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
- 378 Downloads
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).
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.
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.
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 WORDSantibiotics controlled drug delivery fusidic acid PLGA and PHBV microspheres solid-state phase separation
Differential scanning calorimetry
Poly(3-hydroxybutyric acid-co-3-hydroxyvaleric acid)
Poly(L -lactic acid)
Scanning electron microscopy
Glass transition temperature
Enthalpy relaxation temperature
X-ray powder diffraction
Enthalpy of melting
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).
- 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.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
- 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
- 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
- 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
- 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.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
- 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
- 31.Dollery C. Fusidic Acid. Therapeutic Drugs, Vol. 2, Churchill Livingstone, London, New York, Philadelphia, San Francisco, Sydney, Toronto, 1999, p. F177.Google Scholar
- 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
- 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
- 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
- 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