O
`Umted States Patent
`
`[19]
`
`US005656286A
`
`[11] Patent Number:
`
`5,656,286
`
`
`Miranda et a1.
`[45] Date of Patent:
`Aug. 12, 1997
`
`[54] SOLUBILITY PARAMETER BASED DRUG
`DELIVERY SYSTEM AND METHOD FOR
`ALTERmGRIXRUG SATURATION
`CONCENT
`TION
`,
`Inventors: Jesus Miranda; Steven Sablotsky,
`both of Miami Fla.
`
`[75]
`
`[73] Assignee: Noven Pharmaceuticals, Inc.. Miami,
`Fla.
`
`[21] APP!‘ N0" 178558
`[22] Filed:
`Jan. 7, 1994
`
`Related US. Application Data
`.
`,
`.
`[63] Continuauon-m-part “Set-180722342, J‘tn' 27’ 1991’ Pat
`No. 5,474,783, which 15 a conunuauon-m-part of PCF/
`US90/01750, Mar. 23, 1990, which is acontinuation-in—patt
`of Ser. No. 671,7091APL 2, 1991, Pat- No. 5,300,291,which
`is acontinuationJ -part of Ser. No. 295,847, Ian. 11, 1989,
`Pat No. 4,994,267, which is a continuation-in-part of Ser.
`No_ 154,432, Mar. 4, 1933, pat No. 4,814,168.
`6
`Int. Cl.
`...................................................... A61F 13/02
`[51]
`[52] U..S Cl. ............................................. 424/449, 424/448
`[58] Field of Search ...................................... 424/448, 449
`
`[56]
`
`References Cited
`
`..
`
`U'S‘ PMENT DOCUMENTS
`.. 260/37 SB
`7/1976 Penneck
`3,969,308
`424/28
`8/1976 Tsuk et a1.
`3,972,995
`424/23
`9/1981 Keith at 31'
`429L015
`424/28
`9/1981 Keith. et a1.
`4’292’301
`424/28
`6/1983 Nagm et a1.
`4,390,520
`424/28
`3/1984 Keith et a1.
`4,438,139
`424/28
`9/1935 Keith .........
`4,542,013
`4/1986 Sablotsky ____________ 604/896
`4535,452
`6/1986 Jevne et a1.
`.. 523/111
`4,593,053
`5/1987 Cordes et a].
`.. 604/897
`4,668,232
`9/1987 Chien et 31 ..
`-- 604/396
`4,690,633
`313:;
`2,232,331]
`1531;1391----------
`"4:31;:
`,
`,
`SO e ......
`..
`4,699,146 10/1987 Sieverding
`.. 128/640
`4,750,482
`6/1988 Sieverding .............................. 128/156
`
`
`
`
`FOREIGN PATENT DOCUMENTS
`2027053
`4/1991 Canada .
`0201328
`11/1986 European Fat. 011.
`208395
`1/1987 European Pat. Off. .
`0272045
`6/1988 European Pat. Off. .
`0343307
`11/1939 European Pat. Ofi‘.
`_
`0 371 496
`6/1990 European Pat. 0e. .
`0416842
`3/1991
`European Pat. Off. .
`0529123
`3/1993 European Fat 011“.
`,
`54-89017
`7/1979
`Japan .
`58-225010 1fl1983
`Japan .
`2 105 990
`4/1983 United Kin dom .
`91/05529
`5/1991 WIPo.
`g
`93/08795
`5/1993 WIPO ,
`
`OTHER PUBLICATIONS
`Yu et a1, ‘Transdennal Dual—Controlled Delivery of Test-
`osterone and Estradiol: (I) Impact of System Design.” Drug
`d
`1
`14_ 1 8
`1904 1
`1
`Dave/'1" "St- ”mm 7(
`)-
`3 3‘
`( 99 )-
`Ziller et a1., “Control of Crystal Growth in Drug Suspen-
`sions ” Pharm. Ind. 52(8):1017—1022 (1990)_
`,'
`_
`.
`,
`English tansilatlon of Japanese patent application No.
`2—48859
`e Feb. 27 1
`.
`9
`9
`Sloan, K. B. et 31., “Use of Solubility Parameters of Drug
`and Vehicle to Predict Flux 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]
`Ablend of at least two polymers, or at least one polymer and
`a soluble polyvinylpyrrolidone, in combination with a drug
`.
`.
`.
`.
`.
`.
`provrdes a pressure-sensmve adhesive composmon for .a
`fiaFSdel'mal
`(11118 delivery WWI? 111 “’th the drug. 15
`dehvered fi'om the pressure—sensmve adheswe composrtion
`and through denuis when the pressure-sensitive adhesive
`composition is in contact with human sln'n. According to the
`invention, soluble polyvinylpyrrolidone can be used to pre—
`vent crystallization of the drug, without aflecting the rate of
`dl'll
`-
`_
`.
`.
`.
`_
`SitiEndehvery from the pressure sen51t1ve adhes1ve compo
`'
`
`(List continued on next page.)
`
`73 Claims, 19 Drawing Sheets
`
`13
`
`
`
`///////////
`
`
`
`////////////////////////////////
`
`11
`
`
`
`12
`
`  
`
`

 
`
`MYLAN - EXHIBIT 1011
`
`

`

`5,656,286
`
`Page 2
`
`US. PATENT DOCUMENTS
`4,769,013
`9/1933 Lorenz et a1.
`.......................... 604/265
`4,314,163
`3/1939 Samotsky eta]
`424/73
`
`4345031
`7/1939 Sloan .....
`514/2322
`4,333,669
`11/1939 Chien etal.
`424/443
`4,906,169
`3/1990 wen etal
`.. 424/443
`4911916
`3,1990 Clear},
`........
`.. 424,449
`4:931:22“
`6,1990 Kim et 31 __
`.. 424,448
`4,937,393
`1/1991 Salamone etal. .
`123/156
`
`4,994,267
`2/1991 Sablotsky ............ 424/73
`
`5,032,403
`7/1991 Sinnreich
`424/443
`5,059,139 10/1991 Cilento etal.
`.......................... 604/307
`5,071,656 12/1991 Lee et a1.
`................................ 424/448
`
`
`
`6/1992 Khanna ................................ 514/7725
`5,122,543
`............ 424
`7/1992 B1
`5,123.133
`
`3/1992 L3: 81
`424%:
`5141750
`.
`................................
`,
`,
`9/1992 01su1meta1.
`.......................... 424/443
`5,151,271
`
`54544922 “3/1999 GM] at 31- "
`‘ 424/448
`5,230,396
`7/1993 Yeh et a1.
`............................... 424/443
`7/1993 Horsnnann ctal.
`.................... 424/449
`$230,393
`
`..... 424/443
`5,232,702
`3/1993 Pfister etal.
`
`3/1993 Blank ---------------- 424/449
`52324703
`5,252,334 10/1993 Chang et a1.
`--
`424/448
`5,260,064 11/1993 Nakagawa etal
`424/448
`
`. 424/443
`5,262,165
`11/1993 Govil et a1.
`..... 424/445
`5,393,529
`2/1995 Hoflinann et 21.
`
`..
`
`

`

`US. Patent
`
`Aug. 12, 1997
`
`Sheet 1 of 19
`
`5,656,286
`
`FIG. 1
`
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`US. Patent
`
`Aug. 12, 1997
`
`Sheet 5 of 19
`
`5,656,286
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`US. Patent
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`Aug. 12,1997
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`US. Patent
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`Aug. 12, 1997
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`US. Patent
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`Aug. 12, 1997
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`

`1
`SOLUBILITY PARAMETER BASED DRUG
`DELIVERY SYSTEM AND METHOD FOR
`ALTERING DRUG SATURATION
`CONCENTRATION
`
`CROSS-REFERENCE TO RELATED
`APPLICATION
`
`This application is a continuation-in-part of Ser. No.
`07/722,342 filed Jun. 27, 1991, now U.S. Pat. No. 5,474,783,
`which application is a continuation-in—part of PCT applica-
`tion PCT/US90/01750 filed Mar. 28, 1990, and filed nation-
`ally as U.S. Ser. No. 671,709 on Apr. 2, 1991, now U.S. Pat.
`No. 5,300,291; which in turn is a continuation-in-part of
`U.S. 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 U.S. 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 applications 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 afi'ect 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 sldn 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 efiective 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 difficulties in
`
`achieving an acceptable delivery rate of the medicament.
`High 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
`incorporate low concentrations of drug and deliver same at
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`60
`
`65
`
`5,656,286
`
`2
`
`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 diifusivity
`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
`polymers are homopolymeric PVPs and the copolymer vinyl
`
`

`

`5 ,656,286
`
`3
`acetate vinylpyrrolidone. The homopolymeric PVPs are
`known to the pharmaceutical industry under a variety of
`designations including Povidone, Polyvidone,
`Polyvidonum, Polyvidonum solubile, and Poly(l-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. Biihler, 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 diflerent 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
`weight of the total pressure-sensitive adhesive composition.
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`4s
`
`50
`
`55
`
`65
`
`4
`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 086:14 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 pres sure-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 O.1—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
`In particularly preferred embodiments,
`asteroid, such as an estrogen or a progestational agent, or
`combination thereof. In other preferred embodiments. the
`drug may be a fiz—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 difiering solubility
`parameters as defined above to form a pressure-sensitive
`adhesive difl’usion matrix having a net solubility parameter
`which modifies the delivery rate of the drug from the
`pressure-sensitive adhesive diflusion 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
`
`

`

`5 ,656,286
`
`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. Surmnit, N.J.), 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 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
`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 fi‘om 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
`(polyacrylate/polysiloxane) of the present invention;
`FIG. 8 is a graphical representation of average estradiol
`and norethindrone acetate flux through cadaver skin in 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-
`ysiloxanc;
`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
`(polyacrylate/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 difier—
`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 coeflicient (D) and net
`solubility parameter (SP), respectively. for Compositions
`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:
`
`SPMFIDPSSPP,+¢WSPW,
`
`where Q” is the weight percentage of polysiloxane and SPF:
`is the solubility parameter of polysiloxanc. The subscript
`“pa” refers to the polyacrylate;
`FIG. 15 is a plot of diifusion coefficient 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 dilferent 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 difierent 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 diifer 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-
`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
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`4o
`
`45
`
`50
`
`55
`
`65
`
`

`

`5,656,286
`
`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 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 the transderrnal 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
`different 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
`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. V0136. 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./V)”2.
`
`where V=molecu1ar weight/density and AEV=energy of
`vaporization.
`Alternatively written. SP=(AHJV—RTN)1’2 where AH,.=
`heat of vaporization. R=gas constant. and T is the absolute
`temperature. °K. For materials. such as high molecular
`weight polymers. which have vapor pressures too low to
`detect. and thus for which AHV is not available, several
`methods have been developed which use the summation of
`atomic and group contributions to AHV:
`AHvzlliAh‘.
`
`where Ahi is the contribution of the ith atom or group to the
`molar heat of vaporization. One convenient method has been
`proposed by R. F. Fedors. Polymer Engineering and
`Science. Vol. 14. p. 147 (1974). In this method AEvand V are
`be obtained by simply assuming that
`AEv=EiAei and V=Zi ui. where Ae‘ and V. are the additive
`atomic and group contributions for the energy of vapor-
`ization 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).
`
`8
`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 grou s, 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
`Solubili
`' Parameter
`
`Polymers
`
`Addition polymers of
`unsaturated esters
`
`Polymetliyl methacrylate
`Polyethylmethacrylate
`Polymethylacrylate
`Polyethylacrylate
`Hydrocarbon polymers
`
`Polyethylene
`Polystyrene
`Polyisobutylene
`Polyisoprene
`Polybutadiene
`Polyethylene/butylene
`Halogen-containing polymers
`
`Polytetrafluoroethylene
`Polyvinylchloride
`Polyvinylidene chloride
`Polychloroprene
`Polyacrylonitrile
`Condensation polymers
`
`Nylon—66
`Epon resin 1004 (epoxy)
`Polysiloxanes
`
`Polydimethylsiloxane
`Copolymers
`
`(cal/cm3)1’Z
`
`(I/cm3)“2
`
`9.3
`9. 1
`9.7
`9.2
`
`8.1
`9.1
`7.7
`8.1
`8.4
`7.9
`
`6.2
`9.5
`12.2
`9.4
`12.7
`
`13.6
`9.7
`
`7.3
`
`'
`
`19.0
`18.6
`19.8
`18.8
`
`16.6
`18.6
`15.7
`16.6
`16.6
`16.2
`
`12.7
`19.4
`24.9
`19.2
`26.0
`
`27.8
`19.8
`
`14.9
`
`Polybutadienero-acrylonitrile:
`75/25 to 70/30
`Polybutadiene-co-styrene:
`17.4
`8.5
`75/25 to 72/28
`
`
`9.25
`
`18.9
`
`excerpted from Kraton ® Thermoplastic Rubber Shell Chemical Co. Product
`Brochure Number SC