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Formulation of Topical Flurbiprofen Solid Lipid Nanoparticle Gel Formulation Using Hot Melt Extrusion Technique

  • Research Article
  • Active and Passive Permeation Enhancement Strategies for Transdermal Delivery of Bioactive Compounds
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Abstract

Hot melt extrusion (HME) has been used for the formulation of topical solid lipid nanoparticle (SLN) gel without using any other size reduction technique including high pressure homogenization or sonication. SLN formulation solely using HME has not been applied to other drugs except IBU. Therefore, the purpose of the present study was to formulate FLB SLN solely using HME technique and evaluate the SLN formulation in inflammation animal model. Stable 0.5% w/v FLB SLN gel with particle size < 250 nm, PI < 0.3 and EE of > 98% was prepared. Differential scanning calorimetry (DSC) thermogram showed that the drug was converted to amorphous form in the HME process. Additionally, rheological studies demonstrated that FLB SLN gel and marketed FLB gel showed shear thinning property. FLB SLN formulation showed significantly (p < 0.05) higher peak force required to spread the formulation as compared to marketed FLB formulation. Stability studies showed that FLB SLN gel was stable for a month at room temperature and 2–4°C. Moreover, in vitro permeation test (IVPT) and ex vivo skin deposition study results revealed that FLB SLN gel showed significant (p < 0.05) increase in drug deposition in dermal layer and drug permeation as compared to control marketed formulation. Further, in vivo anti-inflammatory study showed equivalent inhibition of rat paw edema using 0.5% w/v FLB SLN gel which has 10 times less strength compared to control formulation. Overall, FLB SLN formulation was successfully manufactured solely using HME technique which resulted in enhanced the skin permeation of FLB and superior anti-inflammatory activity.

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References

  1. Sharadha M, et al. An overview on topical drug delivery system–updated review. International Journal of Research in Pharmaceutical Sciences. 2020;11(1):368–85.

    Article  CAS  Google Scholar 

  2. Griffin T, et al. Potentiation of antitumor immunotoxins by liposomal monensin. JNCI: J National Cancer Inst. 1993;85(4):292–8.

    Article  CAS  Google Scholar 

  3. Boakye CH, Patel K, Singh M. Doxorubicin liposomes as an investigative model to study the skin permeation of nanocarriers. Int J Pharm. 2015;489(1–2):106–16.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Doddapaneni R, et al. Tumor neovasculature-targeted cationic PEGylated liposomes of gambogic acid for the treatment of triple-negative breast cancer. Drug Delivery. 2016;23(4):1232–41.

    Article  CAS  PubMed  Google Scholar 

  5. Marepally S, et al. Design, synthesis of novel lipids as chemical permeation enhancers and development of nanoparticle system for transdermal drug delivery. PLoS ONE. 2013;8(12): e82581.

    Article  PubMed  PubMed Central  Google Scholar 

  6. Patel K, et al. Tumor stromal disrupting agent enhances the anticancer efficacy of docetaxel loaded PEGylated liposomes in lung cancer. Nanomedicine. 2016;11(11):1377–92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Patel K, et al. Combination approach of YSA peptide anchored docetaxel stealth liposomes with oral antifibrotic agent for the treatment of lung cancer. Mol Pharm. 2016;13(6):2049–58.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Godugu C, Doddapaneni R, Singh M. Honokiol nanomicellar formulation produced increased oral bioavailability and anticancer effects in triple negative breast cancer (TNBC). Colloids Surf, B. 2017;153:208–19.

    Article  CAS  Google Scholar 

  9. Patel AR, Chougule M, Singh M. EphA2 targeting pegylated nanocarrier drug delivery system for treatment of lung cancer. Pharm Res. 2014;31(10):2796–809.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Shaik MS, Chatterjee A, Singh M. Effects of monensin liposomes on the cytotoxicity, apoptosis and expression of multidrug resistance genes in doxorubicin-resistant human breast tumour (MCF-7/dox) cell-line. J Pharm Pharmacol. 2004;56(7):899–907.

    Article  CAS  PubMed  Google Scholar 

  11. Mehnert W, Mäder K. Solid lipid nanoparticles: production, characterization and applications. Adv Drug Deliv Rev. 2012;64:83–101.

    Article  Google Scholar 

  12. Hou D, et al. The production and characteristics of solid lipid nanoparticles (SLNs). Biomaterials. 2003;24(10):1781–5.

    Article  CAS  PubMed  Google Scholar 

  13. Zoabi A, Touitou E, Margulis K. Recent advances in nanomaterials for dermal and transdermal applications. Colloids and Interfaces. 2021;5(1):18.

    Article  CAS  Google Scholar 

  14. Scioli Montoto S, Muraca G, Ruiz ME. Solid lipid nanoparticles for drug delivery: pharmacological and biopharmaceutical aspects. Front Mol Biosci. 2020;319.

  15. Singh M, Ferdous AJ, Jackson TL. Stealth monensin liposomes as a potentiator of adriamycin in cancer treatment. J Control Release. 1999;59(1):43–53.

    Article  CAS  PubMed  Google Scholar 

  16. Patel G, et al. Nanoliposomal dry powder formulations. Methods Enzymol. 2009;464:167–91.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Pham DT, Tran PH, Tran TT. Development of solid dispersion lipid nanoparticles for improving skin delivery. Saudi Pharmaceutical Journal. 2019;27(7):1019–24.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Passos JS, et al. Development, skin targeting and antifungal efficacy of topical lipid nanoparticles containing itraconazole. Eur J Pharm Sci. 2020;149: 105296.

    Article  CAS  PubMed  Google Scholar 

  19. Geetha T, et al. Sesamol-loaded solid lipid nanoparticles for treatment of skin cancer. J Drug Target. 2015;23(2):159–69.

    Article  CAS  PubMed  Google Scholar 

  20. Shadambikar G, et al. Formulation development of itraconazole PEGylated nano-lipid carriers for pulmonary aspergillosis using hot-melt extrusion technology. International journal of pharmaceutics: X. 2021;3: 100074.

    CAS  Google Scholar 

  21. Patil H, et al. Continuous production of fenofibrate solid lipid nanoparticles by hot-melt extrusion technology: a systematic study based on a quality by design approach. AAPS J. 2015;17(1):194–205.

    Article  CAS  PubMed  Google Scholar 

  22. Bhagurkar AM, Repka MA, Murthy SN. A novel approach for the development of a nanostructured lipid carrier formulation by hot-melt extrusion technology. J Pharm Sci. 2017;106(4):1085–91.

    Article  CAS  PubMed  Google Scholar 

  23. Bagde A, et al. Formulation of topical ibuprofen solid lipid nanoparticle (SLN) gel using hot melt extrusion technique (HME) and determining its anti-inflammatory strength. Drug Deliv Transl Res. 2019;9(4):816–27.

    Article  CAS  PubMed  Google Scholar 

  24. Fang J-Y, et al. Lipid nano/submicron emulsions as vehicles for topical flurbiprofen delivery. Drug Delivery. 2004;11(2):97–105.

    Article  CAS  PubMed  Google Scholar 

  25. Cody SL, Fegley RD, Hoy MR. Enhanced delivery of topical compositions containing flurbiprofen. Google Patents. 1998.

  26. Czyrski, A., Determination of the lipophilicity of ibuprofen, naproxen, ketoprofen, and flurbiprofen with thin-layer chromatography. J Chemistry., 2019. 2019.

  27. Fiume MM, et al. Safety assessment of triethanolamine and triethanolamine-containing ingredients as used in cosmetics. Int J Toxicol. 2013;32(3_suppl):59S-83S.

    Article  PubMed  Google Scholar 

  28. Kulkarni SB, Singh M, Betageri GV. Encapsulation, stability and in-vitro release characteristics of liposomal formulations of colchicine. J Pharm Pharmacol. 1997;49(5):491–5.

    Article  CAS  PubMed  Google Scholar 

  29. Chowdhury N, et al. Liposomes co-loaded with 6-phosphofructo-2-kinase/fructose-2, 6-biphosphatase 3 (PFKFB3) shRNA plasmid and docetaxel for the treatment of non-small cell lung cancer. Pharm Res. 2017;34(11):2371–84.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Affram K, et al. Smart thermosensitive liposomes for effective solid tumor therapy and in vivo imaging. PLoS ONE. 2017;12(9): e0185116.

    Article  PubMed  PubMed Central  Google Scholar 

  31. Shaik MS, et al. Long-circulating monensin nanoparticles for the potentiation of immunotoxin and anticancer drugs. J Pharm Pharmacol. 2001;53(5):617–27.

    Article  CAS  PubMed  Google Scholar 

  32. Boakye CH, et al. Ultra-flexible nanocarriers for enhanced topical delivery of a highly lipophilic antioxidative molecule for skin cancer chemoprevention. Colloids Surf, B. 2016;143:156–67.

    Article  CAS  Google Scholar 

  33. Akhlaq M, et al. A simple high-performance liquid chromatographic practical approach for determination of flurbiprofen. Journal of Advanced Pharmaceutical Technology & Research. 2011;2(3):151.

    Article  CAS  Google Scholar 

  34. Pignatello R, et al. Flurbiprofen-loaded acrylate polymer nanosuspensions for ophthalmic application. Biomaterials. 2002;23(15):3247–55.

    Article  CAS  PubMed  Google Scholar 

  35. Kryscio DR, et al. Spreadability measurements to assess structural equivalence (Q3) of topical formulations—a technical note. AAPS PharmSciTech. 2008;9(1):84–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Salau O, Bagde A, Kalvala A, Singh M. Enhancement of transdermal permeation of cannabinoids and their pharmacodynamic evaluation in rats. Int J Pharm. 2022;624:122016.

  37. Desai PR, et al. Dermal microdialysis technique to evaluate the trafficking of surface-modified lipid nanoparticles upon topical application. Pharm Res. 2012;29(9):2587–600.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Mallampati R, et al. Evaluation of EpiDerm full thickness-300 (EFT-300) as an in vitro model for skin irritation: studies on aliphatic hydrocarbons. Toxicol In Vitro. 2010;24(2):669–76.

    Article  CAS  PubMed  Google Scholar 

  39. Fulzele SV, et al. Estimation of proinflammatory biomarkers of skin irritation by dermal microdialysis following exposure with irritant chemicals. Toxicology. 2007;237(1–3):77–88.

    Article  CAS  PubMed  Google Scholar 

  40. Babu R, Chatterjee A, Singh M. Assessment of skin irritation and molecular responses in rat skin exposed to nonane, dodecane and tetradecane. Toxicol Lett. 2004;153(2):255–66.

    Article  CAS  PubMed  Google Scholar 

  41. Babu RJ, et al. Percutaneous absorption and anti-inflammatory effect of a substance P receptor antagonist: spantide II. Pharm Res. 2004;21(1):108–13.

    Article  CAS  PubMed  Google Scholar 

  42. Patlolla RR, et al. Dermal microdialysis of inflammatory markers induced by aliphatic hydrocarbons in rats. Toxicol Lett. 2009;185(3):168–74.

    Article  CAS  PubMed  Google Scholar 

  43. Aburahma MH, Badr-Eldin SM. Compritol 888 ATO: a multifunctional lipid excipient in drug delivery systems and nanopharmaceuticals. Expert Opin Drug Deliv. 2014;11(12):1865–83.

    Article  CAS  PubMed  Google Scholar 

  44. Yong-Tai Z, et al. Solid lipid nanoparticles formulated for transdermal aconitine administration and evaluated in vitro and in vivo. J Biomed Nanotechnol. 2015;11(2):351–61.

    Article  Google Scholar 

  45. Hassan H, et al. Central composite design for formulation and optimization of solid lipid nanoparticles to enhance oral bioavailability of acyclovir. Molecules. 2021;26(18):5432.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Tran T, Rades T, Müllertz A. Formulation of self-nanoemulsifying drug delivery systems containing monoacyl phosphatidylcholine and Kolliphor® RH40 using experimental design. Asian J Pharm Sci. 2018;13(6):536–45.

    Article  PubMed  Google Scholar 

  47. Khan MFA, et al. Hydrogel containing solid lipid nanoparticles loaded with argan oil and simvastatin: preparation, in vitro and ex vivo assessment. Gels. 2022;8(5):277.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Deuschle VCKN, et al. Physical chemistry evaluation of stability, spreadability, in vitro antioxidant, and photo-protective capacities of topical formulations containing Calendula officinalis L. leaf extract. Brazil J Pharm Sci. 2015;51:63–75.

    Article  CAS  Google Scholar 

  49. Patere N, S, et al. Compritol® 888 ATO a lipid excipient for sustained release of highly water soluble active: formulation, scale-up and IVIVC study. Curr Drug Deliv. 2013;10(5):548–56.

    Article  CAS  PubMed  Google Scholar 

  50. Mancini G, et al. Increased therapeutic efficacy of SLN containing etofenamate and ibuprofen in topical treatment of inflammation. Pharmaceutics. 2021;13(3):328.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Pham CV, et al. Development of ibuprofen-loaded solid lipid nanoparticle-based hydrogels for enhanced in vitro dermal permeation and in vivo topical anti-inflammatory activity. Journal of Drug Delivery Science and Technology. 2020;57: 101758.

    Article  CAS  Google Scholar 

  52. Jain S, et al. Solid lipid nanoparticles bearing flurbiprofen for transdermal delivery. Drug Delivery. 2005;12(4):207–15.

    Article  CAS  PubMed  Google Scholar 

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Funding

Authors are thankful to National Institute on Minority Health and Health Disparities of National Institutes of Health, Grant/Award Number: U54 MD007582 for providing the funding for this research work.

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Authors and Affiliations

  1. College of Pharmacy and Pharmaceutical Sciences, Institute of Public Health, Florida A&M University, Tallahassee, Florida, 32307, USA

    Arvind Bagde, Emmanual Kouagou & Mandip Singh

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  1. Arvind Bagde
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  2. Emmanual Kouagou
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  3. Mandip Singh
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Contributions

Arvind Bagde: substantial contributions to the conception or design of the work; or the acquisition, analysis, or interpretation of data for the work and drafting the work or revising it critically for important intellectual content.

Emmanual Kouagou: substantial contributions to the conception or design of the work; or the acquisition, analysis, or interpretation of data for the work.

Mandip Singh: final approval of the version to be published and agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

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Correspondence to Mandip Singh.

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Bagde, A., Kouagou, E. & Singh, M. Formulation of Topical Flurbiprofen Solid Lipid Nanoparticle Gel Formulation Using Hot Melt Extrusion Technique. AAPS PharmSciTech 23, 257 (2022). https://doi.org/10.1208/s12249-022-02410-w

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