United States Patent [w]
`Rovati et al.
`
`US006156335A
`[ii] Patent Number:
`[45] Date of Patent:
`
`Mill
`6,156,335
`Dec. 5, 2000
`
`[54] PREPARATION WITH AN ACRYLIC-BASED,
`ADHESIVE COPOLYMERIC MATRIX FOR
`THE TRANSDERMAL DELIVERY OF
`ESTRADIOL
`
`[75]
`
`Inventors: Luigi Rovati; Lucio Rovati; Francesco
`Makovec, all ol Monza, Italy; Giinter
`Cordes, Leichlingen; Wilfried Fischer,
`Bad Tolz, both of Germany
`
`[73] Assignee: Rotta Research Laboratorium S.p.A.,
`Monza, Italy
`08/244,132
`
`[21] Appl. No.:
`
`[22] PCT Filed:
`
`[86] PCT No.:
`
`Nov. 24, 1992
`PCT/EP92/02704
`
`Jul. 15, 1994
`§ 371 Date:
`§ 102(e) Date: Jul. 15, 1994
`[87] PCT Pub. No.: WO93/10772
`PCT Pub. Date: Jun. 10, 1993
`
`[30]
`
`Foreign Application Priority Data
`T091A0907
`Nov. 25, 1991
`[IT]
`Italy
`[51] Int. CI.7
`A61F 13/02
`[52] U.S. CI
`424/448; 424/449
`
`[58] Field of Search
`
`424/448, 449
`
`[56]
`
`References Cited
`
`U.S. PATENT DOCUMENTS
`
`4,906,475
`4,994,267
`
`3/1990 Kim
`2/1991 Sablotsky
`
`424/449
`. 424/78
`
`Primary Examiner—Thurman K. Page
`Assistant Examiner—Isis 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 17p-estradiol to the skin.
`The transdermal patch is formed by an outer covering, a
`matrix containing from 1% to 5% (w/w) 17p-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-ethylhexyl 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
`may be added.
`
`8 Claims, 1 Drawing Sheet
`
`E
`U )
`a.
`
`6 0 -
`
`50 -
`
`40 -
`
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`
`70 -i *
`i K
`/ ^
`I \
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`I
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`I
`
`Estradiol in serum
`DERMESTRIL
`•­
`Reference OTP A-
`A
`/ \
`\
`\
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`N *
`\
`\
`\
`\
`A
`\ s
`\
`
`Time of application
`
`r
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`
`24
`
`T
`
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`48
`72
`Time (h)
`
`\
`\
`\
`
`i
`
`96
`
`1
`120
`
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`
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`
`MYLAN - EXHIBIT 1019
`
`

`

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`
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`
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`120
`
`1
`
`96
`
`i
`
`\
`1 \ \
`
`\
`
`Time (h)
`72
`48
`
`24
`T
`
`Time of application
`
`\
`
`A
`\
`\
`\
`\
`\ *
`\ \
`
`\
`/ \
`A
`
`1
`I
`I
`I
`I
`
`Reference OTP A-
`#-
`DERMESTRIL
`Estradiol in serum
`
`*
`
`I
`I \ /
`/ \
`/ \
`
`0
`r
`ft
`
`0 J
`
`10 -
`
`20 -
`
`30 -
`
`40 -
`
`50 -
`
`60 -
`
`70 -i
`
`Q-
`o>
`E
`
`

`

`This application is a 371 of PCT/EP92/02704 filed Nov.
`24, 1992.
`
`5
`
`6,156,335
`
`1
`PREPARATION WITH AN ACRYLIC-BASED,
`ADHESIVE COPOLYMERIC MATRIX FOR
`THE TRANSDERMAL DELIVERY OF
`ESTRADIOL
`
`2
`The transdermal systems based on a diffusion-rate limit­
`ing membranes involve various problems. For instance any
`small hole in the membrane causes inevitably 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
`BACKGROUND OF THE INVENTION
`ingredient but often causes skin irritation or sensitisation.
`1° The absorption enhancers may also be absorbed through the
`1. Field of the Invention
`skin causing unwanted systemic side effects.
`The invention relates to pharmaceutical delivery systems
`In general the systems with diffusion-rate limiting mem­
`and more particularly to preparations for transdermal admin­
`branes do not allow to achieve constant release rates of the
`istration of estradiol.
`active ingredient, which is disadvantageous since usually the
`2. Brief Description of Related Art
`15 therapeutic treatments require that the active ingredient is
`Introduction
`released over a prolonged period of time.
`Ovarian secretion of IVfi-estradiol is lacking in postmeno­
`Another possible structure of transdermal systems is that
`pausal women. In many women this physiological phenom­
`of the so-called "monolithic" systems. In these systems the
`enon induces progressive hypotrophy of the urogenital sys­
`20 active ingredient is dissolved or dispersed in a "matrix",
`tem as well as characteristic vasomotor symptoms, often
`which becomes the drug reservoir and contains also the
`followed by osteoporosis affecting particularly the vertebral
`pressure sensitive adhesives which assure the adhesion of
`column.
`the transdermal system to the skin. In these systems the
`These climacteric symptoms can be prevented by an
`release of the active ingredient from the matrix takes place
`by diffusion, which is driven by the chemical potential of the
`exogenous estrogen-based hormone replacement therapy.
`active ingredient resulting from the concentration gradient
`However, the oral administration of IVfS-estradiol
`anc} the thermodynamic properties of the components of the
`(hereinafter referred to as "estradiol") has problems, since
`matrix.
`the hormone is modified in the intestine and in the liver and
`Many patents have recently been published on OTP based
`produces high blood levels of its metabolites such as
`on matrjx SyStems
`estradiol sulfate, estrone and estrone sulfate which may
`accumulate in the organism, if the administration is pro- 30
`Thus, for example, EP patent 0 379 045 describes an OTP
`longed. One of the undesired effects of the oral administra­
`in which the system contains 2% estradiol dispersed in a
`tion of estradiol is the increased synthesis by the liver of
`matrix constituted by an acrylic polymer, an ethylene/vinyl
`proteins, including the substrate of renin, with a possible
`acetate copolymer, gums and adhesives. Lecithin, butylene
`consequent increase in arterial pressure.
`35 diglycol and propylene diglycol are used as absorption
`The oral route can be bypassed by the transdermal admin­
`enhancers.
`istration of estradiol, which delivers the active ingredient
`EP patent 0 371 496 describes an OTP in which estradiol
`directly into the systemic circulation. However, the diffusion
`is dispersed in a matrix constituted by acrylic polymers,
`of estradiol through the skin is difficult. To improve it, a
`vinyl acetate, gums and silicone, containing also various
`special transdermal systems must be developed that can
`40 enhancers such as oleic acid, ethanol and glycols.
`enhance the absorption of estradiol, such as an especially
`JP patent 02 196 714 described the use of a matrix
`designed, estradiol containing, pressure sensitive adhesive
`constituted by a copolymer based on 2-ethylhexyl acrylate
`patch, i.e. an Estradiol Transdermal Patch (hereinafter
`and vinyl pyrrolidone, and absorption enhancers consisting
`referred to as "OTP").
`of lactic esters formed by C1-C20 alcohols.
`The OTP represents a considerable therapeutic progress,
`EP patent 0 341 202 describes the use of methyl pyrroli-
`over the conventional oral administration, since it avoids the
`done and eucalyptol as enhancers.
`"first pass effect" and delivers estradiol directly into the
`A last example is EP-A-88 394.3, which describes a
`systemic circulation in quantities comparable to those which
`transdermal patch containing as enhancers polysorbate 80,
`are physiologically produced by the ovaries.
`A widely used OTP is represented by a reservoir in which 50 polyoxyethylene ethers and aliphatic alcohols with high
`molecular weight.
`estradiol is dissolved in ethanol gelatinised with, for
`The use of enhancers to improve the absorption of estra­
`example, hydroxypropyl cellulose. The reservoir is con­
`tained by a membrane, through which estradiol diffuses to
`diol through the skin is clear from the quoted patent litera­
`the skin. In this system the membrane becomes the
`ture.
`diffusion-rate limiting component of the OTP, as it is the 55
`In order to avoid the drawbacks connected with the
`case of an OTP already on the market.
`enhancers (skin irritation, systemic side effects) the absorp­
`Various patents have been applied for in connection with
`tion of the active ingredient can be improved by increasing
`its thermodynamic activity in the matrix, for example by
`OTPs provided with diffusion-rate limiting membranes and
`the use of solvents such as ethanol, alone or in mixture, for
`increasing its concentration. This, however, often leads to
`dissolving or dispersing estradiol in the drug reservoir, and 60 supersaturated matrices due to the limited solubility of the
`active ingredients. In order to stabilise the supersaturation,
`for improving its absorption through the skin. Thus, for
`additives must be included in the matrix (cfr. for example,
`example, GB patent 2158 355 describes the use of a com­
`DE-C-3 933 460). Nevertheless the systems remain in
`bination of propylene glycol and glycerol in variable ratios;
`U.S. Pat. No. 4,658,343 described the use of polyethylene
`metastable conditions and the incorporated active ingredi-
`glycol monolaurate as agent for improving the skin- 65 ents may crystallise during time, decreasing their thermo­
`penetration of estradiol ("enhancer"), and EP patent 0 147
`dynamic activity, which is the driving force for diffusion
`146 describes the use of methanol for the same purpose.
`through the skin. The physical stability of these systems is
`
`

`

`6,156,335
`
`SUMMARY OF THE INVENTION
`
`4
`3
`ingredient is dissolved or dispersed in a suitable pressure-
`therefore not predictable. The crystallisation of the active
`sensitive adhesive copolymeric matrix, and which surpris­
`ingredients may also change the adhesive properties of the
`ingly avoids the need of substances to improve the absorp­
`transdermal patch, jeopardising the adhesion of the matrix to
`the skin and the reliable drug absorption.
`tion of the drug through the skin (enhancers), or of
`The matrix of "monolithic" transdermal patches must 5 supersaturated solutions of the active ingredient, thus pre­
`venting problems of skin compatibility and of stability of the
`therefore comply with several prerequisites. In fact the
`whole system.
`active ingredient must be provided by a notable thermody­
`A specific embodiment concerns a transdermal medicated
`namic potential and nevertheless it must be stable in time.
`patch which is characterised in that the components of the
`Since the matrix contains also the pressure sensitive adhe-
`sives which stick the patch to the skin, it must have good « adhesive copolymers are obtained by radical polymerization
`of 2-ethylhexyl acrylate, methyl acrylate, acrylic acid, vinyl
`"tack" properties.
`acetate, hydroxyethyl acrylate or mixtures thereof, possibly
`Nevertheless the patch must be easily removable from the
`with quantities of less than 0.5% (w/w) of other additives in
`skin after use, and during this procedure the matrix must
`the adhesive copolymers.
`remain attached to the outer covering and not to the skin.
`A specific embodiment of the invention concerns a trans­
`The adhesives must not "creep", because in this case the 15
`dermal medicated patch in which the adhesive copolymers
`patch would stick to the container. As already pointed out,
`of the matrix are obtained by radical polymerization of (w/w
`the matrix should not contain absorption enhancers, in order
`of the matrix) about 50% to 70% (preferably 55% to 65%
`to prevent skin irritation or sensitisation. In addition,
`and especially 61% to 64%) 2-ethylhexyl acrylate, about
`obviously, all the components of the matrix must be well
`20 20% to 40% (preferably 24% to 32% and especially 25% to
`tolerated by the skin, even after repeated and prolonged
`28%) methyl acrylate, about 2% to 8% (preferably 3% to 5%
`applications of the patches.
`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
`Several formulations were investigated in order to opti- 25 eSpeciaiiy about 1%) hydroxyethyl acrylate.
`mize the matrix of the OTP described in this invention. Most
`Small quantities of less than 0.5% of other substances
`formulations were based on acrylic copolymers, to which
`may also be used to improve the adhesive properties and the
`different substances were added in order to improve the
`strength of the matrix
`adhesive quality of the matrix, for example
`According to the invention no cross-linker is used in the
`hydroabiethylalochol, glycerylester of hydrated 30 adhesive copolymer, such as titanium acetylacetonate, as it
`collophonium, pentaester of hydrated collophonium, methy-
`is suggested by the prior art, in order to avoid creeping of the
`lester of partially hydrated collophonium, or a-methylstyrol/
`adhesives onto the removable protective liner and therefore
`styrol copolymers. All these formulations had to be dis­
`sticking of the patch to its container. The problem of
`carded because of crystallisation of the active ingredient or
`creeping is surprisingly avoided in the invention by using
`impairment of its release rate.
`35 the described copolymers obtained by radical polymeriza­
`Based on this experience a monolithic matrix was devel­
`tion.
`oped which represents a definite improvement over the
`The OTP according to the invention is characterized by a
`present state of the art, since it eliminates or reduces to a
`content of 17p-estradiol from 1% to 5%, preferably 2.0% to
`minimum the main disadvantages of the transdermal patches
`2.5%, (w/w) of the weight of the adhesive copolymers.
`known up to now and previously described. In fact the new 40
`A specific embodiment of the invention concerns a trans­
`invention provides a system for the transdermal administra­
`dermal patch which contains about 4 mg 17p-estradiol per
`tion of estradiol which is well tolerated, is stable, is
`18 to 20 cm2 of patch area.
`effective, prevents the crystallisation of the active ingredient
`A specific embodiment of the invention of the transdermal
`in the matrix, ensures adequate and extended levels of the
`patch comprises an outer covering of suitable protective
`active ingredient in blood, and has very good tack and 45 materials, which forms the external backing foil of the patch
`adhesive properties.
`and is constituted by a foil of thin, flexible and water-
`impermeable material, preferably selected from the group of
`BRIEF DESCRIPTION OF THE DRAWING
`polyester, polyurethane, polyethylene and/or polyvinyl chlo­
`ride. Finally, the transdermal patch according to the inven-
`The accompanying drawing is a graph showing a com­
`parison of the averages of serum estradiol levels in 20 50 tion comprises a removable protective liner, preferably
`constituted by a foil of paper or polyester which is preferably
`postmenopausal women during the application for 96 hours
`silicone-coated on one or both sides and that is easily
`of an OTP of the invention (Dermestril) or a reference OTP.
`removed at the time of use without impairing the transder-
`DETAILED DESCRIPTION OF THE
`mal patch.
`PREFERRED EMBODIMENTS OF THE
`55 According to the additional embodiment of the invention,
`INVENTION
`a process is described for the production of a transdermal
`patch for the extended release of 17p-estradiol to the skin,
`According to the invention the above mentioned features
`which is characterized in that pressure-sensitive adhesive
`were provided by a transdermal patch for the extended
`copolymers containing 17(3-estradiol as active ingredient are
`release of 17p-estradiol onto the skin consisting of:
`60 spread onto a removable protective liner and then covered
`a) an outer covering (backing foil);
`by another liner which becomes the outer covering.
`b) pressure-sensitive adhesive copolymers constituting
`Alternatively the pressure-sensitive adhesive copolymers
`the matrix in which the active ingredient is dissolved or
`containing 17p-estradiol are spread on a water-impermeable
`dispersed (drug reservoir);
`foil which becomes the outer covering, and are then covered
`c) a protective liner which is removed at the time of use; 65 by the protected liner.
`The invention describes a new transdermal patch for the
`Still alternatively the pressure-sensitive adhesive copoly­
`extended release of estradiol to the skin, in which the active
`mers containing 17p-estradiol are spread on an intermediate
`
`

`

`6,156,335
`
`60
`
`5
`6
`polymerization of 1038 g 2-ethylhexyl acrylate, 520 g
`liner (usually a siliconized paper sheet) and then covered by
`methyl acrylate, 68 g of acrylic acid, 87 g vinyl acetate, and
`the foil of the outer covering to which the copolymers adhere
`17 g hydroxyethyl acrylate.
`firmly. In the final manufacturing process the intermediate
`liner is removed and substituted by the protective liner.
`A quantity of 40 g of 17p-estradiol was dissolved or finely
`According to a predetermined embodiment of the claimed 5 suspended in a mixture of solvents constituted by 1 liter of
`process the transdermal patch can be produced as follows:
`propan-2-ol and 1.5 liters of ethyl acetate. This solution was
`the pressure-sensitive adhesive copolymers are dissolved
`added, under stirring, to the mixture of copolymers, pre­
`pared as described above.
`in an organic solvent (adhesive mixture);
`The mixture was stirred until a homogeneous mass was
`17p-estradiol, dissolved or dispersed in an organic solvent
`or in a mixture of solvents, is dissolved or dispersed in 10
`obtained and this was evaporated to produce a mixture with
`the adhesive mixture by stirring, at a concentration
`a consistency appropriate for spreading on the appropriate
`from 1% to 5% (w/w) of the dry weight of the pressure-
`liners. Then the adhesive mixture containing the active
`sensitive adhesive copolymers;
`ingredient was spread onto a foil of silicone-coated paper or
`the obtained mixture is concentrated by evaporation of
`polyester and dried at a temperature between 30° and 80° C.
`some of the solvents and then spread onto the remov- to
`produce a film of matrix weighing about 98 g/m2 (±5%)
`able protective liner, preferably constituted by a foil of
`as the dry weight, corresponding to about 2.2 g of 17|3-
`paper or polyester which is silicone-coated on one or
`estradiol per m2 of the dry matrix,
`both sides; alternatively the mixture is spread onto the
`Finally, a polyester foil, about 15 /an thick, was stuck on
`foil of the outer covering, constituted by water- 20 the matrix to form the outer covering of the patch,
`impermeable materials preferably selected from the
`Individual circular patches having areas of 18 cm2, each
`group of polyester, polyurethane, polyethylene and/or
`containing about 4 mg of the active ingredient were cut from
`polyvinyl chloride; still alternatively the mixture is
`the composite medicated foil to form the final transdermal
`spread on an intermediate liner, preferably constituted
`patch.
`by a sheet of paper, preferably siliconized on one or on 25
`In summary, the steps of preparing the estradiol transder­
`both sides;
`mal patch (OTP) according to the present invention consist
`the solvent is evaporated at a temperature from 30° to 80°
`substantially of:
`C. with or without applying a vacuum;
`adding a solution of a fine suspension of estradiol to a
`a foil of thin, flexible and water-impermeable material
`suitable mixture of copolymers of acrylates and vinyl
`constituting the outer covering is applied, or, alterna- 30
`acetate;
`lively the final protective liner is applied or alterna­
`spreading a thin layer of the mixture formed by the
`tively the intermediate liner is removed and replaced by
`dispersion of the active ingredient in the acrylic copoly­
`the final protective liner, according one of the three
`mers on a protective liner of silicone-coated paper or
`procedures outlined above as examples;
`polyester to be removed at the time of use;
`the produced composite medicated foil is cut into portions 35
`drying the liquid adhesive film
`formed by the acrylic
`of appropriate shape and surface, such that they contain
`copolymers and containing estradiol, at a temperature
`the required quantity of the active ingredient suitable
`between 30° and 80° C. in order to evaporate the
`for the therapeutic use, and in this way the final
`solvent, with or without applying vacuum;
`transdermal patches are obtained.
`applying a foil of thin, flexible, water-impermeable mate­
`The appropriate qualitative-quantitative selection of the 40
`rial which constitutes the outer covering of the patch;
`acrylic components of the final copolymer obtained by
`cutting the composite medicated foil produced as above
`radical polymerization, i.e. 2-ethylhexyl acrylate, acrylic
`described into portions having the desired shape and
`acid and hydroxyethyl acrylate, and of vinyl acetate which
`surface, for example 18 cm2 for patches containing 4
`acts as solvent for the active ingredient, is suitable for a
`mg estradiol;
`transdermal system for the extended release of estradiol 45
`alternative procedures are also possible, such as spreading
`which is stable in time and does not give rise to crystalli­
`the adhesive mixture onto the outer covering or onto an
`sation of the active ingredient in the matrix.
`intermediate liner. The following manufacturing steps
`Moreover, as will be described below, the serum levels of
`are then made in order to produce the appropriate final
`estradiol in menopausal patients obtained after having
`composite medicated foil.
`applied the transdermal patch to their skin, are more constant 50
`Release of estradiol in vitro
`during the application time than during the application of a
`The release of estradiol from the OTP produced according
`patch provided with a diffusion-rate limiting membrane and
`to the invention ("DERMESTRIL") was tested in vitro with
`ethanol as enhanced. Surprisingly the extent of absorption
`the following procedure.
`after the application of the invented OTP was similar to that
`55 Discs cut from DERMESTRIL OTP, with surface areas of
`of the enhanced system.
`6 cm2 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
`glass vessel and a rotating blade.
`The distance between the support and the blade, which
`rotated at a speed of 50 revolutions per minute, was 2.5 cm
`and the dissolution liquid was constituted by 900 ml of water
`at 32° C.
`Portions of 1 ml of the solution were withdrawn at 2, 4,
`65 6, 8, 12, 24 and 36 hours after the start of the experiment,
`and the estradiol content was determined by HPLC. The test
`was repeated 6 times.
`
`EXAMPLE 1
`(Production of a transdermal patch containing 4 mg of
`estradiol)
`The production process of the transdermal patch accord­
`ing to the present invention, containing 4 mg of 17(3-
`estradiol as the active ingredient per 18 cm2 of patch area
`(hereinafter referred to as "DERMESTRIL"), is illustrated
`further by the following, non-limiting example.
`An adhesive mixture was prepared dissolving in 3 liters of
`ethylacetate a mixture of copolymers obtained by radical
`
`

`

`7
`The quantities of released estradiol, expressed as milli­
`grams and as percent of the nominal content of estradiol in
`DERMESTRIL at the various times, are given in table 1.
`
`6,156,335
`
`8
`
`-continued
`
`Estradiol pp/ml ± SD
`
`5
`
`10
`
`Hours
`
`DERMESTRIL
`
`Reference OTP
`
`72
`84
`96
`108
`120
`Cmax
`'-max
`AUC (0-96 h)
`
`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
`
`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
`
`15
`
`20
`
`40
`
`Score
`
`ERYTHEMA
`
`OEDEMA
`
`0
`1
`2
`3
`
`No effect
`Slight
`Moderate
`Intense
`
`No effect
`Slight oedema
`Moderate oedema
`Severe oedema
`
`TABLE 1
`
`Milligrams and percent of estradiol released
`in the in vitro test
`
`Time (h)
`
`mg
`
`% of nominal
`
`2
`4
`6
`12
`24
`36
`
`0.66
`0.95
`1.25
`1.70
`2.48
`3.20
`
`16.5
`23.8
`31.2
`42.5
`61.9
`80.0
`
`Table 1 shows that from 6 to 36 hours, the release kinetics
`is linear and can be expressed by the equation:
`
`i?=0.8966+0.646x/i
`
`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
`DERMESTRIL is the same as that from Reference OTP, and
`this is a surprising result because DERMESTRIL does not
`where R=mg of estradiol released and h=time in hours.
`contain absorption enhancers.
`Table 1 shows also that about 30% of the estradiol
`Tolerability by the skin
`contained in the patch had been released after 6 hours, about 25
`The skin tolerability to the OTP prepared according to the
`60% after 24 hours and about 80% after 36 hours.
`invention was evaluated on 10 female guinea pigs weighing
`Bioavailability of estradiol from DERMESTRIL
`between 300 and 400 g.
`The patches were applied to the previously shaved left
`The bioavailability study was carried out in postmeno-
`scapular region of the animals. An area of patch of 2x2 cm
`pausal women. DERMESTRIL was compared with an OTP
`commercially available and characterized by a diffusion rate 30 cut from DERMESTRIL and thus containing about 0.89 mg
`limiting membrane and containing ethanol as solvent and
`estradiol, was stuck on the shaved skin and left there for
`absorption enhancer (hereinafter called "Reference OTP").
`about 6 hours. The tolerability of the patch was evaluated by
`Two DERMESTRIL patches prepared according to the
`the appearance of erythema or oedema after 24 hours of
`invention, and containing each 4 mg of estradiol per 18 cm2
`application, according to the following scores.
`or two Reference OTPs, also containing 4 mg of estradiol, 35
`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
`The test was repeated using the same scores after 7 days,
`found (Cm(n:), of the times to the peak (tm(n.) and of the area 45 in order to record a possible sensitization induced by the
`under the concentration/time curve (AUC) in the period
`patch.
`0-96 hours after administration.
`The overall sum of the scores related to erythema for the
`Table 2
`10 animals was 1 of 30, because only 1 animal out of 10
`showed a slight erythema (30 is the maximum score
`Estradiol levels in serum at various times after the appli­
`cation of 2 OTPs according to the invention 50 obtainable).
`(DERMESTRIL) or of 2 commercial OTPs (Reference
`No animal presented oedema.
`OTP), Both, DERMESTRIL and the Reference OTP contain
`In the sensitisation challenge carried out after 7 days, no
`each 4 mg estradiol. Averages and SD of 20 subjects.
`animal had erythema or oedema, demonstrating that the
`patches were well tolerated and did not induce sensitization
`55 under the experimental conditions.
`
`Estradiol pp/ml ± SD
`
`DERMESTRIL
`
`Reference OTP
`
`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
`
`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
`
`Hours
`o
`2
`6
`8
`12
`24
`36
`48
`60
`
`EXAMPLES 2 to 5 AND COMPARATIVE
`EXAMPLES 1 TO 7
`Table 3 summarized the composition of the matrix of
`60 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 compounds are quantitatively listed in table 3. The
`resulting OTPs were tested for stability and also, in six
`65 human subjects, for adhesion and skin compatibility. The
`results obtained with the eleven formulations are also
`reported in table 3.
`
`

`

`6,156,335
`
`10
`9
`impermeable material, selected from the group of polyester,
`The results clearly show that formulations No. 1 to 4 and
`polyurethane, polyethylene and/or polyvinyl chloride mate­
`particularly No. 1 exhibit the properties required for the
`rials.
`matrix of a "monolithic" transdermal patch. Conversely
`6. Aprocess for the production of a transdermal medicated
`other formulations, which are here listed as Comparative
`Examples 1 to 7, had disadvantages, for instance discolou- 5 patch according to claim 1, characterized in that pressure-
`sensitive adhesive copolymers containing 17|3-estradiol as
`ration (formulations No. 6 to 10), unacceptable skin com­
`active ingredient are spread onto a removable protective
`patibility (formulation No. 5), or unacceptable tack proper­
`liner and then covered by an outer covering.
`ties (formulations No. 6, 7, 9 and 11).
`
`TABLE 3
`
`Percentage of monomers in the acrylic copolymers and other substances
`in different formulations. Properties of the matrix obtained with these
`copolymers.
`
`Examples
`
`Comparative Examples
`
`Formulation No.
`
`Substances
`
`2-EHA
`HA
`VA
`AA
`GMA
`HEA
`TA.
`HR
`Features
`
`2
`1
`
`3
`2
`
`4
`3
`
`5
`4
`
`1
`5
`
`2
`6
`
`3
`7
`
`4
`8
`
`5
`9
`
`6
`10
`
`7
`11
`
`61.5
`62.6
`26.4 33.0
`5.6
`0.0
`4.4
`5.5
`0.0
`0.0
`1.0
`0.0
`0.0
`0.0
`0.0
`0.0
`
`63.4 57.6
`21.5 19.5
`9.8
`8.9
`3.6
`3.3
`0.1
`0.1
`1.8
`1.6
`0.0
`0.0
`0.0
`9.1
`
`66.9
`0.0
`28.0
`0.0
`0.2
`5.0
`0.0
`0.0
`
`62.2
`26.4
`5.6
`4.3
`0.1
`1.0
`0.4
`0.0
`
`64.2
`59.2 56.6
`63.1 64.0
`21.5 16.5 25.1
`24.0 16.5
`5.3
`5.1 14.0
`9.8 14.0
`4.1
`3.9
`2.8
`3.5
`2.7
`0.1
`0.1
`0.0
`0.0
`0.1
`1.0
`0.9
`2.5
`1.8
`2.5
`0.4
`0.4
`0.0
`0.3
`0.3
`4.8
`9.1
`0.0
`0.0
`0.0
`
`Estrad. solub.
`Discoloration
`Tack on skin
`Skin compat.
`
`G
`
`G
`G
`
`G
`
`G
`M
`
`G
`
`M
`M
`
`G
`
`G
`M
`
`G
`
`G
`B
`
`G
`
`B
`G
`
`G
`
`B
`G
`
`G
`
`G
`M
`
`G
`
`B
`G
`
`G
`
`G
`M
`
`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
`
`What is claimed is:
`1. A transdermal medicated patch for the extended release
`of 17p-estradiol to the skin, consisting of pressure-sensitive
`adhesive copolymers in which the active ingredient is dis- 45
`solved or dispersed, supported by a water-impermeable foil
`and covered by a protective liner which is removed at the
`time of use, wherein the pressure-sensitive adhesive copoly­
`mers are obtained by radical copolymerization of
`
`7. Aprocess for the production of a transdermal medicated
`patch according to claim 6„ which comprises:
`dissolving pressure-sensitive adhesive copolymers in an
`organic solvent to form an adhesive mixture;
`dissolving - 17P-estradiol, in the adhesive mixture by
`stirring at a concentration from 1% to 5% by weight of
`the dry weight of the pressure-sensitive adhesive
`copolymers; and
`spreading the solution onto a removable protective liner.
`8. A transdermal medicated patch according to claim 1,
`wherein the pressure-sensitive adhesive copolymers are
`55 obtained by radical copolymerization of (w/w or the matrix)
`
`so
`
`55 to 65 weight %
`24 to 32 weight %
`3 to 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 17[J-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 17|3-estradiol per
`18 to 20 cm2 of patch area.
`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. A transdermal patch according to claim 1, characterized
`by an outer covering constituted by a foil of a water-
`
`60
`
`65
`
`61 to 64%
`25 to 28%
`4 to 5%
`4 to 5%
`about 1%
`
`2-ethylhexyl acrylate
`methyl acrylate
`acrylic acid
`vinyl acetate and
`hydroxyethyl acrylate.
`
`