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Development of a Topical 48-H Release Formulation as an Anti-scarring Treatment for Deep Partial-Thickness Burns

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Abstract

The purpose of this study was to develop pirfenidone (PF) ointment formulations for a dose finding study in the prophylactic treatment of deep partial-thickness burns in a mouse model. A preformulation study was performed to evaluate the solubility of PF in buffers and different solvents and its stability. Three different formulations containing 1, 3.5, and 6.5% w/w PF were prepared and optimized for their composition for testing in mice. Optimized formulations showed promising in vitro release profiles, in which 20–45% of PF was released in the first 7 h and 70–90% released within 48 h. The rheological properties of the ointment remained stable throughout storage at 25 ± 2°C/60% RH. Animal studies showed treatments of burn wounds during the inflammatory stage of wound healing with PF ointments at different drug concentrations had no adverse effects on reepithelization. Moreover, 6.5% PF ointment (F3) reduced the expression of pro-inflammatory cytokines IL-12p70 and TNFα. This study suggests that hydrocarbon base ointment could be a promising dosage form for topical delivery of PF in treatment of deep partial-thickness burns.

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Funding

RD performed this study at the US Army Institute of Surgical Research during her sabbatical leave from the University of Pavia, Italy. Her stipend was supported by an appointment to the Postgraduate Research Participation Program at the US Army Institute of Surgical Research administered by the Oak Ridge Institute for Science and Education through an interagency agreement between the US Department of Energy and US Army Medical Research and Materiel Command (USAMRMC). This work was supported in part through the Congressionally Directed Medical Research Programs, USAMRMC W81XWH-15-2-0083, and the Naval Medical Research Center’s Advanced Medical Development program (MIPR N3239815MHX040).

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Authors and Affiliations

  1. Dental and Craniofacial Trauma Research and Tissue Regeneration, US Army Institute of Surgical Research, 3650 Chambers Pass, JBSA Fort Sam, Houston, Texas, 78234-7767, USA

    Rossella Dorati, Jorge L. Medina & Kai P. Leung

  2. Department of Drug Sciences, University of Pavia, V.le Taramelli 12, 27100, Pavia, Italy

    Rossella Dorati

  3. College of Pharmacy, University of Kentucky, Lexington, Kentucky, USA

    Patrick P. DeLuca

Authors
  1. Rossella Dorati
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  2. Jorge L. Medina
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  3. Patrick P. DeLuca
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  4. Kai P. Leung
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Corresponding author

Correspondence to Kai P. Leung.

Ethics declarations

This study has been conducted in compliance with the Animal Welfare Act, the implementing Animal Welfare Regulations, and the principles of the Guide for the Care and Use of Laboratory Animals.

Conflict of Interest

The authors declare that they have no conflict of interest.

Disclosure

The opinions or assertions contained herein are the private views of the authors and are not to be construed as official or as reflecting the views of the Department of the Army or the Department of Defense.

Electronic supplementary material

Supplemental Figure 1

Histological mouse skin sections 3 days after a deep partial-thickness burn treated with pirfenidone ointment. Images depict H&E stained sections from burn wounds 3 days after thermal injury and treated with A) placebo, B) 1%, C) 3.5%, and D) 6.5% pirfenidone ointment. Black arrow heads point to the burn wound edges showing a loss of the epidermis between. Insets are from the areas marked by the lines indicating the left burn wound edge. Left of the black arrows in the insets point at the leading edge of the intact epidermis. (GIF 291 kb)

High-resolution image (TIF 4274 kb)

Supplemental Figure 2

Histological mouse skin sections 12 days after a deep partial-thickness burn treated with pirfenidone ointment. Images depict H&E stained sections from burn wounds 12 days after thermal injury and treated with A) placebo, B) 1%, C) 3.5%, and D) 6.5%pirfenidone ointment. Many of the wounds completely reepithelialized 12 days after the burn and most were close to full reepithelialization. Black arrow heads point at the left wound edges or wound centers. Insets are from the areas marked by the brackets. Left of the black arrows if present in the insets point at the leading edge of the intact epidermal layer. (GIF 375 kb)

High-resolution image (TIF 7969 kb)

Supplemental Figure 3

Histological mouse skin sections 22 days after a deep partial-thickness burn treated with pirfenidone ointment. Images depict H&E stained sections from burn wounds 22 days after thermal injury and treated with A) placebo, B) 1%, C) 3.5%, and D) 6.5% pirfenidone ointment. Most burn wounds completely reepithelialized 22 days after the burn injury. (GIF 477 kb)

High-resolution image (TIF 6997 kb)

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Dorati, R., Medina, J.L., DeLuca, P.P. et al. Development of a Topical 48-H Release Formulation as an Anti-scarring Treatment for Deep Partial-Thickness Burns. AAPS PharmSciTech 19, 2264–2275 (2018). https://doi.org/10.1208/s12249-018-1030-3

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  • DOI: https://doi.org/10.1208/s12249-018-1030-3

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