AAPS PharmSciTech

, Volume 19, Issue 4, pp 1869–1881 | Cite as

Biodegradable Ingredient-Based Emulgel Loaded with Ketoprofen Nanoparticles

  • Rabia Gul
  • Naveed Ahmed
  • Naseem Ullah
  • Muhammad Ijaz Khan
  • Abdelhamid Elaissari
  • Asim.ur. Rehman
Research Article
  • 76 Downloads

Abstract

Biodegradable materials are extensively employed to design nanocarriers that mimic extracellular environment in arthritis. The aim of this study was to formulate and characterize biocompatible, biodegradable ketoprofen-loaded chitosan-chondroitin sulfate (CHS-CS) nanoparticles with natural ingredients for transdermal applications. Polymers used in the design of nanocarriers are biodegradable and produce synergistic anti-inflammatory effect for the treatment of arthritis. For transdermal application, argan oil-based emulgel is utilized to impart viscosity to the formulation. Furthermore, naturally occurring argan oil synergizes anti-inflammatory effect of formulation and promotes skin penetration. CHS and CS form nanoparticles by polyelectrolyte complex formation or complex coacervation at pH 5.0. These particles were loaded into argan oil-based emulgel. Employing this method, nanoparticles were formulated with particle size in the range of 300–500 nm. These nanocarriers entrapped ketoprofen and showed more than 76% encapsulation efficiency and 77% release of the ketoprofen at pH 7.4 within 72 h. Drug releases from CHS-CS nanoparticles by mechanism of simple diffusion. Nanoparticle-loaded argan oil emulgel significantly enhanced skin penetration of ketoprofen as compared to marketed gel (p < 0.05). Nanocarriers prepared successfully delivered drug through transdermal route using natural ingredients.

Graphical abstract

Key words

arthritis biocompatible chitosan chondroitin sulfate transdermal drug delivery system 

Notes

Compliance with Ethical Standards

Conflict of Interest

The authors declare that they have no conflict of interest.

References

  1. 1.
    Van Vollenhoven RF. Treatment of rheumatoid arthritis: state of the art 2009. Nat Rev Rheumatol. 2009;5(10):531–41.CrossRefPubMedGoogle Scholar
  2. 2.
    Dolati S, Sadreddini S, Rostamzadeh D, Ahmadi M, Jadidi-Niaragh F, Yousefi M. Utilization of nanoparticle technology in rheumatoid arthritis treatment. Biomed Pharmacother. 2016;80:30–41.CrossRefPubMedGoogle Scholar
  3. 3.
    Prausnitz MR, Mitragotri S, Langer R. Current status and future potential of transdermal drug delivery. Nat Rev Drug Discov. 2004;3(2):115–24.CrossRefPubMedGoogle Scholar
  4. 4.
    Cevc G, Vierl U. Nanotechnology and the transdermal route: a state of the art review and critical appraisal. J Control Release. 2010;141(3):277–99.CrossRefPubMedGoogle Scholar
  5. 5.
    Alexander A, Dwivedi S, Giri TK, Saraf S, Saraf S, Tripathi DK. Approaches for breaking the barriers of drug permeation through transdermal drug delivery. J Control Release. 2012;164(1):26–40.CrossRefPubMedGoogle Scholar
  6. 6.
    Escobar-Chávez JJ, Revilla-Vázquez AL, Domínguez-Delgado CL, Rodríguez-Cruz IM, Aléncaster NC, Díaz-Torres R. Nanocarrier systems for transdermal drug delivery: INTECH Open Access Publisher; 2012.Google Scholar
  7. 7.
    Mir M, Ishtiaq S, Rabia S, Khatoon M, Zeb A, Khan GM, et al. Nanotechnology: from in vivo imaging system to controlled drug delivery. Nanoscale Res Lett. 2017;12(1):500.CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Katikaneni S. Transdermal delivery of biopharmaceuticals: dream or reality? Ther Deliv. 2015;6(9):1109–16.CrossRefPubMedGoogle Scholar
  9. 9.
    Prow TW, Grice JE, Lin LL, Faye R, Butler M, Becker W, et al. Nanoparticles and microparticles for skin drug delivery. Adv Drug Deliv Rev. 2011;63(6):470–91.CrossRefPubMedGoogle Scholar
  10. 10.
    Badri W, Eddabra R, Fessi H, Elaissari A. Biodegradable polymer based nanoparticles: dermal and transdermal drug delivery. J Colloid Sci Biotechnol. 2014;3(2):141–9.CrossRefGoogle Scholar
  11. 11.
    Carmona-Ribeiro AM. Biomimetic nanoparticles: preparation, characterization and biomedical applications. Int J Nanomedicine. 2010;5:249.CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Kumari A, Yadav SK, Yadav SC. Biodegradable polymeric nanoparticles based drug delivery systems. Colloids Surf B: Biointerfaces. 2010;75(1):1–18.CrossRefPubMedGoogle Scholar
  13. 13.
    Rinaudo M. Main properties and current applications of some polysaccharides as biomaterials. Polym Int. 2008;57(3):397–430.CrossRefGoogle Scholar
  14. 14.
    Chaudhary Z, Ahmed N, Ur-Rehman A, Khan GM. Lipid polymer hybrid carrier systems for cancer targeting: a review. International Journal of Polymeric Materials and Polymeric Biomaterials. 2017 (just-accepted).Google Scholar
  15. 15.
    Hamidi M, Azadi A, Rafiei P. Hydrogel nanoparticles in drug delivery. Adv Drug Deliv Rev. 2008;60(15):1638–49.CrossRefPubMedGoogle Scholar
  16. 16.
    Bodnar M, Hartmann JF, Borbely J. Preparation and characterization of chitosan-based nanoparticles. Biomacromolecules. 2005;6(5):2521–7.CrossRefPubMedGoogle Scholar
  17. 17.
    Rampino A, Borgogna M, Blasi P, Bellich B, Cesàro A. Chitosan nanoparticles: preparation, size evolution and stability. Int J Pharm. 2013;455(1):219–28.CrossRefPubMedGoogle Scholar
  18. 18.
    Piai JF, Rubira AF, Muniz EC. Self-assembly of a swollen chitosan/chondroitin sulfate hydrogel by outward diffusion of the chondroitin sulfate chains. Acta Biomater. 2009;5(7):2601–9.CrossRefPubMedGoogle Scholar
  19. 19.
    Hansson A, Di Francesco T, Falson F, Rousselle P, Jordan O, Borchard G. Preparation and evaluation of nanoparticles for directed tissue engineering. Int J Pharm. 2012;439(1):73–80.CrossRefPubMedGoogle Scholar
  20. 20.
    Shelke NB, James R, Laurencin CT, Kumbar SG. Polysaccharide biomaterials for drug delivery and regenerative engineering. Polym Adv Technol. 2014;25(5):448–60.CrossRefGoogle Scholar
  21. 21.
    Malfait A-M, Schnitzer TJ. Towards a mechanism-based approach to pain management in osteoarthritis. Nat Rev Rheumatol. 2013;9(11):654–64.CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Voilley N, de Weille J, Mamet J, Lazdunski M. Nonsteroid anti-inflammatory drugs inhibit both the activity and the inflammation-induced expression of acid-sensing ion channels in nociceptors. J Neurosci. 2001;21(20):8026–33.CrossRefPubMedGoogle Scholar
  23. 23.
    Beetge E, du Plessis J, Müller DG, Goosen C, van Rensburg FJ. The influence of the physicochemical characteristics and pharmacokinetic properties of selected NSAID’s on their transdermal absorption. Int J Pharm. 2000;193(2):261–4.CrossRefPubMedGoogle Scholar
  24. 24.
    Van Leerdam M, Vreeburg E, Rauws E, Geraedts A, Tijssen J, Reitsma J, et al. Acute upper GI bleeding: did anything change&quest. Am J Gastroenterol. 2003;98(7):1494–9.CrossRefPubMedGoogle Scholar
  25. 25.
    Yiyun C, Na M, Tongwen X, Rongqiang F, Xueyuan W, Xiaomin W, et al. Transdermal delivery of nonsteroidal anti-inflammatory drugs mediated by polyamidoamine (PAMAM) dendrimers. J Pharm Sci. 2007;96(3):595–602.CrossRefGoogle Scholar
  26. 26.
    Zhang Z, Huang G. Micro- and nano-carrier mediated intra-articular drug delivery systems for the treatment of osteoarthritis. J Nanotechnol. 2012;2012(2012):1–11.CrossRefGoogle Scholar
  27. 27.
    Hadgraft J, du Plessis J, Goosen C. The selection of non-steroidal anti-inflammatory agents for dermal delivery. Int J Pharm. 2000;207(1):31–7.CrossRefPubMedGoogle Scholar
  28. 28.
    Bishnoi M, Jain A, Hurkat P, Jain SK. Chondroitin sulphate: a focus on osteoarthritis. Glycoconj J. 2016;33(5):693–705.CrossRefPubMedGoogle Scholar
  29. 29.
    Onishi H, Isoda Y, Matsuyama M. In vivo evaluation of chondroitin sulfate-glycyl-prednisolone for anti-arthritic effectiveness and pharmacokinetic characteristics. Int J Pharm. 2013;456(1):113–20.CrossRefPubMedGoogle Scholar
  30. 30.
    Schneiders W, Reinstorf A, Ruhnow M, Rehberg S, Heineck J, Hinterseher I, et al. Effect of chondroitin sulphate on material properties and bone remodelling around hydroxyapatite/collagen composites. J Biomed Mater Res A. 2008;85((3):638–45.CrossRefGoogle Scholar
  31. 31.
    Monfort J, Pelletier J-P, Garcia-Giralt N, Martel-Pelletier J. Biochemical basis of the effect of chondroitin sulphate on osteoarthritis articular tissues. Ann Rheum Dis. 2008;67(6):735–40.CrossRefPubMedGoogle Scholar
  32. 32.
    Aubry-Rozier B. Role of slow-acting anti-arthritic agents in osteoarthritis (chondroitin sulfate, glucosamine, hyaluronic acid). Rev Med Suisse. 2012;8(332):571–2. 4, 6PubMedGoogle Scholar
  33. 33.
    Calamia V, Lourido L, Fernández-Puente P, Mateos J, Rocha B, Montell E, et al. Secretome analysis of chondroitin sulfate-treated chondrocytes reveals anti-angiogenic, anti-inflammatory and anti-catabolic properties. Arthritis Res Ther. 2012;14(5):1.CrossRefGoogle Scholar
  34. 34.
    Legendre F, Baugé C, Roche R, Saurel A, Pujol J. Chondroitin sulfate modulation of matrix and inflammatory gene expression in IL-1β-stimulated chondrocytes–study in hypoxic alginate bead cultures. Osteoarthr Cartil. 2008;16(1):105–14.CrossRefPubMedGoogle Scholar
  35. 35.
    Chan P-S, Caron JP, Orth MW. Effect of glucosamine and chondroitin sulfate on regulation of gene expression of proteolytic enzymes and their inhibitors in interleukin-1-challenged bovine articular cartilage explants. Am J Vet Res. 2005;66(11):1870–6.CrossRefPubMedGoogle Scholar
  36. 36.
    Jomphe C, Gabriac M, Hale TM, Héroux L, Trudeau LÉ, Deblois D, et al. Chondroitin sulfate inhibits the nuclear translocation of nuclear factor-κB in interleukin-1β-stimulated chondrocytes. Basic Clin Pharmacol Toxicol. 2008;102(1):59–65.PubMedGoogle Scholar
  37. 37.
    Lemarchand C, Gref R, Couvreur P. Polysaccharide-decorated nanoparticles. Eur J Pharm Biopharm. 2004;58(2):327–41.CrossRefPubMedGoogle Scholar
  38. 38.
    Liu Z, Jiao Y, Wang Y, Zhou C, Zhang Z. Polysaccharides-based nanoparticles as drug delivery systems. Adv Drug Deliv Rev. 2008;60(15):1650–62.CrossRefPubMedGoogle Scholar
  39. 39.
    Suh J-KF, Matthew HW. Application of chitosan-based polysaccharide biomaterials in cartilage tissue engineering: a review. Biomaterials. 2000;21(24):2589–98.CrossRefPubMedGoogle Scholar
  40. 40.
    El Abbassi A, Khalid N, Zbakh H, Ahmad A. Physicochemical characteristics, nutritional properties, and health benefits of argan oil: a review. Crit Rev Food Sci Nutr. 2014;54(11):1401–14.CrossRefPubMedGoogle Scholar
  41. 41.
    Villareal MO, Kume S, Bourhim T, Bakhtaoui FZ, Kashiwagi K, Han J, et al. Activation of MITF by argan oil leads to the inhibition of the tyrosinase and dopachrome tautomerase expressions in B16 murine melanoma cells. Evid Based Complement Alternat Med. 2013;2013:1–9.CrossRefGoogle Scholar
  42. 42.
    Avsar U, Halici Z, Akpinar E, Yayla M, Harun U, Hasan TA, et al. The effects of argan oil in second-degree burn wound healing in rats. Ostomy Wound Manage. 2016;62(3):26–34.PubMedGoogle Scholar
  43. 43.
    Khallouki F, Younos C, Soulimani R, Oster T, Charrouf Z, Spiegelhalder B, et al. Consumption of argan oil (Morocco) with its unique profile of fatty acids, tocopherols, squalene, sterols and phenolic compounds should confer valuable cancer chemopreventive effects. Eur J Cancer Prev. 2003;12(1):67–75.CrossRefPubMedGoogle Scholar
  44. 44.
    Guillaume D, Charrouf Z. Argan oil and other argan products: use in dermocosmetology. Eur J Lipid Sci Technol. 2011;113(4):403–8.CrossRefGoogle Scholar
  45. 45.
    Jardim KV, Joanitti GA, Azevedo RB, Parize AL. Physico-chemical characterization and cytotoxicity evaluation of curcumin loaded in chitosan/chondroitin sulfate nanoparticles. Mater Sci Eng C. 2015;56:294–304.CrossRefGoogle Scholar
  46. 46.
    Santo VE, Gomes ME, Mano JF, Reis RL. Chitosan–chondroitin sulphate nanoparticles for controlled delivery of platelet lysates in bone regenerative medicine. J Tissue Eng Regen Med. 2012;6(S3):s47–59.CrossRefPubMedGoogle Scholar
  47. 47.
    Tsai HY, Chiu CC, Lin PC, Chen SH, Huang SJ, Wang LF. Antitumor efficacy of doxorubicin released from crosslinked nanoparticulate chondroitin sulfate/chitosan polyelectrolyte complexes. Macromol Biosci. 2011;11(5):680–8.CrossRefPubMedGoogle Scholar
  48. 48.
    Elkomy MH, Elmenshawe SF, Eid HM, Ali AM. Topical ketoprofen nanogel: artificial neural network optimization, clustered bootstrap validation, and in vivo activity evaluation based on longitudinal dose response modeling. Drug Deliv. 2016:1–13.Google Scholar
  49. 49.
    Ramasamy T, Tran TH, Cho HJ, Kim JH, Kim YI, Jeon JY, et al. Chitosan-based polyelectrolyte complexes as potential nanoparticulate carriers: physicochemical and biological characterization. Pharm Res. 2014;31(5):1302–14.CrossRefPubMedGoogle Scholar
  50. 50.
    Müller M. Sizing, shaping and pharmaceutical applications of polyelectrolyte complex nanoparticles. Polyelectrolyte complexes in the dispersed and solid state II: Springer; 2012. p. 197–260.Google Scholar
  51. 51.
    Abdullah TA, Ibrahim NJ, Warsi MH. Chondroitin sulfate-chitosan nanoparticles for ocular delivery of bromfenac sodium: improved permeation, retention, and penetration. Int J Pharm Investig. 2016;6(2):96–105.CrossRefPubMedPubMedCentralGoogle Scholar
  52. 52.
    M-k Y, K-m C, C-s H, Y-c H, J-j Y. Novel protein-loaded chondroitin sulfate–chitosan nanoparticles: preparation and characterization. Acta Biomater. 2011;7(10):3804–12.CrossRefGoogle Scholar
  53. 53.
    Van der Gucht J, Spruijt E, Lemmers M, Stuart MAC. Polyelectrolyte complexes: bulk phases and colloidal systems. J Colloid Interface Sci. 2011;361(2):407–22.CrossRefPubMedGoogle Scholar
  54. 54.
    Maravajhala V, Dasari N, Sepuri A, Joginapalli S. Design and evaluation of niacin microspheres. Indian J Pharm Sci. 2009;71(6):663–9.CrossRefPubMedPubMedCentralGoogle Scholar
  55. 55.
    Sugita P, Ambarsari L. Optimization of ketoprofen-loaded chitosan nanoparticle ultrasonication process. Procedia Chem. 2015;16:673–80.CrossRefGoogle Scholar
  56. 56.
    Sugita P, Ambarsari L, Sari Y, Nugraha Y. Ketoprofen encapsulation optimization with chitosan-alginate cross-linked with sodium tripolyphosphate and its release mechanism determination using in vitro dissolution. Int J Res Rev Appl Sci. 2013;14(1):141–9.Google Scholar
  57. 57.
    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
  58. 58.
    Cirri M, Bragagni M, Mennini N, Mura P. Development of a new delivery system consisting in “drug–in cyclodextrin–in nanostructured lipid carriers” for ketoprofen topical delivery. Eur J Pharm Biopharm. 2012;80(1):46–53.CrossRefPubMedGoogle Scholar
  59. 59.
    Umerska A, Corrigan OI, Tajber L. Design of chondroitin sulfate-based polyelectrolyte nanoplexes: formation of nanocarriers with chitosan and a case study of salmon calcitonin. Carbohydr Polym. 2017;156:276–84.CrossRefPubMedGoogle Scholar
  60. 60.
    Maculotti K, Tira EM, Sonaggere M, Perugini P, Conti B, Modena T, et al. In vitro evaluation of chondroitin sulphate-chitosan microspheres as carrier for the delivery of proteins. J Microencapsul. 2009;26(6):535–43.CrossRefPubMedGoogle Scholar
  61. 61.
    Piai JF, Lopes LC, Fajardo AR, Rubira AF, Muniz EC. Kinetic study of chondroitin sulphate release from chondroitin Sulphate/chitosan complex hydrogel. J Mol Liq. 2010;156(1):28–32.CrossRefGoogle Scholar
  62. 62.
    Charrouf Z, Guillaume D. Argan oil: occurrence, composition and impact on human health. Eur J Lipid Sci Technol. 2008;110(7):632–6.CrossRefGoogle Scholar
  63. 63.
    He W, Guo X, Xiao L, Feng M. Study on the mechanisms of chitosan and its derivatives used as transdermal penetration enhancers. Int J Pharm. 2009;382(1):234–43.CrossRefPubMedGoogle Scholar
  64. 64.
    Gul R, Ahmed N, Shah KU, Khan GM, Rehman A. Functionalised nanostructures for transdermal delivery of drug cargos. J Drug Target. 2018;26(2):110–22.CrossRefPubMedGoogle Scholar

Copyright information

© American Association of Pharmaceutical Scientists 2018

Authors and Affiliations

  1. 1.Department of PharmacyQuaid-i-Azam UniversityIslamabadPakistan
  2. 2.Department of PharmacyUniversity of SwabiSwabiPakistan
  3. 3.Univ LyonUniversity Claude Bernard Lyon-1LyonFrance

Personalised recommendations