Inhalation

INH0223

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Inhalation February 2023 27 are dissolved in a common spray solvent system at up to 2% solids. Spray drying is often most success- ful from high volatility organic systems. However, for lung delivery, aqueous-based systems are often pre- ferred to minimize the amount of residual solvents delivered to the lung. For the two programs, water or water/ethanol blends are used to appropriately solu- bilize the drugs and excipients. e solution is then fed into the spray dryer via a two-fluid atomizer, where the appropriate droplet size is formed and subsequently dried using a heated drying gas stream [3]. Each of the formulations dis- cussed below was spray dried on a customized spray dryer with a total gas flow of 35 kg/hr with solu- tions flow rates and outlet temperatures appropriate to achieve a thermodynamic balance and adequate drying conditions. e target particle size distribu- tion is centered around 1.5 µm, resulting in par- ticles which allow for deposition across the lung when combined with the size increase afforded by the combination of the hygroscopic agent and the high humidity environment of the lung. is is an intentional strategy to drive a high percent deposi- tion in the deep lung. e Hindle/Longest Labs at VCU demonstrated a difference in deposition of a similar formulation on a Next Generation Impactor (NGI) at low and high humidity [4]. Due to the functional relationship with humidity, relative humidity at the outlet of the dryer becomes a key control parameter during manufacture. Sim- ilarly, controls must be taken with respect to pack- aging and handling during testing. If laboratories are prone to medium-to-high ambient humidities, a controlled environmental chamber may be necessary for any characterization. and Figure 2 together paint an effective picture of the benefits of direct lung delivery compared to standard-of-care IV treatment. is article focuses on the formulation development and selection of Quench Medical EEG dry pow- der formulations in the development of two clini- cal treatments for lung diseases. Budesonide will be used to treat local lung inflammation and gemcit- abine will be dosed for the treatment of non-small- cell lung cancer. EEG allows for highly targeted drug delivery into the lungs and can be robustly manufac- tured via a spray-drying particle engineering method. is dry powder inhalation platform can be flexibly scaled according to manufacturers' needs and may be appealing for a variety of inhalation-based therapies. Excipient enhanced growth formulation: An overview e EEG formulation platform results in a three- component engineered particle with the active phar- maceutical ingredient as one obvious component. e remaining two excipients are functional, including a surface modifier and a hygroscopic agent. e surface modifier of choice is often leucine, which migrates to the surface of particles and is used to enhance the dispersion of powder during inhalation. e hygro- scopic component acts to draw water into the parti- cles, increasing their size and resulting in deposition of even the finest particles [2]. eir contribution makes it necessary to include a high fraction of ultra- fine particles, <1 µm, to allow for deep lung delivery. e hygroscopic agents explored in subsequent sec- tions are sodium chloride and mannitol. Generation of the ultrafine composite particles can be achieved by spray drying. e three components Figure 1 Efficacy of inhaled EEG gemcitabine formulation with matched dose and half-dose vs IV standard- of-care. Reprinted with permission [1]. Lung Weight (grams) 20 15 10 5 0 No Cancer Untreated Standard IV 1 mg/kg Quench EEG 0.5 mg/kg Quench EEG 1 mg/kg P < 0.0001 P = 0.0605 P = 0.0001 Figure 2 Tumor burden via histology of cancerous lesions in purple with (A) inhaled EEG gemcitabine formulations (0.5 mg/kg) and (B) standard-of-care IV gemcitabine (1 mg/kg). Reprinted with permission [1]. A) B)

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