United States Patent m
`Chien et al.
`
`US005145682A
`[ii] Patent Number:
`[45] Date of Patent:
`
`5,145,682
`Sep. 8,1992
`
`[75]
`
`[54] TRANSDERMAL ABSORPTION DOSAGE
`UNIT FOR POSTMENOPAUSAL
`SYNDROME TREATMENT AND PROCESS
`FOR ADMINISTRATION
`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] Appl. No.: 320,570
`Mar. 8,1989
`Filed:
`[22]
`
`Related U.S. Application Data
`Continuation-in-part of Ser. No. 868,709, May 30,
`1986, Pat. No, 4,883,669.
`Int. a.5
`U.S. CI.
`
`[63]
`
`[51]
`[52]
`
`A61F 13/02
`424/448; 424/447;
`424/449
`424/448, 449, 447
`
`[58] Field of Search
`References Cited
`[56]
`U.S. PATENT DOCUMENTS
`3,896,934 12/1976 Zaffaroni
`4,053,580 10/1977 Chien et al
`4,291,014 9/1981 Keith et al
`4,300,820 11/1981 Shah
`4,336,243 6/1982 Sanvordeker et al
`4,460,372 8/1984 Campbell et al
`
`. 424/449
`. 424/449
`. 424/486
`424/80 X
`. 424/449
`,. 424/486
`
`424/80 X
`.. 424/448
`
`4,693,887 8/1987 Shah
`4,906,169 3/1990 Chien et al
`Primary Examiner—Thurman K. Page
`Assistant Examiner—Leon R. Home
`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
`mer layer 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 amount of 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 polymer layers, 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 syndrome treat­
`ment using the novel dosage units.
`
`20 Claims, 18 Drawing Sheets
`
`0. B
`
`0. 7
`
`0. 6
`
`G. 5
`
`PERMEATION RATE
`
`G. 4
`(MCG/SU. CM. MR ± S.D.)
`0. 3 -
`
`WITHOUT
`" 3IHANCES
`\
`
`0. 2
`
`0. 1
`
`G. 0
`
`ENHANCING EFFECT OF ALKAN0IC ACID ON THE
`HUMAN CADAVER SKIN PERtCATION RATE OF ESTRADIOL
`
`TRANSDERMAL ESTRADIOL DELIVERY SYSTEM
`
`N - 3
`
`ADULT CAUCASIAN FEMALE CADAVER SKIN
`
`2
`
`6
`4
`8
`10
`n in CH3CCHs)nC00H
`
`12
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`14-
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`  
`
`

 
`
`MYLAN - EXHIBIT 1009
`
`

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`WITHOUT
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`0. 1
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`H
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`O
`I M
`
`N = 3
`
`TRANSDERMAL ESTRADIOL DELIVERY SYSTEM
`
`HUMAN CADAVER SKIN PERMEATION RATE OF ESTRADIOL
`
`ENHANCING EFFECT OF ALKANOIC ACID ON THE
`
`0. 3
`(MCG/S(1. CM. MR ± S.D.)
`C. 4
`
`PERMEATION RATE
`
`•. 5
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`
`0. 7
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`0. 6
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`

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`WITHOUT
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`H O
`
`I
`
`N - 3
`
`TRANSDERMAL ESTRADIOL DELIVERY SYSTEM
`
`HUMAN CADAVER SKIN PERMEATION RATE OF ESTRADIOL
`
`ENHANCING EFFECT OF AUOWCl ON THE
`
`0. 3
`(MC6/SQ. CM. HR + S.D.)
`
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`

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`
`TRANSDERMAL ESTRADIOL DELIVERY SYSTEM
`
`HUMAN CADAVER SKIN PERMEATION RATE OF ESTRADIOL
`EFFECT OF CONCENTRATION OF N-DECYL ALCOHOL ON THE
`
`2. 0
`(MCG/SQ. CM. HR + S.D.)
`PERMEATION RATE 2. 5
`
`3. 0
`
`3. 5
`
`4. 0
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`CONCENTRATION (Xw/w) OF N-DECYL ALCOHOL
`
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`20. 0
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`10. 0
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`DRUG LOADING <X w/w)
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`TRANSDERMAL ESTRADIOL DELIVERY SYSTEM
`
`HUMAN CADAVER SKIN PERMEATION RATE OF ESTRADIOL
`
`EFFECT OF DRUG LOADING ON THE
`
`0. 0
`
`0. 0
`
`0- 5
`
`1. 0
`
`1. 5
`
`2. 0
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`
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`250
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`
`ADULT CAUCASIAN FEMALE CADAVER SKIN
`
`i
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`100
`
`i
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`50
`
`0. 0
`
`0. 5
`
`1. 0
`
`1. 5
`
`N = 3
`
`TRANSDERMAL ESTRADIOL DELIVERY SYSTEM
`
`HUMAN CADAVER SKIN PERMEATION RATE OF ESTRADIOL
`
`EFFECT OF THICKNESS OF COATING ON THE
`
`2. 0
`(MCG/SQ. CM. HR ± S.D.)
`2. 5
`
`PERMEATION RATE
`
`3. 0
`
`3. 5
`
`4. 0 -
`
`4. 5
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`5. 0
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`14
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`12
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`10
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`8
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`6
`i
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`4
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`TRANSDERMAL ESTRADIOL DELIVERY SYSTEM
`
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`3. 0
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`3. 5
`
`4. 0
`
`4. 5
`
`5. 0
`
`5. 5
`
`6. 0 ~
`
`(MC6/SQ. CM. HR
`
`PERMEATION RATE
`
`A 45 C
`. • 37 C
`o ROOM TEMP.
`
`ESTRADIOL SKIN PERMEATION RATES FROM STABILITY SAMPLES
`
`6. 5
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`7. 0
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`7. 5
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`DURATION OF STUDY
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`160
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`1
`
`140
`
`120
`1
`
`100
`1
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`80
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`60
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`N = 3
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`
`HUMAN CADAVER SKIN PERMEATION PROFILES OF ESTRADIOL
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`50
`
`100
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`150
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`ADULT CAUCASIAN FEMALE CADAVER SKIN
`
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`
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`w
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`0. 0
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`0. 1
`
`0. 2
`
`N = 3
`
`0. 3
`(MCG/SQ. CM. HR ± S.D.)
`0. 4
`
`PERMEATION RATE
`
`0. 5
`
`0. 6
`
`0. 7
`
`TRANSDERMAL ETHYNYL ESTRADIOL DELIVERY SYSTEM
`
`HUMAN CADAVER SKIN PERMEATION RATE OF ETHYNYL ESTRADIOL
`
`ENHANCING EFFECT OF FATTY ALCOHOL ON THE
`
`O. 8
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`

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`10. 0
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`ADULT CAUCASIAN FEMALE CADAVER SKIN
`
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`1
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`15. 0
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`0. 0 L
`
`0. 5
`
`1. 0
`
`(MCG/SQ. CM. HR ± S.D.)
`1. 5
`
`PERMEATION RATE
`
`N - 3
`
`2. 0
`
`2. 5
`
`TRANSDERMAL ETHYNYL ESTRADIOL DELIVERY SYSTEM
`
`HUMAN CADAVER SKIN PERMEATION RATE OF ETHYNYL ESTRADIOL
`
`EFFECT OF CONCENTRATION OF N-DECYL ALCOHOL ON THE
`
`3. 0
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`
`DRUG LOADING (% w/w)
`
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`N = 3
`
`TRANSDERMAL ETHYNYL ESTRADIOL DELIVERY SYSTEM
`
`1.5
`(MCG/SQ. CM. HR + S.D.)
`2. 0
`
`PERMEATION RATE
`
`2. 5
`
`3. 0
`
`3. 5
`
`4. 0
`
`HUMAN CADAVER SKIN PERMEATION RATE OF ETHYNYL ESTRADIOL
`
`EFFECT OF DRUG LOADING ON THE
`
`

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`
`A 45 C
`37 C
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`
`2. 0
`2. 5
`3. 0
`3. 5
`4. 0
`4. 5
`PERMEATION RATE
`5. 0
`5. 5
`6. 0
`6. 5
`7. 0
`ETHYNYL ESTRADIOL SKIN PERMEATION RATES FROM STABILITY SAMPLES
`
`SAMPLING TIME (WEEKS)
`
`14
`i
`TRANSDERMAL ETHYNYL ESTRADIOL DELIVERY SYSTEM
`
`12
`i
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`8
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`
`THICKNESS (microns) OF OPPANOL B80
`
`1
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`500
`
`400
`
`300
`1
`
`200
`
`i
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`100
`1
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`H*
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`ESTRADERM TTS-50
`
`(D
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`N - 3
`
`A POLYACRYLATE RESERVOIR POLYMER
`• SILICONE RESERVOIR POLYMER
`
`Tri-layor Transdermal Estradiol Dal ivory System
`
`ON THE HUMAN CADAVER SKIN PERMEATION RATE OF ESTRADIOL
`
`EFFECT OF THICKNESS OF OPPANOL B80 MIDDLE LAYER
`
`0
`
`0. 0
`
`0.2
`
`0. 4
`0. 6
`(MC6/SQ. CM. HR ± S.D.)
`0.8 r
`
`PERMEATION RATE
`1. 0
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`1.2
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`1. 4 r
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`1.6
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`i
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`8
`i
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`10
`
`ADULT CAUCASIAN MALE CADAVER SKIN
`
`4
`x
`
`2
`
`0
`
`0. 0
`
`0. 2
`
`ESTRADERM TTS-50
`
`\
`
`0
`
`N - 3
`
`0. 4
`(MCG/SQ. CM. HR ± S,D.)
`
`PERMEATION RATE
`
`0. 6
`
`TRI-LAYER TRANSDERMAL ESTRADIOL DELIVERY SYSTEM
`
`ON THE HUMAN CADAVER SKIN PERMEATION RATE OF ESTRADIOL
`EFFECT OF CHAIN LENGTH OF FATTY ALCOHOLS AS ENHANCER
`
`0.8
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`

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`ADULT CAUCASIAN MALE CADAVER SKIN
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`0. 5
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`i
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`0. 0
`
`0. 0
`
`0. 2
`
`0. 4
`
`N - 3
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`(MCG/SQ. CM. HR+S.D,)
`0. 6
`PERMEATION RATE
`0.8
`
`Estradiol Loading Dosa (ZW/W)
`1. 0
`3. 0
`
`2. 5
`
`2. 0
`i
`
`1.5
`i
`
`ON THE HUMAN CADAVER SKIN PERMEATION RATE OF ESTRADIOL
`EFFECT OF ESTRADIOL LOADING DOSE IN THE RESERVOIR POLYMER
`
`1. 0
`
`TRI-LAYER TRANSDERMAL ESTRADIOL DELIVERY SYSTEM
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`

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`ESTRADERM TTS-50
`
`\
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`i
`
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`
`N - 3
`
`TRI-LAYER TRANSDERMAL ESTRADIOL DELIVERY SYSTEM
`
`ON THE HUMAN CADAVER SKIN PERMEATION RATE OF ESTRADIOL
`EFFECT OF THICKNESS OF ENHANCER-CONTAINING UPPER LAYER
`
`THICKNESS (MICRONS) OF UPPER LAYER
`
`100 200 300 400 500 600 700 800
`
`0
`
`0. 0
`
`0. 2
`
`0. 4
`(MCG/SQ. CM. HR ± S.D.)
`PERMEATION RATE
`
`0. 5
`
`0.8
`
`1.0
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`

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`
`CONCENTRATION (%W/W) OF N-DECYL ALCOHOL
`
`35
`i
`
`<D
`
`30
`i
`
`25
`i
`
`ADULT CAUCASIAN MALE CADAVER SKIN
`
`20
`i
`
`15
`i
`
`M cr>
`
`o
`M
`
`ESTRADERM TTS-50
`
`10
`i
`
`5
`i
`
`0
`
`0.0
`
`0.2
`0. 4
`
`N - 3
`
`0.6
`(MCG/SQ. CM. HR ± S.D.)
`0. 8
`PERMEATION RATE
`1. 0
`
`1.2
`
`1. 4
`EFFECT OF CONCENTRATION OF n-DECYL ALCOHOL IN THE UPPER LAYER
`
`ON THE HUMAN CADAVER SKIN PERMEATION RATE OF ESTRADIOL
`
`TRI-LAYER TRANSDERMAL ESTRADIOL DELIVERY SYSTEM
`
`

`

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`in V# OS
`H*
`en
`
`V#
`
`00
`
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`h-»
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`CO
`
`VO
`v©
`00
`
`C/5
`
`9
`P
`•a
`cc
`d
`
`DURATION OF STUDY (HOURS)
`
`120
`
`100
`i
`
`80
`
`ADULT CAUCASIAN MALE CADAVER SKIN
`
`60
`1
`
`40
`
`20
`L
`
`0
`0.0 U&
`
`M
`
`o
`M
`
`PK
`
`C)
`
`N - 3
`
`# ESTRADERd 775-50
`O RUTGERS' TRI-UYER SYSTEM
`
`HUMAN CADAVER SKIN PERMEATION PROFILES OF ESTRADIOL
`
`10. 0
`
`20. 0
`
`30. 0
`
`40. 0
`
`50. 0
`
`60.0
`
`70.0 -
`
`80. 0
`
`HR ± S.D.)
`(MCG/SQ. CM.
`
`Q
`
`

`

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

`

`5
`
`15
`
`30
`
`5,145,682
`
`'
`
`•
`
`1
`TRANSDERMAL ABSORPTION DOSAGE UNIT
`FOR POSTMENOPAUSAL SYNDROME
`TREATMENT AND PROCESS FOR
`ADMINISTRATION
`
`2
`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
`CROSS-REFERENCE TO RELATED
`tered estrogen occurs by first-pass through the liver, it
`APPLICATIONS
`being almost completely metabolized. Therefore, oral
`This application is a continuation-in-part of U.S. ap-
`administration of estradiol is not a satisfactory means of
`plication Ser. No. 06/868,709, filed May 30, 1986 U.S. 10 replacing normal levels of estradiol. It has been found
`that by transdermal administration, estradiol can be
`Pat. No. 4,883,669.
`provided, in only a fraction of the amount required in
`TECHNICAL FIELD
`oral dosing, to achieve adequate levels of estradiol,
`This invention relates to a novel transdermal absorp­
`which the body for one or more reasons is not naturally
`tion dosage unit adapted for postmenopausal syndrome
`producing to provide adequate levels in women to pre­
`treatment comprising a backing layer and an adjoining
`vent body conditions and symptoms caused by such
`layer of a biologically acceptable adhesive polymer in
`inadequate levels. Also, by transdermal administration
`which estradiol or another steroidal pharmaceutical
`of estradiol, for example, the unwanted estradiol metab­
`having estrogenic activity is microdispersed in mi-
`olites produced by first-pass hepatic metabolism are
`croreservoirs formed of selected transdermal absorp- 2°
`greatly reduced. An additional advantage of trans­
`tion enhancing agents. The adhesive layer provides the
`dermal administration is the attainment of more con-
`means by which the dosage unit adheres to the skin of
`stant levels of estradiol and other estrogenic steroids.
`the subject being administered said estrogenic pharma­
`The need for estradiol replacement therapy is caused
`ceutical and permits transdermal absorption of said
`by menopause (the cessation of ovarian function), ooph­
`estrogenic pharmaceutical. An amount of a progestin 25
`orectomy (loss of one or both ovaries by surgery) or by
`can also be incorporated into the adhesive polymer
`pituitary failure. Replacement estrogenic therapy is an
`layer to diminish any side effects encountered in post­
`important need. Besides the need to alleviate the meno­
`menopausal syndrome treatment. Additionally, the in­
`pausal symptoms caused by estrogenic steroid defi­
`vention relates to an improved process for administra­
`ciency, there are additional contributions of such re­
`tion in postmenopausal syndrome treatment.
`placement estrogenic therapy associated with osteopor­
`osis (loss of bone mass) and atherosclerosis. There is
`BACKGROUND ART
`clearly a need for improvements in means and methods
`It has been found that certain pharmaceuticals are
`for postmenopausal syndrome and other estrogenic
`absorbed to a degree through the skin. This is referred
`steroid therapy. Even though it has been found that
`to as transdermal pharmaceutical absorption. One 35
`estradiol itself or estradiol in the form of certain deriva-
`means of effecting transdermal absorption has been to
`tives such as mono- or di-esters (e.g., acetate esters) can
`distribute the pharmaceutical within a polymeric disc or
`be absorbed transdermally, it is desired that improved
`a container of a gel, which is brought into contact with
`transdermal estradiol and other estrogenic steroid ab-
`an area of the skin of the subject to be treated with the
`.
`pharmaceutical. Also, ointments or lotions containing a 40 sorption dosage unit forms and processes of transdermal
`administration be developed. A number of benefits
`desired pharmaceutical have been applied to an area of
`would result.
`the skin of the subject to be treated. Problems encoun­
`tered in such treatment include inadequate control over
`SUMMARY OF INVENTION
`the rate and duration of transdermal absorption or the
`This invention relates to a transdermal dosage unit for
`rate can be too slow in the case of certain dosage forms, 45
`treatment of postmenopausal syndrome having the fol­
`especially from pharmaceutical-containing discs or
`lowing:
`pharmaceutical-containing gel container dosage units or
`a) a backing layer which is substantially impervious
`pads. It has been found that the transdermal absorption
`to an effective estrogen to be delivered transder­
`rates of certain pharmaceuticals can be increased by use
`mally from the adhesive polymer disc layer and
`of transdermal absorption enhancing agents with the 50
`any other components of the adhesive polymer disc
`pharmaceutical to be absorbed when compounding the
`layer; and
`polymeric disc or the pharmaceutical-containing gel.
`b) an adhesive layer which is adhered to said backing
`It is desired to improve the dosage unit forms or
`layer and which had dispersed therein in- mi-
`devices by which pharmaceuticals are transdermally
`croreservoirs an effective amount of an estrogen
`absorbed, especially in view of the importance of ad- 55
`effective in treatment of postmenopausal syn­
`ministration of pharmaceuticals by this means. Desired
`drome, said adhesive polymers being biocompati­
`transdermal absorption of pharmaceuticals would pro­
`ble, compatible with said estrogen and permitting
`vide an avoidance of gastrointestinal incompatibility
`said estrogen to be transdermally absorbed; said
`with the pharmaceuticals and unwanted destruction of
`adhesive polymer disc layer having one or more
`the pharmaceutical by metabolism in the gastrointesti- 60
`transdermal absorption enhancing agents microdis­
`nal tract and by a "first pass" hepatic metabolism. The
`persed therein, said transdermal absorption agent
`transdermal absorption minimizes inter- and intra-
`or agents selected from biocompatible compounds
`patient variations regarding such incompatibilities and
`metabolisms. By transdermal absorption, it is deemed
`having at least six carbon atoms and which are
`capable of forming microreservoirs during micro-
`possible to provide more constant pharmaceutical con- 65
`dispersion with said adhesive polymer and estrogen
`centration in the body and to realize a greater pharma­
`ceutical efficiency. It is possible, by proper transdermal
`to encapsulate said estrogen in said adhesive poly­
`absorption, to reduce the frequency of effective dosing.
`mer used to make said adhesive polymer disc layer
`
`

`

`•
`.
`
`5,145,682
`3
`4
`polymer selected is compatible with the estrogen and
`and being substantially insoluble or insoluble in
`other active pharmaceuticals, permits their release for
`water;
`transdermal absorption and is free or sufficiently free
`said dosage unit capable of delivering a dosage amount
`from any biologically unacceptable components.
`of said estrogen for at least seven successive days.
`A suitable derivative of estradiol or other estrogenic
`The microreservoirs suitably have diameters in the 5
`steroids used in formulating the polymer matrix disc
`range of from about 1 to about 150 microns and desir­
`layer is commonly an ester which is biologically com­
`ably from about 2 to about 10 microns. It is understood
`patible and can be absorbed effectively transdermally.
`that some minor amount by weight of the transdermal
`Also, it is ordinarily desired that such esters are biocon-
`absorption enhancing agent component can be present
`in microreservoirs having diameters somewhat lesser or 10 vertible by components of the skin or other portions of
`greater than the above referred to ranges so long as the
`the body such as hydrolytical enzymes (e.g., esterase) to
`effectiveness of the dosage units provided by this inven-
`estradiol or other desired estrogenic steroid. If the de-
`tion is retained. rivative
`is an ester, the derivative can be a mono- or
`The adhesive polymer layer also adheres the dosage
`di-ester if the estrogenic steroid has two esterifiable
`unit in intimate contact with the skin of the subject 15 groups. In the case of estradiol, it has hydroxy groups at
`the 3- and 17- positions and therefore the 3-mono and
`being treated to permit the estrogen to be absorbed
`17-mono as well as the 3,17 diesters can be made by
`transdermally.
`generally known esterification methods. Some ester
`Optionally, an additional adhesive layer can be
`derivatives will be absorbed more readily than the basic
`formed using the same or a different adhesive polymer
`which is also biocompatible and placed in intimate 20 estradiol or other estrogenic steroid. In selection of
`contact with the surface of the estrogen-containing
`ester derivatives, it is ordinarily preferred that the ester
`adhesive polymer layer containing the estrogen steroid.
`derivative be absorbed more effectively than the basic
`This adhesive layer can contain one or more effective
`compound and bioconverts efficiently, after absorption,
`transdermal absorption enhancing agents or be free of
`to estradiol or other basic estrogenic steroid used. Val-
`these agents.
`25 erate mono- and di-esters of estradiol are presently con-
`Optionally, another layer can be included in the dos-
`sidered to be desirable esters. In formulating the adhe-
`age units between the estrogen-containing adhesive
`sive layer, it is desirable at times to utilize two or more
`polymer layer and the adhesive layer which has present
`pharmaceuticals, such as the combination of a estradiol
`an effective amount of one or more enhancing agents. In
`ester, like estradiol valerate, with an amount of estra-
`this separating layer, it is preferable to have present 30 diol. Also, one estrogenic steroid either in the form of
`little or no estrogen, progestin or enhancing agents. The
`the basic compound or derivative such as a bioconverti-
`separating layer can be made using adhesive polymers
`ble ester, or combinations thereof, can be combined
`such as used in making the estrogen-containing adhesive
`with another steroid which has a different efficacy, such
`polymer layer, for example, with a bioacceptable poly-
`as a progestogen or a synthetic progestin, in a suitable
`isobutylene or poly acrylic adhesive, which permits the 35 amount in order to minimize potential side effect of the
`estrogen in the layer to be transmitted for transdermal
`estrogenic postmenopausal syndrome therapy,
`absorption being presently preferred. Additionally, it is
`It has been found suitable to add the natural progesto-
`presently preferred that the separating layer be free of
`gen, progesterone, or a synthetic progestin, such as
`any substantial amount of transdermal absorption en-
`levonorgestrel, in an appropriate amount to the estro-
`hancing agent.
`40 gen-adhesive mixture used in making the adhesive layer.
`The estrogen-containing adhesive polymer layer can
`It has further been found to be advantageous to add
`alternatively be made with the estrogen such as estra-
`effective amounts of selected surfactants, such as bi-
`diol present in microdispersed form without substantial
`ocompatible non-ionic surfactants sold under the desig-
`use of the transdermal absorption enhancing agents
`nations Tween 20 and Tween 60, to the combination of
`described above.
`45 estrogen such as estradiol and transdermal absorption
`The backing layer is made from materials that are
`enhancing agent, such as n-decyl alcohol. The amount
`substantially impermeable with regard to the pharma-
`of such surfactant used can vary. However, an amount
`ceuticals of the transdermal dosage unit. It can be made
`of such surfactant in the range of 0.25 to 1 part based on
`of polymers such as polyethylene, polypropylene, poly-
`100 parts of the final estrogin-adhesive mixture used to
`vinylchloride, polyesters such as poly(ethylene phthal- 50 form the adhesive layer has been found satisfactory,
`The adhesive polymer layers can be formed by spray­
`ate), and foils such as laminates of polymer films with
`metallic foils such as aluminum foil.
`ing or by solvent casting or laminating. The concentra­
`The estrogen-containing adhesive layer is suitably
`tion of transdermal absorption enhancing agent, if em­
`fabricated from biologically acceptable adhesive poly­
`ployed, can be reduced in the portion of the adhesive
`mers, such as a suitable polyacrylic adhesive polymers, 55 polymer layer means, especially if less than desired
`silicone adhesive polymer or a polyisobutylene adhe­
`adhesion is realized in the adhesive layer, by applying
`sive. The estrogen is suitably dispersed in the adhesive
`the surface portion of the adhesive layer separately
`polymer. For example, it has been found suitable to
`wherein the adhesive composition has a lower concen­
`form a mixture with a biocompatible, liquid transdermal
`tration of transdermal absorption enhancing agent. The
`absorption enhancing agent. It has been found in many 60 adhesive polymer layer is desirably thin in the micron-
`cases that certain straight-chain saturated alkanols, such
`range thickness, suitably 10-200 microns in thickness,
`as n-decyl alcohol, work in a satisfactory manner in the
`desirably about 20 to 180 microns, and preferably about
`mixture of estrogen and adhesive polymer. The adhe­
`30 to 150 microns in thickness.
`sive polymer is added to the mixture of estrogen and
`The absorption rate of the transdermal pharmaceuti-
`n-decyl alcohol and the resulting combination is mixed 65 cal absorption dosage units of the invention can be
`and dispersed thoroughly. The estrogen-adhesive poly­
`increased, such as by having an Enhancing Factor of at
`least 1.2, preferably at least 1.3, and more preferably at
`mer mixture is applied as a thin layer to the backing
`least about 1.5. Enhancing Factor is defined as the ratio
`layer and is dried. Care must be taken that the adhesive
`
`

`

`5,145,682
`
`15
`
`20
`
`25
`
`30
`
`•
`.
`
`T Me
`
`Me
`—Si—O—Si—O
`Me
`Me
`
`Linear Polydimethylsiloiume
`
`R
`O
`R ROSiOR H
`O
`O
`O
`Si—O—Si—O—Si—O
`o
`O
`O
`R
`R
`Silicate Resin
`
`6
`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-
`10 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-
`35 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:
`
`5
`of normalized permeation rate [in nicg/cm2/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
`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-50.
`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
`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- 40
`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- 45
`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 so
`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.
`wherein Me is methyl and R is -Si(CH3)3 and x and y
`FIG. 14 is a graph showing the effect of estradiol 55 represent independent numbers of repeating units suffi-
`loading dose in the reservoir adhesive polymer layer of
`cient to provide the desired properties in the adhesive
`a dosage unit on the human cadaver skin permeation
`polymer and other polymer layers,
`rate of estradiol.
`For example, adhesive polymer products or amine-
`FIG. 15 is a graph showing the effect of the thickness
`resistant adhesive polymer products sold by Dow Cor-
`of enhancer-contanining upper layer in a dosage unit on 60 ning, such as the ones sold under the designations of
`the human cadaver skin permeation rate of estradiol.
`DC-355, Bio-PSA and X7-2920 medical adhesives, are
`FIG. 16 is a graph showing the effect of concentra-
`suitable for use in making the adhesive layer. The adhe-
`tion of n-decyl alcohol in the upper layer of a dosage
`sive polymer must be biologically acceptable and chem-
`unit on the human cadaver skin permeation rate of estra-
`ically compatible with the pharmaceuticals and the
`diol.
`65 transdermal absorption enhancing agents. Certain poly-
`FIG. 17 is a graph comparing human cadaver skin
`acrylic adhesive polymers in the form of an alkyl ester,
`permeation profiles of estradiol from a Rutgers tri-layer
`amide, free acid, or the like or polyisobutylene adhesive
`dosage unit as compared to Estraderm.
`polymers can also be used with some pharmaceuticals
`
`

`

`.
`
`Polyisobutylene Adhesive
`
`CH3
`
`C—CH2—
`
`5
`
`CH3
`
`Polyacrylic Adhesive
`
`H
`I
`CH2—c
`I c=o
`I o
`I
`H
`
`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
`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 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
`10 progesterone per part of estradiol or about 0.5 to about
`5 parts of a progestin such as levonorgestrel per p