(19) United States
`(12) Patent Application Publication (10) Pub. No.: US 2006/0078601 A1
`(43) Pub. Date: Apr. 13, 2006
`
`Kanios et al.
`
`US 20060078601Al
`
`(54) COMPOSITIONS AND METHODS FOR
`DELIVERING ESTRADIOL IN
`TRANSDERMAL DRUG DELIVERY
`SYSTEMS
`
`(75)
`
`Inventors: David Kanios, Miami, FL (US); Rod
`Hartwig, Miami, FL (US)
`
`Correspondence Address:
`DICKSTEIN SHAPIRO MORIN & OSHINSKY
`LLP
`2101 L Street, NW
`Washington, DC 20037 (US)
`
`(73) Assignee: Noven Pharmaceuticals, Inc.
`
`(21) Appl. No.:
`
`11/245,084
`
`(22)
`
`Filed:
`
`Oct. 7, 2005
`
`Related US. Application Data
`
`(60) Provisional application No. 60/616,862, filed on Oct.
`8, 2004.
`
`Publication Classification
`
`(51)
`
`Int. Cl.
`(2006.01)
`A61K 9/70
`(52) US. Cl.
`.............................................................. 424/449
`
`(57)
`
`ABSTRACT
`
`A blend of at least two polymers in combination with a drug
`provides a pressure-sensitive adhesive composition for a
`transdermal drug delivery system in which the drug is
`delivered from the pressure-sensitive adhesive composition
`and through dermis when the pressure-sensitive adhesive
`composition is in contact with human skin.
`
`  
`
`

 
`
`MYLAN - EXHIBIT 1029
`
`

`

`Patent Application Publication Apr. 13, 2006 Sheet 1 of 2
`
`US 2006/0078601 A1
`
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`Patent Application Publication Apr. 13, 2006 Sheet 2 of 2
`
`US 2006/0078601 A1
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`US 2006/0078601 A1
`
`Apr. 13, 2006
`
`COMPOSITIONS AND METHODS FOR
`DELIVERING ESTRADIOL IN TRANSDERMAL
`DRUG DELIVERY SYSTEMS
`
`[0001] This application claims the benefit of provisional
`application 60/616,862 filed Oct. 8, 2004, which is hereby
`incorporated by reference in its entirety.
`
`FIELD OF THE INVENTION
`
`[0002] This invention relates generally to transdermal
`drug delivery systems, and more particularly to pharmaceu-
`tically acceptable adhesive matrix compositions. The inven-
`tion additionally relates to transdermal drug delivery sys-
`tems providing substantially zero order drug release profiles
`for an extended period of time of up to seven days or longer.
`
`BACKGROUND OF THE INVENTION
`
`[0003] The present invention relates to transdermal deliv-
`ery systems, their method of making and method of use. In
`particular, the present invention is directed to a transdermal
`drug delivery system for the topical application of one or
`more active agents contained in one or more polymeric
`and/or adhesive carrier layers, proximate to a non-drug
`containing polymeric and/or adhesive coating that is applied
`to either the transdermal system’s backing or release liner.
`The adhesive coated backing or release liner may be pro-
`cessed or manufactured separately from the polymeric and/
`or adhesive drug carrier layers when drug loss or other
`system concerns are prevalent, and combined prior to topical
`application. The drug delivery rate and profile can be further
`controlled by adjusting certain characteristics of the poly-
`mers and/or adhesives themselves or of the method of
`
`making the system, relative to the active agent’s properties
`in this transdermal system.
`
`BACKGROUND OF THE INVENTION
`
`[0004] The use of a transdermal drug delivery system as a
`means for administering therapeutically effective amounts
`of an active agent is well known in the art. Transdermal
`devices or systems can be categorized in many different
`ways, but
`those commonly called transdermal patches,
`incorporate the active agent into a carrier, usually a poly-
`meric and/or a pressure-sensitive adhesive fonnulation.
`
`[0005] Many factors influence the design and performance
`of such drug delivery devices, such as the individual drugs
`themselves, the physical/chemical characteristics of the sys-
`tem’s components themselves and their performance/behav-
`ior relative to other system components once combined,
`external/environmental conditions during manufacturing
`and storage thereafter, the properties of the topical site of
`application, the desired rate of drug delivery and onset, the
`drug delivery profile, and the intended duration of delivery.
`Cost, appearance, size and ease of manufacturing are also
`important considerations. The ability to deliver a therapeu-
`tically eflective amount of the drug in accordance with the
`intended therapy or treatment is the goal.
`
`[0006] The simplest in design is one in which the drug is
`incorporated into a pressure-sensitive adhesive carrier layer,
`each surface of which is aflixed to a polymeric film/layeri
`one serving as the backing (to anchor the carrier layer and
`control passage of environmental influences in and system
`components out during use) and the other serving as a
`
`removable liner (to protect the carrier layer prior to use but
`removed upon topical application of the carrier layer).
`However, when addressing all the design and performance
`factors and considerations to achieve the goal, this system
`alone cannot always provide the best method.
`
`In this regard, a drug’s delivery rate is affected by
`[0007]
`its degree of saturation and solubility in the carrier compo—
`sition. Depending on the active agent itself or the dosage
`necessary to be therapeutically effective, the amount of drug
`needed to be incorporated into a single, adhesive carrier or
`matrix composition (i.e., drug loading) can adversely affect
`or be adversely affected by, such carrier or matrix.
`
`[0008] Drug carrier compositions typically require one or
`more processing solvents, usually organic solvents, in which
`to incorporate the active agent and/or allow the polymeric/
`adhesive carrier to be more easily coated onto a backing or
`release liner. Removal of such solvents is necessary for
`avoiding problems associated with residual solvent amounts,
`such as irritation at
`the topical site of application, drug
`degradation, drug instability, loss of adhesive or cohesive
`properties impacting attachment of the system to the user
`and loss of desired delivery amount or rate. Solvent removal
`requires that elevated temperatures be applied to the carrier
`composition to evaporate such solvents. But at the same
`time, removal of solvents by use of elevated temperatures
`can also remove or evaporate other desirable components,
`such as the active agent and drug permeation enhancers.
`Their loss can even occur at temperatures below which such
`components may otherwise volatilize by virtue of their
`interaction with each other and with the other carrier com-
`ponents (relative volatility or reactivity).
`
`[0009] Transdermal carrier compositions based on acrylic
`pressure-sensitive adhesive polymers are often preferred for
`their ability to incorporate or solubilize many drugs. In order
`to provide for adequate wear properties and drug release
`from the composition, acrylic-based pressure-sensitive
`adhesives are typically polymerized with functional mono-
`mers to provide functional groups on the acrylic-based
`adhesive. A problem associated with the use of such acrylic-
`based polymers with functional groups is that due to the
`generally high solubility of the drug, a large amount of drug
`generally must be incorporated into the composition to
`saturate it and provide an adequate drug release to the skin
`of the user. In use with low molecular weight drugs or
`controlled substances, the loss of the drug in the manufac-
`turing process again can be a significant problem.
`
`[0010] Attempts have been made to utilize rate controlling
`membranes and/or multiple layers, and to dissolve or sus-
`pend certain drugs in thermoplastic type carrier composi-
`tions without
`the use of solvents. These drug delivery
`devices generally do not allow a great amount of flexibility
`in effectively controlling the release rate of a variety of
`drugs, which in turn also severely limits their therapeutic
`application, and are expensive or burdensome to manufac-
`ture. Moreover, multiple adhesive layers are often required
`to aflix the other layers or membranes to each other, and/or
`to the site of topical application.
`
`[0011] Thus, it would therefore be desirable to provide a
`system for use with many types of drugs,
`in which the
`permeation rate and profile can be easily adjusted while
`providing an active agent-containing carrier composition
`formulated in a simple and cost effective manner.
`
`

`

`US 2006/0078601 A1
`
`Apr. 13, 2006
`
`SUMMARY OF THE INVENTION
`
`[0012] Based upon the foregoing, it is an object of the
`present invention to overcome the limitations of the prior
`transdermal systems, and to provide a transdermal drug
`delivery system which allows selective modulation of drug
`permeation and delivery rates and profiles.
`
`[0013] Another object is to provide a transdermal system,
`which is simple and inexpensive to manufacture, while
`preventing or minimizing drug loss and/or other volatile
`components in the composition. The present invention pro-
`vides a transdermal drug delivery system for the topical
`application of one or more active agents contained in one or
`more polymcric and/or adhcsivc carricr laycrs, proximate to
`a non-drug containing polymeric and/or adhesive coating
`that is applied to either the transdermal system’s backing or
`release liner, manufactured to optimize drug loading while
`providing desirable adhesion to skin or mucosa as well as
`providing modulation of the drug delivery and profile.
`
`[0014] The invention is further directed to a transdermal
`delivery system comprising a backing composite comprising
`a non-drug containing polymeric and/or adhesive coating
`affixed or applied to a drug-impermeable layer. An active
`agent carrier layer comprising a pressure-sensitive adhesive
`composition and a drug incorporated therein, which may
`also contain low boiling point or volatile components such
`as permeation enhancers, is affixed to the backing compos-
`ite. The polymeric coating is designed to provide control of
`permeation rate, onset and profile of the active agent from
`the system. The agent-carrier composition may comprise
`one or more layers. The agent-carrier composition may
`comprise at least one layer formed of a blend of at least one
`acrylic-based polymer and at least one silicone-based poly-
`mer, to serve as a pressure-sensitive adhesive composition
`for applying the system to the dermis, or a blend of acrylic-
`based polymers. The non-drug containing acrylic-based or
`other polymer coating designed to interact with the drug
`composition layer(s).
`
`[0015] The invention is also directed to compositions and
`methods of controlling drug delivery rates, onset and pro-
`files of at least one active agent in a transdermal delivery
`system, comprising the use of a non-drug containing acrylic-
`based polymer and/or adhesive coating one surface of which
`is applied to either the transdermal system’s backing or
`release liner and the other surface is affixed to a drug
`containing carrier composition layer, wherein the delivery
`rate, onset of delivery (lag time) and delivery profile of a
`drug may be selectively modulated by one or more of (a)
`increasing or decreasing the thickness or coat weight of the
`acrylic—based polymer and/or adhesive coating per cm2 as
`applied to the backing or release liner of the system or (b)
`manipulating the moiety or functionality of the acrylic-based
`polymer and/or adhesive coating. Either the non-drug con-
`taining coating or the carrier composition must also be a
`pressure-sensitive adhesive when used as area of attachment
`to the skin or mucosa of the user. The drug carrier compo-
`sition may be comprised of (a) one or more acrylic-based
`polymers having one or more functionality or (b) one or
`more silicone-based polymers having one or more silanol
`contents (capping) and/or resin to polymer ratios, alone or in
`combination, and are present in proportions to provide a
`desired solubility for the drug. Further manipulation of drug
`delivery, onset and profiles can be achieved by varying the
`concentrations of the drug in the drug-loaded carrier.
`
`[0016] For a better understanding of the present invention,
`together with other and further objects thereof, reference is
`made to the following description, taken in conjunction with
`the accompanying drawings, and its scope will be pointed
`out in the appending claims.
`
`BRIEF DESCRIPTION OF THE DRAWINGS
`
`[0017] FIG. 1 shows a schematic cross-sectional view of
`a transdermal delivery device according to an embodiment
`of the invention prior to use.
`
`[0018] FIG. 2 shows a schematic cross-section of the
`agent-carrier assembly and backing assembly according to
`the embodiment of the present invention as shown in FIG.
`1, prior to lamination together.
`
`[0019] FIG. 3 is a graphic representation of the effects on
`drug delivery, onset and profile of estradiol with different
`functionalities/moieties of acrylic-based adhesives in the
`polymeric coating.
`
`[0020] FIG. 4 is a graphic representation of the effects on
`drug delivery, onset and profile of estradiol with varying
`coat weights of an acrylic-based adhesive coating.
`
`DETAILED DESCRIPTION OF THE
`PREFERRED EMBODIMENTS
`
`In the following description, embodiments of the
`[0021]
`invention are set forth, and terms are used in describing such
`embodiments, wherein:
`
`[0022] The term “topical” or “topically” is used herein in
`its conventional meaning as referring to direct contact with
`an anatomical site or surface area on a mammal including
`skin, teeth, nails and mucosa.
`
`[0023] The term “mucosa” as used herein means any moist
`anatomical membrane or surface on a mammal such as oral,
`buccal, vaginal, rectal, nasal or ophthalmic surfaces. Simi-
`larly, “skin” is meant to include mucosa, which further
`includes oral, buccal, nasal, rectal and vaginal mucosa.
`
`[0024] The term “transdermal” refers to delivery, admin-
`istration or application of a drug by means of direct contact
`with tissue, such as skin or mucosa. Such delivery, admin-
`istration or application is also known as percutaneous,
`dermal, transmucosal and buccal.
`
`[0025] As used herein, the terms “blend” and “mixture”
`are used herein to mean that there is no, or substantially no,
`chemical
`reaction or crosslinking (other
`than simple
`H-bonding) between the different polymers in the polymer
`matrix. However, crosslinking between a single polymer
`component is fully contemplated to be within the scope of
`the present invention.
`
`[0026] The term “adhesive” means a substance, inorganic
`or organic, natural or synthetic that is capable of surface
`attachment at the intended topical application site by itself or
`functions as an adhesive by admixture with tackifiers, plas-
`ticizers, cross-linking agents or other additives. In the most
`preferred embodiment, the carrier of the present invention is
`a “pressure-sensitive adhesive” which refers to a viscoelastic
`material which adheres instantaneously to most substrates
`with the application of very slight pressure and remains
`permanently tacky. A polymer or dermal composition is a
`pressure-sensitive adhesive within the meaning of the term
`
`

`

`US 2006/0078601 A1
`
`Apr. 13, 2006
`
`as used herein if it has the adhesive properties of a pressure-
`sensitive adhesive per se or functions as a pressure-sensitive
`adhesive by admixture with tackifiers, plasticizers, cross-
`linking agents or other additives.
`
`[0027] As used herein, a “polymer composition of two or
`more polymers” is defined as a physical blend of at least two
`polymers and can include 3 or more polymers. The two or
`more polymers may include the acrylic-based polymers
`described herein and can optionally include other polymers
`discussed more fully below.
`
`[0028] The term “acrylic-based” polymer is defined as any
`polyacrylate, polyacrylic, acrylate and acrylic polymer. The
`acrylic-based polymers can be any of the homopolymers,
`copolymers, terpolymers, and the like of various acrylic
`acids or esters. The acrylic-based polymers useful in prac-
`ticing the invention are polymers of one or more monomers
`of acrylic acids and other copolymerizable monomers. The
`acrylic-based polymers also include copolymers of alkyl
`acrylates and/or methacrylates and/or copolymerizable sec-
`ondary monomers. Acrylic-based polymers with functional
`groups as described more fully below, are copolymerized
`with functional monomers.
`
`[0029] As used herein, “functionality” is broadly defined
`as a measure of the type and quantity of functional groups
`that a particular acrylic-based polymer has.
`
`[0030] As used herein, “functional monomers or groups,”
`are monomer units in acrylic-based polymers which have
`reactive chemical groups which modify the acrylic-based
`polymers directly or provide sites for further reactions.
`Examples of functional groups include carboxyl, epoxy and
`hydroxy groups.
`
`[0031] As used herein “non-functional acrylic-based poly-
`mer” is defined as an acrylic-based polymer that has no or
`substantially no functional reactive moieties present in the
`acrylic. These are generally acrylic esters which can be
`copolymerized with other monomers which do not have
`functional groups, such as vinyl acetate.
`
`[0032] The term “carrier” as used herein refers to any
`non-aqueous material known in the art as suitable for
`transdermal drug delivery administration, and includes any
`polymeric material
`into which an active agent may be
`solubilized in combination or admixture with the other
`
`ingredients of the composition. The polymeric materials
`preferably comprise adhesives and, in particular, pressure-
`sensitive adhesives. The carrier material is typically used in
`an amount of about 40% to about 95%, and preferably from
`about 50% to about 80%, by weight based on the dry weight
`of the total carrier composition.
`
`[0033] The term “carrier composition” may also refer to
`enhancers, solvents, co-solvents and other types of additives
`useful for facilitating transdermal drug delivery.
`
`[0034] The carrier compositions of the present invention
`can also contain one or more non-aqueous solvents and/or
`co-solvents. Such solvents and/or co-solvents are those
`
`known in the art, and are non-toxic, pharmaceutically
`acceptable substances, preferably non-aqueous
`liquids,
`which do not substantially negatively affect the adhesive
`properties or the solubility of the active agents at
`the
`concentrations used. The solvent and/or co-solvent can be
`
`for the active agent or for the carrier materials, or both.
`
`[0035] Suitable solvents include volatile processing liq-
`uids such as alcohols (e.g., methyl, ethyl, isopropyl alcohols
`and methylene chloride); ketones (e.g., acetone); aromatic
`hydrocarbons such as benzene derivatives (e.g., xylenes and
`toluenes); lower molecular weight alkanes and cycloalkanes
`(e.g., hexanes, heptanes and cyclohexanes); and alkanoic
`acid esters (e.g., ethyl acetate, n-propyl acetate,
`isobutyl
`acetate, n-butyl acetate isobutyl isobutyrate, hexyl acetate,
`2-ethylhexyl acetate or butyl acetate); and combinations and
`mixtures thereof. Other suitable co-solvents include poly-
`hydric alcohols, which include glycols, triols and polyols
`such as ethylene glycol, diethylene glycol, propylene glycol,
`dipropylene glycol,
`trimethylene glycol, butylene glycol,
`polyethylene glycol, hexylene glycol, polyoxethylene, glyc-
`erin, trimethylpropane, sorbitol, polyvinylpyrrolidone, and
`the like. Alternatively, co-solvents may include glycol ethers
`such as ethylene glycol monoethyl ether, glycol esters,
`glycol ether esters such as ethylene glycol monoethyl ether
`acetate and ethylene glycol diacetate; saturated and unsat-
`urated fatty acids, mineral oil, silicone fluid, lecithin, retinol
`derivatives and the like, and ethers, esters and alcohols of
`fatty acids. As will be described in more detail hereafter, the
`solvents or co-solvents used in accordance with the inven-
`
`tion are desirably a low volatile solvent that does not require
`excessive temperatures for evaporation thereof.
`
`[0036] The term “solubilized” is intended to mean that in
`the carrier composition there is an intimate dispersion or
`dissolution of the active agent at the crystalline, molecular
`or ionic level, such that crystals of the active agent cannot
`be detected using a microscope having a magnification of
`25x. As such, the active agent is considered herein to be in
`“non-crystallized” form when in the compositions of the
`present invention.
`
`[0037] As used herein “flux” is defined as the percutane-
`ous absorption of drugs through the skin, and is described by
`Fick’s first law of diffusion:
`
`J=—D(de/dx),
`
`[0038] where J is the flux in g/cmZ/sec, D is the diffusion
`coefficient of the drug through the skin in cmZ/sec and
`de/dx is the concentration gradient of the active agent
`across the skin or mucosa.
`
`[0039] As used herein, “therapeutically effective” means
`an amount of an active agent that is sufficient to achieve the
`desired local or systemic effect or result, such as to prevent,
`cure, diagnose, mitigate or treat a disease or condition, when
`applied topically over the duration of intended use. The
`amounts necessary are known in the literature or may be
`determined by methods known in the art, but typically range
`from about 0.1 mg to about 20,000 mg, and preferably from
`about 0.1 mg to about 1,000 mg, and most preferably from
`about 0.1 to about 500 mg per human adult or mammal of
`about 75 kg body weight per 24 hours.
`
`[0040] 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 not departing from the scope of the
`invention.
`
`[0041] The term “user” or “subject” is intended to include
`all warm-blooded mammals, preferably humans.
`
`

`

`US 2006/0078601 A1
`
`Apr. 13, 2006
`
`[0042] Unless defined otherwise, all technical and scien-
`tific terms used herein have the same meaning as commonly
`understood by one of ordinary skill in the art to which the
`invention pertains. Although any methods and materials
`similar or equivalent to those described herein can be used
`in the practice for testing of the present
`invention,
`the
`preferred materials and methods are described herein.
`
`[0043] Referring to FIG. 1, the most preferred embodi-
`ment of the invention, transdermal drug delivery system 10
`comprises a carrier composition layer 12 incorporating the
`active agent. Surface 14 of the adhesive carrier composition
`layer 12 is affixed to release liner 15 to protect the carrier
`layer prior to use but which is removed upon topical
`application of the carrier layer to the skin or mucosa of the
`user. A non-drug containing polymeric and/or adhesive
`coating 18 is affixed to backing 20 on one surface, with the
`other surface being affixed to carrier composition layer 12.
`Backing composite 16 comprises coating 18 affixed to
`backing 20, which as described later, is made or processed
`separately from carrier composition layer 12 affixed to
`release liner 15.
`
`[0044] Carrier composition layer 12 can comprise any
`polymer or adhesive generally known in the art for formu-
`lating a drug carrier composition, and include all of the
`non-toxic natural and synthetic polymers known or suitable
`for use in transdermal systems including solvent-based, hot
`melt and grafted adhesives, and may be used alone or in
`combinations, mixtures or blends. Examples include acrylic-
`based,
`silicone-based,
`rubbers, gums, polyisobutylenes,
`polyvinylethers, polyurethanes, styrene block copolymers,
`styrene/butadiene polymers, polyether block amide copoly-
`mers, ethylene/vinyl acetate copolymers, and vinyl acetate
`based adhesives, and bioadhesives set forth in U.S. Pat. No.
`6,562,363 which is expressly incorporated by reference in its
`entirety.
`
`[0045] The term “silicone-based” polymer is intended to
`be used interchangeably with the terms siloxane, polysilox-
`ane, and silicones as used herein and as known in the art. The
`silicone-based polymer may also be a pressure-sensitive
`adhesive, with a polysiloxane adhesive prepared by cross-
`linking an elastomer,
`typically a high molecular weight
`polydiorganosiloxane, with a resin,
`to produce a three-
`dimensional siloxane structure, via a condensation reaction
`in an appropriate organic solvent. The ratio of resin to
`elastomer is a critical factor that can be adjusted in order to
`modify the physical properties of polysiloxane adhesives.
`Sobieski, et al., “Silicone Pressure Sensitive Adhesives,”
`Handbook of Pressure-Sensitive Adhesive Technology. 2nd
`ed., pp. 508-517 (D. Satas, ed.), Van Nostrand Reinhold,
`New York (1989). Further details and examples of silicone
`pressure-sensitive adhesives which are useful in the practice
`of this invention are described in the following U.S. Pat.
`Nos. 4,591,622; 4,584,355; 4,585,836; and 4,655,767, all
`expressly incorporated by reference in their entireties. Suit-
`able silicone pressure-sensitive adhesives are commercially
`available and include the silicone adhesives sold under the
`
`trademarks BIO-PSA® by Dow Corning Corporation,
`Medical Products, Midland, Mich. (such as -2685, -3027,
`-3122,
`-4101,
`-4102,
`-4203, -4301, -4302, -4303,
`-4401
`-4403,
`-4501,
`-4503,
`-4602,
`-4603 and -4919). Capped
`silicones with high resin content are preferred.
`
`In the practice of the preferred embodiments of the
`[0046]
`invention,
`the acrylic-based polymer can be any of the
`
`homopolymers, copolymers, terpolymers, and the like of
`various acrylic acids. In such preferred embodiments, the
`acrylic-based polymer constitutes from about 2% to about
`95% of the total dry weight of the of the carrier composition,
`and preferably from about 2% to about 90%, and more
`preferably from about 2% to about 85%, wherein the amount
`of the acrylic-based polymer is dependent on the amount and
`type of drug used.
`[0047] The acrylic-based polymers usable in the invention
`are polymers of one or more monomers of acrylic acids and
`other copolymerizable monomers. The acrylate polymers
`also include copolymers of alkyl acrylates and/or methacry-
`lates and/or copolymerizable secondary monomers or mono-
`mers with functional groups. By varying the amount of each
`type of monomer added,
`the cohesive properties of the
`resulting acrylate polymer can be changed as is known in the
`art. In general, the acrylate 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.
`[0048] Acrylate monomers which can be used include
`acrylic acid, methacrylic acid, methyl acrylate, methyl meth-
`acrylate,butyl acrylate, butyl methacrylate, hexyl acrylate,
`hexyl methacrylate, 2-ethylbutyl
`acrylate, 2-ethylbutyl
`methacrylate, isooctyl acrylate, isooctyl methacrylate, 2-eth-
`ylhexyl acrylate, 2-ethylhexyl methacrylate, decyl acrylate,
`decyl methacrylate, dodecyl acrylate, dodecyl methacrylate,
`tridecyl acrylate, and tridecyl methacrylate.
`[0049] 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, dimethy-
`laminoethyl acrylate, dimethylaminoethyl methacrylate,
`tert-butylaminoethyl acrylate,
`tert-butylaminoethyl meth-
`acrylate, methoxyethyl acrylate and methoxyethyl meth-
`acrylate.
`[0050] Suitable acrylic-based polymers may also be a
`pressure-sensitive adhesive which are commercially avail-
`able and include the acrylic-based adhesives sold under the
`trademarks Duro-Tak® by National Starch and Chemical
`Corporation, Bridgewater, N]. (such as 87-2287, -4098,
`-2852, -2196, -2296, -2194, -2516, -2070, -2353, -2154,
`-2510, -9085, -9088 and 73-9301). Other suitable acrylic-
`based adhesives include those sold by Cytec Surface Spe-
`cialties, St. Louis, Mo., under the trademarks Gelva® Mul-
`tipolymer Solution (such as 2480, 788, 737, 263, 1430,
`1753, 1151, 2450, 2495, 3087 and 3235) and those under the
`trademark Eudragit® by Roehm Pharma GmbH, Darrnstadt,
`Federal Republic of Germany.
`[0051] The carrier composition may comprise blends of
`acrylic-based polymers, silicone-based polymers and rub-
`bers based upon their differing solubility parameters, alone
`or in combination with other polymers, for example poly-
`vinylpyrrolidone, as more fully described in U.S. Pat. Nos.
`5,474,783; 5,656,286; 5,958,446; 6,024,976; 6,221,383; and
`6,235,306; which are incorporated herein in their entirety.
`The amount of each polymer is selected to adjust
`the
`saturation concentration of the drug in the multiple polymer
`system, and to result in the desired rate of delivery of the
`drug from the system and through the skin or mucosa.
`[0052] Combinations of acrylic-based polymers based on
`their functional groups is also contemplated. Acrylic-based
`
`

`

`US 2006/0078601 A1
`
`Apr. 13, 2006
`
`polymers having functional groups are copolymers or ter-
`polymers which contain in addition to nonfunctional mono-
`mer units, further monomer units having free functional
`groups. The monomers can be monofunctional or polyfunc-
`tional. These functional groups include carboxyl groups,
`hydroxy groups, amino groups, amido groups, epoxy
`groups, etc. Preferred functional groups are carboxyl groups
`and hydroxy groups. Preferred carboxyl functional mono-
`mers include acrylic acid, methacrylic acid, itaconic acid,
`maleic acid, and crotonic acid. Preferred hydroxy functional
`monomers
`include 2-hydroxyethyl methacrylate, 2-hy-
`droxyethyl acrylate, hydroxymethyl acrylate, hydroxym-
`ethyl methacrylate, hydroxyethyl acrylate, hydroxyethyl
`methacrylate, hydroxypropyl acrylate, hydroxypropyl meth-
`acrylate, hydroxybutyl acrylate, hydroxybutyl methacrylate,
`hydroxyamyl acrylate, hydroxyamyl methacrylate, hydroxy-
`hexyl acrylate, hydroxyhexyl methacrylate. Non-functional
`acrylic-based polymers can include any acrylic based poly-
`mer having no or substantially no free functional groups.
`The acrylic based polymer can include homopolymers,
`copolymers and terpolymers. The monomers used to pro-
`duce the polymers can include alkyl acrylic or methacrylic
`esters such as methyl acrylate, ethyl acrylate, propyl acry-
`late, amyl acrylate, butyl acrylate, 2-ethylbutyl acrylate,
`hexyl acrylate, heptyl acrylate, octyl acrylate, nonyl acry-
`late, 2—ethylhexyl acrylate, decyl acrylate, dodecyl acrylate,
`tridecyl acrylate, glycidyl acrylate and the corresponding
`methacrylic esters.
`
`[0053] Both the acrylic-based polymer having substan-
`tially no functional groups and acrylic-based polymers hav-
`ing functional groups can optionally include further modi-
`fying monomers. These modifying monomers can include
`any conceivable monomer that is capable of undergoing
`vinyl polymerization. For example,
`the incorporation of
`styrene monomers can be used to increase the glass transi-
`tion temperature and are sometimes used to improve the
`cohesive strength. The copolymerization of vinyl acetate
`monomers with acrylic esters are also used to form acrylic-
`based polymers. Ethylene can also be copolymerized with
`acrylic esters and vinyl acetate to give suitable acrylic-based
`polymers.
`
`[0054] For example, a composition will require less of a
`functional acrylic that contains 20% by weight of functional
`groups as opposed to one that contains 0.5% by weight of
`functional groups to achieve the same effect required for
`solubility and flux. Broadly speaking, the amount of func-
`tional acrylic is generally within the range of about 1 to 99
`weight % and preferably 5 to 95 weight %, more preferably
`20 to 75 weight %, even more preferably 30 to 65 weight %,
`based on the total polymer content of the transdermal
`composition. The amount of non-functional acrylic or
`acrylic with a functional group which does not have as great
`of an affinity for the drug, is within the range of about 99 to
`1 weight %, preferably 95 to 5 weight %, more preferably 75
`to 20 weight % and even more preferably 30 to 65 weight %,
`based on the total polymer content of the composition.
`
`[0055] Further details and examples of acrylic-based
`adhesives, functional monomers, and polymers which have
`no functional groups and 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,
`NY. (1989); “Acrylic and Methacrylic Ester Polymers,”
`
`1, 2nd ed., pp
`Polymer Science and Engineering, Vol.
`234-268, John Wiley & Sons, (1984); US. Pat. No. 4,390,
`520; and US. Pat. No. 4,994,267 all ofwhich are expressly
`incorporated by reference in their entireties.
`
`[0056] The required proportions of acrylic-based or other
`polymers used are generally dependant on the specific drug,
`its desired