Pharmaceutical Research

, Volume 26, Issue 7, pp 1644–1656 | Cite as

PLGA and PHBV Microsphere Formulations and Solid-State Characterization: Possible Implications for Local Delivery of Fusidic Acid for the Treatment and Prevention of Orthopaedic Infections

  • Chiming Yang
  • David Plackett
  • David Needham
  • Helen M. Burt
Research Paper

Abstract

Purpose

To develop and characterize the solid-state properties of poly(DL-lactic-co-glycolic acid) (PLGA) and poly(3-hydroxybutyric acid-co-3-hydroxyvaleric acid) (PHBV) microspheres for the localized and controlled release of fusidic acid (FA).

Methods

The effects of FA loading and polymer composition on the mean diameter, encapsulation efficiency and FA released from the microspheres were determined. The solid-state and phase separation properties of the microspheres were characterized using DSC, XRPD, Raman spectroscopy, SEM, laser confocal and real time recording of single microspheres formation.

Results

Above a loading of 1% (w/w) FA phase separated from PLGA polymer and formed distinct spherical FA-rich amorphous microdomains throughout the PLGA microsphere. For FA-loaded PLGA microspheres, encapsulation efficiency and cumulative release increased with initial drug loading. Similarly, cumulative release from FA-loaded PHBV microspheres was increased by FA loading. After the initial burst release, FA was released from PLGA microspheres much slower compared to PHBV microspheres.

Conclusions

A unique phase separation phenomenon of FA in PLGA but not in PHBV polymers was observed, driven by coalescence of liquid microdroplets of a DCM-FA-rich phase in the forming microsphere.

KEY WORDS

antibiotics controlled drug delivery fusidic acid PLGA and PHBV microspheres solid-state phase separation 

Abbreviations

BSEM

Backscattering SEM

DSC

Differential scanning calorimetry

FA

Fusidic acid

HV

Hydroxyvaleric acid

PHBV

Poly(3-hydroxybutyric acid-co-3-hydroxyvaleric acid)

PLGA

Poly(DL-lactic-co-glycolic acid)

PLLA

Poly(L -lactic acid)

PMMA

Poly(methylmethacrylate)

SEM

Scanning electron microscopy

Tg

Glass transition temperature

Tm

Melting temperature

Tr

Enthalpy relaxation temperature

XRPD

X-ray powder diffraction

ΔHm

Enthalpy of melting

ΔHr

Enthalpy relaxation

Notes

ACKNOWLEDGMENTS

We would like to thank Dr. Tim Smith and Renishaw plc, Wotton-under-Edge, UK for his assistance and the use of the confocal Raman microscope. We also like to thank John Jackson, Kevin Letchford, Sam Gilchrist and Ben Wasserman for their excellent technical assistance and discussion. This work was supported by Canadian Institutes of Health Research (CIHR) New Emerging Team (NET) Grant. In addition, the authors would like to thank Natural Sciences and Engineering Council of Canada (NSERC) for financial support to C.Y. in the form of a NSERC Postgraduate Scholarship-Doctoral (PGS-D).

Supplementary material

11095_2009_9875_MOESM1_ESM.avi (5.3 mb)
ESM 1 (AVI 5.34 MB)

References

  1. 1.
    Trampuzand A, Widmer AF. Infections associated with orthopedic implants. Curr Opin Infect Dis 2006;19:349–56.CrossRefGoogle Scholar
  2. 2.
    Atkinsand B, Gottlieb T. Fusidic acid in bone and joint infections. Int J Antimicrob Agents 1999;12:S79–93. doi: 10.1016/S0924-8579(98)00077-6.CrossRefGoogle Scholar
  3. 3.
    Darleyand AP, MacGowan ESR. Antibiotic treatment of Gram-positive bone and joint infections. J Antimicrob Chemother 2004;53:928–35. doi: 10.1093/jac/dkh191.CrossRefGoogle Scholar
  4. 4.
    Segreti J, Trenholme GM, Nelson JA. Prolonged suppressive antibiotic therapy for infected orthopaedic prostheses. Clin Infect Dis 1998;27:711–3. doi: 10.1086/514951.PubMedCrossRefGoogle Scholar
  5. 5.
    Tattevin P, Cremieux AC, Pottier P, et al. Prosthetic joint infection: when can prosthesis salvage be considered? Clin Infect Dis 1999;2:292–5. doi: 10.1086/520202.CrossRefGoogle Scholar
  6. 6.
    Bengtson S, Borgquist L, Lindgren L. Cost analysis of prophylaxis with antibiotics to prevent infected knee arthroplasty. Br Med J 1989;299:719–20.CrossRefGoogle Scholar
  7. 7.
    Hill C, Flamant R, Mazas F, Evrard J. Prophylactic cefazolin versus placebo in total hip replacement. Report of a multicentre double-blind randomised trail. Lancet 1981;1:795–6. doi: 10.1016/S0140-6736(81)92678-7.PubMedCrossRefGoogle Scholar
  8. 8.
    Periti P, Mini E, Mosconi G. Antimicrobial prophylaxis in orthopedic surgery: the role of teicoplanin. J Antimicrob Chemother 1998;41:329–40. doi: 10.1093/jac/41.3.329.PubMedCrossRefGoogle Scholar
  9. 9.
    Periti P, Stringa G, Mini E. Comparative multicenter trail of teicoplanin versus cefazolin for antimicrobial prophylaxis in prosthetic joint implant surgery. Italian study group for antimicrobial prophylaxis in orthopedic surgery. Eur J Clin Microbiol Infect Dis 1999;18:119. doi: 10.1007/s100960050238.CrossRefGoogle Scholar
  10. 10.
    Rauschmann MA, Wichelhaus TA, Stirnal V, Dingeldein E, Zichner L, Schnettler R, Alt V. Nanocrystalline hydroxyapatite and calcium sulphate as biodegradable composite carrier material for local delivery of antibiotics in bone infections. Biomaterials 2005;26:2677–84. doi: 10.1016/j.biomaterials.2004.06.045.PubMedCrossRefGoogle Scholar
  11. 11.
    Hassenand MJ, Spangehl AD. Practical applications of antibiotic-loaded bone cement for treatment of infected joint replacements. Clin Orthop Relat Res 2004;427:79–85.CrossRefGoogle Scholar
  12. 12.
    Adams K, Couch L, Cierny G, Calhoun J, Mader JT. In vitro and in vivo evaluation of antibiotic diffusion from antibiotic-impregnated polymethylmethacrylate beads. Clin Orthop 1992;278:244–52.PubMedGoogle Scholar
  13. 13.
    Kanellakopoulouand K, Giamarellos-Bourboulis EJ. Carrier systems for the local delivery of antibiotics in bone infections. Drugs 2000;59:1223–32. doi: 10.2165/00003495-200059060-00003.CrossRefGoogle Scholar
  14. 14.
    Hoff SF, Fitzgerald Jr RH, et al. The depot administration of penicillin G and gentamicin acrylic bone cement. J Bone Jt Surg 1981;63:798–804.Google Scholar
  15. 15.
    Holmand NJ, vejlsgaard R. The in vitro elution of gentamicin sulphate from methylmethacrylate bone cement-A comparative study. Acta Orthop Scand 1976;47:144–8.CrossRefGoogle Scholar
  16. 16.
    Vogt S, Kuehn KD, Ege W, Pawlik K, Schnabelrauch M. Novel polylactide-based release systems for local antibiotic therapies. Materialwissenschaft und Werkstofftechnik 2003;34:1041–7. doi: 10.1002/mawe.200300701.CrossRefGoogle Scholar
  17. 17.
    Wahlig H, Dingeldein E, Bergmann R, Reuss K. The release of gentamicin from polymethylmethacrylate beads: an experimental and pharmacokinetics study. J Bone Jt Surg 1978;60:270.Google Scholar
  18. 18.
    Wang G, Liu SJ, Ueng SW-N, Chan EC. The release of cefazolin and gentamicin from biodegradable PLA/PGA beads. Int J Pharm 2004;273:203–12. doi: 10.1016/j.ijpharm.2004.01.010.PubMedCrossRefGoogle Scholar
  19. 19.
    Naraharisetti PK, Lew MDN, Fu YC, Lee DJ, Wang CH. Gentamicin-loaded discs and microspheres and their modifications: characterization and in vitro release. J Control Release 2005;102:345–59. doi: 10.1016/j.jconrel.2004.10.016.PubMedCrossRefGoogle Scholar
  20. 20.
    Yenice I, Calis S, Atilla B, Kas HS, Oezalp M, Ekizoglu M, Bilgili H, Hincal AA. In vitro/in vivo evaluation of the efficiency of teicoplanin-loaded biodegradable microparticles formulated for implantation to infected bone defects. J Microencapsul 2003;20:705–17. doi: 10.1080/0265204031000154179.PubMedCrossRefGoogle Scholar
  21. 21.
    Gursel I, Korkusuz F, Turesin F, Gurdal Alaeddinoglu N, Hasirci V. In vivo application of biodegradable controlled antibiotic release systems for the treatment of implant-related osteomyelitis. Biomaterials 2000;22:73–80. doi: 10.1016/S0142-9612(00)00170-8.CrossRefGoogle Scholar
  22. 22.
    Rossi S, Azghani AO, Omri A. Antimicrobial efficacy of a new antibiotic-loaded poly(hydroxybutyric-co-hydroxyvaleric acid) controlled release system. J Antimicrob Chemother 2004;54:1013–8. doi: 10.1093/jac/dkh477.PubMedCrossRefGoogle Scholar
  23. 23.
    Yagmurlu MF, Korkusuz F, Gursel I, Korkusuz P, Ors U, Hasirci V. Sulbactam-cefoperazone polyhydroxybutyrate-co-hydroxyvalerate (PHBV) local antibiotic delivery system: in vivo effectiveness and biocompatibility in the treatment of implant-related experimental osteomyelitis. J Biomed Materi Res 1999;46:494–503. doi: 10.1002/(SICI)1097-4636(19990915)46:4<494::AID-JBM7>3.0.CO;2-E.CrossRefGoogle Scholar
  24. 24.
    Jacob E, Cierny G, Fallon MT, McNeill JF, Siderys GS. Evaluation of biodegradable cefazolin sodium microspheres for the prevention of infection in rabbits with experimental open tibial fractures stabilized with internal fixation. J Orthop Res 1993;11:404–11. doi: 10.1002/jor.1100110312.PubMedCrossRefGoogle Scholar
  25. 25.
    Jacob E, Cierny G, Zorn K, McNeill JF, Fallon MT. Delayed local treatment of rabbit tibial fractures with biodegradable cefazolin microspheres. Clin Orthop Relat Res 1997;336:278–85. doi: 10.1097/00003086-199703000-00036.PubMedCrossRefGoogle Scholar
  26. 26.
    Jacob E, Setterstrom JA, Bach DE, Heath Iii JR, McNiesh LM. Cierny G. Evaluation of biodegradable ampicillin anhydrate microspheres for local treatment of experimental staphylococcal osteomyelitis. Clin Orthop Relat Res 1991;267:237–44.PubMedGoogle Scholar
  27. 27.
    Li H, Chang J. Preparation, characterization and in vitro release of gentamicin from PHBV/wollastonite composite microspheres. J Control Release 2005;107:463–73. doi: 10.1016/j.jconrel.2005.05.019.PubMedCrossRefGoogle Scholar
  28. 28.
    Sendil D, Gursel I, Wise DL, Hasirci V. Antibiotic release from biodegradable PHBV microparticles. J Control Release 1999;59:207–17. doi: 10.1016/S0168-3659(98)00195-3.PubMedCrossRefGoogle Scholar
  29. 29.
    Mandell LA, Mandell GL, Bennett JE, Dolin R. Fusidic Acid. Mandell, Douglas and Bennett’s Principles and Practic of Infectious Diseases, Vol. 5, Churchill Livingstone, Philadelphia, 2000, p. 306.Google Scholar
  30. 30.
    Christiansen K. Fusidic acid adverse drug reactions. Int J Antimicrob Agents 1999;12(Suppl 2):S3–9. doi: 10.1016/S0924-8579(98)00068-5.PubMedCrossRefGoogle Scholar
  31. 31.
    Dollery C. Fusidic Acid. Therapeutic Drugs, Vol. 2, Churchill Livingstone, London, New York, Philadelphia, San Francisco, Sydney, Toronto, 1999, p. F177.Google Scholar
  32. 32.
    Turnidge J. Fusidic acid pharmacology, pharmacokinetics and pharmacodynamics. Int J Antimicrob Agents 1999;12:S23–34. doi: 10.1016/S0924-8579(98)00071-5.PubMedCrossRefGoogle Scholar
  33. 33.
    Andrews HJ, Arden GP, Hart GM, Owen JW. Deep infection after total hip replacement. J Bone Jt Surg 1981;63B:53–7.Google Scholar
  34. 34.
    Coombs RR, Menday AP. Fusidic acid in orthopaedic infections due to coaguluase-negative staphylococci. Curr Med Res Opin 1985;9:587–90.PubMedGoogle Scholar
  35. 35.
    Bouillet R, Bouillet B, Kadima N, Gillard J. Treatment of chronic osteomyelitis in Africa with plaster implants impregnated with antibiotics. Acta Orthop Belg 1989;55:1–11.PubMedGoogle Scholar
  36. 36.
    Mackey D, Varlet A, Debeaumont D. Antibiotic loaded plaster of paris pellets: an in vitro study of a possible method of local antibiotic therapy in bone infection. Clin Orthop and Relat Res 1982;167:263–8.Google Scholar
  37. 37.
    Mousset B, Benoit MA, Delloye C, Bouillet R, Gillard J. Biodegradable implants for potential use in bone infection. An in vitro study of antibiotic-loaded calcium sulphate. Int Orthop 1995;19:157–61. doi: 10.1007/BF00181861.PubMedCrossRefGoogle Scholar
  38. 38.
    Cevher E, Orhan Z, Sensoy D, Ahiskali R, Kan PL, Sagirli O, Mulazimoglu L. Sodium fusidate-poly(D,L-lactide-co-glycolide) microspheres: preparation, characterisation and in vivo evaluation of their effectiveness in the treatment of chronic osteomyelitis. J Microencapsul 2007;24:577–95. doi: 10.1080/02652040701472584.PubMedCrossRefGoogle Scholar
  39. 39.
    O’Donnell PB, McGinity JW. Preparation of microspheres by the solvent evaporation technique. Adv Drug Deliv Rev 1997;28:25–42. doi: 10.1016/S0169-409X(97)00049-5.PubMedCrossRefGoogle Scholar
  40. 40.
    Liggins RT, Burt HM. Paclitaxel loaded poly(L-lactic acid) microspheres: properties of microspheres made with low molecular weight polymers. Int J Pharm 2001;222:19–33. doi: 10.1016/S0378-5173(01)00690-1.PubMedCrossRefGoogle Scholar
  41. 41.
    Liggins RT, Burt HM. Paclitaxel loaded poly(l-lactic acid) (PLLA) microspheres II. The effect of processing parameters on microsphere morphology and drug release kinetics. Int J Pharm 2004;281:103–6. doi: 10.1016/j.ijpharm.2004.05.027.PubMedCrossRefGoogle Scholar
  42. 42.
    Liggins RT, Burt HM. Paclitaxel-loaded poly(L-lactic acid) microspheres 3: Blending low and high molecular weight polymers to control morphology and drug release. Int J Pharm 2004;282:61–71. doi: 10.1016/j.ijpharm.2004.05.026.PubMedCrossRefGoogle Scholar
  43. 43.
    Gangrade N, Price JC. Simple gas chromatographic headspace analysis of residual organic solvent in microspheres. J Pharm Sci 1992;81:201–202. doi: 10.1002/jps.2600810221.PubMedCrossRefGoogle Scholar
  44. 44.
    Gangrade N, Price JC. Poly(hydroxybutyrate-hydroxyvalerate) microspheres containing progesterone: preparation, morphology and release properties. J Microencapsul 1991;8:185–202. doi: 10.3109/02652049109071487.PubMedCrossRefGoogle Scholar
  45. 45.
    Gunaratne LMWK, Shanks RA. Melting and thermal history of poly(hydroxybutyrate-co-hydroxyvalerate) using step-scan DSC. Thermochimica Acta 2005;430:183–90. doi: 10.1016/j.tca.2005.01.060.CrossRefGoogle Scholar
  46. 46.
    Duncan PB, Needham D. Microdroplet dissolution into a second-phase solvent using a micropipet technique: test of the Epstein-Plesset model for an aniline–water system. Langmuir 2006;22:4190–7. doi: 10.1021/la053314e.PubMedCrossRefGoogle Scholar
  47. 47.
    Freita A, Merkle HP, Gander B. Microencapsulation by solvent extraction/evaporation: reviewing the state of the art of microsphere preparation process technology. J Control Release 2005;102:313–32. doi: 10.1016/j.jconrel.2004.10.015.CrossRefGoogle Scholar
  48. 48.
    Mohamed F, van der Walle CF. Engineering biodegradable polyester particles with specific drug targeting and drug release properties. J Pharm Sci 2008;97:71–87. doi: 10.1002/jps.21082.PubMedCrossRefGoogle Scholar
  49. 49.
    Panyam J, Williams D, Dash A, Leslie-Pelecky D, Labhasetwar V. Solid-state solubility influences encapsulation and release of hydrophobic drugs from PLGA/PLA nanoparticles. J Pharm Sci 2004;93:1804–14. doi: 10.1002/jps.20094.PubMedCrossRefGoogle Scholar
  50. 50.
    Vasanthavada M, Tong WQ, Joshi Y, Kislalioglu MS. Phase behavior of amorphous molecular dispersions II: role of hydrogen bonding in solid solubility and phase separation kinetics. Pharm Res 2005;22:440–8. doi: 10.1007/s11095-004-1882-y.PubMedCrossRefGoogle Scholar
  51. 51.
    Vasanthavada M, Tong WQ, Joshi Y, Kislalioglu MS. Phase behavior of amorphous molecular dispersions I: determination of the degree and mechanism of solid solubility. Pharm Res 2004;21:1598–606. doi: 10.1023/B:PHAM.0000041454.76342.0e.PubMedCrossRefGoogle Scholar
  52. 52.
    Ma GH, Nagai M, Omi S. Study on preparation and morphology of uniform artificial polystyrene-poly(methyl methacrylate) composite microspheres by employing the spg (shirasu porous glass) membrane emulsification technique. J Colloid Interface Sci 1999;214:264–82. doi: 10.1006/jcis.1999.6188.PubMedCrossRefGoogle Scholar
  53. 53.
    Vega E, Gamisans F, Garcia ML, Chauvet A, Lacoulonche F, Egea MA. PLGA nanospheres for the ocular delivery of flurbiprofen: drug release and interactions. J Pharm Sci. 2008;97:1–12.CrossRefGoogle Scholar
  54. 54.
    Garcia A, Iriarte M, Uriarte C, Iruin JJ, Etxeberria A, del Rio J. Antiplasticization of a polyamide: a positron annihilation lifetime spectroscopy study. Polymer 2004;45:2949–57. doi: 10.1016/j.polymer.2004.02.045.CrossRefGoogle Scholar
  55. 55.
    Slark AT. The effect of intermolecular forces on the glass transition of solute-polymer blends. Polymer 1997;38:2407–14. doi: 10.1016/S0032-3861(96)00782-3.CrossRefGoogle Scholar
  56. 56.
    Bouissou C, Rouse JJ, Price R, van der Walle CF. The influence of surfactant on PLGA microsphere glass transition and water sorption: remodeling the surface morphology to attenuate the burst release. Pharm Res 2006;23:1295–305. doi: 10.1007/s11095-006-0180-2.PubMedCrossRefGoogle Scholar
  57. 57.
    Anderson JM, Shive MS. Biodegradation and biocompatibility of PLA and PLGA microspheres. Adv Drug Deliv Rev 1997;28:5–24. doi: 10.1016/S0169-409X(97)00048-3.PubMedCrossRefGoogle Scholar
  58. 58.
    Miller RA, Brady JM, Cutright DE. Degradation rates of oral resorbable implants (polylactates and polyglycolates): rate modification with changes in PLA/PGA copolymer ratios. J Biomed Materi Res 1977;11:711–9. doi: 10.1002/jbm.820110507.CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2009

Authors and Affiliations

  • Chiming Yang
    • 1
  • David Plackett
    • 2
  • David Needham
    • 3
  • Helen M. Burt
    • 1
  1. 1.Faculty of Pharmaceutical SciencesThe University of British ColumbiaVancouverCanada
  2. 2.Risø National Laboratory for Sustainable EnergyTechnical University of Denmark—DTURoskildeDenmark
  3. 3.Department of Mechanical Engineering and Material ScienceDuke UniversityDurhamUSA

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