Patent Application
20070027285
The present invention relates to cross linked polyurethanes or polyurethane ureas and processes for their preparation. The polyurethanes are biostable and creep resistant which makes them useful in the manufacture of biomaterials and medical devices, articles or implants, in particular orthopaedic implants such as spinal disc prostheses.
The development of methodology1,2 to incorporate high proportions of siloxane segments as part of the polyurethane structure has resulted in the production of a range of thermoplastic siloxanepolyurethanes (Elast-Eon™) with biostability and mechanical properties suitable for a variety of medical implants. These thermoplastic polyurethanes are used in a range of cardiovascular, interventional cardiology and cardiac rhythm management applications. Materials that are used in medical implants subjected to cyclic strains or compressions such as orthopaedic implants require excellent flex-fatigue and creep resistance. Thermoplastic polymers generally exhibit a significant level of permanent deformation (creep) under tensile and compression loads. As a consequence, thermoplastic polyurethanes have limited use in load-bearing applications such as orthopaedic implants where dimensional stability is critical for optimum performance of the implant. There is a need for biostable polyurethanes which possess creep resistance.
According to the present invention there is provided a cross linked polyurethane or polyurethane urea having an NCO/OH or NH2 stoichiometry of 1-1.015 which comprises a soft segment which is formed from:
at least one polyether macrodiol and/or at least one polycarbonate macrodiol; and
(a) at least one polysiloxane macrodiol, at least one polysiloxane macrodiamine and/or at least one silicon-based polycarbonate; and/or
a hard segment which is formed from:
(b) a polyisocyanate; and
(c) at least one di-functional chain extender,
wherein the soft segment and/or the hard segment are further formed from:
(d) at least one cross linking agent.
Further according to the present invention there is provided a compound of formula (V):
which is a suitable silicon-containing cross linking agent for use in forming the polyurethanes of the present invention.
The present invention also provides a process for preparing the polyurethanes defined above which comprises the steps of:
The present invention further provides a process for preparing the polyurethanes defined above which comprises the steps of:
The polyurethanes of the present invention are biostable and creep resistant. These properties make the polyurethanes useful in the manufacture of biomaterials and medical devices, articles or implants.
Thus, the present invention also provides a material, device, article or implant which is wholly or partly composed of the polyurethanes defined above.
In the Examples, reference will be made to the accompanying drawings in which:
In the description of the invention, except where the context requires otherwise due to express language or necessary implication, the words “comprise” or variations such as “comprises” or “comprising” are used in an inclusive sense, i.e. to specify the presence of the stated features but not to preclude the presence or addition of further features in various embodiments of the invention.
The cross linking agent (e) which forms part of the soft and/or hard segment preferably has 3 or more functional groups. The functional group may be any type of group which can react with isocyanate and is preferably selected from OH or NR′R″ in which R′ and R″ are the same or different and selected from H, CO2H and C1-6 alkyl, preferably H and C1-4 alkyl.
Examples of tri, tetra, hexa and octa-hydroxyl functional cross linking agents include trimethylol propane (TMP), trifunctional polyether polyol based on propoxylated glycerines such as Voranol 2770, pentaerythritol (PE), pentaerythritol tetrakis(2-mercapto acetate), dipentaerythritol (DPE) and tripentaerythritol (TPE).
An example of an amine cross linker is triethanol amine.
When cross linking agents such as TMP are incorporated into the hard segment of the polyurethane, the expected general structure is shown in Scheme I below:
The introduction of cross linking may cause some changes to polyurethane morphology. The effect may be minor if the desired improvement in creep resistance can be achieved by relatively lower level of cross linking, minimising the disruption to the hard segment ordering.
It will be appreciated that silicon-containing cross linking agents may also be used in the polyurethanes of the present invention. Examples include cyclic siloxanes of the formula (VII):
wherein
An example of a cyclic siloxane is tetramethyl tetrahydroxy propyl cyclotetrasiloxane of formula (V) shown above. Another suitable silicon-containing cross linking agent is 1,3(6,7-dihydroxy ethoxypropyl)tetramethyl disiloxane of formula (VI):
The soft and hard segments of the polyurethanes typically phase separate and form separate domains. The hard segments organise to from ordered (crystalline) domains while the soft segments remain largely as amorphous domains and the two in combination is responsible for the excellent mechanical properties of polyurethanes. The introduction of cross links will affect this phase separation and the ordering of the hard and/or soft domains.
The soft segment which is formed from components (a) and (b) is preferably a combination of at least two macrodiols, at least two macrodiamines or at least one macrodiol and at least one macrodiamine.
Suitable polyether macrodiols include those represented by the formula (I)
HO—[(CH2)m—O]n—H (I)
wherein
m is an integer of 4 or more, preferably 5 to 18; and
n is an integer of 2 to 50.
Polyether macrodiols of formula (I) wherein m is 5 or higher such as polyhexamethylene oxide (PHMO), polyheptamethylene oxide, polyoctamethylene oxide (POMO) and polydecamethylene oxide (PDMO) are preferred over the conventional polytetramethylene oxide (PTMO). The more preferred macrodiols and their preparation are described in Gunatillake et al3 and U.S. Pat. No. 5,403,912. Polyethers such as PHMO described in these references are particularly useful as they are more hydrophobic than PTMO and more compatible with polysiloxane macrodiols. The preferred molecular weight range of the polyether macrodiol is about 200 to about 5000, more preferably about 200 to about 1200. It will be understood that the molecular weight values referred to herein are “number average molecular weights”.
Suitable polycarbonate macrodiols include poly(alkylene carbonates) such as poly(hexamethylene carbonate) and poly(decamethylene carbonate); polycarbonates prepared by reacting alkylene carbonate with alkanediol for example 1,4-butanediol, 1,10-decanediol (DD), 1,6-hexanediol (HD) and/or 2,2-diethyl 1,3-propanediol (DEPD); and silicon based polycarbonates prepared by reacting alkylene carbonate with 1,3-bis(4-hydroxybutyl)-1,1,3,3-tetramethyldisiloxane (BHTD) and/or alkanediols.
It will be appreciated when both the polyether and polycarbonate macrodiols are present, they may be in the form of a mixture or a copolymer. An example of a suitable copolymer is a copoly(ether carbonate) macrodiol represented by the formula (II)
wherein
R1 and R2 are the same or different and selected from an optionally substituted straight chain, branched or cyclic alkylene, alkenylene, alkynylene or heterocyclic radical; and
m and n are integers of 1 to 20.
Although the compound of formula (II) above indicates blocks of carbonate and ether groups, it will be understood that they also could be distributed randomly in the main structure.
The polysiloxane macrodiol or macrodiamine may be represented by the formula (III):
wherein
A and A′ are OH or NHR wherein R is H or an optionally substituted straight chain, branched or cyclic, saturated or unsaturated hydrocarbon radical, preferably C1-6 alkyl, more preferably C1-4 alkyl;
R1, R2, R3 and R4 are the same or different and selected from hydrogen or an optionally substituted straight chain, branched or cyclic, saturated or unsaturated hydrocarbon radical;
R5 and R6 are the same or different and selected from an optionally substituted straight chain, branched or cyclic alkylene, alkenylene, alkynylene or heterocyclic radical; and
p is an integer of 1 or greater.
Preferred polysiloxanes are polysiloxane macrodiols which are polymers of the formula (III) wherein A and A′ are hydroxy and include those represented by the formula (IIIa):
wherein
R1 to R6 and p are as defined in formula (III) above.
A preferred polysiloxane is PDMS which is a compound of formula (IIIa) wherein R1 to R4 are methyl and R5 and R6 are as defined above. Preferably R5 and R6 are the same or different and selected from propylene, butylene, pentylene, hexylene, ethoxypropyl (—CH2CH2OCH2CH2CH2—), propoxypropyl and butoxypropyl.
The polysiloxane macrodiols may be obtained as commercially available products such as X-22-160AS from Shin Etsu in Japan or prepared according to known procedures. The preferred molecular weight range of the polysiloxane macrodiol is about 200 to about 6000, more preferably about 500 to about 2500.
Other preferred polysiloxanes are polysiloxane macrodiamines which are polymers of the formula (III) wherein A is NH2, such as, for example, amino-terminated PDMS.
Suitable silicon-based polycarbonates include those described in International Patent Publication No. WO 98/54242, the entire content of which is incorporated herein by reference.
A preferred silicon-based polycarbonate has the formula (IV):
wherein
R1, R2, R3, R4 and R5 are as defined in formula (III) above;
R6 is an optionally substituted straight chain, branched or cyclic alkylene, alkenylene, alkynylene or heterocyclic radical;
R7 is a divalent linking group, preferably O, S or NR8;
R8 and R9 are same or different and selected from hydrogen or an optionally substituted straight chain, branched or cyclic, saturated or unsaturated hydrocarbon radical;
A and A′ are as defined in formula (III) above;
m, y and z are integers of 0 or more; and
x is an integer of 0 or more.
Preferably z is an integer of 0 to about 50 and x is an integer of 1 to about 50. Suitable values for m include 0 to about 20, more preferably 0 to about 10. Preferred values for y are 0 to about 10, more preferably 0 to about 2.
A preferred polycarbonate is a compound of the formula (IV) wherein A and A′ are hydroxy which is a polycarbonate macrodiol of the formula (IVa):
wherein
R1 to R9, m, y, x and z are as defined in formula (IV) above.
Particularly preferred polycarbonate macrodiols are compounds of the formula (IVa) wherein R1, R2, R3 and R4 are methyl, R8 is ethyl, R9 is hexyl, R5 and R6 are propyl or R4 butyl and R7 is 0 or —CH2—CH2—, more preferably R5 and R6 are propyl when R7 is 0 and R5 and R6 are butyl when R7 is —CH2—CH2—. The preferred molecular weight range of the polycarbonate macrodiol is about 400 to about 5000, more preferably about 400 to about 2000.
In a particularly preferred embodiment, the soft segment is a combination of PDMS or amino-terminated PDMS with a polyether of the formula (I) such as PHMO and/or a silicon-based polycarbonate such as siloxy carbonate.
The term “polyisocyanate” is used herein in its broadest sense and refers to di or higher isocyanates such as polymeric 4,4′-diphenylmethane diisocyanate (MDI). The polyisocyanate is preferably a diisocyanate which may be aliphatic or aromatic diisocyanates such as, for example MDI, methylene biscyclohexyl diisocyanate (H12MDI), p-phenylene diisocyanate (p-PDI), trans-cyclohexane-1,4-diisocyanate (CHDI), 1,6-diisocyanatohexane (DICH), 1,5-diisocyanatonaphthalene (NDI), para-tetramethylxylenediisocyanate (p-TMXDI), meta-tetramethylxylene diisocyanate (m-TMXDI), 2,4-toluene diisocyanate (2,4-TDI) isomers or mixtures thereof or isophorone diisocyanate (IPDI). MDI is particularly preferred.
The term “di-functional chain extender” in the present context means any compound having two functional groups per molecule, which are capable of reacting with the isocyanate group and generally have a molecular weight range of about 500 or less, preferably about 15 to about 500, more preferably about 60 to about 450.
The di-functional chain extender may be selected from diol or diamine chain extenders. Examples of diol chain extenders include 1,4-butanediol, 1,6-hexanediol, 1,8-octanediol, 1,9-nonanediol, 1,10-decanediol, 1,12-dodecanediol,1,4-cyclohexanediol, 1,4-cyclohexanedimethanol, p-xyleneglycol, 1,3-bis(4-hydroxybutyl)tetramethyldisiloxane, 1,3-bis(6-hydroxyethoxypropyl)tetramethyldisiloxane and 1,4-bis(2-hydroxyethoxy)benzene. Suitable diamine chain extenders include 1,2-ethylenediamine, 1,3-propanediamine,1,4-butanediamine, 1,3-bis(3-aminopropyl)tetramethyldisiloxane, 1,3-bis(4-aminobutyl)tetramethyldisiloxane and 1,6-hexanediamine.
The chain extender may also be a silicon-containing chain extender of the type described in International Patent Publication No. WO 99/03863, the entire contents of which are incorporated herein by reference. Such chain extenders include a silicon-containing diol of the formula (VI):
wherein
R1, R2, R3, R4, R5 and R6 are as defined in formula (III) above;
R7 is as defined in formula (IV) above, more preferably O; and
q is 0 or greater, preferably 2 or less.
Preferred silicon-containing diols of the formula (VI) are 1,3-bis(4-hydroxybutyl)tetramethyl disiloxane (BHTD) (compound of formula (VI) wherein R1, R2, R3 and R4 are methyl, R5 and R6 are butyl and R7 is O), 1,4-bis(3-hydroxypropyl)tetramethyl disilylethylene (compound of formula (VI) wherein R1, R2, R3 and R4 are methyl, R5, and R6, are propyl and R7 is ethylene) and 1-4-bis(3-hydroxypropyl)tetramethyl disiloxane, more preferably BHTD.
The silicon-containing chain extender of formula (VI) may be combined with the diol or diamine chain extenders described above. In a particularly preferred embodiment the chain extender of formula (VI) is BHTD and the diol chain extender is BDO.
The silicon chain extender and diol or diamine chain extender can be used in a range of molar proportions with decreasing tensile properties as the molar percentage of the silicon chain extender increases in the mixture. A preferred molar percentage of silicon chain extender relative to the diol or diamine chain extender is about 1 to about 70%, more preferably about 60%. For example, when the chain extender is a combination of BHTD and BDO, then the relative proportions of these components is preferably 40% BHTD and 60% BDO.
Although the preferred chain extender contains one diol or diamine chain extender and one silicon-containing diol, it will be understood that combinations of more than one diol or diamine chain extender may be used in the polyurethanes of the present invention.
The “hydrocarbon radical” may include alkyl, alkenyl, alkynyl, aryl or heterocyclyl radicals.
The term “alkyl” denotes straight chain, branched or mono- or poly-cyclic alkyl, preferably C1-12 alkyl or cycloalkyl, more preferably C1-6 alkyl, most preferably C1-4 alkyl. Examples of straight chain and branched alkyl include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, amyl, isoamyl, sec-amyl, 1,2-dimethylpropyl, 1,1-dimethylpropyl, pentyl, neopentyl, hexyl, 4-methylpentyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 1,2,2-trimethylpropyl, 1,1,2-trimethylpropyl, heptyl, 5-methylhexyl, 1-methylhexyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 4,4-dimethylpentyl, 1,2-dimethylpentyl, 1,3-dimethylpentyl, 1,4-dimethylpentyl, 1,2,3-trimethylbutyl, 1,1,2-trimethylbutyl, 1,1,3-trimethylbutyl, octyl, 6-methylheptyl, 1-methylheptyl, 1,1,3,3-tetramethylbutyl, nonyl, 1-, 2-, 3-, 4-, 5-, 6- or 7-methyloctyl, 1-, 2-, 3-, 4- or 5-ethylheptyl, 1-, 2- or 3-propylhexyl, decyl, 1-, 2-, 3-, 4-, 5-, 6-, 7- and 8-methylnonyl, 1-, 2-, 3-, 4-, 5- or 6-ethyloctyl, 1-, 2-, 3- or 4-propylheptyl, undecyl, 1-, 2-, 3-, 4-, 5-, 6-, 7-, 8- or 9-methyldecyl, 1-, 2-, 3-, 4-, 5-, 6- or 7-ethylnonyl, 1-, 2-, 3-, 4- or 5-propyloctyl, 1-, 2- or 3-butylheptyl, 1-pentylhexyl, dodecyl, 1-, 2-, 3-, 4-, 5-, 6-, 7-, 8-, 9- or 10-methylundecyl, 1-, 2-, 3-, 4-, 5-, 6-, 7- or 8-ethyldecyl, 1-, 2-, 3-, 4-, 5- or 6-propylnonyl, 1-, 2-, 3- or 4-butyloctyl, 1,2-pentylheptyl and the like. Examples of cyclic alkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl and the like.
The term “alkenyl” denotes groups formed from straight chain, branched or mono- or poly-cyclic hydrocarbon groups having at least one double bond, preferably C2-12 alkenyl, more preferably C2-6 alkenyl. The alkenyl group may have E or Z stereochemistry where applicable. Examples of alkenyl include vinyl, allyl, 1-methylvinyl, butenyl, iso-butenyl, 3-methyl-2-butenyl, 1-pentenyl, cyclopentenyl, 1-methyl-cyclopentenyl, 1-hexenyl, 3-hexenyl, cyclohexenyl, 1-heptenyl, 3-heptenyl, 1-octenyl, cyclooctenyl, 1-nonenyl, 2-nonenyl, 3-nonenyl, 1-decenyl, 3-decenyl, 1,3-butadienyl, 1,4-pentadienyl, 1,3-cyclopentadienyl, 1,3-hexadienyl, 1,4-hexadienyl, 1,3-cyclohexadienyl, 1,4-cyclohexadienyl, 1,3-cycloheptadienyl, 1,3,5-cycloheptatrienyl, 1,3,5,7-(cycloocta-tetraenyl) and the like.
The term “alkynyl” denotes groups formed from straight chain, branched, or mono- or poly-cyclic hydrocarbon groups having at least one triple bond. Examples of alkynyl include ethynyl, 1-propynyl, 1- and 2-butynyl, 2-methyl-2-propynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, 10-undecynyl, 4-ethyl-1-octyn-3-yl, 7-dodecynyl, 9-dodecynyl, 10-dodecynyl, 3-methyl-1-dodecyn-3-yl, 2-tridecynyl, 11-tridecynyl, 3-tetradecynyl, 7-hexadecynyl, 3-octadecynyl and the like.
The term “aryl” denotes single, polynuclear, conjugated and fused residues of aromatic hydrocarbons. Examples of aryl include phenyl, biphenyl, terphenyl, quaterphenyl, phenoxyphenyl, naphthyl, tetrahydronaphthyl, anthracenyl, dihydroanthracenyl, benzanthracenyl, dibenzanthracenyl, phenanthrenyl and the like.
The term “heterocyclyl” denotes mono- or poly-cyclic heterocyclyl groups containing at least one heteroatom selected from nitrogen, sulphur and oxygen. Suitable heterocyclyl groups include N-containing heterocyclic groups, such as, unsaturated 3 to 6 membered heteromonocyclic groups containing 1 to 4 nitrogen atoms, for example, pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl or tetrazolyl; saturated 3 to 6 membered heteromonocyclic groups containing 1 to 4 nitrogen atoms, such as pyrrolidinyl, imidazolidinyl, piperidino or piperazinyl; unsaturated condensed heterocyclic groups containing 1 to 5 nitrogen atoms, such as, indolyl, isoindolyl, indolizinyl, benzimidazolyl, quinolyl, isoquinolyl, indazolyl, benzotriazolyl or tetrazolopyridazinyl; unsaturated 3 to 6-membered heteromonocyclic group containing an oxygen atom, such as, pyranyl or furyl; unsaturated 3 to 6-membered heteromonocyclic group containing 1 to 2 sulphur atoms, such as, thienyl; unsaturated 3 to 6-membered heteromonocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, such as, oxazolyl, isoazolyl or oxadiazolyl; saturated 3 to 6-membered heteromonocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, such as, morpholinyl; unsaturated condensed heterocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, such as, benzoxazolyl or benzoxadiazolyl; unsaturated 3 to 6-membered heteromonocyclic group containing 1 to 2 sulphur atoms and 1 to 3 nitrogen atoms, such as thiazolyl or thiadiazolyl; saturated 3 to 6-membered heteromonocyclic group containing 1 to 2 sulphur atoms and 1 to 3 nitrogen atoms, such as, thiadiazolyl; and unsaturated condensed heterocyclic group containing 1 to 2 sulphur atoms and 1 to 3 nitrogen atoms, such as benzothiazolyl or benzothiadiazolyl.
In this specification, “optionally substituted” means that a group may or may not be further substituted with one or more groups selected from oxygen, nitrogen, sulphur, alkyl, alkenyl, alkynyl, aryl, halo, haloalkyl, haloalkenyl, haloalkynyl, haloaryl, hydroxy, alkoxy, alkenyloxy, alkynyloxy, aryloxy, carboxy, benzyloxy, haloalkoxy, haloalkenyloxy, haloalkynyloxy, haloaryloxy, nitro, nitroalkyl, nitroalkenyl, nitroalkynyl, nitroaryl, nitroheterocyclyl, azido, amino, alkylamino, alkenylamino, alkynylamino, arylamino, benzylamino, acyl, alkenylacyl, alkynylacyl, arylacyl, acylamino, acyloxy, aldehydo, alkylsulphonyl, arylsulphonyl, alkylsulphonylamino, arylsulphonylamino, alkylsulphonyloxy, arylsulphonyloxy, heterocyclyl, heterocycloxy, heterocyclylamino, haloheterocyclyl, alkylsulphenyl, arylsulphenyl, carboalkoxy, carboaryloxy, mercapto, alkylthio, arylthio, acylthio and the like.
Preferably, the amount of hard segment in the polyurethanes of the present invention is about 15 to about 100 wt %, more preferably about 20 to about 70 wt %, most preferably about 30 to about 60 wt %. However, it will be appreciated that this amount is dependent on the type of soft segment polymer used, in particular the molecular weight range of the soft segment which is generally about 300 to about 3000, more preferably about 300 to about 2500, most preferably about 500 to about 2000.
The soft segment preferably includes macrodiols derived from 40 to 98 wt %, more preferably 40 to 90%, of polysiloxane and 2 to 60 wt %, more preferably 10 to 60 wt % of a polyether and/or polycarbonate macrodiol.
The weight ratio of polysiloxane and/or silicon-based polycarbonate to polyether and/or polycarbonate in the preferred soft segment may be in the range of from 1:99 to 99:1. A particularly preferred ratio of polysiloxane to polyether and/or polycarbonate which provides increased degradation resistance, stability and clarity is 80:20. Another preferred ratio of polysiloxane and/or silicon-based polycarbonate to polyether and/or polycarbonate when the chain extender includes a silicon-containing chain extender such as BHTD is 40:60.
The polyurethanes of the present invention may be prepared by any technique familiar to those skilled in the manufacture of polyurethanes. These include one or two-step bulk or solution polymerisation procedures. The polymerisation can be carried out in conventional apparatus or within the confines of a reactive injection moulding or mixing machines.
In a one-step bulk polymerisation procedure the appropriate amount of components (a), (b) and (e) are mixed with the chain extender (d) first at temperatures in the range of about 45 to about 100° C., more preferably about 60 to about 80° C. If desired a catalyst such as stanneous octoate or dibutyltin dilaurate at a level of about 0.001 to about 0.5 wt % based on the weight of the total ingredients may be added to the initial mixture. Molten polyisocyanate (c) is then added and mixed thoroughly to give a homogeneous polymer liquid and cured by pouring the liquid polymer into Teflon—coated trays and heating in an oven to about 100° C.
The polyurethanes are preferably prepared by a two-step method where a prepolymer having terminally reactive polyisocyanate groups is prepared by reacting components (a) and (b) as defined above with a polyisocyanate component (c). The prepolymer is then reacted with the chain extender (d) and the cross linking agent (e).
The processes described above here do not generally cause premature phase separation and yield polyurethanes that are compositionally homogeneous and transparent having high molecular weights. These processes also have the advantage of not requiring the us of any solvent to ensure that the soft and hard segments are compatible during synthesis.
A further advantage of the incorporation of polysiloxane segments is the relative ease of processing of the polyurethane by conventional methods such as reactive injection moulding, rotational moulding, compression moulding and foaming without the need of added processing waxes. If desired, however, conventional polyurethane processing additives such as catalysts for example dibutyl tin dilaurate (DBTD), stannous oxide (SO), 1,8-diazabicyclo[5,4,0]undec-7-ene (DABU), 1,3-diacetoxy-1,1,3,3-tetrabutyldistannoxane (DTDS), 1,4-diaza-(2,2,2)-bicyclooctane (DABCO), N,N,N′,N′-tetramethylbutanediamine (TMBD) and dimethyltin dilaurate (DMTD); antioxidants for example Irganox (Registered Trade Mark); radical inhibitors for example trisnonylphenyl phosphite (TNPP); stabilisers; lubricants for example Irgawax (Registered Trade Mark); dyes; pigments; inorganic and/or organic fillers; and reinforcing materials can be incorporated into the polyurethane during preparation. Such additives are preferably added to the macrodiol mixture in step (i) of the processes of the present invention.
The polyurethanes of the present invention are particularly useful in preparing biomaterials and medical devices, articles or implants as a consequence of their biostability and creep resistance.
The term “biostable” is used herein in its broadest sense and refers to a stability when in contact with cells and/or bodily fluids of living animals or humans.
The term “biomaterial” is used herein in its broadest sense and refers to a material which is used in situations where it comes into contact with the cells and/or bodily fluids of living animals or humans.
The medical devices, articles or implants may include catheters; stylets; bone suture anchors; vascular, oesophageal and bilial stents; cochlear implants; reconstructive facial surgery; controlled drug release devices; components in key hole surgery; biosensors; membranes for cell encapsulations; medical guidewires; medical guidepins; cannularizations; pacemakers, defibrillators and neurostimulators and their respective electrode leads; ventricular assist devices; orthopaedic joints or parts thereof including spinal discs and small joints; cranioplasty plates; intraoccular lenses; urological stents and other urological devices; stent/graft devices; device joining/extending/repair sleeves; heart valves; vein grafts; vascular access ports; vascular shunts; blood purification devices; casts for broken limbs; vein valve, angioplasty, electrophysiology and cardiac output catheters; and tools and accessories for insertion of medical devices, infusion and flow control devices.
It will be appreciated that polyurethanes having properties optimised for use in the construction of various medical devices, articles or implants and possessing creep resistance will also have other non-medical applications. Such applications may include toys and toy components, shape memory films, pipe couplings, electrical connectors, zero-insertion force connectors, Robotics, Aerospace actuators, dynamic displays, flow control devices, sporting goods and components thereof, body-conforming devices, temperature control devices, safety release devices and heat shrink insulation.
The invention will now be described with reference to the following non-limiting examples.
A series of four polyurethanes were prepared to illustrate the effect of incorporating the tri-functional cross linker trimethylol propane (TMP) on creep resistance and mechanical properties.
Raw Materials: Poly(hexamethylene oxide) (PHMO) was synthesised and purified according to previously reported method (Gunatillake P A, Meijs G F, Chatelier R C, McIntosh and Rizzardo E., Polymer Int. 27, 275 (1992). PHMO was degassed at 135° C. under vacuum (0.01 torr) for 2 h. α,ω-bis(6-hydroxy-ethoxypropyl)-polydimethylsiloxane (PDMS) was purchased from Shin-Etsu (Japan) and degassed at 105° C. under vacuum (0.01 torr) for 4 h. 1,3-Bis(4-hydroxybutyl) 1,1,3,3-tertamethyldisiloxane (BHTD, Silar Laboratories) was degassed at ambient temperature under vacuum (0.01 torr) for several hours (˜12 h). 1,4-butanediol (BDO, Aldrich) was degassed and dried at 105° C. for 2 h prior to use.
The moisture content of all reagents was determined using Columetric Karl-Fisher titration. The moisture level of all reagents remained below 150 ppm.
The hydroxy number of the polyols (PDMS and PHMO) and of BHTD was determined using ASTM 2628 method.
The following procedure illustrates the preparation of the prepolymer used to make all four polyurethanes.
A mixture of PDMS (200.00 g, MW 927.0) and PHMO (50.00 g, MW 710.0) was degassed at 105° C. for 2 h under vacuum (0.01 torr). Molten MDI (102.71 g) was weighed into a three-neck round bottom flask equipped with mechanical stirrer, dropping funnel and nitrogen inlet. The flask was heated in an oil bath at 70° C. The degassed macrodiol mixture (200.0 g) was then added through a dropping funnel over a period of 45 minutes. After the addition is over, the reaction mixture was heated for 2 h with stirring under nitrogen at 80° C. The prepolymer mixture was then degassed at 80° C. under vacuum (0.01 torr) for about 1 h. The vacuum was released slowly under nitrogen atmosphere and 280.0 g of the degassed pre-polymer mixture was weighed into a tall dry polypropylene beaker and immediately placed in a nitrogen circulating oven at 80° C.
The un cross linked thermoplastic polyurethane PU-0 was prepared by reacting prepolymer (280.00 g) and a mixture of BDO (9.0769 g) and BHTD (19.2479 g). The chain extender mixture was weighed into a wet-tared 50 mL plastic syringe and added to the prepolymer with high speed stirring (4500 rpm) using a Silverson Mixer. The stirring continued for 2 min after addition of chain extender mixture. The polymer mixture was then poured into several Teflon-cloth lined aluminium moulds to produce 3 mm and 10 mm thick sheets. The polymer in moulds was first cured under 4 ton nominal pressure in a compression moulding press at 100° C. for 2 hours followed by further curing for 15 h in a nitrogen circulating oven at 100° C.
The cross linked polyurethanes were prepared by incorporating various amounts of TMP as indicated in Table 1. Three different concentrations of TMP replacing 10, 20 and 40 mol-% of BDO used in the formulation of un cross linked polyurethane (PU-0) were used. This corresponds to cross link density of 1.4, 2.8 and 5.5%, respectively for PU-10, PU-20 and PU-40, expressed as mol-% cross linker relative to the total number of moles of reagents used. The following procedure which illustrates the preparation PU-20 describes the general procedure used in making all cross linked polyurethanes.
BDO (7.2611 g) and TMP cross linker (1.792) were mixed in a round bottom flask and stirred for about 2 min at 40° C. temperature to obtain a homogenous solution. 19.2479 g BHTD weighed separately was then added to this flask and stirred for about 30 minutes to obtain a homogenous solution. The chain extender mixture and cross linker (28.301 g) were then weighed into a wet-tarred syringe and added into the pre-polymer mixture (280.0 g) while high speed (4500 rpm) stirring using Silverson Mixer. Stirring was continued for about 2 min after addition. The polymer mixture was poured into Teflon-cloth lined aluminium moulds to produce 3 mm and 10 mm sheets. The polymer in moulds was first cured under 4 ton nominal pressure in a compression moulding press at 100° C. for 2 hours followed by further curing for 15 h in a nitrogen circulating oven at 100° C.
Mechanical Properties and Procedures for Testing Mechanical Properties and Tensile Creep for the Polyurethanes of Example 1
The material was conditioned at ambient conditions for 48 h before testing.
Specimen Type
The introduction of cross linking caused a reduction in tensile strength, elongation at break and modulus, however, the materials retained strengths over 20 MPa. It is surprising that such low modulus materials with high strength can be achieved with a relatively low level of cross linking.
Resistance to Tensile Creep
The resistance to tensile creep was measured on dumbbell shaped test specimens using an Instron Tester The test specimen was loaded to 60N (in about 10 sec), translating to a stress of approximately 5 MPa, and held for 2 hours. After 2 hours the specimen was taken off the Instron and the gauge length was measured intermittently for 2 hours. The results are summarised in
The results clearly demonstrate that the cross linked polyurethanes were significantly more resistant to creep compared to un cross linked polyurethane. Increasing cross link density increased the creep resistance and the material with the highest cross link density showed complete recovery after removing the load.
Effect of Cross Linking on Polymer Solubility
The polymers prepared in Example 1 were tested for their solubility/swelling in N,N-dimethylformamide (DMF), a good solvent for polyurethanes. A rectangular specimen of polymer (approximately 1 g) was placed in excess DMF (˜30 mL) at 50° C. for 48 h. The excess DMF was wiped off from the polymer surface by using Kimwipe and weighed again to calculate the swelling ratio, expressed as the % weight gain relative to the dry sample. The results shown in Table 3 illustrate that the cross linked polymers swelled in DMF indicating the synthesis was successful and the presence of covalent cross linking.
aThe GPC analysis of PU-0 showed a number average molecular weight of 106,00 and polydispersity of 2.7.
This example illustrates the preparation of a polyurethane using the tetra-functional cross linker pentaerythritol (PE). The amount of PE used corresponds to 20 mol % of the BDO chain extender resulting in an effective cross link density of 2.653, expressed as mol-% of all components.
A mixture of PDMS (200.00 g, MW 927.0) and PHMO (50.00 g, MW 710.0) was degassed at 105° C. for 2 h under vacuum (0.01 torr). Molten MDI (102.71 g) was weighed into a three-neck round bottom flask equipped with mechanical stirrer, dropping funnel and nitrogen inlet. The flask was heated in an oil bath at 70° C. The degassed macrodiol mixture (200.0 g) was then added through a dropping funnel over a period of 45 minutes. After the addition is over, the reaction mixture was heated for 2 h with stirring under nitrogen at 80° C. The prepolymer mixture was then degassed at 80° C. under vacuum (0.01 torr) for about 1 h. The vacuum was released slowly under nitrogen atmosphere and 280.0 g of the degassed pre-polymer mixture was weighed into a tall dry polypropylene beaker and immediately placed in a nitrogen circulating oven at 80° C.
BDO (7.2611 g) and pentaerythritol cross linker (PE, 1.3706 cg) was mixed in a round bottom flask and stirred for about 2 min at 40° C. temperature to obtain a homogenous solution. The mixture (8.6317 g) was weighed into a plastic syringe. 1,3-Bis(4-hydroxybutyl)1,1,3,3-tetramethyldsiloxane (BHTD, 19.2479 g) was weighed separately into a plastic syringe. BDO/PE and BHTD were added into the pre-polymer mixture (280.0 g) while stirring at high speed (4500 rpm) using Silverson Mixer and stirring continued for about 2 minutes. The polymer mixture was then poured into several Teflon-cloth lined aluminium moulds to produce 3 mm, and 10 mm thick sheets. The polymer in moulds was first cured under 4 ton nominal pressure in a compression moulding press at 100° C. for 2 hours followed by further curing for 15 h in a nitrogen circulating oven at 100° C.
This example illustrates the preparation of a polyurethane using the hexa-functional cross linker dipentaerythritol (DPE). The amount of DPE used corresponds to 20 mol % of the BDO chain extender.
A mixture of PDMS (200.00 g, MW 927.0) and PHMO (50.00 g, MW 710.0) was degassed at 105° C. for 2 h under vacuum (0.01 torr). Molten MDI (102.71 g) was weighed into a three-neck round bottom flask equipped with mechanical stirrer, dropping funnel and nitrogen inlet. The flask was heated in an oil bath at 70° C. The degassed macrodiol mixture (200.0 g) was then added through a dropping funnel over a period of 45 minutes. After the addition was over, the reaction mixture was heated for 2 h with stirring under nitrogen at 80° C. The prepolymer mixture was then degassed at 80° C. under vacuum (0.01 torr) for about 1 h. The vacuum was released slowly under nitrogen atmosphere and 280.0 g of the degassed prepolymer mixture was weighed into a tall dry polypropylene beaker and immediately placed in a nitrogen circulating oven at 80° C.
BDO (7.2611 g) and DPE cross linker (1.7073 g) were mixed in a round bottom flask separately whereas 1,3-Bis(4-hydroxybutyl)1,1,3,3-tetramethyldsiloxane (BHTD, 19.2479 g) was weighed separately into a plastic syringe. The BDO/DPE mixture was heated until it was a clear solution and added into the prepolymer mixture along with BHTD (19.24 g) while stirring at high speed (5000 rpm) using Silverson Mixer and stirring continued for about 2 minutes. The polymer mixture was then poured into several Teflon-cloth lined aluminium moulds to produce 3 mm, and 10 mm thick sheets. The polymer in moulds was first cured under 4 ton nominal pressure in a compression moulding press at 100° C. for 2 hours followed by further curing for 15 h in a nitrogen circulating oven at 100 C.°.
This example illustrates the preparation of a polyurethane using the octa-functional cross linker tripentaerythritol (TPE). The amount of TPE used corresponds to 20 mol % of the BDO chain extender.
A mixture of PDMS (200.00 g, MW 927.0) and PHMO (50.00 g, MW 710.0) was degassed at 105° C. for 2 h under vacuum (0.01 torr). Molten MDI (102.71 g) was weighed into a three-neck round bottom flask equipped with mechanical stirrer, dropping funnel and nitrogen inlet. The flask was heated in an oil bath at 70° C. The degassed macrodiol mixture (200.0 g) was then added through a dropping funnel over a period of 45 minutes. After the addition was over, the reaction mixture was heated for 2 h with stirring under nitrogen at 80° C. The prepolymer mixture was then degassed at 80° C. under vacuum (0.01 torr) for about 1 h. The vacuum was released slowly under nitrogen atmosphere and 280.0 g of the degassed prepolymer mixture was weighed into a tall dry polypropylene beaker and immediately placed in a nitrogen circulating oven at 80° C.
BDO (7.2611 g) and TPE cross linker (TPE, 1.88 g) were mixed in a round bottom flask separately whereas 1,3-Bis(4-hydroxybutyl)1,1,3,3-tetramethyldsiloxane (BHTD, 19.2479 g) was weighed separately into a plastic syringe. The BDO/TPE mixture was heated until it was a clear solution and added into the prepolymer mixture along with BHTD (19.24 g) while stirring at high speed (5000 rpm) using Silverson Mixer and stirring continued for about 2 minutes. The polymer mixture was then poured into several Teflon-cloth lined aluminium moulds to produce 3 mm, and 10 mm thick sheets. The polymer in moulds was first cured under 4 ton nominal pressure in a compression moulding press at 100° C. for 2 hours followed by further curing for 15 h in a nitrogen circulating oven at 100 C.°.
This example illustrates the addition of the tri-functional cross linker TMP of Example 1 to a polyurethane which does not include the silicon-containing chain extender BHTD.
A mixture of PDMS (200.00 g, MW 927.0) and PHMO (50.00 g, MW 710.0) was degassed at 105° C. for 2 h under vacuum (0.01 torr). Molten MDI (102.71 g) was weighed into a three-neck round bottom flask equipped with mechanical stirrer, dropping funnel and nitrogen inlet. The flask was heated in an oil bath at 70° C. The degassed macrodiol mixture (200.0 g) was then added through a dropping funnel over a period of 45 minutes. After the addition was over, the reaction mixture was heated for 2 h with stirring under nitrogen at 80° C. The prepolymer mixture was then degassed at 80° C. under vacuum (0.01 torr) for about 1 h. The vacuum was released slowly under nitrogen atmosphere and 280.0 g of the degassed prepolymer mixture was weighed into a tall dry polypropylene beaker and immediately placed in a nitrogen circulating oven at 80° C.
BDO (8.079 g) and TMP cross linker (4.287 g) were mixed in a round bottom flask and heated to 40° C. to obtain a clear solution. The BDO/TMP mixture was then added into the prepolymer mixture while stirring at high speed (5000 rpm) using Silverson Mixer and stirring continued for about 2 minutes. The polymer mixture was then poured into several Teflon-cloth lined aluminium moulds to produce 3 mm, and 10 mm thick sheets. The polymer in moulds was first cured under 4 ton nominal pressure in a compression moulding press at 100° C. for 2 hours followed by further curing for 15 h in a nitrogen circulating oven at 100 C.°.
This example illustrates the addition of the tri-functional cross linker TMP of Example 1 to the polyurethane of Examples 1 to 4 in which the amount of BHTD is reduced with constant BDO.
A mixture of PDMS (200.00 g, MW 927.0) and PHMO (50.00 g, MW 710.0) was degassed at 105° C. for 2 h under vacuum (0.01 torr). Molten MDI (102.71 g) was weighed into a three-neck round bottom flask equipped with mechanical stirrer, dropping funnel and nitrogen inlet. The flask was heated in an oil bath at 70° C. The degassed macrodiol mixture (200.0 g) was then added through a dropping funnel over a period of 45 minutes. After the addition was over, the reaction mixture was heated for 2 h with stirring under nitrogen at 80° C. The prepolymer mixture was then degassed at 80° C. under vacuum (0.01 torr) for about 1 h. The vacuum was released slowly under nitrogen atmosphere and 280.0 g of the degassed prepolymer mixture was weighed into a tall dry polypropylene beaker and immediately placed in a nitrogen circulating oven at 80° C.
BDO (9.076 g) and TMP cross linker (3.603 g) were mixed in a round bottom flask separately whereas BHTD (7.7093 g) was weighed separately into a plastic syringe. The BDO/TMP mixture was added into the prepolymer mixture along with BHTD (19.24 g) while stirring at high speed (5000 rpm) using Silverson Mixer and stirring continued for about 2 minutes. The polymer mixture was then poured into several Teflon-cloth lined aluminium moulds to produce 3 mm, and 10 mm thick sheets. The polymer in moulds was first cured under 4 ton nominal pressure in a compression moulding press at 100° C. for 2 hours followed by further curing for 15 h in a nitrogen circulating oven at 100 C.°.
This example illustrates the addition of a silicon-containing cross linking agent of formula (VI) to the polyurethane of Examples 1 to 4 in which the amount of cross linking agent of formula (VI) used corresponds to 20 mol % of the BDO chain extender.
A mixture of PDMS (200.00 g, MW 927.0) and PHMO (50.00 g, MW 710.0) was degassed at 105° C. for 2 h under vacuum (0.01 torr). Molten MDI (102.71 g) was weighed into a three-neck round bottom flask equipped with mechanical stirrer, dropping funnel and nitrogen inlet. The flask was heated in an oil bath at 70° C. The degassed macrodiol mixture (200.0 g) was then added through a dropping funnel over a period of 45 minutes. After the addition was over, the reaction mixture was heated for 2 h with stirring under nitrogen at 80° C. The prepolymer mixture was then degassed at 80° C. under vacuum (0.01 torr) for about 1 h. The vacuum was released slowly under nitrogen atmosphere and 280.0 g of the degassed prepolymer mixture was weighed into a tall dry polypropylene beaker and immediately placed in a nitrogen circulating oven at 80° C.
BDO (7.2611 g) and 1,3(6,7-dihydroxy ethoxy propyl)tetramethyl disiloxane cross linker (SC) (4.762 g) was mixed in a round bottom flask separately whereas 1,3-bis(4-hydroxybutyl)1,1,3,3-tetramethyldisiloxane (BHTD, 19.2479 g) was weighed separately into a plastic syringe. The BDO/SC mixture was added into the prepolymer mixture along with BHTD (19.24 g) while stirring at high speed (5000 rpm) using Silverson Mixer and stirring continued for about 2 minutes. The polymer mixture was then poured into several Teflon-cloth lined aluminium moulds to produce 3 mm, and 10 mm thick sheets. The polymer in moulds was first cured under 4 ton nominal pressure in a compression moulding press at 100° C. for 2 hours followed by further curing for 15 h in a nitrogen circulating oven at 100° C.
Mechanical Properties and Procedures for Testing Mechanical Properties and Tensile Creep for the Polyurethanes of Examples 2 to 7
Method for Testing Films
Conditioning
The material is kept in the room in which it is to be tested for at least 48 hours prior to testing. The temperature of the room averages 23° C.
Specimen Type
These results show that the higher functional cross linkers such as DPE improve the creep resistance significantly.
This example illustrates the preparation of a polyurethane using the trifunctional macrodiol, Voranol 2070, a trifunctional polyether polyol based on proproxylated glycerine having a number average molecular weight of 700 as a cross linking agent. This polyurethane does not contain any cross linker in the hard segment.
The prepolymer containing PDMS, PHMO AND MOI was prepared as described in Example 1.
The cross linked polyurethanes were prepared by incorporating two different amounts of Voranol 2070. The amounts of Voranol 2070 corresponded to 20 and 40 mole % of BDO used in the formulation of the un crosslinked polyurethane (PU-0).
BDO, BHTD and Voranol 2070 were mixed together in a round bottom flask for 30 min to obtain a homogeneous solution. The mixture was then weighed into a wet tared syringe and added into the prepolymer mixture while high speed (4500 rpm) stirring using the Silverson mixer. Stirring was continued for about 2 min after the addition. The polymer was poured into Teflon coated moulds to produce 3 mm thick sheets. The polymer was first cured under 4 ton nominal pressure in a compression moulding press at 100° C. for 2 hours followed by further curing for 15 h in a nitrogen circulating oven at 100° C.
Mechanical Properties for the Polyurethanes of Example 8
The mechanical properties were tested using the procedures described in Example 1.
It will be appreciated by persons skilled in the art that numerous variations and/or modifications may be made to the invention as shown in the specific embodiments without departing from the spirit or scope of the invention as broadly described. The present embodiments are, therefore, to be considered in all respects as illustrative and not restrictive.
| Number | Date | Country | Kind |
|---|---|---|---|
| 2003906639 | Nov 2003 | AU | national |
This application is a continuation under 35 U.S.C. 111(a) of International Application No. PCT/AU2004/001662 filed Nov. 26, 2004 and published in English as WO 2005/052019 A1 on Jun. 9, 2005, which claims priority from Australian Application No. 2003906639 filed Nov. 28, 2003, which applications are incorporated herein by reference.
| Number | Date | Country | |
|---|---|---|---|
| Parent | PCT/AU04/01662 | Nov 2004 | US |
| Child | 11440575 | May 2006 | US |
