Inhaled mycophenolate mofetil formulations for the prevention of lung allograft rejection
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The use of lung transplantation, a life saving intervention, has been increasing over the last thirty years with a disappointing median survival of only 4.8 years. Despite the progress made in immunosuppressive therapies, allograft rejection following transplantation is the leading cause of death. As part of the immunosuppressive therapy, mycophenolate mofetil (MMF), the ester prodrug of mycophenolic acid (MPA) has proven its efficacy among heart, liver, kidney as well as lung transplanted patients. However, due to its rapid excretion, high daily doses are necessary and lead to serious side effects, forcing the patient to stop and change their course of treatment. Administration of drugs to the lungs is known to minimize local and systemic side effects by employing a lower amount of drug, to increase patient compliance and to improve the efficacy of the treatment. Therefore, developing novel MMF formulations for targeted delivery to the lungs will broaden the therapeutic options against lung transplant rejection. Within the framework of this dissertation, the development of an inhaled formulation of MMF was investigated. MMF must be metabolized by carboxylesterases to become active and its metabolism suffers from high inter- and intra-patient variability. The first objective of this dissertation was to investigate the occurrence of MMF hydrolysis in the lung. The second objective was to study the in vivo deposition,metabolism and distribution in rats, of an inhaled micron-size MMF suspension in comparison to inhaled IV Cellcept® and oral Cellcept®, the currently marketed products. According to the in vitro results, MMF is metabolized in human lung cells by carboxylesterases. The in vivo results showed an incomplete metabolism of MMF when delivered as a suspension due to the limited dissolution of the drug in the lungs. Following inhalation, the MMF suspension achieved higher and more prolonged concentration of the total drug in the lungs and lymphoid tissues as compared to the inhaled IV Cellcept®. The pulmonary delivery of the MMF suspension was able to achieve similar levels of drug in the lungs, higher levels in the lymphoid tissues and significantly lower levels in the systemic circulation when compared to the levels obtained from the oral gavage of oral Cellcept®. Ultimately, this dissertation demonstrated that the administration of micron-size MMF suspension offers a great potential for pulmonary administration.