United States Patent [w]
`Miranda et al.
`
`[54] SOLUBILITY PARAMETER BASED DRUG
`DELIVERY SYSTEM AND METHOD FOR
`ALTERING DRUG SATURATION
`CONCENTRATION
`
`[75]
`
`Inventors: Jesus Miranda; Steven Sablotsky,
`both of Miami, Fla.
`
`[73] Assignee: Noven Pharmaceuticals, Inc., Miami,
`Fla.
`
`Notice:
`
`This patent is subject to a terminal dis­
`claimer.
`
`[21] Appl. No.: 08/907,906
`Aug. 11, 1997
`[22] Filed:
`
`Related U.S. Application Data
`
`[62] Continuation ol application No. 08/178,558, Jan. 7, 1994,
`Pat. No. 5,656,286, which is a continuation-in-part ol appli­
`cation No. 07/722,342, Jun. 27, 1991, which is a continua­
`tion-in-part ol application No. 07/671,709, filed as applica
`tion No. PCT/US90/01750, Mar. 28, 1990, which is a
`continuation-in-part ol application No. 07/295,847, Jan. 11,
`1989, Pat. No. 4,994,267, which is a continuation-in-part ol
`application No. 07/164,482, Mar. 4, 1988, Pat. No. 4,814,
`168.
`[51] Int. CI.7
`[52] U.S. CI
`[58] Field of Search
`
`A61F 13/02
`... 424/449; 424/448
`424/448, 449
`
`[56]
`
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`
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`424/28
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`424/28
`424/28
`424/28
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`... 523/111
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`
`US006024976A
`[ii] Patent Number:
`[45] Date of Patent:
`
`Illlllllllllllllll
`
`6,024,976
`*Feb. 15, 2000
`
`FOREIGN PATENT DOCUMENTS
`2027053
`4/1991 Canada .
`0-201-828 11/1986 European Pat. Off.
`208395
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`0-272-045
`6/1988 European Pat. Off.
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`5/1991 WIPO .
`WO 93/08795
`5/1993 WIPO .
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`97/116689
`
`4/1997 WIPO .
`
`OTHER PUBLICATIONS
`
`Sloan, K. B. et al., "Use of Solubility Parameters of Drug
`and Vehicle to Predict Flux Through Skin", The Journal of
`Investigative Dermatalogy, vol. 87 (No. 2) pp. 244-252
`(Aug. 1986).
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`osterone and Estradiol: (1) Impact of System Design," Drug
`Devel. Indust. Pharm. 17(14): 1883-1904 (1991).
`
`(List continued on next page.)
`
`Primary Examiner—Jyothsna Venkat
`Attorney, Agent, or Firm—Foley & Lardner
`ABSTRACT
`[57]
`
`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
`transdermal drug delivery system in which the drug is
`delivered from the pressure-sensitive adhesive composition
`and through dermis when the pressure-sensitive adhesive
`composition is in contact with human skin. 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
`sition.
`
`(List continued on next page.)
`
`66 Claims, 19 Drawing Sheets
`
`13
`
`r
`
`m
`
`m
`m
`
`i
`
`11
`
`2
`
`10
`
`12
`
`  
`
`

 
`
`MYLAN - EXHIBIT 1033
`
`

`

`6,024,976
`Page 2
`
`U.S. PATENT DOCUMENTS
`9/1987 Chienetal
`9/1987 Shah
`9/1987 Belsole
`10/1987 Sieverding
`6/1988 Sieverding
`9/1988 Lorenz et al. ...
`3/1989 Sablotsky et al.
`7/1989 Sloan
`11/1989 Chienetal
`3/1990 Chienetal
`3/1990 Cleary
`6/1990 Kim et al
`1/1991 Salamone et al.
`2/1991 Sablotsky
`7/1991 Sinnreich
`10/1991 Cilento et al. ...
`12/1991 Lee et al
`6/1992 Khanna
`7/1992 Blank
`8/1992 Lee et al
`9/1992 Otsuka et al. ...
`10/1992 Govil et al
`
`4,690,683
`4,693,887
`4,696,821
`4,699,146
`4,750,482
`4,769,013
`4.814.168
`4,845,081
`4,883,669
`4.906.169
`4,911,916
`4,931,281
`4,987,893
`4,994,267
`5,032,403
`5,059,189
`5,071,656
`5,122,543
`5,128,138
`5,141,750
`5,151,271
`5,154,922
`
`.. 604/896
`.... 424/19
`.. 424/448
`.. 128/640
`.. 128/156
`.. 604/265
`.... 424/78
`514/232.2
`.. 424/448
`.. 424/448
`.. 424/449
`.. 424/448
`.. 128/156
`.... 424/78
`.. 424/448
`.. 604/307
`.. 424/448
`514/772.5
`.. 424/449
`.. 424/448
`.. 424/443
`.. 424/448
`
`5,230,896
`5,230,898
`5.232.702
`5.232.703
`5,252,334
`5,260,064
`5,262,165
`5,393,529
`5,676,968
`
`7/1993 Yeh et al
`7/1993 Horstmann et al.
`8/1993 Pfister et al
`8/1993 Blank
`10/1993 Chiang et al
`11/1993 Nakagawa et al.
`11/1993 Govil et al
`2/1995 Hoffmann et al.
`10/1997 Lip et al
`
`OTHER PUBLICATIONS
`
`424/443
`424/449
`424/448
`424/449
`424/448
`424/448
`424/448
`424/445
`424/448
`
`Ziller et al., "Control of Crystal Growth in Drug Suspen­
`sions," Pharm. Ind. 52(8):1017-1022 (1990).
`Kuhnert-Brandstatter et al., "Kristalisationsvorgange in
`Suspensionen von Steroidhormonen," Sci. Pharm.
`35(4):287-297 (1967).
`English translation of Japanese patent application No.
`2^18859, filed Feb. 27, 1990.
`English translation of European Patent Application No.
`0-201-828 (1986).
`English translation of WO 93/08795 (PCT/EP92/02478).
`
`

`

`U.S. Patent
`
`Feb.15,2000
`
`Sheet 1 of 19
`
`6,024,976
`
`FIG. 1
`
`I m
`m
`m
`
`13
`
`m
`
`ii
`
`12
`
`10
`
`FLUX
`(|j.g/cmA2/hr)
`
`24
`
`2 0 -
`
`1 6 -
`
`1 2 -
`
`g
`
`4 •
`
`0
`
`FIG. 2
`
`20.8
`
`13.4
`
`9.5
`
`EXAMPLE 1
`
`21
`
`Nitro - Dur
`PRODUCT
`
`M
`
`Transderm - Nitro
`
`

`

`Q\
`<1
`
`K)
`o
`9\
`
`SC
`*"b
`IN>
`JD
`ZA sr
`
`o o o
`
`tN>
`
`9
`n
`&:
`
`Vi
`d
`
`* ACR/POLYMER RATIOS
`
`OF 45/55, W/W
`
`EXAMPLE 5
`
`ACR/SI *
`
`A
`
`EXAMPLE 4
`ACR/PIB *
`
`ADHESIVE COMPOSITION
`
`EXAMPLE 3
`ACR/EVA *
`
`'A
`
`EXAMPLE 2
`
`ACR
`
`21
`
`z
`
`12.5
`
`16.0
`
`26.2
`
`25.4
`
`FIG, 3
`
`0
`
`4 •
`
`Q
`
`12-
`
`16-
`
`20-
`
`24-
`
`28-
`
`(|ig/cmA2/hr)
`
`FLUX
`
`

`

`<i
`
`o\ o K)
`
`o
`Ui
`
`!Z5 sr
`
`®
`®
`O
`K>
`Oi
`
`n
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`
`rt> =
`&:
`
`VI
`d
`
`ACRYLIC: SILOXANE POLYMER RATIO (W/W)
`
`100.0:0.0 81.6:18.4 62.5:37.5 43.2:56.8 21.7:78.3 0.0:100.0 Nitro-Dur®
`Zl
`
`a
`
`id
`
`2
`
`2.95
`
`IT"
`
`4.54
`
`P:
`
`4.2
`
`4.92
`
`5.21
`
`FIG. 4
`
`1.57
`
`3.16
`
`0
`
`2
`
`4 ~
`
`7
`
`((ig/cmA2/hr)
`
`FLUX
`
`

`

`Q\
`<1
`
`4^
`
`as o
`
`MS
`o
`
`sr rD
`
`o
`o o
`N>
`in
`
`rD
`
`9
`&:
`
`cc
`d
`
`(EXAMPLE 7)
`
`SILICONE/ACRYLIC
`A
`
`(EXAMPLE 8)
`
`ACRYLIC
`
`A
`
`(EXAMPLE 9)
`
`SILICONE
`
`0.0
`
`0.1 -
`
`0.210
`
`m
`
`0.190
`
`0.2 -
`
`([ig/cmA2/hr)
`
`FLUX
`
`0.354
`
`v.
`
`FIG. 5
`
`0.3 -
`
`0.4
`
`

`

`U.S. Patent
`
`Feb.15, 2000
`
`Sheet 5 of 19
`
`6,024,976
`
`o
`LL
`
`r
`
`r
`
`DC
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`
`(EXAMPLE 16)
`
`(EXAMPLE 14)
`
`SILICONE
`
`SILICONE/ACRYLIC
`
`ACRYLIC
`
`0.213
`
`0.354
`
`rq
`
`1.082
`
`FIG. 7
`
`0.0
`
`0.2-
`
`0.4-
`
`0.6-
`
`0.8-
`
`1.0-
`
`1.2
`
`(|ig/cinA2/hr)
`
`FLUX
`
`

`

`U.S. Patent
`
`Feb. 15, 2000
`
`Sheet 7 of 19
`
`6,024,976
`
`r-»
`
`CO
`
`CD O
`eg
`LU
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`
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`
`g EXAMPLE 18
`
`^ EXAMPLE 17
`
`SI/ACR RATIO
`
`x\:
`
`m
`
`FIG. 9
`
`0
`
`1
`
`FLUX RATIO
`
`E2/NAC
`
`3
`
`

`

`OS
`<1
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`
`(EXAMPLE 23)
`
`SILICONE/ACRYLIC
`
`(EXAMPLE 22)
`
`ACRYLIC
`
`12.01
`
`8.80
`
`FIG. 10
`
`0
`
`3.87
`
`(|Lig/cmA2/hr)
`
`FLUX
`
`10 -
`
`

`

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`
`EXAMPLE 27
`
`COMPOSITION
`
`EXAMPLE 26
`m
`
`EXAMPLE 25
`
`EXAMPLE 24
`
`21.6
`
`20.6
`
`16.9
`
`19.1
`
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`
`27.6
`
`FIG. 11
`
`0
`
`4 -
`
`g
`
`12-
`
`16-
`
`20-
`
`24-
`
`28-
`
`32
`
`(fig/cmA2/hr)
`
`FLUX
`
`

`

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`
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`
`(EXAMPLE 29)
`
`SILICONE/ACRYLIC
`
`0.49
`
`r
`
`0.54
`
`FIG. 12
`
`0.0
`
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`
`0.2 -
`
`0.3 -
`
`0.4 -
`
`0.5 -
`
`0.6 -
`
`0.7
`
`(|ig/cmA2/hr)
`
`FLUX
`
`

`

`U.S. Patent
`
`Feb. 15, 2000
`
`Sheet 12 of 19
`
`6,024,976
`
`LO
`03
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`

`

`U.S. Patent
`
`Feb. 15,2000
`
`Sheet 13 of 19
`
`6,024,976
`
`CO
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`

`U.S. Patent
`
`Feb. 15, 2000
`
`Sheet 14 of 19
`
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`• EXAMPLE 45
`
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`
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`
`TIME (hrs)
`
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`
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`
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`
`FIG. 16
`
`0
`
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`
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`
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`AVERAGE FLUX
`
`1.0-
`
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`
`

`

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`
`EXAMPLE 47
`
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`
`EXAMPLE 48
`
`EXAMPLE 49
`
`EXAMPLE 46
`
`0.506
`
`0.478 m
`
`EXAMPLE 50
`
`EXAMPLE 51
`
`EXAMPLE 52
`
`EXAMPLE 53
`
`FIG. 17
`
`0.0
`
`0.1 -
`
`0.2 -
`
`0.3 -
`
`0-4 -
`
`0.5 -
`
`0.6 -
`
`0.7 -
`
`0.8
`
`AVERAGE ESTRADIOL FLUX
`
`((ig/cmA2/hr)
`
`

`

`<1 as
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`as
`
`MS
`O
`
`CZ3 sr
`
`fD
`fD
`
`O o o
`
`rD
`
`0
`
`C/3
`d
`
`0.712
`
`0.889
`
`0.89
`
`EXAMPLE 53
`
`0.837
`
`0.809
`
`0.855
`
`0.842
`
`EXAMPLE 49
`
`EXAMPLE 52
`
`EXAMPLE 50
`
`EXAMPLE 51
`
`EXAMPLE 48
`
`EXAMPLE 47
`
`1
`
`0.8
`
`0.6
`
`ESTRADIOL CONCENTRATION (%, W/W)
`0.1
`
`0.5
`
`0.4
`
`m
`
`0.2
`
`0.05
`
`o
`
`0.751
`
`0.817
`
`EXAMPLE 46
`
`o.o
`
`0.2 -
`
`0.4 -
`
`0.6 -
`
`0.8 -
`
`1.0 -
`
`1.2
`
`AVERAGE NETA FLUX
`
`(|ig/cmA2/hr)
`
`FIG. 18
`
`

`

`o\
`
`-C-.
`K)
`o
`OS
`
`Ms
`o
`cc
`fD
`fD
`
`CZ3 sr
`
`o o
`o
`U\
`
`rD
`
`9
`ft
`
`(/J
`d
`
`^ NETAFLUX
`
`^ ESTRADIOL FLUX
`
`10
`zm
`
`0.164
`
`% POLYVINYL PYRROLIDONE
`
`5
`
`2.5
`
`0
`
`o.o
`
`0.14
`
`0.2-
`
`EXAMPLE 57
`
`EXAMPLE 56
`
`EXAMPLE 55
`
`54
`EXAMPLE
`
`0.4-
`
`AVERAGE DRUG FLUX
`
`(|ig/cmA2/hr)
`
`0.531
`
`0.668
`
`0.61
`
`0.648
`
`0.6-
`
`0.8
`
`FIG. 19
`
`

`

`o\
`
`o
`ON
`
`SO
`
`o
`
`CZ3 sr
`
`rD
`
`o o o
`
`rD
`
`9
`n
`
`O)
`d
`
`96
`
`72
`
`TIME (hrs)
`
`48
`
`24
`T
`
`EXAMPLE 91
`
`EXAMPLE 45
`
`FIG. 20
`
`0
`
`0.0
`
`0.2-
`
`0.4-
`
`0.6-
`
`0-8 -
`
`1.0-
`
`1.2-
`
`1.4-
`
`1.6
`
`((ig / cmA2 / hr)
`ESTRADIOL FLUX
`
`

`

`6,024,976
`
`5
`
`25
`
`1
`SOLUBILITY PARAMETER BASED DRUG
`DELIVERY SYSTEM AND METHOD FOR
`ALTERING DRUG SATURATION
`CONCENTRATION
`
`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
`CROSS-REFERENCE TO RELATED
`crystals (drugs and/or additives) is generally undesirable. If
`APPLICATION
`the drug is present in crystalline form, it is not available for
`release from the system, and therefore not available for
`This application is a continuation of Ser. No. 08/178,558
`delivery. Moreover, although drug crystals can first dissolve
`filed Jan. 7, 1994, now U.S. Pat, No. granted Aug. 12, 1997.
`from the system> such a process is usually
`This application is a continuation-in-part of Ser. No. 10 and then release
`rate-limiting and tends to reduce delivery.
`07/722,342 filed
`Jun. 27, 1991, which application is a
`Crystal size and distribution thus become important
`continuation-in-part of PCT application PCT/US90/01750
`parameters which must be controlled in order to control
`filed Mar. 28, 1990, and filed nationally as U.S. Ser. No.
`delivery. These parameters are, however, usually difficult to
`671,709 on Apr. 2, 1991; which in turn is a continuation-
`in-part of U.S. patent application Ser. No. 295,847, filed Jan. 15 control. Failure to control crystal size and distribution can
`11,1989, now U.S. Pat. No. 4,994,267 issued Feb. 19,1991;
`result in products whose appearance suggests that the manu­
`facturing process by which they are produced is not under
`which is a continuation-in-part of U.S. patent application
`control. More importantly, the presence of large crystals,
`Ser. No. 164,482, filed Mar. 4, 1988 now U.S. Pat. No.
`particularly in excessive amounts, can be detrimental to
`4,814,168, granted Mar. 21, 1989 all of which patents and
`applications are hereby incorporated by reference. All appli- 20 adhesive-type transdermals. Crystals on the surface of the
`cations and patents are assigned to Noven Pharmaceuticals,
`adhesive system can result in loss of tack. Furthermore,
`Inc. of Miami, Fla.
`surface crystals can come into direct contact with the skin,
`and could cause skin irritation.
`,
`...
`.
`,,
`•
`, •
`,,
`, r
`BACKGROUND OF THE INVENTION
`1 here is a need in the art tor an adhesive composition tor
`transdermal delivery systems which can prevent or suppress
`This invention relates generally to transdermal drug deliv-
`crystallization of drugs therein.
`ery systems, and more particularly, to a transdermal drug
`therefore, an object of this invention to provide a
`delivery composition wherein a blend of polymers is utilized
`it
`transdermal drug delivery system wherein the rate of drug
`to affect the rate of drug delivery from the composition.
`More specifically, a plurality of polymers including a soluble 30 delivery from the transdermal composition may be select-
`polyvinylpyrrolidone having differing solubility parameters,
`ably modulated.
`preferably immiscible with each other, adjusts the solubility
`It is another object of this invention to provide a trans­
`of the drug in a polymeric adhesive system formed by the
`dermal drug delivery system wherein the rate of drug
`blend, affects the maximum concentration of the drug in the
`delivery from the transdermal composition may be select-
`system, and modulates the delivery of the drug from the
`35 ably modulated by adjusting the solubility and/or diffusivity
`composition and through the dermis.
`of the drug in the multiple polymer adhesive system.
`The use of a transdermal composition, for example a
`•
`i
`-J
`u-
`t c
`It is also an object of this invention to provide a trans-
`. .
`•
`•
`•
`,.
`T
`,
`pressure-sensitive adhesive containing a medicament,
`, ,
`.
`n - i
`.
`u
`•
`i
`dermal drug delivery system wherein the multiple polymer
`r
`namely, a drug, as a means of controlling drug delivery
`.
`•
`•
`i
`t
`i
`i
`J
`,
`,
`,
`, •
`• „
`•
`„,
`adhesive system is simple to manufacture,
`through the skin at essentially a constant rate, is well known. 40
`It is a further object of this invention to provide a
`Such known delivery systems involve incorporation of a
`transdermal drug delivery system wherein drug-loading of a
`medicament into a carrier such as a polymeric matrix and/or
`multiple polymer adhesive system may be selectably varied
`a pressure-sensitive adhesive formulation. The pressure-
`without adverse effects on drug delivery rate and adhesive
`sensitive adhesive must adhere effectively to the skin and
`permit migration of the medicament from the carrier through 45 Properties, such as adhesion, tack, and shear resistance,
`It is additionally an object of this invention to provide a
`the skin and into the bloodstream of the patient.
`transdermal drug delivery system wherein a novel multiple
`Drug concentration in a monolithic transdermal delivery
`polymer adhesive system is provided which has desirable
`system can vary widely depending on the drug and polymers
`physical properties.
`used. For example, certain drugs are effective in low doses
`and therefore the transdermal formulation may involve low 50
`SUMMARY OF THE INVENTION
`concentrations, illustratively 5% or less by weight of the
`The foregoing and other objects are achieved by this
`medicament in an adhesive. Other drugs, such as
`invention which provides a transdermal drug delivery sys­
`nitroglycerin, require large doses to be effective and the
`tem wherein a blend of at least two polymers, or at least one
`transdermal formulation therefore may involve high drug
`concentrations, approximately between 5 to 40% or more by 55 polymer and a soluble polyvinylpyrrolidone permits
`increased loading of a drug and adjusts the solubility of a
`weight in an adhesive. Low concentrations of medicament
`drug in the blend and thereby modulates the delivery of the
`typically do not critically affect the adhesion, tack, and shear
`drug from the system and through the dermis.
`resistance properties of the adhesive. However, low drug
`In accordance with one aspect of the invention, an
`concentrations in the adhesive can result in difficulties in
`achieving an acceptable delivery rate of the medicament, so improved pressure-sensitive adhesive composition of the
`High concentrations, on the other hand, frequently affect the
`type which is suitable as a matrix for controlled release of a
`adhesion properties of the adhesives. The deleterious effects
`drug therefrom comprises a blend of a rubber-based
`are particularly exacerbated by drugs which also act as
`pressure-sensitive adhesive and a soluble polyvinylpyrroli­
`plasticizers or solvents for the polymeric adhesive (e.g.,
`done (PVP).
`nitroglycerin in polyacrylates).
`The term "polyvinylpyrrolidone," or "PVP" refers to a
`There is a need in the art for an adhesive composition for
`polymer, either a homopolymer or copolymer, containing
`transdermal drug delivery systems which can selectably
`N-vinylpyrrolidone as the monomeric unit. Typical PVP
`
`T
`
`65
`
`

`

`6,024,976
`
`15
`
`4
`3
`weight of the total pressure-sensitive adhesive composition,
`polymers are homopolymeric PVPs and the copolymer vinyl
`while the polyacrylate polymer is preferably present in an
`acetate vinylpyrrolidone. The homopolymeric PVPs are
`amount ranging from about 5% to about 85%. Preferably, the
`known to the pharmaceutical industry under a variety of
`designations including Povidone, Polyvidone,
`ratio of the polyacrylate polymer to the rubber-based
`Polyvidonum, Polyvidonum solubile, and Poly(l-vinyl-2- 5 pressure-sensitive adhesive is from about 2:98 to about 96:4,
`pyrrolidone). The copolymer vinyl acetate vinylpyrrolidone
`and more preferably from about 2:98 to about 86:14 by
`is known to the pharmaceutical industry as Copolyvidon,
`weight.
`Copolyvidone, and Copolyvidonum.
`In both binary and ternary blends, soluble PVP is prefer­
`The term "soluble" when used with reference to PVP
`ably present in the pressure-sensitive adhesive composition
`means that the polymer is soluble in water and generally is 1° in an amount ranging from about 1% to about 20% by
`not substantially cross-linked, and has a molecular weight of
`weight of the total pressure-sensitive adhesive composition.
`less than about 2,000,000. See, generally, Buhler, KOLLI-
`The pressure-sensitive adhesive compositions may further
`DON®: POLYVINYLPRYRROLIDONE FOR THE
`include enhancers, fillers, co-solvents, and excipients as are
`PHARMACEUTICAL INDUSTRY, BASF Aktiengesell-
`known in the art for use in such compositions.
`schaft (1992).
`In a dermal adhesive composition embodiment of the
`It has been surprisingly found that use of a soluble PVP
`invention, a multiple polymer adhesive system comprises a
`results in the ability to form a film
`that does not contain
`blend of 14-94% by weight of a rubber-based pressure-
`particles of insoluble PVP and in the ability to employ
`sensitive adhesive, 5-85% by weight of a polyacrylate
`polymer, and 2-10% by weight of a soluble PVP, and the
`higher concentrations of drug without resulting in increased
`crystallization of the drug.
`20 multiple polymer adhesive system comprises about 50-99%
`by weight of the dermal adhesive composition. This multiple
`In accordance with another embodiment of the invention,
`polymer adhesive system is combined with a drug in the
`an improved pressure-sensitive adhesive composition of the
`amount of 0.1-50% by weight of the total dermal adhesive
`type which is suitable as a matrix for controlled release of a
`drug therefrom comprises a blend of a rubber-based 25 composition. Optional additives, such as co-solvent for the
`pressure-sensitive adhesive having a first
`solubility
`drug (up to 30% by weight) and enhancers (up to 20% by
`parameter, a polyacrylate polymer having a second solubil-
`weight) may be included in the dermal adhesive composi-
`ity parameter, and a soluble PVP, the first
`and second
`tion.
`solubility parameters preferably being different from one
`In transdermal drug delivery system embodiments, incor-
`another by an increment of at least 2 (J/cm3)1/2. The blend, 30 porating a drug in the improved pressure-sensitive adhesive
`therefore, has a characteristic net solubility parameter.
`composition, the characteristic net solubility parameter can
`be preselected to adjust the saturation concentration of the
`In accordance with further embodiment of the invention,
`drug in the composition and thereby control the release of
`an improved pressure-sensitive adhesive composition of the
`the drug. The saturation concentration of the drug may be
`type which is suitable as a matrix for controlled release of a
`35 adjusted either upward or downward depending upon
`drug therefrom comprises a blend of a rubber-based
`whether the rate of release is to be enhanced or retarded.
`pressure-sensitive adhesive having a first
`solubility
`parameter, and a polyacrylate polymer having a second
`In particularly preferred embodiments, the drug is a
`solubility parameter, the first and second solubility param­
`steroid, such as an estrogen or a progestational agent, or
`eters preferably being different from one another by an
`combination thereof. In other preferred embodiments, the
`increment of at least 2 (J/cm3)1/2
`. The blend, therefore, has 40 drug may be a P2-adrenergic agonist, such as albuterol, or a
`a characteristic net solubility parameter.
`cardioactive agent, such as nitroglycerin. In still other
`embodiments, the drug is a cholinergic agent, such as
`Particularly preferred embodiments include binary blends
`pilocarpine, or an antipsychotic such as haloperidol or a
`comprising a rubber-based pressure-sensitive adhesive and a
`tranquilizer/sedative such as alprazolam.
`soluble PVP, wherein the rubber-based pressure-sensitive
`adhesive is a polysiloxane. Polysiloxane is preferably 45
`The transdermal drug delivery system may comprise a
`present in the pressure-sensitive adhesive composition in an
`monolithic adhesive matrix device in some embodiments.
`amount ranging from about 9% to about 97% by weight of
`The transdermal drug delivery system may further include a
`the total pressure-sensitive adhesive composition.
`backing material and a release liner as is known in the art.
`Other particularly preferred embodiments include ternary
`The saturation concentration of a drug in a transdermal
`blends comprising a rubber-based pressure-sensitive 50 drug delivery system of the type having a drug-containing
`adhesive, a polyacrylate polymer, and a soluble PVP,
`pressure-sensitive adhesive diffusion matrix is adjusted in
`wherein the rubber-based pressure-sensitive adhesive is a
`accordance with an aspect of the present invention by
`polysiloxane. Polysiloxane is preferably present in the
`blending at least two polymers having differing solubility
`pressure-sensitive adhesive composition in an amount rang­
`parameters as defined above to form a pressure-sensitive
`ing from about 9% to about 97% by weight of the total 55 adhesive diffusion matrix having a net solubility parameter
`pressure-sensitive adhesive composition, while the poly­
`which modifies the delivery rate of the drug from the
`acrylate polymer is preferably present in an amount ranging
`pressure-sensitive adhesive diffusion matrix and through the
`from about 5% to about 85%. Preferably, the ratio of the
`dermis.
`polyacrylate polymer to the rubber-based pressure-sensitive
`BRIEF DESCRIPTION OF THE DRAWINGS
`adhesive is from about 2:98 to about 96:4, and more 60
`Comprehension of the invention is facilitated by reading
`preferably from about 2:98 to about 86:14 by weight.
`the following detailed description, in conjunction with the
`Other particularly preferred embodiments include blends
`annexed drawing, in which:
`comprising a rubber-based pressure-sensitive adhesive and a
`FIG. 1 is a schematic illustration of a monolithic trans-
`polyacrylate polymer, wherein the rubber-based pressure-
`sensitive adhesive is a polysiloxane. Polysiloxane is prefer- 65 dermal drug delivery device of the present invention;
`FIG. 2 is a graphic representation of the steady-state
`ably present in the pressure-sensitive adhesive composition
`nitroglycerin flux rates through cadaver skin in vitro from a
`in an amount ranging from about 9% to about 97% by
`
`

`

`25
`
`DETAILED DESCRIPTION OF PREFERRED
`EMBODIMENTS
`
`6,024,976
`
`6
`calculated using a weighted average of the solubility param­
`eters of the individual polymers comprising the matrix:
`
`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-
`SPncr0psSPps+0paSPpa,
`Geigy Corporation, Summit, N.J.), and NITRO-DUR® (a 5
`trademark of Key Pharmaceuticals, Inc., Kenilworth, N.J.);
`where 0ps is the weight percentage of polysiloxane and SP^
`FIG. 3 is a graphical representation which summarizes in
`is the solubility parameter of polysiloxane. The subscript
`vitro nitroglycerin flux results through cadaver skin for the
`"pa" refers to the polyacrylate;
`polymeric systems of Examples 2-5. The composition of
`FIG-
`i® a plot 0f diffusion coefficient versus net
`,
`, m
`,
`
` „ .
`,
`
`
` ,
` ,
`„
`.
`N
`.
`
`Example 2 (polyacrylate-only adhesive) is compared to the 1° SQ]L||-)j]j^y parameter'
`multiple polymer compositions of Examples 3, 4, and 5, in
`'
`FIG. 16 shows the average flux of estradiol for two
`which the polyacrylate is blended with an ethylene vinyl
`compositions of this invention containing a soluble PVP;
`acetate, a polyisobutylene, and a polysiloxane, respectively;
`FIG. 17 shows estradiol flux through the human epidermis
`FIG. 4 is a graphical representation of the steady-state
`from a PVP-containing compositions of this invention;
`nitroglycerin flux through cadaver skin in vitro from a
`FIG. i8 shows norethindrone flux through human epider-
`multiple polymer transdermal adhesive system of Example
`mis in a composition of this invention containing estradiol
`6 comprising various weight ratios of polyacrylate and
`and soluble PVP;
`polysiloxane;
`FIG. 19 shows average estradiol and norethindrone
`FIG. 5 is a graphical representation of steady-state estra- 20 acetate flux from a composition of this invention containing
`diol flux through cadaver skin in vitro from the drug delivery
`varying concentrations of soluble PVP; and
`systems of the prior art, specifically single polymeric adhe-
`FIG. 20 shows the effect of soluble PVP on estradiol flux
`sives of silicone and acrylic, as compared to a multiple
`through human epidermis,
`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
`In one aspect of the present invention, a pressure-sensitive
`from 22 to 99 hours for a multiple polymer transdermal
`adhesive composition is provided which comprises a blend
`adhesive system comprising various weight ratios of poly­
`of at least two polymers and a soluble PVP, and a drug. The
`acrylate and polysiloxane;
`30 blend of at least two polymers is herein referred to as a
`FIG. 7 is a graphical representation of steady-state nore­
`multiple polymer adhesive system. The term "blend" is used
`thindrone acetate flux through cadaver skin in vitro from the
`herein to mean that there is no, or substantially no, chemical
`drug delivery systems of the prior art, specifically single
`reaction or cross-linking (other than simple H-bonding)
`polymeric adhesives of silicone and acrylic, as compared to
`between the different polymers in the multiple polymer
`a multiple polymer transdermal adhesive system 35 adhesive system,
`(polyacrylate/polysiloxane) of the present invention;
`As used herein, the term "pressure-sensitive adhesive"
`FIG. 8 is a graphical representation of average estradiol
`refers to a viscoelastic material which adheres instanta-
`and norethindrone acetate flux through cadaver skin in vitro
`neously to most substrates with the application of very slight
`for a multiple polymer transdermal adhesive system com­
`pressure and remains permanently tacky. A polymer is a
`prising both drugs and various weight ratios of polyacrylate 40 pressure-sensitive adhesive within the meaning of the term
`and polysiloxane;
`as used herein if it has the properties of a pressure-sensitive
`adhesive per se or functions as a pressure-sensitive adhesive
`FIG. 9 is a graphical representation showing the ratio of
`by admixture with tackifiers, plasticizers or other additives.
`average estradiol to norethindrone acetate flux (estradiol flux
`divided by norethindrone acetate flux) through cadaver skin
`The term pressure-sensitive adhesive also includes mix­
`in vitro for a multiple polymer transdermal adhesive system 45
`tures of different polymers and mixtures of polymers, such
`comprising various weight ratios of polyacrylate and pol­
`as polyisobutylenes (PIB), of different molecular weights,
`ysiloxane;
`wherein each resultant mixture is a pressure-sensitive. In the
`last case, the polymers of lower molecular weight in the
`FIG. 10 is a graphical representation of steady-state flux
`of pilocarpine through cadaver skin in vitro from the drug 50 mixture are not considered to be "tackifiers," said term being
`delivery systems of the prior art, specifically single poly-
`reserved for additives which differ other than in molecular
`meric adhesives of silicone and acrylic, as compared to a
`weight from the polymers to which they are added,
`multiple polymer transdermal adhesive system
`As used herein, the term "rubber-based pressure-sensitive
`(polyacrylate/polysiloxane) of the present invention;
`adhesive" refers to a viscoelastic material which has the
`FIG. 11 is a graphical representation of steady-state 55 properties of a pressure-sensitive adhesive and which con-
`tains at least one natural or synthetic elastomeric polymer.
`albuterol and nitroglycerin flux through cadaver skin in vitro
`from multiple polymer transdermal adhesive systems
`As used herein, the term "drug," and its equivalent,
`(polyacrylate/polysiloxane) of the present invention
`"bioactive agent," is intended to have its broadest interpre­
`(Examples 24-27), and NITRO-DUR®, respectively;
`tation as any therapeutically, prophylactically and/or phar-
`FIG. 12 is a graphical representation of steady-state go macologically or physiologically beneficial active
`estradiol flux through cadaver skin in vitro from two differ­
`substance, or mixture thereof, which is delivered to a living
`organism to produce a desired, usually beneficial, effect.
`ent multiple polymer transdermal adhesive systems
`polyacrylate/polysiloxane and polyacrylate/polybutylene;
`More specifically, any drug which is capable of producing
`FIGS. 13 and 14 show the relationship of flux rate (J)
`a pharmacological response, localized or systemic, irrespec-
`plotted against apparent diffusion coefScient (D) and net 65 tive of whether therapeutic, diagnostic, or prophylactic in
`solubility parameter (SP), respectively, for Compositions
`nature, in plants or animals is within the contemplation of
`I-VI of Example 6. The net solubility parameter, SP„et, was
`the invention. Also within the contemplation of the inven-
`
`

`

`6,024,976
`
`TABLEIA
`
`Solubility Parameter
`
`Polymers
`
`(cal/cm3)172
`
`(J/cm3)17