Effects of antibiotic physicochemical properties on their release kinetics from biodegradable polymer microparticles

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.

Figure 1

Representative scanning electron micrographs of whole MPs and cut MPs to demonstrate external and internal morphology of cefazolin (a,b,c,d), ciprofloxacin (e,f,g,h), clindamycin (i,j,k,l), colistin (m,n,o,p), doxycycline (q,r,s,t), and vancomycin (u,v,w,x) of 10 wt% whole, 10 wt% cut, 20 wt% whole, and 20 wt% cut MPs, respectively. For comparison, blank MPs are shown whole and cut in (y) and (z), respectively. Whole MPs are shown at 100x magnification, and cut MPs are shown at 500x magnification. The scale bar represents 100 μm for rows 1 and 3 and (y), and 50 μm for rows 2 and 4 and (z).

Figure 2

Release curves for a) cefazolin, b) ciprofloxacin, c) clindamycin, d) colistin, e) doxycycline, and f) vancomycin loaded PLGA microparticles at 10 wt% and 20 wt%. Significant differences between release rates during different phase are indicated by letters. For ciprofloxacin loaded MPs, there is a significant different between 10 wt% and 20 wt% loaded MPs during Phase 1 (p<0.05). For colistin loaded PLGA MPs, Phase 2 and Phase 3 are significantly different between 10 wt% and 20 wt% loaded MPs (p<0.05). Ciprofloxacin and doxycycline 10 wt% loaded MPs demonstrate increased release of antibiotic during Phase 3 compared to 20 wt% loaded MPs, and vancomycin loaded MPs demonstrate increased release from 20 wt% MPs compared to 10 wt% MPs in phase 4 (p<0.05). Cumulative percent release is the same between 10 wt% and 20 wt% for any antibiotic (p>0.05).