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`United States Patent am! ‘I‘yafimmrk Office
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`JAMES KLEIN
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`KENNETH BOONE
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`LEONARD
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`WAGENER
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`GAINESVILLE, FL
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`GAINESVILLE, FL
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`REGISTRATION NO. 46 853
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`SIGNATURE
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`TYPED or PRINTED NAME Glenn P. Ladwig
`
`TELEPHONE (352)375—8100
`
`Docket Number: UF»572P
`
`

`

`1
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`Docket No.: UF—572P
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`DESCRIPTION
`
`POLYETI—IYLENE BASED BIOACTIVE 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-O70326l and DMR-03l4110.
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`Accordingly, the government has certain rights in this invention.
`
`BACKGROUND OF THE INVENTION
`
`The term “metathesis” refers to a mutual transalkylidenation of alkenes and alkynes
`
`in the presence of catalysts. Reactions of this type are employed in many industrially
`
`important processes. A review may be found in: M. Schuster, S. Blechert, Angew. Chem,
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`1997, 10922124; and S. Armstrong, J. Chem. Soc, Perkin Trans. 1998, 1:371. Metathesis
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`reactions include the oligomerization and polymerization of acyclic dienes (ADMET) and the
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`synthesis of carbocycles and heterocycles having various ring sizes by ring closing
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`metathesis (RCM). Crossed metatheses of different alkenes are also known (Brurnmer, O. et
`
`al, Chem. Eur. J, 1997, 3:441). For the aforementioned metathesis reactions, it is possible
`
`to use, for example, the ruthenium—alkylidenc compounds described in WO—A-93/201 1 1, the
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`ruthenium—based catalyst systems described by A. W. Stumpf, E. Saive, A. Deomceau and A.
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`F. Noels in J. Chem. Soc, Chem. Commun, 1995, 1127-1128, or the catalyst systems
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`described by P. Schwab, R. H. Grubbs and J. W. Ziller in J Am. Chem. Soc, 1996, 118, 100
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`(see also WO 96/04289) as catalysts. The above publications, and all other publications,
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`published patent applications, and patents cited hereafter. are incorporated herein by
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`reference in their entirety.
`
`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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`Docket No.: UF—S 721’
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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, J. B, et al, die
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`Makromomo/ekulare Chemie, 1993, 142657; Grubbs, R. H. and W. th, .Macromolecules,
`
`1994,
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`27:6700),
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`tclechelic polyethylene
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`(llillmyer, M. A.,
`
`“The Preparation of
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`Functionalized Polymers by Ring—Opening Metathesis Polymerization”, Ph.D. Dissertation,
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`California Institute of Technology, 1995), ethylene/vinyl alcohol copolymers (Valenti, D. J.
`
`and K. B. Wagener, Macromolecules, E998 3122764) and polyethylene with precisely spaced
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`alkyl side chains (Valenti, D. J. and K. B. Wagener, Macromolecules, 1997, 30:6688).
`
`Polymerized dienes and methods for preparing them by step propagation, condensation type
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`polymerization of acyclic dienes are described in US. Patent No. 5,110,885 (Wagener er al.)
`
`and US. Patent No. 5,290,895 (Wagener et 61].).
`
`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
`
`(Wagener et al.) and US. Patent No. 7,172,755 (\Nagener at al.). Figure 1 ofU.S. Patent No.
`
`6,107,237 shows some examples of metathesis reactions that are useful for constructing
`
`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 functionalities. 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. 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. US. Patent No. 4,496,758 describes metathesis and cross—metathesis
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`of alkenyl esters to produce unsaturated monomers which can be used in polymer synthesis.
`
`US Patent No. 5,146,017 describes metathesis of partially fluorinated alkenes.
`
`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
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`double bonds. Other properties may be manipulated such as toughness, thermal stability,
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`permeability, crystallinity, etc.
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`Metathesis polymers are often prepared, isolated, and purified prior to hydrogenation.
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`Additional hydrogenating agents
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`are
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`then added and hydrogenation is
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`effected.
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`Disadvantages are loss of product during isolation and purification after the first step, 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. J. and K. B. Wagoner, 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 Hillmyer 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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`100:1.
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`McLain, et al. (McLain, S. J., et 61]., Proceedings PMSE, 1997, 762246) reported a
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`one—pot procedure for producing ethylene/methyl aerylate eopolymers by the ROMP of ester—
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`functionalized 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 (cg, WCls/SnBut4) and then another catalyst must be added for
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`3O
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`hydrogenation. Further, in some cases hydrogen halides can be produced in this process. An
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`4
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`Docket No.: UF-572P
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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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`lt
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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 (Wagoner at 611.).
`
`For some time, metathesis polymerization reactions and organic metathesis reactions
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`forming small molecules required that a liquid state be achieved.
`
`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
`
`be performed at least in part in the solid state, allowing advantages associated with the use of
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`low reaction temperatures (e. g., longer catalyst life) and solvent—less in—situ processing. US.
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`Patent No. 6,660,813 (VVagener et a1.) describes an [Tn-Sim 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
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`may involve biologically active polymers, polymer—drug conjugates, polymer—protein
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`conjugates, and other covalent constructs of bioactive molecules (R. Duncan, “Polymer
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`therapeutics for tumor specific delivery”, Chem. & Ind, 1997, 7262—264). An exemplary
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`class of
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`a polymer—drug conjugate is derived from copolymers of hydroxypropyl
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`Docket No.: UF—S 72P
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`methacrylamide (HPMA), which have been extensively studied for the conjugation of
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`cytotoxic drugs for cancer chemotherapy (R. Duncan, Anti—Cancer Drugs, 1992, 5:210; D.
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`Putnam er al., Adv. Polym. Sci, 1995, 122(55): 123; R. Duncan et al., STP Pharma, 1996,
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`6:23—263). The polymers used to develop polymer therapeutics may also be separately
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`developed for other biomedical applications that require the polymer be used as a material.
`
`Thus, drug release matrices
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`(including microparticles
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`and nanoparticles), hydrogels
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`(including injectable gels and Viscous solutions) and hybrid systems (eg, liposomes with
`
`conjugated poly(ethylene glycol) on the outer surface) and devices (including rods, pellets,
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`capsules, films, gels) can be fabricated for tissue or site specific drug delivery. Polymers are
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`also widely used clinically as excipients in drug formulation. Within these three broad
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`application areas: (1) physiologically soluble molecules, (2) materials, and (3) excipients,
`
`biomedical polymers provide a broad technology platform for optimizing the efficacy of an
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`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
`
`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 vinyl substituent.
`
`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.
`
`BRIEF SUMMARY OF THE INVENTION
`
`The present invention concerns an acyclic diene metathesis (ADMET) chemistry—
`
`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 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.
`
`By using a dicne acid precursor, such as 3,3 acid, 6,6 acid, 9,9 acid, or 18,18 acid
`
`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.
`
`Functionalized polymers prepared by the methods of the invention can be used to
`
`produce a broad range of commercially important products such as drug delivery agents
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`(prodrugs), chromatography reagents (e. g., for use in separatory reagents), biemimetics, and
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`biodegradable polymers. For example, branched funetionalized 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.
`
`Polymers of the invention can be used to make materials that biodegrade more
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`quickly than conventional carbon—based linear polymers (6g, polyethylene). Such materials
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`can be fashioned into films for use in packaging, bags, and the like, that would quickly be
`
`degraded (eg, by chemical or microorganisnrmediated processes) in landfills. Similarly,
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`such materials can be fashioned into medical implants designed to slowly degrade in vivo.
`
`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.
`
`In one embodiment of the invention, the monomer is an alpha omega diene monomer
`
`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
`
`polymerization to yield a polyethylene polymer with precise branches of the corresponding
`
`biologically active molecule. There are many examples of vinyl groups attached to a drug
`
`molecule in the scientific literature, but this is the first instance in which the precise location
`
`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
`
`being hydrophobic to hydrophilic, and are preferably non—toxic.
`
`The biologically active molecule can be cleaved from the polymer by chemical or
`
`enzymatic hydrolysis, yielding the polymer, which remains useful, eg, as a coating, along
`
`with the biologically active molecule and the spacer (if present) can easily be eliminated
`
`from the body. Surface density of the biologically active molecule can be modulated with
`
`the varying number of methylene units between the terminal alkenes which directly translates
`
`to polymer architecture.
`
`The polymers of the invention are useful in a wide variety of pharmaceutical and
`
`biomedical applications. For example, the polymers may be formulated as coatings for drug
`
`tablets, contact lens coatings, coatings for surgical implants and medical devices, as gels, and
`
`as
`
`ingredients
`
`in pharmaceutical
`
`solutions
`
`including delayed-release pharmaceutical
`
`formulations and targeted pharmaceutical formulations.
`
`BRIEF DESCRIPTION OF THE DRAWINGS
`
`Figure 1 shows a schematic representation of a reaction of the invention.
`
`Figure 2 shows a schematic representation of a reaction of the invention.
`
`Figure 3 shows a schematic representation of a reaction of the invention.
`
`Figure 4 shows the chemical structure of ibuprofen, with a diene attached thereto.
`
`Figure 5 shows the chemical structure of naproxen, with a diene attached thereto.
`
`Figure 6 shows the chemical structure of 2-(undec—lO-enyl)tridec-lZ-enoic acid.
`
`Figure 7 shows the chemical structure of 2-(undec~10-enyl)tridec—12-en-1—ol.
`
`Figure 8 shows the chemical structure of (S)—2-(undec—l0-enyl)tridec-l2—enyl 2-(4-
`
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`isobutylphenyl)propan0ate.
`
`Figure 9 shows the chemical structure of (S)-2-(undec-lO-enyl)tridec-12-enyl 2—(6-
`
`methoxynapthalen-2-yl)propanoate.
`
`F igu re
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`1 0
`
`shows
`
`the
`
`chemical
`
`structure
`
`of
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`(S )—2 —(2 —(2 ~(2—
`
`hydroxycthoxy)cthoxy)cthoxy)cthy1 2-(6-meth0xynaphthalen—2—yl)propanoate.
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`Figure
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`11
`
`shows
`
`the
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`chemical
`
`structure
`
`of
`
`(S)-lO—hydroxydecyl
`
`2—(4—
`
`isobutylphenyl)propanoate.
`
`Figure
`
`12
`
`shows
`
`the
`
`ch emic al
`
`structure
`
`0 f
`
`(S)—2—(2-(2—(2—
`
`hydroxyethoxy)ethoxy)ethoxy)ethyl 2-(6-methoxynaphthalen-Z-yl)propanoate.
`
`Figure
`
`13
`
`shows
`
`the
`
`chemical
`
`structure
`
`of
`
`(S)—lO—hydroxydecyl
`
`2—(6-
`
`methoxynaphthalen-2~yl)propanoate.
`
`Figure 14 shows
`
`the chemical
`
`structure of (S)—l4—(4-isobutylphenyI)—l3-oxo-
`
`3,6,9,l2-tetroxapcntadccyl 2-(undcc-l U—cnyl)tridec—12-enoate.
`
`Figure
`
`1 5
`
`shows
`
`the
`
`chemical
`
`structure
`
`of
`
`(S)- I 0—(2—(4-
`
`isobutylphenyl)propanoyloxy)decyl 2-(undec-IO—enyl)tridec~12~enoate.
`
`Figure 16 shows the chemical structure of (S)—l4-(6-methoxynaphthalen-2-yl)—l3-
`
`oxo-3 ,6,9, l 2-tctroxapcntadecyl 2-(undec-10—enyl)tridec—12-enoate.
`
`Figure 17 shows the chemical structure of (S)—lO—(2—(6—methoxynaphthalen—2—
`
`yl)propanoyloxy)decyl 2—(undec—l O—enyl)tridcc—12—cnoatc.
`
`Figure 18 shows diverging schemes,
`
`illustrating distinctions between a prior
`
`approach (top scheme) and embodiments of methods of the invention (lower scheme).
`
`Figure 19 shows the chemical structure of a polymer of the invention, wherein the
`
`biologically active molecule is an antibiotic.
`
`Figure 20 shows the chemical structure of a polymer of the invention, wherein the
`
`biologically active molecule is an analgesic.
`
`Figure 21 shows the chemical structure of a polymer of the invention, wherein the
`
`biologically active molecule is an antibacterial compound.
`
`DETAILED DESCRIPTION OF THE INVENTION
`
`The polymers of the invention include a covalently attached biologically active
`
`molecule (erg, a drug) covalently attached (in a variable amount) through monomer design.
`
`This family of polymer materials has a very well known primary polymer structure.
`
`In the
`
`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. Advantageously, the
`
`polymer of the invention can be produced in a manner in which the following is controlled
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`(predetermined): (a) the amount of the bioactive agent; (b) the architecture of the resulting
`
`polymer (126., the specific location of the bioactive molecules on the polymer); and (c) how
`
`fast the bioactive agent is released or exposed. Furthermore, depending on the amount of
`
`residual catalyst remaining in the polymer after synthesis, these materials can be nearly non-
`
`toxic.
`
`The polymers of the invention can be prepared by ADMET chemistry utilizing a
`
`suitable catalyst as illustrated in Figures 1-3.
`
`In general, the reactions include two steps. The
`
`method comprises producing or providing biologically active molecule (drug)—branched
`
`diene monomers, and using ADMET to polymerize the monomers into a polymer product.
`
`Using the method, polyolefin polymers having bioactive molecules positioned at precise
`
`locations pendant
`
`to the backbone are produced.
`
`The bioactive molecules can be
`
`incorporated into the monomers and polymers of the invention by various linkages (cg,
`
`decanediol ester drugs, tetraethylene glycol ester drugs, etc). Thus, in addition to other
`
`subject matter, the invention provides biologically active molecule—tunctionalized polymers;
`
`(2) methods of making such polymers; and (3) products incorporating such polymers.
`
`Examples of products incorporating one or more polymers of the invention as components
`
`include biomaterials designed and constructed to be placed in or onto the body, or to contact
`
`fluid or tissue of the body. Products incorporating one or more polymers of the invention can
`
`be medical devices that have one or more surfaces that contact blood or other bodily tissues
`
`in the course of their operation, such as vascular grafts, stents, heart valves, orthopedic
`
`devices, catheters, shunts, and the like.
`
`Figure 18 shows two diverging schemes, illustrating distinctions between a prior
`
`method (upper scheme) and certain embodiments of methods of the invention (lower
`
`scheme). Both schemes of Figure 18 are initiated with a diene acid. The 9,9 acid is shown
`
`in Figure 18; however, one skilled in the art would appreciate that other starting materials
`
`such as the 3,3 acid, 6,6 acid, or 18,18 acid may be used, for example. The two approaches
`
`diverge at the point where the carboxylic acid functionality of the diene is covalently linked.
`
`At the top right of Figure 18, an amino acid (or a polypeptide) is added through a stable
`
`amide bond (as labeled).
`
`'l‘hc amide/peptide bond is very stable to chemical hydrolysis and is
`
`readily cleaved by amidase enzymes, which are generally not present
`
`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
`
`are generally stable in the body (not readily degrading).
`
`The product of the lower scheme (lower right of Figure 18) is a polymer prodrug.
`
`In
`
`generally, a prodrug is unreactive and is metabolized to the biologically active form (or more
`
`biologically active form), 1.6., to the active pharmaceutical species, in the body.
`
`In some
`
`embodiments of the invention (including that shown in Figure 18,
`
`lower scheme),
`
`the
`
`materials are designed to have two ester linkages available for hydrolysis (cleavage).
`
`It is
`
`advantageous to obtain a polymer prodrug that is stable enough to assemble and reach the
`
`intended anatomical site (target), yet reactive enough to be readily cleaved off when it is at
`
`the target site. The “R” group in the tower scheme in Figure 18, between the two oxygen
`
`atoms,
`
`is the spacer and can be varied to be long or short, and can be hydrophobic or
`
`hydrophilic,
`
`for example, depending upon the desired properties. Advantageously,
`
`the
`
`polymer materials of the invention can be designed to degrade in the body at a controlled rate
`
`through cleavable linkages.
`
`In one embodiment, the polymer of the invention is a prodrug, wherein the bioactive
`
`molecule is therapeutic.
`
`In this and other embodiments, the polymer may be formed as a
`
`coating, solution, gel, nanoparticle (e. g., nanosphere), microparticle (ag, microsphere), or
`
`other formulation appropriate for the intended application.
`
`The embodiments described herein illustrate adaptations of the methods and
`
`compositions of the invention. Nonetheless, from the description of these embodiments, other
`
`aspects of the invention can also be made and/or practiced.
`
`General Methods
`
`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
`
`are described in the Polymer Handbook (4th Edition), eds, Brandup et 01., New York, John
`
`Wiley and Sons, 1999; and Polymer Synthesis and Characterization: A Laboratory Manual,
`
`eds. Sandler er (2]., Academic Press, 1998. Concepts and methods relating more specifically
`
`to metathesis chemistry are described in Alkene Metathesis in Organic Synthesis. Springer—
`
`Verlag: Berlin, 1998 and Olefin Metathesis and Metathesis Polymerization, 2nd ed;
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`Academic: San Diego, 1997. ADMET is described with particularity in Lindmark—Hamburg,
`
`M. and Wagener, K. B. ll/facromolec'ules 1987, 20:2949; VVagener el (11., Macromolecules
`
`1990, 2325155; Smith et al, Macromolecules 2000, 33:3781-3794; Watson, M. D. and
`
`\Nagener, K. B, Macromolecules, 2000, 33:3196—3201, Watson M. D. and Wagener K. B.,
`
`Macromolecules,
`
`2000,
`
`33:8963-8970;
`
`and Watson M. D.
`
`and Wagener K. B.
`
`Macromolecules, 2000, 331541 1-5417.
`
`Monomers
`
`in methods of the invention, a diene molecule functionalized with a bioaetive
`
`molecule, or chain thereof, is used as a monomer that is polymerized by ADMET. Any type
`
`of diene molecule funetionalized with a bioactive molecule (or chain thereof) that is capable
`
`of being polymerized by the metathesis method taught herein may be used as the monomer.
`
`Two or more (eg, 3, 4, 5, 6, 7, 8 or more) different monomers of this type may also be used
`
`to produce co—polymers.
`
`By using a diene, such as 3,3 acid, 6,6 acid, 9,9 acid, or 18,18 acid monomers, the
`
`amount of biologically active molecule (drug) on the polymer backbone can be varied at
`
`exact intervals and thereby controlled.
`
`For example,
`
`the 3,3 acid will result in a drug
`
`molecule on every ninth carbon for the resultant polymer, the 6,6 acid would yield a drug
`
`molecule every fifteenth carbon, the 9,9 acid would yield a drug molecule every twenty—first
`
`carbon, and the 18,18 acid would provide a drug molecule every thirty-ninth carbon on the
`
`backbone. The formula for this d