a2) United States Patent
`US 6,521,250 B2
`(10) Patent No.:
`Meconiet al.
`(45) Date of Patent:
`Feb. 18, 2003
`
`
`US006521250B2
`
`(54) TRANSDERMAL THERAPEUTIC SYSTEM
`CONTAINING ESTRADIOL
`
`(75)
`
`Inventors: Reinhold Meconi, Neuwied; Frank
`Seibertz, Bad [lénningen/Ariendorf;
`Michael Horstmann, Neuwied; Rainer
`Lichtenberger, Darmstadt, all of (DE)
`
`(73) Assignees: LTS Lohmann Therapie-Systeme
`GmbH, Neuwied (DE); Merck Patent
`GmbH, Darmstadt (DE)
`
`(*) Notice:
`
`Subject to any disclaimer, the term of this
`patent is extended or adjusted under 35
`US.C. 154(b) by 0 days.
`
`(21) Appl. No.: 09/522,925
`
`(22)
`
`(65)
`
`Filed:
`
`Mar. 10, 2000
`
`Prior Publication Data
`US 2002/0012691 A1 Jan. 31, 2002
`
`Related U.S. Application Data
`
`(63) Continuation of application No. 08/961,039, filed on Oct.
`30, 1997, which is a continualion-in-part of application No.
`08/545,703, filed as application No. PCT/EP94/01279 on
`Apr. 25, 1994, now abandoned.
`
`(30)
`
`Foreign Application Priority Data
`
`May 6, 1993
`Oct. 27, 1993
`
`cececcsccsscestessessesesseestsseeseeees 43 14 970
`(DE)
`(DE) oo. eee eee eeeceeesetrenenerene 43 36 557
`
`Int. Ch? oe A61F 13/00; A61K 9/70
`(51)
`(52) US. Cheee 424/443; 424/448; 424/449
`(58) Field of Search... 424/443, 448,
`424/449
`
`(56)
`
`References Cited
`U.S. PATENT DOCUMENTS
`
`4,379,454 A
`4,624,605 A
`4,668,232 A *
`
`........... 604/897
`4/1983 Campbellet al.
`... 604/307
`11/1986 Nuwayser.........
`
`5/1987 Cordes etal... 604/897
`
`5,306,503 A *
`5,393,529 A *
`5,928,666 A *
`
`4/1994 Muller et ale ccssccsccsee 424/449
`
`.......... 424/445
`2/1995 Hoffmann et al.
`7/1999 Farinas et al... 424/449
`
`FOREIGN PATENT DOCUMENTS
`
`DE
`DE
`DE
`DE
`DE
`EP
`EP
`FP
`EP
`EP
`EP
`EP
`EP
`WoO
`
`2 006 969
`3 810 896
`3 205 258
`3 743 946
`4 223 360
`0 072 251
`0 186 O19
`0 275 716
`0 285 563
`0 328 806
`0 421 454
`0 483 370
`0 607 434
`87/07138
`
`10/1970
`10/1988
`2/1991
`6/1991
`4/1993
`2/1983
`7/1986
`7/1988
`10/1988
`8/1989
`4/1991
`5/1992
`7/1994
`12/1987
`
`OTHER PUBLICATIONS
`
`Friend et al., Journal of Controlled Release, vol. 7 (1988)pp.
`243-250.
`
`Friend et al., Journal of Controlled Release, vol. 9 (1989)pp.
`33-41.
`
`* cited by examiner
`
`Primary Examiner—Thurman K. Page
`Assistant Examiner—S. Howard
`(74) Attorney, Agent, or Firm—Wenderoth, Lind & Ponack,
`L.LP.
`
`(57)
`
`ABSTRACT
`
`An active-substance-containing transdermal therapeutic sys-
`tem for the controlled release of estradiol or its pharmaceu-
`tically acceptable able derivatives alone or combined with
`gestagens consisting of a layer, an active-substance-
`containing reservoir which is banded thereto and produced
`by using pressure sensitive adhesives, and a removable
`protective layer is characterized by the fact that the pressure
`sensitive adhesive comprises esters of colophony.
`
`24 Claims, No Drawings
`
`  
`
`

 
`
`MYLAN - EXHIBIT 1020
`
`

`

`US 6,521,250 B2
`
`1
`TRANSDERMAL THERAPEUTIC SYSTEM
`CONTAINING ESTRADIOL
`
`This application is a continuation of application Ser. No.
`08/961,039, filed Oct. 30, 1997, which application is a
`continuation of now abandoned application Ser. No. 08/545,
`703, filed Feb. 12, 1996, which application is a national
`stage application of International Application No. PCT/
`EP94/01279, filed Apr. 25, 1994.
`BACKGROUNDOF THE INVENTION
`
`10
`
`2
`danger of the active substance being recrystallized in the
`course of time.
`It is known from DE-OS 32 05 258 and EP 0 285 563 to
`
`administer estradiol and ethanol simultaneously in a patch
`formulation. However, the production of this patch is very
`expensive, and the wearing comfort after application is low
`because of missing flexibility.
`EP 0 285 563 describes a transdermal therapeutic system
`for the combined application of estrogens and gestagens.
`The reservoir has the active substance formulation, option-
`ally a membrane, and ethanol as percutaneous absorption
`improving agent. Since the release of the active substance is
`mainly controlled by the membrane, this transdermal thera-
`peutic system is completely different
`from the active-
`substance-containing patch according to the present inven-
`tion. In the patch described in said publication, the adhesive
`has the mere function of fastening the patch to the skin. The
`fact
`that
`it can contribute to the control of the active
`
`its main function but merely
`substance release is not
`a—probably even undesired—side effect. It is a so-called
`“pouch patch” since the active substance preparation is
`present in a pouch consisting of an impermeable backing
`layer and a membrane having an adhesive layer. As a
`consequence of its complicated structure, the production of
`this patch is very expensive since the individual components
`have to be produced separately and then joined in an
`additional step to form a patch.
`EP 0 275 716 describes a two-layer transdermal thera-
`peutic system—in contrast
`to the single-layer system
`according to the present invention—for the simultaneous
`administration of one or several estrogens which are dis-
`solved or microdispersed in the polymeric layer. In addition
`to the active substances,
`the pressure sensitive adhesive
`layer comprises substances improving the transdermal
`absorption. Polymeric and pressure sensitive adhesive layer
`may consist of polyacrylates, silicones, or polyisobutylenes.
`EP 0 072 251 describes a flexible,
`liquid-absorbing
`medicinal bandage. The substrate which is attached to the
`flexible backing layer consists of a hydrophilic matrix based
`on hydrophilic high-molecular polysaccharides and/or poly-
`acrylic acid, polyacrylamide, ethylene-vinyl acetate-
`copolymers, and other polymers as well as of a liquid phase
`based on a solution or emulsion of carbohydrate, proteins,
`multivalent alcohols, and different active substances,
`amongst others hormones. The main feature ofthis invention
`is the moisture-absorbing adhesive.
`EP 0 328 806 describes a transdermal therapeutic system
`without membrane;
`its matrix consists of a polyacrylate
`adhesive, a solvent, a penetration enhancer, and estrogens,
`the derivatives and combinations thereof.
`
`WO 87/07 138 describes an estradiol patch based on a
`backing layer, an active-substance-containing matrix and a
`pressure sensitive adhesive covered with a removable pro-
`teclive layer. The matrix and pressure sensilive adhesive are
`manufactured in technologically very expensive operations
`by homogenizing, degassing, coating, drying, and separat-
`ing. According to an embodiment, the backing layer has to
`be coated with a pressure sensitive adhesive, resulting in an
`additional operation. The individual parts are joined in a
`separate step. lor this reason, the production ofthis patch is
`very expensive and complicated.
`U.S. Pat. No. 4,624,665 describes systems comprising the
`active substance in microencapsulated form within the res-
`ervoir. The reservoir is embedded betweenthe backing layer
`and a membrane. The outer edge of the system is provided
`with a pressure sensitive adhesive. The structure and the
`
`The present inventionrelates to a transdermal therapeutic
`system for the controlled release of estradiol or its pharma-
`ceutically acceptable derivatives alone or combined with
`gestagens, such as levonorgestrel, to human or animal skin.
`The present invention [further relates to the use and to a
`process for the production of this system.
`In the therapy of various discases, transdermal therapeutic
`systems (TTS) have been introduced on the market. Also,
`transdermal therapeutic systems containing the estrogenic -
`active substance 17-B-estradiol used as therapeutic agent for
`climacteric complaints and—for some time now—against
`osteoporosis are commercially available and show good
`therapeutic results.
`Levonorgestrel is a synthetic gestagen derivative which
`has mainly been used in contraceptives in combination with
`orally effective estrogens. In such preparations gestagens,
`consequently including levonorgestrel, have the function to
`cause a “physiologic” abstraction hemorrhage which is as
`short and rapid as possible by mcans of an adcquatc trophic
`premedication of the uterus. There are also hints that the
`gestagen addition has a protective effect against the risk of
`endometrial tumors.
`
`15
`
`25
`
`30
`
`For this reason, it is appropriate to use a cyclic treatment
`also for the indication of postmenopausal complaints,1.e., to
`make use of a temporary fixed drug combination consisting
`of estrogens (e.g., estradiol) and gestagens (e.g.,
`levonorgestrel). A combination of the two active substances
`in a common, monolithic transdermal therapeutic system
`which would have to be applied only once a day or even
`once ta twice a weekis particularly interesting. Owingto its
`high cfficicncy and permeativity through the skin levonorg-
`estrel is excellently suitable for such a system.
`Experimental systems for the transdermal delivery of
`levonorgestrel are described in literature (Friend et. al., J.
`Controlled Release 7, 243-250 (1988)). However, according
`to this estimation, permeation improvers (enhancers), e.g.,
`alkyl esters of short-chain fatty acids, are required for the
`successful transdermal therapy with sufficiently small sys-
`tem surfaces (Friendet. al., J. Controlled Release 9, p. 33-40
`(1989)).
`the transdermal application of
`Numerous devices for
`estrogens and gestagens have been disclosed. Nakagawaet
`al. (EP-A 0 483 370) obtained a matrix-lype transdermal
`therapeutic system for estradiol alone by using styrene-
`isoprene block copolymer, moisture-absorbing polymer
`domains, and the enhancer (and antipruritic agent) crotami-
`ton. Another conception is the simultaneous application of
`estradiol and an enhancer (ethanol)
`in a membrane-
`controlled reservoir system (Campbell et al., U.S. Pat. No.
`4,379,454); this can also be used in a combined adminis-
`tration form comprising the gestagen norethisterone acetate
`(Frankhauser and Schenkel, DE 3 810 896).
`However, transdermal therapeutic systems for the release
`of estradiol and/or gestagens have the disadvantage that they
`either contain ethanol or that
`they exhibit
`the potential
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`35
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`

`

`US 6,521,250 B2
`
`3
`production of this system are very complicated since the
`active substance has to be microencapsulated and homoge-
`neously distributed in a liquid phase whichis then embedded
`between backing layer and membranein additional process
`steps. In addition, this system mustthen be provided with an
`adhesive edge and covered with a protective layer.
`Additionally, EP 0 186 019 describes active substance
`patches wherein water-swellable polymers are added to a
`rubber/adhesive-resin-mass and from whichestradiol can be
`released. However, it turned out that the release of estradiol
`from these active substance patches is too low and does not
`meet the therapeutic requirements.
`DE-OS 20 06 969 describes a patch or pressure sensitive
`adhesive dressing exhibiting system action; it contains con-
`traceptive substances whichare incorporated in the adhesive
`component or in the adhesive film. ‘This publication dis-
`closes that the adhesive may be an acrylate.
`DE-OS 39 33 460 describes an estrogen-containing active
`substance patch based on homo and/or copolymers with at.
`least one derivative of the acrylic acid or with methacrylic
`acid in combination with water-swellable substances.
`
`10
`
`15
`
`it turned out that pressure sensitive adhesive
`However,
`transdermal therapeutic matrix systems which comprise the
`active substance in a partially or completely dissolved form
`involve the potential risk that the active substance recrys-
`tallizes in the course of time. Thus the active substance
`release decreases and the estrogen-containing patch does no
`longer meet the therapeutic requirements.
`Another drawback of systems accordingto the state of the
`art is the use of enhancers, this results in a fundamentally
`undesired additional skin affcction including the risk of
`irritation. Additional disadvantages lie in the expensive
`construction of these systems (use of several active-
`substance-containing layers, use of controlling membranes),
`generally rendering the finished product unacceptable for the
`user.
`
`BRIEF SUMMARY OF THE INVENTION
`
`It is accordingly the object of the present invention to
`avoid the above disadvantages and to provide a stable,ie.,
`recrystallization-free, estrogen-containing patch or transder-
`mal
`therapeutic system whose release does not change
`through storage, wherein the structure is to be designed as
`thin as possible, and during whose therapeutic application
`the skin—beyond the active substances estradiol and
`gestagen—is not
`treated with skin affecting substances
`(enhancers).
`DETAILED DESCRIPTION OF THE
`INVENTION
`
`Mostsurprisingly, it turned out that this object is achieved
`by the fact that the estrogen-containing pressure sensitive
`adhesive is mainly composed of esters of colophony.
`In this connection it
`is of advantage that a styrene-
`isoprene block copolymer and hydrogenated resin acids or
`their derivatives are additionally uscd in the active layer
`which, for example, comprises a therapeutically required
`quantity of the active substances estradiol and levonorg-
`estrel.
`
`the
`A combination of the two inactive ingredients,
`styrene-isoprene block copolymer serving as cohesive
`component, and the hydrogenated resin acids or their deriva-
`tives serving as tackifying substances, not only results in a
`rubber adhesive with good tackiness and cohesiveness but
`also provides excellent biopharmaceutical properties,
`in
`
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`65
`
`4
`particular good skin tolerance and permeation capability,
`and avoids recrystallization of the active substances.
`Thus, the present inventionrelates to a transdermal thera-
`peutic system for the controlled release of estradiol or its
`pharmaceutically acceptable derivatives alone or combined
`with gestagens, consisting of a backing layer, an active-
`substance-containing reservoir which is connected thereto
`and is produced by using pressure sensitive adhesives, and
`a removable protective layer, with the pressure sensitive
`adhesive comprising esters of colophony andinactive ingre-
`dients.
`
`Examples of esters of colophony include, for example,
`methyl esters, the glycerolester, the pentaerythritol ester, the
`pentaerythritol ester modified with maleic acid, the glycerol
`ester modified with maleic acid, and the triethylene glycol
`ester. The proportion of colophony esters in the estradiol-
`containing pressure sensitive adhesive amounts to 55-92%-
`wt., preferably 60—-90%-wt., and most preferably 70-88%-
`wt.
`In addition,
`the pressure sensitive adhesive may
`comprise esters of hydrogenated colophony. Particularly
`preferred esters of colophony include the triethylene glycol
`ester,
`the glycerol ester, and the pentaerythritol ester of
`hydrogenated colophony.
`the estradiol-
`According to another embodiment,
`containing pressure sensitive adhesive may additionally
`comprise polymers selected from the group consisting of
`styrene-butadiene-styrene block copolymers, styrene-
`isoprene-styrene block copolymers, styrene-ethylene-
`butylene-styrene block copolymers, ethylene-vinyl acetate
`copolymers, polyvinyl pyrrolidone, cellulose derivatives,
`and polymers based on acrylic acid and methacrylic acid
`derivatives. These polymers are contained in the estradiol-
`containing adhesive massat a concentration of 6—-25%-wt.
`The reservoir of the estradiol-containing patch, wherein
`recrystallization does not occur, comprises estradiol and its
`pharmaceutically acceptable derivatives alone or in combi-
`nation with gestagens at a total concentration of 2-15%-wt.,
`namely at a molar ratio of 1:1 to 1:10. Generally,
`the
`estradiol is present in the active layer in an amountof 0.2 to
`2% by weight, preferably between 0.7 and 1.4% by weight.
`The amountof levonorgestrel in the active layer is between
`0.1 and 1.6% by weight. In addition, the levonorgestrel
`and/or the estradiol may be present partially in a suspension.
`The estradiol-containing reservoir may comprise at least
`one component of the group including anti-ageing agents,
`plasticizers, antioxidants, and absorption improvers. Suit-
`able plasticizers are knownto those skilled in the art and are
`described, for example,
`in DE 37 43 946. Usually,
`the
`proportion of plasticizers in the estradiol-containing reser-
`voir amounts to 0-5%-wt.
`
`the active-substance-containing reservoir
`In addition,
`comprises anti-ageing agents at a concentration of 0-1%-wt.
`These are knownto those skilled in the art and described, for
`example, in DE 37 43 946.
`The estradiol-containing reservoir may either be produced
`from solution or from a melt.
`In case the reservoir fails to exhibit sufficient self-
`tackiness to the skin, it may be provided with a pressure-
`sensitive adhesive layer or with a pressure-sensitive adhe-
`sive edge. This ensures that the transdermal patch adheres to
`the skin over the whole application period.
`A particularly preferred construction of the transdermal
`estradiol-containing patch is the matrix system wherein, as
`is generally known, the matrix controls the active substance
`release which complies with the vi-law according to Higu-
`chi. However, this is not
`to exclude the possibility that
`
`

`

`US 6,521,250 B2
`
`5
`particular cases might require the membrane system. In this
`case, a membrane controlling the active substance release is
`located between the reservoir and the pressure sensitive
`adhesive layer.
`The thickness of the transdermal patch depends on the
`therapeutic requirements and may be adapted accordingly.
`Usually, it ranges from 0.03-0.4 mm. The thickness of the
`active substance layer of the reservoiris between 30 and 300
`um, preferably between 70 and 120 um.
`In addition, a preferred application form is a monolithic
`matrix-type transdermal therapeutic system which consists
`of a backing layer substantially impermeable to the active
`substances, the actually active matrix layer (comprising the
`active substances and inactive ingredients according to the
`present invention) and of a removable protective layer.
`The examples will show that these systems—although
`having a simpler construction and being made at lower
`expenditure than those according to the state of the art—
`have improved and more constant permeation characteristics |
`for both active substances.
`
`10
`
`15
`
`Surprisingly, it turned out that such a formulation which
`is composed of mainly lipophilic and comparatively low-
`diffusible polymers andresins results in human bloodlevels
`which cannot be obtained with systems according to the
`state of the art at a comparable low expenditure.
`Until today, rubber adhesives have been regarded as being
`less suitable for the release of estradiol to the skin. For
`example, EP 0 186 01 9 describes the idea to use rubber
`adhesives (in this case by adding water-swellable
`substances), this is contradicted in EP 0 421 454 (p. 2, line
`54 ff.): a sufficient release of estradiolis not given in the case
`of these low diffusible and only slightly soluble polymers.
`Both substances which are essential to use according to
`the present invention, styrene-isoprene block copolymer and
`hydrogenated resin acids or their derivatives, have success-
`fully been used for long as classic base materials of pressure
`sensitive adhesive patches and they have a goodtolerance.
`The term “hydrogenated resin acids” means compounds
`derived from the natural product “colophony”. Colophonyis
`widely used as a mixture of native resin acids, above all in
`chemically modified form, in consumer goods, cosmetics,
`food packages, chewing gum,etc.it is the resinous residue
`of the raw product turpentine balsam remaining after dis-
`tilling off turpentine oil; turpentine balsam originates from
`different pine trees in mainly subtropical-mediterranean
`climatic zones.
`
`The crude product is a brittle, resinous mass softening at
`about 73-80° C. and having a density of about 1.07 g/ml.
`The modification of colophony for the purpose of using it in
`transdermal therapeutic systems serves to stabilize it against
`the influence of oxygen by hydrogenation and to improve
`the alkali stability by esterification. Hydrogenation and
`derivatization, if necessary, render the material more suit-
`able for the intended purpose. Important esters which can be
`used for the purpose according to the present invention
`include, for example, glycerol esters, pentaerythritol esters,
`methyl esters, and other derivatives of hydrogenated colo-
`phony well tolerated by the skin.
`Synthetic rubber polymers play an important role in the
`production of transdermal therapeutic systems and wound
`dressings. Their advantage lies in the fact that the mechani-
`cal properties of transdermal therapeutic systems are con-
`siderably improved. In this respect,
`the styrene-isoprene-
`styrene block copolymers have proved to be particularly
`suitable. By dividing the polymer chain into a middle block
`of still mobile long-chain polyisoprene units and the two
`
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`
`6
`polystyrene ends as “anchor points”, a three-dimensional
`network is formedin the matrix, this ensures a substantially
`constant geometry, even during storage. In this connectionit
`is not decisive which molecular weight or which ratio
`between the proportion of the styrene domains and the
`polyisoprene domainsreally exists. On the contrary, adjust-
`ing the correct tackiness and cohesion is the important
`factor. For example, an increased resin proportion results in
`an improved tackiness to the skin but also in a softer
`consistency of the matrix. In general, the proportion of the
`block copolymer will amount to about one third, the rest
`remaining after the active substance addition are biocom-
`patible resin derivatives. Typically,
`the proportion of the
`styrene-isoprene block copolymer
`in the active layer
`amounts to 10-45% by weight, preferably 15-33% by
`weight.
`Although a single-layer structure of the transdermalthera-
`peutic system exhibits advantages because of the simple
`function,
`it
`is easily possible according to the present
`invention to provide such a matrix system, e.g., with a thin
`additional adhesive layer directed towards the skin. Also, for
`the purpose of obtaining an improved anchoringeffect on the
`backing laycr a thin pressure sensitive adhesive layer may be
`laminated. Such additional layers may consist of a rubber-
`resin-mixture but also,
`for example, of acrylic-ester-
`containing copolymers. They may be used even if not
`charged with active substances prior to lamination, since a
`diffusion compensation takes place during short-time inter-
`mediate storage of the complete laminate.
`The transdermal patch is prepared by the followingsteps:
`kneading the mixture of esters of colophonyat an elevated
`temperature until homogenization, incorporating active
`substance(s) and at least one polymerat the solution
`temperature, coating a removable protective layer with
`the active-substance-containing adhesive mass after
`homogenization, and laminating the backing layer.
`The present invention will be illustrated in more detail by
`the following examples.
`EXAMPLE1
`
`73.1 g triethylene glycol ester of hydrogenated colophony
`(Staybelite Ester 3E/by Hercules) and
`9.8 g glycerol ester of hydrogenated colophony
`(Staybelite Ester 10E/by Hercules)
`are mixed by kneading at 100° C. for 5 minutes. Then 2.5 ¢
`of estradiol are added. Kneading is continued for 30 min-
`utes. After heating to 140° C., 14.6 g ethyl cellulose NSONF
`(by Hercules) are added in portions, and then kneading is
`continued for 2.5 hours.
`In a hot melt coating line (die coating system) the active-
`substance-containing adhesive mass thus obtained is coated
`onto a removable protective layer (Hostaphan RN 100,
`coated on one side with silicone—by Kalle) in such a
`mannerthat an active-substance-containing reservoir having
`a mass per unit area of 80 g/m? results. An impermeable
`backing layer (polyester sheet, thickness 15 um) is lami-
`nated on this reservoir. Subsequently, active substance
`patches of 16 cm* are punched.
`EXAMPLE2
`
`The manufacture is in accordance with Example 1, with
`the plasticizer being kneaded together with the two Staybe-
`lite esters 3E and 10E.
`
`EXAMPLES3-9
`
`Manufacture according to Example 1, however with the
`raw products and quantities as listed in Table 1
`(manufacturing formula).
`
`

`

`US 6,521,250 B2
`
`7
`
`Analytic procedure
`The active substance release of the transdermal patches
`having a size of 16 cm? is determined according to the
`Rotating bottle-method described in U.S. Pat. No. XXII in
`0.9% salt solution at 37° C.
`To measure the mice skin penetration, the skin of hairless
`mice is placed in the Franz-cell. An estradiol-containing
`patch having an area of 2.54 cm?is stuck onto the skin, and
`the active substance release is measured al 37° C. (acceptor
`medium: 0.9% saline). (literature: Umesh V. Banakar Phar-
`maceutical dissolution testing (1st edition—1991)).
`The recrystallization testing is carried out visually against
`the light.
`The results are listed in ‘lable 2.
`
`TABLE 1
`
`manufacturing formula (indications in g
`
`Ethyl cellulose _Staybelite Ester Plasticizer
`
`Estra- Anti-
`
`8
`siliconized polyester sheet of 100 wm thickness in a con-
`tinuouscoating line in such a mannerthat a layer thickness
`of 110 g/m?(relative to the solvent-free portion) results. The
`coating is dricd at 40° C., 60° C., 75° C., and 125° C. for 3
`minutes each. A polyester sheet of 12 um thickness is
`immediately placed on the dry layer without air-bubbles
`under roll pressure (laminated). Transdermal systems of 20
`cm* are obtained by punching using a wad punch.
`EXAMPLE11
`
`Manufacture of a system according to the invention
`1.5 g 17-B-estradiol
`1.5 g levonorgestrel
`70.0 g styrene-isoprene-styrene block copolymer
`150.0 g thermoplastic ester resin of colophonyderivatives
`are melted and combined by kneading in a heatable kneader
`at 150° C. under nitrogen within 24 h. On a continuous
`coating line, a polyester sheet of 19 um thickness is coated
`with the melt at a layer thickness of 100 wm. This may be
`effected at 140° C. in a hot melt coater, or at about 80-100°
`C. by means of an extruder. Subsequently, a siliconized
`polyester sheet of 150 um thickness, precoated with 20 g/m”
`of an acrylic ester copolymer (Durotak®280-2516),
`is
`placed on the dried layer (laminated) without air-bubbles
`and underroll pressure. Transdermal systems of 20 cm? are
`obtained by punching using a wad punch.
`Whatis claimedis:
`1. A transdermal therapeutic system for the controlled
`release of estradiol or a pharmaceutically acceptable deriva-
`tive thereof, said system comprising a backing layer; an
`active-substance-containing reservoir whichis bondedto the
`backing layer and which comprises pressure sensitive adhe-
`sive and estradiol or a pharmaceutically acceptable deriva-
`tive thereof combined with a gestagen; and a removable
`protective layer, wherein the pressure sensitive adhesive
`comprises
`(a) a styrene-isoprene block copolymer, and
`(b) a hydrogenated resin acid or its derivatives in an
`amount of 55-92% wt.
`2. The transdermal therapeutic system according to claim
`1, wherein the pressure sensitive adhesive comprises the
`hydrogenated resin acid or its derivatives in an amount of
`60-90% wt.
`3. The transdermal therapeutic system according to claim
`1, wherein the pressure sensitive adhesive comprises the
`hydrogenated resin acid or its derivatives in an amount of
`70-88% wt.
`4. The transdermal therapeutic system according to claim
`1, wherein the active-substance-containing reservoir com-
`prises the active substances estradiol and levonorgestrel, as
`the gestagen, wherein the polymeris styrcnc-isoprene block
`copolymer.
`5. The transdermal therapeutic system according to claim
`1, wherein the derivatives of the hydrogenated acid resins
`are esters selected from the group consisting of methylester,
`glycerol ester, pentaerythritol ester, pentaerythritol ester
`modified with maleic add, glycerol ester modified with
`maleic acid, and triethylene glycolester.
`6. The transdermal therapeutic system according to claim
`1, wherein the concentration of estradiol or its pharmaceu-
`tically acceptable derivatives in the active-substance-
`containing reservoir is between 0.2 and 2 percent by weight.
`7. The transdermal therapeutic system according to claim
`6, wherein the concentration of the estradiol or its pharma-
`ceutically acceptable derivative in the active-substance-
`containing reservoir is between 0.7 and 1.4 percent by
`weight.
`
`10
`
`15
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`60
`
`65
`
`Ex.
`1
`2
`3
`4
`5
`6
`7
`
`8
`
`diol oxidants
`2.5
`2.5
`2.5
`2.5
`0.1 BAT
`2.5
`0.1 BHA
`2.5
`2.5 G1
`BHT:BHA
`=i
`
`2.5
`
`10E Miglyol 812
`3E
`NSONF
`98 —
`B1
`14.6
`9.6
`2.0
`71.6
`14.3
`10.0
`2.0
`75.4
`10.1
`10.3
`2.0
`77.5
`77
`95
`2.0
`WN.6
`14.3
`14.3 6 95
`2.0
`14.3
`716
`95
`2.0
`
`14.3
`
`71.6
`
`96
`
`2.0 isopropyl
`palmitate
`9,5(&) 2.0
`
`71.6
`14.3
`9
`BHT = butyl hydroxytoluene
`BHA = butyl hydroxyanisole
`& = Foral 105 (pentaerythritol ester of hydrogenated colophony)
`
`2.5
`
`TABLE 2
`
`Results of Analysis
`Estradiol
`content in-vitro-release
`
`Mice skin
`penetration
`
`Hg/16 cm? yg/l6 cm? + 24h yg/l6 cm? + 24h
`3200
`614
`225
`3200
`1240
`300
`3200
`722
`235
`3200
`713
`268
`3200
`624
`28
`3200
`624
`249
`3200
`620
`205
`3200
`686
`232
`3200
`2400
`25
`
`Re-
`erystalli-
`
`zation
`no
`"
`"
`"
`"
`"
`"
`"
`consider-
`able
`
`Ex.
`1
`2
`3
`4
`5
`6
`7
`8
`9
`acc. to
`DE
`3933460
`
`The Table shows that a considerably improved penetration through the
`mice skin is obtained, as evidenced by the comparative example under DE
`3933460. Analogously, there is no recrystallization in the Examples
`according to the present invention.
`
`EXAMPLE10
`
`1.0 g 17-B-estradiol
`1.3 g levonorgestrel
`60.0 g Cariflex®TR 1107 (styrene-isoprene-styrene block
`copolymer), 138.0 g Foral®&5 (thermoplastic ester
`resin of colophony derivatives)
`200.0 g benzine (boiling range 80-100° C.)
`are stirred in a cylindrical glass vessel at room temperature
`until an even suspension results and then coated on a
`
`

`

`US 6,521,250 B2
`
`9
`8. The transdermal therapeutic system according to claim
`4, wherein the concentration of levonorgestrel in the active-
`substance-containing reservoir is between 0.1 and 1.6 per-
`cent by weight.
`9. ‘The transdermal therapeutic system according to claim
`1, wherein the active-substance-containing reservoir has a
`layer thickness between 30 and 300 um.
`10. The transdermal
`therapeutic system according to
`claim 9, wherein the thickness of the active-substance-
`containing reservoir is between 70 and 120 wm.
`11. The transdermal
`therapeutic system according to
`claim 4, wherein the amount of styrene-isoprene block
`copolymerin the active-substance-containing reservoir is 10
`to 45 percent by weight.
`therapeutic system according to
`12. The transdermal
`claim 11, wherein the amountof the styrene-isoprene block
`copolymerin the active-substance-containing reservoir is 15
`to 33 percent by weight.
`therapeutic system according to
`13. The transdermal
`claim 1, wherein at least one of the active substances,
`levonorgestrel as the gestagen orestradiol or its pharmaceu-
`tically acceptable derivative is present partially in suspen-
`sion.
`therapeutic system according to
`14. The transdermal
`claim 11, wherein part of the estradiol is present in the form
`of estradiol crystals, with the estradiol crystals substantially
`consisting of precipitated estradiol anhydrate.
`15. The transdermal
`therapeutic system according to
`claim 11, wherein the hydrogenated resin acid orits deriva-
`tive comprises esters of hydrogenated colophony.
`16. The transdermal
`therapeutic system according to
`claim 1, whercin the reservoir comprises estradiol or a
`pharmaceutically acceptable derivative of estradiol in com-
`bination with a gestagen in a concentration totaling 2-15%
`wt., wherein the molar ratio of estradiol or its pharmaceu-
`tically acceptable derivative to the gestagen is 1:1 to 1:10.
`17. The transdermal
`therapeutic system according to
`claim 1, wherein the reservoir comprises at least one com-
`
`
`
`10
`ponent selected from the group consisting of an anti-ageing
`agent, a plasticizer, an antioxidant, and an absorption
`improver, with the plasticizer being contained in a concen-
`tration of 0-5% wt. and the anti-ageing agent being con-
`tained in a concentration of 0.1% wt.
`
`5
`
`therapeutic system according to
`18. The transdermal
`claim 1, wherein the pressure sensitive adhesiveis a solvent-
`based pressure sensitive adhesive.
`19. The transdermal
`therapeutic system according to
`claim 1, wherein the pressure sensitive adhesive is a hot-
`melt pressure sensitive adhesive.
`20. The transdermal
`therapeutic system according to
`claim 11, wherein the reservoir consists of a plurality of
`layers.
`therapeutic system according to
`21. The transdermal
`claim 1, wherein the reservoir is provided with an additional
`pressure sensitive adhesive layer or with a pressure sensitive
`adhesive edge.
`therapeutic system according to
`22. The transdermal
`claim 21, wherein a membrane which controls the active
`substance release is located between the reservoir and the
`additional pressure sensitive adhesive layer.
`23. A process for the production of a transdermal thera-
`pe