Advertisement

AAPS PharmSciTech

, Volume 19, Issue 8, pp 3584–3598 | Cite as

Lipid Architectonics for Superior Oral Bioavailability of Nelfinavir Mesylate: Comparative in vitro and in vivo Assessment

  • Tejashree Belubbi
  • Sukhada Shevade
  • Vivek Dhawan
  • Vinay Sridhar
  • Anuradha Majumdar
  • Rute Nunes
  • Francisca Araújo
  • Bruno Sarmento
  • Kalpa Nagarsenker
  • Frank Steiniger
  • Alfred Fahr
  • Aniket Magarkar
  • Alex Bunker
  • Mangal Nagarsenker
Research Article Theme: Lipid-Based Drug Delivery Strategies for Oral Drug Delivery
Part of the following topical collections:
  1. Theme: Lipid-Based Drug Delivery Strategies for Oral Drug Delivery

Abstract

Nelfinavir mesylate (NFV), a human immunodeficiency virus (HIV) protease inhibitor, is an integral component of highly active anti retro viral therapy (HAART) for management of AIDS. NFV possesses pH-dependent solubility and has low and variable bioavailability hampering its use in therapeutics. Lipid-based particulates have shown to improve solubility of poorly water soluble drugs and oral absorption, thereby aiding in improved bioavailability. The current study compares potential of vesicular and solid lipid nanocarriers of NFV with drug nanocrystallites and microvesicular systems like cochleates in improving bioavailability of NFV. The paper outlines investigation of systems using in vitro models like in vitro lipolysis, in vitro release, and permeation through cell lines to predict the in vivo potential of nanocarriers. Finally, in vivo pharmacokinetic study is reported which provided proof of concept in sync with results from in vitro studies.

Graphical Abstract

KEY WORDS

SLN LeciPlex® liposomes nanosuspension cochleates molecular dynamic simulation Caco-2:HT29-MTX co-culture 

Notes

Acknowledgements

Authors thank Macleods Pharmaceuticals from providing the gift sample of Nelfinavir Mesylate, Lipoid GmBH, Germany, for providing gift sample of Lecithin. We are grateful to Frank Steiniger for his assistance in Cryo-TEM imaging and Nilesh Kulkarni, Tata Institute of Fundamental Research for X-Ray Diffraction studies.

Funding Information

Tejashree Belubbi, Sukhada Shevade, Vivek Dhawan, Mangal S. Nagarsenker, Kalpa Nagarsenker, and Alfred Fahr are thankful to Indian Council of Medical Research (ICMR), New Delhi, India (Project No: 50/12/2013/BMS) and BundesministeriumfürBildung und Forschung (BMBF), Bonn, Germany, for financial assistance, travel, and accommodation.

Supplementary material

12249_2018_1156_MOESM1_ESM.pdf (221 kb)
ESM 1 (PDF 221 kb)

References

  1. 1.
    Moretton MA, Taira C, Flor S, Bernabeu E, Lucangioli S, Höcht C, et al. Novel nelfinavir mesylate loaded d-α-tocopheryl polyethylene glycol 1000 succinate micelles for enhanced pediatric anti HIV therapy: in vitro characterization and in vivo evaluation. Colloids Surf B: Biointerfaces. 2014;123:302–10.CrossRefPubMedGoogle Scholar
  2. 2.
    Benet LZ, Broccatelli F. Oprea TI. BDDCS applied to over 900 drugs. AAPS J. 2011;13(4):519–47.CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Shono Y, Jantratid E, Dressman JB. Precipitation in the small intestine may play a more important role in the in vivo performance of poorly soluble weak bases in the fasted state: case example nelfinavir. Eur J Pharm Biopharm. 2011;79(2):349–56.CrossRefPubMedGoogle Scholar
  4. 4.
    Williams GC, Sinko PJ. Oral absorption of the HIV protease inhibitors: a current update. Adv Drug Deliv Rev. 1999;39(1):211–38.CrossRefPubMedGoogle Scholar
  5. 5.
    Patel A, Shelat P, Lalwani A. Development and optimization of solid self-nanoemulsifying drug delivery system (S-SNEDDS) using Scheffe’s design for improvement of oral bioavailability of nelfinavir mesylate. Drug Deliv Transl Res. 2014;4(2):171–86.CrossRefPubMedGoogle Scholar
  6. 6.
    Kalepu S, Manthina M, Padavala V. Oral lipid-based drug delivery systems-an overview. Acta Pharm Sin B. 2013;3(6):361–72.CrossRefGoogle Scholar
  7. 7.
    Fricker G, Kromp T, Wendel A, Blume A, Zirkel J, Rebmann H, et al. Phospholipids and lipid-based formulations in oral drug delivery. Pharm Res. 2010;27(8):1469–86.CrossRefPubMedGoogle Scholar
  8. 8.
    Date AA, Srivastava D, Nagarsenker MS, Mulherkar R, Panicker L, Aswal V, et al. Lecithin-based novel cationic nanocarriers (LeciPlex) I: fabrication, characterization and evaluation. Nanomedicine. 2011;6(8):1309–25.CrossRefPubMedGoogle Scholar
  9. 9.
    Jain AS, Shah SM, Nagarsenker MS, Nikam Y, Gude RP, Steiniger F, et al. Lipid colloidal carriers for improvement of anticancer activity of orally delivered quercetin: formulation, characterization and establishing in vitro-in vivo advantage. J Biomed Nanotechnol. 2013;9(7):1230–40.CrossRefPubMedGoogle Scholar
  10. 10.
    Date AA, Nagarsenker MS, Patere S, Dhawan V, Gude R, Hassan P, et al. Lecithin-based novel cationic nanocarriers (Leciplex) II: improving therapeutic efficacy of quercetin on oral administration. Mol Pharm. 2011;8(3):716–26.CrossRefPubMedGoogle Scholar
  11. 11.
    Dhawan VV, Joshi GV, Jain AS, Nikam YP, Gude RP, Mulherkar R, et al. Apoptosis induction and anti-cancer activity of LeciPlex formulations. Cell Oncol. 2014;37(5):339–51.CrossRefGoogle Scholar
  12. 12.
    Li J, Wang X, Zhang T, Wang C, Huang Z, Luo X, et al. A review on phospholipids and their main applications in drug delivery systems. Asian J Pharm Sci. 2015;10(2):81–98.CrossRefGoogle Scholar
  13. 13.
    Zarif L, Graybill JR, Perlin D, Najvar L, Bocanegra R, Mannino RJ. Antifungal activity of amphotericin B cochleates against Candida albicans infection in a mouse model. Antimicrob Agents Chemother. 2000;44(6):1463–9.CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Abraham MJ, Murtola T, Schulz R, Páll S, Smith JC, Hess B, et al. GROMACS: high performance molecular simulations through multi-level parallelism from laptops to supercomputers. SoftwareX. 2015;1:19–25.CrossRefGoogle Scholar
  15. 15.
    Jo S, Kim T, Iyer VG, Im W. CHARMM-GUI: a web-based graphical user interface for CHARMM. J Comput Chem. 2008;29(11):1859–65.CrossRefGoogle Scholar
  16. 16.
    Jo S, Im W. CHARMM-GUI: brining advanced computational techniques to web interface. Biophys J. 2011;100(3):156a.Google Scholar
  17. 17.
    Klauda JB, Venable RM, Freites JA, O’Connor JW, Tobias DJ, Mondragon-Ramirez C, et al. Update of the CHARMM all-atom additive force field for lipids: validation on six lipid types. J Phys Chem B. 2010;114(23):7830–43.CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Jorgensen WL, Chandrasekhar J, Madura JD, Impey RW, Klein ML. Comparison of simple potential functions for simulating liquid water. J Chem Phys. 1983;79(2):926–35.CrossRefGoogle Scholar
  19. 19.
    Humphrey W, Dalke A, Schulten K. VMD: visual molecular dynamics. J Mol Graph. 1996;14(1):33–8.CrossRefGoogle Scholar
  20. 20.
    Essmann U, Perera L, Berkowitz ML, Darden T, Lee H, Pedersen LG. A smooth particle mesh Ewald method. J Chem Phys. 1995;103(19):8577–93.CrossRefGoogle Scholar
  21. 21.
    Hess B, Bekker H, Berendsen HJ, Fraaije JG. LINCS: a linear constraint solver for molecular simulations. J Comput Chem. 1997;18(12):1463–72.CrossRefGoogle Scholar
  22. 22.
    Nosé S. A unified formulation of the constant temperature molecular dynamics methods. J Chem Phys. 1984;81(1):511–9.CrossRefGoogle Scholar
  23. 23.
    Hoover WG. Canonical dynamics: equilibrium phase-space distributions. Phys Rev A. 1985;31(3):1695–7.CrossRefGoogle Scholar
  24. 24.
    Parrinello M, Rahman A. Polymorphic transitions in single crystals: a new molecular dynamics method. J Appl Phys. 1981;52(12):7182–90.CrossRefGoogle Scholar
  25. 25.
    Pereira C, Araújo F, Barrias CC, Granja PL, Sarmento B. Dissecting stromal-epithelial interactions in a 3D in vitro cellularized intestinal model for permeability studies. Biomaterials. 2015;56:36–45.CrossRefPubMedGoogle Scholar
  26. 26.
    Araújo F, Sarmento B. Towards the characterization of an in vitro triple co-culture intestine cell model for permeability studies. Int J Pharm. 2013;458(1):128–34.CrossRefPubMedGoogle Scholar
  27. 27.
    Antunes F, Andrade F, Araújo F, Ferreira D, Sarmento B. Establishment of a triple co-culture in vitro cell models to study intestinal absorption of peptide drugs. Eur J Pharm Biopharm. 2013;83:427–35.CrossRefPubMedGoogle Scholar
  28. 28.
    Nagarsekar K, Ashtikar M, Thamm J, Steiniger F, Schacher F, Fahr A, et al. Electron microscopy and theoretical modeling of cochleates. Langmuir. 2014;30(44):13143–51.CrossRefPubMedGoogle Scholar
  29. 29.
    Larsen AT, Sassene P, Müllertz A. In vitro lipolysis models as a tool for the characterization of oral lipid and surfactant based drug delivery systems. Int J Pharm. 2011;417(1):245–55.CrossRefPubMedGoogle Scholar
  30. 30.
    Dahan A, Hoffman A. Rationalizing the selection of oral lipid based drug delivery systems by an in vitro dynamic lipolysis model for improved oral bioavailability of poorly water soluble drugs. J Control Release. 2008;129(1):1–10.CrossRefGoogle Scholar
  31. 31.
    Thomas N, Holm R, Rades T, Müllertz A. Characterising lipid lipolysis and its implication in lipid-based formulation development. AAPS J. 2012;14(4):860–71.CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Abdelwahed W, Degobert G, Stainmesse S, Fessi H. Freeze-drying of nanoparticles: formulation, process and storage considerations. Adv Drug Deliv Rev. 2006;58(15):1688–713.CrossRefPubMedGoogle Scholar
  33. 33.
    Dhawan V, Magarkar A, Joshi G, Makhija D, Jain A, Shah J, et al. Stearylated cycloarginine nanosystems for intracellular delivery-simulations, formulation and proof of concept. RSC Adv. 2016;6(114):113538–50.CrossRefGoogle Scholar

Copyright information

© American Association of Pharmaceutical Scientists 2018

Authors and Affiliations

  • Tejashree Belubbi
    • 1
  • Sukhada Shevade
    • 1
  • Vivek Dhawan
    • 1
  • Vinay Sridhar
    • 2
  • Anuradha Majumdar
    • 2
  • Rute Nunes
    • 3
    • 4
    • 5
    • 6
  • Francisca Araújo
    • 3
    • 4
    • 5
    • 6
  • Bruno Sarmento
    • 3
    • 4
    • 6
  • Kalpa Nagarsenker
    • 7
  • Frank Steiniger
    • 8
  • Alfred Fahr
    • 7
  • Aniket Magarkar
    • 9
    • 10
  • Alex Bunker
    • 9
  • Mangal Nagarsenker
    • 1
  1. 1.Department of PharmaceuticsBombay College of PharmacyMumbaiIndia
  2. 2.Department of PharmacologyBombay College of PharmacyMumbaiIndia
  3. 3.INEB - Instituto de Engenharia BiomédicaUniversidade do PortoPortoPortugal
  4. 4.I3S, Instituto de Investigação e Inovação em SaúdeUniversidade do Porto4200-135 PortoPortugal
  5. 5.ICBAS - Instituto Ciências Biomédicas Abel SalazarUniversidade do PortoPortoPortugal
  6. 6.CESPU-Instituto de Investigação e Formação Avançada em Ciências e Tecnologias da SaúdeGandraPortugal
  7. 7.Department of Pharmaceutical TechnologyFriedrich-Schiller-University JenaJenaGermany
  8. 8.Center for Electron Microscopy, Jena University HospitalFriedrich Schiller University JenaJenaGermany
  9. 9.Centre for Drug Research, Division of Pharmaceutical Bioscience, Faculty of Pharmacy, University of HelsinkiHelsinkiFinland
  10. 10.Academy of Sciences of the Czech RepublicPragueCzech Republic

Personalised recommendations