The Effect of Polymer Blends on the In Vitro Release/Degradation and Pharmacokinetics of Moxidectin-Loaded PLGA Microspheres

Abstract

To investigate the effect of polymer blends on the in vitro release/degradation and pharmacokinetics of moxidectin-loaded PLGA microspheres (MOX-MS), four formulations (F1, F2, F3 and F4) were prepared using the O/W emulsion solvent evaporation method by blending high (75/25, 75 kDa) and low (50/50, 23 kDa) molecular weight PLGA with different ratios. The addition of low-molecular-weight PLGA did not change the release mechanism of microspheres, but sped up the drug release of microspheres and drastically shortened the lag phase. The in vitro degradation results show that the release of microspheres consisted of a combination of pore diffusion and erosion, and especially autocatalysis played an important role in this process. Furthermore, an accelerated release method was also developed to reduce the period for drug release testing within one month. The pharmacokinetic results demonstrated that MOX-MS could be released for at least 60 days with only a slight blood drug concentration fluctuation. In particular, F3 displayed the highest AUC and plasma concentration (AUC_0-t = 596.53 ng/mL·d, C_{ave (day 30-day 60)} = 8.84 ng/mL), making it the optimal formulation. Overall, these results indicate that using polymer blends could easily adjust hydrophobic drug release from microspheres and notably reduce the lag phase of microspheres.

Keywords: PLGA microspheres; in vitro release; moxidectin; pharmacokinetics; polymer blends.

Figure 1

SEM images of MOX-MS.

Figure 2

PXRD curves of moxidectin, blank microspheres, MOX-MS (F1–F4), physical mixture of moxidectin and blank microspheres.

Figure 3

Shadow images of water droplets on F1 (A), F2 (B), F3 (C) and F4 (D).

Figure 4

In vitro release profile of MOX-MS in 10 mM PBS solution (pH 7.4, containing 0.5% SDS and 0.02% NaN₃) with a shaking speed of 100 rpm at 37 °C (the ratio of PLGA (75/25, 75 kDa) to PLGA (50/50, 23 kDa): F1 = 1:0; F2 = 9:1; F3 = 2:1; F4 = 1:1).

Figure 5

The accelerated in vitro release profiles of MOX-MS at 50 °C (A) and at 60 °C (B).

Figure 6

The in vitro degradation process of MOX-MS incubated in 10 mM PBS solution (pH 7.4, containing 0.5% SDS and 0.02%NaN₃) at 37 °C: (A) mass changes of MOX-MS; (B) polymer Mw changes of MOX-MS; (C) pH changes of release medium.

Figure 7

SEM images of MOX-MS during different periods in vitro.

Figure 8

Schematic illustration of the in vitro release mechanism of MOX-MS. From I to II: Drugs on the surface of the microspheres diffused into the release medium formed the initial burst release. From II to III: Wrinkles on the surface of the microspheres gradually disappeared, and only a small amount of drugs was released; thus, the microspheres entered a long lag phase. From III to IV: Many pores formed, accompanied by a large amount of drug released from microspheres at nearly zero-order and the microspheres entered an erosion-controlled release phase.

Figure 9

Plasma concentration–time profiles of moxidectin after a single subcutaneous injection of moxidectin solution (A) or MOX-MS (B) (1 mg/kg). (n = 6; mean ± SD).