Atty. Dkt. No. 041457-0992
`
`IN THE UNITED STATES PATENT AND TRADEMARK OFFICE
`Juan Mantelle
`Applicant:
`
`Title:
`
`Transdermal Estrogen Device and Delivery
`
`Prior Appl. No.: 12/216,811
`
`Prior Appl.
`Filing Date:
`
`7/10/2008
`
`Examiner:
`
`Unassigned
`
`Art Unit:
`
`Unassigned
`
`CONTINUING PATENT APPLICATION
`TRANSMITTAL LETTER
`
`Commissioner for Patents
`P.O. Box 1450
`Alexandria, VA 22313-1450
`
`Commissioner:
`
`Transmitted herewith for filing under 37 C.F.R. § 1.53(b) is a:
`
`f X ] Continuation
`
`f ] Division
`
`[ ] Continuation-In-Part (CIP)
`
`of the above-identified copending prior application in which no patenting, abandonment, or
`termination of proceedings has occurred. Priority to the above-identified prior application is
`hereby claimed under 35 U.S.C. § 120 for this continuing application. The entire disclosure
`
`of the above-identified prior application is considered as being part of the disclosure of the
`accompanying continuing application and is hereby incorporated by reference therein.
`
`Enclosed are:
`
`[ X ] Application Data Sheet (37 CFR 1.76) (2 pages).
`
`[ X ] Description, Claim(s), and Abstract (27 pages).
`
`[ X ] Drawing (1 sheet, Figure 1).
`
`[ X ] Executed Declaration and Power of Attorney (3 pages).
`
`4822-8678-9904.1
`
` 
`

 
` 
`0001
`
`MYLAN - EXHIBIT 1035
`Part 1 of 2
`
`

`

`Atty. Dkt. No. 041457-0992
`
`The adjustment to the number of sheets for EPS-Web filing follows:
`
`Number of
`Sheets
`28
`
`x
`
`EFS-Web
`Adjustment
`75%
`
`The filing fee is calculated below:
`
`Number
`Filed
`
`Included
`in
`Basic Fee
`
`Number of Sheets for EFS-Web
`
`21
`
`Extra
`
`Rate
`
`$380.00 -
`
`$620.00
`$250.00
`
`$310.00
`$60.00 -
`
`$250.00 =
`
`$450.00 =
`$130.00
`
`Fee
`Totals
`
`$380.00
`
`$620.00
`$250.00
`
`$0.00
`$0.00
`
`$250.00
`
`$0.00
`$130.00
`
`$1630.00
`0
`$0.00
`$1630.00
`
`Basic Filing
`Fee
`Search Fee
`Examination
`Fee
`Size Fee
`Total
`Claims:
`Independents
`
`[ ]
`
`21
`20
`
`4
`
`100
`20
`
`3
`
`= 0
`
`—
`
`^
`
`x
`x
`
`x
`
`+
`If any Multiple Dependent Claim(s) present:
`Surcharge under 37 CFR 1.16(e) for late payment of +
`filing fee
`
`SUBTOTAL: =
`Small Entity Fees Apply (subtract V-i of above): =
`Basic Filing Fee Reduction for Filing via EFS-Web
`TOTAL FILING FEE: =
`
`The required filing fees are not enclosed but will be submitted in response to the
`Notice to File Missing Parts of Application.
`
`4822-8678-9904.1
`
`0002 
`
`

`

`Please direct all correspondence to the undersigned attorney or agent at the address
`indicated below.
`
`Atty. Dkt. No. 041457-0992
`
`Date
`
`o/O
`
`FOLEY & LARDNER LLP
`Customer Number: 22428
`Telephone:
`(202) 295-4094
`Facsimile:
`(202) 672-5399
`
`Respectfully submitted,
`
`n
`
`Courtenay C. Brinckerhoff
`Attorney for Applicant
`Registration No. 37,288
`
`4822-8678-9904.1
`
`0003 
`
`

`

`Application Data Sheet
`
`Application Information
`
`Application Type::
`Subject Matter::
`Suggested classification::
`Suggested Group Art Unit::
`CD-ROM or CD-R?::
`Computer Readable Form (CRF)?::
`Title::
`Attorney Docket Number::
`Request for Early Publication?::
`Request for Non-Publication?::
`Suggested Drawing Figure::
`Total Drawing Sheets::
`Small Entity?::
`Petition included?::
`Secrecy Order in Parent Appl.?::
`
`Applicant Information
`
`Regular
`Utility
`
`None
`No
`Transdermal Estrogen Device and Delivery
`041457-0992
`No
`No
`1
`1
`No
`No
`No
`
`Applicant Authority Type::
`Inventor
`Primary Citizenship Country:: US
`Status::
`Full Capacity
`Given Name::
`Juan
`Family Name::
`Manteile
`City of Residence-
`Miami
`State or Province of
`FL
`Residence::
`Country of Residence::
`Street of mailing address::
`
`US
`10821 S.W. 92 Avenue
`
`4829-2360-3216.1
`
`Page # 1
`
`Initial 07/20/12
`
`0004 
`
`

`

`City of mailing address::
`State or Province of mailing
`address::
`Postal or Zip Code of mailing
`address::
`
`Miami
`FL
`
`33176
`
`Correspondence Information
`
`Correspondence Customer Number:: 22428
`PTOMailWashington@foley.com
`E-Mail address::
`
`Representative Information
`
`Representative Customer
`Number::
`
`22428
`
`Domestic Priority Information
`
`Application::
`
`Continuity Type::
`
`This Application
`
`Continuation of
`
`Foreign Priority Information
`
`Country::
`
`Application
`number::
`
`Assignee Information
`
`Parent
`Application::
`12/216,811
`
`Parent Filing
`Date::
`7/10/2008
`
`Filing Date::
`
`Priority Claimed::
`
`Assignee Name::
`
`NOVEN PHARMACEUTICALS, INC.
`
`4829-2360-3216.1
`
`Page # 2
`
`Initial 07/20/12
`
`0005 
`
`

`

`Attorney Docket No.: 041457-0857
`
`TRANSDERMAL ESTROGEN DEVICE AND DELIVERY
`
`FIELD OF THE INVENTION
`[0001] Described herein are compositions and methods for the transdermal delivery
`of estrogen.
`
`BACKGROUND
`[0002] This invention relates generally to transdermal drug delivery 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
`designed for 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.
`[0003] Transdermal delivery systems (adhesive patches) as dosage forms have been
`the subject of a vast number of patent applications over the last 25 years, yielding
`many patents 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 pharmacokinetic parameters to satisfy physician and
`patient demand is more daunting. Parameters to be considered during commercial
`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 amount of drug at a desired delivery rate over the intended duration of
`use, adequate adhesion at the anatomical site of application, integrity (e.g., minimal
`curling, wrinkling, delaminating and slippage) with minimal discomfort, 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 manufacturing and production aspects of commercial
`product development (e.g., the identity and costs of materials, equipment, and labor)
`
`0006 
`
`

`

`Attorney Docket No.: 041457-0857
`
`and supporting analytical methods required for regulatory compliance also can be
`significant.
`[0004] 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 transdermal drug delivery system that still exhibits
`acceptable pharmacokinetic properties. Still, because size directly impacts costs (e.g.,
`costs of component materials, costs of packaging materials, costs for production and
`manufacturing equipment, 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 systems.
`SUMMARY
`[0005]
`In accordance with one embodiment, there is provided 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/cm2 estradiol and achieves an estradiol flux that is greater than
`0.01 mg/cm2/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 present in a ratio of from about 1:2 to about 1:6, based on the
`total weight of the acrylic and silicone adhesives.
`
`0007 
`
`

`

`Attorney Docket No.: 041457-0857
`
`[0006]
`In some embodiments, the penetration enhancer comprises oleyl alchol or
`dipropylene glycol, or both.
`[0007]
`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 amount of estradiol effective to
`deliver an amount of estradiol selected from the group consisting of about 0.025,
`0.0375, 0.05, 0.075 and 0.1 mg/day.
`[0008]
`In some embodiments, the polymer matrix has a coat weight of greater than
`about 10 mg/cm2. In some embodiments, the polymer matrix has a coat weight
`selected from the group consisting of about 12.5 and about 15 mg/ cm2.
`[0009]
`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 cm2 and is effective to deliver an amount of
`estradiol per day of about 0.025, 0.0375, 0.05, 0.075 and 0.1 mg/day, respectively.
`(0010]
`In accordance with some embodiments, there is provided a method for
`administering estradiol, comprising applying to the skin or mucosa of 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/cm2 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 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 cm2 and is
`effective to deliver an amount of estradiol per day of about 0.025, 0.0375, 0.05, 0.075
`and 0.1 mg/day, respectively.
`[0011]
`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 polymer blend comprising an
`acrylic adhesive, a silicone adhesive, and soluble PVP, and applying the polymer
`matrix to a support layer such that the system includes greater than 0.156 mg/cm2
`
`•y
`
`0008 
`
`

`

`•
`
`•
`
`«
`
`Attorney Docket No.: 041457-0857
`
`0
`
`estradiol. 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 .
`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 polymer matrix is
`applied to the support layer at a coat weight of greater than about 10 mg/cm2. In some
`embodiments, the polymer matrix coat weight is selected from the group consisting of
`about 12.5 and about 15 mg/ cm2.
`
`BRIEF DESCRIPTION OF THE DRAWINGS
`
`[0012] Figure 1 illustrates the estradiol flux (fj.g/cm2/hr) over time (0-81 hours) from
`transdermal delivery systems according to the invention (A & •), as compared to
`Vivelle-Dot® (•).
`
`DETAILED DESCRIPTION
`[0013] The field 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 properties while
`remaining acceptable to patients. For example, when selecting the size of a
`transdermal delivery system, it is necessary to balance factors that 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
`Pharmaceutcials Inc.) is available in five different active surface areas (2.5, 3.75, 5.0,
`7.5 and 10.0 cm2) 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/cm2 estradiol.
`[0014]
`In accordance with some embodiments, the present invention 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
`
`0009 
`
`

`

`Attorney Docket No.: 041457-0857
`
`invention includes transdermal drug delivery systems that achieve daily dosages that
`are about equal to a Vivelle-Dot® product, in a smaller sized system. The ability to
`provide a smaller system without sacrificing daily dosage represents a significant
`advance.
`[0015] 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 development of smaller transdermal drug delivery systems that achieve
`comparable daily dosages. This result was surprising 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 known that increasing coat weight
`could increase delivery rate or flux, and thus permit the development of a smaller
`system while maintaining daily dosage.
`[0016]
`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 known estrogen devices
`(such as Vivelle-Dot®, manufactured by Noven Pharmaceutcials 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/cm2/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
`times the flux of the Vivelle-Dot® products. In some embodiments, the systems have
`a greater coat weight than other known estrogen devices. For example, in some
`embodiments, the systems have a coat weight such that the amount of estradiol per
`unit area is greater than the 0.156 mg/cm2 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 some
`aspects, the invention permits the use of smaller devices to achieve comparable drug
`delivery.
`DEFINITIONS
`{OOITJ Technical and scientific terms used herein have the meanings commonly
`understood by one of ordinary skill in the art to which the present invention pertains,
`unless otherwise defined. Reference is made herein to various methodologies known
`
`0010
`
`

`

`Attorney Docket No.: 041457-0857
`
`to 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
`reference in their entireties as though set forth in full. Any suitable materials and/or
`methods known to those of ordinary 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 reference is made in the following description and
`examples are obtainable from commercial sources, unless otherwise noted.
`[0018] 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.
`[0019] The term "about" and the use of ranges in general, whether or not qualified
`by the term about, means that the number comprehended is not limited to the exact
`number set forth herein, and is intended to 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 which it 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% of the particular term.
`[0020] 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 composition at issue, of the excluded component.
`[0021] 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.
`[0022] 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
`administered in a subject in need of such treatment. It is emphasized that a
`therapeutically effective amount or therapeutic level of a drug will not always be
`effective in treating the conditions/diseases described herein, even though such
`dosage is deemed to be a therapeutically effective amount by those of skill in the art.
`
`-6-
`
`0011
`
`

`

`Attorney Docket No.: 041457-0857
`
`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 practices as needed to treat a specific subject and/or condition/disease.
`[0023] As used herein, "active surface area" means the surface area of the drug-
`containing layer of the transdermal drug delivery system.
`[0024] As used 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.
`[0025] As used herein, "estrogen" includes estrogenic steroids such as estradiol
`(17-P-estradiol), estradiol benzoate, estradiol 17p-cypionate, estropipate, equilenin,
`equilin, estriol, estrone, ethinyl estradiol, conjugated estrogens, esterified estrogens,
`and mixtures thereof.
`[0026] 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 Pick's first
`law of diffusion:
`J = _D (dCm/dx)
`
`where J is the flux in g/cm2/sec, D is the diffusion coefficient of the drug through the
`skin or mucosa in cm2/sec and dCm/dx is the concentration gradient of the drug across
`the skin or mucosa.
`[0027] As used herein, the term "transdermal" refers to delivery, administration or
`application of a drug by means of direct contact with skin or mucosa. Such delivery,
`administration or application is also known as dermal, percutaneous, transmucosal
`and buccal. As used herein, "dermal" includes skin and mucosa, which includes oral,
`buccal, nasal, rectal and vaginal mucosa.
`[0028] As used herein, "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
`
`0012 
`
`

`

`Attorney Docket No.: 041457-0857
`
`adverse physiological response, and without being appreciably decomposed 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 transdermal 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 may be provided with separate adhesion means (such as a separate adhesive
`layer) for application and adherence to the user's skin.
`10029] 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 is an "adhesive" if it has the properties of an adhesive per 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
`pressure-sensitive adhesive polymer or a bioadhesive polymer, with estrogen
`dissolved or dispersed therein. The polymer matrix also may comprise tackifiers,
`plasticizers, crosslinking agents or other additives described herein. U.S. Patent
`6,024,976 describes polymer blends that are useful in accordance with the transdermal
`systems described herein. The entire contents of U.S. Patent 6,024,976 is
`incorporated herein by reference.
`[0030] As used herein, the term "pressure-sensitive adhesive" refers to a viscoelastic
`material which adheres instantaneously to most substrates with the application of very
`slight pressure and remains permanently tacky. A polymer is 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.
`[0031] The term pressure-sensitive adhesive also includes mixtures of different
`polymers and mixtures of polymers, such as polyisobutylenes (PIB), of different
`molecular weights, wherein each resultant mixture is a pressure-sensitive adhesive. In
`the last case, the polymers of lower molecular weight in the mixture are not
`
`- 8 -
`
`0013 
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`

`

`Attorney Docket No.: 041457-0857
`
`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.
`[0032]
`In some embodiments, the polymer matrix is a pressure-sensitive adhesive at
`room temperature and has other desirable characteristics for adhesives used in the
`transdermal drug delivery art. Such characteristics include good adherence 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 (Tg), measured using a differential scanning calorimeter,
`of between about -70 0C. and 0 0C.
`[00331 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 contains at least one natural or synthetic elastomeric polymer.
`[0034]
`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 transdermal drug delivery system is monolithic,
`meaning that it comprises a single polymer matrix layer comprising a pressure-
`sensitive adhesive or bioadhesive with drug dissolved or dispersed therein, and no
`rate-controlling membrane.
`[0035] The transdermal drug delivery system also may include a drug impermeable
`backing layer or film. In some embodiments, the backing layer is adjacent one face of
`the polymer matrix layer. When present, the backing layer protects the polymer
`matrix layer (and any other layers present) from the environment and prevents loss of
`the drug and/or release of other components to the environment during vise. Materials
`suitable for use as backing layers are well-known known in 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 laminates. A typical backing material has a
`thickness in the range of 2 to 1000 micrometers.
`[0036] 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
`
`-9-
`
`0014 
`
`

`

`Attorney Docket No.: 041457-0857
`
`expose the polymer matrix layer and/or an adhesive layer prior to topical application.
`Materials suitable for use as release liners are well-known known in the art and
`include the commercially available products of Dow Coming Corporation designated
`Bio-Release® liner and Syl-off® 7610 and 3M's 1022 Scotch Pak.
`[0037] A used herein, a "monolithic" transdermal drug delivery system may include
`a backing layer and/or release liner.
`[0038]
`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
`
`[0039] 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, plasticizers, crosslinking agents or other
`additives.
`[0040] The acrylic polymer can include copolymers, terpolymers and
`multipolymers. For example, the acrylic polymer can be any of the homopolymers,
`copolymers, terpolymers, and the like of various acrylic acids. In some embodiments,
`the acrylic polymer constitutes from about 2% to about 95% by weight of the polymer
`content of the polymer matrix, including about 3% to about 90% find about 5% to
`about 85%, such as 2% to 95%, 3% to 90% and 5% to 85%. In some embodiments,
`the amount and type of acrylic polymer is dependent on the type and amount of
`estrogen used.
`[0041] Acrylic polymers useful in practicing the invention include polymers of one
`or more monomers of acrylic acids and other copolymerizable monomers. The acrylic
`polymers also include copolymers of alkyl acrylates and/or methacrylates and/or
`copolymerizable secondary monomers or monomers with functional groups.
`Combinations of acrylic-based polymers based on their functional groups is also
`contemplated. Acrylic-based polymers having functional groups include copolymers
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`and terpolymers which contain, in addition to nonfunctional monomer units, further
`monomer units having free functional groups. The monomers can be monofunctional
`or polyfunctional. By varying the amount of each type of monomer added, the
`cohesive properties of the resulting acrylic polymer can be changed as is known in the
`art. In some embodiments, the acrylic polymer is composed of at least 50% by weight
`of an acrylate or alkyl acrylate monomer, from 0 to 20% of a functional monomer
`copolymerizable with the acrylate, and from 0 to 40% of other monomers.
`[0042] Acrylate monomers which can be used include acrylic acid and methacrylic
`acid and alkyl acrylic or methacrylic esters such as methyl acrylate, ethyl acrylate,
`propyl acrylate, amyl acrylate, butyl acrylate, butyl methacrylate, hexyl acrylate,
`hexyl methacrylate, heptyl acrylate, octyl acrylate, nonyl acrylate, 2-ethylbutyl
`acrylate, 2-ethylbutyl methacrylate, isooctyl acrylate, isooctyl methacrylate, 2-
`ethylhexyl acrylate, 2-ethylhexyl methacrylate, decyl acrylate, decyl methacrylate,
`dodecyl acrylate, dodecyl methacrylate, tridecyl acrylate, tridecyl methacrylate,
`glycidyl acrylate, and corresponding methacrylic esters.
`[0043] Non-functional acrylic-based polymers can include any acrylic based
`polymer having no or substantially no free functional groups.
`[0044] Functional monomers, copolymerizable with the above alkyl acrylates or
`methacrylates, which can be used include acrylic acid, methacrylic acid, maleic acid,
`maleic anhydride, hydroxyethyl acrylate, hydroxypropyl acrylate, acrylamide,
`dimethylacrylamide, acrylonitrile, dimethylaminoethyl acrylate, dimethylaminoethyl
`methacrylate, tert-butylaminoethyl acrylate, tert-butylaminoethyl methacrylate,
`methoxyethyl acrylate and methoxyethyl methacrylate.
`[0045] As used herein, "functional monomers or groups," are monomer units
`typically in acrylic-based polymers which have reactive chemical groups which
`modify the acrylic-based polymers directly or which provide sites for further
`reactions. Examples of functional groups include car boxy 1, epoxy, hydroxyl,
`sulfoxyl, and amino groups. Acrylic-based polymers having functional groups
`contain, in addition to the nonfunctional monomer units described above, further
`monomer units having free functional groups. The monomers can be monofunctional
`or polyfunctional. These functional groups include carboxyl groups, hydroxy groups,
`amino groups, amido groups, epoxy groups, etc. Typical carboxyl functional
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`monomers include acrylic acid, methacrylic acid, itaconic acid, maleic acid, and
`crotonic acid. Typical hydroxy functional monomers include 2-hydroxyethyl
`methacrylate, 2-hydroxyethyl acrylate, hydroxymethyl acrylate, hydroxymethyl
`methacrylate, hydroxyethyl acrylate, hydroxyethyl methacrylate, hydroxypropyl
`acrylate, hydroxypropyl methacrylate, hydroxybutyl acrylate, hydroxybutyl
`methacrylate, hydroxyamyl acrylate, hydroxyamyl methacrylate, hydroxyhexyl
`acrylate, hydroxyhexyl methacrylate. As noted above, in some embodiments, the
`acrylic polymer does not include such functional groups.
`[0046] Further details and examples of acrylic adhesives which are suitable in the
`practice of the invention are described in Satas, "Acrylic Adhesives," Handbook of
`Pressure-Sensitive Adhesive Technology, 2nd ed., pp. 396-456 (D. Satas, ed.). Van
`Nostrand Reinhold, New York (1989); "Acrylic and Methacrylic Est