Skip to main content

Advertisement

SpringerLink
Log in

Dermatokinetic assessment of luliconazole-loaded nanostructured lipid carriers (NLCs) for topical delivery: QbD-driven design, optimization, and in vitro and ex vivo evaluations

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

Abstract

The present study is concerned with the QbD-based design and development of luliconazole-loaded nanostructured lipid carriers (NLCs) hydrogel for enhanced skin retention and permeation. The NLCs formulation was optimized employing a 3-factor, 3-level Box-Behnken design. The effect of formulation variable lipid content, surfactant concentration, and sonication time was studied on particle size and % EE. The optimized formulation exhibited particle size of 86.480 ± 0.799 nm; 0.213 ± 0.004 PDI, ≥ − 10 mV zeta potential and 85.770 ± 0.503% EE. The in vitro release studies revealed sustained release of NLCs up to 42 h. The designed formulation showed desirable occlusivity, spreadability (0.748 ± 0.160), extrudability (3.130 ± 1.570), and the assay was found to be 99.520 ± 0.890%. The dermatokinetics assessment revealed the Cmax Skin to be ~ 2-fold higher and AUC0–24 to be ~ 3-fold higher in the epidermis and dermis of NLCs loaded gel in contrast with the marketed cream. The Tmax of both the formulations was found to be 6 h in the epidermis and dermis. The obtained results suggested that luliconazole NLCs can serve as a promising formulation to enhance luliconazole’s antifungal activity and also in increasing patient compliance by reducing the frequency of application.

Graphical abstract

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

Access this article

Log in via an institution

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

Similar content being viewed by others

Availability of data and materials

The authors declare that data supporting the findings of this study are available within the article and its supplementary data files.

Abbreviations

NLCs:

Nanostructured lipid carriers

QTPP:

Quality target product profile

CQA:

Critical quality attributes

CMA:

Critical material attributes

CPP:

Critical process parameters

BBD:

Box Behnken design

ATR:

Attenuated total reflectance

EE:

Entrapment efficiency

PDI:

Polydispersibility Index

TWEL:

Transepidermal water loss

QbD:

Quality by design

References

  1. Teodorescu F, Quéniat G, Foulon C, Lecoeur M, Barras A, Boulahneche S, et al. Transdermal skin patch based on reduced graphene oxide: a new approach for photothermal triggered permeation of ondansetron across porcine skin. J Control Release. 2017;245:137–46.

    Article  CAS  Google Scholar 

  2. Ajello L. A taxonomic review of the dermatophytes and related species. Med Mycol [Internet]. 1968 [cited 2020 Feb 2];6:147–59. Available from: https://academic.oup.com/mmy/article-lookup/doi/https://doi.org/10.1080/00362176885190271.

  3. Kapileshwari GR, Barve AR, Kumar L, Bhide PJ, Joshi M, Shirodkar RK. Novel drug delivery system of luliconazole - formulation and characterisation. J Drug Deliv Sci Technol. Elsevier; 2020;55:101302.

  4. Mishra AK, Kumar A, Singh H, Verma S, Sahu JK, Mishra A. Chemistry and pharmacology of luliconazole (imidazole derivative): a novel bioactive compound to treat fungal infection-a mini review. Curr Bioact Compd. Bentham Science Publishers Ltd.; 2018;15:602–9.

  5. Girdhar V, Patil S, Banerjee S, Singhvi G. Nanocarriers for drug delivery: mini review. Curr Nanomedicine [Internet]. 2018 [cited 2019 Jan 7];8:88–99. Available from: http://www.eurekaselect.com/161719/article.

  6. Jain S, Krishna Cherukupalli S, Mahmood A, Gorantla S, Krishna Rapalli V, Kumar Dubey S, et al. Emerging nanoparticulate systems: preparation techniques and stimuli responsive release characteristics. J Appl Pharm Sci [Internet]. 2019 [cited 2019 Sep 4];9:130–43. Available from: http://www.japsonline.com.

  7. Kansagra H, Mallick S. Microemulsion-based antifungal gel of luliconazole for dermatophyte infections: formulation, characterization and efficacy studies. J Pharm Investig. Springer Netherlands; 2016;46:21–8.

  8. Kumar M, Shanthi N, Mahato AK, Soni S, Rajnikanth PS. Preparation of luliconazole nanocrystals loaded hydrogel for improvement of dissolution and antifungal activity. Heliyon. 2019;5:e01688.

    Article  Google Scholar 

  9. Garcia ML, Souto EB, Doktorovová S, Kovac AB. European Journal of Pharmaceutics and Biopharmaceutics Preclinical safety of solid lipid nanoparticles and nanostructured lipid carriers : current evidence from in vitro and in vivo evaluation ˇ evic. 2016;108:235–52.

    Google Scholar 

  10. Müller RH, Radtke M, Wissing SA. Solid lipid nanoparticles (SLN) and nanostructured lipid carriers (NLC) in cosmetic and dermatological preparations. Adv Drug Deliv Rev. 2002;54(Suppl 1):S131–55.

    Article  Google Scholar 

  11. Kumar S, Randhawa JK. High melting lipid based approach for drug delivery: solid lipid nanoparticles. Mater Sci Eng C [Internet]. Elsevier; 2013 [cited 2019 Mar 31];33:1842–52. Available from: https://www.sciencedirect.com/science/article/pii/S0928493113000507.

  12. Mahmood A, Rapalli VK, Waghule T, Gorantla S, Dubey SK, Saha RN, et al. UV spectrophotometric method for simultaneous estimation of betamethasone valerate and tazarotene with absorption factor method: Application for in-vitro and ex-vivo characterization of lipidic nanocarriers for topical delivery. Spectrochim Acta - Part A Mol Biomol Spectrosc. Elsevier B.V.; 2020;235:118310.

  13. Rapalli VK, Singhvi G, Dubey SK, Gupta G, Chellappan DK, Dua K. Emerging landscape in psoriasis management: from topical application to targeting biomolecules. Biomed Pharmacother [Internet]. 2018 [cited 2019 Mar 19];106:707–13. Available from: http://www.ncbi.nlm.nih.gov/pubmed/29990862.

  14. Singhvi G, Manchanda P, Krishna Rapalli V, Kumar Dubey S, Gupta G, Dua K. MicroRNAs as biological regulators in skin disorders. Biomed Pharmacother [Internet]. Elsevier Masson; 2018 [cited 2019 Mar 31];108:996–1004. Available from: https://www.sciencedirect.com/science/article/pii/S0753332218341040.

  15. Mundstock A, Lee G. Saturation solubility of nicotine, scopolamine and paracetamol in model stratum corneum lipid matrices. Int J Pharm Elsevier. 2014;473:232–8.

    Article  CAS  Google Scholar 

  16. Singhvi G, Dubey SK, Patil S, Girdhar V. Nanocarriers for topical drug delivery: approaches and advancements. Nanosci &Nanotechnology-Asia [Internet]. 2018 [cited 2018 Nov 16];8. Available from: http://www.eurekaselect.com/160578/article.

  17. Rapalli VK, Waghule T, Hans N, Mahmood A, Gorantla S, Dubey SK, et al. Insights of lyotropic liquid crystals in topical drug delivery for targeting various skin disorders. J Mol Liq Elsevier B.V.; 2020. p. 113771.

  18. Garcês A, Amaral MH, Sousa Lobo JM, Silva AC. Formulations based on solid lipid nanoparticles (SLN) and nanostructured lipid carriers (NLC) for cutaneous use: a review. Eur J Pharm Sci. 2018;112:159–67.

    Article  Google Scholar 

  19. Singhvi G, Banerjee S, Khosa A. Lyotropic liquid crystal nanoparticles: a novel improved lipidic drug delivery system. Org Mater as Smart Nanocarriers Drug Deliv [Internet]. William Andrew Publishing; 2018 [cited 2018 Aug 6];471–517. Available from: https://www.sciencedirect.com/science/article/pii/B9780128136638000117.

  20. Thotakura N, Kumar P, Wadhwa S, Raza K, Katare P. Dermatokinetics as an important tool to assess the bioavailability of drugs by topical nanocarriers. Curr Drug Metab. Bentham Science Publishers Ltd.; 2017;18:404–11.

  21. Rapalli VK, Khosa A, Singhvi G, Girdhar V, Jain R, Dubey SK. Application of QbD principles in nanocarrier-based drug delivery systems. Pharm Qual by Des [Internet]. Academic Press; 2019 [cited 2019 Aug 19];255–96. Available from: https://www.sciencedirect.com/science/article/pii/B9780128157992000149.

  22. Rapalli VK, Sharma S, Roy A, Alexander A, Singhvi G. Solid lipid nanocarriers embedded hydrogel for topical delivery of apremilast: in-vitro, ex-vivo, dermatopharmacokinetic and anti-psoriatic evaluation. J Drug Deliv Sci Technol [Internet]. Elsevier; 2021 [cited 2021 Mar 3];63:102442. Available from: https://linkinghub.elsevier.com/retrieve/pii/S1773224721001222.

  23. Ameeduzzafar, Qumber M, Alruwaili NK, Bukhari SNA, Alharbi KS, Imam SS, et al. BBD-based development of itraconazole loaded nanostructured lipid carrier for topical delivery: in vitro evaluation and antimicrobial assessment. J Pharm Innov. 2020.

  24. 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; 2017 [cited 2018 Jul 26];517:413–31. Available from: https://www.sciencedirect.com/science/article/pii/S0378517316311437.

  25. Waghule T, Rapalli VK, Singhvi G, Manchanda P, Hans N, Dubey SK, et al. Voriconazole loaded nanostructured lipid carriers based topical delivery system: QbD based designing, characterization, in-vitro and ex-vivo evaluation. J Drug Deliv Sci Technol. Editions de Sante; 2019;52:303–15.

  26. Chauhan MK, Sharma PK. Optimization and characterization of rivastigmine nanolipid carrier loaded transdermal patches for the treatment of dementia. Chem Phys Lipids. Elsevier Ireland Ltd; 2019;224.

  27. Cecília V, Nunes K, Augusto R, Deuschle N, Rocha M, Athayde ML. antioxidant , and photo-protective capacities of topical formulations containing Calendula officinalis L . leaf extract. 2015;51.

  28. Wavikar PR, Vavia PR. Rivastigmine-loaded in situ gelling nanostructured lipid carriers for nose to brain delivery. J Liposome Res. 2015;25:141–9.

    Article  CAS  Google Scholar 

  29. Wavikar P, Vavia P. Nanolipidgel for enhanced skin deposition and improved antifungal activity. AAPS PharmSciTech. 2013;14:222–33.

    Article  CAS  Google Scholar 

  30. Kakkar V, Kaur IP, Kaur AP, Saini K, Singh KK. Topical delivery of tetrahydrocurcumin lipid nanoparticles effectively inhibits skin inflammation: in vitro and in vivo study. Drug Dev Ind Pharm. Taylor & Francis; 2018;44:1701–12.

  31. Teeranachaideekul V, Chantaburanan T, Junyaprasert VB. Influence of state and crystallinity of lipid matrix on physicochemical properties and permeation of capsaicin-loaded lipid nanoparticles for topical delivery. J Drug Deliv Sci Technol [Internet]. Elsevier; 2017 [cited 2019 Sep 25];39:300–7. Available from: https://www.sciencedirect.com/science/article/pii/S1773224717300898?via%3Dihub.

  32. Han F, Yin R, Che X, Yuan J, Cui Y, Yin H, et al. Nanostructured lipid carriers (NLC) based topical gel of flurbiprofen: design, characterization and in vivo evaluation. Int J Pharm. 2012;439:349–57.

    Article  CAS  Google Scholar 

  33. Rapalli VK, Kaul V, Gorantla S, Waghule T, Dubey SK, Pandey MM, et al. UV Spectrophotometric method for characterization of curcumin loaded nanostructured lipid nanocarriers in simulated conditions: method development, in-vitro and ex-vivo applications in topical delivery. Spectrochim Acta Part A Mol Biomol Spectrosc [Internet]. Elsevier; 2020 [cited 2019 Aug 21];224:117392. Available from: https://www.sciencedirect.com/science/article/pii/S1386142519307826.

  34. Rapalli VK, Singhvi G, Gorantla S, Waghule T, Dubey SK, Saha RN, et al. Stability indicating liquid chromatographic method for simultaneous quantification of betamethasone valerate and tazarotene in in vitro and ex vivo studies of complex nanoformulation. J Sep Sci Wiley-VCH Verlag. 2019;42:3413–20.

    Article  CAS  Google Scholar 

  35. Raza K, Singh B, Singla S, Wadhwa S, Garg B, Chhibber S, et al. Nanocolloidal carriers of isotretinoin: antimicrobial activity against Propionibacterium acnes and dermatokinetic modeling. Mol Pharm. 2013;10:1958–63.

    Article  CAS  Google Scholar 

  36. Vitorino C, Almeida J, Gonçalves LM, Almeida AJ, Sousa JJ, Pais AACC. Co-encapsulating nanostructured lipid carriers for transdermal application: from experimental design to the molecular detail. J Control Release. 2013;167:301–14.

    Article  CAS  Google Scholar 

  37. Shimojo AAM, Fernandes ARV, Ferreira NRE, Sanchez-Lopez E, Santana MHA, Souto EB. Evaluation of the influence of process parameters on the properties of resveratrol-loaded NLC using 22 full factorial design. Antioxidants. 2019;8:272.

    Article  CAS  Google Scholar 

  38. Jannin V, Bioscience L. The application of Gattefossé products : a 2005–2006 literature review. 2017.

  39. Kamble RN, Mehta PP, Kumar A. Efavirenz self-nano-emulsifying drug delivery system: in vitro and in vivo evaluation. AAPS PharmSciTech. Springer New York LLC; 2016;17:1240–7.

  40. de Souza IDL, Saez V, de Campos VEB, Mansur CRE. Size and vitamin E release of nanostructured lipid carriers with different liquid lipids. Surfactants and Preparation Methods Macromol Symp. 2019;383:1800011.

    Article  Google Scholar 

  41. Shah KA, Date AA, Joshi MD, Patravale VB. Solid lipid nanoparticles (SLN) of tretinoin: potential in topical delivery. Int J Pharm Elsevier. 2007;345:163–71.

    Article  CAS  Google Scholar 

  42. Mandpe L, Pokharkar V. Quality by design approach to understand the process of optimization of iloperidone nanostructured lipid carriers for oral bioavailability enhancement. 2013;7450:1–10.

    Google Scholar 

  43. Dora CP, Singh SK, Kumar S, Datusalia AK, Deep A. Development and characterization of nanoparticles of glibenclamide by solvent displacement method. Acta Pol Pharm - Drug Res. 2010;67:283–90.

    CAS  Google Scholar 

  44. Rangaraj N, Pailla SR, Chowta P, Sampathi S. Fabrication of ibrutinib nanosuspension by quality by design approach: intended for enhanced oral bioavailability and diminished fast fed variability. AAPS PharmSciTech. Springer: New York LLC; 2019. p. 20.

    Google Scholar 

  45. El-housiny S, Atef M, Eldeen S, El-attar YA, Salem A, Attia D, et al. Fluconazole-loaded solid lipid nanoparticles topical gel for treatment of pityriasis versicolor : formulation and clinical study. Drug Deliv. Informa Healthcare USA, Inc; 2018;25:78–90.

  46. Bunjes H. Structural properties of solid lipid based colloidal drug delivery systems. Curr Opin Colloid Interface Sci 2011. p. 405–11.

  47. 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. 2013;111:755–63.

    Article  CAS  Google Scholar 

  48. Fang JY, Fang CL, Liu CH, Su YH. Lipid nanoparticles as vehicles for topical psoralen delivery: solid lipid nanoparticles (SLN) versus nanostructured lipid carriers (NLC). Eur J Pharm Biopharm. 2008;70:633–40.

    Article  CAS  Google Scholar 

  49. Freitas C, Müller RH. Correlation between long-term stability of solid lipid nanoparticles (SLN(TM)) and crystallinity of the lipid phase. Eur J Pharm Biopharm [Internet]. Eur J Pharm Biopharm; 1999 [cited 2021 Mar 24];47:125–32. Available from: https://pubmed.ncbi.nlm.nih.gov/10234536/.

  50. Becker K, Salar-Behzadi S, Zimmer A. Solvent-free melting techniques for the preparation of lipid-based solid oral formulations [Internet]. Pharm Res Springer New York LLC; 2015 [cited 2021 Mar 24]. p. 1519–45. Available from: /pmc/articles/PMC4381087/

  51. Ying LQ, Misran M. Rheological and physicochemical characterization of alpha-tocopherol loaded lipid nanoparticles in thermoresponsive gel for topical application. Malaysian J Fundam Appl Sci. 2017;13:248–52.

    Google Scholar 

  52. Na YG, Huh HW, Kim MK, Byeon JJ, Han MG, Lee HK, et al. Development and evaluation of a film-forming system hybridized with econazole-loaded nanostructured lipid carriers for enhanced antifungal activity against dermatophytes. Acta Biomater: Acta Materialia Inc; 2019.

    Google Scholar 

  53. Desai P, Patlolla RR, Singh M. Interaction of nanoparticles and cell-penetrating peptides with skin for transdermal drug delivery. Mol Membr Biol Taylor & Francis. 2010;27:247–59.

    Article  CAS  Google Scholar 

  54. Uchida K, Nishiyama Y, Yamaguchi H. In vitro antifungal activity of luliconazole (NND-502), a novel imidazole antifungal agent. J Infect Chemother Springer Japan. 2004;10:216–9.

    Article  CAS  Google Scholar 

  55. Maeda J, Nanjoh Y, Koga H, Toga T, Makimura K, Tsuboi R. In vitro antifungal activity of luliconazole against Trichophyton spp: comparative study using a combination test method to determine the MIC and MFC of topical antifungal drugs. Japanese J Med Mycol [Internet]. Japanese Society for Medical Mycology; 2016 [cited 2021 Mar 24];57:J1–6. Available from: https://pubmed.ncbi.nlm.nih.gov/26936346/.

  56. Waghule T, Sankar S, Rapalli VK, Gorantla S, Dubey SK, Chellappan DK, et al. Emerging role of nanocarriers based topical delivery of anti‐fungal agents in combating growing fungal infections. Dermatol Ther [Internet]. John Wiley & Sons, Ltd; 2020 [cited 2020 Jul 6];dth.13905. Available from: https://onlinelibrary.wiley.com/doi/abs/ https://doi.org/10.1111/dth.13905.

  57. Mahmood A, Rapalli VK, Waghule T, Gorantla S, Singhvi G. Luliconazole loaded lyotropic liquid crystalline nanoparticles for topical delivery: QbD driven optimization, in-vitro characterization and dermatokinetic assessment. Chem Phys Lipids [Internet]. Elsevier; 2021 [cited 2020 Dec 27];234:105028. Available from: https://linkinghub.elsevier.com/retrieve/pii/S0009308420301596.

  58. Waghule T, Rapalli VK, Gorantla S, Saha RN, Dubey SK, Puri A, et al. Nanostructured lipid carriers as potential drug delivery systems for skin disorders. Curr Pharm Des. Bentham Science Publishers Ltd.; 2020;26.

  59. Waghule T, Patil S, Rapalli VK, Girdhar V, Gorantla S, Kumar Dubey S, et al. Improved skin-permeated diclofenac-loaded lyotropic liquid crystal nanoparticles: QbD-driven industrial feasible process and assessment of skin deposition. Liq Cryst [Internet]. Taylor and Francis Ltd.; 2020 [cited 2020 Dec 25];0:1–19. Available from: https://www.tandfonline.com/doi/full/ https://doi.org/10.1080/02678292.2020.1836276.

  60. Rapalli VK, Waghule T, Gorantla S, Dubey SK, Saha RN, Singhvi G. Psoriasis: pathological mechanisms, current pharmacological therapies, and emerging drug delivery systems. Elsevier BV: Drug Discov Today; 2020.

    Google Scholar 

  61. Paredes AJ, McKenna PE, Ramöller IK, Naser YA, Volpe‐Zanutto F, Li M, et al. Microarray patches: poking a hole in the challenges faced when delivering poorly soluble drugs. Adv Funct Mater [Internet]. Wiley-VCH Verlag; 2021 [cited 2021 Mar 18];31:2005792. Available from: https://onlinelibrary.wiley.com/doi/ https://doi.org/10.1002/adfm.202005792.

  62. Permana AD, Paredes AJ, Volpe-Zanutto F, Anjani QK, Utomo E, Donnelly RF. Dissolving microneedle-mediated dermal delivery of itraconazole nanocrystals for improved treatment of cutaneous candidiasis. Eur J Pharm Biopharm. Elsevier B.V.; 2020;154:50–61.

  63. Kaur IP, Kakkar S. Topical delivery of antifungal agents. Expert Opin Drug Deliv 2010. p. 1303–27.

Download references

Acknowledgements

The authors are thankful to the BASF for providing Lutrol® F 127 and Kolliphor EL; IOI Oleo GmbH for providing Dynasan 114, Miglyol 812, and Miglyol 810; and Gattefosse for providing Precirol ATO 5, Compritol 888 ATO, Labrasol ALF, Labrafil M 2125 CS, Labrafil M 1944 CS, Labrafac CC, and Myristol and Gangwal Chemicals Pvt. Ltd. for providing luliconazole as gift samples for our research work.

Author information

Author notes

  1. Arisha Mahmood and Vamshi Krishna Rapalli contributed equally to this work.

Authors and Affiliations

  1. Industrial Research Laboratory, Department of Pharmacy, Birla Institute of Technology and Science, Pilani Campus, 333031, Pilani, India

    Arisha Mahmood, Vamshi Krishna Rapalli, Srividya Gorantla, Tejashree Waghule & Gautam Singhvi

Authors
  1. Arisha Mahmood
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Vamshi Krishna Rapalli
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Srividya Gorantla
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Tejashree Waghule
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Gautam Singhvi
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Arisha Mahmood: investigation, acquisition of data, analysis and interpretation, writing—original draft; Vamshi Krishna Rapalli: methodology, investigation, acquisition of data, analysis and interpretation, writing-original draft; Srividya Gorantla: validation, visualization, review; Tejashree Waghule: validation, visualization, review; Gautam Singhvi: resources, conceptualization, investigation, project administration; review and editing.

Corresponding author

Correspondence to Gautam Singhvi.

Ethics declarations

Ethical approval

All applicable institutional and/or national guidelines for the care and use of animals were followed.

Consent for publication

Authors have no issue to publish and data was not submited anywhere else.

Competing interests

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.

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file1 (DOCX 324 KB)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Mahmood, A., Rapalli, V.K., Gorantla, S. et al. Dermatokinetic assessment of luliconazole-loaded nanostructured lipid carriers (NLCs) for topical delivery: QbD-driven design, optimization, and in vitro and ex vivo evaluations. Drug Deliv. and Transl. Res. 12, 1118–1135 (2022). https://doi.org/10.1007/s13346-021-00986-7

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s13346-021-00986-7

Keywords

Search

Navigation