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US 2016003 0362A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2016/0030362 A1 Liao et al. (43) Pub. Date: Feb. 4, 2016

(54) SILICONE-CONTAINING ACRYLC Publication Classification POLYMERS FORTRANSIDERMAL DRUG DELIVERY COMPOSITIONS (51) Int. Cl. A69/70 (2006.01) Applicants: Jun Liao, Miami, FL (US); Jilin Zhang, A619/00 (2006.01) (71) CSF230/08 (2006.01) Miami, FL (US); Puchun Liu, Miami, A63L/27 (2006.01) FL (US); Steven Dinh, Miami, FL (US) A613 L/4525 (2006.01) A613 L/468 (2006.01) (72) Inventors: Jun Liao, Miami, FL (US); Jilin Zhang, A613 L/4458 (2006.01) Miami, FL (US); Puchun Liu, Miami, A63/37 (2006.01) FL (US); Steven Dinh, Miami, FL (US) (52) U.S. Cl. CPC ...... A61 K9/7084 (2013.01); A61 K3I/4458 Assignee: NOVEN PHARMACEUTICALS, (2013.01); A61 K9/0014 (2013.01); A61 K (73) 3 1/137 (2013.01); A61 K3I/27 (2013.01); INC., Miami, FL (US) A61 K3I/4525 (2013.01); A61 K31/4168 (2013.01); C08F 230/08 (2013.01) (21) Appl. No.: 14/810,962 (57) ABSTRACT Described herein are silicone-containing acrylic polymers useful, for example, in transdermal drug delivery composi (22) Filed: Jul. 28, 2015 tions, to methods of making and using them, to transdermal drug delivery compositions comprising them, and to methods of making and using Such transdermal drug delivery compo Related U.S. Application Data sitions. The polymers are particular Suitable for formulating (60) Provisional application No. 62/031.325, filed on Jul. amine drugs, such as amphetamine, methylphenidate, 31, 2014. , and . Patent Application Publication Feb. 4, 2016 Sheet 1 of 5 US 2016/0030362 A1

FIGURE 1

O 4. 8 12 16 2O 24 Time (hours) L -HRNO7O-132-4 --Daytrana ----- n Patent Application Publication Feb. 4, 2016 Sheet 2 of 5 US 2016/003O362 A1

FIGURE 2 234.5 OOOO 1. O

8 12 16 2O 24 Time (hours) --RNOO7-141-2 -E-Daytrana Patent Application Publication Feb. 4, 2016 Sheet 3 of 5 US 2016/003O362 A1

FIGURE 3

300

2OO - i.

100

Time (hours) a-RNO76-39-3 -- R1204232-A1 Patent Application Publication Feb. 4, 2016 Sheet 4 of 5 US 2016/003O362 A1

FIGURE 4

O 4. 8 12 16 2O 24 Time (hours) see RNO33-44-3 --Exelon Patent Application Publication Feb. 4, 2016 Sheet 5 of 5 US 2016/003O362 A1

FIGURES

2O.O --

15.0

1.O.O

3. 5.O

O.O :

s Time (hours) are RN1OO-122-1 -- RN100-122-2 ...-...-...------...-a,c-ossessessessososcowrocessosososorors US 2016/0030362 A1 Feb. 4, 2016

SILICONE-CONTAINING ACRYLC the composition, because many drugs have a plasticizing POLYMERS FORTRANSIDERMAL DRUG effect. Further, a relatively large amount of drug may remain DELIVERY COMPOSITIONS in the composition after use. On the other hand, the solubility of many drugs in silicone pressure-sensitive adhesives is not CROSS-REFERENCE TO RELATED Sufficient to achieve satisfactory drug loading and drug flux. APPLICATIONS However, silicone pressure-sensitive adhesives can be used in combination with acrylic pressure-sensitive adhesives to bal 0001. This application claims the benefit under 35 USC ance Some of the properties outlined above. S119(e) to U.S. provisional application 62/031.325, filed Jul. 0006 Compositions comprising blends of silicone pres 31, 2014, the entire contents of which are incorporated herein Sure-sensitive adhesives and acrylic pressure-sensitive adhe by reference in their entirety. sives Suffer from other disadvantages, however. For example, many silicone pressure-sensitive adhesives and acrylic pres FIELD Sure-sensitive adhesives are physically incompatible. Such 0002 The present invention relates generally to silicone that it is difficult to achieve homogenous blends of the poly containing acrylic polymers useful, for example, in transder mers, and blends that are formed may exhibit phase separa mal drug delivery compositions, to methods of making and tion during further processing or storage. Moreover, silicone using them, to transdermal drug delivery compositions com pressure-sensitive adhesives that include silanol groups may prising them, and to methods of making and using Such trans be reactive with drugs that have a reactive amine moiety, and dermal drug delivery compositions. may be associated with poor physical properties and chemical stability problems, such as, for example, a release liner peel BACKGROUND force that increases over time. 0003. Many factors influence the design and performance 0007. Therefore, there remains a need for polymers that of transdermal drug delivery compositions. These include the are useful in transdermal drug delivery compositions, includ individual drugs themselves, the physical and chemical char ing polymers that are useful in transdermal drug delivery acteristics of the compositions components and their perfor compositions for amine group-containing drugs. mance and behavior relative to other components, external and environmental conditions during manufacturing and Stor SUMMARY OF THE INVENTION age, properties of the application site, the desired rate of drug 0008. In accordance with some embodiments, there are delivery and therapeutic onset, the desired drug delivery pro provided compositions for the transdermal delivery of an file, and the intended duration of delivery, among others. amine drug in the form of a flexible finite system for topical 0004. A major design choice in the preparation of a trans application, comprising a polymer matrix comprising a drug dermal drug delivery composition relates to the polymer.com and a silicone-containing acrylic polymer. In some embodi ponents of the composition, e.g., the polymers used in the ments, the silicone-containing acrylic polymer is a non-reac drug-containing carrier layer and/or any non-drug containing tive silicone-containing acrylic polymer made from one or polymer layers. Typically, the polymers are pressure-sensi more non-reactive acrylic monomers and one or more non tive adhesives, but different pressure-sensitive adhesive poly reactive silicone-containing acrylic monomers, wherein the mers have different properties that make them more or less non-reactive monomers and polymer do not react with amine advantageous for use in a given composition. Factors consid groups of the amine drug. In some embodiments, the silicone ered when selecting polymers for use in a transdermal drug containing acrylic polymer is made from one or more non delivery composition may include, for example, the solubility reactive acrylic monomers selected from the group consisting of the drug(s) to be formulated in the polymer, whether the of methyl acrylate, methyl methacrylate, butyl acrylate, butyl polymer includes any reactive moieties that may react with methacrylate, hexyl acrylate, hexyl methacrylate, 2-ethylbu any reactive moieties of the drug or other components of the tyl acrylate, 2-ethylbutyl methacrylate, isooctyl acrylate, composition, the physical compatibility of the polymer with isooctyl methacrylate, 2-ethylhexyl acrylate, 2-ethylhexyl other components of the composition, the desired physical methacrylate, decyl acrylate, decyl methacrylate, dodecyl properties of the composition (e.g., tackiness and wear prop acrylate, dodecyl methacrylate, tridecyl acrylate, tridecyl erties), the desired pharmacokinetic properties of the compo methacrylate, octyl acrylamide, hydroxyethyl acrylate, and sition (e.g., the rate and duration of drug delivery), etc. vinyl-group containing monomers, such as vinyl acetate and 0005. Two classes of pressure-sensitive adhesives widely vinyl pyrrolidone, and one or more non-reactive silicone used in transdermal drug delivery compositions include containing acrylic monomers, wherein the non-reactive acrylic pressure-sensitive adhesives and silicone pressure monomers do not react with amine groups of the amine drug. sensitive adhesives. Generally speaking, most drugs exhibit a In some embodiments, the silicone-containing acrylic poly relatively high solubility in acrylic pressure-sensitive adhe mer is made from one or more of methyl acrylate monomers, sives and a relatively low solubility in silicone pressure-sen methyl methacrylate monomers, 2-ethylhexyl acrylate mono sitive adhesives. Mixtures of acrylic pressure-sensitive adhe mers, butyl acrylate monomers, amide-containing monomers sives and silicone pressure-sensitive adhesives have been and/or vinyl group-containing monomers, and one or more used to balance these properties. For example, while a drug non-reactive silicone-containing acrylic monomers, wherein must be solubilized in the carrier composition in order to be the non-reactive monomers do not react with amine groups of delivered transdermally, high solubility can inhibit drug flux the amine drug. out of the composition Such that a high concentration of drug 0009. In accordance with any embodiments, the drug may may be required in order to achieve satisfactory (e.g., thera be an amine drug selected from the group consisting of peutically effective) drug flux. Formulating a transdermal amphetamine, methylphenidate, rivastigmine, , drug delivery composition with a high concentration of drug fentanyl, paroxetine clonidine, amiodarone, , also may undermine the desired physical characteristics of , benztropine, , , bupivacaine, US 2016/0030362 A1 Feb. 4, 2016 chlorpheniramine, , , cyclopento 10018 FIG.3 shows in vitro flux data (flux, ug/cm/hr) of late, , , dicyclomine, diltiazem, amphetamine from a composition comprising a silicone-con , , ethopropazine, , homa taining acrylic polymeras described herein as compared to a tropine, , . , , oxybu composition comprising acrylic pressure-sensitive adhesives. tin, , , , I0019 FIG. 4 shows in vitro flux data (flux, ug/cm/hr) of , , procycli dine, , rivastigmine from a composition comprising a silicone-con , , , theophylline, toltero taining acrylic polymer as described herein as compared to dine, , , , and tropi Exelon(R). camide. 0020 FIG. 5 shows in vitro flux data (flux, ug/cm/hr) of 0010. In accordance with any embodiments, composition paroxetine from compositions comprising a silicone-contain may further comprise a backing and/or a release liner. ing acrylic polymeras described herein. 0011. In accordance with other embodiments, there are provided methods for the transdermal delivery of an amine drug, comprising topically applying a composition as DETAILED DESCRIPTION described herein to the skin or mucosa of a subject in need 0021 Described herein are silicone-containing acrylic thereof. polymers useful, for example, in transdermal drug delivery 0012. In accordance with other embodiments, there are compositions. In specific embodiments, the polymers are provided uses of a silicone-containing acrylic polymer in the Suitable for use with amine drugs. preparation of a medicament for the transdermal delivery of an amine drug, such as to provide treatment or prevention of DEFINITIONS any condition for which the amine drug is useful for treating or preventing. 0022 Technical and scientific terms used herein have the 0013. In accordance with other embodiments, there are meanings commonly understood by one of ordinary skill in provided compositions in the form of a flexible finite system the art to which the present invention pertains, unless other for topical application, comprising a polymer matrix com wise defined. Reference is made herein to various method prising a drug and a silicone-containing acrylic polymer, for ologies known to those of ordinary skill in the art. Publica use in the transdermal delivery of an amine drug, such as for tions and other materials setting forth Such known use in treating or preventing any condition for which the methodologies to which reference is made are incorporated amine drug is useful for treating or preventing. herein by reference in their entireties as though set forth in 0014. In accordance with other embodiments, there are full. Any suitable materials and/or methods known to those of provided methods of manufacturing a composition for the ordinary skill in the art can be utilized in carrying out the transdermal delivery of an amine drug in the form of a flexible present invention. However, specific materials and methods finite system for topical application, comprising forming a are described. Materials, reagents and the like to which ref polymer matrix blend by blending an amine drug and a sili erence is made in the following description and examples are cone-containing acrylic polymer in a solvent, applying the obtainable from commercial sources, unless otherwise noted. polymer matrix blend to a Support layer, and removing any 0023. As used herein, the singular forms “a,” “an,” and remaining solvent. “the designate both the singular and the plural, unless 0.015. In accordance with other embodiments, there are expressly stated to designate the singular only. provided methods of manufacturing a silicone-containing 0024. The term “about' and the use of ranges in general, acrylic polymer, comprising copolymerizing acrylic mono whether or not qualified by the term about, means that the mers with silicone-containing acrylic monomers. In specific number comprehended is not limited to the exact number set embodiments, the acrylic monomers and silicone-containing forth herein, and is intended to refer to ranges substantially acrylic monomers are non-reactive with amine groups. In within the quoted range while not departing from the scope of Some embodiments, the silicone-containing acrylic polymer the invention. As used herein, “about will be understood by is comprised of 1-99% by weight acrylic monomers and persons of ordinary skill in the art and will vary to some extent 99-1% by weight silicone-containing acrylic monomers, on the context in which it is used. If there are uses of the term based on the total dry weight of the polymer. In some embodi which are not clear to persons of ordinary skill in the art given ments, the silicone-containing acrylic polymer is comprised the context in which it is used, “about will meanup to plus or of up to 50% by weight acrylic monomers and at least 50% by minus 10% of the particular term. weight silicone-containing acrylic monomers, based on the 0025. The phrase “substantially free” as used herein total dry weight of the polymer. In other embodiments, the means that the described composition (e.g., polymer matrix, silicone-containing acrylic polymer is comprised of at least etc.) comprises less than about 5%, less than about 3%, or less 50% by weight acrylic monomers and up to 50% by weight than about 1% by weight, based on the total weight of the silicone-containing acrylic monomers, based on the total dry composition at issue, of the excluded component(s). weight of the polymer. 0026. As used herein “subject' denotes any mammal in need of drug therapy, including humans. For example, a Sub BRIEF DESCRIPTION OF THE DRAWINGS ject may be suffering from or at risk of developing a condition 0016 FIG. 1 shows in vitro flux data (flux, ug/cm/hr) of that can be treated or prevented with an amine drug, or may be methylphenidate from a composition comprising a silicone taking an amine drug health maintenance purposes. containing acrylic polymeras described herein as compared 0027. As used herein, the terms “topical and “topically' to Daytrana(R). mean application to a skin or mucosal Surface of a mammal, I0017 FIG.2 shows in vitro flux data (flux, ug/cm/hr) of while the terms “transdermal” and “transdermal” connote methylphenidate from a composition comprising an acrylic passage through the skin or mucosa (including oral, buccal, pressure-sensitive adhesive as compared to Daytrana(R). nasal, rectal and vaginal mucosa), into Systemic circulation. US 2016/0030362 A1 Feb. 4, 2016

Thus, the compositions described herein may be applied topi 0034. In some embodiments, the polymer matrix is a pres cally to a subject to achieve transdermal delivery of an amine Sure-sensitive adhesive at room temperature and exhibits drug. desirable physical properties, such as good adherence to skin, 0028. As used herein, the phrases “therapeutically effec ability to be peeled or otherwise removed without substantial tive amount” and “therapeutic level” mean that drug dosage trauma to the skin, retention of tack with aging, etc. or plasma concentration in a Subject, respectively, that pro 0035. As used herein, the term “amine drugs' refers to any vides the specific pharmacological effect for which the drug is physiologically active agent comprising an amine group, administered in a Subject in need of Such treatment. It is including a primary, secondary, and/or tertiary amine group. emphasized that a therapeutically effective amount or thera Non-limiting examples of amine drugs include amphetamine, peutic level of a drug will not always be effective in treating methylphenidate, rivastigmine, rotigotine, fentanyl, paroxet the conditions/diseases described herein, even though Such ine, and clonidine. Further examples are discussed in more dosage is deemed to be a therapeutically effective amount by detail below. those of skill in the art. For convenience only, exemplary 0036) Silicone-Containing Acrylic Polymers dosages, drug delivery amounts, therapeutically effective 0037. Described herein are silicone-containing acrylic amounts and therapeutic levels are provided below with ref polymers that can be made by copolymerizing acrylic mono erence to adult human Subjects. Those skilled in the art can mers with silicone-containing acrylic monomers. In specific adjust Such amounts in accordance with standard practices as embodiments, the monomers do not include functional needed to treat a specific Subject and/or condition/disease. groups that are reactive with amine drugs, as discussed in 0029. As used herein, “active surface area” means the more detail below. That is, in specific embodiments, the Surface area of the drug-containing polymer matrix of the monomer are non-reactive monomers, as discussed in more transdermal drug delivery system. detail below. In further specific embodiments, the polymers 0030 The compositions described herein are in a “flex are comprised only of non-reactive monomers. Such that the ible, finite form.” As used herein, the phrase “flexible, finite polymers are non-reactive. form' means a substantially solid form capable of conform 0038. As used herein, “non-reactive monomer' and “non ing to a surface with which it comes into contact, and capable reactive polymer includes any monomers or polymers that of maintaining contact so as to facilitate topical application. do not include functional groups that are reactive with amine Such systems in general are known in the art and commer groups of amine drugs. cially available. Such as transdermal drug delivery patches. 0039. As used herein, “functional groups are reactive The compositions comprise a drug-containing polymer chemical groups present on acrylic-based monomer units matrix that releases an active agent (such as an amine drug) which modify the acrylic-based polymers directly or which upon application to the skin (or any other Surface noted provide sites for further reactions. As used herein, “functional above). In some embodiments, the composition in flexible, groups, includes chemical groups that are reactive with finite form may include a backing layer and/or a release liner amine groups of amine drugs, and that are not reactive with layer in addition to a drug-containing polymer matrix layer. amine groups of amine drugs. General examples of functional groups include carboxyl, epoxy, hydroxyl, Sulfoxyl, and 0031. As used herein, “drug-containing polymer matrix' amino groups. Typical carboxyl functional monomers refers to a polymer composition which contains one or more include acrylic acid, methacrylic acid, itaconic acid, maleic drugs, such as an amine drug, and a polymer. Such as a acid, and crotonic acid. Typical hydroxyl functional mono pressure-sensitive adhesive polymer or a bioadhesive poly mers include 2-hydroxyethyl methacrylate, 2-hydroxyethyl mer. A polymer is an “adhesive' or “bioadhesive' if it has the acrylate, hydroxymethyl acrylate, hydroxymethyl methacry properties of adhesiveness per se. Other polymers can func late, hydroxyethyl acrylate, hydroxyethyl methacrylate, tion as an adhesive or bioadhesive by the addition of tackifi hydroxypropyl acrylate, hydroxypropyl methacrylate, ers, plasticizers, crosslinking agents, skin permeation hydroxybutyl acrylate, hydroxybutyl methacrylate, enhancers, or other excipients. Thus, in Some embodiments, hydroxyamyl acrylate, hydroxyamyl methacrylate, hydroxy the polymer optionally comprises tackifiers, plasticizers, hexyl acrylate, hydroxyhexyl methacrylate. Of these func crosslinking agents or other additives known in the art. tional groups, “non-reactive functional groups are those 0032. As used herein, the term “pressure-sensitive adhe groups that are not reactive with amine groups of amine sive' refers to a viscoelastic material which adheres instan drugs. Thus, for example, hydroxyl groups and amino groups taneously to most Substrates with the application of very are “non-reactive” functional groups in the context of amine slight pressure and remains permanently tacky. As noted drugs. Vinyl esters, such as vinyl acetate, may be reactive with above, a polymer is a pressure-sensitive adhesive polymer if primary amine drugs (e.g., amphetamine) and secondary it has the properties of a pressure-sensitive adhesive per se. amine drugs (e.g., methylphenidate), but are not generally Other polymers may function as a pressure-sensitive adhesive reactive (e.g., are “non-reactive') with tertiary amine drugs, by admixture with tackifiers, plasticizers or other additives. (e.g., rivastigmine and fentanyl). Thus, in Some embodi The term pressure-sensitive adhesive also includes mixtures ments, polymers with these functional groups can be included of different polymers. in a composition as “non-reactive' polymers, depending on 0033. As used herein, the term “non-reactive component' the drug being formulated. As noted above, in some embodi identifies components that do not contain functional groups ments, the acrylic polymer does not include reactive func with active hydrogenatoms or functional groups with hydro tional groups, such as carboxyl, epoxy, and Sulfoxyl groups, gen atoms available for chemical reaction or interaction with which are generally reactive with amine drugs. an amine drug, such as, for example, carboxyl, hydroxyl, 0040. Examples of suitable non-reactive acrylic mono amine, thiol, silanol, Sulfoxyl, or epoxy groups. As used mers include alkyl acrylates and alkyl methacrylates, such as herein, non-reactive components may include amide group methyl acrylate, methyl methacrylate, butyl acrylate, butyl containing monomers (e.g., components with amido groups). methacrylate, hexyl acrylate, hexyl methacrylate, 2-ethylbu US 2016/0030362 A1 Feb. 4, 2016 tyl acrylate, 2-ethylbutyl methacrylate, isooctyl acrylate, loxybutyl)-dimethyl-(trimethylsiloxy)-silane, (3-methacry isooctyl methacrylate, 2-ethylhexyl acrylate, 2-ethylhexyl loxybutyl)-monomethyl-bis(trimethylsiloxy)-silane, methacrylate, decyl acrylate, decyl methacrylate, dodecyl (3-methacryloxybutyl)-tris(trimethylsiloxy)-silane, (4-acry acrylate, dodecyl methacrylate, tridecyl acrylate, and tridecyl loxybutyl)-dimethyl-(trimethylsiloxy)-silane, (4-acryloxy methacrylate, amide-group containing-monomers such as butyl)-monomethyl-bis(trimethylsiloxy)-silane, (4-acry octyl acrylamide. As noted above, depending on the drug loxybutyl)-tris(trimethylsiloxy)-silane, being formulated, additional Suitable non-reactive acrylic (4-methacryloxybutyl)-dimethyl-(trimethylsiloxy)-silane, monomers may include, hydroxyl-containing monomers (4-methacryloxybutyl)-monomethyl-bis(trimethylsiloxy)- Such as hydroxyethyl acrylate, and vinyl group-containing silane, (4-methacryloxybutyl)-tris(trimethylsiloxy)-silane, monomers such as vinyl acetate and vinyl pyrrolidone. (2-acryloxy-2-methylpropyl)-dimethyl-(trimethylsiloxy)-si 0041. In specific embodiments, a silicone-containing lane, (2-acryloxy-2-methylpropyl)-monomethyl-bis(trim acrylic polymeras described herein is made from monomers ethylsiloxy)-silane, (2-acryloxy-2-methylpropyl)-tris(trim including methyl acrylate, methyl methacrylate, 2-ethylhexyl ethylsiloxy)-silane, (2-methacryloxy-2-methylpropyl)- acrylate, butyl acrylate, amide-containing monomers and dimethyl-(trimethylsiloxy)-silane, (2-methacryloxy-2- vinyl group-containing monomers. In further specific methylpropyl)-monomethyl-bis(trimethylsiloxy)-silane, embodiments a silicone-containing acrylic polymer as (2-methacryloxy-2-methylpropyl)-tris(trimethylsiloxy)-si described herein is made from up to four types of monomers lane, (2-acryloxy-1,2-dimethylethyl)-dimethyl-(trimethylsi selected from (1) methyl acrylate or methyl methacrylate loxy)-silane, (2-acryloxy-1,2-dimethylethyl)-monomethyl monomers; (2) 2-ethylhexyl acrylate or butyl acrylate mono bis(trimethylsiloxy)-silane, (2-acryloxy-1,2-dimethylethyl)- mers, (3) amide-containing monomers, and (4) vinyl group tris(trimethylsiloxy)-silane, (2-methacryloxy-1,2- containing monomers. Thus, for example, a silicone-contain dimethylethyl)-dimethyl-(trimethylsiloxy)-silane, ingacrylic polymeras described herein may be made from the (2-methacryloxy-1,2-dimethylethyl)-monomethyl-bis(trim following monomers: (1) methyl acrylate or methyl meth ethylsiloxy)-silane, (2-methacryloxy-1,2-dimethylethyl)-tris acrylate; (2) 2-ethylhexyl acrylate or butyl acrylate, (3) (trimethylsiloxy)-silane, (2-acryloxy-1,1-dimethylethyl)- optionally, an amide-containing monomer, and (4) optionally, dimethyl-(trimethylsiloxy)-silane, (2-acryloxy-11 a vinyl group-containing monomer. dimethylethyl)-monomethyl-bis(trimethylsiloxy)-silane, (2-acryloxy-1,1-dimethylethyl)-tris(trimethylsiloxy)-silane, 0042 Examples of suitable silicone-containing acrylic (2-methacryloxy-1,1-dimethylethyl)-dimethyl-(trimethylsi monomers include acrylic monomers with a silicone moiety, loxy)-silane, (2-methacryloxy-1,1-dimethylethyl)-monom such as siloxysilanes and polydimethylsiloxanes of different ethyl-bis(trimethylsiloxy)-silane, (2-methacryloxy-1,1-dim molecular weights, such as 3-acryloxypropyl tri(trimethylsi ethylethyl)-tris(trimethylsiloxy)-silane, (2-acryloxy-2.2- loxy)silane, 3-methacryloxypropyl tri(trimethylsiloxy)si dimethylethyl)-dimethyl-(trimethylsiloxy)-silane, lane, mono-vinyl terminated polydimethylsiloxane, (2-acry (2-acryloxy-2,2-dimethylethyl)-monomethyl-bis(trimethyl loxyethyl)-dimethyl-(trimethylsiloxy)-silane, siloxy)-silane, (2-acryloxy-2,2-dimethylethyl)-tris(trimeth (2-acryloxyethyl)-monomethyl-bis(trimethylsiloxy)-silane, ylsiloxy)-silane, (2-methacryloxy-2,2-dimethylethyl)-dim (2-acryloxyethyl)-tris(trimethylsiloxy)-silane, (2-methacry ethyl-(trimethylsiloxy)-silane, (2-methacryloxy-2.2- loxyethyl)-dimethyl-(trimethylsiloxy)-silane, (2-methacry dimethylethyl)-monomethyl-bis(trimethylsiloxy)-silane, loxyethyl)-monomethyl-bis(trimethylsiloxy)-silane, (2-methacryloxy-2,2-dimethylethyl)-tris(trimethylsiloxy)- (2-methacryloxyethyl)-tris(trimethylsiloxy)-silane, (2-acry silane, (3-acryloxy-1-methylpropyl)-dimethyl-(trimethylsi loxy-1-methylethyl)-dimethyl-(trimethylsiloxy)-silane, loxy)-silane, (3-acryloxy-1-methylpropyl)-monomethyl-bis (2-acryloxy-1-methylethyl)-monomethyl-bis(trimethylsi (trimethylsiloxy)-silane, (3-acryloxy-1-methylpropyl)-tris loxy)-silane, (2-acryloxy-1-methylethyl)-tris(trimethylsi (trimethylsiloxy)-silane, (3-methacryloxy-1-methylpropyl)- loxy)-silane, (2-methacryloxy-1-methylethyl)-dimethyl-(tri dimethyl-(trimethylsiloxy)-silane, (3-methacryloxy-1- methylsiloxy)-silane, (2-methacryloxy-1-methylethyl)- methylpropyl)-monomethyl-bis(trimethylsiloxy)-silane, monomethyl-bis(trimethylsiloxy)-silane, (2-methacryloxy (3-methacryloxy-1-methylpropyl)-tris(trimethylsiloxy)-si 1-methylethyl)-tris(trimethylsiloxy)-silane, lane, (3-acryloxy-2-methylpropyl)-dimethyl-(trimethylsi (2-acryloxypropyl)-dimethyl-(trimethylsiloxy)-silane, loxy)-silane, (3-acryloxy-2-methylpropyl)-monomethyl-bis (2-acryloxypropyl)-monomethyl-bis(trimethylsiloxy)-si (trimethylsiloxy)-silane, (3-acryloxy-2-methylpropyl)-tris lane, (2-acryloxypropyl)-tris(trimethylsiloxy)-silane, (2-methacryloxypropyl)-dimethyl-(trimethylsiloxy)-silane, (trimethylsiloxy)-silane, (3-methacryloxy-2-methylpropyl)- (2-methacryloxypropyl)-monomethyl-bis(trimethylsiloxy)- dimethyl-(trimethylsiloxy)-silane, (3-methacryloxy-2- silane, (2-methacryloxypropyl)-tris(trimethylsiloxy)-silane, methylpropyl)-monomethyl-bis(trimethylsiloxy)-silane, and (3-acryloxypropyl)-dimethyl-(trimethylsiloxy)-silane, (3-methacryloxy-2-methylpropyl)-tris(trimethylsiloxy)-si (3-acryloxypropyl)-monomethyl-bis(trimethylsiloxy)-si lane, etc. lane, (3-methacryloxypropyl)-dimethyl-(trimethylsiloxy)-si 0043. In specific embodiments, a silicone-containing lane, (3-methacryloxypropyl)-monomethyl-bis(trimethylsi acrylic polymer as described herein includes 3-tris(trimeth loxy)-silane, (2-acryloxybutyl)-dimethyl-(trimethylsiloxy)- ylsilyloxy)silyl)propyl meth-acrylate (TRIS), mono-vinyl silane, (2-acryloxybutyl)-monomethyl-bis(trimethylsiloxy)- terminated polydimethylsiloxane (PDMS), or a combination silane, (2-acryloxybutyl)-tris(trimethylsiloxy)-silane, thereof (2-methacryloxybutyl)-dimethyl-(trimethylsiloxy)-silane, 0044) The adhesion properties of the polymers can be (2-methacryloxybutyl)-monomethyl-bis(trimethylsiloxy)- selected and adjusted by selecting and controlling the mono silane, (2-methacryloxybutyl)-tris(trimethylsiloxy)-silane, mers and monomer ratios. In general, the polymer may be (3-acryloxybutyl)-dimethyl-(trimethylsiloxy)-silane, comprised of the acrylic monomers and silicone-containing (3-acryloxybutyl)-monomethyl-bis(trimethylsiloxy)-silane, acrylic monomers in any relative amounts. In some embodi (3-acryloxybutyl)-tris(trimethylsiloxy)-silane, (3-methacry ments, the polymer is comprised of 1-99% by weight acrylic US 2016/0030362 A1 Feb. 4, 2016

monomers and 99-1% by weight silicone-containing acrylic Antioxidants monomers, based on the total dry weight of the polymer. In specific embodiments, the polymer is comprised of up to 50% 0051. In some embodiments, the polymer matrix includes by weight acrylic monomers and at least 50% by weight an antioxidant. In some embodiments, the antioxidant is silicone-containing acrylic monomers, based on the total dry butylhydroxytoluene (BHT) and/or butylhydroxyanisole weight of the polymer. In other specific embodiments, the (BHA). In other embodiments, the antioxidant is, addition polymer is comprised of at least 50% by weight acrylic mono ally or alternatively, tertiary-butylhydroquinone (TBHQ), mers and up to 50% by weight silicone-containing acrylic alpha tocopherol, ascorbic-acid, ascorbyl palmitate, propyl gallate, fumaric acid, malic acid, Sodium ascorbate, sodium monomers, based on the total dry weight of the polymer. metabisulfite, and the like. In some embodiments, the anti 0045 Polymer Matrix (Drug-Containing Layer) oxidant is a non-reactive component as discussed above. In specific embodiments, the antioxidant (or combinations 0046. The silicone-containing acrylic polymers described thereof) are used in a total amount of from about 0 to about herein are useful, for example, as a polymer component of a 1.0% by weight, including from about 0.1 to about 1.0% by polymer matrix of a transdermal drug delivery composition. weight, such as about 0.1% by weight, about 0.25% by 0047. In some embodiments, the transdermal drug deliv weight, and about 0.5% by weight, based on the dry weight of ery composition is a monolithic system wherein the polymer the polymer matrix. matrix comprising silicone-containing acrylic polymer(s) and active agent(s) is the only polymeric layer of the system Penetration Enhancers (although the system may additionally comprise a backing and release liner). In other embodiments, the transdermal 0052. In some embodiments, the polymer matrix com drug delivery composition is a multi-layer system, wherein prises one or more penetration enhancer(s). A "penetration the silicone-containing acrylic polymer(s) are present in one enhancer is an agent known to accelerate the delivery of the or more of a drug-containing layer and a non-drug-containing drug through the skin. These agents also have been referred to layer. as accelerants, adjuvants, and Sorption promoters, and are 0048. In accordance with any of these embodiments, the collectively referred to herein as "enhancers.” This class of drug-containing layer may consist of the silicone-containing agents includes those with diverse mechanisms of action, acrylic polymer(s) and active agent(s), e.g., the drug-contain including those which have the function of improving percu ing layer is formulated only with the silicone-containing taneous absorption, for example, by changing the ability of acrylic polymer(s) and active agent(s). Alternatively, the the stratum corneum to retain moisture, softening the skin, drug-containing layer may include other components. In improving the skin's permeability, acting as penetration Some embodiments, the drug-containing layer includes other assistants or hair-follicle openers or changing the State of the polymer(s). Such as may be effective to improve the physical skin including the boundary layer. In some embodiments, the or pharmacokinetic properties of the compositions, such as penetration enhancer is a non-reactive component as dis drug solubility, drug flux, adhesion, resistance to crystal for cussed above. mation, resistance to cold flow, etc. The other polymer(s) may 0053 Illustrative penetration enhancers include but are be selected from acrylic polymers, silicone polymers, rubber not limited to polyhydric alcohols such as dipropylene glycol, based polymers, such as one or more rubber-based pressure propylene glycol, and polyethylene glycol, oils such as olive sensitive adhesives, such as natural or synthetic polyisoprene, oil, squalene, and lanolin; fatty ethers such as cetyl ether and polybutylene, polyisobutylene, styrene-butadiene polymers, oleyl ether; fatty acid esters such as isopropyl myristate; urea styrene-isoprene-styrene block copolymers (such as Kraton R and urea derivatives such as allantoin which affect the ability D1111 KT), hydrocarbon polymers, such as butyl rubber, of keratin to retain moisture; polar solvents such as dimethy halogen-containing polymers, such as polyacrylic-nitrile, idecylphosphoxide, methyloctylsulfoxide, dimethyllauryla polytetrafluoroethylene, polyvinylchloride, polyvinylidene mide, dodecylpyrrolidone, isosorbitol, dimethylacetonide, chloride, and polychlorodiene, and other copolymers thereof. dimethylsulfoxide, decylmethylsulfoxide, and dimethylfor Additionally or alternatively, as discussed above, the polymer mamide which affect keratin permeability; salicylic acid matrix may comprise a non-adhesive polymer, Such as ethyl which softens the keratin; amino acids which are penetration cellulose. assistants; benzyl nicotinate which is a hair follicle opener; 0049. In some embodiments, the drug-containing layer and higher molecular weight aliphatic Surfactants such as includes one or more other components, including other com lauryl sulfate salts which change the surface state of the skin ponents typically used in transdermal drug delivery compo and drugs administered. Other agents include oleic and sitions, such as antioxidants, skin permeation enhancers, linoleic acids, ascorbic acid, panthenol, butylated hydroxy tackifiers, plasticizers, crosslinking agents, or other excipi toluene, tocopherol, tocopheryl acetate, tocopheryllinoleate, ents known in the art. In some embodiments, any such com propyl oleate, and isopropyl palmitate. ponents are non-reactive, as discussed above. 0054. In some embodiments, the polymer matrix does not 0050. When silicone-containing acrylic polymers as comprise a penetration enhancer. described herein are used to formulate amine drugs, a higher 0055 When present, a penetration enhancer typically is drug flux can be achieved as compared to formulating the used in an amount up to about 30% by dry weight of the same amount of the same drug in a corresponding composi polymer matrix, including up to 30% by weight, up to about tion based on acrylic polymers. Moreover, compositions 20% by weight, including 20% by weight, or up to about 10% made using silicone-containing acrylic polymers exhibit by weight, up to 10% by weight, or up to 5% by weight, good stability and satisfactory (e.g., stable) release liner peel including up to 5% by weight, based on the dry weight of the force over time. polymer matrix. US 2016/0030362 A1 Feb. 4, 2016

Tackifying Agents ticularly advantageous to use non-reactive monomers, non reactive polymers, and other non-reactive components, as 0056. In some embodiments, the polymer matrix com prises one or more tackifying agents, such as aliphatic hydro discussed above. carbons, mixed aliphatic and aromatic hydrocarbons, aro 0064. As noted above, the term “amine drugs’ refers to matic hydrocarbons, Substituted aromatic hydrocarbons, any physiologically active agent comprising an amine group. hydrogenated esters, polyterpenes, silicone fluid, mineral oil including a primary, secondary, and/or tertiary amine group. and hydrogenated wood rosins. In some embodiments, the Non-limiting examples of amine drugs include amphetamine, polymer matrix includes one or more tackifying agents methylphenidate, rivastigmine, rotigotine, fentanyl, paroxet selected from rosinesters, aliphatic hydrocarbon resins, aro ine and clonidine. matic hydrocarbon resins, terpene resins, polybutene, and 0065 Amphetamine (alpha-methylphenethylamine) is a hydrogenated polybutene. chiral drug. The commercially available oral amphetamine product Adderall(R) includes several different amphetamine salts, including amphetamine Sulfate, amphetamine saccha Other Excipients rate, and amphetamine aspartate monohydrate, in an overall 0057. In some embodiments, the polymer matrix includes ratio of d-amphetamine to 1-amphetamine of 3:1. Amphet one or more thickeners, fillers, and/or other additives or com amine may be used, for example, for achieving central ner ponents known for use in transdermal drug delivery systems. vous system stimulation, for the treatment of Attention Defi 0058 For example, in some embodiments, the polymer cit Disorder (ADD) and/or Attention Deficit/Hyperactivity matrix includes one or more of soluble and insoluble polyvi Disorder (ADHD), and/or for the treatment of narcolepsy. nylpyrrolidones (PVP), ethylene-vinyl acetate copolymers, 0.066 Methylphenidate (a-phenyl-2-piperidineacetic acid cellulose derivatives, and silicone dioxide (SiO2), and other methyl ester) is a chiral drug. While commercially available components. methylphenidate products (such as the oral product Ritalin R 0059. In some embodiments, the polymer matrix includes tablets and the transdermal product Daytrana(R) patch) include one or more binders, such as , which “bind the other a 50:50 (racemic) mixture of d- and 1-threo-methylphenidate, ingredients; one or more rheological agents (thickeners) con it is believed that the d-threo-methylphenidate isomer has taining silicone, such as fumed silica, reagent grade sand, greater pharmacological activity. The compositions precipitated silica, amorphous silica, colloidal silicon diox described herein may beformulated with any isomer of meth ide, fused silica, Silica gel, quartz and particulate siliceous ylphenidate, although compositions comprising a racemic materials commercially available as Syloid R. Cabosil R. mixture of d- and 1-threo-methylphenidate, or comprising Aerosil R, and Whitelite R, such as for enhancing the uniform primarily the d-threo-methylphenidate isomer may be most consistency or continuous phase of the composition or coat commercially relevant. ing. 0067 Methylphenidate, including methylphenidate base 0060. Other additives and excipients include diluents, sta in particular, has a secondary amine moiety and a methyl ester bilizers, fillers, clays, buffering agents, biocides, humectants, moiety, and is unstable and undergoes degradation in the anti-irritants, preservatives, plasticizing agents, cross-linking presence of reactive functional groups, such as active hydro agents, flavoring agents, colorants, pigments and the like. gen atoms or functional groups with hydrogen atoms avail 0061 These substances can be present in any amount suf able for chemical reaction or interaction with methylpheni ficient to impart the desired properties to the composition, and date, such as, for example, carboxyl, hydroxyl, amine, thiol, are typically used in amounts totaling up to 50%, including silanol or epoxy groups, which may be present in polymers, from about 0.1% to about 30%, by weight based on the dry enhancers, excipients and other components that typically weight of the polymer matrix. As noted above, in some may be used in transdermal compositions. Major degradants embodiments, any such components are non-reactive compo of methylphenidate include ritalinic acid and erythol isomer, nentS. whose concentrations increase significantly with increasing 0062. In some embodiments, a drug-containing polymer amounts (by weight) of functional groups. Such degradation matrix layer of a transdermal drug delivery composition com can greatly reduce the amount of the active species present in prises the following components by weight, based on the dry a composition after storage, thus reducing the amount of weight of the drug-containing polymer matrix layer: 1% to active methylphenidate available for drug delivery. Thus, in 50% drug, including 2% to 30% drug. 50% to 90% silicone Some embodiments, the methylphenidate compositions containing acrylic copolymer(s), including 70% to 90% sili described herein are formulated without components that cone-containing acrylic copolymers; 0% to 50% of other have such functional groups. That is, in Some embodiments, optional components, such as, for example, non-reactive the compositions described herein are formulated only with non-reactive components as defined above and discussed in acrylic pressure-sensitive adhesives, tackifiers, antioxidant, more detail below. absorption enhancers, etc. 0068 Rivastigmine, (S)-3-1-(dimethylamino)ethylphe nyl N-ethyl-N-methylcarbamate, is a tertiary amine drug. It is Active Agents a parasympathomimetic or agent approved for the 0063 As noted above, the silicone-containing acrylic treatment of mild to moderate dementia of the Alzheimer's polymers described herein are useful, for example, as a poly type and dementia due to Parkinson's disease. The drug can mer component of a polymer matrix of a transdermal drug be administered orally or transdermally. The commercially delivery composition. In general, the polymers are useful in available transdermal rivastigmine product (ExelonR) is compositions for the transdermal delivery of any active agent. designed for daily use and comprises four layers: a backing In specific embodiments, the polymers are used in composi layer, a polymer-drug matrix layer, and adhesive layer and a tions for the transdermal delivery of amine drugs. When the release liner. The Exelon(R) patch is available in two sizes, a 5 polymers are used to formulate amine drugs, it can be par cm patch that includes 9 mg rivastigmine and delivers about US 2016/0030362 A1 Feb. 4, 2016

4.6 mg rivastigmine in 24 hours, and a 10 cm patch that loss of the drug and/or release of other components to the includes 18 mg rivastigmine and delivers about 9.5 mg in 24 environment during use. Materials Suitable for use as back hours rivastigmine. (The 10 cm patch that provides a dose of ings are well-known known in the art and can comprise films 9.5 mg/24 hours is the recommended effective dose.) of polyester, polyethylene, vinyl acetate resins, ethylene/vi 0069 Rotigotine, (S)-6-propyl(2-thiophen-2-ylethyl) nyl acetate copolymers, polyvinyl chloride, polyurethane, amino-5,6,7,8-tetrahydronaphthalen-1-ol, is a tertiary amine and the like, metal foils, non-woven fabric, cloth and com drug used to treat Parkinson's disease (PD) and restless legs mercially available laminates. A typical backing material has syndrome (RLS). Current 1-day patch products deliver 1,2,3, a thickness in the range of 2 to 1000 micrometers. Suitable 4, 6 and 8 mg/day of rotigotine for the treatment of Parkin backing materials include commercially available backings son's disease or restless legs syndrome. films, such as breathable backings such as 3M CoTranTM 0070 Fentanyl, N-(1-(2-phenylethyl)-4-piperidinyl)-N- backings which feature low moisture vaportransmission rate phenylpropanamide, a tertiary amine drug is used to treat and high oxygen transmission, non-breathable laminate pain. Current 3-day patch products deliver 12.5, 25, 50, 75 backings such as 3M Scotchpak R) backings (3M, St. Paul, and 100 ug/hr offentanyl for pain management. Minn.) and Dow(R) backings (Dow Chemical Company, Mid (0071 Paroxetine, (3S,4R)-3-(2H-1,3-benzodioxol-5- land, Mich.). yloxy)methyl-4-(4-fluorophenyl) , has a second ary amine moiety, and is used to treat major depression, Release Liner obsessive-compulsive disorder, panic disorder, Social anxi ety, post-traumatic stress disorder, generalized anxiety disor 0076 Any of the compositions described herein may der and vasomotor symptoms (e.g. hot flashes and night include a release liner, typically located adjacent the opposite Sweats) associated with menopause. face of the system as compared to the backing layer. When 0072 Clonidine, N-(2,6-dichlorophenyl)-4,5-dihydro present, the release liner is removed from the system prior to 1H-imidazol-2-amine, is used to treat high blood pressure, use to expose the polymer matrix layer prior to topical appli attention-deficit/hyperactivity disorder, anxiety disorders, cation. Materials suitable for use as release liners are well withdrawal (from either , opioids or Smoking), known known in the art and commercially available, and migraine, menopausal flushing, diarrhea and certain pain include silicone-coated polyethylene, polypropylene, polyes conditions. The commercially available transdermal cloni ter, and polystyrene release liners sold under the PRIME dine product, e.g., Catapres-TTSR, is designed to providing LINERTM brand as supplied by Loparex LLC (Cary, N.C.) continuous systemic delivery of clonidine for 7 days at an 3M ScotchpakTM fluoropolymer-coated polyester release lin approximately constant rate. Catapres-TTSR) is available in ers supplied by 3M (St. Paul, Minn.), such as ScotchpakTM three sizes, a 3.5 cm patch that includes 2.5 mg clonidine and 1020, 1022,9741, 9742,9744,9748 and 9755 (fluoropolymer delivers about 0.1 mg clonidine per day, a 7.0 cm patch that coated polyester films), and commercially available products includes 5 mg clonidine and delivers about 0.2 mg clonidine of Dow Corning Corporation designated Bio-Release(R) liner per day, and a 10.5 cm patch that includes 7.5 mg clonidine and Syl-OffR 7610 (both silicone-based). In some embodi and delivers about 0.3 mg clonidine per day. ments, when the polymer matrix comprises a silicone-con 0073. Other tertiary amine drugs include amiodarone, taining acrylic polymer as described herein, a non-silicone amitriptyline, atropine, benztropine, biperiden, bornaprine, containing face adhesive is provided between the polymer bupivacaine, chlorpheniramine, cinnarizine, clomipramine, matrix and a silicone-coated release liner. , darifenacin, dexetimide, dicyclomine, dilt iazem, diphenhydramine, doxepin, ethopropazine, flavoxate, Packaging , imipramine, loxapine, maZaticol, metixene, oxybutin, oxyphencyclimine, phenglutarimide, physostig 0077. The transdermal drug delivery system may be pack mine, piperidolate, pirenzepine, , profenamine, aged or provided in a package. Such as a pouchstock material propiverine, Scopolamine, telenzepine, theophylline, toltero used in the prior art for transdermal drug delivery systems in dine, trimipramine, trihexyphenidyl, tropatepine, and tropi general or for transdermal drug delivery systems for the spe camide. cific tertiary amine drug being formulated (e.g., rivastigmine, 0074 The amount of drug to be incorporated in the poly fentanyl or rotigotine). For example, DuPont's Surlyn R or mer matrix varies depending on the specific drug, the desired Graphic Packaging's Barex R packaging films can be used in therapeutic effect, and the length of time for which the system a pouchstock material. is to provide therapy. Thus, in one embodiment, the compo sition comprises an amount of drug Sufficient to deliverthera Manufacturing Methods peutically effective amounts of drug over the intended appli cation period, such as 12 hours, 24 hours, from 1 day to 3 0078. The compositions described here can be prepared by days, 7 days, or longer, including for 1 day, for 2 days, for 3 methods known in the art, Such as blending (mixing) the days, for 4 days, for 5 days, for 6 days, for 7 days, or for polymer(s) and any other components with an appropriate longer. amount of the active agent (drug) in the presence of an appro priate solvent, Such as a volatile organic solvent, casting the Backing wet blend onto a release liner, followed by evaporation of the 0075 Any of the compositions described herein may Volatile solvent(s) at appropriate drying conditions, laminat include a drug impermeable backing or film, adjacent one ing the dried drug-in-adhesive layer on the release liner onto face of the polymer matrix. (By “impermeable' to the drug is a backing film. meant that no substantial amount of drug loss through the 0079 An exemplary general method for preparing a unit backing layer is observed.) When present, the backing pro final product of a composition as described herein in a flex tects the polymer matrix from the environment and prevents ible, finite form, is as follows: US 2016/0030362 A1 Feb. 4, 2016

0080) 1. Appropriate amounts of one or more polymers, 0091. In accordance with other embodiments, there are Solvent(s) and/or co-solvent(s), and optional other compo provided compositions as described herein for use in the nents) are combined and thoroughly mixed together in a transdermal delivery of active agent, such as for use by topi vessel. cally application to the skin or mucosa of a subject in need 0081 2. The drug is added to the mixture and agitation is thereof. carried out until the drug is uniformly mixed therein. 0092. The following specific examples are included as 0082. 3. The composition is transferred to a coating opera illustrative of the compositions described herein. These tion where it is coated onto a release liner at a controlled examples are in no way intended to limit the scope of the specified thickness. The coated composition is then passed invention. Other aspects of the invention will be apparent to through an oven in order to drive off all volatile processing those skilled in the art to which the invention pertains. Solvents. 0083 4. The composition coated on the release liner is Example 1 then brought into contact with a backing layer and wound into rolls. 0093 Silicone-containing acrylic copolymers are synthe 008.4 5. Appropriate size and shape delivery systems are sized by copolymerization using methodologies known in the die-cut from the roll material and then pouched. art. For example, acrylic monomers are copolymerized with 0085. The order of steps, the amount of the ingredients, silicone-containing acrylic monomers in an appropriate Sol and the amount and time of agitation or mixing may be vent, such as ethyl acetate, with an appropriate initiator. Such important process variables which will depend on the specific as 2,2'-azobisisobutyronitrile (AIBN), at an appropriate tem polymers, active agents, solvents and/or co-solvents, and perature. optional components used in the composition, but these fac 0094 Silicone-containing acrylic copolymer A is pre tors can be adjusted by those skilled in the art. The order in pared as follows: An initial charge containing 9.7 g methyl which each method step is performed can be changed if acrylate (MA), 20.9 g 2-ethylhexyl acrylate (2-EHA), 95.1 g needed without detracting from the invention. 3-(tris(trimethylsilyloxy)silyl)propyl methacrylate (TRIS), I0086. In accordance with any of the embodiments of com 0.074 g AIBN, and 125.5 g ethyl acetate (solvent) is mixed in positions described herein, the size of the final product is, in a 2-L round bottom flask, which is installed with a thermom some embodiments, in the range of from about 2 cm to about eter, condenser, stainless steel stirrer, water bath and dropping 60 cm, including from about 15 cm to about 30 cm, includ funnel. Under stirring, the initial charge is heated to 80° C. ing 12.5 cm, 14.5 cm, 15 cm, 18.75 cm, 22.5 cm, 25 cm, and allowed to reflux for 15 minutes. Then a mixture of 29.0 30 cm, 37.5 cm, and 45 cm. g MA, 62.5g 2-EHA, 285.3 g TRIS, 0.22g AIBN and 377.0 gethyl acetate is uniformly added over 2 hours. After the Methods of Use addition, the flask is held at 80°C. to reflux overnight. Then resulting solution containing polymer A is cooled and poured 0087. The compositions described herein are useful in into a container. The Solids content of the polymer A Solution methods for the transdermal delivery of active agents, such as was tested at 55.8% (w/w). amine drugs, including in therapeutic methods for treating 0.095 A similar process was followed to make silicone conditions for which the active agents are known to be useful, containing polymers B, C, D and E. The properties of these as discussed above. In such embodiments, a composition polymers are summarized in the following table. The molecu comprising atherapeutically effective amount of active agent lar weight of the polymers was measured by the Gel Perme as described herein is topically applied to a subject in need ation Chromatography (GPC) method. The adhesive proper thereof ties were tested according to standard testing procedures. 0088. In some embodiments, the compositions achieve transdermal delivery of active agent over a period oftime of at least about 8 hours, including a period of time of at least about Stain- Shear 8 hours to at least about 12 hours, or longer, including up to Probe Release less (min, Tack Liner Steel 0.75" and including about 24 hours. In some embodiments, the Components (g/0.5 Peel peel width, compositions are formulated for daily application. (weight ratio) Avg MW cm) (g/0.5") (g/0.5") 250 g) 0089. In other embodiments, the compositions achieve transdermal delivery of active agent over a period oftime of at A MAJEHATRIS 184926 1072 11.2 1603.7 3.7 (7.7/16.5/75.8) least about 1 day, at least about 2 days, at least about 3 days, B MAJEHAPDMS 460.256 14.5 O.S 86.6 78.8 at least about 7 days, or longer. In some embodiments, the (33.3/33.3/33.3) compositions are formulated for once or twice weekly appli C MAJEHATRIS 324,339 460.7 4.3 455.3 246.0 cation. (20/5/75) D MAJEHATRIS, 629,506 317.6 4.0 393.7 1414 0090 The compositions described herein achieve a trans PDMS (40/10/ dermal flux of active agent that is sufficient to have a thera 30/20) peutic effect. As used herein, “flux' (also called “permeation E MMAJEHATRIS 175.287 255 15.3 333.4 2013 rate') is defined as the absorption of a drug through skin or (12.5/7.5/80) mucosal tissue, and is described by Fick's first law of diffu PDMS: mono-vinyl terminated polydimethylsiloxane S1O. MMA: methyl methacrylate 0096. As seen from a comparison of the monomer com where J is the flux in ug or mg/cm/hr, D is the diffusion ponents and polymer properties, the properties of the poly coefficient of the drug through the skin or mucosa in cm/hr mers can be selected, adjusted and controlled by selecting the and dCm/dx is the concentration gradient of the drug across monomers and monomer ratios. Further, as discussed above, the skin or mucosa. for drugs that are less soluble in silicone polymers than US 2016/0030362 A1 Feb. 4, 2016 acrylic polymers (e.g. most drugs), increasing the relative amount of the silicone-containing monomer(s) in the poly Peel from Release Liner (g 0.5". n = 3 mers is expected to decrease drug solubility, resulting in an increase in drug flux for a given concentration of drug. Lotti Formulation (wiw) 1M 2M 3M 4M RNOS6- Freshly made 9.2 22.4 39.9 80.6 32-4L Daytrana Example 2 RNO70- 20% MPH - 80% 23.3 2SO 22.4 18.7 132-4L Copolymer B 0097 Methylphenidate was formulated in silicone-con taining acrylic polymer B (described above) to prepare a composition comprising 20% methylphenidate and 80% 0102 The results show that the peel force for the polymer polymer B. Drug flux through human cadaver skin over 24 B composition remained stable and low while that of the hours was assessed in vitro. Results as compared to results Daytrana(R) product increased over time. achieved with the polymer matrix of the commercial Day trana(R) product (20% methylphenidate, 80% blend of acrylic Example 4 pressure-sensitive adhesive polymer and silicone pressure sensitive adhesive polymer) are shown in FIG. 1 and Summa 0103 Amphetamine was formulated in silicone-contain rized below. ing acrylic polymer B (described above) to prepare a compo sition comprising 15% amphetamine and 85% polymer B. 94 hr Flux Flux Drug flux through human cadaver skin over 24 hours was Lotti Formulation (SP9732 Backing) (mcg/cm/h) Ratio assessed in vitro. Results are shown in FIG.3 as compared to flux from a polymer matrix composition prepared with 15% 65654 Daytrana 9.1O 1.O amphetamine in acrylic pressure-sensitive adhesive polymers RNO70-132-4L 20% MPH + 80% Copolymer B 10.48 1.15 with no silicone moiety. 0104. The amphetamine/polymer B composition 0098. The results show that the composition based on described above was applied to a backing and a release liner, polymer Bachieved a drug flux comparable to that of Day and peel force from the release liner was assessed over 4 trana(R). months. Results as compared to results achieved with the 0099 For comparison, the invitro flux from a composition acrylic pressure-sensitive adhesive polymer matrix are shown prepared with 20% methylphenidate in 80% acrylic pressure below.

Peel from Release Liner (g 0.5". n = 3 Lotti Formulation (wiw) 1M 2M 3M 4M 15% Amphetamine + 42.5% Gelva 13.9 62.1 51.8 91.5 3O87 - 42.5% BioPSA 4102 15% Amphetamine + 85.0% 14.8 7.6 4.4 copolymer B sensitive adhesive (Gelva.R. 3087) and from Daytrana(R) are Example 5 plotted in FIG. 2 and summarized below. 0105 Rivastigmine was formulated in silicone-containing acrylic polymer B (described above) to prepare a composition 94 hr Flux comprising 20% rivastigmine and 80% polymer B. Drug flux Lotti Formulation (SP9732 Backing) (mcg/cm/h) Flux Ratio through human cadaver skin over 24 hours was assessed in vitro. Results are shown in FIG. 4 as compared to flux from 4O794 Daytrana 31.7 1.O the commercial Exelon(R) product which includes 20% RNOO7-141-2L 20% MPH - 80% Geva 3O87 17.6 O.S6 rivastigmine. The results show that the flux from the polymer B composition was significantly higher than that from the commercial ExelonR product. 0100. The results indicate that the acrylic pressure-sensi tive adhesive achieves significantly lower flux than the poly mer matrix of the Daytrana(R) product. Formulation 24 hr Flux Flux Lotti (SP9732 Backing) (mcg/cm/h) Ratio Example 3 Exelon Exelon 1911 1.O RNO83-44-3L 20% Rivastigmine + 33.25 1.74 0101 The methylphenidate/polymer B composition 80% Copolymer B described above was applied to a backing and a release liner, and peel force from the release liner was assessed over 4 0106 The rivastigmine/polymer B composition described months. Results as compared to results achieved with the above was applied to a backing and a release liner, and peel commercial Daytrana(R) product are shown below. force from the release liner was assessed over 4 months. US 2016/0030362 A1 Feb. 4, 2016 10

2. The composition of claim 1, wherein the silicone-con Peel from Release Liner (g 0.5". n = 3 taining acrylic polymer is a non-reactive silicone-containing acrylic polymer made from one or more non-reactive acrylic Lotti Formulation (wfw) 1M 2M 3M 4M monomers and one or more non-reactive silicone-containing RNO83- 20% Rivastigmine + 8.8 21.8 31.9 20.8 acrylic monomers, wherein the non-reactive monomers and 44-3L 80.0% copolymer B polymer do not react with amine groups of the amine drug. 3. The composition of claim 1, wherein the silicone-con 0107 The results show that the peel force from release taining acrylic polymer is made from one or more non-reac liner of the polymer B composition remained stable and low tive acrylic monomers selected from the group consisting of after storage for 4 months at ambient conditions. methyl acrylate, methyl methacrylate, butyl acrylate, butyl methacrylate, hexyl acrylate, hexyl methacrylate, 2-ethylbu Example 6 tyl acrylate, 2-ethylbutyl methacrylate, isooctyl acrylate, 0108 Paroxetine was formulated in silicone-containing isooctyl methacrylate, 2-ethylhexyl acrylate, 2-ethylhexyl acrylic polymer E (described above) to prepare compositions methacrylate, decyl acrylate, decyl methacrylate, dodecyl comprising 2.5% paroxetine and 97.5% polymer E and 5% acrylate, dodecyl methacrylate, tridecyl acrylate, tridecyl paroxetine and 95% polymer E. Drug flux through human methacrylate, octyl acrylamide, hydroxyethyl acrylate, and cadaver skin over 72 hours was assessed in vitro. Results are vinyl pyrrolidone, vinyl acetate, and one or more non-reactive shown in FIG. 5. The results show that the flux from the silicone-containing acrylic monomers, wherein the non-reac polymer E composition was directly correlated with the drug tive monomers do not react with amine groups of the amine loading concentration. drug. 0109 The paroxetine/polymer E compositions described 4. The composition of claim 1, wherein the silicone-con above were applied to a backing and a release liner, and peel taining acrylic polymer is made from (i) one or more acrylic force from the release liner was assessed over 4 months at monomers selected from the group consisting of methyl acry ambient condition. Results are shown below. late monomers, methyl methacrylate monomers, 2-ethyl

Peel from Release Liner OS' n = 3

Lotti Formulation (wfw) O 2M 4M RN100-122-1L 2.5% Paroxetine + 97.5% copolymer E 37.5 29.3 21.7 RN100-122-2L 5% Paroxetine + 95% copolymer E 42.4 19.2 17.0

0110. The results show that the peel force from release hexyl acrylate monomers, butyl acrylate monomers, amide liner of the polymer E composition remained low after stor containing monomers and vinyl-group containing age for 4 months at ambient condition. monomers, and (ii) one or more non-reactive silicone-con taining acrylic monomers, wherein the non-reactive mono Example 7 mers do not react with amine groups of the amine drug. 0111 Clonidine was formulated in silicone-containing 5. The composition of claim 1, wherein the silicone-con acrylic polymer B, C, or D (described above) to prepare a taining acrylic polymer is made from (i) up to four types of composition comprising 2% clonidine and 98% polymer B, C acrylic monomers selected from the group consisting of (1) or D. The compositions were applied to backings and release methyl acrylate and methyl methacrylate monomers; (2) liners, and peel force from the release liner was assessed over 2-ethylhexyl acrylate and butyl acrylate monomers, (3) 4 months at ambient condition. amide-containing monomers, and (4) vinyl group-containing

Peel from Release Liner (g/0.5". n = 3 Lotti Formulation (wfw) 1M 2M 3M RNO90-90-1L 2% clonidine + 98.0% copolymer B 10.4 14.6 12.4 13.6 RNO90-90-2L 2% clonidine + 98.0% copolymer C 10.8 14.3 14.4 16.6 RNO90-90-3L 2% clonidine + 98.0% copolymer D 10.9 14.3 17.1 22.5

0112 The results show that the peel force from release monomers, and one or more non-reactive silicone-containing liner of the silicone-containing acrylic polymer compositions acrylic monomers, wherein the non-reactive monomers do remained low and stable after storage for 4 months at ambient not react with amine groups of the amine drug. condition. 6. The composition of claim 1, wherein the silicone-con taining acrylic polymer is made from one or more silicone What is claimed is: containing acrylic monomers selected from the group con 1. A composition for the transdermal delivery of an amine sisting of siloxy silanes and polydimethylsiloxanes, and one drug in the form of a flexible finite system for topical appli or more acrylic monomers. cation, comprising a polymer matrix comprising a drug and a 7. The composition of claim 1, wherein the silicone-con silicone-containing acrylic polymer. taining acrylic polymer is made from one or more non-reac US 2016/0030362 A1 Feb. 4, 2016 tive silicone-containing acrylic monomers selected from the polymer matrix blend by blending an amine drug and a sili group consisting of 3-acryloxypropyl tri(trimethylsiloxy)si cone-containing acrylic polymer in a solvent, applying the lane, 3-methacryloxypropyl tri(trimethylsiloxy)silane, and polymer matrix blend to a Support layer, and removing any mono-vinyl terminated polydimethylsiloxane, and one or remaining solvent. more non-reactive acrylic monomers, wherein the non-reac 14. A method of manufacturing a silicone-containing tive monomers do not react with amine groups of the amine acrylic polymer, comprising copolymerizing acrylic mono drug. mers with silicone-containing acrylic monomers. 8. The composition of claim 1, wherein the drug is an amine drug selected from the group consisting of amphet 15. The method of claim 14, wherein the acrylic monomers amine, methylphenidate, rivastigmine, rotigotine, fentanyl. and silicone-containing acrylic monomers are non-reactive paroxetine clonidine, amiodarone, amitriptyline, atropine, with amine groups. benztropine, biperiden, bornaprine, bupivacaine, chlorphe 16. The method of claim 14, wherein the silicone-contain niramine, cinnarizine, clomipramine, cyclopentolate, ing acrylic polymer is comprised of 1-99% by weight acrylic darifenacin, dexetimide, dicyclomine, diltiazem, diphenhy monomers and 99-1% by weight silicone-containing acrylic dramine, doxepin, ethopropazine, flavoxate, homatropine, monomers, based on the total dry weight of the polymer. imipramine, loxapine, maZaticol, metixene, Oxybutin, 17. The method of claim 16, wherein the silicone-contain oxyphencyclimine, phenglutarimide, physostigmine, piperi ing acrylic polymer is comprised of up to 50% by weight dolate, pirenzepine, procyclidine, profenamine, propiverine, acrylic monomers and at least 50% by weight silicone-con Scopolamine, telenZepine, theophylline, , trimi taining acrylic monomers, based on the total dry weight of the pramine, trihexyphenidyl, tropatepine, and . polymer. 9. The composition of claim 1, wherein the drug is an amine drug selected from the group consisting of amphet 18. The method of claim 16, wherein the silicone-contain amine, methylphenidate, rivastigmine, paroxetine and cloni ing acrylic polymer is comprised of at least 50% by weight dine. acrylic monomers and up to 50% by weight silicone-contain 10. The composition of claim 1, further comprising a back ing acrylic monomers, based on the total dry weight of the ing. polymer. 11. The composition according to claim 10, further com 19. Use of a silicone-containing acrylic polymer in the prising a release liner. preparation of a medicament for the transdermal delivery of 12. A method for the transdermal delivery of an amine an amine drug. drug, comprising topically applying a composition as claimed in claim 1 to the skin or mucosa of a subject in need 20. Compositions in the form of a flexible finite system for thereof. topical application, comprising a polymer matrix comprising 13. A method of manufacturing a composition for the trans a drug and a silicone-containing acrylic polymer, for use in dermal delivery of an amine drug in the form of a flexible the transdermal delivery of an amine drug. finite system for topical application, comprising forming a k k k k k