Methylprednisolone-loaded PLGA microspheres: a new formulation for sustained release via intra-articular...

Area of Science:

• Pharmacology
• Biomaterials Science
• Drug Delivery Systems

Background:

• Intra-articular (i.a.) administration is a common route for delivering corticosteroids like methylprednisolone (MP) to treat joint inflammation.
• Poly(d,l-lactide-co-glycolide) microspheres (PLGA MS) are frequently used as drug delivery vehicles due to their biocompatibility and tunable degradation rates.
• Understanding the pharmacokinetic profiles of MP delivered via different formulations is crucial for optimizing therapeutic outcomes and minimizing systemic exposure.

Purpose of the Study:

• To compare the pharmacokinetic profiles of methylprednisolone (MP) released from poly(d,l-lactide-co-glycolide) microspheres (PLGA MS) versus a commercially available methylprednisolone acetate (MPA) suspension following intra-articular administration in rats.
• To evaluate the impact of formulation on the systemic absorption and distribution of MP.
• To indirectly assess the in vivo anti-inflammatory efficacy by observing extra-articular effects.

Main Methods:

• A validated liquid chromatography-electrospray ionization tandem mass spectrometry (LC-ESI-MS/MS) method was employed to quantify MP concentrations in rat plasma.
• Pharmacokinetic parameters, including peak plasma concentration (Cmax), area under the curve (AUC), and time to peak concentration (tmax), were calculated for both MP-PLGA MS and MPA suspension.
• Carrageenan-induced paw edema was used as an in vivo model to indirectly assess the anti-inflammatory activity of the administered formulations.

Main Results:

• MP released from PLGA MS demonstrated a lower peak plasma concentration (Cmax = 13.7 ± 4.3 ng/mL) and a significantly smaller area under the curve (AUC(0-72h) = 198 ± 45 ng·mL⁻¹·h) compared to MPA suspension (Cmax = 18.4 ± 2.7 ng/mL, AUC(0-72h) = 943 ± 249 ng·mL⁻¹·h).
• MP-PLGA MS resulted in a rapid increase in plasma MP concentration, reaching its maximum at tmax = 0.8 ± 0.3 h, whereas MPA suspension showed a much later tmax of 32.0 ± 13.9 h.
• The MP-PLGA MS formulation exhibited reduced anti-inflammatory activity in the carrageenan-induced paw edema model compared to the MPA suspension, consistent with its lower systemic exposure.

Conclusions:

• Intra-articular administration of MP-PLGA MS leads to distinct pharmacokinetic behavior compared to MPA suspension, characterized by faster initial release but lower overall systemic exposure.
• The PLGA MS formulation offers a potential strategy for controlled methylprednisolone release, influencing its pharmacokinetic profile and potentially its therapeutic window.
• Further investigation into the long-term efficacy and safety of MP-PLGA MS is warranted, considering the observed differences in pharmacokinetic and anti-inflammatory profiles.