U.S. patent application number 10/283355 was filed with the patent office on 2004-05-06 for fentanyl suspension-based silicone adhesive formulations and devices for transdermal delivery of fentanyl.
Invention is credited to Bhatia, Kuljit Singh, Govil, Sharad K., Miller, Kenneth J. II.
Application Number | 20040086551 10/283355 |
Document ID | / |
Family ID | 32174649 |
Filed Date | 2004-05-06 |
United States Patent
Application |
20040086551 |
Kind Code |
A1 |
Miller, Kenneth J. II ; et
al. |
May 6, 2004 |
Fentanyl suspension-based silicone adhesive formulations and
devices for transdermal delivery of fentanyl
Abstract
Silicone adhesive formulations are provided, in which fentanyl
particles are suspended one or more a solvated silicone adhesives.
The formulations can be used for manufacturing improved,
matrix-type transdermal devices for administering fentanyl.
Inventors: |
Miller, Kenneth J. II; (St.
Albans, VT) ; Govil, Sharad K.; (Essex, VT) ;
Bhatia, Kuljit Singh; (Scottsdale, AZ) |
Correspondence
Address: |
ROTHWELL, FIGG, ERNST & MANBECK, P.C.
1425 K STREET, N.W.
SUITE 800
WASHINGTON
DC
20005
US
|
Family ID: |
32174649 |
Appl. No.: |
10/283355 |
Filed: |
October 30, 2002 |
Current U.S.
Class: |
424/449 ;
514/317 |
Current CPC
Class: |
Y10T 156/10 20150115;
A61K 31/445 20130101; A61P 25/04 20180101; A61K 9/7069
20130101 |
Class at
Publication: |
424/449 ;
514/317 |
International
Class: |
A61K 031/445; A61K
009/70 |
Claims
What is claimed is:
1. A monolithic patch for administering fentanyl transdermally to
an individual, comprising: (a) a backing layer substantially
impervious to the fentanyl to be administered transdermally; (b) a
fentanyl-containing adhesive layer in contact with at least a
portion of the backing layer, the adhesive layer being cast from a
formulation comprising a blend of fentanyl particles suspended in
one or more solvated silicone adhesives; and (c) a removable
release liner in contact with the adhesive layer.
2. The patch of claim 1, wherein the one or more solvated silicone
adhesives is a heptane-solvated silicone adhesive.
3. The patch of claim 2, wherein the adhesive layer comprises about
1% to about 10% w/w fentanyl.
4. The patch of claim 3, wherein the adhesive layer comprises about
3% to about 7% w/w fentanyl.
5. The patch of claim 4, wherein the adhesive layer comprises about
4% w/w fentanyl.
6. The patch of claim 2, wherein the adhesive layer comprises about
5% to about 15% w/w fentanyl.
7. The patch of claim 6, wherein the adhesive layer comprises about
8% to about 12% w/w fentanyl.
8. The patch of claim 7, wherein the adhesive layer comprises about
9.5% w/w fentanyl.
9. The patch of claim 8, wherein the adhesive layer comprises about
9.1% w/w fentanyl.
10. The patch of claim 1, wherein the fentanyl is the fentanyl free
base.
11. The patch of claim 1, wherein the backing layer is a
polyolefin.
12. The patch of claim 1, wherein the fentanyl is suspended
uniformly in the solvated silicone adhesives as small
particles.
13. The patch of claim 1, wherein the fentanyl-containing adhesive
layer is cast from a formulation comprising a blend of a slurry of
fentanyl in a silicone fluid blended with one or more solvated
silicone adhesives.
14. The patch of claim 13, wherein the fentanyl-containing layer
comprises up to about 25% w/w silicone fluid.
15. The patch of claim 14, wherein the fentanyl-containing layer
comprises about 2% to about 10% w/w silicone fluid.
16. The patch of claim 15, wherein the fentanyl-containing layer
comprises about 6.5% w/w silicone fluid.
17. The patch of claim 13, wherein the silicone fluid comprises
polydimethylsiloxane.
18. The patch of claim 1, which further comprises a fentanyl-free
adhesive layer between and in contact with said backing layer and
said fentanyl-containing adhesive layer which extends at least
partially beyond said fentanyl-containing adhesive layer.
19. The patch of claim 18, wherein the fentanyl-containing adhesive
layer is cast from a formulation comprising a blend of a slurry of
fentanyl in a silicone fluid blended with one or more solvated
silicone adhesives.
20. The patch of claim 19, wherein the fentanyl-containing layer
comprises up to about 25% w/w silicone fluid.
21. A method for making a laminate, which is useful for making a
monolithic patch for transdermal administration of fentanyl,
comprising: a) selecting a solvent that can substantially or fully
solvate a silicone adhesive while keeping fentanyl, when blended
with the solvated adhesive, suspended in the solvated adhesive; b)
blending fentanyl particles with one or more silicone adhesives
which are solvated with the above solvent, to form a blend
formulation in which fentanyl particles are suspended in the
solvated adhesives; c) casting the blend formulation onto a support
material; and d) removing the solvent, to produce a laminate
containing the support material and a fentanyl
suspension-containing adhesive layer.
22. The method of claim 21, wherein the support material is a
backing layer or release liner.
23. The method of claim 21, wherein the blend formulation is
treated prior to the casting step to disperse the fentanyl
throughout the formulation and particle size is maintained by
passing the formulation through a high shear colloid mill,
homogenizer, or other mixing device.
24. The method of claim 21, wherein the solvent is heptane.
25. The method of claim 24, wherein the silicone adhesive is
solvated in about 20% to about 50% heptane.
26. The method of claim 25, wherein the silicone adhesive is
solvated in about 30% heptane.
27. The method of claim 21, wherein the fentanyl is the fentanyl
free base.
28. The method of claim 21, wherein fentanyl particles are
suspended uniformly in the solvated silicone adhesives as small
particles.
29. A method for making a laminate, which is useful for making a
monolithic patch for transdermal administration of fentanyl,
comprising: a) selecting a solvent that can substantially or fully
solvate a silicone adhesive while keeping fentanyl particles, when
blended with the solvated adhesive, suspended in the solvated
adhesive; b) solvating said silicone adhesive in said solvent; c)
forming a slurry of fentanyl particles in a silicone fluid; d)
blending the slurry from step c) with the solvated silicone
adhesive of step b) so as to form a blend formulation in which
fentanyl particles are suspended in the solvated adhesive; e)
casting the blend formulation onto a support material; and f)
removing the solvent to produce a laminate containing the support
material and a fentanyl suspension-containing adhesive layer.
30. The method of claim 29, wherein the support material is a
backing layer or release liner.
31. The method of claim 29, wherein the solvated silicone adhesive
is divided into a first portion and a second portion, the slurry of
fentanyl particles is blended with a first portion of the solvated
silicone adhesive, the resulting blend is passed through a mixing
device to form a suspension, and the resulting suspension is
blended with the second portion of the solvated silicone
adhesive.
32. The method of claim 29, wherein the solvent is heptane.
33. The method of claim 32, wherein the silicone adhesive is
solvated in about 20% to about 50% heptane.
34. The method of claim 29, wherein the fentanyl is fentanyl free
base.
35. The method of claim 29, wherein fentanyl particles are
suspended uniformly in the solvated silicone adhesive as small
particles.
36. A method for administering fentanyl transdermally to an
individual in need of such administration, comprising applying to
the skin of the individual a monolithic patch comprising: (a) a
backing layer substantially impervious to the fentanyl to be
administered transdermally; and (b) a fentanyl-containing adhesive
layer in contact with the backing layer, the adhesive layer being
cast from a formulation comprising a blend of fentanyl suspended in
one or more solvated silicone adhesives.
37. The method of claim 36, wherein the solvated silicone adhesives
are heptane-solvated silicone adhesives.
38. The method of claim 37, wherein the adhesive layer comprises
about 1% to about 10% w/w fentanyl.
39. The method of claim 38, wherein the adhesive layer comprises
about 3% to about 7% w/w fentanyl.
40. The method of claim 39, wherein the adhesive layer comprises
about 4% w/w fentanyl.
41. The method of claim 40, wherein the fentanyl is administered
transdermally for a period of about 3 days.
42. The method of claim 37, wherein the adhesive layer comprises
about 5% to about 15% w/w fentanyl.
43. The method of claim 42, wherein the adhesive layer comprises
about 8% to about 12% fentanyl.
44. The method of claim 43, wherein the adhesive layer comprises
about 9.5% w/w fentanyl.
45. The method of claim 37, wherein the adhesive layer comprises
about 9.1% w/w fentanyl.
46. The method of claims 44, wherein the fentanyl is administered
transdermally for a period of about 7 days.
47. The method of claims 45, wherein the fentanyl is administered
transdermally for a period of about 7 days.
48. The method of claim 36, wherein the fentanyl is the fentanyl
free base.
49. The method of claim 36, wherein the fentanyl-containing
adhesive layer is cast from a formulation comprising a blend of a
slurry of fentanyl in silicone fluid blended with one or more
solvated silicone adhesives.
50. The method of claim 49, wherein the fentanyl-containing
adhesive layer comprises up to about 25% w/w silicone fluid.
51. The method of claim 50, wherein the fentanyl-containing
adhesive layer comprises about 2% to about 10% w/w silicone
fluid.
52. The method of claim 51, wherein the fentanyl-containing
adhesive layer comprises about 6.5% w/w silicone fluid.
53. The method of claim 48, wherein fentanyl particles are
suspended uniformly in the solvated silicone adhesives as small
particles.
54. The method of claim 36, wherein the backing layer is a
polyolefin.
Description
FIELD OF THE INVENTION
[0001] The present invention relates generally to the field of
transdermal drug delivery. More particularly, the present invention
relates to fentanyl suspension-based, silicone pressure sensitive
adhesive formulations and their use in making devices for improved
transdermal delivery of fentanyl.
BACKGROUND OF THE INVENTION
[0002] A pressure sensitive adhesive is a material that adheres to
a surface with slight pressure and releases from the surface with
negligible transfer of the adhesive to the surface. Silicone
pressure sensitive adhesives in particular have been used for
transdermal drug delivery, which involves administering a drug by
adhering a drug-containing device or patch to a patient's skin.
[0003] One type of transdermal patch is a polymer matrix or
monolithic device in which the active agent is contained in a
polymer matrix film through which the active agent diffuses to the
skin. Such patches are preferred because they are relatively
simpler to manufacture and more comfortable to wear compared to
reservoir-type devices. Transdermal patches having a monolithic
polymer film layer in which the active agent is contained are
disclosed in U.S. Pat. No. 4,839,174, as well as in U.S. Pat. Nos.
4,908,213 and 4,943,435.
[0004] Fentanyl is an opioid analgesic which, in clinical settings,
exerts its principle pharmacologic effects on the central nervous
system. Its primary actions of therapeutic value are analgesia and
sedation, and it is indicated for the management of chronic pain in
patients who require opioid analgesia for pain that is typically
unmanageable by lesser means. In particular, fentanyl is used
clinically for the relief of acute postoperative and chronic cancer
pain.
[0005] Transdermal patches containing silicone pressure sensitive
adhesive compositions are described in U.S. Pat. No. 5,232,702
(Pfister et al.), WO 00/33812 (Miranda et al.), WO 96/40085
(Mantelle et al.), and U.S. Pat. No. 5,603,947, all fully
incorporated herein by reference.
[0006] U.S. Pat. No. 5,232,702 describes silicone pressure
sensitive adhesives containing (i) a silicone fluid, (ii) a
silicate resin, and (iii) a cohesive strengthening agent. In one
embodiment, the pressure sensitive adhesive includes a high
molecular weight polydimethylsiloxane as the silicone fluid.
Organic solvents disclosed as suitable for dissolving the silicone
fluid and the silicate resin include aromatics such as toluene and
xylene; aliphatics such as heptane and hexane; chlorinated solvents
such as 1,1,1-trichloroethane and trichlorotrifluoroethane;
fluorocarbons such as Freon 113; aliphatic esters such as ethyl
acetate; and mixtures thereof. Example D describes how transdermal
adhesive matrix-type patches were prepared containing 17-beta
estradiol, a skin penetration enhancer (PGML), a high silanol
containing silicone pressure sensitive adhesive, and calcium
stearate as the cohesive strengthening agent. Two different high
silanol containing adhesives were used, both of which were prepared
in a xylene solvent by homogenously mixing a silicate resin,
xylene, and a silicone fluid. The mixture was then heated, stripped
of non-volatile content, and eventually redissolved in hexane to a
non-volatile content of 50 wt %. The final 17-beta
estradiol-containing adhesive solution was cast onto a polyester
release liner, allowed to air dry, and then laminated onto a
polyester backing film.
[0007] WO 00/33812 describes a transdermal patch for administering
a volatile liquid drug, such as nicotine. The transdermal patch
contains a backing layer, a pressure sensitive silicone adhesive
layer and a pressure sensitive acrylic adhesive layer containing
the drug, and a removable release liner layer. The silicone
adhesive layer is prepared by dissolving a silicone adhesive in
hexane. WO 00/33812 reports (at p. 6) that other solvents, such as
heptane and toluene, are not suitable because they require higher
processing temperatures and thus result in more drug degradation
and/or evaporation during coating and drying.
[0008] WO 96/40085 describes transdermal matrix patches for
administering drugs, such as selegiline, nitroglycerin and
nicotine, which are liquid at normal room temperature. WO 96/40085
suggests making a monolithic matrix of the drug in an adhesive by
mixing one or more polymeric adhesives, preferably polyacrylate and
polysiloxane, and the drug in a volatile solvent, casting the
mixture, and evaporating the solvent. Examples of volatile solvents
provided are isopropanol, ethanol, xylene, toluene, hexane,
cyclohexane, heptane, ethyl acetate and butyl acetate.
[0009] Similarly, U.S. Pat. No. 5,603,947 describes in Example 1
the use of heptane to cast a silicone adhesive layer in nicotine
patches.
[0010] In both of the above references, the drugs are dissolved in
the silicone adhesives prior to casting.
[0011] Transdermal patches containing fentanyl in a silicone
pressure sensitive adhesive are also known in the art, as
described, for example, in U.S. Pat. No. 4,588,580 (Gale et al.)
and U.S. Pat. No. 5,186,939 (Cleary et al.), also fully
incorporated herein by reference.
[0012] U.S. Pat. No. 4,588,580 describes in Example 6 a
fentanyl-containing monolithic patch that was made using Dow
Corning amine resistant silicone adhesive and silicone medical
fluid having 10 and 20 percent fentanyl base dispersed therein.
[0013] U.S. Pat. No. 5,186,939 describes a laminated composite for
administering fentanyl transdermally, including an adhesive-drug
reservoir layer comprising fentanyl dissolved in an amine-resistant
polydimethylsiloxane. Example 1 describes that a
fentanyl-containing pressure sensitive adhesive composition was
prepared consisting of 1.8% fentanyl base, 4% permeation enhancer
(PGML), 2.0% silicone oil (Dow Corning Medical Fluid) and 92.5%
amine resistant polydimethylsiloxane (Dow Corning X7-2900)
dissolved in trichlorotrifluoroethane (freon) to provide a 50%
solution.
[0014] In addition, a fentanyl-containing, reservoir-type
transdermal patch as approved by the FDA is described in the 2002
Physician's Desk Reference. Duragesic.RTM. is a rectangular
transparent patch comprising a protective liner and four functional
layers. Proceeding from the outer surface toward the surface
adhering to the skin, these layers are: 1) a backing layer of
polyester film; 2) a drug reservoir of fentanyl and alcohol USP
gelled with hydroxyethyl cellulose; 3) an ethylene-vinyl acetate
copolymer membrane that controls the rate of fentanyl delivery to
the skin surface; and 4) a fentanyl containing silicone
adhesive.
[0015] The present invention is believed to offer improvements and
advantages over prior fentanyl-containing transdermal devices.
SUMMARY OF THE INVENTION
[0016] One aspect of the invention is a fentanyl-containing,
silicone pressure sensitive adhesive formulation comprising a blend
of fentanyl suspended in a solvated silicone pressure sensitive
adhesive. The selected solvent is one that can substantially or
fully solvate or dissolve the adhesive while keeping the fentanyl
suspended in the solvated adhesive.
[0017] The formulation of the invention can be made by blending
fentanyl particles directly with one or more solvated silicone
adhesives to form a suspension of fentanyl particles in the
solvated adhesive(s). Alternatively, the formulation can be made by
first combining the fentanyl particles with a silicone fluid to wet
the particles and form a slurry, which slurry then can be blended
with the solvated silicone adhesive(s) to also form a suspension of
fentanyl particles in the solvated adhesive(s).
[0018] The above formulations are useful for making monolithic
devices for improved transdermal administration of fentanyl.
[0019] Thus, another aspect of the invention is a method for making
a laminate, which is useful for making a monolithic patch for
transdermal administration of fentanyl. The method comprises the
steps of:
[0020] a) selecting a solvent that can substantially or fully
solvate a silicone adhesive while keeping fentanyl particles, when
blended with the solvated adhesive, suspended in the solvated
adhesive;
[0021] b) blending fentanyl particles with one or more silicone
adhesives which are solvated with the above solvent, to form a
blend formulation in which fentanyl particles are suspended in the
solvated adhesives;
[0022] c) casting the blend formulation onto a support material;
and
[0023] d) removing the solvent, to produce a laminate containing
the support material and a fentanyl suspension-containing adhesive
layer.
[0024] In a preferred embodiment, the blend formulation formed in
step (b) is further treated prior to the casting step.
[0025] The blend formulation preferably is cast onto a backing
layer or release liner. The solvent can be removed during drying by
evaporation from the adhesive layer. The laminate can be further
processed to produce a monolithic device containing a backing
layer, fentanyl suspension-containing adhesive layer, and release
liner.
[0026] A further aspect of the invention then is a monolithic patch
for administering fentanyl transdermally to an individual
comprising:
[0027] (a) a backing layer substantially impervious to the fentanyl
to be administered transdermally;
[0028] (b) a fentanyl-containing adhesive layer in contact with at
least a portion of the backing layer, the adhesive layer being cast
from a formulation comprising a blend of fentanyl particles
suspended in one or more solvated silicone adhesives; and
[0029] (c) a removable release liner in contact with the adhesive
layer.
[0030] A still further aspect of the invention is a method for
administering fentanyl transdermally to an individual in need of
such administration, comprising applying to the skin of the
individual a monolithic patch comprising:
[0031] (a) a backing layer substantially impervious to the fentanyl
to be administered transdermally; and
[0032] (b) a fentanyl-containing adhesive layer in contact with the
backing layer, the adhesive layer being cast from a formulation
comprising a blend of fentanyl particles suspended in one or more
solvated silicone adhesives.
[0033] In a preferred embodiment, the selected solvent is
heptane.
[0034] An adhesive layer according to the present invention was
found to provide improved transdermal release of fentanyl, as well
as improved adhesion of transdermal devices to skin. Also with the
present invention, greater amounts of fentanyl can be delivered
from the patch than from solution-based matrix patches, thus
leaving lower residual amounts of fentanyl in the patch after
administration.
[0035] The present invention provides non-invasive sustained
analgesia for periods ranging from 24 hours to 168 hours, and
preferably for 72 hours to 84 hours (about 3 to 31/2 days) or 72
hours to 168 hours (about 3 to 7 days). Preferred embodiments of
the invention include 3 day (72 hours) and 7 day (168 hours)
patches.
BRIEF DESCRIPTION OF THE FIGURES
[0036] FIG. 1A is a elevational cross-sectional view of an
embodiment of a transdermal medical device or patch in accordance
with the invention.
[0037] FIG. 1B is a elevational cross-sectional view of an
embodiment of a suspension-cast laminate of the invention.
[0038] FIG. 2 is a graph comparing in vitro transdermal delivery
rates of fentanyl for a 3-day suspension blend-based device of the
invention, a 3-day solution blend-based recrystallized device, and
a Duragesic transdermal patch.
[0039] FIG. 3 is a graph comparing in vitro transdermal delivery
rates of fentanyl for a 7-day suspension blend-based device of the
invention and a 7-day solution blend-based recrystallized
device.
[0040] FIG. 4 is a graph comparing rates of fentanyl release for a
3-day suspension blend-based device of the invention and a 3-day
solution blend-based recrystallized device.
[0041] FIG. 5 is a graph comparing rates of fentanyl release for a
7-day suspension blend-based device of the invention and a 7-day
solution blend-based recrystallized device.
[0042] FIG. 6 is a graph showing the in vitro transdermal delivery
rate of fentanyl for 7 days from a suspension blend-based device of
the invention made without silicone fluid.
[0043] FIG. 7 is a graph showing the in vitro rate of fentanyl
release from a suspension blend-based device of the invention made
without silicone fluid.
DETAILED DESCRIPTION OF THE INVENTION
[0044] The present invention provides formulations in which
fentanyl particles are suspended in a solvent-based silicone
adhesive. The fentanyl suspension is produced by blending fentanyl
particles with a solvent-based silicone adhesive. The selected
solvent is one that can substantially or fully solvate or dissolve
the silicone adhesive. The selected solvent also must be suitable
for preventing high concentrations, e.g., greater than about 1.0%
w/w (dry weight), of fentanyl particles from dissolving in the
solvated adhesive.
[0045] The total amount of fentanyl need not be suspended in the
solvated adhesive, thus allowing for instances when a portion of
the fentanyl is dissolved in the solvated adhesive. In the
discussion below, the focus will be on "suspended particles" or
"suspensions" of fentanyl, but it is to be understood that this
does not exclude those embodiments in which a small proportion of
the fentanyl is dissolved in the solvated adhesive.
[0046] The solvent preferably is heptane, but also may be selected
from other organic solvents, preferably closely related aliphatic
solvents such hexane and octane, for example, as long as the
selected solvent exhibits the above-described dissolution
features.
[0047] The formulations made in accordance with the present
invention are used to manufacture improved devices for delivering
fentanyl transdermally, particularly monolithic transdermal
patches. The devices may be manufactured by casting the formulation
onto a support material such as a backing layer or release liner to
form a fentanyl suspension-containing adhesive layer, which can be
further processed to make a transdermal patch for delivering
fentanyl.
[0048] Thus, to manufacture a device having the advantages of the
present invention, one must first produce a formulation comprising
a liquid blend of fentanyl particles suspended in a solvated
silicone adhesive, which formulation then is subsequently processed
to make the device. Alternative methods for producing or achieving
a fentanyl suspension-containing adhesive layer according to the
invention may be apparent to persons skilled in the art, and these
alternative methods thus also fall within the scope of the present
invention.
[0049] In a preferred embodiment, one or more silicone pressure
sensitive adhesives is dissolved in heptane, while fentanyl
particles are mixed with a silicone fluid to form a slurry. The
slurry of fentanyl in silicone fluid then is blended with a portion
of the heptane-solvated silicone adhesive and passed through a high
shear colloid mill or other mixing device to form a suspension.
This suspension then is blended with the remaining heptane-solvated
silicone adhesive to form the final (and more dilute) suspension.
The composition then is cast onto a release liner and passed
through an oven(s) to drive off the heptane. A backing film then is
laminated onto the dried adhesive matrix.
[0050] In another preferred embodiment, the device or patch is
produced by casting a blend of heptane-solvated adhesive(s) and
suspended (solid) fentanyl alkaloid particles. A slurry is produced
by mixing fentanyl directly with a portion of the heptane-solvated
silicone adhesive(s). No silicone fluid is used. This slurry then
is passed through a colloid mill or similar mixing device to form a
suspension. This suspension then is blended with the remaining
heptane-solvated silicone adhesive(s) to form the final (and more
dilute) suspension that can be cast onto a release liner and passed
through an oven to drive off the heptane. A backing film then is
laminated onto the dried adhesive matrix.
[0051] The silicone pressure sensitive adhesive preferably is
solvated in about 20% to about 50% heptane, and more preferably in
about 30% heptane. In addition to contributing to formation of a
fentanyl suspension, other advantages of using heptane include
decreased toxicity as compared to other solvents, which include,
for example, toluene, xylene and other aromatics generally.
[0052] In a preferred embodiment, fentanyl particles are suspended
uniformly in the solvated silicone adhesive as small particles,
preferably crystalline particles.
[0053] In the present invention, it is believed that as fentanyl
leaves the system during the course of wear, the suspended drug in
the system dissolves and replenishes the delivered drug. The
present invention as a result maintains a level thermodynamic
activity (driving force) for the drug over long periods of wear. No
other type of reservoir is known to have such capability. The
present invention thus permits long periods of delivery without
requiring that a large excess of fentanyl be present.
[0054] Suitable silicone adhesives include pressure sensitive
adhesives made from silicone polymer and resin. The polymer to
resin ratio can be varied to achieve different levels of tack.
Examples of useful silicone adhesives which are commercially
available include the standard BioPSA.RTM. series (7-4400, 7-4500
and 7-4600 series) and the amine compatible (endcapped) BioPSA.RTM.
series (7-4100, 7-4200 and 7-4300 series) manufactured by Dow
Corning. Preferred heptane-solvated silicone adhesives include
BIO-PSA.RTM. 7-4201, BIO-PSA.RTM. 7-4301, and BIO-PSA.RTM.
7-4501.
[0055] In one embodiment, in which silicone medical fluid is used,
the preferred amount of silicone pressure sensitive adhesive used
is from about 75% to about 99% w/w (dry weight), and more
preferably from about 80% to about 90% w/w (dry weight).
[0056] In another embodiment, in which one or more different
silicone adhesives may be used, optionally in the presence of
silicone medical fluid, the preferred combined amount of silicone
pressure sensitive adhesive is from about 75% to about 99% w/w (dry
weight), more preferably from about 85% to about 95% w/w (dry
weight), and most preferably about 91% w/w (dry weight).
[0057] Preferred silicone fluids include high molecular weight
polydimethylsiloxane, Dimethicone NF (Dow 360 Silicone Medical
Fluid, 100 cSt and other viscosities). Preferred amounts of
silicone fluid are from about 0% w/w to about 25% w/w (dry weight),
more preferably from about 2% w/w to about 10% w/w (dry weight),
even more preferably from about 5% w/w to about 8.5% w/w (dry
weight), and most preferably about 6.5% w/w (dry weight). Preferred
viscosities of the silicone fluid are from about 20 cSt to about
350 cSt, and most preferably about 100 cSt.
[0058] Alternatives to silicone fluid, such as mineral oil, also
may be used and are within the scope of the invention.
[0059] The width or thickness of the adhesive layer (shown as 14 in
each of FIGS. 1A and 1B) is that width which provides at least
sufficient adhesion of the device to the skin of the host. The
width or thickness also may vary depending upon such factors as the
amount of drug to be delivered from the composition or adhesive
layer and the desired wear period. The thickness of the adhesive
layer will usually range from about 10 to 300 .mu.m, more
preferably 70 to about 140 .mu.m. Expressed alternatively, the
adhesive layer will be present at about 1 to about 30 mg/cm.sup.2,
more preferably about 7 to about 14 mg/cm.sup.2. Variations also
can be determined as a matter of routine experimentation by those
of ordinary skill in the art. The width also need not be uniform
and may vary around the perimeter of the device, e.g., to provide a
specific geometric shape or to provide a tab for removal of a
protective liner.
[0060] Fentanyl is administered preferably in the free base form.
Fentanyl alkaloid powder is available from Mallinckrodt. In another
embodiment, an analgetically effective relative of fentanyl may be
administered, including sufentanil, carfentanil, lofentanil, and
afentanil. The quantity of fentanyl contained in the adhesive layer
is preferably that quantity sufficient to provide a
pharmaceutically or physiologically effective dosage rate of the
active agent to a host in need thereof. The quantity of fentanyl
also is sufficient to maintain at least a partial suspension of the
fentanyl in a solvated adhesive. This quantity can be readily
determined by those of ordinary skill in the art without undue
experimentation.
[0061] In one embodiment, preferred amounts are about 1% to about
10% w/w (dry weight), more preferably about 3% to about 7% w/w (dry
weight), and most preferably about 4.0% w/w (dry weight) of
fentanyl.
[0062] In another embodiment, preferred amounts are about 5% to
about 15% w/w (dry weight), more preferably about 8% to about 12%
w/w (dry weight), and most preferably about 9.1% w/w (dry weight)
of fentanyl.
[0063] Preferred delivery rates will usually be in the range of
about 5 to about 250 .mu.g/hour, more preferably about 10
.mu.g/hour to about 100 .mu.g/hour, and most preferably about 25,
50, 75 and 100 .mu.g/hour.
[0064] A flux enhancer to promote the penetration of the fentanyl
through the skin may be included in the adhesive layer. Suitable
enhancers include those described in U.S. Pat. No. 4,573,966,
including, monovalent, saturated and unsaturated aliphatic and
cycloaliphatic alcohols having 6 to 12 carbon atoms such as
cyclohexanol, lauryl alcohol and the like; aliphatic and
cycloaliphatic hydrocarbons such as mineral oil; cycloaliphatic and
aromatic aldehydes and ketones such as cyclohexanone; N,N-di(lower
alkyl) acetamides such as N,N-diethyl acetamide, N,N-dimethyl
acetamide, N-(2-hydroxyethyl) acetamide, and the like; aliphatic
and cycloaliphatic esters such as isopropyl myristate and
lauricidin; N,N-di(lower alkyl) sulfoxides such as decylmethyl
sulfoxide; essential oils, nitrated aliphatic and cycloaliphatic
hydrocarbons such as N-methyl-2-pyrrolidone and azone; salicylates,
polyalkylene glycol silicates; aliphatic acids such as oleic acid
and lauric acid, terpenes such as cineole, surfactants such as
sodium lauryl sulfate, siloxanes such as hexamethyl siloxane;
mixtures of the above materials; and the like.
[0065] The backing layer (identified as 12 in each of FIGS. 1A and
1B) is preferably a thin film or sheet. In some instances, because
of the area of skin to which the device is to be attached, the
device, and therefore the backing layer 12, may be opaque or
colored for cosmetic reasons. In one embodiment, it is a clear
layer that is occlusive with respect to the active agent or drug,
printed matter thereon. The backing layer 12 normally provides
support and a protective covering for the device.
[0066] The backing layer 12 is preferably made of a material or
combination of materials that is preferably impermeable, or at
least substantially impermeable, to the adhesive layer and the
fentanyl contained therein.
[0067] Suitable materials for the backing layer 12 include those
known in the art for use with pressure sensitive adhesives. For
example, the backing layer 12 can comprise a polyolefin, including
polyethylene; a polyester; multi-layer EVA film and polyester;
polyurethane; or combinations thereof. A preferred backing material
is MEDIFLEX.RTM. 1000, a polyolefin manufactured by Mylan
Technologies, Inc. Other suitable materials include, for example,
cellophane, cellulose acetate, ethyl cellulose, plasticized vinyl
acetate-vinyl chloride copolymers, ethylene-vinyl acetate
copolymer, polyethylene terephthalate, nylon, polyethylene,
polypropylene, polyvinylidene chloride (e.g., SARAN),
ethylene-methacrylate copolymer (Surlyn), paper, cloth, aluminum
foil and polymer-metal composites.
[0068] The material that forms the backing layer 12 may be flexible
or non-flexible. Preferably, a flexible backing layer is employed
to conform to the shape of the body member to which the device is
attached.
[0069] In one embodiment, the medical device (10 in each of FIGS.
1A and 1B) contains a protective release liner (identified as 16 in
each of FIGS. 1A and 1B) attached to the device at the surface to
be adhered to the skin, namely the fentanyl-containing adhesive
layer. The release liner 16 is removed before the device 10 is
placed on the skin. The release liner 16 is thus made of a
material(s) that permits the liner to be easily stripped or peeled
away from the adjacent pressure sensitive adhesive layer. The
release liner 16 may be made of the same materials suitable for use
in the backing layer 12 as discussed above. Such material is
preferably made removable or releasable from the adhesive layer,
for example, by conventional treatment with silicon polymers,
fluoropolymers (e.g., Teflon) or other suitable coatings on the
surface thereof. The removal of the device 10 from the release
liner 16 may also be provided by mechanical treatment of the
release liner 16, e.g., by embossing the release liner.
[0070] Suitable release liners include those known in the art for
use with pressure sensitive adhesive compositions. For example, the
release liner can comprise a fluorosilicone coated polyester. A
preferred release liner is MEDIRELEASE.RTM. 2500, manufactured by
Mylan Technologies, Inc., or a fluoropolymer-treated polyester,
such as Scotchpak.RTM. 1022, manufactured by 3M
Pharmaceuticals/D.D.S. The release liner 16, however, can comprise
various layers, including paper or paper-containing layers or
laminates; various thermoplastics, such as extruded polyolefins,
such as polyethylene; various polyester films; foil liners; other
such layers, including fabric layers, coated or laminated to
various polymers, as well as extruded polyethylene, polyethylene
terephthalate, various polyamides, and the like.
[0071] In one embodiment, the release liner 16 includes a laminate
of an outer foil layer and an inner layer of plastic, such as
polyethylene or the like, which is rendered releasable not only by
means of a siliconized coating, but which also includes an embossed
or roughened surface. Embossment is described in U.S. Pat. No.
6,010,715 (Bertek), which is fully incorporated herein by
reference.
[0072] In one embodiment of this invention, the patch further
comprises a fentanyl-free adhesive layer in between the backing
layer 12 and the fentanyl-containing adhesive layer 14. This
additional adhesive layer extends beyond at least a portion of the
fentanyl-containing adhesive layer to provide a further surface
area that can adhere to the skin of the wearer, thereby enhancing
the adhesive qualities of the device or patch. The size and shape
of the backing layer will be essentially co-extensive with the size
and shape of this additional adhesive Layer. This fentanyl-free
adhesive layer can comprise any conventional adhesive, such as a
polyisobutylene or an acrylic acid polymer, such as alkyl acrylate
or methacrylate polymers, as found in any of a variety of
commercially available transdermal patches or tapes.
[0073] The compositions of this invention possess sufficient
adhesive properties that once the release liner is removed and the
composition is applied to the skin the composition can remain in
place for a period of time sufficient to distribute the desired
amount of the drug contained therein with a low incidence of
debonding.
[0074] One skilled in the transdermal art would readily recognize
the possible sizes of devices or patches in accordance with the
invention. The patch sizes preferably vary depending on the desired
delivery rates of fentanyl, preferably increasing in size as the
desired delivery rate increases. Preferred delivery rates are from
about 5 to about 300 .mu.g/hr, more preferably about 50 to about
200 .mu.g/hr, and most preferably about 25, 50, 75 and 100
.mu.g/hour. These delivery rates correspond to patch sizes of 1.25
to about 75 cm.sup.2, more preferably about 12.5 to about 50
cm.sup.2, and most preferably 6.25, 12.5, 18.75, and 25 cm.sup.2,
respectively.
[0075] The device 10, once formed, may be kept sealed in an
air-tight pouch prior to use. The device of the present invention
is used in the same manner as those devices which are conventional
in the prior art. In particular, the release liner 16 attached to
the skin-side surface of the adhesive layer 14 of the device 10 for
contact with the skin or mucosa of the host is removed and such
surface of the adhesive layer 14 is applied to the desired area of
the skin or mucosa.
[0076] The host or individual to which an active agent is
administered by means of the inventive device may be any host in
which fentanyl has the desired effect. The host may be, for
example, a mammal such as a human being, or any warm-blooded or
cold-blooded animal. The advantage of administering fentanyl may be
therapeutic or experimental. The device of this invention may also
be used for any other advantageous purpose.
[0077] Various embodiments of the present invention were prepared
and tested in accordance with testing procedures recognized in the
art. In particular, release of fentanyl from recrystallized
laminates was compared to fentanyl release from suspension-cast
laminates in accordance with the invention.
[0078] Four active laminates as described in Table 3 were made and
tested for in vitro transdermal delivery, in vitro rate of release,
and Polyken probe tack. In addition, the gross nature of the four
blends was qualitatively assessed. The results are summarized
below.
[0079] Formulation Descriptions of Fentanyl From Recrystallized vs.
Suspension-Cast Laminates
1 TABLE 3 Fentanyl Blend Solvent Blend Lot # 4.0% w/w Heptane (30%)
Suspension R6J0001 4.0% w/w Ethyl Acetate Solution 246P110C (41%)
9.5% w/w Heptane (30%) Suspension 246P114A 9.5% w/w Ethyl Acetate
Solution 246P118A (55%)
[0080] In Vitro Transdermal Delivery of Fentanyl from
Recrystallized vs. Suspension-Cast Laminates
[0081] FIG. 2 shows the cumulative in vitro transdermal delivery of
fentanyl from laminates identical in content, but produced by
different procedures. The lot R6J0001 was produced by casting a
blend of heptane-solvated silicone adhesive and suspended (solid)
fentanyl alkaloid particles. A slurry of fentanyl in 360 Medical
Fluid (dimethicone NF) and a portion of the heptane-solvated
silicone adhesive were blended and passed through a high shear
colloid mill to form a suspension. This suspension was then blended
with the remaining heptane-solvated silicone adhesive to form the
final (and more dilute) suspension that was cast onto a release
liner and passed through ovens to drive off the heptane. The final
step in this process was laminating a backing film onto the dried
adhesive matrix.
[0082] The recrystallized formulation (246P110C) was produced by
casting a blend of ethyl acetate-solvated adhesive and dissolved
fentanyl alkaloid. In this process, the fentanyl was combined with
the 360 Medical Fluid and the ethyl acetate-solvated silicone
adhesive. The fentanyl dissolved completely to form a true
solution. This solution blend was then cast onto the release liner
and dried in an oven, whereupon the fentanyl crystallized. The
final step in this process also was laminating the backing film
onto the dried adhesive matrix.
[0083] Table 4 shows the comparison of the above two formulations
tested (which are theoretically identical in their dry form).
2TABLE 4 360 Residual Medical Solvent Lot Descrip- Fluid (Trace
Number tion Adhesive (100cSt) Fentanyl quantities) R6J0001 Clinical
89.5% w/w 6.5% w/w 4.0% w/w Heptane Manu- (7-4201) factured 6.25
cm.sup.2 25 .mu.g/hr 246P110C Labora- 89.5% w/w 6.5% w/w 4.0% w/w
Ethyl tory (7-4202) Acetate Recrys- tallized Laminate 4%
Fentanyl
[0084] FIG. 2 shows that the 3-day suspension-cast formulation
delivered in vitro more fentanyl per unit time than the
recrystallized formulation.
[0085] Table 5 shows a comparison of the (wet) composition of a
suspension blend formulation and the final (dry) composition of an
adhesive matrix according to the invention.
3 TABLE 5 Component Wet (w/w) Dry (w/w) Fentanyl 2.86% 4.0% Bio-PSA
.RTM. 7-4201 92.49% 90.5% Silicone Adhesive 360 Medical Fluid 4.65%
6.5% (100 cSt)
[0086] FIG. 3 shows the cumulative in vitro transdermal delivery of
fentanyl from 7-day patches, also identical in content, but
produced by different procedures. Lot 246P114A was produced by
casting a blend of heptane-solvated silicone adhesive and suspended
(solid) fentanyl alkaloid particles. In this process, the fentanyl
was wetted with the 360 Medical Fluid and the resulting slurry
combined with the heptane-solvated silicone adhesive to form a
final suspension. This suspension was then cast onto the release
liner and dried in an oven. The final step in this process was
laminating the backing film onto the dried adhesive matrix.
[0087] The recrystallized formulation (246P118A) was produced by
casting a blend of ethyl acetate-solvated adhesive and fentanyl.
This blend was created by combining the fentanyl with the 360
Medical Fluid and the ethyl acetate-solvated silicone adhesive. All
of the fentanyl dissolved in the blend. This blend was then cast
onto the release liner and dried in an oven. The final step in this
process was also laminating the backing film onto the dried
adhesive matrix.
[0088] Table 6 shows the compositions of the two above formulations
(which are theoretically identical in their dry form).
4TABLE 6 360 Residual Medical Solvent Lot Descrip- Fluid (Trace
Number tion Adhesive (100cSt) Fentanyl quantities) 246P114A Labor-
84.0% w/w 6.5% w/w 9.5% w/w Heptane atory (7-4201) Suspen- sion
Blend Laminate 9.5% Fentanyl 246P118A Labor- 84.0% w/w 6.5% w/w
9.5% w/w Ethyl atory (7-4202) Acetate Recrys- tallized Laminate
9.5% Fentanyl
[0089] FIG. 3 shows that the 7-day suspension-cast and
recrystallized formulations were the same in terms of in vitro
transdermal fentanyl delivery.
[0090] In another embodiment of the invention, FIG. 6 shows the
cumulative in vitro transdermal delivery of fentanyl from a 7 day
patch in accordance with the present invention. The lot R6J0014 was
produced by casting a blend of heptane-solvated silicone
adhesive(s) and suspended (solid) fentanyl alkaloid particles. A
slurry was produced by mixing fentanyl directly with a portion of
the heptane-solvated silicone adhesive(s). No silicone fluid was
used. This slurry was then passed through a colloid mill to form a
suspension. This suspension was then blended with the remaining
heptane-solvated silicone adhesive to form the final (and more
dilute) suspension that was cast onto a release liner and passed
through ovens to drive off the heptane. The final step in this
process was laminating a backing film onto the dried adhesive
matrix. Table 7 shows the final (dry) composition of the adhesive
matrix.
5 TABLE 7 Component w/w g/m.sup.2 Fentanyl 9.09% 10 Bio-PSA .RTM.
7-4201 45.455% 50 Silicone Adhesive Bio-PSA .RTM. 7-4301 45.455% 50
Silicone Adhesive
[0091] Table 8 shows a comparison of the (wet) composition of the
suspension blend formulation and the final (dry) composition of the
adhesive matrix shown in Table 7.
6 TABLE 8 Component Wet (w/w) Dry (w/w) Fentanyl 6.54% 9.09%
Bio-PSA .RTM. 7-4201 46.73% 45.455% Silicone Adhesive Bio-PSA .RTM.
7-4301 46.73% 45.455% Silicone Adhesive
[0092] Table 9 also shows a comparison of the (wet) composition of
a suspension blend formulation and the final (dry) composition of
an adhesive matrix, according to another embodiment in which no
silicone fluid was used.
7 TABLE 9 Component Wet (w/w) Dry (w/w) Fentanyl 6.85% 9.5% Bio-PSA
.RTM. 7-4201 46.58% 45.25% Silicone Adhesive Bio-PSA .RTM. 7-4301
46.58% 45.25% Silicone Adhesive
[0093] The ratio of adhesives used together may be adjusted without
undue effort to improve adhesive properties, if necessary or
desired.
[0094] Rate of Release of Fentanyl from Recrystallized vs.
Suspension-Cast Laminates
[0095] FIG. 4 shows the rate of fentanyl release for the two lots
R6J0001 and 246P110C tested for in vitro transdermal delivery.
[0096] FIG. 5 shows the rate of fentanyl release for lots 246114A
and 246P118A tested for in vitro transdermal delivery.
[0097] FIG. 7 shows the rate of release for lot R6J0014 tested for
in vitro transdermal delivery.
[0098] The above results show that the recrystallized laminates
(246P110C and 246P118A) release fentanyl much faster than
suspension-cast laminates (R6J0001, 246P114A and R6J0014) in
accordance with the invention, i.e., more than 80% of the fentanyl
is released within the first hour from the recrystallized
laminates. The above differences may be due to fentanyl in the
recrystallized laminates crystallizing at the release liner
surface, which also may explain why the recrystallized laminates
had no measurable tack, as shown below.
[0099] In contrast, in the suspension-cast laminates, fentanyl
crystals were found to be evenly distributed throughout the matrix,
rather than only at the release liner surface.
[0100] Polyken Probe Tack of Recrystallized and Suspension-Cast
Laminates
[0101] The suspension-cast fentanyl laminates were also found to
possess superior adhesive properties, as compared with the
solution-cast laminates. As a result, more thorough measurements of
Polyken probe tack were collected to quantitate any differences
between the two processes (suspension-cast vs. solution-cast).
Table 10 summarizes the results of the tack testing on these
laminates.
8TABLE 10 Formulation Process Lot # Tack (g/cm.sup.2) (4% fentanyl)
Suspension-cast R6J0001 2335 (n = 4) (4% fentanyl) Recrystallized
246p110C 0 (no adhesion to probe) (9.5% fentanyl) Suspension-cast
246p114A 1499 (n = 6) (9.5% fentanyl) Recrystallized 246p118A 0 (no
adhesion to probe)
[0102] Table 10 shows that the solution-cast laminates have no
measurable tack compared to the suspension-cast laminates.
[0103] Table 11 shows the results of tack testing for the 7 day
patch (lot R6J0014)
9 TABLE 11 Polyken Probe Tack (g/cm.sup.2) 1451 .+-. 280
[0104] Photomicrographs were taken to compare qualitative
observations of laminates produced from either solution blends or
suspension blends.
[0105] The overall composition of laminate pairs produced from
solution and suspension blends was the same, the only difference
being the solvent used to solvate the adhesive blend. As the
solvent was removed from the solution blends, the fentanyl
crystallized.
[0106] In the suspension blend composition (R6J0001), fentanyl
particles were more or less round and about 10 to 20.mu.m in
diameter. Also present in the laminates are some agglomerates
(about 30 to 60 .mu.m in diameter), but very few single
(rod-shaped) crystals.
[0107] In the solution blend composition (246p110c), very small
crystals appeared throughout the laminate (too small to accurately
measure their size). Clearer, low-density spots were visible to the
naked eye. Under the microscope, these spots were found to have a
relatively large crystal-agglomerate in the middle (.about.100
.mu.m) surrounded by a crystal-free area. It was hypothesized that
a large, low-energy crystal grew at the expense of the surrounding
crystals. About 4-8 such agglomerates were seen in each 10 cm.sup.2
laminate sample. Therefore, the solution blend tended to produce a
laminate containing larger, discrete crystalline particles while
the suspension blend produced a laminate with smaller, more evenly
dispersed particles.
[0108] Two additional suspension blend and solution blend
compositions were tested and compared. The overall composition of
the laminates produced from the solution and suspension blends also
was the same, the only difference being the solvent used to solvate
the adhesive. As above, removal of the solvent from the solution
blend caused the fentanyl to crystallize.
[0109] In the 7-day suspension blend composition (246p114A), the
appearance was similar to the analogous 3-day suspension laminate
above (R6J0001). In particular, most of the fentanyl particles were
round in shape with a few rod-shaped crystals at the
adhesive-release liner interface. Particle and agglomerate sizes
also were similar to those in the 3-day suspension-cast laminate,
although many more agglomerates were observed (as expected at a
significantly higher drug load).
[0110] In the recrystallized 7-day blend composition (246p118A),
the crystal shape and size was similar to the analogous 3-day
solution-cast laminate (246p110C). However, as expected, many more
agglomerates were observed in the 7-day laminates than in the 3-day
laminate.
[0111] Devices made in accordance with the present invention are
useful for inducing analgesia and sedation. Specific uses include
the management of chronic pain in patients who require opioid
analgesia for pain, such as for relief of acute postoperative and
chronic cancer pain. Other possible uses include treatment of other
chronic body pain, such as back pain and arthritis pain.
[0112] The invention is further illustrated by the following
examples, which are not intended to be limiting.
EXAMPLE 1
[0113] Fentanyl free base (0.0245 kg) is uniformly dispersed in 360
Medical Fluid, 100 cSt (0.061 kg), in a glass jar with the help of
a Ultra-Turrax T 8 dispersing unit for 20 minutes. This premix is
added slowly to heptane-solvated BIO-PSA.RTM. 7-4201 (0.751 kg),
70% w/w solids content, with continuous mixing utilizing a
Glass-Col mixer. This is mixed for 20 minutes. Using a
Warner-Mathis KTF coater, the mixture is then coated onto a release
liner (Scotchpak.RTM. 1022) and then dried at 78.degree. C. for
about 10 minutes to obtain a coat weight of 99.1 g/m.sup.2. The
dried film is then laminated onto a backing film (MediFlex.RTM.
1000). Patches of appropriate size are then die-cut from the
laminate prior to analyses.
EXAMPLE 2
[0114] Fentanyl free base (3.20 g) and 360 Medical Fluid, 100 cSt
(4.00 g) are added in a 4 ounce glass jar. To this jar half of the
pre-weighed heptane-solvated BIO-PSA.RTM. 7-4201 (103.34 g), 70.45%
w/w solids content, is added. This mix is then homogenized with the
help of a dispersing unit (D7801, Dottingen, TYP-1020 L) for 3
minutes. To this mixture the remaining half of the heptane-solvated
BIO-PSA.RTM. 7-4201 is added. This blend is mixed with a simple lab
blender for 3 minutes. Using a fixed knife, the blend is then
coated onto a release liner (ScotchPak.TM. 1022) and then dried at
75.degree. C. for 10 minutes to obtain a coat weight of 90-100
g/m.sup.2. The dried film is then laminated onto a backing film
(Mediflex.RTM. 1000). Patches of appropriate size are then die-cut
from the laminate prior to analysis.
EXAMPLE 3
[0115] Fentanyl free base (2.00 g) is homogenized in 360 Medical
Fluid-100 cSt (5.00 g) in a 4 ounce glass jar with the help of a
dispersing unit (D7801, Dottingen, TYP-1020 L) for 3 minutes. To
this premix heptane-solvated BIO-PSA.RTM. 7-4201 (61.43 g), 70% w/w
solids content, is added. This blend is mixed with a simple lab
blender for 3 minutes. Using a fixed knife, the blend is then
coated onto a release liner (ScotchPak.TM. 1022) and then dried at
room temperature for 5 minutes and 70.degree. C. for 10 minutes to
obtain a coat weight of 90-100 g/m.sup.2. The dried film is then
laminated onto a backing film (Mediflex.RTM. 1000). Patches of
appropriate size are then die-cut from the laminate prior to
analysis.
EXAMPLE 4
[0116] Fentanyl free base (2.00 g) and 360 Medical Fluid-100 cSt
(1.63 g) are added in a 4 ounce glass jar. To this jar, half of the
pre-weighed heptane-solvated BIO-PSA.RTM. 7-4201 (30.34 g), 70.45%
w/w solids content, is added. This mix is then homogenized with the
help of a dispersing unit (D7801, Dottingen, TYP-1020 L) for 3
minutes. To this mixture the remaining half of the heptane-solvated
BIO-PSA.RTM. 7-4201 is added. This blend is mixed with a simple lab
blender for 3 minutes. Using a fixed knife, the blend is then
coated onto a release liner (ScotchPak.RTM. 1022) and then dried at
75.degree. C. for 10 minutes to obtain a coat weight of 90-100
g/m.sup.2. The dried film then is laminated onto a backing film
(Mediflex.RTM. 1000). Patches of appropriate size are then die-cut
from the laminate prior to analysis.
EXAMPLE 5
[0117] Fentanyl free base (3.17 g), 360 Medical Fluid-100 cSt (2.
17 g), and heptane-solvated BIO-PSA.RTM. 7-4201 (39.74 g), 70.45%
w/w solids content, are added in a 4 ounce glass jar. This mix then
is homogenized with the help of a dispersing unit (D7801,
Dottingen, TYP-1020 L) for 3 minutes to fully disperse fentanyl.
Using a fixed knife, the blend is then coated onto a release liner
(ScotchPak.TM. 1022) and then dried at 72.degree. C. for 10 minutes
to obtain a coat weight of 90-100 g/m.sup.2. The dried film is then
laminated onto a backing film (Mediflex.RTM. 1000). Patches of
appropriate size are then die-cut prior to analysis.
EXAMPLE 6
[0118] Fentanyl free base (3.17 g), heptane-solvated BIO-PSA.RTM.
7-4201 [21.41 g, 70.45% w/w solids content], and heptane-solvated
BIO-PSA.RTM. 7-4301 [19.85 g, 76.00% w/w solids content], are added
in a 4 ounce glass jar. This mix is then homogenized with the help
of a dispersing unit (D7801, Dottingen, TYP-1020 L) for 3 minutes
to fully disperse fentanyl. Using a fixed knife, the blend is then
coated onto a release liner (ScotchPak.TM. 1022) and then dried at
72.degree. C. for 10 minutes to obtain a coat weight of 110
g/m.sup.2. The dried film then is laminated onto a backing film
(Mediflex.RTM. 1000). Patches of appropriate size then are die-cut
prior to analysis.
EXAMPLE 7
[0119] Fentanyl free base (12.73 g) and heptane-solvated
BIO-PSA.RTM. 7-4301 (181.82 g, 70.0% w/w solids content) were added
to an 8 oz glass jar. This mixture was then homogenized with a
dispersing unit (Vertishear, 20 mm diameter shaft) for 3 minutes to
fully disperse the fentanyl particles. Using a doctor blade, the
blend was coated onto a release liner (ScotchPak.TM. 1022) and
dried at 72.degree. C. for 10 minutes to obtain a coat weight of
100-110 g/m.sup.2. The dried film was then laminated onto a backing
film (Mediflex.RTM. 1000). Patches of appropriate size were then
die-cut from the finished laminate to form the delivery
systems.
[0120] The publications and other materials used herein to
illuminate the background of the invention, as well as provide
additional details respecting the practice of the invention, are
incorporated herein by reference to the same extent as if they were
specifically and individually indicated to be incorporated by
reference.
[0121] While the invention has been disclosed by reference to the
details of preferred embodiments of the invention, it is to be
understood that the disclosure is intended in an illustrative
rather than a limiting sense, as it is contemplated that
modifications will readily occur to those skilled in the art,
within the spirit of the invention and the scope of the appended
claims.
* * * * *