An Intra-articular, Extended-release Formulation of Triamcinolone Acetonide under Investigation for the Treatment of Osteoarthritis of the Knee
In the 1950’s, intra-articular injection of a corticosteroid (in particular hydrocortisone acetate) became an accepted treatment for what at the time were termed “arthritic” joints. Over ensuing decades, various synthetic corticosteroids, including Triamcinolone acetonide, were approved by the Food and Drug Administration (FDA) with labeling for short-term administration in osteoarthritis and other indications. Use of intra-articular corticosteroid treatment has grown steadily over the last 60 years, and 6.3 million injections for knee osteoarthritis (OA) in the US were reported in 2015. Among the nearly 12 million Medicare beneficiaries with knee OA, more than 25% received IA corticosteroid injections, and the number of intra-articular injections per patient doubled between 1999 and 2013.
Zilretta™ (FX006), Flexion’s lead investigational drug candidate, was developed with the goal of enhancing the clinical effect of intra-articular corticosteroid treatment. Zilretta™ is an extended-release formulation of Triamcinolone acetonide designed to prolong local residence following intra-articular injection. Zilretta™ is formulated using proprietary microsphere technology combining Triamcinolone acetonide with a poly lactic-co-glycolic acid (PLGA) matrix. Zilretta™ has received Fast Track Designation from the FDA. This designation is given to a drug in clinical development that is intended to treat a serious condition and addresses unmet medical need. Implicit in the definition of unmet medical need is the potential to provide a benefit over that observed with available therapies. An NDA (New Drug Application) for FX006 was submitted to the FDA in December 2016.
Zilretta™(FX006) is formulated as a suspension of microspheres measuring approximately 45 microns in diameter. Within each microsphere, small crystals of Triamcinolone are embedded in a poly lactic-co-glycolic acid (PLGA) co-polymer matrix (Figure 1A).
In vitro, release of TA from the microsphere commences immediately, and scanning electron micrographs reveal the formation of nano-channels, approximately 500 nanometers in diameter, on the smooth, largely intact, microsphere surface (Figure 1B). These nano-channels, limit both egress of TA from the microsphere’s interior and internal hydration of the polymer, prolonging drug release and slowing PLGA erosion. In the final stage of release, the PLGA matrix degrades to oligomeric poly-acid units and then to lactic and glycolic acids, followed by elimination as carbon dioxide and water.
Figure 1. FX006, an intra-articular, extended-release formulation of Triamcinolone acetonide in a poly lactic-co-glycolic acid (PLGA) co-polymer matrix.
(A) Within each microsphere, small crystals of Triamcinolone (red) are embedded in a PLGA matrix (green).
(B) In the initial phase of release, small channels (green circles) of approximately 500 nanometers in diameter appear on the smooth, largely intact, surface of the microsphere, slow the release of Triamcinolone from the microsphere.