Preparation and evaluation of PCL-PEG-PCL micelles as potential nanocarriers for ocular delivery of dexamethasone

Abstract

Objectives: Micelles have been studied as nanoparticulate drug delivery systems for improving the topical ocular delivery of hydrophobic drugs. The objective of this study was to develop and characterize dexamethasone-loaded polycaprolactone-polyethylene glycol-polycaprolactone (PCL-PEG-PCL) micelles to improve patient compliance and enhance the ocular bioavailability of poorly water-soluble drugs.

Materials and methods: The PCL-PEG-PCL copolymers were synthesized via the ring opening polymerization of ε-caprolactone in the presence of PEG. The resulting purified copolymers were characterized by GPC, NMR, FTIR, XRD and DSC. The critical micelle concentrations (CMCs) of the mentioned copolymers were determined. Dexamethasone was loaded into polymeric micelles by film hydration method, and dexamethasone-loaded micelles were characterized by TEM and DLS. Drug release kinetics and ex vivo corneal permeability were also determined.

Results: The CMC of the synthetized copolymers was approximately 0.03 mg/ml. Aqueous solutions of the resulting copolymers (400 mg/ml) rapidly formed a gel in situ at 34°C. The TEM results exhibited the successful formation of spherical micelles. The size of the prepared micelles was approximately 40 nm. Formulated micelles sustained the release of the incorporated dexamethasone for 5 days.

Conclusion: Data from ex vivo permeability tests indicated that PCL-PEG-PCL micelles can be suitable candidates for the ocular delivery of dexamethasone and, likely, other hydrophobic drugs.

Keywords: Block copolymer; Critical micelle concentration; Dexamethasone; Micelle; Ocular drug delivery.

Figure 1

Synthesis scheme of the PCL-PEG-PCL copolymer

Figure 2

Micelle preparation procedure via film hydration method

Figure 3

FTIR spectroscopy of dexamethasone (a), PEG₁₅₀₀ (b), blank copolymer (c), dried dexamethasone/copolymer film (d)

Figure 4

¹H-NMR spectrum of the PCL-PEG-PCL copolymer.

Figure 5

GPC chromatogram of the PCL-PEG-PCL copolymer

Figure 6

XRD diffractogram of dexamethasone (a), PEG₁₅₀₀ (b), dried dexamethasone/copolymer film (c), blank copolymer (d), and physical mixture (e)

Figure 7

DSC thermogram of dexamethasone (a), PEG1500 (b), dried dexamethasone/copolymer film (c), blank copolymer (d), and physical mixture (e)

Figure 8

A) Shear stress versus shear rate of the solution containing 40% w/v copolymer in water at a) 25 °C and b) 34 °C; B) Apparent viscosity (log scale) versus shear rate of the solution containing 40% w/v copolymer in water at a) 25 °C and b) 34 °C.

Figure 9

TEM image of the PCL-PEG-PCL micelles

Figure 10

A) Fluorescence emission spectrum of pyrene (6.2× 10^-5 M) in polymer solution of 10^-3 mg/ml (….) (i.e., below the CMC) and 10^-1 mg/ml (—) (i.e., above the CMC); B) Plot of the intensity ratio (I_I/I_III) of pyrene emission spectra as a function of PCL-PEG-PCL concentration in logarithmic scale

Figure 11

Cumulative percent release of dexamethasone from the micelles and marketed drop

Figure 12

Cumulative amount of drug penetrated through the unit surface area of the bovine corneal membrane in unit of time from the micelles and marketed drop

Figure 13

Histopathological evaluation of the bovine cornea sections, untreated (A), treated with micelles (B) (magnitude X)