Skip to main content

Advertisement

SpringerLink
Log in

Prednisolone-Loaded PLGA Microspheres. In Vitro Characterization and In Vivo Application in Adjuvant-Induced Arthritis in Mice

  • Research Article
  • Published:
AAPS PharmSciTech Aims and scope Submit manuscript

Abstract

This study aimed at preparation of a sustained-release steroidal treatment for chronic inflammatory conditions, such as rheumatoid arthritis. To achieve such a goal, biodegradable poly-lactide-co-glycolide prednisolone-loaded microspheres were prepared using o/w emulsion solvent evaporation method. Formulation parameters were adjusted so as to optimize the microsphere characteristics. The prepared microspheres exhibited smooth and intact surfaces, with average size range not exceeding 65 µm. The encapsulation efficiency percent of most microsphere formulations fell within the range of 25–68%. Drug release from these microspheres took place over 4 weeks, with near-to-zero-order patterns. Two successful formulations were chosen for the treatment of unilateral arthritis, induced in mice using Freund's complete adjuvant (FCA). Inflammatory signs of adjuvant arthritis included severe swelling of the FCA-injected limbs, in addition to many histopathological lesions. These included inflammatory cell infiltration, synovial hyperplasia, cartilage, and bone erosion. Parenteral administration of the selected formulae dramatically reduced the swelling of the FCA-injected limbs. In addition, histological examination revealed that the microsphere treatment protocol efficiently protected cartilages and bones of mice, injected with FCA initial and booster doses, from erosion. These results could not be achieved by a single prednisolone dose of 5 mg/kg.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

REFERENCES

  1. Bao L, Zhu Y, ElHassan AM, Wu Q, Xiao B, Zhu J, et al. Adjuvant-induced arthritis: IL-1â, IL-6 and TNF-α are up-regulated in the spinal cord. Neuroimmunology (Neuroreport). 2001;12(18):3905–8.

    CAS  Google Scholar 

  2. Gauldie SD, McQueen DS, Clarke CJ, Chessell IP. A robust model of adjuvant-induced chronic unilateral arthritis in two mouse strains. J Neurosci Methods. 2004;139:281–91.

    Article  PubMed  Google Scholar 

  3. Rannou F, Francois M, Corvol MT, Berenbaum F. Cartilage breakdown in rheumatoid arthritis. Joint Bone Spine. 2006;73:29–36.

    Article  CAS  PubMed  Google Scholar 

  4. Mythilypriya R, Shanthi P, Sachdanandam P. Salubrious effect of kalpaamruthaa, a modified indigenous preparation in adjuvant induced arthritis in rats—a biochemical approach. Chem Biol Interact. 2008;173(2):148–58.

    Article  CAS  PubMed  Google Scholar 

  5. Kumar VL, Roy S, Schgal R, Padhy BM. A comparative study on the efficacy of rofecoxib in monoarticular arthritis induced by latex of Calotropis procera and Freund's complete adjuvant. Inflammopharmacol. 2006;14:17–21.

    Article  CAS  Google Scholar 

  6. Zhang L, Li J, Yu S-C, Jin Y, Lv X-W, Zou Y-H, et al. Therapeutic effects and mechanisms of total flavonoids of Turpinia arguta seen on adjuvant arthritis in rats. J Ethnopharmacol. 2008;116:167–72.

    Article  CAS  PubMed  Google Scholar 

  7. Ding CH, Li Q, Xiang ZY, Zhou AW, Jones G, Xu SY. Oral administration of type II collagen suppresses pro-inflammatory mediator production by synoviocytes in rats with adjuvant arthritis. Clin Exp Immunol. 2003;132:416–23.

    Article  CAS  PubMed  Google Scholar 

  8. Knight B, Katz DR, Isenberg DA, Ibrahim MA, LePage S, Huchings P, et al. Induction of adjuvant arthritis in mice. Clin Exp Immunol. 1992;90:459–65.

    Article  CAS  PubMed  Google Scholar 

  9. Chillingworth NL, Donaldson NF. Characterisation of a Freund's complete adjuvant-induced model of chronic arthritis in mice. J Neurosci Methods. 2003;128:45–52.

    Article  PubMed  Google Scholar 

  10. Bulej P, Kuchar M, Panajotova V, Jegorov A. Pharmacological profile of 4-(2', 4'-difluorobiphenyl-4-yl)- 2-methylbutyric acid (deoxoflobufen). Arzneimittelforschung. 2005;55(8):466–72.

    CAS  PubMed  Google Scholar 

  11. Hildebrandt G, Jahns J, Hindemith M, Spranger S, Sack U, Kinne RW, et al. Effects of low dose radiation therapy on adjuvant induced arthritis in rats. Int J Radiat Biol. 2000;76(8):1143–53.

    Article  CAS  PubMed  Google Scholar 

  12. Hambleton P, McMahon S. Drug actions on delayed-type hypersensitivity in rats with developing and established adjuvant arthritis. Agents Actions. 1990;29(3/4):328–32.

    Article  CAS  PubMed  Google Scholar 

  13. Tachibana M, Inoue N, Yoshida E, Matsui M, Ukai Y, Yanu J. Anti-inflammatory effect and low ulcerogenic activity of etodolac, a cyclooxygenase-2 selective non-steroidal anti-inflammatory drug, on adjuvant-induced arthritis in rats. Pharmacology. 2003;68:96–104.

    Article  CAS  PubMed  Google Scholar 

  14. Palakurthi S, Vyas SP, Diwan PV. Biodisposition of PEG-coated lipid microspheres of indomethacin in arthritic rats. Int J Pharm. 2005;290:55–62.

    Article  CAS  PubMed  Google Scholar 

  15. Yordanov M, Deleva A, Ivanovska N. Host resistance against Candida albicans infection in mice with adjuvant induced arthritis. Mycopathologia. 2001;153:77–82.

    Article  Google Scholar 

  16. Lundberg IE, Grundtman C, Larsson E, Klareskog L. Corticosteroids—from an idea to clinical use. Best Pract Res Clin Rheumatol. 2004;18(1):7–19.

    Article  CAS  PubMed  Google Scholar 

  17. Boers M. Glucocorticoids in rheumatoid arthritis: a senescent research agenda on the brink of rejuvenation? Best Pract Res Clin Rheumatol. 2004;18(1):21–9.

    Article  CAS  PubMed  Google Scholar 

  18. Barnes PJ. Corticosteroids: the drugs to beat. Eur J Pharmacol. 2006;533:2–14.

    Article  CAS  PubMed  Google Scholar 

  19. Adcock IM. Corticosteroids: limitations and future prospects for treatment of severe inflammatory disease. Drug Discov Today Ther Strat. 2004;1(3):321–8.

    Article  CAS  Google Scholar 

  20. Vanniasinghe AS, Bender V, Manolios N. The potential of liposomal drug delivery for the treatment of inflammatory arthritis. Semin Arthritis Rheum. 2009;39(3):182–96.

    Article  CAS  PubMed  Google Scholar 

  21. Wolfe F. The epidemiology of drug treatment failure in rheumatoid arthritis. Baillières Clin Rheumatol. 1995;9(4):619–32.

    Article  CAS  PubMed  Google Scholar 

  22. Smith A, Hunneyball I. Evaluation of poly(lactic acid) as a biodegradable drug delivery system for parenteral administration. Int J Pharm. 1986;30:215–20.

    Article  CAS  Google Scholar 

  23. Khaled AK, Sarhan HA, Ibrahim MA, Naguib YW. Controlled-release prednisolone poly (dl-lactide) microspheres: impact of formulation parameters, characterization and release mechanism. Bull Pharm Sci, Assiut Univ. 2008;31(1):49–67.

    CAS  Google Scholar 

  24. Redmon MP, Hickey AJ, DeLuca PP. Prednisolone-21-acetate (poly glycolic) acid microspheres: influence of matrix characteristics on release. J Control Release. 1989;9:99–109.

    Article  CAS  Google Scholar 

  25. Esposito E, Meregatti E, Cortesi R. Hyaluronan-based microspheres for drug delivery: a comparative study. Int J Pharm. 2005;288:35–49.

    Article  CAS  PubMed  Google Scholar 

  26. Burgess DJ, Davis SS, Tomlinson E. Potential use of albumin microspheres as a drug delivery system. 1. Preparation and in vitro release of steroids. Int J Pharm. 1987;39:129–36.

    Article  CAS  Google Scholar 

  27. Onishi H, Oosegi T, Machida Y, Ku S, McGinity JW. Preparation and in vitro evaluation of chitosan microspheres containing prednisolone: comparison of simple and conjugate microspheres. Drug Dev Ind Pharm. 2005;31:597–605.

    Article  CAS  PubMed  Google Scholar 

  28. Oosegi T, Onishi H, Machida Y. Gastrointestinal distribution and absorption behavior of Eudragit-coated chitosan–prednisolone conjugate microspheres in rats with TNBS-induced colitis. Int J Pharm. 2008;348:80–8.

    Article  CAS  PubMed  Google Scholar 

  29. Oosegi T, Onishi H, Machida Y. Novel preparation of enteric-coated chitosan-prednisolone conjugate microspheres and in vitro evaluation of their potential as a colonic delivery system. Eur J Pharm Biopharm. 2008;68:260–6.

    Article  CAS  PubMed  Google Scholar 

  30. Brannon-Peppas L, Vert M. Polylactic and polyglycolic acids as drug delivery carriers. In: Wise D, editor. Handbook of pharmaceutical controlled release technology. New York: Marcel Dekker Inc.; 2000. p. 99–130.

    Google Scholar 

  31. Park S-B, Jeon Y-J, Haam S, Park H-Y, Kim Y-S. Preparation of chitosan microspheres using membrane emulsification and its size modeling. J Microencapsul. 2004;21(5):539–52.

    Article  CAS  PubMed  Google Scholar 

  32. Jeffery H, Davis SS, O'Hagan DT. The preparation and characterization of poly(lactide-co-glycolide) microparticles. I: Oil-in-water emulsion solvent evaporation. Int J Pharm. 1991;77:169–75.

    Article  Google Scholar 

  33. Chen PC, Park YJ, Chang LC, Kohane DS, Bartlett RR, Langer R, et al. Injectable microparticle–gel system for prolonged and localized lidocaine release. I. In vitro characterization. J Biomed Mater Res A. 2004;70:412–9.

    Article  PubMed  CAS  Google Scholar 

  34. Luan X, Bodmeier R. Modification of the tri-phasic drug release pattern of leuprolide acetate-loaded poly(lactide-co-glycolide) microparticles. Eur J Pharm Biopharm. 2006;63:205–14.

    Article  CAS  PubMed  Google Scholar 

  35. Bodmeier R, McGinity JW. The preparation and evaluation of drug-containing poly (dl-lactide) microspheres formed by the solvent evaporation method. Pharm Res. 1987;4(6):465–71.

    Article  CAS  PubMed  Google Scholar 

  36. Martinez-Sancho C, Herrero-Vanrell R, Negro S. Poly (d,l-lactide-co-glycolide) microspheres for long-term intravitreal delivery of aciclovir: influence of fatty and non-fatty additives. J Microencapsul. 2003;20(6):799–810.

    Article  CAS  PubMed  Google Scholar 

  37. Siepmann J, Goepferich A. Mathematical modeling of bioerodible, polymeric drug delivery systems. Adv Drug Deliv Rev. 2001;48:229–47.

    Article  CAS  PubMed  Google Scholar 

  38. Arifin DY, Lee LY, Wang C-H. Mathematical modeling and simulation of drug release from microspheres: implications to drug delivery systems. Adv Drug Deliv Rev. 2006;58:1274–325.

    Article  CAS  PubMed  Google Scholar 

  39. Lewis DH. Controlled release of bioactive agents from lactide/glycolide polymers. In: Chasin M, Langer R, editors. Biodegradable polymers as drug delivery systems. New York, USA: Marcel Dekker; 1990. p. 1–40.

    Google Scholar 

  40. Chen X, Ooi CP. Hydrolytic degradation and drug release properties of ganciclovir-loaded biodegradable microspheres. Acta Biomater. 2008;4(4):1046–56.

    Article  CAS  PubMed  Google Scholar 

  41. Blanco MD, Sastre RL, Teijon C, Olmo R, Teijon JM. Degradation behaviour of microspheres prepared by spray-drying poly(d, l-lactide) and poly(d, l-lactide-co-glycolide) polymers. Int J Pharm. 2006;326:139–47.

    Article  CAS  PubMed  Google Scholar 

  42. Park TG. Degradation of poly(lactic-co-glycolic acid) microspheres: effect of copolymer composition. Biomaterials. 1995;16:1125–30.

    Article  Google Scholar 

  43. Blasi P, D'Souza SS, Selmin F, DeLuca PP. Plasticizing effect of water on poly(lactide-co-glycolide). J Control Release. 2005;108:1–9.

    Article  CAS  PubMed  Google Scholar 

  44. Klose D, Siepmann F, Elkharraz K, Siepmann J. PLGA-based drug delivery systems: importance of the type of drug and device geometry. Int J Pharm. 2008;354:95–103.

    Article  CAS  PubMed  Google Scholar 

  45. Blackham A, Burns JW, Farmer JB, Radziwonik H, Westwick J. An X-ray analysis of adjuvant arthritis in the rat. The effect of prednisolone and indomethacin. Agents Actions. 1977;71:145–51.

    Article  Google Scholar 

Download references

ACKNOWLEDGEMENTS

The authors would like to thank Al-Kahira Pharmaceutical Company for supplying prednisolone. This research was not financially supported by any institution or any funding agency.

Author information

Authors and Affiliations

  1. Department of Pharmaceutics, Faculty of Pharmacy, Minia University, Minia, Egypt

    Khaled A. Khaled, Hatem A. Sarhan & Youssef W. Naguib

  2. Department of Pharmaceutics, Faculty of Pharmacy, King Saud University, Riyadh, 11451, Kingdom of Saudi Arabia

    Mohamed Abbas Ibrahim

  3. Department of Histology, Faculty of Medicine, Minia University, Minia, Egypt

    Azza H. Ali

Authors
  1. Khaled A. Khaled
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Hatem A. Sarhan
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Mohamed Abbas Ibrahim
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Azza H. Ali
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Youssef W. Naguib
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Mohamed Abbas Ibrahim.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Khaled, K.A., Sarhan, H.A., Ibrahim, M.A. et al. Prednisolone-Loaded PLGA Microspheres. In Vitro Characterization and In Vivo Application in Adjuvant-Induced Arthritis in Mice. AAPS PharmSciTech 11, 859–869 (2010). https://doi.org/10.1208/s12249-010-9445-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1208/s12249-010-9445-5

KEY WORDS

Search

Navigation