during manuscript preparation. All authors read and confirmed the final manuscript.

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Correspondence to Nermin E. Eleraky.

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On behalf of all the authors, Nermin E. Eleraky, Ph.D. declares that they have no conflict of interest.

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Eleraky, N.E., Swarnakar, N.K., Mohamed, D.F. et al. Permeation-Enhancing Nanoparticle Formulation to Enable Oral Absorption of Enoxaparin. AAPS PharmSciTech 21, 88 (2020). https://doi.org/10.1208/s12249-020-1618-2

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