University of Texas at Austin Austin, Texas, United States
Purpose: Nicotine is a widely used stimulant drug that can be found in tobacco products. However, tobacco smoke contains thousands of harmful chemicals, which are known to cause fatal lung disease and cancer. Some noxious chemicals can also be found in e-cigarette aerosols as well. The objective of this study is to develop a nicotine dry powder for inhalation that does not contain harmful inactive ingredients. In this study, thin film freezing (TFF), a particle engineering technology, was used to produce high potency nicotine dry powders for inhalation that are highly aerosolizable. We evaluated aerosol performance of the powder with different nicotine loading and excipients. Methods: Nicotine bitartrate dihydrate (25 ~ 100% w/w) and excipients (i.e., mannitol, lactose, leucine, glycine, lysine, and trileucine) were dissolved in a binary solvent system of water and acetonitrile (70/30 v/v) at solid concentrations between 0.25 and 1.0 % (w/v). The solutions were then rapidly frozen by dropping it onto the cryogenically cooled (−100 °C) stainless steel rolling drum. The frozen thin films were collected and the solvents were removed by sublimation using a shelf lyophilizer (SP Scientific, Gardiner, NY). Aerosol performance of the nicotine dry powders for inhalation was assessed using a Next Generation Pharmaceutical Impactor (NGI) (MSP Co., Shoreview, MN). Size #3 capsules (Quali-V®-I Extra Dry capsule, Qualicaps Inc., Whitsett, NC) were manually filled with the nicotine dry powder formulations and placed into Plastiape high resistance RS00 dry powder inhalers. The powders were dispersed into the NGI through the USP induction port with a total air volume of 4 L at a flow rate of 58 L/min (4kPa pressure drop). The nicotine contents collected from the capsule, device, adapter, induction port, and stages 1 through the micro-orifice collector (MOC) were analyzed by HPLC. Aerodynamic properties were calculated using Copley Inhaler Testing Data Analysis Software (CITDAS). Fine particle fraction (FPF) was determined as the percent delivered dose with a fine particle dose of an aerodynamic diameter less than 5 µm. Results: TFF produced brittle matrix amorphous nicotine dry powders for inhalation. Nicotine (75% w/w) with leucine (25% w/w) dry powder exhibited the best aerosol performance with a FPF of 94.08% and mass median aerodynamic diameter (MMAD) of 0.68 µm. While nicotine dry powder without excipients presented a low FPF of 17.6%, nicotine (90% w/w) with leucine (10% w/w) resulted in high aerosol performance with FPF of 80.46% and MMAD of 1.26 µm. Among the tested excipients, leucine achieved the best aerosol performance, followed by trileucine. Nicotine dry powders with other excipients tested demonstrated relatively poor aerosol performance. 1H NMR showed that the nicotine was chemically intact and no loss of nicotine was observed after the TFF process. Conclusion: Highly aerosolizable nicotine dry powders for inhalation were successfully developed without harmful excipients using TFF technology. By inhaling nicotine as a dry powder, the toxic chemicals can be avoided, and the number and amount of excipients to be inhaled can be minimized with high potency ( >75 %) nicotine powders. TFF nicotine powder for inhalation is a promising alternative formulation to deliver nicotine while minimizing adverse effects caused by toxic chemicals and excipients.
Acknowledgements:
Funding: This research was funded by TFF Pharmaceuticals, Inc. through a sponsored research agreement at The University of Texas at Austin. Conflicts of Interest: Williams and Moon report a relationship with TFF Pharmaceuticals, Inc. that includes consulting or advisory, equity or stocks.
Table 1. Aerodynamic properties of nicotine dry powders for inhalation (n=3)
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