JP2003512414A - Transdermal drug delivery device - Google Patents

Abstract

  (57) [Summary] System for transdermal delivery of compound (R)-(Z) -1-azabicyclo [2.2.1] heptane-3-one, O- [3 (3-methoxyphenyl) -2-propynyl] oxime and An apparatus is disclosed. These devices include a drug-containing adhesive reservoir layer and a skin-contacting adhesive layer that acts as a rate controlling membrane. These devices also include a drug-containing adhesive reservoir layer and a skin-contacting adhesive layer, with a membrane disposed between the two adhesive layers. The compounds are muscarinic agonists useful for treating various cognitive disorders, including Alzheimer's disease.

Description

Detailed Description of the Invention

FIELD OF THE INVENTION The present invention relates to (R)-(Z) -1-azabicyclo [2.2.1] heptane-3-
Provided are drug-containing adhesive systems for transdermal delivery of on, O- [3 (3-methoxyphenyl) -2-propynyl] oxime, as well as transdermal drug delivery devices comprising one or more of these systems. .

BACKGROUND OF THE INVENTION The compound (R)-(Z) -1-azabicyclo [2.2.1] heptan-3-one, O- [3 (3-methoxyphenyl) -2-propynyl] oxime is muscarinic. Being a drug, this property makes this compound have many therapeutic properties. For example, the compound is characterized as an analgesic, as a sleep aid and as a symptom of senile dementia, Alzheimer's disease, Huntington's chorea, tardive dyskinesia, hyperkinesia, mania, or decreased production or release of brain acetylcholine. It is useful for the treatment of other diseases. In Lauffer et al., US Pat. No. 5,306,718, this compound and other compounds of this class are described in detail.

Transdermal drug delivery devices are designed to deliver a drug through the skin of a patient, resulting in a relatively constant drug delivery over an extended period of time. Generally, including a reservoir device in which the drug is present in a liquid reservoir and drug delivery is controlled by a rate controlling membrane, and a drug-containing adhesive device in which the drug is present in a normally solid matrix, including a pressure sensitive skin adhesive. Thus, transdermal drug delivery devices have many possible designs. Other components, such as skin permeation enhancers, can be added to the matrix depending on the skin's permeability to the drug. However, if the skin is very drug permeable, measures must be taken to control the diffusion of the drug through the skin in order to provide stable, long-term drug delivery.

SUMMARY OF THE INVENTION The present invention provides (R)-(Z) -1-azabicyclo [2.2.1] heptane-3-
Provided are drug-containing adhesive systems for transdermal delivery of on, O- [3- (3-methoxyphenyl) -2-propynyl] oxime, and transdermal drug delivery devices comprising one or more of these systems. To do.

More specifically, the transdermal drug delivery device of the present invention controls the rate at which a drug is delivered to the skin of a subject. In one aspect of the invention, the rate of drug delivery is controlled by a rate controlling adhesive layer disposed between the drug reservoir layer and the skin. In another aspect of the invention, the rate of drug delivery is controlled by a rate controlling membrane disposed between the drug reservoir layer and the skin contact adhesive layer.

The present invention applies the transdermal drug device of the present invention to the skin of a subject and provides a therapeutically effective amount of (R)-(Z) -1-azabicyclo [2.2.1] heptane-3-. On, O
Inducing production or release of brain acetylcholine in a subject, including leaving the device in contact with the skin for a time sufficient to deliver-[3- (3-methoxyphenyl) -2-propynyl] oxime to the subject. Further provided is a method of treating a disease characterized by a decrease.

DETAILED DESCRIPTION OF THE INVENTION Drug Compound (R)-(Z) -1-azabicyclo [2.2.1] heptan-3-one, O- [3- (3-methoxyphenyl) -2-propynyl] Oximes (referred to herein as "drugs" or "compounds") are selective m1 / m4 muscarinic agonists useful in the treatment of various diseases characterized by decreased production or release of brain acetylcholine. Such diseases include senile dementia, Alzheimer's disease, Huntington's chorea, tardive dyskinesia, hyperkinesia, and mania. The compounds are also useful as analgesics and sleep aids. The structure of the compound is:

[Chemical 1]

The compound exists in many isomeric forms, including stereoisomers and geometric isomers. This compound can exist in two possible geometric forms known as E-oximes and Z-oximes. The pharmacological activity lies in the Z-oxime. Therefore,
The compositions of the present invention include Z-oxime in an amount sufficient to produce the desired therapeutic effect. The invention includes compositions containing the drug in any therapeutically effective stereochemical form or isomer. US Patent No. 5,306,718 (Lauffer et al.);
, 346, 911 (Augelli-Szafran et al.);
No. 812 (Bucsh et al.); And No. 5,534,522 (Ando et al.) (
All of which are incorporated herein by reference), the structure, chemical properties, synthetic, and isomeric properties of the drug are described in detail.

This compound can be used in the device of the present invention in the form of its free base or in the form of a pharmaceutically acceptable salt. Examples of such salts include the hydrochloride, sulphate, phosphate, acetate, benzoate, citrate, malonate, salicylate, malate, fumarate, oxalate of this compound. , Succinate, tartrate, lactate,
Included are gluconate, ascorbate, maleate, aspartate, benzenesulfonate, methanesulfonate and ethanesulfonate, and hydroxymethanesulfonate and hydroxyethanesulfonate (eg J. Pharm. Sci. 66 (1), pp. 1-19 (1977)). Generally, when mixed with one of the adhesive polymers described below,
It is preferred to select the form of the compound that is less susceptible to isomerization from the active Z form to the inactive E form. The free base form of the compound is preferred primarily because of its relatively slow conversion rate in the adhesive polymers used in the devices of the present invention.

Adhesives In many situations pressure sensitive adhesives are used in the device of the present invention. The drug reservoir layer of the device consists of a mixture of drug and pressure sensitive adhesive, and the device is adhered to the skin of the subject by the layer of pressure sensitive adhesive. An adhesive layer is used in some of the devices of the invention to control the drug delivery rate as well as to adhere the device to the skin of the subject.

One or more types of adhesive polymers used in the device of the present invention include (R
)-(Z) -1-Azabicyclo [2.2.1] heptan-3-one, O- [3-
It should be substantially chemically inert to (3-methoxyphenyl) -2-propynyl] oxime (eg, it should not decompose the compound when reacted with it. It should not cause or promote the conversion of the body to the E isomer)), preferably a pressure sensitive skin adhesive. Chemical stability was determined by making the device of the present invention and storing it under the conditions of 25 ° C. and 60% relative humidity and (R)-(Z) -1-azabicyclo [2.2. 1] Heptane-3
It can be determined by testing for the concentration of -one, O- [3- (3-methoxyphenyl) -2-propynyl] oxime. The amount of drug is approximately 95% of the initial amount of drug in the device when stored at 25 ° C. and 60% relative humidity for 6 months.
It is preferred that it is greater than wt%, preferably greater than about 97 wt%. More preferably, the amount of drug is greater than about 95%, preferably greater than about 97% by weight of the initial amount of drug in the device when stored for 1 year at 25 ° C and 60% relative humidity.

Accelerated chemical stability has been demonstrated by making the device of the present invention and storing it under the conditions of 40 ° C. and 75% relative humidity and (R)-(Z) -1-azabicyclo [ 2.
2.1] heptan-3-one, O- [3- (3-methoxyphenyl) -2-propynyl] oxime concentration can be measured by testing. The amount of drug, when stored at 40 ° C. and 75% relative humidity for 3 months, is preferably greater than about 95% by weight of the initial amount of drug in the device, preferably greater than about 97% by weight, and stored for 6 months. When applied, it is preferred that the initial amount of drug in the device be greater than about 90%, preferably greater than about 93%.

Examples of suitable types of adhesives include acrylates, natural rubber, synthetic rubbers (eg polyisobutylene, polysiloxane, polyurethane), and other pressure sensitive skin adhesives well known in the art. These adhesive polymers may be present alone or in combination.

Acrylate copolymers are the preferred pressure sensitive adhesives for use in the device of the present invention. Suitable acrylate copolymers for use in the adhesive layer are preferably from about 45 to about 95 wt%, more preferably 55 to 95 wt%, based on the total weight of all monomers in the copolymer, from 4 to 10 alkyl groups. One or more types of A monomers selected from the group consisting of alkyl acrylates containing 4 carbon atoms and alkyl methacrylates containing 4 to 10 carbon atoms in the alkyl group.
Examples of suitable alkyl acrylates and alkyl methacrylates are n-butyl acrylate and n-butyl methacrylate, n-pentyl acrylate and n-pentyl methacrylate, n-hexyl acrylate and n-hexyl methacrylate, acrylics. Isoheptyl acid and isoheptyl methacrylate, n-acrylic acid
Nonyl and n-nonyl methacrylate, n-decyl acrylate and n-decyl methacrylate, isohexyl acrylate and isohexyl methacrylate, 2-ethyloctyl acrylate and 2-ethyloctyl methacrylate, isooctyl acrylate and isooctyl methacrylate, And 2-ethylhexyl acrylate and 2-ethylhexyl methacrylate. Preferred alkyl acrylates include isooctyl acrylate, 2-ethylhexyl acrylate, n-butyl acrylate, and cyclohexyl acrylate. Isooctyl acrylate is a particularly preferred A monomer.

The acrylate copolymer further comprises from about 5 to about 55% by weight, more preferably from about 5 to about 40% by weight, of one or more types of B monomers, based on the total weight of all monomers in the copolymer. Suitable B monomers include monomers containing a functional group selected from the group consisting of carboxylic acid, sulfonamide, urea, carbamate, carboxamide, hydroxy, amino, oxy, oxo, and cyano. Exemplary B-monomers include acrylic acid, methacrylic acid, maleic acid, hydroxyalkyl acrylates containing 2 to 4 carbon atoms in the hydroxyalkyl group, hydroxymethacrylates containing 2 to 4 carbon atoms in the hydroxyalkyl group. Alkyl, acrylamide, methacrylamide, alkyl-substituted acrylamide having 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 acrylate containing 1 to 4 carbon atoms in the alkoxy group, alkoxyethyl methacrylate containing 1 to 4 carbon atoms in the alkoxy group, 2-ethoxyethoxyethyl acrylate , Furfuryl acrylate, furfuryl methacrylate, tetrahydrofurfuryl acrylate, tetrahydrofurfuryl methacrylate, propylene glycol monomethacrylate, propylene oxide methyl ether acrylate, di (lower) alkylaminoethyl acrylate, di (lower) alkylamino methacrylate Ethyl, di (lower alkyl) aminopropyl methacrylamide, acrylonitrile,
And methacrylonitrile. Preferred B monomers include acrylic acid, methacrylic acid, acrylamide, methacrylamide, and vinyl acetate.

The copolymer is optionally copolymerizable with A and B monomers and comprises about 500 to about 500,000, preferably about 2,000 to about 100,000.
More preferably, it may further comprise a substantially linear macromonomer having a weight average molecular weight of about 5,000 to about 30,000. If a macromonomer is used, it is generally present in an amount of about 20 wt% or less, preferably about 10 wt% or less, based on the total weight of all monomers in the copolymer. Suitable macromonomers include polymethylmethacrylate, styrene / acrylonitrile, polyethers, and polystyrene macromonomers. Examples of useful macromonomers and their preparations are described in Krampe et al., US Pat. No. 4,693,776, the disclosure of which is incorporated herein by reference.

The copolymers described above can be prepared by methods well known to those skilled in the art, eg US Pat. No. RE 24,906 (Ulrich), US Pat. No. 4,732,8.
08 (Krampe et al.) And International Publication No. WO 96/08229 (G
Arbe et al.), the disclosures of which are incorporated herein by reference.

The inherent viscosity of the copolymer is such that when the copolymer is used in the device of the present invention, it will eventually yield a suitable pressure sensitive adhesive. The inherent viscosity of the copolymer is preferably from about 0.2 dl / g to about 2 dl / g,
More preferably, it is from about 0.5 dl / g to about 1.6 dl / g.

If desired, the adhesive layer may include types and amounts of components (eg, plasticizers, tackifiers, etc.) that improve the adhesive polymer properties that can be readily determined by one of ordinary skill in the art.

Device One preferred transdermal drug delivery device of the present invention is two directly bonded to each other.
Two adhesive layers are used. The first adhesive layer, which does not come into contact with the subject's skin, comprises the polymer and the drug and serves as the drug reservoir layer. The second adhesive layer in contact with the subject's skin controls the rate at which the drug is delivered to the subject and helps adhere the device to the subject's skin. The second adhesive layer comprises a rate controlling polymer. Therefore,
Due to the presence of the second adhesive layer on the device, the skin permeation profile of the device is
When measured using the test method described below, the composition of the second adhesive layer will vary as compared to a similar device that is identical to the first adhesive layer. This control of drug delivery rate may be due to the difference in drug affinity for the two different adhesive layers and the difference in diffusion rate of the drug through the two different adhesive layers. The difference in drug affinity and / or diffusion in these two adhesive layers as well as the relative thickness of the adhesive layers allows control of the drug delivery rate. This system is called an "adhesive speed control system".

In a particularly preferred embodiment of the adhesive rate control system, the adhesive used in the two layers is such that the second adhesive layer has a lower affinity for the drug than the first adhesive layer. Selected to be made of polymer. "Low affinity" means that the drug is preferentially present in the reservoir layer so that when the system is in equilibrium, the mass% drug in the reservoir layer is greater than the mass% drug in the rate controlling layer. means. The difference in the affinity of the two polymers for the drug as well as the relative thickness of the adhesive layer allows for controlled drug delivery rates.

The first adhesive layer (also known as the reservoir layer) of the adhesive speed control device preferably consists of an acrylate copolymer of the type described above. Preferred copolymers are from about 60 to about 80 wt%, preferably about 65 to about 75 wt% isooctyl acrylate, about 4 to about 15 wt%, preferably about 5 to 5 wt%, based on total monomer weight.
About 10% by weight acrylamide, and about 15 to about 35% by weight, preferably about 1
It is a terpolymer consisting of 5 to about 25% by weight vinyl acetate, and a particularly preferred monomer weight ratio is about 75/5/20 isooctyl acrylate / acrylamide /
It is vinyl acetate. Another preferred copolymer is about 54 to about 77 wt% isooctyl acrylate, about 18 to about 39 wt% vinyl acetate, and about 2 to about 10 wt% polymethylmethacrylate macromonomer, based on total monomer weight. (
PMMA), with a particularly preferred weight ratio of about 59/38 /
3 isooctyl acrylate / vinyl acetate / PMMA.

The reservoir layer of the device comprises sufficient drug to deliver a therapeutically effective amount of drug to the subject over the delivery period. A therapeutically effective amount of a drug is an amount sufficient to alleviate the symptoms of the disease being treated. The exact amount depends on the exact nature of the disease being treated,
Generally, the dose administered will range from 0.07 to 700 mg / day, preferably from about 0.1 to about 50 mg /, depending on the condition of the patient, and other factors well known to those of skill in the art.
Day, most preferably about 1 to about 30 mg / day. To deliver this amount of drug, the reservoir layer preferably comprises from about 5 to about 45 wt% drug, based on the total weight of the reservoir layer. More preferably, the reservoir layer comprises about 20 to about 35% by weight drug.

The device of the present invention delivers a therapeutically effective amount of a compound over an extended period of time, preferably about 1 to about 14 days, more preferably about 1 day, most preferably about 7 days.

The device of the present invention delivers a therapeutically effective serum concentration of a drug to a subject over a delivery period. A therapeutically effective serum concentration of a drug is an amount sufficient to alleviate the symptoms of the disease being treated. The exact amount will depend on the exact nature of the disease to be treated, the condition of the patient, and other factors well known to those of skill in the art, but serum concentrations generally range from about 0.2 to about 100 ng / mL. , Preferably 20-60 ng / mL
Is.

It is also preferred that the transdermal drug delivery rate be relatively constant over the extended period in which the device of the invention is used to deliver a therapeutically effective amount of the compound. The rate of transdermal drug delivery, known as the transdermal flux, is defined as the rate at which a drug penetrates the skin. In the in vitro skin permeation test described below, the flux measures the amount of drug in the receptor fluid (ie, the amount of drug that has permeated the skin) before removing and replacing the receptor fluid. And divided by the area of the skin and the time the drug has penetrated the skin. The flux for each time interval is shown as the average flux over that time interval. If more than one time interval is included in an experiment, the maximum and minimum flux for the duration of the entire experiment can be determined (eg, time intervals of 3 hours, 6 hours, 12 hours, and 24 hours). If it is hours, flux values of 0-3 hours, 3-6 hours, 6-12 hours, and 12-24 hours are obtained). The ratio of maximum flux to minimum flux is preferably 1.0 to about 4.0, more preferably 1.0 to about 2.0.

In some cases, there is a period (sometimes referred to as “lag time”) of low transdermal flux at the beginning of the application period. If a short time interval is chosen at the beginning of the permeation experiment, the initial value of the transdermal flux may be quite small because of the lag time, which makes the calculated maximum-to-minimum flux ratio fairly large. To determine the ratio of maximum flux to minimum flux, it is understood that the flux values during the first 24 hours of the permeation experiment are not included in the determination of the minimum flux unless half the maximum flux value is reached. Should be. If the flux at any time interval exceeds half the maximum flux value, that value and all subsequent flux values are used to determine the minimum flux.

The second adhesive layer, also known as the speed control layer, is a second adhesive layer and a similar device in which the composition of the second adhesive layer is the same as the first adhesive layer. In comparison, it comprises a different polymer than the first adhesive layer so as to alter the skin permeation profile of the device. The polymers in the first and second adhesive layers may differ, for example, in the type and amount of monomer, reaction, crosslinking, degree of branching, and copolymer alignment. The polymer of the adhesive rate control device is preferably polyisobutylene (PIB). This is because this 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 PIBs generally have a viscosity average MW of about 40,000 to about 70,000 and high molecular weight PIBs generally have a viscosity average MW of about 900,000 to 2,000,000. Have. High and low molecular weight polymers are about 5/1
Are mixed at low MW / high MW ratios of about 1/1, preferably about 3/1. PIB
Mixtures of and acrylic copolymers can also be used. A preferred combination comprises a mixture of one or more polyisobutylene and about 75/5/20 isooctyl acrylate / acrylamide / vinyl acetate copolymer in a PIB: acrylate ratio of about 95: 5 to about 80:20.

Another preferred transdermal drug delivery device of the present invention comprises at least three distinct layers. The first layer comprises an adhesive that acts as a drug reservoir. The second layer comprises a rate controlling membrane adhered to one side of the first layer. The third layer comprises an adhesive that is adhered to the side of the membrane opposite the side of the membrane that is in contact with the first layer. When the device is used, this third layer contacts the subject's skin. This type of device is called a "membrane speed controller".

As in the case of the adhesive rate control device, the preferred reservoir layer of the membrane rate control device consists of an acrylate copolymer in combination with the drug. The preferred copolymer is
About 60 to about 80% by weight, preferably about 65 to about 7 based on the total weight of the monomers.
5% by weight isooctyl acrylate, about 4 to about 15% by weight, preferably about 5
A terpolymer consisting of about 10% by weight acrylamide and about 15 to about 35% by weight, preferably about 15 to about 25% by weight vinyl acetate, with a particularly preferred monomer weight ratio of about 75/5/20. It is isooctyl acrylate / acrylamide / vinyl acetate. Another preferred copolymer is based on total monomer mass.
A copolymer of about 54 to about 77 wt% isooctyl acrylate, about 18 to about 39 wt% vinyl acetate, and about 2 to about 10 wt% polymethylmethacrylate macromonomer (PMMA), with a particularly preferred weight ratio. Is about 59/38
/ 3 isooctyl acrylate / vinyl acetate / PMMA. The reservoir layer is
Generally, from about 5 to about 45% by weight, based on the total weight of the reservoir layer, preferably
Contains from about 20 to about 35% by weight drug.

The membrane is selected to control velocity. Due to the presence of the rate controlling membrane in the device, the skin permeation profile of the device changes when measured using the test method described below as compared to a similar device without the rate controlling membrane. As a suitable membrane,
Included are continuous film membranes and pore membranes. A particularly preferred membrane is a continuous film membrane made from an ethylene: vinyl acetate copolymer containing about 2 to about 28 wt% vinyl acetate. The most preferred membrane is ethylene containing about 9% by weight vinyl acetate:
It is a continuous film membrane made from a vinyl acetate copolymer. The thickness of the membrane is generally about 25 μm to about 100 μm, preferably about 50 μm.

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

The skin contact layer may be initially free of drug as the drug is expected to diffuse from the reservoir layer to the skin contact layer over time and may include a drug at about the same concentration as the reservoir layer. Good.

The desired properties for transdermal drug delivery devices are well known to those of ordinary skill in the art. For example, it is desirable to have a sufficiently small cold flow that the device of the present invention is stable to flow during storage. It is also preferred that it adheres well to the skin and peels cleanly from the skin. In order to obtain cold flow resistance, the preferred degree of skin adhesion and clean peeling, the amount and structure of the comonomer in the copolymer, the inherent viscosity of the copolymer, and the amount and type of any auxiliaries or additives are used in the adhesive layer. Are selected to obtain the desired balance of these properties.

The transdermal drug delivery device of the present invention also comprises a support. The support is flexible so that the device fits closely to the skin. Suitable support materials include polyethylene (especially low density polyethylene, linear low density polyethylene, metallocene polyethylene, high density polyethylene), polypropylene, polyester (eg polyethylene terephthalate), randomly oriented nylon fibers.
Included are conventional flexible support materials used in pressure sensitive adhesive tapes such as nted nylon fibers, ethylene-vinyl acetate copolymers, polyurethanes, natural fibers (eg rayon). Polyethylene terephthalate-
Laminated supports such as aluminum-polyethylene composites are also suitable. The support should be substantially inert to the components of the adhesive layer.

The transdermal drug delivery device of the present invention can be made using methods for making multi-layer devices well known in the art. For example, the adhesive layer may be coextruded on the support or release liner, continuously extruded or coated on the support or release liner, on the support or release liner. May be coated separately and then the two adhesive layers may be laminated together. Suitable release liners include conventional release liners with known sheet materials such as polyester fabrics, polyethylene fabrics, polystyrene fabrics, or polyethylene coated papers coated with a suitable fluoropolymer or silicone based coating.

Preferably, the adhesive rate control system of the present invention is made by making the reservoir layer and the skin contact layer separately. Generally, the reservoir layer is made by mixing the adhesive copolymer with the drug and one or more suitable organic solvents (eg, methanol, ethanol, isopropanol, ethyl acetate, etc.). The mixture is agitated until a uniform coating formulation is obtained. Then, using conventional coating methods (eg, knife coating or extrusion die coating), about 14.7 mg / cm ² to about 37.5 mg / c.
The reservoir coating formulation is applied to the release liner with a wet thickness of about 880 μm to 2200 μm, sufficient to obtain a dry reservoir layer of m ² . The coated release liner is dried and then laminated to a support. Generally, the skin contact layer comprises one or more rate controlling adhesives and a suitable organic solvent (eg, methanol, ethanol, isopropanol,
Ethyl acetate, heptane, hexane, etc.) are mixed together and stirred until uniform. The formulation is then applied to the release liner using conventional coating methods such as knife coating or extrusion die coating. The skin contact adhesive layer is coated with a thickness sufficient to obtain a dry skin contact adhesive layer having a thickness of about 10 μm to about 40 μm. The coated liner is dried, then the release liner is removed from the reservoir layer and the exposed adhesive surface is laminated to the adhesive surface of the skin contact adhesive layer. The appropriately sized patch can then be cut from the resulting laminate. In another manufacturing method, the adhesive copolymer was coated onto a liner and coated as a further step in the process (eg, using the method disclosed in US Pat. No. 5,688,523 (Garbe et al.)). Drugs can be added to the adhesive copolymer.

The membrane velocity control device of the present invention can be produced by producing the reservoir layer as described above. The reservoir layer formulation can be coated onto a release liner, dried and laminated to a support. Wet thickness of the reservoir layer is about 880
μm to about 2200 μm. Skin contact adhesive coating formulations are prepared with the same adhesive polymer or different adhesives or combinations of adhesives, as well as reservoir coating formulations. This formulation is then added to about 5 μm to about 50 μm.
It is applied to the release liner using conventional coating methods (eg knife coating or extrusion die coating) to obtain a dry thickness of μm. Allow the coated liner to dry. Then, this is attached to the film. By removing the release liner from the reservoir layer and bonding the exposed adhesive surface of the reservoir layer to the membrane surface of the skin contact adhesive layer,
Assemble the device. The appropriately sized patch can then be cut from the resulting laminate.

[0039]   The following examples are provided to further illustrate the present invention.

Examples In Vitro Skin Permeation Test Methods The following test methods were used to obtain the skin permeation data shown in the following examples. A vertical diffusion cell is used with human cadaver skin.

When assessing a transdermal drug delivery device, the release liner is removed from the 2.0 cm ² patch, the patch is applied to the skin and pressed into uniform contact with the skin. The resulting patch / skin laminate is placed patch side up so that it passes across the opening in the bottom of the diffusion cell. Assemble the diffusion cell and place 10 mL of warm (32 ° C.) receptor liquid (0.
Fill with 1M phosphate buffer, pH 6). Stir the receptor liquid using a magnetic stirrer. Cover the sampling port when not in use.

The cell is then placed in a chamber at constant temperature (32 ± 2 ° C.) and humidity (50 ± 10% relative humidity). Throughout the experiment, the receptor liquid is magnetically stirred to ensure a uniform sample and a reduced diffusion barrier on the dermis side of the skin. The entire volume of receptor liquid is collected at specified time intervals and immediately replaced with fresh liquid. The recovered liquid is filtered through a 0.45 μm filter. Then, high performance liquid chromatography (column: Zorbax SB-CN, 50
X 2.1 mm ID; mobile phase: phosphate buffer containing 87 v% triethylamine (p
H3.0), 13v% acetonitrile; Flow rate: 2 mL / min; Detector: UV
, 240 nm; runtime: 1 min; injection volume: 5 μL), the final 1-2 m
L is (R)-(Z) -1-azabicyclo [2.2.1] heptan-3-one, O
Analyze for-[3- (3-methoxyphenyl) -2-propynyl] oxime. Calculate the cumulative amount of (R)-(Z) -1-azabicyclo [2.2.1] heptan-3-one, O- [3- (3-methoxyphenyl) -2-propynyl] oxime that penetrates the skin. To do.

Drug Content Method for Stability A transdermal drug delivery device (20 cm ² patch) was placed in a bag (BAREX ^™ / aluminum /
Put it in polyester or BAREX ^™ / aluminum / paper laminate) and seal it under 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, about 22 ℃), 40 ℃
It was stored under one or more of temperature and 50 ° C. temperature. The drug content of the patch was tested before storage and after a preset storage time. An internal standard solution was prepared by adding 1.0 g of ethyl paraben to 1000 mL of tetrahydrofuran (THF). Remove the liner from the 10 20 cm ² patches,
The patch was placed in a 1 quart (0.95 L) jar. The support and the coating agent,
Extraction was performed with 500 mL of internal standard solution. The sample was shaken for at least 24 hours. 5 mL of the resulting solution was then placed in a 4 ounce (118.3 mL) jar and 100 mL of 50:50 (v: v) acetonitrile / water was added to the jar and shaken for about 60 minutes. A diluted solution of the sample was prepared. An aliquot of the diluted solution was then placed in an analytical autosampler vial. High performance liquid chromatography (column: Zorbax SB-CN 5 μm particle size, 25 cm × 4
． 6 mm; Mobile phase: 82:18 (v / v) pH 3 buffer / acetonitrile; buffer is 7.7 × 10 ⁻⁴ M triethylamine in potassium phosphate solution (pH 3 with phosphoric acid.
． Flow rate: 2.0 mL / min; detector: UV at 240 nm; injection volume: 5 μL; run time: 15 minutes). Results are reported as the percentage of residual drug relative to the initial amount of drug.

Adhesive Preparation The adhesives used in the following examples were generally prepared according to the methods described below.

Preparation of isooctyl acrylate: acrylamide: vinyl acetate (75: 5: 20) copolymer isooctyl acrylate (621.0 g), acrylamide (41.4 g),
By combining vinyl acetate (165.6 g), 2,2′-azobis (2,4-dimethylpentanenitrile) (1.656 g), ethyl acetate (884.5 g), and methanol (87.48 g), A masterbatch was prepared. A portion (400 g) of the resulting solution was placed in a 1 quart (0.95 L) amber glass bottle. The bottle was purged with nitrogen at a flow rate of 1 L / min for 2 minutes. The bottle was sealed and placed in a rotating water bath at 45 ° C. for 24 hours to cause essentially complete polymerization. The copolymer was diluted with ethyl acetate: methanol (250 g, 90:10 v: v) to 26.05% solids.

Preparation of Isooctyl Acrylate: Vinyl Acetate: Polymethyl Methacrylate Macromonomer (59: 38: 3) Copolymer Vinyl acetate (80.37 g), Polymethylmethacrylate macromonomer (E
LVACITE ^™ 1010 (available from ICI Acrylics) 6.34
5 g), ethyl acetate (271.95 g), and methanol (8.41 g) 1
A quart (0.95 L) amber glass bottle was filled and then roller mixed until a solution was obtained. Isooctyl acrylate (124.875) was added to this solution.
g) and 2,2′-azobis (2-methylbutyronitrile) (0.3173 g)
) Was added. The bottle was purged with nitrogen at a flow rate of 1 L / min for 2 minutes. Seal the bottle,
It was placed in a rotary water bath at 57 ° C. for 23 hours. The copolymer was ethyl acetate (62.78 g
) And methanol (1.94 g) to about 38% solids.

Preparation of Isooctyl Acrylate: Vinyl Acetate: Polymethyl Methacrylate Macromonomer (55: 38: 7) Copolymer Vinyl acetate (80.37 g), Polymethylmethacrylate macromonomer (E
LVACITE ^™ 1010 (available from ICI Acrylics) 14.8
0 g) and ethyl acetate (370.80 g) were charged into a 1 quart (0.95 L) amber glass bottle and then roller mixed until a solution was obtained. To this solution was added isooctyl acrylate (116.32g) and 2,2'-azobis (2-methylbutyronitrile) (0.3173g). The bottle was purged with nitrogen at a flow rate of 1 L / min for 2 minutes. The bottle was sealed and placed in a rotating water bath at 57 ° C for 23 hours. The resulting copolymer was 28.5% solids in ethyl acetate.

Preparation of Polyisobutylene Adhesive Solution Low molecular weight polyisobutylene (OPPANOL ^™ B10 polyisobutylene (BA
74.99 g) (available from SF), high molecular weight polyisobutylene (OPPANO
L ^™ B100 polyisobutylene 24.96 g), heptane (270.0 g), and ethyl acetate (180.0 g) were combined and mixed until all the polyisobutylene was dissolved.

Preparation of "Dry Adhesive" A dry adhesive was prepared by knife coating a solution of an acrylate adhesive copolymer onto a release liner. The adhesive coated release liner was oven dried to remove solvent and reduce residual monomer concentration.
The dried adhesive was then stripped from the release liner and stored in a container until use.

Membranes Some of the membranes used in the following examples are commercially available (eg, COTRAN ^™ 9702, COTRAN ^™ 9717, COTRAN ^™ 9726, and COTR ^™).
AN ^™ 9728 thickness controlled EVA film (EVA controlled cali
per membrane), all available from 3M Company). Other membranes are produced by conventional extrusion methods (eg, quenching rolls).
It was prepared from a commercial resin using a thermal extrusion to. An example of a suitable resin is ELVAX ^™ ethylene-vinyl acetate (E
VA) copolymers (available from DuPont). In the examples below, the designation "X% EVA" means a membrane made from an ethylene-vinyl acetate copolymer containing X wt% vinyl acetate.

Example 1 A transdermal drug delivery device having two separate adhesive layers separated by a membrane was made as described below.

Dry adhesive (isooctyl acrylate / acrylamide / vinyl acetate 75/5
/20,8.84 g), (R)-(Z) -1-azabicyclo [2.2.1] heptan-3-one, O- [3- (3-methoxyphenyl) -2-propynyl] oxime ( 1.17 g), and solvent (ethyl acetate / methanol 90/10 v / v,
A coating formulation was prepared by combining 30 g) and then mixing until a uniform coating formulation was obtained.

A reservoir adhesive layer was prepared as follows. The coating formulation is applied to a release liner (Daubert 164P silicone coated release liner) 60
It was knife coated with a wet thickness of mil (1524 μm). The resulting coating liner is dried at room temperature for 5 hours, then the support (SCOTC
HPAK ^™ 1109 polyester film laminate; available from 3M Company).

A skin contact adhesive layer was prepared as follows. Apply the coating formulation to a release liner (Daubert 164P silicone coated release liner) 10
It was knife coated with a wet thickness of mil (254 μm). The resulting coating liner was dried at room temperature for at least 1 hour and then the exposed adhesive side was laminated to a membrane (12% EVA film, 2 mil / 51 μm).

The release liner was removed from the reservoir adhesive layer and the exposed adhesive surface was then laminated to the membrane surface of the skin contact adhesive layer. Patches were stamped from the resulting laminate. Each patch has 5 layers: support; 11.7 wt% (R
)-(Z) -1-Azabicyclo [2.2.1] heptan-3-one, O- [3-
Reservoir adhesive layer containing (3-methoxyphenyl) -2-propynyl] oxime; membrane; 11.7% by weight of (R)-(Z) -1-azabicyclo [2.2.1].
Heptan-3-one, O- [3- (3-methoxyphenyl) -2-propynyl]
A skin contact adhesive layer containing an oxime; and a release liner. Skin penetration through human cadaver skin was measured using the test method described above. The skin permeation data is shown in Table 2 below. Each value in Table 2 is the average of three independent measurements.

Examples 2 to 20 Using the method of Example 1, (R)-(Z) -1-azabicyclo [2.2.1] heptan-3-one, O- [3-] in the adhesive layer. (3-methoxyphenyl)-
A set of transdermal drug delivery devices was made that differed in the concentration of 2-propynyl] oxime, the coating weight of the reservoir adhesive layer, and the EVA percentage in the membrane. The composition is shown in Table 1 below. In each example, the adhesive used was isooctyl acrylate / acrylamide / vinyl acetate 75/5/20 and the coating formulation contained 25% solids, (R)-(Z) -1- Azabicyclo [2.2
． The concentration of 1] heptan-3-one, O- [3- (3-methoxyphenyl) -2-propynyl] oxime was the same in both adhesive layers and the skin contact adhesive layer was 10 mils (254 μm). Coated at a wet thickness, the film is 2 mils (51μ
The thickness was m). Skin penetration through human cadaver skin was measured using the test method described above. The skin permeation data is shown in Table 2 below. Each value in Table 2 is 3
It is the average of two independent measurements.

[0057]

[Table 1]

[0058]

[Table 2]

Example 21 Dry adhesive (isooctyl acrylate / acrylamide / vinyl acetate 75/5
/20,13.7 g), (R)-(Z) -1-azabicyclo [2.2.1] heptan-3-one, O- [3- (3-methoxyphenyl) -2-propynyl] oxime ( 1.54 g), and a solvent (ethyl acetate / methanol 90/10 v / v,
A coating formulation was prepared by combining 45 g) and then mixing until a uniform coating formulation was obtained.

A reservoir adhesive layer was created as follows. The coating formulation was knife coated onto a release liner (SCOTCHPAK ^™ 9742 fluoropolymer coated release liner (available from 3M Company)) at a wet thickness of 30 mils (762 μm). The resulting coating liner was dried at room temperature for 60-90 minutes and then the exposed adhesive surfaces of the two parts of the coating liner were laminated together. The release liner was removed from one side and the exposed adhesive side was laminated to a support (SCOTCHPAK ^™ 1109 polyester film laminate).

A skin contact adhesive layer was prepared as follows. The coating formulation was knife coated onto a release liner (SCOTCHPAK ^™ 9742 fluoropolymer coated release liner) at a wet thickness of 7 mils (178 μm). The resulting coating liner was dried at room temperature for 60-90 minutes and then the exposed adhesive side was laminated to a membrane (4.5% EVA film, 2 mil / 51 μm).

The release liner was removed from the reservoir adhesive layer and the exposed adhesive surface was then laminated to the membrane surface of the skin contact adhesive layer. Patches were stamped from the resulting laminate. Each patch has 5 layers: support; 10% by weight of (R)-
(Z) -1-Azabicyclo [2.2.1] heptan-3-one, O- [3- (3
-Methoxyphenyl) -2-propynyl] oxime-containing reservoir adhesive layer; membrane; 10% by weight of (R)-(Z) -1-azabicyclo [2.2.1] heptan-3-one, O-. A skin contact adhesive layer containing [3- (3-methoxyphenyl) -2-propynyl] oxime; and a release liner. Skin penetration through human cadaver skin was measured using the test method described above. The skin permeation data is shown in Table 4 below.
Shown in. In Table 4, each value is the average of 3 independent measurements.

Examples 22-38 Using the method of Example 21, (R)-(Z) -1-azabicyclo [2.2.1] heptan-3-one, O- [3-] in the adhesive layer. (3-methoxyphenyl)
Of 2-propynyl] oxime, adhesive used, and EVA in membrane
A set of transdermal drug delivery devices with different percentages was created. The composition is shown in Table 3 below. In each example, the same adhesive was used for both layers, (R)-(Z)-
The concentration of 1-azabicyclo [2.2.1] heptan-3-one, O- [3- (3-methoxyphenyl) -2-propynyl] oxime was the same in both adhesive layers and the film was 2 mils. The thickness was (51 μm). Skin penetration through human cadaver skin was measured using the test method described above. The skin permeation data is shown in Table 4 below. Table 4
Each value in is the average of three independent measurements.

[0064]

[Table 3]

[0065]

[Table 4]

Example 39 Dry adhesive (isooctyl acrylate / acrylamide / vinyl acetate 75/5
/ 20,5200g), ethyl acetate (17.56Kg), methanol (1.96)
Kg), and (R)-(Z) -1-azabicyclo [2.2.1] heptane-3.
-One, O- [3- (3-methoxyphenyl) -2-propynyl] oxime (1
A coating formulation was prepared by combining 300 g) and mixing until a uniform coating formulation was obtained. The formulation was left to stand until all air bubbles had disappeared.

A reservoir adhesive layer was created as follows. The coating formulation was die coated onto a release liner (SCOTCHPAK ^™ 1022 Fluoropolymer coated release liner) (pump speed and die gap were selected to obtain a coating dry mass of 13 mg / cm ² ± 4%). The resulting coating liner was heated to 140 ° F (60 ° C) for 2 minutes at 190 ° F (
Oven dried at 88 ° C for 2 minutes, 240 ° F (116 ° C) for 2 minutes.
The adhesive surface of the first portion of the coating liner was attached to a support (SCOTCHPAK ^™ 1109 polyester film laminate), the release liner was removed,
The exposed adhesive surface was laminated to the adhesive surface of the second portion of the coating release liner. The resulting reservoir adhesive layer had a coating dry weight of 26.
It was mg / cm ² ± 4%.

A skin contact adhesive layer was prepared as follows. The coating formulation was die coated onto a release liner (SCOTCHPAK ^™ 1022 fluoropolymer coated release liner) (pump speed and die gap were selected to obtain a coating dry mass of 2.5 mg / cm ² ± 4%). . The resulting coating liner was heated to 140 ° F (60 ° C) for 2 minutes at 190 ° F.
Oven (88 ° C) for 2 minutes, 240 ° F (116 ° C) for 2 minutes,
The adhesive surface was then coated with a 9% EVA film (2 mil / 51 μm) (COTRAN ^™ 970).
2 control path EVA film).

The release liner was removed from the reservoir adhesive layer and the exposed adhesive surface was then laminated to the membrane surface of the skin contact adhesive layer. Patches were stamped from the resulting laminate. Each patch has 5 layers: support; 20% by weight of (R)-
(Z) -1-Azabicyclo [2.2.1] heptan-3-one, O- [3- (3
-Methoxyphenyl) -2-propynyl] oxime-containing reservoir adhesive layer; membrane; 20% by weight of (R)-(Z) -1-azabicyclo [2.2.1] heptan-3-one, O-. A skin contact adhesive layer containing [3- (3-methoxyphenyl) -2-propynyl] oxime; and a release liner. Skin penetration through human cadaver skin was measured using the test method described above. The skin permeation data is shown in Table 5 below.
Shown in. In Table 5, each value is the average of 15 independent measurements. The drug content stability data is shown in Table 6 below.

[0070]

[Table 5]

[0071]

[Table 6]

Example 40 A transdermal drug delivery device having two separate adhesive layers directly adhered was made as described below.

[0073]   The reservoir adhesive layer was created as follows. Dry adhesive (isooctyl acrylate)
Chill / acrylamide / vinyl acetate 75/5/20, 35.0 g), ethyl acetate
(135.0 g), methanol (15.1 g), and (R)-(Z) -1-a
Zabicyclo [2.2.1] heptan-3-one, O- [3- (3-methoxyphen
Nyl) -2-propynyl] oxime (15.0 g) is mixed to form a uniform coat.
Mix until a wing formulation was obtained. The formulation was applied to a release liner (SCOTCH
PAK^TM1022 Fluoropolymer Coated Release Liner 60 mil (1
Knife coating with a wet thickness of 524 μm). Resulting coat
The wing liner is dried at room temperature for 3 hours, then the support (SCOTCHPAK ^TM 1109 polyester film laminated material).

The skin contact layer was prepared as follows. The above polyisobutylene adhesive solution,
The release liner was knife coated with a wet thickness of 7 mils (178 μm). The coating liner was dried at room temperature. The "dry" adhesive layer was about 0.7 mils (17.8 μm) thick.

The release liner was removed from the reservoir adhesive layer and the exposed adhesive surface was then laminated to the adhesive surface of the skin contact adhesive layer. Patches were stamped from the resulting laminate. Each patch has four layers: support; isooctyl acrylate / acrylamide / vinyl acetate 75/5/20 adhesive to 30 wt% (R).
-(Z) -1-azabicyclo [2.2.1] heptan-3-one, O- [3- (
It consisted of a reservoir adhesive layer containing 3-methoxyphenyl) -2-propynyl] oxime; a skin contact layer consisting of polyisobutylene adhesive; and a release liner. The sample was left for at least about 12 hours to allow the drug to diffuse from the reservoir layer to the skin contact layer. Skin penetration through human cadaver skin was measured using the test method described above. The skin permeation data is shown in Table 8 below. In Table 8, each value is the average of 3 independent measurements.

Examples 41-58 Using the method of Example 40, (R)-(Z) -1-azabicyclo [2.2.1] heptan-3-one, O- [3- (in the reservoir layer. A set of transdermal drug delivery devices was made that differed in the concentration of 3-methoxyphenyl) -2-propynyl] oxime and the dry thickness of the skin contact layer. The composition is shown in Table 7 below. In each example, the reservoir layer adhesive was isooctyl acrylate / acrylamide / vinyl acetate 75/5/20. The reservoir layer was coated with a wet thickness of 60 mils (1524 μm). The skin contact layer was polyisobutylene (PIB). Skin penetration through human cadaver skin was measured using the test method described above. Skin permeation data is shown in Tables 8 and 10 below. Each value in Tables 8 and 10 is the average of three independent measurements.

[0077]

[Table 7]

[0078]

[Table 8]

Examples 59-61 Using the general method of Example 40, a set of transdermal drug delivery devices with different compositions of skin contact adhesive was made. The composition is shown in Table 9 below. A skin contact adhesive composition was prepared by mixing solvated isooctyl acrylate / acrylamide / vinyl acetate 75/5/20 with the above polyisobutylene adhesive solution. The coating formulation for the skin contact layer contains about 19% solids, 8 mils (203
μm) wet thickness. In each example, the reservoir layer adhesive was isooctyl acrylate / acrylamide / vinyl acetate 75/5/20 and the reservoir layer was 25% (R)-(Z) -1-azabicyclo [2. 2.
1] heptan-3-one, O- [3- (3-methoxyphenyl) -2-propynyl] oxime was included. The coating formulation for the reservoir layer contained 25% solids and was coated at a wet thickness of 60 mils (1524 μm). Skin penetration through human cadaver skin was measured using the test method described above. The skin permeation data is shown in Table 10 below. In Table 10, each value is the average of 3 independent measurements.

[0080]

[Table 9]

[0081]

[Table 10]

[0082] Example 62   The reservoir adhesive layer was created as follows. Dry adhesive (isooctyl acrylate)
Chill / acrylamide / vinyl acetate 75/5/20, 4200 g), ethyl acetate
(16200 g) Methanol (1800 g), and (R)-(Z) -1-aza
Bicyclo [2.2.1] heptan-3-one, O- [3- (3-methoxyphenyi
) -2-propynyl] oxime (1800 g) is mixed and a uniform coat
The coating formulation was prepared by mixing until the coating formulation was obtained.
. The formulation was left to stand until all air bubbles had disappeared. Apply the coating formulation to the release coating.
Inner (SCOTCHPAK^TM1022 fluoropolymer coating release liner
Die coated (13mg / cm)²± 4% coating dryness
The pump speed and die gap were chosen so that the volume was obtained). as a result
The resulting coating liner was heated at 140 ° F (60 ° C) for 2 minutes at 190 ° F.
Oven dried at (88 ° C) for 2 minutes, 240 ° F (116 ° C) for 2 minutes
. Attach the adhesive surface of the first part of the coating liner to the support (SCOTCHPAK ^TM 1109 polyester film laminated material) and remove the release liner
Affix the exposed adhesive surface to the adhesive surface of the second part of the coating release liner.
Got together The resulting coating dry weight of the reservoir adhesive layer was 2
6 mg / cm²It was ± 4%.

A skin contact adhesive layer was prepared as follows. Low molecular weight polyisobutylene (OP
PANOL B-10,900g), high molecular weight polyisobutylene (OPPANO
A coating formulation was prepared by combining LB-100, 300 g) and heptane (3006 g) and mixing until a uniform coating formulation was obtained. The formulation was left to stand until all air bubbles had disappeared. The coating formulation was die coated onto a release liner (one side silicone coated release liner) (pump speed and die gap were selected to obtain a coating dry weight of 1.53 mg / cm ² ± 4%). . The resulting coating liner was 185 ° F (85 ° C) for 2 minutes at 125 ° F (52 ° C).
Oven) for 2 minutes at 225 ° F (107 ° C) for 2 minutes.

The release liner was removed from the reservoir adhesive layer and the exposed adhesive surface was then laminated to the adhesive surface of the skin contact adhesive layer. The silicone release liner was replaced with a fluoropolymer release liner (SCOTCHPAK ^™ 1022 fluoropolymer coated release liner). Patches were stamped from the resulting laminate. Each patch has four layers: support; 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 adhesive (acrylate / acrylamide / vinyl acetate 75/5/20) reservoir adhesive layer; polyisobutylene skin contact adhesive layer; and release liner became.
Samples for at least about 12 to diffuse the drug from the reservoir layer to the skin contact layer.
Left for hours. Skin penetration through human cadaver skin was measured using the test method described above. The skin permeation data is shown in Table 11 below. Each value in Table 11 is 15
It is the average of two independent measurements. The drug content stability data is shown in Table 12 below.

[0085]

[Table 11]

[0086]

[Table 12]

Examples 63-75 Using the general method of Example 21, a set of transdermal drug delivery devices with different coating weights for the skin contact adhesive layer and the reservoir layer was made (see Table 13). thing). In each example, the same adhesive (isooctyl acrylate / acrylamide / vinyl acetate 75/5/20) was used for both layers and (R)-(Z) -1-azabicyclo [2.2.1] heptane. The concentration of -3-one, O- [3- (3-methoxyphenyl) -2-propynyl] oxime was 20%. In each example, the membrane was 2 mils (51 μm) thick and had an EVA percentage of 9%. Skin penetration through human cadaver skin was measured using the test method described above. The skin permeation data is shown in Table 14 below. In Table 14, each value is the average of 5 independent measurements.

[0088]

[Table 13]

[0089]

[Table 14]

Example 76 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 a solvent (ethyl acetate / methanol 90/10 v / v, 7
A coating formulation was prepared by combining 0 g) and then mixing until a uniform coating formulation was obtained. Apply the coating formulation to a release liner (Daubert 164P silicone coated release liner).
It was knife coated with a wet thickness of 5 mils (635 μm). The resulting coating liner was dried and laminated to a support (SCOTCHPAK ^™ 1109 polyester film laminate; available from 3M Company). The drug content stability data is shown in Table 15 below.

[0091]

[Table 15]

Example 77 Dry adhesive (isooctyl acrylate / vinyl acetate / polymethylmethacrylate macromonomer 55/38/7, 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 (ethyl acetate / methanol 90/10 v / v, 70 g) were combined, then A coating formulation was prepared by mixing until a uniform coating formulation was obtained. The coating formulation was knife coated onto a release liner (Daubert 164P silicone coated release liner) at a wet thickness of 25 mils (635 μm). The resulting coating liner is dried and the support (SCO
TCHPAK ^™ 1109 polyester film laminate; available from 3M Company). The drug content stability data is shown in Table 16 below.

[0093]

[Table 16]

The invention has been described with reference to several aspects of the invention. The foregoing detailed description and examples are provided only for clarity of understanding, and unnecessary limitations should not be understood from the detailed description and examples. It will be apparent to those skilled in the art that many modifications can be made to the described embodiments without departing from the spirit and scope of the invention. Therefore, the scope of the invention should not be limited to the precise details of the compositions and structures described herein, but rather by the words of the following claims.

─────────────────────────────────────────────────── ─── Continued Front Page (51) Int.Cl. ⁷ Identification Code FI Theme Coat (Reference) A61P 25/14 A61P 25/14 25/16 25/16 25/20 25/20 25/28 25/28 29 / 00 29/00 43/00 111 43/00 111 C07D 487/04 137 C07D 487/04 137 487/08 487/08 (81) Designated countries EP (AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE), OA (BF, BJ, CF, CG, CI, CM, GA, GN, GW, ML, MR, NE, SN, TD, TG), AP (GH, GM, KE, LS, MW, MZ, SD, SL, SZ, TZ, UG, ZW), EA (AM, AZ, BY, KG, KZ, MD, RU) , TJ, TM), AE, A , AL, AM, AT, AU, AZ, BA, BB, BG, BR, BY, BZ, CA, CH, CN, CR, CU, CZ, DE, DK, DM, DZ, EE, ES, FI, GB, GD, GE, GH, GM, HR, HU, ID, IL, IN, IS, JP, KE, KG, KP, KR, KZ, LC, LK, LR, LS, LT, LU, LV, MA , MD, MG, MK, MN, MW, MX, MZ, NO, NZ, PL, PT, RO, RU, SD, SE, SG, SI, SK, SL, TJ, TM, TR, TT, TZ, UA, UG, UZ, VN, YU, ZA, ZW F-term (reference) 4C050 AA03 BB04 CC04 EE01 FF01 GG04 HH01 4C076 AA74 AA94 BB31 CC01 EE07A EE10A EE13A EE26A EE27A EE48A EE56A EE57A EE58A FF31 4C086 AA01 AA02 CB03 MA02 MA03 MA05 MA07 MA32 MA63 NA12 ZA02 ZA05 ZA08 ZA15 ZA16 ZC02

Claims (33)

[Claims] 1. A transdermal delivery of the drug (R)-(Z) -1-azabicyclo [2.2.1] heptan-3-one, O- [3 (3-methoxyphenyl) -2-propynyl] oxime. And (b) a drug reservoir layer comprising a therapeutically effective amount of the drug and a first pressure sensitive adhesive, and (b) adhered to one side of the drug reservoir layer to provide the drug and A skin contacting layer comprising a second pressure sensitive adhesive. 2. The first pressure-sensitive adhesive has one or more types of A selected from the group consisting of (a) alkyl (meth) acrylate containing 4 to 10 carbon atoms in the alkyl group. One or more kinds of ethylenically unsaturated B containing a monomer and (b) a functional group selected from the group consisting of carboxylic acid, sulfonamide, urea, carbamate, carboxamide, hydroxy, amino, oxy, oxo, and cyano. The device of claim 1 comprising an acrylic copolymer including a copolymer of the monomers: 3. The apparatus of claim 2, wherein the one or more A monomers is selected from the group consisting of isooctyl acrylate, 2-ethylhexyl acrylate, butyl acrylate, and cyclohexyl acrylate. . 4. The one or more types of B monomers are acrylic acid,
The device of claim 2 selected from the group consisting of methacrylic acid, acrylamide, vinyl acetate, and methacrylamide. 5. The apparatus of claim 2, wherein the acrylic copolymer further comprises one or more types of substantially linear macromonomers copolymerizable with the A and B monomers. 6. The device of claim 1, wherein the second pressure sensitive adhesive comprises polysiloxane, acrylate, natural rubber, or synthetic rubber. 7. The device of claim 6, wherein the second pressure sensitive adhesive layer comprises polyisobutylene. 8. The device of claim 1, wherein the drug is present in the reservoir layer in an amount of about 5% to about 45% by weight, based on the total weight of the reservoir layer. 9. Transdermal delivery of the drug (R)-(Z) -1-azabicyclo [2.2.1] heptan-3-one, O- [3 (3-methoxyphenyl) -2-propynyl] oxime. And (b) a drug reservoir layer comprising a therapeutically effective amount of the drug and a first pressure sensitive adhesive, and (b) a rate controlling membrane adhered to one surface of the drug reservoir layer. And (c) a skin contact layer that is adhered to a surface of the membrane opposite the surface of the membrane that is in contact with the reservoir layer and that includes a second pressure sensitive adhesive. 10. The device of claim 9, wherein the first pressure sensitive adhesive and the second pressure sensitive adhesive independently comprise an acrylic copolymer. 11. The device of claim 9, wherein the skin contact layer also comprises a drug. 12. One or more types of A monomers independently selected from the group consisting of (a) alkyl (meth) acrylates containing 4 to 10 carbons in the alkyl group. And (b) one or more kinds of ethylenically unsaturated B monomers containing a functional group selected from the group consisting of carboxylic acid, sulfonamide, urea, carbamate, carboxamide, hydroxy, amino, oxy, oxo, and cyano. 11. The device of claim 10, comprising a copolymer consisting of: 13. The device of claim 12, wherein the one or more A monomers is selected from the group consisting of isooctyl acrylate, 2-ethylhexyl acrylate, butyl acrylate, and cyclohexyl acrylate. . 14. The apparatus of claim 12, wherein each of the one or more types of B monomers is independently selected from the group consisting of acrylic acid, methacrylic acid, acrylamide, vinyl acetate, and methacrylamide. . 15. The apparatus of claim 12, wherein at least one of the acrylic copolymers further comprises one or more types of substantially linear macromonomers copolymerizable with A and B monomers. 16. The rate control membrane comprises ethylene vinyl acetate copolymer,
The device according to claim 9. 17. The drug may be about 5 to 5 based on the total mass of the reservoir layer.
The device of claim 9, wherein the device is present in the reservoir layer in an amount of about 45% by weight. 18. A method of treating a disease characterized by decreased production or release of brain acetylcholine in a mammal, applying the device of claim 1 to said mammal and in a therapeutically effective amount. (R)-(Z) -1-azabicyclo [
2.2.1] Leave the device in contact with the skin for a time sufficient to deliver the heptan-3-one, O- [3 (3-methoxyphenyl) -2-propynyl] oxime to the mammal. A method comprising: 19. The method of claim 18, wherein the disease is Alzheimer's disease. 20. A method of treating a disease characterized by reduced production or release of brain acetylcholine in a mammal, applying the device of claim 9 to said mammal, and in a therapeutically effective amount. (R)-(Z) -1-azabicyclo [
2.2.1] Leave the device in contact with the skin for a time sufficient to deliver the heptan-3-one, O- [3 (3-methoxyphenyl) -2-propynyl] oxime to the mammal. A method comprising: 21. The method of claim 20, wherein the disease is Alzheimer's disease. 22. A method of treating a disorder characterized by decreased production or release of brain acetylcholine in a mammal, which comprises:
)-(Z) -1-Azabicyclo [2.2.1] heptan-3-one, O- [3 (
3-methoxyphenyl) -2-propynyl] oxime, from about 0.1 to about 50.0
Delivered to a mammal in an amount of mg / 20 cm ² patch / day, whereby (R)-(Z) -1-azabicyclo [2.2.1] heptan-3-one, O- [in said mammal. A method comprising bringing a serum concentration of 3 (3-methoxyphenyl) -2-propynyl] oxime to about 0.2 to about 100 ng / mL for a period of about 2 to about 14 days. 23. (R)-(Z) -1-azabicyclo [2.2.1] heptan-3-one, O- [3 (3-methoxyphenyl) -2-propynyl] oxime is 1.0. Delivered in an amount of ˜30.0 mg / 20 cm ² patch / day, in the mammal (R)-(Z) -1-azabicyclo [2.2.1] heptan-3-one, O- [3 (3 23. The method of claim 22, wherein the serum concentration of -methoxyphenyl) -2-propynyl] oxime is about 20 to about 60 ng / mL and the period is about 7 days. 24. A method of treating a disorder characterized by decreased production or release of brain acetylcholine in a mammal, which comprises:
)-(Z) -1-Azabicyclo [2.2.1] heptan-3-one, O- [3 (
3-methoxyphenyl) -2-propynyl] oxime, from about 0.1 to about 50.0
A method comprising delivering to a mammal an amount of mg / 20 cm ² patch / day, wherein the ratio of maximum flux to minimum flux is 1.0 to about 4.0 for a period of about 2 to about 14 days. 25. The ratio of the maximum flux to the minimum flux is 1.0 to about 2.0.
25. The method of claim 24, wherein 26. A method of treating a disorder characterized by decreased production or release of brain acetylcholine in a mammal, said method comprising:
)-(Z) -1-Azabicyclo [2.2.1] heptan-3-one, O- [3 (
3-methoxyphenyl) -2-propynyl] oxime, about 7.5 to about 50.0
A method comprising delivering to a mammal an amount of mg / 20 cm ² patch / day for a period of about 1 to about 14 days. 27. A method of treating a disease characterized by decreased production or release of brain acetylcholine in a mammal, which comprises a therapeutic amount of (R)-(Z) -1-azabicyclo by a transdermal drug delivery device. [2.2.1] heptan-3-one, O
-[3 (3-methoxyphenyl) -2-propynyl] oxime, from about 2 to about 14
A method comprising delivering to a mammal for a period of days. 28. A method of treating a disease in a mammal characterized by decreased production or release of brain acetylcholine, the method comprising:
)-(Z) -1-Azabicyclo [2.2.1] heptan-3-one, O- [3 (
3-methoxyphenyl) -2-propynyl] oxime is delivered to a mammal, whereby (R)-(Z) -1-azabicyclo [2.2.1] in said mammal.
] Heptan-3-one, O- [3 (3-methoxyphenyl) -2-propynyl]
The serum concentration of oxime was adjusted to about 0.2 to about 100 ng / m for a period of about 1 to about 14 days.
L. a method. 29. The method of claim 28, wherein the serum concentration is about 20 to about 60 ng / mL. 30. Transdermal delivery of the drug (R)-(Z) -1-azabicyclo [2.2.1] heptan-3-one, O- [3 (3-methoxyphenyl) -2-propynyl] oxime. A device for treating a drug comprising a pressure sensitive adhesive layer comprising a therapeutically effective amount of the drug, the amount of said drug being stored in the device at 25 ° C and 60% relative humidity for a period of at least 6 months. A device that exceeds about 95% by mass of the initial amount. 31. The device of claim 30, wherein the period of time is one year. 32. Transdermal delivery of the drug (R)-(Z) -1-azabicyclo [2.2.1] heptan-3-one, O- [3 (3-methoxyphenyl) -2-propynyl] oxime. An apparatus for storing a drug having a pressure-sensitive adhesive layer containing a therapeutically effective amount of the drug, and storing the drug at a temperature of 40 ° C. and 75% relative humidity for a period of 6 months. A device in which the amount exceeds about 90% by weight. 33. Transdermal delivery of the drug (R)-(Z) -1-azabicyclo [2.2.1] heptan-3-one, O- [3 (3-methoxyphenyl) -2-propynyl] oxime. A device for storing a pressure-sensitive adhesive layer containing a therapeutically effective amount of the drug, the amount of the drug being initially stored in the device when stored at 40 ° C. and 75% relative humidity for a period of 3 months. A device in which the amount exceeds about 95% by weight.