Degradation, Intra-Articular Biocompatibility, Drug Release, and Bioactivity of Tacrolimus-Loaded Poly(d-l-lactide-PEG)-b-poly(l-lactide) Multiblock Copolymer-Based Monospheres.

This study is about a formulation developed for sustained intra-articular release of tacrolimus, an anti-inflammatory drug. The drug’s release rates were adjustable via modifying polymer composition. The formulation was tested on rat knees to evaluate its biocompatibility and its effectiveness in delivering the drug locally without systemic effects, confirming its potential use in treating inflammatory joint diseases.

Research Method and Formulation Development

• The researchers aimed to develop a formulation that delivers the anti-inflammatory drug tacrolimus into the joint for an extended duration. This was achieved by loading the drug into biodegradable microspheres made of poly(d-l-lactide-PEG)–poly(l-lactide) multiblock copolymers.
• The microspheres were 30 μm in size and could release the drug over a period ranging from 7 to more than 42 days, depending on the formulation. The release kinetics of the drug was adjusted by altering the polymer composition, specifically the hydrophobic-hydrophilic block ratio.

In vivo Evaluation

• The researchers further evaluated the formulation with the most sustained release (lasting one month) through in vivo experiments. They injected rat knees with three different doses of tacrolimus loaded monospheres. Control knees were injected with saline.
• Monitoring with micro-computed tomography (micro-CT) and histological analysis showed no destructive changes to the cartilage—signifying good biocompatibility. However, minor osteophyte formation (bone growth usually caused by damage to a joint) was observed in a dose-dependent manner, suggestive of local drug release and therapeutic action.

In Vivo Drug Release and Therapeutic Action

• To check in vivo drug release, they injected tacrolimus monospheres into horse joints and took multiple blood and synovial fluid samples at different time intervals.
• The entire four-week follow-up showed sustained intra-articular release with nearly no systemic drug concentrations (<1 ng/mL). This confirmed the feasibility of localized intra-articular drug delivery without instigating systemic effects.
• Intra-articular injection of unloaded monospheres led to a temporary inflammatory reaction, as shown by the total synovial leucocyte count after 72 hours. This reaction was substantially reduced in the joints injected with tacrolimus loaded monospheres, demonstrating the drug’s local anti-inflammatory action.

Conclusion

• These results suggest that the formulation’s local anti-inflammatory effects without systemic side-effects could be beneficial in treating inflammatory joint diseases, including osteoarthritis.