PCT
`
`WORLD mafia
`
`INTERNATIONAL APPLICATION PUBLISHED
`
`‘
`
`I H
`
`‘
`
`”I
`
`Illlll
`
`
`
`NO
`
`960311931
`
`(51) International Patent Classification 6 :
`
`AGIK ”70’ 31/565’ 47,12
`
`(43) International Publication Date:
`
`8 February 1996 (08.02.96)
`
`(21) International Application Number:
`
`(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
`SA. [GR/GR]; Agias Malina Street, PO. Box 59, GR-190
`02 Peania Attica (GR).
`
`(72) Inventor; and
`(75) Inventor/Applicant (for US only): FOI‘INOS. Spiros [GR/GR];
`18a 1. Statha Street, GR-106 02 Kolonaki (GR).
`
`(74) Agents: CRISP. David, Norman et 31.; D. Young & Co., 21
`New Fetter Lane, London EC4A IDA (GB).
`
`European patent (AT,
`. IE, IT, LU, MC, NL,
`, G. CI. CM, GA. GN,
`patent (KE, MW, SD,
`
`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.
`
`a flux enhancer.
`
`(54) Title: TRANSDERMAL DELIVERY DEVICE CONTAINING AN ESTROGEN
`
`MODIFIED FRANZ DIFFUSION CELL
`
`|IllIillllIllllllllllllillllllillllllllllllll
`‘JHIM11HIHHIHHIIHHIIHHHIHHHHI
`
`.HEHHH llilllél
`
`(57) Abstract
`
`A composition for use in a uansdermal drug delivery system is described. The composition comprises an adhesive, an estrogen, and
`
`
`
`
`
`WORLD mafia
`
`INTERNATIONAL APPLICATION PUBLISHED
`
`‘
`
`I H
`
`‘
`
`”I
`
`Illlll
`
`
`
`NO
`
`960311931
`
`(51) International Patent Classification 6 :
`
`AGIK ”70’ 31/565’ 47,12
`
`(43) International Publication Date:
`
`8 February 1996 (08.02.96)
`
`(21) International Application Number:
`
`(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
`SA. [GR/GR]; Agias Malina Street, PO. Box 59, GR-190
`02 Peania Attica (GR).
`
`(72) Inventor; and
`(75) Inventor/Applicant (for US only): FOI‘INOS. Spiros [GR/GR];
`18a 1. Statha Street, GR-106 02 Kolonaki (GR).
`
`(74) Agents: CRISP. David, Norman et 31.; D. Young & Co., 21
`New Fetter Lane, London EC4A IDA (GB).
`
`European patent (AT,
`. IE, IT, LU, MC, NL,
`, G. CI. CM, GA. GN,
`patent (KE, MW, SD,
`
`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.
`
`a flux enhancer.
`
`(54) Title: TRANSDERMAL DELIVERY DEVICE CONTAINING AN ESTROGEN
`
`MODIFIED FRANZ DIFFUSION CELL
`
`|IllIillllIllllllllllllillllllillllllllllllll
`‘JHIM11HIHHIHHIIHHIIHHHIHHHHI
`
`.HEHHH llilllél
`
`(57) Abstract
`
`A composition for use in a uansdermal drug delivery system is described. The composition comprises an adhesive, an estrogen, and
`
`
`
`
`
`MYLAN - EXHIBIT 1012
`
`
`
`FOR THE PURPOSES OF INFORMATION ONLY
`
`Codes used to identify States party to the PCI‘ on the front pages of pamphlets publishing international
`applications under the PCT.
`
`Viei Nam
`
`United Kingdom
`Georgia
`Guinea
`Greece
`Hungary
`Ireland
`Italy
`Japan
`Kenya
`Kyrgyuan
`Democratic People's Republic
`of Korea
`Republic of Korea
`Kazakhstan
`Liechtenstein
`Sri Lanka
`Luxembourg
`Larvia
`Monaco
`Republic of Moldova
`Madagascar
`Mali
`Mongolia
`
`AT
`All
`33
`BE
`BF
`BC
`31
`BR
`BY
`CA
`CF
`CG
`
`Austria
`Australia
`Barbados
`Belgium
`Burkina Faso
`Bulgaria
`Benin
`Brazil
`Belarus
`Canada
`Central African Republic
`Congo
`Switzerland
`com d'lvoire
`Cameroon
`China
`Czechoslovakia
`Czech Republic
`
`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 Sales of America
`Uzbekistan
`
`
`
`W0 96/031 19
`
`PCT/EP95I02938
`
`Transdermai 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 (JA. Balfur and RC. Heel, Drugs fl, 4, 561 - 582, 1990).
`
`17-51 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 estradioi
`
`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.
`
`10
`
`15
`
`20
`
`30
`
`SUBSTITUTE SHEET (RULE 26)
`
`
`
`W0 96/03 1 19
`
`PCT[EMS/02938
`
`-7-
`
`Administration of estradiol to post-menopausal women has been found to
`
`make post-menopausal symptoms (hot flushes, sweating, nervousness, sleep
`
`disturbance) less intense.
`
`5
`
`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, US patent #4906169 (transdermal
`
`10
`
`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
`
`15
`
`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 closes with the same efficacy because of
`
`20
`
`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
`
`Ix) UI
`
`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
`
`30
`
`days.
`
`SUBSTITUTE SHEET (RULE 26)
`
`
`
`W0 96/031 19
`
`PCTIEP95I02938
`
`4‘
`-3-
`
`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/cm’lhr 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
`
`10
`
`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, US. Patent #4,906,475/6.3.1990 - Transdermal
`
`estrogen/progestin dosage unit, system and process, by Chien Y. et aI.,
`
`Rutgers, the State University of New Jersey, WO 90/06736).
`
`There are basically two types of transdermal drug delivery systems:
`
`20
`
`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)
`
`
`
`WO 96103119
`
`PCT/EP95/02938
`
`-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
`
`VI
`
`Occlusive cover sheet 6.
`
`Adhesive matrix drug reservoir 7.
`
`Release liner 8.
`
`(as illustrated in Figure 2)
`
`10
`
`15
`
`20
`
`25
`
`30
`
`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 reducedadhesiveness 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.
`
`SUBSTITUTE SHEET (RULE 26)
`
`
`
`WO 96/03119
`
`PCTIRES/02938
`
`-3-
`
`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.
`
`5
`
`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
`
`10
`
`composition for use in a transdermal drug delivery system comprising:-
`
`(a)
`
`(b)
`
`(c)
`
`an adhesive;
`
`an estrogen; and
`
`a flux enhancer.
`
`15
`
`Preferably, the adhesive is at least one acrylic adhesive.
`
`Preferably, the adhesive is a mixture of two acrylic adhesives.
`
`20
`
`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 % WM.
`
`25
`
`Preferably, the amount of estrogen is 2% w/w.
`
`Preferably, the estrogen is 17-13 estradiol, ethimyl-estradiol or combinations
`
`thereof.
`
`30
`
`Preferably, the preceding claims wherein the amount of flux enhancer is from
`
`about 0.1 to about 20%.
`
`SUBSTITUTE SHEET (RULE 26)
`
`
`
`WO 96/03119
`
`PCT[ENS/02938
`
`Preferably, the amount of flux enhancer is about 5%.
`
`—6-
`
`Preferably. the flux enhancer is linoleic acid.
`
`5
`
`Preferably, the estrogen is combined with a progestin.
`
`10
`
`15
`
`Preferably, the amount of progestin is from about 0.1 to about 10% wlw.
`
`Preferably, the amount of progestin is about 4% WM.
`
`Preferably,
`
`the progestin
`
`is
`
`norethidrone
`
`acetate,
`
`levonorgestrel
`
`or
`
`medroxyprogesterone.
`
`Preferably, the preceding claims further comprising an antioxidant.
`
`Preferably, the antioxidant is butylhydroxytoluene (BHT).
`
`Preferably, there are a plurality of compositions.
`
`20
`
`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
`
`25
`
`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
`
`30
`
`is capable of being peeled off and discarded prior to use of the transdermal
`
`delivery system.
`
`SUBSTlTUTE SHEET (RULE 26)
`
`
`
`W0 96/031 19
`
`PCT[EMS/02938
`
`Preferably. the release liner is of either polymeric or paper origin.
`
`-7-
`
`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
`
`U1
`
`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
`
`10
`
`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
`
`15
`
`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.
`
`20
`
`Figure 3 is a transdermal delivery system according to the present invention.
`
`Figure 4 is a modified Franz diffusion cell.
`
`25
`
`Figure 5 is a graph showing the flux of estradiol through human stratum
`
`corneum lfl m.
`
`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).
`
`SUBSTITUTE SHEET (RULE >26)
`
`
`
`W0 96/03 1 19
`
`PCT[EMS/02938
`
`Figure 8 is a graph showing estradiol TDS drug release.
`
`-3-
`
`Figure 9 illustrates a shear test of the present invention.
`
`5
`
`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
`
`10
`
`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
`
`15
`
`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
`
`20
`
`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
`
`25
`
`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:
`
`30
`
`a)
`
`a backing layer 9, which is substantially impermeable to the estradiol
`
`and progestin(s) to be delivered transdermally;
`
`SUBSTITUTE SHEET (RULE 26)
`
`
`
`W0 96/031 19
`
`PCT[EMS/02938
`
`-9-
`
`b)
`
`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
`
`5
`
`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
`
`10
`
`c)
`
`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
`
`15
`
`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.
`
`20
`
`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.
`
`25
`
`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
`
`30
`
`polyester substance sold by release by Release Technologies by Release
`
`Technologies.
`
`SUBSTlTUTE SHEET (RULE 26)
`
`
`
`WO 96/03119
`
`PCT[ENS/02938
`
`-10-
`
`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.
`
`5
`
`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.
`
`10
`
`Single Adhesive Formulation
`
`Table 1
`
`I-—I_--i'-
`W
`
`
`
`QUALITY
`
`
`
`COMPONENT
`
`
`
`
`
`
`Table 2
`
`Mixed Adhesive Formulation
`
`20
`
`25
`
`
`
`
`
`__--i-
`e va
`': 3
`(-0l 0 ratio -y weight
`Vu tipo ymer
`o ution
`in a dried coating) _
`
`
`
`Inc an: acn
`
`
`
`-uty 'ydroxy o uene = ' —
`
`
`
`
`
`
`
`
`This invention is illustrated further by the following examples. Examples are
`
`30
`
`not to be seen as limiting the scope of invention.
`
`SUBSTITUTE SHEET (RULE 26)
`
`
`
`W0 96/031 19
`
`PCT/EP95102938
`
`-11-
`
`WEN—W-
`
`Preparation of adhesive mixture and transdermal delivery device
`
`The following ingredients are used in preparing the hormone containing
`
`5
`
`adhesive matrix: estradiol, Gelva, linoleic acid and butylhydroxytoluene (BHT)
`
`To 759 of adhesive (Gelva 737 with a total solids content of about 33.8%)
`
`solution in toluene ethylacetate and ethanol. estradiol (0.59) and linoleic acid
`
`(1.259) are added. 200il of BHT solution in isopropanol (0.6g BHT per 100ml
`
`10
`
`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.
`
`15
`
`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 at70° C for 15 minutes and it is then
`
`laminated with a polyester layer on the corona-treated (roughened) side.
`
`20
`
`The process ends with cutting the multi-Iayer 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
`
`30
`
`of in vitro data, J. lnvest. Derm. 6_4, 190-195, 1975.
`
`SUBSTITUTE SHEET (RULE 26)
`
`
`
`W0 96/031 19
`
`PCT[ENS/02938
`
`-12-
`
`A typical experimental setup for flux measurements (modified Franz diffusion
`
`cell), illustrated in Figure 4, comprises a) Glass lid 12, b) Backing sheet 9. 0)
`
`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, AM. and Christophers,
`
`10
`
`E., in Preparation of isolated sheets of human stratum corneum. Arch. Derm.,
`
`@, 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 i 1°C.
`
`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 (Q, = ig . cm '2) permeated per unit of area
`
`at any time (t) is calculated by using the following formula.
`
`20
`
`Ix) U\
`
`30
`
`SUBSTITUTE SHEET (RULE 26)
`
`
`
`W0 96/031 19
`
`PCT/EP95/02938
`
`Qt = (fr,=0 (Cn.V) /A
`
`-13-
`
`where C,, 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 (0.6360m2).
`
`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
`
`10
`
`in the graph of Figure 6.
`
`A comparative study of skin flux determination between estradiol transdermal
`
`system described in the Example 1 and SYSTEN 50 Lot 3AO1AZ (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
`
`umulatlve uxes ig cm)
`
`
`
`15
`
`20
`
`ransdermal
`
`“Incrementa
`ques (19 cm
`system
`ratio (sample to reference)
`— Mm Mm Im- <~24h> [ma] (4--
`h)
`straoio
`.11
`.I4
`:
`.11
`.
`.
`“—HMfl
`
`'
`
`V
`
`I
`
`°
`
`‘
`
`4.-
`
`.
`
`.
`
`Average
`
`.-1
`
`.o
`
`'
`
`.
`
`.
`
`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
`
`30
`
`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
`
`SUBSTlTUTE SHEET (RULE 26)
`
`
`
`WO 96/03119
`
`PCT/EP95/02938
`
`treatment, and 3) higher production output.
`
`-14-
`
`m S
`
`tability of the transdermal delivery device
`
`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
`
`10
`
`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
`
`15
`
`the release rate of estradiol from the matrix employing a standard drug release
`
`test (U.S. Pharmacopeia XXll, p.1581).
`
`The results of such measurements are given in the graph of Figure 8.
`
`20
`
`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.
`
`25
`
`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
`
`30
`
`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)
`
`
`
`W0 96/031 19
`
`PCT[EDS/02938
`
`-15-
`
`Table 4
`
`Effect of linoleic acid on estradiol flux
`
`rans-erma Ie Ivery IEVICB
`
`
`
`U!
`
`10
`
`4% estradiol &
`2% linoleic acid
`
`4% estradiol &
`5% linoleic acid
`
`3% estradiol &
`
`
`
`
`
`
`
`ux in Ig/cm
`
`0.073
`
`0. 076
`
`0 072
`
`0.080
`
`0 133
`
`0.138
`
`0.090
`
`0.100
`
`0.120
`
`0.130
`
`
`
`
`
`
`
`
`5% linoleic acid
`15 Inn—“mire-
`
`1.5% estradiol 8.
`5% linoleic acid
`I.
`
`2% estradiol &
`
`5% linoleic acid
`
`20
`
`
`
`
`
`As it is indicated above. various estradiol/linoleic acid combinations result in
`
`25
`
`various flux rates.
`
`Differences occurred in experimental results are mostly based upon the skin
`
`donor(s).
`
`30
`
`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
`
`35
`
`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)
`
`
`
`WO 96/03119
`
`PCT[ENS/02938
`
`-16-
`
`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
`
`UI
`
`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
`
`10
`
`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
`
`15
`
`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
`
`20
`
`this invention) and of the control article (Estraderm ‘l'l'S 25 igl24h. 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
`
`25
`
`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.
`
`SUBSTITUTE SHEET (RULE 26)
`
`
`
`WO 96/03119
`
`PCTIEP95I02938
`
`-17-
`
`'
`
`Table 5
`
`Skin irritation test
`
`abetNo-
`
`
`eaction-
`
`U1
`
`10
`
`
`
`
`
`
`
`
`
`
`
`
`
`W"
`
`‘
`
`' W
`(mm-mi:-
`_-_mr--iz-mz-
`
`20
`
`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.
`
`25
`
`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 TI'S patch, according to the
`
`method described by Buehler in Archives of Derm. m, 171, 1965.
`
`30
`
`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
`
`35
`
`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)
`
`
`
`W0 96/03 1 19
`
`PCT[ENS/02938
`
`-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
`
`5
`
`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
`
`Number
`
`'
`
`I I
`
`I
`
`I
`
`I
`
`I
`
`I I
`
`I I
`
`I I
`
`I I
`
`I I
`
`I I
`
`10
`
`
`
`20
`
`-
`
`I I
`
`I I
`
`I
`
`I I
`
`I I
`
`I I
`
`I
`
`I
`
`I I
`
`I I
`
`I
`
`I
`
`I I
`
`I I
`
`I I
`
`I
`
`I
`
`I I
`
`I
`
`I
`
`I
`
`I
`
`I
`
`I
`
`I I
`
`I I
`
`I I
`
`I
`
`I
`
`I I
`
`I I
`
`
`
`I
`
`I I
`
`IW'
`IWI
`
`I
`
`I
`
`I
`
`I I
`
`I I
`
`I I
`
`I I
`
`.—Anhnal
`
`
`lllllllll
`
`
`W"
`
`
`
`
`
`
`I
`
`I
`
`I I
`
`I I
`
`I
`
`I
`
`-
`
`'
`
`'
`
`I I
`
`I I
`
`I I
`
`I I
`
`I
`
`I
`
`I I
`
`I
`
`I I
`
`I
`
`I
`
`I
`
`I
`
`I I
`
`I
`
`I
`
`30
`
`b) UI
`
`
`-MI I
`
`-EWWW
`-EWW
`
`-Emmw
`
`-Emwm
`-EWI I
`
`
`
`
`I
`
`I
`
`I
`
`I
`
`I
`
`I
`
`I
`
`I
`
`I I
`
`I
`
`I
`
`I I
`
`I I
`
`I
`
`I
`
`I I
`
`I
`
`I
`
`I I
`
`I
`
`I
`
`I I
`
`I I
`
`I I
`
`I
`
`I
`
`I
`
`I
`
`I I
`
`I I
`
`I
`
`I
`
`I I
`
`I
`
`I
`
`I I
`
`I I
`
`I
`
`I
`
`I I
`
`SUBSTITUTE SHEET (RULE 26)
`
`
`
`W0 96/03 1 19
`
`PCT[ENS/02938
`
`-19-
`
`Table 7
`
`Skin sensitisation test: Challenge phase
`
`Animal
`
`Number
`
`Hours After Patch Application
`
`
`
`
`
`
`
`
`
`
`
`10
`
`15
`
`25
`
`'
`
`'
`
`'
`
`'
`
`I I
`
`I I
`
`I I
`
`I I
`
`I I
`
`I I
`
`I
`
`I I
`
`I I
`
`I I
`
`I I
`
`I I
`
`I
`
`I
`
`I I
`
`I I
`
`I I
`
`I I
`
`I I
`
`I I
`
`I I
`
`
`
`
`
`
`
`
`
`I I
`
`I I
`
`I I
`
`I
`
`I
`
`I I
`
`I
`
`I
`
`I I
`
`I I
`
`I I
`
`I I
`
`m'
`
`-W
`
`-H"'
`
`-H"
`
`-m'
`
`-H"
`-H'
`-m'
`
`w'
`
`-H"
`
`
`O .
`
`I V
`
`I
`
`V
`
`.
`‘ OIOI
`
`v A
`
`30
`
`The following Table presents the results obtained during challenge phase in
`
`the negative control animals.
`
`SUBSWTUTESHEET(RULE26)
`
`
`
`WO 96/03119
`
`PCT/EP95102938
`
`-20-
`
`Table 8
`
`Skin sensitisation test: Challenge phase (Negative control)
`
`Animal
`Number OBS
`
`U!
`
`
`
`A= Estraderm TTS Patch (Left Flank)
`
`B: Estradiol Transdermal Patch (Right Flank)
`
`30
`
`The results of the positive control animals obtained from induction and
`
`challenge phase are presented below.
`
`SUBSTITUTE SHEET (RULE 26)
`
`
`
`W0 96/031 19
`
`PCT/EP95I02938
`
`-21-
`
`Table 9
`
`Skin Sensitisation Test: Induction Phase (Positive Control)
`
`Animal
`
`Dermal Reactions The Day After Patch Removal
`
`
`
`
`
`
`Number .------
`
`
`Haul-“II
`
`
`
`
`
`
`
`
`
`
`
`
`
`10
`
`15
`
`SUBSTITUTE SHEET (RULE 26)
`
`
`
`W0 96/031 19
`
`PCT/EP95/02933
`
`.22-
`
`Table 10
`
`Skin Sensitisation Test: Challenge Phase (Positive Control)
`
`
`
`Animal
`
`10
`
`
`
`
`Number ._——
`
`
`-H—--i-
`-E-.--_
`
`
`-E—--f-
`
`Hours After Patch Application
`
`
`
`
`
`
`SUBSTITUTE SHEET (RULE 26)
`
`
`
`W0 96/031 19
`
`PCT/EP95/02938
`
`-23-
`
`Under the conditions of this test, the estradiol transdermal system would not
`
`be considered a sensitizer in the guinea pig. There is no comparative
`
`difference of sensitization between the tested estradiol transdermal system and
`
`Estraderm control patch.
`
`Skin irritation and sensitisation studies for each of the components (i.e. BHT,
`
`linoleic acid) of the transdermal delivery system described in this invention, did
`
`not show any degree of the irritation and sensitisation.
`
`10
`
`Example no. 7.
`
`Shear test on estradiol transdermal delivery system.
`
`The dosage units derived from the Example 1 are evaluated.
`
`15
`
`The adhesiveness of the system introduced by the present invention was
`
`evaluated by measuring the cohesive strength of the formulation matrix. A
`
`shear test, as illustrated in Figure 9, is performed according to a standard Test
`
`Procedure: A-0150 introduced by Monsanto Chemical Co.
`
`20
`
`in this test,
`
`the patch is attached to a standard steel plate 18 using a
`
`controlled pressure, and force 19 is applied to effect "sliding" of the patch from
`
`the test plate (adapted from British Pharmacopeia, Vol. II, p. A217, 1993). The
`
`results of the test are expressed as the time it takes for the patch to come off
`
`the plate, when a given force is applied.
`
`The results of this test are summarized in the following table:
`
`SUBSTITUTE SHEET (RULE 26)
`
`
`
`W0 96/031 19
`
`PCT[EDS/02938
`
`-24-
`
`Table 1 1
`
`Adhesion properties of the estradiol transdermal unit
`
`VI
`
`10
`
`
`
`system to the steel plate occured in
`all cases
`
`system to the steel plate occured in
`all cases
`
`Average 293/std.dev. = 28
`
`SUBSTITUTE SHEET (RULE 26)
`
`
`
`W0 96/031 19
`
`PCT/EMSl02938
`
`CLAIMS
`
`-25-
`
`1.
`
`'
`
`A composition for use in
`
`a transdermal drug delivery system
`
`comprising:-
`
`5
`
`(a)
`
`an adhesive;
`
`(b)
`
`an estrogen; and
`
`10
`
`(c)
`
`a flux enhancer.
`
`2.
`
`A composition according to claim 1 wherein the adhesive is at least one
`
`acrylic adhesive.
`
`15
`
`3.
`
`A composition according to claim 2 wherein the adhesive is a mixture
`
`of two acrylic adhesives.
`
`4.
`
`A composition according to claim 3 wherein the two acrylic adhesives
`
`are in a dry weight ratio of about 80% to about 20% respectively.
`
`20
`
`5.
`
`A composition according to any one of claims 1 to 4 wherein the amount
`
`of estrogen is from about 0.1 to about 8 % WM.
`
`6.
`
`A composition according to claim 5 wherein the amount of estrogen is
`
`25
`
`2% WM.
`
`7.
`
`A composition accor
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