United States Patent
`(11) Patent Number:
`6,156,335
`[45] Date of Patent:
`Dec. 5, 2000
`Rovati et al.
`
`[19]
`
`US006156335A
`
`[54]
`
`[75]
`
`PREPARATION WITH AN ACRYLIC-BASED,
`ADHESIVE COPOLYMERIC MATRIX FOR
`THE TRANSDERMAL DELIVERY OF
`ESTRADIOL
`
`Inventors: Luigi Rovati; Lucio Rovati; Francesco
`Makovec,all of Monza, Italy; Giinter
`Cordes, Leichlingen; Wilfried Fischer,
`Bad Télz, both of Germany
`
`[73] Assignee: Rotta Research Laboratorium S.p.A.,
`Monza,Italy
`
`[21] Appl. No.:
`
`08/244,132
`
`[22]
`
`[86]
`
`PCT Filed:
`
`Nov. 24, 1992
`
`PCT No::
`
`PCT/EP92/02704
`
`§ 371 Date:
`
`Jul. 15, 1994
`
`§ 102(e) Date:
`
`Jul. 15, 1994
`
`[87]
`
`PCT Pub. No.: WO93/10772
`
`PCT Pub. Date: Jun. 10, 1993
`
`[30]
`Foreign Application Priority Data
`Nov. 25, 1991
`[IT]
`Italy)
`ceessessscsssseeessesssseeseen TO91A0907
`[51]
`Tint, C07 occececcceccsesessssessssstessssseesssees A61F 13/02
`[52] U.S. Che occ eeeseseseseeeeseeneeenees 424/448; 424/449
`
`[58] Field of Search oo...eee 424/448, 449
`
`[56]
`
`References Cited
`U.S. PATENT DOCUMENTS
`
`4,906,475
`4,994,267
`
`3/1990 Kim vaccccccsssccsssseassssesssssseees 424/449
`2/1991 Sablotsky 0... 424/78
`
`Primary Examiner—Thurman K. Page
`Assistant Examiner—tsis Ghali
`Attorney, Agent, or Firm—Pitney, Hardin, Kipp & Szuch,
`LLP
`
`[57]
`
`ABSTRACT
`
`The invention is represented by a transdermal medicated
`patch for the extended release of 17f-estradiol to the skin.
`The transdermal patch is formed by an outer covering, a
`matrix containing from 1% to 5% (w/w) 17B-estradiol, and
`a protective liner which is removed before use. The matrix
`is formed of pressure-sensitive adhesive acrylic copolymers,
`in which the active ingredient is dissolved or dispersed. The
`acrylic copolymers are obtained by radical copolymerization
`of 2-cthylhcexyl acrylate, methyl acrylate, acrylic acid, vinyl
`acetate, hydroxyethyl acrylate or a mixture thereof. Option-
`ally quantities of less than 0.5% (w/w) of other substances
`nay be added.
`
`8 Claims, 1 Drawing Sheet
`
`Estradiol
`
`in serum
`
`DERMESTRIL
`
`#————e
`
`Reference OTP &——-——nt
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`Time of application ————_4
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`24
`48
`72
`96
`120
`
`Time (h)
`
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`
`

  
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`U.S. Patent
`
`Dec. 5, 2000
`
`6,156,335
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`6,156,335
`
`1
`PREPARATION WITH AN ACRYLIC-BASED,
`ADHESIVE COPOLYMERIC MATRIX FOR
`THE TRANSDERMAL DELIVERY OF
`ESTRADIOL
`
`This application is a 371 of PCT/EP92/02704filed Nov.
`24, 1992.
`
`BACKGROUND OF THE INVENTION
`
`1. Field of the Invention
`
`The invention relates to pharmaceutical delivery systems
`and moreparticularly to preparations for transdermal admin-
`istration of estradiol.
`
`2. Brief Description of Related Art
`Introduction
`
`10
`
`15
`
`Ovarian secretion of 17{-estradiolis lacking in postmeno-
`pausal women. In many womenthis physiological phenom-
`enon induces progressive hypotrophy of the urogenital sys-
`tem as well as characteristic vasomotor symptoms, often °
`followed by osteoporosis affecting particularly the vertebral
`column.
`
`These climacteric symptoms can be prevented by an
`exogenous estrogen-based hormone replacement
`therapy.
`However,
`the oral administration of 17-estradiol
`(hereinafter referred to as “estradiol’”) has problems, since
`the hormone is modified in the intestine and in the liver and
`
`produces high blood levels of its metabolites, such as
`estradiol sulfate, estrone and estrone sulfate which may
`accumulate in the organism, if the administration is pro-
`longed. One of the undesired effects of the oral administra-
`tion of estradiol is the increased synthesis by the liver of
`proteins, including the substrate of renin, with a possible
`consequent increase in arterial pressure.
`The oral route can be bypassed by the transdermal admin-
`istration of estradiol, which delivers the active ingredient
`directly into the systemic circulation. However, the diffusion
`of estradiol through the skin is difficult. To improve it, a
`special transdermal systems must be developed that can
`enhance the absorption of estradiol, such as an especially
`designed, estradiol containing, pressure sensitive adhesive
`patch, ie. an Estradiol Transdermal Patch (hereinafter
`referred to as “OTP”).
`The OTPrepresents a considerable therapeutic progress,
`overthe conventional oral administration, since it avoids the
`“first pass effect” and delivers estradiol directly into the
`systemic circulation in quantities comparable to those which
`are physiologically produced bythe ovaries.
`Awidely used OTPis represented by a reservoir in which
`estradiol
`is dissolved in ethanol gelatinised with,
`for
`example, hydroxypropyl cellulose. The reservoir is con-
`tained by a membrane, through whichestradiol diffuses to
`the skin.
`In this system the membrane becomes the
`diffusion-rate limiting component of the OTP, as it is the
`case of an OTP already on the market.
`Various patents have been applied for in connection with
`OTPs provided with diffusion-rate limiting membranes and
`the use of solvents such as ethanol, alone or in mixture, for
`dissolving or dispersing estradiol in the drug reservoir, and
`for improving its absorption through the skin. Thus, for
`example, GB patent 2158 355 describes the use of a com-
`bination of propylene glycol and glycerol in variable ratios;
`USS. Pat. No. 4,658,343 described the use of polyethylene
`glycol monolaurate as agent for improving the skin-
`penetration of estradiol (“enhancer”), and EP patent 0 147
`146 describes the use of methanol for the same purpose.
`
`2
`The transdermal systems based on a diffusion-rate limit-
`ing membranesinvolve various problems. For instance any
`small hole in the membrane causesinevitably the breakdown
`of the whole transdermal system.
`These systems often require the use of absorption
`enhancers, which ultimately act by disrupting the intercel-
`lular connections of the superficial layers of the skin. This
`effect increase the permeability of the skin to the active
`ingredient but often causes skin irritation or sensitisation.
`The absorption enhancers may also be absorbed through the
`skin causing unwanted systemic side effects.
`In general the systems with diffusion-rate limiting mem-
`branes do not allow to achieve constant release rates of t
`active ingredient, whichis disadvantageoussince usually t
`therapeutic treatments require that the active ingredient 1
`released over a prolonged period of time.
`Another possible structure of transdermal systcmsis that
`of the so-called “monolithic” systems. In these systems the
`active ingredient is dissolved or dispersed in a “matrix”,
`which becomes the drug reservoir and contains also the
`pressure sensitive adhesives which assure the adhesion of
`the transdermal system to the skin. In these systems t
`release of the active ingredient from the matrix takes place
`by diffusion, whichis driven by the chemical potential of t
`active ingredient resulting from the concentration gradient
`and the thermodynamic properties of the components of the
`matrix.
`
`
`
`30
`
`35
`
`Manypatents have recently been published on OTP based
`on matrix systems.
`Thus, for example, EP patent 0 379 045 describes an OTP
`in which the system contains 2% estradiol dispersed in a
`matrix constituted by an acrylic polymer, an ethylene/vinyl
`acetate copolymer, gums and adhesives. Lecithin, butylene
`diglycol and propylene diglycol are used as absorption
`enhancers.
`
`EP patent 0 371 496 describes an OTP in whichestradiol
`is dispersed in a matrix constituted by acrylic polymers,
`vinyl acetate, gums and silicone, containing also various
`enhancers such as oleic acid, ethanol and glycols.
`JP patent 02 196 714 described the use of a matrix
`constituted by a copolymer based on 2-ethylhexyl acrylate
`and vinyl pyrrolidone, and absorption enhancers consisting
`of lactic esters formed by C,—C,, alcohols.
`EP patent 0 341 202 describes the use of methyl pyrroli-
`done and eucalyptol as enhancers.
`A last example is EP-A-88 394.3, which describes a
`transdermal patch containing as enhancers polysorbate 80,
`polyoxyethylene ethers and aliphatic alcohols with high
`molecular weight.
`The use of enhancers to improve the absorption of estra-
`diol through the skin is clear from the quoted patent litera-
`ture.
`In order to avoid the drawbacks connected with the
`enhancers(skin irritation, systemic side effects) the absorp-
`tion of the active ingredient can be improved by increasing
`its thermodynamic activity in the matrix, for example by
`increasing its concentration. This, however, often leads to
`supersaturated matrices due to the limited solubility of the
`active ingredients. In order to stabilise the supersaturation,
`additives must be included in the matrix (cfr. for example,
`DE-C-3 933 460). Nevertheless the systems remain in
`metastable conditions and the incorporated active ingredi-
`ents may crystallise during time, decreasing their thermo-
`dynamic activity, which is the driving force for diffusion
`through the skin. The physical stability of these systems is
`
`45
`
`50
`
`55
`
`60
`
`65
`
`

`

`6,156,335
`
`3
`therefore not predictable. The crystallisation of the active
`ingredients may also change the adhesive properties of the
`transdermalpatch, jeopardising the adhesion of the matrix to
`the skin and the reliable drug absorption.
`The matrix of “monolithic” transdermal patches must
`therefore comply with several prerequisites.
`In fact
`the
`active ingredient must be provided by a notable thermody-
`namic potential and nevertheless it must be stable in time.
`Since the matrix contains also the pressure sensitive adhe-
`sives which stick the patch to the skin, it must have good
`“tack” properties.
`Nevertheless the patch must be easily removable from the
`skin after use, and during this procedure the matrix must
`remain attached to the outer covering and notto the skin.
`The adhesives must not “creep”, because in this case the
`patch would stick to the container. As already pointed out,
`the matrix should not contain absorption enhancers, in order
`to prevent skin irritation or sensitisation.
`In addition,
`obviously, all the components of the matrix must be well
`tolerated by the skin, even after repeated and prolonged °
`applications of the patches.
`
`10
`
`15
`
`SUMMARYOF THE INVENTION
`
`Several formulations were investigated in order to opti-
`mize the matrix of the OTP described in this invention. Most
`
`to which
`formulations were based on acrylic copolymers,
`different substances were added in order to improve the
`adhesive quality of
`the matrix,
`for example
`hydroabicthylalochol, glyccrylester of hydrated
`collophonium, pentaester of hydrated collophonium, methy-
`lester of partially hydrated collophonium, or a-methylstyrol/
`styrol copolymers. All these formulations had to be dis-
`carded because of crystallisation of the active ingredient or
`impairmentof its release rate.
`Based on this experience a monolithic matrix was devel-
`oped which represents a definite improvement over the
`present state of the art, since it eliminates or reduces to a
`minimumthe main disadvantages of the transdermal patches
`knownup to now andpreviously described. In fact the new
`invention provides a system for the transdermal administra-
`tion of estradiol which is well
`tolerated,
`is stable,
`is
`effective, prevents the crystallisation of the active ingredient
`in the matrix, ensures adequate and extended levels of the
`active ingredient in blood, and has very good tack and
`adhesive properties.
`BRIEF DESCRIPTION OF THE DRAWING
`
`The accompanying drawing is a graph showing a com-
`parison of the averages of scrum cstradiol levels in 20
`postmenopausal women during the application for 96 hours
`of an OTPofthe invention (Dermestril) or a reference OTP.
`DETAILED DESCRIPTION OF THE
`PREFERRED EMBODIMENTS OF THE
`INVENTION
`
`According to the invention the above mentioned features
`were provided by a transdermal patch for the extended
`release of 17-estradiol onto the skin consisting of:
`a) an outer covering (backing foil);
`b) pressure-sensitive adhesive copolymers constituting
`the matrix in which the active ingredientis dissolved or
`dispersed (drug reservoir);
`c) a protective liner which is removed at the time of use;
`The invention describes a new transdermal patch for the
`extended release of estradiol to the skin, in whichthe active
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`60
`
`65
`
`4
`ingredient is dissolved or dispersed in a suilable pressure-
`sensitive adhesive copolymeric matrix, and which surpris-
`ingly avoids the need of substances to improve the absorp-
`tion of the dmg through the skin (enhancers), or of
`supersaturated solutions of the active ingredient, thus pre-
`venting problemsof skin compatibility and of stability of the
`whole system.
`A specific embodiment concerns a transdermal medicated
`patch which is characterised in that the components of the
`adhesive copolymers are obtained by radical polymerization
`of 2-ethylhexyl acrylate, methyl acrylate, acrylic acid, vinyl
`acetate, hydroxyethyl acrylate or mixtures thereof, possibly
`with quantities of less than 0.5% (w/w) ofother additives in
`the adhesive copolymers.
`A specific embodiment of the invention concernsa trans-
`dermal medicated patch in which the adhesive copolymers
`of the matrix are obtained by radical polymerization of (w/w
`of the matrix) about 50% to 70% (preferably 55% to 65%
`and especially 61% to 64%) 2-ethylhexyl acrylate, about
`20% to 40% (preferably 24% to 32% and especially 25% to
`28%) methyl acrylate, about 2% to 8% (preferably 3% to 5%
`and especially 4% to 5%) acrylic acid, about 2% to 10%
`(preferably 3% to 7% and especially 4% to 5%) vinyl
`acetate, and about 0.5% to 3% (preferably 0.7% to 1.5% and
`especially about 1%) hydroxyethyl acrylate.
`Small quantities of less than 0.5% of other substances
`mayalso be used to improve the adhesive properties and the
`strength of the matrix.
`According to the invention no cross-linker is used in the
`adhesive copolymer, such astitanium acetylacetonate, as it
`is suggested by the priorart, in order to avoid creeping ofthe
`adhesives onto the removable protective liner and therefore
`sticking of the patch to its container. The problem of
`creeping is surprisingly avoided in the invention by using
`the described copolymers obtained by radical polymeriza-
`tion.
`
`The OTPaccording to the invention is characterized by a
`content of 17$-estradiol from 1% to 5%, preferably 2.0% to
`2.5%, (w/w) of the weight of the adhesive copolymers.
`A specific embodiment of the invention concernsa trans-
`dermal patch which contains about 4 mg 17£-estradiol per
`18 to 20 cm? of patch area.
`Aspecific embodimentof the invention of the transdermal
`patch comprises an outer covering of suitable protective
`materials, which forms the external backing foil of the patch
`and is constituted by a foil of thin, flexible and water-
`impermeable material, preferably selected from the group of
`polyester, polyurethane, polyethylene and/or polyvinyl chlo-
`ride. Finally, the transdermal patch according to the inven-
`tion comprises a
`removable protective liner, preferably
`constituted bya foil of paper or polyester whichis preferably
`silicone-coated on one or both sides and that
`is easily
`removed at the time of use without impairing the transder-
`malpatch.
`According to the additional embodimentof the invention,
`a process is described for the production of a transdermal
`patch for the extended release of 17-estradiol to the skin,
`which is characterized in that pressure-sensitive adhesive
`copolymers containing 17{-estradiolas active ingredientare
`spread onto a removable protective liner and then covered
`by another liner which becomes the ouler covering.
`Alternatively the pressure-sensitive adhesive copolymers
`containing 17-estradiol are spread on a water-impermeable
`foil which becomesthe outer covering, and are then covered
`by the protected liner.
`Still alternatively the pressure-sensitive adhesive copoly-
`mers containing 17(-estradiol are spread on an intermediate
`
`

`

`6,156,335
`
`6
`polymerization of 1038 g 2-ethylhexyl acrylate, 520 g
`methyl acrylate, 68 g of acrylic acid, 87 g vinyl acetate, and
`17 g hydroxyethyl acrylate.
`A quantity of 40 g of 178-estradiol wasdissolvedorfinely
`suspended in a mixture of solvents constituted by 1 liter of
`propan-2-ol and 1.5 liters of cthyl acctatc. This solution was
`added, understirring, to the mixture of copolymers, pre-
`pared as described above.
`The mixture wasstirred until a homogeneous mass was
`obtained and this was evaporated to produce a mixture with
`a consistency appropriate for spreading on the appropriate
`liners. Then the adhesive mixture containing the active
`ingredient was spread onto a foil of silicone-coated paper or
`polyester and dried at a temperature between 30° and 80° C.
`to produce a film of matrix weighing about 98 g/m? (+5%)
`as the dry weight, corresponding to about 2.2 g of 17B-
`estradiol per m* of the dry matrix.
`Finally, a polyester foil, about 15 4m thick, was stuck on
`the matrix to form the outer covering of the patch.
`Individual circular patches having areas of 18 cm’, each
`containing about 4 mgof the active ingredient were cut from
`the composite medicated foil to form the final transdermal
`patch.
`In summary, the steps of preparing the estradiol transder-
`mal patch (OTP) according to the present invention consist
`substantially of:
`adding a solution of a fine suspension of estradiol to a
`suitable mixture of copolymers of acrylates and vinyl
`acetate;
`
`spreading a thin layer of the mixture formed by the
`dispersion ofthe active ingredient in the acrylic copoly-
`mers on a protective liner of silicone-coated paper or
`polyester to be removed at the time of use;
`drying the liquid adhesive film formed by the acrylic
`copolymers and containing estradiol, at a temperature
`between 30° and 80° C.
`in order to evaporate the
`solvent, with or without applying vacuum;
`applying a foil of thin, flexible, water-impermeable mate-
`rial which constitutes the outer covering of the patch;
`cutting the composite medicated foil produced as above
`described into portions having the desired shape and
`surface, for example 18 cm? for patches containing 4
`mg estradiol;
`alternative proceduresare also possible, such as spreading
`the adhesive mixture onto the outer covering or onto an
`intermediate liner. The following manufacturing steps
`are then madein order to produce the appropriate final
`composite medicated foil.
`Release of estradiol in vitro
`
`10
`
`15
`
`.
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`5
`liner (usually a siliconized paper sheet) and then covered by
`the foil of the outer covering to which the copolymers adhere
`firmly. In the final manufacturing process the intermediate
`liner is removed and substituted by the protective liner.
`According to a predetermined embodimentof the claimed
`process the transdermal patch can be produced as follows:
`the pressure-sensitive adhesive copolymers are dissolved
`in an organic solvent (adhesive mixture);
`17f-estradiol, dissolved or dispersed in an organic solvent
`or in a mixture of solvents,is dissolved or dispersed in
`the adhesive mixture by stirring, at a concentration
`from 1% to 5% (w/w)ofthe dry weightof the pressure-
`sensitive adhesive copolymers;
`the obtained mixture is concentrated by evaporation of
`someof the solvents and then spread onto the remov-
`able protective liner, preferably constituted by a foil of
`paper or polycstcr which is siliconc-coated on one or
`both sides; alternatively the mixture is spread onto the
`foil of the outer covering, constituted by water-
`impermeable materials preferably selected from the
`group of polyester, polyurethane, polyethylene and/or
`polyvinyl chloride; still alternatively the mixture is
`spread on an intermediate liner, preferably constituted
`by a sheet of paper, preferably siliconized on one or on
`both sides;
`the solvent is evaporated at a temperature from 30° to 80°
`C. with or without applying a vacuum;
`a foil of thin, flexible and water-impermeable material
`constituting the outer covering is applied, or, alterna-
`tively the final protective liner is applied or alterna-
`tively the intermediate lincr is removed and replaced by
`the final protective liner, according one of the three
`procedures outlined above as examples;
`the produced composite medicated foil is cut into portions
`of appropriate shape and surface, such that they contain
`the required quantity of the active ingredient suitable
`for the therapeutic use, and in this way the final
`transdermal patches are obtained.
`The appropriate qualitative-quantitative selection of the
`acrylic components of the final copolymer obtained by
`radical polymerization,
`i.e. 2-ethylhexyl acrylate, acrylic
`acid and hydroxyethyl acrylate, and of vinyl acetate which
`acts as solvent for the active ingredient, is suitable for a
`transdermal system for the extended release of estradiol
`whichis stable in time and does not give rise to crystalli-
`sation of the active ingredient in the matrix.
`Moreover, as will be described below, the serum levels of
`estradiol
`in menopausal patients obtained after having
`applied the transdermalpatchto their skin, are more constant
`during the application time than during the application of a
`patch provided with a diffusion-rate limiting membrane and
`ethanol as enhanced. Surprisingly the extent of absorption
`after the application of the invented OTP wassimilarto that
`of the enhanced system.
`
`EXAMPLE 1
`
`Therelease of estradiol from the OTP produced according
`to the invention (“DERMESTRII.”) was tested in vitro with
`the following procedure.
`Discs cut from DERMESTRIL OTP,with surface areas of
`6 cm? and containing about 1.33 mg of estradiol, were
`applied to a support deposited on the base of the dissolution
`test apparatus according to USP XXII, consisting of a 1 liter
`(Production of a transdermal patch containing 4 mg of
`glass vessel and a rotating blade.
`estradiol)
`The distance between the support and the blade, which
`The production process of the transdermal patch accord-
`rotated at a speed of 50 revolutions per minute, was 2.5 cm
`ing to the present
`invention, containing 4 mg of 17B-
`and the dissolution liquid was constituted by 900 mlof water
`at 32° C.
`estradiol as the active ingredient per 18 cm? of patch area
`(hereinafter referred to as “DERMESTRIL”), is illustrated
`Portions of 1 ml of the solution were withdrawnat 2, 4,
`further by the following, non-limiting example.
`6, 8, 12, 24 and 36 hours after the start of the experiment,
`
`An adhesive mixture was prepared dissolvingin3liters of and the estradiol content was determined by HPLC. Thetest
`ethylacetate a mixture of copolymers obtained by radical
`was repeated 6 times.
`
`55
`
`60
`
`65
`
`

`

`7
`The quantities of released estradiol, expressed as milli-
`grams and as percent of the nominal content of estradiol in
`DERMESTRILat the various times, are given in table 1.
`
`6,156,335
`
`TABLE1
`
`Milligrams and percent of estradiol released
`in the in vitro test
`
`Time (h)
`2
`4
`6
`12
`24
`
`36
`
`mg
`0.66
`0.95
`1.25
`1.70
`2.48
`
`3.20
`
`% of nominal
`16.5
`23.8
`31.2
`42.5
`61.9
`
`80.0
`
`Table 1 showsthat from 6 to 36 hours, the release kinetics
`is linear and can be expressed by the equation:
`
`R=0.896640.646xA
`
`where R=mgofestradiol released and h=time in hours.
`Table 1 shows also that about 30% of the estradiol
`contained in the patch had beenreleased after 6 hours, about
`60% after 24 hours and about 80% after 36 hours.
`Bioavailability of estradiol from DERMESTRIL
`The bioavailability study was carried out in postmeno-
`pausal women. DERMESTRIL was compared with an OTP
`commercially available and characterized by a diffusion rate
`limiting membrane and containing ethanol as solvent and
`absorption enhancer(hereinafter called “Reference OTP”).
`Two DERMESTRIL patches prepared according to the
`invention, and containing each 4 mgofestradiol per 18 em?
`or two Reference O'l'Ps, also containing 4 mg ofestradiol,
`were applied on the skin of the subjects for a single
`application of 96 hours.
`Studied were 20 subjects and the patches were applied
`according to a cross-over design, with a suitable wash-out
`period between the two treatments.
`Estradiol
`in blood serum was determined by a RIA
`method. The estradiol serum levels expressed in pg/ml are
`given in the accompanying drawing and in table 2. Table 2
`gives also the averages of the maximum concentrations
`found (C,,,,), of the times to the peak (t,,,,.) and of the area
`under the concentration/time curve (AUC) in the period
`0-96 hours after administration.
`Table 2
`
`Estradiol levels in serumat various times after the appli-
`cation of 2 OTPs according to the invention
`(DERMESTRIL) or of 2 commercial OTPs (Reference
`OTP), Both, DERMESTRILand the Reference OTP contain
`each 4 mgestradiol. Averages and SD of 20 subjects.
`
`Hours
`
`Estradiol pp/ml + SD
`DERMESTRIL
`
`0
`2
`6
`8
`12
`24
`36
`48
`60
`
`1.96 + 3.94
`5.34 + 7.87
`25.27 + 34.54
`42.46 + 31.52
`55.07 + 46.51
`51.86 + 28.63
`56.28 + 32.87
`44.43 + 24.13
`47.74 + 30.17
`
`Reference OTP
`
`2.06 + 3.81
`31.13 + 29.45
`67.65 + 42.57
`68.91 + 25.86
`61.35 + 21.26
`53.35 + 16.76
`61.37 + 23.31
`49.34 + 18.37
`42.78 + 21.19
`
`5
`
`10
`
`15
`
`40
`
`50
`
`55
`
`60
`
`65
`
`8
`
`-continued
`
`Estradiol pp/ml + SD
`DERMESTRIL
`
`41.02 + 22.29
`40.03 + 19.87
`35.18 + 19.73
`8.80 + 6.51
`7.01 + 5.91
`66.18 + 45.0
`35.00 + 19.8
`4286 + 2409
`
`Reference OTP
`
`30.48 + 15.34
`22.33 + 12.87
`19.85 + 9.16
`7.49 + 5.39
`5.76 + 4.89
`87.35 + 29.87
`18.80 + 18.99
`4268 + 1226
`
`Hours
`
`72
`84
`96
`108
`120
`Crax
`tax
`AUC (0-96 h)
`
`From the results given in table 2 it can be concluded that
`the areas under the concentration/time curves (AUC) do not
`differ significantly after the two treatments. In fact the
`AUC(0-96) after DERMESTRIL was 4286+2409 (SD), and
`after the Reference OTP was 4268+1226 (SD).
`This demonstrate that the bioavailability of estradiol from
`DERMESTRILis the sameas that from Reference OTP, and
`this is a surprising result because DERMESTRIL does not
`contain absorption enhancers.
`Tolerability by the skin
`The skin tolerability to the OTP prepared according to the
`invention was evaluated on 10 female guinea pigs weighing
`between 300 and 400 g.
`The patches were applied to the previously shaved left
`scapular region of the animals. An area of patch of 2x2 cm
`cut from DERMESTRIL and thus containing about 0.89 mg
`estradiol, was stuck on the shaved skin and left there for
`about 6 hours. The tolerability of the patch was evaluated by
`the appearance of erythema or oedema after 24 hours of
`application, according to the following scores.
`
`Score
`
`ERYTHEMA
`
`OEDEMA
`
`0
`1
`2
`3
`
`Noeffect
`Slight
`Moderate
`Intense
`
`Noeffect
`Slight oedema
`Moderate oedema
`Severe oedema
`
`The test was repeated using the same scores after 7 days,
`in order to record a possible sensitization induced by the
`patch.
`The overall sum of the scores related to erythemafor the
`10 animals was 1 of 30, because only 1 animal out of 10
`showed a slight erythema (30 is the maximum score
`obtainable).
`No animal presented oedema.
`In the sensitisation challenge carried out after 7 days, no
`animal had erythema or oedema, demonstrating that the
`patches were well tolerated and did not induce sensitization
`under the experimental conditions.
`EXAMPLES2 to 5 AND COMPARATIVE
`EXAMPLES1 TO 7
`
`Table 3 summarized the composition of the matrix of
`Examples 1 to 5 and of the Comparative Examples 1 to 7.
`The corresponding formulations of the matrix containing the
`copolymers obtained by radical polymerization of the
`acrylic compoundsare quantitatively listed in table 3. The
`resulting OTPs were tested for stability and also, in six
`human subjects, for adhesion and skin compatibility. The
`results obtained with the eleven formulations are also
`
`reported in table 3.
`
`

`

`6,156,335
`
`9
`The results clearly show that formulations No. 1 to 4 and
`particularly No. 1 exhibit the properties required for the
`matrix of a “monolithic” transdermal patch. Conversely
`other formulations, which are here listed as Comparative
`Examples 1 to 7, had disadvantages, for instance discolou-
`ration (formulations No. 6 to 10), unacceptable skin com-
`patibility (formulation No. 5), or unacceptable tack proper-
`ties (formulations No. 6, 7, 9 and 11).
`
`10
`impermeable material, selected from the group of polyester,
`polyurethane, polyethylene and/or polyvinyl chloride mate-
`rials.
`
`6. Aprocess for the productionof a transdermal medicated
`patch according to claim 1, characterized in that pressure-
`sensitive adhesive copolymers containing 17f-estradiol as
`active ingredient are spread onto a removable protective
`liner and then covered by an outer covering.
`
`TABLE 3
`
`Percentage of monomers in the acrylic copolymers and other substances
`in different formulations. Properties of the matrix obtained with these
`copolymers.
`
`Formulation No.
`
`1
`
`Examples
`3
`4
`2
`3
`
`5
`4
`
`1
`5
`
`Comparative Examples
`3
`4
`5
`7
`8
`9
`
`2
`6
`
`6
`10
`
`7
`i
`
` 2
`
`Substances
`
`2-EHA
`HA
`VA
`AA
`GMA
`HEA
`TA.
`HR
`Features
`
`Estrad. solub.
`Discoloration
`Tack on skin
`Skin compat.
`
`62.6
`264
`5.6
`4.4
`0.0
`1.0
`0.0
`0.0
`
`G
`-
`G
`G
`
`615
`33.0
`0.0
`5.5
`0.0
`0.0
`0.0
`0.0
`
`-
`G
`M
`
`634
`215
`9.8
`3.6
`0.1
`1.8
`0.0
`0.0
`
`G
`-
`M
`M
`
`576
`195
`89
`3.3
`01
`1.6
`0.0
`91
`
`G
`-
`G
`M
`
`669
`0.0
`28.0
`0.0
`0.2
`5.0
`0.0
`0.0
`
`G
`-
`G
`B
`
`62.2
`264
`5.6
`4.3
`0.1
`1.0
`0.4
`0.0
`
`G
`+
`B
`G
`
`63.1
`215
`9.8
`3.5
`0.1
`1.8
`0.3
`0.0
`
`G
`+
`B
`G
`
`640
`165
`140
`27
`O01
`2.5
`0.3
`0.0
`
`G
`+
`G
`M
`
`59.2
`25.1
`5.3
`41
`0.0
`1.0
`0.4
`48
`
`G
`+
`B
`G
`
`56.6
`240
`5.1
`3.9
`0.0
`0.9
`0.4
`9.1
`
`G
`+
`G
`M
`
`64.2
`16.5
`14.0
`2.8
`0.1
`2.5
`0.0
`0.0
`
`G
`-
`s
`G
`
`Legenda: B = Bad; M = Medium; G = Good; S = Too strong; + = Present; - = Absent
`Substances:
`2-EHA = 2-Ethylhexylacrylate
`HA = Methylacrylate
`VA = Vinyl acetate
`AA = Acrylic acid
`GMA = Glycidylmethacrylate
`HEA = Hydroxyethylacrylate
`TA = Titanium acetylacetonate
`HR = Hydrocarbon resin
`
`Whatis claimed is:
`1. A transdermal medicated patch for the extended release
`of 17B-estradiol to the skin, consisting of pressure-sensitive
`adhesive copolymers in which the active ingredientis dis-
`solved or dispersed, supported by a water-impermeable foil
`and covered bya protective liner which is removed at the
`time of use, wherein the pressure-sensitive adhesive copoly-
`mers are obtained by radical copolymerization of
`
`55 to 65 weight %
`24 to 32 weight %
`3 lo 5 weight %
`3 to 7 weight %
`0.7 to 1.5 weight %
`
`2-ethylhexyl acrylate
`methyl acrylate
`acrylic acid
`vinyl acetate and
`hydroxyethyl acrylate.
`
`2. A transdermal medicated patch according to claim 1,
`characterized by a content of 176-estradiol from 1% to 5%
`by weight of the adhesive copolymers.
`3. A transdermal medicated patch according to claim 1,
`characterized by a content of about 4 mg 17f-estradiol per
`18 to 20 cm? ofpatcharea.
`4. A transdermal medicated patch according to claim 1
`characterized in that the patch comprises a removable pro-
`tective liner constituted by a sheet of paper.
`5. Atransdermal patch according to claim 1, characterized
`by an outer covering constituted by a foil of a water-
`
`7. Aprocessfor the production ofa transdermal medicated
`patch according to claim 6,, which comprises:
`dissolving pressure-sensitive adhesive copolymers in an
`organic solvent to form an adhesive mixture;
`dissolving - 17$-estradiol, in the adhesive mixture by
`stirring at a concentration from 1% to 5% by weight of
`the dry weight of the pressure-sensilive adhesive
`copolymers; and
`spreading the solution onto a removable protectiveliner.
`8. A transdermal medicated patch according to claim 1,
`wherein the pressure-sensitive adhesive copolymers are
`obtained by radical copolymerization of (w/w or the matrix)
`
`
`61 to 64%
`2-ethylhexyl acrylate
`25 to 28%
`methyl acrylate
`4 to 5%
`acrylic acid
`4 to 5%
`vinyl acetate and
`about 1%
`hydroxyethyl acrylate. --
`
`45
`
`5.wn
`
`60
`
`65
`
`