Prepolymers useful in biomedical devices

Abstract: A novel polyurethane based prepolymer useful in biomedical devices which provides high oxygen permeability and superior physical properties.

Description: The invention relates to prepolymers especially useful as monomers that can be formed into biomedical devices. Heretofore, biomedical materials especially useful commercially as contact lenses have been based upon polymers and/or copolymers of a select set of chemistries. Methylmethacrylic acid type chemistries form the oldest type, the polymers from which poly(methylmethacrylates) (PMMA) have been surpassed by hydrogel chemistries based upon poly(hydroxyethyl methacrylate) (pHEMA) or polyvinyl pyrrolidinone (pNVP), and copolymers of HEMA and NVP. These materials form the basis for most soft contact lenses. Silicone chemistries have played a lesser role in the marketplace, but have offered higher oxygen permeabilities than their hydrogel counterparts. They have, however, presented certain performance characteristics which limit their application - specifically surface wettability problems. Copolymers employing PMMA types of chemistry have been employed in conjunction with silicone chemistry and hydrogel chemistry to produce a wide assortment of materials which have the common characteristics of high oxygen permeability and high modulus (rigidity). These materials have been characterized as hard gas permeable or rigid gas permeable materials. Urethane chemistries have not been employed commercially in the contact lens market despite significant work in the area such as US-A-3,786,034 which relates to hard, hydrophilic polyurethane material formed from reacting a specific polyol with a polyfunctional isocyanate. US-A-3,821,186 teaches similar materials as US-A-3,786,034. US-A-4,136,250 teaches a polymer formed by reacting a high molecular weight polydimethyl siloxane diol with 2 mole equivalents of isophorone diisocyanate and then reacting with excess hydroxy-containing monomers. Essentially, this is a soft segment prepolymer endcapped with ethylenically reactive endcaps. These materials are relatively weak and in their hydrated form show low degrees of elongation. US-A-4,309,526 teaches adhesive compositions which employ low molecular weight polyols reacted with diisocyanates and short chain cycloaliphatic or aromatic diols, endcapped with hydrophilic endcaps. Various characteristics such as oxygen permeability are not mentioned. US-A-4,359,553 teaches polyurethane diacrylate compositions useful as biomedical materials which are formed by reacting a diol of MW 200 to 20,000 with 2 mole equivalents diisocyanate which is then reacted with diethyleneglycol diacrylate to form the water soluble polyurethane. Specific applications taught in the patent are as controlled release matrices. US-A-4,740,533 teaches materials which are block copolymers of polyoxyalkylenes and polysiloxanes which have no hard segments. US-A-4,780,488 teaches a prepolymer with only a central soft segment endcapped with hydroxyethyl methacrylate endcaps or the like. The art does not disclose polyurethane prepolymers useful as biomedical materials with the hard-soft-hard or the soft-hard-soft configurations disclosed herein which are oxygen permeable and still exhibit exemplary physical strength characteristics. Nor does the art teach that these prepolymers are useful as biomedical materials. The present invention provides a prepolymer material consisting of prepolymers represented by the general formulae : E(*D*A*D*G) a *D*A*D*E' or E(*D*G*D*A) a *D*G*D*E' where A denotes a divalent polymeric radical chosen from the group of wherein R P denotes a straight or branched alkylene group with 1 to 6 carbon atoms and n, n' and n'' are the same or different integers such that the sum of n, n' and n'' provides for a moiety weight of said divalent polymer radical between 2,000 and 10,000; R F denotes a fluorinated straight or branched alkylene radical with 1 to 6 carbon atoms and m, m' and m'' are the same or different integers such that the sum of m, m' and m'' provides for a moiety weight of said divalent polymeric radical of between 400 and 10,000; R S denotes an alkyl radical or a short chain fluorinated alkyl radical with 1 to 3 carbon atoms; and p provides a moiety weight of 400 to 10,000; D denotes an alkylene diradical, an alkyl cycloalkylene diradical, a cycloalkylene diradical, an alkylarylene diradical or an arylene diradical, with 6 to 30 carbon atoms; G denotes an alkylene diradical, a cycloalkylene diradical, an alkyl cycloalkylene diradical, an aromatic diradical or an alkylaromatic diradical with 1 to 40 carbon atoms which may have ether, thio, or amine linkages in the main chain; * denotes a urethane or ureido linkage; and E and E' denote polymerizable unsaturated organic radicals represented by the general chemical formula wherein R¹ denotes a divalent alkylene radical with 1 to 10 carbon atoms; R² denotes a -H or -CH₃ radical; R³ denotes a -H radical or an alkyl radical with 1 to 6 carbon atoms or a radical where Y is -O-, -S- or -NH- and R⁴ denotes an alkyl radical with 1 to 12 carbon atoms; X denotes Ar denotes an aromatic radical with 6 to 30 carbon atoms; a is at least 1; w is 0 to 6; x is 0 or 1; and y is 0 or 1. These prepolymers are especially useful in forming copolymerizates with ethylenically unsaturated monomers which are known and used in the biomedical materials field. The resultant copolymers have a combination of oxygen permeability, surface wettability and physical strength in dry and/or hydrated forms otherwise unavailable. The prepolymers of the present invention are especially useful in making biomedical materials due to this combination of physical strength and high oxygen permeability when copolymerized with state of the art ethylenically unsaturated biomedical monomers. The combination of advantaegous properties is achieved due to the specific chemistry inherent in the claimed prepolymer. The prepolymers of the invention can be represented by the general formulae: E(*D*A*D*G) a *D*A*D*E' or E(*D*G*D*A) a *D*G*D*E' wherein A, D, E, E', G, * and a are as defined hereinabove. The prepolymers upon polymerization form two domains which can be characterized as hard and soft domains, respectively. The soft domain generally have glass transition temperatures (Tg s) lower than room temperature whereas the hard domains have Tg s higher than room temperature. Upon polymerization, the hard segments of the prepolymer associate with one another and the soft segments form the soft domain which account for the oxygen permeability of the polymeric mass. The combination of hard and soft segments provides the polymer with superior mechanical properties otherwise unavailable. The hard segments of the prepolymer are formed by the reaction of the short chain diol with the diisocyanate. Thus, in the formulae supra , the "hard segments" are represented by the *D*G*D* portions of the formulae. Thus termed, formula (i) represents a hard-soft-hard prepolymer and formula (ii) represents a soft-hard-soft prepolymer. The isocyanates which can be used in preparation of the invention include, toluene diisocyanate, 4,4'-diphenyl diisocyanate, 4,4'-diphenylene methane diisocyanate, p-phenylene diisocyanate, dianisidine diisocyanate, 1,5 napthalene diisocyanate, 4,4'-diphenyl ether diisocyanate, 4,4'(dicyclohexyl)methane diisocyanate, 1,3-bis-(isocyanato methyl)cyclohexane, cyclohexane diisocyanato, tetrachlorophenylene diisocyanate, isophorone diisocyanate, and 3,5-diethyl-4,4'-diisocyanato diphenyl methane. Other diisocyanates which may be used are higher molecular weight diisocyanate formed by reacting polyamines which are terminally capped with primary or secondary amines, or polyhydric alcohols with excess of any of the above described diisocyanates. In general, these high molecular weight diisocyanates will have the general formula wherein R is a divalent organic radical with 2 to about 20 carbon atoms, X is -O-, or -NR′-, where R is -H or a lower alkyl, and B is a divalent organic radical. The diisocyanate is reacted with low molecular weight diols or glycols such as 2,2-(4,4′ dihydroxydiphenyl)propane (bisphenol-A), 4,4′-iso-propylidine dicyclohexanol (hydrogenated biphenol-A), ethoxylated bisphenol-A, propoxylated bisphenol-A, 2,2-(4,4′-dihydroxydiphenyl)pentane, α,α′-(4,4′-dihydroxydiphenyl)-p-diisopropyl benzene, 1,3 cyclohexane diol, 1,4-cyclohexane diol-1,4-cyclohexane dimethanol, bicyclic and tricyclic diols such as 4,8-bis-(hydroxymethyl)-tricyclo [5.2.1.0 2,6 ] decane, neopentyl glycol, 1, 4 butanediol, 1,3-propanediol, 1,5-pentanediol, diethylene glycol, triethylene glycol and the like. These hard segments as mentioned before form hard domains in the final polymer or copolymer by association via hydrogen bonding with other rigid segments. The degree of association within the hard domain can be modified by controlling the amount of hydrogen bonding between the segments by either 1) decreasing the overall weight content of the hard segment in the prepolymer by increasing the molecular weight of the soft segment or 2) by decreasing the amount of hydrogen bonding density in the hard segment by either using relatively soft, longer chained diols, or by using primary amines or secondary amines capped low molecular weight compounds in conjunction with the diisocyanates rather than the diols. The hard segments are then reacted with a relatively high molecular weight polymer which is α,ω-endcapped with two active hydrogens, usually hydroxyl groups. These segments form the so-called soft segment of the prepolymer. Various types of high molecular weight polymers can be used including in general polymers of the following formulae a) HO (CH₂) (R P O) n (CH₂) OH; b) HO (CH₂) (R P O) m (CH₂) OH; and c) Formulae a) represents polyoxyalkyleneglycols which are generally commercially available in the molecular weight range called for in the present invention. These diols include polymers prepared from the epoxides: ethylene oxide 1,2-propylene oxide, 1,2-butylene oxide, 2,2 epoxydecane, 1,2-epoxyoctane, 2,3-epoxy norborane, 1,2-epoxy-3-ethoxy propane, 2,2-epoxy-3-phenoxypropane, 2,3-epoxypropyl-4-methoxy phenyl ether, tetrahydrofluran, 1,2-epoxy-3-cyclohexyloxy propane, oxetane, 1,2-epoxy-5-hexene, 1,2-epoxyethylbenzene, 1,2-epoxy-1-methoxy-2-methylpropane, benzyloxy propylene oxide and combinations thereof. The preferred polymers of this class are polypropylene glycols of molecular weights, 2000, 3000 and 4000 and more, and polyoxyethylene polyoxypropylene block copolymers with molecular weight greater than 2000. Formulae b) represents polyfluoroethers with α,ω-active hydrogens. This class of polymers can be synthesized per the heading of US-A-3,810,874. Generally, these polymers should have molecular weights between 400 and 10,000 to be useful in the present invention. Formulae c) represents α,ω-dihydroxyl alkyl endblocked polysiloxane which for the purpose of the present invention should have a molecular weight in the range of 400 to 10,000. These polysiloxanes can be synthesized by reacting a disiloxane of the general formula with cyclopolydimethyl siloxane under acidic conditions. Alternately, the disiloxane can be replaced with dimethoxydimethylsilane or diethoxy dimethyl silane to produce the α,ω-dihydroxy endcapped polysiloxanes. The endcapping monomers used in the prepolymer are generally represented by the formula as defined supra . The Stage B reaction product is reacted with an excess of suitable acrylate or methacrylate esters containing a hydroxy or amine group on the non-acrylate or non-methacrylate portion of the monomer to form the endcaps of the above formula. Suitable endcap monomers include hydroxyethyl acrylate, hydroxyethyl methacrylate, aminoethyl methacrylate, 3 hydroxypropyl methacrylate, amino propyl methacrylate, hydroxyhexylacrylate, t-butylaminoethyl methacrylate, monoacrylate or monomethacrylate esters of bisphenol-A and/or bisphenol-B. The prepolymers of the present invention are formed by two general synthetic approaches. One approach produces the hard-soft-hard prepolymer while the second approach produces the soft-hard-soft prepolymer. Variations of each scheme will be found to be necessary for specific rigid/soft segment combinations, as illustrated in the examples. HARD-SOFT-HARD PREPOLYMER SYNTHETIC SCHEMES The scheme used to produce this type of prepolymer employs three stages to produce the final prepolymer. The first stage (STAGE A) involvs reacting 2 mole equivalents of diisocyanate with about 1 mole equivalent low molecular weight diols described herein. If these diols are represented by the symbol ▴G▴ , where ▴ denotes a hydroxyl radical and G represents the rest of the diol compound, and the diisocyanate functional compound is represented by D where  represents an isocyanate radical, the STAGE A reaction can be schematically represented as follows: 2D + ▴G▴ → D*G*D where * denotes a urethane or a ureido linkage. STAGE A produces a so-called "Hard" segment. As is known to those skilled in polymer chemistry, the product D*G*D is the mathematical average of all reaction product molecules. The reaction product of the actual reaction will contain O and D(*G*D) c *G*D with c≧2. Again, the formulae are numerical averages. STAGE B involves reacting about one half mole equivalent of a α,ω-diol endcapped long chain polymer with the reaction product of STAGE A. If ▴A▴ represents the long chain diol the STAGE B Reaction is 2D*G*D + ▴A▴ → [D*G*D*]₂A In STAGE C, the reaction product from STAGE B is reacted with a molar excess of an endcapping monomer which has: 1) hydroxyl or amine functionality; and 2) some polymerizable unsaturation. If the endcapper is represented by the symbol E▴ , where is -OH or -NH₂ or -NH-, the reaction proceeds generally as [D*G*D*]₂A + 2E▴ → [E*D*G*D*]₂A Optionally, STAGE B can be run with molar excess of A to produce multiblock polymers of the general formula (D*G*D*A) a *D*G*D where a is at least 1. This reaction product would be endcapped in STAGE C above. SOFT-HARD-SOFT PREPOLYMER SYNTHETIC SCHEME The second general synthetic scheme using the same nomenclature described is represented by the following general formulae: STAGE A 2  D  + ▴A▴ → [D*]₂A STAGE B 2[D*]₂A + ▴G▴ → [D*A*D*]₂G STAGE C [D*A*D*]₂G + 2E▴ → [E*D*A*D*]₂G In general, each of the reaction stages is run until the reactive step is complete. Reaction progress in STAGES A and B reactants may be monitored by acid base titration. The isocyanate content is calculated by the difference of acid equivalents between a stock solution dibutylamine and its reaction product with the diisocyanate reaction intermediate. The reaction can also be monitored by ATR-IR for the appearance/disappearance of peaks at 1700 cm⁻¹, which indicates the presence of and 2250 cm⁻¹ which indicates consumption of -N=C=O. It is found that the synthesis of the prepolymer can be run neat or in solution. A wide range of aprotic solvents can be used to synthesize the prepolymers of the present invention. Solvents useful in the synthesis include toluene, methylene, chloride, benzene, cyclohexane, hexane, heptane and the like. Preferred solvents are toluene, methylene chloride and mixtures thereof. Reaction of the prepolymer precursors may be accomplished in the presence or absence of catalysts for urethane reactions, such catalysts being well known in the art. The first step of prepolymer synthesis where diisocyanate is first reacted with a short carbon chain (2 to 30 carbon atoms) diol, particularly where an aromatic diisocyanate is used, proceeds very rapidly, even in the absence of any catalyst. In fact, during the step of reacting diisocyanate and short chain diol, temperature control may be required in order to avoid/minimize side reactions. Preferably, the first step of prepolymer synthesis in accordance with the present invention is carried out below about 100°C, most suitably within the range of from about 60°C to about 90°C. Thereafter, the second step of the reaction is carried out at comparable temperatures, preferably within the range of from about 40°C to 70°C. The final step of prepolymer formation suitably is effected at temperatures of from about room temperature to about 100°C, with a narrow range of from about 40°C to about 50°C being most preferred. As will be apparent to those skilled in the art, optimal reaction conditions, such as temperatures and duration, are selected for each individual reaction system to achieve conditions that produce a favorable rate of reaction without fostering undesirable side reactions. Among the suitable catalysts for use in prepolymer formation are tin salts and organic tin esters, such as dibutyl tin dilaurate, tertiary amines, such as triethyl diamine and other recognized catalysts, such as 1,4-diaza (2.2.2)-bicyclooctane (DABCO). The prepolymers of the present invention are particularly useful as comonomers with ethylenically reactive monomers useful in the field of biomedical materials. In general, these monomers are the hydroxyalkyl acrylates and diacrylates such as hydroxyethyl acrylate, hydroxypropyl acrylate, and the corresponding methacrylate compounds, including cyclohexyl methacrylate, methyl methacrylate, isobornyl methacrylate, lauryl methacrylate, triethylene glycol dimethacrylate, isobuty methacrylate and tetrahydrofurfuryl methacrylate. Other useful unsaturated reactive monomers are acrylamides, methacrylamides, pyrrolidinones, styrene and acrylonitrile and other monomers known in the art including fluorinated analogs of all of the previously mentioned monomers and the organo silicone comonomers known in the art. Specific fluorocomonomers include: (2,2,2-trifluoroethyl) itaconate (hexafluoroisopropyl) itaconate (1H, 1H-perfluorooctyl) itaconate (1H, 1H, 11lH-perfluoroundecyl) itaconate (perfluoro-t butyl) itaconate (pentafluorophenyl) itaconate (2H, 2H-perfluorobenzyl) itaconate (pentafluorophenylmethyl) itaconate (decafluorocyclohexyl) itaconate (1H-perfluorocyclohexyl) methyl itaconate (1,1,1-trifluoroisopropyl) itaconate 1-methyl-4-(hexafluoroisopropyl) monoitaconate 4-(hexafluoroisopropyl) monoitaconate 1-(1H, 1H-perfluorooctyl)-4-hexafluoroisopropyl) itaconate and methacrylate analogs thereof. Specific organosilicon comonomers include: tris(2-acetoxyethyldimethylsiloxy)silylpropyl acrylate and methacrylate tris(2-carboxyethyldimethylsiloxy)silylpropyl acrylate and methacrylate tris(3-hydroxypropyldimethylsiloxy)silylpropyl acrylate and methacrylate acrylate and methacrylate functional, fluorosubstituted alkyl/aryl siloxanes such as: tris(3,3,3 trifluoropropyl dimethylsiloxy) silyl propyl acrylate and methacrylate tris[3-heptafluoroisopropoxy propyl)] dimethysiloxy silylpropyl acrylate and methacrylate tris(pentafluorophenyl dimethysiloxy)silyl propyl acrylate and methacrylate Other potentially useful organosilicon comonomers include: p-(pentamethyldisiloxanyl) styrene bis(trimethylsiloxy) pyrrolidinonyldimethyl siloxy-silylpropyl acrylate and methacrylate. When used as comonomers these materials can be used from 5 to 85 weight percent of the final copolymer weight with the balance comprising the prepolymer portion. Other di-ethylenically reactive monomers can also be used to effect the mechanical and surface properties. Such crosslinks are generally employed in the 0.1 to 5 wt % range. The polymers and copolymers are formed by a free radical mechanism using a wide variety of known free radical catalysts such as the diacyl peroxides such as benzoyl peroxide; dialkyl peroxides such as di-tert, -butyl peroxide; ketone peroxides such as methylethyl ketone peroxide; and peresters which readily hydrolyze, e.g. tert-butyl peracetate, tert-butyl perbenzoate, di-tert-butyl diperphthalate, etc. A particularly useful class of peroxy initiators are the organic hydroperoxides such as cumene hydroperoxide, methylethyl ketone hydroperoxide, tert-butyl hydroperoxide, etc. The initiators should be used at a concentration of about 0.01 percent to about 10 percent by weight of the total formulation, preferably about 0.1 percent to about 5 percent by weight. Another useful class of initiators comprises carbonyl-containing ultraviolet-activated free radical generators, such as acetophenone, benzophenone, and the benzoin ethers. Other suitable UV initiators are known in the art. Initiator mixtures may also be used. Solvents can be used in the final copolymerization and/or polymerization process. Solvent choice will depend upon the solubility parameters of the prepolymer and of the comonomers used, if any, and should be chosen to allow full solubilization of all polymerizate components. In certain instances, the copolymerization process should be carried out without solvent. For instance, when 2-hydroxyethyl methacrylate (HEMA) is copolymerized with one of the prepolymers formed with polyethylene glycol, use of toluene causes the HEMA to form heterogenous domains which are not stable under aggressive hydrolytic conditions. Some of the preferred copolymers are polymerized from the following comonomer mixtures: Various homopolymers and copolymers films can be formed and characterized by standard testing procedures such as: 1. Tensile strength (g/mm²) and modulus of elasticity can be measured per ASTM test method D1708. 2. Elongation can be measured per ASTM 1708. 3. Initial tear strength and propagation tear strength can be measured per ASTM 1438. 4. Oxygen permeabilities can be measured by the method reported by Relojo, M. et al in Contact and Intraocular Lens Medical Journal , Vol. 3, issued p. 27 (1977) and edge effects can be accounted for per the methods described by Fatt, et al. in International Contact Lens Clinic , V. 14, p. 389 (1987). 5. Water content can be measured per a gravimetric method. 6. Refractive index can be measured per typical methods on hydrated samples using a refractometer. As mentioned, the prepolymers of the present invention are particularly useful in forming shaped articles used in biomedical applications. These polymers and copolymers can be used to make biomedical devices i.e. shaped articles, such as dialyzer diaphragms, to prepare artificial kidneys and other biomedical implants, such as disclosed in US-A-2,976,576 and US-A-3,220,960. The instant polymers and copolymers can be used in preparing therapeutic bandages as disclosed in US-A-3,428,043. The instant polymers and copolymers can also be used in preparing medical surgical devices e.g. heart valves, vessel substitutes, intrauterine devices, membranes and other films, dialyzer diaphragms, catheters, mouth guards, denture liners and other such devices as disclosed in Shephard US-A-3,618,231. The instant polymers and copolymers can be used to modify collagen to make blood vessels, urinary bladders and other such devices as disclosed in US-A-3,563,925. The instant polymers and copolymers can be used to make catheters as disclosed in US-A-3,566,874. The instant polymers and copolymers can be used as semipermeable sheets for dialysis, artificial dentures and all of such disclosures as set forth in US-A-3,607,848. The instant polymers and copolymers can be used in ophthalmic prostheses and all other uses disclosed in US-A-3,679,504. They may also be used as a polymeric matrix for controlled release of active pharmaceutical agents. In the following examples which illustrate the invention, the properties of such films derived from the claimed prepolymer and combinations of prepolymers with various comonomers are described. For certain comonomers which employed "hydrophilic" comonomers, the films were hydrated to "hydrogel" states-their physical properties were measured as hydrated. EXAMPLE 1 SYNTHESIS OF HARD-SOFT-HARD PREPOLYMER BASED ON TOLUENE-2,4-DIISOCYANATE 2 mole equivalents of toluene-2,4-diisocyanate (TDI) were dissolved in toluene with one mole equivalent hydrogenated bisphenol A (HBPA) in a resin kettle with constant stirring under nitrogen. This STAGE A reaction was run at 60-90°C for 2-3 hours in the presence of 0.5 wt% "DABCO" catalyst. One mole equivalent of polypropylene glycol with a molecular weight of about 1000 was then slowly added to the reaction mixture and reacted for 2-3 hours at 60-80°C under nitrogen. Excess 2-hydroxyethyl methacrylate (HEMA) was added to the isocyanate terminated STAGE B reaction mixture and then reacted to completion. Variations of the above synthesis were run by substituting neopentylglycol (NPG) for the hydrogenated Bisphenol A, and by substituting various molecular weight polypropylene glycols for the PPG-1000. The resulting prepolymers were homopolymerized between treated glass plates in the presence of a free radical catalyst, benzoin methylether. The polymerization was UV initiated in toluene. The solvent was removed by vacuum and the resultant films were characterized. The results obtained are reported in TABLE 1. The oxygen permeability of the homopolymers increase as the molecular weight of the polypropylene glycol increased. EXAMPLE 2 HARD-SOFT-HARD PREPOLYMER USING ISOPHORONE DIISOCYANATE (IPDI) The same basic synthetic procedure as described in the previous example was employed except that, due to the decreased reactivity of isophorone diisocyanate relative to toluene diisocyanate, higher levels of reaction catalyst were used. Reaction conditions and summary of the cured homopolymer films is reported in TABLE 2. Once again, the oxygen permeability of the cured prepolymer increased with increasing molecular weight of the polypropylene glycol polymer. These prepolymers did not produce yellowed films as the TDI materials did upon hydrolytic testing. EXAMPLE 3 4,4-DI-CYCLOHEXYL METHANE DIISOCYANATE BASED HARD-SOFT-HARD PREPOLYMERS Hard-soft-hard prepolymers were synthesized per the examples supra except that H₁₂-MDI was used. Films were cured from 30°% prepolymer solution in toluene as reported in TABLE 3. In general, the H₁₂-MDI prepolymers produced films with greater tear strengths than the TDI or IPDI diisocyanate based systems and were slightly less oxygen permeable. EXAMPLE 4 COPOLYMERS OF IPDI BASED HARD-SOFT-HARD PREPOLYMERS WITH HYDROPHILIC MONOMERS A hard-soft-hard prepolymer produced with isophorone diisocyanate (IPDI), neopentyl glycol (NPG), polypropylene glycol with a molecular weight of 4000 and 2-hydroxethyl methacrylate was copolymerized with a hydrophilic comonomer. Various copolymers of this prepolymer (INP4H) with various comonomers were made and tested. The general scheme for making the copolymer involved mixing the prepolymer with the comonomer in a 30-70 wt% solution in toluene in the presence of a known free radical catalyst. The solutions were placed between treated glass plates and polymerized. The films were then physically characterized. Specific hydrophilic comonomers used were 2-hydroxethyl methacrylate and N-2-vinylpyrrolidinone. The characteristics of these copolymers are disclosed in TABLE 4. Several interesting features are displayed by the resultant films. In general, the contact angle of the material was lowered as the content of hydrophilic comonomers increased, as did water content. However, oxygen permeability decreased as the water content of the hydrated material increased. Normally, water content and O₂ permeability of hydrogel materials is directly related rather than inversely related. EXAMPLE 5 POLYMER ALLOYS OF POLYMERIZED HARD-SOFT-HARD MATERIALS A homopolymer of INP4H was prepared and then soaked in a solution of N-vinyl pyrrolidinone containing a free radical catalyst. The films were then subjected to UV radiation in order to polymerize the N-vinylpyrrolidone. Based upon analysis of the extracted parties of the polymerized polymer alloy, wt% of polymerized N-vinyl pyrrolidinone could be calculated. The characteristics of these polymer alloys are reported in TABLE 5. It was observed that these alloy materials felt much more slippery than the copolymers made from the same monomer combinations. EXAMPLE 6 COPOLYMERS OF HARD-SOFT-HARD PREPOLYMER (INP4H) WITH FLUOROMONOMERS In the interest of producing copolymers with less lipid uptake values certain fluorinated comonomers, octafluoropentyl methacrylate (OFPMA) and hexafluoro isopropyl methacrylates, (HFIPMA) were copolymerized with INP4H prepolymers in various ratios. The cured copolymer films are characterized in TABLE 6. As the fluoro content of the copolymer was increased the oleic acid pickup decreased with a concomitant decrease in oxygen permeability. The samples with 80 wt% fluoromonomer content were too brittle to characterize. EXAMPLE 7 COPOLYMERS OF INP4H WITH SILICONE MONOMERS Various copolymers were produced from combinations of INP4H with tris(trimethylsiloxy)silylpropyl methacrylate (referred to as tris) and 2-hydroxyethyl methacrylate and characterized in TABLE 7. These copolymers exhibit very good oxygen permeabilities and oleic acid uptake characteristics as well as vastly superior tear strengths and tensile moduli with respect to pHEMA. EXAMPLE 8 HYDROLYTIC STABILITY OF INP4H/HEMA COPOLYMERS Hydrolytic stability testings of INPD4H/HEMA copolymers formed in toluene were conducted by subjecting the copolymeric samples to hostile aqueous conditions (either acidic or basic H₂O at elevated temperatures) for extended periods of up to 14 days. These copolymers showed consistent and significant loss of mass during the hydrolytic testing which indicated that the copolymerization process was not efficient. Chemical analysis of the extracted portion revealed that the portion being extracted was largely an oligomeric product of the 2-hydroxyethyl methacrylate. Subsequently, INP4H/HEMA/TRIS copolymers were produced without aid of a solvent. These copolymers proved to be hydrolytically stable under the same conditions as the toluene solution produced polymers had been treated under. EXAMPLE 9 SYNTHESIS OF HARD-SOFT-HARD PREPOLYMERS USING POLYSILOXANE DIOLS AND COPOLYMERS THEREOF α,ω-bis(hydroxybutyldimethylsily) polysiloxane was prepared by reacting dimethoxydimethylsilane with 1,3-bis(4-hydroxybutyl)tetramethyldisiloxane in water under acidic conditions. The average molecular weight of the polymer was about 3100. Using the general synthetic scheme for hard-soft-hard prepolymers with the above long chain diol, isophorone diisocyanate (IPDI), neopentylglycol (NPG) and 2-hydroxyethyl methacrylate end blocker (HEMA), a prepolymer was formed (INS3H). This prepolymer was copolymerized with 2-hydroxyethyl methacrylate in various ratios. The characteristics of these copolymers is reported in TABLE 8. These films were all hydrolytically stable. EXAMPLE 10 TERPOLYMERS OF INP4H PREPOLYMERS Terpolymers of INP4H/TRIS/glycerol methacrylate (GM) and INP4H/TRIS/N-N-dimethylacrylamide (DMM) were prepared and evaluated. The characteristics of these films is summarized in TABLES 9A and 9B. These terpolymers provide soft hydrogel type materials with excellent oxygen permeability and physical strength characteristics. INP4H: TRIS: DMA O₂ DK 30 : 50 : 20 80 25 : 50 : 25 75 EXAMPLE 11 HARD-SOFT-HARD URETHANE SILICONE PREPOLYMERS WITH "SOFTER" HARD PORTIONS Siloxane containing prepolymers were produced as before except 1,4 butanediol or diethyleneglycol was used in place of neopentyl glycol. In general, the homopolymers and copolymers of these materials had lower modulis and tear strengths than their neopentyl glycol based counterparts. IBS4H Prepolymer is formed using the general scheme for hard-soft-hard prepolymers using isophorone diisocyanate, 1,4-butanediol, the α,ω-hydroxyalkyl endcapped polydimethylsiloxane described earlier with a molecular weight of about 4000, and 2-hydroxyethyl methacrylate. IBS3H Prepolymer is the same prepolymer as IBS4H except with a lower molecular weight polydimethylsiloxane. IDS4H and IDS3H are equivalent to IBS4H and IBS3H, respectively, except diethyleneglycol was used in place of 1,4 butanedial. The physical characteristics of copolymers formed from these prepolymers with dimethylacrylamide (DMA) and/or tris (trimethylsiloxy)silyl propyl methacrylate are reported in TABLE 10. All of the prepolymers were hydrolytically stable. EXAMPLE 12 SOFT-HARD-SOFT PREPOLYMERS According to the general scheme for producing soft-hard-soft prepolymers were formed using 2-hydroxyethyl- methacrylate (HEMA), isophorone diisocyanate (IPDI), neopentyl glycol (NPG) and a disilanol endcapped polydimethysiloxane with an average molecular weight of about 1500 (Si-1500). The general chemical structure of the prepolymer was HEMA-IPDI-Si-1500-IPDI-NPG-IPDI-Si-1500-HEMA Copolymers of the above prepolymer were formed with N-N-Dimethylacrylamide and tris(trimethylsiloxy)silylpropylmethacrylate as reported in TABLE 11. COMPARATIVE EXAMPLE SOFT SEGMENT PREPOLYMER To illustrate the beneficial properties of the invention a comparative prepolymer was formed from 2-hydroxyethyl methacrylate (HEMA), isophorone diisocyanate (IPDI) and an α,ω-dihydroxyalkyl endcapped polydimethyl siloxane with an average molecular weight of about 3000 (Si-3000). The structure of the prepolymer was HEMA-IPDI-Si-3000-IPDI-HEMA Copolymers of this prepolymer with N-N-dimethyl acrylamide and tris(trimethylsiloxy)silylpropyl-methacrylate are characterized in TABLE 12. These copolymers displayed much lower tear, modulus and tensile strength than the copolymers of the present invention.

Claims: Claims for the following Contracting States : DE, FR, GB, IT, SE A prepolymer material consisting of prepolymers represented by the general chemical formulae E(*D*A*D*G) a *D*A*D*E' or E(*D*G*D*A) a *D*G*D*E' where A denotes a divalent polymeric radical chosen from the group of wherein R P denotes a straight or branched alkylene group with 1 to 6 carbon atoms, and n, n' and n'' are the same or different integers such that the sum of n, n' and n'' provides for a moiety weight of said divalent polymeric radical of between 2,000 and 10,000; R F denotes a fluorinated straight or branched alkylene radical with 1 to 6 carbon atoms and m, m' and m'' are the same or different integers such that the sum of m, m' and m'' provides for a moiety weight of said divalent polymeric radical of between 400 and 10,000; R S denotes an alkyl radical or a short chain fluorinated alkyl radical with 1 to 3 carbon atoms; and p is an integer such that the total moiety weight of said divalent polymeric radical is from 400 to 10,000; D denotes an alkylene diradical, an alkyl cycloalkylene diradical, a cycloalkylene diradical, an alkylarylene diradical or an arylene diradical, with 6 to 30 carbon atoms; G denotes an alkylene diradical, a cycloalkylene diradical, an alkyl cycloalkylene diradical, an aromatic diradical or an alkylaromatic diradical with 1 to 40 carbon atoms which may have ether, thio or amine linkages in the main chain; * denotes a urethane or ureido linkage; and E and E' denote polymerizable unsaturated organic radicals represented by the general chemical formula: wherein R¹ denotes a divalent alkylene radical with 1 to 10 carbon atoms; R² denotes a -H or -CH₃ radical; R³ denotes a -H radical or an alkyl radical with 1 to 6 carbon atoms or a radical where Y is -O-, -S- or -NH- and R⁴ denotes an alkyl radical with 1 to 12 carbon atoms; X denotes Ar denotes an aromatic radical with 6 to 30 carbon atoms; a is at least 1; w is 0 to 6; x is 0 or 1; and y is 0 or 1. The prepolymer of Claim 1 wherein the polymeric radical, A, is selected from (1) a polyethylene glycol diradical with a molecular weight of at least about 2000; (2) a dialkyl endcapped polydimethylsiloxane radical with a molecular weight of at least 400; (3) dialkyl endcapped polydifluoroalkylsiloxane polymer with a molecular weight of at least 400; and (4) a fluoroalkyl ether with a molecular weight of at least about 400. A prepolymer according to Claim 2, wherein the D radical is formed from the group of diisocyanates consisting of isophorone diisocyanate, toluene diisocyanate and 4,4'-dicyclohexyl methane diisocyanate. A prepolymer according to Claim 2 or Claim 3, wherein the G radical is formed from the group of diols consisting of neopentyl glycol, 1,4-butanediol, diethylene glycol and triethylene glycol. A copolymer material formed by polymerizing a comonomer mixture comprised of: (I) the prepolymer described by the general chemical formulae: E(*D*A*D*G) a *D*A*D*E' or E(*D*G*D*A) a *D*G*D*E' wherein A, D, E, E', G, * and a are as defined in Claim 1, and (II) an ethylenically unsaturated comonomer. The copolymer of Claim 5 wherein the polymeric radical of component (I), A, is polyethylene radical with a molecular weight of at least about 2,000. The copolymer of Claim 6 wherein component (I) comprises 15 to 95 weight percent of the comonomer mixture and said ethylenically unsaturated comonomer comprises 5 to 85 weight percent of said comonomer mixture. The copolymer of Claim 7 which further comprises a diethylenically reactive crosslinker. The copolymer of Claim 8 wherein said ethylenically unsaturated comonomer is chosen from 2-hydroxyethyl methacrylate, N-vinyl-2-pyrrolidinone, methacrylic acid, dimethyl acrylamide and glycerol methacrylate. The copolymer of Claim 5 wherein the polymeric radical of component (I), A, is a dialkyl endcapped polydimethylsiloxane radical with a molecular weight of at least 400. The copolymer of Claim 10 wherein component (I) comprises 15 to 95 weight percent of the comonomer mixture and said ethylenically unsaturated comonomer comprises 5 to 85 weight percent of said comonomer mixture. The copolymer of Claim 11 wherein said ethylenically unsaturated comonomer is chosen from 2-hydroxyethyl methacrylate, N-vinyl-2-pyrrolidinone, methacrylic acid, dimethyl acrylamide and glycerol methacrylate. The copolymer of Claim 12 which further comprises 5 to 40 weight percent organosilicon comonomer. The copolymer of Claim 5 wherein the polymeric radical of component (I), A, is a poly(fluoroalkyl)ether with a molecular weight of at least 400. A copolymer formed by polymerizing a comonomer mixture comprised of: (I) the prepolymer described by the general chemical formulae: E(*D*A*D*G) a *D*A*D*E' or E(*D*G*D*A( a *D*G*D*E' wherein A, D, E, E', G, * and a are as defined in Claim 1, and (II) an organosilicon comonomer. The copolymer of Claim 15 wherein said organosilicon monomer is tris(trimethylsiloxy)silylpropyl methacrylate. The copolymer of Claim 16 which comprises 20-50 wt % prepolymer (I), and 20-40 weight percent tris(trimethylsiloxy)silyl propyl methacrylate. The copolymer of Claim 17 which further comprises 10-35 weight percent of one of the following hydrophilic comonomers: dimethacrylamide; glycerol methacrylate; 2-hydroxyethyl methacrylate; and N-vinyl-2-pyrrolidinone. A copolymer formed by polymerizing a comonomer mixture comprised of: (I) the prepolymer described by the general chemical formulae: E(*D*A*D*A) a *D*A*D*E' or E(*D*G*D*A) a *D*G*D*E' wherein A, D, E, E', G, * and a are as defined in Claim 1, and (II) an ethylenically unsaturated fluoroorgano comonomer. A biomedical device made from a polymer comprising the prepolymer of any preceding claim. Claims for the following Contracting State : ES A process for preparing a prepolymer material consisting of prepolymers represented by the general chemical formula: E(*D*G*D*A) a *D*G*D*E where A denotes a divalent polymeric radical chosen from the group of (CH₂) n '-O-(R P O) n - (CH₂) n '' (CH₂) m '-O-(R F O) m -(CH₂) m '' wherein R P denotes a straight or branched alkylene group with 1 to 6 carbon atoms, and n, n' and n'' are the same or different integers such that the sum of n, n' and n'' provides for a moiety weight of said divalent polymeric radical of between 2,000 and 10,000; R F denotes a fluorinated straight or branched alkylene radical with 1 to 6 carbon atoms and m, m' and m'' are the same or different integers such that the sum of m, m' and m'' provides for a moiety weight of said divalent polymeric radical of between 400 and 10,000; R S denotes an alkyl radical or a short chain fluorinated alkyl radical with 1 to 3 carbon atoms; and p is an integer such that the total moiety weight of said divalent polymeric radical is from 400 to 10,000; D denotes an alkylene diradical, an alkyl cycloalkylene diradical, a cycloalkylene diradical, an alkylarylene diradical or an arylene diradical, with 6 to 30 carbon atoms; G denotes an alkylene diradical, a cycloalkylene diradical, an alkyl cycloalkylene diradical, an aromatic diradical or an alkylaromatic diradical with 1 to 40 carbon atoms which may have ether, thio or amine linkages in the main chain; * denotes a urethane or ureido linkage; and E denotes a polymerizable unsaturated organic radical represented by the general chemical formula: wherein R¹ denotes a divalent alkylene radical with 1 to 10 carbon atoms; R² denotes a -H or -CH₃ radical; R³ denotes a -H radical or an alkyl radical with 1 to 6 carbon atoms or a radical where Y is -O-, -S- or -NH- and R⁴ denotes an alkyl radical with 1 to 12 carbon atoms; X denotes Ar denotes an aromatic radical with 6 to 30 carbon atoms; a is at least 1; w is 0 to 6; x is 0 or 1; and y is 0 or 1; which process comprises: (a) reacting 2 mole equivalents of a diisocyanate of the formula: D wherein D is as defined above, and  represents an isocyanate radical, with about 1 mole equivalent of a diol of the formula: ▴G▴ wherein G is as defined above, and ▴ represents a hydroxy radical, to form a product of the formula: D*G*D wherein * is as defined above, (b) reacting the product of step (a) with a molar excess of a α,ω-diol endcapped long chain polymer of the formula: ▴A▴ wherein A and ▴ are as defined above, to form a product of the formula: (D*G*D*A) a *D*G*D wherein a is as defined above; and (c) reacting the product of step (b) with a molar excess of an endcapper of the formula: E▴ wherein E and ▴ are as defined above, to form the desired prepolymer. A process for preparing a prepolymer material consisting of prepolymers represented by the general chemical formula: E(*D*G*D*A) a *D*G*D*E where A, D, E, G and * are as defined in Claim 1, which process comprises: (a) reacting 2 mole equivalents of a diisocyanate of the formula: D wherein D is as defined above and  represents an isocyanate radical, with about 1 mole equivalent of a diol of the formula: ▴A▴ wherein A is as defined above and ▴ represents a hydroxy radical, to form a product of the formula: [D*]₂A wherein * is as defined above; (b) reacting the product of step (a) with a molar excess of a diol of the formula: ▴G▴ wherein G and ▴ are as defined above, to form a product of the formula: (D*A*D*G) a *D*A*D wherein a is as defined above; and (c) reacting the product of step (b) with a molar excess of an endcapper of the formula: E▴ wherein E and ▴ are as defined above, to form the desired prepolymer. A process according to Claim 1 or Claim 2, wherein the polymeric radical, A, is selected from (1) a polyethylene glycol diradical with a molecular weight of at least about 2000; (2) a dialkyl endcapped polydimethylsiloxane radical with a molecular weight of at least 400; (3) dialkyl endcapped polydifluoroalkylsiloxane polymer with a molecular weight of at least 400; and (4) a fluoroalkyl ether with a molecular weight of at least about 400. A process according to Claim 3, wherein said diisocyanate of the formula D is selected from isophorone diisocyanate, toluene diisocyanate and 4,4'-dicyclohexyl methane diisocyanate. A process according to Claim 3 or Claim 4, wherein said diol of the formula ▴G▴ is selected from neopentyl glycol, 1,4-butanediol, diethylene glycol and triethylene glycol. A process for making a copolymer, comprising preparing a prepolymer of the general chemical formulae: E(*D*A*D*G) a *D*A*D*E or E(*D*G*D*A) a *D*G*D*E wherein A, D, E, G, * and a are as defined in Claim 1, by a process according to any preceding claim, and thereafter polymerizing a mixture of said prepolymer with an ethylenically unsaturated comonomer. A process according to Claim 6 wherein said polymeric radical, A, of said prepolymer is polyethylene radical with a molecular weight of at least about 2,000. A process according to Claim 7, wherein said prepolymer comprises 15 to 95 weight percent of the comonomer mixture and said ethylenically unsaturated comonomer comprises 5 to 85 weight percent of said comonomer mixture. A process according to Claim 8, wherein said polymerizable mixture further comprises a diethylenically reactive crosslinker. A process according to Claim 9, wherein said ethylenically unsaturated comonomer is chosen from 2-hydroxyethyl methacrylate, N-vinyl-2-pyrrolidinone, methacrylic acid, dimethyl acrylamide and glycerol methacrylate. A process according to Claim 6, wherein said polymeric radical, A, of said prepolymer is a dialkyl endcapped polydimethylsiloxane radical with a molecular weight of at least 400. A process according to Claim 11, wherein said prepolymer comprises 15 to 95 weight percent of the comonomer mixture and said ethylenically unsaturated comonomer comprises 5 to 85 weight percent of said comonomer mixture. A process according to Claim 12, wherein said ethylenically unsaturated comonomer is chosen from 2-hydroxyethyl methacrylate, N-vinyl-2-pyrrolidinone, methacrylic acid, dimethyl acrylamide and glycerol methacrylate. A process according to Claim 13, wherein said polymerizable mixture further comprises 5 to 40 weight percent organosilicon comonomer. A process according to Claim 6, wherein said polymeric radical of said prepolymer is a poly(fluoroalkyl)ether with a molecular weight of at least 400. A process for making a copolymer, comprising preparing a prepolymer of the general chemical formulae: E(*D*A*D*G) a *D*A*D*E or E(*D*G*D*A( a *D*G*D*E wherein A, D, E, G, * and a are as defined in Claim 1, by a process according to any one of Claims 1-5, and thereafter polymerizing a mixture of said prepolymer and an organosilicon comonomer. A process according to Claim 16, wherein said organosilicon monomer is tris(trimethylsiloxy)silylpropyl methacrylate. A process according to Claim 17, wherein there is made a copolymer which comprises 20-50 wt % of said prepolymer and 20-40 weight percent of tris(trimethylsiloxy)silyl propyl methacrylate. A process according to Claim 18, wherein there is made a copolymer which further comprises 10-35 weight percent of one of the following hydrophilic comonomers: dimethacrylamide; glycerol methacrylate; 2-hydroxyethyl methacrylate; and N-vinyl-2-pyrrolidinone. A process for making a copolymer, comprising preparing a prepolymer of the general chemical formulae: E(*D*A*D*A) a *D*A*D*E or E(*D*G*D*A) a *D*G*D*E wherein A, D, E, G, * and a are as defined in Claim 1, by a process according to any one of Claims 1-5, and thereafter polymerizing an ethylenically unsaturated fluoroorgano comonomer. A method of making a biomedical device, comprising fabricating said device from a polymer comprising a prepolymer prepared by a process according to any one of Claims 1-5.

Inventors: BACCEI LOUIS J, LAI YU-CHIN, BACCEI, LOUIS J., LAI, YU-CHIN
Applicants: BAUSCH & LOMB, BAUSCH & LOMB INCORPORATED
Application year: 1990
Main classification: C08G18
IPC codes: C08G18, C08F290, C08F299, C08G77, G02C7