RU2789194C2 - Percutaneous delivery system, using microporous membrane containing pores filled with solvent - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: group of inventions relates to medicine, namely to percutaneous delivery systems. The percutaneous delivery system includes: a skin-touching adhesive layer for attachment of the system to the use’s skin; a reservoir drug layer including adhesive polymer, donepezil hydrochloride, and a drug carrier composition; and microporous membrane located between the adhesive layer and the reservoir drug layer. Microporous membrane includes a set of pores filled with a composition for the treatment using membrane, different from the drug carrier composition. The skin-touching adhesive layer contains adhesive based on copolymer of acrylic acid and vinyl acetate, a non-ionogenic surfactant, aliphatic alcohol with a long chain, and composite citric acid ether. The drug carrier composition includes a non-ionogenic surfactant, aliphatic alcohol with a long chain, composite citric acid ether, and a hydrophilic solvent. In this case, the composition for the treatment using membrane does not contain a hydrophilic solvent, and it contains certain amounts of sorbitan monolaurate, lauryl lactate, and triethyl citrate. A method for the treatment of Alzheimer’s disease includes application to the subject’s skin of the percutaneous delivery system, where the specified application leads to the formation of the main donepezil form for delivery to the skin. A method for percutaneous delivery of the main donepezil form includes: use of the percutaneous delivery system and fixation of the system on the user’s skin for delivery of the main donepezil form from the system to the skin.

EFFECT: provision of a means and a method for percutaneous delivery, using which subsequent and efficient delivery of therapeutic amount of donepezil occurs during a long period of time.

13 cl, 7 dwg, 8 tbl, 9 ex

Description

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] The present application requests priority over U.S. Provisional Application. No. 62/537414, filed July 26, 2017, which is incorporated into the present invention by reference.

FIELD OF TECHNOLOGY TO WHICH THE INVENTION RELATES

[0002] An object described in the present invention are transdermal delivery systems for delivering an active agent, where the systems include a microporous membrane containing pores, which include a composition for treatment with a membrane.

BACKGROUND OF THE INVENTION

[0003] Transdermal drug delivery systems can be effective means of administering active pharmaceutical agents that may have disadvantages when administered by other routes, such as oral or parenteral. However, the delivery of many drugs over a long period of time (for example, for several days or more) is difficult. Transdermal delivery of essential (ie, alkaline) drugs can be particularly difficult due to poor skin permeability. In addition, some active agents have poor or low solubility in the adhesive and/or other components used in typical transdermal formulations. In addition, there is a need for stable, long-term active agents (eg, 1-10 days or more) that provide stable and effective release of the agent over the period of administration and have adhesion suitable for long-term administration.

[0004] Active agents for transdermal delivery are usually used in their neutral form, since the neutral form usually penetrates the skin much better 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 and into the skin. Therefore, transdermal patches usually contain as much of the active agent dissolved in the adhesive matrix as the means of dissolution in the adhesive matrix allow, often with solubilizers to increase its solubility. Alternatively, neutral, solid particles of the active agent are sometimes dispersed in the adhesive matrix if the rate of dissolution of the particles is such that a constant supply of the dissolved active agent is ensured.

[0005] However, for many active agents, the neutral form is much more difficult to solubilize and/or introduce into a composition, system, or drug for administration to a patient or subject. If the drug has low solubility in the adhesive matrix, as for the non-ionized neutral form, it is difficult to include enough drug in the solubilized form in the adhesive to deliver a therapeutic amount over several days. An additional complication is that the dissolved active agent may crystallize in the adhesive matrix during drug preparation, such as during solvation, coating and drying. In addition, many active agents in neutral form are less stable than in salt form. Therefore, there is a need for compositions, systems, and medicaments that include an adhesive matrix as a component of a layer that can consistently and efficiently deliver a therapeutic amount of the active agent over an extended period of time.

[0006] The above examples of related prior art and associated limitations are illustrative and not exclusive. Other limitations of the related prior art will become apparent to those skilled in the art upon consideration of the description and associated drawings.

SUMMARY OF THE INVENTION

[0007] The following objects and their embodiments described and illustrated below are typical and illustrative and do not limit the scope of the invention.

[0008] A first aspect is a transdermal delivery system, a system including a skin-contacting adhesive layer for attaching the system to a user's skin; the drug reservoir layer includes an active agent and a drug carrier composition; and a microporous membrane located between the adhesive layer and the drug reservoir layer, the microporous membrane includes a plurality of pores and a membrane treatment composition, wherein the membrane treatment composition occupies 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 another embodiment, the membrane treatment composition is isolated within or within the pores of a microporous membrane. In another embodiment, the membrane treatment composition fills the pores of the microporous membrane. In one embodiment, the microporous membrane is a flat sheet of microporous membrane.

[0010] In some embodiments, 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 of the drug carrier composition are the same and both differ from the drug carrier composition that resides in the drug reservoir layer. In one embodiment, the drug carrier composition differs from the membrane treatment composition and the contact adhesive layer of the drug carrier composition by the presence of a hydrophilic solvent.

[0011] In some embodiments, the membrane treatment composition includes a nonionic surfactant, a long chain aliphatic alcohol, a citric acid ester, and/or combinations thereof.

[0012] In some embodiments, the active agent is a water insoluble base and the drug carrier composition includes a nonionic surfactant, a long chain aliphatic alcohol, a citric acid ester, and/or combinations thereof.

[0013] In some embodiments, the implementation of the microporous membrane is a microporous polypropylene.

[0014] In some embodiments, the implementation of the microporous membrane contains pores with an average size of from about 0.001 microns to about 100 microns.

[0015] In some embodiments, the pore size is from about 0.010 microns to about 0.100 microns.

[0016] In some embodiments, the pore size is from about 0.040 microns to about 0.050 microns.

[0017] In some embodiments, the implementation of the microporous membrane has a porosity of from about 30% to about 50%.

[0018] In some embodiments, the drug reservoir layer further comprises glycerol.

[0019] In some embodiments, the implementation of glycerin is contained in an amount of from about 5 wt.% to about 15 wt.%.

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

[0021] In some embodiments, the drug reservoir layer further comprises a cross-linked polyvinylpyrrolidone.

[0022] In some embodiments, the implementation of cross-linked polyvinylpyrrolidone is contained in an amount of from about 10 wt.% to about 20 wt.%.

[0023] In some embodiments, the active agent administered to the subject is formed in situ in the drug reservoir layer by the reaction of a pharmaceutically acceptable salt of the active agent and an amphoteric base.

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

[0025] In some embodiments, the amphoteric inorganic compound in the drug reservoir layer is an alkali metal salt.

[0026] In some embodiments, the alkali metal salt is sodium bicarbonate.

[0027] In some embodiments, the active agent administered to the subject is donepezil base.

[0028] In some embodiments, the pharmaceutically acceptable salt is donepezil hydrochloride.

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

[0030] In some embodiments, the implementation of the reservoir layer of the drug contains from about 5 wt.% to about 15 wt.% triethylcitrate.

[0031] In some embodiments, the implementation of the reservoir layer of the drug contains from about 0.5 wt.% to about 5 wt.% sorbitan monolaurate.

[0032] In some embodiments, the drug reservoir layer contains from about 0.5% to about 5% lauryl lactate.

[0033] In some embodiments, the implementation of the reservoir layer of the drug contains from about 0.1 wt.% to about 2 wt.% ascorbyl palmitate.

[0034] In some embodiments, the drug reservoir layer contains from about 35 wt.% to about 50 wt.% copolymer of acrylic acid and vinyl acetate.

[0035] In some embodiments, the drug carrier composition contains triethyl citrate, lauryl lactate, sorbitan monolaurate, or combinations thereof.

[0036] In some embodiments, the implementation of the composition of the drug carrier contains from about 60 wt.% to about 75 wt.% triethylcitrate.

[0037] In some embodiments, the implementation of the composition of the drug carrier contains from about 10 wt.% to about 17 wt.% sorbitan monolaurate.

[0038] In some embodiments, the implementation of the composition of the drug carrier contains from about 15 wt.% to about 25 wt.% lauryl lactate.

[0039] In some embodiments, the implementation of the composition of the drug carrier contains about 66.7 wt.% triethylcitrate; about 20.0 wt.% lauryl lactate; and about 13.3 wt.% sorbitan monolaurate.

[0040] In some embodiments, the drug reservoir layer contains from about 10% to about 20% by weight of the drug carrier composition.

[0041] In some embodiments, the implementation of the reservoir layer of the drug contains about 16.0 wt.% donepezil hydrochloride; about 2.6 wt.% sodium bicarbonate; about 10.0 wt.% triethylcitrate; about 3.0 wt.% lauryl lactate; about 2.0 wt.% sorbitan lactate; about 10.0 wt.% glycerol; about 15.0 wt.% cross-linked polyvinylpyrrolidone; about 0.5 wt.% ascorbyl palmitate; and about 40.9 wt.% copolymer of acrylic acid and vinyl acetate.

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

[0043] In some embodiments, the membrane treatment composition contains from about 60 wt.% to about 75 wt.% triethyl citrate.

[0044] In some embodiments, the implementation of the composition for treatment with a membrane contains from about 10 wt.% to about 17 wt.% sorbitan monolaurate.

[0045] In some embodiments, the implementation of the composition for treatment with a membrane contains from about 15 wt.% to about 25 wt.% lauryl lactate.

[0046] In some embodiments, the membrane treatment composition contains about 66.7 wt.% triethyl citrate; about 20.0 wt.% lauryl lactate; and about 13.3 wt.% sorbitan monolaurate.

[0047] In some embodiments, the system is formulated to deliver a dose of about 5 mg to about 10 mg of donepezil base per day.

[0048] In some embodiments, the skin-contacting adhesive layer comprises a contact adhesive layer of the drug carrier composition.

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

[0050] In some embodiments of the contact adhesive layer, the drug carrier composition is contained in the contact adhesive layer in an amount of from about 10 wt.% to about 20 wt.%.

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

[0052] In some embodiments, the pharmaceutically acceptable salt is memantine hydrochloride.

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

[0054] In some embodiments, the drug carrier composition contains octyldodecanol.

[0055] In some embodiments, the implementation of octyldodecanol is contained in an amount of from about 5 wt.% to about 15 wt.%.

[0056] In some embodiments, the drug reservoir layer contains from about 25 wt.% to about 40 wt.% copolymer of acrylic acid and vinyl acetate.

[0057] In some embodiments, the skin-contacting adhesive layer contains hydrophilic fumed silica in an amount of from about 5% to about 10% by weight.

[0058] In some embodiments, the membrane treatment composition comprises octyldodecanol.

[0059] In some embodiments, the implementation of the system is prepared to receive a dose equal to from about 1 mg to about 30 mg of memantine base per day.

[0060] In some embodiments, the implementation of the reservoir layer of the drug contains about 25 wt.% memantine hydrochloride; about 9.73 wt.% sodium bicarbonate; about 7.0 wt.% octyldodecanol; about 10.0 wt.% glycerol; about 15.0 wt.% cross-linked polyvinylpyrrolidone; and about 33.27 wt.% acrylic acid-vinyl acetate copolymer.

[0061] In some embodiments, the implementation of the adhesive layer in contact with the skin contains from about 5 wt.% to about 15 wt.% octyldodecanol.

[0062] In some embodiments, the implementation of the contact adhesive layer contains about 10 wt.% octyldodecanol.

[0063] In some embodiments, the active agent is fingolimod.

[0064] In some embodiments, the pharmaceutically acceptable salt is fingolimod hydrochloride.

[0065] In some embodiments, the implementation of the skin-contacting adhesive layer contains a copolymer of acrylic acid and vinyl acetate.

[0066] In some embodiments, the implementation of the copolymer of acrylic acid and vinyl acetate is contained in an amount of from about 60 wt.% to about 75 wt.%.

[0067] In some embodiments, the skin-contacting adhesive layer comprises polyisobutylene.

[0068] In some embodiments, the implementation of polyisobutylene is contained in an amount of from about 65 wt.% to about 90 wt.%.

[0069] In some embodiments, the skin-contacting adhesive layer further comprises a cross-linked polyvinylpyrrolidone.

[0070] In some embodiments, crosslinked polyvinylpyrrolidone is present in an amount of from about 15% to about 25% by weight.

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

[0072] In some embodiments, the first cover layer comprises a polyester laminate.

[0073] In some embodiments, the implementation of the adhesive top layer contains polyisobutylene, polybutene, cross-linked polyvinylpyrrolidone, acrylic adhesive, copolymer of acrylic acid and vinyl acetate, or combinations thereof.

[0074] In some embodiments, the implementation of the adhesive top layer contains a copolymer of acrylic acid and vinyl acetate.

[0075] In some embodiments, the implementation of the second cover layer contains a non-woven material made of polyester.

[0076] In some embodiments, the transdermal delivery systems described herein may further include a backing layer, including a film, nonwoven, woven, laminate, or combinations thereof, where the backing layer is in contact with the skin-contacting adhesive layer on the side opposite intermediate layer.

[0077] In some embodiments, the protective layer is a silicone-coated polymer film or paper.

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

[0079] Another aspect is a method for transdermal delivery of an active agent, comprising using any of the transdermal delivery systems described above, attaching or instructing to attach the system to the user's skin to deliver the active agent from the system to the skin, where (i) the time period to establish a constant flow at least about 20% less than for a system without a membrane treatment composition in the pores of the microporous membrane, (ii) the amount of time to establish a constant flow from the system is at least about 20% less than for a system without a membrane treatment composition treating with the membrane in the pores of the microporous membrane; and/or (iii) the active agent diffuses from the system onto the skin at least 20% faster than for the system without the membrane treatment composition in the pores of the microporous membrane.

[0080] Another object is a method of treating Alzheimer's disease, including the use of any of the transdermal delivery systems containing the active agent, such as donepezil base or memantine base, described above, for application to the skin of the patient.

[0081] Another object is a method of treating Alzheimer's disease, obsessive-compulsive disorder, anxiety disorder, attention deficit hyperactivity disorder (ADHD) or opioid dependence, comprising applying any of the transdermal delivery systems containing memantine described above to the skin of the patient.

[0082] Another object is a method of obtaining a system for transdermal delivery of an active agent, including using a skin-contacting adhesive layer to attach the system to the skin of the user; using a drug reservoir layer containing an active agent and a drug carrier composition; treating a microporous membrane containing a plurality of pores with a membrane treatment composition to form a pretreated microporous membrane, wherein at least a portion of the pores of the pretreated microporous membrane contains the membrane treatment composition; and using an intermediate layer located between the skin-contacting adhesive layer and the drug reservoir layer, where the intermediate layer contains a pre-treated microporous membrane;

[0083] In some embodiments of the production method, the microporous membrane comprises microporous polypropylene.

[0084] In some embodiments of the method for preparing the active agent of the drug reservoir layer, it is formed in situ by the reaction of a pharmaceutically acceptable salt of the active agent and an amphoteric base.

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

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

[0087] In some embodiments of the preparation method, the pore size is from about 0.040 microns to about 0.050 microns.

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

[0089] In some embodiments of the preparation method, the step of treating the microporous membrane with the membrane treatment composition comprises contacting the microporous membrane with the membrane treatment composition to saturate the microporous membrane with the membrane treatment composition and removing excess of the membrane treatment composition. using a saturated microporous membrane.

[0090] In some embodiments of the preparation method, the membrane treatment composition comprises a nonionic surfactant, a long chain aliphatic alcohol, a citric acid ester, or combinations thereof.

[0091] In some embodiments of the production method, the amphoteric inorganic basic compound is sodium bicarbonate.

[0092] In some embodiments of the preparation method, the active agent is donepezil base and the pharmaceutically acceptable salt is donepezil hydrochloride.

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

[0094] In some embodiments of the method of obtaining the composition of the drug carrier contains about 66.7 wt.% triethylcitrate; about 20.0 wt.% lauryl lactate; and about 13.3 wt.% sorbitan monolaurate.

[0095] In some embodiments of the method of obtaining a composition for treatment with a membrane contains about 66.7 wt.% triethylcitrate; about 20.0 wt.% lauryl lactate; and about 13.3 wt.% sorbitan monolaurate.

[0096] In some embodiments of the preparation method, the active agent is memantine and the pharmaceutically acceptable salt is memantine hydrochloride.

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

[0100] In some embodiments of the preparation method, the active agent is fingolimod base and the pharmaceutically acceptable salt is fingolimod hydrochloride.

[0101] In some embodiments, the production method further comprises the step of using the first cover layer in contact with the drug reservoir layer; using an adhesive top layer in contact with the first cover layer on the side opposite the drug reservoir layer; and using the second cover layer in contact with the adhesive top layer on the side opposite the first cover layer.

BRIEF DESCRIPTION OF THE DRAWINGS

[0102] FIG. 1A-1D are illustrations of transdermal delivery systems in accordance with some embodiments;

[0103] In FIG. 2A shows the mean plasma donepezil concentration in ng/mL versus time in days in humans treated with the transdermal donepezil delivery system (mugs) for 1 week or with donepezil 5 mg orally on day 1 and day 7. (triangles);

[0104] In FIG. 2B plots the mean plasma concentration of donepezil in ng/mL over a 24-hour period after oral administration of a donepezil 5 mg tablet (triangles) and after removal of the donepezil transdermal delivery system (circles);

[0105] In FIG. 3 is a plot of the projected mean plasma donepezil concentration in ng/mL in the last week of a 28-day (4-week) treatment period with a transdermal delivery system designed to administer 10 mg/day for a week (solid line) and for 28 days. with a daily oral donepezil tablet (dotted line);

[0106] In FIG. 4 is a bar graph showing the number of subjects per group treated with the donepezil transdermal delivery system for 1 week and observed skin irritation after patch removal, where an open bar indicates no skin irritation and a solid bar indicates mild skin irritation;

[0107] In FIG. 5A shows the mean plasma concentration of donepezil in ng/mL on each day at week 5 in subjects of a clinical study where subjects were treated with donepezil administered transdermally from a transdermal patch with a first surface area (solid line) and a second, larger surface area (dashed line). line), and donepezil administered orally, where the plasma concentration of donepezil in patients who were treated orally is indicated by a solid thick line on days 6-7, and the dotted line shows the projected daily plasma concentration for oral treatment; And

[0108] In 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 where subjects were treated as indicated in FIG. 5A; the shaded column corresponds to subjects treated with the smaller once-a-weekly applied transdermal patch, the vertical-hatched column corresponds to subjects who were treated with the larger once-a-weekly applied transdermal patch, and the horizontal-shaded column corresponds to subjects treated with oral donepezil;

[0109] In FIG. 6 shows mean skin flux for transdermal memantine delivery devices in µg/cm ² ⋅h versus time in hours from an in vitro skin permeability study;

[0110] In FIG. Figure 7 shows the mean skin flux of donepezil μg/cm ² ⋅h in vitro versus time in hours from an in vitro skin permeability study for a transdermal system including a pretreated microporous membrane (squares) compared to the skin flux for a transdermal donepezil delivery system. , in which the microporous membrane is untreated (circles).

DETAILED DESCRIPTION OF THE INVENTION

I. Definitions

[0111] Below in the present invention, various objects are described in more detail. However, such objects may be embodied in many different forms and should not be construed as being limited to the embodiments of the present invention; rather, these embodiments are provided so that the present invention is complete and complete and its scope is clear to those skilled in the art.

[0112] If a range of values is specified, it should be understood that every intermediate value between the upper and lower limit values of the range and any other set or intermediate value in this set range are included in the present invention. For example, if a range of 1 µm to 8 µm is established, it should be understood that 2 µm, 3 µm, 4 µm, 5 µm, 6 µm, and 7 µm are also explicitly disclosed, as well as a range of values greater than or equal to 1 µm, and a range of values , less than or equal to 8 µm.

[0113] Variables in the singular also include variables in the plural, unless the context clearly dictates otherwise. Thus, for example, reference to "polymer" includes reference to one polymer, as well as two or more identical or different polymers, reference to "inert filler" includes reference to one inert filler, as well as two or more identical or different polymers. inert fillers, etc.

[0114] The term "about" immediately preceding a numerical value means a range of ±10% of that value, e.g., "about 50" means from 45 to 55, "about 25000" means from 22500 to 27500, etc., if from context of the present invention does not follow otherwise or is inconsistent with such an interpretation. For example, a list of numerical values such as "about 49, about 50, about 55," about 50" means a range of less than half the interval(s) between the previous and following values, for example, from more than 49.5 to less than 52, 5. In addition, the expressions "less about" or "more than about" should be interpreted taking into account the definition of the term "about" given in the present invention.

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

[0116] The "adhesive matrix" described in the present invention includes matrices made in a single batch, for example, matrices made by dip molding in a solution or extrusion, as well as matrices made in two or more batches, which are then compressed or combined .

[0117] "Donepezil" as used herein means 2,3-dihydro-5,6-dimethoxy-2-[[1-(phenylmethyl)-4-piperidinyl]methyl]-1H-inden-1-one.

[0118] The terms "treatment", "therapy", "therapeutic" and the like, as used in the present invention, include any course of medical intervention directed at a pathological condition, and includes not only a permanent cure, but also the prevention, elimination of a disease, or even stages carried out to relieve the disease or the symptoms of the disease.

[0119] The term "skin" as used herein means skin or mucosal tissue, including the inner surface of body cavities that have a mucosal lining. The term "skin" should be interpreted to include "mucous tissue" and vice versa.

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

[0121] The expression "pharmaceutically acceptable" is used in the present invention in relation to those compounds, salts, compositions, dosage forms, etc., which, based on the results of careful medical clinical evaluation, are suitable for use in contact with tissues of humans and / or other mammals without excessive toxicity, irritation, allergic reaction, or other difficulty or complication with a reasonable benefit/risk ratio. In some aspects, "pharmaceutically acceptable" means approved by a federal or state government regulatory agency, or listed in the USP or other generally legal Pharmacopoeias, for use in mammals (eg, animals) and more preferably in humans.

[0122] The terms "transdermal" or "transdermal delivery" as used herein means the application of an active agent to an individual's body surface such that the agent passes through the body surface, such as the skin, and into the individual's bloodstream. The term "transdermal" includes transmucosal administration, i.e., application of a drug to the mucosa (eg, sublingual, buccal, vaginal, rectal) of an individual such that the agent passes through the mucosal tissue and into the individual's bloodstream.

[0123] The term "treatment" is used in the present invention, for example, in relation to methods of treating a disorder, such as Alzheimer's disease, and usually includes the administration of a compound or composition that reduces the frequency or delays the onset of symptoms of a pathological condition (for example, Alzheimer's disease) in a subject compared to a subject who did not receive the compound or composition. It may include the prevention, amelioration, or cessation of symptoms, clinical signs, and underlying pathological condition in such a manner that the subject's condition is improved or stabilized (eg, regression of mental state).

[0124] The compositions of the present invention may contain, consist essentially of, or consist of the disclosed components.

[0125] All percentages, parts or ratios are based on total weight of topical compositions and all changes are at about 25°C unless otherwise noted.

[0126] While retaining the right to exclude or withdraw any individual member of any such group, including subranges or combinations of subranges within a group that may be claimed according to a range or in any similar manner, less than the full scope of the invention may be claimed for any reason. In addition, while retaining the right to exclude or withdraw any individual substituents, analogs, compounds, ligands, structures, or groups thereof, or any members of a claimed group, for any reason, less than the full scope of the invention may be claimed.

[0127] In the present invention, reference is made to various patents, patent applications and publications. The disclosures of these patents, patent applications and publications in their entirety are incorporated herein by reference to more fully describe the state of the art known to those skilled in the art at the date of the present invention. The present invention is decisive in cases where there is an inconsistency between the cited patents, patent applications and publications and the present invention.

[0128] For convenience, here are some of the terms used in the description, examples and claims. Unless otherwise defined, all technical and scientific terms used in the present invention have the same meanings as known to a person with a general background in the technical field to which the present invention pertains.

II. Transdermal delivery system and compositions for use in the transdermal delivery system

[0129] A transdermal delivery system for systemic delivery of a water-insoluble drug base is provided. The transdermal system typically includes a skin-contacting adhesive layer and a drug reservoir layer where the two layers are separated by an intermediate layer that includes a microporous membrane that has been pre-treated with the membrane treatment composition. The system may include additional layers as described in the knife. Now the composition of the layers in the system is described.

[0130] In some embodiments, the drug reservoir contains donepezil or a derivative thereof as the active agent. Donepezil is an acetylcholinesterase inhibitor with the chemical structure: 2,3-dihydro-5,6-dimethoxy-2-[[1-(phenylmethyl)-4-piperidinyl]methyl]-1 H -inden-1-one:

Donepezil has a molecular weight of 379.5 and is lipophilic (Log P =3.08-4.11).

[0131] In some embodiments, the drug reservoir contains, as an active ingredient, memantine or a derivative thereof. Memantine (NAMENDA) is a compound that belongs to the class of adamantane active agents. In some embodiments, the compound comprises the structure of Formula I. In another embodiment, memantine is also known as 3,5-dimethylmethyladamantan-1-amine; 1-amino-3,5-dimethylmethyladamantane; 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:

Formula I

[0132] In some embodiments, the drug reservoir layer contains fingolimod or a derivative thereof as the active agent.

[0133] The reservoir layer of the drug may further include auxiliary components, usually contained in pharmaceutical compositions in the form and in the accepted in the art amounts. For example, the compositions may contain additional compatible pharmaceutically active materials for combination therapy, e.g. donepezil (ARICEPT®), memantine, rivastigmine (EXCELON®), galantamine (RAZADIN®), icopezil, pyridostigmine, edrophonium, neostigmine, physostigmine, Huperzine A, fenserin , tacrine, including an L-type calcium channel blocker selected from the group consisting of amlodipine, felodipine, isradipine, lacidipine, lercanidipine, nicardipine, nifedipine, nimodipine, nitrendipine, nisoldipine, or (+) isopropyl-2-methoxyethyl-4-(2- chloro-3-cyanophenyl)-1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylate; or a combination thereof. See U.S. Patent Publication. No. 2009/0156639.

[0134] The drug reservoir layer in one embodiment is a composition comprising an adhesive matrix comprising an adhesive polymer, a drug carrier composition, and a donepezil base formed in situ in the drug reservoir layer after the transdermal system is applied to the skin by the reaction of the donepezil salt and alkali metal salts, or other amphoteric basic compound. The drug reservoir layer is prepared using a salt form of donepezil, eg, donepezil hydrochloride (HCl), and an alkali metal salt, which react in situ to form a donepezil base for applying a transdermal system to the skin. The alkali metal salt may 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.

[0135] The drug reservoir also includes a drug carrier composition. In one embodiment, the drug carrier composition is a solvent composition comprising 1, 2, 3, or 4 solvents. In one embodiment, the drug carrier composition contains triethyl citrate; and in other embodiments, glycerol and/or sorbitan monolaurate are further contained. In another embodiment, the drug carrier composition contains an α-hydroxy acid as an additional solvent. Typical solvents for α-hydroxy acids are esters of lactic acid or glycolic acid and an example is lauryl lactate. In one embodiment, the drug carrier composition comprises, consists essentially of, or consists of triethyl citrate, sorbitan monolaurate, lauryl lactate, and glycerin.

[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 an example and typically include polyacrylate, which is a polymer or copolymer of a monomer or monomers selected from the group consisting of acrylic acid esters and methacrylic acid esters. Other monomers may be included, such as acrylic acid and vinyl acetate. In embodiments, the acrylic polymer is based on acrylic acid esters such as 2-ethylhexyl acrylate (2-EHA) and ethyl acrylate. In some embodiments, the polyacrylate polymer is a polymer or copolymer of a monomer or monomers selected from the group consisting of acrylic acid and vinyl acetate. In embodiments, the acrylic adhesive polymer contains pendent carboxy (-COOH) or hydroxy (-OH) functional groups. In embodiments, the acrylic adhesive polymer contains at least one of the following: polyacrylate, polymethacrylate, derivatives thereof, and copolymers thereof. In embodiments, the acrylic adhesive comprises an acrylate copolymer comprising acrylic acid ester monomers, acrylic acid monomers, and/or vinyl acetate monomers. One example is a copolymer of acrylic acid and vinyl acetate. 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.

[0137] The drug reservoir may also include a copolymer such as a polyvinylpyrrolidone/vinyl acetate copolymer, an acrylic acid/vinyl acetate copolymer, or a vinyl acetate/ethylene acetate copolymer. In one embodiment, the copolymer is a vinyl acetate/N-vinylpyrrolidone copolymer such as the copolymer sold under the name Plasdon™ 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.

[0138] The drug reservoir may also include polyvinylpyrrolidone (PVP). PVP is a water-soluble polymer comprising N-vinylpyrrolidone monomer and is available in various forms, including crosslinked and non-crosslinked. In some working examples in the present invention, the cross-linked PVP is included in the drug reservoir.

[0139] In some embodiments, the drug reservoir contains at least about 25-80 wt.% adhesive polymers, based on the weight of the drug reservoir (including subranges). In embodiments, the drug reservoir contains 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 %, not less than about 30-70%, not less than about 40-70%, not less than about 50-70%, not less than about 60-70%, not less than about 25-60%, not less than about 30-60%, not less than about 40-60%, not less than about 50-60%, not less than about 25-50%, not less than about 30-50%, not less than about 40-50%, not less than about 25-40%, not less than about 30-40% or not less than about 25-30% adhesive polymer or copolymer or mixture of polymers and/or copolymers (all percentages are by weight). It should be understood that the adhesive matrix of the drug reservoir may include one or more or at least one adhesive polymer or copolymer. In embodiments, the drug reservoir contains at least about 5-75% individual polymer, based on the total weight of the polymers in the matrix. In embodiments, the drug reservoir contains 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% single polymer.

[0140] In one exemplary drug reservoir, a matrix is used that contains or primarily consists of a donepezil base formed in situ by the reaction of donepezil.HCl and sodium bicarbonate; a drug carrier composition consisting of a mixture of triethyl citrate, sorbitan monolaurate and glycerin; and a polymeric, adhesive matrix of crosslinked polyvinylpyrrolidone and an acrylic acid/vinyl acetate copolymer. Another exemplary drug reservoir uses a composition comprising an adhesive matrix that contains or essentially consists of a donepezil base formed in situ by the reaction of about 10-25 wt% donepezil HCl and about 1-5 wt% sodium bicarbonate; about 5-15 wt.% triethylcitrate; about 0.5-5 wt.% sorbitan monolaurate; about 5-15 wt.% glycerol; about 5-25 wt.% cross-linked polyvinylpyrrolidone; and about 30-50% by weight of an acrylate-vinyl acetate copolymer. In another example, a composition is used comprising an adhesive matrix essentially consisting of donepezil base formed in situ from the reaction of about 14-18 wt% donepezil HCl and about 2-5 wt% sodium bicarbonate; about 8-12 wt.% triethylcitrate; about 1.5-2.5 wt.% sorbitan monolaurate; about 9-11 wt.% glycerol; about 13-17 wt.% cross-linked polyvinylpyrrolidone; and about 40-42 wt.% acrylate-vinyl acetate copolymer.

[0141] The drug reservoir described herein and above is for use in a transdermal delivery system, where the system further comprises a skin-contact adhesive. The skin-contacting adhesive layer can be made from any of the adhesive materials described in the present invention. The skin-contacting adhesive layer in one embodiment contains about 50-90 wt.% adhesive polymer or copolymer, or about 55-90 wt.%, or about 60-90 wt.%, about 65-90 wt.%, about 70- 90 wt.%, about 75-90 wt.% or about 80-90 wt.%. In one embodiment, the skin-contact adhesive comprises an acrylic acid/vinyl acetate copolymer. In another embodiment, the skin-contacting adhesive layer further comprises a polyvinylpyrrolidone, such as a crosslinked polyvinylpyrrolidone.

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

[0143] In one embodiment, the biocompatible polymer is a PIB-based matrix comprising PIB Oppanol B100 (BASF, MW=1100000), PIB Oppanol B 12 (BASF, MW=51000, MW/MN=3.2) and polybutene (PB) Indopol H1900 (oligomers from INEOS, MW=4500, MW/MN=1.8). The mass ratio of the components of the PIB matrix is: PIB Oppanol B100: PIB Oppanol B 12: Indopol H1900=10:50:40 (see, Brantseva et al. , European Polymer Journal , 76, 228-244, 2016).

[0144] In one embodiment, the skin-contacting adhesive layer comprises a biocompatible polymer comprising 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 99.9 or more, where all values are given in terms of the weight of the adhesive layer. In particular, the weight % content of biocompatible polymer in the adhesive layer is about 50%-95%, preferably about 60%-80%, based on the entire adhesive layer in contact with the skin. In some embodiments, the amount of biocompatible polymer in the skin-contacting 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%.

[0145] The skin-contacting adhesive layer may also include the skin-contacting adhesive layer of the drug carrier composition. In embodiments, the skin-contacting adhesive layer comprises, as the contact adhesive layer of the drug carrier composition, one or more of the following: a citric acid ester, a surfactant, and/or an alpha hydroxy acid. In one embodiment, the skin-contacting adhesive layer comprises, as the contact adhesive layer of the drug carrier composition, one or more of the following: triethyl citrate, sorbitan monolaurate, and/or lauryl lactate. In one embodiment, the manufactured skin-adhesive adhesive layer does not include a pharmaceutically active agent intended for systemic delivery—for example, the ingredients combined to form the skin-adhesive adhesive layer and/or contact adhesive layer of the drug carrier composition do not include a base form or saline a drug form such as donepezil base or donepezil salt. During use, after the skin-contacting adhesive layer is applied to the skin of the user, the main form of the active agent, which is formed in situ in the drug reservoir, is distributed in the drug carrier composition of the drug reservoir, then distributed and transferred to the treatment composition with a membrane in a microporous membrane and then distributed and moved into the contact adhesive layer of the drug carrier composition for delivery to the user's skin.

[0146] The drug carrier composition for the skin-contacting adhesive layer and/or the adhesive matrix of the drug reservoir can be selected from a wide range of such compounds known in the art. In some embodiments, a drug carrier composition for use in an adhesive layer or matrix includes, but is 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. No. 8874879, which is included in the present invention by reference. It should be understood that the compositions of the present invention may include one or more or at least one drug carrier composition. In embodiments, the passage or penetration enhancer is included in an amount of about 1-10%, about 2-5%, about 2-10%, based on the weight of the adhesive matrix (including subranges).

[0147] In one embodiment, the contact adhesive layer of the drug carrier composition and the membrane treatment composition contains 1, 2, or 3 identical solvents. In one embodiment, the contact adhesive layer of the drug carrier composition and the membrane treatment composition contain the same solvents. For example, in one embodiment, the contact adhesive layer of the drug carrier composition and the membrane treatment composition each contain citrate, a surfactant, and/or an alpha hydroxy acid. In one embodiment, the drug carrier composition (in the drug reservoir) contains a hydrophilic solvent that is not contained in or excluded from the membrane treatment composition or the contact adhesive layer of the drug carrier composition.

[0148] The skin-contacting adhesive layer and/or the adhesive matrix of the drug reservoir may further include one or more matrix modifiers. Without being limited by theory, it can be assumed that the matrix modifier facilitates the homogenization of the adhesive matrix. A possible mechanism of this process is the sorption of hydrophilic fragments. Thus, known matrix modifiers which absorb water to some extent can be used. For example, possible matrix modifiers include colloidal silica, fumed silica, cross-linked polyvinylpyrrolidone (PVP), soluble PVP, cellulose derivatives (e.g., hydroxypropyl cellulose (HPC), hydroxyethyl cellulose (HEC)), polyacrylamide, polyacrylic acid, polyacrylic acid salt, or clay, such as kaolin or bentonite. A typical commercially available fumed silica is Cab-O-Sil (Cabot Corporation, Boston, Mass.). It is also possible to use hydrophilic mixtures as described in US Patent Publication No. 2003/0170308, for example mixtures of PVP and PEG or PVP, PEG and a water-swellable polymer such as ^EUDRAGIT® L100-55. In embodiments, the matrix modifier is separately included 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. adhesive matrix (including subbands). In some embodiments, the implementation of the matrix modifier does not include ethylcellulose.

[0149] The skin-contacting adhesive layer and/or adhesive matrix of the drug reservoir may further include other conventional additives such as adhesives, antioxidants, cross-linking or curing agents, pH adjusters, pigments, dyes, persistent particles, conductive agents, antimicrobial agents , opacifiers, gelling agents, viscosity modifiers or thickening agents, stabilizing agents, and the like, known in the art. In those embodiments where adhesion is to be reduced or eliminated, conventional anti-stick agents can also be used. Other agents, such as antimicrobials, may also be added to prevent storage spoilage, ie to inhibit the growth of microorganisms such as yeasts and molds. Suitable antimicrobials are generally selected from the group consisting of p-hydroxybenzoic acid methyl and propyl esters (ie, methyl and propyl paraben), sodium benzoate, sorbic acid, imidourea, and combinations thereof. These additives and their amounts are chosen such that they do not significantly interfere with the desired chemical and physical characteristics of the adhesive and/or active agent.

[0150] The skin-contacting adhesive layer and/or adhesive matrix of the drug reservoir may also additionally contain anti-irritant additives to minimize or eliminate potential skin irritation and/or skin damage caused by the drug, enhancer, or other components of the composition. Suitable anti-irritant additives include, for example: α-tocopherol; monoamine oxidase inhibitors, in particular phenyl alcohols such as 2-phenyl-1-ethanol; glycerol; salicylic acids and salicylates; ascorbic acids and ascorbates; ionophores such as monensin; amphiphilic amines; ammonium chloride; N-acetylcysteine; cis-urocanic acid; capsaicin; chloroquine; and corticosteroids.

[0151] In some embodiments, the skin-contacting adhesive layer optionally contains fine silica, such as hydrophobic fumed silica, which can effectively adsorb hydrophobic drugs and other hydrophobic ingredients. By using a small amount of hydrophobic colloidal silica as the inert excipient (from about 3% to about 20%, preferably from about 5% to about 10% in the formulation), diffusion of the active ingredient through the matrix can be controlled during storage. Examples of fine silica for use in compositions include, but are not limited to, high purity amorphous anhydrous colloidal silica for use in pharmaceutical products, sold under the name AEROSIL, e.g. AEROSIL®90, AEROSIL®130, AEROSIL®150, AEROSIL® 200, AEROSIL®300, AEROSIL®380, AEROSIL®OX50, AEROSIL®TT600, AEROSIL®MOX80, AEROSIL®COK84, AEROSIL®R202, AEROSIL®R805, AEROSIL®R812, AEROSIL®812S, AEROSIL®R972 and/or AEROSIL® R974, or as fumed silica, any other fumed silica can be used, especially AEROSIL®200 and/or AEROSIL®R972.

[0152] In one embodiment, the skin-contacting adhesive layer comprises at least about 40 wt. % fine silica, based on the weight of the entire adhesive layer, including at least about 1 wt. %, based on the weight of the adhesive layer, including at least about 3%, 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 wt.%, where all values are based on the weight of the entire adhesive layer.

[0153] A transdermal delivery system including a drug reservoir adhesive matrix and a skin-contacting adhesive may be configured in a variety of configurations, and some non-limiting examples are shown in FIGS. 1A-1D. Fig. 1A illustrates a transdermal delivery system 10 including a drug reservoir 12 and a contact adhesive 14 separated by a microporous membrane or a non-rate regulating material such as a bonding layer and a polyester or polypropylene nonwoven fabric 16. A cover layer 18 and a backing layer 20 are also present. Fig. 1B illustrates a second embodiment of a transdermal delivery system 22 including a first drug reservoir 24 and a second drug reservoir 26, the first and second drug reservoirs separated by a non-rate controlling material such as a tie layer consisting of a polyester or polypropylene nonwoven fabric. , 28. The contact adhesive layer 30 is for attaching the system to the user's skin, where the rate control membrane 32 controls the release of the therapeutic agent from the second drug reservoir into the contact adhesive and ultimately onto the user's skin. There is also a protective layer 34 and a cover layer 36. In FIG. 1C shows another embodiment of a transdermal delivery system 40 including a drug reservoir 42 and a contact adhesive layer 44 that is designed to attach the system to the user's skin. There is also a cover layer 46 and a protective layer 48.

[0154] FIG. 1D shows another embodiment of a transdermal delivery system for systemic delivery of an active agent. The system 50 includes, in series from the skin-side 52 to the outer, environmental side 54, a skin-side adhesive layer 56 for attaching the system to the user's skin. In one embodiment, the skin-contacting adhesive layer is made from an adhesive that does not contain an active agent or salt thereof. However, after storage and/or during use, the skin-contacting adhesive layer contains 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-contacting adhesive layer is an intermediate layer 58. The intermediate layer may be, for example, a polyester nonwoven or a drug rate control membrane such as microporous polyethylene or polypropylene. The intermediate layer has opposing sides, a skin-facing layer (which is in contact with the skin-contacting adhesive layer 56) and an environmental side. On the environmental side of the intermediate layer, there is a drug reservoir layer 60. The drug reservoir layer is made with an adhesive material, a pharmaceutically acceptable salt of an active agent, and an alkali metal salt. The last two components interact in situ to form the base form of the active agent in the drug reservoir layer, which is delivered to the user after application of the system to the skin. In contact with the drug reservoir layer is a first cover layer 62 and in contact with the first cover layer is an adhesive top layer 64. A second cover layer 66 is in contact with the adhesive top layer and with the environment. In one embodiment, the adhesive top layer 64 consists of two different adhesive layers—for example, a first layer of polyisobutylene and polybutene with or without the inclusion of crosslinked polyvinylpyrrolidone and a second layer of acrylic adhesive.

[0155] Accordingly, in one embodiment, a transdermal delivery system for systemic delivery of an active agent is provided. The system includes a skin-contacting adhesive layer arranged in series from the skin-contacting side to the outer, environmental-facing side for attaching the system to the user's skin, the skin-contacting adhesive layer is optionally made of an adhesive that does not contain an active agent or a salt thereof. The intermediate layer is in direct contact with the skin-contacting adhesive layer. On the opposite surface of the intermediate layer is a drug reservoir layer comprising (i) optionally an acrylic acid/vinyl acetate copolymer, (ii) a drug carrier composition described in the present invention, and (iii) an active agent formed in situ by the reaction of the hydrochloride of the active agent and alkali metal salts. The first cover layer is in contact with the drug reservoir layer, and the adhesive top layer is in contact with the first cover layer. The second cover layer is in contact with the adhesive top layer and with the environment.

[0156] The interlayer, also referred to as a fabric layer, membrane, or bonding layer, can be made from any suitable material, including, but not limited to, polyesters, vinyl acetate polymers and copolymers, polyethylenes, and combinations thereof. In one embodiment, the interlayer is a non-woven layer of polyester fibers, such as a film sold under the name Reemay® (Kavon Filter Products Co.). In some embodiments, the implementation of the intermediate layer does not affect the rate of release of the active agent from the adhesive layers.

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

[0158] Other materials used in the manufacture of the microporous membrane include, but are not limited to, polycarbonates, i.e. linear polyesters of carboxylic acids in which carbonate groups repeat in the polymer chain, aromatic compounds with a phosgenated dihydroxy group, such as bisphenol; polyvinyl chlorides; polyamides such as polyhexamethylene adipamide and other such polyamides commonly known as nylon M; modacrylic copolymers such as styrene-acrylic acid copolymers; applicable polysulfones, such as the type characterized by diphenylene sulfone groups in their linear chain; halogenated polymers such as polyvinylidene fluoride, polyvinyl fluoride and polyfluorohalocarbons; polychloroethers and other such thermoplastic polyethers; acetal polymers such as polyformaldehydes; acrylic resins such as polyacrylonitrile polymethyl poly(vinyl alcohol), polystyrene derivatives such as poly(sodium styrenesulfonate) and polyvinylbenzyltrimethyl ammonium chloride, poly(hydroxyethyl methacrylate), poly(isobutyl vinyl ether); and a large number of copolymers, which can be obtained by the reaction of used in different ratios of monomers from the above list of polymers are also useful for obtaining speed control structures applicable in the present invention.

[0159] Diffusion of the active agent through microporous polymeric materials, such as microporous polypropylene, can be difficult. The polymers are impermeable to active drugs except through the channels of the pores, and even then the active agent cannot diffuse through the pores unless it is in a vapor state. Thus, if a microporous membrane is used to make a transdermal delivery system as it was made, it may take an excessive amount of time to get the diluent (i.e., drug carrier composition) out of the drug reservoir layer for distribution into the pores and then an active dispensing agent to deliver the diluent to the pores. As a result, it may take a long time for the active agent to arrive at its destination.

[0160] The rate of release of the active agent across the microporous membrane can be significantly increased if the microporous membrane is pre-treated with a suitable delivery diluent or membrane treatment composition. Pretreated, as used in the present invention, means that the microporous membrane is treated with the membrane treatment composition to fill the pores of the microporous membrane prior to incorporation of the microporous membrane into the transdermal system. The pores of the microporous membrane are filled with or contain the membrane treatment composition prior to or at the time the microporous membrane is incorporated into the transdermal system. The rate of release of the active agent across the microporous membrane depends on several factors such as the diffusion coefficient and solubility of the active agent in the membrane treatment composition and the thickness and porosity of the microporous material. For the flow of an 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 compared to the pore size, the absolute value of the pore size, and the number of pores or void content (porosity) in the material are important determinants of solubility and diffusion coefficient of the agent into and through the membrane.

[0161] In some embodiments, the implementation of the microporous membrane may have a porosity in the range from about 30% to about 50%, from about 35% to about 45%, or from about 40% to about 42%. For example, a microporous membrane may 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%.

[0162] In some embodiments, the implementation of the microporous membrane may contain pores with an average size in the range from about 0.001 microns to about 100 microns, from about 1 microns to about 10 microns, from about 0.010 microns to about 0.100 microns, or from about 0.040 microns to about 0.050 µm. For example, the average pore size may 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 microns.

[0163] The microporous membrane can be pre-treated with the same or different diluents or membrane treatment composition and thereafter, the diluent or drug carrier composition is contained in the drug reservoir layer. In some embodiments, the microporous membrane is pretreated with a membrane treatment composition that includes a solvent, a surfactant, an emulsifier, a viscosity increasing agent, a stabilizer, a plasticizer, and/or combinations thereof. In some embodiments, the membrane treatment composition does not include a solvent. In some embodiments, the surfactant is a nonionic surfactant. In some embodiments, the microporous membrane is pre-treated with citrate. In some embodiments, the citrate is triethyl citrate. In some embodiments, the microporous membrane is pre-treated with lauryl lactate. In some embodiments, the microporous membrane is pre-treated with 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.

[0164] In one embodiment, the microporous membrane has a plurality of pores filled with or contains a membrane treatment composition that is different from the drug carrier composition in the drug reservoir layer and is connected by a fluid channel to the microporous membrane. In one embodiment, the membrane treatment composition does not include (ie, exclude) a solvent in which the salt form of the active agent is soluble. In one embodiment, the membrane treatment composition does not include (ie, 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, glycerol (glycol), acetonitrile, 1-propanol, N,N-dimethylformamide, and dimethyl sulfoxide. .

[0165] In some embodiments, the contact adhesive layer and/or drug carrier composition may include a hydrophilic material or component that is not included in the membrane treatment composition. In one embodiment, the hydrophilic material that is contained in the contact adhesive layer and/or drug carrier composition, but not contained in the membrane treatment composition, is a hydrophilic solvent such as, but not limited to, glycerol, water, and their mixtures. Other hydrophilic materials include, but are not limited to, propylene glycols and low molecular weight polyethylene glycols. In one embodiment, the microporous membrane is made from a hydrophobic material and a hydrophobic microporous membrane is obtained; an example is a polypropylene microporous membrane or a polyethylene microporous membrane. A hydrophilic material, such as a hydrophilic solvent in a drug carrier composition that is in a drug reservoir, does not diffuse or penetrate into the microporous membrane or into the pores of the microporous membrane due to the hydrophobicity of the membrane material. The hydrophilic material in the drug carrier composition in the drug reservoir layer facilitates and promotes in situ formation of the water-insoluble base active agent from its pharmaceutically acceptable salt. After formation of the main form of the active agent in the drug reservoir layer, the main form of the active agent is solubilized with at least one component in the drug carrier composition and at least one component in the membrane treatment composition, so that the main form of the active agent diffuses from the reservoir drug layer into and through the hydrophobic pores of the microporous membrane. In one embodiment, the drug carrier composition and the membrane treatment composition contain 1, 2, or 3 of the same solvents, although 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 both contain citrate, a surfactant and/or an alpha hydroxy acid, and the drug carrier composition contains a hydrophilic solvent that is excluded from or not contained in the composition for membrane treatment.

[0166] The drug carrier composition (i) allows the salt form of the active agent to dissolve and/or suspend in the drug reservoir layer, (ii) facilitates in situ reaction of the salt form of the active agent with the base form of the active agent, and (iii) allows the base form of the active agent to means to dissolve or solubilize in the drug reservoir to diffuse into the microporous membrane and into the contact adhesive layer.

[0167] The membrane treatment composition allows the base form of the active agent to dissolve or be suspended in it and diffuse into and through the microporous membrane. The membrane treatment composition may be liquid or solid and may be a good or bad solvent system for the base form of the drug. A membrane treatment composition that does not readily dissolve the base form of the drug is desirable when a slow or slow release from the transdermal system is desired, and of course the reverse is true if a high release rate is desired.

[0168] The materials selected for the membrane treatment composition should be non-toxic and in which 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. This means that the microporous membrane is chemically stable in the membrane treatment composition. Materials that are applicable to impregnate, fill or saturate the pores or micropores of the microporous membrane may be polar, semi-polar or non-polar. Materials for use in a membrane treatment composition, in addition to those listed above, include, but are not limited to, pharmaceutically acceptable alcohols containing from 6 to 25 carbon atoms, such as hexanol, cyclohexanol, benzyl alcohol, 1,2-butanediol, glycerin, and amyl alcohol, and octyldodecanol; hydrocarbons containing from 5 to 12 carbon atoms such as n-hexane, cyclohexane, and ethylbenzene; aldehydes and ketones containing from 4 to 10 carbon atoms, such as heptylaldehyde, cyclohexanone and benzaldehyde; esters containing from 4 to 10 carbon atoms, such as amyl acetate and benzyl propionate; essential oils such as eucalyptus, rue, cumin, limonene, thyme oil and l-pinene; halogenated hydrocarbons containing from 2 to 8 carbon atoms such as n-hexyl chloride, n-hexyl bromide and cyclohexyl chloride; or mixtures of any of the above materials.

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

[0170] The thickness of the microporous membrane may vary depending on the type of material and the desired characteristics of the microporous membrane (eg, porosity, pore size, diffusion time of the active agent through the membrane). In some embodiments, the implementation of the microporous membrane has a thickness equal to from about 5 to about 200 microns. In some embodiments, the microporous membrane has a thickness of about 10 to about 150 microns, about 10 to about 125 microns, about 10 to about 100 microns, about 10 to about 75 microns, about 10 to about 50 microns, from about 5 to about 45 microns, from about 5 to about 30 microns, from about 10 to about 30 microns, from about 15 to about 30 microns, or from about 20 to about 30 microns. In some embodiments, the implementation of the microporous membrane has a thickness equal to from about 22 to about 28 microns. In some embodiments, the implementation of the microporous membrane has a thickness equal to from about 24 to about 26 microns. In some embodiments, the implementation of the microporous membrane has a thickness of about 25 microns. It should be understood that the thickness values given are merely typical and the actual thickness may be greater or lesser as needed for the particular preparation.

[0171] The microporous membrane can be pre-treated in a variety of ways. Typically, pretreatment involves contacting the microporous membrane with the membrane treatment composition in a sufficient manner and for a sufficient amount of time. In some embodiments, pretreatment of the microporous membrane comprises contacting the microporous membrane with the membrane treatment composition to saturate the microporous membrane with the membrane treatment composition and remove excess membrane treatment composition from the saturated microporous membrane. In some embodiments, the microporous membrane is soaked 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 over the microporous membrane until the microporous membrane becomes saturated, and then the excess membrane treatment composition is removed.

[0172] The pre-treatment of the microporous membrane with the membrane treatment composition can be of varying degrees. In some embodiments, a portion of the pores of the microporous membrane contains a membrane treatment composition. In some embodiments, about one third, about half, about two thirds, or about three quarters of the pores contain the membrane treatment composition. In some embodiments, all pores contain a membrane treatment composition. In some embodiments, a portion of the pores containing the membrane treatment composition is 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 in the occupied pores. In some embodiments, all pores of the microporous membrane are completely filled with the membrane treatment composition and thus the microporous membrane is saturated with the membrane treatment composition.

[0173] The transdermal delivery system may include an adhesive topsheet. The adhesive top layer of the delivery system in FIG. 1D in one embodiment includes a mixture of polyisobutylene and polybutene. In another embodiment, the adhesive top layer includes a first layer and a second layer, the first layer includes a mixture of polyisobutylene, polybutene and crosslinked polyvinylpyrrolidone, and the second layer includes an acrylic adhesive. Polyisobutylene is a vinyl polymer containing isobutylene monomer. In one embodiment, the biocompatible polymer is a PIB-based matrix containing PIB Oppanol B100 (BASF, MW=1100000), PIB Oppanol B 12 (BASF, MW=51000, MW/MN=3.2) and polybutene (PB) Indopol H1900 (oligomers from INEOS, MW=4500, MW/MN=1.8). The weight ratio of the components of the PIB-based matrix is: PIB Oppanol B100:PIB Oppanol B 12:Indopol H1900=10:50:40 (see, Brantseva et al. , European Polymer Journal , 76, 228-244, 2016). Polybutene is a viscous, non-drying liquid polymer obtained by copolymerizing 1- and 2-butene with a small amount of isobutylene. In some embodiments, the polybutene in one embodiment has a molecular weight of about 750-6000 Da, preferably about 900-4000 Da, and more preferably about 900-3000 Da. In some embodiments, the blend contains polybutene mixed with polyisobutylene in an amount of about 40% by weight. More often, polybutene is contained in a mixture with polyisobutylene in an amount of 20-50 wt.% or 25-45 wt.%.

[0174] The transdermal delivery system may include a cover layer that forms a structural element to contain or support the underlying adhesive layer(s). The cover layer can be formed from any suitable material known in the art. In some embodiments, the cover layer is a barrier layer. In some embodiments, the implementation of the cover layer is preferably impermeable or substantially impervious to moisture. In one exemplary embodiment, the cover layer has a water vapor transmission rate of less than about 50 g/m ² -day. In some embodiments, the cover layer is preferably inert and/or does not absorb components of the adhesive layer, including the active agent. In some embodiments, the implementation of the cover layer preferably prevents the release of the components of the adhesive layer through the cover layer. The cover layer may be elastic or non-elastic. The cover layer is preferably at least partially elastic, so that the cover layer is capable of at least partially conforming to the shape of the skin to which the patch is applied. In some embodiments, the implementation of the cover layer is elastic, so that the cover layer takes the form of the skin, which is applied to the patch. In some embodiments, the implementation of the cover layer is elastic enough to maintain contact at the application site during movements, for example, when moving the skin. In general, the material used for the cover layer should allow the device to conform to the contours of the skin or other site to which it is applied and to be worn comfortably in areas of the skin, such as joints or fold positions, that are normally subjected to mechanical stretch with little or no separation. from the skin due to differences in the elasticity or firmness of the skin and the device.

[0175] In some embodiments, the implementation of the cover layer is formed from one or more of the following: film, nonwoven material, woven material, laminate, and combinations thereof. In some embodiments, the implementation of the film is a polymer film, consisting 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 cover layer is formed from one or more of the following: polyethylene terephthalate, various nylons, polypropylene, metallized polyester films, polyvinylidene chloride, and aluminum foil. In some embodiments, the cover layer is a fabric formed from one or more of the following: polyesters such as polyethylene terephthalate, polyurethane, polyvinyl acetate, polyvinylidene chloride, and polyethylene. In one preferred, but non-limiting embodiment, the cover layer is formed from a polyester film laminate. One preferred polyester film laminate is a polyethylene-polyester laminate, such as the laminate sold under the name SCOTCHPAK™ #9723.

[0176] In embodiments, the device includes a protective layer at least partially in contact with at least the adhesive layer to protect the adhesive layer prior to application. The protective layer is usually a removable layer that is removed prior to applying the device to the treatment site. In some embodiments, the implementation of the protective layer preferably does not absorb the components of the adhesive layer, including the active agent. In some embodiments, the backsheet is impermeable to the adhesive layer components (including the active agent) and prevents release of the adhesive layer components through the backsheet. In some embodiments, the backsheet is formed from one or more of the following: film, nonwoven, woven, laminate, and combinations thereof. In some embodiments, the protective layer is a silicone-coated polymer film or paper. In some non-limiting embodiments, the barrier layer is a silicone-coated polyethylene terephthalate (PET) film, a fluorocarbon film, or a fluorocarbon-coated PET film.

[0177] The thickness and/or size of the device and/or adhesive matrices can be determined by techniques known in the art based on at least one of the following: wear resistance and/or required dose. It should be understood that the application site of the device affects wear resistance in view of the available application site size and application site utilization (eg, the need for elasticity to move the substrate). In some embodiments, the implementation of the device and/or adhesive matrix has a thickness equal to about 25-500 microns. In some embodiments, the implementation of the device and/or adhesive matrix has a thickness of about 50-500 microns. In some embodiments, the implementation of the patch has a size in the range of about 16 cm ² -225 cm ² . It should be understood that the thickness and size indicated in the present invention are merely typical and the actual thickness and/or size may be less or more in accordance with the need for a particular preparation.

[0178] The manufacture of the transdermal delivery system is carried out by those skilled in the art in a standard manner and includes casting or extruding all adhesive layers onto a suitable film, such as a backing layer or other 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 layered on top of each other to form the final system.

[0179] Transdermal delivery systems and drug reservoir adhesive matrices were made to illustrate the embodiments described in the present invention. Examples 1-9 show typical compositions and delivery systems. As described in Example 1, the transdermal delivery system includes a drug reservoir and a contact adhesive with a rate controlling membrane interposed between the drug reservoir and the contact adhesive as shown in FIG. 1A. A drug reservoir in the form of a solid monolithic adhesive reservoir was prepared using an acrylic acid/vinyl acetate copolymer as adhesive with a drug carrier composition of triethyl citrate, lauryl lactate and ethyl acetate. The drug reservoir contains about 5 wt% donepezil hydrochloride and sodium bicarbonate to form the donepezil base in situ . A contact adhesive layer was prepared containing the same acrylic acid/vinyl acetate copolymer as an adhesive, as well as triethyl citrate, lauryl lactate and ethyl acetate as a drug carrier composition. A rate control membrane for controlling the diffusional delivery of donepezil base from the drug reservoir, separates the drug reservoir and the contact adhesive.

III. Methods of treatment

[0180] A method for transdermal delivery of a therapeutic agent to a subject is provided. In embodiments, the method includes treating one or more central nervous system (CNS) disorders using the delivery systems described herein. Examples of CNS disorders include, but are not limited to, dementia (e.g., Alzheimer's disease, Parkinson's disease, Pick's disease, frontotemporal dementia, multi-infarct dementia, normal pressure hydrocephalus, Huntington's disease (HD), and mild cognitive impairment (MCI) ), pathological conditions on the background of diseases of the nervous system, pathological conditions on the background of dementia, such as epilepsy, epileptic conditions, acute pain, chronic pain, chronic neuropathic pain, they can be treated using the systems and methods described in the present invention. Epileptic states include complex partial, simple partial, partial with secondary generalization, generalized - including absence, major (tonic clonic), tonic, atonic, myoclonic, neonatal and infantile seizures. Additional specific epileptic syndromes are juvenile myoclonic epileptic seizure, Lennox-Gastaut syndrome, mesial temporal lobe epilepsy, nocturnal frontal lobe epilepsy, progressive epilepsy with mental retardation, and progressive myoclonic epileptic seizure. The systems and methods described herein are also useful in the treatment and prevention of pain caused by disorders including cerebrovascular disease, motor neuron disease (eg, amyotrophic lateral sclerosis (ALS), spinal muscular atrophy, Tay-Sachs disease, Sandhoff disease, familial spastic paraplegia), neurodegenerative diseases (eg, familial Alzheimer's disease, prion diseases, cerebellar ataxia, Friedreich's ataxia, SCA, Wilson's disease, retinitis pigmentosa (RP), ALS, adrenoleukodystrophy, Menke's Sx, cerebral autosomal dominant arteriopathy with subcortical infarcts ( CADASIL); spinal muscular atrophy, familial ALS, muscular dystrophies, Charcot-Marie-Tooth disease, neurofibromatosis, Hippel-Lindau disease, fragile X syndrome, spastic paraplegia, psychiatric disorders (eg, panic syndrome, generalized anxiety disorder, phobic syndromes all types, mania, manic depressive psychosis, hypomania, unipolar depression, depression, stress disorders, post-traumatic stress disorder (PTSD), somatoform disorders, personality disorders, psychosis, and schizophrenia) and drug or drug dependence (eg, alcohol, stimulants (eg, crack , cocaine, AIDS, meth), opioids, and nicotine), tuberous sclerosis and Waardenburg syndrome), strokes (eg, thrombotic, embolic, thromboembolic, hemorrhagic, venoconstrictive, and venous), movement disorders (eg, Parkinson's disease (PD), dystonia, mild essential tremor, tardive dystonia, tardive dyskinesia, and Tourette's syndrome), ataxic syndromes, disorders of the sympathetic nervous system (eg, Shy-Drager syndrome, olivoponocerebellar degeneration, striatonigral degeneration, Parkinson's disease (PD), Huntington's disease (HD), Guillain's disease) Barre, causalgia, complex regional pain syndrome types I and II, diabetic neuropathy and alcoholic neuropathy), cranial nerve disorders (eg, trigeminal neuropathy, trigeminal neuralgia, Meniere's syndrome, glossopharyngeal neuralgia, dysphagia, dysphonia, and cranial nerve palsies), myelopathy, traumatic brain injury and spinal cord injury, radiation brain injury, multiple sclerosis , postmeningeal syndrome, prion diseases, myelitis, sciatica, neuropathies (eg, Guillain-Barré disease, diabetes associated with dysproteinemias, transthyretin-induced neuropathies, HIV-associated neuropathy, Lyme disease-associated neuropathy, herpes zoster-associated neuropathy, carpal tunnel syndrome, carpal tunnel syndrome, amyloid-induced neuropathy, leprosy neuropathy, Bell's palsy, compression neuropathy, sarcoidosis-induced neuropathy, cranial polyneuritis, heavy metal neuropathy, transition metal neuropathy, drug-induced neuropathy), lesions e axons of the brain, encephalopathy and chronic fatigue syndrome. The systems and methods described in the present invention are also applicable to the treatment of multiple sclerosis, in particular relapsing remission multiple sclerosis, and the prevention of relapse of multiple sclerosis and/or relapsing remission multiple sclerosis. All of the above disorders can be treated using the systems and methods described in the present invention.

[0181] In embodiments, the present invention relates to compositions and devices comprising donepezil that are useful for treating, delaying progression, delaying onset, slowing progression, preventing, providing remission, and improving symptoms of a cognitive impairment or disease. In embodiments, donepezil compositions and devices are intended to support mental function, including but not limited to at least one of the following: maintaining thinking, memory, speaking skills, and regulating or alleviating one or more behavioral symptoms. cognitive impairment or disease. In embodiments, the cognitive impairment is Alzheimer's disease. In preferred embodiments, the cognitive impairment is dementia of the Alzheimer's type. In embodiments, compositions and devices comprising donepezil are for use in the treatment of, and the like, mild, moderate, or severe Alzheimer's disease.

[0182] The terms "treatment", "therapy", "therapeutic", etc., when used in the present invention, includes any course of medical intervention aimed at a pathological condition, and includes not only the permanent cure of the disease, but also the prevention of the disease, the control with it, or even stages carried out to mitigate the course of the disease or the symptoms of the disease. For example, with respect to methods of treating a disorder such as Alzheimer's disease, an embodiment typically includes administering an active agent that reduces the frequency or delays the onset of symptoms of the condition in a subject compared to a subject not receiving the active agent. This may include the reversal, amelioration or elimination of symptoms, clinical signs, and underlying pathology of the pathological condition in such a way that improvement or stabilization of the subject's pathological condition (eg, regression of mental abilities) occurs.

[0183] In one embodiment, therapeutic embodiments are carried out by interacting the tissues of the subject, for example, skin tissue, with the transdermal delivery systems of the present invention.

[0184] In another embodiment, therapeutic embodiments are carried out by transdermal administration of the active agent to a subject, for example, a patient suffering from a CNS disorder such as Alzheimer's disease and/or dementia. The term "administration" is the application as a drug, for example, the placement of the active agent in such a way that such a drug is administered, for example, transdermally and is effective for achieving the intended purpose.

[0185] The "subject" or "patient" for which the administration of a therapeutic agent is an effective therapeutic regimen for a disease or disorder is preferably a human, but may be any animal, including a laboratory animal in the context of a study or screening or activity study experiment. Thus, as one of ordinary skill in the art can readily understand, the methods and systems of the present invention relate to an agent particularly suitable for administration to any animal, in particular a mammal, including but not limited to only them, humans, domestic animals such as cats or dogs, farm animals such as, but not limited to, cattle, horses, goats, sheep and pigs, wild animals (in nature or in a zoo) used for research animals such as mice, rats, rabbits, goats, sheep, pigs, dogs, cats, etc., bird species such as chickens, turkeys, songbirds, etc., for example, for veterinary medicine.

[0186] Treatment of a subject with the systems can be monitored by techniques 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 examining the subject's symptoms in a quantitative manner, for example, by recording a decrease in the frequency of adverse symptoms, behavior or seizures, or an increase in the time of prolonged worsening of symptoms. With successful treatment of the subject, the condition improves (ie, the frequency of relapses decreases or the time to long-term progression increases).

[0187] A method is provided for treating a suitable pathological condition with an active agent using typical transdermal delivery systems (also referred to as a transdermal device or devices) described in the present invention. In embodiments, the present invention relates to devices comprising an active agent that are useful for treating, delaying progression, delaying onset, slowing progression, preventing, providing remission, and improving symptoms of cognitive impairment or disease and multiple sclerosis. In embodiments, devices comprising an active agent are designed to support mental function, including but not limited to at least one of the following: maintaining thinking, memory, speaking skills, and regulating or alleviating one or more behavioral symptoms. cognitive impairment or disease. In embodiments, the cognitive impairment is Alzheimer's disease. In preferred embodiments, the cognitive impairment is dementia of the Alzheimer's type. In embodiments, devices comprising memantine are for use in the treatment of, and the like, mild, moderate, or severe Alzheimer's disease. In other embodiments, devices comprising fingolimod are provided for use in the treatment of multiple sclerosis, the prevention and/or reduction of relapse rates of multiple sclerosis, in particular relapsing remission multiple sclerosis.

[0188] In one embodiment, the methods relate to the treatment of CNS disorders or autoimmune disorders in a subject in need thereof by interacting the subject's tissue with one or more transdermal delivery systems. The terms "transdermal" and "topical" are used in the present invention in the broadest sense to refer to the application of the active agent, for example, memantine or donepezil, or fingolimod, to the surface of the skin or mucous membrane of an animal, including humans, so that the drug passes through the surface. body, such as the skin, and into the individual's bloodstream. The term "transdermal" includes transmucosal administration, i.e., administration of a drug to the mucosal surface (eg, sublingual, buccal, vaginal, rectal) of an individual such that the agent passes through the mucosal tissue and into the individual's bloodstream.

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

[0190] The terms "skin" tissue or "skin" tissue as used herein are defined to include tissues covered by a stratum corneum or zona pellucida and/or other mucous membranes. The term further includes mucosal tissue, including the interior surfaces of body cavities, eg, buccal, nasal, rectal, vaginal, and the like, which have a mucosal lining. The term "skin" should be understood to include "mucous tissue" and vice versa.

[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 the age of 65 and nearly 30% of people over the age of 85 (Sozio et al ., Neurophsychiatric Disease and Treatment , 2012, 8:361-368), including loss of cognitive function and behavioral ability. The causes of Alzheimer's disease are not fully understood. Since Alzheimer's disease is associated with reduced levels of various cerebral neurotransmitters, including acetylcholine (Ach), current treatment includes the administration of cholinesterase inhibitors. Cholinesterase inhibitors reduce the hydrolysis of acetylcholine in the synaptic cleft by inhibiting cholinesterase and/or butyrylcholinesterase, resulting in an increase in acetylcholine resulting in improved neurotransmission ( Id .).

[0192] The transdermal devices described in the present invention can be made 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 should be understood that the total dose of active agent in terms of percutaneous device is determined by the size of the device and the content of the active agent in the adhesive matrix. In one embodiment, the active agent is donepezil free base. A lower drug content of donepezil base may be effective compared to the salt form (eg, donepezil hydrochloride). The ability to include less drug to ensure efficacy results in a lower profile for the device (thinner) and/or smaller size, both of which are desirable to reduce discomfort. In some embodiments, the exposure period of the applied percutaneous 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 some embodiments, the active agent is released from the adhesive matrix as a continuous and/or sustained release over the application period.

[0193] A method for transdermal delivery of donepezil base to a subject is provided. In the method, the transdermal delivery system is applied to the skin, and after the transdermal delivery system is applied to the subject's skin, donepezil base is delivered transdermally and a systemic blood concentration of the agent (or metabolite) is provided, which in the equilibrium state is bioequivalent to oral administration of the therapeutic agent. As shown below, bioequivalences are found (a) for a 90% confidence interval relative mean C _max and AUC of a therapeutic agent administered from a transdermal delivery system and via oral delivery, equal to from 0.80 to 1.25 or 0.70-1, 43, or found (b) for a 90% confidence interval of the geometric means of the ratios of AUC and C _max of a therapeutic agent administered from a transdermal delivery system and using oral delivery, equal to from 0.80 to 1.25 or 0.70-1, 43.

[0194] Standard PK parameters commonly used to assess the effect of a dosage form in vivo (in other words, when administered to an animal or humans) include C _max (peak plasma drug concentration), T _max (time for which peak drug concentration is established ) and AUC (area under the plasma concentration-time curve). Techniques for determining and evaluating these parameters are well known in the art. The desired pharmacokinetic profile of the transdermal delivery systems described herein includes, but is not limited to: (1) C _max for the transdermally delivered form of donepezil as determined in mammalian plasma after administration, which is bioequivalent to C _max for the orally delivered or intravenously delivered dosage form means administered in the same dose; and/or (2) AUC for the transdermally delivered form of donepezil as measured in mammalian plasma after administration, i.e. preferably bioequivalent to the AUC for the orally delivered or intravenously delivered form of the drug administered at the same dose; and/or (3) T _max for a transdermally delivered form of donepezil as determined in mammalian plasma after administration, i.e., about 80-125% of T _max for an orally delivered or intravenously delivered form of the drug administered at the same dose. Preferably, the transdermal delivery system has a PK profile that includes a combination of two or more of the characteristics (1), (2) and (3) indicated in the previous phrase. Preferably, the transdermal delivery system has a PK profile that includes one or both of characteristics (1) and (2).

[0195] In the field of pharmaceutical development, the term "bioequivalence" is easily understood and analyzed by a person skilled in the art. Different regulatory bodies have strict criteria and tests to assess whether two drug products are bioequivalent. These criteria and tests are commonly used in the pharmaceutical industry and bioequivalence assessment is considered a standard form of action in drug development programs in which the characteristics and performance of one product are compared with data for another product. In fact, when applying for approval to market certain types of products (eg, those investigated under the FDA's "Abbreviated New Drug Application"), it is necessary to show that the improved product is bioequivalent to the reference product.

[0196] In one embodiment, the method comprises providing and/or administering a transdermal delivery system comprising donepezil base to a subject on an empty stomach, which is bioequivalent to administering the agent (in base or salt form) orally or intravenously to a subject also on an empty stomach, specifically as defined in the guidelines according to C _max and AUC established by the US Food and Drug Administration and the relevant European Regulatory Authority (EMEA). In another embodiment, the method includes providing and/or administering a transdermal delivery system comprising donepezil base to a subject on an empty stomach, which is bioequivalent to administering the agent (in base or salt form) orally or intravenously to the subject also on an empty stomach or after a meal. According to US FDA and Europe's EMEA guidelines, two products or methods are bioequivalent if the 90% confidence intervals (CI) for AUC and C _max are between 0.80 and 1.25 (T _max results do not refer to bioequivalence for regulatory purposes) . Europe's EMEA has previously used a different standard which requires a 90% CI for an AUC of 0.80 to 1.25 and a 90% CI for a C _max of 0.70 to 1.43. Methods for determining C _max and AUC are well known in the art.

[0197] The transdermal delivery system made in accordance with example 1 was studied in vivo for the systemic delivery of donepezil as described in example 4. In this in vivo study, 6 people were treated with a transdermal delivery system applied to their skin and used for one week and then removed. Another group of 6 were treated with orally administered donepezil ( ^ARICPET® ) at a dose of 5 mg given on day 1 and day 7 of the study. Blood samples were taken from subjects and plasma donepezil concentrations were determined. The results are shown in FIG. 2A-2B.

[0198] FIG. 2A shows the mean plasma concentration of donepezil in ng/mL in humans treated with the donepezil transdermal delivery system (circles) for 1 week or with donepezil 5 mg orally on day 1 and day 7 (triangles). The transdermal donepezil delivery system provides a plasma concentration similar to that of oral delivery of a similar dose of donepezil. Accordingly, in one embodiment, a method for transdermal administration of donepezil is provided by applying a transdermal delivery system that provides a pharmacokinetic profile that is bioequivalent to the pharmacokinetic profile obtained from oral administration of donepezil.

[0199] FIG. 2B is a graph with an enlarged view of the FIGS. 2A data for the 24-hour period after oral administration of a 5 mg donepezil tablet (triangles) and after removal of the donepezil transdermal delivery system (circles). The transdermal delivery system after its removal provides a prolonged constant concentration of donepezil in plasma over 24 hours, close to that observed within 24 hours after oral administration.

[0200] In FIG. 3 is a plot of the projected mean plasma donepezil concentration in ng/mL in the last week of a 28-day (4-week) treatment period with a transdermal delivery system designed to administer 10 mg/day for a week (solid line) and for 28 days. with a daily oral donepezil tablet (dotted line). Plasma fluctuations after oral administration were eliminated by a transdermal system where a fresh patch was applied weekly and a constant plasma concentration was maintained during the treatment period. The transdermal delivery system provides a constant plasma concentration of donepezil over an extended period of time (eg, 3 days, 5 days, 7 days, 14 days) when the plasma concentration is substantially constant or differs by no more than about 10%, 15% , 20% or 30% of the plasma concentration provided by daily oral administration of a similar dose of donepezil.

[0201] In the study in Example 4, six subjects who were treated with the donepezil transdermal delivery system for a week were monitored for several days after the delivery system was removed from their skin for signs of skin irritation. In FIG. 4 is a bar graph showing the number of subjects out of 6 per group and the number of skin irritations observed during the period after removal of the delivery system, where the open bar indicates no skin irritation and the solid bar indicates mild skin irritation. The delivery system resulted in no or mild skin irritation 1 hour after removal and any mild skin irritation resolved within 1 or 2 days.

[0202] In another study, humans were treated with a transdermal delivery system designed to deliver systemically an amount of donepezil that is bioequivalent to oral donepezil 10 mg daily. The projected pharmacokinetic parameters C _max , AUC and C _min for the two delivery routes are compared in Table 1.

Table 1: Projected pharmacokinetic parameters

PK parameter at steady state Transdermal delivery system once a week Donepezil 10 mg orally once a day Geometric mean ratio (transcutaneous:
oral) Geometric mean C _max (ng/ml) 40.6 45.6 0.890 Geometric mean C _min (ng/ml) 34.2 30.8 1.110 Geometric mean AUC _week (ng-h/ml) 6367 6165* 1.033

[0203] Accordingly, in one embodiment, a method for delivering donepezil base to a subject is provided. The method includes using a transdermal delivery system comprising donepezil and applying or instructions for applying the transdermal delivery system to the skin of a subject. The method provides transdermal delivery of donepezil that is bioequivalent to oral administration of a therapeutic agent, where bioequivalence is based on (a) a 90% confidence interval of the relative mean _Cmax and AUC of the therapeutic agent administered from a transdermal delivery system and via oral delivery, equal to 0.70-1 .43 or from 0.80 to 1.25 or (b) 90% confidence interval for the ratios of AUC and C _max of the therapeutic agent administered from the transdermal delivery system and via oral delivery, equal to 0.70-1.43 or from 0.80 to 1.25.

[0204] Example 5 describes a human study in which transdermal patches comprising donepezil were tested and compared with orally administered donepezil. In this study, patients were enrolled in a 6-month, 3-period, randomized, cross-over study comparing stationary pharmacokinetic profiles of once-daily oral donepezil ( ^ARICEPT® ) and donepezil from a transdermal patch preparation. Used transdermal two sizes, A and B, except for the surface area of the transdermal patches were in all respects the same. During the study, participants in each treatment group received one week of donepezil 5 mg/day, followed by 4 weeks of donepezil 10 mg/day delivered from a once-a-weekly applied transdermal patch in two sizes (group 1 and group 2) or orally (group 3). Pharmacokinetic studies were performed during the fourth week for the 10 mg/day treatment regimen when plasma concentrations reached steady state. To study the pharmacokinetics, blood samples from subjects treated percutaneously were taken daily during the fourth week. For pharmacokinetic studies in subjects receiving oral donepezil, blood samples were taken on the last day of the fourth week. The mean plasma donepezil concentration in ng/mL is shown in FIG. 5A for each day of study week 5, where the solid line corresponds to the lower surface area transdermal patch and the dotted line corresponds to the higher surface area transdermal patch. The bold broad line on days 6-7 shows the mean plasma concentration in subjects treated with oral donepezil, and the dotted line shows the projected daily plasma concentration for oral treatment. Mean plasma donepezil concentrations in subjects treated with the transdermal patch were bioequivalent to plasma donepezil concentrations in a subject treated with oral donepezil. For larger and smaller transdermal patches, dose proportionality was found. Table 2 lists the primary pharmacokinetic parameters in evaluating the bioequivalence of the smaller surface area transdermal patch used in the study.

table 2

Primary pharmacokinetic parameter Geometric Mean Ratio (%) of Smaller Patch to Oral Dose Ratio Limits of bioequivalence (target value 80-125%) AUC (ng-h/ml) 104.7% 95.2-115.2 Cmax _ss (ng/ml) 91.6% 83.1-100.8

[0205] Gastrointestinal related adverse events, nausea, vomiting, and diarrhea reported by subjects in the clinical study above, shown in FIG. 5A are shown in FIG. 5b. Subjects treated with the smaller transdermal patch (solid bar) and larger transdermal patch (vertical-hatched bar) experienced a lower incidence of nausea, vomiting, and diarrhea than subjects treated with oral (horizontal-hatched bar) donepezil. The number of subjects who experienced nausea with transdermal administration of donepezil 10 mg/day was 4 times less than with oral administration. The number of subjects who experienced diarrhea with transdermal administration of 10 mg/day donepezil was 2 times less than with oral administration.

[0206] Accordingly, in one embodiment, a composition and method for delivering donepezil to a subject is provided. The composition, when applied to the skin of a subject, provides transdermal delivery of donepezil with a plasma concentration of donepezil that is bioequivalent to oral donepezil at steady state, and/or results in a number of gastrointestinal-related adverse events that is two, three, four, or five times less than subjects treated with the same oral dose of donepezil (i.e., the oral dose is equal to the transdermal dose, so that subjects were treated with the same oral or transdermal dose of donepezil). In one embodiment, donepezil administered orally is the salt form of donepezil and onepezil administered transdermally is the base of donepezil. In one embodiment, the number of gastrointestinal-related adverse events is 2-5, 2-4, and 2-3 times less, and in another embodiment, the number of gastrointestinal-related adverse events is at least about two times, not less than about three times, not less than about four times, or not less than about five times less than in subjects who were treated with the same dose of oral donepezil. In one embodiment, the delivery of donepezil is for the treatment of Alzheimer's disease.

[0207] The transdermal devices described in the present invention can be made for long-term use and/or continuous administration of the active agent. The FDA has approved memantine doses of 2 mg, 5 mg, 7 mg, 10 mg, 14 mg, 21 mg, and 28 mg. It should be understood that the total dose of active agent in terms of percutaneous device is determined by the size of the device and the content of the active agent in the adhesive matrix. In one embodiment, the active agent is memantine in free base form. A lower content of the drug - memantine can be effective compared to the salt form (for example, memantine hydrochloride). The ability to include less drug to ensure efficacy results in a lower profile for the device (thinner) and/or smaller size, both of which are desirable to reduce discomfort. In some embodiments, the exposure period of the applied percutaneous 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 some embodiments, the active agent is released from the adhesive matrix as a continuous and/or sustained release over the application period.

[0208] A method for transdermal delivery of memantine to a subject is provided. In the method, the transdermal delivery system is applied to the skin, and after the transdermal delivery system is applied to the subject's skin, memantine is delivered transdermally and a systemic blood concentration of the agent (or metabolite) is provided, which at equilibrium is bioequivalent to oral administration of the therapeutic agent. As shown below, bioequivalences are found (a) for a 90% confidence interval relative mean C _max and AUC of a therapeutic agent administered from a transdermal delivery system and via oral delivery of 0.80 to 1.25, or found (b) for 90% confidence interval of the geometric mean ratios of AUC and C _max of the therapeutic agent administered from the transdermal delivery system and via oral delivery, equal to from 0.80 to 1.25.

[0209] Standard pharmacokinetic (PK) parameters commonly used to assess the effect of a dosage form (in other words, when administered to an animal or human) include C _max (peak plasma drug concentration), T _max (time for which peak drug concentration is established means) and AUC (area under the plasma concentration-time curve). Techniques for determining and evaluating these parameters are well known in the art. The desired pharmacokinetic profile of the transdermal delivery systems described herein includes, but is not limited to: (1) C _max for the transdermal delivered form of memantine as determined in mammalian plasma after administration, which is bioequivalent to the C _max for the orally delivered or intravenously delivered dosage form means administered in the same dose; and/or (2) the AUC for the transdermal delivered form of memantine, as determined in mammalian plasma after administration, which is preferably bioequivalent to the AUC for the orally delivered or intravenously delivered form of the drug administered at the same dose; and/or (3) T _max for a transdermally delivered form of memantine as determined in mammalian plasma after administration, i.e., about 80-125% of T _max for an orally delivered or intravenously delivered form of the drug administered at the same dose. Preferably, the transdermal delivery system has a PK profile that includes a combination of two or more of the characteristics (1), (2) and (3) indicated in the previous phrase. In another embodiment, the transdermal delivery system has a PK profile comprising one or both of characteristics (1) and (2).

[0210] In the field of pharmaceutical development, the term "bioequivalence" is easily understood and analyzed by a person skilled in the art. Different regulatory bodies have strict criteria and tests to assess whether two drug products are bioequivalent. These criteria and tests are commonly used in the pharmaceutical industry and bioequivalence assessment is considered a standard form of action in drug development programs in which the characteristics and performance of one product are compared with data for another product. In fact, when applying for approval to market certain types of products (eg, those investigated under the FDA's "Abbreviated New Drug Application"), it is necessary to show that the improved product is bioequivalent to the reference product.

[0211] In one embodiment, the method includes providing and/or applying a transdermal delivery system comprising donepezil base to a subject on an empty stomach, which is bioequivalent to administering the agent (in base or salt form) orally or intravenously to a subject also on an empty stomach, specifically as defined in the guidelines according to C _max and AUC established by the US Food and Drug Administration and the relevant European Regulatory Authority (EMEA). In another embodiment, the method includes providing and/or administering a transdermal delivery system comprising donepezil base to a subject on an empty stomach, which is bioequivalent to administering the agent (in base or salt form) orally or intravenously to the subject also on an empty stomach or after a meal. According to US FDA and Europe's EMEA guidelines, two products or methods are bioequivalent if the 90% confidence intervals (CI) for AUC and C _max are between 0.80 and 1.25 (T _max results do not refer to bioequivalence for regulatory purposes) . Europe's EMEA has previously used a different standard which requires a 90% CI for an AUC of 0.80 to 1.25 and a 90% CI for a C _max of 0.70 to 1.43. Methods for determining C _max and AUC are well known in the art.

[0212] Accordingly, in one embodiment, a method for delivering a memantine base to a subject is provided. The method includes using a transdermal delivery system comprising memantine and applying or instructions for applying the transdermal delivery system to the skin of a subject. The method provides transdermal delivery, which is bioequivalent to the administration of a therapeutic agent orally, where the bioequivalence is based on (a) a 90% confidence interval of the relative average C _max and AUC of the therapeutic agent administered from the transdermal delivery system and using oral delivery, equal to from 0.70 to 1 ,43 or from 0.80 to 1.25 or (b) 90% confidence interval for the geometric mean ratios for AUC and C _max of the therapeutic agent administered from the transdermal delivery system and via oral delivery from 0.70 to 1, 43 or from 0.80 to 1.25.

[0213] Examples 6 and 7 show other exemplary compositions and delivery systems. As indicated in Example 6, a transdermal delivery system was prepared comprising a drug reservoir layer and a contact adhesive layer, and a layer with a rate regulating membrane interposed between the drug reservoir and the contact adhesive layers as shown in FIG. 1A. A drug reservoir in the form of a solid monolithic adhesive reservoir was prepared using an acrylic acid/vinyl acetate copolymer and a cross-linked polyvinylpyrrolidone (PVP-CLM) adhesive, as well as the indicated solubilizing agents, carriers, and optionally penetrating agents (Table 3). The drug reservoir contains about 25 wt% memantine hydrochloride and 9.73 wt% sodium bicarbonate for in situ formation of memantine base. A contact adhesive layer containing a higher alcohol and a biocompatible polymer was synthesized. In the second embodiment, the contact adhesive contains a higher alcohol and a biocompatible polymer, as well as dispersed silicon dioxide. To control the diffusional delivery of memantine base from the drug reservoir, a rate control membrane can be inserted between the drug reservoir and the contact adhesive.

Table 3: Transdermal delivery systems with two formulations of contact adhesive

COMPONENTS Medicine reservoir Contact adhesive #1 Contact adhesive #2 Dry Composition (%) Dry Composition (%) Dry Composition (%) Memantine HCl 25% 0 0 Bicarbonate of soda 9.73% 0 0 Octyldodecanol 10% 10% 10% Glycerol 10% 0 0 Fine Silica (AEROSIL ^® 200) 0 0 7% Cross-linked polyvinylpyrrolidone (KOLLIDON ^® CL-M) 15% 20% 0 Acrylic acid/vinyl acetate copolymer (DURO-TAK ^® 387/87-2287) 30.3% 0 0 Polyisobutylene/polybutene 0 70% 83% Total 100% 100% 100%

[0214] As indicated in Example 6, transdermal delivery systems were prepared and include a drug reservoir and a skin-contacting adhesive layer separated by an intermediate layer. The drug reservoir in typical systems contains an acrylic acid/vinyl acetate copolymer and a crosslinked polyvinylpyrrolidone (KOLLIDON-CLM). These base materials are mixed with the indicated carriers and solvents, memantine hydrochloride and sodium bicarbonate (Table 4). The drug reservoir contains about 25 wt% memantine hydrochloride and 9.73 wt% sodium bicarbonate for in situ formation of memantine base. The adhesive layer in contact with the skin contains a higher alcohol and a biocompatible polymer.

Table 4: Transdermal delivery system

Medicine reservoir Contact adhesive Dry Composition (%) Dry Composition (%) Memantine HCl 25% 0 Bicarbonate of soda 9.7% 0 Octyldodecanol 7% 10% Glycerol 10% 0 Cross-linked polyvinylpyrrolidone (KOLLIDON ^® CL-M) 15% 20% Acrylic acid/vinyl acetate copolymer (DURO-TAK ^® 387/87-2287) 33.3% 0 Polyisobutylene/polybutene 0 70% Total 100% 100%

[0215] A memantine-containing transdermal system was prepared as described in Example 7 to demonstrate the delivery of an active agent derived from the amine salt form of the active agent and an amphoteric inorganic base compound. The memantine-containing transdermal system was examined in vitro by determining the release of memantine from the system and through human skin, and the results are shown in FIG. 6 (squares). Approximately 18 hours after application of the transdermal system to the skin, a constant flow rate of about 12-15 µg/cm ² -h is established. The flow rate remains constant for about 6.5 days and then decreases. Accordingly, in one embodiment, a transdermal delivery system for delivering the base form of the active agent is prepared from the amine salt form of the active agent and sodium bicarbonate, and a skin flux rate or penetration rate is obtained that is therapeutic for at least about 3 days or 5 days, or 7 days (or 3-7 days). In one embodiment, the constant in vitro skin flux rate was reduced by no more than 15%, 20%, 25%, or 30% over at least about 3 days, or 5 days, or 7 days (or 3-7 days). Thus, in vitro skin flux measured at time y differs from in vitro skin flux measured at an earlier adjacent time x , where x and y are time points, within a measurement period of 3 days, 5 days or 7 days less than 15%, 20%, 25% or 30%.

[0216] Also made comparative examples to illustrate proposed in the present invention the compositions, systems and methods described in the present invention. In FIG. 6 shows that adhesive compositions (transdermal systems) made using the three main forms of the drug (lozenges), with the salt form of the amine of the drug but without sodium bicarbonate (circles) or the salt form of the amine of the drug and the amphoteric inorganic base compound, but when the pKa of the amphoteric inorganic basic compound is not less, but greater than for the amine salt form of the active agent (triangles). In these Comparative Examples in vitro, skin flux of the drug is sufficient for treatment.

[0217] A transdermal delivery system for donepezil comprising a microporous membrane layer that has been pretreated with a membrane treatment composition is described in Example 9. A comparative example of a transdermal system in which the microporous membrane was left untreated is also described. An in vitro comparison of skin flux was made and the results are shown in FIG. 7. It can be seen that treatment of the microporous membrane with the membrane treatment composition increases the overall flux of donepezil through the skin and this flux is maintained for an increased period of time.

IV. Examples

[0218] The following examples are illustrative in nature and are not restrictive in any way.

EXAMPLE 1

Donepezil transdermal delivery system

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

Obtaining a drug reservoir

[0220] Sorbitan monolaurate ( ^SPAN® 20, 1.20 g) was dissolved in 6.00 g of triethyl citrate and mixed with 1.80 g of lauryl lactate and 89.69 g of ethyl acetate. 6.00 g of glycerol was added and mixed. 9.00 g of donepezil hydrochloride and 1.82 g of sodium bicarbonate were added and dispersed into the mixture. Then 12.00 g of cross-linked, micronized polyvinylpyrrolidone ( ^Kollidon® CL-M) was added and the mixture was homogenized. 43.93 g of acrylic acid/vinyl acetate copolymer (Duro- ^Tak® 387-2287, 50.5% solids content) was added to the homogenized drug dispersion and thoroughly mixed. The wet adhesive preparation was applied to the backing layer and dried using a laboratory coater (Werner Mathis) to give a dry coating with a surface density of 12 mg/cm ² .

Obtaining a contact adhesive:

[0221] Sorbitan monolaurate ( ^SPAN® 20, 0.60 g) was dissolved in 3.0 g triethyl citrate and mixed with 0.9 g lauryl lactate, 25.45 g ethyl acetate and 1.34 g isopropyl alcohol. 6.00 g of cross-linked, micronized polyvinylpyrrolidone ( ^Kollidon® CL-M) was added and the mixture was homogenized. 38.61 g of acrylic acid/vinyl acetate copolymer (Duro- ^Tak® 387-2287, 50.5% solids content) was added to the homogenized mixture and thoroughly mixed. The wet adhesive preparation was applied to the protective layer and dried to give a dry coating with an areal density of 5 mg/cm ² .

Lamination and cutting

[0222] A rate-regulating membrane ( ^CELGARD® 2400 or ^Reemay® 2250) was layered on the adhesive side of the drug reservoir. The contact adhesive was then overlaid on top of the rate control membrane laminated to the drug reservoir. The protective layer on the side of the drug reservoir was replaced and laminated with the cover film. The final five-layer laminate was cut into transdermal patches.

[0223] The mass content in % of the components in the transdermal delivery system is shown below in table 1.1.

Table 1.1

Ingredient wt% in drug reservoir wt% in contact adhesive total wt.% in the delivery system Donepezil HCl 5.2% - 3.6% Bicarbonate of soda 1.1% - 0.74% sorbitan monolaurate ( ^Span® 20) 0.7% 0.8% 0.73% triethyl citrate 3.5% 3.9% 3.6% Lauryl lactate 1.05% 1.2% 1.1% ethyl acetate 52.3% 33.5% 46.6% Glycerol 3.5% - 2.4% Cross-linked micronized polyvinylpyrrolidone (Kollidon ^® CL-M) 7.0% 7.9% 7.3% Acrylic acid/vinyl acetate copolymer (Duro- ^Tak® 387-2287) 25.6% 50.9% 33.4% Isopropyl alcohol - 1.8% 0.54%

EXAMPLE 2

Donepezil transdermal delivery systems

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

Obtaining a drug reservoir

[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 into the mixture. Cross-linked, micronized polyvinylpyrrolidone ( ^KOLLIDON® CL-M) was then added and the mixture was homogenized. An acrylic acid/vinyl acetate copolymer (DURO- ^TAK® 387-2287, 50.5% solids content) was added to the homogenized drug dispersion and thoroughly mixed. The wet adhesive preparation was applied to the backing layer and dried using a laboratory coater (Werner Mathis).

Obtaining a contact adhesive

[0226] Sorbitan monolaurate ( ^SPAN® 20) was dissolved in triethyl citrate and mixed with lauryl lactate. Cross-linked, micronized polyvinylpyrrolidone ( ^Kollidon® CL-M) was added and the mixture was homogenized. An acrylic acid/vinyl acetate copolymer (DURO- ^TAK® 387-2287, 50.5% solids content) was added to the homogenized mixture and thoroughly mixed. The wet adhesive preparation was applied to the protective layer and dried.

Lamination and cutting

[0227] A rate-regulating membrane ( ^CELGARD® 2400) was layered on the adhesive side of the drug reservoir. The contact adhesive was then overlaid on top of the rate control membrane laminated to the drug reservoir. The protective layer on the side of the drug reservoir was replaced and laminated with the cover film. The final five-layer laminate was cut into transdermal patches.

[0228] The mass content in % of the components in the transdermal delivery system is shown below in table 2.1.

Table 2.1

Ingredient Drug reservoir (in terms of solids % wt./wt.) Contact adhesive (in terms of dry substances, % wt./wt.) Donepezil HCl 16.0 0 Bicarbonate of soda 2.6 0 triethyl citrate 10.0 10.0 Lauryl lactate 3.0 3.0 Sorbitan monolaurate (SPAN ^® 20) 2.0 2.0 Glycerol 10.0 0 PVP-CLM ( ^KOLLIDONE® -CLM) 15.0 20.0 Acrylic acid/vinyl acetate copolymer (Duro- ^Tak® 387-2287) 41.4 65.0

EXAMPLE 3

Donepezil transdermal delivery systems

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

Obtaining a drug reservoir:

[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 into the mixture. Then, fine silica ( ^AEROSIL® 200 Pharma) was added and the mixture was homogenized. Acrylic acid/vinyl acetate copolymer (DURO- ^TAK® 387-2287, 50.5% solids content) was added to the homogenized drug dispersion, and dimethylaminoethyl methacrylate-butyl methacrylate-methyl methacrylate copolymer ( ^EUDRAGIT® EPO) was added and thoroughly mixed. The wet adhesive preparation was applied to the backing layer and dried using a laboratory coater (Werner Mathis).

Obtaining a contact adhesive:

[0231] Sorbitan monolaurate ( ^SPAN® 20) was dissolved in triethyl citrate and mixed with lauryl lactate. Cross-linked, micronized polyvinylpyrrolidone ( ^KOLLIDON® CL-M) was added and the mixture was homogenized. An acrylic acid/vinyl acetate copolymer (Duro- ^Tak® 387-2287, 50.5% solids content) was added to the homogenized mixture and mixed thoroughly. The wet adhesive preparation was applied to the protective layer and dried.

Lamination and cutting

[0232] A rate-regulating membrane ( ^CELGARD® 2400) was layered on the adhesive side of the drug reservoir. The contact adhesive was then overlaid on top of the rate control membrane laminated to the drug reservoir. The protective layer on the side of the drug reservoir was replaced and laminated with the cover film. The final five-layer laminate was cut into transdermal patches.

[0233] The mass content in % of the components in the transdermal delivery system is shown below in table 3.1.

Table 3.1

Ingredient Drug reservoir (in terms of solids % wt./wt.) Contact adhesive (on a dry matter basis, % w/w) Donepezil HCl 25.0 0 Copolymer of dimethylaminoethyl methacrylate, butyl methacrylate, methyl methacrylate (EUDRAGIT ^® EPO) 17.7 0 triethyl citrate 10.0 10.0 Lauryl lactate 6.0 6.0 Sorbitan monolaurate (SPAN ^® 20) 2.0 2.0 Fine Silica (AEROSIL ^® 200 Pharma) 7.0 0 Glycerol 10.0 0 PVP-CLM ( ^KOLLIDONE® -CLM) 0 20.0 Acrylic acid/vinyl acetate copolymer (Duro- ^Tak® 387-2287) 24.3 64.0

EXAMPLE 4

In vivo administration of donepezil from the transdermal donepezil delivery system

[0234] Transdermal delivery systems including donepezil were prepared as described in Example 1. Twelve (12) people were randomized into two groups for treatment with the transdermal delivery system (n=6) or with orally administered donepezil (ARICPET®), 5 mg was given on day 1 and day 7 of the study. The transdermal delivery system was applied to the skin and kept for a week and then removed. Blood samples were taken daily from subjects treated with the transdermal delivery system. Blood samples were taken at hourly intervals on day 1 and day 7 in the group of subjects treated with orally delivered donepezil and again on days 8, 10, 12, and 14. Mean plasma concentrations of donepezil in the group of treated subjects are shown in fig. 2A-2B.

EXAMPLE 5

In vivo administration of donepezil from the transdermal donepezil delivery system

[0235] Transdermal delivery systems comprising donepezil were prepared as described in Example 2. Patients were enrolled in the study and randomly divided into three treatment groups for a 5 week treatment study. Group 1 (n=52) and Group 2 (n=51) patients were treated with the transdermal system of Example 2, where Group 1 patients used a patch with less surface area (Patch A) than Group 2 patients (Patch B). Except for the dimensions, patch A and patch B were identical. In the first week of the study, patients in Group 1 and Group 2 used patches designed to deliver 5 mg of donepezil from a weekly patch. After an initial 7 day period, patients were given a transdermal system designed to be used for 7 days (percutaneous patch once a week) to deliver 10 mg donepezil per day, in which case patch A differed from patch B only in surface area. The transdermal systems were replaced weekly for 4 weeks. Group 3 patients (n=54) were treated with a daily oral dose of donepezil (ARICEPT) of 5 mg for 7 days followed by a daily dose of donepezil (ARICEPT) of 10 mg for 4 weeks.

[0236] Subjects of group 1 and group 2 blood samples were taken daily during the fourth week of administration of 10 mg, when plasma concentrations became constant. The subjects of group 3 blood samples were taken on the last day of the fourth week of administration of 10 mg/day. The mean plasma concentration of donepezil for the treatment groups at the fourth week of 10 mg dosing is shown in FIG. 5A, where subjects were treated with donepezil administered transdermally from transdermal patch A (lower surface area, solid line), transdermal patch B (higher surface area, dotted line), and orally administered donepezil (bold broad line on days 6-7). ), as well as a dotted line showing the projected daily plasma concentration for oral treatment.

[0237] FIG. 5B is a bar graph showing the number of gastrointestinal-related adverse events (nausea, vomiting, and diarrhea) reported by subjects in the study, where the shaded bar corresponds to subjects treated with the smaller once-weekly applied transdermal patch, the shaded the bar with vertical lines corresponds to subjects treated with the larger once-weekly applied transdermal patch and the bar with hatched horizontal lines corresponds to subjects treated with oral donepezil.

EXAMPLE 6

Memantine transdermal delivery system

[0238] A transdermal delivery system including memantine was prepared as follows.

Obtaining a drug reservoir:

[0239] The memantine salt and the alkali metal salt were dissolved in a mixture of ethyl acetate, isopropyl alcohol, propylene glycol and levulinic acid to give a clear solution. In one embodiment, fine silica ( ^AEROSIL® 200P) was added and the mixture was homogenized. An acrylic acid/vinyl acetate copolymer (DURO- ^TAK® 387-2287) was added to the homogeneous mixture and stirred until the mixture became homogeneous.

[0240] The adhesive mixture was applied to a layer of siliconized polyethylene terephthalate and dried using a Werner Mathis coater at 60° C. for 8 minutes to form a dry adhesive layer.

[0241] The transdermal delivery system was prepared using two of the dry adhesive layers with a polyester nonwoven fabric sandwiched between the two adhesive layers. Then the applied layer of polyethylene terephthalate was replaced with a cover film.

Obtaining a contact adhesive

[0242] Octyldodecanol, cross-linked, micronized polyvinylpyrrolidone ( ^KOLLIDON® CL-M) and an optional solvent were mixed and the mixture was homogenized. Polyisobutylene (PIB, 10/50/40) was added to the homogenized mixture and thoroughly mixed. The wet adhesive preparation was applied to the protective layer and dried.

Lamination and cutting

[0243] An intermediate layer ( ^CELGARD® 2400 or ^Reemay® 2250) was layered on the adhesive side of the drug reservoir. The contact adhesive was then overlaid on top of the rate control membrane laminated to the drug reservoir. The protective layer on the side of the drug reservoir was replaced and laminated with the cover film.

[0244] The transdermal delivery systems were then cut from the laminate.

EXAMPLE 7

Transdermal preparation of memantine salt with sodium bicarbonate

Receipt of a drug in an adhesive (drug reservoir)

[0245] 2.0 g of Glycerol 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. 5.0 g of memantine hydrochloride and 1.95 g of sodium bicarbonate were dispersed in the solution by stirring. 3.0 g of cross-linked polyvinylpyrrolidone (Kollidon® CL-M) was added to the dispersion and homogenized using a Silverson homogenizer-mixer. 11.99 g of acrylate copolymer (Duro-Tak® 387-2287, 50.5% solids content) was added to the homogenized dispersion and thoroughly mixed. The wet adhesive preparation was applied to the backing layer and dried using a Werner Mathis coater to give a dry coating with an areal density of 15 mg/cm ² .

Obtaining a contact adhesive

[0246] 2.0 g of Octyldodecanol was mixed with 20.67 g of n-heptane. After adding 4.00 g of cross-linked polyvinylpyrrolidone (Kollidon® CL-M) to the solution, the mixture was homogenized using a Silverson homogenizer-mixer. To the homogenized mixture was added, 23.33 g of polyisobutylene adhesive (60% solids content) was mixed and thoroughly. The wet adhesive preparation was applied to the protective layer and dried to give a dry coating with an areal density of 5 mg/cm ² .

Lamination and cutting

[0247] A polypropylene microporous membrane ( ^Celgard® 2400) was laminated between the drug-in-adhesive layer and the contact adhesive layer. The drug side backing layer in the adhesive was replaced and laminated with a 3M Scotchpak® 1012 closure. The final five layer laminate was cut into patches.

Skin flux study in vitro

[0248] Dermatome-prepared human cadaver skin was obtained from a skin bank and frozen prior to use. The skin was placed in water at 60°C for 1-2 min, and after thawing, the epidermis was carefully separated from the dermis. The epidermis was used immediately or wrapped and frozen for later use.

[0249] An in vitro skin flux study was performed using a Franz-type diffusion cell with an active diffusion area of 0.64 cm ² . The epidermis was fixed between the donor and receptor compartments of the diffusion cell. The transdermal delivery system was placed on the skin and the two compartments were tightly fastened together.

[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 with a magnetic stir bar in the receptor compartment. The temperature was maintained at 32 ± 0.5°C. Samples were taken periodically from the receptor solution and the receptor solution was replaced with fresh phosphate buffer solution. The content of the drug (memantine) in the samples was determined using LCMS.

[0251] The results for the flow profile are shown in FIG. 7 (squares). The flow in this example was relatively high and remained relatively constant for 7 days.

EXAMPLE 8

In vivo administration of memantine via a transdermal delivery system

[0252] Transdermal delivery systems including memantine were prepared as described in Example 1. People were randomized into two groups for treatment with the transdermal delivery system or with orally administered memantine ( ^NAMENDA® ), 7 mg given on day 1 and on day 7 studies. The transdermal delivery system was applied to the skin and kept for a week and then removed. Blood samples were taken daily from subjects treated with the transdermal delivery system. Blood samples were taken at hourly intervals on day 1 and day 7 in the group of subjects treated with orally delivered memantine, and again on days 8, 10, 12 and 14. The mean plasma concentration of memantine in the group of treated subjects was determined.

EXAMPLE 9

Donepezil HCl transdermal system with microporous membrane

Pretreatment of a Microporous Membrane with a Membrane Treatment Composition

[0253] In this example, a polypropylene microporous membrane ( ^Celgard® 2400) having 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 a second with an untreated membrane, to compare the in vitro skin flux profiles of the two systems.

[0254] Received a composition for treatment with a membrane containing 66.67% wt./wt. triethyl citrate, 20.00% w/w lauryl lactate, and 13.33% wt./wt. sorbitan monolaurate. Triethyl acetate was thoroughly mixed with lauryl lactate and a clear solution was obtained. Sorbitan monolaurate was then added to the mixture and thoroughly mixed using high shear to obtain a hazy homogeneous composition. The cloudy liquid was then applied to the membrane with a coating doctor blade to saturate the membrane with the liquid mixture. After saturation, the initially white membrane turned into a translucent membrane. The excess of the membrane treatment composition was then removed by rubbing.

Obtaining a drug reservoir

[0255] 1.20 g of Sorbitan monolaurate ( ^SPAN® 20) was dissolved in a mixture of 6.00 g of triethyl citrate and mixed with 1.80 g of lauryl lactate and 89.69 g of ethyl acetate. 6.00 g of glycerol was added and mixed. A mixture of 9.00 g of donepezil hydrochloride and 1.82 g of sodium bicarbonate was dispersed. After adding 12.00 g of cross-linked polyvinylpyrrolidone ( ^Kollidon® CL-M) to the dispersed drug solution, the mixture was thoroughly homogenized. 43.93 g of acrylate copolymer (Duro- ^Tak® 387-2287, 50.5% solids content) was added to the homogenized drug dispersion and thoroughly mixed. Ascorbyl palmitate was added. The wet adhesive preparation was applied to the backing layer and dried using a laboratory coater (Werner Mathis) to give a dry coating with a surface density of 12 mg/cm ² .

Obtaining a contact adhesive

[0256] 0.60 g of Sorbitan monolaurate ( ^SPAN® 20) was dissolved in 3.00 g of triethyl citrate and mixed with 0.9 g of lauryl lactate, 25.45 g of ethyl acetate and 1.34 g of isopropyl alcohol. After adding 6.00 g of cross-linked polyvinylpyrrolidone ( ^Kollidon® CL-M), the mixture was homogenized. 38.61 g of acrylate copolymer (Duro- ^Tak® 387-2287, 50.5% solids content) was added to the homogenized mixture and thoroughly mixed. The wet adhesive preparation was applied to the protective layer and dried to give a dry coating with an areal density of 5 mg/cm ² .

Obtaining the final five-layer donepezil TDS laminate, cutting and application

[0257] A polypropylene rate control membrane ( ^Celgard® 2400) pre-treated with the membrane treatment composition was layered onto the adhesive side of the drug reservoir. The contact adhesive was then overlaid on top of the rate control membrane laminated to the drug reservoir. The protective layer on the drug reservoir was replaced with a cover film. The final five-layer laminate was cut into patches and each test patch was applied individually. The resulting transdermal delivery system includes a drug reservoir layer and a contact adhesive layer with a rate control layer of a microporous membrane sandwiched between the drug reservoir and the contact adhesive layers, as shown in FIG. 1A.

[0258] The transdermal delivery system (TDS) donepezil formulation of this example is described in Table 9.1.

Table 9.1: Donepezil.HCl TDS with pretreated microporous membrane

Layer Ingredient Tradename % w/w Upper layer Polyester Woven Fabric KOB 052 15 mil Acrylate adhesive DuroTak 87-2052/2287/2051 8 mg/cm2 separating layer polyester laminate Scotchpak 1012 2 mil Drug reservoir (coating density: 12 mg/cm ² ) Donepezil hydrochloride N/A 16.0% Bicarbonate of soda N/A 2.6% triethyl citrate N/A 10.0% Glycerol N/A 10.0% Lauryl lactate Ceraphyl 31 3.0% Sorbitan laurate SPAN 20 2.0% Crospovidone Kollidon CL-M 15.0% Ascorbyl palmitate N/A 0.5% Acrylic adhesive -Duro-Tak 87-2287 DuroTak 87-2287 40.9% Total 100% Microporous membrane (diluent coating density: 1.11 mg/cm ² ) Microporous polypropylene membrane Celgard 2400 1 mil triethyl citrate DN 66.7% Lauryl lactate Ceraphyl 31 20.0% Sorbitan laurate SPAN 20 13.3% Total 100% Contact adhesive (coating density: 5 mg/cm ² ) triethyl citrate DN 10.0% Lauryl lactate Ceraphyl 31 3.0% Sorbitan laurate SPAN 20 2.0% Crospovidone Kollidon CL-M 20.0% Acrylate adhesive DuroTak 87-2287 65.0% Total 100% protective layer Silicone Coated Polyester Film 3 mil

*DN - no data

[0259] Donepezil TDS controls were prepared in the same manner using an untreated ^Celgard® 2400 membrane instead of the treated membrane.

[0260] After equilibration for 2 weeks at room temperature, in vitro skin flux from the patches was determined as follows:

Getting skin

[0261] Dermatome-prepared human cadaver skin was obtained from a skin bank and frozen prior to use. The skin was placed in water at 60°C for 1-2 min, and after thawing, the epidermis was carefully separated from the dermis. The epidermis was used immediately or wrapped and frozen for later use.

Skin flux study in vitro

[0262] An in vitro skin flux study was performed using a Franz-type diffusion cell with an active diffusion area of 0.64 cm ² . The epidermis was fixed between the donor and receptor compartments of the diffusion cell. The patch was placed on the skin and the two compartments were tightly fastened to each other.

[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 with 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 the drug content was determined using high performance liquid chromatography (HPLC).

[0264] Results are calculated as the amount of drug diffused through the epidermis in cm ² /h.

[0265] The results are shown in FIG. 7. Each value is the average of three skin donors, 4 replicates for each donor. The untreated membrane patch had a lower flow profile even after 2 weeks of equilibration.

[0266] Although a number of exemplary aspects and embodiments have been discussed above, certain modifications, permutations, additions, and subcombinations thereof will be known to those skilled in the art. Therefore, the appended claims and the following claims are intended to be interpreted as including all such modifications, permutations, additions, and subcombinations thereof, as being within their spirit and scope.

Claims (24)

1. A transdermal delivery system, including: a skin-contacting adhesive layer for attaching the system to the user's skin; a drug reservoir layer comprising an adhesive polymer, donepezil hydrochloride, and a drug carrier composition; And a microporous membrane located between the adhesive layer and the drug reservoir layer, the microporous membrane includes a plurality of pores filled with a composition for treatment with a membrane different from the composition of the drug carrier, wherein the skin-contacting adhesive layer comprises an acrylic acid-vinyl acetate copolymer adhesive, a nonionic surfactant, a long chain aliphatic alcohol, and a citric acid ester, wherein the drug carrier composition comprises a nonionic surfactant, a long chain aliphatic alcohol, a citric acid ester and a hydrophilic solvent, wherein the membrane treatment composition does not contain a hydrophilic solvent, and it contains from 8 to 25 wt.% sorbitan monolaurate, from 10 to 30 wt.% lauryl lactate and from 55 to 80 wt.% triethylcitrate. 2. The system of claim 1 wherein the plurality of pores are filled with the membrane treatment composition prior to placing the microporous membrane between the adhesive layer and the drug reservoir layer. 3. The system according to any one of paragraphs. 1, 2, wherein the drug carrier composition comprises a nonionic surfactant, a long chain aliphatic alcohol, a citric acid ester, or combinations thereof. 4. The system of any one of the preceding claims, wherein the drug carrier composition comprises a hydrophilic solvent, a nonionic surfactant, a long chain aliphatic alcohol, a citric acid ester, or combinations thereof. 5. The system of claim 4 wherein the hydrophilic solvent in the drug carrier composition is glycerol. 6. The system of claim 3 or 4 wherein the nonionic surfactant is sorbitan monolaurate, a long chain aliphatic alcohol, lauryl lactate or octyldodecanol and the citric acid ester is triethyl citrate. 7. The system of any one of the preceding claims, wherein the drug reservoir layer further comprises an amphoteric base. 8. The system of claim 7 wherein the donepezil hydrochloride and the amphoteric base compound react in situ in the drug reservoir layer after the system is applied to the user's skin to form the base form of donepezil. 9. The system of any one of the preceding claims, wherein the skin-contacting adhesive layer comprises a contact adhesive layer of the drug carrier composition. 10. The system of claim 9, wherein the contact adhesive layer of the drug carrier composition comprises a nonionic surfactant, a long chain aliphatic alcohol, a citric acid ester, or combinations thereof. 11. The system of claim 9 wherein the contact adhesive layer of the drug carrier composition is different from the drug carrier composition. 12. A method of treating Alzheimer's disease, including applying to the skin of a subject a transdermal delivery system according to any one of paragraphs. 1-11 wherein said application results in the base form of donepezil for delivery to the skin. 13. The method of transdermal delivery of the basic form of donepezil, including: using a transdermal delivery system according to any one of paragraphs. 1-11, attachment to the user's skin to deliver the base form of donepezil from the system to the skin, where (i) the time period to establish a constant flow is at least 20% less than for a system without a membrane treatment composition in the pores of the microporous membrane, (ii) the period of time to establish a constant flow from the system is at least 20% less than for a system without a membrane treatment composition in the pores of the microporous membrane; and/or (iii) donepezil diffuses from the system to the skin at least 20% faster than for the system without the membrane treatment composition in the pores of the microporous membrane.

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