as) United States
`a2) Patent Application Publication co) Pub. No.: US 2009/0041831 Al
`
`(43) Pub. Date: Feb. 12, 2009
`Miller, II et al.
`
`US 20090041831A1
`
`(54)
`
`FENTANYL SUSPENSION-BASED SILICONE
`ADHESIVE FORMULATIONS AND DEVICES
`FOR TRANSDERMAL DELIVERY OF
`FENTANYL
`
`(75)
`
`Inventors:
`
`Kenneth J. Miller, II, St. Albans,
`VT (US); Sharad K. Govil, Essex,
`VT (US); Kuljit Singh Bhatia,
`Scottsdale, AZ (US)
`
`Correspondence Address:
`DARBY & DARBYP.C.
`P.O. BOX 770, Church Street Station
`New York, NY 10008-0770 (US)
`
`(73)
`
`Assignee:
`
`Mylan Laboratories, Canonsburg,
`PA (US)
`
`(21)
`
`Appl. No.:
`
`12/260,050
`
`(22)
`
`Filed:
`
`Oct. 28, 2008
`
`Related U.S. Application Data
`
`(63) Continuation of application No. 11/743,411, filed on
`May2, 2007, Continuation of application No. 11/723,
`111, filed on Mar. 16, 2007, said application No.
`11/743,411 is a continuation of application No.
`11/438,391, filed on May 23, 2006, now abandoned,
`said application No. 11/723,111 is a continuation of
`application No. 11/438,391, filed on May 23, 2006,
`now abandoned,whichis a continuation of application
`No. 10/283,355, filed on Oct. 30, 2002, now aban-
`doned.
`
`Publication Classification
`
`(51)
`
`Int. Cl.
`(2006.01)
`AGIK 9/70
`(2006.01)
`AGIK 31/445
`(52) US. C0. coeccccccccccccccescsssessssssssssnneenes 424/448; 514/329
`
`(57)
`
`ABSTRACT
`
`Silicone adhesive formulations are provided, in which fenta-
`nyl particles are suspended one or more a solvated silicone
`adhesives. The formulations can be used for manufacturing
`improved, matrix-type transdermaldevices for administering
`fentanyl.
`
`
`
`  
`
`

 
`
`MYLAN- EXHIBIT 1032
`
`

`

`Patent Application Publication
`
`Feb. 12,2009 Sheet 1 of 7
`
`US 2009/0041831 Al
`
`10
`
`

`

`Patent Application Publication
`
`Feb. 12,2009 Sheet 2 of 7
`
`US 2009/0041831 Al
`
`In vitro delivery of 3-day Clinical, 3-day Recrystallized, and
`Duragesic Patches (3 Donors, 2 to 6 Chambers per Donor)
`-e- Clinical
`lot-FIBJ10001 (Suspension Blend: 4%
`Fentanyl, 8.6% 360 Medical Fluid)
`—s- Duragesic 100ug/hr Lot 8910192
`-=- 246p110C (Solution Blend, Recrystallized
`Laminate: 4% Fentanyl, 6.5% 360 Medical
`Fluid)
`
`300
`
`
`
`
` “
`
`250
`5
`‘SS 200
`Be
`2&2 150
`‘oo
`C=
`Bs 100
`50
`
`=m
`
`0
`
`24
`
`48
`
`72
`
`Time (hr)
`
`FIG.2
`
`

`

`Patent Application Publication
`
`Feb. 12,2009 Sheet 3 of 7
`
`US 2009/0041831 Al
`
`In vitro delivery of 7-day Suspension vs. 7—day
`Recrystallized (3 Donors, 6 Chambers/Donor)
`
`—@ 246p114A (Suspension Blend: 9.5% Fentanyl,
`6.6% 980 Medical Fluid)
`7007 _. 246p118A (Solution Blend, Recrystallized
`Laminate: 9.5% Fentanyl, 6.5% 360 Medical
`~
`600
`Lan
`=
`uid)
`38 500
`3 © 400
`22
`= 300
`=S 200
`5Le
`
`
`
`0
`
`24
`
`48
`
`72
`
`96
`
`120
`
`144
`
`168
`
`192
`
`Time (hr)
`
`FIG.3
`
`

`

`Patent Application Publication
`
`Feb. 12,2009 Sheet 4 of 7
`
`US 2009/0041831 Al
`
`Fentanyl Rate of Release
`
`-® 246P110C (Solution Blend, Recrystallized Laminate: 4% Fentanyl,
`6.5% 360 Medical Fluid)
`-® Clinical Lot FIBJO001 (Suspension Blend: 4% Fentanyl, 8.5% 360
`140%-Medical Fluid)
`
`
`
`PotencyClaim
`
`120%
`
`100%
`
`80%
`
`60%
`
`40%
`
`20%
`
`0%
`
`0
`
`1
`
`2
`
`3
`
`4
`
`5
`
`6
`
`7
`
`8
`
`9
`
`Time (hr)
`
`FIG.4
`
`

`

`Patent Application Publication
`
`Feb. 12,2009 Sheet 5 of 7
`
`US 2009/0041831 Al
`
`Fentanyl Rate of Release
`
`—- Fu) (Suspension Blend: 9.5% Fentanyl, 8.5% 360 Medical
`-# 246p118A (Solution Blend, Recrystallized Laminate: 9.5%
`149%-Fentanyl, 6.5% 360 Medical Fluid)
`
`Fluid
`
`
`
`PotencyClaim
`
`120%
`
`100%
`
`80%
`
`60%
`
`40%
`
`20%
`
`4
`
`0
`
`1
`
`2
`
`3
`
`4
`
`5
`
`6
`
`7
`
`8
`
`9
`
`Time (hr)
`
`FIG.5
`
`

`

`Patent Application Publication
`
`Feb. 12,2009 Sheet 6 of 7
`
`US 2009/0041831 Al
`
`
`
`
`
`FentanylDeliveredpg/cm2(Cumulative)
`
`In Vitro Transdermal Delivery of Fentanyl for 7 Days From
`Suspension Blend Made Without 360 Medical Fluid
`
`800
`
`700
`
`600
`
`500
`
`400
`
`300
`
`200
`
`100
`
`24
`
`48
`
`96
`72
`Time (hr)
`
`FIG.6
`
`120
`
`144
`
`168
`
`

`

`Patent Application Publication
`
`Feb. 12,2009 Sheet 7 of 7
`
`US 2009/0041831 Al
`
`In Vitro Rate of Release of Fentanyl From
`Suspension Blend Made Without 360 Medical Fluid
`
`100%
`
`75%
`
`5 50%
`
`oO
`
`25%
`
`0%
`
`0
`
`1
`
`2
`
`3
`
`5
`
`6
`
`7
`
`4
`Time (hr)
`FIG.7
`
`

`

`US 2009/0041831 Al
`
`Feb. 12, 2009
`
`FENTANYL SUSPENSION-BASED SILICONE
`ADHESIVE FORMULATIONS AND DEVICES
`FOR TRANSDERMAL DELIVERY OF
`FENTANYL
`
`CROSS-REFERENCE TO RELATED
`APPLICATIONS
`
`[0001] The instant application is a continuing application
`of currently pending U.S. patent application Ser. No. 11/743,
`411 filed May 2, 2007 and is a continuing application of
`currently pending U.S. patent application Ser. No. 11/723,
`111 filed Mar. 16, 2007. Both the °411 and 111 applications
`are continuations of U.S. patent application Ser. No. 11/438,
`391, filed May 23, 2006, which is a continuation of U.S.
`patent application Ser. No. 10/283,355, filed Oct. 30, 2002.
`Each of the 411, °111, °391, and °355 applications are incor-
`porated by referencein their entirety. Applicants claim benefit
`and priority under 35 U.S.C. §120.
`
`FIELD OF THE INVENTION
`
`[0002] Thepresent invention relates generally to thefield of
`transdermal drug delivery. More particularly,
`the present
`invention relates to fentanyl suspension-based, silicone pres-
`sure sensitive adhesive formulations and their use in making
`devices for improved transdermaldelivery of fentanyl.
`
`BACKGROUNDOF THE INVENTION
`
`[0003] 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 adhesiveto the surface.
`Silicone pressure sensitive adhesives in particular have been
`used for transdermal drug delivery, which involves adminis-
`tering a drug by adhering a drug-containing device or patch to
`a patient’s skin.
`[0004] One type of transdermal patch is a polymer matrix
`or monolithic device in which the active agent is contained in
`a polymermatrix film through whichthe active agentdiffuses
`to the skin. Such patches are preferred becausetheyare rela-
`tively simpler to manufacture and more comfortable to wear
`compared to reservoir-type devices. Transdermal patches
`having a monolithic polymerfilm 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.
`[0005]
`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, andit 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 reliefof
`acute postoperative and chronic cancer pain.
`[0006] Transdermal patches containing silicone pressure
`sensitive adhesive compositions are described in U.S. Pat.
`No. 5,232,702 (Pfister et al.), WO 00/33812 (Mirandaetal.),
`WO 96/40085 (Mantelle et al.), and U.S. Pat. No. 5,603,947,
`all fully incorporated herein by reference.
`[0007] U.S. Pat. No. 5,232,702 describes silicone pressure
`sensitive adhesives containing (1) a siliconefluid,(11) a silicate
`resin, and(iii) a cohesive strengthening agent. In one embodi-
`ment, the pressure sensitive adhesive includes a high molecu-
`lar weight polydimethylsiloxaneas the silicone fluid. Organic
`solvents disclosed as suitable for dissolvingthe 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 andtrichlorotrifluoro-
`ethane; fluorocarbons suchas 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-vola-
`tile content of 50 wt %. Thefinal 17-beta estradiol-containing
`adhesive solution was cast onto a polyester release liner,
`allowed to air dry, and then laminated onto a polyester back-
`ing film.
`[0008] 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 sensi-
`tive silicone adhesive layer and a pressure sensitive acrylic
`adhesive layer containing the drug, and a removable release
`liner layer. The silicone adhesivelayer is prepared by dissolv-
`ing 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.
`[0009] 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 sol-
`vent. Examples of volatile solvents provided are isopropanol,
`ethanol, xylene, toluene, hexane, cyclohexane, heptane, ethyl
`acetate and butyl acetate.
`[0010]
`Similarly, U.S. Pat. No. 5,603,947 describes in
`Example 1 the use ofheptane to cast a silicone adhesive layer
`in nicotine patches.
`[0011]
`In both of the above references, the drugs are dis-
`solved in the silicone adhesivesprior to casting.
`[0012] Transdermal patches containing fentanyl in a sili-
`cone pressure sensitive adhesive are also knownintheart, as
`described, for example, in U.S. Pat. Nos. 4,588,580 (Gale et
`al.) and 5,186,939 (Cleary et al.), also fully incorporated
`herein by reference.
`[0013] U.S. Pat. No. 4,588,580 describes in Example 6 a
`fentanyl-containing monolithic patch that was made using
`Dow Corning amineresistant silicone adhesive andsilicone
`medical fluid having 10 and 20 percent fentanyl base dis-
`persed therein.
`[0014] US. Pat. No. 5,186,939 describes a laminated com-
`posite 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 adhe-
`sive composition was prepared consisting of 1.8% fentanyl
`base, 4% permeation enhancer (PGML), 2.0% silicone oil
`(Dow Coming Medical Fluid) and 92.5% amineresistant
`polydimethylsiloxane (Dow Coming X7-2900) dissolved in
`trichlorotrifluoroethane(freon) to provide a 50% solution.
`
`

`

`US 2009/0041831 Al
`
`Feb. 12, 2009
`
`In addition, a fentanyl-containing, reservoir-type
`[0015]
`transdermal patch as approvedby the FDA is describedin the
`2002 Physician’s Desk Reference. Duragesic.RTM.is a rect-
`angular 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
`backinglayer ofpolyester film; 2) a drug reservoir of fentanyl
`and alcohol USP gelled with hydroxyethyl] cellulose; 3) an
`ethylene-vinyl acetate copolymer membranethatcontrols the
`rate of fentany] delivery to the skin surface; and 4) a fentanyl
`containing silicone adhesive.
`[0016] The present invention is believed to offer improve-
`ments and advantages over prior fentanyl-containing trans-
`dermal devices.
`
`SUMMARYOF THE INVENTION
`
`[0017] One aspect ofthe invention is a fentany]l-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 sub-
`
`stantially or fully solvate or dissolve the adhesive while keep-
`ing the fentanyl suspendedin the solvated adhesive.
`[0018] 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 solvatedsilicone adhesive
`(s) to also form a suspension of fentanyl particles in the
`solvated adhesive(s).
`[0019] The above formulations are useful for making
`monolithic devices for improved transdermal administration
`of fentanyl.
`[0020] Thus, another aspect ofthe 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:
`[0021]
`a) selecting a solvent that can substantially or
`fully solvate a silicone adhesive while keeping fentany]
`particles, when blended with the solvated adhesive, sus-
`pendedin the solvated adhesive;
`[0022]
`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 suspendedin the solvated adhesives;
`[0023]
`c) casting the blend formulation onto a support
`material; and
`[0024]
`d) removing the solvent, to produce a laminate
`containing the support material and a fentanyl suspen-
`sion-containing adhesive layer.
`[0025]
`In a preferred embodiment, the blend formulation
`formed in step (b) is further treated prior to the casting step.
`[0026] 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-con-
`taining adhesive layer, andrelease liner.
`[0027] A further aspectofthe invention then 1s a monolithic
`patch for administering fentanyl transdermally to an indi-
`vidual comprising: (a) a backing layer substantially impervi-
`ous to the fentanyl to be administered transdermally; (b) a
`fentanyl-containing adhesive layer in contact with atleast a
`
`portion of the backing layer, the adhesive layer being cast
`from a formulation comprising a blend of fentanyl]particles
`suspendedin one or moresolvated silicone adhesives; and (c)
`a removablerelease liner in contact with the adhesive layer.
`[0028] A still further aspect ofthe invention is a method for
`administering fentanyl] transdermally to an individual in need
`of such administration, comprising applyingto the skin ofthe
`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]particles
`suspendedin one or more solvated silicone adhesives.
`[0029]
`Ina preferred embodiment, the selected solvent is
`heptane.
`[0030] Anadhesive layer accordingto the present invention
`was foundto provide improved transdermalrelease of fenta-
`nyl, 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.
`[0031] The present invention provides non-invasive sus-
`tained 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
`
`FIG. 1A is an elevational cross-sectional view of an
`[0032]
`embodiment of a transdermal medical device or patch in
`accordance with the invention.
`
`FIG. 1B is an elevational cross-sectional view of an
`[0033]
`embodimentof a suspension-cast laminate of the invention.
`[0034]
`FIG. 2 is a graph comparing in vitro transdermal
`delivery rates of fentanyl for a 3-day suspension blend-based
`device ofthe invention, a 3-day solution blend-basedrecrys-
`tallized device, and a Duragesic transdermal patch.
`[0035]
`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.
`[0036]
`FIG. 4is a graph comparingrates of fentanyl]release
`for a 3-day suspension blend-based device of the invention
`and a 3-day solution blend-basedrecrystallized device.
`[0037] FIG.5isa graph comparingrates of fentanyl release
`for a 7-day suspension blend-based device of the invention
`and a 7-day solution blend-basedrecrystallized device.
`[0038]
`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 withoutsilicone fluid.
`
`FIG. 71isa graph showingthein vitro rate offentanyl
`[0039]
`release from a suspension blend-based device ofthe invention
`made withoutsilicone fluid.
`
`
`
`DETAILED DESCRIPTION OF THE INVENTION
`
`invention provides formulations in
`[0040] The present
`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
`
`

`

`US 2009/0041831 Al
`
`Feb. 12, 2009
`
`other solvents, which include, for example, toluene, xylene
`solvent also must be suitable for preventing high concentra-
`and other aromatics generally.
`tions, e.g., greater than about 1.0% w/w (dry weight), of
`[0048]
`In a preferred embodiment, fentanyl particles are
`fentanyl particles from dissolving in the solvated adhesive.
`suspended uniformly in the solvated silicone adhesive as
`[0041] The total amountof fentanyl] need not be suspended
`small particles, preferably crystalline particles.
`in the solvated adhesive, thus allowing for instances when a
`[0049]
`In the present invention,it is believed that as fenta-
`portion ofthe fentany] is dissolved in the solvated adhesive. In
`nyl leaves the system during the course of wear, the sus-
`the discussion below, the focus will be on “suspended par-
`pended drug in the system dissolves andreplenishesthe deliv-
`ticles”or “suspensions”of fentanyl, butit is to be understood
`that this does not exclude those embodiments in whichasmall
`ered drug. The present invention as a result maintains a level
`thermodynamicactivity (driving force) for the drug over long
`proportion of the fentanyl is dissolved in the solvated adhe-
`sive.
`periods of wear. No other type of reservoir is known to have
`such capability. The present invention thus permits long peri-
`ods of delivery without requiring that a large excess of fen-
`tany] be present.
`[0050]
`Suitable silicone adhesives include pressure sensi-
`tive adhesives made from silicone polymer and resin. The
`polymerto resin ratio can be varied to achieve differentlevels
`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.RIM. 7-4201, BIO-PSA.RTM. 7-4301, and BIO-PSA.
`RTM.7-4501.
`
`[0042] 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.
`
`[0043] 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 layeror release liner to form a fentanyl suspension-
`containing adhesive layer, which can be further processed to
`make a transdermal patch for delivering fentanyl.
`[0044] Thus, to manufacture a device having the advan-
`tages of the present invention, one mustfirst produce a for-
`mulation comprising a liquid blend of fentanyl]particles sus-
`pended in a solvated silicone adhesive, which formulation
`then is subsequently processed to make the device. Alterna-
`tive methods for producing or achieving a fentanyl suspen-
`sion-containing adhesive layer according to the invention
`may be apparent to personsskilled in the art, and these alter-
`native methodsthusalso fall within the scope ofthe present
`invention.
`
`In a preferred embodiment, one or more silicone
`[0045]
`pressure sensitive adhesives is dissolved in heptane, while
`fentanyl particles are mixed with a silicone fluid to form a
`slurry. The slurry of fentanylin 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 thefinal (and more dilute) suspension. The composition
`thenis cast onto a release liner and passed through an oven(s)
`to drive offthe heptane. A backingfilm then is laminated onto
`the dried adhesive matrix.
`
`the device or
`In another preferred embodiment,
`[0046]
`patch is produced by casting a blend of heptane-solvated
`adhesive(s) and suspended(solid) fentany] alkaloid particles.
`A slurry is produced by mixing fentany] directly with a por-
`tion of the heptane-solvated silicone adhesive(s). Nosilicone
`fluid is used. This slurry then is passed through a colloid mill
`or similar mixing device to form a suspension. This suspen-
`sion then is blended with the remaining heptane-solvated
`silicone adhesive(s) to form the final (and more dilute) sus-
`pension that can be cast onto a release liner and passed
`through an ovento drive off the heptane. A backing film then
`is laminated onto the dried adhesive matrix.
`
`[0047] 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
`
`Inone embodiment, in which silicone medicalfluid
`[0051]
`is used, the preferred amountof 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%
`wiw (dry weight).
`[0052]
`In another embodiment, in which one or moredif-
`ferent silicone adhesives may be used, optionally inthe pres-
`ence of silicone medical
`fluid,
`the preferred combined
`amountofsilicone 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 prefer-
`ably about 91% w/w (dry weight).
`[0053] Preferred silicone fluids include high molecular
`weight polydimethylsiloxane, Dimethicone NF (Dow 360
`Silicone Medical Fluid, 100 cSt and other viscosities). Pre-
`ferred amounts ofsilicone fluid are from about 0% w/w to
`
`about 25% w/w (dry weight), more preferably from about 2%
`wiw to about 10% w/w (dry weight), even more preferably
`from about 5% w/w to about 8.5% w/w (dry weight), and
`mostpreferably about 6.5% w/w (dry weight). Preferred vis-
`cosities ofthe siliconefluid are from about 20 cSt to about 350
`
`cSt, and most preferably about 100 cSt.
`[0054] Alternatives to silicone fluid, such as mineraloil,
`also may be used and are within the scope of the invention.
`[0055] The width or thickness of the adhesive layer (shown
`as 14 in each of FIGS. 1A and 1B) is that width which
`providesat 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 amountof 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 um, more preferably 70 to about 140 um.
`Expressed alternatively, the adhesive layer will be presentat
`about 1 to about 30 mg/cm?, morepreferably about7 to about
`14 mg/cm”. 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 removalofa protectiveliner.
`
`

`

`US 2009/0041831 Al
`
`Feb. 12, 2009
`
`Fentanyl is administered preferably in the free base
`[0056]
`form. Fentany] alkaloid powderis available from Mallinck-
`rodt. In another embodiment, an analgetically effective rela-
`tive of fentanyl may be administered, including sufentanil,
`carfentanil, lofentanil, and afentanil. The quantity of fentany]
`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 fentany] also is sufficient to maintain
`at least a partial suspension of the fentanyl in a solvated
`adhesive. This quantity can be readily determinedby those of
`ordinary skill in the art without undue experimentation.
`[0057]
`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.
`[0058]
`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 mostprefer-
`ably about 9.1% w/w(dry weight) of fentanyl.
`[0059]
`Preferred delivery rates will usually be in the range
`of about 5 to about 250 pg/hour, more preferably about 10
`ug/hour to about 100 ug/hour, and most preferably about 25,
`50, 75 and 100 ug/hour.
`[0060] 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 unsat-
`urated aliphatic and cycloaliphatic alcohols having 6 to 12
`carbon atoms such as cyclohexanol, lauryl alcohol and the
`like; aliphatic and cycloaliphatic hydrocarbons such as min-
`eral oil; cycloaliphatic and aromatic aldehydes and ketones
`such as cyclohexanone; N,N-di(loweralkyl) acetamides such
`as N,N-diethyl acetamide, N,N-dimethyl acetamide, N-(2-
`hydroxyethyl) acetamide,
`and the like;
`aliphatic and
`cycloaliphatic esters such as isopropy] myristate andlaurici-
`din; N,N-di(loweralkyl) sulfoxides such as decylmethy] sul-
`foxide; essential oils, nitrated aliphatic and cycloaliphatic
`hydrocarbons such as N-methyl-2-pyrrolidone and azone;
`salicylates, polyalkylene glycolsilicates; aliphatic acids such
`as oleic acid andlauric acid, terpenes such as cineole, surfac-
`tants such as sodium lauryl sulfate, siloxanes such as hexam-
`ethyl siloxane; mixtures of the above materials; and the like.
`[0061] The backinglayer (identified as 12 in each of FIGS.
`1A and 1B) is preferably a thin film or sheet. In some
`instances, because ofthe area of skin to which the deviceis 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 agentor drug, printed matter thereon. The backing
`layer 12 normally provides support and a protective covering
`for the device.
`
`[0062] The backing layer 12 is preferably made of a mate-
`rial or combination of materials that is preferably imperme-
`able, or at least substantially impermeable, to the adhesive
`layer and the fentanyl contained therein.
`[0063]
`Suitable materials for the backing layer 12 include
`those knownin the art for use with pressure sensitive adhe-
`sives. 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-viny] acetate copolymer,
`polyethylene terephthalate, nylon, polyethylene, polypropy-
`lene, polyvinylidene chloride (e.g., SARAN), ethylene-meth-
`acrylate copolymer(Surlyn), paper, cloth, aluminum foil and
`polymer-metal composites.
`[0064] 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
`whichthe deviceis attached.
`
`In one embodiment, the medical device (10 in each
`[0065]
`of FIGS. 1A and 1B)containsa protective release liner (iden-
`tified as 16 in each of FIGS. 1A and 1B)attachedto the device
`at the surface to be adheredto the skin, namely the fentanyl-
`containing adhesive layer. The release liner 16 is removed
`before the device 10 is placed on the skin. Therelease liner 16
`is thus madeof 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 orreleas-
`able 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
`removalofthe device 10 from therelease liner 16 mayalso be
`provided by mechanicaltreatmentofthe releaseliner 16, e.g.,
`by embossing the release liner.
`[0066]
`Suitable release liners include those knownin theart
`for use with pressure sensitive adhesive compositions. For
`example,
`the release liner can comprise a fluorosilicone
`coated polyester. A preferred release liner is MEDIRELEA-
`SE.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 paperor paper-containing layers or laminates; vari-
`ous 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, andthelike.
`[0067]
`In one embodiment, the release liner 16 includes a
`laminate of an outer foil layer and an innerlayerof plastic,
`such as polyethyleneorthelike, which is rendered releasable
`not only by meansofa siliconized coating, but which also
`includes an embossed or roughened surface. Embossmentis
`described in U.S. Pat. No. 6,010,715 (Bertek), which is fully
`incorporated herein by reference.
`[0068]
`In one embodimentof this invention, the patch fur-
`ther comprises a fentanyl-free adhesive layer in between the
`backing layer 12 and the fentanyl-containing adhesive layer
`14. This additional adhesive layer extends beyondat least a
`portion ofthe 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 essen-
`tially co-extensive with the size and shapeof this additional
`adhesive layer. This fentanyl-free adhesive layer can com-
`prise any conventional adhesive, such as a polyisobutylene or
`an acrylic acid polymer, such as alkyl acrylate or methacry-
`late polymers, as found in any of a variety of commercially
`available transdermalpatchesortapes.
`[0069] The compositions of this invention possess suffi-
`cient adhesive properties that once the release liner is
`
`

`

`US 2009/0041831 Al
`
`Feb. 12, 2009
`
`removed and the composition is applied to the skin the com-
`position 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.
`[0070] One skilled in the transdermal art would readily
`recognize the possible sizes of devices or patches in accor-
`dance with the invention. The patch sizes preferably vary
`depending on the desired delivery rates of fentanyl, prefer-
`ably increasing in size as the desired delivery rate increases.
`Preferred delivery rates are from about 5 to about 300 ug/hr,
`morepreferably about 50 to about 200 pg/hr, and mostpref-
`erably about 25,