Skip to main content
Log in

Quality by design (QbD)–based fabrication of atazanavir-loaded nanostructured lipid carriers for lymph targeting: bioavailability enhancement using chylomicron flow block model and toxicity studies

  • Original Article
  • Published:
Drug Delivery and Translational Research Aims and scope Submit manuscript

Abstract

Atazanavir (ATV) is widely used as anti-HIV agent having poor aqueous solubility needs to modulate novel drug delivery system to enhance therapeutic efficiency and safety. The main objective of the present work was to fabricate ATV-loaded nanostructured lipid carriers (NLCs) employing quality by design (QbD) approach to address the challenges of bioavailability and their safety after oral administration. Herein, the main objective was to identify the influencing variables for the production of quality products. Considering this objective, quality target product profile (QTPP) was assigned and a systematic risk assessment study was performed to identify the critical material attributes (CMAs) and critical process parameter (CPP) having an influence on critical quality attributes (CQAs). Lipid concentrations, surfactant concentrations, and pressure of high-pressure homogenizer were identified as CMAs and CPP. ATV-NLCs were prepared by emulsification-high pressure homogenization method and further lyophilized to obtain solid-state NLCs. The effect of formulation variables (CMAs and CPP) on responses like particle size (Y1), polydispersity index (Y2), and zeta potential (Y3) was observed by central composite rotatable design (CCRD). The data were statistically evaluated by ANOVA for confirmation of a significant level (p < 0.05). The optimal conditions of NLCs were obtained by generating design space and desirability value. The lyophilized ATV-NLCs were characterized by DSC, powder X-ray diffraction, and FT-IR analysis. The morphology of NLCs was revealed by TEM and FESEM. In vitro study suggested a sustained release pattern of drug (92.37 ± 1.03%) with a mechanism of Korsmeyer-Peppas model (r2 = 0.925, and n = 0.63). In vivo evaluation in Wistar rats showed significantly higher (p < 0.001) plasma drug concentration of ATV-NLCs as compared to ATV-suspension using chylomicron flow block model. The relative bioavailability of ATV-NLCs was obtained to be 2.54 folds. Thus, a safe and promising drug targeting system was successfully developed to improve bioavailability and avoiding first-pass effect ensures to circumvent the acute-toxicity of liver.

Graphical abstract

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.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8
Fig. 9
Fig. 10

Similar content being viewed by others

Availability of data and materials

Data available on request from the authors.

References

  1. Makwana V, Jain R, Patel K, Nivsarkar M, Joshi A. Solid lipid nanoparticles (SLN) of Efavirenz as lymph targeting drug delivery system: elucidation of mechanism of uptake using chylomicron flow blocking approach. Int J Pharm [Internet]. Elsevier B.V.; 2015;495:439–46. https://doi.org/10.1016/j.ijpharm.2015.09.014.

  2. Giacalone G, Hillaireau H, Fattal E. Improving bioavailability and biodistribution of anti-HIV chemotherapy. Eur J Pharm Sci [Internet]. Elsevier B.V.; 2015;75:40–53. https://doi.org/10.1016/j.ejps.2015.04.011.

  3. Shaligram Mahajan H, Patil PH. Central composite design-based optimization of lopinavir vitamin E-TPGS Micelle: In Vitro Characterization and In Vivo Pharmacokinetic Study. Colloids Surfaces B Biointerfaces [Internet]. Elsevier B.V.; 2020;111149. https://doi.org/10.1016/j.colsurfb.2020.111149.

  4. Dahan A, Hoffman A. Evaluation of a chylomicron flow blocking approach to investigate the intestinal lymphatic transport of lipophilic drugs. Eur J Pharm Sci. 2005;24:381–8.

    Article  CAS  Google Scholar 

  5. Singh G, Pai RS. Optimized self-nanoemulsifying drug delivery system of atazanavir with enhanced oral bioavailability: in vitro/in vivo characterization. Expert Opin Drug Deliv. 2014;11:1023–32.

    Article  CAS  Google Scholar 

  6. Singh G, Pai RS. Atazanavir-loaded Eudragit RL 100 nanoparticles to improve oral bioavailability: Optimization and in vitro/in vivo appraisal. Drug Deliv. 2016;23:532–9.

    Article  CAS  Google Scholar 

  7. Devi K, Pai R. Antiretrovirals: need for an effective drug delivery. Indian J Pharm Sci. 2006;68:1–6.

    Article  CAS  Google Scholar 

  8. Chattopadhyay N, Zastre J, Wong HL, Wu XY, Bendayan R. Solid lipid nanoparticles enhance the delivery of the HIV protease inhibitor, atazanavir, by a human brain endothelial cell line. Pharm Res [Internet]. 2008;25:2262–71. https://doi.org/10.1007/s11095-008-9615-2.

  9. Singh B, Diwan A. Effect of process parameters on formulation of solid lipid nanoparticles of protease inhibitor. Atazanavir Pharma Res. 2012;7:1–15.

    Google Scholar 

  10. Fukushima K, Terasaka S, Haraya K, Kodera S, Seki Y, Wada A, et al. Pharmaceutical approach to HIV protease inhibitor atazanavir for bioavailability enhancement based on solid dispersion system. Biol Pharm Bull. 2007;30:733–8.

    Article  CAS  Google Scholar 

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

    Article  Google Scholar 

  12. Müller RH, Freitas C, zur Mühlen A, Mehnert W. Solid lipid nanoparticles (SLN) for controlled drug delivery. Eur J Pharm Sci [Internet]. 1996;4:S75. http://www.sciencedirect.com/science/article/pii/S0928098797862434.

  13. Nasirizadeh S, Malaekeh-Nikouei B. Solid lipid nanoparticles and nanostructured lipid carriers in oral cancer drug delivery. J Drug Deliv Sci Technol [Internet]. Elsevier; 2020;55:101458. https://doi.org/10.1016/j.jddst.2019.101458.

  14. 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;17:249–56.

    Article  CAS  Google Scholar 

  15. Kumar S, Narayan R, Ahammed V, Nayak Y, Naha A, Nayak UY. Development of ritonavir solid lipid nanoparticles by Box Behnken design for intestinal lymphatic targeting. J Drug Deliv Sci Technol [Internet]. Elsevier B.V.; 2018;44:181–9. https://doi.org/10.1016/j.jddst.2017.12.014.

  16. Cirri M, Bragagni M, Mennini N, Mura P. Development of a new delivery system consisting in ‘“ drug – in cyclodextrin – in nanostructured lipid carriers ”’ for ketoprofen topical delivery. Eur J Pharm Biopharm [Internet]. Elsevier B.V.; 2012;80:46–53. https://doi.org/10.1016/j.ejpb.2011.07.015.

  17. Jaiswal P, Gidwani B, Vyas A. Nanostructured lipid carriers and their current application in targeted drug delivery. Artif Cells, Nanomedicine, Biotechnol [Internet]. 2016;44:27–40. https://doi.org/10.3109/21691401.2014.909822.

  18. Shevalkar G, Vavia P. Solidified nanostructured lipid carrier (S-NLC) for enhancing the oral bioavailability of ezetimibe. J Drug Deliv Sci Technol [Internet]. Elsevier; 2019;53:101211. https://doi.org/10.1016/j.jddst.2019.101211.

  19. Naseri N, Valizadeh H, Zakeri-Milani P. Solid lipid nanoparticles and nanostructured lipid carriers: structure preparation and application. Adv Pharm Bull [Internet]. 2015;5:305–13. https://doi.org/10.15171/apb.2015.043.

  20. Garg NK, Sharma G, Singh B, Nirbhavane P, Tyagi RK, Shukla R, et al. Quality by Design (QbD)-enabled development of aceclofenac loaded-nano structured lipid carriers (NLCs): an improved dermatokinetic profile for inflammatory disorder(s). Int J Pharm [Internet]. Elsevier B.V.; 2017;517:413–31. https://doi.org/10.1016/j.ijpharm.2016.12.010.

  21. Tsai MJ, Wu PC, Huang Y Bin, Chang JS, Lin CL, Tsai YH, et al. Baicalein loaded in tocol nanostructured lipid carriers (tocol NLCs) for enhanced stability and brain targeting. Int J Pharm [Internet]. Elsevier B.V.; 2012;423:461–70. https://doi.org/10.1016/j.ijpharm.2011.12.009.

  22. Aji Alex MR, Chacko AJ, Jose S, Souto EB. Lopinavir loaded solid lipid nanoparticles (SLN) for intestinal lymphatic targeting. Eur J Pharm Sci. 2011;42:11–8.

    Article  CAS  Google Scholar 

  23. Ahammed V, Narayan R, Paul J, Nayak Y, Roy B, Shavi G V., et al. Development and in vivo evaluation of functionalized ritonavir proliposomes for lymphatic targeting. Life Sci [Internet]. Elsevier Inc.; 2017;183:11–20. https://doi.org/10.1016/j.lfs.2017.06.022.

  24. Bonde S, Bonde CG, Prabhakar B. Quality by design based development and validation of HPLC method for simultaneous estimation of paclitaxel and vinorelbine tartrate in dual drug loaded liposomes. Microchem J [Internet]. Elsevier; 2019;149:103982. https://doi.org/10.1016/j.microc.2019.103982.

  25. Shekhawat P, Pokharkar V. Risk assessment and QbD based optimization of an Eprosartan mesylate nanosuspension: in-vitro characterization, PAMPA and in-vivo assessment. Int J Pharm [Internet]. Elsevier; 2019;567:118415. https://doi.org/10.1016/j.ijpharm.2019.06.006.

  26. Kincl M, Turk S, Vrečer F. Application of experimental design methodology in development and optimization of drug release method. Int J Pharm. 2005;291:39–49.

    Article  CAS  Google Scholar 

  27. Singh A, Neupane YR, Mangla B, Kohli K. Nanostructured lipid carriers for oral bioavailability enhancement of exemestane: formulation design, In Vitro, Ex Vivo, and In Vivo Studies. J Pharm Sci [Internet]. Elsevier Ltd; 2019;108:3382–95. https://doi.org/10.1016/j.xphs.2019.06.003.

  28. Jazuli I, Annu, Nabi B, moolakkadath T, Alam T, Baboota S, et al. Optimization of nanostructured lipid carriers of lurasidone hydrochloride using Box-Behnken design for brain targeting: in vitro and in vivo studies. J Pharm Sci [Internet]. Elsevier Ltd; 2019;108:3082–90. https://doi.org/10.1016/j.xphs.2019.05.001.

  29. Alam T, Khan S, Gaba B, Haider MF, Baboota S, Ali J. Adaptation of quality by design-based development of isradipine nanostructured–lipid carrier and its evaluation for in vitro gut permeation and in vivo solubilization fate. J Pharm Sci [Internet]. Elsevier Ltd; 2018;107:2914–26. https://doi.org/10.1016/j.xphs.2018.07.021.

  30. Rangaraj N, Pailla SR, Shah S, Prajapati S, Sampathi S. QbD aided development of ibrutinib-loaded nanostructured lipid carriers aimed for lymphatic targeting: evaluation using chylomicron flow blocking approach. Drug Deliv Transl Res. Drug Delivery and Translational Research; 2020;

  31. Shailesh S. Chalikwar , Sanjay J. Surana , Sameer N. Goyal KKC& PVD. Solid self-microemulsifying nutraceutical delivery system for hesperidin using quality by design: Assessment of biopharmaceutical attributes and shelf-life. J Microencapsul [Internet]. Taylor & Francis; 2020;0:000. https://doi.org/10.1080/02652048.2020.1851788.

  32. ICH guideline Q8(R2). ICH harmonised tripartite guideline pharmaceutical development. Curr Step 4 version. 2009;1–24.

  33. Pallagi E, Ambrus R, Szabó-Révész P, Csóka I. Adaptation of the quality by design concept in early pharmaceutical development of an intranasal nanosized formulation. Int J Pharm [Internet]. Elsevier B.V.; 2015;491:384–92. https://doi.org/10.1016/j.ijpharm.2015.06.018.

  34. Manteghi R, Pallagi E, Olajos G, Csóka I. Pegylation and formulation strategy of anti-microbial peptide (AMP) according to the quality by design approach. Eur J Pharm Sci [Internet]. Elsevier B.V.; 2020;144:105197. https://doi.org/10.1016/j.ejps.2019.105197.

  35. Dangre PV, Phad RD, Surana SJ, Chalikwar SS. Quality by Design ( QbD ) Assisted fabrication of fast dissolving buccal film for clonidine hydrochloride : exploring the quality attributes. Adv Polym Technol. 2019;2019:1–13.

    Article  Google Scholar 

  36. Luo T, Wu C, Duan L. Fishbone diagram and risk matrix analysis method and its application in safety assessment of natural gas spherical tank. J Clean Prod [Internet]. Elsevier Ltd; 2018;174:296–304. https://doi.org/10.1016/j.jclepro.2017.10.334.

  37. ICH guideline Q2(R1). ICH harmonised tripartite guideline, validation of analytical procedures: text and methodology. Curr. Step 4 version Parent Guidel. dated 27 Oct. 1994 2005 p. 13.

  38. Kumbhar DD, Pokharkar VB. Engineering of a nanostructured lipid carrier for the poorly water-soluble drug, bicalutamide : physicochemical investigations. Colloids Surfaces A Physicochem Eng Asp [Internet]. Elsevier B.V.; 2013;416:32–42. https://doi.org/10.1016/j.colsurfa.2012.10.031.

  39. Chalikwar SS, Belgamwar VS, Talele VR, Surana SJ, Patil MU. Formulation and evaluation of Nimodipine-loaded solid lipid nanoparticles delivered via lymphatic transport system. Colloids Surfaces B Biointerfaces [Internet]. Elsevier B.V.; 2012;97:109–16. https://doi.org/10.1016/j.colsurfb.2012.04.027.

  40. Ferreira M, Chaves LL, Lima SAC, Reis S. Optimization of nanostructured lipid carriers loaded with methotrexate: a tool for inflammatory and cancer therapy. Int J Pharm. 2015;492:65–72.

    Article  CAS  Google Scholar 

  41. Abbou A, Kadri N, Dahmoune F, Chergui A, Remini H, Berkani F, et al. Optimising functional properties and chemical composition of Pinus halepensis Mill. Seeds protein concentrates. Food Hydrocoll [Internet]. Elsevier Ltd; 2020;100:105416. https://doi.org/10.1016/j.foodhyd.2019.105416.

  42. Shete H, Patravale V. Long chain lipid based tamoxifen NLC. Part I: Preformulation studies, formulation development and physicochemical characterization. Int J Pharm [Internet]. Elsevier B.V.; 2013;454:573–83. https://doi.org/10.1016/j.ijpharm.2013.03.034.

  43. Das S, Ng WK, Kanaujia P, Kim S, Tan RBH. Formulation design, preparation and physicochemical characterizations of solid lipid nanoparticles containing a hydrophobic drug: effects of process variables. Colloids Surfaces B Biointerfaces [Internet]. Elsevier B.V.; 2011;88:483–9. https://doi.org/10.1016/j.colsurfb.2011.07.036.

  44. Liu H, Rivnay B, Avery K, Myung JH, Kozak D, Landrau N, et al. Optimization of the manufacturing process of a complex amphotericin B liposomal formulation using quality by design approach. Int J Pharm [Internet]. Elsevier B.V.; 2020;585:119473. https://doi.org/10.1016/j.ijpharm.2020.119473.

  45. Karakucuk A, Celebi N, Teksin ZS. Preparation of ritonavir nanosuspensions by microfluidization using polymeric stabilizers: I. A Design of Experiment approach. Eur J Pharm Sci [Internet]. Elsevier B.V.; 2016;95:111–21. https://doi.org/10.1016/j.ejps.2016.05.010.

  46. Neupane YR, Srivastava M, Ahmad N, Kumar N, Bhatnagar A, Kohli, Kanchan. Lipid based nanocarrier system for the potential oral delivery of decitabine: formulation design, characterization, ex vivo, and in vivo assessment. Int J Pharm [Internet]. Elsevier B.V.; 2014;477:601–12. https://doi.org/10.1016/j.ijpharm.2014.11.001.

  47. Kumar R, Singh A, Garg N, Siril PF. Solid lipid nanoparticles for the controlled delivery of poorly water soluble non-steroidal anti-inflammatory drugs. Ultrason Sonochem [Internet]. 2018;40:686–96. https://doi.org/10.1016/j.ultsonch.2017.08.018.

  48. Kaur R, Ajitha M. Transdermal delivery of fluvastatin loaded nanoemulsion gel: preparation, characterization and in vivo anti-osteoporosis activity. Eur J Pharm Sci [Internet]. Elsevier; 2019;136:104956. https://doi.org/10.1016/j.ejps.2019.104956.

  49. Li HL, Zhao X Bin, Ma YK, Zhai GX, Li LB, Lou HX. Enhancement of gastrointestinal absorption of quercetin by solid lipid nanoparticles. J Control Release [Internet]. Elsevier B.V.; 2009;133:238–44. https://doi.org/10.1016/j.jconrel.2008.10.002.

  50. Garg NK, Singh B, Sharma G, Kushwah V, Tyagi RK, Jain S, et al. Development and characterization of single step self-assembled lipid polymer hybrid nanoparticles for effective delivery of methotrexate. RSC Adv [Internet]. 2015;5:62989–99. http://xlink.rsc.org/?DOI=C5RA12459J.

  51. U.S. Department of Health and Human Services. Guidance for industry: characterization and qualification of cell substrates and other biological starting materials used in the production of viral vaccines for the prevention and treatment of infectious diseases. Biotechnol Law Rep. 2005;1–27.

  52. Dahan A, Mendelman A, Amsili S, Ezov N, Hoffman A. The effect of general anesthesia on the intestinal lymphatic transport of lipophilic drugs: comparison between anesthetized and freely moving conscious rat models. Eur J Pharm Sci. 2007;32:367–74.

    Article  CAS  Google Scholar 

  53. Patil-Gadhe A, Pokharkar V. Montelukast-loaded nanostructured lipid carriers : Part I Oral bioavailability improvement. Eur J Pharm Biopharm [Internet]. Elsevier B.V.; 2014;88:160–8. https://doi.org/10.1016/j.ejpb.2014.05.019.

  54. Tiwari R, Pathak K. Nanostructured lipid carrier versus solid lipid nanoparticles of simvastatin: comparative analysis of characteristics, pharmacokinetics and tissue uptake. Int J Pharm [Internet]. Elsevier B.V.; 2011;415:232–43. https://doi.org/10.1016/j.ijpharm.2011.05.044.

  55. Pardeshi CV, Belgamwar VS. Improved brain pharmacokinetics following intranasal administration of N,N,N-trimethyl chitosan tailored mucoadhesive NLCs. Mater Technol [Internet]. Taylor & Francis; 2020;35:249–66. https://doi.org/10.1080/10667857.2019.1674522.

  56. Nassimi M, Schleh C, Lauenstein HD, Hussein R, Hoymann HG, Koch W, et al. A toxicological evaluation of inhaled solid lipid nanoparticles used as a potential drug delivery system for the lung. Eur J Pharm Biopharm [Internet]. Elsevier B.V.; 2010;75:107–16. https://doi.org/10.1016/j.ejpb.2010.02.014.

  57. Gurumukhi VC, Bari SB. Fabrication of efavirenz loaded nano-formulation using quality by design (QbD) based approach: exploring characterizations and in vivo safety. J Drug Deliv Sci Technol [Internet]. Elsevier; 2020;56:101545. https://doi.org/10.1016/j.jddst.2020.101545.

  58. Gokhale JP, Mahajan HS, Surana SS. Quercetin loaded nanoemulsion-based gel for rheumatoid arthritis: in vivo and in vitro studies. Biomed Pharmacother [Internet]. Elsevier; 2019;112:108622. https://doi.org/10.1016/j.biopha.2019.108622.

  59. Amasya G, Aksu B, Badilli U, Onay-Besikci A, Tarimci N. QbD guided early pharmaceutical development study: production of lipid nanoparticles by high pressure homogenization for skin cancer treatment. Int J Pharm [Internet]. Elsevier B.V.; 2019;563:110–21. https://doi.org/10.1016/j.ijpharm.2019.03.056.

  60. Fangueiro JF, Andreani T, Egea MA, Garcia ML, Souto SB, Silva AM, et al. Design of cationic lipid nanoparticles for ocular delivery: development, characterization and cytotoxicity. Int J Pharm [Internet]. Elsevier B.V.; 2014;461:64–73. https://doi.org/10.1016/j.ijpharm.2013.11.025.

  61. Shah B, Khunt D, Bhatt H, Misra M, Padh H. Application of quality by design approach for intranasal delivery of rivastigmine loaded solid lipid nanoparticles: effect on formulation and characterization parameters. Eur J Pharm Sci [Internet]. Elsevier B.V.; 2015;78:54–66. https://doi.org/10.1016/j.ejps.2015.07.002.

  62. Wissing SA, Kayser O, Müller RH. Solid lipid nanoparticles for parenteral drug delivery. Adv. Drug Deliv. Rev. 2004. p. 1257–72.

  63. Bhise K, Kashaw SK, Sau S, Iyer AK. Nanostructured lipid carriers employing polyphenols as promising anticancer agents: quality by design (QbD) approach [Internet]. Int. J. Pharm. Elsevier B.V.; 2017. p. 506–15. https://doi.org/10.1016/j.ijpharm.2017.04.078.

  64. Shegokar R, Singh KK, Müller RH. Production & stability of stavudine solid lipid nanoparticles—from lab to industrial scale. Int J Pharm [Internet]. Elsevier B.V.; 2011;416:461–70. https://doi.org/10.1016/j.ijpharm.2010.08.014.

  65. Khosa A, Reddi S, Saha RN. Nanostructured lipid carriers for site-specific drug delivery. Biomed Pharmacother [Internet]. Elsevier; 2018;103:598–613. https://doi.org/10.1016/j.biopha.2018.04.055.

  66. Han F, Li S, Yin R, Liu H, Xu L. Effect of surfactants on the formation and characterization of a new type of colloidal drug delivery system: nanostructured lipid carriers. Colloids Surfaces A Physicochem Eng Asp. 2008;315:210–6.

    Article  CAS  Google Scholar 

  67. Shah R, Eldridge D, Palombo E, Harding I. Lipid nanoparticles: production, characterization and stability. 2015;11–23. https://doi.org/10.1007/978-3-319-10711-0.

  68. Espinosa-Olivares MA, Delgado-Buenrostro NL, Chirino YI, Trejo-Márquez MA, Pascual-Bustamante S, Ganem-Rondero A. Nanostructured lipid carriers loaded with curcuminoids: physicochemical characterization, in vitro release, ex vivo skin penetration, stability and antioxidant activity. Eur J Pharm Sci [Internet]. Elsevier; 2020;155:105533. https://doi.org/10.1016/j.ejps.2020.105533.

  69. Üstündaǧ-Okur N, Gökçe EH, Bozbiyik DI, Eǧrilmez S, Özer Ö, Ertan G. Preparation and in vitro-in vivo evaluation of ofloxacin loaded ophthalmic nano structured lipid carriers modified with chitosan oligosaccharide lactate for the treatment of bacterial keratitis. Eur J Pharm Sci. 2014;63:204–15.

    Article  Google Scholar 

  70. Fan H, Liu G, Huang Y, Li Y, Xia Q. Development of a nanostructured lipid carrier formulation for increasing photo-stability and water solubility of Phenylethyl Resorcinol. Appl Surf Sci [Internet]. Elsevier B.V.; 2014;288:193–200. https://doi.org/10.1016/j.apsusc.2013.10.006.

  71. Iqbal R, Ahmed S, Jain GK, Vohora D. Design and development of letrozole nanoemulsion: a comparative evaluation of brain targeted nanoemulsion with free letrozole against status epilepticus and neurodegeneration in mice. Int J Pharm [Internet]. Elsevier B.V.; 2019;565:20–32. https://doi.org/10.1016/j.ijpharm.2019.04.076.

  72. Dan N. Nanostructured lipid carriers: effect of solid phase fraction and distribution on the release of encapsulated materials. Langmuir. 2014;30:13809–14.

    Article  CAS  Google Scholar 

  73. Chitturi SR, Somannavar YS, Peruri BG, Nallapati S, Sharma HK, Budidet SR, et al. Gradient RP-HPLC method for the determination of potential impurities in atazanavir sulfate. J Pharm Biomed Anal [Internet]. Elsevier B.V.; 2011;55:31–47. https://doi.org/10.1016/j.jpba.2011.01.002.

  74. Prathyusha M, Manjunath K, Tippanna S, Shivanandappa B. Bixin loaded solid lipid nanoparticles for enhanced hepatoprotection—preparation, characterisation and in vivo evaluation. Int J Pharm. 2014;473:485–92.

    Article  Google Scholar 

  75. Sherwood WJ, D. Atmurr S. Patent Application Publication ( 10 ) Pub . No .: US 2005 / 0131113 A1. 2005;1:6–9.

  76. Mendes AI, Silva AC, Catita JAM, Cerqueira F, Gabriel C, Lopes CM. Miconazole-loaded nanostructured lipid carriers ( NLC ) for local delivery to the oral mucosa: improving antifungal activity. Colloids Surfaces B Biointerfaces [Internet]. Elsevier B.V.; 2013;111:755–63. https://doi.org/10.1016/j.colsurfb.2013.05.041.

  77. EAG Laboratories. Characterization of polymers using differential scanning calorimetry (DSC) importance of characterizing thermal characterization of polymers using differential scanning calorimetry (DSC). 2017;1–5. f: file:///C:/Users/hamil/Downloads/white-paper-characterization-of-polymers-using-differential-scanning-calorimetry-dsc-m-012816.pdf

  78. Bose S, Michniak-kohn B. Preparation and characterization of lipid based nanosystems for topical delivery of quercetin. Eur J Pharm Sci [Internet]. 2013;48:442–52. https://doi.org/10.1016/j.ejps.2012.12.005.

  79. Madan J, Pandey RS, Jain V, Katare OP, Chandra R, Katyal A. Poly ( ethylene )-glycol conjugated solid lipid nanoparticles of noscapine improve biological half-life, brain delivery and efficacy in glioblastoma cells. Nanomedicine Nanotechnology, Biol Med [Internet]. Elsevier Inc.; 2013;9:492–503. https://doi.org/10.1016/j.nano.2012.10.003.

  80. Kim B Do, Na K, Choi HK. Preparation and characterization of solid lipid nanoparticles (SLN) made of cacao butter and curdlan. Eur J Pharm Sci. 2005;24:199–205.

  81. Kumbhar DD, Pokharkar VB. Physicochemical investigations on an engineered lipid – polymer hybrid nanoparticle containing a model hydrophilic active, zidovudine. Colloids Surfaces A Physicochem Eng Asp [Internet]. Elsevier B.V.; 2013;436:714–25. https://doi.org/10.1016/j.colsurfa.2013.07.044.

  82. Jose S, Anju SS, Cinu TA, Aleykutty NA, Thomas S, Souto EB. In vivo pharmacokinetics and biodistribution of resveratrol-loaded solid lipid nanoparticles for brain delivery. Int J Pharm [Internet]. Elsevier B.V.; 2014;474:6–13. https://doi.org/10.1016/j.ijpharm.2014.08.003.

  83. Chen Y, Yang X, Zhao L, Almásy L, Garamus VM, Willumeit R, et al. Preparation and characterization of a nanostructured lipid carrier for a poorly soluble drug. Colloids Surfaces A Physicochem Eng Asp [Internet]. Elsevier B.V.; 2014;455:36–43. https://doi.org/10.1016/j.colsurfa.2014.04.032.

  84. Shrivastava S, Gidwani B, Kaur CD. Development of mebendazole loaded nanostructured lipid carriers for lymphatic targeting: optimization, characterization, in-vitro and in-vivo evaluation. Part Sci Technol [Internet]. Taylor & Francis; 2020;0:1–11. https://doi.org/10.1080/02726351.2020.1750515.

  85. Xing Q, Song J, You X, Xu D, Wang K, Song J, et al. Microemulsions containing long-chain oil ethyl oleate improve the oral bioavailability of piroxicam by increasing drug solubility and lymphatic transportation simultaneously. Int J Pharm [Internet]. Elsevier B.V.; 2016;511:709–18. https://doi.org/10.1016/j.ijpharm.2016.07.061.

  86. 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 [Internet]. 2015;5:96437–47. http://xlink.rsc.org/?DOI=C5RA14588K.

  87. Shete H, Chatterjee S, De A, Patravale V. Long chain lipid based tamoxifen NLC. Part II: pharmacokinetic, biodistribution and in vitro anticancer efficacy studies. Int J Pharm [Internet]. Elsevier B.V.; 2013;454:584–92. https://doi.org/10.1016/j.ijpharm.2013.03.036.

  88. Pokharkar V, Patil-Gadhe A, Kaur G. Physicochemical and pharmacokinetic evaluation of rosuvastatin loaded nanostructured lipid carriers: influence of long- and medium-chain fatty acid mixture. J Pharm Investig. Springer Netherlands; 2018;48:465–76.

  89. Permana AD, Tekko IA, McCrudden MTC, Anjani QK, Ramadon D, McCarthy HO, et al. Solid lipid nanoparticle-based dissolving microneedles: a promising intradermal lymph targeting drug delivery system with potential for enhanced treatment of lymphatic filariasis. J Control Release [Internet]. Elsevier; 2019;316:34–52. https://doi.org/10.1016/j.jconrel.2019.10.004.

  90. Nerurker MM, Burton PS, Borchardt RT. The use of surfactants to enhance the permeability of peptides through Caco-2 cells by inhibition of an apically polarized efflux system. Pharm. Res. 1996. p. 528–34.

  91. Ukai H, Iwasa K, Deguchi T, Morishita M, Katsumi H, Yamamoto A. Enhanced intestinal absorption of insulin by capryol 90, a novel absorption enhancer in rats: Implications in oral insulin delivery. Pharmaceutics. 2020;12:1–16.

    Article  Google Scholar 

Download references

Acknowledgements

The authors are thankful to Lupin Research Park, Aurangabad, for providing a gift sample of pure Atazanavir. The authors are grateful to Management and Principal of R. C. Patel Institute of Pharmaceutical Education and Research (RCPIPER), Shirpur, for providing various research facilities.

Author information

Authors and Affiliations

Authors

Contributions

All authors read and approved the final manuscript.

Corresponding author

Correspondence to Vishal C. Gurumukhi.

Ethics declarations

Ethics approval and consent to participate

All the animal experiments were performed according to the ARRIVE guidelines and UK Animals (Scientific Procedures) Act, 1986, and associated guidelines.

Conflict of interest

The authors declare no competing interests.

Additional information

Publisher's Note

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

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary file1 (DOCX 503 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Gurumukhi, V.C., Bari, S.B. Quality by design (QbD)–based fabrication of atazanavir-loaded nanostructured lipid carriers for lymph targeting: bioavailability enhancement using chylomicron flow block model and toxicity studies. Drug Deliv. and Transl. Res. 12, 1230–1252 (2022). https://doi.org/10.1007/s13346-021-01014-4

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s13346-021-01014-4

Keywords

Navigation