A Four-Part Study to Determine the Safety, Tolerability and Pharmacokinetics of the Oxette (Registered Trademark) Nicotine Inhaler, Including a Comparison with the Nicorette (Registered Trademark) Inhaler

INTERVENTION: This study has been divided into four parts as described below. Part A: Single blind, randomised, multi dose‐level study to evaluate the tolerability and pharmacokinetics of orally inhaled nicotine via the Oxette (Registered Trademark) Nicotine Inhaler pack at three doses of nicotine – low, medium and high. Two single different dose levels of nicotine will be inhaled using the device on a single study day, approximately 6 hrs apart. Part A High dose is 0.084% w/w Nicotine, Medium dose is 0.056% w/w Nicotine, Low dose is 0.028% w/w Nicotine. Part B:Open label/single blind, randomised, 3‐way crossover study to evaluate the pharmacokinetics of two dose levels of the Oxette (Registered Trademark) Nicotine Inhaler pack in comparison to the Nicorette (Registered Trademark) Inhaler. Two single different dose levels of nicotine will be inhaled using the Oxette device and one single dose level of nicotine will be inhaled using the Nicorette device over 3 days. One dose will be inhaled per day. There will be approximately 18hr break before moving to the next dose. The 2 dose levels will be determined based on the data obtained from Part A. Part C: Open label study to evaluate the tolerability and venous pharmacokinetics of repeat doses of orally inhaled nicotine via the Oxette (Registered Trademark) Nicotine Inhaler system at one dose level of nicotine. One dose level of nicotine will be inhaled using the Oxette device twelve times a day for one day. The dose level will be determined based on the data obtained from Parts A and B. Subjects will only participate in one of the three parts. The Oxette Inhaler pack and the Nicorette Inhaler differ in appearance and formulation of the nicotine. The devices used to inhale the nicotine also differ in appearance and functionality. Part D: Open label, randomised, 2‐way crossover study to determine the venous pharmacokinetics of orally inhaled nicotine at the medium dose level (0.056%w/w) delivered via the Oxette (Registered Trademark) Nicotine Inhaler device in comparison to the Nicorette (Registered Trademark) Inhaler (10mg). CONDITION: Smoking Addiction PRIMARY OUTCOME: To compare the pharmacokinetic profile of the Oxette (Registered Trademark) Nicotine Inhaler pack with the Nicorette (Registered Trademark) Inhaler (10 mg). To determine the pharmacokinetic profile of a single dose of the Oxette (Registered Trademark) Nicotine Inhaler pack at three nicotine strengths. To determine the pharmacokinetic profile of repeat dose of the Oxette (Registered Trademark) Nicotine Inhaler pack. SECONDARY OUTCOME: A comparison of the plasma nicotine pharmacokinetic parameters (Cmax, Tmax and AUC) of orally inhaled nicotine delivered via the Oxette (Registered Trademark) Nicotine Inhaler device and the Nicorette (Registered Trademark) Inhaler. To determine effects following use of the Oxette (Registered Trademark) Nicotine Inhaler pack on craving satiation and smoking urges. To also determine the effect on aspects of nicotine withdrawal following use of the Oxette (Registered Trademark) Nicotine Inhaler pack.This will be assessed using patient questionnaires. To determine safety and tolerability of the Oxette (Registered Trademark) Nicotine Inhaler pack at a range of doses of nicotine. . This will be assessed by clinical assessments and medical tests. INCLUSION CRITERIA: 1. Smoking male or female with a minimum age of at least 18 years and maximum age of 55 years. 2.Smoke greater than or equal to 10 manufactured cigarettes per day for the last year. 3. Smoke within 1 hour of waking. 4. Expired carbon monoxide greater than 10ppm at screening. 5. Body weight of at least 50 kg with a BMI range of 18.5 – 32. 6. Availability of participant for the entire study period and willingness to adhere to protocol requirements, as evidenced by a signed, Informed Consent Form. 7. Normal findings in the physical examination, vital signs and a 12 lead ECG. 8. Women must be using one effective barrier method of contraception, be postmenopausal for at least 12 months prior to trial entry, or surgically sterile. Women of child‐bearing potential must complete a serum pregnancy test prior to the first administration with a negative result.