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WO2001030316A2 - Dispositifs d'administration transdermique de medicaments - Google Patents

Dispositifs d'administration transdermique de medicaments Download PDF

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Publication number
WO2001030316A2
WO2001030316A2 PCT/US2000/029702 US0029702W WO0130316A2 WO 2001030316 A2 WO2001030316 A2 WO 2001030316A2 US 0029702 W US0029702 W US 0029702W WO 0130316 A2 WO0130316 A2 WO 0130316A2
Authority
WO
WIPO (PCT)
Prior art keywords
drug
oxime
heptan
azabicyclo
methoxyphenyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/US2000/029702
Other languages
English (en)
Other versions
WO2001030316A3 (fr
Inventor
Steve J. Dreyer
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
3M Innovative Properties Co
Original Assignee
3M Innovative Properties Co
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority to IL14911500A priority Critical patent/IL149115A0/xx
Priority to AU17533/01A priority patent/AU1753301A/en
Priority to MXPA02004151A priority patent/MXPA02004151A/es
Priority to JP2001532736A priority patent/JP2003512414A/ja
Priority to CA002388611A priority patent/CA2388611A1/fr
Priority to KR1020027005442A priority patent/KR20020047298A/ko
Priority to NZ518436A priority patent/NZ518436A/xx
Priority to HU0203282A priority patent/HUP0203282A3/hu
Application filed by 3M Innovative Properties Co filed Critical 3M Innovative Properties Co
Priority to EP00980246A priority patent/EP1229905A2/fr
Publication of WO2001030316A2 publication Critical patent/WO2001030316A2/fr
Publication of WO2001030316A3 publication Critical patent/WO2001030316A3/fr
Priority to NO20022013A priority patent/NO20022013L/no
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
    • A61K9/7023—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms
    • A61K9/703—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms characterised by shape or structure; Details concerning release liner or backing; Refillable patches; User-activated patches
    • A61K9/7038—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer
    • A61K9/7046—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer the adhesive comprising macromolecular compounds
    • A61K9/7053—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer the adhesive comprising macromolecular compounds obtained by reactions only involving carbon to carbon unsaturated bonds, e.g. polyvinyl, polyisobutylene, polystyrene
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/439—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom the ring forming part of a bridged ring system, e.g. quinuclidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
    • A61K9/7023—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms
    • A61K9/703—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms characterised by shape or structure; Details concerning release liner or backing; Refillable patches; User-activated patches
    • A61K9/7038—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer
    • A61K9/7046—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer the adhesive comprising macromolecular compounds
    • A61K9/7053—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer the adhesive comprising macromolecular compounds obtained by reactions only involving carbon to carbon unsaturated bonds, e.g. polyvinyl, polyisobutylene, polystyrene
    • A61K9/7061—Polyacrylates

Definitions

  • the compound (R)-(Z)-l-azabicyclo[2.2.1]heptan-3-one, O-[3(3-methoxyphenyl)- 2-propynyl]oxime is a muscarinic agonist, which property provides it with a number of therapeutic qualities.
  • the compound is useful as an analgesic agent, as a sleep aid, and in the treatment of the symptoms of senile dementia, Alzheimer's disease, Huntington's chorea, tardive dyskinesia, hyperkinesia, mania or other conditions that are characterized by decreased cerebral acetylcholine production or release.
  • This compound, and other compounds of its class are described in detail in U.S. Patent No. 5,306,718 to
  • the invention provides drug in adhesive systems for the transdermal delivery of (R)-(Z)-l-azabicyclo[2.2.1]heptan-3-one, O-[3-(3-methoxyphenyl)-2-propynyl]oxime and transdermal drug delivery devices containing one or more of these systems. More particularly, the transdermal drug delivery devices of the invention control the rate of delivery of the drug to a subject's skin. In one aspect of the invention, the rate of delivery of the drug is controlled by a rate controlling adhesive layer that is positioned between the drug reservoir layer and the skin. In another aspect of the invention the rate of delivery of the drug is controlled by a rate controlling membrane that is positioned between the drug reservoir layer and the skin contacting adhesive layer.
  • the invention additionally provides a method of treating a condition characterized by decreased cerebral acetylcholme production or release in a subject comprising applying a transdermal drug device of the invention to the skin of a subject and allowing the device to remain in contact with the skin for a time sufficient to deliver a therapeutically effective amount of (R)-(Z)-l-azabicyclo[2.2.1]heptan-3-one, O-[3-(3-methoxyphenyl)-2- propynyljoxime to the subject.
  • the compound (R)-(Z)-l-azabicyclo[2.2.1]heptan-3-one, O-[3-(3-methoxyphenyl)- 2-propynyl]oxime (referred to herein as the "drug” or the “compound”) is a selective ml/m4 muscarinic agonist, useful in the treatment of a variety of conditions that are characterized by decreased cerebral acetylcholine production or release. Such conditions include senile dementia, Alzheimer's disease, Huntington's chorea, tardive dyskinesia, hyperkinesia, mania, and the like.
  • the compound is also useful as an analgesic and sleep aid.
  • the structure of the compound is as follows:
  • the compound exists in a number of isomeric forms, including stereoisomers and geometric isomers.
  • the compound can exist in two possible geometric forms known as E- oxime and Z-oxime.
  • the pharmacological activity resides in the Z-oxime. Therefore, the compositions of the invention contain a sufficient amount of the Z-oxime to provide the desired therapeutic effect.
  • the invention is inclusive of compositions that contain the drug in any of its therapeutically effective stereochemical forms or isomers.
  • the structure, chemistry, synthesis and isomeric properties of the drug are described in detail in U.S. Patent Nos. 5,306,718 (Lauffer et. al.); 5,346,911 (Augelli-Szafran et.
  • the compound can be used in the devices of the invention in its free base form or in the form of a pharmaceutically acceptable salt.
  • Pressure sensitive adhesives are used in the devices of the invention in a number of contexts.
  • the drug reservoir layer of the devices is comprised of a mixture of the drug in a pressure sensitive adhesive, and the device is adhered to the subject's skin by a layer of pressure sensitive adhesive.
  • an adhesive layer is used to control the rate of drug delivery as well as to adhere the device to the subject's skin.
  • the adhesive polymer(s) utilized in the devices of the invention should be substantially chemically inert to (R)-(Z)-l-azabicyclo[2.2.1]heptan-3-one, O-[3-(3- methoxyphenyl)-2-propynyl]oxime (e.g., it should not react with or degrade the compound, and preferably should not cause or accelerate conversion of the Z isomer to the E isomer), and is preferably a pressure sensitive skin adhesive.
  • the amount of drug is more than about 95%, preferably more than about 97%, by weight of the initial amount of drug in the device when stored at 25°C and 60% relative humidity for a period of time of 1 year.
  • Accelerated chemical stability may be measured by preparing devices of the invention, storing them under conditions of 40°C and 75% relative humidity, and testing the devices for concentration of (R)-(Z)-l-azabicyclo[2.2.1]heptan-3-one, O-[3-(3- methoxyphenyl)-2-propynyl]oxime at predetermined storage times.
  • suitable types of adhesives include acrylates, natural rubbers, synthetic rubbers such as polyisobutylenes, polysiloxanes, polyurethanes, and other pressure sensitive skin adhesives known in the art.
  • the adhesive polymers can be present alone or in combination.
  • Acrylate copolymers are preferred pressure sensitive adhesives for use in the devices of the invention.
  • Suitable acrylate copolymers for use in an adhesive layer preferably comprise about 45 to about 95 percent by weight, more preferably 55 to 95 percent by weight, based on the total weight of all monomers in the copolymer, of one or more A monomers selected from the group consisting of alkyl acrylates containing 4 to 10 carbon atoms in the alkyl group and alkyl methacrylates containing 4 to 10 carbon atoms in the alkyl group.
  • alkyl acrylates and methacrylates examples include n-butyl, n-pentyl, n-hexyl, isoheptyl, n-nonyl, n-decyl, isohexyl, 2-ethyloctyl, isooctyl and 2- ethylhexyl acrylates and methacrylates.
  • Preferred alkyl acrylates include isooctyl acrylate, 2-ethylhexyl acrylate, n-butyl acrylate, and cyclohexyl acrylate. Isooctyl acrylate is a particularly preferred A monomer.
  • Exemplary B monomers include acrylic acid, methacrylic acid, maleic acid, a hydroxyalkyl acrylate containing 2 to 4 carbon atoms in the hydroxyalkyl group, a hydroxyalkyl methacrylate containing 2 to 4 carbon atoms in the hydroxyalkyl group, acrylamide, methacrylamide, an alkyl substituted acrylamide containing 1 to 8 carbon atoms in the alkyl group, N-vinyl-N-methyl acetamide, N-vinyl valerolactam, N-vinyl caprolactam, N-vinyl-2-pyrrolidone, glycidyl methacrylate, vinyl 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
  • Suitable macromonomers include polymethylmethacrylate, styrene/acrylonitrile, polyether, and polystyrene macromonomers. Examples of useful macromonomers and their preparation are described in Krampe et al., U.S. Patent 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 and described for example in U.S. Pat. No. RE 24,906 (Ulrich), U.S. Pat. No. 4,732,808 (Krampe et. al.), and International Publication Number WO 96/08229 (Garbe et. al.), the disclosures of which are incorporated herein by reference.
  • the inherent viscosity of the copolymer is such as to ultimately provide a suitable pressure sensitive adhesive when used in a device of the invention.
  • the copolymer has an inherent 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.
  • the adhesive layer can contain components that modify the properties of the adhesive polymer, such as plasticizers, tackifiers, and the like of types and in amounts readily determinable to those of skill in the art.
  • One preferred transdermal drug delivery device of the invention uses two adhesive layers that are laminated directly to one another.
  • the first adhesive layer which does not contact the skin of the subject, comprises a polymer and drug and serves as a drug reservoir layer.
  • the second adhesive layer which does contact the skin of the subject, serves to control the rate of delivery of the drug to the subject and to adhere the device to the subject's skin.
  • the second adhesive layer comprises a polymer that is rate controlling.
  • This control of rate of delivery of the drug may be due to differences in the affinity of the drug for the two different adhesive layers and differences in the rate of diffusion of the drug through the two different adhesive layers. These differences in affinity and/or diffusion of the drug in the two adhesive layers, as well as the relative thickness of the adhesive layers, allows the rate of delivery of the drug to be controlled.
  • This system is referred to as the "adhesive rate controlled system”.
  • Another preferred copolymer is a copolymer of about 54 to about 77 wt-%, based on total monomer weight, of isooctyl acrylate, about 18 to about 39 wt-% vinyl acetate and about 2 to about 10 wt-% of polymethylmethacrylate macromonomer (PMMA), with a particularly preferred weight ratio of about 59/38/3 isooctyl acrylate/vinyl acetate/PMMA.
  • PMMA polymethylmethacrylate macromonomer
  • the reservoir layer of the device contains sufficient drug to deliver a therapeutically effective amount of the drug to a subject over the delivery period.
  • a therapeutically effective amount of the drug is that amount which is sufficient to alleviate the symptoms of the condition being treated.
  • the precise amount will vary with the exact nature of the condition to be treated, the status of the patient, and other factors known to those skilled in the art, but typically the dose to be administered is 0.07 to 700 mg/day, preferably about 0.1 to about 50 mg/day, and most preferably about 1 to about 30 mg/day.
  • the reservoir layer preferably contains about 5 to about 45 wt-% drug based on the total weight of the reservoir layer. More preferably the reservoir layer contains about 20 to about 35 wt-% drug.
  • Devices of the invention provide a therapeutically effective dose of the compound over an extended period of time, preferably from about 1 to about 14 days, more preferably about 1 day, and most preferably about 7 days.
  • Transdermal drug delivery devices of the invention may be prepared using methods of preparing multi-layered devices known in the art.
  • the adhesive layers may be coextruded onto a backing or release liner, the layers can be sequentially extruded or coated onto a backing or release liner, or the layers may be separately coated onto a backing or release liner, then the two adhesive layers can be laminated together.
  • Suitable release liners include conventional release liners comprising a known sheet material such as a polyester web, a polyethylene web, a polystyrene web, or a polyethylene-coated paper coated with a suitable fluoropolymer or silicone based coating.
  • the adhesive rate controlled systems of the invention are prepared by separately preparing reservoir layers and skin contacting layers.
  • the reservoir layer is generally prepared by combining the adhesive copolymer with the drug and appropriate organic solvent or solvents (such as, for example, methanol, ethanol, isopropanol, ethyl acetate, etc). The mixture is stirred until a homogeneous coating formulation is obtained.
  • the reservoir coating formulation is then applied to a release liner using conventional coating methods (e.g., knife coating or extrusion die coating) at a wet thickness of about
  • the coated release liner is allowed to dry and then is laminated onto a backing.
  • the skin contacting layer is generally prepared by combining the rate controlling adhesive(s) with an appropriate organic solvent (such as, for example, methanol, ethanol, isopropanol, ethyl acetate, heptane, hexane, etc.) and stirred until homogeneous.
  • This formulation is then applied to a release liner using conventional coating methods (e.g., knife coating or extrusion die coating).
  • Membrane rate controlled devices of the invention may be prepared by preparing a reservoir layer in the manner described above.
  • the reservoir layer formulation may be coated onto a release liner, dried and then laminated to a backing.
  • the wet thickness of the reservoir layer is about 880 ⁇ m to about 2200 ⁇ m.
  • a skin contacting adhesive coating formulation is prepared in the same manner as the reservoir coating formulation, using the same adhesive polymer or a different adhesive or combination of adhesives.
  • This formulation is then applied to a release liner using conventional coating methods (e.g., knife coating or extrusion die coating) to provide a dry thickness of about 5 ⁇ m to about 50 ⁇ m.
  • This coated liner is allowed to dry. It is then laminated onto a membrane.
  • the devices are assembled by removing the release liner from the reservoir layer and laminating the exposed adhesive surface of the reservoir layer onto the membrane surface of the skin contacting adhesive layer. Patches of the appropriate size may then be cut from the resulting laminate.
  • the release liner is removed from a 2.0 cm 2 patch and the patch is applied to the skin and pressed to cause uniform contact with the skin.
  • the resulting patch/skin laminate is placed patch side up across the orifice of the lower portion of the diffusion cell.
  • the diffusion cell is assembled and the lower portion is filled with 10 mL of warm (32°C) receptor fluid (0.1 M phosphate buffer, pH 6) so that the receptor fluid is in contact with the skin.
  • the receptor fluid is stirred using a magnetic stirrer.
  • the sampling port is covered except when in use.
  • the cell is then placed in a constant temperature (32 ⁇ 2°C) and humidity (50 ⁇ 10% relative humidity) chamber.
  • the receptor fluid is stirred by means of a magnetic stirrer throughout the experiment to assure a uniform sample and a reduced diffusion barrier on the dermal side of the skin.
  • the entire volume of receptor fluid is withdrawn at specified time intervals and immediately replaced with fresh fluid.
  • the withdrawn fluid is filtered through a 0.45 ⁇ m filter.
  • Transdermal drug delivery devices (20 cm 2 patches) were sealed in pouches (BAREXTM/aluminum/polyester or BAREXTM/aluminum/paper laminates) and stored under one or more of the following conditions of 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°C), 40°C temperature, and 50°C temperature.
  • the patches were tested for their drug content before storage and after preset storage times.
  • An internal standard solution was prepared by adding 1.0 g ethyl paraben to 1000 mL tetrahydrofuran (THF).
  • the liner was removed from ten 20 cm 2 patches and the patches were placed in a 1 quart (0.95 L) jar.
  • the backing and coating were extracted using 500 mL of the internal standard solution.
  • the sample was allowed to shake for at least 24 hours.
  • a dilution of the sample was then prepared by placing 5 mL of the resulting solution into a 4 ounce (118.3 mL) jar and adding 100 mL 50:50 (v:v) acetonitrile/water to the jar and shaking for about 60 minutes. An aliquot of the dilution was then placed in an autosampler vial for analysis.
  • the bottle was sealed and placed in a rotating water bath at 45°C for 24 hours to effect essentially complete polymerization.
  • the copolymer was diluted with ethyl acetate:methanol (250 g, 90:10 v:v) to 26.05% solids.
  • Copolymer Vinyl acetate (80.37 g), polymethylmethacrylate macromonomer (14.80 g of ELVACITETM 1010 available from ICI Acrylics),and ethyl acetate (370.80 g) were charged to a 1 quart (0.95 L) amber glass bottle and then mixed on a roller until a solution was obtained.
  • Isooctyl acrylate (116.32 g) and 2,2'-azobis(2-methylbutyronitrile) (0.3173 g) were added to the solution.
  • the bottle was purged for 2 minutes with nitrogen at a flow rate of 1 L per minute.
  • the bottle was sealed and placed in a rotating water bath at 57°C for 23 hours.
  • the resultant copolymer was 28.5% solids in ethyl acetate.
  • Dry adhesive was prepared by knife coating a solution of the acrylate adhesive copolymer onto a release liner.
  • the adhesive coated release liner was oven dried to remove the solvent and reduce the level of residual monomers.
  • the dried adhesive was then stripped from the release liner and stored in a container until used.
  • membranes used in the examples below are commercially available (e.g., COTRANTM 9702, COTRANTM 9717, COTRANTM 9726 and COTRANTM 9728 EVA controlled caliper membranes, all available from 3M Company). Others were prepared from commercially available resins using conventional extrusion methods (e.g., thermal extrusion onto a quenching roll). Examples of suitable resins include ELVAXTM ethylene-vinyl acetate (EVA) copolymers available from DuPont. In the examples that follow, the designation "X% EVA” means a membrane prepared from an ethylene-vinyl acetate copolymer which contains X weight % vinyl acetate.
  • Example 1 Transdermal drug delivery devices having two distinct adhesive layers separated by a membrane were prepared as described below.
  • a coating formulation was prepared by combining dry adhesive (8.84 g of isooctyl acrylate/acrylamide/vinyl acetate 75/5/20), (R)-(Z)-l-azabicyclo[2.2.1]heptan-3-one, O-
  • a reservoir adhesive layer was prepared as follows. The coating formulation was knife coated at a wet thickness of 60 mil (1524 ⁇ m) onto a release liner (Daubert 164P silicone coated release liner). The resulting coated liner was allowed to dry at ambient temperature for 5 hours and then it was laminated onto a backing (SCOTCHPAKTM 1109 polyester film laminate; available from 3M Company).
  • a skin contacting adhesive layer was prepared as follows. The coating formulation was knife coated at a wet thickness of 10 mil (254 ⁇ m) onto a release liner (Daubert 164P silicone coated release liner). The resulting coated liner was allowed to dry at ambient temperature for at least 1 hour and then the exposed adhesive surface was laminated onto a membrane (12% EVA film, 2 mil/51 ⁇ m).
  • the release liner was removed from the reservoir adhesive layer and then the exposed adhesive surface was laminated onto the membrane surface of the skin contacting adhesive layer. Patches were die cut from the resulting laminate. Each patch consisted of
  • a backing a reservoir 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; a membrane; a skin contacting 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.
  • Skin penetration through human cadaver skin was determined using the test method described above. The skin penetration data is shown in Table 2 below where each value is the average of 3 independent determinations.
  • Examples 2 -20 Using the method of Example 1, a set of transdermal drug delivery devices in which the concentration of (R)-(Z)-l-azabicyclo[2.2.1]heptan-3-one, O-[3-(3- methoxyphenyl)-2-propynyl]oxime in the adhesive layers, the coating weight of the reservoir adhesive layer, and the percent of EVA in the membrane were varied was prepared.
  • the compositions are shown in Table 1 below.
  • the adhesive used was isooctyl acrylate/acrylamide/vinyl acetate 75/5/20, the coating formulation contained 25% solids, the concentration of (R)-(Z)-l-azabicyclo[2.2.1]heptan-3-one, O-[3-
  • Example 21 A coating formulation was prepared by combining dry adhesive (13.7 g of isooctyl acrylate/acrylamide/vinyl acetate 75/5/20), (R)-(Z)-l-azabicyclo[2.2.1]heptan-3-one, O- [3-(3-methoxyphenyl)-2-propynyl]oxime (1.54 g) and solvent (45 g of ethyl acetate/methanol 90/10 v/v) and then mixing until a uniform coating formulation was obtained.
  • a reservoir adhesive layer was prepared as follows.
  • the coating formulation was knife coated at a wet thickness of 30 mil (762 ⁇ m) onto a release liner (SCOTCHPAKTM 9742 fluoropolymer coated release liner, available from 3M Company).
  • the resulting coated liner was allowed to dry at ambient temperature for 60 to 90 minutes and then the exposed adhesive surfaces of two portions of the coated liner were laminated to each other.
  • the release liner was removed from one surface and the exposed adhesive surface was laminated onto a backing (SCOTCHPAKTM 1 109 polyester film laminate).
  • a skin contacting adhesive layer was prepared as follows. The coating formulation was knife coated at a wet thickness of 7 mil (178 ⁇ m) onto a release liner
  • the release liner was removed from the reservoir adhesive layer and then the exposed adhesive surface was laminated onto the membrane surface of the skin contacting adhesive layer. Patches were die cut from the resulting laminate. Each patch consisted of 5 layers: a backing; a reservoir adhesive 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 contacting 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. Skin penetration through human cadaver skin was determined using the test method described above. The skin penetration data is shown in Table 4 below where each value is the average of 3 independent determinations. Examples 22 - 38
  • Example 21 Using the method of Example 21, a set of transdermal drug delivery devices in which the concentration of (R)-(Z)-l-azabicyclo[2.2.1]heptan-3-one, O-[3-(3- methoxyphenyl)-2-propynyl]oxime in the adhesive layers, the adhesive used, and the percent of EVA in the membrane were varied was prepared.
  • the compositions are shown in Table 3 below.
  • the same adhesive was used in both layers
  • the concentration of (R)-(Z)-l-azabicyclo[2.2.1]heptan-3-one, O-[3-(3-methoxyphenyl)-2- propynyl]oxime was the same in both adhesive layers, and the membrane was 2 mil (51 ⁇ m) thick.
  • Skin penetration through human cadaver skin was determined using the test method described above. The skin penetration data is shown in Table 4 below where each value is the average of 3 independent determinations.
  • VOAc vinyl acetate
  • PMMAMac polymethylmethacrylate macromonomer
  • Example 39 A coating formulation was prepared by combining dry adhesive (5200 g of isooctyl acrylate/acrylamide/vinyl acetate 75/5/20), ethyl acetate (17.56 Kg), methanol (1.96 Kg), and (R)-(Z)-l-azabicyclo[2.2.1]heptan-3-one, O-[3-(3-methoxyphenyl)-2-propynyl]oxime (1300 g) and mixing until a uniform coating formulation was obtained. The formulation was allowed to stand until all air bubbles had dissipated.
  • a reservoir adhesive layer was prepared as follows.
  • the coating formulation was die coated (The pump speed and die gap were selected to provide a dry coat weight of 13 mg/crrf ⁇ 4%.) onto a release liner (SCOTCHPAKTM 1022 fluoropolymer coated release liner).
  • the resulting coated liner was oven dried at 140°F (60°C) for 2 minutes, at 190°F
  • the adhesive surface of a first section of the coated liner was laminated onto a backing (SCOTCHPAKTM 1 109 polyester film laminate), the release liner was removed and the exposed adhesive surface was laminated to the adhesive surface of a second section of the coated release liner.
  • the resulting reservoir adhesive layer had a dry coat weight of 26 mg/cm 2 ⁇ 4%.
  • a skin contacting adhesive layer was prepared as follows.
  • the coating formulation was die coated (The pump speed and die gap were selected to provide a dry coat weight of 2.5 mg/cm 2 ⁇ 4%.) onto a release liner (SCOTCHPAKTM 1022 fluoropolymer coated release liner).
  • the resulting coated liner was oven dried at 140°F (60°C) for 2 minutes, at 190°F (88°C) for 2 minutes and at 240°F ( 1 16°C) for 2 minutes and then the adhesive surface was laminated to a 9% EVA (2 mil/51 ⁇ m) membrane (COTRANTM 9702 EVA controlled caliper membrane).
  • the release liner was removed from the reservoir adhesive layer and then the exposed adhesive surface was laminated to the membrane surface of the skin contacting adhesive layer. Patches were die cut from the resulting laminate. Each patch consisted of
  • a backing a reservoir adhesive 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 contacting 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.
  • Skin penetration through human cadaver skin was determined using the test method described above. The skin penetration data is shown in Table 5 below where each value is the average of 15 independent determinations. Drug content stability data is shown in Table 6 below.
  • Transdermal drug delivery devices having two distinct adhesive layers directly adhered together were prepared as described below.
  • a reservoir adhesive layer was prepared as follows. Dry adhesive (35.0 g of isooctyl acrylate/acrylamide/vinyl acetate 75/5/20), ethyl acetate (135.0 g), methanol (15.1 g), and (R)-(Z)-l-azabicyclo[2.2.1]heptan-3-one, O-[3-(3-methoxyphenyl)-2- propynyl]oxime (15.0 g) were combined and mixed until a uniform coating formulation was obtained. The formulation was knife coated at a wet thickness of 60 mil (1524 ⁇ m) onto a release liner (SCOTCHPAKTM 1022 fluoropolymer coated release liner). The resulting coated liner was allowed to dry at ambient temperature for 3 hours and then it was laminated onto a backing (SCOTCHPAKTM 1109 polyester film laminate).
  • a skin contacting layer was prepared as follows.
  • the polyisobutylene adhesive solution described above was knife coated at a wet thickness of 7 mil (178 ⁇ m) onto a release liner.
  • the coated liner was allowed to dry at ambient temperature.
  • the "dry" adhesive layer was approximately 0.7 mil (17.8 ⁇ m) thick.
  • the release liner was removed from the reservoir adhesive layer and then the exposed adhesive surface was laminated onto the adhesive surface of the skin contacting adhesive layer. Patches were die cut from the resulting laminate. Each patch consisted of 4 layers: a backing; a reservoir adhesive layer containing 30% by weight of (R)-(Z)-1- azabicyclo[2.2.1]heptan-3-one, O-[3-(3-methoxyphenyl)-2-propynyl]oxime in isooctyl acrylate/acrylamide/vinyl acetate 75/5/20 adhesive; a skin contacting layer of polyisobutylene adhesive; and a release liner.
  • Example 40 Using the method of Example 40, a set of transdermal drug delivery devices in which the concentration of (R)-(Z)-l-azabicyclo[2.2.1]heptan-3-one, O-[3-(3- methoxyphenyl)-2-propynyl]oxime in the reservoir layer and the dry thickness of the skin contacting layer were varied was prepared.
  • the compositions are shown in Table 7 below.
  • the reservoir layer adhesive was isooctyl acrylate/acrylamide/vinyl acetate 75/5/20.
  • the reservoir layer was coated at a wet thickness of 60 mil (1524 ⁇ m).
  • the skin contacting layer was polyisobutylene (PIB). Skin penetration through human cadaver skin was determined using the test method described above. The skin penetration data is shown in Tables 8 and 10 below where each value is the average of 3 independent determinations.
  • Example 40 Using the general method of Example 40, a set of transdermal drug delivery devices was prepared in which the composition of the skin contacting adhesive was varied.
  • the compositions are shown in Table 9 below.
  • the skin contacting adhesive composition was prepared by mixing solvated isooctyl acrylate/acrylamide/vinyl acetate 75/5/20 with the polyisobutylene adhesive solution described above.
  • the coating formulation for the skin contacting layer contained about 19% solids and was coated at a wet thickness of 8 mil (203 ⁇ m).
  • the reservoir layer adhesive was isooctyl acrylate/acrylamide/vinyl acetate 75/5/20 and the reservoir layer contained 25% (R)-(Z)-1- azabicyclo[2.2.1]heptan-3-one, O-[3-(3-methoxyphenyl)-2-propynyl]oxime.
  • the coating formulation for the reservoir layer contained 25% solids and was coated at a wet thickness of 60 mil (1524 ⁇ m). Skin penetration through human cadaver skin was determined using the test method described above. The skin penetration data is shown in Table 10 below where each value is the average of 3 independent determinations.
  • IOA isooctyl acrylate
  • ACM acrylamide
  • VOAc vinyl acetate
  • PIB polyisobutylene
  • Example 62 A reservoir adhesive layer was prepared as follows.
  • a coating formulation was prepared by combining dry adhesive (4200 g of isooctyl acrylate/acrylamide/vinyl acetate 75/5/20), ethyl acetate (16200 g), methanol (1800 g), and (R)-(Z)-1- azabicyclo[2.2.1]heptan-3-one, O-[3-(3-methoxyphenyl)-2-propynyl]oxime (1800 g) and mixing until a uniform coating formulation was obtained. The formulation was allowed to stand until all air bubbles had dissipated.
  • the coating formulation was die coated (The pump speed and die gap were selected to provide a dry coat weight of 13 mg/cm 2 ⁇ 4%.) onto a release liner (SCOTCHPAKTM 1022 fluoropolymer coated release liner).
  • the resulting coated liner was oven dried at 140°F (60°C) for 2 minutes, at 190°F (88°C) for 2 minutes and at 240°F (116°C) for 2 minutes.
  • the adhesive surface of a first section of the coated liner was laminated onto a backing (SCOTCHPAKTM 1 109 polyester film laminate), the release liner was removed and the exposed adhesive surface was laminated to the adhesive surface of a second section of the coated release liner.
  • the resulting reservoir adhesive layer had a dry coat weight of 26 mg/cm 2 ⁇ 4%.
  • a skin contacting adhesive layer was prepared as follows.
  • a coating formulation was prepared by combining low molecular weight polyisobutylene (900 g of OPPANOL B-10), high molecular weight polyisobutylene (300 g of OPPANOL B-100) and heptane (3006 g) and mixing until a uniform coating formulation was obtained. The formulation was allowed to stand until all air bubbles had dissipated. The coating formulation was die coated (The pump speed and die gap were selected to provide a dry coat weight of 1.53 mg/cm ⁇ 4%.) onto a release liner (one side silicone coated release liner).
  • the resulting coated liner was oven dried at 125°F (52°C) for 2 minutes, at 185°F (85°C) for 2 minutes and at 225°F (107°C) for 2 minutes.
  • the release liner was removed from the reservoir adhesive layer and then the exposed adhesive surface was laminated to the adhesive surface of the skin contacting adhesive layer.
  • the silicone release liner was replaced with a fluoropolymer release liner (SCOTCHPAKTM 1022 fluoropolymer coated release liner). Patches were die cut from the resulting laminate.
  • Each patch consisted of 4 layers: a backing; a reservoir adhesive 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 adhesive (acrylate/acrylamide/vinyl acetate 75/5/20) ; a skin contacting polyisobutylene adhesive layer; and a release liner. Samples were allowed to sit for at least about 12 hours to allow drug to diffuse from the reservoir layer into the skin contacting layer. Skin penetration through human cadaver skin was determined using the test method described above. The skin penetration data is shown in Table 11 below where each value is the average of 15 independent determinations. Drug content stability data is shown in Table 12 below.
  • Examples 63-75 Using the general method of Example 21, a set of transdermal drug delivery devices was prepared in which the coating weight of the skin contacting adhesive and the reservoir layer was varied (see table 13).
  • the same adhesive isooctyl acrylate/acrylamide/vinyl acetate 75/5/20
  • the concentration of (R)-(Z)-l-azabicyclo[2.2.1]heptan-3-one, O-[3-(3-methoxyphenyl)-2-propynyl]oxime was 20%.
  • the membrane was 2 mil (51 ⁇ m) thick and the EVA percentage was 9%.
  • Skin penetration through human cadaver skin was determined using the test method described above. The skin penetration data is shown in Table 14 below where each value is the average of 5 independent determinations.
  • Example 76 A coating formulation was prepared by combining dry adhesive (18.0 g of isooctyl acrylate/acrylamide/vinyl acetate 75/5/20), (R)-(Z)-l-azabicyclo[2.2.1]heptan-3-one, O- [3-(3-methoxyphenyl)-2-propynyl]oxime (2.0 g) and solvent (70 g of ethyl acetate/methanol 90/10 v/v) and then mixing until a uniform coating formulation was obtained.
  • the coating formulation was knife coated at a wet thickness of 25 mil (635 ⁇ m) onto a release liner (Daubert 164P silicone coated release liner). The resulting coated liner was dried and laminated onto a backing (SCOTCHPAKTM 1 109 polyester film laminate; available from 3M Company). Drug content stability data is shown in Table 15 below.
  • Example 77 A coating formulation was prepared by combining dry adhesive (18.0 g of isooctyl acrylate/vinyl acetate/polymethylmethacrylate macromonomer 55/38/7), (R)-(Z)-1- azabicyclo[2.2.1]heptan-3-one, O-[3-(3-methoxyphenyl)-2-propynyl]oxime (2.0 g) and solvent (70 g of ethyl acetate/methanol 90/10 v/v) and then mixing until a uniform coating formulation was obtained.
  • the coating formulation was knife coated at a wet thickness of 25 mil (635 ⁇ m) onto a release liner (Daubert 164P silicone coated release liner). The resulting coated liner was dried and laminated onto a backing (SCOTCHPAKTM 1109 polyester film laminate; available from 3M Company). Drug content stability data is shown in Table 16 below.

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  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Dermatology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Medicinal Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)

Abstract

L'invention concerne des systèmes et des dispositifs destinés à l'administration transdermique du composé (R)-(Z)-1-azabicyclo[2.2.1]heptane-3-one, O-[3(3-méthoxyphényl)-2-propynyl]oxime. Ces dispositifs comprennent un médicament contenu dans une couche réservoir adhésive, ainsi qu'une couche adhésive de contact avec la peau, ladite couche adhésive de contact avec la peau tenant lieu de membrane de régulation de débit. Ces dispositifs comprennent également une couche réservoir adhésive et une couche adhésive de contact avec la peau, une membrane étant placée entre ces deux couches adhésives. Le composé est un agoniste muscarinique utilisé dans le traitement d'une pluralité de troubles cognitifs, et notamment de la maladie d'Alzheimer.
PCT/US2000/029702 1999-10-28 2000-10-27 Dispositifs d'administration transdermique de medicaments Ceased WO2001030316A2 (fr)

Priority Applications (10)

Application Number Priority Date Filing Date Title
NZ518436A NZ518436A (en) 1999-10-28 2000-10-27 Transdermal drug delivery devices
MXPA02004151A MXPA02004151A (es) 1999-10-28 2000-10-27 Dispositivos de suministro de medicamento transdermico.
JP2001532736A JP2003512414A (ja) 1999-10-28 2000-10-27 経皮薬物送達装置
CA002388611A CA2388611A1 (fr) 1999-10-28 2000-10-27 Dispositifs d'administration transdermique de medicaments
KR1020027005442A KR20020047298A (ko) 1999-10-28 2000-10-27 경피 약품 전달 장치
IL14911500A IL149115A0 (en) 1999-10-28 2000-10-27 Transdermal drug delivery devices
AU17533/01A AU1753301A (en) 1999-10-28 2000-10-27 Transdermal drug delivery devices
HU0203282A HUP0203282A3 (en) 1999-10-28 2000-10-27 Transdermal drug delivery devices comprising (r)-(z)-i-azabicyclo(2.2.1)heptan-3-one,0-(3(3-methoxyphenyl)-2-propynyl)oxime
EP00980246A EP1229905A2 (fr) 1999-10-28 2000-10-27 Dispositifs d'administration transdermique contenant du (r)-(z)-1- azabicyclo [2.2.1] heptane-3-one, o-[3(3-methoxyphenyl)-2-propynyl oxime
NO20022013A NO20022013L (no) 1999-10-28 2002-04-26 Innretninger for transdermal legemiddellevering

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US16236899P 1999-10-28 1999-10-28
US60/162,368 1999-10-28
US09/697,532 2000-10-26

Publications (2)

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WO2001030316A2 true WO2001030316A2 (fr) 2001-05-03
WO2001030316A3 WO2001030316A3 (fr) 2001-09-20

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012012417A1 (fr) * 2010-07-21 2012-01-26 3M Innovative Properties Company Compositions adhésives transdermiques, dispositifs et procédés
US9017301B2 (en) 2007-09-04 2015-04-28 Mylan Technologies, Inc. Transdermal drug delivery systems comprising a coated release liner
US9198877B2 (en) 2004-03-09 2015-12-01 Mylan Pharmaceuticals, Inc. Transdermal systems containing multilayer adhesive matrices to modify drug delivery
EP2897598A4 (fr) * 2012-09-21 2016-04-27 Mylan Inc Dispositif d'administration de médicament transdermique
US9492401B2 (en) 2004-03-09 2016-11-15 Mylan Technologies, Inc. Transdermal systems containing multilayer adhesive matrices to modify drug delivery

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5346911A (en) * 1990-03-06 1994-09-13 Warner-Lambert Company Azabicyclo and azacyclo oxime and amine cholinergic agents and methods of treatment
US5514812A (en) * 1994-06-10 1996-05-07 Warner-Lambert Company Preparation of stereochemically pure oximes with muscarinic activity
PE17897A1 (es) * 1995-02-17 1997-06-12 Lilly Co Eli Formulacion transdermica en parche del 3-(4-butiltio)-1,2,5-tiadiazol-3-il)-1-azabiciclo (2,2,2) octano

Cited By (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9492401B2 (en) 2004-03-09 2016-11-15 Mylan Technologies, Inc. Transdermal systems containing multilayer adhesive matrices to modify drug delivery
EP1737406B2 (fr) † 2004-03-09 2019-04-17 Mylan Technologies, Inc. Systemes transdermiques contenant des matrices adhesives multicouche pour la modification d'administration de medicaments
US9198877B2 (en) 2004-03-09 2015-12-01 Mylan Pharmaceuticals, Inc. Transdermal systems containing multilayer adhesive matrices to modify drug delivery
US9205062B2 (en) 2004-03-09 2015-12-08 Mylan Pharmaceuticals, Inc. Transdermal systems containing multilayer adhesive matrices to modify drug delivery
US9017301B2 (en) 2007-09-04 2015-04-28 Mylan Technologies, Inc. Transdermal drug delivery systems comprising a coated release liner
US10034840B2 (en) 2010-07-21 2018-07-31 3M Innovative Properties Company Transdermal adhesive compositions, devices and methods
US9375510B2 (en) 2010-07-21 2016-06-28 3M Innovative Properties Company Transdermal adhesive compositions, devices and methods
CN103068944B (zh) * 2010-07-21 2016-03-09 3M创新有限公司 透皮粘合剂组合物、装置及方法
WO2012012417A1 (fr) * 2010-07-21 2012-01-26 3M Innovative Properties Company Compositions adhésives transdermiques, dispositifs et procédés
CN103068944A (zh) * 2010-07-21 2013-04-24 3M创新有限公司 透皮粘合剂组合物、装置及方法
EP3517105A1 (fr) * 2010-07-21 2019-07-31 3M Innovative Properties Co. Compositions adhésives transdermiques, dispositifs et procédés
US10376473B2 (en) 2010-07-21 2019-08-13 3M Innovative Properties Company Transdermal adhesive compositions, devices, and methods
EP2897598A4 (fr) * 2012-09-21 2016-04-27 Mylan Inc Dispositif d'administration de médicament transdermique

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AU1753301A (en) 2001-05-08

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