Methods for preparing transdermal delivery systems

Abstract

The present disclosure provides a method for preparing a drug matrix layer and a transdermal delivery system for delivering donepezil free base to patients suffering from central nervous system disorders, including dementia and Alzheimer's disease. In one embodiment, the present invention provides a method for preparing a drug matrix layer, comprising forming a first mixture containing donepezil HCl polymorph III and sodium bicarbonate, thereby preparing a drug matrix layer. In another embodiment, the present invention provides a drug matrix layer prepared by the method of the present invention.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Patent Application No. 63 / 589,774, filed October 12, 2023, and U.S. Provisional Patent Application No. 63 / 477,434, filed December 28, 2022, each of which is incorporated herein in its entirety for all purposes. [Background technology]

[0002] Transdermal drug delivery systems can be an effective means for administering active pharmaceutical agents that may have disadvantages when administered via other routes, such as oral or parenteral. However, delivery of many drugs over extended periods of time (e.g., several days or longer) is difficult. Transdermal delivery of basic (i.e., alkaline) drugs can be particularly challenging due to poor skin permeability. Furthermore, some active agents have poor or low solubility in the adhesives and / or other components used in typical transdermal formulations. Furthermore, there is a need for stable, long-term administration of active agents (e.g., 1 to 10 days or more) that provides stable, effective release of the agent over the administration period and has suitable adhesion for long-term administration.

[0003] Active agents for transdermal delivery are typically provided in their neutral form because the neutral form typically has much higher skin permeability 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 into the skin through the adhesive matrix. Transdermal patches therefore typically contain as much of the active agent dissolved in the adhesive matrix as possible, often accompanied by a solubilizer to enhance its solubility. Alternatively, neutral, solid particles of the active agent are sometimes dispersed in the adhesive matrix, as long as the dissolution rate of the particles is such that a constant supply of dissolved active agent is provided.

[0004] For many active agents, however, the neutral form is more difficult to solubilize and / or formulate into a composition, system, or medicament for administration to a subject. When a drug has low solubility in an adhesive matrix, similar to the non-ionized neutral form, it is difficult to incorporate a sufficient amount of the drug in a solubilized form in the adhesive to deliver therapeutic levels over multiple days. A further complication is that the dissolved active agent may crystallize within the adhesive matrix during the medicament preparation process, e.g., solvation, coating, and drying. Furthermore, many active agents are less stable in the neutral form than in the salt form. Other challenges with transdermal patches can include backing layer delamination. Therefore, there is a need for compositions, systems, and medicaments having an adhesive matrix as a component layer that can consistently and effectively deliver therapeutic amounts of an active agent over an extended period of time. There is also a need for transdermal patches with improved adhesion between the backing layer and the remainder of the patch to reduce backing layer delamination.

[0005] The foregoing examples of the related art and limitations thereto are intended to be illustrative and not exhaustive. Other limitations of the related art will become apparent to those skilled in the art upon reading this specification and studying the drawings. Summary of the Invention [Means for solving the problem]

[0006] In one embodiment, the present invention provides a method for preparing a drug matrix layer, comprising forming a first mixture comprising donepezil HCl polymorph III and sodium bicarbonate, thereby preparing a drug matrix layer.

[0007] In another embodiment, the present invention provides a drug matrix layer prepared by the method of the present invention.

[0008] In another embodiment, the present invention provides (i) laminating a microporous membrane layer on top of a contact adhesive layer to form a contact adhesive laminate having a top surface and a bottom surface; (ii) preparing a drug matrix layer, forming a first mixture comprising triethyl citrate, lauryl lactate, and ethyl acetate; adding ascorbyl palmitate to the first mixture; adding polyvinylpyrrolidone to the first mixture; adding donepezil HCl polymorph III to the first mixture; adding sorbitan monolaurate to the first mixture; adding sodium bicarbonate and glycerin to the first mixture, wherein the sodium bicarbonate is present in a molar ratio to donepezil HCl of at least 0.85; adding an acrylate polymer to the first mixture; coating the first mixture onto a release liner; drying the coated mixture; removing the release liner, thereby preparing the drug matrix layer; (iii) laminating a drug matrix layer on the top surface of the contact adhesive laminate to form a drug matrix laminate having a top surface and a bottom surface; (iv) laminating a separation layer on the top surface of the drug matrix laminate to form an active laminate having a top surface and a bottom surface, the separation layer comprising a top surface and a bottom surface, the top surface of the separation layer comprising a coating of ethylene vinyl acetate copolymer, and the bottom surface of the separation layer in contact with the top surface of the drug matrix laminate; (v) laminating polyester fibers onto an adhesive overlay layer comprising an acrylate polymer to form a backing layer having a top surface and a bottom surface; (vi) laminating the bottom surface of the backing layer onto the top surface of the active laminate so that the adhesive overlay layer contacts the top surface of the active laminate; (vii) treating the top surface of the separation layer with a corona discharge treatment to form a treated separation layer; Corona discharge treatment is performed with a power of 0.10kW to 0.12kW and 2.1 to 2.6W / ft 2 / min power density, the treated separation layer having a top surface and a bottom surface, the top surface of the treated separation layer having a surface energy of at least 40 dynes; forming a bottom surface of the contact adhesive layer in contact with a first process liner; (viii) removing the first process liner to expose the bottom surface of the contact adhesive layer; (ix) laminating a release liner onto the bottom surface of the contact adhesive layer, thereby forming the transdermal delivery system.

[0009] In another embodiment, the present invention provides a transdermal delivery system prepared by the method of the present invention. [Brief explanation of the drawings]

[0010] [Figure 1A] 1A, 1B, and 1C show an illustration of a transdermal delivery system of the present invention. [Figure 1B] 1A, 1B, and 1C show an illustration of a transdermal delivery system of the present invention. [Figure 1C] 1A, 1B, and 1C show an illustration of a transdermal delivery system of the present invention. [Figure 2] Figure 2 shows the XRPD of donepezil hydrochloride polymorph III. I. Overview DETAILED DESCRIPTION OF THE INVENTION

[0011] The present invention provides a method for preparing a drug matrix layer using donepezil hydrochloride polymorph III. II. Definition

[0012] Various aspects will now be described more fully below. However, such aspects may be embodied in many different forms and should not be construed as limited to the embodiments set forth herein; rather, these embodiments are provided so that this disclosure will be thorough and complete, and will fully convey its scope to those skilled in the art.

[0013] When a range of values ​​is provided, each intervening value between the upper and lower limits of that range, and any other stated or intervening value in that stated range, is intended to be encompassed within the disclosure. For example, if a range of 1 μm to 8 μm is stated, then 2 μm, 3 μm, 4 μm, 5 μm, 6 μm, and 7 μm, as well as ranges of values ​​greater than or equal to 1 μm and ranges of values ​​less than or equal to 8 μm, are also intended to be expressly disclosed.

[0014] The singular forms "a," "an," and "the" include plural references unless the context clearly dictates otherwise. Thus, for example, reference to a "polymer" includes a single polymer as well as two or more of the same or different polymers, reference to an "excipient" includes a single excipient as well as two or more of the same or different excipients, and the like.

[0015] The word "about," when immediately preceding a numerical value, means a range of plus or minus 10% of that value, unless the context of this disclosure indicates otherwise or contradicts such an interpretation; e.g., "about 50" means 45 to 55, "about 25,000" means 22,500 to 27,500, etc. For example, in a list of numerical values, e.g., "about 49, about 50, about 55, etc.," "about 50" means less than half the interval between the preceding and succeeding values, e.g., a range extending from greater than 49.5 to less than 52.5. Furthermore, phrases such as "less than about" a value or "greater than about" a value should be understood in light of the definition of the term "about" provided herein.

[0016] "High-energy surface treatment" refers to a process that increases the surface energy of a surface through the use of a high-energy treatment. Exemplary high-energy surface treatments include corona discharge treatments, which involve exposing a surface to a corona discharge or corona plasma to modify the properties of the surface. A surface exposed to a high-energy surface treatment may be characterized by a higher surface energy, as measured by dynes, compared to the surface energy before the high-energy surface treatment.

[0017] "Contact" refers to the bringing of two objects or surfaces of two objects into close proximity such that they physically touch each other.

[0018] "Microporous membrane" refers to a membrane having a plurality of pores filled with a membrane solvent composition for transporting the active agent from the drug matrix layer to the contact adhesive layer and to the patient.

[0019] "Occlusive material" refers to a material that has low moisture permeability, for example, to reduce or minimize moisture loss from the skin. Occlusive agents can include materials such as silicones, waxes, oils, and the like, as well as various polymers and copolymers.

[0020] "Surface energy" refers to the energy required to move an object across a surface. Surface energy is measured in dynes (g cm / s), which is the force required to accelerate a mass of 1 gram at a rate of 1 centimeter per second per second. 2 ), for example, 1 dyne is 1 x 10 -5 Equivalent to Newton.

[0021] "Alkali salt" refers to, among other things, bases such as sodium carbonate, sodium acetate, sodium bicarbonate, sodium hydroxide, sodium percarbonate, and the like.

[0022] "D90 particle size" refers to a size distribution of a plurality of particles where 90% of the particles have a diameter at or smaller than the stated D90 particle size.

[0023] "Line speed" refers to the speed at which a layer exposed to a high-energy treatment is exposed to and removed from the high-energy treatment. Typical speeds can be in inches or feet per minute.

[0024] "Laminating," "laminate," or "lamination" refers to the process of preparing a material by combining two separate layers into one through the use of heat, pressure, or adhesives.

[0025] "Process liner" refers to a protective layer used before, during, or after lamination of two different layers to protect the surface of one of the layers. The process liner can then be removed from the surface before the next lamination step.

[0026] "Steady-state flux" or "steady-state equilibrium flux" refers to the flux of active agent from a transdermal delivery system that achieves a constant value without substantial change over time.

[0027] "Unit dosage form" refers to a physically discrete unit of therapeutic preparation appropriate for the subject being treated. However, it will be understood that the total daily usage of the compositions of the present invention will be determined by the attending physician within the scope of sound medical judgment. The specific effective dose level for any particular subject or organism will depend on a variety of factors, including the disorder being treated and the severity of the disorder, the activity of the specific active agent used, the specific composition used, the age, weight, general health, sex, and diet of the subject, the time of administration and the excretion rate of the specific active agent used, the duration of treatment, drugs and / or additional treatments used in combination with or simultaneously with the specific compound used, and similar factors well known in the medical arts.

[0028] "Adhesive matrix" as described herein includes matrices made in one piece, such as matrices made via solvent casting or extrusion, as well as matrices formed in two or more parts that are then pressed or bonded together.

[0029] As used herein, the term "therapeutically effective amount" refers to a non-toxic amount of an active agent that is sufficient to provide the desired therapeutic effect. The amount that is "effective" can vary from subject to subject, depending on the age and general condition of the individual, the particular active agent or agents, and the like, as known to those skilled in the art.

[0030] The phrase "pharmaceutically acceptable" is used herein to refer to compounds, salts, compositions, dosage forms, etc., that are suitable, within the scope of sound medical judgment, for use in contact with the tissues of humans and / or other mammals without excessive toxicity, irritation, allergic response, or other problem or complication commensurate with a reasonable benefit / risk ratio. In some aspects, "pharmaceutically acceptable" means approved by a federal or state regulatory agency or listed in the United States Pharmacopoeia or other generally recognized pharmacopeia, for use in mammals (e.g., animals), and more particularly in humans.

[0031] As used herein, the term "transdermal" or "transdermal delivery" refers to the administration of an active agent to a body surface of an individual, such that the active agent passes through the body surface, e.g., the skin, and into the individual's bloodstream. The term "transdermal" is intended to include transmucosal administration, i.e., the administration of a drug to a mucosal (e.g., sublingual, buccal, vaginal, rectal) surface of an individual, such that the agent passes through the mucosal tissue and into the individual's bloodstream.

[0032] The terms "topical delivery system," "transdermal delivery system," and "TDS" refer to routes of drug delivery through skin tissue and are used interchangeably herein.

[0033] As used herein, the terms "skin," "tissue," or "cutaneous" tissue are defined to include tissues covered by the stratum corneum, or stratum lucidum, and / or other mucous membranes. The term further includes mucosal tissue, including the interior surfaces of body cavities, e.g., the oral cavity, nasal cavity, rectum, vagina, etc., which have a mucosal lining. The term "skin" should be construed as including "mucosal tissue," and vice versa.

[0034] The terms "treat," "treating," "treatment," "therapy," "therapeutic," and the like, as used herein, encompass any course of medical intervention aimed at a pathological condition, and include not only permanent cure of the disease, but also further steps taken to prevent, manage, or alleviate the disease or disease symptoms. For example, in reference to methods of treating a disorder, such as Alzheimer's disease, embodiments generally include administration of an active agent that reduces the frequency of, or delays the onset of, symptoms of the medical condition in a subject compared to a subject not receiving the active agent. This can include reversing, reducing, or halting the symptoms, clinical signs, and underlying pathology of the condition in a manner that improves or stabilizes the subject's condition (e.g., decline in mental function).

[0035] A "subject" or "patient" to whom administration of a therapeutic agent is an effective treatment regimen for a disease or disorder is preferably a human, but can be any animal, including laboratory animals in the context of clinical trials or screening or activity experiments. Thus, as can be readily appreciated by one of ordinary skill in the art, the methods and systems provided herein are particularly suitable for veterinary use, for administration to any animal, particularly mammals, including but not limited to humans, domestic animals such as feline or canine subjects, domestic animals such as but not limited to bovine, equine, caprine, ovine, and porcine subjects, wild animals (whether in the wild or in zoos), research animals such as mice, rats, rabbits, goats, sheep, pigs, dogs, cats, and birds such as chickens, turkeys, songbirds, and the like.

[0036] "Therapeutic agent" refers to a drug or medication that can treat an injury, pathology, condition, or symptom (e.g., pain). Representative therapeutic agents include, but are not limited to, donepezil hydrochloride, donepezil free base, memantine, agents useful for treating Alzheimer's disease, and agents useful for treating other conditions and diseases.

[0037] "Mole ratio" refers to the ratio of moles of a first component to moles of a second component, the mole ratio being determined by dividing the moles of the first component by the moles of the second component. III. Preparation of the Drug Matrix Layer

[0038] The present invention provides a method for preparing a drug matrix layer containing donepezil hydrochloride, which is an acetylcholinesterase inhibitor with the chemical structure 2,3-dihydro-5,6-dimethoxy-2-[[1-(phenylmethyl)-4-piperidinyl]methyl]-1H-inden-1-one: [ka] Donepezil has a molecular weight of 379.5 and is lipophilic (logarithmic value 3.08-4.11). Donepezil hydrochloride has the following structure: [ka]

[0039] Donepezil hydrochloride can adopt one of several different crystalline polymorphs or amorphous forms. U.S. Patent Nos. 5,985,864 and 6,140,321 and PCT Publication WO 1997 / 046527 describe several crystalline polymorphs of donepezil hydrochloride, including Polymorph I, Polymorph II, Polymorph III, Polymorph IV, and Polymorph V.

[0040] The drug matrix layer containing donepezil hydrochloride can be prepared by various methods. For example, donepezil hydrochloride polymorph I can be used as a starting point. Donepezil HCl polymorph I is characterized by an X-ray diffraction (XRD) pattern with peaks at 9.9, 10.6, 12.7, 13.1, 13.7, 13.9, 14.9, 15.3, 16.1, 16.9, 17.5, 17.6, 18.4, 19.3, 19.8, 19.9, 21.2, 22.0, 22.5, 23.0, 23.6, 23.8, 23.9, 26.5, 28.0, and 29.5±0.2°2θ. Alternatively, donepezil hydrochloride polymorph III can be used as a starting point.

[0041] In some embodiments, the present invention provides a method of preparing a drug matrix layer, comprising forming a first mixture comprising donepezil HCl polymorph III and sodium bicarbonate, thereby preparing the drug matrix layer.

[0042] In some embodiments, the methods of the present invention include methods wherein donepezil HCl polymorph III is characterized by an X-ray diffraction (XRD) pattern with peaks at 6.6, 15.0, 16.5, 18.5, 20.1, 21.7, 26.0, and 28.2±0.2 degrees 2θ. In some embodiments, the methods of the present invention include methods wherein donepezil HCl polymorph III is further characterized by an XRD pattern with peaks at 18.1, 20.9, 22.3, and 27.2±0.2 degrees 2θ. In some embodiments, the methods of the present invention include methods wherein donepezil HCl polymorph III is characterized by an XRD pattern with peaks at 6.6, 15.0, 16.5, 18.1, 18.5, 20.1, 20.9, 21.7, 22.3, 26.0, 27.2, and 28.2±0.2 degrees 2θ. In some embodiments, the methods of the present invention include those wherein donepezil HCl polymorph III is further characterized by an XRD pattern with peaks at 9.9, 13.0, 15.3, 15.7, 17.4, 19.5, 22.9, 23.9, 24.7, and 28.6±0.2 degrees 2θ. In some embodiments, the methods of the present invention include those wherein donepezil HCl polymorph III is characterized by an XRD pattern with peaks at 6.6, 9.9, 13.0, 15.0, 15.3, 15.7, 16.5, 17.4, 18.1, 18.5, 19.5, 20.1, 20.9, 21.7, 22.3, 22.9, 23.9, 24.7, 26.0, 27.2, 28.2, and 28.6±0.2 degrees 2θ. In some embodiments, the methods of the present invention include those wherein donepezil HCl polymorph III is characterized by an XRD pattern substantially as shown in FIG.

[0043] Sodium carbonate may be present in the first reaction mixture in any suitable amount. For example, sodium bicarbonate may be present in a molar ratio relative to donepezil HCl of 2.0 to 0.5, or 1.9 to 0.6, 1.8 to 0.7, 1.7 to 0.8, 1.6 to 0.8, 1.5 to 0.8, 1.4 to 0.8, 1.3 to 0.8, 1.2 to 0.8, 1.1 to 0.8, 1.6 to 0.9, 1.5 to 1.0, 1.4 to 1.0, 1.3 to 1.0, 1.2 to 1.0, or 1.1 to 1.0. Sodium bicarbonate may be present in a molar ratio of 2.0 to 0.9 relative to donepezil HCl, or a molar ratio of 1.9 to 0.9, 1.8 to 0.9, 1.7 to 0.9, 1.6 to 0.9, 1.5 to 0.9, 1.4 to 0.9, 1.3 to 0.9, 1.2 to 0.9, or 1.1 to 0.9 relative to donepezil HCl. Sodium bicarbonate may be present in a molar ratio of 1.1 to 0.7 relative to donepezil HCl, or a molar ratio of 1.1 to 0.75, 1.0 to 0.80, 1.0 to 0.85, or 1.0 to 0.90 relative to donepezil HCl. Sodium bicarbonate may also be present in a molar ratio relative to donepezil HCl of about 1.5, or 1.45, 1.4, 1.35, 1.3, 1.25, 1.2, 1.15, 1.1, 1.05, 1.0, 0.95, or about 0.9. Sodium bicarbonate may also be present in a molar ratio relative to donepezil HCl of about 1.1, or 1.05, 1.0, 0.95, 0.94, 0.93, 0.92, 0.91, 0.90, 0.89, 0.88, 0.87, 0.86, 0.85, 0.84, 0.83, 0.82, 0.81, or about 0.8.

[0044] In some embodiments, the methods of the present invention include methods in which sodium bicarbonate may be present in the first reaction mixture in a molar ratio relative to donepezil HCl of 1.5 to 0.9. In some embodiments, the methods of the present invention include methods in which sodium bicarbonate may be present in the first reaction mixture in a molar ratio relative to donepezil HCl of 1.4 to 0.9. In some embodiments, the methods of the present invention include methods in which sodium bicarbonate may be present in the first reaction mixture in a molar ratio relative to donepezil HCl of 1.3 to 0.9. In some embodiments, the methods of the present invention include methods in which sodium bicarbonate may be present in the first reaction mixture in a molar ratio relative to donepezil HCl of 1.2 to 0.9. In some embodiments, the methods of the present invention include methods in which sodium bicarbonate may be present in the first reaction mixture in a molar ratio relative to donepezil HCl of 1.1 to 0.9. In some embodiments, the methods of the present invention include methods in which sodium bicarbonate may be present in the first reaction mixture in a molar ratio relative to donepezil HCl of 1.05 to 0.95. In some embodiments, methods of the present invention include methods wherein sodium bicarbonate may be present in the first reaction mixture in a molar ratio to donepezil HCl of from 1.1 to 1.0.

[0045] In some embodiments, the methods of the present invention include those in which sodium bicarbonate may be present in the first reaction mixture in a molar ratio relative to donepezil HCl of at least 0.85. In some embodiments, the methods of the present invention include those in which sodium bicarbonate may be present in the first reaction mixture in a molar ratio relative to donepezil HCl of about 0.88. In some embodiments, the methods of the present invention include those in which sodium bicarbonate may be present in the first reaction mixture in a molar ratio relative to donepezil HCl of about 0.92. In some embodiments, the methods of the present invention include those in which sodium bicarbonate may be present in the first reaction mixture in a molar ratio relative to donepezil HCl of about 0.92. In some embodiments, the methods of the present invention include those in which sodium bicarbonate may be present in the first reaction mixture in a molar ratio relative to donepezil HCl of about 0.95. In some embodiments, methods of the present invention include methods wherein sodium bicarbonate may be present in the first reaction mixture in a molar ratio to donepezil HCl of 0.95.

[0046] In some embodiments, the methods of the present invention include methods where sodium bicarbonate may be present in the first reaction mixture in a molar ratio to donepezil HCl of at least 1.0. In some embodiments, the methods of the present invention include methods where sodium bicarbonate may be present in the first reaction mixture in a molar ratio to donepezil HCl of about 1.0. In some embodiments, the methods of the present invention include methods where sodium bicarbonate may be present in the first reaction mixture in a molar ratio to donepezil HCl of 1.0.

[0047] In some embodiments, the methods of the present invention include those in which sodium bicarbonate may be present in the first reaction mixture in a molar ratio relative to donepezil HCl of at least 0.85. In some embodiments, the methods of the present invention include those in which sodium bicarbonate may be present in the first reaction mixture in a molar ratio relative to donepezil HCl of about 0.88. In some embodiments, the methods of the present invention include those in which sodium bicarbonate may be present in the first reaction mixture in a molar ratio relative to donepezil HCl of about 0.92. In some embodiments, the methods of the present invention include those in which sodium bicarbonate may be present in the first reaction mixture in a molar ratio relative to donepezil HCl of 0.92. In some embodiments, the methods of the present invention include those in which sodium bicarbonate may be present in the first reaction mixture in a molar ratio relative to donepezil HCl of 0.95.

[0048] In some embodiments, the methods of the present invention include forming a first mixture comprising donepezil HCl polymorph III and sodium bicarbonate, wherein the sodium bicarbonate is present in a molar ratio to donepezil HCl of 1.0. In some embodiments, the methods of the present invention include forming a first mixture comprising donepezil HCl polymorph III and sodium bicarbonate, wherein the sodium bicarbonate is present in a molar ratio to donepezil HCl of 0.88. In some embodiments, the methods of the present invention include forming a first mixture comprising donepezil HCl polymorph III and sodium bicarbonate, wherein the sodium bicarbonate is present in a molar ratio to donepezil HCl of 0.92. In some embodiments, the methods of the present invention include forming a first mixture comprising donepezil HCl polymorph III and sodium bicarbonate, wherein the sodium bicarbonate is present in a molar ratio to donepezil HCl of 0.95.

[0049] The drug matrix layer prepared by the methods of the present invention may include other components such as, but not limited to, an adhesive matrix, an acrylate polymer, a drug matrix solvent composition, an alkali salt, and others described herein. In some embodiments, the methods of the present invention include methods further comprising adding one or more of triethyl citrate, lauryl lactate, ascorbyl palmitate, polyvinylpyrrolidone, and sorbitan monolaurate to the first reaction mixture before adding sodium bicarbonate to the first mixture.

[0050] In some embodiments, the methods of the present invention include methods further comprising adding triethyl citrate, lauryl lactate, and ethyl acetate to the first mixture before adding sodium bicarbonate to the first reaction mixture. In some embodiments, the methods of the present invention include methods further comprising adding ascorbyl palmitate to the first mixture before adding sodium bicarbonate to the first reaction mixture. In some embodiments, the methods of the present invention include methods further comprising adding polyvinylpyrrolidone to the first mixture before adding sodium bicarbonate to the first reaction mixture. In some embodiments, the methods of the present invention include methods further comprising adding sorbitan monolaurate to the first mixture before adding sodium bicarbonate to the first reaction mixture. In some embodiments, the methods of the present invention include methods further comprising adding an acrylate polymer to the first mixture.

[0051] In some embodiments, the methods of the present invention further comprise: adding triethyl citrate, lauryl lactate, and ethyl acetate to the first mixture; adding ascorbyl palmitate to the first mixture; adding polyvinylpyrrolidone to the first mixture; adding sorbitan monolaurate to the first mixture; adding an acrylate polymer to the first mixture, thereby preparing a drug matrix layer.

[0052] In some embodiments, the methods of the present invention further comprise: forming a first mixture comprising triethyl citrate, lauryl lactate, and ethyl acetate; adding ascorbyl palmitate to the first mixture; adding polyvinylpyrrolidone to the first mixture; adding donepezil HCl polymorph III to the first mixture; adding sorbitan monolaurate to the first mixture; adding sodium bicarbonate and glycerin to the first mixture, wherein the sodium bicarbonate is present in a molar ratio to donepezil HCl of about 1.0; adding an acrylate polymer to the first mixture, thereby preparing a drug matrix layer.

[0053] In some embodiments, the methods of the present invention further comprise: forming a first mixture comprising triethyl citrate, lauryl lactate, and ethyl acetate; adding ascorbyl palmitate to the first mixture; adding polyvinylpyrrolidone to the first mixture; adding donepezil HCl polymorph III to the first mixture; adding sorbitan monolaurate to the first mixture; adding sodium bicarbonate and glycerin to the first mixture, wherein the sodium bicarbonate is present in a molar ratio to donepezil HCl of about 0.88; adding an acrylate polymer to the first mixture, thereby preparing a drug matrix layer.

[0054] In some embodiments, the methods of the present invention further comprise: forming a first mixture comprising triethyl citrate, lauryl lactate, and ethyl acetate; adding ascorbyl palmitate to the first mixture; adding polyvinylpyrrolidone to the first mixture; adding donepezil HCl polymorph III to the first mixture; adding sorbitan monolaurate to the first mixture; adding sodium bicarbonate and glycerin to the first mixture, wherein the sodium bicarbonate is present in a molar ratio to the donepezil HCl of about 0.92; adding an acrylate polymer to the first mixture, thereby preparing a drug matrix layer.

[0055] In some embodiments, the methods of the present invention further comprise: forming a first mixture comprising triethyl citrate, lauryl lactate, and ethyl acetate; adding ascorbyl palmitate to the first mixture; adding polyvinylpyrrolidone to the first mixture; adding donepezil HCl polymorph III to the first mixture; adding sorbitan monolaurate to the first mixture; adding sodium bicarbonate and glycerin to the first mixture, wherein the sodium bicarbonate is present in a molar ratio to the donepezil HCl of about 0.95; adding an acrylate polymer to the first mixture, thereby preparing a drug matrix layer.

[0056] In some embodiments, methods of the present invention include methods further comprising coating the first mixture onto a release liner and drying the coated mixture. IV. Preparation of Transdermal Delivery Systems

[0057] The transdermal delivery systems of the present invention can be prepared by any suitable means known to those skilled in the art.

[0058] The thickness and / or size of the device and / or adhesive matrix can be determined by one of skill in the art based at least on considerations of wearability and / or dosage requirements. It will be recognized that the administration site for the device will influence wearability considerations due to the available size of the administration site and the use of the administration site (e.g., the need for flexibility to support movement). In some embodiments, the device and / or adhesive matrix has a thickness of about 25-500 μm. In some embodiments, the device and / or adhesive matrix has a thickness of about 50-500 μm. In some embodiments, the patch has a thickness of about 16 cm. 2 ~225cm 2 It will be understood that the thicknesses and sizes provided herein are merely exemplary, and that the actual thickness and / or size may be thinner / smaller or thicker / larger as required for a particular formulation.

[0059] Fabrication of the transdermal delivery system is routinely performed by one skilled in the art and involves casting or extruding each of the adhesive layers onto a suitable film, such as a release liner, or onto another layer of the transdermal delivery system, and drying, if necessary, to remove solvents and / or volatile compounds. The layers of the transdermal delivery system can be laminated together to form the final system.

[0060] Transdermal delivery systems and drug adhesive matrices were prepared to illustrate the embodiments described herein. The Examples show exemplary compositions and delivery systems. As described in Example 1, the transdermal delivery system included a drug matrix layer and a contact adhesive layer with a rate-controlling membrane positioned between the drug matrix layer and the contact adhesive layer, as depicted in Figure 1A. A drug matrix layer in the form of a solid, integrated adhesive reservoir was prepared using an acrylate / vinyl acetate copolymer adhesive with a drug matrix solvent composition—triethyl citrate, lauryl lactate, and ethyl acetate. A contact adhesive layer composed of the same acrylate / vinyl acetate copolymer adhesive as the drug matrix solvent composition and triethyl citrate, lauryl lactate, and ethyl acetate was prepared. The rate-controlling membrane controlled the diffusional release of donepezil free base from the drug matrix layer and separated the drug matrix layer from the contact adhesive layer.

[0061] The transdermal delivery system can be prepared by any suitable means. In some embodiments, the present invention includes a method for preparing a transdermal delivery system, comprising: (i) laminating a microporous membrane layer on top of a contact adhesive layer to form a contact adhesive laminate having a top surface and a bottom surface; (ii) laminating a drug matrix layer on the top surface of the contact adhesive laminate to form a drug matrix laminate having a top surface and a bottom surface; (iii) laminating a separation layer on the top surface of the drug matrix laminate to form an active laminate having a top surface and a bottom surface, the separation layer comprising a top surface and a bottom surface, the top surface of the separation layer comprising a coating of ethylene vinyl acetate copolymer, and the bottom surface of the separation layer in contact with the top surface of the drug matrix laminate; (iv) laminating polyester fibers onto an adhesive overlay layer comprising an acrylate polymer to form a backing layer having a top surface and a bottom surface; (v) laminating the bottom surface of the backing layer onto the top surface of the active laminate such that the adhesive overlay layer contacts the top surface of the active laminate, thereby forming the transdermal delivery system of the present invention.

[0062] The method may include additional steps, such as treating the separation layer with a high-energy surface treatment. In some embodiments, the method further includes, prior to laminating the separation layer onto the top surface of the drug matrix layer, (vi) treating the top surface of the separation layer with a high-energy surface treatment to form a treated separation layer, the treated separation layer comprising a top surface and a bottom surface.

[0063] In some embodiments, the present invention includes a method for preparing a transdermal delivery system, comprising: (i) laminating a microporous membrane layer on top of a contact adhesive layer to form a contact adhesive laminate having a top surface and a bottom surface; (ii) laminating a drug matrix layer on the top surface of the contact adhesive laminate to form a drug matrix laminate having a top surface and a bottom surface; (iii) treating the top surface of the separation layer with a high-energy surface treatment to form a treated separation layer, wherein the top surface of the separation layer comprises a coating of ethylene vinyl acetate copolymer, the treated separation layer comprising a top surface and a bottom surface; (iv) laminating the treated separation layer onto the top surface of the drug matrix laminate to form an active laminate having a top surface and a bottom surface, wherein the bottom surface of the treated separation layer contacts the top surface of the drug matrix laminate; (v) laminating polyester fibers onto an adhesive overlay layer comprising an acrylate polymer to form a backing layer having a top surface and a bottom surface; (vi) laminating the bottom surface of the backing layer onto the top surface of the treated active laminate such that the adhesive overlay layer contacts the top surface of the treated active laminate, thereby forming the transdermal delivery system of the present invention.

[0064] The upper surface of the separation layer can be treated with any suitable high-energy surface treatment to form a treated separation layer. In some embodiments, the high-energy surface treatment is selected from the group consisting of corona discharge treatment, plasma treatment, UV radiation, ion beam treatment, electron beam treatment, and combinations thereof. In some embodiments, the high-energy surface treatment is corona discharge treatment.

[0065] Corona discharge treatment can be carried out using a variety of process parameters, including the power, line speed, and width of the corona treatment electrode, to achieve any suitable power density. Typical power densities include, but are not limited to, 0.1 to 10 W / ft. 2 / min, or 0.5 to 10, or 0.6 to 9, or 0.7 to 8, or 0.8 to 7, or 0.9 to 6, or 1 to 5, or 1.55 to 4, or 2 to 3, or 2.1 to 2.9, or 2.1 to 2.8, or 2.1 to 2.7, or 2.1 to 2.6 W / ft 2 / min. Other power densities include, but are not limited to, approximately 1 W / ft 2 / min, or about 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, or about 3.0 W / ft 2 / min included.

[0066] Corona discharge treatment can be carried out under any suitable conditions. Representative conditions include, but are not limited to, power and line speed. Representative powers include, but are not limited to, 0.001 kW to 1.0 kW, or 0.01 to 1.0 kW, or 0.01 to 0.9 kW, 0.01 to 0.8 kW, 0.01 to 0.7 kW, 0.01 to 0.6 kW, 0.01 to 0.5 kW, 0.02 to 0.04 kW, 0.03 to 0.3 kW, 0.04 to 0.25 kW, 0.05 to 0.20 kW, 0.06 to 0.15 kW, 0.07 to 0.14 kW, 0.08 to 0.13 kW, 0.09 to 0.12 kW, or 0.1 to 1.2 kW. In some embodiments, corona discharge treatment is carried out using a power of 0.01 kW to 1.0 kW. In some embodiments, corona discharge treatment is carried out using a power of 0.05 kW to 0.12 kW. In some embodiments, the corona discharge treatment is carried out using a power of 0.10 kW to 0.12 kW. In some embodiments, the corona discharge treatment is carried out using a power of about 0.11 kW. In some embodiments, the corona discharge treatment is carried out using a power of about 0.24 kW.

[0067] Typical line speeds for corona discharge treatment include, but are not limited to, 1 to 100 feet per minute, or 1 to 95, 1 to 90, 1 to 85, 1 to 80, 1 to 75, 1 to 70, 1 to 65, 1 to 60, 1 to 55, 5 to 50, 5 to 45, 5 to 40, 5 to 35, 5 to 30, 5 to 25, 5 to 20, 6 to 19, 7 to 18, 8 to 17, 9 to 16, 10 to 15, or 11 to 14 feet per minute. Other typical line speeds include, but are not limited to, 10 to 50 feet per minute, or 15 to 45, or 20 to 40 feet per minute. Other exemplary line speeds include, but are not limited to, 10 feet / minute, or 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, or 40 feet / minute.

[0068] In some embodiments, the corona discharge treatment is carried out using a line speed of 1 to 100 feet per minute. In some embodiments, the corona discharge treatment is carried out using a line speed of 20 to 40 feet per minute. In some embodiments, the corona discharge treatment is carried out using a line speed of about 30 feet per minute. In some embodiments, the corona discharge treatment is carried out using a line speed of about 13 feet per minute.

[0069] Corona discharge treatment can provide a treated separation layer with any suitable surface energy. Exemplary surface energies of the treated separation layer include, but are not limited to, at least 10 dynes, or at least 15, 20, 25, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 55, 60, 65, 70, or at least 75 dynes. In some embodiments, the upper surface of the treated separation layer has a surface energy of at least 30 dynes. In some embodiments, the upper surface of the treated separation layer has a surface energy of at least 35 dynes. In some embodiments, the upper surface of the treated separation layer has a surface energy of at least 40 dynes.

[0070] In some embodiments, the upper surface of the treated separation layer has a surface energy greater than the upper surface of the separation layer before the high-energy surface treatment. The upper surface of the treated separation layer may have a surface energy at least 1 dyne greater than the upper surface of the separation layer before the high-energy surface treatment, or at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, or 30 dynes greater than the upper surface of the separation layer before the high-energy surface treatment. In some embodiments, the upper surface of the treated separation layer has a surface energy at least 5 dynes greater than the upper surface of the separation layer before the high-energy surface treatment. In some embodiments, the upper surface of the treated separation layer has a surface energy at least 10 dynes greater than the upper surface of the separation layer before the high-energy surface treatment. In some embodiments, the upper surface of the treated separation layer has a surface energy at least 15 dynes greater than the upper surface of the separation layer before the high-energy surface treatment. In some embodiments, the top surface of the treated separation layer has a surface energy that is at least 20 dynes greater than the top surface of the separation layer prior to the high-energy surface treatment.

[0071] In some embodiments, the bottom surface of the contact adhesive layer contacts the first process liner.

[0072] In some embodiments, the method of preparing a transdermal delivery system includes: (vii) removing a first process liner to expose a bottom surface of the contact adhesive layer; and (viii) laminating a release liner onto the bottom surface of the contact adhesive layer.

[0073] In some embodiments, the present invention provides a transdermal delivery system of the present invention prepared by the method of the present invention.

[0074] In some embodiments, the present invention provides a method for preparing a transdermal delivery system, comprising: (i) laminating a microporous membrane layer on top of a contact adhesive layer to form a contact adhesive laminate having a top surface and a bottom surface; (ii) preparing a drug matrix layer, forming a first mixture comprising triethyl citrate, lauryl lactate, and ethyl acetate; adding ascorbyl palmitate to the first mixture; adding polyvinylpyrrolidone to the first mixture; adding donepezil HCl polymorph III to the first mixture; adding sorbitan monolaurate to the first mixture; adding sodium bicarbonate and glycerin to the first mixture, wherein the sodium bicarbonate is present in a molar ratio to donepezil HCl of at least 1.0; adding an acrylate polymer to the first mixture; coating the first mixture onto a release liner; drying the coated mixture; removing the release liner, thereby preparing a drug matrix layer; (iii) laminating a drug matrix layer on the top surface of the contact adhesive laminate to form a drug matrix laminate having a top surface and a bottom surface; (iv) laminating a separation layer on the top surface of the drug matrix laminate to form an active laminate having a top surface and a bottom surface, the separation layer comprising a top surface and a bottom surface, the top surface of the separation layer comprising a coating of ethylene vinyl acetate copolymer, and the bottom surface of the separation layer in contact with the top surface of the drug matrix laminate; (v) laminating polyester fibers onto an adhesive overlay layer comprising an acrylate polymer to form a backing layer having a top surface and a bottom surface; (vi) laminating the bottom surface of the backing layer onto the top surface of the active laminate so that the adhesive overlay layer contacts the top surface of the active laminate; (vii) treating the top surface of the separation layer with a corona discharge treatment to form a treated separation layer; Corona discharge treatment is performed with a power of 0.10kW to 0.12kW and 2.1 to 2.6W / ft 2 / min power density, the treated separation layer having a top surface and a bottom surface, the top surface of the treated separation layer having a surface energy of at least 40 dynes; forming a bottom surface of the contact adhesive layer in contact with a first process liner; (viii) removing the first process liner to expose the bottom surface of the contact adhesive layer; (ix) laminating a release liner onto the bottom surface of the contact adhesive layer, thereby forming a transdermal delivery system.

[0075] In some embodiments, the present invention provides a method for preparing a transdermal delivery system, comprising: (i) laminating a microporous membrane layer on top of a contact adhesive layer to form a contact adhesive laminate having a top surface and a bottom surface; (ii) preparing a drug matrix layer, forming a first mixture comprising triethyl citrate, lauryl lactate, and ethyl acetate; adding ascorbyl palmitate to the first mixture; adding polyvinylpyrrolidone to the first mixture; adding donepezil HCl polymorph III to the first mixture; adding sorbitan monolaurate to the first mixture; adding sodium bicarbonate and glycerin to the first mixture, wherein the sodium bicarbonate is present in a molar ratio to donepezil HCl of at least 0.85; adding an acrylate polymer to the first mixture; coating the first mixture onto a release liner; drying the coated mixture; removing the release liner, thereby preparing the drug matrix layer; (iii) laminating a drug matrix layer on the top surface of the contact adhesive laminate to form a drug matrix laminate having a top surface and a bottom surface; (iv) laminating a separation layer on the top surface of the drug matrix laminate to form an active laminate having a top surface and a bottom surface, the separation layer comprising a top surface and a bottom surface, the top surface of the separation layer comprising a coating of ethylene vinyl acetate copolymer, and the bottom surface of the separation layer in contact with the top surface of the drug matrix laminate; (v) laminating polyester fibers onto an adhesive overlay layer comprising an acrylate polymer to form a backing layer having a top surface and a bottom surface; (vi) laminating the bottom surface of the backing layer onto the top surface of the active laminate so that the adhesive overlay layer contacts the top surface of the active laminate; (vii) treating the top surface of the separation layer with a corona discharge treatment to form a treated separation layer; Corona discharge treatment is performed with a power of 0.10kW to 0.12kW and 2.1 to 2.6W / ft 2 / min power density, the treated separation layer having a top surface and a bottom surface, the top surface of the treated separation layer having a surface energy of at least 40 dynes; forming a bottom surface of the contact adhesive layer in contact with a first process liner; (viii) removing the first process liner to expose the bottom surface of the contact adhesive layer; (ix) laminating a release liner onto the bottom surface of the contact adhesive layer, thereby forming a transdermal delivery system.

[0076] In some embodiments, the present invention provides a method for preparing a transdermal delivery system, comprising: (i) laminating a microporous membrane layer on top of a contact adhesive layer to form a contact adhesive laminate having a top surface and a bottom surface; (ii) preparing a drug matrix layer, forming a first mixture comprising triethyl citrate, lauryl lactate, and ethyl acetate; adding ascorbyl palmitate to the first mixture; adding polyvinylpyrrolidone to the first mixture; adding donepezil HCl polymorph III to the first mixture; adding sorbitan monolaurate to the first mixture; adding sodium bicarbonate and glycerin to the first mixture, wherein the sodium bicarbonate is present in a molar ratio to donepezil HCl of at least 0.90; adding an acrylate polymer to the first mixture; coating the first mixture onto a release liner; drying the coated mixture; removing the release liner, thereby preparing the drug matrix layer; (iii) laminating a drug matrix layer on the top surface of the contact adhesive laminate to form a drug matrix laminate having a top surface and a bottom surface; (iv) laminating a separation layer on the top surface of the drug matrix laminate to form an active laminate having a top surface and a bottom surface, the separation layer comprising a top surface and a bottom surface, the top surface of the separation layer comprising a coating of ethylene vinyl acetate copolymer, and the bottom surface of the separation layer in contact with the top surface of the drug matrix laminate; (v) laminating polyester fibers onto an adhesive overlay layer comprising an acrylate polymer to form a backing layer having a top surface and a bottom surface; (vi) laminating the bottom surface of the backing layer onto the top surface of the active laminate so that the adhesive overlay layer contacts the top surface of the active laminate; (vii) treating the top surface of the separation layer with a corona discharge treatment to form a treated separation layer; Corona discharge treatment is performed with a power of 0.10kW to 0.12kW and 2.1 to 2.6W / ft 2 / min power density, the treated separation layer having a top surface and a bottom surface, the top surface of the treated separation layer having a surface energy of at least 40 dynes; forming a bottom surface of the contact adhesive layer in contact with a first process liner; (viii) removing the first process liner to expose the bottom surface of the contact adhesive layer; (ix) laminating a release liner onto the bottom surface of the contact adhesive layer, thereby forming a transdermal delivery system.

[0077] In another embodiment, the present invention provides a transdermal delivery system prepared by the method of the present invention. V. Transdermal Delivery Systems

[0078] A transdermal delivery system for the systemic delivery of water-insoluble drug bases is provided. The transdermal system generally consists of a contact adhesive layer and a drug matrix layer, where the two layers are separated by a membrane layer comprising a microporous membrane pretreated with a membrane solvent composition. The system may include additional layers, as described below. The compositions of the layers in the system are now described.

[0079] The transdermal delivery systems of the present invention can have a variety of configurations, as shown in Figures 1A-1C. Figure 1A shows a transdermal delivery system 10 having a backing layer 20, a separation layer 30 having a top surface 31 and a bottom surface 32, a drug matrix layer 40 having a top surface 41 and a bottom surface 42, a membrane layer 50 having a top surface 51 and a bottom surface 52, and a contact adhesive layer 60 having a top surface 61 and a bottom surface 62.

[0080] In some embodiments, the present invention provides (1) a backing layer; (2) a separation layer that has been treated with a high-energy surface treatment, the separation layer having a top surface and a bottom surface, the top surface being in contact with the backing layer; (3) a drug matrix layer comprising donepezil HCl, the adhesive contact layer having a top surface and a bottom surface, the top surface being in contact with the bottom surface of the separating layer; (4) a membrane layer comprising a microporous membrane, the membrane layer having a top surface and a bottom surface such that the top surface is in contact with the bottom surface of the drug matrix layer; (5) a contact adhesive layer having a top surface and a bottom surface, the top surface being in contact with the bottom surface of the membrane layer.

[0081] In some embodiments, the present invention provides (1) a backing layer; (2) a separation layer, the separation layer having a top surface and a bottom surface, the top surface being in contact with the backing layer; (3) a drug matrix layer comprising donepezil HCl and donepezil free base, the drug matrix layer having a top surface and a bottom surface such that the top surface is in contact with the bottom surface of the separation layer; (4) a membrane layer comprising a microporous membrane, the membrane layer having a top surface and a bottom surface such that the top surface is in contact with the bottom surface of the drug matrix layer; (5) A contact adhesive layer having a top surface and a bottom surface, the top surface being in contact with the bottom surface of the membrane layer, the contact adhesive layer comprising donepezil free base in an amount of at least 0.1% (w / w) of the total weight of the contact adhesive layer.

[0082] In some embodiments, the present invention provides (1) a backing layer; (2) a separation layer, the separation layer having a top surface and a bottom surface, the top surface being in contact with the backing layer; (3) a drug matrix layer comprising donepezil HCl and donepezil free base, the drug matrix layer having a top surface and a bottom surface such that the top surface is in contact with the bottom surface of the separation layer; (4) a membrane layer comprising a microporous membrane, the membrane layer having a top surface and a bottom surface such that the top surface is in contact with the bottom surface of the drug matrix layer; (5) A transdermal delivery system comprising: a contact adhesive layer having a top surface and a bottom surface, the top surface being in contact with the bottom surface of the membrane layer, the contact adhesive layer comprising donepezil free base in an amount of 0.1 to 10% (w / w) of the total weight of the contact adhesive layer.

[0083] The transdermal delivery systems of the present invention can have a variety of configurations, as shown in Figures 1A-1C. Figure 1A shows a transdermal delivery system 10 having a backing layer 20, a separation layer 30 having a top surface 31 and a bottom surface 32, a drug matrix layer 40 having a top surface 41 and a bottom surface 42, a membrane layer 50 having a top surface 51 and a bottom surface 52, and a contact adhesive layer 60 having a top surface 61 and a bottom surface 62. Backing Layer

[0084] The transdermal delivery system may include a backing layer that provides a structural element to hold or support the underlying adhesive layer. The backing layer may be formed of any suitable material known in the art. In some embodiments, the backing layer is occlusive. In some embodiments, the backing is preferably impermeable or substantially impermeable to moisture. In one exemplary embodiment, the backing layer has a moisture vapor transmission rate of less than about 50 g / m2-day. In some embodiments, the backing layer is inert. In some embodiments, the backing layer preferably prevents release of components of the adhesive layer through the backing layer. The backing layer may be flexible or inflexible. The backing layer is preferably at least partially flexible so that it can at least partially conform to the shape of the skin to which the patch is applied. In some embodiments, the backing layer is flexible so that it conforms to the shape of the skin to which the patch is applied. In some embodiments, the backing layer is sufficiently flexible to maintain contact at the application site with movement, e.g., skin movement. Typically, the material used for the backing layer should allow the device to conform to the contours of the skin or other application site, to be worn comfortably over an area of ​​the skin, such as a joint or other inflection point, and it will usually be subjected to mechanical strain with little or no possibility of the device becoming dislodged from the skin due to differences in flexibility or elasticity between the skin and the device.

[0085] In some embodiments, the backing layer comprises an elastic polymer film, a polymer fabric, a multidirectional elastic woven fabric, a multidirectional elastic nonwoven fabric, a stretchable polymer film, a stretchable woven fabric, or a stretchable nonwoven fabric.

[0086] In some embodiments, the backing layer is formed from one or more of a film, a nonwoven, a woven, a laminate, and combinations thereof. In some embodiments, the film is a polymer film composed of one or more polymers. Suitable polymers are known in the art and include elastomers, polyester, polyethylene, polypropylene, polyurethane, and polyetheramide. In some embodiments, the backing layer is formed from one or more of polyethylene terephthalate, various nylons, polypropylene, metallized polyester film, polyvinylidene chloride, and aluminum foil. In some embodiments, the backing layer is a fabric formed from one or more of polyester, such as polyethylene terephthalate, polyurethane, polyvinyl acetate, polyvinylidene chloride, and polyethylene. In some embodiments, the backing layer comprises one or more polymers of polyester, polyethylene, polypropylene, polyvinyl chloride, polyethylene vinyl acetate or copolymers thereof, or polyurethane. In some embodiments, the backing layer is formed from a polyester film laminate. In some embodiments, the backing layer is formed from a laminate of polyester and an ethylene vinyl acetate copolymer (EVA) heat seal layer (9% EVA). One particular polyester film laminate is a polyethylene and polyester laminate, such as the laminate sold under the name SCOTCHPAK™ #9723. In some embodiments, the backing layer comprises KOB052. In some embodiments, the backing layer comprises SCOTCHPAK™ #9732.

[0087] In some embodiments, the backing layer has a thickness of about 0.2 to 50 millimeters.

[0088] The transdermal delivery system may include an adhesive overlay. In some embodiments, the backing layer further includes an adhesive overlay layer in contact with the top surface of the separation layer.

[0089] The backing layer can take on a variety of configurations, such as those shown in Figure 1B, which shows a backing layer 20 having an adhesive overlay layer 21.

[0090] The adhesive component in the backing layer can be any of a variety of adhesive materials, such as pressure-sensitive adhesive polymers. Polyacrylate pressure-sensitive adhesive polymers are one example and typically include polyacrylates, which are polymers or copolymers of monomers selected from acrylic acid esters and methacrylic acid esters. Other monomers, such as acrylic acid and vinyl acetate, may also be present. In some embodiments, the acrylic polymer is based on an acrylic ester, such as 2-ethylhexyl acrylate (2-EHA) and ethyl acrylate. In some embodiments, the polyacrylate polymer is a polymer or copolymer of a monomer selected from acrylic acid and vinyl acetate. In some embodiments, the acrylic polymer adhesive has pendant carboxyl (—COOH) or hydroxyl (—OH) functional groups. In some embodiments, the acrylic polymer adhesive comprises at least one of polyacrylate, polymethacrylate, derivatives thereof, and copolymers thereof. In some embodiments, the acrylic adhesive is comprised of an acrylate copolymer containing acrylic ester monomers, acrylic acid, and / or vinyl acetate monomers. Copolymers of acrylic acid and vinyl acetate are one example. Acrylate copolymers are sold under the trade name DURO-TAK®, including, but not limited to, DURO-TAK 87-2287, 387-2516, 387-2051, and 387-2074. In some embodiments, the acrylate polymer includes DURO-TAK 82-2287. In some embodiments, the acrylate polymer includes DURO-TAK 87-2052 / 2287 / 2051.

[0091] In some embodiments, the adhesive overlay layer comprises an acrylate copolymer. separation layer

[0092] In some embodiments, the top surface of the separating layer is treated with a high-energy surface treatment. In some embodiments, the transdermal delivery system includes a separating layer treated with a high-energy surface treatment, the separating layer having a top surface and a bottom surface, such that the top surface is in contact with the backing layer. The separating layer may be formed of any suitable material known in the art. In some embodiments, the separating layer includes at least one of an occlusive material or a breathable material.

[0093] In some embodiments, the separation layer is occlusive. In some embodiments, the backing is preferably impermeable or substantially impermeable to moisture. In one exemplary embodiment, the backing layer has a moisture vapor transmission rate of less than about 50 g / m²-day. In some embodiments, the separation layer is preferably inert and / or does not absorb components of the adhesive layer, including the active agent. In some embodiments, the separation layer preferably prevents release of components of the adhesive layer through the separation layer. The separation layer can be flexible or inflexible. The separation layer is preferably at least partially flexible so that it can at least partially conform to the shape of the skin to which the patch is applied. In some embodiments, the separation layer is flexible so that it conforms to the shape of the skin to which the patch is applied. In some embodiments, the separation layer is sufficiently flexible to maintain contact at the application site with movement, e.g., skin movement. Typically, the material used for the separating layer should allow the device to conform to the contours of the skin or other application site and to be worn comfortably over an area of ​​the skin, such as a joint or other inflection point, which is usually subjected to mechanical strain with little or no possibility of the device becoming dislodged from the skin due to differences in flexibility or elasticity of the skin and the device.

[0094] In some embodiments, the separating layer comprises an elastic polymer film, a polymer fabric, a multidirectional elastic woven fabric, a multidirectional elastic nonwoven fabric, a stretchable polymer film, a stretchable woven fabric, or a stretchable nonwoven fabric. In some embodiments, the separating layer is formed of one or more of a film, a nonwoven fabric, a woven fabric, a laminate, and combinations thereof. In some embodiments, the film is a polymer film composed of one or more polymers. Suitable polymers are known in the art and include elastomers, polyester, polyethylene, polypropylene, polyurethane, and polyetheramide. In some embodiments, the separating layer is formed of one or more of polyethylene terephthalate, various nylons, polypropylene, metallized polyester film, polyvinylidene chloride, and aluminum foil. In some embodiments, the separating layer is a fabric formed of one or more of polyester, such as polyethylene terephthalate, polyurethane, polyvinyl acetate, polyvinylidene chloride, and polyethylene. In some embodiments, the separating layer comprises one or more polymers of polyester, polyethylene, polypropylene, polyvinyl chloride, polyethylene vinyl acetate or copolymers thereof, or polyurethane. In one specific, but non-limiting embodiment, the separation layer is formed of a polyester film laminate. One specific polyester film laminate is a polyethylene and polyester laminate, such as the laminate sold under the name SCOTCHPAK™ #9723. In some embodiments, the separation layer comprises SCOTCHPAK™ #1012. In some embodiments, the separation layer comprises SCOTCHPAK™ #9732.

[0095] In some embodiments, the separating layer comprises one or more polymers selected from polyester, polyethylene, polypropylene, polystyrene, polyvinyl chloride, and polyethylene terephthalate / ethylene vinyl acetate laminate, hi some embodiments, the separating layer comprises polyester.

[0096] In some embodiments, the top surface of the separation layer is treated with a high-energy surface treatment. In some embodiments, the separation layer further comprises a coating of ethylene vinyl acetate copolymer. In some embodiments, the top surface of the separation layer comprises a coating of ethylene vinyl acetate copolymer.

[0097] In some embodiments, the high-energy surface treatment is selected from the group consisting of corona discharge treatment, plasma treatment, UV radiation, ion beam treatment, electron beam treatment, and combinations thereof, hi some embodiments, the high-energy surface treatment is corona discharge treatment.

[0098] In some embodiments, the upper surface of the separation layer comprises a coating of ethylene vinyl acetate copolymer that has been treated with a high-energy surface treatment. In some embodiments, the upper surface of the separation layer comprises a coating of ethylene vinyl acetate copolymer that has been treated with a corona discharge treatment. In some embodiments, the upper surface of the separation layer comprises a coating of ethylene vinyl acetate copolymer that has been treated with a corona discharge treatment performed using about 0.24 kW of power.

[0099] The upper surface of the separation layer treated with a corona discharge treatment can have any suitable surface energy. For example, but not limited to, the upper surface of the separation layer treated with a corona discharge treatment can have a surface energy of at least 20 dynes, or 25, 30, 35, 40, 45, 50, 55, 60, 65, or at least 70 dynes. Alternatively, the upper surface of the separation layer treated with a corona discharge treatment can have a surface energy of, but not limited to, at least 41 dynes, or 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, or at least 60 dynes. In some embodiments, the upper surface of the separation layer has a surface energy of at least 40 dynes. Surface energy can be measured using a variety of techniques and instruments known to those skilled in the art, including but not limited to, a mobile surface analyzer by Kruss, a DyneTEC test kit from Tantec A / S, a cotton swab applicator, a solution-tipped "Dyne Pen," and a full-etch drawdown rod.

[0100] In some embodiments, the present invention provides (1) a backing layer; (2) a separation layer that has been treated with a high-energy surface treatment, the separation layer having a top surface and a bottom surface, the top surface being in contact with the backing layer; (3) a drug matrix layer comprising donepezil HCl and donepezil free base, the drug matrix layer having a top surface and a bottom surface such that the top surface is in contact with the bottom surface of the separation layer; (4) a membrane layer comprising a microporous membrane, the membrane layer having a top surface and a bottom surface such that the top surface is in contact with the bottom surface of the drug matrix layer; (5) A transdermal delivery system comprising: a contact adhesive layer having a top surface and a bottom surface, the top surface being in contact with the bottom surface of the membrane layer, the contact adhesive layer comprising donepezil free base in an amount of 0.1% to 10% (w / w) of the total weight of the contact adhesive layer.

[0101] In some embodiments, the present invention provides (1) a backing layer; (2) a separation layer having a top surface and a bottom surface, the top surface being in contact with the backing layer, the top surface having a surface energy of at least 40 dynes; (3) a drug matrix layer comprising donepezil HCl and donepezil free base, the drug matrix layer having a top surface and a bottom surface such that the top surface is in contact with the bottom surface of the separation layer; (4) a membrane layer comprising a microporous membrane, the membrane layer having a top surface and a bottom surface such that the top surface is in contact with the bottom surface of the drug matrix layer; (5) A transdermal delivery system comprising: a contact adhesive layer having a top surface and a bottom surface, the top surface being in contact with the bottom surface of the membrane layer, the contact adhesive layer comprising donepezil free base in an amount of 0.1 to 10% (w / w) of the total weight of the contact adhesive layer.

[0102] In some embodiments, the present invention provides (1) a backing layer; (2) a separation layer having a top surface and a bottom surface, the top surface being in contact with the backing layer, the top surface having a surface energy of at least 40 dynes; (3) a drug matrix layer comprising donepezil HCl, the drug matrix layer having a top surface and a bottom surface such that the top surface is in contact with the bottom surface of the separation layer; and (4) a membrane layer comprising a microporous membrane, the membrane layer having a top surface and a bottom surface such that the top surface is in contact with the bottom surface of the drug matrix layer; (5) a contact adhesive layer having a top surface and a bottom surface, the top surface being in contact with the bottom surface of the membrane layer. Drug matrix layer

[0103] The transdermal delivery system also includes a drug matrix layer that includes donepezil HCl and has a top surface and a bottom surface such that the top surface is in contact with the bottom surface of the separating layer.

[0104] The drug matrix layer may contain donepezil HCl in any suitable amount, for example, but not limited to, 1 to 50% (w / w), 1 to 45%, 1 to 40%, 5 to 35%, 5 to 30%, 5 to 25%, 10 to 25%, 10 to 20%, 11 to 19%, 12 to 18%, 13 to 17%, or 14 to 16% (w / w). The drug matrix layer may also comprise donepezil HCl in an amount of, but not limited to, about 14.5% (w / w), or about 14.6, 14.7, 14.8, 14.9, 15.0, 15.1, 15.2, 15.3, 15.4, 15.5, 15.6, 15.7, 15.8, 15.9, 16.0, 16.1, 16.2, 16.3, 16.4, or about 16.5% (w / w). In some embodiments, the drug matrix layer may comprise donepezil HCl in an amount of 14-16% (w / w). In some embodiments, the drug matrix layer may comprise donepezil HCl in an amount of about 15% (w / w). In some embodiments, the drug matrix layer may comprise donepezil HCl in an amount of about 15.4% (w / w). In some embodiments, the drug matrix layer may comprise donepezil HCl in an amount of 15.4% (w / w). The weight percentages provided may represent the weight percentage of donepezil HCl relative to the total weight of the drug matrix layer.

[0105] Without being bound by any particular theory, the drug matrix solvent composition (i) allows the salt form of the active agent to be dissolved and / or suspended in the drug matrix layer, (ii) supports the 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 be dissolved or solubilized in the drug matrix layer for diffusion into the microporous membrane and into the contact adhesive layer.

[0106] The drug matrix layer may include various other components, including, but not limited to, donepezil free base, an adhesive matrix, an acrylate polymer, a drug matrix solvent composition, an alkali salt, and others.

[0107] In some embodiments, the drug matrix layer further comprises donepezil free base. The donepezil free base may be present in any suitable amount. For example, the drug matrix layer may comprise donepezil free base in an amount of at least 1% (w / w), or at least 5, 10, 15, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, or at least 35% (w / w) of the total weight of donepezil free base and donepezil hydrochloride, without limitation. The drug matrix layer contains donepezil free base in an amount of, but not limited to, 1 to 50% (w / w), or 5 to 45% (w / w), or 10 to 40% (w / w), or 20 to 40% (w / w), or 21 to 39% (w / w), or 22 to 37% (w / w), or 22 to 36% (w / w), or 22 to 35% (w / w), or 25 to 35% (w / w) of the total weight of donepezil free base and donepezil hydrochloride.

[0108] In some embodiments, the drug matrix layer is a composition comprising an adhesive matrix comprising an adhesive polymer, a drug matrix solvent composition, and donepezil free base generated in situ in the drug matrix layer by reaction of a donepezil salt and an alkali salt or another amphoteric base compound. The drug matrix layer is prepared using a salt form of donepezil, e.g., donepezil hydrochloride (HCl), and an alkali salt that reacts in situ to form donepezil free base.

[0109] In some embodiments, the drug matrix layer further comprises: (i) an acrylate copolymer, (ii) a drug matrix solvent composition comprising glycerin and one or more of lauryl lactate, sorbitan monolaurate, and triethyl citrate, and (iv) an alkali salt comprising sodium bicarbonate.

[0110] The drug matrix layers described herein and above are intended for use in transdermal delivery systems, which additionally include an adhesive component. The adhesive component may be present in an amount of, but not limited to, about 50-90% (w / w), or about 55-90% (w / w), or about 60-90% (w / w), about 65-90% (w / w), about 70-90% (w / w), about 75-90% (w / w), or about 80-90% (w / w) of the adhesive polymer or copolymer. The provided weight percentages may represent the weight percentage of the adhesive polymer or copolymer relative to the total weight of the drug matrix layer. In some embodiments, the skin contact adhesive is comprised of an acrylate / vinyl acetate copolymer. In some embodiments, the adhesive component additionally includes polyvinylpyrrolidone, such as cross-linked polyvinylpyrrolidone.

[0111] The adhesive component in the drug matrix layer can be any of a variety of adhesive materials, such as pressure-sensitive adhesive polymers. Polyacrylate pressure-sensitive adhesive polymers are one example and typically include polyacrylates, which are polymers or copolymers of monomers selected from acrylic acid esters and methacrylic acid esters. Other monomers, such as acrylic acid and vinyl acetate, may also be present. In some embodiments, the acrylic polymer is based on an acrylic ester, such as 2-ethylhexyl acrylate (2-EHA) and ethyl acrylate. In some embodiments, the polyacrylate polymer is a polymer or copolymer of a monomer selected from acrylic acid and vinyl acetate. In some embodiments, the acrylic polymer adhesive has pendant carboxyl (—COOH) or hydroxyl (—OH) functional groups. In some embodiments, the acrylic polymer adhesive comprises at least one of polyacrylate, polymethacrylate, derivatives thereof, and copolymers thereof. In some embodiments, the acrylic adhesive is comprised of an acrylate copolymer containing acrylic ester monomers, acrylic acid, and / or vinyl acetate monomers. Copolymers of acrylic acid and vinyl acetate are one example. Acrylate copolymers are sold under the trade name DURO-TAK®, including, but not limited to, DURO-TAK 87-2287, 387-2516, 387-2051, and 387-2074. In some embodiments, the acrylate polymer comprises DURO-TAK 82-2287.

[0112] In some embodiments, the drug matrix layer comprises at least about 25-80% (w / w) adhesive polymer, based on the weight of the drug matrix layer (including subranges). In some embodiments, the drug matrix layer comprises an adhesive polymer or copolymer or a mixture of polymers and / or copolymers in an amount, including but not limited to, about 35-80%, 30-75%, at least about 40-75%, at least about 50-75%, at least about 60-75%, at least about 25-70%, at least about 30-70%, at least about 40-70%, at least about 50-70%, at least about 60-70%, at least about 25-60%, at least about 30-60%, at least about 40-60%, at least about 50-60%, at least about 25-50%, at least about 30-50%, at least about 40-50%, at least about 25-40%, at least about 30-40%, or at least about 25-30% (w / w). The drug matrix layer may comprise one or more, or at least one, adhesive polymer or copolymer. In some embodiments, the drug matrix layer comprises at least about 5-75% of the individual polymers based on the total weight of the polymers in the matrix. In some embodiments, the drug matrix layer may comprise 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%, In some embodiments, the drug matrix layer comprises an acrylate polymer in an amount of 30-50% (w / w).In some embodiments, the drug matrix layer comprises the acrylate polymer in an amount of 35-45% (w / w). In some embodiments, the drug matrix layer comprises the acrylate polymer in an amount of 37-41% (w / w). In some embodiments, the drug matrix layer comprises the acrylate polymer in an amount of about 39% (w / w). In some embodiments, the drug matrix layer comprises the acrylate polymer in an amount of about 39.1% (w / w). In some embodiments, the drug matrix layer comprises the acrylate polymer in an amount of 39.1% (w / w). In some embodiments, the drug matrix layer comprises the acrylate polymer in an amount of about 39.0% (w / w). In some embodiments, the drug matrix layer comprises the acrylate polymer in an amount of 39.0% (w / w). In some embodiments, the drug matrix layer comprises the acrylate polymer in an amount of about 38.9% (w / w). In some embodiments, the drug matrix layer comprises the acrylate polymer in an amount of 38.9% (w / w). In some embodiments, the drug matrix layer comprises an acrylate polymer in an amount of about 38.8% (w / w). In some embodiments, the drug matrix layer comprises an acrylate polymer in an amount of 38.8% (w / w). In some embodiments, the drug matrix layer comprises an acrylate polymer in an amount of about 38.7% (w / w). In some embodiments, the drug matrix layer comprises an acrylate polymer in an amount of 38.7% (w / w). The weight percentages provided may represent the weight percentage of the acrylate polymer relative to the total weight of the drug matrix layer.

[0113] In some embodiments, the drug matrix solvent composition and the membrane solvent composition have one, two, or three identical solvents. In some embodiments, the drug matrix solvent composition and the membrane solvent composition are composed of the same solvent. For example, the drug matrix solvent composition and the membrane solvent composition each include a citrate ester, a surfactant, and / or an ester of an alpha-hydroxy acid. In some embodiments, the drug matrix solvent composition (in the drug matrix layer) includes a hydrophilic solvent that is excluded from or not present in the membrane solvent composition or the contact adhesive solvent composition.

[0114] In some embodiments, the drug matrix solvent composition includes, but is not limited to, methyl laurate, propylene glycol monolaurate, glycerol monolaurate, glycerol monooleate, lauryl lactate, myristyl lactate, and dodecyl acetate. Additional drug matrix solvent compositions are described in U.S. Patent No. 8,874,879, which is incorporated herein by reference. It is understood that the compositions herein can include one or more, or at least one, drug matrix solvent composition.

[0115] The drug matrix layer also includes a drug matrix solvent composition. In some embodiments, the drug matrix solvent composition includes one, two, three, or four solvents. In some embodiments, the drug matrix solvent composition includes triethyl citrate. In some embodiments, one or both of glycerin and sorbitan monolaurate are additionally present. In some embodiments, an ester of an alpha-hydroxy acid is present as an additional solvent in the drug matrix solvent composition. Exemplary esters of alpha-hydroxy acid solvents are esters of lactic acid or glycolic acid, one example being lauryl lactate. In some embodiments, the drug matrix solvent composition consists of, consists essentially of, or consists of triethyl citrate, sorbitan monolaurate, lauryl lactate, and glycerin.

[0116] In some embodiments, the drug matrix solvent composition may contain hydrophilic materials or components not included in the membrane layer drug matrix solvent composition. In some embodiments, the hydrophilic material present in one or both of the contact adhesive layer and / or the drug matrix solvent composition, but not in the membrane solvent composition, is a hydrophilic solvent, such as, but not limited to, glycerin, water, and mixtures thereof. Other hydrophilic materials include, but are not limited to, propylene glycol and low-molecular-weight polyethylene glycol. In some embodiments, the microporous membrane is made of a hydrophobic material to provide a hydrophobic microporous membrane; examples include a polypropylene microporous membrane or a polyethylene microporous membrane. Without being bound by any particular theory, hydrophilic materials, such as the hydrophilic solvent in the drug matrix solvent composition in the drug matrix layer, do 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 matrix solvent composition in the drug matrix layer promotes and supports the in situ formation of the water-insoluble basic active drug from its pharmaceutically acceptable salt. After the base form of the active agent is formed in the drug matrix layer, the base form of the active agent is solubilized by at least one component in the drug matrix solvent composition and by at least one component in the membrane layer drug matrix solvent composition, allowing the base form of the active agent to diffuse from the drug matrix layer into and through the hydrophobic pores of the microporous membrane. In some embodiments, the drug matrix solvent composition and the membrane solvent composition have one, two, or three identical solvents, but the drug matrix solvent composition and the membrane solvent composition are different. For example, in some embodiments, the drug matrix solvent composition and the membrane solvent composition each include a citrate ester, a surfactant, and / or an α-hydroxy acid, and the drug matrix solvent composition includes a hydrophilic solvent that is excluded from or not present in the membrane layer drug matrix solvent composition.

[0117] In some embodiments, the drug matrix layer comprises the drug matrix solvent composition in an amount of about 10-50% (w / w) of the drug matrix solvent composition, relative to the weight of the drug matrix layer (including subranges). In some embodiments, the drug matrix layer comprises the drug matrix solvent composition in an amount of, but not limited to, about 10-45%, 15-45%, 15-40%, 15-35%, 20-35%, 20-30%, or 25-30% (w / w). The drug matrix layer may also comprise the drug matrix solvent composition in an amount of, but not limited to, about 20% (w / w), or about 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or about 35% (w / w). In some embodiments, the drug matrix layer comprises the drug matrix solvent composition in an amount of about 28% (w / w). In some embodiments, the drug matrix layer comprises the drug matrix solvent composition in an amount of about 27.9% (w / w). In some embodiments, the drug matrix layer comprises the drug matrix solvent composition in an amount of 27.9% (w / w). The weight percentages provided may represent the weight percentage of the drug matrix solvent composition relative to the total weight of the drug matrix layer.

[0118] In some embodiments, the drug matrix solvent composition of the drug matrix layer includes glycerin. Glycerin can be present in any suitable amount in the drug matrix layer. For example, the drug matrix layer can include glycerin in an amount of, but not limited to, about 1-20% (w / w), about 2-19%, about 3-18%, about 4-17%, about 5-16%, about 5-15%, about 6-15%, about 7-15%, about 8-14%, about 9-13%, or about 10-12% (w / w). The drug matrix layer can also include glycerin in an amount of, but not limited to, about 5% (w / w), or about 6, 7, 8, 9, 10, 11, 12, 13, 14, or about 15% (w / w). In some embodiments, the drug matrix layer includes glycerin in an amount of about 11% (w / w). In some embodiments, the drug matrix layer comprises glycerin in an amount of about 11.5% (w / w). In some embodiments, the drug matrix layer comprises glycerin in an amount of 11.5% (w / w). The weight percentages provided may represent the weight percentage of glycerin relative to the total weight of the drug matrix layer.

[0119] In some embodiments, the drug matrix solvent composition of the drug matrix layer comprises triethyl citrate. Triethyl citrate can be present in any suitable amount in the drug matrix layer. For example, the drug matrix solvent composition of the drug matrix layer can comprise triethyl citrate in an amount of, but not limited to, about 1-20% (w / w), about 2-19%, about 3-18%, about 4-17%, about 5-16%, about 5-15%, about 6-15%, about 7-15%, about 8-14%, about 9-13%, or about 10-12% (w / w). The drug matrix layer can also comprise triethyl citrate in an amount of, but not limited to, about 5% (w / w), or about 6, 7, 8, 9, 10, 11, 12, 13, 14, or about 15% (w / w). In some embodiments, the drug matrix layer comprises triethyl citrate in an amount of about 11% (w / w). In some embodiments, the drug matrix layer comprises triethyl citrate in an amount of about 11.2% (w / w). In some embodiments, the drug matrix layer comprises triethyl citrate in an amount of 11.2% (w / w). The weight percentages provided may represent the weight percentage of triethyl citrate relative to the total weight of the drug matrix layer.

[0120] In some embodiments, the drug matrix solvent composition of the drug matrix layer comprises lauryl lactate. Lauryl lactate can be present in any suitable amount in the drug matrix layer. For example, the drug matrix solvent composition of the drug matrix layer can comprise lauryl lactate in an amount of, but not limited to, about 0.1-10% (w / w), about 0.5-10%, about 1-10%, about 1-5%, or about 2-4% (w / w). The drug matrix layer can also comprise lauryl lactate in an amount of, but not limited to, about 1% (w / w), or about 1.5, 2.0, 2.5, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.5, or about 5.0% (w / w). In some embodiments, the drug matrix layer comprises lauryl lactate in an amount of about 3% (w / w). In some embodiments, the drug matrix layer comprises lauryl lactate in an amount of about 3.3% (w / w). In some embodiments, the drug matrix layer comprises lauryl lactate in an amount of 3.3% (w / w). The weight percentages provided may represent the weight percentage of lauryl lactate relative to the total weight of the drug matrix layer.

[0121] In some embodiments, the drug matrix solvent composition of the drug matrix layer comprises sorbitan monolaurate. The sorbitan monolaurate may be present in any suitable amount in the drug matrix layer. For example, the drug matrix layer may comprise, but is not limited to, about 0.1-10% (w / w), or about 0.1-5%, or about 0.5-5%, or about 1-5%, or about 1-3% (w / w) of sorbitan monolaurate. The drug matrix layer may also comprise, but is not limited to, about 1% (w / w), or about 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, or about 2.5% (w / w) of sorbitan monolaurate. In some embodiments, the drug matrix layer comprises, but is not limited to, about 2% (w / w) of sorbitan monolaurate. In some embodiments, the drug matrix layer comprises sorbitan monolaurate in an amount of about 1.9% (w / w). In some embodiments, the drug matrix layer comprises sorbitan monolaurate in an amount of 1.9% (w / w). The weight percentages provided may represent the weight percentage of sorbitan monolaurate relative to the total weight of the drug matrix layer.

[0122] The alkali salt may be, for example, sodium bicarbonate, sodium carbonate, potassium carbonate, potassium bicarbonate, trisodium phosphate, disodium hydrogen phosphate, sodium oxylate, sodium succinate, sodium citrate, or sodium salicylate. In some embodiments, the alkali salt comprises sodium bicarbonate. In some embodiments, the alkali salt consists essentially of sodium bicarbonate. In some embodiments, the alkali salt consists of sodium bicarbonate.

[0123] In some embodiments, the present invention provides (1) a backing layer; (2) a separation layer having a top surface and a bottom surface, the top surface being in contact with the backing layer; (3) a drug matrix layer comprising donepezil HCl, donepezil free base, and sodium bicarbonate, the drug matrix layer having a top surface and a bottom surface, the top surface being in contact with the bottom surface of the separation layer; (4) a membrane layer comprising a microporous membrane, the membrane layer having a top surface and a bottom surface such that the top surface is in contact with the bottom surface of the drug matrix layer; (5) a contact adhesive layer having a top surface and a bottom surface, the top surface being in contact with the bottom surface of the membrane layer.

[0124] In some embodiments, the present invention provides (1) a backing layer; (2) a separation layer having a top surface and a bottom surface, the top surface being in contact with the backing layer; (3) a drug matrix layer comprising donepezil HCl, donepezil free base, and sodium bicarbonate particles having a D90 particle size of 1 μm to 500 μm, wherein the drug matrix layer has a top surface and a bottom surface, such that the top surface is in contact with the bottom surface of the separating layer; (4) a membrane layer comprising a microporous membrane, the membrane layer having a top surface and a bottom surface such that the top surface is in contact with the bottom surface of the drug matrix layer; (5) a contact adhesive layer having a top surface and a bottom surface, the top surface being in contact with the bottom surface of the membrane layer.

[0125] In some embodiments, the present invention provides (1) a backing layer; (2) a separation layer that has been treated with a high-energy surface treatment, the separation layer having a top surface and a bottom surface, the top surface being in contact with the backing layer; (3) a drug matrix layer comprising donepezil HCl, donepezil free base, and sodium bicarbonate, the drug matrix layer having a top surface and a bottom surface, the top surface being in contact with the bottom surface of the separation layer; (4) a membrane layer comprising a microporous membrane, the membrane layer having a top surface and a bottom surface such that the top surface is in contact with the bottom surface of the drug matrix layer; (5) A transdermal delivery system comprising: a contact adhesive layer having a top surface and a bottom surface, the top surface being in contact with the bottom surface of the membrane layer, the contact adhesive layer comprising donepezil free base in an amount of 0.1 to 10% (w / w) of the total weight of the contact adhesive layer.

[0126] The sodium bicarbonate can be of any suitable particle size, for example, but not limited to, 0.1 μm to 1000 μm, or 0.1 μm to 900 μm, or 0.1 μm to 800 μm, or 0.1 μm to 700 μm, or 0.1 μm to 600 μm, or 0.1 μm to 500 μm, or 0.1 μm to 400 μm, or 0.1 μm to 300 μm, or 0.1 μm to 200 μm, or 0.1 μm to 100 μm, or 0.1 μm to 90 μm, or 0.1 μm to 85 μm, or 0.1 μm to 80 μm, or 0.1 μm to 75 μm, may comprise particles having a D90 particle size of 0.1 μm to 70 μm, or 0.1 μm to 65 μm, or 0.1 μm to 60 μm, or 0.1 μm to 65 μm, or 0.1 μm to 60 μm, or 0.1 μm to 55 μm, or 0.1 μm to 50 μm, or 0.1 μm to 45 μm, or 0.1 μm to 40 μm, or 0.1 μm to 35 μm, or 0.1 μm to 30 μm, or 0.1 μm to 25 μm, or 0.1 μm to 20 μm, or 0.1 μm to 15 μm, or 0.1 μm to 10 μm. Sodium bicarbonate may have a particle size of, but not limited to, 1 μm to 1000 μm, 1 μm to 500 μm, 1 μm to 200 μm, 1 μm to 100 μm, 1 μm to 90 μm, 1 μm to 85 μm, 1 μm to 80 μm, 1 μm to 75 μm, 1 μm to 70 μm, 1 μm to 65 μm, 1 μm to 60 μm, or 1 μm to 6 The sodium bicarbonate may include particles having a D90 particle size of, but not limited to, 20 μm to 100 μm, 10 μm to 200 μm, or 5 μm to 300 μm.

[0127] In some embodiments, the sodium bicarbonate comprises particles having a D90 particle size of 0.1 μm to 1000 μm. In some embodiments, the sodium bicarbonate comprises particles having a D90 particle size of 0.1 μm to 200 μm. In some embodiments, the sodium bicarbonate comprises particles having a D90 particle size of 0.1 μm to 100 μm. In some embodiments, the sodium bicarbonate comprises particles having a D90 particle size of 10 μm to 200 μm. In some embodiments, the sodium bicarbonate comprises particles having a D90 particle size of 20 μm to 100 μm. In some embodiments, the sodium bicarbonate comprises particles having a D90 particle size of 0.1 μm to 20 μm.

[0128] The alkali salt may be present in various amounts. For example, the alkali salt may be present in an amount of, but not limited to, about 0.1-10% (w / w), about 0.1-5%, about 0.5-5%, about 1-5%, about 2-4% (w / w), or about 2-3% (w / w). Alternatively, the alkali salt may be present in an amount of, but not limited to, about 2% (w / w), or about 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, or about 3.5% (w / w). In some embodiments, the alkali salt is present in an amount of about 2.7% (w / w). In some embodiments, the alkali salt is present in an amount of 2.7% (w / w). In some embodiments, the alkali salt is present in an amount of about 2.8% (w / w). In some embodiments, the alkali salt is present in an amount of 2.8% (w / w). In some embodiments, the alkali salt is present in an amount of about 2.9% (w / w). In some embodiments, the alkali salt is present in an amount of 2.9% (w / w). In some embodiments, the alkali salt is present in an amount of about 3.0% (w / w). In some embodiments, the alkali salt is present in an amount of 3.0% (w / w). In some embodiments, the alkali salt is present in an amount of about 3.1% (w / w). In some embodiments, the alkali salt is present in an amount of 3.1% (w / w). The weight percentages provided may represent the weight percentage of the alkali salt relative to the total weight of the drug matrix layer.

[0129] Sodium bicarbonate can be present in various amounts. For example, but not limited to, sodium bicarbonate can be present in an amount of about 0.1-10% (w / w), or about 0.1-5%, or about 0.5-5%, or about 1-5%, or about 2-4% (w / w), or about 2-3% (w / w). Alternatively, sodium bicarbonate can be present in an amount, but not limited to, about 2% (w / w), or about 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, or about 3.5% (w / w). In some embodiments, sodium bicarbonate is present in an amount of about 2.7% (w / w). In some embodiments, sodium bicarbonate is present in an amount of 2.7% (w / w). In some embodiments, sodium bicarbonate is present in an amount of about 2.8% (w / w). In some embodiments, sodium bicarbonate is present in an amount of 2.8% (w / w). In some embodiments, sodium bicarbonate is present in an amount of about 2.9% (w / w). In some embodiments, sodium bicarbonate is present in an amount of 2.9% (w / w). In some embodiments, sodium bicarbonate is present in an amount of about 3.0% (w / w). In some embodiments, sodium bicarbonate is present in an amount of 3.0% (w / w). In some embodiments, sodium bicarbonate is present in an amount of about 3.1% (w / w). In some embodiments, the drug matrix layer comprises sodium bicarbonate in an amount of about 3.1% (w / w). In some embodiments, the drug matrix layer comprises sodium bicarbonate in an amount of 3.1% (w / w). The weight percentages provided may represent the weight percentage of sodium bicarbonate relative to the total weight of the drug matrix layer.

[0130] Sodium bicarbonate can be present in any suitable molar ratio to donepezil HCl. For example, sodium bicarbonate can be present in a molar ratio of 1.0 or less, including 0.5 to 1.0, 0.6 to 1.0, 0.7 to 1.0, 0.8 to 1.0, 0.85 to 1.0, 0.9 to 1.0, or 0.95 to 1.0. In some embodiments, sodium bicarbonate can be present in a molar ratio to donepezil HCl of about 0.5, 0.55, 0.6, 0.65, 0.7, 0.75, 0.8, 0.85, 0.86, 0.87, 0.88, 0.89, 0.90, 0.91, 0.92, 0.93, 0.94, 0.95, 0.96, 0.97, 0.98, 0.99, or about 1.0. In some embodiments, sodium bicarbonate may be present in a molar ratio of about 0.88 relative to donepezil HCl. In some embodiments, sodium bicarbonate may be present in a molar ratio of about 0.92 relative to donepezil HCl. In some embodiments, sodium bicarbonate may be present in a molar ratio of about 0.95 relative to donepezil HCl. In some embodiments, sodium bicarbonate may be present in a molar ratio of about 1.0 relative to donepezil HCl.

[0131] In some embodiments, the drug matrix layer comprises sodium bicarbonate in an amount of about 2.7% (w / w), wherein the sodium bicarbonate comprises particles having a D90 particle size of 1 μm to 500 μm. In some embodiments, the drug matrix layer comprises sodium bicarbonate in an amount of about 2.7% (w / w), wherein the sodium bicarbonate comprises particles having a D90 particle size of 0.1 μm to 200 μm. In some embodiments, the drug matrix layer comprises sodium bicarbonate in an amount of about 2.7% (w / w), wherein the sodium bicarbonate comprises particles having a D90 particle size of 0.1 μm to 100 μm. In some embodiments, the drug matrix layer comprises sodium bicarbonate in an amount of about 2.7% (w / w), wherein the sodium bicarbonate comprises particles having a D90 particle size of 0.1 μm to 20 μm. In some embodiments, the drug matrix layer comprises sodium bicarbonate in an amount of 2.7% (w / w), wherein the sodium bicarbonate comprises particles having a D90 particle size of 0.1 μm to 20 μm. The weight percentages provided may represent the weight percentage of sodium bicarbonate relative to the total weight of the drug matrix layer. In some embodiments, the drug matrix layer comprises sodium bicarbonate in an amount of about 2.7% (w / w), wherein the sodium bicarbonate comprises particles having a D90 particle size of 20 μm to 100 μm. In some embodiments, the drug matrix layer comprises sodium bicarbonate in an amount of 2.7% (w / w), wherein the sodium bicarbonate comprises particles having a D90 particle size of 20 μm to 100 μm. The weight percentages provided may represent the weight percentage of sodium bicarbonate relative to the total weight of the drug matrix layer.

[0132] In some embodiments, the drug matrix layer comprises sodium bicarbonate in an amount of about 2.8% (w / w), wherein the sodium bicarbonate comprises particles having a D90 particle size of 1 μm to 500 μm. In some embodiments, the drug matrix layer comprises sodium bicarbonate in an amount of about 2.8% (w / w), wherein the sodium bicarbonate comprises particles having a D90 particle size of 0.1 μm to 200 μm. In some embodiments, the drug matrix layer comprises sodium bicarbonate in an amount of about 2.8% (w / w), wherein the sodium bicarbonate comprises particles having a D90 particle size of 0.1 μm to 100 μm. In some embodiments, the drug matrix layer comprises sodium bicarbonate in an amount of about 2.8% (w / w), wherein the sodium bicarbonate comprises particles having a D90 particle size of 0.1 μm to 20 μm. In some embodiments, the drug matrix layer comprises sodium bicarbonate in an amount of 2.8% (w / w), wherein the sodium bicarbonate comprises particles having a D90 particle size of 0.1 μm to 20 μm. The weight percentages provided may represent the weight percentage of sodium bicarbonate relative to the total weight of the drug matrix layer. In some embodiments, the drug matrix layer comprises sodium bicarbonate in an amount of about 2.8% (w / w), wherein the sodium bicarbonate comprises particles having a D90 particle size of 20 μm to 100 μm. In some embodiments, the drug matrix layer comprises sodium bicarbonate in an amount of 2.8% (w / w), wherein the sodium bicarbonate comprises particles having a D90 particle size of 20 μm to 100 μm. The weight percentages provided may represent the weight percentage of sodium bicarbonate relative to the total weight of the drug matrix layer.

[0133] In some embodiments, the drug matrix layer comprises sodium bicarbonate in an amount of about 2.9% (w / w), wherein the sodium bicarbonate comprises particles having a D90 particle size of 1 μm to 500 μm. In some embodiments, the drug matrix layer comprises sodium bicarbonate in an amount of about 2.9% (w / w), wherein the sodium bicarbonate comprises particles having a D90 particle size of 0.1 μm to 200 μm. In some embodiments, the drug matrix layer comprises sodium bicarbonate in an amount of about 2.9% (w / w), wherein the sodium bicarbonate comprises particles having a D90 particle size of 0.1 μm to 100 μm. In some embodiments, the drug matrix layer comprises sodium bicarbonate in an amount of about 2.9% (w / w), wherein the sodium bicarbonate comprises particles having a D90 particle size of 0.1 μm to 20 μm. In some embodiments, the drug matrix layer comprises sodium bicarbonate in an amount of 2.9% (w / w), wherein the sodium bicarbonate comprises particles having a D90 particle size of 0.1 μm to 20 μm. The weight percentages provided may represent the weight percentage of sodium bicarbonate relative to the total weight of the drug matrix layer. In some embodiments, the drug matrix layer comprises sodium bicarbonate in an amount of about 2.9% (w / w), wherein the sodium bicarbonate comprises particles having a D90 particle size of 20 μm to 100 μm. In some embodiments, the drug matrix layer comprises sodium bicarbonate in an amount of 2.9% (w / w), wherein the sodium bicarbonate comprises particles having a D90 particle size of 20 μm to 100 μm. The weight percentages provided may represent the weight percentage of sodium bicarbonate relative to the total weight of the drug matrix layer.

[0134] In some embodiments, the drug matrix layer comprises sodium bicarbonate in an amount of about 3.0% (w / w), wherein the sodium bicarbonate comprises particles having a D90 particle size of 1 μm to 500 μm. In some embodiments, the drug matrix layer comprises sodium bicarbonate in an amount of about 3.0% (w / w), wherein the sodium bicarbonate comprises particles having a D90 particle size of 0.1 μm to 200 μm. In some embodiments, the drug matrix layer comprises sodium bicarbonate in an amount of about 3.0% (w / w), wherein the sodium bicarbonate comprises particles having a D90 particle size of 0.1 μm to 100 μm. In some embodiments, the drug matrix layer comprises sodium bicarbonate in an amount of about 3.0% (w / w), wherein the sodium bicarbonate comprises particles having a D90 particle size of 0.1 μm to 20 μm. In some embodiments, the drug matrix layer comprises sodium bicarbonate in an amount of 3.0% (w / w), wherein the sodium bicarbonate comprises particles having a D90 particle size of 0.1 μm to 20 μm. The weight percentages provided may represent the weight percentage of sodium bicarbonate relative to the total weight of the drug matrix layer. In some embodiments, the drug matrix layer comprises sodium bicarbonate in an amount of about 3.0% (w / w), wherein the sodium bicarbonate comprises particles having a D90 particle size of 20 μm to 100 μm. In some embodiments, the drug matrix layer comprises sodium bicarbonate in an amount of 3.0% (w / w), wherein the sodium bicarbonate comprises particles having a D90 particle size of 20 μm to 100 μm. The weight percentages provided may represent the weight percentage of sodium bicarbonate relative to the total weight of the drug matrix layer.

[0135] In some embodiments, the drug matrix layer comprises sodium bicarbonate in an amount of about 3.1% (w / w), wherein the sodium bicarbonate comprises particles having a D90 particle size of 1 μm to 500 μm. In some embodiments, the drug matrix layer comprises sodium bicarbonate in an amount of about 3.1% (w / w), wherein the sodium bicarbonate comprises particles having a D90 particle size of 0.1 μm to 200 μm. In some embodiments, the drug matrix layer comprises sodium bicarbonate in an amount of about 3.1% (w / w), wherein the sodium bicarbonate comprises particles having a D90 particle size of 0.1 μm to 100 μm. In some embodiments, the drug matrix layer comprises sodium bicarbonate in an amount of about 3.1% (w / w), wherein the sodium bicarbonate comprises particles having a D90 particle size of 0.1 μm to 20 μm. In some embodiments, the drug matrix layer comprises sodium bicarbonate in an amount of 3.1% (w / w), wherein the sodium bicarbonate comprises particles having a D90 particle size of 0.1 μm to 20 μm. The weight percentages provided may represent the weight percentage of sodium bicarbonate relative to the total weight of the drug matrix layer. In some embodiments, the drug matrix layer comprises sodium bicarbonate in an amount of about 3.1% (w / w), wherein the sodium bicarbonate comprises particles having a D90 particle size of 20 μm to 100 μm. In some embodiments, the drug matrix layer comprises sodium bicarbonate in an amount of 3.1% (w / w), wherein the sodium bicarbonate comprises particles having a D90 particle size of 20 μm to 100 μm. The weight percentages provided may represent the weight percentage of sodium bicarbonate relative to the total weight of the drug matrix layer.

[0136] The drug matrix layer may contain donepezil HCl and sodium bicarbonate in any suitable amount. In some embodiments, the drug matrix layer contains donepezil HCl in an amount of 10-20% (w / w) and sodium bicarbonate in an amount of 1-5% (w / w), the sodium bicarbonate comprising particles having a D90 particle size of 1 μm to 500 μm. In some embodiments, the drug matrix layer contains donepezil HCl in an amount of 14-16% (w / w) and sodium bicarbonate in an amount of 2-4% (w / w), the sodium bicarbonate comprising particles having a D90 particle size of 10 μm to 200 μm.

[0137] In some embodiments, the drug matrix layer comprises donepezil HCl in an amount of about 15% (w / w) and sodium bicarbonate in an amount of about 2.7% (w / w), wherein the sodium bicarbonate comprises particles having a D90 particle size of 20 μm to 100 μm. In some embodiments, the drug matrix layer comprises donepezil HCl in an amount of about 15.4% (w / w) and sodium bicarbonate in an amount of about 2.7% (w / w), wherein the sodium bicarbonate comprises particles having a D90 particle size of 20 μm to 100 μm. In some embodiments, the drug matrix layer comprises donepezil HCl in an amount of 15.4% (w / w) and sodium bicarbonate in an amount of 2.7% (w / w), wherein the sodium bicarbonate comprises particles having a D90 particle size of 20 μm to 100 μm. The weight percentages provided may represent the weight percentage of donepezil HCl relative to the total weight of the drug matrix layer.

[0138] In some embodiments, the drug matrix layer comprises donepezil HCl in an amount of about 15% (w / w) and sodium bicarbonate in an amount of about 2.8% (w / w), wherein the sodium bicarbonate comprises particles having a D90 particle size of 20 μm to 100 μm. In some embodiments, the drug matrix layer comprises donepezil HCl in an amount of about 15.4% (w / w) and sodium bicarbonate in an amount of about 2.8% (w / w), wherein the sodium bicarbonate comprises particles having a D90 particle size of 20 μm to 100 μm. In some embodiments, the drug matrix layer comprises donepezil HCl in an amount of 15.4% (w / w) and sodium bicarbonate in an amount of 2.8% (w / w), wherein the sodium bicarbonate comprises particles having a D90 particle size of 20 μm to 100 μm. The weight percentages provided may represent the weight percentage of donepezil HCl relative to the total weight of the drug matrix layer.

[0139] In some embodiments, the drug matrix layer comprises donepezil HCl in an amount of about 15% (w / w) and sodium bicarbonate in an amount of about 2.9% (w / w), wherein the sodium bicarbonate comprises particles having a D90 particle size of 20 μm to 100 μm. In some embodiments, the drug matrix layer comprises donepezil HCl in an amount of about 15.4% (w / w) and sodium bicarbonate in an amount of about 2.9% (w / w), wherein the sodium bicarbonate comprises particles having a D90 particle size of 20 μm to 100 μm. In some embodiments, the drug matrix layer comprises donepezil HCl in an amount of 15.4% (w / w) and sodium bicarbonate in an amount of 2.9% (w / w), wherein the sodium bicarbonate comprises particles having a D90 particle size of 20 μm to 100 μm. The weight percentages provided may represent the weight percentage of donepezil HCl relative to the total weight of the drug matrix layer.

[0140] In some embodiments, the drug matrix layer comprises donepezil HCl in an amount of about 15% (w / w) and sodium bicarbonate in an amount of about 3.0% (w / w), wherein the sodium bicarbonate comprises particles having a D90 particle size of 20 μm to 100 μm. In some embodiments, the drug matrix layer comprises donepezil HCl in an amount of about 15.4% (w / w) and sodium bicarbonate in an amount of about 3.0% (w / w), wherein the sodium bicarbonate comprises particles having a D90 particle size of 20 μm to 100 μm. In some embodiments, the drug matrix layer comprises donepezil HCl in an amount of 15.4% (w / w) and sodium bicarbonate in an amount of 3.0% (w / w), wherein the sodium bicarbonate comprises particles having a D90 particle size of 20 μm to 100 μm. The weight percentages provided may represent the weight percentage of donepezil HCl relative to the total weight of the drug matrix layer.

[0141] In some embodiments, the drug matrix layer comprises donepezil HCl in an amount of about 15% (w / w) and sodium bicarbonate in an amount of about 3.1% (w / w), wherein the sodium bicarbonate comprises particles having a D90 particle size of 20 μm to 100 μm. In some embodiments, the drug matrix layer comprises donepezil HCl in an amount of about 15.4% (w / w) and sodium bicarbonate in an amount of about 3.1% (w / w), wherein the sodium bicarbonate comprises particles having a D90 particle size of 20 μm to 100 μm. In some embodiments, the drug matrix layer comprises donepezil HCl in an amount of 15.4% (w / w) and sodium bicarbonate in an amount of 3.1% (w / w), wherein the sodium bicarbonate comprises particles having a D90 particle size of 20 μm to 100 μm. The weight percentages provided may represent the weight percentage of donepezil HCl relative to the total weight of the drug matrix layer.

[0142] The drug matrix layer may further comprise one or more matrix modifiers. Without wishing to be bound by theory, it is believed that the matrix modifier promotes homogenization of the adhesive matrix. Sorption of hydrophilic moieties is a possible mechanism for this process. Thus, known matrix modifiers that are water-absorbing to some extent may be used. For example, possible matrix modifiers include colloidal silicone dioxide, fumed silica, cross-linked polyvinylpyrrolidone (PVP), soluble PVP, cellulose derivatives (e.g., hydroxypropyl cellulose (HPC), hydroxyethyl cellulose (HEC)), polyacrylamide, polyacrylic acid, polyacrylate, polyacrylate salts, or clays such as kaolin or bentonite. An exemplary commercially available fumed silica product is Cab-O-Sil (Cabot Corporation, Boston, Massachusetts). Hydrophilic mixtures such as those described in U.S. Published Patent Application No. 2003 / 0170308 can also be used, such as mixtures of PVP and PEG, or PVP, PEG, and a water-swellable polymer, such as EUDRAGIT® L100-55. In some embodiments, the matrix-modifying agent is individually present in an amount of between about 1-25%, about 2-25%, about 5-25%, about 5-7%, about 7-20%, or about 7-25% by weight of the adhesive matrix (including subranges). In some embodiments, the matrix-modifying agent does not comprise ethylcellulose.

[0143] The drug matrix layer may also include a copolymer, such as polyvinylpyrrolidone / vinyl acetate copolymer, acrylate / vinyl acetate copolymer, or vinyl acetate / ethylene acetate copolymer. In some embodiments, the copolymer is a vinyl acetate / N-vinylpyrrolidone copolymer, such as the copolymer sold as Plasdone™ S630 (Ashland). In some embodiments, the polyvinylpyrrolidone-vinyl acetate copolymer is a linear random copolymer of n-vinyl-2-pyrrolidone and vinyl acetate. In some embodiments, the copolymer is a 60:40 copolymer of n-vinyl-2-pyrrolidone and vinyl acetate.

[0144] The drug matrix layer may also contain polyvinylpyrrolidone (PVP). PVP is a water-soluble polymer composed of N-vinylpyrrolidone monomers and is available in various forms, including cross-linked and non-cross-linked. In some examples herein, cross-linked PVP is included in the drug matrix layer. In some embodiments, the cross-linked PVP is crospovidone. In some embodiments, the drug matrix layer further contains crospovidone.

[0145] Crospovidone can be present in the drug matrix layer in any suitable amount. For example, crospovidone can be present in the drug matrix layer in an amount of, but not limited to, 1 to 50% (w / w), 5 to 25%, 10 to 20%, 11 to 19%, 12 to 18%, 13 to 17%, or 14 to 16% (w / w). The drug matrix layer can also contain crospovidone in an amount of, but not limited to, about 13.5% (w / w), or about 13.6, 13.7, 13.8, 13.9, 14.0, 14.1, 14.2, 14.3, 14.4, 14.5, 14.6, 14.7, 14.8, 14.9, 15.0, 15.1, 15.2, 15.3, 15.4, or about 15.5% (w / w). In some embodiments, the drug matrix layer comprises crospovidone in an amount of about 14% (w / w). In some embodiments, the drug matrix layer comprises crospovidone in an amount of 14-16% (w / w). In some embodiments, the drug matrix layer comprises crospovidone in an amount of about 14.4% (w / w). In some embodiments, the drug matrix layer comprises crospovidone in an amount of 14.4% (w / w). The weight percentages provided may represent the weight percentage of crospovidone relative to the total weight of the drug matrix layer.

[0146] The drug matrix layer may further include other conventional additives known in the art, such as adhesives, antioxidants, crosslinking or hardening agents, pH adjusters, pigments, dyes, refractive particles, conductive species, antimicrobial agents, emulsifiers, gelling agents, viscosity modifiers or thickeners, stabilizers, and the like. In embodiments where adhesion needs to be reduced or eliminated, conventional detackifying agents may also be used. Other agents, such as antimicrobial agents, may also be added to prevent spoilage during storage, i.e., inhibit the growth of microorganisms such as yeast and mold. Suitable antimicrobial agents are typically selected from the group consisting of the methyl and propyl esters of p-hydroxybenzoic acid (i.e., methyl and propylparaben), sodium benzoate, sorbic acid, imidurea, and combinations thereof. These additives, and their amounts, are selected in a manner that does not significantly interfere with the desired chemical and physical properties of the adhesive and / or active agent.

[0147] The drug matrix layer may also contain an irritation-reducing additive to minimize or eliminate the possibility of skin irritation and / or damage resulting from the drug, enhancer, or other components of the composition. Suitable irritation-reducing additives include, for example, α-tocopherol, monoamine oxidase inhibitors, particularly phenyl alcohols such as 2-phenyl-1-ethanol, glycerin, salicylic acid and salicylates, ascorbic acid and ascorbate salts, ionophores such as monensin, amphiphilic amines, ammonium chloride, N-acetylcysteine, cis-urocanic acid, capsaicin, chloroquine, and corticosteroids.

[0148] In some embodiments, the drug matrix layer also comprises ascorbic acid. Any suitable ascorbic acid can be used in the transdermal delivery system of the present invention. Exemplary ascorbic acids include, but are not limited to, ascorbyl palmitate and ascorbyl stearate. In some embodiments, the drug matrix layer comprises ascorbyl palmitate.

[0149] The drug matrix layer may contain any suitable amount of ascorbyl palmitate. For example, the drug matrix layer may contain ascorbyl palmitate in an amount of, but not limited to, 0.01-10% (w / w), 0.1-5%, 0.1-4%, 0.1-3%, 0.1-2%, 0.1-1%, 0.2-0.9%, 0.3-0.8%, or 0.4-0.6% (w / w). The drug matrix layer may also contain ascorbyl palmitate in an amount of, but not limited to, about 0.1% (w / w), or 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, or about 1.0% (w / w). In some embodiments, the drug matrix layer contains ascorbyl palmitate in an amount of 0.1-1.0% (w / w). In some embodiments, the drug matrix layer comprises ascorbyl palmitate in an amount of 0.4-0.6% (w / w). In some embodiments, the drug matrix layer comprises ascorbyl palmitate in an amount of about 0.5% (w / w). In some embodiments, the drug matrix layer comprises ascorbyl palmitate in an amount of 0.5% (w / w). The weight percentages provided may represent the weight percentage of ascorbyl palmitate relative to the total weight of the drug matrix layer.

[0150] In some embodiments, the drug matrix layer further comprises acrylate-vinyl acetate copolymer, glycerin, lauryl lactate, sorbitan monolaurate, triethyl citrate, donepezil free base, and sodium bicarbonate.

[0151] In some embodiments, the transdermal delivery system comprises a drug matrix layer comprising or consisting essentially of donepezil free base, donepezil HCl, and sodium bicarbonate; a drug matrix solvent composition mixture of triethyl citrate, sorbitan monolaurate, and glycerin; and a polymeric adhesive matrix of cross-linked polyvinylpyrrolidone and acrylate / vinyl acetate copolymer. In some embodiments, the drug matrix layer comprises or consists essentially of donepezil free base, about 10-25% (w / w) donepezil HCl, about 1-5% (w / w) sodium bicarbonate, about 5-15% (w / w) triethyl citrate, about 0.5-5% (w / w) sorbitan monolaurate, about 5-15% (w / w) glycerin, about 5-25% (w / w) cross-linked polyvinylpyrrolidone, and about 30-50% (w / w) acrylate / vinyl acetate copolymer. The weight percentages provided can represent the weight percentage of each component relative to the total weight of the drug matrix layer.

[0152] In some embodiments, the transdermal delivery system comprises a composition comprising donepezil free base, about 14-18% (w / w) donepezil HCl, and a drug matrix layer consisting essentially of about 2-5% (w / w) sodium bicarbonate, about 8-12% (w / w) triethyl citrate, about 1.5-2.5% (w / w) sorbitan monolaurate, about 10-12% (w / w) glycerin, about 13-17% (w / w) cross-linked polyvinylpyrrolidone, and about 38-40% (w / w) acrylate-vinyl acetate copolymer. The weight percentages provided may represent the weight percentage of each component relative to the total weight of the drug matrix layer.

[0153] A transdermal delivery system having a therapeutic agent may include a separating layer having any of the components described therein. In some embodiments, the separating layer comprises at least one of an occlusive material or a breathable material. In some embodiments, the separating layer comprises an occlusive material. In some embodiments, the separating layer comprises one or more polymers selected from polyester, polyethylene, polypropylene, polystyrene, polyvinyl chloride, and polyethylene terephthalate / ethylene vinyl acetate laminate. In some embodiments, the separating layer comprises a polyester polymer.

[0154] The transdermal delivery system having a therapeutic agent can include an upper surface having any of the components described herein. In some embodiments, the upper surface of the separating layer includes a coating of ethylene vinyl acetate copolymer that has been treated with a high-energy surface treatment.

[0155] The transdermal delivery system containing a therapeutic agent may include a high-energy surface treatment, including any of the treatments described herein. In some embodiments, the high-energy surface treatment is selected from the group consisting of corona discharge treatment, plasma treatment, UV radiation, ion beam treatment, electron beam treatment, and combinations thereof. In some embodiments, the high-energy surface treatment is corona discharge treatment. In some embodiments, the upper surface of the separation layer has a surface energy of at least 40 dynes.

[0156] The transdermal delivery system having a therapeutic agent can include a drug matrix layer having any combination of the components described therein. The therapeutic agent can include any suitable therapeutic agent. For example, the therapeutic agent can include donepezil hydrochloride, donepezil free base, memantine, or a combination thereof.

[0157] In some embodiments, the drug matrix layer further comprises (i) an acrylate copolymer, and (ii) a drug matrix solvent composition comprising glycerin and one or more of lauryl lactate, sorbitan monolaurate, and triethyl citrate. In some embodiments, the drug matrix layer further comprises acrylate-vinyl acetate copolymer, glycerin, lauryl lactate, sorbitan monolaurate, and triethyl citrate. In some embodiments, the drug matrix layer further comprises ascorbyl palmitate.

[0158] A transdermal delivery system having a therapeutic agent may include a microporous membrane layer having any combination of the components described therein. In some embodiments, the microporous membrane comprises polypropylene. In some embodiments, the microporous membrane comprises a plurality of pores. In some embodiments, the plurality of pores in the microporous membrane comprises a solvent composition comprising one or more of triethyl citrate, sorbitan monolaurate, and lauryl lactate. In some embodiments, the microporous membrane comprises polypropylene, and the plurality of pores in the microporous membrane comprise triethyl citrate, sorbitan monolaurate, and lauryl lactate.

[0159] The transdermal delivery system having a therapeutic agent can include a contact adhesive layer having any combination of the components described therein. In some embodiments, the contact adhesive layer comprises a copolymer of acrylate and vinyl acetate. In some embodiments, the contact adhesive layer further comprises one or more solvents: triethyl citrate, sorbitan monolaurate, or lauryl lactate.

[0160] The transdermal delivery system having a therapeutic agent may include a release layer having any combination of the components described therein. In some embodiments, the transdermal delivery system also includes a release layer in contact with the bottom surface of the contact adhesive layer. In some embodiments, the release layer includes a silicone coating material, a fluorocarbon coating material, or a fluorosilicone coating material. In some embodiments, the release layer includes a silicone coating material.

[0161] The drug matrix layer may include any additional ingredients as described herein, hi some embodiments, the drug matrix layer further includes at least one of an acrylate polymer, glycerin, ascorbyl palmitate, lauryl lactate, sorbitan monolaurate, and triethyl citrate.

[0162] The drug matrix layer may be prepared by the methods described herein.

[0163] The drug matrix layer may also include any combination of the ingredients described therein. Membrane layer (middle layer)

[0164] The membrane layer, also referred to as the fabric layer, intermediate layer, or adhesive layer, can be formed of any suitable material, including, but not limited to, polyester, vinyl acetate polymers and copolymers, polyethylene, and combinations thereof. In some embodiments, the membrane layer is a nonwoven layer of polyester fibers, such as a film sold under the name Reemay® (Kavon Filter Products Co.). In some embodiments, the membrane layer does not affect the rate of release of the active agent from the adhesive layer.

[0165] In some embodiments, the membrane layer comprises a microporous membrane. For example, the microporous membrane can be microporous polypropylene or polyethylene. The microporous membrane can help control the rate of drug release from the transdermal delivery system. Several different microporous membranes are commercially available, such as those sold under the name Celgard®, e.g., Celgard® 2400 (Polypore International, LP).

[0166] Other materials useful in forming microporous membranes include, but are not limited to, polycarbonates, i.e., linear polyesters of carbonic acid, formed by phosgenation of dihydroxy aromatics, such as bisphenols, in which carbonate groups repeat in the polymer chain; polyvinyl chloride; polyamides, such as polyhexamethylene adipamide and other polyamides commonly known as nylons; modacrylic copolymers, such as styrene-acrylic acid copolymers; polysulfones, such as those characterized by diphenylene sulfone groups in a linear chain; halogenated polymers, such as polyvinylidene fluoride, polyvinyl fluoride, and polyfluorohalocarbons; polychloroethers and Other such thermoplastic polyethers include acetal polymers such as polyformaldehyde; acrylic resins such as polyacrylonitrile polymethyl poly(vinyl alcohol), derivatives of polystyrene such as poly(sodium styrene sulfonate) and polyvinylbenzyltrimethylammonium chloride), poly(hydroxyethyl methacrylate poly(isobutyl vinyl ether), and the like; numerous copolymers, which can be formed by reacting various ratios of monomers from the foregoing list of polymers, are also useful for preparing rate-controlling structures useful in the present invention. In some embodiments, the microporous membrane comprises polypropylene.

[0167] Without being bound by any particular theory, the diffusion of active agents through microporous polymeric materials, such as microporous polypropylene, can be difficult. The polymer is impermeable to the active agent except in the pore channels, and even then, the active agent cannot diffuse through the pores unless it is in a vaporized state. Thus, if a microporous membrane is used as purchased in the fabrication of a transdermal delivery system, excessive time may be required for the delivery solvent (i.e., drug matrix solvent composition) from the drug matrix layer to be distributed into the pores, and then the active agent to be distributed into the delivery solvent in the pores. The resulting effect is that it may take a long time for the active agent to reach its intended target.

[0168] The release rate of active agents through a microporous membrane can be significantly improved if the microporous membrane is pretreated with a suitable delivery carrier or membrane solvent composition.Pretreatment as used herein refers to exposing the microporous membrane to a membrane solvent composition to fill the pores in the microporous membrane before the microporous membrane is incorporated into a transdermal system.The pores of the microporous membrane are filled with or contain the membrane solvent composition before and at the time the microporous membrane is incorporated into a transdermal system.The release rate of active agents through a microporous membrane depends on several variables, such as the diffusivity and solubility of the active agent in the membrane solvent 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 relative to the pore size, the absolute pore size, and the number of pores or porosity (void fraction) in the material are contributing factors that govern the solubility and diffusivity of the agent into and through the membrane.

[0169] In some embodiments, the microporous membrane comprises a plurality of pores. In some embodiments, the microporous membrane may have a porosity in the range of, but not limited to, about 30% to about 50%, about 35% to about 45%, or about 40% to about 42%. For example, the microporous membrane may have a porosity of, but not limited to, about 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, or 50%.

[0170] In some embodiments, the microporous membrane may have an average pore size ranging from about 0.001 μm to about 100 μm, about 1 μm to about 10 μm, about 0.010 μm to about 0.100 μm, or about 0.040 μm to about 0.050 μm. For example, the average pore size may be, but is not limited to, about 0.035 μm, 0.036 μm, 0.037 μm, 0.038 μm, 0.039 μm, 0.040 μm, 0.041 μm, 0.042 μm, 0.043 μm, 0.044 μm, 0.045 μm, 0.046 μm, 0.047 μm, 0.048 μm, 0.049 μm, or 0.050 μm. In some embodiments, the microporous membrane has an average pore size of about 0.043 μm.

[0171] The microporous membrane may be pretreated with a membrane solvent composition that is the same as or different from the drug matrix solvent composition present in the drug matrix layer. In some embodiments, the microporous membrane is pretreated with a membrane solvent composition comprising a solvent, a surfactant, an emulsifier, a thickener, a stabilizer, a plasticizer, and / or a combination thereof. In some embodiments, the surfactant is a nonionic surfactant. In some embodiments, the microporous membrane is pretreated with a citrate ester. In some embodiments, the citrate ester is triethyl citrate. In some embodiments, the microporous membrane is pretreated with lauryl lactate. In some embodiments, the microporous membrane is pretreated with a sorbitan monoester. In some embodiments, the sorbitan monoester is sorbitan monolaurate (sorbitan laurate). In some embodiments, the membrane layer is pretreated with a membrane solvent composition comprising triethyl citrate, lauryl lactate, and sorbitan monolaurate. In some embodiments, the microporous membrane is pretreated with octyldodecanol.

[0172] In some embodiments, the microporous membrane has a plurality of pores filled with or containing a membrane solvent composition that is different from the drug matrix solvent composition in the drug matrix layer in fluid communication with the microporous membrane. In some embodiments, the membrane solvent composition does not include (i.e., excludes) solvents in which the salt form of the active agent is soluble. In some embodiments, the membrane solvent composition does not include (i.e., excludes) hydrophilic solvents in which the salt form of the active agent is soluble. In some embodiments, the membrane solvent composition does not include (i.e., excludes) polyols, including solvent polyols, such as polyethylene glycol, propylene glycol, glycerin (glycol), acetonitrile, 1-propanol, N,N-dimethylformamide, and dimethyl sulfoxide.

[0173] Without being bound by any particular theory, the membrane solvent composition allows the base form of the active agent to be dissolved or suspended therein and diffusively transport into and through the microporous membrane.

[0174] The materials selected for the membrane solvent composition may be non-toxic and may have the required solubility for the rate-controlling microporous material. In some embodiments, the membrane solvent composition is not a solvent for the material from which the microporous membrane is made. That is, the microporous membrane is chemically stable in the membrane solvent composition. Materials useful for impregnating, filling, or saturating the pores or micropores of the microporous membrane may be polar, semi-polar, or non-polar. Materials for use in the membrane solvent composition in addition to those listed above include, but are not limited to, pharmaceutically acceptable alcohols containing 6 to 25 carbon atoms, such as hexanol, cyclohexanol, benzyl alcohol, 1,2-butanediol, glycerin, and amyl alcohol, and octyldodecanol; hydrocarbons having 5 to 12 carbon atoms, such as n-hexane, cyclohexane, and ethylbenzene; aldehydes and ketones having 4 to 10 carbon atoms, such as heptylaldehyde, cyclohexanone, and benzaldehyde; esters having 4 to 10 carbon atoms, such as amyl acetate and benzyl propionate; ether oils, such as eucalyptus oil, roux oil, cumin oil, limonene, thyme, and 1-pinene; halogenated hydrocarbons having 2 to 8 carbon atoms, such as n-hexyl chloride, n-hexyl bromide, and cyclohexyl chloride; or mixtures of any of the foregoing materials.

[0175] In some embodiments, the plurality of pores in the microporous membrane comprises a membrane solvent composition consisting of one or more of triethyl citrate, sorbitan monolaurate, and lauryl lactate.

[0176] In some embodiments, the microporous membrane comprises triethyl citrate. The triethyl citrate can be present in any suitable amount. For example, the membrane layer comprises triethyl citrate in an amount, including but not limited to, about 50-99% (w / w), about 55-95%, about 55-90%, about 55-85%, about 55-80%, about 60-75%, about 61-74%, about 62-73%, about 63-72%, about 64-71%, about 65-70%, or about 66-69% (w / w). The membrane layer may also comprise triethyl citrate in an amount, without limitation, of about 50% (w / w), or about 55, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 80, 85, 90, or about 95% (w / w). In some embodiments, the membrane layer comprises triethyl citrate in an amount of about 67% (w / w). In some embodiments, the membrane layer comprises triethyl citrate in an amount of about 66.7% (w / w). In some embodiments, the membrane layer comprises triethyl citrate in an amount of 66.7% (w / w). The weight percentages provided may represent the weight percentage of triethyl citrate relative to the total weight of the membrane solvent composition.

[0177] In some embodiments, the microporous membrane comprises lauryl lactate. The lauryl lactate can be present in any suitable amount. For example, the membrane layer can comprise lauryl lactate in an amount of, but not limited to, about 1-50% (w / w), about 1-40%, about 5-35%, about 10-30%, about 15-25%, about 16-24%, about 17-23%, about 18-22%, or about 19-21% (w / w). The membrane layer can also comprise lauryl lactate in an amount, but not limited to, about 5% (w / w), or about 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 35, 40, 45, or about 50% (w / w). In some embodiments, the membrane layer comprises lauryl lactate in an amount of about 20% (w / w). In some embodiments, the membrane layer comprises lauryl lactate in an amount of about 20.0% (w / w). In some embodiments, the membrane layer comprises lauryl lactate in an amount of 20.0% (w / w). The weight percentages provided may represent the weight percentage of lauryl lactate relative to the total weight of the membrane solvent composition.

[0178] In some embodiments, the microporous membrane comprises sorbitan monolaurate. The sorbitan monolaurate can be present in any suitable amount. For example, the membrane layer can comprise, but is not limited to, about 1-50% (w / w), about 1-45%, about 1-40%, about 1-35%, about 1-30%, about 5-25%, about 10-20%, about 10-15%, or about 12-15% (w / w) of sorbitan monolaurate. The membrane layer can also comprise, but is not limited to, about 5% (w / w), or about 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 30, 35, 40, 45, or about 50% (w / w) of sorbitan monolaurate. In some embodiments, the membrane layer comprises sorbitan monolaurate in an amount of about 13% (w / w). In some embodiments, the membrane layer comprises sorbitan monolaurate in an amount of about 13.3% (w / w). In some embodiments, the membrane layer comprises sorbitan monolaurate in an amount of 13.3% (w / w). The weight percentages provided may represent the weight percentage of sorbitan monolaurate relative to the total weight of the membrane solvent composition.

[0179] In some embodiments, the microporous membrane comprises polypropylene and the plurality of pores in the microporous membrane comprises triethyl citrate, sorbitan monolaurate, and lauryl lactate.

[0180] In some embodiments, the membrane solvent composition comprises about 60% (w / w) to about 75% (w / w) triethyl citrate. In some embodiments, the membrane solvent composition comprises triethyl citrate in an amount, including but not limited to, about 55% (w / w) to about 80% (w / w), about 60% (w / w) to about 70% (w / w), about 65% (w / w) to about 75% (w / w), or about 65% (w / w) to about 70% (w / w). In some embodiments, the membrane solvent composition comprises sorbitan monolaurate in an amount of about 10% (w / w) to about 17% (w / w). In some embodiments, the membrane solvent composition comprises sorbitan monolaurate in an amount, including but not limited to, about 8% (w / w) to about 25% (w / w), about 10% (w / w) to about 25% (w / w), about 8% (w / w) to about 17% (w / w), about 12% (w / w) to about 20% (w / w), about 10% (w / w) to about 15% (w / w), or about 12% (w / w) to about 14% (w / w). In some embodiments, the membrane solvent composition comprises lauryl lactate in an amount of about 15% (w / w) to about 25% (w / w). In some embodiments, the membrane solvent composition comprises lauryl lactate in an amount, including but not limited to, about 10% (w / w) to about 30% (w / w), about 15% (w / w) to about 30% (w / w), about 15% (w / w) to about 20% (w / w), about 10% (w / w) to about 25% (w / w), about 10% (w / w) to about 20% (w / w), about 17% (w / w) to about 23% (w / w), about 18% (w / w) to about 22% (w / w), or about 19% (w / w) to about 21% (w / w). In some embodiments, the membrane solvent composition may be formulated with a combination of triethyl citrate, lauryl lactate, and sorbitan monolaurate in any of the ranges listed above. In some embodiments, the membrane solvent composition comprises triethyl citrate in an amount of about 66.7% (w / w), lauryl lactate in an amount of about 20.0% (w / w), and sorbitan monolaurate in an amount of about 13.3% (w / w). In some embodiments, the membrane solvent composition comprises triethyl citrate in an amount of 66.7% (w / w), lauryl lactate in an amount of 20.0% (w / w), and sorbitan monolaurate in an amount of 13.3% (w / w). The weight percentages provided may represent the weight percentage of each component relative to the total weight of the membrane solvent composition.

[0181] The thickness of the microporous membrane can vary depending on the type of material and the desired characteristics of the microporous membrane (e.g., porosity, pore size, time diffusion of the active agent through the membrane). In some embodiments, the microporous membrane has a thickness of about 5 to about 200 μm. In some embodiments, the microporous membrane has a thickness of, but not limited to, about 10 to about 150 μm, about 10 to about 125 μm, about 10 to about 100 μm, about 10 to about 75 μm, about 10 to about 50 μm, about 5 to about 45 μm, about 5 to about 30 μm, about 10 to about 30 μm, about 15 to about 30 μm, or about 20 to about 30 μm. In some embodiments, the microporous membrane has a thickness of, but not limited to, about 22 to about 28 μm. In some embodiments, the microporous membrane has a thickness of about 24 to about 26 μm. In some embodiments, the microporous membrane has a thickness of about 25 μm.

[0182] Microporous membranes can be pretreated in a variety of ways. Generally, pretreating involves contacting the microporous membrane with the membrane solvent composition in a sufficient manner and for a sufficient period of time. In some embodiments, pretreating the microporous membrane involves contacting the microporous membrane with the membrane solvent composition, saturating the microporous membrane with the membrane solvent composition, and removing any excess membrane solvent composition from the saturated microporous membrane. In some embodiments, the microporous membrane is immersed in the membrane solvent composition. In some embodiments, the microporous membrane is immersed in a bath of the membrane solvent composition. In some embodiments, the membrane solvent composition is spread on the microporous membrane until the microporous membrane is saturated, and then the excess membrane solvent composition is removed.

[0183] Pretreatment of the microporous membrane with the membrane solvent composition can vary in extent. In some embodiments, a portion of the pores of the microporous membrane contain the membrane solvent composition therein. In some embodiments, about one-third, about one-half, about two-thirds, or about three-quarters of the pores contain the membrane solvent composition. In some embodiments, all of the pores contain the membrane solvent composition. In some embodiments, the portion of the pores containing the membrane solvent composition is only partially filled. In some embodiments, the membrane solvent composition occupies about one-quarter, about one-third, about one-half, about two-thirds, or about three-quarters of the space within the occupied pores. In some embodiments, all of the pores of the microporous membrane are completely filled with the membrane solvent composition, and the microporous membrane is thus saturated with the membrane solvent composition. contact adhesive layer

[0184] The transdermal delivery system of the present invention includes a contact adhesive layer. The contact adhesive layer may include a variety of components, such as a polymer or copolymer.

[0185] In some embodiments, the contact adhesive layer comprises one or more biocompatible polymers selected from one or more of polyisobutylene (PIB), silicone polymers, acrylate copolymers, butyl rubber, polybutylene, styrene-isoprene-styrene block copolymers, styrene-butadiene-styrene block copolymers, ethylene-vinyl acetate (EVA), mixtures and copolymers thereof, hi some embodiments, the biocompatible polymer is polyisobutylene.

[0186] The contact adhesive layers described herein and above are contemplated for use in transdermal delivery systems, which additionally comprise an adhesive component. The contact adhesive layer may comprise, but is not limited to, about 50-90% (w / w), or about 55-90% (w / w), or about 60-90% (w / w), about 65-90% (w / w), about 70-90% (w / w), about 75-90% (w / w), or about 80-90% (w / w) of an adhesive polymer or copolymer. In some embodiments, the contact adhesive layer comprises an acrylate / vinyl acetate copolymer. In some embodiments, the contact adhesive layer comprises polyvinylpyrrolidone, such as cross-linked polyvinylpyrrolidone.

[0187] The adhesive polymer component of the contact adhesive layer can be any suitable adhesive material, such as a pressure-sensitive adhesive polymer. Polyacrylate pressure-sensitive adhesive polymers are one example and typically include polyacrylates, which are polymers or copolymers of monomers selected from acrylic acid esters and methacrylic acid esters. Other monomers, such as acrylic acid and vinyl acetate, may also be present. In some embodiments, the acrylic polymer is based on an acrylic ester, such as 2-ethylhexyl acrylate (2-EHA) and ethyl acrylate. In some embodiments, the polyacrylate polymer is a polymer or copolymer of a monomer selected from acrylic acid and vinyl acetate. In some embodiments, the acrylic polymer adhesive has pendant carboxyl (—COOH) or hydroxyl (—OH) functional groups. In some embodiments, the acrylic polymer adhesive comprises at least one of polyacrylate, polymethacrylate, derivatives thereof, and copolymers thereof. In some embodiments, the acrylic adhesive is comprised of an acrylate copolymer containing acrylic ester monomers, acrylic acid, and / or vinyl acetate monomers. Copolymers of acrylic acid and vinyl acetate are one example. Acrylate copolymers are sold under the trade name DURO-TAK®, including, but not limited to, DURO-TAK 87-2287, 387-2516, 387-2051, and 387-2074. In some embodiments, the acrylate polymer comprises DURO-TAK 82-2287.

[0188] In some embodiments, the contact adhesive layer comprises at least about 25-80% (w / w) adhesive polymer, based on the weight of the contact adhesive layer (including subranges). In some embodiments, the contact adhesive layer comprises an adhesive polymer or copolymer or blend of polymers and / or copolymers in an amount, including but not limited to, about 35-80%, 30-75%, about 40-75%, about 50-75%, about 60-75%, about 25-70%, about 30-70%, about 40-70%, about 50-70%, about 60-70%, about 25-60%, about 30-60%, about 40-60%, about 50-60%, about 25-50%, about 30-50%, about 40-50%, about 25-40%, about 30-40%, or about 25-30% (w / w). The contact adhesive layer may comprise one or more adhesive polymers or copolymers. In some embodiments, the contact adhesive layer comprises about 5-75% of an individual polymer based on the total weight of the polymers in the contact adhesive layer. In some embodiments, the contact adhesive layer may comprise, but is not limited to, 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% or more of the individual polymers. The individual polymers may be present in amounts of 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% (w / w). In some embodiments, the contact adhesive layer comprises an acrylate polymer in an amount of 50-75% (w / w). In some embodiments, the contact adhesive layer comprises an acrylate polymer in an amount of 60-70% (w / w). In some embodiments, the contact adhesive layer comprises an acrylate polymer in an amount of 63-65% (w / w). In some embodiments, the contact adhesive layer comprises an acrylate polymer in an amount of about 64% (w / w).In some embodiments, the contact adhesive layer comprises an acrylate polymer in an amount of about 64.6% (w / w). In some embodiments, the contact adhesive layer comprises an acrylate polymer in an amount of 64.6% (w / w). The weight percentages provided may represent the weight percentage of the acrylate polymer relative to the total weight of the contact adhesive layer.

[0189] In some embodiments, the contact adhesive layer comprises a copolymer of acrylic acid and vinyl acetate. In some embodiments, the contact adhesive layer comprises Duro-Tak 87-2287 in an amount of about 64.6% (w / w). In some embodiments, the contact adhesive layer comprises Duro-Tak 87-2287 in an amount of 64.6% (w / w). The weight percentages provided may represent the weight percentage of Duro-Tak 87-2287 relative to the total weight of the contact adhesive layer.

[0190] The contact adhesive layer may also include one or more solvents. The contact adhesive layer also includes a contact adhesive solvent composition. In some embodiments, the contact adhesive solvent composition includes one, two, three, or four solvents. In some embodiments, the contact adhesive solvent composition includes triethyl citrate, and in other embodiments, one or both of lauryl lactate and sorbitan monolaurate are additionally present. In some embodiments, the contact adhesive solvent composition consists of, consists essentially of, or consists of triethyl citrate, sorbitan monolaurate, and lauryl lactate.

[0191] In some embodiments, the contact adhesive layer may comprise one or more of methyl laurate, propylene glycol monolaurate, glycerol monolaurate, glycerol monooleate, lauryl lactate, myristyl lactate, and dodecyl acetate. Additional contact adhesive solvent compositions are described in U.S. Patent No. 8,874,879, which is incorporated herein by reference.

[0192] In some embodiments, the contact adhesive layer comprises the contact adhesive solvent composition in an amount of about 5-50% (w / w), based on the weight of the contact adhesive layer (including subranges). In some embodiments, the contact adhesive layer comprises the contact adhesive solvent composition in an amount, including but not limited to, about 5-45%, 5-40%, 5-35%, 5-30%, 5-25%, 10-20, 11-19, 12-18, 13-17, or 14-16% (w / w). Alternatively, the contact adhesive layer comprises the contact adhesive solvent composition in an amount, including but not limited to, about 10% (w / w), or about 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or about 25% (w / w). In some embodiments, the contact adhesive layer comprises the contact adhesive solvent composition in an amount of about 15% (w / w). In some embodiments, the contact adhesive layer comprises the contact adhesive solvent composition in an amount of about 15.6% (w / w). In some embodiments, the contact adhesive layer comprises the contact adhesive solvent composition in an amount of 15.6% (w / w). The weight percentages provided can represent the weight percentage of the contact adhesive solvent composition relative to the total weight of the contact adhesive layer.

[0193] In some embodiments, the contact adhesive solvent composition of the contact adhesive layer includes triethyl citrate. Triethyl citrate can be present in the contact adhesive layer in any suitable amount. For example, the contact adhesive solvent composition of the contact adhesive layer can include triethyl citrate in an amount, including but not limited to, about 1-20% (w / w), about 2-19%, about 3-18%, about 4-17%, about 5-16%, about 5-15%, about 6-15%, about 7-15%, about 8-14%, about 9-13%, or about 9-11% (w / w). Alternatively, the contact adhesive layer can include triethyl citrate in an amount, including but not limited to, about 5% (w / w), or about 6, 7, 8, 9, 10, 11, 12, 13, 14, or about 15% (w / w). In some embodiments, the contact adhesive layer comprises triethyl citrate in an amount of about 10% (w / w). In some embodiments, the contact adhesive layer comprises triethyl citrate in an amount of about 10.5% (w / w). In some embodiments, the contact adhesive layer comprises triethyl citrate in an amount of 10.5% (w / w). The weight percentages provided may represent the weight percentage of triethyl citrate relative to the total weight of the contact adhesive layer.

[0194] In some embodiments, the contact adhesive solvent composition of the contact adhesive layer comprises lauryl lactate. The lauryl lactate can be present in the contact adhesive layer in any suitable amount. For example, the contact adhesive solvent composition of the contact adhesive layer can comprise lauryl lactate in an amount of, but not limited to, about 0.1-10% (w / w), or about 0.5-10%, or about 1-10%, or about 1-5%, or about 2-4% (w / w). Alternatively, the contact adhesive layer can comprise lauryl lactate in an amount of, but not limited to, about 1% (w / w), or about 1.5, 2.0, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.5, or about 5.0% (w / w). In some embodiments, the contact adhesive layer comprises lauryl lactate in an amount of about 3% (w / w). In some embodiments, the contact adhesive layer comprises lauryl lactate in an amount of about 3.1% (w / w). In some embodiments, the contact adhesive layer comprises lauryl lactate in an amount of 3.1% (w / w). The weight percentages provided may represent the weight percentage of lauryl lactate relative to the total weight of the contact adhesive layer.

[0195] In some embodiments, the contact adhesive solvent composition of the contact adhesive layer comprises sorbitan monolaurate. The sorbitan monolaurate can be present in the contact adhesive layer in any suitable amount. For example, the contact adhesive layer can comprise sorbitan monolaurate in an amount of, but not limited to, about 0.1-10% (w / w), or about 0.1-5%, or about 0.5-5%, or about 1-5%, or about 1-3% (w / w). Alternatively, the contact adhesive layer can comprise sorbitan monolaurate in an amount of, but not limited to, about 1% (w / w), or about 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, or about 2.5% (w / w). In some embodiments, the contact adhesive layer comprises sorbitan monolaurate in an amount of about 2% (w / w). In some embodiments, the contact adhesive layer comprises sorbitan monolaurate in an amount of about 2.0% (w / w). In some embodiments, the contact adhesive layer comprises sorbitan monolaurate in an amount of 2.0% (w / w). The weight percentages provided may represent the weight percentage of sorbitan monolaurate relative to the total weight of the contact adhesive layer.

[0196] In some embodiments, the contact adhesive layer further comprises one or more solvents: triethyl citrate, sorbitan monolaurate, or lauryl lactate.

[0197] In some embodiments, the contact adhesive layer is made from an adhesive formulation that does not contain donepezil HCl or donepezil free base. Without being bound by any particular theory, while the contact adhesive layer is not made with donepezil HCl or donepezil free base, donepezil free base may migrate from the drug matrix layer into the contact adhesive layer after preparation of the transdermal delivery system and before administration of the transdermal delivery system to a subject.

[0198] In some embodiments, the contact adhesive layer comprises donepezil free base. In some embodiments, the contact adhesive layer comprises donepezil free base prior to administration of the transdermal delivery system to a subject. The donepezil free base can be present in any suitable amount in the contact adhesive layer. For example, the contact adhesive layer can comprise donepezil free base in an amount, without limitation, of about 0.1-10% (w / w), or about 0.1-5%, or about 0.5-5%, or about 1-5%, or about 1-6%, or about 2-5%, or about 3-5%, or about 4-5%, or about 1-4%, or about 1-3%, or about 1-2%, or about 2-4%, or about 2-3%, or about 3-4% (w / w). Alternatively, the contact adhesive layer may comprise donepezil free base in an amount, without limitation, of about 1% (w / w), or about 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, or about 2.5% (w / w). In some embodiments, the contact adhesive layer comprises donepezil free base in an amount of at least 0.1% (w / w). In some embodiments, the contact adhesive layer comprises donepezil free base in an amount of at least 1% (w / w). In some embodiments, the contact adhesive layer comprises donepezil free base in an amount of about 2% (w / w). In some embodiments, the contact adhesive layer comprises donepezil free base in an amount of about 2.0% (w / w). In some embodiments, the contact adhesive layer comprises donepezil free base in an amount of 1-5% (w / w). In some embodiments, the contact adhesive layer comprises donepezil free base in an amount of 2-4% (w / w). In some embodiments, the contact adhesive layer comprises donepezil free base in an amount of 2-3% (w / w). In some embodiments, the contact adhesive layer comprises donepezil free base in an amount of 2.0% (w / w). Without being bound by any particular theory, the donepezil free base present in the contact adhesive layer is administered to the subject after application of the transdermal delivery system of the present invention to the subject's skin. The weight percentages provided may represent the weight percentage of donepezil free base relative to the total weight of the contact adhesive layer.

[0199] The contact adhesive layer may also include a contact adhesive solvent composition. In some embodiments, the contact adhesive layer includes one or more contact adhesive solvents of a citrate ester, a surfactant, and / or an alpha-hydroxy acid. In some embodiments, the contact adhesive layer includes one or more contact adhesive solvent compositions of triethyl citrate, sorbitan monolaurate, and / or lauryl lactate. In some embodiments, the contact adhesive layer produced does not include a pharmaceutically active agent intended for systemic delivery; for example, the components and / or contact adhesive solvent composition combined to form the contact adhesive layer do not include a base or salt form of the drug, such as donepezil free base or donepezil salt. During use, after the contact adhesive layer is applied to a subject's skin, the base form of the active agent present in the drug matrix layer distributes into the drug matrix solvent composition in the drug matrix layer, then distributes and migrates into the membrane layer solvent composition in the microporous membrane, and then distributes and migrates into the contact adhesive solvent composition for delivery to the subject's skin.

[0200] In some embodiments, the contact adhesive layer optionally comprises highly dispersed silica, e.g., hydrophobic colloidal silica, which can effectively adsorb hydrophobic drugs and other hydrophobic ingredients. The use of hydrophobic colloidal silica as an excipient in a specific percentage (about 3% to about 20%, preferably about 5% to about 10% in the formulation) can control the diffusion of the active ingredient through the matrix during storage. Examples of dispersed silica for use in the composition include, but are not limited to, high-purity amorphous anhydrous colloidal silicon dioxide for use in pharmaceuticals sold under the name AEROSIL®, e.g., AEROSIL® 90, AEROSIL® 130, AEROSIL® 150, AEROSIL® 200, AEROSIL® 300, AEROSIL® 380, AEROSIL® OX50, AEROSIL® TT60 ... IL® MOX80, AEROSIL® COK84, AEROSIL® R202, AEROSIL® R805, AEROSIL® R812, AEROSIL® 812S, AEROSIL® R972, and / or AEROSIL® R974, or any other highly disperse silica, in particular AEROSIL® 200 and / or AEROSIL® R972 can be used as highly disperse silica.

[0201] In some embodiments, the contact adhesive layer comprises at least about 40 wt. % highly dispersed 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. %, all values ​​based on the weight of the entire adhesive layer.

[0202] The contact adhesive layer may further comprise one or more matrix modifiers. Without wishing to be bound by theory, it is believed that the matrix modifiers promote homogenization of the adhesive matrix. Sorption of hydrophilic moieties is a possible mechanism for this process. Thus, known matrix modifiers that are water-absorbing to some degree may be used. For example, possible matrix modifiers include colloidal silicone dioxide, fumed silica, crosslinked polyvinylpyrrolidone (PVP), soluble PVP, cellulose derivatives (e.g., hydroxypropyl cellulose (HPC), hydroxyethyl cellulose (HEC)), polyacrylamide, polyacrylic acid, polyacrylates, or clays such as kaolin or bentonite. An exemplary commercially available fumed silica product is Cab-O-Sil (Cabot Corporation, Boston, Massachusetts). Hydrophilic mixtures such as those described in U.S. Published Patent Application No. 2003 / 0170308 can also be used, such as mixtures of PVP and PEG, or PVP, PEG, and a water-swellable polymer, such as EUDRAGIT® L100-55. In some embodiments, the matrix-modifying agent is individually present in an amount of between about 1-25%, about 2-25%, about 5-25%, about 5-7%, about 7-20%, or about 7-25% by weight of the adhesive matrix (including subranges). In some embodiments, the matrix-modifying agent does not comprise ethylcellulose.

[0203] The contact adhesive layer may also include a copolymer, such as polyvinylpyrrolidone / vinyl acetate copolymer, acrylate / vinyl acetate copolymer, or vinyl acetate / ethylene acetate copolymer. In some embodiments, the copolymer is a vinyl acetate / N-vinylpyrrolidone copolymer, such as the copolymer sold as Plasdone™ S630 (Ashland). In some embodiments, the polyvinylpyrrolidone-vinyl acetate copolymer is a linear random copolymer of n-vinyl-2-pyrrolidone and vinyl acetate. In some embodiments, the copolymer is a 60:40 copolymer of n-vinyl-2-pyrrolidone and vinyl acetate.

[0204] The contact adhesive layer may also comprise polyvinylpyrrolidone (PVP). PVP is a water-soluble polymer composed of N-vinylpyrrolidone monomers and is available in a variety of forms, including cross-linked and non-cross-linked. In some examples herein, cross-linked PVP is included in the contact adhesive layer. In some embodiments, the cross-linked PVP is crospovidone. In some embodiments, the contact adhesive layer further comprises crospovidone.

[0205] Crospovidone can be present in the contact adhesive layer in any suitable amount, including, but not limited to, 1-50% (w / w), 5-25%, 10-20%, 11-19%, 12-18%, 13-17%, or 14-16% (w / w). Alternatively, the contact adhesive layer may contain crospovidone in an amount of, but not limited to, about 19.0% (w / w), or about 19.1, 19.2, 19.3, 19.4, 19.5, 19.6, 19.7, 19.8, 19.9, 20.0, 20.1, 20.2, 20.3, 20.4, 20.5, 20.6, 20.7, 20.8, 20.9, or 21.0% (w / w). In some embodiments, the contact adhesive layer comprises crospovidone in an amount of about 20% (w / w). In some embodiments, the contact adhesive layer comprises crospovidone in an amount of about 19.9% ​​(w / w). In some embodiments, the contact adhesive layer comprises crospovidone in an amount of 19.9% ​​(w / w). The weight percentages provided may represent the weight percentage of crospovidone relative to the total weight of the contact adhesive layer.

[0206] In some embodiments, the contact adhesive layer comprises acrylate-vinyl acetate copolymer in an amount of about 64.6% (w / w), triethyl citrate in an amount of 10.5% (w / w), lauryl lactate in an amount of about 3.1% (w / w), sorbitan monolaurate in an amount of about 2.0% (w / w), and crospovidone in an amount of about 19.9% ​​(w / w). In some embodiments, the contact adhesive layer comprises acrylate-vinyl acetate copolymer in an amount of 64.6% (w / w), triethyl citrate in an amount of 10.5% (w / w), lauryl lactate in an amount of 3.1% (w / w), sorbitan monolaurate in an amount of 2.0% (w / w), and crospovidone in an amount of 19.9% ​​(w / w). The weight percentages provided may represent the weight percentage of each component relative to the total weight of the contact adhesive layer.

[0207] In some embodiments, the present invention provides (1) a backing layer; (2) a separation layer having a top surface and a bottom surface, the top surface being in contact with the backing layer; (3) a drug matrix layer comprising donepezil HCl, donepezil free base, and sodium bicarbonate, wherein the drug matrix layer has a top surface and a bottom surface, the top surface being in contact with the bottom surface of the separation layer, and the donepezil free base is present in an amount of at least 10% (w / w) of the total amount of donepezil free base and donepezil HCl; (4) a membrane layer comprising a microporous membrane, the membrane layer having a top surface and a bottom surface such that the top surface is in contact with the bottom surface of the drug matrix layer; (5) A transdermal delivery system comprising: a contact adhesive layer having a top surface and a bottom surface, the top surface being in contact with the bottom surface of the membrane layer, the contact adhesive layer comprising donepezil free base in an amount of 0.1 to 10% (w / w) of the total weight of the contact adhesive layer. Release liner

[0208] The transdermal delivery system of the present invention may also include a release liner. The release liner may be attached to any other layer of the transdermal delivery system. In some embodiments, the transdermal delivery system includes a release liner that at least partially contacts the contact adhesive layer to protect the contact adhesive layer before application. In some embodiments, the transdermal delivery system also includes a release layer that contacts the bottom surface of the contact adhesive layer.

[0209] The release liner is typically a disposable layer that is removed prior to application of the device to the treatment site. In some embodiments, the release liner preferably does not absorb the components of the contact adhesive layer, including the active agent. In some embodiments, the release liner is impermeable to the components of the contact adhesive layer (including the active agent), preventing release of the components of the contact adhesive layer through the release liner. In some embodiments, the release liner is formed from one or more of a film, a nonwoven, a woven, a laminate, and combinations thereof. In some embodiments, the release liner is a silicone-coated polymer film or paper. In some non-limiting embodiments, the release liner is a silicone-coated polyethylene terephthalate (PET) film, a fluorocarbon film, or a fluorocarbon-coated PET film.

[0210] In some embodiments, the release layer comprises a silicone coating material, a fluorocarbon coating material, or a fluorosilicone coating material. In some embodiments, the release layer comprises a silicone coating material.

[0211] The transdermal delivery systems of the present invention can have a variety of configurations, as shown in Figure 1C, which shows a transdermal delivery system 10 having a backing layer 20 and an adhesive overlay layer 21, a separation layer 30 having a top surface 31 and a bottom surface 32, where top surface 31 comprises an ethyl vinyl acetate coating that has been treated with a high-energy discharge, a drug matrix layer 40 having a top surface 41 and a bottom surface 42, a membrane layer 50 having a top surface 51 and a bottom surface 52, a contact adhesive layer 60 having a top surface 61 and a bottom surface 62, and a release liner 70. VI. Treatment Methods

[0212] Methods for transdermally delivering a therapeutic agent to a subject are provided. In some embodiments, the present invention provides a method for transdermally administering donepezil free base, comprising: (i) removing a release liner from a transdermal delivery system of the present invention; and (ii) adhering the transdermal delivery system to the skin of a subject for a period of up to about 10 days to deliver donepezil free base to the subject.

[0213] In some embodiments, the methods include 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, vascular dementia, normal pressure hydrocephalus, Huntington's disease (HD), and mild cognitive impairment (MCI)). Neurological-related conditions, dementia-related conditions, such as epilepsy, seizure disorders, acute pain, chronic pain, chronic neuropathic pain, etc., may be treated using the systems and methods described herein. Epileptic conditions include complex partial, simple partial, partial with secondary generalization, and generalized - including absence, grand mal (tonic-clonic), tonic, atonic, myoclonic, neonatal, and infantile spasms. Additional specific epilepsy syndromes are juvenile myoclonic epilepsy, Lennox-Gastaut, mesial temporal lobe epilepsy, nocturnal frontal lobe epilepsy, progressive epilepsy with mental retardation, and progressive myoclonic epilepsy. The systems and methods described herein also are useful for treating cerebrovascular diseases, motor neuron diseases (e.g., amyotrophic lateral sclerosis (ALS), spinal motor atrophy, Tay-Sachs disease, Sandoff's disease, familial spastic paraplegia), neurodegenerative diseases (e.g., familial Alzheimer's disease, prion-related diseases, cerebellar ataxia, Friedrich's ataxia, SCA, Wilson's disease, retinitis pigmentosa (RP), ALS, adrenoleukodystrophy, Menkes syndrome, cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), spinal muscular atrophy, familial ALS, muscular dystrophies, Charcot-Marie-Tooth disease, neurofibromatosis, von Hippel-Lindau disease, fragile X syndrome, spastic paraplegia, and the like).paraplesia), psychiatric disorders (e.g., panic syndrome, generalized anxiety disorder, all types of phobic syndromes, mania, manic-depressive disorder, hypomania, unipolar depression, depression, stress disorders, post-traumatic stress disorder (PTSD), somatoform disorders, personality disorders, psychoses, and schizophrenia), and drug dependence (e.g., alcohol, psychostimulants (e.g., crack, cocaine, speed, methamphetamine), opioids, and nicotine), tuberous sclerosis complex, and Waldenburg syndrome syndromes), stroke (e.g., thrombotic, embolic, thromboembolic, hemorrhagic, venoconstrictive, and venous), movement disorders (e.g., Parkinson's disease (PD), dystonia, benign essential tremor, tardive dystonia, tardive dyskinesia, and Tourette's syndrome), ataxia syndromes, disorders of the sympathetic nervous system (e.g., Shy-Drager syndrome, olivopontocerebellar degeneration, striatonigral degeneration, Parkinson's disease (PD), Huntington's disease (HD), Guillain-Barré syndrome, causalgia, complex regional pain syndrome type 1, and Type II and II diabetic neuropathy, and alcoholic neuropathy), cranial neuropathy (e.g., trigeminal neuropathy, trigeminal neuralgia, Meniere's syndrome, glossodigital neuralgia, dysphagia, dysphonia, and cranial nerve palsies), myelopethies, traumatic brain and spinal cord injury, radiation brain injury, multiple sclerosis, postmeningitis syndrome, prion diseases, myelitis, radiculitis, neuropathy (e.g., Guillain-Barré syndrome, diabetes mellitus with dysproteinemia, transthyretin-induced neuropathy) The systems and methods described herein are useful for the treatment and prevention of pain caused by disorders including HIV-associated neuropathy, Lyme disease-associated neuropathy, shingles-associated neuropathy, carpal tunnel syndrome, tarsal tunnel syndrome, amyloid-induced neuropathy, leprosy neuropathy, Bell's palsy, compression neuropathy, sarcoidosis-induced neuropathy, cranial polyneuritis, heavy metal-induced neuropathy, transition metal-induced neuropathy, drug-induced neuropathy), axonal brain injury, encephalopathy, and chronic fatigue syndrome. The systems and methods described herein are also useful for the treatment of multiple sclerosis, particularly relapsing-remitting multiple sclerosis, and for the prevention of relapses in multiple sclerosis and / or relapsing-remitting multiple sclerosis. All of the above disorders can be treated with the systems and methods described herein.

[0214] In some embodiments, compositions and devices comprising donepezil are useful for treating, slowing progression, delaying onset, slowing progression, preventing, providing remission, and ameliorating symptoms of cognitive disorders or diseases. In some embodiments, compositions and devices comprising donepezil are provided to maintain mental function, including, but not limited to, maintaining thinking, memory, speech skills, and / or managing or alleviating one or more behavioral symptoms of cognitive disorders or diseases. In some embodiments, the cognitive disorder is Alzheimer's disease. In some embodiments, the cognitive disorder is Alzheimer's dementia. In some embodiments, compositions and devices comprising donepezil are provided for use in, for example, treating mild, moderate, or severe Alzheimer's disease.

[0215] In some embodiments, therapeutic embodiments are effected by contacting a subject's tissue, eg, skin tissue, with a transdermal delivery system provided herein.

[0216] In some embodiments, therapeutic embodiments are carried out by transdermally administering an active agent to a subject, such as a subject suffering from a CNS disorder, such as Alzheimer's disease and / or dementia. The term "administering" means applying therapeutically, such as by placement of an active agent in such a manner that such agent may be received, e.g., transdermally, and be effective in performing its intended purpose.

[0217] Treatment of a subject using the system can be monitored using methods known in the art. See, for example, Forchetti et al., "Treating Patients with Moderate to Severe Alzheimer's Disease: Implications of Recent Pharmacologic Studies." Prim Care Companion J Clin Psychiatry,7(4):155-161, 2005 (PMID: 16163398). The effectiveness of treatment using the system is preferably evaluated by examining the subject's symptoms in a quantitative manner, for example, by describing a decrease in the frequency of adverse symptoms, behaviors, or attacks, or an increase in the time for persistent worsening of symptoms. In successful treatment, the subject's condition will improve (i.e., the frequency of relapses will decrease or the time to persistent progression will increase).

[0218] Based on the exemplary transdermal delivery systems (also referred to as transdermal devices or devices) described herein, methods for treating appropriate conditions with an active agent are provided. In some embodiments, devices containing an active agent are useful for treating, delaying progression, delaying onset, slowing progression, preventing, providing remission, and ameliorating symptoms of cognitive disorders or diseases and multiple sclerosis. In some embodiments, devices containing an active agent are provided for maintaining mental function, including, but not limited to, maintaining thinking, memory, speech skills, and / or managing or alleviating one or more behavioral symptoms of cognitive disorders or diseases. In some embodiments, the cognitive disorder is Alzheimer's disease. In some embodiments, the cognitive disorder is Alzheimer's dementia. In some embodiments, devices containing donepezil are provided for use in treating mild, moderate, or severe Alzheimer's disease, etc. In other embodiments, devices containing fingolimod are provided for use in treating multiple sclerosis, preventing and / or reducing the frequency of relapses of multiple sclerosis, particularly relapsing-remitting multiple sclerosis.

[0219] In some embodiments, the methods relate to treating a CNS disorder or an autoimmune disorder in a subject in need thereof by contacting the subject's tissue with one or more transdermal delivery systems. The terms "transdermal" and "topical" are used herein in their broadest sense to refer to the administration of an active agent, e.g., memantine or donepezil or fingolimod, to the skin surface or mucosa of an animal, including a human, such that the agent passes through a body surface, e.g., the skin, and enters the individual's bloodstream.

[0220] Alzheimer's disease (AD), the most common cause of late-life dementia, is characterized by cognitive impairment associated with the degeneration of cholinergic neurons. It affects 6-8% of people over the age of 65 and nearly 30% of people over the age of 85 (Sozio et al., Neuropsychiatric Disease and Treatment, 2012, 8:361-368), resulting in the loss of cognitive and behavioral functions. The cause of AD is not yet fully understood. Because AD is associated with decreased levels of several brain neurotransmitters, including acetylcholine (Ach), current treatment involves the administration of cholinesterase inhibitors. Cholinesterase inhibitors inhibit cholinesterase and / or butyrylcholinesterase, thereby reducing the hydrolysis of acetylcholine in the synaptic cleft, thereby increasing acetylcholine levels and improving neurotransmission.

[0221] In some embodiments, the present invention provides a method of treating Alzheimer's disease, comprising applying to the skin of a subject a transdermal delivery system of the present invention to deliver donepezil free base to the subject, thereby treating Alzheimer's disease.

[0222] In some embodiments, the present invention provides a method for transdermal delivery of donepezil free base, comprising securing or directing the securing of a transdermal delivery system of the present invention to the skin of a subject and delivering the base form of the active agent from the system to the skin, wherein (i) the time to reach steady-state flux is at least about 20% faster than a system without a membrane solvent composition in the pores of the microporous membrane, (ii) the system achieves its steady-state equilibrium flux at least 20% faster than a system without a membrane solvent composition in the pores of the microporous membrane, and / or (iii) the active agent diffuses from the system into the skin at least 20% faster than a system without a membrane solvent composition in the pores of the microporous membrane.

[0223] The transdermal devices described herein can be designed for long-term use and / or continuous administration of an active agent. Daily oral doses of 5 mg, 10 mg, and 23 mg of donepezil have been approved by the FDA. It will be appreciated that the total dose of active agent per transdermal device is determined by the size of the device and the loading of the active agent within the adhesive matrix. In one embodiment, the active agent is donepezil in its free base form. Lower drug loadings of donepezil free base can be effective compared to salt forms (e.g., donepezil hydrochloride). The ability to incorporate lower drug loadings to achieve efficacy desirably results in a lower profile (thinner) and / or smaller size for the device, both of which reduce discomfort. In some embodiments, the application period for the transdermal device is between 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 period of application.

[0224] Methods are provided for transdermally delivering donepezil free base to a subject. In the methods, a transdermal delivery system is applied to the skin, and upon application of the transdermal delivery system to the subject's skin, transdermal delivery of donepezil free base occurs, providing a steady-state systemic blood concentration of the drug (or metabolite) that is bioequivalent to oral administration of the therapeutic agent. As discussed below, bioequivalence is confirmed when (a) the 90% confidence intervals for the relative mean Cmax and AUC of the therapeutic agent administered from the transdermal delivery system and via oral delivery are between 0.80 and 1.25 or between 0.70 and 1.43, or (b) the 90% confidence interval for the geometric mean ratio of AUC and Cmax of the therapeutic agent administered from the transdermal delivery system and via oral delivery is between 0.80 and 1.25 or between 0.70 and 1.43.

[0225] Standard PK parameters routinely used to assess the behavior of dosage forms in vivo (i.e., when administered to animal or human subjects) include C (peak concentration of drug in plasma), T (time at which peak drug concentration is achieved), and AUC (area under the plasma concentration vs. time curve). Methods for determining and assessing these parameters are well known in the art. Desirable pharmacokinetic profiles of the transdermal delivery systems described herein include, but are not limited to, the following: (1) a Cmax for the transdermal delivery form of donepezil when assayed in the plasma of a mammalian subject after administration that is bioequivalent to the Cmax for the oral or intravenous delivery form of the drug administered at the same dosage; and / or (2) an AUC for the transdermal delivery form of donepezil when assayed in the plasma of a mammalian subject after administration that is preferably bioequivalent to the AUC for the oral or intravenous delivery form of the drug administered at the same dosage; and / or (3) a Tmax for the transdermal delivery form of donepezil when assayed in the plasma of a mammalian subject after administration that is within about 80-125% of the Tmax for the oral or intravenous delivery form of the drug administered at the same dosage. Preferably, the transdermal delivery system exhibits a PK profile having a combination of two or more of the features (1), (2), and (3) of the preceding sentence. Preferably, the transdermal delivery system exhibits a PK profile having one or both of the features (1) and (2).

[0226] In the field of drug development, the term "bioequivalence" will be readily understood and appreciated by those skilled in the art. Various regulatory agencies have strict standards and tests for assessing whether two drug products are bioequivalent. These standards and tests are commonly used throughout the pharmaceutical industry, and the assessment of bioequivalence is recognized as a standard form of activity in drug development programs in which the characteristics and performance of one product are compared with those of another. In fact, when seeking approval to market certain types of products (such as those evaluated under the FDA's "Abbreviated New Drug Application" process), it is a requirement that the follow-on product be shown to be bioequivalent to the reference product.

[0227] In some embodiments, the method includes providing and / or administering a transdermal delivery system comprising donepezil free base to a subject in a fasted state that is bioequivalent to oral or intravenous administration of the drug (in base or salt form) to a subject in a fasted state, particularly as defined by Cmax and AUC guidelines provided by the U.S. Food and Drug Administration and the corresponding European regulatory agency (EMEA). In some embodiments, the method includes providing and / or administering a transdermal delivery system comprising donepezil free base to a subject in a fasted state that is bioequivalent to oral or intravenous administration of the drug (in base or salt form) to a subject in a non-fasted or fed state. Under U.S. FDA and European EMEA guidelines, two products or methods are bioequivalent if the 90% confidence intervals (CI) for AUC and Cmax are between 0.80 and 1.25 (Tmax measurements are not relevant to bioequivalence for regulatory purposes). The European EMEA previously used a different standard, which required a 90% CI for AUC between 0.80 and 1.25 and a 90% CI between 0.70 and 1.43. Methods for determining Cmax and AUC are well known in the art. VII. Working Examples overview [Example]

[0228] Donepezil HCl polymorph I is characterized by an X-ray diffraction (XRD) pattern with peaks at 9.9, 10.6, 12.7, 13.1, 13.7, 13.9, 14.9, 15.3, 16.1, 16.9, 17.5, 17.6, 18.4, 19.3, 19.8, 19.9, 21.2, 22.0, 22.5, 23.0, 23.6, 23.8, 23.9, 26.5, 28.0, and 29.5±0.2 degrees 2θ. Donepezil HCl polymorphic Form III is characterized by an X-ray diffraction (XRD) pattern with peaks at 6.6, 9.9, 13.0, 15.0, 15.3, 15.7, 16.5, 17.4, 18.1, 18.5, 19.5, 20.1, 20.9, 21.7, 22.3, 22.9, 23.9, 24.7, 26.0, 27.2, 28.2, and 28.6±0.2 degrees 2θ. Example 1 Preparation of a Drug Matrix Layer with Donepezil HCl Polymorph III

[0229] 21.67 kg of triethyl citrate and 6.299 kg of lauryl lactate were mixed with 124.12 kg of ethyl acetate, and then 0.928 kg of ascorbyl palmitate was dissolved using a disperser. 27.79 kg of cross-linked polyvinylpyrrolidone (Kollidon CL-M) was dispersed into the solution and homogenized. 29.64 kg of donepezil hydrochloride polymorph III was added to the homogenized dispersion and mixed using the anchor, turbine, and disperser agitation. The disperser was shut off, and 3.705 kg of sorbitan monolaurate was then added and mixed using the anchor and turbine agitation. The disperser was then restarted, and 5.986 kg of sodium bicarbonate (with a D90 particle size of 20 μm to 100 μm, a molar ratio to donepezil hydrochloride of 1.0:1.0) and 22.15 kg of glycerin were added. Following this, the disperser was turned off again and 147.71 kg of acrylate copolymer (Duro-Tak 387-2287) was added to form the drug matrix wet adhesive formulation.

[0230] The drug matrix wet adhesive formulation was coated onto a release liner and dried to give a 120 g / m 2 A dry coating weight of 1000 mg / kg was obtained, forming a drug matrix dry adhesive formulation. [Table 1] Example 2 Preparation of a Drug Matrix Layer with Donepezil HCl Polymorph III

[0231] Additional drug matrix layers were prepared according to the method of Example 1 using a molar ratio of sodium bicarbonate:donepezil HCl of 0.88:1.0 or 0.92:1.0. Additional drug matrix layers can be prepared according to the method of Example 1 using a molar ratio of sodium bicarbonate:donepezil HCl of 0.95:1.0. [Table 2]

[0232] Although the foregoing invention has been described in some detail by way of illustration and example for purposes of clarity of understanding, those skilled in the art will understand that certain changes and modifications may be practiced within the scope of the appended claims. Also, each reference provided herein is incorporated by reference in its entirety to the same extent as if each reference were individually incorporated by reference. In the event of a conflict between the present application and a reference provided herein, the present application shall control.

Claims

1. 1. A method for preparing a drug matrix layer, comprising: forming a first mixture comprising donepezil HCl polymorph III and sodium bicarbonate, thereby preparing said drug matrix layer.

2. 2. The method of claim 1, wherein the donepezil HCl polymorphic Form III is characterized by an X-ray diffraction (XRD) pattern with peaks at 6.6, 15.0, 16.5, 18.5, 20.1, 21.7, 26.0, and 28.2±0.2 degrees 2θ.

3. 3. The method of claim 1 or 2, wherein the donepezil HCl polymorphic Form III is further characterized by an XRD pattern with peaks at 18.1, 20.9, 22.3, and 27.2±0.2 degrees 2θ.

4. 4. The method of any one of claims 1 to 3, wherein the donepezil HCl polymorphic Form III is further characterized by an XRD pattern with peaks at 9.9, 13.0, 15.3, 15.7, 17.4, 19.5, 22.9, 23.9, 24.7, and 28.6±0.2 degrees 2θ.

5. 5. The method of any one of claims 1 to 4, wherein the donepezil HCl polymorphic Form III is characterized by the XRD pattern substantially as shown in Figure 2.

6. 6. The method of any one of claims 1 to 5, wherein the sodium bicarbonate is present in a molar ratio of at least 0.85 relative to the donepezil HCl.

7. 7. The method of any one of claims 1 to 6, wherein the sodium bicarbonate is present in a molar ratio relative to the donepezil HCl of at least 1.

0.

8. 7. The method of any one of claims 1 to 6, wherein the sodium bicarbonate is present in a molar ratio of 0.88 relative to the donepezil HCl.

9. forming the first mixture comprising donepezil HCl polymorphic Form III and sodium bicarbonate, wherein the sodium bicarbonate is present in a molar ratio of 0.88 to the donepezil HCl. The method of claim 8.

10. 7. The method of any one of claims 1 to 6, wherein the sodium bicarbonate is present in a molar ratio of 0.92 relative to the donepezil HCl.

11. forming the first mixture comprising donepezil HCl polymorphic Form III and sodium bicarbonate, wherein the sodium bicarbonate is present in a molar ratio of 0.92 to the donepezil HCl. The method of claim 10.

12. 8. The method of any one of claims 1 to 7, wherein the sodium bicarbonate is present in a molar ratio of 1.0 relative to the donepezil HCl.

13. forming the first mixture comprising donepezil HCl polymorphic Form III and sodium bicarbonate, wherein the sodium bicarbonate is present in a molar ratio of 1.0 to the donepezil HCl. The method of claim 12.

14. adding triethyl citrate, lauryl lactate, and ethyl acetate to the first mixture; adding ascorbyl palmitate to the first mixture; adding polyvinylpyrrolidone to the first mixture; adding sorbitan monolaurate to the first mixture; adding an acrylate polymer to the first mixture, thereby preparing the drug matrix layer. The method according to any one of claims 1 to 13.

15. coating the first mixture onto a release liner; drying the coated mixture; 15. The method of claim 14, further comprising:

16. A drug matrix layer prepared by the method of any one of claims 1 to 15.

17. 1. A method for preparing a transdermal delivery system, comprising: (i) laminating a microporous membrane layer on top of a contact adhesive layer to form a contact adhesive laminate having a top surface and a bottom surface; (ii) preparing a drug matrix layer, forming a first mixture comprising triethyl citrate, lauryl lactate, and ethyl acetate; adding ascorbyl palmitate to the first mixture; adding polyvinylpyrrolidone to the first mixture; adding donepezil HCl polymorphic Form III to the first mixture; adding sorbitan monolaurate to the first mixture; adding sodium bicarbonate and glycerin to the first mixture, wherein the sodium bicarbonate is present in a molar ratio to the donepezil HCl of at least 0.85; adding an acrylate polymer to the first mixture; coating the first mixture onto a release liner; drying the coated mixture; removing the release liner, thereby preparing the drug matrix layer; (iii) laminating the drug matrix layer onto the top surface of the contact adhesive laminate to form a drug matrix laminate having a top surface and a bottom surface; (iv) laminating a separation layer onto the top surface of the drug matrix laminate to form an active laminate having a top surface and a bottom surface, the separation layer comprising a top surface and a bottom surface, the top surface of the separation layer comprising a coating of ethylene vinyl acetate copolymer, and the bottom surface of the separation layer in contact with the top surface of the drug matrix laminate; (v) laminating polyester fibers onto an adhesive overlay layer comprising an acrylate polymer to form a backing layer having a top surface and a bottom surface; (vi) laminating the bottom surface of the backing layer onto the top surface of the active laminate so that the adhesive overlay layer contacts the top surface of the active laminate; (vii) treating the top surface of the separation layer with a corona discharge treatment to form a treated separation layer; The corona discharge treatment is carried out at a power of 0.10 kW to 0.12 kW and a discharge rate of 2.1 to 2.6 W / ft ２ / min power density, the treated separation layer having a top surface and a bottom surface, the top surface of the treated separation layer having a surface energy of at least 40 dynes; forming a contact adhesive layer such that the bottom surface of the contact adhesive layer contacts a first process liner; (viii) removing the first process liner to expose the bottom surface of the contact adhesive layer; (ix) laminating a release liner onto the bottom surface of the contact adhesive layer, thereby forming the transdermal delivery system.

18. 18. A transdermal delivery system prepared by the method of claim 17.

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