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Developing Topical Formulations Of Rapamycin And Mycophenolic Acid For Targeted Site-specific Immunosuppression In Composite Tissue Allotransplantation
Matthias Weinstock, Rishi Jindal, Robert Sucher, Wenshen Zhan, Marilyn Cost, Lisa Rohan, Lydia Masako Ferreira, Raman Venkatamaranan, W.P. Andrew Lee, Stefan Schneeberger, Gerald Brandacher, Vijay Gor
University of Pittsburgh
2010-04-01
Presenter: Matthias Weinstock
Affidavit:
Director Name:
Author Category: Resident/Fellow
Presentation Category: Basic Science Research
Abstract Category: General Reconstruction
PURPOSE: Composite tissue allografts (CTA offer the opportunity for topical drug therapy that is tailored for site specific immunosuppression that limits systemic exposure to drugs. Currently, topical drugs have only been utilized to treat of acute skin rejection. Tacrolimus and Clobetasol are the only ones commercially available. There are no topical formulations commercially available for rapamycin and mycophenolic acid (MPA), drugs also used in CTA protocols. The skin is the trigger and target of the immune response with different phases of the cascade occurring simultaneously in CTA components. We therefore aimed to develop optimal topical formulations of Rapamycin and MPA for use in combination with Tacrolimus and Clobetasol in CTA. METHODS: Diffusion through skin was simulated with a Franz Diffusion Cells system. Donor compartment was loaded with 400 µl of 3 different solutions: tacrolimus (1mg/ml, control), rapamycin (1mg/ml), MPA (10mg/ml). Samples were collected from recipient compartment at 0h, 1h, 2h, 4h, 6h and 24h. Drug concentrations were analyzed and validated by precalibrated HPLC /LCMS methods. RESULTS: 35% of the original dose of tacrolimus penetrates the membrane (consistent with in vivo studies). Around 18% of the initial dose of rapamycin diffuses across the membrane. With MPA though, 50% of the initial applied dose diffuses into the recipient compartment. CONCLUSION: We have developed and validated a model for measurement of release of Rapamycin, Tacrolimus, Mycophenolic Acid from formulations. Concentration gradient in recipient cell is higher for Mycophenolic Acid than Tacrolimus and Rapamycin. More Mycophenolic Acid may be systemically available when administrated topically.
