United States Patent 5
`Chien et al.
`
`AUTCAAATA
`
`US005145682A
`{11} Patent Number:
`[45] Date of Patent:
`
`5,145,682
`Sep. 8, 1992
`
`[54] TRANSDERMAL ABSORPTION DOSAGE
`UNIT FOR POSTMENOPAUSAL
`SYNDROME TREATMENT AND PROCESS
`FOR ADMINISTRATION
`
`[75]
`
`Inventors:
`
`Yie W. Chien, North Brunswick;
`Te-Yen Chien, Branchburg, both of
`N.J.
`
`[73] Assignee:
`
`Rutgers, The State University of New
`Jersey, New Brunswick, N.J.
`
`(21)
`
`[22]
`
`Appl. No.:
`Filed:
`
`320,570
`
`Mar. 8, 1989
`
`Related U.S. Application Data
`Continuation-in-part of Ser. No. 868,709, May 30,
`1986, Pat. No. 4,883,669.
`Int. C15 oo cece ceeereneeeeeeeees A61F 13/02
`US, Ch.
`.eeeeescteesetereetersserenenees 424/448; 424/447;
`424/449
`Field of Search ............00.00.. 424/448, 449, 447
`References Cited
`
`(63)
`
`[S1]
`[52]
`[58]
`[56]
`
`U.S. PATENT DOCUMENTS
`
`3,896,934 12/1976 Zaffaromi «oo... ecsceeerere 424/449
`4,053,580 10/1977 Chien et al.
`.
`wee 424/449
`
`4,291,014 9/1981 Keith etal. .
`wee 424/486
`
`4,300,820 11/1981 Shah 0...
`
`wee
`4,336,243
`6/1982 Sanvordekeretal. .
`4,460,372
`8/1984 Campbell et al. ........ cee 424/486
`
`4,693,887
`4,906,169
`
`8/1987 Shah ..scssscscsussesssseseseen 424/80 X
`3/1990 Chien et al.
`....ccsesusessen: 424/448
`
`Primary Examiner—Thurman K. Page
`Assistant Examiner—Leon R. Horne
`Attorney, Agent, or Firm—Leroy G. Sinn
`
`ABSTRACT
`[57]
`Transdermal absorption dosage units have been devel-
`oped for treatment of postmenopausal syndrome which
`comprise a backing layer, an adjoining adhesive poly-
`merlayer in which at least minimum effective daily
`doses of an estrogen is microdispersed. Presently pre-
`ferred is use of the natural estrogen, 17-beta-estradiol,
`or ethinyl estradiol or combinations thereof together
`with an amountof a natural progestogen or a progestin
`to minimize any potential side effects. The units use
`bioacceptable adhesive and polymers. An additional
`polymer layer in intimate contact with the estrogen-
`containing layer can be used. Also, a separating layer
`can optionally be used in making the dosage units,
`which separate the two adhesive polymerlayers, which
`permits estrogen transmission from the first adhesive
`polymer layer during treatment. Dosage units are pro-
`vided which transdermally deliver at least minimum
`daily doses of the estrogen for at least one day or for
`multiple days, such as for one week. The invention also
`provides a process for postmenopausal syndrometreat-
`ment using the novel dosage units.
`
`20 Claims, 18 Drawing Sheets
`
`ENHANCING EFFECT OF ALKANOIC ACID ON_THE
`TRADI OL
`HUMAN CAD,
`ES
`AVER SKIN PERMEATION RATE OF
`
`TRANSDERMAL ESTRADIOL DELIVERY SYSTEM
`
`ADULT CAUCASIAN FEMALE CADAVER SKIN
`
`PERMEATION RATE
`
`c. 4
`
`(MCG/SQ. CM. HR + S.D,)
`0.3
`
`WITHOUT
`ENHANCER
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`4
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`10
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`MYLAN- EXHIBIT 1009
`
`

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`
`US. Patent
`
`Sep. 8, 1992
`
`Sheet 1 of 18
`
`5,145,682
`
`
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`

`U.S. Patent
`
`Sep. 8, 1992
`
`Sheet 2 of 18
`
`5,145,682
`
`FIG. 2
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`

`

`U.S. Patent —
`
`Sep. 8, 1992
`
`Sheet 3 of 18
`
`5,145,682
`
`FIG.
`
`3
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`
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`

`U.S. Patent
`
`Sep. 8, 1992
`
`Sheet 4 of 18
`
`5,145,682
`
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`U.S. Patent
`
`Sep. 8, 1992
`
`Sheet 5 of 18
`
`5,145,682
`
`FIG.
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`5
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`

`U.S. Patent
`
`Sep. 8, 1992
`
`Sheet 6 of 18
`
`5,145,682
`
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`

`

`U.S. Patent
`
`Sep. 8, 1992
`
`Sheet 7 of 18
`
`5,145,682
`
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`
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`

`U.S. Patent
`
`Sep. 8, 1992
`
`Sheet 8 of 18
`
`5,145,682
`
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`

`U.S. Patent
`
`Sep. 8, 1992
`
`Sheet 9 of 18
`
`5,145,682
`
`
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`

`U.S. Patent
`
`Sep. 8, 1992
`
`Sheet 10 of 18
`
`5,145,682
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`

`U.S. Patent
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`Sep. 8, 1992
`
`Sheet 11 of 18
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`5,145,682
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`

`U.S. Patent
`
`Sep. 8, 1992
`
`Sheet 12 of 18
`
`5,145,682
`
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`USS. Patent
`
`Sep. 8, 1992
`
`Sheet 14 of 18
`
`5,145,682
`
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`U.S. Patent
`
`Sep. 8, 1992
`
`Sheet 15 of 18
`
`5,145,682
`
`FIG.
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`15
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`U.S. Patent
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`Sep. 8, 1992
`
`Sheet 16 of 18
`
`5,145,682
`
`FIG. 16
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`

`U.S. Patent
`
`Sep. 8, 1992
`
`Sheet 17 of 18
`
`5,145,682
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`

`U.S. Patent
`
`Sep. 8, 1992
`
`Sheet 18 of 18
`
`5,145,682
`
`FIG. 18
`
`
`
`

`

`1
`
`5,145,682
`
`TRANSDERMAL ABSORPTION DOSAGE UNIT
`FOR POSTMENOPAUSAL SYNDROME
`TREATMENT AND PROCESS FOR
`ADMINISTRATION
`
`CROSS-REFERENCE TO RELATED
`APPLICATIONS
`
`This application is a continuation-in-part of U.S. ap-
`plication Ser. No. 06/868,709, filed May 30, 1986 U.S.
`Pat. No. 4,883,669.
`
`TECHNICAL FIELD
`
`This invention relates to a novel transdermal absorp-"
`tion dosage unit adapted for postmenopausal syndrome
`treatment comprising a backing layer and an adjoining
`layer of a biologically acceptable adhesive polymerin
`which estradiol or another steroidal pharmaceutical
`having estrogenic activity is microdispersed in mi-
`croreservoirs formed of selected transdermal absorp-
`tion enhancing agents. The adhesive layer provides the
`means by which the dosage unit adheres to the skin of
`the subject being administered said estrogenic pharma-
`ceutical and permits transdermal absorption of said
`estrogenic pharmaceutical. An amount of a progestin
`can also be incorporated into the adhesive polymer
`layer to diminish any side effects encountered in post-
`menopausal syndrome treatment. Additionally, the in-
`vention relates to an improved process for administra-
`tion in postmenopausal syndrome treatment.
`BACKGROUND ART
`
`It has been found that certain pharmaceuticals are
`absorbed to a degree through the skin. This is referred
`to as
`transdermal pharmaceutical absorption. One
`meansof effecting transdermal absorption has been to
`distribute the pharmaceutical within a polymeric disc or
`a container ofa gel, which is brought into contact with
`an area of the skin of the subject to be treated with the
`pharmaceutical. Also, ointments or lotions containing a
`desired pharmaceutical have been applied to an area of
`the skin of the subject to be treated. Problems encoun-
`tered in such treatment include inadequate control over
`the rate and duration of transdermal absorption or the
`rate can be too slow in the case of certain dosage forms,
`especially from pharmaceutical-containing discs or
`pharmaceutical-containing gel container dosage units or
`pads. It has been found that the transdermal absorption
`rates of certain pharmaceuticals can be increased by use
`of transdermal absorption enhancing agents with the
`pharmaceutical to be absorbed when compounding the
`polymeric disc or the pharmaceutical-containing gel.
`It is desired to improve the dosage unit forms or
`devices by which pharmaceuticals are transdermally
`absorbed, especially in view of the importance of ad-
`ministration of pharmaceuticals by this means. Desired
`transdermal absorption of pharmaceuticals would pro-
`vide an avoidance of gastrointestinal
`incompatibility
`with the pharmaceuticals and unwanted destruction of
`the pharmaceutical by metabolism in the gastrointesti-
`nal tract and by a “first pass” hepatic metabolism. The
`transdermal absorption minimizes inter- and intra-
`patient variations regarding such incompatibilities and
`metabolisms. By transdermal absorption, it is deemed
`possible to provide more constant pharmaceutical con-
`centration in the body andto realize a greater pharma-
`ceutical efficiency. It is possible, by proper transdermal
`absorption, to reduce the frequencyofeffective dosing.
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`Transdermal administration provides most of the ad-
`vantagesof intravenous dosing without the necessity of
`hospitalization and the accompanying discomfort and
`inconvenience.
`The estrogenic steroid estradiolis an illustration of a
`pharmaceutical in which great loss of orally adminis-
`tered estrogen occurs by first-pass through theliver, it
`being almost completely metabolized. Therefore, oral
`administration of estradiol is not a satisfactory means of
`replacing normal levels of estradiol. It has been found
`that by transderma! administration, estradiol can be
`provided, in only a fraction of the amount required in
`oral dosing,
`to achieve adequate levels of estradiol,
`which the body for one or morereasonsis not naturally
`producing to provide adequate levels in womento pre-
`vent body conditions and symptoms caused by such
`inadequate levels. Also, by transdermal administration
`of estradiol, for example, the unwanted estradiol metab-
`olites produced by first-pass hepatic metabolism are
`greatly reduced. An additional advantage of trans-
`dermal administration is the attainment of more con-
`stant levels of estradiol and other estrogenic steroids.
`The need for estradiol replacement therapy is caused
`by menopause (the cessation of ovarian function), ooph-
`orectomy(loss of one or both ovaries by surgery) or by
`pituitary failure. Replacement estrogenic therapy is an
`important need. Besides the need to alleviate the meno-
`pausal symptoms caused by estrogenic steroid defi-
`ciency, there are additional contributions of such re-
`placementestrogenic therapy associated with osteopor-
`osis (loss of bone mass) and atherosclerosis. There is
`clearly a need for improvements in means and methods
`for postmenopausal syndrome and other estrogenic
`steroid therapy. Even though it has been found that
`estradiolitself or estradiol in the form of certain deriva-
`tives such as mono-or di-esters (e.g., acetate esters) can
`be absorbed transdermally, it is desired that improved
`transdermal estradiol and other estrogenic steroid ab-
`sorption dosage unit forms and processes of transdermal
`administration be developed. A number ofbenefits
`would result.
`
`SUMMARYOF INVENTION
`
`This invention relates to a transdermal dosage unit for
`treatment of postmenopausal syndrome having the fol-
`lowing:
`a) a backing layer which is substantially impervious
`to an effective estrogen to be delivered transder-
`mally from the adhesive polymer disc layer and
`any other componentsof the adhesive polymerdisc
`layer; and
`b) an adhesive layer which is adhered to said backing
`layer and which had dispersed therein in- mi-
`croreservoirs an effective amount of an estrogen
`effective in treatment of postmenopausal
`syn-
`drome, said adhesive polymers being biocompati-
`ble, compatible with said estrogen and permitting
`said estrogen to be transdermally absorbed; said
`adhesive polymer disc layer having one or more
`transdermal absorption enhancing agents microdis-
`persed therein, said transdermal absorption agent
`or agents selected from biocompatible compounds
`having at least six carbon atoms and which are
`capable of forming microreservoirs during micro-
`dispersion with said adhesive polymer and estrogen
`to encapsulate said estrogen in said adhesive poly-
`mer used to make said adhesive polymerdisc layer
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`3
`and being substantially insoluble or insoluble in
`water;
`said dosage unit capable of delivering a dosage amount
`of said estrogen for at least seven successive days.
`The microreservoirs suitably have diameters in the
`range of from about 1 to about 150 microns and desir-
`ably from about 2 to about 10 microns.It is understood
`that some minor amount by weight of the transdermal
`absorption enhancing agent component can be present
`in microreservoirs having diameters somewhatlesser or
`greater than the abovereferred to ranges so long as the
`effectiveness of the dosage units provided by this inven-
`tion is retained.
`The adhesive polymer layer also adheres the dosage
`unit in intimate contact with the skin of the subject
`being treated to permit the estrogen to be absorbed
`transdermally.
`Optionally, an additional adhesive layer can be
`formed using the same or a different adhesive polymer
`which is also biocompatible and placed in intimate
`contact with the surface of the estrogen-containing
`adhesive polymerlayer containing the estrogen steroid.
`This adhesive layer can contain one or more effective
`transderma! absorption enhancing agents or be free of
`these agents.
`Optionally, another layer can be included in the dos-
`age units between the estrogen-containing adhesive
`polymerlayer and the adhesive layer which has present
`an effective amountof one or more enhancing agents.In
`this separating layer,
`it is preferable to have present
`little or no estrogen, progestin or enhancing agents. The
`separating layer can be made using adhesive polymers
`such as used in making the estrogen-containing adhesive
`polymerlayer, for example, with a bioacceptable poly-
`isobutylene or polyacrylic adhesive, which permits the
`estrogen in the layer to be transmitted for transdermal
`absorption being presently preferred. Additionally,it is
`presently preferred that the separating layer be free of
`any substantial amount of transdermal absorption en-
`hancing agent.
`The estrogen-containing adhesive polymer layer can
`alternatively be made with the estrogen such as estra-
`diol present in microdispersed form without substantial
`use of the transdermal absorption enhancing agents
`described above.
`The backing layer is made from materials that are
`substantially impermeable with regard to the pharma-
`ceuticals of the transdermal dosage unit. It can be made
`of polymers such as polyethylene, polypropylene, poly-
`vinylchloride, polyesters such as poly(ethylene phthal-
`ate), and foils such as laminates of polymer films with
`metallic foils such as aluminum foil.
`The estrogen-containing adhesive layer is suitably
`fabricated from biologically acceptable adhesive poly-
`mers, such as a suitable polyacrylic adhesive polymers,
`silicone adhesive polymer or a polyisobutylene adhe-
`sive. The estrogen is suitably dispersed in the adhesive
`polymer. For example,
`it has been found suitable to
`form a mixture with a biocompatible, liquid transdermal
`absorption enhancing agent. It has been found in many
`cases that certain straight-chain saturated alkanols, such
`as n-decyl alcohol, workin a satisfactory mannerin the
`mixture of estrogen and adhesive polymer. The adhe-
`sive polymer is added to the mixture of estrogen and
`n-decyl alcohol and the resulting combination is mixed
`and dispersed thoroughly. The estrogen-adhesive poly-
`mer mixture is applied as a thin layer to the backing
`layer and is dried. Care must be taken that the adhesive
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`polymer selected is compatible with the estrogen and
`other active pharmaceuticals, permits their release for
`transdermal absorption and is free or sufficiently free
`from any biologically unacceptable components.
`A suitable derivative of estradiol or other estrogenic
`steroids used in formulating the polymer matrix disc
`layer is commonly an ester which is biologically com-
`patible and can be absorbed effectively transdermally.
`Also,it is ordinarily desired that such esters are biocon-
`vertible by components of the skin or other portions of
`the body such as hydrolytical enzymes(e.g., esterase) to
`estradiol or other desired estrogenic steroid. If the de-
`rivative is an ester, the derivative can be a mono- or
`di-ester if the estrogenic steroid has two esterifiable
`groups. In the case ofestradiol, it has hydroxy groups at
`the 3- and 17- positions and therefore the 3-mono and
`17-mono as well as the 3,17 diesters can be made by
`generally known esterification methods. Some ester
`derivatives will be absorbed morereadilythan the basic
`estradiol or other estrogenic steroid. In selection of
`ester derivatives,it is ordinarily preferred that the ester
`derivative be absorbed more effectively than the basic
`compoundand bioconvertsefficiently, after absorption,
`to estradiol or other basic estrogenic steroid used. Val-
`erate mono- and di-esters of estradiol are presently con-
`sidered to be desirable esters. In formulating the adhe-
`sive layer, it is desirable at times to utilize two or more
`pharmaceuticals, such as the combination of a estradiol
`ester, like estradiol valerate, with an amount ofestra-
`diol. Also, one estrogenic steroid either in the form of
`the basic compound orderivative such as a bioconverti-
`ble ester, or combinations thereof, can be combined
`with anothersteroid which has a differentefficacy, such
`as a progestogen or a synthetic progestin, in a suitable
`amountin order to minimize potential side effect of the
`estrogenic postmenopausal syndrometherapy.
`It has been found suitable to add the natural progesto-
`gen, progesterone, or a synthetic progestin, such as
`levonorgestrel, in an appropriate amount to the estro-
`gen-adhesive mixture used in making the adhesive layer.
`It has further been found to be advantageous to add
`effective amounts of selected surfactants, such as bi-
`ocompatible non-ionic surfactants sold under the desig-
`nations Tween 20 and Tween60, to the combination of
`estrogen such as estradiol and transdermal absorption
`enhancing agent, such as n-decyl alcohol. The amount
`of such surfactant used can vary. However, an amount
`of such surfactantin the range of 0.25 to 1 part based on
`100 parts of the final estrogin-adhesive mixture used to
`form the adhesive layer has been found satisfactory.
`The adhesive polymerlayers can be formed by spray-
`ing or by solvent casting or laminating. The concentra-
`tion of transdermal absorption enhancing agent, if em-
`ployed, can be reduced in the portion of the adhesive
`polymer layer means, especially if less than desired
`adhesion is realized in the adhesive layer, by applying
`the surface portion of the adhesive layer separately
`wherein the adhesive composition has a lower concen-
`tration of transdermal absorption enhancing agent. The
`adhesive polymerlayer is desirably thin in the micron-
`range thickness, suitably 10-200 microns in thickness,
`desirably about 20 to 180 microns, and preferably about
`30 to 150 microns in thickness.
`The absorption rate of the transdermal pharmaceuti-
`cal absorption dosage units of the invention can be
`increased, such as by having an Enhancing Factorofat
`least 1.2, preferably at least 1.3, and more preferably at’
`least about 1.5. Enhancing Factoris defined as the ratio
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`of normalized permeation rate [in mcg/cm?/hr] of a
`dosage unit of this invention with transdermal absorp-
`tion enhancing agent/the normalized permeation rate of
`a corresponding dosage unit without enhancer.
`The inventionalso is a process for administering said
`estrogen with or without added natural progestogen or
`synthetic progestin by applying said dosage unit to the
`skin of the subject to be treated, whereby said pharma-
`ceuticals are transdermally administered to said subject
`to treat menopausal syndrome.
`BRIEF DESCRIPTION OF THE DRAWINGS
`
`FIG. 1 is a graph showing the enhancing effect of
`alkanoic acid in a dosage unit on the human cadaver
`skin permeation rate of estradiol.
`FIG. 2 is a graph showing the enhancing effect of
`alkanol in a dosage unit on the human cadaver skin
`permeation rate of estradiol as a function of alkyl chain
`length.
`FIG. 3 is a graph showing the effect of concentration
`of n-decy] alcohol in a dosage unit on the human ca-
`daver skin permeation rate of estradiol.
`FIG.4 is a graph showingtheeffect of drug loading
`in a dosage unit on the human cadaver skin permeation
`rate of estradiol.
`FIG.5 is a graph showing the effect of thickness of
`coating in a dosage unit on the human cadaver skin
`permeation rate of estradiol.
`FIG.6 is a graph showing estradiol skin permeation
`rates from dosage unit stability samples.
`FIG. 7 is a graph comparing human cadaver skin
`permeation profiles of estradiol absorbed from the Rut-
`gers dosage units as compared to Estraderm TTS-SO.
`FIG. 8 is a graph showing the enhancing effect of
`alkanols in a dosage unit on the human cadaver skin
`permeation rate of ethinyl estradiol as a function of
`alky! chain length.
`FIG.9 is a graph showing the effect of concentration
`of n-decy] alcohol in a dosage unit on the human ca-
`daver skin permeation rate of ethinyl! estradiol.
`FIG.10 is a graph showingthe effect of drug loading
`in a dosage unit on the human cadaver skin permeation
`rate of ethinyl estradiol.
`—
`FIG. 11 is a graph of ethinyl estradiol skin perme-
`ation rates from dosage unit stability samples.
`FIG. 12 is a graph showing, in a dosage unit, the
`effect of thickness of an adhesive polymerlayer separat-
`ing the adhesive polymer drug reservoir layer and an
`enhancer-containing adhesive polymer layer designed
`for contact with skin of subject.
`FIG. 13 is a graph showing the effect of the chain
`length of alkanols as enhancer in a dosage unit on the
`human cadaver skin permeation rate of estradiol.
`FIG. 14 is a graph showing the effect of estradiol
`loading dose in the reservoir adhesive polymer layer of
`a dosage unit on the human cadaver skin permeation
`rate of estradiol. .
`FIG.15 is a graph showing the effect of the thickness
`of enhancer-contanining upperlayer in a dosage unit on
`the human cadaver skin permeation rate of estradiol.
`FIG. 16 is a graph showing the effect of concentra-
`tion of n-decyl alcohol in the upper layer of a dosage
`unit on the human cadaver skin permeation rate of estra-
`diol.
`FIG. 17 is a graph comparing human cadaverskin
`permeation profiles of estradiol from a Rutgerstri-layer
`dosage unit as compared to Estraderm.
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`FIG.18 is a photomicrograph at 635 magnification
`of a section of an adhesive polymer drug reservoir layer
`showing transdermal absorption enhancer microreser-
`voirs containing drug (estradiol).
`DETAILED DESCRIPTION OF THE
`INVENTION AND THE PREFERRED
`EMBODIMENTS
`
`The backing layer can be madeof any suitable mate-
`rial which is impermeable to the pharmaceuticals dis-
`persed within the adjacent adhesive polymer layer. The
`backing layer serves as a protective cover for the estro-
`gen-containing adhesive layer and provides also a sup-
`port function. The backing can be formedsothat it is
`essentially the same size layer as the estrogen-contain-
`ing adhesive layer or it can be of larger dimension so
`that it can extend beyond the side of the estrogen-con-
`taining adhesive layer or overlay the side or sides of the
`estrogen-containing adhesive layer and then can extend
`outwardly in a mannerthat the surface of the extension
`of the backing layer can be a base for an adhesive to
`hold the dosage unit in intimate contact with the skin of
`the subject treated.
`Examples of materials suitable for making the back-
`ing layerarefilms of high and low density polyethylene,
`polypropylene, polyvinylchloride, polyesters such as
`poly(ethylene phthalate), metal foils, metal foil lami-
`nates of such suitable polymerfilms, and the like. Pref-
`erably,
`the materials used for the backing layer are
`laminates of such polymerfilms with a metal foil such as
`aluminum foil. In such laminates, a polymerfilm of the
`laminate will usually be in contact with polymer matrix
`layer. The backing layer can be any appropriate thick-
`ness which will provide the desired protective and sup-
`port functions. A suitable thickness will be from about
`10 to about 200 microns. Desirably, the thickness will be
`from about 15 to about 150 microns, and preferably be
`from about 20 to about 100 microns.
`The adhesive layers are suitably madeusing a silicone
`based pressure sensitive adhesive, such as a (polydime-
`thylsiloxane-silicate resin) copolymer adhesive depicted
`by the following formula:
`
`Ro
`
`O
`H
`ROSiIOR
`R
`oO
`6)
`oO
`Si-O—Si—-0Si0.
`|?
`Oo
`oO
`H
`R
`R
`
`Me
`Me
`O-Si---O— SiO:
`Me
`Me
`
`x
`
`Linear Polydimethylsiloxane
`
`Silicate Resin
`
`wherein Me is methyl and R is -Si(CH3)3 and x and y
`represent independent numbers of repeating units suffi-
`cient to provide the desired properties in the adhesive
`polymer and other polymerlayers.
`For example, adhesive polymer products or amine-
`resistant adhesive polymer products sold by Dow Cor-
`ning, such as the ones sold under the designations of
`DC-355, Bio-PSA and X7-2920 medical adhesives, are
`suitable for use in making the adhesive layer. The adhe-
`sive polymer mustbe biologically acceptable and chem-
`ically compatible with the pharmaceuticals and the
`transdermal! absorption enhancing agents. Certain poly-
`acrylic adhesive polymers in the form ofan alkyl ester,
`amide,free acid, or the like or polyisobutylene adhesive
`polymers can also be used with some pharmaceuticals
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`utilized in the dosage units. Illustrative of suitable adhe-
`sive polymers for use in making the adhesive polymer
`layer are shownby the following formulas:
`
`8
`progestogen can be progesterone or other suitable com-
`pound within the class.
`Instead of a natural progestogen, a synthetic proges-
`tin can be incorporated into the estradiol-adhesive solu-
`tion prior to its use in coating.
`The amount of the progestogen or progestin will
`depend on the estrogen used and the amountdesired to
`diminish any toxic side effects. It has been found suit-
`able, for example, to use about 1.0 to about 10 parts of
`progesterone perpart of estradiol or about 0.5 to about
`5 parts of a progestin such as levonorgestrel per part of
`estradiol used. If another estrogen is used, the amount of
`progestogen or progestin will be adjusted as necessary
`to provide a proper amountof the progestogen or pro-
`gestin per part of estrogen.
`Additionally, an effective amount of a transdermal
`absorption enhancing agent can be incorporated into
`the estradiol-adhesive solution used in the coating pro-
`cess. The enhancing agentsuitably is biocompatible and
`chemically compatible with the drugs used. A suitable
`enhancing agent for this use has been found to be n-
`wherein x represents the number of repeating units
`decy] alcohol, a liquid enhancing agent that is not re-
`sufficient to provide the desired properties in the adhe-
`moved in the normal coating and drying procedure for
`sive polymer andRis H or loweralkyl including ethyl,
`forming the estradiol-adhesive layer. If n-decy] alcohol
`25
`butyl and 2-ethylhexyl.
`is used as the enhancing agent, the amountcan be varied
`pressure-sensitive
`Other
`suitable
`hypoallergenic
`depending upon the enhancement desired,
`the drugs
`contact adhesive compositions can also be used. A pre-
`used, and other factors. Ordinarily, a suitable amount
`ferred adhesive layer is pressure sensitive.
`can be selected from a range of about 1 part to 25 parts
`The adhesive means then is finally covered in con-
`based on 100 parts of the adhesive polymer weight.
`ventional therapeutic practice with a releasable protec-
`Other enhancing agents can be used instead of n-
`tive film layer which is made from materials which are
`decyl alcohol. Other suitable agents have been found to
`substantially impermeable to the pharmaceutical, the
`be n-octanol, lauryl alcohol, caprylic acid, capric acid,
`and lauric acid. Other suitable agents will be suggested
`transdermal absorption enhancing agent and any other
`to those having skill in art in view of the disclosures
`components of the dosage unit. The polymer materials
`hereof.
`and metal foil laminates used for the backing layer can
`The estradiol-adhesive layer can be either covered
`be used to makethe protective layer, provided the layer
`with a suitable release liner (a poly(ethylene phthalate)
`is made strippable or releasable such as by applying
`laminated with aluminum foil) or a Teflon-coated poly-
`conventional siliconizing. A suitable releasable material
`ester film such as sold underthe designation Scotch-Pak
`for use with silicone polymer adhesive DC-355 and
`1022 (by 3M) or Bio-release X7-2741 or X7-2752 (by
`X7-2970 is Scotch Pak 1022 material sold by the 3M
`Dow Corning). The poly(ethylene phthalate) side to
`Company or Bio-Release material sold by Dow Cor-
`which the adhesive-enhancer-progestin coating is ap-
`ning.
`plied, is made strippable by conventional siliconizing or
`In making the dosage units, the estrogen-containing
`by other suitable means. The thickness of the adhesive-
`adhesive layer can be made by dispersing an amountof
`enhancer-progestin layer normally is suitably about 20
`estradio] crystals in an adhesive solution. For example,
`to about 1000 microns, preferably about 50 to about 500
`two parts of estradiol crystals can be added and dis-
`microns.
`persed in 98 parts of a biocompatible polyacrylate solu-
`the estradiol-adhesive layer can be
`Alternatively,
`tion such as sold under the designation Duro-Tak
`covered with an adhesive layer which contains an
`