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Front. Surg. | doi: 10.3389/fsurg.2018.00020

Mycophenolic Acid for Topical Immunosuppression in Vascularized Composite Allotransplantation: Optimizing Formulation and Preliminary Evaluation of Bioavailability and Pharmacokinetics

 Firuz G. Feturi1,  Matthias Weinstock2, Wenchen Zhao3, Wei Zhang4,  Jonas T. Schnider5,  Vasil Erbas6, Sinan Oksuz6,  Jan A. Plock5,  Lisa Rohan4, Alexander Spiess7, Lydia Ferreira2,  Mario G. Solari7,  Raman Venkataramanan3* and  Vijay Gorantla7*
  • 1Pharmaceutical Science, University of Pittsburgh, United States
  • 2Disciplina de Cirurgia Plástica, Escola Paulista de Medicina,Universidade Federal de São Paulo, Brazil
  • 3Pharmaceutical Science, University of Pittsburgh, United States
  • 4Pharmaceutical Sciences, University of Pittsburgh, United States
  • 5Division of Plastic Surgery and Hand Surgery, University Hospital Zurich, Switzerland
  • 6Department of Plastic and Reconstructive Surgery, University of Pittsburgh, United States
  • 7Department of Plastic and Reconstructive Surgery, University of Pittsburgh, United States

ABSTRACT
Aim: Mycophenolic acid (MPA), the active form of the ester prodrug mycophenolate mofetil (MMF), is an FDA approved immunosuppressive drug that has been successfully used in combination systemic therapy with other immunosuppressive drugs for the prevention of acute rejection (AR) following solid organ transplantation (SOT) and vascularized composite allotransplantation (VCA). Systemic use of MPA, however, is associated with gastrointestinal adverse effects. Topical delivery of MPA in VCA could provide graft-targeted immunosuppression with minimal systemic drug exposure and side effects. Our goal was to prepare a topical formulation of MPA with optimal in vitro / in vivo characteristics such as release, permeation, and tissue bioavailability in preparation for safety and efficacy evaluation in VCA.

Materials and Methods: Permeation studies were performed with a solution of MPA (10mg/ml). In vitro release and permeation studies were performed for different semisolid formulations (aladerm, lipoderm, emollient, and versa- base) of MPA (1%w/w) using a Franz diffusion cells. In vivo pharmacokinetic characterization of MPA released from lipoderm was performed in rats.

Results: MPA in solution exhibited a steady state flux (3.8±0.1 µg/cm2/hr) and permeability (1.1x10-7± 3.2x10-9 cm/s). MPA in lipoderm exhibited a steady state flux of 1.12±0.24 µg/cm2/hr, and permeability of 6.2 x10-09 ±1.3 x10-9 cm/s across the biomimetic membrane. The cumulative release of MPA from lipoderm, showed a linear profile over time with a R2 of 0.969. In vivo studies with MPA in lipoderm showed markedly higher local tissue MPA concentrations but lower systemic MPA exposure as compared to parenteral delivery of the same dose of MPA (p<0.05).

Conclusion: We have developed a topical formulation of MPA and demonstrated its in vitro/in vivo permeability characteristics. MPA in lipoderm was identified as the optimal topical formulation with high local exposure but low systemic exposure in vivo. Our study lays the groundwork for future efficacy studies in animal models and for novel topical application of immunosuppressive agent in clinical VCA.

Keywords: Mycophenolic Acid, Topical, Permeability, Immunosuppression, VCA

Received: 14 Apr 2017; Accepted: 19 Feb 2018.

Edited by:

Jason K. Wong, University of Manchester, United Kingdom

Reviewed by:

Kavit Amin, University of Manchester, United Kingdom
Hui-Yun Cheng, Linkou Chang Gung Memorial Hospital, Taiwan  

Copyright: © 2018 Feturi, Weinstock, Zhao, Zhang, Schnider, Erbas, Oksuz, Plock, Rohan, Spiess, Ferreira, Solari, Venkataramanan and Gorantla. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence:
Dr. Raman Venkataramanan, University of Pittsburgh, Pharmaceutical Science, 731 Salk Hall, 3501 Terrace Street, Pittsburgh, 15261, PA, United States, rv@pitt.edu
Dr. Vijay Gorantla, University of Pittsburgh, Department of Plastic and Reconstructive Surgery, 3550 Terrace Street|Scaife Hall|Suite 6B, Pittsburgh, 15261, PA, United States, govisa@gmail.com