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
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
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
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
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
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
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)
Diagram of Nicoderm CQ patch
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
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
0
T ime (hrs)
23.6
23.1
22.6
22
21.5
20.9
20.4
19.8
19.3
18.7
18.2
17.6
17.1
16.5
16
15.4
14.9
14.3
13.8
13.2
12.7
12.1
11.6
11
10.5
9.9
9.35
8.8
8.25
7.7
7.15
6.6
6.05
5.5
4.95
4.4
3.85
3.3
2.75
2.2
1.65
1.1
0.55
Nicotine (mg)
Nicoderm CQ Cumulative Release
25
20
15
Series1
10
5
0
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
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
Packaging
• Kit containing 7, 14, or 21 patches
• Each patch individually packaged in a
tear-able plastic wrapper
• Information booklet in kit
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
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
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
Variants
• Tabbed nicotine patch
• Modified single membrane
• Double-reservoir patch
Tabbed Nicotine Patch
Advantages:
• User Controlled
• Flexibility
• Allows Lower NightTime Release
Disadvantages:
• User Input Required
• Tab Strength
• Tab Irritation
• Edge Considerations
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
Modified Single Membrane
• Provides 24 hr
release
• Rate of overnight release
decrease
• Rate starts to
decrease at 16
hrs
• Graph: Total
release of
nicotine over 24
hr period
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
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
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
Ideal Release
Time(h) Mass1(mg) Mass2(mg)
Flow(mg/h) ∆Mass(mg)
• Each
1
11
11
0
0
2
10 ⅝
10 ¼
1⅛
3
10 ¼
9½
1⅛
4
9⅞
8¾
1⅛
5
9½
8
1⅛
6
9⅛
7¼
1⅛
7
8¾
6½
1⅛
• Flow out
1 ½ of lower
1 ⅞ reservoir is
2 ¼ 1⅛ mg/h
8
8⅜
5¾
1⅛
2⅝
9
8
5
1⅛
3
10
7⅝
4¼
1⅛
11
7¼
3½
1⅛
12
6⅞
2¾
1⅛
reservoir
⅜ starts with
¾ 11 mg
1⅛
• Flow out
of upper
3⅜
reservoir is
3 ¾ ⅜ mg/h
4⅛
Ideal Release Cont.
Time(h) Mass1(mg) Mass2(mg) Flow(mg/h) ∆Mass(mg)
13
6½
2
1⅛
4½
14
6⅛
1¼
1⅛
4⅞
15
5¾
½
½
5¼
16
5⅜
⅜
⅜
5
17
5
⅜
⅜
4⅝
18
4⅝
⅜
⅜
4¼
19
4¼
⅜
⅜
3⅞
20
3⅞
⅜
⅜
3½
21
3½
⅜
⅜
3⅛
22
3⅛
⅜
⅜
2¾
23
2¾
⅜
⅜
2⅜
24
2⅜
⅜
⅜
2
• For 1st
16h, 1⅛
mg flows
out of
lower
reservoir
as ⅜ mg
flows into it
•For last
8h, upper
membrane
determines
flow
Theoretical Drug Release
Time (h)
23.8
23
22.1
21.3
20.4
19.6
18.7
17.9
17
16.2
15.3
14.5
13.6
12.8
11.9
11.1
10.2
9.35
8.5
7.65
6.8
5.95
5.1
4.25
3.4
2.55
1.7
0.85
0
Nicotine (mg)
Cumulative Drug Release
20
18
16
14
12
10
Series1
8
6
4
2
0
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
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
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
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
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!”
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
Questions?