United States Patent
`Wongetal.
`
`15)
`
`{54] METHOD AND DEVICE FOR PROVIDING
`NICOTINE REPLACEMENT THERAPY
`TRANSDERMALLY/TRANSBUCCALLY
`
`[75]
`
`Inventors: OoiWong, Fremont; Kathleen C,
`Farinas, San Francisco; Gary W.
`Cleary, Menlo Park; Chia-Ming
`Chiang, Foster City; Jun Xia,
`Redwood City, all of Calif.
`
`[73] Assignee: Cygnus Terapeutic Systems, Redwood
`City, Calif.
`
`[21] Appl. No.: 278,277
`:
`Filed:
`
`[22]
`
`Jul. 21, 1994
`
`Related U.S. Application Data
`
`OQ ARAAA
`
`US005603947A
`(11) Patent Number:
`(45) Date of Patent:
`
`5,603,947
`Feb. 18, 1997
`
`5,004,610
`4/1991 Osborne ........ceseeeceseseeteneetseeee 424/448
`
`5,016,652
`we 131/270
`5/1991 Rose........
`
`5,064,654
`11/1991 Berner.......0...
`weve 424/448
`5,091,186
`2/1992 Mirandaet al...ssseseseeeee 424/448
`FOREIGN PATENT DOCUMENTS
`.
`0450986 10/1991 European Pat. Off. .
`0469745
`2/1992 European Pat. Off.
`.
`0481443
`4/1992 European Pat. Off.
`.
`0484543
`5/1992 European Pat. Off.
`.
`0524776
`1/1993 European Pat. Off.
`.
`3438284 10/1984 Germany .
`1197-435-A
`1/1988
`Japan .
`04077419-A 7/1990
`Japan .
`91/03998
`4/1991 WIPO.
`91/16085
`10/1991 WIPO.
`WO091/14463
`10/1991 WIPO.
`93/00057
`1/1993 WIPO.
`
`Primary Examiner—D. Gabrielle Phelan
`Attorney, Agent, or Firm—Morrison & Foerster LLP
`
`{63] Continuation-in-part of Ser. No. 247,520, May 23, 1994,
`abandoned, whichis a continuation of Ser. No. 89,971, Jul.
`ABSTRACT
`[57}
`9, 1993, abandoned.
`A skin or buccal patch for providing nicotine replacement
`[51]
`Tint, CUS cecacsssssscsscsscssccscececnsneeseeseseeseeenees A61F 13/00
`
`
`[52] .. 424/448; 424/447; 424/449_therapy which comprises a matrix type laminated composite
`
`[58] Field of Search oo. eeeesesseeees 424/448, 449,
`in which the matrix is composed of a mixtureofnicotine in
`424/447
`a polymer wherein the amount of nicotine in the matrix,
`diffusion coefficient of nicotine in the matrix and the thick-
`ness of matrix are such that the release of nicotine is: (1)
`controlled by the patch; (2) rapid and atarelatively high flux
`over the prescribed wearing time of patch; and (3) such that
`a substantial proportion ofthe nicotineinitially in the patch
`has been released at the end of the prescribed wearing time.
`
`9 Claims, 13 Drawing Sheets
`
`
`
`
`
`  
`
`

 
`
`MYLAN- EXHIBIT 1028
`
`[56]
`
`.
`References Cited
`UME
`NTS
`U.S. PATENT DOC
`
`8/1985 Bannon .....scsssssssssesssesceeseeeneeneee 326/87
`
`7/1988 Kydonieusetal.
`.
`- 424/449
`6/1989 Baker oe
`we 424/447
`
`
`.. 428/448
`10/1989 Reed, Jr.
`7/1990 Baker 02...cccsesesssssssseersssserseees 424/448
`
`4,496,853
`4,758,434
`4,839,174
`4,877,618
`4,943,435
`
`:
`
`
`
`eet ae
`ete se
`
`
`
`
`’™
`
`

`

`U.S. Patent
`
`5,603,947
`
`Feb. 18, 1997
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`Sheet 9 of 13
`
`5,603,947
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`TARGET DOSE
`
`
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`CUMULATIVEDOSE(mg)
`
`CONSTANT FLUX
`
`—— 15mgNTSIl
`
`—-—-— 15mg NICOTROL
`
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`FIG. 11
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`

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`U.S. Patent
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`Feb. 18, 1997
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`U.S. Patent
`
`Feb. 18, 1997
`
`Sheet 13 of 13
`
`5,603,947
`
`
`
`mMCUMULATIVERELEASE
`
`OSKINFLUX
`
`24
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`

`5,603,947
`
`1
`METHOD AND DEVICE FOR PROVIDING
`NICOTINE REPLACEMENT THERAPY
`TRANSDERMALLY/TRANSBUCCALLY
`
`CROSS-REFERENCE TO RELATED
`APPLICATIONS
`
`This application is a continuation-in-part of U.S. patent
`application Ser. No. 08/247,520 filed 23 May 1994 now
`abandoned which in turn is a continuation of U.S. patent
`application Ser. No. 08/089,971 filed 9 Jul. 1993 and now
`abandoned. Thedisclosures of these related applications are
`incorporated by reference herein.
`
`DESCRIPTION
`
`1. Technical Field
`
`This application relates to transdermal/transbuccal nico-
`tine replacement therapy. More particularly, it relates to a
`device for and a method of providing transdermal/transbuc-
`cal nicotine replacement therapy via a unique dosing regi-
`men which is applicable to heavy smokers.
`2. Background of the Invention
`Nicotine replacement therapy is used to provide smokers
`with nicotine from sources other than cigarettes.
`It
`is
`employed as an aid to assist smokers to quit smoking or to
`sate smokers who wish to reduce smoking or who are
`temporarily prevented from smoking for legal and/or social
`reasons.
`
`In nicotine replacementtherapy, the nicotine is typically
`administered parenterally through a body membrane.In the
`case of administering nicotine via chewing gum,the nicotine
`is delivered via the mucosal membranesofthe oral cavity
`(i.e.,
`the buccal mucosa). Nasal administration involves
`transmitting the nicotine to circulation by passage through
`the nasal mucosa. Finally, in the case of transdermal admin-
`istration, the nicotine is passed through the skin to the
`vessels of the circulatory system.
`Nicotine replacement
`therapy patches should provide
`amounts of nicotine to the user that correspondto all or a
`significant proportion of that which the user was provided by
`smoking or other means of consumption. In addition, for
`safety purposes,it is desirable that the device (1) control the
`flux of nicotine through the skin (as opposed to the skin
`controlling the flux) and (2) have a relatively high degree of
`nicotine depletion over the prescribed dosing or wearing
`period. Also to reduce the likelihood of disturbingsleep,it
`is preferable that the patch release nicotine in a manner that
`results in low plasma levels of nicotine during normal
`sleeping hours.
`Currently four different transdermal nicotine replacement
`therapy patches are available commercially in the U.S. Each
`of them is directed to provide nicotine replacement therapy
`for “light” to “medium” smokers. The four patchesare: the
`NICOTROL® system;
`the NICODERM® system;
`the
`PROSTEP® system; and the HABITROL® system. The
`physician inserts for each of these products include graphs
`of nicotine plasma levels vs.
`time. The graph for the
`NICOTROL® 15 mg/day showsthe levels reach about 13
`ng/mL at about 4 hours and decline to about 7 ng/mL at 16
`hours at which time the system is removed. Plasma levels
`then decay to about 2 at 24 hr. The graph for the 21 mg/day
`NICODERMS®system (the largest) showsa rise from a base
`level of 12 ng/mL to about 22 ng/mL followed by a slow
`decline that reaches the base level of 12 ng/mL at 24 hours.
`The largest PROSTEP® system (22 mg/day) rises to about
`
`2
`16 ng/mL over 4 hours from a 5 ng/mL baseline and then
`exhibits a steady decline to the base level at 24 hours.
`Finally, the HABITROL® 21 mg/day system provides a
`plasmalevel that rises from a baseline of 11 ng/mL to just
`over 15 ng/mL at approximately 10 hours and then slowly
`declines from that peak downto the baseline.
`Noneof these systems administers nicotine at levels that
`are suitable for treating heavy smokers.
`
`DISCLOSURE OF THE INVENTION
`
`Oneaspect ofthe invention is a laminated composite for
`providing transdermal or transbuccal nicotine replacement
`therapy to a person needing such therapy over a predeter-
`mined time period, t, comprising in combination:
`(a) a nicotine impermeable backing layer; and
`(b) a matrix layer having a thickness, 1, and comprising a
`mixture of a polymer and a sufficient amountof nico-
`tine to provide said therapy, the nicotine having a
`diffusion coefficient D in the matrix layer, wherein the
`ratio
`
`Dt
`p
`
`is in the range of about 0.5 to 20 and wherein the
`composite controls the rate at which nicotine is admin-
`istered from said matrix across the skin or buccal
`mucosa of the person over at least 50% of t and the
`average flux of nicotine from the matrix layer overt is
`greater than 50 pg/cm?/hr.
`Anotheraspectof the invention is a method for providing
`transdermal ortransbuccal nicotine replacement therapy to a
`person needing such therapy comprising affixing the above
`described laminated composite in diffusional relationship to
`the skin or buccal mucosaof the person.
`
`BRIEF DESCRIPTION OF THE DRAWINGS
`
`15
`
`20
`
`30
`
`35
`
`In the drawings:
`FIGS. 1-3 are cross-sectional diagrams (not to scale) of
`various embodiments of the invention.
`
`FIGS. 4-15 are graphs of the test data described in the
`examples, infra.
`
`45
`
`MODES FOR CARRYING OUT THE
`INVENTION
`
`50
`
`55
`
`60
`
`65
`
`Asused herein the term “nicotine” includes nicotine free
`base and pharmaceutically acceptable salts of nicotine that
`are capable of transdermal/transbuccal administration.
`Asused herein, the term “nicotine replacement therapy”
`intends transdermal or transbuccal administration of nico-
`tine which supplements or substitutes for the nicotine pro-
`vided to an individual via smoking or other modes of
`nicotine consumption (e.g., chewing tobacco).
`The term “heavy smoker” denotes a person whose smok-
`ing provides the smoker with an average daily dose of
`nicotine in the range of about 25 to about 75 mg.
`The term “predetermined time period” intends the time
`period over which the laminated composite ofthe invention
`is designed to administer an effective amount of nicotine.
`This will generally correspond to the prescribed wearing
`time (ie.,
`the time period over which the composite is
`intendedto be affixed to the skin). Naturally, the composite
`may be wor beyond the prescribed time period, but,
`
`

`

`5,603,947
`
`3
`because of the release kinetics of the composite only thera-
`peutically insignificant amounts of nicotine are released
`after the prescribed wearing period. The prescribed wearing
`time will be in the range of 0.5 to 24 hr. In the case of
`composites that are intended to be worn in a once-a-day
`regimen to replace the normal daily amount of nicotine
`previously consumed by the wearer, the preferred prescribed
`wearing time will be approximately 24 hr. Correspondingly,
`in the case of composites that are intended to provide
`therapy over periods during which the weareris legally or
`socially prohibited from smoking, the prescribed wearing
`time will be of significantly shorter duration, usually 1 to 10
`hr. Further patches that are intended for buccal administra-
`tion will usually be of shorter duration, typically 0.5 to 6 hr.
`The devices ofthis invention are “monolith”or “matrix”
`type laminated composite structures in which the nicotineis
`contained within a matrix layer comprised of the nicotine
`blended homogeneously with a polymercarrier. Other mate-
`rials such as plasticizers, permeation enhancers or nicotine
`sorption compositions may also be present in the matrix.
`Such additives may affect the diffusion coefficient of nico-
`tine in the matrix or, when released from the matrix to the
`skin, alter the permeability of the skin to nicotine.
`The diffusion coefficient (D) of nicotine in the matrix and
`the thickness (1) of the matrix affect the kinetics of the
`release of nicotine from the matrix. In this regard the
`diffusion coefficient of nicotine in the matrix will usually be
`in the range of about 1x10 to 1x107!?, more usually
`1x10to 5x10~? cm/sec. Df? is determined by first
`determining in vitro nicotine release (not through skin) from
`the device as described in Example 1, infra. The in vitro
`nicotine release data are analyzed according to “Controlled
`Release of Biologically Active Agents” by Richard W.
`Baker, Wiley Interscience (1987) page 51, equation 3.16.
`Only data up to 60% ofthe nicotine loading are included in
`the analysis. The diffusion coefficient is determined from the
`slopeof the plotofthe in vitro nicotine release (normalized
`by the nicotine loading) versus the squareroot of time. For
`systems such as those shown in FIG. 3 which have an
`additional adhesive layer, equation 3.16 should be used to
`determine an effective D/l. (Note that the Baker analysis of
`data involves drug release from two sides of a matrix. In
`release tests conducted on patches with an impermeable
`backing release only occurs from one side of the matrix.
`Thus,the thickness, 1, used in Baker equation 3.16 should be
`replaced by 2xl, where |
`is the actual
`thickness of the
`matrix).
`The thickness of the matrix layer will normally be in the
`range of 25 to 500 microns, more usually 50 to 350 microns.
`As indicated previously, in the composites of this inven-
`tion the ratio
`
`Dt
`Pp
`
`is in the range of about 0.5 and 20, preferably 0.75 to 10, and
`most preferably 0.75 to 5. One or more ofD, 1, and t may be
`varied within the ranges described above to obtain such a
`ratio.
`
`Another distinguishing characteristic of the devicesof the
`invention is that they, rather than the skin or buccal mucosa
`of the wearer, control the rate at which nicotine is admin-
`istered to the wearer. The relative control by the device and
`by the skin/mucosa may be determined by standard in vitro
`diffusion tests in which the cumulative dose of nicotine (Ad)
`from the device directly into an aqueoussink is compared to
`the cumulative dose of nicotine from the device and through
`
`15
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`60
`
`65
`
`4
`skin/mucosainto the aqueous sink (At). Such comparisons
`are described by Guy, R. H. and Hadgraft, J. in the Inter-
`national Journal of Pharmaceutics (1992) 82:R1-R6. Those
`comparisons permit one to determine the fractional control
`exerted by the device (Fd) which is equal to the cumulative
`dose of nicotine from the device and through skin into the
`sink divided by the cumulative nicotine from the device
`directly into the sink. Thus when these doses are equal Fd=1
`and the device totally controls the delivery ofnicotine to the
`wearer. Correspondingly, when Fd>0.5 the device exerts
`more control than the skin. For the purposes of the present
`invention the device is considered to control the release of
`nicotine when Fd is 20.5 for >50% of the time periodt.
`Control of the release rate of nicotine by the device rather
`than the skin/mucosa makes the invention devices safer to
`use in that the administration of nicotine is not subject to
`variability in skin/mucosa permeability from wearer-to-
`wearer or from site-to-site on the skin/mucosa of an indi-
`vidual wearer. In order to assure that the device controls the
`nicotine release, known skin permeation enhancers may be
`incorporated into the matrix and co-administered with the
`nicotine. Examples, without limitation, of enhancers that
`may be so used are those described or referenced in com-
`monly owned U.S. Pat. No. 4,906,463.
`Yet another characteristic of the invention patchesis that
`they have a relatively high degree ofnicotine depletion over
`the prescribed wearing period. This feature renders the
`devices safer to dispose of in the sense that after use the
`amounts of nicotine which they contain are less likely to
`cause injury to children or pets who may inadvertently
`ingest them. The degree of depletion may be quantified by
`comparing the cumulative amount of nicotine released (as
`determined by standard in vitro diffusion tests of nicotine
`released through skin into an aqueous sink over the pre-
`scribed wearing period, t) with the initial amountof nicotine
`contained in the device (sometimesreferred to as “nicotine
`loading”). In the invention devices over about 40%, more
`usually about 50%, of the initial amount of nicotine is
`released within the first 50% of t. Usually at least about 50%
`of the initial amount of nicotine is released over the entire
`period t. Another aspect of the depletion kinetics of these
`devices is that the averageflux of nicotine from the devices
`is muchhigherin the initial stage of the wearing period than
`in the latter stages of wearing. This reductionin flux may be
`quantitated by comparing the average flux overthelast
`of
`the time period t with the average flux overthe entire period.
`In the patches of the invention the ratio of the average flux
`overthe last % oft to the averageflux over the entire period
`t is less than about 0.4 usually between 0.1 and 0.4. All
`currently available nicotine patches exhibit rates in excess of
`0.4.
`The initial amountof nicotine in the matrix layer will vary
`between about 2 and 100 mg with lower amountsin this
`range being used for shorter duration(i.e., 10 hr or less, 5~50
`mg) or buccal embodiments (2-25 mg) of the device and
`higher amounts in the range (e.g., 50-100 mg) being used
`for once-a-day devices that provide replacement therapy to
`heavy smokers.In the case of devices for heavy smokers, the
`average flux of nicotine from the matrix layer over the time
`period t (measured in vitro by standard diffusion tests) will
`normally be greater than 50 yg/cm*/hr, usually 60 to 125
`ug/cm*/hr.
`The polymer carrier ingredient of the matrix layer is
`selected to provide the requisite diffusion coefficient, D, and
`desired partition coefficient. In this regard the properties of
`the matrix layer are more important than the typeor class of
`polymerusedas a carrier. Thatis the layer needs to provide
`
`

`

`5,603,947
`
`5
`a proper Dt/l” and havea low nicotine solubility (e.g., less
`than about 30% by weight) so that there is good partitioning
`of nicotine into the skin or provide an enhancerto reduce the
`tesistance of the skin to nicotine permeation. Partition
`coefficients may be determined by placing a 50 micronthick
`nicotine-free matrix in a diffusion cell (the samecells as are
`described in Example 1, infra). A 6% solution ofnicotine in
`wateris used as the donorsolution at a volume 21 ml so that
`nicotine concentration in the donor solution remained con-
`stant. Samples are collected as in the flux studies of Example
`1, infra. D and the nicotine concentration in the matrix in
`equilibrium with the donor solution can be obtained by
`fitting the data from the samples with equation 4.24 in
`“Mathematics of Diffusion”, Crank, J., Clarendon Press,
`Oxford (1975) 2nd Ed. The partition coefficient can be
`calculated by dividing the nicotine concentration in the
`donor solution by the concentration in the film in equilib-
`rium with the donor solution. A high partition coefficient
`(above about 1) indicates low solubility of nicotine in the
`matrix. As indicated previously, a high partition coefficient
`enables the device to contro] the release of nicotine. Thatis,
`a matrix with a low nicotine solubility/high partition coef-
`ficient will have a high thermodynamic activity, which in
`turn results inhigh concentration gradients and high nicotine
`flux through the skin.
`It is also believed that the high flux embodiments of the
`invention have a relatively low potential for skin irritation.
`Skin irritation is believed to be associated with nicotine flux
`throughthe skin, the duration of exposureto the flux and the
`nicotine concentration at the skin/matrix interface. Because
`the devices of this invention release nicotine rapidly and
`then taper off (as opposed to relatively constant rate), the
`skin/mucosais subject to high fluxes for a shorter duration
`(even though the average flux over the time period is high).
`Also, because the devices control nicotine release, there is
`no build up of nicotine at the skin/matrix interface.
`It will be appreciated that D may be influenced by the
`concentration of nicotine in the layer or by the presence of
`other matrix ingredients such as plasticizers, permeation
`enhancers, or compounds that sorb nicotine. Also, if the
`matrix itself is to have adhesive properties, the polymer
`carrier must be a pressure sensitive adhesive. When the
`matrix is adhesive the basal surfaceof the layer provides the
`means by which the device is affixed to the skin or mucosa.
`If the matrix is not adhesive, other means(e.g., an under-
`lying layer of adhesive, a peripheral ring of adhesive, an
`adhesive overlay or straps), must be used to affix the device
`to the skin. In all embodiments the matrix layeris in direct
`or indirect diffusional relationship to the skin or mucosa. In
`other words there is a diffusional pathway for nicotine to
`migrate from the matrix layer into the skin or mucosa.
`Examples of polymer carriers that may be used in the matrix
`layer are amine-resistant polydimethylsiloxanes (silicones),
`styrene-ethylene-butylene-styrene block copolymers (Kra-
`tons), styrene-isoprene block copolymers (Durotak), and
`polyisobutylenes.
`In once-a-day embodiments in which (a) the matrix layer
`adheres directly to the skin and is made of a silicone
`adhesive and (b) the nicotine loading is high, it may be
`necessary to include solid, particulate additive(s) that sorb
`nicotine in order to improve the cold flow properties of the
`matrix. Examples of such sorptive materials are sodium
`starch glycolate, silica gel, and calcium, magnesium or
`aluminum silicate. These additives will normally constitute
`about 5 to 20% by weight of the matrix when they are
`present.
`FIG. 1 depicts the structure of one embodiment of a
`nicotine-containing transdermal patch of the invention. The
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`45
`
`30
`
`55
`
`65
`
`6
`device of FIG. 1 is a “monolith” type laminated composite
`structure (the nicotine is contained in a homogeneous adhe-
`sive matrix) which prior to wearing hasthree distinctlayers:
`a conventional nicotine-impermeable backing layer 11 that
`defines the top surface of the device; an underlying matrix
`layer 12 comprised of a homogeneous mixture ofnicotine in
`a pressure-sensitive adhesive polymer carrier as described
`supra; and a conventional removablerelease liner layer 13
`that is removed before the device is placed on the skin. After
`release liner 13 is removed, the lower surface of the matrix
`layer is exposed and defines the basal surface of the device
`which is intended to be in direct adhesive contact with the
`skin.
`
`The backing layer may be made of the nicotine-imper-
`meable polymers or polymer-metal foil laminates that are
`used on the backing layers of the presently available nicotine
`replacement therapy patches. A laminate of polyester (Sch
`upbach) is a preferred backing layer material.
`FIG. 2 shows an alternative device structure to that of
`FIG. 1. The device of FIG. 2 is a five-layer laminated
`composite of: a backing layer 15; an anchor adhesive layer
`16; a nonwoven fabric layer 17; a matrix layer 18; and a
`release liner layer 19. The backing, matrix layer, and release
`liner layers are similar in composition and structure to the
`counterpart layers of the device of FIG. 1. Thus, the device
`of FIG. 2 differs from that of FIG. 1 by the presence of the
`anchor adhesive layer and the nonwovenfabric layer. Those
`layers are present solely for ease of manufacture and or
`improving the physical properties of the device as is known
`in the art (see U.S. Pat. No. 4,915,950). They do not
`materially alter or affect the release pattern of nicotine. The
`anchor adhesive layer is preferably made of the same
`adhesiveas the adhesive ofthe matrix layer. Whenitis, layer
`16,
`is in effect, part of the matrix layer. Conventional
`nonwoven fabrics may be used for layer 17.
`FIG. 3 depicts anotheralternative structure to that shown
`in FIG.1. This device is similar in structure and composition
`to the device of FIG.1, the differences being that the matrix
`layer has no adhesive properties (i.e., the polymer carrier is
`not a pressure sensitive adhesive) and the device includes an
`underlying adhesive layer. Accordingly,
`the device is a
`four-layer laminated composite of: a backing layer 21; a
`non-adhesive matrix layer 22; an adhesive layer 23; and a
`release liner layer 24. The backing layer and release liner
`‘layer perform the same functions as the counterpart layers of
`the device of FIG. 1. The matrix layer, however, being
`nonadhesive does not function as the means by which the
`patch adheresto the skin. Instead, the underlying adhesive
`layer 24 fulfills that function.
`The diffusional surface area (i.e., the area of the basal
`surface of the device through which nicotine diffuses into the
`skin) will normally be in the range of 5 and 40 cm?,
`inclusive. Devices of such surface area which provide the
`nicotine fluxes described above administer nicotine in
`amounts and rates that yield peak wearer plasma levels
`substantially above 25 ng/mL usually substantially above 35
`ng/mL.
`The devices from FIGS. 1-3 may be constructed using
`conventional equipment and procedures used in the fabri-
`cation of laminated composite transdermal drug delivery
`devices. See, for instance, U.S. Pat. No. 4,915,950.
`The following examples further illustrate the invention.
`These examplesare notintended to limit the invention in any
`manner. Unless indicated otherwise, percentages are by
`weight.
`
`

`

`5,603,947
`
`7
`EXAMPLES
`
`Example 1
`
`5
`
`20
`
`25
`
`35
`
`45
`
`55
`
`8
`ml/min and the sample injection volume was 25 pl. The
`retention time of the nicotine peak in the chromatograms
`was3 to 4 minutes. The actual concentration of nicotine was
`directly interpreted from a standard curve constructed for
`each experimental run using knownnicotine solutions.
`Correspondingly in vitro drug release (not through skin)
`studies were made as follows.
`Convex screen patch holder: (The design of the convex
`screen patch holderis described in Hadgraft, J., et al., Int J
`Pharm (1991) 73:125-130.) Following the removal of the
`patchreleaseliner, the test patch was directly attached to the
`apex of the convexscreenofthe holder, with its drug release
`adhesive surface facing upwards. The assembly was then
`slowly dropped to the bottom ofa glass vessel. The convex
`screen patch holder is designed to fit the bottom ofa glass
`vessel relatively snugly and thereby hold the patch in
`position.
`Drugrelease apparatus and procedures: Drugrelease from
`the test patch was conducted with a six-spindle USP Appa-
`ratus 5 employing glass vessels (Hanson Research Corpo-
`ration, Chatsworth, Calif.). The distance between the center
`of the drug release surface of a patch and the bottom edge
`of a paddle was adjusted to 2.5 cm. The paddle speed was
`set at 50 rpm andthe glass vessels were filled with 600 ml
`of deaerated, 0.025N HCl. This volumeofreceptorfluid is
`necessary to keep the released nicotine concentration low at
`a close-to-sink condition throughoutthe entire study while
`not over-diluting the medium. Thereceptorfluid was main-
`tained at 32°+0.3° C. using a solid-state temperature control
`(Hanson Research). Aliquots of 1 ml samples were collected
`withoutfiltering and replacementat 1, 2, 4, 6, 8, 12, 16 and
`24 hr and the samples were analyzed for nicotine content
`using an HPLC system. The apparatus was calibrated using
`USP prednisone and salicylic acid calibrators before, and
`after, the drug release studies.
`HPLCanalysis of nicotine: The HPLC system consisted
`of a high-pressure pump (model 510, Waters, Division of
`Millipore Corporation, Bedford, Mass.), an auto injector/
`auto sampler (WISP 710B, Waters), a variable wavelength
`UV detector (Spectroflow 783, Kratos Analytical Instru-
`ments, Ramsey, N.J.) and an integrator/recorder (SP 4290,
`Spectra-Physics Analytical, San Jose, Calif.). A 50 ul sample
`was injected and analyzed using a Waters pBondapack C18
`reversed phase column (300x3.9 mm) at ambient tempera-
`ture. The mobile phase used was a mixture of 0.25M sodium
`dodecyl
`sulphate:1M sodium acetate:water:acetonitrile
`(8:10:612:370) with a flow rate of 2.0 ml/min and the UV
`detection was set at 254 nm.
`The standard curve was constructed by plotting the peak
`area against the concentration using three different levels of
`nicotine standard solutions in duplicate injections. The rela-
`tive standard deviations (RSD’s), which were the ratios of
`standard deviations to the mean values, for these standards
`were less than 2% in the present study. The nicotine con-
`centration in each sample was determined from its peak area
`with reference to the standard curve and the accumulative
`amountof nicotine released from a patch at the nth time
`point (Q,,) was calculated from the following relationship:
`n=l
`Qn = Cr x (Ve —- Vex@e—Di+ 3% VexG
`
`65
`
`where C,, and C; are the nth and the ith term of the sample
`concentration, respectively, Vz and V. are the receptor and
`the sample volume,respectively. Based onthe patchsize,the
`amount of nicotine released per unit drug diffusional area
`(mg/cm?) at each time point was determined.
`These plots are shownin FIG. 4.
`
`(3 ml thick SO 1022/3M) was laminated
`
`A homogeneous 7% (based on weight of nicotine plus
`adhesive solids) mixture of nicotine in Dow Corning sili-
`cone adhesive 4201 was prepared by mixing an appropriate
`
`in a rotary mixer for at least two hours. The mixture was
`spread evenly with a Gardener knife on a 1.3 mil
`thick
`backing layer (3M 11903M Scotchpak™)to a wet thickness
`of 25 mil. The resulting composite was dried in an oven for
`60-80 minutes at 73° C. to remove solvent from the adhe-
`sive leaving a 350 micron thick matrix layer. A release liner
`a er
`cree-layer feeninesedl composite (corresponding to FIG. 1)
`
`was then cut in 15 cm? pieces. The pieces made each
`contained approximately 37 mg nicotine. The diffusion
`coefiicient ofnicotine in the matrix layer was determined to
`be 9.7x107 cm/sec.
`These devices are intended to administer nicotine over a
`16 hr period. Thus the ratio
`
`Dt
`r
`
`is calculated to be 4.6 for these devices.
`In vitro nicotine skin flux studies were carried out on the
`above-described composites as follows.
`Human cadaver epidermis was removed carefully from
`dermatonedfull thicknessskin after the skin had been heated
`in deionized water at 60° C. for one to two minutes. The
`stripped epidermis was placed between two polyethylene
`plastic sheets and keptin the refrigerator until use. Discs of
`the epidermis with a diameter of %" were punched out with
`a die and tested for leakage. This was done by soaking the
`epidermis in water, then spreading it flat on a plastic sheet,
`andpressingthe topofthe epidermis lightly a few times with
`a piece of laboratory tissue. Leakage of the epidermisled to
`wet spots on the tissue.
`The good epidermisdisc was placed ontopofthe receiver
`cell of a modified Franz vertical diffusion cell assembly. A
`small magnetic stir bar was inserted through the sampling
`port into the donor cell compartment. Composites of the
`samesize as the diffusion cell (0.71 cm*) were cut. (The
`sizes should be the same to avoid contributions from lateral
`diffusion.) The release liner
`from the composites was
`removedandthe resulting two-layer composite was placed
`onto the epidermis. The diffusion cell assemblies were then
`clampedtogether and transferred to a skin permeation room
`(controlled at 32° C.). The receiver cell compartments were
`filled with 8.0 ml ofthe isotonic phosphate buffer of pH 7.0.
`At appropriate sampling time points, a 1.0 ml sample was
`removed from the receptor compartment
`followed by
`replacement of 1.0 ml of fresh buffer.
`The concentration ofnicotine in each sample was assayed
`by an HPLCanalytical method. The HPLC apparatus used
`included a Perkin Elmer autosampler, ISS-200, a Perkin-
`Elmer pump 410B10, and a Perkin Elmer diode array
`detector LC-235. The column was yBondapack (30 cmx3.9
`mm), C18, with particle size of 10 microns obtained from
`Waters. A guard column was used in conjunction with the
`column. The mobile phase contained 0.25M dodecyl sodium
`sulphate:
`1M sodium acetate: water:
`acetonitrile
`(8:10:612:370) with a pH ofabout 3.