United States Patent m
`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, Ha.
`
`[73] Assignee: Noven Pharmaceuticals, Inc., Miami,
`Ha.
`
`[21] Appl. No.: 178,558
`Jan. 7,1994
`[22] Filed:
`
`Related U.S. Application Data
`
`[63] Continuation-in-part of Ser. No. 722,342, Jun. 27,1991, Pat
`No. 5,474,783, which is a continuation-in-part of PCT/
`US90/01750, Mar. 28,1990, which is a continuation-in-part
`of Ser. No. 671,709, Apr. 2,1991, Pat No. 5,300,291, which
`is a continuation-in-part of Ser. No. 295,847, Jan. 11,1989,
`Pat No. 4,994,267, which is a continuation-in-part of Ser.
`No. 164,482, Mar. 4, 1988, Pat No. 4,814,168.
`A61F 13/02
`[51] Int CI.6
`424/449; 424/448
`[52] U.S. CI
`424/448, 449
`[58] Field of Search
`
`[56]
`
`References Cited
`U.S. PATENT DOCUMENTS
`7/1976 Penneck
`3,969,308
`8/1976 Tsuk et al. ..
`3,972,995
`9/1981 Keith etal. .
`4,291,015
`9/1981 Keith etal. .
`4,292,301
`6/1983 Nagai et al.
`4,390,520
`3/1984 Keith etal. .
`4,438,139
`9/1985 Keith
`4,542,013
`4/1986 Sablotsky ....
`4,585,452
`6/1986 Jevne et al. .
`4,593,053
`4,668,232
`5/1987 Cordes et al.
`9/1987 Chien et al.
`4,690,683
`9/1987 Shah
`4,693,887
`9/1987 Belsole
`4,696,821
`4,699,146 10/1987 Sieverding
`6/1988 Sieverding
`4,750,482
`
`260/37 SB
`424/28
`424/28
`424/28
`424/28
`424/28
`424/28
`.... 604/896
`... 523/111
`... 604/897
`... 604/896
`424/19
`.... 424/448
`.... 128/640
`.... 128/156
`
`US005656286A
`[ii] Patent Number:
`[45] Date of Patent:
`
`5,656,286
`Aug. 12, 1997
`
`FOREIGN PATENT DOCUMENTS
`4/1991 Canada.
`2027053
`0201828 11/1986 European Pat. Off..
`1/1987 European Pat. Off. .
`208395
`6/1988 European Pat. Off. .
`0272045
`0343807 11/1989 European Pat. Off. .
`6/1990 European Pat. Off. .
`0 371 496
`3/1991 European Pat. Off. .
`0416842
`3/1993 European Pat. Off. .
`0529123
`7/1979 Japan.
`54-89017
`58-225010 12/1983 Japan.
`4/1983 United Kingdom .
`2 105 990
`5/1991 WIPO .
`91/05529
`93/08795 5/1993 WIPO.
`
`OTHER PUBLICATIONS
`Yu et al., "Transdermal Dual-Controlled Delivery of Test­
`osterone and Estradiol: (I) Impact of System Design," Drug
`Devel. Indust. Pharm. 17(14): 1883-1904 (1991).
`Ziller et al., "Control of Crystal Growth in Drug Suspen­
`sions," Pharm. Ind. 52(8): 1017-1022 (1990).
`English translation of Japanese patent application No.
`2^18859, filed Feb. 27, 1990.
`Sloan, K. B. et al., "Use of Solubility Parameters of Drug
`and Vehicle to Predict Hux Through Skin", The Journal of
`Investigative Dermatology, vol. 87 (No. 2) pp. 244—252
`(Aug. 1986).
`
`Primary Examiner—Jyothsna Venkat
`Attorney, Agent, or Firm—Foley & Lardner
`ABSTRACT
`[57]
`A blend 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.)
`
`73 Claims, 19 Drawing Sheets
`
`fT
`
`1
`m
`
`m
`
`13
`
`m
`
`12
`
`11
`
`2
`
`10
`
`  
`
`

 
`
`MYLAN - EXHIBIT 1011
`
`

`

`5,656,286
`Page 2
`
`U.S. PATENT DOCUMENTS
`9/1988 Lorenz et al. ...
`3/1989 Sablotsky et al.
`7/1989 Sloan
`11/1989 Chienetal
`3/1990 Chienetal
`3/1990 deary
`6/1990 Kim et al
`1/1991 Salamone et al.
`2/1991 Sablotsky
`7/1991 Sinnieich
`10/1991 Cilento et al. ...
`12/1991 Leeetal
`
`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
`
`.. 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
`
`6/1992 Khanna
`5,122,543
`7/1992 Blank
`5,128,138
`8/1992 Leeetal
`5,141,750
`9/1992 Otsuka et al
`5,151,271
`10/1992 Govil et al
`5,154,922
`7/1993 Yeh et al
`5,230,896
`5,230,898
`7/1993 Horstmann et al.
`8/1993 Pfister et al
`5.232.702
`8/1993 Blank
`5.232.703
`5^52,334 10/1993 Chiang et al
`5,260,064 11/1993 Nakagawa et al.
`5,262,165 11/1993 Govil et al
`2/1995 Hoffinann et al.
`5,393,529
`
`514/772.5
`.. 424/449
`.. 424/448
`.. 424/443
`.. 424/448
`.. 424/443
`.. 424/449
`.. 424/448
`.. 424/449
`.. 424/448
`.. 424/448
`.. 424/448
`.. 424/445
`
`

`

`U.S. Patent
`
`Aug. 12, 1997
`
`Sheet 1 of 19
`
`5,656,286
`
`FIG.1
`
`13
`
`1 m
`m
`
`m
`
`12
`
`11
`
`2
`
`m
`
`10
`
`FLUX
`(|ig/cmA2/hr)
`
`24
`
`20-
`
`1 6 -
`
`1 2 -
`
`g
`
`4 ~
`
`0
`
`FIG. 2
`
`20.8
`
`13.4
`
`9.5
`
`m
`
`-i
`
`EXAMPLE
`
`m
`
`Nitro - Dur
`
`PRODUCT
`
`Transderm - Nitro
`
`

`

`ON
`OO
`
`9\
`ui
`ON
`u\
`
`V©
`
`1-15
`
`tO
`JD
`sr
`en
`
`vo
`vo
`
`op
`>
`
`fD 0
`P
`
`a
`
`t/i
`
`* ACR/POLYMER RATIOS
`
`OF 45/55, W/W
`
`EXAMPLE 5
`
`ACR/SI *
`
`EXAMPLE 4
`ACR/PIB *
`
`21
`
`ADHESIVE COMPOSITION
`
`EXAMPLE 3
`ACR/EVA *
`2:
`
`EXAMPLE 2
`
`ACR
`
`2J
`
`0
`
`4 -
`
`g
`
`26.2
`
`W
`
`[Z
`
`25.4
`
`FIG. 3
`
`Vs
`
`12.5
`
`16.0
`
`[Z
`
`12-
`
`16-
`
`20-
`
`24-
`
`28-
`
`(|ig/cmA2/hr)
`
`FLUX
`
`

`

`ON
`QO
`IN>
`Q\
`ON
`Ui
`
`N#
`
`v®
`o its
`CO er re re
`
`Ui
`
`vo <1
`vo
`1°
`CTQ
`e
`•
`
`fD 9
`P
`13
`(Z)
`CI
`
`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®
`'A
`
`'A
`
`'A
`
`21
`
`2.95
`
`m
`
`1.57
`
`3.16
`
`W,
`
`4.2
`
`4.54
`
`4.92
`
`5.21
`
`iz
`
`FIG. 4
`
`41
`
`0
`
`2
`
`4 ~
`
`7
`
`(|ng/cmA2/hr)
`
`FLUX
`
`

`

`QO as
`ON in as
`
`U\
`
`VO
`h—1
`o MS
`a
`Gfi cr
`
`v© -J
`
`VO
`
`bJ
`
`c op
`>
`
`P
`PS
`hfl
`t/>
`CI
`
`(EXAMPLE 7)
`
`SILICONE /ACRYLIC
`
`(EXAMPLE 8)
`
`ACRYLIC
`
`(EXAMPLE 9)
`
`SILICONE
`
`23
`
`0.0
`
`0.1 -
`
`0.354
`
`0.210
`
`FIG. 5
`
`0.190
`
`0.2 -
`
`(jLig/cmA2/hr)
`
`FLUX
`
`0.3 -
`
`0.4
`
`

`

`ON
`QO
`
`in o\
`o\
`ux
`
`\»
`
`vo
`o MS
`Ul
`2-
`fC
`C/3 tr
`
`vo
`
`> P
`
`(TQ
`
`ft
`&
`
`t/j
`d
`
`H EX-13
`m EX-12
`
`g EX.11
`EX.10
`
`22 - 99 HR
`
`0 - 22 HR
`
`STUDY TIME
`
`X
`
`I
`
`\]
`
`FIG. 6
`
`0.0
`
`0.2-
`
`0.4-
`
`0.6-
`
`0.8-
`
`1.0-
`
`1.2-
`
`1.4-
`
`1.6
`
`((ig/cmA2/hr)
`
`FLUX
`
`

`

`0\
`oc
`ON in as
`in
`
`"5
`
`S-
`B-
`OJ
`
`"vO
`vo
`*>>
`
`cp
`>
`
`P
`•A
`SZ2
`ci
`
`(EXAMPLE 15)
`
`(EXAMPLE 16)
`
`(EXAMPLE 14)
`
`SILICONE
`
`SILICONE/ACRYLIC
`
`ACRYLIC
`
`X]
`
`0.213
`
`0.354
`
`5]
`
`1.082
`
`FIG. 7
`
`0.0
`
`0.2-
`
`0.4-
`
`0.6-
`
`0.8-
`
`1.0-
`
`1.2
`
`(jig/cmA2/hr)
`
`FLUX
`
`

`

`ON in ON
`
`ON
`GC
`K)
`
`Ul
`
`(-* "O
`
`-J
`ro
`^
`
`g
`
`N*
`h-i
`op
`•
`
`P
`P
`hd
`CZ)
`d
`
`H EXAMPLE 20
`• EXAMPLE 19
`
`g EXAMPLE 18
`
`^ EXAMPLE 17
`
`NAC
`
`DRUG
`
`E2
`
`[V
`
`F/G.8
`
`0.0
`
`0.1 -
`
`0.2 -
`
`0.3
`
`(|Lig/cmA2/hr)
`
`FLUX
`
`

`

`ON
`v# b* oo
`ON
`o\ in
`Ul
`
`s®
`
`VO
`h-i
`1-15
`o
`00
`ft
`CD
`cz> er
`
`-4
`VO
`VO
`
`> c
`
`to
`op
`
`9
`n
`as
`
`d
`
`£3 EXAMPLE 20
`
`• EXAMPLE 19
`
`EXAMPLE 18
`
`{H EXAMPLE 17
`
`SI /ACR RATIO
`
`FIG. 9
`
`0
`
`1
`
`FLUX RATIO
`
`E2/NAC
`
`2
`
`3
`
`

`

`o\ in
`oi
`
`ON
`00
`fcN>
`OS
`
`N*
`
`(EXAMPLE 21 )
`
`SILICONE
`
`(EXAMPLE 23)
`
`(EXAMPLE 22)
`
`SILICONE /ACRYLIC
`
`ACRYLIC
`
`V©
`o Ms
`vo
`fC
`
`CZl er
`
`o
`V© \o
`
`op
`• c
`
`0
`P
`•A
`O)
`CI
`
`12.01
`
`8.80
`
`FIG. 10
`
`3.87
`
`0
`
`10 -
`
`15
`
`(lLig/cmA2/hr)
`
`FLUX
`
`

`

`00 o\
`ON
`Ul
`ON
`in
`
`\»
`
`V©
`h-1
`© MS
`o
`t—»
`er » rp
`
`5/2
`
`h-i
`ts>
`
`cp
`• c
`
`n
`p
`
`Xfl
`CI
`
`Nitro - Dur
`
`EXAMPLE 27
`
`EXAMPLE 26
`
`EXAMPLE 25
`
`EXAMPLE 24
`
`COMPOSITION
`
`21.6
`
`20.6
`
`16.9
`
`19.1
`
`27.6
`
`FIG. 11
`
`0
`
`4 -
`
`g
`
`12-
`
`16-
`
`20-
`
`24-
`
`28-
`
`32
`
`((Lig/cmA2/hr)
`
`FLUX
`
`

`

`Q\
`00
`ss fco
`OS
`U\
`o\
`in
`
`vo
`© its
`
`re
`05 er re
`
`-a
`vo
`VD
`
`to
`op
`c
`
`S3
`«>
`P
`
`CO
`d
`
`ADHESIVE
`
`(EXAMPLE 28)
`
`POLYISOBUTYLENEI ACRYLIC
`
`(EXAMPLE 29)
`
`SILICONE/ACRYLIC
`
`0.49
`
`F
`
`0.54
`
`FIG. 72
`
`0.0
`
`0.1 -
`
`0.2 -
`
`0.3 -
`
`0.4 -
`
`0.5 -
`
`0.6 -
`
`0.7
`
`(fig/cm A2/hr)
`
`FLUX
`
`

`

`U.S. Patent
`US. Patent
`
`Aug. 12, 1997
`Aug. 12, 1997
`
`Sheet 12 of 19
`Sheet 12 of 19
`
`5,656,286
`5,656,286
`
`o
`
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`
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`
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`
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`
`UL O
`CD
`
`

`

`U.S. Patent
`U.S. Patent
`
`Aug. 12, 1997
`Aug. 12, 1997
`
`Sheet 13 of 19
`Sheet 13 of 19
`
`5,656,286
`5,656,286
`
`o
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`m.
`03
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`

`

`00 o\
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`
`ON
`
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`8,
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`
`&
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`
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`P
`13
`t/5
`d
`
`SOLUBILITY PARAMETER (cal / cmA3 )A1/2
`
`10.0
`
`9.5
`T
`
`9.0
`
`8.5
`
`8.0
`
`7.5
`
`A
`
`A
`
`A
`
`7.0
`0
`
`100-
`
`DIFFUSION COEFFICIENT
`
`(cmA2 / sec)
`
`y = 4.0902e+8 * 10A( -0.83543x) RA2 = 0.853
`
`FIG. 15
`
`200-
`
`A
`
`300
`
`

`

`ON
`oo
`Q\ in o\
`tn
`
`VO
`
`M5
`Q
`ui
`a
`05 cr
`
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`
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`
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`
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`
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`
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`
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`
`• EXAMPLE 45
`
`O EXAMPLE 44
`
`96
`
`—A
`
`72
`T
`
`e
`
`TIME (hrs)
`
`48
`
`A
`
`e
`
`EXAMPLE 44
`
`24
`T
`
`e
`
`EXAMPLE 45
`
`FIG. 16
`
`0
`
`0.0
`
`0.5-
`
`(jig / cmA2/hr)
`AVERAGE FLUX
`
`1.0-
`
`1.5
`
`

`

`QO a\
`K)
`Q\
`Q\ in
`\»
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`
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`03
`d
`
`ESTRADIOL CONCENTRATION (%, W/W)
`
`1
`
`zi
`
`m
`
`0.8
`
`m
`
`0.6
`
`0.5
`
`0.4
`
`0.2
`
`m
`
`m
`
`m
`
`0.1
`
`0.05
`
`sy/.
`
`0.065
`
`0.033
`
`0
`
`0
`
`0.131
`
`t0.224
`
`EXAMPLE 47
`
`EXAMPLE 46
`
`0.357 m
`
`0.282
`
`EXAMPLE 48
`
`EXAMPLE 49
`
`EXAMPLE 50
`
`0.506
`
`0.478
`
`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)
`
`

`

`Q\
`oc
`ON
`o\ in
`in
`
`s*
`
`VO
`h-»
`
`CZJ cr re a
`
`o
`-a
`
`X
`
`i—i
`
`OfQ
`
`•
`
`S3
`n
`PS
`
`cc
`d
`
`m
`
`1
`
`m
`
`0.8
`
`m
`
`0.6
`
`ESTRADIOL CONCENTRATION (%, W/W)
`0.1
`
`0.5
`
`0.4
`
`0.2
`
`0.05
`
`m
`
`m
`
`0
`
`0.837
`
`0.809
`
`0.855
`
`P2
`
`0.842
`
`0.751
`
`V/
`
`0.817
`
`0.712
`
`m
`
`EXAMPLE 53
`
`0.889
`
`0.89
`
`EXAMPLE 52
`
`EXAMPLE 50
`
`EXAMPLE 51
`
`EXAMPLE 48
`
`EXAMPLE 47
`
`EXAMPLE 49
`
`EXAMPLE 46
`
`0.0
`
`0.2 -
`
`0.4 -
`
`0.6 -
`
`0.8 -
`
`1.0 -
`
`1.2
`
`AVERAGE NETA FLUX
`
`(|ig/cmA2/hr)
`
`FIG. 18
`
`

`

`ON
`QO
`K)
`ON
`Ul
`ON
`lit
`
`vo
`o 1-15
`QO
`
`co cr ft £
`
`$
`
`h-k
`
`K>
`
`c cro
`•
`
`ft P
`
`cyj
`d
`
`H NETAFLUX
`
`^ ESTRADIOL FLUX
`
`10
`
`0.164
`
`% POLYVINYL PYRROLIDONE
`5
`WIW
`
`2.5
`*
`
`0
`
`0.0
`
`0.126
`
`0.137
`
`0.14
`
`0.2-
`
`EXAMPLE 57
`
`EXAMPLE 56
`
`EXAMPLE 55
`
`54
`EXAMPLE
`
`0.668
`
`T
`
`0.531
`
`0.61
`
`0.648
`
`0.4-
`
`0.6-
`
`0.8
`
`AVERAGE DRUG FLUX
`
`(|ig/cmA2/hr)
`
`FIG. 19
`
`

`

`ON
`QO
`
`ON
`Ul
`ON
`
`S*
`
`V©
`
`MS
`o
`
`t—k
`
`cc
`1/3 tr
`
`& <1
`
`K>
`
`c oro
`>
`
`P
`rt>
`P
`
`CO
`d
`
`96
`
`72
`
`TIME (hrs)
`
`48
`T
`
`24
`
`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
`
`(jxg / cmA2 / hr)
`ESTRADIOL FLUX
`
`

`

`5,656,286
`
`2
`1
`an adequate and controlled rate or incorporate high concen­
`SOLUBILITY PARAMETER BASED DRUG
`trations of drugs while retaining good physical adhesive
`DELIVERY SYSTEM AND METHOD FOR
`properties.
`ALTERING DRUG SATURATION
`CONCENTRATION
`In transdermal drug delivery systems, the presence of
`5 crystals (drugs and/or additives) is generally undesirable. If
`CROSS-REFERENCE TO RELATED
`the drug is present in crystalline form, it is not available for
`APPLICATION
`release from the system, and therefore not available for
`delivery. Moreover, although drug crystals can first dissolve
`This application is a continuation-in-part of Ser. No.
`and then release from the system, such a process is usually
`07/722342 filed Jun. 27.1991, now U.S. Pat. No. 5,474,783,
`which application is a continuation-in-part of PCT applica- 10 rate-limiting and tends to reduce delivery.
`tion PCr/US90/01750 filed Mar. 28,1990, and filed nation­
`Crystal size and distribution thus become important
`ally as U.S. Ser. No. 671,709 on Apr. 2,1991, now U.S. Pat.
`parameters which must be controlled in order to control
`delivery. These parameters are, however, usually difficult to
`No. 5300,291; which in turn is a continuation-in-part of
`control. Failure to control crystal size and distribution can
`U.S. patent application Ser. No. 295,847, filed Jan. 11,1989,
`result in products whose appearance suggests that the manu­
`now U.S. Pat. No. 4,994,267 issued Feb. 19,1991; which is 15
`facturing process by which they are produced is not under
`a continuation-in-part of U.S. patent application Ser. No.
`control. More importantly, the presence of large crystals,
`164,482, filed Mar. 4, 1988 now U.S. Pat. No. 4,814,168,
`particularly in excessive amounts, can be detrimental to
`granted Mar. 21,1989 all of which patents and applications
`adhesive-type transdermals. Crystals on the surface of the
`are hereby incorporated by reference. All applications and
`patents are assigned to Noven Pharmaceuticals, Inc. of 20 adhesive system can result in loss of tack. Furthermore,
`surface crystals can come into direct contact with the skin,
`Miami, Fla.
`and could cause skin irritation.
`BACKGROUND OF THE INVENTION
`There is a need in the art for an adhesive composition for
`This invention relates generally to transdermal drug deliv- 25 transdermal delivery systems which can prevent or suppress
`crystallization of drugs therein.
`ery systems, and more particularly, to a transdermal drug
`it is, therefore, an object of this invention to provide a
`delivery composition wherein a blend of polymers is utilized
`transdermal drug delivery system wherein the rate of drug
`to affect the rate of drug delivery from the composition.
`delivery from the transdermal composition may be select-
`More specifically, a plurality of polymers including a soluble
`polyvinylpyrrolidone having differing solubility parameters, 30 abiy 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
`ably modulated by adjusting the solubility and/or diffusivity
`composition and through the dermis.
`35 of the drug in the multiple polymer adhesive system.
`The use of a transdermal composition, for example a
`It is also an object of this invention to provide a trans­
`pressure-sensitive adhesive containing a medicament,
`dermal drug delivery system wherein the multiple polymer
`namely, a drug, as a means of controlling drug delivery
`adhesive system is simple to manufacture.
`through the skin at essentially a constantrate, is well known.
`It is a further object of this invention to provide a
`Such known delivery systems involve incorporation of a
`40 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 deKvery rate and adhesive
`sensitive adhesive must adhere effectively to the skin and
`properties, such as adhesion, tack, and shear resistance.
`permit migration of the medicament from the carrier through
`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
`SUMMARY OF THE INVENTION
`concentrations, illustratively 5% or less by weight of the 50
`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
`polymer and a soluble polyvinylpyrrolidone permits
`concentrations, approximately between 5 to 40% or more by
`weight in an adhesive. Low concentrations of medicament 55 increased loading of a drug and adjusts the solubility of a
`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
`concentrations in the adhesive can result in difficulties in
`In accordance with one aspect of the invention, an
`achieving an acceptable delivery rate of the medicament
`improved pressure-sensitive adhesive composition of the
`High concentrations, on the other hand, frequently affect the go 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
`pressure-sensitive adhesive and a soluble polyvinylpyrroli­
`are particularly exacerbated by drugs which also act as
`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 65 polymer, either a homopolymer or copolymer, containing
`N-vinylpyrrolidone as the monomeric unit Typical PVP
`transdermal drug delivery systems which can selectably
`polymers are homopolymeric PVPs and the copolymer vinyl
`incorporate low concentrations of drug and deliver same at
`
`45
`
`

`

`5,656,286
`
`4
`3
`acetate vinylpyrrolidone. The homopolymeric PVPs are
`while the polyacrylate polymer is preferably present in an
`amount ranging from about 5% to about 85%. Preferably, the
`known to the pharmaceutical industry under a variety of
`ratio of the polyacrylate polymer to the rubber-based
`designations including Povidone, Polyvidone,
`pressure-sensitive adhesive is from about 2:98 to about 96:4,
`Polyvidonum, Polyvidonum solubile, and Poly(l-vinyl-2-
`pyirolidone). The copolymer vinyl acetate vinylpyrrolidone 5 and more preferably from about 2:98 to about 086:14 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
`in an amount ranging from about 1% to about 20% by
`not substantially cross-linked, and has a molecular weight of 10 weight of the total pressure-sensitive adhesive composition.
`less than about 2,000,000. See, generally, Biihler, KOLLI-
`The pressure-sensitive adhesive compositions may further
`DON<D: POLYVINYLPRYRROLIDONE FOR THE
`include enhancers, fillers, co-solvents, and exdpients 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 15
`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
`higher concentrations of drug without resulting in increased
`polymer, and 2-10% by weight of a soluble PVP, and the
`crystallization of the drug.
`20 multiple polymer adhesive system comprises about 50-99%
`In accordance with another embodiment of the invention.
`by weight of the dermal adhesive composition. This multiple
`an improved pressure-sensitive adhesive composition of the
`polymer adhesive system is combined with a drug in the
`type which is suitable as a matrix for controlled release of a
`amount of 0.1-50% by weight of the total dermal adhesive
`drug therefrom comprises a blend of a rubber-based
`composition. Optional additives, such as co-solvent for the
`pressure-sensitive adhesive having a first solubility 25 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)172. The blend,
`porating a drug in the improved pressure-sensitive adhesive
`therefore, has a characteristic net solubility parameter.
`30 composition, the characteristic net solubility parameter can
`In accordance with further embodiment of the invention,
`be preselected to adjust the saturation concentration of the
`an improved pressure-sensitive adhesive composition of the
`drug in the composition and thereby control the release of
`type which is suitable as a matrix for controlled release of a
`the drug. The saturation concentration of the drug may be
`drug therefrom comprises a blend of a rubber-based
`adjusted either upward or downward depending upon
`solubility 35 whether the rate of release is to be enhanced or retarded,
`pressure-sensitive adhesive having a first
`parameter, and a polyacrylate polymer having a second
`In particularly preferred embodiments, the drug is
`solubility parameter, the first and second solubility param­
`asteroid, 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
`drug may be a p2-adrenergic agonist, such as albuterol, or a
`a characteristic net solubility parameter.
`40 cardioactive agent, such as nitroglycerin. In still other
`Particularly preferred embodiments include binary blends
`embodiments, the drug is a cholinergic agent, such as
`comprising a rubber-based pressure-sensitive adhesive and a
`pilocarpine, or an antipsychotic such as haloperidol or a
`soluble PVP, wherein the rubber-based pressure-sensitive
`tranquilizer/sedative such as alprazolam.
`adhesive is a polysiloxane. Polysiloxane is preferably
`The transdermal drug delivery system may comprise a
`.
`present in the pressure-sensitive adhesive composition in an 45 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
`drug delivery system of the type having a drug-containing
`adhesive, a polyacrylate polymer, and a soluble PVP, 50
`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
`adhesive diffusion matrix having a net solubility parameter
`pressure-sensitive adhesive composition, while the poly­
`55 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
`adhesive is from about 2:98 to about 96:4, and more
`BRIEF DESCRIPTION OF THE DRAWINGS
`preferably from about 2:98 to about 86:14 by weight.
`Comprehension of the invention is facilitated by reading
`Other particularly preferred embodiments include blends
`the following detailed description, in conjunction with the
`comprising a rubber-based pressure-sensitive adhesive and a
`annexed drawing, in which:
`polyacrylate polymer, wherein the rubber-based pressure-
`FIG. 1 is a schematic illustration of a monolithic trans-
`sensitive adhesive is a polysiloxane. Polysiloxane is prefer­
`ably present in the pressure-sensitive adhesive composition 65 dermal drug deUvery device of the present invention;
`FIG. 2 is a graphic representation of the steady-state
`in an amount ranging from about 9% to about 97% by
`weight of the total pressure-sensitive adhesive composition.
`nitroglycerin flux rates through cadaver skin in vitro from a
`
`60
`
`

`

`5,656,286
`
`6
`calculated using a weighted average of the solubility param­
`eters of the individual polymers comprising the matrix:
`
`SPno^psSPpyfefpaSPp,,,
`where 0ps is the weight percentage of polysiloxane and SP^
`is the solubility parameter of polysiloxane. The subscript
`"pa" refers to the polyacrylate;
`FIG. 15 is a plot of diffusion coefficient versus net
`10 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.
`
`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, N. J.), and Nitro-Dur® (a trademark of 5
`Key Pharmaceuticals, Inc., Kenilworth, N.J.);
`FIG. 3 is a graphical representation which summarizes in
`vitro nitroglycerin flux results through cadaver skin for the
`polymeric systems of Examples 2-5. 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
`through cadaver skin in vitro from a 15
`nitroglycerin flux
`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- 2Q
`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
`DETAILED DESCRIPTION OF PREFERRED
`polymer transdermal adhesive system (polyacrylate/
`EMBODIMENTS
`polysiloxane) of the present invention;
`FIG. 6 is a graphical representation of average estradiol
`In one aspect of the present invention, a pressure-sensitive
`flux through cadaver skin in vitro from 0 to 22 hours and
`adhesive composition is provided which comprises a blend
`from 22 to 99 hours for a multiple polymer transdermal
`of at least two polymers and a soluble PVP, and a drug. The
`adhesive system comprising various weight ratios of poly­
`blend of at least two polymers is herein referred to as a
`acrylate and polysiloxane;
`30 multiple polymer adhesive system. The term "blend" is used
`herein to mean that there is no, or substantially no, chemical
`FIG. 7 is a graphical representation of steady-state nore­
`reaction or cross-linking (other than simple H-bonding)
`thindrone acetate flux through cadaver skin in vitro from the
`between the different polymers in the multiple polymer
`drug delivery systems of the prior art, specifically single
`adhesive system
`polymeric adhesives of silicone and acrylic, as compared to
`As used herein, the term "pressure-sensitive adhesive"
`a multiple polymer transdermal adhesive system 35
`refers to a viscoelastic material which adheres instanta­
`(polyacrylate/polysiloxane) of the present invention;
`neously to most substrates with the application of very slight
`FIG. 8 is a graphical representation of average estradiol
`pressure and remains permanently tacky. A polymer is a
`and norethindrone acetate flux through cadaver skin in vitro
`pressure-sensitive adhesive within the meaning of the term
`for a multiple polymer transdermal adhesive system com­
`as used herein if it has the properties of a pressure-sensitive
`prising both drugs and various weight ratios of polyacrylate 40
`adhesive per se or functions as a pressure-sensitive adhesive
`and polysiloxane;
`by admixture with taddfiers, plastidzers or other additives.
`The term pressure-sensitive adhesive also includes mix-
`FIG. 9 is a graphical representation showing the ratio of
`tures of different polymers and mixtures of polymers, such
`average estradiol to norethindrone acetate flux (estradiol flux
`as polyisobutylenes (PIB), of different molecular weights,
`divided by norethindrone acetate flux) through cadaver skin
`wherein each resultant mixture is a pressure-sensitive. In the
`in vitro for a multiple polymer transdermal adhesive system
`last case, the polymers of lower molecular weight in the
`comprising various weight ratios of polyacrylate and pol-
`mixture are not considered to be 'taddfiers," said term being
`ysiloxane;
`reserved for additives which differ other than in molecular
`FIG. 10 is a graphical representation of steady-state flux
`weight from the polymers to which they are added.
`of pilocarpine through cadaver skin in vitro from the drug
`As used herein, the term "rubber-based pressure-sensitive
`delivery systems of the prior art, specifically single poly­
`adhesive" refers to a viscoelastic material which has the
`meric adhesives of silicone and acrylic, as compared to a
`properties of a pressure-sensitive adhesive and which con­
`multiple polymer transdermal adhesive system
`tains at least one natural or synthetic elastomeric polymer.
`(polyacrylate/polysiloxane) of the present invention;
`As used herein, the term "drug," and its equivalent,
`FIG. 11 is a graphical representation of steady-state
`"bioactive agent," is intended to have its broadest interpre­
`albuterol and nitroglycerin flux through cadaver skin in vitro
`tation as any therapeutically, prophylactically and/or phar­
`from multiple polymer transdermal adhesive systems
`macologically or physiologically beneficial active
`(polyacrylate/polysiloxane) of the present invention
`substance, or mixture thereof, which is delivered to a living
`(Examples 24-27), and Nitro-Dur®, respectively;
`organism to produce a desired, usually beneficial, effect.
`FIG. 12 is a graphical representation of steady-state go
`More specifically, any drug which is capable of producing
`estradiol flux through cadaver skin in vitro from two differ­
`a pharmacological response, localized or systemic, irrespec­
`ent multiple polymer transdermal adhesive systems
`tive of whether therapeutic, diagnostic, or prophylactic in
`polyacrylate/polysiloxane and polyacrylate/polybutylene;
`nature, in plants or animals is within the contemplation of
`FIGS. 13 and 14 show the relationship of flux rate (J)
`the invention. Also within the contemplation of the inven-
`plotted against apparent diffusion coefficient (D) and net 65 tion are such bioactive agents as pestiddes, insect repellents,
`solubility parameter (SP), respectively, for Compositions
`sun screens, cosmetic agents, etc. It should be noted that the
`drugs and/or bioactive agents may be used singly or as a
`I-VI of Example 6. The net solubility parameter. SP^,r was
`
`25
`
`50
`
`55
`
`

`

`5,656,286
`
`20
`
`7
`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 pol