Skip to main content

Advertisement

Log in

Potential of Lipid Nanoparticles (SLNs and NLCs) in Enhancing Oral Bioavailability of Drugs with Poor Intestinal Permeability

  • Review Article
  • Theme: Lipid-Based Drug Delivery Strategies for Oral Drug Delivery
  • Published:
AAPS PharmSciTech Aims and scope Submit manuscript

Abstract

Lipid-based drug delivery systems has become a popular choice for oral delivery of lipophilic drugs with dissolution rate limited oral absorption. Lipids are known to enhance oral bioavailability of poorly water-soluble drugs in multiple ways like facilitating dissolution as micellar solution, enhancing the lymphatic uptake and acting as inhibitors of efflux transporters. Lipid nanoparticles are matrix type lipid-based carrier systems which can effectively encapsulate both lipophilic and hydrophilic drugs. Lipid nanoparticles namely solid lipid nanoparticles (SLN) and nanostructured lipid carriers (NLC) are versatile drug delivery system and can be used for multiple routes of delivery like parenteral, topical, ocular, transdermal, and oral. Lipid nanoparticles are particularly attractive vehicles for peroral delivery of drugs with oral bioavailability problems as they are composed of lipid excipients which are cheap, easily available, and non-toxic; manufacturing technique is simple and readily scalable for large-scale production; the formulations provide controlled release of active components and have no stability issue. A large number of drugs have been incorporated into lipid nanoparticles with the objective of overcoming their poor oral bioavailability. This review tries to assess the potential of lipid nanoparticles for enhancing the oral bioavailability of drugs with permeability limited oral absorption such as drugs belonging to class IV of Biopharmaceutic Classification System (BCS) and protein and peptide drugs and also discusses the mechanism behind the bioavailability enhancement and safety issues related to such delivery systems.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1

Similar content being viewed by others

References

  1. Amidon GL, Lennernaes H, Shah VP, Crison JR. A theoretical basis for a biopharmaceutic drug classification: the correlation of in vitro drug product dissolution and in vivo bioavailability. Pharm Res. 1995;12:413–20.

    CAS  PubMed  Google Scholar 

  2. Lipinski CA. Avoiding investment in doomed drugs—is solubility an industry wide problem? Curr Drug Discov. 2001;1:17–9.

    Google Scholar 

  3. Murakami T, Takano M. Intestinal efflux transporters and drug absorption. Exp Op Drug Met Tox. 2008;4:923–39. https://doi.org/10.1517/17425255.4.7.923.

    Article  CAS  Google Scholar 

  4. Charman WN, Porter CJ, Mithani S, Dressman JB. Physiochemical and physiological mechanisms for the effects of food on drug absorption: the role of lipids and pH. J Pharm Sci. 1997;86:269–82.

    CAS  PubMed  Google Scholar 

  5. Porter CJH, Trevaskis NL, Charman WN. Lipids and lipid-based formulations: optimizing the oral delivery of lipophilic drugs nature reviews. Drug Des Discov. 2007;6:231–48.

    CAS  Google Scholar 

  6. Porter CJH, Charman WN. Intestinal lymphatic transport: an update. Adv Drug Deliv Rev. 2001;50:61–80.

    CAS  PubMed  Google Scholar 

  7. Muchow M, Maincent P, Müller RH. Lipid nanoparticles with a solid matrix (SLN®, NLC®, LDC®) for Oral drug delivery. Drug Dev Ind Pharm. 2008;34:1394–405.

    CAS  PubMed  Google Scholar 

  8. Müller RH et al., Solid-liquid (semi-solid) lipid particles and method of producing highly concentrated lipid particle dispersions, German patent application. 2000; DE199145203.

  9. Chen DB, Yang TZ, Lu WL, Zhang Q. In vitro and in vivo study of two types of long-circulating solid lipid nanoparticles containing paclitaxel. Chem Pharm Bull. 2001;49(11):1444–7.

    CAS  Google Scholar 

  10. Fundaro A, Cavalli R, Bargoni A, Vighetto D, Zara GP, Gasco MR. Non-stealth and stealth solid lipid nanoparticles (SLN) carrying doxorubicin: pharmacokinetics and tissue distribution after i.V. Administration to rats. Pharmacol Res. 2000;42(4):337–43.

    CAS  PubMed  Google Scholar 

  11. Bhandari RK, Kaur IP. Pharmacokinetics, tissue distribution and relative bioavailability of isoniazid-solid lipid nanoparticles international. Aust J Pharm. 2013;441(1–2):202–12.

    CAS  Google Scholar 

  12. Freitas C, Muller 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.

    CAS  Google Scholar 

  13. Freitas C, Muller RH. Correlation between long-term stability of solid lipid nanoparticles (SLN(TM)) and crystallinity of the lipid phase. Eur J Pharm Biopharm. 1999;47(2):125–32.

    CAS  PubMed  Google Scholar 

  14. Freitas C, Muller RH. Stability determination of solid lipid nanoparticles (SLN®) in aqueous dispersion after addition of electrolyte. J Microencapsul. 1999;16(1):59–71.

    CAS  PubMed  Google Scholar 

  15. Dingler A, Gohla S. Production of solid lipid nanoparticles (SLN): scaling up feasibilities. J Microencapsul. 2002;19(1): 11–6. 14. Gohla SH, Dingler A. Scaling up feasibility of the production of solid lipid nanoparticles (SLN). Pharmazie. 2001;56(1):61–3.

    PubMed  Google Scholar 

  16. Harde H, Das M, Jain S. Solid lipid nanoparticles: an oral bioavailability enhancer vehicle. Expert Opin Drug Deliv. 2011;8(11):1407–24. https://doi.org/10.1517/17425247.2011.604311.

    Article  CAS  PubMed  Google Scholar 

  17. Poovi G, Damodharan N. Lipid nanoparticles: a challenging approach for oral delivery of BCS class-II drugs. Future J Pharm Sci. 2018;4(2):191–205.

    Google Scholar 

  18. Poonia N, Kharb R, Lather V, Pandita D. Nanostructured lipid carriers: versatile oral delivery vehicle. Future Sci OA. 2016;2(3):FSO135. https://doi.org/10.4155/fsoa-2016-0030.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Gaba B, Fazil M, Ali A, Baboota S, Sahni JK, Ali J. Nanostructured lipid (NLCs) carriers as a bioavailability enhancement tool for oral administration. Drug Deliv. 2015;22(6):691–700. https://doi.org/10.3109/10717544.2014.898110.

    Article  CAS  PubMed  Google Scholar 

  20. Das S, Chaudhury A. Recent advances in lipid nanoparticle formulations with solid matrix for oral drug delivery. AAPS PharmSciTech. 2011;12(1):62–76. https://doi.org/10.1208/s12249-010-9563-0.

    Article  CAS  PubMed  Google Scholar 

  21. Westesen K, Bunjes H, Koch MHJ. Physicochemical characterization of lipid nanoparticles and evaluation of their drug loading capacity and sustained release potential. J Control Release. 1997;48(2–3):223–36.

    CAS  Google Scholar 

  22. Muller RH, Radtke M, Wissing SA. Nanostructured lipid matrices for improved microencapsulation of drugs. Int J Pharm. 2002;242:121–8.

    CAS  PubMed  Google Scholar 

  23. Hauss DJ. Oral lipid-based formulations. Adv Drug Deliv Rev. 2007;59:667–76.

    CAS  PubMed  Google Scholar 

  24. Souto EB, Muller RH. Lipid NPs: effect on bioavailability and pharmacokinetic changes. Handb Exp Pharmacol. 2010;197:115–41.

    CAS  Google Scholar 

  25. Olbrich C, Gessner A, Kayser O, Muller RH. Lipid-drugconjugate (LDC) NPs as novel carrier system for the hydrophilic antitrypanosomal drug diminazenediaceturate. J Drug Target. 2002;10:387–96.

    CAS  PubMed  Google Scholar 

  26. Jenning V, Lippacher A, Gohla SH. Medium scale production of solid lipid nanoparticles (SLN) by high pressure homogenization. J Microencapsul. 2002;19(1):1–10.

    CAS  PubMed  Google Scholar 

  27. Cavalli R, Caputo O, Marengo E, Pattarino F, Gasco MR. The effect of the components of microemulsions on both size and crystalline structure of solid lipid nanoparticles (SLN) containing a series of model molecules. Pharmazie. 1998;53(6):392–6.

    CAS  Google Scholar 

  28. Gasco MR. Method for producing solid lipid microspheres having a narrow size distribution patent US5250236. 1993.

  29. Igartua M, Saulnier P, Heurtault B, Pech B, Proust JE, Pedraz JL, et al. Development and characterization of solid lipid nanoparticles loaded with magnetite. Int J Pharm. 2002;233(1–2):149–57.

    CAS  PubMed  Google Scholar 

  30. Bondi ML, Azzolina A, Craparo EF, Lampiasi N, Capuano G, Giammona G, et al. Novel cationic solid-lipid nanoparticles as non-viral vectors for gene delivery. J Drug Target. 2007;15(4):295–301.

    CAS  PubMed  Google Scholar 

  31. Sjostrom B, Kaplun A, Talmon Y, Cabane B. Structures of nanoparticles prepared from oil-in-water emulsions. Pharm Res. 1995;12(1):39–48.

    CAS  PubMed  Google Scholar 

  32. Shahgaldian P, Da Silva E, Coleman AW, Rather B, Zaworotko MJ. Para-acyl-calix-arene based solid lipid nanoparticles (SLNs): a detailed study of preparation and stability parameters. Int J Pharm. 2003;253(1–2):23–38.

    CAS  PubMed  Google Scholar 

  33. Trotta M, Debernardi F, Caputo O. Preparation of solid lipid nanoparticles by a solvent emulsification–diffusion technique. Int J Pharm. 2003;257(1–2):153–60.

    CAS  PubMed  Google Scholar 

  34. Hu FQ, Yuan H, Zhang HH, Fang M. Preparation of solid lipid nanoparticles with clobetasol propionate by a novel solvent diffusion method in aqueous system and physicochemical characterization. Int J Pharm. 2002;239(1–2):121–8.

    CAS  PubMed  Google Scholar 

  35. Schubert MA, Muller-Goymann CC. Solvent injection as a new approach for manufacturing lipid nanoparticles—evaluation of the method and process parameters. Eur J Pharm Biopharm. 2003;55(1):125–31.

    CAS  PubMed  Google Scholar 

  36. Cavalcanti SMT, Nunes C, Costa Lima SA, Soares-Sobrinho JL, Reis S. Optimization of nanostructured lipid carriers for zidovudine delivery using a microwave-assisted production method. Eur J Pharm Sci. 2018;122:22–30. https://doi.org/10.1016/j.ejps.2018.06.017.

    Article  CAS  PubMed  Google Scholar 

  37. Onoue S, Sato H, Ogawa K, Kawabata Y, Mizumoto T, Yuminoki K, et al. Improved dissolution and pharmacokinetic behavior of cyclosporine a using high-energy amorphous solid dispersion approach. Int J Pharm. 2010;399(1–2):94–101.

    CAS  PubMed  Google Scholar 

  38. Wacher VJ, Wu CY, Benet LZ. Overlapping substrate specificities and tissue distribution of cytochrome P450 3A and P-glycoprotein: implications for drug delivery and activity in cancer chemotherapy. Mol Carcinog. 1995;13(3):129–34.

    CAS  PubMed  Google Scholar 

  39. Sharma P, Varma MV, Chawla HP, Panchagnula R. Relationship between lipophilicity of BCS class III and IV drugs and the functional activity of peroral absorption enhancers. Farmaco. 2005;60(11–12):870–3.

    CAS  PubMed  Google Scholar 

  40. Tjia JF, Webber IR, Back DJ. Cyclosporin metabolism by the gastrointestinal mucosa. Br J Clin Pharmacol. 1991;31(3):344–6.

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Tarr BD, Yalkowsky SH. Enhanced intestinal absorption of cyclosporine in rats through the reduction of emulsion droplet size. Pharm Res. 1989;6(1):40–3.

    CAS  PubMed  Google Scholar 

  42. Wang K, Qi J, Weng T, Tian Z, Lu Y, Hu K, et al. Enhancement of oral bioavailability of cyclosporine A: comparison of various nanoscale drug-delivery systems. Int J Nanomedicine. 2014;9:4991–9. https://doi.org/10.2147/IJN.S72560 eCollection 2014.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Müller RH, Rungea S, Ravelli V, Mehnerta W, Thünemannc AF, Souto EB. Oral bioavailability of cyclosporine: solid lipid nanoparticles (SLN®) versus drug nanocrystals. Int J Pharm. 2006;317(1):82–9.

    PubMed  Google Scholar 

  44. Rajagopalan N, Chen SC, Chow W. A study of the inclusion complex of amphotericin B with γ-cyclodextrin. Int J Pharm. 1986;29:161–8.

    CAS  Google Scholar 

  45. Wu J-Q, Shao K, Wang X, Wang RY, Cao YH, Yu YQ, et al. In vitro and in vivo evidence for amphotericin B as a P-glycoprotein substrate on the blood-brain barrier. Antimicrob Agents Chemother. 2014;58(8):4464–9. https://doi.org/10.1128/AAC.02535-14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Chaudhari MB, Desai PP, Patel PA. Patravale VB solid lipid nanoparticles of amphotericin B (AmbiOnp): in vitro and in vivo assessment towards safe and effective oral treatment module. Drug Deliv Transl Res. 2016;6(4):354–64. https://doi.org/10.1007/s13346-015-0267-6.

    Article  CAS  PubMed  Google Scholar 

  47. Wahlang B, Pawar YB. Bansal AK identification of permeability-related hurdles in oral delivery of curcumin using the Caco-2 cell model. Eur J Pharm Biopharm. 2011;77(2):275–82. https://doi.org/10.1016/j.ejpb.2010.12.006.

    Article  CAS  PubMed  Google Scholar 

  48. Fang M, Jin Y, Bao W, et al. In vitro characterization and in vivo evaluation of nanostructured lipid curcumin carriers for intragastric administration. Int J Nanomedicine. 2012;7:5395–404. https://doi.org/10.2147/IJN.S36257.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Ji H, Tang J, Li M, Ren J, Zheng N, Wu L. Curcumin-loaded solid lipid nanoparticles with Brij78 and TPGS improved in vivo oral bioavailability and in situ intestinal absorption of curcumin. Drug Deliv. 2016;23(2):459–70. https://doi.org/10.3109/10717544.2014.918677.

    Article  CAS  PubMed  Google Scholar 

  50. Baek JS, Cho CW. Surface modification of solid lipid nanoparticles for oral delivery of curcumin: improvement of bioavailability through enhanced cellular uptake, and lymphatic uptake. Eur J Pharm Biopharm. 2017;117:132–40. https://doi.org/10.1016/j.ejpb.2017.04.013.

    Article  CAS  PubMed  Google Scholar 

  51. Clouser CL, Bonnac L, Mansky LM, Patterson SE. Characterization of permeability, stability and anti-HIV-1 activity of decitabine and gemcitabine divalerate prodrugs. Antivir Chem Chemother. 2014;23(6):223–30. https://doi.org/10.3851/IMP2682.

    Article  CAS  PubMed  Google Scholar 

  52. Neupane YR, Srivastava M, Ahmad N, Kumar N, Bhatnagar A, Kohli K. Lipid based nanocarrier system for the potential oral delivery of decitabine: formulation design, characterization, ex vivo, and in vivo assessment. Int J Pharm. 2014;477(1–2):601–12. https://doi.org/10.1016/j.ijpharm.2014.11.001.

    Article  CAS  PubMed  Google Scholar 

  53. Tamura S, Ohike A, Ibuki R, Amidon GL, Yamashita S. Tacrolimus is a class-II low-solubility high-permeability drug: the effect of P-glycoprotein efflux on regional permeability of tacrolimus in rats. J Pharm Sci. 2002;91:719–29.

    CAS  PubMed  Google Scholar 

  54. Khan S, Shaharyar M, Fazil M, Baboota S, Ali J. Tacrolimus-loaded nanostructured lipid carriers for oral delivery - optimization of production and characterization. Eur J Pharm Biopharm. 2016;108:277–88. https://doi.org/10.1016/j.ejpb.2016.07.017.

    Article  CAS  PubMed  Google Scholar 

  55. Shah JC, Chen JR, Chow D. Preformulation study of etoposide: identification of physicochemical characteristics responsible for the low and erratic Oral bioavailability of etoposide. Pharm Res. 1989;6(5):408–12.

    CAS  PubMed  Google Scholar 

  56. Zhang T, Chen J, Zhang Y, Shen Q, Pan W. Characterization and evaluation of nanostructured lipid carrier as a vehicle for oral delivery of etoposide. Eur J Pharm Sci. 2011;43:174–9.

    CAS  PubMed  Google Scholar 

  57. Beloqui A, Solinís MÁ, Gascón AR, del Pozo-Rodríguez A. Des Rieux a, Préat V. Mechanism of transport of saquinavir-loaded nanostructured lipid carriers across the intestinal barrier. J Control Release. 2013;166(2):115–23.

    CAS  PubMed  Google Scholar 

  58. Beloqui A, Solinís MÁ, des Rieux A, Préat V, Rodríguez-Gascón A. Dextran-protamine coated nanostructured lipid carriers as mucus-penetrating nanoparticles for lipophilic drugs. Int J Pharm. 2014;468(1–2):105–11. https://doi.org/10.1016/j.ijpharm.2014.04.027.

    Article  CAS  PubMed  Google Scholar 

  59. Alex AMR, Chacko AJ, Jose S, Souto EB. Lopinavir loaded solid lipid nanoparticles (SLN) for intestinal lymphatic targeting. Eur J Pharm Sci. 2011;42(1–2):11–8. https://doi.org/10.1016/j.ejps.2010.10.002.

    Article  CAS  Google Scholar 

  60. Hu K, Cao S, Hu F, Feng J. Enhanced oral bioavailability of docetaxel by lecithin nanoparticles: preparation, in vitro, and in vivo evaluation. Int J Nanomedicine. 2012;7:3537–45. https://doi.org/10.2147/IJN.S32880.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Fang G, Tang B, Chao Y, Zhang Y, Xu H, Tang X. Improved oral bioavailability of docetaxel by nanostructured lipid carriers: in vitro characteristics, in vivo evaluation and intestinal transport studies. RSC Adv. 2015;5:96437–47.

    CAS  Google Scholar 

  62. Cho H-J, Park JW, Yoon I-S, Kim D-D. Surface-modified solid lipid nanoparticles for oral delivery of docetaxel: enhanced intestinal absorption and lymphatic uptake. Int J Nanomedicine. 2014;9:495–504. https://doi.org/10.2147/IJN.S56648.

    Article  PubMed  PubMed Central  Google Scholar 

  63. Sparreboom A, van Asperen J, Mayer U, Schinkel AH, Smit JW, Meijer DK, et al. Limited oral bioavailability and active epithelial excretion of paclitaxel (Taxol) caused by P-glycoprotein in the intestine. Proc Natl Acad Sci U S A. 1997;94(5):2031–5.

    CAS  PubMed  PubMed Central  Google Scholar 

  64. Pandita D, Ahuja A, Lather V, Dutta T, Velpandian T, Khar RK. Development, characterization and in vitro assessement of stearylamine-based lipid nanoparticles of paclitaxel. Pharmazie. 2011;66(3):171–7.

    CAS  PubMed  Google Scholar 

  65. Pooja D, Kulhari H, Kuncha M, Rachamalla SS, Adams DJ, Bansal V. And SistlaR. Improving efficacy, Oral bioavailability, and delivery of paclitaxel using protein-grafted solid lipid nanoparticles. Mol Pharm. 2016;13(11):3903–12. https://doi.org/10.1021/acs.molpharmaceut.6b00691.

    Article  CAS  PubMed  Google Scholar 

  66. Lee YH, Sinko PJ. Oral delivery of salmon calcitonin. Adv Drug Deliv Rev. 2000;42(3):225–38.

    CAS  PubMed  Google Scholar 

  67. Uner M, Yener G. Importance of solid lipid nanoparticles (SLN) in various administration routes and future perspectives. Int J Nanomedicine. 2007;2(3):289–300.

    CAS  PubMed  PubMed Central  Google Scholar 

  68. Olbrich C, Kayser O, Müller RH. Lipase degradation of Dynasan 114 and 116 solid lipid nanoparticles (SLN) – effect of surfactants, storage time and crystallinity. Int J Pharm. 2002;237(1–2):119–28.

    CAS  PubMed  Google Scholar 

  69. Dumont C, Bourgeois S, Fessi H, Jannin V. Lipid-based nanosuspensions for oral delivery of peptides, a critical review. Int J Pharm. 2018;541(1–2):117–35. https://doi.org/10.1016/j.ijpharm.2018.02.038.

    Article  CAS  PubMed  Google Scholar 

  70. Chen C, Fan T, Jin Y, Zhou Z, Yang Y, Zhu X, et al. Orally delivered salmon calcitonin-loaded solid lipid nanoparticles prepared by micelle-double emulsion method via the combined use of different solid lipids. Nanomedicine (London). 2013;8(7):1085–100. https://doi.org/10.2217/nnm.12.141.

    Article  CAS  Google Scholar 

  71. Ansari MJ, Anwer MK, Jamil S, Al-Shdefat R, Ali BE, Ahmad MM, et al. Enhanced oral bioavailability of insulin-loaded solid lipid nanoparticles: pharmacokinetic bioavailability of insulin-loaded solid lipid nanoparticles in diabetic rats. Drug Deliv. 2016;23(6):1972–9. https://doi.org/10.3109/10717544.2015.1039666.

    Article  CAS  PubMed  Google Scholar 

  72. Zhao Y, Huang L. Lipid nanoparticles for gene delivery. Adv Genet. 2014;88:13–36. https://doi.org/10.1016/B978-0-12-800148-6.00002-X.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Ball RL, Bajaj P & Whitehead KA Oral delivery of siRNA lipid nanoparticles: Fate in the GI tract Scientific Reports. 2018; 8:2178. https://doi.org/10.1038/s41598-018-20632-6.

  74. Liversidge GG, Cundy KC. Particle size reduction for improvement of oral bioavailability of hydrophobic drugs: I. Absolute oral bioavailability of nanocrystalline danazol in beagle dogs. Int J Pharm. 1995;125(1):91–7.

    CAS  Google Scholar 

  75. Kuksis, A. Absorption of fat soluble vitamins. In: Kuksis A, editor. Fat absorption Vol. 2. Boca Raton: CRC Press. 1987.p-65-86.

  76. Charman SA, Charman WN, Rogge MC, Wilson TD, Dutko FJ, Pouton CW. Self-emulsifying drug delivery systems: formulation and biopharmaceutic evaluation of an investigational lipophilic compound. Pharm Res. 1992;9(1):87–93.

    CAS  PubMed  Google Scholar 

  77. Charman WN. Lipids, lipophilic drugs, and oral drug delivery-some emerging concepts. J Pharm Sci. 2000;89(8):967–78.

    CAS  PubMed  Google Scholar 

  78. Charman WN, Porter CJH. Lipophilic prodrugs designed for intestinal lymphatic transport. Adv Drug Deliv Rev. 1996;19(2):149–69.

    CAS  Google Scholar 

  79. Thomson AB, Schoeller C, Keelan M, Smith L, Clandinin MT. Lipid absorption: passing through the unstirred layers, brush-border membrane, and beyond. Can J Physiol Pharmacol. 1993;71(8):531–55.

    CAS  PubMed  Google Scholar 

  80. Shiau YF, Kelemen RJ, Reed MA. Acidic mucin layer facilitates micelle dissociation and fatty acid diffusion. Am J Phys. 1990;259(4 Pt 1):G671–5.

    CAS  Google Scholar 

  81. Shiau YF, Levine GM. pH dependence of micellar diffusion and dissociation. Am J Physiol-Gastrointest Liv Physiol. 1980;239(3):G177–82.

    CAS  Google Scholar 

  82. Khoo SM, Shackleford DM, Porter CJ, Edwards GA, Charman WN. Intestinal lymphatic transport of Halofantrine occurs after oral administration of a unit-dose lipid-based formulation to fasted dogs. Pharm Res. 2003;20(9):1460–5.

    CAS  PubMed  Google Scholar 

  83. Porter CJ, Trevaskis NL, Charman WN. Lipids and lipid-based formulations: optimizing the oral delivery of lipophilic drugs. Nat Rev Drug Discov. 2007;6(3):231–48.

    CAS  PubMed  Google Scholar 

  84. Eldridge JH, Hammond CJ, Meulbroeck JA, Staas JK, Gilley RM, Tice TR. Controlled vaccine release in the gut-associated lymphoid tissue. I. Orally administered biodegradable microspheres target the Peyer’s patches. J Control Release. 1990;11:205–14.

    CAS  Google Scholar 

  85. Hawley AE, Davis SS, Illum L. Targeting of colloids to lymph nodes: influence of lymphatic physiology and colloidal characteristics. Adv Drug Deliv Rev. 1995;17:129–48.

    CAS  Google Scholar 

  86. Beier R, Gebert A. Kinetics of particle uptake in the domes of Peyer’s patches. Am J Phys. 1998;275(1 Pt 1):G130–7.

    CAS  Google Scholar 

  87. Makhey VD, Guo A, Norris DA, Hu P, Yan J, Sinko PJ. Characterization of the regional intestinal kinetics of drug efflux in rat and human intestine and in Caco-2 cells. Pharm Res. 1998;15:1160–7.

    CAS  PubMed  Google Scholar 

  88. Raghava KM, Lakshmi PK. Overview of P-glycoprotein inhibitors: a rational outlook. Brazil J Pharm Sci. 2012;48(3):353–67. https://doi.org/10.1590/S1984-82502012000300002.

    Article  Google Scholar 

  89. Varma MVS, Ashokraj Y, Dey CS, Panchagnula R. P-glycoprotein inhibitors and their screening: a perspective from bioavailability enhancement. Pharmacol Res. 2003;48(4):347–59.

    CAS  PubMed  Google Scholar 

  90. Shangguan M, Qi J, Lu Y, Wu W. Comparison of the oral bioavailability of silymarin-loaded lipid nanoparticles with their artificial lipolysate counterparts: implications on the contribution of integral structure. Int J Pharm. 2015;489(1–2):195–202. https://doi.org/10.1016/j.ijpharm.2015.05.005.

    Article  CAS  PubMed  Google Scholar 

  91. Abuasal BS, Lucas C, Peyton B, Alayoubi A, Nazzal S, Sylvester PW, et al. Enhancement of intestinal permeability utilizing solid lipid nanoparticles increases γ-tocotrienol oral bioavailability. Lipids. 2012;47(5):461–9. https://doi.org/10.1007/s11745-012-3655-4.

    Article  CAS  PubMed  Google Scholar 

  92. Severino P, Souto EB, Pinho SC, Santana MHA. Hydrophilic coating of mitotane-loaded lipid nanoparticles: preliminary studies for mucosal adhesion. Pharm Dev Technol. 2013;18(3):577–81.

    CAS  PubMed  Google Scholar 

  93. Albrecht K, Bernkop-Schnurch A. Thiomers: forms, functions and applications to nanomedicine. Nanomedicine. 2007;2(1):41–50.

    CAS  PubMed  Google Scholar 

  94. Gradauer K, Dunnhaupt S, Vonach C, et al. Thiomer-coated liposomes harbor permeation enhancing and efflux pump inhibitory properties. J Control Release. 2013;165(3):207–15.

    CAS  PubMed  PubMed Central  Google Scholar 

  95. Fang G, Tang B, Chao Y, Xu H, Gou J, Zhang Y, et al. Cysteine-functionalized nanostructured lipid carriers for oral delivery of docetaxel: a permeability and pharmacokinetic study. Mol Pharm. 2015;12(7):2384–95.

    CAS  PubMed  Google Scholar 

  96. Fonte P, Nogueira T, Gehm C, Ferreira D, Sarmento B. Chitosan-coated solid lipid nanoparticles enhance the oral absorption of insulin. Drug Deliv Transl Res. 2011;1(4):299–308. https://doi.org/10.1007/s13346-011-0023-5.

    Article  CAS  PubMed  Google Scholar 

  97. Sarmento B, Mazzaglia D, Bonferoni MC, Neto AP, Monteiro M, Seabra V. Effect of chitosan coating in overcoming the phagocytosis of insulin loaded solid lipid nanoparticles by mononuclear phagocyte system. Carbohydr Polym. 2011;84(3):919–25.

    CAS  Google Scholar 

  98. Bolhassani A. Potential efficacy of cell-penetrating peptides for nucleic acid and drug delivery in cancer. Biochim Biophys Acta. 2011;1816(2):232–46.

    CAS  PubMed  Google Scholar 

  99. Deshayes S, Morris MC, Divita G, Heitz F. Cell-penetrating peptides: tools for intracellular delivery of therapeutics. Cell Mol Life Sci. 2005;62(16):1839–49.

    CAS  PubMed  Google Scholar 

  100. Dietz GP. Protection by neuroglobin and cell-penetrating peptide mediated delivery in vivo: a decade of research. Comment on Cai et al: TAT-mediated delivery of neuroglobin protects against focal cerebral ischemia in mice. Exp Neurol. 2011;227(1):224–31.

    Google Scholar 

  101. Said Hassane F, Saleh AF, Abes R, Gait MJ, Lebleu B. Cell penetrating peptides: overview and applications to the delivery of oligonucleotides. Cell Mol Life Sci. 2010;67(5):715–26.

    CAS  PubMed  Google Scholar 

  102. Kibria G, Hatakeyama H, Harashima H. A new peptide motif present in the protective antigen of anthrax toxin exerts its efficiency on the cellular uptake of liposomes and applications for a dual-ligand system. Int J Pharm. 2011;412(1–2):106–14.

    CAS  PubMed  Google Scholar 

  103. Madani F, Lindberg S, Langel U, Futaki S, Gräslund A. Mechanisms of cellular uptake of cell-penetrating peptides. J Biophys. 2011;2011:1–10. https://doi.org/10.1155/2011/414729.

    Article  CAS  Google Scholar 

  104. Järver P, Langel U. The use of cell-penetrating peptides as a tool for gene regulation. Drug Discov Today. 2004;9(9):395–402.

    PubMed  Google Scholar 

  105. Zhang Z, Lv H, Zhou J. Novel solid lipid nanoparticles as carriers for oral administration of insulin. Pharmazie. 2009;64(9):574–8.

    CAS  PubMed  Google Scholar 

  106. Fan T, Chen C, Guo H, XuJian J, et.al., Design and evaluation of solid lipid nanoparticles modified with peptide ligand for oral delivery of protein drugs. Eur J Pharm Biopharm 2014; 88(2):518–528.

  107. Baek J, So J, Shin S, Cho C. Solid lipid nanoparticles of paclitaxel strengthened by hydroxypropyl-β-cyclodextrin as an oral delivery system. Int J Mol Med. 2012;30:953–9.

    CAS  PubMed  Google Scholar 

  108. Tian C, Asghar S, Wu Y, Chen Z, Jin X, Yin L, et al. Improving intestinal absorption and oral bioavailability of curcumin via taurocholic acid-modified nanostructured lipid carriers. Int J Nanomedicine. 2017;12:7897–911. https://doi.org/10.2147/IJN.S145988.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Tian C, Asghar S, Wu Y, Kambere Amerigos D, Chen Z, Zhang M, et al. N-acetyl-L-cysteine functionalized nanostructured lipid carrier for improving oral bioavailability of curcumin: preparation, in vitro and in vivo evaluations. Drug Deliv. 2017;24(1):1605–16. https://doi.org/10.1080/10717544.2017.1391890.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Ezzati Nazhad Dolatabadi J, Hamishehkar H, Eskandani M, Valizadeh HJ. Formulation, characterization and cytotoxicity studies of alendronate sodium-loaded solid lipid nanoparticles. Colloids Surf B: Biointerfaces. 2014;117:21–8. https://doi.org/10.1016/j.colsurfb.2014.01.055.

    Article  CAS  PubMed  Google Scholar 

  111. Doktorovova S, Silva AM, Gaivão I, Souto EB, Teixeira JP, Martins-Lopes P. Comet assay reveals no genotoxicity risk of cationic solid lipid nanoparticles. Appl Toxicol. 2014;34(4):395–403. https://doi.org/10.1002/jat.2961.

    Article  CAS  Google Scholar 

  112. Nassimi M, Schleh C, Lauenstein HD, Hussein R, Lübbers K, Pohlmann G, et al. Low cytotoxicity of solid lipid nanoparticles in in vitro and ex vivo lung models. Inhal Toxicol. 2009;21(Suppl 1):104–9. https://doi.org/10.1080/08958370903005769.

    Article  CAS  PubMed  Google Scholar 

  113. Li J, Guo X, Liu Z, Okeke CI, Li N, Zhao H, et al. Preparation and evaluation of charged solid lipid nanoparticles of tetrandrine for ocular drug delivery system: pharmacokinetics, cytotoxicity and cellular uptake studies. Drug Dev Ind Pharm. 2014;40(7):980–7. https://doi.org/10.3109/03639045.2013.795582.

    Article  CAS  PubMed  Google Scholar 

  114. Petersen S, Steiniger F, Fischer D, Fahr A, Bunjes H. The physical state of lipid nanoparticles influences their effect on in vitro cell viability. Eur J Pharm Biopharm. 2011;79(1):150–61. https://doi.org/10.1016/j.ejpb.2011.03.022.

    Article  CAS  PubMed  Google Scholar 

  115. Rawat MK, Jain A, Singh S. In vivo and cytotoxicity evaluation of repaglinide-loaded binary solid lipid nanoparticles after oral administration to rats. J Pharm Sci. 2011;100(6):2406–17. https://doi.org/10.1002/jps.22454.

    Article  CAS  PubMed  Google Scholar 

  116. D M Ridolfi, P D Marcato, D Machado, R A Silva, G Z Justo and N Durán4. In vitro cytotoxicity assays of solid lipid nanoparticles in epithelial and dermal cells. J of Physics: Conference Series 304. 2011; 012032 doi:https://doi.org/10.1088/1742-6596/304/1/012032.

  117. Severino P, Andreani T, Jäger A, Chaud MV, Santana MH, Silva AM, et al. Solid lipid nanoparticles for hydrophilic biotech drugs: optimization and cell viability studies (Caco-2 & HEPG-2 cell lines). Eur J Med Chem. 2014;81:28–34. https://doi.org/10.1016/j.ejmech.2014.04.084.

    Article  CAS  PubMed  Google Scholar 

  118. Silva AH, Filippin-Monteiro FB, Mattei B, Zanetti-Ramos BG, Creczynski-Pasa TB. In vitro biocompatibility of solid lipid nanoparticles. Sci Total Environ. 2012;432:382–8. https://doi.org/10.1016/j.scitotenv.2012.06.018.

    Article  CAS  PubMed  Google Scholar 

  119. Winter E, Dal Pizzol C, Locatelli C, Crezkynski-Pasa TB. Development and evaluation of lipid nanoparticles for drug delivery: study of toxicity in, vitro and in vivo. J Nanosci Nanotechnol. 2016;16(2):1321–30.

    CAS  PubMed  Google Scholar 

  120. Ong YS, Saiful Yazan L, Ng WK, Noordin MM, Sapuan S, Foo JB, et al. Acute and subacute toxicity profiles of thymoquinone-loaded nanostructured lipid carrier in BALB/c mice. Int J Nanomedicine. 2016;11:5905–15. https://doi.org/10.2147/IJN.S114205.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Kanwar R, Gradzielski M, Prevost S, Kaur G, Clemens D, Appavou MS, et al. Effect of lipid chain length on nanostructured lipid carriers: comprehensive structural evaluation by scattering techniques. J Colloid Interface Sci. 2018;534:95–104. https://doi.org/10.1016/j.jcis.2018.08.066.

    Article  CAS  PubMed  Google Scholar 

  122. Müller RH, Rühl D, Runge S, Schulze-Forster K, Mehnert W. Cytotoxicity of solid lipid nanoparticles as a function of the lipid matrix and the surfactant. Pharm Res. 1997;14(4):458–62.

    PubMed  Google Scholar 

  123. How CW, Rasedee A, Abbasalipourkabir R. Characterization and cytotoxicity of nanostructured lipid carriers formulated with olive oil, hydrogenated palm oil, and polysorbate 80. IEEE Trans Nanobioscience. 2013;12(2):72–8. https://doi.org/10.1109/TNB.2012.2232937.

    Article  PubMed  Google Scholar 

  124. Tabatt K, Sameti M, Olbrich C, Müller RH, Lehr C. Effect of cationic lipid and matrix lipid composition on solid lipid nanoparticle-mediated gene transfer. Eur J Pharm Biopharm. 2004;57(2):155–62.

    CAS  PubMed  Google Scholar 

  125. Saedi A, Rostamizadeh K, Parsa M, Dalali N, Ahmadi N. Preparation and characterization of nanostructured lipid carriers as drug delivery system: influence of liquid lipid types on loading and cytotoxicity. Chem Phys Lipids. 2018;216:65–72. https://doi.org/10.1016/j.chemphyslip.2018.09.007.

    Article  CAS  PubMed  Google Scholar 

  126. Rahman HS, Rasedee A, Othman HH, et al. Acute toxicity study of Zerumbone-loaded nanostructured lipid carrier on BALB/c mice model. BioMed Res International. 2014;563930.

  127. Chen Y, Yuan L, Zhou L, Zhang Z, Cao W, Wu Q. Effect of cell-penetrating peptide-coated nanostructured lipid carriers on the oral absorption of tripterine. Int J Nanomedicine. 2012;7:4581–91. https://doi.org/10.2147/IJN.S34991.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Fangueiro JF, Gonzalez-Mira E, Martins-Lopes P, Egea MA, Garcia ML, Souto SB, et al. A novel lipid nanocarrier for insulin delivery: production, characterization and toxicity testing. Pharm Dev Technol. 2013;18(3):545–9.

    CAS  PubMed  Google Scholar 

  129. Müller RH, Staufenbiel S, Keck C. Lipid nanoparticles (SLN, NLC) for innovative consumer care & household products. H&PC Today. 2014;9:18–24.

    Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Sushama Talegaonkar.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Talegaonkar, S., Bhattacharyya, A. Potential of Lipid Nanoparticles (SLNs and NLCs) in Enhancing Oral Bioavailability of Drugs with Poor Intestinal Permeability. AAPS PharmSciTech 20, 121 (2019). https://doi.org/10.1208/s12249-019-1337-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1208/s12249-019-1337-8

KEY WORDS

Navigation