Formulation and Optimization of Solid Lipid Nanoparticle-based Gel for Dermal Delivery of Linezolid using Taguchi Design


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Abstract

Background:Linezolid (LNZ) is a synthetic oxazolidinone antibiotic approved for the treatment of uncomplicated and complicated skin and soft tissue infections caused by gram-positive bacteria. Typically, LNZ is administered orally or intravenously in most cases. However, prolonged therapy is associated with various side effects and lifethreatening complications. Cutaneous application of LNZ will assist in reducing the dose, hence minimizing the unwanted side/adverse effects associated with oral administration. Dermal delivery provides an alternative route of administration, facilitating a local and sustained concentration of the antimicrobial at the site of infection.

Objective:The current research work aimed to formulate solid lipid nanoparticles (SLNs) based gel for dermal delivery of LNZ in the management of uncomplicated skin and soft tissue infections to maximise its benefits and minimise the side effects.

Methods::SLNs were prepared by high-shear homogenisation and ultrasound method using Dynasan 114 as solid lipid and Pluronic F-68 as surfactant. The effect of surfactant concentration, drug-to-lipid ratio, and sonication time was investigated on particle size, zeta potential, and entrapment efficiency using the Taguchi design. The main effect plot of means and signal-to-noise ratio were generated to determine the optimized formulation. The optimized batch was formulated into a gel, and ex-vivo permeation study, in-vitro and in-vivo antibacterial activity were conducted.

Results:The optimised process parameters to achieve results were 2% surfactant concentration, a drug-to-lipid ratio of 1:2, and 360 s of sonication time. The optimized batch was 206.3± 0.17nm in size with a surface charge of -24.4± 4.67mV and entrapment efficiency of 80.90 ± 0.45%. SLN-based gel demonstrated anomalous transport with an 85.43% in vitro drug release. The gel showed a 5.03 ± 0.15 cm zone of inhibition while evaluated for in vitro antibacterial activity against Staphylococcus aureus. Ex-vivo skin permeation studies demonstrated 20.308% drug permeation and 54.96% cutaneous deposition. In-vivo results showed a significant reduction in colony-forming units in the group treated with LNZ SLN-based gel.

Conclusion:Ex-vivo studies ascertain the presence of the drug at the desired site and improve therapy. In-vivo results demonstrated the ability of SLN-based gel to significantly reduce the number of bacteria in the stripped infection model. The utilization of SLN as an LNZ carrier holds significant promise in dermal delivery.

About the authors

Iti Chauhan

Department of Pharmacy, Kharvel Subharti College of Pharmacy, Swami Vivekanand Subharti University

Author for correspondence.
Email: info@benthamscience.net

Lubhan Singh

Department, of Pharmacology, Kharvel Subharti College of Pharmacy, Swami Vivekanand Subharti University

Email: info@benthamscience.net

References

  1. Silverberg B. A structured approach to skin and soft tissue infections (SSTIs) in an ambulatory setting. Clin Pract 2021; 11(1): 65-74. doi: 10.3390/clinpract11010011 PMID: 33535501
  2. Lipsky BA, Silverman MH, Joseph WS. A proposed new classification of skin and soft tissue infections modeled on the subset of diabetic foot infection. Open Forum Infect Dis 2017; 4(1): ofw255. doi: 10.1093/ofid/ofw255 PMID: 28480249
  3. Outpatient management of skin and soft tissue infections in the era of community associated MRSA. 2007. Available from: https://hhs.iowa.gov/sites/default/files/portals/1/files/antibioticresistance/mrsa_outpatient_mgmt.pdf
  4. Grammatikos AP, Falagas ME. Linezolid for the treatment of skin and soft-tissue infections. Expert Rev Dermatol 2008; 3(5): 539-48. doi: 10.1586/17469872.3.5.539
  5. Peppard WJ, Weigelt JA. Role of linezolid in the treatment of complicated skin and soft tissue infections. Expert Rev Anti Infect Ther 2006; 4(3): 357-66. doi: 10.1586/14787210.4.3.357 PMID: 16771613
  6. Kishor K, Dhasmana N, Kamble S, Sahu R. Linezolid induced adverse drug reactions - An update. Curr Drug Metab 2015; 16(7): 553-9. doi: 10.2174/1389200216666151001121004 PMID: 26424176
  7. Linezolid and alcohol/food interactions. Available from: https://www.drugs.com/foodinteractions/linezolid.html (Accessed on: May 23, 2023).
  8. Souto EB, Baldim I, Oliveira WP, et al. SLN and NLC for topical, dermal, and transdermal drug delivery. Expert Opin Drug Deliv 2020; 17(3): 357-77. doi: 10.1080/17425247.2020.1727883 PMID: 32064958
  9. Kumar A, Sawant KK. Solid lipid nanoparticle-incorporated gel: The future treatment for skin infections? Nanomedicine 2013; 8(12): 1901-3. doi: 10.2217/nnm.13.171 PMID: 24279486
  10. Kakadia PG, Conway BR. Solid lipid nanoparticles: A potential approach for dermal drug delivery. Am J Pharmacol Sci 2014; 2(5A): 1-7. doi: 10.12691/ajps-2-5A-1
  11. Bandyopadhyay D. Topical antibacterials in dermatology. Indian J Dermatol 2021; 66(2): 117-25. doi: 10.4103/ijd.IJD_99_18 PMID: 34188265
  12. Neri I, del Giudice M, Novelli A, Ruggiero G, Pappagallo G, Galli L. Ideal features of topical antibiotic therapy for the treatment of impetigo: An Italian expert consensus report. Curr Ther Res Clin Exp 2023; 98: 100690. doi: 10.1016/j.curtheres.2022.100690 PMID: 36712177
  13. Sahu SK, Ram A. Evaluation of linezolid loaded ethosomes for treatment of deep skin infections in diabetic model. Res J Pharm Technol 2018; 11(7): 3023-30. doi: 10.5958/0974-360X.2018.00557.7
  14. Teaima MH, Elasaly MK, Omar SA, El-Nabarawi MA, Shoueir KR. Wound healing activities of polyurethane modified chitosan nanofibers loaded with different concentrations of linezolid in an experimental model of diabetes. J Drug Deliv Sci Technol 2022; 67: 102982. doi: 10.1016/j.jddst.2021.102982
  15. Tu EY, Jain S. Topical linezolid 0.2% for the treatment of vancomycin-resistant or vancomycin-intolerant gram-positive bacterial keratitis. Am J Ophthalmol 2013; 155(6): 1095-1098.e1. doi: 10.1016/j.ajo.2013.01.010 PMID: 23453280
  16. Chauhan I, Singh AP, Yasir M, Verma M, Majhi S, Singh L. Development and characterization of nano-structure lipid carrier-based glabridin cream for cosmetic use. Current Cosmetic Science 2022; 1(2): e090522204500. doi: 10.2174/2666779701666220509221341
  17. Yasir M, Sara UVS. Solid lipid nanoparticles for nose to brain delivery of haloperidol: in vitro drug release and pharmacokinetics evaluation. Acta Pharm Sin B 2014; 4(6): 454-63. doi: 10.1016/j.apsb.2014.10.005 PMID: 26579417
  18. Sakellari GI, Zafeiri I, Batchelor H, Spyropoulos F. Formulation design, production and characterisation of solid lipid nanoparticles (SLN) and nanostructured lipid carriers (NLC) for the encapsulation of a model hydrophobic active. Food Hydrocoll Health 2021; 1: 100024. doi: 10.1016/j.fhfh.2021.100024
  19. Nasr A, Gardouh A, Ghorab M. Novel solid self-nano emulsifying drug delivery system (S-SNEDDS) for oral delivery of Olmesartan Medoxomil: Design, formulation, pharmacokinetic and bioavailability evaluation. Pharmaceutics 2016; 8(3): 20. doi: 10.3390/pharmaceutics8030020 PMID: 27355963
  20. Aggarwal G, Harikumar SL, Jaiswal P, Singh K. Development of self-microemulsifying drug delivery system and solid-self-microemulsifying drug delivery system of telmisartan. Int J Pharm Investig 2014; 4(4): 195-206. doi: 10.4103/2230-973X.143123 PMID: 25426441
  21. Negi LM, Jaggi M, Talegaonkar S. A logical approach to optimize the nanostructured lipid carrier system of irinotecan: Efficient hybrid design methodology. Nanotechnology 2013; 24(1): 015104. doi: 10.1088/0957-4484/24/1/015104 PMID: 23221112
  22. Luan L, Chi Z, Liu C. Chinese white wax solid lipid nanoparticles as a novel nanocarrier of curcumin for inhibiting the formation of Staphylococcus aureus biofilms. Nanomaterials 2019; 9(5): 763. doi: 10.3390/nano9050763 PMID: 31109013
  23. Bhalekar M, Upadhaya P, Madgulkar A. Formulation and characterization of solid lipid nanoparticles for an anti-retroviral drug darunavir. Appl Nanosci 2017; 7(1-2): 47-57. doi: 10.1007/s13204-017-0547-1
  24. Kushwaha AK, Vuddanda PR, Karunanidhi P, Singh SK, Singh S. Development and evaluation of solid lipid nanoparticles of raloxifene hydrochloride for enhanced bioavailability. BioMed Res Int 2013; 2013: 1-9. doi: 10.1155/2013/584549 PMID: 24228255
  25. Joshi M, Patravale V. Nanostructured lipid carrier (NLC) based gel of celecoxib. Int J Pharm 2008; 346(1-2): 124-32. doi: 10.1016/j.ijpharm.2007.05.060 PMID: 17651933
  26. Rompicherla NC, Joshi P, Shetty A, et al. Design, formulation, and evaluation of aloe vera gel-based capsaicin transemulgel for osteoarthritis. Pharmaceutics 2022; 14(9): 1812. doi: 10.3390/pharmaceutics14091812 PMID: 36145560
  27. Verma M, Gautam M, Nanda A, et al. Development, optimization and evaluation of solid lipid nanoparticles of Celecoxib. Pharm Nanotechnol 2023; 11. doi: 10.2174/2211738511666230831143111 PMID: 37653638
  28. Mandal S, Saha K, Pal NK. In vitro antibacterial activity of three indian spices against methicillin-resistant staphylococcus aureus. Oman Med J 2011; 26(5): 319-23. doi: 10.5001/omj.2011.80 PMID: 22125725
  29. Badria F, Mazyed E. Formulation of nanospanlastics as a promising approach for ‎improving the topical delivery of a natural leukotriene inhibitor (3-‎Acetyl-11-Keto-β-Boswellic Acid): Statistical optimization, in vitro ‎characterization, and ex vivo permeation study. Drug Des Devel Ther 2020; 14: 3697-721. doi: 10.2147/DDDT.S265167 PMID: 32982176
  30. Abrha S, Bartholomaeus A, Tesfaye W, Thomas J. Impetigo animal models: A review of their feasibility and clinical utility for therapeutic appraisal of investigational drug candidates. Antibiotics 2020; 9(10): 694. doi: 10.3390/antibiotics9100694 PMID: 33066386
  31. Kugelberg E, Norström T, Petersen TK, Duvold T, Andersson DI, Hughes D. Establishment of a superficial skin infection model in mice by using Staphylococcus aureus and Streptococcus pyogenes. Antimicrob Agents Chemother 2005; 49(8): 3435-41. doi: 10.1128/AAC.49.8.3435-3441.2005 PMID: 16048958
  32. Escárcega-González CE, Garza-Cervantes JA, Vazquez-Rodríguez A, et al. In vivo antimicrobial activity of silver nanoparticles produced via a green chemistry synthesis using Acacia rigidula as a reducing and capping agent. Int J Nanomedicine 2018; 13: 2349-63. doi: 10.2147/IJN.S160605 PMID: 29713166
  33. Ghataty DS, Amer RI, Wasfi R, Shamma RN. Novel linezolid loaded bio-composite films as dressings for effective wound healing: experimental design, development, optimization, and antimicrobial activity. Drug Deliv 2022; 29(1): 3168-85. doi: 10.1080/10717544.2022.2127974 PMID: 36184799
  34. Touching technologies, IOI Oleochemical. Available from: https://www.ioioleo.de/wpcontent/uploads/2020/03/IOI_Oleo_Personal_Care_Product_Catalogue.pdf (Accessed on: June 20, 2023).
  35. Hernández-Esquivel RA, Navarro-Tovar G, Zárate-Hernández E, Aguirre-Bañuelos P. Solid lipid nanoparticles (SLN). IntechOpen 2022. doi: 10.5772/intechopen.102536
  36. Negi LM, Jaggi M, Talegaonkar S. Development of protocol for screening the formulation components and the assessment of common quality problems of nano-structured lipid carriers. Int J Pharm 2014; 461(1-2): 403-10. doi: 10.1016/j.ijpharm.2013.12.006 PMID: 24345574
  37. Adib Z, Ghanbarzadeh S, Kouhsoltani M, Yari A, Hamishehkar H. The effect of particle size on the deposition of solid lipid nanoparticles in different skin layers: A histological study. Adv Pharm Bull 2016; 6(1): 31-6. doi: 10.15171/apb.2016.06 PMID: 27123415
  38. Jenning V, Gysler A, Schäfer-Korting M, Gohla SH. Vitamin A loaded solid lipid nanoparticles for topical use: Occlusive properties and drug targeting to the upper skin. Eur J Pharm Biopharm 2000; 49(3): 211-8. doi: 10.1016/S0939-6411(99)00075-2 PMID: 10799811
  39. Bhattacharjee S. DLS and zeta potential – What they are and what they are not? J Control Release 2016; 235: 337-51. doi: 10.1016/j.jconrel.2016.06.017 PMID: 27297779
  40. Ryman-Rasmussen JP, Riviere JE, Monteiro-Riviere NA. Penetration of intact skin by quantum dots with diverse physicochemical properties. Toxicol Sci 2006; 91(1): 159-65. doi: 10.1093/toxsci/kfj122 PMID: 16443688
  41. Schaefer K. Researchers deliver skin treatments with nucleic acid nanoparticles and moisturizers. 2012. Available from: https://www.cosmeticsandtoiletries.com/research/tech-transfer/news/21842319/researchers-deliver-skintreatments-with-nucleic-acid-nanoparticles-andmoisturizers (Accessed on: Nov 21, 2023).
  42. Samimi S, Maghsoudnia N, Eftekhari RB, Dorkoosh FA. Lipid-based nanoparticles for drug delivery systems. characterization and biology of nanomaterials for drug delivery. In: Mohapatra SS, Ranjan S, Dasgupta N, Mishra RK, Thomas S, Eds. Characterization and Biology of Nanomaterials for Drug Delivery. Elsevier 2019; pp. 47-76. doi: 10.1016/B978-0-12-814031-4.00003-9
  43. Wei L, Yang Y, Shi K, Wu J, Zhao W, Mo J. Preparation and characterization of loperamide-loaded dynasan 114 solid lipid nanoparticles for increased oral absorption in the treatment of diarrhea. Front Pharmacol 2016; 7: 332. doi: 10.3389/fphar.2016.00332 PMID: 27708583
  44. Sun M, Hu X, Zhou X, Gu J. Determination of minor quantities of linezolid polymorphs in a drug substance and tablet formulation by powder X-ray diffraction technique. Powder Diffr 2017; 32(2): 78-85. doi: 10.1017/S0885715617000069
  45. Thatipamula R, Palem C, Gannu R, Mudragada S, Yamsani M. Formulation and in vitro characterization of domperidone loaded solid lipid nanoparticles and nanostructured lipid carriers. Daru 2011; 19(1): 23-32. PMID: 22615636
  46. Chen X, Wang T. Preparation and characterization of atrazine-loaded biodegradable PLGA nanospheres. J Integr Agric 2019; 18(5): 1035-41. doi: 10.1016/S2095-3119(19)62613-4
  47. Siddiqui A, Alayoubi A, El-Malah Y, Nazzal S. Modeling the effect of sonication parameters on size and dispersion temperature of solid lipid nanoparticles (SLNs) by response surface methodology (RSM). Pharm Dev Technol 2014; 19(3): 342-6. doi: 10.3109/10837450.2013.784336 PMID: 23590412
  48. Soleimanian Y, Goli SAH, Varshosaz J, Sahafi SM. Formulation and characterization of novel nanostructured lipid carriers made from beeswax, propolis wax and pomegranate seed oil. Food Chem 2018; 244: 83-92. doi: 10.1016/j.foodchem.2017.10.010 PMID: 29120809
  49. Emami J, Mohiti H, Hamishehkar H, Varshosaz J. Formulation and optimization of solid lipid nanoparticle formulation for pulmonary delivery of budesonide using Taguchi and Box-Behnken design. Res Pharm Sci 2015; 10(1): 17-33. PMID: 26430454
  50. Mei L, Zhang Y, Zheng Y, et al. A novel docetaxel-loaded poly (ε-caprolactone)/pluronic F68 nanoparticle overcoming multidrug resistance for breast cancer treatment. Nanoscale Res Lett 2009; 4(12): 1530-9. doi: 10.1007/s11671-009-9431-6 PMID: 20652101
  51. Ruiz E, Orozco VH, Hoyos LM, Giraldo LF. Study of sonication parameters on PLA nanoparticles preparation by simple emulsion-evaporation solvent technique. Eur Polym J 2022; 173: 111307. doi: 10.1016/j.eurpolymj.2022.111307
  52. Singh AP, Sharma SK, Gaur PK, Gupta DK. Fabrication of mupirocin-loaded nanostructured lipid carrier and its in vitro characterization. Assay Drug Dev Technol 2021; 19(4): 216-25. doi: 10.1089/adt.2020.1070 PMID: 33781090
  53. Kumar R, Yasir M, Saraf SA, Gaur PK, Kumar Y, Singh AP. Glyceryl monostearate based nanoparticles of mefenamic acid: Fabrication and in vitro characterization. Drug Invent Today 2013; 5(3): 246-50. doi: 10.1016/j.dit.2013.06.011
  54. Pandita D, Ahuja A, Velpandian T, Lather V, Dutta T, Khar RK. Characterization and in vitro assessment of paclitaxel loaded lipid nanoparticles formulated using modified solvent injection technique. Pharmazie 2009; 64(5): 301-10. PMID: 19530440
  55. Subramaniam B, Siddik ZH, Nagoor NH. Optimization of nanostructured lipid carriers: Understanding the types, designs, and parameters in the process of formulations. J Nanopart Res 2020; 22(6): 141. doi: 10.1007/s11051-020-04848-0
  56. Velmurugan R, Selvamuthukumar S. Development and optimization of ifosfamide nanostructured lipid carriers for oral delivery using response surface methodology. Appl Nanosci 2016; 6(2): 159-73. doi: 10.1007/s13204-015-0434-6
  57. Liu Y, Liang Q, Liu X, Raza H, Ma H, Ren X. Treatment with ultrasound improves the encapsulation efficiency of resveratrol in zein-gum Arabic complex coacervates. Lebensm Wiss Technol 2022; 153: 112331. doi: 10.1016/j.lwt.2021.112331
  58. Factorial plots and scatterplots for Analyze Taguchi Design. Available from: https://support.minitab.com/en-us/minitab/20/helpand-how-to/statistical-modeling/doe/howto/taguchi/analyze-taguchi-design/interpret-theresults/all-statistics-and-graphs/factorial-plots-andscatterplots/#:~:text=to%2Dnoise%20ratio (Accessed on: Nov 21, 2023).
  59. Bullock AJ, Garcia M, Shepherd J, Rehman I, Sheila MN. Bacteria induced pH changes in tissue-engineered human skin detected non-invasively using Raman confocal spectroscopy. Appl Spectrosc Rev 2020; 55(2): 158-71. doi: 10.1080/05704928.2018.1558232
  60. El-Housiny S, Eldeen MA, El-Attar YA, et al. Fluconazole-loaded solid lipid nanoparticles topical gel for treatment of pityriasis versicolor: Formulation and clinical study. Drug Deliv 2018; 25(1): 78-90. doi: 10.1080/10717544.2017.1413444 PMID: 29239242
  61. Cellet TSP, Pereira GM, Muniz EC, Silva R, Rubira AF. Hydroxyapatite nanowhiskers embedded in chondroitin sulfate microspheres as colon targeted drug delivery systems. J Mater Chem B Mater Biol Med 2015; 3(33): 6837-46. doi: 10.1039/C5TB00856E PMID: 32262476
  62. Heredia NS, Vizuete K, Flores-Calero M, et al. Comparative statistical analysis of the release kinetics models for nanoprecipitated drug delivery systems based on poly(lactic-co-glycolic acid). PLoS One 2022; 17(3): e0264825. doi: 10.1371/journal.pone.0264825 PMID: 35271644
  63. Loo YY, Rukayadi Y, Nor-Khaizura MAR, et al. In vitro antimicrobial activity of green synthesized silver nanoparticles against selected gram-negative foodborne pathogens. Front Microbiol 2018; 9: 1555. doi: 10.3389/fmicb.2018.01555 PMID: 30061871
  64. Nagaich U, Gulati N. Nanostructured lipid carriers (NLC) based controlled release topical gel of clobetasol propionate: design and in vivo characterization. Drug Deliv Transl Res 2016; 6(3): 289-98. doi: 10.1007/s13346-016-0291-1 PMID: 27072979
  65. Atrux-Tallau N, Denis A, Padois K, et al. Skin absorption modulation: Innovative non-hazardous technologies for topical formulations. Open Dermatol J 2010; 4(1): 3-9. doi: 10.2174/1874372201004010003
  66. Mitri K, Shegokar R, Gohla S, Anselmi C, Müller RH. Lipid nanocarriers for dermal delivery of lutein: Preparation, characterization, stability and performance. Int J Pharm 2011; 414(1-2): 267-75. doi: 10.1016/j.ijpharm.2011.05.008 PMID: 21596122
  67. Wavikar P, Vavia P. Nanolipidgel for enhanced skin deposition and improved antifungal activity. AAPS PharmSciTech 2013; 14(1): 222-33. doi: 10.1208/s12249-012-9908-y PMID: 23263751
  68. Escobar-Chávez JJ, Merino-Sanjuán V, López-Cervantes M, et al. The tape-stripping technique as a method for drug quantification in skin. J Pharm Pharm Sci 2008; 11(1): 104-30. doi: 10.18433/J3201Z PMID: 18445368
  69. Dembicka KM, Powell J, O’Connell NH, Hennessy N, Brennan G, Dunne CP. Prevalence of linezolid-resistant organisms among patients admitted to a tertiary hospital for critical care or dialysis. Ir J Med Sci 2022; 191(4): 1745-50. doi: 10.1007/s11845-021-02773-2 PMID: 34505273
  70. Morales G, Picazo JJ, Baos E, et al. Resistance to linezolid is mediated by the cfr gene in the first report of an outbreak of linezolid-resistant Staphylococcus aureus. Clin Infect Dis 2010; 50(6): 821-5. doi: 10.1086/650574 PMID: 20144045
  71. Gu B, Kelesidis T, Tsiodras S, Hindler J, Humphries RM. The emerging problem of linezolid-resistant Staphylococcus. J Antimicrob Chemother 2013; 68(1): 4-11. doi: 10.1093/jac/dks354 PMID: 22949625
  72. Tian Y, Li T, Zhu Y, Wang B, Zou X, Li M. Mechanisms of linezolid resistance in Staphylococci and enterococci isolated from two teaching hospitals in Shanghai, China. BMC Microbiol 2014; 14(1): 292. doi: 10.1186/s12866-014-0292-5 PMID: 25420718
  73. Ngbede EO, Sy I, Akwuobu CA, et al. Carriage of linezolid-resistant enterococci (LRE) among humans and animals in Nigeria: Coexistence of the cfr, optrA, and poxtA genes in Enterococcus faecium of animal origin. J Glob Antimicrob Resist 2023; 34: 234-9. doi: 10.1016/j.jgar.2023.07.016 PMID: 37516354
  74. Stefani S, Bongiorno D, Mongelli G, Campanile F. Linezolid resistance in Staphylococci. Pharmaceuticals 2010; 3(7): 1988-2006. doi: 10.3390/ph3071988 PMID: 27713338
  75. Meka VG, Gold HS. Antimicrobial resistance to linezolid. Clin Infect Dis 2004; 39(7): 1010-5. doi: 10.1086/423841 PMID: 15472854
  76. Ray P, Singh S, Gupta S. Topical antimicrobial therapy: Current status and challenges. Indian J Med Microbiol 2019; 37(3): 299-308. doi: 10.4103/ijmm.IJMM_19_443 PMID: 32003326
  77. Williamson DA, Carter GP, Howden BP. Current and emerging topical antibacterials and antiseptics: Agents, action, and resistance patterns. Clin Microbiol Rev 2017; 30(3): 827-60. doi: 10.1128/CMR.00112-16 PMID: 28592405

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