Advertisement

DARU Journal of Pharmaceutical Sciences

, Volume 26, Issue 1, pp 65–75 | Cite as

Lipid-drug conjugates: a potential nanocarrier system for oral drug delivery applications

  • Subham Banerjee
  • Amit Kundu
Review Article
  • 417 Downloads

Abstract

Hydrophilic drugs are preferred candidates for most routes of drug administration, because of their enhanced solubility and dissolution under aqueous in vivo conditions. However, their hydrophilic nature also leads to decreased permeability across hydrophobic barriers. This is a severe limitation in situations where membrane permeability is the primary factor affecting bioavailability and efficacy of the drug. Highly impermeable cellular membranes or the tight endothelial junctions governing the blood-brain barrier are prime examples of this limitation. In other cases, decreased permeability across mucosal or epithelial membranes may require increased doses, which is an inefficient and potentially dangerous workaround. Covalent conjugation of hydrophilic drugs to hydrophobic moieties like short-chain lipids is a promising strategy for maintaining the critical balance between drug solubility and permeability. This article practically focuses on the production procedure of Lipid drug conjugates (LDCs), various formulation methodologies for preparing LDC nanoparticles with detailed about their in vitro physicochemical characterization at laboratory scale. Moreover, brief overviews on the role of LDCs in novel drug delivery applications as a substrate to various disease therapies are provided.

Graphical Abstract

Three dimensional (3-D) schematic representation of LDCs structures.

Keywords

Lipid drug conjugates Oral administration Drug delivery Hydrophilic drug 

Abbreviations

LNFs

Lipid Nanoparticle Formulations

LDCs

Lipid-drug Conjugates

NPs

Nanoparticles

GIT

Gastrointestinal Tract

ZP

Zeta Potential

PDI

Polydispersity Index

BA

Bioavailability

BCS

Biopharmaceutical Classification Systems

Notes

Acknowledgments

The authors are thankful to their respective institution and university for providing access to necessary literature resources and essential library facilities for writing this review article. Recognition also goes to all the authors of papers, books, patents, websites and all other published sources listed in the references that were used to prepare the contents of this review article.

Compliance with ethical standards

Consent for publication

Not applicable.

Declaration of interest

The authors declare that they have no competing interests.

References

  1. 1.
    Anthony AA, Mumuni AM, Philip FB. Lipid Nanoparticulate Drug Delivery Systems: A Revolution in Dosage Form Design and Development. Recent Advances in Novel Drug Carrier Systems. Intech Open; 2012. Pp. 107–140.Google Scholar
  2. 2.
    Morel S, Terreno E, Ugazio E, Aime S, Gasco MR. NMR relaxometric investigations of lipid nanoparticles (SLN) containining gadolinium (III) complexes. Eur J Pharm Biopharm. 1998;45(2):157–63.CrossRefPubMedGoogle Scholar
  3. 3.
    Muchow M, Maincent P, Müller RH. Lipid nanoparticles with a solid matrix (SLN®, NLC®, LDC®) for oral drug delivery. Drug Dev Ind Pharm. 2008;34(12):1394–405.CrossRefPubMedGoogle Scholar
  4. 4.
    Olbrich C, Gessner A, Kayser O, Mueller RH. Lipid drug conjugate nanoparticles as novel carrier system for the hydrophilic antitrypanosomal drug diminazene aceturate. J Drug Target. 2002;10(5):387–96.CrossRefPubMedGoogle Scholar
  5. 5.
    Das RJ, Baishya K, Pathak K. Recent advancement of lipid drug conjugate as nanoparticulate drug delivery system. Int Res J Pharm. 2013;4(1):73–8.Google Scholar
  6. 6.
    Nakajima N, Ikada Y. Mechanism of amide formation by carbodiimides for bioconjugation in aqueous media. Bioconjug Chem. 1995;6(1):123–30.CrossRefPubMedGoogle Scholar
  7. 7.
    Pignatello R, Spampinato G, Sorrenti V, Di Giacomo C, Vicari L, McGuire JJ, et al. Lipophilic methotrexate conjugates with antitumor activity. Eur J Pharm Sci. 2000;10(3):237–45.CrossRefPubMedGoogle Scholar
  8. 8.
    Sharma P, Dube B, Sawant K. Synthesis of Cytarabine lipid drug conjugate for treatment of meningeal leukemia: development, characterization and In vitro cell line studies. J Biomed Nanotechnol. 2012;8(6):928–37.CrossRefPubMedGoogle Scholar
  9. 9.
    Scriba GK. Phenytoin-lipid conjugates as potential prodrugs of phenytoin. Arch Pharm. 1993;326(8):477–81.CrossRefGoogle Scholar
  10. 10.
    Neupane YR, Sabir MD, Ahmad N, Ali M, Kohli K. Lipid drug conjugate nanoparticle as a novel lipid nanocarrier for the oral delivery of decitabine: Ex-vivo gut permeation studies. Nanotechnology. 2013;24(41):1–11.CrossRefGoogle Scholar
  11. 11.
    Olbrich C, Gessner A, Schröder W, Kayser O, Müller RH. Lipid drug conjugate nanoparticles of the hydrophilic drug diminazene-cytotoxicity testing and mouse serum adsorption. J Control Release. 2004;96(3):425–35.CrossRefPubMedGoogle Scholar
  12. 12.
    Banerjee S, Pillai J. Lipid Nanoparticle Formulations for Enhanced Anti-tuberculosis Therapy. Holban AM, Grumezescu AM. Nanoarchitectonics for Smart Delivery and Drug Targeting. United Kingdom: Elsevier; 2016. Pp 285–313.CrossRefGoogle Scholar
  13. 13.
    Das S, Chaudhury A. Recent advances in lipid nanoparticle formulations with solid matrix for oral drug delivery. AAPS PharmSciTech. 2011;12(1):62–76.CrossRefPubMedGoogle Scholar
  14. 14.
    Banerjee S, Chattopadhyay P, Ghosh A, Goyary D, Karmakar S, Veer V. Influence of process variables on essential oil microcapsule properties by carbohydrate polymer-protein blends. Carbohydr Polym. 2013;93(2):691–7.CrossRefPubMedGoogle Scholar
  15. 15.
    Wen B, Sun Y, Xu Y, Sun J, Liu X, Wang Y, et al. Pharmacokinetic characteristics of the cytarabine prodrug, ilecytarabine, after intravenous and oral administration to rats. Asian J Pharm Sci. 2008;3:200.Google Scholar
  16. 16.
    Knothe G, Kenar JA. Determination of the fatty acid profile by 1H-NMR spectroscopy. Eur J Lipid Sci Technol. 2004;106:88–96.CrossRefGoogle Scholar
  17. 17.
    Ferreira L, Vidal MM, Gil MH. Evaluation of poly(2- hydroxyethyl methacrylate) gels as drug delivery systems at different pH value. Int J Pharm. 2000;194(2):169–80.CrossRefPubMedGoogle Scholar
  18. 18.
    Ren S, Yang S, Zhao Y, Yu T, Xiao X. Preparation and characterization of an ultrahydrophobic surface based on a stearic acid self-assembled monolayer over polyethyleneimine thin films. Surf Sci. 2003;546(2–3):64–74.CrossRefGoogle Scholar
  19. 19.
    Charman WN, Stella VJ, editors. Lymphatic transport of drugs. Boca Raton: CRC Press; 1992.Google Scholar
  20. 20.
    Müller RH, Runge SA, Ravelli V, Thünemann AF, Mehnert W, Souto EB. Cyclosporine-loaded solid lipid nanoparticles (SLN®):drug-lipid physicochemical interactions and characterization of drug incorporation. Eur J Pharm Biopharm. 2008;68(3):535–44.CrossRefPubMedGoogle Scholar
  21. 21.
    Müller RH, Runge S, Ravelli V, Mehnert W, Thünemann AF, Souto EB. Oral bioavailability of cyclosporine: solid lipid nanoparticles (SLN®) versus drug nanocrystals. Int J Pharm. 2006;317(1):82–9.CrossRefPubMedGoogle Scholar
  22. 22.
    Liu D, Liu C, Weiwei Z, Zhang N. Enhanced gastrointestinal absorption of N-3-O-toluyl-fluorouracil by cationic solid lipid nanoparticles. J Nanopart Res. 2010;12(3):975–84.CrossRefGoogle Scholar
  23. 23.
    Zhang J, Fan Y, Smith E. Experimental design for the optimization of lipid nanoparticles. J Pharm Sci. 2009;98(5):1813–9.CrossRefPubMedGoogle Scholar
  24. 24.
    Anton N, Benoit J-P, Saulnier P. Design and production of nanoparticles formulated from nano-emulsion templates-a review. J Control Release. 2008;128(3):185–99.CrossRefPubMedGoogle Scholar
  25. 25.
    Xie S, et al. Formulation, characterization, and pharmacokinetics of praziquantel- loaded hydrogenated castor oil solid lipid nanoparticles. Nanomedicine London. 2010;5(5):693–701.CrossRefGoogle Scholar
  26. 26.
    Sanjula B, Shah FM, Javed A, Alka A. Effect of poloxamer 188 on lymphatic uptake of carvedilol-loaded solid lipid nanoparticles for bioavailability enhancement. J Drug Target. 2009;17(3):249–56.CrossRefPubMedGoogle Scholar
  27. 27.
    Paliwal R, et al. Effect of lipid core material on characteristics of solid lipid nanoparticles designed for oral lymphatic delivery. Nanomedicine. 2009;5(2):184–91.CrossRefPubMedGoogle Scholar
  28. 28.
    Freitas C, Müller RH. Effect of light and temperature on zeta potential and physical stability in solid lipid nanoparticle (SLN) dispersions. Int J Pharm. 1998;168(2):221–9.CrossRefGoogle Scholar
  29. 29.
    Radomska-Soukharev A. Stability of lipid excipients in solid lipid nanoparticles. Adv Drug Deliv Rev. 2007;59(6):411–8.CrossRefPubMedGoogle Scholar
  30. 30.
    Mukherjee B, Santra K, Pattnaik G, Ghosh S. Preparation, characterization and in vitro evaluation of sustained release protein-loaded nanoparticles based on biodegradable polymers. Int J Nanomedicine. 2008;3(4):487–96.CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Tsai MJ, Huang YB, Wu PC, Fu YS, Kao YR, Fang JY, et al. Oral apomorphine delivery from solid lipid nanoparticles with different monostearate emulsifiers: pharmacokinetic and behavioral evaluations. J Pharm Sci. 2011;100(2):547–57.CrossRefPubMedGoogle Scholar
  32. 32.
    Varshosaz J, Minayian M, Moazen E. Enhancement of oral bioavailability of pentoxifylline by solid lipid nanoparticles. J Liposome Res. 2010;20(2):115–23.CrossRefPubMedGoogle Scholar
  33. 33.
    Kakkar V, Singh S, Singla D, Kaur IP. Exploring solid lipid nanoparticles to enhance the oral bioavailability of curcumin. Mol Nutr Food Res. 2010;55(3):495–503.CrossRefPubMedGoogle Scholar
  34. 34.
    Sahana B, Santra K, Basu S, Mukherjee B. Development of biodegradable polymer-based tamoxifen citrate-loaded nanoparticles and effect of some manufacturing process parameters on them: a physicochemical and in vitro evaluation. Int J Nanomedicine. 2010;5(7):621–30.PubMedPubMedCentralGoogle Scholar
  35. 35.
    Shahgaldian P, Da Silva E, Coleman AW, Rather B, Zaworotko MJ. Para-acyl-calixarene based solid lipid nanoparticles (SLNs): a detailed study of preparation and stability parameters. Int J Pharm. 2003;253(1–2):23–38.CrossRefPubMedGoogle Scholar
  36. 36.
    Schwarz C, Freitas C, Mehnert CW, Muller RH. Sterilization and physical stability of drug-free and etomidate- loaded solid lipid nanoparticles. Proc Int Symp Control Release Bioact Mater. 1995;22:766–7.Google Scholar
  37. 37.
    Zur Muhlen A, et al. Atomic force microscopy studies of solid lipid nanoparticles. Pharm Res. 1996;13(9):1411–6.CrossRefPubMedGoogle Scholar
  38. 38.
    Jenning V, Thunemann A, Gohla S. Characterisation of a novel solid lipid nanoparticle carrier system based on binary mixtures of liquid and solid lipids. Int J Pharm. 2000;199(2):167–77.CrossRefGoogle Scholar
  39. 39.
    Sari A, Akcay M, Soylak M, Onal A. Polymer-stearic acid blends as form-stable phase change material for thermal energy storage. J Sci Ind Res. 2005;64:991–6.Google Scholar
  40. 40.
    Dicko A, et al. Biophysical characterization of a liposomal formulation of cytarabine and daunorubicin. Int J Pharm. 2010;391(1–2):248–59.CrossRefPubMedGoogle Scholar
  41. 41.
    Souto EB, Mehnert W, Muller RH. Polymorphic behavior of Comprito l888 ATO as bulk lipid and as SLN and NLC. J Microencapsul. 2006;23(4):417–33.CrossRefPubMedGoogle Scholar
  42. 42.
    Bunjes H, Steiniger F, Richter W. Visualizing the structure of triglyceride nanoparticles in different crystal modifications. Langmuir. 2007;23(7):4005–11.CrossRefPubMedGoogle Scholar
  43. 43.
    Estella-Hermoso de Mendoza A, Rayo M, Mollinedo M, Blanco-Prieto MJ. Lipid nanoparticles for alkyl lysophospholipid edel fosine encapsulation: development and in vitro characterization. Eur J Pharm Biopharm. 2008;68(2):207–13.CrossRefPubMedGoogle Scholar
  44. 44.
    Huang ZR, Hua SC, Yang YL, Fang JY. Development and evaluation of lipid nanoparticles for camptothecin delivery: a comparison of solid lipid nanoparticles, nanostructured lipid carriers, and lipid emulsion. Acta Pharmacol Sin. 2008;29(9):1094–102.CrossRefPubMedGoogle Scholar
  45. 45.
    Banerjee S, Roy S, Nath Bhaumik K, Kshetrapal P, Pillai J. Comparative study of oral lipid nanoparticle formulations (LNFs) for chemical stabilization of antitubercular drugs: physicochemical and cellular evaluation. Artif Cells Nanomed Biotechnol. 2018;26:1–19.CrossRefGoogle Scholar
  46. 46.
    Stela G, Esther I. Conjugates for cancer therapy and diagnosis, patent application number: 20110275590; Publication date: 11, October (2011).Google Scholar
  47. 47.
    Wyatt DA. Taking poorly water-soluble compounds through discovery. In: Recent advances in the formulations and development of poorly soluble drugs. Bulletin Technique Gattefosse. 1999:31–39.Google Scholar
  48. 48.
    Higuchi T. Rate of release of medicaments from ointment bases containing drugs in suspension. J Pharm Sci. 1961;50:874–5.CrossRefPubMedGoogle Scholar
  49. 49.
    Penzesa CB, Schnoller D, Horvati K, Kiss E. Membrane affinity of antituberculosis drug conjugate using lipid monolayer containing mycolic acid. Colloids Surf A Physicochem Eng Asp. 2012;413(5):142–8.CrossRefGoogle Scholar
  50. 50.
    Vadlapudia AD, Vadlapatla RK, Kwatra D, Earla R, Samanta SK. Targeted lipid-based drug conjugates: a novel strategy for drug delivery. Int J Pharm. 2012;434(1–2):315–24.CrossRefGoogle Scholar
  51. 51.
    Paliwal R, Shivani RP, Govind PA, Suresh PV. Biomimetic solid lipid nanoparticles for oral bioavailability enhancement of low molecular weight heparin and its lipid conjugates: In vitro and in-vivo evaluation. Mol Pharm. 2011;8(4):1314–21.CrossRefPubMedGoogle Scholar
  52. 52.
    Sarpietro MG, Ottimo S, Giuffrida MC, Rocco F, Ceruti M, Castelli F. Synthesis of n-squalenoyl cytarabine and evaluation of its affinity with phospholipid bilayers and monolayers. Int J Pharm. 2011;406(1–2):69–77.CrossRefPubMedGoogle Scholar
  53. 53.
    Ali SM, Khan AR, Ahmad MU, Chen P, Sheikh S, Ahmad I. Synthesis and biological evaluation of gemcitabine-lipid conjugate. Bioorg Med Chem Lett. 2005;15(10):2571–4.CrossRefPubMedGoogle Scholar
  54. 54.
    Gessner A, Olbrich C, Schroder W, Kayser O, Muller RH. The role of plasma proteins in brain targeting: species-dependent protein adsorption patterns on brain-specific lipid drug conjugate (LDC) nanoparticles. Int J Pharm. 2001;214(1–2):87–91.CrossRefPubMedGoogle Scholar
  55. 55.
    Kurz M, Scriba GK. Drug-phospholipid conjugates as potential prodrugs: synthesis, characterization, and degradation pancreatic phospholipase A2. Chem Phys Lipids. 2000;107(2):143–57.CrossRefPubMedGoogle Scholar
  56. 56.
    Sugarman SM, Zou Y, Wasan K, Poirot K, Kumi R, Reddy S, et al. Lipid-complexed camptothecin: formulation and initial biodistribution and antitumor activity studies. Cancer Chemother Pharmacol. 1996;37(6):531–8.CrossRefPubMedGoogle Scholar
  57. 57.
    Toth I, Hughes RA, Dekany G, Hillery AM, Ward P. Synthesis and oral uptake studies of lipidic and glyco-lipidic conjugates of β- lactam antibiotics. Liebigs Annalen Der Chemie. 1994;1994(7):685–8.CrossRefGoogle Scholar
  58. 58.
    Lambert DM. Rationale and applications of lipids as prodrug carriers. Eur J Pharm Sci. 2000;11(2):S15–27.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2018

Authors and Affiliations

  1. 1.Department of PharmaceuticsNational Institute of Pharmaceutical Education and Research (NIPER)-GuwahatiGuwahatiIndia
  2. 2.School of PharmacySungkyunkwan UniverfsitySeoulSouth Korea

Personalised recommendations