Abstract
Background: Nicotine, because of its volatility, has a complex dosimetry following inhalation as a vapor/aerosol mix. To better control the dosimetry, nicotine could be formulated with a suitable dry powder excipient for use in a clinical inhaler.Aim and Methods: The aim of this study was to investigate the pharmacokinetic PK profile of two dry powder formulations containing 2.5% or 5% nicotine using three experimental models associated to the PreciseInhale™ aerosolization system: the in vitro DissolvIt dissolution system; the ex vivo isolated, ventilated, and perfused lung (IPL) of the rat; and the in vivo intratracheally intubated rat. Results and Discussion: Following exposure, both nicotine formulations had very rapid and similar dissolution and absorption kinetics in both the DissolvIt and IPL exposure models, with an initial half-time of absorption to the single-pass perfusate of 34 and 72 seconds, respectively. In the intratracheally intubated rat, following a rapid initial equilibration between the lungs and systemic compartments, nicotine had a systemic elimination half-time of 2.3–2.4 hours for both formulations. The rapid pulmonary PK of nicotine was likely close to the theoretical equilibration of a low-binding substance with a tissue-blood partition coefficient close to 1. Conclusions: The data generated with the three experimental models provided a comprehensive picture of the inhalation PK of the two nicotine formulations. In particular, the results showed a very rapid dissolution and absorption of the two nicotine formulations and these results could be highly useful for improving the design and calibration of physiologically based PK models to produce more robust predictions. Abbreviations: AED: animal equivalent dose; BW: body weight; HPLC: high-performance liquid chromatography; IPL: isolated, ventilated, and perfused lung; PK: pharmacokinetics; SEM: scanning electron microscopy; USP: United States Pharmacopeia.
Highlights
Nicotine is an alkaloid with numerous biological effects (Benowitz 2009)
The mass median aerodynamic diameter of the nicotine particles deposited on the DissolvIt glass coverslips was 3.87 ± 0.06 mm for the 2.5% nicotine formulation and 3.95 ± 0.08 mm for the 5% nicotine formulation
The present study has shown the usefulness of combining several experimental models using the PreciseInhaleTM system to investigate different aspects of inhalation exposures to the same dry powder formulations
Summary
Nicotine is an alkaloid with numerous biological effects (Benowitz 2009). Apart from its known effects as a neurological stimulant, nicotine offers potential therapeutic avenues (Caldwell et al 2012; Fagerstro€m 2014). Water solubility is very high, yielding a low Henry’s law constant of 3.0 Â 10À9 atm-m3/mole (US National Library of Medicine 2018) (Medicine) This means that when nicotine is in the vapor phase, its deposition upon inhalation is very rapid and occurs primarily in the buccal mucosa and larger airways, compared to a more peripheral lung deposition when administered via tobacco smoke or tobacco-derived aerosol (Lunell et al 1996). Aim and Methods: The aim of this study was to investigate the pharmacokinetic PK profile of two dry powder formulations containing 2.5% or 5% nicotine using three experimental models associated to the PreciseInhaleTM aerosolization system: the in vitro DissolvIt dissolution system; the ex vivo isolated, ventilated, and perfused lung (IPL) of the rat; and the in vivo intratracheally intubated rat. The results showed a very rapid dissolution and absorption of the two nicotine formulations and these results could be highly useful for improving the design and calibration of physiologically based PK models to produce more robust predictions
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