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. rivastigmine, paroxetine and clonidine. 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, rotigotine, drug delivery composition with a high concentration of drug fentanyl, paroxetine clonidine, amiodarone, amitriptyline, also may undermine the desired physical characteristics of atropine, benztropine, biperiden, bornaprine, bupivacaine, US 2016/0030362 A1 Feb. 4, 2016 chlorpheniramine, cinnarizine, clomipramine, cyclopento 10018 FIG.3 shows in vitro flux data (flux, ug/cm/hr) of late, darifenacin, dexetimide, dicyclomine, diltiazem, amphetamine from a composition comprising a silicone-con diphenhydramine, doxepin, ethopropazine, flavoxate, homa taining acrylic