.
`Ulllted States Patent
`
`[19]
`
`IIIIIIIIIIIIIIlllIIIlllIIIllllllIIIIIIIIIIIIIIIIIIlllllllllllllllllllllll
`USOOSl45682A
`[11] Patent Number:
`
`5,145,682
`
`Chien et al.
`
`[45] Date of Patent:
`
`Sep. 8, 1992 _'
`
`[54] TRANSDERMAL ABSORPTION DOSAGE
`UNIT FOR POSTMENOPAUSAL
`SYNDROME TREATMENT AND PROCESS
`FOR ADMINISTRATION
`
`4,693,887
`4,906,169
`
`8/1987 Shah ................................. 424/sox
`3/1990 Chien et al.
`......................... 424/443
`
`Primary Examiner—Thurman K. Page
`Assistant Examiner—Leon R. Home
`
`[75]
`
`Inventors: Yie w. Chien, North Brunswick;
`Te-Yen Chien, Branchburg, both of
`NJ.
`
`[73] Assignee: Rutgers, The State University of New
`Jersey, New Brunswick, NJ.
`
`'
`
`[21] Appl- No.: 320,570
`_
`[22] F‘led‘
`
`M‘I' 8’ 1989
`
`[63]
`
`Related US‘ Application Data
`Continuation-in-part of Sex, No. 868,709, May 30,
`1986, Pat. No._ 4,883,669.
`Int. Cl.5 .............................................. A61F 13/02
`[51]
`[52] US. Cl. .................................... 424/448- 424/447
`_
`’ 424/446
`[53] Field of Search ........................ 424/448, 449, 447
`
`[56]
`
`Attorney, Agent. or Firm—Leroy 6- Sinn
`[57]
`ABSTRACT
`Transdermal absorption dosage units have been devel-
`oped for treatment of postmenopausal syndrome which
`comprise a backing layer, an adjoining adhesive poly-
`mer layer in which at least minimum effective daily
`doses of an estrogen is microdispersed. Presently pre-
`ferred is use of the natural estrogen,
`l7-beta-estradiol,
`or ethinyl estradiol or combinations thereof together
`with an amount of a natural progestogen or a progestin
`to minimize any potential side effects. The units use
`bioacceptable adhesive and polymers. An additional
`”we? layer in intimate mm“ With the ‘FStmgcn'
`containing layer can be used. Also, a separating layer
`can optionally be used in making the dosage units,
`WhiCh “Pam" “‘6 “V0 adheSiVC 1301”“ layers, “’hiCh
`permits estrogen transmission from the first adhesive
`References CitEd
`polymer layer during treatment. Dosage units are pro-
`U.S. PATENT DOCUMENTS
`vided which transdermally deliver at least minimum
`a arom ............................
`s
`,
`-
`.
`.
`3 896 934 12/1976 2 ff
`.
`daily doses of the estrogen for at least one day or for
`424/449
`4,053,580 10/1977 Chien et a1.
`‘
`multiple days, such as for one week. The invention also
`424/449
`
`4 291 014 9/1981 Keith 31 al
`provides a process for postmenopausal syndrome treat-
`424/486
`4,300,820 11/1981 Shah ....................
`.. 424/80 x mm “mg the “OVCI dosage “nits
`
`4,336,243
`6/1982 Sanvordeker et al.
`424/449
`.
`4,460,372
`8/1984 Campbell et al.
`................... 424/486
`
`20 Claims, 18 Drawing Sheets
`
`0.8
`
`0. 7
`
`0.6
`
`C. 5
`
`E. 4
`
`PERIEATION RATE
`
`(MEG/SI]. 01. HR 1 8.0.)
`U. 3
`
`0.2
`
`ENHANCING EFFECT OF ALKANOIC ACID (N THE
`HJMAN CADAVER SKIN PERPEATION RATE OF ESTRADIOL
`
`TRANSDERI‘IAL ESTRADIOL DELIVERY SYSTEM
`
`ADULT CAUCASIAN FEMALE MDAVER SKIN
`
`Z
`
`4
`
`5
`
`B
`
`10
`
`12
`
`14
`
`n in CH3 (CH2)HEODH
`
`  
`
`

 
`
`MYLAN - EXHIBIT 1009
`
`

`

`US. Patent
`
`Sep.8,l992
`
`Sheetl 0f18
`
`5,145,682
`
`FIG.
`
`1
`
`
`
`
`
`mzhzoo_u<u_oz<¥4<moFummmmwz_uz<Izm
`
`4<zmwnwz<mk Ao.m<mhmmmomhqm
`
`
`zo_H<mzmmmz_¥mmm><o<u2(231
`
`
`awkw>m>mw>H4mmJoHn<mHmm
`
`
`
`
`
`
`
`szwmm><n<um4<£wm2<Hm<u=<uH4=m<
`
`ém
`
`zooucnmzuvmxuc“cEn:mmVm
`
`m.D
`
`NAu
`
`m.D
`
`nH.D
`
`m.D
`
`h.D.
`
`m.D
`
`m.0
`
`v.0
`
`
`
`mh<zzo_p<u:=um
`
`
`
`A.=.wHz:.2;.amxcuzv
`
`

`

`US. Patent
`
`Sep. 8, 1992
`
`Sheet 2 of 18
`
`5,145,682
`
`FIG. 2
`
`
`
`m5:04023—.3moBurma02824170
`
`
`
`40.05pmmom.._.<m29.2.0szz§mmm><o<uz<zzx
`
`
`
`
`
`:52:3
`
`
`
`Swim;>mm>zma.522”.me45.05535.
`
`mmuz<IZm
`
`a;
`
`NH9mmem
`
`
`
`Iomxucfiwxuvmxucwc
`
`0.0
`
`5.0
`
`m.0
`
`Nd
`
`H0
`
`0.0
`
`
`
`a..0“:5.ZQCEZEm
`
`AddHz:.5.33qu
`
`

`

`US. Patent n
`
`Sep. 8, 1992
`
`Sheet 3 of 18
`
`5,145,682
`
`FIG.
`
`3
`
`
`
`
`
`JDIOUJ<J>umDIznoA333020Hh<mkzwuzou
`
`D.mm0.0mD.mND.DND.mmD.n:D.m
`
`0.0
`
`
`
`MI...2040100.4(4>UmolznoZOHH<mhszZDUnohuwuum
`
`
`
`
`
`JOHD<mHmwn5wh<mZDHH<wzmmmszmmm><D<U2523...
`
`
`
`
`
`E55>mw>3mn403<EwmJEmmamzéh
`
`
`
`25m523535m”.zfimfizfi:22
`
`
`
`
`
`.D.N
`
`m.“
`
`0.“
`
`Md
`
`Dd
`
`D.v
`
`m.m
`
`D.m
`
`
`
`m.N92:zoCfizEn.
`
`AddHz:.54&3qu
`
`

`

`US. Patent
`
`Sep. 8, 1992
`
`Sheet 4 of 18
`
`5,145,682
`
`FIG;
`
`4
`
`
`
`MI...20DZHD<DJUDmDn5Human—m
`
`
`
`JDHD<mkmwn5m._.<mZOEkmzmmn.Zwamm><n<uZ<EDI
`
`
`
`
`
`m.N
`
`D.Nm4DAWA...
`
`0.0
`
`
`
`m3\3NuDZHD<DJDamn
`
`
`
`
`
`5.55>mm>3mn4835mmqgmwnwz<mp
`
`
`
`
`
`235mm><a<uWEE”.2<Hw5=5.522
`
`mnz
`
`m4
`
`o.H
`
`m.o
`
`0.0
`
`04‘
`
`m.m
`
`o.m
`
`o.m.
`
`
`
`23..+.z:.5.832:m.mEé222%me
`
`
`

`

`US. Patent
`
`Sep. 8, 1992
`
`Sheet 5 of 18
`
`5,145,682
`
`FIG.
`
`5
`
`
`
`
`
`DZHF<DUnonmzomuuzvmmwzxumlh>KD
`
`0mmDomDmNDDNDmaDD“
`
`Dm
`
`4<zmmnmz<zh JDHD<mHmmnowh<m
`
`ZDHh<w2mmmmemmm><D<uZ<ZDI
`
`
`subm>m>mm>~4maJoma<zkmm
`
`
`
`D.
`
`A..wHm:.29.cw\ouzv
`
`m .
`
`N
`
`m.m
`
`D.m
`
`
`
`mp<¢chh<mzzmm
`
`nu.m
`
`m.v
`
`0.?_
`
`MIhZDUZHP<DUmommmZXUHIhuDhummum
`
`
`
`szwmm><n<um4<zmm.z<Hm<u=<uh4=n<
`
`

`

`US. Patent
`
`Sep. 8, 1992
`
`Sheet 6 of 18
`
`5,145,682
`
`FIG.
`
`6
`
`
`
`
`
`mm.._n_z<m>.:.:m<.pm20mmmwh<mZOHF<mzmmmZHXmJDHD<mHmw
`
`
`
`
`
`
`
`m:“L,NHn:mw.vNo
`
`Amy—mugwthDZHIEZ<m
`
`'l'lllllllal'lll'l'l‘llllllIIllllllll'llvll'llll'l'llll
`lllllllllllllllllllllllllllD.m
`
`
`
`Sukm>m>mw>HJwDJDHD<mHmmJ<Emmowz<mh
`
`dim...zoom
`
`0m.h
`
`D.m
`
`D.u.
`
`m.w
`
`.iD.m
`
`m.‘
`
`wh<mZDHh<wzmwQ
`
`z:.5.83qu
`
`

`

`US. Patent
`
`Sep. 8, 1992
`
`Sheet 7 of 18
`
`5,145,682
`
`FIG.
`
`7
`
`
`
`
`
`JDHD<mmenomeHqun.ZDHP<wzmwmmemmm><a<uZ<ZDI
`
`
`
`DmHDd;DNHOm:0m000%ON
`
`
`
`nmmDDIV>DDFmnoZDHF<KDD
`
`
`Euvmxm
`
`~.Mmepflm.omumtELouubmwQ
`
`0mm
`
`Dom
`
`0mm
`
`Dma
`
`On:
`
`am
`
`DON.5.8323
`
`0
`
`.55Hz:
`
`
`

`

`US. Patent
`
`Sep.8,1992
`
`Sheet 8 of 18
`
`5,145,682
`
`FIG .
`
`8
`
`
`
`
`
`mIHZOJDIDUJ<>Hk<uuDHumuumDZHUZ<IZm
`
`
`
`
`
`JDHO<mHmwJ>Z>Ihmnomh<mZDHF<wzmmlZmemm><D<UZ<EDI
`
`
`
`
`
`
`
`
`
`zmkm>m>mm>H4wnJoHn<mem4>z>=hm4<zmwnwz<mb
`
`
`
`
`
`maNHDHmw#N
`
`
`
`Iowxucnmzuvmxucfic
`
`
`
`szmmm><n<um4<£mmz<~m<u=<uH422<
`
`
`
`
`
`LT/,mmLHPZN
`
`4h=o=PHz
`
`m.0
`
`w.o
`
`H.o
`
`od
`
`m.0
`
`5.0
`
`m.o
`
`m.o
`
`v6
`
`
`
`B5.222ng
`
`23a.5..5.8).qu
`
`
`
`

`

`US. Patent
`
`Sep. 8, 1992
`
`Sheet 9 of 18
`
`5,145,682
`
`FIG. 9
`
`
`
`
`
`JDIDUuEJ>UwDIznon;\3NvZDHF<mkzwuZDu
`
`0.mm0.DM0.mNO.DN0.mH0.DH0.mD.
`
`D
`
`
`
`MI...20ADIDUJ<J>UlezLDZDHh<mkszZQUn5human—m
`
`
`
`
`5.55>mm>3ma4335mm._>z>=._.m_
`
`
`
`5%$355BEE555%52:
`
`
`
`45533:: JDHD<mhmwJ>Z>Ikmnowk<mZDHh<w£mmememw><D<uZ<SDI
`
`D .
`
`D
`
`md
`
`D .
`
`H
`
`Add+a:.5.838:
`
`m A
`
`D.N
`
`D
`
`.m
`
`m
`
`.N
`
`
`
`as.22525..
`
`

`

`US. Patent
`
`Sep. 8, 1992
`
`Sheet 10 of 18
`
`5,145,682
`
`FIG.
`
`10
`
`
`
`NIH20UZHD<DJUDmDnohumuum
`
`
`
`
`
`JDHD<mmeJ>Z>Ihmnowp<mZDHF<wzmmmZmemm><m<uZ<ZDI
`
`
`
`
`
`
`
`
`
`
`zmhw>w>mm>H4mn40Hn<mpmm4>2>=Hm4<zmwnmz<mh
`
`
`
`
`
`
`
`szmmm><n<um4<zmm2<Hm<u=<uF4=n<
`
`m.~.n..mm.“o.“m.oo.n.
`
`
`
`n;\3NvDZHD<DJDDKD
`
`m.H
`
`o.fi
`
`m.o
`
`n_.o
`
`D.¢
`
`m.m
`
`D.m
`
`rd
`
`nu.m
`
`
`
`m~<zzo__<wzzmm
`
`2.”Ha:.5.3285
`
`

`

`US. Patent
`
`Sep.8,1992
`
`Sheet 11 of 18
`
`5,145,682
`
`
`
`
`
`melz<m>PHJHm<Fmzomummh<mZDHH<mzmwmZmeJDHD<mmeJ>Z>Ihm
`
`
`
`
`
`
`
`
`
`FIG.
`
`11
`
`
`.amb<mZDHp<memm_.IIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIa.m
`
`
`I‘ll-III'IILIIllllllllllllllllllill-luluDov
`(lflllul‘C‘KmQv.1.«n,
`
`lfi/.‘plc‘v.‘I.5.OM\OUZV
`
`
`
`him:zoom0m6
`
`umvAV.H.mmCom
`
`m.m
`
`0.5
`
`am.m
`
`
`
`
`
`zwhm>m>mw>~4maJDHD<mhmwJ>Z>Ikw4<zmwomz<mh
`
`
`
`
`
`0“#~NHDHmw¢N‘D
`
`
`
`
`
`AmxmwzvwzHHUZHJm2<m
`
`D.m
`
`m.N
`
`D.N
`
`

`

`US. Patent
`
`Sep. 8, 1992
`
`Sheet 12 of 18
`
`5,145,682
`
`
`
`
`
`EmumxmxLo>u~ODHofinomewHOELwtmcoLhLoxoqlaLk
`
`
`
`
`
`
`
`
`
`mw><4wJDDHZ0mmADZ<QLDnommmszHIknohumuum
`
`
`
`JDHD<mhmmnoup<m20Hh<wzmwmmemmw><n<uZ<ZDIUIFZO
`
`w.u
`
`V.“
`
`N.H
`
`FIG. 12
`
`
`
` 2omnwph2mmn<mhmmm
`
`m.o
`
`m.o
`
`
`
`wh<mzo~h<w2mmm
`
`Add.+.a:.5.cmxouzv
`
`
`
`$258”.8meEfisgaQ1a;
`
`
`6,5852,58::83;O<
`
`
`
`$6625%“a3:825mmwzxumzp
`
`
`
`8m8...com.08on:o
`
`
`

`

`US. Patent
`
`Sep.8,1992
`
`Sheet 13 of 18
`
`5,145,682
`
`FIG.
`
`13
`
`mm><4szH JDHD<mkmmnomh<m
`
`
`ZOHH<mzmmmszmmm><D<U2(221NIHZD
`:upw>m>mw>~4mn40Hn<mhmm4<zmmnwz<mk
`
`
`
`
`
`
`
`
`szmmm><n<um4<zz<Hw<u=<uH4=n<
`
`e
`
`2/
`
`
`
`omumhbmen<mhwm
`
`
`
`
`
`mmuz<Izwm<mJDIDUJ<>hh<unoIHUZNJZH<IUnobumuum
`
`mAu
`
`m.o
`
`v.o
`
`NAu
`
`E;2252;.
`
`2.”H5..5.3285
`
`
`
`:owxucnmxuvmzucw:
`
`«aNHDHmmfiND
`
`

`

`US. Patent
`
`Sep. 8, 1992
`
`Sheet 14 of 18
`
`5,145,682
`
`FIG.
`
`14
`
`
`
`mwx>JDmm~o>mwmmmMIL.2HmmDDDZHD<DJ15:2”.thnohumuum
`
`
`
`
`
`
`
` /omumt.2mmo<Ewm
`
`
`
`
`
`JDHD<mHmmnom._.<m20Hk<mzmwmmemmw><n<u7.22:1NIHzo
`
`553an
`v.o8,33Hz:.5.585
`5.55>mw>3ma40Hn<mhmm4<zmmnwz<mh
`
`
`
`
`
`
`25552353%25523:22
`
`
`
`
`
`nzxxnvumoomcflnquHofinULumm
`
`D.mm.ND.Nm."04m.D0.0
`
`m.o.
`
`D.H
`
`m6
`
`m.D
`
`
`
`m._.<mZD—h<m_zmwn.
`
`

`

`US. Patent
`
`Sep.8,1992
`
`SheetlS of18
`
`5,145,682
`
`FIG.
`
`15
`
`
`
`omlmhpEmma<mbmm
`
`
`
`
`
`szwmm><n<uMJ<Ez<~w<u=<ungn<
`
`
`
`
`
`mm><4wmmzquzhmmmm:noAmzomufizv
`
`DomDonDomDom00¢DomDONDDHD
`
`
`
`
`
`mm><4Emma:DZHZH<PZDUImeZ<IzmnommmZXUHIPnohumuum
`
`
`
`
`
`JDHD<mHmwnowh<mZDHk<mzmmmZmemm><D<UZ<ZDINIHZD
`
`
`
`
`
`zwhm>m>mm>H4ma40Hn<mkwm4<zmwamz<mkmm><4nmmh
`
`
`
`
`
`O.”
`
`m.n_
`
`mu.D
`
`¢.D
`
`N.D
`
`0.0
`
`
`
`wh<mZD—h<wzmwm
`
`..=.mHz:.:u.cmxuuzv
`
`
`
`

`

`US. Patent
`
`Sep. 8, 1992
`
`Sheet 16 of 18
`
`5,145,682
`
`FIG. 16
`
`
`
`
`
`zmkm>w>mm>~4wn40Ha<mhmm4<2mmnwz<mhmw><41Hmh
`
`
`
`
`
`
`
`mm><4mull:m:»2HJDIDUJ<4>anlcnoZDHF<thwUZDUnoPumuum
`
`
`
`JDHD<mHmmnowh<mZDHh<w2mmmszmmw><D<U2(231thZD
`
`
`
`
`
`¢.n
`
`N.H
`
`0.“
`
`
`
`
`
`szmmm><n<um4<z2<Hw<u=<uk4:n<
`
`
`
`
`
`Jozou4<4>umnuznoA3\3Rvonh<mhzmuzou
`
`mmDmmNONm~DHmD
`
`e.
`
`_m.o
`
`#.D
`
`N.D
`
`
`
`
`
` ,2..”Hs..55285m.oBatEmfiEmwBEzEZmzmma
`
`

`

`US. Patent
`
`Sep.8,1992
`
`Sheet 17 of 18
`
`5,145,682
`
`FIG.
`
`17
`
`
`
`JQHD<mhmmnomudmuommZDHh<mzmwQZHXmmm><D<UZ<ZDI
`
`
`
`
`
`ON“
`
`DDH0m0m0*ON
`
`
`
`Amazozv>Q=HmnoonH<m=n
`
`
`
`
`
`szwmw><n<um4<zz<Hm<u=<up4=o<
`
`\
`
`
`
`.mEEEO8-”:EmfifimmOEEG$3-3
`
`
`
`0.0m
`
`Dgun
`
`Dgum
`
`0gum
`
`0Au?
`
`n_.Dm
`
`n_.DN
`
`n_.DH
`
`n_.o
`
`A.:.wHz:
`
`.zo..cw\wuzv
`
`a
`
`

`

`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.
`
`10
`
`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 polymer in
`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
`means of effecting transdermal absorption has been to
`distribute the pharmaceutical within a polymeric disc or
`a container of a 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 and to realize a greater pharma-
`ceutical efficiency. It is possible, by proper transdermal
`absorption, to reduce the frequency of effective closing.
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`Transdermal administration provides most of the ad-
`vantages of intravenous dosing without the necessity of
`hospitalization and the accompanying discomfort and
`inconvenience.
`The estrogenic steroid estradiol is an illustration of a
`pharmaceutical in which great loss of orally adminis-
`tered estrogen occurs by first-pass through the liver, 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 transdermal 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 more reasons is not naturally
`producing to provide adequate levels in women to 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-
`placement estrogenic 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
`estradiol itself 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 of benefits
`would result.
`
`SUMMARY OF 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 components of the adhesive polymer disc
`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 polymer disc 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 [0 microns. It is understood
`that some minor amount by weight of the transdermal
`absorption enhancing agent component can be present
`in microreservoirs having diameters somewhat lesser or
`greater than the above referred 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 polymer layer containing the estrogen steroid.
`This adhesive layer can contain one or more effective
`transdermal 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
`polymer layer and the adhesive layer which has present
`an effective amount of 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
`polymer layer, 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, work in a satisfactory manner in 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 of estradiol, 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 more readily’than 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
`compound and bioconverts efficiently, 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 of estra-
`diol. Also, one estrogenic steroid either in the form of
`the basic compound or derivative such as a bioconverti-
`ble ester, or combinations thereof, can be combined
`with another steroid which has a different efficacy, such
`as a progestogen or a synthetic progestin, in a suitable
`amount in order to minimize potential side effect of the
`estrogenic postmenopausal syndrome therapy.
`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 Tween 60, 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 surfactant in 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 polymer layers 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 polymer layer 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 Factor of at
`least 1.2, preferably at least 1.3, and more preferably at‘
`least about 1.5. Enhancing Factor is defined as the ratio
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`5
`of normalized permeation rate [in mcg/cmz/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 invention also is a process for administering said 5
`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
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`FIG. 18 is a photomicrograph at 635 X 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 made of 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 formed so that 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 manner that 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 layer are films of high and low density polyethylene,
`polypropylene, polyvinylchloride, polyesters such as
`poly(ethylene phthalate), metal foils, metal foil lami-
`nates of such suitable polymer films, and the like. Pref-
`erably,
`the materials used for the backing layer are
`laminates of such polymer films with a metal foil such as
`aluminum foil. In such laminates, a polymer film 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 made using a silicone
`based pressure sensitive adhesive, such as a (polydime-
`thylsiloxane-silicate resin) copolymer adhesive depicted
`by the following formula:
`
`RO
`
`H
`ROSiOR
`R
`0
`O
`O
`Si-O—Si—O—Si-O
`
`Me
`Me
`O—Si "*O—Si-O
`
`Me
`
`Me
`
`at
`
`O
`H
`
`0
`R
`
`0
`R
`
`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 polymer layers.
`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 X74920 medical adhesives, are
`suitable for use in making the adhesive layer. The adhe-
`sive polymer must be biologically acceptable and chem-
`ically compatible with the pharmaceuticals and the
`transdermal absorption enhancing agents. Certain poly-
`acrylic adhesive polymers in the form of an alkyl ester,
`amide, free acid, or the like or polyisobutylene adhesive
`polymers can also be used with some pharmaceuticals
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`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-decyl alcohol in a dosage unit on the human ca-
`daver skin permeation rate of estradiol.
`FIG. 4 is a graph showing the effect 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 35
`alkanols in a dosage unit on the human cadaver skin
`permeation rate of ethinyl estradiol as a function of
`alkyl chain length.
`FIG. 9 is a graph showing the effect of concentration
`of n-decyl alcohol in a dosage unit on the human ca-
`daver skin permeation rate of ethinyl estradiol.
`FIG. 10 is a graph showing the 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 polymer layer 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 showmg 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 55
`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 upper layer 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.
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`FIG. 17 is a graph comparing human cadaver skin
`permeation profiles of estradiol from a Rutgers tri-layer
`dosage unit as compared to Estraderm.
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`

`7
`utilized in the dosage units. Illustrative of suitable adhe-
`sive polymers for use in making the adhesive polymer
`layer are shown by the following formulas:
`
`5,145,682
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`Polyisobutylene Adhesive
`
`r13
`(ii—CH2
`CH3
`
`x
`
`Polyacrylic Adhesive
`
`wherein x represents the number of repeating units
`sufficient to provide the desired properties in the adhe-
`sive polymer and R is H or lower alkyl including ethyl,
`butyl and 2-ethylhexyl.
`pressure-sensitive
`Other
`suitable
`hypoallergenic
`contact adhesive compositions can also be used. A pre-
`ferred adhesive layer is pressure sensitive.
`The adhesive means then is finally covered in con-
`ventional therapeutic practice with a releasable protec-
`tive film layer which is made from materials which are
`substantially impermeable to the pharmaceutical, the
`transdermal absorption enhancing agent and any other
`components of the dosage unit. The polymer materials
`and metal foil laminates used for the backing layer can
`be used to make the protective layer, provided the layer
`is made strippable or releasable such as by applying
`conventional siliconizing. A suitable releasable material
`for use with silicone polymer adhesive DC-355 and
`X7—2970 is Scotch Pak 1022 material sold by the 3M
`Company or Bio-Release material sold by Dow Cor-
`ning.
`In making the dosage units, the estrogen-containing
`adhesive layer can be made by dispersing an amount of
`estradiol crystals in an adhesive solution. For example,
`two parts of estradiol crystals can be added and dis-
`persed in 98 parts of a biocompatible polyacrylate solu-
`tion such as sold under the designation Duro-Tak
`80—1054 by National Starch and Chemical Co.
`(has
`about 36% w/w of solid adhesive). An airtight con-
`tainer can be used for the mixing. The mixture can be
`made homogeneous by gently rotating the container.
`The estradiol-containing mixture can then be readily
`coated onto a drug-impermeable backing layer such as a
`composite sold under the designation Scotch Pak 1109
`by 3M Company. Coating equipment unit can be used
`to coat the backing layer to a desired thickness. A
`coater found satisfactory has been a Werner Mathis
`Laboratory Coater Type LTSV with built-in Labora-
`tory drier LTF. The thickness of the estradiol-adhesive
`layer can be accurately controlled to a desired thick-
`ness, such as to 400 microns, using such a designed
`coater-drier.
`If desired, an amount of a material progestogen can
`be added to the above mixture of estradiol and adhesive
`solution. The amount added will depend upon the
`amount desired in the estradiol-containing layer. The
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`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 amount desired 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 per part 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 amount of 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 agent suitably is biocompatible and
`chemically compatible with the drugs used. A suitable
`enhancing agent for this use has been found to be n-
`decyl alcohol, a liquid