`US005603947A
`
`United States Patent
`
`[19]
`
`[11] Patent Number:
`
`5,603,947
`
`Wong et al.
`
`[45] Date of Patent:
`
`Feb. 18, 1997
`
`[54] METHOD AND DEVICE FOR PROVIDING
`NICOTINE REPLACEMENT THERAPY
`TRANSDERMALLY/TRANSBUCCALLY
`
`5,004,610
`5,016,652
`5,064,654
`5,091,186
`
`4/1991 Osborne ................................. 424/448
`
`5/1991 Rose ........
`131/270
`
`11/1991 Berner .............
`424/448
`........................ 424/448
`2/1992 Miranda et al.
`
`[75]
`
`Inventors: Ooi_Wong, Fremont; Kathleen C.
`Farmas, San Francrsco; Gary W.
`Cleary, Menlo Park; Chia-Ming
`Chiang, Foster City; Jun Xia,
`Redwood City, all Of Calif.
`
`[73] Ass1gr1ee: Cygnus Terapeutlc Systems, Redwood
`CRY, cahf-
`
`[21] App]. No.: 278,277
`.
`Filed:
`
`[22]
`
`Jul-21, 1994
`
`'
`
`FOREIGN PATENT DOCUMENTS
`
`,
`
`.
`.
`.
`.
`.
`
`0450986 10/1991 European Pat. Ofl’.
`0469745
`2/1992 European Pat. Off.
`0481443
`4/1992 European Pat. Off.
`0484543
`5/1992 European Pat. 011.
`0524776
`1/1993 European Pat. Oif.
`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.
`WO91/14463
`10/1991 WIPO.
`93/00057
`1/1993 WIPO .
`
`Related U.S. Application Data
`
`[63] Continuation-impart of Ser. No. 247,520, May 23, 1994,
`abandoned, which is a continuation of Ser. No. 89,971, Jul.
`9, 1993, abandoned.
`
`[51]
`Int. Cl.6 ...................................................... A61F 13/00
`
`[521
`-- 424/448; 424/447; 424/449
`[58] Field of Search ..................................... 424/448, 449,
`424/447
`
`[56]
`
`References Cited
`
`4,496,853
`4,753,434
`4,839,174
`4,877,618
`4,943,435
`
`U'S' PATENT DOCUMENTS
`
`8/1985 Bannon ............. 326/87
`
`7/1988 Kydpnieus ‘31
`~
`-- 424/449
`424/447
`6/1989 Baker ...............
`
` .'.. 428/448
`10/1989 Reed, Jr.
`7/1990 Baker ...................................... 424/448
`
`Primary Examiner—D. Gabrielle Phelan
`Attorney, Agent, or Finn—Morrison & Foerster LLP
`
`[57]
`
`ABSTRACT
`
`A skin or buccal patch for providing nicotine replacement
`therapy which comprises a matrix type laminated composite
`in which the matrix is composed of a mixture of nicotine in
`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 at arelatively high flux
`over the prescribed wearing time of patch; and (3) such that
`a substantial proportion of the nicotine initially in the patch
`has been released at the end of the prescribed wearing time.
`"
`
`9 Claims, 13 Drawing Sheets
`
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`13
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`MYLAN - EXHIBIT 1028
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`US. Patent
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`Feb. 18, 1997
`
`Sheet 1 of 13
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`5,603,947
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`13
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`12
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`US. Patent
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`Feb. 18, 1997
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`CONSTANT FLUX
`
`TARGET DOSE
`
`
`
`—— 15 mg NTS 11
`— — — 15 mg NICOTROL
`
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`5,603,947
`
`1
`NIETHOD AND DEVICE FOR PROVIDING
`NICOTINE REPLACEMENT THERAPY
`TRANSDERMALLY/TRANSBUCCALLY
`
`CROSS-REFERENCE TO RELATED
`APPLICATIONS
`
`This application is a continuation-impart of US. patent
`application Ser. No. 08/247,520 filed 23 May 1994 now
`abandoned which in turn is a continuation of US. patent
`application Ser. No. 08/089,971 filed 9 Jul. 1993 and now
`abandoned. The disclosures 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 replacement therapy, 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 mucosa] membranes of the 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 correspond to 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 disturbing sleep, 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 US. Each
`of them is directed to provide nicotine replacement therapy
`for “light” to “medium” smokers. The four patches are: 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 mgday shows the 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
`NICODERM® system (the largest) shows a 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
`l6 ng/rnL 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
`plasma level 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 down to the baseline.
`None of these systems administers nicotine at levels that
`are suitable for treating heavy smokers.
`
`DISCLOSURE OF THE INVENTION
`
`One aspect of the 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 suflicient amount of nico-
`tine to provide said therapy, the nicotine having a
`difl’usion coefficient D in the matrix layer, wherein the
`ratio
`
`Dr
`F
`
`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 over t is
`greater than 50 ug/cmzlhr.
`Another aspect of the invention is a method for providing
`transdermal or transbuccal nicotine replacement therapy to a
`person needing such therapy comprising aflixing the above
`described laminated composite in difiusional relationship to
`the skin or buccal mucosa of the person.
`
`BRIEF DESCRIPTION OF THE DRAWINGS
`
`10
`
`15
`
`20
`
`25
`
`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
`
`As used herein the term “nicotine” includes nicotine free
`base and pharmaceutically acceptable salts of nicotine that
`are capable of transdermal/transbuccal administration.
`As used 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 of the invention
`is designed to administer an effective amount of nicotine.
`This will generally correspond to the prescribed wearing
`time (i.e.,
`the time period over which the composite is
`intended to be affixed to the skin). Naturally, the composite
`may be worn 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 wearer is 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 of this invention are “monolith” or “matrix”
`type laminated composite structures in which the nicotine is
`contained within a matrix layer comprised of the nicotine
`blended homogeneously with a polymer carrier. Other mate-
`rials such as plasticizers, permeation enhancers or nicotine
`sorption compositions may also be present in the matrix.
`Such additives may afiect 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 difi'usion coeflicient (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 coeflicient of nicotine in the matrix will usually be
`in the range of about 1><10‘6 to lxlO‘lz, more usually
`1x10‘9 to 5X10“7 cmzlsec. D/l2 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% of the nicotine loading are included in
`the analysis. The dilfusion coefficient is determined from the
`slope of the plot of the in vitro nicotine release (normalized
`by the nicotine loading) versus the square root 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 eifective D/lz. (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 2x1, where 1
`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
`[2
`
`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 of D, l, and t may be
`varied within the ranges described above to obtain such a
`ratio.
`
`Another distinguishing characteristic of the devices of 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 aqueous sink is compared to
`the cumulative dose of nicotine from the device and through
`
`4
`skin/mucosa into 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:l
`and the device totally controls the delivery of nicotine 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 period t.
`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—adrninistered 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 patches is that
`they have a relatively high degree of nicotine 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 amount of nicotine
`contained in the device (sometimes referred 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 1. Another aspect of the depletion kinetics of these
`devices is that the average flux of nicotine from the devices
`is much higher in the initial stage of the wearing period than
`in the latter stages of wearing. This reduction in flux may be
`quantitated by comparing the average flux over the last 1/3 of
`the time period t with the average flux over the entire period.
`In the patches of the invention the ratio of the average flux
`over the last 1/3 of t to the average flux 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 amount of nicotine in the matrix layer will vary
`between about 2 and 100 mg with lower amounts in 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 difl'usion tests) will
`normally be greater than 50 pg/cmzlhr, usually 60 to 125
`ug/cmzlhr.
`The polymer carrier ingredient of the matrix layer is
`selected to provide the requisite dilfusion coefiicient, D, and
`desired partition coefficient. In this regard the properties of
`the matrix layer are more important than the type or class of
`polymer used as a carrier. That is the layer needs to provide
`
`10
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`a proper Dt/l2 and have a 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 enhancer to reduce the
`resistance of the skin to nicotine permeation. Partition
`coeflicients may be determined by placing a 50 micron thick
`nicotine-free matrix in a difl’usion cell (the same cells as are
`described in Example 1, infra). A 6% solution of nicotine in
`water is used as the donor solution at a volume :1 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 coeflicient 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 coefiicient
`enables the device to control the release of nicotine. That is,
`a matrix with a low nicotine solubility/high partition coef—
`ficient will have a high thermodynamic activity, which in
`turn results in’high 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
`through the skin, the duration of exposure to 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/mucosa is 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 surface of the layer provides the
`means by which the device is aflixed 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 layer is in direct
`or indirect difl’usional 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
`
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`6
`” type laminated composite
`device of FIG. 1 is a “monoli
`structure (the nicotine is contained in a homogeneous adhe-
`sive matrix) which prior to wearing has three distinct layers:
`a conventional nicotine-irnpenneable backing layer 11 that
`defines the top surface of the device; an underlying matrix
`layer 12 comprised of a homogeneous mixture of nicotine in
`a pressure—sensitive adhesive polymer canier as described
`supra; and a conventional removable release 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 nonwoven fabric 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
`adhesive as the adhesive of the matrix layer. When it is, layer
`16,
`is in eifect, part of the matrix layer. Conventional
`nonwoven fabrics may be used for layer 17.
`FIG. 3 depicts another alternative structure to that shown
`in FIG. 1. This device is similar in structure and composition
`to the device of FIG. 1, the difi‘erences 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 adheres to 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 diifuses into the
`skin) will normally be in the range of 5 and 40 'cm2,
`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 transderrnal drug delivery
`devices. See, for instance, U.S. Pat. No. 4,915,950.
`The following examples further illustrate the invention.
`These examples are not intended to limit the invention in any
`manner. Unless indicated otherwise, percentages are by
`weight.
`
`
`
`5,603,947
`
`7
`EXAMPLES
`
`Example 1
`
`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 1190 SM ScotchpakTMJ to a wet thickness
`of 25 mil. The resulting composite was dried in an oven for
`60—80 minutes at 23° C. to remove solvent from the adhe-
`sive leaving a 350 micron thick matrix layer. A release liner
`la er 3 mil thick ScotchakTM lUZSUSM was laminated
`I
`I
`I U“
`"I
`U
`l
`
`
`
`8
`ml/min and the sample injection volume was 25 pl. The
`retention time of the nicotine peak in the chromatograms
`was 3 to 4 minutes. The actual concentration of nicotine was
`directly interpreted from a standard curve constructed for
`each experimental run using known nicotine 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 holder is described in Hadgraft, J., et al., Int J
`Pharm (1991) 73:125-130.) Following the removal of the
`patch release liner, the test patch was directly attached to the
`apex of the convex screen of the holder, with its drug release
`adhesive surface facing upwards. The assembly was then
`slowly dropped to the bottom of a glass vessel. The convex
`screen patch holder is designed to fit the bottom of a glass
`vessel relatively snugly and thereby hold the patch in
`position.
`Drug release apparatus and procedures: Drug release 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 and the glass vessels were filled with 600 ml
`of dcacratcd, 0.025N BC]. This volume of receptor fluid is
`necessary to keep the released nicotine concentration low at
`a close-to-sink condition throughout the entire study while
`not over-diluting the medium. The receptor fluid was main-
`tained at 32°:l:0.3° C. using a solid-state temperature control
`(Hanson Research). Aliquots of 1 ml samples were collected
`without filtering and replacement at 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.
`HPLC analysis of nicotine: The l-lPLC system consisted
`of a high-pressure pump (model 510, Waters, Division of
`Millipore Corporation, Bedford, Mass), an auto injector/
`auto sampler (WISP 7108, Waters), a variable wavelength
`UV detector (Spectroflow 783, Kratos Analytical Instru-
`ments, Ramsey, NJ.) and an integrator/recorder (SP 4290,
`Spectra—Physics Analytical, San Jose, Calif). A 50 ul sample
`was injected and analyzed using a Waters uBondapack C18
`reversed phase column (300x3.9 mm) at ambient tempera-
`ture. The mobile phase used was a mixture of 0.25M sodium
`dodecyl
`sulphatele sodium acetate:water:acetoniuile
`(8:10:612z370) 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 concenuation using three difl‘erent 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 rticotine con—
`centration in each sample was determined from its peak area
`with reference to the standard curve and the accumulative
`amount of nicotine released from a patch at the nth time
`point (Q,,) was calculated from the following relationship:
`n-l
`
`Qn=CnX[VR-V;X(n-l)]+i=}(:) V:XC§
`
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`three-layer laminated composite (corresponding to FIG. 1)
`was then cut in 15 cm2 pieces. The pieces made each
`contained approximately 37 mg nicotine. The diffusion
`coefficient of nicotine in the matrix layer was determined to
`be 9.7xlO‘a cmzlscc.
`These devices are intended to administer nicotine over a
`16 hr period. Thus the ratio
`
`Dr
`(2
`
`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
`dermatoned full thickness skin after the skin had been heated
`in deionized water at 60° C. for one to two ntinutes. The
`stripped epidermis was placed between two polyethylene
`plastic sheets and kept in the refrigerator until use. Discs of
`the epidermis with a diameter of 5/3“ 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,
`and pressing the top of the epidemtis lightly a few times with
`a piece of laboratory tissue. Leakage of the epidermis led to
`wet spots on the tissue.
`The good epidermis disc was placed on top of the 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
`same size as the dilfusion cell (0.71 cmz) were cut. (The
`sizes should be the same to avoid contributions from lateral
`difi'usion.) The release liner
`from the composites was
`removed and the resulting two-layer composite was placed
`onto the epidermis. The diffusion cell assemblies were then
`clamped together and transferred to a skin permeation room
`(controlled at 32° C.). The receiver cell compartments were
`filled with 8.0 ml of the 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 bufi‘er.
`The concentration of nicotine in each sample was assayed
`by an HPLC analytical method. The HPLC apparatus used
`included a Perkin Elmer autosarnpler, [SS-200, a Perkin-
`Elmer pump 410810, and a Perkin Elmer diode array
`detector LC-235. The column was uBondapack (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:
`acetoniuile
`(8210;612:370) with a pH of about 3.5. The detection wav