Awwad, S;
Abubakre, A;
Angkawinitwong, U;
Khaw, PT;
Brocchini, S;
(2019)
In situ antibody-loaded hydrogel for intravitreal delivery.
European Journal of Pharmaceutical Sciences
, 137
, Article 104993. 10.1016/j.ejps.2019.104993.
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Abstract
Therapeutic protein medicines have transformed the treatment of blinding diseases (e.g. age-related macular degeneration, AMD) during the last 1–2 decades. Many blinding conditions such as AMD are chronic; and require multiple intravitreal injections over a long period to achieve a high and reproducible dose needed for clinical benefit. Prolonging the duration of action of ophthalmic drugs is critical to reduce the frequency of injections. Thermoresponsive hydrogels (e.g. N-isopropylacrylamide, NIPAAM) that collapse in physiological conditions can entrap and sustain the release of a therapeutic protein. However, most NIPAAM hydrogels are not biodegradable and often requires invasive surgery to remove the depot. Here, we report the preparation of a hydrogel derived from NIPAAM and acrylated hyaluronic acid (Ac-HA) as a biodegradable, macromolecular crosslinker. Ac-HA was prepared by the acrylation of hyaluronic acid (HA). Antibody (infliximab (INF), 5.0 mg/mL or bevacizumab (BEVA), 12.5 mg/mL), NIPAAM (0.35 mmol) and Ac-HA (2.0–10.0 mg/mL, 40.0–200.0 nmol) were first mixed prior to redox polymerisation to ensure maximal protein mixing and to shorten the burst release. Hydrogels with lower amounts of Ac-HA (2.0–4.0 mg/mL, 40.0–80.0 nmol) showed favourable lower critical solution temperature (LCST) values and injectability (27–29G) than higher amounts of Ac-HA (>4.0 mg/mL, >80.0 nmol). These hydrogels were further characterised (swelling ratio (SR), water retention (WR) and rheology). All hydrogels degraded in presence of bovine testes hyaluronidase (0–50 U/mL, 37 °C, 100 rpm). Release studies of BEVA-loaded hydrogels were investigated in vitro using the PK-Eye^{TM} model, which estimates the human clearance times of proteins from the back of the eye. Phosphate buffered saline (PBS, pH 7.4, 37 °C) was used rather than simulated vitreous to more effectively map trends between the formulations. A zero-order release profile was observed between days 5 to 50 with 43.3 ± 9.5% protein released at day 50. Determining protein binding and functionality from a formulation is crucial to determine the optimal formulation prior to more detailed studies that might be necessary. BEVA showed binding to human vascular growth endothelial factor (VEGF_{165} throughout the study (two months) while still maintaining a therapeutic dose (123.5 ± 45.6 ng) in the posterior cavity of the PK-Eye_{TM} model. These encouraging results suggest that extended release of proteins in the vitreous can be achieved using injectable hydrogels derived from NIPAAM and HA.
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