POLYMER MATERIAL WHICH IS BACTERISTATIC OR FUNGISTATIC

Abstract: A formed polymer material having bacteriostatic or fungistatic properties and which is the reaction product of: (a) a precursor polymer having at least two active hydrogen atoms capable of imparting to the polymer material elastomeric properties; (b) a chelating agent having at least one active hydrogen atom; (c) from 0 to about 0.2% by weight, based on the weight of the reaction mixture, of a metal-containing urethane formation catalyst; and (d) a polyisocyanate in amounts less than that stoichiometrically equivalent to the active hydrogen atom content of (a) and (b).

Description: POLYMER MATERIAL WHICH IS BACTERU.TATIC OR FUNGISTATIC Th is appl i cation is a continuation- in-part of appl ication Serial No . 550 , 192 fi l ed November 9 , 1983. Background of the Invention This invention relates to polymer materials and more particularly, but not exclusively, to preformed polymeric materials which may be used as an interface between damaged outer human or other animal tissue, such as epidermal or epithelial tissue, (herein-after termed "a wound") and its external environment. This invention also relates to controlled microrelease compositions comprising the polymer materials and an active substance, for example a medication system; for bacteristatic and/or fungistatic treatment; to processes for preparing such polymeric materials and such controlled release compositions; and to methods of utilizing them, especially jji vivo. In the treatment of burns or other post-operative, accidental or pathological tissue damage it has long been desired to provide an improved interface or bandage. Ideally, such an interface should protect the wound from physical trauma; it should prevent agents of infection, such as airborne fungi, bacteria and viruses from gaining access to the wound; it should be transparent to permit visual inspection of the wound; it should prevent maceration of the scab and healing tissue by controlling the moisture of the wound; it should be adequately permeable to gases and vapors; and, as appropriate, it should maintain medication in contact, with the wound. Present gauze dressings, such as leno weave dressings, are opaque after application and need OMPI frequent change to provide observation of healing process and/or to apply medication. This causes patient discomfort, particularly where wound exudate has dried and consolidated the dressing and wound. Moreover, they do not exclude agents of infection. Some limited types of polymer materials have already been suggested for use as a wound dressing, but these have generally been natural and semi -synthetic products such as collagen, gelatin and starch products. These materials are not normally transparent. In addition, proteinaceous materials can be allergenic; and furthermore, they do not control agents of infection, indeed, they may provide a nutrient source. Also, since rejection Is often the subject of natural substitutes, it may be that synthetic substition may reduce such rejection tendencies. U.S. Pat. No. 4,430,043, issued July 20, 1982, and U.S. Pat.. No. 4,460,369, issued July 14, 1984, to D.E. Seymour disclose and claim an adhesive-coated sheet material incorporating anti-bacterial substances. The materials of Seymour are described as an improvement on adhesive-coated sheet materials disclosed and claimed in British Pat. No. 1,280,630. Seymour describes the earlier materials as having been proposed for use as a surgical and dressing material to cover wounds (including burns) and surgical sites. Seymour notes that in this manner, it is effective to keep bacteria from the wound, and to prevent scab formation and inhibit scarring since the layer, while permeable to moisture vapour, obviously slows down the drying time of the wound. The materials are commonly made of polyurethane sheet, such as for example a B. F. Goodrich polyether polyurethane sold under the Trade Name "Estane," which -ifiTE OMPI can be up to three thousandths of an inch (75 microns) in thickness, but is commonly less than 45 microns, e.g. about 30 microns. The film is coated on one surface with a continuous or discontinuous layer of suitable adhesive to approximately the same thickness. By continuous the patentee means that the adhesive covers the whole surface without any gaps or blank spaces; by discontinuous he means that there is a microporous adhesive, or a pattern of lines or dots of adhesive, the pattern covering the whole surface uniformly, but of course leaving occasional gaps between units of adhesive. Both of these expedients are well known in the coating art, but continuous adhesive is preferred by Seymour to plug any small pinholes in the sheet. Although a sheet or material as described in the earlier patent is effective in keeping airborne bacteria from the wound or surgical site, there remains the problem of any bacteria which happen to be present in the site or, more commonly, upon the surrounding skin. In the enclosed conditions provided by such a sheet, bacteria can multiply unduly and lead to infection. It had earlier been proposed to overcome this by liberal application of bacteriocidal or bacteristatic cream or like formulation over and around the wound or surgical site. There are, however, disadvantages in this procedure since the film, if subsequently applied over this moist cream base layer, can corrugate with movement of the body and generally does not adhere. The Seymour invention was based upon the finding that a bacteristatic or bacteriocidal material could be incorporated into the adhesive layer applied to the sheet. The Seymour material consisted of an adhesive-coated sheet material which was liquid-impervious, but had a high moisture-vapour permeability, whereby it was suitable as a wound or burn dressing, or surgical drape or like wound-covering material, wherein the adhesive coating had disseminated throughout its mass an amount of an antibacterial material sufficient to kill bacteria in the wound and surrounding covered skin area. According to Seymour, various types of known materials can be used, e.g.: (i) metal salts, or like compounds with antibacterial metal ions, e.g. copper, mercury or silver, and optionally with additional nonmetallic ions of antibacterial properties; (ii) typical antibiotics, e.g. neomycin, soframycin, bacitracin, polymycin; (iii) antibacterials such as chlorhexidine and its salts; (iv) quaternary ammonium compounds, e.g. cetrimide, do iphen bromide, polymeric quaternaries, and (v) iodophors such as povidone iodine. However, the materials of Seymour could only be effective if the adhesive which contained the bacteriocidal material was placed into contact with the wound, and consequently, with any scab, etc. This in turn means that the highly desirable, non-adhering properties of prior, less bacteristaticly effective, plastic materials were lost. SUMMARY OF THE INVENTION The present invention provides polymer materials suitable, inter alia, for use as wound dressings and which are in addition bacteristatic or fungistatic, -W& OMPI preferably bacteriocidal or fungicidal; while still being compatible with healthly tissue. The present invention provides a formed polymer material which is bacteristatic or fungistatic, and which is the reaction product of: (a) a precursor polymer having at least two active hydrogen atoms and imparting to the moulded or cast polymer material elastomeric properties; (b) a chelating agent having at least one hydrogen atom; (c) from 0 to about 0.2% by weight based on the weight of the reaction mixture of a metal-containing urethane formation catalyst; and (d) a polyisocyanate in amounts less than that stoichiometrically equivalent to the active hydrogen atom content of (a) and (b). Desirably, the polymer is at least partially chemically cross-linked, preferably through urethane linkages. The precursor may be selected from a wide variety of materials provided only that (i) it has at least two active hydrogen atoms with which to react with the polyisocyanate and thereby become incorporated in the polymeric material of the invention, and that (ii) it imparts elastomeric properties to the formed polymeric material of the invention. Examples of suitable precursor polymers include by way of illustration, and not by way of limitation, hydroxy -and/or carboxy- terminated polydiene rubbers (such as, for example, SBR and copolymerized interdependent matrix polymers), especially those prepared by anionic polymerization, and also linear polyesters. A preferred class of precursor polymers includes diols and triols, with diols being particularly preferred. Diols useful in accordance with the present invention include for example, polyalkylene ether glycols such as polybutylene glycol and/or polypropylene glycol, with the latter being especially preferred. Preferably, the molecular weight of the precursor polymer is from about 450 to about 3,000 or more, preferably from about 1,500 to 2,500; most commonly about 2,000. Also, the precursor polymer component may be a mixture of suitable polymers. The essential feature of the chelating agent (component b) is that it can enter into the polymerization reaction conditions while still retaining its ability to act as a chelating agent. Thus, while it may be any chelating agent which has at least one active hydrogen atom, since there are many active hydrogen-containing functional groups which also provide good chelating groups, it is desirable that component (b) is a chelating agent which has three, and preferably at least four, active hydrogen atoms. Component (b) may also comprise a mixture of suitable chelating agents. When the chelating agent has at least three active hydrogen atoms, one of the active hydrogen atoms of the chelating agent can react with a polyisocyanate, having more than two isocyanate groups, to provide a pendant moiety with two remaining active hydrogen atoms in a configuration such that they can more effectively chelate. In the preferred case where the chelating agent has at least four active hydrogen atoms, two of the active hydrogen atoms may react with a polyisocyanate, having at least two isocyanate groups to provide a backbone moiety with at least two remaining active hydrogen atoms, in a configuration such that they can more effectively chelate. OMPI The term "active hydrogen" or "active hydrogen atom" shall be understood to mean a pendant hydrogen atom which will react with an isocyanate to produce a urethane moiety Examples of suitable active hydrogen atom-containing groups include organic acid groups, typically carboxylic acid groups; primary, secondary and tertiary alcohol groups; and primary and secondary amine and amide groups. At least one such group will desirably be present. Other suitable chelating groups include carboxyl groups, carboxylic acid ester groups, and tertiary amine and amide groups. At least one such group may also be present. As examples of those chelating agents containing only active hydrogen atom-containing chelating groups, mention may be made of sugars and sugar alcohols such as sorbitol and mannitol, iminodiacetic acid (HOOC CH.,) £ NH ("IDAA") and its corresponding alcohol. It is particularly preferred, however, that the chelating agent comprises both (i) one or more active hydrogen atom-containing chelating groups, especially carboxylic acid and alcohol groups, and (ii) also one or more chelating groups which do not contain active hydrogen atoms, especially tertiary amine and amide groups. A preferred class of chelating agents includes, those having at least four active hydrogen atom-containing groups and at least two chelating groups which do not contain active hydrogen atoms; for example, tetraethylene pentamine heptacetic acid (TPHA). A particularly preferred subclass comprises compounds of the formula: X 1 R 1 R 2 X 2 N (CR 5 R 6 n N X 4 R 4 R 3 X 3 wherein: X,, X~, X, and X. may be the same or different, each represents a substituted or unsubstituted active hydrogen atom-containing group, preferably a primary, secondary or tertiary alcohol or carboxylic acid group; R,, R 2 , R, amd R. may be the same or different and each represents a substituted or unsubstituted C, to C. alkylene or alkylidene group, preferably a methylene, ethyl ene, or isopropylene group, with the proviso that R, amd R. and/or R_ and R-, may, together with the nitrogen atom to which they are bonded, form a 5 to 8 membered heterocyclic ring; n is an integer from 1 to 5 , preferably 2 or 3; and R ς and R 6 may be the same or different, and each represents a hydrogen atom or a substituted or unsubtituted C, to C.. alkyl group, preferably a hydrogen atom, with the proviso that R-. and R, may, together with the carbon atoms to which they are bonded, form a 5 to 8 membered carboxylic ring. In addition, where n is greater than 1, (i) the several R ς may be the same or different and/or the several R 6 may be the same or different; and/ or (ii) two R 5 and/ or two R, may, together with the carbon atoms to which they are bonded, form a 5 - 8 membered carboxylic system. Ethylene diamine derivatives are especially preferred. Specific examples include ethylenediamine tetracetic acid (EDTA) and its corresponding alcohols, bis-B- hydroxyethylene ethylenediamine diacetic acid and tetrakis-B- hydroxyethylene ethylenediamine; O PI tetrakis-hyrdroxymethylene ethylenediamine (THMED) ; trans-1, 2-diaminocyclohexane-N,N,NJ"N -tetracetic acid (CDTA) and its corresponding alcohols and decalin analogue. Tetrakis-B-hydroxyethylene ethylenediamine and tetrakis-hydroxym thyl ne ethylene diamine are particularly preferred. It is desirable that such chelating agents have a molecular weight of from about 160 to about 325, preferably from about 170 to about 280, Component (c), where present, may be one or more members selected from the variety of metal-containing compounds known to catalyze urethane formations by the reaction between isocyanate group-containing compounds and active hydrogen atom-containing compounds, Suitable metals include cadmium, calcium, cobalt, copper, gold, lead, magnesium, manganese, mercury, nickel, silver, tin, titanium, zinc, and zirconium with calcium and mercury, especially mercury, being preferred. The metal may be present as a simple salt (eg. calcium or zinc 2-ethylhexanoate, cobalt octoate), as an organosalt (eg. phenylmercury acetate, phenylmercury laurate) or as an ester (eg. dibutyltindilaurate). The amount of component (c), where present, is small; typically from about 0.001 to about 0.2% or less preferably from 0.0025 to 0.1%, especially from 0.005 to 0.05%, by weight based on the weight of the reaction mixture. In fact, component (c) need not be present. Thus certain bases, especially tertiary amine-containing compounds, can catalyze the urethane formation reaction; and may be used instead. Examples of such catalysts include ethylene diamine, triethylenediamine (sold under the trade name "DABCO") and triethanoldiamine. A particularly preferred class of such catalysts are those chelating agents which have at least one tertiary amine group ; these compounds are autocatalytic in the presence of an isocyanate. One or more other metals may be introduced into the polymer material to provide bacteristatic and/or fungistatic efficiency. These may be added to the reaction mixture, and may also function as a catalyst to the urethane reaction, or may be subsequently added to the formed polymer material. The polyisocyanate is preferably a diisocyanate. Aromatic diisocyanates are preferred with bis-( -isocyanatophenyl) methane being particularly preferred. As previously pointed out, the polyisocyanate should preferably be present in amounts less than that stoichiometrically equivalent to the active hydrogen atom content of components (a) and (b). This will ensure that the active hydrogen atom-containing groups required for chelation are preserved. Fillers, such as chalk or talc, and plasticizers, such as adipate, phosphate and phthalate esters, for example dioctyl phthalate, may be Incorporated in the polymer material in a manner well known to those skilled in the art. For wound dressing usage, however, it is preferred that filler be omitted so that the resulting dressing may be transparent to enable medical inspection without removal. The present invention also provides a process for the preparation of a polymer material as aforesaid, which process comprises: (i) mixing a precursor polymer having at least two active hydrogen atoms (and capable of imparting to the formed polymer material C PI elastomeric properties) with a chelating agent having at least on active hydrogen atom; (ii) adding a polyisocyanate in amounts less than that stoichiometrically equivalent to the active hydrogen atom content of (a) and (b) ; (iii) forming the resulting composition to provide a polymer material having a desired predetermined con iguration. The weight ratio of precursor polymer to chelating agent is preferably from about 1:1 to about 4:1. The weight ratio of active hydrogen atom-containing components, and plasticizer to polyisocyanate is preferably from about 5:1 to about 11:1. This invention also provides a modified process as aforesaid, which process comprises: (i) taking an isocyanate-terminated prepolymer which imparts to the moulded or cast polymer material visioelastic properties; (ii) mixing the prepolymer with a chelating agent having at least one active hydrogen atom and, if required, a urethane formation catalyst, and (iii) moulding or casting the resulting composition to provide a moulded or cast polymer material. According to the present invention there is also provided a polymer material prepared by the aforementioned process. In accordance with a further aspect of this invention, there is provided a wound dressing, for application to post-operative, accidental (such as burns) or pathological (such as diabetes or hemorrhoids) tissue damage, which comprises a polymer material as aforesaid. The polymer material is preferably formed, in any conventional manner, such as, for example, a sheet, typically less than 1/8", for example from .01 to .1" in thickness. To strengthen the polymer material it may also be desirable to include therein a gauze; for example, a nylon gauze onto which the reaction mixture is cast, moulded or calendered. In use as a wound dressing agent, it is known that certain combinations of metal can exert a synergistic healing effect. Thus, wound healing is found to be greatly facilitated if calcium or magnesium is present with tin or mercury. In the management of tumors the additional presence of selenium is advantageous. Metals can be added or exchanged by swelling the polymer in a swelling agent containing an appropriate metal salt. Thus, the polymer material, optionally containing mercury, may be swollen in a swelling agent containing a calcium and/or magnesium substituted or unstubstituted carboxylate, such as a lactate. The metal is generally added to the polyol mixture at a relatively low level, often as low as about 0.001%, in the form of a soluble salt, and more preferably, in the form of a soluble organo salt. For example, phenyl mercuric acetate. As noted earlier, the metal can also function as a urethane catalyst, its form remaining unchanged throughout the reaction. While I do not limit myself to any one thing by which the mechanism of my invention can be explained, the following. sets forth one theory, based on the use of the preferred bifunctional chelating agent of the alkylene diamine type. On polymerization, all but a few of the metal atoms chelate, the two backbone teritiary nitrogen atoms and the two terminal unreacted hydroxyl groups complete each complex. The level of metal added is such that some tetrol complexes remain unsatisfied; these can play a part in the role of immunological stimulation. This invention further provides a method of treating human or other living tissue with a polymer material as aforesaid, which method comprises applying to a locus in the human or other living tissue a therapeutically effective amount of the polymer material. The locus may comprise a wound as aforesaid or a tumor. In the latter case the application may even involve implantation of the therapeutically effective amount of the polymer material. This invention still further provides an endoprosthesis, for example an osseous or cartiligenous material substitute or a vascular graft which may readily be treated to impart anticoagulant activity, comprising a polymer material as aforesaid. This invention provides surgical instrumentation comprising a polymer material as aforesaid. The surgical instrument may be completely or in part cast from the polymer or coated therewith. The polymer material of the invention is also very suitable for plasmaferesis or asphaferesis. Detailed Description of the Preferred Embodiment The following Examples will serve by way of illustration, and not by way of limitation, to more fully describe the present invention. Parts are by weight unless otherwise stated. EXAMPLE 1 1 part of tetrahydroxym thyl ethylene diamine, 2 parts of a polypropylene glycol of number average molecular weight 2,000 and 0.005 parts of phenyl mercury acetate (as a catalyst) were thoroughly mixed in a reactor for 3 hours at 160°F at a pressure of 20 inches Hg. The water content was maintained at less than 0.05%. The mixture was then cooled to room temperature while maintaining the partial vacuum. 0.6 part of bis-(4-isocyanato henyl) methane (Upjohn Co., Grade 143) was next introduced into the mixture at ambient pressure, and the radical mixture was then stirred and poured onto siliconized microrelease paper to form a polymerized sheet. EXAMPLE 2 Example 1 was repeated with inclusion of 0.6 parts of dioctyl phthatlate as plasticizer, in the mixture. EXAMPLE 3 S_. aureus bacteria were streaked onto bovine blood agar in a Petri dish. This culture was then incubated at 37°C at atmospheric pressure for 24 hours. Then a 1 mm cube of the polymer material of Example 1 was placed in the center of the dish and the incubation was continued. The area of inhibition was observed after 24 hours (day 1) whereupon the cube was removed, washed with phosphate buffer and placed onto a freshly incubated Petri dish culture; and the process was repeated to give the following results: OMPI Day Average Zone Diameter (mm) 1 32.5 2 28.8 3 27.9 4 27.0 5 28.0 8 26.4 15 28.9 22 29.9 29 23.5 365 18.5 These figures indicate a slow microrelease of mercury (confirmed by use of radioactive-doped phenylmercury acetate) for about 1 year with a concomitant bacteristatic effect. The effect is general for both Gram positive and negative bacteria including: diplococci steptococci staphylococci bacilli cocobacilli fusiform bacilli treponema vibrios spirilla sarcinae Several strains of fungi were also destroyed when similarly treated. EXAMPLE 4 100 macrophage cells taken from the peritoneum of an anaesthetized Bab C mouse were counted onto, as control, a clean glass plate. A like number were counted onto a 500 film of the polymer material of Example 1. Both samples were then incubated at 37°C at atmospheric pressure. A further count was made after 4 hours. The average spread, a measure of macrophage activation, on the control was 2% while that on the film was 36%. Incubation was continued and a further count was made 4 hours later. No further spread was observed, indicating that macrophage activation was essentially complete within 4 hours. The activated macrophages were returned to the periotoneum of a Bab C mouse in which tumor growth had been induced by earlier introduction of tumor culture. The macrophages became phagocysistic and all tumors were apparently terminated. The present invention is particularly useful in taking advantage of calcium. Apart from being by far the major component of bone structure, calcium also contributes to many other important physiological functions. There are two which are particularly pertinent in this instance. First, calcium is the essential catalyst in the conversion of prothrombin to thrombin in the process of coagulation. Second, calcium is a stabilizing component in the nucleus of a macrophage such that, if the level is increased or decreased, the micro-organism becomes phagocystically activated. It might also be noted that while coagulation is generally regarded as essentially beneficial and, in the case of hemophillia, critical, there are circumstances where retardation, but not elimination, of the process could be advantageous. For instance, additional supplies of blood transporting immune response organisms could be helpful in dealing with excessive infection at a wound site. The present invention provides a means to take advantage of all of these. Calcium, as a soluble salt, such as gluconate or levulinate, is readily accepted by the polymer and a very loose bonded chelation occurs. In using the >MPI polymer material of the present invention, there is a choice available in both calcium rich and calcium starved applications. In calcium rich applications (that is with many of the chelation sites satisfied with calcium ion), when the polymer is in contact with a wound, abundant calcium is available for: (a)catalization of thrombin and rapid coagulation and/or; (b)because of the weak calcium-complex bond, as a precipitator of immune organism motivation via the macrophage nucleus. In calcium starved applications (that is with the maximum number of uncomplexed chelation sites available on the polymer surface): (a) calcium is attracted from the available blood plasma, thus delaying coagulation and promoting the plasma flow and its attendant micro-organisms and; (b) this calcium is then readily donated to macrophages, thus causing them to become hyperactive. An example of an experiment to support these observations is as follows: EXAMPLE 5 Mice were injected with 1.5ral of a 10% proteose peptone solution 4 days prior to harvest and sacrificed by CO asphyxiation. Then 4.0ml of Alsever's solution was injected and the abdomen massaged. The peritoneum was then incised, the exudate drained, and the supernatant was separated by centrifuge. Macrophages were counted and divided equally into three identical nutrient solutions: OMP- A. control no additives B. added a 1mm cube of high density polyethylene ("HDPE") C. added a 1mm cube of the polymer of Example 1 The three solutions were incubated at 37° C. for one hour and the polymer cubes removed from B and C. The macrophage populations were then introduced to cover-slip slides and incubated for a further two hours. The spread, indicating activation, was counted as: A. control 2 1/ 2% B. HDPE 3 1/2 % C. polymer of Example 1 30% On activation, ameboid macrophages secrete enzymes one of which is Interleuken 1. This enzyme is a trigger for fibroblast activation and therefore, and deposition of collagen and interferon protein.. The normal response time for what may be the vital micro-organisms, is dramatically decreased in the presence of the polymer of Example 1. For example: (i) maximum activation of macrophages: normal - 48 to 72 hours polymer of Example 1 - 3 to 4 hours (ii) fibroblast contribution: normal - 72 hours plus polymer of Example 1 - 6 hours When endothelial cells are introduced to the polymer of Example 1, they adhere and they survive. It is not yet clear under what conditions they divide without additional encouragement. However, if the polymer of Example 1 is micro-coated with fiber-nectin, the cells not only proliferate, but apparently encourage the activity of fibroblasts. -gtJREΛ OMPI A practical example is illustrated by the treatment of a juvenile-onset diabetic, who was sufffering from chronic mellitus ulceration of the tissue adjacent to the lateral malleolus. The lesion had been treated for five yeas without improvement and below the knee ("BK") amputation was imminent. The ulcer site was covered with dressing 2.5" x 2.5" x 0.05", formed from the polymer of Example 1. On examination after three weeks, it was found the tumor had changed to a healthy pink and peripherial cell growth had commenced. The same dressing was then replaced and the site re-examined after a further three weeks. The wound had virtually closed without sign of infection. There was no reoccurrence. The present invention is thus specifically of particular advantage for use in wound dressing; burn management; control of bacterial, fungal, viral, spiroteche and parasitic infections; as an anti-coagulant (Ca-) in vascular grafts; as a coagulant (Ca+) in hemophillia; as a filter component for aspheresis; as a local immuno stimulant; and for anti-tumor activity. The control of calcium at the wound site, selectively as calcium rich or calcium starved, is particularly advantageous and was not heretofore possible. It will, therefore, be understood that since many changes, altervations, and substitutions, can be made in the foregoing procedures, materials, medical applications and the like, without departing from the scope of the invention herein disclosed, it is my intention to be limited only by the appended claims.

Claims: As my invention I claim: 1. A formed polymer material which is bacteristatic or fungistatic and which is the reaction product of: (a) a precursor polymer having at least two active hydrogen atoms and capable of imparting to the moulded or cast polymer material elastomeric properties; (b) a chelating agent having at least one hydrogen atom; (c) from 0 to about 0.2% by weight of the reaction mixture of a metal-containing urethane formation catalyst; and (d) a polyisocyanate in amounts less than that stoichiometrically equivalent to the active hydrogen atom content of (a) and (b). 2. A polymer material according to claim 1 which is chemically cross-linked. 3. A polymer material according to claim 1 wherein said chelating agent has at least four active hydrogen atoms. 4. A polymer material according to claim 3 wherein said chelating agent has at least one chelating group which is free of any active hydrogen. 5. A polymer material according to claim 3 wherein said chelating agent is a compound within the scope of the formula: X 1 R 1 R 2 X 2 N (CR C R 5 R 6 )n N 4 4 R 3 X 3 wherein: X,, X-, X, and X. may be the same or different, and each is a member from the group consisting of substituted and unsubstituted active hydrogen atom-containing groups, R, , R 2 , R 3 and R. may be the same or different, each is a member selected from the group consisting of substituted and unsubstituted C, to C. alkylene radicals, and substituted and unsubstituted C. to C ς alkylidene radicals with the proviso that R. and R. and/or R_ and R_ may, together with the nitrogen atom to which they are bonded, form a 5 to 8 membered heterocyclic ring; n is an integer from 1 to 5; and Rr and R 6 , which may be the same or different, each are a member selected from the group consisting of hydrogen atoms and substituted and unsubstituted C, to C-, alkylene radicals with the proviso that R. and R, may, together with the carbon atom to which they are bonded, form a 5 to 8 membered ring or, (i) the several R 5 may be the same or different and/or the several R fi may be the same or different; and/or (ii) two R, and/or two R 6 may, together with the carbon atoms to which they are bonded, form a 5 to 8 membered ring. 6. A polymer material according to claim 5 wherein said chelating agent is an ethylenediamine derivative. 7. A polymer material according to claim 5 wherein the precursor polymer comprises a diol. 8. A polymer material according to claim 7 wherein the precursor polymer comprises a polyalkylene ether glycol. 9. A polymer material according to claim 7 wherein said glycol comprises polypropylene glycol. 10. A polymer material according to claim 7 wherein said precursor polymer has a molecular weight of from about 450 to about 3,000. 11. A polymer material according to claim 8 wherein said catalyst comprises at least one member selected from the group consisting of organic and inorganic components of cadium, calcium, cobalt, copper, gold, lead, magnesium, manganese, mercury, nickel, silver, tin, titanium, zinc and zirconium. 12. A polymer material according to claim 11 wherein said catylst is a mercury-containing compound. 13. A polymer material according to claim 1 wherein said catalyst is present in amounts from about 0.001% to about 0.2% by weight of the reaction mixture. 14. A polymer material according to claim 8 wherein said isocyanate comprises an aromatic diisocyante. 15. A process for the preparation of a polymer material, the steps which comprise: (i) mixing a precursor polymer, having at least two active hydrogen atoms and capable of imparting to the polymer material elastomeric properties, with a chelating agent having at least four active hydrogen atoms and at least one chelating group which is free of any active hydrogen atoms, (ii) adding to said mixture a polyisocyanate in amounts less than that stoichiometrically equivalent to the active hydrogen atom content of said mixture, from 0 to about 0.2% by weight of a urethane formation catalyst, and from 0 to about 50% by weight of filler, and from 0 to about 50% by weight of plasticizer; and (iv) forming the resulting composition into a desired configuration 16. A process according to claim 15 wherein the weight ratio of precursor polymer to chelating agent is from about 1:1 to about 4:1. 17. A process according to claim 15 wherein the weight ratio of active hydrogen atom-containing components, and plasticizer to polyisocyanate is from about 5:1 to about 11:1 18. A process for the preparation of a polymer material, the steps which comprise: (i) mixing an isocyanate-terminated prepolymer which imparts to the moulded or cast polymer material elato eric properties; with (ii) a chelating agent having both at least two active hydrogen atoms and at least one functional chelating group which is free of active hydrogen atoms, and from 0 to about 0.2% by weight of a urethane formation catalyst; and (iii) forming the resulting composition into a desired configuration. 19. A wound dressing comprising a composite prepared by forming onto a gauze, a polymer material which is bacteristatic or fungistatic and which is the reaction product of: (a) a precursor polymer having at least two active hydrogen atoms and capable of imparting to the moulded or cast polymer material elastomeric properties; (b) a chelating agent having at least four active hydrogen atoms and at least one functional chelating group which is free of active hydrogen atoms; (c) from 0 to about 0.2% by weight of the reaction mixture of a metal-containing urethane formation catalyst; and (d) a polyisocyanate in amounts less than that stoichiometrically equivalent to the active hydrogen atom content of (a) and (b). Sυ £ A ..Mr 1 1 20. A method of treating injured living tissue which comprises applying to the locus of said injured tissue a polymer material which is bacteristatic or fungistatic and which is the reaction product of: (a) a precursor polymer having at least two active hydrogen atoms and capable of imparting to the moulded or cast polymer material elastomeric properties; (b) a chelating agent having at least two active hydrogen atoms and at least one functional chelating group which is free of any active hydrogen atoms; (c) from 0 to about 0.2% by weight of the reaction mixture of a metal-containing urethane formation catalyst; and (d) a polyisocyanate in amounts less than that stoichiometrically equivalent to the active hydrogen atom content of (a) and (b). 21. A method according to claim 20 wherein said polymer material contains at least one member selected from the group consisting of organic and inorganic components of cadium, calcium, cobalt, gold, led, magnesium, manganese, mercury, nickel, silver, tin, titanium, zinc and zirconium. 22. A method according to claim 20 wherein said polymer material controls the concentration of calcium metal available at said locus. 23. A method according to claim 21 wherein said applying to the locus involves implantation of the therapeutically effective amount of the polymer material. 24. An endoprosthesis comprising a polymer material which is bacteristatic or fungistatic and which is the reaction product of: (a) a precursor polymer having at least two active hydrogen atoms and capable of imparting to the O PΪ moulded or cast polymer material elastomeric properties; (b) a chelating agent having at least two active hydrogen atoms, and at least one additional chelating group free from any active hydrogen atoms; (c) from 0 to about 0.2% by weight of the reaction mixture of a metal-containing urethane formation catalyst; and (d) a polyisocyanate in amounts less than that stoichiometrically equivalent to the active hydrogen atom content of (a) and (b). 25. Surgical instrumentation comprising a polymer material which is bacteristatic or fungistatic and which is the reaction product of: (a) a precursor polymer having at least two active hydrogen atoms and capable of imparting to the moulded or cast polymer material elastomeric properties; (b) a chelating agent having at least two active hydrogen atoms, and at least one additional chelating group free from any active hydrogen atoms; (c) from 0 to about 0.2% by weight of the reaction mixture of a metal-containing urethane formation catalyst; and (d) a polyisocyanate in amounts less than that stoichiometrically equivalent to the active hydrogen atom content of (a) and (b). BAD ORfGfNAw OMPI

Inventors: HILES MAURICE, HILES, MAURICE
Applicants: HILES MAURICE, HILES, MAURICE
Application year: 1984
Main classification: C08G18
IPC codes: A61L15, A61L26, A61L27, A61L31, C08G18