RU2779471C2 - Transdermal donepezil delivery system - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: invention relates to a transdermal delivery system for systematic donepezil delivery. The proposed system contains: a skin-contacting adhesive layer for adhesion of the system to the user’s skin, and a drug reservoir containing (i) acrylate copolymer, (ii) glycerin, and (iii) donepezil base forming by a reaction of donepezil HCl and alkaline salt, where alkaline salt is sodium bicarbonate or potassium bicarbonate. A method for donepezil delivery is also proposed.

EFFECT: system is provided for the treatment of Alzheimer’s disease and achieves transdermal therapeutic agent delivery, which is bioequivalent to oral administration of a therapeutic agent, as well as provides stable and effective release of the agent during administration and has suitable adhesion for long-term administration.

23 cl, 10 dwg, 5 tbl, 5 ex

Description

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] The present application claims priority to U.S. Provisional Application No. 62/504408, filed May 10, 2017; U.S. Provisional Application No. 62/504391, filed May 10, 2017; U.S. Provisional Application No. 62/457794, filed February 10, 2017; U.S. Provisional Application No. 62/444763, filed January 10, 2017; U.S. Provisional Application No. 62/444745, filed January 10, 2017; U.S. Provisional Application No. 62/423133, filed November 16, 2016; U.S. Provisional Application No. 62/367542, filed July 27, 2016; and U.S. Provisional Application No. 62/367502, filed July 27, 2016, each of which is incorporated herein by reference in its entirety.

FIELD OF TECHNOLOGY

[0002] The present description relates to a transdermal delivery system made with a salt of donepezil for systemic delivery of donepezil.

BACKGROUND OF THE INVENTION

[0003] Donepezil is an acetylcholinesterase inhibitor having the chemical structure 2,3-dihydro-5,6-dimethoxy-2-[[1-(phenylmethyl)-4-piperidinyl]methyl]-1 H -inden-1-one:

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

[0004] Donepezil hydrochloride oral tablet ( ^ARICEPT® ) is approved in the US for use in the treatment of Alzheimer's disease-related dementia. Due to the nature of cognitive impairment, oral medications may be associated with patient compliance problems, especially in the case of formulations that must be taken throughout the day. Studies are underway to deliver drugs to patients suffering from cognitive impairment by transdermal, injection, or rectal routes. US Pat. No. 7,858,114 describes a transdermal formulation of donepezil for use in the form of a patch for long-term delivery of an anti-dementia drug. US Pat. No. 2014/0370076 describes a transdermal drug delivery system containing donepezil or a salt thereof, which uses an acrylate-rubber hybrid adhesive produced by a process without the use of n-hexane. US Patent No. 4,895,841 issued to Eisai Co., Ltd. describes cyclic amino compounds including donepezil for use in the treatment of dementia, including senile dementia in Alzheimer's disease, Huntington's chorea, Pick's disease, and ataxia. Other transdermal delivery systems suggest the use of a cover sheet or other rate-limiting membrane to control drug delivery from the transdermal device, see for example US Published Application No. 2010/0178307 which describes the use of the first and second cover sheets. Despite these ideas, donepezil transdermal patches or devices are not available in the US.

[0005] Delivery of drugs against dementia over a long period of time (eg, several days or more) is difficult. Transdermal delivery of essential drugs, including donepezil, can be particularly difficult due to their low skin permeability. In addition, some active agents have poor or low solubility in adhesives and/or other components used in typical transdermal formulations. In addition, there is a need for a stable long-term administration of anti-dementia agents (eg, 1-10 days or more) that provides a stable and effective release of the agent over the period of administration and has suitable adhesion for long-term administration.

[0006] Thus, there is a need for transdermal compositions, devices and methods that overcome these shortcomings.

[0007] The foregoing prior art examples and the limitations associated therewith are illustrative and not restrictive. Other limitations of the prior art will become apparent to those skilled in the art upon reading the description and studying the drawings.

BRIEF DESCRIPTION OF THE INVENTION

[008] The aspects and their embodiments described and illustrated below are exemplary and illustrative, and not limiting.

[0009] In one aspect, a transdermal delivery system is provided for the systemic delivery of donepezil. The system comprises a skin-contact adhesive layer for adhering the system to a user's skin and a drug reservoir (drug reservoir layer) containing (i) a solvent composition containing glycerol and one or more of lauryl lactate, sorbitan monolaurate, and triethyl citrate, and (ii) a base donepezil, formed in situ by the reaction of donepezil HCl and an alkaline salt. In one embodiment, the drug reservoir further comprises an acrylate copolymer.

[0010] In one embodiment, the system further comprises an intermediate layer, which in one embodiment is directly on the contact adhesive layer and is located between the contact adhesive layer and the drug reservoir. In one embodiment, the intermediate layer is a microporous membrane containing a plurality of pores. In another embodiment, the plurality of pores in the microporous membrane comprise a solvent composition containing one or more of triethyl citrate, sorbitan monolaurate, and lauryl lactate.

[0011] In another aspect, a transdermal delivery system is provided for the systemic delivery of donepezil. The system comprises, sequentially from the skin-facing side to the outside, a skin-contacting adhesive layer for adhering the system to the user's skin, wherein the skin-contacting adhesive layer is optionally made from an adhesive composition that does not contain donepezil base or donepezil salt. The intermediate layer is in direct contact with the skin-contacting adhesive layer. On the opposite surface of the intermediate layer is a drug reservoir layer containing glycerol and a donepezil base formed in situ by the reaction of donepezil HCl and an alkaline salt.

[0012] In one embodiment, the drug reservoir further comprises an acrylic acid/vinyl acetate copolymer.

[0013] In other embodiments, the implementation of the transdermal system, in addition, contains the first layer of the substrate, and in contact with the first layer of the substrate is an adhesive coating. The second substrate layer may be in contact with the adhesive coating and with the external environment.

[0014] In one embodiment, the skin-contacting adhesive layer comprises an acrylic acid/vinyl acetate copolymer.

[0015] In another embodiment, the skin-contacting adhesive layer further comprises a cross-linked polyvinylpyrrolidone.

[0016] In another embodiment, the skin-contacting adhesive layer comprises a skin-contacting adhesive layer solvent composition that contains one or more solvents selected from the group consisting of triethyl citrate, sorbitan monolaurate, and lauryl lactate. In another embodiment, the contact adhesive layer solvent composition contains at least two of triethyl citrate, sorbitan monolaurate, and lauryl lactate. In another embodiment, the contact adhesive layer solvent composition comprises triethyl citrate, sorbitan monolaurate, and lauryl lactate.

[0017] In one embodiment, the intermediate layer is a rate-controlling membrane for donepezil base.

[0018] In another embodiment, the rate-controlling membrane is a microporous polypropylene.

[0019] In another embodiment, the interlayer is a non-woven polyester.

[0020] In one embodiment, the alkaline salt in the drug reservoir layer is sodium bicarbonate.

[0021] In another embodiment, the drug reservoir layer further comprises triethyl citrate.

[0022] In another embodiment, the drug reservoir layer further comprises one or both of sorbitan monolaurate and lauryl lactate.

[0023] In another embodiment, the adhesive coating contains a mixture of polyisobutylene and polybutene. In another embodiment, the adhesive coating contains one layer or a single layer of acrylate adhesive.

[0024] In one embodiment, the adhesive coating comprises a first layer and a second layer, wherein the first layer contains a mixture of polyisobutylene, polybutene, and crosslinked polyvinylpyrrolidone, and the second layer contains an acrylic adhesive.

[0025] In another aspect, a composition is provided comprising (i) a donepezil base formed in situ by the reaction of donepezil HCl and an alkaline salt; (ii) glycerol (glycerin); and optionally (iii) an acrylic acid/vinyl acetate copolymer.

[0026] In one embodiment, the drug reservoir contains triethyl citrate.

[0027] In another embodiment, the drug reservoir contains sorbitan monolaurate.

[0028] In another embodiment, the drug reservoir contains a crosslinked polyvinylpyrrolidone.

[0029] In another embodiment, the alkaline salt is selected from the group consisting of sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, sodium triphosphate, sodium hydrogen phosphate, sodium oxylate, sodium succinate, sodium citrate, and sodium salicylate.

[0030] In another aspect, a composition is provided essentially consisting of a donepezil base formed in situ by the reaction of donepezil HCl and sodium bicarbonate; a blend of penetration enhancers of triethyl citrate, sorbitan monolaurate and glycerin; and a polymeric adhesive matrix of crosslinked polyvinylpyrrolidone and an acrylic acid/vinyl acetate copolymer.

[0031] In another aspect, a composition is provided essentially consisting of a donepezil base formed in situ by the reaction of about 5-25 wt.% donepezil HCl and about 1-5 wt.% sodium bicarbonate; about 0-15 wt.% triethylcitrate; about 0-5 wt.% sorbitan monolaurate; about 5-15 wt.% glycerol; about 1-10 wt.% lauryl lactate; about 5-25 wt.% cross-linked polyvinylpyrrolidone and about 30-50 wt.% copolymer acrylate-vinyl acetate.

[0032] In another aspect, a composition is provided essentially consisting of donepezil base in situ by reacting about 10-25 wt% donepezil HCl and about 1-5 wt% sodium bicarbonate; about 5-15 wt.% triethylcitrate; about 0.5-5 wt.% sorbitan monolaurate; about 5-15 wt.% glycerol; about 1-10 wt.% lauryl lactate; about 5-25 wt.% cross-linked polyvinylpyrrolidone and about 30-50 wt.% copolymer acrylate-vinyl acetate.

[0033] In another aspect, a composition is provided essentially consisting of donepezil base in situ by reacting about 14-18 wt% donepezil HCl and about 2-5 wt% sodium bicarbonate; approximately 8-12 wt.% triethylcitrate; about 1.5-2.5 wt.% sorbitan monolaurate; about 9-11 wt.% glycerol; about 1-10 wt.% lauryl lactate; approximately 13-17 wt.% cross-linked polyvinylpyrrolidone; and about 40-42 wt.% acrylate-vinyl acetate copolymer.

[0034] In another aspect, a composition is provided essentially consisting of donepezil base in situ by reacting about 10-18 wt% donepezil HCl and about 1-5 wt% sodium bicarbonate; approximately 8-12 wt.% triethylcitrate; about 1.5-2.5 wt.% sorbitan monolaurate; about 9-11 wt.% glycerol; about 1-10 wt.% lauryl lactate; about 13-17 wt.% cross-linked polyvinylpyrrolidone and about 40-42 wt.% acrylate-vinyl acetate copolymer.

[0035] In another aspect, a transdermal device or composition is provided, comprising compositions as described herein: a rate-controlling membrane or non-woven layer; and a skin-contact adhesive.

[0036] In one embodiment, the rate-controlling membrane is a microporous polypropylene membrane.

[0037] In one embodiment, the microporous membrane has a plurality of pores, wherein the plurality of pores comprise a solvent composition containing one or more of triethyl citrate, sorbitan monolaurate, and lauryl lactate.

[0038] In another embodiment, the skin contact adhesive comprises triethyl citrate, an α-hydroxy acid, or both.

[0039] In another embodiment, the α-hydroxy acid is an ester of lactic acid or glycolic acid.

[0040] In one embodiment, the α-hydroxy acid is lauryl lactate.

[0041] In another aspect, a method of treating Alzheimer's disease is provided, wherein a transdermal delivery system, or composition, or system containing a composition, as described herein, is provided for administration to the skin of a patient.

[0042] In another aspect, a method is provided for delivering a therapeutic agent to an individual, the method comprising providing a transdermal delivery system, as described herein, or a transdermal delivery system containing a composition, as described herein, and using or instructing to use the transdermal delivery system on the skin of the individual. The use provides transdermal delivery of a therapeutic agent that is _{bioequivalent} to oral administration of a therapeutic agent, where bioequivalence is defined as follows: up to 1.43 or from 0.80 to 1.25, or (b) the 90% confidence interval of the ratios of AUC and C _max of the therapeutic agent administered via the transdermal delivery system and via oral delivery is from 0.70 to 1.43 or from 0.80 to 1.25.

[0043] In one embodiment, bioequivalence is determined in healthy individuals.

[0044] In another embodiment, bioequivalence is determined on an empty stomach. In one embodiment, bioequivalence is determined after a meal or not on an empty stomach.

[0045] In another embodiment, bioequivalence is determined using the same dose of therapeutic agent administered orally and transdermally. In another embodiment, the dose of therapeutic agent administered transdermally is in the range of 5%, 10%, or 15% of the dose administered orally.

[0046] In another embodiment, the chronic condition is Alzheimer's disease.

[0047] In another embodiment, application or instruction for use includes application or instruction for use once a week.

[0048] In one embodiment, the transdermal delivery system comprises a dose of donepezil base to provide 0.05-25 mg/24 hours, 0.1-25 mg/24 hours, 1-25 mg/24 hours, or 5-10 mg/24 hours.

[0049] In addition to the illustrative aspects and embodiments described above, the following aspects and embodiments will become apparent from the drawings and from a study of the description below.

[0050] Additional embodiments of the systems, methods and compositions of the present invention, and the like. will become clear from the following description, drawings, examples and claims. As can be understood from the description above and below, each feature described herein and each combination of two or more such features are included within the scope of the present invention, provided that the features included in such combination are not mutually exclusive. In addition, any feature or combination of features may be specifically excluded from any embodiment of the present invention. Additional aspects and advantages of the present invention are presented in the following description and claims, in particular when considered in conjunction with the accompanying examples and drawings.

BRIEF DESCRIPTION OF THE DRAWINGS

[0051] Figures 1A-1D are illustrations of transdermal delivery systems according to several embodiments;

[0052] Figure 2A is a plot of mean plasma donepezil concentration, in ng/mL, versus time, per day, in humans treated with donepezil transdermal delivery system (circles) for 1 week, or 5 mg donepezil administered orally on days 1 and 7 (triangles);

[0053] Figure 2B is a graph showing the mean plasma concentration of donepezil, in ng/mL, over 24 hours after oral administration of a donepezil 5-mg tablet (triangles) and after removal of the donepezil transdermal delivery system (circles);

[0054] Figure 3 is a representation showing the calculated mean plasma donepezil concentration, in ng/mL, in the last week of a 28-day (4-week) treatment period with a transdermal delivery system designed to administer 10 mg/day for a week (solid line), with a new patch applied once a week, and for 28 days via donepezil 10 mg daily oral tablet (dotted line);

[0055] Figure 4 is a bar graph of the number of individuals in the donepezil transdermal delivery system group for 1 week and observed skin irritation after patch removal, where open bars indicate no skin irritation and solid bars indicate mild irritation. skin;

[0056] Figure 5A shows the mean plasma donepezil concentration, in ng/mL, each day at week 5 of a human clinical trial where individuals were treated with donepezil administered from a transdermal patch with a first surface area (solid line) and a second larger area surface (dashed line), and orally administered donepezil, where the plasma concentration of donepezil in patients who were treated orally is indicated by a solid thick line on days 6-7, and the dotted line shows the estimated daily plasma concentration for oral treatment; and

[0057] FIG. 5B is a bar graph showing the number of gastrointestinal adverse events (nausea, vomiting, and diarrhea) reported by individuals in a clinical trial where individuals were treated as described in FIG. 5A; wherein bars filled with dashed lines correspond to individuals with the smaller weekly transdermal patch, bars filled with vertical lines correspond to individuals treated with the larger weekly transdermal patch, and bars filled with horizontal lines correspond to individuals treated with oral donepezil.

DETAILED DESCRIPTION

I. Definitions

[0058] In the following, various aspects are described in more detail. However, such aspects may be implemented in a variety of different forms and should not be construed as being limited to the embodiments set forth herein; rather, these embodiments are provided to make the description detailed and complete, and do not fully describe its scope to those skilled in the art.

[0059] When a range of values is provided, every value between the upper and lower limits of the given range and any other value mentioned or included in this range is assumed to be covered by the present invention. For example, if the range from 1 µm to 8 µm is mentioned, it is understood that the value of 2 µm, 3 µm, 4 µm, 5 µm, 6 µm and 7 µm is also described, as well as the range of values greater than or equal to 1 µm, and the range of values , less than or equal to 8 µm.

[0060] The singular form includes the plural of the objects referred to, unless the context clearly indicates otherwise. Thus, for example, a reference to "polymer" includes one polymer as well as two or more of the same or different polymers, a reference to "excipient" includes one excipient as well as two or more of the same or different excipients, and the like.

[0061] The word "about" immediately preceding a numerical value means a range of plus or minus 10% of that value, e.g., "about 50" means 45 to 55, "about 25,000" means 22,500 to 27,500, etc. unless the context of the invention indicates otherwise or contradicts such interpretation. For example, in a list of numerical values such as "about 49, about 50, about 55", "about 50" means a range of less than half the interval(s) between the preceding and following values, for example, from more than 49.5 to less than 52, 5. Moreover, the terms "less than about" the value or "more than about" the value should be understood in view of the definition of the term "approximately" given in the present description.

[0062] The terms "drug" or "active substance" or "therapeutically active substance" are used interchangeably.

[0063] "Adhesive matrix", as described herein, includes matrices made in one piece, for example, matrices made by solvent dip molding or extrusion, as well as matrices made in two or more parts, which are then pressed or bonded together.

[0064] "Donepezil" as used herein refers to 2,3-dihydro-5,6-dimethoxy-2-[[1-(phenylmethyl)-4-piperidinyl]methyl]-1 H -inden-1 -on.

[0065] The terms "treatment", "therapy", "therapeutic" and the like, as used herein, encompass any medical intervention aimed at a pathological condition, and they include not only the cure of a disease, but the prevention of a disease, control or even steps taken to alleviate the disease or symptoms of the disease.

[0066] The term "skin" as used herein refers to skin or mucosal tissue, including the inner surface of body cavities that have a mucosal lining. The term "skin" should be interpreted to include "mucous tissue" and vice versa.

[0067] The term "therapeutically effective amount", as used herein, refers to an amount of active substance that is sufficient to provide the desired therapeutic effect. The amount that is "effective" varies from individual to individual depending on the age and general health of the individual, the particular active agent or agents, and the like, as known to those skilled in the art.

[0068] The expression "pharmaceutically acceptable" is used herein to refer to compounds, salts, compositions, dosage forms, etc., which, in the opinion of the medical professional, are suitable for use in contact with human and / or other mammalian tissues without excessive toxicity, irritation, allergic response or other problem or complication according to an acceptable benefit/risk ratio. In some aspects, "pharmaceutically acceptable" means approved by a federal or state government regulatory agency or listed in the USP or other generally accepted pharmacopeia for use in mammals (eg, animals) and more specifically in humans.

[0069] The terms "transdermal" and "transdermal delivery" as used herein refer to the administration of an active agent to a body surface of an individual such that the agent passes through the body surface, such as the skin, into the individual's bloodstream. The term "transdermal" includes transmucosal administration, ie. administering the drug to a mucosal surface (eg, sublingual, buccal, vaginal, rectal) of an individual such that the agent passes through the mucosal tissue and into the individual's bloodstream.

[0070] The terms "treatment", "therapy", "therapeutic", etc., as used herein, cover any medical intervention aimed at a pathological condition, and they include not only the cure of a disease, but the prevention of a disease, control or even steps taken to alleviate the disease or symptoms of the disease. For example, with respect to methods of treating a disorder such as Alzheimer's disease, embodiments typically include administering a compound or composition that reduces the frequency or slows the onset of symptoms of a medical condition (e.g., Alzheimer's disease) in an individual relative to an individual who is not administered the compound or composition. This may include reversing, reducing, or stopping the symptoms, clinical signs, and underlying pathology of the condition to improve or stabilize the individual's condition (eg, mental recovery).

[0071] the Compositions of the present invention may contain, essentially consist of or consist of the components described.

[0072] All percentages, parts and ratios are based on the total weight of the topical compositions and all measurements were taken at approximately 25°C unless otherwise indicated.

[0073] While retaining the right to limit or exclude any individual members of any such group, the inclusion of any subranges or combinations of subranges in a group that may be claimed according to a range or in any similar manner may be claimed for less than the full amount described for any reason. In addition, while retaining the right to limit or exclude any individual substituents, analogs, compounds, ligands or groups thereof, or any members of a claimed group, less than the full amount described may be claimed for any reason.

[0074] Throughout this writing, various US patents, patent applications, and publications are cited. The contents of these patents, patent applications, access information (e.g., PUBMED or PUBCHEM accession numbers), and publications in their entirety are incorporated herein by reference for a more complete description of the prior art as known to the skilled artisan at the date of this specification. In the event of a conflict between the cited patents, patent applications and publications and the present specification, the present specification shall govern.

[0075] For convenience, certain terms used in the description, examples and claims are presented in the present description. Unless otherwise defined, all technical and scientific terms used in the present description have the same meaning as usually meant by experts in the field to which the invention pertains.

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

[0076] A transdermal delivery system is contemplated for the systemic delivery of donepezil. The transdermal system typically contains a skin-contact adhesive and a drug reservoir. In one embodiment, the system further comprises an intermediate layer, which is typically a fabric or membrane or other non-adhesive material, sandwiched between the drug reservoir and the skin-contacting adhesive. The compositions of the layers in the system are described below.

[0077]In one embodiment the drug reservoir is a composition containing a mixture of solvents and a donepezil base formedin situ by reaction of donepezil salt and alkaline salt. The drug reservoir is made using a salt form of donepezil, such as donepezil hydrochloride (HCl), and an alkaline salt, which reactin situ to form the donepezil base. The alkali salt may be, for example, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, sodium triphosphate, sodium hydrogen phosphate, sodium oxylate, sodium succinate, sodium citrate or sodium salicylate.

[0078]Composition The solvent in the drug reservoir may contain a hydrophilic solvent in which the salt form of the active substance (eg, donepezil hydrochloride), a penetration enhancer, and other solvents are dissolved. In one embodiment, the hydrophilic solvent for solubilization of the salt form of the active substance is a hydrophilic solvent selected from polyethylene glycol, propylene glycol, glycerol (glycol), acetonitrile, 1-propanol, N,N-dimethylformamide, and dimethyl sulfoxide. In one embodiment, and as illustrated in the illustrative examples of this disclosure, the hydrophilic solvent is glycerol. In some embodiments, an α-hydroxy acid is present as a skin penetration enhancer. α-hydroxy acid enhancers are preferably an ester of lactic acid or glycolic acid and an example is lauryl lactate. In another embodiment, the solvent composition also contains triethyl citrate, and in other embodiments, one or both of glycerol and sorbitan (mono)laurate are also present.

[0079]In one embodiment the drug reservoir is a polymeric adhesive layer. The adhesive layer may be formed from any of a variety of adhesive materials such as pressure sensitive adhesive polymers. An example is polyacrylate pressure-sensitive polymers and typically they contain a polyacrylate which is a polymer or copolymer of a monomer or monomers selected from acrylic acid esters and methacrylic acid esters. Other monomers may be present such as acrylic acid and vinyl acetate. In some embodiments, the acrylic polymer is based on acrylic esters such as 2-ethylhexyl acrylate (2-EHA) and ethyl acrylate. In some embodiments, the polyacrylate polymer is a polymer or copolymer of a monomer or monomers selected from acrylic acid and vinyl acetate. In some embodiments, the acrylic polymer adhesive has prominent carboxyl (-COOH) or hydroxyl (-OH) functional groups. In some embodiments, the acrylic adhesive comprises at least one of polyacrylate, polymethacrylate, derivatives thereof, and copolymers thereof. In some embodiments, the acrylic adhesive comprises an acrylate copolymer containing acrylic ester, acrylic acid, and/or vinyl acetate monomers. One example is a copolymer of acrylic acid and vinyl acetate. Acrylate copolymers are sold under the trade name DURO-TAK^® and include, but are not limited to, DURO-TAK 387-2516, 387-2051, 387-2287 and 387-2074.

[0080] The drug reservoir may also contain a copolymer such as a polyvinylpyrrolidone/vinyl acetate copolymer, an acrylic acid/vinyl acetate copolymer, or a vinyl acetate/ethylene acetate copolymer. In one embodiment, the copolymer is a vinyl acetate/ N -vinylpyrrolidone copolymer, such as the copolymer sold as Plasdone ^™ S630 (Ashland). In another embodiment, the polyvinylpyrrolidone-vinyl acetate copolymer is a linear random copolymer of n-vinyl-2-pyrrolidone and vinyl acetate. In one embodiment, the copolymer is a 60:40 copolymer of n-vinyl-2-pyrrolidone and vinyl acetate.

[0081] The drug reservoir may also contain polyvinylpyrrolidone (PVP). PVP is a water-soluble polymer containing N -vinylpyrrolidone monomer and is available in a variety of forms, including crosslinked and non-crosslinked. In some demonstration examples of the present description, the cross-linked PVP is included in the adhesive matrix of the drug reservoir.

[0082] In some embodiments, the implementation of the drug reservoir contains at least about 25-80 wt.% adhesive polymers relative to the mass of the drug reservoir (including subranges). In some embodiments, the drug reservoir contains at least about 35-80%, at least about 30-65%, at least about 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 at least about 60-70%, at least about 25-60%, at least about 30-60%, at least about 40-60%, at least about 50-60%, at least about 25-50 %, at least about 30-50%, at least about 40-50%, at least about 25-40%, at least about 30-40%, or at least about 25-30% adhesive polymer, or copolymer, or a mixture of polymers and/or copolymers (all percentages in wt.%). It will be understood that the adhesive matrix of the drug reservoir may include one or more or at least one adhesive polymer or copolymer. In some embodiments, the drug reservoir adhesive matrix contains at least about 5-75% individual polymer based on the total weight of polymers in the matrix. In some embodiments, the adhesive matrix of the drug reservoir contains at least about 5-10%, 5-15%, 5-20%, 5-25%, 5-30%, 5-40%, 5-50%, 5 -60%, 5-70%, 5-75%, 10-15%, 10-20%, 10-20%, 10-25%, 10-30%, 10-40%, 10-50%, 10 -60%, 10-70%, 10-75%, 15-20%, 15-25%, 15-30%, 15-40%, 15-50%, 15-60%, 15-70%, 15 -75%, 20-25%, 20-30%, 20-40%, 20-50%, 20-60%, 20-70%, 20-75%, 25-30%, 25-40%, 25 -50%, 25-60%, 25-70%, 25-75%, 30-40%, 30-50%, 30-60%, 30-70%, 30-75%, 40-50%, 40 -60%, 40-70%, 40-75%, 50-60%, 50-70%, 50-75%, 60-70%, 60-75% or 70-75% individual polymer.

[0083] An exemplary drug reservoir contains or essentially consists of a donepezil base formed in situ by the reaction of donepezil HCl and sodium bicarbonate; a solvent composition comprising a hydrophilic solvent, a penetration enhancer, and optionally one or both of triethyl citrate and sorbitan monolaurate; crosslinked polyvinylpyrrolidone; and an acrylic acid/vinyl acetate copolymer. In another illustrative drug reservoir, a composition is provided that contains or essentially consists of a donepezil base formed in situ by the reaction of about 5-25 wt.% or 10-25 wt.% donepezil HCl and about 1-5 wt.% sodium bicarbonate ; about 0-15 wt.% or 5-15 wt.% triethylcitrate; about 0-5 wt.% or 0.5-5 wt.% sorbitan monolaurate; about 5-15 wt.% glycerol; about 1-10 wt.% lauryl lactate; about 5-25 wt.% cross-linked polyvinylpyrrolidone; and about 30-65% by weight or 30-50% by weight of an acrylate-vinyl acetate copolymer. In another example, a composition is provided essentially consisting of a donepezil base formed in situ by the reaction of about 10-18 wt.% or 14-18 wt.% donepezil HCl and about 1-5 wt.% or 2-5 wt.% sodium bicarbonate ; approximately 8-12 wt.% triethylcitrate; about 1.5-2.5 wt.% sorbitan monolaurate; about 9-11 wt.% glycerol; about 1-10 wt.% lauryl lactate; approximately 13-17 wt.% cross-linked polyvinylpyrrolidone; and about 40-42 wt.% acrylate-vinyl acetate copolymer. Penetration enhancer, lauryl lactate may be approximately 0.5-10 wt.%, 0.5-7.5 wt.%, 1-10 wt.%, 1-7 wt.%, 1-5 wt.%, 2-7 wt.%, 2-5 wt.%, or 1.5-5 wt.% or 1.5-4 wt.%.

[0084] The drug reservoir as described herein and above is contemplated for use in a transdermal delivery system, where the system further comprises a skin-contact adhesive. The skin-contacting adhesive layer may be made from any of the adhesive materials described herein and above. In one embodiment, the skin-contacting adhesive layer contains about 50-90 wt.% adhesive polymer or copolymer, or about 55-90 wt.%, or about 60-90 wt.%, about 65-90 wt.%, about 70 -90 wt.%, approximately 75-90 wt.%, or approximately 80-90 wt.%. In one embodiment, the skin contact adhesive comprises an acrylic acid/vinyl acetate copolymer. In another embodiment, the skin-contacting adhesive layer further comprises a polyvinylpyrrolidone, such as a cross-linked polyvinylpyrrolidone.

[0085] The skin-contacting adhesive layer may also contain a mixture of solvents, which may contain a penetration enhancing agent. In some embodiments, the skin-contacting adhesive layer comprises a solvent composition that contains a penetration enhancer and one or both of triethyl citrate and sorbitan monolaurate. In one embodiment, the skin-contacting adhesive layer produced does not include a pharmaceutically active agent intended for systemic delivery, for example, the ingredients combined to form the skin-contacting adhesive layer do not include a donepezil base or a donepezil salt. However, the skin-contacting adhesive layer, when manufactured as a transdermal delivery system and stored for some period of time and/or during use, contains a pharmaceutically active agent intended for systemic delivery, since the agent will diffuse from the adhesive matrix of the drug reservoir into the contact with skin adhesive layer.

[0086] The penetration or absorption enhancer in either or both of the skin-contacting adhesive layer and the drug reservoir can be selected from a wide range of such compounds known in the art. In some embodiments, penetration enhancers for use in the adhesive matrix include, but are not limited to, methyl laurate, propylene glycol monolaurate, glycerol monolaurate, glycerol monooleate, lauryl lactate, myristyl lactate, and dodecyl acetate. Additional penetration enhancers are described in US Pat. No. 8,874,879, which is incorporated herein by reference. It will be appreciated that the compositions described herein may include one or more or at least one penetration enhancer. In some embodiments, a penetration or absorption enhancer is included in an amount of about 1-10%, about 2-5%, about 2-10%, based on the weight of the adhesive matrix (including subranges). In other embodiments, the penetration enhancer is present in the drug reservoir and/or contact adhesive layer in an amount of about 0.5-10 wt.%, 0.5-7.5 wt.%, 1-7 wt.%, 1-5 wt.%, 2-7 wt.%, 2-5 wt.%, or 1.5-5 wt.% or 1.5-4 wt.%.

[0087] Any or both of the skin-contacting adhesive layer and drug reservoir may further include one or more matrix modifiers. Without being bound by theory, it is believed that the matrix modifier promotes homogenization of the adhesive matrix. A possible mechanism of this process is the sorption of hydrophilic parts. Thus, known matrix modifiers which absorb water to some extent can be used. For example, possible matrix modifiers include colloidal silica, fumed silica, cross-linked polyvinylpyrrolidone (PVP), soluble PVP, cellulose derivatives (e.g., hydroxypropyl cellulose (HPC), hydroxyethyl cellulose (HEC)), polyacrylamide, polyacrylic acid, polyacrylic acid salt, or clay such like kaolin or bentonite. An exemplary commercial fumed silica product is Cab-O-Sil (Cabot Corporation, Boston, Mass.). It is also possible to use hydrophilic mixtures as described in US Published Application No. 2003/0170308, for example, mixtures of PVP and PEG, or PVP, PEG and a water-swellable polymer such as the polymethacrylate-based copolymers sold under the trade name EUDRAGIT, and, in in particular ^EUDRAGIT® L100-55.

[0088] In some embodiments, the matrix modifier is included individually in the contact adhesive layer in an amount of about 1-40%, about 10-30%, about 15-25%, about 5-7%, about 7-20%, or about 7 -25% based on the weight of the adhesive matrix (including subranges), including at least about 3%, for example, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, about 20% or more, by weight, where all values are given relative to the mass of the entire adhesive contact layer. In some embodiments, the implementation of the matrix modifier does not include ethylcellulose.

[0089] Any or both of the skin-contacting adhesive layer and drug reservoir may further include other conventional additives such as adhesives, antioxidants, cross-linking or curing agents, pH adjusters, pigments, dyes, refractive particles, conductive materials, antimicrobial agents , opacifiers, gelling agents, viscosity modifiers or thickeners, stabilizers, and the like, as is known in the art. In embodiments where adhesion is to be reduced or eliminated, conventional tackifiers may also be used. Other agents, such as antimicrobials, may also be added to prevent storage damage, i. to inhibit the growth of microorganisms such as yeast and mold. Suitable antimicrobials are typically selected from the group consisting of methyl and propyl esters of p-hydroxybenzoic acid (ie, methyl and propyl paraben), sodium benzoate, sorbic acid, imidourea, and combinations thereof. These additives and their amounts are chosen such that they do not significantly interfere with the desired chemical and physical properties of the adhesive and/or active agent.

[0090] Any or both of the skin-contacting adhesive layer and drug reservoir may also contain emollient additives to minimize or eliminate the possibility of skin irritation and/or skin damage due to the drug, enhancer, or other components of the composition. Suitable emollient additives include, for example: α-tocopherol; monoamine oxidase inhibitors, in particular phenyl alcohols such as 2-phenyl-1-ethanol; glycerol; salicylic acids and salicylates; ascorbic acids and ascorbates; ionophores such as monensin; amphiphilic amines; ammonium chloride; N-acetylcysteine; cis-urocanoic acid; capsaicin; chloroquine and corticosteroids.

[0091]A transdermal delivery system containing a drug reservoir and a skin-contacting adhesive may have various configurations, and several non-limiting examples are shown inFig.1A-1D. On theFig.1A illustrated transdermal delivery systemten,containing storage tank12 drug and contact adhesivefourteen, separated by a rate-controlling membrane or a non-rate-controlling material such as a tie layer consisting of non-woven polyester or polypropylene,16. There is also a backingeighteen and protective filmtwenty. Fig.1B a second embodiment of a transdermal delivery system is illustrated22,containing the first drug reservoir24 and a second drug reservoir26wherein the first and second drug reservoirs are separated by a non-rate-controlling material such as a tie layer containing non-woven polyester or polypropylene,28. Contact adhesive layerthirty provides adhesion of the system to the user's skin, where the control membrane32 controls the release of the therapeutic agent from the second drug reservoir into the contact adhesive and ultimately onto the user's skin. There is also a protective film34 and substrate36.On thefig.1C presents another embodiment of a transdermal delivery system40containing a drug reservoir42 and contact adhesive layer44, which ensures that the system adheres to the user's skin. Also included is a backing46 and protective film48.

[0092] FIG. 1D shows another embodiment of a transdermal delivery system for systemic delivery of donepezil base. The system 50 comprises, sequentially from the skin side 52 ' to the outer environmental side 54 ', a skin-contacting adhesive layer 56 for adhering the system to the user's skin. In one embodiment, the skin-contacting adhesive layer to be produced is made from an adhesive formulation that does not contain a donepezil base or a donepezil salt. In direct contact with the skin-contacting adhesive layer is the intermediate layer 58' . The interlayer can be, for example, a nonwoven polyester material or a drug release rate controlling membrane such as microporous polyethylene or polypropylene. The intermediate layer has opposite sides: a skin-facing side (which contacts the skin-contacting adhesive layer 56 ) and an environment-facing side. The drug reservoir 60 is located on the outer side of the intermediate layer. The drug reservoir contains donepezil HCl and an alkaline salt. These components react in situ to form the donepezil base in the drug reservoir, which is delivered to the user after application of the system to the skin. In contact with the drug reservoir layer is a first backing layer 62 , and in contact with the first backing layer is an optional adhesive outer layer 64 . An optional second backing layer 66 is in contact with the adhesive outer layer and with the outside environment. In one embodiment, the optional adhesive outer layer 64 comprises two different adhesive layers, for example, a first layer of polyisobutylene and polybutene with or without crosslinked polyvinylpyrrolidone, and a second layer of acrylic adhesive. In another embodiment, the optional adhesive outer layer 64 comprises a single layer of acrylate adhesive.

[0093] Thus, in one embodiment, a transdermal delivery system is provided for the systemic delivery of donepezil base. The system comprises, sequentially from the side facing the skin to the external environment, a skin-contacting adhesive layer for adhering the system to the user's skin, a skin-contacting adhesive layer, optionally produced from an adhesive composition that does not contain donepezil base or donepezil salt. The intermediate layer is in direct contact with the skin-contacting adhesive layer. On the opposite surface of the intermediate layer is a drug reservoir containing a solvent composition and a donepezil base formed in situ by the reaction of donepezil HCl and an alkaline salt. In one embodiment, the solvent composition contains one or more of triethyl citrate, a surfactant, and a penetration enhancer. In a preferred embodiment, the solvent composition contains triethyl citrate, a surfactant, a penetration enhancer, in the form of an α-hydroxy acid. In one embodiment, the drug reservoir contains an adhesive, which may be an acrylic acid/vinyl acetate copolymer.

[0094] The interlayer, also referred to as a woven layer, membrane, or tie layer, may be formed from any suitable material, including, but not limited to, polyesters, vinyl acetate polymers and copolymers, polyethylenes, and combinations thereof. In one embodiment, the interlayer is a non-woven layer of polyester fibers, such as a film sold under the trade name Reemay® (Kavon Filter Products Co.). In some embodiments, the implementation of the intermediate layer does not affect the rate of release of the active substance from the adhesive layers. In another embodiment, the intermediate layer is a rate-controlling membrane for donepezil base.

[0095] In one embodiment, the intermediate layer is a microporous membrane containing a plurality of pores. In exemplary transdermal systems prepared as described in the Working Examples, a plurality of pores in the microporous membrane contain a solvent composition. In one embodiment, the composition of solvents in the pores of the microporous membrane contains one or more solvents present in any or both of the drug reservoir and the contact adhesive. For example, an exemplary solvent composition contained in the pores of the microporous membrane is one or more of triethyl citrate, a surfactant, a penetration enhancer, in the form of an α-hydroxy acid. Another exemplary embodiment is a solvent composition containing one or more of triethyl citrate, sorbitan monolaurate, and lauryl lactate. In one embodiment, the solvent composition contains 40-80 wt.% triethylcitrate, 5-40 wt.% lauryl lactate and 5-25 wt.% sorbitan laurate. In another embodiment, the solvent composition contains 50-75 wt.% or 55-70 wt.% triethylcitrate, 10-35 wt.% or 15-30 wt.% lauryl lactate and 8-20 wt.% or 10-15 wt.% sorbitan laurate. In one embodiment, the solvent composition contained within the pores of the microporous membrane does not include the hydrophilic solvent present in the drug reservoir. In one embodiment, the solvent composition contained in the pores of the microporous membrane does not include glycerol.

[0096] The microporous membrane can be pretreated with a solvent or solvent composition such that its pores are saturated, filled, or partially filled with the solvent or solvent composition. In one embodiment, the microporous membrane is a polypropylene microporous membrane and may have an average pore size ranging from about 0.001 µm to about 100 µm, from about 1 µm to about 10 µm, from about 0.010 µm to about 0.100 µm, or from about 0.040 µm to about 0.050 µm. For example, the average pore size may be approximately 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 implementation of the microporous membrane has an average pore size of approximately 0.043 microns. In one embodiment, the microporous membrane is a polypropylene microporous membrane and has a porosity in the range of about 30% to about 50%, about 35% to about 45%, or about 40% to about 42%. For example, a microporous membrane may have a porosity of approximately 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49% or 50%.

[0097]In one embodiment adhesive outer layer in the delivery system according tofig.1D contains a mixture of polyisobutylene and polybutene. In another embodiment, the adhesive outer layer comprises a first layer and a second layer, the first layer containing a mixture of polyisobutylene, polybutene and crosslinked polyvinylpyrrolidone, and the second layer containing an acrylic adhesive. Polyisobutylene is a vinyl polymer containing isobutylene monomer. Polybutene is a viscous, non-drying liquid polymer obtained by copolymerizing 1- and 2-butene with a small amount of isobutylene. In some embodiments, the polybutene has a molecular weight of about 750-6000 Daltons, preferably about 900-4000 Daltons, and preferably about 900-3000 Daltons. In some embodiments, the mixture contains a mixture of polybutene with polyisobutylene in an amount of about 40 percent by weight. More commonly, polybutene is present in the polyisobutylene mixture in an amount of 20-50 percent by weight or 25-45 percent by weight. In another embodiment, the adhesive outer layer is a single layer and contains an acrylate copolymer that forms a single layer adhesive outer layer. An exemplary acrylate copolymer is DuroTak^® 387-2052.

[0098] The transdermal delivery system comprises a backing layer that provides a structural element to hold or support the underlying adhesive layer(s). The substrate layer may be formed from any suitable material as is known in the art. In some embodiments, the implementation of the substrate layer is cover. In some embodiments, the substrate is preferably impermeable or substantially impervious to moisture. In one illustrative embodiment, the barrier layer has a water vapor transmission rate of less than about 50 g/m ² -day. In some embodiments, the implementation of the substrate layer is preferably inert and/or does not absorb the components of the adhesive layer, including the active substance. In some embodiments, the backing layer preferably prevents release of adhesive layer components through the backing layer. The backing layer may be flexible or inflexible. Preferably, the backing layer is at least partially flexible such that the backing layer is capable of at least partially conforming to the shape of the skin where the patch is applied. In some embodiments, the backing layer is flexible so that the backing layer conforms to the shape of the skin where the patch is applied. In some embodiments, the backing layer is flexible enough to maintain contact in the application area during movement, such as skin movement. In general, the material used for the backing layer should allow the device to conform to the contours of the skin or other application area, and should be worn comfortably over areas of the skin, such as joints or other fold areas, that are normally subjected to mechanical stress with little or no chance that the device will peel off the skin due to differences in the flexibility or elasticity of the skin or device.

[0099] In some embodiments, the substrate layer is formed from one or more of a film, a nonwoven fabric, a woven fabric, a multilayer plate, and combinations thereof. In some embodiments, the film is a polymer film containing one or more polymers. Suitable polymers are known in the art and include elastomers, polyesters, polyethylene, polypropylene, polyurethanes and polyether amides. In some embodiments, the backing layer is formed from one or more of polyethylene terephthalate, various nylons, polypropylene, metallized polyester films, polyvinylidene chloride, and aluminum foil. In some embodiments, the backing layer is a fabric formed from one or more polyesters such as polyethylene terephthalate, polyurethane, polyvinyl acetate, polyvinylidene chloride, and polyethylene. In one specific, but non-limiting embodiment, the substrate layer is formed from a multilayer polyester film. One particular multilayer polyester film is a polyethylene-polyester multilayer plate, such as the multilayer plate sold under the name SCOTCHPAK ^TM #9723.

[0100] In some embodiments, the device includes a protective sheet at least partially in contact with at least the adhesive layer to protect the adhesive layer prior to use. The protective sheet is typically a discard layer that is removed prior to application of the device to the treatment area. In some embodiments, the implementation of the protective sheet preferably does not absorb the components of the adhesive layer, including the active agent. In some embodiments, the backsheet is preferably impervious to the components of the adhesive layer (including the active agent) and prevents the components of the adhesive layer from passing through the backsheet. In some embodiments, the protective sheet is formed by one or more of a film, a nonwoven fabric, a woven fabric, a laminated plate, and combinations thereof. In some embodiments, the protective sheet is a silicone-coated polymer film or paper. In some non-limiting embodiments, the protective sheet is a silicone-coated polyethylene terephthalate (PET) film, a fluorocarbon film, or a fluorocarbon-coated PET film.

[0101] The thickness and/or size of the device and/or adhesive matrices can be determined by a person skilled in the art, taking into account at least wear factors and/or the required dose. It will be understood that the application area of the device will affect wear due to the available size of the application area and the application of the application area (eg, the need for mobility to maintain movement). In some embodiments, the implementation of the device and/or adhesive matrix has a thickness of approximately 25-500 microns. In some embodiments, the implementation of the device and/or adhesive matrix has a thickness of approximately 50-500 microns. In some embodiments, the implementation of the patch has a size in the range of approximately 16 cm ² -225 cm ² . It will be understood that the indicated thickness and dimension are illustrative only and the actual thickness and/or dimension may be thinner/less or thicker/larger depending on the particular composition.

[0102] The manufacture of the transdermal delivery system is typically carried out by those skilled in the art and involves casting or extruding each of the adhesive words onto a suitable film such as a backsheet or other layer of the transdermal delivery system and drying as necessary to remove solvents and/or or volatile compounds. The layers of the transdermal delivery system may be layered on top of each other to form the final system.

[0103] Transdermal delivery systems and adhesive reservoir matrices were prepared to illustrate the embodiments described herein. Examples 1-3 provide illustrative compositions and delivery systems. As described in Example 1, the transdermal delivery system comprises a drug reservoir and a contact adhesive with a rate controlling membrane located between the drug reservoir and the contact adhesive, as shown in Figure 1A . A drug reservoir in the form of a solid monolithic adhesive reservoir was prepared using an acrylic acid/vinyl acetate copolymer adhesive with a solvent mixture that included a penetration enhancer. In one embodiment, the solvent mixture contains triethyl citrate, lauryl lactate, and sorbitan monolaurate. The drug reservoir contained approximately 5 wt% donepezil hydrochloride and sodium bicarbonate to form the donepezil base in situ . A contact adhesive layer was prepared containing the same acrylic acid/vinyl acetate copolymer adhesive, as well as triethyl citrate, lauryl lactate and ethyl acetate. A rate-controlling membrane for controlling the diffusional release of donepezil base from the drug reservoir separated the drug reservoir and the contact adhesive.

[0104] As described in Examples 2 and 3, transdermal delivery systems were prepared and contained a drug reservoir adhesive matrix and a skin-contact adhesive layer separated by an intermediate layer. The adhesive matrix of the drug reservoir in exemplary systems contained an adhesive acrylic acid/vinyl acetate copolymer and in one example further included crosslinked polyvinylpyrrolidone (Example 2). The acrylic acid/vinyl acetate copolymer was added to a solvent mixture that contained a penetration enhancer (in this embodiment, the solvent mixture was triethyl citrate, sorbitan monolaurate, lauryl lactate and glycerin), donepezil hydrochloride and sodium bicarbonate. The skin-contacting adhesive layer contained sorbitan monolaurate, triethyl citrate and lauryl lactate, as well as an acrylic acid/vinyl acetate copolymer. In these exemplary delivery systems, a microporous membrane to control the rate of release of donepezil base from the drug reservoir adhesive matrix was layered on one side of the rate controlling membrane that was sandwiched between the drug reservoir adhesive matrix and the skin-contacting adhesive. The protective film and substrate were layered to form the final delivery system.

[0105] Thus, in one embodiment, a composition is provided comprising an adhesive matrix comprising or essentially consisting of a donepezil base formed in situ by the reaction of donepezil HCl and sodium bicarbonate; a solvent composition containing triethyl citrate, sorbitan monolaurate and glycerin; and a polymeric adhesive matrix of crosslinked polyvinylpyrrolidone and an acrylic acid/vinyl acetate copolymer. In another embodiment, a composition is provided comprising an adhesive matrix comprising or essentially consisting of a donepezil base formed in situ by the reaction of about 10-25 wt% donepezil HCl and about 1-5 wt% sodium bicarbonate; about 5-15 wt.% triethylcitrate; approximately 0.5-5 wt.% sorbitan monolaurate; about 5-15 wt.% glycerol; about 5-25 wt.% cross-linked polyvinylpyrrolidone; and about 30-50% by weight of an acrylate-vinyl acetate copolymer. In another embodiment, a composition is provided comprising an adhesive matrix comprising or essentially consisting of a donepezil base formed in situ by the reaction of about 14-18 wt% donepezil HCl and about 2-5 wt% sodium bicarbonate; approximately 8-12 wt.% triethylcitrate; about 1.5-2.5 wt.% sorbitan monolaurate; about 9-11 wt.% glycerol; approximately 13-17 wt.% cross-linked polyvinylpyrrolidone; and about 40-42 wt.% acrylate-vinyl acetate copolymer.

[0106] The described compositions are intended for use in a transdermal delivery system for the systemic delivery of donepezil. Adhesive compositions are formulated using the salt form of donepezil and a weak base (alkaline salt) to form in situ the base form of donepezil, which is delivered through the skin for systemic uptake. The transdermal delivery system also contains one or more of triethyl citrate, lauryl lactate, glycerol, sorbitan laurate, and ethyl acetate in the drug reservoir, and one or more of triethyl citrate, lauryl lactate, sorbitan laurate, and ethyl acetate in a skin contact adhesive. In one embodiment, each of the drug reservoir and contact adhesive contains one or more of triethyl citrate, lauryl lactate, and sorbitan laurate. In one embodiment, the skin contact adhesive does not contain glycerin. In another embodiment, the transdermal system comprises a microporous membrane with multiple pores that contain, are filled or partially filled with, or saturated with one or more solvents that are the same as the solvents in one or both of the drug reservoir and the contact adhesive. In one embodiment, the plurality of pores in the microporous membrane comprise a solvent composition that contains one or more of triethyl citrate, lauryl lactate, and sorbitan laurate. Triethyl citrate may be present in the drug reservoir, microporous membrane pores and/or contact adhesive in an amount of about 1-20 wt.%, 2-25 wt.%, 5-15 wt.%, 5-12 wt.%, 7-15 wt.%, 7-12 wt.%, 8-12 wt.%, 9-12 wt.%, 1-8 wt.%, 1-6 wt.%, 1-5 wt.%, 1.5- 5 wt.%, 2-5 wt.% or 2.5-5 wt.% or 2.5-4.5 wt.%. Ethyl acetate may be present in the drug reservoir, microporous membrane dust and/or contact adhesive in an amount of about 25-60 wt.%, where in one embodiment, more ethyl acetate is present in the drug reservoir than in the contact adhesive, where the drug reservoir contains in 1.2, 1.3, 1.4, 1.5, 1.6, 1.7 or 1.8 times more ethyl acetate than the contact adhesive layer. Sorbitan laurate may be present in the drug reservoir, microporous membrane pores, and/or contact adhesive in an amount of about 0.01-5 wt.% or 0.1-5 wt.%, where in one embodiment, sorbitan laurate is present in the drug reservoir and in the contact adhesive in the same amounts (on a w/w basis of the total amount in each layer individually, for example, the percentage by weight in the drug reservoir layer is the same as the percentage by weight in the contact adhesive layer). In another embodiment, the drug reservoir, microporous membrane pores and/or contact adhesive contain lauryl lactate in an amount of approximately 0.1-10 wt.%, 0.5-8 wt.% or 0.5-7 wt.%, 1- 7 wt.%, 1-5 wt.%, 1.5-5 wt.%, 2-5 wt.%, 2.5-5 wt.%, 0.25-5 wt.%, 0.5- 5 wt.% or 0.5-4 wt.%, 0.5-4.5 wt.%. In one embodiment, the drug reservoir contains an amount of lauryl lactate equal to or within the range of about 0.5%, 1%, 5 wt.%, 10 wt.%, 15 wt.%, or 20 wt.% of the amount of lauryl lactate present in the contact adhesive layer.

III. Method of treatment

[0107] Based on the exemplary compositions and transdermal delivery systems (also referred to as transdermal devices or devices) described herein, a method for treating a suitable condition with donepezil is provided. In some embodiments, compositions and devices containing donepezil are useful in treating, delaying progression, delaying onset, slowing progression, preventing, providing remission, and improving symptoms of cognitive impairment or disease. In some embodiments, donepezil-containing compositions and devices are provided to preserve mental function, including, but not limited to, at least one of preserving thinking, memory, speech, and controlling or alleviating one or more behavioral symptoms of a cognitive disorder or disease. . In some embodiments, the implementation of the cognitive disorder is Alzheimer's disease. In specific embodiments, the cognitive impairment is Alzheimer's dementia. In some embodiments, donepezil-containing compositions and devices are provided for use in treatment, etc. mild, moderate or severe Alzheimer's disease.

[0108] Alzheimer's disease is the most common cause of senile dementia and is characterized by cognitive impairment due to the degeneration of cholinergic neurons. Alzheimer's disease affects 6-8% of people aged 65 years and almost 30% of people aged 85 years (Sozio et al. , Neurophsychiatric Disease and Treatment , 2012, 8:361-368), involving cognitive decline and behavioral abilities. The causes of Alzheimer's disease are not yet fully understood. Since Alzheimer's disease is associated with reduced levels of several cerebral neurotransmitters, including acetylcholine (Ach), current treatments include the administration of cholinesterase inhibitors. Cholinesterase inhibitors reduce the hydrolysis of acetylcholine in the synaptic cleft by inhibiting cholinesterase and/or butyrylcholinesterase, resulting in increased levels of acetylcholine leading to improved neurotransmission (ibid.).

[0109] The transdermal devices described herein may be designed for long-term use and/or continuous administration of an active agent. FDA-approved oral daily doses of donepezil are 5 mg, 10 mg, and 23 mg. It will be appreciated that the total dose of active agent per transdermal device will be determined by the size of the device and the drug loading of the adhesive matrix. In one embodiment, the active agent is donepezil in free base form. Compared to the salt form (eg, donepezil hydrochloride), donepezil base may benefit from a lower drug load. The ability to include a lower drug load to achieve efficacy results in a lower device profile (thickness) and/or smaller device size, both of which are desirable to reduce discomfort. In some embodiments, the period of use of the transdermal device is about 1-10 days, 1-7 days, 1-5 days, 1-2 days, 3-10 days, 3-7 days, 3-5 days, 5-10 days, and 5-7 days inclusive. In some embodiments, the active agent is released from the adhesive matrix in a continuous and/or sustained release over the period of application.

[0110] A method for delivering donepezil base transdermally to an individual is provided. In the method, the transdermal delivery system is applied to the skin, and when the transdermal delivery system is applied to the skin of an individual, donepezil base is delivered transdermally, providing a systemic concentration of the substance (or metabolite) in the blood, which in a steady state is biologically equivalent to oral administration of a therapeutic agent. As discussed below, bioequivalence is defined as follows: (a) The 90% confidence interval of the respective mean _Cmax and AUC of the therapeutic administered via the transdermal delivery system and via oral delivery is 0.7 to 1.43 or 0.80 to 1 ,25, or (b) 90% confidence interval of the geometric mean ratios of AUC and C _max of the therapeutic agent administered via the transdermal delivery system and via oral delivery is from 0.7 to 1.43 or from 0.80 to 1.25 .

[0111] Standard PK parameters commonly used to assess the behavior of a dosage form in vivo (in other words, when administered to an animal or human) include C _max (maximum plasma drug concentration), T _max (time when maximum drug concentration is reached) and AUC (area under the plasma concentration versus time curve). Methods for determining and evaluating these parameters are well known in the art. The desired pharmacokinetic profile of the transdermal delivery systems described herein includes, but is not limited to, the following: (1) C _max for the transdermally delivered form of donepezil when assessed in mammalian plasma after administration, which is bioequivalent to the C _max for the orally delivered or intravenously delivered form drug administered in the same dosage; and/or (2) an AUC for the transdermally delivered form of donepezil, as measured in mammalian plasma after administration, which is preferably bioequivalent to the AUC for the orally delivered or intravenously delivered form of the drug administered at the same dosage; and/or (3) T _max for the transdermally delivered form of donepezil, as measured in mammalian plasma after administration, which is in the range of about 80-125% of the T _max for the orally delivered or intravenously delivered 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/or (3) described in the previous sentence. Alternatively, the transdermal delivery system exhibits a PK profile having one or both of features (1) and (2).

[0112] In the field of pharmaceutical development, the term "bioequivalence" is well understood and recognized by those skilled in the art. Various regulatory bodies have specific criteria and tests for assessing whether two drug products are bioequivalent. These criteria and tests are often used in the pharmaceutical industry, and bioequivalence assessment is recognized as a standard form of practice in drug development programs where the performance and efficacy of one product is compared with that of another product. Indeed, approval for market release of certain types of products (eg, products evaluated under the FDA's "Abbreviated New Drug Application") requires that the improved product be shown to be bioequivalent to the reference product.

[0113] In one embodiment, the method comprises providing and/or administering a transdermal delivery system comprising donepezil base to an individual on an empty stomach, which is bioequivalent to administering the agent (in base or salt form) orally or intravenously to an individual also on an empty stomach, specifically as defined by the guidelines. in relation to C _max and AUC given by the US Food and Drug Administration and the relevant European regulatory authority (EMEA). In another embodiment, the method comprises providing and/or administering a transdermal delivery system containing donepezil base to an individual on an empty stomach, which is bioequivalent to administering the agent (in base or salt form) orally or intravenously to the individual, also in a fed or fasted state. According to US FDA and European EMEA guidelines, two products or methods are bioequivalent if the 90% confidence interval (CI) for AUC and C _max is between 0.80 and 1.25 (T _max values are not significant for bioequivalence for regulatory purposes). The European EMEA previously used a different standard which required a 90% CI for an AUC of 0.80 to 1.25 and a 90% CI for a C _max of 0.70 to 1.43. Methods for determining C _max and AUC are well known in the art.

[0114] The transdermal delivery system prepared according to Example 1 was tested in vivo for systemic delivery of donepezil as described in Example 4. In this in vivo study, six people were treated with a transdermal delivery system that was applied to their skin and worn for one weeks and then removed. Another group of six people were treated with orally administered donepezil (ARICPET ^® ) at a dose of 5 mg taken on the first day and on the 7th day of the study. Blood samples were taken from individuals and plasma concentrations of donepezil were determined. The results are shown in Figures 2A-2B .

[0115] Figure 2A shows the mean plasma donepezil concentration, in ng/mL, in humans treated with transdermal donepezil delivery system (circles) for 1 week, or 5 mg donepezil administered orally on day 1 and day 7 (triangles). The donepezil transdermal delivery system provided a plasma concentration similar to that provided by oral delivery of a similar dose of donepezil. Thus, in one embodiment, a method for transdermal administration of donepezil is provided by administering a transdermal delivery system that provides a pharmacokinetic profile that is bioequivalent to that of oral administration of donepezil.

[0116] FIG. 2B is a graph showing a detailed view of the data from FIG. 2A over 24 hours after oral administration of a donepezil 5 mg tablet (triangles) and after removal of the donepezil transdermal delivery system (circles). The transdermal delivery system provides a long-term constant plasma concentration of donepezil for 24 hours after its removal, similar to what was observed within 24 hours after oral administration.

[0117] Figure 3 is a graph showing the estimated mean plasma donepezil concentration, in ng/mL, in the last week of a 28 day (4 week) treatment period with a transdermal delivery system designed to administer 10 mg/day for a week ( solid line) and with donepezil 10 mg oral tablet daily for 28 days (dotted line). There are no fluctuations in plasma as a result of oral administration in the case of the transdermal system, when a fresh patch is applied every week, and a constant plasma concentration is maintained during the treatment period. The transdermal delivery system provides a constant plasma concentration of donepezil over an extended period of time (e.g., 3 days, 5 days, 7 days, 14 days), where the plasma concentration is essentially the same or in the range of approximately 10%, 15%, 20% or 30% of the plasma concentration achieved by daily oral administration of a similar dose of donepezil.

[0118] Referring again to the study in Example 4, six individuals treated with the donepezil transdermal delivery system for one week, for several days after removal of the delivery system from the skin, were monitored for signs of skin irritation. Figure 4 is a bar graph showing the number of individuals out of 6 per group and observed skin irritation over a period of time after removal of the delivery system, where open bars indicate no skin irritation and solid bars indicate mild skin irritation. The delivery system resulted in no or mild irritation within a few hours of removal, and any mild irritation resolved within one or two days.

[0119] In another study, humans were treated with a transdermal delivery system designed to deliver systemically an amount of donepezil that is bioequivalent to orally administered donepezil at a dose of 10 mg once daily. A comparison of the calculated pharmacokinetic parameters Cmax, AUC and Cmin for these two delivery routes is shown in Table 1.

Table 1: Calculated pharmacokinetic parameters

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

[0120] Thus, in one embodiment, a method for delivering donepezil base to an individual is provided. The method includes providing a transdermal delivery system containing donepezil and applying or instructing to apply the transdermal delivery system to the skin of an individual. The method provides for transdermal delivery of donepezil that is bioequivalent to oral administration of a therapeutic agent, wherein bioequivalence is defined by (a) a 90% confidence interval relative to the mean Cmax and AUC of the therapeutic administered via the transdermal delivery system and via oral delivery from 0.70 to 1.43, or from 0.80 to 1.25, or (b) 90% confidence interval for the geometric mean ratios of AUC and Cmax of the therapeutic agent administered via the transdermal delivery system and via oral delivery from 0.70 to 1.43 or from 0.80 to 1.25.

[0121] Example 5 describes a human study comparing transdermal patches containing donepezil and comparing them to orally administered donepezil. In this study, patients were enrolled in a three-period, six-month, randomized crossover study comparing the stationary pharmacokinetic profiles of once daily oral donepezil ( ^ARICEPT® ) with donepezil transdermal patch formulation. The transdermal patch was provided in two sizes, A and B, in addition to the surface area, the transdermal patches were the same in all aspects. During the course of the study, participants in each administration group received donepezil 5 mg/day for a week followed by 4 weeks of donepezil 10 mg/day delivered from two sizes of once-weekly transdermal patches (group 1 and group 2) or orally (group 3). Pharmacokinetic measurements were performed at the fourth week of treatment with 10 mg/day, when plasma concentrations reached steady-state levels. Taking blood samples from individuals who underwent transdermal treatment was carried out every day for the fourth week to determine the pharmacokinetics. Individuals administered oral donepezil had blood drawn on the last day of the fourth week to determine pharmacokinetics. The mean plasma donepezil concentration, in ng/mL, is shown in Figure 5A for each day at week 5 of the study, where the solid line corresponds to the lower surface area transdermal patch and the dotted line corresponds to the higher surface area transdermal patch. The solid bold line corresponding to days 6-7 shows the mean plasma concentration for individuals administered oral donepezil, and the dotted line shows the estimated daily plasma concentration for oral treatment. Mean plasma donepezil concentrations in individuals treated with the transdermal patch were bioequivalent to plasma donepezil concentrations in individuals treated orally with donepezil. Larger and smaller transdermal patches demonstrated dose proportionality. Table 2 presents the main pharmacokinetic bioequivalence parameters for the smaller surface area transdermal patch used in this study.

table 2

Main pharmacokinetic parameter Geometric mean ratio (%) of smaller patch dose to oral dose Limits of bioequivalence
(target 80-125%) AUC (ng-h/ml) 104.7% 95.2-115.2 Cmax _ss (ng/ml) 91.6% 83.1-100.8

[0122] Gastrointestinal adverse events: nausea, vomiting, and diarrhea reported by individuals in the clinical trial mentioned above with respect to Figure 5A are shown in Figure 5B . Individuals treated with the smaller transdermal patch (dashed bars) and larger transdermal patch (vertical solid bars) had a lower incidence of nausea, vomiting, and diarrhea than individuals treated with oral (horizontal bars) donepezil. The number of individuals experiencing nausea was four times lower when donepezil 10 mg/day was administered transdermally relative to oral administration. The number of individuals experiencing diarrhea was two times lower when donepezil 10 mg/day was administered transdermally relative to oral administration.

[0123] Thus, in one embodiment, a composition and method for delivering donepezil to an individual is provided. The composition, when applied to the skin of an individual, provides for transdermal delivery of donepezil to achieve a plasma concentration of donepezil that, at steady state, is bioequivalent to oral administration of donepezil, and/or that provides an amount of gastrointestinal adverse effects that is two times, three times, four times or five times lower than that of individuals treated with the same dose of oral donepezil (i.e., the dose administered orally is equal to the dose administered transdermally, so that individuals are treated with an equal dose of donepezil when administered orally and transdermally) . In one embodiment, the orally administered donepezil is the salt form of donepezil and the transdermally administered donepezil is the donepezil base. In one embodiment, the number of gastrointestinal adverse events is 2-5, 2-4, and 2-3 times lower, and in another embodiment, the number of gastrointestinal adverse events is at least about two times, at least about three times, at least about four times, or at least about five times lower than the number of individuals treated with the same oral dose of donepezil. In one embodiment, the delivery of donepezil is for the treatment of Alzheimer's disease.

IV. Examples

[0124] The following examples are illustrative and are not intended to be limiting.

EXAMPLE 1

Donepezil transdermal delivery system

[0125] A transdermal delivery system containing donepezil was prepared as follows.

[0126] Preparation of the drug reservoir: 1.20 grams of sorbitan monolaurate ( ^SPAN® 20) was dissolved in 6.00 grams of triethyl citrate and mixed with 1.80 grams of lauryl lactate and 89.69 grams of ethyl acetate. 6.00 grams of glycerol was added and mixed. 9.00 grams of donepezil hydrochloride and 1.82 grams of sodium bicarbonate were added and dispersed into the mixture. Then 12.00 grams of cross-linked micronized polyvinylpyrrolidone ( ^Kollidon® CL-M) was added and the mixture was homogenized. 43.93 grams of acrylic acid/vinyl acetate copolymer (Duro-Tak® ^387-2287 , 50.5% solids content) was added to the homogenized drug dispersion and mixed well. The wet adhesive composition was applied to a protective film and dried using a laboratory coater (Werner Mathis) to achieve a dry weight of 12 mg/cm ² coating.

[0127] Preparation of a contact adhesive: 0.60 grams of sorbitan monolaurate ( ^SPAN® 20) was dissolved in 3.0 grams of triethyl citrate and mixed with 0.9 grams of lauryl lactate, 25.45 grams of ethyl acetate, and 1.34 grams of isopropyl alcohol. 6.00 grams of cross-linked micronized polyvinylpyrrolidone ( ^Kollidon® CL-M) was added and the mixture was homogenized. 38.61 grams of acrylic acid/vinyl acetate copolymer (Duro-Tak® ^387-2287 , 50.5% solids content) was added to the homogenized mixture and mixed well. Wet adhesive composition was applied to the protective film and dried, reaching a dry weight of the coating of 5 mg/cm ² .

[0128] Lamination and Stamping : A rate control membrane ( ^CELGARD® 2400 or ^Reemay® 2250) was laminated to the adhesive side of the drug reservoir. The contact adhesive was then laminated to the rate-controlling membrane on which the drug reservoir was laminated. The protective sheet of the side of the drug reservoir was replaced and the substrate was layered.

[0129] The weight percentage of the components in the transdermal delivery system is shown in Table 1.1 below.

Table 1.1

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

EXAMPLE 2

Donepezil transdermal delivery systems

[0130] A transdermal delivery system containing donepezil was prepared as follows.

[0131] Preparation of the drug reservoir: Sorbitan monolaurate ( ^SPAN® 20) was dissolved in triethyl citrate and mixed with lauryl lactate. Glycerin was added and mixed. Donepezil hydrochloride and sodium bicarbonate were added and dispersed into the mixture. Cross-linked micronized polyvinylpyrrolidone ( ^KOLLIDON® CL-M) was then added and the mixture was homogenized. An acrylic acid/vinyl acetate copolymer (DURO- ^TAK® 387-2287, 50.5% solids content) was added to the homogenized drug dispersion and mixed well. The wet adhesive composition was applied to a protective film and dried using a laboratory coater (Werner Mathis).

[0132] Preparation of the contact adhesive: Sorbitan monolaurate ( ^SPAN® 20) was dissolved in triethyl citrate and mixed with lauryl lactate. Cross-linked micronized polyvinylpyrrolidone ( ^Kollidon® CL-M) was added and the mixture was homogenized. Acrylic acid/vinyl acetate copolymer (DURO- ^TAK® 387-2287, 50.5% solids content) was added to the homogenized mixture and mixed well. The wet adhesive composition was applied to a protective film and dried.

[0133] Lamination and Stamping : A polypropylene microporous membrane (Celgard® 2400) was pre-treated by coating it with a mixture of solvents: sorbitan monolaurate, triethyl citrate and lauryl lactate to saturate the membrane with a mixture of solvents. The pretreated membrane was layered on the adhesive side of the drug reservoir. The contact adhesive was then laminated to the rate-controlling membrane on which the drug reservoir was laminated. The protective sheet of the side of the drug reservoir was replaced and the substrate was layered. The final laminate of five layers was stamped into transdermal patches.

[0134] The weight percentage of components in transdermal delivery systems is shown in Table 2.1 below.

Table 2.1

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

EXAMPLE 3

Donepezil transdermal delivery systems

[0135] A transdermal delivery system containing donepezil was prepared as follows.

[0136] Preparation of the drug reservoir: Sorbitan monolaurate ( ^SPAN® 20) was dissolved in triethyl citrate and mixed with lauryl lactate. Glycerin was added and mixed. Donepezil hydrochloride was added and dispersed into the mixture. Fumed silica ( ^AEROSIL® 200 Pharma) was then added and the mixture was homogenized. Acrylic acid/vinyl acetate copolymer (DURO- ^TAK® 387-2287, 50.5% solids content) and dimethylaminoethyl methacrylate-butyl methacrylate-methyl methacrylate copolymer ( ^EUDRAGIT® EPO) were added to the homogenized drug dispersion and mixed well. The wet adhesive composition was applied to a protective film and dried using a laboratory coater (Werner Mathis).

[0137] Obtaining a contact adhesive: Sorbitan monolaurate (SPAN ^® 20) was dissolved in triethyl citrate and mixed with lauryl lactate. Micronized polyvinylpyrrolidone ( ^KOLLIDON® CL-M) was added and the mixture was homogenized. Acrylic acid/vinyl acetate copolymer (DURO- ^TAK® 387-2287, 50.5% solids content) was added to the homogenized mixture and mixed well. The wet adhesive composition was applied to a protective film and dried.

[0138] Lamination and stamping : A polypropylene microporous membrane (Celgard® 2400) was pretreated by coating it with a mixture of solvents: sorbitan monolaurate, triethyl citrate and lauryl lactate to saturate the membrane with a mixture of solvents. The pretreated membrane was layered on the adhesive side of the drug reservoir. The contact adhesive was then laminated to the rate-controlling membrane on which the drug reservoir was laminated. The protective sheet of the side of the drug reservoir was replaced and the substrate was layered. The final laminate of five layers was stamped into transdermal patches.

[0139] The weight percentage of components in transdermal delivery systems is shown in Table 3.1 below.

Table 3.1

Ingredient Medicine reservoir
(dry composition % w/w) Contact adhesive
(dry composition, % w/w) Donepezil HCl 25.0 0 Copolymer of dimethylaminoethyl methacrylate, butyl methacrylate, methyl methacrylate (EUDRAGIT ^® EPO) 17.7 0 triethyl citrate 10.0 10.0 Lauryl lactate 6.0 6.0 Sorbitan monolaurate (SPAN ^® 20) 2.0 2.0 fumed silica (AEROSIL ^® 200 Pharma) 7.0 0 Glycerol 10.0 0 PVP-CLM ( ^KOLLIDONE® -CLM) 0 20.0 Acrylic acid/vinyl acetate copolymer (Duro-Tak® ^387-2287 ) 24.3 64.0

EXAMPLE 4

In Vivo Administration of Donepezil from the Donepezil Transdermal Delivery System

[0140] Transdermal delivery systems containing donepezil were prepared as described in Example 1. Twelve (12) people were randomized into two groups for treatment with either the transdermal delivery system (n=6) or orally administered donepezil ( ^ARICPET® ) , 5 mg taken on the first day and on the 7th day of the study. The transdermal delivery system was applied to the skin and worn for one week and then removed. Blood samples were taken from individuals treated with the transdermal delivery system every day. Blood samples were taken at frequent hourly intervals on days 1 and 7 in the oral delivered donepezil group and again on days 8, 10, 12 and 14. The mean concentration of donepezil in the treatment groups is shown in Figures 2A-2B .

EXAMPLE 5

In Vivo Administration of Donepezil from the Donepezil Transdermal Delivery System

[0141] Transdermal delivery systems containing donepezil were prepared as described in Example 2. Patients were included and randomized into three treatment groups for a five week treatment study. Patients in group 1 (n=52) and group 2 (n=51) were treated with the transdermal system according to example 2, where patients in group 1 wore a patch having a smaller surface area (patch A) than patients in group 2 (patch B). Other than size, patch A and patch B were identical. In the first week of the study, patients in Group 1 and Group 2 wore patches designed to deliver 5 mg of donepezil from a patch applied once a week. After an initial period of 7 days, patients were given a transdermal system designed to be worn for 7 days (transdermal patch to be worn once a week) to deliver 10 mg of donepezil per day, also patch A differing from patch B only in surface area. The transdermal systems were changed every week for 4 weeks. Patients in group 3 (n=54) were treated with a daily oral dose of 5 mg donepezil (ARICEPT) for 7 days followed by a dose of 10 mg donepezil (ARICEPT) once daily for 4 weeks.

[0142] For individuals in Group 1 and Group 2, blood sampling was performed every day during the fourth week of dosing at the 10 mg level when plasma concentrations were steady. For individuals in group 3, blood sampling was performed on the last day of the fourth week of 10 mg/day dosing. The mean plasma donepezil concentration for treatment groups at week 4 of 10 mg dosing is shown in Figure 5A , for individuals treated with donepezil administered transdermally from transdermal patch A (smaller surface area, solid line, transdermal patch B (larger surface area, dotted line). line) and oral donepezil (solid heavy line at days 6-7), and the dotted line shows the estimated daily plasma concentration for oral treatment.

[0143] Figure 5B is a bar graph showing the number of gastrointestinal adverse events (nausea, vomiting, and diarrhea) reported by individuals in the study, where dashed bars correspond to individuals treated weekly with smaller transdermal patches, bars , filled with vertical lines, correspond to individuals treated weekly with larger transdermal patches, and bars, filled with horizontal lines, correspond to individuals treated with oral donepezil.

[0144] Although a number of illustrative aspects and embodiments are described above, certain modifications, permutations, additions, and subcombinations thereof will be apparent to those skilled in the art. Thus, the appended claims and the claims herein below are intended to be interpreted as including all such modifications, permutations, additions and subcombinations to their true spirit and scope.

Claims (43)

1. A transdermal delivery system for the systemic delivery of donepezil, comprising: a skin-contact adhesive layer for adhering the system to the user's skin, and a drug reservoir containing (i) an acrylate copolymer, (ii) glycerol, and (iii) a donepezil base formed by the reaction of donepezil HCl and an alkaline salt, where the alkali salt is sodium bicarbonate or potassium bicarbonate. 2. The system of claim 1 further comprising an intermediate layer directly on the skin-contacting adhesive layer positioned between the skin-contacting adhesive layer and the drug reservoir. 3. The system of claim 1 or 2, wherein the skin-contacting adhesive layer comprises an acrylic acid/vinyl acetate copolymer. 4. The system of claim 3, wherein the skin-contacting adhesive layer further comprises cross-linked polyvinylpyrrolidone. 5. The system of any one of the preceding claims, wherein the skin-contacting adhesive layer comprises a solvent composition comprising one or more solvents selected from the group consisting of triethyl citrate, sorbitan monolaurate, and lauryl lactate. 6. The system according to any one of the preceding claims, wherein the skin-contacting adhesive layer is made from an adhesive composition that does not contain donepezil base or donepezil salt. 7. The system of any one of the preceding claims, wherein the drug reservoir layer further comprises triethyl citrate. 8. The system of claim 7 wherein the drug reservoir layer further comprises one or both of sorbitan monolaurate and lauryl lactate. 9. The system of any one of the preceding claims, wherein the drug reservoir is an adhesive matrix. 10. The system of any one of the preceding claims, further comprising a first substrate layer in contact with the drug reservoir layer, an adhesive coating in contact with the first substrate layer, and a second substrate layer in contact with the adhesive coating. 11. The system of claim 10 wherein the adhesive coating is a single layer containing an acrylate copolymer. 12. The system of claim 10 wherein the adhesive coating comprises a first layer and a second layer, the first layer comprising polyisobutylene and polybutene and the second layer comprising an acrylic adhesive. 13. The system of claim 9 wherein the adhesive matrix comprises an acrylic acid/vinyl acetate copolymer adhesive and a crosslinked polyvinylpyrrolidone. 14. The system according to claim 1, where the drug reservoir includes: sodium bicarbonate as alkaline salt; a solvent composition containing one or more of triethyl citrate, lauryl lactate, sorbitan monolaurate, and glycerin; cross-linked polyvinylpyrrolidone; and an acrylic acid/vinyl acetate copolymer. 15. The system according to claim 1, where the drug reservoir includes: (a) a donepezil base formed by the reaction of about 5-25 wt.% donepezil HCl and about 1-5 wt.% sodium bicarbonate as an alkaline salt; (b) about 0-15 wt.% triethylcitrate; (c) about 0-5 wt.% sorbitan monolaurate; (d) about 5-15 wt.% glycerol; (e) about 1-10 wt.% lauryl lactate; (f) about 5-25 wt.% cross-linked polyvinylpyrrolidone; and (g) about 30-65% by weight of an acrylate-vinyl acetate copolymer. 16. The system of claim 1, wherein the drug reservoir essentially consists of: (a) donepezil base formed by the reaction of about 10-18 wt.% donepezil HCl and about 1-5 wt.% sodium bicarbonate as an alkaline salt; (b) about 8-12 wt.% triethylcitrate; (c) about 1.5-2.5% by weight of sorbitan monolaurate; (d) about 9-11 wt.% glycerol; (e) about 1-10 wt.% lauryl lactate; (e) about 13-17 wt.% cross-linked polyvinylpyrrolidone; and (f) about 40-42% by weight of an acrylate-vinyl acetate copolymer. 17. The system of any one of claims 1 to 4, wherein the skin contact adhesive comprises triethyl citrate, an α-hydroxy acid, or both. 18. The system of claim 17 wherein the α-hydroxy acid is an ester of lactic acid or glycolic acid. 19. The system of claim 18 wherein the α-hydroxy acid is lauryl lactate. 20. A method for delivering donepezil to an individual, comprising: providing a transdermal delivery system according to any one of claims 1-19, and introducing or applying the transdermal delivery system to the skin of an individual. 21. The method of claim 20, wherein the method is for the treatment of an individual with Alzheimer's disease. 22. The method according to any one of claims 20, 21, where the introduction or application includes the introduction or application once a week. 23. The method of any one of claims 20-22, wherein the transdermal delivery system comprises a dose of donepezil base to deliver 1-25 mg/24 hours.

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