`WORLD INTELLECn
`Inte;
`INTERNATIONAL APPLICATION PUBLISHED
`(51) International Patent Classification ^ :
`A61K 9/70, 31/565, 47/12
`
`A1
`
`WO
`
`9603119A1
`
`(43) International Publication Date:
`
`8 February 1996 (08.02.96)
`
`(21) International Application Number:
`
`PCT/EP95/02938
`
`(22) International Filing Date:
`
`25 July 1995 (25.07.95)
`
`(30) Priority Data:
`940100369
`
`26 July 1994 (26.07.94)
`
`GR
`
`(71) Applicant (for all designated States except US): LAVIPHARM
`S.A. [GR/GR]; Agias Marina Street, P.O. Box 59, GR-190
`02 Peania Attica (GR).
`
`(72) Inventor; and
`(75) Inventor/Appikant (for US only): FOTINOS, Spiros [GR/GR];
`18a I. Statha Street, GR-106 02 Kolonaki (GR).
`
`(74) Agents: CRISP, David, Norman et al.; D. Young & Co., 21
`New Fetter Lane, London EC4A IDA (GB).
`
`(81) Designated States: AM, AT, AU, BB, BG, BR, BY, CA, CH,
`CN, CZ, DE, DK, EE, ES, FI, GB, GE, HU, IS, JP, KE,
`KG, KP, KR, KZ, LK, LR, LT, LU, LV, MD. MG, MN,
`MW, MX, NO, NZ, PL, PT, RO, RU, SD, SE, SG, SI, SK,
`TJ, TM, TT, UA, UG, US, UZ, VN, European patent (AT,
`BE, CH, DE, DK, ES, FR, GB, GR, IE, IT, LU, MC, NL,
`PT, SE), OAPI patent (BF, BJ, CF, CG, CI, CM, GA, GN,
`ML, MR, NE, SN, TD, TG), ARIPO patent (KE, MW, SD,
`SZ, UG).
`
`Published
`With international search report.
`Before the expiration of the time limit for amending the
`claims and to be republished in the event of the receipt of
`amendments.
`
`(54) Title: TRANSDERMAL DELIVERY DEVICE CONTAINING AN ESTROGEN
`
`MODIFIED FRANZ DIFFUSION CELL
`
`1
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`12
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`' 11 i 11 1 1 1 H 1 1 1 1 1 i i 111! I i ] I i 11 111N I !
`111 i 1111
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`J
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`(57) Abstract
`
`A composition for use in a transdermal drug deliveiy system is described. The composition comprises an adhesive, an estrogen, and
`a flux enhancer.
`
`
`
`
`
`MYLAN - EXHIBIT 1012
`
`
`
`FOR THE PURPOSES OF INFORMATION ONLY
`
`Codes used to identify States party to the PCT on the front pages of pamphlets publishing international
`applications under the PCT.
`
`AT
`AU
`BB
`BE
`BF
`BG
`BJ
`BR
`BY
`CA
`CF
`CG
`CH
`CI
`CM
`CN
`CS
`CZ
`DE
`DK
`ES
`FI
`FR
`GA
`
`Austria
`Australia
`Barbados
`Belgium
`Burkina Faso
`Bulgaria
`Benin
`Brazil
`Belarus
`Canada
`Central African Republic
`Congo
`Switzerland
`CAte d'lvoire
`Cameroon
`China
`Czechoslovakia
`Czech Republic
`Germany
`Denmark
`Spain
`Finland
`France
`Gabon
`
`GB
`GE
`GN
`GR
`HU
`IE
`IT
`JP
`KE
`KG
`KP
`
`KR
`KZ
`LI
`LK
`LU
`LV
`MC
`MD
`MG
`ML
`MN
`
`United Kingdom
`Georgia
`Guinea
`Greece
`Hungary
`Ireland
`Italy
`Japan
`Kenya
`Kyrgystan
`Democratic People's Republic
`of Korea
`Republic of Korea
`Kazakhstan
`Liechtenstein
`Sri Lanka
`Luxembourg
`Latvia
`Monaco
`Republic of Moldova
`Madagascar
`Mali
`Mongolia
`
`MR
`MW
`NE
`NL
`NO
`NZ
`PL
`PT
`RO
`RU
`SD
`SE
`SI
`SK
`SN
`TD
`TG
`TJ
`TT
`DA
`US
`UZ
`VN
`
`Mauritania
`Malawi
`Niger
`Netherlands
`Norway
`New Zealand
`Poland
`Portugal
`Romania
`Russian Federation
`Sudan
`Sweden
`Slovenia
`Slovakia
`Senegal
`Chad
`Togo
`Tajikistan
`Trinidad and Tobago
`Ukraine
`United States of America
`Uzbekistan
`Viet Nam
`
`
`
`WO 96/03119
`
`PCT/EP95/02938
`
`Transdermal delivery device containing an estrogen
`
`The present invention relates to a device for the administration of estradiol
`alone or in combination with progestin(s), encompassing a specific enhancer
`that achieves elevated transdermal fluxes and optionally an anti-oxidant that
`achieves better product stability and to a method for manufacturing such
`device.
`
`17a-estradiol is the main estrogen produced by the ovaries in pre-menopausal
`women (J.A. Balfur and R.C. Heel, Drugs 40^ 4, 561 - 582, 1990).
`
`17-a estradiol, the naturally occurred estrogen, has mainly been used in two
`areas, such as fertility control and estrogen replacement therapy.
`
`Oral administration of estradiol results in an almost complete degradation of
`this hormone in the digestive tract, due to the phenomenon of first-pass
`hepatic metabolism. Since a large amount of the administered estradiol,
`approximately 90%, is destroyed, a large excess should be administered in
`order to achieve an effective therapeutic result.
`
`It is well-known, that oral administration of estradiol is associated with a
`number of major side effects such as thrombophlebitis and thrombosis,
`pulmonary embolism, coronary thrombosis, myocardial infraction, cerebral
`thrombosis, cerebral hemorrhage and hypertension.
`
`Estrogen replacement therapy is a special need for females on menopause or
`oophorectomy (loss of one or both ovaries by surgery) and/or pituitary failure.
`It can also contribute to osteoporosis (loss of bone mass) and atherosclerosis.
`
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`SUBSTITUTE SHEET (RULE 26)
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`PCT/EP95/02938
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`Administration of estradiol to post-menopausal women has been found to
`make post-menopausal symptoms (hot flushes, sweating, nervousness, sleep
`disturbance) less intense.
`
`Co-administration of progestin has been shown to be advantageous for
`eliminating the side-effects caused by the administration of estradiol itself.
`Thus, in both fertility control and estrogen replacement therapy, the available
`therapeutic dosage schemes contain an effective amount of progestin. [Y.W.
`Chien, T-Y. Chien and Y-C. Huang, U.S patent #4906169 (transdermal
`Estrogen/Progestin Dosage Unit, System and Process), March 6, 1990].
`
`It has been of great importance to develop a delivery system which will provide
`certain advantages such as minimization of side effects, prolonged and
`controlled rate of administration of the hormones, rapid termination of the
`treatment, and improvement of patient compliance.
`
`The introduction of transdermal systems was found to satisfy the above
`requirements, which, thus, permits the use of the natural estrogen, 17a-
`estradiol, and the use of lower daily doses with the same efficacy because of
`reduced first-pass hepatic metabolism and continuous drug input.
`
`A number of transdermal delivery systems of various designs exist. They are
`in general well tolerated, with only 2.5-7% of patients overall having been
`reported to discontinue the use of transdermal delivery due to severe irritation
`problems.
`
`The most frequent problem relates to insufficient adhesion of the transdermal
`"patch" to the skin during wear, resulting in patch loss. Typically, estradiol
`delivery systems are designed to be worn and to deliver the drug for 3 - 4
`days.
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`SUBSTITUTE SHEET (flULE 26)
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`WO 96/03119
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`PCT/EP95/02938
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`Several sizes of transdermal estradiol patches already exist on the market, for
`example, 5, 10, 16 and 20 cm2 containing 2, 4, 3.2 and 8 mg of estradiol
`respectively; the drug is delivered at a rate of 0.21 ig/cm2/hr corresponding to
`delivery rates of 0.025, 0.05, 0.08 and 0.1 mg per 24 hours (for up to 4 days).
`
`A number of patented systems exist for the delivery of estradiol through the
`skin, wherein, some selectively presented, (e.g. - Chien, Yie., W. and Chien,
`Te-Yen, WO 87/07138, Transdermal Absorption Dosage Unit For Estradiol and
`other Estrogenic Steroids and Process for Administration - Transdermal drug
`delivery device using a polymer-filled microporous membrane to achieve
`delayed onset, by Venkatraman S., Cygnus Therapeutic Systems WO
`93/03693 - Solid matrix system for transdermal drug delivery, by Chia-Ming
`Chiang et al, Cygnus Therapeutic Systems, US Patent # 5,252,334
`(12.10.1993) - Estradiol transdermal delivery system, by Kim B. et al., Paco
`Pharmaceutical Services, U.S. Patent #4,906,475/6.3.1990 - Transdermal
`estrogen/progestin dosage unit, system and process, by Chien Y. et al.,
`Rutgers, the State University of New Jersey, WO 90/06736).
`
`There are basically two types of transdermal drug delivery systems:
`
`a)
`
`Liquid reservoir
`Drug impermeable covering 1.
`Drug formulation reservoir 2.
`Rate-controlling membrane 3.
`Adhesion layer 4.
`Release liner 5.
`
`(as illustrated in Figure 1)
`
`SUBSTITUTE SHEET (RULE 26)
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`PCT/EP95/02938
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`.4.
`
`In this case, estradiol is formulated in a liquid medium and the drug is released
`from the system via a polymeric membrane.
`
`b)
`
`Matrix
`Occlusive cover sheet 6.
`Adhesive matrix drug reservoir 7.
`Release liner 8.
`
`(as illustrated in Figure 2)
`
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`In this type of system the drug is formulated directly in the adhesive used
`which is placed directly in contact with the skin.
`
`In general, matrix transdermal delivery system enjoy better patient acceptance,
`because they are considered to be more convenient than liquid reservoir
`systems. Furthermore, liquid patches developed for estradiol usually exhibit
`interactions between the adhesive substance and the semi-solid components
`of the liquid-reservoir, leading to reduced adhesiveness and altered skin flux
`rates.
`
`All the available enhancers could influence the physicochemical properties of
`a final transdermal delivery system, such as adhesion, plasticity etc. In
`general, the selection of all the ingredients for a transdermal delivery system
`is guided by the desired physicochemical properties.
`
`In the present invention, a percentage concentration range of the enhancer is
`proposed, while an optimum concentration, satisfying our needs for the
`desirable "patch" with the appropriate skin flux adhesion and removal
`properties, has been identified.
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`SUBSTITUTE SHEET (RULE 26)
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`PCT/EP95/02938
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`In this invention, linileic acid is used as skin permeation enhancer. This
`unsaturated aliphatic acid alone or in combination has been for years in many
`topical formulations such as cosmetics, toiletries, etc.
`
`It is an object of this invention to provide an improved transdermal estradiol
`delivery system suitable for use in women on fertility control and estrogen
`replacement therapy which overcomes the problems of the prior art systems.
`
`According to a first aspect of the present invention there is provided a
`composition for use in a transdermal drug delivery system comprising:-
`
`(a)
`(b)
`(c)
`
`an adhesive;
`an estrogen; and
`a flux enhancer.
`
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`Preferably, the adhesive is at least one acrylic adhesive.
`
`Preferably, the adhesive is a mixture of two acrylic adhesives.
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`20
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`Preferably, the two acrylic adhesives are in a dry weight ratio of about 80% to
`about 20% respectively.
`
`Preferably, the amount of estrogen is from about 0.1 to about 8 % w/w.
`
`25
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`Preferably, the amount of estrogen is 2% w/w.
`
`Preferably, the estrogen is 17-/? estradiol, ethimyl-estradiol or combinations
`thereof.
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`Preferably, the preceding claims wherein the amount of flux enhancer is from
`about 0.1 to about 20%.
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`SUBSTITUTE SHEET (RULE 26)
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`Preferably, the amount of flux enhancer is about 5%.
`
`•6"
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`Preferably, the flux enhancer is linoleic acid.
`
`5
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`Preferably, the estrogen is combined with a progestin.
`
`Preferably, the amount of progestin is from about 0.1 to about 10% w/w.
`
`Preferably, the amount of progestin is about 4% w/w.
`
`the progestin
`Preferably,
`medroxyprogesterone.
`
`is norethidrone acetate,
`
`levonorgestrel or
`
`Preferably, the preceding claims further comprising an antioxidant.
`
`Preferably, the antioxidant is butylhydroxytoluene (BHT).
`
`Preferably, there are a plurality of compositions.
`
`Preferably, each of the compositions contains different concentrations of
`adhesive, estrogen and flux enhancer.
`
`According to a second aspect of the present invention, there is provided a
`transdermal delivery system comprising an adhesive, an estrogen, and a flux
`enhancer.
`
`Preferably, a part of the adhesive is in contact with a polymeric release liner
`which seals and protects the adhesive during storage, and wherein the liner
`is capable of being peeled off and discarded prior to use of the transdermal
`delivery system.
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`SUBSTITUTE SHEET (RULE 26)
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`Preferably, the release liner is of either polymeric or paper origin.
`
`Preferably, at least a part of the adhesive is in contact with a backing layer
`which is substantially impermeable to the components of the composition the
`backing layer being occlusive or breathable.
`
`Preferably, the controlled delivery of estrogen over a period of 1 to 11 days.
`
`According to a third aspect of the present invention there is provided a method
`of administering estrogen through the skin by use of a transdermal delivery
`system, the delivery system comprising an adhesive, an an estrogen; and a
`flux enhancer.
`
`Embodiments of the present invention will now be described by way of
`example with reference to the drawings in which:-
`
`Figure 1 is a transdermal delivery system having a liquid reservoir.
`
`Figure 2 is a transdermal delivery system having a matrix.
`
`Figure 3 is a transdermal delivery system according to the present invention.
`
`Figure 4 is a modified Franz diffusion cell.
`
`Figure 5 is a graph showing the flux of estradiol through human stratum
`corneum in vitro.
`
`Figure 6 is a graph showing the permeation of estradiol per day from a
`10 sq. cm patch.
`
`Figure 7 is a graph showing the flux of estradiol through human stratum
`corneum in vitro (after storage for 8 weeks at room temperature).
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`SUBSTITUTE SHEET (RULE 26)
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`Figure 8 is a graph showing estradiol TDS drug release.
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`-8-
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`Figure 9 illustrates a shear test of the present invention.
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`It is an advantage of this invention to provide a transdermal delivery system
`which sufficiently delivers in vivo estrogen alone, or in combination with
`progestin, through intact skin at a controlled rate for 1-11 days.
`
`It is another advantage of this invention to provide a transdermal estrogen and
`estrogen/progestin combination through a patch that is of smaller size for the
`same dose than other patches developed todate.
`
`It is another advantage of this invention to provide a transdermal delivery
`system for administration of estrogen or in combination with progestin with
`better stability characteristics than other developed patches.
`
`The present invention is also advantageous in that it relates to the use of
`linoleic acid together with an anti-oxidant, which enhances the rate of estradiol
`permeation and maintains superior product stability, that is innovative and
`unique as well.
`
`This invention offers a simple and effective means of delivering estrogen,
`preferably estradiol and estrogen/progestin combinations through the skin.
`The hormones are formulated with a mixture of dermatologically acceptable
`acrylic adhesives, a flux enhancer preferably linoleic acid and optionally an
`anti-oxidant compound.
`
`The transdermal estradiol or estradiol/progestin delivery systems (illustrated
`in Figure 3) of this invention comprise:
`
`a)
`
`a backing layer 9, which is substantially impermeable to the estradiol
`and progestin(s) to be delivered transdermally;
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`SUBSTITUTE SHEET (RULE 26)
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`WO 96/03119
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`b)
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`PCT/EP95/02938
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`•9*
`an adhesive matrix 10, which is in contact with said backing layer and
`has distributed
`therein an effective amount of estradiol or
`estradiol/progestin combinations with an enhancing agent such as
`linoleic acid and an anti-oxidant
`compound,
`such
`as
`butylhydroxytoluene (BHT) and which secures the dosage unit in
`contact with the skin of the subject being treated for a period of 1-11
`days to permit the hormones to be absorbed transdermally at a
`controlled rate; and
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`c)
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`a release liner 11, which is in contact with said adhesive matrix and
`which is stripped from the unit prior to the use.
`
`The backing layer can be made of any suitable material which is impermeable
`to the estradiol alone or in combination with progestin(s) which are dissolved
`or otherwise distributed in the adhesive matrix. Preferably the materials for
`making the backing layer are commercially available films of Saranex sold by
`Dow Chemicals or of polyethylene sold by 3M, providing thus the desirable
`properties in the adhesive matrix.
`
`The adhesive layer must be made of materials biologically acceptable and
`compatible with said hormones and the skin permeation enhancer. In this
`invention, preferably a pressure-sensitive material is used such as the vinyl
`acetate-acrylate multipolymer of Gelva 737 and/or Gelva 788 resin solution
`sold by Monsanto.
`
`The adhesive layer is then covered with release liner which is made of
`materials impermeable to the hormones, the skin permeation enhancer and
`any other components of the dosage unit, and which is easily stripped or
`released prior the use. Preferably the release liner is made of siliconized
`polyester substance sold by release by Release Technologies by Release
`Technologies.
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`SUBSTITUTE SHEFT (RULE 26)
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`PCT/EP95/02938
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`-10-
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`Skin permeation enhancers, which can be employed for carrying out this
`invention, can widely vary. Specific skin permeation enhancers are distributed
`within the adhesive matrix and result in a good absorption of the hormones.
`
`The above formulation description can be presented in the following tables
`which demonstrate the composition of a transdermal delivery unit consisting
`of (a) a single adhesive substance and (b) a mixture of adhesives.
`
`Table 1
`Single Adhesive Formulation
`
`COMPONENT
`
`QUALITY
`
`17a - estradiol
`(Selva 73?
`Pamolyn 200
`Butyl Hydroxy Toluene (BHT)
`
`Pharmaceutically pure
`Multipolymer Solution
`77% min linoleic acid
`
`Table 2
`Mixed Adhesive Formulation
`
`COMPONENT
`
`QUALITY
`
`17a - estradiol
`Gelva 737/788 (80/20 ratio by weight
`in a dried coating)
`Linoleic acid
`Butyl Hydroxy Toluene (BHT)
`
`Pharmaceutically pure
`Multipolymer Solution
`
`> 96%
`
`QUANTITY
`% w/w
`(on a dry
`basis)
`TO
`SZS
`
`(TF
`
`QUANTITY
`% w/w
`(on a dry
`basis)
`TU
`
`SU
`O
`
`This invention is illustrated further by the following examples. Examples are
`not to be seen as limiting the scope of invention.
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`SUBSTITUTE SHEET (RULE 26)
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`- 1 1 -
`
`Examole no. 1.
`Preparation of adhesive mixture and transdermal delivery device
`
`The following ingredients are used in preparing the hormone containing
`adhesive matrix: estradiol, Gelva, linoleic acid and butylhydroxytoluene (BHT)
`
`To 75g of adhesive (Gelva 737 with a total solids content of about 33.8%)
`solution in toluene ethylacetate and ethanol, estradiol (0.5g) and linoleic acid
`(1.25g) are added. 200il of BHT solution in isopropanol (0.6g BHT per 100ml
`of isopropanol) are added and the mixture is stirred at room temperature until
`all estradiol is dissolved.
`When a mixture of adhesives is used, it consists of 60.5 gr Gelva 737 and 11.0
`gr Gelva 788.
`
`The adhesive mixture is formulated in a transdermal system as follows:
`Using an appropriate coating device such as 15 mil casting knives, a layer of
`the adhesive mixture is coated onto the silicone treated side of polyethylene
`sheet. The coating is dried in an oven at 70° C for 15 minutes and it is then
`laminated with a polyester layer on the corona-treated (roughened) side.
`The process ends with cutting the multi-layer laminate to shapes of the desired
`geometry and size.
`
`Example no. 2.
`Permeability of the transdermal delivery device
`
`The dosage units obtained, as described in the Example 1, are evaluated. The
`transdermal absorption (flux) of estradiol from the adhesive matrix of this
`invention is determined in vitro by using human cadaver skin, according to the
`procedure described by Franz T., In Percutaneous absorption on the relevance
`of in vitro data, J. Invest. Derm. 64, 190-195, 1975.
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`-12-
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`A typical experimental setup for flux measurements (modified Franz diffusion
`cell), illustrated in Figure 4, comprises a) Glass lid 12, b) Backing sheet 9, c)
`Drug in the adhesive matrix 10, d) Skin 13, e) Receiving medium 14, f)
`Sampling arm 15, g) Stirrer 16, h) Receiver compartment 17 and i) Clamp (not
`shown).
`
`For in vitro flux studies, the stratum corneum of human cadaver skin was used.
`Using fresh, post-mortem skin samples, the stratum corneum was separated
`from the skin by the technique described by Kligman, A.M. and Christophers,
`E., in Preparation of isolated sheets of human stratum corneum. Arch. Derm.,
`88, 702, 1963.
`
`The stratum corneum and the transdermal system of the Example 1 were cut
`into approximately 2-3 cm2 squares. A sample of stratum corneum was placed
`onto the flat surface of the flux cell. After removing the release liner from the
`transdermal system, the adhesive matrix was laminated onto the stratum
`corneum, the whole was covered by a glass lid, and secured by a clamp.
`
`The receiver medium was a 0.02 wt.% aqueous solution of sodium azide. The
`assembled cells were placed in a circulating water bath calibrated to maintain
`the skin surface temperature at 32 + 10C.
`
`At predetermined time intervals of 6, 12, 24, 36, 48, and 72 hours, the entire
`content of the receiver was collected for the quantitative determination of
`estradiol, employing an HPLC method adapted from T. Loftsson and N. Bodor,
`Acta Pharm. Nord., 1, 4, 1989.
`
`The receiver was then again filled with fresh receiving medium. Special care
`was taken to avoid accumulation of air bubbles at the skin/solution interface.
`
`The cumulative amount of estradiol (Qt = Ig . cm '2) permeated per unit of area
`at any time (t) is calculated by using the following formula.
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`SUBSTITUTE SHEET (RULE 26)
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`Q» =
`(Cn V) / A
`t
`where Cn is the concentration (ig/ml) of the drug in the receiving medium for
`each sampling time, V is the volume (6.3ml) of receiver solution, and A is the
`cell's diffusional area (0.636cm2).
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`Typical results are shown in the graph of Figure 5.
`
`The flux of estradiol released from a transdermal delivery system of a given
`size can be calculated using the above data. The results obtained are given
`in the graph of Figure 6.
`
`A comparative study of skin flux determination between estradiol transdermal
`system described in the Example 1 and SYSTEM 50 Lot 3A01AZ (a matrix
`patch introduced by Jhonson and Jhonson) is presented in the following Table:
`
`Table 3
`Competitive skin flux studies between Estradiol transdermal system
`and SYSTEN 50
`
`20
`
`T r a n s d e r m a l C u m u l a t i v e f l u x e s ( i g / c m2)
`system
`
`Estradiol
`
`SVSTEN 50
`
`(0-48h)
`3154
`
`(0-24h)
`TT\
`
`T5?
`
`(0-72h)
`T5S
`TE5
`
`"incremental" fluxes (ig/cm2)
`ratio (sample to reference)
`(0-24h)
`(24-48h)
`(48-72h)
`Tm
`TPS
`TTT
`1.10
`1.87
`2.05
`T57
`T5I
`1.00
`1.00
`
`1.00
`
`Average
`
`Tm
`1.67
`T5?
`1.00
`
`25
`
`30
`
`The results from the Table 3 indicate that the estradiol transdermal delivery
`system of the present invention exhibits elevated skin fluxes comparing to that
`of SYSTEN 50. As skin flux rates are the primary parameter of performance
`of a transdermal delivery system, the rates of the above table clearly indicate
`that the transdermal delivery system described in this invention, can be of a
`smaller size that the commercially available. A smaller size "patch" signifies:
`1) a smaller occluded area, therefore less risk of irritation, 2) better aesthetics
`and therefore, convenience, acceptability and compliance by patients under
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`SUBSTITUTE SHEET (RULE 26)
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`WO 96/03119
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`PCT/EP95/02938
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`treatment, and 3) higher production output.
`
`-14-
`
`Example no. 3.
`Stability of the transdermal delivery device
`
`5
`
`10
`
`15
`
`20
`
`25
`
`30
`
`The dosage units described in the Example 1 are evaluated.
`
`The stability of estradiol in the adhesive matrix is determined by measuring
`fluxes of estradiol from the formulation at various intervals during storage of
`the transdermal systems. The graph of Figure 7 showing the results obtained
`after 8 weeks at room temperature, indicates that little change in the product's
`performance occurred during this period.
`
`The stability of the transdermal system can also be evaluated by measuring
`the release rate of estradiol from the matrix employing a standard drug release
`test (U.S. Pharmacopeia XXII, p. 1581).
`
`The results of such measurements are given in the graph of Figure 8.
`
`Samples of the transdermal system were kept at room temperature and at 37°
`C and 45° C for up to 12 weeks, (see also graph of Figure 8). The results
`again indicate that the system's performance remains satisfactory under these
`conditions.
`
`Example no. 4.
`The effect of enhancer on the flux of estradiol through human cadaver skin.
`
`The transdermal units described in the Example 1 are evaluated.
`Various combinations of estradiol and linoleic acid amounts were tested to
`establish an optimum ratio of the drug and enhancer. The following examples,
`presented in the table below, illustrate the effect of various concentrations of
`the two components on the flux of estradiol through human cadaver skin.
`
`SUBSTITUTE SHEET (RULE 26)
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`-15-
`
`Table 4
`Effect of linoleic acid on estradiol flux
`
`Transdermal delivery device
`
`Flux in ig/cm2/h
`
`4% estradiol &
`2% linoleic acid
`
`10
`
`4% estradiol &
`5% linoleic acid
`
`3% estradiol &
`5% linoleic acid
`Estraderm* Control
`
`1.5% estradiol &
`5% linoleic acid
`U7
`2% estradiol &
`5% linoleic acid
`Estraderm" Control
`
`74
`
`0.073
`
`0.076
`
`0.133
`
`TTUST
`
`0.090
`
`0.120
`
`TTUBff
`
`4$
`
`0.072
`
`0.080
`
`0.138
`irm
`0.100
`
`0.130
`
`TTTTO
`
`15
`
`20
`
`25
`
`30
`
`35
`
`As it is indicated above, various estradiol/linoleic acid combinations result in
`various flux rates.
`
`Differences occurred in experimental results are mostly based upon the skin
`donor(s).
`
`Example no. 5.
`Skin irritation and sensitisation studies using estradiol transdermal system.
`
`The transdermal units described in the Example 1 are tested.
`A skin irritation study was conducted in six healthy rabbits of the New Zealand
`white variety.
`
`The back and flanks of each animal are clipped free of fur with an electric
`clipper 12 hours before testing. Just prior to test article application, each rabbit
`
`SUBSTITUTE SHEET (RULE 26)
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`WO 96/03119
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`receives four parallel epidermal abrasions with a sterile needle at one test site
`(left flank), while the skin at the opposite site remains intact.
`
`A 5 cm2 patch of the test article and a 5 cm2 patch of the control article are
`then applied to each site (four sites per rabbit) to an area of skin approximately
`2.7 x 3.7 cm. The patches are covered with a non-reactive tape. The trunk of
`each animal is wrapped with a binder.
`
`After 96 hour exposure, the binders, tape, and patches are removed. The test
`sites are gently sponged with deionized water to remove any residue of test
`article. After at least 30 minutes, the sites are inspected and scored. Another
`evaluation is also conducted at 144 hours after application.
`
`Each test site is examined for dermal reactions using the Draize scoring
`criteria. The primary irritation index of the test article is calculated following
`test completion. A substance with an empirical score of less than 5 would not
`be considered a primary irritant to the skin.
`
`The primary irritation index of the test article (estradiol transdermal system of
`this invention) and of the control article (Estraderm TTS 25 ig/24h. Lot #
`176700, expiration date 05/94) are calculated to be 1.70 and 1.75,
`respectively.
`
`Individual experimental results are given in the following Table. The results for
`the test article of this invention are given first, followed (after /) by the results
`for control article.
`
`The table that follows presents the data for each rabbit.
`
`10
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`15
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`20
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`25
`
`30
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`SUBSTITUTE SHEET (RULE 26)
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`-17-
`
`Table 5
`Skin irritation test
`
`Reaction
`
`96 hours
`Abraded
`Intact
`m
`270
`Erythema:
`W
`171
`Oeadema:
`m
`W5
`Erythema:
`0/0
`Oedema:
`0/0
`TTZ
`1/1
`Erythema:
`17T
`Oedema:
`UTT
`(W
`070
`Erythema:
`0/0
`0/0
`Oedema:
`HI
`TTT
`Erythema:
`m
`m
`Oedema:
`Erythema: M
`HI
`Oedema:
`2/1
`2/2
`
`144 hours
`Intact
`Abraded
`m
`W
`m
`W
`m
`m
`0/0
`0/0
`TTT
`T7T
`TTT
`1/1
`1/0
`W\
`m
`T73"
`1/1
`
`M
`0/1
`172
`
`HI
`2/2
`
`Under the conditions of this test, the transdermal system tested could not be
`considered a primary skin irritant, since the primary irritation index was less
`than 5 and the difference between the test and control scores was not
`significant.
`
`A skin sensitisation study was conducted in 35 healthy albino guinea pig of the
`Hartley strain to evaluate and compare the dermal sensitisation potential of
`estradiol transdermal system and Estraderm TTS patch, according to the
`method described by Buehler in Archives of Derm. 91, 171, 1965.
`
`The estradiol transdermal system was occlusively patched to ten guinea pigs
`and the control patch was occlusively patched to ten guinea pigs, three times
`a week until nine induction applications were conducted. Similarly, five positive
`control guinea pigs were occlusively patched twice a week, with a 0.1%
`solution of 1-chloro-2,4-dinitrobenzene (DNCB) in propylene glycol, until six
`inductions had been completed. Following a recovery period of three weeks,
`the original ten tests and ten controls, ten previously untreated negative control
`animals and the five positive control animals received a challenge patch. All
`
`SUBSTITUTE SHEET (RULE 26)
`
`5
`
`Rabbit No.
`
`No~T
`
`NoT
`
`No3
`
`NoT
`
`NoT
`
`NoT)
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`
`
`5
`
`10
`
`15
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`20
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`25
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`30
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`-18-
`
`sites were scored at 24, 48, and 72 hours after challenge patch removal.
`
`The results obtained are shown in the following Tables 6 and 7. Specifically
`the results referred to the induction of dermal reactions and challenge phase
`for the test article of this invention are given first, followed (after /) by the
`results for the control article.
`
`Table 6
`Skin sensitisation test: Dermal reactions - induction phase
`
`Animal
`Number
`
`Dermal Reaction The Day After Patch Removal
`
`8
`2
`6
`5
`4
`9
`7
`3
`m
`wu
`m
`m
`m
`m W5 m
`0/0
`0/0
`0/0
`0/0
`0/0
`0/0
`0/0
`0/0
`m WJ
`m m
`m
`m W5
`070
`0/0
`0/0
`0/0
`0/0
`0/1
`0/0
`0/0
`0/0
`m
`m
`TJTfT m
`im
`m
`m m
`0/0
`0/0
`0/0
`0/0
`0/0
`0/0
`0/0
`0/0
`m m
`OT m
`T57ff m
`T37U
`070
`0/0
`0/0
`0/0
`0/0
`0/0
`0/0
`0/0
`0/0
`m
`m m m
`(W
`TJTCT
`0/0
`0/0
`0/0
`0/0
`0/0
`0/0
`0/0
`0/0
`MT m m m
`m
`TJTff
`tm
`0/0
`0/0
`0/0
`0/0
`0/0
`0/0
`0/0
`0/0
`m
`m
`m
`m
`m
`m
`m
`070
`o/o
`0/0
`0/0
`0/0
`0/0
`0/0
`0/0
`0/0
`m w> m
`m m
`m wu
`m
`0/0
`0/0
`0/0
`0/0
`0/0
`0/0
`0/0
`0/0
`m m
`m m
`m
`070
`ws m
`0/0
`0/0
`0/0
`0/0
`0/0
`0/0
`0/0
`0/0
`w>
`m
`W)
`m
`m
`m
`TJTff
`070
`0/0
`0/0
`0/0
`0/0
`0/0
`0/0
`0/0
`0/0
`OED: OEDEMA
`*: BALDNESS
`
`SUBSTITUTE SHEET (RULE 26)
`
`1/11
`
`2/12
`
`3/13
`
`4/14
`
`5/15
`
`6/16
`
`7/17
`
`8/18
`
`9/19
`
`1
`OBS
`m
`FFT
`0/0
`OED
`FR m
`0/0
`OED
`m
`bR
`0/0
`OED
`ETC
`0/0
`OED
`m
`ER
`0/0
`OED
`m
`TJTCT
`0/0
`OED
`m
`m
`0/0
`OED
`070
`ER
`0/0
`OED
`070
`m
`0/0
`OED
`ETC m
`0/0
`10/20
`OED
`ER: ERYTHEMA
`
`
`
`5
`
`10
`
`15
`
`20
`
`25
`
`30
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`PCT/EP95/02938
`
`Table 7
`Skin sensitisation test: Challenge phase
`
`Animal
`Number
`
`OBS
`
`24
`
`Hours After Patch Application
`
`1/11
`
`2/12
`
`3/13
`
`4/14
`
`5/15
`
`6/16
`
`FR
`OED
`FR
`OED
`m
`OED
`EFT
`OED
`EE
`OED
`ER
`OED
`m
`OED
`FR
`OED
`FR
`OED
`FR
`10/20
`OED
`ER: ERYTHEMA
`
`7/17
`
`8/18
`
`9/19
`
`070
`0/0
`(370
`0/0
`070
`0/0
`M)
`0/0
`m
`0/0
`T37ff
`0/0
`M
`0/1
`m
`0/0
`m
`0/0
`m
`0/0
`OED: OEDEMA
`
`48
`m
`0/0
`070
`0/0
`m
`0/0
`
`0/0
`m
`0/0
`m
`0/0
`m
`0/0
`m
`0/0
`m
`0/0
`m
`0/0
`
`72
`m
`0/0
`070
`0/0
`m
`0/0
`TW
`0/0
`m
`0/0
`m
`0/0
`m
`0/0
`m
`0/0
`m
`0/0
`wu
`0/0
`
`The following Table presents the results obtained during challenge phase in
`the negative control animals.
`
`SUBSTITUTE SHEET (RULE 26)
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`
`Table 8
`Skin sensitisation test: Challenge phase (Negative control)
`
`Animal
`Number OBS
`
`A
`
`B
`
`A
`
`ETC
`TT
`OED
`0
`EE
`T
`OED
`0
`EFT
`IT
`OED
`0
`ER
`TJ
`OED
`0
`ER
`0
`OED
`0
`ETT
`U
`0
`OED
`ER
`0
`OED
`0
`ER
`TJ
`OED
`0
`ER
`T
`OED
`1
`77
`ER
`0
`OED
`OED: OEDEMA
`ER: ERYTHEMA
`A= Estraderm ITS Patch (Left Flank)
`B= Estradiol Transdermal Patch (Right Flank)
`
`TT
`0
`T
`0
`0
`0
`
`0
`0
`0
`TT
`0
`TJ
`0
`7
`0
`T
`0
`77
`0
`
`0
`0
`T
`0
`0
`0
`TT
`0
`TT
`0
`TT
`0
`TT
`0
`7
`0
`T
`1
`77
`0
`
`26
`
`27
`
`28
`
`29
`
`30
`
`31
`
`32
`
`33
`
`34
`
`35
`
`10
`
`15
`
`20
`
`25
`
`30
`
`B
`
`TJ
`0
`T
`0
`TT
`0
`TT
`0
`0
`0
`o
`0
`o
`0
`
`0
`T
`0
`
`0
`
`A
`
`U
`0
`TT
`0
`TJ
`0
`U
`0
`77
`0
`TT
`0