Controlled release of low-molecular weight, polymer-free corticosteroid coatings suppresses fibrotic encapsulation of implanted medical devices.

Inflammation-driven foreign body reactions, and the frequently associated encapsulation by fibrogenic fibroblasts, reduce the functionality and longevity of implanted medical devices and materials. Anti-inflammatory drugs, such as dexamethasone, can suppress the foreign body reaction for a few days post-surgery, but lasting drug delivery strategies for long-term implanted materials remain an unmet need. We here establish a thin-coating strategy with novel low molecular weight corticosteroid dimers to suppress foreign body reactions and fibrotic encapsulation of subcutaneous silicone implants. The dimer coatings are >75% dexamethasone by mass and directly processable into conformal coatings using conventional solvent-based techniques, such as casting or spray coating without added polymers or binding agents. In vitro, surface erosion of the coating, and subsequent hydrolysis, provide controlled release of free dexamethasone. In a rat subcutaneous implantation model, the resulting slow and sustained release profile of dexamethasone is effective at reducing the number and activation of pro-fibrotic macrophages both acutely and at chronic time points. Consequently, fibroblast activation, collagen deposition and fibrotic encapsulation are suppressed at least 45 days post-implantation. Thus, our approach to protect implants from host rejection is advantageous over polymeric drug delivery systems, which typically have low drug loading capacity (<30%), initial burst release profiles, and unpredictable release kinetics.

Polymer-free corticosteroid dimer implants for controlled and sustained drug delivery.

Polymeric drug carriers are widely used for providing temporal and/or spatial control of drug delivery, with corticosteroids being one class of drugs that have benefitted from their use for the treatment of inflammatory-mediated conditions. However, these polymer-based systems often have limited drug-loading capacity, suboptimal release kinetics, and/or promote adverse inflammatory responses. This manuscript investigates and describes a strategy for achieving controlled delivery of corticosteroids, based on a discovery that low molecular weight corticosteroid dimers can be processed into drug delivery implant materials using a broad range of established fabrication methods, without the use of polymers or excipients. These implants undergo surface erosion, achieving tightly controlled and reproducible drug release kinetics in vitro. As an example, when used as ocular implants in rats, a dexamethasone dimer implant is shown to effectively inhibit inflammation induced by lipopolysaccharide. In a rabbit model, dexamethasone dimer intravitreal implants demonstrate predictable pharmacokinetics and significantly extend drug release duration and efficacy (>6 months) compared to a leading commercial polymeric dexamethasone-releasing implant.