HK1105135B

HK1105135B - Polymeric coupling agents and pharmaceutically-active polymers made therefrom

Info

Publication number: HK1105135B
Application number: HK07110293.6A
Authority: HK
Inventors: Paul J. Santerre; Frank J. Laronde; Mei Li
Original assignee: Interface Biologics Inc.
Priority date: 2004-05-14
Filing date: 2005-05-13
Publication date: 2011-09-02

Description

Polymeric coupling agents and pharmaceutically active polymers prepared therefrom

Technical Field

The present invention relates to polymeric coupling agents useful as intermediates, pharmaceutically active polymers prepared therefrom, compositions comprising the polymers and shaped articles prepared therefrom.

Background

Presently, it is common to use implantable medical devices in a variety of medical conditions, such as drug infusion and hemodialysis. However, implantation of medical devices is often accompanied by the following risks of (1) infection, (2) inflammation, (3) hyperplasia, and (4) blood clotting. It is therefore very important to develop substances capable of enhancing biocompatibility. Biocompatibility is the ability of a substance to elicit an appropriate host response in a particular situation. The host is associated with the environment in which the biological material is placed and varies in location in the blood, bone, cartilage, heart and brain of a human. While any particular population of macromolecules may have this particular biomedical advantage, such materials, once incorporated into biomedical devices, are inherently constrained in their own performance because they do not have the ability to address all of the critical biocompatibility issues associated with the intended particular application. For example, where a material has certain platelet-related anticoagulation properties, it may not have the primary characteristics of a cascade coagulator, nor may it prevent bacterial colonization. Another material may have an antimicrobial effect but be biologically unstable for long term use. The incorporation of multifunctional properties in biomedical devices is often a complex and costly process that almost always compromises the properties or biological function of one polymer with another, yet all blood and tissue contacting devices can benefit from improved biocompatibility. Even clotting, toxicity, inflammation, infection, immune response in the simplest devices can cause death or irreversible damage to the patient. Since most of the interaction of blood and tissue materials occurs at the interface between the biological environment and the medical device, the composition of the outer molecular layer (mostly in the submicron layer) of the polymeric material is related to the biological interaction at the interface. This is a particularly challenging problem for biodegradable polymer systems when continued exposure of a new surface by erosion of the bulk polymer requires continued renewal of the biocompatible part of the surface.

Bioactive agents containing polymer coatings have been developed to improve the biocompatibility of medical device surfaces. Patnaik et al (5) describe a method of attaching a bioactive agent such as heparin (an anti-coagulant) to a polymeric substrate through a hydrophilic isocyanate/amine terminal spacer, the purpose of which is to provide a coating of the bioactive material on the medical device. Researchers have found that bioactive agent activity can be obtained when the spacer group has a molecular weight of about 100-10,000 daltons. But most preferably 4000 daltons. Unfortunately, such a material can only be applied to specific substrates that are not biodegradable and exchangeable for new tissue integration, since heparin is confined to the surface and does not form the main structure of the polymer chain.

Another example of biomaterial design relates to infection control. In the last decade, a number of strategies have been used in an attempt to address issues related to, for example, medical device infection. One approach is to provide a more biocompatible implantable device to reduce bacterial attachment. Silver plated catheters have been used to prevent exit site infections associated with chronic venous access (6) and peritoneal dialysis (7). However, long-term studies have failed to demonstrate a significant reduction in the number and severity of infection at the exit site. In addition, the bacteria's resistance to silver can increase over time with the risk of multiple antibiotic resistance (8).

Since bacterial attachment is a very complex process, it is very difficult to achieve complete prevention of bacterial attachment by passive methods alone. There remains a need for local controlled administration. Advantages of the latter approach include 1) the ability to achieve high and sustained local drug concentrations without systemic toxicity and side effects that can be produced by using sufficient systemic doses to achieve similar local drug concentrations; 2) high levels of local drug concentration can be achieved even with drugs that are rapidly metabolized or unstable when administered systemically; 3) some localized forms of administration may establish and maintain local drug activity by preventing the passage of drug out of the arterial wall or by the application of carriers or drugs that prolong the duration of activity; 4) the possibility of designing a smart drug delivery system that can trigger drug release and/or modulate the release rate depending on the infection condition is provided.

Methods of obtaining compositions comprising a drug and a polymer in a complex form to produce a bioactive agent release coating are known. For example, Chudzik et al (9) formulated a coating complex comprising a biologically active agent (e.g., a drug) and two polymers, namely poly (butyl methacrylate) and poly (ethylene-co-vinyl acetate). Coatings prepared from the above formulations have good durability and elasticity, and have significant drug release, which is particularly useful for devices such as stents and catheters that have significant bending and/or expansion characteristics during delivery and/or application. These devices have the advantage of local delivery at high levels of drug concentration, but they are not capable of maintaining long-term sustained and controlled release of the drug. Ragheb et al (10) have discovered a method for the controlled release of bioactive agents from a polymeric coating. Wherein two polymer coating layers are applied on the medical device. The first coating of the device is an absorbent material such as a parylene derivative. The drug or bioactive agent is deposited in at least a portion of the layer. The second biocompatible polymer layer over the drug and first layer must be porous. The polymer is applied by vapor deposition or plasma deposition. Since the drug release mechanism is fully controlled by the pore size, it is often a technical challenge to make an appropriate pore size distribution on the second layer to meet the requirements of the release model. In addition, this type of system requires multiple processing steps, which increases manufacturing costs and enhances the need for QA/QC steps.

In addition to the traditional diffusion-controlled delivery systems described in the above-mentioned documents, there are certain more sophisticated in situ drug delivery polymers that can alter the potency of the drug by improving the targeted delivery as well as altering the control parameters of the delivery rate. Including biodegradable hydrogels (11), polymerized liposomes (12), bioresorbable polymers (13) and polymeric drugs (14-16). Polymeric drugs include drugs covalently attached to a polymer chain with a pendant group, or even drugs incorporated into the polymer backbone. For example, Nathan et al (17) disclose the conjugated linkage of penicillin V and cephamidin to polyurethane in the form of a pendant antibiotic. Their work showed that the hydrolytically unstable pendants were dissociated and demonstrated antibacterial activity against staphylococcus aureus, enterococcus faecalis and streptococcus pyogenes.

Ghosh et al (18) couple nalidixic acid, a quinolone antibiotic, to the active vinyl molecule in a pendant manner. These vinyl groups are then polymerized to form a polymer that suspends the antibiotic on each monomer. However, having these pendant groups will significantly alter the physical structure of the polymer. A better alternative is to include the drug in a chain-like backbone portion of the polymer. In vivo hydrolysis studies, they reported that 50% of the drug was released within the first 100 hours. The quinolone drugs have been shown to be effective against gram-negative bacteria in the treatment of urinary tract infections, whereas chemical modifications (e.g., ciprofloxacin, norfloxacin, etc.) have a broader spectrum of antibacterial activity. Recent progress in the conjugation of norfloxacin and mannosylated dextran (mannalated dextran) has been reported. The motivation is to increase the absorption of drugs by cells to promote their faster entry into micro-organisms (19). Norfloxacin has been shown to be released from drug/polymer conjugates by enzymatic mediators, and in vivo studies have also shown that drug/polymer conjugates are effective against mycobacterium tuberculosis located in the liver area (20). In this system, the norfloxacin overhang is linked to the amino acid sequence from which it can be cleaved by the action of lysosomal enzymes, cathepsin B.

Santerre (13a) describes the synthesis and use of new materials that, when added to a polymer, can transform the surface into bioactive, and when removed, the overall performance of the polymer is virtually intact. The application is directed to the biomedical field. These materials are oligomeric fluorinated additives with pendant drugs that are delivered to the bulk polymer surface during the movement of the fluorine groups to the air/polymer interface. These materials can deliver large amounts of drugs to surfaces, including antibiotics, anti-coagulants, and anti-inflammatory drugs. However, the modification changes are limited to the surface. This becomes a limitation in biodegradable polymers that may need to remain active at various stages of the polymer bioerosion process.

Santerre and Mittleman (14) teach the synthesis of polymeric materials using pharmacologically active agents as one of the polymeric comonomers. Wherein, 1, 6-diisocyanatohexane and/or 1, 12-diisocyanatododecane monomer or oligomer molecule thereof reacts with antimicrobial agent, ciprofloxacin to generate drug polymer. The pharmacologically active compounds provide enhanced long-term anti-inflammatory, antibacterial, antimicrobial and/or antifungal activity. However, since the carboxylic acid groups and secondary amine groups of ciprofloxacin differ in reactivity with isocyanate groups, the kinetics of the reaction becomes very challenging. In addition, the components must be selective so as to minimize the strength of van der Waals interactions between the drug substance and the hydrogen bonding moieties of the polymer chains, which interactions can delay the effective release of the drug. The improvement of the latter system is therefore that of the biomonomers consisting of drugs and reagents, which, without being bound by theory, can ensure that the drug access is less restricted when the polymer is hydrolysed, and that it has more of the same chemical function for reacting with isocyanate groups or other monomeric reagents.

Publication (S)

(1)Mittelman，MW，″Adhesion to biomaterials″in BacterialAdhesion：Molecular and Ecological diversity，M Fletcher(ed)89-1271996)

(2) Burke, et al, "Applications of materials in medicine and characterization", Biomaterials Science, 1996, Ch.7, pp 283-.

(3)Martin R.Bennett，Michael O′Sullivan，″Mechanism ofangioplasty and stent restenosis：implications for design of rationaltherapy″，Pharmacology & Therapeutics 91(2001)pp 149-166.

(4) Eberhart, r.c., and c.p.clagett, "platlets, cathters, anddthe vessel wall; cathetercoatings, blood flow, and biocompatibility ", semi in Hematology, Vol.28, No.4, Suppl.7, pp 42-48(1991).

(5) U.S. Pat. No.6,096,525-Patnaik, BK. Aug.1, 2000

(6) Groeger j.s. et al, 1993, ann.surg.218: 206-210.

(7) Mittelman m.w., et al, 1994, ann.

(8) Silver s, et al, 1988, ann.rev.microbiol.42: 717-743

(9) U.S. patent No.6,344,035-Chudzik, et al, feb.5, 2002

(10) US patent No.6,299,604-Ragheb, et al Oct.9, 2001

(11) US.patent No.6,703,037-Hubbell et al Mar.9, 2004

(12) Biomaterials, 19: 1877-1884(1998)

(13) U.S. patent No.4,916,193-Tang et al and U.S. patent No.4,994,071-MacGrego

(13a) Application No. 10/162,084, U.S. patent filed 6/7/2002, Santerre, Paul J.

(14) Us patent No.5,798,115-Santerre, Paul j and Mittleman, Marc w. aug.25, 1998.

(15)Modak S.M.，Sampath，L.，Fox，C.L.，Benvenisty A.，Nowygrod，R.，Reemstmau，K.Surgery，Gynecology & Obstertrics，164，143-147(1987).

(16)Bach，A.；Schmidt，H.；Bottiger，B.；Schreiber B.；Bohrer，H.；Motsch，J.；Martin，E.；Sonntag，H.G.，J.Antimicrob.Chemother.，37，315，(1996)

(17)Nathan，A.；Zalipsky，S.；Ertel，S.L.；Agarthos，S.N.；Yarmush，M.L.；Kohn.J.Bioconjugate Chem.1993，4，54-62.)

(18)Ghosh M.Progress in Biomedical polymers，Gebekin CG.Etal(ed)，Plenum press，New York，1990，335-345；Ghosh M.PolymericMaterials，Science&Engineering 1988，59：790-793

(19)Coessens，V.；Schacht，E.，Domurado，D.J.ControlledRelease 1997，47 283-291

(20)Roseeuw，E.；Coessens V.；Schacht E.，Vrooman B.；Domurado，D.；Marchal G.J Mater.Sci：Mater.Med.1999，10，743-746

(21)Hemmerich，K.J.Polymer materials selection forradiationsterilized products，Medical Device & Diagnostic Industry，February，2000

(22)ISO 11137：Sterilization of health care products- Requirements for validation and routine control-Radiation sterilization.

Brief description of the invention

Due to the limited availability as commercial monomers of drugs specifically designed for use in the synthesis of the above-mentioned drug polymers for use in the complexes, there is a need for general synthetic methods for prodrugs. Rather than relying on the chemical functionality inherently provided by commonly available drugs, it would be better to be able to provide monomers with similar multifunctional groups, preferably with similar difunctional groups, for use in the synthesis of the hydrolyzed polymers. The invention relates to a new group of diamine or diol monomers, which simultaneously have the following characteristics: 1) they couple biological or pharmaceutical or biocompatible components via hydrolyzable bonds under mild conditions; 2) they include selectively reactive groups (difunctional or more) (including amines (secondary or primary) and hydroxyl groups) which are useful in the polymerization of polymers produced by subsequent polyesters, polyamides, polyurethanes, polysulfones and many other conventional procedures; 3) they contain selectively hydrolysable groups capable of releasing specific degradation products including biological, pharmaceutical or biocompatible components; 4) their molecular weight may vary depending on the molecular weight of the pharmaceutical or biocompatible agent, and may be as high as 4000, but generally the molecular weight of the molecules is preferably less than 2000, in order to provide them with good mobility of the molecular segments when incorporated into the polymer and good reactivity in the polymerization reaction solution; 5) they can provide strategies to enhance the introduction of important biological, pharmaceutical or biocompatible agents that additionally include functional groups (e.g., sequestered esters, sulfonamides, amides and anhydrides) that are poorly reactive in hydrolysis reactions due to the strong van der waals interactions and hydrogen bonding that exist between the drug polymer backbones. 6) Because these molecules have similar functional groups, they have consistent and more predictable reactivity during conventional polymer formation. The present invention describes a unique method of synthesis of biomonomers and provides examples of their use in the synthesis of polymers and discloses methods of making the polymers for applications in biodegradable materials ranging from biomedical to environmentally related products.

It is an object of the present invention to provide a method for the synthesis of biological coupling agents/biological monomers, including, for example, anti-inflammatory, antibacterial, antimicrobial and/or antifungal drugs as precursors to biological monomers, which have good reactivity in the synthesis of polymers.

It is another object of the present invention to provide a biopolymer comprising said bio-coupling compound/monomer, which is pharmaceutically active.

It is another object of the present invention to provide said polymeric compound alone or in admixture with a compatible polymeric biomaterial or polymeric composite biomaterial for use in the preparation of shaped products having pharmaceutical activity.

It is a further object of the invention to provide said tangible product for use as a medical device, including devices in contact with body fluids and tissues in the biomedical field, or for use in biotechnology for producing anti-infective, anti-inflammatory activity.

It is another object of the present invention to provide said polymer compound alone or in admixture with one of the alkaline polyurethanes, silicones, polyesters, polyethersulfones, polycarbonates, polyolefins or polyamides as a coating which is used as said medical device in the biomedical field for improving anti-infective, anti-inflammatory, antimicrobial, anticoagulant, antioxidant, antiproliferative functions.

It is another object of the invention to provide methods for preparing said biomonomers, polymers comprising said biomonomers, said mixtures and polymers of said shaped articles.

In summary, the present invention provides a unique synthetic method for covalently coupling biologicals or drugs or biocompatible components to such bendable diols or diamines, such as but not limited to triethylene glycol or any other kind of linear diol or diamine, under mild conditions. The bioactive agent must have a reactive group such as a carboxylic, sulfonate or phosphonate group that can be conjugated to a flexible diol or diamine through carbodiimide-mediated reactions. The biologically active agent used in the coupling reaction must also include selectively reactive multifunctional groups, preferably difunctional groups (including amine (secondary or primary amine) and hydroxyl groups) which are later available for polymerization of polyesters, polyamides, polyurethanes, polysulfonamides and any other coupling agent/monomer containing polymeric drugs formed by the classical procedure.

One aspect of the present invention provides a biological coupling agent (biomonomer) having a central portion comprising aromatic, linear or aliphatic (saturated) segments that are bendable (i.e. not restricted to chain-like kinetic motion), e.g. having a theoretical molecular weight of less than 2000 and are hydrolytically-bonded.

Accordingly, the present invention provides a biological coupling agent of formula (III)

PBio-LINK A-PBio(III)

Wherein PBio is a fragment of a biologically active agent or a precursor thereof linked to LINK a by a hydrolysable covalent bond, having at least one functional group to allow stepwise polymerisation to occur; LINKA is a coupled central flexible linear first segment having a theoretical molecular weight of less than 2000 attached to each of said PBio segments.

In the present description and claims, the term "biomonomer" refers to the compounds of formula (III) used in the synthesis of compounds of formula (I) by stepwise polymerization of functional groups.

Most preferably, each PBio fragment is defined as a single functional group that is applied while polymerization occurs stepwise.

Accordingly, another aspect of the present invention provides pharmaceutically active polymeric compounds of formula (I)

Y-[Yn-LINK B-X]m-LINK B(I)

Wherein (i) X is a geminal biological coupler of formula (II)

Bio-LINK A-Bio(II)

Wherein Bio is linked to a biologically active agent fragment of LINK A or a precursor thereof by a hydrolysable covalent bond; LINK a is a coupled central flexible linear first segment with a theoretical molecular weight of less than 2000 attached to each of said Bio fragments;

(ii) y is LINK B-OLIGO; wherein

(a) LINK B is a coupled second segment linking one OLIGO to another and an OLIGO to X or a precursor thereof;

(b) OLIGO is a relatively short length segment of polymer having a molecular weight of less than 5,000 comprising less than 100 monomer repeat units;

(iii) m is 1 to 40; and

(iv) n is selected from 2 to 50.

In another aspect of the invention, a pharmaceutically active polymeric material is provided, which is prepared from the biomonomer as a backbone. Such polymers comprise an oligomer segment having a theoretical molecular weight of less than 5000 and optionally a linking segment, herein referred to as [ LINkB ] covalently coupled to the oligomer segment and the biomonomer, wherein the oligomer segment is herein referred to as [ oligo ].

The term "oligomer segment" refers to repeating units of relatively short length, typically less than about 50 monomer units, and having a molecular weight of less than 10,000, but preferably < 5000. Preferably, [ oligo ] is selected from the group consisting of polyurethane, polyurea, polyamide, polyalkylene oxide, polycarbonate, polyester, polylactone, polysilicone, polyethersulfone, polyolefin, polyethylene, polypeptide, polysaccharide, and ethers and amines attached to these segments.

The term "LINK a molecule" refers to a molecule covalently linked together with a bioactive agent in the biomonomer. Typically, LINK A molecules have a molecular weight in the range of 60 to 2000, preferably 60 to 700, and are multifunctional but preferably difunctional to allow coupling with two bioactive agents. Preferably, the LINK a molecule is synthesized from precursor monomers selected from diols, diamines, and/or compounds containing both amine and hydroxyl groups, and is soluble or insoluble in water. Representative examples of LINK A precursors are set forth in Table 1, but are not limited thereto.

TABLE 1

-ethylene glycol

-butanediol

-hexanediol

-cyclohexanediols

1, 5 pentanediol

-2, 2-dimethyl-1, 3-propanediol

-1, 4-cyclohexanediol

-1, 4-cyclohexanedimethanol

-tris (ethylene glycol)

Poly (ethylene glycol), Mn: 100-2000

-poly (ethylene oxide) diamine; mn: 100-2000

-lysine ester

-silicone diols and diamines

Polyether diols and diamines

Carbonate diols and diamines

-dihydroxyvinyl derivatives

-dihydroxydiphenyl sulfone

-ethylenediamine

-cyclohexanediamine

-1, 2-diamino-2-methylpropane

-3, 3-diamino-N-methyldipropylamine

-1, 4 diaminobutane

-1, 7 diaminoheptane

-1, 8 diaminooctane

The term "LINK B molecule" refers to a molecule that is covalently coupled together with an oligomeric unit to form a second coupling segment in the central portion. Typically, LINK B molecules have a molecular weight in the range of 60 to 2000, preferably 60 to 700, and contain bifunctionality to couple two oligomeric units. Preferably, the LINK B molecule is made from diamines, diisocyanates, disulfonic acids, dicarboxylic acids, diacid chlorides, and dialdehydes. Hydroxyl, amine or carboxylic acid at the end of the oligomeric molecule can react with diamine to form oligomeric amide; reacting with diisocyanate to form oligourethane, oligourea, oligoamide; reacting with disulfonic acid to form oligomeric sulfonic acid ester and oligomeric sulfonamide; reacting with dicarboxylic acid to form oligo-polyester, oligo-amide; reacting with diacid chloride to form oligo-polyester and oligo-amide; and dialdehyde to form oligomeric acetal and oligomeric imine.

The term "pharmaceutical or bioactive agent" or precursor thereof refers to a molecule that can be coupled to the LINK a segment by a hydrolyzable covalent bond. The molecule must possess certain specific and predictable pharmaceutical or biological activities. Typically, the molecular weight of the [ Bio ] unit ranges from 40 to 2000 for drugs, but is higher for biopharmaceuticals depending on the molecular structure. Preferably, the Bio unit is selected from the group consisting of anti-inflammatory agents, antioxidants, anti-coagulants, anti-microbial agents (including fluoroquinolones), cell receptor ligands and bioadhesive molecules, in particular oligopeptides and oligosaccharides, DNA and oligonucleotide sequences of gene sequence linkages, and phospholipid end groups providing cell membrane simulation. The Bio component must have a bifunctional group selected from hydroxyl, amine, carboxylic acid or sulfonic acid so that after coupling with LINK a, the biomonomer can react with the second group of the oligomer segment to form LINK B linkage. The second group may be protected during the reaction of the first group with LINK a.

TABLE 2 typical drug molecules for the synthesis of biomonomer couplers

The invention is of particular value for pharmacologically active compounds which are biologically responsive as hereinbefore described and which are capable of producing pharmacologically active ingredients in vivo. The pharmacologically active ingredient has at least two functional groups, but one of the functional groups has low reactivity with: reacting with diisocyanate to form oligourethane or oligourea, oligoamide; reacting with disulfonic acid to form oligomeric sulfonic acid ester and oligomeric sulfonamide; reacting with dicarboxylic acid to form oligo-polyester, oligo-amide; reacting with diacid chloride to form oligo-polyester and oligo-amide; and reacting with dialdehyde to form oligomeric acetal and oligomeric imine. Such pharmacological agents include fluoroquinolone antibiotics, or anti-coagulants, anti-inflammatory agents, or anti-proliferative agents, as listed in table 2 above.

The invention is particularly useful for drugs in which the pharmacologically active fragment is formed from the antibiotics 7-amino-1-cyclopropyl-4-oxo-1, 4-dihydroquinoline and naphthyridine-3-carboxylic acid described in U.S. Pat. No.4,670,444. The most preferred antibiotics in this class of compounds are 1-cyclopropyl-6-fluoro-1, 4-dihydro-4-oxo-7-piperazine-quinoline-3-carboxylic acid and 1-ethyl-6-fluoro-1, 4-dihydro-4-oxo-7-piperazine-quinoline-3-carboxylic acid, with common names ciprofloxacin and norfloxacin, respectively. Other drugs in this class include sparfloxacin and trovafloxacin.

Without being bound by theory, it is believed that the presence of LINK a as described herein allows for a satisfactory "bio-space" in the bioactive polymer of the present invention, which facilitates hydrolysis in vivo to release the bioactive component. LINK a is able to regulate the range of hydrolysis rates according to changes in chain length, and possibly also according to changes in stereo and conformational structure caused by changes in chain length.

The prior art discloses compounds without the variation of the chain length of LINK a but wherein the chain length of LINK B is between two biological entities, which do not have the above mentioned advantage of a variation of the hydrolysis rate.

The invention aS described below is particularly useful wherein the pharmacologically active fragment is formed from the anti-inflammatory drugs (2S, 3S) -1-acetyl-4-hydroxy-pyrrolidine-2-carboxylic acid (generic name oxasirol) and (2S4aS, 6aS, 6bR, 8aR, 10S, 12aS, 12bR, 14bR) -10-hydroxy-2, 4a, 6a, 6b, 9, 9, 12 a-heptamethyl-13-oxo-1, 2, 3, 4, 4a, 5, 6, 6a, 6b, 7, 8, 8a, 9, 10, 11, 12, 12a, 12b, 13, 14 b-didehydro-picene-2-carboxylic acid (generic name glycyrrhetinic acid).

The invention is particularly useful where the pharmacologically active fragment is formed from the anticoagulant (S) -2- (butane-1-sulfonamide) -3- [4- (4-piperidin-4-yl-butoxy) phenyl]-propionic acid (generic name tirofiban)) And [ (S) -7- ([4, 4']Dipiperidino-l-carbonyl) -4-methyl-3-oxo-2, 3, 4, 5-tetrahydro-1H-benzo [ e][1，4]Diaza derivatives-2-yl]Acetic acid (generic name lotrafiban) formation.

The invention is particularly useful where the pharmacologically active fragment consists of an anti-neuroplasticity agent (. alpha.S, 5S) -alpha-amino-3-chloro-2-isoOxazoleacetoxy-5-acetic acid (generic name acivicin) and 4- [ bis (2-chloroethyl) amino-]-L-phenylalanine (generic name Ikran (Alkeren)).

The oligomer segment preferably has a molecular weight of < 10,000; more preferably < 5,000.

The term "theoretical molecular weight" in this specification is a term for absolute molecular weight resulting from the reaction of reagents used to synthesize any given bioactive polymer. As is well known in the art, the actual measurement of absolute molecular weight is complicated by physical limitations in molecular weight measurements of polymers using gel permeation chromatography. Thus, polystyrene equivalent molecular weights are reported for gel permeation chromatography determination methods. Since many pharmaceutically active compounds absorb light in the UV region, gel permeation chromatography also provides a means to detect the distribution of the pharmaceutically active compound coupled to the polymer chain.

The polystyrene equivalent molecular weight range of the polymeric material used in the present invention is 2X 10³To 1X 10⁶Preferably 2X 10³To 2X 10⁵。

In another aspect, the invention provides compositions comprising a polymer of a biomonomer alone or in admixture with a polymer of a biomonomer, preferably in the form of a polymorph, as described herein.

Representative examples of substrate polymers that may be combined with the bioactive polymers of the present invention include polyurethanes, polysulfones, polycarbonates, polyesters, polyethylenes, polypropylenes, polystyrenes, silicones, poly (acrylonitrile-butadiene styrene), polyamides, polybutadienes, polyisoprenes, polymethyl methacrylates, polyvinyl acetates, polyacrylonitriles, polyvinyl chlorides, polyethylene terephthalates, celluloses, and other polysaccharides. Preferred polymers include polyamides, polyurethanes, silicones, polysulfones, polyolefins, polyesters, polyethylene derivatives, polypeptide derivatives and polysaccharide derivatives. More preferably, the biodegradable substrate polymer comprises a segmented polyurethane, polyester, polycarbonate, polysaccharide or polyamide.

The polymer comprising said biomonomer or the mixed composition of the invention can be used as a surface covering for crops, or, most preferably, the polymer or mixture is of the type which is capable of forming 1) a self-supporting structure, 2) a film; or 3) fibers, preferably knitted or braided. The composition may comprise a surface, preferably a biomedical device or conventional biotechnological application equipment, on the whole or on a part of the object. In the former case, the application may include cardiac assist devices, tissue engineering polymer stents and related devices, heart replacement devices, cardiac septa, intra-aortic balloons, percutaneous cardiac assist devices, extracorporeal circuits, A-V tubes, dialysis components (tubes, filters, membranes, etc.), anergic devices (achoresis units), membrane oxygenators, cardiac bypass components (tubes, filters, etc.), pericardial balloons, contact lenses, auricular implants, sutures, sewing rings, cannulas, contraceptives, syringes, o-rings, bladders, penile implants, drug delivery systems, drains, pacemaker guide isolators, heart valves, blood bags, implantable wire coatings, catheters, vascular stents, angioplasty balloons and devices, bandages, cardiac massage cups, tracheal catheters, breast implant coatings, artificial catheters, craniofacial and maxillofacial modification devices, cardiac implant devices, cardiac assist devices, cardiac implant devices, percutaneous cardiac assist devices, extracorporeal circuits, percutaneous devices, extracorporeal circuits, A-V tubes, dialysis devices, and other devices, Ligament, fallopian tube. The latter applications include the synthesis of bioabsorbable polymers for products that do not harm the environment (including but not limited to trash bags, bottles, cans, storage bags and devices), products that can release agents into the environment to control various biological systems including control of pests, bioactive contaminants, elimination of bacteria or viral agents, products that promote health related factors including enhancing the nutritional value of drinking liquids and foods, or various ointments and creams that can be used with biological systems including humans, animals and others.

In a preferred aspect, the present invention provides a hybrid composition, as described above, comprising a segmented polyurethane, polyester, polycarbonate, polysaccharide, polyamide or silicone and a compatible polymer comprising said biomonomer.

According to the invention, a polymer comprising said biomonomer is synthetically produced in a method comprising polymer segments, i.e. [ oligo ] segments in the polymer backbone, and said biomonomer, said polymer comprising a biochemical function of one of: anti-coagulation, anti-inflammatory, anti-proliferative, antioxidant, antimicrobial potential, cell receptor ligands such as peptide ligands and bioadhesive molecules such as oligosaccharides, oligonucleotide sequences of DNA and gene sequence linkages, or precursors of bioactive components.

The pharmacological activity in vivo may be, for example, anti-inflammatory, antibacterial, antimicrobial, antiproliferative, antifungal, but the invention is not limited to the above biological activities.

Drawings

For a better understanding of the present invention, a preferred embodiment will now be described by way of example and with reference to the accompanying drawings, in which:

FIG. 1 is the proton nuclear magnetic resonance spectrum of biomonomer (coupling agent) NORF-TEG-NORF

FIG. 2 is the carbon nuclear magnetic resonance spectrum of the biomonomer NOF-TEG-NORF

FIG. 3 is a positive electrospray mass spectrum of biomonomer NORF-TEG-NORF

FIG. 4 is proton nuclear magnetic resonance spectrum of biomonomer CIPRO-TEG-CIPRO

FIG. 5 is a carbon nuclear magnetic resonance spectrum of biomonomer CIPRO-TEG-CIPRO

FIG. 6 is a positive electrospray mass spectrum of biomonomer CIPRO-TEG-CIPRO

FIG. 7 proton NMR spectra of POC

FIG. 8 is the carbon nuclear magnetic resonance spectrum of POC

FIG. 9 is a positive electrospray mass spectrum of POC

FIG. 10 is the proton nuclear magnetic resonance spectrum of biomonomer POC-TEG-POC

FIG. 11 is the carbon NMR spectrum of the biomonomer POC-TEG-POC

FIG. 12 is a positive electrospray mass spectrum of POC-TEG-POC

FIG. 13 is proton nuclear magnetic resonance spectrum of PAK

FIG. 14 shows the carbon nuclear magnetic resonance spectrum of PAK

FIG. 15 is a positive electrospray mass spectrum of PAK

FIG. 16 is the proton nuclear magnetic resonance spectrum of biomonomer PAK-TEG-PAK

FIG. 17 is the proton nuclear magnetic resonance spectrum of biomonomer PAK-TEG-PAK

FIG. 18 is a positive electrospray mass spectrum of PAK-TEG-PAK

FIG. 19 is gel permeation chromatography analysis of THDI/PCL/NORF

FIG. 20 is a gel permeation chromatography analysis of THDI/PCL/CIPRO

FIG. 21 is a cytotoxicity assay of control polymers and drug polymers against mammalian cells

FIG. 22 is a graph of norfloxacin release from NF polymers in the presence and absence of cholesterol esterase

FIG. 23 is a bacterial count curve for an implantability test

Description of The Preferred Embodiment

Synthesis of biomonomers

Scheme A depicts a novel method for the preparation of a biological coupler/biomonomer for product D, where R is CH relative to norfloxacin and ciprofloxacin, respectively₂CH₃Or a cyclopropyl group. Typically, the molecular weight of the linkA molecule is 60-2000, preferably 60-700, which must contain at least two functionalities to allow for and at least two [ Bio ] s]The units are coupled. [ Bio ] of]The molecular weight of the units is < 2000, but may be somewhat higher depending on the molecular structure. Preferred is [ Bio]Components include, but are not limited to, the following species and examples: anti-inflammatory agents: non-steroidal-oxaceprol, steroids, glycyrrhetinic acid; anticoagulant enzyme agent: tirofiban, lotrafiban; anti-agglomerating agent: heparin; antiproliferative agents: acivicin and acerolan; antimicrobial agents: fluoroquinolones such as norfloxacin, ciprofloxacin, sparfloxacin and trovafloxacin and other fluoroquinolones.

Scheme a provides a general synthetic method for preparing product D compounds of formula (I):

scheme 1: synthetic route of bioactive monomer

In step a, a pharmaceutically active drug such as norfloxacin or ciprofloxacin (as the hydrochloride salt) is reacted with a protecting group such as a trityl halide in the presence of triethylamine to form an intermediate product in which both the amine group and the carboxylic acid group are protected with trityl. It will be appreciated by those skilled in the art that other protecting groups may be used in embodiments of the invention.

The appropriate trityl halide is reacted with norfloxacin or ciprofloxacin hydrochloride in a suitable solvent, such as chloroform. Many other solvents may also be required depending on the choice of protecting group and solubility of the reagent forming the biomonomer. Suitable trityl halides include trityl chloride and trityl bromide. The preferred trityl halide is trityl chloride. The amount of trityl halide used is 2-4 molar equivalents norfloxacin/ciprofloxacin, preferably 2.2 molar equivalents. Triethylamine was added to the spent HCl, which was a by-product. A slight excess of triethylamine may avoid deprotection of the N-triethylamine group in a subsequent selective hydrolysis step. In the case of ciprofloxacin, 2 to 4-fold excessive molar amount of triethylamine, preferably 3-fold amount, is added to the reaction mixture. The reaction mixture is stirred at 0-60 ℃ for 2-24 hours. The preferred stirring time is 4 hours and the preferred temperature is 25 ℃. A homogeneous solution was obtained. Thereafter, the product A was placed in the reaction solution for the next in situ reaction. In this process, there is no need to isolate product A.

In step B, the reaction product of step A, e.g., norfloxacin/ciprofloxacin in which both the amine and carboxylic acid groups are protected by trityl groups, is selectively deprotected to produce product B containing free carboxylic acid and N-triethylamine groups.

For example, in step B, a large amount of methanol is added to the reaction mixture of step A. The volume of methanol is equal or twice the amount of solvent used in step a. Preferably 1.5 times the volume of the solvent. The reaction mixture is stirred at 25-60 ℃ for 1-24 hours. Preferably, the stirring time is 2 hours, and the preferred temperature is 50 ℃. The selectively deprotected fluoroquinolone material is precipitated from the reaction solution. After the reaction mixture was cooled to room temperature, the reaction solution was filtered to obtain a product B. Using standard recrystallization method with CHCl₃Methanol (9: 1) as solvent further purified product B.

In step C, the purified amine protected fluoroquinolone is coupled on both sides with a diol or diamine (in this example, triethylene glycol is used) that includes a flexible and/or water soluble central moiety.

For example, purified amine protected fluoroquinolone (product B) and tri (ethylene glycol) are coupled in the presence of a suitable coupling agent, such as 1-ethyl-3- (3-dimethylamino-propyl) carbodiimide (abbreviated herein as EDAC) and a suitable base, such as 4- (dimethylamino) pyridine (abbreviated herein as DMAP), wherein the base is a catalyst. Other coupling agents may also include various carbodiimides such as CMC (1-cyclohexyl-3- (2-morpholinoethyl) carbodiimide), DCC (N, N' -dicyclohexyl-carbodiimide), DIC (diisopropylcarbodiimide), and the like, but are not limited thereto. The diol is used in an amount of 0.3 to 0.5 molar equivalents with respect to product B. The preferred amount of diol is 0.475 mole equivalents of product B. The amount of coupler EDAC used is 2 to 10 times the molar equivalent, preferably 8 times the molar equivalent, of product B. The amount of base DMAP used is 0.1-molar equivalent, preferably 0.5 molar equivalent, with respect to product B. The reaction is carried out in a suitable solvent such as dichloromethane, an inert gas such as nitrogen or argon. Other solvents may also be suitable depending on the solubility of product B and the potential reactivity towards the reagents. The reactants are stirred together at 0-50 ℃ for 24 hours to two weeks. The preferred stirring time is 1 week, the preferred temperature is 25 ℃.

After the reaction was complete, the solvent was removed by rotary evaporation. The residue was washed several times with water to remove soluble reagents such as EDAC. The solid was then dissolved in chloroform. The product C described in scheme 1 was obtained from the solution using chloroform as extraction solvent using conventional extraction methods. The product C was further isolated by column chromatography using chloroform/methanol/aqueous ammonia (9.2: 0.6: 0.2) as developing solvent. Product C was further purified using recrystallization techniques using chloroform and methanol.

In step D, the N-triethylamine group on the purified product C is deprotected to produce the corresponding desired pharmaceutical coupling agent/biomonomer.

For example, the appropriate product C is reacted with a small amount of water in a suitable organic solvent, such as dichloromethane, in the presence of a small amount of a weak acid, such as trifluoroacetic acid. The amount of water is 1% to 10% by volume, preferably 1% by volume. Trifluoroacetic acid is used in amounts of 1% to 10% by volume, preferably 2%. The reaction mixture is stirred for 2-24 hours at 0-50 ℃. The preferred temperature is 25 deg.C, and stirring is preferred for 4 hours. The product D precipitated from the reaction solution, was filtered and collected. Using CHCl₃The product was further purified by washing.

Application of biomonomers in polymer synthesis

The pharmaceutically active polymer is synthesized using conventional step-wise polymerization methods known in the art. The multifunctional LINK B molecule and the multifunctional oligomeric molecule react to form a prepolymer. The biomonomer expands the prepolymer chain to form a biomonomer-containing polymer. Non-biological extenders such as ethylenediamine, butanediol, ethylene glycol, and others may also be used. LINKB molecules are preferably, but not limited to, naturally bifunctionality molecules in order to facilitate the formation of linear, biomonomer-containing polymers. Preferred linkB molecules for biomedical and biotechnological applications are diisocyanates: such as 2, 4 toluene diisocyanate, 2, 6 toluene diisocyanate, methylene bis (p-phenyl) diisocyanate, lysine diisocyanato ester, 1, 6 hexane diisocyanate, 1, 12 dodecane diisocyanate, bis-methylene bis (cyclohexyl isocyanate), trimethyl-1, 6 diisocyanatohexane, dicarboxylic acids, di-acid chlorides, disulfonyl chloride, or others. The oligomeric component is preferably, but not limited to, difunctional in order to facilitate the formation of linear polymers comprising the biomonomers. Preferred oligomeric components are terminal diamine and diol reagents of: such as polycarbonates, polysiloxanes, polydimethylsiloxanes, polyethylene-butene copolymers, polybutadienes, polyesters including polycaprolactone, polylactic acid and other polyesters, polyurethane/sulfone copolymers, polyurethanes, polyamides, including oligopeptides (polyalanine, polyglycine or amino acid copolymers) and polyureas, polyalkylene oxides, in particular polypropylene oxide, polyethylene oxide and polybutylene oxide. The molecular weight of the [ oligo ] group is less than 10,000, but preferably less than 5000. Synthesis of the bioactive polymers from the prepolymers can be carried out according to conventional urethane/urea reactions using appropriate reagent compositions, but with an excess of linkB molecules for the purpose of capping the prepolymer ends with linkB molecules. When the prepolymer reaches the desired chain length, the biomonomer is added to extend the prepolymer chain to obtain the final bioactive polymer. Alternatively, a biomonomer may be used instead as an oligomeric group.

Bioactive polymers can be synthesized from different compositions and stoichiometries. Prior to synthesis, the LINK B molecule is preferably subjected to vacuum distillation to remove residual moisture. The biomonomers are dried to remove all water. The oligomeric components were degassed overnight to remove residual moisture and low molecular weight organics.

Although the reactants can be reacted without solvent, in practice, it is preferred to use an organic solvent that is compatible with the chemical properties of the reactants, so as to provide good control over the properties of the final product. Representative organic solvents include, for example, dimethylacetamide, acetone, tetrahydrofuran, diethyl ether, chloroform, dimethylsulfoxide, and dimethylformamide. The preferred reaction solvent is dimethyl sulfoxide (DMSO, Aldrich chemical Co., Milwaukee, Wis.).

In view of the low reactivity of certain diisocyanates, such as DDI and THDI, with oligomeric precursor diols, it is preferred to use catalysts in the synthesis. Representative catalysts are similar to those used in the chemical synthesis of urethanes and include dibutyryl dilaurate, stannous octoate, N' -diethylcyclohexylamine, N-methylmorpholine, 1, 4 diaza (2, 2, 2) bicyclo-octane, and zirconium complexes such as zirconium tetrakis (2, 4-pentanedione) complex.

In the first step of preparing the prepolymer, for example, linkB molecules are added to the oligomeric components, optionally with a catalyst, to form a prepolymer of the bioactive polymer. The reaction mixture is stirred at a temperature of 60 ℃ for a suitable period of time, depending on the reaction components and their stoichiometry. The temperature may vary from 25 to 110 ℃. Subsequently, the biomonomer is added to this prepolymer and, typically, the mixture is reacted overnight. The reaction is terminated with methanol and the reaction product is precipitated in diethyl ether, a mixture of diethyl ether and distilled water or other suitable solvent. The precipitate is dissolved in a suitable solvent such as acetone and then precipitated again in diethyl ether or a mixture of diethyl ether and distilled water. This process was repeated 3 times to remove any residual catalyst compound. After washing, the product was dried under vacuum at 40 ℃.

Alternatively, polyamides can be prepared from the biomonomers using conventional reactions as described below.

Preparation of a product:

the pharmaceutical polymer comprising the biomonomer can be used alone or in combination with an appropriate amount of a base polymer in the production of a product. If mixed together, suitable polymers may include polyurethanes, polyesters, or other substrate polymers. The product can be prepared by the following method: 1) composite processes for subsequent extrusion, injection molding or forming; 2) co-dissolving the base polymer and the bioactive polymer in a solvent having conventional compatibility to be subsequently cast or formed into textile-like fibers in a mold to produce a product; 3) wetting the surface of the product with a solution of a biologically active polymer or a mixture thereof in a solvent having conventional compatibility, wherein a polyurethane or other polymer is added to the solution; or 4) mixed with a hardenable polyurethane, e.g., 2-part hardenable systems, such as a skin. All of the above methods can use either pure polymers containing biomonomer groups or mixtures of the polymers and conventional biomedical polymers.

Thus, the present invention provides the ability to synthesize certain novel polymeric materials with pharmacological or biomolecular properties. When the polymers are used alone or in admixture with certain substances, such as polyurethanes, the bioactive polymers provide a composite with improved pharmaceutical function, particularly for use in medical devices, promoting cellular function and regulation, tissue integration, pre-active blood compatibility and particularly anticoagulant/platelet function, biostability, antimicrobial function and anti-inflammatory function, or in the field of biotechnology with its biological activity.

Applications for these materials include the synthesis of bioresorbable polymers for use in medical device products for delivery of biologicals, drugs or release of biocompatible materials by biodegradation within or upon contact with an organism (human or animal). It includes the production of products in the form of films (cast or thermoplastic), fibers (solvent or melt-spun), forming composite materials of any shape (polymers combined in any form with ceramics, metals or other polymers), injection molding, compression molding, extrusion, and products that may include, but are not limited to: cardiac assist, tissue engineering polymer stents and related devices, cardiac replacement devices, cardiac septal sheets, intra-aortic balloons, percutaneous cardiac assist, extracorporeal circuits, a-V tubes, dialysis components (tubes, filters, membranes, etc.), intolerant devices, membrane oxygenators, cardiac bypass components (tubes, filters, etc.), pericardial balloons, contact lenses, ear cup implants, sutures, sewing rings, cannulas, contraceptives, syringes, o-rings, bladders, penile implants, drug delivery systems, drainage tubes, pacemaker guide isolators, heart valves, blood bags, implantable wire coatings, catheters, vascular stents, angioplasty balloons and devices, bandages, cardiac massage cups, tracheal catheters, breast implant coatings, artificial catheters, craniofacial and collarband remodeling devices, ligaments, fallopian tubes.

Other non-medical applications may include the use of bioabsorbable polymers in products that are not detrimental to the environment (including but not limited to trash bags, bottles, tanks, storage bags and devices, products that can release agents into the environment to control various biological systems including control of pests, bioactive contaminants, elimination of bacteria or viral agents, products that promote health related factors including enhancing the nutritional value of drinking liquids and foods, or various ointments and creams that can be used with biological systems including humans, animals and others).

In these examples, the following abbreviations apply:

NORF (norfloxacin)

CIPRO (ciprofloxacin)

OC (Oxasirox)

POC (protective oxaceros)

TF (tirofiban)

PTF (protective tirofiban)

AK (Aikelan)

PAK (protective Aikelan)

AF (amfenac)

AV (Axiweixin)

BF (bromfenac)

TEG (triethylene glycol)

HDL (1, 6-hexanediol)

HDA (1, 6-hexanediamine)

TrCl (trityl chloride)

DMAP (4- (dimethylamino) pyridine)

EDAC (1-ethyl-3- (3-dimethylamino-propyl) carbodiimide)

TEA (triethylamine)

TFA (trifluoroacetic acid)

THDI (trimethyl-1, 6 diisocyanatohexane)

PCL polycaprolactonediol

AC (adipoyl chloride)

THDI/PCL/TEG (sector polyurethane)

DBTL (dibutyryldilaurate)

DCM (dichloromethane)

DMF (dimethylformamide)

TLC (thin layer chromatography)

CC (column chromatography)

Where appropriate all isocyanate reactions are carried out using DBTL (dibutyryldilaurate) as catalyst.

The structure of the biomonomers was examined using nuclear magnetic resonance.

The molar mass of the synthesized biomonomers was determined using mass spectrometry.

The distribution of [ Bio ] in the drug polymer was determined using gel permeation chromatography and used to estimate the relative molecular weight of the polymer.

The properties of the tin residue on the surface of the drug polymer coating were determined at the 90 degree position using X (ray) photoelectron spectroscopy (to determine the chemical composition). Since tin residues are toxic, removal of tin residues is very important for biological applications.

The evaluation of antimicrobial agent release and degradation was performed in vitro to evaluate the degradation rate for different antimicrobial polymer formulations and to determine the useful life. In these studies, the polymer was incubated with enzymes and the recovery solution separated the degradation products. Hydrolytic enzymes associated with monocyte macrophages, particularly cholesterol esterase and neutrophils (elastase) and a phosphate buffered saline solution pH7 were used for the in vitro test over a 10 week period. The nature of the degradation products can be determined using High Performance Liquid Chromatography (HPLC) in combination with mass spectrometry.

The antimicrobial activity of the culture broth obtained from a drug polymer biodegradation study against p.aeroginosa can be evaluated using the Minimum Inhibitory Concentration (MIC) assay. The turbidity of each culture was recorded for evaluation of the inhibitory properties of the degradation solution of the drug polymer.

After subjecting the drug polymer to gamma-ray (radiation dose: 25Kgy) sterilization, the sterilization stability of the drug polymer was evaluated using a conventional method in the field of medical devices. The samples were measured by GPC measurement before irradiation and after 1-4 weeks after irradiation.

Biocompatibility studies of the drug polymers were performed simultaneously to evaluate the biocompatibility of the control polymer and the drug polymer with mammalian cells. In this study, HeLa cells were cultured directly onto polyurethane polymer membranes and incubated at 37 ℃ for 24 hours. Cell viability was determined by succinate dehydrogenase staining.

In vivo, animal studies are conducted on the substrates, devices or materials of the invention formed in whole or in part of a biologically active polymer. A substance comprising a bioactive polymer or a non-bioactive control polymer was implanted into the peritonitis site of male mice and simultaneously inoculated with p. After 1 week of feeding the rats, the material was removed. The effect of the antimicrobial polymer was evaluated.

Examples

The following examples describe the preparation of the biomonomers and biologically responsive pharmacologically active polymers of the present invention.

Example 1:

NORF-TEG-NORF and CIPRO-TEG-CIPRO are representative examples of the antimicrobial drug comprising a biomonomer of the present invention. This example shows the use of a drug alone or a pharmaceutical composition. The synthesis conditions for the reaction are as follows.

In step A, NORF (1.3g, 4 mmol)/or CIRO hydrochloride (4mmol) in the presence of CIRO with trityl chloride (2.7g, 8.8mmol) and TEA (0.6ml, 8mmol) (Aldrich, 99%)/or 12mmol of TEA in 40ml of CHCl₃The reaction was carried out at room temperature for 4 hours. A clear solution was obtained.

In step B, 40ml of methanol was added to the above clear solution. The mixture was heated to 50 ℃ and stirred for 1 hour, resulting in precipitation in the solution. After the reaction mixture was cooled to room temperature, the precipitate was collected by filtration. Using CHCl₃The precipitate was further purified with methanol to yield 3.4mmol of product B. Typically the yield is over 85%.

In step C, product B (20mmol), TEG (1.44g, 9.5mmol) and DMAP (1.24g, 10mmol) are dissolved in 100ml DCM. EDAC (31g, 160mmol) was then added to the reaction system. The reaction mixture was stirred at room temperature for one week under nitrogen. After the reaction was complete, DCM was removed by rotary evaporation. The residue is washed several times with deionized water to remove by-products of soluble reagents such as urea. The solid was then dissolved in chloroform and washed with deionized water. The crude reaction product is obtained from the solution by extraction. The product C was isolated by column chromatography using chloroform/methanol/aqueous ammonia (9.2: 0.6: 0.2) as developing solvent. Product C was further purified using recrystallization techniques using chloroform and methanol. The yield of product C was 85%.

In step D, purified product C (5.4g, 4.4mmol) was dissolved in chloroform containing 1% by volume of water and 1% by volume of trifluoroacetic acid. The reaction solution was stirred at room temperature for 4 hours. The white solid produced in the reaction was collected by filtration and purified by washing with chloroform. After washing the product D, the product D (i.e. the biomonomer) was dried in a vacuum oven at 40 ℃ for 24 hours. The yield of pure product D (i.e. the biomonomer) was 95%.

Of NORF-TEG-NORF¹H NMR：(400MHz，DMSO).δ：9.33(bs，2H，NH)，8.52(s，2H，H²，ar)，7.66(d，2H，J＝13.6Hz，H⁵，ar)，7.01(d，2H，J＝7.2Hz，H⁸，ar)，4.33(q，4H，J＝6.8Hz，N-CH₂-CH₃)，4.26(t，4H，J＝4.8Hz，CO₂CH₂)，3.71(t，4H，J＝4.8Hz，CO₂CH₂CH₂)3.48-3.28(m, 16H, piperazine), 1.33(t, 6H, J ═ 6.8Hz, NCH₂CH₃)。

[ FIG. 1]

Of NORF-TEG-NORF¹³C NMR: (400MHz, DMSO). δ: 171.9, 164.7, 159.3, 159.0, 153.8, 151.4, 149.0, 143.4, 143.3, 136.4, 123.4, 122.0, 119.0, 116.0, 112.4, 109.4, 106.6, 70.4, 68.9, 63.6, 48.6, 47.1, 43.1, 43.0, 14.6. [ FIG. 2 of the drawings]

ES-MS (m/z,%) of NORF-TEG-NORF (positive model): c₃₈H₄₆F₂N₆O₈The calculated value of (a): 752amu, found: 753, 377(M +2H)⁺. [ FIG. 3 of the drawings]

Of CIPRO-TEG-CIPRO¹H NMR：(400MHz，DMSO).δ：9.16(bs，2H，NH-R)，8.30(s，2H，H²，ar)，7.49(d，2H，J＝13.2Hz，H⁵，ar)，7.34(d，2H，J＝7.6Hz，H⁸，ar)，4.25(t，4H，J＝5.2Hz，N-CH(CH₂)₂)；3.73(t，4H，J＝4.4Hz，CO₂CH₂) 3.46-3.30(m, 16H, piperazine), 1.22(q, 4H, J ═ 6.4Hz, CH (CH)₂CH₂))，1.07(m，4H，CH(CH₂CH₂)). [ FIG. 4 of the drawings]

Of CIPRO-TEG-CIPRO¹³C NMR：(400MHz，DMSO).δ：171.9，164.1，158.7，153.9，151.5，148.4，143.0，142.9，138.1，122.6，122.5，111.9，111.7，109.2，107.0，79.6，70.5，70.4，68.9，63.7，47.0，43.2，35.3，7.9。

[ FIG. 5]

ES-MS (m/z,%) for CIPLO-TEG-CIPLO (positive model): c₄₀H₄₆F₂N₆O₈The calculated value of (a): 776amu, found: 777(M + H)⁺)；389(M+2H)⁺. [ FIG. 6 of the drawings]

Example 2

CIPLO-HDL-CIPLO is an example of the biomonomer of the present invention, and differs from example 1 in that it incorporates hydrophobic linkA molecules rather than hydrophilic linkA molecules. The synthesis conditions for this reaction are shown below.

The reaction conditions for selective protection of the amine groups of the CIPRO are the same as in example 1, steps a and B.

In step C, product B (20mmol), HDL (9.5mmol) and DMAP (1.24g, 10mmol) are dissolved in 100ml DCM. EDAC (31g, 160mmol) was then added to the reaction system. The reaction mixture was stirred at room temperature under nitrogen for 1 week. After the reaction was complete, DCM was removed by rotary evaporation. The residue is washed several times with deionized water to remove by-products of soluble reagents such as urea. The solid was then dissolved in chloroform and washed with deionized water. The crude reaction product is obtained from the solution by extraction. The product C was isolated by column chromatography using chloroform/methanol/aqueous ammonia (9.2: 0.6: 0.2) as developing solvent. Product C was further purified using recrystallization techniques using chloroform and methanol.

In step D, the purified product C (4mmol) was dissolved in chloroform containing 1% by volume of water and 1% by volume of trifluoroacetic acid. The reaction solution was stirred at room temperature for 4 hours. The white solid produced in the reaction was collected by filtration and purified by washing with chloroform. After washing the product D, the product D (i.e. the bio-monomer) was dried in a vacuum oven at 40 ℃ for 24 hours.

Example 3:

NORF-HDA-NORF is an example of a biomonomer of the present invention that differs from example 1 in that a diamine is used to form the amide rather than the ester chain in the biomonomer. The synthesis conditions for the reaction are as follows.

The reaction conditions for selective protection of the amine groups of NORF were the same as in example 1, steps a and B.

Example 4:

OC-TEG-OC is an example of an anti-inflammatory drug comprising a biomonomer of the present invention. The biological monomers are synthesized with Oxaceprol (OC), which leaves a hydroxyl group for subsequent polymerization by reacting the carboxylic acid with the hydroxyl group of TEG. The synthesis conditions for this reaction are as follows.

In step A, OC (11.55mmol) was reacted with t-butyldimethylsiloxane chloride (28.87mmol) and 1, 8-diazabicyclo [5.4.0] undec-7-ene (30.03mmol) in 4ml acetonitrile at 0 ℃ during which time base was added. Then at room temperature overnight. Precipitate is generated in the reaction process, and the precipitate is filtered.

In step B, the filtrate was treated with water (10ml) and then extracted with n-pentane (2X 5 ml). The solvent in the aqueous portion was removed under reduced pressure. The residue was dissolved in methanol (10mL), tetrahydrofuran (5mL) and water (5mL), then treated with 2N aqueous sodium hydroxide (8 mL). The reaction mixture was stirred at room temperature for 1.5 h, adjusted to pH 3 using 1N HCl, concentrated, and filtered. Recrystallization from water gave a precipitate as pure 4(2.79g, 84%).

¹H NMR：(400MHz，CDCl₃)δ：4.87(bs，1H，CO₂H)，4.61(dd，1H，J＝8.0Hz，6.4Hz，CHCO₂H)，4.48(p，1H，J＝4.4Hz，CHOSi)，3.67(dd，1H，J＝10.4Hz，4.8Hz，CHHN)，3.36(dd，1H，J＝10.4Hz，6.0Hz，CHHN)，2.36(dt，2H，J＝13.2Hz，5.2Hz，2H，CH₂CHCO₂H)，2.12(s，3H，COCH₃)，0.86(s，9H，C(CH₃)₃)，0.08(s，3H，SiCH₃)，0.07(s，3H，SiCH₃). [ FIG. 7 of the drawings]

¹³C NMR: (400MHz, CDCl3) Δ: 172.7, 172.3, 70.0, 58.3, 56.2, 37.1, 25.6, 22.2, 17.9, -4.8, -5.0. [ FIG. 8 of the drawings]

ES-MS (m/z,%) (negative model): c₁₃H₂₅NO₄Calculated value of Si: 287amu, found: 286.1. [ FIG. 9 of the drawings]

In step C, product B (3.48mmol), TEG (1.58mmol) and DMAP (0.16mmol) were dissolved in DCM (5ml) and EDAC (3.95mmol) was added to the reaction solution cooled to 0 ℃. The resulting solution was stirred at 0 ℃ for 1 hour, the cooling source was removed, and the mixture was stirred at room temperature for 5 days. The solvent was removed under reduced pressure. Water (20mL) was added and the system was extracted with pentane (3X 10 mL). The pentane extracts were combined, dried over sodium sulfate, filtered and the solvent removed under reduced pressure. 0.74g (67%) of the expected product is obtained.

¹H NMR：(400MHz，CDCl₃)δ：4.87(m，2H，CHCO₂)，4.26(m，2H，CHOSi)，4.05(m，2H，CHHN)，3.74-3.31(m，4H)，3.31(m，2H，CHHN)，2.13(m，4H，CH₂CHCO₂)，2.12(s，6H，COCH₃)，2.0(m，4H)，1.18(m，4H)，0.81(s，18H，C(CH₃)₃)，-0.003(s，6H，SiCH₃)，-0.03(s，6H，SiCH₃). [ FIG. 10 of the drawings]

¹³C NMR：(400MHz，CDCl3)δ：172.3，171.0，72.5，70.6，70.4，64.0，60.3，57.5，57.3，55.9，54.3，52.1，40.4，38.3，34.0，26.6，22.1, 20.9, 17.8, 14.1, -4.8, -5.0. [ FIG. 11 of the drawings]

ES-MS (m/z,%) (Positive model): c₃₂H₆₀N₂O₁₀Si₂The calculated value of (a): 688amu, found 689.3. [ FIG. 12 of the drawings]

In step D, purified product C (0.7mmol) was dissolved in THF (5 ml). The solution was cooled to 0 ℃ before adding tetra-n-butylammonium fluoride (xml, 1.4 mmol). The solution was then stirred at c for 5 minutes, the ice bath removed and stirring continued at ambient temperature for 40 minutes. The solvent was removed under reduced pressure and the residue was treated with water to adjust the solution to pH 3, at which time a precipitate was formed. The precipitate was filtered to obtain the desired product.

Example 5:

TF-TEG-TF is an example of an anti-coagulant alcohol agent comprising a biomonomer of the present invention. The biomonomer is synthesized from Tirofiban (TF) by reacting the carboxylic acid with the hydroxyl groups of TEG and leaving amine groups suitable for subsequent polymerization. The synthesis conditions for this reaction are as follows.

In step A, TF (4mmol) was mixed with trityl chloride (8.8mmol), TEA (8mmol) (Aldrich, 99%) in 40mL CHCl₃The reaction was carried out at medium room temperature for 4 hours to give a clear solution.

In step B, 40ml of methanol was added to the above clear solution. The mixture was heated to 50 ℃ and stirred for 1 hour, resulting in a number of precipitates in the solution. After the reaction mixture was cooled to room temperature, the precipitate was collected by filtration. Using CHCl₃The precipitate was further purified with methanol to give 3.4mmol of product B.

In step C, product B (20mmol), TEG (9.5mmol) and DMAP (1.24g, 10mmol) were dissolved in 100ml DCM and EDAC (31g, 160mmol) was added to the reaction system. The reaction mixture was stirred at room temperature under nitrogen for 1 week. After the reaction was complete, DCM was removed by rotary evaporation. The residue is washed several times with deionized water to remove by-products of soluble reagents such as urea. The solid was then dissolved in chloroform and washed with deionized water. The crude reaction product is obtained from the solution by extraction. The product C was isolated by column chromatography using chloroform/methanol/aqueous ammonia (9.2: 0.6: 0.2) as developing solvent. Product C was further purified using recrystallization techniques using chloroform and methanol.

Example 6:

AK-TEG-AK is an example of an antiproliferative agent comprising a biomonomer of the present invention. The biomonomer is synthesized from Acrilan (AK) by reacting carboxylic acid and hydroxyl group of TEG leaving amine group for subsequent polymerization. The synthesis conditions for this reaction are as follows.

In step A, AK (0.32mmol) was reacted with di-tert-butylcarbonate (0.5mmol) and TEA (0.32mmol) (Aldrich, 99%) in THF (4 ml). The suspension was cooled to 0 ℃ and then the anhydride was added. Dimethylformamide (0.9ml) was added to the reaction mixture for homogenization. The solution was stirred at 0 ℃ for 2 hours and then left at ambient temperature overnight. The solution was then evaporated under reduced pressure and the resulting pale yellow oily residue redissolved in 5% sodium bicarbonate solution (3 ml). The solution was washed with petroleum ether (3X 3ml) and the pH of the aqueous phase was adjusted to 3 with 1N hydrochloric acid solution. The mixture was extracted with ethyl acetate (3X 3 ml). The organic phase was dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The residue was dissolved in a mixture of hexane, ethyl acetate and acetic acid (20: 10: 1) (3 ml). Then purified by chromatography using silica gel column. 115g (86%) of the expected product (R) are obtained_f＝0.49)。

¹H NMR：(400MHz，CDCl₃)δ：11.02(bs，1H，CO₂H)，7.08(d，2H，J＝5.4Hz，Ar-H)，6.64(d，2H，J＝5.4Hz，Ar-H)，4.97(d，1H，J＝5Hz，NH)，4.57(m，1H，CHCO₂H)，3.72-3.59(m，8H，CH₂CH₂Cl)，3.12-2.98(m，2H，CH₂CH)，1.42(s，9H，C(CH₃)₃). [ FIG. 13 of the drawings]

¹³C NMR：(400MHz，CDCl₃) δ: 177.3, 176.6155.4, 144.9, 130.7, 112.3, 80.2, 54.4, 53.6, 40.3, 28.3, 20.8. [ FIG. 14 of the drawings]

ES-MS (m/z,%) (Positive model): c₁₈H₂₆Cl₂N₂O₄The calculated value of (a): 404amu, found: 405.1. [ FIG. 15 of the accompanying drawings]

In step C, product B (0.20mmol), TEG (0.09mmol), DMAP (0.009mmol) were dissolved in DCM (2 ml). To the stirred solution was added dropwise a solution of EDC-HCl (0.22mmol) in dichloromethane (1ml) at 0 ℃ for 10 minutes. The resulting solution was stirred at 0 ℃ for 1 hour, the cooling source was removed, and the mixture was stirred at ambient temperature for 3 days. The progress of the reaction was monitored by thin layer chromatography. Once complete disappearance of the starting material was observed, the reaction solvent was removed under reduced pressure. By column chromatography (R)_f0.93) and the eluent chloroform: methanol (9: 1). 0.8g (73%) of the expected product is obtained.

¹H NMR：(400MHz，CDCl₃)δ：7.03(d，4H，J＝5.4Hz，Ar-H)，6.64(d，4H，J＝5.4Hz，Ar-H)，4.98(d，2H，J＝5.0Hz，NH)，4.55(m，2H， CHCO₂H)，4.28(m，4H，CO₂CH₂)3.72-3.59(m，24H，CH₂CH₂Cl，OCH₂CH₂OCH₂)，3.06-2.95(m，4H，CH₂CH)，1.42(s，18H，C(CH₃)₃). [ FIG. 16 of the drawings]

¹³C NMR：(400MHz，CDCl₃) δ: 177.3, 171.9, 155.0, 144.6, 130.7, 112.5, 79.8, 70.6, 69.0, 64.3, 54.4, 53.7, 40.2, 37.1, 28.3. [ FIG. 17 of the drawings]

ES-MS (m/z,%) (Positive model):C₄₂H₆₂Cl₄N₄O₁₀the calculated value of (a): 922amu, found: 923.2. [ FIG. 18 of the drawings]

In step D, the purified product C (2mmol) was dissolved in chloroform containing 1% by volume of water and 1% by volume of trifluoroacetic acid. The reaction solution was stirred at room temperature for 2 hours. The white solid produced in the reaction was collected by filtration and purified by washing with chloroform. After washing the product D, the product D (i.e. the bio-monomer) was dried in a vacuum oven at 40 ℃ for 24 hours.

Example 7:

THDI/PCL/NORF is an example of a drug-active polyurethane of the present invention containing 15% drug. The reaction conditions are as follows.

1.5g PCL was reacted with 0.27g THDI in 0.06mL dibutyryl dilaurate as catalyst in dimethyl sulfoxide (DMSO) (10mL) for 1 hour under nitrogen atmosphere. The reaction temperature is maintained between 60 and 70 ℃. 0.32g of NORF-TEG-NORF was dissolved in 5ml of DMSO, and then added to the reaction system. The reaction was maintained at 60-70 ℃ for 5 hours and then left overnight at room temperature. The reaction was finally stopped with 1ml of methanol. The final product drug polymer was precipitated in an ether/water (50 v/v%) mixture. The precipitated polymer was then dissolved in acetone and precipitated again in ether. This washing process was repeated three times.

Norfloxacin is the only component in a drug polymer with a strong detectable absorbance at 280nm in the UV range. Thus, the presence of norfloxacin can be detected using an ultraviolet spectrophotometer. FIG. 5 is an overlay of a UV chromatogram of a drug polymer and its conventional Gel Permeation Chromatography (GPC) curve generated using a conventional refractive index detector. Similar data for ciprofloxacin polymers are shown in figure 6. The latter detects all molecules present because it has a dependence on the mass of material eluted from the GPC column over a certain period of time. Thus, comparison of the two sets of data shows that the norfloxacin distribution is the same as the actual molecular weight chain distribution, indicating that there is no preferential coupling of norfloxacin/ciprofloxacin for the low molecular weight chains (as opposed to the high molecular weight chains), and vice versa, suggesting that the norfloxacin/ciprofloxacin couplings are equivalent.

Example 8:

AC/CIPRO is a representative example of pharmacologically active polyamide comprising ciprofloxacin, an antimicrobial drug, according to the present invention. It differs from example 1 in that it is not a polyurethane and shows versatility in the use of biomonomers in a multi-step polymerization reaction. The synthesis method is a conventional polyamide interfacial polycondensation reaction. As described below:

a30 ml aqueous solution of 3.88g (5mmol) of CIRO-TEG-CIRO and 1.06g (10mmol) of sodium carbonate was cooled in an ice bath for 15 minutes and then added as an aqueous phase to a 150ml flask with a stirring rod. 0.915g of adipoyl chloride (AC, 5mmol) in 20ml of dichloromethane was slowly added to the aqueous phase with vigorous stirring. The organic solution was pre-cooled in an ice bath for 15 minutes. Immediately after the addition of the organic phase, 5ml of dichloromethane were added, the organic acid chloride vessel was rinsed, and the solvent was transferred to the reaction flask. The polymerization intermediate was then stirred at maximum speed for an additional 5 minutes. The resulting polymer was collected by filtration. The polymer was then washed with water at least three times. And washed twice with acetone. The product was dried under vacuum at 40 ℃ for 24 hours.

Example 9:

gamma radiation is a common and well established method for sterilizing polymer-based medical devices (21). This technique is then known to cause significant changes in the material being processed. The high energy radiation causes ionization and excitation of the polymer molecules. The stability process of irradiated polymers results in physical and chemical crosslinking or chain scission, which can occur during, immediately after, or days or weeks after irradiation. In this example, the NF and CP polymers are dissolved in a suitable solvent, such as 10% chloroform. The film is formed in a suitable holder, such as a Teflon mold, and placed in an oven at 60 ℃ for drying. The dried film was sterilized by gamma irradiation. The dose employed should be such that a preselected sterility assurance level (22) is achieved. One or both of the following methods may be used in selecting the sterilization dose: (a) selecting a sterilization dose by 1) bioburden information or 2) information obtained by increasing the dose; b) after confirming that 25Kgy is the appropriate dose, it was selected as a sterile dose. 12 membranes (N ═ 3) were prepared for each sample and sterilized by gamma irradiation. The resulting chemical changes were detected at different time points as follows: a) without sterilization (3); b) immediately after sterilization (3): c) two weeks after irradiation (3); d) 1 month after irradiation (3). After gamma irradiation, the films were analyzed using GPC to detect the number average molecular weight (Mn), weight average molecular weight (Mw), and change in polydispersity (Mw/Mn) of the polymer chains before and after irradiation. The results are shown in Table 3. No significant physical and chemical changes of the drug polymer were demonstrated after radiation sterilization.

TABLE 3 Mn, Mw and polydispersity of the polymers before and after irradiation

Sample (I)	Mn g/mol	Mw g/mol	PI
				THDI/PCL/NF： A： B： C：	3.2×10 3.2×10 3.0×10	6.9×10 6.2×10 6.4×10	2.1 2.1 2.1
Immediately after irradiation: a: b: c:	3.0×10 2.9×10 3.2×10	6.2×10 6.2×10 6.3×10	2.0 2.0 2.0
				1 week after irradiation: a: b: c:	2.9×10 3.1×10 2.8×10	6.0×10 6.7×10 6.0×10	2.1 2.2 2.1
2 weeks after irradiation: a: b: c:	2.9×10 3.0×10 3.0×10	6.0×10 6.4×10 6.3×10	2.1 2.1 2.1
				1 month after irradiation: a: b: c:	2.8×10 2.8×10 2.8×10	6.1×10 5.8×10 5.9×10	2.1 2.1 2.1
THDI/PCL/CP： A： B： C：	2.1×10 2.1×10 2.1×10	3.4×10 3.3×10 3.3×10	1.6 1.6 1.6
				immediately after irradiation: a: b: c:	2.1×10 2.3×10 2.3×10	3.4×10 3.6×10 3.7×10	1.6 1.6 1.6

1 week after irradiation: a: b: c:	2.3×10 2.2×10 2.2×10	4.0×10 3.6×10 3.7×10	1.6 1.6 1.6
				2 weeks after irradiation: a: b: c:	2.2×10 2.2×10 2.2×10	3.7×10 3.6×10 3.9×10	1.7 1.7 1.7
1 month after irradiation: a: b: c:	2.1×10 2.1×10 2.1×10	3.4×10 3.6×10 3.5×10	1.6 1.7 1.7

example 10:

this example uses direct contact to determine the in vitro cytotoxicity of non-bioactive control polymers, NF and CP polymers, on mammalian cell lines. In this method, 1ml of polymer DMSO solution containing 1mg/ml, 3mg/ml and 5mg/ml of control polymer or drug polymer, respectively, is placed on a 0.45 μm microporous filter, which is placed on top of agar in a petri dish. Then theThese plates were incubated at 37 ℃ in 5% CO₂Was cultured in a humidified atmosphere for 24 hours. After the solvent has diffused into the agar, the filter with the polymer placed therein is transferred to a new petri dish containing the solidified agar. HeLa cells were seeded on these filters. These plates were incubated at 37 ℃ in a medium containing 5% CO₂Was cultured in a humidified atmosphere for 48 hours. Cells were stained with succinate dehydrogenase staining buffer. The stained area on the filter shows the cytotoxicity of the material. FIG. 7 is a photograph of a scan of stained cells seeded on filters placed with varying amounts of control, NF and CP polymers. There was an area of unstained in each filter. The results indicate that the control polymer and the bioactive polymer have good biocompatibility with mammalian cells.

Example 11:

NF polymers were used to evaluate the ability of hydrolases to degrade materials, preferably releasing drugs. The NF polymers were coated on small glass cylinders and then incubated at 37 ℃ for up to 10 weeks in the presence or absence of hydrolytic enzymes (i.e., cholesterol esterase). Every other week, the NF polymer culture solution was removed and fresh enzyme solution was added. The culture solution was analyzed by High Pressure Liquid Chromatography (HPLC). The standard solution of pure norfloxacin was injected into the HPLC system and a system calibration curve was plotted. And comparing the drug peak area of the culture solution with a calibration curve, and measuring and calculating the concentration of norfloxacin in the culture solution. FIG. 8 shows the release of norfloxacin from NF polymers in the presence or absence of cholesterol esterase. When CE was present, there was a significant release of norfloxacin over 10 weeks. Then in the absence of CE, only some drug was released in the first 6 weeks, which was lower than the drug release of the enzyme culture samples throughout the test.

The NF polymer culture solutions that had been subjected to HPLC assay were also evaluated for antimicrobial activity using bioanalytical methods. A large-dilution Minimal Inhibitory Concentration (MIC) assay was performed to determine the concentration of an antimicrobial agent (norfloxacin) that is capable of inhibiting the growth of pathogens and pseudomonas aeruginosa, often associated with device-related infections. MIC values for this organic and norfloxacin were determined to be 0.8 mug/mL. Buffered control treated culture solutions of enzyme and NF polymer were used in bioanalytical matrices used to assess norfloxacin concentration as a function of incubation time and treatment. The data are shown in Table 4. Antimicrobial activity was only measured within two weeks for NF polymers exposed to buffered (control) broth. However, significant clinical antibiotic levels (> MIC levels) were released by the enzyme-treated NF polymers over a 10 week incubation period. These bioanalytical data showed significant correlation with the HPLC data described above. These test results demonstrate that antibiotics are released from NF polymers under enzymatic activation and that these antibiotics have significant clinical antibacterial activity. In addition, antibiotics have significant clinical concentrations (i.e., MIC levels) for up to 10 weeks

TABLE 4 MIC assay for antimicrobial Activity of degraded NF Polymer solutions

Example 13:

samples of 1X 2cm in size were prepared from the control and CP polymer and were subjected to in vivo animal studies. The sample was implanted into the peritoneal cavity of a male mouse, and the sample was taken out of the mouse after 1 week of life. The test conditions of the present invention are as follows:

for implantation, 5 male Sprague-Dawley rats (Sprague-Dawley) were used per experimental group (250-300 g). After anesthesia, a 2cm incision was made in the abdomen. The cap and leader tissues are excised as they would enclose the specimen. Then, a control sample or a CP sample (1X 2cm) was implanted into the abdominal cavity. The incision is sutured in two layers. After 1 week of life of the animals (mice were monitored daily), samples were taken. Observations made generally include adhesions, abscesses, inflammation, and cysts. As a result, no adhesion, abscess and inflammation were observed in the CP polymer sample group, whereas no significant adhesion, abscess and severe inflammation were observed in the control polymer sample group. The sample is retrieved using sterile surgical instruments. The abdominal cavity was swabbed. The samples were washed in PBS buffer to remove non-adherent cells and then placed in sterile tubes for further bacterial culture. The number of bacteria obtained from the culture of the control and CP samples is shown in FIG. 9. It is clear that the CP samples have an antimicrobial effect and that the number of colony units (CFUs) produced is very low.

Example 12:

examples of biomedical articles in which the bioactive polymers are integrated into polymers using the following methods 1, 2, 3 include, for example, the following articles prepared wholly or partially from polyurethane components: i.e., heart assist, tissue engineering polymer stents and related devices, heart replacement devices, cardiac septal sheets, intra-aortic balloons, percutaneous heart assist, extracorporeal circuits, A-V tubes, dialysis components (tubes, filters, membranes, etc.), anergic devices, membrane oxygenators, heart bypass components (tubes, filters, etc.), pericardial balloons, contact lenses, ear cavity implants, sutures, sewing rings, cannulas, contraceptives, syringes, o-rings, bladder, penile implants, drug delivery systems, drains, pacemaker lead insulators, heart valves, blood bags, implantable wire coatings, catheters, vascular stents, angioplasty balloons and devices, bandages, cardiac massage cups, tracheal tubes, breast implant coatings, artificial catheters, craniofacial and maxillofacial reconstruction devices, ligaments, fallopian tubes, biosensors, and bio-diagnostic substrates.

Non-biomedical articles produced by the method 1) described above include, for example, extruded health care products, biosensor catalytic beds or affinity chromatography column packing, or biosensors as well as bio-diagnostic substrates.

Representative non-medical applications made by method 2) include fibrous membranes used to purify water.

Representative non-medical applications of method 3) include biologically functional dental cavity liners for sterile surfaces.

While the specification describes and illustrates certain preferred embodiments of the invention, it is to be understood that the invention is not limited to these embodiments. Moreover, the invention also includes all embodiments that are functionally or mechanically equivalent to the embodiments described above, as well as all embodiments having the characteristics described and illustrated herein.

Claims

1. A pharmaceutically active polymeric compound of formula (I),

Y-[Yn-LINK B-X]m-LINK B(I)

wherein (i) X is a geminal biological coupler of formula (II)

Bio-LINK A-Bio(II)

Wherein Bio comprises a bioactive agent group linked to LINK A by a hydrolysable covalent bond;

LINK a is a coupled central flexible linear first segment of theoretical molecular weight less than 2000 attached to each of said Bio fragments;

(ii) y is LINK B-OLIGO; wherein

(a) LINK B is a coupled second segment linking one OLIGO to another and OLIGO to X;

(b) OLIGO is a short length polymer segment having a molecular weight of less than 5,000 comprising less than 100 monomer repeat units;

(iii) m is 1 to 40; and

(iv) n is selected from 2 to 50;

wherein LINK A is a coupling segment formed from a dihydroxy or diamine that itself comprises a polyalkyl, polyalkyleneoxide, polyamide, polyester, polyethylene, polyanhydride, or polysiloxane;

wherein LINK B is a coupling segment formed from a bifunctional molecule selected from the group consisting of diamines, diisocyanates, disulfonic acids, dicarboxylic acids, diacid chlorides, and dialdehydes;

wherein the OLIGO is selected from the group consisting of polyurethanes, polyureas, polyamides, polyalkylene oxides, polyesters, silicones, polyethersulfones, polyolefins, polyethylenes, polypeptides, polysaccharides, and segments thereof linked by ethers and amines;

wherein the bioactive agent is selected from the group consisting of anti-inflammatory agents, antiproliferative agents, antimicrobial agents, and antithrombin agents comprising at least two functional groups selected from the group consisting of hydroxyl, amine, carboxylic acid, and sulfonic acid.

2. The compound of claim 1, wherein LINK a is linked to Bio via a carboxylate, amide or sulfonamide.

3. The compound of claim 1, wherein LINK a has a molecular weight selected from 60-700.

4. The compound of claim 1, wherein LINK a is a coupled central bendable curvilinear segment formed from a dihydroxy or diamine selected from ethylene glycol, butylene glycol, hexylene glycol, cyclohexanediol, 1, 5 pentanediol, 2-dimethyl-1, 3 propanediol, 1, 4-cyclohexanediol, 1, 4-cyclohexanedimethanol, tri (ethylene glycol), poly (ethylene oxide) diamine, lysine esters, silicone glycols, carbonate diols, ethylene diamine, cyclohexanediamine, 1, 2-diamino-2 methylpropane, 3-diamino-N-methyldipropylamine, 1, 4-diaminobutane, 1, 7-diaminoheptane, 1, 8-diaminooctane.

5. The compound of claim 1, wherein LINK B has a molecular weight selected from 60-2000.

6. The compound of claim 5, wherein LINK B has a molecular weight selected from 60-700.

7. The compound of claim 1, comprising at least two Bio moieties having different biological activities.

8. The compound of any one of claims 1-6, wherein the Bio has a molecular weight < 4000.

9. The compound of claim 8, wherein the Bio has a molecular weight < 2000.

10. The compound of claim 1, wherein the bioactive agent is an antimicrobial agent.

11. The compound of claim 10, wherein the antimicrobial agent is selected from ciprofloxacin and norfloxacin.

12. The compound of claim 1, wherein the biologically active agent is an anti-inflammatory agent selected from amfenac, aceclofenac, oxaceprol, and glycyrrhetinic acid.

13. The compound of claim 1, wherein the biologically active agent is an anticoagulant enzyme agent selected from the group consisting of bromfenac, tirofiban and lotrafiban.

14. The compound of claim 1, wherein the bioactive agent is an antiproliferative agent selected from acivicin and actyland.

15. The compound of claim 1, wherein the compound is formed by stepwise polymerization of a prepolymer of formula Yn-LINK B and a biological coupling agent of general formula (III):

PBio-LINK A-PBio(III)

wherein PBio comprises the bioactive agent group and LINK a, Y, n and LINK B are as defined in claim 1.

16. A biological coupling agent of the general formula (III),

PBio-LINK A-PBio(III)

wherein the PBio comprises (i) a fluoroquinolone group containing at least two functional groups selected from the group consisting of hydroxyl, amine, carboxylic acid, and sulfonic acid and linked to LINK a by a hydrolyzable covalent bond, and (ii) at least one functional group to allow polymerization to occur in steps;

LINK A is a coupled central flexible linear first segment attached to each of said PBio segments;

wherein LINK A is a coupling segment formed from a dihydroxy or diamine selected from the group consisting of ethylene glycol, butanediol, hexanediol, cyclohexanediol, 1, 5 pentanediol, 2-dimethyl-1, 3 propanediol, 1, 4-cyclohexanediol, 1, 4-cyclohexanedimethanol, tri (ethylene glycol), poly (ethylene oxide) diamine, lysine esters, silicone glycols, carbonate diols, ethylene diamine, cyclohexanediamine, 1, 2-diamino-2 methylpropane, 3-diamino-N-methyldipropylamine, 1, 4-diaminobutane, 1, 7-diaminoheptane, and 1, 8-diaminooctane; .

17. A coupler as claimed in claim 16 wherein LINK a is attached to Bio via a carboxylate, amide or sulfonamide chain.

18. A coupling agent as defined in claim 16 wherein each PBio contains a fluoroquinolone group selected from the group consisting of norfloxacin, ciprofloxacin, sparfloxacin and trovafloxacin.

19. A composition comprising a pharmaceutically active polymeric compound of any one of claims 1-15 admixed with a polymer.

20. The composition of claim 19, wherein the polymer is selected from the group consisting of polyurethanes, polysulfones, polyesters, polyethylenes, polypropylenes, polystyrenes, silicones, poly (acrylonitrile-butadiene styrene), polybutadienes, polyisoprenes, polymethyl methacrylates, polyamines, polyvinyl acetates, polyacrylonitriles, polyvinyl chlorides, polyethylene terephthalates, polyamides, celluloses, and other polysaccharides.

21. The composition of claim 19, wherein the polymer is a segmented polyurethane, a polyester, a polysaccharide, or a silicone.

22. A tangible article, wherein the tangible article is formed from the composition of any of claims 19-21.

23. A tangible article as defined in claim 22 which is an implantable medical device, a self-supporting film or a fiber.

24. A tangible article, wherein the tangible article is formed from the compound of claim 1.

25. A tangible article as defined in claim 24 in the form of an implantable medical device, a self-supporting film, or a fiber.

26. The composition of claim 1, wherein LINK a itself comprises a polyester that is a polycarbonate.

27. The composition of claim 1, wherein the OLIGO is a polyester that is a polycarbonate.

28. The composition of claim 1, wherein LINK B is linked to the other segments through a polyester that is a polycarbonate.

29. The composition of claim 20, wherein the base polymer is a polyester that is a polycarbonate.