US0056562
`e
`5,656,286
`[11] Patent Number:
`United States Patent
`Mirandaet al.
`[45] Date of Patent:
`Aug, 12, 1997
`
`
`uw.
`
`[54] SOLUBILITY PARAMETER BASED DRUG
`DELIVERY SYSTEM AND METHOD FOR
`CONCINTRaNTOR SATURATION
`CONCENTRATION
`.
`Inventors: Jesus Miranda; Steven Sablotsky,
`both of Miami, Fla.
`
`[75]
`
`[73] Assignee: Noven Pharmaceuticals, Inc.. Miami,
`Fla.
`
`[21] Appl. No.: 178558
`[22] Filed:
`Jan. 7, 1994
`Related U.S. Application Data
`oo,
`[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/
`US90/01730, Mar. 28, 1990, which is a continuation-in-pat
`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.
`int. CLS oncenmesnenenennnennnennn AGIF 13/02
`[51]
`.
`[52] US. CL.
`cessessscsssessenssecsteansensseeeseeeneeee 424/449; 424/448
`[58] Field of Search on...ccscsssesssssssssssessees 424/448, 449
`
`[56]
`
`References Cited
`
`FOREIGN PATENT DOCUMENTS
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`91/05529
`5/1991 WIPO.
`93/08795
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`OTHER PUBLICATIONS
`Yu et al., “Transdermal Dual—Controlled Delivery of Test-
`—octerone and Estradiol: (1) Impact of System Design,” Drug
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`Y
`1904
`Devel. Indust. Pharm.
`17(14): 1883-1904 (1991).
`Zier et al., “Control of Crystal Growth in Drug Suspen-
`sions,” Pharm. Ind. §2(8):1017-1022 (1990).
`oo
`:
`__
`English translation of Japanese patent application No.
`248859,filed Feb. 27, 1990.
`ea
`“i
`Sloan, K. B.et al.,
`“Use of Solubility Parameters of Drug
`and Vehicle to Predict Flux Through Skin”, The Journalof
`Investigative Dermatology, vol. 87 (No. 2) pp. 244-252
`(Aug. 1986).
`
`Primary Examiner—Jyothsna Venkat
`U.S. PATENT DOCUMENTS
`Attorney, Agent, or Firm—Foley & Lardner
`260/37 SB
`7/1976 Penneck....
`3,969,308
`we 424/28
`8/1976 Tsuk et al.
`3,972,995
`[57]
`ABSTRACT
`w 424128
`en orhos Ru et a “
`Ablendof at least two polymers,or at least one polymer and
`vow 424/28
`ee
`9/19
`eith etal.
`a soluble polyvinylpyrrolidone, in combination with a drug
`we 424/728
`390,520
`6/1983 Nagai et al.
`..
`id
`iti:
`dhesi
`ition
`f
` 204r8
`4.438.139
`3/1984 Keith et al.
`...
`provides a pressure-sensitive adhesive composition for a
`» 4248
`4,542,013
`9/1985. Keith .......
`transdermal drug delivery system in which the drugis
`4,585,452
`4/1986 Sablotsky .......cssssesssesessecssssesees 604/896
`delivered from the pressure-sensitive adhesive composition
`4,593,053
`6/1986 Jevneetal....
`» 523/111
`and through dermis when the pressure-sensitive adhesive
`4,668,232
`5/1987 Cordeset al.
`. 604/897
`composition is in contact with human skin. Accordingto the
`4,690,683
`9/1987 Chienetal
`.. 604/896
`invention, soluble polyvinylpyrrolidone can be used to pre-
`eee81 4108) oatsvsaneees
`ee ventcrystallization of the drug, without affecting the rate of
`py
`e
`SOLE w.0
`°
`.
`sy:
`4
`_
`4609146 10/1987 Sieverding
`128/640
`rugdelivery from the pressure-sensitive adhesive compo
`
`,
`
`73 Claims, 19 Drawing Sheets
`
`
`
`
`4,750,482
`
`6/1988 Sieverding -........esescceeeee 128/156
`(List continued on next page.)
`
`
`
`  
`
`

 
`
`MYLAN- EXHIBIT 1011
`
`

`

`5,656,286
`
`Page 2
`
`U.S. PATENT DOCUMENTS
`4,769,013
`9/1988 Lorenz et al.
`.....ssssescssnseeeeeenes 604/265
`
`4814168
`3/1989 Sablotsky et a
`* PATS
`4845081
`7/1989 Sloan ....
`31470322
`4,883,669
`11/1989 Chienet al.
`... 424/448
`4906169
`3/1990 Chien et al.
`” oaiaas
`
`4911916
`” 404/449
`3/1990 Cleary sau»
`
`4.931.281
`"424/448
`6/1990 Kimetal. ..
`4,987,893
`1/1991 Salamoneetal. .
`wee 128/156
`
`4,994,267
`2/1991 Sablotsky ..s.scesssssecsssessecssssenene 424/78
`
`5,032,403
`wa. 424/448
`7/1991 Sinnreich...
`5,059,189 10/1991 Cilento et al.
`....cssccsssseeeneeee 604/307
`5,071,656 12/1991 Lee et all.
`......sessceccosssseseeeeneens 424/448
`
` G/U992 Khana ..csccccccccceccecceccecseeeees 514/772.5
`5,122,543
`7/1992 Blank .oeescccccccsssssecsesesesseeseneeeee 424/.
`5,128,138
`8/1992 Lee et al
`fotate
`5141750
`
`
`savassnesensesassssssseeseeeee
`b
`141;
`9/1992 Otsuka et al. semssenmenee 424/443
`5,151,271
`5,154,922 10/1992 Govil et al. .
`» A2AIAAB
`o...eecssesssssssessseneeneenee 424/443
`5,230,896
`7/1993 Yeb et al.
`7/1993 Horstmann etal. oes 424/449
`5,230,898
`8/1993 Pfister et al. .ssssscesssssessnssessees 424/448
`5,232,702
`
`8/1993 Blank «sesesvorsesecesensnsorsecrresnses 424/449
`5,232,703
`..
`ence 424/448
`5,252,334 10/1993 Chiang et al.
`5,260,064 11/1993 Nakagawaetal
`awe 424/448
`5,262,165 11/1993 Govil et al.
`.........
`. 424/448
`
`5,393,529
`2/1995 Hoffmann et all.
`.......csscseseees 424/445
`
`
`
`

`

`U.S. Patent
`
`Aug. 12, 1997
`
`Sheet 1 of 19
`
`5,656,286
`
`FIG. 1
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`U.S. Patent
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`12, 1997
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`5,656,286
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`US. Patent
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`Aug. 12, 1997
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`5,656,286
`
`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.
`07/722.342filed Jun. 27, 1991, now U.S. Pat. No. 5,474,783,
`which application is a continuation-in-part of PCT applica-
`tion PCT/US90/01750filed 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 USS.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 US. 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 polymersis utilized
`to affect the rate of drug delivery from the composition.
`Morespecifically, 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 constantrate, 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 thecarrier through
`the skin and into the bloodstream of the patient.
`Drug concentration in a monolithic transdermal delivery
`system can vary widely depending on the drug and polymers
`used. For example, certain drugs are effective in low doses
`and therefore the transdermal formulation may involve low
`concentrations, illustratively 5% or less by weight of the
`medicament
`in an adhesive. Other drugs, such as
`nitroglycerin, require large doses to be effective and the
`transdermal formulation therefore may involve high drug
`concentrations, approximately between 5 to 40% or more by
`weight in an adhesive. Low concentrations of medicament
`typically do notcritically 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 dmg delivery systems which can selectably
`incorporate low concentrations of drug and deliver sameat
`
`20
`
`25
`
`35
`
`40
`
`45
`
`50
`
`35
`
`60
`
`65
`
`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 diffusivity
`of the drug in the multiple polymer adhesive system.
`It is also an object of this invention to provide a trans-
`dermal drug delivery system wherein the multiple polymer
`adhesive system is simple to manufacture.
`It is a further object of this invention to provide a
`transdermal drug delivery system wherein drug-loading of a
`multiple polymer adhesive system may be selectably varied
`without adverse effects on drug delivery rate and adhesive
`properties, such as adhesion, tack, and shear resistance.
`It is additionally an object of this invention to provide a
`transdermal drug delivery system wherein a novel multiple
`polymer adhesive system is provided which has desirable
`physical properties.
`
`SUMMARY OF THE INVENTION
`
`The foregoing and other objects are achieved by this
`invention which provides a transdermal drug delivery sys-
`tem wherein a blendofat 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 polyvinyipyrroli-
`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(i-vinyl-2-
`pyrrolidone). The copolymer vinyl acetate vinylpyzrolidone
`is known to the pharmaceutical industry as Copolyvidon,
`Copolyvidone, and Copolyvidonum.
`The term “soluble” when used with reference to PVP
`meansthat the polymer is soluble in water and generally is
`not substantially cross-linked, and has a molecular weight of
`less than about 2,000,000. See, generally, Buhler, KOLLI-
`DON®: POLYVINYLPRYRROLIDONE FOR THE
`PHARMACEUTICAL INDUSTRY, BASF Aktiengesell-
`schaft (1992).
`It has been surprisingly found that use of a soluble PVP
`results in the ability to form a film that does not contain
`particles of insoluble PVP and in the ability to employ
`higher concentrations of drug without resulting in increased
`crystallization of the drug.
`In accordance with another embodimentof 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 incrementof at least 2 (J/em*)”. The blend,
`therefore, has a characteristic net solubility parameter.
`In accordance with further embodimentof the invention,
`an improved pressure-sensitive adhesive compositionof the
`type which is suitable as a matrix for controlledrelease of a
`drug therefrom comprises a blend of a rubber-based
`pressure-sensitive adhesive having a first solubility
`parameter, and a polyacrylate polymer having a second
`solubility parameter, the first and second solubility param-
`eters preferably being different from one another by an
`incrementof at least 2 (J/cm*)’”. 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 polymeris 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 anda
`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
`weightof the total pressure-sensitive adhesive composition,
`
`10
`
`15
`
`20
`
`25
`
`35
`
`45
`
`50
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`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 adhesiveis 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 pressure-sensitive adhesive compositions may further
`include enhancers, fillers, co-solvents, and excipients as are
`knownin 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, 585% by weight of a polyacrylate
`polymer, and 2-10% by weight of a soluble PVP, and the
`multiple polymer adhesive system comprises about 30~99%
`by weight of the dermal adhesive composition. This multiple
`polymer adhesive system is combined with a drug in the
`amount of 0.1-50% 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 §,-adrenergic agonist, such as albuterol, or a
`cardioactive agent, such as nitroglycerin.
`In still other
`embodiments,
`the drug is a cholinergic agent, such as
`pilocarpine, or an antipsychotic such as haloperidol or a
`tranquilizer/sedative such as alprazolam.
`The transdermal drug delivery system may comprise a
`monolithic adhesive matrix device in some embodiments.
`The transdermal drug delivery system may further include a
`backing material and a release liner as is known in the art.
`The saturation concentration of a drug in a transdermal
`drug delivery system of the type having a drug-containing
`pressure-sensitive adhesive diffusion matrix is adjusted in
`accordance with an aspect of the present invention by
`blending at least two polymers having differing solubility
`parameters as defined above to form a pressure-sensitive
`adhesive diffusion matrix having a net solubility parameter
`which modifies the delivery rate of the drug from the
`pressure-sensitive adhesive diffusion matrix and through the
`dermis.
`
`BRIEF DESCRIPTION OF THE DRAWINGS
`
`Comprehension of the inventionis 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, Summit, N.J.), and Nitro-Dur® (a trademark of
`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
`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 fiux through cadaver skin in vitro from the drug delivery
`systemsof 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 norethindroneacetate fiux through cadaver skin in vitro
`for a multiple polymer transdermal adhesive system com-
`prising both drugs and various weightratios of polyacrylate
`and polysiloxane;
`FIG. 9 is a graphical representation showing theratio of
`average estradiol to norethindroneacetate flux (estradiol flux
`divided by norethindrone acetate flux) through cadaver skin
`in vitro for a multiple polymer transdermal adhesive system
`comprising various weight ratios of polyacrylate and pol-
`ysiloxane;
`FIG. 10 is a graphical representation of steady-state flux
`of pilocarpine through cadaver skin in vitro from the drug
`delivery systems of the prior art, specifically single poly-
`Meric adhesives of silicone and acrylic, as compared to a
`multiple polymer transdermal adhesive system
`(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 twodiffer-
`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 coefficient (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 averageof the solubility param-
`eters of the individual polymers comprising the matrix:
`
`SP,=B,,SP,+BpasPnas
`
`where @,,, 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
`solubility parameter;
`FIG. 16 shows the average flux of estradiol for two
`compositions of this invention containing a soluble PVP;
`FIG. 17 showsestradiolflux through the human epidermis
`from a PVP-containing compositionsof 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 compositionof this invention containing
`varying concentrations of soluble PVP; and
`FIG. 20 showsthe effect of soluble PVP on estradiol flux
`through human epidermis.
`
`DETAILED DESCRIPTION OF PREFERRED
`EMBODIMENTS
`
`In one aspect ofthe 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 thereis no, or substantially no, chemical
`reaction or cross-linking (other than simple H-bonding)
`between the different polymers in the multiple polymer
`adhesive system.
`As used herein, the term “pressure-sensitive adhesive”
`refers to a viscoelastic material which adheres instanta-
`neously to most substrates with the application of very slight
`pressure and remains permanently tacky. A polymer is a
`pressure-sensitive adhesive within the meaning of the term
`as usedherein if it has the properties of a pressure-sensitive
`adhesive per se or functions as a pressure-sensitive adhesive
`by admixture with tackifiers, plasticizers or other additives.
`The term pressure-sensitive adhesive also includes mix-
`tures of different polymers and mixtures of polymers, such
`as polyisobutylenes (PIB), of different molecular weights,
`wherein each resultant mixture is a pressure-sensitive. In the
`last case, the polymers of lower molecular weight in the
`mixture are not consideredto be “tackifiers,” said term being
`reserved for additives which differ other than in molecular
`weight from the polymers to which they are added.
`- As used herein, the term “rubber-based pressure-sensitive
`adhesive” refers to a viscoelastic material which has the
`properties of a pressure-sensitive adhesive and which con-
`tains at least one natural or synthetic elastomeric polymer.
`As used herein,
`the term “drug,” and its equivalent,
`“bioactive agent,” is intended to have its broadest interpre-
`tation as any therapeutically, prophylactically and/or phar-
`macologically or physiologically beneficial active
`substance, or mixture thereof, which is delivered to a living
`organism to produce a desired, usually beneficial, effect.
`Morespecifically, 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
`
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`5,656,286
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`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 enhancesthe 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 transdermal permeation rate of a drug
`from the multiple polymer adhesive system can be selec-
`tively modulated by adjusting the solubility of the drug in
`the device. As used herein, the term “transdermal perme-
`ation rate” meansthe rate of passage of the drug through the
`skin; which, as known in the art, may or may notbeaffected
`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 bytheir
`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 ofall 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., Vol.36, pages 319-333 (1985). Many
`methods have been developed for the determination of
`solubility parameters, ranging from theoretical calculations
`to totally empirical correlations. The most convenient
`method is Hildebrand’s method, which computes the solu-
`bility parameter from molecular weight. boiling point and
`density data, which are commonly available for many mate-
`rials and which yields values which are usually within the
`range of other methods of calculation:
`
`SP=(AE/V)”,
`
`where V=molecular weight/density and AE,=energy of
`vaporization.
`Alternatively written, SP=(AH,/V-RI/V)'? 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 AH, is not available, several
`methods have been developed which use the summation of
`atomic and group contributions to AH,.
`AHv=5,,Ahy
`
`whereAh,is the contribution ofthe 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 AE,and V are
`be obtained by simply assuming that
`AEv=*,Ae; and V=2, u,. 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).
`
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`15
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`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 showsthe variation of SP with
`molecular weight, free —OH and —COOH groups, the
`degree of cross-linking. Table LA is in (cal/em*)’? and
`(j/em?)”” as calculated by Small’s method.
`
` TABLE IA
`Solubility Parameter
`
`Polymers
`
`Addition polymers of
`unsaturated esters
`
`Polymethyl 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/cm?)!?
`
`(em>)¥2
`
`9.3
`9.1
`97
`9.2
`
`8.1
`91
`V7
`81
`8.4
`719
`
`6.2
`9.5
`12.2
`9.4
`12.7
`
`13.6
`97
`
`73
`
`:
`
`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
`
`Polybutadiene-co-acrylonitrile:
`75125 to 70/30
`Polybutadiene-co-styrene:
`17.