Note: Descriptions are shown in the official language in which they were submitted.
WO 93/00057 r~, ~ / u~Y~ v~
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9 ~ 3
TRAI~St)~:~MAL NICOTINE ABSORPTIOti DOS~GE ~JNIT AN~) PPcOCE;5S
D~
This invention relates to a novel transdermal absorp-
tion dosage unit adapted for administration of nicotine
whe~ein adverse ~eaction in the skin at the site of the
absorption, such as a .eddening o the abso~ption site,
caused by said transder~al ~dministration o f nlcotine, is
p~evented or substantially reduced. Incorporated into the
dosage unit is an aqent which is also transdermally
absorbed, which red~ces or prevents this adverse reaction to
the transdermal absorption of nicotine. Also preferably
i~cluded in the dosage unit is an ingredient which increases
skin wearability o~ the dosage units and desirably also
reduces the amount o~ nicotine lost during the production of
the dosage units and p~efera~ly a furthe~ ing~edient is dis-
persed in the dosage unit which hill reduce any oxidation oS
nicotine during storage. Additionally, this invention
relates to a method for reducing the desire by those persons
who smoke or have smo~ed tobacco to continue that smoking
habit.
~
It has been found that the p~incipal agent in tobacco
S5 whieh creates the habit or craving for the continuity of
smoking tobacco is nicotine. Howeve~, it ~as been found
that the greatest damage to the human syste~ by smokinq
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tobacco does not emanate from the introduction of nicotine
to the ~ody by smoking, but rathe~ by the various othe~
chemical entities which enter into the human body during
smoking, principally into the lungs. These chemical
entities include various tars and hydrocarbons. I~ is
~nderstood that '~ese chemical entitie~ can do considerable
damage to various tissues ~hroughout the human body
including certainly to the lung tissues. Recent studies
have given evidence ~hat these chemical entities which enter
into the lungs of humans who smoke tobacco can cause gene
changes within the lung cells of ~ertain persons ~ho smoke
resulting at ~i~es in an abnormal growth or carcinomas with-
in the lungs.
It h~s been found that if nicotine is introduced into
the body in an alternative ~ay to smoking, ~icotine can
assist in the withdrawal by such smokers from the smo~ing
habit. Nicotine has been introduced into the body by
varioUs means, such as by oral administration. Also, cer-
; tain administration has been proposed by transdermal admin-
istra~ion of nicotine. However, there have been certain
side-effects that have been caused by cextain of these pro-
; 50 posed means of nicotine administration by transder~al means,
such as reddening of the skin at the abso~ption site.
It would be highly advantageous to provide an improved
S5 transdermal dosage unit for administra1ion o nicotine which
would substantially reduoe or prevent such side-effects. ~t
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would also be highly advisable and desired to have such
improved transdermal dosage units for ad~inistration o~
nicotine which would provide an improved means to help a
huma~ subject to cease the habi~ of smoking tobacco.
SU~RY OF INVENTION
: Provided by this invention is a transdermal nicotine
~O absorpticn dosage unit which has the advantage of providing
very substantial reduction o~ prevention o the side-effect
of reddening o~ the skin si~e at which the nicotine is
: transder~ally absorbed. The nicotine transdermal dosage
unit= of ~his invention comprise the following elements:
1) a ~acking layer substantially impervious to the ingre-
; dients of the dosage unit:
. 2) an effective amount of nicot~ne to provide a daily dose
of nicotine to di~inish the desire for smoking;
3) an amouRt of a biocompatible salicylate ester efective
q eo reduce substantially or to prevent a reddening of
the skin at the site of the absorption of nicotine from
the dosage unit;
4) a biocompatible adhesive layer adhered to said backing
layet;
SO 5) optionally a polymer matrix layer separating said adhe-
sive layer and said backing layer whe~ein the backing
layer is adhered to one side of the polymer matrix
layer and t~e adhesive layer is adhered to the opposite
side of the matrix layer;
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W093/000S7 PCT~US9Z/Q5271
f 4 2~ $
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said nicotine and said salicylate ester being distri-
buted in said adhesive layer or said poly~er matrix layer or
both.
. The amount of nicotine to be administered to the hu~an
subject can vary but ordinarily the amount of nicotine found
to be effec~ive has been found ~o be in the range of aoout
10 mg to about ~O mg, ordinarily about ~4 mq being adequate
and satisfac~ory. It is preferable that the nicotine be
released from the dosage unit and transdermally absorbed on
;.~ 2S a c~ntinuous basis throughout a 24-hour period in order to
provide consi~tent sys~emic levels of nicotine effective to
re~uce the desi~e fox th~ subject to smoke.
~he amount o salicylate ester, suitably methyl salicy-
late, to be present ~n the dosage unit will vary depending
upon the pa~ticular dosage unit, ~e length of time the
dosage unit is designed for administering nicotine and other
facto~s. Ordinarily, a continuously delivered amount of
methyl salicylate in the range of about 5 mg to about ZO mg
has been found effective and an amount presently preferred
is in the tange of about 10 mg to about 15 mg per day.
It has also been found advantageous to have present and
mutually distribu~ed in the dosage unit along with the nico-
tine and salicylate ester an amount of an antioxidant that
is biologically acceptable and compatible with the nicotine
. 55 and t~e salicylate ester of the dosage unit and effective in
inhibiting oxidation of nicotine.
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F~rther, it has been found advantageous to have p~esent
an agent that will increase or promote the wearability of
the dosage unit. By wearability is meant the degree of
adhesion of the dosage unit, to the skin of the s~bject
being treated~ which is bioc3mpatible and com~rtable
throughout the period of treatment with the dosa~e unit
under the normal couxse of life of the subject. It has been
found that lsopropyl myristate and certain other agents
providing the properties in the dosage units as provi~ed by
isop~opyl myristate have increased o- cor.~ributed to high
; wearability of the dosage units. It has been found that
such agents as isopropyl myristate also provide the added
prope~ty of reducing loss of nicotine through volatilization
during the production of th~ transdermal dosage units of
; this invention.
'~
; Additionally provided by this invention is a method to
assist humans having the desi~e or craving to smo~e caused
; q by s~oking or exposure to smoking ~o reduce the desi~e or
craving to smoke and thus to assist in breaking the so-
called smoking habit.
,
QE3k~ D DESCRTP~IO~ OF THE I~VENTION AN~ ~HE PREFERRED
The backing layer can be made of any suitable material
;;,
which is i~permeable to the nicotine and other ~omponents
dispersed within the adjacent adhesive layer or the optional
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~ polymer matrix layer. ~he backinq layer serves as a protec-
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tive cover for the dosage unit and provides also a suppo~t
function. The backing laye~ can be formed so that it is
essentially the same size layer as the nicotine-containing
layer ot it can be of larger dimension so that it can extend
beyond the side of the nicotine-containing laye~ or overlay
the side or sides of the nicotine-containing laye~ and then
can extend outwardly in a manne~ that the surface of the
extension of the backing layer can be a base for an adhesive
to hold the dosaqe unit in intimate contact with subjects
being treated.
In making the dosage units ~hich reduce o~ prevent the
unwanted reddening caused at the site of the nicotine trans-
dermal absorption, t~e composition containing the nicotine
can readily bç coated onto a nicotine impermeable backing
layer such as a composite sold under the designation Scotch
Pak 1109 by 3M Company. A coating equipment unit can be
used to coat the backing layer t~ the desired thickness,
coater which can be used is the Warner-Mathis ~a~oratory
Coater Type ~TSv with bui~t-in laboratory dryer ~TF. The
thic~ness of the nicotine-adhesive layer can be accurately
eontrolled to desired thickness such as to 40~ mic~ons,
~sing such a designed coater-drye~.
~he amount of nicotine added to the adhesive solution
used for coating can vary so long a~ there is provided an
efcctive amount of nicotine for transdermal absorption.
Ordinarily it has been found that about a 5 pe~cent amount
of nicotine based upon the total weight o the coating mix-
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(~ 7 2~9~91~
ture of adhesive, nicotine and isopropyl myristate, provides
an effective amount of t~ansdermal abso~ption of nicotine.
T~e a~ount of nicotine can be varied depending upon the rate
o absorption desired, the particular adhesive ~r polymer
material used in making the dosage unit and othe~ factors.
~he effe~tive a.~oun~ can ~e selected from a range of from
about 1 to abou~ ~o percent based upon the weight of the
coating mixture used to make the dosage unit, a more p~efer-
able range being ~rom about ~ to abou~ 10 percent based on
Z5 said weight.
~he a,~ount of me~hyl salicylate or o_~er effective
salicylate ester can also be varied so long as an ef~ective
a~ount 1s utilized to reduce greatly or eliminate the red-
dening of the absorptio~ site of nicotine Srom the t~ans-
dermal dosage units. It has been found that an effective
amo~nt of a salicylate ester can be inco~porated into the
adhesi~e solution in making the adhesive layer or into the
poly~er mixture used in making a polymer matrix sto~age
reservoit, if that is selected. ~t has been ound prefer-
able to use methyl salicylate, however, other effective and
biocompatible esters can be selected such as cther lower
.;, .
al~yl esters, such as ethyl salicylate, glycol salicylate,
benzyl salicylate and the like esters.
It has also been ~ound desirable to us~ a biocompatible
;, 55 age~t ~or enhancing skin wearability of the dosage unit. It
. ~
' is p~e~erable that said agent also ~educes the amount Of
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- ~ 5
loss through volatilization of nicotine in the product~n of
the transdermal dosage units. It presently is preferred to
use isopropyl myristate. Other agents providing the proper-
ties of isopropyl myristate can also be used for this pu~-
lS pose. Other erfective agents can be selected as the skin
wearability enhancer, for example, it can be selected fro~
other effective and ~ioco~patible fatty acid c~mpounds such
~0 as other esters, alcohols and the l~ke. ~auryl a}cohol,
diethyl tartra~e, diethyl citrate and isopropyl adipate,
have been ~ound in illustration to be ef~ective.
Also it has been found desirable to utilize an anti-
oxidant agent to preclude any substantial amount of oxida-
tion of the nicotine of t~e dosage units. It has been ~ound
successful and e~fective to use such biocompatible anti-
oxidant agents as BHT (butylated hydroxy toluene) and AAP
(asco~bic acid palmitate). T~e amount utilized will vary ~s
desired so long as t~ere is an ef~ective reduction or p~e-
4~ vention of nico~ine oxidation. ~t has been found suitable
to utilize about one percent or a~ effective a~ount in the
~ange of about 1 mg to about 8 mg and more preferably within
, the ~ange of about ~ mg to about q ~g in a 10 cm~ dosage
unit.
; SO ~t ~a~ been ound that the t~ansde~mal absorption rate
of nicotine is~approximately 13 micrograms per square centi-
meter of s~in per hour ~rom a controlled polyacrylic adhe-
sive matrix dosage unit with 5 percent nicotine content
based upon the weight of the co~ting mixture described
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9 2~913
a~ove. It has been ~ound that the addition of isop~opyl
my~istate or methyl salicylate o~ othe~ selected salicylate
esters has little ~r no effect on the transdermal ab~o~ption
rate of nicotine at this S percent level.
Examp~es ~f materi~ls suitable for making the bac~ing
13yer are films of high a~d !o~ density polyethylene, poly-
p~opylene, polyurethane, polyvinylchloride, polyesters such
as poly(ethylene phthalate)~ metal foils, metal foil lami-
nates of such suitable poly~er films, and the like. Prefex-
ably, the materials used for the bac~ing layer are laminates
of such polyme~ films with a metal foil such as aluminum
; foil. In such laminates, a polymer film of the laminate
will usually be ~n contac~ with the adhesive layer. ~he
backing layer can be any ~ppropriate thickness ~hich ~ill
provide the desired protective and support functions. A
; s~itable thickness will be from about 10 t~ a~out 200
"ë 40 mi~rons. Desirably, the thic~ness will be from about 20 to
;~ about 150 mic~ons, and preferably be from about 30 to about
100 microns.
ln ~aking the adhesive layer, the adhesive polymer used
; ~ust be biological~y acceptable and compati~le with the
nicotine and salicylate ester and other ingredients used.
Certain polyacrylic adhesive polymers (in the form of an
alkyl ester, amide, free acid, or the like) are suitable and
S5 are presently preferred. Tllustrati~e of suitable poly-
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wos3/0~57 PCT~US92/05271
( lo 2~913
actylic adhesives for us~ in maki~g the adhesive layer are
repre~ented by the following formula:
H
- -C~2 1 ~ ~
CY~
, _ R _ X
: Zo
wherein x represents the number of repeatinq units suffi-
cient to provid_ the desired properties in the adhesive
25polymer and R i~ H or lower al~yl ~ncluding ethyl, butyl and
2-ethylhexyl
Other suitable hypoallergenic pressure-sensitive con-
tact adhesive compositions can also be used. A preferred
adhesive layer is p~essure-sensitive.
35Depending upon pharmaceutical c~mpatibility and othe~
~actors, if desired, the adhesive means can extend in the
form of a ring attached, or example, to an extended portion
of the backing layer 50 that the adhesive layer is adjacent
to ths sidewall of the nicotine-containing disc layer. The
' 1
45width of such adjac~n~ adhesive ring must be adequate to
hold the dosage u~it securely to the subject being treated.
Ordinarily, a suitablD width of such adhesive ring can be
about 0.1 to about l.O cm, preferably about O.Z to about 0.8
cm.
55~he adhesive layer then is finally covered with a
releasable protective ~ilm layer which is made from mate-
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rials w~ich are substantiallv impermeable to nicotine, t~e
salicylate ester, wearability enhancer, and any other compo-
l~ nents of the dosage unit. The polymer materials and metal
foil laminates ~sed for the back~ing layer may also be used
to make the protective layer, provided the laye~ is made
strippable or releasable such as by applying conventional
siliconizing or Teflon coating. A suitable releasable mate-
rial is Scotchpa~ 10~2 maeerial sold by the 3M Company or
Bio-~elease ~aterial by Dow Corning.
I~ making the optional po~ymer .~atrix layer, poly-
acrylic adhesive polymers as described above oan also be
used, s~ch as sold unde~ the designation Duto-Ta~, and ot~er
biocompatible adhesive polymers which provide a çtable
environment for nicotine and the salicylate ester and permit
their release, ca~ suitably be used. Generally spea~ing,
; t~ose polymers and adhesive polymers can be used to form the
, ji
polymer matrix layer which are capable of forming thin walls
or coat~ngs through which nicotine and the salicylate ester
!
are stab~e and can pass at desired controlled ~ates. Suit-
abie polyme~s and adhesive polymers are biologically and
pha~maceutically compatible, non-alle~enic and insoluble in
and compatible with body fluids or tissues with w~ich the
device is contacted. The use of so1uble polymers is to be
avoided since dissolution or etosion of the ~atrix would
. af fect the release rate of the components as well as the
capability o~ the dosa~e unit to ~emain in place for con-
venience of removal~
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` . 12 ~ ~9~13
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The amount of the components used depends upon the
dosage rate of nicotine and other components, especially the
salicylate ester, and the duration of treatment desired in
each dosage unit and the amount which can be incorporated
into the polymer matrix la~er to tetain suitable st~uctural,
diffusion and o~her properties in the inal polymer matrix
layer. It has been found, for example, that nicotine can be
satisfactorily added to the polymer used in making the poly-
me~ layer, such as polyacrylic adhesive polymer. It has
been found to be prefe~able to add and disperse the nicotine
and salicylate ester used in an amount of a selected adhe-
sive polymer solution. T~e mixture of the polymer and co~-
ponents is then thoroughly mixed to form a homogeneous solu-
tion or microdispersion of the n~cotine in the polymer.
After the mixing step, the composition can be subjected, if
desired, to vacuum to remove any entrapped air.
~he mixtute is then applied as by solvent casting tech-
nique, to a suitable substrate, like backing laminate or
release liner or other suitable substrate as described above
w~th regard to making the adhesive layer. The polymer
~attix sheet desirably i~ about 10 to 400 microns, prefer-
ably about 20 to about 300 microns, in thic~ness. The
tesulting polymer matrix sheet is removed from the casting
mach~ne and another layer of medicated polymer, can be
futther coated on the first medicated polymer layer formed
, by direct casting or lamination.
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~ ! 13 2~913
~he dosag~ units either with or without the optional
polymer matrix layer are then covered with a transparent
I0 low-adhesion release liner (e.g., Scotch-Pak 10~2/3M). The
completed dosage layers are the~ cut into dosage units
having various shapes and sizes by using a specially-
designed device cutter, such as a l~ cm2 or 20 cm2 ~ectansu-
lar shape.
The dosa~e units Can be tested for the effectiveness in
protectinq against skin ir~itation as caused by nicotine
transdermal absorption. An acute skin irri~ation test can
. .
be conducted. ~he results are expressed in a score in the
Primary ~ermal Irritation Index (PDII). ~he test is con-
ducted by utilizing yo~ng female New Zealand white rabbits.
~he dosage units are applied to the skin of the rabbits and
She absorption sites are obse~v~d during the test period for
any occurrence of skin ~eddenin~. In the test, the control
, dosage units utilizing a controlled amount of nicotine such
as 5 percent showed no acute skin irritation upon a one-day
testing. ~he scorin~ system is as follows:
",~
~
Result
o Non-~rritant
c ~ Slight Irritant
2 - 5 Moderate Irritant
~ 5 Severe Irritant
SS In the s~in sensitization s~udies, a posi.ive control
~as utilized containing dinitrochlorobenzene in 9S percent
alcohol.
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~ lq 2~49~3
. ~he transdermal absorption of the nicotine and salicy-
late ester f~om the dosage units of this invention is
evaluated by using a s~in specimen from human cadaver by
following the procedure described by Y.W. Chien, K. Valia
and U. B. Doshi in 8~, 11(7) 1195-
., 121~ (1985).
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.~ 15
The following examples are in illustration of the invention
and are not intended to be limiting.
Ex~mple 1
composition for use in ma~ing dosage units of this
invention is made by follo~ing t~e procedure described. An
amoun~ of P2.93 grams o~ material ~ro-~ak solution (D~ro-
Tak 80-1054 used) is added to a q oz. Quorpak bottie. To
that solution there is also added to the bottle q.04 grams
of nicotine, ~.4g grams of isopropyl myrls~ate, 8.09 grams
of methyl salicylate and 0.4 grams of butylated hydroxy-
toluene. ~he mix~ure is mixed fo~ ten ~ou~s to obtain a
homogeneous formulation.
i The composition is coated on a backing layer. The
backing laye is made o~ Scotch Pak 1109 sold by 3M Corpora-
tio~.
The oven te~peratu~e of the coatin~ machine is set at
, 60C and the timer is set at 10 minutes. A coat~ng frame
~umber 1 is installed onto the mac~ine. ~he Scotch Pak 1109
backing material is mounted on the coating frame of the
machine and the position of the doctor knife is adjusted to
p~ovide a thickness of 400 microns onto the backing layer.
~bout 20 gra~s of the homogeneous formulation is poured onto
the backing laye~ and the doctor knife is pul~ed towaxd the
operator to coat a thin ilm of formulation upon t~e SCotch
Pak backing layer. ~he dootor knife is removed and the
control button is activated to advance the coating f~a~e
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~-: 16 2~4913
into the drying cha~ber of the coating machine. The frame
holding the back~ng layer bearing the coating is ~uto~ati-
cally released from the drying chamber and the coated ~ilm
is ~emoved from the coating frame.
A coating fra~e num~er 2 is then installed into the
coating machine. Release liner mate-ial is mou~ted ~nto a
coating ftame number 2. About 20 gra~s of the homogeneo~s
Z nicotine formulation is po~red upon the release line~ and
the doctor knife is pulled toward the operator to coat a
thin film of the formulation upon the release iiner. The
doctor knife is again removed and the controlling but~on is
; activated to advance the coating fram~ bearing the release
liner having coated upon i~ the layer of for~ulation into
"~ the dryi~g chamber. The number 2 frame bearing the coated
release layer is aut~matically released from the dxying
chamber of the coating machine. The coating Sra~e number 2
with the coated release liner is removed from the frame.
Coatin~ frame number 1 bearing the backing laye~ with
'~ the nicotine ~oating layer is reinstalled ~nto the machine
; 45 with the nicotine coa~inq faci~g upward. Also, the ~elease
liner with the coated formulation Srom ~oating rame number
is carefully placed upon the coating layer positioned upon
the backing layer with the coating layer facing downwa~d
upon the first coati~g layer. The t~o layers then become
-~ 5S la~inated to provide a backing layer having adhered thereto
, the nicotine adhesive layer ~aving 9 percent nicotine, 10
h percent isopropyl myristate, 18 percent of methyl salicylate
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and 1 percent of but~lated hydroxYtoluene. The final lami-
nated layer then also has on the opposite side from the
backing layer a release layer adhered to the adhesi~e nico-
-' tine con~aining layer.
. lS The laminated sheet co~taining a backing layer the
nicotir.e adhesive layer and the release layer are fo~med
into 5 cm2 or 10 c~ transderma~ dosage units by using a
cutting press.
,
Exam~e ~
An in-vitro skin permeation procedure described in
Chien et al. referred to herein above was used to evaluate
the per~eability o~ nicotine across human cadaver skin.
Skin permeation flux measure~ents were made at 3~C. The
nicotine concentration in the receptor medium (40~ aqueous-
polyethylene glycol solution) was measured at various time
inter~als. ~he skin flux or transmission of the nicotine
through the cadaver s~in was determined and calculated for
various time intervals.
The skin permeation rate of nicoti~e is relatively
high, for example, about 13 mc~cm~/hr from a polyacrylate
adhesi~e matrix with 5% nicotine concentration. ~t was
determined ~hat the addition of certain of the ingredients,
suc~ as isopropyl ~yristate or methyl salicylate has littlc
or no effect on the skin permeation rate of nicotine as
shown in the fol~owing ~able 1:
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~vY~VV~ PCT/~S92/05271
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Table 1. The Efect of IPM on Nicotine Sk~in Flux
~ormulation,~ngredie,nts ~lu FlUX
~~ ~ (mc~/cm~b~L ~iQ
0 95 14.~7 (1.82) 1.0
5 10 85 16. 15 (O- 57) 1-
' S 20 75 15.57 (1.18) 1.1
,'` 15
At 5 percent nicotine loading, ehe addition of isop~o-
, 20 pyl myristate up to 20 percent did not substantially affect
,, nicotine skLn permeation. The slight increa5e in nicotine
skin permeation fro.~ the patch formulation conta~ning 30%
isopropyl myris~ate was the result of the protective proper-
` ty of isopropyl myristate to prevent nicotine 'rom evapora-
,, tion during the drying of the dosage ~nit sheets as
, described in Example 1 and t~e dilution result of isopropyl
myrista~e to the polyacrylate adhesive matrix, causing a
,' 3S high nicotine diffusivity in a less viscous adhesive matrix.
,,
"' The following experi~en~s show that t~e nicotine con-
~ 40 centration can be varied fro~ 2.5 to 10 pezcent. ~lso, it
.,
" shows that in the prçsence of a set amount of isopropyl
, ~yristate, 20 percçne (w/~), the n~cotine skin pe~meation
,, 45 decreased with dec~easing nicotine concentration in the
- adhesive layer of the dosage units. The data are shown in
~, 50 the following Table Z.
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w~3/~0057 PCT/US92JOS27
` 19 2 ~9 ~91 3
-- Table 2. ~he Effect of ~CT ~oadings on ~C~ Skin ~lux
~or~ulation Ing~;edients Fl~ Flux
~CT I~M l~g~_m~ Ratio
0 9~ 36.39 (2.98) 1.0
~ 10 20 70 60.SO (4.25) 1.7
:; ~.5 20 72.537.23 (2.56) l.o
~0 75 22.50 (2.~4) 0.6
lS 2.5 20 ~7.511.21 ~0.83) 0.3
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When the dosage units were made using ~arious salicy-
late esters, such as methyl salicylate (MSJ, ethyl salicy-
~ late (ES) or glycol salioylate (GS) it was shown that lit~le
: or no enhancing effect on skin permeation rate of nicotine
; resulted, The following Table 3 shows nicotine permeation
from the adhesive formulations for making the dosage unit
containing a constant amount of nicotine and isopropyl
myristate loadings at 9 or 10 percent respectively and
varied salicylate este~ loadings.
The nicotine permeation rate as a function of sali-
cylate loadings in the patch is shown in the following ~able
3:
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Table 3. The Effect of Salicylate ~oadings on NCT skin ~lux
Nicotine S~n
; 10 micromol/5 cm2 ~lux (mcg/cm /hr
MS ES GS
15 9 0 0 ~8 0~ (6 ~9)
~2.2 o o 38.39 (9.32)
i 3~.3 0 0 46.06 (5.71)
o 5.5 0 30.13 (5.85)
0 1~.3 0 32.39 (6.66)
25.2 0 35.56 (6 17)
0 40.5 o 37.09 (13.00)
0 0 22.3 25.93 (1.68)
, ~ 3~.3 31.23 (2.10)
: 0 0 53.1 3Z.26 (5.96)
3~
Exam~le 3
; The dosage units made follo~ing the procedure of
Example 1 whi~h contain methyl ~alicylate ~ith or without
nicoti~e, placebo dosage units or active dosage units,
~especti~ely, were tested on six voung female New Zealand
white rabbits to study the protective effect of salicylate
: ester against skin irritation tredenninq) normally caused by
nicotine transdermal absorption.
~he following Table 4 shows t~e low amo~nt of skin
irritation of the dosage ~nits of the invention having
. methyl salicylate in t~e Primary Dermal Irritation Index
(PDI~).
~ 5S
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w093/000~7 PCT/US92tOS271
~ 21 2~9~ 3
. s
Table 4. P~II S~ores in a Primar~ Skin Irritation Study
L~ SU~ei~P~ Scores*
~; lO Active 0.34
Placebo 0.34
:,.
~Scoring System: PDII Result
O Non-lrritant
c 2 Slight Irritant
2 - 5 Mode~ate ~rritant
.. ~ ~ 5 Severe Irritant
~he ~esults of the testing show that methyl salicylate
containing dosage units showed little or no skin irritation
at the various conce~t~ations of nicotine. The methyl sali-
cylate containing dosage units showed substantially the same
s~in irritation le~el exhibited by place~o dosage units, in
.; contrast to the positive control using the standa~d test
material dinitrochlorobenzene in 95~ ethanol solution. ~he
~coring system i3 as follows:
8 Weak
9-Zq Mild
4 5 29-64 M~derate
65-80 Strong
8l-lOO ~xtreme
They show that the presence of methyl salicylate in the
dosage units containing nicotine eliminated irritation o~
sensitization of skin caused by transdermal abso~ption of
n1co~ine.
. .
:
~ .
n~Y~/VW~ PCT/~S92/05271
f, 22 2~9~3
Exa~e 4
Dosage units were made containing different concentra-
tions of isopropyl myristate. The presence of isop~opyl
myristate and other like agents increase ~he wearability o~
lS adhesion of the dosage units upon the skin of the subject
undergoing nicotin~ transdermal ~bsorption. AlSo, isopropyl
myristate reduces loss of nicotine during the productio~ of
the nicotine containinq dosage units, such as those
described in Example 1.
Dosage units made by the general procedure as described
in Example 1 having a size of S cm2 were extracted with
. solvent to remove n~cotine. ~osage un~ts containing no iso-
propyl myristate and dosage units containing both the 10~
nicotine and 2~ isopropyl myristate were extracted to
determine the amo~nt of nicotine present and the protective
effecS of isopropyl myristate. The Pollowing Table 6 shows
that isopropyl myristate substantially improved the p~even-
, q tion of loss of nicotine during the preparation procedure
for ma~ing the nicotine containinq dosage units.
~5 ~able 6. Recovery of Nicotine from Patches With
and Without IPM
~ormulation InatedientsAmount o~ Nicotine 2ecovered
NC~ IPM ~ (mq/S cmZ Patch)
1~ o 90 3.79 (0.01)
1020 70 ~.14 (0.01)
' 55
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w093/00057 PCT/US92~05271
!-- 23 2 ~ 9 ~ 913
E~a~p~
Dosage units were made containing zero an~ various
1~ a~ounts of an antioxidant, ascorbic acid palmitate or buty
lated hydroxytoluene. Long term stability tests were car-
ried out. The~e tests sho~ed that at high storage tempera-
- tures nicotine was stabilized in the presence of butylated
- hydroxytoluene as compared to corresponding dosage unit
containing no butylated hydroxytoluene. The following ~able
7 shows the loss of r.icotine in the absence o the antioxi-
; dant butyla~ed hydroxytoluene.
Table 7. Recovery of ~icotine Patches without BH~.
3~ 3~ Q~l ~urat on rWeeks~ ~gg~J~ L_~9:
r.t. 0 100%
5 3 99.4%
4 s
The data show that afte~ a sto~age period of 3 weeks at
45 C a loss o~ 9~ of n~cotine was incu~red.
Corresponding dosage units were made incorporating 1~
butylated hydroxytoluene based on the ~eight of the nicotine
composition used to make up the nicotine containing a~hesive
, layer. Tbe following data show that presence of butylated
hydroxytoluene acte~ to protect nicotine against oxidative
deqradation.
''' '
,
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.. ~ WO 93/OoO57 ~ Y~/o5~7 1
q ~g4~3
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Table 8. Recovery of Nicotine from Patches with ~c B~
TemDerature (c) Duration (Wee~s2 Recove~y of
t.t. 0 100~
8 99~1%
26 104.9
: Exa~e ~
The above dosage units are repeated using ethyl salicy-
late or glycol salicylate as the anti-reddening agent. Also
the above dosage units can be made using other antioxidation
~5 agents, such as ascorbic acid palmitate and other wear-
ability enhaneers instead oS isopropyl myristate, which
provide the benefits of isopropyl myristate.
E~fective and biocompatible nicotine salts, solvates
and the like nicotihe compounds which are transdermally
absorbed can b~ uced in making the dosage units described in
the above Example. ~lso, oeher effective and biccompatible
salicylate esters, isopropyl myristate substitutes, oehe~
bioacceptable antioxidants or other components can be used,
, so long as the resulting dosage units are e~fective and ~ave
? the desired properties.
,~,.,; ~
' Following are the steps to manufacture dosagc units
which comprise a backing layer-polymer matrix-adhesive-
release liner:
~,,' .
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wos3/0005~ PCT/VS92/052?1
. ,,~ Z5 ~4~13
; l) Mount Scotch Pak llO9 on t~e coating frame and adjust
the posit~on of the ~octor knife to provide a thickness
of 400 microns (above the Scotch Pak).
2) Pour approximately 20 gm of the homoqeneous polymer
mixture onto Scotch Pak llO9 and pull the doctor ~nife
(toward the operator) to coat a thin fil~ of ~ormula-
tion containing nicotine, me~hyl salicylate and isopro-
pyl myristate as defined in Example l on the Scotch
Pak.
3) 2emove the doctor knife and push contr~lling button to
ad~ance thD ooating ~rame into the drying cha~ber.
4) As the frame is automatically released from the drying
chamber, remove the coating ftame with film-coated
Scotch Pak from the machine and place i~ aside.
: J5 5) Install t~e coating frame No. 2 onto t~e machine.
6) Pour approximately lO gm of the adhesive only on
~elease liner and pull the doctor knife (towa~d the
~perator~ to coat a thin fllm, Z00 microns, of formula-
tion on the release liner.
,, 4S 7) Remove the doctor knife and push the con~olling ~ut~on
to advance the coating ~rame ~o. 2 into the d~ying
chamber.
8) As the ~ram~ is automatically released rom the drying
Chamber, remo~ the coating f~ame No. ~ and put it
` 55 Did~.
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9) Re-install the coating frame No. 1 with the coating
formulation facing upward.
10) Release the release liner from the coating frame ~o. 2
and carefully place it, with the coated formulation
facing do~nward, onto the coated formulation on the
backing laye~ and laminate the two coated f~rmulations
together.
~0 11) Remove the coating frame ~o. 1 rom the machine and
unload the multilaminated sheet.
12) ~ut the multilamina~ed sheet into dosage units of
desired size by using a cutting press.
' .
;;~ 35
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