(279d) Award Submission: Development and Physicochemical Characterization of Tacrolimus-Loaded Nanocomposite Microparticles for the Treatment of Pulmonary Hypertension

Pulmonary arterial hypertension (PAH) is a progressive cardiovascular disease that leads to limited exercise capacity, right heart failure, and ultimately death. The primary treatment options currently available for patients with PAH are based on drugs with vasodilatory properties that improve cardiopulmonary function. Unfortunately, these drugs show no effect on prohibiting the progress of obliterative vascular pathology. Because of this, the only option for many patients to improve their health and quality of life is heart-lung transplantation. Therefore, new approaches to utilize compounds that focus on activating cellular mechanisms to reverse vascular remodeling are under investigation. Improving the function of the bone morphogenetic protein receptor-2 (BMPR2) signaling pathway is a potential direction in the development of improved PAH therapies, as the mutations of BMPR2 have been identified as the main cause of inherited PAH, accounting for 60 to 80% of familial cases. Since challenges exist in clinical application of BMPR2 gene therapy, tacrolimus (TAC) can be applied instead, as it increases signaling through the BMPR2 pathway. However, the application of TAC is hindered by its poor solubility, instability, and poor bioavailability. In addition to these limiting pharmacokinetic properties, systemic side effects such as neurotoxicity and nephrotoxicity also complicate the clinical use of TAC.

To overcome this problem, nanocomposite microparticles (nCmP) in the form of dry powder aerosols can be applied to deliver TAC more safely and effectively. This system is comprised of TAC-loaded acetalated dextran (Ac-Dex) nanoparticles (NP) entrapped in microparticle carriers using the excipient mannitol to allow for the delivery of TAC NP to the lungs. Upon pulmonary administration, the nCmP will deposit on the mucus in the respiratory tract, decompose into free NP and mannitol, and allow the nanoparticles to penetrate the mucus barrier and then release drug to the targeted site in a sustained rate. The goal of the described research was the initial development and physicochemical characterization of the nCmP systems with ability of targeted delivery, improved drug solubility, and potential of efficient penetration of mucus barrier and of controlled release via particle engineering.

The NP were approximately 200 nm in diameter with narrow size distribution both before loading into and after redispersion from nCmP. The NP exhibited smooth, spherical morphology and the nCmP were raisin-like spheres. High encapsulation efficacy was achieved both in the encapsulation of tacrolimus in NP and that of NP in nCmP. nCmP exhibited desirable aerosol dispersion properties allowing them to deposit into the deep lung regions for effective drug delivery. Overall, the designed nCmP system is a promising application in pulmonary TAC delivery for the treatment of PAH due to its novel features including targeted pulmonary delivery, improved solubility of tacrolimus, potential of permeation through mucus barrier, and of controlled drug release