CZ20021496A3 - Systems for transdermal application of medicaments - Google Patents

Description

The invention relates to an adhesive medicament comprising: systems intended for transdermal administration of (R) - (Z) -1-azabicyclo [2.2.1] heptan-3-one-O- [3- (3-methoxyphenyl) -2-propynyl] oxime, and for transdermal delivery systems comprising one or more of the above systems.

BACKGROUND OF THE INVENTION (R) - (Z) -1-Azabicyclo [2.2.1] heptan-3-one-O- [3- (3-methoxyphenyl) -2-propynyl] oxime is an agonist of muscarinic effects and this property leads to the use of said compound in multiple therapeutic applications. For example, the compound is useful as an analgesic, a sleep aid, and a medicament for treating the symptoms of senile dementia, Alzheimer's disease, Huntington's disease, tardive dyskinesia, hyperkinesia, mania, and other conditions characterized by decreased formation or release of cerebral acetylcholine. Said compound and other compounds of this class are described in detail in U.S. Patent No. 5,306,718 to Lauferra et al.

Transdermal delivery systems are intended to deliver the drug across the skin of a patient, said systems providing a relatively constant drug delivery over an extended period of time. There are a number of possible solutions to said systems including drug delivery systems wherein the drug is typically contained in a fluid located in the cartridge and drug delivery is controlled by a rate-controlling membrane, and adhesive systems wherein the drug is contained in a generally solid matrix containing pressure sensitive skin adhesive. Depending on the skin's permeability to the drug, additional ingredients such as skin penetration enhancers can be added to the matrix.

However, if the skin is highly permeable to the drug, skin diffusion control means must be used to provide a stable and prolonged drug transport.

SUMMARY OF THE INVENTION

The invention relates to drug-containing adhesive systems for transdermal administration of (R) - (Z) -1-azabicyclo [2.2.1] heptan-3-one-O- [3- (3-methoxyphenyl) -2-propynyl] oxime, and on transdermal delivery systems comprising one or more of the above systems.

In particular, the invention relates to transdermal delivery systems with a controlled rate of drug delivery to the skin of a patient. According to one aspect of the invention, the drug delivery rate is controlled by an adhesive rate controlling adhesive layer that is disposed between the drug reservoir forming layer and the skin. According to another aspect of the invention, the drug delivery rate is controlled by a delivery rate controlling membrane that is disposed between the drug reservoir forming layer and the skin contact adhesive layer.

In addition, the invention provides a method of treating a subject's condition characterized by reducing the formation or release of cerebral acetylcholine, comprising applying the transdermal delivery system of the invention to the skin of the subject and leaving said system in contact with the skin for sufficient time to administer a therapeutically effective amount of (R) - (Z). -1-azabicyclo [2.2.1] heptan-3-one-O- [3- (3-methoxyphenyl) -2-propynyl] oxime to said subject. ··· 4944 99 · ·· 4994

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DETAILED DESCRIPTION OF THE INVENTION

Drug

The above compound, (R) - (Z) -1-azabicyclo [2.2.1] heptan-3-one-O- [3- (3-methoxyphenyl) -2-propynyl] oxime (also referred to as the drug in the description) or the compound) is a selective agonist of m1 / m4 muscarinic effects, and is useful in the treatment of multiple conditions characterized by a decrease in the formation or release of cerebral acetylcholine. Said conditions include senile dementia, Alzheimer's disease, Huntington's disease, tardive dykinesia, hyperkinesia, mania and the like. The compound is also useful as an analgesic and sleep aid. The structure of the compound is as follows:

All of said compound may exist in multiple isomeric forms including stereoisomers and geometric isomers. The compound may form two possible geometric forms known as E-oxime and Z-oxime. Zoxim has pharmacological activity. Therefore, the compositions of the invention contain a sufficient amount of Zoxime to achieve the desired therapeutic effect. The invention encompasses compositions comprising the drug in all its possible, therapeutically effective stereochemical or isomeric forms. The structure, chemistry, synthesis and isomeric properties of the drug are described in detail in U.S. Patent Nos. 5,306,718 (Lauferr et al.); 5,346,911 (Augelli-Szafran and • · · ·

sp.); 5,514,812 (Bucsh et al.); and 5,534,522 (Ando et al.), all of which are incorporated herein by reference.

Said compound may be used in the systems of the invention in its free form or in the form of a pharmaceutically acceptable salt thereof. Examples of such salts include salts of the compound of the invention with acids such as hydrochloric, sulfuric, phosphoric, acetic, benzoic citric, malonic, salicylic, malic, fumaric, oxalic, succinic, tartaric, lactic, gluconic, ascorbic, maleic, aspartic, benzenesulfonic, methane- and ethanesulfone and hydroxymethane- and hydroxyethane sulfone (see, eg, J.Pharm. Sci. 66 (1), pp. 1-19 (1977)). In general, it is preferred to select a form of the compound which, when coupled with any of the adhesive polymers described below, resists the isomerization of the compound from the active Z form to the inactive E form. The free base compound is advantageous when used in adhesive polymers in the systems of the invention, mainly because of its low conversion rate.

Adhesives

Pressure sensitive adhesives have multiple functions in the systems of the invention. In the systems of the invention, the drug reservoir layer comprises a drug mixture in a pressure-sensitive adhesive wherein the entire system is a pressure-sensitive adhesive layer adhered to the skin of the subject. In some systems, the adhesive layer is intended to control the rate of drug delivery as well as the function of an adhesive to attach the system to the skin of a subject.

Adhesive polymer (s) suitable for use in the present invention should be substantially inert to (R) - (Z) - 1 - (-) - - - - - - - - - - - · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·

-azabicyclo [2.2.1] heptan-3-one-O- [3- (3-methoxyphenyl) -2-propynyl] oxime (for example, it should not react with or induce decomposition of the compound and preferably should not induce or accelerate Z conversion) and is preferably a pressure sensitive adhesive for use on the skin. The chemical stability of the systems according to the invention can be determined by preparing said systems, storing them at 25 ° C and 60% relative humidity and determining the (R) - (Z) -1-azabicyclo [2.2.1] heptan-3-on-O concentrations - [3- (3-methoxyphenyl) -2-propynyl] oxime in systems after the specified storage periods have elapsed. It is preferred that the drug concentration after a storage period of 6 months at 25 ° C and 60% relative humidity be greater than about 95% or more preferably greater than about 97% of the original drug concentration in the system. More preferably, the drug concentration after storage for 1 year at 25 ° C and 60% relative humidity is greater than about 95%, or more preferably, about 97% of the original drug concentration in the system.

An accelerated stability study on chemical stability can be performed by preparing these systems, storing them at 40 ° C and 75% relative humidity and determining the (R) - (Z) -1-azabicyclo [2.2.1] heptan-3-one- O- [3- (3-methoxyphenyl) -2-propynyl] oxime in the systems after the specified storage periods have elapsed. Preferably, the drug concentration after storage for 3 months at 40 ° C and 75% relative humidity is greater than about 95%, or more preferably, about 97% of the original drug concentration in the system, and after storage for 6 months 90%, even more preferably, about 93% of the original drug concentration in the system.

Examples of suitable adhesive types include acrylates, natural gums, synthetic gums such as polyisobutylenes, polysiloxanes, polyurethanes, and other pressure sensitive adhesives for skin application known in the art. Said adhesive polymers may be used singly or in the form of combinations thereof.

Preferred pressure-sensitive adhesives for use in the systems of the invention are acrylate copolymers. Suitable acrylate copolymers for use in the adhesive layer preferably comprise about 45 to about 95% by weight, more preferably 55 to 95% by weight, based on the total weight of all monomers in the copolymers, one or more monomers A selected from C 4 -C 10 alkyl acrylates. in the alkyl group and C 4 -C 10 alkyl methacrylates. Examples of suitable alkyl acrylates and methacrylates include butyl, pentyl, hexyl, isoheptyl, nonyl, decyl, isohexyl, 2-ethyloctyl, isooctyl, 2-ethylhexyl acrylates and methacrylates. Preferred alkyl acrylates include isooctyl acrylate, 2-ethylhexyl acrylate, butyl acrylate and cyclohexyl acrylate. Particularly preferred monomer A is isooctyl acrylate.

The acrylate copolymer further comprises about 5 to about 55% by weight, more preferably about 5 to about 40% by weight based on the total weight of all monomers in the copolymers, of one or more monomers B. Suitable monomers B include monomers containing a functional group selected from carboxyl a sulfonamide group, a urea group, a carboxamide group, a hydroxy, amino, oxy, oxo, and cyano group. Examples of B monomers include acrylic acid, methacrylic acid, maleic acid, hydroxyalkyl acrylate having 2 to 4 carbon atoms in the hydroxyalkyl group, hydroxyalkyl methacrylate having 2 to 4 carbon atoms in the hydroxyalkyl group, acrylamide, methacrylamide, alkyl substituted acrylamide ··· ·················································· Containing 1 to 8 carbon atoms in the alkyl group, N-vinyl-N-methylacetamide, N-vinylvalerolactam, N-vinylcaprolactam, N-vinyl-2-pyrrolidone, glycidyl methacrylate, vinyl acetate, alkoxyethyl- (C 1 -C 4) acrylate, (C 1 -C 4) alkoxyethyl methacrylate, 2-ethoxyethoxyethyl acrylate, furfuryl acrylate, furfuryl methacrylate, tetrahydrofurfuryl methacrylate, propylene glycol monomonomethacrylate, thyletheracrylate, di (lower) alkylaminoethyl acrylate, di (lower) alkylaminoethyl methacrylate, di (lower) alkylaminopropylmethalarylamide, acrylonitrile and methacrylonitrile. Preferred B monomers include acrylic acid, methacrylic acid, acrylamide, methacrylamide and vinyl acetate.

The copolymer may optionally further comprise a substantially linear macromonomer copolymerizable with monomers A and B having a weight average molecular weight in the range of about 500 to about 500,000, preferably in the range of about 2000 to about 100,000, and even more preferably about 5000 to about 30,000. When used, the macromonomer is generally used in an amount of not more than about 20%, preferably not more than about 10% by weight based on the weight of all monomers contained in the copolymer. Suitable macromonomers include polymethyl methacrylate, styrene / acrylonitrile, polyether and polystyrene macromonomers. Examples of suitable macromonomers and their preparation are described in U.S. Patent No. 4,693,776 to Krampe et al., Which is incorporated by reference; of this description by reference.

The copolymers described above can be prepared by methods generally known in the art, such as those described in U.S. Patent No. 5,201,549.

RE 24,906 (Ulrich), US Pat. No. 4,732,808 (Krampe et al.), And International Patent Application No. WO 96/08229 (Garbe et al.). Sp.), Which are incorporated herein by reference.

The intrinsic viscosity of the copolymer is such that ultimately, when used in the systems of the invention, it provides a suitable pressure-sensitive adhesive. Preferably, said copolymer has an intrinsic viscosity in the range of about 0.2 dl / g to about 2 dl / g, more preferably about 0.5 dl / g to about 1.6 dl / g.

If desired, the adhesive layer may comprise other components that modify the properties of the adhesive polymer such as plasticizers, tackifiers, and the like in amounts readily selected by one of ordinary skill in the art.

Application systems

One preferred embodiment of the transdermal delivery system of the invention comprises two adhesive layers superimposed on each other. The first non-skin adhesive layer comprises a polymer and a drug and serves as a drug reservoir forming layer. The second adhesive layer, which is in contact with the subject's skin, controls the rate of drug delivery across the subject's skin and secures the system to the subject's skin. Said second adhesive layer comprises a polymer which controls said rate. Thus, the presence of a second adhesive layer in the system alters the penetration profile achieved with said system as compared to a similar system, however, the adhesive layer having the same composition with the first adhesive layer, wherein said penetration profile is determined by the assay described below. This control of drug delivery rate can be attributed to different drug affinities for two different adhesive layers and different drug diffusion rates through two different layers. Said differences in the affinity and / or diffusion of the drug in the two adhesive layers as well as in the relative thicknesses of the two adhesive layers

The layers allow control of drug delivery rate. Such a system is referred to as an adhesive-controlled rate system.

In a particularly preferred embodiment of the adhesive controlled rate system, the adhesive used in the two layers is selected such that the second adhesive layer is prepared from a polymer having a lower drug affinity than the first adhesive layer. The term lower affinity in this case means that the drug is preferably contained in the storage layer, so that when the system is in equilibrium, the weight percentage of drug in the storage layer is greater than the weight proportion of drug in the transport rate control layer. The differences in the affinity of the two polymers for the drug as well as the relative thicknesses of the adhesive layers thus allow the rate of drug transport to be controlled.

The first adhesive layer, also referred to as the storage layer, contained in the adhesive-controlled rate system preferably comprises an acrylate copolymer of the kind described above. A preferred copolymer is a terpolymer containing, based on the total weight of the monomers, about 60 to about 80% by weight, preferably about 65 to about 75% by weight isooctyl acrylate, about 4 to about 15% by weight, preferably about 5 to about 10% by weight acrylamide and about 15% by weight. up to about 35% by weight, preferably about 15 to about 25% by weight vinyl acetate, and particularly preferably a weight ratio of isooctylacetate / acrylamide / vinyl acetate monomers of about 75/5/20. Another preferred copolymer is a copolymer prepared with from about 54 to about 77% by weight based on the total weight of monomers, iosoctyl acrylate, about 18 to 39% by weight vinyl acetate, and about 2 to about 10% by weight polymethyl methacrylate macromonomer (PMMA), particularly the preferred weight ratio of isooctyl acrylate / vinyl acetate / PMMA is about 59/38/3.

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The storage layer of the system comprises a sufficient amount of drug to administer an effective amount of the drug to a subject in a designated administration period. A therapeutically effective amount of the drug is an amount sufficient to ameliorate the symptoms of the condition to be treated. The exact amount will vary depending on the particular condition to be treated, the condition of the patient and other factors known to those skilled in the art, but the usual dose is 0.07 to 700 mg / day, preferably about 0.1 to about 50 mg / day, and most preferably about 1 mg to about 30 mg / day. For administration of said dose of medicament, the reservoir layer preferably comprises about 5 to about 45% by weight of medicament based on the total weight of the reservoir. Even more preferably, the storage layer comprises about 20 to about 35% by weight of the drug.

The systems of the invention allow the administration of a therapeutically effective dose of the compound over an extended period of time, preferably within about 1 to about 14 days, even more preferably about 1 day, and most preferably about 7 days.

The systems of the invention provide therapeutically effective blood serum levels of the drug during the administration period. A therapeutically effective amount of the drug is an amount sufficient to ameliorate the symptoms of the condition to be treated.

The exact amount varies depending on the particular condition to be treated, the condition of the patient and other factors known to those skilled in the art, but a typical blood serum level of the drug is about 0.2 to about 100 ng / ml, and preferably 20 to 60 ng / ml. ml.

It is also preferred that during the extended period of time over which the systems of the invention are applied, the transdermal drug delivery is relatively constant and a therapeutically effective dose of the compound is administered. The rate of transdermal transport, also referred to as transdermal, is defined as the drug penetration rate of the skin.

In the penetration assay described below, this flow can be determined by determining the amount of drug in the reception fluid (i.e., the amount of drug that passes through the skin) and dividing this amount by the skin area and the time the skin penetration has taken place before removal and replacement of the reception fluid. The flow in each time period is given by the mean flow throughout this time period. If the flow is detected in more than one time period in the experiment, then it is possible to determine the maximum and minimum flow during the whole experiment (eg if the selected time intervals are 3, 6, 12 and 24 hours, then the flow values over time 0-3, 3-6, 6-12 and 12-24 hours). It is preferred that the ratio of maximum flow to minimum flow be between 1.0 and about 4.0, more preferably between 1.0 and about 2.0.

In some cases, there is a period of time at the beginning of the application when the transdermal flow is low, sometimes referred to as the lag phase. If short intervals are selected at the beginning of the penetration evaluation test, the initial values of the transdermal flows are relatively low due to the lag phase, which may result in a relatively high calculated ratio between the maximum and minimum flows. It should be noted here that for the purpose of determining the maximum flow to minimum flow ratio, the flow values established during the first 24 hours of the penetration test are not included in the minimum flow values unless they reach half of the maximum flow value. When the flow in any time period reaches more than half the maximum flow value, this value and the following values are already used to determine the minimum flow value.

The second adhesive layer, also referred to as the rate control layer, comprises a polymer other than the polymer contained in the first adhesive layer, thereby altering the second adhesive layer to alter it. to the skin penetration profile achieved with this system in comparison with a similar system wherein the second adhesive layer has the same composition as the first adhesive layer. The polymers of the first and second adhesives may vary, for example, in types and amounts, monomers, degree of reaction, crosslinking, branching, and sequence of copolymers. The rate-controlling adhesive of the adhesive layer is preferably polyisobutylene (PIB) since it has been found that the polymer has a lower drug affinity 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 a viscosity average molecular weight of from about 40,000 to about 70,000; The high molecular weight PIB typically has a viscosity average molecular weight of about 900,000 to 2,000,000. The high and low molecular weight polymers are combined in a low molecular weight / high molecular weight polymer ratio of about 5/1 to about 1/1, preferably in a ratio of 3/1. Mixtures of PIB and acrylic copolymers may also be used. A preferred combination comprises a mixture of one or more polyisobutylenes and isooctylacrylate / acrylamide / vinyl acetate copolymers having a ratio of about 75/5/20 in a PIB: acrylate ratio of about 95: 5 to about 80:20.

Another preferred transdermal delivery system comprises at least three individual layers. The first layer comprises an adhesive which functions as a drug reservoir. The second layer comprises a rate controlling membrane and is attached to one side of the first layer. The third layer comprises an adhesive, and is attached to a membrane surface opposite the membrane surface in contact with the first layer. This third layer is in contact with the subject's skin when the system is applied. This type of system is referred to as a membrane controlled speed system.

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As in the adhesive-controlled rate-controlled system, the preferred storage layer of the rate-controlled membrane system comprises an acrylate copolymer in combination with the drug.

A preferred copolymer is a terpolymer containing, based on the total weight of the monomers, about 60 to about 80% by weight, preferably about 65 to about 75% by weight isooctyl acrylate, about 4 to about 15% by weight, preferably about 5 to about 10% by weight acrylamide and about 15% by weight. up to about 35% by weight, preferably about 15 to about 25% by weight vinyl acetate, and particularly preferably a weight ratio of isooctylacetate / acrylamide / vinyl acetate monomers of about 75/5/20. Another preferred copolymer is a copolymer prepared with from about 54 to about 77% by weight based on the total weight of monomers, iosoctyl acrylate, about 18 to 39% by weight vinyl acetate, and about 2 to about 10% by weight polymethyl methacrylate macromonomer (PMMA), a particularly preferred weight ratio of isooctyl acrylate / vinyl acetate / PMMA is about 59/38/3. The storage layer typically contains about 5 to 45% by weight of the drug based on the total weight of the storage layer, preferably about 20 to about 35% by weight.

The membrane is selected so that it has the ability to control the speed. The presence of a membrane in the system alters the penetration profile of the system as compared to a similar system which does not include said membrane in determining said penetration profile as described below. Suitable membranes include continuous film membranes and microporous membranes. Particularly preferred membranes are continuous film membranes prepared from ethylene: vinyl acetate copolymers containing about 2 to about 28 weight percent vinyl acetate. Most preferred membranes are continuous film membranes prepared from ethylene: vinyl acetate copolymers containing about 9% vinyl by weight. 9 9 9 9

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Because the rate of drug delivery is membrane-controlled, the polymer used in the second skin-contacting layer can be selected from various adhesive polymers with different drug affinities. The polymer used in this layer may be the same or different as the polymer used in the storage layer. Preferably, the polymer used in the second adhesive layer is a high drug affinity polymer, and more preferably an acrylic copolymer of the type described above is used. A particularly preferred copolymer is a copolymer of isooctyl acrylate, acrylamide and vinyl acetate having an isooctyl acetate / acrylamide / vinyl acetate monomer ratio of about 75/5/20.

The skin-contacting layer need not initially contain any drug because it is believed that over time the drug will diffuse from the storage layer to the contact layer, or it may contain the drug at a concentration similar to the drug concentration in the storage layer.

Desirable properties of the transdermal delivery system are known to those skilled in the art. For example, it is desirable for the system of the invention to exhibit a sufficiently low flow in the unaltered state and thus be stable during storage.

It is also desirable for it to adhere well to the skin and to be perfectly removed from the skin. To achieve flow resistance in the non-applied state, advantageous adhesion properties to the skin and easy removability, the amount and structure of the comonomers in the copolymer, the intrinsic viscosity of the copolymer, and the amounts and types of all other adjuvants are chosen so that .

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The transdermal delivery system of the invention also comprises a cover layer. The liner is flexible to allow the system to adapt to the skin. Suitable cover layer materials include flexible conventional materials used as cover layers of pressure-sensitive adhesive tapes such as polyethylene, especially low density polyethylene, linear low density polyethylene, polyethylene produced by metallocene technology, high density polyethylene, polypropylene, polyesters such as polyethylene terephthalate, random orientation nylon fibers, ethylene (vinyl acetate) copolymer, polyurethane, fibers of natural origin such as silk and the like. It is also possible to suitably use layered composite layers such as polyethylene terephthalate aluminum-polyethylene. The cover layer should be substantially inert to the components contained in the adhesive layer.

The transdermal drug delivery systems of the invention can be prepared by methods for preparing multilayer systems known in the art. For example, the adhesive layers may be coextruded onto the cover layer or the release layer, or the layers may be extruded successively _: or applied to the cover layer or the release layer, or the layers may be separately applied to the cover layer or release layer and then the two Adhesive layers laminated.

Suitable release liners include layers commonly used for this purpose including known sheet materials such as polyester fabric, polyethylene fabric, polystyrene fabric, or polyethylene-coated paper with a coating based on a suitable fluoropolymer or silicone.

Preferably, the adhesive controlled rate systems of the invention are prepared by separately preparing the storage layer and the skin-contacting layers. The storage layer is

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Generally prepared by combining the adhesive copolymer with the drug and a suitable organic solvent or solvents (such as methanol, ethanol, isopropanol, ethyl acetate, etc.). The mixture is stirred until a homogeneous mixture suitable for coating is obtained. Then, the prepared coating composition is applied to the release liner using known coating methods (eg, by wiping or stretching) in a layer having a wet layer thickness of about 880 pm to 2200 pm to form a dry storage layer of about 14.7 mg / cm ² to about 37.5 mg / cm ² . The coated release liner is then allowed to dry and then welded onto the cover layer. The skin contact layer is generally prepared by combining the rate controlling adhesive (s) with a suitable organic solvent (such as methanol, ethanol, isopropanol, ethyl acetate, heptane, hexane, etc.) and mixing until homogeneous.

Then, the obtained product is applied to the release liner using known coating methods (eg, by wiping or stretching by molding). The skin contact adhesive layer is applied at a force sufficient to form a dry adhesive layer having a layer thickness of about 10 µm to about 40 µm.

Then, the coated release liner is allowed to dry, the release liner is removed from the storage layer, and the exposed adhesive surface is overlaid on the adhesive surface of the skin contact adhesive layer. The multi-layer product obtained is then cut into patches of suitable size. In an alternative embodiment, adhesive copolymers may be deposited on the release liner and the drug may be added to the coated adhesive copolymer in a further preparation step, for example, as described in U.S. Patent No. 5,688,523 (Garbe et al.).

Speed controlled membrane systems can be prepared by providing a storage layer as described above. The prepared product can then be applied to a release liner, < 9 9999

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9999 99 99 999 dry it and then overlay it on the top layer. The wet storage layer thickness is about 880 µm to about 2200 µm. The skin contact adhesive coating composition is prepared in the same manner as the coating layer coating using the same adhesive polymer or other adhesive or combination of adhesives. The obtained product is then applied to the release liner by conventional coating methods (eg, by wiping or drawing) to obtain a dry film thickness of about 5 µm to about 50 µm. The coated release liner is then allowed to dry. It is then laminated to a membrane. The system is then assembled by first removing the release liner from the storage layer and then exposing the exposed adhesive surface of the storage layer to the membrane surface of the skin contact adhesive layer. The resulting laminate can then be cut into patches of the desired size.

The invention is further described by the following examples.

DETAILED DESCRIPTION OF THE INVENTION

Evaluation of skin penetration in vitro

The results of the skin penetration tests given in the examples described below were determined by the test method described below. A vertical diffusion cell using cadavernous human skin is used for the assay.

When evaluating the transdermal drug delivery system, the release liner is removed from the 2.0 cm ² patch and the patch is applied by applying pressure to the skin to ensure homogeneous skin contact. The resulting composite patch / skin layer is then applied through the opening at the bottom of the assay cuvette to determine the plaque / skin. Diffusion so that the side with the patch is on the outside. Then the diffusion cuvette is assembled and the bottom is filled with 1.0 ml of heated (32 ° C) reception fluid (0.1 mol / l phosphate buffer, pH 6) so that the reception fluid is in contact with the skin.

The reception fluid is stirred using a magnetic stirrer. The sampling opening is closed except for sampling.

The cuvette is then placed in a thermostat with a constant temperature (32 ± 2 ° C) and humidity (relative humidity 50 ± 10%). The reception fluid is stirred with a magnetic stirrer during the experiment to ensure homogeneity and reduce the diffusion barrier on the dermal side. At the specified time intervals, all the reception fluid present is then collected and replaced immediately with fresh fluid. The collected fluid is then filtered through a 0.45 µm filter. The last 1-2 ml is then analyzed for (R) - (Z) -1-azabicyclo [2.2.1] heptan-3-one-O- [3- (3-methoxyphenyl) -2-propynyl] oxime content with using high performance liquid chromatography (column: Zorbax SB-CN, 50 x 2.1 mm ID; mobile phase: 87% (v / v) phosphate buffer with triethylamine pH adjusted to 3.0, 13% (v / v) acetonitrile; flow rate: 2 ml / min; detection: UV 240 nm; analysis time: 1 minute; injection volume: 5 μΐ). Then the cumulative amount of (R) - (Z) -1-azabicyclo [2.2.1] heptan-3-one-O- [3- (3-methoxyphenyl) -2-propynyl] oxime passed through the skin is calculated.

Determination of drug content used in the stability study

Transdermal drug delivery systems (20 cm ² patches) are sealed into sachets (BAREX ™ / aluminum / polyester or BAREX ™ / aluminum / paper laminate) and stored under some or more different storage conditions: temperature 25 ° C / 60% relative humidity (25 ° C / 60% RH), temperature 40 ° C / 75% relative humidity (40 ° C / 75% RH), room temperature (RT, about 22 ° C), temperature 40 ° C and temperature 50 ° C. The drug content of the patches is determined before the beginning of storage and predetermined storage times. An internal standard solution is prepared by adding 1.0 g of ethylparaben to 1000 ml of tetrahydrofuran. Removable layers were removed from 10 patches of 20 cm ² and the patches were then placed in a 1 quart (0.95 L) container. The cover layer and coatings are extracted using 500 ml of an internal standard solution. Shake the sample for at least 24 hours during extraction. Then. Dilute the sample by measuring 5 mL of the final solution into a 4 ounce (118.3 mL) flask, add 100 mL of 50:50 (v / v) acetonitrile: water and shake the analyzed mixture for about 60 minutes. A portion of the sample is then added to the automatic injection vial for analysis. Samples are analyzed by high performance liquid chromatography (column: Zorbax SB-CN particle size 5 µm, 25 cm x 4.6 mm; mobile phase: pH 3 / acetonitrile buffer 82:18 (v / v); buffer composition triethylamine 7.7 x 10 ^-4 moles / in potassium phosphate solution, pH adjusted to 3.0 with phosphoric acid, flow rate: 2.0 ml / min; detector: UV 240 nm; injection: 5 µl; analysis time: 15 minutes). The results are expressed as the percentage of drug detected as a percentage of the original amount of drug.

Preparation of adhesives

The adhesives used in the examples below are generally prepared by the methods described below.

Preparation of isooctyl acrylate copolymer: acrylamide: vinyl acetate (75: 5: 20) this to this to this to this to this this ·· ···

The mother mixture was prepared by combining isooctyl acrylate (621.0 g), acrylamide (41.4 g), vinyl acetate (165.6 g),

2,2'-azobis (2,4-dimethylpentanitrile) (1.656 g), ethyl acetate (884.5 g) and methanol (87.48 g). A portion (400 g) of the obtained solution was placed in a 1 quart (0.95 L) dark glass bottle. The bottle was then purged with nitrogen at a flow rate of 1 L / min for 2 minutes. The bottle was then sealed and placed in a rotating water bath at 45 ° C for 24 hours to perform substantially complete polymerization. The obtained copolymer was diluted with ethyl acetate: methanol (250 g, 90:10 v / v) to a solids content of 26.05%.

Preparation of isooctyl acrylate: vinyl acetate: polymethylmethacrylate macromonomer (59: 38: 3)

A 1 quart (0.95 L) dark glass bottle is charged with vinyl acetate 80.37 g), a polymethyl methacrylate macromonomer (ELVACITE ™ 1010, 6.345 g, commercially available from ICI Acrylics), ethyl acetate (271.95) g) and methanol (8.41 g) and mix on a shaker until a homogeneous solution is obtained. Then isooctyl acrylate (124.875 g) and 2,2'-azobis (2-methylbutyronitrile) (0.3173) were added to the solution. The bottle was then purged with nitrogen at a flow rate of 1 L / min for 2 minutes. The bottle was then sealed and placed in a rotating water bath at 57 ° C for 23 hours. The obtained copolymer was diluted with ethyl acetate (62.78) and methanol (1.94 g) to a solids content of about 38%.

Preparation of isooctyl acrylate: vinyl acetate: polymethylmethacrylate macromonomer (55: 38: 7)

Vinyl acetate (80.37 g), polymethyl methacrylate macromonomer (ELVACITE ™ 1010, 14.80 g, commercially available from ICI) was added to a 1-quart (0.95 L) dark glass bottle.

• · · · · · • • · · · · · 9 · · · • • · · • «· · • • · · · • · · · · • 9 · • · · ·

Acrylics), ethyl acetate (370.80 g) and the mixture were mixed on a shaker until a homogeneous solution was obtained. Then isooctyl acrylate (116.32 g) and 2,2'-azobis (2-methylbutyronitrile) (0.3173) were added to the solution. The bottle was then purged with nitrogen at a flow rate of 1 L / min for 2 minutes. The bottle was then sealed and placed in a rotating water bath at 57 ° C for 23 hours. The obtained copolymer was diluted with ethyl acetate to a solids content of 28.5%.

Preparation of a solution of polyisobutylene adhesive

Low molecular weight polyisobutylene (OPPANOL ™ BIO polyisobutylene available from BASF, 74.99 g), high molecular weight polyisobutylene (OPPANOL ™ B100 polyisobutylene, 24.96 g), heptane (270.0 g) and ethyl acetate (180 0 g) are combined and mixed until all polyisobutylene is dissolved.

Preparation of dry adhesive

A dry adhesive is prepared by applying a solution of the acrylic adhesive copolymer by wiping onto the release liner. The adhesive-coated release layer is then dried in an oven to remove solvent and reduce residual monomer levels. The dry adhesive is then separated from the release liner and stored in the container until use.

Membranes

Some membranes used in the examples described below are commercially available (eg, calibrated pore size membranes COTRAN ™ 9702, COTRAN ™ 9717, COTRAN ™ 9726 and COTRAN ™ 9728 EVA, available from 3M Company). Others have been prepared from commercially available resins by conventional extrusion methods (e.g., extrusion extrusion). heat on cooled cylinders). Examples of suitable resins include ELVAX ™ ethylene-vinyl acetate (EVA) copolymers from DuPont. In the examples below, the term X% EVA means that the membrane is prepared from an ethylene-vinyl acetate copolymer containing X% by weight vinyl acetate.

Example 1

Transdermal drug delivery systems comprising two separate membrane-separated adhesive layers are prepared as described below.

The coating mixture is prepared by combining dry adhesive (8.84 g isooctyl acrylate / acrylamide / vinyl acetate 75/5/20), (R) - (Z) -1-azabicyclo [2.2.1] heptan-3-one -O- [3- (3-methoxyphenyl) -2-propynyl] oxime (1.17 g) and solvent (30 g ethyl acetate / methanol 90/10 v / v) followed by mixing until reaching homogeneity of the coating composition.

A bonding adhesive layer is prepared as follows. The prepared coating composition was applied by wiping onto a release liner (Daubert 164P silicone coated release liner) at a wet thickness of 60 mil (1524 pm).

The prepared coated release liner is then dried for 5 hours at room temperature and then laminated to a topcoat (SCOTCHPAK ™ 1109 polyester film laminate; available from 3M Company).

The skin contact adhesive layer is prepared as follows. The prepared coating composition is applied by wiping onto the release liner (Daubert 164P silicone coated release liner) at a wet layer thickness of 10 mils. fc fc (254 pm). The prepared coated release liner is then dried for at least one hour at room temperature and then the exposed adhesive surface is laminated to a membrane (12% EVA). film, 2 mil / 51 pm).

The release liner is then removed from the bonding adhesive layer and the exposed adhesive surface is laminated to the skin layer membrane contact surface. The final multilayered product is then cut into patches. Each patch contains 5 layers: a cover layer; a storage layer containing 11.7% by weight of (R) - (Z) -1-azabicyclo [2.2.1] heptan-3-one-O- [3- (3-methoxyphenyl) -2-propynyl] oxime; a membrane; a skin contact adhesive layer containing 11.7% by weight of (R) - (Z) -1-azabicyclo [2.2.1] heptan-3-one-O- [3- (3-methoxyphenyl) -2-propynyl] oxime; and a release liner. Penetration of human cadavernous skin is determined as described above. The results of the skin penetration evaluation are shown in Table 2 below, where each value represents an average value of 3 independent determinations.

Examples 2 to 20

A series of transdermal drug delivery systems were prepared by the method described in Example 1. The concentrations of (R) - (Z) -1-azabicyclo [2.2.1] heptan-3-on-O- [3- (3) (methoxyphenyl) -2-propynyl] oxime in the adhesive layers, the coating weights of the storage adhesive layer and the percentage of EVA in the membranes. The compositions are described below in Table 1. In each example, an isooctyl acrylate / acrylamide / vinyl acetate 75/5/20 mixture was used as the adhesive, the coating composition prepared containing 25% solids, the (R) - (Z) -1- The azabicyclo [2.2.1] heptan-3-one-O- [3- (3-methoxyphenyl) -2-propynyl] oxime was both present in both. Adhesion Adhesion Adhesion Adhesion Adhesion Adhesion Adhesion Adhesion The layers were the same, the skin contact adhesive layer had a wet thickness of 10 mil (254 pm) and a membrane thickness of mil (51 pm). Penetration of human cadavernous skin was determined as described above. The results of the skin penetration evaluation are shown in Table 2 below, where each value represents an average value of 3 independent determinations.

Table 1

Example # Concentration pharmaceuticals Cover thickness wet EVA (%) 1 11.7% 1524 pm 12 2 25% 1905 pm 19 Dec 3 20% 1524 pm 12 • 4 20% 2160 pm 12 5 20% 1524 pm 2 6 20% 1524 pm 12 7 20% 1524 pm 12 8 25% 1143 pm 19 Dec 9 25% 1905 pm 4,5 10 20% 1524 pm 12 11 28.4% 1524 pm 12 12 15% 1905 pm 19 Dec 13 20% 89 9 pm 12 14 15% 1905 pm 4,5 15 Dec 20% 1524 pm 12 16 25% 1143 pm 4,5 17 15% 1143 pm 4,5 18 15% 1143 pm 19 Dec 19 Dec 20% 1524 pm 28 20 May 20% 1524 pm 12

• · • ·· ·

• 4 • • 9 9

Table 2

Penetration of human cadavernous skin Ex. C. Average cumulative penetrated amount (g / ^cm) 3 (h) 6 (h) 12 (h) 24 (h) 48 (h) 72 (h) 96 (h) 120 (h) 144 (h) 168 (h) 1 16 37 90 214 462 673 855 1035 1179 1308 2 21 50 130 343 830 1289 1696 2099 · 2436 2725 3 35 73 165 375 763 1086 1362 1633 1865 2081 4 28 61 151 362 732 1040 1322 1584 1818 1961 5 28 62 152 357 706 919 1056 1170 1263 1350 6 21 49 115 273 612 900 1144 1395 1611 1812 7 22nd 50 125 306 629 875 1137 1372 1554 1703 8 101 230 494 964 1757 2469 3079 3605 4003 4312 9 154 323 619 965 1315 1540 1721 1902 2066 2213 10 46 102 242 493 877 1191 1478 1758 2006 2226 11 123 276 594 1046 1650 2124 2570 3008 3406 3759 12 59 110 239 488 925 1310 1659 1967 2222 2422 13 47 92 196 397 736 1025 1276 1510 1718 1839 14 13 32 83 210 459 633 759 869 964 1048 15 Dec 21 51 135 339 739 1070 1354 1634 1882 2105 16 118 223 429 735 1074 1303 1474 1637 1788  1921 17 129 251 454 686 937 1113 1264 1399 1533 1655 18 35 83 206 466 97 6 1425 1788 2065 2302 2486 19 Dec 66 156 371 818 1690 2462 3074 3538 3919 4213 20 May 182 337 603 962 1494 1964 2390 2780 3140 3456

Example 21 to

The coating composition is prepared by combining a dry adhesive (13.7 g isooctyl acrylate / acrylamide / vinyl acetate 75/5/20), (R) - (Z) -1-azabicyclo [2.2.1] heptan-3-one -O- [3- (3-methoxyphenyl) -2-propynyl] oxime (1.54 g) and solvent (45 g ethyl acetate / methanol 90/10 v / v) followed by mixing until reaching homogeneity of the coating composition.

A bonding adhesive layer is prepared as follows. The prepared coating composition is applied by wiping onto a release liner (SCOTCHPAK ™ 9742 Fluoropolymer Coated Release liner available from 3M Company) at a 30 mil (762 µm) wet layer thickness. The prepared coated release liner is then dried at room temperature for 60 to 90 minutes, and then the exposed adhesive surfaces of the two halves of the release liner overlap each other. Then, the release liner is removed from one side and the exposed adhesive surface is laminated to the cover layer (SCOTCHPAK ™ 1109 polyester film laminate).

The skin contact adhesive layer is prepared as follows. The prepared coating composition is applied by wiping onto a release liner (SCOTCHPAK ™ 9742 Fluoropolymer Coated Release liner) at a wet thickness of 7 mils (178 µm). ^; The prepared coated release liner is then dried at room temperature for 60 to 90 minutes and then the adhesive surface is laminated to a membrane (4.5% EVA film, 2 mil / 51 µm).

The release liner is then removed from the bonding adhesive layer and the exposed adhesive surface is laminated to the skin layer membrane contact surface. From the final multilayered product, the incision patches are then applied. Each patch contains 5 · 9 φ φ · · · · · · · · · · · · · · · · · · · · · · · · · · · · · φ φ φ φ · Layers: cover layer; a storage layer containing 10% by weight of (R) - (Z) -1-azabicyclo [2.2.1] heptan-3-one-O- [3- (3-methoxyphenyl) -2-propynyl] oxime; a membrane; a skin contact adhesive layer containing 10% by weight of (R) - (Z) -1-azabicyclo [2.2.1] heptan-3-one-O- [3- (3-methoxyphenyl) -2-propynyl] oxime; and a release liner. Penetration of human cadavernous skin is determined as described above. The results of the skin penetration evaluation are shown in Table 4 below, where each value represents the average of 3 independent determinations.

Examples 22 to 38

A series of transdermal drug delivery systems were prepared as described in Example 21, wherein the concentrations of (R) - (Z) -1-azabicyclo [2.2.1] heptan-3-on-O- [3- (3) (methoxyphenyl) -2-propynyl] oxime in the adhesive layers, the adhesive used and the percentage of EVA in the membranes. The compositions are described below in Table 3. In each example, the same adhesive, concentration, was used in both layers (R) - (Z) -1-azabicyclo [2.2.1] heptan-3-on-O- [3- ( 3-methoxyphenyl) -2-propynyl] oxime was the same in both adhesive layers and the membrane thickness was 2 mil (51 µm). Penetration of human cadavernous skin was determined as described above. The results of the skin penetration evaluation are shown in Table 4 below, where each value represents the average of 3 independent determinations.

Table 3 • the three titites • the three titites • the three

Example # Concentration pharmaceuticals Adhesive EVA (%) 22nd 10% IOA / ACM / VOAc 75/5 / 20 19 Dec 23 10% IOA / ACM / VOAc 75/5 / 20 28 24 20% IOA / ACM / VOAc 75/5 / 20 4,5 25 20% IOA / ACM / VOAc 75/5 / 20 19 Dec 26 20% IOA / ACM / VOAc 75/5 / 20 28 27 Mar: 30% IOA / ACM / VOAc 75/5 / 20 4,5 28 30% IOA / ACM / VOAc 75/5 / 20 19 Dec 29 30% IOA / ACM / VOAc 75/5 / 20 28 30 10% IOA / VOAc / PMMAMac 59/38/3 4,5 31 10% IOA / VOAc / PMMAMac 59/38/3 19 Dec 32 10% IOA / VOAc / PMMAMac 59/38/3 28 33 20% IOA / VOAc / PMMAMac 59/38/3 4,5 34 20% IOA / VOAc / PMMAMac 59/38/3 19 Dec 35 20% IOA / VOAc / PMMAMac 59/38/3 28 36 30% IOA / VOAc / PMMAMac 59/38/3 4,5 37 30% IOA / VOAc / PMMAMac 59/38/3 19 Dec 38 30% IOA / VOAc / PMMAMac 59/38/3 28

IOA = isooctyl acrylate

ACM = acrylamide

VOAc = vinyl acetate

PMMAMac = polymethyl methacrylate macromonomer ·· ··· ·

Table 4 This To This This To This This To This This To This

Penetration of human cadavernous skin Ex. C. Mean cumulated penetration amount (pg / cm ² ) 3 (h) 6 (h) 12 (h) 24 (h) 48 (h) 72 (h) 96 (h) 120 (h) 144 (h) 168 (h) 21 5 17 54 131 245 338 417 489 564 625 22nd 9 30 88 216 445 660 844 1006 1146 1255 23 2 10 47 149 354 544 692 828 952 1051 24 10 28 82 203 395 548 676 797 924 1033 25 4 27 Mar: 135 393 859 1302 1688 2021 2341 2591 26 3 19 Dec 94 284 658 999 1282 1510 1724 1889 27 Mar: 9 32 89 283 599 831 1018 1178 1333 1462 28 4 14 70 244 619 990 1332 1629 1936 2183 29 1 8 61 234 614 991 1328 1625 1924 ' 2164 30 3 13 50 126 228 309 376 432 492 543 31 3 20 May 83 222 457 653 811 943 1078 1187 32 2 9 41 117 248 358 447 520 590 647 33 6 30 120 311 562 726 858 971. 1092 1199 34 4 22nd 91 257 579 874 1128 1341 1558 1740 35 5 28 123 345 785 1190 1523 1794 2063 2285 36 11 33 100 ALIGN! 250 556 805 994 1137 1280 1399 37 1 6 27 Mar: 93 273 456 612 738 872 990 38 0 4 24 90 270 472 660 817 982 1126

Example 39

The coating composition is prepared by combining a dry adhesive (5200, g isooctyl acrylate / acrylamide / vinyl acetate 75/5/20), ethyl acetate (17.56 kg), methanol (1 g). , 96 kg) and (R) - (Z) -1-azabicyclo [2.2.1] heptan-3-one-O- [3- (3-methoxyphenyl) -2-propynyl] oxime (1.54 g), and followed by mixing until the coating composition is homogeneous. The prepared coating composition is left until all air bubbles have disappeared. The prepared coating composition is extruded (pump speed and nozzle gap selected to provide a dry coating of 13 mg / cm ² ± 4%) on the release liner (SCOTCHPAK ™ 1022 Fluoropolymer Coated Release liner). The prepared coated release liner is then dried in an oven at 140 ° F (60 ° C) for 2 minutes, 2 minutes at 190 ° F (88 ° C) and 2 minutes at 240 ° F (116 ° C). The adhesive surface of the first section of the coated release liner is then laminated to the cover layer (SCOTCHPAK ™ 1109 polyester film laminate), the release layer is then removed, and the exposed adhesive surface is laminated to the adhesive surface of the second section of the coated release liner. The prepared bonding adhesive layer has a dry coating weight of 26 mg / cm ² ± 4%.

The skin contact adhesive layer is prepared as follows. The prepared coating composition is extruded (pump speed and nozzle gap selected to provide a 2.5 mg / cm ² + 4% dry coating) onto the release liner (SCOTCHPAK ™ 1022 Fluoropolymer Coated Release liner). The prepared coated release liner is then dried in an oven at 140 ° F (60 ° C) for 2 minutes, 2 minutes at 190 ° F (88 ° C) and 2 minutes at 240 ° F (116 ° C), and then the adhesive layer is laminated on a 9% EVA (2 mil / 51 µm) membrane. (COTRAN ™ 9702 EVA calibrated pore size).

The release liner is then removed from the bonding adhesive layer and the exposed adhesive surface is laminated to the skin layer membrane contact surface. From the finite multilayer • 9 9 9 9 9 9 9 9 9 9 9 9 99 999 9 9 9999999

ΧΊ 9 9 9 «9 9 9999

S 9999 99 99 ··· 99 99 product is then cut into patches. Each patch contains 5 layers: a cover layer; a storage layer containing 20% by weight of (R) - (Z) -1-azabicyclo [2.2.1] heptan-3-one-O- [3- (3-methoxyphenyl) -2-propynyl] oxime; a membrane; a skin contact adhesive layer containing 20% by weight of (R) - (Z) -1-azabicyclo [2.2.1] heptan-3-one-O- [3- (3-methoxyphenyl) -2-propynyl] oxime; and a release liner.

Penetration of human cadavernous skin is determined as described above. The results of the skin penetration evaluation are shown in Table 5 below, where each value represents the average of the 15 independent determinations. The results of the drug content stability study are shown in Table 6 below.

Table 5

Penetration.human cadavernous skin Mean cumulated penetration amount (pg / cm ² ) 3 (h) 6 (h) 12 (h) 24 (h) 48 (h) 72 (h) 96 (h) 120 (h) 144 (h) 168 (h) 26 54 125 263 516 721 908 1078 1251 1415

Table β

Stability of active ingredient (% of original content) 1 Moon 2 months 3 months 4,5 months 6 months 9 months 12 months 25 ° C / 60% RH 100.1 98.8 99, 4 99.3 97.9 98.4 97.7 40 ° C / 75% RH 98.4 97.9 97.4 96, 7 93.6 -

Example 40 ·· * 444 44 4 ·· ···· · 4 4 4 44 4 4 · • ♦ · 4 4 4 • 4 4 4 4 4 4 4 4 4 ••• 44 · 4 4 4

4444 44 44 444 44 44

System for. transdermal drug delivery containing two separate, interconnected layers is prepared as described below.

A bonding adhesive layer is prepared as follows. Combine dry adhesive (35 g isooctyl acrylate / acrylamide / vinyl acetate 75/5/20), ethyl acetate (135.0 g), methanol (15.1 g) and (R) - (Z) -1 -azabicyclo [2.2.1] heptan-3-one-O- [3- (3-methoxyphenyl) -2-propynyl] oxime (15.0 g) and the mixture was mixed until the coating composition was homogeneous. The prepared coating composition is applied by wiping onto a release liner (SCOTCHPAK ™ 1022 Fluoropolymer Coated Release liner) at a wet layer thickness of 60 mil (1524 µm). The prepared coated release liner is then dried for 3 hours at room temperature and then laminated to a cover layer (SCOTCHPAK ™ 1109 polyester film laminate).

The skin contact layer is prepared as follows. The polyisobutylene adhesive solution described above is wiped onto a release liner in a wet thickness of 7 mils (178 µm). Then, the coated release liner is dried at room temperature. The dry adhesive layer has a thickness of approximately 0.7 mil (17.8 µm).

The release liner is then removed from the storage adhesive layer and the exposed adhesive surface is laminated to the adhesive surface of the skin contact layer. From the final multilayered product, the incision patches are then applied. Each patch contains 4 layers: a cover layer; a storage layer containing 30% by weight of (R) - (Z) -1-azabicyclo [2.2.1] heptan-3-one-O- [3- (3-methoxyphenyl) 2-propynyl] oxime in an adhesive prepared from isooctylacrylate / acrylamide / vinyl acetate 75/5/20; an adhesive layer for contact consisting of a polyisobutylene adhesive; and a removable layer. The samples are left for at least about 12 hours to allow the drug to diffuse from the storage layer into the skin contact layer. Penetration of human cadavernous skin is determined as described above. The results of the skin penetration evaluation are shown in Table 8 below, where each value represents the average of 3 independent determinations.

Examples 41 to 58

A series of transdermal drug delivery systems were prepared as described in Example 40, wherein the concentrations of (R) - (Z) -1-azabicyclo [2.2.1] heptan-3-on-O- [3- (3) (methoxyphenyl) -2-propynyl] oxime in the storage layer and the thickness of the adhesive layer for dry skin contact. The compositions are described below in Table 7. In each example, an isooctylacrylate / acrylamide / vinyl acetate 75/5/20 mixture was used as the adhesive. The storage layer was deposited at a wet thickness of 60 mil (1524 pm). The skin contact layer was prepared from polyisobutylene (PIB). Penetration of human cadavernous skin was determined as described above. The results of the skin penetration evaluation are shown below in Tables 8 and 10, where each value represents an average value of 3 independent determinations.

99 * 9 <9 • · 9

9 9 9 9 9 9 9 9 9

9 · · 9 9 9 9

9

999 99 99

Table 7

Example # Drug concentration Thickness PIB layer (mil / pm) 41 35% 0.4 / 10.2 42 25% 1.0 / 25.4 43 35% 1.0 / 25.4 44 23% 0.7 / 17.8 45 30% 0.7 / 17.8 46 25% 0.4 / 10.2 47 30% 0.7 / 17.8 48 30% 1.1 / 27.9 49 37% 0.7 / 17.8 50 ³⁰ 0.7 / 17.8 51 30% 0.7 / 17.8 52 20% 0.5 / 12.7 53 20% 1.5 / 38.1 54 25% 1.0 / 25.4 55 25% 1.0 / 25.4 56 25% 1.0 / 25.4 57 30% 0.5 / 12.7 58 30% 1.5 / 38.1

»0000 • 0 0 0

0 0 0 0 0

0 0

00 «00 • 9 0 * 00 *

0 0 0 • 0 · 0 ♦

0 0 0 0 0000 00 · 0

Table 8

Penetration of human cadavernous skin Ex. Medium cumulated penetrated amount (pg / cm ²⁾ C. 3 (h) 6 (h) 12 (h) 24 (h) 48 (h) 72 (h) 96 (h) 120 (h) 144 (h) 168 (h) 40 5 24 74 174 377 580 779 975 1164 1348 41  9 28 86 207 447 680 915 1163 1408 1658 42 4 16 46 103 213 322 427 535 644 754 43 6 22nd 62 134 275 412 544 682 815 949 44 2 14 48 114 261 405 550 703 850 1002 45 4 18 57 137 298 460 621 786 950 1118 46 11 36 100 ALIGN! 217 457 686 921 1176 1417 1657 47 3 17 59 137 302 4 58 611 769 933 1092 48 2 9 30 98 208 317 422 535 631 745 49 1 10 43 115 258 402 550 7 04. 858 1013 50 3 19 Dec 66 153 326 494 662 832 996 1165 51 4 19 Dec 63 143 298 449 601 752 901 1052

Examples 59 to 61

A series of systems for transdermal drug delivery were prepared by the method generally described in Example 40, wherein the composition of the skin contact adhesive layer was varied in each system. Said compositions are described below in Table 9. Adhesive skin contact compositions were prepared by mixing solvated isooctylacrylate / acrylamide / vinyl acetate 75/5/20 with a polyisobutylene adhesive solution as described below. The skin contact coating comprises about 19% solids and was applied at a wet thickness of 8 mils (203 µm). In all cases, the storage layer was prepared from iso-octyl · ftftftft · ft · ft · ftft ftftft · · · · · ftftftft · ftft, 9ft · ftftft ftft · ft · ftft · ftft ft · ftft · · ft ·· acrylate / acrylamide / vinyl acetate 75/5/20 and contained 25% (R) - (Z) -1-azabicyclo [2.2.1] heptan-3-one-O- [3- (3-methoxyphenyl) -2-Propynyl] oxime. The storage layer coating contained 25% solids and was applied at a wet thickness of 60 mil (1524 pm). Penetration of human cadavernous skin was determined as described above. The results of the skin penetration evaluation are shown in Table 10 below, where each value represents the average of 3 independent determinations.

Table 9

Example # Skin contact adhesive 59 ^: 95: 5 PIB: IOA / ACM / VOAc 75/5/20 60 87.5: 12.5 PIB: IOA / ACM / VOAc 75/5/20 61 80:20 PIB: IOA / ACM / VOAc 75/5/20

IOA = isooctyl acetate ACM = acrylamide VOAc = vinyl acetate PIB = polyisobutylene

Table .10 ·························································· ·· ·· ·· ··· ·· ··

Penetration of human cadavernous skin Ex. No ' Mean cumulated penetration amount (pg / cm ² ) 3 (h) 6 (h) 13 (h) 24 (h) 48 (h) 72 (h) 96 (h) 120 (h) 144 (h) 168 (h) 52 16 49 120 263 555 867 1177 1486 1793 2008 53 5 13 36 57 132 197 265 332 400 471 54 11 30 81 144 301 461 622 788 962 1137 55 ‘12 31 81 144 304 463 629 789 956 1120 56 9 25 73 139 309 479 655 826 999 1171 57 13 38 112 206 457 743 1020 1323 1651 1997 58 9 24 65 113 231 337 450 554 659 764 59 10 28 78 145 322 515 707 907 1113 1315 60 13 35 93 176 421 693 963 1243 1538 1831 61 11 30 87 157 346 546 745 949 1167 1395

Example 62

The coating mixture is prepared by combining dry adhesive (5200 g isooctyl acrylate / acrylamide / vinyl acetate 75/5/20), ethyl acetate (17.56 kg), methanol (1.96 kg) and (R) - ( Z) -1-azabicyclo [2.2.1] heptan-3-one-O- [3- (3-methoxyphenyl) -2-propynyl] oxime (1.54 g) followed by mixing until the coating composition was homogeneous. The prepared coating composition is left until all air bubbles have disappeared. The prepared coating composition is extruded (pump speed and nozzle gap selected to obtain a dry coating of 13 mg / cm ² ± 4%) on the release liner (SCOTCHPAK ™ 1022 Fluoropolymer Coated Release liner).

The prepared coated release liner is then dried in an oven at 140 ° F (60 ° C) for 2 minutes, 2 minutes at 190 ° F (88 ° C) and 2 minutes at 240 ° F (116 ° C). The adhesive surface of the first section of the coated release liner is then laminated to a cover layer (SCOTCHPAK ™ 1109 polyester film laminate), the release liner is then removed, and the exposed adhesive surface is laminated to the adhesive surface of the second section of the coated release liner. The prepared bonding adhesive layer has a dry coating weight of 26 mg / cm ² ± 4%.

The skin contact adhesive layer is prepared as follows. The coating composition is prepared by combining low molecular weight polyisobutylene (OPPANOL B-10, 900 g), high molecular weight polyisobutylene (OPPANOL B-100, 300 g) and heptane (3006) and mixing until a homogeneous composition is obtained. The prepared composition is left until all air bubbles have disappeared. The prepared coating composition is applied by extrusion (pump speed and nozzle gap selected to provide a dry coating of 1.53 mg / cm ² ± 4%) onto the release liner (silicone coated release liner on one side). The prepared coated release liner is then dried in an oven at 125 ° F (52 ° C) for 2 minutes, 2 minutes at 185 ° F (85 ° C) and 2 minutes at 225 ° F (107 ° C).

The release liner is then removed from the storage adhesive layer and the exposed adhesive surface is laminated to the adhesive surface of the skin contact adhesive layer. The silicone release liner is then replaced with a fluoropolymer release liner (SCOTCHPAK ™ 1022, fluoropolymer coated release liner).

From the finished multilayered product, the incision patches are then used. Each patch contains 4 layers: a cover layer; A storage layer containing 30% by weight of (R) - (Z) -1-azabicyclo [2.2.1].

-heptan-3-one-O- [3- (3-methoxyphenyl) -2-propynyl] oxime and 70% by weight of an adhesive (acrylate / acrylamide / vinyl acetate)

75/5/20); a skin contact adhesive layer comprising a polyisobutylene adhesive; and a release liner. The samples are left for at least 12 hours to allow the drug to diffuse from the storage layer to the skin contact layer. Penetration of human cadavernous skin is determined as described above. The results of the skin penetration evaluation are shown in Table 11 below, where each value represents the average of the 15 independent determinations. The results of the drug content stability study are shown in Table 12 below.

Table 11

Penetration of human cadavernous skin Mean cumulated penetration amount (pg / cm ² ) 3 (h) 6 (h) . 12 (h) 24 (h) 48 (h) 72 (h) 96 (h) 120 (h) 144 (h) 168 (h) 16 34 80 179 396 611 819 1019 1231 1439

Table 12

Stability of active ingredient (% of original content) 1 Moon 2 months 3 months 4,5 months 6 months 9 months 12 months 25 ° C / 60% RH 98.3 98.0 94.8 99, 0 97.4 97.6 98.6 40 ° C / 75% RH 98.4 97.1 95, 1 95.9 92.4 - -

Examples 63 to 75

In a manner generally described in Example 21, a series of transdermal drug delivery systems were prepared wherein the adhesive layer weights varied

for skin contact and storage layers (see Table 13). In all examples, the same adhesive was used in both layers (isooctyl acrylate / acrylamide / vinyl acetate 75/5/20) and the concentration of (R) - (Z) -1-azabicyclo [2.2.1] -heptan-3-one -O- [3- (3-methoxyphenyl) -2-propynyl] oxime was 20%. The membrane thickness in all examples was 2 mil (51 µm) and the percentage EVA content was 9%. Penetration of human cadavernous skin was determined as described above. The results of the skin penetration evaluation are shown in Table 14 below, where each value represents an average value of 5 independent determinations.

Table 13

Example # Skin Contact Weight (mg / cm ² ) Stock layer coating weight (mg / cm ² ) 63 2, 6 26.3 64 2.6 26.3 65 5.0 23.3 66 7.7 20.2 67 7.7 20.2 68 10.0 18.1 69 12.6 13, 9 70 12.6 13, 9 71 2.6 26, 3 72 5.0 26.3 73 7.7 26.3 74 10.0 26, 3 75 12.6 26, 6

Table 14

Penetration of human cadavernous skin Ex. C. Medium cumulated penetrated amount (pg / cm ² ) 3 (h) 6 (h) 12 (h) 24 (h) 48 (h) 72 (h) 96 (h) 120 (h) 14 4 (h) 168 (h) 63 35 85 177 301 562 810 1042 1257 1445 1627 64 33 75 158 222 474 718 964 1140 1294 1446 65 32 76 177 348 554 846 1089 1301 1486 1666 66 34 85 207 404 768 1155 1414 1639 1780 1924 67 33 78 180 304 708 1069 1350 1784 1974 2153 68 50 133 297 548 1013 1372 1662 1892 2074 2255 69 35 82 192 337 915 1375 1726 2012 2236 2434 70 33 83 193 300 791 1261 1616 1900 2125 2323 71 11 47 119 191 420 648 861 1064 1245 1420 72 6 45 125 220 527 806 1043 1261 1449 1626 73 10 48 126 244 559 862 1116 1339 1531 1713 74 23 70. 177 310 717 1088 1383 1631 1835 2028 75 18 87 218 425 822 1189 1497 1758 1979 2185

Example 76

The coating composition is prepared by combining a dry adhesive (isooctyl acrylate / acrylamide / vinyl acetate 75/5/20 18.0 g), (R) - (Z) -1-azabicyclo [2.2.1] heptan-3-one -O- [3- (3-methoxyphenyl) -2-propynyl] oxime (2.0 g) and solvent (70 g ethyl acetate / methanol 90/10 v / v) and then mixed until achieving homogeneity of the coating composition. The prepared coating composition is wiped onto a release liner (Daubert 164P silicone coated release liner) at a wet thickness of 25 mils (635 pm). The prepared coated release liner is then dried and then laminated to a cover layer (SCOTCHPAK ™ 1109 polyester film laminate; available from 3M Company). The results of the drug stability test are shown in Table 15 below.

Table 15

Drug content in stability test (% of original content) 4 weeks 2 months 3 months 6 months RT (r.m.) 100.0 99.9 100.0 99, 7 Deň: 32 ° C 100.0 99.4 98.9 97.7 Deň: 32 ° C 99.2 97.8 96, 6 93, 0

Example 77

The coating composition is prepared by combining a dry adhesive (isooctyl acrylate / vinyl acetate / polymethylmethacrylate macromonomer 55/38/7 18.0 g), (R) - (Z) -1-azabicyclo [2.2.1] heptane-3- on-O- [3- (3-methoxyphenyl) -2-propynyl] oxime (2.0 g) and solvent (70 g ethyl acetate / methanol 90/10 v / v) and then mixed until until the coating composition is homogeneous. The prepared coating composition is wiped onto a release liner (Daubert 164P silicone coated release liner) at a wet thickness of 25 mils (635 pm). The prepared coated release liner is then dried and then laminated to a cover layer (SCOTCHPAK ™ 1109 polyester film laminate; available from 3M Company). The results of the drug stability test are shown in Table 16 below.

• ti ···· ·· ti ti ti ··· ti. ti ti tititi ti ti ti tititi ti ti tititi ti ti tititi ti · ti·iti ti tititi ti tititi

Table 16

Drug content, in stability test (% of original content) 4 weeks 2 months 3 months 6 months RT (rt) 100.0 99, 8 100.0 99.6 Deň: 32 ° C 99, 5 99.0 98.4 96.6 Deň: 32 ° C 98.6 97.1 95, 9 92.9

In the foregoing description, the invention is described by means of several embodiments thereof. The foregoing detailed description and examples are provided for convenience of illustration only and are not intended to limit the invention thereto. It will be apparent to those skilled in the art that various changes may be made to the embodiments described without departing from the spirit and scope of the invention. Thus, the scope of the invention is not limited in detail to the compositions and structures described in the description and examples, but is defined by the appended claims.

Claims (33)

PATENT CLAIMS A system for the transdermal drug administration of (R) - (Z) -1-azabicyclo [2.2.1] heptan-3-one-O- [3- (3-methoxyphenyl) -2-propynyl] oxime, characterized in that: that contains: (a) a medicament reservoir forming layer comprising an effective amount of the medicament and a first pressure sensitive adhesive; and b) a skin contact layer attached to one of the surfaces of the medicament reservoir layer comprising the medicament and the other pressure-sensitive adhesive. 2. The system of claim 1 wherein the first pressure-sensitive adhesive comprises an acrylic copolymer wherein said copolymer comprises a copolymer. (a) one or more monomers A selected from the group consisting of alkyl (meth) acrylates of 4 to 10 carbon atoms in the alkyl group; and b) one or more ethylenically unsaturated monomers B having a functional group selected from the group consisting of carboxyl, sulfonamide, urea, carbamate, carboxamide, hydroxy, amino, oxy, oxo and cyano; 3. The system of claim 2, wherein the monomer A (s) is selected from the group consisting of. isooctyl acrylate, 2-ethylhexyl acrylate, butyl acrylate and cyclohexyl acrylate. ··················································· · «· 4. The system of claim 2 wherein monomer B (monomers) is selected from the group consisting of acrylic acid, methacrylic acid, acrylamide, vinyl acetate, and methacrylamide. The system of claim 2, wherein the acrylic copolymer further comprises one or more substantially linear macromonomers copolymerizable with monomers A, and B. 6. The system of claim 1 wherein the second pressure-sensitive adhesive comprises polysiloxane, acrylate, natural rubber, or synthetic rubber. The system of claim 6 wherein the second pressure-sensitive adhesive comprises polyisobutylene. 8. The system of claim 1 wherein the concentration of drug in the storage layer is about 5 to about 45% by weight based on the total weight of the storage layer. 9. Transdermal drug delivery system, (R) - (Z) —1— -azabicyclo [2.2.1] heptan-3-one-O- [3- (3-methoxyphenyl) -2-propynyl] oxime, characterized in that it contains: (a) a medicament reservoir forming layer comprising an effective amount of the medicament and a first pressure sensitive adhesive; and b) a rate controlling membrane attached to one of the surfaces of the storage layer; and • 4 • 4 • 4 c) a skin contact layer attached to the membrane surface opposite the membrane surface in contact with the storage layer, said layer comprising a second pressure-sensitive adhesive. The system of claim 9, wherein the first and second pressure-sensitive adhesives each independently comprise an acrylic copolymer. The system of claim 9, wherein the skin contact layer also comprises a medicament. The system of claim 10 wherein each acrylic copolymer independently comprises a copolymer (a) one or more monomers A selected from the group consisting of alkyl (meth) acrylates of 4 to 10 carbon atoms in the alkyl group; and b) one or more ethylenically unsaturated monomers B containing a functional group selected from the group consisting of carboxyl, sulfonamide, urea, carbamate, carboxamide, hydroxy, amino, oxy, oxo and cyano. 13. The system of claim 12 wherein monomer A (monomers) is selected from the group consisting of isooctyl acrylate, 2-ethylhexyl acrylate, butyl acrylate, and cyclohexyl acrylate. 14. The system of claim 12 wherein monomer B (monomers) is independently selected from the group consisting of acrylic acid / methacrylic acid, acrylamide, vinyl acetate, and methacrylamide. • this this ·· 9 · 1 · · · · · · · · · · · · · · · · · · · · · · · · · · · The system of claim 12, wherein the acrylic copolymer further comprises one or more substantially linear macromonomers copolymerizable with monomers A, and B. 16. The system of claim 9 wherein the rate controlling membrane comprises an ethylene-vinyl acetate copolymer. 17. The system of claim 9, wherein the drug content of the storage layer is in an amount of about 5 to about 45% by weight based on the total weight of the storage layer. 18. A method of treating a mammal condition characterized by reducing the formation or release of cerebral acetylcholine, comprising administering to said mammal the system of claim 1 and leaving said system in contact with its skin for a time sufficient to administer a therapeutically effective amount of (R) - (Z). -1-azabicyclo [2.2.1] heptan-3-one-O- [3- (3-methoxyphenyl) -2-propynyl] oxime to said mammal. 19. The method of claim 18 wherein said condition is Alzheimer's disease. 20. A method of treating a mammal condition characterized by reducing the formation or release of cerebral acetylcholine, comprising administering to said mammal the system of claim 9 and leaving said system in contact with its skin for a time sufficient to administer a therapeutically effective amount of (R) - (Z). -1 • 4,444 4444 44 44 4 44 4 ·· 4 4 4 4 4 4 4 4 4 4 4 4 5 44 4 4 * 4 4 4 4 4 4 44 444 -azabicyclo [2.2.1] heptan-3-one-O- [3- (3-methoxyphenyl) -2-propynyl] oxime to said mammal. 21. The method of claim 20 wherein said condition is Alzheimer's disease. 22. A method of treating a mammal condition characterized by reducing the formation or release of cerebral acetylcholine, comprising administering (R) - (Z) -1-azabicyclo [2.2.1] heptan-3-on-O- [3- (3- methoxyphenyl) -2-propynyl] oxime to said mammal by administering a transdermal delivery system to administer from about 0.1 to about 50.0 mg / 20 cm ^{2 of the} patch / day to achieve (R) - (Z) -1-azabicyclo [2.2] 1] Heptan-3-one-O- [3- (3-methoxyphenyl) -2-propynyl] oxime in serum of about 0.2 to about 100 ng / ml for about 2 to about 14 days. 23. The method of claim 22 wherein the amount of (R) - (Z) -1-azabicyclo [2.2.1] heptan-3-one-O- [3- (3-methoxyphenyl) -2-propynyl] is administered. ] oxime is from 0.1 to 30.0 mg / 20 cm ² patch / day, the concentration of (R) - (Z) -1-azabicyclo [2.2.1] heptan-3-on-O- [3- (3) Serum-methoxyphenyl) -2-propynyl] oxime, the mammal being about 20 to about 60 ng / ml, and the administration time is about 7 days. A method of treating a mammal condition characterized by reducing the formation or release of cerebral acetylcholine. comprising administering (R) - (Z) -1-azabicyclo [2.2.1] heptan-3-one-O- [3- (3-methoxyphenyl) -2-propynyl] oxime to said mammal by administering a transdermal delivery device of a delivery system of from about 0.1 to about 50.0 mg / 20 cm ^{2 of a} patch / day, wherein the peak flow to minimum flow ratio is between about 1.0 to about 4.0 over a period of about 2 to about 14 days. frfr fr ··· »frfrfr frfr frfr frfrfr frfrfr frfrfr A f \ · ·· «·· Fr · · · fr · · · fr · fr fr fr fr 25. The method of claim 24, wherein the ratio of maximum flow to minimum flow is in the range of 1.0 to about 2.0. 26. A method of treating a mammal condition characterized by reducing the formation or release of cerebral acetylcholine, comprising administering (R) - (Z) -1-azabicyclo [2.2.1] heptan-3-on-O- [3- (3- methoxyphenyl) -2-propynyl] oxime to said mammal by administering a transdermal delivery system to administer from about 7.5 to about 50.0 mg / 20 cm ^{2 of the} patch / day for about 1 to about 14 days. 27. A method of treating a mammal condition characterized by reducing the formation or release of cerebral acetylcholine comprising administering (R) - (Z) -1-azabicyclo [2.2.1] heptan-3-on-O- [3- (3)]. (methoxyphenyl) -2-propynyl] oxime to said mammal by administering a transdermal delivery system to administer a therapeutically effective amount of the drug for about 2 to about 14 days. 28. A method of treating a mammal condition characterized by reducing the formation or release of cerebral acetylcholine, comprising administering (R) - (Z) -1-azabicyclo [2.2.1] heptan-3-on-O- [3- (3- methoxyphenyl) -2-propynyl] oxime to said mammal by administering a transdermal delivery system to achieve (R) - (Z) -1-azabicyclo [2.2.1] heptan-3-on-O- [3- (3-methoxyphenyl) concentration 1-2-propynyl] oxime in a mammalian serum of 0.2 to about 100 ng / ml for about 1 to about 14 days. 29. The method of claim 28, wherein the serum concentration is in the range of about 20 to about 60 ng / ml. · · · · · · · · · · 4 4 4 9 9 9 9 4 4 5 4444 44 44 »· ··· · 4 4 4 4 9 4 4 44 44 A system for the transdermal drug delivery of (R) - (Z) -1-azabicyclo [2.2.1] heptan-3-one-O- [3- (3-methoxyphenyl) -2-propynyl] oxime, characterized by: comprising a pressure-sensitive adhesive layer containing an effective amount of drug, wherein upon storage of the system at 25 ° C and 60% relative humidity for at least 6 months, the drug content is greater than 95% by weight relative to the original drug content. The system of claim 30, wherein said shelf life is 1 year. 32. A system for the transdermal drug delivery of (R) - (Z) -1-azabicyclo [2.2.1] heptan-3-one-O- [3- (3-methoxyphenyl) -2-propynyl] oxime, characterized in that: comprising a pressure-sensitive adhesive layer containing an effective amount of drug, wherein upon storage of the system at 40 ° C and 75% relative humidity for 6 months, the drug content is more than about 90% by weight relative to the original drug content. A system for the transdermal administration of a drug, (R) - (Z) -1-azabicyclo [2.2.1] heptan-3-one-O- [3- (3-methoxyphenyl) -2-propynyl] oxime, characterized in that: comprising a pressure-sensitive adhesive layer containing an effective amount of drug, wherein after storage of the system at 40 ° C and 75% relative humidity for 3 months, the drug content is more than 95% by weight relative to the original drug content.