US 2011 0082266A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2011/0082266A1 Benz et al. (43) Pub. Date: Apr. 7, 2011

(54) THERAPEUTIC POLYMERS AND METHODS Publication Classification OF GENERATION (51) Int. Cl. (76) Inventors: Michael Eric Benz, Ramsey, MN A6II 47/48 (2006.01) (US); Erica M. TenBroek, C08G 65/00 (2006.01) Roseville, MN (US); Lian Leon Luo, Shoreview, MN (US) (52) U.S. Cl...... 525/539; 525/50: 525/410 (21) Appl. No.: 12/766,676 (57) ABSTRACT (22) Filed: Apr. 23, 2010 The invention describes poly(ortho ester) polymers that O O include at least one therapeutic compound in the polymer Related U.S. Application Data backbone. The therapeutic compound includes at least one (60) Provisional application No. 61/249,098, filed on Oct. phenol residue and analiphatic alcohol residue or two or more 6, 2009. phenolic residues.

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THERAPEUTIC POLYMERS AND METHODS OF GENERATION ---Z-POE-F-A-POE.H CROSS REFERENCE TO RELATED APPLICATIONS 0008 wherein each POE and POE, independently, is represented by the formula: 0001. This application claims priority to U.S. provisional patent application Ser. No. 61/249,098, titled “Therapeutic Polymers and Methods of Generation”, filed on Oct. 6, 2009, R11 R11 the contents which are hereby incorporated by reference in their entirety. R10(R).C.. O O C(R)R10

FIELD OF THE INVENTION NX-es-X. 0002 The invention relates generally to poly(ortho ester) 0009 or the formula: polymers that include at least one therapeutic compound in the polymerbackbone. The therapeutic compound includes at least one phenol residue and an aliphatic alcohol residue or R16O OR 15 Rl5O OR 15 two or more phenolic residues. O O BACKGROUND OF THE INVENTION Xin X. R17 H H R17 0003 Biodegradable polymers have found uses in a wide variety of applications ranging from trash bags that decom 0010 wherein: pose in landfills to implantable medical devices that biode 0011 each R. R', and R7 independently represents grade in the body. Most of these applications require that Such hydrogen or an organic group; polymers have adequate physical properties and stability to 0012 each R', R', R', and R' independently repre provide for suitable handling and utility prior to being sub sents an organic group: jected to end use conditions that promote biodegradation. 0013 R' represents oxygen or an organic group and Further, it is often preferable that these same polymers rapidly p=0 or 1; or controllably biodegrade once Subjected to such end use 0014 n=0 or 1: conditions. In addition, it is often desired that biodegradable (0.015 each R' can optionally be joined with R' to polymers used for implantable medical devices be converted form one or more rings; under physiological conditions to materials that do not irritate 0016 geminal R'' and R' groups can optionally be or harm the Surrounding tissue. Many biodegradable poly joined to each other to form rings; mers known in the art lack the combination of physical and/or I0017 each A, optionally, is C(R))R)–(C(R).), chemical properties desired to meet the needs for specific C(R)(R)-, - Ar' ,—Ar"C(R)(R7)—, a group of applications. the formula (Formula III) —Ar C(R). Ar (B) 0004 Current and new applications for biodegradable , —C(=O)— —(C=O)—R—(C=O)—, or com polymers continue to create a need for new polymers that binations thereof provide some or all of the above-described properties. 0.018 R is an organic group; (0.019 each R', R. R. R. and Rindependently repre BRIEF SUMMARY OF THE INVENTION sents hydrogen oran organic group, r is 0 to 20, and one or more of R', R. R. R. and R can optionally be 0005 Poly(ortho ester) polymers, and methods of making joined with one another to form one or more rings; and using poly(ortho ester) polymers are disclosed herein. I0020) Ar' represents a 1.2-heteroarylene group; Poly(ortho ester) polymers as disclosed herein, and compo 0021 Ar' represents a 1.2- or a 1.3-arylene group, or a sitions including Such poly(ortho ester) polymers, can be 1.2- or a 1.3-heteroarylene group, R and R' indepen useful for applications including, for example, medical dently represent hydrogen or an organic group, and R' devices and pharmaceutical compositions. In one embodi and/or R' can optionally be joined with each other or ment, the poly(ortho ester) polymers disclosed herein are with the Ar' group to form one or more rings; biodegradable. 0022 each Ar’ independently represents an arylene 0006. The presently disclosed poly(ortho ester) polymers group, each R independently represents an organic (POE) can offer advantages over poly(ortho ester) polymers group, B represents an aromatic-containing organic known in the art. For example, the presently disclosed poly group having a linking oxygen attached to the aromatic (ortho ester) polymers can hydrolyze at a sufficient rate to be ring, and m=0 or 1; useful for applications that require biodegradable properties, 0023 each x is 1 to about 200: without the necessity of admixing and/or incorporating 0024 each y is 0 to about 200; agents to enhance the hydrolysis rate. 0025) x+y is from 2 to about 400; and 0007. In one aspect, the present disclosure provides a 0026 each Z is a therapeutic agent containing at least polymer including two or more repeat units selected from a one phenoxy residue and at least one hydroxyl residue or repeat unit of the formula (Formula VI): at least a second phenoxy residue. US 2011/0082266 A1 Apr. 7, 2011

0027. It should be understood that the “x's and “y's can be 0032 a compound of the formula (Formula V) random and not necessarily in any order. For example, there can be a repeat of several or many “x's follow by one or more “y's or vice versa. The resultant polymer can be a random Rl5O R17 R17 OR 15 copolymer, a block copolymer or variations thereof. 0028. In one embodiment, the repeat unit only comprises X t R18 i ( andy is always 0. That is, the polymer contains only Z in the R16O p OR 16. backbone along with the ortho ester. 0029. In another aspect, the present disclosure provides a method of preparing a polymer. In one embodiment, the O method includes: combining components including: at least 0033 combinations thereof; wherein: each R and R'7 one hydroxy-containing compound of the formula (Formula independently represents hydrogen oran organic group; each I) HO—Z OH or a mixture of Formula I and Formula (Ia) R'', R. R', and R' independently represents an organic HO—A OH; and at least one orthoester of the formula group; R represents oxygen or an organic group and p-0 or (Formula II) 1; each R' can optionally be joined with R' to form one or more rings; geminal R' and R' groups can optionally be joined to each other to form rings; each A is selected from R14O OR C(R)(R)-(C(R).), C(R)(R) - Ar' , Ar"C (R)(R)—, a group of the formula (Formula III) —Ar’ C (R), Ar (B), , or combinations thereof; each R', R, R. R. and R independently represents hydrogen or an organic group, r is 0 to 20 (particularly 0 to 15 and more 0030 under conditions effective to polymerize at least a portion of the orthoester; and removing byproducts including particularly 0 to 10), and one or more of R',R,R,R, andR ROH: wherein each R and R' independently represents can optionally be joined with one another to form one or more hydrogen or an organic group; each R'' and R' indepen rings, Ar' represents a 1.2-heteroarylene group; Ar' repre dently represents an organic group; each A is selected from sents a 12- or a 1.3-arylene group, or a 12- or a 13-het C(R)(R)-(C(R).), C(R)(R) - Ar' , Ar"C eroarylene group, R and R7 independently represent hydro (R)(R)—, a group of the formula (Formula III) —Ar C gen or an organic group, and Rand/or R' can optionally be (R). Ar' (B), , or combinations thereof; each R', R, joined with each other or with the Ar' group to form one or R. R. and R independently represents hydrogen or an more rings; and each Ar independently represents an arylene organic group, r is 0 to 20 (particularly 0 to 15 and more group, each Rindependently represents an organic group, B particularly 0 to 10), and one or more of R',R,R,R, andR represents an aromatic-containing organic group having a can optionally be joined with one another to form one or more linking oxygen attached to the aromatic ring, and m=0 or 1, rings, Ar" represents a 1.2-heteroarylene group; Ar' repre and Z is a therapeutic agent containing at least one phenoxy sents a 12- or a 1.3-arylene group, or a 12- or a 13-het residue and at least one hydroxyl residue or at least a second eroarylene group, R and R7 independently represent hydro phenoxy residue. gen or an organic group, and Rand/or R' can optionally be 0034. In one aspect, each. A represents a non-cyclic group joined with each other or with the Ar' group to form one or —CH(R')–(C(R).), CH(R)-; each RandR indepen more rings; and each Ar independently represents an arylene dently represents an organic group; each R independently group, each Rindependently represents an organic group, B represents hydrogen or an organic group; and r is 0 to 20. represents an aromatic-containing organic group having a 0035. In another aspect, each A represents a cyclic group linking oxygen attached to the aromatic ring, and m=0 or 1, - C(R)(R)–(C(R).), C(R)(R)-; each R', R, R and and Z is a therapeutic agent containing at least one phenoxy R", independently represents hydrogen or an organic group, r residue and at least one hydroxyl residue or at least a second is 1 to 20 (particularly 1 to 15 and more particularly 1 to 10), phenoxy residue. and each R is an organic group and isjoined with the other to 0031. In another aspect, the present disclosure provides form a ring, e.g., trans-1,4-cyclohexanedimethanol. another method of preparing a polymer. In one embodiment, 0036. In another aspect, the present disclosure provides a the method includes combining components including at method of hydrolyzing a poly(ortho ester) polymer. The least one hydroxy-containing compound of the formula (For method includes: providing a poly(ortho ester) polymer that mula I) HO Z OH or a mixture of Formula I and a com is substantially free of acidic groups, glycolide groups, and pound of the formula (Formula Ia) HO—A OH and at least lactide groups; exposing the poly(ortho ester) polymer to an one ketene acetal under conditions effective to polymerize at aqueous environment; and allowing the poly(ortho ester) least a portion of the at least one ketene acetal, wherein the at polymer to hydrolyze. In an embodiment, the hydrolysis rate least one ketene acetal is selected from a compound of the and/or drug release rate of the poly(ortho ester) polymer is formula (Formula IV) sufficiently high to allow the poly(ortho ester) polymer to be used in applications requiring biodegradability and/or bio erodibility. Generally, when the poly(ortho ester) polymer is used in an application requiring biodegradability and/or bio erodibility, hydrolyzing the poly(ortho ester) polymer includes forming Substantially no acidic byproducts at the hydrolysis site. 0037. As used herein, “a,” “an,” “the “at least one, and “one or more are used interchangeably. US 2011/0082266 A1 Apr. 7, 2011

0038 Also herein, the recitations of numerical ranges by invention belongs. All publications and patents specifically endpoints include all numbers Subsumed within that range mentioned herein are incorporated by reference in their (e.g., 1 to 5 includes 1, 1.5, 2, 2.75, 3, 3.80, 4, 5, etc.). entirety for all purposes including describing and disclosing 0039. The above summary is not intended to describe each the chemicals, instruments, statistical analyses and method disclosed embodiment or every implementation of the present ologies which are reported in the publications which might be disclosure. The description that follows more particularly used in connection with the invention. All references cited in exemplifies illustrative embodiments. In several places this specification are to be taken as indicative of the level of throughout the application, guidance is provided through lists skill in the art. Nothing herein is to be construed as an admis of examples, which examples can be used in various combi sion that the invention is not entitled to antedate Such disclo nations. In each instance, the recited list serves only as a sure by virtue of prior invention. representative group and should not be interpreted as an 0049. A wide variety of biodegradable and/or bioerodible exclusive list. polymers are known in the art. As used herein, "biodegrad 0040. While multiple embodiments are disclosed, still able' and “bioerodible' are used interchangably and are other embodiments of the present invention will become intended to broadly encompass materials including, for apparent to those skilled in the art from the following detailed example, those that tend to break down upon exposure to description. As will be apparent, the invention is capable of physiological environments. Biodegradable and/or bioerod modifications in various obvious aspects, all without depart ible polymers known in the art include, for example, linear ing from the spirit and scope of the present invention. Accord aliphatic polyester homopolymers (e.g., polyglycolide, poly ingly, the detailed descriptions are to be regarded as illustra lactide, polycaprolactone, and polyhydroxybutyrate) and tive in nature and not restrictive. copolymers (e.g., poly(glycolide-co-lactide), poly(glycolide co-caprolactone), poly(glycolide-co-trimethylenecarbon BRIEF DESCRIPTION OF THE DRAWINGS ate), poly(lactic acid-co-lysine), poly(lactide-co-urethane), poly(ester-co-amide)); polyanhydrides; and poly(orthoe 0041 FIG. 1 provides a graphical depiction of the effect of sters). However, many of these polymers lack the combina polymer breakdown products on synovial cell viability mea tion of physical and/or chemical properties desired for certain sured after 24 hours of exposure. applications, particularly in the medical and pharmaceutical 0042 FIG. 2 demonstrates the effect of polymer break fields. down products on IL-1 b secretion from synoviocytes. * Sig 0050 For example, polyglycolide and polylactide homo nificantly different p-0.05 Holm-Sidek post-hoc comparison and co-polymers are converted under physiological condi to cells in media. tions to products including glycolic acid and lactic acid, 0043 FIG. 3 depicts the effect of polymer breakdown respectively. For certain medical device applications, the for products on differentiated chondrocyte viability measured mation of acidic products can limit the utility of such biede after 24 hours of exposure. * Significantly different p-0.05 gradable polymers. Further, many of the biodegradable poly Holm-Sidek post-hoc comparison to cells in media. mers noted above biodegrade at a slower rate than desired for 0044 FIG. 4 demonstrates the effect of polymer break specific applications. down products on IL-1b secretion from differentiated human chondrocytes. * Significantly different p-0.05 Holm-Sidek 0051 Certain poly(orthoesters) are also known to be bio post-hoc comparison to cells in media. degradable polymers. As used herein, a “poly(ortho ester) 0045 FIG. 5 provides total joint scores in the medial refers to a homo- or co-polymer that includes two or more meniscal tear model of osteoarthritis of the rat following (i.e., a plurality) of orthoester repeat units. As used herein, an injection of polymeric microspheres (day 28). Animals were “orthoester repeat unit is a unit including an orthoester treated with the polycurcumin microspheres or animals were containing group that is repeated in the polymer at least once. treated with the polyresveratrol microspheres described in the An orthoester group is a group that includes an RC(OR) Examples. No histopathological changes or signs of toxicity functionality (e.g., an —O—C(R)(OR)—O— or —O—C were noted with either polyphenolic microspheres alone as (OR)-functionality), with the proviso that R is not oxygen. compared to the saline controls. The pain control was treated 0.052 The presently disclosed poly(ortho ester) polymers with an analgesic alone. can offer advantages over poly(ortho ester) polymers known in the art. For example, the presently disclosed poly(ortho ester) polymers can hydrolyze at a sufficient rate to be useful DETAILED DESCRIPTION for applications that require biodegradable properties, with 0046. In the specification and in the claims, the terms out the necessity of admixing and/or incorporating other “including and "comprising are open-ended terms and agents to enhance the hydrolysis rate. If necessary, a base, should be interpreted to mean “including, but not limited to . Such as anhydrous MgO could be used to retard the degrada . . . . These terms encompass the more restrictive terms tion rate. “consisting essentially of and "consisting of 0053. The presently disclosed poly(ortho ester) polymers 0047. It must be noted that as used herein and in the have molecular weights of at least about 10,000, more par appended claims, the singular forms “a”, “an', and “the ticularly at least about 20,000 and even more particularly at include plural reference unless the context clearly dictates least about 40,000 g/mol. This is a great improvement over otherwise. As well, the terms “a” (or “an'), “one or more' and known poly(ortho ester) polymers that typically have “at least one' can be used interchangeably herein. It is also to molecular weights of 10,000 or less. It is believed that by be noted that the terms “comprising”, “including”, “charac selection of the appropriate “Z” and 'A', as discussed herein, terized by and “having can be used interchangeably. it is possible to obtain the molecular weights. Consequently, 0.048. Unless defined otherwise, all technical and scien the increased molecular weight of the poly(ortho ester) poly tific terms used herein have the same meanings as commonly mer of the invention provide for sustained delivery of the drug understood by one of ordinary skill in the art to which this (Z) and are biocompatible. US 2011/0082266 A1 Apr. 7, 2011

0054 Poly(ortho ester) polymers and convenient methods nin, Isorhamnetin, , , Lariciresinol, of preparing such polymers are disclosed herein. Notably the Leucopelargonidin, , Luteolin, Malvidin, Mar presently disclosed poly(orthoesters) include polymers that ingenin, Matairesinol, Methylarzanol, , Naringe are not significantly converted under physiological condi nin, , , Pelargonidin, Peonidin, tions to acidic products. Further, the present disclosure pro Petunidin, , , Pinoresiniol, , vides poly(ortho ester) polymers that can biodegrade at a Pinostilbenoside, Proanthocyanidin, , Punicala sufficiently high rate to enable them to be considered for use gins, , . , Rhaponticin, in specific applications. , Rutin, Secoirodoid, Secoisolariciresinol, 0055. In one aspect, methods of preparing poly(ortho , Silybin, Semimyrtucommulone, Tangeritin, 4.2',4', ester) polymers are disclosed herein. In one embodiment, 6'-Tetrahydroxychalcone. Theaflavins, Thearubigin, 4,4',6'- Such methods include combining components including at Trihydroxyaurone, Tyrosol, Vanillyl alcohol, (-)-Vestitone, least one hydroxy-containing compound (atherapeutic agent, Xanthohumol or combinations thereof. “Z”, as described herein or a mixture of “Z” and a hydroxy 0059. The term “residue' refers to the material that is containing compound 'A', as described herein) and at least devoid of a hydrogenatom. For example, a phenol would be one orthoester, as further described herein below. In another a phenoxide moiety and an alcohol would be a hydroxide or embodiment, Such methods include combining components alcoholate. including at least one hydroxy-containing compound, Z, and 0060. It should be understood that throughout the applica at least one ketene acetal, as further described herein below. tion and claims that the poly(ortho ester) polymers disclosed 0056. For some embodiments, suitable hydroxy-contain herein, and their methods of preparation, will always contain ing compounds include compounds of the formula (Formula at least a small percentage of a Z residue in the polymeric Ia) HO-A OH. “A” can be selected from C(R)(R)- backbone. Suitable ranges are from 0.01% to 100% by (C(R).), C(R)(R) Ar" , Ar"C(R)(R7) , a weight, more particularly, from about 0.1% to about 50%, group of the formula (Formula III) —Ar C(R). Ar more particularly from about 1% to about 40% and most (B), , or combinations thereof. Each R', R. R. R. and R particularly from about 5% to about 30% by weight. independently represents hydrogen oran organic group, r is 0 0061. As used herein, the term “organic group' is used to to 20 (particularly 0 to 15 and more particularly 0 to 10), and mean a hydrocarbon group that is classified as an aliphatic one or more of R',R,R,R, and Rican optionally bejoined group, cyclic group, or combination of aliphatic and cyclic with one another to form one or more rings. Ar' represents a groups (e.g., alkarylandaralkyl groups). In the context of the 1.2-heteroarylene group. Ar' represents a 1.2- or a 1,3- present disclosure, suitable organic groups for polymeriza arylene group, or a 1.2- or a 1.3-heteroarylene group. Rand tion components and polymers disclosed herein are those that R’ independently represent hydrogen or an organic group, do not interfere with the polymerization reactions disclosed and Rand/or R' can optionally be joined with each other or herein. In the context of the present disclosure, the term with the Ar' group to form one or more rings. Each Ar “aliphatic group” means a saturated or unsaturated linear or independently represents an arylene group, each Rindepen branched hydrocarbon group. This term is used to encompass dently represents an organic group, B represents an aromatic alkyl, alkenyl, and alkynyl groups, for example. The term containing organic group having a linking oxygen attached to “alkyl group” means a saturated linear or branched monova the aromatic ring, and m=0 or 1. lent hydrocarbon group including, for example, methyl, 0057. A wide variety of hydroxy-containing compounds ethyl, n-propyl, isopropyl, tent-butyl, amyl, heptyl, and the of the formula (Formula Ia) can be used including, for like. The term “alkenyl group” means an unsaturated, linear example, diethyl tartrate, 2-hydroxybenzyl alcohol, 3-hy or branched monovalent hydrocarbon group with one or more droxybenzyl alcohol, 2,3-dihydroxypyridine, 4,4'-(1-phenyl olefinically unsaturated groups (i.e., carbon-carbon double ethylidene)bisphenol, 4,4'-isopropylidenebis(2,6-dimeth bonds). Such as a vinyl group. The term “alkynyl group' ylphenol), 4,4'-(1,4-phenylenediisopropylidene)bisphenol, means an unsaturated, linear or branched monovalent hydro and combinations thereof. carbon group with one or more carbon-carbon triple bonds. 0058 For all embodiments, suitable hydroxy-containing The term "cyclic group” means a closed ring hydrocarbon compounds include compounds of the formula (Formula I) group that is classified as an alicyclic group, aromatic group, HO—Z-OH. Z is a therapeutic agent containing at least one or heterocyclic group. The term “alicyclic group” means a phenoxy residue and at least one hydroxyl residue or at least cyclic hydrocarbon group having properties resembling those a second phenoxy residue. Alternatively, Z can contain at of aliphatic groups. The term 'aromatic group' or 'aryl least two phenoxy residues. It should be understood that more group” means a mono- or polynuclear aromatic hydrocarbon than two phenoxy groups may be present or the combination group. The term "heterocyclic group” means a closed ring of phenoxys and hydroxys can equal three or more for a hydrocarbon in which one or more of the atoms in the ring is Suitable therapeutic agent. Suitable therapeutic agents that an element other than carbon (e.g., nitrogen, oxygen, Sulfur, have at least one phenoxy group (a phenol) and at least one etc.). hyroxyl or at least two phenoxy groups include , 0062. As a means of simplifying the discussion and the , (+)-1-Acetoxypinoresinol, Arzanol, , recitation of certain terminology used throughout this appli , , Catechin gallate, Chrysin, cation, the terms “group' and "moiety' are used to differen , Curcumin, Cyanidin, , Daphnetin, Del tiate between chemical species that allow for substitution or phinidin, Desoxyrhapontigenin, 7.2'-Dihydroxy-4'-meth that may be substituted and those that do not so allow for oxyisoflavanol, Ellagic acid, Epicatechin, Epigallocatechin, substitution or may not be so substituted. Thus, when the term , Eriodictyol. Fisetin, Gallocatechin, “group' is used to describe a chemical substituent, the Gallocatechin gallate, , Gingerol, , described chemical material includes the unsubstituted group Helipyrone, Hesperidin, Hespertin, 2-Hydroxy formorone and that group with nonperoxidic O. N. S. Si, or Fatoms, for tin, 2-Hydroxyisoflavanone, , Isoliquiritige example, in the chain as well as carbonyl groups or other US 2011/0082266 A1 Apr. 7, 2011

conventional substituents. Where the term "moiety' is used to mula I) can be replaced in part by the compound or com describe a chemical compound or Substituent, only an unsub pounds of formula (Formula Ia) HO—A-OH in an amount stituted chemical material is intended to be included. For up to about 99% by weight but there must always be a per example, the phrase “alkyl group' is intended to include not centage of the compound of formula (Formula I) present in only pure open chain Saturated hydrocarbon alkyl Substitu the process and final product. ents, such as methyl, ethyl, propyl, tert-butyl, and the like, but also alkyl substituents bearing further substituents known in 0067. Optionally, the components can further include, for the art, Such as hydroxy, alkoxy, alkylsulfonyl, halogen example, at least one diol different than the at least one atoms, cyano, nitro, amino, carboxyl, etc. Thus, “alkyl group' hydroxy-containing compound of the formula (Formula I). A includes ether groups, haloalkyls, nitroalkyls, carboxyalkyls, wide variety of diols can be used including, for example, hydroxyalkyls, sulfoalkyls, etc. On the other hand, the phrase diethyleneglycol, triethyleneglycol, tetra(ethyleneglycol), “alkyl moiety' is limited to the inclusion of only pure open 1.2-propanediol. 1,3-propanediol, 1,4-butanediol, neopentyl chain Saturated hydrocarbon alkyl Substituents, such as glycol, 2.5-hexanediol. 1.6-hexanediol. 1,12-dodecanediol. methyl, ethyl, propyl, tert-butyl, and the like. 1,4-cyclohexanedimethanol, 4-hydroxybenzyl alcohol. 4,4'- 0063 For some other embodiments, Sutiable hydroxy biphenol, bis(4-hydroxyphenyl)methane, bisphenol-A, hyd containing compounds include non-cyclic polyols having no roquinone, 1,4-benzenedimethanol, 2-methoxyhydro primary hydroxy groups. Such non-cyclic polyols having non quinone, 2,3-dimethylhydroquinone, and combinations primary hydroxy groups include, for example, diols having thereof. two secondary hydroxy groups. 0068. In another embodiment, a method of preparing a 0064. Non-cyclic polyols having no primary hydroxy poly(ortho ester) polymer includes: combining components groups can be of the formula HO CH(R') (C(R).), CH including: at least one non-cyclic polyol having no primary (R) OH: wherein: each R" and R independently repre hydroxy groups as described herein above; at least one com sents an organic group (e.g., an organic moiety Such as pound of the formula (Formula I), and at least one orthoester methyl); each R independently represents hydrogen or an of the formula (Formula II) organic group (e.g., an organic moiety); and r is 0 to 20. In certain embodiments each R' and R represents methyl; each R represents hydrogen; and ris 0 to 2. Exemplary non-cyclic R1O OR 11 polyols having no primary hydroxy groups include, but are not limited to, 2,3-butanediol. 2.4-pentanediol. 2.5-hex anediol, and combinations thereof. 0065. In one embodiment, a method of preparing a poly (ortho ester) polymer includes: combining components 0069 under conditions effective to polymerize at least a including: at least one hydroxy-containing compound of the portion of the orthoester. The at least one non-cyclic polyol formula (Formula I) HO—Z OH as described herein above having no primary hydroxy groups and the at least one orthoe or a mixture of Formula I and a hydroxy-containing com ster of the formula (Formula II) can be combined in a ratio pound of the formula (Formula Ia) HO—A OH as selected to provide, for example, oligomers, low molecular described herein above; and at least one orthoester of the weight polymers, and/or high molecular weight polymers. formula (Formula II) For embodiments in which polymers are desired (e.g., high molecular weight polymers), the at least one non-cyclic polyol having no primary hydroxy groups and the at least one R14O OR orthoester of the formula (Formula II) typically are combined approximately in a 1:1 molar ratio, respectively, although ratios of from 0.9:1 to 1.1:1, respectively can be used in certain embodiments. The method further includes removing 0066 under conditions effective to polymerize at least a byproducts including ROH. Each RandR'independently portion of the orthoester. The at least one hydroxy-containing represents hydrogen or an organic group. Each R'' and R' compound of the formula (Formula I) HO Z OH and the independently represents an organic group. The components at least one orthoester of the formula (Formula II) can be combined can also include a polymerization agent as combined in a ratio selected to provide, for example, oligo described herein below. Again, it should be understood that mers, low molecular weight polymers, and/or high molecular the compound(s) of the formula (Formula Ia) can be replaced weight polymers. For embodiments in which polymers are in part by the compound of formula (Formula I) HO—Z OH desired (e.g., high molecular weight polymers), the at least in an amount up to about 99% by weight at there must always one hydroxy-containing compound of the formula (Formula be a percentage of the compound of formula (Formula I) I) HO—Z OH and the at least one orthoester of the formula present in the process and final product. (Formula II) typically are combined approximately in a 1:1 0070 Optionally, the components can further include, for molar ratio, respectively, although ratios of from 0.9:1 to example, at least one diol different than the at least one 1.1:1, respectively can be used in certain embodiments. The non-cyclic polyol having no primary hydroxy groups. A wide method further includes removing byproducts including variety of diols can be used including, for example, ethyl ROH. Each RandR' independently represents hydrogen eneglycol, diethyleneglycol, triethyleneglycol, tetra(ethyl or an organic group. Each R'' and R' independently repre eneglycol), 1,3-propanediol. 1,4-butanediol, neopentyl gly sents an organic group. The components combined can also col, 1,6-hexanediol, 1,12-dodecanediol, 1,4- include a polymerization agent as described herein below. It cyclohexanedimethanol, 4-hydroxybenzyl alcohol. 4,4'- should be understood that the compound of the formula (For biphenol, bis(4-hydroxyphenyl)methane, bisphenol-A, US 2011/0082266 A1 Apr. 7, 2011

hydroquinone, 1,4-benzenedimethanol, 2-methoxyhydro acetal of Formula IV and/or Formula V have a purity of at quinone, 2,3-dimethylhydroquinone, and combinations least 98 wt-%, more particulary at least 99 wt-%, and most thereof. particularly at least 99.5 wt-% as measured using the proce 0071. For at least some of the above-described embodi dure of Pogany et al., J. of Chromatography, 508:179-186 ments, conditions effective to polymerize include combining (1990). Ketene acetals can be prepared by methods known in at least a portion of the components without adding a solvent. the art including for example, those described in Crivello et In other embodiments, conditions effective to polymerize al., J. of Polymer Science, 34:3091-3102 (1996); Ng et al., further include combining a solvent, preferably a dry organic Macromolecular Syntheses, 11:23-26 (1992); and U.S. Pat. solvent. In certain embodiments, the solvent preferably forms Nos. 4.513,143 (Nget al.) and 4,532,335 (Helwing). The at an azeotrope with ROH. Suitable solvents include, for least one hydroxy-containing compound of the formula (For example, tetrahydrofuran, dioxane, toluene, methylene chlo mula I) or the mixture of Formula I and Formula Ia and the at ride, chloroform, N-methylpyrrolidone, N,N-dimethylaceta least one ketene acetal of Formula IV and/or Formula V can mide, N,N-dimethylformamide, and combinations thereof. In be combined in a ratio selected to provide, for example, certain embodiments, at least a portion of the components are oligomers, low molecular weight polymers, and/or high combined under an inert atmosphere. molecular weight polymers. For embodiments in which poly 0072 Byproducts of the reaction including, for example, mers are desired (e.g., high molecular weight polymers), the ROH, can be removed, for example, by application of heat at least one hydroxy-containing compound of the formula and/or vacuum to the reaction mixture. When a solvent is (Formula I) and the at least one ketene acetal of Formula IV added, a convenient method of removing such byproducts and/or Formula V typically are combined approximately in a includes distilling the byproducts under azeotropic condi molar ratio of 1:1, respectively. In certain embodiments, theat tions. least one hydroxy-containing compound of the formula (For 0073. Optionally, combining components can further mula I) and the at least one ketene acetal of Formula IV and/or include combining an additional polymerizable compound. A Formula V are combined in a molar ratio such that the at least wide variety of additional polymerizable compounds can be one ketene acetal of Formula IV and/or Formula V is present used including, for example, ketene acetals, monofunctional in a slight molar excess. For example, in certain embodi orthoesters, polyfunctional orthoesters, imagable com ments, the at least one hydroxy-containing compound of the pounds, compounds having latent reactive sites, and combi formula (Formula I) and the at least one ketene acetal of nations thereof. The additional polymerizable compound can Formula IV and/or Formula V are combined in a molar ratio also be an orthoester different than the at least one orthoester of 1 to at least 1.001, particularly in a molar ratio of 1 to at described herein above. least 1.01, and more particularly in a molar ratio of 1 to at least 0074. In another embodiment, a method of preparing a 1.02. in certain embodiments, the at least one hydroxy-con poly(ortho ester) polymer includes: combining components taining compound of the formula (Formula I) and the at least including at least one hydroxy-containing compound of the one ketene acetal of Formula IV and/or Formula V are com formula (Formula I) HO Z OH or a mixture of the com bined in a molar ratio of 1 to at most 1.1, particularly in a pound of the formula (Formula I) and at least one hydroxy molar ratio of 1 to at most 1.05, and more particularly in a containing compound of the formula (Formula Ia) HO—A- molar ratio of 1 to at most 1.03. OH as described herein above and at least one ketene acetal 0077. The components combined can also include a poly under conditions effective to polymerize at least a portion of merization agent as described herein below. the at least one ketene acetal. The at least one ketene acetal is 0078. In certain embodiments, the compound of the for selected from a compound of the formula (Formula IV) mula (Formula IV) is represented by Formula IV.(a): " . R19 R19 R19 R19 > <-RD < R19 R19 R19 R19 0075 a compound of the formula (Formula V) (0079 wherein each Rand R', independently represents hydrogen or an organic group. In certain embodiments, each Rl5O R17 R17 OR 15 RandR' represents hydrogen. 0080 Optionally, the components can further include, for R16O RI), OR 16. example, at least one diol different than the at least one hydroxy-containing compound of the formula (Formula Ia). A wide variety of diols can be used including, for example, O ethyleneglycol, diethyleneglycol, triethyleneglycol, tetra 0076 combinations thereof. Each R and R7 indepen (ethyleneglycol), 1,3-propanediol. 1,4-butanediol, neopentyl dently represents hydrogen or an organic group. Each R', glycol, 2.5-hexanediol. 1.6-hexanediol. 1,12-dodecanediol. R". R', and R' independently represents an organic group. 1,4-cyclohexanedimethanol, 4-hydroxybenzyl alcohol. 4,4'- R" represents oxygen oran organic group and p-0 or 1. Each biphenol, bis(4-hydroxyphenyl)methane, bisphenol-A, hyd R' can optionally be joined with R' to form one or more roquinone, 1,4-benzenedimethanol, 2-methoxyhydro rings, and geminal R' and R' groups can optionally be quinone, 2,3-dimethylhydroquinone, and combinations joined to each other to form rings. The at least one ketene thereof. US 2011/0082266 A1 Apr. 7, 2011

0081. In another embodiment, a method of preparing a primary hydroxy groups and the at least one ketene acetal of poly(ortho ester) polymer includes: combining components Formula IV and/or Formula V are combined in a molar ratio including at least one non-cyclic polyol having no primary of 1 to at most 1.1, particularly in a molar ratio of 1 to at most hydroxy groups as described herein above and at least one 1.05, and more particularly in a molar ratio of 1 to at most ketene acetal under conditions effective to polymerize at least 1.03. a portion of the at least one ketene acetal. The at least one I0084. The components combined can also include a poly ketene acetal is selected from a compound of the formula merization agent as described herein below. (Formula IV) I0085. In certain embodiments, the compound of the for mula (Formula IV) is represented by Formula IV.(a): R R R R9 R19 R19 R19 R19 >=K R3 R9 o1 No R9;

0082 a compound of the formula (Formula V) R19 R19 R19 R19

Rl5O R17 R17 OR 15 I0086 wherein each Rand R', independently represents hydrogen or an organic group. In certain embodiments, each ) t l ( RandR' represents hydrogen. R16O R"), OR 16. I0087 Optionally, the components can further include, for example, at least one diol different than the at least one non-cyclic polyol having no primary hydroxy groups. A wide O variety of diols can be used including, for example, ethyl 0.083 combinations thereof. Each R and R7 indepen eneglycol, diethyleneglycol, triethyleneglycol, tetra(ethyl dently represents hydrogen or an organic group. Each R', eneglycol), 1,3-propanediol. 1,4-butanediol, neopentyl gly R", R', and R' independently represents an organic group. col, 1,6-hexanediol, 1,12-dodecanediol, 1,4- R" represents oxygen oran organic group and p-0 or 1. Each cyclohexanedimethanol, 4-hydroxybenzyl alcohol. 4,4'- R' can optionally be joined with R' to form one or more biphenol, bis(4-hydroxyphenyl)methane, bisphenol-A, rings, and geminal R' and R' groups can optionally be hydroquinone, 1,4-benzenedimethanol, 2-methoxyhydro joined to each other to form rings. The at least one ketene quinone, 2,3-dimethylhydroquinone, and combinations acetal of Formula IV and/or Formula V have a purity of at thereof. least 98 wt-%, more particularly at least 99 wt-%, and most particularly at least 99.5 wt-% as measured using the proce 0088. For at least some of the above-described embodi dure of Pogany et al., J. of Chromatography, 508:179-186 ments, optionally, the components can further include, for (1990). Ketene acetals can be prepared by methods known in example, at least one mono-hydroxy-containing compound. the art including for example, those described in Crivello et A wide variety of mono-hydroxy-containing compounds can al., J. of Polymer Science, 34:3091-3102 (1996); Ng et al., be used including, for example, methanol, ethanol, propanol, Macromolecular Syntheses, 11:23-26 (1992); and U.S. Pat. butanol, pentanol, hexanol, decanol, dodecanol, 2-methoxy Nos. 4.513,143 (Nget al.) and 4,532,335 (Helwing). The at ethanol, 2-ethyoxyethanol, di(ethyleneglycol) monomethyl least one non-cyclic polyol having no primary hydroxy ether, di(ethyleneglycol) monoethyl ether, tri(ethylenegly groups and the at least one ketene acetal of Formula IV and/or col) monomethyl ether, tri(ethyleneglycol) monoethyl ether, Formula V can be combined in a ratio selected to provide, for tetra(ethyleneglycol) monomethyl ether, tetra(ethylenegly example, oligomers, low molecular weight polymers, and/or col) monoethyl ether, and combinations thereof. high molecular weight polymers. For embodiments in which I0089. In some embodiments, conditions effective to poly polymers are desired (e.g., high molecular weight polymers), merize include combining at least a portion of the compo the at least one non-cyclic polyol having no primary hydroxy nents without adding a solvent. In other embodiments, con groups and the at least one ketene acetal of Formula IV and/or ditions effective to polymerize further include combining a Formula V typically are combined approximately in a molar Solvent, particularly a dry organic solvent. Suitable solvents ratio of 1:1, respectively. In certain embodiments, the at least include, for example, tetrahydrofuran, dioxane, toluene, one non-cyclic polyol having no primary hydroxy groups and methylene chloride, chloroform, N-methylpyrrolidone, N.N- the at least one ketene acetal of Formula IV and/or Formula V dimethylacetamide, N,N-dimethylformamide, and combina are combined in a molar ratio Such that the at least one ketene tions thereof. When a solvent is used, components are typi acetal of Formula IV and/or Formula V is present in a slight cally combined to give at least 1% by weight solids, molar excess. For example, in certain embodiments, the at preferably at least 5% by weight solids, and more preferably least one non-cyclic polyol having no primary hydroxy at least 10% by weight solids. When a solvent is used, com groups and the at least one ketene acetal of Formula IV and/or ponents are typically combined to give at most 70% by weight Formula V are combined in a molar ratio of 1 to at least 1.001, solids, preferably at most 60% by weight solids, and more particularly in a molar ratio of 1 to at least 1.01, and more preferably at most 50% by weight solids. In certain embodi particularly in a molar ratio of 1 to at least 1.02. in certain ments, at least a portion of the components are combined embodiments, the at least one non-cyclic polyol having no under an inert atmosphere. US 2011/0082266 A1 Apr. 7, 2011

0090. Optionally, combining components can further tion rate. Typically, rapid addition of the polymerization include combining an additional polymerizable compound. A agent to the other components (e.g., addition over at most 60 wide variety of additional polymerizable compounds can be seconds, and sometimes at most 1 second) can be used for used including, for example, orthoesters, monofunctional producing higher molecular weight poly(ortho ester) poly ketene acetals, polyfunctional ketene acetals, imagable com mers. See, for example, Ng et al., J. of Controlled Release, pounds, compounds having latent reactive sites, and combi 65:367-374 (2000). Typically and preferably, at least a por nations thereof. The additional polymerizable compound can tion of the components are combined under an inert atmo also be a ketene acetal different than the at least one ketene sphere. The reaction temperature can be selected and/or var acetal described herein above. ied as desired to provide a convenient reaction rate. 0091 A polymerization agent can be used to initiate and/ or propagate the polymerization reactions described herein 0097. The polymerization methods disclosed herein can above. A wide variety of polymerization agents can be used provide poly(ortho ester) polymers. In certain embodiments, that are known in the art to catalyze addition polymerizations. the present disclosure provides a polymer including two or Typically, the polymerization agent provides for polymeriza more repeat units selected from a repeat unit of the formula tion through a cationic, an anionic, a free radical, and/or an (Formula VI): organometallic pathway. The polymerization agent may be present in catalytic amounts, or alternatively, may be used in Stoichiometric amounts with partial or total consumption of the polymerization agent during the polymerization reaction. +-z-POE---A-POE,-- 0092. In some embodiments, the polymerization agent includes a Lewis acid or a Bronsted-Lowry acid. Suitable 0098 wherein each POE and POE, independently, is Lewis acids typically include one or more elements such as represented by the formula: Al, Fe, B., Zn, Sb, Ti, Cu, Sn, Si, and the like. Examples of suitable Lewis acids include, for example, boron trifluoride and/or boron trifluoride etherate, Zinc chloride, zinc iodide, R11 R11 Zinc triflate, antimony pentachloride, and the like, and com binations thereof. R10(R).C.. O O C(R)R10 0093 Suitable Bronsted-Lowry acids include, for example, hydrochloric acid, p-toluenesulfonic acid, meth NX-es-X} anesulfonic acid, trifluoromethanesulfonic acid, camphorsul fonic acid, and the like. 0094. The ratio of the polymerization agent to the other 0099 or the formula: components can be varied as desired, and is typically selected to provide the desired reaction time at the selected reaction temperature for the specific polymerization agent. The ratio R16O OR 15 Rl5O OR 15 of the polymerization agent to the other components can also be varied to influence the molecular weight of the resulting polymers, with lower ratios typically resulting in higher OxxR17 H. H. R17 molecular weights. In some embodiments, at least 0.0000001 mole'6, sometimes at least 0.000001 mole'6, and other times at least 0.00001 mole % of polymerization agent is used, 0100 Each R. R', and R7 independently represents based on the total moles of hydroxy-containing compound hydrogen or an organic group. Each R', R', R', and R' and polymerization agents. In some embodiments, at most 30 independently represents an organic group; R' represents mole %, sometimes at most 20 mole %, and other times at oxygen oran organic group and p-0 or 1, and n=0 or 1. Each most 10 mole 96 of polymerization agent is used, based on the R' can optionally be joined with R' to form one or more total moles of hydroxy-containing compound and polymer rings, and geminal R' and R' groups can optionally be ization agents. In certain embodiments, a solution of a Bron Sted-Lowry acid (e.g., 1% by weight p-toluenesulfonic acid) joined to each other to form rings. Z is as defined above. in a solvent (tetrahydrofuran) can be used as a polymerization 0101. In some embodiments, each A is as defined herein agent. above for hydroxy-containing compounds of the formula 0095 Suitable polymerization agents may be monofunc (Formula Ia) HO-A OH. tional (i.e., having one initiation site), difunctional (i.e., hav 0102. In some other embodiments, each A represents the ing two initiation sites), or polyfunctional (i.e., having more non-cyclic group —CH(R') (C(R).), CH(R)-; each than two initiation sites). For cases in which the polymeriza RandR independently represents an organic group (e.g., an tion agent is incorporated into the polymer chain, polyfunc organic moiety); each Rindependently represents hydrogen tional polymerization agents can lead to highly branched oran organic group (e.g., an organic moiety); and r is 0 to 20. polymer structures (e.g., star structures). In certain embodiments, each R" and R represents methyl; 0096. In certain embodiments, components including the each R represents hydrogen; and r is 0 to 2. at least one hydroxy-containing compound and the polymer 0103. In another aspect, each A represents a cyclic group ization agent can be combined neat (e.g., without adding a - C(R)(R)–(C(R).), C(R)(R)-; each R', R, R and Solvent). In other certain embodiments, components includ R", independently represents hydrogen or an organic group, r ing the at least one hydroxy-containing compound and the is 1 to 20 (particularly 1 to 15 and more particularly 1 to 10), polymerization agent can be combined in a dry organic Sol and each R is an organic group and isjoined with the other to vent at a concentration selected to provide a convenient reac form a ring, e.g., trans-1,4-cyclohexanedimethanol. US 2011/0082266 A1 Apr. 7, 2011

0104. In certain embodiments, the POE repeat units of the first optional polymerization agent, if present), which are then formula (Formula VI) is represented by Formula VIa: allowed to react to prepare block and/or graft copolymers. 0113 Block copolymers in which at least one block of the R19 R19 R19 R19 block copolymer is a poly(ortho ester) block including two or more repeat units selected from the group consisting of repeat O O units of Formula VI, repeat units of Formula VII, and combi nations thereof, can be of particular interest for certain appli ">{O X." cations. Theat least one other block of such block copolymers O O can be selected from blocks having a wide variety of repeat R19 R19 19R 19 units including, for example, alpha-hydroxyalkanoates, beta hydroxy alkanoates, gamma-hydroxy alkanoates, delta-hy 0105 wherein each R and R' independently represents droxy alkanoates, epsilon-hydroxy alkanoates, gylcols, car hydrogen or an organic group. bonates, acetals, urethane-containing groups, carbamate containing groups, or combinations thereof. In certain I0106. In certain embodiments, each R" represents hydro embodiments, the at least one other block of such block gen and each R independently represents hydrogen or copolymers can be a polyketal block. In other certain embodi methyl. ments, the at least one other block of such block copolymers 0107. In some embodiments, each A is as defined herein can be a poly(alkyleneglycol) block including alkylene glycol above for hydroxy-containing compounds of the formula repeat units. (Formula Ia) HO-A OH. 0114 Optionally, the poly(ortho ester) polymer can be 0108. In some other embodiments, each A represents the further reacted as a soft segment of a segmented polymer. non-cyclic group —CH(R')—(C(R).), CH(R)-; each Exemplary segmented polymers include, for example, poly RandR independently represents an organic group (e.g., an urethanes, polyethylenes, polycarbonates, polyureas, and organic moiety); each Rindependently represents hydrogen combinations thereof. In some embodiments, copolymers oran organic group (e.g., an organic moiety); and r is 0 to 20. can be formed by starting with an oligomeric or polymeric In certain embodiments, each R" and R represents methyl; macromolecule (e.g., polyethylene glycol) and forming poly each R represents hydrogen; and r is 0 to 2. (ortho ester) blocks thereon by the polymerization of the 0109. In another aspect, each A represents a cyclic group components described herein. In other embodiments, copoly —C(R')(R)–(C(R).), C(R)(R)-; each R', R. Rand mers can be formed by starting with a poly(ortho ester) poly R", independently represents hydrogen oran organic group, r mer and reacting the poly(ortho ester) polymer with addi is 1 to 20 (particularly 1 to 15 and more particularly 1 to 10), tional components (e.g., monomers, oligomers, polymers. and each R is an organic group and isjoined with the other to and/or other reactive compounds). form a ring, e.g., trans-1,4-cyclohexanedimethanol. 0115 Typically and preferably, the poly(ortho ester) poly 0110. In the above-disclosed polymers, any of the R sub mers disclosed herein are biodegradable. Typically, the aver stituents that are “organic groups' can include as at least a age molecular weight (and preferably the weight average portion thereof, for example, an orthoester functionality (e.g., molecular weight) of the polymers disclosed herein is at least at least a portion of Formula II, Formula VI, or Formula VII); 20,000 Daltons, and sometimes at least 50,000 Daltons, a ketene acetal functionality (e.g., at least a portion of For 60,000 Daltons, or even 100,000 Daltons or more. Typically mula IV or Formula V); an imagable functionality (e.g., one the polydispersity index (PDI) of the polymers disclosed or more of a radiopaque functionality Such as an iodinated herein is at most 5, and sometimes at most 3, and other times group, a ferromagnetic functionality, and a magnetic Suscep at most 2. tible functionality such as Fe, Cr, Ni, and Gd); a latent reactive 0116. In another aspect, a poly(ortho ester) polymer that is functionality (e.g., ethylenic unsaturation and/or oxygen Substantially free of acidic groups, glycolide groups, and containing rings Suitable for latent crosslinking after poly lactide groups is disclosed. Preferably, the hydrolysis rate merization); or combinations thereof. and/or drug release rate of the poly(ortho ester) polymer is 0111. The polymers disclosed herein can include a single sufficiently high to allow the poly(ortho ester) polymer to be orthoester-containing repeat unit (i.e., a homopolymer), or used in applications requiring biodegradability and/or bio two or more different repeat units (i.e., a copolymer). In Such erodibility. copolymers, the two or more different repeat units can all be 0117. In another aspect, a poly(ortho ester) polymer hav different orthoester-containing repeat units of Formula VI ing a glass transition temperature (T) of at least 50° C. is and/or Formula VII, or alternatively, one or more orthoester disclosed. Preferably, the hydrolysis rate and/or drug release containing repeat units of Formula VI and/or Formula VII in rate of the poly(ortho ester) polymer is sufficiently high to combination with one or more repeat units that are not of allow the poly(ortho ester) polymer to be used in applications Formula VI or Formula VII (e.g., repeat units that include, for requiring biodegradability and/or bioerodibility. example, ether groups, acetal groups, and/or ketal groups). 0118 While there are a number of different approaches to The polymers disclosed herein can be linear polymers, synthesizing ortho esters, one convenient approach is to react, crosslinkable polymers, and/or crosslinked polymers. for example, resveratrol with a bis(ketene acetal) such as 0112 Copolymers as disclosed herein can be random Detosu, as shown in Scheme 1. The degree of crosslinking in copolymers, alternating copolymers, block copolymers, graft the polymer thus formed can be controlled by the stoichiom copolymers, or combinations thereof. For example, mixtures etry of the starting materials. In the upper product, more than of components can be combined with a polymerization agent one equivalent of Detosu has been used, resulting in a rela to prepare random and/or alternating copolymers. For another tively crosslinked system. In the lower product, equimolar example, one or more components can be combined with a ratios of the starting materials are assumed. While the lower polymerization agent and allowed to react until all the com product is depicted as a perfectly linear polymer, it is to be ponents are consumed, followed by the addition of one or understood that there will be some degree of crosslinking more different components, and optionally additional poly and/or branching, along with a corresponding number of free merization agent (which can be the same or different than the phenol groups. US 2011/0082266 A1 Apr. 7, 2011 10

Scheme 1 OH

O O

N O OH /-(X)-O O O Detosu HO Resveratrol s catalyst

pi

0119 Copolyorthoesters based on resveratrol can also synthesized by using additional diols, as shown in Scheme 2. In this case, 1.6-hexanediol is used. By the selection of diols used as comonomers with resveratrol and by controlling the degree of crosslinking by the ratio of diols to Detosu, copoly mers with a wide range of physical properties, degradation rates, and resveratrol release rates are accessible. US 2011/0082266 A1 Apr. 7, 2011

Scheme 2 OH

O O

-- o o -- HO 1N1-S-1N1 OH O O 1,6-hexanediol Detosu HO Crs Resveratrol s catalyst

O & X O 'Nu-1N1\-1a x O O O O O- - - O O X Oyco

O O

LicO

0120 In another aspect, a method of hydrolyzing a poly 0.122 Poly(ortho ester) polymers as disclosed herein can (ortho ester) polymer is provided. The method includes: pro be used in various combinations for various applications. viding a poly(ortho ester) polymer that is substantially free of They can be used as tissue-bulking agents in urological appli acidic groups, glycolide groups, and lactide groups; exposing cations for bulking the urinary Sphincter to prevent stress the poly(ortho ester) polymer to an aqueous environment; and incontinence or in gastrological applications for bulking of allowing the poly(ortho ester) polymer to hydrolyze. Prefer the lower esophageal sphincter to prevent gastroesophageal ably, the hydrolysis rate and/or drug release rate of the poly reflux disease. They can be used for replacements for nucleus (ortho ester) polymer is sufficiently high to allow the poly pulposis or repair of annulus in intervertebral disc repair (ortho ester) polymer to be used in applications requiring procedures. They can be used as Surgical void fillers, for biodegradability and/or bioerodibility. Preferably, when the example, in reconstructive or cosmetic Surgery (e.g., for fill ing a void after tumor removal). They can be used to repair poly(ortho ester) polymer is used in an application requiring aneurysms, hemorrhagic stroke or other conditions precipi biodegradability and/or bioerodibility, hydrolyzing the poly tated by failure of a blood vessel. They can be used to prevent (ortho ester) polymer includes forming Substantially no Surgical adhesions. They can be used for local pain relief acidic byproducts at the hydrolysis site. when administered in a depot to treat post operative pain or 0121 For certain applications, a poly(ortho ester) polymer sciatica. They can be used to treat systemic pain or chronic as disclosed herein can be blended with another polymer pelvic pain when administered intraspinally, specificially epi (e.g., the same or different than the poly(ortho ester) poly durally. Poly(ortho ester) polymers as disclosed herein can mers disclosed herein) to provide the desired physical and/or further be used for applications such as scaffolds or Supports chemical properties. For example, two poly(ortho ester) poly for the development and/or growth of cells for applications mers having different molecular weights can be blended to including, for example, tissue engineering and the fabrication optimize the release rate of a biologically active agent. For of artificial organs. another example, two poly(ortho ester) polymers having dif I0123 Poly(ortho ester) polymers as disclosed herein can ferent repeat units can be blended to provide desired physical be used in injectable compositions. Such injectable compo and/or chemical properties. For even another example, a poly sitions could be used as tissue bulking agents (e.g., for the (ortho ester) polymer can be blended with another polymer treatment of urinary stress incontinence, for the treatment of that is not a poly(ortho ester) polymer to provide desired gastroesophageal reflux disease, or serving to augment a physical and/or chemical properties. degenerated intervertebral disc), Void fillers (e.g., in cosmetic US 2011/0082266 A1 Apr. 7, 2011 or reconstructive Surgery, such as serving as a replacement for can also include endoprostheses implanted in blood contact in the nucleus pulposis), or as an injectable drug delivery matrix. a human or animal body such as vascular grafts, stents, pace 0124. In some embodiments, no additives would be maker leads, heart Valves, and the like, that are implanted in needed. In some embodiments, one or more polymers can be blood vessels or in the heart. This can also include devices for combined with a solvent such as N-methyl-2-pyrrolidone or temporary intravascular use Such as catheters, guide wires, dimethylsulfoxide (DMSO), which are fairly biocompatible and the like which are placed into the blood vessels or the solvents. The solvent can diffuse away after injection and the heart for purposes of monitoring or repair. A medical device polymer can remain in place. Such materials can be admin can also be fabricated by polymerizing components including istered to a desired site (e.g., a Surgical site) using a syringe, at least one hydroxy-containing compound and compounds catheter, other medical device or by hand. of Formula II, Formula IV, and/or Formula V in a suitable 0.125. Also, injectable compositions could include mold. crosslinkers (such as diacrylates), plasticizers (such as tri ethylcitrate), lipids (soybean oil), poly(ethylene glycol) (in 0.130 Poly(ortho ester) polymers as disclosed herein can cluding those with the ends blocked with methyls or similar also be coated onto a substrate if desired. A coating mixture of groups), silicone oil, partially or fully fluorinated hydrocar the polymer can be prepared using solvents such as toluene, bons, N-methyl-2-pyrrolidone, or mixtures thereof. chloroform, tetrahydrofuran, perfluorinated solvents, and 0126 Polymers disclosed herein can be used in combina combinations thereof. Preferred solvents include those that tion with a variety of particulate materials. For example, they can be rendered moisture-free and/or those that have no active can be used with moisture curing ceramic materials (e.g., hydrogens. The coating mixture can be applied to an appro tricalcium phosphate) for vertebroplasty cements, bone void priate Substrate Such as uncoated or polymer coated medical filling (due to disease such as cancer or due to fracture). They wires, catheters, Stents, prostheses, penile inserts, and the can be used in combination with inorganic materials such as like, by conventional coating application methods. Such hydroxylapatite to form pastes for use in bone healing, seal methods include, but are not limited to, dipping, extruding, ing, filling, repair, and replacement. They can be used as or in spraying, wiping, painting, solvent Swelling, molding and the combination with polymer microspheres that can be reser like. After applying the coating Solution to a substrate, the Voirs for a biologically active agent such as a protein, DNA solvent is preferably allowed to evaporate from the coated plasmid, RNA plasmid, antisense agent, etc. substrate. 0127. Alternatively, poly(orthoesters) as disclosed herein 0131 The materials of a suitable substrate include, but are can be used in combination with other materials to form a not limited to, polymers, metal, glass, ceramics, composites, composite (e.g., a polymer having an additive therein). In and multilayer laminates of these materials. The coating may addition to one or more poly(ortho ester) polymers, compos be applied to metal Substrates such as the stainless steel used ites can include a wide variety of additives, and particularly for guide wires, stents, catheters and other devices. Organic particulate additives, such as, for example, fillers (e.g., Substrates that may be coated with polymers as disclosed including particulate, fiber, and/or platelet material), other herein include, but are not limited to, polyether-polyamide polymers (e.g., polymer particulate materials such as poly block copolymers, polyethylene terephthalate, polyetherure tetrafluoroethylene can result in higher modulus composites), thane, polyesterurethane, other polyurethanes, silicone, natu imaging particulate materials (e.g., barium sulfate for visual ral rubber, rubber latex, synthetic rubbers, polyester-poly izing material placement using, for example, fluoroscopy), ether copolymers, polycarbonates, and other organic biologically derived materials (e.g., bone particles, cartilage, materials. demineralized bone matrix, platelet gel, and combinations 0.132. Additives that can be combined with a poly(ortho thereof), and combinations thereof. Additives can be dis ester) polymer as disclosed herein to form a composition Solved, Suspended, and/or dispersed within the composite. include, but are not limited to, wetting agents for improving For particulate additives, the additive is typically dispersed wettability to hydrophobic surfaces, viscosity and flow con within the composite. trol agents to adjust the Viscosity and thixotropy of the mix 0128 Poly(ortho ester) polymers as described herein can ture to a desired level, antioxidants to improve oxidative be combined with fibers, woven or nonwoven fabric for stability of the coatings, dyes or pigments to impart color or reconstructive Surgery, Such as the in situ formation of a bone radiopacity, and air release agents or defoamers, cure cata plate or a bone prosthesis. lysts, cure accelerants, plasticizers, solvents, stabilizers (cure 0129. In certain embodiments, one or more poly(ortho inhibitors, pot-life extenders), and adhesion promoters. ester) polymers as disclosed herein can be shaped to form a 0.133 Of particular interest for medical and pharmaceuti medical device, preferably a biodegradable medical device. cal applications are compositions that include one or more Shapes can be in the form of a depot, rod, noodle, micro poly(ortho ester) polymers as disclosed herein and a biologi sphere, macrosphere, gel, strip, ribbon, or any other imagin cally active agent. As used herein, a “biologically active able form. The one or more polymers can be shaped by agent' is intended to be broadly interpreted as any agent methods known in the art including compression molding, capable of eliciting a response in a biological system such as, injection molding, casting, extruding, milling, blow molding, for example, living cell(s), tissue(s), organ(s), and being(s). spray drying or combinations thereof. As used herein, a Biologically active agents can include natural and/or syn "medical device' includes devices that have surfaces that thetic agents. Thus, a biologically active agent is intended to contact tissue, bone, blood, or other bodily fluids in the course be inclusive of any Substance intended for use in the diagno of their operation, which fluids are subsequently used in sis, cure, mitigation, treatment, or prevention of disease or in patients. This can include, for example, extracorporeal the enhancement of desirable physical or mental development devices for use in Surgery Such as blood oxygenators, blood and conditions in a subject. pumps, blood sensors, tubing used to carry blood, and the like I0134. The term “subject' as used herein is taken to include which contact blood which is then returned to the patient. This humans, sheep, horses, cattle, pigs, dogs, cats, rats, mice, US 2011/0082266 A1 Apr. 7, 2011

birds, reptiles, fish, insects, arachnids, protists (e.g., proto cides, bactericides, bronchial dilators, beta-adrenergic block Zoa), and prokaryotic bacteria. Preferably, the subject is a ing drugs, contraceptives, cardiovascular drugs, calcium human or other mammal. channel inhibitors, cell Survival factors, chemotherapeutics, 0135 A preferred class of biologically active agents collagenase inhibitors, depressants, diagnostics, diuretics, includes drugs. As used herein, the term "drug means any electrolytes, enzymes, enzyme inhibitors, growth factors, therapeutic agent. Suitable drugs include inorganic and hypnotics, hormones, hypoglycemics, hyperglycemics, organic drugs, without limitation, and include drugs that act muscle contractants, muscle relaxants, neoplastics, glycopro on the peripheral nerves, adrenergic receptors, cholinergic teins, growth factors, nucleoproteins, lipoproteins, lubri receptors, nervous system, skeletal muscles, cardiovascular cants, lubricins, mucins, ophthalmics, protease inhibitors, system, Smooth muscles, blood circulatory system, synaptic psychic energizers, sedatives, Small molecule inhibitors, Ste sites, neuro-effector junctional sites, endocrine system, hor mone systems, immunological system, reproductive system, roids sympathomimetics, parasympathomimetics, tranquiliz skeletal system, autocoid systems, alimentary and excretory ers, urinary tract drugs, vaccines, vaginal drugs, vitamins, systems (including urological systems), histamine systems, collagen, hyaluronic acid and derivatives, anti transformed tissues of any of the above systems in cancer, and inflammatory drugs, angiotensin converting enzymes, poly the like. Such conditions, as well as others, can be advanta nucleotides, polypeptides, polysaccharides, and the like. geously treated using compositions as disclosed herein. 0140 Certain embodiments include a drug selected from 0.136 Suitable drugs include those provided above for growth factors, receptors, and cytokines including but not “Z”, the therapeutic agent incorporated into the poly(ortho limited to IGF-1, VEGF, PDGF, GDNF, GDNF analogs, ester) polymers described herein. BDNF, BMPs, GDF-5, EGF, FGF, HIF-1, HGF, MCP 1,2,3,.or 0.137 Suitable drugs also include biologics, for example, 4, SDF-1, MIP, GM-CSF, G-CSF, IL-10, CDNF, TIMPS, polypeptides (which is used herein to encompass a polymer MIF, RANK, OPG, leptin, LIF, TIMP-1, TIMP-2, ANG-2, of L- or D-amino acids of any length including peptides, TGF-alpha, TGF-beta, HGH, TNF receptor, AKT, CNTF, oligopeptides, proteins, enzymes, hormones, etc.), poly NGF, NT3, and the like. nucleotides (which is used herein to encompass a polymer of 0.141. Other embodiments include a drug selected from nucleic acids of any length including oligonucleotides, hormones or related molecules including but not limited to single- and double-stranded DNA, single- and double insulin, corticotrophin, adrenocorticotrophin, growth hor stranded RNA, DNA/RNA chimeras, etc.), saccharides (e.g., mone, dopamine, osteoponntin, vasoinhibitory peptide mono-, di-, poly-saccharides, and mucopolysaccharides), (VIP), Vasopressin, epinephrine, oxytocin, or Vitamins, viral agents, and other living material, radionu derivatives, SERMs, progesterone, , cortisone, or bis clides, chemotherapeutic agents, and the like. Examples phosphonates. include antithrombogenic and anticoagulant agents such as 0142. Certain embodiments include a drug selected from heparin, coumadin, protamine, and hirudin; antimicrobial indomethacin, Sulindac, diclofenal, etodolac, meclofenate, agents such as antibiotics; antineoplastic agents and anti mefenamic acid, nambunetone, piroXicam, phenylgutaZone, proliferative agents such as etoposide, podophylotoxin; anti meloxicam, dexamethoasone, betamethasone, dipropionate, platelet agents including aspirin and dipyridamole; antimitot diflorsasone diacetate, clobetasol propionate, galobetasol ics (cytotoxic agents) and antimetabolites Such as propionate, amcinomide, ascomycin, baclofen, bupivacaine, methotrexate, colchicine, azathioprine, Vincristine, vinblas beclomethasone dipropionate, betamethasone, celocoxib, tine, fluorouracil, adriamycin, and mutamycinnucleic acids; curcumin, curcumin derivatives, penicillamine, fluocino antidiabetic Such as rosiglitaZone maleate; and anti-inflam mide, hydroxychloroquine, Sulfasalazine, azathioprine, matory agents. Anti-inflammatory agents include glucocorti minocycline, cyclophosphamide, cyclosporine, leflunomide, coids, their salts, and derivatives thereof. Such as cortisol, methotrexate, etanercept, infliximab, beta-, rosigli cortisone, fludrocortisone, Prednisone, Prednisolone, 6C.-me taZone, troglitaZone, pioglitaZone, S-nitrosoglutathione, thylprednisolone, triamcinolone, betamethasone, dexam gliotoxin G, panepoxydone, cycloepoxydontepoxalin, a pro ethasone, beclomethasone, aclomethasone, amcinonide, cle teasome inhibitor (e.g., bortezomib, dipeptide boronic acid, bethasol and clocortolone. lactacystin, bisphosphonate, Zolendronate, epoxomicin), 0138 Classes of drugs include, for example, Plasmid antisense c-myc, triamcinolone acetonide, Valdecoxib, Valer DNA, genes, antisense oligonucleotides and other antisense ate, or combinations thereof. agents, peptides, proteins, protein analogs, antibodies, fusion 0.143 Certain other embodiments include a drug selected proteins, siRNA, shRNA, miRNA, ribozymes, DNAZymes from podophyllotoxin, mycophenolic acid, teniposide, eto and other DNA based agents, viral and non-viral vectors, poside, trans-retinoic acids, 9-cis retinoic acid, 13-cis retinoic lyposomes, cells, stem cells, antineoplastic agents, antipro acid, rapamycin, a rapalog (e.g., Everolimus, ABT-578), liferative agents, antithrombogenic agents, anticoagulant camptothecin, irinotecan, topotecan, pimicrolimus, ascomy agents, antiplatelet agents, antibiotics, anti-inflammatory cin, tacromilus, midazolam, mithramycin, mitobronitol, agents, antimitotic agents, immunosuppressants, growth fac thiotepa, treosulfan, estramusting, chlormethine, carmustine, tors, cytokines, hormones, and combinations thereof. lomustine, buSultan, mephalan, chlorambucil, ifosfamide, 0139 Suitable drugs can have a variety of uses including, cyclophosphamide, doxorubicin, epirubicin, aclarubicin, but are not limited to, anticonvulsants, analgesics, antiparkin daunorubicin, mitosanthrone, bleomycin, cepecitabine, cyt Sons, antiinflammatories (e.g., ibuprofen, fenbufen, corti arabine, fludarabine, cladribine, gemtabine, 5-fluorouracil, Sone, and the like), calcium antagonists, anesthetics (e.g., mercaptopurine, tioguanine, vinblastine, Vincristine, Vin benoximate, benzocaine, procaine, and the like), antibiotics desine, Vinorelbine, amsacrine, bexarotene, crisantaspase, (e.g., ciprofloxacin, norfloxacin, clofoctol, and the like), anti decarbasine, hydroSycarbamide, pentostatin, carboplatin, malarials, antiparasitics, antihypertensives, antihistamines, cisplatin, oxiplatin, procarbazine, paclitaxel, docetaxel, antipyretics, alpha-adrenergic agonists, alpha-blockers, bio epothilone A, epothilone B, epothilone D. baxiliximab, dacli US 2011/0082266 A1 Apr. 7, 2011

Zumab, interferon alpha, interferon beta, maytansine, MDT is used in Subjects prior to or at an earlier stage of disease, the 2007, ropinerole, tranexamic acid, carbamaZeprine, or com prophylactically effective amount will be less than the thera binations thereof. peutically effective amount. 0150. The term “inflammation' is recognized in the art 0144. Certain embodiments include a drug selected from and is intended to encompass the complex series of biological salicylic acid, fenbufen, cortisone, ibuprofen, diflunisal, responses of vascular tissues to harmful stimuli. Such as Sulindac, difluprednate, prednisone, medrysone, acematacin, pathogens, damaged cells, or irritants. Inflammation is a cas indomethacin, meloxicam, camptothecin, benoximate, ben cade of physiological events by the organism to remove the Zocaine, procaine, ciprofloxacin, norfloxacin, clofoctol, dex injurious stimuli as well as initiate the healing process for the amethasone, fluocinolone, ketorolac, pentoxifylline, rapamy tissue. The term “inflammation' as used herein is also cin, ABT-578, gabapentin, baclofen, sulfasalazine, intended to include neural inflammation which can be related bupivacaine, Sulindac, clonidine, etanercept, pegSunercept, to neuronal cell death. or combinations thereof. 0151 Medical devices that include one or more poly(ortho 0145. It should be understood that one or more biologi ester) polymers as disclosed herein and a biologically active cally active agent or drug can be admixed with the poly(ortho agent can have a wide variety of uses. In Such devices, the ester) polymers of the invention. The one or more biologically biologically active agent is preferably disposed in the one or active agent or drug can be coated onto the poly(ortho ester), more polymers. As used herein, the term “disposed' is embedded into the polymer, simply admixed with a mixture intended to be broadly interpreted as inclusive of dispersed, of poly(ortho ester) polymer, etc. Such that the one or more dissolved, Suspended, or otherwise contained at least partially biologically active agent or drug is not covalently bound to therein or thereon. 0152 For example, such devices can be used to deliver a the polymer backbone. biologically active agent to a tissue by positioning at least a 0146 Compositions including a biologically active agent portion of the device including the one or more polymers and a poly(ortho ester) polymeras disclosed herein and can be proximate the tissue and allowing the one or more polymers prepared by suitable methods known in the art. For example, to biodegrade and deliver the biologically active agent dis Such compositions can be prepared by solution processing, posed therein. For another example, Such devices can be used milling, extruding, polymerizing components including at to control the release rate of a biologically active agent from least one hydroxy-containing compound and compounds of a medical device by disposing the biologically active agent in Formula II, Formula IV, and/or Formula IV in the presence of at least one of the one or more polymers. a biologically active agent, and combinations thereof. 0153. The present disclosure is further illustrated by the 0147 Typically, the amount of biologically active agent following examples. It is to be understood that the particular contained by the poly(ortho ester) polymer is determined by examples, materials, amounts, and procedures are to be inter the amount to be delivered and the time period over which it preted broadly in accordance with the scope and spirit of the is to be delivered. Other factors can also contribute to the level disclosure as set forth herein. of biologically active agent present, including, for example, 0154 The following paragraphs enumerated consecu the ability of the composition to form a uniform film on a tively from 1 through 45 provide for various aspects of the substrate. present invention. In one embodiment, in a first paragraph (1), 0148 Compositions including poly(ortho ester) polymers the present invention provides a polymer comprising: as disclosed herein (e.g., with or without a biologically active 0155 a polymer including two or more repeat units agent) can further include additional components. Examples selected from a repeat unit of the formula (Formula VI): of Such additional components include fillers, dyes, pig ments, inhibitors, accelerators, Viscosity modifiers, wetting agents, buffering agents, stabilizers, biologically active --z-POE-et-A-POE-i- agents, polymeric materials, excipients, and combinations thereof. Alternatively, the poly(ortho ester) polymer itself can be an excipient in a composition (e.g., a pharmaceutical com 0156 wherein each POE and POE, independently, is position including a biologically active agent). represented by the formula: 014.9 The compositions of the invention can include a “therapeutically effective amount” or a “prophylactically R11 R11 effective amount of a polymer of the invention. A “therapeu tically effective amount” refers to an amount effective, at R10(R).C.. O O C(R)-R10 dosages and for periods of time necessary, to achieve the desired therapeutic result, e.g., a diminishment or prevention XLR X. of inflammation symptomology or disease process. A thera N-X-es-X. peutically effective amount of the polymer of the invention can vary according to factors such as the disease state, age, sex, and weight of the individual, and the ability of the poly 0157 or the formula: mer to elicit a desired response in the individual, reduction or elimination of pain or inflammation. A therapeutically effec R16O OR 15 Rl5O OR 15 tive amount is also one in which any toxic or detrimental effects of the polymer are outweighed by the therapeutically beneficial effects. A “prophylactically effective amount O X- X.O refers to an amount effective, at dosages and for periods of R17 H H R17 time necessary, to achieve the desired prophylactic result on the disease or condition. Typically, since a prophylactic dose US 2011/0082266 A1 Apr. 7, 2011 15

0158 wherein: 0176 3. The polymer of paragraph 1 wherein the repeat 0159 each R. R', and R7 independently represents unit of the formula (Formula VI) is represented by Formula hydrogen or an organic group: Va: (0160 each R', R', R', and R' independently repre sents an organic group; (0161) R' represents oxygen or an organic group and R19 R19 R19 R19 p=0 or 1; O O (0162 n=0 or 1: (0163 each R' can optionally be joined with R' to ">{ X." form one or more rings; O O i R19 R19 R19 (0164 geminal R'' and R' groups can optionally be R19 joined to each other to form rings; (0165 each A, optionally, is C(R)(R—(C(R).), 0177 wherein: C(R)(R)-,-Ar' ,—Ar"C(R)(R)—, a group of 0.178 each RandR' independently represents hydro the formula (Formula III) —Ar’ C(R). Ar' (B) gen or an organic group. , —C(=O)— —(C=O)—R—(C=O)—, or com (0179 4. The polymer of paragraph 3 wherein each R' binations thereof represents hydrogen and each R independently represents 0166 R is an organic group; hydrogen or methyl. (0167 each R', R. R. R., and Rindependently repre 0180 5. The polymer of any of paragraphs 1 through 4, sents hydrogen oran organic group, r is 0 to 20, and one wherein Z is a Resveratrol or Curcumin residue. or more of R', R. R. R. and R can optionally be 0181 6. The polymer of any of paragraphs 1 through 5, joined with one another to form one or more rings; wherein A is 1.4-cyclohexanedimethanol or 1, 6-hexanediol. (0168 Ar' represents a 1.2-heteroarylene group: 0182 7. The polymer of any of paragraphs 1 through 6, (0169 Ar' represents a 1.2- or a 1,3-arylene group, or a wherein the molecular weight is at least 10,000. 1.2- or a 1.3-heteroarylene group, R and R' indepen 0183 8. The polymer of any of paragraphs 1 through 7, dently represent hydrogen or an organic group, and R' wherein the polymer is stable at 37°C. in an aqueous solution and/or R' can optionally be joined with each other or for at least 7 days. with the Ar' group to form one or more rings; 0.184 9. The polymer of any of paragraphs 1 through 8, (0170 each Ar independently represents an arylene wherein the polymer is biodegradable. group, each R independently represents an organic 0185. 10. A method of preparing a polymer, the method group, B represents an aromatic-containing organic comprising: group having a linking oxygen attached to the aromatic 0186 combining components comprising: ring, and m=0 or 1; 0187 at least one hydroxy-containing compound of the (0171 each x is 1 to about 200: formula (Formula I) 0172 each y, if present, is 0 to about 200; (0173 x+y is from 2 to about 400; and HO-Z OH, or 0.174 each Z is a therapeutic agent containing at least 0188 a mixture of Formula I and one phenoxy residue and at least one hydroxyl residue or HO-A OH, and (Formula Ia) at least a second phenoxy residue. 0175 2. The polymer of paragraph 1, wherein Z is the 0189 at least one orthoester of the formula (Formula II) residue of Apigenin, Astringin, (+)-1-Acetoxypinoresinol, Arzanol, Biochanin A, Campesterol, Catechin, Catechingal late, Chrysin, Columestrol, Curcumin, Cyanidin, Daidzein, R1O OR 11 Daphnetin, Delphinidin, Desoxyrhapontigenin, 7.2'-Dihy droxy-4'-methoxyisoflavanol, Ellagic acid, Epicatechin, Epi R1O C(R9)R10 gallocatechin, Epigallocatechin gallate, Eriodictyol. Fisetin, Gallocatechin, Gallocatechin gallate, Genistein, Gingerol, Glycitein, Helipyrone, Hesperidin, Hespertin, 2-Hydroxy 0.190 under conditions effective to polymerize at least a formoronetin, 2-Hydroxyisoflavanone, Hydroxytyrosol, portion of the orthoester; and Isoliduiritigenin, Isorhamnetin, Isorhapontin, Kaempferol, (0191 removing byproducts comprising R''OH: Lariciresinol, Leucopelargonidin, Liquiritigenin, Luteolin, (0192 wherein each R and R' independently repre Malvidin, Maringenin, Matairesinol, Methylarzanol, sents hydrogen or an organic group: Myricetin, , Oleuropein, Oxyresveratrol, Pelar (0193 each R'' and R' independently represents an gonidin, Peonidin, Petunidin, Piceatannol, Piceid, organic group: Pinoresiniol, Pinostilbene, Pinostilbenoside, Proanthocyani (0194 each A, optionally, is C(R)(R)—(C(R).), din, Pterostilbene, Punicalagins, Quercetin, Resveratrol, Res C(R)(R)-,-Ar' ,—Ar"C(R)(R)—, a group of Veratroloside, Rhaponticin, Rhapontigenin, Rutin, Secoiro the formula (Formula III) —Ar C(R). Ar (B) doid, Secoisolariciresinol, Silibinin, Silybin, , —C(=O)— —(C=O)—R—(C=O)—, or com Semimyrtucommulone, Tangeritin, 4.2',4',6'-Tetrahydroxy binations thereof chalcone. Theaflavins, Thearubigin, 4,4',6'-Trihydroxyau 0.195 R is an organic group; rone, Tyrosol, Vanillyl alcohol, (-)-Vestitone, Xanthohumol (0196) each R', R. R. R. and Rindependently repre or combinations thereof. sents hydrogen oran organic group, r is 0 to 20, and one US 2011/0082266 A1 Apr. 7, 2011 16

or more of R', R. R. R. and R can optionally be 0213 a compound of the formula (Formula IV) joined with one another to form one or more rings; R11 R11 0197) Ar' represents a 1.2-heteroarylene group; (0198 Ar' represents a 1.2- or a 1,3-arylene group, or a R l l R9 1.2- or a 1.3-heteroarylene group, R and R' indepen R13 dently represent hydrogen or an organic group, and R' R9 O1 S. e. and/or R' can optionally be joined with each other or with the Ar' group to form one or more rings; or a compound of the formula (Formula V) (0199 each Ar independently represents an arylene Rl5O R17 R17 OR 15 group, each R independently represents an organic

group, B represents an aromatic-containing organic 18 group having a linking oxygen attached to the aromatic R16O SR OR 16. ring, and m=0 or 1; and 0200 each Z is a therapeutic agent containing at least or combinations thereof one phenoxy residue and at least one hydroxyl residue or 0214 wherein: at least a second phenoxy residue. 0215 each RandR'' independently represents hydro 0201 11. The method of paragraph 10, wherein Z is a gen or an organic group; Resveratrol or Curcumin residue. 0216) each R', R', R', and R' independently repre sents an organic group; 0202 12. The method of either paragraph 10 or 11, (0217) R' represents oxygen or an organic group and wherein A is 1,4-cyclohexanedimethanol or 1.6-hexandiol. p=0 or 1; 0203 13. The method of any of paragraphs 10 through 12, 0218 each R' can optionally be joined with R" to wherein the molecular weight of the polymer is at least form one or more rings; 10,000. 0219 geminal R'' and R' groups can optionally be 0204 14. The method of any of paragraphs 10 through 13, joined to each other to form rings; wherein removing byproducts comprises removing byprod 0220 each A, optionally, is C(R)(R)—(C(R).), C(R)(R)-,-Ar' ,—Ar"C(R)(R)—, a group of ucts under azeotropic conditions. the formula (Formula III) - Art C(R). Ar' (B) 0205 15. The method of any of paragraphs 10 through 14, , —C(=O)— —(C=O)—R—(C=O)—, or com wherein combining components further comprises combin binations thereof ing a polymerization agent. 0221 R is an organic group; 0206 16. The method of paragraph 15, wherein the poly 0222 each R', R. R. R. and Rindependently repre merization agent comprises a Lewis acid or a Bronsted sents hydrogen oran organic group, r is 0 to 20, and one Lowry acid. or more of R', R. R. R. and R can optionally be joined with one another to form one or more rings; 0207 17. The method of paragraph 16, wherein the Bron 0223) Ar' represents a 1.2-heteroarylene group; Sted-Lowry acid is hydrochloric acid, p-toluenesulfonic acid, (0224) Ar' represents a 1.2- or a 1.3-arylene group, or a methanesulfonic acid, trifluoromethanesulfonic acid, cam 1.2- or a 1.3-heteroarylene group, R and R7 indepen phorsulfonic acid, or combinations thereof. dently represent hydrogen or an organic group, and R' 0208. 18. The method of paragraph 16, wherein the Lewis and/or R' can optionally be joined with each other or acid comprises Al, Fe, B., Zn, Sb, Ti, Cu, Sn, Si, or combina with the Ar' group to form one or more rings; tions thereof. 0225 each Ar independently represents an arylene 0209 19. The method of any of paragraphs 10 through 18, group, each R independently represents an organic wherein combining components further comprises combin group, B represents an aromatic-containing organic ing an additional polymerizable compound selected from group having a linking oxygen attached to the aromatic ketene acetals, monofunctional orthoesters, polyfunctional ring, and m=0 or 1; and orthoesters, imagable compounds, compounds having latent 0226 each Z is a therapeutic agent containing at least reactive sites, or combinations thereof. one phenoxy residue and at least one hydroxyl residue or 0210 20. A method of forming a biodegradable medical at least a second phenoxy residue. device, the method comprising preparing a polymer accord 0227. 23. The method of paragraph 22, wherein the com ing to the method of any of paragraphs 10 through 19, wherein pound of the formula (Formula IV) is represented by Formula the components are combined in a mold. IV(a): 0211. 21. A polymer prepared by a method of any of para R19 R19 R19 R19 graphs 10 through 19. R9 O O R9 0212 22. A method of preparing a polymer comprising combining components comprising at least one hydroxy-con taining compound of the formula (Formula I) HO—Z OH R9 O O R9 or a mixture of Formula I and a compound of the formula R19 R'? R19 (Formula Ia) HO—A OH and at least one ketene acetal under conditions effective to polymerize at least a portion of the at least one ketene acetal, wherein the at least one ketene 0228 wherein each R and R', independentlyp y reprerep acetal is: sents hydrogen or an organic group. US 2011/0082266 A1 Apr. 7, 2011

0229 24. The method of paragraph 23 wherein each R subject in need thereof, a therapeutically effective amount of and R' represents hydrogen. a polymer of any of paragraph 1 through 34 wherein the 0230 25. The method of paragraph 22, wherein Z is a polymeric composition is delivering an encapsulated or com Resveratrol or Curcumin residue. mixed therapeutic, such that the pain or inflammation is pre 0231. 26. The method of any of paragraphs 22 through 25, vented, decreased, or alleviated. wherein A is 1,4-cyclohexanedimethanol or 1.6-hexandiol. 0247 40. A method to treat benign growth or cancer 0232 27. The method of any of paragraphs 22 through 26, related neoplasm comprising the step of administering to a wherein the molecular weight of the polymer is at least subject in need thereof, a therapeutically effective amount of 10,000. polymer of any of paragraph 1 through 34 wherein the poly 0233. 28. The method of any of paragraphs 22 through 27, meric composition is delivering an encapsulated or com wherein removing byproducts comprises removing byprod mixed therapeutic, Such that the benign or oncological con ucts under azeotropic conditions. dition is treated. 0234 29. The method of any of paragraphs 22 through 28, 0248 41. The polymer of any of paragraphs 1 through 9, wherein combining components further comprises combin wherein the polymer further contains a drug selected from ing a polymerization agent. baclofen, bupivacaine or midazolam to form a composition. 0235. 30. The method of paragraph 29, wherein the poly 0249 42. The composition of paragraph 41, wherein the merization agent comprises a Lewis acid or a Bronsted drug is admixed with the polymer. Lowry acid. 0250 43. The method of any of paragraphs 37 through 40, 0236 31. The method of paragraph 30, wherein the Bron further comprising administering the composition of para Sted-Lowry acid is hydrochloric acid, p-toluenesulfonic acid, graph 41 or 42. methanesulfonic acid, trifluoromethanesulfonic acid, cam 0251 44. The method of paragraph 39, wherein the phorsulfonic acid, or combinations thereof. inflammation is neural inflammation. 0237. 32. The method of paragraph 30, wherein the Lewis 0252) 45. The method of paragraph 44, wherein the neural acid comprises Al, Fe, B., Zn, Sb, Ti, Cu, Sn, Si, or combina inflammation is associated with neuronal cell death. tions thereof. 0253. The invention will be further described with refer 0238 33. The method of any of paragraphs 22 through 32. ence to the following non-limiting Examples. It will be appar wherein combining components further comprises combin ent to those skilled in the art that many changes can be made ing an additional polymerizable compound selected from in the embodiments described without departing from the ketene acetals, monofunctional orthoesters, polyfunctional scope of the present invention. Thus the scope of the present orthoesters, imagable compounds, compounds having latent invention should not be limited to the embodiments described reactive sites, or combinations thereof. in this application, but only by embodiments described by the 0239 34. A polymer prepared by a method of any of para language of the claims and the equivalents of those embodi graphs 22 through 33. ments. Unless otherwise indicated, all percentages are by 0240 35. A method of forming a biodegradable medical weight. device, the method comprising preparing a polymer accord ing to any of paragraphs 22 through 33, wherein the compo EXAMPLES nents are combined in a mold. 0241 36. A method of preparing a biodegradable medical Example 1 device, the method comprising: 0242 providing a medical device; and 0254 Synthesis in general: All reactions were carried out 0243 applying one or more polymers according any of under nitrogen in a dry box. Glassware and stir bars were paragraphs 22 through 33 to at least a portion of the dried in a 115°C. oven overnight. In a round bottom flask, the device. phenolic material was dissolved in tetrahydrofuran (THF), 0244 37. A method to prevent, decrease or alleviate pain and to this, 9,-diethylidene-2,4,8,10-tetraoxaspiro 5.5 or inflammation comprising the step of administering to a undecane (DETOSU) was added. After all solid materials subject in need thereof, a therapeutically effective amount of were in solution upon magnetically stirring, 1 mL of 1 per a polymer of any of paragraph 1 through 34. Such that the pain cent p-toluenesulfonic acid solution in THF was charged or inflammation is prevented, decreased, or alleviated. from a pipette. The 1,6-trans-hexanedimethanol (t-CHDM) 0245) 38. A method to treat benign growth or cancer and/or 1.6 hexanediol (HD) were later added and stirring related neoplasms comprising the step of administering to a continued overnight (about 16 hours) at the room tempera subject in need thereof, a therapeutically effective amount of ture. The loading details for the Examples I, II, III and IV polymer of any of paragraph 1 through 34. Such that the were listed in the following table. The reactions for the condition is treated. Example I, II and V were found to be gelled after mixing all 0246. 39. A method to prevent, decrease or alleviate pain the materials, and the resulting polymers seemed not to be or inflammation comprising the step of administering to a Soluble in THF.

DETOSU Curcumin Resveratrol t0HDM HD TH Mw Mn (gram) (gram) (gram) (gram) (gram) (mL) (g/mol) (g/mol)

Example I* 15.0370 2.6372 O 4.5961 3.766 SO ND ND Example II* 1S.O.306 1.2363 O 4.86OS 3.987 SO ND ND Example III" 10.04O7 1.8O37 O 6.1047 O SO 2486O 6800 US 2011/0082266 A1 Apr. 7, 2011

-continued

DETOSU Curcumin Resveratrol t0HDM HD TH Mw Mn (gram) (gram) (gram) (gram) (gram) (mL) (g/mol) (g/mol) Example IVs 2.960 O O496 1.S30 O 12900 31OO Example V* 15.5348 2.4847 O 9.6219 O ND ND

Note: *Curcumin from Spectrum, Inc. Lot Number VD1005. "Curcumin from Aldrich, Catalog number 238384. Resveratrol from Aldrich, catalog number R5010. ND = not determined

0255 Stability and Elution (0259 Background: 0256 The material from the Example IV was made into 0260 Polyphenolic polymers could be used to treat dis microshopheres (5 mg, mean size: 15 to 20 micron) and was eases locally, for example in osteoarthritis. There is signifi added to a 0.0067 Mphosphate buffered saline solution (PBS) cant evidence that certain types of polymers elicit an inflam (20 mL, pH 7.4) The microspheres were prepared in a manner matory response from macrophages or other cell types, thus similar to that reported by Hongkee Sah, J. Controlled indicating a potential problem with biocompatibility. One test Release 47 (1997) 233-245, Microencapsulation techniques for inflammatory potential is to measure activation of the using ethylacetate as a dispersed solvent: effects of its extrac NFKKB pathway, a pathway intimately involved in the gen tion rate on the characteristics of PLGA microspheres. The eration of cytokines and enzymes that play a role in the vial was shaken in a 37°C. incubator at 100 rpm. The micro pathogenesis of osteoarthritis. spheres were in free Suspension after one week. At this point, 0261. It is known that the activation of NFkB can lead to high pressure liquid chromatography (HPLC) (conditions increased expression of IL-1B, a cytokine capable of poten provided below) revealed no detectable resveratrol present in tiating an inflammatory response by binding to the IL-1 the buffer solution indicating a very slow release into aqueous receptor and further activating NFKB. IL-1 beta is primarily Solutions or a high stability of the polymer in aqueous solu produced by monocytes, macrophages, T cells and synovio tions. cytes, but also other cell types, such as articular chondrocytes. 0257. In a separate experiment, the microsphere (8.5 mg) 0262 To insure that the therapeutic polymers were not or the polymer (10.5 mg) was dissolved in THF (10 mL) with only non-toxic, but were also not pro-inflammatory, the poly 1 N hydrochloride (100 microliter). Clear solutions formed meric degradation products were screened for their ability to instantaneously. The loadings of resveratrol in the micro elicit IL-1B production both from two cell types representa sphere and the polymer were 11.9% and 11.2 percent, respec tive of those found in the joint space. tively, from the HPLC analyses (as noted in table below) on 0263. Materials: the solution indicating a very slow release or potential insolu 0264. Normal human articular chondrocytes—Lonza, bility in PBS. Note that by histopathology these same micro CatiliCC-2250 spheres were not obvious in the rat knee by 28 days (see 0265 Human sarcoma synoviocytes—ATCC, Cati HTB Example 3 93 0266 T-flasks BD/VWR, Cath353136,47443-882 0267 Cell Titer Glo Promega, Cat #G7571 0268 Cell Titer Blue Promega Mobile phase A Acetonitrile with 0.1% acetic acid Mobile phase B Water with 0.1% acetic acid 0269 Cell culture treated 96 well plate (V-bottom and flat) Isocratic 60% mobile phase A with 40% mobile phase B (0270 DMEM+Glutamax (Gibco)+10% FBS (Hyclone) Detector UV absorbency at 265 nm. (0271 Chondrocyte differentiation media—Lonza Auto injector 10 micro liter CatiliCC-3225 Total flow rate 0.3 mL/min Column ProntoSIL, C18, 4.6 x 150 mm, 5 micron 0272 Chondrocyte basal media—Lonza CatiliCC-3216 Column 30° C. 0273 1N NaOH solution Temperature 0274 QuantiGlo Human IL-1/IL-1F2 Immunoassay (R Sample 25o C. Temperature and D Systems; if QLB00B) Run time 35 minutes 0275 Multi-channel pipetteman Instrument Agilent ChemStation 0276 0.1% A Saponin in HBSS" (0277 TNFalpha (Biosource: #PHC3016) (0278 POE1, POE2, PLA, and PLDA (Lakeshore Bioma Example 2 terials; table 1) 0279 Polycurcuminand Polyresveratrol breakdown prod Polyphenolic Polymers are Nontoxic and Non-In ucts (prepared internally: Table 2) Microspheres were pre flammatory in vitro pared as indicated above (0280 Polymer Forced Degradation Method: 0258 Degraded polymer products from the above poly 0281 Forced degradation was performed on various poly mers were compared with PDL and PDLG breakdown prod mers in order to evaluate in vitro biocompatibility of the ucts for their toxicity and ability to provoke IL-1 beta cytok polymer partial degradation products. The polymers were ine secretion from differentiated human chondrocytes and a degraded by adding 1 gram of polymer to a vial with 5-ml of human synovial cell line. deionized water. The suspension was then placed in an 85°C. US 2011/0082266 A1 Apr. 7, 2011

oven and samples for each polymer were removed after 2 and radation in one day, would be approximately 7.5 mg/ml. As 5 days. The latter time was the point at which either all solid the polymers degraded over a period of days or weeks, 4 was solubilized or there was no additional change to solubil mg/ml was tested as a maximum load for PDL and PDLG ity. After the solutions cooled to room temperature they were byproducts. The POE polyphenolic polymers were tested also sterile filtered into 50-ml polypropylene conical tubes, frozen at higher concentrations so that a toxic endpoint could be on liquid nitrogen, and freeze-dried for 3 days. Samples were established. stored at -40°C. until use. 0287 Cells or micropellets were treated with the degrada 0282. The polymers tested are listed in the following table tion products for 4-6 hours, supernatants removed for IL-1B along with sample references. Complete degradation solu ELISA and products reapplied. Viability was then tested at 24 tions were prepared from monomers. hours using Cell Titer Glo for synoviocytes and Cell Titer

TABLE 1.

Polymer: Lot: Sample: Reference: PDLG8515-7E LP225 2 days at 85°C. 14027-28A-2d Poly(D.L-lactide-co-glycolide).85.15 5 days at 85°C. 14027-28A-5d PDL100-7E LP316 2 days at 85°C. 14027-28B-2d Poly(D.L-lactide) 5 days at 85°C. 14027-28B-Sd POE1-tCHDMsHDDET 13830-06 2 days at 85°C. 14027-28C-2d Polyorthoester with 54% 5 days at 85°C. 14027-28C-Sd transcyclohexanedimethanol, 45%. 1,6 hexanediol, 1% diethyltartrate POE2-tCHDMoo 12811-55 2 days at 85°C. 14027-28D-2d Polyorthoester with 100% 5 days at 85°C. 14027-28D-5d transcyclohexanedimethanol

0283 Forced degradation was performed on polycur Blue for chondrocytes. It was found that the shorter applica cumin and polyresveratrol in order to evaluate in vitro bio tion time allowed for significant stimulation of IL-1B, while compatibility of the polymer partial degradation products. 24 hours was sufficiently long to detect differences intoxicity The polymers were degraded by adding 0.1 grams of polymer between the polymers. to a vial with 5-ml of deionized water. The suspension was 0288 Treatment of cells or pellets with 0.1% saponin was then placed in an 85°C. oven and samples for each polymer used as a positive control for viability. A standard curve with were removed at various time points. After the solutions purified IL-1 B was run with each assay (not shown). Com cooled to room temperature they were sterile filtered into parisons with cells treated with normal medium alone were 50-ml polypropylene conical tubes, frozen on liquid nitrogen, performed using a one-way ANOVA followed by the Holm and freeze-dried for 3 days. Samples were stored at -40°C. Sidek posthoc test. *=Statistically significant (p<0.05) for all until use. The polymers tested are listed in the following table reported data. PDL and PDLG complete degradation prod along with sample references. ucts were tested twice at the higher concentrations. 0289 Results and Discussion: TABLE 2 0290 PDLG and PDL were in general more toxic and were also found to elicit more IL-1 (3 secretion than the other Polymer: Lot: Sample: Reference: polymers tested, particularly when used to treat the synovio Polycurcumin 13358-72 2 days at 85°C. 14027-7OA cytes (FIGS. 1 through 4). Less toxicity was observed with 5 days at 85°C. 14027-7OB Polyresveratrol 13358-54 1 days at 85°C. 14027-7OC the pellets, which can be due to the fact that the chondrocytes 2 days at 85°C. 14027-7OD are less metabolically active and thus not as Susceptible to assault. 0291 PDLG and PDL 2, 5 day and complete breakdown 0284 Cell Culture Methods: products induced significant IL-1B production and toxicity at 0285 Four to five weeks before the start of the assay, 4 mg/ml (FIGS. 1 through 4 and not shown). In some cases the primary isolates of human chondrocytes were seeded, ampli stimulation of IL-1 B secretion was over 50-fold that of con fied, finally dissociated and pelleted in differentiation trols. The same level of toxicity could not be attained with the medium in V-bottom 96 well plates. The pellets were allowed polyphenolic polymer breakdown products unless applied at to differentiate for three to four weeks prior to the start of the 5-10 times this concentration (FIGS. 1 and 3). Since IL-1B assay. Synoviocytes were amplified and then seeded in 96 and the associated NFKB pathway contribute significantly to well plates (10,000 cells/well) the day before the assay was the pathogenesis of disease, this finding provides that the performed. polyphenolic polymers are Superior for use in local delivery 0286 On the day of testing, all polymer degradation prod Strategies. ucts were weighed, resuspended and diluted in complete 0292. It was noted that IL-1 B production could be stimu media. To decide upon concentrations of products for testing, lated by activation of the mitogen activated protein kinase the amount of polymer that would be present in the joint space (MAP kinase) pathway independently of stimulation by at any one time was estimated. The maximum concentration NFKB. MAP kinase also plays a role in the inflammatory of polymer degradation products in the joints of rodents component of osteoarthritis, although due to safety concerns injected with 50 ul of 1.5 mg/ml microspheres, assuming a 10 MAP kinase inhibitors are not used to treat arthritis. If the ul joint space Volume after equilibration and complete deg PDL or PDLG polymers are stimulating inflammation US 2011/0082266 A1 Apr. 7, 2011 20 through activation of this enzyme, it may be of more serious analyzed microscopically and a totaljoint score obtained. The concern, as a delivered anti-inflammatory would not likely total joint score took into account the histopathological dis serve to mitigate this response. position of the cartilage, bone, ligament and synovium and 0293 Conclusion: was assessed by conventional histopathological criteria. 0294 The results of these experiments indicate that the 0300 Results: polyphenolic polymers tested are less inflammatory and less 0301 Animals treated with either polycurcumin or toxic than other commonly tested polymeric compositions. polyresveratrol microspheres bore significantly more weight on their affected legs as compared to controls and measured Example 3 by incapacitance testing 14 days after treatment. In addition, the polyphenolic compounds did not negatively affect the Polyphenolic Microspheres (as Described Above) for histology of the osteoarthritic joint as measured by total joint Local Delivery to the Joint, an in vivo Assessment of score after 28 days (FIG. 5). Pain and Toxicity in an Osteoarthritis Model 0302 Conclusions: 0295 Study Design and Methods: Animals (10/group), 0303. These polyphenolic microspheres can be used to housed 2-3/cage, were anesthetized with Isoflurane and the treat joint pain and were not toxic at the concentrations tested right knee area prepared for Surgery. A skin incision was made in this osteoarthritis model. over the medial aspect of the knee and the medial collateral 0304 Although the present invention has been described ligament exposed by blunt dissection, and then transected. with reference to preferred embodiments, persons skilled in The medial meniscus was cut through the full thickness to the art will recognize that changes may be made in form and simulate a complete tear. The skin was closed with a Suture. detail without departing from the spirit and scope of the Dosing with 50 ul of a 1.5 mg/ml solution polymeric micro invention. All references cited throughout the specification, spheres by the intra-articular route was done on day 7 after including those in the background, are incorporated herein in Surgery in all groups except group 1 (pain control) which was their entirety. Those skilled in the art will recognize, or be able dosed sc, q.d. on days 7-28 only for purposes of pain testing. to ascertain, using no more than routine experimentation, 0296 Pain response testing was accomplished using the many equivalents to specific embodiments of the invention Incapacitance meter on test days for normal values (pre described specifically herein. Such equivalents are intended Surgery), day 7 post-Surgery (prior to treatment), 1 hour post to be encompassed in the scope of the following claims. injection of Sc doses (groups 1) or 3 hours post-injection (IA 1. A polymer comprising: groups, groups 2-8) and then again at 24 hrs post treatment a polymer including two or more repeat units selected from (the next day) then again on days 11, 14, 21 and 28 at 1 hr post a repeat unit of the formula (Formula VI): treatment (group 1). 0297 Animals were placed in the plexiglass housing of --z-POE-et-A-POE-i- the incapacitance meter and allowed to acclimate for approxi mately 5 minutes or until the rat appeared to be calmly stand wherein each POE and POE, independently, is repre ing with both feet on the force plates. The position of the sented by the formula: animal was such that each hind paw rests on a separate force plate. The force exerted by each hind paw was averaged over R11 R11 a 1 second interval, and the mean of three readings constituted 1 data point. The change in hind paw weight distribution was R10(R).C.. O O C(R)-R10 determined by the ratio of weight bearing for right and left limbs and as a % weight bearing for the right hind limb (1,2) XLR-X.ok No 21 1. Bove S. E., et al. Weight bearing as a measure of disease progression and efficacy of anti-inflammatory compounds in a model of monosodium iodoacetate-induced osteoarthritis. or the formula: Osteoarthritis Cartilage. 2003; 11: 821-830. 2. Bove S. E., et al. Surgically induced osteoarthritis in the rat results in the R16O OR 15 Rl5O OR 15 development of both osteoarthritis-like joint pain and second (R-18) ary hyperalgesia. Osteoarthritis Cartilage. 2006; 10: 1041 O O 1048. 0298. On day 28 rats were euthanized, synovial lavages R17 H H R17 performed on right knee using 100 ul of saline (centrifuge and collect Supernatant) and then the right (operated) knee joint wherein: trimmed of muscle and connective tissue and collected into each R. R', and R7 independently represents hydrogen 10% neutral buffered formalin. The patella was removed to or an organic group: allow proper fixation of the joints. The left (normal) knee each R', R', R', and R' independently represents an from rats 1-5 of group 1 was also lavaged and collected into organic group: formalin for normal staining controls. R" represents oxygen or an organic group and p-0 or 1; 0299. Following 3 days in 10% formic acid decalcifier, the n=0 or 1; operated joints were cut into two approximately equal halves each R' can optionally be joined with R' to form one or in the frontal plane and embedded in paraffin. Three sections more rings; were cut from each operated knee at approximately 200 m geminal R'' and R' groups can optionally be joined to steps and stained with toluidine blue. A single section was cut each other to form rings; from each of the 5 left knees from the control group and each A, optionally, —C(R')(R)—(C(R).), C(R) stained with toluidine blue. All 3 sections of each knee were (R)-, -Ar' , —Ar"C(R)(R)—, a group of the US 2011/0082266 A1 Apr. 7, 2011 21

formula (Formula III) —Ar C(R), Ar (B), , 4. The polymer of claim 3 wherein each R" represents C(=O)— —(C=O)—R (C=O) , or combina hydrogen and each Rindependently represents hydrogen or tions thereof; methyl. R is an organic group; 5. The polymer of claim 1, wherein Z is a Resveratrol or each R', R. R. R. and R independently represents Curcumin residue. hydrogen or an organic group, r is 0 to 20, and one or 6. The polymer of claim 1, wherein A is 1,4-cyclohex more of R', R. R. R', and Rican optionally be joined anedimethanol or 1.6-hexanediol. with one another to form one or more rings; 7. The polymer of claim 1, wherein the molecular weight is Ar' represents a 1.2-heteroarylene group; at least 10,000. Ar' represents a 1.2- or a 1.3-arylene group, or a 1.2- or a 8. The polymer of claim 1, wherein the polymer is stable at 1.3-heteroarylene group, RandR independently rep 37°C. in an aqueous solution for at least 7 days. resent hydrogen or an organic group, and Rand/or R' 9. The polymer of claim 1, wherein the polymer is biode can optionally be joined with each other or with the Ar" gradable. group to form one or more rings; 10. A method of preparing a polymer, the method compris each Ar independently represents an arylene group, each 1ng: Rindependently represents an organic group, B repre combining components comprising: sents an aromatic-containing organic group having a at least one hydroxy-containing compound of the for linking oxygen attached to the aromatic ring, and m=0 or mula (Formula I) HO Z OH, or 1; a mixture of Formula I and each X is 1 to about 200; (Formula Ia) HO—A OH, and each y, if present, is 0 to about 200; at least one orthoester of the formula (Formula II) x+y is from 2 to about 400; and each Z is a therapeutic agent containing at least one phe noxy residue and at least one hydroxyl residue or at least R1O OR 11 a second phenoxy residue. 2. The polymer of claim 1, wherein Z is the residue of Apigenin, Astringin, (+)-1-Acetoxypinoresinol, Arzanol, Biochanin A, Campesterol, Catechin, Catechin gallate, Chrysin, Columestrol, Curcumin, Cyanidin, Daidzein, Daph under conditions effective to polymerize at least a portion of netin, Delphinidin, Desoxyrhapontigenin, 7.2'-Dihydroxy the orthoester; and 4'-methoxyisoflavanol, Ellagic acid, Epicatechin, Epigallo removing byproducts comprising ROH: catechin, Epigallocatechin gallate, Eriodictyol. Fisetin, wherein each R and R' independently represents hydro Gallocatechin, Gallocatechin gallate, Genistein, Gingerol, gen or an organic group; Glycitein, Helipyrone, Hesperidin, Hespertin, 2-Hydroxy each R'' and R'' independently represents an organic formoronetin, 2-Hydroxyisoflavanone, Hydroxytyrosol, group; Isoliduiritigenin, Isorhamnetin, Isorhapontin, Kaempferol, each A, optionally, is C(R')(R)-(C(R).), C(R) Lariciresinol, Leucopelargonidin, Liquiritigenin, Luteolin, (R)-, -Ar' , —Ar"C(R)(R)—, a group of the Malvidin, Maringenin, Matairesinol, Methylarzanol, formula (Formula III) —Ar° C(R). Arf (B), , Myricetin, Naringenin, Oleuropein, Oxyresveratrol, Pelar C(=O)— —(C=O)—R (C=O) , or combina gonidin, Peonidin, Petunidin, Piceatannol, Piceid, tions thereof; Pinoresiniol, Pinostilbene, Pinostilbenoside, Proanthocyani R is an organic group: din, Pterostilbene, Punicalagins, Quercetin, Resveratrol, Res each R', R. R. R. and R independently represents Veratroloside, Rhaponticin, Rhapontigenin, Rutin, Secoiro hydrogen or an organic group, r is 0 to 20, and one or doid, Secoisolariciresinol, Silibinin, Silybin, more of R", R. R. R', and Rican optionally be joined Semimyrtucommulone, Tangeritin, 4.2',4',6'-Tetrahydroxy with one another to form one or more rings; chalcone. Theaflavins, Thearubigin, 4,4',6'-Trihydroxyau Ar' represents a 1.2-heteroarylene group; rone, Tyrosol, Vanillyl alcohol, (-)-Vestitone, Xanthohumol Ar' represents a 1.2- or a 1.3-arylene group, or a 1.2- or a or combinations thereof. 1.3-heteroarylene group, Rand R7 independently rep 3. The polymer of claim 1 wherein the repeat unit of the resent hydrogen or an organic group, and Rand/or R' formula (Formula VI) is represented by Formula VIa: can optionally be joined with each other or with the Ar" group to form one or more rings; each Ar independently represents an arylene group, each R19 R19 R19 R19 Rindependently represents an organic group, B repre sents an aromatic-containing organic group having a O O linking oxygen attached to the aromatic ring, and m=0 or 1; and ">{O X."O O O each Z is a therapeutic agent containing at least one phe noxy residue and at least one hydroxyl residue or at least R19 R19 R19 R19 a second phenoxy residue. 11. The method of claim 10, wherein Z is a Resveratrol or wherein: Curcumin residue. each R and R' independently represents hydrogen or an 12. The method claim 10, wherein A is 1,4-cyclohex organic group. anedimethanol or 1.6-hexandiol. US 2011/0082266 A1 Apr. 7, 2011 22

13. The method of claim 10, wherein the molecular weight formula (Formula III) —Ar C(R), Ar (B), , of the polymer is at least 10,000. C(=O)— —(C=O)—R (C=O) , or combina 14-18. (canceled) tions thereof; 19. The method of claim 10, wherein combining compo R is an organic group: nents further comprises combining an additional polymeriZ each R', R. R. R. and R independently represents able compound selected from ketene acetals, monofunctional hydrogen or an organic group, r is 0 to 20, and one or orthoesters, polyfunctional orthoesters, imagable com more of R', R. R. R', and Rican optionally be joined pounds, compounds having latent reactive sites, or combina with one another to form one or more rings; tions thereof. Ar' represents a 1.2-heteroarylene group; 20. (canceled) Ar' represents a 1.2- or a 1.3-arylene group, or a 1.2- or a 21. (canceled) 22. A method of preparing a polymer comprising combin 1.3-heteroarylene group, RandR independently rep ing components comprising at least one hydroxy-containing resent hydrogen or an organic group, and Rand/or R' compound of the formula (Formula I) HO—Z OH or a can optionally be joined with each other or with the Ar" mixture of Formula I and a compound of the formula (For group to form one or more rings; mula Ia) HO—A OH and at least one ketene acetal under each Ar independently represents an arylene group, each conditions effective to polymerize at least a portion of the at Rindependently represents an organic group, B repre least one ketene acetal, wherein the at least one ketene acetal sents an aromatic-containing organic group having a 1S linking oxygen attached to the aromatic ring, and m=0 or a compound of the formula (Formula IV) 1; and each Z is a therapeutic agent containing at least one phe noxy residue and at least one hydroxyl residue or at least a second phenoxy residue. 23. The method of claim 22, wherein the compound of the -R formula (Formula IV) is represented by Formula IV (a):

R19 R19 R19 R19 or a compound of the formula (Formula V) R9 O O R9

RI 5O RI 7 RI 7 ORI 5 R9 O O R9 R19 RR1919 R19 R16O t R 18 OR 16. wherein each R and R', independently represents hydrogen or combinations thereof; or an organic group. wherein: each R and R7 independently represents hydrogen or an 24. The method of claim 23 wherein each R and R' organic group: represents hydrogen. each R', R. R', and R' independently represents an 25. The method of claim 22, wherein Z is a Resveratrol or organic group: Curcumin residue. R" represents oxygen or an organic group and p-0 or 1; 26. The method of claim 22, wherein A is 1,4-cyclohex each R' can optionally be joined with R' to form one or anedimethanol or 1.6-hexandiol. more rings; 27. The method of claim 22, wherein the molecular weight geminal R'' and R' groups can optionally be joined to of the polymer is at least 10,000. each other to form rings; 28-45. (canceled) each A, optionally, is C(R')(R)—(C(R).), C(R) (R)-, -Ar' , —Ar"C(R)(R)—, a group of the