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Updated: Oct 4, 2025
Human Dupuytren's Ex Vivo Culture for the Study of Myofibroblasts and Extracellular Matrix Interactions
Published on: April 18, 2015
Pirfenidone as a potential antifibrotic injectable for Dupuytren's disease
Suchitra Panigrahi1, Amanda Barry2, Scott Multner3
1James L. Winkle College of Pharmacy, University of Cincinnati, Cincinnati, OH, USA.
Abstract:
Dupuytren's disease is a progressive fibrotic condition of the hand that causes contracture of fingers in later stages. Our previous in vitro studies suggest that the transformation of fibroblasts to myofibroblasts induced by transforming growth factor-beta can be inhibited by the addition of the antifibrotic drug, pirfenidone (PFD). We hypothesize that the local delivery of PFD directly to nodules can potentially prevent the progression to cords and, furthermore, that injection of PFD after the resection of cords can limit the recurrence of the disease. The purpose of this research was to develop a PFD injectable solution and to assess its safety in mice. Based on preformulation observations, a sterile solution containing up to 8 mg/0.4 mL of PFD was prepared in a phosphate buffer with and without 15%v/v N-methyl-2-pyrrolidone. Accelerated stability studies suggested that the product should be kept at refrigerated temperature (2-8 °C) for long-term storage. Safety studies involving subcutaneous administration to mice showed that 2-4 mg of PFD in 0.4 mL aqueous buffer did not elicit a significant inflammatory reaction. However, 4 mg PFD in 0.4 mL (FB) of buffer: NMP cosolvent system led to a significant increase in the influx of inflammatory cells and 8 mg PFD (FA) in the cosolvent system was lethal to the animals.
Insights
Pirfenidone (PFD) injectable solutions were developed to treat Dupuytren's disease. Low doses showed no significant inflammation in mice, but higher doses in a cosolvent system were toxic.
Area of Science:
- Biomedical Engineering
- Pharmacology
- Fibrotic Diseases
Background:
- Dupuytren's disease is a fibrotic hand condition causing finger contractures.
- Transforming growth factor-beta-induced fibroblast to myofibroblast transformation is a key mechanism.
- Pirfenidone (PFD) demonstrated antifibrotic properties in vitro.
Purpose of the Study:
- To develop an injectable pirfenidone (PFD) solution for treating Dupuytren's disease.
- To assess the safety and tolerability of PFD injectable solutions in a preclinical mouse model.
Main Methods:
- Formulation of sterile PFD solutions in phosphate buffer with and without N-methyl-2-pyrrolidone (NMP).
- Accelerated stability studies to determine optimal storage conditions.
- Subcutaneous administration of PFD solutions to mice to evaluate inflammatory response and lethality.
Main Results:
- PFD solutions up to 8 mg/0.4 mL were prepared.
- Refrigerated storage (2-8°C) is recommended for long-term stability.
- Low PFD doses (2-4 mg) in aqueous buffer showed minimal inflammation.
- Higher PFD doses (4 mg) in a PFD:NMP cosolvent system induced significant inflammation.
- The highest PFD dose (8 mg) in the cosolvent system was lethal in mice.
Conclusions:
- Injectable PFD solutions can be formulated for potential Dupuytren's disease treatment.
- Safety assessment indicates dose-dependent and formulation-dependent toxicity.
- Further research is needed to optimize PFD delivery systems and confirm efficacy in vivo.
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