Biostable polyurethanes

Abstract

The present invention relates to a biostable polyurethane or polyurea comprising: (a) a soft segment comprising a polysiloxane of the general formula (I); and (b) greater than O and less than 40 wt % of a hard segment which is a reaction product of a diisocyanate and a linear difunctional chain extender, processes for their preparation and their use in the manufacture of biomaterials, devices, articles or implants.

Claims

1. A biostable polyurethane comprising: (a) 60-75 wt-% of a soft segment comprising greater than 98 wt-% of a polysiloxane having a molecular weight in the range of 500 to 1500 of the general formula (I) ##STR00004## in which A and A are N(C.sub.1-C.sub.6)alkyl or O; R.sub.1, R.sub.2 R.sub.3 and R.sub.4 are independently selected from C.sub.1-6 alkyl; R.sub.5 and R.sub.6 are independently selected from C.sub.1-12 alkylene; and p is an integer of 1 or greater; (b) 25-40 wt % of a hard segment which is a reaction product of 20-35 wt-% of a diisocyanate based on the total weight of the polyurethane, and 2-5 wt-% of a linear difunctional chain extender, based on the total weight of the polyurethane, wherein the linear difunctional chain extender consists of a (C.sub.1-C.sub.12)alkane diol or a C.sub.1-C.sub.12 alkane diamine; and (c) wherein the soft segment comprises up to about 2 wt-% of a polyether polyol or a combination polyether polyol and polycarbonate polyol, wherein the polyether polyol comprises polytetramethylene oxide (PTMO), polyhexamethylene oxide (PHMO), polyheptamethylene oxide, polyoctamethylene oxide (POMO) or polydecamethylene oxide (PDMO).

2. The polyurethane according to claim 1, in which the R.sub.1 to R.sub.4 in formula (I) are independently selected from C.sub.1-4 alkyl.

3. The polyurethane according to claim 2, in which R.sub.1 to R.sub.4 in formula (I) are methyl.

4. The polyurethane according to claim 1, in which R.sub.5 and R.sub.6 in formula (I) are independently selected from C.sub.1-4 alkylene.

5. The polyurethane according to claim 1, in which R.sub.5 and R.sub.6 in formula (I) are ethylene or propylene.

6. The polyurethane according to claim 1, in which p in formula (I) is an integer of 5 to 30.

7. The polyurethane according to claim 1, in which the diisocyanate is an aromatic diisocyanate.

8. The polyurethane according to claim 7, in which the aromatic diisocyanate is 4,4-diphenylmethyl diisocyanate (MDI).

9. The polyurethane according to claim 1, in which the chain extender has a molecular weight of 500 or less.

10. The polyurethane according to claim 1, in which the C.sub.1-12 alkane diol is 1,4-butanediol (BDO).

11. A biomaterial, device, article or implant which is wholly or partly composed of the biostable polyurethane according to claim 1.

12. A biomaterial; device, article or implant according to claim 11 which is selected from 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; 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; plastic surgery implants; breast implant shells; lapbands; gastric balloons; tools and accessories for insertion of medical devices, infusion and flow control devices; 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.

13. A polyurethane according to claim 1, in which the amount of soft segment is 65-70 wt %.

14. The polyurethane according to claim 1, in which p in formula (I) is an integer of 8 to 20.

15. The polyurethane according to claim 1, in which the chain extender has a molecular weight of 15 to 500.

16. The polyurethane according to claim 1, in which the chain extender has a molecular weight of 60 to 450.

17. The polyurethane of claim 1, wherein the polycarbonate polyol comprises poly(alkylene carbonates).

18. The polyurethane of claim 1, wherein the polycarbonate polyol comprises poly(hexamethylene carbonate) and poly(decamethylene carbonate).

Description

BRIEF DESCRIPTION OF THE DRAWINGS

(1) In the Examples, reference will be made to the accompanying drawings in which:

(2) FIG. 1 is a graph showing a comparison of the tensile and recovery (5 MPa loading) between E2A and E2A modified;

(3) FIG. 2 is a scanning electron micrograph (SEM) at 5000 times magnification for E2A after 24 days in vitro;

(4) FIG. 3 is a SEM at 5000 times magnification for E2A modified after 24 days in vitro;

(5) FIG. 4 is a graph showing background corrected SAXS intensities as a function of scattering vector: .square-solid. E2A and .box-tangle-solidup. E2A modified; and

(6) FIG. 5 is a graph showing (a) storage (E) and (b) dissipation factor (tan d) as a function of temperature for Elast-Eon 2A. Untreated material (i) and oxidised sample (ii).

EXAMPLES

(7) The invention will now be described with reference to the following non-limiting examples.

Example 1

(8) This example illustrates the preparation and testing of an Elast-Eon 2A (E2A) formulation with 100% silicone in the soft segment.

(9) Synthesis

(10) PDMS (180.00 g, MW 958.15) was degassed at 80 C. for 24 h under vacuum (0.01 torr), the resultant moisture level was <150 parts per million. Molten MDI (1010.63 g, MW 250,00) was weighed into a three-neck round bottom flask equipped with a mechanical stirrer, dropping funnel and nitrogen inlet. The flask was heated in an oil bath at 70 C. The degassed PDMS (2000 g) was then added through a dropping funnel over a period of 2 hours. The PDMS used in this example has the following formula:

(11) ##STR00003##

(12) in which n is 8-20.

(13) After the completion of PDMS addition, the reaction mixture was heated for a further 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 2810 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 (189.3 g, MW 90.00) was previously degassed over 24 h at 60 C. to moisture levels below 50 ppm. The overall stoichiometry was maintained at 1.015. BDO was added into the prepolymer mixture (2810 q) while using a highly dispersive, high shear and high speed mixer such as a Silverson Mixer. The mixture was stirred at high speed (6000 rpm) for about 2 minutes. The polymer mixture was then poured into several Teflon coated moulds and cured to a solid slab for 15 h in a nitrogen circulating oven at 100 C. After full cure the slabs were granulated and extruded in a 25 mm diameter extruder, L/D ratio of 30/1 at a melt temperature of 200 C. The extrudate, in the form of cylindrical rods, was chopped into pellets suitable for further thermoplastic processing.

(14) Tensile Testing

(15) The pellets were compression moulded into 3 mm thick rectangular sheets and samples were cut from these sheets that were subject to various mechanical testing. Table 1 below shows the mechanical data comparison between the two polyurethanes.

(16) TABLE-US-00001 TABLE 1 Si Soft Segment Modulus of Tensile Tear Content Composition Elasticity strength % Strain Strength Durometer Material % PDMS/PHMO (MPa) (MPa) at break (kN/m) Hardness E2A 48 80/20 35 28 500 85 90A E2A 60 100/0 56 27 560 84 90A modified

(17) E2A is made with a soft segment that is a mix of 80 wt % of PDMS 1000 and 20 wt % of PHMO. The ratio of the hard to soft segment in both E2A and the modified version of E2A is 40/60. The hard segment comprises MDI and BDO. The tensile modulus increases with increased PDMS content but all the other properties are comparable.

(18) Creep and Recovery

(19) FIG. 1 is a graph providing a comparison of the tensile creep performance of the polyurethanes. The polyurethanes were loaded to CON (in about 10 sec), translating to a stress of approximately 5 MPa, and held for 30 minutes. After 30 minutes the polyurethane was taken off the Instron and the gauge length was measured intermittently for 30 minutes.

(20) A surprising improvement in creep and recovery performance is noted in the polyurethane containing 100% silicone in the soft segment.

(21) In-Vitro Accelerated Oxidative Ageing

(22) Using the protocol described in E. M. Christenson, J. M. Anderson, A. Hiltner, Journal of Biomed. Mater. Res. A, 2004, 69, 407 in vitro accelerated aging was performed at 37 C.1 C. on unstrained film samples in an oxidative solution of 20% hydrogen peroxide in 0.1 M cobalt chloride. The polyurethane films were treated for 24 days with the change of solutions every 3 days in order to maintain a relatively constant concentration of radicals. Film samples were removed every 6 days, washed thoroughly with water, vacuum dried before using for extraction experiments.

(23) The SEMS at 5000 times magnification of the standard and the modified E2A are shown in FIGS. 2 and 3.

(24) From the results it can be seen that the modified E2A performed even better than standard E2A in terms of very low surface degradation. The biological stability that a 100% silicone content E2A provides is superior to the standard E2A.

Example 2

(25) This example illustrates the preparation and testing of E2A formulations with 100% silicone in the soft segment and varying levels of hard segment content.

(26) Synthesis

(27) The synthesis was exactly the same as that used in Example 1, but the levels of the reactants were different as illustrated in Table 2 below.

(28) TABLE-US-00002 TABLE 2 Formu- Stoi- Hard MDI PDMS BDO lation chiometry segment % (g) (g) (g) 1 1.015 35 910.3 1950 139.7 2 1.015 32.5 860.14 2025 114.86 2 1.015 30 809.97 2100 90.03

(29) These formulations were then compared with equivalent hard block formulations made from a mixed macrodiol (80/20, PDMS/PHMO). The comparative tensile test results set out in Table 3 below.

(30) TABLE-US-00003 TABLE 3 Hard Modulus of Tensile Tear segment Elasticity strength % Strain Strength Durometer Material % (MPa) (MPa) at break (kN/m Hardness Comparative 1 35 18.6 22.5 698 62.5 84A 1 35 21.0 23.1 711 67.1 86A Comparative 2 32.5 12.7 21 676 56 78A 2 32.5 13 22.7 675 58 80A Comparative 3 30 9.5 15.5 790 48.5 76A 3 30 10.0 20.2 799 52 73A

(31) As can be seen in Table 3, the difference in the tensile modulus decreases as the hard segment % decreases. This result is surprising since the difference in the modulus is high when the hard segment content is 40%, as noted in Example 1. This was probably why the Elast-Eon polyurethanes contain a compatibiliser is conjunction with silicone in order to reduce the stiffness of the polyurethanes. However, the stiffness or modulus difference reduces dramatically as the overall % hard segment of the polyurethanes decreases.

(32) Thus, Elast-Eon of equivalent modulus at lower hard segment concentration can be obtained with a soft segment composed entirely of silicone. This is accompanied by corresponding significant increase in biological stability, creep resistance, acid resistance and abrasion resistance.

Example 3

(33) This example illustrates the characterisation of the E2A and E2A modified materials synthesised in Example 1.

(34) Characterisation Methods

(35) Dynamic Mechanical Analysis.

(36) The dynamic mechanical properties of the copolymers were evaluated using a TA-Q800 DMA and a Gas Cooling Accessory (Model CFL-50) for sub-ambient experiments. Film samples were tested in tension from 120 C. to 150 C. at a heating rate of 3 C./min and frequency of 1 Hz; the static force was preset at 1 N with a force track of 125%.

(37) Small-Angle X-Ray Scattering.

(38) SAXS data were collected on Molecular Metrology SAXS instrument consisting of a three-pinhole collimated camera [using a CuK radiation source (=0.154 nm)] and a two-dimensional multi-wire detector. The sample-to-detector distance was 1.5 m.

(39) The polyurethane films were cut into 1 cm1 cm squares, which were stacked to a thickness of approximately 1 mm and secured by tape along the edges. The film stack was supported by placing it between two index cards with a hole for the passage of the x-ray beam. The ensemble was then mounted onto a sample holder provided by Molecular Metrology.

(40) Absolute scattered intensities (in units of cm.sup.1) were determined by calibration with a pre-calibrated cross-linked polyethylene (S-2907) secondary standard; this step is essential in order to obtain quantitative details on segment demixing. A silver behenate secondary standard was used to calibrate the scattering vector.

(41) Results

(42) The results, as observed with the characterisation, indicate important behavioural aspects of the material.

(43) The SAXS results in FIG. 4 show that the polyurethane made with only PDMS in the soft segment has a greater degree of phase separation than the polyurethane made with a blend of polyols, PDMS and PHMO. The data are presented as I/I.sub.eV, where I is the scattered intensity, I.sub.e the intensity scattered by a single electron under identical conditions, and V the irradiated sample volume. The peak position (q.sub.max) is indicative of the mean interdomain spacing, d, by d=2/q.sub.max.

(44) FIG. 5 shows the DMA plot of E2A before and after performing in vitro oxidative ageing. The glass transition temperature of the PDMS phase is 120 C. while that of the PHMO phase 20 C. Upon undergoing oxidation, the PDMS transition is unaffected while the PHMO transition broadens with a decrease in the tan d value and an increase in the storage modulus. This shows that only the PHMO phase is affected on oxidation and is therefore the more susceptible part of the polymer structure in terms of biostability.

(45) It will be understood to persons skilled in the art of the invention that many modifications may be made without departing from the spirit and scope of the invention.