MedinGel™: a controlled-release platform for intraarticular delivery of osteoarthritis drugs

Abstract

Purpose: Current osteoarthritis treatments have clear delivery limitations and are principally designed to treat symptoms. Drawbacks include inefficient penetration of drugs into the joint space, systemic side effects and short duration of action. Drugs administered for systemic release have poor synovial penetration that is required to provide relief from OA-related pain and inflammation. High plasma concentrations of many NSAID compounds lead to severe side effects such as stomach pain and ulcers. And in the case of orally administered celecoxib, warnings of increased risk for heart attack and stroke have been issued. MedinCell will present our company's experience in designing polymer-based delivery technology to circumvent these problems with the goal of improving osteoarthritis treatments. We will discuss the use of our MedinGel™ platform for multi-month local delivery of small molecules and biologics to help control pain, reduce inflammation and promote cartilage repair. Without controlled release capability, drugs injected directly into the joint spaces are often cleared within hours. Yet daily intraarticular injections are untenable, as they would have to be administered by trained clinicians and would severely impact the patients’ quality of life. Additionally, a high frequency of injections into the joint could have increased risk of bacterial infection. By tailoring formulations to specific drugs for a range of delivery durations, MedinCell is confident that intraarticular formulations can deliver a sustained therapeutic drug concentration over multiple months to obviate current concerns and improve both treatment efficacy and patient compliance. Methods: After evaluation of drug solubility and set up of in vitro-release assays, a series of sets of formulations evaluating combinations of polymers at different concentrations were prepared. The MedinGel matrix is composed of mixtures of drug molecules with solubilized, bioresorbable polymers. Within minutes after injection through a fine needle, the aqueous environment of the joint leads to a phase-separation of the formulated polymers and formation of a three-dimensional matrix. This resulting semi-solid hydrogel depot entraps and protects drug molecules within the joint space, and minimizes clearance to the plasma. Results: Candidate formulations that provided a range of drug release rates in vivo were evaluated. The best candidates were then tested by intraarticular injection. MedinCell has designed intraarticular formulations of OA drug therapies that maintained therapeutic synovial concentrations for a 3-month duration in animals. Conclusions: The MedinGel platform enables control over the initial drug burst characteristics, allowing the remainder of the drug to be released over a predetermined duration via polymer hydrolysis and drug diffusion until the depot is completely resorbed. No covalent modification of the active substance is required, which can simplify regulatory and development pathways. We will present data showing differential compartmentalization of drug between joint and plasma when comparing normal injection to MedinGel delivery. Additionally, MedinCell expects that this technology will provide effective delivery of disease-modifying caspase inhibitors and proteins (such as BMP7) for trauma-induced arthritis.