Intra-articular treatment of inflammatory arthritis with microsphere formulations of methotrexate: pharmacokinetics and efficacy determination in antigen-induced arthritic rabbits.

INTRODUCTION: Methotrexate (MTX) encapsulated microspheres release MTX in the joint in a slow, controlled manner following intra-articular injection in healthy rabbits. The objective of this study was to determine the pharmacokinetics of MTX and to evaluate the efficacy following intra-articular treatment of MTX-loaded microspheres in an antigen-induced inflammatory arthritis rabbit model. METHODS: Arthritis was induced in both knee joints of rabbits using ovalbumin. Rabbits were intra-articularly treated with MTX solution or MTX microspheres and plasma concentrations of MTX were determined in the first 8 h following intra-articular treatment. Rabbits were killed 14 days following treatment and histological analysis of rabbit joints was conducted to determine efficacy. RESULTS: Arthritis was successfully induced in the joints of rabbits with the observation of histopathological features resembling rheumatoid arthritis. No significant differences were detected between MTX solution and MTX microspheres treated groups compared to phosphate buffered saline (control) animals. CONCLUSIONS: MTX microspheres effectively delivered the drug to the intra-articular space. However, a high degree of inter-animal variability, the severity of the disease induced and insufficient length of the observation period were suggested to be possible causes for the lack of therapeutic responses to MTX-loaded microspheres treatment.

Intra-articular drug delivery systems: Overcoming the shortcomings of joint disease therapy.

BACKGROUND: Intra-articular drug delivery is very useful for treating local disease flare-ups, synovitis and pain in joints. However, the effectiveness of drugs following intra-articular administration is limited by drug delivery issues. AIM: This review addresses critical drug delivery parameters that influence the biocompatibility, tolerability and efficacy of intra-articular administrations and offers an opinion on aspects of formulation design. METHODS: The relevant literature was reviewed, focusing on factors influencing tissue targeting, safety and effectiveness of particulate formulations. RESULTS/CONCLUSION: Therapeutic applications of novel drug delivery systems for the localized treatment of joints have lagged significantly. Future innovations in the field will require the discovery of new therapeutic agents for regional delivery, combination regimens, novel biomaterials as drug carriers and targeting carriers to specific molecules.

Pharmacokinetic study of methotrexate following intra-articular injection of methotrexate loaded poly(L-lactic acid) microspheres in rabbits.

The pharmacokinetics and tissue distribution of methotrexate (MTX) were investigated following intra-articular injection of either MTX solution or controlled release MTX loaded microspheres in healthy rabbit joints. MTX solution or MTX loaded microspheres (size 30-100 mum) (10 mg MTX) was injected into the right knee joint cavity of rabbits. Blood samples were taken at predetermined times from the jugular vein. Urine samples were also collected over time periods up to 24 h. The major organs and synovial tissues were removed for analysis 6 and 24 h post-injection (n = 4). MTX and 7-OH-MTX concentrations in the plasma and major organs were determined by HPLC. The MTX plasma area under the concentration-time curve (AUC) for rabbits injected with MTX solution was seven fold higher than that of the rabbits injected with MTX microspheres, while t(1/2) and mean residence time (MRT) were not significantly different between two treatment groups. Four fold more MTX was excreted in the urine from rabbits injected with MTX solution compared to those injected with MTX loaded microspheres 24 h following intra-articular injection. The concentration of MTX in the synovial tissues following intra-articular injection was significantly higher in the rabbits injected with microspheres than in the rabbits injected with MTX solution. MTX solution was rapidly cleared from the joint cavity while MTX encapsulated microspheres retained MTX in the joint cavity.

Methotrexate loaded poly(L-lactic acid) microspheres for intra-articular delivery of methotrexate to the joint.

A controlled release delivery system that localizes methotrexate (MTX) in the synovial joint is needed to treat inflammation in rheumatoid arthritis (RA). The purpose of this work was to develop and characterize MTX loaded poly(l-lactic acid) (PLLA) microspheres and evaluate in vivo tolerability and MTX plasma concentrations following intra-articular injection into healthy rabbits. MTX loaded PLLA (2 kg/mole) microspheres were prepared using the solvent evaporation method and characterized in terms of size, molecular weight, thermal properties, and release rates into phosphate buffered saline (PBS) (pH 7.4) at 37 degrees C. Biocompatibility was evaluated by observing the swelling of the joints of the rabbits and histological analysis following the injection of the microspheres. MTX concentrations in the plasma and urine samples of rabbits were evaluated by high-performance liquid chromatography (HPLC). MTX loaded microspheres showed a rapid burst phase followed by a slow release phase. MTX loaded and control microspheres were biocompatible and plasma concentrations of MTX were tenfold higher in rabbits injected intra-articularly with free MTX than MTX microspheres. MTX microspheres may retain the drug in the joint by reducing clearance from the joint into the blood.

The encapsulation of ribozymes in biodegradable polymeric matrices.

Ribozymes are catalytic RNA that bind and cleave specific regions of target RNA. Therefore, protein synthesis by the target RNA may be specifically inhibited by ribozymes. However, ribozymes are rapidly cleared from plasma so effective treatment of proliferative diseases may rely on the repeated administration of these agents to maintain therapeutic ribozyme concentrations. Therefore, the objective of this study was to encapsulate ribozymes in injectable polymeric paste and microsphere formulations to allow for the controlled release of these agents over extended periods of time. Ribozymes were effectively encapsulated in poly(L-lactic acid) (PLLA) and poly(lactic-co-glycolic) (PLGA) microspheres in various size ranges using a modified water-in-oil-in-water emulsion system and in poly(epsilon-caprolactone) (PCL) pastes by physical blending. These formulations released non-degraded ribozymes, in vitro, in a controlled manner. PLLA microspheres released the ribozymes rapidly whereas PLGA released drugs more slowly. The release rate of ribozymes from PCL pastes could be effectively controlled by altering the loading concentration of ribozymes in the paste. These polymeric injectable formulations of ribozymes may allow for the extended treatment of localized disease sites, such as cancer and arthritis, without the need for repeated dosing.