MXPA02004151A - Transdermal drug delivery devices comprising (r) (z) 1 azabicyclo(2.2. 1)heptan 3 one, 0 (3(3 methoxyphenyl) 2 propynyl)oxime. - Google Patents

Abstract

Systems and devices for the transdermal delivery of the compound (R) (Z) 1 azabicyclo[2.2.1]heptan 3 one, 0 [3(3 methoxyphenyl) 2 propynyl]oxime are disclosed. These devices include a drug in adhesive reservoir layer and a skin contacting adhesive layer in which the skin contacting adhesive layer acts as a rate controlling membrane. These devices also include a drug in adhesive reservoir layer and a skin contacting adhesive, where a membrane is placed between the two adhesive layers. The compound is a muscarinic agonist, useful in the treatment of a variety of cognitive disorders, including Alzheimer s Disease.

Description

DEVICES FOR THE SUPPLY OF TRANSDERMAL MEDICINAL PRODUCTS Field of the Invention The invention provides medicaments in adhesive systems for the transdermal delivery of (R) - (Z) -l-azabicyclo-2.2.1] heptan-3-one, O- [3 (3-methoxyphenyl) -2-propynyl] oxime, and devices of • supply of transdermal medication that contains one or more of these systems. BACKGROUND OF THE INVENTION The compound of (R) - (Z) -1- azabicyclo_2.2. l] heptan-3-one, O- [3 (3-methoxyphenyl) -2- • propynyl] oxime, is a muscarinic agonist, whose properties provide it with various qualities 15 therapeutic. For example, the compound is useful as an analgesic agent, such as sleeping pills, in the treatment of the symptoms of senile dementia, Alzheimer's disease, Huntington's disease, tardive dyskinesia, hyperkinesia, manias or other 20 conditions that are characterized by a lower • production or brain release of acetylcholine. This compound and other compounds of its kind that is described in detail in U.S. Pat. No. 5,306,718 to Lauffer et al. The transdermal drug delivery devices are designed to deliver the drug through the skin of a patient providing a relatively constant supply of the drug for an extended period of time. There are several possible designs for the devices, including the reservoir devices, wherein the medicament is typically present in a liquid reservoir and the medicament supply is controlled by means of a velocity-controlling membrane and the medicament in the adhesive devices, in where the medicament is present in a generally solid matrix consisting of a pressure sensitive skin adhesive. Depending on the permeability of the skin to the drug, skin penetration promoters can be added to the matrix. If, however, the skin is highly permeable to the drug, actions must be taken to control diffusion through the skin in order to provide a prolonged stable release of the drug. SUMMARY OF THE INVENTION The invention provides medicaments in adhesive systems for the transdermal administration of (R) - (Z) -1-a-zabicyclo-2.2.1] heptan-3- ona, 0- [3 (3-methoxyphenyl) -2-propynyl] oxime, and devices for the transdermal delivery of medicaments containing one or more of these systems. More particularly, the transdermal drug delivery devices of the invention control the rate of delivery of the medicament to the skin of a subject. In one aspect of the invention, the drug delivery rate is controlled by the rate that controls the adhesive layer that is positioned between the drug reservoir layer and the skin. In another aspect of the invention the drug delivery rate is controlled by means of the rate controlling the membrane that is positioned between the second drug reservoir layer and the adhesive layer that contacts the skin. The invention further provides a method for treating a condition characterized by reduced cerebral production or release of acetylcholine in a subject consisting of applying a transdermal device for the delivery of medicaments of the invention to the skin of a subject and allowing the device to remain in contact with the skin for a sufficient time for providing a therapeutically effective amount of de (R) - (Z) -l-azabicyclo-2.2.1] heptan-3-one, 0- [3 (3-methoxyphenyl) -2-propynyl] oxime, to a patient. DETAILED DESCRIPTION OF THE INVENTION The Drug The compound of (R) - (Z) -l-azabicicl? -2.2.1] heptan-3-one, 0- [3 (3-methoxyphenyl) -2- propynyl] oxime, ( called here as the "drug" or the "compound") is a muscarinic agonist ml / m4, useful in the treatment of a variety of conditions that are characterized by reduced production or cerebral release of acetylcholine. These conditions include senile dementia, Alzheimer's disease, Huntington's disease, tardive dyskinesia, hyperkinesia, manias and the like. The compound is also useful as an analgesic and somnolent. The structure of the compound is as follows: The compound exists in various isomeric forms, including stereoisomers and geometric isomers. The compound can exist in two possible geometric forms known as oxime E and oxime JL, * H? sIAáiiti «j, t¿ &... .t.juJltnt? étillíí Z. The pharmacological activity resides in the oxime Z. Therefore the compositions of the invention contain a sufficient amount of Z -oxime to provide the desired therapeutic effect. The invention includes compositions containing the medicament in any of its therapeutically effective stereochemically isomeric forms or isomers. The structure, chemistry, synthesis and isomeric properties of the medicament are described in detail in US Pat. Nos. 5,306,718 (Lauffer et al.); 5, 346, 911 (Augelli-Szafran et al.); 5,514,812 (Busch et al.); and 5,534,522 (Ando et al), which are incorporated herein by reference. The compound can be used in the devices of the invention in its free base form or in its pharmaceutically acceptable salt form. Examples of these salts include salts of hydrochloric, sulfuric, phosphoric, acetic, benzoic, citric, malonic, salicylic, malic, fumaric, oxalic, succinic, tartaric, lactic, gluconic, ascorbic, maleic, aspartic, benzenosul, phonic, methane and ethanesulfonic acid, and hydroxymethane and hydroxyethane sulfonic acid of the compound (see for example J. Pharm.Sci 66 (1), pp 1-19 (1997)). In general, it is preferred to select a form of the compound that resists isomerization s > . > '5 t •, • f- of the Z form activates the inactive E form when combined with one of the adhesive polymers described below. The free base form of the compound is preferably preferred because of its relatively low conversion rate in the adhesive polymers used in the devices of the invention. Adhesives Pressure sensitive adhesives are used in the devices of the invention in various contexts. The drug reservoir layer of the devices consists of a mixture of the medicament in a pressure sensitive adhesive, and the device is adhered to the skin of the subject by means of a layer of pressure sensitive adhesive. In some devices of the invention, an adhesive layer is used to control the delivery rate of the medicament as well as to adhere the device to the skin of the patient. The adhesive polymers used in the devices of the invention must be substantially chemically inert to (R) - (Z) -1-azabicyclo_2.2.1] heptan-3-one, 0- [3 (3-methoxyphenyl) -2-propynyl] oxime (for example it should not react with or degrade the compound, and preferably should not cause or accelerate the conversion of the Z isomer to the ftítfk ' isomer E) is preferably a pressure sensitive adhesive. Chemical stability can be measured when preparing devices of the invention, stored under conditions of 25 ° C and 60% relative humidity, 5 and testing devices with concentrations (R) - (Z) -l-azabicyclo2.2.1] heptan-3 -one, O- [3 (3-methoxyphenyl) -2-propynyl] oxime with predetermined storage times. It is preferred that the amount of medicament is more than about 10 95%, preferably more than about 97% by weight of the initial amount of medicament in the device when stored 25 ° C and 60% relative humidity for a period of time of 6 months. It is more preferred that the amount of medication be 15 greater than about 95%, preferably more than about 97%, by weight of the initial amount of medicament of the device when stored at 25 ° C and 60% relative humidity for a period of time of 1 year. Accelerated chemical stability can be measured when preparing devices of the invention, stored under conditions of 40 ° C and 75% relative humidity, and testing the devices in concentrations of (R) - (Z) -l-azabicyclo-2.2.1 ] heptan-25 3-one, O- [3 (3-methoxyphenyl) -2-propynyl] oxime for predetermined storage times. It is preferred that the amount of medicine be approximately 95%, preferably more than about 97% by weight of the initial amount of medicament in the device when stored at 25 ° C and 75% relative humidity for a period of time of 3 months, and more than about 90%, preferably more than about 93. % by weight of the initial amount of medication in the device when stored for a period of 6 months. Examples of suitable types of adhesives include acrylates, natural rubbers, synthetic rubbers such as polysiobutylene, polysiloxanes, polyurethanes and other pressure sensitive skin adhesives known in the art. The adhesive polymers may be present alone or in combination. Acrylate copolymers are the preferred pressure sensitive adhesives for use in the devices of the invention. Acrylate copolymers suitable for use in an adhesive layer preferably contain from about 45 to 95 weight percent, more preferably 55 95 weight percent, based on i,.? , *. **.? * jmatm & * .t - * ^ - * »fc *. * -. ^ A *» *? ám * bS ** MÁÍ? »m. total weight of all monomers in the copolymer of one or more monomers A selected from the group consisting of alkyl acrylates containing 4 to 10 carbon atoms in the alkyl group and alkyl methacrylates containing 4 to 10 carbon atoms in the group I rent. Examples of suitable alkyl acrylates and methacrylates include n-butyl, b-pentyl, n-hexyl, isoheptyl, n-nonyl, n-decyl, isohexyl, 2-ethylhexyl, isooctyl and l-ethylhexyl acrylates and methacrylates. Preferred alkyl acrylates include isooctyl acrylate, 2-ethylhexyl acrylate, n-butyl acrylate and • cyclohexyl acrylate. Isooctyl acrylate is the monomer A particularly preferred. The acrylate copolymer further comprises from about 5 to 55 weight percent, more preferably about 5 to 40 weight percent based on the total weight of all monomers in the copolymer of one or more of the B monomers. 20 suitable monomers B include those containing • functional groups selected from the group consisting of carboxylic acid, sulfonamide, urea, carbamate, carboxamide, hydroxy, amino, oxy, oxo and cyano. Exemplary monomers B include acid 25 acrylic, methacrylic acid, maleic acid, a á & *. . * ±? Á *. A., n- * fcJfc..j hydroxyalkyl acrylate containing 2 to 4 carbon atoms in the hydroxyalkyl group, a hydroxyalkyl methacrylate containing 2 to 4 carbon atoms in the hydroxyalkyl group, acrylamide, methacrylamide, an acrylamide substituted with alkyl having from 1 to 8 carbon atoms in the alkyl group, N-vinyl-N-methyl acetamide, N-vinyl valerolactam, N- • vinyl caprolactam, N-vinyl-2-pyrrolidone, glycidyl methacrylate, vinyl, acrylate Of alkoxyethyl containing from 1 to 4 carbon atoms in the alkoxy group, alkoxymethyl methacrylate having from 1 to 4 carbon atoms in the • alkoxy group, 2-ethoxyethoxyethyl acrylate, furfuryl acrylate, furfuryl methacrylate, acrylate, Tetrahydrofurfuryl, tetrahydrofurfuryl methacrylate, propylene glycol monomethacrylate, methyl ether acrylate of propylene oxide, dialkylamino (lower) ethyl acrylate, dilkylamino methacrylate (lower) ethyl, 20 methacrylamide di (lower alkyl) aminopropyl, acrylonitrile and methacrylonitrile. Preferred B monomers include acrylic acid, methacrylic acid, acrylamide, methacrylamide and vinyl acetate. The copolymer optionally can comprise lií ij i. Jltifiíi tir i, kÁ? I ix ***. In addition, a substantially linear macromonomer copolymerizable with the monomers A and B and having an average molecular weight in the range of about 500 to 500,000 preferably about 2,000 to 100,000 and more preferably about 5,000 to 300,000. The macromonomer, when used , is generally present in an amount of not more than about 20%, preferably not more than about 10% by weight based on the total weight of all monomers in the copolymer. Suitable macromonomers include macromonomers of polymethyl methacrylate, styrene / acrylonitrile, polyether, and polystyrene. Examples of useful macromonomers and their preparation are described in Krampe et al., U.S. Pat. 4,693,776 whose description is incorporated by reference. Copolymers written above can be prepared by methods well known to those skilled in the art and described, for example, in U.S. Pat. RE 24,906 (Ulrich), US Pat. No. 4,732,808 (Krampe et al) and international publication no. WO96 / 082289 (Garbe et al), whose descriptions are incorporated by reference.

The inherent viscosity of the copolymer is such that it eventually provides an adequate pressure sensitive adhesive when used in a device of the invention. Preferably the copolymers have an inherent viscosity in the range from about 0.2 dl / g to about 2 dl / g, more preferably from about 0.5 dl / g to 1.6 • dl / g. If desired, the adhesive layer can contain 10 components that modify the properties of the adhesive polymer, such as plasticizers, adhesives and the like of the types and in the quantities readily determinable by those skilled in the art. 15 The devices A preferred transdermal drug delivery system of the invention uses two layers of adhesive that are laminated directly to each other. The first layer of adhesive that does not 20 contact with the skin of the patient, consists of a polymer and a medicine and serves as a layer of drug reservoir. The second adhesive layer, which does not make contact with the patient's skin, serves to control the rate of drug release to the patient. 25 patient and to attach the device to the skin of the patient. The second adhesive layer consists of a polymer that controls the speed. Thus the presence of the second adhesive layer in the device changes the cutaneous penetration profile of the device compared to a similar device where the second adhesive layer is identical in composition to the first adhesive layer, when the profile is determined using the method of test described before. This control of the delivery rate of the medicament may be due to the affinity difference of the medicament for the two different adhesive layers and the differences in the diffusion rate of the medicament through the two layers of different adhesives. These differences in affinity and / or diffusion of the drug in the two adhesive layers, as well as the relative thickness of the adhesive layers, allow the speed of drug delivery to be controlled. This system is called the "speed controlled adhesive system". In a particularly preferred embodiment of the speed controlled adhesive system, the adhesives to be used in the two layers are selected in such a way that the second adhesive layer is made of an adhesive polymer having a lower affinity for the medicament than the first one. i * XÍ¿, í *. * AM, ¿j5¡á2A% .J adhesive layer. With "Less affinity" it is implied that the drug preferably resides in the deposit layer, so that when the system is in equilibrium the weight percentage of the drug in the deposit layer is greater than the percentage by weight of the drug. in the speed control layer. The difference in the affinity of the two polymers of the medicament as well as the relative thickness of the adhesive layers allows it to be 10 control the speed of drug delivery. The first layer also known as the deposit layer of the controlled rate adhesive device preferably consists of an acrylate copolymer of the type described above. A The preferred copolymer is a terpolymer of about 60 to 80% by weight, preferably 65 to 75% by weight based on the total weight of the isooctyl acrylate monomer, about 4 to 15% by weight, preferably about 5 to 10% by weight 20 of acrylamide and about 15 to 35% by weight, Preferably 15 to 25% by weight of vinyl acetate, the weight ratio of monomers being particularly preferred of about 75/5/20 of isooctyl acrylate / acrylamide / ethyl acetate. 25 vinyl. Another preferred copolymer is a copolymer of about 54 to 77% by weight based on the total weight of the isocycotyl acrylate monomer, about 18 to 39% by weight of vinyl acetate and about 2 to 10% by weight of polymethylmethacrylate macromonomer ( PMMA), with a particularly preferred weight ratio of approximately 59/38/3 isoctyl acrylate / vinyl acetate / PMMA. The reservoir layer of the device contains sufficient medicament to deliver a therapeutically effective amount of the medicament to a patient during the delivery period. A therapeutically effective amount of the medication is the amount that is sufficient to alleviate the symptoms of the condition being treated, the condition of the patient and other factors known to those skilled in the art, but typically the dose to be administered is from 0.07 to 700 mg / day, preferably from approximately 0.1 to 50 mg / day, and more preferably from approximately 1 to 30 mg / day. To supply this amount of medicament the reservoir layer preferably contains about 5 to 45% by weight based on the total weight of the reservoir layer. More preferably, the deposit layer contains approximately 20 to 35% by weight. ii.iri.t.r - '. atftej The devices of the invention provide a therapeutically effective dose of the compound over an extended period of time, preferably from about 1 to 14 days, more preferably about 1 day and most preferably about 7 days. days. The devices of the invention provide a therapeutically effective blood level of the medicament to a patient during the period of 10 supply. A therapeutically effective blood novel drug is a quantity that is sufficient to alleviate the symptoms of the condition • what is being treated. The precise amount will vary with the exact nature of the condition that is 15 treating, the condition of the patient, and other factors known to those skilled in the art, but typically the blood serum level is about 0.2 100 ng / ml and preferably 20 to 60 ng / ml. 20 It is also preferred that the supply rate • transdermal drug is relatively constant during the extended period of time that the devices of the invention are used to provide a therapeutically effective dose of the 25 compound. The transdermal delivery rate of The drug, also known as the transdermal flow, is defined as the rate at which the drug penetrates through the skin. In the skin penetration test described below, the flow can be determined by measuring the amount of drug in the recipient fluid (this is the amount of medication that penetrates through the skin) and dividing it by the area of the skin. skin and the time the medication was allowed to penetrate the skin before removing and replacing the fluid receptor. The flow for each time interval is given as the average flow over the entire time interval. When more than one interval is included in an experiment then the maximum and minimum flow for the time period of the whole experiment can then be determined (for example, when the time intervals are 3,6,12 and 24 hours, then they are obtained the flow values for the time intervals of 0-3, 3-6, 6-12 and 12-24). It is preferred that the maximum flow to minimum flow ratio be between 1.0 and 4.0, more preferably between 1.0 and 2.0. In some cases there is a period of time at the beginning of an application period in which the transdermal flow is low, sometimes called a aéirii.afrjjf. ----- '---'- ^^ "delay time". If short time intervals are selected at the start of the penetration experiment, then the initial values of the transdermal flow can be very low due to the delay time which would then make the calculation of the ratio between maximum flow and minimum flow too large, Flow values during the initial 24 hours of a penetration experiment are not included in determining the minimum flow unless they have half of the maximum flow value. Once the flow during any time interval has reached more than half of the maximum flow value, then that value and all subsequent values of the flow are used to determine the minimum flow. The second adhesive layer, also known as the speed controlling layer, consists of a polymer different from the first adhesive layer, such that the second adhesive layer changes the penetration profile in the skin of the device compared to a similar device wherein the second adhesive layer is identical in composition to the first adhesive layer. The polymers in the first and second adhesives may differ, for example in types and amounts of monomers, extension of the r *** »tfßA * é¡ ^ tíáM ^ AM- ^ ijií reaction, cross-linking, branching and copolymer sequences. The polymer of the adhesive device with controlled rate is preferably a polysiobutylene (PIB), since that polymer has been found to have a lower affinity for the drug than the acrylate copolymers described above. More preferably a mixture of low molecular weight PIB and high molecular weight PIB is used. Low molecular weight PIB typically has an average MW viscosity of approximately 40,000 to 70,000; the high molecular weight PIB typically has an average MW viscosity of about 900,000 to 2,000,000. The high and low molecular weight polymers are combined at a low MW / MW high ratio of about 5/1 to 1/1, preferably about 3/1. Acrylic PIB and copolymer blends can also be used. A preferred combination consists of a mixture of one or more polyisobutadienes and a copolymer of about 75/5/20 isoctyl acrylate / acrylamide / vinyl acetate, in a ratio of about 95: 5 to 80:20 PIB: acrylate. Another transdermal drug delivery device of the invention contains at least A -a ^ jAj a ^^ l ^ .. three different layers. The first layer consists of an adhesive that serves as a drug reservoir. The second layer consists of an adhesive that is adhered to the surface of the membrane opposite the surface of the membrane that makes contact with the first layer. This third layer makes contact with the patient's skin when the device is used. The type of device is called as the "speed controlled membrane device". As in the speed controlled adhesive device, the preferred reservoir layer of the controlled rate device consists of an acrylate copolymer in combination with the medicament. A preferred copolymer is a terpolymer of about 60 to 80% by weight, preferably 65 to 75% by weight based on the total weight of the monomer, of isoctyl acrylate, about 4 to 15% by weight, preferably about 5 10% by weight of acrylamide and about 15 to 355 by weight, preferably about 15 to 25% by weight of vinyl acetate, with a particularly preferred weight ratio of the monomers of about 75/5/20 of isooctyl acrylate / acrylamide / ethyl acetate vinyl. Another preferred copolymer is a copolymer of The nitrous oxide is approximately 54 to 77% by weight based on the total weight of the isooctyl acrylate monomer, about 18 to 439% by weight of vinyl acetate and about 2 to 10% by weight. weight of polymethyl methacrylate macromonomer (PMMA) with a preferred weight ratio of approximately 59/38/3 isooctyl acrylate / vinyl acetate / PMMA. The reservoir layer typically contains about 5 to 45% by weight of medicament based on the total weight of the reservoir layer, preferably about 20 to 35% by weight. The membrane is selected in such a way as to control the speed. The presence of the membrane in the device changes the penetration profile in the skin of the device as compared to a similar device that does not have the membrane, when the profile is determined using the test method described below. Suitable membranes include continuous film membranes and microporous membranes. Preferred particulate membranes are continuous film membranes prepared from ethylene: vinyl acetate copolymers containing from about 2 to 28% by weight of vinyl acetate. The most preferred membranes are continuous film membranes l? i * l ^ ht i li i í li li ili i i-Amm lt £ ií * ^ * ??? m.i. The following are prepared from ethylene-vinyl acetate copolymers containing about 9% by weight of vinyl acetate. The thickness of the membrane will generally be from about 25 μm to about 100 μm, preferably the thickness will be about 50 μm. Because the rate of drug delivery is controlled by the membrane the polymer used in the second adhesive layer that contacts the skin can be selected from a variety of polymer adhesives having a range of affinities for the drug, and more preferably is an acrylic copolymer of the type described above. A particularly preferred copolymer is a copolymer of isooctyl acrylate, acrylamide, and vinyl acetate in a monomeric ratio of about 75/5/20 acrylate of isobutyl amine / acrylamide / vinyl acetate. The layer that makes contact with the skin may initially contain no medication as it is expected that over time the medicament will diffuse from the deposit layer to the layer that contacts the skin, or may contain the medicament in a concentration similar to that of the deposit layer.

The desirable properties in a transdermal drug delivery system are well known to those skilled in the art. For example, it is desirable to have a sufficiently reduced cold flow at which the device of the invention is stable to flow after storage. It is also preferred that it adheres well to the skin and separates cleanly from the skin. In order to achieve resistance to cold flow, the preferred levels of skin adhesion and clean release, the amount and structure of the comonomers in the copolymer, the inherent viscosity of the copolymer and the amount and type of any adjuvant or additive are selected such that the adhesive layers they obtain the desired balance of those properties. A transdermal drug delivery device of the invention also consists of a backup. The backrest is flexible in such a way that the device conforms to the skin. Suitable backing materials include conventional flexible backing materials used for pressure sensitive adhesive tapes such as polyethylene, particularly low density polyethylene, linear low density polyethylene, polyethylene . < á¿ ... Á? *, *. m ... m, .- J * -. * ma * i í..Í: i < j? OtLL metallocene, high density polyethylene, polypropylene, polyethers such as polyethylene terephthalate, randomly oriented nylon fibers, ethylene-vinyl acetate copolymer, polyurethane, natural fibers such as rayon or the like. Backs that are laminated such as polyethylene-aluminum-polyethylene terephthalate compounds are also suitable. The backs must be substantially inert to the opacifiers of the adhesive layer. The transdermal drug delivery devices of the invention can be prepared using methods for preparing multi-strand devices known in the art. For example, the adhesive layers may be co-extruded in a backing or release liner, the layers may be extruded or coated sequentially in the backing or removable liner, or the layers may be reopened separately in a backing or release liner, then The two adhesive layers can be laminated together. Suitable release liners include conventional release liners consisting of a known laminate such as a polyester, polyethylene, polyester stripe network or a polyethylene coated paper coated with a suitable coating based on polymer or silicone polymer. Preferably, the controlled rate adhesive systems of the invention are produced by separately preparing the reservoir plates and the layers that contact the skin. The deposit layer is generally prepared by combining the adhesive copolymer with the medicament and the appropriate organic solvent (s) (such as, for example, methanol, ethanol, isopropanol, ethyl acetate, etc.). The mixture is stirred until a homogeneous coating formulation is obtained. The deposit coating formulation is then applied to a release liner using conventional coating methods (for example spatula coating or matrix coating by extrusion) with a wet thickness of about 8880 μm to 2200 μm, sufficient to provide a deposit layer. dry from about 14.7 mg / cm2 to about 37.5 mg / cm2. The coated release liner is allowed to dry and then laminated to a backing. The skin-contacting layer is generally prepared by combining speed-controlled adhesive (s) with an appropriate organic solvent (such as, for example, nol, ethyl acetate, and stirring until homogeneous.) This formulation is then applied to a release liner using conventional coating methods (for example, spatula coating or matrix coating by extrusion.) The layer of adhesive that contacts the skin is coated with sufficient thickness to provide an adhesive layer that contacts the skin of the skin. a thickness of about 10 μm to 40 μm The coated liner is allowed to dry, then the release liner is removed from the deposit layer and the exposed adhesive surface is laminated to the adhesive surface of the adhesive layer that contacts the skin. Patches of the right size can then be cut from the resulting laminates.In an alternative method of production the adhesive copolymers can They are coated in a liner and the medicament is added to the coated adhesive copolymer in an additional step of the process, for example, using the methods described in U.S. Pat. 5,688,523 (Garbe et al). The controlled velocity membrane devices of the invention can be prepared at SUSAAS Í jj »igm .. producing a deposit layer in the manner described above. The deposit layer formulation may be coated on a release liner, dried and then laminated as a backing. The wet thickness 5 of the deposit layer is from about 880 μm to about 2200 μm. An adhesive coating formulation which makes contact with the skin is prepared in the same manner as the deposit coating formulation, which uses the 10 same adhesive polymer or a different adhesive or a combination of adhesives. This formulation is then applied to a release liner using conventional coating methods (e.g., a spatula or spatula coating or coating). 15 with matrix by extrusion) to provide a dry thickness of about 5 μm to 50 μm. This coated liner is allowed to dry. Then it is laminated in a membrane. The devices are assembled on removal when removing the removable liner from the 20 depositing and laminating the exposed adhesive surface of the deposit layer on the membrane surface of an adhesive layer that contacts the skin. Patches of the appropriate size can then be cut out from the resulting laminate. 25 The following examples are provided for * -Xíkk, M & k & t.t ffí- ^ i * ******* "** ^ * M ** * .í * .t further illustrate the invention Examples In Vitro Penetration Test Method Skin penetration data given in the following examples were obtained using the following test method: A vertical diffusion cell with human cadaver skin is used.When a transdermal medicament delivery device is evaluated, the peel liner is removed from a 2.0 cm2 patch and the patch is applied to the skin and pressed to cause uniform contact with the skin.The resulting patch / skin laminate is placed with the patch up in the hole in the lower portion of the diffusion cell.The diffusion cell then is assembled and the lower portion is filled with 10 ml of warm receptor fluid (32 ° C) (phosphate buffer 0.1 M, pH 6) in such a way that the receptor fluid is in contact with the skin. The receiving fluid is stirred using a magnetic stirrer. The sampling port is covered except when in use. The cell is then placed in a chamber with constant temperature (32 ± 2 ° C) and humidity (50 ± 10% relative humidity). The receiving fluid is stirred by means of a magnetic stirrer during the entire n-á experiment to ensure a uniform sample and a reduced diffusion barrier on the dermal side of the skin. The entire volume of the receiving fluid is withdrawn at specific time intervals and immediately replaced with fresh fluid. The extracted fluid is filtered through a 0.45 μm filter. The last 1-2 ml are then analyzed in search of • (R) - (Z) -l-azabicyclo-2.2.1] heptan-3-one, O- [3 (3-methoxyphenyl) -2-propynyl] oxime, using chromatography 10 high performance liquids (Column: Zorbax SB-CBN, 50X 2.1 mm ID, mobile phase: 87% v of phosphate buffer with triethylamine adjusted to a pH of 3.0, 13% v acetonitrile, flow rate: 2ml / min; UV detector; 240 n;; time 1 minute; volume of 15 injection: 5 μl). The cumulative amount of (R) - (Z) -l-azabicyclo-2.2.1] heptan-3-one, 0- [3 (3-methoxyphenyl) -2-propynyl] oxime, which penetrates the skin, is calculated. Drug content method for stability • Transdermal drug delivery devices (20 cm2 patches) were sealed in bolls (BAREX ™ / aluminum / polyester or BAREX ™ / aluminum / paper laminates) and stored 25 under one or more of the following conditions 25 ° C temperature / 60% relative humidity (25 ° C / 60% RH), 40 ° C temperature / 75% relative humidity (40 ° C / 75% RH), room temperature (RT, approx 22 ° C), temperature of 40 ° C and temperature of 50 ° C. - The 5 patches were examined in their medicine content before storage and after predetermined storage times. An internal standard solution was prepared to add 1.9 g of ethyl paraben to 1000 ml of tetrahydrofuran (THF). He 10 liner is removed from 10 patches of 20 cm2 and the patches were placed in a 0.95 bottle 1. The backing and coating were removed using 500 • ml of internal standard solution. The sample was stirred for at least 24 hours. A dilution of the The sample was prepared by placing 5 ml of the resulting solution in a 4-ounce bottle (118.3 ml) and adding 100 ml 50:50 (v: v) acetonitrile / water to the bottle and shaking for about 60 minutes. An aliquot of the dilution was placed in a 20 autosampler for analysis. The analyzes of • Samples were performed by means of high-performance liquid chromatography (Column: Zorbax SB-CBN, articulation size of 5 μ, 25 cm × 4.6 mm, mobile phase: 87:18 (v / v) of phosphate buffer with 25 acetonitrile adjusted to a pH of 3.0, the buffer is a 7.7x104 molar triethylamine in potassium phosphate solution adjusted to a pH of 3.0 of phosphoric acid; Flow rate: 2ml / min; UV detector; 240 nm; 15 minute time; injection volume: 5 μl). The results are reported as the percentage of the amount of medication that remains in the initial amount of medication. Preparation of Adhesives The adhesives used in the following examples were generally prepared according to the methods described below. Preparation of isocotyl acrylate copolymer: acrylamide: vinyl acetate (75: 5: 20) A masterbatch was prepared by combining isooctyl acrylate (621.0 g) acrylamide (41.4 g), vinyl acetate (165.6 g), 2, 2'-azobi s (2,4-dimethylpentanonitrile) (1656 g), ethyl acetate (884.5 g) and methanol (87.48 g). A portion (400 g) of the resulting solution was placed in an amber glass bottle of 0.95 1. The bottle was purged for 2 minutes with nitrogen at a flow rate of 1 1 per minute. The bottle is sealed and placed in a rotating water bath at 45 ° C for 24 hours to effect essentially complete polymerization. The copolymer was diluted with ethyl acetate: methanol (250 g, 90:10 v: v) with 26.05% solids. Preparation of isocotyl acrylate macromonomer copolymer: vinyl acetate: polymethyl methacrylate (59: 38: 3) (80.37 g) of vinyl acetate, polymethyl methacrylate macromonomer (6345 g of ELVACITE ™ 1010 available from ICI Acrilics) were charged. , ethyl acetate (271.95 g) and methanol (8.41 g) were loaded in an amber glass bottle of 0.95 1 and then mixed on a roller until a solution was obtained. Isooctyl acrylate (124.875 g) and 2, 2'-azobis (2-methylbutyronitrile) (0.3173 g) were added to the solution. The bottle was purged for 2 minutes with nitrogen at a flow rate of 1 1 per minute. The bottle is sealed and placed in a rotating water bath at 57 ° C for 23 hours to effect essentially complete polymerization. The copolymer was diluted with ethyl acetate (62.78 g) and methanol (1.94 g) with 38% solids. Preparation of isocotyl acrylate macromonomer copolymer: vinyl acetate: polymethyl methacrylate (55: 38: 7) (80.37 g) of vinyl acetate, polymethyl methacrylate macromonomer (14.80 g of ELVACITE ™ 1010 available from ICI Acrilics) were charged. and ethyl acetate (370.80 g) were loaded into a 0.95 1 amber glass bottle and then mixed on a roller until a solution was obtained. Isooctyl acrylate (116.32 g) and 2,2'-azobis (2-methylbutyronitrile) (0.3173 g) were added to the solution. The bottle was purged for 2 minutes with nitrogen at a flow rate of 1 1 per minute. The bottle is sealed and placed in a rotating water bath at 57 ° C for 23 hours. The resulting copolymer had 28.5% solids in ethyl acetate.

Low molecular weight polyisobutylene (74.99 g of OPPANOL ™ B10 poly isobutylene available from BASF) high molecular weight polyisobutylene (24.96 of OPPANOL ™ B100 polyisobutylene), heptane (270.0 g) and ethyl acetate (180.0 g) combined and mixed until all the polyisobutylene had dissolved. * Polyisobutylene adhesive solution preparation The dry adhesive was placed by spatula coating an acrylate adhesive copolymer solution on the release liner. The adhesive-coated release board was dried in the oven to remove the solvent and reduce the level of residual monomers. The dry adhesive came off of the removable liner and stored in a container until use. Membranes Some of the membranes used in the following examples are commercial (eg, COTRAN ™ 9702 controlled gauge EVA membranes, COTRAN TM 9717, COTRAN ™ 9726 and COTRAN1M 9728, all • available from 3M Company). Others were prepared from commercial resins using methods of 10 conventional extrusion (for example expression ends in a smothering roller). Examples of suitable resins include ethylene-vinyl acetate (EVA) copolymers ELVAXtm from DuPont. In the following examples "X% EVA" means that the The membrane produced from ethylene-vinyl acetate copolymer contains X% by weight of vinyl acetate. Example 1 Transdermal drug delivery devices were produced having two layers of 20 different adhesives separated by means of a • membrane as follows. A coating formulation was prepared by combining the dry adhesive (8.84 g of isooctyl acrylate / acrylamide / vinyl acetate 75/5/20) (R) -25 (Z) -l-azabicyclo-2.2.1] heptan-3 -one, 0- [3 (3- * .rt *? & i * i - *, - i ** Ú r. * r-U ** * to £ My ** .. U > Aya ... methoxyphenyl) -2-propynyl] oxime (1.17 g) and solvent (30 g of acetate / methanol 90/10 v / v) and then mixing until a uniform coating formulation is obtained. A layer of deposit adhesive was prepared in the following manner. The coating formulation was coated with a spatula with a wet thickness of 1524 μm (60 mil) in a release liner (Daubert 164P removable liner coated with silicone). The resulting coated liner was allowed to dry at room temperature for 5 hours and then layered on a backing (SCOTCHPAK ™ 1109 polyester film laminate, distributed by 3M Company). There was a layer of adhesive that makes contact with the skin in the following way,. The coating formulation was coated with a wet thickness of 254 μm (10 mil) on the release liner (Daubert 164P removable liner coated with silicone). The resulting coated liner was allowed to dry at room temperature for 1 hour and then the exposed adhesive surface was laminated on a membrane (film with 12% EVA, 51 μm / 2 mil). The removable liner was removed from the B3fc «* fca ia. < to t deposition adhesive and then the exposed adhesive surface was laminated to the surface of the membrane of the adhesive layer which makes contact with the skin. Patches of the resulting laminate were cut out. Each 5 patch consisted of 5 layers: a backing, a deposit adhesive layer containing 11.7% by weight of (R) - (Z) -l-azabicyclo-2.2.1] heptan-3-one, 0- [3 (3- (methoxyphenyl) -2-propynyl] oxime, a membrane and a release liner. Penetration into the skin at Through the human cadaver skin was determined using the test method described above. The skin penetration data are shown in Table 2 below each value is the average of 3 independent determinations. Examples 2-20 Using the method of example 1, a group of transdermal drug delivery devices in which the concentration of (R) - (Z) -l-azabicyclo-2.2.1] heptan-3-one is varied , 0- [3 (3-20-methoxyphenyl) -2-propynyl] oxime in the adhesive layers, • the weight of the coating of the adhesive layer of deposit, and the percentage of EVA in the membrane. The compositions are shown in the following table 1. In each example the adhesive used was acrylate 25 isooctyl / acrylamide / vinyl acetate 75/5/20, the í tS? .mi ** itrA. * í tütlAC i .. coating formulation contained 25% solids, the concentration of (R) - (Z) -l-azabicyclo-2.2.1] heptan-3-one, 0- [3 (3-methoxyphenyl) -2-propynyl] oxime was the same in both adhesive layers, the adhesive layer that contacts the 5 skin was coated with a wet thickness of 254 μm (10 mil) and the membrane had a thickness of 51 μl (2 mil). Penetration of the skin through the skin • of corpse was determined using the test method described above. The penetration data on the skin is 10 shows in the following table 2 in which the value is the average of 3 independent determinations. • r ^ **, ~ AAÍM *** - *; A ,, *, ^ r.?*-M.i. «..ti» - * ..? I ** lAii * Í. you 00 • Example 21 A coating formulation was prepared by combining the dry adhesive (13.7 g of isocotyl acrylate / acrylamide / vinyl acetate 75/5/20), (R) - (Z) -1- 5 azabicyclo-2.2.1] heptan-3-one, O- [3 (3-methoxy-enyl) -2-propynyl] oxime (1.54 g) and solvent (45 g of ethyl acetate / methanol 90/10 v / v) and then mixed until a uniform coating formulation was obtained. A deposit adhesive layer was prepared as follows. The coating formulation was coated with a spatula with a wet thickness of 762 μm (30 mil) in a release liner (a removable liner coated with fluoropolymer, SCOTCHPAK ™ 9742, distributed by 3M Company). The coated liner The resultant was allowed to dry at room temperature for 60 to 90 minutes and then the exposed adhesive surfaces of two portions of the coated liner were laminated together. The release liner peeled off a surface and the wet thickness of 178 μm (7 mil) on the release liner (a removable liner coated with fluoropolymer, SCOTCHPAK ™ 9742). The resulting coated liner was allowed to dry at room temperature for 60 to 90 minutes and then the exposed adhesive surface was laminated to a membrane (4.5% EVA film, 51 μm / 2 mil). The release liner is removed from the deposit adhesive layer and then the adhesive surface 10 exposed was laminated on the surface of the membrane of the adhesive layer that makes contact with the skin. Patches of the resulting laminate were punched out. Each patch consisted of 5 layers: a backing, a deposit adhesive layer containing 10% by weight of 15 (R) - (Z) -l-azabicyclo-2.2.1] heptan-3-one, 0- [3 (3-methoxyphenyl) -2-propynyl] oxime, a membrane and an adhesive layer that contacts the skin which contains 10% by weight of (R) - (Z) -l-azabicyclo-2.2.1] heptan-3-one, O- [3 (3-methoxyphenyl) -2-propynyl] oxime; a lining Examples 22-38 Using the method of Example 21, a group of transdermal drug delivery devices was produced in which the concentration of (R) - (Z) -l-azabicyclo-2.2.1] heptan-3 is varied. ona, 0- [3 (3-methoxyphenyl) -2-propynyl] oxime in the adhesive layers, the weight of the coating of the adhesive layer of deposit, and the percentage of EVA in the membrane. The compositions are shown in the following table 3. In each example the same adhesive used was used in both layers, the concentration of (R) - (Z) -1- azabicyclo-2.2.1] heptan-3-one , 0- [3 (3-methoxy phenyl) -2-propynyl] oxime was the same in both adhesive layers, and the membrane had a thickness of 51 μl (2 mil). Penetration of the skin through the cadaver skin was determined using the test method described above. The penetration data on the skin is shown in the following table 4 in which the value is the average of 3 independent determinations. táttáá.- 'IfiitÁH xv? mvtt- ti [p * M »^ .-. ^ .-» - ^ a, ^. »^ ....... ^ ... ^. ^^ tte * i, t IOA = isooctyl acrylate ACM = acrylamide VOAc = ethyl acetate PMMAMac = polymethyl methacrylate macromonomer * «- * & *» »Jifera.

• • Example 39 A coating formulation was prepared by combining the dry adhesive (5200 g of isocotyl acrylate / acrylamide / vinyl acetate 75/5/20), ethyl acetate (17.56 kg), methanol (1.96 kg) and (R) - (Z) -1-azabicyclo- 2.2. l] heptan-3-one, O- [3 (3-methoxy-f-3-yl) -2-propynyl] oxime (1.54 g) and mix until a uniform coating formulation is obtained. The formulation was allowed to stand until all the air bubbles had dissipated. A deposit adhesive layer was prepared as follows. The coating formulation was coated with a matrix (pump speed and separation were selected to provide a dry coating weight of 13 mg / cm2 ± 4%) in a release liner (a removable liner coated with fluoropolymer, SCOTCHPAK ™ 1022, distributed by 3M Company). The resulting coated liner was dried in an oven at 60 ° C (140 ° F) for 2 minutes, at 88 ° C (190 ° F) for 2 minutes and at 116 ° C (240 ° F) for 2 minutes. The adhesive surface was a first section of the coated liner was laminated to a backing (SCOTCHPAK ™ 1109 polyester film laminate), the release liner was removed and the exposed adhesive surface was laminated to the adhesive surface of a section of the liner. coated release. The resulting deposit adhesive layer had a dry coating weight of 26 mg / cm2 ± 4%. A layer of adhesive that contacts the skin was produced in the following manner. The coating formulation was matrix coated (pump speed and separation were selected to provide a dry coating weight of 2.5 mg / cm2 ± 4%) on the release liner (a fluoropolymer-coated release liner, SCOTCHPAK ™ 1022). ). The resulting coated liner was allowed to dry at 60 ° C (140 ° F) for 2 minutes, at 88 ° C (190 ° F) for 2 minutes and at 116 ° C (240 ° F) for 2 minutes and then the exposed adhesive surface it was laminated on a 9% EVA membrane (51 μm / 2mil) (COTRAN ™ 9702 EVA controlled gauge membrane). The release liner was removed from the deposit adhesive layer and then the exposed adhesive surface was laminated to the surface of the membrane of the adhesive layer making contact with the skin. Patches of the resulting laminate were punched out. Each patch consisted of 5 layers: a backing, a deposit adhesive layer containing 20% by weight of (R) - (Z) -l-azabicyclo-2.2.1] heptan-3-one, 0- [3 ( 3- methoxyphenyl) -2-propynyl] oxime, a membrane and an adhesive layer which contacts the skin which contains 20% by weight of (R) - (Z) -l-azabicyclo-2.2.1] heptan-3-one, OR - [3 (3-methoxyphenyl) -2-propynyl] oxime; and a removable liner. Penetration into the skin through human cadaver skin was determined using the test method described above. The skin penetration data are shown in Table 5 below each value is the average of 15 independent determinations. The stability of the drug content is shown in table 6.

Uim ± tA-Mu Já.mil. áá = Example 40 Transdermal drug delivery devices having two layers of different adhesives adhered directly to each other were produced in the manner described below. A layer of deposit adhesive was prepared in the following manner. Dry adhesive (35.0 g of isooctyl acrylate / acrylamide / vinyl acetate 75/5/20), ethyl acetate (135.0 g), methanol (15.1 g) and (R) - (Z) -l-azabicyclo-2.2. 1] heptan-3-one, 0- [3 (3-methoxyphenyl) -2-propynyl] oxime (15. Og) were combined and mixed until a uniform coating formulation was obtained. The coating formulation was coated with a spatula with a wet thickness of 1524 μm (60 mil) in a release liner (Daubert 164P removable liner coated with silicone). The resulting coated liner was allowed to dry at room temperature for 5 hours and then layered on a backing (SCOTCHPAK ™ 1109 polyester film laminate, distributed by 3M Company). A layer of adhesive that makes contact with the skin was produced in the following manner. The coating formulation was coated with a wet thickness of 254 μm (10 mil) on the liner removable (a fluoropolymer-coated release liner, SCOTCHPAK ™ 1022). The resulting coated liner was allowed to dry at room temperature for 3 hours and then the exposed adhesive surface 5 was laminated to a backing (SCOTCHPAK ™ 1109 polyester film laminate, distributed by 3M Company). • A layer that makes contact with the skin was produced in the following way. The adhesive solution 10 of polyisobutylene described above was coated with a spatula with a wet thickness of 178 μm (7 mils) in a release liner. The coated liner was left • dry at room temperature. The "dry" adhesive layer had a thickness of approximately 17.8 μm (0.7 15 thousand) . The release liner was removed from the deposit adhesive layer and then the exposed adhesive surface was laminated to the adhesive surface of the adhesive layer. Patches of the resulting laminate-20 were die-cut. Each patch consisted of 4 layers: a backing, a deposit adhesive layer containing 30% by weight of (R) - (Z) -1-azabicyclo-2.2. l] heptan-3-one, O- [3 (3-methoxyphenyl) -2-propynyl] oxime, in isooctyl acrylate / acrylamide / acetate adhesive 25 of vinyl 75/5/20, a layer that makes contact with the skin of adhesive depoliisobut wood and a removable liner. The samples were allowed to stand for approximately 12 hours to allow the medicament to diffuse from the reservoir layer to the layer that contacts the skin. Penetration into the skin through human cadaver skin was determined using the test method described above.

• The skin penetration data is shown in table 8 below each value is the average of 3 10 independent determinations. Examples 41-58 Using the method of Example 40, a group of transdermal drug delivery devices was prepared in which the concentration of (R) - (Z) -1- azabicyclo-2.2.1] heptan-3-one , 0- [3 (3-methoxyphenyl) -2- propynyl] oxime, in the deposition layer and the dry thickness of the layer that makes contact with the skin are varied. The compositions are shown in table 7. In each example the deposition layer adhesive was 20 isooctyl acrylate / acrylamide / vinyl acetate • 75/5/20. The deposit layer was coated to a wet thickness of 1524 μm (60 mil). The layer that makes contact with the skin was polyisobutylene (PIB). The skin penetration data are shown in table 9 25 and 10 below each value is the average of 3 independent determinations • Examples 59-61 Using the general method of Example 40, a group of transdermal drug delivery devices was produced in which the compositions of the skin-contacting adhesive were varied. The compositions are shown in the following Table 9. The adhesive compositions which make contact with the skin were prepared by mixing isooctyl acrylate / acrylamide / vinyl acetate 75/5/20 with the polybutylene adhesive solution described above. The coating formulation for the skin-contacting layer contained approximately 19% solids and was coated with a wet thickness of 203 μm (8 mil). In each example the deposition layer adhesive was isooctyl acrylate / acrylamide / vinyl acetate 75/5/20 and the deposit layer contained 25% of (R) - (Z) -l-azabicyclo-2.2.1] heptan -3-one, 0- [3 (3-methoxyphenyl) -2-propynyl] oxime. The coating formulation for the deposit layer contained 25% solids and was coated with a wet thickness of 1524 μm (60 mil). Penetration of the skin through the human cadaver skin was determined using the test method described above. Skin penetration data are shown in Table 10 below where each value is the average of 3 independent determinations IOA isooctyl acrylate ACM acrylamide VOAc vinyl acetate PIB polyisobutylene J * »? I. ?? é? & .Í • Example 62 A deposit adhesive layer was prepared in the following manner. A coating formulation was prepared by combining dry adhesive (4200 g of isooctyl 5 acrylate / acrylamide / vinyl acetate 75/5/20), ethyl acetate (16200 g), methanol (1800 g) and (R) - ( Z) -l-azabicyclo-2.2.1] heptan-3-one, 0- [3 (3-methoxyphenyl) -2-propynyl] oxime (1800g) were combined and mixed until a formulation of 10 uniform coating. The formulation was allowed to stand until all the air bubbles had dissipated. The coating formulation is • coated with a matrix (the speed of the pump and the separation were selected to provide a 15 dry coating weight of 13 mg / cm2 ± 4%) in a release liner (a fluoropolymer-coated release liner, SCOTCHPAK ™ 1022, distributed by 3M Company). The resulting coated liner was dried in an oven at 60 ° C (140 ° F) for 2 minutes, at 88 ° F 20 C (190 ° F) for 2 minutes and at 116 ° C (240 ° F) for 2 minutes. The adhesive surface was a first section of the coated liner was layered on a backing (SCOTCHPAK ™ 1109 polyester film laminate), the release liner was removed and the exposed adhesive surface was laminated to the backing. * i-t aa ^ ^. atajaJa ^ a-At- ^ i.jt ^^ adhesive surface of a section of the coating liner liner. The resulting deposit adhesive layer had a dry coating weight of 26 mg / cm2 ± 4%. A layer of adhesive that makes contact with the skin was produced in the following manner. The coating formulation was produced by combining low molecular weight polyisobutylene (900 g of OPPANOL B-10), high molecular weight polyisobutylene (300 g of OPPANOL B-100) and heptane (3006 g) and mixed until obtained a uniform coating formulation. The coating formulation was coated with a matrix (pump speed and separation were selected to provide a dry coating weight of 1.53 mg / cm2 ± 4%) in a release liner (removable liner coated on one side with silicone) . The resulting coated liner was baked in the oven at 52 ° C (125 ° F) for 2 minutes, at 85 ° C (185 ° F) for 2 minutes and 107 ° C (225 ° F) for 2 minutes. The release liner was removed from the deposit adhesive layer and then the exposed adhesive surface was laminated to the adhesive surface of the adhesive layer which contacts the skin. The lining .¿¿ ^^ * ^ a- ^ TOFC removable silicone release liner replacement fluoropolymer (a release liner coated with fluoropolymer, SCOTCHPAK ™). Patches of the resulting laminate were punched out. Each patch consisted of 4 layers: a backing, a deposit adhesive layer containing 30% by weight of (R) - (Z) -l-azabicyclo-2.2. l] heptan-3-one, O- [3 (3-methoxyphenyl) -2-propynyl] oxime, 70% isooctyl acrylate / acrylamide / vinyl acetate 75/5/20 adhesive, a layer that makes contact with the skin of polyurethane-butylene adhesive and a removable liner. The samples were allowed to stand for about 12 hours to allow the drug to diffuse from the reservoir layer to the layer that contacts the skin. Penetration into the skin through human cadaver skin was determined using the test method described above. The skin penetration data are shown in Table 11 below each value is the average of 15 independent determinations. The stability data of the drug content is shown in the following table 12.

Examples 63-75 Using the general method of Example 21, transdermal delivery devices in which the drug coating weight of the adhesive which contacts the skin and the reservoir layer is varied (see Table 13) were produced. Each example use the same adhesive (isooctyl acrylate / acrylamide / vinyl acetate 75/5/20) is used in both layers and the concentration of (R) - (Z) - l-azab cycle-2.2.1? ] heptan-3-one, O- [3 (3-me toxy phenyl) -2-propynyl] oxime was 20%. In each example the membrane had a thickness of 51 μm (2 mil) and the EVA percentage was 9%. Penetration into the skin through human cadaver skin was determined using the test method described above. The skin penetration data are shown in Table 14 below each value is the average of 5 independent determinations.

"TTf ^ lHiíH'liroÉÉltt ^ Example 76 A coating formulation was prepared by combining the dry adhesive (18 g of isooctyl acrylate / acrylamide / vinyl acetate 75/5/20) (R) ~ 5 (Z) -l-azabicyclo-2.2.1] heptan -3-one, 0- [3- (3-methoxyphenyl) -2-propynyl] oxime (2.0g) and solvent (70 g acetate / methanol 90/10 v / v) and then mix until W that a uniform coating formulation is obtained. The coating formulation was coated 10 with a spatula with a wet thickness of 635 μm (25 mil) in a removable liner (Daubert 164P removable liner coated with silicone). The resulting coated liner was dried and laminated on a backing (laminated polyester film 15 SCOTCHPAK ™ 1109, distributed by 3M Company). The data on the stability of the drug content is shown in table 15.

• Example 77 A coating formulation was prepared by combining the dry adhesive (18 g isooctyl acrylate / acrylamide / polymethyl methacrylate macromonomer 55/38/7) (R) - (Z) -l-azabicyclo-2.2.1] heptan- 3-one, 0- [3 (3-methoxyphenyl) -2-propynyl] oxime (2.0g) and solvent (70 g of acetate / methanol 90/10 v / v) and then mixing until a coating formulation is obtained uniform. The coating formulation was coated with a spatula with a wet thickness of 635 μm (25 mil) in a release liner (Daubert 164P removable liner coated with silicone). The resulting coated liner was dried and laminated on a backing (SCOTCHPAK ™ 1109 polyester film laminate, distributed by 3M Company). The data on the stability of the drug content is shown in Table 16. llli¿J.ljlll ^ A ^^ ji &laaabAjt.jii- urt p?, --- * .-- * .- -. * -. * - ,. **. *.: .. AA? ^. ÍlA * U ^ I-t * íi.

The present invention has been described with reference to various modalities. The above detailed description and examples have been provided to facilitate understanding only, and unnecessary limitations should not be understood. It will be apparent to those skilled in the art that they can be performed to the described embodiments without departing from the spirit and scope of the invention. Thus the scope of the invention should not be limited to the exact details of the compositions and structures described herein, 10 but rather by the following claims. •

Claims (2)

1. CLAIMS 1. A device for the transdermal delivery of the drug (R) - (Z) -1-azabicyclo- 2.2.1] heptan-3-one, 0- [3 (3-methoxy phenyl) -2-propynyl] which It comprises: (a) a drug reservoir layer consisting of a therapeutically effective amount of the medicament and a first pressure sensitive adhesive and (b) a skin contacting layer adhered to a surface of the reservoir layer of the medicament. medication and consisting of a medication and a second pressure sensitive adhesive. The device of claim 1 wherein the first pressure sensitive adhesive consists of an acrylic copolymer comprising a copolymer selected from: (a) one or more monomers selected from the group consisting of alkyl (meth) acrylates containing 4 10 carbon atoms in the alkyl group, and (b) one or more ethylenically unsaturated B monomers containing a functional group selected from the group consists of acid carboxylic, sulfonamide, urea, carbamate, carboxamide, hydroxy, amino, oxy, oxo and cyano. 3. The device of claim 2 wherein the monomer (s) A is selected from the group consisting of isooctyl acrylate, 2-ethylhexyl acrylate, butyl acrylate and cyclohexyl acrylate. 4. The device of claim 2 wherein the monomer (s) B is selected from the group consisting of acrylic acid, methacrylic acid, acrylamide, vinyl acetate and methacrylamide. The device of claim 2 wherein the acrylic copolymer further comprises one or more substantially linear macromonomers copolymerizable with the monomers A and B. The device of claim 1 wherein the second pressure sensitive adhesive consists of of a polysiloxane, an acrylate, a natural rubber or a synthetic rubber. The device of claim 6 wherein the second layer of pressure sensitive adhesive consists of polyisobutylene. 8. The device of claim 1 wherein the medicament is present in the deposited in an amount of about 5 to 45% by weight based on the total weight of the deposition layer. 9. A device for the transdermal supply of the drug (R) - (Z) -1-azabicyclo-5 2 .2. l] heptan-3-one, 0- [3 (3-methoxy-enyl) -2-propynyl] oxime comprising: (a) a drug reservoir layer consisting of • a therapeutically effective amount of the drug and a first adhesive sensitive to the 10 pressure (b) a membrane that controls the speed adhered to a surface of the deposit layer of • medication; and (c) a layer that contacts the skin adhered to the surface of the membrane opposite the surface of the membrane in contact with the deposit layer and which comprises a second pressure sensitive adhesive. 10. The device of claim 9 wherein the first and second pressure sensitive adhesives. • independently comprise an acrylic copolymer. 11. The device of claim 9 wherein the layer that contacts the skin also includes a medicament. 12. The device of claim 10 in the - ffjftf4"-8 * ^ - • -» - > * • - which each acrylic copolymer independently consists of a copolymer of the following: (a) one or more monomers A selected from the group consisting of alkyl (meta) acrylates what 5 contains from 4 to 10 carbon atoms in the alkyl group and (b) one or more ethylenically unsaturated B monomers containing a functional group selected from the group consists of 10 of carboxylic acid, sulfonamide, urea, carbamate, carboxamide, hydroxy, amino, oxy, oxo and cyano. The device of claim 12 in which the monomer (s) A is selected from the group 15 consisting of isooctyl acrylate, 2-ethylhexyl acrylate, butyl acrylate and cyclohexyl acrylate. The device of claim 12 in which the monomer (s) B is selected from the group ^. 20 consisting of acrylic acid, methacrylic acid, acrylamide, vinyl acetate and methacrylamide. The device of claim 12 wherein the acrylic copolymer further comprises one or more substantially linear macromonomers 25 copolymerizable with monomers A and B. 16. The device of claim 9, wherein the speed controlling membrane consists of an ethylene-vinyl acetate copolymer. The device of claim 9 in which the medicament is present in the deposit layer in an amount of about 5 to 45% by weight based on the total weight of the deposit layer. A method for treating a condition characterized by a reduced production or release of cerebral acetylcholine in a mammal, which consists of applying a device according to claim 1 to a mammal and allowing the device to remain in contact with the skin for a period of time. sufficient time to supply the mammal with a therapeutically effective amount of (R) - (Z) -l-azabicyclo-2.2.1] heptan-3-one, O- [3- (3-methoxy phenyl) -2-propynyl] oxime. 19. The method of claim 18 wherein the condition is Alzheimer's disease. A method for treating a condition characterized by a reduced production or release of cerebral acetylcholine in a mammal, which consists of applying a device according to claim 9 to a mammal and allowing the iA £ i ** - l * lm *, tA *? áá. device remains in contact with the skin for a time sufficient to supply the mammal with a therapeutically effective amount of (R) - (Z) -l-azabicyclo-2.2.1] heptan-3-one, 0- [3 (3-methoxyphenyl -2-propynyl] oxime. 21. The method of claim 20 wherein the condition is Alzheimer's disease. 22. A method for treating a condition characterized by reduced production or release of cerebral acetylcholine in a mammal consisting of supplying (R) - (Z) -l-azabicyclo-2.2.1] heptan-3-one, O- [ 3 (3-methoxyphenyl) -2-propynyl] oxime to a mammal by means of a transdermal drug delivery device in an amount of about 0.1 to 50.0 mg / 20 cm2 patch / day causing the serum concentration of (R) - (Z) -1- azabicyclo-2.2.1] heptan-3-one, O- [3 (3-methoxyphenyl) -2-propynyl] oxime in the mammal is from about 0.2 to 100 ng / ml over a period of time from about 2 to 14 days. 23. A method of claim 22 wherein (R) - (Z) -l-azabicyclo-2.2.1] -heptan-3-one, 0- [3 (3-methoxyphenyl) -2-propinyl] is supplied. oxime in an amount of approximately 0.1 to 30.0 mg / 20 cm2 patch / day causing the serum concentration of (R) - (Z) -l-azabicyclo-2.2.1] heptan-3-one, O- [3 (3-methoxyphenyl) -2-propynyl] oxime in the mammal is from about 20 to 60 ng / ml during a period of time of approximately 7 days. 24. A method for treating a condition characterized by the production or reduced release of cerebral acetylcholine in a mammal consisting of • in supplying (R) - (Z) -l-azabicyclo-2.2.1] heptan-3-one, 0- [3 (3-methoxyphenyl) -2-propynyl] oxime to a 10 mammal by means of a transdermal drug delivery device in an amount of about 0.1 to 50.0 mg / 20 cm2 patch / day wherein the ratio of maximum flow to minimum flow is between 1.0 and about 4.0 during 15 a period of time of approximately 2 to 14 days. 25. The method of claim 24 wherein the ratio of the maximum flow rate to the minimum flow is between 1.0 and about 2.0. 20 26. A method to treat a condition • characterized by the production or reduced release of cerebral acetylcholine in a mammal consisting of supplying (R) - (Z) -l-azabicyclo-2.2.1] heptan-3-one, 0- [3 (3-methoxy-enyl) -2-propynyl] oxime to a 25 mammal by means of a delivery device b,., ** Á .A * - ^ A- * m,; - * - * - -i - * -? & tMMl * lí- > , -m & A transdermal medicament in an amount of about 75 to 50.0 mg / 20 cm2 patch / day for a period of time of about 1 to 14 days. 27. A method for treating a condition characterized by the production or reduced release of cerebral acetylcholine in a mammal consisting of supplying (R) - (Z) -l-azabicyclo-2.2.1] heptan-3-one, 0- [ 3 (3-methoxyphenyl) -2-propynyl] oxime to a mammal by means of a transdermal drug delivery device in a therapeutically effective amount over a period of time from about 2 to 14 days. 28. A method for treating a condition characterized by reduced production or release of cerebral acetylcholine in a mammal consisting of supplying (R) - (Z) -l-azabicyclo-2.2.1] heptan-3-one, O- [ 3 (3-methoxyphenyl) -2-propynyl] oxime to a mammal by means of a transdermal drug delivery device causing the serum concentration of (R) - (Z) -1-azabicyclo-2.2.1] heptan-3 -one, O- [3 (3-methoxyphenyl) -2-propynyl] -oxime in the mammal is from about 0.2 to 100 ng / ml for a period of about 1 to 14 days. 29. The method of claim 28 wherein the serum concentration is between about 20 and 60 ng / ml. 30. A device for the transdermal delivery of the drug (R) - (Z) -1-azabicyclo-5 2.2.1] heptan-3-one, 0- [3 (3-methoxyphenyl) -2-propynyl] -oxime which consists of a pressure-sensitive adhesive layer that contains a quantity therapeutically • effective of the medicament wherein the amount of the medicament is greater than about 95% by weight 10 of the initial amount of the medicament in the device when stored at 25 ° C and a relative humidity of 60% for a period of time of • at least 6 months. 31. The device of claim 30 in which the time period is 1 year. 32. A device for the transdermal delivery of the drug (R) - (Z) -1-azabicyclo-2.2.1] heptan-3-one, 0- [3 (3-methoxyphenyl) -2-propynyl] -oxime consisting of of an adhesive layer sensitive to 20 pressure that contains a quantity therapeutically • effective of the medicament wherein the amount of the medicament is greater than about 90% by weight of the initial amount of the medicament in the device when stored at 40 ° C and a humidity 25 relative of 75% during a period of time of at least 6 months. 33. A device for the transdermal delivery of the drug (R) - (Z) -1- to zabicyclo-2.2.1] heptan-3-one, 0- [3 (3-methoxyphenyl) -2-propynyl] -oxime which consists of a pressure-sensitive adhesive layer containing a therapeutically effective amount of the medicament wherein the amount of the medicament is greater than about 95% by weight of the initial amount of the medicament in the 10 device when stored at 40 ° C and a relative humidity of 75% for a period of time of at least 3 months. fifteen • • * > * I