WO 2009/015274
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`DESCRIPTION
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`POLYETHYLENE BASED BlOAC‘TlVE AGENTS
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`GOVERNMENT SUPPORT
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`The subject matter of this application has been supported by research grants from the
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`National Science Foundation under grant numbers DMR—O703261 and DMR-03141 10.
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`Accordingly, the government has certain rights in this invention.
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`BACKGROUND OF THE INVENTION
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`The term “metathesis” refers to a mutual transalkylidenation of alkenes and alkynes in
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`the presence of catalysts. Reactions of this type are employed in many industrially important
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`processes. A review may be found in: M. Schuster, S. Bleehert, Angew. Chem, 1997,
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`109:2124; and S. Armstrong, J. Chem. Soc, Perkin Trans, 1998, 1:371. Metathesis reactions
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`include the oligomen'zation and polymerization of acyclic dienes (ADMET) and the synthesis
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`of carbocycles and heterocycles having various ring sizes by ring closing metathesis (RCM).
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`Crossed metatheses of different alkenes are also known (Brummer, O. et (2]., Chem. Eur. J,
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`1997, 3:441). For the aforementioned metathesis reactions, it is possible to use, for example,
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`the ruthenium—alkylidene compounds described in W’O—A—93/20111,
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`the ruthenium-based
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`catalyst systems described by A. W. Stumpf, E. Saive, A. Deomceau and A. F. Noels in J.
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`Chem. Soc., Chem. Commun, 1995, 1127—1128, or the catalyst systems described by P.
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`Schwab, R. H. Grubbs and J. W. Ziller in J. Am. Chem. Soc, 1996, 118, 100 (see also VVO
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`96/04289) as catalysts. The above publications, and all other publications, published patent
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`applications, and patents cited hereafter, are incorporated herein by reference in their entirety.
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`Metathesis chemistry has received much attention as a method to obtain precise
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`structural control in polymer synthesis. Recent advances include the synthesis of polyolefin
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`and polyolefin—like polymers through two—step procedures involving ADMET polymerization
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`or ring—opening metathesis polymerization (ROMP), followed by hydrogenation. Examples
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`of such polymerizations include perfectly linear polyethylene (O’Gara,
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`.l. E., et
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`(2]., die
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`MakromomoIekular'e Chemie, 1993, 141657; Grubbs, R. H. and W. Zhe, iMacromolecules,
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`1994, 27:6700), telechelic polyethylene (Hillinyer, M. A., “The Preparation of Functionalized
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`Polymers by Ring-Opening Metathesis Polymerization”, Ph.D. Dissertation, California
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`Institute of Technology, 1995), ethylene/Vinyl alcohol copolyiners (Valenti, D. J. and K. B.
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`Wagener, Macromolecules, 1998 31 22764) and polyethylene with precisely Spaced alkyl side
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`chains (Valenti, D. J. and K. B. Wagener, Macromolecules, 1997, 3026688). Polymerized
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`diencs
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`and methods
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`for preparing them by step propagation,
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`condensation type
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`polymerization of acyclic dienes are described in US. Patent No. 5,110,885 (Wagener et al.)
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`and US. Patent No. 5,290,895 (Wagener er a1)
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`ADMET chemistry—based methods for making polymers incorporating amino acids or
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`polypeptides, and the resulting polymers, are described in US. Patent No. 6,680,051
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`(Wagener er al.) and US. Patent No. 7,172,755 (Wagener ez‘ al.). Figure 1 ofU.S. Patent No.
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`6,107,237 shows some examples of metathesis reactions that are useful for constructing
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`molecules. In instances where it may be desirable that the products be free of carbon——carbon
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`multiple bonds, conversion of these multiple bonds to single bonds (hydrogenation) can
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`significantly influence physical and chemical properties, biological activity, oxidative
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`stability, etc. Substrates may contain a wide group of funetionalities. The potential scope of
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`application of this methodology is vast. The overall result of this process is the formation of
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`carbon—carbon single bonds.
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`This is highly useful
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`in organic synthesis. Unsaturated
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`vegetable oils may be functionalized by cross—metathesis with functionalized olefins and then
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`hydrogenated. Cyclic molecules may be constructed and then hydrogenated. Difunctional
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`monomers with long aliphatic chains, which may otherwise be difficult to product, may
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`easily be synthesized. U.S. Patent No. 4,496,758 describes metathesis and cross~metathcsis
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`of alkenyl esters to produce unsaturated monomers which can be used in polymer synthesis.
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`US. Patent No. 5,146,017 describes metathesis of partially fluorinated alkenes.
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`Metathesis chemistry has been shown to be effective in the synthesis of a broad range
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`of polymers. A common feature of all polymers produced via metathesis is unsaturation in
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`the main chain. Oxidative stability can be increased by removal of this unsaturation.
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`Therefore, polymers which may be difficult to synthesize (or even completely inaccessible)
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`by other means may be produced by metathesis and then value added by saturating the double
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`bonds.
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`Other properties may be manipulated such as
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`toughness,
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`thermal
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`stability,
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`permeability, crystallinity, etc.
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`Mctathesis polymers are often prepared, isolated, and purified plior to hydrogenation.
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`Additional hydrogenating
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`agents
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`are
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`then,
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`added
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`and hydrogenation is
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`effected.
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`Disadvantages are less of product during isolation and purification after the first step,
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`the
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`added effort to conduct reactions in additional vessels, use of additional reagents to effect
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`hydrogenation, and the isolation and purification of the polymer from reagents used in the
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`hydrogenation.
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`These syntheses typically involve first the synthesis and isolation of unsaturated
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`polymers followed by a second hydrogenation step. Two of the more successful methods for
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`hydrogenation are diimide reduction (Valenti, D. I. and K. B. Wagener, supra, 1997) and
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`catalytic hydrogenation with Crabtree's iridium complex (Hillmyer, M. A., supra, 1995). The
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`Valenti method requires an excess of the hydrogenating species and the Hillniyer method
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`attains complete hydrogenation only if the olefin/catalyst ratio was kept less than or equal to
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`100:].
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`McLain, et a1. (McLain, S. J., et al., Proceedings PMSE, 1997, 76:246) reported a
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`one—pot procedure for producing ethylene/methyl aerylate copolymers by the ROMP of ester—
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`fimctionalized cycloolefins using C12 (PCy3)2 Ru=CHCH=CPh2 and then hydrogenating by
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`simply applying hydrogen pressure to the completed ROMP reaction system. The metathesis
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`catalyst residue was assumed to be converted to RuHCl(PCy3)2 in the presence of hydrogen
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`gas. RuHCl(PCy3)2 is an effective hydrogenation catalyst. However, hydrogen pressures of
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`at least 400 psi were required to maintain catalytic activity and achieve greater than 99%
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`reduction.
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`US. Patent No. 5,539,060 describes the one—pot ROMP of cyclic olefins and
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`subsequent hydrogenation without the need for isolation of the polymer from the first step or
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`deactivation of the olefin metathesis catalyst. However, metathesis is effected with a binary
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`catalyst
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`system (eg, WC1(,/SnBut4) and then another catalyst must be added for
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`hydrogenation. Further, in some cases hydrogen halides can be produced in this process. An
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`acid binder is required in these cases as such by-products can cause corrosion in reaction
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`vessels.
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`There are advantages to systems in which olefin metathesis and the subsequent
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`catalytic hydrogenation is conducted in a single vessel where the only added reagents are low
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`cost support materials and hydrogen gas.
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`it
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`is often advantageous for quantitative
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`hydrogenation to be achieved under mild conditions (eg,
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`low to moderate hydrogen
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`pressures and temperatures) and for purification of the final product to be achieved by simple
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`filtration and solvent removal (if used) with minimal loss of product. Such a method is
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`described in US. Patent No. 6,107,237 (Wagener el (11.).
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`For some time, metathesis polymerization reactions and organic metathesis reactions
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`forming small molecules required that a liquid state be achieved.
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`In the case of metathesis
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`polymerization reactions,
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`the reaction proceeds via melt polymerization, often with the
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`addition of other chemicals, such as solvents. Sometimes it is advantageous for metathesis to
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`be performed at least in part in the solid state, allowing advantages associated with the use of
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`low reaction temperatures (6g, longer catalyst life) and solvent—less in—situ processing. US.
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`Patent No. 6,660,813 (Wagener er a1.) describes an in—situ method for performing organic
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`metathesis polymer chemistry in the solid state, which includes the step of providing an
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`organic monomer and a catalyst, the catalyst for driving a metathesis polymerization reaction
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`of the monomer. The organic monomer can be provided as a liquid monomer. The reaction
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`produces reaction products including a polymeric end. product and at
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`least one volatile
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`reaction product. At least a portion of the volatile reaction product is removed during the
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`reaction to favor formation of the reaction product. The reaction can be performed at a
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`temperature below the average melting point of the polymeric end product such that at least a
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`portion of the reaction is performed in the solid phase. The reaction can comprise ADMET
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`chemistry.
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`Polymer therapeutics refers to the use of polymers in biomedical applications and may
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`involve biologically active polymers, polymer~drug conjugates, polymer-protein eonj ugates,
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`and other covalent constructs of bioactive molecules (R. Duncan, “Polymer therapeutics for
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`tumor specific delivery”, Chem. & Ind, 1997, 7:262—264). An exemplary class of a polymer-
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`drug conjugate is derived from copolymers of hydroxypropyl methacrylamide (HPMA),
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`which have been extensively studied for the conjugation of cytotoxic drugs for cancer
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`chemotherapy (R. Duncan, Anti—Cancer Drugs, 1992, 5:210; D. Putnam et at, Adv. Polym.
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`Sci, 1995, 122(55): 123; R. Duncan et (11., S2? Pharma, 1996, 623—263). The polymers
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`used to develop polymer therapeutics may also be separately developed for other biomedical
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`applications that require the polymer be used as a material. Thus, drug release matrices
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`(including mieropartieles and nanopartieles), hydrogels (including inj ectable gels and viscous
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`solutions) and hybrid systems (e.g., liposomes with conjugated poly(ethylene glycol) on the
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`outer surface) and devices (including rods, pellets, capsules, films, gels) can be fabricated for
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`tissue or site specific drug delivery. Polymers are also widely used clinically as excipients in
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`drug formulation. W’ithin these three broad application areas: (1) physiologically soluble
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`molecules, (2) materials, and (3) excipients, biomedical polymers provide a broad technology
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`platform for optimizing the efficacy of an active therapeutic agent.
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`Drugs have been reacted with an acrylate or other vinyl substituent, followed by
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`purification of the vinyl drug monomers and polymerization Via free radical polymerization.
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`The resultant polymers have a tremendous drug—loading capability because every repeat unit
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`has a drug molecule appended to it. A limitation of this approach is that it provides poor
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`control over polymer architecture due to the multiple different side reactions that can be
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`present from a radical polymerization. There can be no pre—determination of how much
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`branching will be obtained with these polymers, and the polydispersity of these materials are
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`often rather large. Solubility of these types of materials varies greatly with the solubility of
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`the drug attached to the backbone along with the type of spacer utilized to connect the drug
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`and the vinyi substituent.
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`It would be advantageous to have available a method that allows both the precise
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`predetermination of polymer architecture and control of drug—loading, and the resulting
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`polymers of such a production method.
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`BRIEF SUMMARY OF THE INVENTION
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`The present invention concerns an acyclic diene metathesis (ADMET) chemistry—
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`based method of making polymers incorporating biologically active (bioactive) molecules,
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`and the polymers formed thereby. The invention provides a step—growth polymerization
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`technique that allows both the precise prcdctcrmination of polymer architecture and control
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`of drug—loading. The pelydispersity of a step-growth polymerization was predicted to be 2,
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`and the inventors are able to confirm this experimentally.
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`By using a diene acid precursor, such as 3,3 acid, 6,6 acid, 9,9 acid, or 18,18 acid
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`monomers, the amount of biologically active molecule (drug) on the polymer backbone can
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`be varied at exact intervals and thereby controlled. Having the capability to vary the drug
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`loading while simultaneously knowing the exact placement of the drug molecules on the
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`polymer is a significant benefit for a drug delivery material.
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`Functionalized polymers prepared by the methods of the invention can be used to
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`produce a broad range of commercially important products such as drug delivery agents
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`(prodrugs), chromatography reagents (eg, for use in separatory reagents), biomimeties, and
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`biodegradable polymers. For example, branched functionalizcd polymers can be used as
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`tissue culture substrates. Such polymers could also be used in an implantable medical device
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`to modify the physiological response to the device.
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`Polymers of the invention can be used to make materials that biodegrade more
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`quickly than conventional carbon—based linear polymers (3g, polyethylene). Such materials
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`can be fashioned into films for use in packaging, bags, and the like, that would quickly be
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`degraded (eg, by chemical or microorganism-mediated processes) in landfills. Similarly,
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`such materials can be fashioned into medical implants designed to slowly degrade in vii/0.
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`For example, the material can be impregnated with a drug for sustained release. The material
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`may also be fashioned into a scaffolding for applications in tissue engineering.
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`In one embodiment of the invention, the monomer is an alpha omega diene monomer
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`with a biologically active molecule (such as a non—steroidal anti—inflammatory drug)
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`covalently attached, which can be polymerized via a step growth condensation type
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`polymerization to yield a polyethylene polymer with precise branches of the corresponding
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`biologically active molecule. There are many examples of vinyl groups attached to a drug
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`molecule in the scientific literature, but this is the first instance in which the precise location
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`of the drug branches is known, and can be pre—determined by rational design.
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`Optionally, the polymers of the invention include one or more spacers connecting the
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`biologically active molecule to the polymer backbone. The spacer utilized can vary from
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`being hydrophobic to hydrophilic, and are preferably non—toxic.
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`The biologically active molecule can be cleaved from the polymer by chemical or
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`enzymatic hydrolysis, yielding the polymer, which remains useful, e.g., as a coating, along
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`with the biologically active molecule and the spacer (if present) can easily be eliminated from
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`the body. Surface density of the biologically active molecule can be modulated with the
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`varying number of methylene units between the terminal alkenes which directly translates to
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`polymer architecture.
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`The polymers of the invention are useful in a wide variety of pharmaceutical and
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`biomedical applications. For example, the polymers may be formulated as coatings for drug
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`tablets, contact lens coatings, coatings for surgical implants and medical devices, as gels, and
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`as
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`ingredients
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`in pharmaceutical
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`solutions
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`including delayed—release pharmaceutical
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`formulations and targeted pharmaceutical formulations.
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`BRIEF DESCRIPTION OF THE DRAWINGS
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`Figure 1 shows a schematic representation of a reaction of the invention.
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`Figure 2 shows a schematic representation of a reaction of the invention.
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`Figure 3 shows a schematic representation of a reaction of the invention.
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`Figure 4 shows the chemical structure of ibuprofen, with a diene attached thereto.
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`Figure 5 shows the chemical structure of naproxen, with. a diene attached thereto.
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`Figure 6 shows the chemical structure of 2—(undec—lO—enyl)tridec—12—en0ic acid.
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`Figure 7 shows the chemical structure of 2—(undec—lO-enyl)tridec—12—en—l—ol.
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`Figure 8 shows the chemical structure of (S)—2—(undec—l0—enyl)tridec—l2-enyl 2-(4—
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`isobutylphenyl)propanoate.
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`Figure 9 shows the chemical structure of (S)—2—(undec~lO—enyl)tridec—l2-enyl 2—(6—
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`methoxynapthalen—Z-yl)propanoate.
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`Figu re
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`shows
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`the
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`chemical
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`structure
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`of
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`(S)—2—(2—(2—(2—
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`hydroxyethoxy)ethoxy)ethoxy)ethyl 2-(6~methoxynaphtlialen~2-yl)propanoate.
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`Figure
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`shows
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`the
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`chemical
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`structure
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`of
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`(S)-10-hydroxydecyl
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`2—(4—
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`isobutylphenyl)propanoate.
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`Figure
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`shows
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`the
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`chemical
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`structure
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`of
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`(S)—2—(2—(2—(2—
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`hydroxyethoxy)ethoxy)ethoxy)ethyl 2—(6—methoxynaphthalen—2~yl)propanoate.
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`Figure
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`13
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`shows
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`the
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`chemical
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`structure
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`of
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`(S)—10—hydroxydecyl
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`2—(6—
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`methoxynaphthalen—2—yl)propanoate.
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`Figure 14 shows
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`the chemical
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`structure of (S)—l4—(4—isobutylphenyl)—l3—oxe—
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`3 ,6,9, l 2—tetroxapentadecyl 2—(undec—10—enyl)tridec~12~enoate.
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`Figure
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`shows
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`the
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`chemical
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`structure
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`of
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`( S)— l 0-(2—(4-
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`isobutylphenyl)propanoyloxy)decyl 2—(undec—l 0—enyl)tridec—l 2—cn0 ate.
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`Figure 16 shows the chemical structure of (S)—14—(6—methoxynaphthalen—2—yl)—l 3—
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`oxo—3,6,9, l Z—tetroxapentadecyl ‘2~(undec—10—enyl)tridec~l 2—enoate.
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`Figure 17 shows the chemical
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`structure of (S)—lO—(2—(6—methoxynaphth 211611-2-
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`yl)propanoyloxy)decyl 2 —(undec-l O—enyl)tri dec—l 2—enoate,
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`Figure 18 shows diverging schemes,
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`illustrating distinctions between a prior
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`approach (top scheme) and embodiments of methods of the invention (lower scheme).
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`Figure 19 shows the chemical structure of a polymer of the invention, wherein the
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`biologically active molecule is an antibiotic.
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`Figure 20 shows the chemical structure of a polymer of the invention, wherein the
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`biologically active molecule is an analgesic.
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`Figure 21 shows the chemical structure of a polymer of the invention, wherein the
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`biologically active molecule is an antibacterial compound.
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`DETAILED DESCRIPTION OF THE INVENTION
`
`The present invention concerns an acyclic diene metathesis (ADMET) chemistry—
`
`based method of making polymers incorporating biologically active (bioactive) molecules,
`
`and the polymers formed thereby. The invention provides a step—growth polymerization
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`technique that allows both the precise predetermination of polymer architecture and control
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`of drug—loading. The polydispersity of a step—growth polymerization was predicted to be 2,
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`and the inventors are able to confirm this experimentally.
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`The polymers of the invention comprise a covalently attached biologically active
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`molecule (2g, a drug) covalently attached (in a variable amount) through monomer design.
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`This family of polymer materials has a very well known primary polymer structure.
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`In the
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`methods of the invention, a diene molecule functionalized with a bioactive molecule, or chain
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`thereof, is used as a monomer that is polymerized by ADMET.
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`Advantageously, the polymer of the invention can be produced in a manner in which
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`the following is controlled (predetermined): (a) the amount of the bioactive agent; (b) the
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`architecture of the resulting polymer (116., the specific location of the bioactive molecules on
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`the polymer); and (c) how fast the bioactive agent is released or exposed. Furthermore,
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`depending on the amount of residual catalyst remaining in the polymer after synthesis, these
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`materials can be nearly non-toxic.
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`The polymers of the invention can be prepared by ADMET chemistry utilizing a
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`suitable catalyst as illustrated in Figures 1~3.
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`In general, the reactions include two steps. The
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`method comprises producing or providing biologically active molecule (drug)—branched diene
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`monomers, and using ADMET to polymerize the monomers into a polymer product. Using
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`the method, polyolefin polymers having bioactive molecules positioned at precise locations
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`pendant to the backbone are produced. The bioactive molecules can be incorporated into the
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`monomers and polymers of the invention by various linkages (e.g., decancdiol ester drugs,
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`tetraethylene glycol ester drugs, etc). Thus, in addition to other subject matter, the invention
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`provides biologically active molecule—functionalized polymers; (2) methods of making such
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`polymers; and (3) products incorporating such polymers. Examples of products incorporating
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`one or more polymers of the invention as components include biomaterials designed and
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`constructed to be placed in or onto the body, or to contact fluid or tissue of the body.
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`Products incorporating one or more polymers of the invention can be medical devices that
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`have one or more surfaces that contact blood or other bodily tissues in the course of their
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`operation, such as vascular grafts, stents, heart valves, orthopedic devices, catheters, shunts,
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`and the like.
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`Figure 18 shows two diverging schemes,
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`illustrating distinctions between a prior
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`method (upper scheme) and certain embodiments of methods of the invention (lower
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`scheme). Both schemes of Figure 18 are initiated with a dicnc acid. The 9,9 acid is shown
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`in Figure 18; however, one skilled in the art would appreciate that other starting materials
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`such as the 3,3 acid, 6,6 acid, or 18,18 acid may be used, for example. The two approaches
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`diverge at the point Where the carboxylic acid functionality of the diene is covalently linked.
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`At the top right of Figure 18, an amino acid (or a polypeptide) is added through a stable
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`amide bond (as labeled). The amide/peptide bond is very stable to chemical hydrolysis and is
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`readily cleaved by amidase enzymes, which are generally not present
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`in the blood or
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`extracellular fluid of the body; thus these bio—olefin materials in the top scheme of Figure 18
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`are generally stable in the body (not readily degrading).
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`The product of the lower scheme (lower right of Figure 18) is a polymer prodrug.
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`In
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`generally, a prodrug is unreactive and is metabolized to the biologically active form (or more
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`biologically active form), z'.e., to the active pharmaceutical species, in the body.
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`In some
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`embodiments of the invention (including that shown in Figure 18,
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`lower scheme),
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`the
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`materials are designed to have two ester linkages available for hydrolysis (cleavage).
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`It is
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`advantageous to obtain a polymer prodrug that is stable enough to assemble and reach the
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`intended anatomical site (target), yet reactive enough to be readily cleaved off when it is at
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`the target site. The “R” group in the lower scheme in Figure 18, between the two oxygen
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`atoms,
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`is the spacer and can be varied to be long or short, and can be hydrophobic or
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`hydrophilic, for example, depending upon the desired properties. Advantageously,
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`the
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`polymer maten'als of the invention can be designed to degrade in the body at a controlled rate
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`through cleavable linkages.
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`In one embodiment, the polymer of the invention is a prodrug, wherein the bioactive
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`molecule is therapeutic.
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`In this and other embodiments, the polymer may be formed as a
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`coating, solution, gel, nanoparticlc (e.g., nanosphere), microparticle (e.g., microsphere), or
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`other formulation appropriate for the intended application.
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`The embodiments described herein illustrate adaptations of the methods
`
`and
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`compositions of the invention. Nonetheless, from the description of these embodiments, other
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`aspects of the invention can also be made and/0r practiced.
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`General Methods
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`The method of the invention can utilize general techniques known in the field of
`
`polymer chemistry. General polymer chemistry concepts and methods that may be utilized
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`are described in the Polymer Handbook (4th Edition), eds, Brandup er al., New York, John
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`Wiley and Sons, 1999; and Polymer Synthesis and Characterization: A Laboratory Manual,
`
`eds. Sandler et al, Academic Press, 1998. Concepts and methods relating more specifically
`
`to metathesis chemistry are described in Alkene Metathesis in Organic Synthesis. Springer—
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`Verlag: Berlin, 1998 and Olefin Metathesis and Metathesis Polymerization, 2nd ed.;
`
`Academic: San Diego, 1997. ADMET is described with particularity in Lindmark—Hamburg,
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`M. and Wagoner, K. B. Macromolecules 1987, 20:2949; Wagener et al., Macromolecules
`
`1990, 2325155; Smith et al., Macromolecules 2000, 33:378l —3794; Watson, M. D. and
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`Wagener, K. B., Macromolecules, 2000, 33:3196—3201; Watson M. D. and Wagener K. B.,
`
`Macromolecules,
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`2000,
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`33:8963—8970;
`
`and Watson M. D.
`
`and Wagener K. B.
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`Macromolecules, 2000, 33:5411—5417.
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`Monomers
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`In methods of the invention, a diene molecule functionalized with a bioactive
`
`molecule, or chain thereof, is used as a monomer that is polymerized by ADMET. Any type
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`of diene molecule functionalized with a bioactive molecule (or chain thereof) that is capable
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`of being polymerized by the metathesis method taught herein may be used as the monomer.
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`Two or more (e. g., 3, 4, 5, 6, 7, 8 or more) different monomers of this type may also be used
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`to produce co—polymers.
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`By using a diene, such as 3,3 acid, 6,6 acid, 9,9 acid, or 18,18 acid monomers, the
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`amount of biologically active molecule (drug) on the polymer backbone can be varied at
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`exact
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`intervals and thereby controlled. For example,
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`the 3,3 acid Will result in a drug
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`molecule on every ninth carbon for the resultant polymer, the 6,6 acid would yield a drug
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`molecule every fifteenth carbon, the 9,9 acid would yield a drug molecule every twenty—first
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`carbon, and the 18,18 acid wouEd provide a drug molecule every thirty—ninth carbon on the
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`backbone. The formula for this design is 2n+2, with n being the spacer. Having the
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`capability to vary the drug-loadin g while still simultaneously knowing the exact placement of
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`the drug molecules is a huge benefit for a. diu g delivery material.
`
`In the examples described below, dienes functionalized with a bioactive molecule
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`(ibuprofen, naproxen) pendant to the backbone of the diene are used. For a description of
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`alkyne metathesis chemistry see, e.g., Zhang et LIL, Youji Huaxue, 2001, 212541—548;
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`Winfried et (11., Eur. J. Chem., 2001, 71117—126; and Brizius er al, J. Am. Chem. Soc, 2000,
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`122:12435-12440.
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`Preferred conditions for condensing such other molecules can be
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`identified by performing the reactions described below under various reaction conditions to
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`identify those under which a particular reaction proceeds efficiently.
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`The conditions
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`described herein can be used as a general guide in setting the ranges of the reaction
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`conditions to be tested.
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`In the experiments described below, standard ACS reagent grade
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`chemicals were used as substrates and are commercially available.
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`Catalysts
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`The ADMET-mediated condensation of a diene according to the invention is
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`facilitated using a metathesis catalyst. Any methathesis catalyst compatible with the methods
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`of the invention may be used. Preferably, metathesis catalysts tolerant to the wide variety of
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`functional groups found in drug molecules and the linkers that connect them to the polymer
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`backbone are utilized. In one embodiment, the catalyst is a ruthenium—based catalyst, such as
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`those found in Grubbs “First Generation” or “Second Generation” catalysts. Hoyveda’s
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`catalysts or modifications to these ruthenium (Ru)-based materials may improve the activity
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`and tolerance of these catalysts.
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`Numerous ADMET catalysts are known. Many of these, however, are not suitable for
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`use with functionalized monomers as the functional groups can interfere with the active site
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`of the catalyst molecule. For this reason, ADMET catalysts known to be tolerant of functional
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`groups may be preferred. A tungsten halide in combination with an aluminum alkyl (e.g.,
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`tungsten hexachloride and ethyl aluminum dichloride) may be effective. However,
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`the
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`molybdenum— and tungsten—based metathesis catalysts are less preferred due to their extreme
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`reactivity to functional groups.
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`Because of their well-known tolerance of functional groups and efficiency of
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`catalysis, Ru—based catalysts are useful in the reactions of the invention. For example, 1,3—
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`dimesityl~4,5—dihydroimidazol~2—ylidene)benzylidene ruthenium dichloride is useful because
`
`of its ability to efficiently catalyze the exemplary reactions described below. Scholl at £21.,
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`Org. Lett, 1999, 1:953). However, the ADMET catalyst can be any of a variety of catalysts
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`capable of effecting metathesis polymerization. Examples include Schrock’s molybdenum
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`alkylidene catalyst, Grubbs’
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`ruthenium benzylidene catalyst, and Grubbs’
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`imidazoliurn
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`catalyst (“Super—Grubbs”). A number of other catalysts may be employed in the reaction was
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`well.
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`Linkers and Spacers
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`Regardless of the particular bioactive active molecule(s) intended to be used,
`
`the
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`reactive functional groups should be protected for the polymerization process. Whatever
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`protection group is used on the bioactive molecule for polymerization, unless it can be
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`cleaved naturally by the body, it should be removed Via dcprotection chemistry in order to
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`have its therapeutic effect in the body. Ester bonds and the tetraethylene and deeanediol
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`spacers have been used in some of the examples due to their availability; however, many
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`more spacers and linkages can be used.
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`A large variety of linkers may be utilized in the polymers and methods of the
`
`invention.
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`In a preferred embodiment, ester linkages are utilized. Depending upon the rate at
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`which these linkers are cleaved in the body, they can be modified to cleave either faster or
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`more slowly. For example, if relatively slower cleavage is desirable, a earbamate, carbonate,
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`or even an amide linker can be utilized. More rapid cleavage could also be achieved by
`
`retaining the ester but adding strong electron—withdrawing groups alpha to the ester. The
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`increased pull of electrons from the ester carbon will increase the rate at which it hydrolyzes.
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`The spacer(s) can be selected to make cleavage of the bioactive molecule in the body
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`more rapid or less rapid.
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`Spacers may be more hydrophobic or more hydrophilic, for
`
`example, depending upon the desired properties. Generally, a hydrophobic spacer (tag,
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`glycols) would be expected to increase enzymatic hydrolysis while slowing chemical
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`hydrolysis. Conversely, a hydrophilic spacer would generally be expected to decrease
`
`enzymatic hydrolysis but
`
`increase chemical hydrolysis. Lack of a spacer would likely
`
`minimize enzymatic hydrolysis but still allow some chemical hydrolysis.
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`As described herein, any biologically active molecule can be used in the polymers and
`
`methods of the invention. The polymers and methods of the invention are particularly
`
`advantageous for delivery of potent drugs that are quickly metabolized by the body. For
`
`example, analgetics
`
`(such as morphine)
`
`and antibacterials and antibiotics
`
`(such as
`
`tetracyclines) can be used. Figures 19—21 show the chemical structures of polymers of the
`
`invention, bearing antibiotic, analgesic, and antibacterial compounds, respectively. The
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`various linkers described herein are compatible with these examples of drugs. Carbonate,
`
`carbamate, ether, and ester linkages each degrade at different rates in the body. Although
`
`various spacers can be selected in designing various embodiments of polymers of the
`
`invention, preferred spacers include methoxy spacers and glycol spacers (cg, ethylene glycol
`
`spacer). Various combinations of linkers and spacers may be used (e.g., carbonate linker and
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`ethylene glycol spacer; carbamate linker and methoxy spacer; ether linker and carbamate
`
`linker, etc).
`
`In one embodiment, the linker is not an amide (a non—amide moiety).
`
`In another
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`embodiment, the bioactive molecule is not connected to the spacer or linker through an amino
`
`acid or peptide.
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`In another embodiment,
`
`the linker is not an amide and the bioactive
`
`molecule is not connected to the space or linker through an amino acid or peptide.
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`Phannaceutical Compositions
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`The subject invention includes pharmaceutical compositions comprising polymers of
`
`the invention that contain bioactive molecules,
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`in association with a pharmaceutically
`
`acceptable carrier.
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`The pharmaceutical compositions of the subject
`
`invention can be
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`for