Pulmonary delivery of tacrolimus for lung transplant and asthma therapy
Since the discovery of cyclosporine in 1971, calcineurin inhibitors have played a critical role in the therapeutic suppression of the immune response. Patients receiving solid organ transplants rely heavily on these medications to prevent the acute and chronic rejection of allografted tissue. Introduction of tacrolimus, the most frequently prescribed calcineurin inhibitor, has lead to improved clinical outcomes for organ transplant recipients; however, little improvement has been noted in lung transplantation. Difficulties with current oral dosing regimens for lung transplant patients stem primarily from drug systemic toxicity, heightened risk of invasive infection, and erratic oral bioavailability. We have proposed that pulmonary delivery of a tacrolimus formulation with improved solubility can provide high lung concentrations, while limiting corresponding systemic levels associated with toxicity. Chapter 2 investigates the pulmonary administration of tacrolimus dispersion for nebulization to lung transplanted rats. Resulting lung and blood levels were determined by appropriate bioanalytical methods. Limited systemic absorption was seen after pulmonary delivery, resulting in a 50 to 1 lung to blood concentration ratio. A 28 day safety and stability evaluation of tacrolimus dispersion for nebulization was conducted in Chapter 3. Results showed no signs of toxicity in Sprague Dawley rats and proved the stability of tacrolimus powder for dispersion for 3 months. For cases of severe asthma, immunosuppression is also necessary to restore normal lungs function and is typically treated with corticosteroids. Corticosteroids, however, are well known for their untoward side effects and can prove ineffective in severe asthmatics that have developed corticosteroid resistance. Chapter 4 investigates the use of tacrolimus dispersion for nebulization for prophylactic treatment of asthma. Efficacy was determined in an asthma-induced animal model by quantification of inflammatory cells and signaling chemicals. In Chapter 5, tacrolimus powder for inhalation is investigated in a novel dry powder inhalation platform. Respirable particles are produced when bulk particles (500 [micrometer]) comprising a matrix of drug/excipient are sheared apart by a marketed inhalation device to produce particles of the appropriate geometric diameter (50 [micrometer]). Biocompatible material with brittle properties were found to produce fine particle fractions (FPF) up to 70.3% and total emitted doses (TED) higher than 95%.