Fabrication and Use of Poly(d,l-lactide-co-glycolide)-Based Formulations Designed for Modified Release of 5-Fluorouracil

Abstract

5-fluorouracil (5-FU) is a chemotherapeutic agent that has been used for the treatment of a variety of malignancies since its initial introduction to the clinic in 1957. Owing to its short biological half-life, multiple dosings are generally required to maintain effective 5-FU plasma concentrations throughout the therapeutic period. Clinical studies have shown that continuous 5-FU administration is generally superior to bolus injection as exhibited by lower toxicities and increased therapeutic efficacy. Optimal therapeutic efficacy, however, is often compromised by the limiting therapeutic index. Whilst oral formulations are also used, these suffer from the drawbacks of variable bioavailability and first-pass metabolism. As a result, sustained release formulations of 5-FU have been investigated in an effort to mimic the kinetics of continuous infusion particularly for situations where local delivery is considered appropriate. The biocompatible, biodegradable, and highly tunable synthetic polymer, poly(d,l-lactide-co-glycolide) (PLGA), is widely used as a vector for sustained drug delivery, however, issues such as insufficient loading and inappropriate burst release kinetics have dogged progress into the clinic for small hydrophilic drugs such as 5-FU. This review provides introductory information about the mechanism of action, pharmacokinetic and physicochemical properties, and clinical use of 5-FU that have contributed to the development of PLGA-based 5-FU release platforms. In addition, this review provides information on fabrication methods used for a range of 5-FU-loaded PLGA formulations and discusses factors affecting the release kinetics of 5-FU as well as the in vitro and in vivo antitumor or antiproliferative efficacy of these platforms.

Sulfasalazine Resolves Joint Stiffness in a Rabbit Model of Arthrofibrosis

“…Drugs were encapsulated in PLGA pellets to localize delivery to the fibrotic joint. PLGA is a bioresorbable polymer that has a long track record for use in prolonging drug release in humans . Pellet delivery allowed drug levels to be steadily maintained for 2–3 weeks, obviating the need for multiple intra‐articular injections while reducing toxicity to normal joint tissues.…”

“…Drug‐loaded PLGA pellets were made by the hot‐melt extrusion method . The goal was to load the maximum amount of drug possible in the pellets, which varies depending on the physical and chemical properties of the drugs and their behavior during the hot‐melt extrusion process.…”

“…Drug elution profiles were characterized in vitro prior to implantation. Elution was measured by incubation of the pellets in phosphate‐buffered saline (PBS) at 37°C in a shaking incubator set to 300 rpm (Fig, B, C, and D) . At each time point, PBS was removed from the pellets and replaced with fresh PBS.…”

“…We hypothesized that local treatment with one or more of the drugs described above would alleviate existing joint stiffness in an established rabbit model, in which fibrosis of the stifle (knee) joint is achieved by inducing hemarthrosis, followed by rigid fixation in flexion . To maintain therapeutic drug levels for up to 3 weeks without resorting to multiple joint injections, fibrosed joints were treated once by implantation of drugs encapsulated in poly[lactic‐co‐glycolic] acid (PLGA) pellets, a well‐established prolonged‐release delivery vehicle . Joint stiffness evaluated by flexion/extension tests served as the primary measure of treatment effects.…”

“…35,36 To maintain therapeutic drug levels for up to 3 weeks without resorting to multiple joint injections, fibrosed joints were treated once by implantation of drugs encapsulated in poly[lactic-co-glycolic] acid (PLGA) pellets, a wellestablished prolonged-release delivery vehicle. 37 Joint stiffness evaluated by flexion/extension tests served as the primary measure of treatment effects. Secondary effects on ACL stability and synovial intimal thickness were also assessed.…”