MXPA00004443A - Radio-opaque polymer biomaterials - Google Patents

Abstract

Iodinated and/or brominated derivatives of aromatic dihydroxy monomers are prepared and polymerized to form radio-opaque polymers. The monomers may also be copolymerized with other dihydroxy monomers. The iodinated and brominated aromatic dihydroxy monomers can be employed as radio-opacifying, biocompatible non-toxic additives for other polymeric biomaterials. Radio-opaque medical implants and drug delivery devices for implantation prepared from the polymers of the present invention are also disclosed.

Description

RADIOOPACOS POLYMERIC BIOMATERIALS GOVERNMENT LICENSE RIGHTS The government of the United States has a paid license in this invention and the right in limited circumstances to require the owner of the patent to license others in reasonable terms as required by the terms of Session Nos. GM-39455 and GM-49849 granted by the US National Institutes of Health CROSS REFERENCE TO RELATED REQUEST This application claims the priority benefit of the patent application of E.U.A. Provisional No. 60 / 064,905, filed on November 7, 1997, the description of which is hereby incorporated by reference.

TECHNICAL FIELD The present invention relates to biodegradable radiopaque polycarbonates and polyarylates and to block copolymers thereof with poly (alkylene) oxide. In particular, the present invention relates to polycarbonates and polyarylates and to the poly (alkylene) oxide block copolymers thereof which are radiopaque as a consequence of being homopolymers and copolymers of dihydroxy monomers having iodinated or brominated aromatic rings as part of its structure.

BACKGROUND OF THE INVENTION Diphenols are monomeric starting materials for polycarbonates, polyiminocarbonates, polyarylates, polyurethanes and the like. The patents of E.U.A. in co-proprietary Nos. 5,099,060 and 5,198,507 describe diphenol compounds derived from amino acids, useful in the polymerization of polycarbonates and polyiminocarbonates. The resulting polymers are useful as degradable polymers in general and as bioerodible materials compatible with tissues for medical uses, in particular. The suitability of these polymers for their end-use application is the result of their polymerization from diphenols derived from the naturally occurring amino acid, L-tyrosine. The descriptions of the patents of E.U.A. Nos. 5,099,060 and 5,198,507 are hereby incorporated by reference. These previously known polymers are strong water-insoluble materials that can best be used as structural implants. The same monomeric diphenols derived from L-tyrosine are also used in the synthesis of polyarylates as described in the patent of E.U.A. in co-ownership No. 5,216,115 and in the synthesis of poly (alkylene) oxide block copolymers with the aforementioned polycarbonates and polyarylates, which is described in the US patent. in co-ownership No. 5,658,995. The descriptions of the patents of E.U.A. Nos. 5,216,115 and 5,658,995 are also incorporated herein by reference. The co-owned international application No. WO98 / 36013 describes dihydroxy monomers prepared from α-, β- and hydroxy acids and L-tyrosine derivatives which are starting materials useful in the polymerization of polycarbonates, polyiminocarbonates, polyarylates and the like. The preparation of polycarbonates, polyarylates and polyiminocarbonates from these monomers is also described. The description of the international application No. WO98 / 36013 is also incorporated herein by way of reference. The synthetic and degradable polymers are currently being evaluated as medical implants in a wide variety of applications, such as orthopedic devices for bone fixation, drug delivery systems, cardiovascular implants and support structures for tissue regeneration / engineering. Such polymers, when used as implants, are not traceable without invasive procedures. A radiopaque polymer would offer the unique advantage of being traceable by routine X-ray imaging. The fate of said implant through several stages of its usefulness could be followed without requiring invasive surgery. Davy et al., J. Dentist., 10 (3). 254-64 (1982), describe brominated derivatives of polymethyl methacrylate which are radiopaque. Copolymerization with non-brominated analogs was necessary to obtain the thermomechanical properties required for their intended use as a denture base. Only on a small scale of certain percentage concentrations of the bromine derivative does the material exhibit acceptable thermomechanical properties. further, there is no description that the materials exhibiting acceptable properties remain biocompatible after the addition of bromine to the polymer structure. Unlike the polymers described in this application, brominated polymethyl methacrylates do not degrade. However, because the bromine atoms are located on the aliphatic ester side chain, on the ester cut of the side chain, the polymer loses its radiopacity. Horak et al., Biomater. 8, 142-5 (1987), describe the triiodobenzoic acid ester of poly (2-hydroxyethyl) methacrylate as useful as a radiopaque marker compound in X-ray images. It was reported that the iodine content affected the contrast, volume, mechanical properties and hydrophobic character of the polymer. An adequate balance of properties, including radio contrast and swelling capacity, was achieved through the optimization of iodine content. Again, this material is not degraded through the main chain and loses radiopacity over the ester cut of the side chain because the iodine atoms are located on the ester side chain. Cabasso et al., J. Appl. Polvm. Sci. 38, 1653-66 (1989), describe the preparation of a coordination complex of radiopaque polymer miscible polymethyl methacrylate and a salt of uranium, uranyl nitrate. The polymer is not degraded through the main chain and the biocompatibility of the uranyl nitrate complex is not reported, nor has the long-term stability of the complex in vivo been established. Cabasso et al., J. Appl. Polvm. Sci .. 4J. 3025-42 (1990), describes the preparation of radiopaque coordination complexes of bismuth bromide and uranyl hexahydrate with polymers prepared from acrylated phosphoryl esters containing 1,3-dioxalan portions derived from polyols such as glycerol, D-mannitol, D-sorbitol, pentaerythritol and di pentaerythritol. The phosphoryl group was selected to provide stronger coordination sites for the bismuth and uranium salts, and to impart adhesive properties to hard tissues. Preliminary biocompatibility data indicated a satisfactory performance, but the polymer is not degraded through the main chain and the long-term stability of the complex in vivo is not reported. Jayakrishnan et al., J. Appl. Polvm. Sci. 44, 743-8 (1992) describes radiopaque polymers of triiodophenyl methacrylate and of the yotalmic ester of 2-hydroxyethyl methacrylate. Polymers of useful molecular weight were not obtained, attributable to the presence of cumbersome iodine atoms in the side chain of the monomer. It was possible to obtain copolymers with non-iodinated analogs in the presence of crosslinking agents, so that up to 25% of the iodized monomer could be incorporated. Preliminary biocompatibility data indicated that the presence of triiodophenyl methacrylate caused hemolysis of the blood.

In addition, the materials were also not degraded through the main chain, and in the case of cutting the ester of the side chain, they would lose their radiopacity due to the iodine atoms that are located in the side chain. Kraft et al., Biomater., 18, 31-36 (1997), describes the preparation of radiopaque polymethyl methacrylates containing iodine. The monomers were ortho- and para-iodine and 2,3,5-triiodobenzoic acid esters of 2-hydroxymethyl methacrylate, and the para-iodophenolic ester of methylmethacrylic acid. The monomers were copolymerized with one or more non-iodinated analogs and a small amount of crosslinkers to produce polymer hydrogels with varying iodine content. It was reported that hydrogels were tolerated by subcutaneous tissues and that the presence of iodine did not severely alter the hydrogel's swelling capacity. No tissue necrosis, abscess formation or acute inflammation was observed, although all the implants were surrounded by a fibrous capsule. However, these materials were also not degraded through the main polymer chain, and upon cutting the ester of the side chain, they lost radiopacity due to the iodine atoms located in the ester side chain. Currently no technology is available to provide radiopaque polymers that degrade through the main polymer chain, such as the tyrosine-derived polymers described above. For the desired use as medical implants, radiopacity is a valuable property. There is a need for radiopaque polymers that degrade through the main polymer chains, such as the tyrosine-derived polymers described above.

BRIEF DESCRIPTION OF THE INVENTION These needs are met by the present invention. It has now been found that the iodination or bromination of the aromatic rings of dihydroxy monomers makes the resultant radiopaque polymers. Significantly, the resulting polymers exhibit adequate mechanical and engineering properties while degrading into relatively non-toxic products after their implantation in vivo. In general, the ability of a species to absorb X-rays is directly related to the atomic number and is approximated by the ratio. M = kl3Z4 + 0.2 where m is the absorption coefficient, I is the wavelength of the incident X ray, Z is the atomic number of the absorbing species and k is the constant of proportionality. Iodine and bromine atoms, due to their high mass, disperse X-rays and impart radiopacity. This is highly significant and allows physicians to visualize any implanted device prepared from a radiopaque polymer by simply forming X-ray images.

In this way, iodinated and / or brominated derivatives of dihydroxy monomers can be prepared and polymerized to form radiopaque polycarbonates and polyarylates. These monomers can also be copolymerized with poly (alkylene) oxides and other dihydroxy monomers. In addition, dihydroxy iodinated and brominated monomers can be used as non-toxic biocompatible additives and radio-opaque for other polymeric biomaterials. Therefore, according to one aspect of the present invention, a non-toxic, radiopaque and biocompatible diphenolic additive is provided for polymeric biomaterials, which has the structure of formula I: Formula I represents a diphenol compound substituted with at least one bromine or iodine atom, wherein each Xi and X2 is independently an iodine or bromine atom, Yi and Y2 are independently between zero and two, inclusive, and Rg is an alkyl, aryl or alkylaryl group with up to 18 carbon atoms. Preferably, Rg contains as part of its structure a carboxylic acid group or a carboxylic acid ester group, wherein the ester is selected from straight and branched alkyl and alkylaryl groups containing up to 18 carbon atoms apart from the rest of the structure of Rg, and ester derivatives of biologically and pharmaceutically active compounds covalently linked to diphenol, which are also not included among the Rg carbons. Rg may also contain non-carbon atoms such as iodine, bromine, nitrogen and oxygen. In particular, R9 may have a structure related to derivatives of the natural amino acid tyrosine, cinnamic acid or 3- (4-hydroxyphenyl) propionic acid. In these cases, Rg assumes the specific structure shown in Figure II. wherein R0 is selected from (-CH = CH-), (-CHJVCHJ »and (-CH2-) d and R4 is selected from (-CH = CH-), (-CHJ CHJ2-) and (-CH2-) a , wherein a and d are independently 0 to 8, inclusive, and J1 and J2 are independently Br or I. Z is H, a free carboxylic acid group, or an ester or amide thereof Z is preferably a pendant group having a structure according to formula IV: O II - C-O-L (IV) wherein L is selected from hydrogen and straight and branched alkyl and alkylaryl groups containing up to 18 carbon atoms and derivatives of biologically and pharmaceutically active compounds covalently linked to Dihydroxy compound. Z can also be a hanging group that has a structure according to the formula IVa: OR II - C-M (Illa) wherein M is selected from -OH, -NH-NH2, -O-R10-OH, -NH-R10-NH2, -NH-R10-OH, a protecting group of the term C and a derivative of a biological or pharmaceutically active compound covalently linked to the pendant functional group by means of an amide bond, wherein a primary or secondary amine is present in the non-derivatized biological or pharmaceutically active compound in the position of the amide bond in the derivative. Z can also be a hanging group that has a structure represented by formula IVb: wherein M is a derivative of a biological or pharmaceutically active compound covalently linked to the pendant functional group by means of R3, wherein R3 is a bond selected from -NH-NH- in the case where in a biologically or pharmaceutically active compound no derivative is present an aldehyde or ketone in the position linked to the pendant functional groups by means of R3; and -NH-NH-, -NH-R10-NH-, -OR- or -NH-, -OR- 0 -O- or -NH-R-, 0-O- in the case where in the compound non-derived biologically or pharmaceutically active a carboxylic acid is present in the position linked to the group functional pendant by means of R3; I or II II - Nhr-Rg-C-OH, - sRg-C-OH, in the case in which a primary or secondary amine or primary hydroxyl in the position linked to the pendant functional group by means of R3 is present in the non-derivatized biological or pharmaceutically active compound. River is selected from alkyl groups containing 2 to 6 atoms of carbon, aromatic groups, a-, ß-,? - and? -aminoacids and sequences of peptides. According to another aspect of the present invention, a non-toxic, radiopaque, and biocompatible dihydroxy additive is provided for polymeric biomaterials, which has the structure of formula III: Formula III represents a dihydroxy compound substituted with at least one bromine or iodine atom, and having a structure related to tyrosine derivatives linked by means of an amine bond to a -, β- or β-hydroxy acid or derivative thereof. Each X2 is independently an iodine or bromine atom; Y2 is 1 or 2; R5 and R6 are each independently selected from H, bromo, iodo and straight and branched alkyl groups having up to 18 carbon atoms; R0 is (-CH2-) d, -CH = CH- or (-CHJV CHJ2-) and R15 is (-CH2-) m, - CH = CH- or (-CHJ CHJ2-), where Ji and J2 are independently Br or I and d and m are independently between 0 and 8, inclusive. Z is the same as that described above with respect to formula II. In accordance with another aspect of the present invention, radiopaque biocompatible polymers are provided having monomeric repeating units defined in the formulas I and Illa: The formula represents a diphenolic unit where Xi, X2, Y1, Y2 and Rg are the same as those described above with respect to formula I. The formula Illa represents an aromatic dihydroxy unit in which X2, Y2, Ro, R5, Re, R15 and Z are the same as those described above. with respect to formula III. The copolymers according to the present invention have a second dihydroxy unit defined in formulas Ib or IIIb.

In the diphenolic subunit of formula Ib, R12 is an alkyl, aryl or alkylaryl group with up to 18 carbon atoms, preferably substituted with a free carboxylic acid pendant group or an ester or amide thereof, wherein the ester or amide is selected from straight alkylaryl and alkyl esters and branched containing up to 18 carbon atoms, apart from the rest of the structure of R12, and derivatives of biologically and pharmaceutically active compound compounds covalently linked to the polymer, which are also not included among the carbons of R12. R12 may also contain non-carbon atoms such as nitrogen and oxygen. In particular, R12 may have a structure related to derivatives of the natural amino acid tyrosine, cinnamic acid or 3 '(4'-hydroxyphenyl) propionic acid. For the tyrosine derivatives, 3 '(4'-hydroxyphenyl) propionic acid and cinnamic acid, R12 assumes the specific structure shown in formula II, in which R0 is -CH = CH- or (-CH2-) dy R4 is -CH = CH- or (-CH2-) a >; where a and d are independently 0 to 8, inclusive. Z is the same as that described above with respect to formula II. In the dihydroxy subunit of formula IIIb, R16 and R17 are each independently selected from H or straight or branched alkyl groups having up to 18 carbon atoms; R-is is -CH = CH- or (-CH2-) d and R19 is -CH = CH- or (-CH2-) e > , where d and e are independently between 0 and 8, inclusive. Z is again the same as that described above with respect to formula II.

Some polymers of this invention may also contain poly (alkylene) oxide blocks as defined in formula VII. In the formula VII, R7 is independently an alkylene group containing up to 4 carbon atoms and k is between about 5 and about 3,000.

- (O-R7) k-0- (Vil) A linker union, designated "A" is defined as O O O II II II - C- or - C-Rg- C- wherein R8 is selected from saturated, unsaturated, substituted and unsubstituted alkyl, aryl and alkylaryl groups containing up to 18 carbon atoms. In this way, the polymers according to the present invention have the structure of formulas VIII and Villa: In both formulas, f and g are the molar ratios of the different subunits. The scale of f and g can be from 0 to 0.99. It is understood that the presentation of both formulas is schematic and that the polymer structures depicted are true random copolymers wherein the different subunits can occur in any random sequence along the base structure of the polymer. The formulas VIII and Villa provide a general chemical description of the polycarbonates when A is Formulas VIII and Villa provide a general description of polyarylates when A is O O II II - C-Rg- c- In addition, several limiting cases can be discerned: when g = 0, the polymer contains only monomeric repeating units substituted with iodine or bromine. If g is any fraction greater than 0 but less than 1, a copolymer is obtained which contains a defined ratio of monomeric repeating units substituted with bromine or iodine, and monomeric repeating units which are free of bromine and iodine. If f = 0, the polymer will not contain any poly (alkylene) oxide block. The frequency at which the poly (alkylene) oxide blocks can be found within the base structure of the polymer increases as the value of f increases. The radiopaque dihydroxy compounds substituted with bromine and iodine of the present invention cover the need for biocompatible biodegradable additives that are miscible with radiopaque polymeric biomaterials and increase the radioopacity of the polymeric materials. Therefore, the present invention also includes the bromo and iodine-substituted radiopaque dihydroxy compounds of the present invention, physically blended, embedded in, or dispersed in a biodegradable and biocompatible polymer matrix. Preferably, the dihydroxy compound is an analogue of a monomeric repeat unit of the matrix polymer. The bromine and iodine-containing polymers of the present invention also meet the need for processable radiopaque biocompatible biodegradable biodegradable polymers whose radiopacity is affected by nothing more than the degradation of the main polymer chain. Therefore, the present invention also includes implantable medical devices containing the radiopaque polymers of the present invention. The radiopaque polymers of the present invention then find application in areas where both structural solid materials and water soluble materials are commonly employed. Polymers can be prepared according to the present invention having suitable film-forming properties. An important phenomenon observed for the polymers of the present invention having poly (alkylene) oxide segments is the temperature-dependent phase transition of the polymer gel or the polymer solution in aqueous solvents. By increasing the temperature, the gel of the polymers undergoes a phase transition to a collapsed state, while the polymer solutions are precipitated at a certain temperature or within certain temperature ranges. The polymers of the present invention having poly (alkylene) oxide segments, and especially those that undergo a phase transition at about 30 ° C-40 ° C after heating can be used as biomaterials for the release of drugs and materials from Clinical implant. Specific applications include films and foils for adhesion prevention and tissue reconstruction. Thus, in another embodiment of the present invention, the poly (alkylene) radiopaque polycarbonate and polyarylate oxide block copolymers can be formed into a sheet or a coating for application to exposed tissues to be used as a barrier for the prevention of adhesions. surgical procedures as described by Urry et al., Mat. Res. Soc. Svmp. Proa, 292. 253-64 (1993). The placement of the radiopaque polymer sheets of the present invention can be followed by X-ray images without invasive surgery. This is particularly useful with endoscopic surgery. Therefore, another aspect of the present invention provides a method to prevent the formation of adhesions between injured tissues by inserting as a barrier between the injured tissues a sheet or a coating of polycarbonate poly (alkylene) radiopaque polycarbonate block copolymers. and polyarylates of the present invention. The poly (alkylene) oxide segments decrease the surface adhesion of the polymers of the present invention. As the value of f increases in the formulas Vil and Villa, the adhesion of surfaces decreases. Polymer coatings containing poly (alkylene) oxide segments according to the present invention, which are resistant to the attachment of useful non-thrombogenic cells and coatings on surfaces in contact with blood, can then be prepared. Said polymers also resist bacterial adhesion in these, and in other medical applications as well. The present invention therefore includes blood contact devices and medical implants having surfaces coated with the polymers of formulas VIII and Villa, wherein f is greater than 0. The surfaces are preferably polymeric surfaces. Methods according to the present invention include implanting in the patient's body a blood contact device or medical implant having a surface coated with the polymers described above of the present invention containing poly (alkylene) oxide segments. Medical implantable or blood contacting devices formed from the polymers of the present invention are also included within the scope of the present invention. Said polymers may or may not have poly (alkylene) oxide segments. The present invention also includes microspheres of the radiopaque polymers of the present invention, useful as contrast agents for X-rays or as drug delivery systems, the location of which can be traced by X-ray images. For the purposes of the present invention, the term "X-ray images" is defined as including essentially any imaging technique that employs X-rays, including the widely practiced procedures of radiography, photography, and computerized axial tomography scans (CT scans). The methods according to the present invention for the preparation of drug delivery systems can also be employed in the preparation of radiopaque microspheres for the delivery of drugs. In another embodiment of the present invention, the polymers are combined with an amount of a biologically or pharmaceutically active compound sufficient for effective on-site or systemic specific delivery as described by Gutowska et al. J. Biomater Res., 29, 811-21 (1995) and Hoffman, J. Controlled Reeléase, 6, 297-305 (1987). The biologically or pharmaceutically active compound can be physically mixed, embedded or dispersed in the polymer matrix as if it were not a radiopaque polymer, eliminating the need for radiopaque filling materials, thereby increasing the drug loading capacity of the matrix polymer. . Another aspect of the present invention provides a method for delivery of systemic or site-specific drug by implanting in the body of a patient in need thereof an implantable drug delivery device containing a therapeutically effective amount of a biologically or pharmaceutically active compound in combination with a radiopaque polymer of the present invention. As mentioned above, derivatives of biologically and pharmaceutically active compounds can be attached to the base structure of the polymer by covalent bonds, which provides for the prologated release of the biologically or pharmaceutically active compound by means of the hydrolysis of the covalent bond with the base structure of the polymer. By varying the value of f in the polymers of formulas VIII and Villa, the hydrophilic / hydrophobic ratios of the polymers of the present invention can be attenuated to adjust the ability of the polymer coatings to modify the cellular behavior. The increase in poly (alkylene) oxide levels inhibits cell attachment, migration and proliferation, the increase in the amount of free carboxylic acid pendant groups promotes cell attachment, migration and proliferation. Therefore, in accordance with yet another aspect of the present invention, a method is provided for regulating cell attachment, migration and proliferation by contacting living cells, tissues or biological fluids containing living cells with the polymers of the present invention. A more complete appreciation of the invention and many other desired advantages can be readily obtained by reference to the following detailed description of the preferred embodiments and claims, which describe the principles of the invention and the best ways currently contemplated to bring it into effect. practice.

DESCRIPTION OF THE DRAWINGS Figure 1 is an X-ray image of a radiopaque polymer pin according to the present invention, implanted in a section of a rabbit femur.

DETAILED DESCRIPTION OF THE INVENTION The present invention provides radiopaque polycarbonates and polyarylates, as well as poly (alkylene) oxide block copolymers thereof, in which radiopacity is derived from the substitution with bromine and iodine of some or all of the aromatic rings in the structure of polymer base. Polymers substituted with bromine and iodine are prepared by brominating or iodinating a premonomer compound prior to the synthesis of the dihydroxy monomer. The dihydroxy monomer is subsequently polymerized by established procedures, alone, or in combination with dihydroxy compounds that are not substituted with bromine or iodine. In particular, dihydroxy compounds substituted with bromine and iodine include diphenols having the structure of formula I wherein Rg is the same as that described above with rct to formula I. Dophenols preferably have the structure of formula II. Among the preferred diphenols are those compounds in which Rg has the structure of formula II wherein R 4 is -CH 2 - or -CHJ 1 -CHJ 2 - and Ro is -CH 2 - or -CH 2 -CH 2 -. Most preferably, R4 is -CHJrCHJ2- and R0 is -CH-. These most preferred compounds are the bromo and iodo-substituted tyrosine dipeptide analogs known as desaminotyrosyl-tyrosine, and the alkyl and alkylaryl esters thereof. In this preferred group, diphenols can be termed tyrosyl-tyrosine dipeptide derivatives from which the N-terminal amino group has been removed. Diphenol compounds that are not substituted with bromine or iodine have the structure of the formula le: wherein R-? 2 is the same as that described above with rct to formula Ib. R12 preferably has the structure shown in Figure II in which Ro is -CH = CH- or (-CH2-) d and R4 is -CH = CH- or (-CH2-) a, wherein a and d are independently 0 to 8. Methods for preparing diphenol monomers in which R9 or R12 contain as a part of their structures a carboxylic acid ester group are described in US Pat. Nos. 5,587,507 and 5,670,602, the descriptions of which are incorporated in the present reference manner. The desaminotirosyl-tyrosine esters that are preferred are the ethyl, butyl, hexyl, octyl and benzyl esters. For the purposes of the present invention, the desaminotirosyl-tyrosine ethyl ester is called DTE, the benzyl ester of desaminotirosyl-tyrosine is called DTBn and the like. For purposes of the present invention, the non-esterified desaminotyrosyl-tyrosine carboxylic acid is called DT. It is not possible to polymerize the polycarbonates, polyarylates and the poly (alkylene) oxide block copolymers thereof having free carboxylic acid pendant groups from the corrnding diphenols with free carboxylic acid pendant groups without the cross reaction of the group of free carboxylic acid with the comonomer. Accordingly, polycarbonates, polyarylates and poly (alkylene) oxide block copolymers thereof which are homopolymers or copolymers of benzyl ester diphenolic monomers such as DTBn can be converted to the corrnding free carboxylic acid homopolymers and copolymers by selective removal of the benzyl groups by the palladium-catalyzed hydrogenolysis method described in the co-pending US patent and co-owned No. 09 / 056,050, filed on April 7, 1998. The description of this application is incorporated herein by reference reference. Catalytic hydrogenolysis is necessary because the capacity of the polymer base structure avoids the use of more aggressive hydrolysis techniques. The dihydroxy compounds substituted with bromine and iodine also include the aliphatic-aromatic dihydroxy compounds having the structure of the formula III in which, R5 Re, R15 X2, Y2 and Z are the same as those described above with respect to formula III. Among the preferred aliphatic-aromatic dihydroxy compounds are the compounds of the formula III wherein R-? 5 is (-CH2-) m, wherein m is 0, Y2 is 1, and R5 and R6 are preferably selected independently of hydrogen and methyl. Z preferably has a structure according to formula IV in which L is hydrogen or an ethyl, butyl, hexyl, octyl or benzyl group. L is most preferably hydrogen or an ethyl or benzyl group. When R5 and Re are hydrogen, and R15 is (-CH2-), where m = 0, the dihydroxy compound is derived from glycolic acid. When R15 is the same, R5 is hydrogen and Re is methyl, the dihydroxy compound is derived from lactic acid. Dihydroxy derivatives of glycolic acid of lactic acid are particularly preferred. Two aliphatic-aromatic dihydroxy compounds that are not substituted with bromine or iodine have the structure of the formula lile: wherein R16, R17 R, R19 and Z are the same as those described above with respect to formula IIIb. Preferably, Ri8 (-CH2-) d, wherein d is 0 and R6 and R7 are independently selected from hydrogen and methyl. Most preferably, one of R 6 and R 17 is hydrogen, while the other is methyl. The Z species that are preferred are the same as those described above with respect to formula III. The dihydroxy-substituted bromine and iodine monomers of the present invention are prepared by well-known iodination and bromination techniques which can be readily employed by those skilled in the art without undue experimentation to prepare the monomeric compounds illustrated in formulas I and III. The substituted phenols from which the dihydroxy monomers of the present invention are prepared undergo ortho-directed halogenation. For this reason, the dihydroxy meta-iodated and brominated monomers are not easily prepared, and the triiodo- and tribromophenyl compounds have not been described. It is intended that said compounds be included within the scope of the present invention, if a convenient method for their synthesis were discovered. Diphenol monomers substituted with iodine and bromine can be prepared, for example, by coupling two phenol compounds in which each or both of the phenol rings are replaced with iodine or bromine. More specifically, the desaminotirosyl-tyrosine esters can be prepared by the methods described in U.S. Patent Nos. 5,587,507 and 5,670,602 incorporated above, using alkyl esters of desaminotyrosine and tyrosine in which each or both compounds are substituted with bromine or iodo. In a particularly preferred embodiment, desaminotyrosine is mono-iodinated in the ortho position on the phenolic ring and subsequently coupled with an alkyl tyrosine ester to obtain a diphenolic monomer substituted with iodine. The aliphatic-aromatic dihydroxy-aromatics substituted with iodine and bromine according to the present invention are prepared by coupling an α-, β- or β-hydroxy acid with a phenolic compound in which each or both of the hydroxy acid and diphenol are substituted with iodine or bromine. For example, an alkyl ester of tyrosine is mono-iodinated in the ortho position on the phenolic ring and subsequently coupled with an α-, β- or β-hydroxy acid according to the method described in International Publication 98/36013 incorporated above for obtaining an aliphatic-aromatic dihydroxy monomer substituted with iodine. The polycarbonate polycarbonate polycarbonate and poly (alkylene) oxide block copolymers thereof having free carboxylic acid pendant groups also can not be polymerized from an aliphatic-aromatic dihydroxy monomer having a free carboxylic acid pendant group due to the cross reaction with the comonomer. The methods for preparing the aliphatic-aromatic dihydroxy monomers of formulas III and I in which L of Z is not hydrogen are described in International Publication No. 98/36013, as the disclosure of which is incorporated herein by reference. L of Z is preferably an ethyl, butyl, hexyl, octyl or benzyl group. The polycarbonate polycarbonates, and poly (alkylene) oxide block copolymers thereof having free carboxylic acid pendant groups can also be prepared by the palladium-catalyzed hydrogenolysis of the corresponding polymers with benzylic esters prepared as described in the application US patent Serial No. 09 / 056,050 mentioned above. Catalytic hydrogenolysis can be carried out as described in this provisional patent application as well. The polycarbonates and polyarylates, alone, or as segments within a poly (alkylene) oxide block copolymer, can be homopolymers with each monomeric dihydroxy subunit having an iodine atom or a bromine atom. The polymers of the present invention also include copolymers of the same polymer units with dihydroxy monomers that are free of iodine and bromine. The molar ratios of the monomeric subunits having bromine and iodine atoms, and the monomeric subunits that are free of bromine and iodine can be varied within the polymers. The polymers according to the present invention include this way homopolymers of a repeating unit having at least one iodine or bromine atom. Said homopolymers have the structure of formulas VIII and Villa in which f and g are both zero. The polymers according to the present invention also include in this manner copolymers having repeating units that are free of bromine and iodine. Said copolymers have the structure of formulas VIII and Villa in which f is zero and g has a number greater than zero but less than one. In the copolymers according to the present invention, g is preferably between about 0.25 and about 0.75. In the homopolymers and copolymers of the formula VIII that is preferred, Rg has the structure of the formula II and R? 2 has the structure of the formula V. The preferred species thereof are the same as those written above with respect to the formula II and formula V. When A of the formulas VI 11 and VI I is: OR II-C - the polymers of the present invention are polycarbonates. When f is zero, the polycarbonate homopolymers and copolymers substituted with iodine and bromine of the present invention can be prepared by the method described in U.S. Patent No. 5,099,060 and in the U.S. patent application. Serial No. 08 / 884,108, filed June 27, 1997, the descriptions of which are also incorporated herein by reference. The method described is essentially the conventional method for polymerizing dihydroxy monomers in polycarbonates. Suitable methods, catalysts and associated solvents are known in the art and are shown in Schnell, Chemistry and Physics of Polycarbonates, (Interscience, New York 1964), the teachings of which are hereby incorporated by reference. The polycarbonate homopolymers and copolymers according to the present invention in which f = 0 have weight average molecular weights ranging from about 20,000 to about 400,000 daltons, and preferably about 100,000 daltons, as measured by gel permeation chromatography (GPC) ) in relation to polystyrene standards without additional correction. When A of the formulas VIII and Villa is: O O II II HO-C-R8-C-OH (X) The polymers of the present invention are polyarylates. The iodo and bromo substituted polyarylate homopolymers and copolymers of the present invention can be prepared by the method described in the US Pat.

E.U.A. No. 5,216,115, in which the dihydroxy monomers are reacted with aliphatic or aromatic dicarboxylic acids in a direct polyesterification mediated by carbodiimide using 4- (dimethylamino) pyridinium p-toluenesulfonate (DPTS) as a catalyst to form aliphatic or aromatic polyarylates. The description of this patent is also incorporated herein by way of reference. It should be mentioned that R8 must not be substituted with functional groups that could react cross-wise. The dicarboxylic acids from which the polyarylate materials of the present invention can be polymerized have the structure of formula X: wherein, for the aliphatic polyarylates, R8 is selected from saturated and unsaturated, substituted and unsubstituted alkyl groups containing up to 18 carbon atoms, and preferably from 4 to 12 carbon atoms. For the aromatic polyarylates, R8 is selected from aryl and alkylaryl groups containing up to 18 carbon atoms, but preferably from 8 to 14 carbon atoms. Again, R8 should not be replaced with functional groups that could cross-react. R8 is still more preferably selected such that the dicarboxylic acids from which the polyarylate starting materials are polymerized are naturally occurring metabolites or important highly biocompatible compounds. Therefore, the preferred aliphatic dicarboxylic acids include the intermediate dicarboxylic acids of the cellular respiration pathway known as the Krebs Cycle. These dicarboxylic acids include alpha-ketoglutaric acid, succinic acid, fumaric acid, maleic acid and oxalacetic acid. Other biocompatible aliphatic dicarboxylic acids that are preferred include sebacic acid, adipic acid, oxalic acid, malonic acid, glutaric acid, pimelic acid, suberic acid and azelaic acid. Among the aromatic dicarboxylic acids that are preferred are terephthalic acid, isophthalic acid and bis (p-carboxyphenoxy) alkanes such as bis (b-carboxyphenoxy) propane. In other words, R8 is most preferably a portion selected from -CH2-C (= 0) -, -CH2-CH2-C (= 0) -, -CH = CH- and (-CH2-) Z, wherein z is an integer between two and eight, inclusive. The iodo and bromo substituted polyarylate homopolymers and copolymers according to the present invention have weight average molecular weights of between about 20,000 and about 400,000 daltons, and preferably about 100,000 daltons, as measured by GPC in relation to polystyrene standards without correction additional. The polycarbonates and polyarylates substituted with iodine and bromine according to the present invention also include random block copolymers with a poly (alkylene) oxide with the structure of formulas VIII or Villa, where f is greater than zero but less than one . The variable species, and the preferred modalities thereof, are the same as those described above with respect to formulas VIII or Villa, except that f is no longer zero and the value for g is less than one, and g may or may not be greater than zero. The mole fraction of alkylene oxide in the block copolymer, f, ranges from about 0.01 to about 0.99. For the block copolymers that are preferred, R7 is ethylene, k is between about 20 and about 200, and the mole fraction of alkylene oxide in the block copolymer, f, preferably ranges from about 0.05 to about 0.75. R may also represent two or more different alkylene groups within a polymer. The block copolymers of the present invention can be prepared by the method described in the U.S.A. No. 5,658,995, the disclosure of which is also incorporated herein by way of reference. The block copolymers have weight average molecular weights of between about 20,000 and about 400,000 daltons, and preferably about 100,000 daltons. The number average molecular weights of the block copolymers are preferably above about 50,000 daltons. Molecular weight determinations are measured by GPC in relation to PEG standards without further correction. For the homopolymers and copolymers according to the present invention having pendant carboxylic acid amide or ester groups, the amide or ester group can be an amide derivative or ester of a pharmaceutically or biologically active compound covalently linked thereto. The covalent bond is via an amide bond when a primary or secondary amine is present in the position of the amide bond in the derivative in the non-derivatized biological or pharmaceutically active compound. The covalent bond is via an ester linkage when a primary hydroxyl is present in the position of the ester linkage in the derivative in the non-derivatized biological or pharmaceutically active compound. The biologically or pharmaceutically active compounds can also be derivatized in a ketone, aldehyde or carboxylic acid group with a linking portion such as the linking portion R3 of the formula Illa, which is covalently linked to the copolymer or diphenol via a linkage of ester or amide. Detailed chemical procedures for the binding of various drugs and ligands to free carboxylic acid groups bound to polymer have been described in the literature. See, for example, US patents. Nos. 5,219,564 and 5,660,822; Nathan et al., Bio. Cone. Chem., 4. 54-62 (1993) and Nathan, Macromolecules, 25, 44-76 (1992). The descriptions of both patents and both articles are hereby incorporated by reference. These publications describe methods by which polymers having free carboxylic acid pendant groups are reacted with portions having reactive functional groups, or which are derived to contain active functional groups to form a polymer conjugate. The order of the reaction can also be reversed. The portion may first be attached to a monomer having a free carboxylic acid pendant group, which is then polymerized to form a polymer in which 100% of the pendant free carboxylic acid groups have portions attached thereto. When a polymer having free carboxylic acid pendant groups is first polymerized and then reacted with a biological or pharmaceutically active compound or derivative thereof to form a polymer conjugate, not all free carboxylic acid pendant groups will have a compound biologically or pharmaceutically active covalently attached to them. Typically, a conjugate is formed in which the biologically or pharmaceutically active compounds bind to at least about 25% of the free carboxylic acid pendant groups. Examples of biologically or pharmaceutically active compounds suitable for use with the present invention include acyclovir, cephradine, malflease, procaine, ephedrine, adriamycin, daunomycin, plumbagin, atropine, quinine, digoxin, quinidine, biologically active peptides, chloro6, cephradine, cephalothin, proline. and proline analogs such as cis-hydroxy-L-proline, melphalan, penicillin V, aspirin, nicotinic acid, chemodeoxycholic acid, chlorambucil and the like. Biologically active compounds, for the purposes of the present invention, are further defined as including cell binding mediators, biologically active ligand and the like. The compounds are covalently linked to the polycarbonate or polyarylate by methods well understood by those skilled in the art. The drug delivery compounds can also be formed by physically combining the biologically or pharmaceutically active compound that will be supplied with the polymers of the present invention. In any case, the polymers of the present invention provide a means by which the drug delivery can be monitored using x-ray imaging without the need to employ a filler material to provide a contrast medium for x-rays. For the purposes of the present invention, the alkyl ester and amide groups within Z are also defined as including entanglement portions, such as molecules with double bonds (e.g., acrylic acid derivatives), which can be attached to the groups of carboxylic acid pendants so that the entanglement increases the resistance of the polymers. As mentioned above, the polymers of the present invention are substituted with iodine or bromine in selected repeating subunits. For the purposes of the present invention, homopolymers (formula VIII or Villa, x = 0) are defined as containing a subunit of iodine or bromine in each subunit. These homopolymers may be polycarbonates or polyarylates which may contain polyalkylene oxide blocks. Homopolymers are best described as novel radiopaque polymers that can have a number of pharmacological and biological activities. Also, for the purposes of the present invention, copolymers (formula VIII or Villa, 0 <x < 1) are defined as containing iodine or bromine in some of the diphenolic subunits. These copolymers may be polycarbonates or polyarylates, which may also contain polyalkylene oxide blocks. The invention described herein also includes various pharmaceutical dosage forms containing the polymers of the present invention. Pharmaceutical dosage forms include those conventionally recognized, for example, tablets, capsules, liquids and oral solutions, drops, parenteral solutions and suspensions, emulsions, oral powders, inhalable solutions or powders, aerosols, topical solutions, suspensions, emulsions, creams, lotions, ointments, transdermal liquids and the like. The pharmaceutical dosage forms may include one or more pharmaceutically acceptable carriers. Said materials are not toxic to the receptors in the doses and concentrations employed, and include diluents, solubilizers, lubricants, suspending agents, encapsulating materials, penetration enhancers, solvents, emollients, thickeners, dispersants, pH regulators such as phosphate, citrate. , acetate and other salts of organic acid, antioxidants such as ascorbic acid, preservatives, low molecular weight peptides (less than about 10 residues) such as polyarginine, proteins such as serum albumin, gelatin or immunoglobulins, other hydrophilic polymers such as poly (vinylpyrrolidinone), amino acids such as glycine, glutamic acid, aspartic acid or arginine, monosaccharides, disaccharides and other carbohydrates, including cellulose or its derivatives, glucose, mannose or dextrins, chelating agents such as EDTA, sugar alcohols such as mannitol or sorbitol, counterions such as sodium and / or tens agents nonionic surfactants such as tween, pluronic or PEG. The drug-polymer compositions of the present invention, regardless of whether they are in the form of polymer-drug conjugates or physical mixtures of polymer and drug, are suitable for applications in which localized drug delivery is desired, as well as in situations where you want a systemic supply. Polymer-drug conjugates and physical mixtures can be implanted in the body of a patient requiring them, by methods that are essentially conventional and well known to those skilled in the art. Hydrolytically stable conjugates are used when the biological or pharmaceutical compound is active in conjugated form. Hydrolyzable conjugates are used when the biological or pharmaceutical compound is not active in conjugated form. The properties of the poly (alkylene) oxide dominate the polymer and the conjugate thereof. The conjugates of the polymers of the present invention with proline and proline analogues such as cis-hydroxy-L-proline can be used in the treatment methods described in the US patent. No. 5,660,822. The description of this patent is incorporated herein by reference. Physical mixtures of drug and polymer are prepared using conventional techniques well known to those skilled in the art. For this drug delivery mode, it is not essential that the polymer has free carboxylic acid pendant groups. The drug components that will be incorporated into the polymer-drug conjugates and physical mixtures of the invention can be provided in a physiologically acceptable carrier, excipient stabilizer, etc., and can be provided in sustained release or regulated release formulations supplemental to the polymeric formulation prepared in this invention. The vehicles and diluents listed above for aqueous dispersions are also suitable for use with conjugates and physical polymer-drug mixtures. Subjects in need of treatment, typically mammals, can be administered with doses of drugs that will provide optimal efficacy, using the polymer-drug combinations of the invention. The dose and method of administration will vary according to the subject and will depend on several factors such as the type of mammal to be treated, sex, weight, diet, current medications, general clinical condition, the particular compounds used, the specific use for which said compounds are employed, and other factors that will be recognized by those skilled in the medical arts. The polymer-drug combinations of the invention can be prepared for storage under conditions suitable for the preservation of drug activity as well as for maintaining the integrity of the polymers, and are typically suitable for storing at ambient or cooling temperatures. Aerosol preparations are typically suitable for nasal or oral inhalation, and may be in the form of powder or solution in combination with a compressed gas, typically compressed air. Additionally, aerosols can be used topically. In general, topical preparations can be formulated to allow someone to apply the appropriate dose in the affected area once a day, and up to three or four times a day, as appropriate. Depending on the particular compound selected, the transdermal delivery may be an option, providing a relatively stable supply of the drug, which is preferred in some circumstances. The transdermal delivery typically involves the use of a compound in solution, with an alcoholic vehicle, optionally a penetration enhancer, such as a surfactant, and other optional ingredients. Transdermal matrix and reservoir delivery systems are examples of suitable transdermal systems. The transdermal delivery differs from conventional topical treatment in that the dosage form delivers a systemic dose of the drug to the patient. The polymer-drug formulations of the invention can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, long unilamellar vesicles and multilamellar vesicles. The liposomes can be used in any of the appropriate administration routes described herein. For example, liposomes can be formulated to be administered orally, parenterally, transdermally or via inhalation. The toxicity of the drug could be reduced by selective drug delivery at the affected site. For example, if the drug is encapsulated in liposome, and injected intravenously, the liposomes used are harvested by vascular cells and thus locally high concentrations of the drug can be released for a time within the wall of the blood vessels, resulting in an action of Improved drug The drugs encapsulated in liposomes are preferably administered parenterally, and particularly, by intravenous injection. The liposomes can be directed to a particular site for drug release. This could counteract the excessive doses that are sometimes necessary to provide a therapeutically useful dose of a drug at the site of activity, and as a consequence, the toxicity and side effects associated with higher doses. The drugs incorporated in the polymers of the invention can desirably incorporate agents to facilitate their systemic delivery to the desired drug target, as long as the delivery agent meets the same criteria as the drugs described above. The active drugs that will be delivered can thus be incorporated with antibodies, antibody fragments, growth factors, hormones, or other target portions, to which the drug molecules are coupled. The polymer-drug combinations of the invention can be made into formed particles such as valves, stents, tubes, prostheses, and the like. Therapeutically effective doses can be determined either by in vitro or in vivo methods. For each particular compound of the present invention, individual determinations should be made to establish the optimum dose required. The scale of the therapeutically effective doses will naturally be influenced by the route of administration, the therapeutic objectives, and the condition of the patient. For the different routes of administration, the absorption efficiency should be determined individually for each drug by methods well known in pharmacology. Likewise, it will be necessary for the therapist to dose the dose and modify the route of administration as required to obtain the optimal therapeutic effect. The determination of effective dose levels, that is, the dose levels necessary to achieve the desired result will be within the scope of the person skilled in the art. Typically, compound applications begin at very low dose levels, increasing the dose levels until the desired effect is achieved. The rate of drug release from the formulations of the invention also varies within the routine of the skilled artisan to determine an advantageous profile depending on the therapeutic conditions that will be treated. A typical dose will be on the scale of about 0.001 mg / k / g to about 1000 mg / k / g, preferably about 0.01 mg / k / g to about 100 mg / k / g, and most preferably about 0.10 mg / k / ga approximately 20 mg / k / g. Advantageously, the compounds of the invention can be administered several times a day, and it is also possible to use other dose regimens. In practicing the methods of the invention, the polymer-drug combinations can be used alone or in combination with other therapeutic or diagnostic agents. The compounds of the invention can be used in vivo, commonly in mammals such as primates, such as humans, sheep, horses, cattle, pigs, dogs, cats, rats and mice or in vitro. The polymers of the present invention are also applied in areas where both solid and solvent soluble materials are commonly employed. Such applications include polymeric support structures in tissue engineering applications and medical implant applications, including the use of the polymers of the present invention to make shaped articles such as vascular grafts and stents, bone plates, sutures, implantable sensors, structures of support for tissue regeneration, and other particles of therapeutic agents that decompose harmlessly within a known period of time. The particles formed can be made by conventional techniques such as extrusion, compression molding, injection molding, solvent casting, spin casting and the like. The polymers of the present invention are soluble in both water and organic media. Likewise, they can be processed for solvent casting techniques and are good film formers. The polymers of the present invention having free carboxylic acid pendant groups can also be used to influence interactions with cells, as presented in the aforementioned international publication No. 98/36013. The incorporation of polyalkylene oxide blocks decreases the adhesion capacity of the polymeric surfaces. Polymers where f is greater than 5 mol% according to formulas VIII or Villa are resistant to cell attachment and may be useful as non-thrombogenic coatings on surfaces in contact with blood. These polymers also resist bacterial adhesion. The polymers formed in this way can be made as a coating on the surface of medical devices for conventional immersion or spray coating techniques to avoid the formation of blood clots or the adhesion of bacteria on the surface of the device. The film-forming properties of polymers with poly (alkylene) oxide can be advantageously combined with resistance to cell attachment to provide films that are used as barriers for the prevention of surgical adhesions. A coating of the polymer of the present invention can be applied to the damaged tissue to provide a surgical adhesion barrier. The polymers of the present invention can be applied in areas where structural solid materials and water soluble materials are commonly employed. These applications include polymer support structures in tissue engineering applications and medical implant applications, including the use of polycarbonates and polyarylates of the present invention to make shaped articles such as vascular grafts and stents, bone plates, sutures, implantable sensors, barriers to prevent surgical adhesion, implantable drug delivery devices, support structures for tissue regeneration, and other articles of therapeutic agents that decompose without causing damage within a known period of time.

Industrial Application Capability The articles formed can be prepared from the polymers of the present invention for medical implant and drug delivery applications. The articles are radiopaque and can be monitored using X-ray images without having to use a filler material to provide X-ray contrast. The following non-limiting examples illustrate certain aspects of the invention. All parts and percentages are mole percent unless otherwise specified and all temperatures are in degrees Celsius. All solvents were of CLAR grade. All other reagents were of analytical grade and used as received. The following examples illustrate the preparation of 3- (3-iodo-4-hydroxyphenyl) propanoic acid-tyrosine ethyl ester (DiTE), and its incorporation into a variety of polymeric structures. Because iodine is present in the DiTE structure, the materials illustrated in the following examples are radiopaque.

EXAMPLE 1 Synthesis of DiTE DiTE (3- (3-iodo-4-hydroxyphenyl) propanoic acid-tyrosine ethyl ester) is a bisphenol that carries an iodine atom in position 3 of one of the two phenolic rings. This bifunctional molecule can be polymerized as illustrated in the subsequent examples. This example describes the method used to introduce the iodine atom into the aromatic ring of (4-hydroxyphenyl) propionic acid, and the coupling of this iodinated derivative with tyrosine ethyl ester to obtain DlTE. Preparation of the solution (a): to an Erlenmeyer flask of 250 mL were added 100 mL of distilled water, 24 g of potassium iodide, and 25 g of iodine. The mixture was stirred overnight until the solids dissolved.

Preparation of solution (b): 16.6 g (0.1 mole) of DAT was placed in a 3-neck Morton-type round bottom flask equipped with a top mixer and a 125 mL addition funnel. 140 mL of 40% trimethylamine solution in water was added, and the mixture was stirred until a clear solution was obtained. Solution (a) was placed in an addition funnel, and was added by dripping into solution (b) while stirring vigorously. The addition of each drop of solution (a) gave a brown color to the reaction mixture. The rate of addition was such that all the color disappeared before adding the next drop. Stirring was continued for 1 hour after the last addition, and the 50 mL of 0.1 M sodium thiosulfate was added to the reaction vessel. The same solution was used to wash the addition funnel. 37% HCl was added by dripping with vigorous mixing until the solution was slightly acidic to litmus, and a solid formed. The mixture was concentrated to half its volume by rotary evaporation, and then extracted with ether. The organic phase was dried over magnesium sulfate, and decolorized using animal charcoal. The suspension was filtered through a small layer of silica gel, and evaporated to dryness. The white solid was recrystallized twice from toluene, recovered by filtration, dried under a stream of nitrogen, and then under high vacuum. Characterization: The DSC analysis showed a melting point scale of 109-111 ° C. 1 H-NMR (DMSO) of the product showed the following peaks (ppm): 2.5 (t, 2H), 2.7 (t, 2H), 6.8 (d, 2H), 7.06 (d, 2H), 10.08 (s, 1 H ), 12.05 (s, 1 H). The reverse phase HPLC showed 3.8% DAT (starting material), and 1.4% of digested product.

Step 2: Preparation of 3- (3-vodo-4-hydroxyphenyl) propionic acid-tyrosine ethyl ester (DlTE) To a 250 mL 3-necked round bottom flask equipped with an overhead stirrer was added 17.0 g (0.0582 moles) ) of DiAT, 12.25 g (0.0585 moles) or ethyl tyrosine ester, and 25 mL of NMP. The mixture was stirred until a clear solution was obtained. The flask was cooled in a water-ice bath, the 11.84 g (0.0619 moles) of EDCI HCl were added in one portion, followed by 15 mL of NMP. The cooling bath was removed after 2.5 hours, and the reaction was allowed to continue overnight at room temperature. 71 mL of ethyl acetate were added, and the stirring was maintained for another 15 minutes. The crude material was transferred to a 500 mL separatory funnel, and extracted once with 75 mL of brine, then with two aliquots (75 and 35 mL) of 3% NaHCO3 / 14% NaCl, followed by 35 mL of aliquots. 0.4 M HCl / 14% NaCl, and finally with brine. The organic phase was dried over magnesium sulfate and treated with activated carbon, filtered and concentrated to a thick syrup, which crystallized in a solid mass after a few hours. The product was triturated in methylene chloride using mechanical stirring, then recovered by filtration and dried under a stream of nitrogen followed by high vacuum.

Characterization: The DSC analysis showed a melting point scale of 110-113 ° C. 1 H NMR (DMSO) showed the following peaks (ppm): 1.1 (t, 3H), 2.35 (t, 2H), 2.65 (m, 2H), 2.85 (m, 2H), 4.05 (q, 2H), 4.35 ( m, 1 H), 6.65 / 6.75 / 6.95 (m, 6H), 7.5 (s, 1 H), 8.25 (d, 1 H), 9.25 (s, 1 H), 10.05 (s, 1 H). The reverse phase HPLC showed 2.2% of DTE (non-iodinated monomer), and non-digested product.

EXAMPLE 2 PolKDiTE carbonate) by solution polymerization This material is the obtained polycarbonate reacted DiTE, obtained in example 1, and phosgene.

Polymerization of DlTE with phosgene A 250 ml 3-necked flask equipped with a mechanical stirrer and an addition funnel was purged with nitrogen for 15 minutes. 7.62 g (15.8 mole) of DiTE were added to the flask followed by 39 mL of methylene chloride and 4.79 mL of distilled pyridine. The mixture was stirred until a clear solution was obtained, then cooled in an ice-water bath. 9.8 mL of 20% phosgene solution in toluene were placed in the addition funnel and added to the reaction flask at a constant rate so that the complete addition was completed in 1.5 hours. The mixture was stirred for an additional hour, and then diluted with 200 mL of THF, and the polymer was precipitated by dropwise placing the solution in a large excess of ether through a filtration funnel. The precipitated polymer was washed with ether, transferred to an evaporation vessel, and dried overnight under a stream of nitrogen. It was redissolved in THF, and precipitated again in a water / ice mixture, using a high speed mixer. The product was then dried under a stream of nitrogen, followed by high vacuum at 40 ° C. Characterization: The composition of the product was confirmed by elemental analysis:% C = 50.60 (theory: 49.52%); % H = 4.21 (theory: 3.96%); % N = 2.65 (theory: 2.75%); % l-24.01 (theory: 24.92%). A Pm of 104K with a polydispersity of 1.8 was determined by GPC in THF against polystyrene standards. DSC showed a Tg of 103.8 ° C. 1 H NMR (DMSO-D6) showed the following peaks (ppm): 1.1 (t, 3H), 2.4 (broad, 2H), 2.75 (broad, 2H), 3.0 (broad, 2H), 4.05 (q, 2H), 4.45 (m, 1 H), 7.3 (m, 6H), 7.8 (s, 1 H), 8.4 (d, 1 H).

EXAMPLE 3 Poly (DlTE-co-5% PEG1K carbonate) by solution polymerization In this example, 5 mol% of PEG 1000 was copolymerized with DiTE through phosgenation by a solution polymerization technique similar to that described in example 2. The resulting material is a random polycarbonate.

Copolymerization of DiTE and PEG1000 A 100 mL 3-necked round bottom flask equipped with an addition funnel and an overhead stirrer was purged with nitrogen for 30 minutes. The flask was charged with 5 g (10.33 mmoles) of DiTE, and 0.545 g (0.55 mmoles) of PEG1000, and then 23 mL of methylene chloride and 3.3 mL of pyridine were added, and the mixture was stirred until a clear solution was obtained. , colorless The flask was cooled in an ice-water bath, and 6.4 mL of 20% phosgene solution in toluene was added by dripping over a period of 90 minutes from the addition funnel. The mixture was diluted with 90 mL of THE, and stirred for an additional hour. The product was isolated by precipitation in 800 mL of ethyl ether, and dried under a stream of nitrogen followed by high vacuum. Characterization: A Pm of 75,500 with a polydispersity of 1.8 was determined by GPC against polystyrene standards, with THF as the mobile phase. The DSC analysis showed Tg of 70 ° C. 1 H-NMR (CDCl 3) showed the following peaks (ppm): 1.2 (t, 3H), 2.45 (broad, 2H), 2.8 (broad, 2H), 2.03 (broad, 2H), 3.65 (s, 4.5 PEG protons) , 4.15 (q, 2H), 4.85 (m, 1 H), 6.05 (broad, 1 H), 7.05 / 7.15 (m, 6H), 7.2 (s, 1 H). The peaks at 7.05 / 7.15 and 7.2 are diagnostic for the presence of an iodine atom on the aromatic polymer system. The 13C NMR decoupled broadband (CDCI3) showed all the expected peaks, and in particular that of the aromatic carbon harboring iodine (90 ppm).

EXAMPLE 4 Poly (D? TE adipate) by solution polymerization This material is an alternative copolymer of diphenol containing iodine DiTE, and adipic acid, an aliphatic diacid. The monomers are linked through an ester linkage to form a polyarylate base structure. This example illustrates the preparation of this copolymer by a condensation reaction promoted by the coupling agent diisopropylcarbodiimide (DIPC).

Copolymerization of DiTE and adipic acid A 100 mL round bottom flask equipped with an overhead stirrer was purged with nitrogen for 1 hour, and then charged with 4,349 g (9.0 mmol) of DiTE, 1315 g (9.0 mmol) of adipic acid , 1.06 of dimethylaminopyridinium p-toluenesulfonate (2.5 mmol), and 68 mL of methylene chloride. The mixture was stirred for 5 minutes, and then 4.2 mL (27 mmol) of DIPC was added in one portion. Stirring was continued overnight at room temperature, then the crude reaction material was filtered, and the polymer was precipitated in 600 mL of isopropanol cooled in a high speed mixer, and isolated by filtration. The polymer was washed in a high speed mixer with 600 mL of cooled isopropanol, and the water / ice mixture of 600 mL. The product was dried overnight under a stream of nitrogen, and then transferred to high vacuum at room temperature. Characterization: a Pm of 67,100 with a polydispersity of 1.9 was determined by GPC against polystyrene standards, with THF as the mobile phase. The DSC analysis showed a Tg of 66.5 ° C. 1 H-NMR (DMSO-D6) showed the following peaks (ppm): 1.1 (t, 3H), 1.75 (broad, 4H), 2.4 (broad, 2H), 2.7 (wide, 6H), 2.95 (wide, 2H) , 4.05 (q, 2H0, 4.45 (m, 1 H), 7.05 / 7.15 (m, 6H), 7.7 (s, 1 H), 8.4 (d, 1 H).

EXAMPLE 5 Manufacture and implantation of radiopaque rods Radiopaque polymers containing iodine can be mixed with non-radiopaque materials in order to manufacture implantable devices that can be detected by X-rays. This example illustrates the preparation of mixtures of poly (DTE carbonate) and poly (DlTE carbonate) in three different ratios, its manufacture in rods, and its implantation in an animal model.

Preparation of radiopaque polymer blends Three mixtures with different ratios of poly (DTE carbonate) (Pm = 103 K) to poly (D? TE carbonate) (Pm = 106 K) were prepared. Weight ratios were 90/10, 75/25 and 50/50. In each case, the polymers were co-dissolved in methylene chloride, and the mixture was precipitated in ether.

Manufacture and implantation of radiopaque rods Uniform rods of 10 mm in length, 2 mm in diameter were obtained by extrusion of molten material at 180 ° C. The rods were implanted in the long rabbit bones, and the implantation sites were detected by X-rays to confirm the radiopacity of the devices. The radiopacity increased with increasing content of poly (DlTE carbonate). The above examples illustrate the radiopacity that can be obtained by Br and substitution in ring I of essentially any polymer containing aromatic ring. These examples, and the description of the preferred embodiments, should be taken as illustrative, and not limiting, of the present invention as defined by the claims. As will be apparent, numerous variations and combinations of the features set forth above can be used without departing from the present invention as set forth in the claims. Said variations do not depart from the spirit and scope of the invention, and said modifications attempt to be included within the scope of the following claims.

Claims (93)

1. NOVELTY OF THE INVENTION CLAIMS 1. - A radiopaque diphenol compound characterized because it has the structure: wherein each X-i and X2 is independently an iodine or bromine atom, Y1 and Y2 are independently between 0, 1 or 2, and R9 is an alkyl, aryl or alkylaryl group with up to 18 carbon atoms.
2. 2. The diphenol according to claim 1, further characterized in that Rg has the structure: wherein R0 is selected from the group consisting of -CH = CH-, -CHJ -? - CHJ2-y (-CH2-) m and R4 is selected from the group consisting of -CH = CH-, -CHJ CHJ2- and (-CH2-) n, where m and n are independently 0 to 8, inclusive, and J1 and J2 are independently Br or I; and Z is selected from the group consisting of hydrogen, a free carboxylic acid group and esters or amides thereof, said ester and amide are selected from the group consisting of straight and branched alkyl and alkylaryl groups containing up to 18 carbon atoms and derivatives of biologically and pharmaceutically active compounds.
3. 3. Diphenol according to claim 2, further characterized in that R4 is -CH2- or CHJrCHJ2- and R0 is CH2- or -CH2-CH2-.
4. 4. Diphenol according to claim 2, further characterized in that Z is a free carboxylic acid group or an ethyl, butyl, hexyl, octyl or benzyl ester or amide thereof.
5. 5. A radiopaque polymeric biomaterial characterized by a biocompatible polymer and the diphenol compound according to claim 1, physically mixed, embedded or dispersed in said polymer in an amount effective to radiopaque said polymer.
6. 6. A radiopaque dihydroxy compound characterized in that it has the structure: wherein, R5 and Re are each independently selected from the group consisting of H, Br, I and straight and branched alkyl groups having up to 18 carbon atoms, Ro is selected from the group consisting of -CH = CH-, -CHJ1-CHJ2- and (-CH2-) and R15 is selected from the group consisting of -CH = CH-, (-CH2-) C- and -CHJ CHJ2-, wherein J1 and J2 are independently Br or I; c and m are independently between 0 and 8, inclusive; each X2 is independently an iodine or bromine atom; Y2 is 1 or 2; and Z is selected from the group consisting of hydrogen, a free carboxylic acid group or an ester or amide thereof, said ester and amide are selected from the group consisting of straight and branched alkyl and alkylaryl groups containing up to 18 carbon atoms and derivatives of biologically and pharmaceutically active compounds.
7. 7. The dihydroxy compound according to claim 6, further characterized in that R15 is -CH- or -CHJ1-CHJ2- and Ro is -CH2- or -CH2-CH2-.
8. 8. The dihydroxy compound according to claim 6, further characterized in that Z is a free carboxylic acid group or an ethyl, butyl, hexyl, octyl or benzyl ester or amide thereof.
9. 9. The dihydroxy compound according to claim 6, further characterized in that R15 is (-CH2-) C, c is 0 and R1 and R2 are independently hydrogen or a methyl group.
10. 10. The dihydroxy compound according to claim 9, further characterized in that R1 and R2 are both hydrogen.
11. 11. The dihydroxy compound according to claim 9, further characterized in that one of R- \ and R2 is hydrogen and the other is a methyl group.
12. 12. The dihydroxy compound according to claim 6, further characterized in that R0 is -CH2- and Z is a carboxylic acid ethyl ester.
13. 13. A radiopaque polymeric biomaterial characterized by a biocompatible polymer and the dihydroxy compound according to claim 6, physically mixed, embedded or dispersed in said polymer in an amount effective to radiopaque said polymer.
14. 14. A radiopaque polymer characterized in that it has the following structure: wherein, X1 and X2 are independently I or Br, Y1 and Y2 are independently 0, 1 or 2, R is independently an alkylene group containing up to 4 carbon atoms; Rg and R12 are independently an alkyl, aryl or alkylaryl group containing up to 18 carbon atoms; A is: O O O II II II - C - or - C - Rg - C - wherein, R8 is selected from the group consisting of unsubstituted or substituted, saturated or unsaturated alkyl, aryl and alkylaryl groups containing up to 18 carbon atoms; k is between about 5 and about 3,000, and f and g are independently between 0 and 0.99, inclusive.
15. 15. The polymer according to claim 14, further characterized in that f and g are both 0. 16. - The polymer according to claim 14, further characterized in that Rg has the structure: wherein, Ro is selected from the group consisting of -CH = CH-, -CHJ CHJ2-y (-CH2-) m, R4 is selected from the group consisting of -CH = CH-, (-CH2-) a - and - CHJ1-CHJ2-, where a and m are independently between 0 and 8, inclusive; J1 and J2 are independently Br or I; and Z is selected from the group consisting of hydrogen, a free carboxylic acid group or an ester or amide thereof, said ester and amide are selected from the group consisting of straight and branched alkyl and alkylaryl groups containing up to 18 carbon atoms and derivatives of biologically and pharmaceutically active compounds. 17. The polymer according to claim 16, further characterized in that g is greater than 0 and R12 has a structure selected from the group consisting of: wherein, R0 is -CH = CH- or (-CH2-) m and R4 is -CH = CH- or (-CH2-) a-, a and m are independently between 0 and 8, inclusive; and Z is selected from the group consisting of hydrogen, a free carboxylic acid group or an ester or amide thereof, said ester and amide are selected from the group consisting of straight and branched alkyl and alkylaryl groups containing up to 18 carbon atoms and derivatives of biologically and pharmaceutically active compounds. 18. The polymer according to claim 17, further characterized because Rg has the structure: and R-I2 has the structure: O II - (CH2) a- C- NH- CH- (CH2-) B (V) Z where a and c are two and b and d are one. 19. The polymer according to claim 17, further characterized in that each Z of R9 and R-? 2 is an ester of a carboxylic acid; wherein each ester group is independently selected from the group consisting of ethyl, butyl, hexyl, octyl and benzyl groups. 20.- A radiopaque polymer characterized by the structure: (Villa) in which (a) R5 and RT are each independently selected from the group consisting of H, Br, I and straight and branched alkyl groups having up to 18 carbon atoms; and R-IT and R17 are each independently selected from the group consisting of H and straight alkyl groups and Branches having up to 18 carbon atoms, with the proviso that if g is zero, R1 and R2 are independently selected from Br or I unless R-15 is -CJ1-CJ2- or Z is a carboxylic acid amide; (b) R-? 5 is selected from the group consisting of -CH = CH-, (-CH2-) C- and -CHJ1-CHJ2-, where J1 and J2 are independently Br or I and c is 0 and 8, inclusive; (c) X2 is I or Br and Y2 is 1 or 2; (d) Z is selected from the group consisting of H, a free carboxylic acid group or an ester or amide thereof; (e) each R7 is an alkylene group containing up to four carbon atoms, with k being between about 5 and about 3,000; (f) A is: O O O II II II - C- or - C- Rs- C- wherein, R8 is selected from the group consisting of saturated and unsaturated, substituted and unsubstituted alkyl, aryl and alkylaryl groups containing up to 18 carbon atoms; (g) each R0 is independently -CH = CH- or (-CH2-) d-, where d is between 0 and 8, inclusive; and (h) f and g vary independently from 0 to less than 1. 21. The polymer according to claim 20, further characterized in that R0 or R15 are (-CH2-) d or (-CH2-) C, respectively, wherein c or d are 0, and R5, R6, R-iß, and R17 are independently hydrogen or a methyl group. 22. The polymer according to claim 21, further characterized in that R5, R6, R6, and R17 are all hydrogen. 23. The polymer according to claim 21, further characterized in that one of R5 and RT or Rie and R17 is hydrogen and the others are methyl. 24. The polymer according to claim 20, further characterized in that each Z is an ester of a carboxylic acid, wherein each ester group is independently selected from the group consisting of ethyl, butyl, hexyl, octyl and benzyl groups. 25. The polymer according to claim 24, further characterized in that both Ro or R-? 5 are (-CH2-) and each Z is an ethyl ester of a carboxylic acid. 26. The polymer according to claim 14 or 20, further characterized in that f is greater than 0. 27.- The polymer according to claim 26, further characterized in that each R7 group is ethylene. 28. The polymer according to claim 26, further characterized in that f is around 0.05 and about 0.95. 29. The polymer according to claim 14 or 20, further characterized in that A is: 30. - The polymer according to claim 14 or 20, further characterized in that A is: O O II II - C- R8- C - 31. - The polymer according to claim 30, further characterized in that R8 is selected from the group consisting of saturated and unsaturated, substituted and unsubstituted alkyl groups containing up to 8 carbon atoms. 32. The polymer according to claim 31, further characterized in that R8 selects the group consisting of -CH2-C (= 0) -, -CH2-CH2-C (= 0), -CH = CH- and ( -CH2) Q, where Q is between 0 and 8, inclusive. 33. - The polymer according to claim 30, further characterized in that R8 is selected from the group consisting of substituted and unsubstituted aryl and alkylaryl groups containing from 13 to 20 carbon atoms. 34. A radiopaque composition characterized by a biocompatible or biocompatible matrix polymer having physically mixed, dispersed or embedded the radiopaque compound according to claim 1 or claim 6. 35. The radiopaque composition according to claim 34, further characterized because said radiopaque compound is an analogue of a monomer from which said matrix polymer is polymerized. 36.-. A radiopaque composition characterized by a biocompatible or bioerodible matrix polymer having mixed or physically embedded therein the radiopaque polymer according to claim 14 or claim 20. 37.- A radiopaque composition characterized by a biocompatible matrix polymer or bioerodible having the radiopaque polymer physically mixed therein, or in accordance with claim 26. 38.- A radiopaque microsphere, characterized in that it is formed from the radiopaque composition according to claim 34. 39.- A microsphere radiopaque, characterized in that it is formed from the radiopaque composition according to claim 36. 40.- A radiopaque microsphere, characterized in that it is formed from the radiopaque composition according to claim 37. 41.- A radiopaque microsphere, characterized because it is formed from the polymer radiopaque according to claim 14 or claim 20. 42.- A radiopaque microsphere, characterized in that it is formed from a radiopaque polymer according to claim 26. 43.- A radiopaque, implantable medical device characterized by the radiopaque composition of according to claim 34. 44. - A radiopaque, implantable medical device characterized by the radiopaque composition according to claim 36. 45. - A radiopaque, implantable medical device characterized in that it is coated with the radiopaque composition according to claim 37. 46.- A radiopaque, implantable medical device characterized by the radiopaque polymer according to claim 26. 47.- A radiopaque, implantable medical device characterized in that it is coated with the radiopaque polymer according to claim 26. 48.- A movie that is used as a A barrier to prevent the formation of surgical adhesions, characterized by the radiopaque polymer according to claim 26. 49.- A film that is used as a barrier to prevent the formation of surgical adhesions, characterized by the radiopaque composition in accordance with the claim 37. 50.- A drug delivery device, characterized by a biological or pharmaceutically active compound in combination with the polymer according to claim 14 or claim 20, wherein said active compound is presented in effective amounts for drug delivery. Systemic or specific therapeutic on site. 51.- The drug delivery device according to claim 50, further characterized in that said active compound is covalently bound to said polymer. 52.- The drug delivery device according to claim 50, further characterized in that said active compound is physically mixed with said polymer or is physically embedded or dispersed in a matrix formed by said polymer. 53. A drug delivery device, characterized by a biological or pharmaceutically active compound in combination with the polymer according to claim 26, further characterized in that said active compound is present in amounts effective for delivery of systemic or specific therapeutic drug in site. 54.- The drug delivery device according to claim 53, further characterized in that said active compound is covalently bound to said polymer. 55.- The drug delivery device according to claim 53, further characterized in that said active compound is physically mixed with said polymer or is physically embedded or dispersed in a matrix formed by said polymer. 56.- A drug delivery device, characterized by a biological or pharmaceutically active compound in combination with the radiopaque composition according to claim 34, wherein said active compound is presented in amounts effective for delivery of systemic or specific therapeutic drug in site. 57.- The drug delivery device according to claim 56, further characterized in that said active compound is covalently bound to either the radiopaque compound or said matrix polymer. 58.- The drug delivery device according to claim 56, further characterized in that said active compound is physically mixed with said radiopaque composition or is physically embedded or dispersed in the polymer matrix of said radiopaque composition. 59.- A drug delivery device, further characterized by a biological or pharmaceutically active compound in combination with the radiopaque composition according to claim 36, wherein said active compound is presented in effective amounts for delivery of systemic or specific therapeutic drug. In place. 60.- The drug delivery device according to claim 59, further characterized in that said active compound is covalently bound to either said radiopaque polymer or said matrix polymer. 61.- The drug delivery device according to claim 59, further characterized in that said active compound is physically mixed with said radiopaque composition or is physically embedded or dispersed in the polymer matrix of said radiopaque composition. 62.- A drug delivery device, characterized by a biological or pharmaceutically active compound in combination with the radiopaque composition according to claim 37, wherein said active compound is presented in amounts effective for delivery of systemic or specific therapeutic drug in site . 63.- The drug delivery device according to claim 62, further characterized in that said active compound is covalently bound to said radiopaque polymer or to said matrix polymer. 64.- The drug delivery device according to claim 62, further characterized in that said active compound is physically mixed with said radiopaque composition or is physically embedded or dispersed in the polymer matrix of said radiopaque composition. 65.- A method for systemic or site-specific drug delivery characterized in that it is implanted in the body of a patient in need thereof by the implantable drug delivery device according to claim 50. 66.- The method of compliance with Claim 65, further characterized in that the active compound is covalently bound to said polymer. 67.- The method according to claim 65, further characterized in that said active compound is physically mixed with said polymer or is physically embedded or dispersed in a matrix formed by said polymer. 68.- A method for systemic or specific drug delivery in situ characterized in that it is implanted in the body of a patient in need thereof by means of the implantable drug delivery device according to claim 53. 69.- The method of compliance with Claim 68, further characterized in that said active compound is covalently bound to said polymer. The method according to claim 68, further characterized in that the active compound is physically mixed with said polymer or is physically embedded or dispersed in a matrix formed by said polymer. 71.- A method for delivery of systemic or specific drug in place characterized in that it is implanted in the body of a patient in need thereof by the implantable drug delivery device according to claim 56. 72.- The method of compliance with claim 71, further characterized in that said active compound is covalently linked to either the radiopaque compound or said matrix polymer. 73. - The method according to claim 71, further characterized in that the active compound is physically mixed with said radiopaque composition or is physically embedded or dispersed in the polymer matrix of said radiopaque composition. 74.- A method for systemic or site-specific drug delivery characterized in that it is implanted in the body of a patient in need thereof by the implantable drug delivery device according to claim 59. 75.- The method of compliance with claim 74, further characterized in that said active compound is covalently bound to either the radiopaque polymer or said matrix polymer. The method according to claim 74, further characterized in that the active compound is physically mixed with said radiopaque composition or is physically embedded or dispersed in the polymer matrix of said radiopaque composition. 77.- A method for delivery of systemic or specific drug in place characterized in that it is implanted in the body of a patient in need thereof by means of the implantable drug delivery device according to claim 62. 78.- The method of compliance with claim 77, further characterized in that the active compound is covalently linked to either the radiopaque polymer or said matrix polymer. 79. The method according to claim 77, further characterized in that the active compound is physically mixed with said radiopaque composition or is physically embedded or dispersed in the polymer matrix of said radiopaque composition. 80.- A method to prevent the formation of adhesions between damaged tissues characterized in that a film or sheet consisting essentially of the polymer according to claim 26 is inserted as a barrier between said damaged tissues. 81.- A method to avoid the formation of adhesions between damaged tissues characterized in that a sheet or film consisting essentially of the composition according to claim 37 is inserted as a barrier between said damaged tissues. 82. A method for regulating cell attachment, migration and proliferation on a polymeric substrate, which comprises contacting living cells, tissues or biological fluids containing living cells with the polymer according to claims 14, 20 or 26. 83.- A method for regulating cell attachment, migration and proliferation on a polymeric substrate, which comprises making contact with living cells, biological tissues or fluids containing living cells with the polymer according to claims 35, 36 or 37. 84. The method according to claim 82 or 83, further characterized in that said polymer is in the form of a coating on a medical implant. 85.- The method according to claim 82 or 83, further characterized in that said polymer is in the form of a film. 86.- The method according to claim 82 or 83, further characterized in that said polymer is in the form of a polymeric fabric support structure. 87.- A pharmaceutical composition characterized by (a) the polymer according to claims 14, 20 or 26, comprising one or more side chains conjugated to a biological or pharmaceutically active compound; and (b) a pharmaceutically acceptable carrier for said polymer conjugate. 88.- A pharmaceutical composition characterized by (a) the polymer according to claims 35, 36 or 37, comprising one or more side chains conjugated to a biological or pharmaceutically active compound; and (b) a pharmaceutically acceptable carrier for said polymer conjugate. 89.- The pharmaceutical composition according to claim 87 or 88, further characterized in that it is in the form of a tablet, capsule, suspension, solution, emulsion, liposome or aerosol. 90.- The pharmaceutical composition according to claim 89, further characterized in that it is in the form of an injectable suspension, solution or emulsion. 91.- The pharmaceutical composition according to claim 89, further characterized in that it is in the form of an injectable liposome composition. 92. - A radiopaque biocompatible polymer comprising monomeric repeating units substituted with at least one bromine or iodine atom, and having the structure: wherein Xi and X2 are independently iodo or bromo, each Y1 and Y2 are independently 0, 1 or 2, and Rg is an alkyl, aryl or alkylaryl group containing up to 18 carbon atoms. 93. A radiopaque biocompatible polymer comprising monomeric repeating units substituted with at least one bromine or iodine atom and having the structure: wherein X2 is independently iodo or bromine, each Y2 is 0, 1 or 2, and R5 and Re are independently selected from the group consisting of hydrogen, bromine, iodine and straight or branched alkyl groups containing up to 18 carbon atoms; R0 is -CH = CH-, (-CHJ1-CHJ2-) or (-CH2-) d and R15 is -CH = CH-, (-CHJ1-CHJ2-) or (-CH2-) m, where J1 and J2 they are independently bromine or iodine, and d and m are independently 0 to 8, inclusive; and Z is independently selected from the group consisting of hydrogen, a free carboxylic acid group and an ester or amide thereof, said ester and amide are selected from the group consisting of straight and branched alkyl and alkylaryl groups containing up to 18 carbon atoms. carbon and derivatives of biologically and pharmaceutically active compounds.