Browsing by Subject "Fixed-dose combination"
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Item Dry powder for inhalation of single and fixed dose combinations of nintedanib, pirfenidone and mycophenolic acid prepared by thin-film freezing technology(2023-04-19) Praphawatvet, Tuangrat; Williams, Robert O., III, 1956-; Peters, Jay I.; Cui, Zhengrong; Smyth, Hugh D.C.Dry powder for inhalation (DPI) exhibits a non-invasive drug delivery that has been developed to achieve the therapeutic efficacies and undesirable side effects of oral administration. Particle engineering technologies have developed inhaled micro- and nanoparticles to achieve sufficient aerodynamic performance for inhalation. The first chapter presents inhaled-nanoparticle properties that overcome the limitation of drug delivery to lung tissue for local or systemic effects. The second chapter presents the thin-film freezing (TFF) process that potentially produces pharmaceutical powders with physical properties to improve oral and pulmonary delivery. The TFF process, a particle engineering technology, produces stable and aerosolized powders of small molecules for inhalation. TFF powders exhibit brittle matrix structures with high surface area, enhancing aerosol characteristics and achieving drug solubility and bioavailability limitations. The third chapter found that the TFF process produces inhaled nintedanib powder with high aerodynamic performance. Moreover, the process parameters, including drug loading and excipients, can affect physical properties and aerodynamic performance. The brittle-matrix characters of the TFF powders, including surface area, powder brittleness and moisture content, were significantly correlated to aerodynamic performance. The fourth chapter presents the development of inhaled fixed-dose combinations of nintedanib, pirfenidone and mycophenolic acid for idiopathic pulmonary fibrosis (IPF) to improve efficacy and safety over oral administration. In this study, we found that the TFF process achieved the challenges in producing inhaled fixed-dose combinations of two- and three-drug formulations with homogenous brittle-matrix powders to provide acceptable aerosol properties for inhalation. The last chapter presents the TFF process improved aerodynamic performance of pirfenidone by cocrystal formation. We found that pirfenidone is glass-forming class 1 that is easily recrystallized during preparation or storage. Therefore, pirfenidone exhibited very low aerosolization that cannot be delivered to lungs. The cocrystal formation of pirfenidone and dicarboxylic acid changed pirfenidone morphology and limited recrystallization that enhanced aerodynamic performance. In conclusion, the TFF process can overcome the challenges in developing dry powder for inhalation of single and fixed dose combinations of nintedanib, pirfenidone and mycophenolic acid.Item Improved inhalation therapies of brittle powders(2013-12) Carvalho, Simone Raffa; Williams, Robert O., 1956-Advancements in pulmonary drug delivery technologies have improved the use of dry powder inhalation therapy to treat respiratory and systemic diseases. Despite remarkable improvements in the development of dry powder inhaler devices (DPIs) and formulations in the last few years, an optimized DPI system has yet to be developed. In this work, we hypothesize that Thin Film Freezing (TFF) is a suitable technology to improve inhalation therapies to treat lung and systemic malignancies due to its ability to produce brittle powder with optimal aerodynamic properties. Also, we developed a performance verification test (PVT) for the Next Generation Cascade Impactor (NGI), which is one of the most important in vitro characterization methods to test inhalation. In the first study, we used TFF technology to produce amorphous and brittle particles of rapamycin, and compared the in vivo behavior by the pharmacokinetic profiles, to its crystalline counterpart when delivered to the lungs of rats via inhalation. It was found that TFF rapamycin presented higher in vivo systemic bioavailability than the crystalline formulation. Subsequently, we investigated the use of TFF technology to produce triple fixed dose therapy using formoterol fumarate, tiotropium bromide and budesonide as therapeutic drugs. We investigated applications of this technology to powder properties and in vitro aerosol performance with respect to single and combination therapy. As a result, the brittle TFF powders presented superior properties than the physical mixture of micronized crystalline powders, such as excellent particle distribution homogeneity after in vitro aerosolization. Lastly, we developed a PVT for the NGI that may be applicable to other cascade impactors, by investigating the use of a standardized pressurized metered dose inhaler (pMDI) with the NGI. Two standardized formulations were developed. Formulations were analyzed for repeatability and robustness, and found not to demonstrate significant differences in plate deposition using a single NGI apparatus. Variable conditions were introduced to the NGI to mimic operator and equipment failure. Introduction of the variable conditions to the NGI was found to significantly adjust the deposition patterns of the standardized formulations, suggesting that their use as a PVT could be useful and that further investigation is warranted.