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Pharmaceutics2021; 13(9); doi: 10.3390/pharmaceutics13091438

Sustained Intra-Articular Release and Biocompatibility of Tacrolimus (FK506) Loaded Monospheres Composed of [PDLA-PEG1000]-b-[PLLA] Multi-Block Copolymers in Healthy Horse Joints.

Abstract: There is an increasing interest in controlled release systems for local therapy in the treatment of human and equine joint diseases, aiming for optimal intra-articular concentrations with no systemic side effects. In this study, the intra-articular tolerability and suitability for local and sustained release of tacrolimus (FK506) from monospheres composed of [PDLA-PEG1000]-b-PLLA multiblock copolymers were investigated. Unloaded and tacrolimus-loaded (18.4 mg tacrolimus/joint) monospheres were injected into the joints of six healthy horses, with saline and hyaluronic acid (HA) in the contralateral joints as controls. Blood and synovial fluid were analysed for the tacrolimus concentration and biomarkers for inflammation and cartilage metabolism. After an initial burst release, sustained intra-articular tacrolimus concentrations (>20 ng/mL) were observed during the 42 days follow-up. Whole-blood tacrolimus levels were below the detectable level (<0.5 ng/mL). A transient inflammatory reaction was observed for all substances, evidenced by increases of the synovial fluid white blood cell count and total protein. Prostaglandin and glycosaminoglycan release were increased in joints injected with unloaded monospheres, which was mitigated by tacrolimus. Both tacrolimus-loaded monospheres and HA transiently increased the concentration of collagen II cleavage products (C2C). A histologic evaluation of the joints at the endpoint showed no pathological changes in any of the conditions. Together, these results indicate the good biocompatibility of intra-articular applied tacrolimus-loaded monospheres combined with prolonged local drug release while minimising the risk of systemic side effects. Further evaluation in a clinical setting is needed to determine if tacrolimus-loaded monospheres can be beneficial in the treatment of inflammatory joint diseases in humans and animals.
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Publication Date: 2021-09-10 PubMed ID: 34575514PubMed Central: PMC8465142DOI: 10.3390/pharmaceutics13091438Google Scholar: Lookup
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  • Journal Article

Summary

This research summary has been generated with artificial intelligence and may contain errors and omissions. Refer to the original study to confirm details provided. Submit correction.

The research study examines the effectiveness and tolerability of using tacrolimus-loaded monospheres for treating joint diseases in humans and horses, reducing systemic side effects and maintaining optimal intra-articular drug concentrations.

Objective of the Research

  • The research aimed to investigate the suitability and tolerability of tacrolimus (FK506) – a drug used in joint disease treatment – when loaded onto monospheres. The researchers explored these monospheres’ potential for localised and sustained drug release within the joints.

Methodology

  • The study treated the joints of six healthy horses with monospheres, both loaded and unloaded with tacrolimus, then compared the results with joints treated with saline and hyaluronic acid (HA) controls.
  • They analyzed synovial fluid and blood samples to monitor tacrolimus concentration, inflammation markers, and cartilage metabolism indicators.

Findings

  • After an initial burst release, the researchers observed sustained intra-articular concentrations of tacrolimus (>20 ng/mL) over a 42-day follow-up. This demonstrates that the drug stays in the joint, potentially providing a longer-lasting treatment.
  • Whole-blood tacrolimus levels remained undetectable, indicating minimal systemic side effects.
  • A temporary inflammation was observed in the synovial fluid as the white blood cell count and total protein increased. This reaction was seen with all substances, not just the test therapy.
  • Release of prostaglandin and glycosaminoglycan was increased in joints treated with unloaded monospheres, but the effect was reduced when tacrolimus was present.
  • Injection of tacrolimus-loaded monospheres and HA temporarily increased the concentration of a cartilage breakdown product (Collagen II cleavage products or C2C), indicating some cartilage degradation that might be linked to the inflammation.
  • Final histologic assessment showed no pathological changes in any of the treatments, implying no adverse effects within the joint.

Conclusion

  • These findings demonstrate the potential benefits of tacrolimus-loaded monospheres for localized, extended joint disease treatment with minimal systemic side effects, suggesting good biocompatibility. The research has cleared the path for further evaluations in a clinical setting to assess potential benefits for treating humans and animals with inflammatory joint diseases.

Cite This Article

APA
Cokelaere SM, Groen WMGAC, Plomp SGM, de Grauw JC, van Midwoud PM, Weinans HH, van de Lest CHA, Tryfonidou MA, van Weeren PR, Korthagen NM. (2021). Sustained Intra-Articular Release and Biocompatibility of Tacrolimus (FK506) Loaded Monospheres Composed of [PDLA-PEG1000]-b-[PLLA] Multi-Block Copolymers in Healthy Horse Joints. Pharmaceutics, 13(9). https://doi.org/10.3390/pharmaceutics13091438

Publication

Pharmaceutics
ISSN: 1999-4923
NlmUniqueID: 101534003
Country: Switzerland
Language: English
Volume: 13
Issue: 9

Researcher Affiliations

Cokelaere, Stefan M
  • Department of Clinical Sciences, Faculty of Veterinary Medicine, Utrecht University, Yalelaan 112, 3584 CM Utrecht, The Netherlands.
  • Sporthorse Medical Diagnostic Centre, Hooge Wijststraat 7, 3584 RC Heesch, The Netherlands.
Groen, Wilhelmina M G A C
  • Department of Clinical Sciences, Faculty of Veterinary Medicine, Utrecht University, Yalelaan 112, 3584 CM Utrecht, The Netherlands.
Plomp, Saskia G M
  • Department of Clinical Sciences, Faculty of Veterinary Medicine, Utrecht University, Yalelaan 112, 3584 CM Utrecht, The Netherlands.
de Grauw, Janny C
  • Department of Clinical Sciences, Faculty of Veterinary Medicine, Utrecht University, Yalelaan 112, 3584 CM Utrecht, The Netherlands.
van Midwoud, Paul M
  • Innocore Pharmaceuticals, L.J. Zielstraweg 1, 9713 GX Groningen, The Netherlands.
Weinans, Harrie H
  • Department of Orthopaedics, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands.
van de Lest, Chris H A
  • Department of Clinical Sciences, Faculty of Veterinary Medicine, Utrecht University, Yalelaan 112, 3584 CM Utrecht, The Netherlands.
  • Department of Biomolecular Health Sciences, Cell Biology and Histology, Faculty of Veterinary Medicine, Utrecht University, Yalelaan 2, 3584 CM Utrecht, The Netherlands.
Tryfonidou, Marianna A
  • Department of Clinical Sciences, Faculty of Veterinary Medicine, Utrecht University, Yalelaan 112, 3584 CM Utrecht, The Netherlands.
van Weeren, P René
  • Department of Clinical Sciences, Faculty of Veterinary Medicine, Utrecht University, Yalelaan 112, 3584 CM Utrecht, The Netherlands.
Korthagen, Nicoline M
  • Department of Clinical Sciences, Faculty of Veterinary Medicine, Utrecht University, Yalelaan 112, 3584 CM Utrecht, The Netherlands.
  • Department of Orthopaedics, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands.

Grant Funding

  • LLP-22 / Dutch Arthritis Society

Conflict of Interest Statement

Innocore Pharmaceuticals provided the monospheres for this study. InnoCore Pharmaceuticals had no influence on the decision to publish the results. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript or in the decision to publish the results.

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