Polymer-mediated delivery of vaccines to treat opioid use disorders and to reduce opioid-induced toxicity.

Vaccines offer a potential strategy to treat opioid use disorders (OUD) and to reduce the incidence of opioid-related overdoses. Vaccines induce opioid-specific polyclonal antibodies that selectively and effectively bind the target opioid and prevent its distribution across the blood-brain barrier. Because antibody-mediated reduction of drug distribution to the brain reduces drug-induced behavior and toxicity, vaccine efficacy depends on the quantity and quality of the antibody response. This study tested whether polymer-mediated delivery could improve vaccine efficacy against opioids as well as eliminate the need for booster injections normally required for a successful immunization. A series of novel biodegradable biocompatible thermogelling pentablock co-polymers were used to formulate a candidate vaccine against oxycodone in mice and rats. Polymer-based delivery of the anti-oxycodone vaccine was equally or more effective than administration in aluminum adjuvant in generating oxycodone-specific antibodies and in reducing oxycodone-induced effects and oxycodone distribution to the brain in mice and rats. The composition and release kinetics of the polymer formulations determined vaccine efficacy. Specifically, a formulation consisting of three simultaneous injections of the anti-oxycodone vaccine formulated in three different polymers with slow, intermediate, and fast release kinetics was more effective than an immunization regimen consisting of three sequential injections with the vaccine adsorbed on aluminum. The novel three-phased polymer vaccine formulation was effective in blocking oxycodone-induced antinociception, respiratory depression and bradycardia in rats.

Evaluation of Intracameral Pentablock Copolymer Thermosensitive Gel for Sustained Drug Delivery to the Anterior Chamber of the Eye.

PURPOSE: To investigate PTSgels (Pentablock copolymers) as an injectable formulation technology for sustained ocular drug delivery. Drug release profile, tolerability, and polymer degradation for one of the thermosensitive, biodegradable, and biocompatible compositions were investigated through intracameral (IC) injection in rabbits. METHODS: New Zealand White rabbit eyes were injected IC (50 µL) with 100 µg near-infrared-immunoglobulin G (NIR-IgG) in balanced salt solution (BSS) or 20% PTSgel; or with PTSgel or BSS alone. Ocular irritation scoring, intraocular pressure (IOP), and corneal thickness (CT) measurement, as well as color and infrared photography, were performed for up to 28 days postinjection. Upon euthanasia at 7, 14, or 28 days, eyes underwent ex vivo imaging (Xenogen IVIS) followed by tissue fixation and histopathology. RESULTS: IC injection of PTSgel (liquid at room temperature) was performed without difficulty using a 31G needle. The polymer quickly gelled in the IC space resulting in an inferior anterior chamber deposit. The tested PTSgel was well tolerated, with no significant changes in IOP or CT. Eyes injected with NIR-IgG in PTSgel had visible NIR-IgG through 9 days postinjection, and ex vivo imaging detected a strong NIR-IgG signal in the anterior chamber through day 28. The gel deposit steadily decreased in size over time and was nearly eliminated by 28 days. CONCLUSIONS: The PTSgel released IgG for 28 days and was well tolerated. The polymer degraded in parallel with drug release. These results demonstrate the potential of intracameral PTSgel formulations for sustained delivery of biologic therapies to the ocular anterior segment.

Sustained Release of Protein Therapeutics from Subcutaneous Thermosensitive Biocompatible and Biodegradable Pentablock Copolymers (PTSgels).

Objective. To evaluate thermosensitive, biodegradable pentablock copolymers (PTSgel) for sustained release and integrity of a therapeutic protein when injected subcutaneously. Materials and Methods. Five PTSgels with PEG-PCL-PLA-PCL-PEG block arrangements were synthesized. In vitro release of IgG from PTSgels and concentrations was evaluated at 37°C. Released IgG integrity was characterized by SDS-PAGE. In vitro disintegration for 10GH PTSgel in PBS was monitored at 37°C over 72 days using gravimetric loss and GPC analysis. Near-infrared IgG in PTSgel was injected subcutaneously and examined by in vivo imaging and histopathology for up to 42 days. Results. IgG release was modulated from approximately 7 days to more than 63 days in both in vitro and in vivo testing by varying polymer composition, concentration of PTSgel aqueous solution, and concentration of IgG. Released IgG in vitro maintained structural integrity by SDS-PAGE. Subcutaneous PTSgels were highly biocompatible and in vitro IgG release occurred in parallel with the disappearance of subcutaneous gel in vivo. Conclusions. Modulation of release of biologics to fit the therapeutic need can be achieved by varying the biocompatible and biodegradable PTSgel composition. Release of IgG parallels disappearance of the polymeric gel; hence, little or no PTSgel remains after drug release is complete.