Accelerated in vitro release testing of implantable PLGA microsphere/PVA hydrogel composite coatings

Abstract

Dexamethasone loaded poly(lactic-co-glycolic acid) (PLGA) microsphere/PVA hydrogel composites have been investigated as an outer drug-eluting coating for implantable devices such as glucose sensors to counter negative tissue responses to implants. The objective of this study was to develop a discriminatory, accelerated in vitro release testing method for this drug-eluting coating using United States Pharmacopeia (USP) apparatus 4. Polymer degradation and drug release kinetics were investigated under "real-time" and accelerated conditions (i.e. extreme pH, hydro-alcoholic solutions and elevated temperatures). Compared to "real-time" conditions, the initial burst and lag phases were similar using hydro-alcoholic solutions and extreme pH conditions, while the secondary apparent zero-order release phase was slightly accelerated. Elevated temperatures resulted in a significant acceleration of dexamethasone release. The accelerated release data were able to predict "real-time" release when applying the Arrhenius equation. Microsphere batches with faster and slower release profiles were investigated under "real-time" and elevated temperature (60°C) conditions to determine the discriminatory ability of the method. The results demonstrated both the feasibility and the discriminatory ability of this USP apparatus 4 method for in vitro release testing of drug loaded PLGA microsphere/PVA hydrogel composites. This method may be appropriate for similar drug/device combination products and drug delivery systems.

Fig. 1

Dexamethasone release from formulation 503H composite coatings at 37°C in PBS (pH 7.4 and pH 2.4), using USP apparatus 4: (△) pH 7.4, and (○) pH 2.4. (Mean±std dev; n=3).

Fig. 2

SEM micrographs of formulation 503H (PLGA microspheres and composites) after exposure to different release conditions (PBS pH 7.4 and pH 2.4) at 37°C over time: (A, B) initial; (C, D) pH 7.4, day 10; (E, F) pH 7.4, day 20; (G, H) pH 2.4, day 10; (I, J) pH 2.4, day 20. Symbols: white arrows - “insideout” degrading microspheres; and black arrows - “outside-in” degrading PLGA microspheres. Top row, microspheres alone, pH 7.4. Second row, composites, pH 7.4. Third row, microspheres alone, pH 2.4. Fourth row, composites, pH 2.4. Scale bar: 20 µm.

Fig. 3

Dexamethasone release from formulation 503H composite coatings in PBS (pH 7.4) and PBS (pH 7.4) containing 10 % (v/v) ethanol at 37°C, using USP apparatus 4: (△) PBS (pH 7.4), and (●) 10 % ethanol (v/v). (Mean±std dev; n=3).

Fig. 4

SEM micrographs of formulation 503H (PLGA microspheres and composites) after exposure to PBS (pH 7.4) containing 10 % (v/v) ethanol at 37°C over time: (A, B) day 1 and (C, D) day 10; Symbols: white arrows - “inside-out” degrading PLGA microspheres, grey arrows - porous hydrogel matrix. Top row, microspheres alone. Second row, composites. Scale bar: 20 µm.

Fig. 5

Dexamethasone release from formulation 503H composite coatings in PBS (pH 7.4) at elevated temperatures, using USP apparatus 4: (△) 37°C, (●) 45°C, (×) 50°C, (○) 53°C and (▲) 60°C. (Mean±std dev; n=3).

Fig. 6

SEM micrographs of formulation 503H composites after exposure to PBS (pH 7.4): (A) 1 day, at 45°C; (B) 7 days, at 45°C; (C) 1 day, at 50°C; (D) 5 days, at 50°C; (E) 3 days, at 53°C; (F) 4 hours, at 60°C; Symbol: white arrow - “inside-out” degrading PLGA microspheres. Scale bar: 20 µm.

Fig. 7

Arrhenius plot of the calculated zero-order rate constants of dexamethasone release from formulation 503H composite coatings as a function of temperature at 45°C, 50°C, 55°C and 60°C (■). Rate constants at 37°C for predicted and experimental values are shown as a cross (×) and an open square (□), respectively.

Fig. 8

Dexamethasone release from composite coatings (formulations DLG2A, DLG3A 503H and DLG4A) in PBS (pH 7.4) at 37°C, using USP apparatus 4: (×) DLG2A, (●) DLG3A, (△) 503H and (▲) DLG4A. (Mean±std dev; n=3).

Fig. 9

Dexamethasone release from composite coatings (formulations 503H, DLG2A, DLG3A and DLG4A) at 60°C in PBS (pH 7.4), using USP apparatus 4: (×) DLG2A, (●) DLG3A, (△) 503H and (■) DLG4A. (Mean±std dev; n=3).