Hot-Melt Extrusion-Based Dexamethasone-PLGA Implants: Physicochemical, Physicomechanical, and Surface Morphological Properties and In Vitro Release Corrected for Drug Degradation

Abstract

Developing bioequivalent (BE) generic products of complex dosage forms like intravitreal implants (IVIs) of corticosteroids such as dexamethasone prepared using hot-melt extrusion (HME), based on biodegradable poly (lactide-co-glycolide) (PLGA) polymers, can be challenging. A better understanding of the relationship between the physicochemical and physicomechanical properties of IVIs and their effect on drug release and ocular bioavailability is crucial to develop novel BE approaches. It is possible that the key physicochemical and physicomechanical properties of IVIs such as drug properties, implant surface roughness, mechanical strength and toughness, and implant erosion could vary for different compositions, resulting in changes in drug release. Therefore, this study investigated the hypothesis that biodegradable ophthalmic dexamethasone-loaded implants with 20% drug and 80% PLGA polymer(s) prepared using single-pass hot-melt extrusion (HME) differ in physicochemical and/or physicomechanical properties and drug release depending on their PLGA polymer composition. Acid end-capped PLGA was mixed with an ester end-capped PLGA to make three formulations: HME-1, HME-2, and HME-3, containing 100%, 80%, and 60% w/w of the acid end-capped PLGA. Further, this study compared the drug release between independent batches of each composition. In vitro release tests (IVRTs) indicated that HME-1 implants can be readily distinguished by their release profiles from HME-2 and HME-3, with the release being similar for HME-2 and HME-3. In the early stages, drug release generally correlated well with polymer composition and implant properties, with the release increasing with PLGA acid content (for day-1 release, R² = 0.80) and/or elevated surface roughness (for day-1 and day-14 release, R² ≥ 0.82). Further, implant mechanical strength and toughness correlated inversely with PLGA acid content and day-1 drug release. Drug release from independent batches was similar for each composition. The findings of this project could be helpful for developing generic PLGA polymer-based ocular implant products.

Keywords: LC-MS/MS; biodegradable; corticosteroid; dexamethasone; hot-melt extrusion (HME); implants; intravitreal; ocular drug delivery systems; poly-(lactide-co-glycolide) PLGA; sustained drug release.

Figure 1

DSC thermograms of dexamethasone, implant dexamethasone formulations HME-1 to 3, PLGA acid, and ester end-capped formulation components.

Figure 2

(A) is the average strength (g), and (B) is the average toughness (g*sec) for with/without dexamethasone implants stored at low or high relative humidity. Mean ± STDEV, n = 6.

Figure 3

AFM images of dexamethasone implants from left to right, no exposure, after day-1, and after day-14 exposure to the PBS (pH 7.4) media.

Figure 4

AFM surface roughness, (A) shows R_q and (B) shows R_a values for implants after exposure to PBS. Mean ± STDEV, n = 3.

Figure 5

Polarized light microscopy (PLM) images of dexamethasone/without drug implant films using a melt-congealing technique at 10× magnification.

Figure 6

The X-ray diffraction patterns of the polymers, implant drug formulations, and the drug dexamethasone.

Figure 7

SEM images of samples under 150×, 230×, and 500× magnifications. (A) No exposure to PBS, (B) after Day-1, and (C) after Day-14.

Figure 8

Release profile similarities. From three different batches manufactured using three different formulation compositions of the drug dexamethasone–PLGA implants analyzing quadruple samples (A–F), each formulation with all data points (panels on the left side or without outliers’ panels on the right side). The 99% TLs (black dashed line, n = 12) were defined with 95% confidence (black dotted line, n = 12). Release values from the test samples (red circles, n = 12). The mean is the solid black line. TL, tolerance limit.

Figure 9

Correlation of cumulative dexamethasone release at end of day-1, -14, -35, and -71 with implant composition.

Figure 10

The correlation of the cumulative dexamethasone release at the end of day-1 and day-14 with the (A) implant average surface roughness (R_a) and (B) root mean square roughness (R_q) measured on the same days using atomic force microscopy. Different roughness measures represent distinct implant compositions, as shown in Figure 4.

Figure 11

Influence of implant composition and relative humidity (RH) on its mechanical properties and dexamethasone release. Correlation of (A) implant mechanical properties (strength and toughness) with implant composition, (B) cumulative dexamethasone release at end of day-1 with mechanical properties, and (C) cumulative dexamethasone release at end of day-14 with mechanical properties. Mechanical properties were measured after storage at relative humidity of about 30 or 75%.