WO2012097078A2 - Viscosupplementary materials - Google Patents

Abstract

A polymer includes at least one of the following repeat units: where R¹ and R² are either the same or different and are individually H, COOR³, COCH₃, CONHR⁴, OR⁴ or SR⁴; wherein the polymer has a number average molecular weight from 1,500,000 g/mol to 2,500,000 g/mol; and with the proviso that both R¹ and R² are not H. Such polymers have a variety of uses including injection into a synovial joint for chondroprotection and as a viscosupplement.

Description

VISCOSUPPLEMENTARY MATERIALS

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. Provisional Application Numbers

61/468,210, filed March 28, 2011, and 61/432,721, filed January 14, 2011, both of which are incorporated herein by reference, in their entirety, for any and all purposes.

FIELD

[0002] The present technology relates generally to polymer materials and the use of these polymers in pharmaceutical and medical device applications.

BACKGROUND

[0003] Osteoarthritis (OA), also known as degenerative joint disease is a noninflammatory joint disease characterized by degeneration of joint cartilage, can affect one or more parts of the body, including the hands and weight-bearing joints such as knees, hips, feet and the spine. When healthy, cartilage allows bones to glide over each other and has a shock absorber function. In osteoarthritis, the surface layer of the cartilage breaks down and wears away, which allows the bones under the cartilage to rub together, causing the common OA symptoms of pain, swelling, and loss of motion of the joint. Furthermore, in joints such as the knees, osteoarthritis is often accompanied by loss of viscosity of the synovial fluid. The synovial fluid is a thick, gel-like substance that cushions the joint and provides lubrication to reduce friction of the bones.

[0004] Osteoarthritis is mainly associated with aging, with a prevalence of approximately 80% in individuals over 65. Despite being a condition that causes most problems to populations after retirement age, osteoarthritis is also rated the highest cause of work loss in the U.S. and Europe. In addition to age, risk factors known to be associated with osteoarthritis include obesity, traumatic injury and overuse due to sports and occupational stresses.

[0005] There is currently no cure for osteoarthritis, and available arthritis therapies are directed at the symptomatic relief of pain, and at improving, or at least maintaining, joint function. Generally, pain relievers such as non-steroidal anti-inflammatory drugs (NSAIDs) or COX-2 inhibitors are used, along with physical therapy. However, in the context of the recent withdrawals of COX-2 inhibitors, physicians are even more limited in their choice of treatment for osteoarthritis. Currently, a majority of the known treatment methods offer pain relief but not lubrication, and condroprotection, a method that prevents the joint or the cartilage from breaking down by using substances which can protect the integrity of the cartilage.

[0006] Viscosupplementation, a procedure involving the injection of gel-like substances (generally hyaluronates or called hyaluronic acid) into a joint to supplement the viscous properties of synovial fluid, has been shown to relieve pain in many osteoarthritis patients who do not get relief from analgesic drugs. The technique has been used in Europe and Asia for several years, but the U.S. Food and Drug Administration did not approve it until 1997. In current procedures of viscosupplementation, hyaluronate preparations are injected to replace or supplement the body's natural hyaluronan, a polysaccharide component of synovial fluid. The injections coat the articular cartilage surface, and thus provide a possible prophylactic barrier for the articular cartilage. However, due to their short lifetime within the joint (about a couple of days), hyaluronate preparations currently available have only limited long-term benefit to the patient and require injection of large quantities of the preparation and/or repeated injections.

[0007] Clearly, there is a need for materials with improved performance for use in viscosupplementation for the treatment of osteoarthritis and other conditions affecting weight-bearing joints. In particular, materials which closely mimic the properties of the natural viscosupplements and which offer effective chondroprotection and lubrication of joints and cartilage tissues are highly desirable.

SUMMARY

[0008] In one aspect, polymers are provided, wherein the polymers have at least one of the following repeat units:

II III

In Formulae I, II or III, R 1 and R 2 are either the same or different and are individually H, COOR³, COCH₃, CONHR⁴, OR⁴ or SR⁴; each occurrence of R³ is independently H, an alkali metal, an alkaline earth metal, a polyethylene glycol group, a triethylene glycol group, an ammonium group, a C₂-C₂₀ alkyl, an alkenyl, an alkynyl, COCH₃, CH₂CH₂OH, or

(CH₂CH₂0)_nR⁵; each occurrence of R⁴ is independently H, an alkali metal, an alkaline earth metal, a polyethylene glycol group, a triethylene glycol group, an ammonium group, an alkyl, an alkenyl, an alkynyl, COCH₃, CH₂CH₂OH, or (CH₂CH₂0)_nR⁵. Each occurrence of R⁵ for a polymer having at least one repeat unit according to Formulae I, II, or II is independently H, alkyl, alkenyl, or alkynyl; and wherein the polymer has a number average molecular weight from 1,500,000 g/mol to 2,500,000 g/mol; and with the proviso that both R¹ and R² are not H.

1 3

[0009] In some embodiments, R is H and R2 is COOR . In some other embodiments,

R is H. According to another embodiment, R is alkyl, aryl, an alkali metal, an alkaline earth metal, or an ammonium group. In some embodiments, R is C₂-C8 alkyl, yet according to

3 3

another embodiment, R is polyethylene glycol. In some embodiments, R is triethylene glycol. In other embodiments, R is an alkali metal or an alkaline earth metal. In some

3 1 embodiments, R is Li, Na, K, Cs, Ca, Mg, or Ba. In some other embodiments, R is H and R₂ is COOR³, and R³ is H, Li, Na, K, Cs, Ca, Mg, or Ba.

[0010] In another aspect, a polymer is provided, the polymer generally represented as:

wherein R⁶, R⁷, R⁸, R⁹, R¹⁰, and R¹¹ are individually H, COOR³, COCH₃, CONHR⁴, OR⁴ or

SR 4^" For each occurrence of R 3 within the polymer, R 3 is independently H, an alkali metal, an alkaline earth metal, a polyethylene glycol group, a triethylene glycol group, an ammonium group, a C₂-C₂₀ alkyl, an alkenyl, an alkynyl, COCH₃, CH₂CH₂OH, or

(CH₂CH₂0)_nR⁵; each occurrence of R⁴ is independently H, an alkali metal, an alkaline earth metal, a polyethylene glycol group, a triethylene glycol group, an ammonium group, an alkyl, an alkenyl, an alkynyl, COCH₃, CH₂CH₂OH, or (CH₂CH₂0)_nR⁵; each occurrence of R⁵ is independently H, an alkyl, an alkenyl, or an alkynyl; and n is an integer from 1 to 20. Repeat units x, y, and z are the same or different and are randomly distributed throughout the polymer; wherein the polymer has a number average molecular weight from 1,500,000 g/mol to 2,500,000 g/mol; and with the proviso that at least one of R⁶, R⁷, R⁸, R⁹, R¹⁰, and R¹¹ is other than H. As used herein, a random co-polymer is a polymer having at least two different repeat units in no particular order and which are randomly distributed throughout the polymer backbone. A random block co-polymer is one in which there are at least two different blocks of two or more repeat units, the blocks being randomly distributed throughout the polymer backbone.

[0011] In some embodiments, R⁶ or R⁷; R⁸ or R⁹; and R¹⁰ or R¹¹ are H. In other embodiments, R⁶ or R⁷; R⁸ or R⁹; and R¹⁰ or R¹¹ are individually COOR³. In other embodiments, R⁶, R⁸, and R¹⁰ are H; and R⁷, R⁹, and R¹¹ are individually COOR³. In other embodiments, each R is individually H, C₂-C8 alkyl, an alkali metal, or an alkaline earth metal; or each R⁴ is individually H, Ci-C₈ alkyl, an alkali metal, or an alkaline earth metal. In other embodiments, at least one R³ or R⁴ is Li, Na, K, Cs, Ca, Mg, or Ba. When the metal is divalent, i.e. Ca, Mg, or Ba, the metal may complex two of the carboxylate groups. In other embodiments, at least one R³ or R⁴ is a triethylene glycol group.

[0012] In some embodiments, the above polymer has a number average molecular weight of about 2,000,000 g/mol. In some embodiments, the polymer has a polydispersity index (PDI), of from about 1 to about 2. In some embodiments, the polymer is a viscous liquid. In some other embodiments, the polymer is a gel. [0013] In another aspect, pharmaceutical compositions are provided which include at least one pharmaceutically acceptable carrier and an effective amount of at least one polymer described above.

[0014] In yet another aspect, methods of chondroprotection of a joint in a subject are provided. The methods include administering to the joint of a subject an effective amount of the polymer described herein. In certain embodiments, the method includes injecting an effective amount of the polymer. In some embodiments, injecting an effective amount of a polymer includes performing a single injection. In other embodiments, injecting an effective amount of a polymer includes performing at least two injections at different time points. Diseased or injured synovial joints that can be treated using these methods include osteoarthritic joints and sport-injured joints, such as joints of the knee, hip, elbow, ankle, and wrist.

[0015] In some embodiments, the method further includes administering an effective amount of at least one active agent to the subject. In some embodiments, the active agent includes a growth factor, a cytokine, a small molecule, an analgesic, an anesthetic, an antimicrobial agent, an antibacterial agent, an antiviral agent, an antifungal agent, an antibiotic, an anti-inflammatory agent, an antioxidant, an antiseptic agent, or a combination of any two or more thereof.

BRIEF DESCRIPTION OF THE DRAWINGS

[0016] FIG. 1 is a graph of the rheological properties (the values of G (storage modulus) and G" (loss modulus)) of an oxanorbornene polymer (2 wt/v%), compared to normal and OA SF (n=3), according to the examples. The values of G (storage modulus) and G" (loss modulus) are plotted as a function of average molecular weight and compared to normal and OA SF.

[0017] FIG. 2 is a graph illustrating the shear thinning properties of oxanorbornene polymers having various molecular weights (2 wt/v%), according to the examples.

[0018] FIG. 3 is a graph of the coefficient of friction data of oxanorbornene polymers having various molecular weights, in comparison to Synvisc^® and Bovine SF, according to the examples. [0019] FIG. 4 is a graph of the histological evaluation, substantial cartilage degradation score, of joints treated with an oxanorbornene polymer (Poly) vs. saline at two different concentrations (0.5% and 2.0%), according to the example. Micrometer

measurements were obtained for areas of tibial cartilage degeneration in which both chondrocyte and proteoglycan loss extended to >50% of the cartilage depth. Higher scores indicate more severe osteoarthritis.

[0020] FIG 5. is a graph of the histological evaluation, total joint score, of rat joints treated with the Polymer vs. saline at two different concentrations (0.25 and 1 wt/v%), according to the examples. The total joint score is overall evaluation of cartilage degradation as a combination of the tibial cartilage degeneration score and osteophyte score. Higher total joint scores indicate more severe osteoarthritis.

[0021] FIG. 6 is a graph of the histological evaluation, osteophyte score, of rat joints treated with the Polymer) vs. saline at two different concentrations (0.25 and 1 wt/v%), according to the examples. Osteophyte formation (bone spur) is highly correlated with progression on OA, and a good indicator of severity of OA. Higher osteophyte scores indicate more severe OA.

[0022] FIG. 7 is a graph of the histological evaluation, bone score, of rat joints treated with the Polymer) vs. saline at two different concentrations (0.25 and 1 wt/v%), according to the examples. Bone score indicates degree of weight loading in a treated joint. Under some circumstances, animals may use a joint less frequently due to pain associated with the treated joint, which will leads to lower bone score.

[0023] FIG. 8 is a graph of bone score in joints using a canine model of osteoarthritis, after treatment with poly(5-oxanorbornane-2-sodium carboxylate salt) having a molecular weight of about 2,000,000 g/mol, versus a control of commercially available Synvisc One^®. The following scoring was used: 0 = normal; 1 = up to 10% of femur width has thickened trabeculae; 2 = 11-30% of femur width has thickened trabeculae; 3 = 31-60% of femur width has thickened trabeculae; 4 = 61-90% of femur width has thickened trabeculae; 5 = >91% of femur wi dth has thickened trabeculae.

DETAILED DESCRIPTION [0024] In the following detailed description, reference may be made to the accompanying drawings, which form a part hereof. In the drawings, similar symbols typically identify similar components, unless context dictates otherwise. The illustrative embodiments described in the detailed description, drawings, and claims are not meant to be limiting. Other embodiments may be utilized, and other changes may be made, without departing from the spirit or scope of the subject matter presented here.

[0025] As used herein, the following definitions of terms shall apply unless otherwise indicated.

[0026] As used herein, "about" will be understood by persons of ordinary skill in the art and will vary to some extent depending upon the context in which it is used. If there are uses of the term which are not clear to persons of ordinary skill in the art, given the context in which it is used, "about" will mean up to plus or minus 10% of the particular term.

[0027] The use of the terms "a" and "an" and "the" and similar referents in the context of describing the elements (especially in the context of the following claims) are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context. Recitation of ranges of values herein are merely intended to serve as a shorthand method of referring individually to each separate value falling within the range, unless otherwise indicated herein, and each separate value is incorporated into the specification as if it were individually recited herein. All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (e.g., "such as") provided herein, is intended merely to better illuminate the embodiments and does not pose a limitation on the scope of the claims unless otherwise stated. No language in the specification should be construed as indicating any non-claimed element as essential.

[0028] The embodiments, illustratively described herein may suitably be practiced in the absence of any element or elements, limitation or limitations, not specifically disclosed herein. Thus, for example, the terms "comprising," "including," "containing," etc., shall be read expansively and without limitation. Additionally, the terms and expressions employed herein have been used as terms of description and not of limitation, and there is no intention in the use of such terms and expressions of excluding any equivalents of the features shown and described or portions thereof, but it is recognized that various modifications are possible within the scope of the claimed technology. Additionally, the phrase "consisting essentially of will be understood to include those elements specifically recited and those additional elements that do not materially affect the basic and novel characteristics of the claimed technology. The phrase "consisting of excludes any element not specified.

[0029] The terms "individual" and "subject" are used herein interchangeably. They refer to a human or another mammal (e.g., primates, dogs, cats, goats, horses, pigs, mice, rabbits, and the like). In certain preferred embodiments, the subject is human. The terms do not denote a particular age, and thus encompass adults, children, and newborns.

[0030] The term "treatment" is used herein to characterize a method or process that is aimed at (1) delaying or preventing the onset of a disease or condition; (2) slowing down or stopping the progression, aggravation, or deterioration of the symptoms of the disease or condition; (3) bringing about ameliorations of the symptoms of the disease or condition; or (4) curing the disease or condition. A treatment may be administered prior to the onset of the disease, for a prophylactic or preventive action. Alternatively or additionally, the treatment may be administered after initiation of the disease or condition for a therapeutic action.

[0031] The term "local," when used herein to characterize the delivery, administration or application of a polymer of the present technology, or a pharmaceutical composition thereof, is meant to specify that the polymer or composition is delivered, administered or applied directly to the site to be treated or in the vicinity of the site to be treated for a localized effect. For example, any of the polymers described herein may be used as a viscosupplement that will generally be injected directly to an osteoarthritic knee joint; or as tissue space filler that will generally be injected directly to a diseased or damaged vocal cord, or to a skin area displaying lines or wrinkles. Preferably, local administration is effected without any significant absorption of components of the polymer into the patient's blood stream (to avoid a systemic effect).

[0032] A "pharmaceutical composition" is defined herein as comprising an effective amount of at least one active ingredient (e.g., any of the above-or below-described polymers), and at least one pharmaceutically acceptable carrier. [0033] As used herein, the term "pharmaceutically acceptable carrier" refers to a carrier medium which does not interfere with the effectiveness of the biological activity of the active ingredient(s) and which is not excessively toxic to the host at the concentration at which it is administered. The term includes solvents, dispersion media, coatings,

antibacterial and antifungal agents, isotonic agents, absorption delaying agents, and the like. The use of such media and agents for pharmaceutically active substances is well known in the art (see for example, Remington 's Pharmaceutical Sciences, E. W. Martin, 18^th Ed., 1990, Mack Publishing Co.: Easton, Pa., which is incorporated herein by reference in its entirety).

[0034] As used herein, the term "effective amount" refers to any amount of a molecule, compound or composition that is sufficient to fulfill its intended purpose(s), i.e., to elicit a desired biological or medicinal response in a tissue or subject. Examples of intended purposes of the described polymers include, but are not limited to, providing

viscosupplementation to a joint, to allow soft tissue augmentation, to prevent or reduce adhesion formation, to facilitate tissue manipulation, and/or to maintain, support or protect soft tissue.

[0035] As used herein, the term "soft tissue augmentation" includes, but is not limited to, dermal tissue augmentation; filling of lines, folds, wrinkles, minor facial depressions, cleft lips and the like, especially in the face and neck; correction of minor deformities due to aging, disease, including in the hands and feet, fingers and toes; augmentation of the vocal cords or glottis to rehabilitate speech; dermal filling of sleep lines and expression lines;

replacement of dermal and subcutaneous tissue lost due to aging; lip augmentation; filling of crow's feet and the orbital groove around the eye; breast augmentation; chin augmentation; augmentation of the cheek and/or nose; filling of indentations in the soft tissue, dermal or subcutaneous, due to, e.g., overzealous liposuction or other trauma; filling of acne or traumatic scars and rhytids; filling of nasolabial lines, nasoglobellar lines and infraoral lines.

[0036] As used herein, the term "soft tissue" includes all tissue of the body except bone. Examples of soft tissue include, but are not limited to, muscles, tendons, fibrous tissues, fat, blood vessels, nerves, and synovial tissues.

[0037] The terms "active agent" and "biologically active agent" are used herein interchangeably. They refer to compounds or entities that alter, inhibit, activate or otherwise affect biological or chemical events. For example, active agents may include, but are not limited to, vitamins, anti-cancer substances, antibiotics, immunosuppressants, anti-viral substances, enzyme inhibitors, opioids, hypnotics, lubricants, tranquilizers, anti-convulsants, muscle relaxants, anti-spasmodics and muscle contractants, anti-glaucoma compounds, modulators of cell-extracellular matrix interactions including cell growth inhibitors and anti- adhesion molecules, vasodilating agents, analgesics, anti-pyretics, steroidal and non-steroidal anti-inflammatory agents, anti-angiogenic factors, anti-secretory factors, anticoagulants and/or antithrombotic agents, local anesthetics, ophthalmics, prostaglandins, anti-depressants, anti-psychotic substances, anti-emetics, imaging agents. A more complete, although not exhaustive, listing of classes and specific drugs suitable for use in the present technology may be found in "Pharmaceutical Substances: Synthesis, Patents, Applications," by A. Kleeman and J. Engel, Thieme Medical Publishing, 1999; and the "Merck Index: An Encyclopedia of Chemicals, Drugs, and Biologicals", S. Budavari et al. (Eds), CRC Press, 1996, both of which are incorporated herein by reference.

[0038] The term "small molecule" refers to molecules, whether naturally occurring or artificially created (e.g., via chemical synthesis) that have a relatively low molecular weight. Preferred small molecules are biologically active in that they produce a local or systemic effect in animals, preferably mammals, more preferably humans. Typically, small molecules have a molecular weight of less than about 1,500 g/mol. In certain preferred embodiments, the small molecule is a drug. Preferably, though not necessarily, the drug is one that has already been deemed safe and effective for use by the appropriate governmental agency or body. For example, drugs for human use listed by the FDA under 21 C.F.R. §§ 330.5, 331 through 361, and 440 through 460; drugs for veterinary use listed by the FDA under 21 C.F.R. .§§ 500 through 589, incorporated herein by reference, are all considered suitable for use with the present polymers.

[0039] The terms "polysaccharide," "carbohydrate," and "oligosaccharide" are used herein interchangeably. They refer to a compound that comprises at least two sugar units, or derivatives thereof. Polysaccharides may be purified from natural sources such as plants or may be synthesized de novo in the laboratory. Polysaccharides isolated from natural sources may be modified chemically to change their chemical or physical properties (e.g., reduced, oxidized, phosphorylated, cross-linked). Carbohydrate polymers or oligomers may include natural sugars (e.g., glucose, fructose, galactose, mannose, arabinose, ribose, xylose, etc.) and/or modified sugars (e.g., 2'-fluororibose, 2'-deoxyribose, etc.). Polysaccharides may also be either straight or branched. They may contain both natural and/or unnatural carbohydrate residues. The linkage between the residues may be the typical ether linkage found in nature or may be a linkage only available to synthetic chemists. Examples of polysaccharides include cellulose, maltin, maltose, starch, modified starch, dextran, poly(dextrose), and fructose. Glycosaminoglycans are also considered polysaccharides. Sugar alcohol, as used herein, refers to any polyol such as sorbitol, mannitol, xylitol, galactitol, erythritol, inositol, ribitol, dulcitol, adonitol, arabitol, dithioerythritol,

dithiothreitol, glycerol, isomalt, and hydrogenated starch hydrolysates.

[0040] An entity is herein said to be "associated with" another entity if they are linked by a direct or indirect, covalent or non-covalent interaction. In certain embodiments, the association is covalent. Desirable non-covalent interactions include hydrogen bonding, van der Walls interactions, hydrophobic interactions, magnetic interactions, electrostatic interactions, or combinations thereof.

[0041] In general, "substituted" refers to a group, as defined below (e.g., an alkyl or aryl group), in which one or more bonds to a hydrogen atom contained therein are replaced by a bond to non-hydrogen or non-carbon atoms. Substituted groups also include groups in which one or more bonds to a carbon(s) or hydrogen(s) atom are replaced by one or more bonds, including double or triple bonds, to a heteroatom. Thus, a substituted group will be substituted with one or more substituents, unless otherwise specified. In some embodiments, a substituted group is substituted with 1 , 2, 3, 4, 5, or 6 substituents. Examples of substituent groups include: halogens (i.e., F, CI, Br, and I); hydroxyls; alkoxy, alkenoxy, alkynoxy, aryloxy, aralkyloxy, carbonyls(oxo), carboxyls, esters, urethanes, thiols, sulfides, sulfoxides, sulfones, sulfonyls, sulfonamides, amines, isocyanates, isothiocyanates, cyanates, thiocyanates, nitro groups, nitriles (i.e., CN), and the like.

[0042] Alkyl groups include straight chain and branched alkyl groups having from 1 to 20 carbon atoms or, in some embodiments, from 1 to 12, 1 to 8, 1 to 6, or 1 to 4 carbon atoms. Alkyl groups further include cycloalkyl groups. Examples of straight chain alkyl groups include those with from 1 to 8 carbon atoms such as methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, and n-octyl groups. Examples of branched alkyl groups include, but are not limited to, isopropyl, iso-butyl, sec-butyl, tert-butyl, neopentyl, isopentyl, and 2,2- dimethylpropyl groups. Representative substituted alkyl groups may be substituted one or more times with substituents such as those listed above. Where the term haloalkyl is used, the alkyl group is substituted with one or more halogen atoms.

[0043] Cycloalkyl groups are cyclic alkyl groups such as, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl groups. In some embodiments, the cycloalkyl group has 3 to 8 ring members, whereas in other embodiments the number of ring carbon atoms range from 3 to 5, 3 to 6, or 3 to 7.

Cycloalkyl groups further include mono-, bicyclic and polycyclic ring systems, such as, for example bridged cycloalkyl groups as described below, and fused rings such as, but not limited to, decalinyl, and the like. In some embodiments, polycyclic cycloalkyl groups have three rings. Substituted cycloalkyl groups may be substituted one or more times with, non- hydrogen and non-carbon groups as defined above. However, substituted cycloalkyl groups also include rings that are substituted with straight or branched chain alkyl groups as defined above. Representative substituted cycloalkyl groups may be mono-substituted or substituted more than once, such as, but not limited to, 2,2-, 2,3-, 2,4- 2,5- or 2,6-disubstituted cyclohexyl groups, which may be substituted with substituents such as those listed above.

[0044] Alkenyl groups include straight and branched chain and cycloalkyl groups as defined above, except that at least one double bond exists between two carbon atoms. Thus, alkenyl groups have from 2 to about 20 carbon atoms, and typically from 2 to 12 carbons or, in some embodiments, from 2 to 8, 2 to 6, or 2 to 4 carbon atoms. In some embodiments, alkenyl groups include cycloalkenyl groups having from 4 to 20 carbon atoms, 5 to 20 carbon atoms, 5 to 10 carbon atoms, or even 5, 6, 7, or 8 carbon atoms. Examples include, but are not limited to, vinyl, allyl, CH=CH(CH₃), CH=C(CH₃)₂, -C(CH₃)=CH₂, -C(CH₃)=CH(CH₃), -C(CH₂CH₃)=CH₂, cyclohexenyl, cyclopentenyl, cyclohexadienyl, butadienyl, pentadienyl, and hexadienyl, among others. Representative substituted alkenyl groups may be mono- substituted or substituted more than once, such as, but not limited to, mono-, di- or tri- substituted with substituents such as those listed above. [0045] Alkynyl groups include straight and branched chain alkyl groups, except that at least one triple bond exists between two carbon atoms. Thus, alkynyl groups have from 2 to about 20 carbon atoms, and typically from 2 to 12 carbons or, in some embodiments, from 2 to 8, 2 to 6, or 2 to 4 carbon atoms. Examples include, but are not limited to, -C≡CH, -C≡C(CH₃), -C≡C(CH₂CH₃), -CH₂C≡CH, -CH₂C≡C(CH₃), and -CH₂C≡C(CH₂CH₃), among others. Representative substituted alkynyl groups may be mono-substituted or substituted more than once, such as, but not limited to, mono-, di- or tri-substituted with substituents such as those listed above.

[0046] Aryl, or arene, groups are cyclic aromatic hydrocarbons that do not contain heteroatoms. Aryl groups include monocyclic, bicyclic and polycyclic ring systems. Thus, aryl groups include, but are not limited to, phenyl, azulenyl, heptalenyl, biphenylenyl, indacenyl, fluorenyl, phenanthrenyl, triphenylenyl, pyrenyl, naphthacenyl, chrysenyl, biphenyl, anthracenyl, indenyl, indanyl, pentalenyl, and naphthyl groups. In some embodiments, aryl groups contain 6-14 carbons, and in others from 6 to 12 or even 6-10 carbon atoms in the ring portions of the groups. Although the phrase "aryl groups" includes groups containing fused rings, such as fused aromatic-aliphatic ring systems (e.g., indanyl, tetrahydronaphthyl, and the like), it does not include aryl groups that have other groups, such as alkyl or halo groups, bonded to one of the ring members. Rather, groups such as tolyl are referred to as substituted aryl groups. Representative substituted aryl groups may be mono- substituted or substituted more than once. For example, monosubstituted aryl groups include, but are not limited to, 2-, 3-, 4-, 5-, or 6-substituted phenyl or naphthyl groups, which may be substituted with substituents such as those listed above.

[0047] The term "aryl," as used herein, refers to stable mono- or polycyclic, unsaturated moieties having preferably 3-14 carbon atoms, each of which may be substituted or unsubstituted. Substituents include, but are not limited to, any of the substituents mentioned below, i.e., the substituents recited below resulting in the formation of a stable compound. The term aryl may refer to a mono- or bicyclic carbocyclic ring system having one or two aromatic rings including, but not limited to, phenyl, naphthyl, tetrahydronaphthyl, indanyl, indenyl and the like. [0048] The term "heteroaryl," as used herein refers to a stable heterocyclic or polyheterocyclic, unsaturated radical having from five to ten ring atoms of which one ring atom is selected from S, O and N; zero, one or two ring atoms are additional heteroatoms independently selected from S, O and N; and the remaining ring atoms are carbon, the radical being joined to the rest of the molecule via any of the ring atoms. Heteroaryl moieties may be substituted or unsubstituted. Substituents include, but are not limited to, any of the substituents mentioned below, i.e., the substituents recited below resulting in the formation of a stable compound. Examples of heteroaryl nuclei include pyridyl, pyrazinyl, pyrimidinyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isooxazolyl, thiadiazolyl, oxadiazolyl, thiophenyl, furanyl, quinolinyl, isoquinolinyl, and the like.

[0049] It will also be appreciated that aryl and heteroaryl moieties, as defined herein, may be attached via an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, alkyl or heteroalkyl moiety and thus also include -aliphatic)aryl, -(heteroaliphatic)aryl, - (aliphatic)heteroaryl, -(heteroa-liphatic)heteroaryl, -alkyl)aryl, -(heteroalkyl)aryl, - (heteroalkyl)aryl, and -heteroalkyl)-heteroaryl moieties. Thus, as used herein, the phrases "aryl or heteroaryl" and "aryl, heteroaryl, -(aliphatic)aryl, -(heteroaliphatic)aryl, - (aliphatic)heteroaryl, -(heteroaliphatic)heteroaryl, -(alkyl)aryl, -(heteroalkyl)aryl, - (heteroalkyl)aryl, and -(heteroalkyl)heteroaryl" are interchangeable.

[0050] "Alkoxy" refers to the group -O-alkyl wherein alkyl is defined herein. Alkoxy includes, by way of example, methoxy, ethoxy, «-propoxy, isopropoxy, «-butoxy, t-butoxy, sec-butoxy, and ft-pentoxy.

[0051] "Thiol" refers to the group -S-alkyl wherein alkyl is defined herein, and R is either H or alkyl.

[0052] "Cyano" refers to the group -CN. "Carbonyl" refers to the divalent group

-C(O)- which is equivalent to -C(=0)-. "Nitro" refers to the group -N0₂. "Oxo" refers to the atom (=0). "Sulfonyl" refers to the divalent group -S(0)₂-. "Thiol" refers to the group -SH. "Thiocarbonyl" refers to the divalent group -C(S)- which is equivalent to -C(=S)-.

"Hydroxy" or "hydroxyl" refers to the group -OH. [0053] The term "amine," as used herein, refers to one, two, or three alkyl groups, as previously defined, attached to the parent molecular moiety through a nitrogen atom. It can refer to alkyl-NH₂, (alkyl)₂NH, or (alkyl)₃N groups. The term "alkylamino" refers to a group having the structure -NHR' wherein R' is an alkyl group, as previously defined; and the term "dialkylamino" refers to a group having the structure— NR'R", wherein R' and R" are each independently alkyl groups. The term "trialkylamino" refers to a group having the structure -NR'R"R' ", wherein R', R", and R' " are each independently alkyl groups. Additionally, R', R", and/or R' ' ' taken together may optionally be -CH₂)_k- where k is an integer from 2 to 6. Examples of amino groups include, but are not limited to, methylamino, dimethylamino, ethylamino, diethylamino, diethylaminocarbonyl, methylethylamino, iso-propylamino, piperidino, trimethylamino, and propylamino.

[0054] The term "carboxylic acid," as used herein, refers to a group of formula -

C0₂H.

[0055] The terms "halo," "halide," and "halogen," as used herein, refers to an atom selected from fluorine, chlorine, bromine, and iodine.

[0056] The term "methylol," as used herein, refers to an alcohol group of structure -

CH₂OH.

[0057] The term "heterocyclic," as used herein, refers to a non-aromatic partially unsaturated or fully saturated 3- to 10-membered ring system, which includes single rings of 3 to 8 atoms in size and bi- and tri-cyclic ring systems which may include aromatic six- membered aryl or aromatic heterocyclic groups fused to a non-aromatic ring. Heterocyclic moieties may be substituted or unsubstituted. Substituents include, but are not limited to, any of the substituents mentioned below, i.e., the substituents recited below resulting in the formation of a stable compound. Heterocyclic rings include those having from one to three heteroatoms independently selected from oxygen, sulfur, and nitrogen, in which the nitrogen and sulfur heteroatoms may optionally be oxidized and the nitrogen heteroatom may optionally be quaternized. [0058] The term "acyl," as used herein, refers to a group comprising a carbonyl group of the formula C=0. Examples of acyl groups include aldehydes, ketones, carboxylic acids, acyl halides, anhydrides, thioesters, amides, urea, carbamate, and carboxylic esters.

[0059] The term "polydispersity index" (PDI), as used herein is a ratio of the weight average molecular weight to the number average molecular weight, which is a measure of the breadth of molecular weight distribution within a sample.

[0060] Currently available treatments for Osteoarthritis(OA) are focused on relieving the symptoms of OA, such as pain, without necessarily affecting the progression of joint damage. Such treatments primarily involve nonsteroidal anti-inflammatory drugs which exhibit several side effects and are only temporarily effective. In addition to providing pain relief, therapies which provide lubrication, as well as chondroprotection by preventing the loss or encouraging the re-growth or healing of damaged joints and cartilage, are highly desirable.

[0061] As used herein, an alkali metal is a member of the first column of the periodic table, including Li, Na, K, Cs, and b. As used herein, an alkaline earth metal is a member of the second column of the periodic table including, Be, Ca, Mg, Sr, and Ba.

Polymers and Compositions

[0062] In general, the present technology is directed to polymers which mimic or have superior properties than that of natural polysaccharides found in vivo, and which have a specific molecular weight range that provides a wide variety of desirable attributes. Outside of this range the polymer performance is poorer. The polymers, which can be viscous liquids or gels, are potential "bio -lubricants" that can find various applications in the biotechnology, pharmaceutical and medical fields.

[0063] Although it is known that certain hydrophilic polymers can be used as medical lubricants and gels, it has surprisingly been observed that oxonorbornene polymers having a certain range of average molecular weight exhibit characteristics necessary for use as an ideal viscosupplement. These polymers have the proper friction properties, including rheology, viscosity and friction data essential for viscosupplement use. Moreover, it has been surprisingly found that these oxonorbornene polymers having the specific average molecular weight are found to exhibit excellent in vivo chondroprotection in addition to their function as bio-lubricants in joints.

[0064] Thus, in one aspect, a polymer is provided, wherein the polymers have at least one of the following repeat units:

II III

1 2

[0065] In Formulas I, II and III, R and R are either the same or different and are individually H, COOR³, COCH₃, CONHR⁴, OR⁴ or SR⁴. For each occurrence of R³ in Formulae I, II or III, R is independently H, an alkali metal, an alkaline earth metal, a polyethylene glycol group, a triethylene glycol group, an ammonium group, a C2-C20 alkyl, an alkenyl, an alkynyl, COCH₃, CH₂CH₂OH, or (CH₂CH₂0)_nR⁵. In Formulae I, II and III each occurrence of R⁴ is independently H, an alkali metal, an alkaline earth metal, a polyethylene glycol group, a triethylene glycol group, an ammonium group, an alkyl, an alkenyl, an alkynyl, COCH₃, CH₂CH₂OH, or (CH₂CH₂0)_nR⁵, while each R⁵ is independently H, alkyl, alkenyl, or alkynyl; and wherein the polymer has a number average molecular weight from 1,500,000 g/mol to 2,500,000 g/mol; and with the proviso that both R¹ and R² are not H.

1 3

[0066] In some embodiments, R is H and R2 is COOR . In some other embodiments,

3 3

R is H, while according to some other embodiments, R is C2-C20 alkyl, aryl, an alkali metal, an alkaline earth metal, or an ammonium group. In some embodiments, R is C2-C8 alkyl, or a polyethylene glycol. In some embodiments, R is triethylene glycol. In other

embodiments, R is an alkali metal. Suitable alkali metals include, but are not limited to, Li,

Na, K, Cs, Ca, Mg, or Ba. In an illustrative embodiment, R is sodium. [0067] The polymers may have a number average molecular weight of from about

1,500,000 g/mol to about 2,500,000 g/mol. In various embodiments, the a number average molecular weight of the polymer is about 1,500,000; 1,600,000; 1,700,000; 1,800,000;

1,900,000; 2,000,000; 2,100,000; 2,200,000; 2,300,000; 2,400,000; or 2,500,000 g/mol, where any stated values can form a lower and/or upper endpoint of a number average molecular weight range as appropriate. In one preferred embodiment, the a number average molecular weight of the polymer is about 2,000,000 g/mol.

[0068] In one preferred embodiment, R¹ is H; R₂ is COOR³; R³ is H, Li, Na, K, Cs,

Ca, Mg, Ba, or a polyethylene glycol group; and the polymer has a number average molecular weight from about 1.8 x 10⁶ g/mol to about 2.2 x 10⁶ g/mol. In some such preferred

3 3 embodiments, R is H, Li, Na, or K. In some such preferred embodiments, R is triethylene glycol.

[0069] In another aspect, a polymer may be generally represented as:

In such a polymer, R⁶, R⁷, R⁸, R⁹, R¹⁰, and R¹¹ are individually H, COOR³, COCH₃,

CONHR⁴, OR⁴ or SR⁴, with the proviso that at least one of R⁶, R⁷, R⁸, R⁹, R¹⁰, and R¹¹ is other than H. For the polymer, each occurrence of R is independently H, an alkali metal, an alkaline earth metal, a polyethylene glycol group, a triethylene glycol group, an ammonium group, a C₂-C₂₀ alkyl, an alkenyl, an alkynyl, COCH₃, CH₂CH₂OH, or (CH₂CH₂0)_nR⁵. For the polymer illustrated above, each occurrence of R⁴ is independently H, an alkali metal, an alkaline earth metal, a polyethylene glycol group, a triethylene glycol group, an ammonium group, an alkyl, an alkenyl, an alkynyl, COCH₃, CH₂CH₂OH, or (CH₂CH₂0)_nR⁵. Each occurrence of substituent R⁵ is independently H, an alkyl, an alkenyl, or an alkynyl.

Subscript n is an integer from 1 to 20, while repeat units x, y, and z can be the same or different and are randomly distributed throughout the polymer. The polymer illustrated has a number average molecular weight from 1,500,000 g/mol to 2,500,000 g/mol. [0070] In some embodiments, ⁶ or R⁷; R⁸ or R⁹; and R¹⁰ or R¹¹ are H. In some other embodiments, R⁶ or R⁷; R⁸ or R⁹; and R¹⁰ or R¹¹ are individually COOR³. According to one embodiment, R⁶, R⁸, and R¹⁰ are H; and R⁷, R⁹, and R¹¹ are individually COOR³. In some embodiments, where present, each R is individually H, C₂-C8 alkyl, an alkali metal, or an alkaline earth metal; or each R⁴ is individually H, Ci-C₈ alkyl, an alkali metal, or an alkaline earth metal. In some embodiments, at least one R³ or R⁴ is Li, Na, K, Cs, Ca, Mg, or Ba. In other embodiments, at least one R³ or R⁴ is a triethylene glycol group. In some embodiments, R⁶, R⁸, and R¹⁰ are H; and R⁷, R⁹, and R¹¹ are individually COOR³; R³ is H, Li, Na, K, Cs, Ca, Mg, Ba or triethylene glycol; and the number average molecular weight of the polymer is from 1.8 x 10⁶ g/mol to 2.2 x 10⁶ g/mol.

[0071] Depending upon the conditions employed for polymerization, the above polymers have a low polydispersity index (PDI). In some embodiments, the polymer has a PDI of from about 1 to about 2. In some embodiments, the polymer has a PDI of from about 1 to about 1.5. In some embodiments, the PDI is from about 1 to about 1.9, from about 1 to about 1.8, from about 1 to about 1.7, from about 1 to about 1.6, from about 1 to about 1.5, from about 1 to about 1.4, from about 1 to about 1.3, from about 1 to about 1.2, from about 1 to about 1.1. In some embodiments, the PDI is about 1. In some embodiments, the PDI is about 1.1. In some embodiments, the PDI is about 1.2. In some embodiments, the PDI is about 1.3.

[0072] The above polymers can be viscous liquids or gels. For example, the polymer may be dissolved or suspended in an aqueous vehicle. In some embodiments, the polymer is dissolved or suspended in an aqueous vehicle from about 0.1 to about 99 wt%. In other embodiments, the polymer is dissolved or suspended in an aqueous vehicle from about 0.1 wt% to about 75 wt%, from about 0.1 wt% to about 50 wt%, from about 0.1 wt% to about 25 wt%, or from about 0.1 wt% to about 15 wt%. In some embodiments, the polymer is prepared as an aqueous solution from about 0.1 wt% to about 10 wt%.

[0073] In another aspect, the present technology provides pharmaceutical

compositions which include one or more of the above polymers. In some embodiments, the composition includes at least one pharmaceutically acceptable carrier and at least one polymer represented by Formula I, II, or III, as described above. [0074] Also provided are polymers that can be formed using two or more of the polymers described above. The polymer may result from the formation of a direct or indirect linkage between the two or more polymers. Examples of direct linkages include covalent bonds and non-covalent bonds. Examples of covalent bonds include, but are not limited to, ester bond, ether bond, urea bond, amide bond, carbonate bond, thiocarbonate bond, thiourea bond, carbamate bond, urethane bond, shift base bond, peptide ligation (e.g, thiozolidine, N- thiazolidine), and carbon-carbon bond. Examples of non-covalent bonds include, but are not limited to, ionic bond, metal ligand bond, metal chelation bond (e.g., calcium or barium coordinated by a carboxylic acid), hydrogen bond, hydrophobic bond, fluorophobic bond, and van der Waals bond. Examples of indirect linkages include, but are not limited to, connecting molecules such as polyethylene glycol, polyacrylic glycol and natural polysaccharides, that can optionally be substituted, for example, with maleimide, activated ester, carboxylic acid, amine, thiol, cysteine, amino acid, acrylate, methacrylate, ester aldehyde, or aldehyde groups.

Preparation of Polymers

[0075] The polymers used in the present technology can be synthesized using commonly used polymerization methods known in the art. For example, in one embodiment, the polymers can be prepared using Ring Opening Metathesis Polymerization (ROMP) of a suitable cyclic olefin using suitable alkylidene catalyst. Significantly, preparation of polymers having specific molecular weight range, which possess desired properties including low coefficient of friction, shear thinning effect at high shear rate, good rheological properties, and moderate viscosity is provided. For example, in one embodiment, polymers which include repeating oxanorbornene units, having a specific range of molecular weights, were prepared according to the following synthetic Scheme I and screened for necessary viscosupplemental characteristics .

[0076] Scheme 1 illustrates the synthesis of a poly(5,6-dihydroxynorborane carboxylate)

(D) or a poly(5,6-dihydroxyoxanorbornane carboxylate) (E) via ROMP of a cyclic olefmic carboxylate (A). A cyclic carboxylate monomer (A) is dissolved in a solvent, and polymerized using a catalyst (a). The polymerization reaction was terminated. The olefinic bonds of the carboxylate polymer (B) may be hydrogenated to form an ethylene backbone polymer, or dihydroxylated to form the di-hydroxy compound (C). The esters of both B and C and may be saponified to produce the carboxylic acids (D) and (E), respectively. D may then be reacted with a reactive group (i.e. R"X in Scheme 1), resulting in functionalization of at least one of the carboxylate groups to provide polymer (F). Additionally, other carboxylate groups may be unsubstituted and/or converted to a carboxylate salt (i.e. M⁺ in Scheme 1). As used herein, an ethylene backbone polymer is one similar to that of polymers A or D above, but with the olefmic groups saturated by hydrogenation.

[0077] Suitable solvents for the preparation of the polymers in Step a include, for example, aromatic solvents, halogenated solvents, alkanes, alcohol, heterocyclic solvents and ketones. Such solvents include, but are not limited to, benzene, toluene, chloroform,

dichloromethane (i.e., methylene chloride), carbon tetrachloride, ethylene chloride, hexane, THF, acetone, dioxane, DMF, DMSO, acetonitrile, ethyl acetate, methanol, ethanol, diethyl ether, isopropanol, o-xylene, or a mixture of any two or more such solvents. In some embodiments, the solvent used in Step a is a mixture of benzene and dichloromethane. Suitable solvents for the dihydroxylation (e.g., Steps b and e) include, but are not limited to benzene, toluene, chloroform, dichloromethane (i.e., methylene chloride), carbon tetrachloride, ethylene chloride, hexane, THF, acetone, dioxane, DMF, DMSO, acetonitrile, ethyl acetate, methanol, ethanol, diethyl ether, isopropanol, o-xylene, or a mixture of any two or more such solvents. For conversion of the ester to a carboxylic acid (e.g., Steps c and d), suitable solvents include, but are not limited to alcohols such as, methanol, ethanol, or iso-propanol; tetrahydrofuran;acetone, dioxane, DMF, DMSO, acetonitrile, or a mixture of any two or more such solvents.

[0078] Any suitable termination agent known in the art can be used to achieve termination of the polymerization reaction. In some embodiments, termination of the

polymerization reaction may be accomplished by the addition of vinyl ethyl ether. [0079] As will be appreciated by one skilled in the art, the synthetic approach described above may be applied to the synthesis of polymers that contain substituents other than carboxylic groups.

[0080] Polymers of the present technology, or pharmaceutical compositions thereof, can be used as condroprotective agents, viscosupplements, viscoelastics, tissue space fillers, anti- adhesive agents, drug delivery agents and in various combination therapies.

[0081] In one aspect, methods for chondroprotection of a joint in a subject are provided.

In one embodiment, the method includes administering an effective amount of a polymer, or a pharmaceutical composition thereof to a subject in need thereof.

[0082] Chondroprotection refers to actions to prevent or slow down progression of cartilage wear, or regenerate cartilage from existing damages by a combination of biomechanical and biochemical reactions. Hyaluronic acid (HA)-derived viscosupplements have been widely used clinically to treat osteoarthritis. HA is a natural substance in synovial joints presumably providing part of cushioning and lubrication function to protect cartilage surfaces within joints. Despite its wide use, many physicians doubt effectiveness of the HA treatments.

[0083] The polymer may be prepared as a pharmaceutical composition prior to administration. The composition may include the polymer and a pharmaceutically acceptable carrier. For example, the polymer may be dissolved or suspended in an aqueous vehicle. In some embodiments, the polymer is dissolved or suspended in an aqueous vehicle from about 0.1 to about 99 wt%. In other embodiments, the polymer is dissolved or suspended in an aqueous vehicle from about 0.1 wt% to about 75 wt%, from about 0.1 wt% to about 50 wt%, from about 0.1 wt% to about 25 wt%, or from about 0.1 wt% to about 15 wt%. In some embodiments of the methods of administration, the polymer is prepared as an aqueous solution from about 0.1 wt% to about 10 wt%, prior to administering.

[0084] The efficacy of a polymer of Formula I, where R¹ is H and R² is COOH, has been demonstrated in an animal OA model - rat menisectomy model, a widely used model to evaluate efficacious chondroprotection by medical treatments. FIGs. 4-7 summarize the study results at two different concentrations (0.5% and 2.0%), of the polymer of the present technology, with 20 animals per group.

[0085] The degree of chondroprotection was evaluated by three criteria: substantial cartilage degradation width (FIG. 4A), osteophyte formation (FIG. 6A), and total joint score (FIG. 5A). The results clearly indicated chondroprotection. Bone score (FIG. 7A) showed no statistically significant difference between the treated and the saline control joint during the 3- week post injection period, supporting the hypothesis that chondroprotection was due to the treatment and not by reduced loading on the joints. In this model, Genzyme's Synvisc-One^® is not statistical different from saline (FIGs. 4B, 5B, 6B and 7B).

[0086] The above polymers were evaluated for their ability to alter the load bearing capacity of an arthritic joint in canines. FIG. 8 illustrates the results from a study that evaluated the efficacy of a polymer of the polymers in increasing the load bearing ability and bone score of joints, using a canine model of osteoarthritis. Briefly, dogs were treated with poly(2-(2-(2- methoxyethoxy)ethoxy)ethanamide l-5,6-dihydroxyoxanorbornane-2-carboxylate) (see Example 6) having a molecular weight of about 2,000,000 g/mol, at different concentrations (20 mg and 40 mg). Synvisc One^®, a cross-linked hyaluronan supplment currently available via prescription, was used as a control in this study. As illustrated by FIG. 8, the poly(2-(2-(2- methoxyethoxy)ethoxy)ethanamide l-5,6-dihydroxyoxanorbornane-2-carboxylate) (Poly), at both doses, was more effective at supplementing the synovial fluid in the joint and improving the joints shock absorbing ability that the Synvisc One^®. It was also observed that a higher bone score was measured for the joint when 40 mg polymer was administered rather than 20 mg.

[0087] The polymers used in the methods have repeat units and molecular weight ranges as defined above. In some embodiments, the polymer is a viscous liquid. In some other embodiments, the polymer is a gel.

[0088] Polymers of the present technology, or pharmaceutical compositions thereof, may be administered using any route of administration effective for achieving the desired effect. Administration will generally be local rather than systemic. Methods of local administration include, but are not limited to, dermal, intradermal, intramuscular, intraperitoneal, subcutaneous, ocular, and intra-articular routes. In some embodiments, the step of administering comprises performing a single injection. In some other embodiments, the step of administering comprises performing at least two injections. If two or more injections are used, they can be administered over a suitable period of time. Thus, in some embodiments, the two injections are performed at least 1 month apart, at least 2 months apart, at least 3 months apart, at least 4 months apart, at least 5 months apart, at least 6 months apart, at least 7 months apart, at least 8 months apart, at least 9 months apart, at least 10 months apart, at least 11 months apart, or at least 12 months apart. In some embodiments, the two injections are performed at least 6 months apart.

[0089] In some embodiments, the method includes performing local administration of an effective amount of the polymer to a tissue of the subject. In some embodiments, the tissue is a soft tissue. In some embodiments, the tissue is a diseased or injured synovial joint, and the polymer is used as a viscosupplement. In other embodiments, the diseased or injured synovial joint is an osteoarthritic joint or a joint-induced joint. In certain embodiments, the diseased or injured synovial joint can be a knee joint, hip joint, elbow joint, ankle joint, and wrist joint. In certain embodiments, the previously repaired synovial joint can be a knee joint, hip joint, elbow joint, ankle joint, and wrist joint. In another embodiment, the polymer is used as a

viscosupplement between a tissue and a metal or ceramic implant. In other embodiments, wherein the polymer is used as a tissue space filler, the tissue is diseased, injured or defective vocal cord; diseased, injured or defective urinary system; diseased, injured, deformed or aging dermal tissue; and diseased, injured or defective intervertebral disc.

[0090] In addition to viscosupplementation and chondroprotection of joints, the polymers of the present technology or pharmaceutical compositions thereof may find other applications, including, but not limited to, viscoelastics, tissue space fillers, anti-adhesive agents, drug delivery agents and in various combination therapies. For example, the subject to be treated using the polymers of the present technology may be undergoing surgery and the tissue to be treated may be involved in the surgery. In some embodiments, the surgery can be ophthalmic surgery and the polymer can then be used as a viscoelastic agent. In other embodiments, the surgery can be an abdominal or gynecological surgery and the polymer can then be used as an anti-adhesive agent. [0091] Examples of subjects that can be treated with the disclosed compositions include birds and mammals such as mice, rats, cows or cattle, horses, sheep, goats, cats, dogs, and primates, including apes, chimpanzees, orangutans, and humans. In one embodiment, the subject is a mammal. In some other embodiments, the subject is a human.

[0092] Dosing of these subjects is dependent on the severity and responsiveness of the infection to be treated, but will normally be one or more doses per day, with course of treatment lasting from several days to several months or until one of ordinary skill in the art determines the delivery should cease. Persons of ordinary skill can easily determine optimum dosage, dosing methodologies and repetition rates.

[0093] In some embodiments, the compositions further include one or more active agents. Additional active agents to be used in the compositions are described later in the application. Exemplary active agent include a growth factor, a cytokine, a small molecule, an analgesic, an anesthetic, an antimicrobial agent, an antibacterial agent, an antiviral agent, an antifungal agent, an antibiotic, an anti-inflammatory agent, an antioxidant, an antiseptic agent, and any combination thereof. In illustrative embodiments, the active agent is collagen, fat, silicone paste, TEFLON paste, calcium hydroxyapatite, hyaluronic acid, hyaluronates, and any combination thereof.

[0094] As indicated above, the polymers can find various applications in the

biotechnology, pharmaceutical and medical fields. For example, polymers of the present technology can be used in viscosupplementation, e.g., in the treatment of osteoarthritic or sport- injured knee joints. They can also be used as viscoelastics, for example, in ophthalmic surgery, as tissue space filler for cosmetic procedures or treatment of urinary incontinence, as anti- adhesives for wound care and as delivery agents.

[0095] Polymers of the present technology can be used as viscosupplements. As already mentioned above, viscosupplementation is a procedure involving injection of gel-like substances (generally hyaluronates, HAs) into a joint to supplement the viscous properties of synovial fluid. HA injections have been found to relieve pain in many osteoarthritis patients, with HAs of higher molecular weights (i.e., higher viscosity) showing better efficacy than those with lower molecular weights (i.e., lower viscosity). However, due to their short lifetime within the joint (about a couple of days), hyaluronate preparations currently available have only limited long- term benefit to the patient and require injection of large quantities of preparation and/or repeated injections.

[0096] Polymers of the present technology may find applications as viscoelastics useful in surgery. Viscoelastic agents used in surgery may perform a number of different functions, including, without limitation, maintenance and support of soft tissue, tissue manipulation, lubrication, tissue protection, and adhesion prevention. As will be appreciated by one skilled in the art, the rheological properties of the polymers will necessarily affect their ability to perform these functions, and, as a result, their suitability for certain surgical procedures.

[0097] Viscoelastics are, for example, used in ophthalmic surgery, such as cataract surgery. Cataracts, which are opacities of the natural ocular lens, can strike people in their 40s and 50s, but they occur most commonly in those over age 60, with a rapid increase in prevalence after that. More than 50% of all Americans 65 and older have cataracts, increasing to 70% among those over 75. In order to improve eyesight, the cataractous lens is surgically removed from the eye and an artificial intraocular lens is inserted in its place. Viscoelastics were introduced in the early 1980s in response to the observation that, during cataract surgery, the underside of the cornea was often damaged due to contact with instruments, devices, fluid bubbles, and intraocular lenses. Because the cells in this region cannot regrow, there was a need to protect them. Thus, during these surgical procedures, viscoelastic materials are typically injected into the anterior chamber of the eye to prevent collapse of the anterior chamber and to protect the delicate eye tissues from damage resulting from physical manipulation. Viscoelastics also gently inflate spaces inside the eye, making it easier to maneuver various tools inside the eye.

[0098] Other examples of ocular surgery procedures that employ viscoelastics include trabeculectomy (i.e., glaucoma filtration surgery) and vitrectomy (i.e., replacement of the vitreous, a normally clear, gel-like substance that fills the center of the eye) which may be performed to clear blood and debris from the eye, to remove scar tissue, or to alleviate traction on the retina. [0099] Polymers of the present technology may find applications as tissue space fillers in any of a wide variety of soft tissue augmentation procedures, including, but not limited to, reconstruction or cosmetic enhancement, treatment for stress urinary incontinence, and treatment of vocal cord problems (e.g., paralysis, atrophy or paresis).

[0100] Tissue space fillers are used to correct deformities or to reconstruct areas that are missing or defective due to surgical intervention, trauma, disease, aging, or congenital condition. Examples of reconstruction or cosmetic enhancement procedures include, but are not limited to, dermal tissue augmentation; filling of lines, folds, wrinkles, minor facial depressions, cleft lips and the like, especially in the face and neck; correction of minor deformities due to aging or disease, including in the hands and feet, fingers and toes; dermal filling of sleep lines and expression lines; replacement of dermal and subcutaneous tissue lost due to aging; lip augmentation; filling of crow's feet and the orbital groove around the eye; breast augmentation; chin augmentation; augmentation of the cheek and/or nose; filling of indentations in the soft tissue, dermal or subcutaneous, due to, e.g., overzealous liposuction or other trauma; filling of acne or traumatic scars and rhytids; filling of nasolabial lines, nasoglabellar lines and infraoral lines.

[0101] Urinary incontinence is an underserved market: There are approximately 40 million people in the U.S. that suffer from urinary incontinence, yet there are only about 250,000 procedures performed each year. Collagen bulking agents are generally used to treat urinary incontinence. They are injected into tissue surrounding the urethra to tighten the urethral sphincter and stop urine from leaking. However, these agents require several injections across multiple appointments. They also have a poor cure rate of approximately 27% to 36%. If the procedure is successful, the success is only temporary as the collagen reabsorbs into the surrounding tissue. A carbon-bead based product (Duraspheremi, Advanced UroScience, Inc., Saint Paul, MN) entered the market in 1999 with the promise of permanence (due to less degradation of the material), but clinical data have not supported those claims and the product appears to have similar performance to collagen. Q-Med AB (Uppsala, Sweden) recently introduced Zuidexml, an HA gel which is reinforced by the addition of dextranomer that promises immediate effects and ease of administration. New biomaterials, such as the described polymers, could impact the market if they require less material, fewer injections and had better longevity.

[0102] In vocal cord disorders such as paralysis, atrophy and paresis, one or both vocal cords are weakened and lack the ability to close and thus vibrate properly, resulting in a soft, breathy or weak voice. The affected cord may also allow food and liquids into the trachea or lungs causing difficulty with swallowing and coughing. Vocal cord paralysis may be caused by chest and neck surgery, brain injury, neck injury, lung or thyroid cancer, certain neurologic conditions, or a viral infection. In older people, vocal cord atrophy is a common problem affecting voice production. Standard treatments of vocal cord disorders include voice therapy and surgery. In surgery, doctors attempt to add bulk to the injured vocal cord by injecting a substance (e.g., fat or collagen) into the cord. This moves the injured cord closer to the non- injured cord, allowing for better contact and improved speech and swallowing. Other substances are being studied for vocal cord augmentation including silicone paste, Teflon paste, calcium hydroxylapatite, and hyaluronic acid.

[0103] Polymers of the present technology may be used as anti-adhesives. Anti- adhesives are devices that keep tissues from abnormally joining together following surgery. These abnormal unions, called adhesions, may form between an incision in the abdominal wall and the small bowel after abdominal surgery, leading to chronic pain or even bowel obstruction. Adhesions also occur following gynecological surgery, resulting in fibrous scarring that may involve the uterus, bladder, bowel or ovaries and fallopian tubes, and that can, in the worst case, lead to infertility. A wide variety of approaches, including use of steroids, non-steroidal antiinflammatory drugs and minimally invasive surgical techniques, have been used in an attempt to prevent adhesions. However, biodegradable barriers appear to be the most promising tools available for keeping adjacent organs separate following surgery (R.B. Arnold et al., Fertil. Steril., 2000, 73: 157-161). Examples of such barriers include, but are not limited to, anti- adhesive membranes that may be laid on localized areas of the peritoneum, such as Interceed Absorbable Adhesion Barrier (Johnson & Johnson Patient Care Inc., New Brunswick, NJ);

Preclude Surgical Membrane (E.L. Gore Co., Flagstaff, AZ) and Seprafilm Surgical Membrane (Genzyme, Cambridge, MA); and viscous gels, such as Hyskon (Pharmacia, Piscataway, NJ); Sepracoat (Genzyme) and Intergel (Lifecore Biomedical, Inc., Chaska, MN).

[0104] The polymers of the present technology, which can be viscous liquids or gels, can be used as delivery agents. For example, a polymer can be used to deliver one or more substances at the location where the polymer is injected (or applied) (e.g., joint, intervertebral disc, urinary system, skin).

[0105] Substances that can be delivered using the polymers include any molecule, agent or compound that is suitable to be delivered to a patient at the location where the polymer is to be injected or applied. For example, a suitable substance may be one or more of a growth factor, a cytokine, a small molecule, an analgesic, an anesthetic, an antimicrobial agent, an antibacterial agent, an antiviral agent, an antifungal agent, an antibiotic, an anti- inflammatory agent, an antioxidant, and an antiseptic agent.

[0106] Association between the polymer and substance may be covalent or non-covalent, direct or through a linker (e.g., a bifunctional agent). The association may be achieved by taking advantage of functional groups present on the polymer and substance. As can be readily appreciated by those skilled in the art, a polymer may be associated with any number of substances, which can be identical or different. In certain embodiments, the association between the polymer and substance is such that, in vivo, the substance is released from the polymer.

[0107] Additional uses and applications of the polymers will be immediately apparent to those skilled in the art.

[0108] In a method of treatment of the present technology, the polymer, or a

pharmaceutical composition thereof, will generally be administered in such amounts and for such a time as is necessary or sufficient to achieved at least one desired result. As will be appreciated by one skilled in the art, the desired result may vary depending on the condition to be treated (e.g. , osteoarthritis, cataract, dermal or subcutaneous tissue loss, urinary incontinence, or vocal cord disorder) and the purpose of the polymer (e.g. , viscosupplementation, tissue augmentation, adhesion prevention, or soft tissue maintenance, support or protection). Thus, for example, in certain embodiments, a polymer of the present technology may be administered to the knee joint of a patient suffering from osteoarthritis in such amounts and for such a time that it provides pain relief, prevents or reduces swelling, prevents or reduces loss of motion of the joint and/or or improves motion of the joint. In other embodiments, a polymer of the present technology may be administered to the eye of a patient undergoing cataract surgery in such amounts that it allows maintenance and support of soft tissue, tissue manipulation, lubrication, tissue protection, or adhesion prevention. In yet other embodiments, a polymer of the present technology may be administered to the skin of a patient undergoing a cosmetic procedure in such amounts and for such a time that lines, folds, wrinkles or minor facial depressions are filled.

[0109] A treatment according to the present technology may include a single dose or a plurality of doses over a period of time. Administration may be one or multiple times daily, weekly (or at some other multiple day interval) or on an intermittent schedule. The exact amount of the polymer, or a pharmaceutical composition thereof, to be administered will vary from subject to subject and will depend on several factors.

[01 10] Depending on the route of administration, effective doses may be calculated according to the body weight, body surface area, or organ size of the subject to be treated.

Optimization of the appropriate dosages can readily be made by one skilled in the art in light of pharmacokinetic data observed in human clinical trials. Alternatively or additionally, the dosage to be administered can be determined from studies using animal models for the particular type of condition to be treated, and/or from animal or human data obtained from agents which are known to exhibit similar pharmacological activities. The final dosage regimen will be determined by the attending surgeon or physician, considering various factors which modify the action of active agent, e.g., the agent's specific activity, the agent's specific half-life in vivo, the severity of the condition and the responsiveness of the patient, the age, condition, body weight, sex and diet of the patient, the severity of any present infection, time of administration, the use (or not) of other concomitant therapies, and other clinical factors.

[01 11] It will be appreciated that methods of treatment of the present technology can be employed in combination with additional therapies (i.e., a treatment according to the present technology can be administered concurrently with, prior to, or subsequently to one or more desired therapeutics or medical procedures). The particular combination of therapies

(therapeutics or procedures) to employ in such a combination regimen will take into account compatibility of the desired therapeutics and/or procedures and the desired therapeutic effect to be achieved.

[01 12] Thus, for example, in methods where a polymer of the present technology is administered as a viscosupplement to a patient suffering from osteoarthritis, the patient may further receive a non-steroidal or steroidal antiinflammatory drug and/or may undergo physical therapy. Alternatively or additionally, the polymer may be administered in combination with another viscosupplement, e.g., hyaluronate, chitosan. Alternatively or additionally, the polymer may be administered in combination with another aqueous soluble polymer, e.g., PEG, PEO, PAA.

[01 13] In some embodiments the present technology, the polymer is administered as part of a surgical or clinical procedure. For example, a polymer used as a viscoelastic agent may be administered during cataract surgery. A polymer used as a tissue space filler may be

administered during surgery for the treatment of urinary incontinence, during a tissue augmentation procedure for treatment of vocal cord problems, or during a cosmetic procedure, e.g., for wrinkle filling. A polymer used as an anti-adhesive agent may be administered during abdominal or gynecologic surgery to prevent formation of adhesions following surgery.

[01 14] Methods of treatment according to the present technology, include administration of the polymer per se or in the form of a pharmaceutical composition. A pharmaceutical composition may include an effective amount of at least one polymer as described herein and at least one pharmaceutically acceptable carrier or excipient.

[01 15] Pharmaceutical compositions may be formulated according to general pharmaceutical practice (see, for example, Remington 's Pharmaceutical Sciences and

Encyclopedia of Pharmaceutical Technology, J. Swarbrick, and J.C. Boylan (Eds.), Marcel Dekker, Inc: New York, 1988). The optimal pharmaceutical formulation can be varied depending upon the route of administration and desired dosage. Such formulations may influence the physical state, stability, rate of in vivo release, and rate of in vivo clearance of the administered compounds. In illustrative embodiments, the formulation will produce liquid or semi-liquid (e.g., gel) pharmaceutical compositions.

[01 16] Pharmaceutical compositions may be formulated in dosage unit form for ease of administration and uniformity of dosage. The expression "unit dosage form," as used herein, refers to a physically discrete unit or amount of the polymer for the patient to be treated. Each unit contains a predetermined quantity of active material calculated to produce the desired effect. It will be understood, however, that the total dosage of the composition will be decided by the attending physician within the scope of sound medical judgment.

[01 17] Formulation of pharmaceutical compositions will mainly depend on the form of administration chosen. In certain embodiments, injectable formulations (e.g., solutions, dispersions, suspensions, emulsions) can be used, for example, for administration to a joint (e.g., knee), an intervertebral disc, the urinary system, or the vocal cord. Injectable formulations can also be used for certain reconstruction or cosmetic procedures. Other procedures may alternatively use gels, lotions, creams, ointments, plasters, bandages, sheets, foams, films, sponges, dressings, or bioadsorbable patches that can be applied to the area in need of treatment. [01 18] Physiologically acceptable carriers, vehicles, and/or excipients for use with pharmaceutical compositions of the present technology can be routinely selected for a particular use by those skilled in the art. These include, but are not limited to, solvents, buffering agents, inert diluents or fillers, suspending agents, dispersing or wetting agents, preservatives, stabilizers, chelating agents, emulsifying agents, anti-foaming agents, ointment bases, penetration enhancers, humectants, emollients, and skin protecting agents.

[01 19] Examples of solvents include water, Ringer's solution, U.S.P., isotonic sodium chloride solution, alcohols, vegetable, marine and mineral oils, polyethylene glycols, propylene glycols, glycerol, and liquid polyalkylsiloxanes. Inert diluents or fillers may be sucrose, sorbitol, sugar, mannitol, microcrystalline cellulose, starches, calcium carbonate, sodium chloride, lactose, calcium phosphate, calcium sulfate, or sodium phosphate. Examples of buffering agents include citric acid, acetic acid, lactic acid, hydrogenophosphoric acid, and diethylamine.

Suitable suspending agents include, for example, naturally-occurring gums (e.g., acacia, arabic, xanthan, and tragacanth gum), celluloses (e.g., carboxymethyl-, hydroxyethyl-, hydroxypropyl-, and hydroxypropylmethylcellulose), alginates and chitosans. Examples of dispersing or wetting agents are naturally-occurring phosphatides (e.g., lecithin or soybean lecithin), condensation products of ethylene oxide with fatty acids or with long chain aliphatic alcohols (e.g., polyoxyethylene stearate, polyoxyethylene sorbitol monooleate, and polyoxyethylene sorbitan monooleate).

[0120] Preservatives may be added to a pharmaceutical composition of the present technology to prevent microbial contamination that can affect the stability of the formulation and cause infection in the patient. Suitable examples of such preservatives include parabens (such as methyl-, ethyl-, propyl-, p-hydroxy-benzoate, butyl-, isobutyl- and isopropyl-paraben), potassium sorbate, sorbic acid, benzoic acid, methyl benzoate, phenoxyethanol, bronopol, bronidox, MDM hydantoin, iodopropylnyl butylcarbamate, benzalconium chloride, cetrimide, and benzylalcohol. Examples of chelating agents include sodium EDTA and citric acid.

[0121] Examples of emulsifying agents include naturally-occurring gums, naturally- occurring phosphatides (e.g., soybean lecithin, sorbitan mono-oleate derivatives), sorbitan esters, monoglycerides, fatty alcohols, and fatty acid esters (e.g., triglycerides of fatty acids). Anti- foaming agents usually facilitate manufacture of the composition, since they dissipate foam by destabilizing the air-liquid interface and allow liquid to drain away from air pockets. Examples of anti-foaming agents include simethicone, dimethicone, ethanol, and ether.

[0122] Examples of gel bases or viscosity- increasing agents are liquid paraffin, polyethylene, fatty oils, colloidal silica or aluminum, glycerol, propylene glycol, carboxyvinyl polymers, magnesium-aluminum silicates, hydrophilic polymers (such as, for example, starch or cellulose derivatives), water-swell able hydrocolloids, carragenans, hyaluronates, and alginates. Ointment bases suitable for use in the pharmaceutical compositions of the present technology may be hydrophobic or hydrophilic; and specific examples include paraffin, lanolin, liquid polyalkylsiloxanes, cetanol, cetyl palmitate, vegetable oils, sorbitan esters of fatty acids, polyethylene glycols, and condensation products between sorbitan esters of fatty acids, ethylene oxide (e.g., polyoxyethylene sorbitan monooleate), and polysorbates.

[0123] Examples of humectants are ethanol, isopropanol glycerin, propylene glycol, sorbitol, lactic acid, and urea. Suitable emollients include cholesterol and glycerol. Examples of skin protectants include vitamin E, allatoin, glycerin, zinc oxide, vitamins, and sunscreen agents.

[0124] In certain embodiments, pharmaceutical compositions of the present technology may, alternatively or additionally, include other types of excipients such as, thickening agents, bioadhesive polymers, and permeation enhancing agents.

[0125] Thickening agents are generally used to increase viscosity and improve bioadhesive properties of pharmaceutical compositions. Examples of thickening agents include, but are not limited to, celluloses, polyethylene glycol, polyethylene oxide, naturally occurring gums, gelatin, karaya, pectin, alginic acid, and povidone. In certain embodiments, a thickening agent is selected for its thioxotropic properties (i.e., has a viscosity that is decreased by shaking or stirring). The presence of such as an agent in a pharmaceutical composition allows the viscosity of the composition to be reduced at the time of administration to facilitate its application, e.g., to a skin area to be repaired, and to increase after application so that the composition remains at the site of administration. [0126] Permeation enhancing agents are vehicles containing specific agents that affect the delivery of active components through the skin. Permeation enhancing agents are generally divided into two classes: solvents and surface active compounds (amphiplilic molecules).

Examples of solvent permeation enhancing agents include alcohols (e.g, ethyl alcohol, isopropyl alcohol), dimethyl formamide, dimethyl sulfoxide, 1 -dodecylazocyloheptan-2-one, N-decyl- methylsulfoxide, lactic acid, N,Ndiethyl-m-toluamide, N-methyl pyrrolidone, nonane, oleic acid, petrolatum, polyethylene glycol, propylene glycol, salicylic acid, urea, terpenes, and

trichloroethanol. The surfactant permeation enhancing agent in the present pharmaceutical compositions may be nonionic, amphoteric, cationic, anionic, or zwitterionic. Suitable nonionic surfactants include poly(oxyethylene)- poly(oxypropylene) block copolymers, commercially known as poloxamers; ethoxylated hydrogenated castor oils; polysorbates, such as Tween 20 or Tween 80. Amphoteric surfactants include quaternized imidazole derivatives; cationic surfactants include cetylpyridinium chloride, "soap" (fatty acid), alkylsulfonic acid salts (the main component of synthetic detergent, such as linear alkyl benzene sulfonate (LAS)), fatty alcohol sulfate (the main component of shampoo or old neutral detergents); and zwitterionic surfactants include the betaines and sulfobetaines.

[0127] Injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use, or by irradiation sterilization (e.g., gamma and e-beam).

[0128] In certain embodiments, the polymer(s) is(are) the only active ingredient(s) in the viscosupplementation composition. In other embodiments, the composition further includes one or more active agents. As already mentioned above, a active agent may be associated with the polymer. Alternatively or additionally, a active agent may be added to the composition of polymer and does not form any associations with the polymer.

[0129] As will be appreciated by one skilled in the art, selection of one or more active agents as component(s) of a pharmaceutical composition will be based on the intended purpose of the pharmaceutical composition (e.g., use in viscosupplementation in the treatment of joints, use as viscoelastics in cataract surgery, use as tissue space fillers for cosmetic procedures, treatment of urinary incontinence or treatment of vocal cord problems, or use as anti-adhesives for wound care).

[0130] In general, the amount of active agent present in the pharmaceutical composition will be the ordinary dosage required to obtain the desired result through local administration. Such dosages are either known or readily determined by the skilled practitioner in the pharmaceutical and/or medical arts.

[0131] Examples of active agents that can be present in a pharmaceutical composition of the present technology include, but are not limited to, analgesics, anesthetics, pain-relieving agents, antimicrobial agents, antibacterial agents, antiviral agents, antifungal agents, antibiotics, anti- inflammatory agents, antioxidants, antiseptic agents, antipruritic agents, immunostimulating agents, and dermatological agents. Specific examples of suitable active agents are provided and discussed below.

[0132] A active agent may be selected for its ability to prevent or alleviate pain, soreness or discomfort, to provide local numbness or anesthesia, and/or to prevent or reduce acute postoperative surgical pain. Thus, suitable pain relieving agents include, but are no limited to, compounds, molecules or drugs which, when applied locally, have a temporary analgesic, anesthetic, numbing, paralyzing, relaxing or calming effect.

[0133] Analgesics suitable for use in the present technology include non-steroidal, antiinflammatory drugs (NSAIDs). NSAIDs have analgesic, antipyretic and antiinflammatory activity. They act peripherally to provide their analgesic effect by interfering with the synthesis of prostaglandin, through cyclooxygenase (COX) inhibition. There are many different types of NSAIDs, including aspirin and other salicylates. Examples include, but are not limited to, ibuprofen, naproxen, sulindac, diclofenac, piroxicam, ketoprofen, diflunisal, nabumetone, etodolac, oxaprozin, and indomethacin. Aspirin is anti-inflammatory when administered in high doses, otherwise it is just a pain killer like acetaminophen. Acetaminophen has similar analgesic and antipyretic effects to the NSAIDs, but does not provide an anti-inflammatory effect. Several of the more potent NSAIDs have been developed into topical products for local administration to painful areas of the body. [0134] Analgesics suitable for use in the present technology also include opioids. As used herein, the term "opioid" refers to any agonists or antagonists of opioid receptors such as the μ-, K-, and δ-opioid receptors and different subtypes. Examples of opioids include, but are not limited to, alfentanil, allylprodine, alphaprodine, amiphenazole, anileridine,

benzeneacetamine, benzoylhydrazone, benzylmorphine, benzitramide, norbinaltorphimine, bremazocine, buprenorphine, butorphanol, clonitazene, codeine, cyclazocine, desomorphine, dextromoramide, dezocine, diampromide, dihydrocodeine, dihydrocodeine enol acetate, dihydromorphine, dimenoxadol, dimepheptanol, dimethylthiambutene, dioxaphetyl butyrate, dipipanone, diprenorphine, eptazocine, ethoheptazine, ethylketocyclazocine,

ethylmethylthiambutene, etonitazene, etorphine, fentanyl, hydrocodone, hydromorphone, hydroxypethidine, isomethadone, ketobemidone, levallorphan, levorphanol, lofentanil, loperamide, meperidine, meptazinol, metazocaine, methadone, metopon, morphine,

morphiceptin, myrophine, nalbuphine, nalmefene, nalorphine, naltrindole, naloxone, naltrexone, narceine, nicomorphine, norlevorphanol, normethadone, normorphine, norpipanone, opium, oxycodone, oxymorphone, papaveretum, papaverine, pentazocine, phenadoxone, phenazocine, phenoperidine, piminodine, piperidine, pirtramide, proheptazine, promedol, propiram, propoxyphene, remifentanil, spiradoline, sufentanil, tilidine, trifluadom, and active derivatives, prodrugs, analogs, pharmaceutically acceptable salts, or mixtures thereof.

[0135] Examples of peptide opioids include, but are not limited to, [Leu⁵] enkephalin,

[Met⁵] enkephalin, DynorphinA, Dynorphin B, a-Neoendorphin, β-Neoendorphin, βπ-ΕηάθΓρηίη, Deltorphin II, Morphiceptin, and active derivatives, analogs, pharmaceutically acceptable salts, or mixtures thereof.

[0136] Tricyclic antidepressants can be useful as adjuvant analgesics. They are known to potentiate the analgesic effects of opioids (V. Ventafridda et al., Paw, 1990, 43: 155-162) and to have innate analgesic properties (M.B. Max et al., Neurology, 1987, 37: 589-596; B.M. Max et al, Neurology, 1988, 38: 1427-1432; R. Kishore-Kumar et al, Clin. Pharmacol. Ther., 1990, 47: 305-312). Tricyclic antidepressants include, but are not limited to, amitriptyline, amoxapine, clomipramine, desipramine, doxepin, imipramine, nortriptyline, protriptyline, and trimipramine. [0137] Anesthetics that are suitable for use in the practice of the present technology include sodium-channel blockers. Examples of sodium-channel blockers include, but are not limited to, ambucaine, amolanone, amylcaine, benoxinate, benzocaine, betoxycaine,

biphenamine, bupivacaine, butacaine, butamben, butanilicaine, butethamine, butoxycaine, carticaine, chloroprocaine, cocaethylene, cocaine, cyclomethycaine, dibucaine, dimethisoquin, dimethocaine, diperodon, dyclonine, ecogonidine, ecogonine, etidocaine, euprocin, fenalcomine, form ocaine, hexylcaine, hydroxyteteracaine, isobutyl p-aminobenzoate, leucinocaine, levoxadrol, lidocaine, mepivacaine, meprylcaine, metabutoxycaine, methyl chloride, myrtecaine, naepaine, octacaine, orthocaine, oxethazaine, parenthoxycaine, phenacaine, phenol, piperocaine, piridocaine, polidocanol, pra.moxine, prilocaine, procaine, propanocaine, proparacaine, propipocaine, propoxycaine, pseudococaine, pyrrocaine, ropivacaine, salicyl alcohol, tetracaine, tolycaine, trimecaine, zolamine, and active derivatives, prodrugs, analogs, pharmaceutically acceptable salts, or mixtures thereof.

[0138] Local anesthetics with different pharmacodynamics and pharmacokinetics may be combined in the pharmaceutical composition in order to improve the effectiveness and tolerance of the composition. For example, the composition may include a euctectic mixture of lidocaine and prilocaine, or a mixture of lidocaine and tetracaine. It has been reported (see, for example, U.S. Pat. Nos. 5,922,340 and 6,046,187) that co-administration of a glucocorticosteroid and a local anesthetic may prolong or otherwise enhance the effect of local anesthetics. Examples of glucocorticosteroids include dexamethazone, cortisone, hydrocortisone, prednisone,

prednisolone, beclomethasone, betamethasone, flunisolide, fluocinolone, acetonide,

fluocinonide, triamcinolone, and the like.

[0139] Locally acting vasoconstrictive agents are also known to provide effective enhancement of local anesthesia, especially when administered through controlled release.

Examples of vasoconstrictor agents include, but are not limited to, catechol amines (e.g., epinephrine, norepinephrine and dopamine); metaraminol, phenylephrine, sumatriptan and analogs, alpha- 1 and alpha-2 adrenergic agonists, such as, for example, clonidine, guanfacine, guanabenz, and dopa (i.e., dihydroxyphenylalanine), methyldopa, ephedrine, amphetamine, methamphetamine, methylphenidate, ethylnorepinephrine ritalin, pemoline, and other sympathomimetic agents. [0140] Anti-infective agents for use in pharmaceutical compositions of the present technology are compounds, molecules or drugs which, when administered locally, have an anti- infective activity (i.e., they can decrease the risk of infection; prevent infection; or inhibit, suppress, combat or otherwise treat infection). Anti-infective agents include, but are not limited to, antiseptics, antimicrobial agents, antibiotics, antibacterial agents, antiviral agents, antifungal agents, anti-protozoan agents, and immunostimulating gents.

[0141] Antiviral agents suitable for use in the present technology include RNA synthesis inhibitors, protein, synthesis inhibitors, immunostimulating agents, and protease inhibitors. Antiviral agents may include, but are not limited to, acyclovir, amantadine hydrochloride, foscarnet sodium, ganciclovir sodium, phenol, ribavirin, vidarabine, or zidovudine.

[0142] Examples of suitable antifungal agents include, but are not limited to, lactic acid, sorbic acid, Amphotericin B, Ciclopirox, Clotrimazole, Enilconazole, Econazole, Fluconazole, Griseofulvin, Halogropin, Introconazole, Ketoconazole, Miconazole, Naftifme, Nystatin, Oxiconazole, Sulconazole, Thiabendazole, Terbinafme, Tolnaftate, Undecylenic acid, Mafenide, Silver Sulfadiazine, and Carbol-Fushsin.

[0143] Antibiotics and other antimicrobial agents may include, but are not limited to, bacitracin; the cephalosporins (such as cefadroxil, cefazolin, cephalexin, cephalothin, cephapirin, cephradine, cefaclor, cefamandole, cefonicid, ceforanide, cefoxitin, cefuroxime, cefoperazone, cefotaxime, cefotetan, ceftazidime, ceftizoxime, cefiriaxone, and meropenem); cycloserine; fosfomycin, the penicillins (such as amdinocillin, arnpicillin, amoxicillin, azlocillin,

bacamipicillin, benzathine penicillin G, carbenicillin, cloxacillin, cyclacillin, dicloxacillin, methicillin, mezlocillin, nafcillin, oxacillin, penicillin G, penicillin V, piperacillin, and ticarcillin); ristocetin; vancomycin; colistin; novobiocin; the polymyxins (such as colistin, colistimathate, and polymyxin B); the aminoglycosides (such as amikacin, gentamicin, kanamycin, neomycin, netilmicin, paromomycin, spectinomycin, streptomycin, and tobramycin), the tetracyclines (such as demeclocycline, doxycycline, methacycline, minocycline, and oxytetracycline); carbapenems (such as imipenem); monobactams (such as aztreonam);

chloramphenicol; clindamycin; cycloheximi de; fucidin; lincomycin; puromycin; rifampicin; other streptomycins; the macrolides (such as erythromycin and oleandomycin); the fluoroquinolones; actinomycin; ethambutol; 5-fluorocytosine; griseofulvin; rifamycins; the sulfonamides (such as sulfacytine, sulfadiazine, sulfisoxazole, sulfamethoxazole, sulfamethizole, and sulfapyridine); and trimethoprim.

[0144] Other antibacterial agents include, but are not limited to, bismuth containing compounds (such as bismuth aluminate, bismuth subcitrate, bismuth subgalate, and bismuth subsalicylate); nitrofurans (such as nitrofurazone, nitrofurantoin, and furazolidone);

metronidazole; imidazole; nimorazole; and benzoic acid.

[0145] Antiseptic agents may include, but are not limited to, benzalkonium chloride, chlorhexidine, benzoyl peroxide, hydrogen peroxide, hexachlorophene, phenol, resorcinol, and cetylpyridinium chloride.

[0146] The risk of infection is directly influenced by a suppressed immune system due to disease or medication. Immunostimulating agents are compounds, molecules or drugs that stimulate the immune system of a patient to respond to the presence of a foreign body, for example, by sending macrophages to the infected site(s). Immunostimulating agents suitable for use in the present technology may be selected from a wide range of therapeutic agents, such as interleukin 1 agonists, interleukin 2 agonists, interferon agonists, R A synthesis inhibitors, and T cell stimulating agents.

[0147] Anti-inflammatory agents for use in pharmaceutical compositions of the present technology are compounds, molecules or drugs which, when administered locally, have an antiinflammatory activity (i.e., they can prevent or reduce the duration and/or severity of inflammation; prevent or reduce injury to cells at the injured/damaged site; prevent or reduce damage or deterioration of surrounding tissue due to inflammation; and/or provide relief from at least one of the manifestations of inflammation such as erythema, swelling, tissue ischemia, itching, fever, scarring, and the like).

[0148] Anti- inflammatory agents include NSAIDs and steroidal anti-inflammatory agents. Examples of NSAIDs can be found above. Examples of steroidal antiinflammatory agents include but are not limited to, aclomethasone dipropionate, flunisolide, fluticasone, budesonide, triamcinolone, triamcinoline acetonide, beclomethasone diproprionate, betamethasone valerate, betamethasone diproprionate, hydrocortisone, cortisone, dexamethason, mometasone furoate, prednisone, methylprednisolone aceponate, and prednisolone.

[0149] Anti- inflammatory agents may, alternatively or additionally, be selected from the wide variety of compounds, molecules, and drugs exhibiting antioxidant activity. Antioxidants are agents that can prevent or reduce oxidative damage to tissue. Examples of antioxidants may include, but are not limited to, vitamin A (retinal), vitamin B (3,4-didehydroretinol), vitamin C (D-ascorbic acid, L-ascorbic acid), a-carotene, β-carotene, γ-carotene, δ-carotene, vitamin E (a-tocopherol), β-tocopherol, γ-tocopherol, δ-tocopherol, tocoquinone, tocotrienol, butylated hydroxy anisole, cysteine, and active derivatives, analogs, precursors, prodrugs,

pharmaceutically acceptable salts or mixtures thereof.

[0150] In certain embodiments, the active agent is a biomolecule that is naturally present in the body and/or that is naturally secreted at an injured or damaged site (i.e., body area) and plays a role in the natural healing process. As will be apparent to those of ordinary skill in the art, variants, synthetic analogs, derivatives, and active portions of these biomolecules can, alternatively, be used in the compositions as long as they exhibit substantially the same type of property/activity as the native biomolecule. Such variants, synthetic analogs, derivatives or active portions are intended to be within the scope of the term "active agents."

[0151] Bioactive biomolecules may be extracted from mammalian tissues and used in the pharmaceutical compositions either crude or after purification. Alternatively, they may be prepared chemically or by conventional genetic engineering techniques, such as via expression of synthetic genes or of genes altered by site-specific mutagenesis.

[0152] Examples of suitable bioactive biomolecules include cytokines and growth factors. Cytokines and growth factors are polypeptide molecules that regulate migration, proliferation, differentiation and metabolism of mammalian cells. A diverse range of these biomolecules have been identified as potentially playing an important role in regulating healing. Examples of cytokines include, but are not limited to, interleukins (ILs) (e.g., IL-I, 1L-2, IL-4 and IL-8), interferons (IFNs) (e.g., IFN-a, IFN-β, and IFN-γ), and tumor necrosis factors (e.g., TNF-a), or any variants, synthetic analogs, active portions or combinations thereof. Examples of growth factors include, but are not limited to, epidermal growth factors (EGFs), platelet- derived growth factors (PDGFs), heparin binding growth factor (HBGFs), fibroblast growth factors (FGFs), vascular endothelial growth factors (VEGFs), insulin-like growth factors (IGFs), connective tissue activating peptides (CTAPs), transforming growth factors alpha (TGF-a) and beta (TGF-β), nerve growth factor ( GFs), colony stimulating factors (GCSF and GM-CSF), and the like, or any variants, synthetic analogs, active portions or combinations thereof.

[0153] Other examples of suitable bioactive biomolecules include proteoglycans, or portions thereof. Proteoglycans are protein-carbohydrate complexes characterized by their glycosaminoglycan (GAG) component. GAGs are highly charged sulfated and carboxylated polyanionic polysaccharides. Examples of GAGs suitable for use in pharmaceutical

compositions of the present technology include, but are not limited to, hyaluronan, chondroitin sulfate, dermatan sulfate, heparan sulfate, and keratan sulfate.

[0154] Still other examples of suitable bioactive biomolecules include adhesion molecules. Adhesion molecules constitute a diverse family of extracellular and cell surface glycoproteins involved in cell-cell and cell-extracellular matrix adhesion, recognition, activation, and migration. Adhesion molecules are essential to the structural integrity and homeostatic functioning of most tissues, and are involved in a wide range of biological processes, including embryogenesis, inflammation, thrombogenesis, and tissue repair. Adhesion molecules include matricellular proteins (e.g., thrombospondins and tenascins), and cell surface adhesion molecules (e.g., integrins, selectins, cadherins, and immunoglobulins).

[0155] The present disclosure is not to be limited in terms of the particular embodiments described in this application, which are intended as illustrations of various aspects. Many modifications and variations can be made without departing from its spirit and scope, as will be apparent to those skilled in the art. Functionally equivalent methods and apparatuses within the scope of the disclosure, in addition to those enumerated herein, will be apparent to those skilled in the art from the foregoing descriptions. Such modifications and variations are intended to fall within the scope of the appended claims. The present disclosure is to be limited only by the terms of the appended claims, along with the full scope of equivalents to which such claims are entitled. It is to be understood that this disclosure is not limited to particular methods, reagents, compounds compositions or biological systems, which can, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting.

[0156] The present technology, thus generally described, will be understood more readily by reference to the following examples, which are provided by way of illustration and are not intended to be limiting of the present technology.

EXAMPLES

[0157] The following examples describe some of the preferred modes of making and practicing the present technology. However, it should be understood that these examples are for illustrative purposes only and are not meant to limit the scope of the technology. Furthermore, unless the description in an Example is presented in the past tense, the text, like the rest of the specification, is not intended to suggest that experiments were actually performed or data were actually obtained.

[0158] The present technology is further illustrated by the following examples, which should not be construed as limiting in any way.

[0159] All reactions were carried out at room temperature in oven-dried glassware. All solvents were distilled prior to use. Gel permeation chromatography (GPC) was performed with THF at a flow rate of 1 mL/min as eluent through a Waters HR-5 organic column or with 0.2 M NaN0₃, 0.01 M NaHP0₄ solution at a flow rate of 0.8 mL/min as eluent through Polymer Laboratories PL aquagel OH 60 column. The molecular weights were measured against Polystyrene standards (3,000 to 7,500,000 g/mol) or Dextran standards (40,000 to 600,000 g/mol). Gel permeation chromatography (GPC) was performed. Proton NMR v IR spectra were recorded on a Varian Inova 4000 MHz spectrometer (for ^!H and ¹³C at 400 and 100.6MHz, respectively), chemical shifts are reported downfield from tetramethylsilane in parts per million. Broad or overlapping peaks, often observed in the spectra of polymers are denoted "br" below.

[0160] Scheme 2 is a representation of the following examples.

[0161] Example 1: Synthesis of methyl-5-oxanorbornene-2-carboxylate (Scheme 2,

Compound A): Furan (18 mL, 247 mmol), methyl acrylate (16.2 mL, 180 mmol) and zinc iodide (17 g, 51 mmol) were stirred neat at 40°C for 48 hours. The solution was then diluted with 100 mL ethyl acetate and washed with 20 mL 0.1 M Na₂S0₃. After drying and filtration, the solvents were removed under reduced pressure to yield an orange liquid.

Vacuum distillation of the orange liquid yielded methyl -5-oxanorborne-2- carboxylate, compound A, as a colorless liquid. 1H NMR (400 MHz, CDC1₃) δ 6.37 (m, 2H), 5.00 (s, 1H), 4.70 (d, J = 4 Hz, 1H), 3.55 (s, 3H), 2.25 (m, 11-1), 1.95 (m, 1H), 1.35 (m, 1H). Shifts are consistent with the exo product. EI m/z = 155 (MH ).

[0162] Example 2: Synthesis of poly(methyl-5-oxanorbornane-2-carboxylate)

(Scheme 2, Compound B). Methy-5-oxanorbornane-2-carboxylate, A, (2 g, 12.9 mmol) was dissolved in 5 mL of benzene. (Dichloro(l,3-dimesityl-4,5-dihydroimidazol-2- ylidene)(phenylmethylene)-(tricyclohexylphosphine)ruthenium) (0.085 mg, 1 μιηοΐ) was then added and the solution was stirred under nitrogen for 4 hours. Ethyl vinyl ether was added to the solution and the solution was stirred for an additional 30 minutes to terminate the polymerization reaction. The solution was poured into 300 mL of methanol and the polymer precipitated. After washing the precipitate with methanol, and drying, poly(methyl-5- oxanorbornane-2-carboxylate), B, was obtained as a white polymer (yield 1.8 g 90 %). 1H NMR (400 MHz, CDC1₃) δ 5.8-5.4 (br, H-5,6), 5-4.4 (br, H-2), 3.6 (br, H ester), 3-1.7 (br, H- 1,3,4). M_w= 2,000,000; PDI = 1.3.

[0163] Example 3: Synthesis of poly(methyl-5,6-dihydroxyoxanorbornane-2- carboxylate) (Scheme 2, Compound C). Poly(ethyl-5-norbornene-2-carboxylate), B (1 g) and TEA-TFA (20 mL; tetraethyl amine - trifluoroacetic acid), were dissolved in CH₂C1₂ (20 mL) and cooled to 5°C with an ice bath. In another ice-cooled flask, 50% H₂0₂ (20 mL) was added to CH₂C1₂ (4.0 mL). To this solution trifluoroacetic anhydride (10 mL) was added drop-wise. The contents of the two flasks were then mixed and the resulting solution was heated at reflux for 18 hours. The solvents were then removed under reduced pressure. Water was added to the residual oil to precipitate a white polymer, C, in 93% yield. 1H NMR (400 MHz, DMSO) δ 5.0-3.0 (br, H-5,6 and OH), 3.6 (br, H ester), 2.5-2 (br, H-1,2,3,4). [0164] For polymer C, the olefinic protons were no longer present in the NM spectrum, and all new proton resonances were observed consistent with their structures.

[0165] Example 4: Synthesis of poly(5-oxanorbornane-2-sodium carboxylate salt)

(Scheme 2, Compound D). Poly(methyl-5-oxaborbornane-2-carboxylate) (B) (1 g) was dissolved in THF (250 mL) and NaOH 1 M (250 mL) was added. The solution was stirred under nitrogen for 24 hours. After evaporation of the organic solvent, polymer D was precipitated by adding HC1 (1M, 250 ml). Subsequent methanol washes and drying yielded 0.85 g (85% yield) of polymer D, a white polymer. 1H NMR (400 MHz, D₂0) δ 5.7-5.2 (br, H-5,6), 4.8-4.3 (br, H-2), 3.1-1.7 (br, H-1,3,4).

[0166] For polymer D, the ester protons were no longer present in the NMR spectrum, and the polymers were found to be water soluble.

[0167] Example 5: Synthesis of poly(5,6-dihydroxyoxanorbornane-2-carboxylic acid) (Scheme 2, Compound E, route e). The hydrophilic polymers was synthesized as follows: Polymers (1 g) was dissolved in water then NMO (1.2 eq by unit) and osmium tetroxide (catalytic amount) were added at room temperature. The solution was stirred for 24 hours at which point the products were precipitated by addition of 2 M HC1. The resulting polymers were dissolved in 1 M NaOH then dialyzed using a 3,400 Da cut-off to remove any resulting impurities. Again the polymers were precipitated by the addition of 1M HC1 to yield white, fibrous polymers 0.8 g (80% yield). 1H NMR (D₂0): δ 4.5-2.8 (br, H-5,6 and OH), 2.9-0.9 (br, H-l, 2, 3, 4).).

[0168] Example 5: Example 6: Synthesis of poly(2-(2-(2- methoxyethoxy)ethoxy)ethanamide 1 -5 ,6-dihydroxyoxanorbornane-2-carboxylate) (Scheme 2, Compound F). Poly(5-oxanorbornane-2-sodium carboxylate salt) (5 g) and 2-(2-(2- methoxyethoxy)ethoxy)ethanamine hydrochloride (2.5 g) in water (200 mL) and citrate buffer (1 M, pH 6, 150 mL). l-ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDCI; 5 g) is then added to the reaction and the reaction is left to react under strong agitation for 24 hours. The polymer is precipitated in HC1 2 M (500 ml) then dissolved in NaHC0₃ 1M (200 ml), precipitated again in HC1 2 M (500 ml), and dissolved back in NaHC0₃ 1M (200 ml). The solution is dialyzed to adjust the pH to 7.4 and to remove starting materials in excess. The product is freeze dry to yield a white polymer (95%). 1H NMR (400 MHz, D₂0) δ 5.7-5.2 (br m, H-5,6), 4.8-4.3 (br m, H-7), 3.4-3.6 (br m, CH₂ TEG), 3.2 (br m, CH₃ TEG), 3.2-1.7 (br m, H-1,2,3,4).

[0169] These transformations in backbone structure from polymers A to E were also monitored by infrared (IR) spectroscopy. The polyolefm B was found to possess IR absorption at 2360 cm^"1 for the alkene. Subsequent dihydroxylation and/or de-esterification of B afforded polymers E and D, respectively and the IR stretches for hydro xyl groups were observed at 3400 cm^"1.

[0170] Polymers B-E were found to display a range of physical properties consistent with their chemical composition. Polymer B is soluble in hydrophobic solvents such as benzene, toluene and chloroform (CHC1₃). The hydroxylated polymer C is not soluble in hydrophobic solvents and slightly soluble in methanol. The hydrophilic polymer D is slightly soluble in methanol and soluble in water, whereas polymers E is soluble only in water.

[0171] Example 7: Physical Properties of Polymers. The polymers prepared using the above methods were tested for their rheological properties, shear thinning properties, friction properties, viscosity and in-vivo chondroprotection.

[0172] Rheological experiments of these polymers were conducted and compared against normal Synovial Fluid (SF) and OA SF. As seen in FIG. 1, measurement of viscoelasticity (G', G") as a function of average molecular weight revealed that polymers with molecular weight≤ 1,000,000 g/mol exhibited too low G' and G" to be used as viscosupplements. G' is the storage modulus and G" is the loss modulus of the various polymers. Moreover, polymers having an average molecular weight of about 2,000,000 g/mol exhibited similar rheological properties as that of the normal SF.

[0173] Viscosity measurements were performed on a RA 1000 controlled strain rheometer from TA Instrument equipped with a peltier temperature control. A 40 mm diameter steel plate with a 2° angle with a gap of 47 um was used for the measurement of the viscosity properties. Viscosity measurement was performed at 25°C. An oscillatory frequency sweep (from 0.01 to 10 Hz) with a controlled strain for a linear response was performed at 25°C. This measures the viscosity of the material. Data are reported at a frequency of 1 Hz. Viscosity data obtained for polymers of the present technology are presented in FIG. 2. It was observed that polymers with molecular weight≤500,000 g/mol exhibited lack of shear thinning properties thereby disqualifying these polymers as potential viscosupplements (Figure 2). Polymers having an average molecular weight of > 1,000,000 g/mol exhibit sufficient shear thinning properties to consider these polymers for

viscosupplement use.

[0174] Coefficient of friction measurements were performed on a RA 1000 controlled strain rheometer from TA Instrument equipped with a peltier temperature control. A 40 mm diameter steel plate was used for the measurement of coefficients of friction. Coefficient of friction measurements were performed at 25°C. A normal force of 5N was applied to the viscoelastic material and an oscillatory frequency sweep (from 0.01 to 10 Hz) with a controlled strain of 1% was performed at 25°C. This measures the oscillation stress of the material, which can then be converted to coefficient of friction using the normal stress. Data are reported at a frequency of 1 Hz. The polymers were tested for their frictional properties and compared against Bovine SF and Synvisc^® as standards. Coefficients of friction for various polymers of the present technology are presented in FIG. 3. As seen from the figure, polymers with molecular weight of≤ 2,000,000 g/mol or > 3,000,000 g/mol have too high a coefficient of friction to be used as viscosupplements. On the other hand, polymers with molecular weight ranging from 2,000,000 g/mol to 3,000,000 g/mol have the proper friction properties essential for viscosupplement use, and had comparable friction properties to that of Bovine SF as well as Synvisc^®.

[0175] The polymers were evaluated for their chondroprotection properties based on three criteria, namely, substantial cartilage degradation width, osteophyte formation and total joint score. The results indicated that the polymers exhibit chondroprotective properties (Figures 4A-D).

[0176] It was surprisingly observed that the polymers having molecular weight of about 1,500,000 to about 2,500,000 best matched the necessary characteristics of an ideal viscosupplement and, therefore, can be effectively employed as viscosupplements for providing lubrication and chondroprotection of joints and tissues. [0177] The polymers also passed all biocompatible studies with no signs of toxicity.

These studies included sensitization tests, irritation tests, Ames reverse mutation assay, two- week muscle implantation test, cytotoxity tests and in vivo toxicity observation in mice.

[0178] Example 8: Demonstration of Chondroprotection in an Animal Model.

Poly(2-(2-(2-methoxyethoxy)ethoxy)ethanamide 1 -5 ,6-dihydroxyoxanorbornane-2- carboxylate) (designated as "Poly" in FIGs. 4-7 and prepared as in Example 6 and having a average molecular weight of 2 MDa was evaluated in the in vivo rat meniscal tear-MLC transaction model. Figures 4-7 summarize the results of the animal studies at two different concentrations of the Polymer (0.25% and 1.0 %) with 20 animals per group, and the degree of chondroprotection was evaluated in three criteria, namely, substantial cartilage degradation width, osteophyte formation, and total joint score. Total joint score, substantial cartilage degeneration width, and osteophyte measurement are indicators to measure severity of osteoarthritis. The results indicate chondroprotection. Bone showed no statistically significant difference between the treated and saline control joint during the 3 -week post injection period, supporting the hypothesis that chondroprotection was due to the treatment and not because of reduced loading on the joints. In an independent study of the same animal model, the commercially available HA viscosupplement, Synvisc-One™ was evaluated for its efficacy compared to a saline control. Those evaluation listed above showed no difference between Synvisc-One™ and saline (Figures 4B, 5B, 6B and 7B).

[0179] Example 9: The above polymers were evaluated for their ability to alter the load bearing capacity of an arthritic joint in canines. FIG. 8 illustrates the results from a study that evaluated the efficacy of a polymer of the polymers in increasing the load bearing ability and bone score of joints, using a canine model of osteoarthritis. Briefly, dogs were treated with poly(2-(2-(2-methoxyethoxy)ethoxy)ethanamide 1-5,6-dihydroxyoxanorbornane- 2-carboxylate); see Example 6, having a molecular weight of about 2,000,000 g/mol, at different concentrations (20 mg and 40 mg). Synvisc One^®, a cross-linked hyaluronan supplment currently available via prescription, was used as a control in this study. As illustrated by FIG. 8, the poly(5-oxanorbornane-2-sodium carboxylate salt) (Poly), at both doses, was more effective at supplementing the synovial fluid in the joint and improving the joints shock absorbing ability that the Synvisc One^®. It was also observed that a higher bone score was measured for the joint when 40 mg polymer was administered rather than 20 mg. EQUIVALENTS

[0180] While certain embodiments have been illustrated and described, it should be understood that changes and modifications can be made therein in accordance with ordinary skill in the art without departing from the technology in its broader aspects as defined in the following claims.

[0181] The embodiments, illustratively described herein may suitably be practiced in the absence of any element or elements, limitation or limitations, not specifically disclosed herein. Thus, for example, the terms "comprising," "including," "containing," etc., shall be read expansively and without limitation. Additionally, the terms and expressions employed herein have been used as terms of description and not of limitation, and there is no intention in the use of such terms and expressions of excluding any equivalents of the features shown and described or portions thereof, but it is recognized that various modifications are possible within the scope of the claimed technology. Additionally, the phrase "consisting essentially of will be understood to include those elements specifically recited and those additional elements that do not materially affect the basic and novel characteristics of the claimed technology. The phrase "consisting of excludes any element not specified.

[0182] The present disclosure is not to be limited in terms of the particular embodiments described in this application. Many modifications and variations can be made without departing from its spirit and scope, as will be apparent to those skilled in the art. Functionally equivalent methods and compositions within the scope of the disclosure, in addition to those enumerated herein, will be apparent to those skilled in the art from the foregoing descriptions. Such modifications and variations are intended to fall within the scope of the appended claims. The present disclosure is to be limited only by the terms of the appended claims, along with the full scope of equivalents to which such claims are entitled. It is to be understood that this disclosure is not limited to particular methods, reagents, compounds compositions or biological systems, which can of course vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting. [0183] In addition, where features or aspects of the disclosure are described in terms of Markush groups, those skilled in the art will recognize that the disclosure is also thereby described in terms of any individual member or subgroup of members of the Markush group.

[0184] As will be understood by one skilled in the art, for any and all purposes, particularly in terms of providing a written description, all ranges disclosed herein also encompass any and all possible subranges and combinations of subranges thereof. Any listed range can be easily recognized as sufficiently describing and enabling the same range being broken down into at least equal halves, thirds, quarters, fifths, tenths, etc. As a non-limiting example, each range discussed herein can be readily broken down into a lower third, middle third and upper third, etc. As will also be understood by one skilled in the art all language such as "up to," "at least," "greater than," "less than," and the like, include the number recited and refer to ranges which can be subsequently broken down into subranges as discussed above. Finally, as will be understood by one skilled in the art, a range includes each individual member.

[0185] Other embodiments are set forth in the following claims.

Claims

What is claimed is:

A ol mer havin at least one of the followin monomeric units:

I II in wherein:

R 1 and R 2 are either the same or different and are individually H, COOR³, COCH₃, CONHR⁴, OR⁴ or SR⁴;

each occurrence of R is independently H, an alkali metal, an alkaline earth metal, polyethylene glycol, triethylene glycol, ammonium, C2-C20 alkyl, alkenyl, alkynyl, COCH₃,

CH₂CH₂OH, (CH₂CH₂0)_nR⁵;

each occurrence of R⁴ is independently H, alkali metal, an alkaline earth metal, polyethylene glycol, triethylene glycol, ammonium, alkyl, alkenyl, alkynyl, COCH₃, CH₂CH₂OH, (CH₂CH₂0)_nR⁵;

each occurrence of R⁵ is independently H, an alkali metal, an alkaline earth metal, an alkyl, an alkenyl, or an alkynyl; and n is an integer from 1 to 20;

wherein the polymer has a number average molecular weight from 1,500,000 g/mol to 2,500,000 g/mol; and

with the proviso that both R 1 and R 2 are not H.

2. The polymer of Claim 1 , wherein R 1 is H and R₂ is COOR 3.

3. The polymer of Claim 1 or 2, wherein R is H, C₂-C₈ alkyl, an alkali metal, or an alkaline earth metal; or R⁴ is H, Ci-C₈ alkyl, an alkali metal, or an alkaline earth metal.

4. The polymer of any one of Claims 1-3, wherein at least one R is present and is H, Li, Na, K, Ca, Mg, or Ba.

5. The polymer of any one of Claims 1-3, wherein at least one R³, or at least one R⁴, is triethylene glycol.

6. The polymer of any one of Claims 1-5, wherein the number average molecular weight is about 2,000,000 g/mol.

7. The polymer of any one of Claims 1-6 having a PDI of from about 1 to about 2.

8. The polymer of Claim 1 , wherein R¹ is H, R² is COOR³, R³ is H, Li, Na, K, Ca, Mg, Ba, or triethylene glycol; and the number average molecular weight of the polymer is from 1.8 x 10⁶ to 2.2 x 10⁶ g/mol.

9. The polymer of any one of Claims 7 or 8, wherein the number average molecular weight of the polymer is about 2 x 10⁶ g/mol.

10. A pharmaceutical composition comprising an effective amount of at least one

polymer of Claim 1 and at least one pharmaceutically acceptable carrier.

11. The pharmaceutical composition of Claim 9 further comprising a active agent.

12. The pharmaceutical composition of Claim 10, wherein the active agent comprises a growth factor, a cytokine, a small molecule, an analgesic, an anesthetic, an antimicrobial agent, an antibacterial agent, an antiviral agent, an antifungal agent, an antibiotic, an anti-inflammatory agent, an antioxidant, an antiseptic agent, or a combination of any two or more thereof.

13. A method of chondroprotection of a joint comprising administering to the joint in a subject an effective amount of a polymer according to any one of Claims 1-9, wherein the polymer provides condroprotection.

14. The method of Claim 13, wherein R¹ is H, R² is COOR³, R³ is H, Li, Na, K, Ca, Mg, Ba, or triethylene glycol; and the number average molecular weight is from 1.8 x 10⁶ to 2.2 x 10⁶ g/mol.

15. The method of Claim 13 or 14, wherein the number average molecular weight is about 2 x 10⁶ g/mol.

16. The method of any one of Claims 13-15, wherein the administering comprises

performing local administration of an effective amount of the polymer to a tissue of the subject.

17. The method of any one of Claims 13-16, wherein the administering comprises

performing a single injection.

18. The method of any one of Claims 13-16, wherein the administering comprises

performing at least two injections.

19. The method of Claim 18, wherein the two injections are performed at least 6 months apart.

20. The method of any one of Claims 13-16, wherein the administering comprises

performing multiple injections.

21. The method of any one of Claims 13-20, wherein the tissue is a diseased or injured synovial joint, and the polymer is a viscosupplement.

22. The method of any one of Claims 13-20, wherein the administering comprises

performing local administration of an effective amount of the polymer to a joint of the subject that contains a ceramic or metal implant.

23. The method of any one of Claims 13-22 further comprising administering an effective amount of at least one active agent to the subject.

24. The method of Claim 23, wherein the active agent comprises a growth factor, a

cytokine, a small molecule, an analgesic, an anesthetic, an antimicrobial agent, an antibacterial agent, an antiviral agent, an antifungal agent, an antibiotic, an antiinflammatory agent, an antioxidant, an antiseptic agent, or a combination of any two or more thereof.

25. A polymer generally represented as:

wherein:

R⁶, R⁷, R⁸, R⁹, R¹⁰, and R¹¹ are individually H, COOR³, COCH₃, CONHR⁴, OR⁴ or SR⁴;

each occurrence of R is independently H, an alkali metal, an alkaline earth metal, a polyethylene glycol group, a triethylene glycol group, an ammonium group, a C2-C20 alkyl, an alkenyl, an alkynyl, COCH₃, CH₂CH₂OH, or (CH₂CH₂0)_nR⁵;

each occurrence of R⁴ is independently H, an alkali metal, an alkaline earth metal, a polyethylene glycol group, a triethylene glycol group, an ammonium group, an alkyl, an alkenyl, an alkynyl, COCH₃, CH₂CH₂OH, or (CH₂CH₂0)_nR⁵;

each occurrence of R⁵ is independently H, an alkali metal, an alkaline earth metal, an alkyl, an alkenyl, or an alkynyl; and

n is an integer from 1 to 20;

repeat units x, y, and z are the same or different and are randomly distributed throughout the polymer;

wherein the polymer has a number average molecular weight from

1,500,000 g/mol to 2,500,000 g/mol; and

with the proviso that at least one of R⁶, R⁷, R⁸, R⁹, R¹⁰, and R¹¹ is other than H.

26. The polymer of Claim 25, wherein R⁶ or R⁷; R⁸ or R⁹; and R¹⁰ or R¹¹ are H.

27. The polymer of Claim 25, wherein R⁶ or R⁷; R⁸ or R⁹; and R¹⁰ or R¹¹ are individually COOR³.

28. The polymer of Claim 25, wherein R⁶, R⁸, and R¹⁰ are H; and R⁷, R⁹, and R¹¹ are individually COOR³.

29. The polymer of any one of Claims 25-28, wherein each R is individually H, C₂-C8 alkyl, an alkali metal, or an alkaline earth metal; or each R⁴ is individually H, Ci-C₈ alkyl, an alkali metal, or an alkaline earth metal.

30. The polymer of any one of Claims 25-29, wherein at least one R³ or at least one R⁴ is H, Li, Na, K, Cs, Ca, Mg, or Ba.

31. The polymer of any one of Claims 25-29, wherein at least one R³ or at least one R⁴ is a triethylene glycol group.

32. The polymer of any one of Claims 25-31, wherein the polymer comprises from 100 to 200,000 x units, from 100 to 200,000 y units, and from 100 to 200,000 z units individually distributed throughout the polymer as a random polymer or a random block-co-polymer.

33. The polymer of any one of Claims 25-32, wherein the number average molecular weight is about 2,000,000 g/mol.

34. The polymer of any one of Claims 25-33 which has a polydispersity index of from about 1 to about 2.

35. The polymer of Claim 25, wherein R⁶, R⁸, and R¹⁰ are H; and R⁷, R⁹, and R¹¹ are individually COOR 3 ; R 3 is H, Li, Na, K, Cs, Ca, Mg, Ba, triethylene glycol, or a mixture of any two or more thereof; and the number average molecular weight of the polymer is from 1.8 x 10⁶ g/mol to 2.2 x 10⁶ g/mol.

36. A pharmaceutical composition comprising an effective amount of at least one

polymer according to any one of Claims 25-35, and at least one pharmaceutically acceptable carrier.

37. The pharmaceutical composition of Claim 36 further comprising an active agent.

38. The pharmaceutical composition of Claim 37, wherein the active agent comprises a growth factor, a cytokine, a small molecule, an analgesic, an anesthetic, an antimicrobial agent, an antibacterial agent, an antiviral agent, an antifungal agent, an antibiotic, an anti-inflammatory agent, an antioxidant, an antiseptic agent, or a combination of any two or more thereof.

39. A method comprising administering to a joint of a subject an effective amount of a polymer according to any one of Claims 25-35, wherein the polymer provides condroprotection to the joint.

40. The method of Claim 39, wherein ⁶, R⁸, and R¹⁰ are H; and R⁷, R⁹, and R¹¹ are individually COOR 3 ; R 3 is H, Li, Na, K, Cs, Ca, Mg, Ba, triethylene glycol, or a mixture of any two or more thereof; and the number average molecular weight of the polymer is from 1.8 x 10⁶ g/mol to 2.2 x 10⁶ g/mol.

41. The method of Claim 39 or 40, wherein the number average molecular weight of the polymer is about 2 x 10⁶ g/mol.

42. The method of Claim 39, 40, or 41, wherein the administering comprises performing local administration of an effective amount of the polymer to a tissue of the subject.

43. The method of any one of Claims 39-42, wherein the administering comprises

performing a single injection.

44. The method of any one of Claims 39-42, wherein the administering comprises

performing at least two injections.

45. The method of Claim 42, wherein each of the at least two injections are performed at least 6 months apart.

46. The method of any one of Claims 39-42, wherein the administering comprises

performing multiple injections.

47. The method of any one of Claims 42-46, wherein the tissue is a diseased or injured synovial joint, and the polymer is a viscosupplement.

48. The method of any one of Claims 39-47, wherein the administering comprises performing local administration of an effective amount of the polymer to a joint of the subject that contains a ceramic or metal implant.

49. The method of any one of Claims 39-48 further comprising administering an effective amount of at least one active agent to the subject with the polymer in a single injection to the joint, as separate injections to the joint, or systemically.

50. The method of Claim 49, wherein the active agent comprises a growth factor, a

cytokine, a small molecule, an analgesic, an anesthetic, an antimicrobial agent, an antibacterial agent, an antiviral agent, an antifungal agent, an antibiotic, an antiinflammatory agent, an antioxidant, an antiseptic agent, or a combination of any two or more thereof.