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`
`USUUSFJ19477A
`
`United States Patent
`[19]
`[11] Patent Number:
`5,919,477
`
`Bevan et al.
`[45] Date of Patent:
`Jul. 6, 1999
`
`[54] TRANSDERMAL SYSTEM FOR
`SIM ULTANEOUS DELIVERY 0]: A NUM BER
`OF ACTIVE PRINCIPLES
`
`'75]
`
`,
`.
`-
`.
`-
`—.
`.
`..
`Invem‘m" Bruno Belan’ Lhwgny 5‘1"“ sauvw’
`Cécile Aillaud, Dijon, both of France
`
`I73] Assignee:
`
`lmhoratoiltes D'Hygiene et de
`Dietetique, Paris, France
`
`121] Appl.No.:
`
`081849,688
`
`[22]
`
`P(?'l‘|-‘iled:
`
`Dee.9,1995
`
`[as] PCTNOJ
`
`PCT1FR95101696
`
`§ 371 Date:
`
`Jun. 11, 1997
`
`§ 102(e) Date: Jun. 11, 1997
`
`[87] PCT Pub. No; “1096119203
`
`PCT Pub. Date: Jun. 27, 1996
`
`|30]
`
`Foreign Application Priority Data
`
`Dec. 21, 1994
`
`[FR]
`
`France ................................... 94 15410
`
`Int. Cl.“ ...................................................... A61F 13102
`[51]
`[52] US. Cl. ............................................. 4241448; 4241449
`[58] Field of Search ...................................... 4241449, 448
`
`[56]
`
`References Cited
`US. PATENT DOCUMENTS
`
`311990 Iieiber ..................................... 4241449
`4,911,707
`.. 00413117
`1111991 Wick
`1116442;
`
`.. 4241448
`1211991 Lee
`5.0711556:
`711997. Muller
`4241449
`5,1284}?
`91199-1 Kochinkc ................................ 1121114113
`5,350,581
`711995 Hoffman" .......................... 4241448
`5,533,731:
`FOREIGN PATENT DOCUMENTS
`
`94110383
`9006736
`
`611991]
`3.11994
`
`“’II’U.
`“’IPO.
`
`Primary Examiner—D. Gabrielle Brouilletle
`Attorney, Agent, or Firm—Carmen l’ili Curtis
`
`[57|
`
`ABSTRACT
`
`A novel system for pereutaneously delivering at least two
`active principles, consisting of at
`least
`two juxtaposed
`devices. The system includes (i) a first device containing a
`mixture of all the active principles in which at least one first
`active principle (A) is present in an amount enabling the
`effective therapeutic dose to be delivered, and at least one
`second active principle (B) is present in an amount smaller
`than the amount needed to deliver the effective therapeutic
`dose; and (ii) one or more additional devices each containing
`a single active principle (B) selected from those in the first
`device and provided in an amount smaller than the amount
`needed to deliver the effective therapeutic dose, said addi—
`tional device(s) being designed to top up the amount ol‘ each
`of the active principles (B) in the system until the elTeetive
`therapeutic dose is achieved.
`
`4,666,441
`
`511.08? Andriola ................................. 6041897
`
`20 Claims, No Drawings
`
`  
`
`

  
`
`MYLAN - EXHIBIT 1013
`
`

`

`5,919,477
`
`1
`TRANSDERYIAL SYSTEM FOR
`SIMULTANEOUS DELIVERY OF A NUMBER
`OF ACTIVE PRINCIPLES
`
`This Application is a 371 of PCTfFRQSr'01696, filed Dec.
`9, 1995.
`
`FIELD OF THE INVENTION
`
`The present invention relates to systems for the transder-
`mal delivery of
`a number of active principles
`simultaneously, said systems being designed so as to facili-
`tate adjustment of the delivered doses of one or more active
`principles and reduce the surface area of such systems in
`order to improve safety and comfort when used by the
`patient.
`
`PRIOR ART
`
`There are numerous devices currently in existence for the
`transdermal delivery of an active principle.
`the
`The composition of these devices is defined for
`purfxrse of (i) ensuring a good physicochernical stability of
`the active principle over time, and (ii) obtaining an optimal
`transdermal absorption llux per unit surface area. Thus the
`dose of active principle delivered in the course of a treatment
`is mainly determined by the surface area of the device
`applied to the skin.
`Now, this surface area must not be so large as to cause
`physical discomfort when the device is used and produce a
`device whose size and esthetic appearance would rule out its
`use altogether. The device must also have good adhesion and
`cohesion properties, making it easy, pleasant and discreet to
`apply when used.
`Thus devices containing a single active principle are
`produced at the present time and satisfy these demands, i.e.
`they are efl‘ectivc, small and comfortable and neither creep
`nor become detached during use.
`0n the other hand, the production of such ellicient sys-
`tems for the delivery of two active principles, or even more
`than two active principles, still presents numerous problems
`which becorue increasingly difficult to solve as the number
`of active principles to be delivered increases.
`Afirst known technical solution among those envisaged in
`the prior art involves transdcrmal systems which consist of
`a single device containing all the active principles mixed
`together. Such systems are described for example in patent
`documents EP-A-0 285 563, WO-A-92r'0f7589, WO-A-92f
`07590 and W0—A—94i06383. Although these systems have
`the advantage of being small,
`they prove generally very
`complex, if not impossible, to perfect.
`In fact, by virtue of their nature and their physicochemical
`properties, the active principles behave in different ways
`towards the corneal
`layer and often have important influ-
`ences on the composition of the device.
`Because the skin has different permeabilities to the active
`principles, each active principle has a different absorption
`flux. It therefore proves virtually impossible to obtain the
`desired therapeutic dose of each active principle to be
`delivered by simultaneously using the same absorption area
`and the same formulation.
`
`Furthermore, if it is necessary to readjust the delivered
`dose of at least one of the active principles during clinical
`development, it is impossible to modify the delivered dose
`of this active principle independently of those of the other
`active principles without having to change the formulation
`of the other components.
`
`2
`Similarly, it is also common for one and the same system
`for the transderrnal delivery of a number of active principles
`to be used for delivering several dosages of these active
`principles according to the patients or pathological condi—
`tions treated.
`
`This will be done by choosing dilIerent surface areas of
`said system on account of the fact that the dose of active
`principle delivered will be proportional to the surface area
`applied to the skin.
`In the case of such a system for the delivery of a number
`of active principles where different posologies are required,
`if at least two active principles do not remain in the same
`dose ratio for all the chosen posologies, or if one active
`principle is delivered at a fixed dose, it will be impossible to
`obtain the different desired posologies by varying the sur—
`face area of the device, since in this case the doses of each
`active principle vary simultaneously as a function of the
`surface area and in constant dose ratios.
`
`In both the above cases, therefore, the benefit of the work
`already put in is lost and comfortable systems with good
`fluxes and good physical properties are forsaken.
`Now.
`the choice of components fon‘ning part of the
`formulation of the device becomes very rapidly restricted as
`the number of active principles increases, the latter often
`imposing conflicting constraints.
`In fact, the active principles may be partially or totally
`incompatible with certain constituents of the formulation
`(resins, solvents, plasticizers, polymers, skin absorption
`promoters, etc). They may have different solubililics and
`stability temperatures and some of them recrystallive over
`time, degrade when applied or can only be used in the
`composition at concentrations which are too low to obtain
`the intended therapeutic dosage. Likewise, there is no uni—
`versal skin absorption promoter for all active principles in
`order to increase their transdermal fluxes. Therefore,
`to
`administer dilferent active principles, it is often necessary to
`use several promoters or solvents. Now, the introduction of
`any new substance may cause or raise problems of irritation
`and the system‘s cohesion or adhesion.
`By the same token, this set of constraints (compatibility,
`solubility, etc.) also affects the different constituents of the
`formulation other than the active principles, thereby cxac—
`erbating the dilIiculties of optimizing their role in the
`formulation and benefiting front the specific advantages they
`can bring.
`In practice, this first technical solution is not workable and
`leads to an impasse or, at best,
`to devices hampered by
`obvious disadvantages for the use of this type of pharma—
`ceutical form.
`
`Asecond known solution for the simultaneous delivery of
`a number of active principles consists in producing a system
`formed of several transderntal devices applied to the skin,
`each device containing a single active principle. Such sys-
`tems are described for example in patent documents “IO—A—
`943’06383, \VO-A-90106736 and W0-A-94,’ 13354.
`This avoids the above problems of compatibility, stability
`and adjustment of the desired dosage. Attainment of the
`desired dose of each active principle is then defined by tile
`surface area of each device.
`
`It is this which constitutes the main disadvantage of this
`solution, because such a system generally has a large overall
`surface area, its size increasing with the number of active
`principles.
`Now,
`in general, the larger a transdcrmal system is, the
`more dilIicult it is to use. This is because it becomes harder
`
`5
`
`If)
`
`‘15
`
`-
`
`3D
`
`35
`
`4E)
`
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`
`

`

`5,919,477
`
`3
`to optimize its adhesion and cohesion properties over the
`whole of the surface area which is to come into contact with
`the skin.
`
`Thus, the larger the system is, the greater will be the risk
`of increasing the likelihood of creep of the adhesive mass
`and hence soiling of the clothes, sensations of pulling,
`discomfort or even irritatiotr of the skin or cohesive rupture
`when the system is removed, making the system less man-
`ageable and acceptable.
`Furthermore, as the dose delivered over time is deter-
`mined by the surface area of the device applied to the skin,
`any increase in surface area increases the risk of partial or
`total detachment of the system or puckering, which can
`result in a loss of activity because of non-uniform contact
`with the skin, particularly over curved parts of the body or
`parts which frequently move.
`Similarly,
`in the case of a reservoir, an inhomogeneous
`distribution over the whole of the surface area which is to
`
`if)
`
`‘15
`
`come into contact with the skin necessarily modifies the
`dose released and does not allow the desired therapeutic
`activity to be achieved. Thus, in the case of an excessively
`large reservoir system, where the liquid or semiliquid
`{solution or gel) containing the active principle tends to
`stagnatc in the lower part ofthe reservoir under the action of
`gravity,
`the surface area utilized will be reduced and the “
`system will ultimately be less effective.
`Another disadvantage of a large system, whatever its
`nature may be, is the risk that it will be poorly accepted by
`the patient because it is too visible and therefore difficult to
`conceal.
`
`3D
`
`The esthetic appearance and the discreetness of the trans-
`dcrmal system, possibly combined with a sensation of
`physical discomfort, are actually important parameters for
`the acceptability of the product and the patient’s compliance
`with the therapeutic treatment.
`All these problems therefore detract from the comfort of
`the system when in use or, even worse, from its therapeutic
`eflicacy when used by the patient.
`The solutions of the prior art are therefore unsatisfactory
`because they do not succeed in reconciling the possibility of
`simply adapting the delivered doses of each of the active
`principles with the production of a system of small overall
`surface area, allowing safer and more comfortable use when
`the system is applied to the skin.
`OBJECT OF THE INVENTION
`
`In the field of the simultaneous transdermal delivery of a
`number of active principles, it would therefore be desirable
`to provide a novel
`technical solution which enables the
`desired compromise to be reached without
`the above-
`mentioned disadvantages.
`It is this object which the present invention proposes to
`achieve through the production of a system for the simul-
`taneous transdermal delivery of at least two active principles
`which makes it possible simply to adjust the dose of each
`active principle to be delivered, while at
`the same time
`having a reduced total surface area.
`SUBJECT 01’ THE INVENTION
`
`is achieved through the
`'lhe above-mentioned object
`production, as a novel industrial product, of a novel system
`for the transdermal delivery of at least two active principles
`which consists of at
`least
`two juxtaposed [or associated)
`dcviocs, said system being characterized in that it comprises
`(i) a first device containing a mixture of all the active
`principles in which at least one first active principle (A)
`
`35
`
`4E)
`
`45
`
`SD
`
`55
`
`6E)
`
`05
`
`4
`in an amount which enables the effective
`is present
`therapeutic dose to be delivered, and at least one second
`active principle (B) is present in an amount which is
`less than that required to deliverthe effective therapeu—
`tic dosc, and
`(ii) one or more additional devices each containing a
`single active principle (B) selected from those present
`in the first device and provided in an amount which is
`less than that required to deliver the effective therapeu—
`tic dose, said additional device or devices making up
`the amount of each of the active principles (B) present
`in the system until
`the effective therapeutic dose is
`obtained.
`
`DETAILED DL‘SCRlP'l'KNV 01“ THE
`INVENTION
`
`The expression "transdermal system” in the present
`invention denotes the association of at least two devices for
`
`the active
`
`the purpose of simultaneously delivering all
`principles by application to the skin.
`“Device” is understood here as meaning any system used
`to deliver at least one active principle transdermally. Such
`devices are generally classed in two major categories:
`reservoir devices, in which the active principle or prin-
`ciples are dissolved in a solvent acting as a vector for
`transporting the active principle across an adhesive or
`non—adhesive microporous membrane; and
`matrix devices, in which the active principle or principles
`are dissolved or dispersed in a polymer network fUt’IIl-
`ing the matrix, which can be self-adhesive or non-
`adhesive.
`
`These devices can be monolayer or multilayer (also called
`lamellar], i.e. formed by the superposition of several matri—
`ces or reservoirs which may or may not contain one or more
`active principles, said matrices or reservoirs optionally
`being separated by microporous membranes.
`The association of at least two devices according to the
`invention can be carried out by techniques known to those
`skilled in the art, for example by sticking onto a support
`coated with adhesive, juxtaposed double coating or heat
`sealing onto a single support. The devices will have a single
`support in the above cases, but it is also possible to manu—
`facture a system in which each device has an identical or
`different independent support, association being effected by
`juxtaposition ofthe devices, for example by heat sealing, or
`by associating the devices on an additional support, always
`by the same techniques.
`The support used maybe any support generally employed
`in occlusive or non—occlusive transdermal systems, of vari—
`able thickness, which is impermeable to the constituents of
`the devices.
`Preferred supports will be for example in the form of a
`polyethylene, polypropylene or polyester film, a composite
`consisting of polyethylene and a vinyl acetateiethylcne
`copolymer, an aluminixed film or else a foam.
`In practical terms, the whole of the system or each of the
`devices may be covered with a protective layer or film which
`can be peeled off before the system is used, it being possible
`for said system itself to be packaged in a leaktight protection
`such as, for example, a polyethylene!raluminum composite.
`A device according to the present invention can he made
`of the materials familiar to those skilled in the art, for
`example natural or synthetic polymers {such as acrylics or
`derivatives thereof, silicones, block copolymers, vinyl
`acetateicthylene copolymers,
`rubbers and derivatives
`thereof, etc), according to the properties of the active
`
`

`

`5,919,477
`
`5
`principles to be delivered. Other appropriate known prod-
`ucts generally used by those skilled in the art may be
`associated with said active principles, examples being solu-
`bilizing agents, plasticizers, resins, stabilizers, bulking
`agents or skin permeation promoters.
`Likewise, the membranes which may be employed are
`those generally used in the art
`in the field of transdermal
`systems, examples being a film of ethylenefvinyl acetate
`copolymer.
`In the case where one or more matrix devices are used in
`
`6
`amoxycillin in association with clavulanic acid, sul-
`fametoxaxole in association with trimethoprim, eryth-
`romycin in association with aoctylsulfafurazolc or
`erythromycin in association with tetracycline.
`Advantagcously, a system in which the active principles
`to be delivered simultaneously are chosen on the one hand
`from estrogen compounds and on the other hand from
`progestin compounds is particularly recommended.
`
`if)
`
`BEST MODE
`
`15
`
`the system according to the present invention, said matrix
`devices are manufactured by the coating techniques gener-
`ally known in the art, either in a solvent phase or by the
`so—called hot melt
`technique (i.e.
`in the absence of a
`solvent}.
`Likewise, in the case where devices of the reservoir type
`are used, said devices are manufactured by the techniques
`known in the art, an example being creation ofthe reservoir
`hy heat—sealing the support onto a membrane and simulta-
`neously or non—simultaneously filling the reservoir.
`In both cases, in the context of industrial production, the
`size of the devices is set
`to the appropriate dimensions,
`according to the amount of active principle or principles
`present per unit surface area, to give the chosen doses of
`active principles to be delivered by the system over a given -
`time.
`
`The transdermal system according to the invention can
`have an)r geometric shape: square, rectangular, circular or
`oval. The dill‘erent devices can be arranged either side-by-
`side or concentrically, each device then winplctcly sur-
`rounding the previous one, or any other geometric construc-
`tion can be used. The devices can optionally be separated or
`surrounded by one or more additional layers, which can be
`adhesive in order to help hold the unit together if necessary.
`Any combination of active principles capable of being
`applied lransdermally and exerting either a topical or a
`systemic action can be used within the framework of the
`present invention.
`The following possible associations may be mentioned
`among these combinations:
`(a) one or more estrogens with one or more progestins,
`natural or synthetic, for contraceptive purposes or in
`the treatment of the symptoms of menopause.
`for
`example estradiol, ethynylestradiol, estriol and deriva-
`tives thereof in aswciaticn with norethisterone acetate,
`norgestrel,
`levonorgestrel, desogestrel, norgestimate,
`lynestrenol, gestodene, nomegestrol acetate or
`dienogest;
`(b) [t—bloclrer and diuretic compounds useful especially in
`cardiovascular diseases, for example timolol, pindolol,
`bufradol, indenolol or nipradinol
`in association with
`amilonide or hydrochlothiazide;
`(c) corticoid and antihistamine compounds useful espe-
`cially in the treatment of allergies,
`for example
`methylprednisolone, prcdnisolone, hydrocortisone,
`beclomethazone or triatucinolone in association with
`
`astemizole, dexchlorpheniramine. eetirizine, diphenyl-
`hydromine chloride or chloro-pheniramine;
`(d) analgesic and anti—inflammatory compounds useful
`especially in the treatment of pain, for example acetyl-
`salicylic acid, paracetamol or noramidopyrine in asso-
`ciation with mefenamic acid,
`llufenamic acid,
`diclofenae, oxyphen—butazone, ibuprofen, naxoprene or
`fenbufene; and
`(e) antibacterial and antibiotic compounds useful espe-
`cially in the treatment of infections,
`for example
`
`3D
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`35
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`
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`
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`
`05
`
`The best mode of carrying out the invention consists in
`using a system for the transdermal delivery of two active
`principles (A and B), characterized in that it comprises
`(i) a first matrix device which is a matrix containing in its
`bulk the active principle A in an amount which enables
`the effective therapeutic dose to be delivered, and the
`active principle B in an amount which is less than that
`necessary to deliver the effective therapeutic dose, and
`(ii) a second matrix device which is a matrix containing
`in its bulk. the active principle B in an amount which
`makes up the amount present in said first matrix device
`until its effective therapeutic dose is obtained.
`In other words, a system is recommended which consists
`of two juxtaposed (or associated) matrices, this system being
`such that a first matrix which contains a mixture of the two
`active principles, where one of the two is delivered at a dose
`which is less than its effective therapeutic dose, is combined
`with a second matrix which contains this same active
`principle and which enables its effective therapeutic dose to
`be delivered.
`
`This system is very useful for the simultaneous delivery
`of an estrogen and a progestin, in particular for the simul—
`taneous delivery of different doses of
`l7-[5-estradiol,
`between 25 and 100 pg per 24 hours, and ditferent doses of
`norethisterone acetate, between 100 and 800 ,ng per 24
`hours, in 17—[5—estradioh’norethistcrone acetate dose ratios of
`1/54 to 1/3 respectively. said doses being therapeutically effec-
`tive in the treatment ofthe symptoms of menopause and the
`resulting cardiovascular risks.
`The advantages and characteristics of the invention will
`be understood more clearly from the following description
`of Examples of systems produced according to the invention
`and experiments comparing them with systems described in
`the prior art. ()fcourse, these details. taken as a whole do not
`in any way imply a limitation but are given by way of
`illustration. The systems according to the invention and the
`comparative systems are produced by dilferent combina-
`tions of the matrix devices described below.
`
`EXAMPLE 1 (device 1)
`
`47.8 g of LEVAPREN® 4501’ (an ethylenefvinyl acetate
`copolymer (abbreviated to EVA below) marketed by
`BAYER), 48 g of crotamiton [N-ethyl-Z-N-(E-
`methylphcnyl)-2-butcnamide] (marketed by BOB-
`llRINGER INGEIJIEIM], 0.2 g of lRGANOX® T5215 (an
`antioxidant marketed by CIBA—GEIGY) and [15.53 g of
`ethyl acetate are placed in a vessel. The mixture is heated for
`5 hours until the ]:'.VA has completely dissolved. It is stirred
`at room temperature for 1 hour and 4 g of norethisterone
`acetate (abbreviated to NETA below), previously dissolved
`in 20 g of tetrahydrofuran, are then added. The mixture
`obtained is stirred for about 30 minutes until it is completely
`homogeneous; it is then left to stand until the bubbles have
`totally disappeared. The [iiass obtained is coated onto a
`siliconizcd polyester film at room temperature (15—25“ C.)
`to give a deposit of material of (100:10) gfmz. The unit
`
`

`

`5,919,477
`
`7
`for 30 minutes and then
`obtained is heated at 70° C.
`transferred to a polyethylene support. The resulting product
`is then cut to appropriate dimensions. If necessary, the cut
`products are packaged in sachets, envelopes or lcaktight
`enclosures.
`
`EXAMPLE 2 (device 2)
`
`The procedure is analogous to Example 1 above using
`49.8 g of I.EV.«\PREN® 450R 44 g of crotamiton, 0.2 g of
`IRGANOX® B215, 116.2 g of ethyl acetate, 2 g of 17—[3-
`estradiol and 4 g ofrtorethisterone aoetate [added at the same
`time as the 17—fi—estradiol), these two hormones being dis-
`solved together in 30 g of tetrahydrofuran.
`
`EXAMPLE 3 (device 3)
`
`It)
`
`‘15
`
`20.7 g of ELVAX® 46]. and 6.9 g of EI.VAX® 46
`{ethylenei’vinyl acetate copolymers marketed by DU PONT)
`and 6 g of ETHOCEL® (ethyl cellulose marketed by DOW
`CHEMICAL) are placed in a vessel, with stirring, and .
`heated to about 130° C. 1.2 g of 17—[3—estradiol and 18.9 g
`of EU'I'ANOI.® (i
`(2-octyldodecanol marketed by
`HENKEL) are then incorporated gradually at 130° C., with
`continued stirring, and the mixture is stirred until
`it
`is
`completely homogeneous. 6.3 g of SURFADONE® [.P300 L
`{N—dodecyl—Z—pyrrolidone marketed by GAF
`CORPORATION) are [lieu added at a temperature of the
`order of 100 to 110° C. and stirring is continued until the
`mixture is perfectly homogeneous. The mixture obtained is
`coated, at a temperature between 100 and 140° C., onto an
`anliadhesive temporary intermediate support, especially a
`siliconized [xtlyester film, at a rate of (100110) gimz. The
`matrix obtained is transferred to a polyethylene support.
`
`3D
`
`EXAMPLE 4 [device 4)
`
`The procedure is identical to Example 3 except that 11 g
`of ELVAX® 46L. 11 g of ELVAX® 46, 5 g of E'I‘HOCL'L®,
`15 g of EUTANOIIED G, 5 g of SURFADONE® I.P300, 1 g
`of 17-[i-estradiol and 2 g of norethisterone acetate are used
`in this case.
`
`EXAMPLE 5 (device 5)
`
`The procedure is identical to Example 3 except that 33.75
`g of EI.VAX® 46L. 11.25 g of ELVAX® 46, 10 g of
`ETHOCEL®, 30.5 g of EUTANOL® G, 4 g of norethister-
`one acetate and 10.5 g of SURFADONE® 1.13300 are used
`in this case.
`
`EXAMPLE 6 [device 6)
`
`13.35 g of KRM‘ON G® 1657 (a poly(styrenei‘ethylenef
`butylencflstyrene) three—block copolymer marketed by
`SHELL), 0.1 g of IRGANOX® 565 (an antioxidant mar-
`keted by ClBA-GEIGY), 12.5 g of ZONKTAC® 105L (a
`tackifying resin marketed by ARIZONA CHEMICAL),
`10.25 g of PARAPOI.® 950 (an n-butenefisobutylene
`copolymer marketed by EXXON CHEMICAL), 10.25 g of
`EU'I‘ANOL® G (2—octyldodecanol marketed by HEIN'KEL)=
`3 g of SURPADONE® Ll’300 (N—dodccyl—Z—pyrrolidone
`marketed by CAI" CORPORATION) and 25.6 g of cyclo-
`hexane are placed in a 250 ml beaker. The mixture is stirred
`for 6 hours, while being heated at 60° C., until the constitu-
`ents have completely dissolved. 0.55 g of norethisterone
`aoetate, previously dissolved in 2.75 g of tetrahydrofuran, is
`then added. The mixture obtained is stirred for 30 minutes
`until it is completely homogeneous, and then left to stand
`until
`the bubbles have totally disappeared. The mixture
`
`35
`
`:10
`
`45
`
`SD
`
`55
`
`60
`
`05
`
`8
`obtained is coated onto a siliconized polyester film at a rate
`of (100110) grin: at room temperature (IS—25° (1). After
`heating at 70° C.
`for 0.5 hour,
`the matrix obtained is
`transferred to a polyethylene support. The product is then cut
`to appropriate dimensions and packaged in sachets if nec—
`essary.
`
`EXAMPLE 7 (device 7)
`
`13.8 g of VECTUR® 4211B [a poly(styrcnciisoprenet
`styrene) three—block copolymer marketed by EXXON
`CHEMICAL], 23.85 g of ECR® 385 (a tackifying resin
`marketed by EXXON CHEMICAL), 0.1 g of IRGANOX®
`565 (an antioxidant marketed by CIBA—GEIGY), 3.5 g of
`SURFADONE® I.P300 (N-dodecyl-2-pyrrolidone mar-
`keted by BOEHRINGER INGEIHEIM), 7.5 g of [AURO—
`GIYCOI.® (a mixture of the monoester and diester of
`propylene glycol and lauric acid, marketed by
`GA'ITEFOSSE) and 19.8 g of ethyl acetate are placed in a
`250 ml beaker. This mixture is stirred, while being heated at
`60c (3., until the compounds have completely dissolved. A
`solution of 1.25 g of norethisterone acetate, previously
`dissolved in 6.25 g 01 tetrahydrol'uran, is then added. The
`resulting mixture is stirred for about 30 minutes until it is
`completely homogeneous. It is left to cool until the bubbles
`have totally disappeared. The resulting mass is coated onto
`a siliconized polyester film at a rate of (1101-10) giro: at
`room temperature (ls—30° (3.). The coating produced is
`heated at 50° C. for at least 30 minutes and then transferred
`to a polyethylene support. The product is cut into shapes of
`the desired dimensions.
`
`The advantages of the present invention were illustrated
`by carrying out ex vivo permeation tests on the abdominal
`skin of male nude mice according to the following protocol:
`
`The amounts of hormones (i.e. steroids) released by a
`transdermal device with a surface area of 2.54 cmz, previ-
`ously cut out with a hollow punch and deposited on a 3.14
`cm2 disk of abdominal skin of a male nude mouse, are
`measured in a static glass cell, thermostated at 37° C, which
`has a receiving compartment with a volume of 11.5 ml
`containing a receiving phase made up of an isotonic
`solutionr’PEG400 mixture (75!25; va).
`
`Samples of the receiving solutions are taken 2:12, 4, 6, 8,
`12, 16, 20 and 24 hours and assayed by liquid chromatog-
`raphy. To allow for the variability of the results associated
`with the intrinsic permeability of the skin samples, each
`permeation experiment for a sample of transdermal device is
`performed on a minimum of 3 to 5 skin samples. The result
`given is the mean obtained [or each device from these
`experiments.
`
`The following mean skin absorption fluxes were thus
`obtained for 17-[i-estradiol
`(Fm) andfor norethisterone
`acetate (FNETA) in the ease of devices 1
`to 7:
`
`Device 'l: FNHA=035=016 gtgfcmth
`Device 2: FES=U.2=U.07 Ictgtcmth 1~‘NETA=U.3¥):0.1
`ngfcm‘t’h
`Device 3: FM=0.61:0.08 ygtcm’fh
`Device f: FE5=0.5710.13 pgfcmzjh FNEm=0-5710-]7
`.trgfcmflh
`Device 5: FNETA=0.5:0.03 ttgfcntci’h
`Device 6: er=0.47=0.05 gtgfcmgth
`Device 7: 1:“.E,,,=0.8910.12 gtgfcmzth
`
`

`

`5,919,477
`
`10
`
`TABLE IV
`
`
`Tables I
`
`9
`to V illustrate the reduction in surface area
`
`obtained by the systems according to the invention, relative
`to a comparative system formed of two juxtaposed devices
`each containing a single active principle, in the case of the
`simultaneous transdermal delivery of 17-[3-estradiol and
`norethisterone acetate.
`
`'l'hus Table I compares a system I according to the
`invention, consisting of devices 4 and 5, with a comparative
`system Ia, consisting of devices 3 and 5.
`Table II compares a system I] according to the invention,
`consisting of devices 2 and 1, with a comparative system Ila,
`consisting of devices 3 and 1.
`Table III compares a system [I] according to the
`invention, consisting of devices 4 and 1, with a comparative
`system Illa, consisting of devices 3 and 1.
`Table IV compares a system IV according to the
`invention, consisting of devices 4 and 6, with a comparative
`system IVa, consisting of devices 3 and 6.
`Table V compares a system V according to the invention,
`consisting ofdevices 4 and T", with a comparative system Va,
`consisting of devices 3 and 7.
`The abbreviations used in these Tables have the following
`meanings:
`SI)1 represents the surface area of the first device,
`expressed in cmz.
`SD3 represents the surface area of the second device,
`expressed in cmz.
`5 represents the total surface area ofthe system formed by
`the juxtaposition of both devices, expressed in cmz.
`G represents the reduction in surface area, expressed as a
`percentage, for the systems according to the invention
`(represented by the second line of the Tables) relative
`to systems formed by the juxtaposition of two devices
`each containing a single active principle [represented
`by the first line of the Tables).
`The first device contains a mixture of 'l7-[3-estradiol and
`norethisterone acetate in the case of the systems according
`to the invention, or 17—[l—estradiol only in the ease of the
`comparative systems.
`The second device always contains norethisterone acetate
`only.
`
`TABLE I
`
`
`ST),
`
`ST):
`
`S
`
`G
`
`Ln
`
`If)
`
`15
`
`35
`
`40
`
`Comparative system In
`3.4
`20.8
`24.2
`System I
`3.6
`15.1"
`20.3
`16.1
`
`
`SD
`
`'I‘ABIJL II
`
`ST},
`8D,.
`S
`G
`
`
`Comparative system Ila
`System II
`
`3.4
`10.4
`
`29.8
`18.1
`
`3.3.2
`25.5
`
`14.1
`
`55
`
`60
`
`TABLE III
`
`
`SI)1
`SI)2
`S
`(1
`
`3.3.2
`29.8
`3.4
`Comparative system Illa
`
`
`
`
`3.6 23.8 2?.4System III 17.3
`
`
`
`
`
`
`
`
`
` SD. SD, S G
`
`Comparative system [Va
`System [V
`
`3.4
`3.6
`
`22.2
`11?
`
`25.6
`21.3
`
`16.8
`
`TABLE V
`
`
`
`SD 1
`5132
`S
`G
`
`Comparative system Va
`System V
`
`3.4
`3.6
`
`11.7
`9.4
`
`15.1
`13
`
`13.9
`
`In the present case it is desired to deliver the following
`therapeutically effective doses:
`50 gig of '17—[i—estradiol per 24 hours, and
`250 gig of norethisterone acetate per 24 hours.
`If it is desired simultaneously to deliver these two hor—
`mones contained in a single device, the ditference in skin
`permeability, i.e. skin absorption flux, between the norethis—
`terone acetate and the IY—B—estradiol must be 5. Now, in
`practice, such a dilference, which is theoretically obtainable
`although already difficult to achieve as such, proves impos-
`sible to obtain if allowance is made for the constraints of
`stability, comfort and adhesive and cohesive properties
`required by the marketing of such a device.
`Thus devices 2 and 4, which have these good physieo—
`chemical properties and oll'er a good level of comfort, do not
`make it possible to achieve adjustment of the desired doses.
`It is impossible to obtain the desired effective dose of
`norethiste rone acetate without a 25-fold and 5-fold increase,
`respectively, in the doses of I7—[fi—estradiol delivered. The
`alternative solution, which uses a system