An Injectable Click-Crosslinked Hydrogel that Prolongs Dexamethasone Release from Dexamethasone-Loaded Microspheres.

Our purpose was to test whether a preparation of injectable formulations of dexamethasone (Dex)-loaded microspheres (Dex-Ms) mixed with click-crosslinked hyaluronic acid (Cx-HA) (or Pluronic (PH) for comparison) prolongs therapeutic levels of released Dex. Dex-Ms were prepared using a monoaxial-nozzle ultrasonic atomizer with an 85% yield of the Dex-Ms preparation, encapsulation efficiency of 80%, and average particle size of 57 µm. Cx-HA was prepared via a click reaction between transcyclooctene (TCO)-modified HA (TCO-HA) and tetrazine (TET)-modified HA (TET-HA). The injectable formulations (Dex-Ms/PH and Dex-Ms/Cx-HA) were fabricated as suspensions and became a Dex-Ms-loaded hydrogel drug depot after injection into the subcutaneous tissue of Sprague Dawley rats. Dex-Ms alone also formed a drug depot after injection. The Cx-HA hydrogel persisted in vivo for 28 days, but the PH hydrogel disappeared within six days, as evidenced by in vivo near-infrared fluorescence imaging. The in vitro and in vivo cumulative release of Dex by Dex-Ms/Cx-HA was much slower in the early days, followed by sustained release for 28 days, compared with Dex-Ms alone and Dex-Ms/PH. The reason was that the Cx-HA hydrogel acted as an external gel matrix for Dex-Ms, resulting in the retarded release of Dex from Dex-Ms. Therefore, we achieved significantly extended duration of a Dex release from an in vivo Dex-Ms-loaded hydrogel drug depot formed by Dex-Ms wrapped in an injectable click-crosslinked HA hydrogel in a minimally invasive manner. In conclusion, the Dex-Ms/Cx-HA drug depot described in this work showed excellent performance on extended in vivo delivery of Dex.

Effect of Drug Carrier Melting Points on Drug Release of Dexamethasone-Loaded Microspheres.

Here, we examined the effect of melting point of drug carriers on drug release of dexamethasone (Dex)-loaded microspheres. We prepared poly(L-lactide-ran-ε-caprolactone) (PLC) copolymers with varying compositions of poly(ε-caprolactone) (PCL) and poly(L-lactide) (PLLA). As the PLLA content increased, the melting points of PLC copolymers decreased from 61 to 43 °C. PLC copolymers in vials solubilized at 40-50 °C according to the incorporation of PLLA into the PCL segment. Dexamethasone (Dex)-loaded PLC (MCxLy) microspheres were prepared by the oil-in-water (O/W) solvent evaporation/extraction method. The preparation yields were above 70%, and the mean particle size ranged from 30 to 90 µm. The MCxLy microspheres also showed controllable melting points in the range of 40-60 °C. Dex-loaded MCxLy microspheres showed similar in vitro and in vivo sustained release patterns after the initial burst of Dex. The in vitro and in vivo order of the Dex release was MC80L20 > MC90L10 > MC95L5, which agreed well with the melting point order of the drug carrier. Using in vivo fluorescence imaging of fluorescein (FI)-loaded microspheres implanted in animals, we confirmed the sustained release of FI over an extended period. In vivo inflammation associated with the PLC microsphere implants was less pronounced than that associated with Poly(lactide-co-glycolide) (PLGA). In conclusion, we successfully demonstrated that it is possible to control Dex release using Dex-loaded MCxLy microspheres with different melting points.