U8005902602A
`
`[19]
`United States Patent
`5,902,602
`[11] Patent Number:
`[45] Date of Patent: May 11, 1999
`Muller et al.
`
`
`
`[54] ESTRADIOL-TTS HAVING WATER-BINDING
`ADDITIVES
`
`5,518,734
`
`5/1996 Stephano et al.
`....................... 424/448
`FOREIGN PATENT DOCUMENTS
`
`[75]
`
`Inventors: Walter Muller; Michael Horstinann,
`both of NeuWied, Germany
`
`[73] Assignee: LTS Lohmann Therapie-Systeme
`GmbH, Neuwied, Germany
`
`0 421 454
`4 223 360
`4 237 453
`
`European Pat. 011'.
`4/1991
`4/1993 Germany .
`8/1993 Germany .
`OTHER PUBLICATIONS
`
`.
`
`[21] Appl. No.:
`
`08/632,490
`
`[22]
`
`[86]
`
`PCT Filed:
`
`Aug. 12,1995
`
`PCT No.:
`
`PCT/EP95/03201
`
`§ 371 Date:
`
`Jun. 7, 1996
`
`§ 102(e) Date:
`
`Jun. 7, 1996
`
`[87]
`
`PCT Pub. No.: W096/05814
`
`PCT Pub. Date: Feb. 29, 1996
`
`[30]
`
`Foreign Application Priority Data
`
`Aug. 20, 1994
`
`[DE]
`
`Germany ............................. 44 29 667
`
`Int. Cl.5 ............................. A61F 13/02, A61L 15/16
`[51]
`[52] US. Cl.
`.......................... 424/449, 424/443, 424/446;
`424/447, 424/448; 514/943; 514/946; 514/947
`[58] Field of Search .................................. 424/443, 446,
`424/447, 448, 449, 514/943, 946, 947
`
`[56]
`
`References Cited
`U.S. PATENT DOCUMENTS
`
`4,764,379
`4,788,062
`4,816,258
`4,863,738
`
`......................... 424/449
`8/1988 Sanders et al.
`424/449
`11/1988 Gale et al.
`
`424/448
`3/1989 Nedberger et al.
`9/1989 Taskovieh ............................... 424/449
`
`IIiguchi, “Physical Chemical Analysis of Percutaneous
`Absorption Process From Creams and Ointments”, J. Soc.
`Cosmetic Chem., 11, pp. 85—97 (1990).
`de
`Brusetta,
`“Structure Cristalline
`et Moleculaire
`I’Oestradiol Hemihydrate”, Acta Cryst. (1972) B28, pp.
`560—567.
`
`Kuhnert—Brandstatter et al., “Thermoanalytische und IR—s-
`pektroskopische Untersuchungen an verschiedenen Kristall-
`formen von Arzneistoffen aus der Ostradiol—und Androstan-
`
`gruppe” Scientia Pharmaceutica, 44 (3), 1976, pp. 177—190.
`
`Primary Examiner—Thurman K. Page
`Assistant Examiner—Kathryne E. Shelborne
`Attorney, Agent, or Firm—Wenderoth, Lind & Ponack,
`L.L.P.
`
`[57]
`
`ABSTRACT
`
`therapeutic system comprising the active
`A transdermal
`substance estradiol and having a layered structure of a
`backing layer which is impermeable to active substances and
`moisture, and active substance-containing matrix, and, if
`necessary, a removable protective layer covering the matrix,
`is characterized by the fact that the matrix comprises glyc-
`erol either comprising a maximum of 1%-Wt. of water or
`being substantially free from water.
`
`19 Claims, No Drawings
`
`  
`
`

  
`
`MYLAN - EXHIBIT 1018
`
`

`

`5,902,602
`
`1
`ESTRADIOL-TTS HAVING WATER-BINDING
`ADDITIVES
`
`The present invention relates to a transdermal therapeutic
`system comprising the active substance estradiol and having
`a layered structure of a backing layer which is impermeable
`to active substances and moisture, an active substance-
`containing matrix, and, if necessary, a removable protective
`layer covering the matrix.
`
`BACKGROUND OF THE INVENTION
`
`In the therapy of several diseases, Transdermal Therapeu-
`tic Systems (TTS) have been introduced on the market for
`some time now.
`
`10
`
`15
`
`2
`Another (theoretic) possibility of increasing the active
`substance flow through the skin is to dissolve more active
`substance molecularly disperse, i.e., crystal-free, in the TTS
`than corresponds to the saturation solubility. The permeation
`rate through the skin increases to the same extent as the
`degree of supersaturation of these systems. However, these
`physical states are thermodynamically unstable, therefore
`these forms of administration are not storable. Within some
`months or years, at the latest, a spontaneous unforeseeable
`precipitation of active substance will take place so that the
`flow rate through the skin gradually decreases to the satu-
`ration flow level; depending on the starting concentration,
`this results in losing a great portion of the initial therapeutic
`activity.
`This process occurring during storage is due to particular
`physicochemical characteristic features of estradiol.
`At room temperature and normal relative air humidity
`(20760% relative humidity), estradiol is not present in one
`of the two known anhydric modifications (I and II) but as a
`semihydrate (Busetta, Acta Cryst. 1972, B28, 560). Owing
`to the layered structure stabilized via hydrogen bridges, and
`because of the diffusional compactness of the crystal
`compound, the hydrate can be subjected to a short-term heat
`treatment to temperatures of about 170° C. without decom-
`position thereof (Kuhnert-Brandstatter and Winkler (1976)
`Scientia Pharmaceutica 44 (3), 177—190). However,
`estradiol—semihydrate can quantitatively be converted into
`the anhydrous form already at about 120° C. by way of
`enlarging the crystal surface by means of micronizing.
`According to the inventors” observations, the transformation
`already takes place at about 90° C. if heating is conducted
`slowly (0.2—1 K/min) and in case of a particularly fine
`substance.
`
`With decreasing partial water vapor pressure, on the other
`hand, estradiol has a higher solubility in some polymers,
`particularly in polyacrylates. According to Fick’s law, higher
`concentrations with otherwise same conditions increase the
`
`diffusion flow through the skin; for this reason such a
`concentration increase is very desirable in transdermal thera-
`peutic systems. However,
`the water introduced with the
`estradiol-semihydrate is already sufficient to cause gradual
`recrystallization from the solution as estradiol-semihydrate
`(Kuhnert-Brandstatter and Winkler (1976) Scientia Pharma-
`ceutica 44 (3), 177—190). During crystallization, the flow
`rate from the system to the skin considerably decreases with
`the diminishing concentration.
`Accordingly, transdermal therapeutic systems are known
`that offer a pharmacotherapeutically satisfying solution by
`exactly regulating the concentration to below the saturation
`solubility of the estradiol-anhydrate (DE-PS 42 37 453) or
`by using partially undissolved, disperse estradiol—anhydrate
`(DE-PS 42 23 360). Even in consideration of this latest state
`of the art, it is important to maintain a sufficiently low
`atmospheric humidity during production and storage of an
`estradiol-TTS in order to avoid large-area precipitation of
`the poorly soluble estradiol-semihydrate.
`To this end, a package having a low water—vapor perme—
`ability can be used in principle. However, owing to the small
`estradiol amounts contained in today’s TTSs, very small
`amounts of humidity are sufficient to cause precipitation of
`the estradiol-semihydrate. If, for example, 2 mg of estradiol
`(anhydrous) are present in a TTS in dissolved form, an
`amount (calculated on the basis of the molecular-weight
`ratios) of only 66.1 ,ug of water can cause complete precipi-
`tation. Using conventional packaging means, it is therefore
`very difficult to exclude entry of such small quantities of
`moisture over storage periods of several years.
`
`Also, TTSs comprising the active substance estradiol
`have been on the market as therapeutic agents for climac—
`teric complaints, and, since a short time ago, also against
`osteoporosis; they have proved successful in therapy.
`In the following the term “estradiol” is to be understood '
`as the anhydrous substance of 17-[3-estradiol.
`A disadvantage of prior art systems is the insufficient
`capability of the active substance to permeate through the
`skin. This cannot be increased beyond a certain limit, the
`so-called “saturation flow”, although several galenic mea-
`sures with respect to the TTS-design have been taken (use of
`multilayer systems, use of controlling membranes, variation
`of the active substance concentration, modification of the
`base polymer, and the like). This finding that the transdermal
`flow of an active substance from the solid, finely dispersed
`phase cannot be increased further in principle, can already
`be found in the still trailblazing works of Higuchi (e.g., T.
`Higuchi; Physical Chemical Analysis of percutaneous
`absorption process from creams and ointments. J. Soc.
`Cosmetic Chem. 11, p. 85—97 (1990).
`The systems described in EP 0 421 454 comprise estradiol
`in an acrylic polymer under addition of “crystallization
`inhibitors” and tackifying resins. Swelling agents are con-
`tained to give protection against premature loss of adhesive
`force.
`
`25
`
`30
`
`35
`
`40
`
`In addition, with a lot of active substances, so-called
`“enhancers” can be added to the TTS during production.
`These are usually liquid admixtures improving the absorp-
`tion properties of human skin; for this reason, they allow the
`absorption of the active substance from a sufficiently small
`TTS-surface.
`
`Readily volatile enhancers, e.g., ethanol used for the
`active substance estradiol, particularly involve problems
`caused by an extreme softening of the TTSs’ adhesive
`layers, and they require additional bulky compartments in
`the system, rendering the TTS unacceptably thick.
`The addition of less volatile, however, mostly less active
`enhancers (e.g., glycerol esters, cyclic amides, eucalyptol)
`allows the production of matrix systems comprising active
`substances and an absorption-promoting component in one
`or several layers. However, the insufficient adhesive force of
`these TTSs is disadvantageous. U.S. Pat. No. 4 863 738
`represents one of many examples claiming the application of
`active substances, e.g., estradiol,
`together with a certain
`enhancer (in this case glycerol monooleate) in an optional
`TTS-matrix and in an optional concentration.
`However, even such a prior art TTS does not permit a
`satisfactory therapy either. The reason is that either the
`chosen enhancers are poorly tolerated by the skin or that the
`systems have unacceptably large surfaces owing to the still
`insufficient flow through the skin.
`
`45
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`50
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`60
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`65
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`

`

`3
`DESCRIPTION OF THE INVENTION
`
`5 ,902,602
`
`4
`EXAMPLES
`
`Example 1
`
`Accordingly, it is the object of the present invention to
`provide a transdermal
`therapeutic system comprising
`estradiol,
`that comprises a long-term protection against
`precipitation of the estradiol—semihydrate, said protection
`being incorporated in the active substance-containing layers
`themselves, and which prevents crystallization to the
`estradiol-semihydrate.
`
`Glycerol is a very polar compound and miscible with
`water in any ratio. Anhydrous glycerol is very hygroscopic
`and can be used as dehydrating agent under certain condi-
`tions. It can be demonstrated by way of experiments that its
`anhydrous form is able to remove crystal water from the
`estradiol-semihydrate. In this connection, the term “anhy-
`drous” or “substantially anhydrous or substantially free from
`water” is to be understood as a water content of less than 1%.
`
`If estradiof—semihydrate is stirred in anhydrous glycerol at
`room temperature for about 24 hours, the flat-shaped crys-
`tals of the semihydrate are converted into thin needles.
`These needles are either the anhydrous estradiol or an
`estradiol-glycerol-solvate. An addition of only 2% of water
`to the glycerol used for this test prevents this reaction. This
`clearly demonstrates that the species resulting during the
`reaction with anhydrous glycerol does not comprise any
`water.
`
`The above-mentioned embodiment of a TTS according to
`the present invention can be realized in different manners.
`The most simple form is a single-layer matrix system whose
`matrix simultaneously has a pressure-sensitive adhesive
`function, rendering a special adhesive layer superfluous. The
`glycerol dispersed in the matrix ensures an equilibrium-
`moisture content over the storage period that is low enough
`to render precipitation of the estradiol-semihydrate impos-
`sible.
`
`If the adhesive force of this layer is insufficient or if direct
`skin contact of this layer is to be avoided, the matrix may be
`laminated with a special skin adhesive layer.
`
`If a membrane which is hardly permeable to estradiol is
`introduced between such a matrix, which comprises estra-
`diol and water-binding disperse glycerol, and the adhesive
`layer, an active substance release is achieved which is
`controlled by the patch rather than by the skin.
`
`In addition to the wide-spread acrylic acid copolymers
`suitable for the use with estradiol, other polymers may also
`be used as base material, such as polyisobutylene, polyvinyl
`acetate and copolymers, synthetic rubber, block polymers of
`styrene and isoprene or of styrene and butadiene, and
`silicones.
`
`the characterizing feature of transdermal
`In any case,
`therapeutic systems according to the present invention is the
`presence of disperse, substantially anhydrous glycerol. In
`this connection, the exact amount of glycerol in the system
`must be chosen such that, on the one hand, the solubility of
`glycerol in the system is exceeded and that it is present as
`separate phase dispersed in small droplets, and, on the other
`hand, that the total moisture-binding capacity in the system
`is sufiicient. An addition in the range of 2 or even 1 percent
`may be considered as minimum amount; the upper limit is
`determined by mechanical values, such as flowability of the
`matrix, adhesive force, and processibility.
`In general, a
`proportion of 10 to 50 percent by weight, preferably between
`10 and 35 percent by weight is desired.
`
`2.0 g of 17-[3-estradiol-semihydrate, micronized is mixed
`with
`
`5
`
`2.75 g of anhydrous glycerol,
`25 g of an acrylic ester copolymer solution (solids content
`42%) and
`5.9 g of colophony-glycerol ester derivative (Staybelite
`Ester SE, of Hercules)
`and subsequently coated on a 100 ,um siliconized poly-
`ester film in such a manner that the coating weight
`amounts to 120 g/m2.
`The coating is dried at.25° C., at 50° C., at 80° C. and at
`95° C., each time for 10 minutes. A 10 um polyester film is
`immediately applied (laminated) on the dry layer under
`roller pressure, avoiding the formation of air bubbles.
`Transdermal systems of 16 cm2 are obtained by punching
`using a wad punch. These are immediately packed into
`moistureproof, heat—sealable bags.
`
`Example 2
`
`2.0 g of 17—[3—estradiol—semihydrate, micronized,
`60.0 g of Carifiex TR 1107® (styrene-isoprene block
`polymer),
`120.0 g of Staybelite Ester 5E (thermoplastic ester gum of
`colophony derivatives),
`50.0 g of viscous paraffin
`50.0 g of anhydrous glycerol
`are rendered molten in an evacuatable kneader at 130° C.
`
`and brought into an externally homogeneous form by means
`of kneading within ten hours.
`The melt is cooled down to 120° C.; in a continuous
`coating line it is subsequently coated onto a siliconized
`polyester film of 1 00 ,um thickness in such a manner that the
`weight per unit area amounts to 200 g/m2.
`Afterwards a polyester film 15 gm thick is applied
`(laminated) under roll pressure on the still hot layer, avoid-
`ing the formation of air bubbles.
`Transdermal systems of 16 cm2 are obtained by punching
`using a wad punch.
`We claim:
`1. A storage stable transdermal therapeutic system com-
`prising the active substance estradiol and having a layered
`structure of a backing layer which is impermeable to active
`substances and moisture, an active substance-containing
`matrix, wherein the matrix comprises at least 2% by weight
`of glycerol that has a maximum of 1%-wt. of water or is
`substantially free from water, said amount of said glycerol
`providing protection against precipitation of estriol semihy-
`drate during storage.
`2. A transdermal therapeutic system according to claim 1,
`wherein the matrix consists of several layers at least one
`layer comprising glycerol that has a maximum of 1%-wt. of
`water or is substantially free from water.
`3. Atransdermal therapeutic system according to claim 1,
`wherein the estradiol contained in the matrix is present as a
`dispersion of an anhydrous crystallizate.
`4. Atransdermal therapeutic system according to claim 1,
`wherein the base material of the matrix or of one of its layers
`is an acrylic-acid ester copolymer.
`5. Atransdermal therapeutic system according to claim 4,
`wherein the acrylic-acid ester copolymer has a solubility for
`the crystallizate of the estradiol of between 0.4 and 3.0%.
`6. A process for the production of a transdermal thera-
`peutic system according to claim 1 which comprises:
`
`10
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`15
`
`'
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`25
`
`30
`
`35
`
`40
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`45
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`50
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`55
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`60
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`65
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`

`

`5,902,602
`
`5
`
`a) preparing a suspension of estradiol-semihydrate and
`water-binding glycerol in a solution, dispersion, or melt
`of the matrix base material,
`b) coating a carrier foil with the suspension, and
`c) drying the applied layer by heating to 50 to 175° C. to
`convert estradiol-semihydrate into anhydrous estradiol.
`7. Aprocess according to claim 6, wherein the resulting
`transdermal therapeutic system is packed into a packaging
`means which can be sealed in a gas-tight manner and that a
`desiccant is additionally added to said package.
`8. Atransdermal therapeutic system according to claim 1,
`which contains in addition a removable protective layer
`covering the matrix.
`9. Atransdermal therapeutic system according to claim 1,
`wherein the matrix comprises between 10 and 50% by
`weight of glycerol that has a maximum of 1% wt, of water
`or is substantially free from water.
`10. A transdermal therapeutic system according to claim
`9, wherein the amount of glycerol is in the range from 10 to
`35% by weight.
`11. A storage stable transdermal therapeutic system com-
`prising the active substance estradiol and having a layered
`structure of a backing layer which is impermeable to active
`substances and moisture, an active substance-containing
`matrix, wherein the matrix contains at least 2% by weight of
`glycerol in disperse form that has a maximum of 1%-wt. of
`water or is substantially free from water.
`12. A transdermal therapeutic system according to claim
`11, wherein the amount of glycerol exceeds its solubility in
`
`6
`the system and the glycerol is present as a separate phase
`dispersed in small droplets therein.
`13. A transdermal therapeutic system according to claim
`11, wherein the matrix consists of several layers at least one
`layer comprising glycerol that has a maximum of 1%—wt. of
`water or is substantially free from water.
`14. A transdermal therapeutic system according to c aim
`11, wherein the estradiol contained in the matrix is present
`as a dispersion of an anhydrous crystallizate.
`15. A transdermal therapeutic system according to c aim
`11, wherein the base material of the matrix or of one of its
`layers is an acrylic-acid ester copolymer.
`16. A transdermal therapeutic system according to c aim
`15, wherein the acrylic-acid ester copolymer has a solubility
`for the crystallizate of the estradiol of between 0.4 and 3.0%.
`17. A transdermal therapeutic system according to c aim
`11, which contains in addition a removable protective layer
`covering the matrix.
`18. A transdermal therapeutic system according to c aim
`11, wherein the matrix comprises between 10 and 50% by
`weight of glycerol that has a maximum of 1%-wt. of water
`or is substantially free from water.
`19. A transdermal therapeutic system according to claim
`18, wherein the amount of glycerol is in the range from 10
`to 35% by weight.
`
`
`
`10
`
`15
`
`25
`
`