Development of high potency voriconazole nanoaggregates for dry powder inhalation

Date

2019-05

Authors

Moon, Chaeho

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Abstract

Orally 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 amounts

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