Injectable liquid polymers extend the delivery of corticosteroids for the treatment of osteoarthritis

Abstract

Drug delivery strategies generally use inert materials, such as high molecular weight polymers, to encapsulate and control the release rate of therapeutic drugs. Diffusion governs release and depends on the ease of permeation of the polymer alongside the device thickness. Yet in applications such as osteoarthritis, the physiological constraints and limited intra-articular joint space prevent the use of large, solid drug delivery implants. Other investigators have explored the use of micro- and nanoparticle drug delivery systems. However, the small size of the systems limits the total drug that may be encapsulated and its short diffusion distance causes rapid release. Ordinarily, the extremely low diffusivity of a polymer fluid would make this an unsuitable delivery system. Our technology takes advantage of specific molecular interactions between drug and polymer, which can control the rate of release beyond diffusion. With this "affinity-based drug delivery", we have shown that delivery rates from solid polymer can be prolonged from hours and days, to weeks and months. In this paper, we demonstrate that this affinity-based mechanism also applies to low diffusivity fluid-phase polymers. They show release rates that are substantially slower than chemically similar polymers incapable of forming those inclusion complexes. The similarity of this study's liquid polymers to the viscoelastic fluids used in current clinical practice makes it an ample delivery system for osteoarthritic application. We confirmed the capacity of anti-inflammatory delivery of corticosteroids: hydrocortisone, triamcinolone, and dexamethasone; from both solid implants and polymer fluids. Further, we demonstrated that viscoelastic properties are widely tunable, and within the range of native synovial fluid. Lastly, we determined these polymer fluids have no impact on the differentiation of mesenchymal stem cells to cartilage and are not cytotoxic to a common cell line.

Inflammation-Modulating Hydrogels for Osteoarthritis Cartilage Tissue Engineering

“…A reasonably high local drug concentration was maintained for a prolonged time when delivered using this vehicle. Another method of hydrophobic drug delivery utilizes host-guest interactions between cyclodextrin (e.g., β-CD, γ-CD) and the hydrophobic drug [59]. Sustained drug delivery can also take the form of microspheres.…”

Cyclodextrin Cationic Polymer-Based Nanoassemblies to Manage Inflammation by Intra-Articular Delivery Strategies

“…To encompass the rapid clearance of free drug (from hours or few days to weeks) a plethora of engineered biomaterials were proposed [ 5 ]. However, sustained intra-articular delivery strategies by means of drug conjugated or entrapped in hydrogels have some limitations such as (i) the chemical modification could inactivate the drug and (ii) the delayed release of a small drug is generally achieved by increasing the crosslinking of the polymer, which could not flow through a syringe and finally not match the mechanical features of the joint [ 6 ]. To contrast the short therapeutic time, decreasing the frequency of administration, thus optimizing the cartilage penetration, more injectable nanoformulations based on cationic polyelectrolyte needed to be proposed for intra-articular delivery [ 7 ].…”

Multifunctional Coating to Simultaneously Encapsulate Drug and Prevent Infection of Radiopaque Agent

“…PDA modification may also promote protein adsorption on the surface of particles [20]. There are different methods to encapsulate drugs, among them I-CD represents excellent drug loading property contributing to inclusion complex formation of CD with a wide array of small molecules [25,26,27,28]. Rivera-Delgado et al synthesized different cyclodextrin polymers to control the delivery rates from solid polymer from hours and days, to weeks and months [28].…”