United States Patent
`US 9,730,900 B2
`(10) Patent No.:
`(12)
`Mantelle
`(45) Date of Patent:
`*Aug. 15, 2017
`
`
`US009730900B2
`
`(54) TRANSDERMAL ESTROGEN DEVICE AND
`DELIVERY
`
`(75)
`
`.
`Juan Mantelle, Miami, FL (US)
`
`.
`Inventor:
`.
`;
`(73) Assignee: Noven Pharmaceuticals, Inc., Miami,
`FL (US)
`:
`:
`:
`:
`Subject to any disclaimer, the term ofthis
`patent is extended or adjusted under 35
`U.S.C. 154(b) by 0 days.
`.
`.
`:
`.
`.
`This patent is subject to a terminal dis-
`claimer.
`
`*
`sae
`(*) Notice:
`
`(21) Appl. No.: 13/553,972
`14.
`Filed:
`
`(22)
`(65)
`
`Jul. 20, 2012
`.
`.
`Prior Publication Data
`US 2013/0156815 Al
`Jun. 20, 2013
`oo.
`Related U.S. Application Data
`.
`Loo.
`.
`(63) Continuation of application No. 12/216,811, filed on
`Jul. 10, 2008, now Pat. No. 8,231,906.
`
`(51)
`
`(2006.01)
`(2006.01)
`(2017.01)
`(2006.01)
`(2006.01)
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`
`
`
`Int. Cl.
`AGIK 31/565
`AGIK 9/70
`AGIK 47/10
`AGIK 4732
`AGIK 9/00
`(52) U.S. CL
`CPC wo. A6IK 9/7069 (2013.01); A61K 9/0014
`(2013.01); A6LK 9/7061 (2013.01); A6IK
`31/565 (2013.01); A6LK 47/10 (2013.01);
`A6I1K 47/32 (2013.01)
`FOREIGN PATENT DOCUMENTS
`(58) Field of Classification Search
`None 0 887075 A2=12/1998EP
`
`See application file for complete search history.
`
`(56)
`
`References Cited
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`OTHER PUBLICATIONS
`
`U.S. PATENT DOCUMENTS
`
`4,390,520 A
`4,559,222 A
`4,584,355 A
`4,585,836 A
`4,591,622 A
`4,624,665 A *
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`.
`(Continued)
`.
`:
`.
`.
`Primary Examiner — Melissa Fisher
`(74) Attorney, Agent, or Firm — Foley & Lardner LLP
`
`ABSTRACT
`(57)
`Described are transdermal drug delivery systems for the
`transdermal administration of estrogen, comprising a poly-
`mermatrix and estrogen. Methods of making and using such
`1
`d
`ib d
`systems also are described.
`
`23 Claims, 1 Drawing Sheet
`
`  
`
`

 
`
`MYLAN- EXHIBIT 1036
`
`

`

`US 9,730,900 B2
`
`Page 2
`
`(56)
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`
`
`
`
`
`
`
`
`
`

`

`U.S. Patent
`
`Aug.15, 2017
`
`US 9,730,900 B2
`
`— Viveile-Dot
`
`—*— Example 1
`—@— Example ta
`
`
`
`(ug/cm/hr)
`
` Fiux
`
`oO
`
`12
`
`24
`
`36
`
`48
`
`60
`
`72
`
`84
`
`Time (hrs)
`
`

`

`US 9,730,900 B2
`
`1
`TRANSDERMAL ESTROGEN DEVICE AND
`DELIVERY
`
`RELATED APPLICATIONS
`
`10
`
`15
`
`35
`
`40
`
`45
`
`50
`
`55
`
`This application is a continuation of U.S. patent applica-
`tion Ser. No.12/216,811, filed Jul. 10, 2008 (now U.S. Pat.
`No. 8,231,906), which is incorporated herein by reference in
`its entirety.
`
`FIELD OF THE INVENTION
`
`Described herein are compositions and methods for the
`transdermal delivery of estrogen.
`
`BACKGROUND
`
`This invention relates generally to transdermaldrug deliv-
`ery systems, and more particularly,
`to transdermal drug
`delivery systems for the delivery of estrogen. The use of a
`transdermal system, for example, a patch comprising a
`pressure-sensitive adhesive containing a drug, as a means of
`delivering drug through the skin is well known. However,
`there remains a need for transdermal drug delivery systems
`designedfor the delivery of specific drugs, such as estrogen,
`and there remains a particular need for smaller transdermal
`drug delivery systems that exhibit desired pharmacokinetic
`properties.
`Transdermal delivery systems (adhesive patches) as dos-
`age forms have been the subject of a vast numberof patent
`applications over the last 25 years, yielding manypatents but
`few commercial products in comparison. To those working
`in the field,
`the relatively small number of commercial
`products is not surprising. Although regulatory, economic,
`and market hurdles play a role in limiting the number of
`products on the market, the task of developing a transdermal
`delivery system that achieves desired physical and pharma-
`cokinetic parametersto satisfy physician and patient demand
`is more daunting. Parameters to be considered during com-
`mercial product development may include drug solubility,
`drug stability (e.g., as may arise from interaction with other
`component materials and/or the environment), delivery of a
`therapeutic amountof drug at a desired delivery rate over the
`intended duration of use, adequate adhesion at the anatomi-
`cal site of application,
`integrity (e.g., minimal curling,
`wrinkling, delaminating and slippage) with minimal discom-
`fort, irritation and sensitization both during use and during
`and after removal, and minimal residual adhesive (or other
`components) after removal. Size also may be important from
`a manufacturing and patient viewpoint, and appearance may
`be important from a patient viewpoint. The physical manu-
`facturing and production aspects of commercial product
`development(e.g., the identity and costs of materials, equip-
`ment, and labor) and supporting analytical methods required
`for regulatory compliance also can be significant.
`Of the physical parameters that are considered when
`developing a commercial transdermal drug delivery system,
`size, e.g., surface area at the site of application,
`is often
`dictated and limited by other physical and pharmacokinetic
`requirements, such as desired drug delivery rates and daily
`dosages. In general,
`it
`is easier to develop a relatively
`“large” transdermal drug delivery system that will achieve
`drug delivery at target therapeutic levels over an intended
`duration of therapy, than it is to develop a smaller transder-
`mal drug delivery system that still exhibits acceptable phar-
`macokinetic properties. Still, because size directly impacts
`costs (e.g., costs of component materials, costs of packaging
`
`2
`materials, costs for production and manufacturing equip-
`ment, labor costs relative to product yield per run time, etc.)
`and patients generally prefer smaller systems to larger ones
`(both for aesthetic reasons and comfort, since a smaller
`surface may permit the use of less aggressive adhesives),
`there is a need for smaller transdermal drug delivery sys-
`tems.
`
`SUMMARY
`
`In accordance with one embodiment, there is provided a
`transdermal drug delivery system comprising a drug con-
`taining layer defining an active surface area and comprising
`a polymer matrix comprising estradiol, wherein the system
`includes greater than 0.156 mg/cm? estradiol and achieves
`an estradiol flux that is greater than 0.01 mg/cm?/day, based
`on the active surface area.
`In some embodiments,
`the
`polymer matrix comprises a polymer blend comprising an
`acrylic adhesive, a silicone adhesive, and soluble PVP. In
`some embodiments, the polymer matrix comprises about
`2-25% by weight acrylic adhesive, about 45-70% by weight
`silicone adhesive, about 2-25% by weight soluble PVP,
`about 5-15% penetration enhancer, and about 0.1-10% by
`weight estradiol, all based on the total dry weight of the
`polymer matrix. In some embodiments, the polymer matrix
`comprises about 20% by weight acrylic adhesive, about
`56.9% by weight silicone adhesive, about 7.5% by weight
`soluble PVP, about 6.0% by weight oleyl alcohol, about
`8.0% by weight dipropylene glycol, and about 1.6% by
`weight estradiol. In some embodiments, the acrylic adhesive
`and silicone adhesive are presentin a ratio of from about 1:2
`to about 1:6, based on the total weight of the acrylic and
`silicone adhesives.
`the penetration enhancer com-
`In some embodiments,
`prises oleyl alchol or dipropylene glycol, or both.
`In some embodiments, the polymer matrix comprises an
`amount of estradiol effective to deliver a therapeutically
`effective amount of estradiol over a period of time selected
`from the group consisting of at least 1 day, at least 2 days,
`at least 3 days, at least 4 days, at least 5 days, at least 6 days
`and at least 7 days. In some embodiments, the polymer
`matrix comprises an amountof estradiol effective to deliver
`an amountof estradiol selected from the group consisting of
`about 0.025, 0.0375, 0.05, 0.075 and 0.1 mg/day.
`In some embodiments, the polymer matrix has a coat
`weight of greater than about 10 mg/cm’. In some embodi-
`ments, the polymer matrix has a coat weight selected from
`the group consisting of about 12.5 and about 15 mg/ cm?.
`In accordance with some embodiments, there is provided
`a transdermal drug delivery system comprising a polymer
`matrix comprising estradiol, wherein the system has an
`active surface area that is about 60% of a size selected from
`the group consisting of 2.5, 3.75, 5.0, 7.5 and 10.0 cm? and
`is effective to deliver an amountofestradiol per day of about
`0.025, 0.0375, 0.05, 0.075 and 0.1 mg/day, respectively.
`In accordance with some embodiments, there is provided
`a method for administering estradiol, comprising applying to
`the skin or mucosaof a subject in need thereof a transdermal
`drug delivery system comprising a drug-containing layer
`defining an active surface area and comprising a polymer
`matrix comprising estradiol, wherein the system includes
`greater than 0.156 mg/cm?estradiol and achieves an estra-
`diol flux that is greater than 0.01 mg/cm?/day, based on the
`active surface area. In some embodiments, the system has an
`active surface area that is about 60% of a size selected from
`the group consisting of 2.5, 3.75, 5.0, 7.5 and 10.0 cm? and
`
`

`

`US 9,730,900 B2
`
`3
`is effective to deliver an amountofestradiol per day of about
`0.025, 0.0375, 0.05, 0.075 and 0.1 mg/day, respectively.
`In accordance with some embodiments, there is provided
`a method of making a transdermal drug delivery system for
`administering estrogen, comprising forming a polymer
`matrix comprising estrogen and a polymerblend comprising
`an acrylic adhesive, a silicone adhesive, and soluble PVP,
`and applying the polymer matrix to a support layer such that
`the system includesgreater than 0.156 mg/cm? estradiol. In
`some embodiments, the system has an active surface area
`that is about 60% ofa size selected from the group consist-
`ing of 2.5, 3.75, 5.0, 7.5 and 10.0 cm?. In some embodi-
`ments, the polymer matrix comprises about 20% by weight
`acrylic adhesive, about 56.9% by weight silicone adhesive,
`about 7.5% by weight soluble PVP, about 6.0% by weight
`oley] alcohol, about 8.0% by weight dipropylene glycol, and
`about 1.6% by weight estradiol. In some embodiments, the
`polymer matrix is applied to the support layer at a coat
`weight of greater than about 10 mg/cm’. In some embodi-
`ments, the polymer matrix coat weight is selected from the
`group consisting of about 12.5 and about 15 mg/ cm?.
`
`BRIEF DESCRIPTION OF THE DRAWINGS
`
`FIG.1 illustrates the estradiol flux (ug/cm?/hr) over time
`(0-81 hours) from transdermaldelivery systems according to
`the invention (A & @), as compared to Vivelle-Dot® (@).
`
`DETAILED DESCRIPTION
`
`Thefield of transdermal delivery systems suffers from the
`problem of needing to balance many different competing
`factors to develop a commercial product that exhibits, for
`example both clinical efficacy and satisfactory wear prop-
`erties while remaining acceptable to patients. For example,
`whenselecting the size of a transdermal delivery system,it
`is necessary to balance factorsthat favor a smaller size (such
`as lower cost, better adhesive performance and improved
`aesthetics) against factors that favor a larger size (such as the
`target delivery rate (flux) and daily dose). The Vivelle-Dot®
`transdermal estradiol product
`(manufactured by Noven
`Pharmaceuticals Inc.) is available in five different active
`surface areas (2.5, 3.75, 5.0, 7.5 and 10.0 cm?) which each
`deliver different amounts of drug per day (0.025, 0.0375,
`0.05, 0.075 and 0.1 mg/day, respectively). Each of the
`Vivelle-Dot® products include 0.156 mg/cm?estradiol.
`In accordance with some embodiments, the present inven-
`tion provides transdermal drug delivery systems for the
`transdermal delivery of estrogen that have a smaller active
`surface area than Vivelle-Dot® but achieve daily dosages
`that are about equal to or greater than the Vivelle-Dot®
`products. For example, the present invention includes trans-
`dermal drug delivery systems that achieve daily dosagesthat
`are about equalto a Vivelle-Dot® product, in a smaller sized
`system. The ability to provide a smaller system without
`sacrificing daily dosage represents a significant advance.
`Applicant surprisingly discovered that increasing the coat
`weight of the drug-containing adhesive layer resulted in an
`increased flux per unit area, and thus permitted the devel-
`opment of smaller transdermal drug delivery systems that
`achieve comparable daily dosages. This result was surpris-
`ing because coat weight is typically selected to control the
`duration of delivery, but
`is not generally understood to
`impact delivery rate. Thus, while it is known in the art to
`increase coat weight to provide delivery over a longer period
`of time, it was not knownthat increasing coat weight could
`
`10
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`15
`
`20
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`25
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`30
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`35
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`40
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`45
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`50
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`55
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`60
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`65
`
`4
`increase delivery rate or flux, and thus permit the develop-
`ment of a smaller system while maintaining daily dosage.
`In accordance with some aspects,
`there are provided
`transdermal drug delivery systems and methods for the
`transdermal delivery of estrogen. In specific embodiments,
`the systems exhibit increased flux than other knownestrogen
`devices (such as Vivelle-Dot®, manufactured by Noven
`Pharmaceuticals Inc.) and, therefore, exhibit increased drug
`delivery per unit area. For example, in some embodiments,
`the systems exhibit a flux greater than the 0.01 mg/cm?/day
`exhibited by the Vivelle-Dot® products, such as a flux that
`is about 1.25, 1.33, 1.5, 1.67, 1.75, 2, 3, 4, or 5 timesthe flux
`of the Vivelle-Dot® products. In some embodiments, the
`systems have a greater coat weight than other knownestro-
`gen devices. For example, in some embodiments, the sys-
`tems have a coat weight such that the amountofestradiol per
`unit area is greater than the 0.156 mg/cm?estradiol of the
`Vivelle-Dot® products, such as a coat weight that is about
`1.25, 1.33, 1.5, 1.67, 1.75, 2, or 3 times the coat weight of
`the Vivelle-Dot® products, or greater. Thus, in accordance
`with someaspects, the invention permits the use of smaller
`devices to achieve comparable drug delivery.
`Definitions
`Technical and scientific terms used herein have the mean-
`
`ings commonly understood by oneof ordinary skill in theart
`to which the present invention pertains, unless otherwise
`defined. Reference is made herein to various methodologies
`knownto those of ordinary skill in the art. Publications and
`other materials setting forth such known methodologies to
`which reference is made are incorporated herein by refer-
`ence in their entireties as though set forth in full. Any
`suitable materials and/or methods known to those of ordi-
`nary skill in the art can be utilized in carrying out the present
`invention. However, specific materials and methods are
`described. Materials, reagents and the like to which refer-
`ence is made in the following description and examples are
`obtainable from commercial
`sources, unless otherwise
`noted.
`
`As used herein, the singular forms “a,” “an,” and “the”
`designate both the singular and the plural, unless expressly
`stated to designate the singular only.
`The term “about” and the use of ranges in general,
`whether or not qualified by the term about, meansthat the
`number comprehendedis not limited to the exact numberset
`forth herein, and is intendedto refer to ranges substantially
`within the quoted range while not departing from the scope
`of the invention. As used herein,“about” will be understood
`by persons of ordinary skill in the art and will vary to some
`extent on the context in whichit is used. If there are uses of
`
`the term which are not clear to persons of ordinary skill in
`the art given the context in which it is used, “about” will
`mean up to plus or minus 10% ofthe particular term.
`The phrase “substantially free” as used herein generally
`means that
`the described composition (e.g.,
`transdermal
`drug delivery system, polymer matrix, etc.) comprises less
`than about 5%, less than about 3%,or less than about 1% by
`weight, based on the total weight of the compositionat issue,
`of the excluded component.
`As used herein “subject” denotes any animal in need of
`drug therapy, including humans. For example, a subject may
`be suffering from or at risk of developing a condition that
`can be treated or prevented with estrogen, or may be taking
`estrogen for health maintenance purposes.
`As used herein,
`the phrases “therapeutically effective
`amount” and “therapeutic level” mean that drug dosage or
`plasma concentration in a subject, respectively, that provides
`the specific pharmacological response for which the drug is
`
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`

`US 9,730,900 B2
`
`5
`administered in a subject in need of such treatment. It is
`emphasizedthat a therapeutically effective amount or thera-
`peutic level of a drug will not alwaysbe effective in treating
`the conditions/diseases described herein, even though such
`dosage is deemedto be a therapeutically effective amount by
`those of skill in the art. For convenience only, exemplary
`dosages, drug delivery amounts,
`therapeutically effective
`amounts and therapeutic levels are provided below with
`reference to adult human subjects. Those skilled in the art
`can adjust such amounts in accordance with standard prac-
`tices as needed to treat a specific subject and/or condition/
`disease.
`As used herein, “active surface area” means the surface
`area of the drug-containing layer of the transdermal drug
`delivery system.
`Asused herein, “coat weight” refers to the weight of the
`drug-containing layer per unit area of the active surface area
`of the transdermal drug delivery system.
`As used herein, “estrogen” includes estrogenic steroids
`such as estradiol (17-f-estradiol), estradiol benzoate, estra-
`diol 17$-cypionate, estropipate, equilenin, equilin, estriol,
`estrone, ethinyl estradiol, conjugated estrogens, esterified
`estrogens, and mixtures thereof.
`As used herein, “flux” (also called “permeation rate’’) is
`defined as the absorption of a drug through skin or mucosal
`tissue, and is described by Fick’s first law of diffusion:
`
`J=-D(dCm/dx)
`
`where J is the flux in g/em”/sec, D is the diffusion coefficient
`of the drug through the skin or mucosa in cm*/sec and
`dCm/dx is the concentration gradient of the drug across the
`skin or mucosa.
`As used herein, the term “transdermal”refers to delivery,
`administration or application of a drug by meansofdirect
`contact with skin or mucosa. Such delivery, administration
`or application is also known as dermal, percutaneous, trans-
`mucosal and buccal. As used herein, “dermal” includes skin
`and mucosa, which includes oral, buccal, nasal, rectal and
`vaginal mucosa.
`Asusedherein, “transdermal drug delivery system”refers
`to a system (e.g., a device) comprising a composition that
`releases estrogen upon application to the skin (or any other
`surface noted above). A transdermal drug delivery system
`may comprise a backing layer, a drug-containing layer, and
`a release liner layer. In some embodiments, the transdermal
`drug delivery system is a substantially non-aqueous, solid
`form, capable of conforming to the surface with which it
`comes into contact, and capable of maintaining such contact
`so as to facilitate topical application without adverse physi-
`ological response, and without being appreciably decom-
`posed by aqueous contact during topical application to a
`subject. Many such systems are known in the art and
`commercially available, such as transdermal drug delivery
`patches. As described below, in one embodiment, the trans-
`dermal drug delivery system comprises a drug-containing
`polymer matrix that comprises a pressure-sensitive adhesive
`or bioadhesive, and is adopted for direct application to a
`user’s (e.g., a subject’s) skin. In other embodiments, the
`polymer matrix is non-adhesive and maybe provided with
`separate adhesion means(such as a separate adhesive layer)
`for application and adherence to the user’s skin.
`As used herein, “polymer matrix” refers to a polymer
`composition which contains one or more drugs. In some
`embodiments,
`the matrix comprises a pressure-sensitive
`adhesive polymer or a bioadhesive polymer.
`In other
`embodiments,
`the matrix does not comprise a pressure-
`sensitive adhesive or bioadhesive. As used herein, a polymer
`
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`20
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`25
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`6
`is an “adhesive”if it has the properties of an adhesiveper se,
`or if it functions as an adhesive by the addition of tackifiers,
`plasticizers, crosslinking agents or other additives. Thus, in
`some embodiments, the polymer matrix comprises a pres-
`sure-sensitive adhesive polymer or a bioadhesive polymer,
`with estrogen dissolved or dispersed therein. The polymer
`matrix also may comprise tackifiers, plasticizers, crosslink-
`ing agents or other additives described herein. U.S. Pat. No.
`6,024,976 describes polymer blends that are useful in accor-
`dance with the transdermal systems described herein. The
`entire contents of U.S. Pat. No. 6,024,976 is incorporated
`herein by reference.
`As used herein, the term “pressure-sensitive adhesive”
`refers to a viscoelastic material which adheres instanta-
`
`neously to most substrates with the application of very slight
`pressure and remains permanently tacky. A polymeris a
`pressure-sensitive adhesive within the meaning of the term
`as used herein if it has the properties of a pressure-sensitive
`adhesive per se or functions as a pressure-sensitive adhesive
`by admixture with tackifiers, plasticizers or other additives.
`The term pressure-sensitive adhesive also includes mix-
`tures of different polymers and mixtures of polymers, such
`as polyisobutylenes (PIB), of different molecular weights,
`wherein each resultant mixture is a pressure-sensitive adhe-
`sive. In the last case,
`the polymers of lower molecular
`weight in the mixture are not considered to be “tackifiers,”
`said term being reserved for additives which differ other than
`in molecular weight from the polymers to which they are
`added.
`
`In some embodiments, the polymer matrix is a pressure-
`sensitive adhesive at room temperature and has other desir-
`able characteristics for adhesives used in the transdermal
`
`drug delivery art. Such characteristics include good adher-
`ence to skin, ability to be peeled or otherwise removed
`without substantial trauma to the skin, retention of tack with
`aging, etc. In some embodiments, the polymer matrix has a
`glass transition temperature (T,), measured using a differ-
`ential scanning calorimeter, of between about -70° C. and 0°
`C.
`
`As used herein, the term “rubber-based pressure-sensitive
`adhesive” refers to a viscoelastic material which has the
`
`properties of a pressure-sensitive adhesive and which con-
`tains at least one natural or synthetic elastomeric polymer.
`In some embodiments,
`the transdermal drug delivery
`system includes one or more additional layers, such as one
`or more additional polymer matrix layers, or one or more
`adhesive layers that adhere the transdermal drug delivery
`system to the user’s skin. In other embodiments, the trans-
`dermal drug delivery system is monolithic, meaning that it
`comprises a single polymer matrix layer comprising a pres-
`sure-sensitive adhesive or bioadhesive with drug dissolved
`or dispersed therein, and no rate-controlling membrane.
`The transdermal drug delivery system also may include a
`drug impermeable backing layer or film. In some embodi-
`ments, the backing layer is adjacent one face of the polymer
`matrix layer. When present, the backing layer protects the
`polymermatrix layer (and any other layers present) from the
`environment and prevents loss of the drug and/orrelease of
`other components to the environment during use. Materials
`suitable for use as backing layers are well-known knownin
`the art and can comprise films of polyester, polyethylene,
`vinyl acetate resins, ethylene/vinyl acetate copolymers,
`polyvinyl chloride, polyurethane, and the like, metal foils,
`non-woven fabric, cloth and commercially available lami-
`nates. A typical backing materialhas a thickness in the range
`of 2 to 1000 micrometers.
`
`

`

`US 9,730,900 B2
`
`7
`The transdermal drug delivery system also may include a
`release liner, typically located adjacent the opposite face of
`the system as compared to the backing layer. When present,
`the release liner is removed from the system prior to use to
`expose the polymer matrix layer and/or an adhesive layer
`prior to topical application. Materials suitable for use as
`release liners are well-known knownin the art and include
`
`the commercially available products of Dow Coming Cor-
`poration designated Bio-Release® liner and Syl-off® 7610
`and 3M’s 1022 Scotch Pak.
`
`A used herein, a “monolithic” transdermal drug delivery
`system may include a backing layer and/or release liner.
`In accordance with some embodiments, the transdermal
`dug delivery system comprises a drug-containing polymer
`matrix layer that comprises a pressure-sensitive adhesive
`blend comprising an acrylic polymer, a silicone polymer,
`and a soluble PVP.
`
`Acrylic Polymers
`The term “acrylic polymer” is used here as in the art
`interchangeably with “polyacrylate,”“polyacrylic polymer,”
`and “acrylic adhesive.” The acrylic-based polymers can be
`any of the homopolymers, copolymers, terpolymers, and the
`like of various acrylic acids or esters. In some embodiments,
`the acrylic-based polymers are adhesive polymers. In other
`embodiments,
`the acrylic-based polymers function as an
`adhesive by the addition of tackifiers, p