6,024,976
`[11] Patent Number:
`[19]
`Ulllted States Patent
`
`Miranda et al.
`[45] Date of Patent:
`*Feb. 15, 2000
`
`USOO6024976A
`
`[54]
`
`[75]
`
`SOLUBILITY PARAMETER BASED DRUG
`DELIVERY SYSTEM AND METHOD FOR
`ALTERING DRUG SATURATION
`CONCENTRATION
`ll’lVeI’ltOI‘SI
`JESUS Miranda; Steven Sablotsky,
`both of Miami, Fla.
`
`[73] Assignee: Noven Pharmaceuticals, Inc., Miami,
`Fla.
`
`[*l
`
`NOtiCCI
`
`This patent is subject to a terminal dis-
`claimer.
`
`FOREIGN PATENT DOCUMENTS
`‘
`11/1991 Canada '
`/1986
`European Pat. Off.
`1/1987 European Pat. Off.
`6/1988 E
`P t. Off.
`11/1989
`1243:2533: P21. Off.
`6/1990 European Pat. Off.
`3/1991
`European Pat. Off.
`3/1993
`European Pat. Off.
`7/1979
`Japan .
`12/1983
`Japan .
`4/1983
`unlted Kingdom '
`5/1991 WIPO .
`5/1993 WIPO .
`
`.
`.
`.
`.
`.
`.
`.
`
`02521723:
`—
`-
`208395
`072727045
`0-343-807
`0 371 496
`0—416-842
`A0529123
`54-89017
`58—225010
`2 105 990
`91/05529
`WO 93/08795
`W0
`
`[21] Appl. No.: 08/907,906
`
`[22]
`
`Filed:
`
`Aug- 11, 1997
`
`97/116689
`
`4/1997 WIPO .
`
`OTHER PUBLICATIONS
`
`[62]
`
`Related U-S- Application Data
`7 1994
`.
`f
`1.
`.
`N 08/178 558 J
`_
`C
`,
`ontinuation o app Ication
`o.
`,
`,
`an.
`,
`Pat. No. 5,656,286, which is a continuation—in—part of appli-
`cation No. 07/722,342,_ Jun. 27, 1991, which is a continua-
`[Ion'ln'Part of app???“ NO- 07/67127092 filed asfippllca'
`23:63:12.:ligiilf—[rfrgt‘giijzliggiic£115;Ni§JO71?299%’,8‘4,71,ICJI;n.1511a
`1989, Pat. No. 4,994,267, which is a continuation-in—part of
`application No. 07/164,482, Mar. 4, 1988, Pat. No. 4,814,
`168.
`
`Int. Cl.7 ...................................................... A61F 13/02
`[51]
`.
`9
`[52] US. Cl.
`............................................. 424/449, 4-4/448
`[58] Field of Search ...................................... 424/448, 449
`
`[56]
`
`References Cited
`
`US. PATENT DOCUMENTS
`260/37 SB
`7/1976 Penneck
`8/1976 Tsuk et al."""""""""""""""""""""" 424/28
`
`9/1981 Keith et a1.
`.. 424/28
`9/1981 Keith ct al.
`............................... 424/28
`6/1983 Nagai et al.
`.............................. 424/28
`3/1984 Keith et a1.
`.. 424/28
`
`9/1985 Keith ~~~~~~~~~
`~~ 424/28
`
`461/1322
`fiablomlt‘yl"
`23:???
`.............................
`,
`evne e a .
`5/1987 Cordes et al.
`.......................... 604/897
`
`3969308
`3’972’995
`4:291:015
`4,292,301
`4,390,520
`4,438,139
`425422013
`12:33:33
`,
`,
`4,668,232
`
`Sloan, K. B. et al., “Use of Solubility Parameters of Drug
`and Vehicle to Predict Flux Through Skin”, The Journal of
`~
`~
`7
`_
`InAvesl‘lfcglgge Dermatalogy, V01. 87 (N0. 2) pp. ‘44 252
`( ug.
`)
`Yu et al., “Transdermal Dual—Controlled Delivery of Test-
`osterone and Estradiol: (1) Impact of SYStem Design,” Drug
`Devel. ”“1““ Pharm. 17(14): 1883—1904 (1991)~
`
`(List continued on next page.)
`
`Primary Examiner—Jyothsna Venkat
`'
`Aflomey) Agent) or F‘rm—FOIeY & Lardner
`[57]
`ABSTRACT
`
`Ablend of at least two polymers, or at least one polymer and
`a soluble polyvinylpyrrolidone, in combination With a drug
`provides a pressure-sensitive adhesive composition for a
`transderinal 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. According to the
`invention, soluble polyvinylpyrrolidone can be used to pre-
`vent crystallization of the drug, Without affecting the rate of
`drug delivery from the pressure-sensitive adhesive compo-
`-
`-
`51““
`
`(List continued on next page.)
`
`66 Claims, 19 Drawing Sheets
`
`13
`
`
`
` ///2/7
`MW2/ 2
`
` 11
`
`//////////////////////
`
`
`
`
`//2
`
`
`
`
`12
`
`  
`
`

 
`
`MYLAN - EXHIBIT 1033
`
`

`

`6,024,976
`
`Page 2
`
`US. PATENT DOCUMENTS
`
`~~~~~~~~~~~~~~~~~~~~~~~~~~~~ 604/896
`9/1987 Chien et a1.
`4,690,683
`94987 $11911 ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ 424/1Q
`496939887
`
`9/1987 Belsole ~~
`424/448
`4,696,821
`10/1987 Sievel'ding ------------------------------ 128/640
`4,699,146
`6/1988 Sieverding .............................. 128/156
`4,750,482
`
`9/1988 Lorenz et a1.
`604/265
`4,769,013
`----- 424/78
`3/1989 Sablotsky et 81-
`49814168
`
`514/2322
`7/1989 Sloan
`4,845,081
`
`11/1989 Chien eta.
`.
`424/448
`4,883,669
`3/1990 Chien et al.
`.
`424/448
`4,906,169
`3/1990 Cleary ..................................... 424/449
`4,911,916
`6/1990 Kim et al.
`............................... 424/448
`4,931,281
`1/1991 Salamone et al.
`128/156
`4,987,893
`
`2/1991 Sablotsky .......... 424/78
`4,994,267
`
`7,1991 Sinnreich .....
`424/448
`5,032,403
`10/1991 Cilento etal.
`604/307
`5,059,189
`
`
`12/1991 Lee et a1.
`..
`424/448
`5,071,656
`6/1992 Khanna ................................ 514/7725
`5,122,543
`3:133: Elank """"""""""""""""""""" 424/449
`g’fif’gg
`
`,
`ee et al.
`..
`424/448
`,
`,
`9/1992 Otsuka etal.
`.......................... 424/443
`5,151,271
`5,154,922 10/1992 Govil et a1.
`............................. 424/448
`
`5,230,896
`............................... 424/443
`7/1993 Yeh et al.
`5,230,898
`7/1993 Horstmann et a1.
`.................... 424/449
`5,232,702
`8/1993 Pfisteretal.
`............................ 424/448
`
`5,232,703
`8/1993 Blank .........
`.. 424/449
`5,252,334 10/1993 Chiang etal.
`.......................... 424/448
`5,260,064
`11/1993 Nakagawa etal.
`..................... 424/448
`
`. 424/448
`5,262,165
`“/1993 GOVfl et a1.
`. 424/445
`2/1995 Hoffmann et al.
`5393529
`
`. 424/448
`5,676,968 10/1997 Lip e161.
`OTHER PUBLICATIONS
`
`Ziller et 211., “Control of Crystal Growth in Drug Suspen-
`Sims,” Pharm. Ind. 52(8):1017—1022 (1990).
`.
`..
`..
`“
`.
`.
`,
`Kuhnert—Brandstatter et
`al.., Kristalisationsvorgange in
`Suspensmnen
`VOIl
`Stermdhormonen,
`Scz.
`Pharm.
`35(4)1287—297 (1967)
`English translation of Japanese patent application No.
`248859, filed Feb. 27, 1990.
`English translation of European Patent Application No.
`0 701 878 1986
`_“
`_ “
`(
`)
`English translation of WO 93/08795 (PCT/EP92/02478).
`
`

`

`US. Patent
`
`Feb. 15, 2000
`
`Sheet 1 0f 19
`
`6,024,976
`
`FIG. 1
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`US. Patent
`
`Feb. 15, 2000
`
`Sheet 5 0f 19
`
`6,024,976
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`

`US. Patent
`
`6,024,976
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`US. Patent
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`Feb. 15, 2000
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`6,024,976
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`

`US. Patent
`
`Feb. 15, 2000
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`6,024,976
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`US. Patent
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`US. Patent
`
`Feb. 15, 2000
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`US. Patent
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`6,024,976
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`

`6,024,976
`
`1
`SOLUBILITY PARAMETER BASED DRUG
`DELIVERY SYSTEM AND METHOD FOR
`ALTERING DRUG SATURATION
`CONCENTRATION
`
`CROSS-REFERENCE TO RELATED
`APPLICATION
`
`This application is a continuation of Ser. No. 08/178,558
`filed Jan. 7, 1994, now U.S. Pat, No. granted Aug. 12, 1997.
`This application is a continuation-in-part of Ser. No.
`07/722,342 filed Jun. 27, 1991, which application is a
`continuation-in-part of PCT application PCT/US90/01750
`filed Mar. 28, 1990, and filed nationally as U.S. Ser. No.
`671,709 on Apr. 2, 1991; which in turn is a continuation-
`in-part of US. patent application Ser. No. 295,847, filed Jan.
`11, 1989, now U.S. Pat. No. 4,994,267 issued Feb. 19, 1991;
`which is a continuation-in-part of US. patent application
`Ser. No. 164,482, filed Mar. 4, 1988 now U.S. Pat. No.
`4,814,168, granted Mar. 21, 1989 all of which patents and
`applications are hereby incorporated by reference. All appli-
`cations and patents are assigned to Noven Pharmaceuticals,
`Inc. of Miami, Fla.
`
`BACKGROUND OF THE INVENTION
`
`This invention relates generally to transdermal drug deliv-
`ery systems, and more particularly, to a transdermal drug
`delivery composition wherein a blend of polymers is utilized
`to affect the rate of drug delivery from the composition.
`More specifically, a plurality of polymers including a soluble
`polyvinylpyrrolidone having differing solubility parameters,
`preferably immiscible with each other, adjusts the solubility
`of the drug in a polymeric adhesive system formed by the
`blend, affects the maximum concentration of the drug in the
`system, and modulates the delivery of the drug from the
`composition and through the dermis.
`The use of a transdermal composition, for example a
`pressure-sensitive adhesive containing a medicament,
`namely, a drug, as a means of controlling drug delivery
`through the skin at essentially a constant rate, is well known.
`Such known delivery systems involve incorporation of a
`medicament into a carrier such as a polymeric matrix and/or
`a pressure-sensitive adhesive formulation. The pressure-
`sensitive adhesive must adhere effectively to the skin and
`permit migration of the medicament from the carrier through
`the skin and into the bloodstream of the patient.
`Drug concentration in a monolithic transdermal delivery
`system can vary widely depending on the drug and polymers
`used. For example, certain drugs are effective in low doses
`and therefore the transdermal formulation may involve low
`concentrations, illustratively 5% or less by weight of the
`medicament
`in an adhesive. Other drugs, such as
`nitroglycerin, require large doses to be effective and the
`transdermal formulation therefore may involve high drug
`concentrations, approximately between 5 to 40% or more by
`weight in an adhesive. Low concentrations of medicament
`typically do not critically affect the adhesion, tack, and shear
`resistance properties of the adhesive. However, low drug
`concentrations in the adhesive can result in difliculties in
`
`achieving an acceptable delivery rate of the medicament.
`IIigh concentrations, on the other hand, frequently affect the
`adhesion properties of the adhesives. The deleterious effects
`are particularly exacerbated by drugs which also act as
`plasticizers or solvents for the polymeric adhesive (e.g.,
`nitroglycerin in polyacrylates).
`There is a need in the art for an adhesive composition for
`transdermal drug delivery systems which can selectably
`
`10
`
`15
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`60
`
`65
`
`2
`incorporate low concentrations of drug and deliver same at
`an adequate and controlled rate or incorporate high concen-
`trations of drugs while retaining good physical adhesive
`properties.
`In transdermal drug delivery systems, the presence of
`crystals (drugs and/or additives) is generally undesirable. If
`the drug is present in crystalline form, it is not available for
`release from the system, and therefore not available for
`delivery. Moreover, although drug crystals can first dissolve
`and then release from the system, such a process is usually
`rate-limiting and tends to reduce delivery.
`Crystal size and distribution thus become important
`parameters which must be controlled in order to control
`delivery. These parameters are, however, usually difficult to
`control. Failure to control crystal size and distribution can
`result in products whose appearance suggests that the manu-
`facturing process by which they are produced is not under
`control. More importantly, the presence of large crystals,
`particularly in excessive amounts, can be detrimental to
`adhesive-type transdermals. Crystals on the surface of the
`adhesive system can result in loss of tack. Furthermore,
`surface crystals can come into direct contact with the skin,
`and could cause skin irritation.
`
`There is a need in the art for an adhesive composition for
`transdermal delivery systems which can prevent or suppress
`crystallization of drugs therein.
`It is, therefore, an object of this invention to provide a
`transdermal drug delivery system wherein the rate of drug
`delivery from the transdermal composition may be select-
`ably modulated.
`It is another object of this invention to provide a trans-
`dermal drug delivery system wherein the rate of drug
`delivery from the transdermal composition may be select-
`ably modulated by adjusting the solubility and/or diffusivity
`of the drug in the multiple polymer adhesive system.
`It is also an object of this invention to provide a trans-
`dermal drug delivery system wherein the multiple polymer
`adhesive system is simple to manufacture.
`It
`is a further object of this invention to provide a
`transdermal drug delivery system wherein drug-loading of a
`multiple polymer adhesive system may be selectably varied
`without adverse effects on drug delivery rate and adhesive
`properties, such as adhesion, tack, and shear resistance.
`It is additionally an object of this invention to provide a
`transdermal drug delivery system wherein a novel multiple
`polymer adhesive system is provided which has desirable
`physical properties.
`SUMMARY OF THE INVENTION
`
`The foregoing and other objects are achieved by this
`invention which provides a transdermal drug delivery sys-
`tem wherein a blend of at least two polymers, or at least one
`polymer and a soluble polyvinylpyrrolidone permits
`increased loading of a drug and adjusts the solubility of a
`drug in the blend and thereby modulates the delivery of the
`drug from the system and through the dermis.
`In accordance with one aspect of the invention, an
`improved pressure-sensitive adhesive composition of the
`type which is suitable as a matrix for controlled release of a
`drug therefrom comprises a blend of a rubber-based
`pressure-sensitive adhesive and a soluble polyvinylpyrroli-
`done (PVP).
`The term “polyvinylpyrrolidone,” or “PVP” refers to a
`polymer, either a homopolymer or copolymer, containing
`N-vinylpyrrolidone as the monomeric unit. Typical PVP
`
`

`

`6,024,976
`
`3
`polymers are homopolymeric PVPs and the copolymer vinyl
`acetate Vinylpyrrolidone. The homopolymeric PVPs are
`known to the pharmaceutical industry under a variety of
`designations including Povidone, Polyvidone,
`Polyvidonum, Polyvidonum solubile, and Poly(’1-vinyl-2-
`pyrrolidone). The copolymer vinyl acetate Vinylpyrrolidone
`is known to the pharmaceutical industry as Copolyvidon,
`Copolyvidone, and Copolyvidonum.
`The term “soluble” when used with reference to PVP
`
`means that the polymer is soluble in water and generally is
`not substantially cross-linked, and has a molecular weight of
`less than about 2,000,000. See, generally, Buhler, KOLLI—
`DON®: POLYVINYLPRYRROLIDONE FOR THE
`
`PHARMACEUTICAL INDUSTRY, BASF Aktiengesell-
`schaft (1992).
`It has been surprisingly found that use of a soluble PVP
`results in the ability to form a film that does not contain
`particles of insoluble PVP and in the ability to employ
`higher concentrations of drug without resulting in increased
`crystallization of the drug.
`In accordance with another embodiment of the invention,
`an improved pressure-sensitive adhesive composition of the
`type which is suitable as a matrix for controlled release of a
`drug therefrom comprises a blend of a rubber-based
`pressure-sensitive adhesive having a first solubility
`parameter, a polyacrylate polymer having a second solubil-
`ity parameter, and a soluble PVP,
`the first and second
`solubility parameters preferably being different from one
`another by an increment of at least 2 (J/cm3)1/2. The blend,
`therefore, has a characteristic net solubility parameter.
`In accordance with further embodiment of the invention,
`an improved pressure—sensitive adhesive composition of the
`type which is suitable as a matrix for controlled release of a
`drug therefrom comprises a blend of a rubber-based
`pressure-sensitive adhesive having a first solubility
`parameter, and a polyacrylate polymer having a second
`solubility parameter, the first and second solubility param-
`eters preferably being different from one another by an
`increment of at least 2 (J/cm3)1/2. The blend, therefore, has
`a characteristic net solubility parameter.
`Particularly preferred embodiments include binary blends
`comprising a rubber-based pressure-sensitive adhesive and a
`soluble PVP, wherein the rubber-based pressure-sensitive
`adhesive is a polysiloxane. Polysiloxane is preferably
`present in the pressure-sensitive adhesive composition in an
`amount ranging from about 9% to about 97% by weight of
`the total pressure-sensitive adhesive composition.
`Other particularly preferred embodiments include ternary
`blends comprising a rubber-based pressure-sensitive
`adhesive, a polyacrylate polymer, and a soluble PVP,
`wherein the rubber-based pressure-sensitive adhesive is a
`polysiloxane. Polysiloxane is preferably present
`in the
`pressure-sensitive adhesive composition in an amount rang-
`ing from about 9% to about 97% by weight of the total
`pressure-sensitive adhesive composition, while the poly-
`acrylate polymer is preferably present in an amount ranging
`from about 5% to about 85%. Preferably, the ratio of the
`polyacrylate polymer to the rubber-based pressure-sensitive
`adhesive is from about 2:98 to about 96:4, and more
`preferably from about 2:98 to about 86:14 by weight.
`Other particularly preferred embodiments include blends
`comprising a rubber-based pressure-sensitive adhesive and a
`polyacrylate polymer, wherein the rubber-based pressure-
`sensitive adhesive is a polysiloxane. Polysiloxane is prefer-
`ably present in the pressure-sensitive adhesive composition
`in an amount ranging from about 9% to about 97% by
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`weight of the total pressure-sensitive adhesive composition,
`while the polyacrylate polymer is preferably present in an
`amount ranging from about 5% to about 85%. Preferably, the
`ratio of the polyacrylate polymer
`to the rubber-based
`pressure-sensitive adhesive is from about 2:98 to about 96:4,
`and more preferably from about 2:98 to about 86:14 by
`weight.
`In both binary and ternary blends, soluble PVP is prefer-
`ably present in the pressure—sensitive adhesive composition
`in an amount ranging from about 1% to about 20% by
`weight of the total pressure-sensitive adhesive composition.
`The pressure-sensitive adhesive compositions may further
`include enhancers, fillers, co-solvents, and excipients as are
`known in the art for use in such compositions.
`In a dermal adhesive composition embodiment of the
`invention, a multiple polymer adhesive system comprises a
`blend of 14—94% by weight of a rubber-based pressure-
`sensitive adhesive, 5—85% by weight of a polyacrylate
`polymer, and 2—10% by weight of a soluble PVP, and the
`multiple polymer adhesive system comprises about 50—99%
`by weight of the dermal adhesive composition. This multiple
`polymer adhesive system is combined with a drug in the
`amount of 01—50% by weight of the total dermal adhesive
`composition. Optional additives, such as co-solvent for the
`drug (up to 30% by weight) and enhancers (up to 20% by
`weight) may be included in the dermal adhesive composi-
`tion.
`
`In transdermal drug delivery system embodiments, incor-
`porating a drug in the improved pressure-sensitive adhesive
`composition, the characteristic net solubility parameter can
`be preselected to adjust the saturation concentration of the
`drug in the composition and thereby control the release of
`the drug. The saturation concentration of the drug may be
`adjusted either upward or downward depending upon
`whether the rate of release is to be enhanced or retarded.
`
`the drug is a
`In particularly preferred embodiments,
`steroid, such as an estrogen or a progestational agent, or
`combination thereof. In other preferred embodiments, the
`drug may be a [32-adrenergic agonist, such as albuterol, or a
`cardioactive agent, such as nitroglycerin.
`In still other
`embodiments,
`the drug is a cholinergic agent, such as
`pilocarpine, or an antipsychotic such as haloperidol or a
`tranquilizer/sedative such as alprazolam.
`The transdermal drug delivery system may comprise a
`monolithic adhesive matrix device in some embodiments.
`The transdermal drug delivery system may further include a
`backing material and a release liner as is known in the art.
`The saturation concentration of a drug in a transdermal
`drug delivery system of the type having a drug-containing
`pressure-sensitive adhesive diffusion matrix is adjusted in
`accordance with an aspect of the present
`invention by
`blending at least two polymers having differing solubility
`parameters as defined above to form a pressure-sensitive
`adhesive diffusion matrix having a net solubility parameter
`which modifies the delivery rate of the drug from the
`pressure-sensitive adhesive diffusion matrix and through the
`dermis.
`
`BRIEF DESCRIPTION OF THE DRAWINGS
`
`Comprehension of the invention is facilitated by reading
`the following detailed description, in conjunction with the
`annexed drawing, in which:
`FIG. 1 is a schematic illustration of a monolithic trans-
`
`dermal drug delivery device of the present invention;
`FIG. 2 is a graphic representation of the steady-state
`nitroglycerin flux rates through cadaver skin in vitro from a
`
`

`

`6,024,976
`
`5
`transdermal drug delivery composition of the present inven-
`tion (formulation of Example 1) and two commercially-
`available nitroglycerin-containing transdermal delivery
`devices: TRANSDERM-NITRO® (a trademark of Ciba-
`Geigy Corporation, Summit, NJ), and NITRO-DUR® (a
`trademark of Key Pharmaceuticals, Inc., Kenilworth, NJ);
`FIG. 3 is a graphical representation which summarizes in
`vitro nitroglycerin flux results through cadaver skin for the
`polymeric systems of Examples 275. The composition of
`Example 2 (polyacrylate-only adhesive) is compared to the
`multiple polymer compositions of Examples 3, 4, and 5, in
`which the polyacrylate is blended with an ethylene vinyl
`acetate, a polyisobutylene, and a polysiloxane, respectively;
`FIG. 4 is a graphical representation of the steady-state
`nitroglycerin flux through cadaver skin in Vitro from a
`multiple polymer transdermal adhesive system of Example
`6 comprising various weight ratios of polyacrylate and
`polysiloxane;
`FIG. 5 is a graphical representation of steady-state estra-
`diol flux through cadaver skin in Vitro from the drug delivery
`systems of the prior art, specifically single polymeric adhe-
`sives of silicone and acrylic, as compared to a multiple
`polymer
`transdermal adhesive system (polyacrylate/
`polysiloxane) of the present invention;
`FIG. 6 is a graphical representation of average estradiol
`flux through cadaver skin in vitro from 0 to 22 hours and
`from 22 to 99 hours for a multiple polymer transdermal
`adhesive system comprising various weight ratios of poly-
`acrylate and polysiloxane;
`FIG. 7 is a graphical representation of steady-state nore-
`thindrone acetate flux through cadaver skin in Vitro from the
`drug delivery systems of the prior art, specifically single
`polymeric adhesives of silicone and acrylic, as compared to
`a multiple polymer
`transdermal adhesive system
`(p01yacrylate/polysiloxane) of the present invention;
`FIG. 8 is a graphical representation of average estradiol
`and norethindrone acetate flux through cadaver skin iti Vitro
`for a multiple polymer transdermal adhesive system com-
`prising both drugs and various weight ratios of polyacrylate
`and polysiloxane;
`FIG. 9 is a graphical representation showing the ratio of
`average estradiol to norethindrone acetate flux (estradiol flux
`divided by norethindrone acetate flux) through cadaver skin
`in vitro for a multiple polymer transdermal adhesive system
`comprising various weight ratios of polyacrylate and pol—
`ysiloxane;
`FIG. 10 is a graphical representation of steady-state flux
`of pilocarpine through cadaver skin in vitro from the drug
`delivery systems of the prior art, specifically single poly-
`meric adhesives of silicone and acrylic, as compared to a
`multiple polymer
`transdermal adhesive system
`(p0lyacrylate/polysiloxane) of the present invention;
`FIG. 11 is a graphical representation of steady—state
`albuterol and nitroglycerin flux through cadaver skin in vitro
`from multiple polymer transdermal adhesive systems
`(polyacrylate/polysiloxane) of the present
`invention
`(Examples 24—27), and NITRO-DUR®, respectively;
`FIG. 12 is a graphical
`representation of steady-state
`estradiol flux through cadaver skin in vitro from two differ-
`ent multiple polymer
`transdermal adhesive systems
`polyacrylate/polysiloxane and polyacrylate/polybutylene;
`FIGS. 13 and 14 show the relationship of flux rate (J)
`plotted against apparent diffusion eoeflicient (D) and net
`solubility parameter (SP), respectively, for Compositions
`net)
`I—VI of Example 6. The net solubility parameter, SP
`was
`
`6
`calculated using a weighted average of the solubility param-
`eters of the individual polymers comprising the matrix:
`
`SPnet=¢pSSPpS+Q§WSRm
`
`where 0P5 is the weight percentage of polysiloxane and SPF:
`is the solubility parameter of polysiloxane. The subscript
`“pa” refers to the polyacrylate;
`FIG. 15 is a plot of diffusion coeflicient versus net
`solubility parameter;
`FIG. 16 shows the average flux of estradiol for two
`compositions of this invention containing a soluble PVP;
`FIG. 17 shows estradiol flux through the human epidermis
`from a PVP-containing compositions of this invention;
`FIG. 18 shows norethindrone flux through human epider-
`mis in a composition of this invention containing estradiol
`and soluble PVP;
`FIG. 19 shows average estradiol and norethindrone
`acetate flux from a composition of this invention containing
`varying concentrations of soluble PVP; and
`FIG. 20 shows the effect of soluble PVP on estradiol flux
`
`through human epidermis.
`
`DETAILED DESCRIPTION OF PREFERRED
`EMBODIMENTS
`
`In one aspect of the present invention, a pressure-sensitive
`adhesive composition is provided which comprises a blend
`of at least two polymers and a soluble PVP, and a drug. The
`blend of at least two polymers is herein referred to as a
`multiple polymer adhesive system. The term “blend” is used
`herein to mean that there is no, or substantially no, chemical
`reaction or cross-linking (other than simple H-bonding)
`between the different polymers in the multiple polymer
`adhesive system.
`As used herein, the term “pressure-sensitive adhesive”
`refers to a viscoelastic material which adheres instanta-
`
`neously to most substrates with the application of very slight
`pressure and remains permanently tacky. A polymer is a
`pressure—sensitive adhesive within the meaning of the term
`as used herein if it has the properties of a pressure-sensitive
`adhesive per se or functions as a pressure-sensitive adhesive
`by admixture with tackifiers, plasticizers or other additives.
`The term pressure-sensitive adhesive also includes mix-
`tures of different polymers and mixtures of polymers, such
`as polyisobutylenes (PIB), of different molecular weights,
`wherein each resultant mixture is a pressure-sensitive. In the
`last case, the polymers of lower molecular weight in the
`mixture are not considered to be “tackifiers,” said term being
`reserved for additives which differ other than in molecular
`weight from the polymers to which they are added.
`As used herein, the term “rubber-based pressure-sensitive
`adhesive” refers to a viscoelastic material which has the
`properties of a pressure—sensitive adhesive and which con—
`tains at least one natural or synthetic elastomeric polymer.
`As used herein,
`the term “drug,” and its equivalent,
`“bioactive agent,” is intended to have its broadest interpre-
`tation as any therapeutically, prophylactically and/or phar-
`macologically or physiologically beneficial active
`substance, or mixture thereof, which is delivered to a living
`organism to produce a desired, usually beneficial, effect.
`More specifically, any drug which is capable of producing
`a pharmacological response, localized or systemic, irrespec-
`tive of whether therapeutic, diagnostic, or prophylactic in
`nature, in plants or animals is within the contemplation of
`the invention. Also within the contemplation of the inven-
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`6,024,976
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`8
`proposed by R. F. Fedors, Polymer Engineering and
`Science, Vol. 14, p. 147 (1974). In this method AE‘, and V are
`be obtained by simply assuming that
`AEV=ZiAei and V=Zivi, where Ael— and vi are the additive
`atomic and group contributions for the energy of vaporiza-
`tion and molar volume, respectively.
`Yet another method of calculating the solubility parameter
`of a material is described by Small, J. Applied Chem. Vol. 3,
`p. 71 (1953).
`Table I-A below sets forth solubility parameters of some
`exemplary adhesive polymers which would be useful in the
`practice of the invention and shows the variation of SP with
`molecular weight, free —OH and —COOH groups,
`the
`degree of cross-linking. Table IA is in (cal/cm3)“2 and
`(J/cm3)1/2 as calculated by Small’s method.
`
`TABLE IA
`
`Solubility Parameter
`
`(cal/cm3)1/2
`
`(J/cm3)1/2
`
`P0 ymers
`Ac dition polymers of
`unsaturated esters
`
`
`
`Po ymethyl methacrylate
`Po yethy niethacrylate
`Po ymethylacrylate
`P0 yethy acrylate
`Hydrocarbon polymers
`
`P0 yethy ene
`P0 ystyrene
`P0 yisobutylene
`P0 yisoprene
`P0 ybutadiene
`P0 yethy ene/butylene
`Ha ogen-containing polymers
`
`P0 ytetra ’uoroethylene
`Po yviny Chloride
`P0 yviny idene chloride
`P0 ychloroprene
`P0 yacry onitrile
`Condensation polymers
`
`
`
`7
`tion are such bioactive agents as pesticides, insect repellents,
`sun screens, cosmetic agents, etc. It should be noted that the
`drugs and/or bioactive agents may be used singly or as a
`mixture of two or more such agents, and in amounts suffi-
`cient to prevent, cure, diagnose or treat a disease or other
`condition, as the case may be.
`The multiple polymer adhesive not only functions as a
`carrier matrix for the drug, but enhances the rate of release
`of the drug, and hence the transdermal permeation rate. In
`some embodiments of the invention, however, the multiple
`polymer adhesive system will function to retard the trans-
`dermal permeation rate.
`A soluble PVP is blended with one or more other poly-
`mers in order to further modulate the transdermal perme-
`ation rate of the drug.
`invention is the
`An important aspect of the present
`discovery that thc transdermal permeation rate of a drug
`from the multiple polymer adhesive system can be selec-
`tively modulated by adjusting the solubility of the drug in ,
`the device. As used herein, the term “transdermal perme-
`ation rate” means the rate of passage of the drug through the
`skin; which, as known in the art, may or may not be affected
`by the rate of release of the drug from the carrier.
`The polymers comprising the multiple polymer adhesive
`system are preferably inert to the drug, and are preferably
`immiscible with each other, as can be surmised by their
`diiferent solubility parameters. Forming a blend of multiple
`polymers results in an adhesive system having a character-
`istic “net solubility parameter,” the selection of which
`advantageously permits a selectable modulation of the deliv-
`ery rate of the drug by adjusting the solubility of the drug in
`the multiple polymer adhesive system.
`Solubility parameter, also referred to herein as “SP,” has
`been defined as the sum of all the intermolecular attractive
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`forces, which are empirically related to the extent of mutual
`solubility of many chemical species. A general discussion of
`solubility parameters is found in an article by Vaughan,
`“Using Solubility Parameters in Cosmetics Formulation," J.
`Soc. Cosmet. Chem, Vol. 36, pages 319—333 (1985). Many
`methods have been developed for the determination of
`solubility parameters, ranging from theoretical calculations
`to totally empirical correlations. The most convenient
`method is Hildebrand’s method, which computes the solu-
`bility parameter from molecular weight, boiling point and
`density data, which are commonly available for many mate-
`rials and which yields values which are usually within the
`range of other methods of calculation:
`
`SP=(AE,