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Effects of Antibiotic Physicochemical Properties on Their Release Kinetics from Biodegradable Polymer Microparticles

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Abstract

Purpose

This study investigated the effects of the physicochemical properties of antibiotics on the morphology, loading efficiency, size, release kinetics, and antibiotic efficacy of loaded poly(DL-lactic-co-glycolic acid) (PLGA) microparticles (MPs) at different loading percentages.

Methods

Cefazolin, ciprofloxacin, clindamycin, colistin, doxycycline, and vancomycin were loaded at 10 and 20 wt% into PLGA MPs using a water-in-oil-in water double emulsion fabrication protocol. Microparticle morphology, size, loading efficiency, release kinetics, and antibiotic efficacy were assessed.

Results

The results from this study demonstrate that the chemical nature of loaded antibiotics, especially charge and molecular weight, influence the incorporation into and release of antibiotics from PLGA MPs. Drugs with molecular weights less than 600 Da displayed biphasic release while those with molecular weights greater than 1,000 Da displayed triphasic release kinetics. Large molecular weight drugs also had a longer delay before release than smaller molecular weight drugs. The negatively charged antibiotic cefazolin had lower loading efficiency than positively charged antibiotics. Microparticle size appeared to be mainly controlled by fabrication parameters, and partition and solubility coefficients did not appear to have an obvious effect on loading efficiency or release. Released antibiotics maintained their efficacy against susceptible strains over the duration of release. Duration of release varied between 17 and 49 days based on the type of antibiotic loaded.

Conclusions

The data from this study indicate that the chemical nature of antibiotics affects properties of antibiotic-loaded PLGA MPs and allows for general prediction of loading and release kinetics.

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Abbreviations

MIC:

Minimum inhibitory concentration

MP:

Microparticle

PBS:

Phosphate buffered saline

PLGA:

Poly(DL-lactic-co-glycolic acid)

PMMA:

Poly(methylmethacrylate)

PVA:

Poly(vinyl alcohol)

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ACKNOWLEDGMENTS AND DISCLOSURES

This work was supported by the Army, Navy, NIH, Air Force, VA and Health Affairs to support the AFIRM II effort, under Award No. W81XWH-14-2-0004. The U.S. Army Medical Research Acquisition Activity, 820 Chandler Street, Fort Detrick MD 21702-5014 is the awarding and administering acquisition office. Opinions, interpretations, conclusions and recommendations are those of the author and are not necessarily endorsed by the Department of Defense. SRS and PPS would like to acknowledge the Baylor College of Medicine Medical Scientist Training Program.

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Authors and Affiliations

  1. Department of Bioengineering, Rice University, MS-142, 6100 Main St., Houston, Texas, 77005, USA

    Sarita R. Shah, Allan M. Henslee, Patrick P. Spicer, Shun Yokota, Sophia Petrichenko, Sachin Allahabadi, F. Kurtis Kasper & Antonios G. Mikos

  2. Department of Chemical and Biomolecular Engineering, MS-362, 6100 Main St., Houston, Texas, 77005, USA

    Antonios G. Mikos

  3. Department of Biochemistry and Cell Biology, Rice University, MS-140, 6100 Main St., Houston, Texas, 77005, USA

    George N. Bennett

  4. Department of Oral and Maxillofacial Surgery, University of Texas Health Science Center at Houston, 7500 Cambridge St., Houston, Texas, 77054, USA

    Mark E. Wong

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  1. Sarita R. Shah
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Correspondence to Antonios G. Mikos.

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Figure S1

Correlations between loading efficiency (%) and charge (a,b), molecular weight (MW; c,d), logP (e,f), and logS (g,h) for 10 wt% loaded PLGA MPs (top row) and 20 wt% loaded PLGA MPs (bottom row). Charge has a positive correlation with loading efficiency for 10 wt% and 20 wt% loaded MPs. MW, logP, and logS have weak to very weak correlation with loading efficiency. (GIF 36 kb)

High Resolution Image (TIFF 11253 kb)

Figure S2

Correlations between release rate (%/day) during the major phase of release and charge (a,b), molecular weight (MW; c,d), logP (e,f), and logS (g,h) for 10 wt% loaded PLGA MPs (top row) and 20 wt% loaded PLGA MPs (bottom row). None of the factors investigated in this study correlate to the release rate. (GIF 34 kb)

High Resolution Image (TIFF 11388 kb)

Figure S3

Correlations between length of lag phase (days) and charge (a,b), molecular weight (MW; c,d), logP (e,f), and logS (g,h) for 10 wt% loaded PLGA MPs (top row) and 20 wt% loaded PLGA MPs (bottom row). MW has a very strong positive correlation with the length of the lag phase and a negative correlation with solubility. Charge and logP do not have strong correlations to length of lag phase. (GIF 33 kb)

High Resolution Image (TIFF 10752 kb)

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Table SII

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Shah, S.R., Henslee, A.M., Spicer, P.P. et al. Effects of Antibiotic Physicochemical Properties on Their Release Kinetics from Biodegradable Polymer Microparticles. Pharm Res 31, 3379–3389 (2014). https://doi.org/10.1007/s11095-014-1427-y

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  • DOI: https://doi.org/10.1007/s11095-014-1427-y

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