PCT
`INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)
`WO 95/24172
`
`WORLD INTELLECfUAL PROPERTY ORGANIZATION
`International Bureau
`
`(51) International Patent Classification 6:
`A61F 13/02, A61L 15/16
`
`(11) International Publication Number:
`
`A1
`
`(43) International Publication Date:
`
`14 September 1995 (14.09.95)
`
`(21) International Application Number:
`
`PCT/US95/00609
`
`(22) International Filing Date:
`
`17 January 1995 (17.01.95)
`
`(81) Designated States: AU, CA, CN, JP, KR, MX, European
`patent (AT, BE, CH, DE, DK, ES, FR, GB, GR, IE, IT,
`LU, MC, NL, PT, SE).
`
`'.
`
`(30) Priority Data:
`08/207,786
`
`7 March 1994 (07.03.94)
`
`Published
`With international search report.
`
`US
`
`(71) Applicant: THERATECH, INC. [US/US]; Suite 100, 417
`Wakara Way, Salt Lake City, UT 84108 (US).
`
`(72) Inventors: EBERT, Charles, D.; 1515 South Canterbury Drive,
`Salt Lake City, UT 84108 (US). VENKATESHWARAN,
`Srinivasan; 2411 Emerson Avenue, Salt Lake City, UT
`84108 (US). HEIDER, Werner; 1569 South 2300 East, Salt
`Lake City, UT 84108 (US). BORSADIA, Suresh; 4887
`South 1710 East, Salt Lake City, UT 84117 (US).
`
`(74) Agent: HOWARTH, Alan, J.; Thorpe, North & Western, Suite
`200, 9035 South 700 East, Sandy, UT 84070 (US).
`
`(54) Title: DRUG-CONTAINING ADHESIVE COMPOSITE TRANSDERMAL DELIVERY DEVICE
`
`10
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`(57) Abstract
`
`A method for making a transdermal drug delivery device for heat sensitive and volatile drugs is disclosed. The device contains a
`drug-containing adhesive composite layer having an impermeable backing material laminated to the distal surface thereof and a proximal
`peelable impermeable backing material adapted for removal for administering a drug to the skin or mucosa laminated to the proximal surface
`thereof. The figure provides a partly schematic, sectional view of the transdermal drug delivery device (10) including the substantially
`drug-impermeable distal backing (14), a drug laden adhesive composite (18) and a substantially drug impermeable proximal release liner
`(22). The adhesive composite (18) is comprised of a distal adhesive layer (19), a proximal adhesive layer (20) and a gelled drug layer (21)
`disposed therebetween. The device is produced by extruding the drug in gel form onto at least one exposed surface of a first or second
`adhesive laminate such that the adhesive layers and gelled drug are combined to form the drug-containing adhesive composite layer having
`the distal and proximal surfaces covered by the respective backing materials. This process is particularly adaptable to the formulation of
`nicotine-containing patches.
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`FOR THE PURPOSES OF INFORMATION ONLY
`
`Codes used to identify States party to the PCT on the front pages of pamphlets publishing international
`applications under the PCT.
`
`AT
`AU
`BB
`BE
`BF
`BG
`BJ
`BR
`BY
`CA
`CF
`CG
`CH
`CI
`CM
`CN
`cs
`cz
`DE
`DK
`ES
`Fl
`FR
`GA
`
`Austria
`Australia
`Barbados
`Belgium
`Burkina Faso
`Bulgaria
`Benin
`Brazil
`Belarus
`Canada
`Central African Republic
`Congo
`Switzerland
`Cbte d'Ivoire
`Cameroon
`China
`Czechoslovakia
`Czech Republic
`Germany
`Denmark
`Spain
`Finland
`France
`Gabon
`
`GB
`GE
`GN
`GR
`HU
`IE
`IT
`JP
`KE
`KG
`KP
`
`KR
`KZ
`LI
`LK
`LU
`LV
`MC
`MD
`MG
`ML
`MN
`
`United Kingdom
`Georgia
`Guinea
`Greece
`Hungary
`Ireland
`Italy
`Japan
`Kenya
`Kyrgystan
`Democratic People's Republic
`of Korea
`Republic of Korea
`Kazakhstan
`Liechtenstein
`Sri Lanka
`Luxembourg
`Latvia
`Monaco
`Republic of Moldova
`Madagascar
`Mali
`Mongolia
`
`MR
`MW
`NE
`NL
`NO
`NZ
`PL
`PT
`RO
`RU
`SD
`SE
`SI
`SK
`SN
`TD
`TG
`TJ
`TT
`UA
`us
`uz
`VN
`
`Mauritania
`Malawi
`Niger
`Netherlands
`Norway
`New Zealand
`Poland
`Portugal
`Romania
`Russian Federation
`Sudan
`Sweden
`Slovenia
`Slovakia
`Senegal
`Chad
`Togo
`Tajikistan
`Trinidad and Tobago
`Ulcraine
`United States of America
`Uzbekistan
`VietNam
`
`"'!
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`•
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`1
`DRUG-CONTAINING ADHESIVE COMPOSITE TRANSDERMAL
`DELIVERY DEVICE
`
`Background of the Invention
`
`This invention relates generally to transdermal
`and transmucosal drug delivery (TDD) devices. More
`particularly, the invention relates to TDD devices for
`delivering heat sensitive or volatile drugs in which
`the drug is extruded as a gel onto an adhesive layer
`following which the surface of the adhesive layer onto
`which the gel has been extruded is laminated with a
`second adhesive layer to form a drug-containing
`adhesive composite device. Chemical enhancers for
`facilitating transport of the drug through the skin or
`mucosa and other additives can also be mixed with the
`drug or into the composite. Thus, the invention
`encompasses a method for making TDD devices using an
`extrusion step to incorporate a gelled drug into a
`dried adhesive layer, and to drug delivery devices
`made using the method. These methods and devices are
`particularly useful for delivering nicotine into the
`body.
`Cigarette smoking is a major risk factor in
`coronary heart disease and is the cause of
`approximately 30% of all cancer deaths. However,
`smoking is difficult to give up, and any smoking
`cessation therapy has to deal with both the
`pharmacological and psychological dependence on
`cigarettes. Modest success has been obtained by
`separating the treatment of these two factors, such as
`by satisfying the pharmacological craving with
`nicotine pills or chewing gum while treating the
`psychological addiction independently.
`One of the most successful approaches relies on
`nicotine chewing gum, which achieves direct delivery
`of nicotine to the systemic circulation by buccal
`absorption. However, nicotine chewing gum tastes bad,
`may lead to mouth ulcers and heartburn, and destroys
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`dental appliances. Further, patient compliance is
`crucial to effectiveness. Other problems with orally
`administered nicotine include stomach upsets, nausea,
`rapid nicotine degradation, and irregular and
`unpredictable blood levels.
`Another approach gaining increasing favor for
`treating the pharmacological dependence on cigarette
`smoking is transdermal delivery of nicotine. The skin
`is ordinarily a very effective barrier to passage of
`materials from the environment into the body.
`However, nicotine is very volatile, highly lipid
`soluble, and permeates the skin easily. For example,
`a comparison of average penetration rates of other
`transdermally administered agents through the skin
`show that nitroglycerin has a skin flux of 10-25
`~g/cm2 ·h, scopolamine 2-8 ~g/cm2 ·h, estradiol 0.01-0.03
`~g/cm2 ·h, clonidine 0.5 ~g/cm2 ·h, and nicotine 100-300
`~g/cm2 ·h. However, nicotine is also very irritating to
`skin and is very toxic. Therefore, development of
`acceptable TDD devices for delivering nicotine has
`required finding ways to minimize the irritation and
`safety problems while supplying effective doses of the
`substance.
`A number of TDD devices for delivering nicotine
`have been described.
`Japanese Laid Open Application
`No. 61-251619 reports a non-controlled release device
`that holds low amounts of the substance and covers a
`relatively large area (70 cm2
`) of skin. U.S. Patent
`No. 4,597,961 to Etscorn discloses a device in which a
`microporous membrane minimally controls release of
`nicotine to the skin such that it is effective for
`only about 45 minutes. U.S. Patent Nos. 4,920,989 and
`5,016,652 to Rose et al. describe a nicotine patch
`that is preferably used with a nicotine aerosol
`spray that is delivered into a patient's mouth. U.S.
`Patent No. 4,943,435 to Baker et al. reports a
`transdermal patch for delivering nicotine for periods
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`of 12-24 hours that includes a nicotine reservoir and
`rate-controlling polymer matrix to regulate nicotine
`diffusion through the skin. U.S. Patent No. 4,908,213
`to Govil et al. discloses a transdermal nicotine patch
`containing an antipruritic to counteract severe
`itching that may occur with transdermal administration
`of nicotine. U.S. Patent No. 4,877,618 to Reed
`teaches a transdermal nicotine patch containing a
`stack of alternating adhesive and interlaminar layers
`for providing a relatively constant rate of diffusion
`through the skin over an extended period of time.
`Methods of fabricating TDD devices have not
`received much attention in the patent literature.
`U.S. Patent No. 4,943,435 to Baker et al. discloses a
`method of making a nicotine patch wherein the nicotine
`is preferably dissolved in an inert polymer matrix
`that controls the rate of nicotine release. The
`percentage by weight of nicotine can be varied
`according to the desired loading in the monolithic
`matrix layer, however, above about 50% nicotine by
`weight the pplymer fails to solidify properly after
`casting, remaining in a gel or fluid form. Thus, this
`method of making nicotine patches is limited to
`polymers and nicotine loads that, when mixed,
`polymerize properly.
`Another problem of drug delivery devices
`containing polymers and volatile drugs is that, even
`if polymerization is achieved in the presence of the
`drug, the polymer-drug combination must be allowed to
`dry. This is a problem for volatile drugs, such as
`nicotine, since the concentration of the volatile drug
`will diminish during drying, especially if the polymer
`is heated in an oven to accelerate drying. Thus, it
`would be advantageous to avoid fabrication methods
`requiring heating or drying after addition of a
`volatile drug to the polymer.
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`Baker also teaches that many of the common
`materials from which components of TDD devices, such
`as backings, adhesives, membranes, matrices, and
`release liners, are dissolved or degraded by nicotine.
`For example, Baker teaches that adhesives become
`stringy, lose their tackiness, or become so heavily
`loaded with nicotine that they deliver a huge burst of
`nicotine when applied to the skin. According to
`Baker, typical grades of polyisobutylene, acrylate, or
`silicone-based adhesives behave this way when exposed
`to nicotine for periods as little as one week. Baker
`further teaches that polymers that swell
`significantly, disintegrate, or dissolve completely in
`the presence of nicotine include many grades of
`polyvinyl chloride, polycarbonate, polystyrene,
`polyethylene terephthalate, polybutyrate,
`polyurethane, ethylene-vinyl acetate copolymers
`(except those with low percentages of vinyl acetate),
`and polyvinylidene chloride.
`U.S. Patent No. 4,915,950 to Miranda et al.
`describes a_method for making TDD devices that
`involves laminating an anchor adhesive layer onto a
`drug-impermeable backing. Similarly, a pressure(cid:173)
`sensitive contact adhesive is laminated onto a release
`liner. Then, an adsorbent source layer is deposited
`onto, preferably, the contact adhesive, or the anchor
`adhesive. A drug in liquid form is then printed onto
`the exposed face of the adsorbent source layer.
`Finally, the anchor adhesive/backing laminate is
`laminated onto the source/contact adhesive/release
`liner laminate to form the finished device. The
`printing step involves depositing the liquid drug onto
`the adsorbent source layer in a substantially uniform
`manner by any of a number of techniques. Use of a
`drug in a liquid form is a substantial problem because
`the drug must wet the surface of the source layer so
`that squeezing of liquid to the periphery of the
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`device during lamination is substantially prevented.
`After deposition, the drug diffuses into one or both
`of the adjacent adhesive layers. Thus, the fabric
`material composing the source layer and its surface
`properties must be carefully selected so that wicking
`into the fabric is carefully controlled. The rate at
`which the liquid drug is printed onto the source layer
`and the subsequent lamination to the adhesive
`laminate,therefore, must be carefully controlled as
`well, which is difficult to do.
`u.s. Patent No. 5,110,599 to Anhauser also
`discloses a method for producing transdermal patches
`through a printing process.
`
`Objects and Summary of the Invention
`An object of the present invention is to provide
`a method of fabricating laminated TDD devices that is
`compatible with volatile or heat-sensitive drugs,
`enhancers, or other components that cannot be
`subjected to drying or heating, such as would occur in
`an oven.
`Another object of the invention is to provide a
`method of making laminated TDD devices wherein
`sorption or wicking of a liquid drug formulation into
`a sorbent layer is not required.
`A further object of the invention is to provide a
`method of making laminated TDD devices that permits
`selection and optimization of drug delivery profiles.
`These and other objects may be accomplished by a
`method for making a TDD device comprising the steps
`of:
`
`(a) providing a first adhesive laminate
`comprising a first drug permeable adhesive layer
`having laminated to one surface thereof a distal
`backing material and having the opposing surface
`exposed;
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`(b) providing a second adhesive laminate
`comprising a second adhesive layer having laminated to
`one surface thereof a proximal peelable release liner
`and having the opposing surface exposed;
`(c)
`extruding the drug, in gel form, onto at
`least one exposed surface of the first or second
`adhesive laminate; and
`(d)
`laminating together the exposed surfaces of
`the first and second adhesive laminates such that the
`adhesive layers and gelled drug are combined to form a
`drug-containing adhesive composite layer having the
`distal backing material covering one surface thereof
`and the proximal peelable release liner covering the
`opposite surface therof.
`In other words, the drug, in gel form and
`optionally containing enhancers, preservatives,
`antioxidants, anti-irritants, solubilization agents,
`and the like, can be extruded onto either or both of
`the exposed surfaces of the first or second adhesive
`layers which are then laminated together to form a
`drug-contain~ng adhesive composite.
`A further aspect of the method is protecting the
`exposed surfaces of both the first and second adhesive
`layers during fabrication of the device with in(cid:173)
`process release liners that are removed prior to
`extrusion of the gelled drug onto an adhesive surface
`and laminating the exposed surfaces of the two
`adhesive layers to form the drug/adhesive composite.
`In this embodiment the extrusion of the gelled drug
`can be made on either adhesive layer followed by
`lamination. Furthermore, if desired, extrusion of the
`gelled drug could also be made on both adhesive
`layers.
`Still another aspect, and more specific
`embodiment, of the method is making TDD devices for
`administering nicotine for smoking cessation therapy.
`Gelled nicotine is formulated by admixture with a
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`gelling agent such as hydroxypropylcellulose. A
`preservative or antioxidant, such as butylated
`hydroxytoluene, can be added to the formulation as
`well.
`
`Brief Description of the Drawings
`FIG. 1 shows a partly schematic, sectional view
`of a TDD device according to the present invention.
`FIG. 2 shows a partly schematic, sectional view
`of a laminated first adhesive intermediate used in
`fabricating the TDD device of FIG. 1.
`FIG. 3 shows a partly schematic, sectional view
`of a laminated second adhesive intermediate used in
`fabricating the TDD device of FIG. 1.
`FIG. 4 shows a partly schematic, sectional view
`of a completed TDD device according to FIG. 1, with
`the addition of an overlapping proximal release liner
`tab.
`
`Detailed Description of the Invention
`Before the present method of making transdermal
`and transmucosal drug delivery devices is disclosed
`and described, it is to be understood that this
`invention is not limited to the particular process
`steps and materials disclosed herein as such process
`steps and materials may vary somewhat.
`It is also to
`be understood that the terminology used herein is used
`for the purpose of describing particular embodiments
`only and is not intended to be limiting since the
`scope of the present invention will be limited only by
`the appended claims.
`It must be noted that, as used in this
`specification and the appended claims, the singular
`forms "a," "an," and "the" include plural referents
`unless the content clearly dictates otherwise. Thus,
`for example, reference to a laminated structure
`containing "a drug" includes a mixture of two or more
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`drugs, reference to "an adhesive" includes reference
`to two or more of such adhesives, and reference to "an
`enhancer" includes reference to a mixture of two or
`more enhancers.
`In describing and claiming the present invention,
`the following terminology will be used in accordance
`with the definitions set out below.
`As used herein, the term "active gel," "gelled
`drug," "drug in gel form," and the like means a drug
`in which a gelling agent is dispersed to obtain
`selected flow and surface tension properties for
`application to laminated patches. Thus, active gel is
`a liquid drug in a viscous yet flowable state, and can
`be a colloidal/biphasic or dissolved mixture of liquid
`drug and a gelling agent. Liquid drug means either a
`drug which is itself a liquid or is dissolved,
`suspended, or dispersed in a selected solvent or
`vehicle. Such a solvent could be a liquid, such as
`ethanol, water, and the like, or a low-viscosity semi(cid:173)
`solid that can be extruded, such as low molecular
`weight polymers, waxes, petroleum jelly, and the like.
`Active gel may also includes enhancers that can be
`added to the formulation to facilitate transport of
`the drug through the skin or mucosa into the body.
`Active gel may also include a combination of drugs,
`gelling agents, enhancers, preservatives,
`antioxidants, anti-irritants, solubilization agents,
`and the like. The term "gel" is meant to apply to the
`functional nature of the thickened drug component
`whether or not the technical definition of a gel is
`met.
`
`As used herein, the term "drug" or
`"pharmacologically active agent" or any other similar
`term means any chemical or biological material or·
`compound suitable for transdermal or transmucosal
`administration by the methods previously known in the
`art and/or by the methods taught in the present
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`invention, that induces a desired biological or
`pharmacological effect, which may include but is not
`limited to (1) affecting living processes,
`(2) having
`a prophylactic effect on the organism and preventing
`an undesired biological effect such as preventing an
`infection,
`(3) alleviating a condition caused by a
`disease, for example, alleviating pain or inflammation
`caused as a result of disease, and/or (4) either
`alleviating, reducing, or completely eliminating the
`disease from the organism. The effect may be local,
`such as providing for a local anaesthetic effect, or
`it may be systemic. This invention is not drawn to
`novel drugs or to new classes of active agents.
`Rather it is limited to devices and methods of making
`said devices for delivery of drugs or agents that
`exist in the art or that may later be established as
`active drugs or agents and that are suitable for
`delivery by the present invention. Such substances
`include broad classes of compounds normally delivered
`into the body, including through body surfaces and
`membranes, including skin and mucosal membranes.
`In
`general, this includes but is not limited to:
`antiinfectives such as antibiotics and antiviral
`agents; analgesics and analgesic combinations;
`anorexics; antihelminthics; antiarthritics;
`antiasthmatic agents; anticonvulsants;
`antidepressants; antidiabetic agents; antidiarrheals;
`antihistamines; antiinflammatory agents; antimigraine
`preparations; antinauseants; antineoplastics;
`antiparkinsonism drugs; antipruritics; antipsychotics;
`antipyretics; antispasmodics; anticholinergics;
`sympathomimetics; xanthine derivatives; cardiovascular
`preparations including potassium and calcium channel
`blockers, beta-blockers, alpha-blockers, and
`antiarrhythmics; antihypertensives; diuretics and
`antidiuretics; vasodilators including general
`coronary, peripheral and cerebral; central nervous
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`system stimulants; vasoconstrictors; cough and cold
`preparations, including decongestants; hormones such
`as estradiol and other steroids, including
`corticosteroids; hypnotics; immunosuppressives;.muscle
`relaxants; parasympatholytics; psychostimulants;
`sedatives; tranquilizers; and nicotine and acid
`addition salts thereof.
`The flux of a drug across the skin or mucosa can
`be increased by changing either the resistance (the
`diffusion coefficient) or the driving force (the
`gradient for diffusion). Similarly, the flux of an
`analyte (a chemical or biological material suitable
`for passage through a biological membrane of which an
`individual might want to know the concentration or
`activity inside the body) across the skin or mucosa
`for collection or analysis on the outside of the body
`can also be increased. Flux may be enhanced by the
`use of so-called penetration or chemical enhancers.
`Chemical enhancers are comprised of two primary
`categories of components, i.e., cell-envelope
`disordering compounds and solvents or binary systems
`containing both cell-envelope disordering compounds
`and solvents.
`Cell envelope disordering compounds are known in
`the art as being useful in topical pharmaceutical
`preparations and function also in analyte withdrawal
`through the skin. These compounds are thought to
`assist in skin penetration by disordering the lipid
`structure of the stratum corneum cell-envelopes. A
`comprehensive list of these compounds is described in
`European Patent Application 43,738, published June 13,
`1982, which is incorporated herein by reference.
`It
`is believed that any cell envelope disordering
`compound is useful for purposes of this invention;
`Exemplary of the cell envelope disordering compounds
`are those represented by the formula:
`R-X
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`-
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`-
`
`wherein R is a straight-chain alkyl of about 7 to 16
`carbon atoms, a non-terminal alkenyl of about 7 to 22
`carbon atoms, or a branched-chain alkyl of from about
`13 to 22 carbon atoms, and X is sorbitan, glycerin,
`OH I
`- COOCH3 I
`- COOC2H5 I
`- OCOCH3 I
`- SOCH3 I
`- p ( CH3) 20 I
`COOC2H40C2H40H,
`-COOCH (CHOH) 4CH20H,
`-COOCH2CHOHCH3 I
`COOCH2CH(OR")CH20R",
`-(OCH2CH2 )m0H,
`-COOR', or -CONR' 2
`-CH3, -C2H5, -C3H7 or -C2H40H; R" is -H,
`where R' is -H,
`or a non-terminal alkenyl of about 7 to 22 carbon
`atoms; and m is 2-6; provided that when R" is an
`alkenyl and X is -OH or -COOH, at least one double
`bond is in the cis-configuration. Preferred cell
`envelope disordering compounds include isopropyl
`myristate, methyl laurate, oleic acid, oleyl alcohol,
`glycerol monooleate, glycerol dioleate, glycerol
`trioleate, glycerol monostearate, glycerol
`monolaurate, propylene glycol monolaurate, and
`sorbitan esters and mixtures thereof.
`Suitable solvents include water; dials, such as
`propylene glycol and glycerol; mono-alcohols, such as
`ethanol, propanol, and higher alcohols; DMSO;
`dimethylformamide; N,N-dimethylacetamide;
`2-pyrrolidone; N-(2-hydroxyethyl) pyrrolidone, N(cid:173)
`methylpyrrolidone, 1-dodecylazacycloheptan-2-one and
`other n-substituted-alkyl-azacycloalkyl-2-ones
`(azones) and the like.
`U.S. Patent 4,537,776, Cooper, issued August 27,
`1985, contains an excellent summary of prior art and
`background information detailing the use of certain
`binary systems for permeant enhancement. Because of
`the completeness of that disclosure, the information
`and terminology utilized therein are incorporated
`herein by reference.
`Similarly, European Patent Application 43,738,
`referred to above, teaches using selected dials as
`solvents along with a broad category of cell-envelope
`disordering compounds for delivery of lipophilic
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`pharmacologically-active compounds. Because of the
`detail in disclosing the cell-envelope disordering
`compounds and the dials, this disclosure of European
`Patent Application 43,738 is also incorporated herein
`by reference.
`A binary system for enhancing metoclopramide
`penetration is disclosed in UK Patent Application GB
`2,153,223 A, published August 21, 1985, and consists
`of a monovalent alcohol ester of a C8-32 aliphatic
`monocarboxylic acid (unsaturated and/or branched if
`C18-32) or a C6-24 aliphatic monoalcohol (unsaturated
`and/or branched if C14-24) and an N-cyclic compound
`such as 2-pyrrolidone, N-methylpyrrolidone and the
`like.
`Combinations of enhancers consisting of
`diethylene glycol monoethyl or monomethyl ether with
`propylene glycol monolaurate and methyl laurate are
`disclosed in U.S. Patent 4,973,468 as enhancing the
`transdermal delivery of steroids such as progestogens
`and estrogens. A dual enhancer consisting of glycerol
`monolaurate and ethanol for the transdermal delivery
`of drugs is shown in U.S. Patent 4,820,720. U.S.
`Patent 5,006,342 lists numerous enhancers for
`transdermal drug administration consisting of fatty
`acid esters or fatty alcohol ethers of C2 to C4
`alkanediols, where each fatty acid/alcohol portion of
`the ester/ether is of about 8 to 22 carbon atoms.
`U.S. Patent 4,863,970 shows penetration-enhancing
`compositions for topical application comprising an
`active permeant contained in a penetration-enhancing
`vehicle containing specified amounts of one or more
`cell-envelope disordering compounds such as oleic
`acid, oleyl alcohol, and glycerol esters of oleic
`acid; a C2 or C3 alkanol and an inert diluent such as
`water.
`Other chemical enhancers, not necessarily
`associated with binary systems, include DMSO or
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`aqueous solutions of DMSO such as taught in Herschler,
`U.S. Patent 3,551,554; Herschler, U.S. Patent
`3,711,602;
`and Herschler, U.S. Patent 3,711,606, and
`the azones (n-substituted-alkyl-azacycloalkyl-2-ones)
`such as noted in Cooper, U.S. Patent 4,557,943.
`Some chemical enhancer systems may possess
`negative side effects such as toxicity and skin
`irritation. U.S. Patent 4,855,298 discloses
`compositions for reducing skin irritation caused by
`chemical enhancer-containing compositions having skin
`irritation properties with an amount of glycerin
`sufficient to provide an anti-irritating effect.
`Thus, anti-irritants can advantageously be added to
`drug/enhancer compositions within the scope of the
`invention.
`The solubility of certain drugs in some adhesives
`used in the adhesive laminates described herein can be
`disadvantageously low. Solubility enhancing agents,
`solubilizing agents, or solubility altering agents can
`be added to the drug formulation to improve drug
`solubility and, hence, drug concentration in the
`adhesive laminates.
`Increasing the drug concentration
`in the adhesive laminates also increases transdermal
`or transdermal flux. Examples of such solubilization
`agents include solvents such as lower chain alcohols,
`diols, and triols, low molecular weight polymers such
`as polyethylene glycol and polypropylene glycol, and
`other substances suitable for increasing the
`solubility of the drug in the adhesive layers.
`The embodiments described in FIGS. 1-4, are
`presented in reference to nicotine as the active drug.
`However, it will be apparent to one skilled in the art
`that any other liquid drug contained in an active gel
`which can be transdermally or transmucosally delivered
`may be substituted in place of nicotine.
`It is to be
`emphasized that the present invention is particularly
`adapted to the formulation of drugs, enhancers, or
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`other ingredients of the formulation that are volatile
`or heat sensitive and that cannot be readily
`formulated under conditions where elevated
`temperatures are required. Since the terms "volatile"
`or "heat sensitive" may be considered to be relative,
`for purposes of definition herein drugs, enhancers, or
`other ingredients of the formulation are considered
`"volatile" or "heat sensitive" when they have a
`melting point, decompose or are deactivated below
`about 100°C, particularly below about 75°C, and most
`particularly below about 50°C.
`Referring to FIG. 1, the TDD device provided by
`the present method is shown generally at 10. The
`device 10 is in the form of a laminated drug(cid:173)
`containing adhesive composite layer adapted to adhere
`to a predetermined area of unbroken skin or mucosal
`tissue. The individual layers of the device 10
`include a substantially drug-impermeable distal
`backing 14, a drug laden adhesive composite 18, which
`is adapted to adhere to the skin or mucosa, and a
`substantially drug impermeable proximal release liner
`22. The adhesive composite 18 is comprised of a
`distal adhesive layer 19, a proximal adhesive layer
`20, and a gelled drug layer 21 disposed therebetween.
`These layers will be described in more detail
`momentarily.
`The distal backing layer 14, in use, defines the
`side of the patch that faces the environment, i.e.,
`distal to the skin or mucosa. The functions of the
`backing layer 14 are to protect the patch and to
`provide an impenetrable layer that prevents loss of
`nicotine (or other liquid or volatile drug) to the
`environment. Thus, the material chosen should be
`nicotine resistant and should be minimally permeable
`to nicotine. Advantageously, the backing material may
`be opaque to protect nicotine from degradation from
`exposure to ultraviolet light. Further, the backing
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`layer 14 should be capable of binding to and
`supporting the other layers of the device, yet should
`be pliable to accommodate the movements of a person
`using the device 10. A preferred material is
`polyester or aluminized polyester, for example
`polyester medical films such as those marketed under
`the tradenames Scotchpak® 1009 or 1109 from 3M
`Corporation. Aluminized polyester has a nicotine
`permeability of less than about 0.2 ~g·100 ~m/cm2 ·h.
`There are limited materials that are sufficiently
`impermeable to nicotine to retain the nicotine load
`adequately during storage or use. However, other low
`permeability materials that may be used, with or
`without modification are those selected from the group
`consisting of metal foils, metalized polyfoils,
`composite foils or films containing polyester such as
`polyester terephthalate, polytetrafluoroethylene
`("TEFLON®")-type materials, or equivalents thereo,
`polyether block amide copolymers (e.g., "PEBAX"
`copolymers), polyethylene methyl methacrylate block
`copolymers such as "NUKRELL111
`" polymers, polyurethanes
`such as "PELLATHANE111
`" or "ESTANE111
`" polymers,
`polyvinylidene chloride (Saran®), nylon, silicone
`elastomers, rubber-based polyisobutylene, styrene,
`styrene-butadiene and styrene-isoprene copolymers,
`polyethylene, and polypropylene
`Although many of these materials were cited by
`U.S. Patent No. 4,943,435 to Baker as being unsuitable
`for use with nicotine, it is considered that, when
`formulated in the manner described herein, the listed
`materials are sufficiently resistant to degradation by
`nicotine to be useful in the presently described
`invention. A thickness of about 0.001 to 0.004 inch
`is preferred, with 0.002 to 0.003 inch more preferred.
`The adhesive(s) used in forming the adhesive/drug
`composite 18 should be nicotine compatible and permit
`a useful nicotine flux. The proximal 20 and distal 19
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