Browsing by Subject "Thin film freezing"
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Item Development of high potency voriconazole nanoaggregates for dry powder inhalation(2019-05) Moon, Chaeho; Williams, Robert O., III, 1956-; Smyth, Hugh DC; Cui, Zhengrong; Watts, Alan B; Koleng, John J; Peters, Jay IOrally inhaled products have well-known benefits. They allow for effective local administration of many drugs for the treatment of pulmonary disease, and they allow for rapid absorption and avoidance of first-pass metabolism of several systemically acting drugs. Several challenges remain, however, such as dosing limitations, low and variable deposition of the drug in the lungs, and high drug deposition in oropharynx region. These challenges have stimulated the development of new delivery technologies. Invasive pulmonary aspergillosis is a deadly fungal infection with a high mortality rate, particularly in immunosuppressed individuals who are receiving treatment for AIDS or cancer, or who have received solid organ or bone marrow transplants. Voriconazole, a triazole antifungal drug, is considered as a first-line therapy for invasive pulmonary aspergillosis, and exhibits efficacy even for patients who have failed other antifungal drug therapies. In this dissertation, high potency (up to 97% w/w) nanoaggregates of crystalline voriconazole composition for dry powder inhalation was developed by using the particle engineering process, thin film freezing. The process was designed such that nanoparticles of mannitol on the surface of the voriconazole nanoaggregates modified the surface texture of these nanoaggregates and thus the aerosolization properties of the powder. This unique particle structure was the result of phase-separated crystalline nanoparticles of mannitol oriented on the surface of voriconazole nanoaggregates, reducing van der Waals forces between voriconazole nanoaggregates. A low level of mannitol modified the surface texture, thus significantly enhancing the aerosol performance of the voriconazole nanoaggregates. Identifying the processing design space is critical for the development of high-potency crystalline voriconazole nanoaggregates into a pharmaceutical product, especially during scale-up, while maintaining the surface texture modification caused by mannitol. Thus, several parameters of the processing design space were evaluated, including: solvent system composition (30–70% v/v water with acetonitrile), processing temperature (−60 °C and −150 °C), solid loading (1%, 2%, and 3% w/v), and scale (200 mg and 90 g). Also, interaction between the device and formulation for dry powder inhalation plays a pivotal role in terms of aerosol performance within the processing design space. Therefore, aerosolization of voriconazole nanoaggregates with different devices, high and low resistance RS01 and RS00, was studied. The results indicated that the solvent composition with higher portion water and lower processing temperature were favorable to aerosolization. Although, the highest level of Aerosolization was achieved with a low resistance RS00 device, a high resistance RS00 device performed consistently regardless of flow rates and dose amountsItem 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.Item Pharmaceutical technologies for improving drug loading in the formulation of solid dispersions(2011-12) O'Donnell, Kevin Patrick; Williams, Robert O., 1956-It is estimated that 90% of new chemical entities in development pipelines exhibit poor aqueous solubility. For compounds not limited by biological membrane permeability, this poor aqueous solubility is the limiting factor in bioavailability. Therefore, the formulation of such drugs has primarily been centered on improving dissolution properties. Traditional approaches for overcoming poor aqueous solubility include salt formation of the active ingredient, complexation, the use of surface active agents, formulation into oil based systems, particle size reduction, or a combination of these methods. More recently amorphous solid dispersions have been explored. Currently, the drug loading within solid dispersions is limited resulting in large quantities of the formulation being required for a therapeutically relevant dose. In the frame of the work herein, Thin Film Freezing was utilized to generate high drug loaded amorphous solid dispersions of the poorly water soluble drug phenytoin utilizing a hydrophilic polymer or an amphiphilic graft copolymer for system stabilization. Additionally a new solvent removal technique, atmospheric freeze drying, was investigated for removal of the solvents used during Thin Film Freezing. The Thin Film Freezing materials were subsequently incorporated into a polymeric carrier for solid dispersion formulation by a novel fusion production technique termed Kinetisol® dispersing. Studies of the solid dispersions produced by Thin Film Freezing revealed an amorphous system had been obtained for both stabilizing polymers. The formulation containing a hydrophilic carrier was capable of achieving supersaturation. Conversely, the amphiphilic graft copolymer demonstrated a phenytoin-polymer interaction resulting in poor dissolution. Atmospheric freeze drying of the Thin Film Freezing product demonstrated that the alternative drying technique generated powders with significantly improved handling properties as a result of reduced electrostatic interactions due to the increased pore size, reduced surface area, larger particle size, and higher, though acceptable, residual solvent levels. The use of Thin Film Freezing powders during Kinetisol Dispersing resulted in a single phase amorphous system while solid dispersions produced from physical mixtures of bulk materials were amorphous two-phase systems. This indicates that the use of amorphous drug compositions during solid dispersion production may increase drug loading in the final system while remaining single phase in nature.Item Repurposing niclosamide : oral and inhaled delivery of niclosamide using hot-melt extrusion and thin film freezing technologies(2023-03-29) Jara Gonzalez, Miguel Orlando; Williams, Robert O., III, 1956-; Smyth, Hugh D; Zhang, Feng; Maniruzzaman, Mohammed; Morales, Javier OThis research aims to enable the repurposing of niclosamide as a viable pharmaceutical product for treating cancer and viral infections, including COVID-19. Niclosamide is a unique drug candidate because although it was approved for use over 60 years ago as an anthelmintic medication, several studies have shown its potential as a multi-targeted cancer therapy, broad-spectrum antiviral (including COVID-19), and antibacterial, among several others. There have previously been several attempts to repurpose niclosamide in clinical trials. Unfortunately, niclosamide is a poorly water-soluble molecule with low bioavailability, which has negatively affected the outcomes of these studies. To overcome this challenge, we developed two different niclosamide formulations based on the targeted disease state as well as the intended route of administration. We prepared an amorphous solid dispersion of niclosamide (Niclosamide ASD) as an oral therapy for prostate cancer and a dried powder inhaler to treat COVID-19 infection. Niclosamide ASD was manufactured using hot-melt extrusion. This ASD generates nanoparticles during its dissolution, increasing niclosamide’s apparent 5 solubility by more than 60-fold (i.e. from 6.6 ± 0.4 to 481.7 ± 22.2 μg/mL) and its oral bioavailability in Sprague–Dawley rats. This formulation generates amorphous nanoparticles during its dissolution, confirmed by cryo-TEM and Wide-angle X-ray scattering. Nevertheless, niclosamide ASD undergoes recrystallization in acidic media, and an enteric oral dosage form of niclosamide ASD was formulated without hindering the generation of nanoparticles while maintaining the increase in the niclosamide’s apparent solubility. The formulation successfully increased niclosamide’s plasma levels in dogs when compared to a niclosamide solution prepared using organic solvents. Niclosamide dried powder inhaler was prepared using the Thin Film Freezing technology (TFF). This formulation proved to be safe after an acute three-day, multi-dose pharmacokinetic study in rats, as evidenced by histopathology analysis. In addition, it achieved lung concentrations above the required IC90 levels of SARS-CoV-2 for at least 24 h after a single administration in Syrian golden hamsters. Efficacy studies confirmed that the formulation effectively reduces viral load in infected hamsters that had been inoculated 24 hours prior with intranasal SARS-CoV-2. This formulation was transferred to a pharmaceutical company and has successfully completed phase 1 clinical trials.