United States Patent [19]
`Wang et al.
`
`111111111111111111111111111111111111111111111111111111111111111111111111111
`US005508038A
`[11] Patent Number:
`[45] Date of Patent:
`
`5,508,038
`Apr. 16, 1996
`
`[54] POLYISOBUTYLENE ADHESIVES FOR
`TRANSDERMAL DEVICES
`
`[75]
`
`Inventors: Karly S. Wang, Newark; James L.
`Osborne, Mountain View; James A.
`Hunt, Fremont; Melinda K. Nelson,
`Sunnyvale, all of Calif.
`
`[73] Assignee: Alza Corporation, Palo Alto, Calif.
`
`[21] Appl. No.: 509,644
`
`[22] Filed:
`
`Apr. 16, 1990
`
`lot. CI.6
`...................................................... A61L 15/00
`[51]
`[52] U.S. CI ........................... 424/448; 424/449; 5251191;
`526/348.7
`[58] Field of Search ..................................... 4241448, 449;
`526/348.7; 5251191
`
`[56]
`
`References Cited
`
`U.S. PATENT DOCUMENTS
`
`3,252,802
`3,433,775
`3,598,122
`3,598,123
`3,721,661
`3,731,683
`3,734,097
`3,845,217
`3,870,794
`3,877,468
`3,923,939
`3,926,188
`3,996,245
`4,031,894
`4,060,084
`4,125,623
`4,144,317
`4,152,499
`4,201,211
`4,262,003
`4,286,592
`4,379,454
`4,425,337
`4,440,740
`4,562,075
`4,573,995
`4,597,961
`4,623,346
`4,627,852
`4,647,580
`4,665,069
`4,680,172
`4,715,387
`4,748,181
`4,758,434
`4,776,850
`
`5/1966 Cunningham ........................... 514/343
`3/1969 Ray et aI. .. .......................... 526/348.7
`8/1971 Zaffaroni.... ................ ............. 1281268
`8/1971 Zaffaroni ................................. 128/268
`3/1973 Susa ..................................... 526/348.7
`5/1973 Zaffaroni ................................. 128/268
`5/1973 Zaffaroni ................................. 128/268
`10/1974 Ferno et aI.
`.. .............................. 426/3
`3/1975 Hutchinson et aI .................... 514/347
`4/1975 Lichtneckert et aI ................... l311959
`1211975 Baker et aI ............................... 264/49
`1211975 Baker et aI ............................. 128/156
`12/1976 Hartog et aI ......................... 260/340.9
`6/1977 UrqUhart et aI. ....................... 424/449
`11/1977 Chaodrasekaran et aI ............. 128/260
`11/1978 Hartog et aI ............................ 4241278
`3/1979 Higuchi et aI. ......................... 128/260
`5/1979 Boezel et aI ......................... 526/348.7
`5/1980 Chaodrasekaran et aI ............. 128/268
`4/1981 Urquhart et aI ........................ 424/267
`9/1981 Chaodrasekarao ...................... 1281260
`4/1983 Campbell et aI ....................... 424/449
`1/1984 Alexaoder et aI. ..................... 424/181
`4/1984 Fix et aI .................................. 424/1.1
`1211985 Rajadhyaksha ......................... 5141788
`3/1986 Cheng et aI. .. ......................... 424/449
`7/1986 Etscorn ................................... 424/448
`11/1986 von Bittera et aI. ................... 424/448
`1211986 von Bittera et aI .................... 424/449
`311987 Roszkowski ............................ 514/464
`5/1987 Rosenberg .............................. 514/222
`7/1987 Leeson .................................... 424/448
`1211987 Rose ........................................ 131/270
`5/1988 Hutchinson et aI .................... 514/343
`7/1988 Kydonieus et aI ..................... 424/449
`10/1988 Guse et ·aI ............................... 424/485
`
`4,797,284
`4,839,174
`Bl 3,598,122
`Bl 3,742,951
`B 1 4,588,580
`
`1/1989 Loper et aI. .. .......................... 424/449
`6/1989 Baker et aI ............................. 424/448
`11/1982 Zaffaroni ................................. 128/268
`11/1982 Zaffaroni ................................. 1281268
`111989 GaIe et aI. .. ............................ 424/449
`
`FOREIGN PATENT DOCUMENTS
`
`57457/86
`81454/87
`0190814
`0117027
`0186071
`0204968Al
`0251425
`0374980
`3438284
`1251619A
`2171906
`8702870A
`88/01516
`
`1111986
`511988
`8/1966
`8/1984
`7/1986
`1211986
`1/1988
`611990
`3/1985
`4/1985
`9/1986
`5/1987
`3/1988
`
`AustraIia ......................... A61K 9170
`AustraIia ......................... A61K 9/66
`Europeao Pat. Off ......... A61L 15/06
`Europeao Pat. Off ........ A61M 37/00
`Europeao Pat. Off. .. ...... A61L 15/03
`Europeao Pat. Off ..
`Europeao Pat. Off .......... A61K 9/00
`Europeao Pat. Off ..
`Germaoy ..................... A81K 311485
`Japao .
`United Kingdom ............. A61K 9/00
`WIPO .
`WIPO.
`
`OTHER PUBLICATIONS
`
`Protective Clothing as a Means of Reducing Nicotine
`Absorption in Tobacco Harvesters; S. H. Gehlbach, M. D.,
`W. A. Williams, B.S., J. I. Freeman, D.V.M. Archives of
`Environmental Health, Mar.lApr. 1979, pp. 111-114.
`A Simplified Procedure for the Gas Chromatographic Deter(cid:173)
`mination of Nicotine: Application of the Method to Mouse
`Skin; C. Carruthers and A. Neilson Mikrochimica Acta
`(Wien) 1980 II, pp. 59-66.
`Nicotine, Resorption and Fate; H. Schievelbein Pharmac.
`Ther. vol. 18. pp. 233-248 (1982).
`Transdermal Administration of Nicotine; J. E. Rose, M. E.
`Jarvik and K. D. Rose Drug and Alcohol Dependence, 13
`(1984) 209-213, Elsevier Sci. Pubs. Ireland.
`Transdermal Nicotine Reduces Cigarette Craving and Nico(cid:173)
`tine Preference; Jed E. Rose, Ph.D., Joseph E. Herskovic,
`Ph.D., Yvonne Trilling, and Murray Jarvik, M.D., Ph.D.,
`Clin Pharmaco1 Ther. (Oct. 1985) vol. 38, No.4.
`6th World Conference on Smoking and Health, Abstracts,
`Nov. 9-12, 1987; Tokyo, Japan.
`
`Primary Examiner-D. Gabrielle Phelan
`Attorney, Agent, or Firm-Steven F. Stone
`
`[57]
`
`ABSTRACT
`
`An in-line adhesive, useful for transdermal delivery devices
`comprising a mixture of high and low molecular weighted
`polyisobutylene having a ratio HMW PIB:LMW PIB in the
`range of about 5-40:95-60 which is substantially free of
`plasticizers and tackifiers is disclosed. The adhesive finds
`particular use as a component of a transdermal delivery
`device for delivering oily non-polar agents such as nicotine,
`benztropine, secoverine, dexsecoverine, and arecoline.
`
`20 Claims, No Drawings
`
`NOVARTIS EXHIBIT 2018
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`

`5,508,038
`
`1
`POLYISOBUTYLENE ADHESIVES FOR
`TRANSDERMAL DEVICES
`
`TECHNICAL FIELD
`
`The invention herein pertains to polyisobutylene (PIB)
`adhesives useful in transdennal drug delivery systems.
`
`BACKGROUND ART
`
`10
`
`2
`by the rate controlling membrane, which can only exert an
`effect on the agent which remains in the reservoir. High
`concentrations of agent in direct contact with the skin can
`also cause irritation, or produce undesirably high initial
`5 plasma levels of the agent.
`Many medically acceptable contact adhesives of the prior
`art are also ineffective in conjunction with agents which are
`capable of plasticizing, solvating, or otherwise causing the
`adhesive to lose its cohesiveness. Such agents, which are
`typically oily, non-polar components such as nicotine, ben(cid:173)
`ztropine, secoverine, dexsecoverine and arecoline, for
`example, can destroy the adhesive properties of a transder(cid:173)
`mal patch, causing premature detachment of the system.
`U.S. Pat. Nos. 4,597,961 and 4,839,174, the disclosures of
`which are incorporated herein by reference, disclose trans-
`15 dennal nicotine delivery devices in which nicotine is present
`in the reservoir. The device of U.S. Pat. No. 4,597,561 uses
`a peripheral adhesive to avoid this type of problem. Copend(cid:173)
`ing, commonly assigned U.S. application Ser. No. 071206,
`546, filed Jun. 14, 1988 now abandoned, the disclosure of
`20 which is incorporated herein by reference, describes a trans(cid:173)
`dennal nicotine delivery system using a subsaturated reser(cid:173)
`voir to cope with this problem.
`Mineral oil is also soluble in some common components
`of transdermal systems, such as ethylene vinyl acetate
`25 copolymers (EVA) and may migrate from the adhesive layer
`into these materials over time. The loss of the plasticizing
`mineral oil in the adhesive can cause changes in the physical
`properties of the adhesive compound, adversely affecting the
`performance of the adhesive.
`According to our invention, it has unexpectedly been
`discovered that certain agents, in the presence of which
`traditional transdermal non-PIB adhesives are plasticized,
`solvated, or lose their adhesive properties, can be delivered
`from a transdennal delivery device using the in-line PIB
`adhesives of this invention which are substantially free of
`tackifiers and plasticizers.
`It is therefore an object of this invention to provide a new
`and useful in-line adhesive for use in transdennal delivery
`40 devices.
`It is another object of this invention to provide in-line
`adhesives for transdennal delivery devices which are useful
`in delivery of agents which have an undesirably high solu(cid:173)
`bility in prior in-line adhesives.
`It is another object of the invention to provide a PIB
`adhesive substantially free of plasticizers and tackifiers.
`It is yet another object of this invention to provide an
`in-line adhesive in a transdennal delivery device which
`rapidly reaches eqUilibrium after manufacture.
`It is yet another object of the invention to provide a
`transdermal delivery system using high and low molecular
`weight PIB substantially free of plasticizers and tackifiers,
`as an in-line adhesive.
`It is another object of this invention to provide PIB
`adhesives substantially free of plasticizers and tackifiers
`having a high penneability for the agent to be delivered, and
`which are suitable as an in-line adhesives in transdermal
`delivery devices having a release rate controlling membrane.
`It is another object of this invention to provide an in-line
`adhesive for use in a transdennal delivery device which is
`relatively non-irritating, is inexpensive, can be used in the
`delivery of oily, non-polar active agents.
`BRIEF DESCRIPTION OF THE INVENTION
`
`30
`
`Transdennal devices for delivery of a variety of biologi(cid:173)
`cally active agents through the skin or mucosa are known to
`the art. Representative systems which use rate controlling
`membranes and in-line adhesives (i.e., adhesives disposed in
`the path of drug or agent migration from the reservoir to the
`skin) are disclosed in U.S. Pat. Nos. 3,598,122; 3,598,123;
`3,742,951; 4,031,894; 4,060,084; 4,144,317; 4,201,211; and
`4,379,454. Subsaturated transdennal devices are disclosed
`in U.S. Pat. No. 4,379,454. U.S. Pat. No. 4,286,592
`describes a transdermal drug delivery device in which the
`PIBfMO adhesive is less permeable to the drug being
`delivered than is the reservoir layer. The limited penneabil-
`ity adhesive layer acts as a rate-controlling member.
`When in-line adhesives are used in transdermal delivery
`devices it is necessary that they exhibit a reasonable per(cid:173)
`meability to the agent being delivered and, when they are
`used in combination with a rate-controlling membrane, the
`adhesive layer preferably exhibits a higher penneability to
`the drug than the rate controlling membrane.
`Mixtures of high and low molecular weight polyisobuty(cid:173)
`lenes (PIB) are known to the art as adhesives, however they
`are relatively impermeable to many drugs. As a result, the
`prior art in-line PIB adhesives usually contain a plasticizer
`such as mineral oil (MO) or polybutene to achieve sufficient
`permeability to permit drug migration through the adhesive 35
`at rates which are therapeutically useful from reasonably
`sized systems.
`A typical fonnulation of the prior art uses a ratio of 1.2M
`molecular weight (MW) PIB:35K MW PIB:MO of about
`1:1.125:2. In such a formulation the high molecular weight
`(HMW) PIB acts as an adhesive base, the low molecular
`weight (LMW) PIB acts as tackifier, and the mineral oil acts
`to plasticize the adhesive and to increase the permeability of
`the adhesive composition to the drug.
`It is also known to include tackifiers to improve the
`adhesive characteristics of medical adhesives. For example,
`Australian application AU-A-57457/86 discloses a self
`adhesive matrix for delivering nitroglycerin which com(cid:173)
`prises a mineral oil-free mixture of high and low molecular
`weight PIB' s with a resinous tackifier. Such tackifiers are
`often natural resinous or rosinous products of undefined
`compositions. Both mineral oil and tackifiers vary in their
`detailed composition from batch to batch and may unpre(cid:173)
`dictably contain components which are irritating or sensi- 55
`tizing to the skin.
`Many medically acceptable contact adhesives of the prior
`art are ineffective in the transdermal delivery of active
`agents which are highly soluble in the adhesives. When the
`agent has a high solubility in the adhesive layer, substantial 60
`quantities of agent migrate from the reservoir through the
`rate controlling membrane and into the adhesive layer as the
`device equilibrates over time. The migration continues until
`the thermodynamic activity of the agent in the adhesive
`equals the thermodynamic activity of the agent in the 65
`reservoir. As a result, the large quantity of the active agent
`in the adhesive layer is released onto the skin without control
`
`45
`
`50
`
`The invention comprises an adhesive which is useful as an
`in-line adhesive in transdermal delivery devices. The adhe-
`
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`

`5,508,038
`
`3
`sive comprises mixtures of high molecular weight (HMW)
`and low molecular weight (LMW) PIBs in weight ratios of
`about 5-40 HMW PIB:95-60LMW PIB which are substan(cid:173)
`tially free of plasticizers and tackifiers. In use, the adhesive
`will also contain dissolved active agent at a concentration
`which is in equilibrium with the concentration of agent in the
`reservoir.
`The adhesive finds particular use as a component of a
`transdennal delivery device for delivery of active agents
`which solvate, plasticize, or adversely affect the adhesive
`properties of conventional in-line adhesives. Such agents
`include nicotine, benztropine, secoverine, dexsecoverine, or
`arecoline for example.
`
`DISCLOSURE OF INVENTION INCLUDING
`BEST MODE
`
`The adhesives of this invention are in-line adhesives for
`transdennal delivery devices, Le., the agent being delivered
`by the system is transported through the adhesive prior to
`reaching the surface of the skin. In its broadest application,
`the adhesives of this invention can be used in monolithic
`transdennal delivery devices which comprise a thin film of
`the agent dispersed in the adhesive which is nonnally
`provided with a protective, agent-impenneable backing
`layer. In this embodiment, the adhesive layer functions as
`both the agent reservoir and the adhesive.
`The adhesives of this invention could also be used as
`release rate-controlling adhesives such as are shown in U.S.
`Pat. No. 4,286,592 which is incorporated herein by refer(cid:173)
`ence, in which an adhesive coating on the drug reservoir
`functions to control release rate and maintain the device on
`the skin.
`The characteristics of the adhesives of this invention,
`however, make them particularly useful as in-line adhesives
`in rate controlled transdennal delivery devices which gen(cid:173)
`erally comprise, an adhesive layer, a reservoir containing the
`agent to be delivered and rate-controlling means disposed
`between the reservoir and adhesive and an agent-impenne(cid:173)
`able backing layer. A strippable release liner preferably
`covers the adhesive layer during storage of the device and is
`removed prior to use. Transdennal delivery devices are
`applied to a patient for a predetermined administration
`period, which can range from several hours up to a week
`depending upon the agent being delivered and the condition
`being treated.
`The tenn, "agent" as used herein refers to any beneficial
`agent or compound that can be delivered by a device herein
`to produce a beneficial and useful result. The tenn includes
`medicines, organic and inorganic drugs, hormones, nutri(cid:173)
`ents, vitamins, food supplements, and other agents that
`benefit an animal or human. It is to be understood that more
`than one agent may be delivered from a device using the
`adhesives of this invention, and that the use of the term
`"agent" in no way excludes the use of two or more such
`•
`agents.
`The term, "plasticizer" as used herein refers to com(cid:173)
`pounds other than the agent being delivered, such as mineral
`oil, polybutene oil, and other low molecular weight hydro(cid:173)
`carbons that act to plasticize PIB adhesives and increase
`their permeability to the agent being delivered. An adhesive
`composition is substantially free of plasticizer if it contains,
`at most, trace amounts of plasticizer and more preferably, no
`plasticizer.
`The term, "tackifier" as used herein refers to materials
`other than PIB that are added to adhesives to increase their
`
`30
`
`4
`tack or stickiness. Such materials are typically natural occur(cid:173)
`ring resinous or rosinous materials or truly synthetic poly(cid:173)
`mer materials. An adhesive is substantially free of tackifier
`if it contains, at most, trace amounts of tackifier and pref-
`5 erably no tackifier.
`The term, "high molecular weight polyisobutylene"
`(HMW PIB) refers to a polyisobutylene composition having
`an average molecular weight in the range of about 450,000
`to about 2,100,000, and preferably from about 990,000 to
`10 about 1,600,000.
`The term, "low molecular weight polyisobutylene"
`(LMW PIB) refers to a polyisobutylene composition having
`an average molecular weight in the range of about 1,000 to
`about 450,000, and preferably from about 35,000 to about
`15 50,000.
`The adhesive composition of this invention contains the
`HMW and LMW PIB in weight ratios (HMW PIB:LMW
`PIB) in the range of about 5-40:95-60, preferably in the
`range of about 10-25:90-75 and most preferred in the range
`20 of about 10-20:90-80. The ratio of HMW PIB to LMW PIB
`which provides an optimal adhesive for a specific agent will
`be dependent upon the identity and concentration of agent
`being delivered.
`It is preferable that extraneous components of the adhe-
`25 sives of this mixture be minimized or eliminated in order to
`minimize the potential for irritation or allergic reaction when
`the transdennal delivery system contacts the skin. However
`dyes, pigments, inert fillers, stabilizers, stiffeners such as
`colloidal silicon dioxide, or other additives other than plas-
`ticizers and tackifiers well known to the art may be added if
`desired.
`The thickness of the adhesive layer will generally be
`between about 1 mil (0.0254 mm) and about 15 mil (0.381
`mm) when used with a rate-controlling membrane. The
`composition and thickness of the adhesive layer will be
`adjusted such that the adhesive layer does not constitute a
`significant permeation barrier to the passage of the agent to
`be delivered as compared to that of the rate-controlling
`40 membrane. Unless the drug involved requires the use of a
`loading dose to rapidly saturate drug delivery sites in the
`skin, the thickness is also preferably selected so that the
`adhesive does not contain a substantial amount and prefer(cid:173)
`ably less than about 15% of the total amount of agent in the
`45 device, particularly in rate-controlled deli very devices.
`Transdermal delivery devices using the adhesives of this
`invention may be of the monolithic or release rate-control(cid:173)
`ling adhesive type but are preferably of the release rate(cid:173)
`controlling membrane type which comprise rate controlling
`50 means between the drug reservoir and the in-line adhesive.
`The rate-controlling means acts to regulate the fiux of the
`agent being delivered to the skin and the rate controlling
`element will have a lower permeability to the agent being
`delivered than the adhesive layer. Materials which are appro-
`55 priate for use with transdermal deli very systems are given in
`the patent application U.S. Ser. No. 071206,546 now aban(cid:173)
`doned, and in U.S. Pat. Nos. 3,797,494 and 4,031,894,
`which are incorporated herein by reference.
`The reservoir of such a transdermal delivery device
`60 contains one or more agents to be delivered, dispersed
`within a matrix. Suitable materials for the matrix of the
`reservoir include, without limitation, natural and synthetic
`rubbers or other polymeric materials, petroleum jelly or
`aqueous gels. When the agent being delivered is nicotine, a
`65 preferred reservoir polymer matrix is fabricated ,from an
`ethylene-vinyl acetate (EVA) copolymer such as is described
`in U.S. Pat. No. 4,144,317, preferably having a vinyl acetate
`
`35
`
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`

`5,508,038
`
`5
`content within the range of about 28 to 60 weight percent.
`Other embodiments of transdermal delivery devices are
`known to the art and are also appropriate for use with the
`adhesives herein. For example, the transdermal delivery
`devices shown in U.S. Pat. Nos. 3,598,123, and 4,588,580, 5
`the disclosures of which are hereby incorporated by refer(cid:173)
`ence, can find application with the adhesives disclosed
`herein.
`The permeability of many agents through pm is relatively
`low in the absence of a plasticizer and for this reason the 10
`in-line pm adhesives of the prior art contained plasticizers
`such as mineral oil or polybutene. We have found that
`certain agents, typically oily, non-polar substances usually
`liquid at ambient temperatures, have acceptable permeation
`through the plasticizer-free pm adhesives of this invention. 15
`It was also found that such agents, while highly soluble in
`typical non-pm adhesives of the prior art whose adhesive
`properties are degraded by the concentrations of such agents
`encountered, exhibit a relatively low solubility in the non(cid:173)
`plasticized pm adhesives of this invention. As a result, the 20
`concentration of agent which is present in the adhesive layer
`upon equilibration is significantly reduced as compared to
`that observed in prior art non-pm adhesives. When used
`with such oily agents, this significantly reduces the degra(cid:173)
`dation caused by the agent, so that the physical integrity and 25
`adhesive characteristics of the adhesives of this invention
`are maintained. Oily, non-polar agents having the desired
`properties include, without limitation, nicotine, benztropine,
`secoverine, dexsecoverine and arecoline.
`A backing layer prevents passage of the agent through the 30
`surface of the reservoir distal to the skin, and provides
`support for the system, if needed. The backing layer is
`impermeable or substantially impermeable to the passage of
`the agent. It can be flexible or nonflexible. Suitable materials
`are well known to the art and include, without limitation, 35
`polyethylene terephthalate, various nylons, polypropylene,
`metalized polyester films, polyvinylidene chloride, and alu(cid:173)
`minum foil.
`A release liner can be included in the transdermal deli very 40
`device as manufactured, as is well known in the art. The
`release liner is removed before the transdermal delivery
`device is applied to the skin.
`In a preferred embodiment a transdermal delivery device
`uses a pm adhesive of this invention together with a 45
`subsaturated reservoir including nicotine.
`The following examples are illustrative of the present
`invention and they are not to be construed as limitations of
`the scope of the invention. Variations and equivalents of
`these examples will be readily apparent to workers skilled in
`the art in light of the present disclosure. All ratios and
`percentages are on a weight basis, and all temperatures are
`in degrees Celsius, unless otherwise noted.
`
`50
`
`6
`Formula D: pm having a MW of 35K was thouroughy
`blended with pm having a MW of 1.2M, in a weight ratio
`of HMW pm:LMW pm of 10:90.
`
`EXAMPLE 2
`
`Subsaturated transdermal drug delivery systems were
`made by extruding a 0.13 mm thick drug reservoir film
`comprising a subsaturated solution of 40% nicotine base in
`60% EVA (40% VA) between an impermeable, pigmented
`aluminized polymer backing (Medpar™) and a high density
`polyethylene (HDPE) rate-controlling membrane 0.05 mm
`thick. This trilaminate was laminated to adhesives of For(cid:173)
`mulae B-D of Example 1 that were solvent cast from
`n-heptane solution onto a 0.076 mm strippable release liner
`formed of fluorocarbon diacrylatelpolyethylene terephtha(cid:173)
`late, (3M 1022) and allowed to reach eqUilibrium. All
`samples exhibited good adhesive properties and had 24 hour
`average in vitro release rates into water at 37° C. of 60
`~gI(cm2 hr), 70 ~g/(cm2 hr), and 72 ~gI(cm2 hr) respectively.
`
`EXAMPLE 3
`
`The procedures of Example 2 were repeated using the
`adhesive of Formula A and substituting, as the drug reser(cid:173)
`voir, a mixture of 70 wt % EVA-40 and 30 wt % nicotine
`base. The weight percent of the nicotine in the adhesive upon
`equilibration was found to be about 11 weight percent.
`The procedures of Example 2 were repeated, using the
`adhesive of formula B with the above 70/30 EVA-40-
`nicotine reservoir. The weight percent of nicotine in the
`adhesive upon equilibration was also found to be about 11
`weight percent.
`The procedures of Example 2 were repeated, using the
`adhesive of Formula B, and reservoir composition of 20%,
`30% and 40% nicotine base in EVA-40. The weight percent
`of nicotine in the pm adhesive after equilibration was found
`to be as follows: 8 wt. percent in the 20% nicotine reservoir
`device; 10 wt. percent in the 30% nicotine reservoir device;
`and 14 wt. percent in the 40% nicotine reservoir device.
`
`EXAMPLE 4
`
`The procedures of Examples 2 and 3 are repeated substi(cid:173)
`tuting a 2 mil (0.0508 mm) low density polyethylene
`(LDPE) membrane for the HDPE membrane and substitut(cid:173)
`ing for the nicotine reservoir solution, 10% benztropine and
`90% EVA-40 to produce transdermal devices for the deliv(cid:173)
`ery of benztropine.
`The devices will exhibit in vitro release rates into water at
`37° C. of about 5-15 ~glcm2 hr and will have good adhesive
`properties.
`
`EXAMPLE 5
`
`EXAMPLE 1
`
`55
`
`The procedures of Examples 2 and 3 are repeated, sub(cid:173)
`stituting for the nicotine reservoir solution, 15% secoverine
`and 85% EVA-40 to produce transdermal devices for the
`delivery of secoverine. The devices will exhibit in vitro
`release rates into water at 37° C. of about 5-15 ~glcm2 hr
`60 and will have good adhesive properties.
`
`pm adhesives according to this invention were prepared
`as follows:
`Formula A: pm having a MW of 35K was thoroughly
`blended with pm having a MW of 1.2M, in a weight ratio
`of HMW pm:LMW pm of 25:75.
`Formula B: pm having a MW of 35K was thoroughly
`blended with pm having a MW of 1.2M, in a weight ratio
`of HMW pm:LMW pm of 20:80.
`Formula C: pm having a MW of 35K was thoroughly 65
`blended with pm having a MW of 1.2M, in a weight ratio
`of HMW pm:LMW pm of 15:85.
`
`EXAMPLE 6
`
`The procedures of Examples 2 and 3 are repeated, sub(cid:173)
`stituting for the nicotine reservoir solution, 15% dexsecov(cid:173)
`erine and 85% EVA-40 to produce trans dermal devices for
`the delivery of dexsecoverine. The devices will exhibit in
`
`NOVARTIS EXHIBIT 2018
`Noven v. Novartis and LTS Lohmann
`IPR2014-00550
`Page 4 of 5
`
`

`

`5,508,038
`
`7
`vitro release rates into water at 37° c. of about 5-15 I!g/cm2
`hr and will have good adhesive properties.
`
`EXAMPLE 7
`
`5
`
`10
`
`40
`
`45
`
`8
`weight in the range of about 1,000-about 450,000,
`the ratio HMW PIB:LMW PIB being in the range of
`5-40:95-60; and
`(ii) said active agent;
`said adhesive being substantially free of plasticizers
`and tackifiers; and
`c) active agent release rate controlling means disposed
`between said reservoir means and said in-line adhesive.
`10. A transdermal nicotine delivery device comprising:
`a) reservoir means containing nicotine as active agent;
`b) an in-line adhesive comprising:
`(i) a polymeric component consisting essentially of a
`mixture of HMW PIB having an average molecular
`weight in the range of about 450,000-about 1,600,
`000 and LMW PIB having an average molecular
`weight in the range of about 1,000-about 450,000,
`the ratio HMW PIB:LMW PIB being in the range of
`5-40:95-60; and
`(ii) nicotine;
`said adhesive being substantially free of plasticizers
`and tackifiers; and
`c) nicotine release rate-controlling means disposed
`between said reservoir means and said in-line adhesive.
`11. The device of claim 9, wherein said active agent is
`selected from the group consisting of nicotine, benztropine,
`secoverine, dexsecoverine and arecoline.
`12. The device of claim 9, 10 or 11 wherein said adhesive
`contains no more than about 50% of said active agent in the
`30 device.
`13. A device for the transdermal administration of nico-
`tine as an active agent, said device comprising:
`a) a subsaturated nicotine reservoir containing up to about
`40 wt % nicotine; and
`b) an adhesive disposed in the path of nicotine migration
`from said nicotine reservoir to the skin, said adhesive
`comprising nicotine dissolved in a polymeric compo(cid:173)
`nent consisting essentially of HMW PIB having an
`average molecular weight in the range of about 450,
`OOO-about 1,600,000 and LMW PIB having an average
`molecular weight in the range of about 1,000-about
`450,000, the ratio of HMW PIB:LMW PIB being in the
`range of about 5-40:95-60, said adhesive being sub(cid:173)
`stantially free of plasticizers and tackifiers.
`14. The device of claim 9, 10 or 13 wherein said ratio is
`in the range of 10-25:90--75.
`15. The device of claim 9, 10 or 13 wherein said ratio is
`in the range of 10-20:90--80.
`16. A device according to claim 10, wherein said nicotine
`release rate-controlling means is high density polyethylene.
`17. A device according to claim 15, wherein said active
`agent reservoir comprises from about 5-40 wt % said active
`agent.
`18. A device according to claim 10, wherein said nicotine
`reservoir comprises from about 60-95 wt % ethylene vinyl
`acetate copolymer having a vinyl acetate content of about
`40%.
`19. A device according to claim 15, wherein said adhesive
`contains no more than about 15 wt % said active agent.
`20. The device of claims 9, 10, 11, 13, 16, or 18 wherein
`said HMW PIB has an average molecular weight of about
`1,200,000 and said LMW PIB has an average molecular
`weight of about 35,000.
`
`The procedures of Example 2 and 3 are repeated, substi-
`tuting for the nicotine reservoir solution, 40% arecoline and
`60% EVA-40 to produce transdermal devices for the deliv(cid:173)
`ery of arecoline. The device will exhibit in vitro release rates
`into water at 37° C. of about 50-100 I!g/cm2 hr and will have
`good adhesive properties.
`While the present invention has been described with
`respect to certain delivery devices, it will be apparent to one
`skilled in the art that variations, modifications and substi(cid:173)
`tutions can be made. These variations, modifications and 15
`substitutions can be made without departing from the scope
`of our invention, which is limited only by the following
`claims.
`We claim:
`1. A polyisobutylene (PIB) adhesive composition for use 20
`in a fransdermal active agent delivery device, said adhesive
`composition comprising an oily, non-polar liquid active
`agent dissolved in a polymeric component consisting essen(cid:173)
`tially of a mixture of high molecular weight (HMW) PIB
`having an average molecular weight in the range of about 25
`450,000-about 1,600,000 and low molecular weight (LMW)
`PIB having an average molecular weight in the range of
`about 1,000-about 450,000, the ratio HMW PIB:LMW PIB
`being in the range of 5-40:95-60; said adhesive composi(cid:173)
`tion being substantially free of plasticizers and tackifiers.
`2. A polyisobutylene adhesive composition for use in a
`trans dermal nicotine delivery device, said adhesive compo(cid:173)
`sition comprising nicotine dissolved in a polymeric compo(cid:173)
`nent consisting essentially of a mixture of HMW PIB having
`an average molecular weight in the range of about 450, 35
`OOO-about 1,600,000 and LMW PIB having an average
`molecular weight in the range of about 1,000-about 450,
`000, the ratio HMW PIB:LMW PIB being in the range of
`5-40:95-60; said adhesive composition being substantially
`free of plasticizers and tackifiers.
`3. The composition of claim 1 or 2, wherein said HMW
`PIB has an average molecular weight in the range of about
`990,000-about 1,600,000 and said LMW PIB has an average
`molecular weight in the range of about 35,000-about
`50,000.
`4. The composition of claim 3, wherein the ratio of HMW
`PIB:LMW PIB is in the range of 10-25:90--75.
`5. The composition of claim 4, wherein the HMW PIB has
`an average molecular weight of about 1,200,000 and said