(12) Patent Application Publication (10) Pub. No.: US 2014/0276478 A1 Liao Et Al

Home , Dexetimide, Oxyphencyclimine, Phenglutarimide, Profenamine

US 20140276478A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2014/0276478 A1 Liao et al. (43) Pub. Date: Sep. 18, 2014

(54) COMPOSITIONS AND METHODS FOR Publication Classification TRANSIDERMAL DELIVERY OF TERTARY AMINEDRUGS (51) Int. Cl. A647/38 (2006.01) (71) Applicant: NOVEN PHARMACEUTICALS, A647/34 (2006.01) INC., Miami, FL (US) A647/32 (2006.01) A63L/27 (2006.01) (72) Inventors: Jun Liao, Miami, FL (US); Takito A69/70 (2006.01) Shima, Miami, FL (US); Puchun Liu, (52) U.S. Cl. Miami, FL (US); Steven Dinh, Miami, CPC ...... A61K 47/38 (2013.01); A61 K3I/27 FL (US) (2013.01); A61 K9/7084 (2013.01); A61 K 47/32 (2013.01); A61 K47/34 (2013.01) (73) Assignee: NOVEN PHARMACEUTICALS, USPC ...... 604/290; 514/490; 604/307; 427/2.31 INC., Miami, FL (US) (57) ABSTRACT (21) Appl. No.: 14/208,348 Described are transdermal drug delivery systems for the transdermal administration of tertiary amine drugs, such as (22) Filed: Mar 13, 2014 rivastigmine, fentanyl or rotigotine, comprising a polymer matrix comprising a free base form of the drug and at least one carboxyl group-containing compound. In some embodi Related U.S. Application Data ments, the systems include a rate-controlling membrane and (60) Provisional application No. 61/793,120, filed on Mar. a skin-contacting face adhesive apart from the polymer 15, 2013. matrix.

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COMPOSITIONS AND METHODS FOR transdermally. The commercially available transdermal TRANSIDERMAL DELIVERY OF TERTARY rivastigmine product (ExelonR) is designed for daily use and AMINEDRUGS comprises four layers: a backing layer, a polymer-drug matrix layer, and adhesive layer and a release liner. The Exelon(R) CROSS-REFERENCE TO RELATED patch is available in two sizes, a 5 cm patch that includes 9 APPLICATIONS mg rivastigmine and delivers about 4.6 mg rivastigmine in 24 0001. This application claims the priority benefits of U.S. hours, and a 10 cm patch that includes 18 mg rivastigmine provisional patent application 61/793,120, filed Mar. 15, and delivers about 9.5 mg in 24 hours rivastigmine. (The 10 2013, the entire contents of which are incorporated herein by cm patch that provides a close of 9.5 mg/24 hours is the reference. recommended effective dose.) 0006 Rotigotine is used to treat Parkinson's disease (PD) FIELD OF THE INVENTION and restless legs syndrome (RLS). Current 1-day patch prod ucts deliver 1, 2, 3, 4, 6 and 8 mg/day of rotigotine for the 0002. Described herein are transdermal drug delivery sys treatment of Parkinson's disease or restless legs syndrome. tems and methods for the transdermal delivery of tertiary amine drugs. In specific embodiments, the transdermal drug 0007 Fentanyl is used to treat pain. Current 3-day patch delivery systems and methods are useful for extended drug products deliver 12.5, 25, 50, 75 and 100 ug/hr offentanyl for delivery, such as drug delivery over a period of time of 3 days, pain management. 7 days, or longer. 0008. There remains a need for transdermal drug delivery systems and methods for the transdermal delivery of tertiary BACKGROUND amine drugs, such as rivastigmine, rotigotine and fentanyl. and there remains a particular need for transdermal drug 0003. This invention relates generally to transdermal drug delivery systems and methods useful for extended drug deliv delivery systems, and more particularly, to transdermal drug ery, such as drug delivery over a period of time of 3 days, 7 delivery systems for the delivery of tertiary amine drugs (such days, or longer. as rivastigmine, fentanyl or rotigotine). The use of a transder mal drug delivery system, for example, a patch comprising a pressure-sensitive adhesive containing a drug, as a means of SUMMARY delivering drug through the skin is well known. However, 0009. In accordance with some embodiments, there are there remains a need for transdermal drug delivery systems provided transdermal drug delivery systems comprising a designed for the delivery of specific classes of drugs, such as polymer matrix comprising the free base form of a tertiary tertiary amine drugs, including rivastigmine, fentanyl and amine drug and at least one carboxyl group-containing com rotigotine, and there remains a need for transdermal drug pound, wherein the relative amounts of free base and carboxyl delivery systems that can provide drug delivery over an group-containing compound is such that greater than 50%, extended period of time, such as over a period of time of 3 such as at least 60% at least 70%, at least 80%, at least 90%, days, or 7 days, or longer. or 100%, of the free base is associated with a carboxylic acid 0004 Transdermal drug delivery systems (adhesive group to form a salt. In some embodiments, at least one patches) as dosage forms have been the Subject of a vast carboxyl group-containing compound is a carrier polymer number of patent applications over the last 25 years, yielding comprising carboxy-functional groups, such as an acrylic many patents but few commercial products in comparison. To pressure-sensitive adhesive polymer comprising carboxy those working in the field, the relatively small number of functional groups, and/or is a polymeric carboxylic acid, Such commercial products is not surprising. Although regulatory, as anionic copolymers based on methacrylic acid and methyl economic, and market hurdles play a role in limiting the methacrylate, carbomer polymers, carbopol polymers, vinyl number of products on the market, the task of developing a polymers containing carboxylic acid groups, carboxyl group transdermal drug delivery system that achieves desired physi containing cellulose polymers and carboxyl group-contain cal and pharmacokinetic parameters to satisfy physician and ing starches. patient demand is more daunting. Parameters to be consid 0010. In any embodiments, the tertiary amine drug is ered during commercial product development may include selected from the group consisting of amiodarone, amitrip drug solubility, drug stability (e.g., as may arise from inter tyline, atropine, benztropine, biperiden, bornaprine, bupiv action with other component materials and/or the environ acaine, chlorpheniramine, cinnarizine, clomipramine, cyclo ment), delivery of a therapeutic amount of drug at a desired pentolate, darifenacin, dexetimide, dicyclomine, diltiazem, delivery rate over the intended duration of use, adequate diphenhydramine, doxepin, ethopropazine, fentanyl, flavox adhesion at the anatomical site of application, integrity (e.g., ate, homatropine, imipramine, loxapine, maZaticol, metix minimal curling, wrinkling, delaminating and slippage) with ene, oxybutin, oxyphencyclimine, phenglutarimide, physos minimal discomfort, irritation and sensitization both during tigmine, piperidolate, pirenzepine, procyclidine, use and during and after removal, and minimal residual adhe profenamine, propiverine, rivastigmine, rotogotine, Scopola sive (or other components) after removal. The physical manu mine, telenzepine, theophylline, tolterodine, trimipramine, facturing and production aspects of commercial product trihexyphenidyl, tropatepine, and tropicamide.rivastigmine. development (e.g., the identity and costs of materials, equip ment, and labor) and Supporting analytical methods required 0011. In some embodiments, the composition does not for regulatory compliance also can be significant. include a penetration enhancer comprising a carboxylic acid 0005 Rivastigmine is a parasympathomimetic or cholin group. In some embodiments, the composition does not ergic agent approved for the treatment of mild to moderate include a monocarboxylic fatty acid. dementia of the Alzheimer's type and dementia due to Par 0012. In any embodiments, the polymer matrix may fur kinson's disease. The drug can be administered orally or ther comprise an antioxidant and/ora plasticizer. US 2014/0276478 A1 Sep. 18, 2014

0013. In specific embodiments, a transdermal drug deliv In accordance with these embodiments, the amount of drug ery system for the transdermal delivery of a tertiary amine and pharmacokinetic properties may be any as noted above drug comprises a polymer matrix comprising: and discussed herein below. 0014) about 10% to about 40% by weight of a free base 0025. Also provided are methods of making a transdermal form of the tertiary amine drug; drug delivery system for a tertiary amine drug, comprising 0015 about 0% to about 90% by weight of a carrier poly combining a polymer matrix comprising a free base form of mer, optionally containing carboxyl-group containing car the tertiary amine drug; a rate-controlling membrane; and a face adhesive comprising a carboxyl group-containing com boxy-functional groups; pound. 0016 about 0% to about 90% by weight of a carboxyl 0026. Also provided are methods for administering a ter group-containing compound; tiary amine drug, comprising applying to the skin or mucosa 0017 optionally, about 0% to about 1% of an antioxidant; of a Subject in need thereof a transdermal drug delivery sys and tem as described herein. Also provided are transdermal drug 0018 optionally, about 0% to about 20% of a pharmaceu delivery system as described herein for use inadministering a tically acceptable excipient, tertiary amine drug to the skin or mucosa of a Subject in need 0.019 wherein the relative amounts of free base and car thereof, or for treating mild to moderate dementia of the boxyl groups is such that greater than 50% of the free base is Alzheimer's type or dementia due to Parkinson's disease (for rivastigmine products), Parkinson's disease (PD) or restless associated with a carboxylic acid group to form a salt. legs syndrome (RLS) (for rotigotine products), or pain (for 0020. In accordance with any embodiments, the polymer fentanyl products). Also provided are uses of a tertiary amine matrix may comprise an amount of tertiary amine drug effec drug in the preparation of the medicament in form of a the tive to deliver a therapeutically effective amount of tertiary transdermal drug delivery systems as described herein for amine drug over a period of time selected from the group administering a tertiary amine drug to the skin or mucosa of a consisting of at least 1 day, at least 2 days, at least 3 days, at subject in need thereof, or for treating mild to moderate least 4 days, at least 5 days, at least 6 days and at least 7 days. dementia of the Alzheimer's type or dementia due to Parkin 0021. In accordance with any embodiments where the ter son's disease (for rivastigmine products), Parkinson's disease tiary amine drug is rivastigmine, the polymer matrix may (PD) or restless legs syndrome (RLS) (for rotigotine prod comprise an amount of rivastigmine effective to deliver at ucts), or pain (for fentanyl products). least about 4.6 mg/day over a period of time selected from the group consisting of at least 1 day, at least 2 days, at least 3 BRIEF DESCRIPTION OF THE DRAWINGS days, at least 4 days, at least 5 days, at least 6 days and at least I0027 FIG. 1 illustrates the rivastigmine flux (ug/cm/hr) 7 days, or may comprise an amount of rivastigmine effective over time (0-168 hours) from a transdermal drug delivery to deliver at least about 9.5 mg/day over a period of time system comprising Composition 1-1 (0), Composition 1-2 selected from the group consisting of at least 1 day, at least 2 (), Composition 1-3 (A), or an Exelon(R) patch (O. top line). days, at least 3 days, at least 4 days, at least 5 days, at least 6 10028 FIG. 2 illustrates the rivastigmine flux (ug/cm/hr) days and at least 7 days, or may comprise about 32-65 mg over time (0-168 hours) from a transdermal drug delivery rivastigmine, or may comprise about 67-126 mg rivastigmine. system comprising Composition 1-6 (0), Composition 1-7 0022. In accordance with any embodiments, the polymer (), Composition 1-8 (A) or an Exelon R patch (O. top line). matrix may have a coat weight of about 10-15 mg/cm. (0029 FIG. 3 illustrates the rivastigmine flux (ug/cm/hr) 0023. Also provided are methods of making a transdermal over time (0-168 hours) from a transdermal drug delivery drug delivery system for a tertiary amine drug, comprising system comprising Composition 1-9 (0), Composition 1-10 forming a polymer matrix comprising a free base form of the (), Composition 1-11 (A) oran ExelonR patch (O. top line). tertiary amine drug and at least one carboxyl group-contain I0030 FIG. 4 illustrates the rivastigmine flux (ug/cm/hr) ing compound, wherein the relative amounts of free base and over time (0-168 hours) from a transdermal drug delivery carboxyl group-containing compound is such that greater system comprising Composition 2-1 (0), Composition 2-2 than 50% of the free base is associated with a carboxylic acid (), Composition 2-3 (A), Composition 2-4 (O), or an group to form a salt. Exelon R patch (O. top line). 0024. Also provided are transdermal drug delivery sys 0031 FIG. 5 illustrates a transdermal drug delivery system tems comprising a polymer matrix comprising the free base 60 as described herein comprising a backing 50, an adhesive form of a tertiary amine drug, a rate-controlling membrane, matrix 52, a rate-controlling membrane 54, a face-adhesive and a face adhesive comprising a carboxyl group-containing 56, and a release liner 58. compound. In accordance with these embodiments, the ter 0032 FIGS. 6 and 7 illustrate the rivastigmine flux (ug/ tiary amine drug and carboxyl group-containing compound cm/hr) over time (0-168 hours) from transdermal drug deliv may be any as noted above and discussed herein below. In ery systems described herein (System 4-1 (); System 4-2 Some embodiments, the rate-controlling membrane com (A)) or an Exelon(R) patch (, top line at 0-48 hours) in an in prises a polymer selected from the group consisting of poly vitro flux study using human skin. ethylene, polyolefin, and/or ethylene vinyl acetate polymers. I0033 FIG. 8 illustrates the rivastigmine flux (ug/cm/hr) In some embodiments, the polymer matrix comprises a poly over time (0-168 hours) from the transdermal drug delivery mer selected from the group consisting of acrylic polymers, systems described herein with a rate-controlling membrane silicon polymers, polyisobutylene polymers, styrene-iso and different face adhesives (5 mg/cm): none (O); silicone prene styrene block copolymers, and mixtures of two or more (); silicone and GELVAR) GMS 3235 (A): silicone and thereof. In some embodiments, the face adhesive comprises a Duro-TakR 9900 (O); silicone and Duro-TakR 87-900A (0). polymer selected from the group consisting of acrylic poly 0034 FIG. 9 illustrates the in vitro rivastigmine flux (ug/ mers, silicon polymers, and mixtures of two or more thereof. cm/hr) overtime (0-168 hours) from transdermal drug deliv US 2014/0276478 A1 Sep. 18, 2014 ery systems described herein with different rate-controlling is emphasized that a therapeutically effective amount or membranes and Duro-Tak.R. 87-2852 face adhesive, or an therapeutic level of a drug will not always be effective in ExelonR patch (, top line at 0-24 hours). treating the conditions/diseases described herein, even though Such dosage is deemed to be a therapeutically effec DETAILED DESCRIPTION tive amount by those of skill in the art. For convenience only, 0035. Described herein are transdermal drug delivery sys exemplary dosages, drug delivery amounts, therapeutically tems and methods for the transdermal delivery of tertiary effective amounts and therapeutic levels are provided below amine drugs, such as rivastigmine, fentanyl or rotigotine. In with reference to adult human subjects. Those skilled in the specific embodiments, the systems achieve delivery of the art can adjust such amounts in accordance with standard drug over an extended time period, Such a period of greater practices as needed to treat a specific Subject and/or condi than one day, Such as a period of at least 3 days, at least 5 days, tion/disease. at least 7 days, or longer. In specific embodiments, the sys 0042. As used herein, “active surface area” means the tems comprise a tertiary amine drug and a carboxyl group Surface area of the drug-containing layer or skin-contacting containing compound in the same layer of the transdermal face adhesive layer of the transdermal drug delivery system. drug delivery system and/or in different layers. 0043. As used herein, "coat weight” refers to the weight of the drug-containing layer per unit area of the active Surface DEFINITIONS area of the transdermal drug delivery system. 0044 As used herein, “rivastigmine' includes rivastig 0.036 Technical and scientific terms used herein have the mine free base, which is a liquid drug with a tertiary amine meanings commonly understood by one of ordinary skill in structure. The chemical name of rivastigmine is (S)-3-1- the art to which the present invention pertains, unless other (dimethylamino)ethylphenyl ethylmethylcarbamate, its wise defined. Reference is made herein to various method empirical formula is CH2N2O and its molecular weight is ologies known to those of ordinary skill in the art. Publica 250.34. tions and other materials setting forth Such known 0045. As used herein, “tertiary amine drug includes any methodologies to which reference is made are incorporated therapeutically active compound with a tertiary amine struc herein by reference in their entireties as though set forth in ture, including amiodarone, amitriptyline, atropine, benz full. Any suitable materials and/or methods known to those of tropine, biperiden, bornaprine, bupivacaine, chlorphe ordinary skill in the art can be utilized in carrying out the niramine, cinnarizine, clomipramine, cyclopentolate, present invention. However, specific materials and methods darifenacin, dexetimide, dicyclomine, diltiazem, diphenhy are described. Materials, reagents and the like to which ref dramine, doxepin, ethopropazine, fentanyl, flavoxate, homa erence is made in the following description and examples are tropine, imipramine, loxapine, maZaticol, metixene, oxybu obtainable from commercial sources, unless otherwise noted. tin, oxyphencyclimine, phenglutarimide, physostigmine, 0037. As used herein, the singular forms “a,” “an and piperidolate, pirenzepine, procyclidine, profenamine, propiv “the designate both the singular and the plural, unless erine, rivastigmine, rotogotine, Scopolamine, telenzepine, expressly stated to designate the singular only. theophylline, tolterodine, trimipramine, trihexyphenidyl, tro 0038. The term “about and the use of ranges in general, patepine, and tropicamide. whether or not qualified by the term about, means that the 0046. As used herein, “flux' (also called “permeation number comprehended is not limited to the exact number set rate') is defined as the absorption of a drug through skin or forth herein, and is intended to refer to ranges substantially mucosal tissue, and is described by Fick's first law of diffu within the quoted range while not departing from the scope of S1O. the invention. As used herein, “about will be understood by persons of ordinary skill in the art and will vary to some extent on the context in which it is used. If there are uses of the term where J is the flux in g/cm/sec. D is the diffusion coefficient which are not clear to persons of ordinary skill in the art given of the drug through the skin or mucosa in cm/sec and dCm/ the context in which it is used, “about will meanup to plus or dX is the concentration gradient of the drug across the skin or minus 10% of the particular term. COSa. 0039. The phrase “substantially free” as used herein gen 0047. As used herein, the term “transdermal” refers to erally means that the described composition (e.g., transder delivery, administration or application of a drug by means of mal drug delivery system, polymer matrix, etc.) comprises direct contact with skin or mucosa. Such delivery, adminis less than about 5%, less than about 3%, or less than about 1% tration or application is also known as dermal, percutaneous, by weight, based on the total weight of the composition or transmucosal and buccal. As used herein, "dermal” includes layer at issue, of the excluded component. skin and mucosa, which includes oral, buccal, nasal, rectal 0040. As used herein “subject' denotes any animal in need and Vaginal mucosa. of drug therapy, including humans. For example, a subject 0048. As used herein, “transdermal drug delivery system' may be suffering from or at risk of developing a condition that refers to a system (e.g., a device) comprising a composition can be treated or prevented with a tertiary amine drug (such as that releases drug upon application to the skin (or any other rivastigmine, fentanyl or rotigotine), or may be taking a ter Surface noted above). A transdermal drug delivery system tiary amine drug (such as rivastigmine fentanyl or rotigotine) may comprise a drug-containing layer, and, optionally, a for health maintenance or other purposes. backing layer and/or a release liner layer. In some embodi 0041 As used herein, the phrases “therapeutically effec ments, the transdermal drug delivery system comprises a tive amount” and “therapeutic level” mean that drug dosage skin-contacting face adhesive layer, a rate-controlling mem or plasma concentration in a Subject, respectively, that pro brane and a drug-containing layer, and, optionally, a backing vides the specific pharmacological response for which the layer and/or a release liner layer. In some embodiments, the drug is administered in a Subject in need of such treatment. It transdermal drug delivery system is a Substantially non-aque US 2014/0276478 A1 Sep. 18, 2014 ous, Solid form, capable of conforming to the Surface with temperature (T), measured using a differential scanning which it comes into contact, and capable of maintaining Such calorimeter, of between about -70° C. and 0°C. contact so as to facilitate topical application without adverse 0055 As used herein, the term “rubber-based pressure physiological response, and without being appreciably sensitive adhesive' refers to a viscoelastic material which has decomposed by aqueous contact during topical application to the properties of a pressure-sensitive adhesive and which a subject. contains at least one natural or synthetic elastomeric polymer. 0049. As described below, in some embodiments, the 0056. In some embodiments, the transdermal drug deliv transdermal drug delivery system comprises a drug-contain ery system includes one or more additional layers. Such as one ing polymer matrix that comprises a pressure-sensitive adhe or more additional polymer matrix layers, one or more adhe sive or bioadhesive, and is adopted for direct application to a sive layers that adhere the transdermal drug delivery system users (e.g., a Subjects) skin. In other embodiments, trans to the user's skin, Such as an adhesive overlay, and/or one or dermal drug delivery system comprises askin-contacting face more rate-controlling membrane. In other embodiments, the adhesive layer separate from the drug-containing polymer transdermal drug delivery system is monolithic, meaning that matrix. In Such embodiments, the polymer matrix optionally it comprises a single polymer matrix layer comprising a pres may be non-adhesive. sure-sensitive adhesive or bioadhesive with drug dissolved or 0050. As used herein, "polymer matrix' refers to a poly dispersed therein, and no rate-controlling membrane. Thus, mer composition which contains one or more drugs. In some as used herein, a “monolithic' transdermal drug delivery embodiments, the matrix comprises a pressure-sensitive system may include a backing layer and/or release liner, and adhesive polymer or a bioadhesive polymer. In other embodi may be provided in a package. ments, the matrix does not comprise a pressure-sensitive 0057 The transdermal drug delivery system also may adhesive or bioadhesive. As used herein, a polymer is an include a drug impermeable backing layer or film. (By “adhesive' if it has the properties of an adhesive per se. A “impermeable' to the drug is meant that no substantial polymer that does not itself functions as an adhesive can be amount of drug loss through the backing layer is observed.) In made to do so by the addition of tackifiers, plasticizers, Some embodiments, the backing layer is adjacent one face of crosslinking agents or other additives. the polymer matrix layer. When present, the backing layer protects the polymer matrix layer (and any other layers 0051. In some embodiments, the polymer matrix com present) from the environment and prevents loss of the drug prises a pressure-sensitive adhesive polymer or a bioadhesive and/or release of other components to the environment during polymer, with drug dissolved or dispersed therein. In some use. Materials suitable for use as backing layers are well embodiments the polymer matrix comprises a polymer that known known in the art and can comprise films of polyester, may or may not be a pressure-sensitive adhesive polymer, and polyethylene, vinyl acetate resins, ethylene/vinyl acetate also comprises tackifiers, plasticizers, crosslinking agents, copolymers, polyvinyl chloride, polyurethane, and the like, enhancers, co-solvents, tillers, antioxidants, solubilizers, metal foils, non-woven fabric, cloth and commercially avail crystallization inhibitors, or other additives described herein. able laminates. A typical backing material has a thickness in U.S. Pat. No. 6,024,976 describes non-limiting examples of the range of 2 to 1000 micrometers. For example, 3M's polymer blends that can be used in the transdermal drug Scotch PakTM 1012 or 9732 backing material (a polyester film delivery systems described herein. The entire contents of U.S. with an ethylene vinyl acetate copolymer heat seal layer) is Pat. No. 6,024.976 is incorporated herein by reference. useful in the transdermal drug delivery systems described 0052. As used herein, the term “pressure-sensitive adhe herein. sive' refers to a viscoelastic material which adheres instan 0058. The transdermal drug delivery system also may taneously to most Substrates with the application of very include a release liner, typically located adjacent the opposite slight pressure and remains permanently tacky. As noted face of the system as compared to the backing layer. When above, a polymer is a pressure-sensitive adhesive within the present, the release liner is removed from the system prior to meaning of the term as used herein if it has the properties of use to expose the polymer matrix layer and/or an adhesive a pressure-sensitive adhesive per se. Other polymers can be layer prior to topical application. Materials Suitable for use as made to function as a pressure-sensitive adhesive by admix release liners are well-known known in the art and include the ture with tackifiers, plasticizers or other additives. commercially available products of Dow Corning Corpora 0053. The term pressure-sensitive adhesive also includes tion designated Bio-Release R liner and Syl-OffR 7610 (both mixtures of different polymers and mixtures of polymers, silicone-based), Loparex’s silicone-coated PET release iner such as polyisobutylenes (PIB), of different molecular films and 3M's ScotchpakTM 1020, 1022, 9741, 9742, 9744, weights, wherein each resultant mixture is a pressure-sensi 9748 and 9755 (fluoropolymer coated polyester films). tive adhesive. In the last case, the polymers of lower molecu 0059. The transdermal drug delivery system may be pack lar weight in the mixture are not considered to be “tackifiers.” aged or provided in a package. Such as a pouchstock material said term being reserved for additives which differ other than used in the prior art for transdermal drug delivery systems in in molecular weight from the polymers, to which they are general or for transdermal drug delivery systems for the spe added. cific tertiary amine drug being formulated (e.g., rivastigmine, 0054. In some embodiments, the polymer matrix and/or fentanyl or rotigotine). For example, DuPont's Surlyn R) can face adhesive is a pressure-sensitive adhesive at room tem be used in a pouchstock material. perature and has other desirable characteristics for adhesives 0060. As noted above, in specific embodiments, the trans used in the transdermal drug delivery art. Such characteristics dermal drug delivery systems described herein achieve drug include good adherence to skin, ability to be peeled or other delivery over an extended time period, such a period of wise removed without substantial trauma to the skin, reten greater than one day, such as a period of at least 3 days, at least tion of tack with aging, etc. In some embodiments, the poly 5 days, at least 7 days, or longer. One challenge encountered mer matrix and/or face adhesive has a glass transition in developing transdermal drug delivery systems that can US 2014/0276478 A1 Sep. 18, 2014 achieve drug delivery over an extended time period relates to of a carrier polymer; about 0% to about 90% by weight of a the difficulty of achieving stable, sustained-delivery of a carboxyl group-containing compound (such as a polymer therapeutically effective amount of drug. comprising carboxylic acid groups); about 0% to about 1% of 0061 For example, tertiary amine drugs (such as rivastig an antioxidant; and about 0% to about 20% of other optional mine, fentanyl or rotigotine) permeate across the skin rela excipients (such as a plasticizer or filler). In specific embodi tively easily through passive pathways. When such drugs are ments, the ratio of the acid and base components are adjusted formulated in a polymer matrix, delivery of the drug generally stoichiometrically such that greater than 50% of the free base is controlled by diffusion of the drug across the skin, which is is associated with a carboxylic acid to form a salt. In some highly dependent on the concentration of the drug in the embodiments, the salt form comprises about at least about matrix. Thus, the flux of the drug tends to drop significantly 60%, at least about 70%, at least about 80%, or at least about over time as the concentration of the drug in the matrix 90%, or more, including about 100%, of the total tertiary decreases. The transdermal drug delivery systems described amine drug content. In accordance with some embodiments, herein address this problem by providing one or more addi the content of the salt form is adjusted with reference to the tional mechanisms of controlling drug delivery. intended application period (e.g., 3 days, 7 days, etc.) in order 0062. It was surprisingly discovered that by providing ter to achieve the desired drug delivery profile. tiary amine drugs in a transdermal drug delivery system with 0065. In accordance with other embodiments, the trans a carboxyl group-containing compound. Such as a carboxyl dermal drug delivery system comprises a drug-containing group-containing acid excipient or acidifying agent and/or a polymer matrix layer that comprises a tertiary amine drug polymer comprising carboxyl functional groups, the delivery (such as rivastigmine, fentanyl or rotigotine) in free base form of the tertiary amine drug from the composition can be con (and, optionally, in a salt form with a with a carboxyl group trolled. For example, carboxyl group-containing compounds containing compound) and a face adhesive layer comprising present in the transdermal drug delivery system may interact a carboxyl group-containing compound. Such as a carboxyl and react with the free base form of the tertiary amine drug to group-containing acid excipient or acidifying agent, or a form a salt. However, while not wanting to be bound by any polymer comprising carboxyl functional groups. In specific theory, it is believed that only the free base form of tertiary embodiments, the face adhesive comprises a carboxyl group amine drugs are available for permeation across the skin. containing polymer, such as a pressure-sensitive adhesive Thus, when a tertiary amine drug is provided in a transdermal polymer comprising carboxy-functional groups. In some drug delivery system with a carboxyl group-containing com embodiments, the face adhesive additionally or alternatively pound, the amount of free base available for transdermal comprises a carboxyl group-containing acidifying agent. delivery will depend on dissociation from the salt form, which 0066. In some embodiments, the face adhesive includes an in turn is regulated by the association/dissociation equilib amount of carboxyl group-containing compound to form a rium between the free base and its carboxylic acid salt forms. salt with at least about 60%, at least about 70%, at least about Thus, again while not wanting to be bound by any theory, it is 80%, or at least about 90%, or more, including about 100%, of believed that the salt present in the system provides a constant the tertiary amine drug present in the system (e.g., formulated source of free base that fluxes out of the system and penetrates in the polymer matrix layer). In accordance with some the skin, thereby permitting sustained, controlled delivery of embodiments, the content of the carboxyl group-containing a pharmaceutically effective amount of drug. In some compound is adjusted with reference to the intended applica embodiments, the carboxyl group-containing compound is tion period (e.g., 3 days, 7 days, etc.) in order to achieve the present in the drug-containing polymer matrix. In other desired drug delivery profile. embodiments, the carboxyl group-containing compound is 0067. In some embodiments, both the polymer matrix and additionally or alternatively present in a separate layer, Such the face adhesive include carboxyl group-containing com as in a skin-contacting face adhesive layer. pounds. In specific embodiments, the total amount of car 0063 Thus, in accordance with some embodiments, the boxyl group-containing compound present in the polymer transdermal drug delivery system comprises a drug-contain matrix and face adhesive is sufficient to form a salt with at ing polymer matrix layer that comprises a tertiary amine drug least about 60%, at least about 70%, at least about 80%, or at (such as rivastigmine, fentanyl or rotigotine) in a salt form least about 90%, or more, including about 100%, of the ter with a carboxyl group-containing compound. Such as a car tiary amine drug present in the system (e.g., formulated in the boxyl group-containing acid excipient or acidifying agent, or polymer matrix layer). In accordance with Some embodi a polymer comprising carboxyl functional groups. In specific ments, the content of the carboxyl group-containing com embodiments, the systems comprise a polymer matrix com pound is adjusted with reference to the intended application prising the free base form of a tertiary amine drug (such as period (e.g., 3 days, 7 days, etc.) in order to achieve the rivastigmine, fentanyl or rotigotine) and a carboxyl group desired drug delivery profile. containing compound. In specific embodiments, the systems 0068 Carrier Polymers comprise a tertiary amine drug in free base form and in a salt 0069. The carrier polymer of the polymer matrix may be form with a carboxyl group-containing compound. In some any polymer Suitable for use in a transdermal drug delivery embodiments, the polymer matrix comprises a carboxyl system. In specific embodiments, the carrier polymer is group-containing polymer, such as a pressure-sensitive adhe chemically compatible with the tertiary amine drug. For sive polymer comprising carboxy-functional groups. In some example, the carrier polymer may be a hydrophilic polymer embodiments, the polymer matrix additionally or alterna approved for pharmaceutical use such as an acrylic polymer, tively comprises a carboxyl group-containing acidifying cellulose polymer, or mixture thereof. In some embodiments, agent. the carrier polymer is a pressure-sensitive adhesive. Such as 0064. In specific embodiments, the compositions com an acrylic pressure-sensitive adhesive. Such as those exem prise a polymer matrix comprising about 10% to about 40% plified below. In some embodiments, the carrier polymer by weight of the free base; about 0% to about 90% by weight includes carboxyl functional groups. In those embodiments, US 2014/0276478 A1 Sep. 18, 2014 the carrier polymer may function as a carboxyl group-con late, dodecyl methacrylate, tridecyl acrylate, tridecyl taining compound, as discussed above. For example, a carrier methacrylate, glycidyl acrylate, and corresponding meth polymer, such as an acrylic pressure-sensitive adhesive poly acrylic esters. mer, may include carboxyl functional groups which can react 0076 Non-functional acrylic-based polymers can include via ionic interactions with the tertiary amine groups of the any acrylic based polymer having no or Substantially no free drug to form a salt. In such embodiments, the polymer matrix functional groups. may require less or none of a separate carboxyl group-con 0077. Functional monomers, copolymerizable with the taining compound (such as an acidifying agent) which may above alkyl acrylates or methacrylates, which can be used resultina polymer matrix with better adhesive properties than include acrylic acid, methacrylic acid, maleic acid, maleic a matrix that comprises a Substantial amount of, for example, anhydride, hydroxyethyl acrylate, hydroxypropyl acrylate, an acidifying agent. acrylamide, dimethyl acrylamide, acrylonitrile, dimethy 0070. As noted above, the carrier polymer may comprise laminoethyl acrylate, dimethylaminoethyl methacrylate, tert from about 0 to about 90% by weight of the polymer matrix. butylaminoethyl acrylate, tert-butylaminoethyl methacry Acrylic Polymers late, methoxyethyl acrylate and methoxyethyl methacrylate. 0071 0078. As used herein, “functional monomers or groups.” 0072. In some embodiments, the polymer carrier com are monomer units typically in acrylic-based polymers which prises an acrylic polymer. The term “acrylic polymer is used have reactive chemical groups which modify the acrylic here as in the art interchangeably with “polyacrylate.” “poly based polymers directly or which provide sites for further acrylic polymer,” and “acrylic adhesive.” The acrylic-based reactions. Examples of functional groups include carboxyl, polymers can be any of the homopolymers, copolymers, ter epoxy, hydroxyl, Sulfoxyl, and amino groups. Acrylic-based polymers, and the like of various acrylic acids or esters. In polymers having functional groups contain, in addition to the Some embodiments, the acrylic-based polymers are adhesive nonfunctional monomerunits described above, further mono polymers. In other embodiments, the acrylic-based polymers mer units having free functional groups. The monomers can function as an adhesive by the addition of tackifiers, plasti be monofunctional or polyfunctional. These functional cizers, crosslinking agents or other additives. groups include carboxyl groups, hydroxy groups, amino 0073. The acrylic polymer can include copolymers, ter groups, amino groups, epoxy groups, etc. Typical carboxyl polymers and multipolymers. For example, the acrylic poly functional monomers include acrylic acid, methacrylic acid, mer can be any of the homopolymers, copolymers, terpoly itaconic acid, maleic acid, and crotonic acid. Typical hydroxy mers, and the like of various acrylic acids. In some functional monomers include 2-hydroxyethyl methacrylate, embodiments, the acrylic polymer constitutes from about 2% 2-hydroxyethyl acrylate, hydroxymethyl acrylate, to about 95% by weight of the polymer content of the polymer hydroxymethyl methacrylate, hydroxyethyl acrylate, matrix, including about 3% to about 90% and about 5% to hydroxyethyl methacrylate, hydroxypropyl acrylate, hydrox about 85%, such as 2% to 95%, 3% to 90% and 5% to 85%. In ypropyl methacrylate, hydroxybutyl acrylate, hydroxybutyl Some embodiments, the amount and type of acrylic polymer methacrylate, hydroxyamyl acrylate, hydroxyamyl meth is dependent on the type and amount of tertiary amine drug acrylate, hydroxyhexyl acrylate, hydroxyhexylmethacrylate. (such as rivastigmine, fentanyl or rotigotine) used. As noted above, in Some embodiments, the acrylic polymer does not include Such functional groups. 0074 Acrylic polymers useful in practicing the invention 007.9 Further details and examples of acrylic adhesives include polymers of one or more monomers of acrylic acids which are suitable in the practice of the invention are and other copolymerizable monomers. The acrylic polymers described in Satas, “Acrylic Adhesives.” Handbook of Pres also include copolymers of alkyl acrylates and/or methacry sure-Sensitive Adhesive Technology, 2nd ed., pp. 396-456 lates and/or copolymerizable secondary monomers or mono (D. Satas, ed.), Van Nostrand Reinhold, New York (1989); mers with functional groups. Combinations of acrylic-based Acrylic and Methacrylic Ester Polymers. Polymer Science polymers based on their functional groups is also contem and Engineering, Vol. 1, 2nd ed., pp. 234-268, John Wiley & plated. Acrylic-based polymers having functional groups Sons, (1984); U.S. Pat. No. 4.390.520; and U.S. Pat. No. include copolymers and terpolymers which contain, in addi 4,994.267, all of which are expressly incorporated by refer tion to nonfunctional monomer units, further monomer units ence in their entireties. having free functional groups. The monomers can be mono 0080 Suitable acrylic polymers also include pressure functional or polyfunctional. By varying the amount of each sensitive adhesives which are commercially available. Such as type of monomer added, the cohesive properties of the result the acrylic-based adhesives sold by Henkel North America ing acrylic polymer can be changed as is known in the art. In under the Duro-TakR) trade name (such as Duro-Tak.R. Some embodiments, the acrylic polymer is composed of at 87-2287, -4098, -2852, -21.96, -2296, -2194, -2825, -2516, least 50% by weight of an acrylate or alkyl acrylate monomer, -2070, -2353, -2154, -2510, -4852, -9085, -9088, -9900, from 0 to 20% of a functional monomer copolymerizable -2051, -2052, -2054, 235A, -2074, -2979, -2525, -2677, with the acrylate, and from 0 to 40% of other monomers. -4287, -502A, -503A, -504A, -900A, -901A and -9301) and 0075 Acrylate monomers which can be used include those sold by Cytec Surface Specialties, St. Louis, Mo., under acrylic acid and methacrylic acid and alkyl acrylic or meth the GELVAR) GMS trade name (such as GELVAR) GMS acrylic esters such as methyl acrylate, ethyl acrylate, propyl 2480, 788, 7883, 737, 263, 1430, 1753, 1151, 2450, 2495, acrylate, amyl acrylate, butyl acrylate, butyl methacrylate, 2499, 3067, 3071, 3083,3087, 3235,9073 and 9083). Other hexyl acrylate, methyl methacrylate, hexyl methacrylate, suitable acrylic adhesives include those sold under the trade heptyl acrylate, octyl acrylate, nonyl acrylate, 2-ethylbutyl mark EUDRAGITR) by Evonik Industries AG, Essen, Ger acrylate, 2-ethylbutyl methacrylate, isooctyl acrylate, isooc many, For example, hydroxy functional adhesives with a tyl methacrylate, 2-ethylhexyl acrylate, 2-ethylhexyl meth reactive functional OH group in the polymeric chain, can be acrylate, decyl acrylate, decyl methacrylate, dodecyl acry used. Non-limiting commercial examples of this type of US 2014/0276478 A1 Sep. 18, 2014

adhesives include both GELVAR GMS 737, 788, and 1151, Such as natural or synthetic polyisoprene, polybutylene, poly and Duro-TakR (DT) 87-2287, -4287, -2510 and -2516. isobutylene, Styrene-butadiene polymers, styrene-isoprene 0081. As noted above, in specific embodiments polymers styrene block copolymers (such as Kraton R. D11 1 KT). comprising carboxyl functional groups are used. Non-limit hydrocarbon polymers, such as butyl rubber, halogen-con ing commercial examples of Such polymers include Duro taining polymers, such as polyacrylic-nitrile, polytetrafluo TakR 87-2194, -21.96, -2852, -2074, -2677, -4852 and roethylene, polyvinylchloride, polyvinylidene chloride, and GELVACR) GMS 9083 and 9073. polychlorodiene, and other copolymers thereof. Additionally I0082 Silicon Polymers or alternatively, as discussed above, the polymer matrix may 0083. In some embodiments, the polymer carrier com comprise a non-adhesive polymer, Such as ethyl cellulose. prises a silicone-based polymer. The term “silicone-based 0090. As noted above, the carrier polymer may comprise polymer is used interchangeably with the terms silicon poly from about 0 to about 90% by weight of the polymer matrix mers, siloxane, polysiloxane, and silicones as used herein and depending on the target content of the salt form. as known in the art. A suitable silicone-based polymer may 0091 Face Adhesive also be a pressure-sensitive adhesive. Thus, in Some embodi 0092. In some embodiments, the transdermal drug deliv ments, the silicone-based polymer is an adhesive polymer. In ery system comprise a skin-contacting face adhesive layer other embodiments, the silicone-based polymer functions as separate from the polymer matrix. In accordance with Such an adhesive by the addition of tackifiers, plasticizers, embodiments, the face adhesive may comprise any one or crosslinking agents, or other additives. more of the polymers described above. In specific embodi 0084 Suitable polysiloxanes include silicone pressure ments, the face adhesive comprises a silicone polymer, Such sensitive adhesives which are based on two major compo as one or more of those described above. In other embodi nents: (i) a polymer or gum and (ii) a tackifying resin. A ments, the face adhesive comprises an acrylic polymer, Such polysiloxane adhesive can be prepared by cross-linking a as a non-functional acrylic polymer, including one or more of gum, typically a high molecular weight polydiorganosilox Duro-Tak.R. 87-9900, -900A, or GELVAR GMS 3235. ane, with a resin, to produce a three-dimensional silicate 0093. In some embodiments, the polymer component(s) structure, via a condensation reaction in an appropriate of the face adhesive are selected to achieve one or more of the organic, Volatile solvent, such as ethylacetate or heptane. The following characteristics: good skin adhesion for the intended ratio of resin to polymer can be adjusted in order to modify the period of application (e.g., at least 1 day, at least 3 days, at physical properties of polysiloxane adhesives. Sobieski, et least 7 days, or longer); minimal resistance to drug diffusion; al., “Silicone Pressure Sensitive Adhesives.” Handbook of minimal solubility for the drug without exhibiting “dumping Pressure-Sensitive Adhesive Technology, 2nd ed., pp. 508 upon initial contact with skin that leads to a “burst effect: 517 (D. Satas, ed.), Van Nostrand Reinhold, New York physical and chemical compatibility with the drug. As dis (1989). cussed above, including a carboxyl group-containing com 0085 Exemplary silicone-based polymers are adhesives pound in the face adhesive Supports the latter characteristic. (e.g., capable of Sticking to the site of topical application), 0094 Carboxyl Group-Containing Compounds including pressure-sensitive adhesives. Illustrative examples 0095. In some embodiments, the polymer matrix and/or of silicone-based polymers having reduced silanol concentra face adhesive layer includes a carboxyl group-containing tions include silicone-based adhesives (and capped polysi compound, Such as a carboxyl group-containing acid excipi loxane adhesives) such as those described in U.S. Pat. No. Re. ent or acidifying agent, or a polymer comprising carboxyl 35.474 and U.S. Pat. No. 6,337,086, which are incorporated functional groups. herein by reference in their entireties, and which are commer (0096 Polymers cially available from Dow Corning Corporation (Dow Corn 0097. As noted above, in some embodiments the carrier ing Corporation, Medical Products, Midland, Mich.) as BIO polymer and/or face adhesive includes carboxyl functional PSAR) 7-4 100, -4200 and -4300 product series, and non groups. In Such embodiments, the polymer may function as a sensitizing, pressure-sensitive adhesives produced with carboxyl group-containing compound. For example, a carrier compatible organic Volatile solvents (such as ethyl acetate or polymer or face adhesive polymer, such as an acrylic pres heptane) and available commercially under their BIO-PSAR) Sure-sensitive adhesive polymer, may include carboxyl func 7-4400 series, -4500 series, such as -4502, and -4600 series. tional groups which can react via ionic interactions with the I0086. Further details and examples of silicone pressure tertiary amine groups of the tertiary amine drug (Such as sensitive adhesives which are useful in the polymer matrices rivastigmine, fentanyl or rotigotine) to form a salt. In Such and compositions and methods described herein are men embodiments, the polymer matrix or face adhesive layer may tioned in the following U.S. Pat. Nos. 4,591,622; 4.584,355; require less or none of a separate carboxyl group-containing 4.585,836; and 4,655,767, which are all expressly incorpo compound (such as an acidifying agent) which may result in rated by reference herein in their entireties. It should also be a polymer matrix or face adhesive with better adhesive prop understood that silicone fluids are also contemplated for use erties than a matrix that comprises a Substantial amount of for in the polymer matrices and methods described herein. example, an acidifying agent. 0087. In some embodiments, the polysiloxane constitutes 0.098 Suitable polymers that include carboxyl functional from about 9% to about 97% of the polymer content of the groups include the carboxy-functional acrylic polymers illus polymer matrix, including about 8% to about 97% and about trated above. Specific examples of Such a polymer include 14% to about 94%, such as 9% to 97%, 8% to 97%, and 14% Duro-Tak(R87-2852, 87-4852, and 87-2194. In embodiments to 94%. where the carboxyl group-containing compound is provided I0088. Other Polymers in a separate layer from the polymer matrix, such as in a face 0089. As noted above, in some embodiments the polymer adhesive layer, the separate layer (e.g., the face adhesive matrix comprises one or more rubber-based polymers. Such layer) may include any of these carboxy-functional acrylic as one or more rubber-based pressure-sensitive adhesives, polymers. US 2014/0276478 A1 Sep. 18, 2014

0099. Acidifying Agents as "enhancers.” This class of agents includes those with 0100. As noted above, in some embodiments the carboxyl diverse mechanisms of action, including those which have the group-containing compound is provided as a carboxyl group function of improving percutaneous absorption, for example, containing acid excipient or acidifying agent. In specific by changing the ability of the stratum corneum to retain embodiments, the carboxyl group-containing compound is a moisture, softening the skin, improving the skin's permeabil carboxylic acid. Such as a polymeric carboxylic acid. In spe ity, acting as penetration assistants or hair-follicle openers or cific embodiments, the carboxylic acid is one that will not changing the state of the skin including the boundary layer. diffuse out of the patch into the skin. In specific embodiments, 0109 Illustrative penetration enhancers include but are the carboxylic acid is a polymer excipient containing car not limited to polyhydric alcohols such as dipropylene glycol, boxyl groups, such as Eudragit(R) L 100 or Eudragitt R S 100 propylene glycol, and polyethylene glycol, oils such as olive polymers (anionic copolymers based on methacrylic acid and oil, squalene, and lanolin; fatty ethers such as cetyl ether and methyl methacrylate in a 1:1 or 1:2 ratio, respectively) and oleyl ether; fatty acid esters such as isopropyl myristate; urea carbomer or carbopol polymers (e.g., synthetic high molecu and urea derivatives such as allantoin which affect the ability lar weight crosslinked polymers of acrylic acid), other vinyl of keratin to retain moisture; polar solvents such as dimeth polymers containing carboxylic acid groups, and carboxyl yldecylphosphoxide, methyloctylsulfoxide, dimethyllauryla containing cellulose or starch, Such as carboxymethyl cellu mide, dodecylpyrrolidone, isosorbitol, dimethylacetonide, lose or starch. In other embodiments the acidifying agent is an dimethylsulfoxide, decylmethylsulfoxide, and dimethylfor acid, such as lactic acid, oleic acid, and the like. mamide which affect keratin permeability; salicylic acid 0101. In some embodiments the carboxyl group-contain which softens the keratin; amino acids which are penetration ing compound is not itself a penetration enhancer, Such as a assistants; benzyl nicotinate which is a hair follicle opener; fatty acid known for use as a penetration enhancer, such as and higher molecular weight aliphatic Surfactants such as oleic acid. Thus, in some embodiments, the transdermal drug lauryl sulfate salts which change the surface state of the skin delivery system does not include a penetration enhancer that and drugs administered. Other agents include oleic and includes a carboxylic acid group. linoleic acids, ascorbic acid, panthenol, butylated hydroxy 0102. In some embodiments the carboxyl group-contain toluene, tocopherol, tocopheryl acetate, tocopheryllinoleate, ing compound is not a monocarboxylic fatty acid, such as propyl oleate, and isopropyl palmitate. capric acid or lauric acid, or a bile acid, Such as a monocar 0110. In some embodiments, the polymer matrix or trans boxylic fatty acid derived from bile, such as glycocholic acid, dermal drug delivery system does not include a penetration glycodeoxycholic acid, cholic acid, deoxycholic acid, tauro enhancer. In some embodiments, the polymer matrix or trans cholic acid, or taurodexycholic acid. Thus, in some embodi dermal drug delivery system does not include a penetration ments, the transdermal drug delivery system does not include enhancer that includes carboxylic acid groups. Thus, in some a monocarboxylic fatty acid, Such as any of these monocar embodiments, the polymer matrix or or transdermal drug boxylic fatty acids. delivery system does not include a penetration enhancer that 0103) As noted above, the carboxyl group-containing includes carboxylic acid groups. compound may be provided in the polymer matrix and/or in a 0111. The polymer matrix and/or face adhesive may fur separate layer from the polymer matrix. Such as in a face ther comprise various thickeners, fillers, and other additives adhesive layer. In Such embodiments, the separate layer (e.g., or components known for use in transdermal drug delivery the face adhesive layer) may include any of these carboxy systems to further modify properties of the matrix or face functional acrylic polymers. adhesive, such as polyvinylpyrrolidone (PVP), ethylene-vi 0104 Antioxidant nyl acetate copolymers, cellulose derivatives, SiO2, and other 0105. In accordance with any of the embodiments components. described herein, the polymer matrix and/or face adhesive layer may comprise an antioxidant. In specific embodiments 0112. In some embodiments, the polymer matrix or trans the antioxidant may be one known for use in transdermal drug dermal drug delivery system does not include cyclodextrin, or delivery systems, such as butylhydroxytoluene (BHT), butyl a complex comprising cyclodextrin and the active agent. hydroxyanisole (BHA), tertiary-butylhydroquinone Thus, in Some embodiments, the polymer matrix or transder (TBHQ), ascorbic acid, ascorbyl palmitate, alpha-tocopherol mal drug delivery system does not include cyclodextrin, or a and its esters, fumaric acid, malic acid, Sodium ascorbate, complex comprising cyclodextrin and the active agent. Sodium metabisulfite, and propyl gallate, and mixtures 0113 Tertiary Amine Drug thereof. As noted above, the antioxidant may comprise from 0114. As noted above, as used herein, “tertiary amine about 0 to about 1%, including from about 0 to about 0.5% by drug includes any therapeutically active compound with a weight of the polymer matrix. tertiary amine structure, including amiodarone, amitriptyline, 0106. Other Components atropine, benztropine, biperiden, bornaprine, bupivacaine, 0107. In accordance with any of the embodiments chlorpheniramine, cinnarizine, clomipramine, cyclopento described herein, the polymer matrix and/or face adhesive late, darifenacin, dexetimide, dicyclomine, diltiazem, polymer may comprise one or more other pharmaceutically diphenhydramine, doxepin, ethopropazine, fentanyl, flavox acceptable excipients, such as a plasticizer, penetration ate, homatropine, imipramine, loxapine, maZaticol, metix enhancer, filler, and the like. In some embodiments, the poly ene, oxybutin, oxyphencyclimine, phenglutarimide, physos mer matrix comprises from about 0% to about 20% of one or tigmine, piperidolate, pirenzepine, procyclidine, more such excipients. profenamine, propiverine, rivastigmine, rotogotine, Scopola 0108. A “penetration enhancer is an agent known to mine, telenzepine, theophylline, tolterodine, trimipramine, accelerate the delivery of the drug through the skin. These trihexyphenidyl, tropatepine, and tropicamide. In some agents also have been referred to as accelerants, adjuvants, embodiments, the tertiary amine drug is rivastigmine, rotogo and sorption promoters, and are collectively referred to herein tine, or fentanyl. US 2014/0276478 A1 Sep. 18, 2014

0115 The amount of tertiary amine drug to be incorpo (0123 Monolithic Systems rated in the polymer matrix varies depending on the specific 0.124. In some embodiments, the system consists essen drug, the desired therapeutic effect, and the length of time for tially of the polymer matrix layer. By “consists essentially of which the system is to provide therapy. As noted above, in the polymer matrix layer” means that the system does not Some embodiments, the composition is designed to achieve contain any other layers that affect drug delivery, Such as an drug delivery over an extended time period, such a period of additional rate-controlling polymer layer, rate-controlling greater than one day, such as a period of at least 3 days, at least membrane, or drug reservoir layer. It will be understood, 4 days, at least 5 days, at least 6 days, at least 7 days, or longer. however, that the system that consists essentially of the poly Thus, in one embodiment, the composition comprises an mer matrix layer may comprise a backing layer and/or release amount of tertiary amine drug sufficient to deliver therapeu liner. tically effective amounts of drug over a period of from 1 day 0.125 Rate-Controlling Membrane to 3 days, 7 days, or longer, including for 1 day, for 2 days, for 0.126. As noted above, in some embodiments, the trans 3 days, for 4 days, for 5 days, for 6 days, for 7 days, or for dermal drug delivery system includes a rate-controlling mem longer. brane disposed between the polymer matrix and the skin 0116. In embodiments where the tertiary amine drug is contacting face adhesive. Rate-controlling membranes are rivastigmine, a therapeutically effective amount of rivastig known in the art. For example, a rate-controlling membrane mine delivered by the composition may be from about 3 to may comprise polyethylene, polyolefin, and/or ethylene vinyl about 12 mg/day, including about 4.6 mg/day and about 9.5 acetate, or other polymer films. Exemplary commercial avail mg/day. Thus, in Some embodiments, the transdermal drug able films Suitable for use as rate-controlling membranes delivery system comprises an amount of rivastigmine effec include 3M CoTranTM polyethylene/vinyl acetate films, such tive to achieve a delivery of from about 3 to about 12 mg/day, as CoTranTM 9719 (polyethylene) (1.7 mil), CoTranTM 9720 including about 4.6 mg/day or about 9.5 mg/day. (polyethylene) (3 mil), CoTranTM 9722 (polyethylene) (3 0117. In embodiments where the tertiary amine drug is mil), CoTranTM 97.18 (polyethylene) (3.6 mil), CoTranTM rotigotine, a therapeutically effective amount of rotigotine 9726 (2% vinyl acetate, 2 mil), CoTranTM 9707 (4.5% vinyl delivered by the composition may be 1, 2, 3, 4, 6 or 8 mg/day acetate, 2 mil), CoTranTM 9702 (9% vinyl acetate, 2 mil), of rotigotine, such as for the treatment of Parkinson's disease CoTranTM 9705 (9% vinyl acetate, 3 mil), CoTranTM 9706 or restless legs syndrome. (9% vinyl acetate, 4 mil), CoTranTM 97.12 (18.5% vinyl 0118. In embodiments where the tertiary amine drug is acetate, 2 mil), CoTranTM 9728 (18.5% vinyl acetate, 2 mil), fentanyl, a therapeutically effective amount offentanyl deliv CoTranTM 9715 (18.5% vinyl acetate, 3 mil), CoTranTM 97.16 ered by the composition may be 12.5, 25, 50, 75 or 100 ug/hr (18.5% vinyl acetate, 4 mil). offentanyl. Such as for pain management. I0127 Drug permeability through the membrane may be 0119. As noted above, in some embodiments, therapeuti selected and controlled by selecting the polymer components cally effective drug delivery rates are sustained over a dura of the membrane, for example, by varying the vinyl acetate tion of application of at least about 1 day, including at least content of an ethylene vinyl acetate polymer, and/or by select about 3 days and at least about 7 days, such as at least 1 day, ing and controlling the density of the membrane, and/or by at least 2 days, at least 3 days, at least 4 days, at least 5 days, selecting and controlling the thickness of the membrane, at least 6 days, and at least 7 days. and/or by other means known in the art. 0120. As noted above, in specific embodiments, the ratio I0128. The system may be of any shape or size suitable for of the acid components (e.g., the carboxyl group-containing transdermal application and of an appropriate sizes for appli components) and base components (e.g., rivastigmine free cation to deliver the desired dose. Such as ranging from about base) are adjusted Stoichiometrically Such that greater than 2 cm to about 50 cm, including about 5 cm, about 10 cm, 50% of the free base is associated with a carboxylic acid to about 20 cm, about 25 cm, about 30 cm, about 35 cm, form a salt. In some embodiments, the salt form comprises about 40 cm, about 45 cm, and about 50 cm. about at least about 60%, at least about 70%, at least about I0129. In specific embodiments relating to rivastigmine, 80%, or at least about 90%, or more, including about 100%, of the system is about 16-24 cm, such as 17.5 cm, 18 cm, 19 the total tertiary amine drug content (e.g., rivastigmine, fen cm, or 23.5 cm and contains about 60-65 mg rivastigmine tanyl or rotigotine content), including at least 60%, at least per unit dose (including 61.9 mg, 63.9 mg, 64 mg) and/or 70%, at least 80%, at least 90% and 100%. delivers a dose of about 4.6 mg/day, and about 32.2 mg over 0121 Transdermal Drug Delivery Systems 7 days. In other specific embodiments, the system is about 0122. As noted above, the carrier polymer may or may not 32-48 cm, such as 35 cm, 36 cm, 38 cm, or 47 cm, and be a pressure sensitive adhesive. Further, as noted above, the contains about 126 mg rivastigmine per unit dose and/or transdermal drug delivery system may be a monolithic device delivers a dose of about 9.5 mg/day, and about 66.5 mg over comprised of the polymer matrix, or may include one or more 7 days. In further specific embodiments relating to rivastig additional layers, such as a face adhesive layer, or may be mine, the system contains about 32-65 mg rivastigmine per provided with a Surrounding adhesive portion. As noted unit dose, or about 67-126 mg rivastigmine per unit dose. above, the transdermal drug delivery system may include a 0.130. The polymer matrices described herein may be pre backing layer on one side of the polymer matrix layer and a pared by methods known in the art. For example, a polymer release liner on the other side of the polymer matrix layer. In matrix can be prepared by blending the components of the multilayer systems, the polymer matrix layer may be the polymer matrix, applying the matrix material to a Support skin-contacting layer (e.g., directly adjacent the release liner) layer Such as a backing layer or release liner (Such as by or may be separated from the skin by one or more intervening calender coating, hot meltcoating, Solution coating, etc.), and layers, and may or may not be directly adjacent the backing removing any remaining solvents. The polymer matrices can layer. As noted above, an optional overlay adhesive film may be formed into systems by methods known in the art, such as be used to strengthen the adhesion of the patch to the skin. by die-cutting into sizes and shapes suitable for use. US 2014/0276478 A1 Sep. 18, 2014

0131 The tertiary amine drug can be added at any stage. In systems described herein are designed for use by patients one embodiment, all polymer matrix components, including Suffering from or at risk of developing Parkinson's disease or the drug, are blended together. The order of steps, amount of restless legs syndrome. ingredients, and the amount and time of agitation or mixing 0144. As noted above, a typical fentanyl dosage ranges can be determined and optimized by the skilled practitioner. from about 10 to about 100 100 lug/hr, including 12.5, 25, 50. An exemplary general method is as follows: 75 or 100 ug/hr of fentanyl. In some embodiments, the fen 0132 Appropriate amounts of Solvent(s), enhancer(s), tanyl systems described herein are designed for use by and organic solvent(s) (for example toluene, or ethyl acetate patients Suffering from or at risk of developing pain. and/or isopropyl alcohol) are combined and thoroughly 0145 The following specific examples are included as mixed together in a vessel. illustrative of the transdermal drug delivery systems and poly 0133. The tertiary amine drug (such as rivastigmie) and mer matrices described herein. These examples are in no way any antioxidant being used (such as BHT) are added to the intended to limit the scope of the invention. Other aspects of mixture and agitation is carried out until the drug is uniformly the invention will be apparent to those skilled in the art to mixed in. which the invention pertains. 0134) Appropriate amounts of acrylic polymer, carboxyl group-containing compound (e.g., acidifying agent), and Example 1 other excipients are then added to the drug mixture, and 0146 Polymer matrices with the following compositions thoroughly mixed. were prepared: 0135 The formulation is then transferred to a coating operation where it is coated onto a protective release liner at a controlled specified thickness. The coated product is then Carboxy Functional passed through an oven in order to drive off all volatile pro DURO-TAK (R) Anti- Target Salt cessing solvents. Composition Polymer oxidant Rivastigmine Percentage 0136. The dried product on the release liner is then joined 1-1 87-4852 79% BHT 190 20% 97% to the backing material and wound into rolls for storage. 1-2 87-4852 76.5% BUT 190 22.5% 82% 0.137 Appropriate size and shape “systems' are die-cut 1-3 87-4852 74% BHT 190 25% 729% from the roll material and then pouched. 1-6 87-2852 79% BHT 190 20% 97% 1-7 87-2852 76.5% BHT 190 22.5% 82% 0.138. Other manufacturing methods are known in the art 1-8 87-2852 74% BHT 190 25% 729% that are suitable for making the systems described herein. 1-9 87-2194 79% BHT 190 20% 69% 0.139. In some embodiments, the coat weight of the poly 1-10 87-219476.5% BHT 190 22.5% 59% mer matrix is selected and tailored to control and/or optimize 1-11 87-21947.4% BHT 190 25% 51% the drug delivery profile. For example, systems with a higher Exelon (R) 87-2353 70% 30% <49% coat weight (e.g., unit weight of polymer matrix per unit area of system) may achieve increased drug flux and improved flux 0147 Each polymer matrix is applied with a coat weight profile. of about 10-15 mg/cm (e.g., 12.5+2.5 mg/cm) to a release liner, and a backing material is applied. Human cadaver skin 0140. Therapeutic Methods permeation studies are performed to assess permeation 0141. In some embodiments, there is provided a method of through the stratum corneum. effecting transdermal drug delivery of a tertiary amine drug, 10148 FIG. 1 illustrates the rivastigmine flux (ug/cm/hr) Such as rivastigmine, fentanyl or rotigotine, by applying a over time (0-168 hours) from a transdermal drug delivery system as described herein to the skin or mucosa of a subject system comprising Composition 1-1 (0), Composition 1-2 in need thereof. In some embodiments, the system is applied (), Composition 1-3 (A), or an Exelon(R) patch (O. top line). over a period of at least about 1 day, at least about 2 days, at 10149 FIG. 2 illustrates the rivastigmine flux (ug/cm/hr) least about 3 days, at least about 4 days, at least about 5 days, over time (0-168 hours) from a transdermal drug delivery at least about 6 days, or at least about 7 days. Such as for 1, 2, system comprising Composition 1-6 (0), Composition 1-7 3, 4, 5, 6 or 7 days, or longer. In some embodiments, the (), Composition 1-8 (A) or an Exelon R patch (O. top line). method is effective to achieve transdermal delivery of thera I0150 FIG. 3 illustrates the rivastigmine flux (ug/cm/hr) peutically effective amounts of drug during the application over time (0-168 hours) from a transdermal drug delivery period. In some embodiments, the method is effective to system comprising Composition 1-9 (0), Composition 1-10 achieve therapeutic levels of drug in the Subject during the .), Composition 1-11 (A) or an ExelonR patch (O. top line). application period. In some embodiments, the method is 0151. The results show that the systems according to the effective to achieve a substantially constant rate of drug deliv invention achieve sustained, controlled flux over a 7-day ery over a period of at least about 1 day, at least about 2 days, application period. at least about 3 days, at least about 4 days, at least about 5 0152 Pharmacokinetic analyses were performed with a days, at least about 6 days, or at least about 7 days, or longer. transdermal system comprising Composition 1-6 as the poly 0142. As noted above, a typical rivastigmine dosage mer matrix layer. ranges from at about 3 to about 12 mg/day, including about 4.6 or 9.5 mg/day. In some embodiments, the rivastigmine systems described herein are designed for use by patients Salt Cmax Cmin Tail Patch Est. Coat Suffering from or at risk of developing dementia associated Composition (%) (24 h) (168 h) Off Size Weight with Alzheimer's disease or Parkinson's disease. 1-6 97 2.6 1.8 31% 47 cm 13.4 mg/cm 0143 AS noted above, a typical rotigotine dosage ranges Exelon (R) <49 11.2 2.8 75%. 10 cm 9 mg/cm’ from about 1 to about 10 mg/day, including 1, 2, 3, 4, 6 or 8 mg/day of rotigotine. In some embodiments, the rotigotine US 2014/0276478 A1 Sep. 18, 2014

The results show that the system comprising Composition1-6 Example 3 as the polymer matrix achieves Sustained, controlled drug 0158 Transdermal drug delivery systems were prepared delivery over a 7-day application period. using Compositions 2-3, 2-4 and 2-8, as follows: Example 2 Est. Size Size 0153 Polymer matrices with the following compositions Coat Weight (4.6 mg/day)) (9.5 mg/day)) were prepared: Composition Salt (%) (mg/cm) (cm) (cm) 2-3 90 12.2 17.5 35 2-4 100 11.2 19 38 2-8 100 14.2 18 36 Carboxy- Target Functional Salt These transdermal drug delivery systems are able to achieve DURO-TAK (R) Anti- Eudragit (R) Per Sustained, controlled delivery of rivastigmine at pharmaceu Composition Polymer oxidant L100 Drug centage tically effective amounts over a period of time of at least 7 days. 2-1 87-285269% BHT 190 30% S6% 2-2 87-2852 63% BHT 190 6% 30% 80% Example 4 2-3 87-2852 60% BHT 190 9% 30% 90% 0159 Transdermal drug delivery systems were prepared 2-4 87-2852 58% BHT 190 11% 30%. 100% as foll 2-5 87-2852 74% BHT 190 25% 72.9% 2-6 87-2852 72.3% BHT 190 1.7% 25% 80% Layer Components 2-7 87-2852 70% BHT 190 4% 25% 90% 2-8 87-2852 68% BHT 190 6% 25%. 100% Backing Mylar (R) M813 Adhesive Matrix 30% Rivastigmine (15 mg/cm) 69% DURO-TAK (R 87-9900 196 BHT Rate-Controlling CoTran TM 9719 (1.7 mil) (System 4-1) ()or 0154 Each polymer matrix is applied with a coat weight Membrane CoTran TM 9720 (3 mil) (System 4-2)(A) of about 10-15 mg/cm (e.g., 12.5+2.5 mg/cm) to a release Face Adhesive 97% BIO-PSA (R 43O2 liner, and a backing material is applied. Human cadaver skin (5 mg/cm) 3% Eudragit (R) L100 permeation studies are performed to assess permeation Release Liner 3M ScotchPak (R) 1022 through the stratum corneum. 0160 FIGS. 6 and 7 illustrate the rivatsigmine flux (ug/ 0155 FIG. 4 illustrates the rivastigmine flux (ug/cm/hr) cm/hr) over time (0-168 hours) from the transdermal drug over time (0-168 hours) from a transdermal drug delivery delivery systems described above (System 4-1 (): System system comprising Composition 2-1 (0), Composition 2-2 4-2 (A)) or an ExelonR patch (, top line at 0–48 hours) in an (), Composition 2-3 (A), Composition 2-4 (O), or an in vitro flux study using human skin from two different Exelon(R) patch (O. top line). donors, respectively. The results show that the systems 0156 The results show that the systems according to the according to the invention achieve Sustained, controlled flux invention achieve sustained, controlled flux over a 7-day over a 7-day period. Further, the results show that the systems application period. according to the invention exhibited less flux variability and less donor-to-donor variability than the Exelon R patch. 0157 Pharmacokinetic analyses were performed with a transdermal system comprising Compositions 2-1 through Example 5 2-8 as the polymer matrix layer, applied at a coat weight of about 12.5 mg/cm to a release liner and backing layer, using 0.161 The flux of rivatsigmine liquid (“infinite-dose” of 0.5 cm pieces. 0.5 ml/cm) across systems prepared using different rate con trolling membranes (with different vinyl acetate contents and different thicknesses) with or without a 5 mg/cm silicone Composition Salt (%) Cmax (24 h) Cmin (168 h) face adhesive was assessed in an in vitro flux study, as shown below. CoTranTM 9720 (PE 3 mil) exhibited the most rate 2-1 56 24.1 4.4 2-2 8O 16.2 4 control. The 5 mg/cm2 silicone face adhesive exhibited a 2-3 90 10.4 3.9 relatively small resistance to drug flux. 2-4 1OO 9.3 3.8 2-5 72 19.1 3.5 2-6 8O 21.3 3.9 Rivastigmine steady-state flux (Lig/cm/hr 2-7 90 13.6 3.5 2-8 1OO 10.9 3.5 CoTrain TM- human Exelon (R) <49 24.8 (8 hr) 1.3 CoTrain TM Silicone face adhesive skin only (5 mg/cm) only (human skin) 32 - 14 The results show that the systems comprising compositions COTran TM 972O 11 8 as described herein as the polymer matrix achieve Sustained, (0% VA) (3 mil) controlled drug delivery over a 7-day application period. US 2014/0276478 A1 Sep. 18, 2014 12

-continued group-containing compound is such that at least 80% of the free base is associated with a carboxylic acid group to form a Rivastigmine steady-state flux (Lig/cm/hr salt. 5. The transdermal drug delivery system according to claim CoTrain TM- human COTran TM Silicone face adhesive skin 1, wherein the relative amounts of free base and carboxyl only (5 mg/cm) only group-containing compound is such that at least 90% of the free base is associated with a carboxylic acid group to form a CoTrain TM 9719 26 salt. (0% VA) (1.7 mil) CoTrain TM 9726 21 19 6. The transdermal drug delivery system according to claim (2% VA) (2 mil) 1, wherein the relative amounts of free base and carboxyl CoTrain TM 9707 34 24 group-containing compound is such that about 100% of the (4.5% VA) (2 mil) CoTrain TM 97.02 73 50 free base is associated with a carboxylic acid group to form a (9% VA) (2 mil) salt. CoTrain TM 9712 230 2S4 7. The transdermal drug delivery system according to claim (18.5% VA (2 mil) 1, wherein at least one carboxyl group-containing compound is a carrier polymer comprising carboxy-functional groups. A similar study was conducted using CoTranTM 9720 with 8. The transdermal drug delivery system according to claim different face adhesives (5 mg/cm): none (O); silicone (); 1, wherein at least one carboxyl group-containing compound silicone and GELVAR GMS 3235 (A); silicone and Dura is an acrylic pressure-sensitive adhesive polymer comprising TakR 9900 (O); silicone and Dura-TakR 87-900A (0). carboxy-functional groups. Results are shown in FIG. 8. As seen in the figure, the face 9. The transdermal drug delivery system according to claim adhesives exhibited a relatively small resistance to drug flux 1, wherein at least one carboxyl group-containing compound as compared to the CoTranTM 9720 alone. is a polymeric carboxylic acid. 10. The transdermal drug delivery system according to Example 6 claim 9, wherein the polymeric carboxylic acid is selected from the group consisting of anionic copolymers based on 0162 Transdermal drug delivery systems were prepared methacrylic acid and methyl methacrylate, carbomer poly using a polymer matrix comprising (on a wt % basis) 30% mers, carbopol polymers, vinyl polymers containing car rivastigmine free base (neat liquid), 69% Duro-Tak.R. 9900 boxylic acid groups, carboxyl group-containing cellulose and 1% BHT, a rate-controlling membrane as set forth below, polymers and carboxyl group-containing starches. and a face adhesive comprised of Duro-Tak.R. 2852. 11. The transdermal drug delivery system according to (0163 CoTranTM 9719 (VA 0%) (O) claim 1, wherein the tertiary amine drug is selected from the (0164 CoTranTM 9719 (VA 2%) () group consisting of amiodarone, amitriptyline, atropine, ben (0165 CoTranTM 9707 (VA 4.5%) (A) Ztropine, biperiden, bornaprine, bupivacaine, chlorphe 0166 FIG. 9 illustrates the in vitro rivastigmine flux (ug/ niramine, cinnarizine, clomipramine, cyclopentolate, cm/hr) over time (0-168 hours) from the transdermal drug darifenacin, dexetimide, dicyclomine, diltiazem, diphenhy delivery systems described above or an Exelon(R) patch (, dramine, doxepin, ethopropazine, fentanyl, flavoxate, homa top line at 0-24 hours). The results show that the systems tropine, imipramine, loxapine, maZaticol, metixene, oxybu according to the invention achieve Sustained, controlled flux tin, oxyphencyclimine, phenglutarimide, physostigmine, over a 7-day application period. Further, the results show that piperidolate, pirenzepine, procyclidine, profenamine, propiv the systems according to the invention exhibited less flux erine, rivastigmine, rotogotine, Scopolamine, telenzepine, variability then Exelon(R) patch. The same formulations were theophylline, tolterodine, trimipramine, trihexyphenidyl, tro used in a 7-day rabbit irritation test and found to be non patepine, and tropicamide.rivastigmine. irritating or mildly irritating. 12. The transdermal drug delivery system according to claim 1, wherein the composition does not include a penetra What is claimed is: tion enhancer comprising a carboxylic acid group. 1. A transdermal drug delivery system comprising a poly 13. The transdermal drug delivery system according to mer matrix comprising the free base form of a tertiary amine claim 1, wherein the composition does not include a mono drug and at least one carboxyl group-containing compound, carboxylic fatty acid. wherein the relative amounts of free base and carboxyl group 14. The transdermal drug delivery system according to containing compound is such that greater than 50% of the free claim 1, wherein the polymer matrix further comprises an base is associated with a carboxylic acid group to form a salt. antioxidant. 2. The transdermal drug delivery system according to claim 15. The transdermal drug delivery system according to 1, wherein the relative amounts of free base and carboxyl claim 1, wherein the polymer matrix further comprises a group-containing compound is such that at least 60% of the plasticizer. free base is associated with a carboxylic acid group to form a 16. The transdermal drug delivery system according to salt. claim 1, wherein the polymer matrix comprises: 3. The transdermal drug delivery system according to claim about 10% to about 40% by weight of a free base form of 1, wherein the relative amounts of free base and carboxyl the tertiary amine drug; group-containing compound is such that at least 70% of the about 0% to about 90% by weight of a carrier polymer, free base is associated with a carboxylic acid group to form a optionally containing carboxyl-group containing car salt. boxy-functional groups; 4. The transdermal drug delivery system according to claim about 0% to about 90% by weight of a carboxyl group 1, wherein the relative amounts of free base and carboxyl containing compound; US 2014/0276478 A1 Sep. 18, 2014 13

optionally, about 0% to about 1% of an antioxidant; and polymer selected from the group consisting of polyethylene, optionally, about 0% to about 20% of a pharmaceutically polyolefin, and/or ethylene vinyl acetate polymers. acceptable excipient, 24. The transdermal drug delivery system according to wherein the relative amounts of free base and carboxyl claim 22, wherein the polymer matrix comprises a polymer groups is such that greater than 50% of the free base is selected from the group consisting of acrylic polymers, sili associated with a carboxylic acid group to form a salt. con polymers, polyisobutylene polymers, styrene-isoprene 17. The transdermal drug delivery system according to styrene block copolymers, and mixtures of two or more claim 1, wherein the polymer matrix comprises an amount of thereof. tertiary amine drug effective to deliver a therapeutically 25. The transdermal drug delivery system according to effective amount of tertiary amine drug over a period of time claim 22, wherein the face adhesive comprises a polymer selected from the group consisting of at least 1 day, at least 2 selected from the group consisting of acrylic polymers, sili days, at least 3 days, at least 4 days, at least 5 days, at least 6 con polymers, and mixtures of two or more thereof. days and at least 7 days. 26. The transdermal drug delivery system according to 18. The transdermal drug delivery system according to claim 22, wherein the system is effective to deliver a thera claim 1, wherein the tertiary amine drug is rivastigmine and peutically effective amount of tertiary amine drug over a the polymer matrix comprises an amount of rivastigmine period of time selected from the group consisting of at least 1 selected from the group consisting of (i) an amount effective day, at least 2 days, at least 3 days, at least 4 days, at least 5 to deliver at least about 4.6 mg/day over a period of time days, at least 6 days and at least 7 days. selected from the group consisting of at least 1 day, at least 2 27. The transdermal drug delivery system according to days, at least 3 days, at least 4 days, at least 5 days, at least 6 claim 22, wherein the tertiary amine drug is rivastigmine and days and at least 7 days; (ii) an amount effective to deliver at the polymer matrix comprises an amount of rivastigmine least about 9.5 mg/day over a period of time selected from the selected from the group consisting of (i) an amount effective group consisting of at least 1 day, at least 2 days, at least 3 to deliver at least about 4.6 mg/day over a period of time days, at least 4 days, at least 5 days, at least 6 days and at least selected from the group consisting of at least 1 day, at least 2 7 days; (iii) about 32-65 mg rivastigmine; and (iv) about days, at least 3 days, at least 4 days, at least 5 days, at least 6 67-126 mg rivastigmine. days and at least 7 days; (ii) an amount effective to deliver at 19. The transdermal drug delivery system according to least about 9.5 mg/day over a period of time selected from the claim 1, wherein the polymer matrix has a coat weight of group consisting of at least 1 day, at least 2 days, at least 3 about 10-15 mg/cm. days, at least 4 days, at least 5 days, at least 6 days and at least 20. A method for administering a tertiary amine drug, 7 days; (iii) about 32-65 mg rivastigmine; and (iv) about comprising applying to the skin or mucosa of a subject in need 67-126 mg rivastigmine. thereofa transdermal drug delivery system according to claim 28. The transdermal drug delivery system according to 1. claim 22, wherein the polymer matrix has a coat weight of 21. A method of making a transdermal drug delivery sys about 10-15 mg/cm. tem for a tertiary amine drug, comprising forming a polymer 29. A method for administering a tertiary amine drug, matrix comprising a free base form of the tertiary amine drug comprising applying to the skin or mucosa of a subject in need and at least one carboxyl group-containing compound, thereof a transdermal drug delivery system according to claim wherein the relative amounts of free base and carboxyl group 22. containing compound is such that greater than 50% of the free 30. A method of making a transdermal drug delivery sys base is associated with a carboxylic acid group to form a salt. tem for a tertiary amine drug, comprising combining 22. A transdermal drug delivery system comprising a poly a polymer matrix comprising a free base form of the ter mer matrix comprising the free base form of a tertiary amine tiary amine drug; drug, a rate-controlling membrane, and a face adhesive com a rate-controlling membrane; and prising a carboxyl group-containing compound. a face adhesive comprising a carboxyl group-containing 23. The transdermal drug delivery system according to compound. claim 22, wherein the rate-controlling membrane comprises a