Pharmaceutical Development and Technology, 1(3), 2857291 (1996)
`
`RESEARCH ARTICLE
`
`Development of a Transdermal Patch of
`Methadone: In Vitro Evaluation Across
`
`Hairless Mouse and Human Cadaver Skin
`
`
`Tapash K. Ghosh* and Alireza Bagherian
`
`Department of Pharmaceutical Sciences, College of Pharmacy and Pharmaceutical
`Sciences, Howard University, Washington, DC 20059
`
`Received March 5, 1996; Accepted June 7, 1996
`
`ABSTRACT
`
`A 3-day monolithic polyacrylate adhesive dispersion type delivery system containing methadone was
`fabricated and in Vitro permeation through hairless mouse and human cadaver skins was conducted.
`The eflect of skin permeation enhancers was also investigated. Skin permeation rate across human
`cadaver skin was found to be lower than that of hairless mouse. Skin permeation profiles across
`both types of skins showed a membrane permeation controlled cumulative amount permeated (Q)
`versus time (t) relationship. Skin permeation rate was found to be dependent on both adhesive film
`thickness and loading dose of the drug in the matrix. Efiective skin permeation rate across the hair-
`less mouse skin was obtained from a patch with 1.5 mm thickness and 15% w/w loading dose. n-
`Decylmethyl sulfoxide and Azone were found to produce an effective skin permeation rate of metha-
`done through human cadaver skin at a 5% w/w concentration. These initial studies demonstrated
`the feasibility of methadone administration through intact skin from a transdermal patch.
`KEY WORDS: Adhesive patch; Azone; Hairless mouse skin; Human cadaver skin; n-Decylmethyl
`sulfoxide; Methadone; Transdermal delivery.
`
`INTRODUCTION
`
`The high prevalence of drug abuse imposes a sub—
`stantial financial burden on those affected and on soci-
`
`ety. Drug abuse is one of the major causes of wide-
`spread illness, high use of medical care services,
`premature death, and considerable costs to society. The
`substance dependency treatment program is one of the
`few options we are left with to halt the increasing trend
`of substance dependency costs. A great deal of research
`
`has been done to assess effectiveness and safety of dif-
`ferent types of chemical agents for treatment of opioid
`dependency. Methadone, which has been used since
`1965 for both detoxification and maintenance therapy,
`is still considered to be the drug of choice for treatment
`of opioid dependency. Methadone is a synthetic mor-
`phine agonist which, as an oral substitute for heroin or
`other morphine-like substances, suppresses the opiate
`agonist abstinence syndrome in patients who are depen-
`dent on these drugs. Peroral administration of metha-
`
`*Correspondence to T. K. Ghosh at his present address: Massachusetts College of Pharmacy and Allied Health Sciences, Bos-
`ton. MA 02115.
`
`Copyright ©1996 by Marcel Dekker, Inc.
`
`285
`
`  
`
`

  
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`MYLAN - EXHIBIT 1014
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`

`

`286
`
`done is inappropriate to patients suffering from nausea,
`vomiting, or dysphagia, whereas parenteral administra-
`tion needs medical supervision. Administration of
`methadone transdcrmally may be a possible approach to
`overcoming these problems. Besides patient conve-
`nience, enhanced and controlled therapeutic responses
`such as avoidance of variable and incomplete bioavail-
`ability and maintenance of steady-state plasma concen—
`tration with much less peak—and-trough variation have
`been reported as the advantages of transdermal drug
`delivery. Transdermal delivery of different narcotic
`analgesics has been reported (14). No study on devel—
`opment of a transdermal patch formulation of methadone
`has been reported so far except an earlier study on hu—
`man cadaver skin permeability of methadone from so-
`lution (5).
`This paper describes preliminary in vitro work on de—
`velopment of a 3—day transderrnal patch of methadone.
`In vitro skin permeation of methadone through hairless
`mouse and human cadaver skins was investigated. The
`effect of n~decylmethyl sulfoxide and Azone, two known
`skin permeation enhancers, on human cadaver skin per—
`meation of methadone was also evaluated.
`
`MATERIALS AND METHODS
`
`Materials
`
`Methadone free base was prepared from commer-
`cially available methadone—BC] (Sigma Chemical Co.,
`St. Louis, MO) and used in the fabrication of the
`polyacrylate adhesive patch. Polyacrylate adhesive was
`obtained as gift from National Starch and Chemical Co.
`(Bridgewater, NJ) and was specially formulated in the
`laboratory for fabrication of patches. Scotch Pak release
`liner, 1022. and Scotch Pak backing membrane, 1066,
`were donated by 3M Co.
`(St. Paul, MN).
`n-
`Decylmethyl sulfoxide (NDMS) was obtained from
`Columbia Organic Chemical Co., Inc. (Camden, SC).
`Azone was obtained from Discovery Therapeutics Inc.
`(Richmond, VA). All other reagents and solvents, either
`high-performance liquid chromatography (HPLC) grade
`or reagent grade. were used as obtained (Fisher Scien-
`tific 0).).
`
`Fabrication of Transdermal Patch
`
`Transdermal monolithic patches for methadone were
`fabricated by a method similar to that recently described
`for other drugs (6—8). Pharmaceutical—grade purified
`acrylic pressure—sensitive adhesive (National Starch and
`
`Ghosh and Bagherian
`
`Chemical Corporation, NJ) was used as the adhesive to
`make the patches. A weighed amount of the drug was
`dispersed homogeneously in the polyacrylate adhesive
`with gentle shaking, and a single transparent layer with
`fixed thickness was made on heat scalable backing
`membrane (Scotch Pak 1066) by using a laboratory
`coating device (Werner Mathis USA Inc., NC). The
`whole system was cured at room temperature in a dust-
`free environment overnight. The laminate was then cov-
`ered by a release liner (Scotch Pak 1022), cut into 1 cm2
`(1 cm x 1 cm) pieces. Optimization of the patch in
`terms of achieving the target delivery rate was done by
`trial and error method through varying the thickness of
`the drug loaded adhesive matrix and also by changing
`the amount of drugs per square centimeter of a patch.
`In the last phase of experiments, formulations contain-
`ing either of the two enhancers were investigated in or»
`der to achieve the desired skin permeation rate and to
`sustain it for 3 days.
`
`Skin Permeation Studies
`
`Either a section of the freshly excised full thickness
`hairless mouse or a section of the properly thawed.
`dermatomed human cadaver skin was mounted on a
`
`side—by-side glass diffusion cell (n = 3) with the stra—
`tum corneum side facing upward and the dermal side
`facing the receptor solution. After carefully removing
`the release liner, a patch was then placed on the stra-
`tum corneum with the drug-releasing surface of the
`patch in intimate contact with the stratum corneum. In
`order to maintain sink condition throughout the experi—
`ment, pH 4.4 acetate buffer was used as the receptor so-
`lution (5). Receptor solution at 37°C was introduced
`into the stirred receptor compartment, which was main—
`tained at 37°C by a circulating water bath. Samples
`from the receptor compartment were withdrawn at pre-
`determined time intervals and immediately replaced by
`an equal volume of fresh buffer solution maintained at
`37°C . Initial experiments confirmed the maintenance of
`sink condition by this procedure. The samples were then
`analyzed by the HPLC procedure described below.
`
`Assay of Methadone
`
`The concentration of methadone in the receptor phase
`was measured by a stability—indicating HPLC assay
`method (5). The HPLC system (Perkin Elmer, Series
`400) consisted of a solvent pump with a fixed 100p in-
`jector, and a Chromsep Spherisorb CN column (100 X
`3.0 mm, 5 pm). The ultraviolet (UV) detector (Perkin—
`
`

`

`Transdermal Methadone Patch
`
`Elmer. LC—95) was set at 292 nm. The mobile phase—
`composed of methanol:0.3% aqueous triethylamine
`(60:40, v/v), adjusted to pH 4.0 with phosphoric acid—
`was set at a flow rate of 0.6 ml/min. Under this con-
`dition methadone showed a retention time of 5.9 min.
`
`Linearity was evaluated over the methadone concentra-
`tion range of 20—500 ug/ml, with a minimum detection
`limit of 5 ug/ml. To measure higher concentration, di—
`lution was made with HPLC grade water prior to injec-
`tion. The lowest (20 rig/ml) and the highest (500 rig/ml)
`samples were assayed over 3 consecutive days to deter-
`mine the coefficient of variation. None of them ex—
`ceeded 5%.
`
`a(pa/cm”)
`
`IE4
`
`8000
`
`5000
`
`4000
`
`2000
`
`O
`
`12
`
`24
`
`48
`36
`Time (hr)
`
`60
`
`72
`
`84
`
`Data Analysis
`
`The experimental skin permeation and release flux of
`methadone from the patch was calculated using a modi-
`fied Fick’s law equation (9):
`
`J = v (dC/dt)/A
`
`(1)
`
`where J is the steady—state flux i(in micrograms/square
`centimeter/hour); dC/dt is the steady~state slope of the
`concentration versus time plot in (micrograms/cubic
`centimeter/hour); V is the volume of the receptor com—
`partment (in cubic centimeters); and A is the diffusional
`area of the membrane (in square centimeters). Skin per—
`meation data were analyzed by plotting the cumulative
`amount of methadone permeated (per unit area) versus
`time. The slope of the linear portion of this plot is the
`skin permeation rate of methadone. The skin perme-
`ation rate was computed using a LOTUS 1-2-3 spread—
`sheet program. The Mann—Whitney test was used to
`verify statistical difference on the data obtained in dif~
`ferent experiments of the present study.
`
`RESULTS AND DISCUSSION
`
`Skin permeation of methadone from different formu—
`lations across
`the male hairless mouse skin or
`
`dermatomed human cadaver skin followed a linear Q
`versus I relationship, as shown in Figs. 1-3. This rela—
`tionship can be explained by Fick’s law of diffusion
`under sink conditions, as described below (9):
`
`J = [(DAK/h]Cdt
`
`(2)
`
`where J is the cumulative amount of drug permeated
`through the skin at
`time
`I, D and K denote the
`diffusivity and partition coefficients of the drug in the
`skin, h represents the thickness of the skin, and Cd is
`
`Figure 1. Effect of film thickness on in vitro permeation pro—
`file of methadone (mean i SD, n = 3) following application
`of the patch to the abdominal skin of hairless mouse.
`
`
`1E4
`
`o(us/cmz)
`
`8000
`
`6000
`
`4000
`
`2000
`
`0
`
`12
`
`24
`
`36
`
`4B
`
`60
`
`72
`
`84
`
`Time (hr)
`
`Figure 2. Effect of loading dose on in vitro permeation pro-
`file of methadone (mean i SD, n = 3) following application
`of the patch to the abdominal skin of hairless mouse.
`
`1E4
`0 Central
`
`0 5X Anne.
`
`A 5% NDMS
`
`3000
`
`Q(vs/on?)
`
`6000
`
`4000
`
`2000
`
`
`
`
`
`Time (hr)
`
`Figure 3. Effect of permeation enhancers on in vitro perme—
`ation profile of methadone (mean : SD, n = 3) following ap-
`plication of the patch to the thigh region of human cadaver
`skin.
`
`

`

`288
`
`the concentration of the drug in the system. Although
`the in vitro release kinetics of methadone from the sys-
`tems showed a linearity of release rate as a function of
`square root of time.
`the in vitro permeation profiles
`through hairless mouse and human skin conform to
`zero—order kinetics because the systems release metha—
`done at a rate which is greater than the skin permeation
`rate. Similar trends have been reported in the literature
`earlier (6.7.10).
`
`Effect of Film Thickness
`
`In order to study the effect of polyacrylate film thick—
`ness, skin permeation studies were conducted with
`patches having 10% (w/w) loading dose and different
`thicknesses. Three different thicknesses (1.0. 1.5, and
`2.0 mm) were studied. In all cases, biphasic skin per-
`meation profiles were observed In the case of the patch
`with 1.0 mm thickness, a steady-state skin permeation
`rate of 94.04 (it 6.02) pgcm’l'hr‘1 was maintained up
`to 36 hr, followed by a drop in the skin permeation rate
`to 36.71 (i 4.21) pg~cm44hrl maintained up to 72 hr.
`In case of patches with 1.5 mm and 2.0 mm thick-
`nesses. initial steady-state skin permeation rates of 84.98
`(i 22.06) and 136.81 (3: 26.04) ug-cm‘Z-hr’l. respec-
`tively. were maintained up to 48 hr. These high initial
`rates were followed by a drop in the skin permeation
`rates
`to 29.11 (i 2.68) and 55.02 (i
`18.18)
`pg-cm’z-hr’l. respectively. maintained up to 72 hr (Fig.
`l). The results are summarized in Table 1. Higher re—
`lease from patches having greater than 1.0 mm thickness
`was also able to sustain the initial higher skin perme—
`ation rate for a longer period (up to 48 hr in 1.5-mm
`and 2.0—mm patches compared to 36 hr in the case of
`the 10—min patch). Due to differences in time intervals
`of phase 1 and phase 11 in patches having 1.0 mm thick-
`ness (0—36. 36—72 hr) versus patches having 1.5 and 2.0
`mm thicknesses (0—48, 48—72 hr). no inference on sta~
`tistical difference could be drawn. However, between
`patches having 1.5 mm and 2.0 mm thicknesses, skin
`permeation rates were significantly different at both
`phase 1 and phase 11 levels (p < 005). Film thickness
`above 2.0 mm was not studied as longer curing time
`was necessary.
`
`Effect of Loading Dose
`
`The next phase of the study was devoted to investi-
`gation of the effect of increasing loading dose in the for-
`mulation. Three different loading doses (10%. 15%, and
`
`Ghosh and Bagherian
`
`Table I
`
`Eflect of Film Thickness on Steady—State Permeationa of
`Methadone from Patches with 10% w/w Loading Dose
`Skin Permeation Rateb
`Thickness
`
`Phase I
`Phase 11
`(mm)
`
`36.71‘1 (4.21)
`94.04C (6.02)
`1.0
`29.11f
`(2.68)
`84.98‘3 (22.05)
`1.5
`
`2.0 53.02f (18.18) 136.81c (26.04)
`
`'Abdominal skin specimen from 8—week-old male hairless mouse.
`bMean (: SD) of 3 determination (pg-cm‘l-h’l).
`C0—36 hr.
`d36—72 hr.
`c0-48 hr.
`I48—72 hr.
`
`20% w/w) were studied under constant patch thickness
`of 1.5-mm. When higher loading doses (15% and 20%
`w/w) were incorporated in the 1.5 mm patches, two
`noticeable changes occurred. Not only was the steady
`state skin permeation rate increased compared to the
`control,
`it was also sustained up to 72 hr. In the case
`of a 15% w/w loading dose. a monophasic skin perme-
`ation profile with a steady—state skin permeation rate of
`103.43 (: 16.84) ug~cm'2-hr‘1 was observed, whereas
`with the 20% w/w loading dose, the same nature of pro—
`file with an even higher steady-state skin permeation rate
`of 122.94 (i 35.34) ug-cm'2~hr‘l was found (Fig. 2;
`Table 2). But the difference in skin permeation rates be—
`tween patches with 15% and 20% loading doses was not
`statistically significant (p > 0.1).
`
`Table 2
`
`Effect of Loading Dose 0n Steady-State Permeationa of
`Methadone from Patches with I .5 mm Thickness
`'
`‘
`.b
`
`Skin Permeation Rate
`Loading dose
`
`
`
` (% w/w) Phase I Phase [I
`
`21.40d (14.65)*
`63.58C (10.47)*
`10
`103.433 (20.10)
`w
`15
`
`20 122.948 (35.34) —
`
`
`‘Abdominal skin specimen from 14 week old male hairless mouse.
`t‘Mean (: SD) of 3 determination (pg-cm’lrh").
`‘048 hr.
`“48-72 hr.
`‘0—72 hr.
`
`'0 and d not statistically different from values reported in Table 1 for
`similar patches (p > 0.05).
`
`

`

`Transdermal Methadone Patch
`
`Effect of Permeation Enhancers in Human
`Cadaver Skin
`
`Skin permeation studies were conducted across derm-
`atomed human cadaver Skin using methadone patches of
`1.5 mm thickness and 15% w/w loading dose. A load—
`ing dose of 20% w/w or a patch with a thickness of 2.0
`mm seemed to compromise the adhesiveness of the for—
`mulation to some extent. Therefore the patch with 15%
`loading dose and 1.5 mm thickness was chosen for
`human cadaver skin permeation studies. To study the
`effect of permeation enhancers,
`two commonly used
`skin permeation enhancers, Azone and n-decylmethyl
`sulfoxide (NDMS), were incorporated separately in the
`above-mentioned formulation at a 5% WW concentra-
`tion.
`
`In all three formulations, biphasic skin permeation
`profiles were observed. But a higher skin permeation
`rate was found to continue up to 12 hr followed by a
`drop in the skin permeation rate which was then main-
`tained up to 72 hr (Fig, 3). In the formulation without
`any enhancer, an initial permeation rate of 98.29
`(i 1.30) ug-cm‘Z-hr’lwas observed up to 12 hor fol—
`lowed by a constant permeation rate of 42.74 (i 8.59)
`ug‘cm‘Z-hr“ maintained up to 72 hr. The change in the
`skin permeation profiles with these formulations may be
`due to inherent difference between hairless mouse and
`human cadaver skins. The same formulation with 5%
`Azone showed the initial rate of 196.82 (i 6.50)
`pg-cm'Z-hr‘1 up to 12 hr followed by a maintenance rate
`of 72.33 (j: 6.80) tig-cm'z‘hr‘1 sustained up to 72 hr.
`In the formulation containing 5% NDMS, the initial and
`final rates were found to be 227.47 (i 26.89) and
`91.59 (i 20.03) ng-cm‘Z-hr“, respectively. Therefore,
`both the enhancers were found to significantly enhance
`the skin permeation rate in both the initial and final
`phases (p < 0.10). The enhancement factors were cal-
`culated and listed in Table 3. Comparing the two en-
`hancers studied, NDMS was found to be significantly
`more effective than Azone in enhancing skin permeation
`of methadone across the human cadaver skin in both the
`initial and the final phases (p < 0.10).
`The first phase of the study was devoted to observa-
`tion of the effect of drug—loaded adhesive film thickness
`on maintainenance a constant rate of skin permeation
`over 3 days. By increasing thickness, maintenance of
`initial skin permeation rate could be increased from 36
`hr to 48 hr. but the target of 72—hr maintenance could
`not be reached. The next phase of the project dealt with
`changing the loading dose in the formulation. The for-
`mulation with 10% w/w loading dose and 1.5 mm thick-
`
`289
`
`Table 3
`
`Efi‘ect 0f Permeation Enhances (5% w/w) on Steady~State
`Permeationa of Methadone from Patches with 15% w/w
`Loading Dose and 1.5 mm Thickness
`
`Enhancer
`
`Skin Permeation Rateb
`Phase lld
`
`Phase Ic
`
`Control
`Azone
`
`42.74
`98.28
`72.33
`196.82
`[1.7]c
`[2.016
`91.59 (20.03)
`227.47 (26.89)
`NDMS
`
`[2.3]e [2.1]e
`
`(1.30)
`(6.50)
`
`(8.59)
`(6.80)
`
`“Skin specimen from the thigh region of a 52—yeariold Caucasian male
`human cadaver
`
`bMean (i SD) of 3 determination (pg‘cm‘z-h”).
`c0—12 hr.
`d12—72 hr.
`eEnhancement factor compared to control under the same condition.
`
`ness was chosen as control based upon permeation rate
`and adhesiveness. The target maintenance period of 72
`hr was achieved when loading dose was increased from
`10 % to 15 % w/w. The same 72-hr maintenance was
`
`also observed in the formulation with 20% w/w loading
`dose with even higher steady—state skin permeation rate.
`But these observations were based on hairless mouse
`
`skin. In order to correlate the hairless mouse skin per-
`meation data obtained with that of human,
`the third
`phase of the experiment was conducted using human
`cadaver skin. In that phase, the effect of skin permeation
`enhancers on skin permeation rate of methadone was
`also investigated. Enhancement of skin permeation rate
`could mean lower loading dose and/or smaller patch size
`for this controlled drug. Compared to the hairless mouse
`skin, the permeation profile of methadone across human
`cadaver skin was different. In human cadaver skin, the
`initial higher skin permeation rate could not be main-
`tained more than 12 hr with the formulation studied. But
`
`a constant skin permeation rate from 12 to 72 hr was
`observed. The enhancement effect of Azone and NDMS
`
`on skin permeation of methadone was also significant.
`To investigate the possible reason for biphasic skin
`permeation profiles observed in some formulations
`across the hairless mouse skin, the contents of the patch-
`es were analyzed before use, at the time point where
`slope changed, and at the end of 72 hr. It was observed
`that as long as the patches were retaining about 40% of
`the original loading dose, the initial steady-state skin
`permeation could be maintained. When the loading dose
`
`

`

`290
`
`dropped below 40%, a corresponding drop in the per—
`meation rate was observed. As a result, the slope of the
`permeation profile decreased to give rise to the biphasic
`skin permeation profile. This biphasic phenomenon
`could probably better be explained in terms of solubil—
`ity of methadone in the polymer matrix. But calculation
`of solubility of methadone in the specially formulated
`adhesive matrix was found to be too difficult. Appar—
`ently no precipitation, crystal formation, or cloudiness
`occurred in the film up to a 20% w/w loading concen—
`tration of methadone studied. Examination of the film
`
`under a polarized microscope also did not reveal forma—
`tion of any crystal. Therefore, it seems that methadone
`did not reach its saturation limit in the adhesive matrix
`
`up to a 20% w/w concentration. But during the course
`of the experiment,
`it is possible that the activity as well
`as the diffusivity of methadone in the patch might have
`changed, which in turn could give rise to a lower skin
`permeation rate (1 1). Loading dose remaining at the end
`of 72 hr was about 25% in all
`the patches showing
`biphasic skin permeation profile. In the case of patches
`with 1.5 mm thickness and 15% and 20% loading
`doses,
`it was found that about 40% of the initial load—
`ing was maintained up to the end of 72 hr of study. This
`may be the reason for maintaining a single steady state—
`skin permeation rate up to 72 hr by these patches.
`Therefore,
`it seemed that a minimum of 40% of the
`initial loading dose needed to be retained by the patch
`to maintain a single steady—state skin permeation rate of
`methadone across the hairless mouse skin.
`
`Skin permeation profiles of methadone from the
`patches across the human cadaver skin were somewhat
`different. It was found that about 22% and 15% of the
`
`total loading dose of methadone permeated in the first
`12 hr from the patches with or without enhancers. re-
`spectively. The rate then slowed down to maintain a
`steady state permeation for the rest of 72 hr. Therefore.
`it seemed that about 80% of the loading dose needed to
`be maintained in the patch in order to sustain the initial
`high skin permeation rate up to 72 hr across the human
`cadaver skin. Comparison of the total amount remain—
`ing from the patches with 1.5 mm thickness and 15%
`loading dose after permeation across the hairless mouse
`and human cadaver skins showed that about 65% of the
`loading dose of methadone permeated across the hair-
`less mouse skin in 72 hr, whereas only about 40% of
`the total loading dose permeated across the human ca—
`daver skin. The result therefore suggested inherent dif‘
`t‘erences in the two types of skins in terms of both rate
`and extent of methadone permeation.
`
`Ghosh and Bagherian
`
`About 62% and 73% of the total methadone was
`
`released at the end of 72 hr from the patches contain—
`ing Azone and NDMS, respectively, as compared to
`40% release from the control. The higher skin perme-
`ation rates compared to control for the first 12 hr and
`following 60 hr proves the efficacy of Azone and
`NDMS in enhancing the permeation of methadone
`across the human cadaver skin.
`
`It has been reported that the effective therapeutic con—
`centration of methadone needed for maintenance therapy
`varies between 100 and 200 ng/ml (12). Assuming the
`desired concentration as 150 ng/ml, and the reported
`total mean body clearance of 1.4 ml-min.‘1-kg‘1 (8),
`it
`is estimated that an input rate of approximately 880
`(590—1180) rig-hr" is needed from the patch to achieve
`that plasma concentration in normal human subjects.
`This means that a lO-cm2 patch with an in vitro skin
`permeation rate of 88 (59—118) pg-cm‘z-hr‘1 should be
`able to maintain the effective therapeutic concentration.
`Based upon our observation in hairless mouse skin, a
`10—cm2 patch (1.5 mm) with either 15% or 20% load—
`ing doses should be able to reach the target delivery
`rate. Our observation with human cadaver skin is some-
`
`what different. It seems that the patch (1.5 mm, 15%
`w/w) without enhancer could maintain effective thera—
`peutic concentration up to 12 hr. After that, the concen—
`tration will go below the effective concentration level.
`But
`the same formulation with enhancers has been
`
`proven to be effective in maintaining the therapeutic
`concentration up to 72 hr. Although skin permeation
`rate declined after the initial 12 hr, the rate maintained
`from 12 to 72 hr was sufficient to maintain an effective
`
`therapeutic concentration up to the targeted 72 hr. In
`cases where a higher delivery rate is needed for patients
`requiring a larger amount of daily dose, the patch size
`could be increased to meet that demand.
`
`In summary, our initial studies demonstrated the fea-
`sibility of methadone administration through intact skirt
`from the developed transdertnal patch. More studies are
`necessary to develop a patch capable of maintaining a
`single steady-state skin permeation rate over 72 hr
`across the human skin. To commercialize the patch,
`additional studies also should be conducted on questions
`such as longvterm stability of methadone in the system,
`viscoelastic properties of the adhesive (i.e., tack, peel
`adhesion, and release force), bioavailability in animal
`and human subjects. metabolism of methadone in the
`skin, and potential skin irritation and sensitization po—
`tentials.
`
`

`

`Transdermal Methadone Patch
`
`REFERENCES
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