Development and preclinical evaluation of quiniodochlor-loaded nanostructured lipid carrier-chitosan gel for topical antifungal therapy
Source abstract
Abstract
BACKGROUND: The rising incidence of superficial fungal infections and the limitations of conventional topical therapies necessitate the development of advanced, targeted delivery systems. OBJECTIVE: This study aimed to develop and evaluate a novel quiniodochlor (QD)-loaded nanostructured lipid carrier (NLC) gel for enhanced topical antifungal therapy. METHODS: 80, and incorporated into a chitosan hydrogel. Formulations were characterized for particle size, polydispersity index (PDI), zeta potential, entrapment efficiency (EE%), drug release, and physicochemical stability. The developed gel was further evaluated for spreadability, extrudability, ex vivo skin permeation/retention, in vitro antifungal activity against Candida albicans, and in vivo skin irritation. RESULTS: The optimized NLCs exhibited nanoscale particle sizes (141.86-250.79) high EE% (> 98%), and low PDI (0.28-0.43). Despite a near-neutral zeta potential, colloidal stability was maintained, attributed to steric stabilization. The NLC gel showed a sustained drug release profile, significantly higher skin retention, and about 1.6-fold larger zone of inhibition against C. albicans compared to a marketed QD cream. Ex vivo studies confirmed enhanced dermal accumulation with negligible transdermal permeation. The formulation demonstrated excellent spreadability and extrudability, and elicited no signs of erythema or edema in an in vivo skin irritation model. CONCLUSION: The developed QD-NLC-chitosan gel presents a promising, safe, and effective topical strategy with enhanced skin targeting, sustained local release, and superior antifungal activity, demonstrating strong potential as an advanced therapeutic alternative for superficial mycoses.
Source: openalex_inverted_index · Quality: baseline
Research context
OpenAlex topics: Advancements in Transdermal Drug Delivery · Advanced Drug Delivery Systems · Essential Oils and Antimicrobial Activity
SciVX discovery tags are terminology-based. OpenAlex topics are source-provided classifications.
References (75)
Show source-provided references
1. Pradhan M, et al. Lipid nanocarriers for topical and transdermal delivery of antifungal agents: current status and future perspectives. J Drug Deliv Sci Technol. 2021;66:102911.10.1016/j.jddst.2021.102911 ↗
2. Souto EB, et al. Clotrimazole-loaded nanostructured lipid carrier hydrogels for topical treatment of candidiasis. Pharmaceutics. 2020;12(2):142.10.3390/pharmaceutics12020142 ↗
3. Berlitz SJ, et al. Clioquinol-loaded nanoemulsion for topical treatment of dermatophytosis: design, characterization, and in vitro activity. Eur J Pharm Sci. 2019;127:330–8.10.1016/j.ejps.2018.11.012 ↗
4. Tateishi J. Subacute myelo-optic neuropathy (SMON) in Japan. With special reference to the autopsy cases. Pathol Int. 2000;50(11):913–7.
5. Yassin MS, et al. Clioquinol: from a systemic neurotoxin to a potential topical therapeutic. CNS Neurol Disorders - Drug Targets. 2019;18(3):191–6.
6. Gupta M, et al. Dermal and transdermal delivery: current landscape and future trends. Curr Drug Deliv. 2021;18(7):839–57.
7. Jain S, et al. Topical delivery of antifungal drugs using lipid-based nanosystems: a review on recent advances and clinical perspectives. J Liposome Res. 2022;32(3):199–215. Highlights topical targeting with lipid nanosystems.
8. Garg A, Sharma GS. Chitosan: a versatile biopolymer for pharmaceutical and biomedical applications. Curr Drug Targets. 2020;21(10):963–78.
9. Khan S, et al. Chitosan-based hydrogels for topical drug delivery: recent innovations and applications. Gels. 2021;7(4):224. (Recent review on chitosan hydrogels for topical use).10.3390/gels7040224 ↗
10. Üner M, Yener G. Importance of solid lipid nanoparticles (SLN) and nanostructured lipid carriers (NLC) in controlled drug delivery systems. Turkish J Pharm Sci. 2019;16(2):241–8.
11. Vasconcelos NG, et al. Antibacterial mechanisms of cinnamon and its constituents: a review. Microb Pathog. 2018;120:198–203.10.1016/j.micpath.2018.04.036 ↗
12. Wang Y, et al. Antifungal activity of cinnamon essential oil and its main components against Candida species: mechanisms and synergism. Front Microbiol. 2020;11:576325.
13. Sacco P, et al. Chitosan-based biomaterials for tissue repair and regeneration: advances and challenges. Mar Drugs. 2021;19(8):420.10.3390/md19080420 ↗
14. Sahariah P, Másson M. Antimicrobial chitosan and chitosan derivatives: a review of the structure–activity relationship. Biomacromolecules. 2017;18(11):3846–68.10.1021/acs.biomac.7b01058 ↗
15. Ahmed TA, Aljaeid BM. Preparation, characterization, and potential application of chitosan, chitosan derivatives, and chitosan metal nanoparticles in pharmaceutical drug delivery. Drug Des Devel Ther. 2016;10:483–507.10.2147/DDDT.S99651 ↗
16. Montenegro L, et al. Nanostructured lipid carriers as a tool for improving topical delivery of natural anti-inflammatory compounds. Pharmaceutics. 2022;14(2):319.10.3390/pharmaceutics14020319 ↗
17. Danaei M, et al. Impact of particle size and polydispersity index on the clinical applications of lipidic nanocarrier systems. Pharmaceutics. 2018;10(2):57.10.3390/pharmaceutics10020057 ↗
18. Karami Z, et al. Synergistic effect of chitosan and lipid nanoparticles on enhanced skin delivery of a lipophilic antioxidant. Int J Biol Macromol. 2021;183:1119–29.10.1016/j.ijbiomac.2021.05.054 ↗
19. Singh Y, et al. Next-generation topical antifungal agents: novel formulations and combination strategies to overcome resistance. Expert Opin Drug Deliv. 2022;19(7):825–40.
20. Kumari S, Kumar Annamareddy SH, Abanti S, Kumar Rath P. Physicochemical properties and characterization of chitosan synthesized from fish scales, crab and shrimp shells. Int J Biol Macromol. 2017;104(Pt B):1697–705. https://doi.org/10.1016/j.ijbiomac.2017.04.119.10.1016/j.ijbiomac.2017.04.119 ↗
21. Müller RH, Shegokar R, Keck CM. 20 years of lipid nanoparticles (SLN & NLC): present state of development & industrial applications. Curr Drug Discov Technol. 2011;8(3):207–27.10.2174/157016311796799062 ↗
22. Khosa A, Reddi S, Saha RN. Nanostructured lipid carriers for site-specific drug delivery. Biomed Pharmacother. 2018;103:598–613.10.1016/j.biopha.2018.04.055 ↗
23. Naseri N, Valizadeh H, Zakeri-Milani P. Solid lipid nanoparticles and nanostructured lipid carriers: structure, preparation and application. Adv Pharm Bull. 2015;5(3):305–13.10.15171/apb.2015.043 ↗
24. Gomaa E, Fathi HA, Eissa NG, Elsabahy M. Methods for preparation of nanostructured lipid carriers. Methods. 2022;199:3–8. https://doi.org/10.1016/j.ymeth.2021.05.003.10.1016/j.ymeth.2021.05.003 ↗
25. Fonte P, Soares S, Costa A, Andrade JC, Seabra V, Reis S, Sarmento B. Effect of cryoprotectants on the porosity and stability of insulin-loaded PLGA nanoparticles after freeze-drying. Biomatter. 2012;2(4):329–39. https://doi.org/10.4161/biom.23246.10.4161/biom.23246 ↗
26. Danaei M, Dehghankhold M, Ataei S, Hasanzadeh Davarani F, Javanmard R, Dokhani A, Khorasani S, Mozafari MR. Impact of Particle Size and Polydispersity Index on the Clinical Applications of Lipidic Nanocarrier Systems. Pharmaceutics. 2018;10(2):57. https://doi.org/10.3390/pharmaceutics10020057.10.3390/pharmaceutics10020057 ↗
27. Indian Pharmacopoeia. 9th ed. Vol III. Ghaziabad: Indian Pharmacopoeia Commission; 2022. pp. 3428–31.
28. Fernández-Torres B, Vásquez-Veiga H, Llovo X, Peiro M Jr, Guarro J. vitro susceptibility to itraconazole, clotrimazole, ketoconazole and terbinafine of 100 isolates of Trichophyton rubrum. Chemotherapy. 2000;46:390–4.10.1159/000007319 ↗
29. Shinde U, Pokharkar S, Modani S. Design and evaluation of microemulsion gel system of nadifloxacin. Indian J Pharm Sci. 2012;74(3):237–47. https://doi.org/10.4103/0250-474X.106066.10.4103/0250-474X.106066 ↗
30. Nicoli S, Penna E, Padula C, Colombo P, Santi P. New insights into the mode of action of ultradeformable vesicles using calcein as hydrophilic fluorescent marker. Eur J Pharm Sci. 2006;29(3–4):181–9. https://doi.org/10.1016/j.ejps.2006.05.013.10.1016/j.ejps.2006.05.013 ↗
31. Abdelbary G, Fahmy RH. Diazepam-loaded solid lipid nanoparticles: design and characterization. AAPS PharmSciTech. 2009;10(1):211–9. https://doi.org/10.1208/s12249-009-9197-2.10.1208/s12249-009-9197-2 ↗
32. Senyigit ZA, Karavana SY, Ilem-Özdemir D, Çalışkan Ç, Waldner C, Şen S, Bernkop-Schnürch A. Design and evaluation of an intravesical delivery system for superficial bladder cancer: preparation of gemcitabine HCl-loaded chitosan–thioglycolic acid nanoparticles and comparison of chitosan/poloxamer gels as carriers. Int J Nanomed. 2015;10:6493–507. . https://doi.org/10.2147/IJN.S9375010.2147/IJN.S93750 ↗
33. Garg AK, Maddiboyina B, Alqarni MHS, et al. Solubility enhancement, formulation development and antifungal activity of luliconazole niosomal gel-based system. J Biomater Sci Polym Ed. 2021;32(8):1009–23. https://doi.org/10.1080/09205063.2021.1892471.10.1080/09205063.2021.1892471 ↗
34. Shivhare UD, Jain KB, Mathur VB, Bhusari KP, Roy A. A formulation development and evaluation of diclofenac sodium gel using water soluble polyacrylamide polymer. Digest J Nanomaterials Biostructures Vol. 2009;4(2):285–90.
35. Panigrahi L, Ghosal SK, Pattnaik S, Maharana L, Barik BB. Effect of permeation enhancers on the release and permeation kinetics of lincomycin hydrochloride gel formulations through mouse skin. Indian J Pharm Sci. 2005;67(6):705–10.
36. Kalaria DR, Patel P, Patravale V, Kalia YN. Comparison of the cutaneous iontophoretic delivery of rasagiline and selegiline across porcine and human skin in vitro. Int J Pharm. 2012;438(1–2):202–8. https://doi.org/10.1016/j.ijpharm.2012.08.043.10.1016/j.ijpharm.2012.08.043 ↗
37. Kalaria DR, et al. Comparison of the cutaneous iontophoretic delivery…(Exemplifies the standard application of the tape-stripping technique for quantitative skin retention studies). 2012.
38. Jacobi U, Kaiser M, Toll R, Mangelsdorf S, Audring H, Otberg N, Lademann J. Porcine ear skin: an in vitro model for human skin. Skin Res Technol. 2007;13(1):19–24. . https://doi.org/10.1111/j.1600-0846.2006.00179.x10.1111/j.1600-0846.2006.00179.x ↗
39. Clinical and Laboratory Standards Institute. Reference method for broth dilution antifungal susceptibility testing of filamentous fungi. 2nd ed. CLSI document M38-A2. Wayne, PA: CLSI; 2008.
40. Durand ML. Bacterial and fungal endophthalmitis. Clin Microbiol Rev. 2017;30:597–613.10.1128/CMR.00113-16 ↗
41. Clinical and Laboratory Standards Institute. Reference method for broth dilution antifungal susceptibility testing of yeasts. 3rd ed. CLSI document M27-A3. Wayne, PA: CLSI; 2008.
42. Alley MC, Scudiero DA, Monks A, et al. Feasibility of drug screening with panels of human tumor cell lines using a microculture tetrazolium assay. Cancer Res. 1988;48(3):589–601.
43. Mosmann T. Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. J Immunol Methods. 1983;65(1–2):55–63. https://doi.org/10.1016/0022-1759(83)90303-4.10.1016/0022-1759(83)90303-4 ↗
44. ISO 10993-5:2009. Biological evaluation of medical devices —Part 5: tests for in vitro cytotoxicity. International Organization for Standardization; 2009.
45. Freshney RI. Culture of animal cells: a manual of basic technique and specialized applications. 7th ed. Wiley-Blackwell; 2016.
46. Percie du Sert N, Hurst V, Ahluwalia A, Alam S, Avey MT, Baker M, Würbel H. The ARRIVE guidelines 2.0: updated guidelines for reporting animal research. PLoS Biol. 2020;18(7):e3000410. https://doi.org/10.1371/journal.pbio.300041010.1371/journal.pbio.3000410 ↗
47. National Research Council (US) Committee for the Update of the Guide for the Care and Use of Laboratory Animals. Guide for the care and use of laboratory animals. 8th ed. National Academies Press (US); 2011.
48. Spielmann H, Hoffmann S, Liebsch M, Botham P, Fentem JH, Eskes C, Zuang V. The ECVAM international validation study on in vitro tests for acute skin irritation: report on the validity of the EPISKIN and EpiDerm assays and on the Skin Integrity Function Test. ATLA Altern Lab Anim. 2007;35(6):559–601. . https://doi.org/10.1177/02611929070350061010.1177/026119290703500610 ↗
49. Gabrielsson J, Weiner D. Pharmacokinetic and pharmacodynamic data analysis: concepts and applications. 5th ed. Swedish Pharmaceutical; 2016.
50. Moldoveanu SC, David V. Liquid–liquid extraction. In: Modern sample preparation for chromatography. 2nd ed. Elsevier; 2022. pp. 177–211. https://doi.org/10.1016/B978-0-12-821405-3.00004-710.1016/B978-0-12-821405-3.00004-7 ↗
51. Bojko B, Reyes-Garcés N, Bessonneau V, Goryński K, Mousavi F, Pawliszyn J. Solid-phase microextraction in metabolomics. TRAC Trends Anal Chem. 2020;131:115988. . https://doi.org/10.1016/j.trac.2020.11598810.1016/j.trac.2020.115988 ↗
52. Christie WW, Han X. Lipid Analysis: Isolation, Separation, Identification and Lipidomic Analysis. 4th ed. Oily; 2020.
53. Zidenga T, Hasegawa PM. Cyanogen Metabolism in Cassava. Annual Plant Reviews Online. 2019;2(3):1–21. https://doi.org/10.1002/9781119312994.apr0690.10.1002/9781119312994.apr0690 ↗
54. Danaei M, Dehghankhold M, Ataei S, Hasanzadeh Davarani F, Javanmard R, Dokhani A, Mozafari MR. Impact of particle size and polydispersity index on the clinical applications of lipidic nanocarrier systems. Pharmaceutics. 2018;10(2):57.10.3390/pharmaceutics10020057 ↗
55. Desai P, Patlolla RR, Singh M. Interaction of nanoparticles and cell-penetrating peptides with skin for transdermal drug delivery. Mol Membr Biol. 2010;27(7):247–59.10.3109/09687688.2010.522203 ↗
56. Fang CL, Al-Suwayeh SA, Fang JY. Nanostructured lipid carriers (NLCs) for drug delivery and targeting. Recent Pat Nanotechnol. 2013;7(1):41–55.10.2174/187221013804484827 ↗
57. Honary S, Zahir F. Effect of zeta potential on the properties of nano-drug delivery systems - a review (Part 2). Trop J Pharm Res. 2013;12(2):265–73.
58. Hady AE, Mohamed WE, Soliman EA, El-Sabbagh OAE. vitro–in vivo evaluation of chitosan–PLGA nanoparticles for potentiated gastric retention and anti-ulcer activity of diosmin. Int J Nanomed. 2019;14:7191–213. https://doi.org/10.2147/IJN.S213836.10.2147/IJN.S213836 ↗
59. Shinde U, Pokharkar S, Modani S. Design and evaluation of microemulsion gel system of nadifloxacin. Indian J Pharm Sci. 2012;74(3):237–47.10.4103/0250-474X.106066 ↗
60. Mishra V, Bansal KK, Verma A, Yadav N, Thakur S, Sudhakar K, Rosenholm JM. Solid lipid nanoparticles: emerging colloidal nano drug delivery systems. Pharmaceutics. 2018;10(4):191.10.3390/pharmaceutics10040191 ↗
61. Ganesan P, Narayanasamy D. Lipid nanoparticles: different preparation techniques, characterization, hurdles, and strategies for the production of solid lipid nanoparticles and nanostructured lipid carriers for oral drug delivery. Sustainable Chem Pharm. 2017;6:37–56.10.1016/j.scp.2017.07.002 ↗
62. Dash S, Murthy PN, Nath L, Chowdhury P. Kinetic modeling on drug release from controlled drug delivery systems. Acta Pol Pharm. 2010;67(3):217–23.
63. Souto EB, Müller RH. Lipid nanoparticles (SLN and NLC) for drug delivery. Nanoparticulate Drug Delivery Systems. CRC; 2008. pp. 103–22.
64. Siepmann J, Peppas NA. Modeling of drug release from delivery systems based on hydroxypropyl methylcellulose (HPMC). Adv Drug Deliv Rev. 2012;64:163–74.10.1016/j.addr.2012.09.028 ↗
65. Pardeshi CV, Belgamwar VS, Surana SJ. Novel colloidal carriers for topical drug delivery. Nanoparticulate Drug Delivery Systems. CRC; 2019. pp. 123–50.
66. Ahad A, Al-Saleh AA, Al-Mohizea AM, Al-Jenoobi FI, Raish M, Yassin AEB, Alam MA. Formulation and characterization of novel soft nanovesicles for enhanced transdermal delivery of eprosartan mesylate. Saudi Pharm J. 2017;25(7):1040–6.10.1016/j.jsps.2017.01.006 ↗
67. Coates J. Interpretation of infrared spectra, a practical approach. Encyclopedia of Analytical Chemistry. Wiley; 2006. pp. 1–23.
68. Movasaghi Z, Rehman S, Rehman IU. Fourier transform infrared (FTIR) spectroscopy of biological tissues. Appl Spectrosc Rev. 2008;43(2):134–79.10.1080/05704920701829043 ↗
69. Fini A, Cavallari C, Ospitali F, Gonzalez-Rodriguez ML. The use of FTIR spectroscopy in the study of the interactions between drugs and polymeric excipients. J Pharm Biomed Anal. 2010;53(3):695–702.
70. Bhattacharjee S. DLS and zeta potential – What they are and what they are not? J Controlled Release. 2016;235:337–51. https://doi.org/10.1016/j.jconrel.2016.06.017.10.1016/j.jconrel.2016.06.017 ↗
71. Mourdikoudis S, Pallares RM, Thanh NTK. Characterization techniques for nanoparticles: comparison and complementarity upon studying nanoparticle properties. Nanoscale. 2018;10(27):12871–934. https://doi.org/10.1039/C8NR02278J.10.1039/C8NR02278J ↗
72. Filipe V, Hawe A, Jiskoot W. Critical evaluation of nanoparticle tracking analysis (NTA) by NanoSight for the measurement of nanoparticles and protein aggregates. Pharm Res. 2010;27(5):796–810. https://doi.org/10.1007/s11095-010-0073-2.10.1007/s11095-010-0073-2 ↗
73. Schreiber SL, Kotz JD. Chemical genetics: where chemistry and biology meet. Nature. 2013;499(7458):276–7.
74. Hussain A, Samad A, Singh SK, et al. Nanoemulsion gel-based topical delivery of an antifungal drug: in vitro activity and in vivo evaluation. Drug Deliv. 2016;23(2):642–57.10.3109/10717544.2014.933284 ↗
75. Naskar S, Sharma S, Kuotsu K. A smart gelatin nanoparticle for delivery of metoprolol succinate: a strategy for enhancing the therapeutic efficacy by improving bioavailability. J Drug Deliv Sci Technol. 2019;53:101214. https://doi.org/10.1016/j.jddst.2019.101214.10.1016/j.jddst.2019.101214 ↗