(12) United States Patent
`Kanios
`
`US006638528B1
`US 6,638,528 B1
`Oct. 28,2003
`
`(io) Patent No.:
`(45) Date of Patent:
`
`(54) COMPOSITIONS AND METHODS TO
`EFFECT THE RELEASE PROFILE IN THE
`TRANSDERMAL ADMINISTRATION OF
`ACTIVE AGENTS
`
`(75)
`
`Inventor: David Kanios, Miami, FL (US)
`
`(73) Assignee: Noven Pharmaceuticals, Inc., Miami,
`FL (US)
`
`( * ) Notice:
`
`Subject to any disclaimer, the term of this
`patent is extended or adjusted under 35
`U.S.C. 154(b) by 0 days.
`
`(21) Appl. No.: 10/086,457
`Mar. 1, 2002
`(22) Filed:
`
`Related U.S. Application Data
`
`FOREIGN PATENT DOCUMENTS
`
`EP
`EP
`EP
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`wo
`WO
`wo
`wo
`
`0 224 981
`0 697 860
`913 158
`WO94/06436
`W094/26257
`W095/22322
`W095/31188
`W096/21433
`W098/17263
`W098/31349
`WO98/39042
`W099/55286
`WOOO/59483
`WOOO/74661
`PCT/US01/01999
`
`6/1987
`4/1994
`6/1999
`3/1994
`11/1994
`8/1995
`11/1995
`7/1996
`4/1998
`7/1998
`9/1998
`11/1999
`10/2000
`12/2000
`8/2001
`
`(60)
`
`(63) Continuation of application No. 09/765,932, filed on Jan. 19,
`2001, now abandoned.
`Provisional application No. 60/177,103, filed on Jan. 20,
`2000.
`(51) Int. CI.7
`(52) U.S. CI.
`
`... A61K 9/70; A61K 13/00
`424/449; 424/448; 424/443;
`424/484
`424/448, 449,
`424/484, 487, 488, 443
`
`(58) Field of Search
`
`(56)
`
`References Cited
`U.S. PATENT DOCUMENTS
`
`4,584,355 A
`4/1986 Blizzard et al.
`4,585,836 A
`4/1986 Homan et al.
`5/1986 Blizzard et al.
`4,591,622 A
`1/1987 Szycher et al.
`4,638,043 A
`4/1987 Woodard et al.
`4,655,767 A
`5/1988 Haggiage et al.
`4,746,509 A
`6/1989 Baker et al.
`4,839,174 A
`6/1989 Sweet et al.
`4,840,796 A
`6/1989 Guillemet et al.
`4,842,864 A
`7/1989 Szycher et al.
`RE32,991 E
`11/1989 Chien et al.
`4,883,669 A
`2/1990 Yanagibashi et al.
`4,900,554 A
`2/1991 Sablotsky
`4,994,267 A
`(List continued on next page.)
`
`OTHER PUBLICATIONS
`
`Dow Chemical Company, "Product Specification Sheet for
`Ethocel FP Polymers," Oct. 1998, U.S.A.
`
`Dow Chemical Company, "Bibliography: ETHOCEL Eth-
`ylcellulose in Pharmaceuticals," Jun. 1996, U.S.A.
`
`(List continued on next page.)
`
`Primary Examiner—Thurman K. Page
`Assistant Examiner—Robert M. Joynes
`(74) Attorney, Agent, or Firm—-Jay G. Kolman, Esq.
`
`(57)
`
`ABSTRACT
`
`Compositions and methods for the transdermal delivery of
`active agents up to a period of seven days or more at
`substantially a zero-order release rate comprising a pharma-
`ceutically acceptable adhesive matrix and a polymeric plas­
`tic material that provides a release rate regulating effect on
`the active agents.
`
`6 Claims, 6 Drawing Sheets
`
`13 y
`
`u
`
`/ t
`
`t ?
`
`12
`
`m
`
`  
`
`

 
`
`MYLAN - EXHIBIT 1030
`
`

`

`US 6,638,528 B1
`Page 2
`
`U.S. PATENT DOCUMENTS
`
`OTHER PUBLICATIONS
`
`5,118,779 A
`5,176,915 A
`5,232,702 A
`5,446,070 A
`5,474,783 A
`5,523,095 A
`5,556,635 A
`5,656,286 A
`5,662,923 A
`5,662,926 A
`5,676,969 A
`5,679,373 A
`5,716,609 A
`5,810,786 A
`5,885,612 A
`5,904,931 A
`5,906,814 A
`6,010,715 A
`6,024,974 A *
`6,143,319 A
`6,190,689 B1
`6,231,885 B1
`6,274,165 B1
`
`6/1992 Szycher
`1/1993 Hoffmann
`8/1993 Pfister et al.
`8/1995 Mantelle
`12/1995 Miranda et al.
`6/1996 Wison et al.
`9/1996 Istin et al.
`8/1997 Miranda et al.
`9/1997 Roreger
`9/1997 Wick et al.
`10/1997 Wick et al.
`10/1997 Wick et al.
`2/1998 Jain et al.
`9/1998 Jackson et al.
`3/1999 Meconi et al.
`5/1999 Lipp et al.
`5/1999 Epstein
`1/2000 Wick et al.
`2/2000 Li
`11/2000 Meconi et al.
`2/2001 Hoffmann et al.
`5/2001 Carrara
`8/2001 Meconi et al.
`
`Dow Chemical Company, "Ethocel Polymers for General
`Applications," Mar. 1998, U.S.A.
`Dow Chemical Company, "Ethocel Premium Polymers for
`Pharmaceutical Applications," May 1996, U.S.A.
`Dow Chemical Company, "Ethocel Premium Ethylcellulose
`in Pharmaceutical Applications," Dec. 1991, U.S.A.
`Wiley-Interscience/John Wiley & Sons, March, Jerry,
`Advanced Organic Chemistry: Reactions, Mechanisms, and
`Structure, 4th Ed., 1992.
`BASF Aktiengesellschaft, Buhler, Kollidon® Polyvinylpyr­
`rolidone for the Pharmaceutical Industry, 2nd Ed., Aug.
`1993.
`Van Nostrand Reinhold, New York, Satas, Donatas, "Acrylic
`Adhesives," pp. 396^-56, 1989, Handbook of Pressure-
`Sensitive Adhesive Technology, 2nd Edition.
`Van Nostrand Reinhold, New York, Sobieski, Loretta, et al.,
`"Silicone Pressure Sensitive Adhesives," pp. 508-517;
`1989, Handbook of Pressure Sensitive Adhesive Technology,
`2nd Ed.
`
`* cited by examiner
`
`424/448
`
`

`

`U.S. Patent
`US. Patent
`
`Oct. 28,2003
`Oct. 28, 2003
`
`Sheet 1 of 6
`Sheet 1 0f 6
`
`US 6,638,528 B1
`US 6,638,528 B1
`
`13
`
`-----------------------------
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`

`

`US 6,638,528 B1
`
`1
`COMPOSITIONS AND METHODS TO
`EFFECT THE RELEASE PROFILE IN THE
`TRANSDERMAL ADMINISTRATION OF
`ACTIVE AGENTS
`
`CROSS-REFERENCE TO RELATED
`APPLICATION
`
`This application is a continuation application of U.S. Ser.
`No. 09/765,932, filed Jan. 19, 2001 now abandoned, which
`is based on and claims the benefit of Provisional Application
`No. 60/177,103, filed Jan. 20, 2000. Both of these applica­
`tions are incorporated in their entirety herein by reference.
`
`FIELD OF THE INVENTION
`This invention relates generally to transdermal drug deliv­
`ery systems, and more particularly to pharmaceutically
`acceptable adhesive matrix compositions, that use polymeric
`plastic materials, in particular insoluble cellulose derivatives
`such as ethyl celluloses, to regulate the drug release profile. 20
`The invention additionally relates to transdermal drug deliv­
`ery systems providing substantially zero order drug release
`profiles for an extended period of time of up to seven days
`or longer.
`
`2
`In a matrix-type device, the active agent is dissolved or
`dispersed in a carrier that typically yields a finite carrier
`form, which can be self-adhesive or non-adhesive. Non-
`adhesive matrix-type devices, that is, those which still rely
`5 upon a separate adhesive means to afSx the device to the
`user, employ a drug permeable adhesive layer (often referred
`to as an "in-line adhesive" since the drug must pass
`through), applied over the drug matrix carrier layer. In an
`attempt to better control the release rate of the drug, such
`devices often employ one or more additional drug permeable
`layers such as rate controlling membranes, or containing
`excipients, such as drug delivery enhancers. Hence, such
`devices are also commonly referred to as multilayer or
`multilaminate.
`In a "monolithic or monolayer" matrix-type device, the
`15 active agent is typically solubilized or homogenously
`blended in an adhesive carrier composition, typically a
`pressure-sensitive adhesive or bioadhesive, which functions
`as both the drug carrier and the means of affixing the system
`to the skin or mucosa. Such devices, commonly referred to
`as drug-in-adhesive devices, are described, for example, in
`U.S. Pat. Nos. 4,994,267, 5,446,070, 5,474,783 and 5,656,
`286, all of which are assigned to Noven Pharmaceuticals,
`Inc., Miami, Fla.
`While matrix-type devices, especially drug-in-adhesive
`devices, have achieved more uniform and controlled drug
`BACKGROUND OF THE INVENTION
`deliver rates, and for longer periods of time, most transder­
`The use of transdermal drug delivery systems as a means
`mal systems remain subject to a higher initial drug release
`to topically administer an active agent is well known. Such
`than is required to achieve therapeutic efScacy. For many
`systems incorporate the active agent into a carrier
`30 drugs and/or therapeutic situations, it would be advanta­
`composition, such as a polymeric and/or pressure-sensitive
`geous to eliminate or suppress this higher initial release and
`adhesive composition, from which the active agent is deliv­
`achieve a "steady state" (zero order) release profile which
`ered through the skin or mucosa of the user.
`uniformly delivers a therapeutically effective amount of
`drug over the extended duration of device's desired use.
`In general, transdermal drug delivery systems are either
`reservoir-type or matrix-type devices. Both types of devices 35
`For example, the high initial release of certain drugs may
`employ a backing layer that forms the protective outer
`cause adverse or undesired effects, or create toxicity
`surface of the finished
`transdermal system and which is
`concerns, thereby foreclosing the use of transdermal admin­
`exposed to the environment during use, and a release liner
`istration. In other instances, the higher initial release may
`or protective layer that forms the inner surface and which
`reduce the amount of drug required for treatment to the point
`covers whatever adhesive means is employed for affixing the 40 of risking underdosing, or may make it impractical to try and
`system to the skin or mucosa of a user. The release liner or
`increase the duration of the device's application while
`protective layer is removed prior to application, exposing
`retaining therapeutic effectiveness. The ability to reduce the
`the adhesive means, which is typically a pressure-sensitive
`frequency of replacing the transdermal drug delivery system
`adhesive.
`would concomitantly increase user compliance, reduce any
`In the "classic" reservoir-type device, the active agent is 45 lag or drop off in efficacious, blood levels, and reduce the
`amount of drug required for treatment (also provided by
`usually dissolved or dispersed in a carrier that typically
`reducing the higher initial blood level associated with the
`yields a non-finite carrier form, like a fluid or gel, and which
`higher release rate).
`is kept separate from the adhesive means used to afSx the
`Therefore, despite the existence of many different types of
`device to the user. The device has a pocket or "reservoir"
`which physically serves to hold the active agent and carrier, 5Q transdermal delivery systems in the art, there remains a
`continuing need for improving the release profile of drugs to
`and which is formed in or by the backing layer itself. A
`achieve substantially zero order, as well as extending the
`peripheral adhesive layer is then used to afSx the device to
`duration of use of each transdermal system.
`the user. The early reservoir-type devices incorporated drugs
`which were readily absorbed through the skin like nitro­
`U.S. Pat. Ser. No. 07/897,269 discloses the use of glycerin
`glycerin and nicotine.
`55 to counteract the burst effect of drugs in transdermal for­
`mulations.
`Such devices have a number of disadvantages including a
`non-uniform drug release profile wherein a high dose of
`It has now been found that the addition of certain poly­
`drug is released initially upon application to the user, often
`meric plastic polymers, in particular insoluble cellulose
`described as a "burst effect." This burst or high initial release
`derivatives such as ethyl celluloses, into a pressure-sensitive
`of drug then drops off after a period of time to a rate that is go adhesive matrix composition, eliminates or suppresses the
`less than is able to achieve a therapeutically effective
`initial high release rate of a drug subject to a first order
`amount. Drug delivery according to this profile is described
`release rate profile such that the system achieves substan­
`as first order release.
`tially zero order release, and is able to maintain a substan­
`tially zero order release profile for an extended period of
`While such classic devices are still in use today, the term
`reservoir is being used interchangeably with matrix-type 65 time up to seven days or longer.
`devices which still rely upon a separate adhesive means used
`Although not wishing to be bound by theory, particularly
`in this case where the structure of the composition has not
`to affix the device to the user.
`
`

`

`US 6,638,528 B1
`
`4
`3
`It is still another object of the invention to achieve a
`been analyzed, it is postulated that the insoluble polymeric
`substantially zero-order release profile of the active agent for
`plastic material affects the uptake/absorption of water or
`an extended period of time of up to seven days or longer, and
`moisture from the application site into the matrix composi­
`effectively continue to deliver the active agent in a thera-
`tion which would otherwise create some of the kinetic
`driving force for release of the drug. This appears especially 5 peutically effective amount,
`It is a further object of the invention to provide a method
`significant in the presence of hydrophobic drugs and/or in
`of eliminating or suppressing the high initial release or burst
`conjunction with the use of hydrophilic crystallization
`of active agent from an adhesive matrix type transdermal
`inhibitors, such as polyvinylpyrrolidones.
`drug delivery system containing a drug subject to a first
`Ethyl celluloses have been extensively used in industrial
`10 order release profile.
`applications since their commercial introduction in the mid-
`It is yet another object of the invention to provide a
`1930s. They are recognized and widely used as well for
`transdermal drug delivery system that can deliver an active
`many different purposes in pharmaceutical applications,
`agent at substantially zero-order for an extended period of
`especially in conjunction with water-sensitive ingredients.
`time in excess of 72 hours and up to seven days or more
`Ethyl celluloses are most frequently used as binders, fillers,
`without substantially increasing the surface area of the
`flavor fixatives,
`controlled release coatings/barriers in 15
`transdermal delivery system.
`microencapsulation and other solid dosage forms, particu­
`larly multiparticulate systems, granulation aids, tablet film
`BRIEF DESCRIPTION OF THE DRAWINGS
`formers and taste maskers.
`FIG. 1 is a schematic illustration of a matrix-type trans­
`The prior art generally discloses the use of insoluble
`dermal drug delivery system of the present invention.
`polymers such as ethyl cellulose as optional components in
`FIG. 2 is a graphical representation comparing the in vitro
`transdermal systems as thickening agents and as cohesive-
`flux rate of estradiol and norethindrone acetate through
`ness strengthening agents which effect the carrier's adhesive
`cadaver skin from a pressure-sensitive adhesive matrix
`properties. For example, U.S. Pat. No. 5,232,702 discloses
`composition of the present invention with the flux rate for a
`the use of a variety of substances that include ethyl cellulose
`25 composition of the prior art.
`and polyvinyl alcohol as cohesive strengthening agents
`FIG. 3 is a graphical representation of the in vitro first
`(reducing flow properties of silicone adhesives) in a trans­
`order flux rate of estradiol through cadaver skin from a
`dermal delivery system.
`transdermal drug delivery system of the prior art as com­
`The present invention is able to regulate the release profile
`pared to the in vitro steady state flux rate of estradiol through
`of the drug in a transdermal system without modifying the 3o cadaver skin from an transdermal drug delivery system of
`adhesive properties of the pressure-sensitive adhesive
`the present invention.
`matrix so that the transdermal system possesses the required
`FIG. 4 is a graphical representation of the in vitro flux
`degree of adhesion and tackiness to remain affixed to the site
`rates of estradiol through cadaver skin from two pressure­
`of application for extended periods of time, which can be
`.
`.
`sensitive adhesive matrix compositions of the present inven-
`seven days or more, but at the same time can be easily ^ tjon usjng various amounts of ethyl cellulose as compared to
`removed as required.
`jjjg
`v^ro f[ux rate 0f estradiol from a pressure-sensitive
`The prior art further generally discloses the use of
`adhesive matrix composition without ethyl cellulose.
`insoluble polymers in transdermal systems as the non-
`FIG. 5 is a graphical representation of the in vitro flux
`adhesive matrix carrier itself, and even as a "suitable adhe-
`rates of estradiol through cadaver skin from pressure-
`sive" for the matrix carrier itself (but which presumably 40 sensitive adhesive matrix compositions of the present inven-
`includes the addition of a plasticizer or tackifier, or plasti-
`tion comparing the effect of varying amounts of ethyl
`cizing liquid drug like nicotine, to create stickiness since
`cellulose with varying amounts of estradiol,
`such polymers are not adhesives). For example, U.S. Pat.
`FIG. 6 is a graphical representation of the in vitro flux
`No. 6,010,715 discloses the use of thermoplastic polymers
`rates 0£ estrac}fol and norethindrone acetate through cadaver
`that are melt-blended with active agents and enhancers that 45 skin from pressure_sensitive adhesive matrix compositions
`are heat stable at the melt temperature of the polymer. The
`comparing the effect of using a combination of ethyl cellu-
`melt-blend can then be thermoformed into carrier layers
`lose and cellulose acetate butyrate versus either polymer
`without the use of common solvents to produce a controlled
`alone
`release layer in a transdermal drug delivery system. Cellu­
`lose derivatives such as ethyl cellulose are generally dis- 50
`closed as "suitable adhesives" for use as the matrix.
`U.S. Pat. No. 5,904,931 discloses the use of ethyl cellu­
`lose as a crystallization inhibitor in a transdermal drug
`delivery system. Cellulose ether and polyvinyl compounds
`are generally described as additional matrix additives.
`
`DETAILED DESCRIPTION OF THE
`INVENTION
`The foregoing and other objects are achieved by this
`invention which provides a transdermal drug delivery sys­
`tem wherein the use of a polymeric plastic material provides
`55 a release rate regulating effect on the active agents incor­
`porated into the adhesive matrix composition.
`SUMMARY OF THE INVENTION
`Unless defined otherwise, all technical and scientific
`terms used herein have the same meaning as commonly
`It is therefore an objective of the present objective to
`understood by one of ordinary skill in the art to which the
`provide for methods and pharmaceutically acceptable
`flexible, finite compositions and systems for the transdermal go invention pertains,
`The term "topical" or "topically" is used herein in its
`administration of active agents that achieve a substantially
`conventional meaning as referring to direct contact with an
`zero-order release profile when applied to a user.
`anatomical site or surface area on a mammal including skin,
`It is another object of the invention to provide an adhesive
`teeth, nails and mucosa.
`matrix-type transdermal drug delivery system which
`achieves a substantially zero-order release profile of the 65
`The term "mucosa" as used herein means any moist
`active agent by incorporating a polymeric plastic material
`anatomical membrane or surface on a mammal such as oral,
`buccal, vaginal, rectal, nasal or ophthalmic surfaces.
`into an adhesive drug matrix.
`
`

`

`US 6,638,528 B1
`
`5
`
`J=-D{dCmldx),
`
`5
`The term "transdermal" as used herein means passage into
`and/or through skin or mucosa for localized or systemic
`delivery of an active agent.
`The term "solubilized" is intended to mean that in the
`carrier composition there is an intimate dispersion or disso­
`lution of the active agent at the crystalline, molecular or
`ionic level. As such, the active agent is considered herein to
`be in "non-crystallized" form when in the compositions of
`the present invention.
`As used herein, the term "flux" is defined as the absorp-
`tion of the drug through the skin or mucosa, and is described
`by Pick's first law of diffusion:
`
`6
`lohde viscometer). Ethyl cellulose polymers having such
`solution viscosities exhibit melting point temperatures in the
`range of about 165° C. to about 200° C. Suitable ethyl
`cellulose polymers are commercially available and include
`those sold under the trademark ETHOCEL® by the Dow
`Chemical Company, Midland, Mich. Preferred ETHOCEL®
`polymers are ETHOCEL® Standard 7, 10, 14 and 20,
`
`Premium or Industrial grad es.
`A crystallization inhibitor or solubility enhancer may also
`be employed in the invention, for example polyvinylpyrroli-
`done polymers, polyethylene oxide, polyacrylic acid, poly-
`vinyl alcohol, silicone dioxide, silica, celluloses and cellu-
`lose derivatives such as hydroxymethyl cellulose,
`hydroxypropyl cellulose, gelatins, gums, starches, dextrins
`and dextrans, sterols, bile acids and other absorptive agents
`15 that possess the capability to absorb and hold water or
`Where J is the flux in g/cm2/sec, D is the diffusion coefS-
`moisture.
`cient of the drug through the skin or mucosa in cm2/sec and
`Particularly preferred compounds are PVPs. The term
`Dcm/dx is the concentration gradient of the drug across the
`"polyvinylpyrrolidone" or "PVP" refers to a polymer, ether
`skin or mucosa.
`a homopolymer or copolymer, containing vinylpyrrolidone
`The phrase "pharmaceutically acceptable flexible, finite"
`20 (also referred to as N-vinylpyrrolidone, N-vinyl-2-
`is intended to mean a solid form capable of conforming to
`pyrrolidone and N-vinyl-2-pyrrolidinone) as a monomeric
`a surface to which it is applied, and which is capable of
`unit. PVP polymers include soluble and insoluble
`maintaining the contact in such solid form so as to facilitate
`homopolymeric PVPs, and copolymers such as
`topical application without adverse physiological response,
`vinylpyrrolidone/vinyl acetate and vinylpyrrolidone/
`and without being appreciably decomposed by aqueous 25 dimethylamino-ethylmethacrylate. The cross-linked hom-
`contact during use by a subject.
`polymer (such as KOLLIDON® CL from BASF) is
`The term "user" or "subject" is intended to include all
`insoluble and is generally known in the pharmaceutical
`warm-blooded mammals, preferably humans.
`industry under the designations polyvinylpolypyrrolidone,
`crospovidone and PVP. The copolymer vinylpyrrolidone-
`The phrase "substantially zero-order" as used herein
`means transdermal delivery of an active agent at a release 30 vinyl acetate is generally known in the pharmaceutical
`industry under the designations Copolyvidon (e), Copoly-
`rate which is approximately constant once steady state is
`vidonum or VP-VAc.
`attained, typically within 12 to 24 hours after topical appli­
`Particularly preferred PVPs are soluble. The term
`cation. While variability in blood levels of active agent are
`"soluble" when used with reference to PVP means that the
`contemplated within the scope of this meaning once steady
`state release is attained, the depletion rate of active agent 35 polymer is soluble in water and generally is not substantially
`over the duration of use should typically not exceed about
`cross-linked, and has a molecular weight of less than about
`2,000,000. See, generally, Buhler, KOLLIDON®: POLYVI-
`20% to about 25%.
`Any polymeric plastic material may be employed for the
`NYLPRYRROLIDONE FOR THE PHARMACEUTICAL
`INDUSTRY, BASF Aktiengesellschaft (1992). Soluble PVP
`present invention provided it is insoluble or substantially
`insoluble in water, and includes cellulose derivatives such as 40 polymers have been identified in the pharmaceutical indus-
`cellulose acetates, (cellulose acetate butyrate, cellulose
`try under a variety of names, the most commonly used
`acetate propionate, cellulose acetate phthalate, etc.), methyl,
`include Povidone, Polyvidon (e), Polyvidonum, poly
`ethyl and propyl celluloses; polycarbonates; polystyrenes;
`(N-vinyl-2-pyrrolidinone, poly (N-vinylbutyrolactam), poly
`(l-vinyl-2-pyrrolidinone, poly [l-(2-oxo-lpyrrolidinyl)
`alkylacrylates such as polymethyl methacrylate, polyethyl
`ethacrylate, polyethylene methacrylate and other lower alkyl 45 ethylene],
`The amount and type of PVP required in the preferred
`acrylates; vinyl polymers; polyurethanes; polyacrylonitriles;
`and mixtures, combinations and multipolymers
`embodiments will depend on the quantity and type of drug
`(copolymers, terpolymers, etc.) thereof.
`present in the adhesive matrix composition, as well as the
`In preferred embodiments, the polymeric plastic material
`type of adhesives, but can be readily determined through
`is a cellulose derivative. Preferred are cellulose esters such 50 routine experimentation,
`Typically, the PVP is present in an amount from about 5%
`as cellulose acetates including cellulose acetate, cellulose
`to about 50% by weight, preferably from about 10% to about
`acetate butyrate, cellulose acetate phthalate, cellulose
`40% by weight based on the dry weight of the total adhesive
`acetate propionate, and cellulose ethers.
`matrix composition. However, the amount of PVP can be
`Copending provisional application, Ser. No. 60/137,827,
`describes the use of cellulose derivatives, particularly eel- 55 higher than 20% for example, up to 40%, depending on the
`lulose esters, as drug solubility enhancers in matrix carrier
`particular drug used and on the desired properties of the
`compositions.
`matrix blend.
`Particularly preferred cellulose ethers are ethyl cellulose
`Said PVP preferably has a molecular weight of about
`polymers. Ethyl cellulose polymers can be manufactured in
`2,000 to 2,000,000, more preferably 5,000 to 100,000, and
`a variety of molecular weights, which translates into a range 60 most preferably 7,000 to 54,000. PVP having a molecular
`weight of about 1,000,000 to about 1,500,000 is also pre­
`of viscosities when in solution. In practicing the subject
`ferred.
`invention, it has been found that solution viscosities ranging
`PVPs are sold to the pharmaceutical industry under the
`from about 3 centipoise to about 49 centipoise are preferred,
`trademarks KOLLIDON by BASF (Parsippanny, N.J.);
`and more preferably from about 6 centipoise to about 40
`centipoise, and optimally from about 6 centipoise to about 65 PLASDONE, POLYPLASDONE and COPOLYMER 958
`22 centipoise (viscosities are for 5% solutions, in 80%
`by ISP Technologies, Wayne, N.J. Preferred PVPs are KOL­
`toluene and 20% ethanol, measured at 25° C. in an Ubbe-
`LIDON 12PF, 17PF, 25, 30, 90 and VA-64.
`
`

`

`US 6,638,528 B1
`
`7
`8
`properties, for example as neutral molecules, components of
`Particularly preferred embodiments of the invention
`molecular complexes or free bases to improve solubility or
`include soluble PVP in a polyacrylate and polysiloxane
`release characteristics; or as pharmaceutically acceptable
`pressure-sensitive adhesive matrix blend.
`The amount and type of polymeric plastic material
`ethers, esters, amides and the like which have desirable
`required in the practice of the invention will depend on the 5 retention and release characteristics but which are easily
`one or more additional materials used in the adhesive matrix
`metabolized at body pH.
`composition, and on the amount and type of active agent(s).
`Compounds may be converted into pharmaceutically
`acceptable salts, and the salts may be converted into phar­
`Generally, the amount of polymeric plastic material to be
`maceutically acceptable free compound using standard pro-
`used is an amount sufScient to deliver a therapeutically
`effective amount of the active agent at a substantially 10 cedures known to those skilled in the art of synthetic organic
`zero-order kinetic rate of delivery for an extended period of
`chemistry and described, for example, by J. March,
`time of at least three days and up to seven days or longer, and
`Advanced Organic Chemistry: Reactions, Mechanisms and
`to eliminate or suppress the high initial release rate of a drug
`Structure, A'h Ed. (New York: Wiley-Interscience, 1992).
`subject to a first order release profile. Typically, the amount
`Acid addition salts are prepared from the free base (e.g.,
`of polymeric plastic material to be used ranges from about 15 compounds having a neutral
`-NH2 or cyclic amine group)
`0.5% to about 30%, preferably from about 2.5% to 20%, and
`using conventional means, involving reaction with a suitable
`more preferably from about 5.0% to 15% by weight based
`acid. An acid addition salt may be converted to the free base
`by treatment with a suitable base. Basic salts of acid
`on the dry weight of the total adhesive matrix composition.
`Amounts greater than 30% typically result in loss of adhe­
`moieties which may be present (e.g., carboxylic acid groups)
`sive properties necessary to maintain the system topically 20 can be prepared in a similar manner using pharmaceutically
`for an extended period of time.
`acceptable inorganic or organic bases. Compounds may also
`The adhesive matrix compositions of the present inven­
`be converted into pharmaceutically acceptable esters. Suit­
`tion are designed to effectively deliver an active agent in a
`able esters include branched or unbranched, saturated or
`therapeutically effective amount for an extended period of
`unsaturated Q to C6 alky esters, for example, methyl, ethyl
`time up to seven days or longer. As used herein, "therapeu- 25 and vinyl esters. Preparation of esters involves functional-
`tically effective" means an amount of an active agent that is
`ization of hydroxyl and/or carboxyl groups which may be
`sufficient to achieve the desired local or systemic effect or
`present. Pharmaceutically acceptable esters may be prepared
`result, such as to prevent, cure, diagnose, mitigate or treat a
`using methods known to those skilled in the art and/or
`disease or condition, when applied topically over the dura­
`described in the pertinent literature. Esters can be recon-
`tion of intended use. Seven days is generally the preferred 30 verted to the free acids, if desired, by using conventional
`hydrogenolysis or hydrolysis procedures. Preparation of
`maximum duration for application of a transdermal drug
`amides and pro-drugs can be performed in an analogous
`delivery system of the present invention because the site of
`manner.
`application is typically adversely affected when occluded for
`Steroids and hormonal active agents (including both
`a period of time greater than seven days. However, if a
`non-occlusive backing material (i.e., permeable to water 35 natural, semi-synthetic and synthetic compounds and their
`derivatives having steroidal or hormonal activity) are pre­
`vapor and/or oxygen) is used, then the transdermal system
`may be applied for periods longer than seven days without
`ferred and include, for example, (a) estrogens such as
`adverse effects occurring, if at all, until a much later time.
`Colpormon, Conjugated Estrogens, Estradiol (17(3- and a-)
`While delivery of drug by the present invention is preferred
`and its Esters (e.g., Acetate, Benzoate, Cypionate, Dipropi-
`for at least a seven-day continuous application, the trans- 40 onate Diacetate, Enanthate, Estradiol-16,17-Hemisuccinate,
`de