Transdermal delivery system having a microporous membrane with solvent-filled pores - Patent Application 20070233337

Abstract

To provide a transdermal delivery system that can stably and effectively release donepezil over a long period of time (e.g., 1 to 10 days or more) and has adhesive strength suitable for long-term administration.SOLUTION: A transdermal delivery system comprises: a skin contact adhesive layer for attaching the transdermal delivery system to the skin of a user; a drug reservoir layer comprising an adhesive polymer, a salt form of donepezil hydrochloride, sodium bicarbonate, ascorbic acid palmitate, and a drug carrier composition; and a microporous membrane disposed between the skin contact adhesive layer and the drug reservoir layer, the microporous membrane comprising a plurality of pores filled with a membrane treatment composition different from the drug carrier composition, the skin contact adhesive layer comprising an acrylic acid / vinyl acetate copolymer adhesive, a nonionic surfactant, a long-chain aliphatic alcohol, and a citric acid ester, the drug carrier composition comprising a nonionic surfactant, a long-chain aliphatic alcohol, a citric acid ester, and a hydrophilic solvent.SELECTED DRAWING: Figure 1A

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. Provisional Application No. 62 / 537,414, filed July 26, 2017, and is incorporated herein by reference.

[0002] FIELD OF THE DISCLOSURE

[0002] The subject matter described herein relates to a transdermal delivery system for delivering an active agent, the system comprising a microporous membrane having pores that contain a membrane treating composition. [Background technology]

[0003]

[0003] Transdermal drug delivery systems can be an effective means for administering active pharmaceutical agents that may have disadvantages when administered via other routes, such as oral or parenteral. However, it is difficult to deliver many drugs over extended periods of time (e.g., more than a few days). Transdermal delivery of basic (i.e., alkaline) drugs can be particularly difficult due to poor skin permeability. In addition, some active agents have poor or low solubility in the adhesives and / or other components used in typical transdermal formulations. Furthermore, there is a need for stable, long-term administration of active agents (e.g., 1-10 days or more) that provides a stable and effective release of the drug over the administration period and has adhesive strength suitable for long-term administration.

[0004]

[0004] Active agents for transdermal delivery are typically provided in their neutral form, because the neutral form is typically much more skin permeable than the corresponding salt form. In conventional transdermal formulations, the neutral form of the active agent is solubilized in an adhesive matrix, and the active agent diffuses through the adhesive matrix into the skin. Thus, transdermal patches typically contain as much of the active agent dissolved in the adhesive matrix as the solubility of the drug in the adhesive matrix allows, and often use a solubilizer to increase its solubility. Alternatively, neutral solid particles of the active agent may be dispersed in the adhesive matrix, as long as the dissolution rate of the particles is such that a constant supply of dissolved active agent is provided.

[0005] However, for many active agents, the neutral form is more difficult to solubilize and / or formulate into a composition, system, or pharmaceutical for administration to a patient or subject. When a drug has low solubility in an adhesive matrix, such as in a non-ionized neutral form, it is difficult to incorporate a sufficient amount of the drug in a solubilized form into the adhesive to deliver therapeutic levels for several days. A further problem is that the dissolved active agent may crystallize within the adhesive matrix during the process of preparing the pharmaceutical, such as solvation, coating, and drying. Furthermore, many active agents are less stable in the neutral form than in the salt form. Thus, there is a need for compositions, systems, and pharmaceuticals having an adhesive matrix as a component layer that can consistently and effectively deliver therapeutic amounts of the active agent over an extended period of time.

[0006]

[0006] The foregoing examples of the related art and limitations associated therewith are intended to be illustrative and not exhaustive. Other limitations of the related art will become apparent to those of ordinary skill in the art upon reading this specification and studying the drawings. Summary of the Invention

[0007]

[0007] The following aspects and embodiments thereof described and illustrated below are meant to be exemplary and illustrative, not limiting in scope.

[0008]

[0008] In a first aspect, there is provided a transdermal delivery system comprising a skin contact adhesive layer for attaching the system to a user's skin, a drug reservoir layer comprising an active agent and a drug carrier composition, and a microporous membrane disposed between the adhesive layer and the drug reservoir layer, the microporous membrane comprising a plurality of pores and a membrane treating composition, the membrane treating composition occupying at least a portion of the pores.

[0009] In some embodiments, the microporous membrane and / or the pores of the microporous membrane are saturated with the membrane treatment composition. In other embodiments, the membrane treatment composition is sequestered in or within the pores of the microporous membrane. In other embodiments, the membrane treatment composition fills the pores of the microporous membrane. In one embodiment, the microporous membrane is a flat sheet microporous membrane.

[0010]

[0010] In one embodiment, the drug carrier composition and the membrane treatment composition are the same. In another embodiment, the drug carrier composition and the membrane treatment composition are different. In one embodiment, the drug carrier composition and the membrane treatment composition are different. In one embodiment, the membrane treatment composition and the contact adhesive layer drug carrier composition are the same, and both are different from the drug carrier composition disposed in the drug reservoir layer. In one embodiment, the drug carrier composition is different from the membrane treatment composition and the contact adhesive layer drug carrier composition due to the presence of a hydrophilic solvent.

[0011] In some embodiments, the membrane treatment composition comprises a non-ionic surfactant, a long chain aliphatic alcohol, a citrate ester, and / or combinations thereof.

[0012] In certain embodiments, the active agent is a water-insoluble base and the drug carrier composition comprises a non-ionic surfactant, a long chain aliphatic alcohol, a citrate ester, and / or combinations thereof.

[0013]

[0013] In one embodiment, the microporous membrane is microporous polypropylene.

[0014] In one embodiment, the microporous membrane has pores with an average pore size of about 0.001 μm to about 100 μm.

[0015] In one embodiment, the pore size is from about 0.010 μm to about 0.100 μm.

[0016] In one embodiment, the pore size is from about 0.040 μm to about 0.050 μm.

[0017] In one embodiment, the microporous membrane has a porosity of about 30% to about 50%.

[0018]

[0018] In one embodiment, the drug reservoir layer further comprises glycerin.

[0019] In one embodiment, glycerin is present in an amount of about 5% to about 15% by weight.

[0020]

[0020] In some embodiments, the membrane treatment composition does not include glycerin.

[0021]

[0021] In one embodiment, the drug reservoir layer further comprises cross-linked polyvinylpyrrolidone.

[0022] In one embodiment, the crosslinked polyvinylpyrrolidone is present in an amount of about 10% to about 20% by weight.

[0023]

[0023] In certain embodiments, the active agent administered to the subject is generated in situ in the drug reservoir by reaction of a pharma- ceutically acceptable salt of the active agent with an amphoteric base compound.

[0024] In one embodiment, the amphoteric inorganic compound in the drug reservoir layer is present in an amount of about 2% to about 5% by weight of the drug reservoir layer.

[0025] In one embodiment, the amphoteric inorganic compound in the drug reservoir layer is an alkali salt.

[0026] In one embodiment, the alkaline salt is sodium bicarbonate.

[0027]

[0027] In one embodiment, the active agent administered to the subject is donepezil base.

[0028]

[0028] In one embodiment, the pharma ceutically acceptable salt is donepezil hydrochloride.

[0029]

[0029] In one embodiment, donepezil hydrochloride is present in the drug reservoir layer in an amount of about 5% to about 25% by weight of the drug reservoir layer.

[0030]

[0030] In one embodiment, the drug reservoir layer comprises about 5% to about 15% triethyl citrate by weight.

[0031]

[0031] In one embodiment, the drug reservoir layer comprises about 0.5% to about 5% by weight of sorbitan monolaurate.

[0032]

[0032] In one embodiment, the drug reservoir layer comprises about 0.5% to about 5% lauryl lactate.

[0033]

[0033] In one embodiment, the drug reservoir layer comprises from about 0.1% to about 2% by weight of ascorbyl palmitate.

[0034] In one embodiment, the drug reservoir layer comprises about 35% to about 50% by weight of a copolymer of acrylic acid and vinyl acetate.

[0035]

[0035] In one embodiment, the drug carrier composition comprises triethyl citrate, lauryl lactate, sorbitan monolaurate, or a combination thereof.

[0036]

[0036] In one embodiment, the drug carrier composition comprises about 60% to about 75% by weight triethyl citrate.

[0037]

[0037] In one embodiment, the drug carrier composition comprises about 10% to about 17% by weight of sorbitan monolaurate.

[0038]

[0038] In one embodiment, the drug carrier composition comprises about 15% to about 25% by weight lauryl lactate.

[0039]

[0039] In one embodiment, the drug carrier composition comprises about 66.7% by weight triethyl citrate, about 20.0% by weight lauryl lactate, and about 13.3% by weight sorbitan monolaurate.

[0040]

[0040] In one embodiment, the drug reservoir layer comprises about 10% to about 20% by weight of the drug carrier composition.

[0041] In one embodiment, the drug reservoir layer comprises about 16.0% by weight donepezil hydrochloride, about 2.6% by weight sodium bicarbonate, about 10.0% by weight triethyl citrate, about 3.0% by weight lauryl lactate, about 2.0% by weight Sorbitan Monolaurate %, about 10.0% by weight glycerin, about 15.0% by weight crosslinked polyvinylpyrrolidone, about 0.5% by weight ascorbyl palmitate, and about 40.9% by weight of a copolymer of acrylic acid and vinyl acetate.

[0042] In some embodiments, the membrane treatment composition includes triethyl citrate, lauryl lactate, sorbitan monolaurate, and / or combinations thereof.

[0043] In one embodiment, the membrane treatment composition comprises about 60% to about 75% by weight of triethyl citrate.

[0044] In one embodiment, the membrane treatment composition comprises about 10% to about 17% by weight of sorbitan monolaurate.

[0045] In one embodiment, the membrane treatment composition comprises about 15% to about 25% by weight lauryl lactate.

[0046]

[0046] In one embodiment, the membrane treatment composition comprises about 66.7% by weight triethyl citrate, about 20.0% by weight lauryl lactate, and about 13.3% by weight sorbitan monolaurate.

[0047] In one embodiment, the system is configured to provide a dose of about 5 mg to about 10 mg of donepezil base per day.

[0048]

[0048] In one embodiment, the skin contact adhesive layer comprises a contact adhesive layer drug carrier composition.

[0049] In some embodiments, the contact adhesive layer drug carrier composition comprises triethyl citrate, lauryl lactate, sorbitan monolaurate, and / or combinations thereof. In one embodiment, the contact adhesive layer drug carrier composition comprises about 66.7% by weight triethyl citrate, about 20.0% by weight lauryl lactate, and about 13.3% by weight sorbitan monolaurate.

[0050] In one embodiment, the contact adhesive layer drug carrier composition is present in the contact adhesive layer in an amount of about 10% to about 20% by weight.

[0051]

[0051] In certain embodiments, the active agent is memantine base.

[0052] In one embodiment, the pharma ceutically acceptable salt is memantine hydrochloride.

[0053]

[0053] In one embodiment, memantine hydrochloride is present in the drug reservoir layer in an amount of about 15% to about 35% by weight.

[0054]

[0054] In one embodiment, the drug carrier composition comprises octyldodecanol.

[0055] In some embodiments, octyldodecanol is present in an amount of about 5% to about 15% by weight.

[0056] In one embodiment, the drug reservoir layer comprises about 25% to about 40% by weight of a copolymer of acrylic acid and vinyl acetate.

[0057] In one embodiment, the skin contact adhesive layer comprises hydrophilic fumed silica in an amount of about 5% to about 10% by weight.

[0058]

[0058] In one embodiment, the membrane treatment composition comprises octyldodecanol.

[0059] In one embodiment, the system is configured to provide a dose of memantine base of about 1 mg to about 30 mg per day.

[0060]

[0060] In one embodiment, the drug reservoir layer comprises about 25% by weight memantine hydrochloride, about 9.73% by weight sodium bicarbonate, about 7.0% by weight octyldodecanol, about 10.0% by weight glycerin, about 15.0% by weight crosslinked polyvinylpyrrolidone, and about 33.27% by weight of a copolymer of acrylic acid and vinyl acetate.

[0061] In one embodiment, the skin contact adhesive layer comprises about 5% to about 15% by weight octyldodecanol.

[0062] In one embodiment, the contact adhesive layer comprises about 10% by weight octyldodecanol.

[0063]

[0063] In one embodiment, the active agent is fingolimod.

[0064]

[0064] In one embodiment, the pharma ceutically acceptable salt is fingolimod hydrochloride.

[0065] In one embodiment, the skin contact adhesive layer comprises a copolymer of acrylic acid and vinyl acetate.

[0066] In some embodiments, the copolymer of acrylic acid and vinyl acetate is present in an amount of about 60% to about 75% by weight.

[0067] In one embodiment, the skin contact adhesive layer comprises polyisobutylene.

[0068] In one embodiment, the polyisobutylene is present in an amount of about 65% to about 90% by weight.

[0069] In one embodiment, the skin contact adhesive layer further comprises crosslinked polyvinylpyrrolidone.

[0070] In one embodiment, the crosslinked polyvinylpyrrolidone is present in an amount of about 15% to about 25% by weight.

[0071]

[0071] In some embodiments, the transdermal delivery systems described herein may further include a first backing layer in contact with the drug reservoir layer, an adhesive overlay in contact with the first backing layer on the side opposite the drug reservoir layer, and a second backing layer in contact with the adhesive overlay on the side opposite the first backing layer.

[0072] In one embodiment, the first backing layer comprises a polyester laminate.

[0073] In some embodiments, the adhesive overlay comprises polyisobutylene, polybutene, crosslinked polyvinylpyrrolidone, an acrylic adhesive, a copolymer of acrylic acid and vinyl acetate, or a combination thereof.

[0074] In one embodiment, the adhesive overlay comprises a copolymer of acrylic acid and vinyl acetate.

[0075] In one embodiment, the second backing layer comprises a woven polyester fabric.

[0076]

[0076] In some embodiments, the transdermal delivery systems described herein may further include a release liner comprising a film, nonwoven, woven, laminate, or combination thereof, wherein the release liner is in contact with the skin contact adhesive layer opposite the intermediate layer.

[0077] In one embodiment, the release liner is a silicone coated polymeric film or paper.

[0078] In some embodiments, the release liner is a silicone coated polyethylene terephthalate (PET) film, a fluorocarbon film, or a fluorocarbon coated PET film.

[0079]

[0079] In another aspect, there is provided a method for transdermal delivery of an active agent comprising providing any one of the above transdermal delivery systems and securing or instructing the system to be secured to the skin of a user to deliver the active agent from the system to the skin, whereby (i) the steady-state flux time lag is at least about 20% faster compared to a system not having the membrane treatment composition in the pores of the microporous membrane, (ii) the system achieves its steady-state equilibrium flux at least 20% faster compared to a system not having the membrane treatment composition in the pores of the microporous membrane, and / or (iii) the active agent diffuses from the system to the skin at least 20% faster compared to a system not having the membrane treatment composition in the pores of the microporous membrane.

[0080]

[0080] In yet another aspect, a method for treating Alzheimer's disease is provided which includes providing either a transdermal delivery system containing an active agent, such as donepezil base or memantine base, as described above for administration to the skin of a patient.

[0081]

[0081] In yet another aspect, a method for treating Alzheimer's disease, obsessive-compulsive disorder, anxiety disorder, attention deficit hyperactivity disorder (ADHD), or opioid dependence is provided, comprising providing to the skin of a patient any of the transdermal delivery systems containing the memantine compounds described above.

[0082]

[0082] In another aspect, a method is provided for making a transdermal delivery system for an active agent, comprising: providing a skin contact adhesive layer for attaching the system to the skin of a user; providing a drug reservoir layer comprising an active agent and a drug carrier composition; treating a microporous membrane having a plurality of pores with a membrane treatment composition to provide a pretreated microporous membrane, wherein at least a portion of the pores of the pretreated microporous membrane contain the membrane treatment composition; and providing an intermediate layer disposed between the skin contact adhesive layer and the drug reservoir layer, wherein the intermediate layer comprises the pretreated microporous membrane.

[0083]

[0083] In one embodiment of the manufacturing method, the microporous polypropylene membrane comprises microporous polypropylene.

[0084]

[0084] In one embodiment of the manufacturing method, the active agent of the drug reservoir layer is generated in situ by reaction of a pharma- ceutically acceptable salt of the active agent with an amphoteric base compound.

[0085]

[0085] In some embodiments of the method of manufacture, the microporous membrane has an average pore size of about 0.001 μm to about 100 μm.

[0086] In some embodiments of the method of manufacture, the pore size is from about 0.010 μm to about 0.100 μm.

[0087] In one embodiment of the method of manufacture, the pore size is from about 0.040 μm to about 0.050 μm.

[0088]

[0088] In some embodiments of the method of manufacture, the microporous membrane has a porosity of about 30% to about 50%.

[0089]

[0089] In one embodiment of the manufacturing method, the step of treating the microporous membrane with the membrane treatment composition includes the steps of contacting the microporous membrane with the membrane treatment composition to saturate the microporous membrane with the membrane treatment composition, and removing any excess membrane treatment composition from the saturated microporous membrane.

[0090]

[0090] In some embodiments of the manufacturing method, the membrane treatment composition includes a nonionic surfactant, a long chain aliphatic alcohol, a citrate ester, or a combination thereof.

[0091]

[0091] In one embodiment of the method of manufacture, the amphoteric inorganic base compound is sodium bicarbonate.

[0092]

[0092] In one embodiment of the method of manufacture, the active agent is donepezil base and the pharma- ceutically acceptable salt is donepezil hydrochloride.

[0093]

[0093] In some embodiments of the manufacturing method, the drug carrier composition comprises triethyl citrate, lauryl lactate, sorbitan monolaurate, or any combination thereof.

[0094]

[0094] In one embodiment of the manufacturing method, the drug carrier composition comprises about 66.7% by weight triethyl citrate, about 20.0% by weight lauryl lactate, and about 13.3% by weight sorbitan monolaurate.

[0095]

[0095] In one embodiment of the manufacturing method, the membrane treatment composition comprises about 66.7% by weight triethyl citrate, about 20.0% by weight lauryl lactate, and about 13.3% by weight sorbitan monolaurate.

[0096]

[0096] In one embodiment of the method of manufacture, the active agent is memantine and the pharma- ceutically acceptable salt is memantine hydrochloride.

[0097]

[0097] In some embodiments of the manufacturing method, both the drug carrier composition and the membrane treatment composition contain octyldodecanol.

[0098]

[0100] In certain embodiments of the method of manufacture, the active agent is fingolimod base and the pharma- ceutically acceptable salt is fingolimod hydrochloride.

[0099]

[0101] In one embodiment, the manufacturing method further includes the steps of providing a first backing layer in contact with the drug reservoir layer, providing an adhesive overlay in contact with the first backing layer opposite the drug reservoir layer, and providing a second backing layer in contact with the adhesive overlay opposite the first backing layer. [Brief description of the drawings]

[0100] [Figure 1A] FIG. 1 is a diagram of a transdermal delivery system according to an embodiment. [Figure 1B] FIG. 1 is a diagram of a transdermal delivery system according to an embodiment. [Figure 1C] FIG. 1 is a diagram of a transdermal delivery system according to an embodiment. [Figure 1D] FIG. 1 is a diagram of a transdermal delivery system according to an embodiment. [Figure 2A] FIG. 1 is a graph of the mean plasma concentrations of donepezil in ng / mL as a function of time in days in human subjects treated for one week with the donepezil transdermal delivery system (circles) or with 5 mg of donepezil administered orally on days 1 and 7 (triangles). [Figure 2B] 1 is a graph showing the mean plasma concentrations of donepezil in ng / mL 24 hours after oral administration of a 5 mg donepezil tablet (triangles) and 24 hours after removal of the donepezil transdermal delivery system (circles). [Diagram 3] Graph showing predicted mean plasma concentrations of donepezil in ng / mL over a 28-day (4-week) treatment period with a transdermal delivery system (solid line) designed to administer 10 mg / day per week with a new patch applied once per week, and over 28 days with a 10 mg daily oral tablet of donepezil (dashed line). [Figure 4] FIG. 1 is a bar graph of the number of subjects in the group treated with the donepezil transdermal delivery system for one week and observed skin irritation after patch removal, where open bars indicate no skin irritation and filled bars indicate mild skin irritation. [Figure 5A]FIG. 1 shows the mean plasma concentrations of donepezil in ng / mL for each day of week 5 of a clinical human study in which subjects were treated with donepezil administered transdermally from a transdermal patch having a first surface area (solid line) and a second, larger surface area (dashed line) and orally administered donepezil. The donepezil plasma concentrations of orally treated patients are shown as the dark bold line on days 6-7 and the dotted line shows the expected daily plasma concentrations for oral treatment. [Figure 5B] FIG. 5B is a bar graph showing the number of gastrointestinal-related adverse events (nausea, vomiting, and diarrhea) reported by subjects in a clinical study in which subjects were treated as described in FIG. 5A, where the bars filled with dashed lines correspond to subjects treated with the smaller size weekly transdermal patch, the bars filled with vertical lines correspond to subjects treated with the larger size weekly transdermal patch, and the bars filled with horizontal lines correspond to subjects treated with oral donepezil. [Figure 6] 1 is a graph of the average skin flux of memantine transdermal delivery devices in μg / cm2·hr in vitro as a function of time in hours in an in vitro skin permeation study. [Figure 7] FIG. 1 is a graph of the mean skin flux of donepezil in vitro in μg / cm2·hr as a function of time in hours in an in vitro skin permeation study of transdermal systems containing a pretreated microporous membrane (squares) compared to the skin flux of donepezil in a transdermal system in which the microporous membrane was untreated (circles). DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0101] I. Definition

[0111] Various aspects are described in more detail below. However, such aspects may be embodied in many different forms and should not be construed as limited to the embodiments set forth herein, but rather, these embodiments are provided so that this disclosure will be thorough and complete, and will fully convey its scope to those skilled in the art.

[0102]

[0112] When a range of values ​​is provided, each intervening value between the upper and lower limits of that range, and any other stated or intervening value within that stated range, is intended to be encompassed within the disclosure. For example, if a range of 1 μm to 8 μm is stated, 2 μm, 3 μm, 4 μm, 5 μm, 6 μm, and 7 μm are also intended to be expressly disclosed, as well as ranges of values ​​above 1 μm and below 8 μm.

[0103]

[0113] The singular forms "a," "an," and "the" include plural referents unless the context clearly indicates otherwise. Thus, for example, reference to a "polymer" includes a single polymer as well as two or more of the same or different polymers, reference to an "excipient" includes a single excipient as well as two or more of the same or different excipients, and so forth.

[0104]

[0114] The word "about", when immediately preceding a numerical value, means a range of plus or minus 10% of that value, unless the context of this disclosure indicates otherwise or contradicts such an interpretation, e.g., "about 50" means 45 to 55, "about 25,000" means 22,500 to 27,500, etc. For example, in a list of numerical values ​​such as "about 49, about 50, about 55", "about 50" means less than half the interval(s) of the preceding or following values, e.g., a range of more than 49.5 to less than 52.5. Furthermore, phrases "less than about" or "more than about" values ​​should be understood in light of the definition of the term "about" provided herein.

[0105]

[0115] The terms "drug" or "active agent" or "therapeutically active agent" are used interchangeably.

[0106]

[0116] "Adhesive matrix" as used herein includes, for example, matrices made by solvent casting or extrusion, as well as matrices formed of two or more pieces that are then pressed or bonded together.

[0107]

[0117] As used herein, "donepezil" refers to 2,3-dihydro-5,6-dimethoxy-2-[[1-(phenylmethyl)-4-piperidinyl]methyl]-1H-inden-1-one.

[0108]

[0118] As used herein, the terms "treatment," "therapy," "therapeutic," and the like encompass any process of medical intervention directed at a pathological condition, and include not only the permanent cure of a disease, but also measures taken to prevent, control, or alleviate a disease or a symptom of a disease.

[0109]

[0119] As used herein, the term "skin" refers to the skin or mucosal tissue, including the inner surface of a body cavity having a mucosal lining. The term "skin" should be interpreted to include "mucosal tissue" and vice versa.

[0110]

[0120] The term "therapeutically effective amount" as used herein refers to a non-toxic but sufficient amount of an active agent to provide the desired therapeutic effect. The amount that is "effective" will vary from subject to subject, depending on the age and general condition of the individual, the particular active agent, etc., as known to those skilled in the art.

[0111]

[0121] The phrase "pharmacologically acceptable" is used herein to refer to compounds, salts, compositions, and / or dosage forms thereof, etc., that are suitable for use in contact with the tissues of humans and / or other mammals without undue toxicity, irritation, allergic response, or other problem or complication, within the scope of sound medical judgment, commensurate with a reasonable benefit / risk ratio. In some embodiments, "pharmacologically acceptable" means approved by a regulatory agency of the Federal or State government or listed in the United States Pharmacopeia or other generally recognized pharmacopoeias for use in mammals (e.g., animals), more particularly humans.

[0112]

[0122] The term "transdermal" or "transdermal delivery" as used herein refers to administration of an active agent to a body surface of an individual such that the agent passes through the body surface, e.g., the skin, and enters the individual's bloodstream. The term "transdermal" is intended to include transmucosal administration, i.e., administration of a drug to a mucosal (e.g., sublingual, buccal, vaginal, rectal) surface of an individual such that the agent passes through the mucosal tissue and enters the individual's bloodstream.

[0113]

[0123] The term "treating" is used herein with respect to methods of treating disorders such as, for example, Alzheimer's disease, and generally includes administration of a compound or composition to a subject who has not received the compound or composition, which reduces the frequency or delays the onset of symptoms of a medical condition (e.g., Alzheimer's disease) in a subject. This includes reversing, reducing, or preventing symptoms, clinical signs, and underlying pathology of a condition in a manner that improves or stabilizes the subject's condition (e.g., regression of a mental institution).

[0114]

[0124] The compositions of the present disclosure can comprise, consist essentially of, or consist of the disclosed components.

[0115]

[0125] All percentages, parts and ratios are based on the total weight of the topical composition unless otherwise specified and all measurements are made at about 25°C.

[0116]

[0126] It is possible to claim less than the complete measurement of the disclosure for any reason by reserving the right to provide for or exclude any individual member of any such group, including any subrange or combination of subranges within a group, which may be claimed according to a range or in any similar manner.Furthermore, it is possible to claim less than the complete measurement of the disclosure for any reason by reserving the right to provide for or exclude any individual substituent, analog, compound, ligand, structure, or group thereof, or any member of a claimed group.

[0117]

[0127] Throughout this disclosure, various patents, patent applications, and publications are referenced. The entire disclosures of these patents, patent applications, and publications are incorporated by reference into this disclosure in order to more fully describe the state of the art as known to those skilled in the art as of the date of this disclosure. This disclosure applies in the examples where there is a conflict between the cited patents, patent applications, and publications and this disclosure.

[0118]

[0128] For convenience, certain terms used in the specification, examples, and claims are collected here. Unless otherwise defined, all technical and scientific terms used in this disclosure have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs.

[0119] II. Transdermal Delivery Systems and Compositions for Use in Transdermal Delivery Systems

[0129] Provided is a transdermal delivery system for systemic delivery of water-insoluble drug-based.Generally, the transdermal system is composed of a skin contact adhesive layer and a drug reservoir layer, and the two layers are separated by an intermediate layer that comprises a microporous membrane that is pretreated with a membrane treatment composition.As described below, the system can include additional layers.The composition of the layers in the system can be described below.

[0120]

[0130] In one embodiment, the drug depot comprises a donepezil compound or a derivative thereof as an active agent. Donepezil is an acetylcholinesterase inhibitor having the chemical structure 2,3-dihydro-5,6-dimethoxy-2-[[1-(phenylmethyl)-4-piperidinyl]methyl]-1H-inden-1-one. [ka] Donepezil has a molecular weight of 379.5 and is lipophilic (LogP value 3.08-4.11).

[0121]

[0131] In one embodiment, the drug depot comprises a memantine compound or a derivative thereof as an active ingredient. Memantine (NAMENDA) is a compound that belongs to the adamantane class of active agents. In one embodiment, the compound comprises the structure shown in Formula I. In another embodiment, the memantine compound is also known as 3,5-dimethyladamantan-1-amine, 1-amino-3,5-dimethyladamantane, 1,3-dimethyl-5-adamantanamine, 3,5-dimethyl-1-adamantanamine, 3,5-dimethyl-1-aminoadamantane, and 3,5-dimethyltricyclo(3.3.1.1(3,7))decan-1-amine. [ka]

[0122]

[0132] In one embodiment, the drug reservoir layer comprises a fingolimod compound or a derivative thereof as the active agent.

[0123]

[0133] The drug reservoir may further comprise adjunct ingredients commonly found in pharmaceutical compositions in their art-established manner and at their art-established levels. For example, the composition may contain additional compatible pharma- ceutical active substances for combination therapy, such as donepezil (ARICEPT®), memantine, rivastigmine (EXCELON®), galantamine (RAZADYNE®), icopezil, pyridostigmine, edrophonium, neostigmine, physostigmine, huperzine A, phenserine, tacrine, L-type calcium channel blockers selected from amlodipine, felodipine, isradipine, lacidipine, lercanidipine, nicardipine, nifedipine, nimodipine, nitrendipine, nisoldipine, or (+)-isopropyl 2-methoxyethyl 4-(2-chloro-3-cyano-phenyl)-1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylate, or combinations thereof. See U.S. Patent Application Publication No. 2009 / 0156639.

[0124]

[0134] In one embodiment, the drug reservoir layer comprises an adhesive polymer, a drug carrier composition, and donepezil base that is generated in situ in the drug reservoir layer after the transdermal system is applied to the skin by reaction of donepezil salt with an alkali salt or another amphoteric base compound. The drug reservoir layer is prepared using a salt form of donepezil, such as donepezil hydrochloride (HCl), and an alkali salt that reacts in situ to form donepezil base after the transdermal system is applied to the skin. The alkali salt can be, for example, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, trisodium phosphate, disodium hydrogen phosphate, sodium oxylate, sodium succinate, sodium citrate, or sodium salicylate.

[0125]

[0135] The drug storage also includes a drug carrier composition. In one embodiment, the drug carrier composition is a solvent composition consisting of one, two, three, or four solvents. In one embodiment, the drug carrier composition includes triethyl citrate, and in another embodiment, one or both of glycerin and sorbitan monolaurate are further present. In another embodiment, an alpha-hydroxy acid is present as an additional solvent in the drug carrier composition. An exemplary alpha-hydroxy acid solvent is an ester of lactic acid or glycolic acid, for example lauryl lactate. In one embodiment, the drug carrier composition consists of, consists essentially of, or consists of triethyl citrate, sorbitan monolaurate, lauryl lactate, and glycerin.

[0126]

[0136] The adhesive component in the drug reservoir can be any of a variety of adhesive materials, such as pressure-sensitive adhesive polymers. Polyacrylate pressure-sensitive adhesive polymers are examples and include polyacrylates, which are typically polymers or copolymers of monomer(s) selected from acrylic acid esters and methacrylic acid esters. Other monomers, such as acrylic acid and vinyl acetate, may be present. In one embodiment, the acrylic polymer is based on acrylic acid esters, such as 2-ethylhexyl acrylate (2-EHA) and ethyl acrylate. In an embodiment, the polyacrylate polymer is a polymer or copolymer of monomer(s) selected from acrylic acid and vinyl acetate. In an embodiment, the acrylic polymer adhesive has pendant carboxyl (-COOH) or hydroxyl (-OH) functional groups. In an embodiment, the acrylic polymer adhesive comprises at least one of polyacrylates, polymethacrylates, derivatives thereof, and copolymers thereof. In an embodiment, the acrylic adhesive is composed of an acrylate copolymer that includes acrylic acid ester monomers, acrylic acid, and / or vinyl acetate monomers. A copolymer of acrylic acid and vinyl acetate is an example. Acrylate copolymers are sold under the trade name DURO-TAK® and include, but are not limited to, DURO-TAK 387-2516, 387-2051, and 387-2074.

[0127]

[0137] The drug reservoir may also include copolymers such as polyvinylpyrrolidone / vinyl acetate copolymer, acrylic acid / vinyl acetate copolymer, or vinyl acetate / ethylene acetate copolymer. In one embodiment, the copolymer is a vinyl acetate / N-vinylpyrrolidone copolymer, such as the copolymer sold as Plasdone™ S630 (Ashland). In another embodiment, the polyvinylpyrrolidone-vinyl acetate copolymer is a linear random copolymer of n-vinyl-2-pyrrolidone and vinyl acetate. In one embodiment, the copolymer is a 60:40 copolymer of n-vinyl-2-pyrrolidone and vinyl acetate.

[0128]

[0138] The drug depot may also include polyvinylpyrrolidone (PVP). PVP is a water-soluble polymer composed of N-vinylpyrrolidone monomers and is available in a variety of forms, including cross-linked and non-cross-linked. In some of the examples herein, cross-linked PVP is included in the drug depot.

[0129]

[0139] In certain embodiments, the drug reservoir comprises at least about 25-80% by weight of adhesive polymer, based on the weight of the drug reservoir (including subranges). In embodiments, the drug reservoir comprises at least about 35-80%, 30-75%, at least about 40-75%, at least about 50-75%, at least about 60-75%, at least about 25-70%, at least about 30-70%, at least about 40-70%, at least about 50-70%, at least about 60-70%, at least about 25-60%, at least about 30-60%, at least about 40-60%, at least about 50-60%, at least about 25-50%, at least about 30-50%, at least about 40-50%, at least about 25-40%, at least about 30-40%, or at least about 25-30% adhesive polymer or copolymer, or mixture of polymers and / or copolymers (all percentages are in weight %). It will be appreciated that the drug reservoir adhesive matrix may comprise one or more, or at least one adhesive polymer or copolymer, in embodiments, the drug reservoir comprises at least about 5-75% of an individual polymer, based on the total weight of the polymers in the matrix. In embodiments, the drug storage is at least about 5-10%, 5-15%, 5-20%, 5-25%, 5-30%, 5-40%, 5-50%, 5-60%, 5-70%, 5-75%, 10-15%, 10-20%, 10-20%, 10-25%, 10-30%, 10-40%, 10-50%, 10-60%, 10-70%, 10-75%, 15-20%, 15-25%, 15-30%, 15-40%, 15-50%, 15-60%, 15-70%, 15-75%, 20 ~25%, 20-30%, 20-40%, 20-50%, 20-60%, 20-70%, 20-75%, 25-30%, 25-40%, 25-50%, 25-60%, 25-70%, 25-75%, 30-40%, 30-50%, 30-60%, 30-70%, 30-75%, 40-50%, 40-60%, 40-70%, 40-75%, 50-60%, 50-70%, 50-75%, 60-70%, 60-75%, or 70-75% of an individual polymer.

[0130]

[0140] One exemplary drug depot contemplates a matrix comprising or consisting essentially of donepezil base formed in situ by reaction of donepezil HCl with sodium bicarbonate, a drug carrier composition mixture of triethyl citrate, sorbitan monolaurate, and glycerin, and a polymeric adhesive matrix of cross-linked polyvinylpyrrolidone and acrylic acid / vinyl acetate copolymer. Another exemplary drug depot contemplates a composition comprising an adhesive matrix comprising or consisting essentially of donepezil base formed in situ by reaction of about 10-25% by weight donepezil HCl with about 1-5% by weight sodium bicarbonate, about 5-15% by weight triethyl citrate, about 0.5-5% by weight sorbitan monolaurate, about 5-15% by weight glycerin, about 5-25% by weight cross-linked polyvinylpyrrolidone, and about 30-50% by weight acrylate-vinyl acetate copolymer. In another example, a composition is contemplated that comprises an adhesive matrix consisting essentially of donepezil base formed in situ by reaction of about 14-18% by weight donepezil HCl with about 2-5% by weight sodium bicarbonate, about 8-12% by weight triethyl citrate, about 1.5-2.5% by weight sorbitan monolaurate, about 9-11% by weight glycerin, about 13-17% by weight crosslinked polyvinylpyrrolidone, and about 40-42% by weight acrylates-vinyl acetate copolymer.

[0131]

[0141] The drug reservoirs described herein and above are contemplated for use in a transdermal delivery system, the system further comprising a skin contact adhesive. The skin contact adhesive layer may be fabricated from any of the adhesive materials listed herein and above. The skin contact adhesive layer, in one embodiment, comprises about 50-90% by weight of an adhesive polymer or copolymer, or about 55-90% by weight, or about 60-90% by weight, about 65-90% by weight, about 70-90% by weight, about 75-90% by weight, or about 80-90% by weight of an adhesive polymer or copolymer. In one embodiment, the skin contact adhesive is comprised of an acrylic acid / vinyl acetate copolymer. In another embodiment, the skin contact adhesive layer further comprises a polyvinylpyrrolidone, such as crosslinked polyvinylpyrrolidone.

[0132]

[0142] In one embodiment, the skin contact adhesive layer comprises one or more biocompatible polymers selected from one or more of polyisobutylene (PIB), silicone polymers, acrylate copolymers, butyl rubber, polybutylene, styrene-isoprene-styrene block copolymers, styrene-butadiene-styrene block copolymers, ethylene vinyl acetate (EVA), mixtures and copolymers thereof, hi one embodiment, the biocompatible polymer is polyisobutylene.

[0133]

[0143] In one embodiment, the biocompatible polymer is a PIB-based matrix comprising PIB Oppanol B100 (BASF, MW=1,100,000), PIB Oppanol B12 (BASF, MW=51,000, MW / MN=3.2), and polybutene (PB) Indopol H1900 (INEOS Oligomer, MW=4500, MW / MN=1.8). The weight ratio between the components of the PIB matrix is ​​as follows: PIB Oppanol B100:PIB Oppanol B 12:Indopol H1900=10:50:40 (see Branteva et al., European Polymer Journal, 76, 228-244, 2016).

[0134]

[0144] In one embodiment, the skin contact adhesive layer is about 40%, about 41%, about 42%, about 43%, about 44%, about 45%, about 46%, about 47%, about 48%, about 49%, about 50%, about 51%, about 52%, about 53%, about 54%, about 55%, about 56%, about 57%, about 58%, about 59%, about 60%, about 61%, about 62%, about 63%, about 64%, about 65%, about 66%, about 67%, about 68%, about 69%, about 70%, about 71%, about 72%, about 73%, about 74%, about 75%, about 76%, about 77%, about 78%, about 79%, about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, about 100%, about 101%, about 102%, about 103%, about 104%, about 105%, about 106%, about 107%, about 108%, about 109%, about 110%, about 111%, about 112%, about 113%, about 114%, about 115%, about 116%, about 117%, about 118%, about 119%, about 120%, about 121%, about 122%, about 123%, about 124%, about 125%, about 126%, about 127%, about 128%, about 129%, about 130%, about 131%, about 132%, about 1 , about 74%, about 75%, about 76%, about 77%, about 78%, about 79%, about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, about 99.9 or more weight percent of the biocompatible polymer in the adhesive layer, all values ​​being based on the weight of the adhesive layer. In particular, the weight percent of the biocompatible polymer in the adhesive layer is about 50% to 95%, in particular about 60% to 80%, of the entire skin contact adhesive layer. In certain embodiments, the amount of biocompatible polymer in the skin contact adhesive layer is at least about 50-90%, 50-85%, 50-80%, 50-75%, 50-70%, 50-65%, 50-60%, 50-55%, 55-95%, 55-90%, 55-85%, 55-80%, 55-75%, 55-70%, 55-65%, 55-60%, 60-95%, 60-90%, 60-85%, 60-80%, %, 60-75%, 60-70%, 60-65%, 65-95%, 65-90%, 65-85%, 65-80%, 65-75%, 65-70%, 70-95%, 70-90%, 70-85%, 70-80%, 70-75%, 75-95%, 75-90%, 75-85%, 75-80%, 80-95%, 80-90%, 80-85%, 85-95%, 85-90%, or 90-95%.

[0135]

[0145] The skin contact adhesive layer may also include a skin contact adhesive layer drug carrier composition. In an embodiment, the skin contact adhesive layer includes one or more of a citrate ester, a surfactant, and / or an alpha hydroxy acid as the contact adhesive layer drug carrier composition. In one embodiment, the skin contact adhesive layer includes one or more of a triethyl citrate, a sorbitan monolaurate, and / or a lauryl lactate as the contact adhesive layer drug carrier composition. In one embodiment, the skin contact adhesive layer as manufactured does not include a medicament active agent intended for systemic delivery, for example, the components combined to form the skin contact adhesive layer and / or the contact adhesive layer drug carrier composition do not include a base or salt form of the drug, such as donepezil base or donepezil salt. In use, after the skin contact adhesive layer is applied to the skin of the user, the base form of the active agent generated in situ in the drug reservoir is distributed into the drug carrier composition of the drug reservoir, then distributed and transferred to the membrane treatment composition in the microporous membrane, and then distributed and transferred to the contact adhesive layer drug carrier composition for delivery to the skin of the user.

[0136]

[0146] The drug carrier composition of either or both of the skin contact adhesive layer and the drug reservoir adhesive matrix may be selected from a wide range of such compounds known in the art. In certain embodiments, drug carrier compositions for use in the adhesive layer or matrix include, but are not limited to, methyl laurate, propylene glycol monolaurate, glycerol monolaurate, glycerol monooleate, lauryl lactate, myristyl lactate, and dodecyl acetate. Additional drug carrier compositions are described in U.S. Patent No. 8,874,879, which is incorporated herein by reference. It will be understood that the compositions herein may include one or more or at least one drug carrier composition. In embodiments, the permeation or penetration enhancer is included in an amount of about 1-10%, about 2-5%, about 2-10% by weight of the adhesive matrix (including subranges).

[0137]

[0147] In one embodiment, the contact adhesive layer drug carrier composition and the membrane treatment composition have one, two, or three identical solvents. In one embodiment, the contact adhesive layer drug carrier composition and the membrane treatment composition are composed of the same solvent. For example, in one embodiment, the contact adhesive layer drug carrier composition and the membrane treatment composition each include a citrate ester, a surfactant, and / or an alpha-hydroxy acid. In one embodiment, the drug carrier composition (drug storage) includes a hydrophilic solvent that is excluded from or not present in the membrane treatment composition or the contact adhesive layer drug carrier composition.

[0138]

[0148] Either or both of the skin contact adhesive layer and the drug reservoir adhesive matrix may further comprise one or more matrix modifiers. Without wishing to be bound by theory, it is believed that the matrix modifiers promote homogenization of the adhesive matrix. Sorption of hydrophilic moieties is a possible mechanism for this process. Thus, known matrix modifiers that are water absorbents to some degree may be used. For example, possible matrix modifiers include colloidal silicon dioxide, fumed silica, crosslinked polyvinylpyrrolidone (PVP), soluble PVP, cellulose derivatives (e.g., hydroxypropyl cellulose (HPC), hydroxyethyl cellulose (HEC)), polyacrylamides, polyacrylic acids, polyacrylates, or clays such as kaolin or bentonite. An exemplary commercially available fumed silica product is Cab-O-Sil (Cabot Corporation, Boston, Mass.). Hydrophilic mixtures such as those described in U.S. Published Patent Application No. 2003 / 0170308 may also be used, such as mixtures of PVP and PEG, or PVP, PEG, and water-swellable polymers such as EUDRAGIT® L100-55. In embodiments, the matrix modifier is individually present in an amount of about 1-25%, about 2-25%, about 5-25%, about 5-7%, about 7-20%, or about 7-25% by weight of the adhesive matrix (including subranges). In some embodiments, the matrix modifier does not include ethylcellulose.

[0139]

[0149] Either or both of the skin contact adhesive layer and the drug reservoir adhesive matrix may further comprise other conventional additives such as adhesives, antioxidants, crosslinking or hardening agents, pH adjusters, pigments, dyes, refractive particles, conductive species, antimicrobial agents, opacifiers, gelling agents, viscosity modifiers or thickeners, stabilizers, and as known in the art. In embodiments where adhesion needs to be reduced or eliminated, conventional anti-adhesive agents may also be used. Other agents such as antimicrobial agents may also be added to prevent spoilage during storage, i.e., inhibit the growth of microorganisms such as yeasts and molds. Suitable antimicrobial agents are typically selected from the group consisting of methyl and propyl esters of p-hydroxybenzoic acid (i.e., methylparaben and propylparaben), sodium benzoate, sorbic acid, imidurea, and combinations thereof. These additives, and the amounts thereof, are selected so as not to significantly interfere with the desired chemical and physical properties of the adhesive and / or active agent.

[0140]

[0150] Either or both of the skin contact adhesive layer and the drug reservoir adhesive matrix may further contain irritation mitigating additives to minimize or eliminate the possibility of skin irritation and / or skin damage resulting from the drug, enhancer, or other components of the composition.Suitable irritation mitigating additives include, for example, α-tocopherol, monoamine oxidase inhibitors, especially phenyl alcohols such as 2-phenyl-1-ethanol, glycerin, salicylic acid and salicylates, ascorbic acid and ascorbate salts, ionophores such as monensin, amphiphilic amines, ammonium chloride, N-acetylcysteine, cis-urocanic acid, capsaicin, chloroquine, and corticosteroids.

[0141]

[0151] In certain embodiments, the skin contact adhesive layer optionally comprises highly dispersible silica, e.g., hydrophobic colloidal silica, which can effectively adsorb hydrophobic drugs and other hydrophobic components. The use of hydrophobic colloidal silica in a specific proportion as an excipient (about 3% to about 20%, preferably about 5% to about 10% in the formulation) can control the diffusion of the active components through the matrix during storage. Examples of dispersible silica for use in the composition include AEROSIL, e.g., AEROSIL® 90, AEROSIL® 130, AEROSIL® 150, AEROSIL® 200, AEROSIL® 300, AEROSIL® 380, AEROSIL® OX50, AEROSIL® TT600, AEROSIL® MOX80, AEROSIL® COK84, AEROSIL® R20 2, high purity amorphous anhydrous colloidal silicon dioxide for use in pharmaceuticals sold under the names AEROSIL® R805, AEROSIL® R812, AEROSIL® 812S, AEROSIL® R972, and / or AEROSIL® R974, or any other highly disperse silica, but are not limited to, in particular AEROSIL® 200 and / or AEROSIL® R972 can be used as the highly disperse silica.

[0142]

[0152] In one embodiment, the skin contact adhesive layer comprises at least about 40% by weight, e.g., at least about 1% by weight, e.g., at least about 3% by weight, e.g., about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, about 20% or more by weight of highly dispersible silica, based on the weight of the entire adhesive layer, all values ​​being based on the weight of the entire adhesive layer.

[0143]

[0153] Transdermal delivery systems comprised of a drug reservoir adhesive matrix and a skin contact adhesive can have a variety of configurations, some non-limiting examples are described in Figures 1A-1D. Figure 1A shows a transdermal delivery system 10 comprised of a drug reservoir 12 and a contact adhesive 14 separated by a non-rate controlling material 16, such as a microporous membrane or a tie layer comprised of non-woven polyester or polypropylene. A backing layer 18 and a release liner 20 are also present. Figure 1B shows a second embodiment of a transdermal delivery system 22 comprised of a first drug reservoir 24 and a second drug reservoir 26, the first and second drug reservoirs being separated by a non-rate controlling material 28, such as a tie layer comprised of non-woven polyester or polypropylene. The contact adhesive layer 30 provides attachment of the system to the skin of the user, and the rate controlling membrane 32 controls the release of therapeutic agent from the second drug reservoir to the contact adhesive and ultimately to the skin of the user. A release liner 34 and a backing layer 36 are also present. Figure 1C shows another embodiment of a transdermal delivery system 40 comprised of a drug reservoir 42 and a contact adhesive layer 44 that provides attachment of the system to the skin of the user. A backing layer 46 and a release liner 48 are also present.

[0144]

[0154] FIG. 1D shows another embodiment of a transdermal delivery system for systemic delivery of an active agent. The system 50 includes a skin contact adhesive layer 56 for attaching the system to the skin of a user, continuing from the skin-facing side 52 to the external environment-facing side 54. In one embodiment, the skin contact adhesive layer is manufactured from an adhesive formulation that does not include the active agent or its salt. However, after storage and / or during use, the skin contact adhesive layer includes the base form of the active agent due to diffusion of the base form of the active agent from the drug reservoir layer. In direct contact with the skin contact adhesive layer is an intermediate layer 58. The intermediate layer can be, for example, a nonwoven polyester material or a drug rate controlling membrane such as microporous polyethylene or polypropylene. The intermediate layer has an opposite side, a skin-facing side (in contact with the skin contact adhesive layer 56), and an environment-facing side. On the environment-facing side of the intermediate layer is a drug reservoir layer 60. The drug reservoir layer is manufactured from an adhesive material, a pharma- ceutically acceptable salt of the active agent, and an alkali salt. The latter two components react in situ to produce a base form of the active agent in the drug reservoir that is delivered to the user after application of the system to the skin. In contact with the drug reservoir is a first backing layer 62, and in contact with the first backing layer is an adhesive overlay 64. A second backing layer 66 is in contact with the adhesive overlay and the environment. In one embodiment, the adhesive overlay 64 is composed of two different adhesive layers, for example a first layer of polyisobutylene and polybutene with or without crosslinked polyvinylpyrrolidone, and a second layer of an acrylic adhesive.

[0145]

[0155] Thus, in one embodiment, a transdermal delivery system for systemic delivery of an active agent is provided. The system includes a skin contact adhesive layer for attaching the system to the skin of a user, from the skin-facing side to the external environment, the skin contact adhesive layer being optionally made from an adhesive formulation that does not include the active agent or its salt. In direct contact with the skin contact adhesive layer is an intermediate layer. On the opposite surface of the intermediate layer is a drug reservoir layer composed of (i) optionally an acrylic acid / vinyl acetate copolymer, (ii) a drug carrier composition as described herein, and (iii) an active agent generated in situ by reaction of the hydrochloride salt of the active agent with an alkali salt. In contact with the drug reservoir layer is a first backing layer, and in contact with the first backing layer is an adhesive overlay. A second backing layer is in contact with the adhesive overlay and the environment.

[0146]

[0156] The intermediate layer, also referred to as a fabric layer, membrane, or tie layer, may be formed of any suitable material, including, but not limited to, polyester, vinyl acetate polymers and copolymers, polyethylene, and combinations thereof. In one embodiment, the intermediate layer is a nonwoven layer of polyester fibers, such as a film sold under the name Reemay® (Kavon Filter Products Co.). In some embodiments, the intermediate layer does not affect the release rate of the active agent from the adhesive layer.

[0147]

[0157] In some embodiments, the intermediate layer comprises a microporous membrane. For example, the microporous membrane can be microporous polypropylene or polyethylene. The microporous membrane can help control the rate of drug release from the transdermal delivery system. Several different microporous membranes are commercially available, such as those sold under the name Celgard®, e.g., Celgard® 2400 (Polypore International, LP).

[0148]

[0158] Other materials useful for forming microporous membranes include polycarbonates, i.e., linear polyesters of carbonic acid in which carbonate groups reoccur in the polymer chain by phosgenation of dihydroxy aromatics such as bisphenols; polyvinyl chloride; polyamides such as polyhexamethylene adipamide and other such polyamides commonly known as nylons; modacrylic copolymers such as styrene-acrylic acid copolymers; polysulfones (e.g., those types characterized by diphenylene sulfone groups in their linear chains are useful); halogenated polyvinylidene fluoride, polyvinyl fluoride, and polyfluorohalocarbons. Polymers such as polychloroethers and other such thermoplastic polyethers, acetal polymers such as polyformaldehyde, acrylic resins such as polyacrylonitrile polymethyl poly(vinyl alcohol), derivatives of polystyrene such as poly(sodium styrenesulfonate) and polyvinylbenzyltrimethylammonium chloride), poly(hydroxyethyl methacrylate) and poly(isobutyl vinyl ether), as well as a number of copolymers which can be formed by reacting various ratios of monomers from the list of polymers above, are also useful in preparing rate-controlling structures useful in the present invention.

[0149]

[0159] Diffusion of active agents through microporous polymeric materials, such as microporous polypropylene, can be difficult. The polymer is impermeable to active agents except through the pore channels, and even then, the active agent cannot diffuse through the pores unless it diffuses in a vaporized state. Thus, when using a purchased microporous membrane in the fabrication of a transdermal delivery system, excessive periods of time may be required for the delivery vehicle (i.e., drug carrier composition) from the drug reservoir to be distributed into the pores, and then for the active agent to be distributed into the delivery vehicle in the pores. The resulting effect is that the active agent may take a long time to reach its intended target.

[0150]

[0160] The release rate of active agent through a microporous membrane can be significantly improved if the microporous membrane is pretreated with a suitable delivery vehicle or membrane treatment composition. Pretreatment, as used herein, refers to exposing the microporous membrane to a membrane treatment composition to fill the pores in the microporous membrane before the microporous membrane is incorporated into a transdermal system. The pores of the microporous membrane are filled with or contain the membrane treatment composition before and at the time the microporous membrane is incorporated into a transdermal system. The release rate of active agent through a microporous membrane depends on several variables, such as the diffusivity and solubility of the active agent in the membrane treatment composition, and the thickness and porosity of the microporous material. For the flow of active agent through the pores of a microporous membrane, the concentration gradient, the thickness of the membrane, the viscosity of the active agent, the size of the active agent molecule relative to the pore size, the absolute value of the pore size, and the number or porosity (porosity) of the pores in the material are the factors that govern the solubility and diffusivity of the agent into and through the membrane.

[0151]

[0161] In some embodiments, the microporous membrane can have a porosity ranging from about 30% to about 50%, from about 35% to about 45%, or from about 40% to about 42%. For example, the microporous membrane can have a porosity of about 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, or 50%.

[0152]

[0162] In some embodiments, the microporous membrane can have an average pore size ranging from about 0.001 μm to about 100 μm, from about 1 μm to about 10 μm, from about 0.010 μm to about 0.100 μm, or from about 0.040 μm to about 0.050 μm. For example, the average pore size can be about 0.035 μm, 0.036 μm, 0.037 μm, 0.038 μm, 0.039 μm, 0.040 μm, 0.041 μm, 0.042 μm, 0.043 μm, 0.044 μm, 0.045 μm, 0.046 μm, 0.047 μm, 0.048 μm, 0.049 μm, or 0.050 μm. In some embodiments, the microporous membrane has an average pore size of about 0.043 μm.

[0153]

[0163] The microporous membrane can be pretreated with a vehicle or membrane treatment composition that is the same or different from the vehicle or drug carrier composition present in the drug reservoir. In some embodiments, the microporous membrane is pretreated with a membrane treatment composition that includes a solvent, a surfactant, an emulsifier, a thickener, a stabilizer, a plasticizer, and / or a combination thereof. In some embodiments, the membrane treatment composition does not include a solvent. In some embodiments, the surfactant is a non-ionic surfactant. In some embodiments, the microporous membrane is pretreated with a citrate ester. In some embodiments, the citrate ester is triethyl citrate. In some embodiments, the microporous membrane is pretreated with lauryl lactate. In some embodiments, the microporous membrane is pretreated with a sorbitan monoester. In some embodiments, the sorbitan monoester is sorbitan monolaurate (sorbitan laurate). In some embodiments, the microporous membrane is pretreated with a membrane treatment composition that includes triethyl citrate, lauryl lactate, and sorbitan monolaurate. In some embodiments, the microporous membrane is pretreated with octyldodecanol.

[0154]

[0164] In one embodiment, the microporous membrane has a plurality of pores filled with or containing a membrane treatment composition that is different from the drug carrier composition in the drug reservoir layer that is in fluid communication with the microporous membrane. In one embodiment, the membrane treatment composition does not include (i.e., excludes) a solvent in which the salt form of the active agent is soluble. In one embodiment, the membrane treatment composition does not include (i.e., excludes) a hydrophilic solvent in which the salt form of the active agent is soluble. In one embodiment, the membrane treatment composition does not include (i.e., excludes) a polyol, including solvent polyols such as polyethylene glycol, propylene glycol, glycerin (glycol), acetonitrile, 1-propanol, N,N-dimethylformamide, and dimethylsulfoxide.

[0155]

[0165] In some embodiments, the contact adhesive layer and / or the drug carrier composition may contain hydrophilic materials or components that are not included in the membrane treatment composition. In one embodiment, the hydrophilic materials present in one or both of the contact adhesive layer and / or the drug carrier composition but not present in the membrane treatment composition are hydrophilic solvents such as, but not limited to, glycerin, water, and mixtures thereof. Other hydrophilic materials include, but are not limited to, propylene glycol and low weight polyethylene glycols. In one embodiment, the microporous membrane is manufactured from a hydrophobic material to provide a hydrophobic microporous membrane, examples being polypropylene microporous membrane or polyethylene microporous membrane. Hydrophilic materials such as hydrophilic solvents in the drug carrier composition present in the drug reservoir do not diffuse or penetrate into the microporous membrane or the pores of the microporous membrane due to the hydrophobicity of the membrane material. The hydrophilic materials in the drug carrier composition in the drug reservoir layer promote and support the in situ formation of the water-insoluble basic active agent from its pharma-ceutically acceptable salt. After the base form of the active agent is formed in the drug reservoir layer, the base form of the active agent diffuses from the drug reservoir layer into and through the hydrophobic pores of the microporous membrane because the base form of the active agent is solubilized by at least one component in the drug carrier composition and at least one component in the membrane treatment composition. In one embodiment, the drug carrier composition and the membrane treatment composition have one, two, or three identical solvents, but the drug carrier composition and the membrane treatment composition are different. For example, in one embodiment, the drug carrier composition and the membrane treatment composition each include a citrate ester, a surfactant, and / or an alpha-hydroxy acid, and the drug carrier composition includes a hydrophilic solvent that is excluded from or not present in the membrane treatment composition.

[0156]

[0166] The drug carrier composition (i) enables the salt form of the active agent to be dissolved and / or suspended in the drug reservoir layer, (ii) supports the in situ reaction of the salt form of the active agent to the base form of the active agent, and (iii) enables the base form of the active agent to be dissolved or solubilized during diffusion into the microporous membrane and contact adhesive layer.

[0157]

[0167] The membrane treatment composition allows the base form of the active agent to dissolve or suspend therein and diffusively migrate into and through the microporous membrane. The membrane treatment composition can be either liquid or solid in nature and can be a poor or good solvent system for the base form of the drug. If a slow or low release rate from the transdermal system is desired, a membrane treatment composition having poor solvent properties for the base form of the drug is desired, and of course, the opposite is true if the desired release rate is high.

[0158]

[0168] The materials selected for the membrane treatment composition must be non-toxic, and the rate-controlling microporous material has the necessary solubility. In another embodiment, the membrane treatment composition is not a solvent for the material from which the microporous membrane is made. That is, the microporous membrane is chemically stable in the membrane treatment composition. Materials useful for impregnating, filling, or saturating the pores or micropores of the microporous membrane can be polar, semi-polar, or non-polar. In addition to those listed above, materials for use in the membrane treatment composition include, but are not limited to, pharma- ceutically acceptable alcohols containing 6 to 25 carbon atoms, such as hexanol, cyclohexanol, benzyl alcohol, 1,2-butanediol, glycerol, and amyl alcohol, and octyldodecanol; hydrocarbons having 5 to 12 carbon atoms, such as n-hexane, cyclohexane, and ethylbenzene; aldehydes and ketones having 4 to 10 carbon atoms, such as heptylaldehyde, cyclohexanone, and benzaldehyde; esters having 4 to 10 carbon atoms, such as amyl acetate and benzyl propionate; ether oils, such as eucalyptus oil, roux oil, cumin oil, limonene, thyme, and l-pinene; halogenated hydrocarbons having 2 to 8 carbon atoms, such as n-hexyl chloride, n-hexyl bromide, and cyclohexyl chloride, or mixtures of any of the foregoing materials.

[0159]

[0169] In some embodiments, the membrane treatment composition comprises about 60% to about 75% by weight of triethyl citrate. In some embodiments, the membrane treatment composition comprises about 55% to about 80% by weight, about 60% to about 70% by weight, about 65% to about 75% by weight, or about 65% to about 70% by weight of triethyl citrate. In some embodiments, the membrane treatment composition comprises about 10% to about 17% by weight of sorbitan monolaurate. In some embodiments, the membrane treatment composition comprises about 8% to about 25% by weight, about 10% to about 25% by weight, about 8% to about 17% by weight, about 12% to about 20% by weight, about 10% to about 15% by weight, or about 12% to about 14% by weight of sorbitan monolaurate. In some embodiments, the membrane treatment composition comprises about 15% to about 25% by weight of lauryl lactate. In some embodiments, the membrane treatment composition comprises about 10% to about 30% by weight, about 15% to about 30% by weight, about 15% to about 20% by weight, about 10% to about 25% by weight, about 10% to about 20% by weight, about 17% to about 23% by weight, about 18% to about 22% by weight, or about 19% to about 21% by weight of lauryl lactate. In some embodiments, the membrane treatment composition can be formulated with any combination of triethyl citrate, lauryl lactate, and sorbitan monolaurate in the ranges listed above. In some embodiments, the membrane treatment composition comprises about 66.7% by weight of triethyl citrate, about 20.0% by weight of lauryl lactate, and about 13.3% by weight of sorbitan monolaurate.

[0160]

[0170] The thickness of the microporous membrane can vary depending on the type of material and the desired properties of the microporous membrane (e.g., porosity, micropore size, time diffusion of active agent through the membrane). In some embodiments, the microporous membrane has a thickness of about 5 to about 200 μm. In some embodiments, the microporous membrane has a thickness of about 10 to about 150 μm, about 10 to about 125 μm, about 10 to about 100 μm, about 10 to about 75 μm, about 10 to about 50 μm, about 5 to about 45 μm, about 5 to about 30 μm, about 10 to about 30 μm, about 15 to about 30 μm, or about 20 to about 30 μm. In some embodiments, the microporous membrane has a thickness of about 22 to about 28 μm. In some embodiments, the microporous membrane has a thickness of about 24 to about 26 μm. In some embodiments, the microporous membrane has a thickness of about 25 μm. It will be understood that the thicknesses provided herein are merely exemplary, and that the actual thickness may be lesser or greater depending on the needs of a particular formulation.

[0161]

[0171] Microporous membranes can be pretreated in a variety of ways. In general, pretreatment involves contacting the microporous membrane with a membrane treatment composition in a sufficient manner and for a sufficient period of time. In some embodiments, pretreatment of the microporous membrane involves contacting the microporous membrane with the membrane treatment composition, saturating the microporous membrane with the membrane treatment composition, and removing any excess membrane treatment composition from the saturated microporous membrane. In some embodiments, the microporous membrane is immersed in the membrane treatment composition. In some embodiments, the microporous membrane is immersed in a bath of the membrane treatment composition. In some embodiments, the membrane treatment composition is spread on the microporous membrane until the microporous membrane is saturated, and then the excess membrane treatment composition is removed.

[0162]

[0172] The pretreatment of the microporous membrane with the membrane treatment composition can vary in extent. In some embodiments, some of the pores of the microporous membrane contain the membrane treatment composition therein. In some embodiments, about one-third, about one-half, about three-half, or about three-quarters of the pores contain the membrane treatment composition. In some embodiments, all of the pores contain the membrane treatment composition. In some embodiments, the portion of the pores that contain the membrane treatment composition are only partially filled. In some embodiments, the membrane treatment composition occupies about one-quarter, about one-third, about one-half, about two-thirds, or about three-quarters of the space within the occupied pores. In some embodiments, all of the pores of the microporous membrane are completely filled with the membrane treatment composition, so that the microporous membrane is saturated with the membrane treatment composition.

[0163]

[0173] The transdermal delivery system can include an adhesive overlay. The adhesive overlay in the delivery system of FIG. 1D is, in one embodiment, composed of a polyisobutylene and polybutene blend. In another embodiment, the adhesive overlay is composed of a first layer and a second layer, the first layer being composed of a polyisobutylene, polybutene, and crosslinked polyvinylpyrrolidone blend, and the second layer being composed of an acrylic adhesive. The polyisobutylene is a vinyl polymer composed of isobutylene monomers. In one embodiment, the biocompatible polymer is a PIB-based matrix including PIB Oppanol B100 (BASF, MW=1,100,000), PIB Oppanol B12 (BASF, MW=51,000, MW / MN=3.2), and polybutene (PB) Indopol H1900 (INEOS oligomer, MW=4500, MW / MN=1.8). The weight ratio between the components of the PIB matrix is ​​as follows: PIB Oppanol B100: PIB Oppanol B 12: Indopol H1900 = 10: 50: 40 (see Branteva et al., European Polymer Journal, 76, 228-244, 2016). Polybutene is a viscous, non-drying liquid polymer prepared by copolymerization of 1-butene and 2-butene with a small amount of isobutylene. In an embodiment, the polybutene in an embodiment has a molecular weight of about 750-6000 Daltons, preferably about 900-4000 Daltons, preferably about 900-3000 Daltons. In an embodiment, the mixture comprises about 40 weight percent polybutene in the polyisobutylene blend. More typically, the polybutene is present in the polyisobutylene blend in an amount of 20-50 weight percent, or 25-45 weight percent.

[0164]

[0174] The transdermal delivery system may include a backing layer that provides a structural element to hold or support the underlying adhesive layer(s). The backing layer may be formed of any suitable material known in the art. In some embodiments, the backing layer is occlusive. In some embodiments, the backing is preferably moisture impermeable or substantially moisture impermeable. In one exemplary embodiment, the barrier layer has a thickness of about 50 g / m 2 The backing layer preferably has a water vapor transmission rate of less than 100-200 days. In some embodiments, the backing layer is preferably inert and / or does not absorb the components of the adhesive layer, including the active agent. In some embodiments, the backing layer preferably prevents the release of the components of the adhesive layer through the backing layer. The backing layer may be flexible or non-flexible. The backing layer is preferably at least partially flexible so that the backing layer can at least partially conform to the shape of the skin to which the patch is applied. In some embodiments, the backing layer is flexible so that the backing layer conforms to the shape of the skin to which the patch is applied. In some embodiments, the backing layer is flexible enough to maintain contact with movements at the application site, e.g., movements of the skin. Typically, the material used for the backing layer should allow the device to follow the contours of the skin or other application site and to be worn comfortably over areas of the skin, such as joints or other inflection points, which are typically subjected to mechanical strain with little or no possibility of the device becoming dislodged from the skin due to differences in flexibility or elasticity between the skin and the device.

[0165]

[0175] In some embodiments, the backing layer is formed of one or more of a film, a nonwoven, a woven, a laminate, and combinations thereof. In some embodiments, the film is a polymeric film composed of one or more polymers. Suitable polymers are known in the art and include elastomers, polyesters, polyethylene, polypropylene, polyurethanes, and polyetheramides. In some embodiments, the backing layer is formed of one or more of polyethylene terephthalate, various nylons, polypropylene, metallized polyester films, polyvinylidene chloride, and aluminum foil. In some embodiments, the backing layer is a fabric formed of one or more of polyesters, such as polyethylene terephthalate, polyurethane, polyvinyl acetate, polyvinylidene chloride, and polyethylene. In one particular, but non-limiting, embodiment, the backing layer is formed of a polyester film laminate. One particular polyester film laminate is a laminate of polyethylene and polyester, such as the laminate sold under the name SCOTCHPAK™ #9723.

[0166]

[0176] In an embodiment, the device includes a release liner that at least partially contacts the adhesive layer to protect the adhesive layer prior to application. The release liner is typically a disposable layer that is removed before applying the device to the treatment site. In some embodiments, the release liner preferably does not absorb the components of the adhesive layer, including the active agent. In some embodiments, the release liner is impermeable to the components of the adhesive layer (including the active agent) and prevents the release of the components of the adhesive layer through the release liner. In some embodiments, the release liner is formed of one or more of a film, a nonwoven, a woven, a laminate, and combinations thereof. In some embodiments, the release liner is a silicone-coated polymer film or paper. In some non-limiting embodiments, the release liner is a silicone-coated polyethylene terephthalate (PET) film, a fluorocarbon film, or a fluorocarbon-coated PET film.

[0167]

[0177] The thickness and / or size of the device and / or adhesive matrix can be determined by one of skill in the art based at least on considerations of wearability and / or dosage required. It is understood that the administration site of the device will impact wearability considerations due to the available size of the administration site and the use of the administration site (e.g., need for flexibility to assist movement). In some embodiments, the device and / or adhesive matrix has a thickness of about 25-500 μm. In some embodiments, the device and / or adhesive matrix has a thickness of about 50-500 μm. In some embodiments, the patch is about 16 cm thick. 2 ~225cm 2 It will be understood that the thicknesses and sizes provided herein are merely exemplary, and that the actual thickness and / or size may be thinner / smaller or thicker / larger as needed for a particular formulation.

[0168]

[0178] Fabrication of the transdermal delivery system is routinely performed by one skilled in the art and involves casting or extruding each adhesive layer onto a suitable film, such as a release liner, or another layer of the transdermal delivery system, and optionally drying to remove solvents and / or volatile compounds. The layers of the transdermal delivery system can be laminated to form the final system.

[0169]

[0179] To illustrate the embodiments described herein, transdermal delivery systems and drug reservoir adhesive matrices were prepared. Examples 1-9 describe exemplary compositions and delivery systems. As described in Example 1, the transdermal delivery system included a drug reservoir and a contact adhesive, as shown in FIG. 1A, with a rate-controlling membrane located between the drug reservoir and the contact adhesive. A drug reservoir in the form of a solid monolithic adhesive reservoir was prepared using an acrylic acid / vinyl acetate copolymer adhesive with a drug carrier composition-triethyl citrate, lauryl lactate, and ethyl acetate. The drug reservoir contained about 5% by weight of donepezil hydrochloride and sodium bicarbonate to generate donepezil base in situ. A contact adhesive layer was prepared composed of the same acrylic acid / vinyl acetate copolymer adhesive with triethyl citrate, lauryl lactate, and ethyl acetate as the drug carrier composition. A rate-controlling membrane separated the drug reservoir and the contact adhesive to control the diffusional release of donepezil base from the drug reservoir.

[0170] III. Treatment method

[0180] Methods are provided for transdermally delivering therapeutic agents to a subject. In embodiments, the methods include treating one or more central nervous system (CNS) disorders using the delivery systems described herein. Examples of CNS disorders include dementia (e.g., Alzheimer's disease, Parkinson's disease, Pick's disease, frontotemporal dementia, vascular dementia, normal pressure hydrocephalus, Huntington's disease (HD), and mild cognitive impairment (MCI)), neurological related conditions, dementia related conditions, such as epilepsy, seizure disorders, acute pain, chronic pain, chronic neuropathic pain, may be treated using the systems and methods described herein. Epileptic conditions include complex partial, simple partial, partial with secondary generalization, absence including generalized, grand mal (tonic-clonic), tonic, atonic, myoclonus, neonatal, and infantile spasms. Additional specific epilepsy syndromes are juvenile myoclonic epilepsy, Lennox-Gastaut, mesial temporal lobe epilepsy, nocturnal frontal lobe epilepsy, progressive epilepsy with mental retardation, and progressive myoclonic epilepsy. The systems and methods described herein are useful in treating a variety of conditions, including cerebrovascular diseases, motor neuron diseases (e.g., amyotrophic lateral sclerosis (ALS), spinal motor atrophy, Tay-Sachs disease, Sandoff disease, familial spastic paraplegia), neurodegenerative diseases (e.g., familial Alzheimer's disease, prion-related diseases, cerebellar ataxia, Friedrich's ataxia, SCA, Wilson's disease, retinitis pigmentosa (RP), ALS, adrenoleukodystrophy, Menke Sx, cerebral autosomal dominant arteriopathy with subcortical infarctions (CADASIL), spinal muscular atrophy, familial ALS, muscular dystrophies, Charcot-Marie-Tooth disease, neurofibromatosis, von Hippel-Lindau, fragile X, spastic paraplegia, Paraplegia, psychiatric disorders (e.g., panic syndromes, generalized anxiety disorder, all types of phobias, mania, manic depression, hypomania, unipolar depression, depression, stress disorders, post-traumatic stress disorder (PTSD), somatoform disorders, personality disorders, psychoses, and schizophrenia), and drug dependence (e.g., alcohol, psychostimulants (e.g., crack, cocaine, speed, meth), opioids, and nicotine), tuberous sclerosis, and Waardenburg syndrome), stroke (e.g., thrombotic, embolic, thromboembolic, hemorrhagic, venous, and venous), movement disorders (e.g., Parkinson's disease (PD), dystonia, benign essential tremor, tardive dystonia,tardive dyskinesia, and Tourette's syndrome), ataxia syndromes, disorders of the sympathetic nervous system (e.g., Scheid-Drager's syndrome, olivopontocerebellar degeneration, striatonigral degeneration, Parkinson's disease (PD), Huntington's disease (HD), Grien-Barre, causalgia, complex pain syndromes types I and II, diabetic neuropathy, and alcoholic neuropathy), cranial nerve disorders (e.g., trigeminal neuropathy, trigeminal neuralgia, Meniere's syndrome, glossopharyngeal neuralgia, dysphagia, dysphonia, and cranial nerve palsy), bone marrow depletion, traumatic brain and spinal cord injury, radiation brain injury, multiple sclerosis, postmeningitis syndrome, prion diseases, myelitis, radiculitis, neuropathy (e.g., For example, the present invention is useful for treating and preventing pain caused by disorders including Guillian-Barre, diabetes associated with dysproteinemia, transthyretin-induced neuropathy, HIV-associated neuropathy, Lyme disease-associated neuropathy, shingles-associated neuropathy, carpal tunnel syndrome, tarsal tunnel syndrome, amyloid-induced neuropathy, Hansen's neuropathy, Bell's palsy, compressive neuropathy, sarcoidosis-induced neuropathy, cranial polyneuropathy, heavy metal-induced neuropathy, transition metal-induced neuropathy, drug-induced neuropathy), anoxic brain injury, encephalopathy, and chronic fatigue syndrome. The systems and methods described herein are also useful for treating multiple sclerosis, particularly relapsing-remitting multiple sclerosis, and preventing relapses of multiple sclerosis and / or relapsing-remitting multiple sclerosis. All of the above disorders may be treated with the systems and methods described herein.

[0171]

[0181] In embodiments, compositions and devices comprising donepezil are provided herein for use in treating, delaying progression, delaying onset, slowing progression, preventing, providing remission, and improving symptoms of cognitive impairment or disease. In embodiments, compositions and devices comprising donepezil are provided for maintaining mental function, including, but not limited to, maintaining thinking, memory, speech skills, and at least one of managing or reducing one or more behavioral symptoms of cognitive impairment or disease. In embodiments, the cognitive impairment is Alzheimer's disease. In certain embodiments, the cognitive impairment is Alzheimer's dementia. In embodiments, compositions and devices comprising donepezil are provided for use in treating mild, moderate, or severe Alzheimer's disease, etc.

[0172]

[0182] As used herein, the terms "treatment", "therapy", "therapeutic" and the like encompass any process of medical intervention directed at a pathological condition, including not only permanent cure of a disease, but also measures taken to prevent, control, or alleviate a disease or symptoms of a disease. For example, with respect to a method of treating a disorder such as Alzheimer's disease, an embodiment generally includes administration of an active agent to a subject not receiving the active agent that reduces the frequency of symptoms of the disease or delays the onset of symptoms of the disease in the subject. This includes reversing, reducing, or preventing symptoms, clinical signs, and underlying pathology of the condition in a manner that improves or stabilizes the subject's condition (e.g., regression of a mental institution).

[0173]

[0183] In one embodiment, the treatment embodiment is carried out by contacting a subject's tissue, for example, skin tissue, with a transdermal delivery system provided herein.

[0174]

[0184] In another embodiment, the therapeutic embodiment is carried out by transdermal administration of an active agent to a subject, e.g., a patient suffering from a CNS disorder, such as Alzheimer's disease and / or dementia. The term "administering" refers to applying such a drug as a therapy, e.g., by placement of the active agent in a manner that is effective to carry out its intended purpose, such as receiving it transdermally.

[0175]

[0185] A "subject" or "patient" to whom administration of a therapeutic agent is an effective treatment regimen for a disease or disorder is preferably a human, but may be any animal, including laboratory animals in the context of testing or screening or activity experiments. Thus, as can be readily understood by those skilled in the art, the methods and systems provided herein are particularly suitable for administration to any animal, particularly mammals, including, but in no way limited to, human, domestic animals such as feline or canine subjects, domestic animals such as bovine, equine, caprine, ovine, and porcine subjects, wild animals (wild or zoo), research animals such as mice, rats, rabbits, goats, sheep, pigs, dogs, cats, and the like, avian species such as chickens, turkeys, songbirds, and the like, for example, for veterinary use.

[0176]

[0186] Treatment of a subject with the system can be monitored using methods known in the art. See, for example, Forchetti et al., "Treating Patients with Moderate to Severe Alzheimer's Disease: Implications of Recent Pharmacologic Studies." Prim Care Companion J Clin Psychiatry, 7(4):155-161, 2005 (PMID:16163398). The effectiveness of treatment using the system is preferably assessed by quantitatively examining the subject's condition, for example, by noting a decrease in the frequency of adverse symptoms, behaviors, or attacks, or an increase in the time of persistent worsening of symptoms. Successful treatment results in an improvement in the subject's condition (i.e., a decrease in the frequency of relapses or an increase in the time to persistent progression).

[0177]

[0187] Based on the exemplary transdermal delivery system (also referred to as a transdermal device or device) described herein, a method for treating a suitable condition with an active agent is provided. In an embodiment, a device containing an active agent is provided herein, which is useful for treating, delaying progression, delaying onset, slowing progression, preventing, providing remission, and improving symptoms of cognitive disorders or diseases and multiple sclerosis. In an embodiment, a device containing an active agent is provided for maintaining mental function, including, but not limited to, maintaining thinking, memory, speech skills, and at least one of managing or reducing one or more behavioral symptoms of cognitive disorders or diseases. In an embodiment, the cognitive disorder is Alzheimer's disease. In a particular embodiment, the cognitive disorder is Alzheimer's dementia. In an embodiment, a device containing memantine is provided for use in treating mild, moderate, or severe Alzheimer's disease, and the like. In another embodiment, a device containing fingolimod is provided for use in treating multiple sclerosis, preventing and / or reducing the frequency of relapses of multiple sclerosis, particularly relapsing-remitting multiple sclerosis.

[0178]

[0188] In one embodiment, the method relates to therapy of CNS disorders or autoimmune disorders in a subject in need thereof by contacting the tissue of the subject with one or more transdermal delivery systems. The terms "transdermal" and "topical" are used in the broadest sense herein and refer to the administration of an active agent, such as memantine or donepezil, or fingolimod, to the skin surface or mucosa of an animal, including humans, whereby the drug passes through a body surface, such as the skin, and enters the individual's bloodstream. The term "transdermal" is intended to include transmucosal administration, i.e., the administration of a drug to the mucosal (e.g., sublingual, buccal, vaginal, rectal) surface of an individual, such that the drug passes through the mucosal tissue and enters the individual's bloodstream.

[0179]

[0189] The terms "topical delivery system," "transdermal delivery system," and "TDS," which refer to the route of drug delivery through skin tissue, are used interchangeably herein.

[0180]

[0190] As used herein, the term "skin" tissue or "dermal" tissue is defined as including tissues covered with the stratum corneum or stratum lucidum and / or other mucous membranes. The term further includes mucosal tissues, including the inner surfaces of body cavities having a mucosal lining, e.g., the cheeks, nose, rectum, vagina, etc. The term "skin" should be construed to include "mucosal tissue" and vice versa.

[0181]

[0191] Alzheimer's disease is the most common cause of senile dementia and is characterized by cognitive impairment associated with the degeneration of cholinergic neurons. Alzheimer's disease affects 6-8% of people over 65 years of age and nearly 30% of people over 85 years of age (Sozio et al., Neurophysiatric Disease and Treatment, 2012, 8:361-368), and is accompanied by loss of cognitive function and behavioral abilities. The causes of Alzheimer's disease are not yet fully understood. Because Alzheimer's disease is associated with reduced levels of several brain neurotransmitters, including acetylcholine (Ach), current treatment involves the administration of cholinesterase inhibitors. Cholinesterase inhibitors reduce the hydrolysis of acetylcholine in the synaptic cleft by inhibiting cholinesterase and / or butyrylcholinesterase, thereby increasing acetylcholine levels and improving neurotransmission (ibid.).

[0182]

[0192] The transdermal devices described herein may be designed for long-term use and / or continuous administration of the active agent. The FDA has approved daily oral doses of donepezil of 5 mg, 10 mg, and 23 mg. It will be understood that the total dose of active agent per transdermal device is determined by the size of the device and the loading of the active agent within the adhesive matrix. In one embodiment, the active agent is donepezil in free base form. Lower drug loading of donepezil base may be effective compared to salt forms (e.g., donepezil hydrochloride). The ability to achieve efficacy with lower drug loading results in thinner and / or smaller devices, both of which are desirable for reducing discomfort. In certain embodiments, the application period of the transdermal device is about 1-10 days, 1-7 days, 1-5 days, 1-2 days, 3-10 days, 3-7 days, 3-5 days, 5-10 days, and 5-7 days, inclusive. In certain embodiments, the active agent is released from the adhesive matrix as a continuous and / or sustained release over the period of application.

[0183]

[0193] A method is provided for transdermally delivering donepezil base to a subject, in which a transdermal delivery system is applied to the skin, and application of the transdermal delivery system to the subject's skin results in transdermal delivery of donepezil base, resulting in a systemic blood concentration of the drug (or metabolite) at steady state that is bioequivalent to oral administration of the therapeutic agent. As described below, bioequivalence is determined by (a) the relative mean C of the therapeutic agent administered from the transdermal delivery system and via oral delivery. max and the 90% confidence interval for AUC is 0.80 to 1.25 or 0.70 to 1.43, or (b) the AUC and C of the therapeutic agent administered from a transdermal delivery system and via oral delivery. max This is established by the 90% confidence interval of the geometric mean ratio being 0.80 to 1.25 or 0.70 to 1.43.

[0184]

[0194] Standard PK parameters routinely used to evaluate the behavior of a dosage form in vivo (i.e., when administered to an animal or human subject) include C max (peak concentration of drug in plasma), T max(time at which peak drug concentration is achieved), and AUC (area under the plasma concentration versus time curve). Methods for determining and evaluating these parameters are well known in the art. Desirable pharmacokinetic profiles of the transdermal delivery systems described herein include, but are not limited to: (1) the C max or a C of a transdermal delivery form of donepezil, as assayed in the plasma of a mammalian subject after administration, that is bioequivalent to an oral or intravenous delivery form. max and / or (2) an AUC of the transdermal delivery form of donepezil, as assayed in the plasma of a mammalian subject following administration, that is preferably bioequivalent to the AUC of an oral or intravenous dosage form of the drug, administered in the same dosage amount, and / or (3) a T max The T of the transdermal delivery form of donepezil, as assayed in the plasma of a mammalian subject after administration, is within about 80-125% of max Preferably, the transdermal delivery system exhibits a PK profile having a combination of two or more of the preceding characteristics (1), (2), and (3). Preferably, the transdermal delivery system exhibits a PK profile having one or both of characteristics (1) and (2).

[0185]

[0195] In the field of drug development, the term "bioequivalence" will be readily understood and appreciated by those skilled in the art. Various regulatory agencies have strict standards and tests to evaluate whether two drugs are bioequivalent. These standards and tests are commonly used throughout the pharmaceutical industry, and the assessment of bioequivalence is recognized as a standard form of activity in drug development programs that compares the characteristics and performance of one product with those of another. Indeed, seeking approval to market certain types of products (e.g., those evaluated under the FDA's "abbreviated new drug" procedure) requires showing that the follow-on product is bioequivalent to the reference product.

[0186]

[0196] In one embodiment, the method is in particular in accordance with the C FDA guidelines provided by the U.S. Food and Drug Administration and the corresponding European regulatory agency (EMEA). max As defined in the AUC and CUC guidelines, the method includes providing and / or administering to a subject in a fasted state a transdermal delivery system comprising donepezil base, which is bioequivalent to oral or intravenous administration of the drug (in base or salt form) to a subject in a fasted state. In another embodiment, the method includes providing and / or administering to a subject in a fasted state a transdermal delivery system comprising donepezil base, which is bioequivalent to oral or intravenous administration of the drug (in base or salt form) to a subject in a non-fasted or fed state. The US FDA and European EMEA guidelines provide for AUC and CUC. max Two products or methods are bioequivalent (T max (Measurements of AUC are not relevant for bioequivalence for regulatory purposes.) The European EMEA has previously used a different standard, which is a 90% CI of AUC of 0.80 to 1.25 and C max The 90% CI for the required 0.70 to 1.43. max Methods for determining the AUC are well known in the art.

[0187]

[0197] The transdermal delivery system prepared according to Example 1 for systemic delivery of donepezil was tested in vivo as described in Example 4. In this in vivo study, six human subjects were treated by applying the transdermal delivery system to their skin and removing it after wearing it for one week. Another group of six human subjects was treated with donepezil (ARICPET®) orally at a dose of 5 mg on days 1 and 7 of the study. Blood samples were taken from the subjects and plasma concentrations of donepezil were determined. The results are shown in Figures 2A-2B.

[0188]

[0198] 2A shows the mean plasma concentrations of donepezil in ng / mL in human subjects treated with the donepezil transdermal delivery system for one week (circles) or with 5 mg of donepezil administered orally on days 1 and 7 (triangles). The donepezil transdermal delivery system provided plasma concentrations similar to those provided from oral delivery of a similar dose of donepezil. Thus, in one embodiment, a method of transdermally administering donepezil is provided by administering a transdermal delivery system that provides a pharmacokinetic profile that is bioequivalent to the pharmacokinetic profile obtained by oral administration of donepezil.

[0189]

[0199] Figure 2B is a graph showing a zoomed-in view of the data points from Figure 2A 24 hours after oral administration of a 5 mg donepezil tablet (triangles) and removal of the donepezil transdermal delivery system (circles), which provides sustained and constant donepezil plasma concentrations 24 hours after its removal, similar to those observed 24 hours after oral administration.

[0190]

[0200] FIG. 3 is a graph showing the predicted mean plasma concentrations of donepezil in ng / mL over the last week of a 28-day (4-week) treatment period with a transdermal delivery system (solid line) designed to administer 10 mg / day for 1 week, and over 28 days with an oral tablet of 10 mg donepezil per day (dashed line). Fluctuations in plasma due to oral administration are eliminated with the transdermal system, and a new patch is applied every week, maintaining a constant plasma concentration over the treatment period. The transdermal delivery system provides a constant plasma concentration of donepezil over a sustained period (e.g., 3, 5, 7, 14 days), with the plasma concentration being essentially the same as or within about 10%, 15%, 20%, or 30% of the plasma concentration achieved with daily oral administration of a similar daily dose of donepezil.

[0191]

[0201] Referring again to the study of Example 4, six subjects treated with the donepezil transdermal delivery system for one week were monitored for several days after removal of the delivery system from their skin for signs of skin irritation. Figure 4 is a bar graph showing the number of subjects from the six in the group and the skin irritation observed in the period following removal of the delivery system, with open bars indicating no skin irritation and filled bars indicating mild skin irritation. The delivery system caused no or mild skin irritation several hours after removal, and any mild irritation resolved within 1-2 days.

[0192]

[0202] In another study, human subjects were treated with a transdermal delivery system designed to deliver an amount of donepezil systemically that is bioequivalent to a once-daily 10 mg dose of orally administered donepezil. The predicted pharmacokinetic parameters for the two delivery routes, C max , AUC, and C min are compared in Table 1. [Table 1]

[0193]

[0203] Thus, in one embodiment, a method for delivering donepezil base to a subject is provided. The method includes providing a transdermal delivery system comprised of donepezil and administering or instructing the administration of the transdermal delivery system to the skin of a subject. The method achieves transdermal delivery of donepezil that is bioequivalent to oral administration of the therapeutic agent, where the bioequivalence is: (a) a relative mean C of the therapeutic agent administered from the transdermal delivery system and via oral delivery of between 0.70 and 1.43, or between 0.80 and 1.25; max and the 90% confidence intervals of AUC, or (b) the AUC and C of the therapeutic agent administered from the transdermal delivery system and via oral delivery of 0.70 to 1.43 or 0.80 to 1.25. max This is established by the 90% confidence interval for the proportion.

[0194]

[0204] Example 5 describes a study conducted in human subjects that investigated transdermal patches containing donepezil and compared them to orally administered donepezil. In this study, patients were enrolled to participate in a 6-month, 3-period randomized crossover study that compared the steady-state pharmacokinetic profile of once-daily oral donepezil (ARICEPT®) with a donepezil transdermal patch formulation. The transdermal patches were provided in two sizes, A and B, but the transdermal patches were identical in all respects except for the surface area. During the study, participants in each treatment group received 5 mg / day of donepezil for one week, followed by 10 mg / day of donepezil delivered once a week from two sizes of transdermal patches (Groups 1 and 2) or orally (Group 3) for four weeks. Pharmacokinetic measurements were assessed during the fourth week of 10 mg / day treatment, when plasma concentrations reached a stable level. Blood samples were taken daily over the fourth week from subjects receiving transdermal treatment to determine pharmacokinetics. Subjects receiving oral donepezil had blood drawn on the last day of week 4 to determine pharmacokinetics. Mean plasma concentrations of donepezil in ng / mL are shown for each day of week 5 of the study in Figure 5A, where the solid lines correspond to the smaller surface area transdermal patch and the dashed lines correspond to the larger surface area transdermal patch. The darker, thicker lines on days 6-7 show the mean plasma concentrations of subjects receiving oral donepezil, and the dotted lines show the expected daily plasma concentrations for oral treatment. The mean plasma concentrations of donepezil in subjects treated with the transdermal patch were bioequivalent to the plasma concentrations of donepezil in subjects treated orally with donepezil. The larger and smaller transdermal patches demonstrated dose proportionality. Table 2 shows the key pharmacokinetic parameters in the bioequivalence evaluation of the smaller surface area transdermal patch used in this study. [Table 2]

[0195]

[0205] The gastrointestinal-related adverse events of nausea, vomiting, and diarrhea reported by subjects in the clinical study described above with respect to Figure 5A are shown in Figure 5B. Subjects treated with the smaller size transdermal patch (dotted filled bars) and larger size transdermal patch (vertical filled bars) had a lower incidence or nausea, vomiting, and diarrhea than subjects treated with oral (horizontal filled bars) donepezil. The number of subjects experiencing nausea was four times lower when 10 mg / day of donepezil was administered transdermally versus orally. The number of subjects experiencing diarrhea was two times lower when 10 mg / day of donepezil was administered transdermally versus orally.

[0196]

[0206] Thus, in one embodiment, compositions and methods for delivering donepezil to a subject are provided. The compositions, when applied to the skin of a subject, provide transdermal delivery of donepezil, achieve plasma concentrations of donepezil that are bioequivalent to oral administration of donepezil at steady state, and / or provide a number of gastrointestinal-related adverse events that are 2-fold, 3-fold, 4-fold, or 5-fold lower than subjects treated orally with the same dose of donepezil (i.e., the dose given orally is equal to the dose given transdermally, so the subject is treated with an equivalent amount of donepezil given orally or transdermally). In one embodiment, the donepezil given orally is a salt form of donepezil, and the donepezil given transdermally is donepezil base. In one embodiment, the number of gastrointestinal-related adverse events is 2-5, 2-4, and 2-3 times lower, and in another embodiment, the number of gastrointestinal-related adverse events is at least about 2-fold, at least about 3-fold, at least about 4-fold, or at least about 5-fold lower than subjects treated orally with the same dose of donepezil. In one embodiment, the delivery of donepezil is for the treatment of Alzheimer's disease.

[0197]

[0207] The transdermal devices described herein may be designed for chronic use and / or continuous administration of the active agent. The FDA has approved doses of memantine of 2 mg, 5 mg, 7 mg, 10 mg, 14 mg, 21 mg, and 28 mg. It will be understood that the total dose of active agent per transdermal device is determined by the size of the device and the loading of the active agent within the adhesive matrix. In an embodiment, the active agent is memantine in free base form. Lower drug loading of memantine may be effective compared to salt forms (e.g., memantine hydrochloride). The ability to achieve efficacy with lower drug loading results in a thinner and / or more compact device, both of which are desirable for reducing discomfort. In certain embodiments, the application period of the transdermal device is about 1-10 days, 1-7 days, 1-5 days, 1-2 days, 3-10 days, 3-7 days, 3-5 days, 5-10 days, and 5-7 days, inclusive. In certain embodiments, the active agent is released from the adhesive matrix as a continuous and / or sustained release over the period of application.

[0198]

[0208] A method is provided for transdermally delivering memantine to a subject, in which a transdermal delivery system is applied to the skin, and application of the transdermal delivery system to the subject's skin results in transdermal delivery of memantine, resulting in a systemic blood concentration of the drug (or metabolite) at steady state that is bioequivalent to oral administration of the therapeutic agent. As described below, bioequivalence is measured by: (a) the relative mean C max and the 90% confidence interval for AUC is 0.80 to 1.25; or (b) the AUC and C of a therapeutic agent administered from a transdermal delivery system and via oral delivery. max This is established by the 90% confidence interval of the ratio being 0.80 to 1.25.

[0199]

[0209] Standard pharmacokinetic (PK) parameters routinely used to assess the behavior of a dosage form in vivo (i.e., when administered to an animal or human subject) include C max (peak concentration of drug in plasma), T max(time at which peak drug concentration is achieved), and AUC (area under the plasma concentration versus time curve). Methods for determining and evaluating these parameters are well known in the art. Desirable pharmacokinetic profiles of the transdermal delivery systems described herein include, but are not limited to: (1) the C max or a C of a transdermal delivery form of memantine, as assayed in the plasma of a mammalian subject after administration, that is bioequivalent to an oral or intravenous delivery form. max and / or (2) an AUC of the transdermal delivery form of memantine, as assayed in the plasma of a mammalian subject following administration, that is preferably bioequivalent to the AUC of an oral or intravenous dosage form of the drug administered in the same dosage amount, and / or (3) a T of an oral or intravenous dosage form of the drug administered in the same dosage amount. max The T of the transdermal delivery form of memantine, as assayed in the plasma of a mammalian subject after administration, is within approximately 80-125% of max Preferably, the transdermal delivery system exhibits a PK profile having a combination of two or more of the preceding characteristics (1), (2), and / or (3). In another embodiment, the transdermal delivery system exhibits a PK profile having a combination of one or both of characteristics (1) and (2).

[0200]

[0210] In the field of drug development, the term "bioequivalence" will be readily understood and appreciated by those skilled in the art. Various regulatory agencies have strict standards and tests to evaluate whether two drugs are bioequivalent. These standards and tests are commonly used throughout the pharmaceutical industry, and the assessment of bioequivalence is recognized as a standard form of activity in drug development programs that compares the characteristics and performance of one product with those of another. Indeed, seeking approval to market certain types of products (e.g., those evaluated under the FDA's "abbreviated new drug" procedure) requires showing that the follow-on product is bioequivalent to the reference product.

[0201]

[0211] In one embodiment, the method is in particular in accordance with the C FDA guidelines provided by the U.S. Food and Drug Administration and the corresponding European regulatory agency (EMEA). max The present invention encompasses providing and / or administering to a fasted subject a transdermal delivery system containing memantine base, as defined by the US FDA and European EMEA guidelines, which is bioequivalent to oral or intravenous administration of the drug (in base or salt form) to a fasted subject. max Two products or methods are bioequivalent (T max (Measurements of AUC are not relevant for bioequivalence for regulatory purposes.) The European EMEA has previously used a different standard, which is a 90% CI of AUC of 0.80 to 1.25 and C max The 90% CI for the required 0.70 to 1.43. max Methods for determining the AUC are well known in the art.

[0202]

[0212] Thus, in one embodiment, a method for delivering memantine base to a subject is provided. The method includes providing a transdermal delivery system comprised of memantine and administering, or instructing the administration of, the transdermal delivery system to the skin of a subject. The method achieves transdermal delivery of memantine that is bioequivalent to oral administration of the therapeutic agent, where the bioequivalence is greater than or equal to (a) a relative mean C of the therapeutic agent administered from the transdermal delivery system and via oral delivery of between 0.70 and 1.43, or between 0.80 and 1.25. max and the 90% confidence intervals of AUC, or (b) the AUC and C of the therapeutic agent administered from the transdermal delivery system and via oral delivery of 0.70 to 1.43 or 0.80 to 1.25. max This is established by the 90% confidence interval of the geometric mean ratio.

[0203]

[0213] Examples 6 and 7 further describe exemplary compositions and delivery systems. As described in Example 6, a transdermal delivery system is prepared comprising a drug reservoir layer as shown in FIG. 1A and a contact adhesive layer with a rate-controlling membrane layer located between the drug reservoir and the contact adhesive layer. A drug reservoir in the form of a solid monolithic adhesive reservoir is prepared using an acrylic acid / vinyl acetate copolymer adhesive and cross-linked polyvinylpyrrolidone (PVP-CLM) with the specified dissolution agents, carriers, and optionally permeation enhancers (Table 3). The drug reservoir contains about 25% by weight memantine hydrochloride and 9.73% by weight sodium bicarbonate to generate memantine base in situ. A contact adhesive layer containing a higher alcohol and a biocompatible polymer is synthesized. In a second variation, the contact adhesive contained a higher alcohol and a biocompatible polymer with dispersed silica. A rate-controlling membrane can be introduced between the drug reservoir and the contact adhesive to control the diffusion release of memantine base from the drug reservoir. [Table 3]

[0204]

[0214] A transdermal delivery system was prepared as described in Example 6, consisting of a drug reservoir and a skin contact adhesive layer separated by an intermediate layer. The drug reservoir in the exemplary system comprises acrylic acid / vinyl acetate copolymer and cross-linked polyvinylpyrrolidone (KOLLIDON-CLM). These base materials are mixed with the specified carriers and solubilizers, memantine hydrochloride, and sodium bicarbonate (Table 4). The drug reservoir contains about 25% by weight memantine hydrochloride and 9.73% by weight sodium bicarbonate to generate memantine base in situ. The skin contact adhesive layer contains a higher alcohol and a biocompatible polymer. [Table 4]

[0205]

[0215] A memantine transdermal system was prepared as described in Example 7 to demonstrate delivery of the active agent formulated from an amine salt form of the active agent and an amphoteric inorganic base compound. The memantine transdermal system was evaluated in vitro by measuring the release of memantine from the system across human skin, and the results are shown in Figure 6 (squares). Approximately 18 hours after application of the transdermal system to the skin, approximately 12-15 μg / cm 2 A steady state flux rate of between 0.1 and 0.5 h was achieved. The flux rate remained stable for about 6.5 days before declining. Thus, in one embodiment, a transdermal delivery system for delivering a base form of an active agent is prepared from an amine salt form of the active agent and sodium bicarbonate, and provides a skin flux rate or permeation rate that is therapeutic for a period of at least about 3 days, or 5 days, or 7 days (or 3-7 days). In one embodiment, the steady state in vitro skin flux rate remains within 15%, 20%, 25%, or 30% for a period of at least about 3 days, or 5 days, or 7 days (or 3-7 days). That is, the in vitro skin flux measured at time point y differs from the in vitro skin flux measured at an adjacent earlier time point x, where x and y are less than 15%, 20%, 25%, or 30% at each time point within the 3-, 5-, or 7-day measurement period.

[0206]

[0216] Comparative examples are also carried out to illustrate the compositions, systems and methods of the present invention described herein. Figure 6 shows adhesive compositions (transdermal systems) prepared with the free base form of drug (diamonds), adhesive compositions (transdermal systems) prepared with the amine salt form of drug without sodium bicarbonate (circles), or adhesive compositions (transdermal systems) prepared with the salt form of amine drug and amphoteric inorganic base compound, where the pKa of the amphoteric inorganic base compound is higher than but not lower than the pKa of the amine salt form of active agent (triangles). In these comparative examples, the in vitro skin flux of drug is insufficient for therapy.

[0207]

[0217] A transdermal system for delivering donepezil comprising a microporous membrane layer pretreated with a membrane treatment composition is described in Example 9. A comparative example of a transdermal system in which the microporous membrane is left untreated is also described. A comparative example in vitro skin flux study was performed and the results are provided in Figure 7. It can be seen that treatment of the microporous membrane with the membrane treatment composition increases the total skin flux of donepezil and maintains this flux over an extended period of time. EXAMPLES

[0208]

[0218] The following examples are illustrative in nature and are not intended to be limiting in any way.

[0209] Example 1 Donepezil transdermal delivery system

[0219] A transdermal delivery system containing donepezil was prepared as follows.

[0210] Preparation of drug stocks

[0220] Sorbitan monolaurate (SPAN® 20, 1.20 grams) was dissolved in 6.00 grams of triethyl citrate and mixed with 1.80 grams of lauryl lactate and 89.69 grams of ethyl acetate. 6.00 grams of glycerin was added and mixed. 9.00 grams of donepezil hydrochloride and 1.82 grams of sodium bicarbonate were added and dispersed in the mixture. 12.00 grams of crosslinked micronized polyvinylpyrrolidone (Kollidon® CL-M) was then added and the mixture was homogenized. 43.93 grams of acrylic acid / vinyl acetate copolymer (Duro-Tak® 387-2287, 50.5% solids) was added to the homogenized drug dispersion and mixed thoroughly. The wet adhesive formulation was coated onto a release liner and dried using a lab coater (Werner Mathis) to obtain a 12 mg / cm2 adhesive formulation. 2 A dry coating weight of 100 g was obtained.

[0211] Preparation of contact adhesive:

[0221] Sorbitan monolaurate (SPAN® 20, 0.60 grams) was dissolved in 3.0 grams of triethyl citrate and mixed with 0.9 grams of lauryl lactate, 25.45 grams of ethyl acetate, and 1.34 grams of isopropyl alcohol. 6.00 grams of crosslinked micronized polyvinylpyrrolidone (Kollidon® CL-M) was added and the mixture was homogenized. 38.61 grams of acrylic acid / vinyl acetate copolymer (Duro-Tak® 387-2287, 50.5% solids) was added to the homogenized mixture and mixed thoroughly. The wet adhesive formulation was coated onto a release liner and dried to give a 5 mg / cm2 adhesive formulation. 2 A dry coating weight of 100 g was obtained.

[0212] Lamination and punching

[0222] A rate controlling membrane (CELGARD® 2400 or Reemay® 2250) was laminated to the adhesive side of the drug reservoir. A contact adhesive was then laminated on top of the A rate controlling membrane laminated with the drug reservoir. The release liner on the drug reservoir side was replaced and laminated with a backing film. The final 5-layer laminate was die cut into transdermal patches.

[0213]

[0223] The weight percentages of the ingredients in the transdermal delivery system are set forth in Table 1.1 below. [Table 5]

[0214] Example 2 Donepezil transdermal delivery system

[0224] A transdermal delivery system containing donepezil was prepared as follows.

[0215] Preparation of drug stocks

[0225] Sorbitan monolaurate (SPAN® 20) was dissolved in triethyl citrate and mixed with lauryl lactate. Glycerin was added and mixed. Donepezil hydrochloride and sodium bicarbonate were added and dispersed in the mixture. Crosslinked micronized polyvinylpyrrolidone (KOLLIDON® CL-M) was then added and the mixture was homogenized. Acrylic acid / vinyl acetate copolymer (DURO-TAK® 387-2287, 50.5% solids) was added to the homogenized drug dispersion and mixed thoroughly. The wet adhesive formulation was coated onto a release liner and dried using a laboratory coater (Werner Mathis).

[0216] Preparation of contact adhesive

[0226] Sorbitan monolaurate (SPAN® 20) was dissolved in triethyl citrate and mixed with lauryl lactate. Crosslinked micronized polyvinylpyrrolidone (Kollidon® CL-M) was added and the mixture was homogenized. Acrylic acid / vinyl acetate copolymer (DURO-TAK® 387-2287, 50.5% solids) was added to the homogenized mixture and mixed thoroughly. The wet adhesive formulation was coated onto a release liner and allowed to dry.

[0217] Lamination and punching

[0227] A rate controlling membrane (CELGARD® 2400) was laminated onto the adhesive side of the drug reservoir. A contact adhesive was then laminated onto the rate controlling membrane laminated with the drug reservoir. The release liner on the drug reservoir side was replaced and laminated with a backing film. The final 5-layer laminate was die cut into transdermal patches.

[0218]

[0228] The weight percentages of the ingredients in the transdermal delivery system are set forth in Table 2.1 below. [Table 6]

[0219] Example 3 Donepezil transdermal delivery system

[0229] A transdermal delivery system containing donepezil was prepared as follows.

[0220] Preparation of drug stocks:

[0230] Sorbitan monolaurate (SPAN® 20) was dissolved in triethyl citrate and mixed with lauryl lactate. Glycerin was added and mixed. Donepezil hydrochloride was added and dispersed in the mixture. Fumed silica (AEROSIL® 200 Pharma) was then added and the mixture was homogenized. Acrylic acid / vinyl acetate copolymer (DURO-TAK® 387-2287, 50.5% solids) and dimethylaminoethyl methacrylate, butyl methacrylate, methyl methacrylate copolymer (EUDRAGIT® EPO) were added to the homogenized drug dispersion and mixed thoroughly. The wet adhesive formulation was coated onto a release liner and dried using a laboratory coater (Werner Mathis).

[0221] Preparation of contact adhesive:

[0231] Sorbitan monolaurate (SPAN® 20) was dissolved in triethyl citrate and mixed with lauryl lactate. Crosslinked micronized polyvinylpyrrolidone (KOLLIDON® CL-M) was added and the mixture was homogenized. Acrylic acid / vinyl acetate copolymer (Duro-Tak® 387-2287, 50.5% solids) was added to the homogenized mixture and mixed thoroughly. The wet adhesive formulation was coated onto a release liner and allowed to dry.

[0222] Lamination and punching

[0232] A rate controlling membrane (CELGARD® 2400) was laminated onto the adhesive side of the drug reservoir. A contact adhesive was then laminated onto the rate controlling membrane laminated with the drug reservoir. The release liner on the drug reservoir side was replaced and laminated with a backing film. The final 5-layer laminate was die cut into transdermal patches.

[0223]

[0233] The weight percentages of the ingredients in the transdermal delivery system are set forth in Table 3.1 below. [Table 7]

[0224] Example 4 In vivo administration of donepezil from donepezil transdermal delivery systems

[0234] The transdermal delivery system containing donepezil was prepared as described in Example 1. Twelve (12) human subjects were randomly divided into two groups for treatment with the transdermal delivery system (n=6) or orally administered donepezil (ARICPET®), 5 mg, on days 1 and 7 of the study. The transdermal delivery system was applied to the skin and worn for one week and then removed. Blood samples were collected daily from subjects treated with the transdermal delivery system. In the group treated with orally administered donepezil, blood samples were collected at frequent time intervals on days 1 and 7, and again at frequent time intervals on days 8, 10, 12, and 14. The mean plasma concentrations of donepezil in the treatment groups are shown in Figures 2A-2B.

[0225] Example 5 In vivo administration of donepezil from donepezil transdermal delivery systems

[0235] A transdermal delivery system containing donepezil was prepared as described in Example 2. Patients were enrolled and randomized into three treatment groups for a 5-week treatment study. Patients in Group 1 (n=52) and Group 2 (n=51) were treated with the transdermal system of Example 2, with Group 1 patients wearing a patch with a smaller surface area (Patch A) than that of Group 2 patients (Patch B). Except for size, Patch A and Patch B were identical. During the first week of the study, patients in Groups 1 and 2 wore a patch designed to deliver 5 mg of donepezil from a once-weekly patch. After the initial 7-day period, patients were given a transdermal system designed to be worn for 7 days (a once-weekly transdermal patch) again delivering 10 mg of donepezil per day, with Patch A differing from Patch B only in surface area. The transdermal systems were replaced weekly for 4 weeks. Patients in group 3 (n=54) were treated orally with donepezil (ARICEPT) at a dose of 5 mg per day for 7 days, followed by donepezil (ARICEPT) at a dose of 10 mg once daily for 4 weeks.

[0226]

[0236] For subjects in Groups 1 and 2, blood samples were taken daily during the fourth week of dosing at the 10 mg level when plasma concentrations were at steady state. For subjects in Group 3, blood samples were taken on the last day of the fourth week of 10 mg / day dosing. The mean plasma concentrations of donepezil for the treatment groups during the fourth week of 10 mg dosing are shown in FIG. 5A, which shows subjects treated with donepezil administered transdermally via transdermal patch A (smaller surface area, solid line), transdermal patch B (larger surface area, dashed line), and oral donepezil (heavy heavy line on days 6-7), with the dotted line indicating the predicted daily plasma concentration for oral treatment.

[0227]

[0237] FIG. 5B is a bar graph showing the number of gastrointestinal-related adverse events (nausea, vomiting, diarrhea) reported by study subjects, where bars with dotted fill correspond to subjects treated with the weekly small size transdermal patch, bars with vertical fill correspond to subjects treated with the weekly larger size transdermal patch, and bars with horizontal fill correspond to subjects treated with oral donepezil.

[0228] Example 6 Memantine transdermal delivery system

[0238] A transdermal delivery system containing memantine is prepared as follows.

[0229] Preparation of drug stocks:

[0239] The memantine salt and alkali salt are dissolved in a mixture of ethyl acetate, about isopropyl alcohol, propylene glycol, and levulinic acid to form a clear solution. In one variation, fumed silica (AEROSIL® 200P) is added and the mixture is homogenized. To the homogenous mixture, acrylic acid / vinyl acetate copolymer (DURO-TAK® 387-2287) is added and mixed until the mixture is homogenous.

[0230]

[0240] The adhesive compound mixture is coated onto a siliconized polyethylene terephthalate liner and dried in a Werner Mathis coater at 60° C. for 8 minutes to obtain a dry adhesive layer.

[0231]

[0241] The transdermal delivery system is fabricated using two dry adhesive layers sandwiched together with a polyester nonwoven fabric between the two adhesive layers. A coated polyethylene terephthalate liner is then replaced with the backing film.

[0232] Preparation of contact adhesive

[0242] Octyldodecanol, crosslinked, micronized polyvinylpyrrolidone (KOLLIDON® CL-M), and any solvent are mixed and the mixture is homogenized. Polyisobutylene (PIB, 10 / 50 / 40) is added to the homogenized mixture and mixed thoroughly. The wet adhesive formulation is coated onto a release liner and allowed to dry.

[0233] Lamination and punching

[0243] An intermediate layer (CELGARD® 2400 or Reemay® 2250) is laminated to the adhesive side of the drug reservoir. A contact adhesive is then laminated on top of the rate controlling membrane laminated with the drug reservoir. The release liner on the drug reservoir side is replaced and laminated with a backing film.

[0234]

[0244] The transdermal delivery systems are then punched out of the laminate.

[0235] Example 7 Transdermal memantine salt formulation using sodium bicarbonate Preparation of Drug in Adhesive (Drug Depot)

[0245] A quantity of 2.0 g of glycerin and 2.0 g of octyldodecanol were mixed with a mixture of 29.35 g of ethyl acetate and 1.86 g of isopropyl alcohol. Into this solution, 5.0 g of memantine hydrochloride and 1.95 g of sodium bicarbonate were dispersed by stirring. To the dispersion, 3.0 g of crosslinked polyvinylpyrrolidone (KOLLIDON® CL-M) was added and homogenized using a Silverson mixer homogenizer. To the homogenized dispersion, 11.99 g of acrylate copolymer (DURO-TAK® 387-2287, 50.5% solids) was added and mixed thoroughly. The wet adhesive formulation was coated onto a release liner and dried using a Werner Mathis coater to obtain a 15 mg / cm2 adhesive. 2 A dry coating weight of 100 g was obtained.

[0236] Preparation of contact adhesive

[0246] 2.0 g of octyldodecanol was mixed with 20.67 g of n-heptane. 4.00 g of crosslinked polyvinylpyrrolidone (KOLLIDON® CL-M) was added to the solution, and the mixture was then homogenized using a Silverson mixer homogenizer. A 23.33 g amount of polyisobutylene adhesive solution (60% solids) was added to the homogenized mixture and mixed thoroughly. The wet adhesive formulation was coated onto a release liner and dried to obtain a 5 mg / cm2 adhesive formulation. 2 A dry coating weight of 100 g was obtained.

[0237] Lamination and punching

[0247] A polypropylene microporous membrane (Celgard® 2400) was laminated between the drug-in-adhesive layer and the contact adhesive layer. The release liner on the drug-in-adhesive side was replaced and laminated with a backing 3M SCOT CHPAK® 1012. The final 5-layer laminate was die cut into patches.

[0238] In vitro skin flux assessment

[0248] Dermatomal human cadaveric skin was obtained from a skin bank and frozen until ready for use. After thawing, the skin was placed in 60°C water for 1-2 minutes and the epidermis was carefully separated from the dermis. The epidermis was either used immediately or wrapped and frozen for later use.

[0239]

[0249] 0.64cm 2 In vitro skin flux studies were carried out using a Franz-type diffusion cell with an active diffusion area of ​​100 μm. The epidermis was mounted between the donor and acceptor compartments of the diffusion cell. The transdermal delivery system was placed on top of the skin and the two compartments were firmly fixed together.

[0240]

[0250] The receptor compartment was filled with 0.01 M phosphate buffer, pH 6.5, containing 0.01% gentamicin. The solution in the receptor compartment was continuously stirred using a magnetic stir bar in the receptor compartment. The temperature was maintained at 32 ± 0.5 °C. Samples were taken from the receptor solution at regular intervals and the receptor solution was replaced with fresh phosphate buffer. The drug content in the samples was analyzed using LCMS for memantine.

[0241]

[0251] The resulting flux profile is shown in Figure 7 (squares). The flux for this example is relatively high and remains relatively constant over the 7 day period.

[0242] Example 8 In vivo administration of memantine by a transdermal delivery system

[0252] A transdermal delivery system containing memantine is prepared as described in Example 1. Human subjects are randomly divided into two groups for treatment with the transdermal delivery system or orally administered memantine (NAMENDA®) and receive 7 mg on days 1 and 7 of the study. The transdermal delivery system is applied to the skin and worn for one week and then removed. Blood samples are taken daily from subjects treated with the transdermal delivery system. In the group treated with orally administered memantine, blood samples are taken at frequent time intervals on days 1 and 7, and again at frequent time intervals on days 8, 10, 12, and 14. The mean plasma concentrations of memantine in the treatment groups are measured.

[0243] Example 9 Donepezil HCl transdermal system with microporous membrane Pretreatment of microporous membranes with membrane treatment compositions

[0253] In this example, a polypropylene microporous membrane (Celgard® 2400) with a typical porosity of 41% and a pore size of 0.043 μm was used as the microporous membrane. Two different donepezil patches were prepared, one with a pretreated polypropylene microporous membrane and one with an untreated membrane, to compare the in vitro skin flux profiles of the two systems.

[0244]

[0254] A membrane treatment composition was prepared with 66.67% w / w triethyl citrate, 20.00% w / w lauryl lactate, and 13.33% w / w sorbitan monolaurate. The triethyl acetate was thoroughly mixed with the lauryl lactate to form a clear solution. The sorbitan monolaurate was then added to the mixture and thoroughly mixed with high shear stirring to form a cloudy homogenous composition. The cloudy liquid was then coated onto a membrane with a coating knife to saturate it with the liquid mixture. Upon saturation, the initially white membrane turned into a translucent membrane. The excess membrane treatment composition was then wiped off to remove it.

[0245] Preparation of drug stocks

[0255] 1.20 grams of sorbitan monolaurate (SPAN® 20) was dissolved in a mixture of 6.00 grams of triethyl citrate and mixed with 1.80 grams of lauryl lactate and 89.69 grams of ethyl acetate. 6.00 grams of glycerin was added and mixed. 9.00 grams of donepezil hydrochloride and 1.82 grams of sodium bicarbonate were dispersed in this mixture. 12.00 grams of crosslinked polyvinylpyrrolidone (Kollidon® CL-M) was added to the drug dispersion solution and the mixture was homogenized thoroughly. 43.93 grams of acrylate copolymer (Duro-Tak® 387-2287, 50.5% solids) was added to the homogenized drug dispersion and mixed thoroughly. Ascorbyl palmitate was added. The wet adhesive formulation was coated onto a release liner and dried using a laboratory coater (Werner Mathis coater) to obtain a 12 mg / cm2 adhesive formulation. 2 A dry coating weight of 100 g was obtained.

[0246] Preparation of contact adhesive

[0256] A quantity of 0.60 grams of sorbitan monolaurate (SPAN® 20) was dissolved in 3.00 grams of triethyl citrate and mixed with 0.9 grams of lauryl lactate, 25.45 grams of ethyl acetate, and 1.34 grams of isopropyl alcohol. 6.00 grams of crosslinked polyvinylpyrrolidone (Kollidon® CL-M) was added and the mixture was homogenized. A quantity of 38.61 grams of acrylate copolymer (Duro-Tak® 387-2287, 50.5% solids) was added to the homogenized mixture and mixed thoroughly. The wet adhesive formulation was coated onto a release liner and dried to obtain a 5 mg / cm2 adhesive formulation. 2 A dry coating weight of 100 g was obtained.

[0247] Preparation of the final 5-layer laminate of Donepezil TDS, punching and pouches

[0257] A polypropylene rate-controlling membrane (Celgard® 2400) pretreated with the membrane treatment composition was laminated to the adhesive side of the drug reservoir. A contact adhesive was then laminated on top of the rate-controlling membrane laminated with the drug reservoir. The release liner on the drug reservoir side was replaced with a backing film. The final 5-layer laminate was die-cut into patches and each test patch was individually bagged. The resulting transdermal delivery system included a drug reservoir layer and a contact adhesive layer with a rate-controlling microporous membrane layer positioned between the drug reservoir and the contact adhesive layer, as shown in FIG. 1A.

[0248]

[0258] The composition of the donepezil transdermal delivery system (TDS) of this example is summarized in Table 9.1. [Table 8]

[0249]

[0259] A control sample of donepezil TDS was prepared in the same manner using an untreated Celgard® 2400 membrane instead of the treated membrane.

[0250]

[0260] After equilibration at room temperature for two weeks, in vitro skin flux from the patches was tested as follows.

[0251] 1. Preparation of Skin

[0261] Dermatomal human cadaveric skin was obtained from a skin bank and frozen until ready for use. After thawing, the skin was placed in 60°C water for 1-2 minutes and the epidermis was carefully separated from the dermis. The epidermis was either used immediately or wrapped and frozen for later use.

[0252] In vitro skin flux test

[0262] 0.64cm 2 In vitro skin flux studies were carried out using Franz-type diffusion cells with an active diffusion area of ​​100 μm. The epidermis was mounted between the donor and acceptor compartments of the diffusion cell. The patch was placed on the skin and the two compartments were firmly fixed together.

[0253]

[0263] The receptor compartment was filled with 0.01 M phosphate buffer, pH 6.5, containing 0.01% gentamicin. The solution in the receptor compartment was continuously stirred using a magnetic stir bar in the receptor compartment. The temperature was maintained at 32° ± 0.5°C. Samples were periodically taken from the receptor solution and analyzed for drug content using high performance liquid chromatography (HPLC).

[0254]

[0264] The result is 1cm per hour. 2 The drug was calculated in terms of the amount of drug diffused through the epidermis per unit area.

[0255]

[0265] The results are plotted in Figure 7. Each data point is the average of three skin donors with four replicates per donor. Patches with untreated membranes show a low flux profile even after two weeks of equilibration.

[0256]

[0266] While several exemplary aspects and embodiments have been discussed above, those skilled in the art will recognize certain modifications, permutations, additions, and subcombinations thereof, and it is therefore intended that the following appended claims, and any claims hereafter introduced, be interpreted to include all such modifications, permutations, additions, and subcombinations that are within their true spirit and scope.

Claims

1. 1. A transdermal delivery system comprising: a skin contact adhesive layer for attaching the transdermal delivery system to the skin of a user; a drug reservoir layer comprising an adhesive polymer, the hydrochloride form of donepezil, sodium bicarbonate, ascorbyl palmitate, and a drug carrier composition; a microporous membrane disposed between the skin contact adhesive layer and the drug reservoir layer, the microporous membrane comprising a plurality of pores filled with a membrane treatment composition different from the drug carrier composition; the skin contact adhesive layer comprises an acrylic acid / vinyl acetate copolymer adhesive, a non-ionic surfactant, a long chain aliphatic alcohol, and a citrate ester; The drug carrier composition comprises a nonionic surfactant, a long-chain aliphatic alcohol, a citrate ester, and a hydrophilic solvent; A transdermal delivery system, wherein the film treatment composition is free of the hydrophilic solvent and comprises about 8-25% by weight sorbitan monolaurate, about 10-30% by weight lauryl lactate, and about 55-80% by weight triethyl citrate.

2. 10. The system of claim 1, wherein the drug carrier composition comprises about 1.5-2.5% by weight sorbitan monolaurate, about 8-12% by weight triethyl citrate, and about 5-15% by weight glycerin.

3. The system of claim 2 , wherein the drug carrier composition further comprises lauryl lactate.

4. The system of any one of claims 1 to 3, wherein the skin contact adhesive layer comprises a contact adhesive layer drug carrier composition.

5. 5. The system of claim 4, wherein the contact adhesive layer drug carrier composition comprises a non-ionic surfactant, a long chain aliphatic alcohol, a citrate ester, or a combination thereof.

6. The system of claim 5 , wherein the contact adhesive layer drug carrier composition is different from the drug carrier composition.

7. The system of claim 1, wherein the drug reservoir layer comprises about 5-25% by weight of donepezil hydrochloride.

8. 8. The system of claim 7, wherein the drug reservoir layer comprises about 16.0% donepezil hydrochloride by weight.

9. 9. The system of claim 8, wherein the drug reservoir layer comprises about 2-5% by weight sodium bicarbonate.

10. 10. The system of claim 9, wherein the drug reservoir layer comprises about 2.6% by weight sodium bicarbonate.

11. The system of claim 10, wherein the drug reservoir layer comprises about 0.1-2% by weight of ascorbyl palmitate.

12. 12. The system of claim 11, wherein the drug reservoir layer comprises about 0.5% by weight ascorbyl palmitate.

13. The drug reservoir layer comprises: about 16.0% by weight of donepezil hydrochloride, About 2.6% by weight of sodium bicarbonate, About 10.0% by weight of triethyl citrate, about 3.0% by weight of lauryl lactate, about 2.0% by weight of sorbitan monolaurate, About 10.0% by weight of glycerin, about 15.0% by weight of crosslinked polyvinylpyrrolidone, About 0.5% by weight of ascorbyl palmitate, and about 40.9% by weight of a copolymer of acrylic acid and vinyl acetate; The system of claim 12 , comprising:

14. 14. The system of any one of claims 1 to 13 for use in treating Alzheimer's disease, wherein application of the system to the skin of a subject generates a base form of donepezil for delivery to the skin of the subject.

15. A system according to any one of claims 1 to 13 for use in delivering the base form of donepezil to a user, comprising: The use, Providing a transdermal delivery system according to any one of claims 1 to 13; and securing, or instructing the system to be secured to, the skin of the user, thereby delivering the base form of the donepezil from the system to the skin, whereby (i) the time to reach steady state flux is at least about 20% faster compared to a system without a membrane treatment composition in the pores of the microporous membrane; (ii) the system achieves its steady-state equilibrium flux at least 20% faster than a system without a membrane treatment composition in the pores of the microporous membrane; and / or (iii) a system, wherein the base form of the donepezil diffuses from the system into the skin at least 20% faster than a system that does not have a membrane treating composition in the pores of the microporous membrane.

Images