US005919477A
`5,919,477
`[11] Patent Number:
`[15
`United States Patent
`Bevanetal.
`[45] Date of Patent:
`Jul. 6, 1999
`
`
`4,911,707
`[54] TRANSDERMAL SYSTEM FOR
`«3/1990 Heiber .....cscssesssssesessssnecsass 424/449
`5,064,422
`SIMULTANEOUS DELIVERY OF A NUMBER
`» 604/307
`11/1991 Wick
`
`5,071,656
`OF ACTIVE PRINCIPLES
`« 424/448
`12/1991 Lee ...
`§,128,137=F/L992 Muller... cccccsstecsssersseennes 424/449
`9/1994 Kochinke wicca 424/443
`.
`,
`a
`-
`aa
`.
`.
`5,350,581
`Inventors: Bruno Bevan, Chevigny Saint Sauveur;
`:
`one
`;
`Cécile Aillaud, Dijon, both of France
`5,538,736
`7/1996 Hoffmann o....cssececscesneeeereeensees 424/448
`FOREIGN PATENT DOCUMENTS
`
`[75]
`
`.
`[73] Assignee: Laboratoires D’ Hygiene et de
`Dietetique, Paris, France
`
`[87]
`
`08/849, 688
`
`[21] Appl. No.:
`—
`Dec. 9, 1995
`PCT Filed:
`[22]
`PCT/FR95/01696
`[86] PCT No.:
`Jun. 11, 1997
`§ 371 Date:
`§ 102(e) Date: Jun. 11, 1997
`sor p
`PCT Pub. No.: WO96/19203
`PCT Pub,Date: Jun. 27, 1996
`:
`,
`[30]
`Foreign Application Priority Data
`Dee. 21, 1994
`[FR]
`France veesscssssssseseeussneuesseen 3, gserg
`[SL]
`Tmte C1 enc cccsssssccssssseeccesssaneessseesecsens A6LF 13/02
`[52] U.S. C1. ooeeeeesseseseneeee 424/448; 424/449
`[58] Field of Search.
`......ccscsscssesssusenssnns 424/449, 448
`
`[56]
`
`References Cited
`U.S. PATENT DOCUMENTS
`
`9406383
`9006736
`
`6/1990 WIPO .
`3/1994 WIPO.
`
`Primary Examiner—D. Gabrielle Brouillette
`Attorney, Agent, or Firm—Carmen Pili Curtis
`(57]
`ABSTRACT
`A novel system for percutaneously delivering at least two
`active principles, consisting of at
`least
`two juxtaposed
`devices. The system includes (i) a first device containing a
`mixture ofall the active principles in whichat least onefirst
`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
`«VTE CE amen inckeedeed tei meithe eect Ureapeane
`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 amountsmaller than the amount
`needed to deliver the effective therapeutic dose, said addi-
`tional device(s) being designed to top up the amount of each
`of the active principles (B) in the system until the effective
`therapeutic dose is achieved.
`
`
`
`4,666,441—S/1987) Andridla .....cceesecceeeeeeeceeseeees 604/897 20 Claims, No Drawings
`
`  
`
`

  
`
`MYLAN- EXHIBIT 1013
`
`

`

`5,919,477
`
`1
`TRANSDERMAL SYSTEM FOR
`SIMULTANEOUS DELIVERY OF A NUMBER
`OF ACTIVE PRINCIPLES
`
`This Application is a 371 of PCT/FR95/01696,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 adjustmentof 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 ofan active principle.
`the
`The composition of these devices is defined for
`purpose of(i) ensuring a good physicochemical stability of
`the active principle over time, and (i1) obtaining an optimal
`transdermal absorption flux per unit surface area. Thus the
`dose ofactive principle delivered in the course ofa 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 ta 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 andsatisfy these demands, i.e.
`they are effective, small and comfortable and neither creep
`nor become detached during use.
`On the other hand, the production of such efficient sys-
`temsfor the delivery of twoactive principles, or even more
`than twoactive principles, still presents numerous problems
`which become increasingly difficult to solve as the number
`of active principles to be delivered increases.
`A first known technical solution among those envisaged in
`the prior art involves transdermal 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-92/07589, WO-A-92/
`07590 and WO-A-94/06383. 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, ifit is necessary to readjust the delivered
`dose of at least one ofthe 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 transdermal delivery of a numberofactive principles
`to be used for delivering several dosages of these active
`principles according to the patients or pathological condi-
`tions treated.
`
`5
`
`This will be done by choosing different 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 forming part of the
`formulation of the device becomesveryrapidly 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 solubilities and
`stability temperatures and some of them recrystallize 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 different active principles,it is often necessary to
`use several promoters or solvents. Now, the introduction of
`any new substance may causc or raise problems ofirritation
`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 exac-
`erbating the difficulties of optimizing their role in the
`formulation andbenefiting from 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 knownsolution for the simultaneous delivery of
`a numberof active principles consists in producing a system
`formed of several transdermal devices applied to the skin,
`each device containing a single active principle. Such sys-
`tems are described for example in patent documents WO-A-
`94/06383, WO-A-90/06736 and WO-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 the
`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 ofactive
`principles.
`Now,
`in general, the larger a transdermal system is, the
`more difficult it is to use. This is because it becomes harder
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`5,919,477
`
`3
`to optimize its adhesion and cohesion properties over the
`whole of the surface area which is ta 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 evenirritation 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
`
`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
`stagnate in the lower part of the reservoir under the action of
`gravity,
`the surface area ulilized 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.
`
`The esthetic appearance and the discreetness ofthe trans-
`dermal 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 therapeutictreatment.
`All these problems therefore detract from the comfort of
`the system whenin use or, even worse, from its therapeutic
`efficacy when usedby 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
`numberofactive 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-
`tancous 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.
`SUBJECTOF THLE INVENTION
`
`is achieved through the
`The above-mentioned object
`production, as a novel industrial product, of a novel system
`for the transdermal delivery ofat least two active principles
`which consists of at
`least
`two juxtaposed (or associated)
`deviccs, said system being characterized in that it comprises
`(i) a first device containing a mixture of all the active
`principles in whichat least one first active principle (A)
`
`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 deliver the effective therapeu-
`tic dose, 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 amountof each of the active principles (B) present
`in the system until
`the effective therapeutic dose is
`obtained.
`
`DETAILED DESCRIPTION OF THE
`INVENTION
`
`The expression “transdermal system” in the present
`invention denotes the association ofat 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 form-
`ing the matrix, which can be self-adhesive or non-
`adhesive.
`
`These devices can be monolayer or multilayer (also called
`lamellar), ic. 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 carricd out by techniqucs known to thosc
`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 of the devices, for example byheat sealing, or
`by associating the devices on an additional support, always
`by the same techniques.
`The support used may be any support generally employed
`in occlusive or non-occlusive transdermal systems, ofvari-
`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 acctatc/cthylene
`copolymer, an aluminized 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 orfilm which
`can be peeled off before the system is used, it being possible
`for said system itself to be packagedin a leaktight protection
`such as, for example, a polyethylene/aluminum composite.
`A device according to the present invention can be 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
`acetate/ethylene copolymers,
`rubbers and derivatives
`thereof, etc.), according to the properties of the active
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`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 ethylene/vinyl acetate
`copolymer.
`In the case where one or more matrix devices are used in
`
`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 bythe
`so-called hot melt
`technique (ie.
`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
`knownin the art, an example being creation of the reservoir
`by 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 ofactive 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.
`
`30
`
`astemizole, dexchlorpheniramine, cetirizine, 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,
`flufenamic acid,
`diclofenac, oxyphen-butazone, ibuprofen, naxoprene or
`fenbufene; and
`(e) antibacterial and antibiotic compounds useful espe-
`cially in the treatment of infections,
`for example
`
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`amoxycillin in association with clavulanic acid, sul-
`fametoxazole in association with trimethoprim, eryth-
`romycin in association with acetylsulfafurazole or
`erythromycin in association with tetracycline.
`Advantageously, 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 compoundsis particularly recommended.
`
`BEST MODE
`
`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 whichis 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 amountpresentin saidfirst matrix device
`until its effective therapeutic dose is obtained.
`In other words, a system is recommended which consists
`oftwojuxtaposed (or associated) matrices, this system being
`such that a first matrix which contains a mixture of the two
`active principles, where one of the twois 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 17-(-estradiol,
`between 25 and 100 we per 24 hours, and different doses of
`norethisterone acetate, between 100 and 800 we per 24
`hours, in 17-B-estradiol/norethisterone acetate dose ratios of
`44 to Vs respectively, said doses being therapeutically effec-
`tive in the treatment of the 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 describedin
`the prior art. Of course, these details taken as a whole donot
`in any way imply a limitation but are given by wayof
`Ulustration. The systems according to the invention and the
`comparative systems are produced by different combina-
`tions of the matrix devices described below.
`
`EXAMPLE1 (device 1)
`
`47.8 ¢ of LEVAPREN® 450P(an ethylene/vinyl acetate
`copolymer (abbreviated to EVA below) marketed by
`BAYER), 48 g of crotamiton [N-ethyl-2-N-(2-
`methylphenyl)-2-butenamidc] (markcted by BOE-
`HRINGER INGELHEIM), 0.2 g of IRGANOX® B215 (an
`antioxidant marketed by CIBA-GEIGY) and 115.53 ¢ of
`ethyl acetate are placedin a vessel.The mixture is heated for
`5 hours until the EVA 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 ts stirred for about 30 minutes until it is completely
`homogeneous;it is then left to stand until the bubbles have
`totally disappeared. The mass obtained is coated onto a
`siliconized polyester film at room temperature (15—25° C.)
`to give a deposit of material of (100£10) g/m*. The unit
`
`The transdermal system according to the invention can
`have any geometric shape: square, rectangular, circular or
`oval. The different devices can be arranged either side-by-
`side or concentrically, each device then completely 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 transdermally and exerting either a topical or a
`systemic action can be used within the framework ofthe
`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 association with norethisterone acetate,
`norgestrel,
`levonorgestrel, desogestrel, norgestimate,
`lynestrenol, gestodene, nomegestrol acetate or
`dienogest;
`(b) B-blocker and diuretic compoundsuseful 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, prednisolone, hydrocortisone,
`beclomethazone or triamcinolone in association with
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`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 leaktight
`enclosures.
`
`EXAMPLE2 (device 2)
`
`The procedure is analogous to Example 1 above using
`49.8 g of LEVAPREN® 450P, 44 g of crotamiton, 0.2 g of
`IRGANOX® B215, 116.2 g of ethyl acetate, 2 g of 17-f-
`estradiol and 4 g of norethisterone acetate (added at the same
`ume as the 17-[-estradiol), these two hormones being dis-
`solved together in 30 g of tetrahydroturan.
`
`EXAMPLE3 (device 3)
`
`20.7 g of ELVAX® 46L and 6.9 g of ELVAX® 46
`(ethylene/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 2
`heated to about 130° C. 1.2 g of 17-()-estradiol and 18.9 g¢
`of EUTANOL® G (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® LP300
`(N-dodecyl-2-pyrrolidone marketed by GAF
`CORPORATION)are then added at a temperature of the
`order of 100 to 110° C. and stirring is continued until the
`mixture is perfectly homogeneous. The mixture obtainedis
`coated, at a temperature between 100 and 140° C., onto an
`antiadhesive temporary intermediate support, especially a
`siliconized polyester film, at a rate of (100+10) g/m. The
`matrix obtained is transferred to a polyethylene support.
`
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`
`EXAMPLE4 (device 4)
`
`‘The procedure is identical to Example 3 except that 11 ¢
`of ELVAX® 46L,11 ¢ of ELVAX@®46, 5 g of ETHOCEL®,
`15 g of EUTANOL® G, 5 g of SURFADONE® LP300, 1 g
`of 17-B-estradiol and 2 g of norethisterone acetate are used
`in this case.
`
`EXAMPLE5 (device 5)
`
`The procedureis identical to Example 3 except that 33.75
`g of ELVAX® 46L, 11.25 g of ELVAX® 46, 10 g of
`ETHOCEL®, 30.5 g of EUTANOL®G, 4 g ofnorethister-
`one acetate and 10.5 g of SURFADONE® LP300 are used
`in this case.
`
`EXAMPLE6 (device 6)
`
`13.35 g of KRATON G® 1657 (a poly(styrene/ethylene/
`butylene/styrene) three-block copolymer marketed by
`SHELL), 0.1 g¢ of IRGANOX® 565 (an antioxidant mar-
`keted by CIBA-GEIGY), 12.5 ¢ of ZONATAC® 105L (a
`tackifying resin marketed by ARIZONA CHEMICAL),
`10.25 g of PARAPOL® 950 (an n-butene/isobutylene
`copolymer marketed by EXXON CHEMICAL), 10.25 2 of
`EUTANOL®G (2-octyldodecanol marketed by HENKEL),
`3 g of SURFADONE® LP300 (N-dodecyl-2-pyrrolidone
`marketed by GAF CORPORATION)and 25.6 g of cyclo-
`hexane are placed in a 250 ml beaker. The mixtureis stirred
`for 6 hours, while being heated at 60° C., until the constitu-
`ents have completely dissolved. 0.55 g of norethisterone
`acetate, previously dissolved in 2.75 g of tetrahydrofuran, is
`then added. The mixture obtained is suirred for 30 minutes
`until it is completely homogeneous, and then left to stand
`until
`the bubbles have totally disappeared. The mixture
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`obtained is coated onto a siliconized polyester film at a rate
`of (100+10) g/m? at room temperature (15—25° C.). 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 ¢ of VECTOR® 4211D [a polvy(styrene/isoprene/
`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 ¢ of
`SURFADONE® LP300 (N-dodecvl-2-pyrrolidone mar-
`keted by BOEHRINGER INGELHEIM),7.5 g of LAURO-
`GLYCOL® (a mixture of the monoester and diester of
`propylene glycol and lauric acid, marketed by
`GATTEFOSSE)and 19.8 g of ethyl acetate are placed in a
`250 ml beaker. This mixture is stirred, while being heated at
`60° C., until the compounds have completely dissolved. A
`solution of 1.25 g of norethisterone acetate, previously
`dissolved in 6.25 g oftetrahydrofuran, 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 (110£10) g/m* at
`room temperature (15—20° C.). The coating produced is
`heated at 50° C. for at least 30 minutes and thentransferred
`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 cm’, previ-
`ously cut out with a hollow punch and deposited on a 3.14
`em? disk of abdominal skin of a male nude mouse, are
`measuredin a static glass ccll, 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
`solution/PEG,5, mixture (75/25; v/v).
`
`Samples of the receiving solutions are taken at 2, 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 deviceis
`performed on a minimum of 3 to 5 skin samples. The result
`given is the mean obtained for each device from these
`experiments.
`
`The following mean skin absorption fluxes were thus
`obtained for 17-f-estradiol (F,,) and/or norethisterone
`acetate (Fy-74) in the case of devices 1
`to 7:
`Device 1: Fyye74=0.35+0.16 no/em*/h
`Device 2: Fes=0.220.07 Heg/em*/h Fypz=0.3940.1
`ug/em~/h
`Device 3: F,-<=0.61+0.08 yg/em?/h
`Device 4: F,-5=0.5740.13 yug/em7/h Fyp74=0.5740.17
`Hg/om*/h
`Device 5: Fyy-74=0.5+0.03 ve/om*/h
`Device 6: Fye7=0.4720.05 wg/em?/h
`Device 7: Fye7y=0.8920.12 xg/em?/h
`
`

`

`5,919,477
`
`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-f-estradiol and
`norethisterone acetate.
`
`ta
`
`10
`
`TABLEIV
`
`
`sD,
`SD,
`5
`G
`
`
`Comparative system [Va
`System [V
`
`3.4
`3.6
`
`22.2
`12-7
`
`25.6
`21.3
`
`16.8
`
`Thus 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 II according to the invention,
`consisting of devices 2 and 1, with a comparative system IIa,
`consisting of devices 3 and1.
`‘Table IIL compares a system IJ] according to the
`invention, consisting of devices 4 and 1, with a comparative
`system I[]a, consisung 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 Vaccording to the invention,
`consisting ofdevices 4 and 7, with a comparative system Va,
`consisting of devices 3 and 7.
`The abbreviations usedin these Tables have the following
`meanings:
`SD,
`represents the surface area of the first device,
`expressed in cm.
`SD, represents the surface area of the second device,
`expressed in cm*.
`S represents the total surface area of the system formed by
`the juxtaposition of both devices, expressed in cm’.
`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 formedby 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 17-f-estradiol and
`norethisterone acetate in the case of the systems according
`to the invention, or 17-B-estradiol only in the case of the
`comparative systems.
`The second device always contains norethisterone acetate
`only.
`
`TABLEI
`
`
`SD,
`
`SD,
`
`5
`
`G
`
`40
`
`Comparative system [a
`3.4
`20.8
`24.2
`
` System [ 3.6 16.7 20.3 16.1
`
`
`
`
`
`
`50
`
`TABLEII
`
`TABLE V
`
`
`
`sD,
`SD,
`5
`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 wg of 17-f-estradiol per 24 hours, and
`250 «vg of norethisterone acetate per 24 hours.
`If it is desired simultaneously to deliver these two hor-
`mones contained in a single device, the difference in skin
`permeability, i.e. skin absorption flux, between the norethis-
`terone acetate and the 17-f-estradiol must be 5. Now, in
`practice, such a difference, 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 physico-
`chemical properties andoffer a goodlevel of comfort, do not
`makeit possible to achieve adjustment of the desired doses.
`It is impossible to obtain the desired effective dose of
`norethisterone acetate without a 2.5-fold and 5-fold increase,
`respectively, in the doses of 17-f-estradiol delivered. The
`alternative solution, which uses a system formed of 2
`juxtaposed matrix devices, one containing the 17-(\-estradiol
`and the other containing the norethisterone acetate, is less
`efficient than the solution according to the invention, which
`affords a reduction in surface area relative to the former by
`virtue of associating a first matrix device containing a
`mixture of the two hormones, in which the concentration of
`norethisterone acetate does not enable the desired dose of
`250 wg per 24 hours to be obtained, with a second device
`containing the norethisterone acetate only, which provides
`the complementary dose necessary for adjustment to 250 ug
`per 24 hours.
`Thus, for a compara