Abstract
Mycophenolic acid (MPA), is the active form of the ester prodrug mycophenolate mofetil (MMF). MMF is an FDA approved immunosuppressive drug that has been successfully used in systemic therapy in combination with other agents for the prevention of acute rejection (AR) following solid organ transplantation (SOT) as well as in vascularized composite allotransplantation (VCA). Systemic use of MMF is associated with gastrointestinal adverse effects. Topical delivery of the prodrug could thus provide graft-targeted immunosuppression while minimizing systemic drug exposure. Our goal was to develop a topical formulation of MPA with optimal in vitro/in vivo characteristics such as release, permeation, and tissue bioavailability to enable safety and efficacy evaluation in clinical VCA.Permeation studies were performed with a solution of MPA (10 mg/ml). In vitro release and permeation studies were performed for different semisolid formulations (Aladerm, Lipoderm, emollient, and VersaBase) of MPA (1% w/w) using a Franz Diffusion Cell System (FDCS). In vivo pharmacokinetic characterization of MPA release from Lipoderm was performed in rats.MPA in solution exhibited a steady state flux (3.8 ± 0.1 µg/cm2/h) and permeability (1.1 × 10−7 ± 3.2 × 10−9 cm/s). MPA in Lipoderm exhibited a steady state flux of 1.12 ± 0.24 µg/cm2/h, and permeability of 6.2 × 10−09 ± 1.3 × 10−9 cm/s across the biomimetic membrane. The cumulative release of MPA from Lipoderm, showed a linear single-phase profile with a R2 of 0.969. In vivo studies with MPA in Lipoderm showed markedly higher local tissue MPA levels and lower systemic MPA exposure as compared to values obtained after intravenous delivery of the same dose of drug (p < 0.05).We successfully developed for the first time, a topical formulation of MPA in Lipoderm with optimal in vitro/in vivo permeability characteristics and no undesirable local or systemic adverse effects in vivo. Our study provides key preliminary groundwork for translational efficacy studies of topical MPA in pre-clinical large animal VCA models and for effectiveness evaluation in patients receiving VCA.
Highlights
mycophenolic acid (MPA) is the active form of mycophenolate mofetil (MMF), which is an immunosuppressive drug used in solid organ transplantation (SOT)
Unlike calcineurin inhibitors like cyclosporine and tacrolimus, MMF is not associated with nephrotoxicity or hepatotoxicity. [22,23,24,25,26] Over the past two decades, MMF has been used in triple therapy regimens in combination with TAC and prednisone in SOT [27,28,29] or vascularized composite allotransplantation (VCA). [30,31,32] It has been used in dual therapy in combination with RAPA in VCA. [33, 34]
Any transdermal drug formulation and delivery must first consider the challenging barrier of the stratum corneum in the skin. [44,45,46,47] Drugs with low molecular weight (≤500 g/ mole), and high lipid solubility offer superior skin penetration and are suitable candidates for topical administration. [48, 49] The goal of this study was to prepare a topical formulation of MPA with optimal in vitro/in vivo characteristics such as release, permeation, and tissue bioavailability for further safety, efficacy and feasibility evaluation in clinical VCA
Summary
Over the past two decades, vascularized composite allotransplantation (VCA) has restored functional, psychosocial and quality of life outcomes in more than 250 patients suffering from devastating, unreconstructable extremity, craniofacial, genitourinary or other tissue defects. [1, 2]The skin component of VCA (unlike in other solid organs), is touted to be the most immunogenic component and offers unique opportunities for graft monitoring (clinicopathologic correlation of rejection) and graft access for management (site-specific therapies). [3, 4] Conceivably, site-specific graft immunosuppression could reduce systemic exposure and global collateral or end-organ adverse effects of chronic systemic immunosuppression, which remains the “state of the art” in VCA. [5,6,7,8]TM Currently, tacrolimus (TAC) (Protopic ointment 0.1%, ® 0.03%, Astellas), and clobetasol (Temovate ointment, cream0.05%, GlaxoSmithKline), are FDA approved for topical use in certain dermatological conditions. [9,10,11,12,13] These topical immunosuppressive drugs have been used in VCA, off-label, to treat acute rejection pro re nata (PRN). [14] Despite their efficacy, these formulations are associated with undesirable local side effects. The greasy formulation reduces medication adherence in patients [15,16,17] Topical clobetasol is associated with skin thinning or atrophy due to the impairment of collagen synthesis. With the exception of tacrolimus or clobetasol, there are no commercially available topical formulations for other widely used systemic immunosuppressive drugs such as mycophenolic acid (MPA), sirolimus (rapamycin, RAPA), and everolimus. MPA is the active form of mycophenolate mofetil (MMF), which is an immunosuppressive drug used in solid organ transplantation (SOT). [22,23,24,25,26] Over the past two decades, MMF has been used in triple therapy regimens in combination with TAC and prednisone in SOT [27,28,29] or VCA. Unlike calcineurin inhibitors like cyclosporine and tacrolimus, MMF is not associated with nephrotoxicity or hepatotoxicity. [22,23,24,25,26] Over the past two decades, MMF has been used in triple therapy regimens in combination with TAC and prednisone in SOT [27,28,29] or VCA. [30,31,32] It has been used in dual therapy in combination with RAPA in VCA. [33, 34]
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