Embossable and Writable Multilaminate Backing - DocsLib

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Home , Naloxone, Opioid antagonist

(19) &

(11) EP 1 534 508 B1

(12) EUROPEAN PATENT SPECIFICATION

(45) Date of publication and mention (51) Int Cl.: of the grant of the patent: B32B 7/06 (2006.01) B32B 33/00 (2006.01) 24.12.2008 Bulletin 2008/52 G09F 3/10 (2006.01) A61K 9/70 (2006.01)

(21) Application number: 03754410.3 (86) International application number: PCT/US2003/026545 (22) Date of filing: 22.08.2003 (87) International publication number: WO 2004/020189 (11.03.2004 Gazette 2004/11)

(54) EMBOSSABLE AND WRITABLE MULTILAMINATE BACKING CONSTRUCTION PRÄGBARE UND BESCHREIBBARE VERBUNDRÜCKSCHICHT CONSTRUCTION DE SUPPORT MULTISTRATIFIEE POUVANT ETRE ALVEOLEE ET INSCRIPTIBLE

(84) Designated Contracting States: (72) Inventor: AUDETT, Jay Douglas AT BE BG CH CY CZ DE DK EE ES FI FR GB GR Mountain View, CA 94040 (US) HU IE IT LI LU MC NL PT RO SE SI SK TR (74) Representative: Williams, Paul Edwin et al (30) Priority: 30.08.2002 US 407126 P Ablett & Stebbing Caparo House (43) Date of publication of application: 101-103 Baker Street 01.06.2005 Bulletin 2005/22 London W1U 6FQ (GB)

(73) Proprietor: ALZA Corporation (56) References cited: Mountain View, CA 94039-7210 (US) EP-A- 0 309 073 WO-A-92/16202 DE-A- 19 724 871 US-A- 5 906 830

Note: Within nine months of the publication of the mention of the grant of the European patent in the European Patent Bulletin, any person may give notice to the European Patent Office of opposition to that patent, in accordance with the Implementing Regulations. Notice of opposition shall not be deemed to have been filed until the opposition fee has been paid. (Art. 99(1) European Patent Convention). EP 1 534 508 B1

Printed by Jouve, 75001 PARIS (FR) 1 EP 1 534 508 B1 2

Description ously are directly laminated to a pressure sensitive adhesive to provide labels having good adhesion. However, Technical Field embossing microporous film after direct lamination to a pressure sensitive adhesive would be problematic. Em- [0001] The present invention relates to a multilaminate 5 bossing such microporous films would result in a poorly backing construction for a transdermal drug delivery sys- resolved image due to the slow intrusion of the adhesive tem. In particular, the invention relates to a system and into the opaque film layer. The slow adhesive flow into method for labeling a transdermal drug delivery system, the pores, accompanied by the crushing of the pores due wherein the outermost layer of the multilaminate backing to embossing would render the film transparent. Further, construction contains an embossable and writable ma- 10 the embossed image would be poorly resolved due to terial. adhesive flow into the pores.

Background of the Invention Summary of the Invention

[0002] The use of microporous materials, including 15 [0006] The present invention is directed to the afore- films, in label application for various packaging materials, mentioned needs in the art, and provides a multilaminate containers, stationary, blood bags, recording paper, backing construction for a transdermal system. In partic- bandages and the like has been described in great detail. ular, the invention relates to a system and method for The following patents U.S. Patent Nos. 6,255,552; labeling a transdermal drug delivery system, wherein the 6,162,858; 5,906,830; 5,871,829; 5,583,171; 5,507,525; 20 outermost layer of the multilaminate backing layer con- 5,484,603; 5,314,421; 4,751,087; 4,334,530 andtains an embossable and writeable material. 3,928,099 describe various ways of labeling packaging [0007] In one aspect, the invention provides a multil- materials, containers, stationary, blood bags and record- aminate backing construction comprising ing paper wherein sheet materials, e.g., microporous materials, containing additives such as inorganic powder, 25 (a) an outer layer (2) comprising a breathable, em- printing inks,swellable agents, coloring agents, fillersetc. bossable and writable material, of porous, micropo- are used to create markings, e.g., etching, scoring, print- rous, microfibrullar, spun-bonded, spun laced, track ing, and writing, on the label. In general, these processes etched, rayon, wood-pulp, spun laced polyester, or require the use of high temperatures and/or the presence coated paper products and combinations thereof; of additives within the microporous film in order to display 30 (b) a tie layer (3), the tie layer disposed on the skin the markings on the surface. proximal surface of the outer layer; and D1, WO9216202 defines (fig. 1; cl.1-3, 13, pages 8 to 10) (c) a base layer (4) disposed on the skin proximal a percutaneous anaesthetic delivery system (transder- surface of the tie layer. mal patch) and comprises a skin conformable (outer) backing layer, an amethocaine (1)-bearing (base) mate- 35 Preferably, rial and an intermediate layer having little or no tendency to absorb the drug (1). (a) the outer layer is a microporous layer or a micro- [0003] Labeling or printing information on transdermal fibrullar layer; and systems has been a challenge. For example, use of printing inks, coloring agents, solvents and other additives 40 (b) the tie layer comprises a secondary drug-con- necessary for printing may adversely interact with the taining reservoir. active agents within the transdermal system. To address these concerns, transdermal systems have been labeled [0008] Preferably, the secondary drug-containing res- using a process not requiring the use of inks. The backing ervoir comprises a beneficial agent and the base layer layer of the transdermal system is labelled by a thermal 45 is a beneficial agent release rate controlling means. embossing process. The polyolefin face of the backing Preferably, the tie layer is multilaminate. The tie layer material is melted under pressure to reveal the label. may contain a secondary drug-containing reservoir. [0004] Notwithstanding some success, the existing [0009] In preferred aspects, the multilaminate backing technology for labeling transdermal systems has not construction of the invention comprises a base layer im- been entirely satisfactory. The additives in the backing 50 permeable to the drug within the drug reservoir or the tie layer and/or the adjacent layers can interact adversely layer, wherein the base layer comprises a material which with the active agents. Additionally the use of high tem- is insoluble in water, alcohol and organic solvents. The peratures to label the transdermal systems may degrade base layer may optionally be a multilaminate layer. In various components of the transdermal systems or cause certain embodiments, the base layer may be a drug re- adhesive flow beyond the perimeter of the backing.55 lease rate controlling means, e.g., a drug release rate These challenges would in turn affect the potency and controlling membrane. The base layer may comprise a stability of the transdermal systems. polymer such as polyolefin laminates (Dow Chemical, [0005] Further, the microporous films described previ- Midland, MI), acrylonitrile copolymer films (BAREX, BP

2 3 EP 1 534 508 B1 4

Chemicals, Koln, Germany), polyethylnapthalene (PEN), material, such as, ethyleneoctene copolymers such as polyethylene terephthalate (PET), PET modified with ad- ENGAGE 8407 (from Dupont-Dow Elastomers), ethyl- hesion improvement coatings such polyacrylates or pol- ene-vinyl acetate copolymer (EVA), low density polyeth- yesters, polyimide, polyurethane, polyethylene, metal- ylene (LDPE), medium density polyethylene (MDPE), lized films and glass coated films where these films can 5 non pressure sensitive formulation of styrenic block co- include ethylene copolymers such as ethylene-vinyl ac- polymer thermoplastic elastomers, and the like. In pre- etate copolymer (EVA), and combinations thereof. In preferred embodiments, the tie layer is formed from ethyle- ferred embodiments, the base layer comprises polyester, neoctene copolymers, as described in greater detail be- such as PET, laminated to a polymer, such as poly- low. urethane, polyethylene, and ethylene copolymers. 10 [0013] The tie layer may comprise a secondary drug- [0010] In preferred embodiments, the base layer is containing reservoir. The secondary drug-containing res- comprised of a polymeric material selected from the ervoir may contain a beneficial agent or an antagonist group consisting of a polyester-polyolefin material such for the beneficial agent, wherein the antagonist is in a as Scotchpak 9735 (PET-PE laminate, 3M), Mediflex form that is not releasable through the base layer. The 1500 (PET-pigmented EVA laminate, Mylan Technolo- 15 skin distal surface of the drug reservoir is disposed on gies), Mediflex 1200 (PET-EVA laminate, Mylan Tech- the outer surface. The secondary drug- containing reser- nologies); Mediflex 1000 (a translucent polyolefin film, voir may be the same size as the other layers of the back- Mylan Technologies), Medifilm 500 series (EVA mem- ing construction or the secondary drug- containing reser- brane material, Mylan Technologies); polyethylenes voir may be inset from the edge of the die cut backing such as low density polyethylene (LDPE), medium den- 20 construction. sity polyethylene (MDPE), high density polyethylene [0014] In certain embodiments, the secondary drug- (HDPE), Kapton polyimide film, and other ethylene co- containing reservoir comprises the drug dispersed within polymer films such as EMA, or EBA copolymer films. a polymer, wherein the drug is substantially insoluble in [0011] The multilaminate backing construction of the the secondary drug- containing reservoir polymer. In cer- invention comprises an outer layer comprising an em- 25 tain embodiments, the drug is dispersed in a matrix com- bossable and writeable material. The outer surface can prising a material which substantially prevents release be scribed with a pen, and can be embossed by applying of the drug; or the drug is complexed with an ionic resin. pressure with an embossing roll before or after lamination In additional embodiments, the secondary drug- contain- of the multilaminate backing construction to a pressure ing reservoir comprises the drug in a multiparticulate sensitive adhesive. The outer layer comprises a breath- 30 form, wherein each particle is individually coated with a able material comprising, porous, microporous, microfi- material which substantially prevents release of the drug. brullar, spun-bonded, spun laced, track etched, rayon In additional embodiments, the secondary drug- contain- (synthetic textile fibers produced by forcing a cellulose ing reservoir comprises beads coated with the drug, solution through fine spinnerets and solidifying the re- wherein the beads may be formed from glass or an inert sulting filaments), wood- pulp, spun laced polyester, coat- 35 or non-dissolvable polymer, and further wherein the coated paper products, and the like, and combinations there- ed beads are optionally coated with or dispersed in ma- of. In preferred embodiments, outer layer comprises low terial which substantially prevents release of the drug. In density polyethylene (LDPE) materials, medium density preferred embodiments, the drug is an opioid antagonist polyethylene (MDPE) materials or high density polyeth- selected from the group consisting of naltrexone, meth- ylene (HDPE) materials, and the like. In preferred em- 40 ylnaltrexone, naloxone, nalbuphine, nalorphine, nalor- bodiments, the outer layer is a single HDPE layer. In ad- phine dinicotinate, nalmefene, nadide, levallorphan, cy- ditional preferred embodiments, the outer layer compris- clozocine and pharmaceutically acceptable salts thereof. es a microporous layer selected from the group consist- In preferred embodiments, the antagonist is present as ing of Solupor microporous UHDPE P01 film (Solupor™ a salt, preferably as a hydrochloride salt of an antagonist manufactured by DSM Desotech, the Netherlands), mi- 45 base. croporous polypropylene, e.g. Celgard microporous PP [0015] These and other embodiments of the present 3401 film (Celgard™ film, Celgard, Inc., Charlotte, NC), invention will readily occur to those of ordinary skill in the RoTrac Polyester Capillary Pore Membranes (OYPHEN art in view of the disclosure herein. GmbH, Germany), spun laced polyester, polypropylene or polyethylene. 50 Brief Description of the Figures [0012] The multilaminate backing construction of the invention comprises a tie layer, wherein the tie layer may [0016] Figure 1 illustrates a cross-section through a be multilaminate. The tie layer preferably comprised of schematic, perspective view of one embodiment of mul- materials having a low melting point that flow easily at tilaminate barking construction according to this inven- high temperatures to allow lamination to the outer layer. 55 tion. The tie layer may be formed from standard materials as [0017] Figure 2 illustrates a cross-section through a known in the art For example, the tie layer is formed from schematic, perspective view of another embodiment of a hydrophobic, a lipophilic and/or a non-polar polymeric multilaminate backing construction according to this in-

3 5 EP 1 534 508 B1 6 vention. proximal surface of the outer layer 2, and the base layer 4 is disposed on the skin proximal surface of the second- Detailed Description of the Invention ary drug-containing reservoir. The secondary drug-containing reservoir may contain a beneficial agent or an Overview: 5 antagonist for a beneficial agent. In certain embodiments of the backing construction 1 of the invention, wherein [0018] The present invention is directed to a multilam- the secondary drug-containing reservoir contains a ben- inate backing construction for a transdermal system eficial agent, the base layer 4 is a drug rate controlling wherein the outermost layer of the multilaminate backing means disposed on the skin proximal surface of the sec- construction can be embossed and be written upon with 10 ondary drug-containing reservoir. In alternative embod- a pen or pencil. In particular, the outermost layer of the iments of the backing construction 1 of the invention, the multilaminate backing construction of the present inven- secondary drug-containing reservoir contains an antag- tion contains an embossable and writable material such onist of a beneficial agent, and preferably, the outer layer as a microporous or microfibrillar film, which is laminated also functions as an antagonist release rate controlling via a tie layer to a base layer. 15 means. [0025] Referring now to Figure 2 a preferred embodi- Definitions: ment of the multilaminate backing construction 11 according to this invention comprises an outer layer 12, a [0019] In describing and claiming the present inven- multilaminate tie layer 13 and a base layer 14. The tie tion, the following terminology will be used in accordance 20 layer comprises a first layer 16 disposed on the skin prox- with the definitions set out below. imal surface of the outer layer 12; a second layer 17 dis- [0020] The singular forms "a," "an" and "the" include posed on the skin proximal surface of the first layer 16; plural referents unless the context clearly dictates other- a third layer 18 disposed on the skin proximal surface of wise. Thus, for example, reference to "a polymer" in- the second layer 17; and a secondary drug-containing cludes a single polymer as well as a mixture of two or 25 reservoir 15. The base layer 14 is configured to provide more different polymers, reference to "a permeation en- a central volume which contains the secondary drug- con- hancer" includes a single permeation enhancer as well taining reservoir 15 in the form of a gel having dissolved as two or more different permeation enhancer in combi- or suspended drug therein. In preferred embodiments, nation, and the like. the first layer 16 is an EVA or LDPE layer, the second [0021] As used herein, the term "drug release control- 30 layer 17 is a PET layer, the third layer 18 is an EVA, ling means" refers to a means to control/regulate the re- LDPE or a polyurethane layer; and the base layer 14 is lease of a drug from the secondary drug- containing res- a drug release rate controlling means. ervoir. [0026] The outer layer 2, 12, of the multilaminate back- [0022] As used herein, the terms "drug" and "active ing construction of the invention comprises an emboss- agent" are used interchangeably and are to be construed 35 able and writeable material. The outer surface can be in the broadest sense to mean any material which is in- scribed with a pen, and can be embossed by applying tended to produce some biological, beneficial, therapeu- pressure with an embossing roll before or after lamination tic, or other intended effect, such as permeation en- of the multilaminate backing construction to a pressure hancement, an antagonist, on the organism to which it sensitive adhesive. The outer layer comprises a breath- is applied. For example, the drug may be a beneficial 40 able material comprising, porous, microporous, microfi- agent or an antagonist of the beneficial agent. brullar, spun-bonded, spun laced, track etched, rayon (synthetic textile fibers produced by forcing a cellulose Modes of Carrying Out the Invention solution through fine spinnerets and solidifying the resulting filaments), wood- pulp, spun laced polyester, coat- [0023] The present invention provides a multilaminate 45 ed paper products, and the like, and a combination there- backing construction for a transdermal drug delivery sys- of. In preferred embodiments, outer layer comprises low tem, the outermost layer of the multilaminate backing density polyethylene (LDPE) materials, medium density construction having an embossable and writable mate- polyethylene (MDPE) materials or high density polyeth- rial. ylene (HDPE) materials, and the like. In preferred em- [0024] Referring now to Figure 1, a preferred embod- 50 bodiments, the release controlling means is a single iment of the multilaminate backing construction 1 accord- LDPE layer. In additional preferred embodiments, the ing to this invention comprises an outer layer 2, a tie layer outer layer comprises a microporous layer selected from 3 wherein the skin distal surface of the tie layer is dis- the groupconsisting of Solupor microporousUHDPE P01 posed on the outer layer 2, and a base layer 4 wherein film (Solupor™ manufactured by DSM Desotech, the the tie layer 3 is disposed on the skin distal surface of 55 Netherlands), microporous polypropylene, e.g. Celgard the base layer 4. In certain embodiments of the backing microporous PP 3401 film (Celgard™ film manufactured construction 1 of the invention, the tie layer 3 is a sec- by Celgard, Inc., Charlotte, NC), RoTrac Polyester Cap- ondary drug-containing reservoir disposed on the skin illary Pore Membranes (OYPHEN GmbH, Switzerland),

4 7 EP 1 534 508 B1 8 spun laced polyester, polypropylene or polyethylene. larly an antagonist-containing reservoir, the antagonist The outer layer is free of any additives and is not directly is dispersed in a matrix comprising a polymeric material laminated to a pressure sensitive adhesive. Alternatively, which substantially prevents release of the antagonist, the outer layer can be coated with low levels of sur- preferably a thermoformable material; or the antagonist factants, for example, pluronic polyethylene oxide-poly- 5 is complexed with an ionic resin. In additional embodi- propylene oxide block copolymers and the like, to provide ments, theantagonist-containing reservoir comprises the further control over the rate of drug release from the un- antagonist in a multiparticulate form, wherein each par- derlying tie layer. ticle is individually coated with a polymeric material which [0027] these embodiments, the outer layer 2, 12, has substantially prevents release of the antagonist, wherein a thickness, of about 0.012nm (0.5 mil) to about 0.125 10 the polymeric material is preferably a thermoformable mm (5 mil); preferably 0.025 mm (1 mil) to about 0.1 mm material. In additional embodiments, the antagonist- con- (4 mil); more preferably 0.0375 mm (1.5 mil) to about taining reservoir comprises beads coated with the antag- 0.0875 mm (3.5 mil); and even more preferably 0.05 mm onist, wherein the beads may be formed from glass or (2 mil) to about 0.0625 mm (2.5 mil). an inert or non-dissolvable polymer, and further wherein [0028] The multilaminate backing construction accord- 15 the coated beads are optionally coated with or dispersed ing to the invention comprises a tie layer 3, 13, wherein in a polymeric material which substantially prevents re- the tie layer may be multilaminate. The tie layer is pref- lease of the antagonist, wherein the polymeric material erably comprised of materials having a low melting point is preferably a thermoformable material. Examples of an- that flow easily at high temperatures to allow lamination tagonist include, but are not limited to, naltrexone, meth- tothe outerlayer 2, 12, suchmaterials excluding pressure 20 ylnaltrexone, naloxone, nalbuphine, nalorphine, nalor- sensitive adhesives and HDPE. HDPE has a very high phine dinicotinate, nalmefene, nadide, levallorphan, cy- melting point and its use in the outer layer would render clozocine and the like, and pharmaceutically acceptable the embossable film prematurely clear due to high lam- salts thereof. Preferably, the antagonist is present as a inating temperatures and coincidental melting of the out- salt. er layer. Incorporation of pressure sensitive material in 25 [0030] As discussed above, the antagonist- containing the outer layer would result in flow of the adhesive into reservoir may comprise the antagonist dispersed within the pores, which would result in the embossable film pre- a polymer. Preferably, the antagonist is dispersed in a maturely turning clear. In certain embodiments, the tie matrix comprising a thermoformable material which sub- layer comprises a secondary drug-containing reservoir. stantially prevents release of the antagonist. Alternative- The secondary drug-containing reservoir may contain a 30 ly, the antagonist is present in a multiparticulate form, beneficial agent or an antagonist for the beneficial agent. wherein each particle is individually coated with a poly- In certain embodiments, when the secondary drug-con- meric material which substantially prevents release of taining reservoir contains an antagonist, the outer layer the antagonist. Preferably, the polymeric material which also functions as a drug release rate controlling means. substantially prevents release of the antagonist is hydro- In certain embodiments, when the second drug- contain- 35 phobic - i.e., substantially prevents release of the antag- ing reservoir contains a beneficial agent, the base layer onist during normal use, minimizes the amount of antag- 4 is a drug release rate controlling means is disposed on onist during incidental/casual exposure to solvents the skin proximal surface of the secondary drug- contain- (moisture e.g., sweat, during a shower), and upon inges- ing reservoir. The secondary drug-containing reservoir tion or immersion in a solvent, releases the antagonist in may be the same size as the other layers of the backing 40 abuse limiting amounts. Preferably, the polymeric mate- construction or the secondary drug-containing reservoir rial has a low melting point to allow processing of the may be inset from the edge of the die cut backing con- antagonist in solid phase and to prevent degradation of struction. The tie layer may be formed from standard ma- the antagonist. Examples of a polymeric material which terials as known in the art. In particular, the tie layer 3, substantially prevents release of the antagonist include, 13, is formed from low melting materials that flow easily 45 but are not limited to, polyethylene, polyoctene, polyvinyl at high temperatures and exclude pressure sensitive ad- acetate, polymethyl acrylate, polymethyl acrylate, poly- hesives and HDPE. For example, the tie layer is formed ethyl acrylate, polystyrene polymers and copolymers and from a hydrophobic, a lipophilic and/or a non- polar poly- mixtures thereof; polystyrene copolymers such as sty- meric material, such as, ethyleneoctene copolymers renic block copolymers (SIS, SBS, SEBS), ethylene co- such as ENGAGE 8407 (from Dupont- Dow Elastomers), 50 polymers such as polyethyleneoctene copolymers, eth- ethylene-vinyl acetate copolymer (EVA), low density pol- ylene-vinyl acetate copolymer (EVA), ethylenemethyl yethylene (LDPE), medium density polyethyleneacrylate copolymers (EMA), ethylene-acrylic acid copol- (MDPE), styrenic block copolymer thermoplastic elas- ymer, ethylene-ethylacrylate copolymer, and the like, tomers, PET, polyurethanes, and the like. In preferred and combinations thereof. embodiments, the tie layer is formed from ethylene-55 [0031] In additional embodiments, the antagonist is octene copolymers, as described in greater detail below. complexed with an ionic resin. Examples of ionic resins [0029] In certain embodiments wherein the tie layer include, but are not limited to sulfonated polystyrene res- contains a secondary drug-containing reservoir, particu- ins, and the like. Preferably the resin contains a sulfonic

5 9 EP 1 534 508 B1 10 acid functionality which when neutralized with the antag- ness of about 0.0125mm (0.5mil) to about 0.1mm (4 mil); onist base forms the sulfonate salt of the antagonist. preferably about 0.015 mm (0.6 mil) to about 0.0875 mm [0032] In additional embodiments, the antagonist- con- (3.5 mil); more preferably 0.025 mm (1 mil) to about 0.08 taining reservoir comprises beads coated with the antag- mm (3.3 mil); and even more preferably about 0.02 mm onist, wherein the spheres or beads may be formed from 5 (1.6 mil) to about 0.075 (3 mil). glass, metals or an inert or non- dissolvable polymer, and [0037] In additional embodiments, the secondary further wherein the coated beads are optionally coated drug-containing reservoir may optionally contain addi- with or dispersed in a polymeric material which substan- tional components such as, permeation enhancers, sta- tially prevents release of the antagonist, as described bilizers, diluents, antioxidants, excipients, gelling agents, above. The beads may be in any shape, size or form, but 10 anti-irritants, vasoconstrictors and ether materials as are are preferably small sized, preferably less than 10 mi- generally known to the transdermal art. crons. Examples of an inert or non-dissolvable polymer [0038] Examples of permeation enhancers include, include, but are not limited to polymethylmethacrylate, but are not limited to, fatty acid esters of glycerin, such polycarbonate and polystyrene. as capric, caprylic, dodecyl, oleic acids; fatty acid esters [0033] In certain embodiments wherein the tie layer 15 of isosorbide, sucrose, polyethylene glycol; caproyl lac- contains a secondary drug- containing reservoir, the sec- tylic acid; laureth-2; laureth-2 acetate; laureth-2 ben- ondary drug-containing reservoir is disposed on the skin zoate; laureth-3 carboxylic acid; taureth-4; laureth- 5 car- proximal surface of the outer layer 2 and the skin distal boxylic acid; oleth- 2; glyceryl pyroglutamate oleate; glyc- surface of the base layer 4. The secondary drug- contain- eryl oleate; N-lauroyl sarcosine; N-myristoyl sarcosine; ing reservoir may be formed from standard materials as 20 N-octyl-2-pyrrolidone; lauraminopropionic acid; polypro- known in the art. For example, the secondary drug-con- pylene glycol-4-laureth-2; polypropylene glycol-4-fau- taining reservoir is formed from a hydrophobic and/or li- reth-5dimethyl lauramide; lauramide diethanolamine pophilic polymeric material, such as, hydrophobic poly- (DEA). Preferred enhancers include, but are not limited urethane, ethylene-vinyl acetate copolymer (EVA) and to, lauryl pyroglutamate (LP), glyceryl monolaurate the like. 25 (GML), glyceryl monocaprylate, glyceryl monocaprate, [0034] In preferred embodiments, when the drug is a glyceryl monooleate (GMO), and sorbitan monolaurate. beneficial agent, the secondary drug-containing reser- Additional examples of suitable permeation enhancers voir comprises about 5 to about 35 wt% of the drug; more are described, for example, in U.S. Patent Nos.: preferably about 10 to about 35 wt% of the drug; and 5,785,991; 5,843,468; 5,882,676; and 6,004,578. even more preferably about 15 to about 30 wt% of the 30 [0039] The multilaminate backing construction accord- drug. Examples of beneficial agent include, but are no ing to this invention comprises a base layer 4, 14, wherein limited to, fentanyl, sufentanil, risperidone, gallantamine, the tie layer 3, 13, is disposed on the skin distal surface norelgestromin, testosterone, estradiol, nicotine, meth- of the base layer 4, 14. The base layer 4, 14, may be ylphenidate, fenoldopam, and the like. Preferably, the multilaminate. The base layer 4 preferably comprises a material forming the secondary drug- containing reservoir 35 polymer such as polyolefin laminates (Dow Chemical, has a solubility for the drug of about 5 wt% to about 40 Midlane, MI), acrylonitrile copolymer films (BAREX, BP wt% of the total polymer composition; more preferably Chemicals, Koln, Germany), polyethylnapthalene (PEN), about 10 wt% to about 35 wt%; and even more preferably polyethylene terephthalate (PET), polyimide, poly- about 15 wt% to about 30 wt% of the total polymer com- urethane, polyethylene, metallized films and glass coat- position. 40 ed films where these films can include ethylene copoly- [0035] In additional preferred embodiments, the drug mers such as ethylene-vinyl acetate copolymer (EVA), is an antagonist, preferably the antagonist is in the salt and combinations thereof. In preferred embodiments, the form and the preferred antagonists are naltrexone, meth- base layer comprises a polyester such as PET laminated ylnaltrexone, naloxone, nalbuphine, nalorphine, nalor- to a polymer such as polyurethane, polyethylene, and phine dinicotinate, nalmefene, nadide, levallorphan and 45 ethylene copolymers. In certain embodiments, the base cyclozocine. When the drug is an antagonist of a bene- layer may be a drug rate controlling means, as described ficial agent, the secondary drug-containing reservoir in greater detail hereinafter. In certain embodiments comprises about 20 to about 70 wt% of the drug; more wherein the secondary drug-containing reservoir con- preferably about 40 to about 65 wt% of the drug; and tains an antagonist, the base layer 4 is impermeable to even more preferably about 50 to about 60 wt% of the 50 the antagonist within the secondary drug-containing res- drug. Preferably, the material forming the secondary ervoir, the base layer comprising a material which is in- drug-containing reservoir 5 has a solubility for the drug soluble in water, alcohol and organic solvents. of about 0 wt% to about 1 wt% of the total polymer com- [0040] In preferred embodiments, the base layer is position; more preferably about 0 wt% to about 0.8 wt%; comprised of a polymeric material selected from the and even more preferably about 0 wt% to about 0.5 wt% 55 group consisting of a polyester-polyolefin material such of the total polymer composition. as Scotchpak 9735 (PET-PE laminate, 3M), Mediflex [0036] In these embodiments, the tie layer 3,13, includ- 1500 (PET-pigmented EVA laminate, Mylan Technolo- ing the secondary drug-containing reservoir, has a thick- gies, Saint Albans, VT), Mediflex 1200 (PET-EVA lami-

6 11 EP 1 534 508 B1 12 nate, Mylan Technologies, SaintAlbans, VT); Mediflex reservoir is adhesive, and a peelable protective layer. 1000 (a translucent polyolefin film, Mylan Technologies, The multilaminate backing construction is laminated via Saint Albans, VT), Medifilm 500 series (EVA membrane a pressure sensitive adhesive to a primary drug- contain- material, Mylan Technologies, Saint Albans, VT); poly- ing reservoir. The primary drug-containing reservoir is ethylenes such as low density polyethylene (LDPE), me- 5 typically formed from a pharmaceutically acceptable dium density polyethylene (MDPE), high density polyeth- pressure sensitive adhesive but, in some cases, can be ylene (HDPE), ethylene methyl acrylate copolymer formed from a non- adhesive material. If the primary drug- (EMA), ethylene ethyl acrylate copolymer (EEA), or eth- containing reservoir is formed from a material that does ylene butyl acrylate copolymer (EBA) copolymers. The not have adequate adhesive properties, the primary base layer preferably has a thickness of about 0.01nm 10 drug-containing reservoir may be formulated with a thin (0.4 mil) to about 0.125 nm (5mil); preferably 0.025nm adhesive coating. The primary drug- containing reservoir (1 mil) to about 0.1 mm (4 mil); more preferably 0.0625 intermediate is optionally laminated to a drug release- mm (1.5 mil) to about 0.0875 mm (3.5 mil); and even rate controlling membrane disposed between the primary more preferably 0.025 mm (1 mil) to about 0.05 mm (2 drug-containing drug reservoir and the peelable protec- mil). 15 tive layer. In subsequent operations, individual transder- [0041] The multilaminate backing construction may mal devices are die-cut, separated and unit-packaged comprise a drug release rate controlling means, prefer- using suitable pouchstock. Transdermal devices are car- ably within the outer layer or within the base layer. In toned using conventional equipment. The resulting certain embodiments, when the secondary drug- contain- transdermal delivery system provides a rate-controlled ing reservoir is an antagonist-containing reservoir, the 20 drug delivery device having embossing and writing ca- outer layer 2, 12, also functions as a drug release rate pabilities. controlling means disposed on the skin distal surface of [0045] Transdermal drug delivery systems having the the secondary drug-containing reservoir. In alternative multilaminate backing construction containing an antag- embodiments, when the secondary drug-containing res- onist-containing reservoir within the tie layer, when used ervoir contains a beneficial agent, the base layer 4, 14, 25 in combination with opioid- delivering transdermal formu- is a drug release rate controlling means disposed on the lations, provide a deterrence to drug abusers attempting skin proximal surface of the secondary drug-containing to misuse the systems, while at the same time, enable reservoir. In preferred embodiments, the tie layer com- embossed labeling or scribing with a pen. prises an antagonist-containing reservoir, and the outer [0046] The multilaminate backing construction is em- layer is a drug release controlling means. 30 bossed by application of pressure without the application [0042] The rate controlling means is preferably made of high temperatures, and without melting the outer layer. of a polymeric material such as ethylene-vinyl acetate Simply applying pressure without increasing the temper- (EVA), polyvinyl chloride (PVC), ethylene-ethyl acrylate ature is sufficient to provide a very striking visual graphic. copolymer, ethylene butylacrylate copolymer,The method of labeling a transdermal system using the polyisobutylene (PIB), polyethylene (PE) such as low 35 multilaminate backing construction of the invention elim- density polyethylene (LDPE), medium density polyethyl- inates the need for solvent-based inks when printing ene (MDPE), high density polyethylene (HDPE), and the transdermal systems by a heat-free embossing tech- like, and a combination thereof; the polymeric materials nique. Additionally, the method of the invention elimi- may be plasticized. In preferred embodiments, the base nates adverse drug-additive interactions, improving sta- layer is a drug release rate controlling means and is ad- 40 bility, thermal sensitivity, therapeutic effects,shelf-life hered to the skin with an acrylic, silicone, polyisobutylene and ease of manufacture of a transdermal drug delivery (PIB) or other pressure sensitive adhesive material. The system. rate controlling means preferably has a thickness of [0047] Additionally, the multilaminate backing con- about 0.012 mm (0.5 mil) to about 0.125 mm (5 mil); struction of the invention is writable, allowing physicians, preferably 0.025 mm (0.6 mil) to about 0.1 mm (4 mil); 45 nurses, or users to write directly on the backing with 3 more preferably 0.0625 mm (0.8 mil) to about 0.0875 mm pen without the ink smearing. This feature is important (3.5 mil). in many clinical settings because physicians and nurses [0043] The multilaminate backing construction can be need to indicate on multiple-day transdermal systems processed with less stretching under web tension be- when replacement is required. If not replaced at the ap- cause of the less extensible outer layer, preferable the 50 propriate time, sub-therapeutic quantities of drug may be Solupor layer, which also provides a surface for emboss- delivered as the drug content in the system depletes. ing and writing. [0048] Further, when the multilaminate backing con- [0044] Transdermal devices are manufactured ac- struction is laminated to a primary drug- containing adhe- cording to known methodology. In general, transdermal sive matrix, the drug cannot penetrate through the mul- devices incorporating this invention comprise a backing 55 tilaminate backing construction into the heat seal layer construction 1, 11, a primary drug-containing reservoir of the pouch material due to the microporous/microfi- disposed on the backing construction, wherein at least brous nature of the outer layer. the skin contacting surface of the primary drug-containing [0049] In additional embodiments, the multilaminate

7 13 EP 1 534 508 B1 14 backing construction is laminated to a pressure sensitive to evaporate the casting solvent to acceptable residual adhesive, enabling bonding to any medical device such limits. The dried secondary drug- containing reservoir film as a blood bag, IV bag, or form-fill-seal transdermal is then laminated to a selected base layer and the lami- patch, e.g. Duragesic ® transdermal fentanyl delivery sys- nate is wound onto the take- up rolls. In another process, tem. 5 the secondary drug-containing reservoir can be formed [0050] A wide variety of materials which can be used using dry-blending and thermal film- forming using equip- for fabricating the various layers of the multilaminate ment known in the art. Preferably, the materials are dry backing construction according to this invention have blended and extruded using a slot die followed by calen- been described above. This invention therefore contem- dering to an appropriate thickness. Parameters such as plates the use of materials other than those specifically 10 drug loading, secondary drug- containing reservoir thick- disclosed herein, including those which may hereafter ness, drug selections, material selections and manufac- become known to the art to be capable of performing the turing process can be varied for preparing drug- contain- necessary functions. ing reservoirs of the current invention, as illustrated in the Examples hereinafter Methods of Manufacture 15 [0054] The primary drug-containing reservoir may be manufactured as described above using known materials [0051] The multilaminate backing construction of the and according to known procedures. invention may be manufactured as follows. The drug- containing reservoirs are manufactured according to Multilaminate Backing construction known methodology, as described in greater detail be- 20 low. [0055] In general, the multilaminate backing construction is manufactured as follows. For example, as illus- Drug-containing Reservoir trated in Figure 1, the tie layer is laminated to the base layer, followed by lamination of the outer layer on the [0052] The secondary drug-containing reservoir can 25 surface of the tie layer distal to the base layer at elevated be formed by dry blending a drug, with a polymeric ma- temperature and pressure. Alternatively, both lamina- terial, preferable a thermoformable material, at high tions could be conducted in a single operation by extrud- shear and temperature using equipment such as sigma ing the tie layer at the required width and thickness di- blade mixers or extruders, either batch-wise or continu- rectly between the outer layer and the base layer prior ously. The extrudate is calendered to the desired thick- 30 to lamination. In general, the lamination is performed at ness between release liners, followed by lamination at a temperature ranging from about 70°C to about 120°C, elevated temperature to a barrier film and/or an analgesic and a pressure ranging from 344 737 Pa to about 827 rate controlling means. Parameters such as drug loading, 371 Pa, at the rate ranging from about 0.0102 m/s to drug-containing reservoir thickness, membrane selec- about 0.012 m/s. tion for the rate controlling means, and surfactant modi- 35 [0056] In an alternative embodiment, wherein the tie fication of the rate controlling means can be varied to layer comprises a secondary drug-containing reservoir, achieve the targeted release rate of drug, as illustrated the multilaminate backing construction, is manufactured in the Examples hereinafter. In preferred embodiments, by laminating sequentially or simultaneously he second- surfactants are coated onto membrane materials forming ary drug-containing reservoir layer to the base layer and the rate controlling means using techniques such as dip- 40 to the outer layer under lamination conditions as de- coating, gravure coating, and the like. scribed above. The secondary drug- containing reservoir [0053] In alternative embodiments, the secondary is manufactured as described earlier. drug-containing reservoirs are manufactured according [0057] In another embodiment of the multilaminate to known methodology as follows. A solution of the pol- backing construction, as illustrated in Figure 2, the tie ymeric reservoir material, as described above, is added 45 layer is a multilaminate layer containing an outermost to a double planetary mixer, followed by addition of de- first layer 16 (EVA/ LDPE layer) on the skin proximal sur- sired amounts of the drug, and optionally, a permeation face of the outer layer, laminated to a second layer 17 enhancer. Preferably, the polymeric secondary drug- (PET layer) disposed on the skin proximal surface of the containing reservoir material is solubilized in an organic first layer 16, the bi-layer is further laminated to a third solvent, e.g., ethanol, ethyl acetate, hexane, and the like. 50 layer 18 (EVA/ LDPE/polyurethane layer) disposed on the The mixer is then closed and activated for a period of skin proximal surface of the second layer 17, and a form time to achieve acceptable uniformity of the ingredients. fill type of a secondary drug-containing reservoir 15. The The mixer is attached by means of connectors to a suit- base layer 14, e.g. a drug release rate controlling means, able casting die located at one end of a casting/ film drying is configured to provide a central volume which contains line. The mixer is pressurized using nitrogen to feed so- 55 the secondary drug-containing reservoir 15 in the form lution to the casting die. Solution is cast as a wet film of a gel having dissolved or suspended drug therein. onto a moving siliconized polyester web. The web is drawn through the lines and a series of ovens are used

8 15 EP 1 534 508 B1 16

Experimental Example 4

[0058] Below are examples of specific embodiments [0064] A multilaminate backing construction using Ro- for carrying out the present invention. The examples are trac Capillary Pore Membrane (Oxyphen, Zug, Switzer- offered for illustrative purposes only, and are not intended 5 land) is prepared, as described in Example 1 above, to limit the scope of the present invention in any way. [0059] Efforts have been made to ensure accuracy Example 5 with respect to numbers used (e.g., amounts, temperatures, etc.), but some experimental error and deviation [0065] A multilaminate backing construction using Cel- should, of course, be allowed for. 10 gard microporous PP 3401 film is prepared, as described [0060] Specific examples of various multilaminate in Example 2 above. backing construction of the invention will be described in the examples set for hereinafter. In the following exam- Example 6 ples all percentages are by weight unless noted other- wise. 15 [0066] A multilaminate backing construction using Ro- trac Capillary Pore Membrane (Oxyphen, Zug, Switrer- Example 1 land)microporous polyester is prepared, as described in Example 2 above. [0061] A polyester-polyolefin transdermal backing material such as Scotchpak 9735 (PET-PE laminate, 3M, 20 Example 7 Cottage Grove, MN), Mediflex 1500 (PET-pigmented EVA laminate, Mylan Technologies, Saint Albans, VT), [0067] A translucent polyolefin film, Mediflex 1000 or Mediflex 1200 (PET-EVA laminate, Mylan Technolo- (Mylan Technologies, Saint Albans, VT), is laminated to gies) are laminated to Solupor microfibrous UHMW- the Solupor microfibrous film P01 via a low melting En- HDPE P01 film (DSM Solutech, Heerlen, the Nether-25 gage 8407 ethylene-octene copolymer. The conditions lands) at-elevated temperature and pressure. The tem- required for the lamination are 80°C, 620 528 Pa and perature required for the lamination is above the melting 0.0152 m/s. The resulting-transdermal backing material point of the polyolefin layer of the backing, usually above can be processed with less stretching under web tension 100°C. The resulting multilaminate is used as a transder- because of the less extensible Solupor layer, which also mal backing, the Solupor surface of which can be scribed 30 provides a surface for embossing and writing. Further, with a pen, and which can be embossed by applying pres- when this backing material is laminated to a primary drug- sure with an embossing roll before or after lamination to containing adhesive matrix, drug cannot penetrate a pressure sensitive adhesive. through the multi-layered backing into the heat seal layer of the pouch material because of the microfibrous nature Example 2 35 of the Solupor layer.

[0062] Mediflex 1200, a polyester- EVA laminate, is Example 8 bonded to a Solupor microfibrous UHMW- HDPE film via a tie layer. The tie layer contains an ENGAGE 8407 eth- [0068] The procedure outlined in Example 7 is followed ylene-octene copolymer (Dupont- Dow Elastomers, DSM 40 except an EVA film is substituted for the LDPE film. The Solutech’s) containing a naltrexone hydrochloride dis- resulting construction provides the benefits outlined in persion. Adequate bonding is achieved by performing a example 7 with the added benefit of providing an addi- hot lamination step at 620 528 Pa, 0.0254 m/s and 100°C. tional drug reservoir in the EVA backing layer. Drug in- The resulting multilayered construction is laminated to a corporation into the EVA film is achieved during its ex- fentanyl-containing adhesive reservoir. The resulting45 trusion or through the slow diffusion of drug into the EVA construction is embossed for identification, can be written after lamination to an active drug-pressure sensitive ad- upon with a ballpoint pen, and contains the antagonist, hesive reservoir. naltrexone hydrochloride, to prevent fentanyl abuse. Example 9 Example 3 50 [0069] A LDPE or EVA membrane material such as [0063] A multilaminate backing construction using Cel- the Medifilm 500 series from Mylan Technologies, is lam- gard microporous PP 3401 film (Celgard Microporous inated to a polyolefin drug reservoir consisting of an EVA- Membrane) is prepared, as described in Example 1 40 drug dispersion, which is, in turn, laminated to the above. 55 Solupor P01 film at 70°C, 344 738 Pa and 0.0152 m/s on hot lamination equipment. The resulting multilayered construction, after lamination to a pressure sensitive adhesive, provides rate-controlled drug delivery, emboss-

9 17 EP 1 534 508 B1 18 ing, and writing capabilities. 5. The multilaminate backing construction according to any preceding claim wherein the outer layer is a mi- Example 10 croporous layer or a microfibrullar layer, and the tie layer comprises a secondary drug- containing reser- [0070] Any of the multilayered constructions described 5 voir. in Examples 1-9 are laminated to a pressure sensitive adhesive, enabling bonding to any medical device such 6. The multilaminate backing construction according to as a blood bag, IV bag, or form- fill-seal transdermal patch claim 5 wherein the tie layer comprises an antago- such as Duragesic transdermal fentanyl delivery system. nist-containing reservoir, wherein the antagonist- [0071] The above-described exemplary embodiments 10 containing reservoir is disposed on the skin proximal are intended to be illustrative in all respects, rather than surface of the outer layer, the antagonist being an restrictive, of the present invention. Thus the present in- antagonist to a beneficial agent. vention is capable of many variations in detailed imple- mentation that can be derived from the description con- 7. The multilaminate backing construction of claim 6 tained herein by a person skilled in the art. All such var- 15 wherein the antagonist is in a form that is not releas- iations and modification are considered to be within the able through the base layer and the outer layer is an scope and spirit of the present invention. antagonist release rate controlling means.

8. The multilaminate backing construction of claim 7 Claims 20 wherein the outer layer is coated with surfactants.

1. A backing construction for use with a primary drug 9. The multilaminate backing construction of claim 6, 7 containing reservoir, characterised in that the or 8 wherein the base layer is impermeable to the backing construction is a multilaminate backing con- antagonist within the antagonist-containing reser- struction comprising; 25 voir.

(a) an outer layer (2) comprising a breathable, 10. The multilaminate backing construction according to embossable and writable material, of porous, claim 5 wherein the secondary drug-containing res- microporous, microfibrullar, spun- bonded, spun ervoir comprises a beneficial agent and the base lay- laced, track etched, rayon, wood-pulp, spun 30 er is a beneficial agent release rate controlling laced polyester, or coated paper products and means. combinations thereof; (b) a tie layer (3), the tie layer disposed on the 11. The multilaminate backing construction according to skin proximal surface of the outer layer; and any preceding claim wherein the tie layer is multil- (c) a base layer (4) disposed on the skin proximal 35 aminate (13). surface of the tie layer. 12. The multilaminate backing construction of claim 11 2. The multilaminate backing construction of claim 1 wherein the tie layer comprises a secondary drug- wherein the outer layer comprises a material select- containing reservoir (15). ed from the group consisting of low density polyeth- 40 ylene (LDPE), medium density polyethylene13. The multilaminate backing construction of claim 11 (MDPE), high density polyethylene (HDPE), ultra or 12 wherein the multilaminate tie layer comprises: high density polyethylene (UHDPE), polypropylene, polyester, and polyethylene. (i) a first layer disposed on the skin proximal sur- 45 face of the outer layer (16); 3. The multilaminate backing construction of claim 1 or (ii) a second layer disposed on the skin proximal 2 wherein the tie layer comprises a hydrophobic, a surface of the first layer (17); lipophilic or a non- polar polymeric material and com- (iii) a third layer disposed on the skin proximal binations thereof. surface of the second layer (18); and 50 (iv) a secondary drug-containing reservoir. 4. The multilaminate backing construction of claim 3 wherein the tie layer comprises ethyleneoctene co- 14. The multilaminate backing construction of claim 13 polymers, ethylene-vinyl acetate copolymer (EVA), wherein the first layer is ethylene-vinyl acetate co- low density polyethylene (LDPE), medium density polymer (EVA) or low density polyethylene (LDPE) polyethylene (MDPE), non pressure sensitive formu- 55 layer; the second layer is a polyethylene terephtha- lation of styrenic block copolymer or thermoplastic late (PET) layer; the third layer is ethylene-vinyl ac- elastomers, and combinations thereof. etate copolymer (EVA); low density polyethylene (LDPE) layer, or a polyurethane layer.

10 19 EP 1 534 508 B1 20

15. The multilaminate backing construction of claim bei der die Bindeschicht ein Antagonist-haltiges Re- 12,13 or 14 wherein the secondary drug-containing servoir umfaßt, wobei das Antagonist- haltige Reser- reservoir comprises a beneficial agent and the base voir auf der der Haut proximalen Oberfläche der äu- layer is a drug release rate controlling means. ßeren Schicht angeordnet ist, der Antagonist ist ein 5 Antagonist gegen ein nützlichesn Mittel.

Patentansprüche 7. Verbundverstärkungskonstruktionnach Anspruch 6, bei der der Antagonist in einer Form vorliegt, die nicht 1. Verstärkungskonstruktion zur Verwendung mit ei- durch die Basisschicht freisetzbar ist und die äußere nem primären Arzneimittel enthaltenden Reservoir, 10 Schicht ist eine Vorrichtung zur kontrollierten Frei- gekennzeichnet dadurch, daß die Verstärkungs- setzungsrate des Antagonisten. konstruktion eine Verbundverstärkungskonstruktion ist, umfassend: 8. Verbundverstärkungskonstruktionnach Anspruch 7, bei der die äußere Schicht mit oberflächenaktiven (a) eine äußere Schicht (2) umfassend ein at- 15 Mitteln beschichtet ist. mungsaktives, prägbares und beschreibbares Material aus poröse, mikroporöse, mikrofibrullä- 9. Verbundverstärkungskonstruktionnach Anspruch 6, ren, nach dem Schmelzspinnverfahren herge- 7 oder 8, bei der die Basisschicht gegenüber dem stellte, wasserstrahlverfestigte, Ätzspur-, Ray- Antagonisten innerhalb des Antagonistenthaltenden on-, Holzzellstoff-, wasserstrahlverfestigte Po- 20 Reservoirs impermeabel ist. lyester-Produkte oder Produkte aus beschich- tetem Papier und deren Kombinationen; 10. Verbundverstärkungskonstruktionnach Anspruch 5, (b) eine Bindeschicht (3), die Bindeschicht ist bei der das sekundäre arzneimittelhaltige Reservoir angeordnet auf der der Haut proximalen Ober- ein nützliches Mittel umfaßt und die Basisschicht ei- fläche der äußeren Schicht; und 25 ne Vorrichtung zur kontrollierten Freisetzungsrate (c) eine Basisschicht (4), die auf der der Haut des nützlichen Mittels ist. proximalen Oberfläche der Bindeschicht angeordnet ist. 11. Verbundverstärkungskonstruktion nach einem der vorherigen Ansprüche, bei der die Bindeschicht ein 2. Verbundverstärkungskonstruktionnach Anspruch 1, 30 Verbund (13) ist. bei der die äußere Schicht ein Material umfaßt, aus- gewählt aus der Gruppe bestehend aus einem Po- 12. Verbundverstärkungskonstruktion nach Anspruch lyethylen mit geringer Dichte (LDPE), Polyethylen 11, bei der die Bindeschicht ein sekundäres arznei- mit mittlerer Dichte (MPDE), Polyethylen mit ultraho- mittelhaltiges Reservoir (15) umfaßt. her Dichte (UHPDE), Polypropylen, Polyester und 35 Polyethylen. 13. Verbundverstärkungskonstruktion nach Anspruch 11 oder 12, bei der die Verbundbindeschicht umfaßt: 3. Verbundverstärkungskonstruktion nach Anspruch 1 oder 2, bei der die Bindeschicht ein hydrophobes, (i) eine erste Schicht, die auf der der Haut pro- ein lipophiles oder ein nicht-polares Material oder 40 ximalen Oberfläche der äußeren Schicht (16) deren Kombination umfaßt. angeordnet ist; (ii) eine zweite Schicht, die auf der der Haut pro- 4. Verbundverstärkungskonstruktionnach Anspruch 3, ximalen Oberfläche der ersten Schicht (17) an- bei der die Bindeschicht Ethylenokten-Copolymer, geordnet ist; Ethylen-Vinyl-Acetat-Copolymer (EVA), Polyethy- 45 (iii) eine dritte Schicht, die auf der der Haut pro- len mit geringer Dichte (LDPE), Polyethylen mit mitt- ximalen Oberfläche der zweiten Schicht (18) an- lerer Dichte (MPDE), druckunempfindliche Formu- geordnet ist; und lierung aus Styrol-Blockcopolymer oder thermopla- (iv) ein sekundäres arzneimittelhaltiges Reser- stischen Elastomeren oder deren Kombinationen voir. umfaßt. 50 14. Verbundverstärkungskonstruktion nach Anspruch 5. Verbundverstärkungskonstruktion nach einem der 13, bei der die erste Schicht ein Ethylen-Vinyl-Ace- vorherigen Ansprüche, bei der die äußere Schicht tat-Copolymer (EVA) oder Polyethylen mit geringer eine mikroporöse Schicht oder eine mikrofibrulläre Dichte (LDPE) ist; die zweite Schicht ein Polyethy- Schicht ist und die Bindeschicht ein sekundäres arz- 55 lenterephthalat (PET) ist; die dritte Schicht ein Ethy- neimittelhaltiges Reservoir umfaßt. len-Vinyl-Acetat-Copolymer (EVA), Polyethylen mit geringer Dichte (LDPE) oder eine Polyurethan- 6. Verbundverstärkungskonstruktionnach Anspruch 5, schicht ist.

11 21 EP 1 534 508 B1 22

15. Verbundverstärkungskonstruktion nach Anspruch un médicament. 12, 13 oder 14, bei der das sekundäre arzneimittelhaltige Reservoir ein nützliches Mittel umfaßt und 6. Structure de support multistratifiée selon la revendi- die Basisschicht eine Kontrollvorrichtung für die Arz- cation 5, dans laquelle la couche de liaison com- neimittelfreisetzungsrate ist. 5 prend un réservoir contenant un antagoniste, le ré- servoir contenant un antagoniste étant disposé sur la surface proximale par rapport à la peau de la cou- Revendications che externe, l’antagoniste étant un antagoniste vis- à-vis d’un agent utile. 1. Structure de support destinée à être utilisée avec un 10 réservoir primaire contenant un médicament, carac- 7. Structure de support multistratifiée selon la revendi- térisée par le fait que la structure de support est cation 6, dans laquelle l’antagoniste se présente une structure de support multistratifiée comprenant : sous une forme qui n’est pas libérable à travers la couche de base et la couche externe est un moyen (a) une couche externe (2) comprenant un ma- 15 de régulation de la vitesse de libération de l’antago- tériau respirant, gaufrable et inscriptible, de pro- niste. duits poreux, micro-poreux, microfibrillaires, non-tissés, hydroliés, à tracé gravé, de rayonne, 8. Structure de support multistratifiée selon la revendi- de pâte de bois, de polyester hydrolié ou de pa- cation 7, dans laquelle la couche externe est revêtue pier enduit et des combinaisons de ceux-ci ; 20 par des agents tensio-actifs. (b) une couche de liaison (3), la couche de liaison étant disposée sur la surface proximale 9. Structure de support multistratifiée selon la revendi- par rapport à la peau de la couche externe ; et cation 6, 7 ou 8, dans laquelle la couche de base est (c) une couche de base (4) disposée sur la sur- imperméable à l’antagoniste à l’intérieur du réservoir face proximale par rapport à la peau de la cou- 25 contenant un antagoniste. che de liaison. 10. Structure de support multistratifiée selon la revendi- 2. Structure de support multistratifiée selon la revendi- cation 5, dans laquelle le réservoir secondaire con- cation 1, dans laquelle la couche externe comprend tenant un médicament comprend un agent utile et la une matière choisie dans le groupe constitué par le 30 couche de base est un moyen de régulation de la polyéthylène basse densité (LDPE), le polyéthylène vitesse de libération de l’agent utile. moyenne densité (MDPE), le polyéthylène haute densité (HDPE), le polyéthylène ultra haute densité 11. Structure de support multistratifiée selon l’une quel- (UHDPE), le polypropylène, le polyester et le poly- conque des revendications précédentes, dans la- éthylène. 35 quelle la couche de liaison est multistratifiée (13).

3. Structure de support multistratifiée selon l’une des 12. Structure de support multistratifiée selon la revendi- revendications 1 ou 2, dans laquelle la couche de cation 11, dans laquelle la couche de liaison com- liaison comprend une matière polymère hydropho- prend un réservoir secondaire (15) contenant un mé- be, une matière polymère lipophile ou une matière 40 dicament. polymère non polaire et des combinaisons de celles- ci. 13. Structure de support multistratifiée selon l’une des revendications 11 ou 12, dans laquelle la couche de 4. Structure de support multistratifiée selon la revendi- liaison multistratifiée comprend : cation 3, dans laquelle la couche de liaison com- 45 prend des copolymères d’éthylène- octène, un copo- (i) une première couche disposée sur la surface lymère d’éthylène-acétate de vinyle (EVA), du poly- proximale par rapport à la peau de la couche éthylène basse densité (LDPE), du polyéthylène externe (16) ; moyenne densité (MDPE), une formulation non sen- (ii) une seconde couche disposée sur la surface sible de la pression de copolymère à blocs styréni- 50 proximale par rapport à la peau de la première ques ou d’élastomères thermoplastiques, et des couche (17) ; combinaisons de ceux-ci. (iii) une troisième couche disposée sur la surface proximale par rapport à la peau de la seconde 5. Structure de support multistratifiée selon l’une quel- couche (18) ; et conque des revendications précédentes, dans la- 55 (iv) un réservoir secondaire contenant un médi- quelle la couche externe est une couche micropo- cament. reuse ou une couche microfibrillaire, et la couche de liaison comprend un réservoir secondaire contenant 14. Structure de support multistratifiée selon la revendi-

12 23 EP 1 534 508 B1 24

cation 13, dans laquelle la première couche est une couche de copolymère d’éthylène-acétate de vinyle (EVA) ou de polyéthylène basse densité (LDPE) ; la seconde couche est une couche de poly(téréphta- late d’éthylène) (PET) ; la troisième couche est une 5 couche de copolymère d’éthylène-acétate de vinyle (EVA), une couche de polyéthylène basse densité (LDPE) ou une couche de polyuréthane.

15. Structure de support multistratifiée selon l’une des 10 revendications 12, 13 ou 14, dans laquelle le réser- voir secondaire contenant un médicament comprend un agent utile et la couche de base est un moyen de régulation de la vitesse de libération du médicament. 15

20

25

30

35

40

45

50

55

13 EP 1 534 508 B1

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REFERENCES CITED IN THE DESCRIPTION

This list of references cited by the applicant is for the reader’s convenience only. It does not form part of the European patent document. Even though great care has been taken in compiling the references, errors or omissions cannot be excluded and the EPO disclaims all liability in this regard.

Patent documents cited in the description

• US 6255552 B [0002] • US 4751087 B [0002] • US 6162858 B [0002] • US 4334530 B [0002] • US 5906830 B [0002] • US 3928099 B [0002] • US 5871829 B [0002] • WO 9216202 A [0002] • US 5583171 B [0002] • US 5785991 A [0038] • US 5507525 B [0002] • US 5843468 A [0038] • US 5484603 B [0002] • US 5882676 A [0038] • US 5314421 B [0002] • US 6004578 A [0038]

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