Gellan Gum/Alginate Microparticles as Drug Delivery Vehicles: DOE Production Optimization and Drug Delivery

Abstract

Gellan gum is a biocompatible and easily accessible polysaccharide with excellent properties to produce microparticles as drug delivery systems. However, the production methods often fail in reproducibility, compromising the translational potential of such systems. In this work, the production of gellan gum-based microparticles was optimized using the coaxial air flow method, and an inexpensive and reproducible production method. A design of experiments was used to identify the main parameters that affect microparticle production and optimization, focusing on diameter and dispersibility. Airflow was the most significant factor for both parameters. Pump flow affected the diameter, while the gellan gum/alginate ratio affected dispersibility. Microparticles were revealed to be sensitive to pH with swelling, degradation, and encapsulation efficiency affected by pH. Using methylene blue as a model drug, higher encapsulation, and swelling indexes were obtained at pH 7.4, while a more pronounced release occurred at pH 6.5. Within PBs solutions, the microparticles endured up to two months. The microparticle release profiles were studied using well-known models, showing a Fickian-type release, but with no alteration by pH. The developed microparticles showed promising results as drug-delivery vehicles sensitive to pH.

Keywords: alginate; coaxial airflow; design of experiments; gellan gum; microparticles.

Figure 1

Flow curves (25 °C) of the Alg:GG solutions (2 wt%) with different ratios of GG and Alg.

Figure 2

GG:Alg microparticle images from (a) run 6, (b) run 3, (c) run 21, and (d) run 10 (see Table 1).

Figure 3

(a) Pareto charts with the effects of the different variables on the particle’s diameter (24 runs, at least 100 microparticles measured for each run) (p-value < 0.05). Empty bars mean significant factor, while full ones are of non-significant. (b) Interaction plots for particle’s diameter between the significant factors the C: air flow and D: pump flow (A: GG:Alg ratio (% w/v) = 50:50; B: bath-nozzle gap = 15 cm). (c) Response surface plot for the particle’s size, with the effect of C: air flow and D: pump flow (A: GG:Alg ratio = 50:50; B: bath-nozzle gap = 15 cm).

Figure 4

Pareto charts with the effects of the different variables on the particle’s dispersibility (24 runs, at least 100 microparticles measured for each run) (p-value < 0.05) (a.1) COV, (b.1) SPAN. (a.2) Interaction plots for particle’s diameter COV between the significant factors the A: GG:Alg ratio and C: air flow (B: bath-nozzle gap = 15 cm; D: pump flow = 5 mL/h); (b.2) Interaction plots for particle’s diameter SPAN between the significant factors the A: GG:Alg ratio and C: air flow (B: bath-nozzle gap = 15 cm; D: pump flow = 5 mL/h); (a.3) Response surface plot for the particle’s diameter COV, with the effect of C: air flow and D: pump flow (A: GG:Alg ratio = 25:75; B: bath-nozzle gap = 15 cm); (b.3) Response surface plot for the particle’s diameter SPAN, with the effect of C: air flow and D: pump flow (A: GG:Alg ratio = 25:75; B: bath-nozzle gap = 15 cm).

Figure 5

(a–c) SEM analysis of dried GG:Alg particles. (d) Swelling indexes of microparticles.

Figure 6

(a) Encapsulation efficiency (E.E.%) and (b) loading capacity (L.C.) with different concentrations of methylene blue (MB) in PBS solutions with pH of 6.5 and 7.4.

Figure 7

(a) FTIR of the GG:Alg microparticles and (b) TGA of GG:Alg microparticles, with and without MB, and MB alone.

Figure 8

(a) Degradation of microparticles within PBS with pH 6.5 and pH 7.4 for 57 days; (b) GG:Alg particles after 28 days in PBS.

Figure 9

Methylene blue cumulative release from GG:Alg particles in PBS at pH 6.5 and 7.4.

Figure 10

General scheme of the coaxial air flow system. (a) Scheme of microparticle’s production near the nozzle, adapted from from [80]. (b) Ampliation of (a).