Formulation of topical ibuprofen solid lipid nanoparticle (SLN) gel using hot melt extrusion technique (HME) and determining its anti-inflammatory strength

  • Arvind Bagde
  • Ketan Patel
  • Shallu Kutlehria
  • Nusrat Chowdhury
  • Mandip SinghEmail author
Original Article


Solid lipid nanoparticles (SLN) have been formulated using various batch processes, e.g., solvent diffusion evaporation, emulsification solvent evaporation followed by size reduction using high-pressure homogenization (HPH) or ultrasonication. However, for the manufacturing of formulations, continuous processes are always preferred over batch processes since they are more efficient and offer better quality of the end product. Hence, we developed topical SLN of ibuprofen (IBU) using hot melt extrusion (HME), prepared a gel formulation, and performed its in vitro and in vivo evaluation. Effect of different variables of HME equipment and materials used in SLN was optimized using design of experiment (DoE) approach. Stable 0.48% IBU SLN with particle size 60.2 ± 4.81 nm and entrapment efficiency 90.41 ± 3.46% were developed which further gelled using 1% carbopol 981A. Drug release study, skin deposition study, and in vivo anti-inflammatory activity studies showed 84.37 ± 4.65% drug release, 12.05 ± 0.81% drug deposition, and 40.17 ± 2.41% edema inhibition respectively in case of IBU SLN gel (IBU-SLN-G) which was significantly higher (p < 0.05) than control IBU gel (C-IBU-G) with 50.11 ± 0.57% drug release, 4.11 ± 1.10% deposition, and 20.08 ± 3.23% edema inhibition respectively. In conclusion, HME offers a single step process for manufacturing for SLN which avoids high stress particle size reduction techniques used for SLN preparation.


Hot melt extrusion Ibuprofen Topical SLN gel Quality by design Rat paw edema 


Compliance with ethical standards

The Institutional Animal Care and Use Committee (IACUC) at Florida A&M University, FL approved all animal protocols that were observed in this study on 10th March 2016 (Protocol number: 016-03; Project number: 861412-3).

Animal studies

All institutional and national guidelines for the care and use of laboratory animals were followed.

Supplementary material

13346_2019_632_MOESM1_ESM.docx (1.3 mb)
ESM 1 (DOCX 1318 kb)


  1. 1.
    Sütő B, Weber S, Zimmer A, Farkas G, Kelemen A, Budai-Szűcs M, et al. Optimization and design of an ibuprofen-loaded nanostructured lipid carrier with a 2 3 full factorial design. Chem Eng Res Des. 2015;104:488–96.CrossRefGoogle Scholar
  2. 2.
    Dasgupta S, Ghosh S, Ray S, Kaurav S, Mazumder B. In vitro & in vivo studies on lornoxicam loaded nanoemulsion gels for topical application. Curr Drug Deliv. 2014;11(1):132–8.CrossRefPubMedGoogle Scholar
  3. 3.
    Rawat M, et al. Lipid carriers: a versatile delivery vehicle for proteins and peptides. Yakugaku Zasshi. 2008;128(2):269–80.CrossRefPubMedGoogle Scholar
  4. 4.
    Uner M, Yener G. Importance of solid lipid nanoparticles (SLN) in various administration routes and future perspectives. Int J Nanomedicine. 2007;2(3):289.PubMedGoogle Scholar
  5. 5.
    Patil H, Feng X, Ye X, Majumdar S, Repka MA. 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.CrossRefPubMedGoogle Scholar
  6. 6.
    Almeida A, Brabant L, Siepmann F, de Beer T, Bouquet W, van Hoorebeke L, et al. Sustained release from hot-melt extruded matrices based on ethylene vinyl acetate and polyethylene oxide. Eur J Pharm Biopharm. 2012;82(3):526–33.CrossRefPubMedGoogle Scholar
  7. 7.
    Crowley MM, Zhang F, Repka MA, Thumma S, Upadhye SB, Kumar Battu S, et al. Pharmaceutical applications of hot-melt extrusion: part I. Drug Dev Ind Pharm. 2007;33(9):909–26.CrossRefPubMedGoogle Scholar
  8. 8.
    Repka MA, Battu SK, Upadhye SB, Thumma S, Crowley MM, Zhang F, et al. Pharmaceutical applications of hot-melt extrusion: part II. Drug Dev Ind Pharm. 2007;33(10):1043–57.CrossRefPubMedGoogle Scholar
  9. 9.
    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.CrossRefPubMedGoogle Scholar
  10. 10.
    Bhagurkar AM, Angamuthu M, Patil H, Tiwari RV, Maurya A, Hashemnejad SM, et al. Development of an ointment formulation using hot-melt extrusion technology. AAPS PharmSciTech. 2016;17(1):158–66.CrossRefPubMedGoogle Scholar
  11. 11.
    Rhee Y-S, Chang SY, Park CW, Chi SC, Park ES. Optimization of ibuprofen gel formulations using experimental design technique for enhanced transdermal penetration. Int J Pharm. 2008;364(1):14–20.CrossRefPubMedGoogle Scholar
  12. 12.
    Tyner KM, et al. Product quality for nanomaterials: current US experience and perspective. Wiley Interdiscip Rev Nanomed Nanobiotechnol. 2015;7(5):640–54.CrossRefPubMedGoogle Scholar
  13. 13.
    Wechsler J. Washington report-FDA proposes flexible oversight for quality systems-manufacturers seek real-world benefits from investment in QbD and risk-management strategies. Pharm Technol. 2008;32(10):32.Google Scholar
  14. 14.
    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. 2015;78:54–66.CrossRefPubMedGoogle Scholar
  15. 15.
    Lionberger RA, Lee SL, Lee LM, Raw A, Yu LX. Quality by design: concepts for ANDAs. AAPS J. 2008;10(2):268–76.CrossRefPubMedGoogle Scholar
  16. 16.
    Azizi M, et al. Efficacy of nano-and microemulsion-based topical gels in delivery of ibuprofen: an in vivo study. J Microencapsul. 2017:1–7.Google Scholar
  17. 17.
    Boakye CH, et al. Enhanced percutaneous delivery of 1,1-bis (3-indolyl)-1-(p-chlorophenyl) methane for skin cancer chemoprevention. J Biomed Nanotechnol. 2015;11(7):1269–81.CrossRefPubMedGoogle Scholar
  18. 18.
    Shah PP, Desai PR, Singh M. Effect of oleic acid modified polymeric bilayered nanoparticles on percutaneous delivery of spantide II and ketoprofen. J Control Release. 2012;158(2):336–45.CrossRefPubMedGoogle Scholar
  19. 19.
    Erdal MS, et al. Colloidal nanocarriers for the enhanced cutaneous delivery of naftifine: characterization studies and in vitro and in vivo evaluations. Int J Nanomedicine. 2016;11:1027.CrossRefPubMedGoogle Scholar
  20. 20.
    Souto E, Mehnert W, Müller R. Polymorphic behaviour of Compritol® 888 ATO as bulk lipid and as SLN and NLC. J Microencapsul. 2006;23(4):417–33.CrossRefPubMedGoogle Scholar
  21. 21.
    Sütő B, et al. Development of ibuprofen-loaded nanostructured lipid carrier-based gels: characterization and investigation of in vitro and in vivo penetration through the skin. Int J Nanomedicine. 2016;11:1201.PubMedGoogle Scholar
  22. 22.
    Dorraj G, Moghimi HR. Preparation of SLN-containing thermoresponsive in-situ forming gel as a controlled nanoparticle delivery system and investigating its rheological, thermal and erosion behavior. Iran J Pharm Res. 2015;14(2):347.PubMedGoogle Scholar
  23. 23.
    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 Surf B: Biointerfaces. 2011;88(1):483–9.CrossRefPubMedGoogle Scholar
  24. 24.
    Rahman Z, Zidan AS, Habib MJ, Khan MA. Understanding the quality of protein loaded PLGA nanoparticles variability by Plackett–Burman design. Int J Pharm. 2010;389(1):186–94.CrossRefPubMedGoogle Scholar
  25. 25.
    Pople PV, Singh KK. Development and evaluation of topical formulation containing solid lipid nanoparticles of vitamin A. AAPS PharmSciTech. 2006;7(4):E63–9.CrossRefGoogle Scholar
  26. 26.
    Buadonpri W, et al. Synthetic curcumin inhibits carrageenan-induced paw edema in arts. J Health Res. 2009;23:11–6.Google Scholar
  27. 27.
    Vinegar R, Schreiber W, Hugo R. Biphasic development of carrageenin edema in rats. J Pharmacol Exp Ther. 1969;166(1):96–103.PubMedGoogle Scholar

Copyright information

© Controlled Release Society 2019

Authors and Affiliations

  • Arvind Bagde
    • 1
  • Ketan Patel
    • 1
    • 2
  • Shallu Kutlehria
    • 1
  • Nusrat Chowdhury
    • 1
  • Mandip Singh
    • 1
    Email author
  1. 1.College of Pharmacy and Pharmaceutical SciencesFlorida A&M UniversityTallahasseeUSA
  2. 2.College of Pharmacy and Health SciencesSt. John’s UniversityQueensUSA

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