Note: Descriptions are shown in the official language in which they were submitted.
CA 02215258 1997-09-25
WO 96/30001 PCT/US96102785
-1-
METHOD OF MAICING A PRESSURE SENSITIVE
SKIN ADHESIVE SHEET MATERIAL
Background of the Invention
Field of the Invention
This invention relates to methods of making pressure sensitive skin adhesive
sheet materials. More particularly this invention relates to methods of making
pressure sensitive skin adhesive sheet materials containing a liquid. In
another
aspect this invention relates to methods of delivering a liquid to the skin.
Description of the Related Art
Pressure sensitive skin adhesives (PSAs) require a balance of viscous and
elastic properties to afford adhesion, cohesion, stretchiness, and elasticity.
PSAs
have sufficient cohesiveness and elasticity so that despite their tackiness
they can be
handled with the fingers and removed from the skin without leaving substantial
residue. Well known uses for PSAs include common adhesive strips and other
wound dressings. They are also used in transdermal drug delivery devices.
A variety of transdermal drug delivery devices have been described.
Devices known to the art include reservoir type devices involving membranes
that
control the rate of drug and/or skin penetration enhancer delivery to the
skin, single
layer devices involving a dispersion or solution of drug and excipients in an
adhesive matrix, and more complex multilaminate devices involving several
distinct
layers, e.g., layers for containing drug, for containing skin penetration
enhancer, for
controlling the rate of release of the drug and/or skin penetration enhancer,
and for
attaching the device to the skin.
When a transdermal drug delivery device incorporates a pressure sensitive
skin adhesive layer comprising a dispersion or solution of drug and/or an
excipient
CA 02215258 1997-09-25
WO 96/30001 PCTIUS96/02785
-2-
in a polymeric matrix, the adhesive layer typically is prepared by dissolving
the
polymer and the drug and/or excipient in a solvent, coating the resulting
solution
onto a web, then oven drying the coated web to evaporate the solvent. This
conventional method has several disadvantages. When the drug and/or excipient
is
volatile or heat sensitive, the oven drying step can lead to loss of drug
and/or
excipient due to either evaporation or to thermal degradation. Also, this
method
requires a solvent based polymer, usually involving a volatile organic
solvent.
Alternatively drug and/or excipient can be coated onto a release liner which
is then laminated onto a polymeric layer in order to apply the drug and /or
excipient
to the polymeric layer. This method avoids the difficulties associated with
heating
of drug and/or excipient but nonetheless has disadvantages: uniformity of drug
and/or excipient content is dependent on the relatively difficult process of
coating
the drug and/or excipient onto the low energy surface of the release liner,
whereupon dewetting often occurs causing the ultimate distribution of the drug
and/or excipient to be different from the distribution made in the coating
process.
Summarv of the Invention
This invention provides a continuous method of making a pressure sensitive
skin adhesive sheet material containing a liquid by combining a coating medium
comprising said liquid with a polymeric base layer, which sheet material
retains
substantially all of the liquid until it is applied to the skin, comprising
the steps of:
(i) providing a base layer of a first polymer,
(ii) applying continuously to said base layer a coating medium
comprising a second polymer dissolved or dispersed in a liquid and
allowing the coating medium to diffuse into the base layer to provide
a pressure sensitive skin adhesive sheet material.
This invention also provides a method of delivering a liquid to the skin,
comprising steps (i) and (ii) above and the further step of (iii) applying the
pressure
sensitive skin adhesive sheet material from step (ii) to the skin without
prior
CA 02215258 1997-09-25
WO 96/30001 PCT/US96/02785
-3-
removal of a substantial amount of the liquid from the pressure sensitive skin
adhesive sheet material.
In the manufacturing method of the invention the second polymer is used as
a thickener in order to adjust the viscosity of the coating medium. This
eliminates
potential adverse affects that conventional thickeners (e.g., clay or silica
gel) may
have on adhesive properties of the ultimate product of the process.
Furthermore,
because the first and second polymers can be the same the manufacturing method
of
the invention does not require that an additional component be incorporated
into
the sheet material merely for the purpose of thickening the coating medium.
The manufacturing method of the invention eliminates the drying step
required in some conventional methods, thus minimizing losses due to
evaporation
and/or thermal degradation. It also permits use of base layer polymers that
are not
based on an organic solvent thus eliminating all need for volatile organic
solvents in
manufacturing. Further, regardless of the type of polymer that is chosen for
the
base layer it can be processed prior to application of the coating medium,
thus
avoiding concerns arising out of physical or chemical instability of
components of
the coating medium (e.g., a drug or an excipient) to base layer processing
conditions. For example, if the base layer polymer is solvent based, in order
to
remove residual solvent oven temperatures may be increased to well above those
that could be tolerated by certain drugs, allowing increased line speeds when
manufacturing a pressure sensitive skin adhesive containing such a drug.
While providing the advantages noted above this invention avoids the
difficulties associated with the liner coating process described above, for
the coating
medium need not be put down over the low energy surface of a release liner.
Brief Description of the Drawings
Figure 1 is a schematic of direct gravure coating.
Figure 2 is a schematic of kiss gravure coating.
Figure 3 is a schematic of extrusion die coating.
CA 02215258 2006-02-20
4
Detailed Description of the Invention
This invention provides a method for making a pressure sensitive skin
adhesive sheet material containing a liquid, e.g., a liquid excipient that
softens a
non-adhesive or poorly adhesive polymer such that it can be used as a pressure
sensitive skin adhesive. The pressure sensitive skin adhesive sheet materials
prepared according to the process of the invention are particularly suitable
for use
in transdermal drug delivery devices involving liquid drugs or liquid
excipients that
affect adhesion, compliance, drug solubility, or the rate at which a drug
penetrates
the skin.
Step (i) of the manufacturing method of the invention provides a base layer
comprising a first polymer. The first polymer can be, but need not be, a
pressure
sensitive skin adhesive by itself. As described in detail below certain
polymers that
are not suitable by themselves as adhesives may become suitably tacky upon
addition of liquid softening agents. Such softening agents can be incorporated
into
the base layer polymer at the outset or they may be added in step (ii) of the
process
of the invention. In any event the first polymer is a polymer that can be used
as the
basis for a pressure sensitive skin adhesive. It is preferably
dermatologically and
pharmaceutically acceptable and substantially chemically inert to any drug
and/or
excipient that is later to be incorporated. Examples of suitable polymers
include
addition polymers, e.g., acrylates such as those disclosed, for example, in
U.S.
Patent RE 24,906 (Ulrich), U.S. Patent No. 4,732,808 (Krampe et al.),.arKi
those disclosed in commonly assigned copending application CA 2,198,390
(Garbe et al.), adhesives, polyisobutylenes polyisoprenes, styrene block
copolymers (e.g., SEBS copolymers, SBS copolymers), and the like, and
condensation polymers such as those used as silicone adhesives as disclosed
in U.S. Pat. No. 5,232,702. Generally the base layer is about 25-600 pm thick.
The base layer can be carried on a substrate, which preferably is
substantially chemically inert and physically inert to the components to be
applied
thereto (e.g., it does not react chemically with such components, nor does it
absorb
CA 02215258 1997-09-25
WO 96/30001 PCT/US96/02785
-5-
or swell with such components). Examples of suitable substrates include
backing
films, release liners, differential release liners (i.e., liners in which both
sides have
release properties but one surface releases more readily than the opposing
surface),
and membranes.
Suitable backing films for use as the substrate include conventional flexible
backing materials used for pressure sensitive adhesive tapes, such as
polyethylene,
particularly low density polyethylene, linear low density polyethylene, high
density
polyethylene, polyester such as polyethylene terephthalate, randomly oriented
nylon
fibers, polypropylene, ethylene:vinyl acetate copolymers, polyurethane, rayon,
and
the like. Backings that are layered, such as polyethylene-polyester-aluminum-
polyethylene composites, are also suitable.
Suitable release liners for use as a substrate include conventional release
liners comprising a known sheet material such as a polyester web, a
polyethylene
web, or a polystyrene web, or a polyethylene-coated paper, coated with a
suitable
fluoropolymer or silicone based coating. Suitable differential release liners
include
conventional differential release liners comprising a known sheet material
such as a
polyester web, a polyethylene web, or a polystyrene web, or a polyethylene-
coated
paper, coated on both surfaces with suitable fluoropolymer or silicone based
coatings. Examples of suitable materials for use in membranes include
polyethylene, low density polyethylene, linear low density polyethylene, high
density
polyethylene, polyurethane, nylon, and ethylene:vinyl acetate copolymers.
Examples of suitable physical forms for the membranes include continuous film,
macroporous membrane, and microporous membrane.
Selection of a substrate depends on the steps involved in the overall
manufacturing process of the pressure sensitive skin adhesive sheet material
and on
the configuration of the final product (e.g., a transdermal drug delivery
device) that
incorporates the sheet material. For example, if the base layer is
manufactured off
line and stored as rollstock, then a differential release liner is a preferred
substrate.
Alternatively, if the base layer is manufactured on line just prior to
application of a
coating medium, then a backing film or a liner having a single release surface
may
CA 02215258 1997-09-25
WO 96/30001 PCT/US96/02785
-6-
be preferred depending on the configuration of the final product that
incorporates
the sheet material.
The base layer can be put down by any conventional coating method, for
example, by die coating or by dissolving the polymer in a solvent, coating the
resulting solution onto a substrate, then oven drying the coated substrate to
evaporate the solvent. Hot-melt, water borne, or radiation curing processing
methods can also be used to put down a base layer.
Step (ii) of the manufacturing process of the invention involves applying a
coating medium to the base layer. The manufacturing method of the invention is
a
continuous method, i.e., the coating medium is applied to the base layer as it
passes
the application means with no intermittent cessation of the relative motion of
the
base layer with respect to the application means, as opposed to an indexed,
incremental, or stepwise method whereby a unit area of the base layer is
indexed
into place, the coating medium is applied, and the indexing and coating
process is
repeated on further unit areas of the base layer. If desired the coating
medium can
be applied in a pattern (e.g., in a series of parallel lines along the length
of the base
layer, in a pattern defined by a patterned printing or coating roll, or a
patterned
coating die, or in a pattern created by a change in coating weight with time).
The coating medium comprises (a) a liquid and (b) a second polymer. In
addition to the liquid and the second polymer, other components such as a
solid
drug or solid excipient can be incorporated into the coating medium.
The liquid is selected from those materials which are suitable for use as a
component of a pressure sensitive skin adhesive and liquid at the operating
temperature of the process and substantially atmospheric pressure. The
operating
temperature can be any temperature suitable to a coating process but is
preferably a
relatively low temperature (e.g., about 20-50 C, more preferably about 20-40
C)
such that the advantages of the process are retained with respect to thermally
labile
materials.
Liquid drugs, liquid excipients, and mixtures thereof can be used.
CA 02215258 1997-09-25
WO 96/30001 PCT/US96/02785
-7-
Examples of suitable liquid drugs include (S)-3-methyl-5-(1-methyl-2-
pyrrolidinyl)isoxazole, nicotine, nitroglycerin, amyl nitrite, ethchlorvynol,
paramethadione, scopolamine, and free bases of certain drugs that are
conventionally used in the form of acid-addition salts.
Suitable liquid excipients include generally oily materials that raise the
compliance value or lower the apparent glass transition temperature (T8) of
the
polymer used as the base layer, including certain materials that have been
used as
skin penetration enhancers or solubilizers in transdermal drug delivery
systems.
Exemplary materials include Cs-C22 fatty acids such as isostearic acid,
octanoic acid,
and oleic acid, C8-C22 fatty alcohols such as oleyl alcohol and lauryl
alcohol, lower
alkyl esters of C8-C22 fatty acids such as ethyl oleate, isopropyl myristate,
butyl
stearate, and methyl laurate, di(lower) alkyl esters of C6-Cs diacids such as
diisopropyl adipate, monoglycerides of C8-C22 fatty acids such as glyceryl
monolaurate, tetrahydrofurfuryl alcohol polyethylene glycol ether,
polyethylene
glycol, propylene glycol, 2-(2-ethoxyethoxy)ethanol, diethylene glycol
monomethyl
ether, and combinations of the foregoing. Alkylaryl ethers of polyethylene
oxide,
polyethylene oxide monomethyl ethers, and polyethylene oxide dimethyl ethers
are
also suitable, as are solubilizers such as dimethyl sulfoxide, glycerol,
ethanol, ethyl
acetate, acetoacetic ester, N-methyl pyrrolidone, and isopropyl alcohol.
Preferred liquid excipients include glyceryl monolaurate, diethylene glycol
monomethyl ether, tetrahydrofurfuryl alcohol polyethylene glycol ether,
diisopropyl
adipate, propylene glycol, isopropyl myristate, ethyl oleate, methyl laurate,
2-(2-
ethoxyethoxy)ethanol, and oleyl alcohol.
A second polymer is combined with the liquid to form the coating medium.
Suitable second polymers include those enumerated above in connection with the
base layer. The second polymer is preferably of the same chemical class (e.g.,
an
acrylate or a styrene block copolymer, as the case may be) as the first
polymer used
in the base layer. More preferably the second polymer contains the same
monomers, and most preferably it contains the same constituent monomers in the
same ratios and is of the same inherent viscosity as the first polymer. The
second
CA 02215258 1997-09-25
WO 96/30001 PCT/US96/02785
-8-
polymer is selected such that it is capable of being dispersed and/or
dissolved in the
liquid. Generally, the liquid and the second polymer can be combined using any
suitable technique that will form a solution or a dispersion of the second
polymer in
the liquid, including stirring, shaking, ultrasonic vibration, and the like.
The liquid
and the second polymer are combined and blended until a substantially
homogeneous coating medium (that is, a coating medium wherein the second
polymer is substantially uniformly distributed throughout the liquid bulk,
e.g., in the
form of a solution or a dispersion) is obtained. In a preferred embodiment of
the
invention the second polymer is soluble in the liquid, and the resulting
coating
medium is a solution.
The identity and relative amount of the liquid and polymer components
incorporated into the coating medium, and the particular base layer polymer
for a
particular application can be readily determined by consideration of the
structure
and properties of the liquid, the first polymer, and the second polymer, along
with
the intended coating process and desired properties of the ultimate product
pressure
sensitive skin adhesive sheet material.
The properties desirable in a pressure sensitive skin adhesive are well known
to those skilled in the art. For example, the adhesive should achieve and
remain in
intimate contact with the skin in order to adhere reliably and, if it
incorporates a
drug or penetration enhancer and is used in a transdermal drug delivery
device,
deliver to the skin at a stable rate. It is desirable for a pressure sensitive
skin
adhesive to have sufficiently little cold flow such that it is stable to flow
upon
storage. It is also preferred that it release cleanly from the skin. In order
to achieve
skin contact, clean release, preferred levels of adhesion, and resistance to
cold flow,
the amount and structure of the monomers in the base layer polymer, the
inherent
viscosity of the base layer polymer, and the amount and structure of the
liquid and
polymer components of the coating medium are preferably selected such that the
resulting pressure sensitive skin adhesive has a compliance value (measured
according to the test method set forth in detail below) in the range 1 x 10's
cm2/dyne to 5 x 10-4 cm2/dyne. Materials having compliance values outside this
CA 02215258 1997-09-25
WO 96/30001 PCT/US96/02785
-9-
range are sometimes suitable for use as pressure sensitive skin adhesives.
However,
those having substantially lower compliance values will generally be
relatively stiff
and have less than optimal skin contact and adhesion to skiii. Those having
substantially higher compliance values will generally have less than optimal
cold
flow and might leave substantial residue when removed from the skin.
Particularly suitable compositions can be readily selected for a given set of
desired properties considering the effects described below:
As regards the first polymer, that is, the polymer in the base layer,
structural
features can be tailored according to intended performance of the ultimate
product
of the process. For example, macromonomers such as those described in U.S.
Pat.
No. 4,732,808 (Krampe et al.) can be incorporated into acrylate polymers in
order
to decrease compliance of the base layer polymer compared to the compliance of
a
like acrylate base layer polymer without macromonomer. Strongly hydrogen
bonding monomers have been found to increase the amount of polar or hydrogen
bonding substances that can be dissolved in a polymer and to decrease the
amount
of generally nonpolar substances that can be dissolved. Further, a strongly
hydrogen bonding copolymer will be a relatively less compliant material.
Therefore
if hydrogen bonding monomers such as acrylic acid or acrylamide are used in a
base
layer polymer a lesser amount of macromonomer will be required in order to
lower
compliance sufficiently to avoid cohesive failure.
A relatively high compliance pressure sensitive skin adhesive involving a
macromonomer will generally have better adhesive properties than a
macromonomer free polymer having the same compliance value. Increasing
macromonomer content generally increases the amount of liquid excipient that
can
be loaded into a pressure sensitive skin adhesive without cohesive failure.
Increasing inherent viscosity will also tend to allow higher loading with
liquid
excipient without cohesive failure.
A change that would increase inherent viscosity of a polymer (such as
increased molecular weight through selection of polymerization conditions
and/or
solvent ratios) will generally decrease compliance.
CA 02215258 1997-09-25
WO 96/30001 PCT/US96102785
-10-
As regards the second polymer, which is incorporated into the coating
medium, it has been found that for some liquids at least a minimum amount of
the
second polymer niust be used in order to obtain a coating medium that will wet
the
base layer of polymer. Substantially uniform wetting is preferred in order
that the
coating medium is substantially uniformly distributed over the desired surface
of the
base layer. The particular structure and amount of second polymer combined
with
the liquid is determined on the basis of the structure the polymer considering
those
parameters known to affect the flow mechanics of coating processes, such as
solubility properties, the wetting relationship between the coating medium and
the
base layer, coating speed, viscosity of the coating medium, surface tension of
the
coating medium, and wet film thickness of the coating medium. Further, it is
well
known to those skilled in the art that rheological properties may render
certain
second polymers unsuitable for use in a particular coating medium due to the
coating method to be used or the intended properties of the final product.
As regards the amount and identity of the liquid material, many of the
liquids enumerated above are known to affect aspects of performance of
pressure
sensitive skin adhesives. Generally they are useful in softening or increasing
the
compliance value and/or lowering the glass transition temperature of otherwise
non-
compliant (and therefore poorly pressure sensitive adhesive) polymers,
rendering
them suitable for use as pressure sensitive skin adhesives. However, the
liquids
enumerated above are generally oily substances that function as plasticizers
when
incorporated in a polymer. Such materials can affect adversely the performance
of a
pressure sensitive skin adhesive, for example by softening it to the point of
cohesive
failure (where substantial polymer residue is left on the skin upon removal
from the
skin), or by separating from the continuous phase and forming an oily layer
that
reduces adhesion of an otherwise adhesive matrix. Also, when liquids phase
separate from the base layer polymer, unstable properties (e.g., decreasing
adhesion
over time or unstable drug delivery rates in a transdermal drug delivery
device) can
result.
CA 02215258 1997-09-25
WO 96/30001 PCT/US96/02785
-11-
Given the several factors discussed above relating to selection of amounts
and types of liquids and second polymers in the coating medium it is not
practical to
enumerate particular preferred amounts in connection with particular
combinations,
but such can be readily determined by those skilled in the art with due
consideration
of the relevant factors. Generally, however, the second polymer is present in
the
coating medium in an amount of about 0.5 to about 30 percent, preferably about
1
to 20 percent, by weight based on the total weight of the coating medium.
The amount of coating medium to be applied to the base layer is generally
not more than that amount which causes the product pressure sertsitive skin
adhesive sheet material to lose adhesion or leave substantial residue on the
skin
when peeled from the skin. Depending upon the identity of the base layer
polymer
and the liquid, high loadings, e.g., up to and in excess of 40% by weight
based on
the total weight of the final pressure sensitive skin adhesive, can be
achieved. In the
event that the liquid comprises a drug it is applied such that the drug is
present in a
therapeutically effective amount, which varies from drug to drug but can be
readily
determined by those skilled in the art considering the particular drug, other
excipients, and the particular intended therapeutic effect.
The method used to apply the coating medium to the base layer can be any
method that is capable of putting a precise amount of coating medium in a
uniform
fashion onto the base layer. Suitable continuous methods include die coating,
reverse gravure and forward gravure coating. Particularly preferred methods,
which are described in detail below, include direct gravure coating, kiss
gravure
coating, and extrusion die coating.
Gravure coating uses a gravure roll having etched, machined, or knurled
recesses on its surface. The coating medium is transferred from the recesses
to the
layer to be coated. The recesses may be of any size or shape, discontinuous
over
the surface, or as used here, continuous over the surface of the roll. A
common
pattern for continuous coatings is a trihelical pattern consisting of diagonal
triangular grooves on the roll surface.
CA 02215258 2006-02-20
-12-
Figure 1 shows a schematic of direct gravure coating. Coating medium 112
is supplied to gravure roll 114 by means of pan 116. The volume of coating
medium 112 in the recesses of gravure roll 114 is then adjusted by means of
doctor
blade 118. Coating medium 112 is coated on to base layer 120 comprising the
first
polymer at nip point 122 by contacting base layer 120 with the coating medium
contained in the recesses of gravure roll 114 by means of impression roll 124.
Factors that have been found to influence coating weight (i.e., the amount of
coating medium that is applied per unit area of base layer) and/or coating
uniformity
include certain gravure roll parameters, identity of the liquid material,
viscosity of
the coating medium, line speed, nip pressure and gravure roll/line speed
ratio. The
gravure roll parameter of particular importance is the volume factor, i.e.,
the
internal recess volume per unit area of the gravure roll surface. A change in
any of
these factors can affect coating weight and/or coating uniformity.
Figure 2-shows a schematic of lciss gravure coating. Coating medium 212 is
supplied to gravure roll 214 by means of pan 216. The volume of coating medium
212 in the recesses of gravure roll 214 is then adjusted by means of doctor
blade
218. Base layer 220 comprising the first polymer is brought into contact with
the
gravure roll by positioning input idler roll 226 and output idler roll 228 to
create a
slight wrap over gravure roll 214. Factors that have been found to influence
coating weight and/or coating uniformity include certain gravure roll
parameters,
identity of the liquid material, viscosity of the coating medium, line speed,
and
gravure roll/line speed ratio. The gravure roll parameter of particular
importance is
the volume factor. A change in any of these factors can affect the coating
weight
and/or uniformity.
Figure 3 shows a schematic of extrusion die coating. Coating medium 312
is placed in feed hopper 330 and from there it is supplied to extrusion die
332 by
means of metering pump 324. Base layer 320 comprising the first polymer is
brought through the space between back-up rol1334 and extrusion die 332, and
extrusion die 332 distributes coating medium 312 across base layer 320.
Factors
that have been found to influence coating weight and/or coating uniformity
include
CA 02215258 1997-09-25
WO 96/30001 PCTIUS96/02785
-13-
identity of the liquid material, viscosity of the coating medium, line speed,
pump
speed, and the amount of space between the extrusion die and the back=up roll.
Die
coating provides several advantages: good crossweb uniformity; the use of a
metering pump provides means for delivering an accurate amount of coating
medium; and the coating medium is enclosed until it is coated, which reduces
the
risk of evaporation or degradation caused by exposure to the atmosphere.
After coating the liquid is allowed to diffuse into the base layer until the
product is sufficiently dry for lamination or wind-up. The length of time that
this
takes is dependent on the coating weight and the type of base layer polymer
and
second polymer, but generally takes only a few (e.g., 1-3) minutes.
The method of the invention optionally comprises the further step of
laminating the exposed surface of the pressure sensitive skin adhesive sheet
material
from step (ii) to a substrate. Examples of suitable substrates include those
enumerated above in connection with the substrate that carries the base layer.
The
preferred substrate depends on the configuration of the final product
incorporating
the sheet material. For example, if the final product is a matrix drug-in-
adhesive
transdermal drug delivery device and the base layer is carried on a release
liner, then
a backing film could be laminated to the exposed surface of the sheet material
to
provide a composite that could be die cut into the desired devices.
Alternatively, if
the sheet material is part of a complex multilaminate device then a membrane
may
be the chosen substrate.
The sheet material from step (ii) can also be laminated to a layer of pressure
sensitive skin adhesive that optionally comprises drug and/or excipient.
A pressure sensitive skin adhesive sheet material made according to the
manufacturing method of the invention retains substantially all of the liquid
until it is
applied to the skin, i.e., the liquid is not intentionally substantially
completely
removed from the sheet material by a process such as evaporation or
extraction. In
the case of a volatile liquid, however, some amount might be removed
incidentally
due to storage or exposure of the sheet material to elevated temperatures
during
processing, such as might be encountered in a manufacturing facility on a hot
day.
CA 02215258 2006-02-20
14
In any event retention of substantially all of the liquid means that at least
about two-
thirds of the liquid, more preferably at least about four-fifths of the
liquid, even
more preferably at least about nine-tenths of the liquid, and most preferably
at least
about 95 percent of the liquid, is retained in the device until it is applied
to the sidn.
In the method of the invention for delivering a liquid to the skin, a pressure
sensitive skin adhesive sheet material prepared according to the above-
described
process is applied to the skin without prior removal of a substantial amount
of the
liquid from the pressure sensitive sheet material, e.g., by volatilization or
extraction,
as described immediately above. When a volatile liquid is delivered
volatilization
can be inhibited by overlaying the pressure sensitive skin adhesive sheet
material on
both surfaces with a sheet material such as a backing or release liner that is
substantially impermeable to the vaporized liquid.
Compliance Test Method
Compliance values can be obtained using a modified version of the Creep
Compliance Procedure described in U.S. Pat. No. 4,737,559 (Kellen). The
release liner is removed from a sample of the material to be tested. The
exposed adhesive surface is folded back on itself in the lengthwise direction
to
produce a "sandwich" configuration, i.e., backing/adhesive/backing. The
"sandwiched" sample is passed through a laminator, or alternatively rolled
with a
hand-operated roller, then two test samples of equal area are cut using a
rectangular die. One test sample is centered on the stationary plate of a
shear-
creep rheometer with the long axis of the test sample centered on the short
axis
of the plate. The small non-stationary plate of the shear-creep rheometer is
centered over the first sample on the stationary plate such that the hook is
facing up and toward the front of the rheometer. The second test sample is
centered on the upper surface of the small non-stationary plate matching the
axial orientation of the first test sample. The large stationary plate is
placed over
the second test sample and the entire assembly is clamped into place. The end
of the small non-stationary plate that is opposite the end with the hook is
connected to a
CA 02215258 1997-09-25
WO 96/30001 PCT/US96102785
-15-
chart recorder. A string is connected to the hook of the small non-stationary
plate
and extended over the front pulley of the rheometer. A weight (e.g., 500 g) is
attached to the free end of the string. The chart recorder is started and at
the same
time the weight is quickly released so that it hangs free. The weight is
removed
after exactly 3 minutes has elapsed. The displacement is read from the chart
recorder. The compliance is then calculated using the equation:
J=2AX
hf
where A is the area of one face of the test sample, h is the thickness of the
adhesive
mass (i.e., two times the matrix thickness of the sample being tested), X is
the
displacement and f is the force due to the mass attached to the string. Where
A is
expressed in cm2, h in cm, X in cm and f in dynes, the compliance value is
given in
cm2/dyne.
The examples set forth below are intended to illustrate the invention.
Example 1
A base layer was prepared in the following manner. An adhesive solution
(74:6:20 isooctyl acrylate:acrylamide:vinyl acetate copolymer, 22 percent
solids in
91:9 ethyl acetate:methanol, inherent viscosity = 1.21 dVg ) was extrusion die
coated onto the non-release side of a silicone coated polyethylene
terephthalate
(PET) release liner (Daubert). The die was equipped with a 20 mil (500 m)
shim.
The coated release liner was oven dried at 150 F (65 C) for 1 minute, at 275 F
(135 C) for 1 minute and at 350 F (177 C) for 1 minute. Four thousand (4,000)
linear yards (36401inear meters) of web with a width of 7 inches (17.8 cm) was
produced.
A coating medium was prepared by dissolving 20 percent by weight of 94:6
isooctyl acrylate:acrylic acid adhesive copolymer in isopropyl myristate. The
resulting medium had a Brookfield viscosity of 1400 centipoise.
CA 02215258 1997-09-25
WO 96/30001 PCT/US96102785
-16-
This coating medium was applied at a line speed of 10 feet/min (3.0
meter/min) to the base layer using direct gravure coating [gravure roll
parameters:
pattern - trihelical; 45 line per inch (18 lines per cm); volume factor - 3.0
x 10'3
in3/in2 (7.6 x 10-3 cm3/cm)]. A web measuring 6.5 inches (16.5 cm) by 20 to 50
feet (6.1 - 15.2 m) was prepared. Sections measuring 2 in by 12 in (5.08 cm by
30.48 cm) were cut from the web lengthwise at three different positions
designated
North (along one edge of the web), South (along the opposite edge of the web),
and Center (down web from and between the North and South samples) and
weighed. The weight of coating medium applied to each section was determined
by
subtracting the weight of the base layer from the total weight of each
section. The
results are shown in Table 1 below.
Examples 2 - 12
Using the method of Example 1, a series of pressure sensitive skin adhesive
sheet materials containing isopropyl myristate (IPM) was prepared. Table 1
shows
the composition of the coating medium, the Brookfield viscosity of the coating
medium, the line speed, and the weight of coating medium applied. In all
examples,
the polymer used to prepare the coating medium was 94:6 isooctyl
acrylate:acrylic
acid adhesive copolymer; the base layer was that prepared in Example 1 and the
coating medium was applied using direct gravure coating employing the gravure
roll
described in Example 1.
a
Table 1
Coating Weight (mg/10 cm ) 2
Example Coating Viscosity Line Speed North Center South
Number Medium (cps) (m/min)
1 20% polymer 1400 3.0 22.23 21.43 21.98
inIPM
2 20% polymer 1400 7.6 18.29 17.96 19.17
in IPM
3 20% polymer 1400 15.2 9.38 10.00 8.16
inIPM
4 10% polymer 275 3.0 28.30 25.70 26.12
in IPM
10% polymer 275 7.6 25.91 25.03 22.02
in IPM
6 10% polymer 275 15.2 23.86 21.18 21.31
in IPM
o0
V
00
tJ1
0
Table I Coating Weight (mg/10 cm )
Example Coating Viscosity Line Speed North Center South
Number Medium (cps) (m/min)
7 Polymer 163 3.0 31.52 30.81 33.74
in IPMI
8 Polymer 163 7.6 25.62 23.15 25.87
in IPMI
9 Polymer 163 15.2 19.42 18.25 19.93
in IPMI 00
Polymer 60 3.0 36.63 37.38 37.79
in IPMZ
11 Polymer 60 7.6 34.07 33.32 34.70
in IPMZ
12 Polymer 60 15.2 28.80 30.73 31.98
in IPMZ
~
J
00
U
Table 1
Coating Weight (mg/10 cm2)
Example Coating Viscosity Line Speed North Center South
Number Medium (cps) (ni/min)
Control IPM 4 3.0 Coating weights were not measured
because the coatings were not uniform
Control IPM 4 15.2 Coating weights were not measured
because the coatings were not uniform
r-F+
1,2 Polymer amount not measured; amount used was that amount needed to obtain
the indicated viscosity.
OO
00
CA 02215258 1997-09-25
WO 96/30001 PCTIUS96/02785
-20-
Examples 13 - 23
Using the method of Example 1, a series of pressure sensitive skin adhesive
sheet materials containing nicotine was prepared. Table 2 shows the
composition of
the coating medium, the Brookfield viscosity of the coating medium, the
coating
method (either direct or kiss gravure coating), the line speed, and the weight
of
coating medium applied. In all examples, the polymer used to prepare the
coating
medium was 74:6:20 isooctyl acrylate: acrylamide:vinylacetate adhesive
copolymer;
the base layer was that prepared in Example 1 and the coating medium was
applied
using the gravure roll described in Example 1. Attempts to uniformly coat
nicotine
neat, i.e. containing 0% polymer, failed.
Table 2
Example Coating Viscosity Coating Line Speed Coating Weight (mg/10 cm2) Number
Medium (cps) Method (m/min) North Center South
13 10% polymer in 892 kiss 3.0 38.18 35.41 37.21
nicotine
14 10% polymer in 892 kiss 7.6 32.94 29.97 32.02
nicotine
15 10% polymer in 892 kiss 15.2 28.13 27.33 28.38
nicotine
N "
16 10% polymer in 892 direct 3.0 33.24 30.18 33.03
nicotine
17 10% polymer in 892 direct 6.1 34.66 31.94 34.16
nicotine
18 7.5% polymer in 340 direct 3.0 37.13 36.21 34.49
nicotine
00
tJt
O
Table 2 0
Example Coating Viscosity Coating Line Speed Coating Weight (mg/10 cm )
Number Medium (cps) Method (m/min) North Center South
19 7.5% polymer in 340 direct 7.6 32.02 31.10 31.27
nicotine
20 5% polymer in 136 direct 7.6 33.91 31.06 31.35
nicotine
21 2.5% polymer in 38 direct 3.0 34.53 32.27 31.40
nicotine
~
N o
22 2.5% polymer in 38 direct 7.6 31.48 31.69 29.13
nicotine
23 2.5% polymer in 38 direct 15.2 32.24 30.39 29.80
nicotine
ro
o0
00
, Ut
CA 02215258 1997-09-25
WO 96/30001 PCTIUS96/02785
-23-
Example 24
A coating medium was prepared by dissolving 5% by weight of 74:6:20
isooctyl acrylate:acrylamide:vinyl acetate adhesive copolymer in nicotine. The
resulting coating medium was applied to 60 linear yards (54.6 linear meters)
of the
base layer prepared in Example 1 using direct gravure coating with the gravure
roll
used in Example 1 at a line speed of 3 m/min. The down web/cross web
uniformity
was evaluated as follows. Samples 1-3 were taken every 1 linear yard (0.9 m)
from
the end of the web. Approximately 20 linear yards (18 m) of web were skipped
over then samples 4-20 were taken every 2 linear yards (1.8 linear meters).
Each
sample consisted of 4 cross web 10 cm2 patches labeled A-D. The patches were
extracted with ethyl acetate and the extract analyzed for nicotine by gas
chromatography. The results are shown in Table 3 below.
CA 02215258 1997-09-25
WO 96/30001 PCT/US96/02785
-24-
Table 3
Nicotine Content (mg/patch)
Sample A B C D
1 36.3 36.3 36.0 34.9
2 36.3 36.1 35.7 35.5
3 36.3 36.0 35.6 35.0
4 36.9 35.9 35.6 34.8
36.8 36.3 36.3 35.1
6 36.2 36.8 36.6 35.5
7 35.2 36.5 36.6 36.6
8 23.8 36.5 36.3 35.4
9 36.2 36.5 36.5 35.6
37.1 36.7 36.3 35.1
11 35.6 36.4 36.3 35.1
12 25.0 36.3 36.2 35.4
13 36.8 36.2 34.7 23.7
14 36.2 36.1 35.2 34.4
36.0 36.2 34.2 34.9
16 35.2 34.6 35.4 34.7
17 35.8 36.3 35.6 35.1
18 35.8 34.4 35.2 34.1
19 35.2 34.9 34.4 32.7
34.3 36.0 34.9 33.6
CA 02215258 1997-09-25
WO 96/30001 PCT/US96/02785
-25-
Examples 25-35
A coating medium was prepared by dissolving 2.5% by weight of 74:6:20
isooctyl acrylate:acrylamide:vinyl acetate adhesive copolymer in nicotine. The
resulting coating medium was applied to about 20 linear feet (6.1 linear
meters) of
the base layer prepared in Example 1 using kiss gravure coating (gravure roll
parameters: pattern - pyramidal; volume factor - 2.0 x 10'3 in3/in2 (5 x 10"3
cm3/cm). During the coating process both the line speed and the gravure roll
speed
were varied. Table 4 below shows the line speed, the gravure roll:line speed
ratio
and the coating weight.
Table 4
Example Line Speed Ratio Coating weight (mg/10 cm )
Number (m/min) North Center South
25 2.9 0.74 19.30 16.20 18.33
26 2.9 1.16 18.33 19.55 19.51
27 2.9 1.37 20.39 19.26 20.97
28 2.9 1.89 21.60 21.18 22.06
29 2.9 3.16 20.30 18.29 20.85
30 7.6 0.80 21.98 20.18 22.10
31 7.6 1.00 22.77 23.15 25.62
32 7.6 1.24 21.85 21.52 23.32
33 7.6 1.48 22.27 20.34 22.31
34 7.6 1.92 21.89 21.22 22.60
35 7.6 3.40 20.68 18.71 20.68
Examples 36-48
Using the method of Example 1, a series of pressure sensitive skin adhesive
sheet materials containing (S)-3-methyl-5-(1-methyl-2-pyrrolidinyl)isoxazole
was
CA 02215258 1997-09-25
WO 96/30001 PCT/US96/02785
-26-
prepared. Table 5 shows the weight percent of polymer in the coating medium,
the
Brookfield viscosity of the coating medium, the line speed, and the weight of
coating medium applied. In all examples, the polymer used to prepare the
coating
medium was 74:6:20 isooctyl acrylate: acrylamide:vinylacetate adhesive
copolymer;
the base layer was that prepared in Example 1 and the coating medium was
applied
using kiss gravure coating (gravure roll parameters: pattern - pyramidal;
volume
factor - 2.0 x 10-3 in3/in2 (5 x 10"3 cm3/cm2).
O
Table 5
Example Wt % Viscosity Line Speed Coating Weight (mg/10 cmZ)
Number Polymer (cps) (m/min) North Center South
36 5.00 179 3.0 22.52 23.06 23.36
37 5.00 179 5.5 28.21 26.16 27.17
38 5.00 179 7.6 27.33 26.08 26.45
39 3.75 88 3.0 24.20 23.32 24.15
40 3.75 88 7.6 25.83 24.40 25.03
41 3.75 88 15.2 25.28 23.65 24.53
N ~-
42 2.50 35 3.0 19.55 18.50 19.72
43 2.50 35 5.5 22.73 19.63 22.44
44 2.50 35 7.6 24.53 23.06 24.11
45 2.50 35 15.2 25.87 24.40 26.12
46 1.25 19 3.0 15.70 15.61 16.20
47 1.25 19 7.6 19.76 19.38 19.72
48 1.25 19 15.2 23.27 22.48 23.36
Control 0 5 3.0 13.02 12.60 13.52
00
U
O
~
Table 5
Example Wt % Viscosity Line Speed Coating Weight (mg/10 cm2)
Number Polymer (cps) (nilmin) North Center South
Control 0 5 7.6 15.70 14.44 14.94
Control 0 5 15.2 16.58 15.91 16.66
N
00
CA 02215258 1997-09-25
WO 96/30001 PCTIUS96/02785
-29-
Examples 49 - 53
Using the method of Example 1, a series of pressure sensitive skin adhesive
sheet materials containing (S)-3-methyl-5-(1-methyl-2-pyrrolidinyl)isoxazole
was
prepared. Table 6 shows the weight percent of polymer in the coating medium,
the
Brookfield viscosity of the coating medium, the line speed, and the weight of
coating medium applied. In all examples, the polymer used to prepare the
coating
medium was 74:6:20 isooctyl acrylate: acrylamide:vinylacetate adhesive
copolymer;
the base layer was that prepared in Example 1 and the coating medium was
applied
using kiss gravure coating (gravure roll parameters: pattern - trihelical;
volume
factor - 2 x 10"3 in3/in2, 5 x 10'3 cm3/cm).
oTable 6
Example Weight % Viscosity Line Speed Coating Weight (mg/10 cm )
Number Polymer (cps) (m/min) North Center South
49 3.75 88 3.0 23.36 23.19 23.11
50 3.75 88 7.6 24.32 25.62 26.66
51 1.25 19 3.0 18.63 17.16 19.30
52 1.25 19 5.5 22.40 18.38 21.47
53 1.25 19 7.6 21.93 20.26 21.81
-
00
CA 02215258 1997-09-25
WO 96/30001 PCT/US96/02785
-31-
Example 54
A pressure sensitive skin adhesive sheet material containing (S)-3-methyl-5-
(1-methyl-2-pyrrolidinyl)isoxazole was prepared in the following manner. A
coating medium having a viscosity of 35 cps was prepared by dissolving 2.5
percent
by weight of 74:6:20 isooctyl acrylate: acrylamide:vinylacetate adhesive
copolymer
in (S)-3-methyl-5-(1-methyl-2-pyrrolidinyl)isoxazole. The resulting coating
medium was applied to 601inear yards (54.61inear meters) of the base layer
prepared in Example 1 using kiss gravure coating [gravure roll parameters:
pattern -
pyramidal; 50 teeth per inch (20 teeth per cm); helix angle of 45 degrees;
inclusion
angle of 110 degrees; volume factor - 2 x 10"3 in3/in2 (5 x 10"3 cm3/cm2)] at
a line
speed of 25 fpm (7.6 m/min). The down web/cross web uniformity of the
resulting
web was evaluated as follows. Four (4) cross web patches (10 cm2 each) were
die
cut every 3 yards (2.7 m) for a total of 80 patches. The patches were
extracted
with ethyl acetate and the extract was assayed for (S)-3-methyl-5-(1-methyl-2-
pyrrolidinyl)isoxazole (drug) content using gas chromatography. The results
are
shown in Table 7 below.
CA 02215258 1997-09-25
WO 96/30001 PCT/US96/02785
-32-
Table 7
Down/cross Drug Content (mg/patch)
A B C D Average
1 22.1 22.5 22.9 22.9 22.6
2 23.3 23.0 23.4 23.4 23.3
3 23.1 23.4 23.5 23.7 23.4
4 23.6 23.7 23.4 24.0 23.7
23.7 23.6 23.6 23.5 23.6
6 23.6 23.7 23.6 24.0 23.7
7 24.0 23.9 23.8 23.3 23.8
8 23.6 23.8 23.9 24.1 23.9
9 23.5 23.5 23.7 23.7 23.6
23.5 24.1 23.9 23.9 23.9
11 23.3 23.3 23.5 23.8 23.5
12 23.2 23.3 23.7 23.4 23.4
13 23.6 23.3 23.7 23.7 23.6
14 23.5 23.1 23.5 23.9 23.5
23.6 23.5 23.3 23.5 23.5
16 23.3 23.2 23.6 23.2 23.3
17 23.4 23.4 23.9 23.1 23.4
18 23.5 23.9 23.8 23.6 23.7
19 23.7 23.7 24.0 23.8 23.8
24.1 23.7 23.6 22.9 23.6
Average 23.4 23.5 23.6 23.6 23.5
SD* 0.40 0.37 0.26 0.35 0.28
RSD** 1.71 1.58 1.09 1.51 1.18
* Standard deviation
* *Relative standard deviation
CA 02215258 1997-09-25
WO 96/30001 PCTIUS96/02785
-33-
Examples 55-70
A series of pressure sensitive skin adhesive sheet materials containing (S)-3-
methyl-5-(1-methyl-2-pyrrolidinyl)isoxazole was prepared in the following
manner.
A coating medium was prepared by dissolving 2.75 weight percent of 74:6:20
isooctyl acrylate: acrylamide:vinylacetate adhesive copolymer in (S)-3-methyl-
5-(1-
methyl-2-pyrrolidinyl)isoxazole. The resulting coating medium was applied
using a
gravure roll to the base layer prepared in Example 1. Table 8 below shows the
gravure roll, the coating method, the line speed, the gravure roll speed and
the
coating weight. Gravure roll 1 had the following parameters: pattern -
trihelical; 50
teeth per inch (20 teeth per cm); helix - 45 degrees; inclusion angle -110
degrees;
land width - 0.0056 in (0.0 142 cm); Z depth - 0.0049 in (0.0 124 cm); volume
factor
- 1.8 x 10-3 in3/in2 (4.6 x 10"3 cm3/cm2). Gravure ro112 had the following
parameters: pattern - trihelical; 70 teeth per inch (27.6 teeth per cm); helix
- 45
degrees; inclusion angle -120 degrees; land width - 0.0045 in (0.0114 cm); Z
depth
- 0.0026 in (0.0066 cm); volume factor - 0.97 x 10"3 in3/in2 (2.46 x
10'3 cm3/cm2).
O
a
Table 8
Example Gravure Coating Line Speed Gravure Roll Coating Weight (mg/10 cm )
Number Roll Method (m/min) (m/min) North Center South
55 1 Kiss 4.6 4.6 19.72 20.29 20.85
56 1 Kiss 7.6 7.6 19.23 18.59 20.73
57 1 Kiss 10.7 10.7 17.90 17.92 18.64
58 1 Kiss 7.6 7.6 18.83 19.07 20.37
59 1 Kiss 7.6 9.1 19.35 20.88 20.33
60 1 Kiss 7.6 10.7 19.64 20.42 20.94 ~
w o
61 1 Direct 4.6 4.6 16.67 16.83 17.11
62 1 Direct 7.6 7.6 17.32 18.41 17.99
63 1 Direct 10.7 10.7 17.54 18.49 18.63
64 2 Kiss 4.6 4.6 10.71 10.80 10.87
65 2 Kiss 7.6 7.6 10.31 9.19 11.26
66 2 Kiss 10.7 10.7 8.98 9.61 9.85
67 2 Kiss 7.6 7.6 9.74 9.54 10.11
68 2 Kiss 7.6 9.1 10.47 10.83 10.77
00
N
. . , .
ow '
Table 8
Example Gravure Coating Line Speed Gravure Roll Coating Weight (mg/10 cm )
Number Roll Method (m/min) (m/min) North Center South
69 2 Kiss 7.6 10.7 10.55 10.12 11.55
70 2 Kiss 7.6 12.2 11.69 11.01 12.64
W ..
J
01
00
tJi
CA 02215258 2006-02-20
-36-
Example 71
A pressure sensitive skin adhesive sheet material containing (S)-3-methyl-5-
(1-methyl-2-pyrrolidinyl)isoxazole was prepared in the following manner.
Adhesive copolymer (75:5:20 isooctyl acrylate: acrylamide:vinyl acetate;
30.2 percent solids in ethyl acetate:methanol (91:9)) was coated onto a 3 mil
(76 M) PET differential release liner (SII.OX*G1K/G4L from AKROSII.. The
coated release liner was oven dried at 60 C for 1 minute, at 121 C for 1
minute,
and at 177 C for 1 minute to provide a base layer of pressure sensitive skin
adhesive consisting of adhesive 6.90 mg/cm2 supported on a differential
release
liner.
A portion of the dried adhesive was stripped from the liner and dissolved in
(S)-3-methyl-5-(1-methyl-2-pyrrolidinyl)isoxazole to provide a coating medium
containing 2.75 percent by weight of adhesive and having a Brookfield
viscosity of
44 cps.
The coating medium was applied to the base layer using direct gravure
coating at a line speed of 25 fpm (7.6 m/min) employing a gravure roll with
the
following parameters: pattern - trihelical; 50 teeth per inch (20 teeth per
cm); helix -
45 degrees; inclusion angle - 110 degrees; land width - 0.0056 in (0.0142 cm);
Z
depth - 0.0049 in (0.0124 cm); volume factor - 1.8 x 10'3 in3/'in~ (4.6 x 10"3
cm3/cm). The resulting coating weight was 1.84 mg/cm2.
Approximately 2.4 minutes after the coating medium was applied to the base
layer the resulting web was laminated to a polyester backing (ScotchpakT"s
1109
polyester film laminate available from the 3M Company) to provide a composite
designated as Composite A. Composite A consisted of, in order, a backing, a
single
layer of adhesive containing (S)-3-methyl-5-(1-methyl-2-
pyrrolidinyl)isoxazole, and
a differential release liner.
The release liner was removed from Composite A and the adhesive side was
laminated to a second section of the coated web to provide Composite B.
Composite B consisted of, in order, a backing, a double layer of adhesive
containing
(S)-3-methyl-5-(1-methyl-2-pyrrolidinyl)isoxazole, and a differential release
liner.
* trademarks
CA 02215258 1997-09-25
WO 96/30001 PCT/US96/02785
-37-
Example 72
A pressure sensitive skin adhesive sheet material containing (S)-3-methyl-5-
(1-methyl-2-pyrrolidinyl)isoxazole was prepared in the following manner.
Adhesive copolymer (75:5:20 isooctyl acrylate: acrylamide:vinyl acetate;
30.2 percent solids in ethyl acetate:methanol (91:9)) was coated onto a 3 mil
(76 M) PET differential release liner (SILOX G1K/G4L from AKROSIL). The
coated release liner was oven dried at 60 C for 1 minute, at 121 C for 1
minute,
and at 177 C for 1 minute to provide a base layer of pressure sensitive skin
adhesive consisting of adhesive 4.06 mg/cm2 supported on a differential
release
liner.
The coating medium prepared in Example 71 was applied to the base layer
using direct gravure coating at a line speed of 25 fpm (7.6 m/min) employing a
gravure roll with the following parameters: pattern - trihelical; 70 teeth per
inch
(27.6 teeth per cm); helix - 45 degrees; inclusion angle -120 degrees; land
width -
0.0045 in (0.0114 cm); Z depth - 0.0026 in (0.0066 cm); volume factor - 0.97 x
10"3
in3/in2 (2.46 x 10-3 cm3/cm). The resulting coating weight was 1.08 mg/cm2.
Approximately 2.4 minutes after the coating medium was applied to the base
layer the resulting web was laminated to a two sided corona treated low
density
polyethylene film to provide a composite designated as Composite C. Composite
C
consisted of, in order, a corona treated low density polyethylene film, a
single layer
of adhesive containing (S)-3-methyl-5-(1-methyl-2-pyrrolidinyl)isoxazole, and
a
differential release liner.
Example 73
Preparation of a Transdermal Drug Delivery Device
A transdermal drug delivery device containing (S)-3-methyl-5-(1-methyl-2-
pyrrolidinyl)isoxazole was prepared in the following manner. The differential
release liner was removed from Composite B of Example 71 and the exposed
adhesive side was laminated to the polyethylene surface of Composite C of
Example
CA 02215258 2006-02-20
-38-
72 to provide a composite designated as Composite D. Composite D consisted of,
in order from the top (i.e. skin distal) layer down, a backing film, a drug-in-
adhesive
reservoir containing (S)-3-methyl-5-(1-methyl-2-pyrrolidinyl)isoxazole, a low
density polyethylene film, a skin-contacting drug-in-adhesive matrix
containing (S)-
3-methyl-5-(1-methyl-2-pyrrolidinyl)isoxazole, and a differential release
liner. The
composite was die cut into patches. The differential release liner is removed
prior
to applying the patch to skin.
Examples 74-78
A series of pressure sensitive skin adhesive sheet materials containing
isopropyl myristate were prepared in the following manner.
A coating medium was prepared by dissolving 10 percent by weight of 91:9
isooctyl acrylate: N-vinylpyrrolidone adhesive copolymer in isopropyl
myristate.
An ultraviolet fluorescent dye (Uvitex) was also incorporated, at the weight
percentage shown in Table 9, as a means of determining coating uniformity.
The coating medium was applied to a 50 m thick base layer (91:9 isooctyl
acrylate: N-vinylpyrrolidone adhesive copolymer) using an extrusion die. The
line
speed, pump speed, and wet coating thickness are shown in Table 9 below. In
all
instance a pump delivering 2.92 cc/rev was used.
The emitted light intensity was measured at 7 different points on the web by
a fluorimeter which excited at 375 nm and collected at 435 nm for a spot size
of
approximately 2 cm2. The light intensities are shown in Table 9 below.
* trademark
. . } ,
O
~
Table 9 0
o
Example Dye Line Pump Wet Light Intensity
Number Wt % Speed Speed Thickness Point Point Point Point Point Point Point
(m/min) (rpm) ( m) 1 2 3 4 5 6 7
74 0.5 18.3 9 7 35.16 36.91 37.12 37.81 36.11 36.42 38.46
75 0.5 10.0 9 13 45.91 45.37 44.16 44.30 43.98 45.06 46.29
76 0.5 10.0 4.5 6.5 33.31 31.83 31.96 32.82 31.27 32.42 34.86
77 0.1 10.0 6 8.7 15.43 15.61 16.23 15.54 15.35 18.52 18.53
78 0.1 10.0 4.5 6.5 13.06 12.70 12.08 11.99 12.36 12.04 13.27
01
00
