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Health Effects of Smoking

Health Effects of Smoking. Smoking is a major risk factor for many diseases cardiovascular diseases cancer thromboembolic diseases Carbon monoxide and oxidant gases in smoke responsible for cardiovascular system effects ~ 1/2 smokers will die prematurely

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Health Effects of Smoking

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  1. Health Effects of Smoking • Smoking is a major risk factor for many diseases • cardiovascular diseases • cancer • thromboembolic diseases • Carbon monoxide and oxidant gases in smoke responsible for cardiovascular system effects • ~ 1/2 smokers will die prematurely • Decreased life expectancy by ~ 8 years

  2. Cigarette Addiction • Nicotine is the addictive agent in cigarette smoke • activates brain reward areas • compulsive use • tolerance to adverse effects such as nausea and an acute increase in blood pressure and heart rate • withdrawal syndrome upon cessation • irritability, anxiety and dysphoria, cravings, poor concentration, increased appetite, sleep disturbance, drowsiness, decreased heart rate, and impaired task performance • tendency to relapse after cessation • persistent use even after learning of the adverse health effects of smoking

  3. Smoking Cessation Therapies • w/o professional help, 2% of smokers quit every year • Of these, < 20% remained abstinent after 1 yr • Market in US: 46.5 million smokers in 2000 & 70% (~32.6 million) wanted to quit • As nicotine is the addictive substance in cigarettes, nicotine is the ideal target for smoking cessation therapies

  4. Nicotine Replacement Therapies • Double quit rates • Do not increase rates of cardiovascular disease • Rarely cause addiction due to release profile • Include nicotine patches, polacrilex gum & lozenge, inhalers & nasal spray, and microtabs

  5. Transdermal Nicotine Delivery • Nicotine patch brands: Nicoderm, Nicotrol, Habitrol, Nicotinell • Easy to use • Increased patient compliance • Less user errors • Longer presence of nicotine in bloodstream • Constant nicotine levels maintained in plasma

  6. Nicoderm Committed Quitters • Nicoderm CQ • Attaches to skin and releases nicotine at a steady rate over 24h period • Program of tapering: • 6 wks using Level 1 (21 mg/day) patches • 2 wks using Level 2 (14 mg/day) patches • 2 wks using Level 3 ( 7 mg/day) patches

  7. Nicoderm CQ 21mg patch • ~ 22 cm2, 200-250 µm thick, 5 layers: • Backing – multilaminate of polyethylene/aluminum/ polyester/ ethylene-vinyl acetate copolymer • Drug reservoir – 40% nicotine base subsaturated in 60% ethylene/vinyl acetate copolymer (EVAc - 40% VA), 13 μm • Rate-controlling membrane – high-density poly ethylene (HDPE) – 50 μm • Adhesive –blend of low and high MW polyisobutylene (PIB) in 90:10 ratio – 50 μm • Strippable release liner – fluorocarbon diacrylate/ polyethylene terephthalate (PET)

  8. Diagram of Nicoderm CQ patch

  9. Release in Nicoderm CQ • 35mg nicotine loaded into patches, ~21mg released over 24h • Steady-state rate of release is ~ 0 order • After application, up to 6h lag until therapeutic dose in bloodstream • Lag only for 1st application if patches replaced every 24h • If patches worn for 16h & taken off before bed, lag occurs every morning

  10. Mathematical Model of Flow • Qout= DaKaDmKm*A*∆C*t DaKa + DmKm L • where Qout is flow out of patch, D is diffusion coefficient of adhesive (a) and rate-controlling membrane (m), and K is partition coefficient • Km = Ka = K, Da <<< Dm • Qout= KDa*A*∆C*t L

  11. Nicoderm CQ Cumulative Release

  12. Delivery Rate vs. Plasma Conc. • where • - Css = steady-state plasma conc. of nicotine • - CL = clearance from blood • - Q = nicotine flow from patch • b/c rate of release and plasma concentrations are directly correlated, reducing rate of delivery to ⅓ should also decrease plasma concentrations by ~ ⅓

  13. Comparing Nicotine Release • Via cigarettes: • Each cig. provides ~1 mg nicotine • 20-28 mg absorbed daily • Plasma conc. maintained at 10-50 ng/mL • Via Nicoderm CQ: • Each patch provides 21 mg daily (⅞ mg/h) • Steady state plasma conc. maintained at ~10 ng/mL • Release from Nicoderm CQ at low end of spectrum for release from cigarettes

  14. Packaging • Kit containing 7, 14, or 21 patches • Each patch individually packaged in a tear-able plastic wrapper • Information booklet in kit

  15. Customer Complaints • Overnight nicotine delivery led to sleeplessness • Nervousness, anxiety during daytime • Adhesion lost after sweating/showering • Behavioral addiction not addressed • Directions on box indicate which level (7, 14, or 21 mg) patch to wear based only on number cigarettes smoked per day • Expensive

  16. Customer Requirements • Deliver nicotine over 24h period • Enough in morning to overcome strongest cravings • Less at night, so no sleeplessness • Adhere under wet and dry conditions • Not cause skin irritation • Occlusive backing (no oozing) • Cost ≤ cigarettes

  17. Redesign Objectives • Decrease rate of overnight release • Three variants • Decrease morning lag time • Increase adhesiveness • Use different adhesive • Address behavioral addiction • Quit Smart plastic cigarettes • Overcome objections about expense • Compare individual patches to cigarette cost on box label • Increase safety of disposal & Improve ease of package opening • Package individual patches in resealable packages

  18. Variants • Tabbed nicotine patch • Modified single membrane • Double-reservoir patch

  19. Tabbed Nicotine Patch • Advantages: • User Controlled • Flexibility • Allows Lower Night-Time Release • Disadvantages: • User Input Required • Tab Strength • Tab Irritation • Edge Considerations

  20. Modified Single Membrane • Nicotine in patch: 24mg • Diffusion Coefficients: • Membrane: Dm = 65*108 cm2/hr • Adhesive: Da = 30*107 cm2/hr • Membrane thickness: 40 μm • Area of patch: ~ 24 cm2 • Rate of release: 1.1 mg/hr

  21. Modified Single Membrane • Provides 24 hr release • Rate of over-night release decrease • Rate starts to decrease at 16 hrs • Graph: Total release of nicotine over 24 hr period

  22. Double-reservoir patch • 7 layer patch: • Backing • Drug reservoir – overnight release • Rate-controlling membrane • Drug reservoir – daytime release • Rate-controlling membrane • Adhesive • Strippable release liner

  23. Mathematical Model • Qout= DaKaDmbKm*A*C2*t DaKa + DmbKmb L • C2 = C2(i) – Q(out) + DmtKmtDr2Kr2/(DmtKmt+Dr2Kr2)*A*C1*t/L • This displays that the rate can be controlled by the thickness of the membrane

  24. Membrane Thickness • Rate-controlling membrane (also HDPE) for overnight release is 3x as thick so overnight release is 1/3 of daytime release • Drug reservoirs 4 µm thick (~⅓ thickness) since drug loading is ~⅓ (conc. of nicotine in 2 reservoirs is equal) • Slower membrane 117 µm thick • Faster membrane 39 µm thick

  25. Ideal Release • Each reservoir starts with 11 mg • Flow out of lower reservoir is 1⅛ mg/h • Flow out of upper reservoir is ⅜ mg/h

  26. Ideal Release Cont. • For 1st 16h, 1⅛ mg flows out of lower reservoir as ⅜ mg flows into it • For last 8h, upper membrane determines flow

  27. Theoretical Drug Release

  28. Cumulative Drug Release

  29. Morning Lag Time • When Nicoderm CQ patches worn 16h, lag of up to 4h before therapeutic plasma conc. • No lag when patches worn 24h and replaced, but if patch taken off before bed, lag every day • With double-reservoir patch, slight lag in morning b/c overnight release low • However, lag is shorter b/c: • some overnight release • daytime release higher than in Nicoderm CQ

  30. Adhesion • Current adhesive does not adhere to skin when wetted • Equate nicotine patch does adhere, both when sweating and when showering, although more irritation when removed • Level of irritation is not high enough to counter benefit of good adhesion • Use adhesive used in Equate patch

  31. QuitSmart Cigarettes • Studies show that using the patch in conjunction with other behavoiral therapies increase rate of success • In one study, ⅔ of those who used the QuitSmart kit to quit remained non-smokers after 6 mo. • BetterQuit Cigarette Substitute can be ordered online • Cost is doubled due to shipping charges

  32. QuitSmart Cigarettes • QuitSmart not well advertised • Increased awareness can be obtained by including info in information booklet contained in Nicoderm CQ kit • Alternatively, if BetterQuit Cigarette Substitute included in some Nicoderm CQ Level 1 kits, total cost for consumer lowered

  33. Cost Comparison • Cost is nearly equivalent • One pack of cigarettes costs ~ $3 – 4 • One patch costs < $4 • One 24 h patch equivalent to 24 h of smoking for pack-a-day smokers • Objection to cost of patches a hurdle • Caption on label of box: “Costs the same per day as a pack of cigarettes!”

  34. Resealable Packaging • Current packaging used for individual patches hard to tear, often must be cut • Nicotine in disposed patches harmful to pets & children • ~14 mg of nicotine left in patch AFTER USE • Resealable, ‘ziplock’ package • easier to open • can be used to seal old patches prior to disposal

  35. Questions?

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