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

Yang, Chang-Kook; Plackett, David; Needham, David; Burt, Helen M.

doi:10.1007/s11095-009-9875-5

Cited by 37 publications

(33 citation statements)

References 57 publications

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“…Raman mapping has previously been applied to pharmaceutical systems including drug loaded polymeric microspheres [22,23], thin polymer films [18,19,24,25] and tablet compound identification [26], specifically using multivariate methods of analysis [27][28][29].…”

Section: Introductionmentioning

confidence: 99%

Chemical and spatial analysis of protein loaded PLGA microspheres for drug delivery applications

Rafati

Boussahel

Shakesheff

et al. 2012

Journal of Controlled Release

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Polymer microspheres for controlled release of therapeutic protein from within an implantable scaffold were produced and analysed using complimentary techniques to probe the surface and bulk chemistry of the microspheres. Time of Flight - Secondary Ion Mass Spectrometry (ToF-SIMS) surface analysis revealed a thin discontinuous film of polyvinyl alcohol (PVA) surfactant (circa 4.5 nm thick) at the surface which was readily removed under sputtering with C(60). Atomic Force Microscopy (AFM) imaging of microspheres before and after sputtering confirmed that the PVA layer was removed after sputtering revealing poly(lactic-co-glycolic) acid(PLGA). Scanning electron microscopy showed the spheres to be smooth with some shallow and generally circular depressions, often with pores in their central region. The occurrence of the protein at the surface was limited to areas surrounding these surface pores. This surface protein distribution is believed to be related to a burst release of the protein on dissolution. Analysis of the bulk properties of the microspheres by confocal Raman mapping revealed the 3D distribution of the protein showing large voids within the pores. Protein was found to be adsorbed at the interface with the PLGA oil phase following deposition on evaporation of the solvent. Protein was also observed concentrated within pores measuring approximately 2 μm across. The presence of protein in large voids and concentrated pores was further scrutinised by ToF-SIMS of sectioned microspheres. This paper demonstrates that important information for optimisation of such complex bioformulations, including an understanding of the release profile can be revealed by complementary surface and bulk analysis allowing optimisation of the therapeutic effect of such formulations.

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Section: Introductionmentioning

confidence: 99%

Chemical and spatial analysis of protein loaded PLGA microspheres for drug delivery applications

Rafati

Boussahel

Shakesheff

et al. 2012

Journal of Controlled Release

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“…A similar kind of phase separation was spectacularly shown to occur in real-time in previous work with Yang [28], where fusidic acid (FA) was seen to precipitate out of a DCM/PLGA/FA solution microdroplet, and even form surface spheroids that were clearly not entrapped or retained in the polymer microsphere. In the current experiment, as shown in Figure 9, the phase-separated Ibp then simply dissolved away, presumably at its own dissolution rate.…”

Section: Ibuprofen Phase-separation From Dcm/plgamentioning

confidence: 54%

“…First used in a non-mechanical way in 1998 to simply position micro-hydrogel beads with and without a loaded-drug (doxorubicin) in a controlled flow field of different pH [23,24], the micropipette technique was then developed by Needham et al [1][2][3][4][25][26][27][28][29][30][31][32][33][34][35][36][37], Tony Yeung et al [38], and others, in a series of papers on adsorption at interfaces and two-phase oil-aqueous systems. It has now become a highly versatile experimental setup that allows a wide variety of studies at microscopic interfaces and with single-and pairs-of microparticles.…”

Section: The Micropipette Techniquementioning

confidence: 99%

“…It has now become a highly versatile experimental setup that allows a wide variety of studies at microscopic interfaces and with single-and pairs-of microparticles. Among other applications, the technique has been established for studying solvent dissolution, measuring fundamental properties such as diffusion coefficients and solubilities of the dissolving liquids [4,27,30], and for evaluating the phase separation, precipitation of droplets containing different solutes upon solvent loss, such as the micro-glassification of proteins by fast removal of water into water-imbibing solvents like octanol [3,31], and drug-containing polymer microspheres by removal of the organic solvent into water [28,29]. It is this last application that has motivated and guided the current studies with poly(lactic-co-glycolic acid) (PLGA) microparticles containing Ibuprofen [34].…”

Section: The Micropipette Techniquementioning

confidence: 99%

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From Single Microparticles to Microfluidic Emulsification: Fundamental Properties (Solubility, Density, Phase Separation) from Micropipette Manipulation of Solvent, Drug and Polymer Microspheres

et al. 2016

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Abstract:The micropipette manipulation technique is capable of making fundamental single particle measurements and analyses. This information is critical for establishing processing parameters in systems such as microfluidics and homogenization. To demonstrate what can be achieved at the single particle level, the micropipette technique was used to form and characterize the encapsulation of Ibuprofen (Ibp) into poly(lactic-co-glycolic acid) (PLGA) microspheres from dichloromethane (DCM) solutions, measuring the loading capacity and solubility limits of Ibp in typical PLGA microspheres. Formed in phosphate buffered saline (PBS), pH 7.4, Ibp/PLGA/DCM microdroplets were uniformly solidified into Ibp/PLGA microparticles up to drug loadings (DL) of 41%. However, at DL 50 wt% and above, microparticles showed a phase separated pattern. Working with single microparticles, we also estimated the dissolution time of pure Ibp microspheres in the buffer or in detergent micelle solutions, as a function of the microsphere size and compare that to calculated dissolution times using the Epstein-Plesset (EP) model. Single, pure Ibp microparticles precipitated as liquid phase microdroplets that then gradually dissolved into the surrounding PBS medium. Analyzing the dissolution profiles of Ibp over time, a diffusion coefficient of 5.5 ± 0.2 × 10 −6 cm 2 /s was obtained by using the EP model, which was in excellent agreement with the literature. Finally, solubilization of Ibp into sodium dodecyl sulfate (SDS) micelles was directly visualized microscopically for the first time by the micropipette technique, showing that such micellization could increase the solubility of Ibp from 4 to 80 mM at 100 mM SDS. We also introduce a particular microfluidic device that has recently been used to make PLGA microspheres, showing the importance of optimizing the flow parameters. Using this device, perfectly smooth and size-homogeneous microparticles were formed for flow rates of 0.167 mL/h for the dispersed phase (Q d ) and 1.67 mL/h for the water phase (Q c ), i.e., a flow rate ratio Q d /Q c of 10, based on parameters such as interfacial tension, dissolution rates and final concentrations. Thus, using the micropipette technique to observe the formation, and quantify solvent dissolution, solidification or precipitation of an active pharmaceutical ingredient (API) or excipient for single and individual microparticles, represents a very useful tool for understanding microsphere-processes and hence can help to establish process conditions without resorting to expensive and material-consuming bulk particle runs.

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“…PHBV is used in tissue engineering of bone [170], cartilage [171], skin [172], and nerves [173]. PHA are also utilized in association with other polymers [174,175] or modified with additives to enhance their stability [176,177]. In dentistry, Ueda et al inserted medium-chain-length PHA into the defect created in a rabbit's mandible, showing osteoconductive properties which promoted bone regeneration.…”

Section: Polyestersmentioning

confidence: 99%

Biodegradable polymers for dental tissue engineering and regeneration

Conte¹,

Riccitiello²,

Luise³

et al. 2017

Biodegradable Polymers: Recent Developments and New Perspectives

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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

Abstract: 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.

Cited by 37 publications

References 57 publications

Chemical and spatial analysis of protein loaded PLGA microspheres for drug delivery applications

Chemical and spatial analysis of protein loaded PLGA microspheres for drug delivery applications

From Single Microparticles to Microfluidic Emulsification: Fundamental Properties (Solubility, Density, Phase Separation) from Micropipette Manipulation of Solvent, Drug and Polymer Microspheres

Biodegradable polymers for dental tissue engineering and regeneration

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