Nicotine Microaerosol Inhaler
Total Page：16
File Type：pdf, Size：1020Kb
Color profile: _DEFAULT.CCM - Generic CMYK Black 150 lpi at 45 degrees ORIGINAL RESEARCH Nicotine microaerosol inhaler 3 Paul G Andrus MD1, Rod Rhem BSc1,2, Jack Rosenfeld PhD , Myrna B Dolovich PEng1,2 1Aerosol Research Laboratory and 2Departments of Medicine, and 3Pathology, McMaster University, Hamilton, Ontario PG Andrus, R Rhem, J Rosenfeld, MB Dolovich. Nicotine Inhalateur de nicotine microaerosol inhaler. Can Respir J 1999;6(6):509-512. en microaérosol OBJECTIVE: To measure the droplet size distribution of a OBJECTIF : Mesurer la distribution de la taille des gouttelet- nicotine pressurized metered-dose inhaler using a nicotine in tes d’un aérosol-doseur sous pression contenant de la nicotine ethanol solution formulation with hydrofluoroalkane as pro- dans une solution d’éthanol et utilisant l’hydrofluoroalkane pellant. comme propulseur. MATERIALS AND METHODS: Sizing was performed at MATÉRIEL ET MÉTHODES : La détermination de la taille room temperature by multistage liquid impinger and quartz a été réalisée à la température ambiante par un impacteur en cas- crystal impactor. cade et un impacteur piézoélectrique. RESULTS: The mass median aerodynamic diameter of the RÉSULTATS : Le diamètre aérodynamique médian de la masse nicotine aerosol produced was measured at 1.6 mm by multi- de l’aérosol de nicotine produit a été mesuré à 1,6 mm par l’im- stage liquid impinger and 1.5 mm by quartz crystal impactor. pacteur en cascade et à 1,5 mm par l’impacteur piézoélectrique. CONCLUSIONS: The inhaler formulation used produces a CONCLUSIONS : La formule utilisée dans l’inhalateur pro- microaerosol of sufficiently fine droplet size that mimics the duit un microaérosol à gouttelettes suffisamment fines qui imite puff-by-puff pulmonary arterial bolus nicotine delivery of to- chaque bouffée de nicotine délivrée au sang artériel par la fu- bacco smoke. The absence of combustion products such as mée de tabac. L’absence des produits de combustion comme la heat, carcinogens and carbon monoxide permits safer nicotine chaleur, les carcinogènes et le monoxyde de carbone permet de delivery via the inhaler than is possible via smoked tobacco. délivrer la nicotine de façon plus sûre avec l’inhalateur qu’il n’est possible de le faire en fumant. Key Words: Hydrofluoroalkane propellant; Microaerosol; Nico- tine; Pressurized metered-dose inhaler; Vapour ith the currently available nicotine replacement ther- within seconds, and this may explain why most individuals Wapy (gum, patch, nasal inhaler, oral vapour inhaler), relapse to cigarette smoking (3-5). While smoking, an indi- most attempts at smoking cessation fail, and relapse rates re- vidual’s peak arterial plasma nicotine concentration may be main over 75% (1). A recent review by Pomerleau (2) has 10 times greater than venous concentrations (6). It is only by given evidence that many, if not most, hard-core smokers absorption through the lungs that the rapid arterial bolus suffer from an underlying psychiatric problem that nicotine nicotine delivery of a cigarette can be achieved, as opposed may help to ameliorate. to the relatively slower venous delivery via buccal or nasal None of the available nicotine delivery devices mentioned mucosa or skin, which is characteristic of described nicotine above mimic a cigarette in terms of the rapid puff-by-puff de- delivery devices including the oral vapour inhaler (3,5). The livery of an arterial nicotine bolus that reaches the brain key to efficient arterial (central nervous system) nicotine de- Correspondence and reprints: Dr Paul Andrus, Aerosol Research Laboratory HSC Rm 1P29, McMaster University, Hamilton, Ontario L8N 3Z5. Telephone 905-521-2100 ext 3348, fax 905-526-8805, e-mail [email protected] Can Respir J Vol 6 No 6 November/December 1999 509 1 G:...Andrus.vp Wed Dec 15 09:58:42 1999 Plate: 1 of 1 Color profile: _DEFAULT.CCM - Generic CMYK Black 150 lpi at 45 degrees Andrus et al To mimic the pharmacokinetic properties of a cigarette, not previously possible with existing CFC inhaler formulations and hardware, we sought to test whether an HFA/etha- nol/nicotine solution formulation could be used to generate a nicotine aerosol with an MMAD under 2 µm for the purpose of displacing tobacco use, either as part of a smoking cessation and/or relapse prevention strategy, or for long term nicotine maintenance. The long term health consequences of pure nicotine use are not known, but the balance of the available evidence suggests that nicotine is not the primary cause of lung can- cer and chronic lung disease caused by tobacco smoke, and that long term nicotine replacement may reduce the enor- mous disease burden created by smoking (12). MATERIALS AND METHODS Figure 1) Log-probability plot of hydrofluoroalkane pressurized metered-dose inhaler nicotine in ethanol solution aerosol droplet Two pMDI canisters were prepared by loading 20 mg size distribution as determined by quartz crystal impactor. By this nicotine base (Sigma Co, Oakville, Ontario) into each, to- method, the mass median aerodynamic diameter is approximately gether with 200 mg ethanol and 10 g HFA-134a propellant m 1.5 m. at –70°C. This yielded 200 puffs per canister at a nominal unit dose of 100 µg/puff, which is approximately that of a livery is in the particle size of the nicotine aerosol. Nicotine single cigarette puff. Canisters, valves and actuators were vapour entering the mouth condenses onto the mucosal sur- obtained from 3M Pharmaceuticals. face of the mouth and throat. Large aerosol droplets affect the Sizing was performed at room temperature using the upper airway as well. Only nicotine carried by fine droplets Multi-Stage Liquid Impinger (MSLI) with 20 mL of 0.2N and vapour that arises from these fine droplets while they are sulfuric acid solvent on each stage. Nicotine concentrations deep within the lung, is available for absorption into the pul- were obtained by ultraviolet (UV) absorbance spectroscopy monary circulation and reaches the brain quickly in high con- at 260 nm (Varian, Cary 50 Probe UV-Visible Spectropho- centration. Cigarette smoke has a mass median aerodynamic tometer, Mulgrave, Victoria, Australia). diameter (MMAD) of 0.4 µm (7). Such small particles de- For each sizing experiment, 10 puffs were discharged at posit mainly in the alveoli of the lung from which they may 30 s intervals into a glass throat attached to the impinger be rapidly absorbed into the pulmonary circulation. with suction air flow set at 60 L/min. Nicotine that depos- Pressurized metered-dose inhalers (pMDI) with chloro- ited on the liquid stages was shown to be stable, although fluorocarbon (CFC) propellants have been typically solid the nicotine base quickly vapourized from the end-stage fil- drug particle (suspension) formulations that deliver about ter. In a separate experiment, approximately half of a 100 µg 10% to 15% of the nominal dose to the lungs, with the ma- dose placed on the end-stage filter was shown to vapourize jority being deposited in the upper airway when inhalation of within 5 s, drawing a lower airflow of 28 L/min through the the dose is performed using the closed mouth technique. The filter. MMAD of the aerosol particles associated with such fractional MSLI sizing data were confirmed using a quartz crystal lung delivery is greater than 3 µm (8). Although such a rela- impactor, the QCM model PC-2 (California Measurements, tively larger particle aerosol could reproduce the minute-to- Sierra Madre, California) at room temperature. Stage drop- minute venous blood nicotine delivery pharmacokinetics of let size cutoffs for the QCM extend well into the submicron tobacco, the arterial pharmacokinetics that describe nicotine range, and the sampling was at 1 L/min. delivery to the brain from tobacco smoke occur on the order of seconds, and would not be approximated by an aerosol greater than 3mm (3,9,10). RESULTS CFCs are being phased out due to their atmospheric ozone The solution formulation resulted in a nicotine aerosol depleting effects. Consequently, alternative formulations us- particle size distribution with a MMAD of approximately ing hydrofluoroalkane (HFA) propellant, which is not ozone 1.6 µm as estimated by the MSLI. Approximately forty- depleting, are being produced. For example, beclomethasone eight per cent of the 100 µg nominal dose/puff was lost as has recently been reformulated (3M Pharmaceuticals, St vapour from the end-stage filter as the experiment pro- Paul, Minnesota) as an HFA/ethanol solution formulation ceeded, because of the volatility of free-base nicotine at that delivers 51% to 60% of the deposited dose to the lower room temperature. The majority of this lost fraction may be respiratory tract. This is due to an unprecedented 1.1 µm assumed to have landed initially on the filter as a fine drop- MMAD of the aerosol droplets, which is made possible by a let because of the limited saturation of nicotine vapour in air liquid drug solution, as opposed to a solid drug particle sus- of 2 µmol/L at room temperature (4), which is approxi- pension formulation (11). mately 10% of the total nicotine concentration of tobacco 510 Can Respir J Vol 6 No 6 November/December 1999 2 G:...Andrus.vp Wed Dec 15 09:59:14 1999 Plate: 1 of 1 Color profile: _DEFAULT.CCM - Generic CMYK Black 150 lpi at 45 degrees Nicotine microaerosol inhaler smoke, and of the aerosol from the present inhaler. This children. In other words, nicotine can be ingested in lethal MSLI sizing data and the assumption of ongoing volatile quantities because its effects are delayed by the gastroin- losses from the filter is supported by QCM sizing data where testinal route of absorption, contrary to the case with respi- the MMAD was measured at approximately 1.5 µm in two ratory inhalation.