Degradation, Intra-Articular Biocompatibility, Drug Release, and Bioactivity of Tacrolimus-Loaded Poly(d-l-lactide-PEG)-b-poly(l-lactide) Multiblock Copolymer-Based Monospheres.
Abstract: The aim of this study was to develop a formulation with a sustained intra-articular release of the anti-inflammatory drug tacrolimus. Drug release kinetics from the prepared tacrolimus loaded monodisperse biodegradable microspheres based on poly(d-l-lactide-PEG)--poly(l-lactide) multiblock copolymers were tunable by changing polymer composition, particularly hydrophobic-hydrophilic block ratio. The monospheres were 30 μm and released the drug, depending on the formulation, in 7 to >42 days. The formulation exhibiting sustained release for 1 month was selected for further in vivo evaluation. Rat knees were injected with three different doses of tacrolimus (10 wt %) loaded monospheres (2.5, 5.0, and 10 mg), contralateral control knees with saline. Micro-CT and histology showed no negative changes on cartilage, indicating good biocompatibility. Minor osteophyte formation was seen in a dose dependent fashion, suggesting local drug release and therapeutic action thereof. To investigate in vivo drug release, tacrolimus monospheres were injected into horse joints, after which multiple blood and synovial fluid samples were taken. Sustained intra-articular release was seen during the entire four-week follow-up, with negligible systemic drug concentrations (<1 ng/mL), confirming the feasibility of local intra-articular drug delivery without provoking systemic effects. Intra-articular injection of unloaded monospheres led to a transient inflammatory reaction, measured by total synovial leucocyte count (72 h). This reaction was significantly lower in joints injected with tacrolimus loaded monospheres, showing not only the successful local tacrolimus delivery but also local anti-inflammatory action. This local anti-inflammatory potential without systemic side-effects can be beneficial in the treatment of inflammatory joint diseases, among which is osteoarthritis.
Publication Date: 2018-05-23 PubMed ID: 33435104DOI: 10.1021/acsbiomaterials.8b00116Google Scholar: Lookup
The Equine Research Bank provides access to a large database of publicly available scientific literature. Inclusion in the Research Bank does not imply endorsement of study methods or findings by Mad Barn.
- 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.
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.
Cite This Article
APA
Sandker MJ, Duque LF, Redout EM, Klijnstra EC, Steendam R, Kops N, Waarsing JH, van Weeren R, Hennink WE, Weinans H.
(2018).
Degradation, Intra-Articular Biocompatibility, Drug Release, and Bioactivity of Tacrolimus-Loaded Poly(d-l-lactide-PEG)-b-poly(l-lactide) Multiblock Copolymer-Based Monospheres.
ACS Biomater Sci Eng, 4(7), 2390-2403.
https://doi.org/10.1021/acsbiomaterials.8b00116 Publication
Researcher Affiliations
- Department of Orthopaedics, Erasmus Medical Centre, Wytemaweg 80, 3015 CN Rotterdam, The Netherlands.
- Department of Orthopaedics, UMC Utrecht, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands.
- InnoCore Pharmaceuticals, L.J. Zielstraweg 1, 9713 GX Groningen, The Netherlands.
- Department of Equine Sciences, Faculty of Veterinary Medicine, Utrecht University, Yalelaan 1, 3584 CL Utrecht, The Netherlands.
- InnoCore Pharmaceuticals, L.J. Zielstraweg 1, 9713 GX Groningen, The Netherlands.
- InnoCore Pharmaceuticals, L.J. Zielstraweg 1, 9713 GX Groningen, The Netherlands.
- Department of Orthopaedics, Erasmus Medical Centre, Wytemaweg 80, 3015 CN Rotterdam, The Netherlands.
- Department of Orthopaedics, Erasmus Medical Centre, Wytemaweg 80, 3015 CN Rotterdam, The Netherlands.
- Department of Equine Sciences, Faculty of Veterinary Medicine, Utrecht University, Yalelaan 1, 3584 CL Utrecht, The Netherlands.
- Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Universiteitsweg 99, 3512 JE Utrecht, The Netherlands.
- Department of Orthopaedics and Department of Rheumatology, UMC Utrecht, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands.
- Department of Biomechanical Engineering, TUDelft, Mekelweg 2, 2628 CD Delft, The Netherlands.
Citations
This article has been cited 2 times.- van der Wijk AE, Georgakopoulou T, Steendam R, Zuidema J, Hordijk PL, Bakker ENTP, van Bavel E. Extravasation of biodegradable microspheres in the rat brain.. Drug Deliv 2023 Dec;30(1):2194579.
- 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. Sustained Intra-Articular Release and Biocompatibility of Tacrolimus (FK506) Loaded Monospheres Composed of [PDLA-PEG(1000)]-b-[PLLA] Multi-Block Copolymers in Healthy Horse Joints.. Pharmaceutics 2021 Sep 10;13(9).
Use Nutrition Calculator
Check if your horse's diet meets their nutrition requirements with our easy-to-use tool Check your horse's diet with our easy-to-use tool
Talk to a Nutritionist
Discuss your horse's feeding plan with our experts over a free phone consultation Discuss your horse's diet over a phone consultation
Submit Diet Evaluation
Get a customized feeding plan for your horse formulated by our equine nutritionists Get a custom feeding plan formulated by our nutritionists
