United States Patent m
`Hevan et al.
`
`[54] TRANSDERMAL SYSTEM FOR
`SIMULTANEOUS DELIVERY OF A NUMBER
`OF ACTIVE PRINCIPLES
`
`[75]
`
`Inventors: Kruno Hevan, Chevigny Saint Sauveur;
`Cecile Aillaud, Dijon, both of France
`
`[73] Assignee:
`
`I bora to ires 1)'Hygiene et de
`Uittetiijue, Paris, France
`08/849,688
`[21] Appl, No,:
`Tfci^ 9,1995
`[22] POT Filed;
`PCTfFR95/01696
`[86] PCT No.:
`Jun. U, 1997
`§371 Date:
`§ i02(c) Date: Jun. U, 1!)97
`[87] PCT Pub, No,: WO96/19203
`PCT Pub. Date: Jun. 27, 199fi
`Foreign Application Priority Data
`130]
`Dec, 2i. f994
`France
`[FRJ
`[51] Int. CI/
`[52] U.S. CI
`[58] Field of Search
`
`94 15416
`A61F 13/02
`424/448; 424/44^
`424/449, 448
`
`[56]
`
`References Cited
`U.S. PATENT DOCUMENTS
`
`Illllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllli
`5,919,477
`Jul. 6,1999
`
`US0059194T7A
`[ii] Patent Number:
`[45] Date of Patent:
`
`4,911,707
`5.U64,422
`5,071,656
`.VI ?H, 1.17
`S3Sri,5Kl
`5,538,736
`
`3/1990 Heiber
`J1/1W1 Wick
`12/1991 Lee
`7/1997 Vlulkr ....
`9/1991 Kochinke
`7/1996 Hoffmann
`POREIGN PATENT DOCUMENTS
`
`424/449
`.. 604/307
`.. 424/448
`.. 47.4/449
`.. 424/443
`424/448
`
`9406383 6/1990 WIPO.
`9006736
`3/1994 WIPO .
`
`Primary Examiner—D. Gabrielle Brouilietle
`Allorney, Agent, or Firm—Carmen Pili Curtis
`ABSTRACT
`157]
`A novel system for percutancoitsly 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 ett'cctivc 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 Ihe amount of each
`of the active principles (B) in ihe system until the effective
`therapeutic dose is achieved.
`
`4,666,441
`
`5/1987 Andriola
`
`604/897
`
`20 Claims, No Drawings
`
`  
`
`

  
`
`MYLAN - EXHIBIT 1013
`
`

`

`5,919,477
`
`1
`TRANSDKRMAL SYSTKM FOR
`SIMULTANEOUS DELIVERY OKA NUMBER
`OK ACTIVE PRINCIPLES
`
`This Application is a 371 of PCT/FR95/01696, filed Dec. 5
`9, 1995.
`
`FIELD OF THE INVENTION
`The present invention relates to systems for the transder­
`mal delivery of a number of active principles 10
`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.
`
`2
`Similarly, il is also common for one and ihe same system
`for Ihe Iransdermal 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 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 arc 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
`PRIOR ART
`active principle vary simultaneously as a function of the
`surface area and in constant dose ratios.
`llicrc arc numerous devices currently in existence for the
`In both the above cases, therefore, the benefit of the work
`transdermal delivery of an active principle.
`already put in is lost and comfortable systems with good
`llic composition of these devices is defined for the
`fluxes and good physical properties are forsaken.
`purpose of (i) ensuring a good physicochemical stability of
`Now, the choice of components forming part of the
`the active principle over time, and (ii) obtaining an optimal
`formulation of the device becomes very rapidly restricted as
`transdermal absorption llux per unit surface area. Thus the
`dose of active principle delivered in the course of a treatment 25 lhe number of active principles increases, the latter often
`imposing conflicting constraints.
`is mainly determined by the surface area of the device
`applied to the skin.
`In fact, the active principles may be partially or totally
`incompatible with certain constituents of the formulation
`Now, this surface area must not be so large as to cause
`(resins, solvents, plasticizers, polymers, skin absorption
`physical discomfort when the device is used and produce a
`device whose size and esthetic appearance would rule out its 30 promoters, etc.). They may have different solubilities and
`stability temperatures and some of them recrystallize over
`use altogether. The device must also have good adhesion and
`time, degrade when applied or can only be used in the
`cohesion properties, making it easy, pleasant and discreet to
`composition at concentrations which are too low to obtain
`apply when used.
`the intended therapeutic dosage. Likewise, there is no uni-
`Thus devices containing a single active principle are
`produced at the present time and satisfy these demands, i.e. -,5 vcrsal skin absorption promoter for all active principles in
`order to increase their transdermal fluxes. Therefore, to
`they arc effective, small and comfortable and neither creep
`administer different active principles, it is often necessary to
`nor become detached during use.
`use several promoters or solvents. Now, the introduction of
`On the other hand, the production of such ellicient sys­
`any new substance may cause or raise problems of irritation
`tems for the delivery of two active principles, or even more
`40 and the system's cohesion or adhesion.
`than two active principles, still presents numerous problems
`By the same token, this set of constraints (compatibility,
`which become increasingly difficult to solve as the number
`solubility, etc.) also affects the different constituents of the
`of active principles to be delivered increases.
`formulation other than the active principles, thereby exac­
`Afirst known technical solution among those envisaged in
`erbating the difficulties of optimizing their role in the
`the prior art involves transdermal systems which consist of
`45 formulation and benefiting from the specific advantages they
`a single device containing all the active principles mixed
`can bring.
`together. Such systems are described for example in patent
`In practice, this first technical solution is not workable and
`documents EP-A-0 285 563, WO-A-92/07589, WO-A-92/
`leads to an impasse or, at best, to devices hampered by
`07590 and WO-A-94/06383. Although these systems have
`obvious disadvantages for the use of this type of pharma­
`the advantage of being small, they prove generally very
`ceutical form.
`complex, if not impossible, to perfect.
`A second known solution for the simultaneous delivery of
`In fact, by virtue of their nature and their physicochemical
`a number of active principles consists in producing a system
`properties, the active principles behave in different ways
`formed of several transdermal devices applied to the skin,
`towards the corneal layer and often have important influ­
`each device containing a single active principle. Such sys­
`ences on the composition of the device.
`tems are described for example in patent documents WO-A-
`Because the skin has different permeabilities to the active
`94/06383, WO-A-90/06736 and WO-A-94/13354.
`principles, each active principle has a different absorption
`This avoids the above problems of compatibility, stability
`flux. It therefore proves virtually impossible to obtain the
`and adjustment of the desired dosage. Attainment of the
`desired therapeutic dose of each active principle to be
`delivered by simultaneously using the same absorption area 60 desired dose of each active principle is then defined by the
`surface area of each device.
`and the same formulation.
`It is this which constitutes the main disadvantage of this
`Furthermore, if it is necessary to readjust the delivered
`solution, because such a system generally has a large overall
`dose of at least one of the active principles during clinical
`surface area, its size increasing with the number of active
`development, it is impossible to modify the delivered dose
`of this active principle independently of those of the other 65 principles,
`Now, in general, the larger a transdermal system is, the
`active principles without having to change Ihe tbrmulalion
`more difficult it is to use. This is because it becomes harder
`of the other components.
`
`15
`
`20
`
`50
`
`55
`
`

`

`5,919,477
`
`i|)
`
`4
`is present in an amount which enables the effective
`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 amount of each of the active principles (B) present
`in the system until the effective therapeutic dose is
`obtained.
`
`3
`to optimize its adhesion and cohesion properties over the
`whole of the surface area which is to come into contact with
`the skin.
`Ilius, the larger the system is, the greater will be the risk
`of increasing the likelihood of creep of the adhesive mass 5
`and hence soiling of the clothes, sensations of pulling,
`discomfort or even irritation 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 lime is deter- 10
`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
`DETAILED DESCRIPTION OF THE
`with the skin, particularly over curved parts of the body or "
`INVLNTION
`parts which frequently move.
`Similarly, in the case of a reservoir, an inhomogeneous
`The expression "transdermal system" in the present
`invention denotes the association of at least two devices for
`distribution over the whole of the surface area which is to
`the purpose of simultaneously delivering all the active
`come into contact with the skin necessarily modifies the
`dose released and does not allow the desired therapeutic " principles by application to the skin,
`activity to be achieved. Thus, in the case of an excessively
`"Device" is understood here as meaning any system used
`large reservoir system, where the liquid or semiliquid
`to deliver at least one active principle transdermally. Such
`(solution or gel) containing the active principle tends to
`devices are generally classed in two major categories:
`stagnate in the lower part of the reservoir under the action of
`reservoir devices, in which the active principle or prin­
`gravity, the surface area utilized will be reduced and the "5
`ciples arc dissolved in a solvent acting as a vector for
`system will ultimately be less effective.
`transporting the active principle across an adhesive or
`Another disadvantage of a large system, whatever its
`non-adhesive microporous membrane; and
`nature may be, is the risk that it will be poorly accepted by
`matrix devices, in which the active principle or principles
`the patient because it is too visible and therefore difiicult to
`are dissolved or dispersed in a polymer network form­
`conceal.
`ing the matrix, which can be self-adhesive or non-
`ITie esthetic appearance and the discreetness of the trans­
`adhesive.
`dermal system, possibly combined with a sensation of
`These devices can be monolayer or multilayer (also called
`physical discomfort, are actually important parameters for
`lamellar), i.e. formed by the superposition of several matri-
`the acceptability of the product and the patient's compliance
`35 ces or reservoirs which may or may not contain one or more
`with the therapeutic treatment.
`active principles, said matrices or reservoirs optionally
`All these problems therefore detract from the comfort of
`being separated by microporous membranes.
`the system when in use or, even worse, from its therapeutic
`The association of at least two devices according to the
`efficacy when used by the patient.
`invention can be carried out by techniques known to those
`The solutions of the prior art are therefore unsatisfactory 40 skilled in the art, for example by sticking onto a support
`because they do not succeed in reconciling the possibility of
`coated with adhesive, juxtaposed double coaling or heat
`sealing onto a single support. The devices will have a single
`simply adapting the delivered doses of each of the active
`support in the above cases, but it is also possible to manu­
`principles with the production of a system of small overall
`facture a system in which each device has an identical or
`surface area, allowing safer and more comfortable use when
`45 different independent support, association being effected by
`the system is applied to the skin.
`juxtaposition of the devices, for example by heat sealing, or
`OBJECT OF THE INVENTION
`by associating the devices on an additional support, always
`In the field of the simultaneous transdermal delivery of a
`by the same techniques.
`The support used may be any support generally employed
`number of active principles, it would therefore be desirable
`to provide a novel technical solution which enables the 50 in occlusive or non-occlusive transdermal systems, of vari-
`desircd compromise to be reached without the above-
`able thickness, which is impermeable to the constituents of
`mentioned disadvantages.
`the devices.
`Preferred supports will be for example in the form of a
`It is this object which the present invention proposes to
`polyethylene, polypropylene or polyester film, a composite
`achieve through the production of a system for the simul­
`taneous transdermal delivery of at least two active principles 55 consisting of polyethylene and a vinyl acetate/ethylcne
`copolymer, an aluminized film or else a foam.
`which makes it possible simply to adjust the dose of each
`In practical terms, the whole of the system or each of the
`active principle to be delivered, while at the same time
`devices may be covered with a protective layer or film which
`having a reduced total surface area.
`can be peeled off before the system is used, it being possible
`SUBJECT OF THE INVENTION
`60 for said system itself to be packaged in a leaktight protection
`ITie above-mentioned object is achieved through the
`such as, for example, a polyethylene/aluminum composite.
`production, as a novel industrial product, of a novel system
`A device according to the present invention can be made
`for the transdermal delivery of at least two active principles
`of the materials familiar to those skilled in the art, for
`which consists of at least two juxtaposed (or associated)
`example natural or synthetic polymers (such as acrylics or
`devices, said system being characterized in that it comprises 05 derivatives thereof, silicones, block copolymers, vinyl
`(i) a first device containing a mixture of all the active
`acetate/ethylene copolymers, rubbers and derivatives
`principles in which at least one first active principle (A)
`thereof, etc.), according to the properties of the active
`
`

`

`5,919,477
`
`5
`
`! _
`
`,0
`
`6
`amoxycillin in association with clavulanic acid, sul-
`fametoxazole in association with trimethoprim, eryth­
`romycin in association with acctylsnlfafiirazole 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 compounds is particularly recommended.
`
`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-
`bili/ing agents, plasticizers, resins, stabilizers, bulking
`agents or skin permeation promoters.
`l ikewise, 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.
`BEST MODE
`In the case where one or more matrix devices arc used in 10
`the system according to the present invention, said matrix
`The best mode of carrying out the invention consists in
`devices arc manufactured by the coating techniques gener­
`using a system for the transdermal delivery of two active
`ally known in the art, either in a solvent phase or by the
`principles (A and B), characterized in that it comprises
`so-called hot melt technique (i.e. in the absence of a
`(i) a first matrix device which is a matrix containing in its
`solvent).
`bulk the active principle A in an amount which enables
`Likewise, in the case where devices of the reservoir type
`the effective therapeutic dose to be delivered, and the
`arc used, said devices arc manufactured by the techniques
`active principle B in an amount which is less than that
`known in the art, an example being creation of the reservoir
`necessary to deliver the effective therapeutic dose, and
`by heat-sealing the support onto a membrane and simulta­
`(ii) a second matrix device which is a matrix containing
`neously or non-simultaneously filling the reservoir.
`in its bulk the active principle B in an amount which
`In both cases, in the context of industrial production, the
`makes up the amount present in said first matrix device
`size of the devices is set to the appropriate dimensions,
`until its effective therapeutic dose is obtained.
`according to the amount of active principle or principles
`In other words, a system is recommended which consists
`present per unit surface area, to give the chosen doses of
`active principles to be delivered by the system over a given 25 0'two juxtaposed (or associated) matrices, this system being
`timc.
`such that a first matrix which contains a mixture of the two
`active principles, where one of the two is delivered at a dose
`llic transdermal system according to the invention can
`which is less than its effective therapeutic dose, is combined
`have any geometric shape: square, rectangular, circular or
`with a second matrix which contains this same active
`oval. The different devices can be arranged either side-by-
`30 principle and which enables its effective therapeutic dose to
`side or concentrically, each device then completely sur­
`be delivered.
`rounding the previous one, or any other geometric construc­
`This system is very useful for the simultaneous delivery
`tion can be used. The devices can optionally be separated or
`of an estrogen and a progestin, in particular for the simul­
`surrounded by one or more additional layers, which can be
`taneous delivery of different doses of 17-(3-estradiol,
`adhesive in order to help hold the unit together if necessary.
`Any combination of active principles capable of being 35 between 25 and 100/(g per 24 hours, and different doses of
`norethisterone acetate, between 100 and 800 /ig per 24
`applied transdcrmally and exerting cither a topical or a
`hours, in 17-p-estradiol/norethisterone acetate dose ratios of
`systemic action can be used within the framework of the
`'/i to Vs respectively, said doses being therapeutically effec­
`present invention.
`tive in the treatment of the symptoms of menopause and the
`The following possible associations may be mentioned
`41) resulting cardiovascular risks.
`among these combinations:
`The advantages and characteristics of the invention will
`(a) one or more estrogens with one or more progestins,
`be understood more clearly from the following description
`natural or synthetic, for contraceptive purposes or in
`of Examples of systems produced according to the invention
`the treatment of the symptoms of menopause, for
`and experiments comparing them with systems described in
`example estradiol, ethynylestradiol, estriol and deriva­
`45 the prior art. Of course, these details taken as a whole do not
`tives thereof in association with uorethisteroiic acetate,
`in any way imply a limitation but are given by way of
`norgestrel, levonorgestrel, desogestrel, norgestimate,
`illustration. The systems according to the invention and the
`lynestrenol, gestodene, nomegestrol acetate or
`comparative systems are produced by different combina­
`dienogest;
`tions of the matrix devices described below.
`(b) p-blocker and diuretic compounds useful especially in
`cardiovascular diseases, for example timolol, pindolol,
`EXAMPLE 1 (device 1)
`bufradol, indenolol or nipradinol in association with
`47.8 g of LEVAPREN® 450P (an ethylene/vinyl acetate
`amilonide or hydrochlothiazide;
`copolymer (abbreviated to EVA below) marketed by
`BAYER), 48 g of crotamiton [N-eIhyl-2-N-(2-
`(c) corticoid and antihistamine compounds useful espe-
`cially in the treatment of a lergies, for example 55 mchyiphcnyn^-butcnamide] (marketed' by BOE-
`HRINGER INGELHEIM), 0.2 g of IRGANOX® B215 (an
`methylprednisolone, prednisolone, hydrocortisone,
`antioxidanl MARKCICD B CIBA-GEIGY) and 115.53 g of
`beclomcthazone or triamcinolone in association with
`astcmizolc, dcxch orpheniraminc, cctinzme, diphenyl-
`ethyl ace|a|e are laced jn a vessel The mixIure is heated for
`hydromine chloride or chloro-phemramine;
`5 hours unli| lhc EVA has complelely dissolved. It is stirred
`(d) analgesic and anti-inflammatory compounds useful 60 a, room icmperature for 1 hour and 4 g of norethisterone
`especially in the treatment of pain, for example acetyl-
`acetate (abbreviated to NETA below), previously dissolved
`20 g of tetrahydrofuran, are then added. The mixture
`salicylic acid, paracetamol or noramidopyrine in asso-
`obtained is stirred for about 30 minutes until it is completely
`ciation with mefenamic acid, llufenamic acid,
`diclofenac, oxyphen-butazone, ibuprofen, naxoprene or
`homogeneous; it is then left to stand until the bubbles have
`fenbufene; and
`(,5 totally disappeared. The mass obtained is coated onto a
`siliconized polyester film at room temperature (15-25° C.)
`(e) antibacterial and antibiotic compounds useful espe­
`to give a deposit of material of (100±10) g/m". The unit
`cially in the treatment of infections, for example
`
`

`

`5,919,477
`
`7
`obtained is heated at 70° C. for 30 minutes and then
`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 leaklight
`enclosures.
`
`5
`
`EXAMPLE 2 (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-|5- 10
`estradiol and 4 g of norethisterone acetate (added at the same
`lime as the 17-p-eslradiol), these two hormones being dis­
`solved together in 30 g of tctrahydrofuran.
`
`8
`obtained is coated onto a siliconized polyester film at a rate
`of (1()(1±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)
`
`EXAMPLE 4 (device 4)
`Ihc procedure is identical lo Example 3 except that II g
`of ELVAX® 46L, 11 g of ELVAX® 46,5 g of ETHOCEL®,
`15 g of EUTANOL® G, 5 g of SURFADONE® LP300, I g
`of I7-|5-estradiol and 2 g of norethisterone acetate are used
`in this case.
`
`13.8 g of VECTOR® 4211D [a poly(slyrcne/isoprcne/
`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
`EXAMPLE 3 (device 3)
`" SURFADONE® LP300 (N-dodecyl-2-pyrrolidone mar­
`keted by BOEHRINGER 1NGELHEIM), 7.5 g of LAURO-
`20.7 g of EI VAX® 46L and 6.9 g of ELVAX® 46
`GLYCOL® (a mixture of the monoester and diester of
`(ethylene/vinyl acetate copolymers marketed by DU PONT)
`propylene glycol and lauric acid, marketed by
`and 6 g of ETHOCEL® (ethyl cellulose marketed by DOW
`CHEMICAL) are placed in a vessel, with stirring, and 20 GATTEFOSSE) and 19.8 g of ethyl acetate are placed in a
`heated to about 130° C. 1.2 g of 17-fi-estradiol and 18.9 g
`250 ml beaker. This mixture is stirred, while being healed at
`of EUTANOL® G (2-octyldodecanol marketed by
`60° C., until the compounds have completely dissolved. A
`HENKEL) are then incorporated gradually at 130° C., with
`solution of 1.25 g of norethisterone acetate, previously
`continued stirring, and the mixture is stirred until it is
`dissolved in 6.25 g of tetrahydrofuran, is then added. ITie
`completely homogeneous. 6.3 g ol SURFADONE® LP300 25 resulting mixture is stirred for about 30 minutes until it is
`(N-dodecyl-2-pyrrolidone marketed by GAP
`complelely homogeneous. It is left lo cool until the bubbles
`CORPORATION) are then added al a temperature of the
`have totally disappeared. The resulting mass is coated onto
`order of 100 to 110° C. and stirring is continued until the
`a siliconized polyester film at a rate of (11()±10) g/m" al
`mixture is perfectly homogeneous. The mixture obtained is
`room temperature (15-20° C). The coaling produced is
`coated, al a temperature between 100 and 140° C., onto an 30
`heated at 50° C. for at leasl 30 minutes and then transferred
`anliadhesive temporary intermediate support, especially a
`to a polyethylene support. The product is cut into shapes of
`siliconized polyester film, at a rate of (I00±10) g/m2. 'ITie
`the desired dimensions.
`matrix obtained is transferred to a polyethylene support.
`The advantages of the present invention were illustrated
`35 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 cm2, 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, thermoslated al 37° C., which
`has a receiving comparlment wilh a volume of 11.5 ml
`containing a receiving phase made up of an isotonic
`mixture (75/25; v/v).
`solution/PEG
`•100
`Samples of the receiving solutions are taken al 2, 4, 6, 8,
`12, 16, 20 and 24 hours and assayed by liquid chromatog­
`raphy. To allow for the variability of the resulls associated
`with the intrinsic permeability of the skin samples, each
`EXAMPLE 6 (device 6)
`50 permeation experimeni for a sample of transdermal device is
`performed on a minimum of 3 lo 5 skin samples. The result
`13.35 g of KRATON G® 1657 (a poly(styrene/ethylene/
`given is the mean obtained for each device from these
`bulylene/slyrene) three-block copolymer marketed by
`experiments.
`SHELL), 0.1 g of IRGANOX® 565 (an antioxidant mar­
`keted by CIBA-GEIGY), 12.5 g of ZONATAC® 105L (a
`The following mean skin absorption fluxes were thus
`tackifying resin marketed by ARIZONA CHEMICAL), 55 obtained for 17-p-eslradiol (F, ,) and/or norethisterone
`10.25 g of PARAPOL® 9.10 (an n-butene/isobutylene
`acetate (F,VA,,) in the case of devices 1 lo 7:
`copolymer marketed by EXXON CHEMICAL), 10.25 g of
`Device 1: FA,£X.1=0.35±0.16//g/cm2/h
`EU TANOL® G (2-octyldodecanol marketed by HENKEL),
`=0.3940.1
`Device 2: F£S=0.2=0.07 /<g/cnr/h F
`3 g of SURFADONE® LP300 (N-dodccyl-2-pyrrolidonc
`A/ETA
`marketed by GAF CORPORATION) and 25.6 g of cyclo- 60
`iig/cm'/h
`hexane are placed in a 250 ml beaker. The mixture is stirred
`Device 3: F/;s=0.61±0.08 Hg/cm2/h
`for 6 hours, while being heated at 60° C., until the constilu-
`=0.57±0.17
`Device 4: F, .J=0.57±0.13 //g/cm2/h F
`enls have completely dissolved. 0.55 g of norethisterone
`NETA
`/ig/cm2/h
`acetate, previously dissolved in 2.75 g of tetrahydrofuran, is
`Device 5: F,v/. „=(l.5i().03 /(g/enr/h
`then added. The mixture obtained is stirred for 30 minutes 65
`Device 6: FA,CM=0.47±0.05 Hg/cnr/h
`until it is completely homogeneous, and then left to stand
`Device 7: FA,EZ1=0.89±0.12/(g/cm2/h
`until the bubbles have totally disappeared. The mixture
`
`EXAMPLE 5 (device 5)
`Ilie procedure is identical lo Example 3 except thai 33.75
`g of ELVAX® 46L, 11.25 g of ELVAX® 46, 10 g of 45
`El l IOCEL®, 30.5 g of EU TANOL® G, 4 g of norethister-
`one acetate and 10.5 g of SURFADONE® LP300 are used
`in this case.
`
`

`

`5,919,477
`
`10
`
`TABLE IV
`
`SD,
`
`3.4
`3.6
`
`SI),
`
`22.2
`17.7
`
`TABLE V
`
`G
`
`16.8
`
`25.6
`21.3
`
`Comparative system Va
`System V
`
`SD,
`
`3.4
`3.6
`
`SD,
`
`11.7
`9.4
`
`S
`
`15.1
`13
`
`G
`
`13.9
`
`to
`
`Comparative system IVi
`System IV
`
`9
`Tables I 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-p-cstradiol and
`norethisterone acetate.
`Ihus Table I compares a system I according to the
`invention, consisting of devices 4 and 5, with a comparative
`system la. 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 Ha.
`consisting of devices 3 and 1.
`Table 111 compares a system III according to the
`invention, consisting of devices 4 and 1, with a comparative "
`In the present case it is desired to deliver the following
`system Ilia, consisting of devices 3 and 1.
`therapeutically effective doses:
`Table IV compares a system IV according to the
`50 f i g of 17-P-estradiol per 24 hours, and
`invention, consisting of devices 4 and 6, with a comparative
`250 /<g of Doreihistcrone acetate per 24 hours,
`_
`system IVa, consisting of devices 3 and 6.
`If it is desired simultaneously to deliver these two hor-
`'Table V compares a system V according to the invention, 'l) mones contained in a single device, the difference in skin
`permeability, i.e. skin absorption flux, between the norethis­
`consisting of devices 4 and 7, with a comparative system Va,
`terone acetate and the 17-(!-estradiol must be 5. Now, in
`consisting of devices 3 and 7.
`practice, such a difference, which is theoretically obtainable
`'The abbreviations used in these Tables have the following
`although already difficult to achieve as such, proves impos­
`meanings:
`es sible to obtain if allowance is made for the constraints of
`SDj represents the surface area of the first device,
`stability, comfort and adhesive and cohesive properties
`expressed in cm2.
`required by the marketing of such a device.
`Thus devices 2 and 4, which have these good physico-
`SI), represents the surface area of the second device,
`chemical properties and offer a good level of comfort, do not
`expressed in car.
`30 make it possible to achieve adjustment of the desired doses.
`S represents the total surface area of the system formed by
`It is impossible to obtain the desired effective dose of
`the juxtaposition of both devices, expressed in cm2.
`norethisterone acetate without a 2.5-fold and 5-fold increase,
`respectively, in the doses of 17-|5-estradiol delivered. The
`(i represents the reduction in surface area, expressed as a
`alternative solution, which uses a system formed of 2
`percentage, for the systems according to the invention
`(represented by the second line of the Tables) relative 35 juxtaposed matrix devices, one containing the 17-|i-estradiol
`and the other containing the norethisterone acetate, is less
`to systems formed by the juxtaposition of two devices
`efficient than the solution according to the invention, which
`each containing a single active principle (represented
`affords a reduction in surface area relative to the former by
`by the first line of the Tables).
`virtue of associating a first matrix device containing a
`The first device contains a mixture of 17-(}-esiradiol and
`mixture of the two hormones, in which the concentration of
`nore