In situ antibody-loaded hydrogel for intravitreal delivery.
Eur J Pharm Sci
; 137: 104993, 2019 Sep 01.
Article
em En
| MEDLINE
| ID: mdl-31302214
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), 5.0â¯mg/mL or bevacizumab (BEVA), 12.5â¯mg/mL), NIPAAM (0.35â¯mmol) and Ac-HA (2.0-10.0â¯mg/mL, 40.0-200.0â¯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 (2.0-4.0â¯mg/mL, 40.0-80.0â¯nmol) showed favourable lower critical solution temperature (LCST) values and injectability (27-29G) than higher amounts of Ac-HA (>4.0â¯mg/mL, >80.0â¯nmol). These hydrogels were further characterised (swelling ratio (SR), water retention (WR) and rheology). All hydrogels degraded in presence of bovine testes hyaluronidase (0-50â¯U/mL, 37⯰C, 100â¯rpm). Release studies of BEVA-loaded hydrogels were investigated in vitro using the PK-Eye™ model, which estimates the human clearance times of proteins from the back of the eye. Phosphate buffered saline (PBS, pHâ¯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⯱â¯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 (VEGF165) throughout the study (two months) while still maintaining a therapeutic dose (123.5⯱â¯45.6â¯ng) in the posterior cavity of the PK-Eye™ 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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Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Acrilamidas
/
Hidrogéis
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Inibidores da Angiogênese
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Bevacizumab
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Infliximab
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Ácido Hialurônico
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Anti-Inflamatórios
Tipo de estudo:
Prognostic_studies
Limite:
Humans
Idioma:
En
Revista:
Eur J Pharm Sci
Ano de publicação:
2019
Tipo de documento:
Article